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  • C07D213/02—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
  • 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
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
  • C07D213/82—Amides; Imides in position 3
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
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  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
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  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• This invention relates to substituted 4-pyridones and their use as inhibitors of neutrophil elastase activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of pulmonary, gastrointestinal and genitourinary diseases, inflammatory diseases of the skin and the eye and other auto-immune and allergic disorders, allograft rejection, and oncological diseases.
• Neutrophil elastase is a 29 kDa serine protease. It is expressed in bone marrow precursor cells, stored in the granula of peripheral blood granulocytes at high concentrations and it is released upon cellular activation. To the substrates of NE belong major elements of the extracellular matrix: elastin, fibronectin, laminin, collagen and proteoglycans. Neutrophil elastase activity leads to ECM degradation, increases migration and chemotaxis of monocytes and vascular smooth muscle cells and directly effects components of the coagulation and fibrinolytic pathways (PAI-1 and TFPI. Increased activity of neutrophil elastase is associated with chronic inflammatory and fibrotic diseases of several organs. Inhibitors of neutrophil elastase will therefore have an important role for the treatment of different diseases like COPD, fibrosis, cancer and others.
• the compounds according to the present invention are effective as inhibitors of neutrophil elastase and exhibit favourable inhibitory potency, as determined by the half maximal inhibitory concentration (IC 50 ), in an enzymatic inhibition assay.
• Some compounds according to the present invention exhibit favourable inhibitory potency, as determined by the half maximal effective concentration (EC 50 ), in a plasma or whole-blood assay, for instance as described in T. Stevens et al., J. Pharm. Exp. Ther. 339, 313-320 (2011).
• Some compounds according to the present invention exhibit favourable in vivo potency, as determined, for example, by the half maximal effective dose (ED 50 ), in a model of human neutrophil elastase-induced lung injury in mice, for instance as described in Tremblay et al., Chest 121, 582-588 (2002) or T. Stevens et al. ( J. Pharm. Exp. Ther. 2011, 339, 313-320).
• ED 50 half maximal effective dose
• Some compounds according to the present invention exhibit favourable metabolic stability in an in vitro microsomal assay for metabolic stability as described in E. Kerns & L. Di, Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, 1 st ed, 2008, chapter 29 and references therein.
• Some compounds according to the present invention exhibit favourable metabolic stability in an in vitro hepatocytes assay for metabolic stability as described in E. Kerns & L. Di, Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, 1 st ed, 2008, chapter 29 and references therein.
• Some compounds according to the present invention exhibit favourable permeability in an in vitro Caco-2 cell layer method for permeability as described in E. Kerns & L. Di, Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, 1 st ed, 2008, chapter 26 and references therein.
• improved permeability is expected to translate into a higher fraction of the drug absorbed in the intestinal tract, thus, resulting in higher dose-normalized systemic exposure (AUC).
• Some compounds according to the present invention exhibit favourable aqueous solubility in a kinetic or thermodynamic solubility method as described in E. Kerns & L. Di, Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, 1 st ed, 2008, chapter 25 and references therein.
• improved aqueous solubility is expected to translate into a higher fraction of the drug absorbed in the intestinal tract resulting in higher dose-normalized systemic exposure (AUC).
• Comparatively higher dose-normalized systemic exposure can be advantageous in several ways: (1) If a certain systemic exposure (AUC) needs to be achieved for efficacy, the drug can be dosed in a lower amount. Lower dosages have the advantages of lower drug load (parent drug and metabolites thereof) for the patient causing potentially less side effects, and lower production costs for the drug product. (2) Comparatively higher dose-normalized systemic exposure (AUC) can lead to increased efficacy or longer duration of action of the drug when the same dose is applied.
• Some compounds according to the present invention exhibit favourable metabolic stability, favourable permeability and favourable aqueous solubility. Accordingly, some compounds of the present invention are expected to exhibit favourable pharmacokinetic (PK) properties, in particular favourable systemic exposure (area under the curve, AUC).
• PK pharmacokinetic
• PK properties can be determined in pre-clinical animal species, for example mouse, rat, dog, guinea pig, mini pig, cynomolgus monkey, rhesus monkey.
• the PK properties of a compound can be described, for example, by the following parameters: Mean residence time (MRT), elimination half-live (t 1/2 ), volume-of-distribution (V D ), area under the curve (AUC), clearance (CL), bioavailability after oral administration (F oral ).
• A is phenyl or a five- or six-membered, aromatic heteroring, wherein one, two or three elements are replaced by an element selected independent from each other from the group consisting of N, O, S and (O ⁇ N + );
• A is a ring system of two fused five- or six-membered, aromatic heterorings, wherein one, two or three elements are replaced by an element selected independent from is each other from the group consisting of N, O, S and (O ⁇ N + );
• R 4 is one of the above mentioned rings carrying the above mentioned optional substituted in meta-position to the element connection R 4 with the compound of formula 1.
• C 1-6 -alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
• radical attachment point(s) to the molecule from the free valences of the group itself.
• the last named subgroup is the radical attachment point, for example, the substituent “aryl-C 1-3 -alkyl-” means an aryl group which is bound to a C 1-3 -alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
• 3-carboxypropyl-group represents the following substituent:
• the asterisk, dashed or dotted line may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
• substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.
• a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc. . . . ) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
• halogen generally denotes fluorine, chlorine, bromine and iodine.
• prodrug refers to (i) an inactive form of a drug that exerts its effects after metabolic processes within the body converting it to a usable or active form, or (ii) a substance that gives rise to a pharmacologically active metabolite, although not itself active (i.e. an inactive precursor).
