llIIlIlllIlIlIllIlIllIllIllIIlIlllIlIIllllIIlllIIlIlllIIlIlllllIIIlllIlIllIIIIIIIIIIIIIIII US 20160015712AI (19) United States (12) Patent Application Publication (Io) Pub. No. : US 2016/0015712 A1 DORSCH et al. (43) Pub. Date: Jan. 21, 2016

(54) TRIAZOLO [4,5-D]PYRIMIDINE Publication Classification DERIVATIVES (51) Int. Cl. (71) Applicant: MERCK PATENT GMBH, Darmstadt 261K31/519 (2006.01) (DE) 261K31/53 77 (2006.01) C07D 519/00 (2006.01) (72) Inventors: Dieter DORSCH, Ober-Ramstadt (DE); C07D 487/04 (2006.01) Guenter HOELZEMANN, (52) U.S. Cl. Seeheim- Jugenheim (DE); Michel CPC ...... 261K31/519 (2013.01); C07D 487/04 CALDERINI, Darmstadt (DE); Ansgar (2013.01);261K31/5377 (2013.01); C07D WEGENER, Heusenstamm (DE); 519/00 (2013.01) Oliver POESCHKE, Wiesbaden (DE) (57) ABSTRACT (73) Assignee: MERCK PATENT GMBH, Darmstadt (DE) Compounds of the formula I

(21) Appl. No. : 14/772, 865

(22) PCT Filed: Feb. 10, 2014 H

(86) PCT No. : PCT/EP2014/000361 II ) 371 (c)(I), NX N (2) Date: Sep. 4, 2015

(30) Foreign Application Priority Data in which R' and R have the meanings indicated in Claim 1, are inhibitors of GCN2, and can be employed, inter alia, for Mar. 5, 2013 (EP) ... 13001110.9 the treatment of cancer. US 2016/0015712 A1 Jan. 21, 2016

TRIAZOLO [4,5-D]PYRIMIDINE [0006] Several mechanistic studies discovered that DERIVATIVES immune escape has an important interface with metabolic alterations within the tumor microenvironment. Here impor- BACKGROUND OF THE INVENTION tant roles in mediating immune tolerance to antigens have been associated to the catabolism ofthe essential amino acids [0001] The invention had the object of finding novel com- tryptophan and arginine, carried out by the enzymes pounds having valuable properties, in particular those which indoleamine 2,3-dioxygenase (IDO) and arginase I (ARG), can be used for the medicaments. preparation of respectively (Bronte and Zanovello, 2005; Muller et al. , [0002] The present invention relates to compounds and to 2005b; Muller and Prendergast, 2007; Munn and Mellor, the use of compounds in which the inhibition, regulation 2007; Popovic et al. , 2007). IDO is a single-chain oxi- and/or modulation of signal transduction by protein kinases, doreductase that catalyzes the degradation of tryptophan to in particular immune-modulatory or stress response kinases, kynurenine. IDO is not responsible for catabolizing excess furthermore to pharmaceutical compositions which comprise dietary tryptophan but to modulate tryptophan level in a local these compounds, and to the use of the compounds for the environment. Elevations in tryptophan catabolism in cancer treatment of kinase-induced diseases. Because protein patients manifest in significantly altered serum concentration kinases regulate nearly every cellular process, including of tryptophan or catabolites and this was correlated to IDO metabolism, cell proliferation, cell differentiation, and cell which is commonly elevated in tumors and draining lymph survival, they are attractive targets for therapeutic interven- nodes. According to several publications IDO over-expres- tion for various disease states. For example, cell-cycle con- sion is associated with poor prognosis in cancer [Okamoto et trol, immune modulation, stress response and angiogenesis, al 2005; Brandacher et al, 2006]. T cells appear to be prefer- in which protein kinases play a pivotal role are cellular pro- entially sensitive to IDO activation, such that when starved cesses associated with numerous disease conditions such as for tryptophan they cannot divide and as a result cannot but not limited to cancer, inflammatory diseases, neurodegen- become activated by an antigen presented to them. Munn and erative diseases, chronic infections, abnormal angiogenesis Mellor and their colleagues, revealed that IDO modulates and diseases related thereto, atherosclerosis, macular degen- immunity by suppressing T-cell activation and by creating eration, diabetes, obesity, and pain. peripheral tolerance to tumor antigens (Mellor and Munn, [0003] Compounds of formula I inhibit the stress response 2004). These mechanism encompass the subversion of eIF2 kinase EIF2AK4 called general control nonderepress- immune cells recruited by the tumor cell to its immediate ible 2 (GCN2). microenvironment or to the tumor-draining lymph nodes Here the tumor antigens that were scavenged antigen- [0004] Many strategies of cancer treatment of solid tumors by cells are cross-presented to the immune focus on the surgically removal of the tumor mass as far as presenting adaptive system. In addition to being directly toleragenic, mature DCs possible and the subsequent eradication of any residual tumor have the capacity to expand regulatory Tcells (Tregs) [Moser cells by radiotherapy and chemotherapy with cytotoxic agents or inhibitors that target cancer cell pathways more 2003]. specifically. However, the success of such approach is limited [0007] Beside tryptophan catabolism the conversion of and often does not persist. This is mainly due to the narrow arginine is increased in a tumor-conditioned microenviron- therapeutic window for such cytotoxic agents (specificity and ment, and numerous reports indicate a role for the activation side effects) and to the capability ofcancer calls to adapt to the ofarginases during tumor growth and development. In tumor- selective pressure applied by cytotoxic or other inhibitory infiltrating myeloid cells, arginine is converted by arginase I agents. The survival of a small number of tumor (stem) cells (ARGI), arginase II (ARG2) to urea and ornithine and oxi- that acquired resistance to the initial treatment can be sufft- dized by the inducible form of nitric oxide synthase (NOS2) cient to seed the regrowth of a tumor. These relapses are in to citrulline and nitric oxide (NO). most cases more difficult to treat compared to that of the [000S] Increased ARG activity is frequently observed in initial tumors. As a consequence the more successful target- patients with colon, breast, lung, and prostate cancer [Ceder- ing of tumor cells may require targeting multiple survival and baum 2004] correlating with the over-expression of ARG and escape mechanism of tumor cells in parallel (Muller & NOS found in prostate cancers [Keskinege et al. 2001, Aal- Prendegast 2007). toma et al. 2001, Wang et al. 2003]. It was shown that ARG [0005] Development of malignancies is accompanied by a activity in infiltrating macrophages impairs antigen-specific major roll up of the cellular physiology. During this process T cell responses and the expression of the CD3 receptor. several qualities are acquired by the cancer cells that are basis Moreover the cumulative activity ofARG and NOS in tumor for immortalization or insensitivity to growth inhibitory sig- associated myeloid cells can generate inhibitory signals to nals. In addition the tumor cells also modify the interaction antigen-specific T lymphocytes that eventually lead to apop- with the microenvironment and beyond. The latter area tosis [Bronte 2003 a; 2003b]. includes the strategies of tumor cells to escape from the [0009] Both, the IDO and the ARG related mechanism immunological surveillance (Muller & Prendegast 2007). merge at the point of sensing the depleted concentration ofthe The immune surveillance limits malignant growth but also respective amino acid concentration. During amino acid dep- provides a selective pressure triggering the evolution of rivation, the eIF2 kinase EIF2AK4 called general control mechanisms for evading the immune response as reviewed by nonderepressible 2 (GCN2) is interacting with the intracellu- [Dunn et al. 2004]. Essentially it has been frequently lar accumulating deacylated tRNA. As a consequence the observed that ablation of T cell immunity is sufficient to GCN2 is assumed to change from an auto-inhibited to an increase tumor incidence [Shankaran et al. 2001] and it is active conformation and further activate by auto-phosphory- believed that immune escape is affecting tumor dormancy lation. Then the only known substrate protein eIF2a becomes versus progression, promoting invasion and metastasis and phosphorylated and as a consequence the complex for trans- negatively impacts on therapeutic response. lation initiation is inhibited [Harding et al. 2000,]. This US 2016/0015712 A1 Jan. 21, 2016

diminishes the general Cap-dependent translation initiation ever I MT was unable to elicit tumor regression in several and by this the corresponding protein production. On the tumor models, suggesting only modest antitumor efficacy other hand this induces the specific expression of stress when IDO inhibition was applied as a monotherapy. related target genes mainly by cap-independent initiation via [0015] In contrast, the combinatory treatment with I MT the activating transcription factor 4 (ATF4). By expressing and a variety of cytotoxic chemotherapeutic agents elicited the respective stress response proteins, e.g. enzymes in the in regression of established MMTV-neu/HER2 tumors, which amino acid metabolism, the cell tries to compensate the par- responded poorly to any single-agent therapy [Muller et al ticular cell stress [Wek et al. 2006]. If the stress persists, the 2005a]. Immunodepletion of CD4+ or CD8+ T cells from the same pathway will switch to promoting cell death via tran- mice before treatment abolished the combinatorial efficacy scription of the pro-apoptotic transcription factor, CCAAT/ observed in this model, confirming the expectation that I MT enhancer-binding protein homologous protein (CHOP) [Oya- acted indirectly through activation of T cell-mediated antitu- domari 2004]. It was shown that tryptophan starvation mor immunity. Important evidence that IDO targeting is triggers a GCN2-dependent stress signaling pathway. In T essential to I MT action was provided by the demonstration cells altering eIF2aphosphorylation and translational initia- that I MT lacks antitumor activity in mice that are genetically tion leading to a cell growth arrest (Munn et al. 2005). deficient for IDO [Hou et al. , 2007] Sharma, et al. [2007] published on the direct IDO-induced [0016] The inhibition of GCN2 would enable to combine and GCN2-dependent activation of mature Tregs. Analo- the two pathway branches of amino acid starvation induced gously Fallarino et al[2006] found a GCN2-dependent con- immunoediting and would reduce the options for the tumor to version of CD4+CD25 —cells to CD25+FoxP3+ Tregs pro- circumvent the inhibition of either branch. Moreover, as ducing IL-10 and TGF[3. Rodriguez et al. [2007] identified detailed above, the GCN2 inhibition provides the opportunity that activation of the GCN2 pathway via tryptophan or argi- for interfering with the tumor metabolism at the same time nine depletion in combination with TCR signaling leads to what may enhance the efficacy of a monotherapy or a com- CD31; chain down regulation, cell cycle arrest and anergy. bination therapy with other anticancer approaches. [0010] Importantly the GCN2 pathway is not only impor- [0017] As mentioned above, the eIF2 kinase GCN2 is acti- tant for the tumoral immune escape but also plays an active vated by interacting with deacylated tRNA that is accumulat- role in modulating tumor survival directly. Ye et al[2010] ing as direct consequence of nutritional deprivation stress. found that the aforementioned transcription factor ATF4 is Other cellular stress factors like UV irridation, redox stress or over-expressed inhuman solid tumors, suggesting an impor- proteasome inhibition can induce GCN2 activation indirectly tant function in tumour progression. Amino acid and glucose [Wek et al 2006]. In all known cases eIF2a becomes phos- deprivation are typical stresses found in solid tumours and phorylated and this induces the specific expression of stress activated the GCN2 pathway to up-regulate ATF4 target related target genes mainly by cap-independent initiation via genes involved in amino acid synthesis and transport. GCN2 the activating transcription factor 4 (ATF4). Mitsuda et al activation/overexpres sion and increased pho spho-eIF2a were (2007) showed that presenilin-I is induced by activating tran- observed in human and mouse tumors compared with normal scription factor 4 (ATF4), regulated by GCN2. Accumulation tissues and abrogation ofATF4 or GCN2 expression signifi- of amyloid-[3 (A[3), which is generated from amyloid precur- cantly inhibited tumor growth in vivo. It was concluded that sor protein by 7-secretase, in cerebral cortex is common and the GCN2-eIF2a-ATF4 pathway is critical for maintaining critical incident in Alzheimer disease. Specifically, presenilin metabolic homeostasis in tumor cells. is an essential for 7-secretase activity. Ohata et al. (2010) [0011] Over all the present biology makes an interference describe a role of GCN2-eIF2u-ATF4 signaling in the regu- with the ARG/IDO pathway attractive for braking up the lation of7-secretase activity in autophagy impaired cells: The tumoral immune escape by adaptive mechanism. impairment of the autophagy-lysosomal system may cause [0012] The interference of GCN2 function is here of par- amino acid imbalance in the cell because autophagy is ticular interest as it is a merging point of the two pathways, the required for maintenance ofamino acid level. The autophagy- IDO and ARG, as well as it provides additional opportunities lysosomal system is discussed as a vital modulator of7-secre- to impede with the tumor metabolism directly. tase activity through GCN2, leading to A[3 accumulation in [0013] Several pathway inhibitors are already considered autophagy deterioration, which may be a possible therapeutic as immune modulators. These inhibitors address mainly the target for reducing A[3 production. 7-Secretase plays an enzymatic function of the IDO or ARG proteins (Muller and important role in the development of Alzheimer disease Scherle, 2006). The application of the arginase inhibitor, (AD). 7-Secretase activity is enriched in autophagic vacuoles N-hydroxy-nor-L-Arg blocks growth of s.c. 3LL lung carci- and it augments amyloid-[3 (A[3) synthesis. noma in mice [Rodriguez 2004]. The NO-donating aspirins [0018] Senile plaques are primarily composed of [3-amy- like NCX 4016 (2-(acetyloxy)-benzoic acid 3-(nitrooxym- loid peptides (AP) derived from amyloid precursor protein ethyl) phenyl ester) have been reported to interfere with the (APP) that has undergone proteolytic processing by I-secre- inhibitory enzymatic activities of myeloid cells. Orally tase (BACE-I) and 7-secretase. O' Connor et al. (2008) found administered NO aspirin normalized the immune status of that BACE-I levels are translationally increased by phospho- tumor-bearing hosts, increased the number and function of rylation of eIF2u. tumor-antigen-specific T lymphocytes, and enhanced the pre- [0019] Inhibition of GCN2 under such disease conditions ventive and therapeutic effectiveness of the antitumor immu- that promote activation of7-secretase or induction ofBACE- I nity elicited by cancer vaccination (DeSanto 2005). with consequence of accumulation of A[3 and plaque forma- [0014] The substrate analogue I methyl-tryptophan (I MT) tion in the brain would provide a valuable avenue to temper or and related molecules have been used widely to target IDO in even stop the progression of neurodegenerative diseases. the cancer context and other settings. Studies by Friberg et al. [0020] It was described that persistent, not acute, parasite (2002) and Uyttenhove et al. (2003) demonstrated that I MT or viral infections are associated to the establishment of can limit the growth of tumors over-expressing IDO. How- immune privileged conditions of even immune competent US 2016/0015712 A1 Jan. 21, 2016 3

host towards the infectious organism or particles. This has increases BACEI levels and promotes amyloidogenesis. been associated to the local induction of IDO expression. Neuron, 60 (2008), pp. 988-1009 Makala et al (J Infect Dis. 2011 Mar. I; 203(5):715-25)show [0030] 9. Dey, M., Cao, C., Sicheri, F. and T. E. Dever. that cutaneous Leishmania major infection stimulated Conserved Intermolecular Salt Bridge Required for Acti- expression of the immune regulatory enzyme indoleamine vation of Protein Kinases PKR, GCN2, and PERK. JBC 2,3 dioxygenase (IDO) in local lymph nodes. Induced IDO 282(9): 6653, 2007. attenuated the T cell stimulatory functions of dendritic cells [0031] 10. Dunn, G. P.; Old, L. J.; Schreiber, R. D. The and suppressed local T cell responses to exogenous and nomi- immunobiology ofcancer immunosurveillance and immu- nal parasite antigens. IDO ablation reduced local inflamma- noediting. Immunity 2004, 21, 137-148. tion and parasite burdens, as did pharmacologic inhibition of [0032] 11.Fallarino, F. U. Grohmann, S.You, B. C. et al. IDO in mice with established infections. de Souza Sales (Clin The combined effects fo tryptophan starvation and tryp- Exp Immunol. 2011 Aug. 165(2):251-63)corroborated the ; tophan catabolites down-regulate T cell receptor zeta- role of indoleamine 2, 3-dioxygenase in lepromatous leprosy chain and induce a regulatory phenotype in na'ive T cells. J. immunosuppression. Boasso et al (Blood. 2007 Apr. 15; 109 Immuno1. 176:6752, 2006. (8):3351-9)foundthatHIVinhibits CD4+ T-cellproliferation [0033] 12. Friberg M, Jennings R, Alsarraj M, Dessureault by inducing indoleamine 2,3-dioxygenase in plasmacytoid Cantor Extermann M et al. Indoleamine 3- dendritic cells and that in vitro inhibition of IDO results in S, A, (2002). 2, contributes to tumor cell evasion T cell- increased CD4(+) T-cell proliferative response in PBMCs dioxygenase of mediated rejection. Int. J Cancer 101: 151-155 from HIV-infected patients 13.Harding H Novoa Zhang Wek [0021] Inhibitor drugs ofthe IDO/GCN2 pathway could be [0034] P, I, Y, Zeng H, R, con- used to enhance host immunity to chronic and persistent Schapira M, Ron D. Regulated translation initiation infections. trols stress-induced gene expression in mammalian cells. Mol Cell. 2000 November; 6(5):1099-108. LITERATURE [0035] 14.Hou DY, Muller A J, Sharma M D, DuHadaway J, Banerjee T, Johnson M et al. (2007). Inhibition of [0022] I.Aaltoma, S.H. , P. K. Lipponen, andV. M. Kosma. indoleamine 2,3-dioxygenase in dendritic cells by stereoi- 2001. Inducible nitric oxide synthase (iNOS) expression somers of I-methyl-tryptophan correlates with antitumor and its prognostic value in prostate cancer. Anticancer Res. responses. Cancer Res 67: 792-801. 21:3101-3106. [0036] 15. Keskinege, A. , S. Elgun, and E.Yilmaz. 2001. [0023] 2. Brandacher, G.; Perathoner, A. ; Ladurner, R.; Possible implications of arginase and diamine oxidase in Schneeberger, S.; Obrist, P.; Winkler, C.; Werner, E. R.; prostatic carcinoma. Cancer Detect. Prev. 25:76-79. Werner-Felmayer, G. Weiss, H. G. Gobel, G. Margreiter, ; ; ; [0037] 16.Mellor A L, Munn D H. (2004). IDO expression R. Konigsrainer, A. Fuchs, D. Amberger, A. Prognostic ; ; ; by dendritic cells: tolerance and tryptophan catabolism. value of indoleamine 3-dioxygenase expression in col- 2, Nat Rev Immunol 4: 762-774. orectal cancer: effect on tumorinfiltrating T cells. Clin. 17.Mitsuda Hayakawa Itoh Ohta Naka- Cancer Res. 2006, 12, 1144-1151. [003S] T, Y, M, K, gawa T. ATF4 regulates gamma-secretase activity during [0024] 3. Bronte V, Zanovello P. (2005). Regulation of amino acid imbalance, Biochem Biophys Res Commun. immune responses L-arginine metabolism. Nat Rev by 2007 Jan 19; 352(3):722-7. Immunol 5: 641-654. [0039] 18. Moser, M. Dendritic cells in immunity and tol- [0025] 4. Bronte, V. P. Serafini, C. De Santo, I. Marigo, V. , erance-do they display opposite functions? Immunity Tosello, A. Mazzoni, D. M. Segal, C. Staib, M. Lowel, G. 2003, 19, 5-8. Sutter, et al. 2003a. IL-4-induced arginase I suppresses alloreactive T cells in tumor-bearing mice. J. Immunol. [0040] 19. Muller, A. J. and P. A. Scherle. Targeting the 170:270-278. mechanisms oftumoral immune tolerance with small-mol- ecule inhibitors. Nat. Rev. Cancer. 6:613,2006. [0026] 5. Bronte, V., P. Serafini, A. Mazzoni, D. M. Segal, Indoleam- and P. Zanovello. 2003b. L-arginine metabolism in [0041] 20. Muller A J, Prendergast G C. (2007). myeloid cells controls T-lymphocyte functions. Trends ine 2,3-dioxygenase in immune suppression and cancer. Immunol. 24:302-306 Curr Cancer Drug Targets 7: 31-40. [0027] 6. Carmela De Santo, Paolo Serafini, Ilaria Marigo, [0042] 21. Muller A J, DuHadaway J B, Sutanto-Ward E, Luigi Dolcetti, Manlio Bolla, )Piero Del Soldato, Cecilia Donover P S, Prendergast G C. (2005a). Inhibition of Melani, Cristiana Guiducci, Mario P. Colombo, Manuela indoleamine 2,3-dioxygenase, an immunomodulatory tar- lezzi, Piero Musiani, Paola Zanovello, and Vincenzo get of the tumor suppressor gene Binl, potentiates cancer Bronte. Nitroaspirin corrects immune dysfunction in chemotherapy. Nature Med 11:312-319. tumor-bearing hosts and promotes tumor eradication by [0043] 22. Muller A J, Malachowski W P, Prendergast G C. cancer vaccination. Proc Natl Acad Sci USA. 2005 March (2005b). Indoleamine 2,3-dioxygenase in cancer: targeting 15; 102(11):4185-4190 pathological immune tolerance with small-molecule inhibitors. Expert Ther Targets 831-849. [002S] 7. Cederbaum, S. D., H. Yu, W. W. Grody, R. M. Opin 9: Kern, P. Yoo, and R. K. Iyer. 2004. Arginases I and II: do [0044] 23. Munn, D. H. , M. D. Sharma, B. Baban, H. P. their functions overlap? Mol. Genet. Metab. 81:S38-44. Harding, Y. Zhang, D. Ron, A. L. Mellor. GCN2 kinase in [0029] 8. T. O' Connor, K. R. Sadleir, E. Maus, R. A. Velli- T cells mediates proliferative arrest and anergy induction quette, J. Zhao, S. L. Cole, W. A. Eimer, B. Hitt, L. A. in response to indoleamine 2,3-dioxygenase. Immunity. Bembinster, S. Lammich, S. F. Lichtenthaler, S. S. Hebert, 22:633, 2005 S. B. De, C. Haass, D. A. Bennett, R. Vassar, Phosphory- [0045] 24. Ohta K, MizunoA, Ueda M, Li S, SuzukiY, Hida lation of the translation initiation factor eIF2alpha Y, Hayakawa-Yano Y, Itoh M, Ohta E, Kobori M, Naka- US 2016/0015712 A1 Jan. 21, 2016

gawa T.Autophagy impairment stimulates PSI expression immune-modulatory or stress response kinases in particular and gamma-secretase activity. Autophagy. 2010; 6(3):345- GCN2, is therefore desirable and an aim ofthe present inven- 52 tion. [0046] 25. Okamoto, A. ; Nikaido, T.; Ochiai, K.; Takakura, [0060] Moreover, aim of this invention is the synthesis of S.; Saito, M. ; Aoki, Y.; Ishii, N. ;Yanaihara, N. ;Yamada, K.; new compounds for the prevention and treatment ofneoplas- Takikawa, O.; Kawaguchi, R.; Isonishi, S.; Tanaka, T.; tic malignancies including, but without being limited to, solid Urashima, M. Indoleamine 2,3-dioxygenase serves as a tumor cancers, cancers of the lymphatic or blood system, of marker of poor prognosis in gene expression profiles of neurodegenerative diseases and chronic infections. serous ovarian cancer cells. Clin. Cancer Res. 2005, 11, [0061] It has been found that the compounds according to 6030-6039. the invention and salts thereof have very valuable pharmaco- [0047] 26. Oyadomari S, Mori M. Roles of CHOP/ logical properties while being well tolerated. GADD153 in endoplasmic reticulum stress. Cell Death [0062] The compounds ofthe formula I can furthermore be Differ. 2004 April; 11(4):381-9. used for the isolation and investigation of the activity or [0048] 27. G C Prendergast, Immune escape as a funda- expression of GCN2. In addition, they are particularly suit- mental trait of cancer: focus on IDO. Oncogene (2008) 27, able for use in diagnostic methods for diseases in connection 3889-3900 with unregulated or disturbed GCN2 activity. [0049] 28. Popovic P J, Zeh III H J, Ochoa J B. (2007). [0063] Compounds of formula I can also inhibit tyrosine Arginine and immunity. J Nutr 137: 1681 S-1686 S. kinases FMS (CSFIR), GSK3u, GSK3[3, FLT3 or FLT4 or combinations of these kinases, preferentially in addition to [0050] 29. Rodriguez, P. C., D. G. Quiceno, J. Zabaleta, B. Ortiz, A. H. Zea, M. B.Piazuelo, A. Delgado, P. Correa, J. inhibitory activity towards GCN2 Brayer, E. M. Sotomayor, S.Antonia, J. B.Ochoa, and A. [0064] Fms-like tyrosine kinase 3 (FLT3), which is also C. Ochoa. Arginase I Production in the Tumor Microenvi- known as FLK-2 (fetal liver kinase 2) and STK-I (stem cell ronment by Mature Myeloid Cells Inhibits T-Cell Receptor kinase I), plays an important role in the proliferation and Expression and Antigen-Specific T-Cell Responses. Canc. differentiation of hematopoietic stem cells. FLT3 receptor Res. 64:5839, 2004 kinase is expressed at very high levels on the cells of more than 80% of myelogenous patients and of a fraction of acute [0051] 30. Rodriguez, P. C., D. G. Quiceno, and A. C. Ochoa. L-arginine availability regulates T-lymphocyte lymphoblastic leukemia cells. Furthermore, the enzyme can cell-cycle progresion. Blood. 109:1568,2007. also be found on cells from patients with chronic myelog- enous leukemia in lymphoid blast crisis. It has been reported [0052] 31.Shankaran, V.; Ikeda, H. ; Bruce, A. T.; White, J. that FLT3 kinase is mutated in 30% of acute myeloid leuke- M. ; Swanson, P. E.; Old, L. J.; Schreiber, R. D. IFNgamma mia and in a subset of acute lymphoblastic leukemia and lymphocytes prevent primary tumour development (AML) as well (Gilliland et al, Blood 100, 1532-1542 and shape tumour immunogenicity. Nature 2001, 410, (ALL) (2002); 1107-1111. Stirewalt et al. , Nat. Rev. Cancer, 3, 650-665 (2003).Activat- ing mutations in FLT3 mutations have been associated with a [0053] 32. Sharma, M. D. B. Baban, P. Chandler, D-Y. , poor prognosis (Malempati et al. Blood, 104, 11 (2004). Hou, N. Singh, H. Yagita, M. Azuma, B. R. Blazar, A. L. , FLT3 inhibitors are being developed and some have shown Mellor, and D. H. Munn. Plasmacytoid dendritic cells from promising clinical effects against AML (Levis et al Int. J. mouse tumor-draining lymph nodes directly activate Hematol, 52, 100-107 (2005). mature Tregs via indoleamine 2,3-dioxygenase. J. Clin. It has been that some small-molecule Invest. 117:2570,2007. [0065] reported of FLT3 inhibitors are effective in inducing apoptosis in cell [0054] 33. Uyttenhove C, Pilotte L, Theate I, Stroobant V, lines with FLT3-activating mutations and prolonging survival Colau D, Parmentier N et al. (2003). Evidence for a of mice that express mutant FLT3 in their bone marrow cells tumoral immune resistance mechanism based on tryp- (Levis et al, Blood, 99, 3885-3891 (2002); Kelly et al, Cancer tophan degradation by indoleamine 2,3-dioxygenase. Nat Cell, I, 421-432 (2002); Weisberg et al, Cancer Cell, I, 433- Med 9: 1269-1274 443 (2002); Yee et al, Blood, 100, 2941-2949 (2002). [0055] 34. Wang, J., M. Torbenson, Q. Wang, J.Y. Ro, and [0066] US patent application 20090054358 describes Flt3 M. Becich. 2003. Expression of inducible nitric oxide syn- inhibitors for immune suppression and in particular for the thase in paired neoplastic and non-neoplastic primary pros- treatment of immune related disorders like organ rejection, tate cell cultures and prostatectomy specimen. Urol. bone marrow transplant rejection, non-myeloablative bone Oncol. 21:117-122. marrow transplant rejection, ankylosing spondylitis, arthritis, 35.Wek R Jiang H Anthony T G. with [0056] C, Y, Coping aplastic anemia. Behcet's disease, type I diabetes mellitus, stress: eIF2 kinases and translational control. Biochem Soc graft-versus-host disease, Graves' disease, autoimmune Trans. 2006 34 February; (Pt I):7-11. hemolytic anemia, Wegener's granulomatosis, hyper IgE [0057] 36.Ye J, Kumanova M, Hart L S, Sloane K, Zhang syndrome, idiopathic thrombocytopenia purpura, rheumatoid H, De Panis D N, Bobrovnikova-Marjon E, Diehl JA, Ron arthritis, Crohn's disease, multiple sclerosis, Myasthenia D, Koumenis C. The GCN2-ATF4 pathway is critical for gravis, psoriasis, and lupus, among other autoimmune dis- tumour cell survival and proliferation in response to nutri- eases. Flt3 Inhibitors might also be used to treat neurological ent deprivation. EMBO J. 2010 Jun. 16; 29(12):2082-96. disorder as neurodegenerative disease, for example a disease [0058] In particular, the present invention relates to com- caused by axonal degeneration. Neurodegenerative diseases pounds and to the use of compounds in which the inhibition, include, for example, multiple sclerosis; demyelinating core regulation and/or modulation of signal transduction by GCN2 disorders, such as multiple sclerosis, acute transverse myeli- plays a role. tis without being limited thereto. [0059] The synthesis of small compounds which specifi- [0067] Scott et al (Bioorg. Med Chem Let. (2008) 18 (17) cally inhibit, regulate and/or modulate signal transduction by p4794) describe CSF-IR inhibitors for the treatment of can- US 2016/0015712 A1 Jan. 21, 2016

