Triazolo[4,5-d]pyrimidine derivatives

专利摘要:
Compounds of the formula (I) in which R1 and R2 have the meanings indicated in Claim 1, are inhibitors of GCN2, and can be employed, inter alia, for the treatment of cancer.
公开号:AU2012367141A1
申请号:U2012367141
申请日:2012-12-21
公开日:2014-09-11
发明作者:Dieter Dorsch；Guenter Hoelzemann；Kai Schiemann；Ansgar Wegener
申请人:Merck Patent GmbH；
IPC主号:C07D487-04

专利说明:
WO 2013/110309 PCT/EP2012/005358 Triazolo[4,5-d]pyrimidine derivatives BACKGROUND OF THE INVENTION 5 The invention had the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments. The present invention relates to compounds and to the use of compounds in 10 which the inhibition, regulation and/or modulation of signal transduction by protein kinases, in particular immune-modulatory or stress response kinases, furthermore to pharmaceutical compositions which comprise these compounds, and to the use of the compounds for the treatment of kinase-induced diseases. 15 Because protein 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, immune modulation, stress response and 20 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, neurodegenerative diseases, chronic infections, abnormal angiogenesis and diseases related thereto, atherosclerosis, macular 25 degeneration, diabetes, obesity, and pain. Compounds of formula I inhibit the stress response elF2 kinase EIF2AK4 called general control nonderepressible 2 (GCN2). 30 Many strategies of cancer treatment of solid tumors focus on the surgically removal of the tumor mass as far as possible and the subsequent eradication of any residual tumor cells by radiotherapy and chemotherapy with cytotoxic agents or inhibitors that target cancer cell pathways more specifically. 35 However, the success of such approach is limited and often does not persist. This is mainly due to the narrow therapeutic window for such cytotoxic agents WO 2013/110309 PCT/EP2012/005358 -2 (specificity and side effects) and to the capability of cancer calls to adapt to the selective pressure applied by cytotoxic or other inhibitory agents. The survival of a small number of tumor (stem) cells that acquired resistance to the initial treatment can be sufficient to seed the regrowth of a tumor. These relapses 5 are in most cases more difficult to treat compared to that of the initial tumors. As a consequence the more successful targeting of tumor cells may require targeting multiple survival and escape mechanism of tumor cells in parallel (Muller & Prendegast 2007). 10 Development of malignancies is accompanied by a major roll up of the cellular physiology. During this process several qualities are acquired by the cancer cells that are basis for immortalization or insensitivity to growth inhibitory signals. In addition the tumor cells also modify the interaction with 15 the microenvironment and beyond. The latter area includes the strategies of tumor cells to escape from the immunological surveillance (Muller & Prendegast 2007). The immune surveillance limits malignant growth but also provides a selective pressure triggering the evolution of mechanisms 20 for evading the immune response as reviewed by [Dunn et al. 2004]. Essentially it has been frequently observed that ablation of T cell immunity is sufficient to increase tumor incidence [Shankaran et al. 2001] and it is believed that immune escape is affecting tumor dormancy versus progression, promoting invasion and metastasis and negatively impacts on 25 therapeutic response. Several mechanistic studies discovered that immune escape has an important interface with metabolic alterations within the tumor microenvironment. Here important roles in mediating immune tolerance to antigens have been 30 associated to the catabolism of the essential amino acids tryptophan and arginine, carried out by the enzymes indoleamine 2,3-dioxygenase (IDO) and arginase I (ARG), respectively (Bronte and Zanovello, 2005; Muller et al., 2005b; Muller and Prendergast, 2007; Munn and Mellor, 2007; Popovic et al., 35 2007).
-- WO 2013/110309 PCT/EP2012/005358 -3 IDO is a single-chain oxidoreductase that catalyzes the degradation of tryptophan to kynurenine. IDO is not responsible for catabolizing excess dietary tryptophan but to modulate tryptophan level in a local environment. Elevations in tryptophan catabolism in cancer patients manifest in significantly 5 altered serum concentration of tryptophan or catabolites and this was correlated to IDO which is commonly elevated in tumors and draining lymph nodes. According to several publications IDO over-expression is associated with poor prognosis in cancer [Okamoto et al 2005; Brandacher et al, 2006]. 10 T cells appear to be preferentially sensitive to IDO activation, such that when starved for tryptophan they cannot divide and as a result cannot become activated by an antigen presented to them. Munn and Mellor and their colleagues, revealed that IDO modulates immunity by suppressing T-cell 15 activation and by creating peripheral tolerance to tumor antigens (Mellor and Munn, 2004). These mechanism encompass the subversion of immune cells recruited by the tumor cell to its immediate microenvironment or to the tumor draining lymph nodes Here the tumor antigens that were scavenged by antigen-presenting cells are cross-presented to the adaptive immune system. 20 In addition to being directly toleragenic, mature DCs have the capacity to expand regulatory Tcells (Tregs) [Moser 2003]. Beside tryptophan catabolism the conversion of arginine is increased in a tumor-conditioned microenvironment, and numerous reports indicate a role for 25 the activation of arginases during tumor growth and development. In tumor infiltrating myeloid cells, arginine is converted by arginase I (ARG1), arginase i (ARG2) to urea and ornithine and oxidized by the inducible form of nitric oxide synthase (NOS2) to citrulline and nitric oxide (NO). 30 Increased ARG activity is frequently observed in patients with colon, breast, lung, and prostate cancer [Cederbaum 2004] correlating with the over expression of ARG and NOS found in prostate cancers [Keskinege et al. 2001, Aaltoma et al. 2001, Wang et al. 2003]. It was shown that ARG activity in infiltrating macrophages impairs antigen-specific T cell responses and the 35 expression of the CD3 receptor. Moreover the cumulative activity of ARG and NOS in tumor associated myeloid cells can generate inhibitory signals to WO 2013/110309 PCT/EP2012/005358 -4 antigen-specific T lymphocytes that eventually lead to apoptosis [Bronte 2003 a; 2003b]. Both, the IDO and the ARG related mechanism merge at the point of sensing the depleted concentration of the respective amino acid concentration. During 5 amino acid deprivation, the elF2 kinase EIF2AK4 called general control nonderepressible 2 (GCN2) is interacting with the intracellular accumulating deacylated tRNA. As a consequence the GCN2 is assumed to change from an auto-inhibited to an active conformation and further activate by auto 10 phosphorylation. Then the only known substrate protein elF2a becomes phosphorylated and as a consequence the complex for translation initiation is inhibited [Harding et al. 2000,]. This diminishes the general Cap-dependent translation initiation and by this the corresponding protein production. On the 15 other hand this induces the specific expression of stress related target genes mainly by cap-independent initiation via the activating transcription factor 4 (ATF4). By expressing the respective stress response proteins, e.g. enzymes in the in amino acid metabolism, the cell tries to compensate the particular cell stress [Wek et al. 2006]. If the stress persists, the same pathway will switch to 20 promoting cell death via transcription of the pro-apoptotic transcription factor, CCAAT/enhancer-binding protein homologous protein (CHOP) [Oyadomari 2004]. It was shown that, tryptophan starvation triggers a GCN2- dependent stress signaling pathway In T cells altering elF2aphosphorylation and 25 translational initiation leading to a cell growth arrest (Munn et al. 2005). Sharma, et al. [2007] published on the direct IDO-induced and GCN2 dependent activation of mature Tregs. Similarly Fallarino et al [2006] found a GCN2-dependent conversion of CD4+CD25- cells to CD25+FoxP3+ Tregs 30 producing IL-10 and TGFOI. Rodriguez et al. [2007] identified that activation of the GCN2 pathway via tryptophan or arginine depletion in combination with TCR signaling leads to CD30 chain down regulation, cell cycle arrest and anergy. 35 Importantly the GCN2 pathway is not only important for the tumoral immune escape but also plays an active role in modulating tumor survival directly. Ye et WO 2013/110309 PCT/EP2012/005358 -5 al [2010] found that the aforementioned transcription factor ATF4 is over expressed inhuman solid tumors, suggesting an important function in tumour progression. Amino acid and glucose deprivation are typical stresses found in solid tumours and activated the GCN2 pathway to up-regulate ATF4 target 5 genes involved in amino acid synthesis and transport. GCN2 activation / overexpression and increased phospho-elF2a were observed in human and mouse tumors compared with normal tissues and abrogation of ATF4 or GCN2 expression significantly inhibited tumor growth in vivo. It was concluded that 10 the GCN2-elF2a-ATF4 pathway is critical for maintaining metabolic homeostasis in tumor cells. Over all the present biology makes an interference with the ARG/IDO pathway 15 attractive for braking up the tumoral immune escape by adaptive mechanism. The interference of GCN2 function is here of particular interest as it is a merging point of the two pathways, the IDO and ARG, as well as it provides additional opportunities to impede with the tumor metabolism directly. 20 Several pathway inhibitors are already considered as immune modulators. These inhibitors address mainly the enzymatic function of the IDO or ARG proteins (Muller and Scherle, 2006). The application of the arginase inhibitor, N-hydroxy-nor-L-Arg blocks growth of s.c. 3LL lung carcinoma in mice 25 [Rodriguez 2004]. The NO-donating aspirins like NCX 4016 (2-(acetyloxy) benzoic acid 3-(nitrooxymethyl) phenyl ester) have been reported to interfere with the inhibitory enzymatic activities of myeloid cells. Orally administered NO aspirin normalized the immune status of tumor-bearing hosts, increased the 30 number and function of tumor-antigen-specific T lymphocytes, and enhanced the preventive and therapeutic effectiveness of the antitumor immunity elicited by cancer vaccination (DeSanto 2005). The substrate analogue 1 methyl-tryptophan (1MT) and related molecules have been used widely to target IDO in the cancer context and other settings. 35 Studies by Friberg et al. (2002) and Uyttenhove et al. (2003) demonstrated that 1 MT can limit the growth of tumors over-expressing IDO. However 1 MT WO 2013/110309 PCT/EP2012/005358 -6 was unable to elicit tumor regression in several tumor models, suggesting only modest antitumor efficacy when IDO inhibition was applied as a monotherapy. In contrast, the combinatory treatment with 1MT and a variety of cytotoxic chemotherapeutic agents elicited regression of established MMTV-neu/HER2 5 tumors, which responded poorly to any single-agent therapy [Muller et al 2005a]. Immunodepletion of CD4+ or CD8+ T cells from the mice, before treatment abolished the combinatorial efficacy observed in this model, confirming the expectation that 1 MT acted indirectly through activation of T 10 cell-mediated antitumor immunity. Important evidence that IDO targeting is essential to 1 MT action was provided by the demonstration that 1 MT lacks antitumor activity in mice that are genetically deficient for IDO [Hou et al., 2007] 15 The inhibition of GCN2 would enable to combine the two pathway branches of amino acid starvation induced immunoediting and would reduce the options for the tumor to circumvent the inhibition of either branch. Moreover, as detailed above, the GCN2 inhibition provides the opportunity for interfering with the tumor metabolism at the same time what may enhance the efficacy of a 20 monotherapy or a combination therapy with other anticancer approaches. As mentioned above, the elF2 kinase GCN2 is activated by interacting with deacylated tRNA that is accumulating as direct consequence of nutritional 25 deprivation stress. Other cellular stress factors like UV irridation, redox stress or proteasome inhibition can induce GCN2 activation indirectly [Wek et al 2006]. In all known cases elF2a becomes phosphorylated and this induces the specific expression of stress related target genes mainly by cap 30 independent initiation via the activating transcription factor 4 (ATF4). .Mitsuda et al (2007) showed that presenilin-1 is induced by activating transcription factor 4 (ATF4), regulated by GCN2. Accumulation of amyloid-p (AP), which is generated from amyloid precursor protein by y-secretase, in cerebral cortex is common and critical incident in Alzheimer disease. 35 Specifically, presenilin is an essential for y-secretase activity. Ohata et al.
WO 2013/110309 PCT/EP2012/005358 -7 (2010) describe a role of GCN2-elF2a-ATF4 signaling in the regulation of y secretase activity in autophagy impaired cells: The impairment of the autophagy-lysosomal system may cause amino acid imbalance in the cell because autophagy is required for maintenance of amino acid level. The autophagy-lysosomal system is discussed as a vital modulator of y-secretase activity through GCN2, leading to As accumulation in autophagy deterioration, which may be a possible therapeutic target for reducing As production. y Secretase plays an important role in the development of Alzheimer disease 10 (AD). y-Secretase activity is enriched in autophagic vacuoles and it augments amyloid-P (AP) synthesis. Senile plaques are primarily composed of p-amyloid peptides (AP) derived from amyloid precursor protein (APP) that has undergone proteolytic 15 processing by P-secretase (BACE-1) and y-secretase. O'Connor et al.(2008) found that BACE-1 levels are translationally increased by phosphorylation of elF2a. 20 Inhibition of GCN2 under such disease conditions that promote activation of y secretase or induction of BACE-1 with consequence of accumulation of As and plaque formation in the brain would provide a valuable avenue to temper or even stop the progression of neurodegenerative diseases. 25 It was described that persistent, not acute, parasite or viral infections are associated to the establishment of immune privileged conditions of even immune competent host towards the infectious organism or particles. This has been associated to the local induction of IDO expression. Makala et al (J Infect 30 Dis. 2011 Mar 1;203(5):715-25) show that cutaneous Leishmania major infection stimulated expression of the immune regulatory enzyme indoleamine 2,3 dioxygenase ([DO) in local lymph nodes. Induced IDO attenuated the T cell stimulatory functions of dendritic cells and suppressed local T cell responses 35 to exogenous and nominal parasite antigens. IDO ablation reduced local inflammation and parasite burdens, as did pharmacologic inhibition of IDO in WO 2013/110309 PCT/EP2012/005358 -8 mice with established infections. de Souza Sales (Clin Exp Immunol. 2011 Aug;165(2):251- 6 3) corroborated the role of indoleamine 2, 3-dioxygenase in lepromatous leprosy immunosuppression. Boasso et al (Blood. 2007 Apr 15;109(8):3351-9) found that HIV inhibits CD4+ T-cell proliferation by inducing 5 indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells and that in vitro inhibition of IDO results in increased CD4(+) T-cell proliferative response in PBMCs from HIV-infected patients Inhibitor drugs of the IDO/GCN2 pathway could be used to enhance host 10 immunity to chronic and persistent infections. Literature: 1. Aaltoma, S.H., P.K. Lipponen, and V.M. Kosma. 2001. Inducible nitric oxide 15 synthase (iNOS) expression and its prognostic value in prostate cancer. Anticancer Res. 21:3101-3106. 2. Brandacher, G.; Perathoner, A.; Ladurner, R.; Schneeberger, S.; Obrist, P.; Winkler, C.; Werner, E. R.; Wemer-Felmayer, G.; Weiss, H. G.; Gobel, G.; Margreiter, R.; Konigsrainer, A.; Fuchs, D.; Amberger, A. Prognostic value of 20 indoleamine 2,3- dioxygenase expression in colorectal cancer: effect on tumorinfiltrating T cells. Clin. Cancer Res. 2006, 12, 1144-1151. 3. Bronte V, Zanovello P. (2005). Regulation of immune responses by L arginine metabolism. Nat Rev Immunol 5: 641-654. 25 4. Bronte, V., P. Serafini, C. De Santo, I. Marigo, V. Tosello, A. Mazzoni, D.M. Segal, C. Staib, M. Lowel, G. Sutter, et al. 2003a. IL-4- induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. J. Immunol. 170:270 278. 30 5. Bronte, V., P. Serafini, A. Mazzoni, D.M. Segal, and P. Zanovello. 2003b. L arginine metabolism in myeloid cells controls T-lymphocyte functions. Trends Immunol. 24:302-306 6. Carmela De Santo, Paolo Serafini, Ilaria Marigo, Luigi Dolcetti, Manlio Bolla,§ Piero Del Soldato, Cecilia Melani, Cristiana Guiducci, Mario P. 35 Colombo, Manuela lezzi, Piero Musiani, Paola Zanovello, and Vincenzo Bronte. Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and WO 2013/110309 PCT/EP2012/005358 -9 promotes tumor eradication by cancer vaccination. Proc Nati Acad Sci U S A. 2005 March 15; 102(11): 4185-4190 7. Cederbaum, S.D., H. Yu, W.W. Grody, R.M. Kern, P. Yoo, and R.K. Iyer. 2004. Arginases I and II: do their functions overlap Mol. Genet. Metab. 5 81:S38-44. 8. T. O'Connor, K.R. Sadleir, E. Maus, R.A. Velliquette, J. Zhao, S.L. Cole, W.A. Eimer, B. Hitt, L.A. Bembinster, S. Lammich, S.F. Lichtenthaler, S.S. Hebert, S.B. De, C. Haass, D.A. Bennett, R. Vassar, Phosphorylation of the 10 translation initiation factor elF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron, 60 (2008), pp. 988-1009 9. Dey, M., Cao, C., Sicheri, F. and T.E. Dever. Conserved Intermolecular Salt Bridge Required for Activation of Protein Kinases PKR, GCN2, and PERK. 15 JBC 282(9): 6653, 2007. 10. Dunn, G. P.; Old, L. J.; Schreiber, R. D. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004, 21, 137-148. 11. Fallarino, F. U. Grohmann, S. You, B.C. et al. The combined effects fo tryptophan starvation and tryptophan catabolites down-regulate T cell receptor 20 zeta-chain and induce a regulatory phenotype in naive T cells. J. Immunol. 176:6752, 2006. 12. Friberg M, Jennings R, Alsarraj M, Dessureault S, Cantor A, Extermann M et al. (2002). Indoleamine 2,3-dioxygenase contributes to tumor 25 cell evasion of T cell-mediated rejection. Int. J Cancer 101: 151-155 13. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000 Nov;6(5):1099-108. 30 14. Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M et al. (2007). Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res 67: 792-801. 15. Keskinege, A., S. Elgun, and E. Yilmaz. 2001. Possible implications of 35 arginase and diamine oxidase in prostatic carcinoma. Cancer Detect. Prev. 25:76-79.
WO 2013/110309 PCT/EP2012/005358 - 10 16. Mellor AL, Munn DH. (2004). IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4: 762-774. 17. Mitsuda T, Hayakawa Y, Itoh M, Ohta K, Nakagawa T. ATF4 regulates gamma-secretase activity during amino acid imbalance, Biochem Biophys Res 5 Commun. 2007 Jan 19;352(3):722-7. 18. Moser, M. Dendritic cells in immunity and tolerance-do they display opposite functions Immunity 2003, 19, 5-8. 19. Muller, A.J. and P.A. Scherle. Targeting the mechanisms of tumoral 10 immune tolerance with small-molecule inhibitors. Nat. Rev. Cancer. 6:613, 2006. 20. Muller AJ, Prendergast GC. (2007). Indoleamine 2,3-dioxygenase in immune suppression and cancer. Curr Cancer Drug Targets 7: 31-40. 15 21. Muller AJ, DuHadaway JB, Sutanto-Ward E, Donover PS, Prendergast GC. (2005a). Inhibition of indoleamine 2,3-dioxygenase, an immunomodulatory target of the tumor suppressor gene Bin1, potentiates cancer chemotherapy. Nature Med 11: 312-319. 22. Muller AJ, Malachowski WP, Prendergast GC. (2005b). Indoleamine 20 2,3-dioxygenase in cancer: targeting pathological immune tolerance with smalk molecule inhibitors. Expert Opin Ther Targets 9: 831-849. 23. Munn, D.H., M.D. Sharma, B. Baban, H.P. Harding, Y. Zhang, D. Ron, A.L. Mellor. GCN2 kinase in T cells mediates proliferative arrest and anergy 25 induction in response to indoleamine 2,3-dioxygenase. Immunity. 22:633, 2005 24. Ohta K, Mizuno A, Ueda M, Li S, Suzuki Y, Hida Y, Hayakawa-Yano Y, Itoh M, Ohta E, Kobori M, Nakagawa T. Autophagy impairment stimulates PS1 30 expression and gamma-secretase activity. Autophagy. 2010 ;6(3):345-52 25. Okamoto, A.; Nikaido, T.; Ochiai, K.; Takakura, S.; Saito, M.; Aoki, Y.; Ishii, N.; Yanaihara, N.; Yamada, K.; Takikawa, 0.; Kawaguchi, R.; Isonishi, S.; Tanaka, T.; Urashima, M. Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin. 35 Cancer Res. 2005, 11, 6030-6039.
WO 2013/110309 PCT/EP2012/005358 - 11 26. Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2004 Apr; 11(4):381-9. 27. GC Prendergast, Immune escape as a fundamental trait of cancer: focus on IDO. Oncogene (2008) 27, 3889-3900 5 28. Popovic PJ, Zeh Ill HJ, Ochoa JB. (2007). Arginine and immunity. J Nutr 137: 1681S-1686 S. 29. Rodriguez, P.C., D.G. Quiceno, J. Zabaleta, B. Ortiz, A.H. Zea, M.B. Piazuelo,A.Delgado, P.Correa, J.Brayer, E.M. Sotomayor, S.Antonia, J.B. 10 Ochoa, and A.C. Ochoa. Arginase I Production in the Tumor Microenvironment by Mature Myeloid Cells Inhibits T-Cell Receptor Expression and Antigen-Specific T-Cell Responses. Canc. Res. 64:5839, 2004 30. Rodriguez, P.C., D.G. Quiceno, and A.C. Ochoa. L-arginine 15 availability regulates T-lymphocyte cell-cycle progresi6n. Blood. 109:1568, 2007. 31. Shankaran, V.; Ikeda, H.; Bruce, A. T.; White, J. M.; Swanson, P. E.; Old, L. J.; Schreiber, R. D. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001, 410, 20 1107-1111. 32. Sharma, M.D., B. Baban, P. Chandler, D-Y. Hou, N. Singh, H. Yagita, M. Azuma, B.R. Blazar, A.L. Mellor, and D.H. Munn. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs 25 via indoleamine 2,3-dioxygenase. J. Clin. Invest. 117:2570, 2007. 33. Uyttenhove C, Pilotte L, Theate 1, Stroobant V, Colau D, Parmentier N et al. (2003). Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3- dioxygenase. Nat Med 9: 1269 30 1274 34. Wang, J., M. Torbenson, Q. Wang, J.Y. Ro, and M. Becich. 2003. Expression of inducible nitric oxide synthase in paired neoplastic and non neoplastic primary prostate cell cultures and prostatectomy specimen. Urol. Oncol. 21:117-122. 35 35. Wek RC, Jiang HY, Anthony TG. Coping with stress: elF2 kinases and translational control. Biochem Soc Trans. 2006 Feb;34 (Pt 1):7-11.
