USOO9062O29B2

(12) United States Patent (10) Patent No.: US 9,062,029 B2 Schadt et al. (45) Date of Patent: *Jun. 23, 2015

(54) PYRIMIDINYL PYRIDAZINONE 417/10 (2013.01); C07D 417/14 (2013.01); DERVATIVES C07D 451/06 (2013.01); C07D 453/02 (2013.01); A61 K3I/501 (2013.01); A61 K (71) Applicant: Merck Patent GmbH, Darmstadt (DE) 3 1/506 (2013.01); A61 K3I/5355 (2013.01): (72) Inventors: Oliver Schadt, Rodenbach (DE); Dieter A6IK3I/5377 (2013.01); A61K3I/55 Dorsch, Ober-Ramstadt (DE); Frank (2013.01); A61K 45/06 (2013.01) Stieber, Heidelberg (DE); Andree (58) Field of Classification Search Blaukat, Schriesheim (DE) CPC C07D 403/14: A61K31/506; A61K31/5377 USPC ...... 514/236.5, 252.02:544/123, 298 (73) Assignee: Merck Patent GmbH, Darmstadt (DE) See application file for complete search history. (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 (56) References Cited U.S.C. 154(b) by 0 days. This patent is Subject to a terminal dis U.S. PATENT DOCUMENTS claimer. 6,242.461 Bl 6/2001 Goldstein 6,403,586 B1 6/2002 Ohkuchi et al. (21) Appl. No.: 14/149,110 8,071,593 B2 12/2011 Schadt et al. 8,173,653 B2 5, 2012 Dorsch et al. (22) Filed: Jan. 7, 2014 8,329,692 B2 12/2012 Schadt et al. 8,580,781 B2 * 1 1/2013 Dorsch et al...... 514,217.06 (65) Prior Publication Data 8,658,643 B2 * 2/2014 Schadt et al...... 514,236.5 2004/O152739 A1 8, 2004 Hanau US 2014/O128396 A1 May 8, 2014 2004/0259863 A1 12/2004 Eggenweiler et al. 2005/0107391 A1 5/2005 Cui et al. 2007, OO15771 A1 1/2007 Matteucci et al. Related U.S. Application Data 2007/0043057 A1 2/2007 Matteucci et al. 2007/0203136 A1 8, 2007 Lu et al. (62) Division of application No. 13/565,914, filed on Aug. 2007/0265272 A1 1 1/2007 Cheng et al. 3, 2012, now Pat. No. 8,658,643, which is a division of 2008.O293719 A1 11/2008 Dorsch et al. application No. 12/668,491, filed as application No. 2009/00981.81 A1 4/2009 Lu et al. PCT/EP2008/005508 on Jul. 4, 2008, now Pat. No. 2009, O124612 A1 5/2009 Albrecht et al. 8,329,692. 2010/O197690 A1 8, 2010 Schadt et al. 2010, O234354 A1 9/2010 Dorsch et al. (30) Foreign Application Priority Data (Continued) Jul. 12, 2007 (DE) ...... 10 2007 032 507 FOREIGN PATENT DOCUMENTS Apr. 29, 2008 (WO)...... PCT/EP2008/OO3473 DE 196 04388 8, 1997 (51) Int. Cl. DE 10 2005 057 924 6, 2007 A6 IK3I/506 (2006.01) (Continued) A 6LX3/5377 (2006.01) CO7D 403/4 (2006.01) OTHER PUBLICATIONS CO7D 403/0 (2006.01) CO7D 40/0 (2006.01) “Cancer MedLine Plus (2009). Accessed Mar 17, 2009. http:// CO7D 40/4 (2006.01) www.nlm.nih.gov/medlineplus/cancer.html. CO7D 405/4 (2006.01) CO7D 409/4 (2006.01) (Continued) CO7D 43/10 (2006.01) CO7D 413/4 (2006.01) CO7D 4 7/10 (2006.01) Primary Examiner — James O Wilson CO7D 417/4 (2006.01) Assistant Examiner — Ebenezer O Sackey CO7D 45/06 (2006.01) (74) Attorney, Agent, or Firm — Millen, White, Zelano & CO7D 453/02 (2006.01) Branigan, P.C. A6 IK3I/50 (2006.01) A 6LX3/5355 (2006.01) A6 IK3I/55 (2006.01) (57) ABSTRACT A6 IK 45/06 (2006.01) (52) U.S. Cl. Compounds selected from the group according to Claim 1 are CPC ...... C07D 403/10 (2013.01); C07D401/10 inhibitors of tyrosine kinases, in particular of Metkinase, and (2013.01); C07D401/14 (2013.01); C07D can be employed, interalia, for the treatment of tumours. 403/14 (2013.01); C07D405/14 (2013.01); C07D 409/14 (2013.01); C07D 413/10 (2013.01); C07D 413/14 (2013.01); C07D 4 Claims, No Drawings US 9,062,029 B2 Page 2