cer. CSF-IR is a member of the class III receptor tyrosine [0072] The compounds ofthe formula I can furthermore be kinases. Colony stimulatory factor I (CSF-I), also known as used for the isolation and investigation of the activity or macrophage/monocyte colony stimulatory factor (M-CSF), expression of GCN2, FMS (CSFIR), GSK3u, GSK3[3, FLT3 binds to CSF-IR, resulting in dimerization, autophosphory- or FLT4. In addition, they are particularly suitable for use in lation, and activation of signal transduction. 1 CSF-I/CSF-IR diagnostic methods for diseases in connection with unregu- signaling is essential for normal monocyte development. In lated or disturbed GCN2, FMS (CSFIR), GSK3u, GSK33, cancer, pro-tumorigenic macrophages have been identified FLT3 or FLT4activity. The host or patient can belong to any and linked to poor prognosis in breast, ovarian, and prostate mammalian species, for example a primate species, particu- cancers. Elevated levels of CSF-I and CSF-IR have been larly humans; rodents, including mice, rats and hamsters; reported in several tumor types, including breast, ovarian, and rabbits; horses, cows, dogs, cats, etc. Animal models are of endometrial cancers, and have also been linked to invasion interest for experimental investigations, providing a model and metastasis. Inhibition of CSF-IR activity could therefore for treatment of human disease. have multiple effects on the tumor through reduction in the [0073] The susceptibility of a particular cell to treatment levels of tumor-associated macrophages (TAMs) and have with the compounds according to the invention can be deter- direct effects on the tumor itself (C. E. Lewis, J. W. Pollard, mined by in vitro tests. Typically, a culture of the cell is Cancer Res. , 66 (2006), p. 605; I. Bingle, N. et al. , J. Pathol. , combined with a compound according to the invention at 196 (2002), p. 254; B.M. Kacinski, Ann. Med. , 27 (1995),p. various concentrations for a period oftime which is sufficient 79; E. Garwood et al. J Clin Oncol 26: 2008). to allow active agents such as anti IgM to induce a cellular [0068] Su J L et al. (Cancer Cell. 2006 March; 9(3):209-23) response such as expression of a surface marker, usually report that the VEGF-C/Flt-4 axis promotes invasion and between about one hour and one week. In vitro testing can be metastasis ofcancer cells. Flt-4, a VEGF receptor, is activated carried out using cultivated cells from blood or from a biopsy by its specific ligand, VEGF-C. The resultant signaling path- sample. The amount of surface marker expressed are assessed way promotes angiogenesis and/or lymphangiogenesis. by flow cytometry using specific antibodies recognising the VEGF-C/Flt-4 axis enhances cancer cell mobility and inva- marker. siveness and contributes to the promotion of cancer cell [0074] The dose varies depending on the specific com- metastasis. Examination of tumor tissues from various types pound used, the specific disease, the patient status, etc. A of cancers revealed high levels of Flt-4 and VEGF-C expres- therapeutic dose is typically sufficient considerably to reduce sion that correlated closely with clinical metastasis and the undesired cell population in the target tissue while the patient survival. Inhibition of FIt-4 kinase could reduce the viability of the patient is maintained. The treatment is gener- invasive capacity in different types of cancer ally continued until a considerable reduction has occurred, for [0069] Combining the inhibitory specificity towards GCN2 example an at least about 50% reduction in the cell burden, with that towards FMS (CSFIR), FLT3 or FLT4 or combina- and may be continued until essentially no more undesired tions of these kinases can be of particular advantages for the cells are detected in the body. treatment of neoplastic malignancies at different disease [0075] For identification of a signal transduction pathway stages. It could combine the effects of stimulating the and for detection of interactions between various signal trans- immune response towards cancer/tumor cells, to reduce the duction pathways, various scientists have developed suitable levels of tumor-associated macrophages as well as the inva- models or model systems, for example cell culture models sive capacity of cancers for metastasis formation. In a further (for example Khwaja et al. , EMBO, 1997, 16, 2783-93) and aspect the combination of inhibitory activities on GCN2 par- models of transgenic animals (for example White et al. , ticularly with inhibition of FLT3 could be advantageous for Oncogene, 2001, 20, 7064-7072). For the determination of the treatment of neurodegenerative disorders as it could syn- certain stages in the signal transduction cascade, interacting ergize suppressive effects on inflammatory processes with the compounds can be utilised in order to modulate the signal (for modulation of protein deposites generation in the brain. In example Stephens et al. , Biochemical J., 2000, 351, 95-105). another aspect the combination of inhibitory activities on The compounds according to the invention can also be used as GCN2 particularly with inhibition of FLT3 could provide reagents for testing kinase-dependent signal transduction advantages for modulating the immune response to treat pathways in animals and/or cell culture models or in the immune related disorders and inflammatory or autoimmune clinical diseases mentioned in this application. diseases. [0076] Measurement of the kinase activity is a technique [0070] In a further embodiment the present invention spe- which is well known to the person skilled in the art. Generic cifically relates to compounds of the formula I which inhibit, test systems for the determination of the kinase activity using regulate and/or modulate signal transduction by GCN2, FMS substrates, for example histone (for example Alessi et al. , (CSFIR), GSK3, GSK313, FLT3 or FLT4 or combinations of FEBSLett. 1996, 399, 3, pages 333-338) or the basic myelin these kinases, to compositions which comprise these com- protein, are described in the literature (for example Campos- pounds, and to processes for the use thereof for the treatment Gonzalez, R. and Glenney, Jr., J.R. 1992, J. Biol. Chem. 267, of diseases and complaints that are -induced or modulated by page 14535). GCN2, FMS (CSFIR), GSK3u, GSK3[3, FLT3 or FLT4 or [0077] For the identification of kinase inhibitors, various combinations of these kinases. assay systems are available. In scintillation proximity assay [0071] Further aim of this invention is the synthesis of new (Sorg et al. , J. of. Biomolecular Screening, 2002, 7, 11-19) compounds for the prevention and treatment of neoplastic and flashplate assay, the radioactive phosphorylation of a malignancies including, but without being limited to, solid protein or peptide as substrate with 7ATP is measured. In the tumor cancers, cancers of the lymphatic or blood system, of presence of an inhibitory compound, a decreased radioactive neurodegenerative diseases, immune related disorders like signal, or none at all, is detectable. Furthermore, homoge- arthritis, psoriasis, lupus, multiple sclerosis or other autoim- neous time-resolved fluorescence resonance energy transfer mune diseases as well as chronic infections. (HTR-FRET) and fluorescence polarisation (FP) technolo- US 2016/0015712 A1 Jan. 21, 2016

gies are suitable as assay methods (Sills et al. , J. of Biomo- [0089] or lecular Screening, 2002, 191-214). [0090] denotes cycloalkyl with 3-7 C-atoms or cyclo- [0078] Other non-radioactive ELISA assay methods use pentenyl, each of which can be mono-, di-, tri-, tetra- or specific phospho-antibodies (phospho-ABs). The phospho- pentasubstituted by A and/or Hal and/or which can be AB binds only the phosphorylated substrate. This binding can mono- or disubstituted by [C(R )~] OR, O[C(R )~] ')~, ')~, ')~] be detected by chemiluminescence using a second peroxi- ( ')~], ( o[ ( ')~], ( I ( ~Ar, [C(R )~]~Het', O[C(R )~]~Het', CN, [C(R )~] dase-conjugated anti-sheep antibody (Ross et al. , 2002, Bio- ~COOR 0[C(R )~]~COOR CONHA chem. J.). CONH~) CONA~) [C(R )~]~NR COA CONR SO~A [0079] Moreover, compounds of formula I inhibit GSK3u NR'SO, A, SO,N(R')„S(O) A, COHet', O[C(R'),] N and GSK3JIJ (glycogen synthase kinase-3 alpha and beta). (R )~) [C(R )~] NR CODA [C(R )~] [0080] GSK3 inhibitors inhibit breast cancer cell growth ~NR COOCH~Ph NR CON(R )~) NHCOO[C(R )~] and thus offer an innovative approach for breast cancers resis- N(R )~, NHCOO[C(R )~] Het', NHCONH[C(R )~] tant to hormone-bases therapy (H. M. Kim et al. PLoS One, , N(R )~, NHCONH[C(R )~] Het', OCONH[C(R )~] 2013; 8(4):e60383). N(R )~, OCONH[C(R )~] Het', CONH(CH~) Het, Antimyeloma inhibitors [0081] activity of GSK3 is CONR NR COA, CONR N(R )~, CONHCyc, COA, reported by C. Fionda et al. , J. Immunol. 2013 Jun. 15; 190 S, NR and/or 0, (12):6662-72). [0091] or [0082] Anticolon cancer activity of GSK3 inhibitors is [0092] denotes piperidinyl, tetrahydropyranyl, pyrrolidi- reported by E. Grissilli et al. , Clin. Cancer Res. 2013 July 15; nyl, azetidinyl, thiolanyl, oxetanyl, 3-aza-bicyclo P.1.0] 19(14):3820-31. hexyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, 4,5, [0083] Antimyeloma activity of GSK3u and GSK3JIJ 6,7-tetrahydro-l H-indazol-5-yl, 4,5,6,7-tetrahydro-l H- inhibitors is reported by S.V. Madhunapantula et al. , Pigment indazo1-6-yl, tetrahydropyrazolyl, tetrahydrofuranyl or Cell Melanoma Res. 2013Aug. 19doi: 10.1111/pcmr. 12156. hexahydropyridazinyl, each ofwhich can be mono-, di-, [0084] GSK3 has been implicated in various diseases such tri-, tetra- or pentasubstituted by A and/or Hal and/or as diabetes, inflammation, cancer, Alzheimer's and bipolar which can be mono- or disubstituted by [C(R )~] OR, ', ') disorder. GSK3 negatively regulates insulin-mediated glyco- o[ ( ').],o [ ( ').l, ( ')., [ ( ').l, , I ( gen synthesis and glucose homeostasis, and increased expres- ~] Het', [C(R )~] Het, CN, [C(R )~] COOR, CO[C sion and activity of GSK3 has been reported in type II dia- (R )~]~N(R )~, CO[C(R )~]~Het', CO[C(R )~]~Het, betics and obese animal models (Geetha Vani Rayasam et al. , NR'COA, NR'SO, A, SO,N(R')„S(O) A, COHet', British Journal of Pharmacology (2009), 156, 885-898). O[C(R )~] N(R )~, O[C(R )~] Het', NHCOOA, NHCON(R )~) NHCOO[C(R )~] N(R )~) NHCOO[C PRIOR ART (R )~] Het', NHCONH[C(R )~] N(R )~, NHCONH[C (R )~] Het', OCONH[C(R )~] N(R )~, OCONH[C [0085] Triazolopyrimidine derivatives are described as (R )~] Het', C(O)R, S, NR and/or 0, GSK3 inhibitors for the treatment of diseases like Alzheimer [0093] R denotes H or unbranched or branched alkyl with or diabetes in WO 2005/012307 Al and in WO 2006/075023 1-6 C-atoms, A2. [0094] Ar denotes phenyl or naphthyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, SUMMARY OF THE INVENTION ( ')z],o ', OI ( ')z],o ', [ ( ')z], ( ')z, o[ [0086] The inventionrelates to compounds of the formula I (R )~]~N(R )~, [C(R )~]~Het', [C(R )~]~Het, NO~, CN, in which [C(R )~]~COOR 0[C(R )~]~COOR CON(R )~) NR COA, NR SO~A, SO~N(R )~, S(O) A, COHet', O[C (R )~] Het', NHCOOA, NHCON(R )~, NHCOO[C(R )~] N(R )~, NHCOO[C(R )~] Het', NHCONH[C(R )~] R' N(R )~, NHCONH[C(R )~] Het', OCONH[C(R )~] N H (R )~, OCONH[C(R )~] Het', S(O) Het', CHO and/or N y' ~ COA, or denotes azulenyl, [0095] Het denotes furyl, thienyl, pyrrolyl, imidazolyl, I/ Nx N pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, [0087] R' denotes Ar or Het, indolizinyl, cinnolinyl, quinolyl, isoquinolyl, benzox- [00SS] R denotes unbranched or branched alkyl with 1-7 azolyl, 1,3-benzodioxolyl, benzothiophenyl, benzofura- C-atoms, wherein two adjacent carbon atoms may form a nyl, imidazopyridyl, dihydroindolyl, quinoxalinyl, imi- double or triple bond and which can be mono-, di-, tri-, dazo[1, 2-a]pyridinyl, benzo[1, 2,5]thiadiazolyl, tetra- or pentasubstituted by Hal and/or which can be naphthyridinyl, 2,3-dihydro-benzo[1, 4]dioxinyl, mono- or disubstituted by OR, N(R )~, Het', CN, quinazolinyl, benzothiazolyl or furo P,2-b]pyridyl, each of COOR OCOOR CONH~) CONHA CONA~) which is unsub stituted or mono- or di substituted by Hal, A, NR COA, NR SO~A, SO~N(R )~, S(O) A, COHet', O[C ( ').],O ', o[ ( ').],O ', [ ( ').l, ( ')., o[ (R )~] N(R )~, O[C(R )~] Het', NHCOOA, NHCON(R ) (R )~]~N(R )~, [C(R )~]~Het', NO~, CN, [C(R )~] NHCOO[C(R )~] N(R )~, NHCOO[C(R )~]~Het', COOR, O[C(R )2] COOR, CON(R )2, NR COA, NHCONH[C(R )~] N(R )~, NHCONH[C(R )~] Het', NR'SO, A, SO,N(R )„S(O)A, COHet', O[C(R'),] OCONH[C(R )~] N(R )~, OCONH[C(R )~] Het' and/ Het', NHCOOA, NHCON(R )~, NHCOO[C(R )~] N or COA, (R )~, NHCOO[C(R )~] Het', NHCONH[C(R )~] N US 2016/0015712 A1 Jan. 21, 2016

(R )~, NHCONH[C(R )~] Het', OCONH[C(R )~] N(R ) pounds which form owing to their mutual attractive force. ~, OCONH[C(R )~] Het', S(O) Het', CHO, COA, S Solvates are, for example, mono- or dihydrates or alcohol- and/or 0, ates. The term pharmaceutically acceptable derivatives is [0096] Het' denotes pyrazolyl, pyridazinyl, pyridinyl, taken to mean, for example, the salts of the compounds oxazolyl, isoxazoyl, oxadiazolyl, pyrazinyl, indolyl, dihy- according to the invention and also so-called prodrug com- dropyrrolyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahy- pounds. droimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tet- rahydro furanyl, dihydropyridyl, tetrahydropyridyl, [0110] As used herein and unless otherwise indicated, the piperidinyl, morpholinyl, hexahydropyridazinyl, hexahy- term "prodrug" means a derivative of a compound of formula dropyrimidinyl, [1,3]dioxolanyl, tetrahydropyranyl or pip- I that can hydrolyze, oxidize, or otherwise react under bio- erazinyl, each of which is unsubstituted or mono- or dis- logical conditions (in vitro or in vivo) to provide an active ubstituted by Hal, A, [C(R )~] OR, O[C(R )~]~OR, compound, particularly a compound of formula I. Examples [C(R ) ] N(R ), [C(R ) ] Het, NO, [C(R ) ] CN, of prodrugs include, but are not limited to, derivatives and [C(R )~]~COOR, O[C(R )~]~COOR, [C(R )~]~CON metabolites of a compound of formula I that include biohy- (R )~, NR COA, NR SO~A, o~ ( )~, (o) drolyzable moieties such as biohydrolyzable amides, biohy- COHet, O[C(R )~] N(R )~, O[C(R )~] Het, NHCOOA, drolyzable esters, biohydrolyzable carbamates, biohydrolyz- NHCON(R )~) NHCOO[C(R )~] N(R )~) NHCOO[C able carbonates, biohydrolyzable ureides, and (R )~] Het, NHCONH[C(R )~] N(R )~, NHCONH[C biohydrolyzable phosphate analogues. In certain embodi- (R )~] -Het, OCONH[C(R )~] N(R )~, OCONH[C(R ) ments, prodrugs of compounds with carboxyl functional CHO, COA, S and/or z]~Het, S(O) Het, 0, groups are the lower alkyl esters of the carboxylic acid. The [0097] Het denotes pyrazolyl, oxadiazolyl, pyridinyl, tria- carboxylate esters are conveniently formed by esteri fying any zolyl, tetrazolyl, pyridazinyl, pyrrolidinyl, azetidinyl, of the carboxylic acid moieties present on the molecule. Pro- azoxetanyl, tetrahydroimidazolyl, tetrahydropyrazolyl, drugs can typically be prepared using well-known methods, tetrahydro furanyl, piperidinyl, morpholinyl, tetrahydropy- such as those described Burger's Medicinal Chemistry and ranyl or piperazinyl, each of which is unsubstituted or by Drug Discovery 6th ed. (Donald J.Abraham ed. 2001, Wiley) mono- or disubstituted by Hal, A, OA, CN, COOA, , CONH~, S(O) A, S(O) Ar, COA and/or 0, and Design and Application of Prodrugs (H. Bundgaard ed. , [0098] Het denotes pyrazolyl, pyridinyl, pyrimidinyl or 1985, Harwood Academic Publishers Gmfh). pyrazinyl, each of which is unsub stituted or mono- or dis- [0111] The expression "effective amount" denotes the ubstituted by Hal, A, [C(R )~] OR, O[C(R )~] OR, amount of a medicament or of a pharmaceutical active ingre- [C(R )~] N(R )~, [C(R )~]~Het, NO~, CN, [C(R )~] dient which causes in a tissue, system, animal or human a COOR, O[C(R COOR, CON(R NR COA, )2] )2, biological or medical response which is sought or desired, for NR'SO, A, SO,N(R')„S(O) A, COHet', O[C(R'),] N example, by a researcher or physician. (R )~, O[C(R )~] Het, NHCOOA, NHCON(R )~, NHCOO[C(R )~] N(R )~, NHCOO[C(R )~] Het, [0112] In addition, the expression "therapeutically effec- NHCONH[C(R )~] N(R )~, NHCONH[C(R )~] Het, tive amount" denotes an amount which, compared with a OCONH[C(R )~] N(R )~, OCONH[C(R )~] Het, S(O)— corresponding subject who has not received this amount, has Het, CHO, COA, S and/or 0, the following consequence: [0099] Ph denotes phenyl, elimi- [0100] Cyc cycloalkyl with 3-7 C-atoms, which can be [0113] improved treatment, healing, prevention or nation a disease, condition, mono- or disubstituted by OH, of syndrome, complaint, [0101] A denotes unbranched or branched alkyl with 1-10 disorder or side-effects or also the reduction in the C-atoms, wherein one, two or three non-adjacent CH- and/ advance of a disease, complaint or disorder. or CH~-groups may be replaced by N-, 0- and/or S-atoms [0114] The expression "therapeutically effective amount" -7H-atoms and wherein I may be replaced by OH, F and/or also encompasses the amounts which are effective for Cl, increasing normal physiological function. [0102] Hal denotes F, Cl, Br or I, [0103] n denotes 0, I or 2, [0115] The invention also relates to the use of mixtures of [0104] m denotes I, 2 or 3, the compounds of the formula I, for example mixtures of two [0105] p denotes 0, I, 2, 3 or 4, diastereomers, for example in the ratio I:I, I:2, I:3, I:4, I:5, and pharmaceutically usable derivatives, solvates, salts, tau- I:10, I:100or I:1000. tomers and stereoisomers thereof, including mixtures thereof [0116] These are particularly preferably mixtures of stere- in all ratios. oisomeric compounds. "Tautomers" refers to isomeric forms The invention also relates to the optically active [0106] of a compound that are in equilibrium with each other. The forms (stereoisomers), the enantiomers, the racemates, the concentrations ofthe isomeric forms will depend on the envi- diastereomers and the hydrates and solvates of these com- ronment the compound is found in and may be different pounds. depending upon, for example, whether the compound is a [0107] The invention also relates to the solvates of the salts solid or is in an organic or aqueous solution. ofthe compounds of formula I, e g. the mono- or dihydrate of the hydrochloride. [0117] The invention relates to the compounds of the for- [0108] Moreover, the invention relates to pharmaceutically mula I and salts thereof and to a process for the preparation of acceptable derivatives of compounds of formula I. compounds of the formula I and pharmaceutically usable [0109] The term solvates of the compounds is taken to salts, solvates, tautomers and stereoisomers thereof, charac- mean adductions of inert solvent molecules onto the com- terised in that US 2016/0015712 A1 Jan. 21, 2016

a compound of the formula II or preferably denotes piperidinyl, tetrahydropyranyl, pyrrolidi- nyl, azetidinyl, thiolanyl, oxetanyl, 3-aza-bicyclo[3. 1.0] hexyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, 4,5,6,7- R' tetrahydro-lH-indazo1-5-yl, 4,5,6,7-tetrahydro-lH-indazol- 6-yl, tetrahydropyrazolyl, tetrahydro furanyl or hexahydropyridazinyl, each of which can be mono-, di-, tri-, Yj tetra- or penta substituted by A and/or Hal and/or which can be mono- or disubstituted by [C(R )~] Het', [C(R )~] Het, SO2N(R )2, S(O) A, [C(R )2] COOR, CO[C(R )2] ( ) [0118] in which R has the meanings indicated in Claim 1, ~, CO[C(R )~] Het', CO[C(R )~] Het, C(O)R, and/or O. is reacted with a compound of the formula III [0128] R particularly preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-hydroxy-cyclohexyl, R III NH~ 4-amino-cyclohexyl, 4-amino-cyclobutyl, 4-hydroxy-cy- [0119] in which R has the meaning indicated in Claim 1 clobutyl, 3-hydroxy-cyclopentyl, 3-amino-cyclopentyl, and/or 3-aminocarbonyl-cyclobutyl, 3-aminocarbonyl-cyclopentyl, a base or acid ofthe formula I is converted into one of its salts. 3-aminocarbonyl-cyclohexyl, tetrahydrofuranyl or 3-[(3-hy- [0120] Above and below, the radicals R' and R have the droxy-3-methyl-butyl) aminocarbonyl] cyclopentyl. meanings indicated for the formula I, unless expressly stated [0129] R preferably denotes H or alkyl having I, 2, 3 or 4 otherwise. C atoms, particularly preferably H or methyl. [0121] For all radicals which occur more than once, their [0130] Ar denotes, for example, o-, m- or p-tolyl, o-, m- or meanings are independent of one another. p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopro- [0122] A denotes alkyl, this is unbranched (linear) or pylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydrox- branched, and has I, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A yphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, preferably denotes methyl, furthermore ethyl, propyl, isopro- m- or p-(N-methylamino)phenyl, o-, m- or p-(N-methylami- pyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also nocarbonyl)phenyl, o-, m- or p-methoxyphenyl, o-, m- or pentyl, I -, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpro- p-ethoxyphenyl, o-, m- or p-ethoxycarbonyl-phenyl, o-, m- or pyl, l-ethylpropyl, hexyl, 1-,2-, 3- or 4-methylpentyl, 1,1-, p-(N, N-dimethylamino)phenyl, o-, m- or p-(N, N-dimethyl- 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, I- or 2-ethylbutyl, aminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl, I -ethyl-1 -methylpropyl, I -ethyl-2-methylpropyl, 1,1,2- or o-, m- or p-(N, N-diethylamino)phenyl, o-, m- or p-fluorophe- 1,2,2-trimethylpropyl, furthermore preferably, for example, nyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, trifluoromethyl. m- or p-(methylsulfonamido)phenyl, o-, m- or p-(methyl- [0123] A very particularly preferably denotes alkyl having sul fonyl)phenyl, o-, m- or p-cyanophenyl, o-, m- or p-carbox- I, 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, propyl, yphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, p-formylphenyl, o-, m- or p-acetylphenyl, o-, m- or p-amino- trifluoromethyl, pentafluoroethyl or I,I,l-trifluoroethyl. sulfonylphenyl, o-, m- or p-[2-(morpholin-4-yl)ethoxy]phe- [0124] Moreover, A denotes e.g. CH~OCH~, CH~CH~OH, nyl, o-, m- or p-[3-(N, N-diethylamino)propoxy]phenyl, fur- OCH, CH,NH„CH, NHCH, or NHCH, CH, . thermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- [0125] Cycloalkyl with 3-7 C-atoms preferably denotes difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclo- dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- heptyl. dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4- [0126] R' particularly preferably denotes 4-methoxyphe- dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4- nyl, 4-ethoxyphenyl, 4-[I-(2-hydroxyethyl)pyrazol-4-yl] chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5- phenyl, 4-[1-(2-methoxyethyl)pyrazo1-4-yl]phenyl, 2-me- chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N, N- thyl-quinolin-6-yl, 4-(2-methoxy-ethoxy)phenyl, 4-(2- dimethylamino- or 3-nitro-4-N, N-dimethylamino-phenyl, methoxy- l-methoxymethyl-ethoxy)phenyl, 4-(tetrahydro- 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5- pyran-4-yloxy)phenyl or 4-(3-hydroxy-3-methyl-butoxy) trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3, 5- phenyl. dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, [0127] R preferably denotes unbranched or branched alkyl 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-dif- with 1-7 C-atoms, wherein two adjacent carbon atoms may luoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro- form a double or triple bond and which can be mono-, di-, tri-, 6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4- tetra- or pentasubstituted by Hal and/or which can be mono- methoxyphenyl, 3-amino-6-methyl-phenyl, 3-chloro-4- or disubstituted by CN, CONH~, CONHA, CONA~ and/or acetamidophenyl or 2,5-dimethyl-4-chlorophenyl. 0[C(R )~] N(R )~) [0131] Ar furthermore preferably denotes phenyl or naph- or thyl, each of which is unsubstituted or mono-, di- or trisub- preferably denotes cycloalkyl with 3-7 C-atoms or cyclopen- stituted by Hal, A, [C(R )~] OR, O[C(R )~] COOR, S(O) tenyl, each of which can be mono-, di-, tri-, tetra- or penta- A, [C(R )~]~Het', O[C(R )~]~Het' and/or [C(R )~]~Het . substituted by A and/or Hal and/or which can be mono- or Moreover, Ar denotes azulenyl. disubstituted by [C(R )~] OR, [C(R )~] N(R )~, [C(R )~] [0132] Het preferably denotes furyl, thienyl, pyrrolyl, imi- ~Ar, [C(R )~]~Het', [C(R )~]~COOR, [C(R )~]~NR COOA, dazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiaz- S(O) A CN CONR SO~A SO~N(R )~) CONH~) CONHA olyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, CONA~, CONH(CH~) Het, [C(R )~] Het', COHet', pyrazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, CONR NR COA, CONR N(R )~, CONHCyc and/or [C(R ) indolizinyl, cinnolinyl, quinolyl, isoquinolyl, benzoxazolyl, ~]~NR COOCH~Ph, 1,3-benzodioxolyl, benzothiophenyl, benzofuranyl, imida- US 2016/0015712 A1 Jan. 21, 2016

zopyridyl, dihydroindolyl, quinoxalinyl, imidazo[1, 2-a]py- [0135] Hal preferably denotes F, Cl or Br, but also I, par- ridinyl, benzo[1, 2,5]thiadiazolyl, naphthyridinyl, 2,3-dihy- ticularly preferably F or Cl. dro-benzo[1, 4]dioxinyl, quinazolinyl, benzothiazolyl or furo [3,2-b]pyrjdy], each of which is unsubstituted or mono- or [0136] Throughout the invention, all radicals which occur disubstitutedby A, Hal, [C(R )z] Het', 0 and/or [C(R )z] more than once may be identical or different, i.e. are indepen- OR . dent of one another. [0133] Het' preferably denotes pyrazolyl, pyridazinyl, The compounds of the formula I may have one or oxazolyl, isoxazoyl, oxadiazolyl, tetrahydro-pyranyl, dihy- [0137] stere- dropyrrolyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahy- more chiral centres and can therefore occur in various droimidazolyl, piperidinyl, morpholinyl or piperazinyl, each oisomeric forms. The formula I encompasses all these forms. of which is unsubstituted or mono- or disubstituted by A, [013S] Accordingly, the invention relates, in particular, to [C(R Het, [C(R [C(R [C(R )z] )z]~CN, )z]~N(R )z, )z] the compounds of the formula I in which at least one of the ~CON(R )z, [C(R )z]~OR and/or O. said radicals has one of the preferred meanings indicated [0134] Het preferably denotes pyrazolyl, oxadiazolyl, pyridinyl, tetrazolyl, pyridazinyl, pyrrolidinyl, azetidinyl, above. Some preferred groups of compounds may be azoxetanyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tet- expressed by the following sub-formulae Ia to Id, which rahydrofuranyl, piperidinyl, morpholinyl, tetrahydropyranyl conform to the formula I and in which the radicals not desig- or piperazinyl, each of which is unsubstituted or monosubsti- nated in greater detail have the meaning indicated for the tuted by A and/or O. formula I, but in which

in Ia. Rz denotes unbranched or branched alkyl with 1-7 C-atoms, wherein two adjacent carbon atoms may form a double or triple bond and which can be mono-, di-, 0i-, tetra- or pentasubstituted by Hal and/or which can be mono- or disubstituted by CN, CONHz, CONHA, CONAz and/or O[C(R )z] N(R )z, or denotes cycloalkyl with 3-7 C-atoms or cyclopentenyl, each of which can be mono-, di-, 0i-, tetra- or pentasubstituted by A and/or Hal and/or which can be mono- or disubstituted by [C(R')z]~OR', [C(R')z]~N(R')z, [C(R')z]~, [C(R')z]~Het', [C(R )z] COOR, [C(R )z] NR COOA, S(O)„A, [C(R )z] Het, COHet', CN, CONR SOzA, SOzN(R )z, CONHz, CONHA, CONAz, CONH(CHz) HeF, CONR NR COA, CONR N(R )z, CONHCyc and/or [C(R )z] NR COOCHzph, or denotes piperidinyl, tetrahydropyrany), pyrrolidinyl, azetidinyl, &io)any), oxetanyl, 3-aza-bicyc)o[3. I.I3]hexy), tetrahydro&iopheny), tetrahydrothiopyrany), 4,6,6,7- tetrahydro-I H-indazo)-s-y), 4,6,6,7-tetrahydro-l H-indazol-6- yl, tetrahydropyrazo)y), tetrahydrofuranyl or hexahydropyridazinyl, each of which can be mono-, di-, tri-, tetra- or pentasubstituted by A and/or Hal and/or which can be mono- or disubstituted by [C(R )z] Het', [C(R )z] Het, SOzN(R )z, S(O)„A, [C(R )z]~COOR, CO[C(R )z]~N(R )z, CO[C(R )z] Het', CO[C(R )z] Het, C(O)R, and/or 0; in Ib Ar denotes phenyl or nappy), each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R )z] OR, O[C(R )z] COOR, S(O)„A, [C(R )z]Het', O[C(R )z] Het' and/or [C(R )z] Het, or denotes azulenyl; in Ic Het' denotes pyrazolyl, pyridazinyl, oxazolyl, isoxazoyl, oxadiazolyl, tetrahydro-pyrany), tetrahydro furanyl, dihydropyrrolyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahydro- imidazolyl, piperidinyl, morpholinyl or piperazinyl, each of which is unsubstituted or mono- or disubstituted by A, [C(R')z]~HeF, [C(R')z]~CN, [C(R')z]~N(R')z, [C(R')z] CON(R')z, [C(R')z] OR'and/or 0; in Id R' denotes Ar or Het, R denotes unbranched or branched alkyl with 1-7 C-atoms, wherein two adjacent carbon atoms may form a double or triple bond and which can be mono-, di-, 0i-, tetra- or pentasubstituted by Hal and/or which can be mono- or disubstituted by CN, CONHz, CONHA, CONAz and/or O[C(R )z] N(R )z, or denotes cycloalkyl with 3-7 C-atoms or cyclopentenyl, each of which can be mono-, di-, tri-, tetra- or pentasubstituted by A and/or Hal and/or which can be mono- or disubstituted by [C(R )z] OR, [C(R )z] N(R )z, [C(R )z] Ar, [C(R )z] Het', [C(R )z] COOR, [C(R )2] NR COOA, S(O)„A, CN, CONR SO2A, US 2016/0015712 A1 Jan. 21, 2016 10

-continued

SOzN(R )z, CONHz, CONHA, CONAz, CONH(CHz) Het, [C(R )z] Het', COHet', CONR NR COA, CONR N(R )z, CONHCyc and/or [C(R )z] NR COOCHzPh, or denotes piperidinyl, tetrahydropyrany), pyrrolidinyl, azetidinyl, &io)any), oxetanyl, 3-aza-bicyc)o[3. 1.I3]hexy), tetrahydro&iopheny), tetrahydro&iopyrany), 4,5,6,7- tetrahydro-1H-indazo)-5-y), 4,5,6,7-tetrahydro-lH-indazol- 6-yl, tetrahydropyrazo)y), tetrahydrofuranyl or hexahydropyridazinyl, each of which can be mono-, di-, n i-, tetra- or pentasubstituted by A and/or Hal and/or which can be mono- or disubstituted by [C(R )z] Het', SOzN(R')z, S(0)„A, [C(R')z] Het', [C(R')z]~COOR', CO[C(R )z] N(R )z, CO[C(R )z] Het', CO[C(R )z] Het, C(0)R, and/or 0, R denotes H or unbranched or branched alkyl with 1-6 C- atoms, denotes phenyl or nappy), each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, [C(R )z] OR, 0[C(R )z] COOR, S(0)„A, [C(R )z] Het', 0[C(R )z] Het' and/or [C(R )z] Het, or denotes azulenyl, Het denotes fury), &ieny), pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, &iazo)y), mazo)y), tetrazo)y), pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, indolizinyl, cinnolinyl, quinolyl, isoquinolyl, benzoxazolyl, 1,3-benzodioxolyl, benzo&iopheny), benzofurany), imidazopyridyl, dihydroindolyl, quinoxalinyl, imidazo[1, 2-a]pyridiny), benzoyl, 2,5]&iadiazo)y), naphthyridinyl, 2,3-dihydro- benzo[1, 4]dioxinyl, quinazolinyl, benzothiazolyl or furo[3, 2-b]pyridy), each of which is unsubstituted or mono- or disubstituted by A, Hal, [C(R )z] Het', 0 and/or [C(R )2] OR, Het' denotes pyrazolyl, pyridazinyl, oxazolyl, isoxazoyl, oxadiazolyl, tetrahydro-pyrany), tetrahydro furany), dihydropyrrolyl, pyrrolidinyl, azetidinyl, oxetanyl, tetra- hydroimidazolyl, piperidinyl, morpholinyl or piperazinyl, each of which is unsubstituted or mono- or disubstituted by A, [C(R )z] Het, [C(R )z] CN, [C(R )z] N(R )z, [C(R')z]~CON(R')z, [C(R')z]~OR' and/or 0, Hed denotes denotes pyrazolyl, oxadiazolyl, pyridinyl, uiazo)y), tetrazo)y), pyridazinyl, pyrrolidinyl, azetidinyl, azoxetanyl, tetrahydroimidazo)y), tetrahydropyrazo)y), tetrahydrofurany), piperidinyl, morpholinyl, tetrahydropyranyl or piperazinyl, each of which is unsubstituted or monosubstituted by A and/or 0, Het denotes pyrazolyl, pyridinyl, pyrimidinyl or pyrazinyl, each of which is unsubstituted or mono- or disubstituted by A, [C(R )z] Hed and/or [C(R )z] OR, Pll denotes phenyl, Cyc cycloalkyl with 3-7 C-atoms, which can be mono- or disubstituted by OH, denotes unbranched or branched alkyl with 1-1I3 C- atoms, wherein one, two or dtree non-adjacent CH- and/or CHz-groups may be replaced by N-, 0- and/or S- atoms and wherein 1-7 H-atoms may be replaced by OH, F and/or Cl, Hal denotes F, Cl, Br or I, denotes I3, 1 or 2, denotes 1, 2 or 3, denotes I3, 1, 2, 3 or 4

and pharmaceutically acceptable salts, so]vates, tautomers [0140] The compounds of the formula I and also the start- and stereoisomers thereof, including mixtures thereof in all ing materials for their preparation are, in addition, prepared ratios. by methods known per se, as described in the literature (for example in the standard works, such as Houben-Wey], Meth- [0139] Particularly preferred are compounds selected from oden der organischen Chemic [Methods of Organic Chemis- the group "A212", "A140", "A187", "A218", "A150", try], Georg-Thieme-Ver]ag, Stuttgart), to be precise Use can "A135" "A167" "A168" "A253" "A293" also be made here of variants known per se which are not mentioned here in greater detail. and pharmaceutically acceptable salts, so]vates, tautomers [0141] The starting compounds of the formulae II and III and stereoisomers thereof, including mixtures thereof in all are generally known. If they are novel, however, they can be ratios. prepared by methods known per se. US 2016/0015712 A1 Jan. 21, 2016

