USOO9403799B2

(12) United States Patent (10) Patent No.: US 9.403,799 B2 Schadt et al. (45) Date of Patent: * Aug. 2, 2016

(54) PYRIMIDINYL-PYRIDAZINONE (52) U.S. Cl. DERVATIVES FOR TREATING ADISEASE CPC ...... C07D 403/10 (2013.01); A61 K9/0014 WHICH IS INFLUENCED BY INHIBITION OF (2013.01); A61 K9/0019 (2013.01); A61 K MET KINASE 9/0031 (2013.01); A61K 9/0048 (2013.01); A61 K9/02 (2013.01); A61 K9/06 (2013.01); (71) Applicant: Merck Patent GmbH, Darmstadt (DE) A61 K9/08 (2013.01); A61 K9/2018 (2013.01); A6 IK3I/501 (2013.01); A61 K3I/506 (72) Inventors: Oliver Schadt, Rodenbach (DE); Dieter (2013.01); A61 K3I/5355 (2013.01); A61 K Dorsch, Ober-Ramstadt (DE); Frank 31/5377 (2013.01); A61 K3I/55 (2013.01); Stieber, Heidelberg (DE); Andree A61K 45/06 (2013.01); A61K 47/02 (2013.01); Blaukat, Schriesheim (DE) C07D401/10 (2013.01); C07D401/14 (2013.01); C07D 403/14 (2013.01); C07D (73) Assignee: MERCK PATENT GMBH, Darmstadt 405/14 (2013.01); C07D 409/14 (2013.01); (DE) C07D 413/10 (2013.01); C07D 413/14 (2013.01); C07D 417/10 (2013.01); C07D (*) Notice: Subject to any disclaimer, the term of this 417/14 (2013.01); C07D 451/06 (2013.01); patent is extended or adjusted under 35 C07D 453/02 (2013.01); A61 K9/19 (2013.01); U.S.C. 154(b) by 0 days. A61 K9/2826 (2013.01) This patent is Subject to a terminal dis (58) Field of Classification Search claimer. CPC ...... A61K 47/02: A61 K9/08: A61 K9/2826; A61 K9/19; A61 K9/0014: A61 K9/0019; (21) Appl. No.: 14/602.921 A61K31/506; A61K31/5355; A61K 31/501; A61K 31/55; A61K31/5377; A61K45/06; (22) Filed: Jan. 22, 2015 C07D 417/10; C07D 417/14: CO7D 451/06; C07D 409/14: CO7D405/14: CO7D 453/02; (65) Prior Publication Data C07D 413/10; C07D 413/14: CO7D 403/14: US 2015/O1334.52 A1 May 14, 2015 CO7D401 (10 USPC ...... 514/236.5, 252.02:544/123, 298 See application file for complete search history. Related U.S. Application Data (62) Division of application No. 14/149.110, filed on Jan. 7, (56) References Cited 2014, now Pat. No. 9,062,029, which is a division of U.S. PATENT DOCUMENTS application No. 13/565,914, filed on Aug. 3, 2012, now Pat. No. 8,658,643, which is a division of application 6,242.461 Bl 6/2001 Goldstein No. 12/668,491, filed as application No. 6,403,586 B1 6/2002 Ohkuchi et al. PCT/EP2008/005508 on Jul. 4, 2008, now Pat. No. (Continued) 8,329,692. FOREIGN PATENT DOCUMENTS (30) Foreign Application Priority Data DE 19604388 8, 1997 Jul. 12, 2007 (DE) ...... 10 2007 032 507 DE 102005057924 6, 2007 Apr. 29, 2008 (WO)...... PCT/EP2008/OO3473 (Continued) (51) Int. Cl. OTHER PUBLICATIONS A6 IK 47/02 (2006.01) A6 IK9/08 (2006.01) “Cancer MedLine Plus (2009). Accessed Mar 17, 2009. http:// A 6LX 9/19 (2006.01) www.nlm.nih.gov/medlineplus/cancer.html. CO7D 4 7/10 (2006.01) (Continued) CO7D 45/06 (2006.01) CO7D 409/4 (2006.01) CO7D 405/4 (2006.01) Primary Examiner — James O Wilson CO7D 453/02 (2006.01) Assistant Examiner — Ebenezer O Sackey CO7D 43/10 (2006.01) (74) Attorney, Agent, or Firm — Millen White Zelano and CO7D 403/4 (2006.01) Branigan, PC: Csaba Henter; Anthony Zelano CO7D 403/0 (2006.01) CO7D 40/0 (2006.01) (57) ABSTRACT CO7D 40/4 (2006.01) CO7D 413/4 (2006.01) Compounds selected from the group according to claim 1 are CO7D 417/4 (2006.01) inhibitors of tyrosine kinases, in particular of Metkinase, and A6 IK3I/50 (2006.01) can be employed, interalia, for the treatment of tumors. A6 IK3I/506 (2006.01) (Continued) 20 Claims, No Drawings US 9,403,799 B2 Page 2

(51) Int. Cl. WO 2009083076 T 2009 A 6LX3/5355 (2006.01) W. S. 23: A 6LX3/5377 (2006.01) WO 2009086041 T 2009 A6 IK3I/55 (2006.01) WO 2009086264 T 2009 A6 IK 45/06 (2006.01) OTHER PUBLICATIONS A6 IK9/00 (2006.01) A6 IK9/02 (2006.01) Berge et al., “Pharmaceutical salts.” Journal of Pharmaceutical Sci A6 IK9/06 (2006.01) ence, 1977, vol. 66, No. 1, pp. 1-19. A6 IK9/20 (2006.01) Berthou, S. et al., “The Met kinase inhibitor SU 11274 exhibits a A61 K9/28 (2006.01) selective inhibition pattern toward different receptor mutated vari ants.” Oncogene, 2004, vol. 23, pp. 5387-5393. (56) References Cited Buchanan, Sean G. “SGX523 is an exquisitely selectively, ATP competitive inhibitor of the MET receptor tyrosine kinase with anti U.S. PATENT DOCUMENTS tumor activity in vivo”. Molecular Cancer Therapeutics, Dec. 2009;8(12): 3181-3190. 8,071,593 B2 12/2011 Schadt et al. Cancer Drug Design and Discovery, Neidle, Stephen, ed. (Elsevier/ 8,173,653 B2 5, 2012 Dorsch et al. 8,329,692 B2 12/2012 Schadt et al. Academic Press), pp. 427-431, 2008. 8,580,781 B2 11/2013 Dorsch et al. Chen et al., Circulation, 2008, vol. 118, pp. 84-95. 8,658,643 B2 * 2/2014 Schadt ...... CO7D 401?10 Database Beilstein, Beilstein Institute for Organic Chemistry, Frank 514,236.5 furt, DE, XPOO2506064, 1991. 2004/O152739 A1 8, 2004 Hanau Database CA (Online) Chemical Abstracts Service, Columbus, Ohio 2004/0259863 A1 12, 2004 Eggenweiler et al. US:2002, Dushamov, D.A.et al., Acylation of 6-halobenzoxazolin 2005/0107391 A1 5/2005 Cui et al. 2007, OO15771 A1 1/2007 Matteucci et al. 2-ones by acid chlorides in the presence of a small quantity of 2007/0043057 A1 2, 2007 Matteucci et al. iron(III) chloride hexahydrate, XP002496356. 2007/0203136 A1 8, 2007 Lu et al. Database CA (Online) Chemical Abstracts Service, Columbus, Ohio 2007/0265272 A1 11/2007 Cheng et al. US: 1979, Domagalina, Eugenia et al. "Acylation of benzoxazolin-2- 2008.O293719 A1 11/2008 Dorsch et al. ones and 3-hydroxyl-1, 2 benzisoxazoles,” XP002496357 Polish 2009/00981.81 A1 4, 2009 Lu et al. Journal of Pharmacology and Pharmacy. 2009, O124612 A1 5/2009 Albrecht et al. 2010/O197690 A1 8, 2010 Schadt et al. Database CA (Online) Chemical Abstracts Service, Columbus, Ohio 2010, O234354 A1 9, 2010 Dorsch et al. US; 1967. Nitta, yoshihiro et al: “Benzoxazolone derivatives.” 2010O273796 A1 10, 2010 Dorsch et al. XPOO2496.358. 2010/0280030 A1 11, 2010 Schadt et al. Databse Beilstein, Beilstein Institute for Organic Chemistry, Frank 2010/0286390 A1 11, 2010 Shigeta et al. furt, DE, XPOO2506065, 2008. 2011/0034474 A1 2, 2011 Dorsch et al. Ettmayer et al. “Lessons Learned from Marketed and Investigational 2011/0092498 A1 4, 2011 Dorsch et al. Prodrugs” J. Med. Chem. (2004), 47 (10):2393-2404. 2011/0098.269 A1 4, 2011 Becknell et al. 2011 0112061 A1 5, 2011 Hu et al. Flouzat, Christine et al. “Synthesis and N-substitution of an uncom 2011/0263596 A1 10, 2011 Schadt et al. mon heterocyclic system: oxazolo5,4-bipyridin-2(1H)-one.” Tetra 2011/0269957 A1 11/2011 Fandricket al. hedron Letters, Bd. 33, Nr. 32, 1992 Seiten 4571-4574, XP00249354. 