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Natl Acad Sci USA, Feb. 2006, vol. 103, No. 7, pp. 23.16-2321. * cited by examiner US 9,062,029 B2 1. 2 PYRIMIDINYL PYRIDAZINONE The present invention specifically relates to compounds of DERVATIVES the formula I which inhibit, regulate and/or modulate signal transduction by Met kinase, to compositions which comprise BACKGROUND OF THE INVENTION these compounds, and to processes for the use thereof for the treatment of Met kinase-induced diseases and complaints, The invention had the object of finding novel compounds Such as angiogenesis, cancer, tumour formation, growth and having valuable properties, in particular those which can be propagation, arteriosclerosis, ocular diseases, such as age used for the preparation of medicaments. induced macular degeneration, choroidal neovascularisation The present invention relates to compounds and to the use and diabetic retinopathy, inflammatory diseases, arthritis, of compounds in which the inhibition, regulation and/or 10 thrombosis, fibrosis, glomerulonephritis, neurodegeneration, modulation of signal transduction by kinases, in particular psoriasis, restenosis, wound healing, transplant rejection, tyrosine kinases and/or serine/threonine kinases, plays a role, metabolic diseases and diseases of the immune system, also furthermore to pharmaceutical compositions which comprise autoimmune diseases, cirrhosis, diabetes and diseases of the these compounds, and to the use of the compounds for the 15 blood vessels, also instability and permeability and the like in treatment of kinase-induced diseases. mammals. In particular, the present invention relates to compounds Solid tumours, in particular fast-growing tumours, can be and to the use of compounds in which the inhibition, regula treated with Met kinase inhibitors. These solid tumours tion and/or modulation of signal transduction by Met kinase include monocytic leukaemia, brain, urogenital, lymphatic plays a role. system, stomach, laryngeal and lung carcinoma, including One of the principal mechanisms by which cellular regu lung adenocarcinoma and Small-cell lung carcinoma. lation is effected is through the transduction of extracellular The present invention is directed to processes for the regu signals across the membrane that in turn modulate biochemi lation, modulation or inhibition of Met kinase for the preven cal pathways within the cell. Protein phosphorylation repre tion and/or treatment of diseases in connection with unregu sents one course by which intracellular signals are propagated 25 lated or disturbed Met kinase activity. In particular, the from molecule to molecule resulting finally in a cellular compounds of the formula I can also be employed in the response. These signal transduction cascades are highly regu treatment of certain forms of cancer. The compounds of the lated and often overlap, as is evident from the existence of formula I can furthermore be used to provide additive or many protein kinases as well as phosphatases. Phosphoryla synergistic effects in certain existing cancer , tion of proteins occurs predominantly at serine, threonine or 30 and/or can be used to restore the efficacy of certain existing tyrosine residues, and protein kinases have therefore been cancer chemotherapies and radiotherapies. classified by their specificity of phosphorylation site, i.e. The compounds of the formula I can furthermore be used serine/threonine kinases and tyrosine kinases. Since phos for the isolation and investigation of the activity or expression phorylation is such a ubiquitous process within cells and of Met kinase. In addition, they are particularly suitable for since cellular phenotypes are largely influenced by the activ 35 use in diagnostic methods for diseases in connection with ity of these pathways, it is currently believed that a number of unregulated or disturbed Met kinase activity. disease states and/or diseases are attributable to either aber It can be shown that the compounds according to the inven rant activation or functional mutations in the molecular com tion have an antiproliferative action in vivo in a Xenotrans ponents of kinase cascades. Consequently, considerable plant tumour model. The compounds according to the inven attention has been devoted to the characterisation of these 40 tion are administered to a patient having a hyperproliferative proteins and compounds that are able to modulate their activ disease, for example to inhibit tumour growth, to reduce ity (for a review see: Weinstein-Oppenheimer et al. Pharma. inflammation associated with a lymphoproliferative disease, &. Therap., 2000, 88,229-279). to inhibit transplant rejection or neurological damage due to The role of the receptor tyrosine kinase Met in human tissue repair, etc. The present compounds are suitable for oncogenesis and the possibility of inhibition of HGF (hepa 45 prophylactic ortherapeutic purposes. As used herein, the term tocyte growth factor) dependent Met activation are described “treatment' is used to refer to both prevention of diseases and by S. Berthou et al. in Oncogene, Vol. 23, No. 31, pages treatment of pre-existing conditions. The prevention of pro 5387-5393 (2004). The inhibitor SU11274 described therein, liferation is achieved by administration of the compounds a pyrrole-indoline compound, is potentially suitable for com according to the invention prior to the development of overt bating cancer. Another Met kinase inhibitor for cancer 50 disease, for example to prevent the growth of tumours, pre therapy is described by J. G. Christensen et al. in Cancer Res. vent metastatic growth, diminish restenosis associated with 2003, 63(21), 7345-55. cardiovascular Surgery, etc. Alternatively, the compounds are A further tyrosine kinase inhibitor for combating cancer is used for the treatment of ongoing diseases by stabilising or reported by H. Hov et al. in Clinical Cancer Research Vol. 10, improving the clinical symptoms of the patient. 6686-6694 (2004). The compound PHA-665752, an indole 55 The host or patient can belong to any mammalian species, derivative, is directed against the HGF receptor c-Met. It is for example a primate species, particularly humans; rodents, furthermore reported therein that HGF and Met make a con including mice, rats and hamsters; rabbits; horses, cows, siderable contribution to the malignant process of various dogs, cats, etc. Animal models are of interest for experimental forms of cancer, such as, for example, multiple myeloma. investigations, providing a model for treatment of human The synthesis of Small compounds which specifically 60 disease. inhibit, regulate and/or modulate signal transduction by The susceptibility of a particular cell to treatment with the tyrosine kinases and/or serine/threonine kinases, in particular compounds according to the invention can be determined by Met kinase, is therefore desirable and an aim of the present in vitro tests. Typically, a culture of the cell is combined with invention. a compound according to the invention at various concentra It has been found that the compounds according to the 65 tions for a period of time which is sufficient to allow the active invention and salts thereofhave very valuable pharmacologi agents to induce cell death or to inhibit migration, usually cal properties while being well tolerated. between about one hour and one week. In vitro testing can be US 9,062,029 B2 3 4 carried out using cultivated cells from a biopsy sample. The Thiadiazinones are described in DE 19604388, WO2003/ viable cells remaining after the treatment are then counted. O37349 WO2007/057093 or WO2007/057092. The dose varies depending on the specific compound used, DihydropyridaZinones for combating cancer are described the specific disease, the patient status, etc. A therapeutic dose in WOO3FO37349 A1. is typically sufficient considerably to reduce the undesired Other pyridazines for the treatment of diseases of the cell population in the target tissue while the viability of the immune system, ischaemic and inflammatory diseases are patient is maintained. The treatment is generally continued known from EP 1 043 317 A1 and EP 1 061 077 A1. until a considerable reduction has occurred, for example an at least about 50% reduction in the cell burden, and may be EPO 738 716 A2 and EP 0 711 759 B1 describe other continued until essentially no more undesired cells are dihydropyridaZinones and pyridazinones as fungicides and detected in the body. 10 insecticides. For identification of a signal transduction pathway and for Other pyridaZinones are described as cardiotonic agents in detection of interactions between various signal transduction U.S. Pat. No. 4,397,854. JP 57-95964 discloses other pathways, various scientists have developed Suitable models pyridaZinones. or model systems, for example cell culture models (for The use of other MET kinase inhibitors for combating example Khwaja et al., EMBO, 1997, 16, 2783-93) and mod 15 cancer is described in WO 2007/075567. els of transgenic animals (for example White et al., Onco gene, 2001, 20, 7064–7072). For the determination of certain SUMMARY OF THE INVENTION stages in the signal transduction cascade, interacting com pounds can be utilised in order to modulate the signal (for The invention relates to compounds selected from the example Stephens et al., Biochemical J., 2000, 351, 95-105). group The compounds according to the invention can also be used as The invention also relates to the optically active forms reagents for testing kinase-dependent signal transduction (stereoisomers), the enantiomers, the racemates, the diaste pathways in animals and/or cell culture models or in the reomers and the hydrates and Solvates of these compounds. clinical diseases mentioned in this application. The term Solvates of the compounds is taken to mean adduc Measurement of the kinase activity is a technique which is 25 tions of inert solvent molecules onto the compounds which well known to the person skilled in the art. Generic test form owing to their mutual attractive force. Solvates are, for systems for the determination of the kinase activity using example, mono- or dihydrates or alkoxides. Substrates, for example histone (for example Alessi et al., The expression “effective amount” denotes the amount of a FEBS Lett. 1996, 399, 3, pages 333-338) or the basic myelin medicament or of a pharmaceutical active ingredient which protein, are described in the literature (for example Campos 30 causes in a tissue, system, animal or human a biological or Gonzalez, R. and Glenney, Jr., J.R. 1992, J. Biol. Chem. 267, medical response which is sought or desired, for example, by page 14535). a researcher or physician. For the identification of kinase inhibitors, various assay In addition, the expression “therapeutically effective systems are available. In Scintillation proximity assay (Sorget amount denotes an amount which, compared with a corre al., J. of. Biomolecular Screening, 2002, 7, 11-19) and flash 35 sponding Subject who has not received this amount, has the plate assay, the radioactive phosphorylation of a protein or following consequence: peptide as substrate with YATP is measured. In the presence of improved treatment, healing, prevention or elimination of a an inhibitory compound, a decreased radioactive signal, or disease, syndrome, condition, complaint, disorder or side none at all, is detectable. Furthermore, homogeneous time effects or also the reduction in the advance of a disease, resolved fluorescence resonance energy transfer (HTR 40 complaint or disorder. FRET) and fluorescence polarisation (FP) technologies are The expression “therapeutically effective amount” also suitable as assay methods (Sills et al., J. of Biomolecular encompasses the amounts which are effective for increasing Screening, 2002, 191-214). normal physiological function. Other non-radioactive ELISA assay methods use specific The invention also relates to the use of mixtures of the phospho-antibodies (phospho-ABs). The phospho-AB binds 45 compounds of the formula I, for example mixtures of two only the phosphorylated substrate. This binding can be diastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, detected by chemiluminescence using a second peroxidase 1:10, 1:100 or 1:1000. conjugated anti-sheep antibody (Ross et al., 2002, Biochem. These are particularly preferably mixtures of stereoiso J.). meric compounds. There are many diseases associated with deregulation of 50 Pharmaceutical Salts and Other Forms cellular proliferation and cell death (apoptosis). The condi The said compounds according to the invention can be used tions of interest include, but are not limited to, the following. in their final non-salt form. On the other hand, the present The compounds according to the invention are suitable for the invention also encompasses the use of these compounds in the treatment of various conditions where there is proliferation form of their pharmaceutically acceptable salts, which can be and/or migration of smooth muscle cells and/or inflammatory 55 derived from various organic and inorganic acids and bases cells into the intimal layer of a vessel, resulting in restricted by procedures known in the art. Pharmaceutically acceptable blood flow through that vessel, for example in the case of salt forms of the compounds according to the invention are for neointimal occlusive lesions. Occlusive graft vascular dis the most part prepared by conventional methods. If the com eases of interest include atherosclerosis, coronary vascular pound according to the invention contains a carboxyl group, disease after grafting, vein graft Stenosis, peri-anastomatic 60 one of its Suitable salts can be formed by reacting the com prosthetic restenosis, restenosis after angioplasty or stent pound with a Suitable base to give the corresponding base placement, and the like. addition salt. Such bases are, for example, alkali metal hydroxides, including potassium hydroxide, Sodium hydrox PRIOR ART ide and lithium hydroxide; alkaline earth metal hydroxides, 65 Such as barium hydroxide and calcium hydroxide; alkali Other pyridazine derivatives are described as MET kinase metal alkoxides, for example potassium ethoxide and sodium inhibitors in WO 2007/065518. propoxide; and various organic bases, such as piperidine, US 9,062,029 B2 5 6 diethanolamine and N-methylglutamine. The aluminium ride, hydrobromide, isethionate, mandelate, meglumine, salts of the compounds are likewise included. In the case of nitrate, oleate, phosphonate, pivalate, sodium phosphate, certain compounds, acid-addition salts can be formed by Stearate, Sulfate, Sulfosalicylate, tartrate, thiomalate, tosylate treating these compounds with pharmaceutically acceptable and tromethamine, but this is not intended to represent a organic and inorganic acids, for example hydrogen halides, restriction. Such as hydrogen chloride, hydrogen bromide or hydrogen The acid-addition salts of basic compounds are prepared iodide, other mineral acids and corresponding salts thereof, by bringing the free base form into contact with a sufficient Such as Sulfate, nitrate or phosphate and the like, and alkyl amount of the desired acid, causing the formation of the salt and monoarylsulfonates, such as ethanesulfonate, toluene in a conventional manner. The free base can be regenerated by Sulfonate and benzenesulfonate, and other organic acids and 10 bringing the salt form into contact with a base and isolating corresponding salts thereof. Such as acetate, trifluoroacetate, the free base in a conventional manner. The free base forms tartrate, maleate. Succinate, citrate, benzoate, Salicylate, differ in a certain respect from the corresponding salt forms ascorbate and the like. Accordingly, pharmaceutically accept thereof with respect to certain physical properties, such as able acid-addition salts of the compounds include the follow solubility in polar solvents; for the purposes of the invention, ing: acetate, adipate, alginate, arginate, aspartate, benzoate, 15 however, the salts otherwise correspond to the respective free benzenesulfonate (besylate), bisulfate, bisulfite, bromide, base forms thereof. butyrate, camphorate, camphorsulfonate, caprylate, chloride, As mentioned, the pharmaceutically acceptable base-addi chlorobenzoate, citrate, cyclopentanepropionate, diglucon tion salts of the compounds are formed with metals oramines, ate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, Such as alkali metals and alkaline earth metals or organic ethanesulfonate, fumarate, galacterate (from mucic acid), amines. Preferred metals are sodium, potassium, magnesium galacturonate, glucoheptanoate, gluconate, glutamate, glyc and calcium. Preferred organic amines are N,N'-dibenzyleth erophosphate, hemisuccinate, hemisulfate, heptanoate, hex ylenediamine, chloroprocaine, choline, diethanolamine, eth anoate, hippurate, hydrochloride, hydrobromide, hydroio ylenediamine, N-methyl-D-glucamine and procaine. dide, 2-hydroxyethanesulfonate, iodide, isethionate, The base-addition salts of acidic compounds according to isobutyrate, lactate, lactobionate, malate, maleate, malonate, 25 the invention are prepared by bringing the free acid form into mandelate, metaphosphate, methanesulfonate, methylben contact with a sufficient amount of the desired base, causing Zoate, monohydrogenphosphate, 2-naphthalenesulfonate, the formation of the salt in a conventional manner. The free nicotinate, nitrate, oxalate, oleate, palmoate, pectinate, per acid can be regenerated by bringing the salt form into contact Sulfate, phenylacetate, 3-phenylpropionate, phosphate, phos with an acid and isolating the free acid in a conventional phonate, phthalate, but this does not represent a restriction. 