(19) TZZ _¥_Z_T (11) EP 2 817 310 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/496 (2006.01) A61K 31/519 (2006.01) 21.03.2018 Bulletin 2018/12 A61K 31/537 (2006.01) A61K 31/5377 (2006.01) A61K 31/55 (2006.01) A61K 31/5513 (2006.01) (2006.01) (2006.01) (21) Application number: 13700849.6 C07D 487/04 C07D 519/00 A61K 31/5386 (2006.01) (22) Date of filing: 22.01.2013 (86) International application number: PCT/EP2013/000189 (87) International publication number: WO 2013/124026 (29.08.2013 Gazette 2013/35) (54) 8-SUBSTITUTED 2-AMINO-[1,2,4]TRIAZOLO[1,5-A]PYRAZINES AS SYK TRYROSINE KINASE INHIBITORS AND GCN2 SERIN KINASE INHIBITORS 8-SUBSTITUIERTE 2-AMINO-[1,2,4-]TRIAZOLO-[1,5-A-]PYRAZINE ALS SYK-TRYROSIN-KINASEHEMMER UND GCN2-SERIN-KINASEHEMMER 2-AMINO-[1,2,4]TRIAZOLO[1,5-A]PYRAZINES SUBSTITUÉES EN 8ÈME POSITION EN TANT QU’INHIBITEURS DE LA TYROSINE KINASE SYK ET EN TANT QU’INHIBITEURS DE LA SÉRINE KINASE GCN2 (84) Designated Contracting States: • KUHN, Daniel AL AT BE BG CH CY CZ DE DK EE ES FI FR GB 64380 Rossdorf (DE) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • ROSS,Tatjana PL PT RO RS SE SI SK SM TR 65760 Eschborn (DE) • BURGDORF, Lars (30) Priority: 21.02.2012 EP 12001153 60385 Frankfurt am Main (DE) (43) Date of publication of application: (56) References cited: 31.12.2014 Bulletin 2015/01 WO-A1-2009/155551 WO-A1-2011/006903 WO-A1-2011/086098 WO-A1-2011/086099 (73) Proprietor: Merck Patent GmbH WO-A1-2012/025186 64293 Darmstadt (DE) • WERMUTH C G: "MOLECULAR VARIATIONS (72) Inventors: BASED ON ISOSTERIC REPLACEMENTS", • DEUTSCH, Carl PRACTICE OF MEDICINAL CHEMISTRY, XX, XX, 64287 Darmstadt (DE) 1996, pages 203-237, XP002190259, Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 817 310 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 817 310 B1 Description BACKGROUND OF THE INVENTION 5 [0001] The invention had the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments. [0002] The present invention relates to compounds and to compounds for use in which the inhibition, regulation and/or modulation of signal transduction by kinases, in particular tyrosine kinases, furthermore to pharmaceutical compositions which comprise these compounds, and to compounds for use for the treatment of kinase-induced diseases. 10 Becauseprotein kinases regulate nearly every cellular process, including metabolism, cell proliferation,cell differentiation, and cell survival, they are attractive targets for therapeutic intervention for various disease states. For example, cell- cycle control and angiogenesis, in which protein kinases play a pivotal role are cellular processes associated with numerous disease conditions such as but not limited to cancer, inflammatory diseases, abnormal angiogenesis and diseases related thereto, atherosclerosis, macular degeneration, diabetes, obesity, and pain. 15 One of the key events in the signaling pathway following the activation of mast cells is activation of the tyrosine kinase Syk. Mast cells play a critical role in asthma and allergic disorders by releasing pro-inflammatory mediators and cytokines. Antigen-mediated aggregation of Fc εRJ, the high-affinity receptor for IgE, results in activation of mast cells. This triggers a series of signaling events resulting in the release of mediators, including histamine, proteases, leukotrienes and cytokines. These mediators cause increased vascular permeability, mucus production, bronchoconstriction, tissue deg- 20 radation and inflammation, thus playing key roles in the etiology and symptoms of asthma and allergic disorders. Syk kinase acts as a central initiator of all subsequent signaling leading to mediator release. The critical role of Syk kinase in the signaling path was demonstrated by the complete inhibition of mediator release by a protein containing the SH2 domains of Syk kinase that functioned as an inhibitor of Syk kinase (J. A.Taylor et al, Molec. and Cell Biol, 15: 4149-4157 (1995). 25 Syk (Spleen-Tyrosine-Kinase) is a 72 kDa non-receptor tyrosine kinase belonging to the subfamily of intracellular tyrosine kinases that comprises ZAP70, Pyk2, Abl, Tie2, KDR and HER, among others. Syk is a major regulator of FcR (Fc γRI, II, III, FcεRI, FcαR) and BCR signaling and is expressed throughout hematopoietic lineage, as well as in fibroblasts, osteoclasts, hepatocytes, epithelial and neuronal cells. In addition to the C terminal kinase domain, SYK exhibits two SH2 domains and over 10 autophosphorylation sites 1. 30 [0003] By means of both its SH2 domains SYK is specifically recruited to phosphorylated ITAMsI mmunoreceptor( Tyrosine-based Activation Motifs present in immunoreceptors such as Fc γRI, IIA, IIIA, Fc αR, FcεRI and BCR, expressed by monocytes, macrophages, mast cells, neutrophils and B cells) and specifically mediates immunoreceptor signaling triggered by activation of those receptors in mast cells, B cells, macrophages, monocytes, neutrophils, eosinophils, NK cells, DC cells platelets and osteoclasts1,2. 