WO 2013/110309 PCT/EP2012/005358 - 12 36. Ye J, Kumanova M, Hart LS, Sloane K, Zhang H, De Panis DN, Bobrovnikova-Marjon E, Diehl JA, Ron D, Koumenis C. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J. 2010 Jun 16;29(12):2082-96. 5 In particular, the present invention relates to compounds and to the use of compounds in which the inhibition, regulation and/or modulation of signal 10 transduction by GCN2 plays a role. The synthesis of small compounds which specifically inhibit, regulate and/or 15 modulate signal transduction by immune-modulatory or stress response kinases in particular GCN2, is therefore desirable and an aim of the present invention. Moreover, aim of this invention is the synthesis of new compounds for the prevention and treatment of neoplastic malignancies including, but without 20 being limited to, solid tumor cancers, cancers of the lymphatic or blood system, of neurodegenerative diseases and chronic infections. It has been found that the compounds according to the invention and salts thereof have very valuable pharmacological properties while being well tol 25 erated. The compounds of the formula I can furthermore be used for the isolation and investigation of the activity or expression of GCN2. In addition, they are 30 particularly suitable for use in diagnostic methods for diseases in connection with unregulated or disturbed GCN2 activity. 35 WO 2013/110309 PCT/EP2012/005358 - 13 Compounds of formula I can also inhibit tyrosine kinases FMS (CSF1R), FLT3 or FLT4 or combinations of these kinases, preferentially in addition to inhibitory activity towards GCN2. 5 Fms-like tyrosine kinase 3 (FLT3), which is also known as FLK-2 (fetal liver kinase 2) and STK-l (stem cell kinase 1), plays an important role in the proliferation and differentiation of hematopoietic stem cells. FLT3 receptor kinase is expressed at very high levels on the cells of more than 80% of myelogenous patients and of a fraction of acute lymphoblastic leukemia cells. Furthermore, the enzyme can also 10 be found on cells from patients with chronic myelogenous leukemia in lymphoid blast crisis. It has been reported that FLT3 kinase is mutated in 30% of acute myeloid leukemia (AML) and in a subset of acute lymphoblastic leukemia (ALL) as well (Gilliland et al, Blood 100, 1532-1542 (2002); Stirewalt et al., Nat. Rev. 15 Cancer, 3, 650-665 (2003). Activating mutations in FLT3 mutations have been associated with a poor prognosis (Malempati et al., Blood, 104, 11 (2004). FLT3 inhibitors are being developed and some have shown promising clinical effects against AML (Levis et al Int. J. Hematol, 52, 100- 107 (2005). 20 It has been reported that some of small-molecule FLT3 inhibitors are effective in inducing apoptosis in cell lines with FLT3-activating mutations and prolonging survival of mice that express mutant FLT3 in their bone marrow cells (Levis et al, Blood, 99, 3885-3891 (2002); Kelly et al, Cancer Cell, 1, 421 25 432 (2002); Weisberg et al, Cancer Cell, 1, 433-443 (2002); Yee et al, Blood, 100, 2941-2949 (2002). US patent application 20090054358 describes Flt3 inhibitors for immune suppression and in particular for the treatment of immune related disorders like organ rejection, bone marrow transplant rejection, non-myeloablative bone 30 marrow transplant rejection, ankylosing spondylitis, arthritis, aplastic anemia, Behcet's disease, type 1 diabetes mellitus, graft-versus-host disease, Graves' disease, autoimmune hemolytic anemia, Wegener's granulomatosis, hyper IgE syndrome, idiopathic thrombocytopenia purpura, rheumatoid arthritis, Crohn's 35 disease, multiple sclerosis, Myasthenia gravis, psoriasis, and lupus, among other autoimmune diseases. Flt3 Inhibitors might also be used to treat WO 2013/110309 PCT/EP2012/005358 - 14 neurological disorder as neurodegenerative disease, for example a disease caused by axonal degeneration. Neurodegenerative diseases include, for example, multiple sclerosis; demyelinating core disorders, such as multiple sclerosis, acute transverse myelitis without being limited thereto. 5 Scott et al (Bioorg. Med Chem Let. (2008) 18 (17) p4794) describe CSF-1R inhibitors for the treatment of cancer. CSF-1 R is a member of the class Ill receptor tyrosine kinases. Colony stimulatory factor 1 (CSF-1), also known as macrophage/monocyte colony stimulatory factor (M-CSF), binds to CSF-1 R, 10 resulting in dimerization, autophosphorylation, and activation of signal transduction.1 CSF-1/CSF-1R signaling is essential for normal monocyte development. In cancer, pro-tumorigenic macrophages have been identified and linked to poor prognosis in breast, ovarian, and prostate cancers. Elevated 15 levels of CSF-1 and CSF-1 R have been reported in several tumor types, including breast, ovarian, and endometrial cancers, and have also been linked to invasion and metastasis. Inhibition of CSF-1 R activity could therefore have multiple effects on the tumor through reduction in the levels of tumor 20 associated macrophages (TAMs) and have direct effects on the tumor itself (C.E. Lewis, J.W. Pollard, Cancer Res., 66 (2006), p. 605; I. Bingle, N. et al., J. Pathol., 196 (2002), p. 254; B.M. Kacinski, Ann. Med., 27 (1995), p. 79; E. Garwood et al. J Clin Oncol 26: 2008). Su JL et al. (Cancer Cell. 2006 Mar;9(3):209-23) report that the VEGF-C/Flt-4 25 axis promotes invasion and metastasis of cancer cells. Flt-4, a VEGF receptor, is activated by its specific ligand, VEGF-C. The resultant signaling pathway promotes angiogenesis and/or lymphangiogenesis. VEGF-C/Flt-4 axis enhances cancer cell mobility and invasiveness and contributes to the 30 promotion of cancer cell metastasis. Examination of tumor tissues from various types of cancers revealed high levels of Flt-4 and VEGF-C expression that correlated closely with clinical metastasis and patient survival. Inhibition of Flt 4 kinase could reduce the invasive capacity in different types of cancer 35 WO 2013/110309 PCT/EP2012/005358 - 15 Combining the inhibitory specificity towards GCN2 with that towards FMS (CSF1 R), FLT3 or FLT4 or combinations of these kinases can be of particular advantages for the treatment of neoplastic malignancies at different disease stages. It could combine the effects of stimulating the immune response 5 towards cancer/tumor cells, to reduce the levels of tumor-associated macrophages as well as the invasive capacity of cancers for metastasis formation. In a further aspect the combination of inhibitory activities on GCN2 particularly with inhibition of FLT3 could be advantageous for the treatment of 10 neurodegenerative disorders as it could synergize suppressive effects on inflammatory processes with the modulation of protein deposites generation in the brain. In another aspect the combination of inhibitory activities on GCN2 particularly with inhibition of FLT3 could provide advantages for modulating the 15 immune response to treat immune related disorders and inflammatory or auto immune diseases. In a further embodiment the present invention specifically relates to compounds of the formula I which inhibit, regulate and/or modulate signal transduction by GCN2, FMS (CSF1R), FLT3 or FLT4 or combinations of these 20 kinases, to compositions which comprise these compounds, and to processes for the use thereof for the treatment of diseases and complaints that are induced or modulated by GCN2, FMS (CSF1 R), FLT3 or FLT4 or combinations of these kinases. . 25 Further aim of this invention is the synthesis of new compounds for the prevention and treatment of neoplastic malignancies including, but without being limited to, solid tumor cancers, cancers of the lymphatic or blood system, of neurodegenerative diseases, immune related disorders like arthritis, 30 psoriasis, lupus, multiple sclerosis or other autoimmune diseases as well as chronic infections. The compounds of the formula I can furthermore be used for the isolation and investigation of the activity or expression of SykGCN2, FMS (CSF1 R), FLT3 or 35 FLT4. In addition, they are particularly suitable for use in diagnostic methods for diseases in connection with unregulated or disturbed SykGCN2, FMS WO 2013/110309 PCT/EP2012/005358 -16 (CSF1R), FLT3 or FLT4activity. The host or patient can belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations, providing a 5 model for treatment of human disease. The susceptibility of a particular cell to treatment with the compounds according to the invention can be determined by in vitro tests. Typically, a 10 culture of the cell is combined with a compound according to the invention at various concentrations for a period of time which is sufficient to allow active agents such as anti IgM to induce a cellular response such as expression of a surface marker, usually between about one hour and one week. In vitro testing 15 can be carried out using cultivated cells from blood or from a biopsy sample. The amount of surface marker expressed are assessed by flow cytometry using specific antibodies recognising the marker. The dose varies depending on the specific compound used, the specific disease, the patient status, etc. A therapeutic dose is typically sufficient 20 considerably to reduce the undesired cell population in the target tissue while the viability of the patient is maintained. The treatment is generally continued until a considerable reduction has occurred, for example an at least about 50% reduction in the cell burden, and may be continued until essentially no more 25 undesired cells are detected in the body. For identification of a signal transduction pathway and for detection of interactions between various signal transduction pathways, various scientists 30 have developed suitable models or model systems, for example cell culture models (for example Khwaja et al., EMBO, 1997, 16, 2783-93) and models of transgenic animals (for example White et al., Oncogene, 2001, 20, 7064 7072). For the determination of certain stages in the signal transduction cascade, interacting compounds can be utilised in order to modulate the signal 35 (for example Stephens et al., Biochemical J., 2000, 351, 95-105). The compounds according to the invention can also be used as reagents for testing WO 2013/110309 PCT/EP2012/005358 - 17 kinase-dependent signal transduction pathways in animals and/or cell culture models or in the clinical diseases mentioned in this application. Measurement of the kinase activity is a technique which is well known to the 5 person skilled in the art. Generic test systems for the determination of the kinase activity using substrates, for example histone (for example Alessi et al., FEBS Left. 1996, 399, 3, pages 333-338) or the basic myelin protein, are described in the literature (for example Campos-Gonzelez, R. and Glenney, 10 Jr., J.R. 1992, J. Biol. Chem. 267, page 14535). For the identification of kinase inhibitors, various assay systems are available. In scintillation proximity assay (Sorg et al., J. of. Biomolecular Screening, 2002, 15 7, 11-19) and flashplate assay, the radioactive phosphorylation of a protein or peptide as substrate with yATP is measured. In the presence of an inhibitory compound, a decreased radioactive signal, or none at all, is detectable. Furthermore, homogeneous time-resolved fluorescence resonance energy 20 transfer (HTR-FRET) and fluorescence polarisation (FP) technologies are suitable as assay methods (Sills et al., J. of Biomolecular Screening, 2002, 191-214). Other non-radioactive ELISA assay methods use specific phospho-antibodies 25 (phospho-ABs). The phospho-AB binds only the phosphorylated substrate. This binding can be detected by chemiluminescence using a second peroxidase-conjugated anti-sheep antibody (Ross et al., 2002, Biochem. J.). PRIOR ART 30 Other triazolopyrimidine derivatives are described as GSK3 inhibitors for the treatment of diseases like Alzheimer or diabtes in WO 2005/012307 Al and in WO 2006/075023 A2. 35 WO 2013/110309 PCT/EP2012/005358 - 18 SUMMARY OF THE INVENTION The invention relates to compounds of the formula 1 5H R' 5R-- N N N i N in which 10 R denotes Ar or Het, R2 denotes furyl, thienyl, pyrrolyl, thiadiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl or tetrazolyl which is unsubstituted or mono- or disubstituted by Hal, A, [C(R 3
)
2 ]pCyc,
[C(R
3
)
2 IpOR 3 , [C(R 3
)
2 ]pN(R 3
)
2 , [C(R 3
)
2 IpAr, [C(R 3
)
2 ]pHetl, NO 2 , CN,
[C(R
3
)
2 ]pCOOR 3 , CON(R 3
)
2 , NR 3 COA, NR 3
SO
2 A, SO 2
N(R
3
)
2 , S(O)nA, COHet', O[C(R 3
)
2 ]mN(R 3
)
2 , O[C(R 3
)
2 ]pHet', NHCOOA, NHCON(R 3
)
2 ,
NHCOO[C(R
3
)
2 ]mN(R 3
)
2 , NHCOO[C(R 3
)
2 ]pHet', NHCONH[C(R 3
)
2 ]m
N(R
3
)
2 , NHCONH[C(R 3
)
2 ]pHet 1 , OCONH[C(R 3
)
2 ]mN(R 3
)
2 , 20 OCONH[C(R 3
)
2 ]pHet, CHO, COA, =S, =NR 3 and/or =0,
R
3 denotes H or A', Ar denotes phenyl or naphthyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R 3
)
2 ]pOR 3 , [C(R 3
)
2 ]pN(R 3
)
2 , [C(R 3
)
2 ]pHet, 25 NO 2 , CN, [C(R) 2 ]pCOOR 3 , CON(R 3
)
2 , NR 3 COA, NR 3
SO
2 A,
SO
2
N(R
3
)
2 , S(O)A, S(O),Het, COHet', O[C(R 3
)
2 ]mN(R 3
)
2 ,
O[C(R
3
)
2 ]pHet', NHCOOA, NHCON(R 3
)
2 , NHCOO[C(R 3
)
2 ]mN(R 3
)
2 ,
NHCOO[C(R
3
)
2 ]pHet, NHCONH[C(R 3
)
2 ]mN(R 3
)
2 , NHCONH[C(R 3
)
2 ]p 30 Het', OCONH[C(R 3
)
2 ]mN(R 3
)
2 , OCONH[C(R 3
)
2 ]pHet', CHO and/or COA, Het denotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, 35 pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl, 1,3-benzodioxolyl, benzothiophenyl, WO 2013/110309 PCT/EP2012/005358 - 19 benzofuranyl, imidazopyridyl, dihydroindolyl, quinoxalinyl, benzo[1,2,5]thiadiazolyl or furo[3,2-b]pyridyl which is unsubstituted or mono- or disubstituted by Hal, A, [C(R 3
)
2 ]pOR 3 , [C(R 3
)
2 ]pN(R 3
)
2 ,
[C(R
3
)
2 ]pHet', N02, CN, [C(R 6
)
2 ]pCOOR 3 , CON(R 3
)
2 , NR3COA, 5 NR 3
SO
2 A, SO 2
N(R
3
)
2 , S(O)nA, COHet 1 , O[C(R) 2 ]mN(R 3
)
2 ,
O[C(R
3
)
2 ]pHet, NHCOOA, NHCON(R 3
)
2 , NHCOO[C(R 3
)
2 ]mN(R 3
)
2 ,
NHCOO[C(R
3
)
2 ]pHet, NHCONH[C(R 3
)
2 ]mN(R 3
)
2 , NHCONH[C(R 3
)
2 1p Het', OCONH[C(R 3
)
2 ]mN(R 3
)
2 , OCONH[C(R 3
)
2 ]pHet, CHO, COA, 10 =S, =NR 3 and/or =0, Het' denotes dihydropyrrolyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahydro imidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydrofuranyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, morpholinyl, hexa 15 hydropyridazinyl, hexahydropyrimidinyl, [1,3]dioxolanyl, tetrahydropyranyl, pyrazolyl, pyridyl or piperazinyl, which is unsubstituted or mono- or disubstituted by Hal, CN, OH, OA, COOA,
CONH
2 , S(O)nA, S(O)nAr, COA, A and/or =O, 20 A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein one or two non-adjacent CH- and/or CH 2 -groups may be replaced by N-, 0- and/or S-atoms and wherein 1-7 H-atoms may be replaced by F or Cl, 25 Cyc denotes cyclic alkyl with 3-7 C-atoms, which is unsubstituted or monosubstituted by [C(R 3
)
2 1pOH, A' denotes unbranched or branched alkyl with 1, 2, 3 or 4 C-atoms, Hal denotes F, Cl, Br or I, 30 n denotes 0, 1 or 2, m denotes 1, 2 or 3, p denotes 0, 1, 2, 3 or 4, and pharmaceutically usable derivatives, solvates, salts, tautomers and 35 stereoisomers thereof, including mixtures thereof in all ratios.
WO 2013/110309 PCT/EP2012/005358 - 20 The invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. 5 The invention also relates to the solvates of the salts of the compounds of formula I, e.g. the mono- or dihydrate of the hydrochloride. Moreover, the invention relates to pharmaceutically acceptable derivatives of 10 compounds of formula I. The term solvates of the compounds is taken to mean adductions of inert solvent molecules onto the compounds which form owing to their mutual attractive force. Solvates are, for example, mono- or dihydrates or alcoholates. 15 The term pharmaceutically acceptable derivatives is taken to mean, for exam ple, the salts of the compounds according to the invention and also so-called prodrug compounds. As used herein and unless otherwise indicated, the term "prodrug" means a 20 derivative of a compound of formula I that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound of formula 1. Examples of prodrugs include, but are not limited to, derivatives and metabolites of a compound of formula I that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable 25 esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. In certain embodiments, prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid. The carboxylate esters are conveniently formed by 30 esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well- known methods, such as those described by Burger 's Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H.Bundgaard ed., 35 1985, Harwood Academic Publishers Gmfh).
WO 2013/110309 PCT/EP2012/005358 - 21 The expression "effective amount" denotes the amount of a medicament or of a pharmaceutical active ingredient which causes in a tissue, system, animal or human a biological or medical response which is sought or desired, for example, by a researcher or physician. 5 In addition, the expression "therapeutically effective amount" denotes an amount which, compared with a corresponding subject who has not received this amount, has the following consequence: improved treatment, healing, prevention or elimination of a disease, syndrome, 10 condition, complaint, disorder or side-effects or also the reduction in the advance of a disease, complaint or disorder. The expression "therapeutically effective amount" also encompasses the amounts which are effective for increasing normal physiological function. 15 The invention also relates to the use of mixtures of the compounds of the formula I, for example mixtures of two diastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000. These are particularly preferably mixtures of stereoisomeric compounds. 20 "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, 25 for example, whether the compound is a solid or is in an organic or aqueous solution. The invention relates to the compounds of the formula I and salts thereof and 30 to a process for the preparation of compounds of the formula I and pharmaceutically usable salts, solvates, tautomers and stereoisomers thereof, characterised in that a) a compound of the formula Il 35 WO 2013/110309 PCT/EP2012/005358 -22 HR 2 H R-N N NH N
NH-
2 5 in which R' and R 2 have the meaning indicated in Claim 1, is reacted with a nitrite, 10 or b) a compound of the formula Ill 15 R L N I N IIl N 20 in which R1 has the meaning indicated in Claim 1, L denotes Cl, Br, I, S-alkyl, SO-alkyl or S0 2 -alkyl, and alkyl has 1, 2, 3 or 4 C atoms, 25 is reacted with a compound of the formula IV R2-NH 2 IV in which R2 has the meaning indicated in Claim 1, and/or 30 a base or acid of the formula I is converted into one of its salts. Above and below, the radicals R 1 and R 2 have the meanings indicated for the formula I, unless expressly stated otherwise. 35 WO 2013/110309 PCT/EP2012/005358 -23 A denotes alkyl, this is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1 5 , 2-, 3- or 4-methylpentyl, 1,1- , 1,2-, 1,3- , 2,2-, 2,3- or 3,3-dimethylbutyl, 1 or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2 trimethylpropyl, furthermore preferably, for example, trifluoromethyl. A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms, 10 preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1,1,1-trifluoroethyl. Moreover, A denotes e.g. CH 2 0CH 3 , CH 2
CH
2 OH, OCH 2
CH
2
NH
2 , CH 2
NHCH
2 or NHCH 2
CH
3 . 15 Cyc preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. R2 preferably denotes furyl, thienyl, pyrrolyl, thiadiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl or tetrazolyl which is 20 unsubstituted or monosubstituted by A, [C(R 3
)
2 ]pCyc, [C(R 3
)
2 ]pAr, [C(R 3
)
2 ]pHet', CN or [C(R 3
)
2 ]pCOOR 3
R
3 preferably denotes H or alkyl having 1, 2, 3 or 4 C atoms, particularly 25 preferably H or methyl. Ar denotes, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m 30 or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- or p-(N-methylaminocarbonyl)phenyl, o-, m or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-ethoxycarbonyl phenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- or p-(N,N-dimethyl aminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl, o-, m- or p-(N,N 35 diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m or p-chlorophenyl, o-, m- or p-(methylsulfonamido)phenyl, o-, m- or p-(methyl- WO 2013/110309 PCT/EP2012/005358 -24 sulfonyl)phenyl, o-, m- or p-cyanophenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-formylphenyl, o-, m- or p-acetylphenyl, o-, m- or p-aminosulfonylphenyl, o-, m- or p-[2-(morpholin-4-yl)ethoxy]phenyl, o-, m- or p-[3-(N,N-diethylamino)propoxylphenyl, furthermore preferably 2,3-, 5 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5 dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5 dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4 chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6 10 chlorophenyl, 2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylamino phenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-di chloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5 15 difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methyl phenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl. Ar furthermore preferably denotes phenyl which is unsubstituted or mono-, di 20 or trisubstituted by Hal, A, [C(R 3
)
2 IpOR 3 , NR 3COA, S(O)nHet' and/or O[C(R 3)2]pHet'. Het preferably denotes pyrazolyl, dihydroindolyl, quinoxalinyl, 25 benzo[1,2,5]thiadiazolyl or pyridyl, which is unsubstituted or monosubstituted by A or [C(R 3
)
2 ]pOR 3 Het' preferably denotes pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, 30 morpholinyl, pyrazolyl, pyridyl or tetrahydropyranyl, which is unsubstituted or monosubstituted by A or =0. Hal preferably denotes F, CI or Br, but also I, particularly preferably F or CI. 35 Throughout the invention, all radicals which occur more than once may be identical or different, i.e. are independent of one another.
WO 2013/110309 PCT/EP2012/005358 - 25 The compounds of the formula I may have one or more chiral centres and can therefore occur in various stereoisomeric forms. The formula I encompasses all these forms. 5 Accordingly, the invention relates, in particular, to the compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds may be expressed by the following sub-formulae la to le, which conform to the formula 10 I and in which the radicals not designated in greater detail have the meaning indicated for the formula I, but in which in la R2 denotes furyl, thienyl, pyrrolyl, thiadiazolyl, imidazolyl, 15 pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl or tetrazolyl which is unsubstituted or monosubstituted by A,
[C(R
3
)
2 ]pCyc, [C(R 3
)
2 ]pAr, [C(R 3
)
2 ]pHet', CN or
[C(R
3
)
2 ]pCOOR 3 ; 20 in lb Ar denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R 3
)
2 ]pOR 3 , NR 3 COA, S(O)nHet' and/or O[C(R 3
)
2 ]pHet'; 25 in Ic Het denotes pyrazolyl, dihydroindolyl, quinoxalinyl, benzo[1,2,5]thiadiazolyl or pyridyl, which is unsubstituted or monosubstituted by A or [C(R 3
)
2 ]pOR 3 ; 30 in Id Het denotes pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, morpholinyl, pyrazolyl, pyridyl or tetrahydropyranyl, which is unsubstituted or monosubstituted by A or =0; in le R 1 denotes Ar or Het', 35 R2 denotes furyl, thienyl, pyrrolyl, thiadiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl WO 2013/110309 PCT/EP2012/005358 - 26 or tetrazolyl which is unsubstituted or monosubstituted by A,
[C(R
3
)
2 ]pCyc, [C(R 3
)
2 ]pAr, [C(R 3
)
2 ]pHet, CN or
[C(R
3
)
2 ]pCOOR 3 ,
R
3 denotes H or methyl, 5 Ar denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R 3
)
2 ]pOR 3 , NR 3 COA, S(O)nHet, and/or O[C(R 3
)
2 ]pHet, Het denotes pyrazolyl, dihydroindolyl, quinoxalinyl, 10 benzo[1,2,5]thiadiazolyl or pyridyl, which is unsubstituted or monosubstituted by A or [C(R 3
)
2 ]pOR 3 , Het' denotes pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, morpholinyl, pyrazolyl, pyridyl or tetrahydropyranyl, which is 15 unsubstituted or monosubstituted by A or =0, A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein one or two non-adjacent CH- and/or CH 2 -groups may be replaced by N- and/or O-atoms and wherein 1-7 H atoms may be replaced by F or Cl, 20 Cyc denotes cyclic alkyl with 3-7 C-atoms, which is unsubstituted or monosubstituted by [C(R 3
)
2 ]pOH, Hal denotes F, Cl, Br or I, 25 n denotes 0, 1 or 2, m denotes 1, 2 or 3, p denotes 0, 1, 2, 3 or 4; 30 and pharmaceutically usable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. The compounds of the formula I and also the starting materials for their 35 preparation are, in addition, prepared by methods known per se, as described in the literature (for example in the standard works, such as Houben-Weyl, WO 2013/110309 PCT/EP2012/005358 - 27 Methoden der organischen Chemie [Methods of Organic Chemistry], Georg Thieme-Verlag, Stuttgart), to be precise Use can also be made here of variants known per se which are not mentioned here in greater detail. 5 The starting compounds of the formulae 11, l1l and IV are generally known. If they are novel, however, they can be prepared by methods known per se. Compounds of the formula I can preferably be obtained by reacting a 10 compound of the formula 11 with a nitrite. Preferred nitrites are anorganic nitrites such as alkali nitrites, particularly preferred is NaNO 2 . Furthermore, preferred nitrites are organic nitrites such as isoamylnitrite. 15 Depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature is between about -30* and 1400, normally between 00 and 1000, in particular between about 10* and about 800. Preferred solvents for alkali nitrites are aqueous mineral acids, e.g. H 2
SO
4 , HCI 20 or mixtures with suitable organic solvents. Preferred solvents for organic nitrites are strong acids like TFA together with hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, 25 carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, 30 ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; 35 esters, such as ethyl acetate, or mixtures of the said solvents.
WO 2013/110309 PCT/EP2012/005358 - 28 Moreover, compounds of the formula I can preferably be obtained by reacting a compound of the formula Ill with a compound of the formula IV. In the compounds of formula Ill L preferably denotes Cl, Br, I, S-alkyl, SO 5 alkyl or S0 2 -alkyl, particularly preferred is Cl. The reaction is generally carried out under conditions known to the skilled artisan and which are known and suitable for the said reaction. Depending on the conditions used, the reaction time is between a few minutes 10 and 14 days, the reaction temperature is between about 0* and 1400, normally between 200 and 1200, in particular between about 600 and about 1100. Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such 15 as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); 20 ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as 25 nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents. Particular preference is given to 2-methoxy-ethanol. 30 Free amino groups can furthermore be acylated in a conventional manner using an acid chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, advantageously in an inert solvent, such as dichloro methane or THF, and/or in the presence of a base, such as triethylamine or pyridine, at temperatures between -60 and +300. 35 Pharmaceutical salts and other forms WO 2013/110309 PCT/EP2012/005358 - 29 The said compounds according to the invention can be used in their final non salt form. On the other hand, the present invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases by 5 procedures known in the art. Pharmaceutically acceptable salt forms of the compounds of the formula I are for the most part prepared by conventional methods. If the compound of the formula I contains a carboxyl group, one of its suitable salts can be formed by reacting the compound with a suitable base to 10 give the corresponding base-addition salt. Such bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides, such as barium hydroxide and calcium hydroxide; alkali metal alkoxides, for example potassium ethoxide 15 and sodium propoxide; and various organic bases, such as piperidine, diethanolamine and N-methylglutamine. The aluminium salts of the compounds of the formula I are likewise included. In the case of certain compounds of the formula I, acid-addition salts can be formed by treating these compounds with pharmaceutically acceptable organic and inorganic 20 acids, for example hydrogen halides, such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and corresponding salts thereof, such as sulfate, nitrate or phosphate and the like, and alkyl- and monoarylsulfonates, such as ethanesulfonate, toluenesulfonate and benzene 25 sulfonate, and other organic acids and corresponding salts thereof, such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like. Accordingly, pharmaceutically acceptable acid-addition salts of the compounds of the formula I include the following: 30 acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphor sulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethane sulfonate, fumarate, galacterate (from mucic acid), galacturonate, gluco 35 heptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemi sulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, WO 2013/110309 PCT/EP2012/005358 - 30 hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate, 5 pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this does not represent a restriction. Furthermore, the base salts of the compounds according to the invention 10 include aluminium, ammonium, calcium, copper, iron(Ill), iron(II), lithium, magnesium, manganese(llI), manganese(ll), potassium, sodium and zinc salts, but this is not intended to represent a restriction. Of the above-men tioned salts, preference is given to ammonium; the alkali metal salts sodium 15 and potassium, and the alkaline earth metal salts calcium and magnesium. Salts of the compounds of the formula I which are derived from pharma ceutically acceptable organic non-toxic bases include salts of primary, sec ondary and tertiary amines, substituted amines, also including naturally occurring substituted amines, cyclic amines, and basic ion exchanger resins, 20 for example arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzyl ethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethyl amine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, 25 glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethyl amine, trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine 30 (tromethamine), but this is not intended to represent a restriction. Compounds of the present invention which contain basic nitrogen-containing groups can be quaternised using agents such as (C,-C4)alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; 35 di(C-C 4 )alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (C1o