2012/0028988 A1 2, 2012 Sakamoto et al. Fujisawa Pharmaceut Co Ltd., “Pyrazolopyridine compound and 2012/004O949 A1 2, 2012 Berthel et al. pharmaceutical use thereof.” Patent Abstracts of Japan, Publication 2012fO29.5908 A1 11, 2012 Schadt et al. Date: Jul. 17, 2001; English Abstract of JP-2001 192384. Glen, H. et al., “E7080, a multi-targeted tyrosin kinase inhibitor FOREIGN PATENT DOCUMENTS Suppresses tumor cell migration and invasion.” BMC Cancer, 2011, vol. 11, No. 309. EP 1061077 12/2000 Golub et al. “Molecular Classification of Cancer: Class Discovery JP 10259 176 9, 1998 and Class Prediction by Gene Expression Monitoring” Science JP 2001 192384 T 2001 (1999), 286:521-537. WO O3O37349 5, 2003 Gould et al., “Salt selection for basic drugs.” International Journal of WO 2004058762 T 2004 Pharmaceutics, 1986, vol. 33, p. 201. WO 2005OO46O7 1, 2005 Guessous, Fadila et al. "An orally Bioavailable c-Met Kinase Inhibi WO 2006O15263 2, 2006 tor Potently Inhibits Brain Tumor Malignancy and Growth'. Anti WO 2007044796 4/2007 WO 2007O64797 6, 2007 Cancer in Medicinal Chemistry, 2010, 10(1):28-35. WO 2007O65518 6, 2007 H. Refaat et al., “Synthesis and Anti-Inflammatory Activity of Cer WO 2007075567 7/2007 tain Piperazinylthienylpyridazine Derivatives.” Arch Pharm Res., WO 2007 130383 11, 2007 vol. 30, No. 7 (2007) pp. 803-811. WO 2007 1323O8 11, 2007 Hackh's Chem Dict, 3rd. Ed., 1944, p. 18. WO 2008008539 1, 2008 Hawley's Condensed Chem Dict. 14th Ed., 2002. WO 2008075068 6, 2008 Hill, K. S. et al., "Met Receptor Tyrosine Kinase Signaling Induces WO 2009006959 1, 2009 Secretion of the Angiogenic Chemokine Interleukin-8/CXCL8 in WO 2009007074 1, 2009 Pancreatic Cancer. PLoS One, Jul. 1, 2012, vol. 7, No. 7, e40420. WO 200905O197 4/2009 http://www.iupac.org/goldbook/A00123.pdf downloaded Oct. 29. WO 2009053737 4/2009 2010. WO 2009063061 5, 2009 WO 2009080314 T 2009 Last accessed on Nov. 22, 2011. WO 2009080364 T 2009 International Search Report “International Application No. PCT/ WO 2009080533 T 2009 EP2008/003696.” Date of Completion Sep. 18, 2008, Date of Mailing WO 2009080534 T 2009 Oct. 1, 2008, 4 pages. WO 2009080555 T 2009 International Search Report for PCT/EP2008/003473 dated Jul. 28, WO 2009080721 T 2009 2008. WO 2009080725 T 2009 International Search Report for PCT/EP2008/005928 dated Dec. 11, WO 2009081197 T 2009 2008. US 9,403,799 B2 Page 3

(56) References Cited tor of HGF and VEGF Receptor Tyrosine Kinases”. Cancer Res 2009:69(20):8009-8016. Dated: Oct. 15, 2009. www.aacrjournals. OTHER PUBLICATIONS Org. Samlowski et al., BJU Int., 2008, vol. 102, No. 2, pp. 162-165, International Search Report of PCT/EP2008/009970 dated Jan. 28, Abstract. 2009. Sampson, Erik R. et al. “The Orally Bioavailable Met Inhibitor International Search Report of PCT/EP2009/002137 (Jun. 4, 2009). International Search Report of PCT/EP2009/003675 (Aug. 26, PF-2341066 Inhibits Osteosarcoma Growth and Osteolysis/Matrix 2009). Production in a Xenograft Model”, Journal of Bone and Mineral International Search Report of PCT/EP2009/005172 dated Jan. 26, Research, 26(6):1283-1294; Dated: Jun. 2011. 2010. Sausville et al. “Contributions of Human Tumor Xenografts to Anti International Search Report of PCT/EP2009/008358 dated Feb. 5, cancer Drug Development' Cancer Res. 2006, 66(7), Apr. 1, 2006. 2010. Search Report for Chilean Patent Application No. 3854-08 filed Dec. Japan Tobacco Inc., “New Amide derivative having vascularization 19, 2008. inhibiting action and its use.” Patent Abstracts of Japan, Publication Singapore Written Opinion for Application No. 2010.07486-2 (Sep. Date: Sep. 29, 1998; English Abstracts of JP-10 259176. 26, 2011). Jin et al., Mol. Cancer Ther., Jul. 2006, vol. 5, pp. 1754-1763. Smolen et al., Proc. Natl Acad Sci USA, Feb. 2006, vol. 103, No. 7, Jin, Hongkuiet al. “MetMAb, the One-Armed 5D5Anti-c-Met Anti pp. 23.16-2321. body, Inhibits Orthotopic Pancreatic Tumor Growth and Improves Souillac et al. Characterization of Delivery Systems, Differential Survival”, Cancer Res 2008:68(11):4360-4368; Jun. 1, 2008, www. Scanning Calorimetry, pp. 217-218 (in Encyclopedia of Controlled aacrjournals.org. Drug Delivery, 1999, John Wiley & Sons. Johnson et al. “Relationships between drug activity in NCI preclini Stella, V. “Prodrugs as therapeutics' Expert Opin. Ther. Patents cal in vitro and in vivo models and early clinical trials.” British (2004), 14(3):277-280. Journal of Cancer (2001) 84(10): 1424-1431. Testa, B. "Prodrug research: futile or fertile?' Biochemical Pharma Knowles, Lynn M. et al. “HGF and c-Met Participate in Paracrine cology, 68 (2004): 2097-2106. Tumorigenic Pathways in Head and Neck Squamous Cell Cancer', Tuynman et al., Br. J. Cancer, 2008, vol. 98, No. 6, pp. 1102-1108, Clin Cancer Res, Jun. 1, 2009; 15(11):3740-3750. www. aacrjournals.org. Abstract. Lala et al. “Role of nitric oxide in tumor progression: Lessons from Ucar, Huseyin et al., “Fries Like' Rearragement: a noveland efficient experimental tumors.” Cancer and Metastasis Review (1998), 17(1), metod for the sythesis of 6-acyl-2(3H)-benzoxazolones and 6-acyl 91-106. 2(3H)-benzothiazoiones Tetrahedron, Bd. Lima, L. M. et al., “Bioisosterism: a useful strategy for molecular Underiner et al., Anti-Cancer Agents in Medicinal Chemistry, 2010, modification and drug design.” Current Medicinal Chemistry, 2005, vol. 10, pp. 7-27. vol. 12, No. 1, pp. 23-49. Vippagunta, S.R. “Crystalline Solids' Advanced Drug Delivery Liu, Xiangdong et al. “A novel kinase inhibitor INCB28060 blocks Reviews 48 (2001):3-26. c-MET-dependent signaling, neoplastic activities, and crosstalk with Wang et al., Clin Cancer Res., Mar. 15, 2012, vol. 18, No. 6, pp. EGFR and HER-3', Clin Cancer Res (45 pages); Published: Sep. 14. 1663-1671. 2011. Wolff et al. Burger's Medicinal Chemistry and Drug Discovery, 5th Locatelli et al., J. Biol. Chem. Jun. 17, 2011, vol. 286, No. 24, pp. Ed. vol. 1: Principles and Practice, 1995, pp.975-977. 21062-21072. Ziegler, D. S. et al., “Resistance of human glioblastoma multiforme M. Goekce et al., “Synthesis of New Mannich Bases of cells to growth factor inhibitors is overcomeby blockade of inhibitors ArylpyridaZinones as Analgesic and Anti-Inflammatory Agents.” of apoptosis proteins.” Journal of Drug Research, vol. 55, No. 6 (2005) pp. 318-325. Zillhardt, Marion et al. Foretinib (GSK1363089), an Orally Available Merck Patent GMBH, “New Aryl-alkyl diazinone derivatives.” Multikinase Inhibitor of c-Met and VEGFR-2, Blocks Proliferation, Espacenet, Publication Date: Aug. 14, 1997; English Abstract of Induces Anoikis, and Impairs Ovarian Ca. DE-196 04388. Zou, Helen Y, et al. An Orally Available Small-Molecule Inhibitor of Morissette et al. “High-throughput crystallization: polymorphs, salts, c-Met, PF-2341066, Exhibits Cytoreductive Antitumor Efficacy co-crystals and Solvates of pharmaceutical Solids.” Advanced Drug through Antiproliferative and Antiangiogenic. Deliver Reviews 2004, 56 275-300. Zou, Helen Y, et al. “Sensitivity of Selected Human tumor Models to Office Action for Related Columbian Patent Application No. PF-04217903, a Novel Selective c-Met Kinase Inhibitor, Molecular 09-138245 dated Sep. 21, 2012. Cancer Therapeutics, American Association. Qian, Fawn et al. “Inhibition of Tumor Cell Growth, Invasion, and Metastasis by EXEL-2880 (XL880, GSK1363089), a Novel Inhibi * cited by examiner US 9,403,799 B2 1. 