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