• prodrug or “prodrug derivative” mean a covalently-bonded derivative, carrier or precursor of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s).
• prodrugs either have metabolically cleavable or otherwise convertible groups and are rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood or by activation via oxidation as in case of thioether groups.
• Most common prodrugs include esters and amide analogs of the parent compounds.
• prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity).
• prodrugs themselves have weak or no biological activity and are stable under ordinary conditions.
• Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: “Design and Applications of Prodrugs”; Design of Prodrugs, H.
• pharmaceutically acceptable prodrug means a prodrug of a compound of the invention which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.
• phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
• examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
• such salts include salts from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine (2,2′-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2′,2′′-nitrilotris(ethanol)), tromethamine, zinc hydroxide, acetic acid, 2.2-dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid,
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
• Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention e.g. trifluoro acetate salts
• Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention also comprise a part of the invention.
• C 1-n -alkyl wherein n is an integer from 2 to 4 or 6 (preferably 4), either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms.
• C 1-5 -alkyl embraces the radicals H 3 C—, H 3 C—CH 2 —, H 3 C—CH 2 —CH 2 —, H 3 C—CH(CH 3 )—, H 3 C—CH 2 —CH 2 —CH 2 —, H 3 C—CH 2 —CH(CH 3 )—, H 3 C—CH(CH 3 )—CH 2 —, H 3 C—C(CH 3 ) 2 —, H 3 C—CH 2 —CH 2 —CH 2 —CH 2 —, H 3 C—CH 2 —CH(CH 3 )—, H 3 C—CH 2 —CH(CH 3 )—CH 2 —, H 3 C—CH(CH 3 )—CH 2 —CH 2 —, H 3 C—CH(CH 3 )—CH 2 —CH 2 —, H 3 C—CH 2 —C(CH 3 ) 2 —, H 3 C—C(CH 3 ) 2 —CH 2 —, H 3 C—CH(
• C n-m -alkylene wherein n is an integer 2 or 3 and m is 4 or 5, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 2 to 5 carbon atoms.
• C 2-4 -alkylene includes —CH 2 —CH 2 —, —CH(CH 3 )—, —CH 2 —CH 2 —CH 2 —, —C(CH 3 ) 2 —, —CH(CH 2 CH 3 )—, —CH(CH 3 )—CH 2 —, —CH 2 —CH(CH 3 )—, —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH(CH 3 )—, —CH(CH 3 )—CH 2 —CH 2 —, —CH 2 —CH(CH 3 )—CH 2 —, —CH 2 —C(CH 3 ) 2 —, —C(CH 3 ) 2 —CH 2 —, —CH(CH 3 )—CH(CH 3 )—, —CH 2 —CH(CH 2 CH 3 )—, —CH(CH 2 CH 3 )—CH 2 —,
• halo added to a “alkyl”, “alkylene” or “cycloalkyl” group (saturated or unsaturated) is such a alkyl or cycloalkyl group meant wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferred is fluorine. Examples include: H 2 FC—, HF 2 C—, F 3 C—.
• C 3-n -cycloalkyl wherein n is an integer from 4 to 6, either alone or in is combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms.
• C 3-6 -cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• aryl as used herein, either alone or in combination with another radical, denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second five- or six-membered, carbocyclic group which may be aromatic, saturated or unsaturated.
• Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.
• a phenyl ring contains 6 elements which are all carbon atoms
• a pyrrol ring contains 5 elements, wherein 4 elements are carbon atoms and the remaining element is a nitrogen atom.
• the term is intended to include all possible isomeric forms.
• the term includes (if not otherwise restricted) the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
• the term is intended to include all possible isomeric forms.
• the term includes (if not otherwise restricted) the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
• the term is intended to include all possible isomeric forms.
• the term includes (if not otherwise restricted) the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
• the compounds according to the present invention and their intermediates may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis.
• the compounds are obtained in analogous fashion to the methods of preparation explained more fully hereinafter, in particular as described in the experimental section.
• the order in carrying out the reaction steps may be varied. Variants of the reaction methods that are known to the one skilled in the art but not described in detail here may also be used.
• the general processes for preparing the compounds according to the invention will become apparent to the one skilled in the art studying the following schemes.
• Starting materials are commercially available or may be prepared by methods that are described in the literature or herein, or may be prepared in an analogous or similar manner.
• Any functional groups in the starting materials or intermediates may be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage within the reaction sequence using methods familiar to the one skilled in the art.
• Starting material I can be prepared as described in US2003/87940.
• Intermediates II can be prepared as described in WO10133973 and US2003/87940 by heating starting material I with amines R—NH 2 in the presence of a strong base, for example sodium tert-butoxide or sodium ethoxide, in an organic solvent, for example ethanol. The reaction usually takes place within 2 to 72 hours. Preferred reaction temperatures are between 50° C. and 150° C.
• the amide coupling (Step B, intermediates II ⁇ intermediates III, intermediates IV ⁇ intermediates V, intermediates VI ⁇ compounds of the invention) can be achieved by reacting carboxylic acid intermediates II, IV or VI with amines R′—NH 2 in the presence of an amide coupling reagent, for example O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) or O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) or propylphosphonic anhydride (PPA), and in the presence of a base, for example triethylamine, diisopropylethylamine (DIPEA, Hünig's base) or N-methyl-morpholine, in an organic solvent, for example dichloromethane, acetonitrile, N,N
• reaction usually takes place within 1 to 72 hours. Preferred reaction temperatures are between 0° C. and 50° C., most preferred room temperature.