2 PYRIMDNYL-PYRIDAZINONE It has been found that the compounds according to the DERVATIVES FORTREATING ADISEASE invention and salts thereofhave very valuable pharmacologi WHICH IS INFLUENCED BY INHIBITION OF cal properties while being well tolerated. MET KINASE The present invention specifically relates to compounds of the formula I which inhibit, regulate and/or modulate signal BACKGROUND OF THE INVENTION transduction by Met kinase, to compositions which comprise these compounds, and to processes for the use thereof for the The invention had the object of finding novel compounds treatment of Met kinase-induced diseases and complaints, having valuable properties, in particular those which can be Such as angiogenesis, cancer, tumour formation, growth and 10 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 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, 15 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 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 25 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 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 30 formula I can furthermore be used to provide additive or lated and often overlap, as is evident from the existence of synergistic effects in certain existing cancer chemotherapies, many protein kinases as well as phosphatases. Phosphoryla and/or can be used to restore the efficacy of certain existing tion of proteins occurs predominantly at serine, threonine or cancer chemotherapies and radiotherapies. tyrosine residues, and protein kinases have therefore been The compounds of the formula I can furthermore be used classified by their specificity of phosphorylation site, i.e. 35 for the isolation and investigation of the activity or expression serine/threonine kinases and tyrosine kinases. Since phos of Met kinase. In addition, they are particularly suitable for phorylation is such a ubiquitous process within cells and use in diagnostic methods for diseases in connection with since cellular phenotypes are largely influenced by the activ unregulated or disturbed Met kinase activity. ity of these pathways, it is currently believed that a number of It can be shown that the compounds according to the inven disease states and/or diseases are attributable to either aber 40 tion have an antiproliferative action in vivo in a Xenotrans rant activation or functional mutations in the molecular com plant tumour model. The compounds according to the inven ponents of kinase cascades. Consequently, considerable tion are administered to a patient having a hyperproliferative attention has been devoted to the characterisation of these disease, for example to inhibit tumour growth, to reduce proteins and compounds that are able to modulate their activ inflammation associated with a lymphoproliferative disease, ity (for a review see: Weinstein-Oppenheimer et al. Pharma. 45 to inhibit transplant rejection or neurological damage due to &. Therap., 2000, 88,229-279). tissue repair, etc. The present compounds are suitable for The role of the receptor tyrosine kinase Met in human prophylactic ortherapeutic purposes. As used herein, the term oncogenesis and the possibility of inhibition of HGF (hepa “treatment' is used to refer to both prevention of diseases and tocyte growth factor) dependent Met activation are described treatment of pre-existing conditions. The prevention of pro by S. Berthou et al. in Oncogene, Vol. 23, No. 31, pages 50 liferation is achieved by administration of the compounds 5387-5393 (2004). The inhibitor SU11274 described therein, according to the invention prior to the development of overt a pyrrole-indoline compound, is potentially suitable for com disease, for example to prevent the growth of tumours, pre bating cancer. Another Met kinase inhibitor for cancer vent metastatic growth, diminish restenosis associated with therapy is described by J. G. Christensen et al. in Cancer Res. cardiovascular Surgery, etc. Alternatively, the compounds are 2003, 63(21), 7345-55. A further tyrosine kinase inhibitor for 55 used for the treatment of ongoing diseases by stabilising or combating cancer is reported by H. Hov et al. in Clinical improving the clinical symptoms of the patient. Cancer Research Vol. 10, 6686-6694 (2004). The compound The host or patient can belong to any mammalian species, PHA-665752, an indole derivative, is directed against the for example a primate species, particularly humans; rodents, HGF receptor c-Met. It is furthermore reported therein that including mice, rats and hamsters; rabbits; horses, cows, HGF and Met make a considerable contribution to the malig 60 dogs, cats, etc. Animal models are of interest for experimental nant process of various forms of cancer, such as, for example, investigations, providing a model for treatment of human multiple myeloma. disease. The synthesis of Small compounds which specifically The susceptibility of a particular cell to treatment with the inhibit, regulate and/or modulate signal transduction by compounds according to the invention can be determined by tyrosine kinases and/or serine/threonine kinases, in particular 65 in vitro tests. Typically, a culture of the cell is combined with Met kinase, is therefore desirable and an aim of the present a compound according to the invention at various concentra invention. tions for a period of time which is sufficient to allow the active US 9,403,799 B2 3 4 agents to induce cell death or to inhibit migration, usually ThiadiaZinones are described in DE 19604388, WO2003/ between about one hour and one week. In vitro testing can be O37349 WO2007/057093 or WO2007/057092. carried out using cultivated cells from a biopsy sample. The DihydropyridaZinones for combating cancer are described in viable cells remaining after the treatment are then counted. WO O3/O37349 A1. The dose varies depending on the specific compound used, the specific disease, the patient status, etc. A therapeutic dose Other pyridazines for the treatment of diseases of the immune is typically sufficient considerably to reduce the undesired system, ischaemic and inflammatory diseases are known cell population in the target tissue while the viability of the from EP 1 043 317 A1 and EP 1 061 077 A1. patient is maintained. The treatment is generally continued EP 0738 716A2 and EP 0 711 759 B1 describe other dihy until a considerable reduction has occurred, for example an at dropyridaZinones and pyridazinones as fungicides and least about 50% reduction in the cell burden, and may be 10 insecticides. continued until essentially no more undesired cells are Other pyridaZinones are described as cardiotonic agents in detected in the body. U.S. Pat. No. 4,397,854. JP 57-95964 discloses other For identification of a signal transduction pathway and for pyridazinones. detection of interactions between various signal transduction The use of other MET kinase inhibitors for combating cancer pathways, various scientists have developed Suitable models 15 is described in WO 2007/075567. or model systems, for example cell culture models (for example