US20100240669A1 - New compounds - Google Patents

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Publication number
US20100240669A1
US20100240669A1 US12/711,716 US71171610A US2010240669A1 US 20100240669 A1 US20100240669 A1 US 20100240669A1 US 71171610 A US71171610 A US 71171610A US 2010240669 A1 US2010240669 A1 US 2010240669A1
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United States
Prior art keywords
alkyl
denotes
group
substituted
fluorine atoms
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US12/711,716
Inventor
Norbert Hauel
Angelo Ceci
Henri Doods
Ingo Konetzki
Juergen Mack
Henning Priepke
Annette Schuler-Metz
Rainer Walter
Dieter Wiedenmayer
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Boehringer Ingelheim International GmbH
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Boehringer Ingelheim International GmbH
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Assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH reassignment BOEHRINGER INGELHEIM INTERNATIONAL GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HAUEL, NORBERT, CECI, ANGELO, KONETZKI, INGO, SCHULER-METZ, ANNETTE, WALTER, RAINER, MACK, JUERGEN, DOODS, HENRI, PRIEPKE, HENNING, WIEDENMAYER, DIETER
Publication of US20100240669A1 publication Critical patent/US20100240669A1/en
Priority to US13/742,175 priority Critical patent/US20130131075A1/en
Abandoned legal-status Critical Current

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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to the compounds of general formula I
  • n, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and X are as defined hereinafter, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases, which have valuable properties, the preparation thereof, the medicaments containing the pharmacologically effective compounds, the preparation thereof and the use thereof.
  • One embodiment 2 of the present invention comprises the compounds of the above general formula I, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1 and denotes
  • An embodiment 3 of the present invention comprises the compounds of the above general formula I, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1 and
  • An embodiment 4 of the present invention comprises the compounds of the above general formula I, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1 and
  • An embodiment 5 of the present invention comprises the compounds of the above general formula I, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1 and
  • An embodiment 6 of the present invention comprises the compounds of the above general formula I, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1 and
  • An embodiment 7 of the present invention consists of the compounds of the above general formula I, wherein R 1 is defined as mentioned hereinbefore under embodiment 1, 2, 3, 4, 5 or 6 and
  • An embodiment 8 of the present invention comprises the compounds of the above general formula I, wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5 or 6 and
  • R 2 denotes H or CH 3 , the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 8 of the present invention comprises the compounds of the above general formula I, wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6 or 7 and
  • R 2 denotes H or CH 3 , the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 9 of the present invention comprises the compounds of the above general formula I, wherein R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6 or 7 and
  • R 2 denotes H, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 10 of the present invention comprises the compounds of the above general formula I, wherein R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8 or 9 and
  • R 3 and R 4 together with the carbon atom to which they are bonded denote a C 3-6 -cycloalkylene group wherein a —CH 2 — unit may be replaced by an oxygen atom, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 11 of the present invention comprises the compounds of the above general formula I, wherein R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8 or 9 and
  • R 3 and R 4 together with the carbon atom to which they are bonded denote a group selected from
  • An embodiment 12 of the present invention comprises the compounds of the above general formula I, wherein R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 and
  • R 5 denotes H or CH 3 , the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 13 of the present invention comprises the compounds of the above general formula I, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 and
  • R 6 denotes H, F, Cl or methyl, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 14 of the present invention comprises the compounds of the above general formula I, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 and
  • An embodiment 15 of the present invention comprises the compounds of general formula Ia
  • An embodiment 16 of the present invention comprises the compounds of general formula Ia, wherein
  • An embodiment 17 of the present invention comprises the compounds of general formula Ia, wherein
  • An embodiment 18 of the present invention comprises the compounds of general formula Ia wherein
  • An embodiment 19 of the present invention comprises the compounds of general formula Ib
  • An embodiment 20 of the present invention comprises the compounds of general formula Ib, wherein
  • An embodiment 21 of the present invention comprises the compounds of general formula Ib, wherein
  • An embodiment 22 of the present invention comprises the compounds of general formula Ib, wherein
  • An embodiment 23 of the present invention comprises the compounds of general formula Ic
  • An embodiment 24 of the present invention comprises the compounds of general formula IC, wherein
  • An embodiment 25 of the present invention comprises the compounds of general formula Ic, wherein
  • An embodiment 26 of the present invention comprises the compounds of general formula Ic, wherein
  • An embodiment 27 of the present invention comprises the compounds of general formula Id
  • An embodiment 28 of the present invention comprises the compounds of general formula I, Ia, Ib, Ic or Id, wherein n, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and X are defined as described hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27 and
  • a further embodiment of the present invention comprises the compounds of the above general formula II, wherein
  • a further embodiment of the present application relates to the use of the compounds of general formula II, wherein R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as hereinbefore defined, the diastereomers, the enantiomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases for preparing compounds of general formula I, which have B1-antagonistic properties.
  • a further embodiment of the present invention comprises the compounds of the above general formula III, wherein
  • a further embodiment of the present application relates to the use of the compounds of general formula III, wherein R 2 , R 3 , and R 4 are as hereinbefore defined, the diastereomers, the enantiomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases for preparing compounds of general formula I which have B1-antagonistic properties.
  • a further embodiment of the present invention comprises the compounds of the above general formula IV, wherein
  • a further embodiment of the present application relates to the use of the compounds of general formula IV, wherein R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as hereinbefore defined, the diastereomers, the enantiomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases for preparing compounds of general formula I which have B1-antagonistic properties.
  • substituents are independent of one another. If for example there are a plurality of C 1-6 -alkyl groups as substituents in one group, in the case of three substituents C 1-6 -alkyl, one may represent methyl, one n-propyl and one tert-butyl.
  • Also included in the subject matter of this invention are the compounds according to the invention, including the salts thereof, in which one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.
  • C 1-3 -alkyl (including those that are part of other groups) are meant alkyl groups with 1 to 3 carbon atoms
  • C 1-4 -alkyl are meant branched and unbranched alkyl groups with 1 to 4 carbon atoms
  • C 1-6 -alkyl are meant branched and unbranched alkyl groups with 1 to 6 carbon atoms
  • C 1-8 -alkyl are meant branched and unbranched alkyl groups with 1 to 8 carbon atoms.
  • Examples include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl and n-octyl.
  • the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. May optionally also be used for the above-mentioned groups.
  • the definitions propyl and butyl include all the possible isomeric forms of the groups in question.
  • propyl includes n-propyl and iso-propyl
  • butyl includes iso-butyl, sec-butyl and tert-butyl.
  • each methylene group may be substituted by up to two and each methyl group may be substituted by up to three fluorine atoms.
  • C 0-2 -alkylene are meant branched and unbranched alkylene groups with 0 to 2 carbon atoms, while a C 0 -alkylene group denotes a bond. Examples include: methylene, ethylene and ethane-1,1-diyl. Moreover the definitions mentioned previously also include those groups wherein each methylene group may be substituted by up to two fluorine atoms.
  • C 3-7 -cycloalkyl (including those that are part of other groups) are meant cyclic alkyl groups with 3 to 7 carbon atoms and by the term “C 3-6 -cycloalkyl” are meant cyclic alkyl groups with 3 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Unless otherwise stated, the cyclic alkyl groups may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
  • C 3-6 -cycloalkylene (including those that are part of other groups) are meant cyclic alkylene groups with 3 to 6 carbon atoms. Examples include: cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene. Unless otherwise stated, the cyclic alkylene groups may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
  • C 2-4 -alkynyl (including those that are part of other groups) are meant branched and unbranched alkynyl groups with 2 to 4 carbon atoms, provided that they have at least one triple bond. Examples include: ethynyl, propynyl or butynyl. Unless stated otherwise, the definitions propynyl and butynyl include all the possible isomeric forms of the groups in question. Thus for example propynyl includes 1-propynyl and 2-propynyl, butynyl includes 1-butynyl, 2-butynyl and 3-butynyl etc.
  • Halogen within the scope of the present invention denotes fluorine, chlorine, bromine or iodine. Unless stated to the contrary, fluorine, chlorine and bromine are regarded as preferred halogens.
  • heterocyclic rings or “heterocyclic group” are meant stable 5- or 6-membered monocyclic ring systems, which may be both saturated and mono- or di-unsaturated and besides carbon atoms may carry one or two heteroatoms, which are selected from among nitrogen, oxygen and sulphur. Both nitrogen and sulphur heteroatoms may optionally be oxidised.
  • the previously mentioned heterocycles may be attached to the rest of the molecule via a carbon atom or a nitrogen atom. The following compounds are mentioned as examples:
  • Cyclic imides includes for example succinimides, maleimide and phthalimide.
  • aryl aromatic ring systems with 6 or 10 carbon atoms. Examples of these are phenyl, 1-naphthyl or 2-naphthyl; the preferred aryl group is phenyl.
  • the aromatic groups may be substituted by one or more groups selected from among methyl, ethyl, n-propyl, iso-propyl, tert-butyl, hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, bromine and iodine, while the groups may be identical or different.
  • heteroaryl are meant five- or six-membered heterocyclic aromatic groups, which may contain one, two, three or four heteroatoms, selected from among oxygen, sulphur and nitrogen, and additionally contain so many conjugated double bonds that an aromatic system is formed. These heteroaryls may additionally be benzo-condensed with a phenyl ring, so as to form nine- or ten-membered bicyclic heteroaryls.
  • heteroaryls mentioned previously may be substituted by one or more groups selected from among methyl, ethyl, n-propyl, iso-propyl, tert-butyl, hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, bromine and iodine, while the groups may be identical or different.
  • any nitrogen atom present in the heteroaryl group may be oxidised, thereby forming an N-oxide.
  • oxo group an oxygen substituent at a carbon atom, which leads to the formation of a carbonyl group —C(O)—.
  • the introduction of an oxo group as substituent at a non-aromatic carbon atom leads to a conversion of a —CH 2 group into a —C(O)— group.
  • the introduction of an oxo group at an aromatic carbon atom leads to the conversion of a —CH— group into a —C(O)— group and may result in the loss of aromaticity.
  • compounds of general formula I may be converted, particularly for pharmaceutical use, into the physiologically acceptable salts thereof with inorganic or organic acids.
  • inorganic acids for this purpose include hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulphuric acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid or p-toluenesulphonic acid
  • organic acids that may be used include malic acid, succinic acid, acetic acid, fumaric acid, maleic acid, mandelic acid, lactic acid, tartaric acid or citric acid.
  • the compounds of general formula I may be converted into the physiologically acceptable salts thereof with inorganic or organic bases, particularly for pharmaceutical applications.
  • inorganic bases include alkali or alkaline earth metal hydroxides, e.g. sodium hydroxide or potassium hydroxide, or carbonates, ammonia, zinc or ammonium hydroxides;
  • organic amines include diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine or dicyclohexylamine.
  • the compounds according to the invention may be present as racemates, provided that they have only one chiral element, but may also be obtained as pure enantiomers, i.e. In the (R) or (S) form.
  • the application also includes the individual diastereomeric pairs of antipodes or mixtures thereof, which are obtained if there is more than one chiral element in the compounds of general formula I, as well as the individual optically active enantiomers of which the above-mentioned racemates are made up.
  • the compound prepared is not limited to one tautomeric form but includes all the tautomeric forms. This also applies particularly to nitrogen-containing heteroaryls:
  • the coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)-N,N—N′,N′-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP).
  • DCC dicyclohexylcarbodiimide
  • DI diisopropyl carbodiimide
  • the reaction speed can be increased.
  • the couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran (THF), acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures.
  • solvents such as dichloromethane, tetrahydrofuran (THF), acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures.
  • an auxiliary base such as diisopropylethylamine (DIPEA, Hünig base) is additionally used.
  • An alternative method of preparing compounds of general formula I consists in linking carboxylic acids of general formula V, wherein all the groups are as hereinbefore defined, with amines of general formula IV, wherein all the groups are as hereinbefore defined.
  • carboxylic acids of general formula V into carboxylic acid chlorides and then react these with amines of general formula IV.
  • Carboxylic acid chlorides are synthesised by methods known from the literature (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, vol. E5/1).
  • the reduction of a nitrile of general formula VI to an amine of general formula III, wherein the group R 2 at the amine nitrogen denotes hydrogen and all the other groups are as hereinbefore defined, may be carried out under standard conditions of catalytic hydrogenolysis with a catalyst such as Raney nickel, for example, in a solvent such as ammoniacal methanol or ethanol or with a reducing agent such as lithium aluminium hydride or sodium borohydride in a solvent such as tetrahydrofuran, optionally in the presence of a Lewis acid such as aluminium chloride.
  • a catalyst such as Raney nickel
  • ketones obtained may also be converted into oximes.
  • the subsequent reduction of the oximes then yields compounds of general formula III.
  • CHO cells that express the cynomolgus BK1-receptor are cultivated in “HAM′S F-12 Medium”. The medium is removed from confluent cultures, the cells are washed with PBS buffer, scraped off or detached using Versene and isolated by centrifuging. Then the cells are homogenised in suspension, the homogenate is centrifuged and resuspended.
  • 200 ⁇ l of the homogenate (50 to 250 ⁇ g protein/assay) are incubated for 60-180 minutes at ambient temperature with 0.5 to 5.0 nM kallidine (DesArg10,Leu9), [3,4-Prolyl-3,43H(N)] and increasing concentrations of the test substance in a total volume of 250 ⁇ l.
  • the incubation is stopped by rapid filtration through GF/B glass fibre filters that have been pre-treated with polyethyleneimine (0.3%).
  • the radioactivity bound to the protein is measured with a TopCount NXT.
  • the radioactivity bound in the presence of 1.0 ⁇ M kallidine (DesArg10) is defined as non-specific binding.
  • the concentration binding curve may be analysed using computer-aided non-linear curve fitting to determine the corresponding K i value for the test substance.
  • novel compounds and their physiologically acceptable salts are suitable for treating diseases and symptoms of diseases caused at least to some extent by stimulation of bradykinin-B1 receptors, or in which antagonisation of the of bradykinin-B1 receptor can bring about an improvement in symptoms.
  • the present invention encompasses the compounds of the above-mentioned general formula I according to the invention for use as medicaments.
  • neuropathic pain such as for example painful neuropathies, pain of diabetic neuropathy, AIDS-associated neuropathic pain non-herpes-associated neuralgia,
  • the compounds are also suitable for treating
  • inflammatory complaints or phenomena caused by sunburn and burns inflammation of the gums, oedema after burns trauma, cerebral oedema and angiooedema, intestinal complaints including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), uveitis; inflammatory skin diseases (such as psoriasis and eczema), vascular diseases of the connective tissue, sprains and fracture, and musculoskeletal diseases with inflammatory symptoms such as acute rheumatic fever, polymyalgia rheumatica, reactive arthritis, rheumatoid arthritis, spondylarthritis, and also osteoarthritis, and inflammation of the connective tissue of other origins, and collagenoses of all origins such as systemic lupus erythematodes, scleroderma, polymyositis, dermatomyos
  • diabetic vasculopathy diabetic neuropathy, diabetic retinopathy
  • diabetic symptoms in insulitis for example hyperglycaemia, diuresis, proteinuria and increased renal excretion of nitrite and kallikrein
  • sepsis and septic shock after bacterial infections or after trauma for example hyperglycaemia, diuresis, proteinuria and increased renal excretion of nitrite and kallikrein
  • sepsis and septic shock after bacterial infections or after trauma (m) syndromes that cause itching and allergic skin reactions
  • neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease
  • osteoporosis epilepsy
  • vascular diseases such as panarteriitis nodosa, polyarthritis nodosa, periarteriitis nodosa, arteriitis temporalis, Wegner's granulomatosis, giant cell arteriitis, arteriosclerosis and erythema nodosum; inflammation of the gums;
  • the substances are suitable for causal treatment in the sense of slowing down or stopping the progress of chronically progressive diseases, particularly osteoarthritis, rheumatoid arthritis and spondylarthritis.
  • the present invention encompasses the use of the compounds of the above-mentioned general formula I according to the invention for preparing a medicament for therapeutic use in the above-mentioned indications.
  • the compounds of general formula I according to the invention are used for the treatment of osteoarthritis, rheumatoid arthritis or COPD.
  • treatment refers to a therapeutic treatment of patients with a manifest, acute or chronic indication, including on the one hand symptomatic (palliative) treatment to relieve the symptoms of the disease and on the other hand causal or curative treatment of the indication with the aim of ending the pathological condition, reducing the severity of the pathological condition or delaying the progression of the pathological condition, depending on the nature or gravity of the indication.
  • the present invention further relates to the use of a compound of general formula I for preparing a medicament for the acute and prophylactic treatment of acute pain, visceral pain, neuropathic pain, inflammatory/pain receptor-mediated pain, tumour pain, headache pain and pain of mixed causes and other diseases as mentioned above.
  • This use is characterised in that it comprises administering an effective amount of a compound of general formula I or a physiologically acceptable salt thereof to a patient requiring such treatment.
  • patient preferably refers to a human being.
  • these substances are also useful in the veterinary medical treatment of domestic pets, exotic animals and farmed animals.
  • the compounds according to the invention For treating pain, it may be advantageous to combine the compounds according to the invention with stimulating substances such as caffeine or other pain-alleviating active compounds. If active compounds suitable for treating the cause of the pain are available, these can be combined with the compounds according to the invention.
  • Non-steroidal antirheumatics such as for example propionic acid derivatives which may be selected from among alminoprofen bucloxic acid, carprofen, fenoprofen, ibuprofen, ketoprofen, naproxen, oxaprozin, pirprofen, pranoprofen and tiaprofenic acid; acetic acid derivatives which may be selected from among indomethacin, acemetacin, alclofenac, isoxepac, sulindac and tolmetin; fenamic derivatives which may be selected from among meclofenamic acid, mefenamic acid and tolfenamic acid; biphenyl-carboxylic acid derivatives; oxicams which may be selected from among meloxicam, piroxicam and tenoxicam; salicylic acid derivatives which may be selected from among acetylsalicylic and sulphasalazine; pyr
  • Opiate receptor agonists which may for example be selected from among morphine, Darvon, tramadol and buprenorphine;
  • Cannabinoid agonists such as for example GW-1000;
  • Sodium channel blockers which may for example be selected from among carbamazepine, mexiletin, pregabalin, tectin and ralfinamide.
  • N-type calcium channel blockers such as for example ziconotide.
  • Serotonergic and noradrenergic modulators which may be selected from among for example duloxetine and amitriptyline.
  • Corticosteroids which may be selected from among for example betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone.
  • Histamine H1-receptor antagonists which may for example be selected from among bromopheniramine, chloropheniramine, dexchloropheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine azatadine, cyproheptadine, antazoline, pheniramine, pyrilamine, loratadine, cetirizine, desloratadine, fexofenadine and levocetirizine.
  • Leukotriene antagonists and 5-lipoxygenase inhibitors which may for example be selected from among zafirlukast, montelukast, pranlukast and zileuton.
  • Local anaesthetics which may for example be selected from among ambroxol and lidocaine.
  • TRVP1 antagonists which may for example be selected from among AZD-1386, JTS-653 and PHE-377.
  • Nicotine receptor agonists such as for example A-366833.
  • P2X3-receptor antagonists such as e.g. A-317491.
  • anti-NGF antibodies and NGF antagonists which may for example be selected from among JNJ-42160443 and PPH 207.
  • NK1 and NK2 antagonists such as e.g. CP-728663.
  • NMDA antagonists which may for example be selected from among CNS-5161, AZ-756 and V-3381.
  • Potassium channel modulators such as e.g. CL-888.
  • GABA modulators such as e.g. baclofen.
  • Anti-migraine drugs such as e.g. sumatriptan, zolmitriptan, naratriptan and eletriptan.
  • the compounds of general formula I may optionally also be used in conjunction with other pharmacologically active substances. It is preferable to use active substances of the type selected from among the betamimetics, anticholinergics, corticosteroids, other PDE4-inhibitors, LTD4-receptor (CysLT1, CysLT2, CysLT3) antagonists, inhibitors of MAP kinases such as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP, LTB4-receptor (BLT1, BLT2) antagonists, EGFR-inhibitors, H1-receptor antagonists, antihistamines, H4-receptor antagonists, PAF-antagonists and PI3-kinase inhibitors CXCR1 and/or CXCR2 receptor antagonists and anti-tussives.
  • the compounds of general formula I may also be used in the form of double or triple combinations thereof, such as for example combinations of compounds of formula I with one or two compounds selected from among
  • Betamimetics used according to the invention are preferably compounds selected from among arformoterol, carmoterol, formoterol, indacaterol, salmeterol, albuterole, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, hexoprenalin, ibuterol, isoetharin, isoprenalin, levosalbutamol, mabuterol, meluadrin, metaproterenol, milveterol, orciprenalin, pirbuterol, procaterol, reproterol, rimiterol, ritodrin, salmefamol, soterenol, sulphonterol, terbutalin, tiaramid, tolubuterol and zinterol or
  • Anticholinergics used according to the invention are preferably compounds selected from among the tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, Ipratropiumsalzen, preferably the bromide salt, aclidinium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine, (3R)-1-phenethyl-3-(9H-xanthene-9-carbonyloxy)-1-azoniabicyclo[2,2,2]octane salts.
  • the cations are the pharmacologically active constituents.
  • the above-mentioned salts may preferably contain chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while the chloride, bromide, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions.
  • the chlorides, bromides, iodides and methanesulphonates are particularly preferred.
  • anticholinergics may be selected from among
  • Corticosteroids used according to the invention are preferably compounds selected from among beclomethasone betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone and tipredane orpregna-1,4-dien-3,20-dione, 6-fluoro-11-hydroxy-16.17-[(1-methylethyliden)-bis(oxy)]-21-[[4-[(nitroxy)methyl]benzoyl]oxy], (6-alpha,11-beta,16-alpha)-(9Cl) (NCX-1024)
  • PDE4-inhibitors used according to the invention are preferably compounds selected from among enprofyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, apremilast, arofyllin, atizoram, oglemilast and tetomilast or
  • LTD4-receptor antagonists used according to the invention are preferably compounds selected from among montelukast, pranlukast and zafirlukast, or (E)-8-[2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl]-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-4-one (MEN-91507),
  • Histamine H1 receptor antagonists used according to the invention are preferably compounds selected from among epinastin, cetirizin, azelastin, fexofenadin, levocabastin, loratadin, mizolastin, ketotifen, emedastin, dimetinden, clemastin, bamipin, cexchlorpheniramin, pheniramin, doxylamine, chlorophenoxamin, dimenhydrinat, diphenhydramin, promethazin, ebastin, olopatadine, desloratidin and meclozin, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.
  • the acid addition salts are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
  • Histamine H4 receptor antagonists used according to the invention are preferably compounds such as for example (5-chloro-1H-indol-2-yl)-(4-methyl-1-piperazinyl)-methanone (JNJ-7777120), optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.
  • compounds such as for example (5-chloro-1H-indol-2-yl)-(4-methyl-1-piperazinyl)-methanone (JNJ-7777120), optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.
  • acid addition salts selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate are used.
  • MAP Kinase inhibitors used according to the invention are preferably compounds selected from among:
  • Neurokinin (NK1 or NK2) antagonists used according to the invention are preferably compounds selected from among: Saredutant, Nepadutant and Figopitant, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates thereof.
  • Antitussive substances used according to the invention are preferably compounds selected from among hydrocodone, caramiphen, carbetapentane and dextramethorphane, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates thereof.
  • Substances of preferred CXCR1 or CXCR2 antagonists used according to the invention are preferably compounds such as e.g. 3-[[3-[(dimethylamino)carbonyl]-2-hydroxyphenyl]amino]-4-[[(R)-1-(5-methylfuran-2-yl)propyl]amino]cyclobut-3-ene-1,2-dione (SCH-527123),
  • the dosage necessary for obtaining a pain-alleviating effect is, in the case of intravenous administration, expediently from 0.01 to 3 mg/kg of body weight, preferably from 0.1 to 1 mg/kg, and, in the case of oral administration, from 0.1 to 8 mg/kg of body weight, preferably from 0.5 to 3 mg/kg, in each case 1 to 3 times per day.
  • the compounds prepared according to the invention can be administered intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, aerosol formulations being particularly suitable for inhalation.
  • customary pharmaceutical preparations such as tablets, coated tablets, capsules, powders, suspensions, solutions, metered-dose aerosols or suppositories, if appropriate together with one or more customary inert carriers and/or diluents, for example with maize starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances, such as hardened fat, or suitable mixtures thereof.
  • customary inert carriers and/or diluents for example with maize starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbito
  • the acid, base and salt solutions used for working up the reaction solutions are aqueous systems having the stated concentrations.
  • silica gel from Millipore 35 to 70 ⁇ m
  • Alox E. Merck, Darmstadt, Alumina 90 standardized, 63 to 200 ⁇ m, article No. 1.01097.9050
  • DMSO dimethylsulphoxide HATU 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate RP reverse phase R t retention time tert tertiary TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate TEA triethylamine THF tetrahydrofuran
  • Method 7 Column: YMC-Pack ODS-AQ, 3 ⁇ M, 4.6 ⁇ 75 mm
  • Method 8 Column: Zorbax Stable Bond C18, 1.8 ⁇ M, 3 ⁇ 30 mm
  • Method 11 Column: X Terra C18, 3.5 ⁇ M, 4.6 ⁇ 50 mm
  • Method 14 Column: Zorbax Stable Bond C18, 3.5 ⁇ M, 4.6 ⁇ 75 mm
  • the compounds of general formula I may be prepared from the following intermediates A, B and C:
  • AAV 3 Cleaving the Tert-Butyloxycarbonyl Protective Group
  • the nitrile group of the diphenylamine intermediate product thus obtained was then reduced to the aminomethyl group with the addition of Raney nickel at 55° C. and 3 bar excess hydrogen pressure and the product obtained was purified by chromatography.
  • the intermediate A with an alpha-alkylbenzyl group e.g. A1, A4, A5
  • the nitrile derivative (1 mol-equivalent) was dissolved in diethyl ether and at 0 to 5° C. it was added with stirring to a solution of alkylmagnesium bromide (4 mol-equivalents) in diethyl ether and then stirred for another 30 minutes approx.
  • the reaction mixture was then stirred into 1M hydrochloric acid at ⁇ 5° C. and the alkylketone thus obtained was isolated and purified by chromatography in the usual way.
  • Another possible way of reducing the oxime to the corresponding amine is by catalytic hydrogenation.
  • the oxime was hydrogenated in methanolic ammonia solution after the addition of Raney nickel at 50° C. and at an excess hydrogen pressure of 50 psi until the uptake of hydrogen had ended. If necessary, the amine thus obtained was purified by chromatography.
  • reaction is carried out under protective gas (argon).
  • a mixture of 2.39 g (12 mmol) 1-(4-bromophenyl)ethanone, 0.99 mL (8 mmol) 4-(difluoromethoxy)aniline, 2.21 g (16 mmol) potassium carbonate, 150 mg (0.8 mmol) copper iodide and 180 mg (1.6 mmol) L-proline in 12 mL DMSO was stirred for 72 hours at 95° C.
  • the reaction mixture was added to water, mixed with a little ammonia extracted twice with tert-butyl-methylether.
  • the combined organic phases were dried on sodium sulphate and evaporated to dryness in vacuo.
  • the residue was purified by column chromatography (silica gel, petroleum ether+30% ethyl acetate). The product was further reacted directly.
  • the aqueous phase was acidified with 4 molar hydrochloric acid and extracted three times with diethyl ether.
  • the combined organic phases were dried on sodium sulphate and evaporated to dryness in vacuo.
  • the residue was mixed with dichloromethane and the precipitate formed was suction filtered and dried in the circulating air dryer at 55° C.
  • reaction was carried out under protective gas (nitrogen). 860 mg (3.27 mmol) 5-(2-(trifluoromethyl)phenylamino)picolinic acid nitrile in 5 mL diethyl ether at ⁇ 10° C. were added dropwise to 9.34 mL (13.07 mmol) of a 1.4 molar solution of methylmagnesium bromide in toluene/THF (3:1) and the mixture was left for 15 minutes at this temperature with stirring. The reaction mixture was combined with saturated ammonium chloride solution, neutralised with 1 molar aqueous hydrochloric acid at ⁇ 5° C. and extracted with tert-butylmethylether. The organic phase was evaporated to dryness in vacuo.
  • Example (1d) Analogously to Example (1d) the title compound was prepared from 6-(aminomethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine (from 41a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).

Abstract

The present invention relates to the compounds of general formula I
Figure US20100240669A1-20100923-C00001
wherein n, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and X are defined as described hereinafter, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases, which have valuable properties, the preparation thereof, the medicaments containing the pharmacologically effective compounds, the preparation thereof and the use thereof.

Description

  • The present invention relates to the compounds of general formula I
  • Figure US20100240669A1-20100923-C00002
  • wherein n, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and X are as defined hereinafter, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases, which have valuable properties, the preparation thereof, the medicaments containing the pharmacologically effective compounds, the preparation thereof and the use thereof.
    • DETAILED DESCRIPTION OF THE INVENTION
  • In the above general formula I in one embodiment 1
    • n denotes one of the numbers 0, 1 or 2,
    • R1 denotes
      • (a) a C1-6-alkyl group optionally substituted by a group R1.1,
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (c) a substituted C3-6-cycloalkyl group optionally substituted by a group R1.2 wherein a —CH2— unit may be replaced by a —C(O)— group,
      • (d) an aryl-C0-2-alkylene group optionally substituted by 1, 2 or 3 groups R1.3,
      • (e) a five-membered heteroaryl-C0-2-alkylene group optionally substituted by 1, 2 or 3 groups R1.4, which contains at least one N, O or S atom and which optionally additionally contains one, two or three further N-atoms and which may additionally be benzo-condensed,
      • (f) a six-membered heteroaryl-C0-2-alkylene group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms and which may additionally be benzo-condensed,
      • (g) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4 substituted, which contains one, two or three N-atoms,
      • (h) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group,
      • (i) —O—R1.1.1,
      • (j) —NR1.1.3R1.1.4 or
      • (k) —C(═NR1.5)—CN,
    • R1.1 denotes halogen, —NO2, —CN, C3-6-cycloalkyl, —OR1.1.1, —SR1.1.1, —C(O)R1.1.1, —S(O)2—R1.1.2, —O—S(O)—R1.1.1, —CO2R1.1.1, —O—C(O)—R1.1.1, —NR1.1.3R1.1.4, —NR1.1,3-C(O)—R1.1.1, —NR1.1,3-C(O)—R1.1.1, —NR1.1,3-CO2—R1.1.1 or —C(O)—NR1.1.3R1.1.4,
    • R1.1.1 denotes
      • (a) H,
      • (b) C1-4-alkyl,
      • (c) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (d) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1,
      • (e) C3-6-cycloalkyl or
      • (f) a pyridyl group optionally substituted by 1, 2 or 3 groups R1.1.1.2,
    • R1.1.1.1 independently of one another denote
      • (a) halogen, —NO2, —CN, —OH, —O—C1-4-alkyl, C3-6-cycloalkyl, C1-4-alkyl or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R1.1.1.2 independently of one another denote halogen or C1-4-alkyl,
    • R1.1.2 denotes
      • (a) C1-4-alkyl,
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (c) —O—C1-4-alkyl or
      • (d) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1 substituted,
    • R1.1.3,
    • R1.1.4 independently of one another denote
      • (a) H,
      • (b) a C1-4-alkyl group optionally substituted by 1, 2 or 3 groups R1.1.4.1,
      • (c) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1,
      • (d) C3-6-cycloalkyl, or
    • R1.1.3 and R1.1.4 together with the N atom to which they are attached form a 5- or 6-membered heterocyclic ring, which may additionally contain a further heteroatom selected from N, O and S, or
    • R1.1.3 and R1.1.4 together with the N atom to which they are attached, form a cyclic imide,
    • R1.1.4.1 independently of one another halogen denote —NH2, —NH(C1-4-alkyl), —N(C1-4-alkyl)2 or —SO2—R1.1.2,
    • R1.2 denotes halogen, —NO2, —CN, OH, —O—CH3 or phenyl,
    • R1.3 denotes
      • (a) halogen, —NO2, —CN, —OR1.1.1, —SR1.1.1, —CO2R1.1.1, C1-6-alkyl or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R1.4 independently of one another denote
      • (a) halogen, —NO2, —CN, —OR1.1.1, —SR1.1.1, —S(O)—R1.1.2, —S(O)2—R1.1.2, —NR1.1.3R1.1.4, —N(R1.4.1)—C(O)—C1-4-alkyl, C1-6-alkyl,
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, or
      • (c) an oxo group,
    • R1.4.1 denotes H or C1-4-alkyl,
    • R1.5 denotes —OH or —O—C1-3-alkyl,
    • R2 denotes
      • (a) H,
      • (b) C1-4-alkyl,
      • (c) C1-4-alkyl-C(O)—,
    • R3 and R4 together with the carbon atom to which they are bound denote a C3-6-cycloalkylene group optionally substituted by a group R3.1 wherein a —CH2— unit may be replaced by a heteroatom O, N, S or by a group CO, SO or SO2,
    • R3.1 denotes H, —OH,
    • R5 denotes
      • (a) H,
      • (b) C1-4-alkyl,
      • (c) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R6 independently of one another denote
      • (a) H, halogen, —CN, —OH, C1-6alkyl, C3-7-cycloalkyl, —O—C1-4-alkyl, —O—CF3, —O—C3-6-cycloalkyl, —N(C1-3-alkyl)2, —C(O)—NH2, —(SO2)NH2, —SO2—C1-3-alkyl, or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R7 denotes
      • (a) H, halogen, —CN, —OH,
      • (b) C1-6-alkyl
      • (c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (d) C3-7-cycloalkyl,
      • (e) —O—C1-6-alkyl,
      • (f) —O—C3-7-cycloalkyl,
      • (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
      • (h) —C(O)—R7.1,
      • (i) —S—C1-4alkyl, —SO2—R7.2,
      • (j) a five-membered heteroaryl group optionally substituted by one or two C1-3-alkyl groups which is selected from among pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl, or
      • (k) a six-membered heteroaryl group optionally substituted by one or two C1-3-alkyl groups which is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
    • R7.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
    • R7.2 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl and
    • R8 denotes H, halogen, C1-4-alkyl,
    • R9 denotes H, halogen, C1-4-alkyl,
    • R9 denotes
      • (a) H, halogen, —CN, —OH,
      • (b) C1-6-alkyl,
      • (c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (d) C3-7-cycloalkyl,
      • (e) C2-4-alkynyl,
      • (f) —O—C1-6-alkyl,
      • (g) —O—C3-7-cycloalkyl,
      • (h) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
      • (i) —C(O)—R9.1,
      • (j) —S—C1-4-alkyk, —SO—C1-4-alkyl, —SO2—C1-4-alkyl,
      • (j) —S—C1-4-alkyl, —SO—C1-4—SO2—C1-4-alkyl,
    • R9.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
    • R10 denotes H, halogen, C1-4-alkyl,
    • R11 denotes
      • (a) H, halogen, —CN, —OH,
      • (b) C1-6-alkyl,
      • (c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (d) C3-7-cycloalkyl,
      • (e) —O—C1-6-alkyl,
      • (f) —O—C3-7-cyloalkyl,
      • (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
      • (h) —C(O)—R11.1,
      • (i) —S—C1-3-alkyl, —SO2—R11.2,
      • (j) a five-membered heteroaryl group optionally substituted by one or two C1-3-alkyl groups which is selected from among pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl, or
      • (k) a six-membered heteroaryl group optionally substituted by one or two C1-3-alkyl groups which is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
    • R11.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
    • R11.2 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl and
    • X independently of one another denote C—R6 or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • One embodiment 2 of the present invention comprises the compounds of the above general formula I, wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1 and denotes
    • R1 denotes
      • (a) a C1-6-alkyl group optionally substituted by a group R1.1,
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (c) a C3-6-cycloalkyl group optionally substituted by a group R1.2 wherein a —CH2-unit may be replaced by a —C(O)— group,
      • (d) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
      • (e) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups
        • R1.4, which contains at least one N, O or S atom and which optionally additionally contains one, two or three further N-atoms,
      • (f) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
      • (g) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
      • (h) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group,
      • (i) —O—R1.1.1 or
      • (j) —NR1.1.3R1.1.4,
    • R1.1 denotes —CN, C3-6-cycloalkyl, —OR1.1.1, —NR1.1.3R1.1.4,
    • R1.1.1 denotes
      • (a) H,
      • (b) C1-4-alkyl,
      • (c) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R1.1.3,
    • R1.1.4 independently of one another denote
      • (a) H,
      • (b) C1-4-alkyl,
      • (c) C3-6-cycloalkyl, or
    • R1.1.3 and R1.1.4 together with the N atom to which they are attached form a 5- or 6-membered heterocyclic ring, which may additionally contain a further heteroatom selected from N, O and S, or
    • R1.2 denotes halogen, —NO2, —CN, —OH, —O—CH3 or phenyl,
    • R1.3 independently of one another denote
      • (a) halogen, —NO2, —CN, C1-6-alkyl or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R1.4 independently of one another denote)
      • (a) halogen, —NO2, —CN, —OR1.1.1, —NR1.1.3R1.1.4, —N(R1.4.1)—C(O)—C1-4-alkyl, C1-6-alkyl, or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
    • R1.4.1 denotes H or C1-4-alkyl,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 3 of the present invention comprises the compounds of the above general formula I, wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1 and
    • R1 denotes
      • (a) a C1-6-alkyl group optionally substituted by a group R1.1,
      • (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
      • (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which contains at least one N, O or S atom and which optionally additionally contains one, two or three further N-atoms,
      • (d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
      • (e) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
      • (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group,
    • R1.1 denotes —CN, C3-6-cycloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
    • R1.3 independently of one another denote
      • (a) F, Cl, Br, —OH, —OCH3, C1-6-alkyl or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
    • R1.4 independently of one another denote
      • (a) F, Cl, Br, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —N(C2-3-alkyl)2-NH—C(O)—C1-4-Alkyl, C1-6-alkyl, or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
        the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 4 of the present invention comprises the compounds of the above general formula I, wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1 and
    • R1 denotes
      • (a) a C1-6-alkyl group optionally substituted by a group R1.1,
      • (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
      • (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups
        • R1.4, which is selected from among
  • Figure US20100240669A1-20100923-C00003
      • (d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4 which is selected from among
  • Figure US20100240669A1-20100923-C00004
      • (e) a nine-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is selected from among
  • Figure US20100240669A1-20100923-C00005
      • (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, which is selected from among
  • Figure US20100240669A1-20100923-C00006
    • R1.1 denotes —CN, cyclopropyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
    • R1.3 independently of one another denotes
      • (a) F, Cl, Br, —OH, —OCH3, —OCF3, C1-4-alkyl or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
    • R1.4 independently of one another denotes
      • (a) F, Cl, Br, —OH, —OCH3, —OCF3, —NH2, —NH—C1-4-alkyl, —N(C1-4-alkyl)2, —NH—C(O)—C1-4-alkyl, C1-6-alkyl, or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
        the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 5 of the present invention comprises the compounds of the above general formula I, wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1 and
    • R1 is selected from among
  • Figure US20100240669A1-20100923-C00007
    Figure US20100240669A1-20100923-C00008
    Figure US20100240669A1-20100923-C00009
  • the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 6 of the present invention comprises the compounds of the above general formula I, wherein R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1 and
    • R1 is selected from among
  • Figure US20100240669A1-20100923-C00010
    Figure US20100240669A1-20100923-C00011
    Figure US20100240669A1-20100923-C00012
  • the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 7 of the present invention consists of the compounds of the above general formula I, wherein R1 is defined as mentioned hereinbefore under embodiment 1, 2, 3, 4, 5 or 6 and
    • n denotes one of the numbers 0, 1 or 2,
    • R2 denotes
      • (a) H,
      • (b) C1-4-alkyl,
    • R3 and R4 together with the carbon atom to which they are bound denote a C3-6-cycloalkylene group optionally substituted by a group R3.1 wherein a —CH2 unit may be replaced by a heteroatom O, N, S or by a group CO, SO or SO2,
    • R3.1 denotes H, —OH,
    • R5 denotes
      • (a) H,
      • (b) C1-4-alkyl,
      • (c) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R6 independently of one another denotes
      • (a) H, halogen, —CN, —OH, C1-6-alkyl, C3-7-cycloalkyl, —O—C1-4-alkyl, —O—CF3, —O—C3-6-cycloalkyl, —N(C1-3-alkyl)2, —C(O)—NH2, —(SO2)NH2, —SO2—C1-3-alkyl, or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R7 denotes
      • (a) H, halogen, —CN, —OH,
      • (b) C1-6-alkyl,
      • (c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (d) C3-7-cycloalkyl,
      • (e) —O—C1-6-alkyl,
      • (f) —O—C3-7-cycloalkyl,
      • (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
      • (h) —C(O)—R7.1,
      • (i) —S—C1-4-alkyl,
    • R7.1 denotes —NH2, —OH, —O—C1-8-alkyl,
    • R8 denotes H, halogen, C1-4-alkyl,
    • R9 denotes
      • (a) H, halogen, —CN, —OH,
      • (b) C1-6-alkyl,
      • (c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (d) C3-7-cycloalkyl,
      • (e) C2-4-alkynyl,
      • (f) —O—C1-6-alkyl,
      • (g) —O—C3-7-cycloalkyl,
      • (h) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
      • (i) —C(O)—R9.1,
      • (j) —S—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl,
    • R9.1 denotes —NH2, —OH, —O—C1-8-alkyl,
    • R10 denotes H, halogen, C1-4-alkyl,
    • R11 denotes
      • (a) H, halogen, —CN, —OH,
      • (b) C1-6-alkyl,
      • (c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (d) C3-7-cycloalkyl,
      • (e) —O—C1-6-alkyl,
      • (f) —O—C3-7-cycloalkyl,
      • (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
      • (h) —C(O)—R11.1,
      • (i) —S—C1-3-alkyl,
    • R11.1 denotes —NH2, —OH, —O—C1-8-alkyl, and
    • X independently of one another represent C—R6 or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 8 of the present invention comprises the compounds of the above general formula I, wherein R1, R3, R4, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5 or 6 and
  • R2 denotes H or CH3,
    the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 8 of the present invention comprises the compounds of the above general formula I, wherein R1, R3, R4, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6 or 7 and
  • R2 denotes H or CH3,
    the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 9 of the present invention comprises the compounds of the above general formula I, wherein R1, R2, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6 or 7 and
  • R2 denotes H,
    the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 10 of the present invention comprises the compounds of the above general formula I, wherein R1, R2, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8 or 9 and
  • R3 and R4 together with the carbon atom to which they are bonded denote a C3-6-cycloalkylene group wherein a —CH2— unit may be replaced by an oxygen atom,
    the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 11 of the present invention comprises the compounds of the above general formula I, wherein R1, R2, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8 or 9 and
  • R3 and R4 together with the carbon atom to which they are bonded denote a group selected from
  • Figure US20100240669A1-20100923-C00013
  • the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 12 of the present invention comprises the compounds of the above general formula I, wherein R1, R2, R5, R6, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 and
  • R5 denotes H or CH3,
    the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 13 of the present invention comprises the compounds of the above general formula I, wherein R1, R2, R3, R4, R5, R7, R8, R9, R10, R11, n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 and
  • R6 denotes H, F, Cl or methyl,
    the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 14 of the present invention comprises the compounds of the above general formula I, wherein R1, R2, R3, R4, R5, R6, n and X are defined as mentioned hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 and
    • R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
    • R8 denotes H,
    • R9 denotes F, Cl, Br, C1-4-alkyl, —S—C1-4-alkyl,
    • R10 denotes H and
    • R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 15 of the present invention comprises the compounds of general formula Ia
  • Figure US20100240669A1-20100923-C00014
  • wherein
    • R1 denotes
      • (a) a C1-6-alkyl group optionally substituted by a group R1.1,
      • (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
      • (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which contains at least one N, O or S atom and which optionally additionally contains one, two or three further N-atoms,
      • (d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
      • (e) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
      • (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group,
    • R1.1 denotes —CN, C3-6-cycloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
    • R13 independently of one another denotes
      • (a) F, Cl, Br, —OH, —OCH3, C1-6-alkyl or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
    • R1.4 independently of one another denotes
      • (a) F, Cl, Br, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —NH—C(O)—C1-4-alkyl, C1-6-alkyl, or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R2 denotes H or CH3,
    • R3 and R4 together with the carbon atom to which they are bonded denote a C3-6-cycloalkylene group wherein a —CH2 unit may be replaced by an oxygen atom,
    • R5 denotes H or C1-4-alkyl,
    • R6 denotes H, F, Cl, Br or C1-4-alkyl,
    • R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
    • R9 denotes F, Cl, Br, C1-4-alkyl, —S—C1-4-alkyl,
    • R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
    • X denotes CH or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 16 of the present invention comprises the compounds of general formula Ia, wherein