30 manner. The free acid forms differ in a certain respect from Furthermore, the base salts of the compounds according to the corresponding salt forms thereof with respect to certain the invention include aluminium, ammonium, calcium, cop physical properties, such as solubility in polar solvents; for per, iron(III), iron(II), lithium, magnesium, manganese(III), the purposes of the invention, however, the salts otherwise manganese(II), potassium, Sodium and Zinc salts, but this is correspond to the respective free acid forms thereof. not intended to represent a restriction. Of the above-men 35 If a compound according to the invention contains more tioned salts, preference is given to ammonium; the alkali than one group which is capable of forming pharmaceutically metal salts sodium and potassium, and the alkaline earth acceptable salts of this type, the invention also encompasses metal salts calcium and magnesium. Salts of the compounds multiple salts. Typical multiple salt forms include, for which are derived from pharmaceutically acceptable organic example, bitartrate, diacetate, difumarate, dimeglumine, non-toxic bases include salts of primary, secondary and ter 40 diphosphate, disodium and trihydrochloride, but this is not tiary amines, Substituted amines, also including naturally intended to represent a restriction. occurring Substituted amines, cyclic amines, and basic ion With regard to that stated above, it can be seen that the exchanger resins, for example arginine, betaine, caffeine, expression “pharmaceutically acceptable salt in the present chloroprocaine, choline, N,N'-dibenzylethylenediamine connection is taken to mean an active ingredient which com (benzathine), dicyclohexylamine, diethanolamine, diethy 45 prises a compound in the form of one of its salts, in particular lamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, if this Saltform imparts improved pharmacokinetic properties ethanolamine, ethylenediamine, N-ethylmorpholine, N-eth on the active ingredient compared with the free form of the ylpiperidine, glucamine, glucosamine, histidine, hydrabam active ingredient or any other salt form of the active ingredi ine, isopropylamine, lidocaine, lysine, meglumine, N-me ent used earlier. The pharmaceutically acceptable salt form of thyl-D-glucamine, morpholine, piperazine, piperidine, 50 the active ingredient can also provide this active ingredient polyamine resins, procaine, purines, theobromine, triethano for the first time with a desired pharmacokinetic property lamine, triethylamine, trimethylamine, tripropylamine and which it did not have earlier and can even have a positive tris(hydroxymethyl)methylamine (tromethamine), but this is influence on the pharmacodynamics of this active ingredient not intended to represent a restriction. with respect to its therapeutic efficacy in the body. Compounds of the present invention which contain basic 55 The invention furthermore relates to medicaments com nitrogen-containing groups can be quaternised using agents prising at least one compound according to the invention Such as (C-C)alkyl halides, for example methyl, ethyl, iso and/or tautomers and Stereoisomers thereof, including mix propyl and tert-butyl chloride, bromide and iodide; di(C-C) tures thereof in all ratios, and optionally excipients and/or alkyl sulfates, for example dimethyl, diethyl and diamylsul adjuvants. fate; (Co-Cs)alkyl halides, for example decyl, dodecyl 60 Pharmaceutical formulations can be administered in the lauryl, myristyl and stearyl chloride, bromide and iodide; and form of dosage units which comprise a predetermined aryl(C-C)alkyl halides, for example benzyl chloride and amount of active ingredient per dosage unit. Such a unit can phenethyl bromide. Both water- and oil-soluble compounds comprise, for example, 0.5 mg to 1 g, preferably 1 mg to 700 according to the invention can be prepared using Such salts. mg, particularly preferably 5 mg to 100 mg. of a compound The above-mentioned pharmaceutical salts which are pre 65 according to the invention, depending on the condition ferred include acetate, trifluoroacetate, besylate, citrate, treated, the method of administration and the age, weight and fumarate, gluconate, hemisuccinate, hippurate, hydrochlo condition of the patient, or pharmaceutical formulations can US 9,062,029 B2 7 8 be administered in the form of dosage units which comprise a granulated by wetting it with a binder, such as, for example, predetermined amount of active ingredient per dosage unit. syrup, starch paste, acadia mucilage or solutions of cellulose Preferred dosage unit formulations are those which comprise or polymer materials and pressing it through a sieve. As an a daily dose or part-dose, as indicated above, or a correspond alternative to granulation, the powder mixture can be run ing fraction thereof of an active ingredient. Furthermore, through a tabletting machine, giving lumps of non-uniform pharmaceutical formulations of this type can be prepared shape, which are broken up to form granules. The granules using a process which is generally known in the pharmaceu can be lubricated by addition of Stearic acid, a stearate salt, tical art. talc or mineral oil in order to prevent sticking to the tablet Pharmaceutical formulations can be adapted for adminis casting moulds. The lubricated mixture is then pressed to give tration via any desired suitable method, for example by oral 10 (including buccal or Sublingual), rectal, nasal, topical (includ tablets. The compounds according to the invention can also be ing buccal, Sublingual or transdermal), vaginal or parenteral combined with a free-flowing inert excipient and then pressed (including Subcutaneous, intramuscular, intravenous or intra directly to give tablets without carrying out the granulation or dermal) methods. Such formulations can be prepared using dry-pressing steps. A transparent or opaque protective layer all processes known in the pharmaceutical art by, for 15 consisting of a shellac sealing layer, a layer of Sugar or poly example, combining the active ingredient with the mer material and a gloss layer of wax may be present. Dyes excipient(s) or adjuvant(s). can be added to these coatings in order to be able to differen Pharmaceutical formulations adapted for oral administra tiate between different dosage units. tion can be administered as separate units, such as, for Oral liquids, such as, for example, Solution, syrups and example, capsules or tablets; powders or granules; Solutions elixirs, can be prepared in the form of dosage units so that a or Suspensions in aqueous or non-aqueous liquids; edible given quantity comprises a pre-specified amount of the com foams or foam foods; or oil-in-water liquid emulsions or pound. Syrups can be prepared by dissolving the compound water-in-oil liquid emulsions. in an aqueous Solution with a suitable flavour, while elixirs are Thus, for example, in the case of oral administration in the prepared using a non-toxic alcoholic vehicle. Suspensions form of a tablet or capsule, the active-ingredient component 25 can be formulated by dispersion of the compound in a non can be combined with an oral, non-toxic and pharmaceuti toxic vehicle. Solubilisers and emulsifiers, such as, for cally acceptable inert excipient, such as, for example, ethanol, example, ethoxylated isostearyl alcohols and polyoxyethyl glycerol, water and the like. Powders are prepared by com ene Sorbitol ethers, preservatives, flavour additives. Such as, minuting the compound to a Suitable fine size and mixing it for example, peppermint oil or natural Sweeteners or saccha with a pharmaceutical excipient comminuted in a similar 30 manner, such as, for example, an edible carbohydrate. Such rin, or other artificial Sweeteners and the like, can likewise be as, for example, starch or mannitol. A flavour, preservative, added. dispersant and dye may likewise be present. The dosage unit formulations for oral administration can, if Capsules are produced by preparing a powder mixture as desired, be encapsulated in microcapsules. The formulation described above and filling shaped gelatine shells therewith. 35 can also be prepared in Such away that the release is extended Glidants and lubricants, such as, for example, highly disperse or retarded, such as, for example, by coating or embedding of silicic acid, talc, magnesium Stearate, calcium Stearate or particulate material in polymers, wax and the like. polyethylene glycol in solid form, can be added to the powder The compounds according to the invention and salts, Sol mixture before the filling operation. A disintegrant or solubi Vates and physiologically functional derivatives thereof can liser, Such as, for example, agar-agar, calcium carbonate or 40 also be administered in the form of liposome delivery sys Sodium carbonate, may likewise be added in order to improve tems, such as, for example, Small unilamellar vesicles, large the availability of the medicament after the capsule has been unilamellar vesicles and multilamellar vesicles. Liposomes taken. can be formed from various phospholipids, such as, for In addition, if desired or necessary, suitable binders, lubri example, cholesterol, Stearylamine or phosphatidylcholines. cants and disintegrants as well as dyes can likewise be incor 45 The compounds according to the invention and the salts, porated into the mixture. Suitable binders include starch, Solvates and physiologically functional derivatives thereof gelatine, natural Sugars, such as, for example, glucose or can also be delivered using monoclonal antibodies as indi beta-lactose, Sweeteners made from maize, natural and Syn vidual carriers to which the compound molecules are thetic rubber, Such as, for example, acacia, tragacanth or coupled. The compounds can also be coupled to Soluble poly Sodium alginate, carboxymethylcellulose, polyethylene gly 50 mers as targeted medicament carriers. Such polymers may col, waxes, and the like. The lubricants used in these dosage encompass polyvinylpyrrolidone, pyran copolymer, polyhy forms include Sodium oleate, sodium Stearate, magnesium droxypropylmethacrylamido-phenol, polyhydroxyethylas Stearate, Sodium benzoate, sodium acetate, Sodium chloride partamidophenol or polyethylene oxide polylysine, Substi and the like. The disintegrants include, without being tuted by palmitoyl radicals. The compounds may furthermore restricted thereto, starch, methylcellulose, agar, bentonite, 55 xanthan gum and the like. The tablets are formulated by, for be coupled to a class of biodegradable polymers which are example, preparing a powder mixture, granulating or dry suitable for achieving controlled release of a medicament, for pressing the mixture, adding a lubricant and a disintegrant example polylactic acid, poly-epsilon-caprolactone, polyhy and pressing the entire mixture to give tablets. A powder droxybutyric acid, polyorthoesters, polyacetals, polydihy mixture is prepared by mixing the compound comminuted in 60 droxypyrans, polycyanoacrylates and crosslinked or amphi a suitable manner with a diluent or a base, as described above, pathic block copolymers of hydrogels. and optionally with a binder, such as, for example, carboxym Pharmaceutical formulations adapted for transdermal ethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, administration can be administered as independent plasters a dissolution retardant, Such as, for example, paraffin, an for extended, close contact with the epidermis of the recipi absorption accelerator, Such as, for example, a quaternary 65 ent. Thus, for example, the active ingredient can be delivered salt, and/or an absorbant, such as, for example, bentonite, from the plaster by iontophoresis, as described in general kaolin or dicalcium phosphate. The powder mixture can be terms in Pharmaceutical Research, 3(6), 318 (1986). US 9,062,029 B2 9 10 Pharmaceutical compounds adapted for topical adminis for the treatment of neoplastic growth, for example colon or tration can be formulated as ointments, creams, Suspensions, breast carcinoma, is generally in the range from 0.1 to 100 lotions, powders, Solutions, pastes, gels, sprays, aerosols or mg/kg of body weight of the recipient (mammal) per day and oils. particularly typically in the range from 1 to 10 mg/kg of body For the treatment of the eye or other external tissue, for weight per day. Thus, the actual amount per day for an adult example mouth and skin, the formulations are preferably mammal weighing 70 kg is usually between 70 and 700 mg. applied as topical ointment or cream. In the case of formula where this amount can be administered as a single dose per tion to give an ointment, the active ingredient can be day or usually in a series of part-doses (such as, for example, employed either with a paraffinic or a water-miscible cream two, three, four, five or six) per day, so that the total daily dose base. 10 is the same. An effective amount of a salt or solvate or of a Alternatively, the active ingredient can be formulated to physiologically functional derivative thereof can be deter give a cream with an oil-in-water cream base or a water-in-oil mined as the fraction of the effective amount of the compound base. according to the invention per se. It can be assumed that Pharmaceutical formulations adapted for topical applica similar doses are suitable for the treatment of