[0142] Compounds of the formula I can preferably be late, ascorbate and the like. Accordingly, pharmaceutically obtained by reacting a compound of the formula II with a acceptable acid-addition salts of the compounds of the for- compound of the formula Ill. mula I include the following: acetate, adipate, alginate, argin- [0143] The reaction is generally carried out under condi- ate, aspartate, benzoate, benzenesulfonate (besylate), bisul- tions known to the skilled artisan and which are known and fate, bisulfite, bromide, butyrate, camphorate, camphor- suitable for the said reaction, which belongs to the nucleo- sulfonate, caprylate, chloride, chlorobenzoate, citrate, philic substitutions on heteroaromatic ring systems. Depend- cyclopentanepropionate, digluconate, dihydrogenphosphate, ing on the conditions used, the reaction time is between a few dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, minutes and 14 days, the reaction temperature is between galacterate (from mucic acid), galacturonate, gluco-hep- about 0' and 140, normally between 20' and 120', in particu- tanoate, gluconate, glutamate, glycerophosphate, hemisucci- lar between about 60' and about 110'. Examples of suitable nate, hemi-sulfate, heptanoate, hexanoate, hippurate, hydro- inert solvents are hydrocarbons, such as hexane, petroleum chloride, hydrobromide, hydroiodide, ether, benzene, toluene or xylene; chlorinated hydrocarbons, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, such as trichloroethylene, 1,2-dichloroethane, carbon tetra- lactate, lactobionate, malate, maleate, malonate, mandelate, chloride, chloroform or dichloromethane; alcohols, such as metaphosphate, methanesulfonate, methylbenzoate, mono- methanol, ethanol, isopropanol, n-propanol, n-butanol or tert- hydrogenphosphate, 2-naphthalenesulfonate, nicotinate, butanol; ethers, such as diethyl ether, diisopropyl ether, tet- nitrate, oxalate, oleate, palmoate, pectinate, persulfate, phe- rahydrofuran (THF) or dioxane; glycol ethers, such as ethyl- nylacetate, 3-phenylpropionate, phosphate, phosphonate, ene glycol monomethyl or monoethyl ether, ethylene glycol phthalate, but this does not represent a restriction. dimethyl ether (diglyme); ketones, such as acetone or Furthermore, the base salts the compounds butanone; amides, such as acetamide, dimethylacetamide or [0147] of according to the invention include aluminium, ammonium, dimethylformamide (DMF); nitriles, such as acetonitrile; sul- calcium, iron(III), iron(II), lithium, magnesium, foxides, such as dimethyl sulfoxide (DMSO); carbon disul- copper, potassium, sodium and zinc fide; carboxylic acids, such as formic acid or acetic acid; nitro manganese(III), manganese(II), but this is not intended to represent a restriction. the compounds, such as nitromethane or nitrobenzene; esters, salts, Of above-mentioned salts, preference is given to ammonium; the such as ethyl acetate, or mixtures of the said solvents. alkali metal salts sodium and potassium, and the alkaline [0144] Particular preference is given to 2-methoxyethanol. earth metal salts calcium and magnesium. Salts of the com- [0145] Free amino groups can furthermore be acylated in a pounds of the formula I which are derived from pharmaceu- conventional manner using an acid chloride or anhydride or tically acceptable organic non-toxic bases include salts of alkylated using an unsubstituted or substituted alkyl halide, primary, secondary and tertiary amines, substituted amines, advantageously in an inert solvent, such as dichloromethane also including naturally occurring substituted amines, cyclic or THF, and/or in the presence of a base, such as triethylamine amines, and basic ion exchanger resins, for example arginine, or pyridine, at temperatures between —60 and +30'. betaine, caffeine, chloroprocaine, choline, N, N'-dibenzyleth- ylenediamine (benzathine), dicyclohexylamine, diethanola- Pharmaceutical Salts and Other Forms mine, diethylamine, 2-diethylaminoethanol, 2-dimethylami- [0146] The said compounds according to the invention can noethanol, ethanolamine, ethylenediamine, be used in their final non-salt form. On the other hand, the N-ethylmorpholine, N-ethylpiperidine, glucamine, glu- present invention also encompasses the use of these com- cosamine, histidine, hydrabamine, isopropylamine, pounds in the form oftheir pharmaceutically acceptable salts, lidocaine, lysine, meglumine, N-methyl-D-glucamine, mor- which can be derived from various organic and inorganic pholine, piperazine, piperidine, polyamine resins, procaine, acids and bases by procedures known in the art. Pharmaceu- purines, theobromine, triethanolamine, triethylamine, trim- tically acceptable salt forms of the compounds ofthe formula ethylamine, tripropylamine and tris(hydroxymethyl)methy- I are for the most part prepared by conventional methods. If lamine (tromethamine), but this is not intended to represent a the compound ofthe formula I contains a carboxyl group, one restriction. of its suitable salts can be formed by reacting the compound [014S] Compounds of the present invention which contain with a suitable base to give the corresponding base-addition basic nitrogen-containing groups can be quaternised using salt. Such bases are, for example, alkali metal hydroxides, agents such as -C~)alkyl halides, for example methyl, including potassium hydroxide, sodium hydroxide and (C, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; lithium hydroxide; alkaline earth metal hydroxides, such as di(C, -C~)alkyl sulfates, for example dimethyl, diethyl and barium hydroxide and calcium hydroxide; alkali metal alkox- diamyl sulfate; (C,~-C, 8)alkyl halides, for example decyl, ides, for example potassium ethoxide and sodium propoxide; dodecyl, lauryl, myristyl and stearyl chloride, bromide and and various organic bases, such as piperidine, diethanolamine iodide; and aryl(C, -C~)alkyl halides, for example benzyl and N-methylglutamine. The aluminium salts of the com- chloride and phenethyl bromide. Both water- and oil-soluble pounds of the formula I are likewise included. In the case of compounds according to the invention can be prepared using certain compounds ofthe formula I, acid-addition salts can be such salts. formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids, for example hydro- [0149] The above-mentioned pharmaceutical salts which gen halides, such as hydrogen chloride, hydrogen bromide or are preferred include acetate, trifluoroacetate, besylate, cit- hydrogen iodide, other mineral acids and corresponding salts rate, fumarate, gluconate, hemisuccinate, hippurate, hydro- thereof, such as sulfate, nitrate or phosphate and the like, and chloride, hydrobromide, isethionate, mandelate, meglumine, alkyl- and monoarylsulfonates, such as ethanesulfonate, tolu- nitrate, oleate, phosphonate, pivalate, sodium phosphate, enesulfonate and benzenesulfonate, and other organic acids stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and corresponding salts thereof, such as acetate, trifluoroac- and tromethamine, but this is not intended to represent a etate, tartrate, maleate, succinate, citrate, benzoate, salicy- restriction. US 2016/0015712 A1 Jan. 21, 2016 12

[0150] Particular preference is given to hydrochloride, fers from the atomic mass or mass number of the atom which dihydrochloride, hydrobromide, maleate, mesylate, phos- usually occurs naturally. Examples of isotopes which are phate, sulfate and succinate. readily commercially available and which can be incorpo- [0151] The acid-addition salts of basic compounds of the rated into a compound of the formula I by well-known meth- formula I are prepared bringing the free base form into ods include isotopes of hydrogen, carbon, nitrogen, by oxygen,' contact with a sufficient amount of the desired acid, causing phos-phorus, fluo-rine and chlorine, for example H, H, C, ' ' ' ' ' the formation of the salt in a conventional manner. The free C N 0 0 'P P S F and Cl, respectively. base can be regenerated by bringing the salt form into contact [015S] A compound of the formula I, a prodrug, thereof or with a base and isolating the free base in a conventional a pharmaceutically acceptable salt of either which contains manner. The free base forms differ in a certain respect from one or more of the above-mentioned isotopes and/or other the corresponding salt forms thereof with respect to certain iso-topes of other atoms is intended to be part of the present physical properties, such as solubility in polar solvents; for invention. An isotope-labelled compound ofthe formula I can the purposes of the invention, however, the salts otherwise be used in a number of beneficial ways. For example, an correspond to the respective free base forms thereof. isotope-labelled compound of the formula I into which, for ' [0152] As mentioned, the pharmaceutically acceptable example, a radioisotope, such as H or C, has been incor- base-addition salts of the compounds of the formula I are porated is suitable for medicament and/or substrate tissue formed with metals or amines, such as alkali metals and distribution assays. These radioisotopes, i.e. tritium ( H) and alkaline earth metals or organic amines. Preferred metals are carbon-14 (' C), are particularly preferred owing to simple sodium, potassium, magnesium and calcium. Preferred preparation and excellent detectability. Incor-po-ra-tion of organic amines are N, N'-dibenzylethylenediamine, chlorop- heavier isotopes, for example deuterium ( H), into a com- rocaine, choline, diethanolamine, ethylenediamine, N-me- pound of the formula I has therapeutic advantages owing to thyl-D-glucamine and procaine. the higher metabolic stability of this isotope-labelled com- [0153] The base-addition salts of acidic compounds pound. Higher metabolic stability translates directly into an according to the invention are prepared by bringing the free increased in vivo half-life or lower dosages, which under acid form into contact with a sufficient amount of the desired most circumstances would represent a preferred embodi- base, causing the formation of the salt in a conventional ment ofthe present invention. An isotope-labelled compound manner. of the formula I can usually be prepared by carrying out the [0154] The free acid can be regenerated by bringing the salt procedures dis-closed in the synthesis schemes and the form into contact with an acid and isolating the free acid in a related description, in the example part and in the preparation conventional manner. The free acid forms differ in a certain part in the present text, replacing a non-isotope-labelled reac- respect from the corresponding salt forms thereof with tant by a readily available isotope-labelled reactant. respect to certain physical properties, such as solubility in [0159] Deuterium ( H) can also be incorporated into a com- polar solvents; for the purposes of the invention, however, the pound of the formula I for the purpose in order to manipulate salts otherwise correspond to the respective free acid forms the oxidative metabolism of the compound by way of the thereof. primary kinetic isotope effect. The primary kinetic isotope [0155] If a compound according to the invention contains effect is a change of the rate for a chemical reaction that more than one group which is capable of forming pharma- results from exchange of isotopic nuclei, which in turn is ceutically acceptable salts this the invention also of type, caused by the change in ground state energies necessary for encompasses multiple salts. Typical multiple salt forms covalent bond formation after this isotopic exchange. include, for bitartrate, diacetate, difumarate, dime- example, Exchange of a heavier isotope usually results in a lowering of disodium and but glumine, diphosphate, trihydrochloride, the ground state energy for a chemical bond and thus cause a this is not intended to represent a restriction. reduction in the rate in rate-limiting bond breakage. If the [0156] With regard to that stated above, it can be seen that bond breakage occurs in or in the vicinity of a saddle-point salt" the expression "pharmaceutically acceptable in the region along the coordinate of a multi-product reaction, the present connection is taken to mean an active ingredient product distribution ratios can be altered substantially. For which comprises a compound of the formula I in the form of explanation: if deuterium is bonded to a carbon atom at a one of its salts, in particular ifthis salt form imparts improved non-exchangeable position, rate di fferences ofk~~=2-7 are pharmacokinetic properties on the active ingredient com- typical. If this rate difference is successfully applied to a pared with the free form of the active ingredient or any other corn-pound of the formula I that is susceptible to oxidation, salt form of the active ingredient used earlier. The pharma- the profile of this compound in vivo can be drastically modi- ceutically acceptable salt form of the active ingredient can fied and result in improved pharmacokinetic properties. also provide this active ingredient for the first time with a [0160] When discovering and developing therapeutic desired pharmacokinetic property which it did not have ear- agents, the person skilled in the art attempts to optimise lier and can even have a positive influence on the pharmaco- pharmacokinetic parameters while retaining desirable in vitro dynamics of this active ingredient with respect to its thera- properties. It is reasonable to assume that many corn-pounds peutic efficacy in the body. with poor pharmacokinetic profiles are susceptible to oxida- tive metabolism. In vitro liver microsomal assays currently Isotopes available provide valuable information on the course of oxi- [0157] There is furthermore intended that a compound of dative metabolism of this type, which in turn permits the the formula I includes isotope-labelled forms thereof. An rational design of deuterated compounds ofthe formula I with isotope-labelled form of a compound of the formula I is improved stability through resistance to such oxidative meta- identical to this compound apart from the fact that one or bolism. Significant improvements in the pharmacokinetic more atoms of the compound have been replaced by an atom profiles of compounds of the formula I are thereby obtained, or atoms having an atomic mass or mass number which dif- and can be expressed quantitatively in terms of increases in US 2016/0015712 A1 Jan. 21, 2016 13

the in vivo half-life (t/2), concentration at maximum thera- [0166] Pharmaceutical formulations adapted for oral peutic effect (C ), area under the dose response curve administration can be administered as separate units, such as, (AUC), and F; and in terms of reduced clearance, dose and for example, capsules or tablets; powders or granules; solu- materials costs. tions or suspensions in aqueous or non-aqueous liquids; [0161] The following is intended to illustrate the above: a edible foams or foam foods; or oil-in-water liquid emulsions water-in-oil compound of the formula I which has multiple potential sites or liquid emulsions. of attack for oxidative metabolism, for example benzylic [0167] Thus, for example, in the case of oral administration hydrogen atoms and hydrogen atoms bonded to a nitrogen in the form of a tablet or capsule, the active-ingredient com- atom, is prepared as a series of analogues in which various ponent can be combined with an oral, non-toxic and pharma- combinations of hydrogen atoms are replaced by deuterium ceutically acceptable inert excipient, such as, for example, atoms, so that some, most or all ofthese hydrogen atoms have ethanol, glycerol, water and the like. Powders are prepared by been replaced by deuterium atoms. Half-life determinations comminuting the compound to a suitable fine size and mixing enable favourable and accurate determination ofthe extent of it with a pharmaceutical excipient comminuted in a similar the extent to which the improve-ment in resistance to oxida- manner, such as, for example, an edible carbohydrate, such tive metabolism has improved. In this way, it is deter-mined as, for example, starch or mannitol. A flavour, preservative, that the half-life of the parent compound can be extended by dispersant and dye may likewise be present. up to 100% as the result of deuterium-hydrogen exchange of [0168] Capsules are produced by preparing a powder mix- this type. ture as described above and filling shaped gelatine shells [0162] Deuterium-hydrogen exchange in a compound of therewith. Glidants and lubricants, such as, for example, the formula I can also be used to achieve a favourable modi- highly disperse silicic acid, talc, magnesium stearate, calcium fication of the metabolite spectrum of the starting compound stearate or polyethylene glycol in solid form, can be added to in order to diminish or eliminate undesired toxic metabolites. the powder mixture before the filling operation. A disinte- For example, if a toxic metabolite arises through oxidative grant or solubiliser, such as, for example, agar-agar, calcium carbon-hydrogen (C H) bond cleavage, it can reasonably be carbonate or sodium carbonate, may likewise be added in assumed that the deuterated analogue will greatly diminish or order to improve the availability of the medicament after the eliminate production of the unwanted metabolite, even if the capsule has been taken. particular oxidation is not a rate-determining step. Further [0169] In addition, if desired or necessary, suitable binders, information on the state of the art with respect to deuterium- lubricants and disintegrants as well as dyes can likewise be hydrogen exchange may be found, for example in Hanzlik et incorporated into the mixture. Suitable binders include al. , J. Org. Chem. 55, 3992-3997, 1990, Reider et al. , J. Org. starch, gelatine, natural sugars, such as, for example, glucose Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, or beta-lactose, sweeteners made from maize, natural and 1985, Gillette et al, Biochemistry 33(10) 2927-2937, 1994, synthetic rubber, such as, for example, acacia, tragacanth or and Jarman et al. Carcinogenesis 16(4), 683-688, 1993. sodium alginate, carboxymethylcellulose, polyethylene gly- [0163] The invention furthermore relates to medicaments col, waxes, and the like. The lubricants used in these dosage comprising at least one compound of the formula I and/or forms include sodium oleate, sodium stearate, magnesium pharmaceutically acceptable salts, solvates, tautomers and stearate, sodium benzoate, sodium acetate, sodium chloride stereoi somers thereof, including mixtures thereof in all ratios, and the like. The disintegrants include, without being and optionally excipients and/or adjuvants. restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by, for Pharmaceutical formulations can be administered in [0164] example, preparing a powder mixture, granulating or dry- the form units which a predetermined of dosage comprise pressing the mixture, adding a lubricant and a disintegrant amount of active ingredient per dosage unit. Such a unit can and pressing the entire mixture to give tablets. A powder comprise, for example, 0.5 to I preferably I to 700 mg g, mg mixture is prepared by mixing the compound comminuted in mg, particularly preferably 5 mg to 100 mg, of a compound a suitable manner with a diluent or a base, as described above, according to the invention, on the condition depending and optionally with a binder, such as, for example, carboxym- treated, the method of administration and the age, weight and ethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, condition the or pharmaceutical formulations can of patient, a dissolution retardant, such as, for example, paraffin, an be administered in the form units which a of dosage comprise absorption accelerator, such as, for example, a quaternary predetermined amount of active ingredient per dosage unit. salt, and/or an absorbant, such as, for example, bentonite, Preferred dosage unit formulations are those which comprise kaolin or dicalcium phosphate. The powder mixture can be a daily dose or part-dose, as indicated above, or a correspond- granulated by wetting it with a binder, such as, for example, ing fraction thereof of an active ingredient. Furthermore, syrup, starch paste, acadia mucilage or solutions of cellulose pharmaceutical formulations of this type can be prepared or polymer materials and pressing it through a sieve. As an which known in the pharmaceu- using a process is generally alternative to granulation, the powder mixture can be run tical art. through a tabletting machine, giving lumps of non-uniform [0165] Pharmaceutical formulations can be adapted for shape, which are broken up to form granules. The granules administration via any desired suitable method, for example can be lubricated by addition of stearic acid, a stearate salt, by oral (including buccal or sublingual), rectal, nasal, topical talc or mineral oil in order to prevent sticking to the tablet (including buccal, sublingual or transdermal), vaginal or casting moulds. The lubricated mixture is then pressed to give parenteral (including subcutaneous, intramuscular, intrave- tablets. The compounds according to the invention can also be nous or intradermal) methods. Such formulations can be pre- combined with a free-flowing inert excipient and then pressed pared using all processes known in the pharmaceutical art by, directly to give tablets without carrying out the granulation or for example, combining the active ingredient with the excipi- dry-pressing steps. A transparent or opaque protective layer ent(s) or adjuvant(s). consisting of a shellac sealing layer, a layer of sugar or poly- US 2016/0015712 A1 Jan. 21, 2016 14

mer material and a gloss layer of wax may be present. Dyes [0177] Pharmaceutical formulations adapted for topical can be added to these coatings in order to be able to differen- application to the eye include eye drops, in which the active tiate between different dosage units. ingredient is dissolved or suspended in a suitable carrier, in [0170] Oral liquids, such as, for example, solution, syrups particular an aqueous solvent. and elixirs, can be prepared in the form ofdosage units so that [0178] Pharmaceutical formulations adapted for topical a given quantity comprises a pre-specified amount of the application in the mouth encompass lozenges, pastilles and compound. Syrups can be prepared by dissolving the com- mouthwashes. pound in an aqueous solution with a suitable flavour, while [0179] Pharmaceutical formulations adapted for rectal elixirs are prepared using a non-toxic alcoholic vehicle. Sus- administration can be administered in the form of supposito- pensions can be formulated by dispersion ofthe compound in ries or enemas. a non-toxic vehicle. Solubilisers and emulsifiers, such as, for [0180] Pharmaceutical formulations adapted for nasal example, ethoxylated isostearyl alcohols and polyoxyethyl- administration in which the carrier substance is a solid com- ene sorbitol ethers, preservatives, flavour additives, such as, prise a coarse powder having a particle size, for example, in for example, peppermint oil or natural sweeteners or saccha- the range 20-500 microns, which is administered in the man- rin, or other artificial sweeteners and the like, can likewise be ner in which snuff is taken, i.e. by rapid inhalation via the added. nasal passages from a container containing the powder held [0171] The dosage unit formulations for oral administra- close to the nose. Suitable formulations for administration as tion can, if desired, be encapsulated in microcapsules. The nasal spray or nose drops with a liquid as carrier substance formulation can also be prepared in such a way that the encompass active-ingredient solutions in water or oil. release is extended or retarded, such as, for example, by [0181] Pharmaceutical formulations adapted for adminis- coating or embedding of particulate material in polymers, tration by inhalation encompass finely particulate dusts or wax and the like. mists, which can be generated by various types ofpressurised dispensers with aerosols, nebulisers or insufllators. [0172] The compounds ofthe formula I and salts, solvates, tautomers and stereoisomers thereof can also be administered [0182] Pharmaceutical formulations adapted for vaginal in the form of liposome delivery systems, such as, for administration can be administered as pessaries, tampons, example, small unilamellar vesicles, large uni lamellar creams, gels, pastes, foams or spray formulations. vesicles and multilamellar vesicles. Liposomes can be [0183] Pharmaceutical formulations adapted for parenteral formed from various phospholipids, such as, for example, administration include aqueous and non-aqueous sterile cholesterol, stearylamine or phosphatidylcholines. injection solutions comprising antioxidants, buffers, bacte- riostatics and solutes, by means of which the formulation is [0173] The compounds of the formula I and the salts, sol- rendered isotonic with the blood ofthe recipient to be treated; vates, tautomers and stereoisomers thereof can also be deliv- and aqueous and non-aqueous sterile suspensions, which may ered using monoclonal antibodies as individual carriers to comprise suspension media and thickeners. The formulations which the compound molecules are coupled. The compounds can be administered in single-dose or multidose containers, can also be coupled to soluble polymers as targeted medica- for example sealed ampoules and vials, and stored in freeze- ment carriers. Such polymers may encompass polyvinylpyr- dried (lyophilised) state, so that only the addition ofthe sterile rolidone, pyran copolymer, polyhydroxypropylmethacryla- carrier liquid, for example water for injection purposes, midophenol, polyhydroxy-ethylaspartamidophenol or immediately before use is necessary. Injection solutions and polyethylene oxide polylysine, substituted by palmitoyl radi- suspensions prepared in accordance with the recipe can be cals. The compounds may furthermore be coupled to a class prepared from sterile powders, granules and tablets. of biodegradable polymers which are suitable for achieving controlled release of a medicament, for example polylactic [0184] It goes without saying that, in addition to the above acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, particularly mentioned constituents, the formulations may usual in the art with polyorthoesters, polyacetals, polydihydroxypyrans, polycy- also comprise other agents respect to the particular formulation; formula- anoacrylates and crosslinked or amphipathic block copoly- type of thus, for example, mers of hydrogels. tions which are suitable for oral administration may comprise flavours. [0174] Pharmaceutical formulations adapted for transder- [0185] A therapeutically effective amount of a compound mal administration can be administered as independent plas- oftheformulaIdependsonanumberoffactors, including, for ters for extended, close contact with the epidermis of the example, the age and weight of the animal, the precise con- recipient. Thus, for example, the active ingredient can be dition that requires treatment, and its severity, the nature of delivered from the plaster by iontophoresis, as described in the formulation and the method of administration, and is general terms in Pharmaceutical Research, 3(6), 318 (1986). ultimately determined by the treating doctor or vet. However, [0175] Pharmaceutical compounds adapted for topical an effective amount of a compound according to the invention administration can be formulated as ointments, creams, sus- is generally in the range from 0.I to 100mg/kg ofbody weight pensions, lotions, powders, solutions, pastes, gels, sprays, of the recipient (mammal) per day and particularly typically aerosols or oils. in the range from I to 10mg/kg of body weight per day. Thus, [0176] For the treatment of the eye or other external tissue, the actual amount per day for an adult mammal weighing 70 for example mouth and skin, the formulations are preferably kg is usually between 70 and 700 mg, where this amount can applied as topical ointment or cream. In the case of formula- be administered as a single dose per day or usually in a series tion to give an ointment, the active ingredient can be of part-doses (such as, for example, two, three, four, five or employed either with a paraffinic or a water-miscible cream six) per day, so that the total daily dose is the same. An base. Alternatively, the active ingredient can be formulated to effective amount of a salt, solvate, tautomer and stereoisomer give a cream with an oil-in-water cream base or a water-in-oil thereof can be determined as the fraction of the effective base. amount of the compound according to the invention per se. It US 2016/0015712 A1 Jan. 21, 2016 15

can be assumed that similar doses are suitable for the treat- ing of the individual components of the treatment. Combina- ment of other conditions mentioned above. tion products ofthis type employ the compounds according to [01S6] The disclosed compounds of the formula I can be the invention. administered in combination with other known therapeutic [0207] The invention furthermore relates to medicaments agents including agents for the treatment of RA (rheumatoid comprising at least one compound of the formula I and/or arthritis). As used here, the term "agents for the treatment of pharmaceutically acceptable salts, solvates, tautomers and RA" relates to any agent which is administered to a patient stereoisomers thereof, including mixtures thereof in all ratios, with RA for the purposes of treating the RA. and at least one further medicament active ingredient. [01S7] The medicaments below are preferably, but not [020S] The invention also relates to a set (kit) consisting of exclusively, combined with the compounds of the formula I: separate packs of 1.NSAIDs (non-steroidal anti-inflammatory drugs) and anal- [0209] (a) an effective amount of a compound of the for- gesics mula I and/or pharmaceutically acceptable salts, solvates, 2. Glucocorticoids (low oral doses) tautomers and stereoisomers thereof, including mixtures 3. Conventional disease-modifying antirheumatic drugs thereof in all ratios, and (DMARDs) [0210] (b) an effective amount of a further medicament [01SS] Methotrexate active ingredient. [01S9] Leflunomide [0211] The set comprises suitable containers, such as boxes, individual bottles, or ampoules. The set for [0190] Sulfasalazine bags may, example, comprise separate ampoules, each containing an [0191] Hydroxycloroquine effective amount of a compound of the formula I and/or [0192] Azathioprine pharmaceutically acceptable salts, solvates, tautomers and [0193] Ciclosporin stereoisomers thereof, including mixtures thereof in all ratios, Minocycline [0194] and an effective amount of a further medicament active ingre- [0195] Gold — dient in dissolved or lyophilised form. 4. Biologic response modifiers (BRMs) &target molecules/ [0212] "Treating" as used herein, means an alleviation, in immune cells involved in the inflammatory and process, whole or in part, of symptoms associated with a disorder or include the following agents: disease, or slowing, or halting of further progression or wors- [0196] TNF inhibitors ening ofthose symptoms, or prevention or prophylaxis ofthe [0197] etanercept (Enbrel) disease or disorder in a subject at risk for developing the [019S] infliximab (Remicade) disease or disorder. [0199] adalimumab (Humira) [0213] The term "effective amount" in connection with a [0200] B-cell-directed therapy compound of formula (I) can mean an amount capable of [0201] rituximab (Rituxan) alleviating, in whole or in part, symptoms associated with a [0202] T-cell/B-cell coactivation signal inhibitor disorder or disease, or slowing or halting further progression [0203] abatacept (Orencia) or worsening of those symptoms, or preventing or providing [0204] IL-I receptor antagonist prophylaxis for the disease or disorder in a subject having or at risk for developing a disease disclosed herein, such as [0205] anakinra (Kineret) inflammatory conditions, immunological conditions, cancer, metabolic conditions, neurodegenerative conditions, chronic MECHANISM OF ACTION infections or conditions treatable or preventable by inhibition of a kinase or a kinase pathway, in one embodiment, the Golimumab Fully humanized monoclonal GCN2 pathway. In another embodiment this relates to con- antibody to TNF ditions treatable or preventable inhibition of a kinase or a Certolizumab pegol Anti-TNF agent with just the Fab by portion attached to the kinase pathway, from the group of GCN2, FMS (CSFIR), polyethylene glycol FLT3 or FLT4 or combinations thereof. In one embodiment Tocilizumab Humanized monoclonal anti-IL-6 an effective amount of a compound of formula (I) is an antibody that binds to the soluble amount that inhibits a kinase in a cell, such as, for example, in and membrane-expresses IL-6 subject' receptor vitro or in vivo. In some embodiments, the effective amount Ocrelizumab Humanized-second generation ofthe compound of formula (I) inhibits the kinase in a cell by anti-CD20 antibody that depletes B 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99%, cells compared to the activity ofthe kinase in an untreated cell. The Ofatumumab Human monoclonal anti-CD20 IgGI antibody effective amount ofthe compound offormula (I), for example Denosumab Fully humanized monoclonal in a pharmaceutical composition, may be at a level that will antibody that binds to and inhibits exercise the desired effect; for example, about 0.005 mg/kg of the receptor activator for nuclear a s weight to about 10 o a s factor-kB ligand subject' body mg/kg f body TRU-016 New class of CD20-directed weight in unit dosage for both oral and parenteral adminis- protein therapeutics tration. Oral small molecules Cytoplasmic targets (JAK, Syk, MAP kinase USE inhibitors) Tolerogens (dnaJPll Immunotherapy based on T-cell [0214] The present compounds are suitable as pharmaceu- tolerization tical active ingredients for mammals, especially for humans, in the treatment of immune modulatory and stress response [0206] A combined treatment of this type can be achieved kinase-induced diseases. These diseases include neoplastic with the aid of simultaneous, consecutive or separate dispens- malignancies including, but without being limited to, solid US 2016/0015712 A1 Jan. 21, 2016 16