    • R1 denotes
      • (a) a C1-6-alkyl group optionally substituted by a group R1.1,
      • (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
      • (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups
        • R1.4, which is selected from among
  • Figure US20100240669A1-20100923-C00015
      • (d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is selected from among
  • Figure US20100240669A1-20100923-C00016
      • (e) a nine-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is selected from among
  • Figure US20100240669A1-20100923-C00017
      • (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, which is selected from among
  • Figure US20100240669A1-20100923-C00018
    • R1.1 denotes —CN, cyclopropyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
    • R1.3 denotes independently of one another
      • (a) F, Cl, Br, —OH, —OCH3, —OCF3, C1-4-alkyl or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
    • R1.4 denotes independently of one another
      • (a) F, Cl, Br, —OH, —OCH3, —OCF3, —NH2, —NH—C1-4-alkyl, —N(C1-4-alkyl)2, —NH—C(O)—C1-4-alkyl, C1-6-alkyl, or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R2 denotes H or CH3,
    • R3 and R4 together with the carbon atom to which they are bonded denote a C3-6-cycloalkylene group wherein a —CH2 unit may be replaced by an oxygen atom,
    • R5 denotes H or CH3,
    • R6 denotes H, F, Cl or methyl,
    • R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
    • R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
    • R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
    • X denotes CH or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 17 of the present invention comprises the compounds of general formula Ia, wherein
    • R1 denotes a group selected from
  • Figure US20100240669A1-20100923-C00019
    Figure US20100240669A1-20100923-C00020
    Figure US20100240669A1-20100923-C00021
    • R2 denotes H or CH3,
    • R3 and R4 together with the carbon atom to which they are bonded denote a C3-6-cycloalkylene group wherein a —CH2 unit may be replaced by an oxygen atom,
    • R5 denotes H or CH3,
    • R6 denotes H, F, Cl or methyl,
    • R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
    • R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
    • R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
    • X denotes CH or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 18 of the present invention comprises the compounds of general formula Ia wherein
    • R1 denotes a group selected from
  • Figure US20100240669A1-20100923-C00022
    Figure US20100240669A1-20100923-C00023
    Figure US20100240669A1-20100923-C00024
    • R2 denotes H or CH3,
    • R3 and R4 together with the carbon atom to which they are bound denote a C3-6-cycloalkylene group wherein a —CH2 unit may be replaced by an oxygen atom,
    • R5 denotes H or CH3,
    • R6 denotes H, F, Cl or methyl,
    • R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
    • R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
    • R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
    • X denotes CH or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 19 of the present invention comprises the compounds of general formula Ib
  • Figure US20100240669A1-20100923-C00025
  • wherein
    • R1 denotes
      • (a) a C1-6-alkyl group optionally substituted by a group R1.1,
      • (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
      • (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which contains at least one N, O or S atom and which optionally additionally contains one, two or three further N-atoms,
      • (d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
      • (e) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
  • (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R14, in which a —CH2— unit may be replaced by a —C(O)— group,
    • R1.1 denotes —CN, C3-6-cycloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
    • R1.3 denotes independently of one another
      • (a) F, Cl, Br, —OH, —OCH3, C1-6-alkyl or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
    • R1.4 denotes independently of one another
      • (a) F, Cl, Br, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —NH—C(O)—C1-4-alkyl, C1-6-alkyl, or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R2 denotes H or CH3,
    • R5 denotes H or C1-4-alkyl,
    • R6 denotes H, F, Cl, Br or C1-4-alkyl,
    • R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
    • R9 denotes F, Cl, Br, C1-4-alkyl, —S—C1-4-alkyl,
    • R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
    • X denotes CH or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 20 of the present invention comprises the compounds of general formula Ib, wherein
    • R1 denotes
      • (a) a C1-6-alkyl group optionally substituted by a group R1.1,
      • (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
      • (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which is selected from among
  • Figure US20100240669A1-20100923-C00026
      • (d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is selected from among
  • Figure US20100240669A1-20100923-C00027
      • (e) a nine-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is selected from among
  • Figure US20100240669A1-20100923-C00028
      • (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, which is selected from among
  • Figure US20100240669A1-20100923-C00029
    • R1.1 denotes —CN, cyclopropyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
    • R1.3 denotes independently of one another
      • (a) F, Cl, Br, —OH, —OCH3, —OCF3, C1-4-alkyl or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
    • R1.4 denotes independently of one another
      • (a) F, Cl, Br, —OH, —OCH3, —OCF3, —NH2, —NH—C1-4-alkyl, —N(C1-4-alkyl)2, —NH—C(O)—C1-4-alkyl, C1-6-alkyl, or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R2 denotes H or CH3,
    • R5 denotes H or CH3,
    • R6 denotes H, F, Cl or methyl,
    • R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
    • R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
    • R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
    • X denotes CH or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 21 of the present invention comprises the compounds of general formula Ib, wherein
    • R1 denotes a group selected from
  • Figure US20100240669A1-20100923-C00030
    Figure US20100240669A1-20100923-C00031
    Figure US20100240669A1-20100923-C00032
    • R2 denotes H or CH3,
    • R5 denotes H or CH3,
    • R6 denotes H, F, Cl or methyl,
    • R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
    • R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
    • R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
    • X denotes CH or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 22 of the present invention comprises the compounds of general formula Ib, wherein
    • R1 denotes a group selected from
  • Figure US20100240669A1-20100923-C00033
    Figure US20100240669A1-20100923-C00034
    Figure US20100240669A1-20100923-C00035
    • R2 denotes H,
    • R5 denotes H or CH3,
    • R6 denotes H, F, Cl or methyl,
    • R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
    • R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
    • R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
    • X denotes CH or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 23 of the present invention comprises the compounds of general formula Ic
  • Figure US20100240669A1-20100923-C00036
  • wherein
    • R1 denotes
      • (a) a C1-6-alkyl group optionally substituted by a group R1.1,
      • (b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
      • (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which contains at least one N, O or S atom and which optionally additionally contains one, two or three further N-atoms,
      • (d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
      • (e) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4 which contains one, two or three N-atoms,
      • (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, wherein a —CH2— unit may be replaced by a —C(O)— group,
    • R11 denotes —CN, C3-6-cycloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
    • R1.3 independently of one another denote
      • (a) F, Cl, Br, —OH, —OCH3, C1-6-alkyl or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
    • R1.4 independently of one another denote
      • (a) F, Cl, Br, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —NH—C(O)—C1-4-alkyl, C1-6-alkyl, or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R2 denotes H or CH3,
    • R5 denotes H or C1-4-alkyl,
    • R6 denotes H, F, Cl, Br or C1-4-alkyl,
    • R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
    • R9 denotes F, Cl, Br, C1-4-alkyl, —S—C1-4-alkyl,
    • R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
    • X denotes CH or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 24 of the present invention comprises the compounds of general formula IC, wherein
    • R1 denotes
      • (a) a C1-6-alkyl group optionally substituted by a group R1.1,
      • (b) a phenyl group optionally substituted by 1, 2 or 3 groups R13,
      • (c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which is selected from among
  • Figure US20100240669A1-20100923-C00037
      • (d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is selected from among
  • Figure US20100240669A1-20100923-C00038
      • (e) a nine-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is selected from among
  • Figure US20100240669A1-20100923-C00039
      • (f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, which is selected from among
  • Figure US20100240669A1-20100923-C00040
    • R1.1 denotes —CN, cyclopropyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
    • R13 independently of one another denotes
      • (a) F, Cl, Br, —OH, —OCH3, —OCF3, C1-4-alkyl or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
    • R1.4 independently of one another denote
      • (a) F, Cl, Br, —OH, —OCH3, —OCF3, —NH2, —NH—C1-4-alkyl, —N(C1-4-alkyl)2, —NH—C(O)—C1-4-alkyl, C1-6-alkyl, or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R2 denotes H or CH3,
    • R5 denotes H or CH3,
    • R6 denotes H, F, Cl or methyl,
    • R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
    • R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
    • R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
    • X denotes CH or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 25 of the present invention comprises the compounds of general formula Ic, wherein
    • R1 denotes a group selected from
  • Figure US20100240669A1-20100923-C00041
    Figure US20100240669A1-20100923-C00042
    Figure US20100240669A1-20100923-C00043
    • R2 denotes H or CH3,
    • R5 denotes H or CH3,
    • R6 denotes H, F, Cl or methyl,
    • R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
    • R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
    • R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
    • X denotes CH or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 26 of the present invention comprises the compounds of general formula Ic, wherein
    • R1 denotes a group selected from
  • Figure US20100240669A1-20100923-C00044
    Figure US20100240669A1-20100923-C00045
    Figure US20100240669A1-20100923-C00046
    • R2 denotes H or CH3,
    • R5 denotes H or CH3,
    • R6 denotes H, F, Cl or methyl,
    • R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
    • R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
    • R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
    • X denotes CH or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 27 of the present invention comprises the compounds of general formula Id
  • Figure US20100240669A1-20100923-C00047
  • wherein
    • R1 denotes a group selected from
  • Figure US20100240669A1-20100923-C00048
    • R3 and R4 together with the carbon atom to which they are attached denote a C3-6-cycloalkylene group wherein a —CH2 unit may be replaced by an oxygen atom,
    • R5 denotes H or CH3,
    • R6 denotes C1 or CH3,
    • R7 denotes H or F,
    • X denotes CH or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • An embodiment 28 of the present invention comprises the compounds of general formula I, Ia, Ib, Ic or Id, wherein n, R1, R3, R4, R5, R6, R7, R8, R9, R10, R11 and X are defined as described hereinbefore in embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27 and
    • R2 denotes H,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • The following are mentioned as examples of most particularly preferred compounds of the above general formula I:
  • No. Structure
    (1)
    Figure US20100240669A1-20100923-C00049
    (2)
    Figure US20100240669A1-20100923-C00050
    (3)
    Figure US20100240669A1-20100923-C00051
    (4)
    Figure US20100240669A1-20100923-C00052
    (5)
    Figure US20100240669A1-20100923-C00053
    (6)
    Figure US20100240669A1-20100923-C00054
    (7)
    Figure US20100240669A1-20100923-C00055
    (8)
    Figure US20100240669A1-20100923-C00056
    (9)
    Figure US20100240669A1-20100923-C00057
    (10)
    Figure US20100240669A1-20100923-C00058
    (11)
    Figure US20100240669A1-20100923-C00059
    (12)
    Figure US20100240669A1-20100923-C00060
    (13)
    Figure US20100240669A1-20100923-C00061
    (14)
    Figure US20100240669A1-20100923-C00062
    (15)
    Figure US20100240669A1-20100923-C00063
    (16)
    Figure US20100240669A1-20100923-C00064
    (17)
    Figure US20100240669A1-20100923-C00065
    (18)
    Figure US20100240669A1-20100923-C00066
    (19)
    Figure US20100240669A1-20100923-C00067
    (20)
    Figure US20100240669A1-20100923-C00068
    (21)
    Figure US20100240669A1-20100923-C00069
    (22)
    Figure US20100240669A1-20100923-C00070
    (23)
    Figure US20100240669A1-20100923-C00071
    (24)
    Figure US20100240669A1-20100923-C00072
    (25)
    Figure US20100240669A1-20100923-C00073
    (26)
    Figure US20100240669A1-20100923-C00074
    (27)
    Figure US20100240669A1-20100923-C00075
    (28)
    Figure US20100240669A1-20100923-C00076
    (29)
    Figure US20100240669A1-20100923-C00077
    (30)
    Figure US20100240669A1-20100923-C00078
    (31)
    Figure US20100240669A1-20100923-C00079
    (32)
    Figure US20100240669A1-20100923-C00080
    (33)
    Figure US20100240669A1-20100923-C00081
    (34)
    Figure US20100240669A1-20100923-C00082
    (35)
    Figure US20100240669A1-20100923-C00083
    (36)
    Figure US20100240669A1-20100923-C00084
    (37)
    Figure US20100240669A1-20100923-C00085
    (38)
    Figure US20100240669A1-20100923-C00086
    (39)
    Figure US20100240669A1-20100923-C00087
    (40)
    Figure US20100240669A1-20100923-C00088
    (41)
    Figure US20100240669A1-20100923-C00089
    (42)
    Figure US20100240669A1-20100923-C00090
    (43)
    Figure US20100240669A1-20100923-C00091
    (44)
    Figure US20100240669A1-20100923-C00092
    (45)
    Figure US20100240669A1-20100923-C00093
    (46)
    Figure US20100240669A1-20100923-C00094
    (47)
    Figure US20100240669A1-20100923-C00095
    (48)
    Figure US20100240669A1-20100923-C00096
    (49)
    Figure US20100240669A1-20100923-C00097
    (50)
    Figure US20100240669A1-20100923-C00098
    (51)
    Figure US20100240669A1-20100923-C00099
    (52)
    Figure US20100240669A1-20100923-C00100
    (53)
    Figure US20100240669A1-20100923-C00101
    (54)
    Figure US20100240669A1-20100923-C00102
    (55)
    Figure US20100240669A1-20100923-C00103
    (56)
    Figure US20100240669A1-20100923-C00104
    (57)
    Figure US20100240669A1-20100923-C00105
    (58)
    Figure US20100240669A1-20100923-C00106
    (59)
    Figure US20100240669A1-20100923-C00107
    (60)
    Figure US20100240669A1-20100923-C00108
    (61)
    Figure US20100240669A1-20100923-C00109
    (62)
    Figure US20100240669A1-20100923-C00110
    (63)
    Figure US20100240669A1-20100923-C00111
    (64)
    Figure US20100240669A1-20100923-C00112
    (65)
    Figure US20100240669A1-20100923-C00113
    (66)
    Figure US20100240669A1-20100923-C00114
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    (68)
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    (69)
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    Figure US20100240669A1-20100923-C00118
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    Figure US20100240669A1-20100923-C00119
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    (73)
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    Figure US20100240669A1-20100923-C00342
    (289)
    Figure US20100240669A1-20100923-C00343
    (290)
    Figure US20100240669A1-20100923-C00344
    (291)
    Figure US20100240669A1-20100923-C00345
    (292)
    Figure US20100240669A1-20100923-C00346
    (293)
    Figure US20100240669A1-20100923-C00347
    (294)
    Figure US20100240669A1-20100923-C00348
    (295)
    Figure US20100240669A1-20100923-C00349
    (296)
    Figure US20100240669A1-20100923-C00350
    (297)
    Figure US20100240669A1-20100923-C00351
    (298)
    Figure US20100240669A1-20100923-C00352
    (299)
    Figure US20100240669A1-20100923-C00353
    (300)
    Figure US20100240669A1-20100923-C00354
    (301)
    Figure US20100240669A1-20100923-C00355
    (302)
    Figure US20100240669A1-20100923-C00356
    (303)
    Figure US20100240669A1-20100923-C00357
    (304)
    Figure US20100240669A1-20100923-C00358
    (305)
    Figure US20100240669A1-20100923-C00359
    (306)
    Figure US20100240669A1-20100923-C00360
    (307)
    Figure US20100240669A1-20100923-C00361
    (308)
    Figure US20100240669A1-20100923-C00362
    (309)
    Figure US20100240669A1-20100923-C00363
    (310)
    Figure US20100240669A1-20100923-C00364
    (311)
    Figure US20100240669A1-20100923-C00365
    (312)
    Figure US20100240669A1-20100923-C00366
    (313)
    Figure US20100240669A1-20100923-C00367
    (314)
    Figure US20100240669A1-20100923-C00368
    (315)
    Figure US20100240669A1-20100923-C00369
    (316)
    Figure US20100240669A1-20100923-C00370
    (317)
    Figure US20100240669A1-20100923-C00371
    (318)
    Figure US20100240669A1-20100923-C00372
    (319)
    Figure US20100240669A1-20100923-C00373
    (320)
    Figure US20100240669A1-20100923-C00374
    (321)
    Figure US20100240669A1-20100923-C00375
    (322)
    Figure US20100240669A1-20100923-C00376
    (323)
    Figure US20100240669A1-20100923-C00377
    (324)
    Figure US20100240669A1-20100923-C00378
    (325)
    Figure US20100240669A1-20100923-C00379
    (326)
    Figure US20100240669A1-20100923-C00380
    (327)
    Figure US20100240669A1-20100923-C00381
    (328)
    Figure US20100240669A1-20100923-C00382
    (329)
    Figure US20100240669A1-20100923-C00383
    (330)
    Figure US20100240669A1-20100923-C00384
    (331)
    Figure US20100240669A1-20100923-C00385
    (332)
    Figure US20100240669A1-20100923-C00386
    (333)
    Figure US20100240669A1-20100923-C00387
    (334)
    Figure US20100240669A1-20100923-C00388
    (335)
    Figure US20100240669A1-20100923-C00389
    (336)
    Figure US20100240669A1-20100923-C00390
    (337)
    Figure US20100240669A1-20100923-C00391
    (338)
    Figure US20100240669A1-20100923-C00392
    (339)
    Figure US20100240669A1-20100923-C00393
    (340)
    Figure US20100240669A1-20100923-C00394
    (341)
    Figure US20100240669A1-20100923-C00395
    (342)
    Figure US20100240669A1-20100923-C00396
    (343)
    Figure US20100240669A1-20100923-C00397
    (344)
    Figure US20100240669A1-20100923-C00398
    (345)
    Figure US20100240669A1-20100923-C00399
    (346)
    Figure US20100240669A1-20100923-C00400
    (347)
    Figure US20100240669A1-20100923-C00401
    (348)
    Figure US20100240669A1-20100923-C00402
    (349)
    Figure US20100240669A1-20100923-C00403
    (350)
    Figure US20100240669A1-20100923-C00404
    (351)
    Figure US20100240669A1-20100923-C00405
    (352)
    Figure US20100240669A1-20100923-C00406
    (353)
    Figure US20100240669A1-20100923-C00407
    (354)
    Figure US20100240669A1-20100923-C00408
    (355)
    Figure US20100240669A1-20100923-C00409
    (356)
    Figure US20100240669A1-20100923-C00410
    (357)
    Figure US20100240669A1-20100923-C00411
    (358)
    Figure US20100240669A1-20100923-C00412
    (359)
    Figure US20100240669A1-20100923-C00413
    (360)
    Figure US20100240669A1-20100923-C00414
    (361)
    Figure US20100240669A1-20100923-C00415
    (362)
    Figure US20100240669A1-20100923-C00416
    (363)
    Figure US20100240669A1-20100923-C00417
    (364)
    Figure US20100240669A1-20100923-C00418
    (365)
    Figure US20100240669A1-20100923-C00419
    (366)
    Figure US20100240669A1-20100923-C00420
    (367)
    Figure US20100240669A1-20100923-C00421
    (368)
    Figure US20100240669A1-20100923-C00422
    (369)
    Figure US20100240669A1-20100923-C00423
    (370)
    Figure US20100240669A1-20100923-C00424
    (371)
    Figure US20100240669A1-20100923-C00425
    (372)
    Figure US20100240669A1-20100923-C00426
    (373)
    Figure US20100240669A1-20100923-C00427
    (374)
    Figure US20100240669A1-20100923-C00428
    (375)
    Figure US20100240669A1-20100923-C00429
    (376)
    Figure US20100240669A1-20100923-C00430
    (377)
    Figure US20100240669A1-20100923-C00431
    (378)
    Figure US20100240669A1-20100923-C00432
    (379)
    Figure US20100240669A1-20100923-C00433
    (380)
    Figure US20100240669A1-20100923-C00434
    (381)
    Figure US20100240669A1-20100923-C00435
    (382)
    Figure US20100240669A1-20100923-C00436
    (383)
    Figure US20100240669A1-20100923-C00437
    (384)
    Figure US20100240669A1-20100923-C00438
    (385)
    Figure US20100240669A1-20100923-C00439
    (386)
    Figure US20100240669A1-20100923-C00440
    (287)
    Figure US20100240669A1-20100923-C00441
    (388)
    Figure US20100240669A1-20100923-C00442
    (389)
    Figure US20100240669A1-20100923-C00443
    (390)
    Figure US20100240669A1-20100923-C00444
    (391)
    Figure US20100240669A1-20100923-C00445
    (392)
    Figure US20100240669A1-20100923-C00446
    (393)
    Figure US20100240669A1-20100923-C00447
    (394)
    Figure US20100240669A1-20100923-C00448
    (395)
    Figure US20100240669A1-20100923-C00449
    (396)
    Figure US20100240669A1-20100923-C00450

    the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • A further embodiment of the present invention comprises the compounds of general formula II
  • Figure US20100240669A1-20100923-C00451
  • wherein
    • n denotes one of the numbers 0, 1 or 2,
    • R2 denotes
      • (a) H,
      • (b) C1-4-alkyl,
      • (c) C1-4-alkyl-C(O)—,
    • R5 denotes
      • (a) H,
      • (b) C1-4-alkyl,
      • (c) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R6 independently of one another denotes
      • (a) H, halogen, —CN, —OH, C3-7-cycloalkyl, —O—C1-4-alkyl, —O—CF3, —O—C3-6-cycloalkyl, —N(C1-3-alkyl)2, —C(O)—NH2, —(SO2)NH2, —SO2—C1-3-alkyl, or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R7 denotes
      • (a) H, halogen, —CN, —OH,
      • (b) C1-6-alkyl,
      • (c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (d) C3-7-cycloalkyl,
      • (e) —O—C1-6-alkyl,
      • (f) —O—C3-7-cycloalkyl,
      • (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
      • (h) —C(O)—R7.1,
      • (i) —S—C1-4-alkyl, —SO2—R7.2,
      • (j) a five-membered heteroaryl group optionally substituted by one or two C1-3-alkyl groups which is selected from among pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl, or
      • (k) a six-membered heteroaryl group optionally substituted by one or two C1-3-alkyl groups which is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
    • R7.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
    • R7.2 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl and
    • R8 denotes H, halogen, C1-4-alkyl,
    • R9 denotes
      • (a) H, halogen, —CN, —OH,
      • (b) C1-6-alkyl
      • (c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (d) C3-7-cycloalkyl,
      • (e) C2-4-alkynyl,
      • (f) —O—C1-6-alkyl,
      • (g) —O—C3-7-cycloalkyl,
      • (h) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
      • (i) —C(O)—R9.1,
      • (j) —S—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl,
    • R9.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
    • R19 denotes H, halogen, C1-4-alkyl,
    • R11 denotes
      • (a) H, halogen, —CN, —OH,
      • (b) C1-6-alkyl,
      • (c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (d) C3-7-cycloalkyl,
      • (e) —O—C1-6-alkyl,
      • (f) —O—C3-7-cycloalkyl,
      • (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
      • (h) —C(O)—R11.1,
      • (i) —S—C1-3-alkyl, —SO2—R11.2,
      • (j) a five-membered heteroaryl group optionally substituted by one or two C1-3-alkyl groups which is selected from among pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl, or
      • (k) a six-membered heteroaryl group optionally substituted by one or two C1-3-alkyl groups which is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
    • R11.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
    • R11.2 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl and
    • X independently of one another denotes C—R6 or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • A further embodiment of the present invention comprises the compounds of the above general formula II, wherein
    • n denotes one of the numbers 0, 1 or 2,
    • R2 denotes H or CH3,
    • R5 denotes H or CH3,
    • R6 denotes H, F, Cl or methyl,
    • R7 denotes H, F, Cl, Br, —CN, CF3, CHF2,
    • R8 denotes H,
    • R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
    • R10 denotes H,
    • R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
    • X independently of one another represent C—R6 or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • The following compounds are mentioned as examples of particularly preferred compounds of the above general formula II:
  • No. Structure
    (1.1)
    Figure US20100240669A1-20100923-C00452
    (1.2)
    Figure US20100240669A1-20100923-C00453
    (1.3)
    Figure US20100240669A1-20100923-C00454
    (1.4)
    Figure US20100240669A1-20100923-C00455
    (1.5)
    Figure US20100240669A1-20100923-C00456
    (1.6)
    Figure US20100240669A1-20100923-C00457
    (1.7)
    Figure US20100240669A1-20100923-C00458
    (1.8)
    Figure US20100240669A1-20100923-C00459
    (1.9)
    Figure US20100240669A1-20100923-C00460
    (1.10)
    Figure US20100240669A1-20100923-C00461
    (1.11)
    Figure US20100240669A1-20100923-C00462
    (1.12)
    Figure US20100240669A1-20100923-C00463
    (1.13)
    Figure US20100240669A1-20100923-C00464
    (1.14)
    Figure US20100240669A1-20100923-C00465
    (1.15)
    Figure US20100240669A1-20100923-C00466
    (1.16)
    Figure US20100240669A1-20100923-C00467
    (1.17)
    Figure US20100240669A1-20100923-C00468
    (1.18)
    Figure US20100240669A1-20100923-C00469
    (1.19)
    Figure US20100240669A1-20100923-C00470
    (1.20)
    Figure US20100240669A1-20100923-C00471
    (1.21)
    Figure US20100240669A1-20100923-C00472
    (1.22)
    Figure US20100240669A1-20100923-C00473
    (1.23)
    Figure US20100240669A1-20100923-C00474
    (1.24)
    Figure US20100240669A1-20100923-C00475
    (1.25)
    Figure US20100240669A1-20100923-C00476
    (1.26)
    Figure US20100240669A1-20100923-C00477
    (1.27)
    Figure US20100240669A1-20100923-C00478
    (1.28)
    Figure US20100240669A1-20100923-C00479
    (1.29)
    Figure US20100240669A1-20100923-C00480
    (1.30)
    Figure US20100240669A1-20100923-C00481
    (1.31)
    Figure US20100240669A1-20100923-C00482

    the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • A further embodiment of the present application relates to the use of the compounds of general formula II, wherein R2, R5, R6, R7, R8, R9, R10 and R11 are as hereinbefore defined, the diastereomers, the enantiomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases for preparing compounds of general formula I, which have B1-antagonistic properties.
  • A further embodiment of the present invention comprises the compounds of general formula III
  • Figure US20100240669A1-20100923-C00483
  • wherein
    • R1 denotes
      • (a) a C1-6-alkyl group optionally substituted by a group R1.1,
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (c) a C3-6-cycloalkyl group optionally substituted by a group R1.2 wherein a —CH2-unit may be replaced by a —C(O)— group,
      • (d) an aryl-C0-2-alkylene group optionally substituted by 1, 2 or 3 groups R1.3,
      • (e) a five-membered heteroaryl-C0-2-alkylene group optionally substituted by 1, 2 or 3 groups R1.4, which contains at least one N, O or S atom and which optionally additionally contains one, two or three further N-atoms and which may additionally be benzo-condensed,
      • (f) a six-membered heteroaryl-C0-2-alkylene group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms and which may additionally be benzo-condensed,
      • (g) a nine or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
      • (h) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, wherein a —CH2— unit may be replaced by a —C(O)— group,
      • (i) —O—R1.1.1,
      • (j) —NR1.1.3R1.14 or
      • (k) —C(═NR1.5)—CN,
    • R1.1 denotes halogen, —NO2, —CN, C3-6-cycloalkyl, —OR1.1.1, —SR1.1.1, —C(O)R1.1.1, —S(O)2—R1.1.2, —O—S(O)2—R1.1.1, —CO2R1.1.1, —O—C(O)—R1.1.4, —NR1.1,3-C(O)—R1.1.1, —NR1.1,3-C(O)—R1.1.1, —NR1.1,3-CO2—R1.1.1 or —C(O)—NR1.1.3R1.1.4,
    • R1.1.1 denotes
      • (a) H,
      • (b) C1-4-alkyl,
      • (c) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (d) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1,
      • (e) C3-6-cycloalkyl or
      • (f) a pyridyl group optionally substituted by 1, 2 or 3 groups R1.1.1.2,
    • R1.1.1.1 independently of one another denotes
      • (a) halogen, —NO2, —CN, —OH, —O—C1-4-alkyl, C3-6-cycloalkyl, C1-4-alkyl or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R1.1.1.2 independently of one another denotes halogen or C1-4-alkyl,
    • R1.1.2 denotes
      • (a) C1-4-alkyl,
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (c) —O—C1-4-alkyl or
      • (d) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1,
    • R1.1.3,
    • R1.1.4 independently of one another denote
      • (a) H,
      • (b) a C1-4-alkyl group optionally substituted by 1, 2 or 3 groups R1.1.4.1,
      • (c) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1,
      • (d) C3-6-cycloalkyl, or
    • R1.1.3 and R1.1.4 together with the N atom to which they are attached form a 5- or 6-membered heterocyclic ring, which may additionally contain a further heteroatom selected from N, O and S, or
    • R1.1.3 and R1.1.4 together with the N atom to which they are attached, form a cyclic imide,
    • R1.1.4.1 independently of one another denote halogen, —NH2, —NH(C1-4-alkyl), —N(C1-4-alkyl)2 or —SO2—R1.1.2,
    • R1.2 denotes halogen, —NO2, —CN, OH, —O—CH3 or phenyl,
    • R1.3 denotes
      • (a) halogen, —NO2, —CN, —OR1.1.1, —SR1.1.1, —CO2R1.1.1, C1-6-alkyl or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R1.4 independently of one another denotes
      • (a) halogen, —NO2, —CN, —OR1.1.1, —SR1.1.1, —S(O)—R1.1.2, —S(O)2—R1.1.2, —NR1.1.3R1.1.4, —N(R1.4.1)—C(O)—C1-4-alkyl, C1-6-alkyl,
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, or
      • (c) a oxo group,
    • R1.4.1 denotes H or C1-4-alkyl,
    • R1.5 denotes —OH or —O—C1-3-alkyl,
    • R2 denotes
      • (a) H,
      • (b) C1-4-alkyl,
      • (c) C1-4-alkyl-C(O)—,
    • R3 and R4 together with the carbon atom to which they are attached denote a C3-6-cycloalkylene group optionally substituted by a group R3.1 wherein a —CH2— unit may be replaced by a heteroatom O, N, S or by a group CO, SO or SO2, and
    • R3.1 denotes H, —OH,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • A further embodiment of the present invention comprises the compounds of the above general formula III, wherein
    • R1 is selected from among
  • Figure US20100240669A1-20100923-C00484
    Figure US20100240669A1-20100923-C00485
    Figure US20100240669A1-20100923-C00486
    Figure US20100240669A1-20100923-C00487
    Figure US20100240669A1-20100923-C00488
    • R2 denotes H or CH3,
    • R3 and R4 together with the carbon atom to which they are attached denote a C3-6-cycloalkylene group optionally substituted by a group R3.1 wherein a —CH2— unit may be replaced by a heteroatom O, N, S or by a group CO, SO or SO2, and
    • R3.1 denotes H, —OH,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • The following compounds are mentioned as examples of most particularly preferred compounds of the above general formula III:
  • No. Structure
    (2.1)
    Figure US20100240669A1-20100923-C00489
    (2.2)
    Figure US20100240669A1-20100923-C00490
    (2.3)
    Figure US20100240669A1-20100923-C00491
    (2.4)
    Figure US20100240669A1-20100923-C00492
    (2.5)
    Figure US20100240669A1-20100923-C00493
    (2.6)
    Figure US20100240669A1-20100923-C00494
    (2.7)
    Figure US20100240669A1-20100923-C00495
    (2.8)
    Figure US20100240669A1-20100923-C00496
    (2.9)
    Figure US20100240669A1-20100923-C00497
    (2.10)
    Figure US20100240669A1-20100923-C00498
    (2.11)
    Figure US20100240669A1-20100923-C00499

    the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • A further embodiment of the present application relates to the use of the compounds of general formula III, wherein R2, R3, and R4 are as hereinbefore defined, the diastereomers, the enantiomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases for preparing compounds of general formula I which have B1-antagonistic properties.
  • A further embodiment of the present invention comprises the compounds of general formula IV
  • Figure US20100240669A1-20100923-C00500
  • wherein
    • n denotes one of the numbers 0, 1 or 2,
    • R2 denotes
      • (a) H,
      • (b) C1-4-alkyl,
      • (c) C1-4-alkyl-C(O)—,
    • R3 and R4 together with the carbon atom to which they are attached denote a C3-6-cycloalkylene group optionally substituted by a group R3.1 wherein a —CH2— unit may be replaced by a heteroatom O, N, S or by a group CO, SO or SO2,
    • R3.1 denotes H, —OH,
    • R5 denotes
      • (a) H,
      • (b) C1-4-alkyl,
      • (c) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R6 independently of one another denote
      • (a) H, halogen, —CN, —OH, C1-6-alkyl, C3-7-cycloalkyl, —O—C1-4-alkyl, —O—CF3, —O—C3-6-cycloalkyl, —N(C1-3-alkyl)2, —C(O)—NH2, —(SO2)NH2, —SO2—C1-3-alkyl, or
      • (b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
    • R7 denotes
      • (a) H, halogen, —CN, —OH,
      • (b) C1-6-alkyl,
      • (c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (d) C3-7-cycloalkyl,
      • (e) —O—C1-6-alkyl,
      • (f) —O—C3-7-cycloalkyl,
      • (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
      • (h) —C(O)—R7.1,
      • (i) —S—C1-4-alkyl, —SO2—R7.2,
      • (j) a five-membered heteroaryl group optionally substituted by one or two C1-3-alkyl groups which is selected from among pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl, or
      • (k) a six-membered heteroaryl group optionally substituted by one or two C1-3-alkyl groups which is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
    • R7.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-6-alkyl or —O—C3-7-cycloalkyl,
    • R7.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl and
    • R8 denotes H, halogen, C1-4-alkyl,
    • R9 denotes
      • (a) H, halogen, —CN, —OH,
      • (b) C1-6-alkyl,
      • (c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (d) C3-7-cycloalkyl,
      • (e) C2-4-alkynyl,
      • (f) —O—C1-6-alkyl
      • (g) —O—C3-7-cycloalkyl,
      • (h) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
      • (i) —C(O)—R9.1,
      • (j) —S—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl,
    • R9.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
    • R10 denotes H, halogen, C1-4-alkyl,
    • R11 denotes
      • (a) H, halogen, —CN, —OH,
      • (b) C1-6-alkyl,
      • (c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
      • (d) C3-7-cycloalkyl,
      • (e) —O—C1-6-alkyl,
      • (f) —O—C3-7-cycloalkyl,
      • (g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
      • (h) —C(O)—R11.1,
      • (i) —S—C1-3-alkyl, —SO2—R11.2,
      • (j) a five-membered heteroaryl group optionally substituted by one or two C1-3-alkyl groups which is selected from among pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl, or
      • (k) a six-membered heteroaryl group optionally substituted by one or two C1-3-alkyl groups which is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
    • R11.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
    • R11.2—NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl and
    • X independently of one another denotes C—R6 or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • A further embodiment of the present invention comprises the compounds of the above general formula IV, wherein
    • n denotes one of the numbers 0, 1 or 2,
    • R2 denotes H or CH3,
    • R3 and R4 together with the carbon atom to which they are attached denote a C3-6-cycloalkylene group optionally substituted by a group R3.1 wherein a —CH2 unit may be replaced by a heteroatom O, N, S or by a group CO, SO or SO2,
    • R3.1 denotes H, —OH,
    • R5 denotes H or CH3,
    • R6 denotes H, F, Cl or methyl,
    • R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
    • R8 denotes H,
    • R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
    • R10 denotes H,
    • R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
    • X independently of one another denotes C—R6 or N,
      the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • The following compounds are mentioned as examples of most particularly preferred compounds of the above general formula IV:
  • No. Structure
    (3.1)
    Figure US20100240669A1-20100923-C00501
    (3.2)
    Figure US20100240669A1-20100923-C00502
    (3.3)
    Figure US20100240669A1-20100923-C00503
    (3.4)
    Figure US20100240669A1-20100923-C00504
    (3.5)
    Figure US20100240669A1-20100923-C00505
    (3.6)
    Figure US20100240669A1-20100923-C00506
    (3.7)
    Figure US20100240669A1-20100923-C00507
    (3.8)
    Figure US20100240669A1-20100923-C00508
    (3.9)
    Figure US20100240669A1-20100923-C00509
    (3.10)
    Figure US20100240669A1-20100923-C00510
    (3.11)
    Figure US20100240669A1-20100923-C00511
    (3.12)
    Figure US20100240669A1-20100923-C00512
    (3.13)
    Figure US20100240669A1-20100923-C00513
    (3.14)
    Figure US20100240669A1-20100923-C00514
    (3.15)
    Figure US20100240669A1-20100923-C00515
    (3.16)
    Figure US20100240669A1-20100923-C00516
    (3.17)
    Figure US20100240669A1-20100923-C00517
    (3.18)
    Figure US20100240669A1-20100923-C00518
    (3.19)
    Figure US20100240669A1-20100923-C00519
    (3.20)
    Figure US20100240669A1-20100923-C00520
    (3.21)
    Figure US20100240669A1-20100923-C00521
    (3.22)
    Figure US20100240669A1-20100923-C00522

    the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
  • A further embodiment of the present application relates to the use of the compounds of general formula IV, wherein R2, R5, R6, R7, R8, R9, R10 and R11 are as hereinbefore defined, the diastereomers, the enantiomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases for preparing compounds of general formula I which have B1-antagonistic properties.
    • Terms and Definitions Used
  • Unless otherwise stated, all the substituents are independent of one another. If for example there are a plurality of C1-6-alkyl groups as substituents in one group, in the case of three substituents C1-6-alkyl, one may represent methyl, one n-propyl and one tert-butyl.
  • Within the scope of this application, in the definition of possible substituents, these may also be represented in the form of a structural formula. If present, an asterisk (*) in the structural formula of the substituent is to be understood as being the linking point to the rest of the molecule.
  • Also included in the subject matter of this invention are the compounds according to the invention, including the salts thereof, in which one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.
  • By the term “C1-3-alkyl” (including those that are part of other groups) are meant alkyl groups with 1 to 3 carbon atoms, by the term “C1-4-alkyl” are meant branched and unbranched alkyl groups with 1 to 4 carbon atoms, by the term “C1-6-alkyl” are meant branched and unbranched alkyl groups with 1 to 6 carbon atoms, and by the term “C1-8-alkyl” are meant branched and unbranched alkyl groups with 1 to 8 carbon atoms. Examples include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl and n-octyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. May optionally also be used for the above-mentioned groups. Unless stated otherwise, the definitions propyl and butyl include all the possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl.
  • Moreover the definitions mentioned previously also include those groups wherein each methylene group may be substituted by up to two and each methyl group may be substituted by up to three fluorine atoms.
  • By the term “C0-2-alkylene” are meant branched and unbranched alkylene groups with 0 to 2 carbon atoms, while a C0-alkylene group denotes a bond. Examples include: methylene, ethylene and ethane-1,1-diyl. Moreover the definitions mentioned previously also include those groups wherein each methylene group may be substituted by up to two fluorine atoms.
  • By the term “C3-7-cycloalkyl” (including those that are part of other groups) are meant cyclic alkyl groups with 3 to 7 carbon atoms and by the term “C3-6-cycloalkyl” are meant cyclic alkyl groups with 3 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Unless otherwise stated, the cyclic alkyl groups may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
  • By the term “C3-6-cycloalkylene” (including those that are part of other groups) are meant cyclic alkylene groups with 3 to 6 carbon atoms. Examples include: cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene. Unless otherwise stated, the cyclic alkylene groups may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
  • By the term “C2-4-alkynyl” (including those that are part of other groups) are meant branched and unbranched alkynyl groups with 2 to 4 carbon atoms, provided that they have at least one triple bond. Examples include: ethynyl, propynyl or butynyl. Unless stated otherwise, the definitions propynyl and butynyl include all the possible isomeric forms of the groups in question. Thus for example propynyl includes 1-propynyl and 2-propynyl, butynyl includes 1-butynyl, 2-butynyl and 3-butynyl etc.
  • “Halogen” within the scope of the present invention denotes fluorine, chlorine, bromine or iodine. Unless stated to the contrary, fluorine, chlorine and bromine are regarded as preferred halogens.
  • By the term “heterocyclic rings” or “heterocyclic group” are meant stable 5- or 6-membered monocyclic ring systems, which may be both saturated and mono- or di-unsaturated and besides carbon atoms may carry one or two heteroatoms, which are selected from among nitrogen, oxygen and sulphur. Both nitrogen and sulphur heteroatoms may optionally be oxidised. The previously mentioned heterocycles may be attached to the rest of the molecule via a carbon atom or a nitrogen atom. The following compounds are mentioned as examples:
  • Figure US20100240669A1-20100923-C00523
  • “Cyclic imides” includes for example succinimides, maleimide and phthalimide.
  • By the term “aryl” (including those that are part of other groups) are meant aromatic ring systems with 6 or 10 carbon atoms. Examples of these are phenyl, 1-naphthyl or 2-naphthyl; the preferred aryl group is phenyl. Unless otherwise stated, the aromatic groups may be substituted by one or more groups selected from among methyl, ethyl, n-propyl, iso-propyl, tert-butyl, hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, bromine and iodine, while the groups may be identical or different.
  • By the term “heteroaryl” are meant five- or six-membered heterocyclic aromatic groups, which may contain one, two, three or four heteroatoms, selected from among oxygen, sulphur and nitrogen, and additionally contain so many conjugated double bonds that an aromatic system is formed. These heteroaryls may additionally be benzo-condensed with a phenyl ring, so as to form nine- or ten-membered bicyclic heteroaryls.
  • The following are examples of five- or six-membered heteroaromatic groups:
  • Figure US20100240669A1-20100923-C00524
  • The following are examples of nine- or ten-membered heteroaromatic groups:
  • Figure US20100240669A1-20100923-C00525
  • Unless otherwise stated, the heteroaryls mentioned previously may be substituted by one or more groups selected from among methyl, ethyl, n-propyl, iso-propyl, tert-butyl, hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, bromine and iodine, while the groups may be identical or different.
  • In addition, any nitrogen atom present in the heteroaryl group may be oxidised, thereby forming an N-oxide.
  • By the term “oxo group” is meant an oxygen substituent at a carbon atom, which leads to the formation of a carbonyl group —C(O)—. The introduction of an oxo group as substituent at a non-aromatic carbon atom leads to a conversion of a —CH2 group into a —C(O)— group. The introduction of an oxo group at an aromatic carbon atom leads to the conversion of a —CH— group into a —C(O)— group and may result in the loss of aromaticity.
  • If they contain suitable basic functions, for example amino groups, compounds of general formula I may be converted, particularly for pharmaceutical use, into the physiologically acceptable salts thereof with inorganic or organic acids. Examples of inorganic acids for this purpose include hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulphuric acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid or p-toluenesulphonic acid, while organic acids that may be used include malic acid, succinic acid, acetic acid, fumaric acid, maleic acid, mandelic acid, lactic acid, tartaric acid or citric acid.
  • In addition, the compounds of general formula I, if they contain suitable carboxylic acid functions, may be converted into the physiologically acceptable salts thereof with inorganic or organic bases, particularly for pharmaceutical applications. Examples of inorganic bases include alkali or alkaline earth metal hydroxides, e.g. sodium hydroxide or potassium hydroxide, or carbonates, ammonia, zinc or ammonium hydroxides; examples of organic amines include diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine or dicyclohexylamine.
  • The compounds according to the invention may be present as racemates, provided that they have only one chiral element, but may also be obtained as pure enantiomers, i.e. In the (R) or (S) form.
  • However, the application also includes the individual diastereomeric pairs of antipodes or mixtures thereof, which are obtained if there is more than one chiral element in the compounds of general formula I, as well as the individual optically active enantiomers of which the above-mentioned racemates are made up.
  • Compounds with a carbon double bond may be present in both the E and Z form.
  • If a compound is present in different tautomeric forms, the compound prepared is not limited to one tautomeric form but includes all the tautomeric forms. This also applies particularly to nitrogen-containing heteroaryls:
  • Figure US20100240669A1-20100923-C00526
    • Preparation Methods
  • According to the invention the compounds of general formula I are obtained by methods known per se, for example by the following methods:
    • (A) Amide Coupling:
  • Figure US20100240669A1-20100923-C00527
  • The linking of carboxylic acids of general formula II as shown, wherein all the groups are as hereinbefore defined, with amines of general formula III, wherein all the groups are as hereinbefore defined, to form carboxylic acid amides of general formula I wherein all the groups are as hereinbefore defined, may be carried out by conventional methods of amide formation.
  • The coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)-N,N—N′,N′-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) the reaction speed can be increased. The couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran (THF), acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures. If necessary, an auxiliary base such as diisopropylethylamine (DIPEA, Hünig base) is additionally used.
    • B) Amide Coupling:
  • Figure US20100240669A1-20100923-C00528
  • An alternative method of preparing compounds of general formula I consists in linking carboxylic acids of general formula V, wherein all the groups are as hereinbefore defined, with amines of general formula IV, wherein all the groups are as hereinbefore defined.
  • The compounds of general formula V are either commercially obtainable or may be prepared by methods known from the literature
  • It is also possible to convert the carboxylic acids of general formula V into carboxylic acid chlorides and then react these with amines of general formula IV. Carboxylic acid chlorides are synthesised by methods known from the literature (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, vol. E5/1).
    • (C) Reduction of the Nitrile Group:
  • Figure US20100240669A1-20100923-C00529
  • The reduction of a nitrile of general formula VI to an amine of general formula III, wherein the group R2 at the amine nitrogen denotes hydrogen and all the other groups are as hereinbefore defined, may be carried out under standard conditions of catalytic hydrogenolysis with a catalyst such as Raney nickel, for example, in a solvent such as ammoniacal methanol or ethanol or with a reducing agent such as lithium aluminium hydride or sodium borohydride in a solvent such as tetrahydrofuran, optionally in the presence of a Lewis acid such as aluminium chloride.
  • Compounds of general formula III, wherein the group R2 at the amine nitrogen denotes not hydrogen but an alkyl group, for example, may also be prepared from compounds of general formula VI. Thus, for example, the reaction of a nitrile of general formula VI with an alkyl Grignard reagent produces ketones which can be converted by reductive amination into the compounds of general formula III. The reductive amination is carried out using known methods, for example with a reducing agent such as sodium triacetoxyborohydride, sodium borohydride or sodium cyanoborohydride, conveniently in a solvent such as tetrahydrofuran or dichloromethane optionally substituted by the addition of acetic acid.
  • Alternatively the ketones obtained may also be converted into oximes. The subsequent reduction of the oximes then yields compounds of general formula III.
    • (D) Nucleophilic Aromatic Substitution or Transition-Metal-Catalysed Coupling:
  • Figure US20100240669A1-20100923-C00530
  • The reaction of an aniline of general formula VIII, wherein all the groups are as hereinbefore defined, with a nitrile of general formula VII, wherein X, R6 and n are as hereinbefore defined, and Hal denotes a fluorine, chlorine or bromine atom, is carried out using known methods, for example in a solvent such as tetrahydrofuran, dimethylformamide or dimethylsulphoxide and conveniently in the presence of a base such as triethylamine, sodium hydroxide solution or potassium carbonate at a temperature of 20° C. to 160° C. If the aniline of general formula VIII is liquid, the reaction may also be carried out without a solvent and additional base.
  • An alternative method of preparing compounds of general formula VI is the palladium-catalysed reaction of a nitrile of general formula VII, wherein Hal denotes bromine or chlorine, with an aniline of general formula VIII. Reaction conditions for this reaction, which is also known as a Buchwald-Hartwig reaction, are known from the literature.
  • Description of the Method of Binding the cynoBK1-Receptor
  • CHO cells that express the cynomolgus BK1-receptor are cultivated in “HAM′S F-12 Medium”. The medium is removed from confluent cultures, the cells are washed with PBS buffer, scraped off or detached using Versene and isolated by centrifuging. Then the cells are homogenised in suspension, the homogenate is centrifuged and resuspended. After the protein content has been determined 200 μl of the homogenate (50 to 250 μg protein/assay) are incubated for 60-180 minutes at ambient temperature with 0.5 to 5.0 nM kallidine (DesArg10,Leu9), [3,4-Prolyl-3,43H(N)] and increasing concentrations of the test substance in a total volume of 250 μl. The incubation is stopped by rapid filtration through GF/B glass fibre filters that have been pre-treated with polyethyleneimine (0.3%). The radioactivity bound to the protein is measured with a TopCount NXT. The radioactivity bound in the presence of 1.0 μM kallidine (DesArg10) is defined as non-specific binding. The concentration binding curve may be analysed using computer-aided non-linear curve fitting to determine the corresponding Ki value for the test substance.