other conditions tion to the eye include eye drops, in which the active ingre 15 mentioned above. dient is dissolved or Suspended in a suitable carrier, in par The invention furthermore relates to medicaments com ticular an aqueous solvent. prising at least one compound according to the invention Pharmaceutical formulations adapted for topical applica and/or tautomers and Stereoisomers thereof, including mix tion in the mouth encompass lozenges, pastilles and mouth tures thereofinall ratios, and at least one further medicament washes. active ingredient. Pharmaceutical formulations adapted for rectal adminis The invention also relates to a set (kit) consisting of sepa tration can be administered in the form of Suppositories or rate packs of CCS. (a) an effective amount of a compound according to the Pharmaceutical formulations adapted for nasal administra invention and/or tautomers and stereoisomers thereof, tion in which the carrier Substance is a Solid comprise a coarse 25 including mixtures thereof in all ratios, and powder having a particle size, for example, in the range (b) an effective amount of a further medicament active 20-500 microns, which is administered in the manner in ingredient. which Snuff is taken, i.e. by rapid inhalation via the nasal The set comprises Suitable containers. Such as boxes, indi passages from a container containing the powder held close to vidual bottles, bags or ampoules. The set may, for example, the nose. 30 comprise separate ampoules, each containing an effective Suitable formulations for administration as nasal spray or amount of a compound according to the invention and/or nose drops with a liquid as carrier substance encompass tautomers and stereoisomers thereof, including mixtures active-ingredient Solutions in water or oil. thereof in all ratios, Pharmaceutical formulations adapted for administration and an effective amount of a further medicamentactive ingre by inhalation encompass finely particulate dusts or mists, 35 dient in dissolved or lyophilised form. which can be generated by various types of pressurised dis Use pensers with aerosols, nebulisers or insufflators. The present compounds are Suitable as pharmaceutical Pharmaceutical formulations adapted for vaginal adminis active ingredients for mammals, especially for humans, in the tration can be administered as pessaries, tampons, creams, treatment of tyrosine kinase-induced diseases. These diseases gels, pastes, foams or spray formulations. 40 include the proliferation of tumour cells, pathological Pharmaceutical formulations adapted for parenteral neovascularisation (or angiogenesis) which promotes the administration include aqueous and non-aqueous sterile growth of Solid tumours, ocular neovascularisation (diabetic injection solutions comprising antioxidants, buffers, bacte retinopathy, age-induced macular degeneration and the like) riostatics and Solutes, by means of which the formulation is and inflammation (psoriasis, rheumatoid arthritis and the rendered isotonic with the blood of the recipient to be treated: 45 like). and aqueous and non-aqueous sterile Suspensions, which may The present invention encompasses the use of the com comprise Suspension media and thickeners. The formulations pounds according to the invention and/or physiologically can be administered in single-dose or multidose containers, acceptable salts and solvates thereof for the preparation of a for example sealed ampoules and vials, and stored in freeze medicament for the treatment or prevention of cancer. Pre dried (lyophilised) state, so that only the addition of the sterile 50 ferred carcinomas for the treatment originate from the group carrier liquid, for example water for injection purposes, cerebral carcinoma, urogenital tract carcinoma, carcinoma of immediately before use is necessary. Injection Solutions and the lymphatic system, stomach carcinoma, laryngeal carci Suspensions prepared in accordance with the recipe can be noma and lung carcinoma. A further group of preferred forms prepared from Sterile powders, granules and tablets. of cancer are monocytic leukaemia, lung adenocarcinoma, It goes without saying that, in addition to the above par 55 Small-cell lung carcinomas, pancreatic cancer, glioblastomas ticularly mentioned constituents, the formulations may also and breast carcinoma. comprise other agents usual in the art with respect to the Also encompassed is the use of the compounds according particular type of formulation; thus, for example, formula to Claim 1 according to the invention for the preparation of a tions which are Suitable for oral administration may comprise medicament for the treatment or prevention of a disease in flavours. 60 which angiogenesis is implicated. Atherapeutically effective amount of a compound accord Such a disease in which angiogenesis is implicated is an ing to the invention depends on a number of factors, includ ocular disease, Such as retinal vascularisation, diabetic retin ing, for example, the age and weight of the animal, the precise opathy, age-induced macular degeneration and the like. condition that requires treatment, and its severity, the nature The use of compounds according to the invention and/or of the formulation and the method of administration, and is 65 physiologically acceptable salts and Solvates thereof for the ultimately determined by the treating doctor or vet. However, preparation of a medicament for the treatment or prevention an effective amount of a compound according to the invention of inflammatory diseases also falls within the scope of the US 9,062,029 B2 11 12 present invention. Examples of Such inflammatory diseases The solid tumour is furthermore preferably selected from include rheumatoid arthritis, psoriasis, contact dermatitis, the group lung adenocarcinoma, Small-cell lung carcinomas, delayed hypersensitivity reaction and the like. pancreatic cancer, glioblastomas, colon carcinoma and breast Also encompassed is the use of the compounds according carcinoma. to the invention for the preparation of a medicament for the Preference is furthermore given to the use for the treatment treatment or prevention of a tyrosine kinase-induced disease of a tumour of the blood and immune system, preferably for or a tyrosine kinase-induced condition in a mammal, in which the treatment of a tumour selected from the group of acute to this method a therapeutically effective amount of a com myeloid leukaemia, chronic myeloid leukaemia, acute lym pound according to the invention is administered to a sick phatic leukaemia and/or chronic lymphatic leukaemia. 10 The disclosed compounds according to the invention can mammal in need of Such treatment. The therapeutic amount be administered in combination with other known therapeutic varies according to the specific disease and can be determined agents, including anticancer agents. As used here, the term by the person skilled in the art without undue effort. 'anticancer agent” relates to any agent which is administered The present invention also encompasses the use com to a patient with cancer for the purposes of treating the cancer. pounds of the formula I and/or physiologically acceptable 15 The anti-cancer treatment defined herein may be applied as salts and Solvates thereof for the preparation of a medicament a sole therapy or may involve, in addition to the compound of for the treatment or prevention of retinal vascularisation. the invention, conventional Surgery or radiotherapy or che Methods for the treatment or prevention of ocular diseases, motherapy. Such may include one or more of Such as diabetic retinopathy and age-induced macular degen the following categories of anti-tumour agents: eration, are likewise part of the invention. The use for the (i) antiproliferative/antineoplastic/DNA-damaging agents treatment or prevention of inflammatory diseases. Such as and combinations thereof, as used in medical oncology, rheumatoid arthritis, psoriasis, contact dermatitis and delayed Such as alkylating agents (for example cis-platin, carbopl hypersensitivity reaction, as well as the treatment or preven atin, , , , tion of bone pathologies from the group osteosarcoma, chloroambucil, buSulphan and ); antimetabo osteoarthritis and rickets, likewise falls within the scope of 25 lites (for example Such as fluoropyrimidines the present invention. like 5- and , , , The expression “tyrosine kinase-induced diseases or con cytosine arabinoside, hydroxyurea and ); anti ditions” refers to pathological conditions that depend on the tumour antibiotics (for example , like adria activity of one or more tyrosine kinases. Tyrosine kinases mycin, , , daunomycin, , either directly or indirectly participate in the signal transduc 30 , mitomycin-C, and mithramy cin); antimitotic agents (for example Vinca alkaloids, like tion pathways of a variety of cellular activities, including , , and , and proliferation, adhesion and migration and differentiation. taxoids, like taxol and taxotere); topoisomerase inhibitors Diseases associated with tyrosine kinase activity include pro (for example epipodophyllotoxins, like and teni liferation of tumour cells, pathological neovascularisation 35 poside, , , and camptoth that promotes the growth of Solid tumours, ocular neovascu ecin) and cell-differentiating agents (for example all-trans larisation (diabetic retinopathy, age-induced macular degen retinoic acid, 13-cis-retinoic acid and fenretinide); eration and the like) and inflammation (psoriasis, rheumatoid (ii) cytostatic agents, such as antioestrogens (for example arthritis and the like). tamoxifen, toremifene, raloxifene, droloxifene and The compounds according to the invention can be admin 40 iodoxyfene), oestrogen receptor downregulators (for istered to patients for the treatment of cancer, in particular example fulvestrant), antiandrogens (for example bicaluta fast-growing tumours. mide, flutamide, nilutamide and cyproterone acetate), The invention thus relates to the use of compounds accord LHRH antagonists or LHRH agonists (for example goser ing to the invention and tautomers and stereoisomers thereof, elin, leuprorelin and buserelin), progesterones (for including mixtures thereof in all ratios, for the preparation of 45 example megestrol acetate), aromatase inhibitors (for a medicament for the treatment of diseases in which the example as anastroZole, letrozole, Vorazole and exemes inhibition, regulation and/or modulation of kinase signal tane) and inhibitors of 5C.-reductase, such as finasteride; transduction plays a role. (iii) agents which inhibit cancer cell invasion (for example Preference is given here to Met kinase. metalloproteinase inhibitors, like marimastat, and inhibi Preference is given to the use of compounds according to 50 tors of urokinase plasminogen activator receptor function); the invention and tautomers and stereoisomers thereof, (iv) inhibitors of growth factor function, for example such including mixtures thereof in all ratios, for the preparation of inhibitors include growth factor antibodies, growth factor a medicament for the treatment of diseases which are influ receptor antibodies (for example the anti-erbb2 antibody enced by inhibition of tyrosine kinases by the compounds trastuzumab HerceptinTM and the anti-erbbl antibody according to Claim 1. 55 cetuximab C225), farnesyl transferase inhibitors, Particular preference is given to the use for the preparation tyrosine kinase inhibitors and serine/threonine kinase of a medicament for the treatment of diseases which are inhibitors, for example inhibitors of the epidermal growth influenced by inhibition of Met kinase by the compounds factor family (for example EGFR family tyrosine kinase according to the invention according to Claim 1. inhibitors, such as N-(3-chloro-4-fluorophenyl)-7- Especial preference is given to the use for the treatment of 60 methoxy-6-(3-morpholinopropoxy) quinazolin-4-amine a disease where the disease is a solid tumour. (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis The solid tumour is preferably selected from the group of (2-methoxyethoxy)guinazolin-4-amine (erlotinib, OSI tumours of the lung, squamous epithelium, the bladder, the 774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7- stomach, the kidneys, of head and neck, the oesophagus, the (3-morpholinopropoxy)-quinazolin-4-amine (CI 1033)), cervix, the thyroid, the intestine, the liver, the brain, the pros 65 for example inhibitors of the platelet-derived growth factor tate, the urogenital tract, the lymphatic system, the stomach family and for example inhibitors of the hepatocyte growth and/or the larynx. factor family; US 9,062,029 B2 13 14 (v) antiangiogenic agents, such as those which inhibit the aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT effects of vascular endothelial growth factor, (for example (gene-directed enzyme pro-drug therapy) approaches, the anti-vascular endothelial cell growth factor antibody Such as those using cytosine deaminase, thymidine kinase bevacizumab AvastinTM, compounds such as those dis or a bacterial nitroreductase enzyme, and approaches for closed in published international patent applications WO 5 increasing patient tolerance to chemotherapy or radio 97/22596, WO 97/30035, WO 97/32856 and WO therapy, such as multi-drug resistance gene therapy; and 98/13354) and compounds that work by other mechanisms (ix) immunotherapy approaches, including, for example, ex (for example linomide, inhibitors of integrin CVB3 function Vivo and in-vivo approaches for increasing the immunoge and angiostatin): nicity of patient tumour cells, such as transfection with (vi) vessel-damaging agents, such as combretastatin A4 and 10 cytokines, such as interleukin 2, interleukin 4 or granulo compounds disclosed in international patent applications cyte-macrophage colony stimulating factor, approaches WO 99/02166, WO 00/40529, WO 00/41669, WO for decreasing T-cell energy, approaches using transfected O1/92224, WO 02/04434 and WO 02/08213; immune cells, such as cytokine-transfected dendritic cells, (vii) antisense therapies, for example those which are directed approaches using cytokine-transfected tumour cell lines, to the targets listed above, such as ISIS 2503, an anti-Ras 15 and approaches using anti-idiotypic antibodies. antisense; The medicaments from Table 1 below are preferably, but (viii) gene therapy approaches, including, for example, not exclusively, combined with the compounds of the formula approaches for replacement of aberrant genes. Such as I. TABLE 1. Alkylating agents Cyclophosphamide Melphalan Hexamethylmelamine Mechloroethamine Streptozocin chloroambucil Platinum agents ZD-0473 (AnorMED) Spiroplatin Lobaplatin (Aetema) Carboxyphthalatoplatinum (Johnson Tetraplatin Matthey) Ormiplatin BBR-3464 Iproplatin (Hoffrnann-La Roche) SM-11355 (Sumitomo) AP-5280 (Access) AZacytidine Tomludex Gemcitabine Trimetrexate Deoxycoformycin 5-fluorouracil 2-chlorodesoxyadenosine Raltitrexed 6- Hydroxyurea 6-Thioguanine (SuperGen) (Bioenvision) 2-fluorodesoxycytidine rofulven (MGI Pharrna) Methotrexate DMDC (Hoffmann-La datrexate Roche) Ethynylcytidine (Taiho) Topoisomerase Amsacrine (SuperGen) inhibitors Epirubicin meSylate Etoposide (Daiichi) or Quinamed (ChemGenex) Gimatecan (Sigma-Tau) rinotecan (CPT-11) Diflomotecan (Beaufour 7-Ethyl-10- psen) hydroxycamptothecin TAS-103 (Taiho) Topotecan (Spectrum) Dexrazoxanet -107088 (Merck & Co) (TopoTarget) BNP-1350 (BioNumerik) (Novuspharrna) CKD-602 (Chong Kun Rebeccamycin analogue Dang) (Exelixis) KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna) Antitumour