tumor cancers, cancers of the lymphatic or blood system, the treatment or prevention of a immune-modulatory or stress proliferation oftumour cells, pathological neovascularisation response kinase-induced disease or a immune-modulatory or (or angiogenesis) which promotes the growth of solid stress response kinase-induced condition in a mammal, in tumours, neurodegenerative diseases (Alzheimer, demyeli- which to this method a therapeutically effective amount of a nating core disorders multiple sclerosis and the like), immune compound according to the invention is administered to a sick related disorders like arthritis, psoriasis, lupus, or other mammal in need of such treatment. The therapeutic amount autoimmune diseases as well as chronic infections. varies according to the specific disease and can be determined [0215] The present invention encompasses the use of the by the person skilled in the art without undue effort. compounds of the formula I and/or physiologically accept- [0222] The present invention also encompasses the use able salts and solvates thereof for the preparation of a medi- compounds of the formula I and/or physiologically accept- cament for the treatment or prevention of cancer. Preferred able salts and solvates thereof for the preparation of a medi- carcinomas for the treatment originate from the group cere- cament for the treatment or prevention of retinal vascularisa- bral carcinoma, urogenital tract carcinoma, carcinoma of the tion. The expression "immune-modulatory or stress response lymphatic system, stomach carcinoma, laryngeal carcinoma kinase-induced diseases or conditions" refers to pathological and lung carcinoma. A further group of preferred forms of conditions that depend on the activity of one or more cancer are monocytic leukaemia, lung adenocarcinoma, immune-modulatory or stress response kinases. immune- small-cell lung carcinomas, pancreatic cancer, glioblasto- modulatory or stress response kinases either directly or indi- mas, melanomas and breast carcinoma. A further group of rectly participate in the signal transduction pathways of a preferred forms of cancer include, but is not limited to, cer- variety of cellular activities, including proliferation, adhesion vical cancer, neuroblastoma, testicular cancer, macroglobu- and migration and differentiation. Diseases associated with linemia and sarcomas. immune-modulatory or stress response kinase activity [0216] Also encompassed is the use of the compounds include neoplastic malignancies (solid tumor cancers, can- according to Claim 1 according to the invention and/or physi- cers of the lymphatic or blood system and the like), of neu- ologically acceptable salts and solvates thereof for the prepa- rodegenerative diseases, immune related disorders like arthri- ration of a medicament for the treatment or prevention of a tis, psoriasis, lupus, multiple sclerosis or other autoimmune neurological disorder, particularly a neurodegenerative dis- diseases as well as chronic infections. ease, for example a disease caused by axonal degeneration or [0223] The present invention specifically relates to com- by protein plaque deposition. Neurodegenerative diseases pounds of the formula I and pharmaceutically acceptable include, for example, demyelinating core disorders, such as salts, solvates, tautomers and stereoisomers thereof, includ- multiple sclerosis, acute transverse myelitis, amyotrophic lat- ing mixtures thereof in all ratios, for the use for the treatment eral sclerosis, Creutzfeldt-Jakob disease or Alzheimer dis- of diseases in which the inhibition, regulation and/or modu- ease. lation inhibition of GCN2 plays a role. [0217] Further encompassed is the use of the compounds according to Claim 1 according to the invention and/or physi- [0224] The present invention specifically relates to com- ologically acceptable salts and solvates thereof for the prepa- pounds of the formula I and pharmaceutically acceptable ration of a medicament for the treatment of chronic infec- salts, solvates, tautomers and stereoisomers thereof, includ- tions. Such a chronic infection could relate to parasites like ing mixtures thereof in all ratios, for the use for the inhibition lei shmania to leprosy or to viral infection by HIV and the like. of GCN2. [021S] Further encompassed is the use of the compounds [0225] The present invention specifically relates to com- according to Claim 1 according to the invention and/or physi- pounds of the formula I and pharmaceutically acceptable ologically acceptable salts and solvates thereof for the prepa- salts, solvates, tautomers and stereoisomers thereof, includ- ration of a medicament for the treatment or prevention of a ing mixtures thereof in all ratios, for the use for the treatment disease in which angiogenesis is implicated. of neoplastic malignancies (solid tumor cancers, cancers of [0219] Such a disease in which angiogenesis is implicated the lymphatic or blood system and the like), of neurodegen- is an ocular disease, such as retinal vascularisation, diabetic erative diseases, immune related disorders like arthritis, pso- retinopathy, age-induced macular degeneration and the like. riasis, lupus, multiple sclerosis or other autoimmune diseases [0220] The present invention encompasses the use of the as well as chronic infections. compounds of the formula I and/or physiologically accept- [0226] Especial preference is given to the use for the treat- able salts and solvates thereof for the preparation of a medi- ment of a disease where the disease is a neoplastic malignan- cament for the treatment or prevention of immune related cies. disorder like ankylosing spondylitis, arthritis, aplastic ane- [0227] The neoplastic malignancies is preferably selected mia, Behcet's disease, I diabetes mellitus, graft-versus- type from the group of tumours of the lung, squamous epithelium, host disease, Graves' disease, autoimmune hemolytic ane- the bladder, the stomach, the kidneys, of head and neck, the mia, Wegener's granulomatosis, syndrome, hyper IgE oesophagus, the cervix, the thyroid, the intestine, the liver, the idiopathic thrombocytopenia purpura, rheumatoid arthritis, brain, the prostate, the urogenital tract, the lymphatic system, Crohn's disease, multiple sclerosis, Myasthenia gravis, pso- the stomach and/or the larynx. riasis, and lupus, among other autoimmune diseases. It might also be used treat organ rejection, bone marrow transplant [022S] The neoplastic malignancies is furthermore prefer- rejection, non-myeloablative bone marrow transplant rejec- ably selected from the group lung adenocarcinoma, small- tion, enhance bone marrow engraftment after non-myeloab- cell lung carcinomas, pancreatic cancer, glioblastomas, colon lative conditioning regimens, and combinations thereof carcinoma and breast carcinoma. [0221] Also encompassed is the use of the compounds of [0229] Preference is furthermore given to the use for the the formula I and/or physiologically acceptable salts and treatment of a neoplastic malignancies of the blood and solvates thereof for the preparation of a medicament for the immune system, preferably for the treatment of a tumour US 2016/0015712 A1 Jan. 21, 2016 17

selected from the group of acute myeloid leukaemia, chronic include, but are not limited to, non-ANCA (anti-neutrophil myeloid leukaemia, acute lymphatic leukaemia and/or cytoplasmic autoantibody) vasculitis (e.g., wherein GCN2 chronic lymphatic leukaemia. function is associated with neutrophil adhesion, diapedesis [0230] The present invention specifically relates to meth- and/or activation), psoriasis, asthma, allergic rhinitis, allergic ods for treating or preventing an inflammatory condition, conjunctivitis, chronic urticaria, hives, anaphylaxis, bronchi- immunological condition, autoimmune condition, allergic tis, chronic obstructive pulmonary disease, cystic fibrosis, condition, rheumatic condition, thrombotic condition, can- inflammatory bowel disease, irritable bowel syndrome, gout, cer, infection, neurodegenerative disease, neuroinflammatory Crohn's disease, mucous colitis, ulcerative colitis, allergy to disease, cardiovascular disease or metabolic condition, com- intestinal antigens (such as gluten enteropathy), diabetes prising administering to a subject in need thereof an effective (e.g., Type I diabetes and Type II diabetes) and obesity. In amount of a compound of formula I or a pharmaceutically some embodiments, the inflammatory condition is a derma- acceptable salt, tautomer, stereoisomer or solvate thereof. tologic condition, such as, for example, psoriasis, urticaria, [0231] In another aspect provided herein are methods of hives, eczema, scleroderma, or dermatitis. In other embodi- inhibiting a kinase in a cell expressing said kinase, compris- ments, the inflammatory condition is an inflammatory pul- ing contacting said cell with an effective amount of a com- monary condition, such as, for example, asthma, bronchitis, pound of formula I or a pharmaceutically acceptable salt, chronic obstructive pulmonary disease (COPD), or adult/ tautomer, stereoisomer or solvate thereof. In one embodiment acute respiratory distress syndrome (ARDS). In other the kinase is GCN2 or mutants or isoforms thereof, or com- embodiments, the inflammatory condition is a gastrointesti- binations of two or more thereof. nal condition, such as, for example, inflammatory bowel dis- [0232] Representative immunological conditions that com- ease, ulcerative colitis, Crohn' s disease, idiopathic inflamma- pounds of formula I are useful for treating or preventing tory bowel disease, irritable bowel syndrome, or spastic include, but are not limited to, Behcet's syndrome, non-al- colon. lergy mast cell diseases (e.g., mastocytosis and treatment of [0237] Representative infections that compounds of for- anaphylaxis), ankylosing spondylitis, osteoarthritis, rheuma- mula I are useful for treating or preventing include, but are not toid arthritis (RA), multiple sclerosis, lupus, inflammatory limited to, bacterial, parasitic, prion, viral infections or hel- bowel disease, ulcerative colitis, Crohn's disease, myasthenia minth infestation. gravis, Grave's disease, transplant rejection, humoral trans- Representative cancers that compounds formula I plant rejection, non-humoral transplant rejection, cellular [023S] of are useful for treating or preventing include, but are not lim- transplant rejection, immune thrombocytopenic purpura ited to, cancer of the head, neck, eye, mouth, throat, esopha- (ITP), idiopathic thrombocytopenic purpura, diabetes, immu- bronchus, nological response to bacterial, parasitic, helminth infestation gus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder, uterine, cervix, or viral infection, eczema, dermatitis, graft versus host dis- breast, ovaries, testicles or other reproductive ease, Goodpasture's disease, hemolytic disease of the new- organs, skin, thyroid, blood, nodes, liver, pancreas, brain, born, autoimmune hemolytic anemia, anti-phospholipid syn- lymph kidney, central nervous solid tumors and blood-borne drome, ANCA-associated vasculitis, Churg-Strauss system, tumors. syndrome, Wegeners granulomatosus, pemphigus vulgaris, serum sickness, mixed cryoglobulinemia, peripheral neur- [0239] Representative cardiovascular diseases that com- opathy associated with IgM antibody, microscopic polyangii- pounds of formula I are useful for treating or preventing tis, Hashimoto's thyroiditis, Sjogrens syndrome, fibrosing include, but are not limited to, restenosis, atherosclerosis and conditions (such as those dependent on the innate or adaptive its consequences such as stroke, myocardial infarction, immune systems or local mesenchyma cells) or primary bil- ischemic damage to the heart, lung, gut, kidney, liver, pan- iary cirrhosis. creas, spleen or brain. [0233] Representative autoimmune conditions that com- [0240] Representative metabolic conditions that com- pounds of formula I are useful for treating or preventing pounds of formula I are useful for treating or preventing include, but are not limited to, autoimmune hemolytic anemia include, but are not limited to, obesity and diabetes (e.g., Type (AIHA), Behcet's syndrome, Crohn's disease, type I diabe- I and II diabetes). In a particular embodiment, provided tes, Goodpasture's disease, Grave's disease, Hashimoto's herein are methods for the treatment or prevention of insulin thyroiditis, idiopathic thrombocytopenic purpura, lupus, resistance. In certain embodiments, provided herein are multiple sclerosis, amyotrophic lateral sclerosis, myasthenia methods for the treatment or prevention of insulin resistance gravis, pemphigus vulgaris, primary biliary cirrhosis, rheu- that leads to diabetes (e.g., Type II diabetes). In another matoid arthritis, scleroderma, Sjogren's syndrome, ulcerative embodiment, provided herein are methods for the treatment colitis, or Wegeners granulomatosus. or prevention of syndrome X or metabolic syndrome. In [0234] Representative allergic conditions that compounds another embodiment, provided herein are methods for the of formula I are useful for treating or preventing include, but treatment or prevention of Type II diabetes, Type I diabetes, are not limited conjunc- to, anaphylaxis, hay fever, allergic slow-onset Type I diabetes, diabetes insipidus (e.g., neuro- tivitis, allergic rhinitis, allergic asthma, atopic dermatitis, genic diabetes insipidus, nephrogenic diabetes insipidus, dip- eczema, urticaria, mucosal disorders, tissue disorders and sogenic diabetes insipidus, or gestagenic diabetes insipidus), certain gastrointestinal disorders. diabetes mellitus, gestational diabetes mellitus, polycystic [0235] Representative rheumatic conditions that com- ovarian syndrome, maturity-onset diabetes, juvenile diabetes, pounds of formula I are useful for treating or preventing insulin-dependant diabetes, non-insulin dependant diabetes, include, but are not limited to, rheumatoid arthritis, gout, malnutrition-related diabetes, ketosis-prone diabetes, predia- ankylosing spondylitis, or osteoarthritis. betes (e.g., impaired glucose metabolism), cystic fibrosis [0236] Representative inflammatory conditions that com- related diabetes, hemochromatosis and ketosis-resistant dia- pounds of formula I are useful for treating or preventing betes. US 2016/0015712 A1 Jan. 21, 2016 18

[0241] Representative neurodegenerative and neuroin- treatment and/or prevention of diseases selected from the flammatory diseases that compounds of formula I are useful group leisltmania, mycobacteria, including M. leprae, M. for treating or preventing include, but are not limited to, tuberculosis and/or M. avium, leisltmania, plasmodium, Huntington's disease, Alzheimer's disease, viral (e.g., HIV) human immunodeficiency virus, Epstein Barr virus, Herpes or bacterialassociated encephalitis and damage. simplex virus, hepatitis C virus. [0242] In another embodiment, provided herein are meth- [0250] Moreover, the present invention specifically relates ods for the treatment or prevention of fibrotic diseases and to compounds of the formula I and pharmaceutically accept- disorders. In a particular embodiment, provided herein are able salts, solvates, tautomers and stereoisomers thereof, methods for the treatment or prevention of idiopathic pulmo- including mixtures thereof in all ratios, for the use for the nary fibrosis, myelofibrosis, hepatic fibrosis, steatofibrosis inhibition of GSK3. and steatohepatitis. [0251] The disclosed compounds of the formula I can be [0243] In another embodiment, provided herein are meth- administered in combination with other known therapeutic ods for the treatment or prevention ofdiseases associated with agents, including anticancer agents. As used here, the term thrombotic events such as but not limited to atherosclerosis, "anticancer agent" relates to any agent which is administered myocardial infarction and ischemic stroke. to a patient with cancer for the purposes oftreating the cancer. [0244] The present invention specifically relates to com- [0252] The anti-cancer treatment defined herein may be pounds of the formula I and pharmaceutically acceptable applied as a sole therapy or may involve, in addition to the salts, solvates, tautomers and stereoisomers thereof, includ- compound of the invention, conventional surgery or radio- ing mixtures thereof in all ratios, for the use for the treatment therapy or chemotherapy. Such chemotherapy may include and/or prevention of inflammatory conditions, immunologi- one or more of the following categories of anti-tumour cal conditions, autoimmune conditions, allergic conditions, agents: rheumatic conditions, thrombotic conditions, cancer, infec- (I) antiproliferative/antineoplastic/DNA-damaging agents tions, neurodegenerative diseases, neuroinflammatory dis- and combinations thereof, as used in medical oncology, such eases, cardiovascular diseases, and metabolic conditions, the as alkylating agents (for example cis-platin, carboplatin, methods comprising administering to a subject in need cyclophosphamide, nitrogen mustard, melphalan, chloroam- thereof an effective amount of a compound of claim 1. bucil, busulphan and nitrosoureas); antimetabolites (for [0245] Moreover, the present invention specifically relates example antifolates such as fluoropyrimidines like 5-fluorou- to compounds for the use for the treatment and/or prevention racil and tegafur, raltitrexed, methotrexate, cytosine arabino- of cancer, where the cancer to be treated is a solid tumour or side, hydroxyurea and gemcitabine); antitumour antibiotics a tumour of the blood and immune system. (for example anthracyclines, like adriamycin, bleomycin, [0246] Moreover, the present invention specifically relates doxorubicin, daunomycin, epirubicin, idarubicin, mitomy- to compounds, for the use for the treatment and/or prevention cin-C, dactinomycin and mithramycin); antimitotic agents of cancer, where the where the tumour originates from the (for example vinca alkaloids, like vincristine, vinblastine, group of acute myeloid leukaemia, chronic myeloid leu- vindesine and vinorelbine, and taxoids, like taxol and taxo- kaemia, acute lymphatic leukaemia and/or chronic lymphatic tere); topoisomerase inhibitors (for example epipodophyllo- leukaemia. toxins, like etoposide and teniposide, amsacrine, topotecan, [0247] Moreover, the present invention specifically relates irinotecan and camptothecin) and cell-differentiating agents to compounds, for the use for the treatment and/or prevention (for example all-trans-retinoic acid, 13-cisretinoic acid and ofcancer, where the solidtumour originates from the group of fenretinide); tumours of the epithelium, the bladder, the stomach, the kid- (ii) cytostatic agents, such as antioestrogens (for example neys, ofhead and neck, the esophagus, the cervix, the thyroid, tamoxifen, toremifene, raloxifene, droloxifene and iodoxy- the intestine, the liver, the brain, the prostate, the uro-genital fene), oestrogen receptor downregulators (for example ful- tract, the lymphatic system, the stomach, the larynx, the vestrant), antiandrogens (for example bicalutamide, fluta- bones, including chondosarcoma and Ewing sarcoma, germ mide, nilutamide and cyproterone acetate), LHRH cells, including embryonal tissue tumours, and/or the lung, antagonists or LHRH agonists (for example goserelin, leu- from the group of monocytic leukaemia, lung adenocarci- prorelin and buserelin), progesterones (for example mege- noma, small-cell lung carcinomas, pancreatic cancer, glio- strol acetate), aromatase inhibitors (for example as anastro- blastomas, neurofibroma, angiosarcoma, breast carcinoma zole, letrozole, vorazole and exemestane) and inhibitors of and/or maligna melanoma. So.-reductase, such as finasteride; [0248] Moreover, the present invention specifically relates (iii) agents which inhibit cancer cell invasion (for example to for the use for the treatment and/or prevention of diseases metalloproteinase inhibitors, like marimastat, and inhibitors selected from the group rheumatoid arthritis, systemic lupus, of urokinase plasminogen activator receptor function); asthma, multiple sclerosis, osteoarthritis, ischemic injury, (iv) inhibitors of growth factor function, for example such giant cell arteritis, inflammatory bowel disease, diabetes, cys- inhibitors include growth factor antibodies, growth factor tic fibrosis, psoriasis, Sjogrens syndrom and transplant organ receptor antibodies (for example the anti-erbb2 antibody tras- rej ection. tuzumab [Herceptin™] and the anti-erbbl antibody cetux- [0249] Moreover, the present invention specifically relates imab [C225]), farnesyl transferase inhibitors, tyrosine kinase to compounds for the use for the treatment and/or prevention inhibitors and serine/threonine kinase inhibitors, for example of diseases selected from the group Alzheimer's disease, inhibitors of the epidermal growth factor family (for example Down's syndrome, hereditary cerebral hemorrhage with EGFR family tyrosine kinase inhibitors, such as N-(3-chloro- amyloidosis-Dutch Type, cerebral amyloid angiopathy, 4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy) Creutzfeldt-Jakob disease, frontotemporal dementias, Hun- quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphe- tingon's disease, Parkinson's disease. Moreover, the present nyl)-6, 7-bis(2-methoxyethoxy)quinazolin-4-amine (erlo- invention specifically relates to compounds for the use for the tinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophe- US 2016/0015712 A1 Jan. 21, 2016 19

nyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI (viii) gene therapy approaches, including, for example, 1033)),for example inhibitors of the platelet-derived growth approaches for replacement of aberrant genes, such as aber- factor family and for example inhibitors of the hepatocyte rant p53 or aberrant BRCAI or BRCA2, GDEPT (gene- growth factor family; directed enzyme pro-drug therapy) approaches, such as those using cytosine deaminase, thymidine kinase or a bacterial (v) antiangiogenic agents, such as those which inhibit the nitroreductase enzyme, and approaches for increasing patient effects ofvascular endothelial growth factor, (for example the tolerance to chemotherapy or radiotherapy, such as multi- anti-vascular endothelial cell growth factor antibody bevaci- drug resistance gene therapy; and zumab [Avastin™],compounds such as those disclosed in (ix) immunotherapy approaches, including, for example, ex- published international patent applications WO 97/22596, vivo and in-vivo approaches for increasing the immunogenic- WO 97/30035, WO 97/32856 and WO 98/13354) and com- ity of patient tumour cells, such as transfection with cytok- pounds that work by other mechanisms (for example lino- ines, such as interleukin 2, interleukin 4 or granulocyte- mide, inhibitors of integrin (uv[33 function and angiostatin); macrophage colony stimulating factor, approaches for (vi) vessel-damaging agents, such as combretastatin A4 and decreasing T-cell anergy, approaches using trans fected compounds disclosed in international patent applications WO immune cells, such as cytokine-transfected dendritic cells, 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO approaches using cytokine-trans fected tumour cell lines, and 02/04434 and WO 02/08213; approaches using anti-idiotypic antibodies. (vii) antisense therapies, for example those which are directed [0253] The medicaments from Table I below are prefer- to the targets listed above, such as ISIS 2503, an anti-Ras ably, but not exclusively, combined with the compounds of antisense; the formula I.

TABLE I

Alkylating agents Cyclophosphamide Lomustine Busulfan Procarbazine Ifosfamide Altretamine Melphalan Estramustine phosphate Hexamethylmelamine Mechloroethamine Thiotepa Streptozocin chloroambuci1 Temozolomide Dacarbazine Semustine Carmustine Platinum agents Cisplatin Carboplatin Oxaliplatin ZD-0473 (AnorMED1 Spiroplatin Lob ap latin (Aetemai Carboxyphthalatoplatinum Satraplatin (Johnson Tetrap latin Matthey) Ormiplatin BBR-3464 Iproplatin (Hoffmann-La Roche) SM-11366 (Sumitomoi AP-6280 (Accessi Antimetab o lite s Azacytidine Tomudex Gemcitabine Trimetrexate Capecitabine Deoxyco formycin 6-fluorouraci Fludarabine Floxuridine Pentostatin 2-chlorodesoxyadenosine Raltitrexed 6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGeni Cytarabine Clofarabine (Bioenvisioni 2-fluorodesoxycytidine Irofulven (MGI Pharrnai Methotrexate DMDC (Hoffmann-La Idatrexate Roche) Ethynylcytidine (Taihoi Topoisomerase Amsacrine Rubitecan (SuperGeni inhibitors Epirubicin Exatecan mesylate Etoposide (Daiichii Teniposide or Quinamed (ChemGenexi mitoxantrone Gimatecan (Sigma- Taui

Irinotecan (CPT-I I 1 Diflomotecan (Beaufour- 7-efltyi-10- Ipseni hydroxycamptothecin TAS-103 (Taihoi Topotecan Elsamitrucin (Specuumi Dexrazoxanet J-107088 (Merck & Coi (Tope Target) BNP-1360 (BioNumeriki Pixantrone (Novuspharrnai CKD-602 (Chong Kun Rebeccamycin analogue Dang) (Exefixisi KW-2170 (Kyowa Hakkoi BBR-3676 (Novuspharrnai Antitumour Dactinomycin (Actinomycin Amonafide antibiotics Di Azonafide Doxorubicin (Adriamycini Anthrapyrazole Deoxyrubicin Oxantrazole Valrubicin Losoxantrone US 2016/0015712 A1 Jan. 21, 2016 20

TABLE 1-continued

Daunorubicin Bleomycin sulfate (Daunomycini (B!enoxani Epirubicin Bleomycinic acid Therarubicin Bleomycin A Idarubicin Bleomycin B Rubidazon Mitomycin C Plicamycinp MEN-10755 (Menarinii Porfiromycin GPX-100 (Gem Cyanomorpholinodoxorubicin Pharmaceutica!si Mitoxantron (Novantron) Antimitotic agents Paclitaxel SB 408075 Docetaxel (GlaxoSmithKline) Colchicine E7010 (Abbotti Vinblastine PG-TXL (Cefl Vincristine Therapeutics) Vinorelbine IDN 5109 (Bayeri Vindesine A 105972 (Abbotti Dolastatin 10 (NCIi A 204197 (Abbotti Rhizoxin (Fuj isawai LU 223651 (BASFi Mivobulin (Warner- D 24851 (ASTA Medica) Lambert) ER-86526 (Eisa!i Cemadotin (BASFi Combretastatin A4 (BMSi RPR 109881A (Aventisi Isohomohalichondrin-B TXD 258 (Aventisi (PharmaMari Epothilone B (Novartisi ZD 6126 (AstraZeneca) T 900607 (Tu!ariki PEG-Paclitaxel (Enzoni T 138067 (Tu!ariki AZ10992 (Asahii Cryptophycin 52 (Efi Liflyi !DN-5109 (Indenai Vinflunine (Fabrei AVLB (Prescient Auristatin PE (Teikoku NeuroPharmai Hormone) Azaepothilon B (BMSi BMS 247550 (BMSi BNP-7787 (BioNumeriki BMS 184476 (BMSi CA-4-prodrug (OXIGENEi BMS 188797 (BMSi Dolastatin-10 (NrHi Taxoprexin (Protargai CA-4 (OXIGENEi Aromatase Aminoglutethimide Exemestan inhibitors Letrozole Atamestan (BioMedicinesi Anastrazole YM-511 (Yamanouchii Formestan Thymidylate Pemetrexed (Efi LII!yi Nolatrexed (Eximiasi synthase ZD-9331 (BTGi CoFactor ™(BioKeysi inhibitors DNA antagonists Trabectedin (PhatmaMari Mafosfamide (Baxter Glufosfamide (Baxter International) International) Apaziquone (Specuum Albumin+ 32P (Isotope Pharmaceutica!si Solutions) 06-benzylguanine Thymectacin (NewBioticsi (Pafigenti Edotreotid (Novartisi Farnesyl Arglabin (NuOnco!ogy Tipifarnib (Johnson & trans ferase Labs) Johnson) inhibitors Ionafarnib (Schering- Perillyl alcohol (DOR Plough) BioPharmai BAY-43-9006 (Bayeri Pump inhibitors CBT-I (CBA Pharmai Zosuqutdar Tariquidar (Xenovai trihydrochloride (Eli LII!yi MS-209 (Schering AGi Biricodar dicitrate (Vertexi Histone acetyl Tacedinaline (Pfizeri Pivaloyloxymethyl butyrate trans ferase inhibitors SAHA (Aton Pharmai (Titani MS-275 (Schering AGi Depsipeptide (Fujisawai Metalloproteinase Neovastat (Aeterna Laboratories) CMT-3 (Co!!aGenexi inhibitors Marimastat (British Biotech) BMS-275291 (Cefltechi Ribonucleoside Gallium maltolate (Titani Tezacitabine (Aventisi reductase inhibitors Triapin (Vioni Didox (Mo!ecu!es for Hea!flti TNF-alpha Virulizin (Lorus Therapeutics) Revimid (Ce!genei agonistsl CDC-394 (Ce!genei antagonists Endothelin-A receptor Atrasentan (Abboti YM-598 (Yamanouchii antagonists ZD-4054 (AstraZeneca) Retinoic acid receptor Fenretinide (Johnson & Alitretinoin (Ligandi agonists Johnson) LGD-1550 (Ligandi US 2016/0015712 A1 Jan. 21, 2016 21

TABLE 1-continued

Immunomodulators Interferon Dexosome therapy (Anosysi Oncophage (Antigenicsi Pentrix (Australian Cancer GMK (Progenicsi Technologyi Adenocarcinoma vaccine JSF-154 (Trageni (Biomirai Cancer vaccine (Intercefli CTP-37 (AVI BioPharmai Norelin (Biostari JRX-2 (Immune-Rxi BLP-25 (Biomirai PEP-005 (Pepfin Biotech) MGV (Progenicsi Synchrovax vaccines (CTL P-Aieflun (Dovetaili Immunoi CLL-Thera (Vasogeni Melanoma vaccine (CTL Immunoi p21-RAS vaccine (Gem- Vaxi Hormonal and Oestrogens Prednisone antihormonal Conjugated oestrogens Methylprednisolone agents Ethynyloestradiol Prednisolone chlorotrianisene Aminoglutethimide Idenestrol Leuprolide Hydroxyprogesterone Goserelin caproate Leuporelin Medroxyprogesterone Bicalutamide Testosterone Flutamide Testosterone propionate Octreotide Fluoxymesterone Nilutamide Methyltestosterone Mitotan Diethylstilbestro1 P-04 (Novogeni Megestro1 2-Methoxyoestradiol (Entre Tamoxifen Medi Toremo fi Arzoxifen (Efi Liflyi Dexamethasone Photodynamic Talaporfin tLIght Sciences) Pd-Bacteriopheophorbid agents Theralux (Theratechnoiogiesi (Yedai Motexafin-Gadolinium Lutetium- Texaphyrin (Pharmacycficsi (Pharmacycficsi Hypericin Tyrosine kinase Imatinib (Novattisi Kahalide F (PhatmaMari inhibitors Leflunomide(Sugen/Pharmaciai CEP-701 (Cephaioni ZDI839 (AstraZeneca) CEP-751 (Cephaioni Erlotinib (Oncogene Science) MLN518 (Mifleniumi Canertjnib (Pfizeri PKC412 (Novattisi Squaiamine (Genaerai Phenoxodio1 0 SU5416 (Pharmaciai Trastuzumab (Genentechi SU6668 (Pharmaciai C225 (ImCIonei ZD4190 (AstraZenecai rhu-Mab (Genentechi ZD6474 (AstraZenecai MDX-H210 (Medarexi Vatalanib (Novartisi 2C4 (Genentechi PKI166 (Novattisi MDX-447 (Medarexi GW2016 (GiaxoSmiflt- ABX-EGF (Abgenixi Kfinei IMC-ICI I (ImCIonei EKB-509 (Wyethi EKB-569 (Wyethi Various agents SR-27897 (CCK-A inhibitor, BCX-1777 (PNP inhibitor, Sanofi-Syntheiaboi BioCrysti Tocladesine (cycfic AMP Ranpirnase (ribonuciease agonist, Ribaphatmi stimulant, Aifacefli Alvocidib (CDK inhibitor, Galarubicin (RNA synthesis Aventisi inhibitor, Dong-Ai CV-247 (COX-2 inhibitor, Tirapazamine (reducing Ivy Medical) agent, SRI International) P54 (COX-2 inhibitor, N-Acetylcysteine (reducing Phytopharmi agent, Zamboni CapCell ™(CYP450 R-Flurbiprofen (NF-kappaB stimulant, Bavarian Nordic) inhibitor, Encore) GCS-IOO (gat3 antagonist, 3CPA (NF-kappaB GiycoGenesysi inhibitor, Active Biotech) G17DT immunogen (gastrin Seocalcitol (vitamin D inhibitor, Aphtoni receptor agonist, Leoi Efaproxiral (oxygenator, 131-I-TM-601 (DNA Allos Therapeutics) antagonist, PI-88 (heparanase inhibitor, TransMoiecuiari Progeni Eflornithin (ODC inhibitor, Tesmilifen (histamine antagonist, ILEX Oncology) YM BioSciencesi Minodronic acid Histamine (histamine H2 (osteociast inhibitor, receptor agonist, Maxim) Yamanouchii Tiazofurin (IMPDH inhibitor, Indisulam (p53 stimulant, US 2016/0015712 A1 Jan. 21, 2016 22

TABLE I-continued

Ribapharmi Eisaii Cilengitide (integrin antagonist, Aplidin (PPT inhibitor, Merck KGaAi PharmaMari SR-31747 (IL-I antagonist, Rituximab (CD20 antibody, Sanofi-Syntheiaboi Genentechi CCI-779 (m TOR kinase Gemtuzumab (CD33 inhibitor, Wyefiti antibody, Wyeth Ayersti Exisulind (PDE-V inhibitor, PG2 (haematopoiesis Cell Pathways) promoter, Pharmagenesisi CP-461 (PDE-V inhibitor, Immunol ™(triciosan Cell Pathways) moufitwash, Endo) AG-2037 (CART inhibitor, Triacetyluridine (uridine Pfizer) prodrug, Weiistati WX-UKI (piasminogen SN-4071 (sarcoma agent, activator inhibitor, Wiiexi Signature BioScience) PBI-1402 (PMN stimulant, TransMID-107 ™ ProMetic LifeSciencesi (immunotoxin, KS Bortezomib (proteasome Biomedixi inhibitor, Millennium) PCK-3146 (apoptosis SRL-172 (T-ceII stimulant, promoter, Procyoni SR Phatmai Doranidazole (apoptosis TLK-286 (giutafiuone-S promoter, Petal trans ferase inhibitor, Tefiki CHS-828 (cytotoxic agent, PT-100 (growfit factor Leoi agonist, Point Therapeutics) Trans-retinic acid Midostaurin (PKC inhibitor, (differentiator, NIHi Novartisi MX6 (apoptosis promoter, Bryostatin-I (PKC stimulant, MAXIAi GPC Biotech) Apomine (apoptosis CDA-H (apoptosis promoter, promoter, ILEX Oncology) Everfifei Urocidin (apoptosis SDX-101 (apoptosis promoter, promoter, Bionichei Saimedixi Ro-31-7463 (apoptosis Ceflatonin (apoptosis promoter, promoter, La Roche) Chem Genexi Brostallicin (apoptosis promoter, Pharmaciai

[0254] The disclosed compounds of the formula I can be Topoisomerase Inhibitors administered in combination with other known therapeutic agents, including anticancer agents. As used here, the term [0259] such as etoposide, irinotecan, razoxane, sobuzox- "anticancer agent" relates to any agent which is administered ane, teniposide, topotecan; amonafide, belotecan, elliptinium to a patient with cancer for the purposes oftreating the cancer. acetate, voreloxin; [0255] The anti-cancer treatment defined above may be applied as a monotherapy or may involve, in addition to the Microtubule Modifiers herein disclosed compounds of formula I, conventional sur- or or medicinal Such medicinal gery radiotherapy therapy. [0260] such as cabazitaxel, docetaxel, eribulin, ixabepi- therapy, e. a chemotherapy or a targeted therapy, may g. lone, paclitaxel, vinblastine, vincristine, vinorelbine, vin- include one or more, but preferably one, of the following desine, vinflunine; anti-tumor agents: fosbretabulin, tesetaxel; Alkylating Agents [0256] such as altretamine, bendamustine, busulfan, car- Antimetabolites mustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, [0261] such as asparaginase, azacitidine, calcium levofo- melphalan, mitobronitol, mitolactol, nimustine, ranimustine, linate, capecitabine, cladribine, cytarabine, enocitabine, temozolomide, treosulfan, mechloretamine, carbo- thiotepa, floxuridine, fludarabine, fluorouracil, gemcitabine, mercap- fotemustine, glufosfamide, palifosfa- quone; apaziquone, topurine, methotrexate, nelarabine, pemetrexed, pralatrexate, mide, trofosfamide, uramustine, TH-302, pipobroman, azathioprine, thioguanine, carmo fur; VAL-083; doxifluridine, elacytarabine, raltitrexed, sapacitabine, Platinum Compounds tega fur ', trimetrexate; [0257] such as carboplatin, cisplatin, eptaplatin, miri- platine hydrate, oxaliplatin, lobaplatin, nedaplatin, picopl- Anticancer Antibiotics atin, satraplatin; lobaplatin, nedaplatin, picoplatin, satrapl- atin; [0262] such as bleomycin, dactinomycin, doxorubicin, epi- DNA Altering Agents rubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, [0258] such as amrubicin, bisantrene, decitabine, mitox- daunurobicin, antrone, procarbazine, trabectedin, clofarabine; plicamycin; amsacrine, brostallicin, pixantrone, laromustine' aclarubicin, peplomycin, pirarubicin; US 2016/0015712 A1 Jan. 21, 2016 23