  • Test results of the cynoBK1-receptor binding assay:
  • % inhibition at
    Example No. 10 μmol/L Ki [nM]
    (1) 54
    (2) 100 25
    (3) 65
    (4) 109
    (5) 88
    (6) 59
    (7) 100
    (8) 75
    (9) 78
    (10) 58
    (11) 99
    (12) 78
    (13) 101
    (14) 84
    (15) 99
    (16) 91
    (17) 75
    (18) 67
    (19) 96
    (20) 81
    (21) 68
    (22) 60
    (23) 110
    (24) 107
    (25) 86
    (26) 109
    (27) 104
    (28) 101 0.6
    (29) 113 6.2
    (30) 111 13
    (31) 112 13
    (32) 93 200
    (33) 110 1.9
    (34) 94 >500
    (35) 111 70
    (36) 113 21
    (37) 77 >500
    (38)
    (39) 110 5.5
    (40) 110 2.9
    (41) 108 2.6
    (42) 89
    (43) 94 36
    (44) 109 7.0
    (45) 104 2
    (46) 88 290
    (47) 94 39
    (48) 71
    (49) 103 365
    (50) 115 0.7
    (51) 112 38
    (52) 63 312
    (53) 101 197
    (54) 112 3.8
    (55) 108 3.3
    (56) 99
    (57) 111 77
    (58) 109
    (59) 22
    (60) 84
    (61) 97 >500
    (62) 60
    (63) 108 118
    (64) 109 98
    (65) 76
    (66) 81
    (67) 63
    (68) 78
    (69) 42
    (70) 107
    (71) 80
    (72) 89 416
    (74) 56
    (75) 71
    (76) 80
    (77) 96
    (78) 73
    (79) 104 292
    (80) 88
    (81) 113
    (82) 107
    (83) 113 9
    (84) 104 90
    (85) 93
    (86) 108 100
    (87) 112
    (88) 80
    (89) 96
    (90) 109 135
    (91) 100
    (92) 110 62
    (93) 84
    (94) 57
    (95) 86
    (96) 78
    (97) 132
    (98) 103 417
    (99) 96
    (100) 103
    (102) 105 87
    (103) 87
    (104) 54
    (105) 113 20
    (106) 69
    (107) 95
    (108) 101 135
    (109) 27
    (110) 33
    (111) 20
    (112) 45
    (113) 7
    (114) 77 >500
    (115) 99 >500
    (116) 83 >500
    (117) 111 2.8
    (118) 109 64
    (119) 82 375
    (120) 113 2.4
    (121) 113 2
    (122) 113 6.3
    (123) 110 8.3
    (124) 112 33
    (125) 108 12
    (126) 103 46
    (127) 108 17
    (128) 103 84
    (129) 107 11
    (130) 101 101
    (131) 105 33
    (132) 98 180
    (133) 101
    (134) 101 4.7
    (135) 106 15
    (136) 104 42
    (138) 107 6.7
    (139) 107 2.8
    (140) 106 14
    (141) 100 7.6
    (142) 106 12
    (143) 106 12
    (144) 97 126
    (145) 99 2.8
    (146) 107 7.6
    (147) 107 4.4
    (148) 96
    (149) 100
    (150) 105 37
    (151) 107 1.8
    (152) 105 3.2
    (153) 106 9.7
    (154) 101 89
    (155) 101 143
    (156) 107 8.5
    (157) 96 56
    (158) 101 115
    (159) 91 97
    (160) 106 17
    (161) 69 >500
    (162) 104 17
    (163) 87 288
    (164) 106 3.4
    (165) 101
    (166) 104 45
    (167) 104 19
    (168) 90 235
    (169) 90 292
    (170) 104 35
    (171) 97
    (172) 100 9.8
    (173) 105 2.7
    (174) 99
    (175) 96 63
    (176) 100
    (177) 99
    (178) 107 11
    (179) 101
    (180) 106 1.6
    (181) 99 19
    (182) 99 20
    (183) 100 21
    (184) 99
    (185) 87
    (186) 82
    (187) 100
    (188) 92 43
    (189) 96 >500
    (190) 91
    (191) 56
    (192) 95
    (193) 101
    (194) 95
    (195) 42 >500
    (196) 82 >500
    (197) 81 >500
    (198) 64 >500
    (200) 92
    (201)
    (202)
    (203) 1.9
    (204) 402
    (205) 17
    (206) 5.1
    (207) 84
    (208) 6.8
    (209) 73
    (210) 187
    (211) 25
    (212) 8
    (213) 1.9
    (214) 13
    (215) 3.5
    (216) 7.8
    (217) 12
    (218) 3.7
    (219) 8.9
    (220) 15
    (221) 13
    (222) 68
    (223) 75
    (224) 6.3
    (225) 68
    (226) 157
    (227) 97
    (228) 78
    (229) 27
    (230) 6.1
    (231) 4.2
    (232) 5.6
    (233) 10
    (234) 105
    (235) 489
    (236) 8.2
    (237) 151
    (238) 6.6
    (239) 182
    (240) 506
    (241) 68
    (242) 15
    (243) 28
    (244) 8.4
    (245) 18
    (246) 21
    (247) 3.9
    (248) 276
    (249) 518
    (250) 175
    (251) 14
    (252) 120
    (253) 49
    (254) 257
    (255) 15
    (256) 72
    (257) 17
    (258) 37
    (259) 394
    (260) 43
    (261) 456
    (262) 37
    (263) 485
    (264) 60
    (265) 75
    (266) 78
    (267) 5.5
    (268) 281
    (269) 47
    (270) 51
    (271) 17
    (272) 35
    (273) 141
    (274) 4.0
    (275) 405
    (276) 17
    (277) 10
    (278) 16
    (279) 5.5
    (280) 25
    (281) 21
    (282) 7.9
    (283) 1.3
    (284) 5.1
    (285) 27
    (286) 36
    (287) 11
    (288) 9.1
    (289) 21
    (290) 46
    (291) 40
    (292) 7.2
    (293) 65
    (294) 1.2
    (295) 31
    (296) 28
    (297) 59
    (298) 0.7
    (299) 222
    (300) 45
    (301) 1.1
    (302) 42
    (303) 82
    (304) 135
    (305) 76
    (306) 2.0
    (307) 54
    (308) 427
    (309) 184
    (310) 39
    (311) 349
    (312) 57
    (313) 95
    (314) 15
    (315) 40
    (316) 57
    (317) 30
    (318) 316
    (319) 58
    (320) 19
    (321) 57
    (322) 12
    (323) 69
    (324) 22
    (325) 374
    (326) 504
    (327) 89
    (328) 33
    (329) 24
    (330) 35
    (331) 66
    (332) 41
    (333) 89
    (334) 20
    (335) 28
    (336) 567
    (337) 312
    (338) 27
    (339) 49
    (340) 28
    (341) 69
    (342) 50
    (343) 7.2
    (344) 1.9
    (345) 17
    (346) 48
    (347) 12
    (348) 31
    (349) 648
    (350) 43
    (351) 24
    (352) 59
    (353) 52
    (354) 27
    (355) 433
    (356) 22
    (357) 44
    (358) 37
    (359) 125
    (360) 2.5
    (361) 10
    (362) 101
    (363) 45
    (364) 77
    (365) 376
    (366) 33
    (367) 508
    (368) 42
    (369) 37
    (370) 1.4
    (371) 6.1
    (372) 24
    (373) 95
    (374) 5.5
    (375) 48
    (376) 61
    (377) 45
    (378) 4.6
    (379) 5.5
    (380) 6.5
    (381) 93
    (382) 6.8
    (383) 225
    (384) 21
    (385) 9.4
    (386) 15
    (387) 10
    (388) 386
    (389) 15
    (390) 7.3
    (391) 9.3
    (392) 11
    (393)
    (394)
    (395) 37
    (396) 6.6
    • Indications
  • In view of their pharmacological properties, the novel compounds and their physiologically acceptable salts are suitable for treating diseases and symptoms of diseases caused at least to some extent by stimulation of bradykinin-B1 receptors, or in which antagonisation of the of bradykinin-B1 receptor can bring about an improvement in symptoms.
  • In a further aspect the present invention encompasses the compounds of the above-mentioned general formula I according to the invention for use as medicaments.
  • In view of their pharmacological effect the substances are suitable for the treatment of
  • (a) acute pain such as for example toothache, peri- and postoperative pain, traumatic pain, muscle pain, the pain caused by burns, sunburn, trigeminal neuralgia, pain caused by colic, as well as spasms of the gastro-intestinal tract or uterus;
    (b) visceral pain such as for example chronic pelvic pain, gynaecological pain, pain before and during menstruation, pain caused by pancreatitis, peptic ulcers, interstitial cystitis, renal colic, cholecystitis, prostatitis, angina pectoris, pain caused by irritable bowel, non-ulcerative dyspepsia and gastritis, prostatitis, non-cardiac thoracic pain and pain caused by myocardial ischaemia and cardiac infarct;
    (c) neuropathic pain such as for example painful neuropathies, pain of diabetic neuropathy, AIDS-associated neuropathic pain non-herpes-associated neuralgia, post-zoster neuralgia, nerve damage, cerebro-cranial trauma, pain of nerve damage caused by toxins or chemotherapy, phantom pain, pain of multiple sclerosis, nerve root tears and painful traumatically-caused damage to individual nerves, and central pain such as for example pain after stroke, spinal injuries or tumours;
    d) inflammatory/pain receptor-mediated pain in connection with diseases such as for example osteoarthritis, rheumatoid arthritis, rheumatic fever, tendo-synovitis, bursitis, tendonitis, gout and gout-arthritis, traumatic arthritis, vulvodynia, damage to and diseases of the muscles and fascia, juvenile arthritis, spondylitis, psoriasis-arthritis, myositides, dental disease, influenza and other viral infections such as colds, systemic lupus erythematodes or pain caused by burns,
    (e) tumour pain associated with cancers such asfe lymphatic or myeloid leukaemia, Hodgkin's disease, non-Hodgkin's lymphomas, lymphogranulomatosis, lymphosarcomas, solid malignant tumours and extensive metastases;
    (f) headache diseases of various origins, such as for example cluster headaches, migraine (with or without aura) and tension headaches.
    (g) painful conditions of mixed origin, such as for example chronic back pain including lumbago, or fibromyalgia.
  • The compounds are also suitable for treating
  • (h) inflammatory complaints or phenomena caused by sunburn and burns, inflammation of the gums, oedema after burns trauma, cerebral oedema and angiooedema, intestinal complaints including Crohn's disease and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), uveitis; inflammatory skin diseases (such as psoriasis and eczema), vascular diseases of the connective tissue, sprains and fracture, and musculoskeletal diseases with inflammatory symptoms such as acute rheumatic fever, polymyalgia rheumatica, reactive arthritis, rheumatoid arthritis, spondylarthritis, and also osteoarthritis, and inflammation of the connective tissue of other origins, and collagenoses of all origins such as systemic lupus erythematodes, scleroderma, polymyositis, dermatomyositis, Sjögren syndrome, Still's disease or Felty syndrome;
    (i) inflammatory changes connected with diseases of the airways such as bronchial asthma, including allergic asthma (atopic and non-atopic) as well as bronchospasm on exertion, occupationally induced asthma, viral or bacterial exacerbation of an existing asthma and other non-allergically induced asthmatic diseases;
    (j) chronic bronchitis and chronic obstructive pulmonary disease (COPD) including pulmonary emphysema, viral or bacterial exacerbation of chronic bronchitis or chronic obstructive bronchitis, acute adult respiratory distress syndrome (ARDS), bronchitis, lung inflammation, allergic rhinitis (seasonal and all year round) vasomotor rhinitis and diseases caused by dust in the lungs such as aluminosis, anthracosis, asbestosis, chalicosis, siderosis, silicosis, tabacosis and byssinosis, exogenous allergic alveolitis, cystic fibrosis, bronchiectasis, pulmonary diseases in alpha1-antitrypsin deficiency and cough;
    (k) diabetes mellitus and its effects (such as e.g. diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy) and diabetic symptoms in insulitis (for example hyperglycaemia, diuresis, proteinuria and increased renal excretion of nitrite and kallikrein);
    (l) sepsis and septic shock after bacterial infections or after trauma;
    (m) syndromes that cause itching and allergic skin reactions;
    (n) damage to the central nervous system;
    (o) wounds and tissue damage;
    (p) benign prostatic hyperplasia and hyperactive bladder;
    (q) neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease;
    (m) osteoporosis;
    epilepsy;
    (q) vascular diseases such as panarteriitis nodosa, polyarthritis nodosa, periarteriitis nodosa, arteriitis temporalis, Wegner's granulomatosis, giant cell arteriitis, arteriosclerosis and erythema nodosum;
    inflammation of the gums;
    (r) disorders of the motility or spasms of respiratory, genito-urinary, gastro-intestinal including biliary or vascular structures and organs;
    (s) post-operative fever;
    (t) for the treatment and prevention of cardiovascular diseases such as high blood pressure and related complaints;
    (u) for the treatment and prevention of cancer and related complaints;
    (v) for the treatment and prevention of psychiatric diseases such as depression;
    (w) for the treatment and prevention of urinary incontinence and related complaints;
    (x) for the treatment and prevention of morbid obesity and related complaints;
    (y) for the treatment and prevention of atherosclerosis and related complaints.
    (z) for the treatment and prevention of epilepsy.
  • The substances are suitable for causal treatment in the sense of slowing down or stopping the progress of chronically progressive diseases, particularly osteoarthritis, rheumatoid arthritis and spondylarthritis.
  • In another aspect the present invention encompasses the use of the compounds of the above-mentioned general formula I according to the invention for preparing a medicament for therapeutic use in the above-mentioned indications.
  • Preferably, the compounds of general formula I according to the invention are used for the treatment of osteoarthritis, rheumatoid arthritis or COPD.
  • The term “treatment” or “therapy” refers to a therapeutic treatment of patients with a manifest, acute or chronic indication, including on the one hand symptomatic (palliative) treatment to relieve the symptoms of the disease and on the other hand causal or curative treatment of the indication with the aim of ending the pathological condition, reducing the severity of the pathological condition or delaying the progression of the pathological condition, depending on the nature or gravity of the indication.
  • The present invention further relates to the use of a compound of general formula I for preparing a medicament for the acute and prophylactic treatment of acute pain, visceral pain, neuropathic pain, inflammatory/pain receptor-mediated pain, tumour pain, headache pain and pain of mixed causes and other diseases as mentioned above. This use is characterised in that it comprises administering an effective amount of a compound of general formula I or a physiologically acceptable salt thereof to a patient requiring such treatment.
  • The term “patient” preferably refers to a human being.
  • In addition to their suitability as therapeutic drugs for humans, these substances are also useful in the veterinary medical treatment of domestic pets, exotic animals and farmed animals.
    • Combinations
  • For treating pain, it may be advantageous to combine the compounds according to the invention with stimulating substances such as caffeine or other pain-alleviating active compounds. If active compounds suitable for treating the cause of the pain are available, these can be combined with the compounds according to the invention.
  • The following compounds may be used for combination therapy, for example:
  • Non-steroidal antirheumatics (NSAR) such as for example propionic acid derivatives which may be selected from among alminoprofen bucloxic acid, carprofen, fenoprofen, ibuprofen, ketoprofen, naproxen, oxaprozin, pirprofen, pranoprofen and tiaprofenic acid; acetic acid derivatives which may be selected from among indomethacin, acemetacin, alclofenac, isoxepac, sulindac and tolmetin; fenamic derivatives which may be selected from among meclofenamic acid, mefenamic acid and tolfenamic acid; biphenyl-carboxylic acid derivatives; oxicams which may be selected from among meloxicam, piroxicam and tenoxicam; salicylic acid derivatives which may be selected from among acetylsalicylic and sulphasalazine; pyrazolones which may be selected from among apazone and feprazone; and coxibs which may be selected from among celecoxib and etoricoxib).
  • Opiate receptor agonists which may for example be selected from among morphine, Darvon, tramadol and buprenorphine;
  • Cannabinoid agonists such as for example GW-1000;
    Sodium channel blockers which may for example be selected from among carbamazepine, mexiletin, pregabalin, tectin and ralfinamide.
  • N-type calcium channel blockers such as for example ziconotide.
  • Serotonergic and noradrenergic modulators which may be selected from among for example duloxetine and amitriptyline.
  • Corticosteroids which may be selected from among for example betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone.
  • Histamine H1-receptor antagonists which may for example be selected from among bromopheniramine, chloropheniramine, dexchloropheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine azatadine, cyproheptadine, antazoline, pheniramine, pyrilamine, loratadine, cetirizine, desloratadine, fexofenadine and levocetirizine.
  • Leukotriene antagonists and 5-lipoxygenase inhibitors which may for example be selected from among zafirlukast, montelukast, pranlukast and zileuton.
  • Local anaesthetics which may for example be selected from among ambroxol and lidocaine.
  • TRVP1 antagonists which may for example be selected from among AZD-1386, JTS-653 and PHE-377.
  • Nicotine receptor agonists such as for example A-366833.
  • P2X3-receptor antagonists such as e.g. A-317491.
  • anti-NGF antibodies and NGF antagonists which may for example be selected from among JNJ-42160443 and PPH 207.
  • NK1 and NK2 antagonists such as e.g. CP-728663.
  • NMDA antagonists which may for example be selected from among CNS-5161, AZ-756 and V-3381.
  • Potassium channel modulators such as e.g. CL-888.
  • GABA modulators such as e.g. baclofen.
  • Anti-migraine drugs such as e.g. sumatriptan, zolmitriptan, naratriptan and eletriptan.
  • For treating one or more of the above-mentioned respiratory complaints it may be advantageous to combine the compounds of general formula I according to the invention with other active substances for treating respiratory complaints. If suitable active substances for treating the cause of the respiratory complaints are available, these may be combined with the compounds according to the invention.
  • The compounds of general formula I may optionally also be used in conjunction with other pharmacologically active substances. It is preferable to use active substances of the type selected from among the betamimetics, anticholinergics, corticosteroids, other PDE4-inhibitors, LTD4-receptor (CysLT1, CysLT2, CysLT3) antagonists, inhibitors of MAP kinases such as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP, LTB4-receptor (BLT1, BLT2) antagonists, EGFR-inhibitors, H1-receptor antagonists, antihistamines, H4-receptor antagonists, PAF-antagonists and PI3-kinase inhibitors CXCR1 and/or CXCR2 receptor antagonists and anti-tussives.
  • The compounds of general formula I may also be used in the form of double or triple combinations thereof, such as for example combinations of compounds of formula I with one or two compounds selected from among
      • betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors and LTD4-antagonists,
      • anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors and LTD4-antagonists,
      • PDE4-inhibitors, corticosteroids, EGFR-inhibitors and LTD4-antagonists,
      • EGFR-inhibitors, PDE4-inhibitors and LTD4-antagonists,
      • EGFR-inhibitors and LTD4-antagonists,
      • CCR3-inhibitors, iNOS-inhibitors (inducible nitric oxide synthase-inhibitors), (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (hereinafter referred to as “BH4”) and the derivatives thereof which are mentioned in WO 2006/120176, and SYK-inhibitors (spleen tyrosine kinase inhibitors),
      • anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors and MRP4-inhibitors.
  • Combinations of three active substances of one of the above mentioned categories of compounds are also covered by the invention.
  • Betamimetics used according to the invention are preferably compounds selected from among arformoterol, carmoterol, formoterol, indacaterol, salmeterol, albuterole, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, hexoprenalin, ibuterol, isoetharin, isoprenalin, levosalbutamol, mabuterol, meluadrin, metaproterenol, milveterol, orciprenalin, pirbuterol, procaterol, reproterol, rimiterol, ritodrin, salmefamol, soterenol, sulphonterol, terbutalin, tiaramid, tolubuterol and zinterol or
    • 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,
    • 8-{2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
    • 8-{2-[2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
    • 8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
    • 8-{2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
    • N-(5-{2-[3-(4.4-diethyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenylymethanesulphonamide,
    • N-(5-{2-[3-(4,4-diethyl-6-fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenylymethanesulphonamide,
    • N-(5-{2-[3-(4,4-diethyl-6-methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide,
    • N-(5-{2-[1,1-dimethyl-3-(2-oxo-4,4-dipropyl-4H-benzo[d][1,3]oxazin-1-yl)-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenylymethanesulphonamide,
    • 8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
    • 8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
    • 8-{2-[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
    • 8-{2-[1,1-dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
    • N-[2-hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide,
    • 8-hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)-1H-quinolin-2-one,
    • 8-hydroxy-5-[(1R)-1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1H-quinolin-2-one,
    • 5-[(1R)-2-(2-{-4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,
    • [3-(4-{6-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-5-methyl-phenyl]-urea,
    • 4-((1R)-2-{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol,
    • 3-(4-{6-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide,
    • 3-(3-{7-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)-benzenesulphonamide,
    • 4-((1R)-2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol,
    • N-1-Adamantanyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethyl}amino)propyl]phenyl}acetamide,
    • (1R)-5-{2-[6-(2.2-difluoro-2-phenyl-ethoxy)-hexylamino]-1-hydroxy-ethyl}-8-hydroxy-1H-quinolin-2-one
    • (R,S)-4-(2-{[6-(2.2-difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxyl-methyl)phenol,
    • (R,S)-4-(2-{[6-(2.2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxyl-methyl)phenol,
    • (R,S)-4-(2-{[4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxyl-methyl)phenol,
    • (R,S)-4-(2-{[6-(4,4-difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxyl-methyl)phenol,
    • (R,S)-5-(2-{[6-(2.2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-8-hydroxyquinolin-2(1H)-one,
    • (R,S)-[2-({[2.2-difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol,
    • 4-(1R)-2-{[6-(2.2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxyl-methyl)phenol,
    • (R,S)-2-(hydroxymethyl)-4-(1-hydroxy-2-{[4.4.515-tetrafluoro-6-(3-phenylpropoxy)-hexyl]amino}ethyl)phenol,
    • (R,S)-[5-(2-{[6-(2.2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]formamide,
    • (R,S)-4-[2-({6-[2-(3-bromophenyl)-2.2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol,
    • (R,S)—N-[3-(1.1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]-ethyl}amino)hexyl]oxy}ethyl)phenyl]-urea,
    • 3-[3-(1,1-difluoro-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}ethyl)phenyl]imidazolidin-2,4-dione,
    • (R,S)-4-[2-({6-[2.2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol,
    • 5-((1R)-2-{[6-(2.2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one,
    • 4-((1R)-2-{[4,4-difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxyl-methyl)phenol,
    • (R,S)-4-(2-{[6-(3.3-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxylmethyl)phenol,
    • (R,S)-(2-{[6-(2.2-difluoro-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol,
    • (R,S)-4-(2-{[6-(2.2-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxylmethyl)phenol,
    • 3-[2-(3-chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazole-7-yl)-ethylamino]-ethyl}-propionamide,
    • N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazole-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamide,
    • 7-[2-(2-{3-[2-(2-chloro-phenyl)-ethylamino]-propylsulphanyl}-ethylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one,
      optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. Preferably, according to the invention, the acid addition salts of the betamimetics are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
  • Anticholinergics used according to the invention are preferably compounds selected from among the tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, Ipratropiumsalzen, preferably the bromide salt, aclidinium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine, (3R)-1-phenethyl-3-(9H-xanthene-9-carbonyloxy)-1-azoniabicyclo[2,2,2]octane salts. In the above-mentioned salts the cations are the pharmacologically active constituents. As anions X− the above-mentioned salts may preferably contain chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while the chloride, bromide, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions. Of all the salts the chlorides, bromides, iodides and methanesulphonates are particularly preferred.
  • Other anticholinergics may be selected from among
      • tropenol 2,2-diphenylpropionate-methobromide,
      • scopine 2,2-diphenylpropionate-methobromide,
      • scopine 2-fluoro-2,2-diphenylacetate methobromide,
      • tropenol 2-fluoro-2,2-diphenylacetate methobromide,
      • tropenol 3,3′,4,4′-tetrafluorobenzilate methobromide,
      • scopine 3,3′,4,4′-tetrafluorobenzilate methobromide,
      • tropenol 4,4′-difluorobenzilate methobromide,
      • scopine 4,4′-difluorobenzilate methobromide,
      • tropenol 3,3′-difluorobenzilate methobromide,
      • scopine 3,3′-difluorobenzilate methobromide,
      • tropenol 9-hydroxy-fluorene-9-carboxylate methobromide,
      • tropenol 9-fluoro-fluorene-9-carboxylate methobromide,
      • scopine 9-hydroxy-fluorene-9-carboxylate methobromide,
      • scopine 9-fluoro-fluorene-9-carboxylate methobromide,
      • tropenol 9-methyl-fluorene-9-carboxylate methobromide,
      • scopine 9-methyl-fluorene-9-carboxylate methobromide,
      • cyclopropyltropine benzilate methobromide,
      • cyclopropyltropine 2,2-diphenylpropionate methobromide,
      • cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide,
      • cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide,
      • cyclopropyltropin 9-methyl-xanthene-9-carboxylate methobromide,
      • cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide,
      • cyclopropyltropine methyl 4,4′-difluorobenzilate methobromide,
      • tropenol 9-hydroxy-xanthene-9-carboxylate methobromide,
      • scopine 9-hydroxy-xanthene-9-carboxylate methobromide,
      • tropenol 9-methyl-xanthene-9-carboxylate methobromide,
      • scopine 9-methyl-xanthene-9-carboxylate methobromide,
      • tropenol 9-ethyl-xanthene-9-carboxylate methobromide,
      • tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide, and
      • scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide.
  • The above-mentioned compounds may also be used as salts within the scope of the present invention, wherein the metho-X salts are used instead of the methobromide, where X may have the meanings given for X− hereinbefore.
  • Corticosteroids used according to the invention are preferably compounds selected from among beclomethasone betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone and tipredane orpregna-1,4-dien-3,20-dione, 6-fluoro-11-hydroxy-16.17-[(1-methylethyliden)-bis(oxy)]-21-[[4-[(nitroxy)methyl]benzoyl]oxy], (6-alpha,11-beta,16-alpha)-(9Cl) (NCX-1024)
    • 16,17-butylidenedioxy-6,9-difluoro-11-hydroxy-17-(methylthio)androst-4-en-3-one (RPR-106541),
    • (S)-fluoromethyl 6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate,
    • (S)-(2-oxo-tetrahydrofuran-3S-yl) 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate, and
    • cyanomethyl 6-alpha,9-alpha-difluoro-11-beta-hydroxy-16alpha-methyl-3-oxo-17alpha-(2,2,3,3-tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17beta-carboxylate,
      optionally in the form of their racemates, enantiomers or diastereomers and optionally in the form of the salts and derivatives thereof, the solvates and/or hydrates thereof. Every reference to steroids includes a reference to any salts or derivatives, hydrates or solvates thereof which may exist. Examples of possible salts and derivatives of the steroids may be: alkali metal salts, such as for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, dichloroacetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
  • PDE4-inhibitors used according to the invention are preferably compounds selected from among enprofyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, apremilast, arofyllin, atizoram, oglemilast and tetomilast or
    • 5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamid]-8-methoxy-quinoline (D-4418),
    • N-(3,5-dichloro-1-oxido-4-pyridinyl)-carboxamid]-8-methoxy-2-(trifluoromethyl)-quinoline (D-4396 (Sch-351591)), N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indol-3-yl]glyoxylamide (AWD-12-281 (GW-842470)), 9-[(2-fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-purin-6-amine (NCS-613),
    • 4-[(2R)-2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridine (CDP-840),
    • N-[(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepin-3-yl]-4-pyridinecarboxamide (PD-168787),
    • 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-1-(2-methoxyethyl)-2(1H)-pyridinone (T-440),
    • 2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-2-pyridinyl]-4-(3-pyridinyl)-1(2H)-phthalazinone (T-2585),
    • (3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine (V-11294A),
    • beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide (CDC-801),
    • imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one, 9-ethyl-2-methoxy-7-methyl-5-propyl-(D-22888)
    • 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl], (3S,5S)-2-piperi-dinone (HT-0712),
    • 4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxido-4-pyridinyl)ethyl]-alpha,alpha-bis(trifluoromethyl)-benzenemethanol (L-826141),
    • N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide,
    • (−)p-[4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s]-[1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide,
    • (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone,
    • 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-S-methyl-isothioureido]-benzyl)-2-pyrrolidone,
    • cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid],
    • 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-cyclohexan-1-one,
    • cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],
    • (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,
    • (S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,
    • 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo-[4.3-a]pyridine and
    • 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo-[4.3-a]pyridine,
      optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. Preferably, according to the invention, acid addition salts are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
  • EGFR-inhibitors used according to the invention are preferably compounds selected from among cetuximab, trastuzumab, panitumumab (=ABX_EGF), Mab ICR-62, gefitinib, canertinib and erlotinib or
    • 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
    • 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
    • 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
    • 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
    • 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,
    • 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
    • 4-[(R)-(1-phenyl-ethyl)amino]-6-({[4N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
    • 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
    • 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
    • 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,
    • 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,
    • 4-[(3-chloro-4-fluorophenyl)amino]-6-({-4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,
    • 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,
    • 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
    • 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
    • 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,
    • 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)-amino]-quinazoline,
    • 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine,
    • 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,
    • 4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,
    • 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,
    • 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,
    • 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulphonylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-ethynyl-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,
    • 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,
    • 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexane-1-yloxy}-7-methoxy-quinazoline,
    • 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,
    • 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexane-1-yloxy]-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexane-1-yloxy]-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexane-1-yloxy]-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N—[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,
    • 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,
    • 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline;
    • [4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]-amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,
    • 4-[(3-chloro-4-fluorophenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)carbonyl]-piperazin-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-quinazoline,
    • 4-[(3-chloro-4-fluorophenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline,
    • 4-[(3-chloro-4-fluorophenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,
    • 4-[(3-chloro-4-fluorophenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, and
    • 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N-[(ethoxy-carbonyl)methyl]amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxy-quinazoline,
      optionally in the form of their racemates, enantiomers or diastereomers, optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. Preferably, according to the invention, acid addition salts are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
  • LTD4-receptor antagonists used according to the invention are preferably compounds selected from among montelukast, pranlukast and zafirlukast, or (E)-8-[2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethenyl]-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-4-one (MEN-91507),
    • 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]-butyric acid (MN-001),
    • 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic acid,
    • 1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid and
    • [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid,
      optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. Preferably, according to the invention, acid addition salts are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate. By salts or derivatives which the LTD4-receptor antagonists may optionally be capable of forming are meant, for example: alkali metal salts, such as for example sodium or potassium salts, alkaline earth salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
  • Histamine H1 receptor antagonists used according to the invention are preferably compounds selected from among epinastin, cetirizin, azelastin, fexofenadin, levocabastin, loratadin, mizolastin, ketotifen, emedastin, dimetinden, clemastin, bamipin, cexchlorpheniramin, pheniramin, doxylamine, chlorophenoxamin, dimenhydrinat, diphenhydramin, promethazin, ebastin, olopatadine, desloratidin and meclozin, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. Preferably, according to the invention, the acid addition salts are selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.
  • Histamine H4 receptor antagonists used according to the invention are preferably compounds such as for example (5-chloro-1H-indol-2-yl)-(4-methyl-1-piperazinyl)-methanone (JNJ-7777120), optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. Preferably, according to the invention, acid addition salts selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate are used.
  • MAP Kinase inhibitors used according to the invention are preferably compounds selected from among:
    • Bentamapimod (AS-602801)
    • Doramapimod,
    • 5-carbamoylindole (SD-169),
    • 6-[(aminocarbonyl)(2,6-difluorophenyl)amino]-2-(2,4-difluorophenyl)-3-pyridinecarboxamide (VX-702),
    • alpha-[2-[[2-(3-pyridinyl)ethyl]amino]-4-pyrimidinyl]-2-benzothiazoleacetonitrile (AS-601245),
    • 9,12-epoxy-1H-diindolo[1,2,3-fg:3′.2′.1′-kl]pyrrolo[3,4-i][1.6]benzodiazocine-10-carboxylic acid (CEP-1347), and
    • 4-[3-(4-chlorophenyl)-5-(1-methyl-4-piperidinyl)-1H-pyrazol-4-yl]-pyrimidine (SC-409),
      optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates thereof.
  • Neurokinin (NK1 or NK2) antagonists used according to the invention are preferably compounds selected from among: Saredutant, Nepadutant and Figopitant, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates thereof.
  • Antitussive substances used according to the invention are preferably compounds selected from among hydrocodone, caramiphen, carbetapentane and dextramethorphane, optionally in the form of their racemates, enantiomers, diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates thereof.
  • Substances of preferred CXCR1 or CXCR2 antagonists used according to the invention are preferably compounds such as e.g. 3-[[3-[(dimethylamino)carbonyl]-2-hydroxyphenyl]amino]-4-[[(R)-1-(5-methylfuran-2-yl)propyl]amino]cyclobut-3-ene-1,2-dione (SCH-527123),
  • optionally in the form of its racemates, enantiomers, diastereomers and optionally in the form of its pharmacologically acceptable acid addition salts, prodrugs, solvates or hydrates.
  • The dosage necessary for obtaining a pain-alleviating effect is, in the case of intravenous administration, expediently from 0.01 to 3 mg/kg of body weight, preferably from 0.1 to 1 mg/kg, and, in the case of oral administration, from 0.1 to 8 mg/kg of body weight, preferably from 0.5 to 3 mg/kg, in each case 1 to 3 times per day. The compounds prepared according to the invention can be administered intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, aerosol formulations being particularly suitable for inhalation. They can be incorporated into customary pharmaceutical preparations, such as tablets, coated tablets, capsules, powders, suspensions, solutions, metered-dose aerosols or suppositories, if appropriate together with one or more customary inert carriers and/or diluents, for example with maize starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances, such as hardened fat, or suitable mixtures thereof.
    • EXPERIMENTAL SECTION
  • Generally, there are mass spectra and 1H NMR spectra for the compounds that have been prepared. The ratios given for the eluants are in volume units of the solvents in question. For ammonia, the given volume units are based on a concentrated solution of ammonia in water.
  • Unless indicated otherwise, the acid, base and salt solutions used for working up the reaction solutions are aqueous systems having the stated concentrations.
  • For chromatographic purification, silica gel from Millipore (MATREX™, 35 to 70 μm) or Alox (E. Merck, Darmstadt, Alumina 90 standardized, 63 to 200 μm, article No. 1.01097.9050) is used.
  • In the descriptions of the experiments, the following abbreviations are used:
  • TLC thin layer chromatograph
    DIPEA diisopropylethylamine
    • DMA N,N-dimethylacetamide
  • DMAP 4-dimethylaminopyridine
    • DMF N,N-dimethylformamide
  • DMSO dimethylsulphoxide
    HATU 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
    RP reverse phase
    Rt retention time
    tert tertiary
    TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate
    TEA triethylamine
    THF tetrahydrofuran
  • The following analytical HPLC methods were used:
  • Method 1: Column: Interchim Strategy C18, 5 μM, 4.6×50 mm
      • Detection: 220-320 nm
      • Eluant A: water/0.1°)/0 acetic acid
      • Eluant B: acetonitrile
      • Gradient:
  • time in min % A % B flow rate in mL/min
    0.0 95.0 5.0 3.0
    0.3 95.0 5.0 3.0
    2.0 2.0 98.0 3.0
    2.4 2.0 98.0 3.0
    2.45 95.0 5.0 3.0
    2.8 95.0 5.0 3.0
    • Method 2: Column: Merck Cromolith Flash RP18e, 4.6×25 mm
      • Eluant A: water/0.1% formic acid
      • Eluant B: acetonitrile/0.1% formic acid
      • Gradient:
  • time in min % A % B flow rate in mL/min
    0.0 90.0 10.0 1.6
    2.7 10.0 90.0 1.6
    3.0 10.0 90.0 1.6
    3.3 90.0 10.0 1.6
    • Method 3: Column: YMC-Pack ODS-AQ, 3 μM, 4.6×75 mm
      • Eluant A: water/0.15% formic acid
      • Eluant B: acetonitrile
      • Gradient:
  • time in min % A % B flow rate in mL/min
    0.0 95.0 5.0 1.6
    2.0 10.0 90.0 1.6
    5.0 10.0 90.0 1.6
    5.5 90.0 10.0 1.6
    • Method 4: Column: Zorbax Stable Bond C18, 1.8 μM, 3×30 mm
      • Eluant A: water/0.15% formic acid
      • Eluant B: acetonitrile
      • Gradient:
  • time in min % A % B flow rate in mL/min
    0.0 95.0 5.0 1.6
    1.0 10.0 90.0 1.6
    2.5 10.0 90.0 1.6
    2.75 95.0 5.0 1.6
    • Method 5: Column: Sunfire C18, 3.5 μM, 4.6×50 mm
      • Detection: 180-820 nm
      • Eluant A: water/0.1% trifluoroacetic acid
      • Eluant B: acetonitrile/0.1% trifluoroacetic acid
      • Temperature: 40° C.
      • Gradient:
  • time in min % A % B flow rate in mL/min
    0.0 95.0 5.0 1.5
    2.0 0.0 100.0 1.5
    2.5 0.0 100.0 1.5
    2.6 95.0 5.0 1.5
    • Method 6: Column: Sunfire C18, 3.5 μM, 4.6×50 mm
      • Detection: 180-820 nm
      • Eluant A: water/0.1% trifluoroacetic acid
      • Eluant B: acetonitrile/0.1% trifluoroacetic acid
      • Temperature: 40° C.
      • Gradient:
  • time in min % A % B flow rate in mL/min
    0.0 95.0 5.0 1.5
    2.0 0.0 100.0 1.5
    3.0 0.0 100.0 1.5
    3.4 95.0 5.0 1.5
    • Method 7: Column: YMC-Pack ODS-AQ, 3 μM, 4.6×75 mm
      • Eluant A: water/0.15% formic acid
      • Eluant B: acetonitrile
      • Gradient:
  • time in min % A % B flow rate in mL/min
    0.0 95.0 5.0 1.6
    4.5 10.0 90.0 1.6
    5.0 10.0 90.0 1.6
    5.50 90.0 10.0 1.6
    • Method 8: Column: Zorbax Stable Bond C18, 1.8 μM, 3×30 mm
      • Eluant A: water/0.15% formic acid
      • Eluant B: acetonitrile
      • Gradient:
  • time in min % A % B flow rate in mL/min
    0.0 95.0 5.0 1.6
    2.00 50.0 50.0 1.6
    2.25 10.0 90.0 1.6
    2.50 10.0 90.0 1.6
    2.75 95.0 5.0 1.6
    • Method 9: Column: Zorbax Stable Bond C18, 1.8 μM, 3×30 mm
      • Eluant A: water/0.15% formic acid
      • Eluant B: acetonitrile
      • Gradient:
  • time in min % A % B flow rate in mL/min
    0.0 95.0 5.0 1.6
    2.25 10.0 90.0 1.6
    2.50 10.0 90.0 1.6
    2.75 95.0 5.0 1.6
    • Method 10: Column: Zorbax Stable Bond C18, 3.5 μM, 4.6×75 mm
      • Eluant A: water/0.15% formic acid
      • Eluant B: acetonitrile
      • Gradient:
  • time in min % A % B flow rate in mL/min
    0.0 95.0 5.0 1.6
    4.5 10.0 90.0 1.6
    5.0 10.0 90.0 1.6
    5.50 90.0 10.0 1.6
    • Method 11: Column: X Terra C18, 3.5 μM, 4.6×50 mm
      • Detection: 180-820 nm
      • Eluant A: water/0.1% trifluoroacetic acid
      • Eluant B: acetonitrile/0.1% trifluoroacetic acid
      • Temperature: 40° C.
      • Gradient:
  • time in min % A % B flow rate in mL/min
    0.0 95.0 5.0 1.5
    2.0 0.0 100.0 1.5
    3.0 0.0 100.0 1.5
    3.4 95.0 5.0 1.5
    • Method 12: Column: Merck Cromolith Flash RP18e, 4.6×25 mm
      • Eluant A: water/0.1% formic acid
      • Eluant B: acetonitrile/0.1% formic acid
      • Gradient:
  • time in min % A % B flow rate in mL/min
    0.0 90.0 10.0 1.6
    2.7 10.0 90.0 1.6
    3.0 10.0 90.0 1.6
    3.3 95.0 5.0 1.6
    • Method 13: Column: Merck Cromolith SpeedROD RP-18e, 4.6×50 mm
      • Eluant A: water/0.1% formic acid
      • Eluant B: acetonitrile/0.1% formic acid
      • Gradient:
  • time in min % A % B flow rate in mL/min
    0.0 90.0 10.0 1.5
    4.5 10.0 90.0 1.5
    5.0 10.0 90.0 1.5
    5.5 95.0 5.0 1.5
    • Method 14: Column: Zorbax Stable Bond C18, 3.5 μM, 4.6×75 mm
      • Eluant A: water/0.15°)/0 formic acid
      • Eluant B: acetonitrile
      • Gradient:
  • time in min % A % B flow rate in mL/min
    0.0 95.0 5.0 1.6
    2.0 10.0 90.0 1.6
    5.0 10.0 90.0 1.6
    5.5 90.0 10.0 1.6
  • The following preparative methods were used for the reversed-phase chromatography:
    • Method 1: Column: Atlantis C18, 5 μM, 100×30 mm
      • Detection: 210-500 nm
      • Eluant A: water/0.1% trifluoroacetic acid
      • Eluant B: acetonitrile
      • Gradient:
  • time in min % A % B flow rate in mL/min
    0.0 95.0 5.0 5
    0.5 95.0 5.0 50
    8.0 5.0 95.0 50
    9.0 5.0 95.0 50
    9.5 95.0 5.0 50
    10.0 95.0 5.0 50
    10.1 95.0 5.0 5
    • Method 2: Column: Varian Pursuit 5 μM, 50×200 mm
      • Eluant A: water/0.1% trifluoroacetic acid
      • Eluant B: acetonitrile/0.1% trifluoroacetic acid
      • Gradient:
  • time in min % A % B flow rate in mL/min
    0.0 95.0 5.0 180
    1.15 95.0 5.0 180
    12.4 2.0 98.0 180
    14.0 2.0 98.0 180
    15.3 95.0 5.0 180
    15.3 95.0 5.5 180
    • Method 3: Column: YMC-Pack ODS-AQ 5 μM, 30×100 mm
      • Eluant A: water/0.15% formic acid
      • Eluant B: acetonitrile
      • Gradient:
  • time in min % A % B flow rate in mL/min
    0.0 95.0 5.0 50
    2.0 95.0 5.0 50
    6.0 10.0 90.0 50
    12.0 10.0 90.0 50
    13 90.0 10.0 50
    • Preparation of the Starting Compounds
  • The compounds of general formula I may be prepared from the following intermediates A, B and C:
  • Figure US20100240669A1-20100923-C00531
    Figure US20100240669A1-20100923-C00532
    • AAV 1: Amide Coupling
  • A solution of the carboxylic acid component (1 mol-equivalent), triethylamine (2.5 mol-equivalents) and TBTU (1.1 mol-equivalents) in THF was stirred for 30 minutes at ambient temperature. Then the amine component (1.1 mol-equivalent as hydrochloride) was added and stirring was continued overnight. Then the mixture was evaporated down, mixed with water, made alkaline with dilute potassium carbonate solution and extracted with ethyl acetate. The product was isolated and purified by column chromatography (either silica gel or reversed phase chromatography).
    • AAV 2: Ester Hydrolysis
  • 2N sodium hydroxide solution (2 mol-equivalents) was added to a solution of the ester (1 mol-equivalent) in methanol and the mixture was stirred for 1 to 5 hours at ambient temperature. Then it was acidified with acetic acid and the mixture was evaporated to dryness in vacuo. The crude product thus obtained was purified in the normal way by column chromatography on silica gel.
    • AAV 3: Cleaving the Tert-Butyloxycarbonyl Protective Group
  • A solution of the tert-butoxycarbonyl-amino compound (1 mol-equivalent) in dichloromethane was combined with trifluoroacetic acid (3 to 10 mol-equivalents) and stirred at ambient temperature until the protective group had been cleaved completely. The reaction mixture was then evaporated to dryness and the crude product thus obtained was purified by chromatography.
    • AAV 4: Preparation of the Intermediate A
  • Figure US20100240669A1-20100923-C00533
  • A solution of the aniline component (1 mol-equivalent) and a strong base such as e.g. potassium-tert-butoxide (1 mol-equivalent) in DMSO was stirred for one hour at ambient temperature, then combined with the 4-fluoro-benzonitrile component (1 mol-equivalent) and stirred overnight at approx. 80° C. For working up the mixture was filtered through Alox and evaporated to dryness in vacuo.
  • The nitrile group of the diphenylamine intermediate product thus obtained was then reduced to the aminomethyl group with the addition of Raney nickel at 55° C. and 3 bar excess hydrogen pressure and the product obtained was purified by chromatography. In order to prepare the intermediate A with an alpha-alkylbenzyl group (e.g. A1, A4, A5) the nitrile derivative (1 mol-equivalent) was dissolved in diethyl ether and at 0 to 5° C. it was added with stirring to a solution of alkylmagnesium bromide (4 mol-equivalents) in diethyl ether and then stirred for another 30 minutes approx. The reaction mixture was then stirred into 1M hydrochloric acid at −5° C. and the alkylketone thus obtained was isolated and purified by chromatography in the usual way.
  • A solution of the ketone thus obtained (1 mol-equivalent) in acetonitrile was combined with triethylamine (2 mol-equivalents) and hydroxylamine-hydrochloride (1.3 mol-equivalents) and refluxed for 4 hours. Then water was added and the mixture was extracted with dichloromethane. The resulting oxime was isolated from the organic phase and purified by conventional methods.
  • A solution of the oxime (1 mol-equivalent) in methanol was combined with methanolic hydrochloric acid (6.6 mol-equivalents). After the addition of zinc powder (1.4 mol-equivalents) the mixture was refluxed for 3 hours with stirring. After cooling the mixture was combined with water and extracted with dichloromethane. If necessary, the amine thus obtained was purified by chromatography.
  • Another possible way of reducing the oxime to the corresponding amine is by catalytic hydrogenation. For this, the oxime was hydrogenated in methanolic ammonia solution after the addition of Raney nickel at 50° C. and at an excess hydrogen pressure of 50 psi until the uptake of hydrogen had ended. If necessary, the amine thus obtained was purified by chromatography.
    • Preparation of the Intermediates A
  • Figure US20100240669A1-20100923-C00534
  • The following intermediates A1 to A31 were prepared according to general working method AAV4:
    • Intermediate A1 [6-(1-amino-ethyl)-5-fluoro-pyridin-3-yl]-(4-chloro-2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00535
  • HPLC: Rt=1.98 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=334
    • Intermediate A2 (6-aminomethyl-pyridin-3-yl)-(4-isopropyl-2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00536
  • HPLC: Rt=1.95 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=310
    • Intermediate A3 (6-aminomethyl-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00537
  • HPLC: Rt=1.74 minutes (method 13)
  • Mass spectrum (ESI): [M+H]+=302
    • Intermediate A4 2-[6-(1-amino-ethyl)-5-fluoro-pyridin-3-ylamino]-5-fluoro-benzonitrile
  • Figure US20100240669A1-20100923-C00538
  • HPLC: Rt=1.39 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=275; [M−H]−=273
    • Intermediate A5 [6-(1-amino-ethyl)-5-fluoro-pyridin-3-yl]-(4-bromo-2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00539
  • HPLC: Rt=1.92 minutes (method 2)
    • Intermediate A6 (4-aminomethyl-phenyl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00540
  • Mass spectrum (ESI): [M+H]+=285
  • thin layer chromatogram (silica gel, CH2Cl2/ethanol 19:1): Rf=0.16
    • Intermediate A7 (6-aminomethyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00541
  • HPLC: Rt=2.06 minutes (method 3)
  • Mass spectrum (ESI): [M+H]+=286; [M−H]−=284
    • Intermediate A8 (6-aminomethyl-5-chloro-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00542
  • Mass spectrum (ESI): [M+H]+=320; [M−H]−=320
    • Intermediate A9 (6-aminomethyl-pyridin-3-yl)-(4-bromo-2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00543
  • HPLC: Rt=1.97 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=346
    • Intermediate A10 (6-aminomethyl-5-chloro-pyridin-3-yl)-(2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00544
  • thin layer chromatogram (silica gel, CH2Cl2/ethanol/NH4OH 9:1:0.1): Rf=0.52
    • Intermediate A11 (4-aminomethyl-3-fluoro-phenyl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00545
  • Mass spectrum (ESI): [M+H]+=303
  • thin layer chromatogram (silica gel, CH2Cl2/ethanol 19:1): Rf=0.08
    • Intermediate A12 (4-aminomethyl-3-fluoro-phenyl)-(2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00546
  • Mass spectrum (ESI): [M−H]−=283
  • thin layer chromatogram (silica gel, CH2Cl2/ethanol 19:1): Rf=0.09
    • Intermediate A13 (6-aminomethyl-5-chloro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00547
  • Mass spectrum (ESI): [M+H]+=320
  • thin layer chromatogram (silica gel, CH2Cl2/ethanol/NH4OH 9:1:0.1): Rf=0.58
    • Intermediate A14 (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00548
  • Mass spectrum (ESI): [M+H]+=304
  • thin layer chromatogram (silica gel, CH2Cl2/ethanol/NH4OH 9:1:0.1): Rf=0.56
    • Intermediate A15 (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00549
  • Mass spectrum (ESI): [M+H]+=320; [M−H]−=318
    • Intermediate A16 (6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00550
  • HPLC: Rt=1.44 minutes (method 2)
    • Intermediate A17 (4-aminomethyl-phenyl)-(2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00551
  • HPLC: Rt=1.36 minutes (method 1)
  • Mass spectrum (ESI): [M+H−NH3]+=250
    • Intermediate A18 (6-aminomethyl-5-chloro-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00552
  • HPLC: Rt=2.05 minutes (method 2)
    • Intermediate A19 (4-aminomethyl-3-fluoro-phenyl)-(6-fluoro-2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00553
  • thin layer chromatogram (silica gel, CH2Cl2/ethanol 9:1): Rf=0.18
    • Intermediate A20 2-(6-aminomethyl-5-fluoro-pyridin-3-ylamino)-benzonitrile
  • Figure US20100240669A1-20100923-C00554
  • HPLC: Rt=1.14 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=243
    • Intermediate A21 (6-aminomethyl-5-methyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00555
  • HPLC: Rt=1.79 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=300
    • Intermediate A22 (4-aminomethyl-phenyl)-(4-chloro-2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00556
  • Mass spectrum (ESI): [M+H−NH3]+=284/286
    • Intermediate A23 (6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00557
  • Mass spectrum (ESI): [M+H]+=286
    • Intermediate A24 (6-aminomethyl-pyridin-3-yl)-(4-bromo-2-chloro-6-fluorophenyl)-amine
  • Figure US20100240669A1-20100923-C00558
  • HPLC: Rt=1.87 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=330
    • Intermediate A25 (6-aminomethyl-pyridin-3-yl)-(2-bromo-6-fluoro-phenyl)-amine
  • Figure US20100240669A1-20100923-C00559
  • HPLC: Rt=2.18 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=296
    • Intermediate A26 (6-aminomethyl-5-methyl-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00560
  • HPLC: Rt=2.33 minutes (method 2)
    • Intermediate A27 (6-aminomethyl-5-methyl-pyridin-3-yl)-(2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00561
  • Mass spectrum (ESI): [M+H]+=282
    • Intermediate A28 (6-aminomethyl-pyridin-3-yl)-(4-chloro-2-difluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00562
  • HPLC: Rt=1.66 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=284
    • Intermediate A29 (4-aminomethyl-3-fluoro-phenyl)-(4-chloro-2-trifluoromethyl-phenyl)-amine
  • Figure US20100240669A1-20100923-C00563
  • HPLC: Rt=1.83 minutes (method 2)
    • Intermediate A30 2-(4-aminomethyl-3-fluoro-phenylamino)-benzonitrile
  • Figure US20100240669A1-20100923-C00564
  • HPLC: Rt=1.38 minutes (method 2)
    • Intermediate A31 (4-aminomethyl-phenyl)-(4-bromo-2-trifluoromethyl-phenyl)amine
  • Figure US20100240669A1-20100923-C00565
  • HPLC: Rt=1.81 minutes (method 2)
    • Preparation of the Intermediates B
  • Figure US20100240669A1-20100923-C00566
  • The following Intermediates B1 to B11 were prepared by amide coupling according to general working method AAV1 and subsequent ester saponification according to general working method AAV2:
    • Intermediate B1 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid
  • Figure US20100240669A1-20100923-C00567
  • Mass spectrum (ESI): [M+H]+=208; [M−H]−=206
    • Intermediate B2 (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid
  • Figure US20100240669A1-20100923-C00568
  • HPLC: Rt=0.85 minutes (method 7)
  • Mass spectrum (ESI): [M+H]+=252
    • Intermediate B3 (S)-3-[(pyrimidine-5-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid
  • Figure US20100240669A1-20100923-C00569
  • Mass spectrum (ESI): [M+H]+=238; [M−H]−=236
    • Intermediate B4 1-[(5-amino-pyridine-3-carbonyl)-amino]-cyclopropanecarboxylic acid
  • Figure US20100240669A1-20100923-C00570
  • Mass spectrum (ESI): [M+H]+=222
    • Intermediate B5 (S)-3-[(3H-imidazo[4,5-b]pyridin-6-carbonyl)-amino]-tetrahydro-furan-3-carboxylic acid
  • Figure US20100240669A1-20100923-C00571
  • HPLC: Rt=1.49 minutes (method 3)
  • Mass spectrum (ESI): [M−H]−=275
    • Intermediate B6 (S)-3-[(2-methylamino-pyrimidine-5-carbonyl)-amino]-tetrahydro-furan-3-carboxylic acid
  • Figure US20100240669A1-20100923-C00572
  • HPLC: Rt=0.47 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=267
    • Intermediate B7 (S)-3-[(2-methyl-pyrimidine-5-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid
  • Figure US20100240669A1-20100923-C00573
  • HPLC: Rt=0.43 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=252; [M−H]−=250
    • Intermediate B8 (S)-3-[(5-hydroxy-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid
  • Figure US20100240669A1-20100923-C00574
  • HPLC: Rt=0.48 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=253
    • Intermediate B9 (S)-3-[(6-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid
  • Figure US20100240669A1-20100923-C00575
  • HPLC: Rt=0.33 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=252; [M−H]−=250
    • Intermediate B10 (S)-3-[(6-oxo-1,6-dihydro-pyridazine-4-carbonyl)-amino]-tetrahydro-furan-3-carboxylic acid
  • Figure US20100240669A1-20100923-C00576
  • HPLC: Rt=0.33 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=254
    • Intermediate B11 1-[(2-methyl-pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid
  • Figure US20100240669A1-20100923-C00577
  • Mass spectrum (ESI): [M+H]+=222; [M−H]−=220
  • The following Intermediates B12 to B15 may be prepared analogously:
    • Intermediate B12:
  • Figure US20100240669A1-20100923-C00578
    • Intermediate B13:
  • Figure US20100240669A1-20100923-C00579
  • intermediate B14:
  • Figure US20100240669A1-20100923-C00580
    • Intermediate B15:
  • Figure US20100240669A1-20100923-C00581
    • Preparation of the Intermediates C
  • Figure US20100240669A1-20100923-C00582
  • The following Intermediates C1 to C22 were prepared by amide coupling according to general working method AAV1 and subsequent cleaving of the tert-butyloxycarbonyl-protective group according to general working method AAV3:
    • Intermediate C1 1-amino-cyclopropanecarboxylic acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00583
  • HPLC: Rt=1.55 minutes (method 13)
  • Mass spectrum (ESI): [M−H]−=383
    • Intermediate C2 1-amino-cyclopropanecarboxylic acid-[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00584
  • HPLC: Rt=2.33 minutes (method 7)
  • Mass spectrum (ESI): [M+H]+=369; [M−H]−=367
    • Intermediate C3 (S)-3-amino-tetrahydrofuran-3-carboxylic acid-[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00585
  • Mass spectrum (ESI): [M+H]+=433
    • Intermediate C4 1-amino-cyclopropanecarboxylic acid-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00586
  • HPLC: Rt=1.65 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=429
    • Intermediate C5 (S)-3-amino-tetrahydrofuran-3-carboxylic acid-[3-chloro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00587
  • Mass spectrum (ESI): [M+H]+=433
    • Intermediate C6 (S)-3-amino-tetrahydrofuran-3-carboxylic acid-[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00588
  • Mass spectrum (ESI): [M+H]+=417
    • Intermediate C7 1-amino-cyclopropanecarboxylic acid-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00589
  • HPLC: Rt=1.50 minutes (method 2)
    • Intermediate C8 3-amino-oxetan-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00590
    • (a) 3-dibenzylamino-oxetan-3-carbonitrile
  • A solution of 3-oxetanone (908 mg, 12.6 mmol), dibenzylamine (6.08 mL, 31.6 mmol) and trimethylsilylcyanide (2.00 mL, 15.8 mmol) in 20 mL concentrated acetic acid was stirred overnight at 60° C. After cooling it was adjusted to pH 10 with concentrated ammonia and the solution was extracted with chloroform. After evaporation, the crude product was obtained, which was purified by chromatography through silica gel.