Khwaja et al., EMBO, 1997, 16, 2783-93) and mod SUMMARY OF THE INVENTION els of transgenic animals (for example White et al., Onco gene, 2001, 20, 7064–7072). For the determination of certain The invention relates to compounds selected from the stages in the signal transduction cascade, interacting com group pounds can be utilised in order to modulate the signal (for The invention also relates to the optically active forms example Stephens et al., Biochemical J., 2000, 351, 95-105). (stereoisomers), the enantiomers, the racemates, the diaste The compounds according to the invention can also be used as reomers and the hydrates and Solvates of these compounds. reagents for testing kinase-dependent signal transduction The term Solvates of the compounds is taken to mean adduc pathways in animals and/or cell culture models or in the 25 tions of inert solvent molecules onto the compounds which clinical diseases mentioned in this application. form owing to their mutual attractive force. Solvates are, for Measurement of the kinase activity is a technique which is example, mono- or dihydrates or alkoxides. well known to the person skilled in the art. Generic test systems for the determination of the kinase activity using The expression “effective amount” denotes the amount of a Substrates, for example histone (for example Alessi et al., medicament or of a pharmaceutical active ingredient which FEBS Lett. 1996, 399, 3, pages 333-338) or the basic myelin 30 causes in a tissue, system, animal or human a biological or protein, are described in the literature (for example Campos medical response which is sought or desired, for example, by Gonzalez, R. and Glenney, Jr., J.R. 1992, J. Biol. Chem. 267, a researcher or physician. page 14535). In addition, the expression “therapeutically effective For the identification of kinase inhibitors, various assay amount denotes an amount which, compared with a corre systems are available. In Scintillation proximity assay (Sorget 35 sponding Subject who has not received this amount, has the al., J. of. Biomolecular Screening, 2002, 7, 11-19) and flash following consequence: plate assay, the radioactive phosphorylation of a protein or improved treatment, healing, prevention or elimination of a peptide as substrate with YATP is measured. In the presence of disease, syndrome, condition, complaint, disorder or side an inhibitory compound, a decreased radioactive signal, or effects or also the reduction in the advance of a disease, none at all, is detectable. Furthermore, homogeneous time 40 complaint or disorder. resolved fluorescence resonance energy transfer (HTR The expression “therapeutically effective amount” also FRET) and fluorescence polarisation (FP) technologies are encompasses the amounts which are effective for increasing suitable as assay methods (Sills et al., J. of Biomolecular normal physiological function. Screening, 2002, 191-214). The invention also relates to the use of mixtures of the Other non-radioactive ELISA assay methods use specific 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 9,403,799 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 9,403,799 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 excipient mer material and a gloss layer of wax may be present. Dyes (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 prespecified 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 droxypropylmethacrylamidophenol, 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 9,403,799 B2 9 10 Pharmaceutical compounds adapted for topical adminis breast carcinoma, is generally in the range from 0.1 to 100 tration can be formulated as ointments, creams, Suspensions, mg/kg of body weight of the recipient (mammal) per day and lotions, powders, Solutions, pastes, gels, sprays, aerosols or particularly typically in the range from 1 to 10 mg/kg of body oils. weight per day. Thus, the actual amount per day for an adult For the treatment of the eye or other external tissue, for mammal weighing 70 kg is usually between 70 and 700 mg. example mouth and skin, the formulations are preferably where this amount can be administered as a single dose per applied as topical ointment or cream. In the case of formula day or usually in a series of part-doses (such as, for example, tion to give an ointment, the active ingredient can be two, three, four, five or six) per day, so that the total daily dose employed either with a paraffinic or a water-miscible cream is the same. An effective amount of a salt or solvate or of a base. Alternatively, the active ingredient can beformulated to 10 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 mentioned above. dient is dissolved or Suspended in a suitable carrier, in par 15 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 inven Pharmaceutical formulations adapted for nasal administra tion and/or tautomers and Stereoisomers thereof, including tion in which the carrier Substance is a Solid comprise a coarse mixtures thereof in all ratios, and powder having a particle size, for example, in the range 25 (b) an effective amount of a further medicament active ingre 20-500 microns, which is administered in the manner in dient. 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. comprise separate ampoules, each containing an effective Suitable formulations for administration as nasal spray or 30 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, dient in dissolved or lyophilised form. which can be generated by various types of pressurised dis 35 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. include the proliferation of tumour cells, pathological Pharmaceutical formulations adapted for parenteral 40 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: like). and aqueous and non-aqueous sterile Suspensions, which may 45 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 ferred carcinomas for the treatment originate from the group carrier liquid, for example water for injection purposes, 50 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 Small-cell lung carcinomas, pancreatic cancer, glioblastomas ticularly mentioned constituents, the formulations may also 55 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. which angiogenesis is implicated. Atherapeutically effective amount of a compound accord 60 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 physiologically acceptable salts and Solvates thereof for the ultimately determined by the treating doctor or vet. However, 65 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 for the treatment of neoplastic growth, for example colon or present invention. Examples of Such inflammatory diseases US 9,403,799 B2 11 12 include rheumatoid arthritis, psoriasis, contact dermatitis, The solid tumour is furthermore preferably selected from delayed hypersensitivity reaction and the like. the group lung adenocarcinoma, Small-cell lung carcinomas, Also encompassed is the use of the compounds according pancreatic cancer, glioblastomas, colon carcinoma and breast to the invention for the preparation of a medicament for the carcinoma. treatment or prevention of a tyrosine kinase-induced disease 5 Preference is furthermore given to the use for the treatment or a tyrosine kinase-induced condition in a mammal, in which of a tumour of the blood and immune system, preferably for to this method a therapeutically effective amount of a com the treatment of a tumour selected from the group of acute pound according to the invention is administered to a sick myeloid leukaemia, chronic myeloid leukaemia, acute lym mammal in need of Such treatment. The therapeutic amount phatic leukaemia and/or chronic lymphatic leukaemia. 