Hormones/Antagonists Vaccines

[0263] such as abarelix, abiraterone, bicalutamide, buser- [0270] such as sipuleucel; vitespen, emepepimut-S, elin, calusterone, chlorotrianisene, degarelix, dexametha- oncoVAX, rindopepimut, troVax, MGN-1601, MGN- sone, estradiol, fluocortolone fluoxymesterone, flutamide, 1703; fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mito- [0271] Miscellaneous alitretinoin, bexarotene, bortezomib, tane, nafarelin, nandrolone, nilutamide, octreotide, predniso- everolimus, ibandronic acid, imiquimod, lenalidomide, len- lone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, tinan, metirosine, mifamurtide, pamidronic acid, pegaspar- trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, gase, pentostatin, sipuleucel, sizofiran, tamibarotene, tem- deslorelin, epitiostanol, orteronel, enzalutamide' sirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat; Aromatase Inhibitors celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib, lonidamine, nimorazole, [0264] such as aminoglutethimide, anastrozole, exemes- panobinostat, peretinoin, plitidepsin, pomalidomide, pro- tane, fadrozole, letrozole, testolactone; codazol, ridaforolimus, tasquinimod, telotristat, thymalfasin, formestane; tirapazamine, tosedostat, trabedersen, ubenimex, valspodar, gendicine, picibanil, reolysin, retaspimycin hydrochloride trebananib '3, virulizin carfilzomib', endostatin, Small Molecule Kinase Inhibitors immucothel, belinostat, MGN-1703 ' [0265] such as crizotinib, dasatinib, erlotinib, imatinib, Prop. INN (Proposed International Nonproprietary Name) lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sor- Rec. INN (Recommended International Nonproprietary afenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefi- Names) tinib, axitinib; USAN (United States Adopted Name) afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovi- tinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, 4 no INN. masitinib, midostaurin, motesanib, neratinib, orantinib, peri- fosine, ponatinib, radotinib, rigosertib, tipifarnib, tivantinib, [0272] The following abbreviations refer respectively to tivozanib, trametinib, pimasertib, brivanib alaninate, cedi- the definitions below: aq (aqueous), h (hour), g (gram), L ranib, apatinib, cabozantinib S-malate ', ibrutinib', ico- (liter), mg (milligram), MHz (Megahertz), min. (minute), mm tinib, buparlisib, cipatinib, cobimetinib' idelalisib', (millimeter), mmol (millimole), mM (millimolar), m.p. fedratinib ', XL-647; (melting point), eq (equivalent), ml (milliliter), pl (microli- ter), ACN (acetonitrlle), AcOH (acetic acid), CDC13 (deuter- Photosensitizers ated chloroform), CD3OD (deuterated methanol), CH3CN (acetonitrlle), c-hex (cyclohexane), DCC (dicyclohexyl car- [0266] such as methoxsalen; bodiimide), DCM (dichloromethane), DIC (diisopropyl car- porfimer sodium, talaporfin, temoporfin; bodiimide), DIEA (diisopropylethyl-amine), DMF (dimeth- ylformamide), DMSO (dimethylsulfoxide), DMSO-d~ (deuterated (I-(3-dimethyl-amino- Antibodies dimethylsulfoxide), EDC propyl)-3-ethylcarbodiimide), ESI (Electro-spray ioniza- [0267] such as alemtuzumab, besilesomab, brentuximab tion), EtOAc (ethyl acetate), Et~0 (diethyl ether), EtOH vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, (ethanol), HATU (dimethylamino-([1, 2,3]trlazolo[4, 5-b]py- panitumumab, rituximab, tositumomab, trastuzumab, beva- rldin-3-yloxy)-methylene]-dimethyl-ammonium hexafluo- cizumab, pertuzumab '; rophosphate), HPLC (High Performance Liquid Chromatog- raphy), i-PrOH (2-propanol), K~CO3 (potassium carbonate), catumaxomab, elotuzumab, epratuzumab, farletuzumab, LC (Liquid Chromatography), MeOH (methanol), MgSO4 mogamulizumab, necitumumab, nimotuzumab, obinutu- (magnesium sulfate), MS (mass spectrometry), MTBE (Me- zumab, ocaratuzumab, oregovomab, ramucirumab, rilotu- thyl tert-butyl ether), NaHCO3 (sodium bicarbonate), NaBH4 mumab, siltuximab, tocilizumab, zalutumumab, zanoli- (sodium borohydrlde), NMM (N-methyl morpholine), NMR mumab, matuzumab, dalotuzumab' ', onartuzumab', (Nuclear Magnetic Resonance), PyBOP (benzotriazole-I-yl- racotumomab', tabalumab', EMD-525797, nivolumab' oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), RT (room temperature), Rt (retention time), SPE (solid phase Cytokines extraction), TBTU (2-(I-H-benzotrlazole-l-yl)-1, 1,3,3-tet- ramethyluromium tetrafluoro borate), TEA (triethylamine), [026S] such as aldesleukin, interferon alfa, interferon TFA (trifluoroacetic acid), THF (tetrahydro furan), TLC (Thin alfa2a, interferon alfa2b '; celmoleukin, tasonermin, Layer Chromatography), UV (Ultraviolet). teceleukin, oprelvekin', recombinant interferon beta-1 a4; Description of the In Vitro Assays Drug Conjugates GCN2: Assay Principle & Conditions [0269] such as denileukin diftitox, ibritumomab tiuxetan, iobenguane I123, prednimustine, trastuzumab emtansine, [0273] This assay can quantificate the activity of the serin estramustine, gemtuzumab, ozogamicin, aflibercept; cintre- kinase GCN2 (general control non-derepressible-2). dekin besudotox, edotreotide, inotuzumab ozogamicin, nap- [0274] This kinase is involved in the stress metabolism of tumomab estafenatox, oportuzumab monatox, technetium cells. It is activated upon starvation (amino acid depletion). Its (99mTc) arcitumomab' vintafolidel'; natural substrate is eIF2a (eukaryotic initiation factor 2 alpha US 2016/0015712 A1 Jan. 21, 2016 24

subunit), a translation factor, which gets activated (phospho- [0284] The analysis and quantification of phosphorylated rylated) by GCN2 in case of an amino acid bottleneck in the GCN2 is done by scanning the plates in the Acumen Explorer cells. This in turn leads to a halt of the protein synthesis. system (TTPLabtech). The obtained data are normalised Inhibition of GCN2 results in stopping this mechanism: The against the untreated control wells (DMSO only) and cell can not stop protein production upon "starvation" stress. expressed as % effect values. The determination of ICso val- [0275] The assay is run in two steps: the enzymatic reaction ues is done by using the Graph Pad Prism software. and the detection step. In the first step GCN2 is incubated with 10 pM ATP and 80 nM of the GFP-labelled substrate Gsk3u eIF2alpha at room temperature. [0285] GSK3u (h) is incubated with 8 mM MOPS pH 7,0, [0276] The enzymatic reaction is stopped by addition of 0.2 mM EDTA, 20 pM EDTA. The amount of phosphorylated eIF2alpha is deter- YRRAAVPPSPSLSRHSSPHQS(p)EDEEE (phosphor GS2 mined by TR-FRET (Lanthascreen): A complex is formed 10mM Mg-acetate and [gamma-33P-ATP](specific consisting of antibody and GFP labelled phospho-eIF2a, peptide), activity 500 cpm/Pmol, concentration as required). which allows a FRET upon exitation at 340 nm. approx. The reaction is initiated the addition of the MgATP. After [0277] The GCN2-activity is directly proportional to the by incubation for 40 minutes at the room temperature, the Reac- ratio of fluorescence units at the emission wavelenghth 520 tion is stopped the addition of 3% phosphoric acid solu- nm (phosphopeptide-sensitive wavelength=emission of by tion. 10pL ofreaction is then spotted onto a P30 filtermat and GFP) to the units at 495 nm (reference wavelength=emission washed three times for 5 minutes in 50 mM phosphoric acid of Terbium-chelate). and once in methanol prior to drying and scintillation count- Final Concentrations in the Enzymatic Reaction ing. The assay is performed at 10 pM ATP or Km ATP. The ATP concentration used for the Km ATP protocol is 10 pM [0278] ATP whereas the actual KM ATP for GSK3u (h) is 10 pM.

Gsk3[3 Hepes, pH 7.0 60 mM MgCIz 10 mM [0286] GSK3[3 (h) is incubated with 8 mM MOPS pH 7,0, MnClz 6 mM 0.2 mM EDTA, 20 pM YRRAAVPPSPSLSRHSSPHQS(p) BSA 0.1% mM Mg-acetate and DMSO 1% EDEEE (phosphor GS2 peptide), 10 ATP 10 11M [gamma-33P-ATP] (specific activity approx. 500 cpm/Pmol, DTT 2 mM concentration as required). The reaction is initiated by the GFP-eIF2a 80 nM (substrate) addition ofthe MgATP. After incubation for 40 minutes at the GCN2 30 nM (enzymei room temperature, the Reaction is stopped by the addition of 3%phosphoric acid solution. 10pL ofreaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in Assay Procedure 50 mM phosphoric acid and once in methanol prior to drying and scintillation counting. The assay is performed at 10 pM [0279] ATP or Km ATP. The ATP concentration used for the Km ATP protocol is 10 pM ATP whereas the actual KM ATP for GSK3u is 10 pM. 4uL enzyme solution (in assay buffer) (h) 1.6 11L compound (in cmpd dilution buffer/6. 3% DMSO) Incubation 20 min at RT 'H NMR: 4uL substrate/ATP mix (in assay buffer) Incubation 90 min at RT Bruker 400- or 500 MHz 10 11L stop/detection mix (in antibody dilution buffer) Incubation 60 min at RT Readout Landtascreen 340/496/620 [0287] HPLC/MS conditions A column: Chromo lith Performance ROD RP-18e, 50x4.6 mm gradient: A:B=96:4to 0:100in 2.8 min Cellular Assay for the Determination ofCompound Activities flow rate: 2.40 ml/min eluent A: water+0. 05% formic acid Human U2OS cells (2000 cells/well) are seeded into [0280] Eluent B:acetonitrile+0. 04% formic acid 384-well plates and incubated for 20 hours. wavelength: 220 nm [0281] The next day, the cells are treated with the test com- mass spectroscopy: positive mode pounds and incubated for 2 hours. Then, tryptophanol, at a final concentration of 600 PM, is added to the cells and those are incubated for 30 minutes. HPLC/MS Conditions B [0282] The analysis of cellular GCN2 activities is done by [02SS] column: Chromolith Performance ROD RP-18e, immuno cytochemistry. 100x3 mm [0283] Briefly, cells are fixated on the well surfaces by gradient: A:B=99:I to 0:100in 1.8 min formaldehyde and permeabilised with Triton X-100.The pri- flow rate: 2.0 ml/min mary antibody (anti-phospho-eIF2alpha (Ser51, Cell Signal- eluent A: water+0. 05% formic acid ling Technology, ¹3398) is incubated on the treated cells for eluent acetonitrile+0. formic acid 20 hours, followed by a 60 minutes incubation of the second- B: 04% ary antibody (anti-rabbit-lgG-Alexa 488; Molecular Probes wavelength: 220 nm ¹11008). mass spectroscopy: positive mode US 2016/0015712 A1 Jan. 21, 2016 25

HPLC/MS Conditions C slowly. The reaction mixture is stirred for 3 hours at room temperature. The solvent is evaporated and the residue is [0289] column: Chromolith Performance ROD RP-18e, taken up in water (100 ml). The solid is filtered off, washed 100x3 mm with water and dried under vacuum to afford (2-chloro-5- gradient: A:B=99:I to 0:100in 3.5 min nitro-pyrimidin-4-yl)-(4-methoxy-phenyl)-amine as orange flow rate: 2.0 ml/min crystals; HPLC/MS 1.94 min [M+H]281; 'H NMR (400 eluent A: water+0. 05% formic acid (B), MHz, DMSO-de) ft [ppm]1035 (s, IH), 9.11 (s, IH), 7.46-7. Eluent B:acetonitrile+0. 04% formic acid 39 (m, 2H), 7.03-6.96 (m, 2H), 3.79 (s, 3H). wavelength: 220 nm mass spectroscopy: positive mode [0293] A solution of (2-chloro-5-nitro-pyrlmidin-4-yl)-(4- [0290] Above and below, all temperatures are indicated in ' methoxy-phenyl)-amine (8.13 g, 29.0 mmol) in THE (90 ml) C. In the following examples, "conventional work-up" is hydrogenated with sponge-nickel as catalyst (2.0 g) at room means: water is added if necessary, the pH is adjusted, if temperature and under atmospheric pressure. The catalyst is necessary, to values between 2 and 10, depending on the filtered off and the filtrate is evaporated. The residue is chro- constitution of the end product, the mixture is extracted with matographed on a silica gel column with cyclohexane/ethyl ethyl acetate or dichloromethane, the phases are separated, acetate as eluent to afford 2-chloro-N4-(4-methoxy-phenyl)- the organic phase is dried over sodium sulfate and evaporated, pyrimidine-4, 5-diamine as reddish brown solid; HPLC/MS 'H and the residue is purified by chromatography on silica gel 1.68 min (B), [M+H]251; NMR (400 MHz, DMSO-de) ft and/or by crystallisation. Rf values on silica gel; eluent: ethyl [ppm]8. 51 (s, I H), 7.57-7.49 (m, 2H), 7.60 (s, I H), 7.58-7.49 acetate/methanol 9:1. (m, 2H), 6.99-6.91 (m, 2H), 5.19 (s, 2H), 3.76 (s, 3H). [0294] To a solution of 2-chloro-N4-(4-methoxy-phenyl)- EXAMPLES pyrimidine-4, 5-diamine (2.59 g, 10.3 mmol) in acetonitrile (22 ml) is added butyl nitrite (1.81 ml, 15.5 mmol) and the Preparation of Intermediates reaction mixture is stirred for I hour at 80' C. The reaction mixture is cooled to room temperature and evaporated. The Synthesis o 5-chloro-3-(4-methoxy-phenyl)-3H- f [I, residue is chromatographed on a silica gel column with cyclo- 2,3]triazolo [4,5-d]pyrimidine hexane/ethyl acetate as eluent to afford 5-chloro-3-(4-meth- [0291] oxy-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidine as off- white crystals; HPLC/MS 2.23 min (A), [M+H]262; 'H NMR (400 MHz, DMSO-de) ft [ppm] 9.82 (s, IH), 7.93 (d, J=9.0 Hz, Cl N Cl H2N 2H), 7.26 (d, J=9.0 Hz, 2H), 3.88 (s, 3H). ~ H OP) [0295] The following compounds are prepared analo- YN d gously: NO2 0

H

H2/Ni THF

H ty) [0296] S-chloro-3-(4-ethoxy-phenyl)-3H-[1, 2,3]trlazolo acetoniu ile [4,5-d]pyrimidine; grey powder; HPLC/MS 2.87 min (C), [M+H]276;

/

Vj X /

[0297] S-chloro-3-(4-morpholin-4-yl-phenyl)-3H-[1, 2,3] [0292] To a solution of 2,4-dichloro-5-nitro-pyrimidine triazolo[4, 5-d]pyrimidine; yellow solid; (5.82 g, 30 mmol) in dioxane (90 ml) is added N-ethyldiiso- propylamine (5.61 ml, 33 mmol) slowly and under external [0298] HPLC/MS 1.87 min (B), [M+H]317; 'H NMR (400 cooling with ice. Then, still under cooling, a solution of MHz, DMSO-de) ft [ppm]9. 80 (s, IH), 7.88-7.80 (m, 2H), p-anisidine (4.06 g, 33 mmol) in dioxane (12 ml) is added 7.26-7.19 (m, 2H), 3.82-3.75 (m, 4H), 3.29-3.22 (m, 4H); US 2016/0015712 A1 Jan. 21, 2016 26

afford (2-chloro-5-nitro-pyrimidin-4-yl)-quinolin-6-yl- amine as orange crystals; HPLC/MS 1.67 min (A), [M+H] 302. [0302] A solution of (2-chloro-5-nitro-pyrimidin-4-yl)- quinolin-6-yl-amine (793 mg, 2.63 mmol) in THF (20 ml) is hydrogenated with sponge-nickel as catalyst (LO g) at room temperature and under atmospheric pressure. Ater 20 hours, the catalyst is filtered off and the filtrate is evaporated to afford 2-chloro-N -quinolin-6-yl-pyrimidine-4, 5-diamine as brown-red crystals; HPLC/MS 1.27 min (A), [M+H]272. [0303] To a slurry of 2-chloro-N -quinolin-6-yl-pyrimi- [0299] (R)-1-[4-(5-chloro-[1,2,3]triazolo[4, 5-d]pyrimi- dine-4, 5-diamine (562 mg, 2.07 mmol) in 37% aqueous din-3-yl)-phenyl]-pyrrolidin-3-ol, yellow solid; HPLC/MS hydrochloric acid (9ml) is added sodium nitrite (286 mg, 4.14 1.76 min [M+H]317; 'H NMR (500 MHz, DMSO-d~) 6 (B), mmol) and the reaction mixture is stirred for 2 hours at room 9.78 (s, 1H), 7.73 (d, J=9.0 Hz, 2H), 6.76 (d, J=9.0 Hz, [ppm] temperature. The reaction mixture is evaporated. The residue 2H), 5.00 (d, J=3.8 Hz, 1H), 4.45 (m, 1H), 3.50 (dd, J=103, is triturated with heptane to afford crude 6-(5-chloro-[1, 2,3] 4.8 Hz, 1H), 3.47-334 (m, 2H), 3.21-3.14 (m, 1H), 2.09 (dtd, triazolo[4, 5-d]pyrimidin-3-yl)-quinoline hydrochloride, J=13.2, 8.5, 4.8 Hz, 1H), 2.01-1.90 (m, 1H). which is used as such for the following reactions; HPLC/MS 1.91 min (A), [M+H]283. Synthesis of 6-(5-chloro- [1,2,3]triazolo [4,5-d]pyri- [0304] The following compounds are prepared analo- midin-3-yl)-quinoline hydrochloride gously: [0300]

Cl N Cl H2N NHPr12Et + YN 610XRIle NO2 N

H Cl N N H2/Ni [0305] S-chloro-3-(6-methoxy-pyridin-3-yl)-3H-[1, 2,3] YN triazolo[4, 5-d]pyrimidine; light brown crystals; HPLC/MS NO2 N 2.50 min (C), [M+H]263;

H Cl N N ~ NO

NH2 N

N / [0306] 1-[4-(5-chloro-[1,2,3]triazolo[4, 5-d]pyrimidin-3- yl)-phenyl]-pyrrolidin-2-one; HPLC/MS 1.73 min (B), / [M+H]315;

x HCl

[0301] To a solution of 6-aminoquinoline (401 mg, 2.78 mmol) in dioxane (15 ml) is added 2,4-dichloro-5-nitro-py- rimidine (491 mg, 2.53 mmol) slowly and under external cooling with ice. Then, still under cooling, N-ethyldiisopro- pylamine (0.47 ml, 2.78 mmol) is added slowly. The reaction [0307] S-chloro-3-(4-fluoro-phenyl)-3H-[1, 2,3]triazolo[4, mixture is stirred for 3 hours at room temperature. The solvent 5-d]pyrimidine; HPLC/MS 2.25 min (A), [M+H]250; 'H is evaporated and the residue is taken up in water. The solid is NMR (400 MHz, DMSO-d~) ft [ppm]9. 85 (s, 1H), 8.11 (dd, filtered off, washed with water and dried under vacuum to J=9.0, 4.8 Hz, 2H), 7.59 (t, J=8.7 Hz, 2H). US 2016/0015712 A1 Jan. 21, 2016 27

Synthesis of 5-chloro-3-(4-chloro-3-fluoro-phenyl)- [0312] The following compounds are prepared analo- 3H-[1,2,3]triazolo[4, 5-d]pyrimidine gously:

[0308]

Cl~ N Cl H2N F

Yi

NO2 Cl H N s c EtOAc/EtOH NO2 Cl [0313] 6-(5-chloro-[1, 2,3]triazolo[4, 5-d]pyrlmidin-3-yl)- H 3-dimethyl-1, 3-dihydro-indo1-2-one; beige powder; N F 3, NaNO2 HPLC/MS 2.00 min (A), [M+H]315; HC1 N NH2 Cl Cl

F

~~N N

Yj [0314] S-chloro-3-[4-(2-methoxy-ethoxy)-phenyl]-3H-[1, 2,3]triazolo[4, 5-d]pyrimidine; beige powder; HPLC/MS 2.15 min (A), [M+H]306; [0309] To a solution of 2,4-dichloro-5-nitro-pyrimidine (1.04 g, 5 36 mmol) in THF (20 ml) is added 4-chloro-3- fluoro-phenylamine (678 mg, 4.66 mmol) slowly and under external cooling with ice. Then, still under cooling, a solution oftriethylamine (0.65 ml, 4.66 mmol) in THF (5 ml) is added m) slowly. The reaction mixture is stirred for I hour at room temperature. The solids are filtered off and washed with THF. ~~N The filtrate is evaporated and crystallized from methanol to N afford (4-chloro-3-fluoro-phenyl)-(2-chloro-5-nitro-pyrlmi- din-4-yl)-amine as yellow crystals; HPLC/MS 2.98 min (C), [M+H] 303. [0315] 6-(5-chloro-[1, 2,3]triazolo[4, 5-d]pyrlmidin-3-yl)- quinoxaline; yellow HPLC/MS 1.93 min [0310] To a solution of (4-chloro-3-fluoro-phenyl)-(2- powder; (A), [M+H]284; chloro-5-nitro-pyrlmidin-4-yl)-amine (1.28 g, 4.23 mmol) in a mixture of ethyl acetate (17ml) and ethanol (12ml) is added tin(II)chloride (4.01 g, 21.2 mmol) and the reaction mixture is Synthesis of 3-[4-(5-chloro-[1,2,3]trlazolo[4, 5-d] stirred for 2 hours at 70' C. The reaction mixture is basified pyrimidin-3-yl)-phenoxy]-propionic acid with saturated sodium carbonate solution, filtered over a pad of Celite and the residue is washed with ethyl acetate. The [0316] organic phase of the filtrate is separated, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with dichloromethane/methanol as eluent to Cl ~ N Cl afford 2-chloro-N4-(4-chloro-3-fluoro-phenyl)-pyrimidine- Yi 4,5-diamine as brown crystals; HPLC/MS 2.60 min (C), [M+H] 273. NO2 H2N [0311] To a slurry of 2-chloro-N4-(4-chloro-3-fluoro-phe- nyl)-pyrimidine-4, 5-diamine (617 mg, 2.26 mmol) in 37% aqueous hydrochloric acid (10 ml) is added sodium nitrite and (312 mg, 4.53 mmol) the reaction mixture is stirred for 2 H hours at room temperature. Ice is added to the reaction mix- ture. The resulting precipitate is filtered off, washed with 0 SnC12 water and dried under vacuum to afford 5-chloro-3-(4-chloro- VQ EtOAc/ 3-fluoro-phenyl)-3H-[1, 2,3]trlazolo[4, 5-d]pyrimidine as O+ EtOH brown powder; HPLC/MS 3.03 min (C), [M+H]284. US 2016/0015712 A1 Jan. 21, 2016 28

-continued Synthesis of 3-(4-bromo-phenyl)-5-chloro-3H-[1, 2, H 3]triazolo[4, 5-d]pyrimidine Cl N N 0 NaNO2 [0320]

NH2 0 Cl ~ N Cl H2N DtPEA Ti OH E NO2 Br H 0 N E C1 0 EtOAc/EtOH NO2 Br H N E tyl

N acetoniu ile NH2 Yj Br

[0317] To a solution of 2,4-dichloro-5-nitro-pyrimidine (1.02 g, 5.25 mmol) in THF (20 ml) is added 3-(4-amino- phenoxy)-propionic acid methyl ester (1.02 g, 5.25 mmol) slowly and under external cooling with ice. Then, still under cooling, diisopropylethylamine (1.07 ml, 630 mmol) is added slowly. The reaction mixture is stirred for I hour at [0321] To a solution of 4-bromoaniline (3.78 g, 22.0mmol) room temperature. The solids are filtered off and washed with in dioxane (100ml) is added 2,4-dichloro-5-nitro-pyrimidine THF. The filtrate is evaporated and the residue is chromate- (3.88 g, 20 mmol) slowly and under external cooling with ice. graphed on a silica gel column with cyclohexane/ethyl acetate Then, still under cooling, diisopropylethylamine (3.74 ml, as eluent to afford 3-[4-(2-chloro-5-nitro-pyrlmidin-4- 22.0 mmol) is added slowly. The reaction mixture is stirred ylamino)-phenoxy]-propionic acid methyl ester as dark red for I hour at room temperature. The solids are filtered off and crystals; HPLC/MS 2.73 min (C), [M+H]353. washed with THF. The filtrate is taken up in water, the solids are filtered off, washed with water and dried under vacuum to [0318] To a solution of3-[4-(2-chloro-5-nitro-pyrlmidin-4- afford (4-bromo-phenyl)-(2-chloro-5-nitro-pyrimidin-4-yl)- ylamino)-phenoxy]-propionic acid methyl ester (1.54 g, 437 amine; HPLC/MS 2.08 min [M+H]331. mmol) in a mixture ofethyl acetate (20 ml) and ethanol (5 ml) (B), is added tin(II)chloride (2.49 g, 13.1 mmol) and the reaction [0322] To a solution of (4-bromo-phenyl)-(2-chloro-5-ni- mixture is stirred for I hours at 70' C. The reaction mixture is tro-pyrlmidin-4-yl)-amine (5.97 g, 18.13 mmol) in a mixture basified with saturated sodium carbonate solution, filtered of ethyl acetate (100 ml) and ethanol (50 ml) is added tin(II) over a pad of Celite and the residue is washed with ethyl chloride (10.3 g, 54.4 mmol) and the reaction mixture is acetate. The organic phase of the filtrate is separated, dried stirred for I hour at 70' C. The reaction mixture is cooled to over sodium sulfate and evaporated. The residue is chromato- room temperature, basified with saturated sodium carbonate graphed on a silica gel column with cyclohexane/ethyl acetate solution, filtered over a pad of Celite and the residue is as eluent to afford 3-[4-(5-amino-2-chloro-pyrlmidin-4- washed with ethyl acetate. The organic phase of the filtrate is separated, dried over sodium sulfate and evaporated. The ylamino)-phenoxy]-propionic acid methyl ester as brown oil, residue is chromatographed on a silica gel column with cyclo- which crystallizes on standing; HPLC/MS 2.24 min (C), hexane/ethylacetate as eluent to afford N4-(4-bromo-phe- [M+H] 323. nyl)-2-chloro-pyrimidine-4, 5-diamine as light brown pow- [0319] To a slurry of 3-[4-(5-amino-2-chloro-pyrlmidin-4- der; HPLC/MS 1.86 min (B), [M+H]301. acid ester ylamino)-phenoxy]-propionic methyl (139g, 430 [0323] To a solution ofN4-(4-bromo-phenyl)-2-chloro-py- mmol) in 37% aqueous hydrochloric acid (13 ml) is added rimidine-4, 5-diamine (333 g, 11.1 mmol) in acetonitrile (50 sodium nitrite (594 8.61 mmol) and the reaction mixture mg, ml) is added butyl nitrite (1.72 g, 16.7 mmol) and the reaction is stirred for 3 hours at room temperature. Ice is added to the mixture is stirred for I hour at 70' C. The reaction mixture is reaction mixture. The resulting precipitate is filtered off, cooled to room temperature and evaporated. The residue is washed with water and dried under vacuum to afford 3-[4-(5- chromatographed on a silica gel column with cyclohexane/ chloro-[1, 2,3]triazolo[4, 5-d]pyrimidin-3-yl)-phenoxy]-pro- ethyl acetate as eluent to afford 3-(4-bromo-phenyl)-5- pionic acid as light yellow powder; HPLC/MS 233 min (C), chloro-3H-[1, 2,3]triazolo[4, 5-d]pyrimidine as brown pow- [M+H] 320. der; HPLC/MS 2.09 min (B), [M+H]312. US 2016/0015712 A1 Jan. 21, 2016 29

[0324] The following compound is synthesized analo- [0329] The following compounds are prepared analo- gously: gously:

[3-(4-ethoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d]pyri- midin-5-yl]-prop-2-ynyl-amine ("A 1 ") [0330]

~~N N

[0325] S-chloro-3-(4-iodo-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidine; N ~~N [0326] HPLC/MS 3.10 min (C), [M+H]358. N

Example 1 [0331] HPLC/MS 2.71 min (C), [M+H]295; 'H NMR (500 MHz, DMSO-de) ft [ppm]930 (s, 1H), 8.45 (s, 1H), 8.07 (s, Synthesis of (1-methyl-1 i H-pyrazol-4-ylmethyl)-(3- 2H), 7.21-7.14 (m, 2H), 4.19-4.09 (m, 4H), 3.06 (s, 1H), 1.38 quinolin-6-y1-3H-[1, 2,3]triazolo [4,5-d]pyrimi din-5- (t, J=7.0, 3H); yl)-amine ("B1") 3,3-dimethyl-6- (5-[(5-methyl-pyrazin-2-ylmethyl)- 3- [0327] amino]-[1, 2,3]triazolo[4, 5-d]-pyrimidin-3-yl)-1, dihydro-indol-2-one ("B2") N / [0332]

/

N x HCl

N N N N —N 2-me&oxyethettol 100' C. Vj

NHp N [0333]azolo[,HPLC/MS 1.83 min (A), [M+H]402; 'H NMR (500 MHz, DMSO-de) ft [ppm]10. 61 (s, 1H), 9.29 (s, 1H), 8.84-8. N / 71 (m, 1H), 8.59 (s, 1H), 8.52-8.44 (m, 1H), 7.73-7.60 (m, —N / 2H), 7.55-7.45 (m, 1H), 4.77-4.67 (m, 2H), 2.45 (s, 3H), 1.32 (s, 6H);

(3-[4-(2-methoxy-ethoxy)-phenyl] -3H- [1,2,3]tri- 5-d]pyrimidin-5-yl )-(5-methyl-pyrazin-2- Yj ylmethyl)-amine ("B3") [0334]

[0328] A solution of crude 6-(5-chloro-[1, 2,3]triazolo[4, 5- d]pyrimidin-3-yl)-quinoline hydrochloride (85 mg, ca. 0.15 mmol) and (1-methylpyrazol-4-yl)methanamine (18.4 mg, 0.17 mmol) in 2-methoxyethanol is heated to 100' C. (5 ml) N and stirred at this temperature for 2 hours. The reaction mix- ture is evaporated and the residue is chromatographed on a silica gel column with ethyl acetate/methanol as eluent to afford (1-methyl-1H-pyrazol-4-ylmethyl)-(3-quinolin-6-yl- N 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-yl)-amine as yellow powder; HPLC/MS 1.99 min (C), [M+H]358; 'H NMR (400 MHz, DMSO-de) ft [ppm]930 (s, 1H), 9.00 (dd, J=4.2, 1.7 Vj' Hz, 1H), 8.83 (s, 1H), 8.65 (d, J=9.2 Hz, 1H), 8.58-8.50 (m, 2H), 830 (d, J=93 Hz, 1H), 7.70-7.62 (m, 2H), 7.44 (s, 1H), 4.47 (d, J=5.3 Hz, 2H), 3.75 (s, 3H). US 2016/0015712 A1 Jan. 21, 2016 30

azolo[, [0335] HPLC/MS 1.90 min (A), [M+H]393; 'H NMR (500 (3-[4-(2-methoxy-ethoxy)-phenyl] -3H- [1,2,3]tri- MHz, DMSO-d~) 6 [ppm]9. 28 (s, IH), 8.76-8.69 (m, IH), 5-d]pyrimidin-5-yl )-(I-methyl-I H-pyrazol-4- 8.56-8.43 (m, 2H), 7.99-7.82 (m, 2H), 7.23-7.10 (m, 2H), ylmethyl)-amine ("B6") 76-4. 21-4. 72-3. 4. 62 (m, 2H), 4. 17 (m, 2H), 3. 69 (m, 2H), [0340] 334 (s, 3H), 2.45 (s, 3H);