C
18 )alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl WO 2013/110309 PCT/EP2012/005358 - 31 chloride, bromide and iodide; and aryl(C-C 4 )alkyl halides, for example benzyl chloride and phenethyl bromide. Both water- and oil-soluble compounds according to the invention can be prepared using such salts. 5 The above-mentioned pharmaceutical salts which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, 10 sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, but this is not intended to represent a restriction. Particular preference is given to hydrochloride, dihydrochloride, hydrobromide, 15 maleate, mesylate, phosphate, sulfate and succinate. The acid-addition salts of basic compounds of the formula I are prepared by bringing the free base form into contact with a sufficient amount of the desired acid, causing the formation of the salt in a conventional manner. The free base 20 can be regenerated by bringing the salt form into contact with a base and isolating the free base in a conventional manner. The free base forms differ in a certain respect from the corresponding salt forms thereof with respect to certain physical properties, such as solubility in polar solvents; for the 25 purposes of the invention, however, the salts otherwise correspond to the respective free base forms thereof. As mentioned, the pharmaceutically acceptable base-addition salts of the 30 compounds of the formula I are formed with metals or amines, such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine. 35 WO 2013/110309 PCT/EP2012/005358 - 32 The base-addition salts of acidic compounds according to the invention are prepared by bringing the free acid form into contact with a sufficient amount of the desired base, causing the formation of the salt in a conventional manner. The free acid can be regenerated by bringing the salt form into contact with an 5 acid and isolating the free acid in a conventional manner. The free acid forms differ in a certain respect from the corresponding salt forms thereof with respect to certain physical properties, such as solubility in polar solvents; for the purposes of the invention, however, the salts otherwise correspond to the 10 respective free acid forms thereof. If a compound according to the invention contains more than one group which is capable of forming pharmaceutically acceptable salts of this type, the 15 invention also encompasses multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to represent a restriction. 20 With regard to that stated above, it can be seen that the expression "phar maceutically acceptable salt" in the present connection is taken to mean an active ingredient which comprises a compound of the formula I in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic 25 properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property 30 which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body. The invention furthermore relates to medicaments comprising at least one 35 compound of the formula I and/or pharmaceutically acceptable salts, solvates, WO 2013/110309 PCT/EP2012/005358 - 33 tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or adjuvants. Pharmaceutical formulations can be administered in the form of dosage units 5 which comprise a predetermined amount of active ingredient per dosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a compound according to the invention, depending on the condition treated, the method of administration 10 and the age, weight and condition of the patient, or pharmaceutical formulations can be administered in the form of dosage units which comprise a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those which comprise a daily dose or part-dose, as 15 indicated above, or a corresponding fraction thereof of an active ingredient. Furthermore, pharmaceutical formulations of this type can be prepared using a process which is generally known in the pharmaceutical art. Pharmaceutical formulations can be adapted for administration via any desired 20 suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations can be prepared using all processes known in the 25 pharmaceutical art by, for example, combining the active ingredient with the excipient(s) or adjuvant(s). Pharmaceutical formulations adapted for oral administration can be adminis 30 tered as separate units, such as, for example, capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. 35 Thus, for example, in the case of oral administration in the form of a tablet or capsule, the active-ingredient component can be combined with an oral, non- WO 2013/110309 PCT/EP2012/005358 - 34 toxic and pharmaceutically acceptable inert excipient, such as, for example, ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a pharmaceutical excipient comminuted in a similar manner, such as, for example, an edible 5 carbohydrate, such as, for example, starch or mannitol. A flavour, preservative, dispersant and dye may likewise be present. Capsules are produced by preparing a powder mixture as described above 10 and filling shaped gelatine shells therewith. Glidants and lubricants, such as, for example, highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. A disintegrant or solubiliser, such as, for 15 example, agar-agar, calcium carbonate or sodium carbonate, may likewise be added in order to improve the availability of the medicament after the capsule has been taken. In addition, if desired or necessary, suitable binders, lubricants and disin 20 tegrants as well as dyes can likewise be incorporated into the mixture. Suitable binders include starch, gelatine, natural sugars, such as, for example, glucose or beta-lactose, sweeteners made from maize, natural and synthetic rubber, such as, for example, acacia, tragacanth or sodium alginate, carboxymethyl 25 cellulose, polyethylene glycol, waxes, and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrants include, without being restricted thereto, starch, methylcellulose, 30 agar, bentonite, xanthan gum and the like. The tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing the mixture, adding a lubricant and a disintegrant and pressing the entire mixture to give tablets. A powder mixture is prepared by mixing the compound comminuted in a suitable manner with a diluent or a base, as described above, and optionally 35 with a binder, such as, for example, carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, a dissolution retardant, such as, for example, WO 2013/110309 PCT/EP2012/005358 - 35 paraffin, an absorption accelerator, such as, for example, a quaternary salt, and/or an absorbant, such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder, such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymer materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be run through a tabletting machine, giving lumps of non-uniform shape, which are broken up to form granules. The granules can be lubricated by addition of stearic acid, a stearate 10 salt, talc or mineral oil in order to prevent sticking to the tablet casting moulds. The lubricated mixture is then pressed to give tablets. The compounds according to the invention can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the 15 granulation or dry-pressing steps. A transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material and a gloss layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units. 20 Oral liquids, such as, for example, solution, syrups and elixirs, can be prepared in the form of dosage units so that a given quantity comprises a pre-specified amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution with a suitable flavour, while elixirs are prepared using 25 a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersion of the compound in a non-toxic vehicle. Solubilisers and emulsifiers, such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavour additives, such as, for example, peppermint oil or natural 30 sweeteners or saccharin, or other artificial sweeteners and the like, can likewise be added. The dosage unit formulations for oral administration can, if desired, be en capsulated in microcapsules. The formulation can also be prepared in such a 35 way that the release is extended or retarded, such as, for example, by coating or embedding of particulate material in polymers, wax and the like.
WO 2013/110309 PCT/EP2012/005358 - 36 The compounds of the formula I and salts, solvates, tautomers and stereoisomers thereof can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large 5 unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as, for example, cholesterol, stearylamine or phosphatidyicholines. 10 The compounds of the formula I and the salts, solvates, tautomers and stereoisomers thereof can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds can also be coupled to soluble polymers as targeted medicament 15 carriers. Such polymers may encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxy ethylaspartamidophenol or polyethylene oxide polylysine, substituted by palmitoyl radicals. The compounds may furthermore be coupled to a class of biodegradable polymers which are suitable for achieving controlled release of 20 a medicament, for example polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels. 25 Pharmaceutical formulations adapted for transdermal administration can be administered as independent plasters for extended, close contact with the epidermis of the recipient. Thus, for example, the active ingredient can be 30 delivered from the plaster by iontophoresis, as described in general terms in Pharmaceutical Research, 3(6), 318 (1986). Pharmaceutical compounds adapted for topical administration can be for mulated as ointments, creams, suspensions, lotions, powders, solutions, 35 pastes, gels, sprays, aerosols or oils.
WO 2013/110309 PCT/EP2012/005358 - 37 For the treatment of the eye or other external tissue, for example mouth and skin, the formulations are preferably applied as topical ointment or cream. In the case of formulation to give an ointment, the active ingredient can be employed either with a paraffinic or a water-miscible cream base. Alternatively, 5 the active ingredient can be formulated to give a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical formulations adapted for topical application to the eye include 10 eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, in particular an aqueous solvent. Pharmaceutical formulations adapted for topical application in the mouth 15 encompass lozenges, pastilles and mouthwashes. Pharmaceutical formulations adapted for rectal administration can be ad ministered in the form of suppositories or enemas. 20 Pharmaceutical formulations adapted for nasal administration in which the carrier substance is a solid comprise a coarse powder having a particle size, for example, in the range 20-500 microns, which is administered in the manner in which snuff is taken, i.e. by rapid inhalation via the nasal passages from a 25 container containing the powder held close to the nose. Suitable formulations for administration as nasal spray or nose drops with a liquid as carrier substance encompass active-ingredient solutions in water or oil. 30 Pharmaceutical formulations adapted for administration by inhalation encom pass finely particulate dusts or mists, which can be generated by various types of pressurised dispensers with aerosols, nebulisers or insufflators. Pharmaceutical formulations adapted for vaginal administration can be 35 administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
WO 2013/110309 PCT/EP2012/005358 - 38 Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions comprising antioxidants, buffers, bacteriostatics and solutes, by means of which the formulation is 5 rendered isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may comprise suspension media and thickeners. The formulations can be administered in single-dose or multidose containers, for example sealed ampoules and vials, and stored in 10 freeze-dried (lyophilised) state, so that only the addition of the sterile carrier liquid, for example water for injection purposes, immediately before use is necessary. Injection solutions and suspensions prepared in accordance with the recipe can be prepared from sterile powders, granules and tablets. 15 It goes without saying that, in addition to the above particularly mentioned constituents, the formulations may also comprise other agents usual in the art with respect to the particular type of formulation; thus, for example, for mulations which are suitable for oral administration may comprise flavours. 20 A therapeutically effective amount of a compound of the formula I depends on a number of factors, including, for example, the age and weight of the animal, the precise condition that requires treatment, and its severity, the nature of the 25 formulation and the method of administration, and is ultimately determined by the treating doctor or vet. However, an effective amount of a compound according to the invention is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the 30 range from 1 to 10 mg/kg of body weight per day. Thus, the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as a single dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same. An effective amount of a salt, 35 solvate, tautomer and stereoisomer thereof can be determined as the fraction of the effective amount of the compound according to the invention per se. It WO 2013/110309 PCT/EP2012/005358 - 39 can be assumed that similar doses are suitable for the treatment of other conditions mentioned above. The disclosed compounds of the formula I can be administered in combination 5 with other known therapeutic agents including agents for the treatment of RA (rheumatoid arthritis). As used here, the term "agents for the treatment of RA" relates to any agent which is administered to a patient with RA for the purposes of treating the RA. 10 The medicaments below are preferably, but not exclusively, combined with the compounds of the formula 1: 1. NSAIDs (non-steroidal anti-inflammatory drugs) and analgesics 15 2. Glucocorticoids (low oral doses) 3. Conventional disease-modifying antirheumatic drugs (DMARDs) - Methotrexate - Leflunomide - Sulfasalazine 20 - Hydroxycloroquine - Azathioprine - Ciclosporin - Minocycline 25 - Gold 4. Biologic response modifiers (BRMs) -> target molecules/ immune cells involved in the inflammatory process, and include the following agents: 30 - TNF inhibitors - etanercept (Enbrel) - infliximab (Remicade) - adalimumab (Humira) 35 - B-cell-directed therapy - rituximab (Rituxan) WO 2013/110309 PCT/EP2012/005358 -40 - T-cell/B-cell coactivation signal inhibitor - abatacept (Orencia) - IL-1 receptor antagonist 5 - anakinra (Kineret) MECHANISM OF ACTION Golimumab Fully humanized monoclonal antibody to TNF 10 Certolizumab pegol Anti -TNF agent with just the Fab portion attached to the polyethylene glycol Tocilizumab Humanized monoclonal anti-IL-6 antibody that binds to the soluble and membrane-expresses IL-6 receptor 15 Ocrelizumab Humanized-second generation anti-CD20 antibody that depletes B cells Ofatumumab Human monoclonal anti-CD20 IgG1 antibody Denosumab Fully humanized monoclonal 20 antibody that binds to and inhibits the receptor activator for nuclear factor-kB ligand TRU-015 New class of CD20-directed protein therapeutics Oral small molecules Cytoplasmic targets (JAK, Syk, MAP kinase 25 inhibitors) Tolerogens (dnaJP1) Immunotherapy based on T-cell tolerization 30 A combined treatment of this type can be achieved with the aid of simulta neous, consecutive or separate dispensing of the individual components of the treatment. Combination products of this type employ the compounds according to the invention. 35 WO 2013/110309 PCT/EP2012/005358 -41 The invention furthermore relates to medicaments comprising at least one compound of the formula I and/or pharmaceutically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient. 5 The invention also relates to a set (kit) consisting of separate packs of (a) an effective amount of a compound of the formula I and/or pharmaceuti cally acceptable salts, solvates, tautomers and stereoisomers thereof, in 10 cluding mixtures thereof in all ratios, and (b) an effective amount of a further medicament active ingredient. 15 The set comprises suitable containers, such as boxes, individual bottles, bags or ampoules. The set may, for example, comprise separate ampoules, each containing an effective amount of a compound of the formula I and/or pharmaceutically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, 20 and an effective amount of a further medicament active ingredient in dissolved or lyophilised form. "Treating" as used herein, means an alleviation, in whole or in part, of 25 symptoms associated with a disorder or disease, or slowing, or halting of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder in a subject at risk for developing the disease or disorder. 30 The term "effective amount" in connection with a compound of formula (1) can mean an amount capable of alleviating, in whole or in part, symptoms associated with a disorder or disease, or slowing or halting further progression or worsening of those symptoms, or preventing or providing prophylaxis for the 35 disease or disorder in a subject having or at risk for developing a disease disclosed herein, such as inflammatory conditions, immunological conditions, WO 2013/110309 PCT/EP2012/005358 -42 cancer, metabolic conditions, neurodegenerative conditions, chronic infections or conditions treatable or preventable by inhibition of a kinase or a kinase pathway, in one embodiment, the GCN2 pathway. In another embodiment this relates to conditions treatable or preventable by inhibition of a kinase or a 5 kinase pathway, from the group of GCN2, FMS (CSF1 R), FLT3 or FLT4 or combinations thereof. In one embodiment an effective amount of a compound of formula (I) is an amount that inhibits a kinase in a cell, such as, for example, in vitro or in vivo. In some embodiments, the effective amount of the 10 compound of formula (1) inhibits the kinase in a cell by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99%, compared to the activity of the kinase in an untreated cell. The effective amount of the compound of formula (1), for example in a pharmaceutical composition, may be at a level that will exercise 15 the desired effect; for example, about 0.005 mg/kg of a subject's body weight to about 10 mg/kg of a subject's body weight in unit dosage for both oral and parenteral administration. 20 USE The present compounds are suitable as pharmaceutical active ingredients for mammals, especially for humans, in the treatment of immune modulatory and stress response kinase-induced diseases. These diseases include neoplastic 25 malignancies including, but without being limited to, solid tumor cancers, cancers of the lymphatic or blood system, the proliferation of tumour cells, pathological neovascularisation (or angiogenesis) which promotes the growth of solid tumours, neurodegenerative diseases (Alzheimer, demyelinating core 30 disorders multiple sclerosis and the like), immune related disorders like arthritis, psoriasis, lupus, or other autoimmune diseases as well as chronic infections. The present invention encompasses the use of the compounds of the formula I and/or physiologically acceptable salts and solvates thereof for the preparation 35 of a medicament for the treatment or prevention of cancer. Preferred carcinomas for the treatment originate from the group cerebral carcinoma, WO 2013/110309 PCT/EP2012/005358 -43 urogenital tract carcinoma, carcinoma of the lymphatic system, stomach carcinoma, laryngeal carcinoma and lung carcinoma. A further group of preferred forms of cancer are monocytic leukaemia, lung adenocarcinoma, small-cell lung carcinomas, pancreatic cancer, glioblastomas, melanomas and 5 breast carcinoma. A further group of preferred forms of cancer include, but is not limited to, cervical cancer, neuroblastoma, testicular cancer, macroglobulinemia and sarcomas. Also encompassed is the use of the compounds according to Claim 1 ac 10 cording to the invention and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment or prevention of a neurological disorder, particularly a neurodegenerative disease, for example a disease caused by axonal degeneration or by protein plaque deposition. 15 Neurodegenerative diseases include, for example, demyelinating core disorders, such as multiple sclerosis, acute transverse myelitis, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease or Alzheimer disease. 20 Further encompassed is the use of the compounds according to Claim 1 ac cording to the invention and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment of chronic infections. Such a chronic infection could relate to parasites like leishmania to 25 leprosy or to viral infection by HIV and the like. Further encompassed is the use of the compounds according to Claim 1 ac cording to the invention and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment or prevention of 30 a disease in which angiogenesis is implicated. Such a disease in which angiogenesis is implicated is an ocular disease, such as retinal vascularisation, diabetic retinopathy, age-induced macular degeneration and the like. 35 WO 2013/110309 PCT/EP2012/005358 -44 The present invention encompasses the use of the compounds of the formula I and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment or prevention of immune related disorder like ankylosing spondylitis, arthritis, aplastic anemia, Behcet's disease, type 1 5 diabetes mellitus, graft-versus-host disease, Graves' disease, autoimmune hemolytic anemia, Wegener's granulomatosis, hyper IgE syndrome, idiopathic thrombocytopenia purpura, rheumatoid arthritis, Crohn's disease, multiple sclerosis, Myasthenia gravis, psoriasis, and lupus, among other autoimmune 10 diseases. It might also be used treat organ rejection, bone marrow transplant rejection, non-myeloablative bone marrow transplant rejection,enhance bone marrow engraftment after non-myeloablative conditioning regimens, and combinations thereof 15 Also encompassed is the use of the compounds of the formula I and/or physio logically acceptable salts and solvates thereof for the preparation of a medicament for the treatment or prevention of a immune-modulatory or stress response kinase-induced disease or a immune-modulatory or stress response kinase-induced condition in a mammal, in which to this method a 20 therapeutically effective amount of a compound according to the invention is administered to a sick mammal in need of such treatment. The therapeutic amount varies according to the specific disease and can be determined by the person skilled in the art without undue effort. 25 The present invention also encompasses the use compounds of the formula I and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment or prevention of retinal vascularisation. The expression "immune-modulatory or stress response kinase-induced 30 diseases or conditions" refers to pathological conditions that depend on the activity of one or more immune-modulatory or stress response kinases. immune-modulatory or stress response kinases either directly or indirectly participate in the signal transduction pathways of a variety of cellular activities, including proliferation, adhesion and migration and differentiation. Diseases associated with immune-modulatory or stress response kinase activity include neoplastic malignancies ( solid tumor cancers, cancers of the lymphatic or WO 2013/110309 PCT/EP2012/005358 -45 blood system and the like), of neurodegenerative diseases, immune related disorders like arthritis, psoriasis, lupus, multiple sclerosis or other autoimmune diseases as well as chronic infections. 5 The present invention specifically relates to compounds of the formula I and pharmaceutically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for the use for the treatment of diseases in which the inhibition, regulation 10 and/or modulation inhibition of GCN2 plays a role. The present invention specifically relates to compounds of the formula I and pharmaceutically acceptable salts, solvates, tautomers and stereoisomers 15 thereof, including mixtures thereof in all ratios, for the use for the inhibition of GCN2. The present invention specifically relates to compounds of the formula I and pharmaceutically acceptable salts, solvates, tautomers and stereoisomers 20 thereof, including mixtures thereof in all ratios, for the use for the treatment of neoplastic malignancies (solid tumor cancers, cancers of the lymphatic or blood system and the like), of neurodegenerative diseases, immune related disorders like arthritis, psoriasis, lupus, multiple sclerosis or other autoimmune 25 diseases as well as chronic infections. Especial preference is given to the use for the treatment of a disease where the disease is a neoplastic malignancies. 30 The neoplastic malignancies is preferably selected from the group of tumours of the lung, squamous epithelium, the bladder, the stomach, the kidneys, of head and neck, the oesophagus, the cervix, the thyroid, the intestine, the liver, the brain, the prostate, the urogenital tract, the lymphatic system, the stomach 35 and/or the larynx.