  • C18H18N2O (278.35)
  • Mass spectrum (ESI): [M+H]+=279
    • (b) 3-dibenzylamino-oxetan-3-carboxylic acid
  • A solution of 3-dibenzylamino-oxetan-3-carbonitrile (370 mg, 1.33 mmol) and 5 mL 4M sodium hydroxide solution in 20 mL ethanol was refluxed overnight, then neutralised with 1M hydrochloric acid neutralisiert and evaporated to dryness. The crude product thus obtained was purified by chromatography.
  • C18H19NO3 (297.35)
  • Mass spectrum (ESI): [M+H]+=298
    • (c) 3-dibenzylamino-oxetan-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Prepared from 3-dibenzylamino-oxetan-3-carboxylic acid and 4-(2-trifluoromethyl-phenyl-amino)-benzylamine by amide coupling according to general working method AAV1.
  • C32H30F3N3O2 (545.59)
  • Mass spectrum (ESI): [M+H]+=546
    • (d) 3-amino-oxetan-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • 3-dibenzylamino-oxetan-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide (32.0 mg, 0.059 mmol) was dissolved in 10 mL methanol, combined with 20 mg Pd/charcoal (10%) and debenzylated at ambient temperature under 3 bar hydrogen pressure.
  • C18H18F3N3O2 (365.35)
  • HPLC: Rt=1.93 minutes (method 5)
  • Mass spectrum (ESI): [M+H]+=366
    • Intermediate C9 (S)-3-amino-tetrahydrofuran-3-carboxlic acid-2-fluoro-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00591
  • Mass spectrum (ESI): [M+H]+=416
    • Intermediate C10 1-amino-cyclopropanecarboxylic acid-2-fluoro-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00592
  • Mass spectrum (ESI): [M+H]+=386
    • Intermediate C11 (S)-3-amino-tetrahydrofuran-3-carboxylic acid-2-fluoro-4-(2-fluoro-6-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00593
  • Mass spectrum (ESI): [M+H]+=416
    • Intermediate C12 1-amino-cyclopropanecarboxylic acid-2-fluoro-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00594
  • Mass spectrum (ESI): [M+H]+=368
    • Intermediate C13 1-amino-cyclopropanecarboxylic acid-[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00595
  • Mass spectrum (ESI): [M+H]+=387
    • Intermediate C14 (S)-3-amino-tetrahydrofuran-3-carboxylic acid-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00596
  • HPLC: Rt=1.99 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=398
    • Intermediate C15 1-amino-cyclopropanecarboxylic acid-[3-chloro-5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00597
  • Mass spectrum (ESI): [M+H]+=385
    • Intermediate C16 (S)-3-amino-tetrahydrofuran-3-carboxylic acid-[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00598
  • HPLC: Rt=1.34 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=399
    • Intermediate C17 (S)-3-amino-tetrahydrofuran-3-carboxylic acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00599
  • HPLC: Rt=2.35 minutes (method 2)
    • Intermediate C18 (S)-3-amino-tetrahydrofuran-3-carboxylic acid-4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00600
  • HPLC: Rt=2.41 minutes (method 2)
    • Intermediate C19 1-amino-cyclopropanecarboxylic acid-[5-(4-fluoro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00601
  • HPLC: Rt=1.24 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=383
    • Intermediate C20 1-amino-cyclopropanecarboxylic acid-[3-methyl-5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00602
  • HPLC: Rt=1.30 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=365
    • Intermediate C21 1-amino-cyclopropanecarboxylic acid-[5-(4-chloro-2-difluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00603
  • HPLC: Rt=1.48 minutes (method 2)
  • Mass spectrum (ESI): [M+H]+=367
    • Intermediate C22 (S)-3-amino-tetrahydrofuran-3-carboxylic acid 2-fluoro-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00604
  • Mass spectrum (ESI): [M+H]+=398
  • The following intermediates C23 to C25 may be prepared analogously:
    • Intermediate C23:
  • Figure US20100240669A1-20100923-C00605
    • Intermediate C24:
  • Figure US20100240669A1-20100923-C00606
    • Intermediate C25:
  • Figure US20100240669A1-20100923-C00607
    • Preparation of the End Compounds: Example 1 Pyrimidine-5-carboxylic acid N-(1-(4-(2,3-dichlorophenylamino)benzyl-carbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00608
    • 1a) ethyl 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylate
  • A solution of 15.74 g (126.9 mmol) pyrimidine-5-carboxylic acid, 43.57 mL (312.6 mmol) triethylamine and 44.61 g (138.9 mmol) TBTU in 460 mL THF was stirred for 30 minutes at ambient temperature. Then 9.11 g (127.3 mmol) ethyl 1-amino-cyclopropane-carboxylate hydrochloride were added and the mixture was stirred further overnight. Then the mixture was evaporated down and the residue was combined with 200 mL water, made alkaline with dilute potassium carbonate solution and extracted with ethyl acetate. The intermediate product was purified by column chromatography (silica gel, dichloromethane+0-4% methanol).
  • Yield: 95% of theory
  • C11H13N3 O 3 (235.24)
  • Rt=1.23 min. method 1
    • 1b) 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid
  • 28.39 mL of a 2N sodium hydroxide solution were added to a solution of 13.36 g (56.79 mmol) ethyl 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylate in 240 mL methanol and the mixture was stirred for one hour at ambient temperature. Then it was acidified with concentrated acetic acid and evaporated to dryness in vacuo. The crude product thus obtained was purified by column chromatography (silica gel, dichloromethane+5-30% 10% acetic acid in methanol).
  • Yield: 100% of theory
  • C9H9N3O3 (207.19)
  • Rt=1.23 min. method 1
    • 1c) N-(4-aminomethyl)phenyl)-2,3-dichloraniline-trifluoroacetate
  • A solution of 32 mg (0.2 mmol) 2,3-dichloroaniline and 22 mg (0.2 mmol) potassium-tert-butoxide in 9 mL DMSO was stirred for one hour at ambient temperature, then combined with 24 mg (0.2 mmol) 4-fluorobenzonitrile and stirred further overnight at 80° C. For working up the reaction mixture was filtered through Alox B, washed with DMF and evaporated to dryness in vacuo. The residue was hydrogenated in 100 μL methanolic ammonia solution with 20 mg Raney nickel as catalyst at 55° C. under a hydrogen pressure of 3 bar for 5 hours. Then the catalyst was filtered off, the filtrate was freed from the solvent and the crude product was purified by HPLC (method 1).
  • Yield: 47% of theory
  • C13H12Cl2N2 (267.15)
    • 1d) pyrimidine-5-carboxylic acid N-(1-(4-(2,3-dichlorophenylamino)benzylcarbamoyl)-cyclopropyl)amide
  • 0.5 mL (3.6 mmol) triethylamine, 433 mg (1.35 mmol) TBTU and 326 mg (1.2 mmol) N-(4-aminomethyl)phenyl)-2,3-dichloroaniline-trifluoroacetate (from 1c) were added to a solution of 250 mg (1.2 mmol) 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b) in 15 mL tetrahydrofuran. The mixture was stirred overnight at ambient temperature, then evaporated to dryness and purified by HPLC (method 1).
  • Yield: 16% of theory
  • C22H19Cl2N5O3 (456.32)
  • Rt=2.1 min. method 5
    • Example 2 Pyrimidine-5-carboxylic acid-N-(1-(4-(2-chlorophenylamino)benzylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00609
    • 2a) N-(4-(aminomethyl)phenyl)-2-chloroaniline
  • Analogously to method (1c) the title compound was prepared starting from 2-chloroaniline, 4-fluorobenzonitrile and Raney nickel.
  • C13H9ClN2 (228.68)
    • 2b) pyrimidine-5-carboxylic acid-N-(1-(4-(2-chlorophenylamino)benzylcarbamoyl)cyclo-propyl)amide
  • Analogously to method (1d) the title compound was prepared starting from N-(4-(aminomethyl)phenyl)-2-chloroaniline (from 2a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C22H20ClN5O2 (421.88)
  • Rt=2.13 min. method 6
    • Example 3 Pyrimidine-5-carboxylic acid-N-(1-(4-(phenylamino)benzylcarbamoyl)cyclo-propyl)amide
  • Figure US20100240669A1-20100923-C00610
    • 3a) 4-(aminomethyl)-N-phenylaniline
  • Analogously to method (1c) the title compound was prepared starting from aniline, 4-fluorobenzonitrile and Raney nickel.
  • C13H14N2 (199.26)
    • 3b) pyrimidine-5-carboxylic acid-N-(1-(4-(phenylamino)benzylcarbamoyl)cyclopropyl)-amide
  • Analogously to method (1d) the title compound was prepared starting from 4-(aminomethyl)-N-phenylaniline (from 3a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C22H20ClN5O2 (421.88)
  • Rt=1.82 min. method 5
    • Example 4 Pyrimidine-5-carboxylic acid-N-(1-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00611
    • 4a) N-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)aniline
  • Analogously to method (1c) the title compound was prepared starting from 2-(trifluoromethyl)aniline, 4-fluorobenzonitrile and Raney nickel.
  • C14H13F3N2 (266.26)
    • 4b) pyrimidine-5-carboxylic acid-N-(1-(4-(2-(trifluoromethyl)phenylamino)benzyl-carbamoyl)cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared starting from N-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)aniline (from 4a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C23H20F3N5O2 (455.43)
  • Rt=2.27 min. method 6
    • Example 5 5-oxo-pyrrolidine-2-carboxylic acid-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00612
    • 5a) 1-amine-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide
  • A solution of 376 mg (1.87 mmol) 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid in 20 mL DMF was combined with 0.4 mL (2.85 mmol) triethylamine and 600 mg (1.87 mmol) TBTU and stirred for 5 minutes at ambient temperature. Then 500 mg N-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)aniline (from 4a) were added and the mixture was stirred at ambient temperature over the weekend. The mixture was then filtered through
  • Alox B, washed with DMF:methanol=9:1 and evaporated to dryness in vacuo. The residue was combined with a 1:1 mixture of dichloromethane and trifluoroacetic acid and stirred for one hour at ambient temperature. The reaction mixture was evaporated to dryness in vacuo and the crude product was purified by column chromatography (silica gel, dichloromethane+2-8% methanol:ammonia=9:1).
  • Yield: 16% of theory
  • C22H19Cl2N5O3 (456.32)
    • 5b) 5-oxo-pyrrolidine-2-carboxylic acid-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • Analogously to method (1d) the title compound was prepared starting from 1-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 5a) and 5-oxopyrrolidine-2-carboxylic acid.
  • C23H23F3N4O3 (460.46)
  • Rt=1.89 min. method 5
  • Examples 6 to 22 that follow were prepared analogously to method (1d) from 1-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide and the corresponding acids:
    • Example 6 1-(4-dimethylamino-butyrylamino)-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00613
  • C24H29F3N4O2 (462.5)
  • Rt=1.67 min. method 5
    • Example 7 1-(3,3,3-trifluoro-propionylamino)-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00614
  • C21H19F6N3O2 (459.4)
  • Rt=2.21 min. method 5
    • Example 8 1-(3-dimethylamino-propionylamino)-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00615
  • C23H27F3N4O2 (448.5)
  • Rt1.67 min. method 5
    • Example 9 2,4-dihydroxy-pyrimidine-5-carboxylic acid-{1-[4-(2-trifluoromethyl-phenyl-amino)-benzylcarbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00616
  • C23H20F3N5O4 (487.4)
  • Rt=1.93 min. method 5
    • Example 10 1-(5-dimethylamino-pentanoylamino)-cyclopropanecarboxylic acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00617
  • C25H31F3N4O2 (476.5)
  • Rt=1.69 min. method 5
    • Example 11 N-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-nicotinamide
  • Figure US20100240669A1-20100923-C00618
  • C24H21F3N4O2 (454.4)
  • Rt=1.79 min. method 5
    • Example 12 1-(2-dimethylamino-acetylamino)-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00619
  • C22H25F3N4O2 (434.5)
  • Rt=1.68 min. method 5
    • Example 13 1-propionylamino-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenyl-amino)-benzylamide
  • Figure US20100240669A1-20100923-C00620
  • C21H22F3N3O2 (405.4) Rt=2.09 min. method 5
    • Example 14 1-(2-methoxy-acetylamino)-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00621
  • C21H22F3N3O3 (421.4)
  • Rt=2.07 min. method 5
    • Example 15 1-(cyclopropanecarbonyl-amino)-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00622
  • C22H22F3N3O2 (417.4)
  • Rt=2.13 min. method 5
    • Example 16 1-pentanoylamino-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenyl-amino)-benzylamide
  • Figure US20100240669A1-20100923-C00623
  • C23H26F3N3O2 (433.5)
  • Rt=2.24 min. method 5
    • Example 17 1-methyl-1H-imidazol-4-carboxylic acid-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00624
  • C23H22F3N5O2 (457.5) method 5
    • Example 18 1-methyl-4H-imidazole-2-carboxylic acid-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00625
  • C23H22F3N5O2 (457.5)
  • Rt=1.88 min. method 5
    • Example 19 1-(2-cyclopropyl-acetylamino)-cyclopropanecarboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00626
  • C23H24F3N3O2 (431.5)
  • Rt=2.18 min. method 5
    • Example 20 N-{1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-benzamide
  • Figure US20100240669A1-20100923-C00627
  • C25H22F3N3O2 (453.5)
  • Rt=2.25 min. method 5
    • Example 21 Pyridine-2-carboxylic acid {1-[4-(2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00628
  • C24H21F3N4O2 (454.4)
  • Rt=2.20 min. method 5
    • Example 22 1-methyl-piperidine-4-carboxylic acid {1-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00629
  • C25H29F3N4O2 (474.5)
  • Rt=1.68 min. method 5
    • Example 23 1-(2,2,2-trifluoracetamido)-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)-cyclopropanecarboxamide
  • Figure US20100240669A1-20100923-C00630
  • Analogously to method (1d) the title compound was prepared starting from 1-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 5a) and trifluoroacetic acid.
  • C20H17F6N3O2 (445.37)
  • Rt=2.27 min. method 5
    • Example 24 N-(1-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)cyclopropyl)-isoxazole-5-carboxamide
  • Figure US20100240669A1-20100923-C00631
  • 20 mg (0.15 mmol) isoxazole-5-carbonyl chloride were added to a solution of 35 mg (0.1 mmol) 1-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 5a) and 70 μL (0.50 mmol) triethylamine in 1 mL DMF and the mixture was stirred overnight at ambient temperature. The reaction mixture was purified by preparative RP-HPLC-MS with an eluant gradient (water:acetonitrile+0.1% trifluoroacetic acid=95:5 to 5:95).
  • Yield: 29% of theory
  • C22H19F3N4O3 (444.41)
  • Rt=2.42 min. method 6
    • Example 25 Pyrimidine-5-carboxylic acid N-(1-(1-(4-(4-(difluoromethoxy)phenylamino)-phenyl)ethylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00632
    • 25a) 1-(4-(4-(difluoromethoxy)phenylamino)phenyl)ethanone
  • The reaction is carried out under protective gas (argon). A mixture of 2.39 g (12 mmol) 1-(4-bromophenyl)ethanone, 0.99 mL (8 mmol) 4-(difluoromethoxy)aniline, 2.21 g (16 mmol) potassium carbonate, 150 mg (0.8 mmol) copper iodide and 180 mg (1.6 mmol) L-proline in 12 mL DMSO was stirred for 72 hours at 95° C. The reaction mixture was added to water, mixed with a little ammonia extracted twice with tert-butyl-methylether. The combined organic phases were dried on sodium sulphate and evaporated to dryness in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether+30% ethyl acetate). The product was further reacted directly.
  • Yield: 33% of theory
  • C15H13F2NO2 (277.27)
  • Rt=1.98 min. method 1
    • 25b) (Z)-1-(4-(4-(difluoromethoxy)phenylamino)phenyl)ethanone-oxime
  • A mixture of 1.08 g (3.9 mmol) 1-(4-(4-(difluoromethoxy)phenylamino)phenyl)ethanone and 0.92 mL (15.58 mmol) aqueous 50% hydroxylamine solution in 10 mL ethanol was stirred for 3 hours at 100° C. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by preparative HPLC (method 2).
  • Yield: 19% of theory
  • C15H14F2N2O2 (292.28)
  • Rt=1.96 min. method 1
  • 25c) 4-(1-aminoethyl)-N-(4-(difluoromethoxy)phenyl)aniline
  • 0.22 g (0.75 mmol) (Z)-1-(4-(4-(difluoromethoxy)phenylamino)phenyl)ethanone-oxime in 20 mL methanolic ammonia solution were hydrogenated with the addition of 50 mg Raney nickel at 50° C. at a hydrogen pressure of 50 psi for 5 hours. Then the catalyst was filtered off and the filtrate was evaporated to dryness. The crude product thus obtained was further reacted directly.
  • C15H16F2N2O (278.3)
  • Rt=1.37 min. method 1
  • 25d) pyrimidine-5-carboxylic acid N-(1-(1-(4-(4-(difluoromethoxy)phenylamino)phenyl)-ethylcarbamoyl)cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared starting from 4-(1-aminoethyl)-N-(4-(difluoromethoxy)phenyl)aniline (from 25c) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C24H23F2N5O3 (467.47)
  • Rt=1.78 min. method 1
    • Example 26 5-(trifluoromethyl)-N-(1-(4-(2-(trifluoromethyl)phenylamino)-benzylcarbamoyl)cyclopropyl)nicotinamide
  • Figure US20100240669A1-20100923-C00633
    • 26a) 5-(trifluoromethyl)nicotinic acid
  • A solution of 1.5 g 3-bromo-5-(trifluoromethyl)pyridine in 50 ml of toluene was added dropwise at −75° C. to a mixture of 9.96 mL (15.9 mmol) 1.6 molar butyllithium solution in hexane and 3.98 mL (8 mmol) 2 molar butylmagnesium chloride solution in diethyl ether and 10 mL THF. After 20 minutes 20 g (454 mmol) dry ice were added and the mixture was again stirred for 20 minutes at −75° C. and for 3 hours at RT. The reaction mixture was combined with 50 mL 1 molar sodium hydroxide solution and extracted twice with diethyl ether. The aqueous phase was acidified with 4 molar hydrochloric acid and extracted three times with diethyl ether. The combined organic phases were dried on sodium sulphate and evaporated to dryness in vacuo. The residue was mixed with dichloromethane and the precipitate formed was suction filtered and dried in the circulating air dryer at 55° C.
  • Yield: 9% of theory
  • C7H4F3NO2 (191.11)
    • 26b) 5-(trifluoromethyl)-N-(1-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-cyclopropyl)nicotinamide
  • Analogously to method (1d) the title compound was prepared starting from 1-amine-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 5a) and 5-(trifluoromethyl)nicotinic acid (from 26a).
  • C22H20F3N5O3 (459.42)
  • Rt=2.41 min. method 6
    • Example 27 5-methyl-N-(1-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-cyclopropyl)-1,3,4-oxadiazole-2-carboxamide
  • Figure US20100240669A1-20100923-C00634
    • 27a) 5-methyl-N-(1-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)cyclopropyl)-1,3,4-oxadiazole-2-carboxamide
  • Analogously to method (1d) the title compound was prepared starting from 1-amine-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 5a) and 5-methyl-1,3,4-oxadiazole-2-carboxylic acid.
  • C22H20F3N5O3 (459.42)
  • Rt=1.66 min. method 6
    • Example 28 Pyrimidine-5-carboxylic acid-N-(1-(4-(4-(methylthio)-2-(trifluoromethyl)phenylamino)benzylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00635
    • 28a) N-(4-(aminomethyl)phenyl)-4-(methylthio)-2-(trifluoromethyl)aniline
  • Analogously to method (1c) the title compound was prepared starting from 4-(methylthio)-2-(trifluoromethyl)aniline and 4-fluorobenzonitrile.
  • C15H15F3N2S (312.35)
  • Rt=1.88 min. method 2
    • 28b) pyrimidine-5-carboxylic acid-N-(1-(4-(4-(methylthio)-2-(trifluoromethyl)phenylamino)benzylcarbamoyl)cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared starting from N-(4-(aminomethyl)phenyl)-4-(methylthio)-2-(trifluoromethyl)aniline (from 28a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C24H22F3N5O2S (501.53)
  • Rt=2.33 min. method 2
    • Example 29 N-(1-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-cyclopropyl)thiazole-5-carboxamide
  • Figure US20100240669A1-20100923-C00636
    • 29a) N-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)aniline
  • Analogously to method (1c) the title compound was prepared starting from 2-trifluoromethyl-4-fluoraniline and 4-fluorobenzonitrile.
  • C14H8F4N2 (280.22)
  • Rt=0.38 min. method 4
    • 29b) tert-butyl 1-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-cyclopropylcarbamate
  • 0.98 mL (7.04 mmol) triethylamine and 1.24 g (3.87 mmol) TBTU were added to a solution of 710 mg (3.52 mmol) 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid in 60 mL DMF and the mixture was stirred for 30 minutes at ambient temperature. Then 1 g N-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)aniline was added and the mixture was stirred for 1 hour at ambient temperature. The reaction mixture was evaporated to dryness in vacuo. The residue was taken up in ethyl acetate and washed twice with 5% sodium hydrogen carbonate solution. The organic phase was dried on sodium sulphate and evaporated to dryness in vacuo.
  • Yield: 96% of theory
  • C23H25F4N3O3 (467.46)
  • Rt=1.50 min. method 4
    • 29c) 1-amino-N-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl)-cyclopropanecarboxamide
  • 1.57 g (3.36 mmol) tert-butyl 1-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl-carbamoyl)cyclopropylcarbamate in 10 mL diethyl ether were combined with 20 mL 4 molar hydrogen chloride in dioxane and stirred for 10 minutes at ambient temperature. The reaction mixture was combined with ethyl acetate and made alkaline with saturated potassium carbonate solution. The organic phase was dried on sodium sulphate and evaporated to dryness in vacuo.
  • Yield: 101% of theory
  • C18H17F4N3O (367.34)
  • Rt=1.33 min. method 4
    • 29d) N-(1-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzylcarbamoyl)cyclopropyl)-thiazole-5-carboxamide
  • Analogously to method (1d) the title compound was prepared starting from 1-amino-N-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 29c) and thiazole-5-carboxylic acid.
  • C22H18F4N4O3S (478.46)
  • Rt=2.76 min. method 3
    • Example 30 N-(4-(4-fluoro-2-(trifluoromethyl)phenylamine)benzyl)-1-(3,3,3-trifluoro-propanamido)cyclopropanecarboxamide
  • Figure US20100240669A1-20100923-C00637
    • 30a) N-(4-(4-fluoro-2-(trifluoromethyl)phenylamine)benzyl)-1-(3,3,3-trifluoropropanamido)cyclopropanecarboxamide
  • 44.0 mg (0.15 mmol) 3,3,3-trifluoropropionyl chloride, dissolved in 5 mL dichloromethane, were added dropwise to a solution of 110.2 mg (0.3 mmol) 1-amino-N-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 29c) and 80 μL (0.6 mmol) triethylamine in 10 mL dichloromethane. Then the reaction mixture was left at ambient temperature for the weekend with stirring and it was then purified by preparative RP-HPLC-MS (method 3). The eluate was made alkaline with conc. Ammonia and the acetonitrile was distilled off. The aqueous mixture was extracted with ethyl acetate and the organic phase was dried on sodium sulphate and evaporated to dryness in vacuo.
  • Yield: 44% of theory
  • C21H18F7N3O2 (477.38)
  • Rt=2.85 min. method 3
    • Example 31 N-(1-(4-(4-fluoro-2-(trifluoromethyl)phenylamine)benzylcarbamoyl)-cyclopropyl)isoxazole-5-carboxamide
  • Figure US20100240669A1-20100923-C00638
  • Analogously to method (30a) the title compound was prepared starting from 1-amino-N-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 29c) and isoxazole-5-carbonyl chloride.
  • C22H18F4N4O3 (462.4)
  • Rt=2.79 min. method 3
    • Example 32 Pyrimidine-5-carboxylic acid-N-(1-(4-(4-(methylsulphonyl)-2-(trifluoromethyl)phenylamine)benzylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00639
  • 34 mg (0.2 mmol) 3-chloroperoxybenzoic acid were added to 66 mg (0.13 mmol) pyrimidine-5-carboxylic acid-N-(1-(4-(4-(methylthio)-2-(trifluoromethyl)-phenylamino)benzylcarbamoyl)cyclopropyl)amide (from 28b), dissolved in 5 mL dichloromethane, and the mixture was left at ambient temperature overnight with stirring. Then the mixture was added to saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic phase was dried through a phase separation cartridge and the filtrate was evaporated to dryness in vacuo.
  • Yield: 40% of theory
  • C24H22F3N5O4S (533.52)
  • Rt=1.84 min. method 2
    • Example 33 Pyrimidine-5-carboxylic acid-N-(1-(4-(4-fluoro-2-(trifluoromethyl)phenylamine)benzylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00640
  • Analogously to method (1d) the title compound was prepared starting from 1-amino-N-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 29c) and pyrimidine-5-carboxylic acid.
  • C23H19F4N5O2 (473.42)
  • Rt=2.09 min. method 2
    • Example 34 1-(2-(pyrimidin-5-yl)acetamido)-N-(4-(2-(trifluoromethyl)phenylamino)-benzyl)cyclopropanecarboxamide
  • Figure US20100240669A1-20100923-C00641
  • Analogously to method (1d) the title compound was prepared starting from 1-amino-N-(4-(4-fluoro-2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide (from 29c) and pyrimidine-5-carboxylic acid.
  • C24H22F3N5O2 (469.46)
  • Rt=2.21 min. method 6
    • Example 35 Pyrimidine-5-carboxylic acid-N-(1-(4-(2-cyanphenylamine)benzylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00642
    • 35a) tert-butyl-4-aminobenzylcarbamate
  • 92.65 g (424.5 mmol) di-tert-butyl-dicarbonate were added to 61.85 g (424.4 mmol) 4-aminomethyl-aniline dissolved in 850 mL chloroform and the mixture was stirred at ambient temperature until no more educt was present. The mixture was evaporated to dryness in vacuo and the residue was recrystallised from ethyl acetate/hexane (approx. 3 mL/g).
  • Yield: 66% of theory
  • C12H18N2O2 (222.28)
  • Rf=0.49 hexane:ethyl acetate (1/1)
    • 35b) tert-butyl-4-(2-cyanophenylamino)benzylcarbamate
  • The reaction was carried out under protective gas (nitrogen). 8 mg (0.01 mmol) of tris(dibenzylideneacetone)dipalladium and 17 mg (0.04 mmol) Xantphos were added to 100 mg (0.45 mmol) tert-butyl-4-aminobenzylcarbamate, 138 mg (0.63 mmol) potassium sulphate and 98 mg (0.54 mmol) 2-bromobenzonitrile in 5 mL toluene. The mixture was stirred overnight at 110° C. and then the inorganic salts were filtered off. The filtrate was evaporated to dryness in vacuo and the residue was purified through an RP column with a solvent gradient (water/acetonitrile+0.1% trifluoroacetic acid).
  • Yield: 82% of theory
  • C19H21N3O2 (323.39)
  • Rt=2.57 min. method 2
    • 35c) 2-(4-(aminomethyl)phenylamino)benzonitrile-2,2,2-trifluoroacetate
  • 119 mg (0.37 mmol) tert-butyl 4-(2-cyanophenylamino)benzylcarbamate were dissolved in 5 mL dichloromethane and combined with 1 mL (13.06 mmol) trifluoroacetic acid. The reaction was stirred overnight at ambient temperature and then evaporated to dryness in vacuo.
  • Yield: 99% of theory
  • C14H13N3*C2HF3O2 (337.3)
  • Rt=1.30 min. method 2
    • 35d) pyrimidine-5-carboxylic acid-N-(1-(4-(2-cyanophenylamine)benzylcarbamoyl)cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared starting from 2-(4-(aminomethyl)phenylamino)benzonitrile 2,2,2-trifluoroacetate (from 35c) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C23H20N6O2 (412.44)
  • Rt=1.84 min. method 2
    • Example 36 Pyrimidine-5-carboxylic acid-N-(1-(4-(2-cyano-4-fluorophenylamine)benzyl-carbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00643
    • 36a) Tert-butyl-4-(2-cyano-4-fluorophenylamino)benzylcarbamate
  • Analogously to method (35b) the title compound was prepared starting from tert-butyl-4-aminobenzylcarbamate (from 35a), potassium sulphate, 2-bromo-5-fluorobenzonitrile, tris(dibenzylideneacetone)dipalladium and Xantphos.
  • C19H20FN6O2 (341.38)
  • Rt=2.61 min. method 2
    • 36b) 2-(4-(aminomethyl)phenylamino)-5-fluorobenzonitrile 2,2,2-trifluoroacetate
  • Analogously to method (35c) the title compound was prepared starting from tert-butyl-4-(2-cyano-4-fluorophenylamino)benzylcarbamate and trifluoroacetic acid.
  • C14H12FN3*C2HF3O2 (355.29)
  • Rt=1.39 min. method 2
    • 36c) pyrimidine-5-carboxylic acid-N-(1-(4-(2-cyano-4-fluorophenylamine)benzylcarbamoyl)cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared from 2-(4-(aminomethyl)phenylamino)-5-fluorobenzonitrile 2,2,2-trifluoroacetate (from 36b) and 1-[(pyrimidine-5-carbonyl)amino]-cyclopropanecarboxylic acid (from 1b).
  • C23H19FN6O2 (430.43)
  • Rt=1.91 min. method 2
    • Example 37 Pyrimidine-5-carboxylic acid-N-(1-(4-(4-fluorophenylamino)benzylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00644
    • 37a) 4-(aminomethyl)-N-(4-fluorophenyl)aniline
  • Analogously to method (1c) the title compound was prepared starting from 2-bromo-4-fluoro-aniline, 4-fluorobenzonitrile and Raney nickel.
  • C13H13FN2 (216.25)
    • 37b) pyrimidine-5-carboxylic acid-N-(1-(4-(4-fluorophenylamino)benzylcarbamoyl)cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared from 4-(aminomethyl)-N-(4-fluorophenyl)aniline (from 37a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C22H20FN5O2 (405.43)
  • mass spectroscopy [M+H]+=406
    • Example 38 Pyrimidine-5-carboxylic acid-N-(1-((5-(2-chlorophenylamino)-3-fluoropyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00645
    • 38a) 6-(aminomethyl)-N-(2-chlorophenyl)-5-fluoropyridin-3-amine
  • Analogously to method (1c) the title compound was prepared starting from 2-chloro-aniline, 2-cyano-3,5-difluoropyridine and Raney nickel.
  • C12H11FN3 (251.69)
  • Rt=1.295 min. method 1
    • 38b) pyrimidine-5-carboxylic acid-N-(1-((5-(2-chlorophenylamino)-3-fluoropyridin-2-yl)-methylcarbamoyl)cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared from 6-(aminomethyl)-N-(2-chlorophenyl)-5-fluoropyridin-3-amine (from 38a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C21H18FN6O2 (440.86)
  • Rt=1.73 min. method 1
    • Example 39 Pyrimidine-5-carboxylic acid-N-(1-((5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00646
    • 39a) 6-(aminomethyl)-N-(2-(trifluoromethyl)phenyl)pyridin-3-amine
  • Analogously to method (1c) the title compound was prepared starting from 2-(trifluoromethyl)aniline, 5-fluoro-picolinic acid nitrile and Raney nickel.
  • C13H12F3N3 (267.25)
  • Rt=1.29 min. method 1
    • 39b) pyrimidine-5-carboxylic acid-N-(1-((5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)-methylcarbamoyl)cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared from 6-(aminomethyl)-N-(2-(trifluoromethyl)phenyl)pyridin-3-amine (from 39a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C22H19F3N6O2 (456.42)
  • Rt=1.39 min. method 1
    • Example 40 Pyrimidine-5-carboxylic acid-N-(1-(1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00647
    • 40a) 5-(2-(trifluoromethyl)phenylamino)picolinic acid nitrile
  • 820 mg (6.72 mmol) 5-fluoropicolinic acid nitrile and 0.84 mL (6.72 mmol) 2-(trifluoromethyl)aniline in 10 mL DMSO were combined with 1.51 g (13.43 mmol) potassium-tert-butoxide and stirred for 2 hours at ambient temperature. The mixture was poured onto an aqueous sodium chloride solution and extracted with tert-butylmethylether. The organic phase was evaporated to dryness in vacuo and the crude product thus obtained was purified by HPLC (method 2).
  • Yield: 54% of theory
  • C13H8F3N3 (263.22)
    • 40b) 1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethanone
  • The reaction was carried out under protective gas (nitrogen). 860 mg (3.27 mmol) 5-(2-(trifluoromethyl)phenylamino)picolinic acid nitrile in 5 mL diethyl ether at −10° C. were added dropwise to 9.34 mL (13.07 mmol) of a 1.4 molar solution of methylmagnesium bromide in toluene/THF (3:1) and the mixture was left for 15 minutes at this temperature with stirring. The reaction mixture was combined with saturated ammonium chloride solution, neutralised with 1 molar aqueous hydrochloric acid at −5° C. and extracted with tert-butylmethylether. The organic phase was evaporated to dryness in vacuo.
  • Yield: 96% of theory
  • C14H11F3N2O (280.25)
  • Rt=1.97 min. method 1
    • 40c) (Z)-1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethanone-oxime
  • 0.73 mL (12.42 mmol) of a 50% aqueous hydroxylamine solution were added to 870 mg (3.1 mmol) 1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethanone in 5 mL ethanol. The mixture was stirred for 2 hours at 100° C. and then the solvents were distilled off.
  • Yield: 98% of theory
  • C14H12F3N3O (295.26)
  • Rt=1.75 min. method 1
    • 40d) 6-(1-aminoethyl)-N-(2-(trifluoromethyl)phenyl)pyridin-3-amine
  • 900 mg (3.05 mmol) (Z)-1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethanone-oxime and 100 mg Raney nickel in 25 mL methanolic ammonia were hydrogenated for 1.5 days at ambient temperature and 50 psi hydrogen pressure. The reaction mixture was filtered, evaporated to dryness and then further reacted directly.
  • Yield: 96% of theory
  • C14H14F3N3 (281.28)
  • Rt=1.33 min. method 1
    • 40e) pyrimidine-5-carboxylic acid-N-(1-(1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethylcarbamoyl)cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared from 6-(1-aminoethyl)-N-(2-(trifluoromethyl)phenyl)pyridin-3-amine (from 40d) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C23H21F3N6O2 (470.45)
  • Rt=1.46 min. method 1
    • Example 41 Pyrimidine-5-carboxylic acid-N-(1-((5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00648
    • 41a) 6-(aminomethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine
  • Analogously to method (1c) the title compound was prepared starting from 2-trifluoromethyl-4-fluoro-aniline, 2-cyano-5-fluoropyridine and Raney nickel.
  • C13H11F4N3 (285.24)
  • Rt=1.50 min. method 9
    • 41b) pyrimidine-5-carboxylic acid-N-(1-((5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Analogously to Example (1d) the title compound was prepared from 6-(aminomethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine (from 41a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C22H18F4N6O2 (474.41)
  • Rt=2.96 min. method 7
    • Example 42 Pyrimidine-5-carboxylic acid-N-(1-((5-(5-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00649
    • 42a) 6-(aminomethyl)-N-(5-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine
  • Analogously to method (1c) the title compound was prepared starting from 2-fluoro-6-(trifluoromethyl)aniline, 2-cyano-5-fluoropyridine and Raney nickel.
  • C13H11F4N3 (281.24)
  • Rt=1.95 min. method 8
    • 42b) pyrimidine-5-carboxylic acid-N-(1-((5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared starting from 6-(aminomethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine (from 41a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C22H18F4N6O2 (474.41)
  • Rt=3.10 min. method 7
    • Example 43 (S)-pyrimidine-5-carboxylic acid-N-(3-((5-(4-fluoro-2-(trifluoromethyl)phenyl-amino)pyridin-2-yl)methylcarbamoyl)tetrahydrofuran-3-yl)amide
  • Figure US20100240669A1-20100923-C00650
    • 43a) (S)-phenethyl-3-aminotetrahydrofuran-3-carboxylate
  • 19.37 g (50 mmol) (S)-phenethyl-3-aminotetrahydrofuran-3-carboxylate (S)-2-hydroxy-2-phenylacetate were suspended in 75 mL THF and 75 mL water, combined with 6.3 g (75 mmol) sodium hydrogen carbonate and stirred for 3 hours at ambient temperature.
  • The mixture was extracted twice with dichloromethane. The organic phases were washed with 14% sodium chloride solution, dried on sodium sulphate and evaporated to dryness in vacuo. The crude product thus obtained was further reacted directly.
  • Yield: 85% of theory
  • C13H17NO3 (235.28)
  • Rt=1.19 min. method 1
    • 43b) (S)-ohenethyl-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylate
  • 4.43 mL (40.3 mmol) N-methylmorpholine and 5.69 g (17.7 mmol) TBTU were added to a solution of 2 g (16.1 mmol) pyrimidine-5-carboxylic acid in 50 mL DMF. The mixture was left for 30 minutes at ambient temperature with stirring and then combined with 3.8 g (16.16 mmol) (S)-phenethyl-3-aminotetrahydrofuran-3-carboxylate. The mixture was stirred overnight at ambient temperature and then evaporated to dryness. The crude product thus obtained was purified by HPLC (method 2).
  • Yield: 93% of theory
  • C18H19N3O4 (341.36)
  • Rt=1.60 min. method 1
    • 43c) (S)-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylic acid
  • 60.24 mL (60.24 mmol) of a 1 molar sodium hydroxide solution were added to a solution of 5.14 g (15.1 mmol) (S)-phenethyl 3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylate in 97 mL ethanol. The mixture was stirred for 1 hour at ambient temperature and then acidified with 4 molar hydrochloric acid. The purification was carried out by HPLC (method 2).
  • Yield: 93% of theory
  • C10H11N3O4 (237.21)
  • Rt=0.87 min. method 1
    • 43d) pyrimidine-5-carboxylic acid-(S)—N-(3-((5-(4-fluoro-2-(trifluoromethyl)phenylamino)-pyridin-2-yl)methylcarbamoyntetrahydrofuran-3-yl)amide
  • Analogously to method (1d) the title compound was prepared from 6-(aminomethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine (from 41a) and (S)-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylic acid (from 43c).
  • C23H20F4N6O3 (504.44)
  • Rt=2.86 min. method 7
    • Example 44 Pyrimidine-5-carboxylic acid-N-(1-((5-(2-fluoro-6-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00651
    • 44a) 6-(aminomethyl)-N-(2-fluoro-6-(trifluoromethyl)phenyl)pyridin-3-amine
  • Analogously to method (1c) the title compound was prepared starting from 2-trifluoromethyl-5-fluoro-aniline, 2-cyano-5-fluoropyridine and Raney nickel.
  • C13H11F4N3 (285.24)
  • Rt=1.95 min. method 8
    • 44b) pyrimidine-5-carboxylic acid-N-(1-((5-(2-fluoro-6-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared starting from 6-(aminomethyl)-N-(2-fluoro-6-(trifluoromethyl)phenyl)pyridin-3-amine (from 44a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C22H18F4N6O2 (474.41)
  • Rt=2.71 min. method 7
    • Example 45 Pyrimidine-5-carboxylic acid-N-(1-(1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00652
    • 45a) 5-(4-fluoro-2-(trifluoromethyl)phenylamino)picolinic acid nitrile
  • Analogously to method (40a) the title compound was prepared starting from 5-fluoro-picolinic acid nitrile, 4-fluoro-2-(trifluoromethyl)aniline and potassium-tert-butoxide in DMSO.
  • C13H8F3N3 (281.21)
  • Rt=1.40 min. method 4
    • 45b) 1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethanone
  • Analogously to method (40b) the title compound was prepared from methylmagnesium bromide and 5-(4-fluoro-2-(trifluoromethyl)phenylamino)picolinic acid nitrile.
  • C14H11F4N2O (298.24)
  • Rt=1.43 min. method 4
  • 45c) (E)-1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethanone-oxime
  • Analogously to method (40c) the title compound was prepared starting from 1-(5-(2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethanone and a 50% aqueous hydroxylamine solution.
  • C14H11F4N3O (313.25)
  • Rt=1.31 min. method 4
    • 45d) 6-(1-aminoethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine
  • Analogously to method (40d) the title compound was prepared starting from (E)-1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethanone-oxime and Raney nickel.
  • C14H14F4N3 (299.27)
  • Rt=1.65 min. method 9
    • 45e) pyrimidine-5-carboxylic acid-N-(1-(1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethylcarbamoyl)cyclopropyl)amide
  • Analogously to method (1d) 6-(1-aminoethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine (from 45d) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b) were reacted to form the title compound.
  • C23H20F4N6O2 (488.44)
  • Rt=3.01 min. method 7
    • Example 46 (S)-pyrimidine-5-carboxylic acid-N-(3-((5-(2-fluoro-6-(trifluoromethyl)phenyl-amino)pyridin-2-yl)methylcarbamoyl)tetrahydrofuran-3-yl)amide
  • Figure US20100240669A1-20100923-C00653
  • Analogously to method (1d) the title compound was prepared from 6-(aminomethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine (from 41a) and (S)-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylic acid (from 43c).
  • C23H20F4N6O3 (504.44)
  • Rt=2.74 min. method 7
    • Example 47 (S)-pyrimidine-5-carboxylic acid-N-(-3-(1-(5-(4-fluoro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)ethylcarbamoyl)tetrahydrofuran-3-yl)amide
  • Figure US20100240669A1-20100923-C00654
  • Analogously to method (1d) the title compound was prepared from 6-(1-aminoethyl)-N-(4-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine (from 45d) and (S)-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylic acid (from 43c).
  • C24H22F4N6O3 (518.46)
  • Rt=3.00 min. method 7
    • Example 48 (S)-pyrimidine-5-carboxylic acid-N-(3-((5-(5-fluoro-2-(trifluoromethyl)phenyl-amino)pyridin-2-yl)methylcarbamoyl)tetrahydrofuran-3-yl)amide
  • Figure US20100240669A1-20100923-C00655
  • Analogously to method (1d) the title compound was prepared from 6-(aminomethyl)-N-(5-fluoro-2-(trifluoromethyl)phenyl)pyridin-3-amine (from 42a) and (S)-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylic acid (from 43c).
  • C23H20F4N6O3 (504.44)
  • Rt=3.15 min. method 7
    • Example 49 Pyrimidine-5-carboxylic acid-N-(1-((5-(2-methyl-6-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00656
    • 49a) 6-(aminomethyl)-N-(2-methyl-6-(trifluoromethyl)phenyl)pyridin-3-amine
  • Analogously to method (1c) the title compound was prepared from 2-methyl-6-(trifluoromethyl)-aniline and 2-cyano-5-fluoropyridine with Raney nickel as catalyst.