10 The disclosed compounds according to the invention can varies according to the specific disease and can be determined be administered in combination with other known therapeutic by the person skilled in the art without undue effort. agents, including anticancer agents. As used here, the term The present invention also encompasses the use com 'anticancer agent” relates to any agent which is administered pounds of the formula I and/or physiologically acceptable to a patient with cancer for the purposes of treating the cancer. salts and Solvates thereof for the preparation of a medicament 15 The anti-cancer treatment defined herein may be applied as for the treatment or prevention of retinal vascularisation. a sole therapy or may involve, in addition to the compound of Methods for the treatment or prevention of ocular diseases, the invention, conventional Surgery or radiotherapy or che Such as diabetic retinopathy and age-induced macular degen motherapy. Such chemotherapy may include one or more of eration, are likewise part of the invention. The use for the the following categories of anti-tumour agents: treatment or prevention of inflammatory diseases. Such as (i) antiproliferative/antineoplastic/DNA-damaging agents rheumatoid arthritis, psoriasis, contact dermatitis and delayed and combinations thereof, as used in medical oncology, hypersensitivity reaction, as well as the treatment or preven Such as alkylating agents (for example cis-platin, carbopl tion of bone pathologies from the group osteosarcoma, atin, cyclophosphamide, nitrogen mustard, melphalan, osteoarthritis and rickets, likewise falls within the scope of chloroambucil, buSulphan and nitrosoureas); antimetabo the present invention. 25 lites (for example antifolates Such as fluoropyrimidines The expression “tyrosine kinase-induced diseases or con like 5-fluorouracil and tegafur, raltitrexed, methotrexate, ditions” refers to pathological conditions that depend on the cytosine arabinoside, hydroxyurea and gemcitabine); anti activity of one or more tyrosine kinases. Tyrosine kinases tumour antibiotics (for example anthracyclines, like adria either directly or indirectly participate in the signal transduc mycin, bleomycin, doxorubicin, daunomycin, epirubicin, tion pathways of a variety of cellular activities, including 30 idarubicin, mitomycin-C, dactinomycin and mithramy cin); antimitotic agents (for example Vinca alkaloids, like proliferation, adhesion and migration and differentiation. Vincristine, vinblastine, vindesine and vinorelbine, and Diseases associated with tyrosine kinase activity include pro taxoids, like taxol and taxotere); topoisomerase inhibitors liferation of tumour cells, pathological neovascularisation (for example epipodophyllotoxins, like etoposide and teni that promotes the growth of Solid tumours, ocular neovascu 35 poside, amsacrine, topotecan, irinotecan and camptoth larisation (diabetic retinopathy, age-induced macular degen ecin) and cell-differentiating agents (for example all-trans eration and the like) and inflammation (psoriasis, rheumatoid retinoic acid, 13-cis-retinoic acid and fenretinide); arthritis and the like). (ii) cytostatic agents, such as antioestrogens (for example The compounds according to the invention can be admin tamoxifen, toremifene, raloxifene, droloxifene and istered to patients for the treatment of cancer, in particular 40 iodoxyfene), oestrogen receptor downregulators (for fast-growing tumours. example fulvestrant), antiandrogens (for example bicaluta The invention thus relates to the use of compounds accord mide, flutamide, nilutamide and cyproterone acetate), ing to the invention and tautomers and stereoisomers thereof, LHRH antagonists or LHRH agonists (for example goser including mixtures thereof in all ratios, for the preparation of elin, leuprorelin and buserelin), progesterones (for a medicament for the treatment of diseases in which the 45 example megestrol acetate), aromatase inhibitors (for inhibition, regulation and/or modulation of kinase signal example as anastroZole, letrozole, Vorazole and exemes transduction plays a role. tane) and inhibitors of 5C.-reductase, such as finasteride; Preference is given here to Met kinase. (iii) agents which inhibit cancer cell invasion (for example Preference is given to the use of compounds according to metalloproteinase inhibitors, like marimastat, and inhibi the invention and tautomers and stereoisomers thereof, tors of urokinase plasminogen activator receptor function); including mixtures thereof in all ratios, (iv) inhibitors of growth factor function, for example such for the preparation of a medicament for the treatment of inhibitors include growth factor antibodies, growth factor diseases which are influenced by inhibition of tyrosine receptor antibodies (for example the anti-erbb2 antibody kinases by the compounds according to claim 1. trastuzumab HerceptinTM and the anti-erbbl antibody 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-meth Especial preference is given to the use for the treatment of 60 oxy-6-(3-morpholinopropoxy)guinazolin-4-amine (gefi a disease where the disease is a solid tumour. tinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-meth The solid tumour is preferably selected from the group of oxyethoxy)guinazolin-4-amine (erlotinib, OSI-774) and tumours of the lung, squamous epithelium, the bladder, the 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-mor stomach, the kidneys, of head and neck, the oesophagus, the pholinopropoxy)guinazolin-4-amine (CI 1033)), for cervix, the thyroid, the intestine, the liver, the brain, the pros- 65 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 9,403,799 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 anergy, 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 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 Rubidazon Mitomycin C US 9,403,799 B2 15 16 TABLE 1-continued 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) Melanoma vaccine (CTL CLL-Thera (Vasogen) US 9,403,799 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 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) 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) 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) AG-2037 (GART inhibitor, Triacetyluridine (uridine US 9,403,799 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 