US 2011 0190248A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0190248 A1 Himmelsbach et al. (43) Pub. Date: Aug. 4, 2011

(54) CYCLOHEXYLOXY SUBSTITUTED A6IP 29/00 (2006.01) HETEROCYCLES, PHARMACEUTICAL A6IP37/08 (2006.01) COMPOSITIONS CONTAINING THESE A6IP II/00 (2006.01) COMPOUNDS AND PROCESSES FOR A6IP II/06 (2006.01) PREPARING THEMI A6IP II/4 (2006.01) A6IP35/00 (2006.01) (75) Inventors: Frank Himmelsbach, 52) U.S. C S14/171: 514/252.17:544,293 Mittelbiberach (DE); Birgit Jung, (52) U.S. Cl...... s • s Laupheim (DE); Ralf Lotz, (57) ABSTRACT Schemmerhofen (DE) The present invention relates to cyclohexyloxy-substituted (73) Assignee: Boehringer Ingelheim heterocycles of general formula (I) International GmbH, Ingelheim am Rhein (DE) (I) (21) Appl. No.: 13/057,872 R NN1 H (22) PCT Filed: Jul. 23, 2009 O (86). PCT No.: PCT/EP2009/059510 s O l N2 Rd N1 Rb, S371 (c)(1), (2), (4) Date: Mar. 21, 2011 N-A (30) Foreign Application Priority Data the tautomers, the stereoisomers, the mixtures thereof and the Aug. 8, 2008 (EP) ...... O8104995.9 salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids, which have valuable Publication Classification pharmacological properties, particularly an inhibitory effect (51) Int. Cl. on signal transduction mediated by tyrosine kinases, the use A 6LX 3/57 (2006.01) thereof for the treatment of diseases, particularly tumoral A6 IK3I/56 (2006.01) diseases as well as benign prostatic hyperplasia (BPH), dis CO7D 403/2 (2006.01) eases of the lungs and airways and the preparation thereof. US 2011/O 190248 A1 Aug. 4, 2011

CYCLOHEXYLOXY SUBSTITUTED 0007 or HETEROCYCLES, PHARMACEUTICAL 0008 a group selected from among COMPOSITIONS CONTAINING THESE 0009 C-alkyl, C-alkyl-O, C-alkenyl, C COMPOUNDS AND PROCESSES FOR alkynyl, phenyl, phenyl-O, phenyl-C-alkyl- and PREPARING THEMI phenyl-C-alkyl-O, heteroaryl, heteroaryl-O. heteroaryl-C-alkyl and heteroaryl-C-alkyl-O. while the above-mentioned phenyl groups are mono- or disubstituted by R groups, 0001. The present invention relates to cyclohexyloxy-sub 0010 and stituted heterocycles of general formula I0011 R denotes hydrogen, 0012 or 0013 a group selected from among (I) R H 0014 F, Cl, Brand CH, NN1 I0015I R' denotes hydrogen, oran optionally substituted group selected from among C-alkyl, C-cycloalkyl O and C-e-cycloalkyl-C-alkyl, s O 0016 R denotes hydrogen, oran optionally substituted l 2 Rb, group selected from among C-alkyl, C-cycloalkyl, N Rd N1 C-cycloalkyl-C-alkyl, C-alkyl-CO, C-cy cloalkyl-CO, C-cycloalkyl-C-alkyl-CO, C NHA alkyl-SO, C-cycloalkyl-SO, C-cycloalkyl-C- alkyl-SO, phenyl-CO—and phenyl-SO, 10017 R denotes hydrogen or the tautomers, the stereoisomers, the mixtures thereof and the 0018 a group selected from among salts thereof, particularly the physiologically acceptable salts 0019 F, Cl, Br, I, OH, C-alkyl, C-alkyl-O, C thereof with inorganic or organic acids, which have valuable alkyl-O substituted by 1 to 3 fluorine atoms, C.- pharmacological properties, particularly an inhibitory effect cycloalkyl-O, C-7-cycloalkyl-C-alkyl-O, tetrahy on signal transduction mediated by tyrosine kinases, the use drofuran-3-yl-O, tetrahydropyran-3-yl-O. thereof for the treatment of diseases, particularly tumoral tetrahydro-pyran-4-yl-O, tetrahydrofuranyl-C- diseases as well as benign prostatic hyperplasia (BPH), dis alkyl-O and tetrahydropyranyl-C-alkyl-O. eases of the lungs and airways and the preparation thereof. 0020 or 0002 The problem of the present invention is to prepare (0021) R' C-alkyl, wherein the linking of the new compounds which on the basis of their pharmaceutical groups R* may take place via each Catom of the alkyl effectiveness as tyrosine-kinase inhibitors, may be used grOup, therapeutically, i.e. for the treatment of pathophysiological 0022 or processes caused by hyperfunction of tyrosine kinases. (0023) R' C-alkyl-O, wherein the group R is separated from the oxygenatom by at least2C atoms, DETAILED DESCRIPTION OF THE INVENTION 0024 or 0025 a group selected from among 0003. It has surprisingly been found that the problem men 0026 pyrrolidin-2-yl-C-alkyl-O, pyrrolidin-3-yl tioned above is solved by compounds of formula (I), wherein C-alkyl-O, piperidin-2-yl-Ca-alkyl-O, piperidin the groups R* to R and A have the meanings given hereinaf 3-yl-C-alkyl-O, piperidin-4-yl-Ca-alkyl-O, ter. The present invention therefore relates to compounds of aZepan-2-yl-C-alkyl-O. azepan-3-yl-C-alkyl-O. general formula (I), aZepan-4-yl-C-alkyl-O. morpholin-2-yl-Ca alkyl-O, morpholin-3-yl-C-alkyl-O. 1-(C- alkyl)-pyrrolidin-2-yl-Ca-alkyl-O. 1-(C-alkyl)- (I) pyrrolidin-3-yl-C-alkyl-O. 1-(C-alkyl)- RS -H piperidin-2-yl-C-alkyl-O, 1-(C-alkyl)- piperidin-3-yl-C-alkyl-O, 1-(C-alkyl)- piperidin-4-yl-C-alkyl-O. 1-(C-alkyl)-azepan N1 N O O 2-yl-C-alkyl-O. 1-(C-alkyl)-azepan-3-yl-C- alkyl-O. 1-(C-alkyl)-azepan-4-yl-C-alkyl-O. se Rd -R 4-(C-alkyl)-morpholin-2-yl-C-alkyl-O and 4-(C-alkyl)-morpholin-3-yl-C-alkyl-O. RC N-A 0027 wherein 10028) R' denotes a group, which may be identical or different, selected from among wherein 0029 OH, C-alkyl-O, C-cycloalkyl-O, NH, 0004 R* denotes a phenyl or 1-phenylethyl group, C-alkyl-NH. (C-alkyl).N. (2-methoxyethyl) wherein the phenyl nucleus is substituted in each case by N. pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, the groups R' to R, where morpholin-4-yl, 1,4-oxazepan-4-yl, 2-oxa-5-aza 0005) R' and R which may be identical or different, bicyclo[2.2.1]hept-5-yl, 3-oxa-8-aza-bicyclo[3.2. denote hydrogen or a group selected from among 1 oct-8-yl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, 0006 F, Cl, Br, I, OCHF, OCHF OCF, CHF, piperazin-1-yl 4-(C-alkyl)-piperazin-1-yl, 1,4- CHF, CF, CN, NO, NH, and OH, diazepan-1-yl 4-(C-alkyl)-1,4-diazepan-1-yl, US 2011/O 190248 A1 Aug. 4, 2011

HCO. NH, C-alkyl-CO. NH, C-alkyl-O- tis, cystic fibrosis or mucoviscidosis, alpha-1-antitrypsin C-alkyl-CO. NH, C-alkyl-O CO. NH, deficiency, cough, pulmonary emphysema, interstitial lung HNCONH, C-alkyl-NH CO. NH, (C- diseases, alveolitis, hyperreactive airways, nasal polyps, pull alkyl)-N CONN, pyrrolidin-1-yl-CO. NH, pip monary oedema, pneumonitis of different origins, e.g. radia eridin-1-yl-CO. NH, piperazin-1-yl-CO. NH, tion-induced or caused by aspiration or infectious pneumoni 4-(C-alkyl)-piperazin-1-yl-CO—NH, morpho tis, collagenoses such as lupus erythematodes, systemic lin-4-yl-CO. NH and C-alkyl-SO. NH, Sclerodermy, sarcoidosis and Boeck's disease. while the pyrrolidinyl, piperidinyl, azepan-1-yl, piperazinyl, 0047. It is also particularly preferred to use the compounds 1,4-diazepan-1-yl, morpholinyl and 1,4-oxazepan-4-yl of formula (I) in cases of inflammatory orallergic complaints groups mentioned above in the definition of the group R may in which autoimmune reactions are involved. It is also par each additionally be substituted by one or two C-alkyl ticularly preferred to use the compounds of formula (I) in groups, cases of a disease in the form of benign or malignant tumours. 0030 and 0048. The invention further relates to a pharmaceutical wherein the above-mentioned phenyl groups are mono- or formulation containing a compound of formula (I). disubstituted by groups R, wherein 0049 Preferably an orally administered pharmaceutical I0031. Rdenotes hydrogen, or formulation containing a compound of formula (I) is used. 0032 a group, which may be identical or different, 0050. The invention further relates to medicament combi selected from among F, Cl, Br, I, OH, CN, C-alkyl, nations which contain, besides one or more compounds of C-alkyl-O, CHF, CF - O CHF and formula (I), as further active Substances, one or more com —O—CF, pounds selected from among the categories of betamimetics, 0033 and anticholinergics, corticosteroids, further PDE4-inhibitors, unless stated otherwise, the above-mentioned alkyl groups LTD4-antagonists, EGFR-inhibitors, dopamine agonists, may be straight-chain or branched, H1-antihistamines, PAF-antagonists and PI3-kinase inhibi 0034. A denotes —CO or - C -alkylene, tors or double or triple combinations thereof. 0035 wherein the -C-C-alkylene group may be 0051 Suitable betamimetics used are preferably com 1-, 2-, 3- or 4-substituted by a group R, pounds selected from among arformoterol, carmoterol, for 0036 and moterol, indacaterol, salmeterol, albuterol, bambuterol, 0037 R which may be identical or different, denotes bitolterol, broXaterol, carbuterol, clenbuterol, fenoterol, hydrogen, or hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalb 0038 a group selected from among OH, C-C- utamol, mabuterol, meluadrine, metaproterenol, milveterol, alkyl and —O-C-C-alkyl orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, optionally in the form of the tautomers, the racemates, the ritodrine, Salmefamol, Soterenol, Sulphonterol, terbutaline, enantiomers, the diastereomers and the mixtures thereof, and tiaramide, tolubuterol, Zinterol and optionally the pharmacologically acceptable acid addition 0052 6-hydroxy-8-1-hydroxy-2-[2-(4-methoxy-phe salts thereof, and the solvates and hydrates thereof. nyl)-1,1-dimethyl-ethylamino-ethyl-4H-benzo[1,4]ox 0039. Preferred compounds of formula (I) are those azin-3-one wherein 0053 8-2-[2-(2,4-difluoro-phenyl)-1,1-dimethyl-ethy 0040) R' denotes a group selected from among lamino-1-hydroxy-ethyl-6-hydroxy-4H-benzo[1,4]ox 3-chloro-2-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, azin-3-one 5-chloro-2-fluoro-phenyl, 2-fluoro-3-methyl-phenyl, 0054 8-2-[2-(3,5-difluoro-phenyl)-1,1-dimethyl-ethy 2-fluoro-5-methyl-phenyl, 4-fluoro-3-methyl-phenyl lamino-1-hydroxy-ethyl-6-hydroxy-4H-benzo[1,4]ox and 3-chloro-2-methyl-phenyl, azin-3-one 0041) R' and R which may be identical or different, 0055 8-2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethy 0042 denote hydrogen or C-alkyl, lamino-1-hydroxy-ethyl-6-hydroxy-4H-benzo[1,4]ox 10043) R' denotes C-alkyl-O, azin-3-one unless stated otherwise, the above-mentioned alkyl groups 0056 8-2-[2-(4-fluoro-phenyl)-1,1-dimethyl-ethy may be straight-chain or branched, lamino-1-hydroxy-ethyl-6-hydroxy-4H-benzo[1,4]ox 0044) Adenotes—CHCH, whereinthe—CHCH azin-3-one group may be substituted by 1 or 2 methyl groups, 0057 N-(5-2-3-(4,4-diethyl-2-oxo-4H-benzod1.3 optionally in the form of the tautomers, the racemates, the oxazin-1-yl)-1,1-dimethyl-propylamino-1-hydroxy enantiomers, the diastereomers and the mixtures thereof, and ethyl)-2-hydroxy-phenyl)-methanesulphonamide optionally the pharmacologically acceptable acid addition 0058 N-(5-2-3-(4,4-diethyl-6-fluoro-2-oxo-4H-benzo salts thereof, and the solvates and hydrates thereof. d1.3oxazin-1-yl)-1,1-dimethyl-propylamino-1-hy 0045. The invention further relates to compounds of for droxy-ethyl)-2-hydroxy-phenyl)-methanesulphonamide mula (I) for use as medicaments. Preferably the compounds 0059 N-(5-2-3-(4,4-diethyl-6-methoxy-2-oxo-4H of formula (I) are used in cases of inflammatory or allergic benzod1.3oxazin-1-yl)-1,1-dimethyl-propylamino-1- diseases of the airways. hydroxy-ethyl)-2-hydroxy-phenyl)-methanesulphona 0046. The compounds of formula (I) are particularly pref mide erably used in cases of a disease selected from among chronic 0060 N-(5-2-1,1-dimethyl-3-(2-oxo-4,4-dipropyl-4H bronchitis, acute bronchitis, bronchitis caused by bacterial or benzod1.3oxazin-1-yl)-propylamino-1-hydroxy viral infection or fungi or helminths, allergic bronchitis, toxic ethyl)-2-hydroxy-phenyl)-methanesulphonamide bronchitis, chronic obstructive bronchitis (COPD), asthma 0061 8-2-1,1-dimethyl-3-(2-oxo-2,3-dihydro-ben (intrinsic orallergic), paediatric asthma, bronchiectasis, aller Zoimidazol-1-yl)-propylamino]-1-hydroxy-ethyl-6-hy gic alveolitis, allergic or non-allergic rhinitis, chronic sinusi droxy-4H-benzo 1.4 oxazin-3-one