• carboxylic acid intermediates can be activated first as described in US2003/87940, for example with 1,1′-carbonyldiimidazole (CDI) in DMF, followed by reaction with the amine R′—NH 2 .
• CDI 1,1′-carbonyldiimidazole
• bromination agents for example bromine or N-bromosuccinimide
• iodination agents for example iodine, iodinechloride (I—Cl) or N-iodosuccinimide
• organic solvent for example acetic acid, methanol, ethanol, dichloromethane, acetonitrile, N,N-dimethylformamide, tetrahydrofuran or mixtures thereof.
• the halogenation reaction usually takes place within 1 to 72 hours.
• Step D intermediates IV ⁇ intermediates VI, intermediates V ⁇ compounds according to the invention
• aryl or heteroaryl boronic acids R′′—B(OH) 2 or the corresponding boronic esters in the presence of a palladium catalyst, for example tetrakis(triphenylphosphine)palladium(0) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
• a base for example, potassium carbonate, barium dihydroxide or cesium carbonate
• organic solvent for example toluene, benzene, ethanol, ethylene glycol dimethyl ether, acetonitrile, dioxane or mixtures thereof, optionally in the presence of water.
• Preferred reaction temperatures are between 50° C. and 150° C.
• the alkylation of the pyridone nitrogen can be achieved by reacting intermediate VII with alkylating agents, for example alkyl bromides, alkyl iodides, alkyl tosylates, alkyl mesylates or dialkyl sulfates, in the presence of a base, for example sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide or cesium carbonate, in an organic solvent, N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP) or dimethylacetamide (DMA).
• alkylating agents for example alkyl bromides, alkyl iodides, alkyl tosylates, alkyl mesylates or dialkyl sulfates
• a base for example sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide or cesium carbonate
• DMF N,N-dimethylformamide
• NMP N-methyl-2-pyrrolidone
• Preparation 2 is prepared following the procedure for preparation 1, substituting 4-methylsulfonylbenzylamine hydrochloride with C-(5-methanesulfonyl-pyridin-2-yl)-methylamine.
• Preparation 3d is prepared following the procedure for preparation 4, substituting 3-(difluoromethyl)phenylboronic acid with 3-(trifluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 340; Retention time HPLC: 0.99 min (Z018_S04).
• Preparation 6a is prepared following the procedure for preparation 3b, substituting isopropylamine with cyclopropylamine.
• ESI mass spectrum: [M+H] + 194; Retention time HPLC: 0.53 min (Z002 — 002).
• Preparation 6b is prepared following the procedure for preparation 3c, substituting preparation 3b with preparation 6a.
• ESI mass spectrum: [M+H] + 272 (bromine isotope pattern); Retention time HPLC: 0.79 min (Z002 — 002).
• Preparation 6c is prepared following the procedure for preparation 4, substituting preparation 3c with preparation 6b and 3-(difluoromethyl)phenylboronic acid with 3-(trifluoromethyl)phenylboronic acid.
• Preparation 7a is prepared following the procedure for preparation 3b, substituting isopropylamine with cyclobutylamine.
• ESI mass spectrum: [M+H] + 208; Retention time HPLC: 0.62 min (Z002 — 002).
• Preparation 7b is prepared following the procedure for preparation 3c, substituting preparation 3b with preparation 7a.
• ESI mass spectrum: [M+H] + 286 (bromine isotope pattern); Retention time HPLC: 0.86 min (Z002 — 002).
• Preparation 7c is prepared following the procedure for preparation 4, substituting preparation 3c with preparation 7b and 3-(difluoromethyl)phenylboronic acid with 3-(trifluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 352; Retention time HPLC: 0.67 min (Z003 — 001).
• Preparation 8a is prepared following the procedure for preparation 3b, substituting isopropylamine with cyclopentylamine.
• ESI mass spectrum: [M+H] + 222; Retention time HPLC: 0.72 min (Z002 — 002).
• Preparation 8b is prepared following the procedure for preparation 3c, substituting preparation 3b with preparation 8a.
• ESI mass spectrum: [M+H] + 300 (bromine isotope pattern); Retention time HPLC: 0.90 min (Z002 — 002).
• Preparation 8c is prepared following the procedure for preparation 4, substituting preparation 3c with preparation 8b and 3-(difluoromethyl)phenylboronic acid with 3-(trifluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 366; Retention time HPLC: 0.71 min (Z003 — 001).
• Preparation 9 is prepared following the procedure for preparation 4, substituting preparation 3c with preparation 8b.
• ESI mass spectrum: [M+H] + 348; Retention time HPLC: 0.61 min (Z003 — 001).
• Preparation 10a is prepared following the procedure for preparation 3b, substituting isopropylamine with ethylamine.
• ESI mass spectrum: [M+H] + 182; Retention time HPLC: 0.63 min (Z002 — 006).
• Preparation 10b is prepared following the procedure for preparation 3c, substituting preparation 3b with preparation 10a.
• ESI mass spectrum: [M+H] + 260 (bromine isotope pattern); Retention time HPLC: 0.89 min (Z002 — 007).
• Preparation 10c is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 10b.
• ESI mass spectrum: [M+H] + 427 (bromine isotope pattern); Retention time HPLC: 0.77 min (Z003 — 001).