  • C14H14F3N3 (281.28)
  • Rt=1.52 min. method 2
    • 49b) pyrimidine-5-carboxylic acid-N-(1-((5-(2-methyl-6-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared from 6-(aminomethyl)-N-(2-methyl-6-(trifluoromethyl)phenyl)pyridin-3-amine (from 49a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C22H18F4N6O2 (470.45)
  • Rt=1.57 min. method 2
    • Example 50 Pyrimidine-5-carboxylic acid-N-(1-((5-(4-methoxy-2-(trifluoromethyl)phenyl-amino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00657
    • 50a) 6-(aminomethyl)-N-(4-methoxy-2-(trifluoromethyl)phenyl)pyridin-3-amine
  • Analogously to method (1c) the title compound was prepared starting from 2-amino-5-methoxybenzotrifluoride and 2-cyano-5-fluoropyridine with Raney nickel as catalyst.
  • C14H14F3N3O (297.28)
  • Rf=0.21 ethyl acetate/methanol/ammonia=9:1:0.1
    • 50b) pyrimidine-5-carboxylic acid-N-(1-((5-(4-methoxy-2-(trifluoromethyl)phenylamino)-pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared from 6-(aminomethyl)-N-(4-methoxy-2-(trifluoromethyl)phenyl)pyridin-3-amine (from 50a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C23H21F3N6O3 (486.45)
  • Rt=2.82 min. method 7
    • Example 51 Pyrimidine-5-carboxylic acid-N-(1-((5-(4-methyl-2-(trifluoromethyl)phenyl-amino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00658
    • 51a) 6-(aminomethyl)-N-(4-methyl-2-(trifluoromethyl)phenyl)pyridin-3-amine
  • Analogously to method (1c) the title compound was prepared from 2-amino-5-methylbenzotrifluoride and 2-cyano-5-fluoropyridine using Raney nickel.
  • C14H14F3N3 (281.28)
  • Rt=1.63 min. method 2
    • 51b) pyrimidine-5-carboxylic acid-N-(1-((5-(4-methyl-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • 0.1 mL (0.56 mmol) DIPEA and 87 mg (0.27 mmol) O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N′,N′-tetramethyluronium tetrafluoroborate, dissolved in 0.5 mL DMF, were added to a solution of 50 mg (0.24 mmol) 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b) in 2 mL THF. The mixture was left for 15 minutes at ambient temperature with stirring and then 82 mg (0.29 mmol) of 6-(aminomethyl)-N-(4-methyl-2-(trifluoromethyl)phenyl)pyridin-3-amine (from 51a) in 0.5 mL DMF were added. The mixture was stirred overnight at ambient temperature and then purified by HPLC (Microsorb C18; 41.4×250 mm with acetonitrile/water/trifluoroacetic acid=10/90/0.1 =>100/0/0.1).
  • Yield: 33% of theory
  • C23H21F3N6O2 (470.45)
  • Rt=1.63 min. method 2
    • Example 52 Pyrimidine-5-carboxylic acid-N-(1-((5-(2,4-bis(trifluoromethyl)phenylamino)-pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00659
    • 52a) 6-(aminomethyl)-N-(2,4-bis(trifluoromethyl)phenyl)pyridin-3-amine
  • Analogously to method (1c) the title compound was prepared from 2,4-bis(trifluoromethyl)aniline and 2-cyano-5-fluoropyridine using Raney nickel.
  • C14H11F6N3 (335.25)
    • 52b) pyrimidine-5-carboxylic acid-N-(1-((5-(2,4-bis(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared from 6-(aminomethyl)-N-(2,4-bis(trifluoromethyl)phenyl)pyridin-3-amine (from 52a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C23H18F6N6O2 (524.42)
  • Rt=3.63 min. method 10
    • Example 53 Pyrimidine-5-carboxylic acid-N-(1-((5-(4-bromo-2-methylphenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00660
    • 53a) 5-(4-bromo-2-(trifluoromethyl)phenylamino)picolinonitrile
  • Analogously to method (40a) the title compound was prepared starting from 2-cyano-5-fluoropyridine, 2-amino-5-bromo-benzotrifluoride and potassium-tert-butoxide with DMSO as solvent.
  • C13H7BrF3N3 (342.11)
  • Rt=2.50 min. method 2
    • 53b-1) 6-(aminomethyl)-N-(4-bromo-2-methylphenyl)pyridin-3-amine 2,2,2-trifluoroacetate
  • 1.65 mL (3.3 mmol) 2 molar lithium aluminium hydride solution in THF were added to a solution of 564 mg (1.65 mmol) 5-(4-bromo-2-(trifluoromethyl)phenylamino)picolinic acid nitrile in 5 mL THF. The reaction mixture was stirred for 30 minutes at ambient temperature and then mixed with water. The salts were suction filtered and the filtrate was evaporated down in vacuo. The residue was purified by HPLC (with solvent gradient, acetonitrile and water with 0.1% trifluoroacetic acid). 2 products are formed.
  • Yield: 65% of theory
  • C13H14BrN3*C2HF3O2 (406.2)
  • Rt=1.63 min. method 2
    • 53b-2) 6-(aminomethyl)-N-(4-bromo-2-(trifluoromethyl)phenyl)pyridin-3-amine
  • Yield: 11% of theory
  • C13H11BrFF3N3 (346.15)
  • Rt=1.72 min. method 2
    • 53c) pyrimidine-5-carboxylic acid-N-(1-((5-(4-bromo-2-methylphenylamino)pyridin-2-yl)-methylcarbamoyl)cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared starting from 6-(aminomethyl)-N-(4-bromo-2-methylphenyl)pyridin-3-amine 2,2,2-trifluoroacetate (from 53b-1) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C22H21BrN6O2 (481.35)
  • Rt=1.61 min. method 2
    • Example 54 Pyrimidine-5-carboxylic acid-N-(1-((5-(4-bromo-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00661
  • Analogously to method (1d) the title compound was prepared from 6-(aminomethyl)-N-(4-bromo-2-(trifluoromethyl)phenyl)pyridin-3-amine (from 53b-2) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C22H18BrF3N6O2 (535.32)
  • Rt=1.82 min. method 2
    • Example 55 Pyrimidine-5-carboxylic acid-N-(1-((5-(4-chloro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00662
    • 55a) 5-(4-chloro-2-(trifluoromethyl)phenylamino)picolinonitrile
  • The reaction took place under protective gas (nitrogen). 21 mg (0.04 mmol) Xantphos and 10 mg (0.01 mmol) tris(dibenzylideneacetone)dipalladium were added to a solution of 100 mg (0.55 mmol) 5-bromo-2-cyanopyridine, 93 μL (0.66 mmol) 2-amino-5-chlorobenzotrifluoride and 167 mg (0.77 mmol) potassium phosphate in 5 mL toluene. The mixture was stirred overnight at 110° C., the salts were filtered off and the filtrate was evaporated to dryness in vacuo. The residue was purified by HPLC (with eluant gradient, acetonitrile and water with 0.1% trifluoroacetic acid).
  • Yield: 68% of theory
  • C13H7ClF3N3 (297.66)
  • Rt=2.53 min. method 2
    • 55b) 6-(aminomethyl)-N-(4-chloro-2-(trifluoromethyl)phenyl)pyridin-3-amine
  • Analogously to method (53b) the title compound was prepared starting from 5-(4-chloro-2-(trifluoromethyl)phenylamino)picolinic acid nitrile and 2 molar lithium aluminium hydride solution.
  • C13H11ClF3N3 (301.69)
  • Rt=1.72 min. method 2
    • 55c) pyrimidine-5-carboxylic acid-N-(1-((5-(4-chloro-2-(trifluoromethyl)phenylamino)pyridin-2-yl)methylcarbamoyl)cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared from 6-(aminomethyl)-N-(4-chloro-2-(trifluoromethyl)phenyl)pyridin-3-amine (from 55b) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1b).
  • C22H18ClF3N6O2 (490.87)
  • Rt=1.76 min. method 2
    • Example 56 5-oxo-N—((S)-3-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-tetrahydrofuran-3-yl)pyrrolidine-2-carboxamide
  • Figure US20100240669A1-20100923-C00663
    • 56a) (S)-phenethyl-3-(tert-butoxycarbonylamino)tetrahydrofuran-3-carboxylate
  • 2 g (9.18 mmol) di-tert-butyldicarbonate and 11.29 mL (9.18 mmol) TEA were added to a solution of 1.8 g (7.65 mmol) (S)-phenethyl 3-aminotetrahydrofuran-3-carboxylate (from 43a) in 30 mL dichloromethane. The mixture was stirred overnight at ambient temperature and then more di-tert-butyldicarbonate and 50 mg dimethylaminopyridine were added. The reaction mixture was evaporated to dryness in vacuo and the residue was taken up in 50 mL dioxane and stirred for 6 hours at 60° C. The solvent was distilled off and the residue was divided between ethyl acetate and 0.5 molar potassium hydrogen sulphate solution. The organic phase was washed with sodium hydrogen sulphate solution, dried on sodium sulphate and evaporated to dryness in vacuo. The residue was purified on silica gel with petroleum ether/ethyl acetate in the ratio 4:1.
  • Yield: 63% of theory
  • C18H25NO5 (335.39)
  • Rt=2.05 min. method 1
    • 56b) (S)-3-tert-butoxycarbonylamino)tetrahydrofuran-3-carboxylic acid
  • 8.94 mL (17.89 mmol) 2 molar sodium hydroxide solution were added to a solution of 1.5 g (4.47 mmol) (S)-phenethyl-3-(tert-butoxycarbonylamino)tetrahydrofuran-3-carboxylate in 20 mL ethanol. The mixture was stirred for 2 hours at ambient temperature and then 8.94 mL (17.89 mmol) 2 molar hydrochloric acid were added thereto. The mixture was evaporated down, the residue was suspended in ethanol and the salts were suction filtered. The filtrate was freed from the solvent and further reacted in crude form.
  • Yield: 100% of theory
  • C10H17NO5 (231.25)
  • Rt=1.53 min. method 1
    • 56c) (S)-tert-butyl-3-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-tetrahydrofuran-3-ylcarbamate
  • Analogously to method (1d) the title compound was prepared from N-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)aniline (from 4a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 56b).
  • C24H28F3N3O4 (479.49)
    • 56d) (S)-3-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)tetrahydrofuran-3-carboxamide
  • 2 g (4.17 mmol) (S)-tert-butyl-3-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)-tetrahydrofuran-3-ylcarbamate were stirred in 15 mL of a 1:1 mixture of dichloromethane and trifluoroacetic acid for 30 minutes at ambient temperature. After evaporation of the reaction mixture the residue was dissolved in dichloromethane, made basic with 4 molar sodium hydroxide solution and added to a phase separation cartridge. The filtrate was freed from the solvent and the crude product was chromatographed on silica gel with cyclohexane/ethyl acetate in the ratio 1:1 and then a second time with dichloromethane/methanol in the ratio 9:1.
  • Yield: 77% of theory
  • C19H20F3N3O2 (379.38)
  • Rt=1.97 min. method 6
    • 56e) (S)-5-oxo-N-(-3-(4-(2-(trifluoromethyl)phenylamino)benzylcarbamoyl)tetrahydro-furan-3-yl)pyrrolidine-2-carboxamide
  • Analogously to method (1d) the title compound was prepared starting from (S)-3-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)tetrahydrofuran-3-carboxamide (from 56d) and 5-oxopyrrolidine-2-carboxylic acid.
  • C24H25F3N4O4 (490.49)
  • Rt=1.84 min. method 5
  • Examples 57 to 107 that follow were prepared analogously to the method (1d) from (S)-3-amino-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)tetrahydrofuran-3-carboxamide and the corresponding acids.
    • Example 57 (S)-6-amino-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-nicotinamide
  • Figure US20100240669A1-20100923-C00664
  • C25H24F3N5O3 (499.5)
  • Rt=1.66 min. method 5
    • Example 58 (S)-6-methyl-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-nicotinamide
  • Figure US20100240669A1-20100923-C00665
  • C26H25F3N4O3 (498.5)
  • Rt=1.69 min. method 5
    • Example 59 3-(2-pyridin-2-yl-acetylamino)-tetrahydro-furan-3-carboxylic acid 4-(2-tri-fluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00666
  • C26H25F3N4O3 (498.5)
  • Rt=1.64 min. method 5
    • Example 60 (S)-3-Rtetrahydro-furan-3-carbonylyaminoFtetrahydro-furan-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00667
  • C24H26F3N3O4 (477.5)
  • Rt=1.96 min. method 5
    • Example 61 (S)-2-chloro-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-isonicotinamide
  • Figure US20100240669A1-20100923-C00668
  • C25H22ClF3N4O3 (518.9)
  • Rt=2.15 min. method 5
    • Example 62 (S)-6-oxo-1,6-dihydro-pyridazine-3-carboxylic acid {3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-amide
  • Figure US20100240669A1-20100923-C00669
  • C24H22F3N5O4 (501.5)
  • Rt=1.91 min. method 5
    • Example 63 (S)-2-amino-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-isonicotinamide
  • Figure US20100240669A1-20100923-C00670
  • C25H24F3N5O3 (499.5)
  • Rt=1.64 min. method 5
    • Example 64 (S)-pyridazine-4-carboxylic acid {3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-amide
  • Figure US20100240669A1-20100923-C00671
  • C24H22F3N5O3 (485.5)
  • Rt=1.92 min. method 5
    • Example 65 (S)-tetrahydropyran-4-carboxylic acid {3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00672
  • C25H28F3N3O4 (491.5)
  • Rt=1.97 min. method 5
    • Example 66 (S)-3-(2-cyano-2-hydroxyimino-acetylamino)-tetrahydro-furan-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00673
  • C22H20F3N5O4 (475.4)
  • Rt=2.07 min. method 5
    • Example 67 (S)-6-chloro-pyridine-2-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-amide
  • Figure US20100240669A1-20100923-C00674
  • C25H22ClF3N4O3 (518.9)
  • Rt=2.25 min. method 5
    • Example 68 (S)-5-methoxy-furan-2-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00675
  • C25H24F3N3O5 (503.5)
  • Rt=2.12 min. method 5
    • Example 69 (S)-3-[(3-oxo-cyclohexanecarbonyl)-amino]-tetrahydro-furan-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00676
  • C26H28F3N3O4 (503.5)
  • Rt=2.00 min. method 5
    • Example 70 (S)-6-hydroxy-pyridine-2-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00677
  • C25H23F3N4O4 (500.5)
  • Rt=1.94 min. method 5
    • Example 71 (S)-1-methyl-5-oxo-pyrrolidine-3-carboxylic acid {3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00678
  • C25H27F3N4O4 (504.5)
  • Rt=1.85 min. method 5
    • Example 72 (S)-6-amino-pyridine-2-carboxylic acid {3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00679
  • C25H24F3N5O3 (499.5)
  • Rt=1.72 min. method 5
    • Example 73 (S)-5-hydroxy-1H-pyrazole-3-carboxylic acid {3-[4-(2-trifluoromethyl-phenyl-amino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00680
  • C23H22F3N5O4 (489.5)
  • Rt=1.89 min. method 5
    • Example 74 (S)-pyridazine-3-carboxylic acid {3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00681
  • C24H22F3N5O3 (485.5)
  • Rt=2.02 min. method 5
    • Example 75 (S)-3-[(3-methoxy-cyclobutanecarbonyl)-amino]-tetrahydro-furan-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00682
  • C25H28F3N3O4 (491.5)
  • Rt=2.02 min. method 5
    • Example 76 (S)-6-oxo-piperidine-3-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00683
  • C25H27F3N4O4 (504.5)
  • Rt=1.81 min. method 5
    • Example 77 (S)-4-methyl-pyrimidine-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00684
  • C25H24F3N5O3 (499.5)
  • Rt=1.96 min. method 5
    • Example 78 (S)-3-[(3-oxo-cyclopentanecarbonyl)-amino]-tetrahydrofuran-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00685
  • C25H26F3N3O4 (489.5)
  • Rt=1.97 min. method 5
    • Example 79 (S)-2-methoxy-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-isonicotinamide
  • Figure US20100240669A1-20100923-C00686
  • C26H25F3N4O4 (514.5)
  • Rt=2.11 min. method 5
    • Example 80 (S)-2,4-dimethyl-pyrimidine-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00687
  • C26H26F3N5O3 (513.5)
  • Rt=1.95 min. method 5
    • Example 81 (S)-2-methoxy-pyrimidine-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenyl-amino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00688
  • C25H24F3N5O4 (515.5)
  • Rt=2.04 min. method 5
    • Example 82 (S)-2-methylamino-pyrimidine-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00689
  • C25H25F3N6O3 (514.5)
  • Rt=1.91 min. method 5
    • Example 83 (S)-2-methyl-pyrimidine-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00690
  • C25H24F3N5O3 (499.5)
  • Rt=1.97 min. method 5
    • Example 84 (S)-1-methyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00691
  • C26H25F3N4O4 (514.5)
  • Rt=1.90 min. method 5
    • Example 85 (S)-oxazole-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00692
  • C23H21F3N4O4 (474.4)
  • Rt=1.97 min. method 5
    • Example 86 (S)-2-hydroxy-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-isonicotinamide
  • Figure US20100240669A1-20100923-C00693
  • C25H23F3N4O4 (500.5)
  • Rt=1.85 min. method 5
    • Example 87 (S)-5-hydroxy-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-nicotinamide
  • Figure US20100240669A1-20100923-C00694
  • C25H23F3N4O4 (500.5)
  • Rt=1.72 min. method 5
    • Example 88 (S)-1-methyl-1H-[1.2.3]triazole-4-carboxylic acid {3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00695
  • C23H23F3N6O3 (488.5)
  • Rt=1.99 min. method 5
    • Example 89 (S)-thiazole-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydro-furan-3-yl}-amide
  • Figure US20100240669A1-20100923-C00696
  • C23H21F3N4O3S (490.5)
  • Rt=2.01 min. method 5
    • Example 90 (S)-2-hydroxy-pyrimidine-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenyl-amino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00697
  • C24H22F3N5O4 (501.5)
  • Rt=1.79 min. method 5
    • Example 91 (S)-3-(3,3,3-trifluoro-2-methyl-propionylamino)-tetrahydrofuran-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00698
  • C23H23F6N3O3 (503.4)
  • Rt=2.18 min. method 5
    • Example 92 (S)-5-methoxy-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-nicotinamide
  • Figure US20100240669A1-20100923-C00699
  • C26H25F3N4O4 (514.5)
  • Rt=1.85 min. method 5
    • Example 93 (S)-furan-3-carboxylic acid {3-[4-(2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00700
  • C24H22F3N3O4 (473.4)
  • Rt=2.09 min. method 5
    • Example 94 (S)-furan-2-carboxylic acid {3-[4-(2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00701
  • C24H22F3N3O4 (473.4)
  • Rt=2.08 min. method 5
    • Example 95 (S)—N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-isonicotinamide
  • Figure US20100240669A1-20100923-C00702
  • C25H23F3N4O3 (484.5)
  • Rt=1.71 min. method 5
    • Example 96 (S)-pyrazine-2-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00703
  • C24H22F3N5O3 (485.5)
  • Rt=2.06 min. method 5
    • Example 97 (S)-3-(3-hydroxy-benzoylamino)-tetrahydrofuran-3-carboxylic acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00704
  • C26H24F3N3O4 (499.5)
  • Rt=2.03 min. method 5
    • Example 98 (S)-6-hydroxy-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-nicotinamide
  • Figure US20100240669A1-20100923-C00705
  • C25H23F3N4O4 (500.5)
  • Rt=1.84 min. method 5
    • Example 99 (S)-3-(4-methoxy-benzoylamino)-tetrahydrofuran-3-carboxylic acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00706
  • C27H26F3N3O4 (513.5)
  • Rt=2.16 min. method 5
    • Example 100 (S)-3-(3-methoxy-benzoylamino)-tetrahydrofuran-3-carboxylic acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00707
  • C27H26F3N3O4 (513.5)
  • Rt=2.18 min. method 5
    • Example 101 (S)-3-(2-methoxy-benzoylamino)-tetrahydrofuran-3-carboxylic acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00708
  • C27H26F3N3O4 (513.5)
  • Rt=2.22 min. method 5
    • Example 102 (S)-3-(3,5-dihydroxy-benzoylamino)-tetrahydrofuran-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00709
  • C26H24F3N3O5 (515.5)
  • Rt=1.93 min. method 5
    • Example 103 (S)-3-(3,5-dimethoxy-benzoylamino)-tetrahydrofuran-3-carboxylic acid-4-(2-trifluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00710
  • C28H28F3N3O5 (543.5)
  • Rt=2.20 min. method 5
    • Example 104 (S)-3-(2-pyridin-3-yl-acetylamino)-tetrahydrofuran-3-carboxylic acid-4-(2-tri-fluoromethyl-phenylamino)-benzylamide
  • Figure US20100240669A1-20100923-C00711
  • C26H25F3N4O3 (498.5)
  • Rt=1.64 min. method 5
    • Example 105 (S)-5-amino-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-nicotinamide
  • Figure US20100240669A1-20100923-C00712
  • C25H24F3N5O3 (499.5)
  • Rt=1.65 min. method 5
    • Example 106 (S)-1H-pyrazole-3-carboxylic acid {3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00713
  • C23H22F3N5O3 (473.5)
  • Rt=1.96 min. method 5
    • Example 107 (S)-6-fluoro-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}nicotinamide
  • Figure US20100240669A1-20100923-C00714
  • C25H22F4N4O3 (502.5)
  • Rt=2.10 min. method 5
    • Example 108 1-(3-ethylureido)-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)cyclopropanecarboxamide
  • Figure US20100240669A1-20100923-C00715
  • A solution of 55 mg (0.16 mmol) 1-amine-N-(4-(2-(trifluoromethyl)phenylamino)benzyl)-cyclopropanecarboxamide (from 5a) in 2 mL dichloromethane was combined with 68 μL (0.49 mmol) TEA and 16 μL (0.2 mmol) ethylisocyanate and stirred overnight at ambient temperature. Then ethylisocyanate was added another three times and the mixture was stirred at ambient temperature or at 60° C. Then the reaction mixture was evaporated to dryness in vacuo and purified by RP-HPLC-MS with an eluant gradient (water/acetonitrile=1:1 to 1:20+0.1% trifluoroacetic acid).
  • Yield: 79% of theory
  • C21H23F3N4O2 (420.43)
  • Rt=2.27 min. method 5
    • Example 109 Pyrimidine-5-carboxylic acid-N-(1-(4-(methyl(phenyl)amino)benzylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00716
    • 109a) 4-(aminomethyl)-N-methyl-N-phenylaniline
  • Analogously to method (1c) the title compound was prepared from N-methylaniline and 4-fluorobenzonitrile.
  • C14H16N2 (212.3)
    • 109b) pyrimidine-5-carboxylic acid-N-(1-(4-(methyl(phenyl)amino)benzylcarbamoyl)-cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared starting from 4-(aminomethyl)-N-methyl-N-phenylaniline (from 109a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropane-carboxylic acid (from 1b).
  • C23H23N5O2 (401.47)
  • Rt=2.87 min. method 5
    • Example 110 Pyrimidine-5-carboxylic acid-N-(1-(4-((2-chlorophenyl)(methyl)amino)-benzylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00717
    • 110a) N-(4-(aminomethyl)phenyl)-2-chloro-N-methylaniline
  • Analogously to Example (1c) the title compound was prepared starting from 2-chloro-N-methylaniline and 4-fluorobenzonitrile.
  • C14H15ClN2 (246.74)
    • 110b) pyrimidine-5-carboxylic acid-N-(1-(4-((2-chlorophenyl)(methyl)amino)benzylcarbamoyl)cyclopropyl)amide
  • Analogously to Example (1d) the title compound was prepared starting from N-(4-(aminomethyl)phenyl)-2-chloro-N-methylaniline (from 110a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropane-carboxylic acid (from 1b).
  • C23H22ClN5O2 (435.91)
  • Rt=2.23 min. method 11
    • Example 111 Pyrimidine-5-carboxylic acid-N-(1-(4-(ethyl(phenyl)amino)benzylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00718
    • 111a) 4-(aminomethyl)-N-ethyl-N-phenylaniline
  • Analogously to method (1c) the title compound was prepared starting from N-ethylaniline and 4-fluorobenzonitrile.
  • C15H18N2 (226.32)
    • 111b) pyrimidine-5-carboxylic acid-N-(1-(4-(ethyl(phenvflamino)benzylcarbamoyl)-cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared from 4-(aminomethyl)-N-ethyl-N-phenylaniline (from 111a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropane-carboxylic acid (from 1b).
  • C24H25N5O2 (415.49)
  • Rt=2.26 min. method 11
    • Example 112 Pyrimidine-5-carboxylic acid-N-(1-(4-((4-methoxyphenyl)(methyl)amino)benzylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00719
    • 111a) 4-(aminomethyl)-N-(4-methoxyphenyl)-N-methylaniline
  • Analogously to method (1c) the title compound was prepared starting from 4-methoxy-N-methylaniline and 4-fluorobenzonitrile using Raney nickel.
  • C15H18N2O (242.32)
    • 112b) pyrimidine-5-carboxylic acid-N-(1-(4-((4-methoxyphenyl)(methyl)amino)benzyl-carbamoyl)cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared starting from 4-(aminomethyl)-N-(4-methoxyphenyl)-N-methylaniline (from 112a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropane-carboxylic acid (from 1b).
  • C24H25N5O3 (431.49)
  • Rt=2.13 min. method 11
    • Example 113 Pyrimidine-5-carboxylic acid-N-(1-(4-(methyl(o-tolyl)amino)benzylcarbamoyl)cyclopropyl)amide
  • Figure US20100240669A1-20100923-C00720
    • 113a) N-(4-(aminomethyl)phenyl)-2-chloro-N-methylaniline
  • Analogously to method (1c) N-methyl-o-toluidine and 4-fluorobenzonitrile were reacted using Raney nickel to obtain the title compound.
  • C15H18N2 (226.32)
    • 113b) pyrimidine-5-carboxylic acid-N-(1-(4-(methyl(o-tolyl)amino)benzylcarbamoyl)-cyclopropyl)amide
  • Analogously to method (1d) the title compound was prepared from N-(4-(aminomethyl)phenyl)-2-chloro-N-methylaniline (from 113a) and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropane-carboxylic acid (from 1b).
  • C24H25N5O2 (415.49)
  • Rt=2.26 min. method 11
    • Example 114 Pyrimidine-5-carboxylic acid-{1-[4-(2-cyano-5-fluoro-phenylamino)-benzyl-carbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00721
    • 114a) tert-butyl [4-(2-cyano-5-fluoro-phenylamino)-benzyl]-carbamate
  • Prepared analogously to the method in (55a) from 2-bromo-4-fluoro-benzonitrile and tert-butyl (4-amino-benzyl)-carbamate.
  • Yield: 60% of theory
  • C19H20FN3O2 (341.38)
  • Rt=2.65 min. method 12
    • 114b) 2-(4-aminomethyl-phenylamino)-4-fluoro-benzonitrile di-trifluoroacetate
  • 92 mg (0.27 mmol) tert-butyl [4-(2-cyano-5-fluoro-phenylamino)-benzyl]-carbamate were stirred in 1 mL trifluoroacetic acid and 5 mL dichloromethane for 1 hour at ambient temperature. Then the reaction mixture was evaporated to dryness in vacuo.
  • Yield: 96% of theory
  • C14H12FN3*2C2HF3O2 (469.31)
  • Rt=1.41 min. method 12
    • 114c) pyrimidine-5-carboxylic acid {1-[4-(2-cyano-5-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • 83 mg (0.21 mmol) TBTU, 146 μL (1.0 mmol) triethylamine and 122 mg (0.21 mmol) 2-(4-aminomethyl-phenylamino)-4-fluoro-benzonitrile di-trifluoroacetate were added to a solution of 54 mg (0.26 mmol) 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid in 5 mL DMF. The mixture was stirred overnight at ambient temperature and then the solvents were distilled off in vacuo. The residue was purified by chromatography (RP with eluant gradient, acetonitrile and water with 0.1% trifluoroacetic acid).
  • Yield: 69% of theory
  • C23H19FN6O2 (430.44)
  • Rt=1.91 min. method 12
    • Example 115 Pyrimidine-5-carboxylic acid {1-[4-(2-cyano-3-fluoro-phenylamino)-benzyl-carbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00722
    • 115a) tert-butyl 4-(2-cyano-3-fluoro-phenylamino)-benzyl]-carbamate
  • The title compound was obtained from 2-bromo-6-fluoro-benzonitrile and tert-butyl (4-amino-benzyl)-carbamate analogously to method (55a).
  • C19H20FN3O2 (341.38)
  • Rt=2.65 min. method 12
    • 115b) 2-(4-aminomethyl-phenylamino)-6-fluoro-benzonitrile di-trifluoroacetate
  • The title compound was prepared from tert-butyl [4-(2-cyano-3-fluoro-phenylamino)-benzyl]-carbamate analogously to method (114b).
  • C14H12FN3*2C2HF3O2 (469.31)
  • Rt=1.46 min. method 12
    • 115c) pyrimidine-5-carboxylic acid-{1-[4-(2-cyano-3-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • The title compound was obtained analogously to method (114c) from 2-(4-aminomethyl-phenylamino)-6-fluoro-benzonitrile di-trifluoroacetate and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid.
  • Yield: 44% of theory
  • C23H19FN6O2 (430.44)
  • Rt=1.94 min. method 12
    • Example 116 Pyrimidine-5-carboxylic acid-{1-[4-(2-cyano-6-fluoro-phenylamino)-benzyl-carbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00723
    • 116a) tert-butyl [4-(2-cyano-6-fluoro-phenylamino)-benzyl]-carbamidate
  • The title compound was prepared from 2-bromo-3-fluoro-benzonitrile and tert-butyl (4-amino-benzyl)-carbamate according to method (55a).
  • C19H20FN3O2 (341.38)
  • Rt=2.50 min. method 12
    • 116b) 2-(4-aminomethyl-phenylamino)-3-fluoro-benzonitrile di-trifluoroacetate
  • Preparation of the title compound from tert-butyl [4-(2-cyano-6-fluoro-phenylamino)-benzyl]-carbamate analogously to method (114b).
  • C14H12FN3*2C2HF3O2 (469.31)
  • Rt=1.27 min. method 12
    • 116c) pyrimidine-5-carboxylic acid {1-[4-(2-cyano-6-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • The title compound was prepared analogously to method (114c) from 2-(4-aminomethyl-phenylamino)-3-fluoro-benzonitrile di-trifluoroacetate and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid.
  • C23H19FN6O2 (430.44)
  • Rt=1.78 min. method 12
    • Example 117 Pyrimidine-5-carboxylic acid {1-[4-(4-ethoxy-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00724
    • 117a) 444-ethoxy-2-trifluoromethyl-phenylamino)-benzonitrile
  • 276 mg (2.28 mmol) 4-fluoro-benzonitrile and 550 mg (2.28 mmol) 4-ethoxy-2-trifluoromethyl-phenylamine-hydrochloride were dissolved in 10 mL DMSO and combined with 639 mg (5.69 mmol) potassium-tert-butoxide while cooling with ice. The reaction mixture was stirred overnight at ambient temperature, diluted with water and extracted with diethyl ether. The organic phase was dried on sodium sulphate and evaporated down. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate=9:1).
  • Yield: 20% of theory
  • C16H13F3N2O (306.28)
  • mass spectroscopy [M+H]+=307
    • 117b) (4-aminomethyl-phenyl)-(4-ethoxy-2-trifluoromethyl-phenyl)-amine
  • 140 mg (0.46 mmol) 4-(4-ethoxy-2-trifluoromethyl-phenylamino)-benzonitrile in 10 mL methanolic ammonia were hydrogenated with Raney nickel as catalyst at 50 psi hydrogen pressure. The catalyst was filtered off and the filtrate was freed from the solvent.
  • C16H17F3N2O (310.31)
    • 117c) pyrimidine-5-carboxylic acid {1-[4-(4-ethoxy-2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-cyclopropyl}-amide
  • 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid and (4-aminomethyl-phenyl)-(4-ethoxy-2-trifluoromethyl-phenyl)-amine were refluxed analogously to method (1d). After the end of the reaction the solvent was distilled off and the residue was combined with ethyl acetate, extracted with sodium hydrogen carbonate solution and dried on sodium sulphate. The solution was evaporated down in vacuo and the residue was purified on a silica gel column (dichloromethane/ethanol=19:1)
  • C25H24F3N5O3 (499.49)
  • mass spectroscopy [M+H]+=500
    • Example 118 Pyrimidine-5-carboxylic acid (1-{-4-[4-(2,2-difluoro-ethoxy)-2-trifluoromethyl-phenylamino]-benzylcarbamoyl}-cyclopropyl)-amide hydrochloride
  • Figure US20100240669A1-20100923-C00725
    • 118a) 4-[4-(2,2-difluoro-ethoxy)-2-trifluoromethyl-phenylamino]-benzonitrile
  • The title compound was obtained analogously to method (117a) from 4-fluoro-benzonitrile and 4-(2,2-difluoro-ethoxy)-2-trifluoromethyl-phenylamine.
  • Yield: 32% of theory
  • C16H11F5N2O (342.26)
  • mass spectroscopy [M+H]+=343
    • 118b) (4-aminomethyl-phenyl)-[4-(2,2-difluoro-ethoxy)-2-trifluoromethyl-phenyl]-amine
  • The title compound was prepared analogously to method (117b) from 4-[4-(2,2-difluoro-ethoxy)-2-trifluoromethyl-phenylamino]-benzonitrile.
  • C16H15F5N2O (346.30)
  • mass spectroscopy [M+H−NH3]+=330
    • 118c) pyrimidine-5-carboxylic acid (1-{4-[4-(2,2-difluoro-ethoxy)-2-trifluoromethylphenylamino]-benzylcarbamoyl}-cyclopropyl)-amide hydrochloride
  • (4-aminomethyl-phenyl)-[4-(2,2-difluoro-ethoxy)-2-trifluoromethyl-phenyl]-amine and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid were refluxed analogously to method (1d). The reaction mixture was then purified by chromatography (RP, acetonitrile/water+0.15% formic acid). The fractions containing product were evaporated down, made alkaline with aqueous ammonia solution and extracted with ethyl acetate. Then the organic phases were evaporated down, the residue was dissolved in ethyl acetate, an acid pH was created with hydrochloric acid and the solvent was distilled off.
  • Yield: 56% of theory
  • C25H22F5N5O3*HCl (571.93)
  • Rt=3.96 min method 10
    • Example 119 Pyrimidine-5-carboxylic acid-{1-[4-(4-isopropoxy-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00726
    • 119a) 4-(4-isopropoxy-2-trifluoromethyl-phenylamino)-benzonitrile
  • Prepared analogously to method (117a) from 4-fluoro-benzonitrile and 4-isopropoxy-2-trifluoromethyl-phenylamine.
  • Yield: 37% of theory
  • C17H15F3N2O (320.31)
  • mass spectroscopy [M+H]+=321
    • 119b) (4-aminomethyl-phenyl)-(4-isopropoxy-2-trifluoromethyl-phenyl)-amine
  • The title compound was obtained according to method (117b) from 4-(4-isopropoxy-2-trifluoromethyl-phenylamino)-benzonitrile.
  • C17H19F3N2O (324.34)
  • mass spectroscopy [M+H−NH3]+=308
    • 119c) pyrimidine-5-carboxylic acid {1-[4-(4-isopropoxy-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • (4-aminomethyl-phenyl)-(4-isopropoxy-2-trifluoromethyl-phenyl)-amine and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid were reacted analogously to method (1d).
  • After the chromatographic purification (RP, acetonitrile/water+0.15% formic acid) of the reaction mixture the hydrochloride was prepared as described in method (118c).
  • Yield: 28% of theory
  • C26H26F3N5O3*HCl (549.97)
  • Rt=2.72 min method 14
    • Example 120 Pyrimidine-5-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00727
    • 120a) 3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile
  • While cooling with ice 7.21 g (64.2 mmol) potassium-tert-butoxide were added to a solution of 6.00 g (42.8 mmol) 3,5-difluoro-pyridine-2-carbonitrile and 7.67 g (42.8 mmol) 2-fluoro-6-trifluoromethyl-phenylamine in 240 mL DMSO. The reaction mixture was stirred for 2 hours at ambient temperature, mixed with water and extracted with diethyl ether. The organic phases were dried on sodium sulphate and evaporated down. The residue was purified by chromatography (silica gel, petroleum ether with 0-15% ethyl acetate).
    • 120b) (6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-phenyl)-amine
  • 3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridine-2-carbonitri le was hydrogenated analogously to method (1c). The product obtained was further reacted directly.
    • 120c) pyrimidine-5-carboxylic acid (1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • (6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-phenyl)-amine and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid were reacted analogously to method (1d). For working up solvent was distilled off. Then the residue was mixed with water, made alkaline with potassium carbonate solution and extracted with ethyl acetate. The organic phases were washed with water, dried on sodium sulphate and evaporated down. The crude product remaining was purified by chromatography.
  • C22H17F5N6O2 (492.40)
  • mass spectroscopy [M+H]+=493
    • Example 121 Pyrimidine-5-carboxylic acid-(1-{1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]ethylcarbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00728
    • 121a) 1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone
  • At −25° C. a solution of 2.70 g (9.02 mmol) (6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-phenyl)-amine in 50 mL diethyl ether was added dropwise to 12 mL of a 3 molar methylmagnesium bromide solution in 50 mL diethyl ether. The reaction mixture was heated to 5° C. and then while being cooled combined with 1 molar aqueous hydrochloric acid. Then the organic phase was separated off, dried on sodium sulphate and evaporated down. The residue was used in the next reaction without any further purification.
  • C14H9F5N2O (316.23)
  • mass spectroscopy [M+H]+=317
    • 121b) 1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone-oxime
  • 1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone was reacted analogously to method (40c). For working up the reaction mixture was evaporated down, mixed with water and extracted with ethyl acetate. The organic phases were washed with water and sodium chloride solution and dried on sodium sulphate. After the solvent has been distilled off the residue was purified by chromatography (silica gel, dichloromethane with 2-6% methanol).
  • C14H10F5N3O (331.24)
  • mass spectroscopy [M+H]+=332
    • 121c) 6-(1-amino-ethyl)-5-fluoro-pyridin-3-yl]-(2-fluoro-6-trifluoromethyl-phenyl)-amine
  • The reaction of 1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone-oxime was carried out analogously to method (40d). The crude product was purified by chromatography (silica gel, ethyl acetate with 0-10% methanol/ammonia=9:1).
  • C14H12F5N3 (317.26)
  • mass spectroscopy [M+H]+=318
    • 121d) pyrimidine-5-carboxylic acid-(1-{1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amide
  • 6-(1-amino-ethyl)-5-fluoro-pyridin-3-yl]-(2-fluoro-6-trifluoromethyl-phenyl)-amine and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid were reacted analogously to method (1d). For working up the reaction mixture was evaporated down and made alkaline with potassium carbonate solution. The solid was filtered off, washed with water and dried. Then the residue was purified by chromatography on a silica gel column and the fractions containing product were freed from the solvent. The hydrochloride was obtained by dissolving the residue in an amount of ethyl acetate and combining it with ethereal hydrochloric acid.
  • C23H19F5N6O2*2HCl (579.35)
  • mass spectroscopy [M+H]+=507
  • The (R)- and (S)-enantiomer of Example 121 were obtained by chiral HPLC(SFC) from the racemic compound (column: Deicel AD-H, 250×20 mm, eluant: 80% supercritical carbon dioxide and 20% isopropanol with 0.2% diethylamine, flow rate: 70 mL/min).
    • Example 122 5-amino-N-(1-{1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00729
    • 122a) tert-butyl (1-{1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-carbamate
  • 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid and 6-(1-amino-ethyl)-5-fluoro-pyridin-3-yl]-(2-fluoro-6-trifluoromethyl-phenyl)-amine were reacted and worked up as described in method (121d). In the final chromatographic purification a silica gel column was used (petroleum ether with 30-50% ethyl acetate).
    • 122b) 1-amino-cyclopropanecarboxylic acid-{1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl}-amide
  • 400 mg (0.80 mmol) tert-butyl(1-{1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-carbamate in 10 mL dichloromethane were combined with 3 mL of 4 molar hydrochloric acid in dioxane and stirred for two hours at ambient temperature. Then the solvents were distilled off. The residue was further reacted directly.
    • 122c) 5-amino-N-(1-{1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-nicotinamide
  • 1-amino-cyclopropanecarboxylic acid {1-[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl}-amide dihydrochloride and 5-amino-nicotinic acid were reacted and worked up as described in method (121d). During the chromatographic purification through silica gel dichloromethane with 0-15% methanol was used as eluant.
  • C24H21F5N6O2*2HCl (593.38)
  • mass spectroscopy [M+H]+=521
    • Example 123 Pyrimidine-5-carboxylic acid-(1-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00730
    • 123a) 1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone
  • 39.7 mL of a 1.4 molar methylmagnesium bromide solution in toluene/THF (3:1) and 200 mL diethyl ether were taken and cooled to −30° C. Then 3.90 g (13.9 mmol) 5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile in 100 mL diethyl ether were added and the reaction mixture was left overnight with heating to ambient temperature and with stirring. The reaction mixture was mixed with 1 molar aqueous hydrochloric acid and stirred for some time. The organic phase was separated off, dried on sodium sulphate and evaporated down. The crude product was used in the next reaction without any further purification.
  • C14H10F4N2O2 (298.24)
  • mass spectroscopy [M+H]+=299
    • 123b) 1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone-oxime
  • 1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone was reacted and worked up analogously to method (121b). During the subsequent column chromatography on silica gel dichloromethane/ethanol 50:1 was used as eluant.
  • C14H11F4N3O (313.25)
    • 123c) [6-(1-amino-ethyl)-pyridin-3-yl]-(2-fluoro-6-trifluoromethyl-phenyl)-amine
  • 1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone-oxime was hydrogenated analogously to method (40d). The crude product was purified by chromatography (silica gel, dichloromethane with 2 to 5% methanol/ammonia 10:1).
  • C14H13F4N3 (299.27))
  • Rt=2.76 min. method 7
    • 123d) pyrimidine-5-carboxylic acid (1-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amide
  • [6-(1-amino-ethyl)-pyridin-3-yl]-(2-fluoro-6-trifluoromethyl-phenyl)-amine and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid were reacted analogously to method (1d). For working up the reaction mixture was evaporated down, combined with ethyl acetate and washed with sodium hydrogen carbonate solution. The organic phase was dried on sodium sulphate and the solvent was distilled off. The residue was purified by chromatography (silica gel, dichloromethane/ethanol=50:1).
  • C23H20F4N6O2 (488.44)
  • mass spectroscopy [M+H]+=489
    • Example 124 5-amino-N-(1-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00731
    • 124a) tert-butyl (1-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-carbamate
  • 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid and [6-(1-amino-ethyl)-pyridin-3-yl]-(2-fluoro-6-trifluoromethyl-phenyl)-amine were reacted and worked up as described in method (123d). The crude product was used in the next reaction without being purified by column chromatography.
  • C23H26F4N4O3 (482.47)
  • mass spectroscopy [M+H]+=483
    • 124b) 1-amino-cyclopropanecarboxylic acid {1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl}-amide hydrochloride
  • Reaction of tert-butyl (1-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl-carbamoyl}-cyclopropyl)-carbamate analogously to method (122b).
  • C18H18F4N4O*HCl (418.82)
  • mass spectroscopy [M+H]+=383
    • 124c) 5-amino-N-(1-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl-carbamoyl}-cyclopropyl)-nicotinamide
  • 1-amino-cyclopropanecarboxylic acid {1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]ethyl}-amide hydrochloride and 5-aminonicotinic acid were reacted analogously to method (1d). For working up the reaction mixture was evaporated down, combined with ethyl acetate and washed with sodium hydrogen carbonate solution. The organic phase was dried on sodium sulphate and the solvent was distilled off. The residue was purified by chromatography (silica gel, dichloromethane/ethanol=9:1).
  • C24H22F4N6O2 (502.46)
  • mass spectroscopy [M+H]+=503
    • Example 125 5-amino-N-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00732
    • 125a) tert-butyl (1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-carbamate
  • Reaction of (6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-phenyl)-amine and 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid analogously to method (1d). After the end of the reaction the solution was evaporated down and made alkaline with potassium carbonate solution. The precipitate was filtered off, washed with water and dried.
  • C22H23F5N4O3 (486.44)
    • 125b) 1-amino-cyclopropanecarboxylic acid-{1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl}-amide
  • Tert-butyl (1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-carbamate was reacted analogously to method (122b).
  • C17H15F5N4O*2HCl (459.24)
    • 125c) 5-amino-N-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • 5-amino-nicotinic acid and 1-amino-cyclopropanecarboxylic acid {1-[5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethyl}-amide were reacted as described in method (121d). During the chromatographic purification through silica gel dichloromethane and 0 to 15% methanol were used as eluant.
  • C23H19F5N6O2*2HCl (579.35)
  • mass spectroscopy [M+H]+=507
    • Example 126 Pyrimidine-5-carboxylic acid-(1-{[5-(4-bromo-2-chloro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00733
    • 126a) 5-(4-bromo-2-chloro-phenylamino)-pyridine-2-carbonitrile
  • 250 mg (2.0 mmol) 5-fluoro-pyridine-2-carbonitrile were added at ambient temperature to a solution of 423 mg (2.0 mmol) 4-bromo-2-chloroaniline and 459 mg (4.0 mmol) potassium-tert-butoxide in 4 mL DMSO. The reaction mixture was stirred overnight, then combined with sodium chloride solution and extracted with tert-butyl-methylether. The organic phases were dried on sodium sulphate and evaporated down.
  • C12H7BrClN3 (308.56)
  • mass spectroscopy [M+H]+=308
    • 126b) (6-aminomethyl-pyridin-3-yl)-(4-bromo-2-chloro-phenyl)-amine
  • A solution of 250 mg 5-(4-bromo-2-chloro-phenylamino)-pyridine-2-carbonitrile in 4 mL THF was added dropwise to 0.8 mL of a 2 molar solution of lithium aluminium hydride in THF at ambient temperature. Then the reaction mixture was refluxed for 20 minutes. It was carefully hydrolysed with water and extracted with THF. The organic phases were washed with sodium chloride solution, dried on sodium sulphate and evaporated down. The residue was purified by chromatography (RP, eluant: acetonitrile and water with 0.1% trifluoroacetic acid).
  • C12H11BrClN3 (312.59)
  • mass spectroscopy [M+H]+=311
    • 126c) pyrimidine-5-carboxylic acid-(1-{[5-(4-bromo-2-chloro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Prepared analogously to method (51b) from (6-aminomethyl-pyridin-3-yl)-(4-bromo-2-chloro-phenyl)-amine and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid.
  • C21H18BrClN6O2 (501.76)
  • mass spectroscopy [M+H]+=501
    • Example 127 (S)-pyrimidine-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-amide
  • Figure US20100240669A1-20100923-C00734
  • (S)-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylic acid and N-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)aniline were reacted analogously to method (51b). The final purification was carried out by chromatography (RP, eluant: acetonitrile and water with 0.2% trifluoroacetic acid).
  • C24H22F3N5O3 (485.46)
  • mass spectroscopy (ESI): [M+H]+=486
    • Example 128 Pyridazine-4-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00735
    • 128a) tert-butyl (1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-carbamate
  • Reaction of tert-butyl (1-carbamoyl-cyclopropyl)-carbamate and (6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-phenyl)-amine analogously to method (1d). For working up the reaction mixture was evaporated down and made alkaline with potassium carbonate solution. The product precipitated was filtered off, washed with water and dried.
  • C22H23F5N4O3 (486.44)
  • Rt=2.30 min. method 12
    • 128b) 1-amino-cyclopropanecarboxylic acid [3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide dihydrochloride
  • Tert-butyl (1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-carbamate was reacted as described in method (122b).
  • C17H15F5N4O*2HCl (459.24)
  • Rt=1.50 min. method 12
    • 128c) pyridazine-4-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • 1-amino-cyclopropanecarboxylic acid [3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide dihydrochloride and pyridazine-4-carboxylic acid were reacted analogously to method (1d) and then purified by chromatography (RP, eluant: acetonitrile and water with 0.1% trifluoroacetic acid).
  • Yield: 47% of theory
  • C22H17F5N6O2 (492.40)
  • mass spectroscopy (ESI): [M+H]+=493
  • The following Examples 129 to 137 were prepared analogously to method (128c) from 1-amino-cyclopropanecarboxylic acid [3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide dihydrochloride and the corresponding carboxylic acid.