US 2011/O 190248 A1 Aug. 4, 2011 nate or p-toluenesulphonate are preferred as counter-ions. Of Sone, etiprednol, flunisolide, fluticaSone, loteprednol, all the salts the chlorides, bromides, iodides and methane mometasone, prednisolone, prednisone, rofileponide, triamci Sulphonates are particularly preferred. nolone, tipredane and 0098. Other specified compounds are: I0131 pregna-1,4-diene-3,20-dione, 6-fluoro-1 1-hy 0099 tropenol 2,2-diphenylpropionate methobromide, droxy-16,17-(1-methylethylidene) bis(oxy)-21-4-(ni 0100 scopine 2,2-diphenylpropionate methobromide, trooxy)methylbenzoyloxy-, (6-alpha,11-beta, 16-al 0101 scopine 2-fluoro-2,2-diphenylacetate methobro pha)-(9CI) (NCX-1024) mide, I0132) 16,17-butylidenedioxy-6,9-difluoro-1 1-hydroxy 0102 tropenol 2-fluoro-2,2-diphenylacetate methobro 17-(methylthio)androst-4-en-3-one (RPR-106541), mide; 0.133 (S)-fluoromethyl 6,9-difluoro-17-(2-furanylcarbo 0103 tropenol 3.3',4,4-tetrafluorobenzilate methobro nyl)oxy-11-hydroxy-16-methyl-3-oxo-androsta-1,4-di mide, ene-17-carbothionate 0104 scopine 3,3',4,4-tetrafluorobenzilate methobro 0.134 (S)-(2-oxo-tetrahydro-furan-3S-yl) 6,9-difluoro mide, 11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta 0105 tropenol 4,4'-difluorobenzilate methobromide, 1,4-diene-17-carbothionate, 0106 scopine 4,4'-difluorobenzilate methobromide, 0.135 cyanomethyl 6-alpha,9-alpha-difluoro-11-beta-hy 0107 tropenol 3,3'-difluorobenzilate methobromide, droxy-16alpha-methyl-3-oxo-17alpha-(2,2,3,3-tetrameth 0.108 scopine 3,3'-difluorobenzilate methobromide: ylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17beta 0109 tropenol 9-hydroxy-fluorene-9-carboxylate carboxylate, methobromide: 0110 tropenol 9-fluoro-fluorene-9-carboxylate metho optionally in the form of the racemates, enantiomers or dias bromide; tereomers thereof and optionally in the form of the salts and 0111 scopine 9-hydroxy-fluorene-9-carboxylate derivatives thereof, the solvates and/or hydrates thereof. Any methobromide: reference to steroids includes a reference to any salts or 0112 scopine 9-fluoro-fluorene-9-carboxylate metho derivatives, hydrates or solvates thereof which may exist. bromide; Examples of possible salts and derivatives of the steroids may 0113 tropenol 9-methyl-fluorene-9-carboxylate be: alkali metal salts, such as for example Sodium or potas methobromide: sium salts, Sulphobenzoates, phosphates, isonicotinates, 0114 scopine 9-methyl-fluorene-9-carboxylate metho acetates, dichloroacetates, propionates, dihydrogen phos bromide; phates, palmitates, pivalates or furoates. 0115 cyclopropyltropine benzilate methobromide: (0.136 PDE4-inhibitors which may be used are preferably 0116 cyclopropyltropine 2,2-diphenylpropionate compounds selected from among enprofyllin, theophyllin, methobromide: roflumilast, arifilo (cilomilast), tofimilast, pumafentrin, lir 0117 cyclopropyltropine 9-hydroxy-xanthene-9-car imilast, apremilast, arofyllin, atizoram, oglemilast, tetomilas boxylate methobromide: tnd 0118 cyclopropyltropine 9-methyl-fluorene-9-car 0.137 5-(N-(2,5-dichloro-3-pyridinyl)-carboxamid-8- boxylate methobromide: methoxy-quinoline (D-4418), 0119 cyclopropyltropine 9-methyl-xanthene-9-car 0.138 N-(3,5-dichloro-1-oxido-4-pyridinyl)-carboxa boxylate methobromide: mid-8-methoxy-2-(trifluoromethyl)-quinoline (D-4396 I0120 cyclopropyltropine 9-hydroxy-fluorene-9-car (Sch-351591)), N-(3,5-dichloropyrid-4-yl)-1-(4-fluo boxylate methobromide: robenzyl)-5-hydroxy-indol-3-ylglyoxylic acid amice I0121 cyclopropyltropine methyl 4,4'-difluorobenzilate (AWD-12-281 (GW-842470)), 9-(2-fluorophenyl)me methobromide. thyl-N-methyl-2-(trifluoromethyl)-9H-purin-6-amine 0.122 tropenol 9-hydroxy-xanthene-9-carboxylate (NCS-613), methobromide: 0.139 4-(2R)-2-3-(cyclopentyloxy)-4-methoxyphenyl I0123 scopine 9-hydroxy-xanthene-9-carboxylate 2-phenylethyl-pyridine (CDP-840), methobromide: 0140 N-(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phe 0.124 tropenol 9-methyl-xanthene-9-carboxylate nylpyrrolo3.2.1-jk]1.4benzodiazepin-3-yl-4-pyridin methobromide: ecarboxamide (PD-168787), (0.125 scopine 9-methyl-xanthene-9-carboxylate 0141 4-6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naph methobromide: thalenyl)-1-(2-methoxyethyl)-2(1H)-pyridinone (T-440), 0.126 tropenol 9-ethyl-xanthene-9-carboxylate metho 0.142 2-4-6,7-diethoxy-2,3-bis(hydroxymethyl)-1- bromide; naphthalenyl)-2-pyridinyl)-4-(3-pyridinyl)-1 (2H)-ph I0127 tropenol 9-difluoromethyl-xanthene-9-carboxy thalazinone (T-2585), late methobromide; 0.143 (3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethy I0128 scopine 9-hydroxymethyl-xanthene-9-carboxy lamino-8-isopropyl-3H-purine (V-11294A), late methobromide, 0144) beta-3-(cyclopentyloxy)-4-methoxyphenyl-1,3- 0129. The above-mentioned compounds may also be used dihydro-1,3-dioxo-2H-Isoindole-2-propanamide (CDC as salts within the scope of the present invention, wherein 801), instead of the methobromide the salts metho-X are used, 0145 ilmidazo 1.5-alpyrido3.2-epyrazin-6(5H)-one, wherein X may have the meanings given hereinbefore for X. 9-ethyl-2-methoxy-7-methyl-5-propyl-(D-22888) 0130. As corticosteroids it is preferable to use compounds 0146 5-3-(cyclopentyloxy)-4-methoxyphenyl-3-(3- selected from among beclomethasone, betamethasone, methylphenyl)methyl-, (3S,5S)-2-piperidinone (HT budesonide, butiXocort, ciclesonide, deflazacort, dexametha 0712),

US 2011/O 190248 A1 Aug. 4, 2011

0237 4-(3-chloro-4-fluoro-phenyl)amino-6-1-(2-me optionally in the form of the racemates, enantiomers or dias thyl-morpholin-4-yl)carbonyl-piperidin-4-yloxy-7- tereomers thereof and optionally in the form of the pharma methoxy-quinazoline, cologically acceptable acid addition salts thereof, the Solvates 0238 4-(3-chloro-4-fluoro-phenyl)amino-6-1-(S,S)- and/or hydrates thereof. Preferably, according to the inven (2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl-piperi tion, acid addition salts are selected from among the hydro din-4-yloxy-7-methoxy-quinazoline, chloride, hydrobromide, hydriodide, hydrosulphate, hydro 0239 4-(3-chloro-4-fluoro-phenyl)amino-6-1-(N- phosphate, hydromethaneSulphonate, hydronitrate, methyl-N-2-methoxyethyl-amino)carbonyl-piperidin-4- hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, yloxy-7-methoxy-quinazoline, hydrotartrate, hydroxalate, hydroSuccinate, hydrobenzoate 0240 4-(3-chloro-4-fluoro-phenyl)amino-6-(1-ethyl and hydro-p-toluenesulphonate. piperidin-4-yloxy)-7-methoxy-quinazoline, 0259. The LTD4-receptor antagonists used are preferably 0241 4-(3-chloro-4-fluoro-phenyl)amino-6-1-(2- compounds selected from among montelukast, pranlukast, methoxyethyl)carbonyl-piperidin-4-yloxy-7-methoxy Zafirlukast, and (E)-8-2-4-4-(4-fluorophenyl)butoxylphe quinazoline, nyl]ethenyl-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-4-one 0242 4-(3-chloro-4-fluoro-phenyl)amino-6-1-(3- methoxypropyl-amino)-carbonyl-piperidin-4-yloxy-7- (MEN-91507) methoxy-quinazoline, 0260 4-6-Acetyl-3-3-(4-acetyl-3-hydroxy-2-propy 0243 4-(3-chloro-4-fluoro-phenyl)amino-6-cis-4-(N- lphenylthio)propoxy-2-propylphenoxy-butyric acid methaneSulphonyl-N-methyl-amino)-cyclohexan-1- (MN-001) yloxy-7-methoxy-quinazoline, 0261 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl) 0244 4-(3-chloro-4-fluoro-phenyl)amino-6-cis-4-(N- phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcy acetyl-N-methyl-amino)-cyclohexan-1-yloxy-7-meth clopropane-acetic acid, oxy-quinazoline, 0262 1-(((1(R)-3(3-(2-(2,3-dichlorothieno3.2-bipyri 0245 4-(3-chloro-4-fluoro-phenyl)amino-6-(trans-4- din-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methyl methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazo ethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid line, 0263. 2-2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl 0246 4-(3-chloro-4-fluoro-phenyl)amino-6-trans-4- oxymethylphenyl)acetic acid (N-methanesulphonyl-N-methyl-amino)-cyclohexan-1- optionally in the form of the racemates, enantiomers or dias yloxy-7-methoxy-quinazoline, tereomers thereof and optionally in the form of the pharma 0247 4-(3-chloro-4-fluoro-phenyl)amino-6-(trans-4- cologically acceptable acid addition salts thereof, the Solvates dimethylamino-cyclohexan-1-yloxy)-7-methoxy and/or hydrates thereof. Preferably, according to the inven quinazoline, tion, acid addition salts are selected from among the hydro 0248 4-(3-chloro-4-fluoro-phenyl)amino-6-(trans-4- chloride, hydrobromide, hydriodide, hydrosulphate, hydro {N-(morpholin-4-yl)carbonyl-N-methyl-amino-cyclo phosphate, hydromethaneSulphonate, hydronitrate, hexan-1-yloxy)-7-methoxy-quinazoline, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, 0249 4-(3-chloro-4-fluoro-phenyl)amino-6-2-(2,2- hydrotartrate, hydroxalate, hydroSuccinate, hydrobenzoate dimethyl-6-oxo-morpholin-4-yl)-ethoxy-7-(S)-(tetrahy and hydro-p-toluenesulphonate. By salts orderivatives which drofuran-2-yl)methoxy-quinazoline, the LTD4-receptor antagonists may optionally be capable of 0250 4-(3-chloro-4-fluoro-phenyl)amino-6-(1-meth forming are meant, for example: alkali metal salts, such as for anesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, example Sodium or potassium salts, alkaline earth metal salts, 0251 4-(3-chloro-4-fluoro-phenyl)amino-6-(1-cyano Sulphobenzoates, phosphates, isonicotinates, acetates, propi piperidin-4-yloxy)-7-methoxy-quinazoline, onates, dihydrogen phosphates, palmitates, pivalates or 0252 3-Cyano-4-(3-chloro-4-fluorophenyl)amino)-6- furoates. 4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl)amino-7- 0264. The histamine H1 receptor antagonists used are ethoxy-quinoline; preferably compounds selected from among epinastine, ceti 0253) 4-(3-chloro-4-fluoro-phenyl)amino-6-4-(ho rizine, azelastine, feXofenadine, levocabastine, loratadine, momorpholin-4-yl)-1-oxo-2-buten-1-yl)amino-7-(S)- mizolastine, ketotifen, emedastine, dimetindene, clemastine, (tetrahydrofuran-3-yl)oxy-quinazoline, bamipine, ceXchlorpheniramine, pheniramine, doxylamine, 0254 4-(3-chloro-4-fluoro-phenyl)amino-7-(2-4-(S)- chlorophenoxamine, dimenhydrinate, diphenhydramine, (2-oxo-tetrahydrofuran-5-yl)-carbonyl-piperazin-1-yl)- promethazine, ebastine, olopatadine, desloratidine and ethoxy)-6-(vinylcarbonyl)amino-quinazoline, meclozine, optionally in the form of the racemates, enanti 0255 4-(3-chloro-4-fluoro-phenyl)amino-7-2-((S)-6- omers, diastereomers thereofandoptionally in the form of the methyl-2-oxo-morpholin-4-yl)-ethoxy-6-(vinylcarbo pharmacologically acceptable acid addition salts, Solvates or nyl)amino-quinazoline, hydrates thereof. According to the invention these acid addi 0256 4-(3-chloro-4-fluoro-phenyl)amino-7-4-((R)-6- tion salts are preferably selected from among the hydrochlo methyl-2-oxo-morpholin-4-yl)-butyloxy-6-(vinylcarbo ride, hydrobromide, hydriodide, hydrosulphate, hydrophos nyl)amino-quinazoline, phate, hydromethanesulphonate, hydronitrate, hydromaleate, 0257 4-(3-chloro-4-fluoro-phenyl)amino-7-4-((S)-6- hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, methyl-2-oxo-morpholin-4-yl)-butyloxy-6-(vinylcarbo hydroxalate, hydroSuccinate, hydrobenzoate and hydro-p- nyl)amino-quinazoline, und toluenesulphonate. 0258 4-(3-chloro-4-fluorophenyl)amino-6-(4-N-2- 0265. The PAF antagonists used are preferably com (ethoxycarbonyl)-ethyl-N-(ethoxycarbonyl)methyl pounds selected from among lexipafant and 4-(2-chlorophe amino-1-oxo-2-buten-1-yl)aminol-7-cyclopropyl nyl)-9-methyl-2-3 (4-morpholinyl)-3-propanon-1-yl)-6H methoxy-quinazoline, thieno-3.24-1.2.4 triazolo 4.3-a 1.4 diazepine US 2011/O 190248 A1 Aug. 4, 2011