• Preparation 11a is prepared following the procedure for preparation 3b, substituting isopropylamine with (R)-2-aminobutane.
• ESI mass spectrum: [M+H] + 210; Retention time HPLC: 0.86 min (Z002 — 006).
• Preparation 11b is prepared following the procedure for preparation 3c, substituting preparation 3b with preparation 11a.
• ESI mass spectrum: [M+H] + 288 (bromine isotope pattern); Retention time HPLC: 1.08 min (Z002 — 006).
• Preparation 11c is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 11b.
• ESI mass spectrum: [M+H] + 455 (bromine isotope pattern); Retention time HPLC: 0.93 min (Z018_S04).
• Preparation 12a is prepared following the procedure for preparation 3b, substituting isopropylamine with (S)-2-aminobutane.
• ESI mass spectrum: [M+H] + 210; Retention time HPLC: 0.86 min (Z002 — 006).
• Preparation 12b is prepared following the procedure for preparation 3c, substituting preparation 3b with preparation 12a.
• ESI mass spectrum: [M+H] + 288 (bromine isotope pattern); Retention time HPLC: 1.08 min (Z002 — 006).
• Preparation 12c is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 12b.
• ESI mass spectrum: [M+H] + 455 (bromine isotope pattern); Retention time HPLC: 0.93 min (Z018_S04).
• Preparation 13a is prepared following the procedure for preparation 3b, substituting isopropylamine with 2-methoxyethylamine.
• ESI mass spectrum: [M+H] + 212; Retention time HPLC: 0.65 min (Z002 — 005).
• Preparation 13c is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 13b and HTBU with TBTU as coupling reagent.
• ESI mass spectrum: [M+H] + 505; Retention time HPLC: 1.11 min (Z002 — 005).
• Preparation 14a is prepared following the procedure for preparation 3b, substituting isopropylamine with tetrahydrofuran-3-ylamine.
• ESI mass spectrum: [M+H] + 224; Retention time HPLC: 0.55 min (Z002 — 006).
• Preparation 14b is prepared following the procedure for preparation 3c, substituting preparation 3b with preparation 14a.
• ESI mass spectrum: [M+H] + 302 (bromine isotope pattern); Retention time HPLC: 0.71 min (Z018_S04).
• Preparation 14c is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 14b.
• ESI mass spectrum: [M+H] + 469 (bromine isotope pattern); Retention time HPLC: 0.82 min (Z018_S04).
• Preparation 15a is prepared following the procedure for preparation 3b, substituting isopropylamine with 3-aminopentane.
• ESI mass spectrum: [M+H] + 224; Retention time HPLC: 0.76 min (Z018_S04).
• Preparation 15b is prepared following the procedure for preparation 3c, substituting preparation 3b with preparation 15a.
• ESI mass spectrum: [M+H] + 302 (bromine isotope pattern); Retention time HPLC: 0.91 min (Z018_S04).
• Preparation 15c is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 15b.
• ESI mass spectrum: [M+H] + 469 (bromine isotope pattern); Retention time HPLC: 0.94 min (Z018_S04).
• Preparation 17 is prepared following the procedure for preparation 5, substituting 4-methylsulfonylbenzylamine hydrochloride with C-(5-methanesulfonyl-pyridin-2-yl)-methylamine.
• Preparation 18 is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 7b and 4-methylsulfonylbenzylamine hydrochloride with C-(5-methanesulfonyl-pyridin-2-yl)-methylamine.
• Preparation 19 is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 11b and 4-methylsulfonylbenzylamine hydrochloride with C-(5-methanesulfonyl-pyridin-2-yl)-methylamine.
• Preparation 20 is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 12b and 4-methylsulfonylbenzylamine hydrochloride with C-(5-methanesulfonyl-pyridin-2-yl)-methylamine.
• Preparation 22 is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 13b, 4-methylsulfonylbenzylamine hydrochloride with C-(5-methanesulfonyl-pyridin-2-yl)-methylamine and HBTU with TBTU.
• Preparation 22 is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 14b and 4-methylsulfonylbenzylamine hydrochloride with C-(5-methanesulfonyl-pyridin-2-yl)-methylamine.
• ESI mass spectrum: [M+H] + 470 (bromine isotope pattern); Retention time HPLC: 0.77 min (Z018_S04).
• Preparation 23 is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 15b and 4-methylsulfonylbenzylamine hydrochloride with C-(5-methanesulfonyl-pyridin-2-yl)-methylamine.
• ESI mass spectrum: [M+H] + 470 (bromine isotope pattern); Retention time HPLC: 0.91 min (Z018_S04).
• Preparation 24 is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 7b and 4-methylsulfonylbenzylamine hydrochloride with C-(5-methyl-[1,3,4]oxadiazol-2-yl)-methylamine.
• Preparation 25 is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 11b and 4-methylsulfonylbenzylamine hydrochloride with C-(5-methyl-[1,3,4]oxadiazol-2-yl)-methylamine.
• Preparation 26 is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 12b and 4-methylsulfonylbenzylamine hydrochloride with C-(5-methyl-[1,3,4]oxadiazol-2-yl)-methylamine.
• Preparation 17 is prepared following the procedure for preparation 5, substituting 4-methylsulfonylbenzylamine hydrochloride with 4-methylsulfinylbenzylamine hydrochloride (Array, A1176-1).
• Preparation 28 is prepared following the procedure for preparation 5, substituting 4-methylsulfonylbenzylamine hydrochloride with 4-methanesulfonyl-3-methyl-benzylamine (FCHGROUP).