    • Example 129 2-methoxy-pyrimidine-5-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00736
  • C23H19F5N6O3*C2HF3O2 (636.45)
  • mass spectroscopy (ESI): [M+H]+=523
    • Example 130 N-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-2-hydroxy-isonicotinamide
  • Figure US20100240669A1-20100923-C00737
  • C23H18F5N5O3 (507.41)
  • mass spectroscopy (ESI): [M+H]+=508
    • Example 131 N-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methyl-nicotinamide
  • Figure US20100240669A1-20100923-C00738
  • C24H20F5N5O2 (505.44)
  • mass spectroscopy (ESI): [M+H]+=506
    • Example 132 1-methyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00739
  • C24H20F5N5O3 (521.44)
  • mass spectroscopy (ESI): [M+H]+=522
    • Example 133 2-methylamino-pyrimidine-5-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00740
  • C23H20F5N7O2 (521.44)
  • mass spectroscopy (ESI): [M+H]+=522
    • Example 134 2-methyl-pyrimidine-5-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00741
  • C23H19F5N6O2 (506.43)
  • mass spectroscopy (ESI): [M+H]+=507
    • Example 135 Thiazole-5-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00742
  • C21H16F5N5O2S (497.44)
  • mass spectroscopy (ESI): [M+H]+=498
    • Example 136 6-hydroxy-pyridine-2-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00743
  • C23H18F5N5O3 (507.41)
  • mass spectroscopy (ESI): [M+H]+=508
    • Example 137 Isoxazole-5-carboxylic acid-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00744
  • C21H16F5N5O3 (481.38)
  • mass spectroscopy (ESI): [M+H]+=482
    • Example 138 2-methoxy-pyrimidine-5-carboxylic acid (1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00745
    • 138a) tert-butyl (1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-carbamate
  • Reaction of (6-aminomethyl-pyridin-3-yl)-(4-bromo-2-trifluoromethyl-phenyl)-amine and 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid analogously to method (1d). Then the reaction mixture was evaporated down and the residue was chromatographed (RP, eluant: acetonitrile and water with 0.1% trifluoroacetic acid)
  • C22H24BrF3N4O3 (529.35)
  • mass spectroscopy (ESI): [M+H]+=529
    • 138b) 1-amino-cyclopropanecarboxylic acid [5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide trifluoroacetate
  • 150 mg (0.28 mmol) tert-butyl (1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-carbamate in 2.5 mL dichloromethane were combined with 1 mL trifluoroacetic acid and stirred for one hour at ambient temperature. The solvent was distilled off and the residue was further reacted directly.
  • Yield: 100% of theory
  • C17H16BrF3N4O*C2HF3O2 (543.26)
  • Rt=1.59 min. method 12
    • 138c) 2-methoxy-pyrimidine-5-carboxylic acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • The product was prepared according to method (1d) from 1-amino-cyclopropanecarboxylic acid [5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide trifluoroacetate and 2-methoxy-pyrimidine-5-carboxylic acid.
  • C23H20BrF3N6O3 (565.34)
  • mass spectroscopy (ESI): [M+H]+=565
  • The following Examples 139 to 141 were prepared from 1-amino-cyclopropanecarboxylic acid [5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide trifluoroacetate and the corresponding carboxylic acid according to method (1d).
    • Example 139 2-methyl-pyrimidine-5-carboxylic acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00746
  • C23H20BrF3N6O2 (549.34)
  • mass spectroscopy (ESI): [M+H]+=549
    • Example 140 6-hydroxy-pyridine-2-carboxylic acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00747
  • C23H19BrF3N5O3 (550.33)
  • mass spectroscopy (ESI): [M+H]+=550
    • Example 141 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-hydroxy-nicotinamide
  • Figure US20100240669A1-20100923-C00748
  • C23H19BrF3N5O3 (550.33)
  • mass spectroscopy (ESI): [M+H]+=550
    • Example 142 5-amino-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00749
    • 142a) benzyl 1-[(5-amino-pyridine-3-carbonyl)-amino]-cyclopropanecarboxylate
  • 5-amino-nicotinic acid and benzyl 1-amino-cyclopropanecarboxylate hydrochloride were coupled according to method (1d). For working up the reaction mixture was evaporated down, combined with potassium carbonate solution and extracted with ethyl acetate. The organic phases were washed with water, dried on sodium sulphate and freed from the solvent in vacuo. The residue was chromatographed on a silica gel column (eluant: dichloromethane with 0-10% methanol).
    • 142b) 1-[(5-amino-pyridine-3-carbonyl)-amino]-cyclopropanecarboxylic acid
  • 1.90 g (6.1 mmol) benzyl 1-[(5-amino-pyridine-3-carbonyl)-amino]-cyclopropanecarboxylate were dissolved in 70 mL methanol and hydrogenated with palladium on charcoal (10%) as catalyst at 3 bar hydrogen pressure. The catalyst was filtered off and the filtrate was evaporated down. For purification the residue was stirred with diethyl ether, filtered and dried.
  • Yield: 85% of theory
  • C10H11N3O3 (221.21)
  • mass spectroscopy (ESI): [M+H]+=222
    • 142c) 5-amino-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • 1-[(5-amino-pyridine-3-carbonyl)amino]-cyclopropanecarboxylic acid and (6-aminomethyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)amine were reacted analogously to method (1d). Following the chromatographic purification (RP, eluant: acetonitrile and water with 0.15% formic acid) the fractions containing product were made alkaline with potassium carbonate solution. Then the acetonitrile was distilled off and extracted with ethyl acetate. The organic phases were dried on sodium sulphate, freed from the solvent and triturated with diisopropylether.
  • C23H20F4N6O2 (488.44)
  • mass spectroscopy (ESI): [M+H]+=489
    • Example 143 3H-imidazo[4,5-b]pyridine-6-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00750
    • 143a) benzyl 1-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-cyclopropanecarboxylate
  • Prepared from 3H-imidazo[4,5-b]pyridine-6-carboxylic acid and benzyl 1-amino-cyclopropanecarboxylate hydrochloride analogously to method (142a).
  • C18H16N4O3 (336.35)
  • mass spectroscopy (ESI): [M+H]+=337
    • 143b) 1-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-cyclopropanecarboxylic acid
  • Obtained from the reaction of benzyl 1-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-cyclopropanecarboxylate according to method (142b).
  • C11H10N4O3 (246.22)
  • Rt=1.64 min. method 10
    • 143c) 3H-imidazo[4,5-b]pyridine-6-carboxylic acid (1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • The compound was obtained by reacting 1-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-cyclopropanecarboxylic acid and (6-aminomethyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine analogously to (142c).
  • C24H19F4N7O2 (513.45)
  • mass spectroscopy (ESI): [M+H]+=514
    • Example 144 6-amino-pyrazine-2-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00751
    • 144a) tert-butyl (1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-carbamate
  • 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid and (6-aminomethyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine were coupled with TBTU analogously to method (1d). The reaction mixture was evaporated down, combined with ethyl acetate and washed with sodium hydrogen carbonate solution. Then the organic phase was dried on sodium sulphate and freed from the solvent. The residue was purified on a silica gel column with dichloromethane/ethanol as eluant in the ratio 1:50 to 1:20.
  • C22H24F4N4O3 (468.45)
  • mass spectroscopy (ESI): [M+H]+=469
    • 144b) 1-amino-cyclopropanecarboxylic acid [5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide hydrochloride
  • 1.00 g (2.14 mmol) tert-butyl (1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-carbamate were dissolved in 30 mL dioxane and after the addition of 3.2 mL 4 molar hydrochloride solution in dioxane stirred overnight at ambient temperature. The solvent was distilled off in vacuo and the residue was further reacted directly.
  • C17H16F4N4O*HCl (404.79)
  • mass spectroscopy (ESI): [M+H]+=369
    • 144c) 6-amino-pyrazine-2-carboxylic acid (1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Obtained analogously to method (142c) from 1-amino-cyclopropanecarboxylic acid [5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide hydrochloride and 6-amino-pyrazine-2-carboxylic acid.
  • C22H19F4N7O2 (489.43)
  • mass spectroscopy (ESI): [M+H]+=490
    • Example 145 2-methylamino-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00752
    • 145a) tert-butyl (1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-carbamate
  • 1-(tert-butoxycarbonyl-amino)-cyclopropanecarboxylic acid and (6-aminomethyl-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-amine were coupled as described in method (1d). For working up the reaction mixture was mixed with water and extracted with dichloromethane. The organic phases were dried on sodium sulphate and evaporated down.
  • C22H24ClF3N4O3 (484.90)
  • Rt=2.23 min. method 12
    • 145b) 1-amino-cyclopropanecarboxylic acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide trifluoroacetate
  • 906 mg (1.40 mmol) tert-butyl (1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-carbamate in 5 mL dichloromethane were combined with 2 mL trifluoroacetic acid and stirred for one hour at ambient temperature. Then the solvent was distilled off in vacuo and the residue was reacted without any further purification.
  • C17H16ClF3N4O*C2HF3O2 (498.81)
  • Rt=1.54 min. method 12
    • 145c) 2-methylamino-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • 1-amino-cyclopropanecarboxylic acid [5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide trifluoroacetate and 2-methylamino-pyrimidine-5-carboxylic acid were reacted analogously to method (1d). Then the reaction mixture was purified by chromatography (RP, eluant: acetonitrile and water with 0.1% trifluoroacetic acid).
  • C23H21ClF3N17O2 (519.91)
  • mass spectroscopy (ESI): [M+H]+=520
  • Examples 146 to 149 were prepared analogously from 1-amino-cyclopropanecarboxylic acid [5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide and the corresponding carboxylic acid.
    • Example 146 2-methoxy-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00753
  • C23H20ClF3N6O3 (520.89)
  • mass spectroscopy (ESI): [M+H]+=521
    • Example 147 2-methyl-pyrimidine-5-carboxylic acid (1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00754
  • C23H20ClF3N6O2 (504.89)
  • mass spectroscopy (ESI): [M+H]+=505
    • Example 148 1-methyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00755
  • C24H21ClF3N5O3 (519.90)
  • mass spectroscopy (ESI): [M+H]+=520
  • Rt=1.74 min. method 13
    • Example 149 Thiazole-5-carboxylic acid (1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00756
  • C21H17ClF3N5O2S (495.91)
  • mass spectroscopy (ESI): [M+H]+=496
  • Rt=1.84 min. method 13
    • Example 150 3-amino-isoxazole-5-carboxylic acid (1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00757
  • Prepared according to method (142c) from 1-amino-cyclopropanecarboxylic acid [5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide hydrochloride and 3-amino-isoxazole-5-carboxylic acid.
  • C21H18F4N6O3 (478.40)
  • mass spectroscopy (ESI): [M+H]+=479
    • Example 151 Pyrimidine-5-carboxylic acid (1-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide dihydrochloride
  • Figure US20100240669A1-20100923-C00758
  • 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid and (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine were reacted analogously to method (1d). The reaction mixture was evaporated down, combined with potassium carbonate solution and extracted with ethyl acetate. The organic phases were washed with water and sodium chloride solution, dried on sodium sulphate and freed from the solvent. After the chromatographic purification of the residue (RP, eluant: water and acetonitrile with formic acid) the fractions containing product were made alkaline with ammonia, the acetonitrile was distilled off and the remainder was extracted with ethyl acetate. The product was precipitated from the organic solution with ethereal hydrochloride solution after drying with sodium sulphate.
  • C22H17F5N6O2*2HCl (565.32)
  • mass spectroscopy (ESI): [M+H]+=493
    • Example 152 5-amino-N-(1-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide dihydrochloride
  • Figure US20100240669A1-20100923-C00759
  • Obtained analogously to the method of Example 147 from 5-amino-nicotinic acid and 1-amino-cyclopropanecarboxylic acid-[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide. In the chromatographic purification, however, a silica gel column was used (eluant: dichloromethane with 5 to 12% methanol).
  • C23H19F5N6O2*2HCl (579.35)
  • mass spectroscopy (ESI): [M+H]+=507
    • Example 153 (S)-pyrimidine-5-carboxylic acid (3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydro-furan-3-yl)-amide dihydrochloride
  • Figure US20100240669A1-20100923-C00760
  • Prepared from (S)-3-(pyrimidine-5-carboxamido)tetrahydrofuran-3-carboxylic acid and (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine analogously to Example 150. The column chromatographic purification used a silica gel column and dichloromethane with 0 to 7% methanol as eluant.
  • C23H19F5N6O3*2HCl (595.35)
  • mass spectroscopy (ESI): [M+H]+=523
    • Example 154 (S)-5-amino-N-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00761
    • 154a) butyl (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylate
  • 5-amino-nicotinic acid and butyl (S)-3-amino-tetrahydrofuran-3-carboxylate were coupled with TBTU analogously to method (1d). For working up the reaction mixture was evaporated down, combined with potassium carbonate solution and extracted with ethyl acetate. The organic phases were washed with water and sodium chloride solution, dried on sodium sulphate and freed from the solvent. The residue was chromatographed on a silica gel column (eluant: dichloromethane with 5 to 10% methanol).
  • C15H21N3O4 (307.35)
  • mass spectroscopy (ESI): [M+H]+=308
    • 154b) (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydro-furan-3-carboxylic acid
  • 2.45 g (7.97 mmol) butyl (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylate in 50 mL methanol were combined with 16 mL 1 molar sodium hydroxide solution and stirred for one hour at ambient temperature. After the addition of 16 mL of 1 molar hydrochloric acid the solvents were distilled off in vacuo. The residue was dissolved in ethanol and the inorganic salts were filtered off. Then the filtrate was evaporated down.
  • Yield: 99% of theory
  • C11H13N3O4 (251.24)
  • mass spectroscopy (ESI): [M+H]+=252
    • 154c) (S)-5-amino-N-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide-dihydrochloride
  • (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid and (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine were reacted and purified as described in method (154a). Following the chromatographic purification the product was dissolved in ethyl acetate and precipitated with ethereal hydrochloride solution.
  • C24H21F5N6O3*2HCl (609.38)
  • mass spectroscopy (ESI): [M+H]+=537
    • Example 155 (S)-pyrimidine-5-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00762
  • A solution of 64 mg (0.27 mmol) (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetra-hydrofuran-3-carboxylic acid, 93 mg (0.28 mmol) O-[(ethoxycarbonyl)cyano-methyleneamino]-N,N,N′,N′-tetramethyluronium-tetrafluoroborate (TOTU) and 139 μL (0.81 mmol) DIPEA in 1 mL DMF was stirred for 1 hour at ambient temperature, then combined with 144 mg (0.41 mmol) N-(4-(aminomethyl)phenyl)-2-(trifluoromethyl)aniline and left to stand overnight. Then the mixture was purified by chromatography (RP with gradient, eluant: acetonitrile and water with 0.2% trifluoroacetic acid).
  • Yield: 18% of theory
  • C24H22F3N5O3 (485.46)
  • mass spectroscopy (ESI): [M+H]+=486
  • Rt=2.15 min. method 12
    • Example 156 (S)-5-amino-N-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide dihydrochloride
  • Figure US20100240669A1-20100923-C00763
  • (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid and (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine were reacted and purified as described in method (154a). Following the chromatographic purification the product was dissolved in ethyl acetate and precipitated with ethereal hydrochloride solution.
  • C24H21F5N6O3*2HCl (609.38)
  • mass spectroscopy (ESI): [M+H]+=537
    • Example 157 (S)-5-amino-N-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00764
  • Obtained from (S)-3-[(5-amino-pyridine-3-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid and (6-aminomethyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine according to method (142c).
  • C24H22F4N6O3 (518.46)
  • mass spectroscopy (ESI): [M+H]+=519
    • Example 158 (S)-pyrimidine-5-carboxylic acid-(3-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide dihydrochloride
  • Figure US20100240669A1-20100923-C00765
  • Prepared analogously to method (154a) from (S)-3-[(pyrimidine-5-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid and (6-aminomethyl-5-fluoro-pyridin-3-yl)-(2-fluoro-6-trifluoromethyl-phenyl)-amine.
  • C23H19F5N6O3*2HCl (595.35)
  • mass spectroscopy (ESI): [M+H]+=523
    • Example 159 (S)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydro-furan-3-yl)-amide
  • Figure US20100240669A1-20100923-C00766
    • 159a) butyl (S)-3-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-tetrahydro-furan-3-carboxylate
  • Prepared from 3H-imidazo[4,5-b]pyridine-6-carboxylic acid and butyl (S)-3-amino-tetrahydrofuran-3-carboxylate as described in method (154a), with no chromatographic purification.
  • C16H20N4O4 (332.36)
  • Rt=1.99 min. method 13
    • 159b) (S)-3-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-tetrahydro-furan-3-carboxylic acid
  • 400 mg (1.20 mmol) butyl (S)-3-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-tetrahydrofuran-3-carboxylate were dissolved in 10 mL THF and 5 mL ethanol, combined with 1.2 mL 2 molar lithium hydroxide solution and stirred overnight at ambient temperature. Then the solvents were distilled off and the residue was combined with 2.4 mL 1 molar aqueous hydrochloric acid. The mixture was evaporated down in vacuo and residual water was eliminated by repeated azeotropic distillation with ethanol.
  • C12H12N4O4 (276.25)
  • mass spectroscopy (ESI): [M−H]+=275
    • 159c) (S)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Prepared from (S)-3-[(3H-imidazo[4,5-b]pyridine-6-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid and (6-aminomethyl-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine analogously to method (154a).
  • C25H21F4N7O3 (543.47)
  • mass spectroscopy (ESI): [M+H]+=544
    • Example 160 Pyrimidine-5-carboxylic acid-(1-{[5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00767
    • 160a) tert-butyl (5-bromo-3-fluoro-pyridin-2-ylmethyl)-carbamate
  • 581 mg (2.41 mmol) C-(5-bromo-3-fluoro-pyridin-2-yl)-methylamine were dissolved in 5 mL triethylamine and 1.5 mL water and while the mixture was being cooled with the ice bath 630 mg (2.89 mmol) di-tert-butyl-dicarbonate were added. Then the reaction mixture was stirred overnight. The solvent was distilled off and the residue was purified by chromatography (RP with eluant gradient, eluant: acetonitrile and water with 0.2% trifluoroacetic acid). The fractions containing product were neutralised with triethylamine and evaporated down.
  • Yield: 40% of theory
  • C11H14BrFN2O2 (305.14)
  • Rt=2.29 min. method 12
    • 160b) tert-butyl[5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamate
  • 132 mg (0.97 mmol) 2-amino-5-fluorobenzonitrile and 295 mg (0.97 mmol) tert-butyl (5-bromo-3-fluoro-pyridin-2-ylmethyl)-carbamate were reacted and worked up analogously to method (55a).
  • Yield: 15% of theory
  • C18H18F2N4O2 (360.36)
  • Rt=2.35 min. method 12
    • 160c) 2-(6-aminomethyl-5-fluoro-pyridin-3-ylamino)-5-fluoro-benzonitrile-trifluoroacetate
  • 51 mg (0.14 mmol) tert-butyl [5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamate were stirred with 1.5 mL trifluoroacetic acid and 2.5 mL dichloromethane for 3 hours at ambient temperature. Then the reaction mixture was evaporated down in vacuo and further reacted directly.
  • Yield: 94% of theory
  • C13H10F2N4*C2HF3O2 (374.27)
  • Rt=1.17 min. method 12
    • 160d) pyrimidine-5-carboxylic acid-(1-{[5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • 28 mg (0.13 mmol) 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid and 50 mg (0.13 mmol) 2-(6-aminomethyl-5-fluoro-pyridin-3-ylamino)-5-fluoro-benzonitrile were reacted with TBTU using DMF as solvent analogously to method (1d).
  • Yield: 50% of theory
  • C22H17F2N7O2 (449.13)
  • mass spectroscopy (ESI): [M+H]+=450
  • Rt=1.67 min. method 12
    • Example 161 Pyrimidine-5-carboxylic acid {1-[4-(2-cyano-4-trifluoromethoxy-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00768
    • 161a) tert-butyl (4-bromo-benzyl)-carbamate
  • 2.35 g (11 mmol) di-tert-butyl-dicarbonate in 20 mL dichloromethane were added dropwise to a solution of 2.00 g (8.99 mmol) 4-bromobenzylamine hydrochloride and 6.26 mL triethylamine in 30 mL dichloromethane while being cooled with the ice bath. Then the mixture was stirred overnight and then evaporated down. The residue was dissolved in ethyl acetate, acidified with citric acid and then washed with water and sodium hydrogen carbonate solution. The organic phase was dried on sodium sulphate and freed from the solvent.
  • Yield: 96% of theory
  • C12H16BrNO2 (286.17)
  • mass spectroscopy (ESI): [M+H]+=286
    • 161b) tert-butyl [4-(2-cyano-4-trifluoromethoxy-phenylamino)-benzyl]-carbamate
  • Tert-butyl (4-bromo-benzyl)-carbamate and 2-amino-5-trifluoromethoxy-benzonitrile were reacted analogously to method (55a).
  • C20H20F3N3O3 (407.39)
  • mass spectroscopy (ESI): [M+H]+=408
  • Rt=4.63 min. method 13
    • 161c) 2-(4-aminomethyl-phenylamino)-5-trifluoromethoxy-benzonitrile-trifluoroacetate
  • To cleave the protective group tert-butyl [4-(2-cyano-4-trifluoromethoxy-phenylamino)-benzyl]-carbamate was treated with trifluoroacetic acid in dichloromethane. Then the solvent was distilled off and the residue was chromatographed (RP with eluant gradient, eluant: acetonitrile and water with 0.2% trifluoroacetic acid).
  • C15H12F3N3O*C2HF3O2 (421.29)
  • mass spectroscopy (ESI): [M+H]+=308
  • Rt=2.45 min. method 13
    • 161d) pyrimidine-5-carboxylic acid-{1-[4-(2-cyano-4-trifluoromethoxy-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • 166 mg (0.39 mmol) of 2-(4-aminomethyl-phenylamino)-5-trifluoromethoxy-benzonitrile-trifluoroacetate and 82 mg (0.39 mmol) 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid were coupled analogously to method (1d).
  • Yield: 33% of theory
  • C24H19F3N6O3 (496.44)
  • mass spectroscopy (ESI): [M+H]+=497
  • Rt=2.24 min. method 13
    • Example 162 Pyrimidine-5-carboxylic acid {1-[4-(4-chloro-2-cyano-phenylamino)-benzyl-carbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00769
  • Prepared by the same reaction sequence (Buchwald reaction, cleaving of protective group, amide linking) as in Example 161 starting from tert-butyl (4-bromobenzyl)-carbamate.
  • C23H19ClN6O2 (446.89)
  • mass spectroscopy (ESI): [M+H]+=447
  • Rt=2.10 min. method 13
    • Example 163 (S)-pyrimidine-5-carboxylic acid (3-{1-[5-(4-chloro-2-trifluoromethyl-phenyl-amino)-pyridin-2-yl]-ethylcarbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00770
    • 163a) 1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone
  • 500 mg (1.68 mmol) 5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile in 5 mL diethyl ether were added dropwise at −5° C. to a solution of 2.2 mL of 3 molar methylmagnesium bromide in diethyl ether. The reaction mixture was hydrolysed with ammonium chloride solution and combined with 1 molar hydrochloric acid and tert-butylmethylether. The organic phase was separated off, dried on sodium sulphate and evaporated down
  • Yield: 50% of theory
  • C14H10ClF3N2O (314.69)
  • mass spectroscopy (ESI): [M+H]+=315
    • 163b) 1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone-oxime
  • 266 mg (0.85 mmol) 1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone, 73 mg (1.04 mmol) hydroxylamine-hydrochloride and 238 μL (1.69 mmol) triethylamine were refluxed overnight in 15 mL acetonitrile with stirring. Then the reaction mixture was mixed with water and extracted with dichloromethane. The organic phase was dried on sodium sulphate and evaporated down. The residue was used in the next reaction without any further purification.
  • Yield: 79% of theory
  • C14H11ClF3N3O (329.71)
  • Rt=2.27 min. method 12
    • 163c) [6-(1-amino-ethyl)-pyridin-3-yl]-(4-chloro-2-trifluoromethyl-phenyl)-amine
  • 220 mg (0.67 mmol) 1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone-oxime in 1 mL methanol were mixed batchwise with 50 mg zinc powder and 1.1 mL of 4 molar hydrochloric acid in methanol and then refluxed for 3 hours with stirring. Then water was added to the mixture and it was extracted with dichloromethane. The organic phases were dried on sodium sulphate and evaporated down.
  • Yield: 62% of theory
  • C14H13ClF3N3 (315.72)
  • Rt=1.76 min. method 12
    • 163d) (S)-pyrimidine-5-carboxylic acid-(3-{1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-tetrahydrofuran-3-yl)-amide
  • The compound was obtained from (S)-3-[(pyrimidine-5-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid and [6-(1-amino-ethyl)-pyridin-3-yl]-(4-chloro-2-trifluoromethyl-phenyl)-amine analogously to method (51b).
  • C24H22ClF3N6O3 (534.93)
  • mass spectroscopy (ESI): [M+H]+=535
  • Rt=1.86 min. method 12
    • Example 164 Pyrimidine-5-carboxylic acid (1-{1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amide trifluoroacetate
  • Figure US20100240669A1-20100923-C00771
  • Obtained analogously to method (1d) from [6-(1-amino-ethyl)-pyridin-3-yl]-(4-chloro-2-trifluoromethyl-phenyl)-amine and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid.
  • C23H20ClF3N6O2*C2HF3O2 (618.92)
  • mass spectroscopy (ESI): [M+H]+=505
  • Rt=1.84 min. method 12
    • Example 165 tert-butyl [5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamate
  • Figure US20100240669A1-20100923-C00772
    • 165a) tert-butyl [5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamate
  • Prepared analogously to method (55a) from tert-butyl (5-bromo-3-fluoro-pyridin-2-ylmethyl)-carbamate and 4-chloro-2-trifluoromethyl-phenylamine.
  • C18H18ClF4N3O2 (419.80)
  • mass spectroscopy (ESI): [M+H]+=420
    • 165b) (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-amine hydrochloride
  • 50 mg (0.12 mmol) tert-butyl [5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamate in 3 mL dioxane were combined with 2 mL of semi-concentrated hydrochloric acid and stirred for two hours at 60° C. After evaporation of the reaction mixture residual water was eliminated by azeotropic distillation with toluene.
  • Rt=1.73 min. method 12
    • 165c) tert-butyl [5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamate
  • Prepared from (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-chloro-2-trifluoromethyl-phenyl)-amine hydrochloride and 1-[(pyrimidine-5-carbonyl)amino]-cyclopropanecarboxylic acid analogously to method (1d).
  • C22H17ClF4N6O2 (508.86)
  • mass spectroscopy (ESI): [M+H]+=509
  • Rt=2.12 min. method 12
    • Example 166 Pyrimidine-5-carboxylic acid-(1-{[5-(2,4-dichloro-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00773
    • 166a) 5-(2,4-dichloro-phenylamino)-pyridine-2-carbonitrile
  • 1.33 g (8.2 mmol) 2,4-dichloroaniline in 30 mL DMSO were combined with 1.38 g (12.3 mmol) potassium-tert-butoxide and stirred for one hour at ambient temperature. Then 1.00 g (8.2 mmol) of 2-cyano-5-fluoropyridine in 20 mL DMSO was added and the mixture was stirred for a further six hours. It was diluted with dichloromethane, washed with sodium chloride solution, dried on sodium sulphate and evaporated down. The residue was chromatographed on a silica gel column (eluant: petroleum ether/ethyl acetate=4:1).
  • Yield: 44% of theory
  • C12H7Cl2N3 (264.11)
  • Rt=2.46 min. method 12
    • 166b) (6-aminomethyl-pyridin-3-yl)-(2,4-dichloro-phenyl)-amine
  • 3.56 mL of a 2 molar solution of lithium aluminium hydride in THF were added at −10° C. to 0.94 g (3.6 mmol) 5-(2,4-dichloro-phenylamino)-pyridine-2-carbonitrile in 60 mL THF. The mixture was stirred for 30 minutes at ambient temperature, then mixed with water and filtered. The solid was washed with THF and the filtrate was evaporated to dryness.
  • C12H11Cl2N3 (268.14)
  • mass spectroscopy (ESI): [M+H]+=268
    • 166c) pyrimidine-5-carboxylic acid-(1-{[5-(2,4-dichloro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Obtained from (6-aminomethyl-pyridin-3-yl)-(2,4-dichloro-phenyl)-amine and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid analogously to method (1d).
  • C21H18Cl2N6O2 (457.31)
  • mass spectroscopy (ESI): [M+H]+=457
    • Example 167 Pyrimidine-5-carboxylic acid (1-{[5-(2-bromo-4-chloro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00774
    • 167a) 5-(2-bromo-4-chloro-phenylamino)-pyridine-2-carbonitrile
  • Prepared from 2-bromo-4-chloroaniline and 2-cyano-5-fluoropyridine analogously to (166a).
  • C12H7BrClN3 (308.56)
  • mass spectroscopy (ESI): [M+H]+=308
    • 167b) (6-aminomethyl-pyridin-3-yl)-(2-bromo-4-chloro-phenyl)-amine-trifluoroacetate
  • 5-(2-bromo-4-chloro-phenylamino)-pyridine-2-carbonitrile was reduced analogously to method (166b) with lithium aluminium hydride. The subsequent purification, however, was carried out by chromatography (RP with eluant gradient, eluant: acetonitrile and water with 0.1% trifluoroacetic acid).
  • C12H11BrClN3 (312.59)
  • mass spectroscopy (ESI): [M+H]+=312
    • 167c) pyrimidine-5-carboxylic acid-(1-{[5-(2-bromo-4-chloro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Prepared analogously to method (1d) from (6-aminomethyl-pyridin-3-yl)-(2-bromo-4-chloro-phenyl)-amine-trifluoroacetate and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid.
  • C21H18BrClN6O2 (501.76)
  • mass spectroscopy (ESI): [M+H]+=501
    • Example 168 6-methylamino-pyrazine-2-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00775
  • 61 mg (0.40 mmol) 6-methylamino-pyrazine-2-carboxylic acid, 162 mg (0.40 mmol) 1-amino-cyclopropanecarboxylic acid [5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide hydrochloride and 167 μL (1.20 mmol) triethylamine were placed in 7 mL THF and 1 mL DMF, combined with 154 mg (0.48 mmol) TBTU and then stirred for 4 days at ambient temperature. The THF was distilled off and the residue was purified by chromatography (RP with eluant gradient, eluant: water and acetonitrile with formic acid). Then the fractions containing product were made alkaline with potassium carbonate solution. The acetonitrile was distilled off and the residue was extracted with ethyl acetate. The organic phases were dried on sodium sulphate, freed from the solvent and triturated with diisopropylether.
  • Yield: 34% of theory
  • C23H21F4N7O2 (503.45)
  • mass spectroscopy (ESI): [M+H]+=504
    • Example 169 2-amino-oxazole-5-carboxylic acid (1-{[5-(4-fluoro-2-trifluoromethyl-phenyl-amino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00776
    • 169a) tert-butyl [5-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropylcarbamoyl)-oxazol-2-yl]-carbamate
  • Obtained from 2-tert-butoxycarbonylamino-oxazole-5-carboxylic acid and 1-amino-cyclo-propanecarboxylic acid [5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide hydrochloride analogously to the method for Example 168. However, in the working up, no chromatographic purification was carried out.
  • C26H26F4N6O5 (578.52)
  • Rt=3.19 min. method 14
    • 169b) 2-amino-oxazole-5-carboxylic acid (1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • The protective group of the compound tert-butyl [5-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropylcarbamoyl)-oxazol-2-yl]-carbamate was cleaved using the method described for intermediate step (144b).
  • C21H18F4N6O3 (478.40)
  • mass spectroscopy (ESI): [M+H]+=479
  • Rt=2.71 min. method 7
    • Example 170 1-(2-cyano-2-methyl-acetylamino)-cyclopropanecarboxylic acid [5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00777
  • Reaction of 40 mg (0.40 mmol) cyanomethyl-acetic acid and 162 mg (0.40 mmol) 1-amino-cyclopropanecarboxylic acid [5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide hydrochloride analogously to the method for Example 168.
  • Yield: 28% of theory
  • C21H19F4N5O2 (449.40)
  • mass spectroscopy (ESI): [M+H]+=450
  • Rt=3.03 min. method 7
    • Example 171 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-2-hydroxy-isonicotinamide
  • Figure US20100240669A1-20100923-C00778
  • 150 mg (0.165 mmol) of 1-amino-cyclopropanecarboxylic acid [5-(4-bromo-2-tri-fluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide tri-trifluoroacetate were added to a solution of 23 mg (0.165 mmol) 2-hydroxyisonicotinic acid, 56 mg (0.174 mmol) TBTU and 114 μL (0.661 mol) DIPEA in 0.5 mL DMF after 5 minutes stirring at ambient temperature. Then the reaction mixture was left to stand overnight and then chromatographed (RP with gradient, eluant: acetonitrile and water with 0.2% trifluoroacetic acid).
  • Yield: 69% of theory
  • C23H19BrF3N6O3 (550.33)
  • mass spectroscopy (ESI): [M+H]+=550
  • Rt=1.73 min. method 12
  • The following Examples 172 to 179 were prepared analogously from 1-amino-cyclopropanecarboxylic acid-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide tri-trifluoroacetate and the corresponding acids.
    • Example 172 Thiazole-5-carboxylic acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00779
  • Yield: 94% of theory
  • C21H17BrF3N5O2S (540.36)
  • mass spectroscopy (ESI): [M+H]+=540
  • Rt=1.88 min. method 12
    • Example 173 6-amino-N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide trifluoroacetate
  • Figure US20100240669A1-20100923-C00780
  • Yield: 89% of theory
  • C23H20BrF3N6O2*C2HF3O2 (663.37)
  • mass spectroscopy (ESI): [M+H]+=549
    • Example 174 Pyridazine-4-carboxylic acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00781
  • Yield: 71% of theory
  • C22H18BrF3N6O2 (535.32)
  • mass spectroscopy (ESI): [M+H]+=535
  • Rt=1.80 min. method 12
    • Example 175 2-dimethylamino-pyrimidine-5-carboxylic acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00782
  • Yield: 67% of theory
  • C24H23BrF3N7O2 (578.39)
  • mass spectroscopy (ESI): [M+H]+=578
  • Rt=1.99 min. method 12
    • Example 176 2,6-dihydroxy-pyrimidine-4-carboxylic acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00783
  • Yield: 46% of theory
  • C22H18BrF3N6O4 (567.32)
  • mass spectroscopy (ESI): [M+H]+=567
  • Rt=1.74 min. method 12
    • Example 177 1-methyl-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00784
  • Yield: 71% of theory
  • C24H2113CF3N5O3 (564.36)
  • mass spectroscopy (ESI): [M+H]+=564
  • Rt=1.78 min. method 12
    • Example 178 5-amino-N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00785
  • Yield: 99% of theory
  • C23H20BrF3N6O2*C2HF3O2 (663.37)
  • mass spectroscopy (ESI): [M+H]+=549
  • Rt=1.68 min. method 12
    • Example 179 Pyrimidine-5-carboxylic acid (1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00786
    • 179a) 5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridine-2-carbonitrile
  • Obtained from 2-cyano-3,5-difluoropyridine and 4-bromo-2-trifluoromethyl-phenylamine analogously to method (40a).
  • C13H6BrF4N3 (360.11)
  • mass spectroscopy (ESI): [M+H]+=360
  • Rt=2.68 min. method 12
    • 179b) (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-bromo-2-trifluoromethyl-phenyl)-amine
  • 171 mg (0.48 mmol) 5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridine-2-carbonitrile were dissolved in 3 mL pyridine, 1.5 mL glacial acetic acid and 1.5 mL water and combined with 459 mg (5.22 mmol) sodium hypophosphite and Raney nickel. Then the mixture was hydrogenated for three hours at 55° C. and 3 bar hydrogen pressure. The catalyst was filtered off, the filtrate was evaporated to dryness and the residue was purified by chromatography (RP with gradient, eluant: acetonitrile and water with 0.2% trifluoroacetic acid).
  • C13H10BrF4N3 (364.14)
  • mass spectroscopy (ESI): [M+H]+=364
  • Rt=1.79 min. method 13
    • 179c) pyrimidine-5-carboxylic acid (1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • 54 mg (0.26 mmol) 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid, 36 μL triethylamine and 105 mg (0.31 mmol) TBTU in 4 mL DMF were stirred for 5 minutes at ambient temperature and then combined with another 144 μL triethylamine and 95 mg (0.26 mmol) (6-aminomethyl-5-fluoro-pyridin-3-yl)-(4-bromo-2-trifluoromethyl-phenyl)-amine. The reaction mixture was stirred overnight and then evaporated to dryness. The residue was purified by chromatography (RP with gradient, eluant: acetonitrile and water with 0.2% trifluoroacetic acid).
  • C22H17BrF4N6O2 (553.31)
  • mass spectroscopy (ESI): [M+H]+=553
  • Rt=2.20 min. method 13
    • Example 180 Pyrimidine-5-carboxylic acid-(1-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00787
    • 180a) 1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone
  • A solution of 3.27 g (9.56 mmol) 5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile in 100 mL diethyl ether was added dropwise to 5.42 mL 3 molar methylmagnesium bromide in diethyl ether while being cooled with the ice bath. Then the reaction mixture was allowed to come up to ambient temperature and stirred for another hour. The mixture was combined with 2.5 mL 1 molar hydrochloric acid and then evaporated to dryness. The residue was purified by chromatography (RP with gradient, eluant: acetonitrile and water with 0.2% trifluoroacetic acid).
  • C14H10BrF3N2O (359.14)
  • Rt=2.57 min. method 12
    • 180b) 1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone-oxime
  • 702 mg (1.96 mmol) 1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethanone, 182 mg hydroxylamine-hydrochloride and 549 μl (3.91 mmol) triethylamine in 25 mL acetonitrile were refluxed for 1.5 hours. The solvent was distilled off and the residue was combined with dichloromethane and triethylamine and filtered through silica gel. The filtrate was freed from the solvent and used directly in the next reaction. 870 mg product.
    • 180c) [6-(1-amino-ethyl)-pyridin-3-yl]-(4-bromo-2-trifluoromethyl-phenyl)-amine trifluoroacetate
  • A solution of 870 mg (approx. 85%, 2.0 mmol) 1-[5-(4-bromo-2-trifluoromethyl-phenyl-amino)-pyridin-2-yl]-ethanone-oxime in 20 mL methanol was combined with 6 mL 10 molar hydrochloric acid in methanol and 567 mg zinc and refluxed for 3 hours. Then the mixture was filtered and the filtrate was freed from the solvent. The residue was purified by chromatography (RP with gradient, eluant: acetonitrile and water with 0.2% trifluoroacetic acid).
  • Yield: 78% over two steps
  • C14H13BrF3N3 (360.17)
  • mass spectroscopy (ESI): [M+H]+=360
  • Rt=1.83 min. method 12
    • 180d) pyrimidine-5-carboxylic acid-(1-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amide
  • Analogously to method (179c) from 190 mg (0.92 mmol) 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid and 330 mg (0.69 mmol) [6-(1-amino-ethyl)-pyridin-3-yl]-(4-bromo-2-trifluoromethyl-phenyl)-amine trifluoroacetate.
  • Yield: 55% of theory
  • C23H20BrF3N6O2—C2HF3O2 (663.37)
  • mass spectroscopy (ESI): [M+H]+=549
  • Rt=1.92 min. method 12
  • The (R)- and (S)-enantiomer of Example 180 were obtained by chiral HPLC(SFC) from the racemic compound (column: Deicel ASH, 250 mm×10 mm, flow rate: 10 mL/min, eluant: 70% supercritical carbon dioxide and 30% isopropanol with 0.2% triethylamine).
    • Example 181 2-methyl-pyrimidine-5-carboxylic acid {1-[4-(2-cyano-4-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00788
    • 181a) tert-butyl {1-[4-(2-cyano-4-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-carbamate
  • 877 mg (4.36 mmol) 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid and 2.58 (60%, 4.36 mmol) 2-(4-aminomethyl-phenylamino)-5-fluoro-benzonitrile trifluoroacetate were coupled analogously to method (179c).
  • Yield: 30% of theory
  • C23H25FN4O3 (424.47)
  • mass spectroscopy (ESI): [M−H]+=423
  • Rt=2.39 min. method 13
    • 181b) 1-amino-cyclopropanecarboxylic acid 4-(2-cyano-4-fluoro-phenylamino)-benzylamide trifluoroacetate
  • 560 mg (1.32 mmol) 2-(4-aminomethyl-phenylamino)-5-fluoro-benzonitrile trifluoroacetate in 15 mL dichloromethane were combined with 15 mL trifluoroacetic acid and stirred at ambient temperature. Then the reaction mixture was evaporated to dryness and purified by chromatography (RP with gradient, eluant: acetonitrile and water with 0.2% trifluoroacetic acid).
  • C18H17FN4O*C2HF3O2 (438.38)
  • mass spectroscopy (ESI): [M−H]+=325
  • Rt=1.56 min. method 13
    • 181c) 2-methyl-pyrimidine-5-carboxylic acid-{1-[4-(2-cyano-4-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • Prepared analogously to method (179c) from 42 mg (0.29 mmol) 2-methyl-pyrimidine-5-carboxylic acid and 167 mg (75%, 0.29 mmol) 1-amino-cyclopropanecarboxylic acid-4-(2-cyano-4-fluoro-phenylamino)-benzylamide trifluoroacetate.
  • Yield: 83% of theory
  • C24H21FN6O2 (444.46)
  • mass spectroscopy (ESI): [M+H]+=445
  • Rt=1.92 min. method 13
  • Examples 182 and 183 were prepared analogously from 1-amino-cyclopropanecarboxylic acid-4-(2-cyano-4-fluoro-phenylamino)-benzylamide trifluoroacetate and the corresponding carboxylic acids.
    • Example 182 2-methoxy-pyrimidine-5-carboxylic acid-{1-[4-(2-cyano-4-fluoro-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00789
  • Yield: 28% of theory
  • C24H21FN6O3 (460.46)
  • mass spectroscopy (ESI): [M+H]+=461
  • Rt=2.03 min. method 13
    • Example 183 2-methylamino-pyrimidine-5-carboxylic acid-{1-[4-(2-cyano-4-fluoro-phenyl-amino)-benzylcarbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00790
  • Yield: 58% of theory
  • C24H22FN7O2 (459.48)
  • mass spectroscopy (ESI): [M+H]+=460
  • Rt=1.91 min. method 13
    • Example 184 2-amino-thiazole-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenyl-amino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00791
    • 184a) 2-acetylamino-thiazole-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Prepared from 1-amino-cyclopropanecarboxylic acid-[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide hydrochloride and 2-acetylamino-thiazole-5-carboxylic acid analogously to method (142c).
  • Yield: 51% of theory
  • C23H20F4N6O3S (536.50)
  • Rt=2.96 min. method 7
    • 184b) 2-amino-thiazole-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • 110 mg (0.21 mmol) 2-acetylamino-thiazole-5-carboxylic acid (1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide were stirred overnight at 80° C. in 5 mL 4 molar hydrochloric acid. Then the reaction mixture was made alkaline with potassium carbonate solution and the precipitated solid was filtered off, washed with water and dried.
  • Yield: 43% of theory
  • C21H18F4N6O2S (494.47)
  • mass spectroscopy (ESI): [M+H]+=495
  • Rt=2.73 min. method 7
  • Examples 185 and 186 were prepared analogously from 1-amino-cyclopropanecarboxylic acid-[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide hydrochloride and the corresponding acetylamino-carboxylic acid.
    • Example 185 5-amino-2H-pyrazole-3-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00792
  • C21H19F4N7O2 (477.42)
  • mass spectroscopy (ESI): [M+H]+=478
  • Rt=2.69 min. method 7
    • Example 186 2-amino-4-methyl-thiazole-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00793
  • C22H20F4N6O2S (508.49)
  • mass spectroscopy (ESI): [M+H]+=509
  • Rt=2.67 min. method 7
    • Example 187 Pyrimidine-5-carboxylic acid (1-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide dihydrochloride
  • Figure US20100240669A1-20100923-C00794
    • 187a) 3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile
  • A solution of 5.00 g (28.9 mmol) 3,5-dichloro-pyridine-2-carbonitrile and 5.18 g (28.9 mmol) 4-fluoro-2-trifluoromethyl-phenylamine in 75 mL DMSO was combined with 5.05 g (45.0 mmol) potassium-tert-butoxide while being cooled and then stirred for 30 minutes at ambient temperature. The reaction mixture was stirred into water and then extracted with diethyl ether. The organic phases were washed with water and sodium chloride solution, dried on sodium sulphate and evaporated down. The residue was purified by chromatography through a silica gel column (petroleum ether with 5 to 15% ethyl acetate).
  • Yield: 45% of theory
    • 187b) (6-aminomethyl-5-chloro-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine
  • A solution of 100 mg (0.32 mmol) 3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile in 3 mL THF was combined at ambient temperature with 31 μL borane-dimethylsulphide complex and then stirred overnight. Methanol was then added carefully and the mixture was evaporated to dryness. The residue was used in the next reaction without any further purification.
    • 187c) pyrimidine-5-carboxylic acid (1-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide dihydrochloride
  • Prepared from (6-aminomethyl-5-chloro-pyridin-3-yl)-(4-fluoro-2-trifluoromethyl-phenyl)-amine and 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid analogously to the method for Example 151.
  • C22H17ClF4N6O2*2HCl (581.78)
  • mass spectroscopy (ESI): [M+H]+=509
  • Rt=3.68 min. method 10
    • Example 188 Pyrimidine-5-carboxylic acid-(3-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-(S)-tetrahydro-furan-3-yl)-amide
  • Figure US20100240669A1-20100923-C00795
  • A solution of 59 mg (0.25 mmol) (S)-3-[(pyrimidine-5-carbonyl)-amino]-tetrahydrofuran-3-carboxylic acid and 48 mg (0.30 mmol) N,N′-carbonyldiimidazole in 5 mL DMF was stirred for one hour at 50° C. and then combined with 89 mg (0.25 mmol) [6-(1-amino-ethyl)-pyridin-3-yl]-(4-bromo-2-trifluoromethyl-phenyl)-amine and 45 μL (0.26 mmol) DIPEA. It was then stirred for another hour at ambient temperature. The reaction mixture was purified by chromatography (RP with eluant gradient, eluant: acetonitrile and water with 0.2% trifluoroacetic acid).
  • Yield: 41% of theory
  • C24H22BrF3N6O3 (579.37)
  • mass spectroscopy (ESI): [M+H]+=579
  • Rt=1.93 min. method 12
    • Example 188a Pyrimidine-5-carboxylic acid-(3-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00796
  • Separation of diastereomers by chiral HPLC (column: Daicel ASH; 250×4.6 mm; 5 μm; 25° C.; eluant CO2/(isopropanol+0.2% diethylamine) 80:20; flow: 10 mL/min) Rt=5.32-7.15 minutes
    • Example 188b Pyrimidine-5-carboxylic acid (3-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl]-ethylcarbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00797
  • Separation of diastereomers by chiral HPLC (column: Daicel ASH; 250×4.6 mm; 5 μm; 25° C.; eluant CO2/(isopropanol+0.2% diethylamine) 80:20; flow: 10 mL/min)
  • Rt=8.23-10.51 minutes
    • Example 189 Pyrimidine-5-carboxylic acid (1-{[5-(2-chloro-4-methyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00798
  • Analogously to Example 1d) the product was prepared by amide coupling from 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid and (6-aminomethyl-pyridin-3-yl)-(2-chloro-4-methyl-phenyl)-amine using TBTU as coupling reagent and diisoproylethylamine as base.
  • C22H21ClN6O2 (436.90)
  • Mass spectrum (ESI): [M+H]+=437
  • M−H]−=435
  • Rt=1.59 min (method 2)
    • Example 190 Pyrimidine-5-carboxylic acid (1-{[5-(2-chloro-4-fluoro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00799
  • Analogously to Example 1d) the product was prepared by amide coupling from 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropane-carboxylic acid and (6-aminomethyl-pyridin-3-yl)-(2-chloro-4-fluoro-phenyl)-amine, using TBTU as coupling reagent and diisoproylethylamine as base.