WO 2013/110309 PCT/EP2012/005358 -46 The neoplastic malignancies is furthermore preferably selected from the group lung adenocarcinoma, small-cell lung carcinomas, pancreatic cancer, glioblas tomas, colon carcinoma and breast carcinoma. Preference is furthermore given to the use for the treatment of a neoplastic malignancies of the blood and immune system, preferably for the treatment of a tumour selected from the group of acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia. 10 The present invention specifically relates to methods for treating or preventing an inflammatory condition, immunological condition, autoimmune condition, allergic condition, rheumatic condition, thrombotic condition, cancer, infection, 15 neurodegenerative disease, neuroinflammatory disease, cardiovascular disease or metabolic condition, comprising administering to a subject in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt, tautomer, stereoisomer or solvate thereof. 20 In another aspect provided herein are methods of inhibiting a kinase in a cell expressing said kinase, comprising contacting said cell with an effective amount of a compound of formula I or a pharmaceutically acceptable salt, tautomer, stereoisomer or solvate thereof. In one embodiment the kinase is GCN2 or 25 mutants or isoforms thereof, or combinations of two or more thereof. Representative immunological conditions that compounds of formula I are useful for treating or preventing include, but are not limited to, Behcet's syndrome, non-allergy mast cell diseases (e.g., mastocytosis and treatment of 30 anaphylaxis), ankylosing spondylitis, osteoarthritis, rheumatoid arthritis (RA), multiple sclerosis, lupus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, Grave's disease, transplant rejection, humoral transplant rejection, non-humoral transplant rejection, cellular 35 transplant rejection, immune thrombocytopenic purpura (ITP), idiopathic thrombocytopenic purpura, diabetes, immunological response to bacterial, WO 2013/110309 PCT/EP2012/005358 -47 parasitic, helminth infestation or viral infection, eczema, dermatitis, graft versus host disease, Goodpasture's disease, hemolytic disease of the newborn, autoimmune hemolytic anemia, anti-phospholipid syndrome, ANCA-associated vasculitis, Churg-Strauss syndrome, Wegeners granulomatosus, pemphigus 5 vulgaris, serum sickness, mixed cryoglobulinemia, peripheral neuropathy associated with IgM antibody, microscopic polyangiitis, Hashimoto's thyroiditis, Sjogrens syndrome, fibrosing conditions (such as those dependent on the innate or adaptive immune systems or local mesenchyma cells) or primary 10 biliary cirrhosis. Representative autoimmune conditions that compounds of formula I are useful for treating or preventing include, but are not limited to, autoimmune hemolytic anemia (Al HA), Behcet's syndrome, Crohn's disease, type I diabetes, 15 Goodpasture's disease, Grave's disease, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, lupus, multiple sclerosis, amyotrophic lateral sclerosis, myasthenia gravis, pemphigus vulgaris, primary biliary cirrhosis, rheumatoid arthritis, scleroderma, Sjogren's syndrome, ulcerative colitis, or Wegeners 20 granulomatosus. Representative allergic conditions that compounds of formula I are useful for treating or preventing include, but are not limited to, anaphylaxis, hay fever, allergic conjunctivitis, allergic rhinitis, allergic asthma, atopic dermatitis, eczema, 25 urticaria, mucosal disorders, tissue disorders and certain gastrointestinal disorders. Representative rheumatic conditions that compounds of formula I are useful for treating or preventing include, but are not limited to, rheumatoid arthritis, gout, 30 ankylosing spondylitis, or osteoarthritis. Representative inflammatory conditions that compounds of formula I are useful for treating or preventing include, but are not limited to, non-ANCA (anti-neutrophil cytoplasmic autoantibody) vasculitis (e.g., wherein GCN2 function is associated 35 with neutrophil adhesion, diapedesis and/or activation), psoriasis, asthma, allergic rhinitis, allergic conjunctivitis, chronic urticaria, hives, anaphylaxis, bronchitis, WO 2013/110309 PCT/EP2012/005358 -48 chronic obstructive pulmonary disease, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, gout, Crohn's disease, mucous colitis, ulcerative colitis, allergy to intestinal antigens (such as gluten enteropathy), diabetes (e.g., Type I diabetes and Type il diabetes) and obesity. In some embodiments, the inflammatory condition is a dermatologic condition, such as, for example, psoriasis, urticaria, hives, eczema, scleroderma, or dermatitis. In other embodiments, the inflammatory condition is an inflammatory pulmonary condition, such as, for example, asthma, bronchitis, chronic obstructive pulmonary disease 10 (COPD), or adult/acute respiratory distress syndrome (ARDS). In other embodiments, the inflammatory condition is a gastrointestinal condition, such as, for example, inflammatory bowel disease, ulcerative colitis, Crohn's disease, idiopathic inflammatory bowel disease, irritable bowel syndrome, or spastic colon. 15 Representative infections that compounds of formula I are useful for treating or preventing include, but are not limited to, bacterial, parasitic, prion, viral infections or helminth infestation. Representative cancers that compounds of formula I are useful for treating or 20 preventing include, but are not limited to, cancer of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, 25 pancreas, brain, central nervous system, solid tumors and blood-borne tumors. Representative cardiovascular diseases that compounds of formula I are useful for treating or preventing include, but are not limited to, restenosis, atherosclerosis and its consequences such as stroke, myocardial infarction, ischemic damage to 30 the heart, lung, gut, kidney, liver, pancreas, spleen or brain. Representative metabolic conditions that compounds of formula I are useful for treating or preventing include, but are not limited to, obesity and diabetes (e.g. , Type I and II diabetes). In a particular embodiment, provided herein are methods 35 for the treatment or prevention of insulin resistance. In certain embodiments, provided herein are methods for the treatment or prevention of insulin resistance WO 2013/110309 PCT/EP2012/005358 - 49 that leads to diabetes (e.g., Type 11 diabetes). In another embodiment, provided herein are methods for the treatment or prevention of syndrome X or metabolic syndrome. In another embodiment, provided herein are methods for the treatment or prevention of Type Il diabetes, Type I diabetes, slow-onset Type I diabetes, 5 diabetes insipidus (e.g., neurogenic diabetes insipidus, nephrogenic diabetes insipidus, dipsogenic diabetes insipidus, or gestagenic diabetes insipidus), diabetes mellitus, gestational diabetes mellitus, polycystic ovarian syndrome, maturity-onset diabetes, juvenile diabetes, insulin-dependant diabetes, non-insulin 10 dependant diabetes, malnutrition-related diabetes, ketosis-prone diabetes, pre diabetes (e.g. , impaired glucose metabolism), cystic fibrosis related diabetes, hemochromatosis and ketosis-resistant diabetes. Representative neurodegenerative and neuroinflammatory diseases that 15 compounds of formula I are useful for treating or preventing include, but are not limited to, Huntington's disease, Alzheimer's disease, viral (e.g., HIV) or bacterial associated encephalitis and damage. In another embodiment, provided herein are methods for the treatment or 20 prevention of fibrotic diseases and disorders. In a particular embodiment, provided herein are methods for the treatment or prevention of idiopathic pulmonary fibrosis, myelofibrosis, hepatic fibrosis, steatofibrosis and steatohepatitis. In another embodiment, provided herein are methods for the treatment or 25 prevention of diseases associated with thrombotic events such as but not limited to atherosclerosis, myocardial infarction and ischemic stroke. The present invention specifically relates to compounds of the formula I and pharmaceutically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for the use for the treatment and/or prevention of inflammatory conditions, immunological conditions, autoimmune conditions, allergic conditions, rheumatic conditions, thrombotic conditions, cancer, infections, neurodegenerative diseases, neuroinflammatory 35 diseases, cardiovascular diseases, and metabolic conditions, the methods WO 2013/110309 PCT/EP2012/005358 - 50 comprising administering to a subject in need thereof an effective amount of a compound of claim 1. Moreover, the present invention specifically relates to compounds for the use 5 for the treatment and/or prevention of cancer, where the cancer to be treated is a solid tumour or a tumour of the blood and immune system. 10 Moreover, the present invention specifically relates to compounds, for the use for the treatment and/or prevention of cancer, where the where the tumour originates from the group of acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia. 15 Moreover, the present invention specifically relates to compounds, for the use for the treatment and/or prevention of cancer, where the solid tumour originates from the group of tumours of the epithelium, the bladder, the stomach, the kidneys, of head and neck, the esophagus, the cervix, the 20 thyroid, the intestine, the liver, the brain, the prostate, the uro-genital tract, the lymphatic system, the stomach, the larynx, the bones, including chondosarcoma and Ewing sarcoma, germ cells, including embryonal tissue tumours, and/or the lung, from the group of monocytic leukaemia, lung 25 adenocarcinoma, small-cell lung carcinomas, pancreatic cancer, glioblastomas, neurofibroma, angiosarcoma, breast carcinoma and /or maligna melanoma. 30 Moreover, the present invention specifically relates to for the use for the treatment and/or prevention of diseases selected from the group rheumatoid arthritis, systemic lupus, asthma, multiple sclerosis, osteoarthritis, ischemic injury, giant cell arteritis, inflammatory bowel disease, diabetes, cystic fibrosis, psoriasis, Sj6grens syndrom and transplant organ rejection. 35 WO 2013/110309 PCT/EP2012/005358 - 51 Moreover, the present invention specifically relates to compounds for the use for the treatment and/or prevention of diseases selected from the group Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis-Dutch Type, cerebral amyloid angiopathy, Creutzfeldt-Jakob 5 disease, frontotemporal dementias, Huntington's disease, Parkinson's disease. Moreover, the present invention specifically relates to compounds for the use for the treatment and/or prevention of diseases selected from the group 10 leishmania, mycobacteria, including M. leprae, M. tuberculosis and/or M. avium, leishmania, plasmodium, human immunodeficiency virus, Epstein Barr virus, Herpes simplex virus, hepatitis C virus. 15 The disclosed compounds of the formula I can be administered in combination with other known therapeutic agents, including anticancer agents. As used here, the term "anticancer agent" relates to any agent which is administered to a patient with cancer for the purposes of treating the cancer. 20 The anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti- tumour agents: 25 (i) antiproliferative/antineoplastic/DNA-damaging agents and combina tions thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chloroambucil, busulphan and nitrosoureas); antimetabolites (for 30 example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (for example anthracyclines, like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin) ; antimitotic agents (for example vinca alkaloids, like 35 vincristine, vinblastine, vindesine and vinorelbine, and taxoids, like taxol and taxotere) ; topoisomerase inhibitors (for example epipodophyllotoxins, like WO 2013/110309 PCT/EP2012/005358 - 52 etoposide and teniposide, amsacrine, topotecan, irinotecan and camptothecin) and cell-differentiating agents (for example all-trans-retinoic acid, 13-cis retinoic acid and fenretinide); (ii) cytostatic agents, such as antioestrogens (for example tamoxifen, 5 toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor downregulators (for example fulvestrant), antiandrogens (for example bi calutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), 10 progesterones (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase, such as finasteride; (iii) agents which inhibit cancer cell invasion (for example metallo 15 proteinase inhibitors, like marimastat, and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptinm] and the anti-erbbl antibody 20 cetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6- (3-morpholinopropoxy) quinazolin 25 4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis (2 methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3 chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (Cl 1033)), for example inhibitors of the platelet-derived growth factor family and for 30 example inhibitors of the hepatocyte growth factor family; (v)antiangiogenic agents, such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastinm], compounds such as those disclosed in published international patent applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other WO 2013/110309 PCT/EP2012/005358 - 53 mechanisms (for example linomide, inhibitors of integrin avp3 function and angiostatin); (vi) vessel-damaging agents, such as combretastatin A4 and compounds disclosed in international patent applications WO 99/02166, WO 00/40529, 5 WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) antisense therapies, for example those which are directed to the tar gets listed above, such as ISIS 2503, an anti-Ras antisense; (viii) gene therapy approaches, including, for example, approaches for re 10 placement of aberrant genes, such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches, such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme, and approaches for increasing patient tolerance to 15 chemotherapy or radiotherapy, such as multi-drug resistance gene therapy; and (ix) immunotherapy approaches, including, for example, ex-vivo and in vivo approaches for increasing the immunogenicity of patient tumour cells, such as transfection with cytokines, such as interleukin 2, interleukin 4 or 20 granulocyte-macrophage colony stimulating factor, approaches for decreasing T-cell anergy, approaches using transfected immune cells, such as cytokine transfected dendritic cells, approaches using cytokine-transfected tumour cell lines, and approaches using anti-idiotypic antibodies. 25 The medicaments from Table 1 below are preferably, but not exclusively, com bined with the compounds of the formula 1. Table 1. Alkylating agents Cyclophosphamide Lomustine 30 Busulfan Procarbazine Ifosfamide Altretamine Melphalan Estramustine phosphate Hexamethylmelamine Mechloroethamine Thiotepa Streptozocin chloroambucil Temozolomide 35 Dacarbazine Semustine Carmustine WO 2013/110309 PCT/EP2012/005358 - 54 Platinum agents Cisplatin Carboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin (Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson Tetraplatin Matthey) 5 Ormiplatin BBR-3464 lproplatin (Hoffrnann-La Roche) SM-1 1355 (Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine Tomudex Gemcitabine Trimetrexate 10 Capecitabine Deoxycoformycin 5-fluorouracil Fludarabine Floxuridine Pentostatin 2-chlorodesoxyadenosine Raltitrexed 6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen) 15 Cytarabine Clofarabine (Bioenvision) 2-fluorodesoxycytidine Irofulven (MGI Pharrna) Methotrexate DMDC (Hoffmann-La Idatrexate Roche) Ethynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan (SuperGen) 20 inhibitors Epirubicin Exatecan mesylate Etoposide (Daiichi) Teniposide or Quinamed (ChemGenex) mitoxantrone Gimatecan (Sigma- Tau) Irinotecan (CPT-1 1) Diflomotecan (Beaufour 7-ethyl-10- Ipsen) 25 hydroxycamptothecin TAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum) Dexrazoxanet J-1 07088 (Merck & Co) (TopoTarget) BNP-1350 (BioNumerik) Pixantrone (Novuspharrna) CKD-602 (Chong Kun Rebeccamycin analogue Dang) (Exelixis) KW-2170 (Kyowa Hakko) 30 BBR-3576 (Novuspharrna) Antitumour Dactinomycin (Actinomycin Amonafide antibiotics D) Azonafide Doxorubicin (Adriamycin) Anthrapyrazole Deoxyrubicin Oxantrazole 35 Valrubicin Losoxantrone Daunorubicin Bleomycin sulfate 1 (Daunomycin) (Blenoxan) WO 2013/110309 PCT/EP2012/005358 - 55 Epirubicin Bleomycinic acid Therarubicin Bleomycin A Idarubicin Bleomycin B Rubidazon Mitomycin C Plicamycinp MEN-10755 (Menarini) 5 Porfiromycin GPX-100 (Gem Cyanomorpholinodoxo- Pharmaceuticals) rubicin Mitoxantron (Novantron) Antimitotic agents Paclitaxel SB 408075 Docetaxel (GlaxoSmithKline) 10 Colchicine E7010 (Abbott) Vinblastine PG-TXL (Cell Vincristine Therapeutics) Vinorelbine IDN 5109 (Bayer) Vindesine A 105972 (Abbott) Dolastatin 10 (NCI) A 204197 (Abbott) 15 Rhizoxin (Fujisawa) LU 223651 (BASF) Mivobulin (Warner- D 24851 (ASTA Medica) Lambert) ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4 (BMS) RPR 109881A (Aventis) lsohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) Epothilone B (Novartis) ZD 6126 (AstraZeneca) 20 T 900607 (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) Azaepothilon B (BMS) 25 BMS 247550 (BMS) BNP- 7787 (BioNumerik) BMS 184476 (BMS) CA-4-prodrug (OXiGENE) BMS 188797 (BMS) Dolastatin-10 (NrH) 1 Taxoprexin (Protarga) CA-4 (OXiGENE) Aromatase Aminoglutethimide Exemestan inhibitors Letrozole Atamestan (BioMedicines) 30 Anastrazole YM-511 (Yamanouchi) Formestan Thymidylate Pemetrexed (Eli Lilly) Nolatrexed (Eximias) synthase ZD-9331 (BTG) CoFactorTm (BioKeys) inhibitors 35 DNA antagonists Trabectedin (PharmaMar) Mafosfamide (Baxter Glufosfamide (Baxter International) WO 2013/110309 PCT/EP2012/005358 - 56 International) Apaziquone (Spectrum Albumin + 32P (Isotope Pharmaceuticals) Solutions) 06-benzylguanine Thymectacin (NewBiotics) (Paligent) Edotreotid (Novartis) 5 Farnesyl Arglabin (NuOncology Tipifarnib (Johnson & transferase Labs) Johnson) inhibitors lonafarnib (Schering- Perillyl alcohol (DOR Plough) BioPharma) BAY-43-9006 (Bayer) 10 Pump inhibitors CBT-1 (CBA Pharma) Zosuquidar Tariquidar (Xenova) trihydrochloride (Eli Lilly) MS-209 (Schering AG) Biricodar dicitrate (Vertex) Histone acetyl Tacedinaline (Pfizer) Pivaloyloxymethyl butyrate transferase in- SAHA (Aton Pharma) (Titan) 15 hibitors 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 inhibi- tech) Didox (Molecules for tors Gallium maltolate (Titan) Health) 20 Tiapin (Vion) TNF-alpha Virulizin (Lorus Therapeu- Revimid (Celgene) agonists/ tics) antagonists CDC-394 (Celgene) 25 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) 30 Immunomodula- Interferon Dexosome therapy (Ano tors Oncophage (Antigenics) sys) GMK (Progenics) Pentrix (Australian Cancer Adenocarcinoma vaccine Technology) (Biomira) JSF-154 (Tragen) CTP-37 (AVI BioPharma) Cancer vaccine (Intercell) 35 JRX-2 (Immuno-Rx) Norelin (Biostar) PEP-005 (Peplin Biotech) BLP-25 (Biomira) Synchrovax vaccines (CTL MGV (Progenics) WO 2013/110309 PCT/EP2012/005358 - 57 Immuno) !3-Alethin (Dovetail) Melanoma vaccine (CTL CLL-Thera (Vasogen) Immuno) p21-RAS vaccine (Gem Vax) 5 Hormonal and Oestrogens Prednisone antihormonal Conjugated oestrogens Methylprednisolone agents Ethynyloestradiol Prednisolone chlorotrianisene Aminoglutethimide Idenestrol Leuprolide Hydroxyprogesterone Goserelin 10 caproate Leuporelin Medroxyprogesterone Bicalutamide Testosterone Flutamide Testosterone propionate Octreotide Fluoxymesterone Nilutamide Methyltestosterone Mitotan 15 Diethylstilbestrol P-04 (Novogen) Megestrol 2-Methoxyoestradiol (En Tamoxifen treMed) Toremofin Arzoxifen (Eli Lilly) Dexamethasone Photodynamic Talaporfin (Light Sciences) Pd-Bacteriopheophorbid 20 agents Theralux (Theratechnolo- (Yeda) gies) Lutetium-Texaphyrin Motexafin-Gadolinium (Pharmacyclics) (Pharmacyclics) Hypericin Tyrosine kinase Imatinib (Novartis) Kahalide F (PharmaMar) 25 inhibitors Leflunomide(Sugen/Phar- CEP- 701 (Cephalon) macia) CEP-751 (Cephalon) ZD1839 (AstraZeneca) MLN518 (Millenium) Erlotinib (Oncogene Sci- PKC412 (Novartis) ence) Phenoxodiol 0 Canertjnib (Pfizer) Trastuzumab (Genentech) Squalamine (Genaera) C225 (ImClone) 30 SU5416 (Pharmacia) rhu-Mab (Genentech) SU6668 (Pharmacia) MDX-H210 (Medarex) ZD4190 (AstraZeneca) 2C4 (Genentech) ZD6474 (AstraZeneca) MDX-447 (Medarex) Vatalanib (Novartis) ABX-EGF (Abgenix) PK1166 (Novartis) IMC-1C11 (ImClone) 35 GW2016 (GlaxoSmith Kline) EKB-509 (Wyeth) WO 2013/110309 PCT/EP2012/005358 - 58 EKB-569 (Wyeth) Various agents SR-27897 (CCK-A inhibi- BCX-1777 (PNP inhibitor, tor, Sanofi-Synthelabo) BioCryst) Tocladesine (cyclic AMP Ranpirnase (ribonuclease agonist, Ribapharm) stimulant, Alfacell) 5 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 T m (CYP450 R-Flurbiprofen (NF-kappaB 10 stimulant, Bavarian Nordic) inhibitor, Encore) GCS-lOO (gal3 antagonist, 3CPA (NF-kappaB GlycoGenesys) inhibitor, Active Biotech) G17DT immunogen (gas- Seocalcitol (vitamin D trin inhibitor, Aphton) receptor agonist, Leo) Efaproxiral (oxygenator, 131-1-TM-601 (DNA 15 Allos Therapeutics) antagonist, PI-88 (heparanase inhibi- TransMolecular) tor, Progen) Eflornithin (ODC inhibitor, Tesmilifen (histamine an- ILEX Oncology) tagonist, YM BioSciences) Minodronic acid Histamine (histamine H2 (osteoclast inhibitor, receptor agonist, Maxim) Yamanouchi) 20 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) 25 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, Immunol t m (triclosan Cell Pathways) mouthwash, Endo) AG-2037 (GART inhibitor, Triacetyluridine (uridine 30 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) 35 inhibitor, Millennium) PCK-3145 (apoptosis SRL-172 (T-cell stimulant, promoter, Procyon) I SR Pharma) Doranidazole (apoptosis WO 2013/110309 PCT/EP2012/005358 - 59 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) 5 Midostaurin (PKC inhibitor, MX6 (apoptosis promoter, Novartis) MAXIA) Bryostatin-1 (PKC stimu- Apomine (apoptosis lant, GPC Biotech) promoter, ILEX Oncology) CDA-ll (apoptosis pro- Urocidin (apoptosis moter, Everlife) promoter, Bioniche) SDX-101 (apoptosis pro- Ro-31-7453 (apoptosis 10 moter, Salmedix) promoter, La Roche) Ceflatonin (apoptosis pro- Brostallicin (apoptosis moter, ChemGenex) promoter, Pharmacia) The disclosed compounds of the formula I and pharmaceutically acceptable 15 solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, preferably can be administered in combination with immunmodulators, preferably with anti-PDL-1- or IL-12. 20 The following abbreviations refer respectively to the definitions below: aq (aqueous), h (hour), g (gram), L (liter), mg (milligram), MHz (Megahertz), min. (minute), mm (millimeter), mmol (millimole), mM (millimolar), m.p. (melting point), eq (equivalent), mL (milliliter), L (microliter), ACN (acetonitrile), AcOH (acetic acid), 25 CDCI 3 (deuterated chloroform), CD 3 0D (deuterated methanol), CH 3 CN (acetonitrile), c-hex (cyclohexane), DCC (dicyclohexyl carbodiimide), DCM (dichloromethane), DIC (diisopropyl carbodiimide), DIEA (diisopropylethyl-amine), DMF (dimethylformamide), DMSO (dimethylsulfoxide), DMSO-d 6 (deuterated dimethylsulfoxide), EDC (1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI 30 (Electro-spray ionization), EtOAc (ethyl acetate), Et 2 O (diethyl ether), EtOH (ethanol), HATU (dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene] dimethyl-ammonium hexafluorophosphate), HPLC (High Performance Liquid Chromatography), i-PrOH (2-propanol), K 2
CO