• ESI mass spectrum: [M+H] + 455 (bromine isotope pattern); Retention time HPLC: 0.74 min (Z011_S03).
• Preparation 29 is prepared following the procedure for preparation 5, substituting 4-methylsulfonylbenzylamine hydrochloride with C-(1,1-dioxo-2,3-dihydro-1H-1 ⁇ 6 -benzo[b]thiophen-5-yl)-methylamine (FCHGROUP).
• Example 1.1 The following Examples are prepared as described for Example 1.1, employing the corresponding alkylating agents instead of iodoethane, respectively.
• Example 3.1 The following examples are prepared as described for Example 3.1, substituting N-methylmorpholine with triethylamine and employing the appropriate amines, respectively.
• Example 5.1 The following examples are prepared as described for Example 5.1, employing the appropriate aryl- or heteroarylboronic acids.
• Example 6 is prepared as described for Example 3.1, substituting preparation 3 with preparation 6 and substituting C-(5-methyl-1,3,4-oxadiazol-2-yl)-methylamine with 4-methylsulfonylbenzylamine hydrochloride.
• ESI mass spectrum: [M+H] + 505; Retention time HPLC: 0.60 min (Z003 — 001).
• Example 7 is prepared as described for Example 9, substituting preparation 3 with preparation 7 and substituting C-(5-methyl-1,3,4-oxadiazol-2-yl)-methylamine with 4-methylsulfonylbenzylamine hydrochloride.
• ESI mass spectrum: [M+H] + 519; Retention time HPLC: 1.06 min (Z003 — 001).
• Example 8.1 is prepared following the procedure for Example 3.1, substituting preparation 3 with preparation 8.
• ESI mass spectrum: [M+H] + 461; Retention time HPLC: 1.03 min (Z003 — 001).
• Example 9.2 is prepared as described for Example 3.1, substituting preparation 3 with preparation 8 and substituting C-(5-methyl-1,3,4-oxadiazol-2-yl)-methylamine with 4-methylsulfonylbenzylamine hydrochloride.
• ESI mass spectrum: [M+H] + 533; Retention time HPLC: 1.08 min (Z003 — 001).
• Example 9.2 is prepared as described for Example 3.1, substituting preparation 3 with preparation 9 and substituting C-(5-methyl-1,3,4-oxadiazol-2-yl)-methylamine with 4-methylsulfonylbenzylamine hydrochloride.
• ESI mass spectrum: [M+H] + 515; Retention time HPLC: 1.02 min (Z003 — 001).
• Example 10 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 10 and 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 475; Retention time HPLC: 0.95 min (Z003 — 001).
• Example 11.1 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 11 and 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 503; Retention time HPLC: 0.96 min (Z003 — 001).
• Example 11.2 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 11 and 3-(trifluoromethyl)phenylboronic acid with 2-(trifluoromethyl)pyridine-4-boronic acid.
• ESI mass spectrum: [M+H] + 522; Retention time HPLC: 0.92 min (Z003 — 001).
• Example 12.1 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 12.
• ESI mass spectrum: [M+H] + 521; Retention time HPLC: 1.05 min (Z003 — 001).
• Example 12.2 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 12 and 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 503; Retention time HPLC: 0.96 min (Z003 — 001).
• Example 12.3 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 12 and 3-(trifluoromethyl)phenylboronic acid with 2-(trifluoromethyl)pyridine-4-boronic acid.
• ESI mass spectrum: [M+H] + 522; Retention time HPLC: 0.92 min (Z003 — 001).
• Example 13 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 13.
• ESI mass spectrum: [M+H] + 523; Retention time HPLC: 1.18 min (Z003 — 003).
• Example 14.1 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 14.
• ESI mass spectrum: [M+H] + 517; Retention time HPLC: 0.77 min (Z011_S03).
• Example 14.2 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 14 and 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 535; Retention time HPLC: 0.94 min (Z003 — 001).
• Example 15.1 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 15.
• ESI mass spectrum: [M+H] + 535; Retention time HPLC: 1.11 min (Z018_S04).
• Example 15.2 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 15 and 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 517; Retention time HPLC: 1.06 min (Z018_S04).
• Example 15.3 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 15 and 3-(trifluoromethyl)phenylboronic acid with 2-(trifluoromethyl)pyridine-4-boronic acid.
• ESI mass spectrum: [M+H] + 536; Retention time HPLC: 1.02 min (Z018_S04).
• Example 17.1 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 17.
• ESI mass spectrum: [M+H] + 508; Retention time HPLC: 1.03 min (Z003 — 001).
• Example 17.2 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 17 and 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 490; Retention time HPLC: 0.86 min (Z003 — 001).
• Example 17.3 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 17 and 3-(trifluoromethyl)phenylboronic acid with 2-(trifluoromethyl)pyridine-4-boronic acid.
• ESI mass spectrum: [M+H] + 509; Retention time HPLC: 0.81 min (Z003 — 001).
• Example 18.1 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 18.
• ESI mass spectrum: [M+H] + 520; Retention time HPLC: 1.06 min (Z003 — 001).
• Example 18.2 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 18 and 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 502; Retention time HPLC: 0.91 min (Z003 — 001).
• Example 19.1 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 19.
• ESI mass spectrum: [M+H] + 522; Retention time HPLC: 1.01 min (Z003 — 001).
• Example 19.2 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 19 and 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 504; Retention time HPLC: 0.91 min (Z003 — 001).