0266 6-(2-chlorophenyl)-8.9-dihydro-1-methyl-8-(4- 0276 Also included in the subject-matter of this invention morpholinyl)carbonyl-4H.7H-cyclo-penta-4,5thieno are the compounds according to the invention, including the 3.2-f 1.2.4 triazolo 4.3-a 1.4 diazepine, salts thereof, wherein one or more hydrogen atoms, for optionally in the form of the racemates, enantiomers, diaste example one, two, three, four or five hydrogen atoms, are reomers thereof and optionally in the form of the pharmaco replaced by deuterium. logically acceptable acid addition salts, Solvates or hydrates 0277. Where a hyphen open on one side"- is used in the thereof. According to the invention these acid addition salts structural formula of a substituent, this hyphen is to be under are preferably selected from among the hydrochloride, hydro stood as the linkage point to the remainder of the molecule. bromide, hydriodide, hydroSulphate, hydrophosphate, The substituent replaces the corresponding groups R. R. hydromethanesulphonate, hydronitrate, hydromaleate, etc. If no hyphen open on one side is used in the structural hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, formula of a Substituent, the linkage point to the remainder of hydroxalate, hydroSuccinate, hydrobenzoate and hydro-p- the molecule is clear from the structural formula itself. toluenesulphonate. 0278 Compounds of general formula (I) may contain acid 0267. The dopamine receptoragonists used are preferably groups, primarily carboxyl groups, and/or basic groups such compounds selected from among bromocriptin, cabergoline, as e.g. amino functions. Compounds of general formula (I) alpha-dihydroergocryptine, lisuride, pergolide, pramipexol. may therefore be present as internal salts, as Salts with phar roXindol, ropinirol, talipexol, tergurid and vioZan, optionally maceutically useable inorganic acids such as hydrochloric in the form of the racemates, enantiomers, diastereomers acid, Sulphuric acid, phosphoric acid, Sulphonic acid or thereof and optionally in the form of the pharmacologically organic acids (such as for example maleic acid, fumaric acid, acceptable acid addition salts, Solvates or hydrates thereof. citric acid, tartaric acid or acetic acid) or as salts with phar According to the invention these acid addition salts are pref maceutically useable bases such as alkali metal or alkaline erably selected from among the hydrochloride, hydrobro earth metal hydroxides or carbonates, Zinc or ammonium mide, hydriodide, hydroSulphate, hydrophosphate, hydroxides or organic amines such as e.g. diethylamine, tri hydromethanesulphonate, hydronitrate, hydromaleate, ethylamine, triethanolamine, inter alia. For preparing the hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, alkali metal and alkaline earth metal salts of the compound of hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p- formula (I), it is preferable to use the alkali metal and alkaline toluenesulphonate. earth metal hydroxides and hydrides, while the hydroxides 0268 Substances of preferred PI3 kinase antagonists that and hydrides of the alkali metals, particularly sodium and may be used are preferably compounds selected from among potassium are preferred, and sodium and potassium hydrox 0269 5-(Quinoxalin-6-ylmethylene)thiazolidine-2,4-di ide are particularly preferred. (See also Pharmaceutical Salts, one (AS-605240), S. M. Birge et al., J. Pharm. Sci. (1977), 66, 1-19) 0270 2-(6-amino-9H-purin-9-yl)methyl-5-methyl-3- 0279. As already mentioned, the compounds of general (2-methylphenyl)-4(3H)-quinazolinone (C-87114), formula (I) may be converted into the salts thereof, particu 0271 2-Methyl-2-4-3-methyl-2-oxo-8-(quinoline-3- larly for pharmaceutical use, into the pharmacologically yl)-2,3-dihydroimidazo 4.5-cquinolin-1-ylphenylpro acceptable acid addition salts thereof with an inorganic or pionitrile (BEZ-235), organic acid. Suitable acids for this purpose include for optionally in the form of the racemates, enantiomers, diaste example Succinic acid, hydrobromic acid, acetic acid, reomers thereof and optionally in the form of the pharmaco fumaric acid, maleic acid, methanesulphonic acid, lactic acid, logically acceptable acid addition salts, prodrugs, Solvates or phosphoric acid, hydrochloric acid, Sulphuric acid, tartaric hydrates thereof. acid or citric acid. In addition, mixtures of the above-men tioned acids may be used. Terms and Definitions Used 0280. The present invention relates to the respective com pounds, optionally in the form of the individual diastere 0272. By the term “optionally substituted” is meant within omers, mixtures of the individual diastereomers and/or indi the scope of the invention the above-mentioned group, vidual enantiomers, mixtures of the individual enantiomers or optionally Substituted by a lower-molecular group. Examples racemates thereof, in the form of the tautomers as well as in of lower-molecular groups regarded as chemically meaning the form of the free bases or the corresponding acid addition ful are groups consisting of 1-25 atoms. Preferably such salts with pharmacologically acceptable acids—such as for groups have no negative effect on the pharmacological effi example acid addition salts with hydrohalic acids—for cacy of the compounds. For example the groups may com example hydrochloric or hydrobromic acid or organic prise: acids—such as for example tartaric acid, fumaric acid, citric 0273 Straight-chain or branched carbon chains, option acid or methanesulphonic acid. ally interrupted by heteroatoms, optionally substituted 0281 "Protective groups” for the purposes of the present by rings, heteroatoms or other common functional invention is a collective term for organic groups with which groups. certain functional groups of a molecule containing a number 0274 Aromatic or non-aromatic ring systems consist of active centres can temporarily be protected from attack by ing of carbon atoms and optionally heteroatoms, which reagents so that reactions take place only at the desired (un may in turn be substituted by functional groups. protected) sites. The protective groups should be introduced 0275 A number of aromatic or non-aromatic ring sys selectively under mild conditions. They must be stable for the tems consisting of carbon atoms and optionally heteroa duration of the protection under all the conditions of the toms which may be linked by one or more carbon chains, reactions and purifying procedures which are to be carried optionally interrupted by heteroatoms, optionally Sub out; racemisations and epimerisations must be suppressed. stituted by heteroatoms or other common functional Protective groups should be capable of being cleaved again groups. under mild conditions selectively and ideally in high yields. US 2011/O 190248 A1 Aug. 4, 2011

The choice of a Suitable protective group, the reaction condi iso-propyl. n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, tions (solvent, temperature, duration, etc.), and also the iso-pentyl, neo-pentyl or hexyl. The abbreviations Me, Et, options for removing a protective group are known in the art n-Pr. i-Pr, n-Bu, i-Bu, t-Bu, etc. may optionally also be used (e.g. Philip Kocienski, Protecting Groups, 3rd ed. 2004, THI for the above-mentioned groups. Unless stated otherwise, the EME, Stuttgart, ISBN: 3131370033). definitions propyl, butyl, penty1 and hexyl include all the 0282. By an “organic solvent' is meant, within the scope possible isomeric forms of the groups in question. Thus, for of the invention, an organic, low-molecular Substance which example, propyl includes n-propyl and iso-propyl, butyl can dissolve other organic Substances by a physical method. includes iso-butyl, sec-butyl and tert-butyl etc. To be suitable the prerequisite for the solvent is that neither 0297. By the term “C-alkylene' (including those which the dissolving Substance nor the dissolved Substance should are part of other groups) are meant branched and unbranched be chemically altered during the dissolving process, i.e. the alkylene groups with 1 to 3 carbon atoms. Preferred are alky components of the solution should be recoverable in their lene groups with 1 to 2 carbon atoms. Examples include: original form by physical separation processes Such as distil methylene, ethylene, propylene and 1-methylethylene. lation, crystallisation, Sublimation, evaporation or adsorp Unless stated otherwise, the definition propylene includes all tion. For various reasons, not only the pure solvents but also the possible isomeric forms of the groups in question with the mixtures that combine the dissolving properties may be used. same number of carbons. Thus, for example, propylene also Examples include: includes 1-methylethylene. 0283 alcohols, preferably methanol, ethanol, propanol, 0298 By the term “C-alkenyl' (including those which butanol, octanol, cyclohexanol: are part of other groups) are meant alkenyl groups with 2 to 3 0284 glycols, preferably ethyleneglycol, diethyleneg carbonatoms, if they have at least one double bond. Examples lycol; include: ethenyl or vinyl. Unless stated otherwise, the defini 0285 ethers/glycolethers, preferably diethyl ether, tert tion “C-alkenyl' includes all the possible isomeric forms butyl-methylether, dibutylether, anisol, dioxane, tet of the groups in question with the same number of carbons. rahydrofuran, mono-, di-, tri-, polyethyleneglycol Thus, for example, propenyl includes 1-propen-1-yl, 1-pro ethers; pen-2-yl and 2-propen-1-yl. 0286 ketones, preferably acetone, butanone, cyclohex 0299. By the term “C-alkynyl' (including those which anone, are part of other groups) are meant alkynyl groups with 2 to 3 0287 esters, preferably acetic acid esters, glycolesters: carbon atoms, if they have at least one triple bond. Examples 0288 amides and other nitrogen compounds, prefer include: ethynyl or propynyl. Unless stated otherwise, the ably dimethylformamide, pyridine, N-methylpyrroli definition “C-alkynyl' includes all the possible isomeric done, acetonitrile; forms of the groups in question with the same number of 0289 Sulphur compounds, preferably carbon disul carbons. Thus, for example, propynyl includes propyn-1-yl phide, dimethylsulphoxide, Sulpholane; and 2-propyn-1-yl. 0290 nitro compounds, preferably nitrobenzene: 0291 halogenated hydrocarbons, preferably dichlo 0300. By the term “C-7-cycloalkyl (including those romethane, chloroform, tetrachlormethane, tri- and tet which are part of other groups) are meant cyclic alkyl groups rachloroethene, 1,2-dichloroethane, chlorofluorocar with 3 to 7 carbon atoms. Examples include: cyclopropyl, bons; cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Unless 0292 aliphatic or alicyclic hydrocarbons, preferably otherwise Stated, the cyclic alkyl groups may be substituted benzines, petroleum ether, cyclohexane, methylcyclo by one or more groups selected from among methyl, ethyl, hexane, decaline, terpene-L.; or iso-propyl, tert-butyl, hydroxy and fluorine. 0293 aromatic hydrocarbons, preferably benzene, tolu 0301 By the term “aryl' (including those which are part of ene, o-Xylene, m-Xylene, p-Xylene; other groups) are meant aromatic ring systems with 6, 10 or or corresponding mixtures thereof. 14 carbon atoms. Examples include: phenyl, naphthyl, 0294 The term diastereomerically pure describes within anthracenyl or phenanthrenyl, the preferred aryl group being the scope of the present invention compounds of formula (I), phenyl. Unless otherwise stated, the aromatic groups may be which are present in a diastereomeric purity of at least 85% substituted by one or more groups R. Particularly preferably de, preferably at least 90% de, particularly preferably >95% the term “aryl' in each case denotes a phenyl group which is de. The term de (diastereomeric excess) is known in the art mono- or disubstituted by R, wherein the substituents R and describes the optical purity of diastereomeric com may be identical or different and pounds. 0302) R denotes hydrogen, or 0295 The term enantiomerically pure describes within the 0303 a group, which may be identical or different, Scope of the present invention compounds of formula (I), selected from among F, Cl, Br, I, OH, CN, C-alkyl, which are present in an enantiomerical purity of at least 85% C-alkyl-O, CHF, CF, —O CHF and ee, preferably at least 90% ee, particularly preferably >95% —O CF. ee. The termee (enantiomeric excess) is known in the art and (0304. By the term “heteroaryl” are meant 5-10-membered describes the optical purity of chiral compounds. mono- or bicyclic heteroaryl rings, wherein up to three C 0296. By the term "C-alkyl” (including those which are atoms may be replaced by one or more heteroatoms selected part of other groups) are meant branched and unbranched from among oxygen, nitrogen or Sulphur, these rings contain alkyl groups with 1 to 6 carbon atoms and by the term "Ca ing Sufficient conjugated double bonds to form an aromatic alkyl are meant branched and unbranched alkyl groups with system. Each of the above-mentioned heterocycles may 1 to 4 carbon atoms. Preferred are alkyl groups with 1 to 4 optionally also be fused to a benzene ring. The heteroaryl carbonatoms, particularly preferably alkyl groups with 1 to 2 rings may, unless otherwise described, carry one or more carbon atoms. Examples include: methyl, ethyl, n-propyl. substituents, for example. The ring may be linked to the US 2011/O 190248 A1 Aug. 4, 2011 10 molecule via a carbon atom or, if available, via a nitrogen 4-yl-0, tetrahydrofuranyl-Ca-alkyl-O- and atom. The following are examples of five- or six-membered tetrahydropyranyl-C-alkyl-O. heterocyclic aromatic groups: O 0315I R' C-alkyl, wherein the linking of the groups R* may take place via each C atom of the alkyl group, o 2 O 0316) R' C-alkyl-O, wherein the group R is sepa {O C). O. O. rated from the oxygen atom by at least 2 C atoms, N N N S. a NN N1 N? NN O 0317 a group selected from among \ { C \, f \ / 0318 pyrrolidin-2-yl-C-alkyl-O, pyrrolidin-3-yl-C. N O 4-alkyl-O, piperidin-2-yl-Ca-alkyl-O, piperidin-3-yl C-alkyl-O, piperidin-4-yl-C-alkyl-O. azepan-2-yl o-N e 4. C-alkyl-O. azepan-3-yl-C-alkyl-O. azepan-4-yl C-alkyl-O, morpholin-2-yl-Ca-alkyl-O, morpholin 3-yl-C-alkyl-O. 1-(C-alkyl)-pyrrolidin-2-yl-C- alkyl-O. 1-(C-alkyl)-pyrrolidin-3-yl-Ca-alkyl-O, NOOC NN 2 s N N1 N s 4. 1-(C-alkyl)-piperidin-2-yl-C-alkyl-O. 1-(C- alkyl)-piperidin-3-yl-C-alkyl-O. 1-(C-alkyl)-pip eridin-4-yl-C-alkyl-O. 1-(C-alkyl)-azepan-2-yl 0305 Examples of 5-10-membered bicyclic heteroaryl C-alkyl-O. 1-(C-alkyl)-azepan-3-yl-C-alkyl-O. rings include pyrrolizine, indole, indolizine, isoindole, inda 1-(C-alkyl)-azepan-4-yl-C-alkyl-O. 4-(Cis Zole, purine, quinoline, isoquinoline, quinoxaline, benzimi alkyl)-morpholin-2-yl-C-alkyl-O and 4-(C-alkyl)- dazole, benzofuran, benzothiophene, benzothiazole, ben morpholin-3-yl-Ca-alkyl-O , Zoisothiazole, pyridopyrimidine, pteridine, preferably C-alkyl-O particularly preferably CH pyrimidopyrimidine. O—, (0306 Particularly preferably, the term “heteroaryl wherein the pyrrolidinyl, piperidinyl, azepan-1-yl, piperazi denotes a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl nyl, 1,4-diazepan-1-yl, morpholinyl and 1,4-oxazepan-4-yl group, which is mono- or disubstituted in each case by the groups mentioned above in the definition of the group R may group R, wherein the substituents R may be identical or each additionally be substituted by one or two C-alkyl different and R is as hereinbefore defined. groups, 0307 "Halogen' within the scope of the present invention and denotes fluorine, chlorine, bromine or iodine. Unless stated to the contrary, fluorine, chlorine and bromine are regarded as wherein the above-mentioned phenyl groups are mono- or preferred halogens. disubstituted by groups R. 0308 The substituent R* may represent a phenyl or 1-phe 0319. The substituent R' may denote hydrogen or nylethyl group, preferably a phenyl group, wherein the phe 0320 a group selected from among nyl nucleus is substituted in each case by the groups R' to R. 0321 F, Cl, Br, I, OCHF, OCHF, OCF, CHF, CHF, 0309 Particularly preferably the substituent R" denotes a CF, CN, NO, NH, and OH, or group, selected from among 3-chloro-2-fluoro-phenyl, 0322 a group selected from among 3-chloro-4-fluoro-phenyl, 5-chloro-2-fluoro-phenyl, 0323 C-alkyl, C-alkyl-O, C-alkenyl, C-alky 2-fluoro-3-methyl-phenyl, 2-fluoro-5-methyl-phenyl, nyl, 4-fluoro-3-methyl-phenyl- and 3-chloro-2-methyl-phenyl. 0324 phenyl, phenyl-O, phenyl-C-alkyl- and phe Most particularly preferably the substituent R" denotes a nyl-C-alkyl-O, heteroaryl, heteroaryl-O, heteroaryl 3-chloro-2-fluoro-phenyl group. C-alkyl and heteroaryl-C-alkyl-O. 0310. The substituent R may represent hydrogen, or an 0325 wherein the above-mentioned phenyl groups are optionally Substituted group selected from among C-alkyl, mono- or disubstituted by groups R. Co-cycloalkyl- and C-cycloalkyl-C-alkyl, preferably preferably hydrogen, fluorine, chlorine, bromine or methyl, hydrogen and C-alkyl, particularly preferably hydrogen particularly preferably hydrogen, fluorine, chlorine or and methyl. methyl. 0311. The substituent R may represent hydrogen, or an optionally Substituted group selected from among C-alkyl, 10326) The substituent R may represent hydrogen or C-cycloalkyl- and C-cycloalkyl-C-alkyl, C-alkyl 0327 a group selected from among CO, C-cycloalkyl-CO— and C-cycloalkyl-C-alkyl 0328 F, Cl, Br, I, OCHF, OCHF, OCF, CHF, CHF, CO, C-alkyl-SO, C-cycloalkyl-SO- and C-cy CF, CN, NO, NH, and OH, or cloalkyl-C-alkyl-SO, phenyl-CO— and phenyl-SO, 0329 a group selected from among preferably hydrogen and C-alkyl, particularly preferably 0330 C-alkyl, C-alkyl-O, C-alkenyl, C-alky hydrogen and methyl. nyl, phenyl, phenyl-O, phenyl-C-alkyl and phenyl 0312. The substituent R may denote hydrogen or C-alkyl-O, heteroaryl, heteroaryl-O, heteroaryl-C- 0313 a group selected from among alkyl and heteroaryl-C-alkyl-O, wherein the above 0314 F, Cl, Br, I, OH, C-alkyl, C-alkyl-O, C mentioned phenyl groups are mono- or disubstituted by alkyl-O substituted by 1 to 3 fluorine atoms, C-7-cy groups R. cloalkyl-O, C-7-cycloalkyl-C-alkyl-O, tetrahydrofu preferably hydrogen, fluorine, chlorine or methyl, particu ran-3-yl-O, tetrahydropyran-3-yl-O, tetrahydro-pyran larly preferably hydrogen, fluorine or chlorine. US 2011/O 190248 A1 Aug. 4, 2011