Dactinomycin (Actinomycin Amonafide antibiotics D) Azonafide Doxorubicin (Adriamycin) Anthrapyrazole Deoxyrubicin Oxantrazole Valirubicin Bleomycin sulfate (Daunomycin) (Blenoxan) Epirubicin Bleomycinic acid Therarubicin Bleomycin A darubicin Bleomycin B Rubidazon US 9,062,029 B2 15 16 TABLE 1-continued Plicamycinp MEN-10755 (Menarini) Porfiromycin GPX-100 (Gem Cyanomorpholinodoxo Pharmaceuticals) rubicin Mitoxantron (Novantron) Antimitotic agents SB 408075 (GlaxoSmithKline) Colchicine E7010 (Abbott) Vinblastine PG-TXL (Cell Vincristine Therapeutics) Vinorelbine IDN 5109 (Bayer) Vindesine A 105972 (Abbott) Dolastatin 10 (NCI) A 204197 (Abbott) Rhizoxin (Fujisawa) LU 223651 (BASF) Mivobulin (Warner D 24851 (ASTA Medica) Lambert) ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4 (BMS) RPR 109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) Epothillone B (Novartis) ZD 6126 (AstraZeneca) T900607 (Tularik) PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin 52 (Eli Lilly) !DN-5109 (Indena) (Fabre) AVLB (Prescient Auristatin PE (Teikoku NeuroPharma) Hormone) AZaepothillon B (BMS) BMS 247550 (BMS) BNP-7787 (BioNumerik) BMS 184476 (BMS) CA-4-prodrug (OXiGENE) BMS 188797 (BMS) Dolastatin-10 (NrH) Taxoprexin (Protarga) CA-4 (OXiGENE) Aromatase Aminoglutethimide Exemestan inhibitors Letrozole Atamestan (BioMedicines) Anastrazole YM-511 (Yamanouchi) Formestan Thymidylate (Eli Lilly) Nolatrexed (Eximias) synthase ZD-9331 (BTG) CoFactor TM (Biokeys) inhibitors DNA antagonists (PharmaMar) (Baxter (Baxter International) International) Apaziquone (Spectrum Albumin + 32P (Isotope Pharmaceuticals) Solutions) O6-Benzylguanine Thymectacin (NewBiotics) (Paligent) Edotreotid (Novartis) Farnesyl Arglabin (NuOncology (Johnson & transferase Labs) ohnson) inhibitors Ionafarnib (Schering Perillyl alcohol (DOR Plough) BioPharma) BAY-43-9006 (Bayer) Pump inhibitors CBT-1 (CBA Pharma) ZoSuquidar Tariquidar (Xenova) trihydrochloride (Eli Lilly) MS-209 (Schering AG) Biricodar dicitrate (Vertex) Histone acetyl Tacedinaline (Pfizer) Pivaloyloxymethylbutyrate transferase SAHA (Aton Pharma) (Titan) inhibitors MS-275 (Schering AG) Depsipeptide (Fujisawa) Metalloproteinase Neovastat (Aeterna Labo CMT-3 (CollaGenex) inhibitors ratories) BMS-275291 (Celltech) Ribonucleoside Marimastat (British Bio Tezacitabine (Aventis) reductase tech) Didox (Molecules for inhibitors Gallium maltolate (Titan) Health) Triapin (Vion) TNF-alpha Virulizin (Lorus Therapeu Revimid (Celgene) agonists tics) antagonists CDC-394 (Celgene) Endothelin-A re (Abbot) YM-598 (Yamanouchi) ceptor antagonists ZD-4054 (AstraZeneca) Retinoic acid re Fenretinide (Johnson & (Ligand) ceptor agonists Johnson) LGD-1550 (Ligand) Immunomodulators Interferon Dexosome therapy Oncophage (Antigenics) (Anosys) GMK (Progenics) Pentrix (Australian Cancer Adenocarcinoma vaccine Technology) (Biomira) JSF-154 (Tragen) CTP-37 (AVI BioPharma) Cancer vaccine (Intercell) JRX-2 (Immuno-RX) Norelin (Biostar) PEP-005 (Peplin Biotech) BLP-25 (Biomira) Synchrovax vaccines (CTL MGV (Progenics) Immuno) 3-Alethin (Dovetail) Melanoma vaccine (CTL CLL-Thera (Vasogen) US 9,062,029 B2 17 18 TABLE 1-continued Immuno) p21-RAS vaccine (GemVax) Hormonal and Oestrogens Prednisone antihormonal Conjugated oestrogens Methylprednisolone agents Ethynyloestradiol Prednisolone chlorotrianisene Aminoglutethimide Idenestrol Leuprolide Hydroxyprogesterone Goserelin caproate Leuporelin Medroxyprogesterone Bicalutamide Testosterone Flutamide Testosterone propionate Octreotide Fluoxymesterone Nilutamide Methyltestosterone Mitotan Diethylstilbestrol P-04 (Novogen) Megestrol 2-Methoxyoestradiol Tamoxifen (EntreMed) Toremofin Arzoxifen (Eli Lilly) Dexamethasone Photodynamic (Light Sciences) Pd-Bacteriopheophorbid agents Theralux (Theratechnolo (Yeda) gies) Lutetium-Texaphyrin Motexafin-Gadolinium (Pharmacyclics) (Pharmacyclics) Hypericin Tyrosine kinase Imatinib (Novartis) Kahalide F (PharmaMar) inhibitors Leflunomide(Sugen CEP-701 (Cephalon) Pharmacia) CEP-751 (Cephalon) ZDI839 (AstraZeneca) MLN518 (Millenium) Erlotinib (Oncogene PKC412 (Novartis) Science) Phenoxodiol O Canertinib (Pfizer) Trastuzumab (Genentech) Squalamine (Genaera) C225 (ImClone) SU5416 (Pharmacia) rhu-Mab (Genentech) SU6668 (Pharmacia) MDX-H210 (Medarex) ZD4190 (AstraZeneca) 2C4 (Genentech) ZD6474 (AstraZeneca) MDX-447 (Medarex) (Novartis) ABX-EGF (Abgenix) PKI166 (Novartis) IMC-1C11 (ImClone) GW 2016 (GlaxoSmith Kline) EKB-509 (Wyeth) EKB-569 (Wyeth) Various agents SR-27897 (CCK-A inhibi BCX-1777 (PNP inhibitor, tor, Sanofi-Synthelabo) BioCryst) Tocladesine (cyclic AMP Ranpirinase (ribonuclease agonist, Ribapharm) stimulant, Alfacell) (CDK inhibitor, Galarubicin (RNA synthe Aventis) sis inhibitor, Dong-A) CV-247 (COX-2 inhibitor, Tirapazamine (reducing Ivy Medical) agent, SRI International) P54 (COX-2 inhibitor, N-Acetylcysteine (reducing Phytopharm) agent, Zambon) CapCell TM (CYP450 R-Flurbiprofen (NF-kappaB stimulant, Bavarian Nordic) inhibitor, Encore) GCS-IOO (gal3 antagonist, 3CPA (NF-kappaB GlycoGenesys) inhibitor, Active Biotech) G17DT immunogen (gas Seocalcitol (vitamin D trin inhibitor, Aphton) receptor agonist, Leo) (oxygenator, 31-I-TM-601 (DNA Allos Therapeutics) antagonist, PI-88 (heparanase inhibi TransMolecular) tor, Progen) Eflornithin (ODC inhibitor, Tesmilifen (histamine an LEXOncology) tagonist, YM BioSciences) Minodronic acid Histamine (histamine H2 (osteoclast inhibitor, receptor agonist, Maxim) Yamanouchi) (IMPDH inhibi indisulam (p53 stimulant, tor, Ribapharm) Eisai) Cilengitide (integrin an Aplidin (PPT inhibitor, tagonist, Merck KGaA) PharmaMar) SR-31747 (IL-1 antagonist, Rituximab (CD20 antibody, Sanofi-Synthelabo) Genentech) CCI-779 (mTOR kinase Gemtuzumab (CD33 inhibitor, Wyeth) antibody, Wyeth Ayerst) (PDE-V inhibitor, PG2 (haematopoiesis Cell Pathways) promoter, Pharmagenesis) CP-461 (PDE-V inhibitor, mmunolTM (triclosan Cell Pathways) mouthwash, Endo) AG-2037 (GART inhibitor, Triacetyluridine (uridine US 9,062,029 B2 19 20 TABLE 1-continued Pfizer) prodrug, Wellstat) WX-UK1 (plasminogen SN-4071 (sarcoma agent, activator inhibitor, Wilex) Signature BioScience) PBI-1402 (PMN stimulant, TransMID-107 TM ProMetic LifeSciences) (immunotoxin, KS (proteasome Biomedix) inhibitor, Millennium) PCK-3145 (apoptosis SRL-172 (T-cell stimulant, promoter, Procyon) SR Pharma) Doranidazole (apoptosis TLK-286 (glutathione-S promoter, Pola) transferase inhibitor, Telik) CHS-828 (cytotoxic agent, PT-100 (growth factor Leo) agonist, Point Therapeu Trans-retinic acid tics) (differentiator, NIH) Midostaurin (PKC inhibitor, MX6 (apoptosis promoter, Novartis) MAXIA) Bryostatin-1 (PKC stimu Apomine (apoptosis lant, GPC Biotech) promoter, ILEX Oncology) CDA-II (apoptosis pro Urocidin (apoptosis moter, Everlife) promoter, Bioniche) SDX-101 (apoptosis pro Ro-31-7453 (apoptosis moter, Salmedix) promoter, La Roche) Ceflatonin (apoptosis pro Brostallicin (apoptosis moter, ChemGenex) promoter, Pharmacia) Alkylating agents Cyclophosphamide Lomustine Busulfan Procarbazine Ifosfamide Altretamine Melphalan Estramustine phosphate Hexamethylmelamine Mechloroethamine Thiotepa Streptozocin chloroambucil Temozolomide Dacarbazine Semustine Carmustine Platinum agents Cisplatin Carboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin (Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson Tetraplatin Matthey) Ormiplatin BBR-3464 Iproplatin (Hoffrnann-La Roche) SM-11355 (Sumitomo) AP-5280 (Access) Antimetabolites AZacytidine Tomludex Gemcitabine Trimetrexate Capecitabine Deoxycoformycin 5-fluorouracil Fludarabine Floxuridine Pentostatin 2-chlorodesoxyadenosine Raltitrexed 6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen) Cytarabine Clofarabine (Bioenvision) 2-fluorodesoxycytidine rofulven (MGI Pharrna) Methotrexate DMDC (Hoffmann-La datrexate Roche) Ethynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan (SuperGen) inhibitors Epirubicin Exatecan meSylate Etoposide (Daiichi) Teniposide or Quinamed (ChemGenex) mitoxantrone Gimatecan (Sigma-Tau) rinotecan (CPT-11) Diflomotecan (Beaufour 7-Ethyl-10 psen) hydroxycamptothecin TAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum) Dexrazoxanet -107088 (Merck & Co) (TopoTarget) BNP-1350 (BioNumerik) Pixantrone (Novuspharrna) CKD-602 (Chong Kun Rebeccamycin analogue Dang) (Exelixis) KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna) Antitumour Dactinomycin (Actinomycin Amonafide antibiotics D) Azonafide Doxorubicin (Adriamycin) Anthrapyrazole Deoxyrubicin Oxantrazole Valirubicin Losoxantrone Daunorubicin Bleomycin sulfate (Daunomycin) (Blenoxan) Epirubicin Bleomycinic acid Therarubicin Bleomycin A darubicin Bleomycin B US 9,062,029 B2 21 22 TABLE 1-continued Rubidazon Mitomycin C Plicamycinp MEN-10755 (Menarini) Porfiromycin GPX-100 (Gem Cyanomorpholinodoxo Pharmaceuticals) rubicin Mitoxantron (Novantron) Antimitotic agents Paclitaxel SB 408075 Docetaxel (GlaxoSmithKline) Colchicine E7010 (Abbott) Vinblastine PG-TXL (Cell Vincristine Therapeutics) Vinorelbine IDN 5109 (Bayer) Vindesine A 105972 (Abbott) Dolastatin 10 (NCI) A 204197 (Abbott) Rhizoxin (Fujisawa) LU 223651 (BASF) Mivobulin (Warner D 24851 (ASTA Medica) Lambert) ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4 (BMS) RPR 109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) Epothillone B (Novartis) ZD 6126 (AstraZeneca) T900607 (Tularik) PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin 52 (Eli Lilly) !DN-5109 (Indena) Vinflunine (Fabre) AVLB (Prescient Auristatin PE (Teikoku NeuroPharma) Hormone) AZaepothillon B (BMS) BMS 247550 (BMS) BNP-7787 (BioNumerik) BMS 184476 (BMS) CA-4-prodrug (OXiGENE) BMS 188797 (BMS) Dolastatin-10 (NrH) Taxoprexin (Protarga) CA-4 (OXiGENE) Aromatase Aminoglutethimide Exemestan inhibitors Letrozole Atamestan (BioMedicines) Anastrazole YM-511 (Yamanouchi) Formestan Thymidylate Pemetrexed (Eli Lilly) Nolatrexed (Eximias) Synthase ZD-9331 (BTG) CoFactor TM (Biokeys) inhibitors DNA antagonists Trabectedin (PharmaMar) Mafosfamide (Baxter Glufosfamide (Baxter International) International) Apaziquone (Spectrum Albumin + 32P (Isotope Pharmaceuticals) Solutions) O6-Benzylguanine Thymectacin (NewBiotics) (Paligent) Edotreotid (Novartis) Farnesyl Arglabin (NuOncology Tipifarnib (Johnson & transferase Labs) ohnson) inhibitors Ionafarnib (Schering Perillyl alcohol (DOR Plough) BioPharma) BAY-43-9006 (Bayer) Pump inhibitors CBT-1 (CBA Pharma) ZoSuquidar Tariquidar (Xenova) trihydrochloride (Eli Lilly) MS-209 (Schering AG) Biricodar dicitrate (Vertex) Histone acetyl Tacedinaline (Pfizer) Pivaloyloxymethylbutyrate transferase SAHA (Aton Pharma) (Titan) inhibitors MS-275 (Schering AG) Depsipeptide (Fujisawa) Metalloproteinase Neovastat (Aeterna Labo CMT-3 (CollaGenex) inhibitors ratories) BMS-275291 (Celltech) Ribonucleoside Marimastat (British Bio Tezacitabine (Aventis) reductase tech) Didox (Molecules for inhibitors Gallium maltolate (Titan) Health) Triapin (Vion) TNF-alpha Virulizin (Lorus Therapeu Revimid (Celgene) agonists tics) antagonists CDC-394 (Celgene) Endothelin-A re Atrasentan (Abbot) YM-598 (Yamanouchi) ceptor antagonists ZD-4054 (AstraZeneca) Retinoic acid re Fenretinide (Johnson & Alitretinoin (Ligand) ceptor agonists Johnson) LGD-1550 (Ligand) Immunomodulators Interferon Dexosome therapy Oncophage (Antigenics) (Anosys) GMK (Progenics) Pentrix (Australian Cancer Adenocarcinoma vaccine Technology) (Biomira) JSF-154 (Tragen) CTP-37 (AVI BioPharma) Cancer vaccine (Intercell) JRX-2 (Immuno-RX) Norelin (Biostar) PEP-005 (Peplin Biotech) BLP-25 (Biomira) Synchrovax vaccines (CTL MGV (Progenics) Immuno) 3-Alethin (Dovetail) US 9,062,029 B2 23 24 TABLE 1-continued Melanoma vaccine (CTL CLL-Thera (Vasogen) mmuno) p21-RAS vaccine (GemVax) Hormonal and Oestrogens Prednisone antihormonal Conjugated oestrogens Methylprednisolone agents Ethynyloestradiol Prednisolone chlorotrianisene Aminoglutethimide denestrol Leuprolide Hydroxyprogesterone Goserelin caproate Leuporelin Medroxyprogesterone Bicalutamide Testosterone Flutamide Testosterone propionate Octreotide Fluoxymesterone Nilutamide Methyltestosterone Mitotan Diethylstilbestrol P-04 (Novogen) Megestrol 2-Methoxyoestradiol Tamoxifen (EntreMed) Toremofin Arzoxifen (Eli Lilly) Dexamethasone Photodynamic Talaporfin (Light Sciences) Pd-Bacteriopheophorbid agents Theralux (Theratechnolo (Yeda) gies) Lutetium-Texaphyrin Motexafin-Gadolinium (Pharmacyclics) (Pharmacyclics) Hypericin Tyrosine kinase Imatinib (Novartis) Kahalide F (PharmaMar) inhibitors Leflunomide(Sugen CEP-701 (Cephalon) Pharmacia) CEP-751 (Cephalon) ZDI839 (AstraZeneca) MLN518 (Millenium) Erlotinib (Oncogene PKC412 (Novartis) Science) Phenoxodiol O Canertinib (Pfizer) Trastuzumab (Genentech) Squalamine (Genaera) C225 (ImClone) SU5416 (Pharmacia) rhu-Mab (Genentech) SU6668 (Pharmacia) MDX-H210 (Medarex) ZD4190 (AstraZeneca) 2C4 (Genentech) ZD6474 (AstraZeneca) MDX-447 (Medarex) Vatalanib (Novartis) ABX-EGF (Abgenix) PKI166 (Novartis) IMC-1C11 (ImClone) GW2O16 (GlaxoSmithKline) EKB-509 (Wyeth) EKB-569 (Wyeth) Various agents SR-27897 (CCK-A inhibi BCX-1777 (PNP inhibitor, tor, Sanofi-Synthelabo) BioCryst) Tocladesine (cyclic AMP Ranpirinase (ribonuclease agonist, Ribapharm) stimulant, Alfacell) Alvocidib (CDK inhibitor, Galarubicin (RNA synthe Aventis) sis inhibitor, Dong-A) CV-247 (COX-2 inhibitor, Tirapazamine (reducing Ivy Medical) agent, SRI International) P54 (COX-2 inhibitor, N-Acetylcysteine (reducing Phytopharm) agent, Zambon) CapCell TM (CYP450 R-Flurbiprofen (NF-kappaB stimulant, Bavarian Nordic) inhibitor, Encore) GCS-IOO (gal3 antagonist, 3CPA (NF-kappaB GlycoGenesys) inhibitor, Active Biotech) G17DT immunogen (gas Seocalcitol (vitamin D trin inhibitor, Aphton) receptor agonist, Leo) Efaproxiral (oxygenator, 31-I-TM-601 (DNA Allos Therapeutics) antagonist, PI-88 (heparanase inhibi TransMolecular) tor, Progen) Eflornithin (ODC inhibitor, Tesmilifen (histamine an LEXOncology) tagonist, YM BioSciences) Minodronic acid Histamine (histamine H2 (osteoclast inhibitor, receptor agonist, Maxim) Yamanouchi) Tiazofurin (IMPDH inhibi indisulam (p53 stimulant, tor, Ribapharm) Eisai) Cilengitide (integrin an Aplidin (PPT inhibitor, tagonist, Merck KGaA) PharmaMar) SR-31747 (IL-1 antagonist, Rituximab (CD20 antibody, Sanofi-Synthelabo) Genentech) CCI-779 (mTOR kinase Gemtuzumab (CD33 inhibitor, Wyeth) antibody, Wyeth Ayerst) Exisulind (PDE-V inhibitor, PG2 (haematopoiesis Cell Pathways) promoter, Pharmagenesis) CP-461 (PDE-V inhibitor, mmunolTM (triclosan Cell Pathways) mouthwash, Endo) US 9,062,029 B2 25 26 TABLE 1-continued AG-2037 (GART inhibitor, Triacetyluridine (uridine Pfizer) prodrug, Wellstat) WX-UK1 (plasminogen SN-4071 (sarcoma agent, activator inhibitor, Wilex) Signature BioScience) PBI-1402 (PMN stimulant, TransMID-107 TM ProMetic LifeSciences) (immunotoxin, KS Bortezomib (proteasome Biomedix) inhibitor, Millennium) PCK-3145 (apoptosis SRL-172 (T-cell stimulant, promoter, Procyon) SR Pharma) Doranidazole (apoptosis TLK-286 (glutathione-S promoter, Pola) transferase inhibitor, Telik) CHS-828 (cytotoxic agent, PT-100 (growth factor Leo) agonist, Point Therapeu Trans-retinic acid tics) (differentiator, NIH) Midostaurin (PKC inhibitor, MX6 (apoptosis promoter, Novartis) MAXIA) Bryostatin-1 (PKC stimu Apomine (apoptosis lant, GPC Biotech) promoter, ILEX Oncology) CDA-II (apoptosis pro Urocidin (apoptosis moter, Everlife) promoter, Bioniche) SDX-101 (apoptosis pro Ro-31-7453 (apoptosis moter, Salmedix) promoter, La Roche) Ceflatonin (apoptosis pro Brostallicin (apoptosis moter, ChemGenex) promoter, Pharmacia)