• Example 19.3 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 19 and 3-(trifluoromethyl)phenylboronic acid with 2-(trifluoromethyl)pyridine-4-boronic acid.
• ESI mass spectrum: [M+H] + 523; Retention time HPLC: 0.87 min (Z003 — 001).
• Example 20.1 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 20.
• ESI mass spectrum: [M+H] + 522; Retention time HPLC: 1.01 min (Z003 — 001).
• Example 20.2 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 20 and 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 504; Retention time HPLC: 0.92 min (Z002 — 006).
• Example 20.3 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 20 and 3-(trifluoromethyl)phenylboronic acid with 2-(trifluoromethyl)pyridine-4-boronic acid.
• ESI mass spectrum: [M+H] + 523; Retention time HPLC: 0.87 min (Z003 — 001).
• Example 21 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 21.
• ESI mass spectrum: [M+H] + 524; Retention time HPLC: 1.30 min (Z002 — 005).
• Example 22 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 22.
• ESI mass spectrum: [M+H] + 518; Retention time HPLC: 0.74 min (Z011_S03).
• Example 23.1 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 23.
• ESI mass spectrum: [M+H] + 536; Retention time HPLC: 1.00 min (Z018_S04).
• Example 23.2 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 23 and 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 518; Retention time HPLC: 1.01 min (Z018_S04).
• Example 23.3 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 23 and 3-(trifluoromethyl)phenylboronic acid with 2-(trifluoromethyl)pyridine-4-boronic acid.
• ESI mass spectrum: [M+H] + 537; Retention time HPLC: 0.98 min (Z018_S04).
• Example 24.2 is prepared following the procedure for Example 24.1, substituting 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 429; Retention time HPLC: 0.89 min (Z003 — 001).
• Example 25.1 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 25.
• ESI mass spectrum: [M+H] + 449; Retention time HPLC: 1.03 min (Z003 — 001).
• Example 25.2 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 25 and 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 431; Retention time HPLC: 0.90 min (Z003 — 001).
• Example 26 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 26 and 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 431; Retention time HPLC: 0.90 min (Z003 — 001).
• Example 27.1 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 27.
• ESI mass spectrum: [M+H] + 491; Retention time HPLC: 1.41 min (Z002 — 006).
• Example 27.2 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 27 and 3-(trifluoromethyl)phenylboronic acid with 2-(trifluoromethyl)pyridine-4-boronic acid.
• ESI mass spectrum: [M+H] + 492; Retention time HPLC: 1.28 min (Z002 — 006).
• Example 28.1 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 28.
• ESI mass spectrum: [M+H] + 521; Retention time HPLC: 0.90 min (Z011_S03).
• Example 28.2 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 28 and 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 503; Retention time HPLC: 0.84 min (Z011_S03).
• Example 28.3 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 28 and 3-(trifluoromethyl)phenylboronic acid with 2-(trifluoromethyl)pyridine-4-boronic acid.
• ESI mass spectrum: [M+H] + 522; Retention time HPLC: 0.81 min (Z011_S03).
• Example 29.1 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 29.
• ESI mass spectrum: [M+H] + 519; Retention time HPLC: 0.87 min (Z011_S03).
• Example 29.2 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 29 and 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 501; Retention time HPLC: 0.81 min (Z011_S03).
• Example 29.3 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 29 and 3-(trifluoromethyl)phenylboronic acid with 2-(trifluoromethyl)pyridine-4-boronic acid.
• ESI mass spectrum: [M+H] + 520; Retention time HPLC: 0.79 min (Z011_S03).
• racemic example 27.1 147 mg are separated by chiral HPLC (Daicel IB, 250 mm ⁇ 20 mm, 10% MeOH+0.2% diethylamine in supercritical CO 2 , 40° C.).
• Preparation 31c is prepared as described for Example 3.1, substituting N-methylmorpholine with triethylamine and substituting C-(5-methyl-[1,3,4]oxadiazol-2-yl)-methylamine with 4-cyclopropanesulfonyl-benzylamine (preparation 31b).
• 3-Chloroperoxybenzoic acid (77%, 8.3 g, 37.2 mmol) is added to a mixture of 2-(3-fluoro-4-methylsulfanyl-benzyl)-isoindole-1,3-dione (preparation 32a, 6.00 g, 18.9 mmol) and dichloromethane (580 mL). After 1 h saturated aqueous sodium thiosulfate solution is added, and the mixture is extracted with dichloromethane. The organic layer is dried under reduced pressure, and the residue is purified by flash chromatography on silica (cyclohexane/ethyl acetate 5:1).
• the purified intermediate 2-(3-fluoro-4-methylsulfonyl-benzyl)-isoindole-1,3-dione (5.50 g, 15.6 mmol) is dissolved in a mixture of methanol (250 mL) and dichloromethane (250 mL). Hydrazine hydrate (4.6 g, 78.4 mmol) is added, and the mixture is stirred at 60° C. for 3 h. The mixture is filtered, and the filtrate is treated with water. The mixture is extracted with ethyl acetate, and the organic layer is dried over Na 2 SO 4 and concentrated under reduced pressure.
• Example 33 is prepared as described for Example 32, substituting preparation 3 with preparation 4.
• ESI mass spectrum: [M+H] + 507; Retention time HPLC: 0.54 min (001_CA07).
• Preparation 34c is prepared in analogy to preparation 32b, using 2-(2-fluoro-4-methylsulfanyl-benzyl)-isoindole-1,3-dione (preparation 34b) as starting material.