0331. The substituent R may represent hydrogen, or wherein 0332 a group selected from among F, Cl, Brand CH R. R. and A are as hereinbefore defined and Z' denotes a preferably hydrogen. leaving group Such as a halogen atom, e.g. a chlorine or 0333. The substituent R may represent a group, which bromine atom, a Sulphonyloxy group Such as a methane may be identical or different, selected from among Sulphonyloxy or p-toluenesulphonyloxy group or a hydroxy 0334 OH, C-alkyl-O, C-cycloalkyl-O, NH, C group. alkyl-NH. (C-alkyl).N. (2-methoxyethyl)-N, pyrroli 0342. With a compound of general formula (III), wherein din-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, Z' denotes a halogen atom or a sulphonyloxy group, the 1,4-oxazepan-4-yl, 2-oxa-5-aza-bicyclo2.2.1]hept-5- reaction is expediently carried out in a solvent Such as etha y1, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl, 8-oxa-3-aza-bi nol, isopropanol, acetonitrile, toluene, tetrahydrofuran, diox cyclo3.2.1]oct-3-yl, piperazin-1-yl 4-(C-alkyl)-pip ane, dimethylformamide, dimethylsulphoxide or N-meth erazin-1-yl, 1.4-diazepan-1-yl 4-(C-alkyl)-1,4- ylpyrrolidinone, preferably in the presence of a base Such as diazepan-1-yl, HCO. NH, C-alkyl-CO. NH, C potassium carbonate, potassium-tert-butoxide, sodium alkyl-O C-alkyl-CO. NH, C-alkyl-O CO hydride or N-ethyl-diisopropylamine, at temperatures in the NH, HNCONH, C-alkyl-NH CO. NH, (C- range from 20°C. to 160° C., for example attemperatures in alkyl)-N CONH, pyrrolidin-1-yl-CO. NH, the range from 60° C. to 140° C. piperidin-1-yl-CO. NH, piperazin-1-yl-CO. NH, (0343 With a compound of general formula III wherein Z' 4-(C-alkyl)-piperazin-1-yl-CO. NH and morpholin denotes a hydroxy group, the reaction is carried out in the 4-yl-CO. NH and C-alkyl-SO. NH-. presence of a dehydrating agent, preferably in the presence of 0335) The substituent R may represent hydrogen, or a phosphine and an aZodicarboxylic acid derivative such as 0336 a group, which may be identical or different, e.g. triphenylphosphine/diethyl azodicarboxylate, conve niently in a solvent such as methylene chloride, acetonitrile, Selected from among tetrahydrofuran, dioxane, toluene or ethyleneglycol diethyl 0337 F. Cl, Br, I, OH, CN, C-alkyl, C-alkyl-O, ether attemperatures between -50 and 150°C., but preferably CHF, CF, —O CHF and —O—CF. attemperatures between -20 and 80° C. 0338 A may denote —CO or —C-C-alkylene, prefer 0344 b) In order to prepare compounds of general formula ably —CHCH I wherein R and R each denote a hydrogen atom and A 0339 wherein the C-C-alkylene group may be 1-, represents a —CO— group, reacting a compound of general 2-, 3- or 4-, preferably 1- or 2-substituted by a group R. formula (0340. The substituent R, which may be identical or dif ferent, may represent hydrogen, or a group selected from (IV) among OH, C-C-alkyl and —O-C-C-alkyl, preferably R H methyl. A particularly preferred definition of A is NN1 —CH2CH2—. O N1 N Methods of Preparation le O, 0341 The following methods are suitable, for example, N Rd 2 for preparing compounds of general formula (I): wherein a) reacting a compound of general formula R" and Rare as hereinbefore defined, with an alkali metal cyanide and ammonium carbonate. (II) 0345 The reaction is carried out for example in a solvent R H or mixture of Solvents such as methanol, ethanol, ethanol/ NN1 water or isopropanol at temperatures between ambient tem perature and 120° C. Further references to the synthesis of N O NH. hydantoins can be found for example in the following publi cation: - 0346 Meusel, M. Guetschow, M., Organic Preparations N Ra and Procedures International (2004), 36(5), 391-443. c) reacting a compound of general formula (V) wherein (V) R" and Rare as hereinbefore defined, with a compound of O general formula