  • C21H16ClFN6O2 (440.86)
  • Mass spectrum (ESI): [M+H]+=441
  • Rt=1.50 min (method 2)
    • Example 191 Pyrimidine-5-carboxylic acid (1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclohexyl)-amide
  • Figure US20100240669A1-20100923-C00800
    • 191a) 1-amino-cyclohexanecarboxylic acid [5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • 61 mg (0.25 mmol) 1-tert-butoxycarbonylamino-cyclohexanecarboxylic acid, 80 mg (0.25 mmol) TBTU and 53 μL (0.38 mmol) triethylamine in 2 mL DMF were stirred for 5 minutes at ambient temperature and then mixed with 67 mg (0.25 mmol) (6-aminomethyl-pyridin-3-yl)-(2-trifluoromethyl-phenyl)-amine. The reaction mixture was then stirred overnight and purified by chromatography (RP with eluting gradient, eluant: acetonitrile and water with 0.1% trifluoroacetic acid). 93 mg of the isolated Boc-protected amine were stirred for 2 hours at ambient temperature in 5 mL of a 1:1 mixture of dichloromethane and trifluoroacetic acid. The reaction mixture was evaporated to dryness and then purified by chromatography (RP with eluting gradient, eluant: acetonitrile and water with 0.1% trifluoroacetic acid).
  • Yield: 68% of theory (as trifluoroacetate)
  • mass spectroscopy [M+H]+=393
  • Rt=1.70 min method 6
    • 191b) pyrimidine-5-carboxylic acid-(1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclohexyl)-amide
  • Prepared from 1-amino-cyclohexanecarboxylic acid [5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide and pyrimidine-5-carboxylic acid analogously to method 191a).
  • Yield: 37% of theory
  • C25H25F3N6O2 (498.51)
  • Mass spectrum (ESI): [M+H]+=499
  • [M−H]−=497
  • Rt=1.84 min (method 5)
    • Example 192 Pyrimidine-5-carboxylic acid (3-hydroxy-1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopentyl)-amide
  • Figure US20100240669A1-20100923-C00801
    • 192a) 1-amino-3-hydroxy-cyclopentanecarboxylic acid [5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • 1-tert-butoxycarbonylamino-3-hydroxy-cyclopentanecarboxylic acid and (6-aminomethyl-pyridin-3-yl)-(2-trifluoromethyl-phenyl)-amine were reacted analogously to method 191a).
  • Yield: 49% of theory (as trifluoroacetate)
  • mass spectroscopy [M+H]+=395
  • Rt=1.62 min method 6
    • 192b) pyrimidine-5-carboxylic acid (3-hydroxy-1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopentyl)-amide
  • The target compound was prepared from 1-amino-3-hydroxy-cyclopentanecarboxylic acid [5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide and pyrimidine-5-carboxylic acid analogously to method 191a).
  • Yield: 55% of theory
  • C24H23F3N6O3 (500.48)
  • Mass spectrum (ESI): [M+H]+=501
  • Rt=1.66 min (method 5)
    • Example 193 Pyrimidine-5-carboxylic acid (3-oxo-1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopentyl)-amide
  • Figure US20100240669A1-20100923-C00802
  • 10 mg pyrimidine-5-carboxylic acid (3-hydroxy-1-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopentylyamide in 1 mL acetonitrile were mixed with 8 mg Dess-Martin-Periodinane reagent and stirred for 1 hour at ambient temperature. Then the reaction mixture was purified by chromatography (RP with eluting gradient, eluant: acetonitrile and water with 0.1% trifluoroacetic acid).
  • Yield: 90% of theory
  • C24H21F3N6O3 (498.46)
  • Mass spectrum (ESI): [M+H]+=499
  • [M−H]−=497
  • Rt=1.73 min (method 5)
    • Example 194 Pyrimidine-5-carboxylic acid (1-oxo-3-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydro-1lambda*4*-thiophen-3-yl)-amide
  • Figure US20100240669A1-20100923-C00803
    • 194a) 3-amino-1-oxo-tetrahydrothiophene-3-carboxylic acid [5-(2-trifluoromethyl-phenyl-amino)-pyridin-2-ylmethyl]-amide
  • The product was obtained from 3-tert-butoxycarbonylamino-1-oxo-tetrahydro-thiophene-3-carboxylic acid and (6-aminomethyl-pyridin-3-yl)-(2-trifluoromethyl-phenyl)-amine analogously to method 191a).
  • Yield: 96% of theory (as trifluoroacetate)
  • mass spectroscopy [M+H]+=413
  • Rt=1.62 min method 6
    • 194b) pyrimidine-5-carboxylic acid (1-oxo-3-{[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydro-thiophen-3-yl)-amide
  • Prepared from 3-amino-1-oxo-tetrahydro-thiophene-3-carboxylic acid-[5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide and pyrimidine-5-carboxylic acid analogously to method 191a).
  • Yield: 58% of theory
  • C23H21F3N6O3S (518.52)
  • Mass spectrum (ESI): [M+H]+=519
  • [M+H]+=517
  • Rt=1.66 min (method 5)
    • Example 195 4-{6-[({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-methyl]-pyridin-3-ylamino}-3-trifluoromethyl-benzoic acid
  • Figure US20100240669A1-20100923-C00804
  • 469 (0.91 mmol) methyl 4-{6-[({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)methyl]-pyridin-3-ylamino}-3-trifluoromethyl-benzoate were stirred overnight in 5 mL of 1N aqueous sodium hydroxide solution and 20 mL ethanol at ambient temperature. Then the reaction mixture was neutralised with 1N aqueous hydrochloric acid and evaporated to dryness. The residue was dissolved in methanol and DMF, filtered and then chromatographed (RP with eluting gradient, eluant: acetonitrile and water with 0.2% trifluoroacetic acid).
  • Yield: 69% of theory
  • C23H19F3N6O4 (500.44)
  • Mass spectrum (ESI): [M+H]+=501
  • [M−H]−=499
    • Example 196 Methyl 4-{6-[({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-methyl]-pyridin-3-ylamino}-3-trifluoromethyl-benzoate
  • Figure US20100240669A1-20100923-C00805
    • 196a) methyl 4-(6-cyano-pyridin-3-ylamino)-3-trifluoromethyl-benzoate
  • 1190 mg (3.48 mmol) 5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile, 221 μL (1.6 mmol) triethylamine and 97 mg (0.13 mmol) Pd(ddpf)Cl2 in 10 mL methanol and 2 mL DMF were heated to 50° C. in an autoclave under a carbon monoxide pressure of 5 bar for 60 hours. After removal of the solvents by distillation the residue was dissolved in acetonitrile and methanol and filtered. The filtrate was then evaporated down and purified by chromatography (1st column: RP with eluting gradient, eluant: acetonitrile and water with 0.1% trifluoroacetic acid; 2nd column: silica gel, eluant: dichloromethane).
  • Yield: 78% of theory
  • mass spectroscopy [M+H]+=322
    • 196b) methyl 4-(6-aminomethyl-pyridin-3-ylamino)-3-trifluoromethyl-benzoate
  • 860 mg (2.7 mmol) methyl 4-(6-cyano-pyridin-3-ylamino)-3-trifluoromethyl-benzoate in 30 mL methanolic ammonia were hydrogenated at ambient temperature under a hydrogen pressure of 50 psi in the presence of 100 mg Raney nickel. The catalyst was filtered off and the filtrate was freed from solvent.
  • Yield: 76% of theory
  • mass spectroscopy [M+H]+=326
    • 196c) methyl 4-{6-[({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-methyl]-pyridin-3-ylamino}-3-trifluoromethyl-benzoate
  • 191 mg (0.92 mmol) 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid, 305 mg (0.95 mmol) TBTU and 203 μL (1.85 mmol) N-methylmorpholine in 3 mL DMF were stirred for 5 minutes at ambient temperature. The solution was combined with 300 mg (0.92 mmol) methyl 4-(6-aminomethyl-pyridin-3-ylamino)-3-trifluoromethyl-benzoate and left to stand over the weekend. Then the reaction mixture was purified by chromatography (RP with eluting gradient, eluant: acetonitrile and water with 0.2% trifluoroacetic acid).
  • Yield: 62% of theory
  • C24H21F3N6O4 (514.46)
  • Mass spectrum (ESI): [M+H]+=515
  • Rt=1.73 min (method 12)
    • Example 197 Pyrimidine-5-carboxylic acid (1-{[5-(4-cyano-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00806
  • 55 mg (0.18 mmol) pyrimidine-5-carboxylic acid {1-[(5-amino-pyridin-2-ylmethyl)-carbamoyl]-cyclopropyl}-amide, 33 mg (0.18 mmol) 4-fluoro-3-(trifluoromethyl)benzonitrile and 42 mg (0.35 mg) potassium-tert-butoxide in 5 mL DMSO were stirred for 1 h at 50° C. The reaction mixture was filtered and the filtrate was purified by chromatography (RP with eluting gradient, eluant: acetonitrile and water with 0.2% trifluoroacetic acid).
  • Yield: 23% of theory
  • C23H18F3N7O2 (481.44)
  • Mass spectrum (ESI): [M+H]+=482
  • [M−H]−=480
  • Rt=1.69 min (method 12)
    • Example 198 Pyrimidine-5-carboxylic acid (1-{[5-(4-carbamoyl-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00807
  • A solution of 50 mg (0.10 mmol) 4-{6-[({1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarbonyl}-amino)-methyl]-pyridin-3-ylamino}-3-trifluoromethyl-benzoic acid, 33 mg (0.10 mmol) TBTU and 12 μL (0.11 mmol) N-methylmorpholine in 0.5 mL DMF was stirred for 3 minutes at ambient temperature, then combined with 17 μL (0.11 mmol) 2,4-dimethoxybenzylamine, stirred for a further 10 minutes and left to stand overnight. In order to cleave the benzyl group the mixture was combined with 10 mL dichloromethane and 10 mL trifluoroacetic acid, left to stand overnight and evaporated to dryness. The residue was filtered and then purified by chromatography (RP with eluting gradient, eluant: acetonitrile and water with 0.2% trifluoroacetic acid).
  • Yield: 6% of theory
  • C23H20F3N7O3 (499.45)
  • Mass spectrum (ESI): [M+H]+=500
  • [M−H]−=498
    • Example 199 Pyrimidine-5-carboxylic acid {1-[4-(4-methoxy-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00808
  • Obtained from 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid and (4-aminomethyl-phenyl)-(4-methoxy-phenyl)-amine analogously to method 191a).
  • Yield: 37% of theory
  • C23H23N5O3 (417.47)
  • Mass spectrum (ESI): [M+H]+=418
  • [M−H]−=416
  • Rt=1.83 min (method 12)
    • Example 200 Pyrimidine-5-carboxylic acid (1-{[5-(2-chloro-6-fluoro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00809
  • Coupling of 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid and (6-amino-methyl-pyridin-3-yl)-(2-chloro-6-fluoro-phenyl)-amine trifluoroacetate with TBTU analogously to method 191a).
  • C21H18ClFN6O2 (440.86)
  • Mass spectrum (ESI): [M+H]+=441
  • [M−]−=439
  • Rt=1.38 min (method 2)
    • Example 201 Pyrimidine-5-carboxylic acid {1-[4-(4-methoxy-2-methyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00810
  • Prepared from 1-[(pyrimidine-5-carbonyl)amino]-cyclopropanecarboxylic acid and (4-aminomethyl-phenyl)-(4-methoxy-2-methyl-phenyl)-amine according to method 191a).
  • C24H25N5O3 (431.49)
  • Mass spectrum (ESI): [M+H]+=432
  • [M+H]+=430
  • Rt=1.97 min (method 12)
    • Example 202 Pyrimidine-5-carboxylic acid (1-{4-[(4-methoxy-2-methyl-phenyl)-methyl-amino]-benzylcarbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00811
  • 73 mg (0.35 mmol) of 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid and 57 mg (0.35 mmol) CDI were stirred for 30 minutes at 50° C. in 5 mL DMF. 90 mg (0.35 mmol) (4-aminomethyl-phenyl)-(4-methoxy-2-methyl-phenyl)-methyl-amine and 101 μL diisopropylethylamine were added at ambient temperature and the mixture was left overnight with stirring. The solvent was distilled off and the residue was dissolved in methanol and purified by chromatography (RP with eluting gradient, eluant: acetonitrile and water with 0.2% trifluoroacetic acid).
  • Yield: 19% of theory
  • C25H27N5O3 (445.52)
  • Mass spectrum (ESI): [M+H]+=446
  • Rt=2.16 min (method 12)
    • Example 203 Pyrimidine-5-carboxylic acid-(1-{1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00812
  • Prepared from intermediates A1 and B1 according to AAV1
  • C23H19ClF4N6O2 (522.89)
  • Rt=2.30 minutes method 2
  • The racemate was separated into the enantiomers by chiral HPLC (column: Daicel AD-H 250×20 mm; 5 μm; 25° C.; eluant CO2/isopropanol (+0.2% diethylamine) 80:20; flow: 10 mL/min).
    • Example 203a (R)-pyrimidine-5-carboxylic acid-(1-{1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-yl]ethylcarbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00813
  • Analytical chiral HPLC (column: Daicel AD-H; 250×4.6 mm; 5 μm; 25° C.; eluant CO2/isopropanol 80:20; flow: 4 mL/min)
  • Rt=1.62 minutes
    • Example 203b (S)-pyrimidine-5-carboxylic acid-(1-{1-[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00814
  • Analytical chiral HPLC (column: Daicel AD-H; 250×4.6 mm; 5 μm; 25° C.; eluant CO2/isopropanol 80:20; flow: 4 mL/min)
  • Rt=2.29 minutes
    • Example 204 Pyrimidine-5-carboxylic acid(1-{[5-(4-isopropyl-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00815
  • Prepared from intermediates A2 and B1 according to AAV1
  • C25H25F3N6O2 (498.51)
  • Rt=1.95 minutes (method 2)
    • Example 205 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-hydroxy-nicotinamide
  • Figure US20100240669A1-20100923-C00816
  • Prepared from intermediate C1 and 5-hydroxynicotinic acid according to AAV1
  • C23H19ClF3N5O3 (505.88)
  • Rt=1.74 minutes (method 13)
    • Example 206 6-amino-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00817
  • Prepared from intermediate Cl and 6-aminonicotinic acid according to AAV1
  • C23H20ClF3N6O2 (504.90)
  • Rt=1.60 minutes (method 13)
    • Example 207 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-2-hydroxy-isonicotinamide
  • Figure US20100240669A1-20100923-C00818
  • Prepared from intermediate Cl and 2-hydroxy-isonicotinic acid according to AAV1
  • C23H19ClF3N6O3 (505.88)
  • Rt=1.69 minutes (method 13)
    • Example 208 2,6-dihydroxy-pyrimidine-4-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00819
  • Prepared from intermediate Cl and 2,6-dihydroxy-pyrimidine-4-carboxylic acid according to AAV1
  • C22H18ClF3N6O4 (522.87)
  • Rt=1.70 minutes (method 13)
    • Example 209 Pyridazine-4-carboxylic acid (1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00820
  • Prepared from intermediate Cl and pyridazine-4-carboxylic acid according to AAV1
  • C22H18ClF3N6O2 (522.87)
  • Rt=1.76 minutes (method 13)
    • Example 210 2-dimethylamino-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00821
  • Prepared from intermediate Cl and 2-dimethylamino-pyrimidine-5-carboxylic acid according to AAV1
  • C24H23ClF3N7O2 (533.94)
  • Rt=1.94 minutes (method 13)
    • Example 211 6-hydroxy-pyridine-2-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00822
  • Prepared from intermediate C1 and 6-hydroxy-pyridine-2-carboxylic acid according to AAV1
  • C23H19ClF3N5O3 (505.88)
  • Rt=1.75 minutes method 13
    • Example 212 Pyrimidine-5-carboxylic acid-(1-{1-[5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-yl]ethylcarbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00823
  • Prepared from intermediates A4 and B1 according to AAV1
  • C23H19F2N7O2 (463.45)
  • Rt=1.81 minutes method 2
  • The racemate was separated into the enantiomers by chiral HPLC (column: Deicel AD-H 250×20 mm; 5 μm; 25° C.; eluant CO2/isopropanol (+0.2% diethylamine) 80:20; flow: 10 mL/min):
    • Example 212a (R)-pyrimidine-5-carboxylic acid-(1-{1-[5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00824
  • Rt=2.75 minutes
    • Example 212b (S)-pyrimidine-5-carboxylic acid-(1-{1-[5-(2-cyano-4-fluoro-phenylamino)-3-fluoro-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00825
  • Rt=5.12 minutes
    • Example 213 Pyrimidine-5-carboxylic acid-(1-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00826
  • Prepared from intermediates A5 and B1 according to AAV1
  • C23H19BrF4N6O2 (567.34)
  • Rt=2.34 minutes (method 2)
  • The racemate was separated into the enantiomers by chiral HPLC:
    • Example 213a (R)-pyrimidine-5-carboxylic acid-(1-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00827
  • Analytical chiral HPLC (column: Daicel AD-H; 250×4.6 mm; 5 μm; 25° C.; eluant CO2/isopropanol 80:20; flow: 4 mL/min)
  • Rt=1.78 minutes
    • Example 213b (S)-pyrimidine-5-carboxylic acid-(1-{1-[5-(4-bromo-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-yl]-ethylcarbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00828
  • Analytical chiral HPLC (column: Daicel AD-H; 250×4.6 mm; 5 μm; 25° C.; eluant CO2/isopropanol 80:20; flow: 4 mL/min)
  • Rt=2.55 minutes
    • Example 214 (S)-5-amino-N-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00829
  • Prepared from intermediates A6 and B2 according to AAV1
  • C25H23F4N5O3 (517.48)
  • Rt=3.33 minutes (method 7)
    • Example 215 6-oxo-5,6-dihydro-pyridazine-4-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00830
  • Prepared from intermediate C2 and 6-oxo-5,6-dihydro-pyridazine-4-carboxylic acid according to AAV1
  • C22H18F4N6O3 (490.42)
  • Rt=2.80 minutes (method 7)
    • Example 216 (S)-pyrimidine-5-carboxylic acid-(3-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00831
  • Prepared from intermediates A8 and B3 according to AAV1
  • C23H19ClF4N6O3 (538.89)
  • Rt=3.86 minutes (method 7)
    • Example 217 5-amino-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00832
  • Prepared from intermediate Cl and 5-aminonicotinic acid according to AAV1.
  • C23H20ClF3N6O2 (504.90)
  • Rt=2.01 minutes (method 2)
    • Example 218 5-amino-N-(1-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00833
  • Prepared from intermediates A8 and B4 according to AAV1
  • C23H19ClF4N6O2 (522.89)
  • Rt=3.21 minutes (method 7)
    • Example 219 (S)-5-amino-N-(3-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00834
  • Prepared from intermediates A8 and B2 according to AAV1
  • C24H21ClF4N6O3 (552.91)
  • Rt=3.22 minutes (method 7)
    • Example 220 (S)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid-(3-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00835
  • Prepared from intermediates A8 and B5 according to AAV1
  • C25H20ClF4N7O3 (577.92)
  • Rt=3.62 minutes (method 7)
    • Example 221 1-methyl-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00836
  • Prepared from intermediate C2 and 1-methyl-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid according to AAV1
  • C23H20F4N6O3 (504.44)
  • Rt=2.95 minutes (method 7)
    • Example 222 (S)-5-amino-N-(3-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00837
  • Prepared from intermediates A9 and B2 according to AAV1
  • C24H22BrF3N6O3 (579.37)
  • Rt=1.88 minutes (method 2)
    • Example 223 (S)-pyrimidine-5-carboxylic acid-(3-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00838
  • Prepared from intermediates A9 and B3 according to AAV1
  • C23H20BCF3N6O3 (565.35)
  • Rt=1.74 minutes (method 2)
    • Example 224 (S)-2-methylamino-pyrimidine-5-carboxylic acid-(3-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00839
  • Prepared from intermediate C3 and 2-methylamino-pyrimidine-5-carboxylic acid according to AAV1
  • C24H22ClF4N7O3 (567.93)
  • Rt=3.89 minutes (method 7)
    • Example 225 (S)-3-(3,3,3-trifluoro-propionylamino)-tetrahydrofuran-3-carboxylic acid-[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00840
  • Prepared from intermediate C3 and 3,3,3-trifluoro-propionic acid according to AAV1
  • C21H18ClF7N4O3 (542.84)
  • Rt=4.18 minutes (method 7)
    • Example 226 (S)-5-amino-N-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00841
  • Prepared from intermediates A3 and B2 according to AAV1
  • C24H22ClF3N6O3 (534.92)
  • Rt=1.57 minutes (method 2)
    • Example 227 6-methylamino-pyridazine-4-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00842
  • Prepared from intermediate C2 and 6-methylamino-pyridazine-4-carboxylic acid according to AAV1
  • C23H21F4N7O2 (503.46)
  • Rt=1.55 minutes (method 5)
    • Example 228 (S)-pyrimidine-5-carboxylic acid-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00843
  • Prepared from intermediates A3 and B3 according to AAV1
  • C23H20ClF3N6O3 (520.90)
  • Rt=1.74 minutes (method 2)
    • Example 229 (S)-5-amino-N-(3-{[3-chloro-5-(2-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00844
  • Prepared from intermediates A10 and B2 according to AAV1
  • C24H22ClF3N6O3 (534.92)
  • Rt=3.19 minutes (method 7)
    • Example 230 (S)-2-methoxy-pyrimidine-5-carboxylic acid-(3-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00845
  • Prepared from intermediate C3 and 2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
  • C24H21ClF4N6O4 (568.91)
  • Rt=4.01 minutes (method 7)
    • Example 231 (S)-5-amino-N-{3-[2-fluoro-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-nicotinamide
  • Figure US20100240669A1-20100923-C00846
  • Prepared from intermediates A11 and B2 according to AAV1
  • C25H22F5N5O3 (535.47)
  • Rt=1.23 minutes (method 2)
    • Example 232 2-methyl-pyrimidine-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00847
  • Prepared from intermediate C2 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1
  • C23H20F4N6O2 (488.44)
  • Rt=1.94 minutes (method 2)
    • Example 233 2-methoxy-pyrimidine-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00848
  • Prepared from intermediate C2 and 2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
  • C23H20F4N6O3 (504.44)
  • Rt=2.00 minutes (method 2)
    • Example 234 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-hydroxy-nicotinamide
  • Figure US20100240669A1-20100923-C00849
  • Prepared from intermediate C4 and 6-hydroxy-nicotinic acid according to AAV1
  • C23H19BrF3N5O3 (550.33)
  • Rt=1.79 minutes (method 2)
    • Example 235 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-methoxy-nicotinamide
  • Figure US20100240669A1-20100923-C00850
  • Prepared from intermediate C4 and 6-methoxy-nicotinic acid according to AAV1
  • C24H21BrF3N5O3 (564.36)
  • Rt=1.84 minutes (method 2)
    • Example 236 (S)-5-amino-N-{3-[2-fluoro-4-(2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]etrahydrofuran-3-yl}-nicotinamide
  • Figure US20100240669A1-20100923-C00851
  • Prepared from intermediates A12 and B2 according to AAV1
  • C25H23F4N5O3 (517.48)
  • Rt=3.07 minutes (method 3)
    • Example 237 (S)-5-amino-N-(3-{[3-chloro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00852
  • Prepared from intermediate C5 and 5-aminonicotinic acid according to AAV1
  • C24H21ClF4N6O3 (552.91)
  • Rt=3.28 minutes (method 3)
    • Example 238 (S)-2-methoxy-pyrimidine-5-carboxylic acid-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00853
  • Prepared from intermediate C6 and 2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
  • C24H2iF5N6O4 (552.46)
  • Rt=3.62 minutes (method 3)
    • Example 239 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-hydroxy-nicotinamide
  • Figure US20100240669A1-20100923-C00854
  • Prepared from intermediate Cl and 6-hydroxy-nicotinic acid according to AAV1
  • C23H19ClF3N5O3 (505.88)
  • Rt=1.71 minutes (method 2)
    • Example 240 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-methoxy-nicotinamide
  • Figure US20100240669A1-20100923-C00855
  • Prepared from intermediate Cl and 6-methoxy-nicotinic acid according to AAV1
  • C24H21ClF3N5O3 (519.91)
  • Rt=1.75 minutes (method 2)
    • Example 241 (S)-2-methylamino-pyrimidine-5-carboxylic acid-(3-{[3-chloro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00856
  • Prepared from intermediate C5 and 2-methylamino-pyrimidine-5-carboxylic acid according to AAV1
  • C24H22ClF4N7O3 (567.93)
  • Rt=4.64 minutes (method 3)
    • Example 242 (S)-pyrimidine-5-carboxylic acid-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00857
  • Prepared from intermediates A15 and B3 according to AAV1
  • C23H19ClF4N6O3 (538.89)
  • Rt=2.15 minutes (method 2)
    • Example 243 N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-hydroxy-nicotinamide
  • Figure US20100240669A1-20100923-C00858
  • Prepared from intermediate C2 and 5-hydroxynicotinic acid according to AAV1
  • C23H19F4N5O3 (489.43)
  • mass spectroscopy (ESI): [M+H]+=490
  • [M−H]−=488
    • Example 244 6-amino-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl-nicotinamide
  • Figure US20100240669A1-20100923-C00859
  • Prepared from intermediate C2 and 6-aminonicotinic acid according to AAV1
  • C23H20F4N6O2 (488.44)
  • mass spectroscopy (ESI): [M+H]+=489
  • [M−H]−=487
    • Example 245 2-isopropyl-pyrimidine-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00860
  • Prepared from intermediate C2 and 2-isopropyl-pyrimidine-5-carboxylic acid according to AAV1
  • C25H24F4N6O2 (516.50)
  • mass spectroscopy (ESI): [M+H]+=517
    • Example 246 2-trifluoromethyl-pyrimidine-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00861
  • Prepared from intermediate C2 and 2-trifluoromethyl-pyrimidine-5-carboxylic acid according to AAV1
  • C23H17F7N6O2 (542.41)
  • mass spectroscopy (ESI): [M+H]+=543
    • Example 247 2-ethylamino-pyrimidine-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00862
  • Prepared from intermediate C2 and 2-ethylamino-pyrimidine-5-carboxylic acid according to AAV1
  • C24H23F4N7O2 (517.48)
  • mass spectroscopy (ESI): [M+H]+=518
  • Rt=1.58 minutes (method 5)
    • Example 248 2-piperidin-1-yl-pyrimidine-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00863
  • Prepared from intermediate C2 and 2-piperidin-1-yl-pyrimidine-5-carboxylic acid according to AAV1
  • C27H27F4N7O2 (557.55)
  • mass spectroscopy (ESI): [M+H]+=558
    • Example 249 5-acetylamino-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00864
  • Prepared from intermediate C2 and 5-acetylaminonicotinic acid according to AAV1
  • C25H22F4N6O3 (530.48) mass spectroscopy (ESI): [M+H]+=531
    • Example 250 2-pyrrolidin-1-yl-pyrimidine-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00865
  • Prepared from intermediate C2 and 2-pyrrolidin-1-yl-pyrimidine-5-carboxylic acid according to AAV1
  • C26H25F4N7O2 (543.52)
  • mass spectroscopy (ESI): [M+H]+=544
    • Example 251 6-acetylamino-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00866
  • Prepared from intermediate C2 and 6-acetylamino-nicotinic acid according to AAV1
  • C25H22F4N6O3 (530.48)
  • mass spectroscopy (ESI): [M+H]+=531
    • Example 252 6-dimethylamino-pyridazine-4-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00867
  • Prepared from intermediate C2 and 6-dimethylamino-pyridazine-4-carboxylic acid according to AAV1
  • C24H23F4N7O2 (517.48)
  • mass spectroscopy (ESI): [M+H]+=518
    • Example 253 6-chloro-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00868
  • Prepared from intermediate C2 and 6-chloro-nicotinic acid according to AAV1
  • C23H18ClF4N5O2 (507.87)
  • mass spectroscopy (ESI): [M+H]+=508
    • Example 254 N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-trifluoromethyl-nicotinamide
  • Figure US20100240669A1-20100923-C00869
  • Prepared from intermediate C2 and 6-trifluoromethyl-nicotinic acid according to AAV1
  • C24H18F7N5O2 (541.43)
  • mass spectroscopy (ESI): [M+H]+=542
    • Example 255 1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00870
  • Prepared from intermediate C2 and 1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid according to AAV1
  • C25H20F4N6O2 (512.47)
  • mass spectroscopy (ESI): [M+H]+=513
    • Example 256 6-cyano-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00871
  • Prepared from intermediate C2 and 6-cyano-nicotinic acid according to AAV1
  • C24H18F4N6O2 (498.44)
  • mass spectroscopy (ESI): [M+H]+=499
    • Example 257 2-acetylamino-thiazole-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00872
  • Prepared from intermediate C2 and 2-acetylamino-thiazole-5-carboxylic acid according to AAV1
  • C23H20F4N6O3S (536.51)
  • mass spectroscopy (ESI): [M+H]+=537
    • Example 258 (S)-2-methoxy-pyrimidine-5-carboxylic acid-(3-{[3-chloro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00873
  • Prepared from intermediate C3 and 2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
  • C24H21ClF4N6O4 (568.91)
  • Rt=3.99 minutes (method 3)
    • Example 259 (S)—N-(3-{[3-chloro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-5-methylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00874
  • Prepared from intermediate C3 and 5-methylamino-nicotinic acid according to AAV1
  • C25H23ClF4N6O3 (566.94)
  • Rt=3.59 minutes (method 3)
    • Example 260 (S)—N-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-5-methylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00875
  • Prepared from intermediate C6 and 5-methylamino-nicotinic acid according to AAV1
  • C25H23F5N6O3 (550.49)
  • Rt=3.81 minutes (method 3)
    • Example 261 (S)-3-(3,3,3-trifluoro-propionylamino)-tetrahydrofuran-3-carboxylic acid-[3-chloro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00876
  • Prepared from intermediate C5 and 3,3,3-trifluorpropionic acid according to AAV1
  • C21H18ClF7N4O3 (542.84)
  • Rt=4.11 minutes (method 3)
    • Example 262 6-amino-pyridazine-4-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00877
  • Prepared from intermediate C2 and 6-amino-pyridazine-4-carboxylic acid according to AAV1
  • C22H19F4N7O2 (489.43)
  • Rt=1.81 minutes (method 6)
    • Example 263 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-dimethylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00878
  • Prepared from intermediate C1 and 6-dimethylamino-nicotinic acid according to AAV1
  • C25H24ClF3N6O2 (532.95)
  • Rt=1.90 minutes (method 2)
    • Example 264 1-methyl-1H-benzimidazole-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00879
  • Prepared from intermediate C1 and 1-methyl-1H-benzimidazole-5-carboxylic acid according to AAV1
  • C26H22ClF3N6O2 (542.95)
  • Rt=1.72 minutes (method 2)
    • Example 265 2-amino-1H-benzimidazole-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00880
  • Prepared from intermediate C1 and 2-amino-1H-benzimidazole-5-carboxylic acid according to AAV1
  • C25H21ClF3N7O2 (543.93)
  • mass spectroscopy (ESI): [M+H]+=544
    • Example 266 1H-benzimidazole-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00881
  • Prepared from intermediate C1 and 1H-benzimidazole-5-carboxylic acid according to AAV1
  • C25H20ClF3N6O2 (528.92)
  • Rt=1.79 minutes (method 2)
    • Example 267 (S)-2-methyl-pyrimidine-5-carboxylic acid-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00882
  • Prepared from intermediate C6 and (S)-2-methyl-pyrimidine-5-carboxylic acid according to AAV1
  • C24H21F5N6O3 (536.46)
  • Rt=3.91 minutes (method 3)
    • Example 268 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-dimethylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00883
  • Prepared from intermediate C4 and 6-dimethylamino-nicotinic acid according to AAV1
  • C25H24BrF3N6O2 (577.40)
  • Rt=2.09 minutes (method 2)
    • Example 269 (S)—N-(3-{[3-chloro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-5-methylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00884
  • Prepared from intermediate C3 and 5-methylaminonicotinic acid according to AAV1
  • C25H23ClF4N6O3 (566.94)
  • Rt=3.66 minutes (method 3)
    • Example 270 N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00885
  • Prepared from intermediate C2 and 5-methylaminonicotinic acid according to AAV1
  • C24H22F4N6O2 (502.47)
  • Rt=1.97 minutes (method 2)
    • Example 271 (S)-5-amino-N-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00886
  • Prepared from intermediates A15 and B2 according to AAV1
  • C24H21ClF4N6O3 (552.91)
  • Rt=2.48 minutes (method 2)
    • Example 272 N-(1-{[3-fluoro-5-(2-fluoro-6-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00887
  • Prepared from intermediate C7 and 5-methylaminonicotinic acid according to AAV1
  • C24H21F5N6 O 3 (520.46)
  • Rt=1.87 minutes (method 2)
    • Example 273 5-amino-N-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-oxetan-3-yl}-nicotinamide
  • Figure US20100240669A1-20100923-C00888
  • Prepared from intermediate C8 and 5-aminonicotinic acid according to AAV1
  • C24H22F3N5O3 (485.46)
  • Rt=2.17 minutes (method 6)
    • Example 274 (S)-2-methyl-pyrimidine-5-carboxylic acid-{3-[2-fluoro-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00889
  • Prepared from intermediate C9 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1
  • C25H22F5N5O3 (535.47)
  • Rt=3.61 minutes (method 3)
    • Example 275 5-acetylamino-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00890
  • Prepared from intermediate Cl and 5-acetylamino-nicotinic acid according to AAV1
  • C25H22ClF3N6O3 (546.93)
  • Rt=1.78 minutes (method 2)
    • Example 276 (S)-2-methylamino-pyrimidine-5-carboxylic acid-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00891
  • Prepared from intermediates A15 and B6 according to AAV1
  • C24H22ClF4N7O3 (567.93)
  • Rt=2.16 minutes (method 2)
    • Example 277 (S)-2-methyl-pyrimidine-5-carboxylic acid-(3-{[5-(4-chloro-2-trifluoromethylphenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00892
  • Prepared from intermediates A15 and B7 according to AAV1
  • C24H21ClF4N6O3 (552.91)
  • Rt=2.50 minutes (method 2)
    • Example 278 (S)-pyrimidine-5-carboxylic acid-(3-{[3-chloro-5-(4-chloro-2-trifluoromethylphenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00893
  • Prepared from intermediates A18 and B3 according to AAV1
  • C23H19Cl2F3N6O3 (555.34)
  • Rt=2.56 minutes (method 2)
    • Example 279 (S)-2-methyl-pyrimidine-5-carboxylic acid-{3-[2-fluoro-4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00894
  • Prepared from intermediate C22 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1
  • C25H23F4N5O3 (517.48)
  • Rt=1.97 minutes (method 7)
    • Example 280 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00895
  • Prepared from intermediate Cl and 5-methylaminonicotinic acid according to AAV1
  • C24H22ClF3N6O2 (518.92)
  • Rt=1.96 minutes (method 2)
    • Example 281 (S)-2-methylamino-pyrimidine-5-carboxylic acid-(3-{[3-chloro-5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00896
  • Prepared from intermediates A18 and B6 according to AAV1
  • C24H22Cl2F3N7O3 (584.38)
  • Rt=2.56 minutes (method 2)
    • Example 282 (S)-2-methyl-pyrimidine-5-carboxylic acid-(3-{[3-chloro-5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00897
  • Prepared from intermediates A18 and B7 according to AAV1
  • C24H21Cl2F3N6O3 (569.37)
  • Rt=2.59 minutes (method 2)
    • Example 283 2-methyl-pyrimidine-5-carboxylic acid-{1-[2-fluoro-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00898
  • Prepared from intermediate C10 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1
  • C24H20F5N5O2 (505.44)
  • Rt=1.33 minutes (method 7)
    • Example 284 6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00899
  • Prepared from intermediate Cl and 6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid according to AAV1
  • C22H18ClF3N6O3 (506.87)
  • Rt=2.13 minutes (method 2)
    • Example 285 (S)-5-amino-N-(3-{[3-chloro-5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00900
  • Prepared from intermediates A18 and B2 according to AAV1
  • C24H21Cl2F3N6O3 (569.37)
  • Rt=2.34 minutes (method 2)
    • Example 286 (S)—N-(3-{[3-chloro-5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-5-hydroxy-nicotinamide
  • Figure US20100240669A1-20100923-C00901
  • Prepared from intermediates A18 and B8 according to AAV 1
  • C24H20Cl2F3N5O4 (570.35)
  • Rt=2.52 minutes (method 2)
  • mass spectroscopy (ESI): [M+H]+=570; [M−H]−=568
    • Example 287 (S)-pyrimidine-5-carboxylic acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00902
  • Prepared from intermediates A6 and B3 according to AAV1
  • C24H21F4N5O3 (503.45)
  • Rt=2.43 minutes (method 2)
    • Example 288 (S)-2-methyl-pyrimidine-5-carboxylic acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00903
  • Prepared from intermediates A6 and B7 according to AAV1
  • C25H23F4N5O3 (517.48)
  • Rt=2.64 minutes (method 2)
    • Example 289 (S)-2-methylamino-pyrimidine-5-carboxylic acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00904
  • Prepared from intermediates A6 and B6 according to AAV1
  • C25H24F4N6O3 (532.50)
  • Rt=2.44 minutes (method 2)
    • Example 290 (S)-5-amino-N-{3-[2-fluoro-4-(2-fluoro-6-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-nicotinamide
  • Figure US20100240669A1-20100923-C00905
  • Prepared from intermediate C11 and 5-aminonicotinic acid according to AAV1
  • C25H22F5N5O3 (535.47)
  • Rt=1.63 minutes (method 7)
    • Example 291 (S)-2-methyl-pyrimidine-5-carboxylic acid-{3-[2-fluoro-4-(2-fluoro-6-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00906
  • Prepared from intermediate C11 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1
  • C25H22F5N5O3 (535.47)
  • Rt=1.83 minutes (method 7)
    • Example 292 (S)-2-methyl-pyrimidine-5-carboxylic acid-(3-{[3-chloro-5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00907
  • Prepared from intermediates A10 and B7 according to AAV1
  • C24H22ClF3N6O3 (534.92)
  • Rt=1.78 minutes (method 7)
    • Example 293 (S)-6-amino-N-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00908
  • Prepared from intermediates A15 and B9 according to AAV1
  • C24H21ClF4N6O3 (552.91)
  • Rt=2.14 minutes (method 2)
    • Example 294 2-methyl-pyrimidine-5-carboxylic acid-{1-[2-fluoro-4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00909
  • Prepared from intermediate C12 and 2-methylpyrimidine-5-carboxylic acid according to AAV1
  • C24H21F4N5 O 2 (487.45)
  • Rt=1.91 minutes (method 7)
    • Example 295 Pyrimidine-5-carboxylic acid-(1-{[5-(2-cyano-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00910
  • Prepared from intermediates A20 and B1 according to AAV1
  • C22H18FN7O2 (431.43)
  • Rt=1.62 minutes (method 2)
    • Example 296 Pyrimidine-5-carboxylic acid-{1-[4-(2-cyano-phenylamino)-2-fluoro-benzyl-carbamoyl]-cyclopropyl}-amide
  • Figure US20100240669A1-20100923-C00911
  • Prepared from intermediates A30 and B1 according to AAV1
  • C23H19FN6O2 (430.44)
  • Rt=1.88 minutes (method 2)
    • Example 297 (S)-6-amino-N-(3-{[3-chloro-5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00912
  • Prepared from intermediates A18 and B9 according to AAV1
  • C24H21Cl2F3N6O3 (569.37)
  • Rt=2.46 minutes (method 2)
    • Example 298 2-methyl-pyrimidine-5-carboxylic acid-(1-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00913
  • Prepared from intermediate C13 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1
  • C23H19F5N6O2 (506.43)
  • Rt=1.74 minutes (method 7)
    • Example 299 (S)-thiazole-5-carboxylic acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00914
  • Prepared from intermediate C14 and thiazole-5-carboxylic acid according to AAV1
  • C23H20F4N4O3S (508.49)
  • Rt=2.43 minutes (method 2)
    • Example 300 (S)-2-methoxy-pyrimidine-5-carboxylic acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00915
  • Prepared from intermediate C14 and 2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
  • C25H23F4N5O4 (533.48)
  • Rt=2.61 minutes (method 2)
    • Example 301 2-methyl-pyrimidine-5-carboxylic acid-(1-{[3-chloro-5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00916
  • Prepared from intermediate C15 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1
  • C23H20ClF3N6O2 (504.90)
  • Rt=1.79 minutes (method 7)
    • Example 302 N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methyl-nicotinamide
  • Figure US20100240669A1-20100923-C00917
  • Prepared from intermediate C2 and 5-methyl-nicotinic acid according to AAV1
  • C24H21F4N5 O 2 (487.45)
  • Rt=1.96 minutes (method 2)
    • Example 303 2-methyl-thiazole-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenyl-amino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00918
  • Prepared from intermediate C2 and 2-methyl-thiazole-5-carboxylic acid according to AAV1
  • C22H19F4N5O2S (493.48)
  • Rt=2.07 minutes (method 2)
    • Example 304 (S)-2-methylamino-pyrimidine-5-carboxylic acid-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00919
  • Prepared from intermediates A7 and B6 according to AAV1
  • C24H23F4N7O3 (533.48)
  • Rt=1.88 minutes (method 2)
    • Example 305 (S)—N-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-5-methylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00920
  • Prepared from intermediate C14 and 5-methylaminonicotinic acid according to AAV1
  • C26H25F4N5O3 (531.51)
  • Rt=1.83 minutes (method 7)
    • Example 306 Pyrimidine-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00921
  • Prepared from intermediates A21 and B1 according to AAV1
  • C23H20F4N6O2 (488.44)
  • Rt=1.81 minutes (method 2)
    • Example 307 (S)-2-methyl-pyrimidine-5-carboxylic acid-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00922
  • Prepared from intermediates A7 and B7 according to AAV1
  • C24H22F4N6O3 (518.47)
  • Rt=2.32 minutes (method 2)
    • Example 308 (S)—N-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-5-methyl-nicotinamide
  • Figure US20100240669A1-20100923-C00923
  • Prepared from intermediates C14 and 5-methylnicotinic acid according to AAV1
  • C26H24F4N4O3 (516.49)
  • Rt=2.45 minutes (method 2)
    • Example 309 (S)-6-amino-N-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydrofuran-3-yl}-nicotinamide
  • Figure US20100240669A1-20100923-C00924
  • Prepared from intermediates C14 and 6-aminonicotinic acid according to AAV1
  • C25H23F4N5O3 (517.48)
  • Rt=2.09 minutes (method 2)
    • Example 310 (S)-2-isopropyl-pyrimidine-5-carboxylic acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00925
  • Prepared from intermediates C14 and 2-isopropyl-pyrimidine-5-carboxylic acid according to AAV1
  • C27H27F4N5O3 (545.53)
  • Rt=2.60 minutes (method 2)
    • Example 311 (S)—N-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-5-methylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00926
  • Prepared from intermediates C16 and 5-methylamino-nicotinic acid according to AAV1
  • C25H24F4N6O3 (532.50)
  • Rt=2.22 minutes (method 2)
    • Example 312 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-methyl-nicotinamide
  • Figure US20100240669A1-20100923-C00927
  • Prepared from intermediates C1 and 6-methyl-nicotinic acid according to AAV1
  • C24H21ClF3N5O2 (503.91)
  • Rt=2.17 minutes (method 2)
    • Example 313 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methoxy-nicotinamide
  • Figure US20100240669A1-20100923-C00928
  • Prepared from intermediates C1 and 5-methoxy-nicotinic acid according to AAV1
  • C24H21ClF3N5O3 (519.91)
  • Rt=2.29 minutes (method 2)
    • Example 314 (S)-2-methoxy-pyrimidine-5-carboxylic acid-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00929
  • Prepared from intermediates C17 and 2-methoxy-pyrimidine-5-carboxylic acid according to AAV1
  • C24H21ClF4N6O4 (568.91)
  • Rt=2.53 minutes (method 2)
    • Example 315 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-methyl-nicotinamide
  • Figure US20100240669A1-20100923-C00930
  • Prepared from intermediates C4 and 6-methyl-nicotinic acid according to AAV1
  • C24H21BrF3N5O2 (548.36)
  • Rt=2.24 minutes (method 2)
    • Example 316 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methoxy-nicotinamide
  • Figure US20100240669A1-20100923-C00931
  • Prepared from intermediates C4 and 5-methoxy-nicotinic acid according to AAV1
  • C24H21BrF3N5O3 (564.36)
  • Rt=2.34 minutes (method 2)
    • Example 317 (S)-2-methyl-pyrimidine-5-carboxylic acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00932
  • Prepared from intermediates A22 and B7 according to AAV1
  • C25H23ClF3N5O3 (533.94)
  • Rt=2.60 minutes (method 2)
    • Example 318 (S)-6-amino-N-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydrofuran-3-yl}-nicotinamide
  • Figure US20100240669A1-20100923-C00933
  • Prepared from intermediates A22 and B9 according to AAV1
  • C25H23ClF3N5O3 (533.94)
  • Rt=2.25 minutes (method 2)
    • Example 319 (S)—N-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-5-methylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00934
  • Prepared from intermediates C17 and 5-methylamino-nicotinic acid according to AAV1
  • C25H23ClF4N6O3 (566.94)
  • Rt=2.21 minutes (method 2)
    • Example 320 (S)-5-amino-N-(3-{[3-fluoro-5-(2-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00935
  • Prepared from intermediates A23 and B2 according to AAV1
  • C24H22F4N6O3 (518.47)
  • Rt=1.52 minutes (method 7)
    • Example 321 (S)-5-amino-N-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzyl-carbamoyl]-tetrahydrofuran-3-yl}-nicotinamide
  • Figure US20100240669A1-20100923-C00936
  • Prepared from intermediates A22 and B2 according to AAV1
  • C25H23ClF3N5O3 (533.94)
  • Rt=2.36 minutes (method 2)
    • Example 322 (S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00937
  • Prepared from intermediates C14 and 6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid according to AAV1
  • C24H21F4N5O4 (519.45)
  • Rt=2.39 minutes (method 2)
    • Example 323 (S)-2-methylamino-pyrimidine-5-carboxylic acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00938
  • Prepared from intermediates A22 and B6 according to AAV1
  • C25H24ClF3N6O3 (548.95)
  • Rt=2.57 minutes (method 2)
    • Example 324 (S)-pyrimidine-5-carboxylic acid-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00939
  • Prepared from intermediates A21 and B3 according to AAV1.
  • C24H22F4N6O3 (518.47)
  • Rt=1.80 minutes (method 2)
  • mass spectroscopy (ESI): [M+H]+=519
  • [M−H]−=517
    • Example 325 Pyrimidine-5-carboxylic acid-(1-{[5-(4-bromo-2-chloro-6-fluoro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00940
  • Prepared from intermediates A24 and B1 according to AAV1.
  • C21H17BrClFN6O2 (519.76)
  • Rt=2.01 minutes (method 2)
    • Example 326 Pyrimidine-5-carboxylic acid-(1-{[5-(2-bromo-6-fluoro-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00941
  • Prepared from intermediates A25 and B1 according to AAV1.
  • C21H18BrFN6O2 (485.32)
  • Rt=1.64 minutes (method 2)
    • Example 327 (S)-2-methoxy-pyrimidine-5-carboxylic acid-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00942
  • Prepared from intermediates C16 and 2-methoxy-pyrimidine-5-carboxylic acid according to AAV1.
  • C24H22F4N6O4 (534.47)
  • Rt=1.98 minutes (method 2)
    • Example 328 (S)-2-ethylamino-pyrimidine-5-carboxylic acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00943
  • Prepared from intermediates C14 and 2-ethylamino-pyrimidine-5-carboxylic acid according to AAV1.
  • C26H26F4N6O3 (546.52)
  • Rt=2.62 minutes (method 2)
    • Example 329 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-ethylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00944
  • Prepared from intermediates C1 and 6-ethylamino-nicotinic acid according to AAV1.
  • C26H24ClF3N6O2 (532.95) Rt=2.32 minutes (method 2)
    • Example 330 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-propylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00945
  • Prepared from intermediates C1 and 6-propylamino-nicotinic acid according to AAV1.
  • C26H26ClF3N6O2 (546.98)
  • Rt=2.04 minutes (method 2)
    • Example 331 (S)—N-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-5-hydroxy-nicotinamide
  • Figure US20100240669A1-20100923-C00946
  • Prepared from intermediates A15 and B8 according to AAV1.