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) 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 9,403,799 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) Immuno Interferon Dexosome therapy modulators 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 9,403,799 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 9,403,799 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. the assay plate. The Met kinase and the substrate poly Ala 30 Glu-Lys-Tyr. (p.AGLT 6:2:5:1), are incubated for 3 hrs at ASSAYS room temperature with radioactively labelled P-ATP in the presence and absence of test Substances in a total Volume of The compounds of the formula I described in the examples 100 ul. The reaction is terminated using 150 ul of a 60 mM were tested by the assays described below and were found to EDTA solution. After incubation for a further 30 minat room have kinase inhibitory activity. Other assays are known from 35 temperature, the Supernatants are filtered off with Suction, and the literature and could readily be performed by the person the wells are washed three times with 200 ul of 0.9% NaCl skilled in the art (see, for example, Dhanabal et al., Cancer Solution each time. The measurement of the bound radioac Res. 59:189-197: Xin et al., J. Biol. Chem. 274:9116-9121: tivity is carried out by means of a scintillation measuring Sheu et al., Anticancer Res. 18:4435-4441; Ausprunk et al., 40 instrument (Topcount NXT, Perkin-Elmer). Dev. Biol. 38:237-248; Gimbrone et al., J. Natl. Cancer Inst. The full value used is the inhibitor-free kinase reaction. 52:413-427; Nicosia et al., In Vitro 18:538-549). This should be approximately in the range 6000-9000 cpm. Measurement of Met Kinase Activity The pharmacological Zero value used is staurosporin in a final According to the manufacturer's data (Met, active, upstate, concentration of 0.1 mM. The inhibitory values (IC50) are catalogue No. 14-526), Met kinase is expressed for the pur 45 determined using the RS1 MTS program. poses of protein production in insect cells (Sf21; S. fru giperda) and Subsequent affinity-chromatographic purifica Kinase reaction conditions per well: tion as “N-terminal 6His-tagged' recombinant human protein 30 Jul of assay buffer in a baculovirus expression vector. 10 ul of substance to be tested in assay buffer with 10% of DMSO The kinase activity can be measured using various avail 50 10 pil of ATP (final concentration 1 M cold, 0.35 ICiof'P-ATP) 50 pil of Metkinase/substrate mixture in assay buffer; able measurement systems. In the Scintillation proximity (10 ng of enzyme?well, 50 ng of pAGLT/well) method (Sorget al., J. of Biomolecular Screening, 2002, 7. Solutions used: 11-19), the flashplate method or the filter binding test, the Assay buffer: radioactive phosphorylation of a protein or peptide as Sub SOMEHEPES 3 mM magnesium chloride strate is measured using radioactively labelled ATP (P-ATP, 55 3M sodium orthovanadate P-ATP). In the case of the presence of an inhibitory com 3 mM manganese(II) chloride pound, a reduced radioactive signal, or none at all, can be 1 mM dithiothreitol (DTT) pH = 7.5 (to be set using sodium hydroxide) detected. Furthermore, homogeneous time-resolved fluores Stop solution: cence resonance energy transfer (HTR-FRET) and fluoroes 60 mM Titriplex III (EDTA) cence polarisation (FP) technologies can be used as assay 60 P-ATP: Perkin-Elmer; methods (Sills et al., J. of Biomolecular Screening, 2002, Metkinase: Upstate, Cat. No. 14-526, Stock 1 g/10 ul: spec. 191-214). activity 954 U/mg: Other non-radioactive ELISA assay methods use specific Poly-Ala-Glu-Lys-Tyr, 6:2:5:1: Sigma Cat. No. P1152 phospho-antibodies (phospho-ABs). The phospho-antibody only binds the phosphorylated substrate. This binding can be 65 In-Vivo Tests (Figure. 1/1) detected by chemiluminescence using a second peroxidase Experimental Procedure: Female Balb/C mice (breeder: conjugated antibody (Ross et al., 2002, Biochem. J.). Charles River Wiga) were 5 weeks old on arrival. They were US 9,403,799 B2 27 28 acclimatised to our keeping conditions for 7 days. Each are carried out in a 3L Silica-Rod column with a 210 second mouse was Subsequently injected Subcutaneously in the pel gradient from 20 to 100% waterfacetonitrile/0.01% of tri vic area with 4 million TPR-Met/NIH3T3 cells in 100 ul of fluoroacetic acid, at a flow rate of 2.2 ml/min, and detection PBS (without Ca++ and Mg++). After 5 days, the animals at 220 nm. were randomised into 3 groups, so that each group of 9 mice HPLC Analyses (Method A) had an average tumour volume of 110 ul (range: 55-165). 100 Column: Chromolith RP 18e 100.3 mm ul of vehicle (0.25% methylcellulose/100 mMacetate buffer, Flow rate: 2 ml/min pH 5.5) were administered daily to the control group, and 200 Solvent A: HO--0.1% of trifluoroacetic acid mg/kg of “A56” or A91 dissolved in the vehicle (volume Solvent B: acetonitrile+0.1% of trifluoroacetic acid likewise 100 ul/animal) were administered daily to the treat 10 Gradient 5 min ment groups, in each case by gastric tube. After 9 days, the 0-4 min: 99:1->1:99 controls had an average volume of 1530 uland the experiment 4-5 min: 1:99-1:99 was terminated. HPLC Analyses (Method B) Measurement of the Tumour Volume: The length (L) and 15 Column: Chromolith RP 18e 100.3 mm breadth (B) were measured using a Vernier calliper, and the Flow rate: 4 ml/min tumour volume was calculated from the formula LxBxB/2. Solvent A: HO--0.05% of HCOOH Keeping Conditions: 4 or 5 animals per cage, feeding with Solvent B: acetonitrile+10% of solvent A Gradient 8 min commercial mouse food (Sniff). 0-1 min: 99:1->99:1 The compounds A18 and A22 have a significant anti 1-7 min: 99:1-1:99 tumoural action. 7-8 min: 1:99->1:99 Above and below, all temperatures are indicated in C. In HPLC Analysis (Method C) the following examples, "conventional work-up” means: Flow rate: 2 ml/min water is added if necessary, the pH is adjusted, if necessary, to 25 99:01-0:100 water+0.1% (vol.) of TFA:acetonitrile+0.1% values between 2 and 10, depending on the constitution of the (vol.) of TFA end product, the mixture is extracted with ethyl acetate or 0.0 to 0.2 min: 99:01 dichloromethane, the phases are separated, the organic phase 0.2 to 3.8 min: 99:01-->0:100 3.8 to 4.2 min: 0:100 is dried over Sodium Sulfate and evaporated, and the residue is 30 purified by chromatography on silica gel and/or by crystalli Column: Chromolith Performance RP18e; 100 mm long, sation. Rf values on silica gel; eluent: ethyl acetate/methanol internal diameter 3 mm, wavelength: 220 nm 9:1. Retention time Rt in minutes min. Mass spectrometry (MS): EI (electron impact ionisation) M" EXAMPLE 1 (COMPARATIVE EXAMPLE) FAB (fast atom bombardment) (M--H)" 35 ESI (electrospray ionisation) (M+H) The preparation of the compounds APCI-MS (atmospheric pressure chemical ionisation-mass 6-(1-methyl-1H-pyrazol-4-yl)-2-3-5-(2-morpholin-4- spectrometry) (M--H)". ylethoxy)pyrimidin-2-yl)-benzyl-2H-pyridazin-3-one Mass spectrometry (MS): EI (electron impact ionisation) M" 40 (“A229), FAB (fast atom bombardment) (M--H)" 2-3-(5-bromopyrimidin-2-yl)benzyl-6-(1-methyl-1H ESI (electrospray ionisation) (M+H)" pyrazol-4-yl)-2H-pyridazin-3-one (A230) and APCI-MS (atmospheric pressure chemical ionisation-mass 2-3-(5-hydroxypyrimidin-2-yl)benzyl-6-(1-methyl-1H spectrometry) (M--H)". pyrazol-4-yl)-2H-pyridazin-3-one (A231) HPLC/MS Analyses is carried out analogously to the following scheme