(III) lsN Rd N Rc1 N-A wherein R. R. Rand A are as hereinbefore defined, with a halogenating agent, for example an acid halide Such as thio nyl chloride, thionyl bromide, phosphorus trichloride, phos phorus pentachloride, phosphorus oxychloride, or triph US 2011/O 190248 A1 Aug. 4, 2011 enylphosphine/carbon tetrachloride or triphenylphosphine/ wherein R* denotes a group selected from among Cla-alkyl, N-chlorosuccinimide to obtain an intermediate compound of C2-alkyl Substituted by 1 to 3 fluorine atoms, C-7-cy cloalkyl, C-7-cycloalkyl-C-alkyl, tetrahydrofuran-3-yl. general formula (VI), tetrahydropyran-3-yl, tetrahydro-pyran-4-yl, tetrahydrofura (VI) nyl-C-alkyl and tetrahydropyranyl-C-alkyl, Z2 O 0350 R C-alkyl, wherein the group R is sepa O rated from Z by at least 2 C atoms, Na O O 0351 a group selected from among ls Rb, 0352 pyrrolidin-2-yl-C-alkyl, pyrrolidin-3-yl-C- N Ra alkyl, piperidin-2-yl-C-alkyl, piperidin-3-yl-C- N-A alkyl, piperidin-4-yl-C-alkyl, azepan-2-yl-Ca Rc1 alkyl, azepan-3-yl-C-alkyl, azepan-4-yl-C-alkyl, morpholin-2-yl-Ca-alkyl, morpholin-3-yl-Ca-alkyl, wherein R, R, R and Aare as hereinbefore defined and Z 1-(C-alkyl)-pyrrolidin-2-yl-Ca-alkyl, 1-(C- denotes a halogen atom Such as a chlorine or bromine atom, alkyl)-pyrrolidin-3-yl-Ca-alkyl, 1-(C-alkyl)-piperi and Subsequent reaction with a compound of general formula din-2-yl-Ca-alkyl, 1-(C-alkyl)-piperidin-3-yl-C- (VII), alkyl, 1-(C-alkyl)-piperidin-4-yl-C-alkyl, 1-(C- R NH, (VII), alkyl)-azepan-2-yl-Ca-alkyl, 1-(C-alkyl)-azepan-3- yl-Ca-alkyl, 1-(C-alkyl)-azepan-4-yl-Ca-alkyl, wherein R is as hereinbefore defined, or the salts thereof. 4-(C-alkyl)-morpholin-2-yl-Ca-alkyl, 4-(C- 0347 The reaction with the halogenating agent is option alkyl)-morpholin-3-yl-C-alkyl, ally carried out in a solvent such as methylene chloride, and chloroform, acetonitrile or toluene and optionally in the pres Zdenotes a leaving group such as a halogen atom, an alkyl ence of a base such as N,N-diethylaniline, triethylamine or Sulphonyloxy, arylsulphonyloxy or a hydroxy group. N-ethyl-diisopropylamine at temperatures in the range from 0353. If the leaving group is a halogen atom such as a 20° C. to 160° C., preferably from 40° C. to 120° C. Prefer chlorine, bromine or iodine atom or an alkylsulphonyloxy or ably, however, the reaction is carried out with thionyl chloride arylsulphonyloxy group Such as the methanesulphonyloxy or and catalytic amounts of dimethylformamide at the boiling p-toluenesulphonyloxy group, the reaction is preferably car temperature of the reaction mixture or with phosphorus oxy ried out in the presence of an organic or inorganic base such chloride in acetonitrile in the presence of triethylamine at the as potassium carbonate, sodium hydride or N-ethyl-diisopro boiling temperature of the reaction mixture or with triph pylamine. If the leaving group is a hydroxy group, the reac enylphosphine/carbon tetrachloride or with triphenylphos tion is carried out in the presence of a dehydrating agent, phine/N-chlorosuccinimide in acetonitrile. preferably in the presence of a phosphine and an azodicar 0348. The reaction of the compound of general formula boxylic acid derivative such as e.g. triphenylphosphine? di (VI) with the compound of general formula (VII) or the salts ethylazodicarboxylate. thereof is conveniently carried out in a solvent such as etha e) In order to prepare compounds of general formula I nol, isopropanol, acetonitrile, dioxane or dimethylforma wherein Rd denotes a R' C-alkyl-O-group, wherein mide, optionally in the presence of a base Such as potassium the group R is separated from the oxygenatom by at least 2 carbonate, triethylamine or N-ethyl-diisopropylamine, at Catoms, and R' denotes a group selected from among NH2, temperatures in the range from 20°C. and 160°C., preferably C-alkyl-NH. (C-alkyl).N. (2-methoxyethyl)-N, pyrroli from 60° C. to 120° C. However, the reaction is preferably din-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, 1,4- carried out in isopropanol at the boiling temperature of the oxazepan-4-yl, 2-oxa-5-aza-bicyclo2.2.1]hept-5-yl, 3-oxa reaction mixture. 8-aza-bicyclo[3.2.1]oct-8-yl, 8-Oxa-3-aza-bicyclo[3.2.1]oct 0349 The reaction of a compound of general formula (V) 3-yl, piperazin-1-yl 4-(C-alkyl)piperazin-1-yl, 1.4- to obtain a compound of general formula (I) may also be diazepan-1-yl 4-(C-alkyl)-1,4-diazepan-1-yl: reacting a carried out as a one-pot reaction, for example inacetonitrile in compound of general formula the presence of triethylamine. d) In order to prepare compounds of general formula I wherein R* denotes one of the optionally substituted alkyloxy groups mentioned hereinbefore: O Rb (X) reacting a compound of general formula RS-H / (VIII) RS-H C--O 4. O O.RC A Nr. O ...Asia se OH " wherein R", R, R and Aare as hereinbefore defined and Z' denotes a leaving group Such as a halogen atom, e.g. a chlo -N-A rine or bromine atom or a Sulphonyloxy group Such as a wherein R", R, R and Aare as hereinbefore defined, with a methaneSulphonyloxy or p-toluenesulphonyloxy group, with compound of general formula H. R', (XI) Zi-Ra, (DX) wherein R' is as hereinbefore defined. US 2011/O 190248 A1 Aug. 4, 2011 f) In order to prepare compounds of general formula I wherein wherein R, R, R and Aare as hereinbefore defined and R R" denotes a hydrogen atom: denotes a protective group, for example an optionally Substi cleaving a protective group from a compound of general tuted benzyl group or a formyl, acetyl, trifluoroacetyl, meth formula oxycarbonyl, ethoxycarbonyl, tert.-butoxycarbonyl or benzy loxycarbonyl group. 0358. The protective group is cleaved, for example, hydro (XII) lytically in an aqueous solvent, e.g. in water, isopropanol/ RS-H water, acetic acid/water, tetrahydrofuran/water or dioxane/ water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or Sulphuric acid or in the presence of an N1 N O O alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimeth - Rd -R'. ylsilane, attemperatures between 0 and 120°C., preferably at temperatures between 10 and 100° C. 0359 An optionally substituted benzyl group, or a benzy -N-A loxycarbonylbenzyl group is cleaved, for example, hydro genolytically, e.g. with hydrogen in the presence of a catalyst wherein R, R, R and Aare as hereinbefore defined and R. Such as palladium/charcoal in a suitable solvent Such as denotes a protective group, for example an optionally Substi methanol, ethanol, ethyl acetate or glacial acetic acid, option tuted benzyl group, a tert.-butyl group or a 2-(trimethylsilyl) ally with the addition of an acid such as hydrochloric acid at ethyl group. temperatures between 0 and 100° C., but preferably at ambi 0354 An optionally substituted benzyl group is for ent temperatures between 20 and 60°C., and under a hydro example cleaved hydrogenolytically, e.g. with hydrogen in gen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. the presence of a catalyst Such as palladium/charcoal in a 0360. A tert-butyloxycarbonyl group is preferably Suitable solvent such as methanol, ethanol, ethyl acetate or cleaved by treatment with an acid such as trifluoroacetic acid glacial acetic acid, optionally with the addition of an acid or hydrochloric acid, optionally using a solvent Such as meth Such as hydrochloric acid, at temperatures between 0 and ylene chloride, dioxane, methanol or diethyl ether. 100° C., but preferably at ambient temperatures between 20 0361. A trifluoroacetyl group is preferably cleaved by and 60° C., and under a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. However, a 2,4-dimethoxybenzyl treatment with an acid Such as hydrochloric acid, optionally group is preferably cleaved in trifluoroacetic acid in the pres in the presence of a solvent Such as acetic acid attemperatures ence of anisol, thioanisol, pentamethylbenzene or triethylsi between 50 and 120° C. or by treatment with sodium hydrox lane. ide Solution, optionally in the presence of a solvent such as 0355 An optionally substituted benzyl group or a tert.- tetrahydrofuran attemperatures between 0 and 50° C. butyl group may for example also be cleaved by treating with 0362. Other suitable protective groups and possible ways an acid such as trifluoroacetic acid, hydrochloric acid or of introducing and cleaving them are described for example in hydrobromic acid, optionally using a solvent Such as meth “Protective Groups in Organic Synthesis” by Theodora W. ylene chloride or toluene, optionally in the presence of ani Greene and Peter G. M. Wuts, Wiley-VCH, or Philip Kocien sole, thioanisole, pentamethylbenzene or triethylsilane. ski, Protecting Groups, 3rd ed. 2004, THIEME. 0356. A 2-(trimethylsilyl)ethyl group is cleaved for h) In order to prepare compounds of general formula I example by treatment with fluorides such as tetrabutylammo wherein A denotes a —C-C-alkylene group: nium fluoride, optionally using a solvent such as tetrahydro cyclising a compound of general formula furan or dioxane. 0357. Other suitable protective groups and possible ways of introducing and cleaving them are described for example in R H (XIV) “Protective Groups in Organic Synthesis” by Theodora W. NN1 Greene and Peter G. M. Wuts, Wiley-VCH, or Philip Kocien ski, Protecting Groups, 3rd ed. 2004, THIEME. O g) In order to prepare compounds of general formula I wherein R denotes a hydrogen atom: s O cleaving a protective group from a compound of general N - Ra Z5 formula Rb Re1 N YA-N/ H R H (XIII) NN1 wherein R. R. R. and R are as hereinbefore defined. A denotes a -C-C-alkylene group and Zdenotes a leaving O group Such as a halogen atom, a hydroxy or alkyloxy group. s O 0363. If the leaving group is a hydroxy group, the reaction l 2 Rb, is carried out in the presence of a dehydrating agent Such as N Rd N1 N,N'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, 0-(benzotriazol-1-yl)-N.N.N'N'-tetramethyluronium-tet rafluoroborate (TBTU) or O-(7-azabenzotriazol-1-yl)-N.N. N',N'-tetramethyluronium-hexafluorophosphate (HATU), conveniently in a solvent such as methylene chloride, N.N- US 2011/O 190248 A1 Aug. 4, 2011 dimethylformamide, acetonitrile, tetrahydrofuran, dioxane or Sodium hydroxide or potassium hydroxide or aprotically, e.g. ethyleneglycol diethyl ether attemperatures between -50° C. in the presence of iodotrimethylsilane, at temperatures and 100° C., but preferably attemperatures between -20°C. between 0 and 120° C., preferably at temperatures between and 60° C. 10 and 100° C. 0364. If the leaving group is a halogen atom, the reaction 0375. A benzyl, methoxybenzyl or benzyloxycarbonyl is preferably carried out in the presence of a base Such as group, however, is cleaved by hydrogenolysis, for example, triethylamine or N-ethyl-diisopropylamine, conveniently in a e.g. with hydrogen in the presence of a catalyst Such as pal solvent such as methylene chloride, N,N-dimethylforma ladium/charcoal in a Suitable solvent Such as methanol, etha mide, acetonitrile, tetrahydrofuran, dioxane or ethylenegly nol, ethyl acetate or glacial acetic acid, optionally with the col diethyl ether at temperatures between -50° C. and 100° addition of an acid such as hydrochloric acid attemperatures C., but preferably attemperatures between -20°C. and 60° C. between 0 and 100° C., but preferably at ambient tempera 0365. If the leaving group is an alkyloxy group, the reac tures between 20 and 60°C., and under a hydrogen pressure tion is optionally carried out in the presence of a base Such as of 1 to 7 bar, but preferably from 3 to 5 bar. A 2,4-dimethoxy potassium carbonate, Sodium hydroxide, triethylamine or benzyl group, however, is preferably cleaved in trifluoroace N-ethyl-diisopropylamine, conveniently in a solvent such as tic acid in the presence of anisole, thioanisole, pentamethyl methanol, ethanol, isopropanol, methylene chloride, N.N- benzene or triethylsilane. dimethylformamide, acetonitrile, tetrahydrofuran, dioxane or 0376. A tert-butyl or tert-butyloxycarbonyl group is pref ethyleneglycol diethyl ether attemperatures between -50° C. erably cleaved by treatment with an acid such as trifluoroace and 120°C., but preferably attemperatures between 0°C. and tic acid or hydrochloric acid or by treating with iodotrimeth 800 C. ylsilane, optionally using a solvent such as methylene 0366. If according to the invention a compound of general chloride, dioxane, methanol or diethyl ether. formula I is obtained which contains an amino, alkylamino or 0377. A trifluoroacetyl group is preferably cleaved by imino group, this may be converted by acylation or Sulpho treatment with an acid Such as hydrochloric acid, optionally nylation into a corresponding acyl or Sulphonyl compound of in the presence of a solvent Such as acetic acid attemperatures general formula I, wherein the acylating agents used may be between 50 and 120° C. or by treatment with sodium hydrox for example carboxylic acid halides, carboxylic acid anhy ide Solution, optionally in the presence of a solvent such as drides and carboxylic acids with activating agents such as tetrahydrofuran attemperatures between 0 and 50° C. N,N'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide 0378. Other suitable protective groups and possible ways or O-(benzotriazol-1-yl)-N.N.N'N'-tetramethyluronium-tet of introducing and cleaving them are described for example in rafluoroborate and Sulphonyl halides as Sulphonylating “Protective Groups in Organic Synthesis” by Theodora W. agents, and/or Greene and Peter G. M. Wuts, Wiley-VCH, or Philip Kocien 0367 if a compound of general formula I is obtained ski, Protecting Groups, 3rd ed. 2004, THIEME. which contains an amino, alkylamino or imino group, it may 0379 Moreover, the compounds of general formula I be converted by alkylation or reductive alkylation into a cor obtained may be resolved into their enantiomers and/or dias responding alkyl compound of general formula I and/or tereomers, as mentioned hereinbefore. Thus, for example, 0368 if a compound of general formula I is obtained cis/trans mixtures may be resolved into their cis and trans which contains analkoxycarbonyl group, it may be converted isomers, and compounds with at least one optically active by ester cleaving into a carboxylic acid, and/or carbon atom may be separated into their enantiomers. 0369 if a compound of general formula I is obtained 0380 Thus, for example, the cis/trans mixtures obtained which contains analkoxycarbonyl group, it may be converted may be resolved by chromatography into the cis and trans by reaction with anamine into a carboxylic acid amide deriva isomers thereof, the compounds of general formula I obtained tive and/or which occur as racemates may be separated by methods 0370 if a compound of general formula I is obtained known perse (cf. Allinger N. L. and Eliel E. L. In “Topics in which contains a carboxy group, it may be converted by Stereochemistry”, Vol. 6, Wiley Interscience, 1971) into their reaction with an amine into a carboxylic acid amide deriva optical antipodes and compounds of general formula I with at tive. least 2 asymmetric carbon atoms may be resolved into their 0371. In the reactions described hereinbefore any reactive diastereomers on the basis of their physical-chemical differ groups present such as hydroxy, amino, alkylamino or imino ences using methods known per se, e.g. by chromatography groups may be protected during the reaction by conventional and/or fractional crystallisation, and, if these compounds are protective groups which are cleaved again after the reaction. obtained in racemic form, they may Subsequently be resolved 0372 For example a protecting group for a hydroxy group into the enantiomers as mentioned above. might be the trimethylsilyl, acetyl, trity1, benzyl or tetrahy 0381. The enantiomers are preferably separated by col dropyranyl group. umn separation on chiral phases or by recrystallisation from 0373) Protecting groups for an amino, alkylamino or an optically active solvent or by reacting with an optically imino group might be, for example, the formyl, acetyl, trif active Substance which forms salts or derivatives such as e.g. luoroacetyl, ethoxycarbonyl, tert.-butoxycarbonyl, benzy esters or amides with the racemic compound, particularly loxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxyben acids and the activated derivatives or alcohols thereof, and Zyl group. separating the diastereomeric mixture of salts or derivatives 0374. Any protective group used is optionally subse thus obtained, e.g. on the basis of their differences in solubil quently cleaved for example by hydrolysis in an aqueous ity, whilst the free antipodes may be released from the pure Solvent, e.g. in water, isopropanol/water, acetic acid/water, diastereomeric salts or derivatives by the action of suitable tetrahydrofuran/water or dioxane/water, in the presence of an agents. Optically active acids in common use are e.g. the D acid Such as trifluoroacetic acid, hydrochloric acid or Sulphu and L-forms of tartaric acid or dibenzoyltartaric acid, di-o- ric acid or in the presence of an alkali metal base Such as tolyltartaric acid, malic acid, mandelic acid, camphorsul US 2011/O 190248 A1 Aug. 4, 2011 phonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (-)-men -continued thol and an optically active acyl group in amides, for example, Z2 may be a (+)- or (-)-menthyloxycarbonyl. 0382 Furthermore, the compounds of formula I obtained N21 O may be converted into the salts thereof, particularly for phar maceutical use into the physiologically acceptable salts with lsN O inorganic or organic acids or bases. Acids which may be used N Ra -R" for this purpose include for example hydrochloric acid, N N hydrobromic acid, Sulphuric acid, methaneSulphonic acid, 1NA ethaneSulphonic acid, benzenesulphonic acid, p-toluenesul phonic acid, phosphoric acid, fumaric acid, Succinic acid, (VI) benzoic acid, Salicylic acid, mandelic acid, lactic acid, mal onic acid, citric acid, L-malic acid, L-tartaric acid or maleic 0386 Starting from a compound of general formula (XV), acid. Suitable bases for this purpose include for example wherein PG denotes a protective group Such as for example Sodium hydroxide solution, potassium hydroxide solution, benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl, the reac calcium hydroxide, diethanolamine or N-methyl-D-glucam tion is carried out with a compound of general formula (III) 1C. analogously to the previously described processa) to obtain a 0383. The compounds of general formulae II to XXIII compound of general formula (XVI). The compounds of gen used as starting materials are known from the literature to eral formula (XV) are known from the literature (cf. E.g. WO some extent or may be obtained by methods known from the 2004/108664 or WO 2007/003486) or may be obtained by literature (cf. Examples I to V), optionally with the additional methods known from the literature. introduction of protecting groups. 0387. The cleaving of the protective group from a com 0384 Standard processes for preparing the starting mate pound of general formula (XVI) to obtain a compound of rials are described for example in “March's Advanced general formula (V) is carried out, if PG denotes benzyl, with Organic Chemistry’ by Michael B. Smith and Jerry March, hydrogen, for example, in the presence of a catalyst Such as Wiley-VCH or in “Science of Synthesis/Houben-Weyl pub palladium/charcoal. The cleaving of the protective group if lished by Thieme. PG denotes 4-methoxybenzyl or 2,4-dimethoxybenzyl may 0385 One possible method of obtaining compounds of also be carried out oxidatively (e.g. with cerium (IV)-ammo general formula (V) and (VI) is as follows: nium nitrate or with 2,3-dichloro-5,6-dicyano-1,4-benzo quinone) or with acids (e.g. with trifluoroacetic acid in the presence of anisole, thioanisole, pentamethylbenzene or tri Scheme 1 ethylsilane). Z 0388 A compound of general formula (V) may then be O converted into a compound of general formula (VI), as described in the previous process c). The meanings for R. R. -R R.A, Z and Z in the compounds of Scheme 1 are defined as O N mentioned hereinbefore. RC -NNy PG.N. OH 0389 Another possible way of obtaining compounds of N (III) general formula (XVI) is as follows: --