[3-(4-chloro-3-fluoro-phenyl)-3H-[1, 2,3]triazolo[4, N 5-d]pyrlmidin-5-yl]-(I -methyl- IH-pyrazol-4-ylm- ethyl)-amine ("B4")

[0336]

C1 ~N N N / —N [0341] HPLC/MS 1.91 min (A), [M+H]381; 'H NMR (500 MHz, DMSO-d~) 6 [ppm]9. 22 (s, IH), 838 (s, IH), 8.04 (d, J=8.5 Hz, 2H), 7.59 (s, IH), 7.38 (s, IH), 7.22 (m, 2H), 4.38 (s, 2H), 4.19 (t, J=4.5 Hz, 2H), 3.75 (s, 3H), 3.73-3.67 (m, 2H), 333 3H); Yj (s, Is opropyl-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d]pyrimidin-5-yl]-amine ("A2") [0342]

[0337] HPLC/MS 2.70 min (C), [M+H]359; 'H NMR (400 MHz, DMSO-d~) 6 [ppm]9. 27 (s, IH), 8.60 (t, J=5.1 Hz, IH), 831 (dd, J=10.6, 2.4 Hz, IH), 8.16 (d, J=8.9 Hz, IH), 7.91 (t, J=8.5 Hz, IH), 7.63 (s, IH), 7.40 (s, IH), 4.41 (d, J=5.8 Hz, 2H), 3.76 (s, 3H);

(5-methyl-pyrazin-2-ylmethyl)-(3-quinoxalin-6-yl- ~~N 3H-[1,2,3]trlazolo[4, 5-d]-pyrlmidin-5-yl)-amine N O'B5") [0343] HPLC/MS 1.98 min (B), [M+H]285; 'H NMR (500 [0338] MHz, DMSO-d~) 6 [ppm]9. 26-9.19 (m, IH), 8.08-7.93 (m, 3H), 7.19 (d, J=8.9, 2H), 4.28-4.06 (m, IH), 3.85 (s, 3H), 1.24-1.18 (m, 6H);

[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5-d] ~/X ~ pyrimidin-5-yl]-(tetrahydro-pyran-4-yl)-amine N C'A3") [0344] / N Vj'

N

~~N N

[0339] HPLC/MS 1.79 min (A), [M+H]371; 'H NMR (400 [0345] HPLC/MS 1.80 min (B), [M+H]327; 'H NMR (500 MHz, DMSO-d~) 6 [ppm] 9.38 (s, I H), 9.08 (d, J=1.9 Hz, IH), MHz, DMSO-d~) 6 [ppm]9. 33-9.21 (m, IH), 8.18-7.88 (m, 9.05 (d, J=1.9 Hz, IH), 8.94 (t, J=5.4 Hz, IH), 8.86 (s, IH), 3H), 7.23-7.11 (m, 2H), 4.16-3.94 (m, IH), 3.92-3.87 (m, 8.64 (s, 2H), 8.53 (s, IH), 834 (d, J=9.1 Hz, IH), 4.75 (d, 2H), 3.85 (s, 3H), 3.47-337 (m, 2H), 1.95-1.79 (m, 2H), J=5.9 Hz, 2H), 2.44 (s, 3H); 1.63-1.51 (m, 2H); US 2016/0015712 A1 Jan. 21, 2016 31

cyclopropyl- [3-(4-methoxy-phenyl)-3H- [1,2,3]tria- 2-(3,4-difluoro-phenyl)-2-[3-(6-methoxy-pyridin-3- zolo [4,5-d]pyrimidin-5-yl]-amine ("A4") yl)-3H-[1, 2,3]triazolo[4, 5-d]-pyrimidin-5-ylamino]- ethanol ("B8") [0346] [0352]

F OH

N N ~~N N Yj N

[0347] HPLC/MS 1.89 min (B), [M+H]283; 'H NMR (500 [0353] HPLC/MS 2.62 min (C), [M+H]400; 'H NMR (500 MHz, DMSO-d~) 6 [ppm]9. 23 (s, 1H), 831-8.02 (m, 3H), MHz, DMSO-d~) 6 [ppm]9. 30 (s, 1H), 8.76 (s, 1H), 8.54 (d, 7.18 (d, J=8.7, 2H), 3.85 (s, 3H), 2.84 (s, 1H), 0.78-0.71 (m, J=7.4 Hz, 1H), 832 (s, 1H), 8.26 (dd, J=8.8, 2.9 Hz, 1H), 7.46 2H), 0.59-0.54 (m, 2H); (ddd, J=11.8, 7.9, 2.1 Hz, 1H), 7.41-732 (m, 1H), 7.25 (ddd, J=9.8, 4.7, 2.6 Hz, 1H), 7.09 (d, J=8.9 Hz, 1H), 5.24 (s, 1H), [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d] 4.98 (q, J=7.1 Hz, 1H), 3.97 (s, 3H), 3.74 (dd, J=10.9, 7.5 Hz, pyrimidin-5-yl]-oxetan-3-yl-amine ("A5") 1H), 3.67 (dd, J=11.0, 5.7 Hz, 1H);

[0348] [3-(4-ethoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d]pyri- midin-5-yl]-[2-(1H-pyrazol-4-yl)-ethyl]-amine O'B9") [0354]

H N —N

~~N N

[0349] HPLC/MS 1.29 min (B), [M+H]299; Yj [3-(4-ethoxy-phenyl)-3H- [1,2,3]triazolo [4,5-d]pyri- mi din-5-yl] -[2-(1-methyl-1H-pyrazol-4-yl)-ethyl]- amine("B7") [0355] HPLC/MS 1.77 min (B), [M+H]351; 'H NMR (400 MHz, DMSO-d~) 6 54 9.23 8.19 [0350] [ppm]12. (s, 1H), (s, 1H), (s, 1H), 8.02 (d, J=8.7 Hz, 2H), 7.56 (s, 1H), 737 (s, 1H), 7.17 (d, J=8.8 Hz, 2H), 4.12 (q, J=7.0 Hz, 2H), 3.54-3.44 (m, 2H), 2.77 (t, J=7.5 Hz, 2H), 1 37 (t, J=7.0 Hz, 3H);

trans-4-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4, 5-d]pyrimidin-5-yl amino] -cyclohexano1 ("A6") [0356]

HOII„, Vj' H QN N [0351] HPLC/MS 1.85 min (B), [M+H]365; 'H NMR (500 rN N r MHz, DMSO-d~) 6 [ppm]9. 23 (s, 1H), 8.20-8.14 (m, 1H), 8.05-7.99 (m, 2H), 7.50 (s, 1H), 7.27 (s, 1H), 7.20-7.14 (m, 2H), 4.13 (q, J=7.0, 2H), 3.76 (s, 3H), 3.51-3.44 (m, 2H), [0357] HPLC/MS 1.70 min (B), [M+H]341; 'H NMR (400 2.76-2.69 (m, 2H), 1 37 (t, J=7.0, 3H); MHz, DMSO-d~) 6 [ppm] 9.21 (s, 1H), 8.05 (d, J=8.5 Hz, 2H), US 2016/0015712 A1 Jan. 21, 2016 32

7.93 (d, J=7.8 Hz, 1H), 7.20 (d, J=8.8 Hz, 3H), 4.63 (d, J=43 trans-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4, Hz, 1H), 3.86 (s, 3H), 3.71 (m, 1H), 3.4 (m, 1H), 1.91 (m, 4H), 5-d]pyrimidin-5-ylamino]-cyclopentanol ("A10") 1.43-1.21 (m, 4H); [0364] tert-butyl-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5-d]pyrimidin-5-yl]-amine ("A7") pH [0358]

N

N Yj /z ~~N N N

racemic mixture; HPLC/MS 1.69 min [M+H]327; 'H [0359] HPLC/MS 2.09 min (B), [M+H]299; 'H NMR (500 (B), NMR (500 MHz, DMSO-d~) 6 [ppm]9. 21 (s, 1H), 8.14 (d, MHz, DMSO-d~) 6 [ppm] 9.23 (s, 1H), 8.01 (d, J=8.5 Hz, 2H), J=6.0 Hz, 1H), 8.05 (d, J=8.3 Hz, 2H), 7.20 (m, J=83 Hz, 7.72 (s, 1H), 7.23-7.16 (m, 2H), 3.85 (s, 3H), 1.44 (s, 9H); 2H), 4.51 (m, 1H), 437 (m, 1H), 4.23 (m, 1H), 3.85 (s, 3H), 2.15 1.92 1.76 1.52 N-(1, 1 -dioxothio lan-3-yl)-3-(4-methoxyphenyl) tria- (m, 1H), (m, 2H), (m, 1H), (m, 1H); zolo[4, 5-d]pyrimidin-5-amine ("A8") [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5-d] [0360] pyrimidin-5-yl]-phenethyl-amine ("B10") [0365]

Yj

[0361] HPLC/MS 1.71 min (B), [M+H]361; 'H NMR (400 MHz, DMSO-d~) 6 [ppm]9. 34 (s, 1H), 8.55 (s, 1H), 8.01 (bs, Vj 2H), 7.19 (d, J=9.0 Hz, 2H), 4.66 (s, 1H), 3.85 (s, 3H), 3.57 (dd, J=13.5, 7.6 Hz, 1H), 3.45-333 (m, 1H), 3.29-3.12 (m, 2H), 2.27 (m, 1H); [0366] HPLC/MS 2.13 min (B), [M+H]347; 'H NMR (400 MHz, DMSO-d~) 6 [ppm]9. 23 (s, 1H), 8.21 (s, 1H), 8.04 (d, [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d] J=8.7, 2H), 733-7.24 (m, 4H), 7.23-7.15 (m, 3H), 3.86 (s, pyrimidin-5-yl]-(1-propyl-cyclopropyl)-amine "A9") 3H), 3.62-3.50 (m, 2H), 2.95-2.87 (m, 2H);

[0362] benzyl-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4, 5-d]pyrimidin-5-yl]-amine 30 ("B1 1") [0367]

Yj

Yj [0363] HPLC/MS 2.16 min (B), [M+H]325; 'H NMR (500 MHz, DMSO-d~) 6 [ppm]9. 21 (s, 1H), 8.39 (s, 1H), 8.17 (d, J=8.6, 2H), 7.20 (d, J=8.7, 2H), 3.85 (s, 3H), 1.70-1.59 (m, 2H), 1.45-1.34 (m, 2H), 0.87 (t, J=7.4, 3H), 0.80-0.63 (m, [036S] HPLC/MS 2.05 min (B), [M+H]333; 'H NMR (500 4H); MHz, DMSO-d~) 6 [ppm]9. 25 (s, 1H), 8.75-8.64 (m, 1H), US 2016/0015712 A1 Jan. 21, 2016 33

7.98-7.92 (m, 2H), 7.44-7.27 (m, 4H), 7.22 (t, J=7.3, 1H), [0374] HPLC/MS 1.44 min (A), [M+H]383; 'H NMR (400 7.19-7.12 (m, 2H), 4.54 (d, J=5.7, 2H), 3.85 (s, 3H); MHz, DMSO-d~/TFA-d, ) 6 [ppm]9. 28 (s, 1H), 8.07 (m, 2H), 7.20 (d, J=8.5 Hz, 2H), 3.89 (s, 3H), 3.82-3.25 (m, 12H), 2.96 (4-[3-(4-Methoxy-phenyl)-3H- [1,2,3]triazolo [4,5-d] (s, 3H), 2.15-2.08 (m, 2H); pyrimidin-5-ylamino]-cyclohexyl)-methanol O'A11") trans-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4, 5-d]pyrimidin-5-ylamino]-1-trifluoromethyl-cyclo- [0369] pentanol ("A67") [0375] HO

F OH ..„, H F H QN F N ~N N r ~~N N [0370] HPLC/MS 1.87 min (B), [M+H]355; 'H NMR (400 MHz, DMSO-d~/TFA-di) 6 [ppm]9. 50 (s, 1H), 8.09-8.02 (m, 2H), 7.23-7.14 (m, 2H), 4.22-4.15 (m, 1H), 3.89 (s, 3H), 3.44 [0376] HPLC/MS 1.95 min (B), [M+H]395; (d, J=5.9 Hz, 2H), 1.89 (m, 2H), 1.77-1.59 (m, 5H), 1.51 (m, 2H); trans-2-(4-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d]pyrimi din-5-ylamino]-cyclohexyl )-ethanol cyclopentyl-[3-(4-methoxy-phenyl)-3H-[1, 2,3]tria- C'A72") zolo[4, 5-d]pyrimidin-5-yl]-amine ("A12") [0377] [0371] Q C:~, X ~ / N N ~N N ~~N N

[037S] HPLC/MS 2.65 min (C), [M+H]369; 'H NMR (500 [0372] HPLC/MS 2.12 min (B), [M+H]311; 'H NMR (500 MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 25 (s, 1H), 8.03 (m, 2H), MHz, DMSO-d~) 6 [ppm]9. 25 (s, 1H), 8.75-8.64 (m, 1H), 7.19 (d, J=7.6 Hz, 2H), 3.87 (s, 3H), 3.76 (m, 1H), 3.47 (t, 7.98-7.92 (m, 2H), 7.44-7.27 (m, 4H), 7.22 (t, J=7.3, 1H), J=6.4 Hz, 2H), 2.01 (m, 2H), 1.83-1.76 (m, 2H), 1.44-1.29 7.19-7.12 (m, 2H), 4.54 (d, J=5.7, 2H), 3.85 (s, 3H); (m, 5H), 1.10-0.99 (m, 2H);

[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d] c is-2- (4-[3-(4-methoxy-phenyl)-3H- [1,2,3]triazolo pyrimidin-5-yl]-[3-(4-methyl-piperazin-1-yl)-pro- [4,5-d]pyrimi din-5-ylamino]-cyclohexyl )-ethanol pyl] -amine ("A13") O'A73") [0373] [0379]

0— HO H PN N ~N N N ~N N [03SO] HPLC/MS 2.67 min (C), [M+H]369; 'H NMR (500 MHz, DMSO-d~) 6 [ppm]9. 27 (s, 1H), 8.06-8.01 (m, 2H), US 2016/0015712 A1 Jan. 21, 2016 34

7.23-7.15 (m, 2H), 4.02-3.98 (m, 1H), 3.86 (s, 3H), 3.45 (t, [03S6] HPLC/MS 1.96 min (C), [M+H]403; 'H NMR (400 J=6.8 Hz, 2H), 1.78 (m, 2H), 1.63-1.41 (m, 8H), 1.40-1.33 MHz, DMSO-de, TFA-dt) ft [ppm]9. 29 (s, 1H), 8.21 (d, J=7.7 (m, 1H); Hz, 2H), 8.08 (m, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.18 (d, J=9.1 Hz, 1H), 4.23 (m, 3H), 3.88 (s, 3H), 3.48 (m, 2H), 2.18 (m, [2-(2-amino-ethoxy)-ethyl]-[3-(4-methoxy-phenyl)- 2H) 1.73 (m, 2H); 3H-[1,2,3]triazolo[4, 5-d]-pyrimidin-5-yl]-amine formate ("A74") (cis)-N-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4, 5-d]pyrimidin-5-yl]-N', N'-dimethyl-cyc lop entane- 1, [0381] 3-diamine ("A108")

[0387]

O~

QN N ~~N N ~N N

[03S2] HPLC/MS 1.41 min (B), [M+H]330; 'H NMR (400 MHz, DMSO-de, TFA-dt) ft [ppm]9. 25 (s, 1H), 8.18-7.89 (m, [03SS] HPLC/MS 1.45 min (B), [M+H]354. 3H), 7.19 (d, J=8.8, 2H), 3.85 (s, 3H), 3.66-3.49 (m, 6H), 2.85 (t, J=5.4, 2H); Example 2

[3-(3-amino-propoxy)-propyl]-[3-(4-methoxy-phe- Synthesis of [3-(4-methoxy-phenyl)-3H-[1, 2,3]tria- nyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5-yl]-amine zolo[4, 5-d]pyrimidin-5-yl]-methyl-amine ("A14") formate ("A76") [0389] [0383]

water + CHgNHr 80' p/' ~ C. N ~N N Vj

[03S4] HPLC/MS 1.43 min (B), [M+H]358; 'H NMR (400 MHz, DMSO-de, TFA-dt) ft [ppm]934-9. 19 (m, 1H), 8.18- 7.90 (m, 3H), 7.19 (d, J=8.7, 2H), 3.85 (s, 3H), 3.51-337 (m, 6H), 2.79-2.71 (m, 2H), 1.91-1.77 (m, 2H), 1.71 (p, J=6.5, 2H);

[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d] pyrimidin-5-yl]-(3, 4,5,6-tetrahydro-2H-[1, 4']bipy- ridinyl-4-yl)-amine ("A82") [0385] [0390] A slurry of S-chloro-3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidine (131 mg, 0.50 mmol) in aque- ous methylamine solution (40% by weight, 2 ml) is heated to 80' C. in a closed reaction vial and stirred at this temperature for 30 minutes. The mixture is cooled to room temperature and excess water is added. The solid is filtered off, washed with water and dried under vacuum to afford [3-(4-methoxy- phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5-yl]-methyl- ~~N N amine as off-white crystals; HPLC/MS 2.42 min (C), [M+H] 257; 'H NMR (400 MHz, DMSO-de) ft [ppm]9. 22 (s, 1H), 8.05 (, 3H), 7.19 (d, J=8.6 Hz, 2H), 3.85 (s, 3H), 2.90 (m, 3H). US 2016/0015712 A1 Jan. 21, 2016 35

[0391] The following compound is prepared analogously: [0395] The following compounds are prepared analo- gously: ethyl-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5- d]pyrimidin-5-yl]-amine ("A16") [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5-d] pyrimidin-5-yl]-(2, 2,6,6-tetramethyl-piperi din-4-yl)- [0392] HPLC/MS 2.64 min (C), [M+H]271; 'H NMR (400 amine ("A17") MHz, DMSO-d~) 6 9.36 8.08 J=9.0 [ppm] (s, 1H), (d, Hz, 2H), [0396] 7.23-7.14 (m, 2H), 432 (p, J=6.5 Hz, 1H), 3.88 (s, 3H), 2.05 (m, 2H), 1.76 (m, 2H), 1.72-1.59 (m, 2H).

Example 3 H Synthesis of [3-(4-methoxy-phenyl)-3H-[1, 2,3]tria- zolo [4,5-d]pyrimidin-5-yl]-(1, 2,2,6,6-pentamethyl- PN piperidin-4-yl)-amine ("A15") N ~N [0393] N

[0397] HPLC/MS 1.89 min (C), [M+H]382; 'H NMR (400 MHz, DMSO-d~) 6 [ppm]9. 22 (s, 1H), 8.17-8.10 (m, 2H), 8.06 (d, J=7.2 Hz, 1H), 7.14-7.07 (m, 2H), 4.23 (dtd, J=11.6, 7.9, 3.6 Hz, 1H), 3.83 (s, 3H), 1.88 (dd, J=12.2, 3.5 Hz, 2H), 1.26-1.02 (m, 15H);

[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5-d] pyrimidin-5-yl]-(1-methyl-pip eri din-4-yl)-amine Vj' O'A18") [0398]

N

2- th «y th N 1DD' C. N NHp )—; N ~~N N

[0399] HPLC/MS 1.72 min (C), [M+H]340; Vj' [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5-d] pyrimi din-5-yl] -(3-methyl-3-aza-bi cyclo [3.LO]hex- 6-yl)-amine ("A19") [0400] [0394] A solution of 5-chloro-3-(4-methoxy-phenyl)-3H- [1,2,3]triazolo[4, 5-d]pyrimidine (131 mg, 0.50 mmol) and 4-amino-1, 2,2,6,6-pentamethylpiperidine (104 mg, 0.60 O~ mmol) in 2-methoxyethanol (1 ml) is heated to 100' C. and —N N stirred at this temperature for 1 hour. The reaction mixture is cooled to room temperature and partitioned between dichlo- romethane and 2 N NaOH. The organic phase is evaporated and the residue is chromatographed on a silica gel column with methanol/dichloromethane as eluent to afford [3-(4- ~~N N methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d]pyrimidin-5-yl]- (1,2,2,6,6-pentamethyl-pip eri din-4-yl)-amine as light yellow crystals; HPLC/MS 1.87 min (C), [M+H]396; 'H NMR (400 [0401] HPLC/MS 1 33 min (B), [M+H]338; 'H NMR (400 MHz, DMSO-d~) 6 [ppm]8. 21-8.08 (m, 2H), 8.05 (d, J=7.2 MHz, DMSO-d~) 6 [ppm]9. 22 (s, 1H), 8.24 (s, 1H), 8.15 (d, Hz, 1H), 7.14-7.07 (m, 2H), 4.21-4.03 (m, 1H), 3.84 (s, 3H), J=8.5 Hz, 2H), 7.20 (d, J=8.7 Hz, 2H), 3.86 (s, 3H), 3.06 (d, 2.22 (s, 3H), 1.97-1.82 (m, 2H), 1.41 (d, J=12.1 Hz, 2H), 1.11 J=8.8 Hz, 2H), 2.88 (s, 1H), 2.35 (d, J=7.7 Hz, 2H), 2.25 (s, (s, 12H). 3H), 1.62 (s, 2H). US 2016/0015712 A1 Jan. 21, 2016 36

Example 4 8.04 (d, J=8.6 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H), 435 (dd, J=16.4, 8.4 Hz, 1H), 3.85 (s, 3H), 230 (m, 2H), 2.11-2.01 (m, Synthesis of 4-[3-(4-methoxy-phenyl)-3H-[1, 2,3] 2H), 1.72 (m, 2H); triazolo [4,5-d]pyrimi din-5-ylamino]-l-methyl-pyrro- lidin-2-one ("A20") [2-(4-chloro-phenyl)-cyclopropyl]-[3-(4-methoxy- [0402] phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5-yl]- amine ("A22") [0407]

N

0 Cl ~~N N N 2-me&oxyethettol H ~(P) 100' C. [0408] HPLC/MS 2.24 min (B), [M+H]393: 'H NMR (500 x HC1 MHz, DMSO-de) ft [ppm]9. 27 (s, 1H), 8.69-8.59 (m, 1H), NHp 7.90-7.85 (m, 2H), 7.36 (d, J=8.1, 2H), 7.22 (d, J=83, 2H), 6.82-6.75 (m, 2H), 3.82 (s, 3H), 2.95-2.85 (m, 1H), 2.03-1.96 (m, 1H), 1.50-1.44 (m, 1H), 1 33-L25 (m, 1H); N [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5-d] pyrimidin-5-yl]-(4, 5,6,7-tetrahydro- 1H-indazol-5- yl)-amine ("A23") Vj' [0409]

[0403] To a solution of 5-chloro-3-(4-methoxy-phenyl)- H 3H-[1,2,3]triazolo[4, 5-d]-pyrimidine (97 mg, 0.37 mmol) and 4-amino-1-methyl-pyrrolidin-2-one hydrochloride (65 mg, 037 mmol) in 2-methoxyethanol (3 ml) is added N-eth- PN yldiisopropylamine (0.13 ml, 0.75 mmol). The mixture is N heated to 100' C. and stirred at this temperature for 1 hour. ~N The reaction mixture is evaporated and the residue is chro- N matographed on a silica gel column with methanol/dichlo- romethane as eluent to afford 4-[3-(4-methoxy-phenyl)-3H- HPLC/MS 1.70 min (B), [M+H]363; 'H NMR (500 MHz, [1,2,3]triazolo-[4, 5-d]pyrimidin-5-ylamino]- 1 -methyl- DMSO-de) ft [ppm]1233 (s, 1H), 9.25 (s, 1H), 8.17 (d, J=7.1 pyrrolidin-2-one as off-white powder; Hz, 1H), 8.03 (d, J=8.5 Hz, 2H), 7.18 (d, J=9.0 Hz, 2H), [0404] HPLC/MS 1.62 min [M+H]34; 'H NMR (500 (B), 4.16-4.10 (m, 1H), 3.83 (s, 3H), 2.94-2.87 (m, 1H), 2.84-2.75 MHz, DMSO-de) ft [ppm]9. 29 (s, 1H), 8.50 (s, 1H), 8.04 (d, (m, 1H), 2.73-2.62 (m, 1H), 2.61-2.51 (m, 1H), 2.21-2.13 (m, J=8.8 Hz, 2H), 7.20 J=8.6 Hz, 3H), 4.53-4.47 1H), (d, (m, 1H), 1.79 (m, 1H); 3.85 (s, 3H), 3.74 (dd, J=10.2, 73 Hz, 1H), 3.36 (m, 1H), 2.74 (s, 3H), 2.72-2.65 (m, 1H), 2.46-2.38 (m, 1H). trans-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4, The following compounds are prepared analo- [0405] 5-d]pyrimidin-5-yl amino] -cyclobutano1 ("A24") gously: cyclobutyl-[3-(4-methoxy-phenyl)-3H-[1, 2,3]tria- zolo [4,5-d]pyrimidin-5-yl]-amine ("A21") [0410]

~N N N ~~N N [0406] HPLC/MS 2.02 min (B), [M+H]297; 'H NMR (400 MHz, DMSO-de) ft [ppm] 9.23 (s, 1H), 8.41 (d, J=6.8 Hz, 1H), US 2016/0015712 A1 Jan. 21, 2016 37

[0411] HPLC/MS 1.66 min (B), [M+H]313; 'H NMR (500 [0417] HPLC/MS 1.81 min (B), [M+H]327; 'H NMR (400 MHz, DMSO-d~) 6 [ppm] 9.23 (s, 1H), 8.42 (d, J=53 Hz, 1H), MHz, DMSO-d~) 6 [ppm]9. 39 (s, 1H), 8.07 (d, J=9.0 Hz, 2H), 8.03 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 5.03 (d, J=4.4 7.23-7.14 (m, 2H), 4.40 (tt, J=7.7, 5 3 Hz, 1H), 4.27 (tt, J=5.4, Hz, 1H), 4.37-4.29 (m, 2H), 3.86 (s, 3H), 2.35-2.26 (m, 2H), 3.7 Hz, 1H), 3.88 (s, 3H), 2.23 (ddd, J=13.5, 7.8, 5.7 Hz, 1H), 2.25-2.17 (m, 2H); 2.14-2.01 (m, 1H), 1.78 (m, 4H);

cis-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5- [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5-d] d]pyrimidin-5-ylamino]-cyclobutanol ("A25") pyrimidin-5-yl]-(S)-tetrahydro furan-3-yl-amine O'A28") [0412] [0418]

N ~~N N ~~N N [0413] HPLC/MS 1.68 min (B), [M+H]313; 'H NMR (500 MHz, DMSO-d~) 6 [ppm]9. 22 (s, 1H), 836 (d, J=5.7 Hz, 1H), [0419] HPLC/MS 1.79 min (B), [M+H]313; 'H NMR (400 8.04 (d, J=8.6 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 5.06 (d, J=5.9 MHz, DMSO-d~) 6 [ppm]9. 27 (s, 1H), 837 (m, 1H), 8.03 (m, Hz, 1H), 3.91 (m, 1H), 3.85 (s, 3H), 3.84-3.76 (m, 1H), 2H), 7.20 (d, J=8.5 Hz, 2H), 4.41 (m, 1H), 3.95 (m, 1H), 3.85 2.70-2.57 (m, 2H), 1.94-1.85 (m, 2H); (s, 3H), 3.74 (q, J=7.9 Hz, 1H), 3.65 (m, 1H), 3.28 (m, 1H), 2.19 (m, 1H), 1.98 (m, 1H); cis-4-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5- d]pyrimidin-5-ylamino]-cyclohexanol ("A26") trans-3-[3-(4-bromo-phenyl)-3H-[1, 2,3]triazolo[4, 5- d]pyrimidin-5-ylamino]cyclopentanol ("A29") [0414] [0420]

HO Br N H

HOi ~N f/ N ~~N N rN N r

[0415] HPLC/MS 1.77 min [M+H]341; 'H NMR (500 azo1o, (B), [0421] HPLC/MS 1.86 min (B), [M+H]375/378; 'H NMR MHz, DMSO-d~) 6 [ppm]9. 22 (s, 1H), 8.18-7.79 (m, 3H), (400 MHz, DMSO-d~) 6 [ppm] 9.23 (s, 1H), 8.24 (d, J=6.4 Hz, 7.18 (d, J=8.3 Hz, 2H), 4.40 (m, 1H), 3.85 (s, 3H), 3.75 (m, 1H), 8.17 (d, J=8.5 Hz, 2H), 7.85 (d, J=8.5 Hz, 2H), 4.50 (m, J=4.4 Hz, 1H), 3.4 (m, 1H), 1.78 (m, 2H), 1.73-1.61 (m, 4H), 1H), 4.39 (q, J=6.9 Hz, 1H), 4.24 (m, 1H), 2.16 (m, 1H), 1.57-1.47 (m, 2H); 1.99-1.85 (m, 2H), 1.76 (m, 1H), 1.63-1.50 (m, 2H); cis-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5- (3-[4-(2-methoxy-ethoxy)-phenyl] -3H- [1,2,3]tri- d]pyrimidin-5-ylamino]-cyclopentanol ("A27") 5-d]pyrimi din-5-yl )-(3-pyridin-2-yl-propyl)- [0416] amine ("A68") [0422] HO

H o~o N

N

~~N ~~N N N US 2016/0015712 A1 Jan. 21, 2016 38

[0423] HPLC/MS 1.87 min (C), [M+H]406; 'H NMR (400 [2-(5-fluoro-1H-indol-3-yl)-ethyl]-13-[4-(2-meth- MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 27 (s, 1H), 8.75 (d, J=5.8 oxy-ethoxy)-phenyl]-3H-[1, 2,3]triazolo[4, 5-d]pyri- Hz, 1H), 8.47 (t, J=7.8 Hz, 1H), 8.02 (m, 3H), 7.86 (t, J=6.9 midin-5-yl )-amine ("A84") Hz, 1H), 7.23-7.14 (m, 2H), 4.26-4.19 (m, 2H), 3.79-3.71 (m, [0430] 2H), 3.56 (t, J=6.4 Hz, 2H), 338 (s, 3H), 3.17 (t, J=7.7 Hz, 2H), 2.17 (p, J=6.8 Hz, 2H);

[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d] pyrimidin-5-yl]-[1-(2-morpholin-4-yl-ethyl)-piperi- din-4-yl]-amine ("A78") o~o [0424] N )—;

~~N N

[0431] HPLC/MS 2.91 min (C), [M+H]448; 'H NMR (500 MHz, DMSO-d~, TFA-d, ) 6 [ppm] 9.32 (s, 1H), 8.07-8.02 (m, 2H), 736 (dd, J=8.8, 4.5 Hz, 1H), 732 (dd, J=9.9, 2.5 Hz, 1H), 7.28 (s, 1H), 7.22-7.15 (m, 2H), 6.90 (td, J=9.2, 2.5 Hz, [0425] HPLC/MS 1.33 min (B), [M+H]439; 1H), 4.25-4.19 (m, 2H), 3.79-3.69 (m, 4H), 3.38 (s, 3H), 3.08 (t, J=7.4 Hz, 2H); (1S,3R)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d]pyrimidin-5-ylamino]-cyc lop entanecarboxylic [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5-d] acid ("A79") pyrimidin-5-yl]-[1-(2-pyrrolidin-1-yl-ethyl)-piperi- din-4-yl]-amine ("A86") [0426] [0432]

OH 0 .J..., PN rN N

HPLC/MS 1.26 min [0427] HPLC/MS 1.80 min (B), [M+H]355; 'H NMR (400 [0433] (B), [M+H]423; MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 26 (s, 1H), 8.04 (m, 2H), 4-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d] 7.23-7.16 (m, 2H), 4.27 (m, 1H), 3.87 (s, 3H), 2.81 (p, J=8.5 pyrimidin-5-ylamino]-piperidin-2-one ("A87") Hz, 1H), 239-2.26 (m, 1H), 2.07-1.81 (m, 4H), 1.70 (m, 1H); [0434] (1R,3S)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d]pyrimidin-5-ylamino]-cyc lop entanecarboxylic acid ("A81") [0428] H