3 (potassium carbonate), LC (Liquid 35 Chromatography), MeOH (methanol), MgSO 4 (magnesium sulfate), MS (mass spectrometry), MTBE (Methyl tert-butyl ether), NaHCO 3 (sodium bicarbonate), WO 2013/110309 PCT/EP2012/005358 - 60 NaBH 4 (sodium borohydride), NMM (N-methyl morpholine), NMR (Nuclear Magnetic Resonance), PyBOP (benzotriazole-1-yI-oxy-tris-pyrrolidino phosphonium hexafluorophosphate), RT (room temperature), Rt (retention time), SPE (solid phase extraction), TBTU (2-(1-H-benzotriazole-1-yl)-1,1,3,3 tetramethyluromium tetrafluoro borate), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TLC (Thin Layer Chromatography), UV (Ultraviolet). Description of the in vitro assays 10 GCN2: Assay principle & conditions This assay can quantificate the activity of the serin kinase GCN2 (general control non-derepressible-2). 15 This kinase is involved in the stress metabolism of cells. It is activated upon starvation (amino acid depletion). Its natural substrate is elF2a (eukaryotic initiation factor 2 alpha subunit), a translation factor, which gets activated (phosphorylated) by GCN2 in case of an amino acid bottleneck in the cells. 20 This in turn leads to a halt of the protein synthesis. Inhibition of GCN2 results in stopping this mechanism: The cell can not stop protein production upon "starvation" stress. 25 The assay is run in two steps: the enzymatic reaction and the detection step. In the first step GCN2 is incubated with 10 pM ATP and 80 nM of the GFP labelled substrate elF2alpha at room temperature. The enzymatic reaction is stopped by addition of EDTA. The amount of phosphorylated elF2alpha is determined by TR-FRET (Lanthascreen): A 30 complex is formed consisting of antibody and GFP labelled phospho-elF2a, which allows a FRET upon exitation at 340 nm. The GCN2-activity is directly proportional to the ratio of fluorescence units at the emission wavelenghth 520 nm (phosphopeptide-sensitive wavelength = emission of GFP) to the units at 495 nm (reference wavelength = emission of Terbium-chelate). 35 Final concentrations in the enzymatic reaction WO 2013/110309 PCT/EP2012/005358 -61 Hepes, pH 7.0 50 mM MgC1 2 10 mM MnC1 2 5 mM BSA 0.1% 5 DMSO 1% ATP 10 uM DTT 2 mM GFP-elF2a 80 nM (substrate) 10 GCN2 30 nM (enzyme) Assay procedure 4 uL enzyme solution (in assay buffer) 15 1.5 uL compound (in cmpd dilution buffer/6.3% DMSO) Incubation 20 min at RT 4 uL substrate/ATP mix (in assay buffer) Incubation 90 min at RT 10 uL stop/detection mix (in antibody dilution buffer) 20 Incubation 60 min at RT Readout Lanthascreen 340/495/520 Cellular assay for the determination of compound activities 25 Human U2OS cells (2000 cells/well) are seeded into 384-well plates and incubated for 20 hours. The next day, the cells are treated with the test compounds and incubated for 2 hours. Then, tryptophanol, at a final concentration of 600 pM, is added to the 30 cells and those are incubated for 30 minutes. The analysis of cellular GCN2 activities is done by immunocytochemistry. Briefly, cells are fixated on the well surfaces by formaldehyde and permeabilised with Triton X-100. The primary antibody (anti-phospho 35 elF2alpha (Ser51, Cell Signalling Technology, #3398) is incubated on the WO 2013/110309 PCT/EP2012/005358 -62 treated cells for 20 hours, followed by a 60 minutes incubation of the secondary antibody (anti-rabbit-IgG-Alexa 488; Molecular Probes # 11008). The analysis and quantification of phosphorylated GCN2 is done by scanning the plates in the Acumen Explorer system (TTPLabtech). The obtained data 5 are normalised against the untreated control wells (DMSO only) and expressed as % effect values. The determination of IC5o values is done by using the Graph Pad Prism software. 10 HPLC/MS conditions A column: Chromolith PerformanceROD RP-18e, 100 x 3 mm 2 gradient: A:B = 99:1 to 0:100 in 1.8 min flow rate: 2.0 ml/min 15 eluent A: water + 0.05 % formic acid eluent B: acetonitrile + 0.04 % formic acid wavelength: 220 nm mass spectroscopy: positive mode 20 HPLC/MS conditions B column: Chromolith PerformanceROD RP-18e, 50 x 4.6 mm 2 gradient: A:B = 96:4 to 0:100 in 2.8 min flow rate: 2.40 ml/min 25 eluent A: water + 0.05 % formic acid Eluent B: acetonitrile + 0.04 % formic acid wavelength: 220 nm mass spectroscopy: positive mode 30 HPLC/MS conditions C column: Chromolith PerformanceROD RP-18e, 100 x 3 mm 2 gradient: A:B = 99:1 to 0:100 in 3.5 min flow rate: 2.0 mI/min 35 eluent A: water + 0.05 % formic acid WO 2013/110309 PCT/EP2012/005358 - 63 Eluent B: acetonitrile + 0.04 % formic acid wavelength: 220 nm mass spectroscopy: positive mode Above and below, all temperatures are indicated in*C. In the following ex amples, "conventional work-up" means: water is added if necessary, the pH is adjusted, if necessary, to values between 2 and 10, depending on the constitution of the end product, the mixture is extracted with ethyl acetate or 10 dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or by crystallisation. Rf values on silica gel; eluent: ethyl acetate/methanol 9:1. 15 Example 1 Synthesis of [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-y]-(1 phenyl-1 H-pyrazol-4-yl)-amine ("Al") 20 H CI N C H 2 N N(iPr) 2 Et CI N N N -N 2 o dioxane N - O 25 -N H2N N N-N
H
2 /Pd N-N H THF HN N N(iPr) 2 Et HN N N NH O 30 ~dioxane I N 30 NH 0
NO
2 0 2 NaNO 2 0 ~ N N
H
2
SO
4 /water N N N 35 N
NN
WO 2013/110309 PCT/EP2012/005358 -64 2.46 g (19.0 mmol) Diisopropylethylamine are added slowly to a solution of 3.36 g (17.3 mmol) 2,4-dichloro-5-nitropyrimidine and 2.13 g (17.3 mmol) p anisidine in 30 ml dioxane. The mixture is stirred for 3 hours at room 5 temperature. Then it is partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with ethyl acetate/cyclohexane as eluent giving (2-chloro-5-nitro-pyrimidin-4-yl)-(4-methoxy-phenyl)-amine as 10 orange crystals; HPLC/MS (B): 2.24 min, [M+HJ 281; 1 H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.35 (s, 1H), 9.11 (s, 1H), 7.42 (m, 2H), 7.00 (m, 2H), 3.79 (s, 3H). 15 284 g (19.0 mmol) Diisopropylethylamine are added to a solution of 561 mg (2.00 mmol) (2-chloro-5-nitro-pyrimidin-4-yl)-(4-methoxy-phenyl)-amine and 350 mg (2.00 mmol) 1-phenyl-1H-pyrazol-4-ylamine in 6 ml dioxane. The mixture is stirred for 16 hours at room temperature. Then water is added to the reaction mixture, the resulting precipitate is filtered off, washed with water and 20 dried under vacuum giving N 4 -(4-methoxy-phenyl)-5-nitro-N 2 -(1-phenyl-1 H pyrazol-4-yl)-pyrimidine-2,4-diamine as yellow crystals; HPLC/MS (B): 2.50 min, [M+H] 404. 25 A solution of 800 mg (1.98 mmol) N 4 -(4-Methoxy-phenyl)-5-nitro-N 2 -(1 -phenyl 1 H-pyrazol-4-yl)-pyrimidine-2,4-diamine in 20 ml THF is hydrogenated with 200 mg palladium on charcoal as catalyst at room temperature and under atmospheric pressure. The catalyst is filtered off; the filtrate is evaporated and 30 dried under vacuum giving N 4 -(4-methoxy-phenyl)-N 2 -(1-phenyl-1 H-pyrazol-4 yl)-pyrimidine-2,4,5-triamine as greenish crystals; HPLC/MS (A): 1.45 min, [M+H] 374; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pM] = 8.63 (s, 1H), 8.26 (s, 1H), 8.10 (s, 1H), 7.61 (d, J=3.3, 2H), 7.53 (d, J=8.9, 2H), 7.50 (d, J=8.0, 2H), 7.41 (t, J=7.9, 35 2H), 7.22 (t, J=7.3, 1H), 6.93 (d, J=9.0, 2H), 4.22 (s, 2H), 3.72 (s, 3H).
WO 2013/110309 PCT/EP2012/005358 - 65 A suspension of 373 mg (1.00 mmol) N 4 -(4-methoxy-phenyl)-N 2-(1-phenyl-1H pyrazol-4-yl)-pyrimidine-2,4,5-triamine in 80 ml water is treated with 14.3 ml concentrated sulfuric acid and then with 138 mg (2.00 mmol) sodium nitrite. The mixture is stirred for 16 hours at room temperature. Aqueous sodium 5 hydroxide is added to the reaction mixture to reach an alkaline pH-value. Then the mixture is extracted with dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with dichloromethane/methanol as eluent giving "Al" as yellow 10 crystals; HPLC/MS (B): 2.52 min, [M+H] 385; 1 H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.59 (s, 1H), 9.44 (s, 1H), 8.72 (s, 1H), 8.04 (d, J=8.7, 2H), 7.88 (d, J=0.4, 1H), 7.74 (d, J=7.8, 2H), 7.52 (t, J=8.0, 2H), 7.33 (t, J=7.4, 1H), 7.26 (d, J=8.9, 2H), 3.90 (s, 3H). 15 The synthesis of [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-djpyrimidin-5-yl] (1-methyl-1 H-pyrazol-3-yl)-amine ("A2") is performed analogously N 20 N /N O N N HPLC/MS (A): 1.75 min, [M+H] 323. 25 Example 2 Synthesis of [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yI]-(1H 30 pyrazol-4-yl)-amine ("A3") 35 WO 2013/110309 PCT/EP2012/005358 -66 H HNi CI H NaNO CI N N N 2 NY NO O- YH d C
N
N2 "TF " H2C yNI 5 ~ N 0 H 2 N 0 HN H O N 2-methoxy-ethanol N 10 100* C N A solution of 1.86 g (6.64 mmol) (2-chloro-5-nitro-pyrimidin-4-yl)-(4-methoxy phenyl)-amine (from example 1) in 20 ml THF is hydrogenated with 1.0 g sponge-nickel as catalyst at room temperature and under atmospheric 15 pressure. The catalyst is filtered off; the filtrate is evaporated and dried under vacuum giving 2-chloro-N -(4-methoxy-phenyl)-pyrimidine-4,5-diamine as grey solid; HPLC/MS (A): 1.63 min, [M+H] 251; 1 H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 8.51 (s, 1H), 7.56 (m, 3H), 6.95 (d, 20 J=9.1, 2H), 5.19 (s, 2H), 3.76 (s, 3H). A solution of 1.51 g (6.02 mmol) 2-chloro-N 4 -(4-methoxy-phenyl)-pyrimidine 4,5-diamine in 75 ml 37% aqueous hydrochloric acid is treated with 852 mg (12.4 mmol) sodium nitrite. The mixture is stirred for 16 hours at room 25 temperature. Aqueous sodium hydroxide is added to the reaction mixture to reach a neutral pH-value. Then the mixture is extracted with dichloromethane. The organic phase is dried over sodium sulfate and evaporated giving 5 chloro-3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine as brown solid; 30 HPLC/MS (A): 1.89 min, [M+H] 262; 1H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 9.82 (s, 1H), 7.93 (d, J=9.1, 2H), 7.26 (d, J=9.1, 2H), 3.88 (s, 3H). 35 A solution of 262 mg (1.00 mmol) 5-chloro-3-(4-methoxy-phenyl)-3H [1,2,3]triazolo[4,5-d]pyrimidine and 183 mg (1.00 mmol) 4-amino-pyrazole-1- WO 2013/110309 PCT/EP2012/005358 -67 carboxylic acid tert-butyl ester in 2.5 ml 2-methoxy-ethanol is stirred for 3 hours at 100* C. The reaction mixture is cooled to room temperature and water is added. The resulting precipitate is filtered off, washed with water and dried. The crude product is recrystallized from isopropanol giving "A3" as brown 5 crystals; HPLC/MS (A): 1.6 min, [M+H] 309; 'H NMR (400 MHz, DMSO) 6 = 12.54 (s, 1H), 10.33 (s, 1H), 9.36 (s, 1H), 7.98 (d, J=9.0, 2H), 7.83 (s, 1H), 7.23 (d, J=8.8, 2H), 3.88 (s, 3H). 10 The following compounds are prepared analogously (3-phenyl-3H-[1,2,3]triazolo[4,5-dlpyrimidin-5-y)-(1 H-pyrazol-4-yl)-amine ("A4") H HN N N-N N N HPLC/MS (B): 1.78 min, [M+H) 279; 20 [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-dlpyrimidin-5-yl]-(1 H-pyrazol-4-yl) amine ("A5")
-
H HN/ N o /N 25 NN N: HPLC/MS (C): 2.31 min, [M+H] 323. 30 Example 3 Synthesis of [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-(1 piperidin-4-yl-1H-pyrazol-4-yl)-amine ("A6") 35 WO 2013/110309 PCT/EP2012/005358 -68 0-- 0 H 00 O -O N N N 2-methoxy- O' ethanol 0- N 0 N-N C N19 + 3 N-N N,5N N 100 0 C . HN N N + HN N N NH 2 N- ,-N 10 A solution of 183 mg (0.70 mmol) 5-chloro-3-(4-methoxy-phenyl)-3H [1,2,3]triazolo[4,5-d]pyrimidine (from example 2) and 186 mg (0.70 mmol) 4-(4 amino-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester in 1.8 ml 2 methoxy-ethanol is stirred for 4 hours at 100* C. The reaction mixture is cooled 15 to room temperature, concentrated under vacuum and the residue is chromatographed on a silica gel column with dichloromethane/methanol as eluent giving two products: 4-{4-[3-(4-Methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamino] 20 pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester as yellow solid; HPLC/MS (B): 2.00 min, [M+H] 492; [3-(4-Methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-(1 -piperidin-4-yl 1 H-pyrazol-4-yl)-amine ("A6") as grey crystals; HPLC/MS (B): 1.35 min, [M+H] 392; 25 1H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.41 (s, 1H), 9.38 (s, 1H), 8.88 (s, 1H), 8.04 (s, 1H), 8.01 (d, J=8.7, 2H), 7.70 (s, 1H), 7.30 (d, J=8.0, 2H), 4.45 (m, 1H), 3.89 (s, 3H), 3.3 (m, 2H), 3.03 (t, J=11.5, 2H), 2.15 (m, 4H). 30 The following compound is prepared analogously [3-(4-Ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-(1 -piperidin-4-yl 1 H-pyrazol-4-yl)-amine ("A7") 35 WO 2013/110309 PCT/EP2012/005358 - 69 HN 0 N N N 5 N N HPLC/MS (C): 2.31 min, [M+H] 323. 10 Example 4 Synthesis of [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-[1 (1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-yl]-amine ("A8") 15 O'C 1+ -~ N 2-methoxy-ethanol N-N CIN + -. 20 N NN 100 0 C N HN N N
NH
2 N N 25 A solution of 105 mg (0.40 mmol) 5-chloro-3-(4-methoxy-phenyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine (from example 2) and 86.7 mg (0.40 mmol) 1-(1 methyl-piperidin-4-yl)-1 H-pyrazol-4-ylamine hydrochloride in 1.0 ml 2-methoxy ethanol is stirred for 4 hours at 1000 C. The reaction mixture is cooled to room temperature, concentrated under vacuum and the residue is chromatographed 30 on a silica gel column with dichloromethane/methanol as eluent giving "A8" as yellow crystals; HPLC/MS (A): 1.35 min, [M+H] 492; 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.40 (bs, 1H), 9.37 (s, 1H), 8.06 (s, 1H), 8.01 (d, J=8.7, 2H), 7.69 (s, 1H), 7.29 (d, J=7.9, 2H), 4.37 (m, 1H), 3.89 35 (s, 3H), 3.31 (m, 2H), 2.96 (m, 2H), 2.66 (s, 3H), 2.22 (m, 4H).
WO 2013/110309 PCT/EP2012/005358 - 70 The following compounds are prepared analogously: [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-[1 -(3-methoxy propyl)-1 H-pyrazol-4-y]-amine ("A9") 5 N- H IN N N N N 10 NN HPLC/MS (A): 1.76 min, [M+H] 381; (1-benzyl-1 H-pyrazol-4-yl)-[3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5 15 d]pyrimidin-5-yl]-amine ("Al0") 0 20 H N N~ N~ N N N HPLC/MS (A): 1.91 min, [M+H] 399; 25 [1 -(1 -methyl-piperidin-4-y)-1 H-pyrazol-4-yl]-(3-phenyl-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl)-amine ("Al 1") H 30 N N N N N HPLC/MS (A): 1.34 min, [M+H] 376; 35 With 2-amino-4-methyloxazole the compound WO 2013/110309 PCT/EP2012/005358 - 71 [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-[4-methyl-5H oxazol-(2Z)-ylidene]-amine ("A12") 5 N-N 0 N N N is obtained; 10 HPLC/MS (B): 1.89 min, [M+H] 324; according to 'H-NMR, the compound has the tautomeric structure depicted above; 15 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 9.66 (s, 1H), 7.98 (d, J=9.0, 2H), 7.42 (s, 2H), 7.24 (d, J=9.0, 3H), 3.88 (s, 5H), 2.51 (s, 3H); [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-[1 -(tetrahydro 20 pyran-4-yl)-1 H-pyrazol-4-yl]-amine ("A13") N- H / N O9 NN N O 25 N:N HPLC/MS (B): 2.02 min, [M+H] 393; [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yI]-[1 -(2-pyrrolidin- 1 30 yl-ethyl)-1H-pyrazol-4-yl]-amine ("A14") Ol JN NX N 35 HPLC/MS (A): 1.37 min, [M+H] 406; WO 2013/110309 PCT/EP2012/005358 - 72 [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-[1 -(tetrahydro pyran-4-yl)-l H-pyrazol-4-yl]-amine ("A1 5") 5 O 0 HN N N 10 HPLC/MS (A): 2.55 min; 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.36 (s, 1H), 9.36 (s, 1H), 8.11 (s, 1H), 7.99 (d, J=8.7, 2H), 7.61 (s, 1H), 7.22 (d, J=8.6, 2H), 4.37 (m, 1H), 4.15 (q, J=6.9, 2H), 3.97 (m, 2H), 3.49 (t, J=11.4, 2H), 2.03 (d, J=11.7, 2H), 1.89 15 (m, 2H), 1.39 (t, J=7.0, 3H); [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-(1 H-tetrazol-5-yi) amine ("A16") 20 .-- N H N O N , N N H N 25 NN HPLC/MS (C): 2.13 min, [M+HJ 311; 1 H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 13.38 (s, 1H), 11.46 (s, 1H), 9.50 (s, 1H), 8.03 (d, J=8.2, 2H), 7.79 (s, 1H), 7.20 (d, J=8.2, 2H), 3.87 (s, 3H). 30 [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-y]-(2H-[1,2,4]triazol 3-yl)-amine ("A17") 35 WO 2013/110309 PCT/EP2012/005358 - 73 N$H Nl N N N-N N N 5 N:N HPLC/MS (C): 1.83 min, [M+H] 323; 1 H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 15.74 (s, 1H), 11.94 (s, 1H), 9.63 (s, 1H), 8.06 (d, J=9.0, 2H), 7.27 (d, J=9.0, 2H), 3.93 (s, 3H); 10 [3-(4-methoxy-phenyl)-3H-[1,2,3]tiazolo[4,5-d]pyrimidin-5-yl]-(1 -methyl-1 H pyrazol-4-yi)-amine ("A18") 0 H 15 -N -N N NN N N N HPLC/MS (A): 1.70 min, [M+H] 323; 20 4-{4-[3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]-pyrazol 1-yl}-cyclohexanol ("A19") 2 5 H O N N N~ N N N N 30 HPLC/MS (C): 2.46 min, [M+H] 421. Example 5 35 Synthesis of [3-(4-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-[l (tetrahyd ro-pyran-4-yl)-1 H-pyrazol-4-yl]-amine ("A20") WO 2013/110309 PCT/EP2012/005358 -74
NH
2 H H CI N C+ NEt 3 N H2Ni CI N N ''NO2THF No 2 F THF N-NH 2 F 5 F 0 F F NaN N CO N-N NaNO 2 H 2 N 0 .. 10 HCI N 2-methoxy-ethanol HN N Under external cooling with ice, 2.22 g (20.0 mmol) 4-fluoroaniline is added dropwise to a solution of 4.46 g (23.0 mmol) 2,4-dichloro-5-nitropyrimidine in 15 20 ml THF. Then a solution of 2.77 ml (20.0 mmol) triethylamine in 5 ml THF is added slowly under external cooling with ice. The reaction mixture is stirred for 1 hour at room temperature. The precipitate is filtered off and washed with THF. The filtrate is evaporated and crystallized from tert-butyl-methylether 20 giving (2-chloro-5-nitro-pyrimidin-4-yl)-(4-fluoro-phenyl)-amine as yellow crystals; HPLC/MS (B): 2.26 min, [M+H] 269; 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.44 (s, 1H), 9.15 (s, 1H), 7.55 (dd, J=8.9, 5.0, 2H), 7.28 (t, J=8.8, 2H). 25 A solution of 3.46 g (12.89 mmol) (2-chloro-5-nitro-pyrimidin-4-yl)-(4-fluoro phenyl)-amine in 40 ml THF is hydrogenated with 2.0 g sponge-nickel as catalyst at room temperature and under atmospheric pressure. The catalyst is filtered off and the filtrate is evaporated giving 2-chloro-N 4 -(4-fluoro-phenyl) 30 pyrimidine-4,5-diamine as dark oil; HPLC/MS (B): 1.88 min, [M+H] 239. To a solution of 2.34 g (9.81 mmol) 2-chloro-N 4 -(4-fluoro-phenyl)-pyrimidine 4,5-diamine in 40 ml 37% aqueous hydrochloric acid 1.49 g (21.6 mmol) 35 sodium nitrite are added in portions. The mixture is stirred for 2 hours at room temperature. The precipitate is filtered off, washed with water and dried under WO 2013/110309 PCT/EP2012/005358 -75 vacuum giving 5-chloro-3-(4-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine as grey crystals. From the mother liquor a second crop of product is obtained. HPLC/MS (B): 2.25 min, [M+H] 250; 1H NMR (400 MHz, DMSO-dr) 6 [pm] = 9.85 (s, 1H), 8.11 (dd, J=8.9, 4.8, 5 2H), 7.59 (t, J=8.8, 2H). A solution of 74.9 mg (0.30 mmol) 5-chloro-3-(4-fluoro-phenyl)-3H [1,2,3]triazolo[4,5-d]pyrimidine and 60.2 mg (0.36 mmol) 1 -(tetrahydro-pyran-4 10 yl)-l H-pyrazol-4-ylamine in 0.5 ml 2-methoxy-ethanol is stirred for 4 hours at 90* C. The reaction mixture is cooled to room temperature. The solvent is partially removed under vacuum and the residue is purified by preparative HPLC yielding "A20" as brown amorphous solid; HPLC/MS (B): 2.1 min, [M+H] 15 381; 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.42 (s, 1H), 9.40 (s, 1H), 8.18 (dd, J=9.0, 4.8, 2H), 8.09 (s, 1H), 7.66 (s, 1H), 7.56 (t, J=8.7, 2H), 4.39 (m, 1H), 3.99 (m, 2H), 3.50 (t, J=11.4, 2H), 2.03 (m, 2H), 1.91 (m, 2H). 20 Example 5a Synthesis of (1-methyl-1 H-pyrazol-4-yl)-[3-(1-methyl-1 H-pyrazol-4-yl)-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-yl}-amine ("A21") 25 N-N Cl N Cl 2 N- N(iPr) 2 Et H lkl + ~ N - ~ HN N N N NO xHCI dioxane HN N 30
NO
2 N N-N N N
H
2 /Ni H NaNO 2 HN N N THF N- H 2
SO
4 HN N N 35
NH
2 N/ N' WO 2013/110309 PCT/EP2012/005358 -76 2.17 g (16.8 mmol) Diisopropylethylamine are added slowly to a suspension of 776 mg (4.00 mmol) 2,4-dichloro-5-nitropyrimidine and 1.07 g (17.3 mmol) 1 methyl-1 H-pyrazole-4-ylamine in 15 ml dioxane. The mixture is stirred for 5 hours at room temperature. Water is added to the reaction mixture. The 5 resulting precipitate is filtered off, washed with water and dried under vacuum giving N 2,N 4-bis(1-methylpyrazol-4-yl)-5-nitro-pyrimidine-2,4-diamine as yellow crystals; HPLC/MS (B): 1.59 min, [M+H] 316. 10 This material is hydrogenated with Nickel sponge catalyst in THF as described in previous examples giving N 2
,N
4 -bis-(1 -methyl-1 H-pyrazol-4-yl)-pyrimidine 2,4,5-triamine as grey crystals; HPLC/MS (A): 1.03 min, [M+H] 286; 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 8.31 (s, 2H), 8.13 (s, 1H), 7.76 (s, 15 1H), 7.57 (s, 1H), 7.49 (s, 1H), 7.33 (s, 1H), 4.05 (s, 2H), 3.82 (s, 3H), 3.76 (s, 3H). A suspension of 80 mg (0.28 mmol) N 2
,N
4 -bis-(1-methyl-1 H-pyrazol-4-yl) pyrimidine-2,4,5-triamine in 23 ml water is treated with 4 ml concentrated 20 sulfuric acid and then with 39 mg (0.56 mmol) sodium nitrite. The reaction mixture is stirred for 90 minutes at room temperature. The reaction mixture is partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a 25 silica gel column with methanol/dichloromethane as eluent giving "A21" as off white crystals; HPLC/MS (A) 1.42 min, [M+H] 297; 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.33 (s, 1H), 9.33 (s, 1H), 8.48 (s, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.63 (s, 1H), 4.00 (s, 3H), 3.85 (s, 3H). 30 The following compounds are prepared analogously: compound structure and/or name prep. nr. analog 35 example WO 2013/110309 PCT/EP2012/005358 - 77 "A22" F NN N N N 5 N 3-(4-fluorophenyl)-N-[1 -(1 -methyl-4-piperidyl)pyrazol-4 yl]triazolo[4,5-d]pyrimidin-5-amine "A23"1 0 10 N 4 N N "'N 3-(4-methoxyphenyl)-N-[1 -(oxetan-3-yl)pyrazo-4 15 yl]triazolo[4,5-d]pyrimidin-5-amine HPLC/MS (B) 1.96 min, [M+H] 365; 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.44 (s, 1H), 9.37 (s, 1H), 8.25 (s, 1H), 8.03 (d, J=8.0, 2H), 7.75 (s, 1H), 7.26 (d, J=8.0, 2H), 5.55 (m, 1H), 4.98 20 (t, J=6.8, 2H), 4.86 (t, J=6.3, 2H), 3.87 (s, 3H) "A24"HN N N N N N 2 N N -- I 25 N 25 3-(1 -methylpyrazol-4-yl)-N-(1 H-pyrazol-4-yl)triazolo[4,5 d]pyrimidin-5-amine N H N N N N 30 N N N N
N-
N N-[1 -(1 -methyl-4-piperidyl)pyrazol-4-yl]-3-( 1 methylpyrazol-4-yl)triazolo[4,5-d]pyrimidin-5-amine 35 WO 2013/110309 PCT/EP2012/005358 - 78 "A26" -. N_ H 4 NX N N N N N-[1 -[1 -(2-methoxyethyl)-4-piperidyl]pyrazol-4-yl]-3-(4 methoxyphenyl)triazolo[4,5-d]pyrimidin-5-amine HPLC/MS (A) 1.39 min, [M+H] 450; 10 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.38 (s, 1H), 9.37 (s, 1H), 8.11 (s, 1H), 8.02 (d, J=8.6, 2H), 7.61 (s, 1H), 7.25 (d, J=8.4, 2H), 4.15 (bs, 1H), 3.50 (bs, 2H), 3.28 (s, 3H), 3.04 (bs, 2H), 2.08 (m, 8H) "A27" 15 NK4N N N -N 3-[4-(2-methoxyethoxy)phenyl]-N-[1 -(1 -methyl-4 20 piperidyl)pyrazol-4-yl]triazolo[4,5-d]pyrimidin-5-amine HPLC/MS (C) 1.79 min, [M+H] 450; 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.38 (s, 1H), 9.36 (s, 1H), 8.11 (s, 1H), 8.01 (d, J=8.6, 2H), 7.61 (s, 1H), 7.26 (d, J=8.6, 2H), 4.26 - 4.16 (m, 25 4H), 3.76 - 3.68 (m, 2H), 3.35 (s, 3H), 3.05 (s, 2H), 2.40 (s, 4H), 2.11 2.07 (m, 2H), 1.99 (s, 2H) "A28 " N N 0 N N 4 N N 30 N N 3-(4-ethoxyphenyl)-N-[1 -(1 -methyl-4-piperidyl)pyrazol-4 ylltriazolo[4,5-d]pyrimidin-5-amine 35 HPLC/MS (B) 1.84 min, [M+H] 420; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.39 (s, 1H), 9.37 (s, 1H), 8.75 WO 2013/110309 PCT/EP2012/005358 - 79 (br, 1H), 8.02 (m, 3H), 7.70 (s, 1H), 7.25 (d, J=8.5, 2H), 4.40 (m, 1H), 4.17 (q, J=6.9, 2H), 3.41 (m, 2H), 3.05 (m, 2H), 2.73 (s, 3H), 2.23 (m, 4H), 1.39 (t, J=7.0, 3H) "A29" 0 5 N N4 N- N N - N 10 3-(6-methoxy-3-pyridyl)-N-[1 -(2-pyrrolidin-1 ylethyl)pyrazo-4-yl]triazolo[4,5-d]pyrimidin-5-amine "A30" N N N ,N N N N N 15 -N N ' 3-(2-methoxy-4-pyridyl)-N-[1 -(1 -methyl-4 piperidyl)pyrazol-4-yljtriazolo[4,5-d]pyrimidin-5-amine HPLC/MS (C) 1.49 min, [M+H] 407; 20 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.54 (s, 1H), 9.41 (s, 1H), 8.48 (d, J=5.6, 1H), 8.10 (s, 1H), 7.87 (d, J=5.4, 1H), 7.72 (s, 2H), 4.51 - 4.42 (m, 1H), 3.99 (s, 3H), 3.61 - 3.54 (m, 2H), 3.21 - 3.13 (m, 2H), 2.81 (s, 3H), 2.37 - 2.30 (m, 2H), 2.27 - 2.23 (m, 2H) 25 "A31" 10 1 N N N N2 N N N 30 3-(4-ethoxyphenyl)-N-[1 -(2-methoxyethyl)pyrazol-4 ylltriazolo[4,5-djpyrimidin-5-amine 35 WO 2013/110309 PCT/EP2012/005358 - 80 "A326' Na 0-4 N N N N N N N 5 N, 3-(6-methoxy-3-pyridyl)-N-[1 -(1 -methyl-4 piperidyl)pyrazol-4-ylltriazolo[4,5-dlpyrimidin-5-amine "A33" N HNO _ H / 0 10 N I/ X' N N- N 11 N N I 3-(2-methoxy-4-pyridyl)-N-[1 -(4-piperidyl)pyrazol-4 15 yI]triazolo[4,5-dlpyrimidin-5-amine "A3411 0 HON N4 20N [2-[[4-[I3-(4-ethoxyphenyI)triazolo[4 ,5-dipyrimid in-5 yI]aminolpyrazol-1 -yI]methyl]cyclopropyl]methanol A35" H a N H0-3 NHN N N 3-(6-methoxy-3-pyridyl)-N-[1 -(4-piperidyl)pyrazol-4 30 yI]triazolo[4,5-dlpyrimidin-5-amine "A3611 HO-aH N /N 35 N' WO 2013/110309 PCT/EP2012/005358 - 81 NN N-( 1-methylpyrazol-4-yi)-3-[4-(2 10 morpholinoethoxy)phenyl]triazolo[4,5-d]pyrimidin-5 amine "A38" 0 s0 4 15 0 HN N N IN methyl 4-113-(4-methoxyphenyl)triazolo[4, 5-d]pyrimid in 20 5-yI]amino]thiophene-3-carboxylate "A3901"I o N 0 N 25N methyl 4-[[3-(4-methoxypheny)triazolo[4,5-d]pyrimid in 5-yI]amino]-1 -methyl-pyrrole-2-ca rboxylate "A401" N H 30 HN / 7 - 4 N N N NN 4-[[3-(4-methoxyphenyl)triazolo[4, 5-dipyrim idin-5 35 yllamino]l H-imidazole-5-carbonitrile WO 2013/110309 PCT/EP2012/005358 - 82 "A41" 0 N H 4 N--O N N 5 N N-[3-(4-methoxyphenyl)triazolo[4,5-d]pyrimidin-5-yIl]-3 phenyl-1,2,4-oxadiazol-5-amine "A42" 0 10 4 NN NH N N1 N 15 N-[4-[2-[[3-(4-methoxyphenyl)triazolo[4,5-d]pyrimidin-5 yl]amino]thiazol-4-yljphenyl]acetamide HPLC/MS (B) 1.44 min, [M+H] 407; "A43" N 20 N H KIIN I N / NN N N , 25 1 -[4-[5-[(1 -tetrahyd ropyran-4-ylpyrazok4 yl)amino]triazolo[4,5-d]pyrimidin-3-yl]phenyl]pyrrolidin-2 one HPLC/MS (C) 1.88 min, [M+H] 446; 30 'H NMR (500 MHz, DMSO-d 6 ) 8 [pm] = 10.40 (s, 1H), 9.38 (s, 1H), 8.19 8.10 (m, 3H), 8.03 - 7.96 (m, 2H), 7.62 (s, 1H), 4.42 - 4.33 (m, 1H), 4.04 3.97 (m, 2H), 3.94 (t, J=7.0, 2H), 3.53 - 3.45 (m, 2H), 2.57 (t, J=8.1, 2H), 2.17 - 2.09 (m, 2H), 2.09 - 2.02 (m, 2H), 1.97 - 1.84 (m, 2H) 35 WO 2013/110309 PCT/EP2012/005358 - 83 "A44" cl 4 >4a H O F4 N NF N 5 N [3-(4-chloro-3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl]-[1 -(1 -methyl-piperidin-4-y)-1 H-pyrazol 4-yl]-amine HPLC/MS (B) 1.94 min, [M+H] 428; 10 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.51 (s, 1H), 9.40 (s, 1H), 8.28 (d, J=9.8, 1H), 8.05 (m, 3H), 7.73 (s, 1H), 4.46 (m, 1H), 3.51 (m, 2H), 3.15 (m, 2H), 2.78 (s, 3H), 2.29 (m, 4H) "A45" N- H 4 15 /N 0 N- N [3-(6-butoxy-pyridin-3-yI)-3H-[1,2,3]triazolo[4,5 20 d]pyrimidin-5-yI]-[1-(1-methyl-piperidin-4-yl)-1H-pyrazol 4-yl]-amine HPLC/MS (B) 2.02 min, [M+H] 449; 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.41 (s, 1H), 9.39 (s, 1H), 8.91 25 8.86 (m, 1H), 8.38 - 8.32 (m, 1H), 8.06 (s, 1H), 7.64 (s, 1H), 7.13 (d, J=8.8, 1H), 4.41 - 4.33 (m, 3H), 4.25 - 4.14 (m, 1H), 3.08 (s, 1H), 2.44 (s, 4H), 2.16 - 2.09 (m, 2H), 2.08 - 2.00 (m, 2H), 1.82 - 1.71 (m, 2H), 1.54 - 1.40 (m, 2H), 1.27 - 1.16 (m, 1H), 1.00 - 0.92 (m, 3H) 30 "A46" 4 0 N H 0 N N 3-5 [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5- WO 2013/110309 PCT/EP2012/005358 - 84 yl]-(1-ethyl-1 H-pyrazol-4-yi)-amine HPLC/MS (B) 2.61 min, [M+H] 351; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.34 (s, 1H), 9.36 (s, 1H), 8.03 7.97 (m, 3H), 7.62 (s, 1H), 7.26 - 7.17 (m, 2H), 4.19 - 4.08 (m, 4H), 1.42 5 1.35 (m, 6H) "A47" N H 4 N/N N N 10 NaN [3-(6-butoxy-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5 d]pyrimid in-5-yl]-[1 -(tetrahyd ro-pyra n-4-yl)-1 H-pyrazol-4 yl]-amine 15 HPLC/MS (B) 2.45 min, [M+H] 436; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.41 (s, 1H), 9.38 (s, 1H), 8.95 8.86 (m, 1H), 8.34 (dd, J=8.9, 2.8, 1H), 8.10 (s, 1H), 7.61 (s, 1H), 7.11 (d, J=8.9, 1 H), 4.41 - 4.34 (m, 3H), 3.99 - 3.92 (m, 2H), 3.54 - 3.44 (m, 2H), 20 2.09 - 1.99 (m, 2H), 1.96 - 1.85 (m, 2H), 1.81 - 1.71 (m, 2H), 1.52 - 1.40 (m, 2H), 0.96 (t, J=7.4, 3H) "A48" N qN 4 N 0 25 NN N N N 1-(4-{5-[1-(1-methyl-piperidin-4-yI)-1 H-pyrazol-4 ylamino]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yI}-phenyl) pyrrolidin-2-one HPLC/MS (A) 1.33 min, [M+H] 459; 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.40 (s, 1H), 9.37 (s, 1H), 8.15 (m, 3H), 8.00 (d, J=8.5, 3H), 7.59 (s, 1H), 4.09 (m, 1H), 3.95 (t, J=7.0, 2H), 2.89 35 (d, J=11.0, 2H), 2.57 (t, J=8.0, 2H), 2.22 (s, 3H), 2.13 (dt, J=15.1, 7.6, 2H), WO 2013/110309 PCT/EP2012/005358 - 85 2.05 (m, 4H), 1.89 (m, 2H) "A49" 4 N H0 5 N N / N N _ N [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yl]-[1 -(3-methoxy-propyl)-1 H-pyrazol-4-yi]-amine 10 HPLC/MS (B) 2.61 min, [M+H] 395; 1 H NMR (500 MHz, DMSO-ds) 6 [pm] = 10.35 (s, 1H), 9.36 (s, 1H), 8.02 7.97 (m, 3H), 7.62 (s, 1H), 7.23 (d, J=8.5, 2H), 4.19 - 4.10 (m, 4H), 3.33 3.24 (m, 2H), 3.20 (s, 3H), 1.99 (p, J=6.6, 2H), 1.39 (t, J=7.0, 3H) 15 "A50" _ cl 4 H -F N N N 20 [3-(4-chloro-3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl]-[1 -(3-methoxy-propyl)-1 H-pyrazol-4-yl] amine HPLC/MS (B) 2.79 min, [M+H] 403; 25 'H NMR (500 MHz, DMSO-ds) 6 [pm] = 10.47 (s, 1H), 9.40 (s, 1H), 8.30 (d, J=10.2, 1H), 8.09 (d, J=8.8, 1H), 8.02 (s, 1H), 7.95 (t, J=8.4, 1H), 7.64 (s, 1H), 4.19 - 4.13 (m, 2H), 3.33 - 3.25 (m, 2H), 3.21 (s, 3H), 2.06 - 1.97 (m, 2H) 30 "A51" 4 01 H 0 N N N NN 35 N [1 -(2-tert-butoxy-ethyl)-1 H-pyrazol-4-yi]-[3-(4-ethoxy- WO 2013/110309 PCT/EP2012/005358 - 86 phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yI]-amine HPLC/MS (B) 2.89 min, [M+H] 423; 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.34 (s, 1H), 9.35 (s, 1H), 8.02 7.97 (m, 3H), 7.64 (s, 1H), 7.22 (d, J=8.6, 2H), 4.21 - 4.09 (m, 4H), 3.63 (t, 5 J=5.5, 2H), 1.39 (t, J=6.9, 3H), 1.03 (s, 9H) "A52" N H / N/ N NN N 10 N N N-N [1-(1-methyl-piperidin-4-yi)-1 H-pyrazol-4-yi]-(3-quinolin 3-yI-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-amine 15 HPLC/MS (B) 1.77 min, [M+H] 427; 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.49 (s, 1H), 9.66 (d, J=2.6, 1H), 9.45 (s, 1H), 9.13 (d, J=2.8, 1H), 8.27 - 8.16 (m, 2H), 8.13 (s, 1H), 7.97 7.87 (m, 1H), 7.85 - 7.74 (m, 1H), 7.68 (s, 1H), 4.18 - 4.10 (m, 1H), 2.97 (s, 2H), 2.48 - 2.33 (m, 4H), 2.32 - 2.18 (m, 1H), 2.10 - 1.89 (m, 3H), 1.27 20 1.11 (m, 1H) "A53" cl 4 0 ~ HF N N 25 N N N N [1 -(2-tert-butoxy-ethyl)-1 H-pyrazol-4-yi]-[3-(4-chloro-3 fluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl] amine 30 HPLC/MS (B) 3.09 min, [M+H] 431; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.47 (s, 1H), 9.39 (s, 1H), 8.32 8.26 (m, 1H), 8.12 - 8.06 (m, 1H), 8.04 (s, 1H), 7.94 (t, J=8.4, 1H), 7.64 (s, 1H), 4.21 - 4.15 (m, 2H), 3.64 (t, J=5.6, 2H), 1.02 (s, 9H) 35 WO 2013/110309 PCT/EP2012/005358 - 87 "A54" 4 N'N H N N N N [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yl]-[1 -(2-pyrazol-1 -yl-ethyl)-1 H-pyrazol-4-yl]-amine HPLC/MS (B) 2.47 min, [M+H] 417; 10 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.33 (s, 1H), 9.34 (s, 1H), 7.99 7.92 (m, 2H), 7.73 (s, 1H), 7.66 (s, 1H), 7.45 - 7.37 (m, 2H), 7.29 - 7.22 (m, 2H), 6.11 (s, 1H), 4.57 - 4.48 (m, 4H), 4.17 (q, J=6.9, 2H), 1.41 (t, J=6.9, 3H) 15 "A55" N H 3 N N N C HN N NsN 20 [3-(6-butoxy-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl]-[1 -(2-piperidin-4-yl-ethyl)-1 H-pyrazol-4 yl]-amine HPLC/MS (B) 1.78 min, [M+H] 463; 25 lH NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.40 (s, 1H), 10.07 (s, 1H), 9.38 (s, 1H), 8.91 - 8.79 (m, 1H), 8.34 (dd, J=8.8, 2.7, 1H), 7.98 (s, 1H), 7.59 (s, 1H), 7.12 (d, J=8.9, 1H), 4.38 (t, J=6.7, 2H), 4.10 (t, J=7.2, 2H), 2.88 (d, J=12.1, 2H), 2.41 - 2.31 (m, 1H), 1.81 - 1.71 (m, 2H), 1.69 (q, J=7.0, 2H), 30 1.59 (d, J=12.3, 2H), 1.53- 1.41 (m, 2H), 1.24 (s, 2H), 1.11 -0.98 (m, 2H), 0.97 (t, J=7.4, 3H) 35 WO 2013/110309 PCT/EP2012/005358 - 88 "A56" 4 H N~.N N N 5 N'..N {3-[4-(2-methoxy-ethoxy)-phenyl]-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl}-(1 -methyl-1 H-pyrazol-4-yl)-amine HPLC/MS (B) 2.26 min, [M+H] 367; 10 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.33 (s, 1H), 9.36 (s, 1H), 8.00 (d, J=8.7, 2H), 7.93 (s, 1H), 7.62 (s, 1H), 7.27 (d, J=8.5, 2H), 4.26 - 4.19 (m, 2H), 3.76 - 3.68 (m, 2H), 3.35 (s, 3H), 3.28 (s, 3H) "A57" 4