• ESI mass spectrum: [M+H] + 204; Retention time HPLC: 1.40 min (0-30HPLC).
• Example 34 is prepared as described for Example 32, substituting preparation 32b with preparation 34c.
• ESI mass spectrum: [M+H] + 525; Retention time HPLC: 0.86 min (005_CA01).
• Example 35 is prepared as described for Example 32, substituting preparation 32b with preparation 34c and substituting preparation 3 with preparation 4.
• ESI mass spectrum: [M+H] + 507; Retention time HPLC: 0.53 min (002_CA07).
• Preparation 36b is prepared in analogy to preparation 32b, using 2-(4-methanesulfanyl-2-methyl-benzyl)-isoindole-1,3-dione (preparation 36a) as starting material.
• ESI mass spectrum: [M+H] + 200; Retention time HPLC: 2.12 min (CD00).
• Example 36 is prepared as described for Example 32, substituting preparation 32b with preparation 36b.
• ESI mass spectrum: [M+H] + 521; Retention time HPLC: 0.86 min (005_CA01).
• Example 37 is prepared as described for Example 32, substituting preparation 32b with preparation 36b and substituting preparation 3 with preparation 4.
• ESI mass spectrum: [M+H] + 503; Retention time HPLC: 0.54 min (001_CA07).
• Preparation 38a is prepared as described for Preparation 5, substituting preparation 3c with preparation 3 and substituting 4-methylsulfonylbenzylamine hydrochloride with 5,7-dihydroimidazo[1,2-C]thiazol-2-ylmethanamine (Chembridge).
• Preparation 39a is prepared following the procedure for preparation 5, substituting 4-methylsulfonylbenzylamine hydrochloride with (5-methanesulfonylthiophen-2-yl)methanamine hydrochloride (Enamine).
• Example 39 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 39a.
• ESI mass spectrum: [M+H] + 513; Retention time HPLC: 0.89 min (Z011_S03).
• Example 40 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 39a and replacing 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 495; Retention time HPLC: 0.82 min (Z011_S03).
• Preparation 41a is prepared following the procedure for preparation 3b, substituting isopropylamine with (S)-1-methoxy-2-propylamine.
• ESI mass spectrum: [M+H] + 226; Retention time HPLC: 0.65 min (Z018_S04).
• Preparation 41b is prepared following the procedure for preparation 3c, substituting preparation 3b with preparation 41a.
• ESI mass spectrum: [M+H] + 304 (bromine isotope pattern); Retention time HPLC: 0.81 min (Z018_S04).
• Preparation 41c is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 41b.
• ESI mass spectrum: [M+H] + 471 (bromine isotope pattern); Retention time HPLC: 0.88 min (Z018_S04).
• Example 41 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 41c.
• ESI mass spectrum: [M+H] + 537; Retention time HPLC: 1.02 min (Z018_S04).
• Example 42 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 41c and replacing 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 519; Retention time HPLC: 0.97 min (Z018_S04).
• Preparation 43a is prepared following the procedure for preparation 3b, substituting isopropylamine with (R)-1-methoxy-2-propylamine.
• ESI mass spectrum: [M+H] + 226; Retention time HPLC: 0.65 min (Z018_S04).
• Preparation 43b is prepared following the procedure for preparation 3c, substituting preparation 3b with preparation 43a.
• ESI mass spectrum: [M+H] + 304 (bromine isotope pattern); Retention time HPLC: 0.81 min (Z018_S04).
• Preparation 43c is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 43b.
• ESI mass spectrum: [M+H] + 471 (bromine isotope pattern); Retention time HPLC: 0.88 min (Z018_S04).
• Example 43 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 43c.
• ESI mass spectrum: [M+H] + 537; Retention time HPLC: 1.04 min (Z018_S04).
• Example 44 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 43c and replacing 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid.
• ESI mass spectrum: [M+H] + 519; Retention time HPLC: 0.97 min (Z018_S04).
• Example 45 is prepared as described for Example 1.1, substituting iodoethane with 1-bromo-2-fluoroethane and substituting DMF with NMP.
• ESI mass spectrum: [M+H] + 511; Retention time HPLC: 0.99 min (Z018_S04).
• Example 46 is prepared as described for Example 1.1, substituting iodoethane with 2-bromo-1,1-difluoroethane and substituting DMF with NMP.
• ESI mass spectrum: [M+H] + 529; Retention time HPLC: 0.86 min (Z011_S03).
• Example 47 is prepared as described for Example 32, substituting preparation 32b with 4-methanesulfonyl-2-methoxy-benzylamine (preparation described in WO2006/67462).
• ESI mass spectrum: [M+H] + 537; Retention time HPLC: 1.03 min (Z017_S04).
• Example 48 is prepared as described for Example 3.1, substituting C-(5-Methyl-[1,3,4]oxadiazol-2-yl)-methylamine with preparation 48c and substituting N-methylmorpholine with triethylamine.
• ESI mass spectrum: [M+H] + 517; Retention time HPLC: 0.85 min (005_CA01).
• Example 49 is prepared as described for Example 32, substituting preparation 32b with 4-methanesulfonyl-3-methoxy-benzylamine (preparation described in WO2004/43924).
• ESI mass spectrum: [M+H] + 537; Retention time HPLC: 1.03 min (Z018_S04).
• Example 50 is prepared as described for Example 32, substituting preparation 3 with preparation 4 and substituting preparation 32b with preparation 48c.
• ESI mass spectrum: [M+H] + 499; Retention time HPLC: 0.54 min (001_CA07).