  • C24H20ClF4N5O4 (553.90)
  • Rt=2.48 minutes (method 2)
    • Example 332 (S)-pyrimidine-5-carboxylic acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00947
  • Prepared from intermediates C18 and pyrimidine-5-carboxylic acid according to AAV1.
  • C24H21ClF3N5O3 (519.91)
  • Rt=2.57 minutes (method 2)
    • Example 333 (S)-2-methoxy-pyrimidine-5-carboxylic acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00948
  • Prepared from intermediates C18 and 2-methoxy-pyrimidine-5-carboxylic acid according to AAV1.
  • C25H23ClF3N5O4 (549.93)
  • Rt=2.72 minutes (method 2)
    • Example 334 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-ethylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00949
  • Prepared from intermediates C4 and 6-ethylamino-nicotinic acid according to AAV1.
  • C25H24CBrF3N6O2 (577.40)
  • Rt=2.01 minutes (method 2)
    • Example 335 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-propylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00950
  • Prepared from intermediates C4 and 6-propylamino-nicotinic acid according to AAV1.
  • C26H26BrF3N6O2 (591.43)
  • Rt=2.12 minutes (method 2)
    • Example 336 (S)-thiazole-5-carboxylic acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00951
  • Prepared from intermediates C18 and thiazole-5-carboxylic acid according to AAV1.
  • C23H20ClF3N4O3S (524.95)
  • Rt=2.58 minutes (method 2)
    • Example 337 (S)—N-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-5-methoxy-nicotinamide
  • Figure US20100240669A1-20100923-C00952
  • Prepared from intermediates C18 and 5-methoxy-nicotinic acid according to AAV1.
  • C26H24ClF3N4O4 (548.95)
  • Rt=2.62 minutes (method 2)
    • Example 338 (S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00953
  • Prepared from intermediates A22 and B10 according to AAV1.
  • C24H21ClF3N5O4 (535.91)
  • Rt=2.28 minutes (method 2)
    • Example 339 5-chloro-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00954
  • Prepared from intermediates C2 and 5-chloro-nicotinic acid according to AAV1.
  • C23H18ClF4N5O2 (507.87)
  • Rt=2.18 minutes (method 2)
    • Example 340 N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-trifluoromethyl-nicotinamide
  • Figure US20100240669A1-20100923-C00955
  • Prepared from intermediates C2 and 5-trifluoromethyl-nicotinic acid according to AAV1.
  • C24H18F7N5O2 (541.43)
  • Rt=2.32 minutes (method 2)
    • Example 341 N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-methyl-nicotinamide
  • Figure US20100240669A1-20100923-C00956
  • Prepared from intermediates C2 and 6-methyl-nicotinic acid according to AAV1.
  • C24H21F4N5O2 (487.45)
  • Rt=1.85 minutes (method 2)
    • Example 342 (S)-5-amino-N-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00957
  • Prepared from intermediates A21 and B2 according to AAV1.
  • C25H24F4N6O3 (487.45)
  • Rt=1.85 minutes (method 2)
    • Example 343 N-(1-{[5-(4-bromo-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-methylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00958
  • Prepared from intermediates C4 and 6-methylamino-nicotinic acid according to AAV1.
  • C24H22BrF3N6O2 (563.38)
  • Rt=2.32 minutes (method 2)
    • Example 344 2-methyl-pyrimidine-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00959
  • Prepared from intermediates C19 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1.
  • C24H22F4N6O2 (502.47)
  • Rt=1.84 minutes (method 2)
    • Example 345 (S)-2-methyl-pyrimidine-5-carboxylic acid-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00960
  • Prepared from intermediates A26 and B7 according to AAV1.
  • C25H24ClF3N6O3 (548.95)
  • Rt=2.16 minutes (method 2)
    • Example 346 (S)-5-amino-N-(3-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00961
  • Prepared from intermediates A26 and B2 according to AAV1.
  • C25H24ClF3N6O3 (548.95)
  • Rt=2.23 minutes (method 2)
    • Example 347 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-methylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00962
  • Prepared from intermediates C1 and 6-methylamino-nicotinic acid according to AAV1.
  • C24H22ClF3N6O2 (518.92)
  • Rt=1.85 minutes (method 2)
    • Example 348 (S)-6-amino-N-(3-{[3-fluoro-5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00963
  • Prepared from intermediates A14 and B9 according to AAV1.
  • C24H21F5N6O3 (536.46)
  • Rt=1.96 minutes (method 2)
  • mass spectroscopy (ESI): [M+H]+=537
  • [M−H]−=535
    • Example 349 (S)-6-amino-N-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00964
  • Prepared from intermediates A7 and B9 according to AAV1.
  • C24H22F4N6O3 (518.47)
  • mass spectroscopy (ESI): [M+H]+=519
  • [M−H]−=517
    • Example 350 2-hydroxy-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00965
  • Prepared from intermediates C1 and 2-hydroxy-pyrimidine-5-carboxylic acid according to AAV1.
  • C22H18ClF3N6O3 (506.87)
  • Rt=2.42 minutes (method 2)
    • Example 351 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-fluoro-nicotinamide
  • Figure US20100240669A1-20100923-C00966
  • Prepared from intermediates C1 and 5-fluoro-nicotinic acid according to AAV1.
  • C23H18ClF4N5O2 (507.87)
  • Rt=1.96 minutes (method 2)
    • Example 352 5-chloro-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00967
  • Prepared from intermediates C1 and 5-chloro-nicotinic acid according to AAV1.
  • C23H18Cl2F3N5O2 (524.33)
  • Rt=2.10 minutes (method 2)
    • Example 353 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methyl-nicotinamide
  • Figure US20100240669A1-20100923-C00968
  • Prepared from intermediates C1 and 5-methyl-nicotinic acid according to AAV1.
  • C24H21ClF3N5O2 (503.91)
  • Rt=1.86 minutes (method 2)
    • Example 354 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-trifluoromethyl-nicotinamide
  • Figure US20100240669A1-20100923-C00969
  • Prepared from intermediates C1 and 5-trifluoromethyl-isonicotinic acid according to AAV1.
  • C24H18ClF6N5O2 (557.88)
  • Rt=2.22 minutes (method 2)
    • Example 355 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-2-fluoro-isonicotinamide
  • Figure US20100240669A1-20100923-C00970
  • Prepared from intermediates C1 and 2-fluoro-isonicotinic acid according to AAV1.
  • C23H18ClF4N5O2 (507.87)
  • Rt=2.02 minutes (method 2)
    • Example 356 3-methoxy-isoxazole-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00971
  • Prepared from intermediates C1 and 3-methoxy-isoxazole-5-carboxylic acid according to AAV1.
  • C22H19ClF3N5O4 (509.87)
  • Rt=1.96 minutes (method 2)
    • Example 357 Isothiazole-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00972
  • Prepared from intermediates C1 and isothiazole-5-carboxylic acid according to AAV1.
  • C21H17ClF3N5O2S (495.91)
  • Rt=1.88 minutes (method 2)
    • Example 358 Isothiazol-4-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00973
  • Prepared from intermediates C1 and isothiazole-4-carboxylic acid according to AAV1.
  • C21H17ClF3N5O2S (495.91)
  • Rt=1.84 minutes (method 2)
    • Example 359 (S)-5-amino-N-(3-{[3-methyl-5-(2-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-tetrahydrofuran-3-yl)-nicotinamide
  • Figure US20100240669A1-20100923-C00974
  • Prepared from intermediates A27 and B2 according to AAV1.
  • C25H25F3N6O3 (514.51)
  • Rt=1.51 minutes (method 2)
    • Example 360 2-methyl-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00975
  • Prepared from intermediates A26 and B11 according to AAV1.
  • C24H22ClF3N6O2 (518.92)
  • Rt=2.11 minutes (method 2)
    • Example 361 5-amino-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00976
  • Prepared from intermediates A26 and B4 according to AAV1.
  • C24H22ClF3N6O2 (518.92)
  • Rt=1.83 minutes (method 2)
    • Example 362 1-(2,2,2-trifluoro-acetylamino)-cyclopropanecarboxylic acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00977
  • Prepared from intermediates C1 and trifluoroacetic acid according to AAV1
  • C19H15ClF6N4O2 (480.79)
  • Rt=2.15 minutes (method 2)
    • Example 363 1-(3,3,3-trifluoro-propionylamino)-cyclopropanecarboxylic acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00978
  • Prepared from intermediates C1 and 3,3,3-trifluoro-propionic acid according to AAV1
  • C20H17ClF6N4O2 (494.82)
  • Rt=2.07 minutes (method 2)
    • Example 364 1-(2-cyano-acetylamino)-cyclopropanecarboxylic acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00979
  • Prepared from intermediates C1 and 2-cyano-acetic acid according to AAV1.
  • C20H17ClF3N5O2 (451.83)
  • Rt=1.85 minutes (method 2)
    • Example 365 (S)-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00980
  • Prepared from intermediates C14 and 1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid according to AAV1.
  • C27H23F4N5O3 (541.50)
  • Rt=2.14 minutes (method 2)
    • Example 366 (S)-2-methyl-pyrimidine-5-carboxylic acid-(3-{[3-methyl-5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C00981
  • Prepared from intermediates A27 and B7 according to AAV1
  • C25H25F3N6O3 (514.51)
  • Rt=1.84 minutes (method 2)
    • Example 367 1-cyano-1-(cyclopropanecarbonyl-amino)-cyclopropanecarboxylic acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00982
  • Prepared from intermediates C1 and 1-cyano-1-cyclopropanecarboxylic acid according to AAV1.
  • C22H19ClF3N5O2 (477.87)
  • Rt=1.96 minutes (method 2)
    • Example 368 1-(2-cyano-2-methyl-acetylamino)-cyclopropanecarboxylic acid-[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-amide
  • Figure US20100240669A1-20100923-C00983
  • Prepared from intermediates C1 and 2-cyano-2-methyl-acetic acid according to AAV1.
  • C21H19ClF3N5O2 (465.86)
  • Rt=1.92 minutes (method 2)
    • Example 369 Isoxazole-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00984
  • Prepared from intermediates C1 and isoxazole-5-carboxylic acid according to AAV1.
  • C21H17ClF3N5O3 (479.84)
  • Rt=1.89 minutes (method 2)
    • Example 370 2-amino-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00985
  • Prepared from intermediates C1 and 2-amino-pyrimidine-5-carboxylic acid according to AAV1.
  • C22H19ClF3N7O2 (505.89)
  • Rt=2.11 minutes (method 2)
    • Example 371 2-ethyl-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00986
  • Prepared from intermediates C1 and 2-ethyl-pyrimidine-5-carboxylic acid according to AAV1.
  • C24H22ClF3N6O2 (518.92)
  • Rt=2.38 minutes (method 2)
    • Example 372 1H-pyrazole-4-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00987
  • Prepared from intermediates C1 and 1H-pyrazole-4-carboxylic acid according to AAV1.
  • C21H18ClF3N6O2 (478.86)
  • Rt=1.69 minutes (method 2)
    • Example 373 1-methyl-1H-pyrazole-4-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00988
  • Prepared from intermediates C1 and 1-methyl-1H-pyrazole-4-carboxylic acid according to AAV1.
  • C22H20ClF3N6O2 (492.89)
  • Rt=1.74 minutes (method 2)
    • Example 374 2-methyl-pyrimidine-5-carboxylic acid-(1-{[3-methyl-5-(2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00989
  • Prepared from intermediates C20 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1.
  • C24H23F3N6O2 (484.48)
  • Rt=1.81 minutes (method 2)
    • Example 375 5-amino-N-(1-{[3-methyl-5-(2-trifluoromethyl-phenylamino)-pyridin-2-yl-methyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00990
  • Prepared from intermediates C20 and 5-amino-nicotinic acid according to AAV1.
  • C24H23F3N6O2 (484.48)
  • Rt=1.29 minutes (method 2)
    • Example 376 N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methoxy-nicotinamide
  • Figure US20100240669A1-20100923-C00991
  • Prepared from intermediates C2 and 5-methoxy-nicotinic acid according to AAV1.
  • C24H21F4N5O3 (503.45)
  • Rt=2.02 minutes (method 2)
    • Example 377 N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-methylamino-nicotinamide
  • Figure US20100240669A1-20100923-C00992
  • Prepared from intermediates C2 and 6-methylamino-nicotinic acid according to AAV1.
  • C24H22F4N6O2 (502.47)
  • Rt=2.01 minutes (method 2)
    • Example 378 6-amino-5-bromo-N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-nicotinamide
  • Figure US20100240669A1-20100923-C00993
  • Prepared from intermediates C1 and 6-amino-5-bromo-nicotinic acid according to AAV1.
  • C23H19BrClF3N6O2 (583.79)
  • Rt=1.91 minutes (method 2)
    • Example 379 2-cyclopropylamino-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00994
  • Prepared from intermediates C1 and 2-cyclopropylamino-pyrimidine-5-carboxylic acid according to AAV1.
  • C25H23ClF3N7O2 (545.95)
  • Rt=2.29 minutes (method 2)
    • Example 380 2-propylamino-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00995
  • Prepared from intermediates C1 and 2-propylamino-pyrimidine-5-carboxylic acid according to AAV1.
  • C25H25ClF3N7O2 (547.97)
  • Rt=2.42 minutes (method 2)
    • Example 381 (S)—N-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-5-methoxy-nicotinamide
  • Figure US20100240669A1-20100923-C00996
  • Prepared from intermediates C14 and 5-methoxy-nicotinic acid according to AAV1.
  • C26H24F4N4O4 (532.49)
  • Rt=2.50 minutes (method 2)
    • Example 382 2-isopropylamino-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00997
  • Prepared from intermediates C1 and 2-isopropylamino-pyrimidine-5-carboxylic acid according to AAV1.
  • C25H25ClF3N7O2 (547.97)
  • Rt=2.41 minutes (method 2)
    • Example 383 (S)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid-{3-[4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C00998
  • Prepared from intermediates C14 and 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid according to AAV1.
  • C27H23F4N5O3 (541.50)
  • Rt=2.48 minutes (method 2)
    • Example 384 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C00999
  • Prepared from intermediates C2 and 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid according to AAV 1.
  • C25H20F4N6O2 (512.47)
  • Rt=2.27 minutes (method 2)
    • Example 385 2-cyano-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C01000
  • Prepared from intermediates C1 and 2-cyano-pyrimidine-5-carboxylic acid according to AAV1.
  • C23H17ClF3N7O2 (515.88)
  • Rt=2.39 minutes (method 2)
    • Example 386 2-methyl-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-difluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C01001
  • Prepared from intermediates C21 and 2-methyl-pyrimidine-5-carboxylic acid according to AAV1.
  • C23H21ClF2N6O2 (486.91)
  • Rt=1.68 minutes (method 2)
    • Example 387 (S)-2-methyl-pyrimidine-5-carboxylic acid-(3-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-3-methyl-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-yl)-amide
  • Figure US20100240669A1-20100923-C01002
  • Prepared from intermediates A21 and B7 according to AAV1.
  • C25H24F4N6O3 (532.50)
  • Rt=1.86 minutes (method 2)
    • Example 388 (S)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C01003
  • Prepared from intermediates C18 and 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid according to AAV1.
  • C27H23ClF3N5O3 (557.96)
  • mass spectroscopy (ESI): [M+H]+=558
  • [M−H]−=556
    • Example 389 N-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-6-cyclopropylamino-nicotinamide
  • Figure US20100240669A1-20100923-C01004
  • Prepared from intermediates C1 and 6-cyclopropylamino-nicotinic acid according to AAV1.
  • C26H24ClF3N6O2 (544.96)
  • Rt=1.67 minutes (method 2)
    • Example 390 2-ethoxy-pyrimidine-5-carboxylic acid-(1-{[5-(4-chloro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-amide
  • Figure US20100240669A1-20100923-C01005
  • Prepared from intermediates C1 and 2-ethoxy-pyrimidine-5-carboxylic acid according to AAV1.
  • C24H22ClF3N6O3 (534.92)
  • Rt=1.99 minutes (method 2)
    • Example 391 6-amino-N-(1-{[5-(4-fluoro-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-cyclopropyl)-5-methyl-nicotinamide
  • Figure US20100240669A1-20100923-C01006
  • Prepared from intermediates C2 and 6-amino-5-methyl-nicotinic acid according to AAV1.
  • C24H22F4N6O2 (502.47)
  • Rt=1.38 minutes (method 2)
    • Example 392 (S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid-{3-[4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C01007
  • Prepared from intermediates A17 and B10 according to AAV1.
  • C24H22F3N5O4 (501.46)
  • Rt=2.09 minutes (method 2)
    • Example 393 (S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid-{3-[2-fluoro-4-(4-fluoro-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C01008
  • Prepared from intermediates A11 and B10 according to AAV1.
  • C24H20F5N5O4 (537.44)
  • Rt=2.15 minutes (method 2)
    • Example 394 (S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid-{3-[4-(4-chloro-2-trifluoromethyl-phenylamino)-2-fluoro-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C01009
  • Prepared from intermediates A29 and B10 according to AAV1.
  • C24H20ClF4N5O4 (553.90)
  • Rt=2.31 minutes (method 2)
    • Example 395 (S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid-{3-[4-(4-bromo-2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydrofuran-3-yl}-amide
  • Figure US20100240669A1-20100923-C01010
  • Prepared from intermediates A31 and B10 according to AAV1.
  • C24H21BrF3N5O4 (580.35)
  • Rt=2.32 minutes (method 2)
    • Example 396 (S)-6-oxo-1,6-dihydro-pyridazine-4-carboxylic acid {3-[2-fluoro-4-(2-trifluoromethyl-phenylamino)-benzylcarbamoyl]-tetrahydro-furan-3-yl}-amide
  • Figure US20100240669A1-20100923-C01011
  • Prepared from intermediates A12 and B10 according to AAV1.
  • C24H21F4N5O4 (519.45)
  • Rt=1.35 minutes (method 7)
  • mass spectroscopy (ESI): [M+H]+=520
  • [M−H]−=518
  • The following Examples describe pharmaceutical formulations which contain as active substance any desired compound of general formula I, without restricting the scope of the present invention thereto:
    • Example I Dry Ampoule with 75 mg of Active Compound Per 10 ml Composition:
  • Active compound 75.0 mg
    Mannitol 500 mg
    Water for injection ad 10.0 ml
    • Production:
  • Active compound and mannitol are dissolved in water. The charged ampoules are freeze dried. Water for injection is used to dissolve to give the solution ready for use.
    • Example II Tablet with 50 mg of Active Compound Composition:
  • (1) Active compound 50.0 mg
    (2) Lactose 98.0 mg
    (3) Maize starch 50.0 mg
    (4) Polyvinylpyrrolidone 15.0 mg
    (5) Magnesium stearate  2.0 mg
    215.0 mg 
    • Production:
  • (1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is admixed to the dry granules. Tablets are compressed from this mixture, biplanar with a bevel on both sides and dividing groove on one side.
  • Diameter of the tablets: 9 mm.
    • Example III Tablet with 350 mg of Active Compound Composition:
  • (1) Active compound 350.0 mg
    (2) Lactose 136.0 mg
    (3) Maize starch  80.0 mg
    (4) Polyvinylpyrrolidone  30.0 mg
    (5) Magnesium stearate  4.0 mg
    600.0 mg
    • Production:
  • (1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is admixed to the dry granules. Tablets are compressed from this mixture, biplanar with a bevel on both sides and dividing groove on one side.
  • Diameter of the tablets: 12 mm.
    • Example IV Capsule with 50 mg of Active Compound Composition:
  • (1) Active compound 50.0 mg
    (2) Maize starch dried 58.0 mg
    (3) Lactose powdered 50.0 mg
    (4) Magnesium stearate  2.0 mg
    160.0 mg 
    • Production:
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.
  • This powder mixture is packed into hard gelatine two-piece capsules of size 3 in a capsule-filling machine.
    • Example V Capsules with 350 mg of Active Compound Composition:
  • (1) Active compound 350.0 mg
    (2) Maize starch dried  46.0 mg
    (3) Lactose powdered  30.0 mg
    (4) Magnesium stearate  4.0 mg
    430.0 mg
    • Production:
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous stirring.
  • This powder mixture is packed into hard gelatine two-piece capsules of size 0 in a capsule-filling machine.
    • Example VI Suppositories with 100 mg of Active Compound
  • 1 suppository comprises:
  •
    Active compound 100.0 mg
    Polyethylene glycol (M.W. 1500) 600.0 mg
    Polyethylene glycol (M.W. 6000) 460.0 mg
    Polyethylene sorbitan monostearate 840.0 mg
    2000.0 mg 

Claims (32)

1. A compound of the formula I
Figure US20100240669A1-20100923-C01012
wherein
n denotes one of the numbers 0, 1 or 2,
R1 denotes
(a) a C1-6-alkyl group optionally substituted by a group R1.1,
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
(c) a substituted C3-6-cycloalkyl group optionally substituted by a group R1.2 wherein a —CH2— unit may be replaced by a —C(O)— group,
(d) an aryl-C0-2-alkylene group optionally substituted by 1, 2 or 3 groups R1.3,
(e) a five-membered heteroaryl-C0-2-alkylene group optionally substituted by 1, 2 or 3 groups R1.4, which contains at least one N, O or S atom and which optionally additionally contains one, two or three further N-atoms and which may additionally be benzo-condensed,
(f) a six-membered heteroaryl-C0-2-alkylene group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms and which may additionally be benzo-condensed,
(g) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4 substituted, which contains one, two or three N-atoms,
(h) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group,
(i) —O—R1.1.1,
(i) —NR1.1.3R1.1.4 or
(k) —C(═NR15)—CN,
R1.1 denotes halogen, —NO2, —CN, C3-6-cycloalkyl, —OR1.1.1, —SR1.1.1, —C(O)R1.1.1, —S(O)2—R1.1.2, —O—S(O)2—R1.1.1, —CO2R1.1.1, —O—C(O)—R1.1.1, —NR1.1.3R1.1.4, —NR1.1,3-C(O)—R1.1.1, —NR1.1,3-C(O)—R1.1.1, —NR1.1,3-CO2—R1.1.1 or —C(O)—NR1.1.3R1.1.4,
R1.1.1 denotes
(a) H,
(b) C1-4-alkyl,
(c) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
(d) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1,
(e) C3-6-cycloalkyl or
(f) a pyridyl group optionally substituted by 1, 2 or 3 groups R1.1.1.2,
R1.1.1.1 independently of one another denote
(a) halogen, —NO2, —CN, —OH, C3-6-cycloalkyl, C1-4-alkyl or
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R1.1.1.2 independently of one another denote halogen or C1-4-alkyl,
R1.1.2 denotes
(a) C1-4-alkyl,
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
(c) —O—C1-4-alkyl or
(d) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1 substituted,
R1.1.3,
R1.1.4 independently of one another denote
(a) H,
(b) a C1-4-alkyl group optionally substituted by 1, 2 or 3 groups R1.1.4.1,
(c) a phenyl group optionally substituted by 1, 2 or 3 groups R1.1.1.1,
(d) C3-6-cycloalkyl, or
R1.1.3 and R1.1.4 together with the N atom to which they are attached form a 5- or 6-membered heterocyclic ring, which may additionally contain a further heteroatom selected from N, O and S, or
R1.1.3 and R1.1.4 together with the N atom to which they are attached, form a cyclic imide,
R1.1.4.1 independently of one another halogen denote —NH2, —NH(C1-4-alkyl), —N(C1-4-alkyl)2 or —SO2—R1.1.1,
R1.2 denotes halogen, —NO2, —CN, OH, —O—CH3 or phenyl,
R1.3 denotes
(a) halogen, —NO2, —CN, —OR1.1.1, —SR1.1.1, —CO2R1.1.1, C1-6-alkyl or
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R1.4 independently of one another denote
(a) halogen, —NO2, —CN, —OR1.1.1, —SR1.1.1, —S(O)—R1.1.2, —S(O)2—R1.1.2, —NR1.1.3R1.1.4, —N(R)1.4.1)—C(O)—C1-4-alkyl, C1-6-alkyl,
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, or
(c) an oxo group,
R1.4.1 denotes H or C1-4-alkyl,
R1.5 denotes —OH or —O—C1-3-alkyl,
R2 denotes
(a) H,
(b) C1-4-alkyl,
(c) C1-4-alkyl-C(O)—,
R3 and R4 together with the carbon atom to which they are bound denote a C3-6-cycloalkylene group optionally substituted by a group R3.1 wherein a —CH2— unit may be replaced by a heteroatom O, N, S or by a group CO, SO or SO2,
R3.1 denotes H, —OH,
R5 denotes
(a) H,
(b) C1-4-alkyl,
(c) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R6 independently of one another denote
(a) H, halogen, —CN, —OH, C3-7-cycloalkyl, —O—C1-4-alkyl, —O—CF3, —O—C3-6-cycloalkyl, —N(C1-3-alkyl)2, —C(O)—NH2, —(SO2)NH2, —SO2—C1-3-alkyl, or
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R7 denotes
(a) H, halogen, —CN, —OH,
(b) C1-6-alkyl
(c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
(d) C3-7-cycloalkyl,
(e) —O—C1-6-alkyl,
(f) —O—C3-7-cycloalkyl,
(g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
(h) —C(O)—R7.1,
(i) —S—C1-4-alkyl, —SO2—R7.2,
(j) a five-membered heteroaryl group optionally substituted by one or two C1-3-alkyl groups which is selected from among pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl, or
(k) a six-membered heteroaryl group optionally substituted by one or two C1-3-alkyl groups which is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
R7.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-6-alkyl or —O—C3-7-cycloalkyl,
R7.2 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl and
R8 denotes H, halogen, C1-4-alkyl,
R9 denotes
(a) H, halogen, —CN, —OH,
(b) C1-6-alkyl
(c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
(d) C3-7-cycloalkyl,
(e) C2-4-alkynyl,
(f) —O—C1-6-alkyl,
(g) —O—C3-7-cycloalkyl,
(h) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
(i) —C(O)—R9.1,
(j) —S—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl,
R9.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-6-alkyl or —O—C3-7-cycloalkyl,
R10 denotes H, halogen, C1-4-alkyl,
R11 denotes
(a) H, halogen, —CN, —OH,
(b) C1-6-alkyl,
(c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
(d) C3-7-cycloalkyl,
(e) —O—C1-6-alkyl,
(f) —O—C3-7-alkyl,
(g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
(h) —C(O)—R11.1,
(i) —S—C1-3-alkyl, —SO2—R11.2,
(j) a five-membered heteroaryl group optionally substituted by one or two C1-3-alkyl groups which is selected from among pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl, or
(k) a six-membered heteroaryl group optionally substituted by one or two C1-3-alkyl groups which is selected from among pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl,
R11.1 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, —OH, —O—C1-8-alkyl or —O—C3-7-cycloalkyl,
R11.2 denotes —NH2, —NH(C1-6-alkyl), —N(C1-6-alkyl)2, N-acetidinyl, N-pyrrolidinyl, N-piperidinyl or N-morpholinyl and
X independently of one another denote C—R6 or N,
or a salt thereof.
2. A compound of the formula I according to claim 1, wherein:
R1 denotes
(a) a C1-6-alkyl group optionally substituted by a group R1.1,
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
(c) a C3-6-cycloalkyl group optionally substituted by a group R1.2 wherein a —CH2-unit may be replaced by a —C(O)— group,
(d) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
(e) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which contains at least one N, O or S atom and which optionally additionally contains one, two or three further N-atoms,
(f) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
(g) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
(h) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group,
(i) —O—R1.1.1 or
(j) —NR1.1.3R1.1.4,
R1.1 denotes —CN, C3-6-cycloalkyl, —OR1.1.1, —NR1.1.3R1.1.4,
R1.1.1 denotes
(a) H,
(b) C1-4-alkyl,
(c) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R1.1.3,
R1.1.4 independently of one another denote
(a) H,
(b) C1-4-alkyl,
(c) C3-6-cycloalkyl, or
R1.1.3 and R1.1.4 together with the N atom to which they are attached form a 5- or 6-membered heterocyclic ring, which may additionally contain a further heteroatom selected from N, O and S, or
R1.2 denotes halogen, —NO2, —CN, —OH, —O—CH3 or phenyl,
R1.3 independently of one another denote
(a) halogen, —NO2, —CN, —OR1.1.1, C1-6-alkyl or
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R1.4 independently of one another denote
(a) halogen, —NO2, —CN, —NR1.1.3R1.1.4, —N(R1.4.1)—C(O)—C1-4-alkyl, C1-6-alkyl, or
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
R1.4.1 denotes H or C1-4-alkyl,
or a salt thereof.
3. A compound of the formula I according to claim 1, wherein:
R1 denotes
(a) a C1-6-alkyl group optionally substituted by a group R1.1,
(b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
(c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which contains at least one N, O or S atom and which optionally additionally contains one, two or three further N-atoms,
(d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
(e) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
(f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group,
R1.1 denotes —CN, C3-6-cycloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
R1.3 independently of one another denote
(a) F, Cl, Br, —OH, —OCH3, C1-6-alkyl or
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
R1.4 independently of one another denote
(a) F, Cl, Br, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —N(C2-3-alkyl)2, —NH—C(O)—C1-4-alkyl, C1-6-alkyl, or
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
or a salt thereof.
4. A compound of the formula I according to claim 1, wherein:
R1 denotes
(a) a C1-6-alkyl group optionally substituted by a group R1.1,
(b) a phenyl group optionally substituted by 1, 2 or 3 groups R13,
(c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which is
Figure US20100240669A1-20100923-C01013
(d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4 which is
Figure US20100240669A1-20100923-C01014
(e) a nine-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is
Figure US20100240669A1-20100923-C01015
(f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, which is
Figure US20100240669A1-20100923-C01016
R1.1 denotes —CN, cyclopropyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
R1.3 independently of one another denotes
(a) F, Cl, Br, —OH, —OCH3, —OCH3, C1-4-alkyl or
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
R1.4 independently of one another denotes
(a) F, Cl, Br, —OH, —OCH3, —OCF3, —NH2, —NH—C1-4-alkyl, —N(C1-4-alkyl)2, —NH—C(O)—C1-4-alkyl, C1-6-alkyl, or
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
or a salt thereof.
5. A compound of the formula I according to claim 1, wherein:
R1 is
Figure US20100240669A1-20100923-C01017
Figure US20100240669A1-20100923-C01018
Figure US20100240669A1-20100923-C01019
or a salt thereof.
6. A compound of the formula I according to claim 1, wherein:
R1 is
Figure US20100240669A1-20100923-C01020
Figure US20100240669A1-20100923-C01021
Figure US20100240669A1-20100923-C01022
or a salt thereof.
7. A compound of the formula I according to claim 1, wherein:
n denotes one of the numbers 0, 1 or 2,
R2 denotes
(a) H,
(b) C1-4-alkyl,
R3 and R4 together with the carbon atom to which they are bound denote a C3-6-cycloalkylene group optionally substituted by a group R3.1 wherein a —CH2— unit may be replaced by a heteroatom O, N, S or by a group CO, SO or SO2,
R3.1 denotes H, —OH,
R5 denotes
(a) H,
(b) C1-4-alkyl,
(c) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R6 independently of one another denotes
(a) H, halogen, —CN, —OH, C3-7-cycloalkyl, —O—CF3, —O—C3-6-cycloalkyl, —N(C1-3-alkyl)2, —C(O)—NH2, —(SO2)NH2, —SO2—C1-3-alkyl, or
(a) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R7 denotes
(a) H, halogen, —CN, —OH,
(b) C1-6-alkyl,
(c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
(d) C3-7-cycloalkyl,
(e) —O—C1-6-alkyl,
(f) —O—C3-7-alkyl,
(g) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
(h) —C(O)—R7.1,
(i) —S—C1-4-alkyl,
R7.1 denotes —NH2, —OH, —O—C1-8-alkyl,
R8 denotes H, halogen, C1-4-alkyl,
R9 denotes
(a) H, halogen, —CN, —OH,
(b) C1-6-alkyl,
(c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
(d) C3-7-cycloalkyl,
(e) C2-4-alkynyl,
(f) —O—C1-6-alkyl,
(g) —O—C3-7-alkyl,
(h) —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2,
(i) —C(O)—R9.1,
(j) —S—C1-4-alkyl, —SO—C1-4-alkyl, —SO2—C1-4-alkyl,
R9.1 denotes —NH2, —OH, —O—C1-8-alkyl,
R10 denotes H, halogen, C1-4-alkyl,
R11 denotes
(a) H, halogen, —CN, —OH,
(b) C1-6-alkyl,
(c) C1-3-alkyl or —O—C1-3-alkyl, wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
(d) C3-7-cycloalkyl,
(e) —O—C1-6-alkyl,
(f) —O—C3-7-alkyl,
(g) —NH2, —NH(O1-3-alkyl), —N(C1-3-alkyl)2,
(h) —C(O)—R11.1,
(i) —S—C1-3-alkyl,
R11.1 denotes —NH2, —OH, —O—C1-8-alkyl, and
X independently of one another represent C—R6 or N,
or a salt thereof.
8. A compound of the formula I according to claim 1, wherein:
R2 denotes H or CH3,
or a salt thereof.
9. A compound of the formula I according to claim 1, wherein:
R2 denotes H,
or a salt thereof.
10. A compound of the formula I according to claim 1, wherein:
R3 and R4 together with the carbon atom to which they are bonded denote a C3-6-cycloalkylene group wherein a —CH2— unit may be replaced by an oxygen atom,
or a salt thereof.
11. A compound of the formula I according to claim 1, wherein:
R3 and R4 together with the carbon atom to which they are bonded denote
Figure US20100240669A1-20100923-C01023
or a salt thereof.
12. A compound of the formula I according to claim 1, wherein:
R5 denotes H or CH3,
or a salt thereof.
13. A compound of the formula I according to claim 1, wherein:
R6 denotes H, F, Cl or methyl,
or a salt thereof.
14. A compound of the formula I according to claim 1, wherein:
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3 or CHF2,
R8 denotes H,
R9 denotes F, Cl, Br, C1-4-alkyl, —S—C1-4-alkyl,
R10 denotes H and
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3 or CHF2,
or a salt thereof.
15. A compound of the formula Ia,
Figure US20100240669A1-20100923-C01024
wherein
R1 denotes
(a) a C1-6-alkyl group optionally substituted by a group R1.1,
(b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
(c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which contains at least one N, O or S atom and which optionally additionally contains one, two or three further N-atoms,
(d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
(e) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
(f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2 unit may be replaced by a —C(O) group,
R1.1 denotes —CN, C3-6-cycloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
R13 independently of one another denotes
(a) F, Cl, Br, —OH, —OCH3, C1-6-alkyl or
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
R1.4 independently of one another denotes
(a) F, Cl, Br, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —NH—C(O)—C1-4-alkyl, C1-6-alkyl, or
(a) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R2 denotes H or CH3,
R3 and R4 together with the carbon atom to which they are bonded denote a C3-6-cycloalkylene group wherein a —CH2— unit may be replaced by an oxygen atom,
R5 denotes H or C1-4-alkyl,
R6 denotes H, F, Cl, Br or C1-4-alkyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
X denotes CH or N,
or a salt thereof.
16. A compound of the formula Ia according to claim 14, wherein
R1 denotes
(a) a C1-6-alkyl group optionally substituted by a group R1.1,
(b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
(c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which is
Figure US20100240669A1-20100923-C01025
(d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is
Figure US20100240669A1-20100923-C01026
(e) a nine-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is
Figure US20100240669A1-20100923-C01027
(f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, which is
Figure US20100240669A1-20100923-C01028
R1.1 denotes —CN, cyclopropyl, —OH, —OCH3, —NH2, —NHCH3, or —N(CH3)2,
R1.3 denotes independently of one another
(a) F, Cl, Br, —OH, —OCH3, —OCF3, or C1-4-alkyl or
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
R1.4 denotes independently of one another
(a) F, Cl, Br, —OH, —OCH3, —OCF3, —NH2, —NH—C1-4-alkyl, —N(C1-4-alkyl)2, —NH—C(O)—C1-4-alkyl, or C1-6-alkyl, or
(a) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R2 denotes H or CH3,
R3 and R4 together with the carbon atom to which they are bonded denote a C3-6-cycloalkylene group wherein a —CH2 unit may be replaced by an oxygen atom,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
X denotes CH or N,
or a salt thereof.
17. A compound of the formula Ia according to claim 14, wherein
R1 denotes
Figure US20100240669A1-20100923-C01029
Figure US20100240669A1-20100923-C01030
Figure US20100240669A1-20100923-C01031
R2 denotes H or CH3,
R3 and R4 together with the carbon atom to which they are bonded denote a C3-6-cycloalkylene group wherein a —CH2 unit may be replaced by an oxygen atom,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
X denotes CH or N,
or a salt thereof.
18. A compound of the formula Ia according to claim 15, wherein
R1 denotes
Figure US20100240669A1-20100923-C01032
Figure US20100240669A1-20100923-C01033
Figure US20100240669A1-20100923-C01034
R2 denotes H or CH3,
R3 and R4 together with the carbon atom to which they are attached denote a C3-6-cycloalkylene group wherein a —CH2— unit may be replaced by an oxygen atom,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
X denotes CH or N,
or a salt thereof.
19. A compounds of the formula Ib
Figure US20100240669A1-20100923-C01035
wherein:
R1 denotes
(a) a C1-6-alkyl group optionally substituted by a group R1.1,
(b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
(c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which contains at least one N, O or S atom and which optionally additionally contains one, two or three further N-atoms,
(d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
(e) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
(f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group,
R1.1 denotes —CN, C3-6-cycloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
R1.3 denotes independently of one another
(a) F, Cl, Br, —OH, —OCH3, C1-6-alkyl or
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
R1.4 denotes independently of one another
(a) F, Cl, Br, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —NH—C(O)—C1-4-alkyl, C1-6-alkyl, or
(a) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R2 denotes H or CH3,
R5 denotes H or C1-4-alkyl,
R6 denotes H, F, Cl, Br or C1-4-alkyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
X denotes CH or N,
or a salt thereof.
20. A compound of the formula Ib according to claim 17, wherein
R1 denotes
(a) a C1-6-alkyl group optionally substituted by a group R1.1,
(b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
(c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which is
Figure US20100240669A1-20100923-C01036
(d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is
Figure US20100240669A1-20100923-C01037
(e) a nine-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is
Figure US20100240669A1-20100923-C01038
(f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, which is
Figure US20100240669A1-20100923-C01039
R1.1 denotes —CN, cyclopropyl, —OH, —OCH3, —NH2, —NHCH3, or —N(CH3)2,
R1.3 denotes independently of one another
(a) F, Cl, Br, —OH, —OCH3, —OCF3, C1-4-alkyl or
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
R1.4 denotes independently of one another
(a) F, Cl, Br, —OH, —OCH3, —OCF3, —NH2, —NH—C1-4-alkyl, —N(C1-4-alkyl)2, —NH—C(O)—C1-4-alkyl, C1-6-alkyl, or
(a) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R2 denotes H or CH3,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
X denotes CH or N,
or a salt thereof.
21. A compound of the formula Ib according to claim 17, wherein
R1 denotes
Figure US20100240669A1-20100923-C01040
Figure US20100240669A1-20100923-C01041
Figure US20100240669A1-20100923-C01042
R2 denotes H or CH3,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
X denotes CH or N,
or a salt thereof.
22. A compound of the formula Ib according to claim 19, wherein
R1 denotes
Figure US20100240669A1-20100923-C01043
Figure US20100240669A1-20100923-C01044
Figure US20100240669A1-20100923-C01045
R2 denotes H,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
X denotes CH or N,
or a salt thereof.
23. A compound of the formula Ic,
Figure US20100240669A1-20100923-C01046
wherein
R1 denotes
(a) a C1-6-alkyl group optionally substituted by a group R1.1,
(b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
(c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which contains at least one N, O or S atom and which optionally additionally contains one, two or three further N-atoms,
(d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
(e) a nine- or ten-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which contains one, two or three N-atoms,
(f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, in which a —CH2— unit may be replaced by a —C(O)— group,
R1.1 denotes —CN, C3-6-cycloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
R1.3 denotes independently of one another
(a) F, Cl, Br, —OH, —OCH3, C1-6-alkyl or
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
R1.4 denotes independently of one another
(a) F, Cl, Br, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —NH—C(O)—C1-4-alkyl, or
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R2 denotes H or CH3,
R5 denotes H or C1-4-alkyl,
R6 denotes H, F, Cl, Br or C1-4-alkyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
X denotes CH or N,
or a salt thereof.
24. A compound of the formula Ic according to claim 20, wherein
R1 denotes
(a) a C1-6-alkyl group optionally substituted by a group R1.1,
(b) a phenyl group optionally substituted by 1, 2 or 3 groups R1.3,
(c) a five-membered heteroaryl group optionally substituted by 1, 2 or 3 groups R1.4, which is
Figure US20100240669A1-20100923-C01047
(d) a six-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is
Figure US20100240669A1-20100923-C01048
(e) a nine-membered heteroaryl group optionally substituted by 1 or 2 groups R1.4, which is
Figure US20100240669A1-20100923-C01049
(f) a 5- or 6-membered heterocyclic group optionally substituted by 1 or 2 groups R1.4, which is
Figure US20100240669A1-20100923-C01050
R1.1 denotes —CN, cyclopropyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2,
R1.3 denotes independently of one another
(a) F, Cl, Br, —OH, —OCH3, —OCF3, C1-4-alkyl or
(b) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms, and
R1.4 denotes independently of one another
(a) F, Cl, Br, —OH, —OCH3, —OCF3, —NH2, —NH—C1-4-alkyl, —N(C1-4-alkyl)2, —NH—C(O)—C1-4-alkyl, C1-6-alkyl, or
(a) a C1-3-alkyl group wherein each methylene group may be substituted by 1 or 2 fluorine atoms and each methyl group may be substituted by 1, 2 or 3 fluorine atoms,
R2 denotes H or CH3,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
X denotes CH or N,
or a salt thereof.
25. A compound of the formula Ic according to claim 20, wherein
R1 denotes
Figure US20100240669A1-20100923-C01051
Figure US20100240669A1-20100923-C01052
Figure US20100240669A1-20100923-C01053
R2 denotes H or CH3,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
X denotes CH or N,
or a salt thereof.
26. A compound of the formula Ic according to claim 23, wherein
R1 denotes
Figure US20100240669A1-20100923-C01054
Figure US20100240669A1-20100923-C01055
Figure US20100240669A1-20100923-C01056
R2 denotes H or CH3,
R5 denotes H or CH3,
R6 denotes H, F, Cl or methyl,
R7 denotes H, F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2,
R9 denotes F, Cl, Br, C1-4-alkyl, —O—C1-4-alkyl, —S—C1-4-alkyl,
R11 denotes F, Cl, Br, —CN, C1-4-alkyl, CF3, CHF2, and
X denotes CH or N,
or a salt thereof.
27. A compound of the formula Id,
Figure US20100240669A1-20100923-C01057
wherein
R1 denotes
Figure US20100240669A1-20100923-C01058
R3 and R4 together with the carbon atom to which they are attached denote a C3-6-cycloalkylene group wherein a —CH2 unit may be replaced by an oxygen atom,
R5 denotes H or CH3,
R6 denotes C1 or CH3,
R7 denotes H or F, and
X denotes CH or N,
or a salt thereof.
28. A compound according to claim 1 selected from the group consisting of:
No. Structure (1)
Figure US20100240669A1-20100923-C01059
 (2)
Figure US20100240669A1-20100923-C01060
 (3)
Figure US20100240669A1-20100923-C01061
 (4)
Figure US20100240669A1-20100923-C01062
 (5)
Figure US20100240669A1-20100923-C01063
 (6)
Figure US20100240669A1-20100923-C01064
 (7)
Figure US20100240669A1-20100923-C01065
 (8)
Figure US20100240669A1-20100923-C01066
 (9)
Figure US20100240669A1-20100923-C01067
 (10)
Figure US20100240669A1-20100923-C01068
 (11)
Figure US20100240669A1-20100923-C01069
 (12)
Figure US20100240669A1-20100923-C01070
 (13)
Figure US20100240669A1-20100923-C01071
 (14)
Figure US20100240669A1-20100923-C01072
 (15)
Figure US20100240669A1-20100923-C01073
 (16)
Figure US20100240669A1-20100923-C01074
 (17)
Figure US20100240669A1-20100923-C01075
 (18)
Figure US20100240669A1-20100923-C01076
 (19)
Figure US20100240669A1-20100923-C01077
 (20)
Figure US20100240669A1-20100923-C01078
 (21)
Figure US20100240669A1-20100923-C01079
 (22)
Figure US20100240669A1-20100923-C01080
 (23)
Figure US20100240669A1-20100923-C01081
 (24)
Figure US20100240669A1-20100923-C01082
 (25)
Figure US20100240669A1-20100923-C01083
 (26)
Figure US20100240669A1-20100923-C01084
 (27)
Figure US20100240669A1-20100923-C01085
 (28)
Figure US20100240669A1-20100923-C01086
 (29)
Figure US20100240669A1-20100923-C01087
 (30)
Figure US20100240669A1-20100923-C01088
 (31)
Figure US20100240669A1-20100923-C01089
 (32)
Figure US20100240669A1-20100923-C01090
 (33)
Figure US20100240669A1-20100923-C01091
 (34)
Figure US20100240669A1-20100923-C01092
 (35)
Figure US20100240669A1-20100923-C01093
 (36)
Figure US20100240669A1-20100923-C01094
 (37)
Figure US20100240669A1-20100923-C01095
 (38)
Figure US20100240669A1-20100923-C01096
 (39)
Figure US20100240669A1-20100923-C01097
 (40)
Figure US20100240669A1-20100923-C01098
 (41)
Figure US20100240669A1-20100923-C01099
 (42)
Figure US20100240669A1-20100923-C01100
 (43)
Figure US20100240669A1-20100923-C01101
 (44)
Figure US20100240669A1-20100923-C01102
 (45)
Figure US20100240669A1-20100923-C01103
 (46)
Figure US20100240669A1-20100923-C01104
 (47)
Figure US20100240669A1-20100923-C01105
 (48)
Figure US20100240669A1-20100923-C01106
 (49)
Figure US20100240669A1-20100923-C01107
 (50)
Figure US20100240669A1-20100923-C01108
 (51)
Figure US20100240669A1-20100923-C01109
 (52)
Figure US20100240669A1-20100923-C01110
 (53)
Figure US20100240669A1-20100923-C01111
 (54)
Figure US20100240669A1-20100923-C01112
 (55)
Figure US20100240669A1-20100923-C01113
 (56)
Figure US20100240669A1-20100923-C01114
 (57)
Figure US20100240669A1-20100923-C01115
 (58)
Figure US20100240669A1-20100923-C01116
 (59)
Figure US20100240669A1-20100923-C01117
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Figure US20100240669A1-20100923-C01118
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Figure US20100240669A1-20100923-C01119
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Figure US20100240669A1-20100923-C01120
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Figure US20100240669A1-20100923-C01441
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Figure US20100240669A1-20100923-C01442
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Figure US20100240669A1-20100923-C01443
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Figure US20100240669A1-20100923-C01444
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Figure US20100240669A1-20100923-C01445
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Figure US20100240669A1-20100923-C01446
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Figure US20100240669A1-20100923-C01447
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Figure US20100240669A1-20100923-C01448
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Figure US20100240669A1-20100923-C01449
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Figure US20100240669A1-20100923-C01450
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Figure US20100240669A1-20100923-C01451
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Figure US20100240669A1-20100923-C01452
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Figure US20100240669A1-20100923-C01453
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Figure US20100240669A1-20100923-C01454
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Figure US20100240669A1-20100923-C01455
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Figure US20100240669A1-20100923-C01456
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Figure US20100240669A1-20100923-C01457
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Figure US20100240669A1-20100923-C01458
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Figure US20100240669A1-20100923-C01459
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Figure US20100240669A1-20100923-C01460
or a salt thereof.
29. A physiologically acceptable salt of a compound according to any one of claims 1 to 28.
30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28 or a physiologically acceptable salt thereof, together with an inert carrier and/or diluent.
31. A method for treatment of acute pain, visceral pain, neuropathic pain, inflammatory/pain receptor-mediated pain, tumour pain and headache which comprises administration to a host in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 28 or a physiologically acceptable salt thereof.
32. A method for treatment of osteoarthritis which comprises administration to a host in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 28 or a physiologically acceptable salt thereof.
US12/711,716 2009-02-26 2010-02-24 New compounds Abandoned US20100240669A1 (en)

Priority Applications (1)

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