N
15 N N N [3-(6-butoxy-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-d] 20 pyrimidin-5-yl]-(1-ethyl-1 H-pyrazol-4-yl)-amine HPLC/MS (B) 2.94 min, [M+H] 380; lH NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.83 (s, 1H), 10.39 (s, 1H), 9.38 (s, 1H), 9.08 - 9.01 (m, 1H), 8.51 - 8.34 (m, 2H), 7.94 (s, 1H), 7.68 (s, 1H), 25 4.11 (q, J=7.3, 2H), 2.16 (s, 3H), 1.39 (t, J=7.3, 3H) "A58" H O 4 N- H S N N 30 N-{5-[5-(1-ethyl-1 H-pyrazol-4-ylamino) [1,2,3]triazolo[4,5-dlpyrimidin-3-yI]-pyridin-2-yl} acetamide HPLC/MS (B) 1.68 min, [M+H] 356; 35 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.83 (s, 1H), 10.39 (s, 1H), 9.38 WO 2013/110309 PCT/EP2012/005358 - 89 (s, 1H), 9.08 - 9.01 (m, 1H), 8.51 - 8.34 (m, 2H), 7.94 (s, 1H), 7.68 (s, 1H), 4.11 (q, J=7.3, 2H), 2.16 (s, 3H), 1.39 (t, J=7.3, 3H) "A59" H 0 4 HO N N N N-(5-{5-[1 -((trans)-2-hydroxymethyl-cyclopropylmethyl) 10 1 H-pyrazol-4-ylamino]-[1,2,3]triazolo[4,5-d]pyrimidin-3 yl}-pyridin-2-yi)-acetamide HPLC/MS (B) 1.60 min, [M+HI 421; lH NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.81 (s, 1H), 10.39 (s, 1H), 9.39 15 (s, 1H), 9.05 (d, J=2.6, 1H), 8.50 - 8.33 (m, 2H), 8.00 (s, 1H), 7.69 (s, 1H), 7.56 (s, 1H), 4.46 (t, J=5.4, 1H), 4.10 - 4.03 (m, 1H), 3.93 - 3.85 (m, 1H), 3.28 - 3.23 (m, 1H), 2.16 (s, 3H), 1.14 - 0.98 (m, 2H), 0.53 - 0.42 (m, 2H) "A60" NH 2 4 20 NN HO N N N ((trans)-2-{4-[3-(6-amino-pyridin-3-yl)-3H 25 [1,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]-pyrazol-1 yimethyl}-cyclopropyl)-methano HPLC/MS (C) 1.52 min, [M+H] 379 "A61" 4 N:- H N 30 N N N'N (1-ethyl-1 H-pyrazol-4-yl)-(3-quinolin-3-yl-3H 35 [1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-amine HPLC/MS (B) 2.04 min, [M+H] 358; WO 2013/110309 PCT/EP2012/005358 - 90 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.46 (s, 1H), 9.68 (d, J=2.5, 1H), 9.44 (s, IH), 9.14 (s, 1H), 8.28 - 8.15 (m, 2H), 8.03 (s, 1H), 7.95 - 7.86 (m, 1H), 7.79 (t, J=7.4, 1H), 7.70 (s, 1H), 4.11 (q, J=7.3, 2H), 1.37 (t, J=7.3, 3H) 5 "A62" 4 N--N N HN N N N :- 1,N 10 N (1-ethyl-1 H-pyrazol-4-yl)-[3-(2-methoxy-pyridin-4-yt)-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine HPLC/MS (B) 2.03 min, [M+H] 338; 15 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.50 (s, 1H), 9.39 (s, 1H), 8.44 (d, J=5.7, 1H), 8.05 (s, 1H), 7.84 (d, J=5.2, 1H), 7.78 (s, 1H), 7.63 (s, 1H), 4.21 - 4.10 (m, 2H), 3.98 (s, 3H), 1.44 (t, J=7.3, 3H) "A63" H F 4 /N 20 N N N N N N (1-ethyl-1 H-pyrazol-4-yI)-[3-(4-fluoro-phenyl)-3H 25 [1,2,3]triazolo[4,5-d]pyrimidin-5-yI]-amine HPLC/MS (B) 2.11 min, [M+H] 325; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 9.38 (s, 1H), 8.21 - 8.11 (m, 2H), 7.99 (s, 1H), 7.62 (s, 1H), 7.59 - 7.48 (m, 3H), 4.13 (q, J=7.3, 2H), 1.38 (t, J=7.3, 3H) 30 "A64" 4 N0 N N 35N WO 2013/110309 PCT/EP2012/005358 - 91 [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yl]-(1-phenyl-1 H-pyrazol-4-yl)-amine HPLC/MS (C) 3.17 min, [M+H] 399; 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.59 (s, 1H), 9.43 (s, 1H), 8.72 (s, 5 1H), 8.05 - 7.99 (m, 2H), 7.89 (s, 1H), 7.77 - 7.71 (m, 2H), 7.56 - 7.47 (m, 2H), 7.33 (t, J=7.4, 1H), 7.24 (d, J=8.5, 2H), 4.17 (q, J=6.9, 2H), 1.41 (t, J=7.0, 3H) "A65" 4 10 N 0 N 1 NN N -N 15N {3-[4-(2-methoxy-ethoxy)-phenyl]-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl-[1 -(2-pyrazol-1 -yl-ethyl)-1 H-pyrazol-4 yl]-amine 20 HPLC/MS (C) 2.32 min, [M+H] 447; 'H NMR (400 MHz, DMSO-ds) 6 [pm] = 10.33 (s, 1H), 9.35 (s, 1H), 8.01 7.92 (m, 2H), 7.73 (s, 1H), 7.65 (s, 1H), 7.45 - 7.37 (m, 2H), 7.29 (d, J=8.5, 2H), 6.11 (s, 1 H), 4.57 - 4.49 (m, 4H), 4.27 - 4.20 (m, 2H), 3.77 - 3.70 (m, 2H), 3.35 (s, 3H) 25 "A66" OH 4 N-N HN N N 30 N 4-[5-(1 -ethyl-1 H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5 d]pyrimidin-3-yl]-phenol HPLC/MS (C) 1.36 min, [M+H] 323; 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.29 (s, 1H), 9.34 (s, 1H), 8.35 (s, 35 1H), 7.97 (d + s, 2H), 7.64 (s, 1H), 7.65 (s, 1H), 6.70 (d, J=8.9, 1H), 6.45 (s, WO 2013/110309 PCT/EP2012/005358 - 92 2H), 4.11 (q, J=7.3, 2H), 1.38 (t, J=7.3, 3H) 'A67" N H4 5 7 NNNH N 5 Na NN NNH -NH 3-{5-[1 -(1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-ylamino] [1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzamide 10 HPLC/MS (C) 1.38 min, [M+H] 419; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.46 (s, 1H), 9.40 (s, 1H), 8.75 (s, 1H), 8.30 - 8.13 (m, 4H), 8.06 (d, J=7.6, 1H), 7.78 (t, J=7.9, 1H), 7.58 (s, 2H), 4.19 (m, 1H), 2.90 (m, 2H), 2.27 (s, 3H), 2.17 (m, 2H), 1.97 (m, 4H) "A68" H N 4 15 N - N NN N N NH 2 20 3-[5-(1-ethyl-1 H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5 d]pyrimidin-3-yl]-benzamide HPLC/MS (C) 1.65 min, [M+H] 350; 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.46 (s, 1H), 9.39 (s, 1H), 8.85 (s, 1H), 8.30 - 8.26 (m, 1H), 8.22 (s, 2H), 8.04 (d, J=7.8, 1H), 7.78 (t, J=7.9, 25 1H), 7.63 (s, 1H), 7.55 (s, 1H), 4.20 (q, J=7.2, 2H), 1.36 (t, J=7.2, 3H) "A69" 0 4
N
N N / NH2 NN 30 7 . N NN 4-{5-[1-(1-methyl-piperidin-4-y)-1H-pyrazol-4-ylamino] [1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzamide 35 HPLC/MS (C) 1.33 min, [M+H] 419; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.45 (s, 1H), 9.40 (s, 1H), 8.27 (d, WO 2013/110309 PCT/EP2012/005358 - 93 J=8.5, 2H), 8.19 (d, J=8.5, 2H), 8.13 (d, J=9.5, 2H), 7.68 (s, 1H), 7.54 (s, 1H), 4.13 (m, 1H), 2.93 (m, 2H), 2.27 (s, 3H), 2.18 (m, 2H), 2.12 - 1.87 (m, 4H) "A70" N 0 4 5 N NH 2 N N N-::::N 10 4-[5-(1 -ethyl-1 H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5 d]pyrimidin-3-yl]-benzamide HPLC/MS (C) 1.63 min, [M+H] 350; 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.43 (s, 1H), 9.39 (s, 1H), 8.32 15 8.26 (m, 2H), 8.22 - 8.10 (m, 3H), 8.01 (s, 1H), 7.69 (s, 1H), 7.52 (s, 1H), 4.15 (q, J=7.3, 2H), 1.41 (t, J=7.3, 3H) "A71" N H 4 N N N N 20 N NaN (1-ethyl-1 H-pyrazol-4-yl)-(3-quinolin-6-yl-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-amine HPLC/MS (C) 1.84 min, [M+H] 358; 25 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.45 (s, 1H), 9.42 (s, 1H), 9.05 9.00 (m, 1H), 8.84 - 8.79 (m, 1H), 8.61 - 8.54 (m, 2H), 8.34 (d, J=9.1, 1H), 8.09 (s, 1H), 7.73 - 7.65 (m, 2H), 4.13 (q, J=7.3, 2H), 1.37 (t, J=7.3, 3H) "A72" F 4 30 N-N HN YNN ON N N 35 2-[5-(1 -ethyl-1 H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5 d]pyrimidin-3-yl]-5-fluoro-benzonitrile WO 2013/110309 PCT/EP2012/005358 - 94 HPLC/MS (C) 1.96 min, [M+H] 350; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.47 (s, 1H), 9.42 (s, 1H), 8.33 8.26 (m, 1H), 8.16 - 8.11 (m, 1H), 8.03 - 7.95 (m, 1H), 7.85 (s, 1H), 7.59 (s, IH), 4.15 - 4.01 (m, 2H), 1.39 - 1.29 (m, 3H) 5 "A73" N H NN Na N N' 10 [1 -(1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-yil]-(3-quinolin 7-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-amine HPLC/MS (C) 1.49 min, [M+H] 463; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.51 (s, 1H), 9.43 (s, 1H), 9.06 (d, 15 J=2.9, 1H), 9.00 (s, 1H), 8.51 (d, J=5.2, 1H), 8.43 (d, J=8.8, 1H), 8.34 - 8.25 (m, 2H), 7.67 (dd, J8.2, 4.1, 1H), 7.61 (s, 1H), 4.18 - 4.09 (m, 1H), 2.86 (d, J=11.3, 2H), 2.22 (s, 3H), 2.11 - 1.92 (m, 6H) "A74" N- H F 4 _ N 20 N N 7 NJN N
-
I CN N- N 5-fluoro-2-{5-[1-(1-methyl-piperidin-4-yl)-1 H-pyrazol-4 25 ylamino]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzonitrile formate salt HPLC/MS (C) 1.47 min, [M+HJ 419 "A75" N H 4 N 30 N N N NS N=N 35 [1 -(1 -methyl-piperidin-4-y)-1 H-pyrazol-4-yl]-(3-quinolin 6-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-amine WO 2013/110309 PCT/EP2012/005358 - 95 HPLC/MS (C) 1.47 min, [M+H] 427; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.48 (s, 1H), 9.43 (s, 1H), 9.07 9.01 (m, 1H), 8.80 (s, 1H), 8.61 (d, J=8.4, 1H), 8.57 - 8.51 (m, 1H), 8.33 (d, J=9.1, 1H), 8.17 (s, 1H), 7.69 (dd, J=8.3, 4.2, 1H), 7.66 (s, 1H), 4.18 - 4.10 5 (m, 1H), 2.97 - 2.91 (m, 2H), 2.34 (s, 3H), 2.28 - 2.23 (m, 2H), 2.08 - 2.01 (m, 2H), 2.01 - 1.89 (m, 2H) "A76" N4 0
H
10 N N N O N N {1 -[1 -(2-methoxy-ethyl)-piperidin-4-yI]-1 H-pyrazol-4-yl} [3-(2-methoxy-pyridin-4-yl)-3H-[1,2,3]triazolo[4,5 15 d]pyrimidin-5-yl]-amine HPLC/MS (C) 1.55 min, [M+H] 401; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.52 (s, 1H), 9.40 (s, IH), 8.43 (d, J=5.7, 1H), 8.13 (s, 1H), 7.86 - 7.81 (m, 1H), 7.79 (s, 1H), 7.59 (s, 1H), 20 4.18 - 4.08 (m, 1H), 4.00 (s, 3H), 3.48 (t, J=5.7, 2H), 3.26 (s, 3H), 3.04 (d, J=1 1.0, 2H), 2.57 (t, J=5.6, 2H), 2.21 (t, J=1 1.7, 2H), 2.10 - 2.03 (m, 2H), 2.02 - 1.92 (m, 2H) "'A77"1 4 /N 25 N N N NsN [3-(5-methoxy-pyridin-2-yl)-3H-[1,2,3]triazolo[4,5 30 d]pyrimidin-5-yl]-[1-(1-methyl-piperidin-4-yl)-1H-pyrazol 4-yl]-amine HPLC/MS (C) 1.36 min, [M+H] 407; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 9.39 (s, 1H), 8.48 (s, 1H), 8.14 (s, 35 1H), 8.07 - 7.96 (m, 2H), 7.90 - 7.83 (m, 1 H), 7.72 (s, 1 H), 4.48 - 4.38 (m, 1H), 3.99 (s, 3H), 3.56 - 3.50 (m, 2H), 3.21 - 3.10 (m, 2H), 2.78 (s, 3H), WO 2013/110309 PCT/EP2012/005358 - 96 2.32 - 2.21 (m, 4H) 'A78" N 4 0H 0 N N 5 'Y N N [3-(2-methoxy-pyridin-4-yl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl]-[1 -(tetrahyd ro-pyra n-4-yi)-1 H-pyrazol-4 10 yl]-amine HPLC/MS (C) 2.01 min, [M+H] 394; 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.52 (s, 1H), 9.39 (s, 1H), 8.43 (d, J=5.7, 1H), 8.15 (s, 1H), 7.85 - 7.80 (m, 1H), 7.79 (s, 1H), 7.61 (s, 1H), 15 4.46 - 4.36 (m, 1H), 4.05 - 3.99 (m, 2H), 3.98 (s, 3H), 3.56 - 3.45 (m, 2H), 2.09 - 1.91 (m, 4H) "A79" N H- 4 N,/ N N N 1 N /N 20 N N-N [3-(1-ethyl-1 H-pyrazol-4-yI)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl]-[1 -(1 -methyl-piperidin-4-yl)-1 H-pyrazol 25 4-yl]-amine HPLC/MS (C) 1.36 min, [M+H] 394; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.36 (s, 1H), 9.34 (s, 1H), 8.53 (s, 1H), 8.11 - 7.99 (m, 2H), 7.70 (s, 1H), 4.34 - 4.22 (m, 3H), 3.32 - 3.14 (m, 30 4H), 2.51 (s, 3H), 2.19 - 2.02 (m, 4H), 1.48 (t, J=7.3, 3H) "A80" N 4 /D H 04 /NN NH 2 35 NN 35~ WO 2013/110309 PCT/EP2012/005358 - 97 4-{5-[1 -(tetra hyd ro-pyra n-4-yl)-1 H-pyrazol-4-ylamino] [1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzamide HPLC/MS (C) 1.63 min, [M+H] 406; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.44 (s, 1H), 9.40 (s, 1H), 8.30 5 8.16 (m, 4H), 8.16 - 8.08 (m, 2H), 7.69 (s, 1H), 7.50 (s, 1H), 4.43 - 4.35 (m, 1H), 4.03 - 3.95 (m, 2H), 3.54 - 3.44 (m, 2H), 2.09 - 2.00 (m, 2H), 1.97 1.86 (m, 2H) "A81" N- H C1 /_N 10 N NF o N N:N [3-(4-chloro-3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5 15 d]pyrimidin-5-yl]-[1 -(tetrahyd ro-pyran-4-yl)-1 H-pyrazol-4 yl]-amine HPLC/MS (C) 2.73 min, [M+H] 415; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.48 (s, 1H), 9.41 (s, 1H), 8.32 (d, 20 J=9.9, 1H), 8.16 - 8.04 (m, 2H), 7.94 (t, J=8.4, 1H), 7.66 (s, OH), 4.44 - 4.36 (m, 1 H), 4.02 - 3.95 (m, 3H), 3.55 - 3.44 (m, 3H), 2.07 - 1.87 (m, 5H) "A82" N7 N N N o /N 25 N N N-N (3-quinolin-6-y-3H-[1,2,3]triazolo[4,5-djpyrimidin-5-yi) [1 -(tetrahyd ro-pyra n-4-yl)-1 H-pyrazol-4-yl]-amine 30 HPLC/MS (C) 2.11 min, [M+H] 414 "A83" N 4 NN g N N N 35N N N 35 N N WO 2013/110309 PCT/EP2012/005358 - 98 [3-(1 -ethyl-1 H-pyrazol-4-yI)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl]-[1 -(tetrahyd ro-pyran-4-yl)-1 H-pyrazol-4 yl]-amine HPLC/MS (C) 1.73 min, [M+H] 381; 5 1 H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.34 (s, 1H), 9.34 (s, 1H), 8.53 (s, 1H), 8.14 - 8.05 (m, 2H), 7.65 (s, 1H), 4.44 - 4.34 (m, 1H), 4.29 (q, J=7.3, 2H), 4.01 - 3.93 (m, 2H), 3.53 - 3.43 (m, 2H), 2.06 - 1.86 (m, 4H), 1.48 (t, J=7.3, 3H) 10 "A84" 0 4 N- HN / N N N 15 N N 6-[5-(1-ethyl-1 H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5 d]pyrimidin-3-yl]-3,3-dimethyl-1,3-dihydro-indol-2-one HPLC/MS (C) 2.25 min, [M+H] 390; 20 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.65 (s, 1H), 10.38 (s, 1H), 9.37 (s, 1H), 8.01 (s, 1H), 7.77 - 7.70 (m, 1H), 7.68 - 7.48 (m, 3H), 4.13 (q, J=7.3, 2H), 1.43 - 1.27 (m, 9H) "A85" N O 4 N HN 25 N //N N=N 3,3-dimethyl-6-{5-[1 -(tetrahydro-pyran-4-yl)-1 H-pyrazol 30 4-ylamino]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-1,3 dihydro-indol-2-one HPLC/MS (C) 1.87 min, [M+H] 446; 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.63 (s, 1H), 10.42 (s, 1H), 9.38 35 (s, 1H), 8.16 (s, 1H), 7.70 (dd, J=7.9, 1.9, 1H), 7.59 (d, J=8.0, 2H), 7.51 (s, 1 H), 4.41 - 4.31 (m, 1 H), 4.00 - 3.90 (m, 2H), 3.46 (td, J=1 1.8, 2.0, 2H), WO 2013/110309 PCT/EP2012/005358 - 99 2.11 - 1.99 (m, 2H), 1.93 - 1.78 (m, 2H), 1.34 (s, 6H) "A86" N H N N /a N N N N 5 - t (3-quinolin-7-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yi) [1 -(tetrahyd ro-pyran-4-yl)-1 H-pyrazol-4-yi]-amine 0 HPLC/MS (C) 2.25 min, [M+H] 414; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.53 (s, 1H), 9.43 (s, 1H), 9.08 9.00 (m, 2H), 8.55 - 8.51 (m, 1H), 8.46 - 8.40 (m, 1H), 8.34 - 8.27 (m, 2H), 7.67 (dd, J=8.3, 4.2, 1H), 7.62 (s, 1H), 4.47 - 4.38 (m, 1H), 4.01 - 3.94 (m, 2H), 3.55 - 3.45 (m, 2H), 2.08 - 1.94 (m, 4H) 15 "A87" 4 NN 0 N N N N N 20 {3-[4-(2-methoxy-ethoxy)-phenyl]-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-y}-[1 -(tetrahyd ro-pyra n-4-yl)-1 H-pyrazol-4 yl]-amine HPLC/MS (C) 2.34 min, [M+H] 437; 25 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.37 (s, 1H), 9.37 (s, 1H), 8.11 (s, 1H), 8.00 (d, J=8.9, 2H), 7.62 (s, 1H), 7.25 (d, J=8.6, 2H), 4.43 - 4.33 (m, 1H), 4.25 - 4.18 (m, 2H), 4.01 - 3.93 (m, 2H), 3.75 - 3.69 (m, 2H), 3.55 3.44 (m, 2H), 3.34 (s, 3H), 2.08 - 1.98 (m, 2H), 1.96 - 1.82 (m, 2H) 30 "A88" N 4 N N N N 35 [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yl]-[l -(3-methyl-butyl)-1 H-pyrazol-4-yl]-amine WO 2013/110309 PCT/EP2012/005358 -100 HPLC/MS (C) 2.57 min, [M+HI 393; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.34 (s, 1H), 9.36 (s, 1H), 8.01 7.95 (m, 3H), 7.59 (s, 1H), 7.22 (d, J=8.3, 2H), 4.19 - 4.08 (m, 4H), 1.70 1.62 (m, 2H), 1.54 - 1.45 (m, 1H), 1.39 (t, J=6.9, 3H), 0.90 (d, J=6.6, 6H) 5 "A89" N- H 4 NN N N N N.N 10 [3-(1 -ethyl-1 H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl]-[1 -(3-methyl-butyl)-1 H-pyrazol-4-yi] amine HPLC/MS (C) 2.13 min, [M+H] 367; 15 1 H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.32 (s, 1H), 9.34 (s, 1H), 8.56 8.48 (m, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.62 (s, 1H), 4.29 (q, J=7.3, 2H), 4.12 (t, J=7.3, 2H), 1.68 (q, J=7.1, 2H), 1.52 - 1.43 (m, 4H), 0.90 (d, J=6.6, 6H) 20 "A90" 4 N- N N N N. 25 [1-(3-methyl-butyl)-1 H-pyrazol-4-yl]-(3-quinolin-6-yI-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-amine HPLC/MS (C) 2.23 min, [M+H] 400; 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.46 (s, 1H), 9.44 (s, 1H), 9.04 (d, 30 J=2.7, 1H), 8.81 (s, 1H), 8.59 (dd, J=14.9, 8.7, 2H), 8.34 (d, J=9.0, 1H), 8.10 (d, J=8.4, 1H), 7.70 (dd, J=8.3, 4.2, 1H), 7.65 (s, 1H), 4.14 - 4.08 (m, 2H), 1.66 (dd, J=14.2, 6.9, 2H), 1.55 - 1.44 (m, 1H), 0.85 (d, J=6.4, 6H) 35 WO 2013/110309 PCT/EP2012/005358 - 101 "A91" H4 N 5 N (1-ethyl-1 H-pyrazol-4-yl)-[3-(1 H-indazol-5-yl)-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-yI]-amine HPLC/MS (C) 1.74 min, [M+H] 347; 10 1 H NMR (400 MHz, DMSO-d 6 ) 5 [pm] = 13.40 (s, 1H), 10.36 (s, 1H), 9.39 (s, 1 H), 8.49 (s, 1 H), 8.29 (s, 1 H), 8.07 - 8.02 (m, 2H), 7.85 (d, J=8.9, 1 H), 7.60 (s, 1H), 4.11 (q, J=7.3, 2H), 1.36 (t, J=7.3, 3H) "A92" N - H 4 _N N NN~ 15 O N N H WNN [3-(1 H-indazol-6-yI)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yl]-[l -(tetrahyd ro-pyran-4-yl)-1 H-pyrazol-4-yi]-amine 20 HPLC/MS (C) 1.74 min, [M+H] 403; 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 13.42 (s, 1H), 10.38 (s, 1H), 9.39 (s, 1H), 8.47 (d, J=1.4, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 8.04 (d, J=8.9, 1H), 7.84 (d, J=8.9, 1H), 7.59 (s, 1H), 4.01 - 3.85 (m, 3H), 3.46 (td, J=11.7, 2.0, 25 2H), 2.04 - 1.95 (m, 2H), 1.87 - 1.79 (m, 2H) "A93" N- H H 4 N N 30 N-:::N [3-(1 H-indazol-5-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yl]-[l -(1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-yi]-amine HPLC/MS (C) 1.40 min, [M+H] 416 35 WO 2013/110309 PCT/EP2012/005358 - 102 "A94" N H N NN O NN/ N N -:.N N 5 (3-quinoxalin-6-yl-3H-[1,2,3]triazolo[4,5-dipyrimidin-5-yl) [1 -(tetrahyd ro-pyran-4-yl)-1 H-pyrazol-4-yi]-amine HPLC/MS (C) 2.24 min, [M+H] 415; H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.55 (s, 1H), 9.44 (s, 1H), 9.10 10 9.00 (m, 3H), 8.73 - 8.64 (m, 1H), 8.40 (d, J=9.1, 1H), 8.28 (s, 1H), 7.62 (s, 1 H), 4.47 - 4.35 (m, 1 H), 4.01 - 3.95 (m, 2H), 3.57 - 3.43 (m, 2H), 2.06 1.97 (m, 4H) "A95" N H H F 4 N N_ 15 NN F N tIN -N N FF N
N-
[1-(1-methyl-piperidin-4-yI)-1H-pyrazol-4-yl]-[3-(2 20 trifluoromethyl-1 H-benzoimidazol-5-yl)-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-yI]-amine HPLC/MS (C) 1.52 min, [M+H] 484; H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.42 (s, IH), 9.40 (s, 1H), 8.45 (d, 25 J=1.5, 1H), 8.17 (s, 1H), 8.07 (dd, J=8.8, 2.0, 1H), 7.98 (d, J=8.8, 1H), 7.63 (s, 1H), 4.25 - 4.11 (m, 1H), 3.03 (d, J=10.9, 2H), 2.43 - 2.33 (m, 5H), 2.16 2.06 (m, 2H), 2.03 - 1.92 (m, 2H) "A96" / 3 HN O0 30 N H _N N N N N N N 35 {3-[4-(2-methoxy-ethoxy)-phenyl]-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl}-(1-pyrrolidin-3-yl-1 H-pyrazol-4-yl)- WO 2013/110309 PCT/EP2012/005358 - 103 amine HPLC/MS (C) 1.78 min, [M+HJ 422; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.43 (s, 1H), 9.39 (s, 1H), 9.14 (s, 2H), 8.10 (s, 1H), 8.00 (d, J=8.4, 2H), 7.76 (s, 1H), 7.27 (d, J=7.8, 2H), 5.19 5 5.11 (m, 1H), 4.26 - 4.17 (m, 2H), 3.76 - 3.69 (m, 2H), 3.62 (dd, J=12.4, 7.2, 1H), 3.51 (dd, J=12.4, 4.0, 1H), 3.44 - 3.26 (m, 4H), 2.46 - 2.35 (m, 1H), 2.30 - 2.20 (m, IH) "A97" N- H 3 10 N. HN N N N -N [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 15 yl]-[l -(2-piperidin-4-yl-ethyl)-1 H-pyrazol-4-yl]-amine HPLC/MS (C) 1.93 min, [M+H] 434; H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.38 (s, 1H), 9.37 (s, 1H), 8.50 (br, 2H), 8.00 (m, 3H), 7.65 (s, 1H), 7.23 (d, J=8.1, 2H), 4.15 (q, J=6.4, 4H), 3.19 20 (d, J=12.0, 2H), 2.76 (t, J=11.7, 2H), 1.83 - 1.71 (m, 4H), 1.49 - 1.27 (m, 7H) "A98" F 4 _N NNC HO N N 25 N ((trans)-2-{4-[3-(4-chloro-3-fluoro-phenyl)-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]-pyrazol-1 ylmethyl}-cyclopropyl)-methanol 30 HPLC/MS (C) 2.13 min, [M+H] 415 35 WO 2013/110309 PCT/EP2012/005358 -104 "A99'' 0 4 N N N N N 1-[3-(4-{3-[4-(2-methoxy-ethoxy)-phenyl]-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-ylamino}-pyrazol-1 -yl) 10 pyrrolidin-1 -yl]-ethanone HPLC/MS (C) 2.16 min, [M+H] 464 "A100" N- H 4 N O 15 N N NN 1-[4-(2-{4-[3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino]-pyrazol-1 -yl}-ethyl)-piperidin-1 -yl] ethanone 20 HPLC/MS (C) 2.45 min, [M+H] 476 "AlOl" N- 4 NaN N N N 25 N';N [1-(1-methyl-piperidin-4-yI)-1H-pyrazol-4-yl]-(3 quinoxalin-6-y-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yI) amine 30 HPLC/MS (C) 1.49 min, [M+H] 428; 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.53 (s, 1H), 9.44 (s, 1H), 9.11 9.02 (m, 3H), 8.68 (dd, J=9.3, 2.4, 1H), 8.40 (d, J=9.1, 1H), 8.25 (s, 1H), 7.62 (d, J=0.5, 1H), 4.20 - 4.07 (m, 1H), 2.89 (d, J=11.1, 2H), 2.27 (s, 3H), 35 2.16 - 1.92 (m, 6H) WO 2013/110309 PCT/EP2012/005358 - 105 "A102" N H CI 4 X/N N N ~N a HO Fu N 5 4-{4-[3-(4-chloro-3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino]-pyrazol-1 -yl}-cyclohexanol HPLC/MS (C) 2.62 min, [M+H] 429 "A103" N: H CI 4 10 N N N ~N a
-