O 21 C N CsCO3 S1S-N" " n - M - -N \ 2 Na2 N Br

N -e- n PoCl2(PPh3)2 KOACDMF Na2 Br US 9,403,799 B2 29 30 O -continued 21

N N s s Y n Sodium perborate -- -N N e N 2 B-1 O THF Water O

O 21 N N H O s N- N PPh/DIAD THF -N e N N 4\o 'A231' 21 O s N-N N r -NN2 Na2 ---

12.4 g (43.6 mmol) of 5-bromo-2-(3-chloromethylphenyl) 30 pyridazin-3-one in 55 ml of THF and 55 ml of water, and the pyrimidine and 14.2 g (43.6 mmol) of caesium carbonate are mixture is stirred at room temperature for 2 hours. The reac added to a suspension of 7.68 g (43.6 mmol) of 6-(1-methyl tion mixture is filtered through kiesel-Buhr with suction. The 1H-pyrazol-4-yl)-2H-pyridazin-3-one in 90 ml of DMF, and filtrate is concentrated to about half the original volume in the mixture is stirred at room temperature for 24 hours. The 35 vacuo and adjusted to a pH of 1 using 2 N hydrochloric acid. reaction mixture is added to 400 ml of water. The resultant The resultant precipitate is filtered off with suction, washed precipitate is filtered off with suction, washed with water and with water and dried in vacuo: 2-3-(5-hydroxypyrimidin-2- dried in vacuo: 2-3-(5-bromopyrimidin-2-yl)benzyl-6-(1- yl)benzyl-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3- methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one as yellow one as pale-beige crystals; m.p. 239°C.; ESI 361. brown crystals; m.p. 184° C.: ESI 423, 425. 40 394 mg (1.50 mmol) of triphenylphosphine and 242 ul 10.9 g (42.9 g) of bis(pinacolato)diboron and 9.72 g (99.0 (2.00 mmol) of 4-(2-hydroxyethyl)morpholine are added mmol) of potassium acetate are added to a suspension of 14.0 successively to a suspension of 360 mg (1.00 mmol) of 2-3- g(33.0 mmol) of 2-3-(5-bromopyrimidin-2-yl)benzyl-6-(1- (5-hydroxypyrimidin-2-yl)benzyl-6-(1-methyl-1H-pyra methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one in 65 ml of 45 Zol-4-yl)-2H-pyridazin-3-one in 2 ml of THF. 294 ul (1.50 DMF, and the mixture is heated to 70° C. under nitrogen. mmol) of diisopropylazodicarboxylate are then slowly added After stirring for 15 minutes at this temperature, 695mg (0.99 dropwise with ice-cooling. The resultant solution is stirred at mmol) of bis(triphenylphosphine)palladium(II) chloride are room temperature for 18 hours. The reaction mixture is added, and the reaction mixture is stirred at 70° C. under evaporated in vacuo, and the oily residue is dissolved in nitrogen for 18 hours. The reaction mixture is allowed to cool 50 2-propanol. The solid which forms after some time is filtered to room temperature, water and dichloromethane are added, off with suction, washed with 2-propanol and tert-butyl the mixture is filtered through kieselguhr, and the organic methyl ether and dried in vacuo: 6-(1-methyl-1H-pyrazol-4- phase is separated off. The organic phase is dried over sodium yl)-2-3-5-(2-morpholin-4-ylethoxy)pyrimidin-2-ylben Sulfate, evaporated, and the residue is recrystallised from 55 Zyl-2H-pyridazin-3-one (A229') as colourless crystals; 2-propanol: 6-(1-methyl-1H-pyrazol-4-yl)-2-3-5-(4.4.5.5- m.p. 134°C.: ESI 474; tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-ylben 'H-NMR (d-DMSO): 8 ppm=2.48 (m, 4H), 2.73 (t, Zyl-2H-pyridazin-3-one as grey crystals; m.p. 204°C.; J=5.5 Hz, 2H), 3.57 (m, 4H), 3.87 (s.3H), 4.30 (t, J=5.5 Hz, H-NMR (d-DMSO): 8 ppm=1.34 (s, 12H), 3.87 (s, 2H), 5.33 (s. 2H), 7.05 (d. J=9.5 Hz, 1H), 7.43 (dt, J–7.3 Hz, 3H), 5.35 (s. 2H), 7.05 (d. J=9.6 Hz, 1H), 7.52 (m, 2H), 7.80 60 J=1.5 Hz, 1H), 7.47 (t, J–7.5 Hz, 1H), 7.80 (d. J=9.5 Hz, 1H), (d. J=9.6 Hz, 1H), 7.89 (s, 1H), 8.21 (s, 1H), 8.35 (m, 1H), 7.89 (s.1H), 8.21 (s, 1H),8.22(dt, J–7.5 Hz, J-1.5 Hz, 1H), 8.45 (bs, 1H), 9.01 (s. 2H). 8.28 (bs, 1H), 8.64 (s. 2H). 8.50 g (85.1 mmol) of sodium perborate are added in por Salt formation from A229 gives the p-toluenesulfonate tions with ice-cooling to a suspension of 13.4 g (28.4 mmol) 65 and the phosphate. of 6-(1-methyl-1H-pyrazol-4-yl)-2-3-5-(4.4.5.5-tetram The following compounds are obtained analogously under ethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)benzyl-2H standard conditions

US 9,403,799 B2 33 34 -continued O 21

N

N

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 25 taining fractions are combined, evaporated, the residue is solid is filtered off with suction, washed with diethyl ether and 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. 30 ESI 493; 25 ml (25 mmol) of a 1 M solution of diisobutylaluminium 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 tertbutyl 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 35 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 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% 3-(1-3-5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2-yl)- benzyl-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, hydrobromide

US 9,403,799 B2 37 38 magnesium Stearate is pressed in a conventional manner to -continued give tablets in Such a way that each tablet contains 10 mg of active ingredient. No. Name A12 3-(1-3-5-(1-Methylpiperidin-4-ylmethoxy) EXAMPLE F: Dragees pyrimidin-2-yl)benzyl-6-oxo-1,6- dihydropyridazin-3-yl)benzonitrile, fumarate A13 3-(1-3-5-(1-Methylpiperidin-4-ylmethoxy) Tablets are pressed analogously to Example E and Subse pyrimidin-2-yl)benzyl-6-oxo-1,6- quently coated in a conventional manner with a coating of dihydropyridazin-3-yl)benzonitrile, maleate, and Sucrose, potato starch, talc, tragacanth and dye. A14 3-(1-3-5-(1-Methylpiperidin-4-ylmethoxy) 10 pyrimidin-2-yl)benzyl-6-oxo-1,6- EXAMPLE G: Capsules dihydropyridazin-3-yl)benzonitrile, p-tosylate 2 kg of active ingredient of the formula I are introduced into or a tautomer or Stereoisomer thereof. hard gelatine capsules in a conventional manner in Such away wherein the pharmaceutical formulation is in the form of that each capsule contains 20 mg of the active ingredient. 15 one or more dosage units, which is provided either as a single dose per day or in a series of doses of two or more EXAMPLE H: Ampoules per day so that the total daily dose would be the same as A solution of 1 kg of active ingredient of the formula I in 60 for the single dose per day, and 1 of bidistilled water is sterile filtered, transferred into wherein said single or series of daily doses comprise 0.5 ampoules, lyophilised under Sterile conditions and sealed mg to 1 g of said active ingredient, or under sterile conditions. Each ampoule contains 10 mg of 0.1 to 100 mg of said active ingredient per kg of body active ingredient. weight of the intended recipient mammal. 