OH PN N rN H N PN [0435] HPLC/MS 1.59 min (B), [M+H]340; 'H NMR (500 N MHz, DMSO-d~, TFA-d, 6 9.29 8.14-7.93 rN ) [ppm] (s, 1H), (m, 2H), 7.19 (d, J=9.1 Hz, 2H), 435 (m, 1H), 3.88 (s, 3H), 3.41 N r (m, 1H), 3.33 (ddd, J=13.1, 8.9, 4.7 Hz, 1H), 2.82 (dd, J=17.4, 6.1 Hz, 1H), 2.56-2.48 (m, 1H), 2.28-2.03 (m, 1H), 1.90 (m, [0429] HPLC/MS 1.81 min (B), [M+H]355; 1H); US 2016/0015712 A1 Jan. 21, 2016 39

[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d] (trans)-3-[3-(5-methoxy-pyridin-2-yl)-3H-[1, 2,3] pyrimidin-5-yl]-((S)-1-pyri din-4-yl-pyrrolidin-3-yl)- triazolo [4,5-d]pyrimidin-5-yl amino] -cyclopentano1 amine ("A88") O'A 99") [0436] [0441]

NQ

N N

~~N ~~N N N

[0437] HPLC/MS 1.99 min (C), [M+H]389; 'H NMR (400 [0442] HPLC/MS 1.96 min (C), [M+H]328; 'H NMR (400 MHz, DMSO-d~) 6 [ppm]13.7 (s, 1H), 931 (s, 1H), 8.55 (s, MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 26 (s, 1H), 839 (d, J=3.0 1H), 8.21 (d, J=6.8 Hz, 2H), 8.06 (m, 2H), 7.19 (d, J=8.5 Hz, Hz, 1H), 8.03 (d, J=8.2 Hz, 1H), 7.75 (dd, J=9.0, 3.1 Hz, 1H), 2H), 6.85 (d, J=6.9 Hz, 3H), 4.67 (m, 1H), 3.85 (m, 4H), 3.72 4.45 (m, 1H), 4.24 (tt, J=5.9, 3.2 Hz, 1H), 3.96 (s, 3H), 2.14 (m, 2H), 3.61 (m, 2H), 2.37 (dq, J=13.7, 73 Hz, 1H), 2.24 (m, (m, 1H), 1.94 (m, 2H), 1.75 (dt, J=133, 6.7 Hz, 1H), 1.60-1. 1H); 1(1R,3S)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo 44 (m, 2H). [4,5-d]pyrimidin-5-ylamino]-cyclopentyl)-carbamic acid benzyl ester ("A89") (1S,3R)-3-[3-(4-iodo-phenyl)-3H-[1, 2,3]triazolo[4, 5- d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid O'A101")

[0443]

N HO N=N )—; 'H [0438] HPLC/MS 2.08 min (B), [M+H]460; NMR (500 ~~N MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 26 (s, 1H), 8.06 (m, 2H), N 7.42-734 (m, 4H), 7.34-7.28 (m, 1H), 7.19 (d, J=8.6 Hz, 2H), 5.04 2H), 4.29 1H), 3.95 J=7.2 Hz, 1H), 3.87 (s, (m, (p, (s, [0444] HPLC/MS 2.02 min (B), [M+H]451; 'H NMR (400 3H), 2.45-2.35 (m, 1H), 2.01 (dq, J=13.8, 73 Hz, 1H), 1.91 MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 27 (s, 1H), 8.09 (d, J=8.9 (dq, J=13.5, 7.4, 7.0 Hz, 1H), 1.81-1.70 (m, 1H), 1.70-1.61 Hz, 2H), 8.05-7.91 (m, 2H), 435 (m, 1H), 2.85 (p, J=8.5 Hz, (m, 1H), 1.60-1.51 (m, 1H); 1H), 237 (dt, J=14.6, 7.7 Hz, 1H), 1.99 (m, 4H), 1.76 (m, 1H); [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d] (trans)-3-(3-quinolin-6-y1-3H-[1, 2,3]triazo1o 5-d] pyrimidin-5-yl]-(R)-tetrahydro furan-3-yl-amine [4, pyrimidin-5-ylamino)-cyclopentanol ("A102") O'A 98") [0445] [0439]

„.Q; N N N ~~N N ~~N N [0440] HPLC/MS 1.81 min (B), [M+H]313; 'H NMR (400 MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 28 (s, 1H), 8.07 (d, J=8.5 [0446] HPLC/MS 1.52 min (B), [M+H]348; 'H NMR (500 Hz, 2H), 7.24-7.16 (m, 2H), 4.51 (m, 1H), 4.02-3.85 (m, 5H), MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 43 (dd, J=5.2, 1.4 Hz, 3.77 (td, J=8.1, 5.7 Hz, 1H), 3.72 (m, 1H), 2.25 (dq, J=12.6, 1H), 934-9.26 (m, 3H), 9.09 (d, J=10.3 Hz, 1H), 8.56 (d, 7.6 Hz, 1H), 2.10-1.97 (m, 1H); J=9.3 Hz, 1H), 8.21 (dd, J=8.4, 5.2 Hz, 1H), 4.56 (m, 1H), US 2016/0015712 A1 Jan. 21, 2016 40

430 (m, 1H), 2.28-2.20 (m, 1H), 2.09 (m, 1H), 2.00 (ddt, trans-l-(4-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo J=12.8, 8.4, 6.0 Hz, 1H), 1.80 (m, 1H), 1.63 (m, 2H); [4,5-d]pyrimidin-5-ylamino]-cyclohexyl)-piperidin- 4-ol formate ("A106") (S)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5- [0453] d]pyrimidin-5-ylamino]-piperidine-1-carboxylic acid tert-butyl ester ("A103") O~ [0447] H HO N

a~N N .„„H [0454] HPLC/MS 1.43 min (B), [M+H]424; 'H NMR (500 MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 28 (m, 1H), 8.13 (s, 1H), 8.11-7.92 (m, 2H), 7.19 (d, J=8.7 Hz, 2H), 3.97 (m, 1H), 3.87 (s, 3H), 3.7 (m, 1H), 3.44 (d, J=11.4 Hz, 1H), 332-3.18 (m, ~~N 3H), 3.05 J=12.5 Hz, 1H), 2.23-2.09 4H), 2.05-1.97 N (t, (m, (m, 1H), 1.97-1.86 (m, 1H), 1.85-1.78 (m, 1H), 1.73-1.57 (m, 3H), 1.50-1.37 (m, 2H); [044S] HPLC/MS 2.15 min (B), [M+H]426; c is-1-(4-[3-(4-methoxy-phenyl)-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5-ylamino]-cyclohexyl)-piperidin- [3-(4-methoxy-phenyl)-3H-[1, 3]triazolo 5-d] 2, [4, 4-ol formate ("A107") pyrimidin-5-yl]-(1-methyl-piperi din-3-yl)-amine formate ("A104") [0455]

[0449]

HO N

N

N N

~~N N

~N 'H N [0456] HPLC/MS 1.48 min (B), [M+H]424; NMR (500 MHz, DMSO-d~) 6 [ppm]9. 30 (s, 1H), 8.13 (s, 1H), 8.04 (m, 2H), 7.19 (d, J=8.9 Hz, 2H), 4.18 (m, 1H), 3.87 (s, 3H), [0450] HPLC/MS 1.39 min (B), [M+H]340; 3.74-3.63 (m, 1H), 3.44-337 (m, 1H), 332-3.21 (m, 3H), 3.11-3.02 (m, 1H), 2.18-1.77 (m, 6H), 1.75-1.58 (m, 3H); (R)-3-[3-(4-methoxy-phenyl)-3H- [1,2,3]triazolo [4,5- [3-(4-methoxy-phenyl)-3H-[1, triazo1o 5-d] d]pyrimidin-5-ylamino]-piperidine-1-carboxylic acid 2,3] [4, pyrimidin-5-yl]-KR)-1-pyri din-4-yl-pyrrolidin-3-yl)- tert-butyl ester ("A105") amine ("A109")

[0451] [0457]

H Q QN N rNr ~~N N N

[045S] "A109" hydrochloride: HPLC/MS 2.00 min (C), [0452] HPLC/MS 2.15 min (B), [M+H]426; [M+H]389; US 2016/0015712 A1 Jan. 21, 2016 41

(1S,3S)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o (1R,3R)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5-d]pyrimidin-5-ylamino]-cyc lop entanecarboxylic [4,5-d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid methyl ester ("A110") acid methyl ester ("A113")

[0459] [0465]

H QN N N rN rN N r N r

[0460] HPLC/MS 1.97 min (B), [M+H]369; [0466] HPLC/MS 1.89 min (B), [M+H]369;

((1S,3S)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]tria- ((1R,3R)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]tria- zolo[4, 5-d]pyrimidin-5-ylamino]-cyclopentyl)- zolo[4, 5-d]pyrimidin-5-ylamino]-cyclopentyl)- methanol ("Al 1 1") methanol ("A114")

[0461] [0467]

OH

N N N N rN N

[0462] HPLC/MS 1.80 min (B), [M+H]341; [0468] HPLC/MS 1.77 min (B), [M+H]341; ((1S,3R)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]tria- zolo[4, 5-d]pyrimidin-5-ylamino]-cyclopentyl)- [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5-d] methanol ("A112") pyrimidin-5-yl]-[(R)-1-(1-methyl-1H-pyrazol-4-yl)- pyrrolidin-3-yl]-amine ("A115") [0463] [0469]

',Yi rN N ~~N N

[0464] HPLC/MS 1.79 min (B), [M+H]341; HPLC/MS 1.72 min (B), [M+H]392. US 2016/0015712 A1 Jan. 21, 2016 42

Example 5 J=8.6 Hz, 2H), 7.19-7.15 (m, 1H), 3.92-3.87 (m, 1H), 3.85 (s, 3H), 3.74 (m, 1H), 2.64 (m, 2H), 1.98-1.88 (m, 2H), 1 38 (s, 9H). Synthesis of (c is-3- [3-(4-methoxy-phenyl)-3H- [1,2, 3]triazolo [4,5-d]pyrimidin-5-yl amino] -cyclobutyl )- [0472] The following compounds are prepared analo- carbamic acid tert-butyl ester ("A30")and cis-N-[3- gously: (4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d] pyrimidin-5-yl]-cyclobutane-1, 3-diamine (trans-3- [3-(4-methoxy-phenyl)-3H- [1,2,3]triazolo hydrochloride ("A31") [4,5-d]pyrimidin-5-ylamino]-cyclobutyl)-carbamic acid tert-butyl ester ("A32") [0470] [0473]

N Vj rN N r

[0474] HPLC/MS 1.99 min (B), [M+H]412; 'H NMR (400 x.X MHz, DMSO-d~) 6 [ppm] 9.24 (s, 1H), 8.49 (d, J=4.9 Hz, 1H), 8.03 (d, J=8.5 Hz, 2H), 7.25 (m, 1H), 7.23-7.10 (m, 2H), 4.28 8- 88 «8 88 (m, 1H), 4.09 (m, 1H), 3.85 (s, 3H), 230 (m, 4H), 1 39 (s, 80' C. 9H);

(4-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d] pyrimidin-5-ylamino]-cyclohexylmethyl)-carbamic acid tert-butyl ester ("A33") [0475] p— 4N Hci in dioxane

Yj N

NH2 [0476] HPLC/MS 2.13 min (B), [M+H]454;

4-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d] pyrimidin-5-ylamino]-piperidine-1-carboxylic acid HN N tert-butyl ester ("A34")

N [0477] N N

[0471] A solution of 5-chloro-3-(4-methoxy-phenyl)-3H- [1,2,3]triazolo[4, 5-d]pyrimidine (144 mg, 0.55 mmol) and cis-(3-amino-cyclobutyl)-carbamic acid tert-butyl ester (113 mg, 0.61 mmol) in 2-methoxyethanol (3 ml) is heated to 80' C. and stirred at this temperature for 18 hours. The reaction N mixture is evaporated and the residue is chromatographed on rN N r a silica gel column with cyclohexane/ethyl acetate as eluent to afford cis-(3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cyclobutyl)-carbamic acid tert- [0478] HPLC/MS 2.14 min (B), [M+H]426; 'H NMR (400 butyl ester as light pink powder; HPLC/MS 2.02 min (B), MHz, DMSO-d~) 6 [ppm]9. 24 (s, 1H), 8.02 (m, 3H), 7.19 (d, [M+H]412; 'H NMR (500 MHz, DMSO-d~) 6 [ppm]9. 24 (s, J=8.6 Hz, 2H), 3.95 (m, 2H), 3.92 (s, 3H), 3.23-3.10 (m, 1H), 1H), 8.42 (d, J=5.8 Hz, 1H), 8.05 (d, J=8.9 Hz, 2H), 7.22 (d, 2.92 (m, 1H), 2.78 (m, 1H), 1.92-1.83 (m, 2H), 1.40 (m, 11H); US 2016/0015712 A1 Jan. 21, 2016 43

(trans-3- [3-(4-methoxy-phenyl)-3H- [1,2,3]triazolo (S)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5- [4,5-d]pyrimidin-5-ylamino]-cyclopentyl)-carbamic d]pyrimidin-5-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester ("A35") acid tert-butyl ester ("A66") [0485] [0479]

H ~~N N

~Nr [04S6] HPLC/MS 2.04 min (B), [M+H]412. N [04S7] To a solution of lucis-3-[3-(4-methoxy-phenyl)-3H- [1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cyclobutyl)- carbamic acid tert-butyl ester (49.4 mg, 0.12 mmol) in a mixture of dioxane (1 ml) and methanol (1 ml) is added 4 N HC1 in dioxane (2 ml). The reaction mixture is stirred for 2 [04SO] racemate, HPLC/MS 2.07 min (B), [M+H]426; 'H hours at room temperature. The precipitate that has formed is NMR (500 MHz, DMSO-d~/TFA-d, ) 6 [ppm]9. 30 (s, 1H), filtered off, washed with dioxane and dried under vacuum to 8.08 (d, J=8.1 Hz, 2H), 7.19 (d, J=9.1 Hz, 2H), 4.42 (m, 1H), afford cis-N-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5- 4.03 (p, J=7.0 Hz, 1H), 3.88 (s, 3H), 2.23-2.14 (m, 1H), 2.05 d]pyrimidin-5-yl]-cyclobutane-1, 3-diamine hydrochloride (m, 1H), 1.98-1.91 (m, 2H), 1.64 (m, 1H), 1.57-1.49 (m, 1H), ("A31")as cream-coloured powder; HPLC/MS 1.41 min (B), 'H 1.42 (s, 9H); [M+H]312; NMR (400 MHz, DMSO-d~) 6 [ppm]9. 29 (s, 1H), 8.53 (s, 1H), 8.27 (s, 3H), 8.04 (d, J=8.4 Hz, 2H), 7.25-7.16 (m, 3H), 4.09 (m, 1H), 3.87 (s, 3H), 3.50 (m, 1H), 3- [3-(4-methoxy-phenyl)-3H- [1,2,3]triazolo [4,5-d] 2.70 (m, 2H), 2.19 (m, 2H). pyrimidin-5-ylamino]-azetidine-1-carboxylic acid [0488] The following compounds are prepared analo- tert-butyl ester ("A36") gously:

[0481] (3-aza-bicyclo [3/ LO]hex-6-yl)- [3-(4-methoxy-phe- nyl)-3H-[1, 2,3]triazolo [4,5-d]pyrimidin-5-yl]-amine hydrochloride ("A37") [0489]

H pN~ QN 0 N ~N N r ~~N N

[04S2] HPLC/MS 2.05 min (B), [M+H]398; [0490] HPLC/MS 1 32 min (B), [M+H]324; 'H NMR (500 MHz, DMSO-d~) 6 [ppm]9. 65-9.56 (m, 2H), 9.30 (m, 2H), (R)-3-[3-(4-methoxy-phenyl)-3H- [1,2,3]triazolo [4,5- 8.45-8.41 (m, 1H), 8.20 (d, J=8.6 Hz, 2H), 7.24 (d, J=8.5 Hz, d]pyrimidin-5-ylamino]-pyrrolidine-1-carboxylic 2H), 3.86 (s, 3H), 3.40 (m, 3H), 2.98-2.92 (m, 1H), 2.00 (m, acid tert-butyl ester ("A65") 2H); trans-N-[3-(4-methoxy-phenyl)-3H-[1, 3]triazolo [0483] 2, [4, 5-d]pyrimidin-5-yl]-cyclobutane-1, 3-diamine hydro- chloride ("A38") [0491]

N ~~N N ~N N

[04S4] HPLC/MS 2.04 min (B), [M+H]412; US 2016/0015712 A1 Jan. 21, 2016 44

[0492] HPLC/MS 1.33 min (B), [M+H]312; 'H NMR (400 Hz, 2H), 7.19 (d, J=9.0 Hz, 2H), 4.53 (m, 1H), 3.88 (s, 3H), MHz, DMSO-d~/TFA-d, ) 6 [ppm]9. 28 (s, 1H), 8.05 (d, J=8.5 3.77 (p, J=7.0 Hz, 1H), 2.37-2.19 (m, 2H), 2.18-2.06 (m, 2H), Hz, 2H), 7.19 (d, J=9.1 Hz, 2H), 4.67 (m, 1H), 3.89 (m, 4H), 1.81-1.64 (m, 2H); 2.58 (m, 4H); [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5-d] (4-aminomethyl-cyclohexyl)-[3-(4-methoxy-phenyl)- pyrimidin-5-yl]-(R)-pyrrolidin-3-yl-amine hydro- 3H-[1,2,3]triazolo[4, 5-d]-pyrimidin-5-yl]-amine chloride ("A69") hydrochloride ("A39") [0499] [0493] HpN

N

~~N ~~N N N

[0500] HPLC/MS 1.41 min (B), [M+H]312; 'H NMR (400 HPLC/MS 1.44 min 'H NMR [0494] (B), [M+H]354; (500 MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 28 (s, 1H), 8.05 (m, 2H), 6 23 03 J=8.2 MHz, DMSO-d~) [ppm] 9. (s, 1H), 8. (d, Hz, 2H), 7.18 (d, J=9.0 Hz, 1H), 4.66 (m, 1H), 3.88 (s, 3H), 3.57 (m, J=8. 72-2. 7.97 (m, 4H), 7.19 (d, 2 Hz, 2H), 3.85 (m, 4H), 2. 65 1H), 3.52-3.42 (m, 1H), 337 (m, 2H), 233 (m, 1H), 2.20 (m, (m, 2H), 2.07-2.01 (m, 1H), 1.95 (m, 1H), 1.88-1.81 (m, 2H), 1H); 1.63-1.55 (m, 1H), 1 31 (m, 2H), 1.16-1.04 (m, 2H); [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5-d] [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d] pyrimidin-5-yl]-(S)-pyrrolidin-3-yl-amine hydro- pyrimidin-5-yl]-piperidin-4-yl-amine hydrochloride chloride ("A77") ("A40") [0501] [0495]

N

N

~~N N ~~N N

[0496] HPLC/MS 1.39 min [M+H]326; 'H NMR (400 (B), [0502] HPLC/MS 1.37 min (B), [M+H]312; MHz, DMSO-d~/TFA-d, ) 6 [ppm]9. 29 (s, 1H), 8.05 (m, 2H), 7.23-7.14 (m, 2H), 4.18 (m, 1H), 3.88 (s, 3H), 3.41 (m, 2H), 13-[4-(1-methyl-1 H-pyrazol-4-yl)-phenyl]-3H-[1, 3.12 (m, 1H), 3.04 (td, J=12.7, 2.9 Hz, 1H), 2.16 (m, 2H), 1.84 2, 3]triazolo 5-d]pyrimidin-5-yl )-(R)-pyrrolidin-3-yl- (m, 2H); [4, amine ("A116")

trans-N- [3-(4-methoxy-phenyl)-3H- [1,2,3]triazolo [4, [0503] 5-d]pyrimidin-5-yl]-cyclopentane-1, 3-diamine hydrochloride ("A41")

[0497]

N

~~N ~~N N N

[0498] HPLC/MS 1.39 min (B), [M+H]326; 'H NMR (400 [0504] "A116" Hydrochloride HPLC/MS 1.36 min (B), MHz, DMSO-d~/TFA-d, ) 6 [ppm]9. 29 (s, 1H), 8.07 (d, J=7.6 [M+H]362; US 2016/0015712 A1 Jan. 21, 2016 45

((cis)-3-[3-(4-methoxy-phenyl)-3H- [1,2,3]triazolo [4, (1R,3R) N3-[3-(4-methoxy-phenyl)-3H-[1, 2,3] 5-d]pyrimidin-5-ylamino]-cyclopentylmethyl )-car- triazolo[4, 5-d]pyrimidin-5-yl]-cyclo pentane-, 3-di- bamic acid tert-butyl ester ("A117") amine ("A120")

[0505] [0511]

~~N ~~N N N

[0512] "A120" hydrochloride HPLC/MS 1.42 min (B), [0506] HPLC/MS 2.12 min [M+H]440; (B), [M+H]326;

(1S,3R)-N3-(3-[4-(1-methyl-1H-pyrazol-4-yl)-phe- (1S,3R) N3-(3-(4-[1-(2-methoxy-ethyl)-1H-pyra- nyl]-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5-yl)-cyclo- zo1-4-yl]-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimi- pentane-1, 3-diamine ("A118") din-5-yl)-cyclopentane-1, 3-diamine ("A121") [0507] [0513]

N N— N NQ N ~~N N [0514] HPLC/MS 1.42 min (B), [M+H]420; [0508] HPLC/MS 1.43 min (B), [M+H]376; K1R,3S)-3-aminomethyl-cyclopentyl)-[3-(4-meth- oxy-phenyl)-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5- 3R)-N3-(3-quinolin-6-y1-3H-[1, 5- (1S, 2,3]triazolo[4, yl]-amine ("A122") d]pyrimidin-5-yl)-cyc lop entane-1, 3-diamine O'A119") [0515] [0509]

N

H N~j NHp N ~~N N N

~~N N

[0510] HPLC/MS 1.33 min (B), [M+H]347; [0516] HPLC/MS 1.46 min (B), [M+H]340; US 2016/0015712 A1 Jan. 21, 2016 46

(1R,3R) N-(3-(4-[1-(2-methoxy-ethyl)-1H-pyra- [3-(2-methyl-quinolin-6-yl)-3H-[1, 2,3]triazo1o [4,5- zo1-4-yl]-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimi- d]pyrimidin-5-yl]-(R)-pyrrolidin-3-yl-amine din-5-yl)-cyclopentane-1, 3-diamine ("A123") O'A126")

[0517] [0523]

~~N N

[051S] HPLC/MS 1.44 min (B), [M+H]420; [0524] HPLC/MS 1.25 min (C), [M+H]390. (1R,3R) N-[3-(2-methyl-quinolin-6-yl)-3H-[1, 2,3] triazolo[4, 5-d]pyrimidin-5-yl]-cyclopentane-1, 3- Example 6 diamine ("A124") Synthesis of 1-(3-[3-(4-methoxy-phenyl)-3H-[1, [0519] 2,3] triazolo[4, 5-d]pyrimidin-5-ylamino]-piperidin-l-yl)- ethanone ("A42") and [3-(4-methoxy-phenyl)-3H- [1, 2,3]triazolo [4,5-d]pyrimidin-5-yl]-piperidin-3-yl- amine hydrochloride ("A43")

[0525]

H yt' /'

~~N N

[0520] HPLC/MS 1.57 min (C), [M+H]361; Vj

(1R,3R) N-(3-(4-[1-(2-3thoxy-ethyl)-1H-pyrazol- 4-yl] -phenyl )-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5- yl)-cyclopentane-1, 3-diamine ("A125")

2- [0521] y«yyy DIPEA 80' C. NH2 x HCl N

/ + Hct water

N 90' C.

[0522] HPLC/MS 1.49 min (C), [M+H]434; US 2016/0015712 A1 Jan. 21, 2016 47

-continued [0529] A solution of 5-chloro-3-(4-methoxy-phenyl)-3H- [1,2,3]triazolo[4, 5-d]pyrimidine (81 mg, 031 mmol) and trans-cyclohexane-1, 4-diamine (72 mg, 0.63 mmol) in 2-methoxyethanol (3 ml) is heated to 80' C. and stirred at this temperature for 18 hours. The reaction mixture is evaporated and the residue is chromate-graphed on a silica gel column with dichloromethane/methanol as eluent to afford trans-N- [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d]pyrimidin- S-yl]-cyclohexane-1, 4-diamine as light pink powder; HPLC/ Yj MS 1.39 min (B), [M+H]340; 'H NMR (400 MHz, DMSO- d~) b [ppm]9. 25 (s, 1H), 8.09 (d, J=7.5 Hz, 1H), 8.03 (d, J=8.6 Hz, 2H), 7.19 (d, J=8.6 Hz, 2H), 637 (bs, 2H), 3.86 (s, 3H), [0526] To a solution of 5-chloro-3-(4-methoxy-phenyl)- 3.70 (m, 1H), 2.87 (m, 1H), 1.99 (m, 4H), 1 37 (m, 4H). 3H-[1,2,3]triazolo[4, 5-d]-pyrimidine (118 mg, 0.45 mmol) [0530] The following compounds are prepared analogously and 1-(3-amino-piperidin-1-yl)-ethanone hydrochloride cis-N-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyri- (88.4 mg, 0.50 mmol) in 2-methoxyethanol (3 ml) is added midin-5-yl]-cyclohexane-1, 4-diamine ("A45") N-ethyldiisopropylamine (0.15 ml, 0.90 mmol). The mixture 'H is heated to 80' C. and stirred at this temperature for 1 hour. [0531] HPLC/MS 1.43 min (B), [M+H]340; NMR (400 The reaction mixture is evaporated and the residue is chro- MHz, DMSO-d~) b [ppm]9. 29 (s, 1H), 8.02 (m, 2H), 7.88 (m, matographed on a silica gel column with ethyl acetate/metha- 3H), 7.20 (d, J=9.1 Hz, 2H), 3.93 (m, 1H), 3.86 (s, 3H), 3.13 nol as eluent to afford 1-(3-[3-(4-methoxy-phenyl)-3H-[1, 2, (m, 1H), 1.99 (m, 2H), 1.74 (m, 6H); 3]triazolo[4, 5-d]pyrimidin-5-ylamino]-piperidin-l-yl)- ethanone as light pink powder; HPLC/MS 1.71 min (B), N-[3-(4-iodo-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyri- [M+H]368. midin-5-yl]-cyclohexane-1, 4-diamine ("A53") [0527] To a suspension of 1-(3-[3-(4-methoxy-phenyl)- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-piperidin-l- [0532] yl)-ethanone (73 mg, 0.20 mmol) in water (1 ml) is added 37% aqueous hydrochloric acid (134 pl). The mixture is heated to 90' C. and stirred at this temperature for 44 hours. The reaction mixture is evaporated and lyophilized to afford [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5-d]pyrimidin- 5-yl]-piperidin-3-yl-amine hydrochloride as orange powder; PN HPLC/MS 1.38 min (B), [M+H]326. N Example 7 ~N N Synthesis of trans-N-[3-(4-methoxy-phenyl)-3H-[1, 3]triazolo[4, 5-d]pyrimidin-5-yl]-cyclohexane-1, 4- 2, [0533] HPLC/MS 1.98 min (C), [M+H]436; 'H NMR (400 diamine ("A44") MHz, DMSO-d~, TFA-d, ) b [ppm]9. 27 (s, 1H), 8.02 (m, 4H), [0528] 3.81 (m, 1H), 3.10 m, 1H), 2.15-2.03 (m, 4H), 1.48 (m, 4H);

N-[3-(4-morpho lin-4-yl-phenyl)-3H-[1, 2,3]triazo1o [4,5-d]pyrimidin-5-yl]-cyclohexane-1, 4-diamine NHp C'A64")

[0534] 2- th«y h 80' C.

NHp Vj HpN

NHp

~~N N

Yj [0535] HPLC/MS 1 38 min (B), [M+H]395; 'H NMR (400 MHz, DMSO-d~, TFA-d, ) b [ppm]9. 28 (s, 1H), 8.10 (d, J=9.1 Hz, 2H), 7.40 (d, J=8.7 Hz, 2H), 3.95-3.84 (m, 5H), 3.40 (m, 4H), 3.09 (m, 1H), 2.08 (m, 4H), 1.61-1.40 (m, 4H); US 2016/0015712 A1 Jan. 21, 2016 48

N-[3-(4-fluoro-phenyl)-3H-[1, 2,3]triazolo[4, 5-d] J=9.3 Hz, 1H), 8.24 (dd, J=8.5, 5.3 Hz, 1H), 4.00-3.94 (m, pyrimidin-5-yl]-(trans)-cyclohexane-1, 4-diamine 1H), 3.12 (m, 1H), 2.14 (m, 4H), 1.69-1.41 (m, 4H); O'A75") N-(3- [4-(tetrahydro-pyran-4-yloxy)-phenyl]-3H- [1, [0536] 2,3]triazolo[4, 5-d]pyrimidin-5-yl)-trans-cyclohex- ane-1, 4-diamine O'A127") [0542] HpN '"'N

HpN

~~N .„„H N

[0537] HPLC/MS 1.84 min (C), [M+H]328; 'H NMR (400 MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 28 (s, 1H), 8.21 (dd, J=8.9, 4.8 Hz, 2H), 7.42 (t, J=8.8 Hz, 2H), 3.85 (m, 1H), ~~N 3.12-3.06 (m, 1H), 2.17-2.04 (m, 4H), 1.61-1.44 (m, 4H); N

trans-N-[3-(5-morpho lin-4-yl-pyri din-2-yl)-3H-[1, 2, [0543] HPLC/MS 1.47 min (B), [M+H]410; 3]triazolo[4, 5-d]pyrimidin-5-yl]-cyclohexane-1, 4- diamine O'A96") (S)-1-(4-[5-(4-amino-cyclohexylamino)-[1, 2,3]tria- zolo [4,5-d]pyrimi din-3-yl] -phenyl )-pyrrolidin-3-ol [0538] O'A128") [0544]

HpN OH

HpN N .„„H N

~~N N N

[0539] HPLC/MS 1.31 min [M+H]396; 'H NMR (400 ~~N (B), N MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 28 (s, 1H), 8.43-8.36 (m, 1H), 7.89 (d, J=5.2 Hz, 1H), 7.65 (dd, J=9.0, 3.1 Hz, 1H), 3.93-3.63 (m, 5H), 334 (m, 14H), 3.06 (m, 1H), 2.06 (m, 4H), [0545] HPLC/MS 1.37 min (B), [M+H]395; 1.47 (m, 4H); N-(3-[4-(1-methyl-1H-pyrazol-4-yl)-phenyl]-3H-[1, N-(3-quinolin-6-y1-3H-[1, 2,3]triazolo[4, 5-d]pyrimi- 2,3]triazolo[4, 5-d]pyrimidin-5-yl)-trans-cyclohex- din-5-yl)-cyclohexane-1, 4-diamine O'A100") ane-1, 4-diamine O'A129")

[0540] [0546]

HpN N

N HpN

~~N N N

~~N N [0541] HPLC/MS 1.33 min (B), [M+H]361; 'H NMR (400 MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 46 (dd, J=53, 1.5 Hz, 1H), 9.41-9.29 (m, 3H), 9.10 (dd, J=93,23 Hz, 1H), 8.59 (d, [0547] HPLC/MS 1.43 min (B), [M+H]390. US 2016/0015712 A1 Jan. 21, 2016 49

Example 8 mmol) and triethylamine (581 1, 4.19 mmol). The mixture is heated to 100' C. and stirred at this temperature for 90 min- Synthesis of 3-(4-(5-[3-(4-nitro-pyrazol-1-yl)-propy- utes. The reaction mixture is evaporated and the residue is lamino]-[1, 2,3]triazolo[4, 5-d]-pyrimidin-3-yl)-phe- chromatographed on a silica gel column with dichlo- noxy)-propionic acid ("A46") and 3-(4-(5-[3-(4- romethane/methanol as eluent to afford 3-(4-(5-[3-(4-nitro- amino-pyrazo1-1-yl)-propylamino]- [1,2,3]triazolo [4, pyrazol-1-yl)-propylamino]-[1, 2,3]triazolo[4, 5-d]pyrimi- 5-d]pyrimidin-3-yl)-phenoxy)-propionic acid din-3-yl)-phenoxy)-propionic acid as grey powder; C'A47") [0550] HPLC/MS 233 min (C), [M+H]454; 'H NMR (500 MHz, DMSO-de) 6 [ppm]12. 4 (bs, 1H), 9.24 (s, 1H), 8.88 (s, [0548] 1H), 8.25 (s, 1H), 8.18 (t, J=5.8 Hz, 1H), 7.98 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.6 Hz, 2H), 4.27 (m, 4H), 3.37 (m, 2H), 2.74 (t, J=6.0 Hz, 2H), 2.16 (m, 2H). HO [0551] A solution of 3-(4-(5-[3-(4-nitro-pyrazol-1-yl)- propylamino]-[1, 2,3]triazolo[4, 5-d]pyrimidin-3-yl)-phe- noxy)-propionic acid (63 mg, 0.14 mmol) in THE (20 ml) is hydrogenated with palladium on carbon as catalyst (0.1 g) at room temperature and under atmospheric pressure. After 20 hours, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by preparative HPLC to afford 3-(4- (5-[3-(4-amino-pyrazol-l-yl)-propylamino]-[1, 2,3]triazolo [4,5-d]pyrimidin-3-yl)-phenoxy)-propionic acid as white amorphous solid; HPLC/MS 1.73 min (C), [M+H]424; 'H NMR (500 MHz, DMSO-de) 6 [ppm]9. 75 (bs, 3H), 9.27 (s, Yj 1H), 8.22 (s, 1H), 8.04 (d, J=83 Hz, 2H), 7.95 (s, 1H), 7.55 (s, 1H), 7.21 (d, J=8.9 Hz, 2H), 4.29 (t, J=6.0 Hz, 2H), 4.24 (m, Npp 2H), 3,4 (m, 2H), 2.77 (t, J=6.0 Hz, 3H), 2.12 (m, 2H).