A combined treatment of this type can be achieved with the 25 Flashplate Method (Met Kinase) aid of simultaneous, consecutive or separate dispensing of the The test plates used are 96-well Flashplate R microtitre individual components of the treatment. Combination prod plates from Perkin Elmer (Cat. No. SMP200). The compo ucts of this type employ the compounds according to the nents of the kinase reaction described below are pipetted into invention. 30 the assay plate. The Met kinase and the substrate poly Ala Assays Glu-Lys-Tyr. (p.AGLT 6:2:5:1), are incubated for 3 hrs at The compounds of the formula I described in the examples room temperature with radioactively labelled P-ATP in the were tested by the assays described below and were found to presence and absence of test Substances in a total Volume of have kinase inhibitory activity. Other assays are known from 100 ul. The reaction is terminated using 150 ul of a 60 mM 35 EDTA solution. After incubation for a further 30 minat room the literature and could readily be performed by the person temperature, the Supernatants are filtered off with Suction, and skilled in the art (see, for example, Dhanabal et al., Cancer the wells are washed three times with 200 ul of 0.9% NaCl Res. 59:189-197: Xin et al., J. Biol. Chem. 274:9116-9121: Solution each time. The measurement of the bound radioac Sheu et al., Anticancer Res. 18:4435-4441; Ausprunk et al., tivity is carried out by means of a scintillation measuring Dev. Biol. 38:237-248; Gimbrone et al., J. Natl. Cancer Inst. 40 instrument (Topcount NXT, Perkin-Elmer). 52:413-427; Nicosia et al., In Vitro 18:538-549). The full value used is the inhibitor-free kinase reaction. Measurement of Met Kinase Activity This should be approximately in the range 6000-9000 cpm. According to the manufacturer's data (Met, active, upstate, The pharmacological Zero value used is staurosporin in a final catalogue No. 14-526), Met kinase is expressed for the pur concentration of 0.1 mM. The inhibitory values (IC50) are poses of protein production in insect cells (Sf21; S. fru 45 determined using the RS1 MTS program. giperda) and Subsequent affinity-chromatographic purifica Kinase reaction conditions per well: tion as “N-terminal 6His-tagged' recombinant human protein 30 ul of assay buffer 10 ul of substance to be tested in assay buffer with 10% of in a baculovirus expression vector. DMSO The kinase activity can be measured using various avail 50 10 ul of ATP (final concentration 1 uM cold, 0.35 uCi of able measurement systems. In the Scintillation proximity *P-ATP) method (Sorget al., J. of Biomolecular Screening, 2002, 7. 50 ul of Met kinase/substrate mixture in assay buffer; 11-19), the flashplate method or the filter binding test, the (10 ng of enzyme?well, 50 ng of paGLT/well) radioactive phosphorylation of a protein or peptide as Sub Solutions used: strate is measured using radioactively labelled ATP ('P-ATP, 55 Assay buffer: P-ATP). In the case of the presence of an inhibitory com 50 nM HEPES pound, a reduced radioactive signal, or none at all, can be 3 mM magnesium chloride detected. Furthermore, homogeneous time-resolved fluores 3 uM sodium orthovanadate cence resonance energy transfer (HTR-FRET) and fluoroes 3 mM manganese(II) chloride cence polarisation (FP) technologies can be used as assay 60 1 mM dithiothreitol (DTT) methods (Sills et al., J. of Biomolecular Screening, 2002, pH-7.5 (to be set using sodium hydroxide) 191-214). Stop solution: Other non-radioactive ELISA assay methods use specific 60 mM Titriplex III (EDTA) phospho-antibodies (phospho-ABs). The phospho-antibody P-ATP: Perkin-Elmer; only binds the phosphorylated substrate. This binding can be 65 Met kinase: Upstate, Cat. No. 14-526, Stock 1 lug/10 ul; detected by chemiluminescence using a second peroxidase spec. activity 954 U/mg: conjugated antibody (Ross et al., 2002, Biochem. J.). Poly-Ala-Glu-Lys-Tyr, 6:2:5:1: Sigma Cat. No. P1 152 US 9,062,029 B2 27 28 In-vivo Tests (FIG. 1/1) HPLC/MS Analyses Experimental procedure: Female Balb/C mice (breeder: are carried out in a 3LSilica-Rod column with a 210 second Charles River Wiga) were 5 weeks old on arrival. They were gradient from 20 to 100% waterfacetonitrile/0.01% of trifluo acclimatised to our keeping conditions for 7 days. Each roacetic acid, at a flow rate of 2.2 ml/min, and detection at 220 mouse was subsequently injected Subcutaneously in the pel- 5 . HPLC Analyses (Method A) vic area with 4 million TPR-Met/NIH3T3 cells in 100 ul of Column: Chromolith RP 18e 100.3 mm PBS (without Ca++ and Mg++). After 5 days, the animals Flow rate: 2 ml/min were randomised into 3 groups, so that each group of 9 mice Solvent A: H2O+0.1% of trifluoroacetic acid had an average tumour volume of 110 ul (range: 55-165). 100 Solvent B: acetonitrile+0.1% of trifluoroacetic acid ul of vehicle (0.25% methylcellulose/100 mMacetate buffer, 10 Gradient 5 min pH 5.5) were administered daily to the control group, and 200 0-4 min: 99:1->1:99 mg/kg of “A56” or A91 dissolved in the vehicle (volume 4-5 min: 1:99-1:99 HPLC Analyses (Method B) likewise 100 ul/animal) were administered daily to the treat Column: Chromolith RP 18e 100.3 mm ment groups, in each case by gastric tube. After 9 days, the 15 Flow rate: 4 ml/min controls had an average volume of 1530 uland the experiment Solvent A: HO--0.05% of HCOOH was terminated. Solvent B: acetonitrile+10% of solvent A Measurement of the tumour volume: The length (L) and Gradient 8 min breadth (B) were measured using a Vernier calliper, and the 0-1 min: 99:1->99:1 tumour volume was calculated from the formula LxBxB/2. 1-7 min: 99:1-1:99 Keeping conditions: 4 or 5 animals per cage, feeding with 7-8 min: 1:99->1:99 commercial mouse food (Sniff). HPLC Analysis (Method C) The compounds A18 and A22 have a significant anti Flow rate: 2 ml/min tumoural action. 99:01-0:100 water+0.1% (vol.) of TFA: acetonitrile+0.1% 25 (vol.) of TFA Above and below, all temperatures are indicated in C. In 0.0 to 0.2 min: 99:01 the following examples, "conventional work-up” means: 0.2 to 3.8 min: 99:01->0:100 water is added if necessary, the pH is adjusted, if necessary, to 3.8 to 4.2 min: 0:100 values between 2 and 10, depending on the constitution of the Column: Chromolith Performance RP18e; 100 mm long, end product, the mixture is extracted with ethyl acetate or internal diameter dichloromethane, the phases are separated, the organic phase 30 3 mm, wavelength: 220 nm is dried over sodium sulfate and evaporated, and the residue is Retention time Rt in minutes min. purified by chromatography on silica gel and/or by crystalli sation. Rf values on silica gel; eluent: ethyl acetate/methanol Example 1 9:1. Mass spectrometry (MS): EI (electron impact ionisation) M" 35 Comparative Example FAB (fast atom bombardment) (M--H)" The preparation of the compounds ESI (electrospray ionisation) (M+H)+ 6-(1-methyl-1H-pyrazol-4-yl)-2-3-5-(2-morpholin-4- APCI-MS (atmospheric pressure chemical ionisation-mass ylethoxy)pyrimidin-2-yl)-benzyl-2H-pyridazin-3-one spectrometry) (M--H)". 40 (“A229), Mass spectrometry (MS): EI (electron impact ionisation) M" 2-3-(5-bromopyrimidin-2-yl)benzyl-6-(1-methyl-1H FAB (fast atom bombardment) (M--H)" pyrazol-4-yl)-2H-pyridazin-3-one (A230) and ESI (electrospray ionisation) (M+H) 2-3-(5-hydroxypyrimidin-2-yl)benzyl-6-(1-methyl-1H APCI-MS (atmospheric pressure chemical ionisation-mass pyrazol-4-yl)-2H-pyridazin-3-one (A231) spectrometry) (M--H)". is carried out analogously to the following scheme