2. A method according to claim 1, wherein the pharmaceu The invention claimed is: 25 tical composition is in the form of said single or series of daily 1. A method for treating a disease which is influenced by doses and which comprise 1 mg to 700 mg of said active inhibition of Met kinase, wherein treating does not include ingredient, or 1 to 10 mg of said active ingredient per kg of prevention, or a method for stabilizing or improving the clini body weight of the intended recipient mammal. cal symptoms of a disease which is influenced by inhibition of 3. A method according to claim 1, wherein the pharmaceu Met kinase, 30 tical composition is in the form of said single dose and which comprising administering to a Subject having said disease a comprises 5 mg to 100 mg of said active ingredient. pharmaceutical composition, 4. A method according to claim 1, wherein the pharmaceu comprising tical composition contains 3-(1-3-5-(1-Methylpiperidin-4- a pharmaceutically acceptable carrier, and ylmethoxy)pyrimidin-2-yl)benzyl-6-oxo-1,6-dihydropy an active ingredient selected from the group consisting of 35 ridazin-3-yl)benzonitrile, hydrochloride monohydrate. 5. A method according to claim 1, wherein said disease is a Solid tumour. No. 6. A method according to claim 1, wherein said disease is a Solid tumour which originates from the group consisting of A1 -pyrazo (2-morpholi A ylethoxy)pyrimi 40 tumors of the squamous epithelium, the bladder, the stomach, the kidneys, of head and neck, the oesophagus, the cervix, the A2 thyroid, the intestine, the liver, the brain, the prostate, the hoxy)pyrimidin urogenital tract, the lymphatic system, the stomach, the lar idazin-3-one, meSylate A3 H-pyrazol-4-yl)-2-3-5- ynx and the lung. 4 hoxy)pyrimidin 45 7. A method according to claim 1, wherein said disease is a yridazin-3-one, besylate Solid tumour which originates from the group consisting of A4 H-pyrazol-4-yl)-2-3-5- monocytic leukaemia, lung adenocarcinoma, Small-cell lung 4 hoxy)pyrimidin -2H-pyridazin-3-one, p-tosylate carcinomas, pancreatic cancer, glioblastomas and breast car A5 hyl-1H-pyrazol-4-yl)-2-3-5- cinoma. hoxy)pyrimidin 50 8. A method according to claim 1, wherein said disease is a b e l Z. 2 yridazin-3-one, fumarate hyl-1H-pyrazol-4-yl)-2-3-5- Solid tumour which originates from the group consisting of ethoxy)pyrimidin lung adenocarcinoma, Small-cell lung carcinomas, pancreatic -2H-pyridazin-3-one, maleate cancer, glioblastomas, colon carcinoma and breast carci hylpiperidin-4-ylmethoxy) Oa. pyrimidin-2-yl)benzyl-6-oxo-1,6- 55 9. A method according to claim 1, wherein said disease is a idazin-3-yl)benzonitrile, hy rochloride tumour of the blood and immune system. A8 hylpiperidin-4-ylmethoxy) 10. A method according to claim 1, wherein said disease is pyrimidin-2-yl)benzyl-6-oxo-1,6- a tumour which originates from the group consisting of acute idazin-3-yl)benzonitrile, hydrobromide -Methylpiperidin-4-ylmethoxy) myeloid leukaemia, chronic myeloid leukaemia, acute lym pyrimidin-2-yl)benzyl-6-oxo-1,6- 60 phatic leukaemia and chronic lymphatic leukaemia. dihydropyridazin-3-yl)benzonitrile, mesylate 11. A method according to claim 1, further comprising A10 3-(1-3-5-(1-Methylpiperidin-4-ylmethoxy) administering a pharmaceutically active compound, which is pyrimidin-2-yl)benzyl-6-oxo-1,6- dihydropyridazin-3-yl)benzonitrile, besylate not a compound of claim 1. A11 3-(1-3-5-(1-Methylpiperidin-4-ylmethoxy) 12. A method according to claim 1, wherein the disease is pyrimidin-2-yl)benzyl-6-oxo-1,6- 65 a Solid tumour which originates from the group consisting of dihydropyridazin-3-yl)benzonitrile, malate tumors of the squamous epithelium, the bladder, the stomach, the kidneys, of head and neck, the oesophagus, the cervix, the US 9,403,799 B2 39 40 thyroid, the intestine, the liver, the brain, the prostate, the 17. A method according to claim 13, wherein said disease urogenital tract, the lymphatic system, the stomach, the lar is a tumour of the blood and immune system. ynx and the lung, or the disease is a solid tumour which originates from the group consisting of monocytic leukaemia, 18. A method according to claim 13, wherein said disease lung adenocarcinoma, Small-cell lung carcinomas, pancreatic is a tumour which originates from the group consisting of cancer, glioblastomas and breast carcinoma, or the disease is acute myeloid leukaemia, chronic myeloid leukaemia, acute a Solid tumour which originates from the group consisting of lymphatic leukaemia and chronic lymphatic leukaemia. lung adenocarcinoma, Small-cell lung carcinomas, pancreatic 19. A method according to claim 1, which is for stabilizing cancer, glioblastomas, colon carcinoma and breast carci or improving the clinical symptoms of a disease which is noma, or the disease is a tumour of the blood and immune system, or the disease is a tumour which originates from the 10 influenced by inhibition of Met kinase. group consisting of acute myeloid leukaemia, chronic 20. A method according to claim 19, wherein the disease is myeloid leukaemia, acute lymphatic leukaemia and chronic a Solid tumour which originates from the group consisting of lymphatic leukaemia. tumors of the squamous epithelium, the bladder, the stomach, 13. A method according to claim 1, which is for treating a the kidneys, of head and neck, the oesophagus, the cervix, the disease which is influenced by inhibition of Met kinase, 15 thyroid, the intestine, the liver, the brain, the prostate, the wherein treating does not include prevention. urogenital tract, the lymphatic system, the stomach, the lar 14. A method according to claim 13, wherein said disease ynx and the lung, or the disease is a solid tumour which is a solid tumour. originates from the group consisting of monocytic leukaemia, 15. A method according to claim 13, wherein said disease is a solid tumour which originates from the group consisting lung adenocarcinoma, Small-cell lung carcinomas, pancreatic of tumors of the squamous epithelium, the bladder, the stom cancer, glioblastomas and breast carcinoma, or the disease is ach, the kidneys, of head and neck, the oesophagus, the cer a Solid tumour which originates from the group consisting of vix, the thyroid, the intestine, the liver, the brain, the prostate, lung adenocarcinoma, Small-cell lung carcinomas, pancreatic the urogenital tract, the lymphatic system, the stomach, the cancer, glioblastomas, colon carcinoma and breast carci larynx and the lung. 25 noma, or the disease is a tumour of the blood and immune 16. A method according to claim 13, wherein said disease system, or the disease is a tumour which originates from the is a solid tumour which originates from the group consisting group consisting of acute myeloid leukaemia, chronic of monocytic leukaemia, lung adenocarcinoma, Small-cell myeloid leukaemia, acute lymphatic leukaemia and chronic lung carcinomas, pancreatic cancer, glioblastomas, colon car lymphatic leukaemia. cinoma and breast carcinoma. k k k k k