lsN Rd Scheme 2 (XV) O Z

O PG NN O O lsS. * - - O N Rd -R' PG.N. OH N N N (XVII) - NA ls (XVI) N Rd O (XV) O O HN PG NN O lsN * - - O N Rd -R S. -- N Rd 1NAN N O (V) (XVIII) US 2011/O 190248 A1 Aug. 4, 2011 16

0391 Another possible way of obtaining compounds of -continued general formula (XXI) is as follows: O Scheme 3 PG O n N Z. -e- O N N Rd O O1 R", (XIX) O O NHPG PGN OH PG O N (XXIII) NN O Hs lsN Ra lsN Rd S O1 R (XV) NHPG O (XX) PG O O n N O PG O ls R NN O N Ra O1 Hip NHPG lsN Rd O1 R (XXI) NHPG 0392 Starting from a compound of general formula (XV), (XXI) wherein PG denotes a protective group Such as for example O benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl, the reac PG O tion is carried out with a compound of general formula NN O (XXIII) analogously to the previously described processa) to form a compound of general formula (XXI). The meanings of lsSa R -e- N Rd O1 R", PG, PG, Rand Z' in the compounds of Scheme 3 areas hereinbefore defined. NH2 0393 As already mentioned hereinbefore, the compounds of general formula (I) according to the invention and the (XXII) physiologically acceptable salts thereof have valuable phar O macological properties, particularly an inhibiting effect on PG O signal transduction mediated by the Epidermal Growth Factor n N receptor (EGF-R), whilst this may be achieved for example by inhibiting ligand bonding, receptor dimerisation or lsS. O tyrosine kinase itself. It is also possible to block the transmis N Ra -R" sion of signals to components located further downstream. N 0394 The following Examples are intended to illustrate RC -NNy the present invention without restricting it: (XVI) Preparation of the Starting Compounds Example I 0390 Starting from a compound of general formula (XV), Methyl cis/trans-(S)-(2-amino-ethyl)-methyl-amino-4-4- wherein PG denotes a protective group Such as for example (3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6- benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl, the reac yloxy)-cyclohexyl)-acetate tion is carried out with a compound of general formula (XVII) 0395 analogously to the previously described processa) to form a compound of general formula (XVIII). After cleaving of the ketal to form the ketone, the reaction is carried out to obtain a compound of general formula (XX) (analogously to e.g. WO C NH 2008/079735). After reduction of the double bond (analo gously to e.g. WO 2008/079735) the protective group PG' is F O cleaved to form a compound of general formula (XXII). The other steps leading to a compound of general formula (XVI) o Olv, -N are carried out for example analogously to Examples III, II, I, and 1. The meanings of R,R,R, A and Z' in the compounds S.-- re of Scheme 2 are defined as hereinbefore. PG' denotes a pro O tective group, for example formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl 0396. A mixture of 970 mg methyl cis/trans-(S)-(2-tert.- and R' denotes a C-alkyl group, for example methyl or butoxycarbonylamino-ethyl)-methyl-aminol-4-4-(3- ethyl. chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6- US 2011/O 190248 A1 Aug. 4, 2011 yloxy)-cyclohexyl)-acetate, 2 ml trifluoroacetic acid and 8 (4) methyl cis/trans-(S)-4-4-(3-chloro-2-fluoro ml methylene chloride is stirred overnight at ambient tem phenylamino)-7-methoxy-quinazolin-6-yloxy-cy perature. Then the reaction mixture is evaporated down in clohexyl)-methyl-(2-methylamino-ethyl)-amino vacuo, leaving a brownish solid, which is reacted further acetate without any further purification. 0397. Yield: 700 mg (85% of theory) 0407 0398. Mass spectrum (ESI"): m/z 546, 548 M+H" 0399. The following compounds are obtained analogously to Example I: (1) methyl cis/trans-(S)-amino-4-4-(3-chloro-2- fluoro-phenylamino)-7-methoxy-quinazolin-6- yloxy-cyclohexyl)-acetate C NH 04.00 F too s r NH C NH O O F Na O ls, O NH2 (0408 Mass spectrum (ESI"): m/z 560, 562 M+H" (5) methyl cis-(R)-(2-amino-ethylamino)-4-4-(3- chloro-2-fluoro-phenylamino)-7-methoxy-quinaZo lin-6-yloxy-cyclohexyl)-acetate 04.09 nol/conc.04.01 R-value:Xmmonia 0.42 50:10) (silica gel, methylene chloride/metha 0402 Mass spectrum (ESI): m/z. 489, 491 M+H" (2) methyl cis/trans-(S)-(2-amino-ethylamino)-4-4- (3-chloro-2-fluoro-phenylamino)-7-methoxy quinazolin-6-yloxy)-cyclohexyl)-acetate C NH 0403 F N21 O lsSa N O n1n NH,

C NH O F N21 O lsSa N , C n1n NH, 0410 Mass spectrum (ESI): m/z 530, 532 M+HI O O (6) methyl cis-(R)-amino-4-4-(3-chloro-2-fluoro phenylamino)-7-methoxy-quinazolin-6-yloxy-cy clohexyl)-acetate 0404 Mass spectrum (ESI"): m/z 532,534 M+H" (3) methyl cis/trans-(S)-4-4-(3-chloro-2-fluoro 0411 phenylamino)-7-methoxy-quinazolin-6-yloxy-cy clohexyl)-(2-methylamino-ethylamino)-acetate 0405

C NH

F O C NH N21 F N2 O ls NH2 N O lsSa , O O O

04.06 Mass spectrum (ESI"): m/z 546, 548 M+H" 0412 Mass spectrum (ESI"): m/z 489, 491 M+H" US 2011/O 190248 A1 Aug. 4, 2011 18

(7) methyl trans-(R)-(2-amino-ethylamino)-4-4-(3- (8) methyl trans-(R)-amino-4-4-(3 -chloro-2- chloro-2-fluoro-phenylamino)-7-methoxy-quinazo- fluoro-phenylamino)-7-methoxy-quinazolin-6- lin-6-yloxy)-cyclohexyl)-acetate yloxy)-cyclohexyl)-acetate 0415 0413

C NH F N21 O,/... C NH ls NH2 N O F N21 O., ls O NO N O n1n NH, O O 0416 Mass spectrum (ESI"): m/z 489, 491 M+H" Example II Methyl cis/trans-(S)-(2-tert.-butoxycarbonylamino ethyl)-methyl-amino--4-4-3-chloro-2-fluoro phenylamino)-7-methoxy-quinazolin-6-yloxy-cy clohexyl)-acetate 0414 Mass spectrum (ESI"): m/z 532,534 M+H" 0417

C NH

F O N21 O

0418 240 ul of a 37% aqueous formaldehyde solution, 100 ul glacial acetic acid and 500 mg sodium triacetoxyboro hydride are added to 1.00 g methyl cis/trans-(S)-(2-tert.-bu toxycarbonylamino-ethylamino)-4-4-(3-chloro-2-fluoro phenylamino)-7-methoxy-quinazolin-6-yloxy cyclohexyl-acetate in 30 ml of tetrahydrofuran. The reaction mixture is stirred overnight at ambient temperature, diluted with ethyl acetate, combined with 10% potassium carbonate Solution and vigorously stirred. The organic phase is sepa rated off, washed with water and saturated sodium chloride Solution, dried on magnesium Sulphate and evaporated down. 0419 Yield: 970 mg (95% of theory) 0420 Mass spectrum (ESI): m/z =646, 648 M+H" US 2011/O 190248 A1 Aug. 4, 2011 19

0421. The following compound is obtained analogously to 0425 490 mg tert. Butyl (2-oxo-ethyl)-carbamate fol Example II: lowed by 180 ul glacial acetic acid and 150 mg sodium triacetoxyborohydride are added to 1.50 g methyl cis/trans (1) methyl cis/trans-(S)-2-(tert-butoxycarbonyl- (S)-amino-4-4-(3-chloro-2-fluoro-phenylamino)-7-meth methyl-amino)-ethyl-methyl-amino } -4-4-(3 oxy-quinazolin-6-yloxy -cyclohexyl -acetate in 40 ml of tet chloro-2-fluoro-phenylamino)-7-methoxy-chaZolin- rahydrofuran. The reaction mixture is stirred overnight at 6-yloxy)-cyclohexyl)-acetate ambient temperature, then another 70 mg tert. Butyl (2-oxo ethyl)-carbamate and 150 mg sodium triacetoxyborohydride are added and the mixture is stirred for a further four hours at 0422 ambient temperature. For working up the reaction mixture is

C NH

0423 Mass spectrum (ESI"): m/z =660, 662 M+H" diluted with 20 ml of ethyl acetate, combined with 10 ml 10% potassium carbonate solution and stirred thoroughly. The Example III aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are washed with Satu Methyl cis/trans-(S)-(2-tert.-butoxycarbonylamino rated Sodium chloride Solution, dried on magnesium Sulphate ethylamino)-4-4-(3-chloro-2-fluoro-phenylamino)- and evaporated down. The crude product is reacted further 7-methoxy-quinazolin-6-yloxy-cyclohexyl)-acetate without any further purification. 0424 0426 Mass spectrum (ESI"): m/z =632, 634 M+H"

C NH

US 2011/O 190248 A1 Aug. 4, 2011

Example IV (2) methyl trans-(R)-tert-butoxycarbonylamino-4- 4-(3-chloro-2-fluoro-phenylamino)-7-methoxy methyl cis/trans-(S)-tert-butoxycarbonylamino-4- quinazolin-6-yloxy)-cyclohexyl)-acetate 4-(3-chloro-2-fluoro-phenylamino)-7-methoxy quinazolin-6-yloxy)-cyclohexyl)-acetate 0443 0435

C NH C NH F N21 O., F N21 O ls NH O lsSa , NH O ^^ N-NiskO N O Sk O C.O

0436 10.00 g 4-(3-chloro-2-fluoro-phenylamino)-7- 0444 Mass spectrum (ESI): m/z 589, 591 M+H" methoxy-quinazolin-6-ol in 70 ml N,N-dimethylformamide are heated to 50° C., combined with 7.00 g potassium car bonate as well as 14.00 g methyl cis/trans-(S)-tert.-butoxy Example V carbonylamino-(4-methaneSulphonyloxy-cyclohexyl)-ac etate and heated to 80° C. The reaction mixture is stirred Methyl cis/trans-(S)-tert.-butoxycarbonylamino-(4- overnight at 80°C., then another 3.50 g methyl cis/trans-(S)- methaneSulphonyloxy-cyclohexyl)-acetate tert-butoxycarbonylamino-(4-methanesulphonyloxy-cyclo hexyl)-acetate and 2.60 g potassium carbonate are added. 0445 0437. After a further four hours at 80° C. the reaction mixture is cooled and diluted with ethyl acetate and water. The aqueous phase is separated off and extracted with ethyl O acetate. The combined organic phases are dried on magne | sium Sulphate and evaporated down. The crude product is -SEO purified by chromatography through a silica gel column with O methylene chloride/methanol/conc. Ammonia (99/1/0.1 auf 8/2/0.1) as eluant. H 0438 Yield: 5.90 g (32% of theory) 0439 Mass spectrum (ESI): m/z 589, 591 M+H" 0440 The following compounds are obtained analogously DCr) O to Example IV: O (1) methyl cis-(R)-tert-butoxycarbonylamino-4-4- (3-chloro-2-fluoro-phenylamino)-7-methoxy quinazolin-6-yloxy)-cyclohexyl)-acetate 0446 5.20 ml methanesulphonic acid chloride are slowly added dropwise to 17.55g methyl cis/trans-(S)-tert.-butoxy 0441 carbonylamino-(4-hydroxy-cyclohexyl)-acetate (see WO2004/110436) and 10.50 ml triethylamine in 170 ml methylene chloride while cooling with an ice bath, the tem perature being kept below 10°C. Then the reaction mixture is C NH heated to ambient temperature and stirred overnight. 0447 For working up 50 ml saturated sodium hydrogen carbonate solution are added. The aqueous phase is separated lsSa NH O off and extracted with methylene chloride. The combined N O r K organic phases are washed with Saturated Sodium chloride O Solution, dried on magnesium Sulphate and evaporated down. O A viscous oil remains which is further reacted without any further purification. 0448 Yield: 21.70 g (97% of theory) 0442. Mass spectrum (ESI"): m/z 589, 591 M+H" 0449 Mass spectrum (ESI"): m/z383 (MNH." US 2011/O 190248 A1 Aug. 4, 2011 22