• Human neutrophil elastase was purchased from Calbiochem (Cat. No. 324681) and the elastase substrate MeOSuc-Ala-Ala-Pro-Val-AMC from Bachem (Cat. No.: I-1270). All other materials were of the highest grade commercially available.
• Compound buffer 100 mM Tris, 500 mM NaCl, adjusted to pH 7.5
• Assay buffer 100 mM Tris, 500 mM NaCl, adjusted to pH 7.5, containing 0.01% BSA.
• Test compounds were prediluted in DMSO and subsequently in compound buffer (5% DMSO final). 5 ⁇ L of these compound dilutions were mixed with 10 ⁇ l Neutrophil elastase (9 ng/ml in assay buffer) in a black 384 well OptiPlate (Perkin Elmer, Cat No.: 6007270) and incubated for 15 min at room temperature. Subsequently 10 ⁇ L substrate solution in assay buffer were added (250 ⁇ M final concentration) and the plates were incubated for 60 min at room temperature. After inactivation of the enzyme, fluorescence intensities were measured at 380 nm excitation and 460 nm emission wavelengths.
• Each plate contains wells with a high value control (DMSO+enzyme+substrate) and wells with a low value control (DMSO+inactivated enzyme+substrate).
• 1050 values were estimated using a sigmoidal concentration response curve with variable slope. Means of low values were taken as 0%, means of high values as 100%. 1050 values of selected compound in the Neutrophil Elastase assay:
• Example IC50 [nM] 1.1 33 1.2 12 1.3 28 1.4 59 1.5 30 1.6 77 1.7 37 10 29 11.1 8 11.2 35 12.1 9 12.2 12 12.3 54 13 42 14.1 20 14.2 27 15.1 8 15.2 8 15.3 24 16 63 17.1 73 17.2 15 17.3 77 18.1 32 18.2 35 19.1 10 19.2 10 19.3 40 2.1 57 2.2 20 2.3 30 2.4 73 20.1 15 20.2 11 20.3 63 21 43 22 27 23.1 12 23.2 5 23.3 46 24.1 57 24.2 55 25.1 37 25.2 30 26 22 27.1 9 27.2 51 28.1 7 28.2 6 28.3 27 29.1 4 29.2 3 29.3 15 30.1 13 30.2 11 3.1 38 3.2 97 3.3 90 3.4 62 3.5 64 3.6 89 3.7 40 3.8 65 3.9 20 4.1 98 4.10 42 4.11 18 4.12 69 4.13 20 4.14 11 4.2 60 4.3 27 4.4 72 4.5 51 4.6 28 4.7 45 4.8 10 4.9
• the aqueous solubility of examples of this invention is determined by comparing the amount dissolved in buffer to the amount dissolved in an acetonitrile/water (1/1) solution. Starting from a 10 mM DMSO stock solution, aliquots are diluted with acetonitrile/water (1/1) and McIlvaine buffer pH 6.8, respectively. After 24 h of shaking, the liquid phase is filtered and analyzed by LC-UV. The amount dissolved in buffer is compared to the amount dissolved in the acetonitrile/water (1/1) solution. Solubility is measured from 0.001 to 0.125 mg/ml at a DMSO concentration of 2.5%. According to this method, the aqueous solubility at pH 6.8 of example 4.14 is determined to be 0.076 mg/mL and the aqueous solubility at pH 6.8 of example 27.1A is determined to be 0.081 mg/mL.
• the compounds of general formula I may be used on their own or combined with other active substances of formula I according to the invention.
• the compounds of general formula I may optionally also be combined with other pharmacologically active substances. These include, B2-adrenoceptor-agonists (short and long-acting), anti-cholinergics (short and long-acting), anti-inflammatory steroids (oral and topical corticosteroids), cromoglycate, methylxanthine, dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4-inhibitors, PDE7-inhibitors, LTD4 antagonists, EGFR-inhibitors, Dopamine agonists, PAF antagonists, Lipoxin A4 derivatives, FPRL1 modulators, LTB4-receptor (BLT1, BLT2) antagonists, Histamine H1 receptor antagonists, Histamine H4 receptor antagonists, dual Histamine H1/H3-receptor antagonists, PI3-kinase inhibitors,
• the compounds of the invention and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as inhibitors of neutrophil elastase, and thus may be used in the treatment of:
• respiratory tract obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; alpha1-antitrypsin deficiency; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and is related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculi
• skin psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia greata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis; cutaneous lymphomas, non-melanoma
• eyes blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral, fungal, and bacterial;
• nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male and female);
• allograft rejection acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
• oncology treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,
• infectious diseases virus diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, para-influenza; bacterial diseases such as tuberculosis and mycobacterium avium , leprosy; other infectious diseases, such as fungal diseases, chlamydia, Candida, aspergillus , cryptococcal meningitis, Pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis.
• virus diseases such as genital warts, common warts, plant
• a therapeutically effective dose will generally be in the range from about 0.01 mg to about 100 mg/kg of body weight per dosage of a compound of the invention; preferably, from about 0.1 mg to about 20 mg/kg of body weight per dosage.
• the dosage range would be from about 0.7 mg to about 7000 mg per dosage of a compound of the invention, preferably from about 7.0 mg to about 1400 mg per dosage.
• Some degree of routine dose optimization may be required to determine an optimal dosing level and pattern.
• the active ingredient may be administered from 1 to 6 times a day.
• the actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease.
• the active ingredient will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.

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