PdCl2(PPh3)2 KOAC DMF US 9,062,029 B2 29 30 -continued O 21

N N s N Y n Sodium perborate Hos -N THF Y2 Nn 2 B-O Water

O

21 O N N HO O s s Y n PPh/DIAD o N THF N e N 4 No

21 O s N-N N r -NN2 N2 ---

12.4 g (43.6 mmol) of 5-bromo-2-(3-chloromethylphenyl) 30 vacuo and adjusted to a pH of 1 using 2 N hydrochloric acid. pyrimidine and 14.2 g (43.6 mmol) of caesium carbonate are The resultant precipitate is filtered off with suction, washed added to a suspension of 7.68 g (43.6 mmol) of 6-(1-methyl with water and dried in vacuo: 2-3-(5-hydroxypyrimidin-2- 1H-pyrazol-4-yl)-2H-pyridazin-3-one in 90 ml of DMF, and yl)benzyl-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3- the mixture is stirred at room temperature for 24 hours. The one as pale-beige crystals; m.p. 239°C.; ESI 361. reaction mixture is added to 400 ml of water. The resultant 35 394 mg (1.50 mmol) of triphenylphosphine and 242 ul precipitate is filtered off with suction, washed with water and (2.00 mmol) of 4-(2-hydroxyethyl)morpholine are added dried in vacuo: 2-3-(5-bromopyrimidin-2-yl)benzyl-6-(1- successively to a suspension of 360 mg (1.00 mmol) of 2-3- methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one as yellow (5-hydroxypyrimidin-2-yl)benzyl-6-(1-methyl-1H-pyra brown crystals; m.p. 184° C.: ESI 423, 425. Zol-4-yl)-2H-pyridazin-3-one in 2 ml of THF. 294 ul (1.50 10.9 g (42.9 g) of bis(pinacolato)diboron and 9.72 g (99.0 40 mmol) of diisopropylazodicarboxylate are then slowly added mmol) of potassium acetate are added to a suspension of 14.0 dropwise with ice-cooling. The resultant solution is stirred at g(33.0 mmol) of 2-3-(5-bromopyrimidin-2-yl)benzyl-6-(1- room temperature for 18 hours. The reaction mixture is methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one in 65 ml of evaporated in vacuo, and the oily residue is dissolved in DMF, and the mixture is heated to 70° C. under nitrogen. 2-propanol. The solid which forms after some time is filtered After stirring for 15 minutes at this temperature, 695mg (0.99 45 off with suction, washed with 2-propanol and tert-butyl methyl ether and dried in vacuo: 6-(1-methyl-1H-pyrazol-4- mmol) of bis(triphenyl-phosphine)palladium(II) chloride are yl)-2-3-5-(2-morpholin-4-ylethoxy)pyrimidin-2-ylben added, and the reaction mixture is stirred at 70° C. under Zyl-2H-pyridazin-3-one (A229') as colourless crystals; nitrogen for 18 hours. The reaction mixture is allowed to cool m.p. 134° C.; ESI 474; to room temperature, water and dichloromethane are added, H-NMR (d-DMSO): 8 ppm=2.48 (m, 4H), 2.73 (t, the mixture is filtered through kieselguhr, and the organic 50 J=5.5 Hz, 2H), 3.57 (m, 4H), 3.87 (s.3H), 4.30 (t, J=5.5 Hz, phase is separated off. The organic phase is dried over sodium 2H), 5.33 (s. 2H), 7.05 (d. J=9.5 Hz, 1H), 7.43 (dt, J–7.3 Hz, Sulfate, evaporated, and the residue is recrystallised from J=1.5 Hz, 1H), 7.47 (t, J–7.5 Hz, 1H), 7.80 (d.J=9.5 Hz, 1H), 2-propanol: 6-(1-methyl-1H-pyrazol-4-yl)-2-3-5-(4.4.5.5- 7.89 (s.1H),8.21 (s, 1H),8.22 (dt, J=7.5 Hz, J-1.5 Hz, 1H), tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-ylben 8.28 (bs, 1H), 8.64 (s. 2H). Zyl-2H-pyridazin-3-one as grey crystals; m.p. 204°C.; 55 Salt formation from A229 gives the p-toluenesulfonate 'H-NMR (d-DMSO): 8 ppm=1.34 (s, 12H), 3.87 (s, and the phosphate. 3H), 5.35 (s. 2H), 7.05 (d. J=9.6 Hz, 1H), 7.52 (m, 2H), 7.80 The following compounds are obtained analogously under (d. J=9.6 Hz, 1H), 7.89 (s, 1H), 8.21 (s, 1H), 8.35 (m, 1H), standard conditions 8.45 (bs, 1H), 9.01 (s. 2H). 8.50 g (85.1 mmol) of sodium perborate are added in por 60 tions with ice-cooling to a suspension of 13.4 g (28.4 mmol) of 6-(1-methyl-1H-pyrazol-4-yl)-2-3-5-(4.4.5.5-tetram Compound ESI ethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)benzyl-2H No. Name and or structure M+H" A232 6-(1-Methyl-1H-pyrazol-4-yl)-2-3-5-(2- 474 pyridazin-3-one in 55 ml of THF and 55 ml of water, and the morpholin-4-yl-ethoxy)pyrimidin-2-yl)benzyl mixture is stirred at room temperature for 2 hours. The reac 65 2H-pyridazin-3-one, hydrochloride (from tion mixture is filtered through kiesel-Buhr with suction. The “A229) filtrate is concentrated to about half the original volume in