0450. The following compounds are obtained analogously 0458. A mixture of 700 mg methyl (2-amino-ethyl)-me to Example V: thyl-amino-4-4-(3-chloro-2-fluoro-phenylamino)-7- methoxy-quinazolin-6-yloxy)-cyclohexyl)-acetate, 7 ml of (1) methyl cis-(R)-tert.-butoxycarbonylamino-(4- methanol and 0.65 ml 4N sodium hydroxide solution is stirred methaneSulphonyloxy-cyclohexyl)-acetate for three hours at ambient temperature. Then the reaction 0451 mixture is evaporated down and extracted with ethyl acetate. O The organic phase is dried on magnesium Sulphate and evapo rated down. The flask residue is purified by chromatography -SEO through a silica gel column with methylene chloride/metha nol/conc. ammonia (98/2/0.1 auf 8/2/0.1) as eluant. The crude O product is stirred with diisopropylether, suction filtered and H dried. 0459 Yield: 300 mg (46% of theory) 0460 Mass spectrum (ESI"): m/z 514, 516 M+H" r)O 0461 The following compounds are obtained analogously O to Example 1: (1) cis/trans-(S)-3-(4-4-(3-chloro-2-fluoro-pheny 0452. The starting material, methyl cis-(R)-tert-butoxy lamino)-7-methoxy-quinazolin-6-yloxy-cyclo carbonylamino-(4-hydroxy-cyclohexyl)-acetate, is obtained hexyl-piperazin-2-one starting from (R)-4-hydroxy-phenylglycine analogously to WO2004f1 10436. 0462 0453 Mass spectrum (ESI"): m/z. 366 M+H" (2) methyl trans-(R)-tert.-butoxycarbonylamino-(4- methaneSulphonyloxy-cyclohexyl)-acetate C NH 0454) F N21 O ls 4, NH N I D O N H 10463) R-value: 0.20 (silica gel, methylene chloride/metha nol/conc. ammonia=90:10:1) 0464) Mass spectrum (ESI"): m/z 500, 502 M+H" 0465. The cis/trans-mixture is separated by supercritical liquid chromatography under the following conditions: 0455 The starting material, methyl trans-(R)-tert.-bu column: Daicel ASH 20x250 mm toxycarbonylamino-(4-hydroxy-cyclohexyl)-acetate, is eluant: CO/methanol (+0.2% diethylamine) (60:40) obtained starting from (R)-4-hydroxy-phenylglycine analo flow: 70 ml/min gously to WO2004/110436. injection volume: 450 ul 0456 Mass spectrum (ESI): m/z. 366 M+H" sample concentration: 100 mg/1 0466. The assignment of the isomers is carried out by Preparation of the End Compounds 1H-NMR spectroscopy (400 MHz, dimethylsulphoxide-d6) Example 1 a) cis-(S)-3-(4-4-(3-chloro-2-fluoro-phenylamino)- cis/trans-(S)-3--4-4-(3-chloro-2-fluoro-phenylamino)-7- 7-methoxy-quinazolin-6-yloxy)-cyclohexyl-piper methoxy-quinazolin-6-yloxy)-cyclohexyl)-4-methyl-piper azin-2-one azin-2-one 0467 0457

C NH C NH F O F N21 O N21 H N N ls , N N O k N O I O N D H characteristic signal at 4.75 (1H, m) US 2011/O 190248 A1 Aug. 4, 2011

b) trans-(S)-3-(4-4-(3-chloro-2-fluoro-pheny (4) cis-(R)-3-(4-4-(3-chloro-2-fluoro-pheny lamino)-7-methoxy-quinazolin-6-yloxy-cyclo lamino)-7-methoxy-quinazolin-6-yloxy-cyclo hexyl-piperazin-2-one hexyl-piperazin-2-one 0468 0475

C NH

C NH

F O N21 ls NH N O D O N characteristic signal at 4.42 (1H, m) H (2) trans-(S)-3-(4-4-(3-chloro-2-fluoro-pheny 0476. The cyclisation is carried out in methanol in the lamino)-7-methoxy-quinazolin-6-yloxy-cyclo presence of triethylamine at ambient temperature. hexyl)-1-methyl-piperazin-2-one 0477 Mass spectrum (ESI"): m/z 500, 502 M+H" 0469 (5) trans-(R)-3-(4-4-(3-chloro-2-fluoro-pheny lamino)-7-methoxy-quinazolin-6-yloxy-cyclo hexyl-piperazin-2-one C NH 0478 F O

lsN A. a. NH CON O O & D N

(0470) R, value:0.31 (silica gel, methylene chloride/metha ls,--- OO, no1/conc. Ammonia=90:10:1) O N 0471 Mass spectrum (ESI"): m/z 514, 516 M+H" H (3) cis/trans-(S)-3-(4-4-(3-chloro-2-fluoro-pheny lamino)-7-methoxy-quinazolin-6-yloxy-cyclo 0479. The cyclisation is carried out in methanol in the hexyl-1,4-dimethyl-piperazin-2-one presence of triethylamine at ambient temperature. 0480 Mass spectrum (ESI"): m/z 500, 502 M+H" 0472 Biological Test 0481. The biological properties of the new compounds are C NH investigated as follows, for example: 0482. The inhibition of the EGF-R-mediated signal trans F Na O mission can be demonstrated e.g. with cells which express human EGF-R and whose survival and proliferation depend ls 4, N on stimulation by EGF or TGF-alpha. A murine haematopoi etic cell line is genetically modified so as to express func tional human EGF-R. The proliferation of this cell line can N O I D therefore be stimulated by EGF. 0483 The test is carried out as follows: or 0484. The cells are cultivated in RPMI/1640 medium. The proliferation is stimulated with 20 ng/ml of human EGF (0473) R, value:0.35 (silica gel, methylene chloride/metha (Promega). To investigate the inhibitory activity of the com no1/conc. Ammonia=90:10:1) pounds according to the invention these compounds are dis 0474 Mass spectrum (ESI"): m/z =528, 530 M+H" solved in 100% dimethylsulphoxide (DMSO) and added to US 2011/O 190248 A1 Aug. 4, 2011 24 the cultures in various dilutions, the maximum DMSO con treat other diseases caused by abnormal function of tyrosine centration being 1%. The cultures are incubated for 48 hours kinases. Such as e.g. epidermal hyperproliferation (psoriasis), at 37° C. benign prostatic hyperplasia (BPH), inflammatory processes, 0485. In order to determine the inhibitory activity of the diseases of the immune system, hyperproliferation of hae compounds according to the invention the relative cell num matopoietic cells, the treatment of nasal polyps, etc. ber is measured in O.D. Units using the Cell Titer 96TM AQueous Non-Radioactive Cell Proliferation Assay 0492. By reason of their biological properties the com (Promega). The relative cell number is calculated as a per pounds according to the invention may be used on their own centage of the control and the concentration of active Sub or in conjunction with other pharmacologically active com stance which inhibits the proliferation of the cells by 50% pounds, for example in tumourtherapy, in monotherapy or in (IC50) is derived therefrom. conjunction with other anti-tumour therapeutic agents, for 0486 The compounds of general formula (I) according to example in combination with topoisomerase inhibitors (e.g. the invention exhibit IC50 values of <10 micromolar, prefer etoposide), mitosis inhibitors (e.g. vinblastine), compounds ably <1 micromolar, for example. which interact with nucleic acids (e.g. cisplatin, cyclophos phamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons), antibodies, etc. For treating respiratory Inhibition of the EGFR Compound dependent proliferation tract diseases, these compounds may be used on their own or (Example No.) ICsonM in conjunction with other therapeutic agents for the airways, Such as Substances with a secretolytic (e.g. ambroXol, N-ace 1 1.O tylcysteine), broncholytic (e.g. tiotropium or ipratropium or 1(1a) 10 1(1b) 1.4 fenoterol, Salmeterol, salbutamol) and/or anti-inflammatory 1(2) 1.O activity (e.g. theophylline or glucocorticoids). 1(3) 1.O 1(4) 12.5 0493 For treating diseases in the region of the gastrointes 1(5) 1.6 tinal tract, these compounds may also be administered on their own or in conjunction with Substances having an effect on motility or secretion. These combinations may be admin Indications istered either simultaneously or sequentially. 0487. As has been found, the compounds of formula (I) are Formulations characterised in that by their versatility in the therapeutic field. Particular mention should be made of the possible appli 0494 The compounds according to the invention may be cations for which the compounds of formula (I) according to administered by oral, transdermal, inhalative, parenteral or the invention are preferably used on the basis of their phar Sublingual route. The compounds according to the invention maceutical efficacy as tyrosine inhibitors. are present as active ingredients in conventional preparations, 0488. The compounds of general formula (I) according to for example in compositions consisting essentially of an inert the invention thus inhibit signal transduction by tyrosine pharmaceutical carrier and an effective dose of the active kinases, as demonstrated by the example of the human EGF Substance, such as for example tablets, coated tablets, cap receptor, and are therefore useful for treating pathophysi Sules, lozenges, powders, Solutions, Suspensions, emulsions, ological processes caused by hyperfunction of tyrosine syrups, Suppositories, transdermal systems etc. An effective kinases. These are e.g. benign or malignant tumours, particu dose of the compounds according to the invention is between larly tumours of epithelial and neuroepithelial origin, 0.1 and 5000, preferably between 1 and 500, more preferably metastasisation and the abnormal proliferation of Vascular between 5-300 mg/dose for oral administration, and between endothelial cells (neoangiogenesis). 0.001 and 50, preferably between 0.1 and 10 mg/dose for 0489. The compounds according to the invention are also intravenous, Subcutaneous or intramuscular administration. useful for preventing and treating diseases of the airways and For inhalation, according to the invention, Solutions contain lungs which are accompanied by increased or altered produc ing 0.01 to 1.0, preferably 0.1 to 0.5% active substance are tion of mucus caused by stimulation of tyrosine kinases, e.g. suitable. For administration by inhalation the use of powders, in inflammatory diseases of the airways Such as chronic bron ethanolic or aqueous solutions is preferred. It is also possible chitis, chronic obstructive bronchitis, asthma, bronchiectasis, to use the compounds according to the invention as a Solution allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, for infusion, preferably in a physiological Saline or nutrient C.1-antitrypsin deficiency, or coughs, pulmonary emphy saline Solution. sema, pulmonary fibrosis and hyperreactive airways. 0495. The compounds according to the invention may be 0490 The compounds are also suitable for treating dis used on their own or in conjunction with other active Sub eases of the gastrointestinal tract and bile duct and gallblad stances according to the invention, optionally also in conjunc der which are associated with disrupted activity of the tion with other pharmacologically active Substances. Suitable tyrosine kinases, such as may be found e.g. in chronic inflam formulations include, for example, tablets, capsules, Supposi matory changes such as cholecystitis, Crohn's disease, ulcer tories, Solutions, syrups, emulsions or dispersible powders. ative colitis, and ulcers in the gastrointestinal tract or Such as Corresponding tablets may be obtained for example by mix may occur in diseases of the gastrointestinal tract which are ing the active Substance(s) with known excipients, for associated with increased secretions, such as Menetrier's dis example inert diluents, such as calcium carbonate, calcium ease, secreting adenomas and protein loss syndrome. phosphate or lactose, disintegrants such as maize starch or 0491. In addition, the compounds of general formula I and alginic acid, binders such as starch or gelatine, lubricants the physiologically acceptable salts thereof may be used to Such as magnesium Stearate or talc and/or agents for delaying US 2011/O 190248 A1 Aug. 4, 2011

release, Such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise -continued several layers. polyvinylpyrrollidone 10.0 mg 0496 Coated tablets may be prepared accordingly by hydroxypropylmethylcellulose 15.0 mg coating cores produced analogously to the tablets with Sub magnesium Stearate 1.5 mg stances normally used for tablet coatings, for example colli done or shellac, gumarabic, talc, titanium dioxide or Sugar. To 230.0 mg achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed Preparation: release, possibly using the excipients mentioned above for the 0504 The active substance is mixed with calcium phos tablets. phate, corn starch, polyvinyl-pyrrolidone, hydroxypropylm 0497 Syrups containing the active substances or combi ethylcellulose and half the specified amount of magnesium nations thereof according to the invention may additionally stearate. Blanks 13 mm in diameter are produced in a tablet contain a Sweetener Such as saccharine, cyclamate, glycerol making machine and these are then rubbed through a screen or Sugar and a flavour enhancer, e.g. a flavouring Such as with a mesh size of 1.5 mm using a suitable machine and Vanillin or orange extract. They may also contain Suspension mixed with the rest of the magnesium Stearate. This granulate adjuvants or thickeners such as Sodium carboxymethyl cellu is compressed in a tablet-making machine to form tablets of lose, wetting agents such as, for example, condensation prod the desired shape. ucts of fatty alcohols with ethylene oxide, or preservatives 0505 Weight of core: 230 mg Such as p-hydroxybenzoates. 0506 die: 9 mm, convex 0498 Solutions for injection are prepared in the usual way, 0507. The tablet cores thus produced are coated with a film e.g. with the addition of preservatives such as p-hydroxyben consisting essentially of hydroxypropylmethylcellulose. The Zoates, or stabilisers such as alkali metal salts of ethylenedi amine tetraacetic acid, and transferred into injection vials or finished film-coated tablets are polished with beeswax. ampoules. 0508 Weight of coated tablet: 245 mg. 0499 Capsules containing one or more active substances B) Tablets Containing 100 mg of Active Substance or combinations of active Substances may for example be prepared by mixing the active substances with inert carriers Composition: Such as lactose or Sorbitol and packing them into gelatine capsules. 0509 1 tablet contains: 0500 Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral active substance 100.0 mg fats or polyethyleneglycol or the derivatives thereof. lactose 80.0 mg 0501 Forpharmaceutical use the compounds according to corn starch 34.0 mg the invention are generally used for warm-blooded verte polyvinylpyrrollidone 4.0 mg brates, particularly humans, in doses of 0.01-100 mg/kg of magnesium Stearate 2.0 mg body weight, preferably 0.1-15 mg/kg. For administration 220.0 mg they are formulated with one or more conventional inert car riers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium Stearate, polyvi nylpyrrolidone, citric acid, tartaric acid, water, water?ethanol, Method of Preparation: water/glycerol, water/sorbitol, water/polyethylene glycol, 0510. The active substance, lactose and starch are mixed propylene glycol, Stearyl alcohol, carboxymethylcellulose or together and uniformly moistened with an aqueous Solution fatty substances such as hard fat or suitable mixtures thereof of the polyvinylpyrrolidone. After the moist composition has to produce conventional galenic preparations such as plain or been screened (2.0 mm mesh size) and dried in a rack-type coated tablets, capsules, powders, Suspensions, Solutions, drier at 50° C. it is screened again (1.5 mm mesh size) and the sprays or Suppositories. lubricant is added. The finished mixture compressed to form 0502. The Examples which follow illustrate the present tablets. invention without restricting its scope: 0511 Weight of tablet: 220 mg 0512 Diameter: 10 mm, biplanar, facetted on both sides Examples of Pharmaceutical Formulations and notched on one side. A) Coated Tablets Containing 75 mg of Active Substance C) Tablets Containing 150 mg of Active Substance Composition: Composition: 0503 1 tablet core contains: 0513. 1 tablet contains:

active Substance 75.0 mg active substance 150.0 mg calcium phosphate 93.0 mg powdered lactose 89.0 mg corn starch 35.5 mg corn starch 40.0 mg US 2011/O 190248 A1 Aug. 4, 2011 26