N HO -N 4-{4-[3-(4-chloro-3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5 15 djpyrimidin-5-ylamino]-pyrazol-1 -yl}-cyclohexanol HPLC/MS (C) 2.49 min, [M+H] 429 "A1 04" N 4 N H N N 20 HO N N {(trans)-2-[4-(3-quinoxalin-6-yl-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino)-pyrazol-1 -ylmethyl]-cyclopropyl) 25 methanol HPLC/MS (C) 1.78 min, [M+H] 417 "Al05 N H 4 30 N-N HO N NN 4-[4-(3-quinoxalin-6-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidin 5-ylamino)-pyrazol-1 -yll-cyclohexanol 35 HPLC/MS (C) 1.85 min, [M+H] 429 WO 2013/110309 PCT/EP2012/005358 -106 "A106" H N 5 N N N N N N -N 5 (1-ethyl-1 H-pyrazol-4-yl)-[3-(1-ethyl-1 H-pyrazol-4-yl)-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine HPLC/MS (C) 1.75 min, [M+H] 325; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.33 (s, IH), 9.34 (s, 1H), 8.54 (s, 10 1H), 8.09 (s, IH), 8.03 (s, 1H), 7.64 (s, 1H), 4.30 (q, J=7.3, 2H), 4.13 (q, J=7.3, 2H), 1.48 (t, J=7.3, 3H), 1.39 (t, J=7.3, 3H) "A107" N 0 4 HO 15 N O N-a N=N 4-(4-{3-[4-(2-methoxy-ethoxy)-phenyl]-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-ylamino}-pyrazol-1 -yl) 20 cyclohexanol HPLC/MS (C) 2.29 min, [M+HJ 451; lH NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.37 (s, 1H), 9.36 (s, 1H), 8.12 (s, 1H), 8.03 (d, J=8.4, 2H), 7.57 (s, 1H), 7.27 (d, J=8.3, 2H), 4.49 (s, 1H), 4.25 25 4.21 (m, 2H), 4.16 - 4.09 (m, 1H), 3.86 (s, 1H), 3.74 - 3.70 (m, 2H), 3.35 (s, 3H), 2.14 - 2.06 (m, 2H), 1.85 - 1.71 (m, 4H), 1.66 - 1.58 (m, 2H) "A108" N- 4 N / N O O 30 HO' N N N NN 4-(4-{3-[4-(2-methoxy-ethoxy)-phenyl]-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-ylamino}-pyrazol-1 -yl) 35 cyclohexanol WO 2013/110309 PCT/EP2012/005358 - 107 HPLC/MS (C) 2.20 min, [M+H] 451; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.34 (s, 1H), 9.35 (s, 1H), 8.06 7.96 (m, 3H), 7.59 (s, 1H), 7.24 (d, J=8.8, 2H), 4.64 (d, J=4.2, 1H), 4.24 4.20 (m, 2H), 4.12 - 4.04 (m, 1H), 3.74 - 3.71 (m, 1H), 3.54 - 3.46 (m, 2H), 5 3.35 (s, 3H), 2.09 - 1.90 (m, 4H), 1.71 (dd, J=23.2, 11.4, 2H), 1.37 (q, J=10.7, 2H) "A109" N- H 4 N 10 HO N N NsN 4-{4-[3-(6-methoxy-pyridin-3-y)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino]-pyrazol-1 -yi}-cyclohexanol 15 HPLC/MS (C) 2.15 min, [M+H] 408 "A110" N- H F4 />N a c 0 /N -N 20 N:::. [3-(3-chloro-4-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yI]-[1-(tetrahydro-pyran-4-y)-1 H-pyrazol-4 yl]-amine 25 HPLC/MS (C) 2.69 min, [M+H] 415 "A111" F 4 -Na N H -cI NXN N N NC NN 30 N [3-(3-chloro-4-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl]-[1-(1-methyl-piperidin-4-yl)-1H-pyrazol 4-yl]-amine 35 HPLC/MS (C) 1.92 min, [M+H] 428 WO 2013/110309 PCT/EP2012/005358 -108 "A112" N H4 N N N 5 (1 -oxetan-3-yl-1 H-pyrazol-4-yl)-(3-quinolin-7-yl-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-amine HPLC/MS (B) 1.81 min, [M+H] 386; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.60 (s, 1H), 9.46 (s, 1H), 9.09 (s, 10 1H), 8.99 (d, J=1.4, 1H), 8.54 (d, J=8.2, 1H), 8.47 (dd, J=8.8, 2.1, 1H), 8.34, m, 2H), 7.83 (s, 1H), 7.68 (dd, J=8.1, 4.1, 1H), 5.61 (m, 1H), 4.96 (m, 4H) "A113" N- H N," N 15 N NN 4-{5-[1 -(tetrahydro-pyran-4-yl)-1 H-pyrazol-4-ylamino] [1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-benzoic acid methyl 20 ester HPLC/MS (B) 2.10 min, [M+H] 421; 'H NMR (500 MHz, DMSO-ds) 6 [pm] = 10.49 (s, 1H), 9.42 (s, 1H), 8.37 (d, J=8.4, 2H), 8.27 (d, J=8.3, 2H), 8.17 (s, 1H), 7.66 (s, 1H), 4.41 (m, 1H), 4.00 (dd, J=11.1, 3.1, 2H), 3.93 (s, 3H), 3.52 (t, J=11.2, 2H), 2.08 (d, J=11.7, 2H), 25 1.93 (qd, J=12.1, 4.3, 2H) "Al 14" Cl 4 O H F N N N N 30 N N [3-(4-chloro-3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5 dlpyrimidin-5-yl]-[1-(2-morpholin-4-yl-ethyl)-1 H-pyrazol 35 4-yl]-amine HPLC/MS (B) 1.70 min, [M+H] 444; WO 2013/110309 PCT/EP2012/005358 -109 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.46 (s, 1H), 9.39 (s, 1H), 8.29 (d, J=10.5, 1H), 8.17 - 8.00 (m, 2H), 7.95 (t, J=8.4, 1H), 7.64 (s, 1H), 4.23 (t, J=6.6, 2H), 3.63 - 3.41 (m, 4H), 2.71 (t, J=6.6, 2H), 2.45 - 2.35 (m, 4H) "Al15" 4 50 0 H NN N N / '- N N 10 [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yl]-[l-(2-morpholin-4-yl-ethyl)-1 H-pyrazol-4-yl]-amine HPLC/MS (C) 1.61 min, [M+H] 436; 1 H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.34 (s, 1H), 9.35 (s, 1H), 8.02 (s, 15 1H), 8.01 - 7.94 (m, 2H), 7.63 (s, 1H), 7.24 (d, J=8.5, 2H), 4.22 (t, J=6.5, 2H), 4.15 (q, J=7.0, 2H), 3.58 - 3.53 (m, 4H), 2.69 (t, J=6.7, 2H), 2.42 2.36 (m, 4H), 1.39 (t, J=7.0, 3H) "Al 16" F 4 20 0 N N N F N N N NN [3-(3,4-difluoro-phenyl)-3H-[1,2,3]triazolo[4,5 25 d]pyrimidin-5-yl]-[1 -(tetrahydro-pyran-4-yl)-1 H-pyrazol-4 yl]-amine HPLC/MS (C) 2.57 min, [M+H] 399; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.45 (s, 1H), 9.39 (s, 1H), 8.34 30 8.28 (m, 1H), 8.10 (s, 1H), 8.05 - 7.99 (m, 1H), 7.83 - 7.75 (m, 1H), 7.64 (s, IH), 4.43 - 4.34 (m, 1H), 4.01 - 3.94 (m, 2H), 3.53 - 3.45 (m, 2H), 2.06 1.98 (m, 2H), 1.97 - 1.86 (m, 2H) 35 WO 2013/110309 PCT/EP2012/005358 -110 "Al 17" 4 N N ,- 0 N 5 NsN 4-[5-(1 -ethyl-1 H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5 d]pyrimidin-3-yl]-benzoic acid methyl ester HPLC/MS (B) 2.14 min, [M+H] 365; 10 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.45 (s, 1H), 9.39 (s, 1H), 8.37 (d, J=8.5, 2H), 8.26 (d, J=8.2, 2H), 8.02 (s, 1H), 7.65 (s, 1H), 4.16 (q, J=7.1, 2H), 3.92 (s, 3H), 1.41 (t, J=7.2, 3H) "A118" 4 HN F 15 NN N N N N. N N [3-(3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yl]-[1-(1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-yl]-amine 20 HPLC/MS (C) 1.79 min, [M+H] 394; 1 H NMR (500 MHz, DMSO-d 6 ) 5 [pm] = 10.44 (s, 1H), 9.39 (s, 1H), 8.14 8.07 (m, 2H), 8.07 - 8.02 (m, 1 H), 7.77 - 7.70 (m, 1 H), 7.62 (s, 1 H), 7.45 7.38 (m, 1H), 4.13 - 4.04 (m, 1H), 2.91 - 2.84 (m, 2H), 2.23 (s, 3H), 2.12 25 2.00 (m, 4H), 1.98 - 1.87 (m, 2H) "A119" N- H OH 6 0 N la -N 30 NeN 2-(4-{5-[1 -(tetrahydro-pyran-4-yl)- 1 H-pyrazol-4-ylamino] [1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-phenyl)-propan-2-ol HPLC/MS (B) 1.87 min, [M+H] 421; 35 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.41 (s, 1H), 9.38 (s, 1H), 8.18 (s, 1H), 8.05 (d, J=8.3, 2H), 7.78 (d, J=8.3, 2H), 7.62 (s, 1H), 5.19 (s, 1H), 4.38 WO 2013/110309 PCT/EP2012/005358 - 111 (m, 1H), 3.99 (dd, J=11.2, 3.1, 2H), 3.49 (t, J=11.3, 2H), 2.06 (d, J=l1.7, 2H), 1.89 (m, 2H), 1.51 (s, 6H) "A120" F 4 5 N NH F N _ N N N N, [3-(3,4-difluoro-phenyl)-3H-[1,2,3]triazolo[4,5 10 d]pyrimidin-5-yl]-[1 -(1 -methyl-piperidin-4-yl)-1 H-pyrazol 4-yi]-amine HPLC/MS (C) 1.61 min, [M+H] 412 "Al 21" HO 6 N-H 15 N N 'X N-N NN 2-{4-[5-(1-ethyl-1 H-pyrazol-4-ylamino) 20 [1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-phenyl}-propan-2-o HPLC/MS (B) 1.88 min, [M+H] 365; 1 H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.36 (s, 1H), 9.37 (s, 1H), 8.05 (d, J=8.3, 2H), 8.01 (s, 1H), 7.77 (d, J=8.1, 2H), 7.66 (s, 2H), 5.19 (s, 1H), 4.13 25 (q, J=7.3, 2H), 1.51 (s, 6H), 1.40 (t, J=7.2, 3H) "Al 22" 4 0a HF N N N /N~N N_ , 30 N [3-(3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yi]-[l -(tetrahyd ro-pyran-4-yl)-1 H-pyrazol-4-yi]-amine HPLC/MS (B) 2.11 min, [M+HI 381; 35 1 H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.45 (s, 1H), 9.40 (s, 1H), 8.18 8.02 (m, 3H), 7.78 - 7.70 (m, 1H), 7.64 (s, 1H), 7.42 (t, J=8.4, 1H), 4.44 - WO 2013/110309 PCT/EP2012/005358 -112 4.34 (m, 1 H), 4.02 - 3.94 (m, 2H), 3.56 - 3.43 (m, 2H), 2.09 - 1.99 (m, 2H), 1.92 (qd, J=l1.9, 4.4, 2H) "A123" N'N H O '' N 5 N NsN [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 10 yl]-(1 -methyl-1 H-pyrazol-3-yl)-amine HPLCIMS (B) 2.20 min, [M+H] 337; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.55 (s, 1H), 9.39 (s, 1H), 8.01 7.97 (m, 2H), 7.60 (d, J=2.2, 1H), 7.22 - 7.18 (m, 2H), 6.65 (d, J=2.2, 1H), 4.14 (q, J=6.9, 2H), 3.77 (s, 3H), 1.38 (t, J=7.0, 3H) 15 "A124" N H 4 N N /
/
NN N N 20 N:N [3-(5-methoxy-pyridin-2-yI)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yIl]-[1-(2-pyrazol-1-yI-ethyl)-1 H-pyrazol-4 yl]-amine HPLC/MS (C) 2.07 min, [M+H] 404; 25 1H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.35 (s, 1H), 9.35 (s, 1H), 8.48 (s, 1H), 7.99 (d, J=8.8, 1H), 7.87 - 7.77 (m, 2H), 7.68 (s, 1H), 7.42 (s, 1H), 7.35 (s, 1H), 6.09 (s, 1H), 4.52 (s, 4H), 3.99 (s, 3H) "Al 25" 3 30 'NO HND N N NN [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 35 yll-[I-(3-piperidin-4-yl-propyl)-1 H-pyrazol-4-yi]-amine WO 2013/110309 PCT/EP2012/005358 -113 HPLC/MS (C) 1.96 min, [M+H] 448; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.37 (s, 1H), 9.38 (s, 1H), 8.42 (s, 1H), 8.12 (d, J=6.6, 1H), 8.03 - 7.96 (m, 3H), 7.65 (s, 1H), 7.24 (d, J=8.2, 2H), 4.17 (q, J=6.9, 2H), 4.10 (t, J=6.8, 2H), 3.23 (d, J=12.2, 2H), 2.80 (dd, 5 J=22.4, 11.1, 2H), 1.83 - 1.73 (m, 4H), 1.55 - 1.46 (m, 1H), 1.41 (t, J=7.0, 3H), 1.23 - 1.15 (m, 4H) "A126" 4 F H 10 N N N N N N N N [3-(3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yl]-[l -(2-pyrazol-1 -yl-ethyl)-1 H-pyrazol-4-yil]-amine 15 HPLC/MS (B) 2.04 min, [M+H] 391; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.42 (s, 1H), 9.38 (s, 1H), 8.06 8.00 (m, 2H), 7.81 - 7.68 (m, 3H), 7.40 (d, J=34.4, 4H), 4.56 - 4.50 (m, 4H) "Al 27" N- OH 20 N. N 0 N N N WNN 25 2-(1 -{4-[5-(1-ethyl-1 H-pyrazol-4-ylamino) [1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-phenyl}-1 -methyl ethoxy)-ethanol HPLC/MS (A) 1.67 min, [M+H] 409; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.39 (s, 1H), 9.38 (s, 1H), 8.10 (d, 30 J=8.2, 3H), 8.02 (s, 1H), 7.75 (d, J=7.9, 3H), 7.63 (s, 1H), 4.13 (q, J=7.3, 2H), 3.53 (t, J=5.6, 2H), 3.24 (t, J=5.5, 2H), 1.55 (s, 6H), 1.39 (t, J=7.3, 3H) 35 WO 2013/110309 PCT/EP2012/005358 -114 "A128" 8 N-H N F N N N 5 N (1 -ethyl-i H-pyrazol-4-yl)-{3-[4-(1 -fluoro-1 -methyl-ethyl) phenyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl}-amine HPLC/MS (A) 1.93 min, [M+H] 367; 10 lH NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.40 (s, 1H), 9.39 (s, 1H), 8.16 (d, J=8.2, 2H), 8.02 (s, 1H), 7.75 (d, J=8.0, 2H), 7.66 (s, 1H), 4.14 (q, J=7.3, 2H), 1.75 (d, J=22.2, 6H), 1.40 (t, J=7.3, 3H) "Al129" N H 3 N 15 ''A12' F N NL N H I NN [3-(3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 20 yll-[1-(3-piperidin-4-yl-propyl)-1 H-pyrazol-4-yl]-amine HPLC/MS (C) 1.93 min, [M+H] 422; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.47 (s, 1H), 9.40 (s, 1H), 8.43 (s, 1 H), 8.14 - 8.09 (m, 1 H), 8.07 - 8.00 (m, 2H), 7.76 (dd, J=14.8, 7.7, 1 H), 7.65 (s, 1H), 7.41 (t, J=7.7, 1H), 4.10 (t, J=6.9, 2H), 3.23 (d, J=12.4, 2H), 2.80 25 (q, J=11.9, 2H), 1.84 - 1.71 (m, 4H), 1.55 - 1.46 (m, 1H), 1.25 - 1.15 (m, 4H) "A130" H 7 N N OH 0 N O N ,o N 30 1 WNN 2-[1-methyl-1-(4-{5-[1-(tetrahydro-pyran-4-yl)-1
H
pyrazol-4-ylamino]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl} phenyl)-ethoxy]-ethanol 35 HPLC/MS (A) 1.66 min, [M+H] 465; WO 2013/110309 PCT/EP2012/005358 -115 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.42 (s, 1H), 9.39 (s, 1H), 8.19 (s, 1H), 8.11 (d, J=8.2, 2H), 7.75 (d, J=8.2, 2H), 7.60 (s, 1H), 4.56 (t, J=5.5, 1H), 4.39 (m, 1H), 3.98 (dd, J=l1.0, 3.0, 2H), 3.51 (m, 4H), 3.24 (t, J=5.6, 2H), 2.01 (m, 2H), 1.89 (m, 2H), 1.55 (s, 6H) 5 "A131" H O4 NN N-- N NN N 10 [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yI]-(3-methyl-isoxazol-5-yl)-amine HPLC/MS (A) 1.94 min, [M+H] 338; 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 11.89 (s, 1H), 9.59 (s, 1H), 8.00 15 7.94 (m, 2H), 7.27 - 7.22 (m, 2H), 6.28 (s, 1H), 4.16 (q, J=7.0, 2H), 2.23 (s, 3H), 1.39 (t, J=6.9, 3H) "A132" N0 0 S H N 20N N-NN N N [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 25 yl]-(5-pyridin-4-yl-[1,3,4]thiadiazol-2-yI)-amine HPLC/MS (A) 1.43 min, [M+H] 418; H NMR (400 MHz, DMSO-ds) 6 [pm] = 10.26 (s, 1H), 10.03 - 9.98 (m, 2H), 8.65 (s, 2H), 8.60 - 8.55 (m, 2H), 8.12 - 8.07 (m, 2H), 7.33 - 7.26 (m, 2H), 30 4.19 (q, J=6.9, 2H), 1.41 (t, J=6.9, 3H) 35 WO 2013/110309 PCT/EP2012/005358 - 116 "Al 33" 4 N 5 N~- N N / N [1 -(2-pyrazol-1 -yI-ethyl)-1 H-pyrazol-4-y]-{3-[4 10 (pyrrolidine- 1-sulfonyl)-phenyl]-3H-[ 1,2, 3]triazolo[4 ,5-d] pyrimidin-5-yl}-amine HPLC/MS (C) 2.47 min, [M+H] 506; H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.48 (s, 1H), 9.41 (s, 1H), 8.44 (d, J=8.4, 3H), 8.19 (d, J=8.2, 2H), 7.81 (s, 1H), 7.66 (s, 1H), 7.44 (s, 1H), 7.35 15 (s, 1H), 4.56 (s, 4H), 3.27 -3.23 (in, 4H), 1.71 (t, J=6.7, 4H) "A134" -- 4 N SN/ N 20 N N " N N [11-(2-pyrazol-1-y l-ethyl)-1H-pyrazol-4-yl]-(3-quinolin-7-yI 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yI)-amine 25 HPLC/MS (B) 1.84 min, [M+H] 424; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.50 (s, 1H), 9.44 (s, 1H), 9.04 (dd, J=4.2, 1.7, 1H), 8.99 (s, 1H), 8.55 (d, J=8.1, 1H), 8.44 (d, J=8.6, 1H), 8.35 (d, J=8.7, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.67 (dd, J=8.2, 4.2, 1H), 7.49 (s, 1H), 305 7.36 (s, 1H), 4.61 (dd, J=15.6, 4.7, 4H) "Al 35" H 2 N 4 N N N 35 N N
N
WO 2013/110309 PCT/EP2012/005358 - 117 4-{5-[1-(2-pyrazol-1 -yi-ethyl)-1 H-pyrazol-4-ylamino] [1,2,3]triazolo[4,5-d]pyrimidin-3-yi}-benzenesulfonamide HPLC/MS (C) 2.04 min, [M+H] 452; 1H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.44 (s, 1H), 9.39 (s, 1H), 8.34 (d, 5 J=9.3, 2H), 8.17 (d, J=9.3, 2H), 7.72 (d, J=13.6, 3H), 7.55 (s, 2H), 7.44 (s, 1H), 7.40 (s, 1H), 4.55 (s, 4H) "A1 36" 4 N KN 10 N H O 0See N N N N N NN 15 [1 -(1 -methyl-piperidin-4-yi)-1 H-pyrazol-4-yl]-{3-[4 (pyrrolidine-1 -sulfonyl)-phenyl]-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl}-amine HPLC/MS (B) 1.65 min, [M+H] 509 "A137" N H 4 20 N/N HO N O NsN 25 4-{4-[3-(6-methoxy-pyridin-3-yI)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino]-pyrazol-1 -yl}-cyclohexanol HPLC/MS (C) 2.24 min, [M+H] 408; 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.40 (s, 1H), 9.38 (s, 1H), 8.90 (s, 30 1H), 8.40 (d, J=8.6, 1H), 8.06 (s, 1H), 7.60 (s, 1H), 7.18 (d, J=8.8, 1H), 4.46 (d, J=3.3, 1H), 4.14 - 4.07 (m, 1H), 3.98 (s, 3H), 3.84 (d, J=3.0, 1H), 2.10 (qd, J=12.4, 3.5, 2H), 1.86 - 1.53 (m, 6H) 35 WO 2013/110309 PCT/EP2012/005358 - 118 "A138" 0 N-- H N N O O N N 5 N.N 4-{4-[3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino]-pyrazol-1 -yl}-morpholin-3-one HPLC/MS (B) 1.66 min, [M+H] 408; 10 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.46 (s, 1H), 9.41 (s, 1H), 8.06 (s, 1H), 8.01 (d, J=8.0, 2H), 7.75 (s, 1H), 7.21 (m, 2H), 4.35 (s, 2H), 4.09 (t, J=5.1, 2H), 3.88 (m, 5H) "A139" 4 15 ~N H N N N N N N N N [1 -(1 -methyl-piperidin-4-yi)-1 H-pyrazol-4-yl]-[3-(1 -methyl 20 1 H-pyrazol-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl] amine HPLC/MS (C) 1.46 min, [M+H] 380 "A140" N 4 -N 25 N N N H / NLN -N 30 (1',5'-dimethyl-1 H, 1'H-[3,4']bipyrazolyl-5-yl)-[3-(4-ethoxy phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine HPLC/MS (A) 1.76 min, [M+H] 417; H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 12.43 (s, 1H), 10.57 (s, 1H), 9.40 (s, 1H), 8.01 - 7.96 (m, 2H), 7.67 (s, 1H), 7.20 - 7.16 (m, 2H), 6.81 (s, 1H), 35 4.16 (q, J=6.9, 2H), 3.80 (s, 3H), 2.36 (s, 3H), 1.40 (t, J=6.9, 3H) WO 2013/110309 PCT/EP2012/005358 -119 "A141" N- H N/ N N N O HO N N 5 NaN 4-{4-[3-(5-methoxy-pyridin-2-yl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino]-pyrazol-1 -yl}-cyclohexanol HPLC/MS (C) 2.07 min, [M+H] 408; 10 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.40 (s, 1H), 9.36 (s, 1H), 8.48 (s, 1H), 8.28 (s, 1H), 8.07 (d, J=8.8, 1H), 7.81 (dd, J=8.7, 2.3, 1H), 7.55 (s, 1H), 4.53 (s, 1H), 4.18 - 4.08 (m, 1H), 3.98 (s, 3H), 3.91 - 3.84 (m, 1H), 2.10 (qd, J=12.3, 3.3, 2H), 1.85 - 1.70 (m, 4H), 1.66 - 1.55 (m, 2H) "A142" N- 4 H0 15 N O Na N N /N N NH 2 N ~Nj N=N 20 4-{5-[1 -(1 -methyl-piperidin-4-y)-1 H-pyrazol-4-ylamino] [1,2,3]triazolo[4,5-djpyrimidin-3-yl}-benzenesulfonamide HPLC/MS (C) 1.59 min, [M+H] 455 "A143" N- H 25 N/ N O HO N N N N 4-{4-[3-(5-methoxy-pyridin-2-y)-3H-[1,2,3]triazolo[4,5 30 d]pyrimidin-5-ylamino]-pyrazol-1 -yl}-cyclohexanol HPLC/MS (C) 1.99 min, [M+H] 408 35 WO 2013/110309 PCT/EP2012/005358 - 120 "A144" N- 8 N/N F /N o N 5 NsN {3-[4-(1 -fluoro-1 -methyl-ethyl)-phenyl]-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-yl}-[1 -(tetrahyd ro-pyran 4-yl)-1 H-pyrazol-4-yl]-amine 10 HPLC/MS (A) 1.91 min, [M+H] 423 "A145" N H 9 N N N 15 N N 4-[4-(3-quinolin-7-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 ylamino)-pyrazol-1-yl]-morpholin-3-one HPLC/MS (A) 1.56 min, [M+H] 429 20 "A146" 4 H 1 N 0 N, O H N N 25 NaN (5-tert-butyl-2H-pyrazol-3-yl)-[3-(4-ethoxy-phenyl)-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine HPLC/MS (A) 1.99 min, [M+HJ 379; 30 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 12.06 (s, 1H), 10.45 (s, 1H), 9.37 (s, 1 H), 8.06 (d, J=8.8, 2H), 7.18 - 7.13 (m, 2H), 6.62 (s, 1 H), 4.13 (q, J=7.0, 2H), 1.38 (t, J=7.0, 3H), 1.31 (s, 9H) 35 WO 2013/110309 PCT/EP2012/005358 - 121 "A147" 4 O N N N N N N N NN 5 ~N/ [3-(1-methyl-1 H-pyrazol-3-yI)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl]-[1 -(tetrahyd ro-pyran-4-yl)-1 H-pyrazol-4 yl]-amine 10 HPLC/MS (C) 1.95 min, [M+H] 367 "A148" N 10 NHH /N NH2 N 15 N N':::N {3-[4-(1-amino-1 -methyl-ethyl)-phenyl]-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-(1-ethyl-1 H-pyrazol 4-yl)-amine 20 HPLC/MS (A) 1.32 min, [M+H] 364; 1 H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.39 (s, 1H), 9.38 (s, 1H), 8.30 (s, 1H), 8.09 (d, J=8.2, 2H), 7.99 (s, 1H), 7.86 (d, J=8.1, 2H), 7.68 (s, 1H), 4.13 (q, J=7.3, 2H), 1.53 (s, 6H), 1.40 (t, J=7.2, 3H) 25 "A149" 4 3N N N N 30 4-(2-{4-[3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino]-pyrazol-1 -yl}-ethyl)-morpholin-3 one 35(16mM ]5 HPLC/MS (A) 1.69 min, [M+H] 450; WO 2013/110309 PCT/EP2012/005358 - 122 'H NMR (500 MHz, DMSO-ds) 6 [pm] = 10.40 (s, 1H), 9.37 (s, 1H), 8.06 7.96 (m, 3H), 7.66 (s, 1H), 7.26 (d, J=9.1, 2H), 4.29 (t, J=6.1, 2H), 4.16 (q, J=6.9, 2H), 3.94 - 3.88 (m, 2H), 3.66 (t, J=6.1, 2H), 3.63 - 3.58 (m, 2H), 3.01 - 2.93 (m, 2H), 1.39 (t, J=7.0, 3H) 5 "A150" 0 4 NO N 10 N' 1-(3-{4-[3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino]-pyrazol-1-yl}-azetidin-1-yl)-2 15 methoxy-ethanone HPLC/MS (A) 1.73 min, [M+H] 450; 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.43 (s, 1H), 9.38 (s, 1H), 8.14 (s, 1H), 8.06 - 7.94 (m, 2H), 7.77 (s, 1H), 7.28 - 7.18 (m, 2H), 5.32 - 5.25 (m, 1H), 4.64 (t, J=8.9, IH), 4.46 - 4.34 (m, 2H), 4.20 - 4.12 (m, 3H), 3.96 (s, 20 2H), 3.30 (s, 3H), 1.39 (t, J=6.9, 3H) "A51" HO 4 H0 N N H N 25 NN N1 N N N 1-(2-{4-[3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino]-pyrazol-1-yl}-ethyl)-pyrrolidin-3-oI 30 HPLC/MS (A) 1.41 min, [M+H] 436; 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.34 (s, 1H), 9.36 (s, 1H), 8.03 7.94 (m, 3H), 7.62 (s, 1H), 7.23 (d, J=8.6, 2H), 4.67 - 4.60 (m, 1H), 4.21 4.09 (m, 5H), 2.79 (t, J=6.6, 2H), 2.72 (dd, J=9.6, 6.3, 1H), 2.57 (q, J=7.7, 35 1H), 2.48 - 2.43 (m, 1H), 2.30 (dd, J=9.7, 3.8, 1H), 1.93 - 1.84 (m, 1H), WO 2013/110309 PCT/EP2012/005358 - 123 1.54 - 1.44 (m, 1H), 1.39 (t, J=6.9, 3H) "A152" N 10 , _H N N
NH
2 5 NN WN N' N {3-[4-(1-amino-1-methyl-ethyl)-phenyl]-3H [1,2,3]triazolo[4,5-d]pyrimid in-5-yl}-[1 -(tetrahyd ro-pyran 10 4-yl)-1 H-pyrazol-4-yil]-amine formate salt HPLC/MS (A) 1.33 min, [M+H] 403 [M-NH 2 ] 1 H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.42 (s, 1H), 9.38 (s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 8.08 (d, J=8.3, 2H), 7.86 (d, J=8.2, 2H), 7.63 (s, 1H), 4.38 15 (tt, J=11.4, 4.2, 1H), 3.99 (dd, J=11.1, 3.1, 2H), 3.50 (t, J=11.4, 2H), 2.06 (m, 2H), 1.89 (m, 2H), 1.51 (s, 6H) "A153" N- H cl 4 IN N N Z 20 NN 7 NN [3-(4-chloro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yl]-[1 -(1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-yl]-amine 25 HPLC/MS (C) 1.91 min, [M+H] 410 "A154" NH 4 1 N Fi 30 S N F O O N-:__N [3-(3-chloro-4-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5 djpyrimidin-5-ylj-[1 -(1 -methanesulfonyl-piperidin-4-yl) 35 1 H-pyrazol-4-yi]-amine HPLC/MS (C) 2.64 min, [M+H] 492 WO 2013/110309 PCT/EP2012/005358 - 124 "A155" N H 4 5 N N Cl N 5 1 NN [3-(4-chloro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yl]-[l -(tetrahyd ro-pyra n-4-yl)-1 H-pyrazol-4-yl]-amine HPLC/MS (C) 2.66 min, [M+H] 397 10 "A156" / 4 0 H
O
/-N N N 15 'N' (1-ethyl-1 H-pyrazol-4-yl)-[3-(3,4,5-trimethoxy-phenyl) 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yI]-amine HPLC/MS (A) 1.75 min, [M+H] 397 20 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.31 (s, 1H), 9.37 (s, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.44 (s, 2H), 4.09 (q, J=7.2, 2H), 3.89 (s, 6H), 3.76 (s, 3H), 1.35 (t, J=7.2, 3H) "A157" H 4 N /N 25 N' N N / N N N (3-benzo[1,2,5]thiadiazol-5-yl-3H-[1,2,3]triazolo[4,5 30 d]pyrimidin-5-yl)-(1 -ethyl-1 H-pyrazol-4-yi)-amine HPLC/MS (A) 1.86 min, [M+HJ 365 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.52 (s, 1H), 9.44 (s, 1H), 8.98 (s, 1H), 8.60 (d, J=8.3, 1H), 8.43 (d, J=9.3, 1H), 8.10 (s, 1H), 7.68 (s, 1H), 4.15 35 (q, J=7.2, 2H), 1.42 (t, J=7.3, 3H) WO 2013/110309 PCT/EP2012/005358 - 125 Example 6 Synthesis of "Al 19" 5 0 5 0 OH N-N / N-N CeCl 3 / + CH 3 MgCI a- 10 HN N THF HN N N 10N N' N-, To a suspension of 1.06 g (2.52 mmol) 4-{5-[1-(tetrahydro-pyran-4-yl)-1 H 15 pyrazol-4-ylamino]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzoic acid methyl ester in 30 ml THF are added 835 mg (3.39 mmol) cerium(Ill) chloride (1.33 g, 5.38 mmol). The mixture is flushed with nitrogen and stirred at room temperature for 1 hour. Then methylmagnesium chloride (20% solution in THF, 4.75 ml, 13.07 mmol) is added and the reaction mixture is stirred at room 20 temperature for another hour. The reaction mixture is diluted with THF and saturated sodium chloride solution is added carefully. The mixture is stirred thoroughly and filtered with suction. The organic phase of the filtrate is separated, dried over sodium sulfate and evaporated. The residue is 25 chromatographed on a silica gel column with methanol/dichloromethane as eluent to afford 2-(4-{5-[1 -(tetrahyd ro-pyran-4-yl)-1 H-pyrazol-4-ylamino] [1,2,3]triazolo[4,5-dipyrimidin-3-yl}-phenyl)-propan-2-ol ("A 119") as yellow solid; HPLC/MS 1.87 min (B), [M+H] 421; 30 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.41 (s, 1H), 9.38 (s, 1H), 8.18 (s, 1H), 8.05 (d, J=8.3, 2H), 7.78 (d, J=8.3, 2H), 7.62 (s, 1H), 5.19 (s, 1H), 4.38 (m, 1H), 3.99 (dd, J=11.2, 3.1, 2H), 3.49 (t, J=11.3, 2H), 2.06 (d, J=11.7, 2H), 1.89 (m, 2H), 1.51 (s, 6H). 35 WO 2013/110309 PCT/EP2012/005358 - 126 Example 7 Synthesis of "A127" 5 OH O OH N-N N-N / 7 OH p-TosOH HN N N + HN N N N 'N HO Nii 10 U- 14j N N To a suspension of 2-{4-[5-(1-ethyl-1 H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5 d]pyrimidin-3-yIl]-phenyl}-propan-2-ol (138 mg, 0.38 mmol) in ethane-1,2-diol (1 15 ml) is added toluene-4-sulfonic acid monohydrate (89 mg, 0.42 mmol). The reaction mixture is stirred for 16 hours at ambient temperature. The mixture is then heated to 800 C and the resulting clear solution is stirred at this temperature for 1 hours. The reaction mixture is cooled to room temperature 20 and water is added. The resulting precipitate is filtered off and washed with water. The residue is chromatographed on a silica gel column with dichloromethane/methanol as eluent to afford 2-(1-{4-[5-(1-ethyl-1H-pyrazol-4 ylamino)-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-phenyl}-1 -methyl-ethoxy)-ethanol ("A127") as yellow powder; HPLC/MS 1.67 min (A), [M+H] 409; 25 'H NMR (500 MHz, DMSO-d 6 ) 6 [pm] = 10.39 (s, 1H), 9.38 (s, 1H), 8.10 (d, J=8.2, 3H), 8.02 (s, 1H), 7.75 (d, J=7.9, 3H), 7.63 (s, 1H), 4.13 (q, J=7.3, 2H), 3.53 (t, J=5.6, 2H), 3.24 (t, J=5.5, 2H), 1.55 (s, 6H), 1.39 (t, J=7.3, 3H). 30 Example 8 Synthesis of "A128" 35 WO 2013/110309 PCT/EP2012/005358 -127 OH F N-N DAST N-N 5 HN N N~ II N
CH
2 Cl 2 HN N N N Y N 10 A suspension of 2-{4-[5-(1 -ethyl-1 H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5 d]pyrimidin-3-yl]-phenyl}-propan-2-ol (138 mg, 0.38 mmol) in dichloromethane (3 ml) is cooled to -78* C. Diethylaminosulfurtrifluoride (201 pl, 1.52 mmol) is added. The reaction mixture is allowed to reach room temperature over 1 hour. The reaction mixture is evaporated and the residue is treated with water and 15 saturated sodium hydrogen carbonate solution. The solids are filtered off and chromatographed on a silica gel column with dichloromethane/methanol as eluent to afford (1-ethyl-1 H-pyrazol-4-yl)-{3-[4-(1 -fluoro-1 -methyl-ethyl)-phenyl] 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl}-amine ("A128") as yellow powder; 20 HPLC/MS 1.93 min (A), [M+H] 367; 1 H NMR (500 MHz, DMSO-ds) 5 [pm] = 10.40 (s, 1H), 9.39 (s, 1H), 8.16 (d, J=8.2, 2H), 8.02 (s, 1H), 7.75 (d, J=8.0, 2H), 7.66 (s, 1H), 4.14 (q, J=7.3, 2H), 1.75 (d, J=22.2, 6H), 1.40 (t, J=7.3, 3H). 25 example 9 Synthesis of "A138" 30 35 WO 2013/110309 PCT/EP2012/005358 -128 CI N,N-N O toluene H Cs 2
CO
3 NN-N N,_ _ _ _ N-N 5 + 0 r O N-N CH 3 CN
NO
2 reflux r.t.
NO
2 Cl
NO
2 0 10 0 O 'A138"
H
2 NN CINN 30 N-N NxN Pd/C _ HN N N 15
NH
2 2-methoxyethanol N N 90* C Example 10 20 Synthesis of "A148" OH N-N N 3 25 CF 3 COOH N-N HN N + NaN 3 " N CH 2 Cl 2 HN N N, 30
NH
2 N-N Zn/AcOH T HN N N 35 TH N N WO 2013/110309 PCT/EP2012/005358 - 129 To a suspension of 2-{4-[5-(1-ethyl-1 H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5 d]pyrimidin-3-yl]-phenyl}-propan-2-ol (237 mg, 0.65 mmol) and sodium azide (186 mg, 2.86 mmol) in dichloromethane (2.5 ml) is added dropwise under external cooling a solution of trifluoroacetic acid (822 pl, 10.7 mmol) in 5 dichloromethane (2.5 ml). The reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is partitioned between dichloromethane and diluted aqueous ammonia. The organic phase is dried over sodium sulfate and evaporated to afford {3-[4-(1-azido-1-methyl-ethyl)-phenyl]-3H 10 [1,2,3]triazolo[4,5-d]pyrimidin-5-yl}-(1 -ethyl-1 H-pyrazol-4-yl)-amine as yellow green powder; HPLC/MS 2.01 min (A), [M+H] 390. To a slurry of {3-[4-(I-azido-1-methyl-ethyl)-phenyl]-3H-[1,2,3]triazolo[4,5 15 d]pyrimidin-5-yl}-(1-ethyl-1H-pyrazol-4-yl)-amine (171 mg, 0.44 mmol) and zinc dust (117 mg, 1.79 mmol) in THF (5 ml) is added acetic acid (230 pl, 4.0 mmol) and the mixture is stirred for 16 hours at room temperature. The suspension is quenched with THF/dichloromethane/ethyl acetate. The mixture is filtered with suction and the residue is washed with methanol. The filtrate is evaporated 20 and the residue is purified by preparative HPLC to afford {3-[4-(1-amino-1 methyl-ethyl)-phenyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl}-(1-ethyl-1 H pyrazol-4-yl)-amine ("A148") formate salt as white powder; HPLC/MS 1.32 min (A), [M+H] 364; 25 'H NMR (400 MHz, DMSO-d 6 ) 6 [pm] = 10.39 (s, 1H), 9.38 (s, 1H), 8.30 (s, 1H), 8.09 (d, J=8.2, 2H), 7.99 (s, 1H), 7.86 (d, J=8.1, 2H), 7.68 (s, 1H), 4.13 (q, J=7.3, 2H), 1.53 (s, 6H), 1.40 (t, J=7.2, 3H). 30 35 WO 2013/110309 PCT/EP2012/005358 - 130 Pharmacological data Table 2 GCN2 inhibition of some representative compounds of the formula 1 5 Compound IC 50 GCN2 IC 50 GCN2 Compound IC 50 GCN2 IC 50 GCN2 No. (enzyme (cell assay) No. (enzyme (cell assay) assay) assay) 10 "Al" B C "A76" A C "A2" C "A77" A B "A3" A C "A78" A "A4" A C "A79" A B "A5" A "A80" B A 15 __ __ _ "A6" A B "A81" A B "A7" A "A82" B B "A8" A B "A83" A C "A9" B "A84" A B 20 "A1 0" C "A85" A B "A11" B B "A86" A "Al 2" C "A87" A B "A1 A "A88" A 25 "A14" A "A89" A "Al 5" A "A90" A "A17" C "A91" A B "A 18" A "A92" A A 30 "A1 9" A "A93" A C "A20" A "A94" A "A21" A "A95" A C "A23" A B 35 "A26" A B "A96" A B "A27" A B "A97" A B WO 2013/110309 PCT/EP2012/005358 - 131 "A28" A B "A98" A B "A30" A B "A99" A C "A42" B "Al 00" A C "A43" A "AlOl" A C 5 "A44" A B "Al 02" B "A45" B "Al 03" A A "A46" A B "Al 04" A "A47" B "Al 05" A 10 "A48" A B "Al 06" A C "A49" A C "Al 07" A B "A50" A "Al 08" A C "A51" A B "Al09" B 15 "A52" A "Al 10" B "A53" B "A1ll" B C "A54" A B "A112" B "A55" B "Al 13" A 20 "A56" A B "Al 14" B "A57" B "A115" A C "A58" A "Al 16" B "A59" B "A117" A B "A60" B "Al 18" A B 25 "A61" A "Al19" A B "A62" A "A120" B C "A63" A "Al2l" A B "A64" A "A122" A B 30 "A65" A B "A124" A C "A66" A "A125" A A "A67" A C "A126" A C "A68" B C "A127" A B 35 "A69" A B "A128" A B WO 2013/110309 PCT/EP2012/005358 -132 "A70" A C "A129" A "A71" A B "A130" A B "A72" B "A133" A "A73" A C "A134" B 5 "A74" B "Al 35" A "A75" A B "Al 36" B "A137" B "A143" A "A138" A "A144" A 10 "A139" B "A145" B "A140" B "A147" B "A141" A "A148" B "A142" A "A149" A 15 "A150" A "A151" A "A152" A "A153" A "A154" B 20 IC 50 : <0.3pM=A 0.3-3piM=B 3-50pM = C The compounds shown in Table 1 are particularly preferred compounds according to the invention. 25 30 35 WO 2013/110309 PCT/EP2012/005358 -133 The following examples relate to medicaments: Example A: Injection vials A solution of 100 g of an active ingredient of the formula I and 5 g of disodium 5 hydrogenphosphate in 3 1 of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient. 10 Example B: Suppositories A mixture of 20 g of an active ingredient of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and allowed 15 to cool. Each suppository contains 20 mg of active ingredient. Example C: Solution A solution is prepared from 1 g of an active ingredient of the formula 1, 9.38 g of NaH 2
PO
4 - 2 H 2 0, 28.48 g of Na 2 HPO4 - 12 H 2 0 and 0.1 g of benzalkonium 20 chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 1 and sterilised by irradiation. This solution can be used in the form of eye drops. 25 Example D: Ointment 500 mg of an active ingredient of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions. 30 Example E: Tablets A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed in a conventional manner to give tablets in such a way that each tablet contains 35 10 mg of active ingredient.
WO 2013/110309 PCT/EP2012/005358 -134 Example F: Dragees Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye. 5 Example G: Capsules 2 kg of active ingredient of the formula I are introduced into hard gelatine 10 capsules in a conventional manner in such a way that each capsule contains 20 mg of the active ingredient. Example H: Ampoules 15 A solution of 1 kg of active ingredient of the formula I in 60 I of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient. 20 25 30 35