35 [0004] Upon BCRcross linking,tyrosine residuesat the ITAM motifs of the cytosolictail ofthe Ig α /Igβ are phosphorylated by the Src-family kinase Lyn, generating docking sites for SYK that is thus recruited to the BCR immunocomplex. SYK is then phosphorylated and activated by the Src-family kinase Lyn. Upon activation, SYK will phosphorylate the adaptor protein BLNK allowing its interaction with both BTK and PLC γ2 via their respective SH2 domains. SYK phosphorylated 2+ -and thus activated- BTK will in turn phosphorylate and activate PLC γ2 leading to IP 3 formation, Ca mobilization, PKC 40 and MAPK activation and consequent NFAT, AP-1 and NFκB transcription factor activation, resulting in activation and surface marker expression, cytokine release, survival and proliferation of B cells 3. In mast cells, allergen activated Fc εRI is phosphorylated by LYN and FYN and recruits SYK which is in turn phosphorylated by LYN and further autophospho- rylated, becoming fully activated. Activated SYK phosphorylates the two adaptor molecules NTAL and LAT creating more docking sites for SH2 containing proteins such as PLCγ1, vav, and the p85 regulatory subunit of PI3K, resulting 45 in mast cell degranulation and cytokine production4. Syk’s critical role in signal transduction of mast cells is confirmed by reproducible observation that the 10-15% of basophils (circulating mast cells) from human donors that cannot de- granulate have reduced amounts of Syk protein5,6. In addition, SYK is required for the bone resorption activity of oste- oclasts. Upon stimulation of osteoclasts by αvβ3 integrin, SYK becomes phosphorylated, most likely by c-Src, in a DAP- 12 / FcγRII dependent mechanism, leading to SPL-76 and Vav3 phosphorylation and subsequent cytoskeletal reorgan- 50 isation. SYK deficient osteoclasts are inactive and show defective cytoskeletal reorganisation. In correlation with this, SYK deficient embryos show defective skeletal mass 7,8. [0005] BCR-mediated activation of B-cells in the lymph nodes, as well as FcR-mediated activation of dendritic cells, monocytes, macrophages, neutrophils and mast cells in the joints, are essential components of the cellular patho- physiological mechanisms taking place during rheumaoid arthritis (RA). Moreover, activation of osteoclasts leads to the 55 bone and cartilage destruction which are hallmarks of this pathology 9. SYK signaling should therefore play a pivotal role during the development of arthritis, both at the periphery and on the site of inflammation10. Indeed, an orally available Syk inhibitor R406 -developed by Rigel- induced a significant improvement of clinical scores and significantly reduced serum cytokine concentrations, as well as bone erosion, in a murine model of RA 11,12. Moreover, this inhibitor has shown 2 EP 2 817 310 B1 efficacy (ACR scores improvement) and good tolerability in RA Phase II studies in humans 13,14,15. [0006] In SLE B cells contriubute essentially towards pathogenesis via production of autoanibodies resulting in immune complex formation, stimulation of Fc receptors and finally in an excessive and chronic activation of inflammation. In a murine model of SLE treatment with a Syk inhibitor resulted in a reduction of numbers of class-switched germinal center, 5 marginal zone, newly formed and follicular B cells and therefore in disease mitigating effects 18. Although TCR signals are transmited by the intracellular tyrosine kinase ZAP-70 in thymocytes and naïve T cells, several studies indicate that differentiated effector T cells, such as those involved in the pathophysiology of Multiple sclerosis (MS) or systemic lupus erythematosus (SLE), show a down regulation of the TCRzeta chain and a concomitant upreg- ulation of the TCR/CD3 chain and its interaction with FcR γ. Those studies show that the TCR/CD3/FcRgamma complex 10 in effector cells recruits and activates Syk, instead of ZAP-70, tyrosine kinase. This physiologic switch in TCR signaling occurs exclusively in effector, and not naive or memory T cells 16,17,18. Not surprisingly then, SYK inhibitors have been shown to delay disease progression and to improve survival in murine models of SLE17,18,19,10,21. [0007] SYK inhibitors may also find a use in asthma, allergy, multiple sclerosis and other diseases such as thrombo- cytopenia purpura and T or B cell lymphomas 1,10,14,22-35. 15 Treatment of prediseased NZB/W mice with a Syk inhibitor prevented the development of renal disease demonstrated by reduced glomerular sclerosis, tubular damage, proteinuria and BUN levels 18.