F) Suspension Containing 50 mg of Active Substance -continued Composition: colloidal silica 10.0 mg polyvinylpyrrollidone 10.0 mg 0523 100 ml of suspension contain: magnesium Stearate 1.0 mg 300.0 mg active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 g Preparation: propyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g 0514. The active substance mixed with lactose, corn starch 70% sorbitol solution 20.00 g and silica is moistened with a 20% aqueous polyvinylpyrroli flavouring 0.30 g done solution and passed through a screen with a mesh size of dist. water ad 100 ml 1.5 mm. The granules, dried at 45° C., are passed through the same screen again and mixed with the specified amount of magnesium Stearate. Tablets are pressed from the mixture. Preparation: 0515 Weight of tablet: 300 mg 0524. The distilled water is heated to 70° C. The methyl 0516 die: 10 mm, flat and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved D) Hard Gelatine Capsules Containing 150 mg of Active therein with stirring. The solution is cooled to ambient tem Substance perature and the active Substance is added and homoge Composition: neously dispersed therein with stirring. After the Sugar, the sorbitol solution and the flavouring have been added and 0517. 1 capsule contains: dissolved, the Suspension is evacuated with stirring to elimi nate air. 0525) 5 ml of Suspension contain 50 mg of active Sub active substance 150.0 mg Stance. corn starch (dried) approx. 180.0 mg lactose (powdered) approx. 87.0 mg G) Ampoules Containing 10 mg Active Substance magnesium Stearate 3.0 mg Composition: approx. 420.0 mg 0526 Preparation: active substance 10.0 mg 0518. The active substance is mixed with the excipients, 0.01N hydrochloric acid C.S. passed through a screen with a mesh size of 0.75 mm and double-distilled water ad 2.0 ml homogeneously mixed using a suitable apparatus. The fin ished mixture is packed into size 1 hard gelatine capsules. 0519 Capsule filling: approx. 320 mg Preparation: Capsule shell: size 1 hard gelatine capsule. 0520 0527 The active substance is dissolved in the necessary amount of 0.01 NHCl, made isotonic with common salt, E) Suppositories Containing 150 mg of Active Substance filtered sterile and transferred into 2 ml ampoules. Composition: H) Ampoules Containing 50 mg of Active Substance 0521 1 suppository contains: Composition: 0528 active substance 150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg active substance 50.0 mg 0.01N hydrochloric acid C.S. 2,000.0 mg double-distilled water ad 10.0 ml

Preparation: Preparation: 0522. After the suppository mass has been melted the 0529. The active substance is dissolved in the necessary active Substance is homogeneously distributed therein and the amount of 0.01 NHCl, made isotonic with common salt, melt is poured into chilled moulds. filtered sterile and transferred into 10 ml ampoules. US 2011/O 190248 A1 Aug. 4, 2011 27

I) Capsules for Powder Inhalation Containing 5 Mg of Active a group selected from among Substance F, Cl, Br, I, OCHF, OCHF, OCF, CHF, CHF, CF, CN, NO, NH, and OH, 0530 1 capsule contains: O a group selected from among Ca-alkyl, C-alkyl-O, C-alkenyl, C-alkynyl, active substance 5.0 mg phenyl, phenyl-O, phenyl-C-alkyl, phenyl-C-alkyl lactose for inhalation 15.0 mg O, heteroaryl, heteroaryl-O, heteroaryl-C-alkyl, het eroaryl-C-alkyl-O, wherein the above-mentioned 20.0 mg phenyl groups are mono- or disubstituted by R groups, and R denotes hydrogen, Preparation: O a group selected from among 0531. The active substance is mixed with lactose for inha F, Cl, Brand CH, lation. The mixture is packed into capsules in a capsule R" denotes hydrogen, or an optionally substituted group making machine (weight of the empty capsule approx. 50 Selected from among C-alkyl, C-cycloalkyl and mg). Co-cycloalkyl-C-alkyl, R denotes hydrogen, or an optionally Substituted group Selected from among C6-alkyl, Cs-e-cycloalkyl, C.- weight of capsule: 70.0 mg cycloalkyl-C-alkyl, C-alkyl-CO, C-cycloalkyl size of capsule = 3 CO, C-cycloalkyl-C-alkyl-CO, C-alkyl-SO, C-cycloalkyl-SO, C-cycloalkyl-C-alkyl-SO, phenyl-CO— and phenyl-SO, J) Solution for Inhalation for Hand-Held Nebulisers Contain R" denotes hydrogen or ing 2.5 mg Active Substance a group selected from among F, Cl, Br, I, OH, C-alkyl, C-alkyl-O, C-alkyl-O 0532. 1 spray contains: substituted by 1 to 3 fluorine atoms, C-cycloalkyl-O, C-7-cycloalkyl-C-alkyl-O, tetrahydrofuran-3-yl-O. tetrahydropyran-3-yl-O, tetrahydro-pyran-4-yl-O, tet active Substance 2.500 mg rahydrofuranyl-C-alkyl-O- and tetrahydropyranyl benzalkonium chloride 0.001 mg C-alkyl-O. 1N hydrochloric acid C.S. O ethanol/water (50/50) ad 15.000 mg R" Cla-alkyl, wherein the linking of the groups R* may take place via each C atom of the alkyl group, O Preparation: R C-alkyl-O, wherein the group R is separated 0533. The active substance and benzalkonium chloride are from the oxygen atom by at least 2 C atoms, dissolved in ethanol/water (50/50). The pH of the solution is O adjusted with 1N hydrochloric acid. The resulting solution is a group selected from among filtered and transferred into suitable containers for use in pyrrolidin-2-yl-C-alkyl-O. pyrrolidin-3-yl-C- hand-held nebulisers (cartridges). alkyl-O, piperidin-2-yl-C-alkyl-O, piperidin-3-yl C-alkyl-O, piperidin-4-yl-Ca-alkyl-O. azepan-2- 0534 Contents of the container: 4.5 g. yl-Ca-alkyl-O. azepan-3-yl-C-alkyl-O. azepan 1. A compound of formula (I) 4-yl-C-alkyl-O, morpholin-2-yl-Ca-alkyl-O. morpholin-3-yl-C-alkyl-O. 1-(C-alkyl)-pyrroli din-2-yl-C-alkyl-O. 1-(C-alkyl)-pyrrolidin-3- (I) yl-C-alkyl-O. 1-(C-alkyl)-piperidin-2-yl-Ca R nN.1 H alkyl-O. 1-(C-alkyl)-piperidin-3-yl-C-alkyl-O. 1-(C-alkyl)-piperidin-4-yl-Ca-alkyl-O. 1-(C- O alkyl)-azepan-2-yl-C-alkyl-O, 1-(C-alkyl)- r O aZepan-3-yl-C-alkyl-O. 1-(C-alkyl)-azepan-4- l 2 Rb yl-C-alkyl-O, 4-(C-alkyl)-morpholin-2-yl-Ca N Rd N1 alkyl-O and 4-(C-alkyl)-morpholin-3-yl-Ca alkyl-O, N-A wherein RC R" denotes a group, which may be identical or different, selected from among OH, C-alkyl-O, C-cy wherein: cloalkyl-O, NH, C-alkyl-NH. (C-alkyl).N. R" denotes a phenyl or 1-phenylethyl group, wherein the (2-methoxyethyl)-N, pyrrolidin-1-yl, piperidin-1-yl. phenyl nucleus is substituted in each case by the groups aZepan-1-yl, morpholin-4-yl, 1,4-oxazepan-4-yl, 2-oxa R" to R, wherein 5-aza-bicyclo[2.2.1]hept-5-yl, 3-oxa-8-aza-bicyclo[3. R" and R which may be identical or different, denote 2.1]oct-8-yl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piper hydrogen or azin-1-yl 4-(C-alkyl)-piperazin-1-yl, 1,4-diazepan US 2011/O 190248 A1 Aug. 4, 2011 28

1-yl 4-(C-alkyl)-1,4-diazepan-1-yl, HCO. NH, A denotes —CH2CH2, wherein the —CH2CH2— group C-alkyl-CO—NH, C-alkyl-O-C-alkyl-CO— may be substituted by 1 or 2 methyl groups, NH, C-alkyl-O CO. NH, HNCONH, C-alkyl optionally in the form of the tautomers, the racemates, the NH CO. NH, (C-alkyl)-N CONH, pyrrolidin-1- enantiomers, the diastereomers and the mixtures thereof, and yl-CO. NH, piperidin-1-yl-CO. NH, piperazin-1-yl optionally the pharmacologically acceptable acid addition CO. NH, 4-(C-alkyl)-piperazin-1-yl-CO. NH, salts thereof. morpholin-4-yl-CO. NH and C-alkyl-SO. NH, 3. (canceled) wherein the pyrrolidinyl, piperidinyl, azepan-1-yl, piper 4. A method for the treatment of inflammatory or allergic azinyl, 1,4-diazepan-1-yl, morpholinyl and 1,4-ox diseases of the airways comprising administering to a patient in need thereof a therapeutically effective amount of a com aZepan-4-yl groups mentioned above in the definition of pound according to claim 1 or a pharmacologically accept the group R may each additionally be substituted by one able acid addition salt thereof. or two C-alkyl groups, 5. The method according to claim 4 wherein the inflamma and tory or allergic disease of the airways is selected from among wherein the above-mentioned phenyl groups is mono- or chronic bronchitis, acute bronchitis, bronchitis caused by disubstituted by R groups, wherein bacterial or viral infection or fungi or helminths, allergic R denotes hydrogen, or bronchitis, toxic bronchitis, chronic obstructive bronchitis a group, which may be identical or different, selected (COPD), asthma (intrinsic or allergic), paediatric asthma, from among bronchiectasis, allergic alveolitis, allergic or non-allergic F, Cl, Br, I, OH, CN, C-alkyl, C-alkyl-O, CHF, rhinitis, chronic sinusitis, cystic fibrosis or mucoviscidosis, CF, —O—CHF and —O CF, alpha-1-antitrypsin deficiency, cough, pulmonary emphy and sema, interstitial lung diseases, alveolitis, hyperreactive air unless stated otherwise, the above-mentioned alkyl groups ways, nasal polyps, pulmonary oedema, pneumonitis of dif may be straight-chain or branched, ferent origins, e.g. radiation-induced or caused by aspiration A denotes —CO or —C-C-alkylene, or infectious pneumonitis, collagenoses such as lupus erythe wherein the -C-C-alkylene group may be 1-, 2-, 3- or matodes, systemic Sclerodermy, sarcoidosis and Boeck's dis 4-substituted by a group R, CaSC. and 6. The method according to claim 4, characterised in that it relates to inflammatory or allergic conditions in which R” which may be identical or different, denotes hydrogen, autoimmune reactions are involved. O 7. A method for the treatment of benign or malignant a group selected from among OH, C-C-alkyl and tumours comprising administering to a patient in need thereof —O-C-C-alkyl, a therapeutically effective amount of a compound according optionally in the form of the tautomers, the racemates, the to claim 1 or a pharmacologically acceptable acid addition enantiomers, the diastereomers and the mixtures thereof, and salt thereof. optionally the pharmacologically acceptable acid addition 8. A pharmaceutical formulation containing a compound salts thereof. of formula (I) according to claim 1. 2. The compounds according to claim 1, 9. An orally administered pharmaceutical formulation wherein: according to claim 8. R" denotes a group selected from among 3-chloro-2- 10. A medicament combinations which contains, besides fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 5-chloro-2- one or more compounds of formula (I) according to claim 1, fluoro-phenyl, 2-fluoro-3-methyl-phenyl, 2-fluoro-5- as further active Substances, one or more compounds selected methyl-phenyl, 4-fluoro-3-methyl-phenyl and 3-chloro from among the categories of betamimetics, anticholinergics, 2-methyl-phenyl group, corticosteroids, further PDE4-inhibitors, LTD4-antagonists, RandR which may be identical or different, EGFR-inhibitors, dopamine agonists, H1-antihistamines, denote hydrogen or C-alkyl, PAF-antagonists and PI3-kinase inhibitors or double or triple R" denotes C-alkyl-O, combinations thereof. unless stated otherwise, the above-mentioned alkyl groups may be straight-chain or branched,