权利要求:
Claims (18)
[1] 1. Compounds of the formula I 5 2HR R-N N N I N in which 10 R denotes Ar or Het, R 2 denotes furyl, thienyl, pyrrolyl, thiadiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl or tetrazolyl which is unsubstituted or mono- or disubstituted by Hal, A, 15 [C(R 3 ) 2 ]pCyc, [C(R 3 ) 2 ]pOR 3 , [C(R 3 ) 2 ]pN(R 3 ) 2 , [C(R 3 ) 2 ]pAr, [C(R 3 ) 2 ]pHet', NO 2 , CN, [C(R 3 ) 2 pCOOR 3 , CON(R 3 ) 2 , NR 3 COA, NR 3 SO 2 A, SO 2 N(R 3 ) 2 , S(O),A, COHet', O[C(R 3 ) 2 ]mN(R 3 ) 2 , O[C(R 3 ) 2 ]pHet', NHCOOA, NHCON(R 3 ) 2 , NHCOO[C(R 3 ) 2 ]mN(R 3 ) 2 , 20 NHCOO[C(R 3 ) 2 ]pHet', NHCONH[C(R 3 ) 2 ]mN(R 3 ) 2 , NHCONH[C(R 3 ) 2 ]pHet, OCONH[C(R 3 ) 2 ]mN(R 3 ) 2 , OCONH[C(R 3 ) 2 ]pHet, CHO, COA, =S, =NR 3 and/or =0, R 3 denotes H or A', 25 Ar denotes phenyl or naphthyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R 3 ) 2 ]pOR 3 , [C(R 3 ) 2 ]pN(R 3 ) 2 , [C(R 3) 2 ]pHet', NO 2 , CN, [C(R ) 2 ]pCOOR 3, CON(R 3)2, NR 3COA, NR 3 SO 2 A, SO 2 N(R 3 ) 2 , S(O)nA, S(O),Het', COHet, O[C(R 3 ) 2 ]mN(R 3 ) 2 , O[C(R 3 ) 2 ]pHet', NHCOOA, NHCON(R 3 ) 2 , 30 NHCOO[C(R 3 ) 2 ]mN(R 3 ) 2 , NHCOO[C(R 3 ) 2 ]pHet', NHCONH[C(R 3 ) 2 ]mN(R 3 ) 2 , NHCONH[C(R 3 ) 2 ]pHet', OCONH[C(R 3 ) 2 ]mN(R 3 ) 2 , OCONH[C(R 3 ) 2 ]pHet', CHO and/or COA, 35 Het denotes furyl, thieny, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, WO 2013/110309 PCT/EP2012/005358 -136 pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimid azolyl, indazolyl, quinolyl, 1,3-benzodioxolyl, benzothiophenyl, benzofuranyl, imidazopyridyl, dihydroindolyl, quinoxalinyl, benzo[1,2,5]thiadiazolyl or furo[3,2-b]pyridyl which is 5 unsubstituted or mono- or disubstituted by Hal, A, [C(R 3 ) 2 ]pOR 3 , [C(R 3 ) 2 ]pN(R 3 ) 2 , [C(R 3 ) 2 ]pHet, NO 2 , CN, [C(R 6 ) 2 JpCOOR 3 , CON(R 3 ) 2 , NR 3 COA, NR 3 SO 2 A, SO 2 N(R 3 ) 2 , S(O)nA, COHet, O[C(R 3 ) 2 ]mN(R 3 ) 2 , O[C(R 3 ) 2 ]pHet', NHCOOA, 10 NHCON(R 3 ) 2 , NHCOO[C(R 3 ) 2 ]mN(R 3 ) 2 , NHCOO[C(R 3 ) 2 ]pHet, NHCONH[C(R 3 ) 2 ]mN(R 3 ) 2 , NHCONH[C(R 3 ) 2 ]pHet', OCONH[C(R 3 ) 2 ]mN(R 3 ) 2 , OCONH[C(R 3 ) 2 ]pHet', CHO, COA, =S, =NR 3 and/or =0, 15 Het' denotes dihydropyrrolyl, pyrrolidinyl, azetidinyl, oxetanyl, tetra hydroimidazolyl, dihydropyrazolyl, tetrahyd ropyrazolyl, tetrahydrofuranyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, morpholinyl, hexahydropyridazinyl, hexahydropyrimidinyl, 20 [1,3]dioxolanyl, tetrahydropyranyl, pyrazolyl, pyridyl or piperazinyl, which is unsubstituted or mono- or disubstituted by Hal, CN, OH, OA, COOA, CONH 2 , S(O)nA, S(O),Ar, COA, A and/or =0, 25 A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein one or two non-adjacent CH- and/or CH 2 -groups may be replaced by N-, 0- and/or S-atoms and wherein 1-7 H atoms may be replaced by F or Cl, 30 Cyc denotes cyclic alkyl with 3-7 C-atoms, which is unsubstituted or monosubstituted by [C(R 3 ) 2 ]pOH, A' denotes unbranched or branched alkyl with 1, 2, 3 or 4 C atoms, 35 Hal denotes F, Cl, Br or I, n denotes 0, 1 or 2, WO 2013/110309 PCT/EP2012/005358 -137 m denotes 1, 2 or 3, p denotes 0, 1, 2, 3 or 4, and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 5
[2] 2. Compounds according to Claim 1 in which R 2 denotes furyl, thienyl, pyrrolyl, thiadiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl or tetrazolyl 10 which is unsubstituted or monosubstituted by A, [C(R 3 ) 2 ]pCyc, [C(R 3 ) 2 ]pAr, [C(R 3 ) 2 ]pHet, CN or [C(R 3 ) 2 }pCOOR 3 , and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 15
[3] 3. Compounds according to Claim 1 or 2 in which Ar denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R 3 ) 2 1pOR 3 , NR 3 COA, S(O),Het and/or O[C(R 3 ) 2 ]pHet', 20 and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.
[4] 4. Compounds according to one or more of Claims 1-3 in which 25 Het denotes pyrazolyl, dihydroindolyl, quinoxalinyl, benzo[1,2,5]thiadiazolyl or pyridyl, which is unsubstituted or monosubstituted by A or [C(R 3 ) 2 ]pOR 3 , and pharmaceutically acceptable solvates, salts, tautomers and 30 stereoisomers thereof, including mixtures thereof in all ratios.
[5] 5. Compounds according to one or more of Claims 1-4 in which Het' denotes pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, morpholinyl, pyrazolyl, pyridyl or tetrahydropyranyl, which is unsubstituted or 35 monosubstituted by A or =0, WO 2013/110309 PCT/EP2012/005358 - 138 and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.
[6] 6. Compounds according to one or more of Claims 1-5 in which 5 R4 1 denotes Ar or Het, R2 denotes furyl, thienyl, pyrrolyl, thiadiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl or tetrazolyl which is unsubstituted or monosubstituted by A, [C(R 3 ) 2 ]pCyc, 10 [C(R 3 ) 2 ]pAr, [C(R 3 ) 2 ]pHet', CN or [C(R 3 ) 2 ]pCOOR 3 R 3 denotes H or methyl, Ar denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R 3 ) 2 ]pOR 3 , NR 3 COA, S(O),Het' and/or 15 O[C(R 3 ) 2 ]pHetl, Het denotes pyrazolyl, dihydroindolyl, quinoxalinyl, benzo[1,2,5]thiadiazolyl or pyridyl, which is unsubstituted or monosubstituted by A or [C(R 3 ) 2 ]pOR 3 Het' denotes pyrrolidinyl, azetidinyl, oxetanyl, piperidinyl, morpholinyl, 20 pyrazolyl, pyridyl or tetrahydropyranyl, which is unsubstituted or monosubstituted by A or =0, A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein one or two non-adjacent CH- and/or CH 2 -groups may be 25 replaced by N- and/or O-atoms and wherein 1-7 H-atoms may be replaced by F or Cl, Cyc denotes cyclic alkyl with 3-7 C-atoms, which is unsubstituted or monosubstituted by [C(R 3 ) 2 ]pOH, 30 Hal denotes F, Cl, Br or I, n denotes 0, 1 or 2, m denotes 1, 2 or 3, 35 p denotes 0, 1, 2, 3 or 4, WO 2013/110309 PCT/EP2012/005358 - 139 and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.
[7] 7. Compounds according to Claim 1, selected from the group 5 No. Name "A1 [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-dlpyrimidin-5-yl] (1-phenyl-1 H-pyrazol-4-yl)-amine 10 "A2" [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl] (1-methyl-1 H-pyrazol-3-yl)-amine "A3" [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl] (1 H-pyrazol-4-yl)-amine 15 "A4" (3-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-(1 H-pyrazol 4-yl)-amine "A5" [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl] (1 H-pyrazol-4-yl)-amine "A6" [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-djpyrimidin-5-yl] 20 (1-piperidin-4-yl-1 H-pyrazol-4-yl)-amine "A7" [3-(4-Ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl] (1 -piperidin-4-yl-1 H-pyrazol-4-yl)-amine "A8" [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-y] 25 [1 -(1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-yl]-amine "A9" [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl] [1 -(3-methoxy-propyl)-1 H-pyrazol-4-yl]-amine "Al 0" (1 -benzyl-1 H-pyrazol-4-yl)-[3-(4-methoxy-phenyl)-3H 30 [1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine "All" [1 -(1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-ylj-(3-phenyl-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-amine "Al 2" [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-y] 35 [4-methyl-5 H-oxazol-(2Z)-ylidene]-a mine WO 2013/110309 PCT/EP2012/005358 - 140 "Al 3" [3-(4-methoxy-phenyl)-3H-[1 ,2 ,3]triazolo[4,5-d]pyrimidin-5-yll [1 -(tetra hyd ro-pyra n-4-y)- 1 H-pyrazol-4-yil-amine "Al 4" [3-(4-methoxy-phenyl)-3H-[l ,2,3ltriazolo[4,5-d]pyrimidin-5-yl] [1 -(2-pyrrolid in-i -yi-ethyl)- 1 H-pyrazol-4-yi]-amine 5"A l 5"9 [3-(4-ethoxy-phenyl)-3H-[l ,2, 3Jtriazolo[4, 5-d]pyrimidin-5-yl] [1 -(tetrahyd ro-pyra n-4-yI)-l H-pyrazol-4-ylI-amine "Al16" [3-(4-methoxy-phenyl)-3 H-[l ,2,3jtriazolo[4 ,5-djpyrimid in-5-yI] (1 H-tetrazol-5-yi)-amine 10 "A l 7" [3-(4-methoxy-phenyl)-3H-[l ,2,3]triazolo[4,5-d]pyrimidin-5-y] (2H-[1 ,2 ,4]triazol-3-yI)-amine "A l 8" [3-(4-methoxy-phenyl)-3H-[l ,2 ,3]triazolo[4 ,5-dipyrimid in-5-yI] (1 -methyl-i H-pyrazol-4-yl)-amine 15 "A l 9" 4-{4-13-(4-ethoxy-phenyl)-3H-[l ,2 ,3]triazolo[4, 5-dipyrimid in-5 ylamino]-pyrazol-1 -yl}-cyclohexanol "A20" [3-(4-fluoro-phenyl)-3H-(l ,2 ,3ltriazolo[4,5-dlpyrimid in-5-yI]-[l (tetrahyd ro-pyran-4-yi)-l H-pyrazol-4-yII-amine 20 "A21" (I1-methyl-i H-pyrazol-4-yI)-[3-( 1-methyl-i H-pyrazol-4-yl)-3H [1 ,2,3]triazolo[4,5-d]pyrimidin-5-yI]-amine '#,,2" 3-(4-fluorophenyl)-N-[l -(l -methyl-4-piperidyl)pyrazol-4 yI]triazolo[4,5-d]pyrimidin-5-amine "A2Q3" 3-(4-methoxyphenyl)-N-[l -(oxetan-3-yl)pyrazol-4 25 ylltriazolo[4 ,5-dlpyrimidin-5-amine ",U411 3-(l1 -methylpyrazol-4-yl)-N-(l H-pyrazol-4-yI)triazolo[4 ,5 d]pyrimidin-5-amine "A25" N-[l -(1 -methyl-4-piperidyl)pyrazol-4-y]-3-( 1 -methylpyrazol-4 30 yI)triazolo[4,5-d]pyrimidin-5-amine "A2Q69 N-[l -[1 -(2-methoxyethyl)-4-piperidyllpyrazol-4-yl]-3-(4 methoxyphenyl)triazolo[4,5-d]pyrimidin-5-amine "tA27"1 3-[4-(2-methoxyethoxy)pheny]-N-[l -(l -methyl-4 35 piperidyl)pyrazol-4-ylltriazolo[4,5-d]pyrimidin-5-amine WO 2013/110309 PCT/EP2012/005358 - 141 "A28" 3-(4-ethoxyphenyl)-N-[1 -(1 -methyl-4-piperidyl)pyrazol4 yljtriazolo[4,5-d]pyrimidin-5-amine "A29" 3-(6-methoxy-3-pyridyl)-N-[1 -(2-pyrrolidin-1 -ylethyl)pyrazol-4 yl]triazolo[4,5-d]pyrimidin-5-amine "A30" 3-(2-methoxy-4-pyridyl)-N-[1 -(1 -methyl-4-piperidyl)pyrazol-4 yl]triazolo[4,5-d]pyrimidin-5-amine "A31" 3-(4-ethoxyphenyl)-N-[1 -(2-methoxyethyl)pyrazol-4 yl]triazolo[4,5-d]pyrimidin-5-amine 10 "A32" 3-(6-methoxy-3-pyridyl)-N-[1 -(1 -methyl-4-piperidyl)pyrazol-4 yl]triazolo[4,5-d]pyrimidin-5-amine "A33" 3-(2-methoxy-4-pyridyl)-N-[1 -(4-piperidyl)pyrazol-4 yl]triazolo[4,5-dlpyrimidin-5-amine 15 "A34" [2-[[4-[[3-(4-ethoxyphenyl)triazolo[4,5-d]pyrimidin-5 yl]amino]pyrazol-1 -yl]methyl]cyclopropyl]methanol "A35" 3-(6-methoxy-3-pyridyl)-N-[1 -(4-piperidyl)pyrazol-4 yl]triazolo[4,5-d]pyrimidin-5-amine 20 "A36" 4-[4-[[3-(2-methoxy-4-pyridyl)triazolo[4,5-d]pyrimidin-5 yl]amino]pyrazol-1 -yl]cyclohexanol "A37" N-(1 -methylpyrazol-4-yl)-3-[4-(2-morpholino ethoxy)phenyl]triazolo[4,5-d]pyrimidin-5-amine "A38" methyl 4-[[3-(4-methoxyphenyl)triazolo[4,5-d]pyrimidin-5 25 yl]amino]thiophene-3-carboxylate "A39" methyl 4-[[3-(4-methoxyphenyl)triazolo[4,5-d]pyrimidin-5 yl]amino]-1 -methyl-pyrrole-2-carboxylate "A40" 4-[[3-(4-methoxyphenyl)triazolo[4,5-d]pyrimidin-5-yl]amino] 30 1H-imidazole-5-carbonitrile "A41" N-[3-(4-methoxyphenyl)triazolo[4,5-djpyrimidin-5-yl]-3-phenyl 1,2,4-oxadiazol-5-amine "A42" N-[4-[2-[[3-(4-methoxyphenyl)triazolo[4,5-d]pyrimidin-5 35 yllamino]thiazol-4-yl]phenyl]acetamide WO 2013/110309 PCT/EP2012/005358 - 142 "A43" 1-[4-[5-[(1 -tetrahyd ropyra n-4-ylpyrazol-4-yl)amino]triazolo[4,5 d]pyrimidin-3-yljphenyljpyrrolidin-2-one "A44" [3-(4-chloro-3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d] pyrimidin-5-yi]-[1 -(1-methyl-piperidin-4-yl)-1 H-pyrazol-4-yl] amine "A45" [3-(6-butoxy-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yl]-[1-(1-methyl-piperidin-4-yl)-1 H-pyrazol-4-yl]-amine "A46" [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl] 10 (1-ethyl-1 H-pyrazol-4-yl)-amine "A47" [3-(6-butoxy-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yl]-[1 -(tetrahyd ro-pyran-4-yl)-1 H-pyrazol-4-yil]-amine "A48" 1-(4-{5-[1 -(1 -methyl-piperidin-4-yi)-1 H-pyrazol-4-ylamino] 15 [1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-phenyl)-pyrrolidin-2-one "A49" [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yI] [1-(3-methoxy-propyl)-1 H-pyrazol-4-yl]-amine "A50" [3-(4-chloro-3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5 20 d]pyrimidin-5-yl]-[1 -(3-methoxy-propyl)-1 H-pyrazol-4-yl]-amine "A51" [1 -(2-tert-butoxy-ethyl)-1 H-pyrazol-4-yI]-[3-(4-ethoxy-phenyl) 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylI]-amine "A52" [1 -(1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-yIl]-(3-quinolin-3-yl 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yI)-amine 25 "A53" [1 -(2-tert-butoxy-ethyl)-1 H-pyrazol-4-yl]-[3-(4-chloro-3-fluoro phenyl)-3H-[1, 2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine "A54" [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl] [1 -(2-pyrazol-1 -yl-ethyl)-1 H-pyrazol-4-yi]-amine 30 "A55" [3-(6-butoxy-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yl]-[1 -(2-piperidin-4-yl-ethyl)-1 H-pyrazol-4-yl]-amine "A56" {3-[4-(2-methoxy-ethoxy)-phenyl]-3H-[1,2,3]triazolo[4,5-d] pyrimidin-5-yl-(1 -methyl-1 H-pyrazol-4-yl)-a mine 35 "A57" [3-(6-butoxy-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yl]-(1 -ethyl-1 H-pyrazol-4-yl)-amine WO 2013/110309 PCT/EP2012/005358 - 143 "A58" N-{5-[5-(l -ethyl-1 H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5 djpyrimidin-3-ylj-pyridin-2-yl}-acetamide "A59" N-(5-{5-[1-((trans)-2-hydroxymethyl-cyclopropylmethyl)-1 H pyrazol-4-ylamino]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-pyridin 5 2-yl)-acetamid "A60" ((trans)-2-{4-[3-(6-amino-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino]-pyrazol-1 -ylmethyl}-cyclopropyl) methanol 10 "A61" (1-ethyl-1 H-pyrazol-4-yl)-(3-quinolin-3-yl-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-yi)-amine "A62" (1 -ethyl-1 H-pyrazol-4-yl)-[3-(2-methoxy-pyridin-4-yl)-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine 15 "A63" (1 -ethyl-1 H-pyrazol-4-yl)-[3-(4-fluoro-phenyl)-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine "A64" [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl] (1-phenyl-1 H-pyrazol-4-yi)-amine 20 "A65" {3-[4-(2-methoxy-ethoxy)-phenyl]-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-y}-[1 -(2-pyrazol-1 -yl-ethyl)-1 H-pyrazol-4-yl] amine "A66" 4-[5-(1-ethyl-1 H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5-d] pyrimidin-3-yl]-phenol 25 "A67' 3-{5-[1 -(1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-ylamino] [1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzamide "A68" 3-[5-(1 -ethyl-1 H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5-d] pyrimidin-3-yl]-benzamide 30 'A69" 4-{5-[1 -(1 -methyl-piperidin-4-yi)-1 H-pyrazol-4-ylamino] [1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzamide "A70" 4-[5-(1 -ethyl-1 H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5-d] pyrimidin-3-yl]-benzamide 35 "A71" (1-ethyl-1 H-pyrazol-4-yl)-(3-quinolin-6-yl-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-amine WO 2013/110309 PCT/EP2012/005358 - 144 "A72" 2-[5-(1-ethyl-1 H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5-d] pyrimidin-3-yll-5-fluoro-benzonitrile "A73" [1 -(1 -methyl-piperidin-4-y)-1 H-pyrazol-4-yI]-(3-quinolin-7-yl 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yI)-amine "A74" 5-fluoro-2-{5-[1 -(1 -methyl-piperidin-4-y)-1 H-pyrazol-4 ylamino]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzonitrile "A75" [1 -(1 -methyl-piperidin-4-y)-1 H-pyrazol-4-yl]-(3-quinolin-6-yl 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yI)-amine 10 "A76" {1 -[1 -(2-methoxy-ethyl)-piperidin-4-yl]-1 H-pyrazol-4-yl}-[3-(2 methoxy-pyridin-4-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl] amine "A77" [3-(5-methoxy-pyridin-2-yl)-3H-[1,2,3]triazolo[4,5-d pyrimidin 15 5-yl]-[l1 -(1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-yi]-amine "A78" [3-(2-methoxy-pyridin-4-yI)-3H-[1,2,3]triazolo[4,5-d]pyrimidin 5-yl]-[1 -(tetrahyd ro-pyran-4-y)-1 H-pyrazol-4-yl]-amine "A79" [3-(1 -ethyl-1 H-pyrazol-4-y)-3H-[1,2,3]triazolo[4,5-d]pyrimidin 20 5-yl]-[1 -(1-methyl-piperidin-4-yl)-1 H-pyrazol-4-yl]-amine "A80" 4-{5-[1 -(tetrahydro-pyran-4-yl)-1 H-pyrazol-4-ylamino] [1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzamide "A81" [3-(4-chloro-3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5 d]pyrimid in-5-yl]-[1 -(tetrahyd ro-pyran-4-yl)-1 H-pyrazol-4-yl] 25 amine "A82" (3-quinolin-6-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)-[1 (tetrahydro-pyran-4-yl)-1 H-pyrazol-4-yi]-amine "A83" [3-(1 -ethyl-1 H-pyrazol-4-y)-3H-[1,2,3]triazolo[4,5-d]pyrimidin 30 5-yl]-[1 -(tetrahyd ro-pyran-4-yl)-1 H-pyrazol-4-yl]-amine "A84" 6-[5-(1-ethyl-1 H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5 d]pyrimidin-3-yl]-3,3-dimethyl-1,3-dihydro-indol-2-one "A85" 3,3-dimethyl-6-{5-[1 -(tetra hyd ro-pyran-4-yl)-1 H-pyrazol-4 35 ylamino]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-1,3-dihydro-indol 2-one WO 2013/110309 PCT/EP2012/005358 - 145 "lA8611 (3-quinolin-7-yI-3H-[1 ,2,3]triazolo[4,5-dlpyrimidin-5-yl)-[1 (tetra hydro-pyran-4-yi)-1 H-pyrazof-4-ylJ-amine "A8711 {3-[4-(2-methoxy-ethoxy)-phenyl-3H-[1 ,2,3]triazolo[4, 5 d] pyrim id i n-5-yl}-[1 -(tetra hyd ro-pyra n-4-yl)- 1 H-pyrazol-4-yII amine "A88" [3-(4-ethoxy-phenyl)-3H-[1 ,2 ,3ltriazolo[4, 5-dipyrimid in-5-yl] [1 -(3-methyl-butyl)- 1 H-pyrazol-4-yll-amine "A89" [3-(l -ethyl-i H-pyrazol-4-yI)-3H-[1 ,2, 3ltriazolo[4,5-dlpyrimidin 10 5-yI]-[1 -(3-methyl-butyl)- 1 H-pyrazol-4-yi]-amine "A90" [1 -(3-methyl-butyl)- 1 H-pyrazol-4-yI]-(3-quinoli n-6-yl-3H [1 ,2,3]triazolo[4,5-dlpyrimidin-5-yI)-amine "A91" (1 -ethyl-I H-pyrazol-4-yl)-[3-(1 H-indazol-5-yl)-3H 15 [1,2 ,3]triazolo[4,5-d]pyrimidin-5-yI]-amine "A92" [3-(l H-indazol-6-yI)-3H-[1 ,2,3]triazolo[4, 5-d]pyrimidin-5-yI-[1 (tetrahydro-pyran-4-y)-1 H-pyrazol-4-yli-amine "A93" [3-(l H-indazol-5-yI)-3H-[1 ,2 , 3triazolo[4, 5-dipyrimid in-5-yl]-[1 20 ___ (1 -methyl-piperidin-4-y)-1 H-pyrazol-4-yll-amine "A9411 (3-quinoxalin-6-y-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-5-y)-[1 (tetra hyd ro-pyra n-4-yl)- 1 H-pyrazol-4-yl]-amine "A9511 [1 -(1 -methyl-piperid in-4-yi)-1 H-pyrazol-4-yl]-[3-(2 trifluoromethyl-1 H-benzoimidazol-5-yI)-3H-[1 ,2,3ltriazolo[4,5 25 djpyrimidin-5-yJ]-amine "A96" {3-14-(2-methoxy-ethoxy)-phenyl]-3 H-[1 ,2 ,3]triazolo[4, 5 d]pyrimidin-5-yl}-(1 -pyrrolidin-3-yl-1 H-pyrazol-4-yi)-amine "A97" [3-(4-ethoxy-phenyl)-3H-[1 ,2 ,3]triazolo[4 ,5-dipyrimid in-5-yl] 30 [1 -(2-piperidin-4-yl-ethyl)-1 H-pyrazol-4-yI]-a mine "_'A_98' ((trans)-2-{4-13-(4-chioro-3-fluoro-phenyi)-3H [1 ,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-pyrazol-1 -ylmethyl} cyclopropyl)-methanof 35 WO 2013/110309 PCT/EP2012/005358 - 146 "A99" 1-[3-(4-{3-[4-(2-methoxy-ethoxy)-phenyl]-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-ylamino}-pyrazol-1 -yl) pyrrolidin-1 -yI]-ethanone "Al 00" 1-[4-(2-{4-[3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino]-pyrazol-1 -yl}-ethyl)-piperidin-1 -yl] ethanone "A101" [1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-(3-quinoxalin-6-y 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yI)-amine 10 "A102" 4-{4-[3-(4-chloro-3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino]-pyrazol-1-yl}-cyclohexanol "Al 03" 4-{4-[3-(4-chloro-3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5 djpyrimidin-5-ylamino]-pyrazol-1-yl}-cyclohexanol 15 "A104" {(trans)-2-[4-(3-quinoxalin-6-yt-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino)-pyrazol-1 -ylmethyl]-cyclopropyl} methanol "Al 05" 4-[4-(3-quinoxalin-6-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 20 ylamino)-pyrazol-1 -yl]-cyclohexanol "Al 06" (1-ethyl-1 H-pyrazol-4-yl)-[3-(1 -ethyl-1 H-pyrazol-4-yl)-3H [1,2,3]triazolo[4,5-d]pyrimidin-5-yI]-amine "Al 07" 4-(4-{3-[4-(2-methoxy-ethoxy)-phenyl]-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino}-pyrazol-1 -yl)-cyclohexanol 25 "Al 08" 4-(4-{3-[4-(2-methoxy-ethoxy)-phenyl]-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino}-pyrazol-1 -yl)-cyclohexanol "Al 09" 4-{4-[3-(6-methoxy-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino]-pyrazol-1 -yl}-cyclohexanol 30 "Al 10" [3-(3-chloro-4-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylj-[1 -(tetrahyd ro-pyran-4-yi)-1 H-pyrazol-4-y] amine "Al 11" [3-(3-chloro-4-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5 35 d]pyrimidin-5-yl]-[l -(1 -methyl-piperidin-4-yl)-l H-pyrazol-4-yl] amine WO 2013/110309 PCT/EP2012/005358 - 147 "Al 12" (1 -oxetan-3-yl-1 H-pyrazol-4-yl)-(3-quinolin-7-yl-3H [1,2,3]triazolo[4,5-djpyrimidin-5-yl)-amine "Al 13" 4-{5-[1 -(tetrahydro-pyran-4-y)-1 H-pyrazol-4-ylamino] [1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzoic acid methyl ester 5 "Al 14" [3-(4-chloro-3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl]-[1 -(2-morpholin-4-yl-ethyl)-1 H-pyrazol-4-yi] amine "Al 15" [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl] 10 [1-(2-morpholin-4-yl-ethyl)-1 H-pyrazol-4-yi]-amine "Al 16" [3-(3,4-difluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yl]-[1 -(tetrahyd ro-pyran-4-yl)-1 H-pyrazol-4-yl]-amine "A 117" 4-[5-(1-ethyl-1 H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5 15 d]pyrimidin-3-yl]-benzoic acid methyl ester "Al 18" [3-(3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-y]-[1 (1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-yl]-amine "Al 19" 2-(4-{5-[1 -(tetrahyd ro-pyran-4-yi)-1 H-pyrazol-4-ylamino] 20 [1,2,3]triazolo[4,5-d]pyrimidin-3-yJ)-phenyl)-propan-2-o "Al 20" [3-(3,4-difluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 yl]-[1 -(1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-yl]-amine "Al 21" 2-{4-[5-(l -ethyl-1 H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5 d]pyrimidin-3-yl]-phenyl)-propan-2-o 25 "A122" [3-(3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-[l (tetrahyd ro-pyran-4-yl)-1 H-pyrazol-4-yl]-amine "Al 23" [3-(4-ethoxy-phenyl)-3H-[ 1,2,3]triazolo[4,5-d]pyrimidin-5-yl] (1-methyl-1 H-pyrazol-3-yl)-amine 30 "Al 24" [3-(5-methoxy-pyridin-2-y)-3H-[1,2,3]triazolo[4,5-d]pyrimidin 5-yl]-[l -(2-pyrazol-1 -yl-ethyl)-1 H-pyrazol-4-yl]-amine "Al 25" [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl] [1 -(3-piperidin-4-yl-propy)-1 H-pyrazol-4-yi]-amine 35 "Al 26" [3-(3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5-dpyrimidin-5-yl]-[1 (2-pyrazol-1 -yl-ethyl)-l H-pyrazol-4-yl]-amine WO 2013/110309 PCT/EP2012/005358 - 148 "Al 27" 2-(1 -{4-[5-(1 -ethyl-i H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5 djpyrimidin-3-yl]-phenyl}-1-methyl-ethoxy)-ethanoI "Al 28" (1-ethyl-1 H-pyrazol-4-yl)-{3-[4-(1-fluoro-1-methyl-ethyl) phenyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl}-amine "A129" [3-(3-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-[1 (3-piperidin-4-yl-propyl)-1 H-pyrazol-4-yi]-amine "Al 30" 2-[1 -methyl-1 -(4-{5-[1 -(tetrahydro-pyran-4-yl)-1 H-pyrazol-4 ylamino]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-phenyl)-ethoxy] 10 ethanol "Al 31" [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl] (3-methyl-isoxazol-5-yi)-amine "A132" [3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl] 15 (5-pyridin-4-yl-[1,3,4]thiadiazol-2-yI)-amine "Al 33" [1 -(2-pyrazol-1 -yl-ethyl)-1 H-pyrazol-4-yI]-{3-[4-(pyrrolidine-1 sulfonyl)-phenyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl}-amine "Al 34" [1 -(2-pyrazol-1 -yl-ethyl)-1 H-pyrazol-4-yl]-(3-quinolin-7-yI-3H 20 [1,2,3]triazolo[4,5-dlpyrimidin-5-yl)-amine "A135" 4-{5-[1-(2-pyrazol-1 -yi-ethyl)-1 H-pyrazol-4-ylamino] [1,2,3]triazolo[4,5-d]pyrimidin-3-yI}-benzenesulfonamide "A136" [1-(1-methyl-piperidin-4-yl)-lH-pyrazol-4-yl]-{3-[4-(pyrrolidine 1-sulfonyl)-phenyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl} 25 amine "A137" 4-{4-[3-(6-methoxy-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino]-pyrazol-1 -yl}-cyclohexanol "Al 38" 4-{4-[3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin 30 5-ylamino]-pyrazol-1 -yl}-morpholin-3-one "A139" [1 -(1 -methyl-piperidin-4-yl)-1 H-pyrazol-4-yl]-[3-(1-methyl-1 H pyrazol-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yi]-amine "Al 40" (1',5'-dimethyl-1 H,1'H-[3,4']bipyrazolyl-5-yl)-[3-(4-ethoxy 35 phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine WO 2013/110309 PCT/EP2012/005358 - 149 "A141" 4-{4-[3-(5-methoxy-pyridin-2-yl)-3H-[1,2,3]triazolo[4,5 djpyrimidin-5-ylamino]-pyrazol-1-yl}-cyclohexanol "A142" 4-{5-[1 -(1 -methyl-piperidin-4-yi)-l H-pyrazol-4-ylamino] [1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzenesulfonamide "A143" 4-{4-[3-(5-methoxy-pyridin-2-yl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-ylamino]-pyrazol-1 -yi}-cyclohexanol "A144" {3-[4-(1-fluoro-1-methyl-ethyl)-phenyl]-3H-[1,2,3]triazolo[4,5 d]pyrimid in-5-yl}-[1 -(tetrahyd ro-pyran-4-yi)-1 H-pyrazol-4-yl] 10 amine "A145" 4-[4-(3-quinolin-7-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5 ylamino)-pyrazol-l-yI]-morpholin-3-one "A146" (5-tert-butyl-2H-pyrazol-3-yl)-[3-(4-ethoxy-phenyl)-3H 15 [1,2,3]triazolo[4,5-d]pyrimidin-5-yI]-amine "A147" [3-(1-methyl-1 H-pyrazol-3-yl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl]-[l -(tetrahyd ro-pyran-4-yl)-1 H-pyrazol-4-yl] amine 20 "A148" {3-[4-(1-amino-1-methyl-ethyl)-phenyl]-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl}-(1-ethyl-1H-pyrazol-4-yl)-amine "A149" 4-(2-{4-[3-(4-ethoxy-phenyl)-3H-[1,2,3]trazolo[4,5-d]pyrimidin 5-ylamino]-pyrazol-1 -yl}-ethyl)-morpholin-3-one "A150" 1-(3-{4-[3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin 25 5-ylamino]-pyrazol-1 -yl}-azetidin-1 -yl)-2-methoxy-ethanone "Al 51" 1-(2-{4-[3-(4-ethoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin 5-ylamino]-pyrazol-1 -yl}-ethyl)-pyrrolidin-3-ol "Al 52" {3-[4-(1-amino-1 -methyl-ethyl)-phenyll-3H-[1,2,3]triazolo[4,5 30 d]pyrimidin-5-yl}-[1 -(tetra hyd ro-pyra n-4-yl)-l H-pyrazol-4-yl] amine "Al 53" [3-(4-chloro-phenyl)-3H-[ 1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-[1 (1-methyl-piperidin-4-yl)-l H-pyrazol-4-yl]-amine 35 WO 2013/110309 PCT/EP2012/005358 - 150 "A154" [3-(3-chloro-4-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5 d]pyrimidin-5-yl]-[1-(1-methanesulfonyl-piperidin-4-y)-1 H pyrazol-4-yl]-amine "A155" [3-(4-chloro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-[l 5 (tetrahyd ro-pyran-4-yl)-1 H-pyrazol-4-yl]-amine "Al 56" (1-ethyl-1 H-pyrazol-4-yl)-[3-(3,4,5-trimethoxy-phenyl)-3H [1,2,3]triazolo[4,5-dipyrimidin-5-yl]-amine "Al 57" (3-benzo[1,2,5]thiadiazol-5-yl-3H-[1,2,3]triazolo[4,5 10 d]pyrimidin-5-yl)-(1-ethyl-1 H-pyrazol-4-yl)-amine and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 15
[8] 8. Process for the preparation of compounds of the formula I according to Claims 1-7 and pharmaceutically acceptable salts, solvates, tautomers and stereoisomers thereof, characterised in that 20 a) a compound of the formula Il HR R2 N~ NHH N -- NHI 122 in which R and R2 have the meaning indicated in Claim 1, 30 is reacted with a nitrite, or 35 b) a compound of the formula IlI WO 2013/110309 PCT/EP2012/005358 - 151 R L Ni 5 :N IlN in which R 1 has the meaning indicated in Claim 1, L denotes Cl, Br, I, S-alkyl, SO-alkyl or S0 2 -alkyl, and alkyl has 1, 2, 3 or 4 C atoms, 10 is reacted with a compound of the formula IV R 2-NH 2 IV in which R 2 has the meaning indicated in Claim 1, 15 and/or a base or acid of the formula I is converted into one of its salts.
[9] 9. Medicaments comprising at least one compound of the formula I and/or 20 pharmaceutically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and optionally an pharmaceutically acceptable carrier, excipient or vehicle. 25
[10] 10. Compounds of the formula I and pharmaceutically acceptable salts, solvates, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for the use for the treatment and/or prevention of inflammatory conditions, immunological conditions, autoimmune conditions, allergic conditions, rheumatic conditions, thrombotic 30 conditions, cancer, infections, neurodegenerative diseases, neuroinflammatory diseases, cardiovascular diseases, and metabolic conditions, the methods comprising administering to a subject in need thereof an effective amount of a compound of claim 1. 35 WO 2013/110309 PCT/EP2012/005358 - 152
[11] 11. Compounds according to claim 10 for the use for the treatment and/or prevention of cancer, where the cancer to be treated is a solid tumour or a tumour of the blood and immune system. 5
[12] 12. Compounds according to claim 11, where the solid tumour originates from the group of tumours of the epithelium, the bladder, the stomach, the kidneys, of head and neck, the esophagus, the cervix, the thyroid, the 10 intestine, the liver, the brain, the prostate, the uro-genital tract, the lymphatic system, the stomach, the larynx, the bones, including chondosarcoma and Ewing sarcoma, germ cells, including embryonal tissue tumours, and/or the lung, from the group of monocytic leukaemia, 15 lung adenocarcinoma, small-cell lung carcinomas, pancreatic cancer, glioblastomas, neurofibroma, angiosarcoma, breast carcinoma and /or maligna melanoma.
[13] 13. Compounds according to claim 10 for the use for the treatment and/or 20 prevention of diseases selected from the group rheumatoid arthritis, systemic lupus, asthma, multiple sclerosis, osteoarthritis, ischemic injury, giant cell arteritis, inflammatory bowel disease, diabetes, cystic fibrosis, psoriasis, Sj6grens syndrom and 25 transplant organ rejection.
[14] 14. Compounds according to claim 10 for the use for the treatment and/or prevention of diseases selected from the group 30 Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis-Dutch Type, cerebral amyloid angiopathy, Creutzfeldt Jakob disease, frontotemporal dementias, Huntington's disease, Parkinson's disease. 35
[15] 15. Compounds according to claim 10 for the use for the treatment and/or prevention of diseases selected from the group WO 2013/110309 PCT/EP2012/005358 - 153 leishmania, mycobacteria, including M. leprae, M. tuberculosis and/or M. avium, leishmania, plasmodium, human immunodeficiency virus, Epstein Barr virus, Herpes simplex virus, hepatitis C virus. 5
[16] 16. Medicaments comprising at least one compound of the formula I and/or pharmaceutically acceptable salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient. 10
[17] 17. Set (kit) consisting of separate packs of (a) an effective amount of a compound of the formula I and/or pharmaceutically acceptable salts, solvates, salts and stereoisomers 15 thereof, including mixtures thereof in all ratios, and (b) an effective amount of a further medicament active ingredient.
[18] 18. The compound 20 [3-(4-methoxy-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-[4-methyl 5H-oxazol-(2Z)-ylidene]-amine ("A12") and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios. 25 30 35

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EP2807161B1|2017-10-04|

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CA2862694C|2020-07-28|

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US9409914B2|2016-08-09|

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IL233808A|2018-03-29|

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BR112014016884A2|2017-06-27|

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CN104066734B|2017-03-29|

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ES2655264T3|2018-02-19|

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AU2012367141B2|2016-12-22|

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ZA201406323B|2016-08-31|

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JP6063482B2|2017-01-18|

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CA2862694A1|2013-08-01|

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US20140378431A1|2014-12-25|

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EP2807161A1|2014-12-03|

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JP2015505541A|2015-02-23|

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AR089810A1|2014-09-17|

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MX2014008864A|2014-12-15|

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法律状态:
2017-04-20| FGA| Letters patent sealed or granted (standard patent)|

优先权:

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申请号 | 申请日 | 专利标题

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EP12000558.2||2012-01-28||

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EP12000558||2012-01-28||

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PCT/EP2012/005358|WO2013110309A1|2012-01-28|2012-12-21|Triazolo[4,5-d]pyrimidine derivatives|

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