US 9,062,029 B2 33 34 syntinued 21 N nS S-N N NCl 2 O N “A257

17.7 g (67.8 mmol) of triphenylphosphine are added to a 264 mg (1.30 mmol) of 3-(6-oxo-1,6-dihydropyridazin-3- suspension of 13.0 g (56.5 mmol) of methyl 3-(5-hydroxypy 15 yl)benzonitrile and 397 mg (1.5 mmol) of triphenylphosphine rimidin-2-yl)benzoate and 13.4 g (62.1 mmol) of N-Boc are added successively to a solution of 313 mg (1.00 mmol) of piperidinylmethanol in 115 ml of THF, and the mixture is {3-5-(1-methylpiperidin-4-ylmethoxy)pyrimidin-2-yl)- cooled to 5°C. 13.3 ml (67.8 mmol) of diisopropylazodicar phenyl)methanol in 2 ml of THF. The reaction mixture is boxylate are added dropwise to the suspension held at this cooled in an ice bath, and 294 ul (1.5 mmol) of diisopropyl temperature over the course of 45 minutes with stirring. The aZodicarboxylate are added dropwise with stirring. The reac reaction mixture is stirred at room temperature for 1 hour. A further 22.2 g (84.7 mmol) of triphenylphosphine and 16.6 ml tion mixture is stirred at room temperature for 18 hours and (84.7 mmol) of diisopropyl azodicarboxylate are subse evaporated. The residue is chromatographed on a silica-gel quently added. The reaction mixture is stirred at room tem column with dichloromethane/methanol. The product-con perature for 18 hours and evaporated in vacuo. The resultant taining fractions are combined, evaporated, the residue is solid is filtered off with suction, washed with diethyl ether and 25 digested with tert-butyl methyl ether, filtered off with suction chromatographed on a silica-gel column with dichlo and dried in vacuo: 3-(1-3-5-(1-methylpiperidin-4-yl romethane/methanol as eluent: tert-butyl 4-2-(3-methoxy methoxy)-pyrimidin-2-yl)benzyl-6-oxo-1,6-dihydropy carbonylphenyl)pyrimidin-5-yloxymethyl-piperidine-1- ridazin-3-yl)benzonitrile as colourless crystals; m.p. 177°C.; carboxylate as lemon-yellow crystals; m.p. 166°C.; ESI 428. ESI 493; 25 ml (25 mmol) of a 1 M solution of diisobutylaluminium 30 H-NMR (d-DMSO): 8 ppm=1.33 (m. 2H), 1.75 (m, hydride in THF are added dropwise under nitrogen to a sus 3H), 1.89 (m, 2H), 2.17 (s.3H), 2.80 (m, 2H), 4.05 (d. J–6.1 pension of 1.71 g (3.99 mmol) of tert-butyl 4-2-(3-methoxy Hz, 2H), 5.45 (s. 2H), 7.16 (d. J=10 Hz, 1H), 7.49 (m, 2H), carbonylphenyl)pyrimidin-5-yloxymethylpiperidine-1-car 7.73 (t, J=7.8 Hz, 1H), 7.93 (d. J=7.8 Hz, 1H), 8.17 (d. J=10 boxylate in 20 ml of THF. The reaction mixture is stirred at HZ, 1H), 8.24 (m, 2H), 8.38 (m, 2H), 8.64 (s. 2H). room temperature for 1 hour, and 1 ml of a saturated sodium 35 Salt formation from “A257 gives the hemisulfate, citrate, sulfate solution is added. The resultant precipitate is filtered tartrate, Sulfate. Succinate and hydrochloride. off with suction and washed with THF and hot 2-propanol. The filtrate is evaporated and recrystallised from tert-butyl Example 4 methyl ether: {3-5-(1-methylpiperidin-4-ylmethoxy)pyri midin-2-yl)phenyl)methanol as beige crystals; m.p. 175° C.; 40 The following compounds are obtained analogously to ESI 314. Example 3 under Standard conditions

Compound ESI No. Name and for structure M+H" 2.233 ml of 1N hydrochloric acid are added to 1 g of A257 in 150 ml of acetone, giving a clear solution. The solution is filtered, stirred at room temperature for 16 h, and the precipitated product 3-(1-3-5-(1-methyl piperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl-6-oxo-1,6- dihydropyridazin-3-yl)benzonitrile, hydrochloride mono hydrate (A7) is separated off. H NMR (400 MHz, DMSO-d) 8 ppm) 10.374 (sb, 1H), 8.658 (s, 2H), 8.381 (m, 2H), 8.243 (m, 2H), 8.175 (d. 1H), 7.932 (d. 1H), 7.723 (t, 1H), 7.495 (m, 2H), 7.163 (d. 1H), 5.452 (s. 2H), 4.095 (d. 1H), 3.440 (m, 2H), 2.723 (s, 3H), 2.058 (m, 1H), 1.982 (m, 2H), 1.613 (m, 2H): Elemental analysis: Actual Nominal

C = 63.6% C = 63.7% H = 5.6% H = 5.7% N = 15.2% N = 15.4% O = 8.9% O = 8.8% C = 6.0% C = 6.5% A8 3-(1-3-5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2-yl)- benzyl-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, hydrobromide 3-(1-3-5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2-yl)- benzyl-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, meSylate

US 9,062,029 B2 37 38 Example B magnesium Stearate is pressed in a conventional manner to give tablets in Such a way that each tablet contains 10 mg of Suppositories active ingredient. A mixture of 20 g of an active ingredient of the formula I 5 Example F with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and allowed to cool. Each Sup Dragees pository contains 20 mg of active ingredient. Tablets are pressed analogously to Example E and Subse Example C 10 quently coated in a conventional manner with a coating of Sucrose, potato starch, talc, tragacanth and dye. Solution Example G A Solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH2PO2 H2O, 28.48 g of 15 Capsules NaHPO.12 HO and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the 2 kg of active ingredient of the formula I are introduced into solution is made up to 1 1 and sterilised by irradiation. This hard gelatine capsules in a conventional manner in Sucha way Solution can be used in the form of eye drops. that each capsule contains 20 mg of the active ingredient. 2O Example D Example H Ointment Ampoules 500 mg of an active ingredient of the formula I are mixed 25 A solution of 1 kg of active ingredient of the formula I in 60 with 99.5g of Vaseline under aseptic conditions. 1 of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under Sterile conditions and sealed Example E under sterile conditions. Each ampoule contains 10 mg of active ingredient. Tablets 30 The invention claimed is: 1. A pharmaceutical formulation, comprising A mixture of 1 kg of active ingredient of the formula I, 4 kg a pharmaceutically acceptable carrier, and of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of an active ingredient selected from the group consisting of

No. Name and or structure

A1 6-(1-Methyl-1H-pyrazol-4-yl)-2-3-5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl)- benzyl -2H-pyridazin-3-one, sulfate A2 6-(1-Methyl-1H-pyrazol-4-yl)-2-3-5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl)- benzyl -2H-pyridazin-3-one, meSylate A3 6-(1-Methyl-1H-pyrazol-4-yl)-2-3-5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl)- benzyl -2H-pyridazin-3-one, besylate A4 6-(1-Methyl-1H-pyrazol-4-yl)-2-3-5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl)- benzyl -2H-pyridazin-3-one, p-tosylate A5 6-(1-Methyl-1H-pyrazol-4-yl)-2-3-5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl)- benzyl -2H-pyridazin-3-one, fumarate A6 6-(1-Methyl-1H-pyrazol-4-yl)-2-3-5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl)- benzyl -2H-pyridazin-3-one, maleate A7 3-(1-3-5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl-6-oxo-1,6- ihydro pyridazin-3-yl)benzonitrile, hydrochloride monohydrate A8 3-(1-3-5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl-6-oxo-1,6- pyridazin-3-yl)benzonitrile, hydrobromide A9 3-(1-3-5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl-6-oxo-1,6- pyridazin-3-yl)benzonitrile, mesylate “A10' 3-(1-3-5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl-6-oxo-1,6- ihydro pyridazin-3-yl)benzonitrile, besylate “A11' 3-(1-3-5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl-6-oxo-1,6- ihydro pyridazin-3-yl)benzonitrile, malate A12 3-(1-3-5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl-6-oxo-1,6- ihydro pyridazin-3-yl)benzonitrile, fumarate “A13 3-(1-3-5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl-6-oxo-1,6- ihydro pyridazin-3-yl)benzonitrile, maleate and US 9,062,029 B2 39 40 -continued

No. Name and or structure A14 3-(1-3-5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2-yl)benzyl-6-oxo-1,6- dihydropyridazin-3-yl)benzonitrile, p-tosylate

or a tautomer or stereoisomer thereof, 700 mg of said active ingredient, or 1 to 10 mg of said active wherein the pharmaceutical formulation is in the form of 10 ingredient per kg of body weight of the intended recipient one or more dosage units, mammal. which is provided either as a single dose per day or in a series of doses of two or more per day so that the total 3. A pharmaceutical formulation according to claim 1, daily dose would be the same as for the single dose per wherein said single dose comprises 5 mg to 100 mg of said day, and active ingredient. wherein said single or series of daily doses comprise 0.5 15 4. A pharmaceutical formulation according to claim 1, mg to 1 g of said active ingredient, or 0.1 to 100 mg of said active ingredient per kg of body weight of the which contains 3-(1-3- 5-(1-Methylpiperidin-4-yl intended recipient mammal. methoxy)pyrimidin-2-yl)benzyl -6-oxo-1,6-dihydro-py 2. A pharmaceutical formulation according to claim 1, ridazin-3-yl)benzonitrile, hydrochloride monohydrate. wherein said single or series of daily doses comprise 1 mg to k k k k k