Example 9

~N 2- th yth N Synthesis of 2-dimethylamino-1-(4-[3-(4-methoxy- 0ie&ylemine phenyl)-3H-[1, 2,3]triazolo-[4, 5-d]pyrimidin-5- 100' C. ylamino]-pip eridin-1-yl )-ethanone ("A48") x 2 HCl [0552] NHp

HO H N Npp

~N N Hp Q Pd/C N / Vj' /z N

TBTU Vj' HOBt NMM DMF HO 0

N

~N N

[0549] To a solution of 3-(4-nitro-pyrazol-1-yl)-propy- Vj' lamine dihydrochloride (340 mg, 1.40 mmol) in 2-methoxy- ethanol (20 ml) is added 3-[4-(5-chloro-[1, 2,3]-triazolo[4, 5- d]pyrimidin-3-yl)-phenoxy]-propionic acid (447 mg, 1.40 US 2016/0015712 A1 Jan. 21, 2016 50

[0553] To a solution of [3-(4-methoxy-phenyl)-3H-[1, 2,3] 3-dimethylamino-1-(3-[3-(4-methoxy-phenyl)-3H- triazolo[4, 5-d]pyrimidin-5-yl]-piperidin-4-yl-amine hydro- [1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-azetidin- chloride (163 mg, 0.45 mmol) and N, N-dimethyl-glycine 1-yl)-propan-1-one ("A63") (5L6 mg, 0.50 mmol) in DMF (3 ml) is added 0-(benzotria- zol-1 -yl)-N, N, N', N'-tetramethyluronium tetrafluoroborate [0558] (TBTU) (209 mg, 0.65 mmol), 1-hydroxybenzotriazol hydrate (HOBt) (20. 3 mg, 0.13 mmol) and 4-methyl-mor- pholine (NMM) (0.16 ml, 1.50 mmol) and the reaction mix- ture is stirred for 1 hour at room temperature. The reaction mixture is partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with methanol/dichloromethane as eluent to afford 2-dimethy- lamino —(4-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5- ~~N d]pyrimidin-5-ylamino]-piperidin-1-yl)-ethanone as white N powder; HPLC/MS 1.43 min (B), [M+H]411; 'H NMR (500 MHz, DMSO-d~/TFA-di) 6 [ppm]9. 24 (s, 1H), 8.02 (m, 2H), 7.14 (d, J=9.0Hz, 2H), 435 (d, J=16.2 Hz, 1H), 4.28 (m, 1H), [0559] HPLC/MS 1.38 min (B), [M+H]397; 4.24 (d, J=16.1 Hz, 1H), 4.07 (m, 1H), 3.82 (s, 3H), 3.64 (dq, J=13.8, 3.2 Hz, 1H), 3.20 (t, J=12.4 Hz, 1H), 3.02 (m, 1H), 2-dimethylamino-1-((R)-3-[3-(4-methoxy-phenyl)- 2.82 (s, 3H), 2.81 (s, 3H), 2.00 (m, 2H), 1.58 (m, 1H), 1.48 (m, 5-d]-pyrimidin-5-ylamino]- 1H). 3H-[1,2,3]triazolo[4, pyrrolidin-1-yl)-ethanone formate ("A83" [0554] The following compounds are prepared analo- gously: [0560]

3-dimethylamino-1-(4-[3-(4-methoxy-phenyl)-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5-yl amino] -piperi- din-1-yl)-propan-1-one ("A49")

[0555]

~~N N

[0561] HPLC/MS 1.40 min (B), [M+H]397; 'H NMR (400 MHz, DMSO-d~/TFA-d, ) 6 [ppm]9. 19 (s, 3H), 8.00 (m, 3H), [0556] HPLC/MS 1.42 min (B), [M+H]425; 'H NMR (500 7.09 (m, 2H), 4.52 (m, 1H), 4.08 (m, 2H), 3.79 (s, 3H), 3.68 MHz, DMSO-d~/TFA-d, 6 [ppm]9. 28 (s, 2H), 8.05 (m, 2H), ) (dt, J=l 1.1, 6.0 Hz, 1H), 3.64-3.33 (m, 3H), 2.85-2.76 (m, 7.19 (d, J=8.6 Hz, 2H), 432 (m, 1H), 4.06 (m, 1H), 3.92-3.87 6H), 230-2.02 (m, 2H); (m, 1H), 3.86 (s, 3H), 332 (t, J=6.8 Hz, 2H), 3.24 (m, 1H), 2.98-2.83 (m, 3H), 2.82 (s, 6H), 2.01 (m, 2H), 1.56 (m, 1H), 1.46 (m, 1H). 3-dimethylamino-1-((R)-3-[3-(4-methoxy-phenyl)- 3H-[1,2,3]triazolo[4, 5-d]-pyrimidin-5-ylamino]- 2-dimethylamino-1-(3-[3-(4-methoxy-phenyl)-3H- pyrrolidin-1-yl)-propan-1-one formate ("A85") [1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-azetidin- 1-yl )-ethanone ("A62") [0562]

[0557]

N

~~N N ~~N N

[0563] HPLC/MS 1.39 min (B), [M+H]411; US 2016/0015712 A1 Jan. 21, 2016 51

1-((R)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo 1-((S)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d]pyrimidin-5-ylamino]-pyrrolidin-l-yl)-2- [4,5-d]pyrimi din-5-ylamino]-pyrrolidin-l-yl )-2- pyrazol-1-yl-ethanone ("A90") pyrazol-1-yl-ethanone ("A93")

[0564] [0570]

N~ H gN / N ~ gN N N c N N ~~N N ~~N N

[0565] HPLC/MS 1.73 min (B), [M+H]420; 'H NMR (500 MHz, DMSO-d~/TFA-d, ) 6 [ppm]9. 29 (s, 1H), 8.09 (m, 2H), [0571] HPLC/MS 1.69 min (B), [M+H]420; 7.79 (m, 1H), 7.74-7.56 (m, 1H), 7.20 (m, 2H), 636 (m, 1H), 5.27-5.03 (m, 2H), 4.55 (m, 1H), 3.88 (s, 3H), 3.84-3.57 (m, 3-dimethyl amino-1-KR)-3-(3-[4-(1-methyl-1H-pyra- 3H), 3.57-332 (m, 1H), 2.40-1.99 (m, 2H); zo1-4-yl)-phenyl] -3H- [1,2,3]triazolo [4,5-d]pyrimi- din-5-ylamino )-pyrrolidin-1-yl)-propan-1-one 2-dimethylamino-1-((S)-3-[3-(4-methoxy-phenyl)- O'A130") 3H-[1,2,3]triazolo[4, 5-d]-pyrimidin-5-ylamino]- pyrrolidin-1-yl)-ethanone formate ("A91") [0572] [0566]

N / N / g N=N ~~N N

[0573] "A130" formate HPLC/MS 1.43 min (B), [M+H] [0567] HPLC/MS 1.43 min (B), [M+H]397; 461;

3-dimethylamino-1-((S)-3-[3-(4-methoxy-phenyl)- 3-(4-methyl-pip erazin-1-yl)-1-((R)-3-(3-[4-(1-me- 3H-[1,2,3]triazolo[4, 5-d]-pyrimidin-5-ylamino]- thyl-1 H-pyrazol-4-yl)-phenyl]-3H-[1, 2,3]triazolo [4, pyrrolidin-1-yl)-propan-1-one formate ("A92") 5-d]pyrimidin-5-ylamino )-pyrrolidin-1-yl)-propan- 1-one ("A131") [0568] [0574]

Q

N /

~~N / N

N / / [0569] HPLC/MS 1.47 min (B), [M+H]411; 'H NMR (500 () N~N MHz, DMSO-d~) 6 [ppm]930 (s, 1H), 8.13 (s, 1H), 8.11-7.98 (m, 2H), 7.20 (m, 2H), 4.56 (m, OH), 3.87 (s, 3H), 3.83 (dd, J=10.7, 6.1 Hz, 1H), 3.77-3.64 (m, 1H), 3.64-3.41 (m, 2H), 337-3.26 (m, 2H), 2.81 (m, 7H), 238-L98 (m, 2H); [0575] HPLC/MS 1.39 min (B), [M+H]516; US 2016/0015712 A1 Jan. 21, 2016 52

1-((R)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo Example 10 [4,5-d]pyrimidin-5-ylamino]-pyrrolidin-l-yl)-3-(4- methyl-piperazin-1-yl)-propan-1-one ("A132") Synthesis of [3-(4-methoxy-phenyl)-3H-[1, 2,3]tria- zolo[4, 5-d]pyrimidin-5-yl]-[2-(4-methyl-piperazin-1- [0576] yl)-ethyl]-amine ("A50") [0582]

yyyl THF / / g C) N=N Yj NH2

[0577] "A132" formate HPLC/MS 1.43 min (B), [M+H] 466;

3-(4-methyl-piperazin-1-yl)-1-[(R)-3-(3-quinolin-6- y1-3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino)- pyrrolidin-1-yl]-propan-1-one ("A133") [0578] Yj

[05S3] To a solution of 5-chloro-3-(4-methoxy-phenyl)- 3H-[1,2,3]triazolo[4, 5-d]-pyrimidine (200 mg, 0.76 mmol) in THF (4 ml) is added triethylamine (107pl, 0.76 mmol). The reaction mixture is stirred for 1 hour at room temperature. The reaction mixture is partitioned between dichloromethane and water. The is dried over sodium sulfate and N=N organic phase C) evaporated. The residue is chromatographed on a silica gel column with dichloromethane/methanol to afford [3-(4- methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d]pyrimidin-5-yl]- [2-(4-methyl-piperazin-1-yl)-ethyl]-amine as off-white pow- [0579] "A133" formate HPLC/MS 1 35 min (B), [M+H] der; HPLC/MS 1.47 min (A), [M+H]369; 'H NMR (500 487; MHz, DMSO-d~) b [ppm] 9.22 (s, 1H), 8.03 (d, J=8.2 Hz, 2H), 7.92 (m, 1H), 7.17 (d, J=9.0 Hz, 2H), 3.85 (s, 3H), 3.49-3.41 3-(4-methyl-piperazin-1-yl)-1-((R)-3-[3-(2-methyl- (m, 2H), 330 (m, 2H), 2.53 (m, 2H), 2.45 (m, 2H), 230 (m, quinolin-6-yl)-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5- 4H), 2.14 (s, 3H). ylamino]-pyrrolidin-1-yl)-propan-1-one ("A134") [05S4] The following compounds are prepared analo- gously: [0580] [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5-d] pyrimidin-5-yl]-(3-pyrroli din-1-yl-propyl)-amine O'A61")

N [0585] / I PN N ~N Yj N

[05S6] HPLC/MS 1.59 min (A), [M+H]354; 'H NMR (500 [05S1] HPLC/MS 1.31 min (B), [M+H]501. MHz, DMSO-d~, TFA-d, ) b [ppm] 9.28 (s, 1H), 8.08-8.03 (m, US 2016/0015712 A1 Jan. 21, 2016 53

2H), 7.20 (d, J=8.9 Hz, 2H), 3.88 (s, 3H), 3.62-3.47 (m, 4H), Example 11 331-3.23 (m, 2H), 3.08-2.98 (m, 2H), 2.07-1.97 (m, 4H), 1.89 (m, 2H); Synthesis of trans-3-(3-[4-(I -methyl-I H-pyrazol-4- yl)-phenyl]-3H-[1, 2,3]trlazolo[4, 5-d]pyrimidin-5- - (R)-I (4-[5-((trans)-4-amino-cyclohexylamino)- [1,2, ylamino)-cyclopentanol ("A51") 3]triazolo[4, 5-d]pyrimidin-3-yl]-phenyl)-pyrrolidin- 3-ol ("A70") [0593] [0587] Br

H2N

Vj' N ~~N /r N N

'H N~ [05SS] HPLC/MS 1.36 min (B), [M+H]395; NMR (500 N MHz, DMSO-de, TFA-dt) ft [ppm]9. 25 (s, IH), 7.87 (m, 2H), 6.74 (d, J=9.0 Hz, 2H), 4.48 (tt, J=4.9, 2.6 Hz, IH), 3.75 (m, PdCl dppf I H), 3.51 (dd, J=10.2, 4.8 Hz, I H), 3.45 (td, J=9.0, 7.0 Hz, K2COg IH), 339 (td, J=8.7, 3.5 Hz, IH), 3.24-3.17 (m, IH), 3.10-3. ~B dioxatte/water 01 (m, I 2.17-1.94 (m, 6H), 1.54-137 (m, 4H); 0 H), 80' C.

I -(4-[5-Ktrans)-4-amino-cyclohexyl amino)-[1, 2,3] triazolo [4,5-d]pyrimidin-3-yl]-phenyl)-pyrrolidin-2- one ("A71") N~ N [0589]

HO

H2N "'NH

N

N ~~N Yj Iy N N

[0590] HPLC/MS 1.36 min (B), [M+H]393; 'H NMR (400 [0594] A suspension of (trans)-3-P-(4-bromo-phenyl)- MHz, DMSO-de, TFA-dt) ft [ppm]9. 29 (s, IH), 8.21 (d, J=8.5 3H-[1,2,3]triazolo[4, 5-d]-pyrimidin-5-ylamino]-cyclopen- Hz, 2H), 7.98-7.91 (m, 2H), 3.95 (t, J=7.0 Hz, 2H), 3.88 (m, tanol (146 mg, 039mmol), I -methyl-4-(4, 4,5,5-tetramethyl- IH), 3.10 (m, IH), 2.57 (m, 2H), 2.23-2.07 (m, 6H), 1.51 (m, [1,3,2]dioxaborolan-2-yl)- I H-pyrazole (106mg, 0.51 mmol) 4H); and potassium carbonate (163mg, 1.17mmol) in a mixture of dioxane (I ml) and water (0.1 ml) is flushed with nitrogen and (3-[4-(2-methoxy-ethoxy)-phenyl]-3H-[1, 2,3]trla- heated to 80' C. under stirring. Dichloro[1, 1'-bis(diphe- zolo[4, 5-d]pyrimidin-5-yl)-P-(4-methoxy-phenyl)- nylphosphino) ferrocene]palladium(II) dichloromethane propyl] -amine ("A80") adduct (32 mg, 0.04 mmol) is added and the reaction is stirred under nitrogen in a closed reaction vial at 80' C. for 18 hours. [0591] The reaction mixture is allowed to reach room temperature. The precipitate that has formed is filtered off, washed with O~O water and dried under vacuum to afford (trans)-3-(3-[4-(1- methyl-I H-pyrazol-4-yl)-phenyl]-3H-[1, 2,3]triazolo[4, 5-d] pyrimidin-5-ylamino)-cyclopentanol as grey powder; HPLC/MS 1.66 min (B), [M+H]377; 'H NMR (400 MHz, DMSO-de) ft [ppm]9. 23 (s, IH), 8.24 (s, IH), 8.17 (d, J=8.1 Hz, 2H), 8.08 (m, IH), 7.96 (s, IH), 7.83 (d, J=8.3 Hz, 2H), 4.55 (s, IH), 4.42 (m, I H), 4.25 (m, IH), 3.89 (s, 3H), 3.57 (s, 3H), 2.18 (m, I H), 2.00-1.86 (m, 2H), 1.82-1.74 (m, IH), 1.54 [0592] HPLC/MS 3.05 min (C), [M+H]435. (m, 2H). US 2016/0015712 A1 Jan. 21, 2016 54

[0595] The following compounds are prepared analo- Example 12 gously: Chiral separation of "A10"into "A55" and "A56" [0600] N-(3-(4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]- phenyl)-3H-[1, 2,3]triazolo[4, 5-d]-pyrimidin-5-yl)- HO cyclohexane-1, 4-diamine ("A52")

[0596] chirat column

N

N N /y N "Al 0" racemic mixture

HO

from N-[3-(4-iodo-phenyl)-3H- [1,2,3]triazolo [4,5-d]pyrimi- din-5-yl]-cyclohexane-1, 4-diamine ("A53", example 7) and Vj' 1-(2-methoxy-ethyl)-4-(4, 4,5,5-tetramethyl-[1, 3,2]diox- aborolan-2-yl)-1H-pyrazole; "A55" HO [0597] HPLC/MS 1.89 min (C), [M+H]434; 'H NMR (400 MHz, DMSO-de/TFA-dt) ft [ppm]9. 29 (s, 1H), 8.24 (s, 1H), 8.18 (d, J=8.4 Hz, 2H), 8.02 (s, 1H), 7.88-7.80 (m, 2H), 4.37 (t, J=5.2 Hz, 2H), 3.87 (m, 1H), 3.79 (t, J=5.2 Hz, 2H), 331 (s, 3H), 3.10 (m, 1H), 2.12 (m, 4H), 1.52 (m, 4H);

N-(3-[4-(l-ethyl-lH-pyrazol-4-yl)-phenyl]-3H-[1, 2, Yj 3]triazolo[4, 5-d]pyrimidin-5-yl)-(trans)-cyclohex- ane-1, 4-diamine trifluoroacetate ("A54") "A56"

[0598] [0601] (trans)-3-[3-(4-Methoxy-phenyl)-3H-[1, 2,3]tria- zolo[4, 5-d]pyrimidin-5-ylamino]-cyclopentanol ("A10") is chromatographed on a Chiralpak AD column with heptane/ ethanol as eluent to afford two enantiomers: First eluted enantiomer: "A55", light yellow powder; HPLC/ N MS 1.69 min (B), [M+H]327 (absolute configuration arbi- trarily assigned) H2N Second eluted enantiomer "A56", light yellow powder; L HPLC/MS 1.72 min (B), [M+H]327 (absolute configuration arbitrarily assigned). Example 13

N Synthesis of trans-3-(3-(4-[1-(2-hydroxy-ethyl)-1H- pyrazo1-4-yl] -phenyl )-3H-[1,2,3]triazolo [4,5-d]pyri- ~~N N midin-5-ylamino)-cyclopentanol ("A57") [0602] Br HO from "A53" and l-ethyl-4-(4, 4,5,5-tetramethyl-[1, 3,2]diox- aborolan-2-yl)-1H-pyrazole; [0599] HPLC/MS 1.95 min (C), [M+H]404; 'H NMR (400 MHz, DMSO-de/TFA-dt) ft [ppm]9. 28 (s, 1H), 8.27 (d, J=0.8 Hz, 1H), 8.17 (d, J=83 Hz, 2H), 8.01 (s, 1H), 7.92-7.70 (m, Vj' 2H), 4.24 (q, J=73 Hz, 2H), 3.84 (m, 1H), 3.09 (m, 1H), 2.28-1.99 (m, 4H), 1.68-1.27 (m, 7H). US 2016/0015712 A1 Jan. 21, 2016 55

-continued [0603] A suspension of (trans)-3-[3-(4-bromo-phenyl)- 3H-[1,2,3]triazolo[4, 5-d]-pyrimidin-5-ylamino]-cyclopen- tanol (195mg, 0.52 mmol), I-[2-(tetrahydro-pyran-2-yloxy)- ethyl]-4-(4, 4,5,5-tetramethyl-[1, 3,2]dioxaboro lan-2-yl)- I H- pyrazole (219mg, 0.68 mmol) and potassium carbonate (216 mg, 1.57 mmol) in a mixture ofdioxane (2 ml) and water (0.2 ml) is flushed with nitrogenis(diphenylphoand heated to 80' C. under stir- PdCf dppf ring. Dichloro [1,1'-b sphino) ferro cene] -palla- N Kr CO1 dium(II) dichloromethane adduct (43 mg, 0.05 mmol) is i / dioxane/water added and the reaction is stirred under nitrogen in a closed 80' C. reaction vial at 80' C. for 18 hours. The reaction mixture B—0 evaporated and the residue is chromatographed on a silica gel / column with dichloromethane/methanol as eluent to afford 0 (trans)-3-[3-(4-( I -[2-(tetrahydro-pyran-2-yloxy)-ethyl] -I H- pyrazol-4-yl )-phenyl)-3H-[1, 2,3]trlazolo[4, 5-d]pyrimidin- 5-ylamino]-cyclopentanol as yellow powder; HPLC/MS 1.82 min (B), [M+H]491. [0604] To a solution of (trans)-3-[3-(4-( I-[2-(tetrahydro- pyran-2-yloxy)-ethyl]-I H-pyrazol-4-yl)-phenyl)-3H-[1, 2,3] triazolo[4, 5-d]pyrimidin-5-ylamino]-cyclopentanol (72 mg, 035 mmol) in dichloromethane (6 ml) is added hydrochloric acid in dioxane (4 M, 410 pl) and the reaction mixture is HC1 stirred for I hour at room temperature. The solids are filtered dtoxane off, washed with dichloromethane and dried under vacuum to afford (trans)-3-(3-(4-[I-(2-hydroxy-ethyl)-IH-pyrazol-4- yl] -phenyl )-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5- ylamino)-cyclopentanol hydrochloride as light brown solid; HPLC/MS 1.55 min (B), [M+H]407

[0605] 'H NMR (500 MHz, DMSO-de, TEA-dt) ft [ppm]8. 29 (s, I H), 8.18 (m, 2H), 8.03 (s, I H), 7.86 (d, J=83 Hz, 2H), 4.47 (m, IH), 4.27 (m, IH), 4.22 (t, J=5.6 Hz, 2H), 3.81 (t, J=5.6 Hz, 2H), 2.19 (m, I H), 2.04-1.89 (m, 2H), 1.80 (m, IH), 1.56 (m 2H).

N Example 14

Synthesis of (IS,3R)-N-[3-(4-methoxy-phenyl)-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5-yl]-cyclopentane- 1,3-diamine ("A58") [first enantiomer] and (IR,3S)- N- [3-(4-methoxy-phenyl)-3H- [1,2,3]triazolo [4,5-d] pyrimidin-5-yl]-cyclopentane-1, 3-diamine ("A59") [second enantiomer]

[0606]

EtNHPrir CH1OCHrCHrOH 80' C. ~N N

NHr

chiral column US 2016/0015712 A1 Jan. 21, 2016 56

-continued

N

N

N ~~N N N

N

H2N

~N ~N N N

[0607] To a solution of 5-chloro-3-(4-methoxy-phenyl)- oxy-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5-yl]-cy- 3H-[1,2,3]triazolo[4, 5-d]pyrimidine (525 mg, 2.01 mmol) clopentane-1, 3-diamine hydrochloride as white solid; HPLC/ and cis-3-amino-cyclopentyl)-carbamic acid tert-butyl ester MS 1.44 min (B), [M+H]326. hydrochloride (521 mg, 2.20 mmol) in 2-methoxyethanol (15 ml) is added N-ethyldiisopropylamine (0.75 ml, 4.41 mmol). Example 15 The mixture is heated to 80' C. and stirred at this temperature for 3 hours. The reaction mixture is allowed to cool to room Synthesis of ((1R,3S)-3-[3-(4-methoxy-phenyl)-3H- temperature. The solids are filtered off, washed with metha- [1,2,3]triazolo [4,5-d] -pyrimi din-5-ylamino]-cyclo- nol and dried under vacuum to afford (cis-3-[3-(4-methoxy- pentyl )-(4-methyl-piperazin-1-yl)-methanone phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cy- C'A60") clopentyl)-carbamic acid tert-butyl ester as beige powder; [0612] HPLC/MS 2.06 min (B), [M+H]426 [0608] (cis-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d]pyrimidin-5-ylamino]-cyclopentyl)-carbamic acid tert-butyl ester is chromatographed on a Chiralpak AD-H column with supercritical carbon dioxide/methanol(contain- ing 0.5% diethylamine) 80: 20 as eluent to afford two enan- tiomers: [0609] First eluted enantiomer: tert-butyl N-[(1S,3R)-3- [[3-(4-methoxyphenyl)-triazo1o [4,5-d]pyrimi din-5-yl] amino]cyclopentyl]carbamate, white solid. Second eluted enantiomer: tert-butyl N-[(1R,3S)-3-[[3-(4-methoxyphe- Vj nyl)-triazolo [4,5-d]pyrimi din-5-yl] amino] cyclopentyl] car- bamate; light beige solid [0610] tert-Butyl N-[(1S,3R)-3-[[3-(4-methoxyphenyl) triazolo[4, 5-d]pyrimidin-5-yl] amino] cyclopentyl]carbamate (136 mg, 032 mmol) is slurried in hydrogen chloride in dioxane (4 M solution, 1.1 ml) and methanol (0.5 ml) is ?/' added. The reaction mixture is stirred for 3 hours at room 0 ~N temperature. The solids are filtered off, washed with dichlo- N romethane and dried under vacuum to afford (1S,3R) N3- [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o 5-d]pyrimidin- [4, [0613] To a solution of (1R,3S)-3-[3-(4-methoxy-phenyl)- 5-yl]-cyclopentane-1, 3-diamine hydrochloride as white 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cyclopen- solid; HPLC/MS 1.47 min (B), [M+H]326; 'H NMR (500 tanecarboxylic acid (142 mg, 0.40 mmol) in DMF (2 ml) are MHz, DMSO-de, TFA-d, 6 28 8.10-8.04 ) [ppm]9. (s, 1H), (m, added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide 2H), 7.23-7.16 (m, 2H), 430 (m, 1H), 3.87 (s, 3H), 3.60 (q, hydrochloride (153mg, 0.80 mmol), 1-hydroxybenzotriazole J=7.5 Hz, 1H), 2.11-1.99 (m, 2H), 1.89-1.73 (m, 2H), 1.67 hydrate (122 mg, 0.80 mmol) and 1-methylpiperazine (47.7 (dt, J=14.3, 7.5 Hz, 1H). mg, 0.48 mmol) and the reaction mixture is stirred for 3 hours [0611] tert-Butyl N-[(1R,3S)-3-[[3-(4-methoxyphenyl) at room temperature. The reaction mixture is partitioned triazolo[4, 5-d]pyrimidin-5-yl] amino] cyclopentyl]carbamate between water and ethylacetate. The organic phase is dried is treated similarly to afford afford (1R,3S) N3-[3-(4-meth- over sodium sulfate and evaporated. The residue is chromato- US 2016/0015712 A1 Jan. 21, 2016 57

graphed on a silica gel column with dichloromethane/metha- -continued nol as eluent to afford ((1R,3S)-3-[3-(4-methoxy-phenyl)- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]- N~ cyclopentyl)-(4-methyl-piperazin-1-yl)-methanone as white N powder; HPLC/MS 1.49 min (B), [M+H]437; 'H NMR (500 MHz, DMSO-de, TFA-dt) ft [ppm]9. 27 (s, 1H), 8.06 (m, 2H), HO 7.24-7.15 (m, 2H), 4.56 (m, 1H), 437 (m, 1H), 4.21 (m, 1H), 3.88 (s, 3H), 3.45 (m, 3H), 3.24 (m, 1H), 3.01 (m, 3H), 2.86 (s, 3H), 2.25 (dt, J=14.4, 7.4 Hz, 1H), 2.11-1.60 (m, 5H). [0614] The following compound is prepared analogously:

((1S,3R)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]tria- N zolo[4, 5-d]pyrimidin-5-ylamino]-cyclopentyl)-(4- N methyl-piperazin-1-yl)-methanone ("A97") Yj // N [0615]

[0618] HPLC/MS 1.50 min (B), [M+H]378; 'H NMR (400 MHz, DMSO-de) ppm [ppm]9. 35-9.21 (m, 1H), 8.96-8.86 (m, 1H), 8.40-8.24 (m, 2H), 8.24-7.99 (m, 3H), 4.65-434 (m, 2H), 4.29-4.18 (m, 1H), 3.91 (s, 3H), 2.23-2.03 (m, 1H), 2.03-1.84 (m, 2H), 1.84-1.62 (m, 1H), 1.62-1.41 (m, 2H).

~~N N Example 17

Synthesis of trans-N-(3-[4-(2-morpholin-4-yl- [0616] HPLC/MS 1.49 min (B), [M+H]437; 'H NMR (500 ethoxy)-phenyl]-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin- MHz, DMSO-de, TFA-dt) ft [ppm]9. 25 (s, 1H), 8.05 (m, 2H), S-yl)-cyclohexane-1, 4-diamine ("A95") 7.23-7.16 (m, 2H), 4.52 (m, 1H), 4.30 (s, 1H), 4.21 (m, 1H), 3.87 (s, 3H), 3.56-3.43 (m, 2H), 338 (t, J=13.5 Hz, 1H), 3.22 (m, 1H), 3.12-3.00 (m, 1H), 3.00-2.90 (m, 2H), 2.84 (s, 3H), [0619] 2.23 (m, 1H), 2.05-1.98 (m, 1H), 1.97-1.89 (m, 2H), 1.88-1. 82 (m, 1H), 1.75 (m, 1H). NHr Example 16

Synthesis of trans-3- (3-[5-(1-methyl-1H-pyrazo1-4- yl)-pyridin-2-yl]-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin- 5-ylamino )-cyclopentanol ("A94")

[0617] N

Vj // N

HO / ~N DIEA 2-medtoxyedtano1 allylpalladiumchloride 80' C. Yj NHr Y+

HO

0/ (,) CsrCOg N PdChdppf toluene KrCOg 110' C. Yj // dioxane/water OH N 80' C. US 2016/0015712 A1 Jan. 21, 2016 58

-continued

NH2

F tyl acetoniu ile 70' C.

N Cl~ N NH N Yj ly Yi N N NH2

[0620] HPLC/MS 1.41 min [M+H]439; 'H NMR (500 / (C), 0 MHz, DMSO-de, TFA-dt) ft [ppm]9. 26 (s, IH), 8.13 (s, IH), 8.12-8.02 (m, 2H), 732-7.24 (m, 2H), 4.50 (t, J=4.8 Hz, 2H), 4.07-3.99 (m, 2H), 3.85-3.71 (m, 3H), 3.67 (t, J=4.9 Hz, 2H), x HCl 3.60 (d, J=12.5 Hz, 2H), 3.29 m, 2H), 3.07 (m, IH), 2.13-2.01 1.54-138 4H). (m, 4H), (m, NH2 DIPEA Example 18 CHgOCH2CH2OH 80' C. Synthesis of (IR,3R)-3-(3-[4-(2-methoxy-ethoxy)- phenyl]-3H-[1, 2,3]triazolo [4,5-d]pyrimidin-5- ylamino)-cyclopentanecarboxylic acid amide Vj O'A135") / [0621] 0

HHCF, HOH Cl~ N Cl FtlOXHtle NEts

Yi THE N 3-5' C. NO2 Yj

NH2 / 0

H2N +7

H IR ~ THF Vj' Cl ~ N NH Yi N NO2 [0622] In a reaction flask, 2,4-dichloro-5-nitro-pyrimidine (41.7 g, 215 mmol) is dissolved in THF (250 ml) and the US 2016/0015712 A1 Jan. 21, 2016 59

solution is cooled in an ice bath. Under stirring and external [0630] 'H NMR (500 MHz, DMSO-d~, TFA-d, ) 6 9.23 (s, cooling (3-5' C.), a solution of 4-(2-methoxy-ethoxy)-phe- IH), 8.05 (bs, 2H), 7.17 (d, J=8.8 Hz, 2H), 4.31 (bs, IH), nylamine (35.9 g, 215 mmol) in THF (250 ml) is added 4.24-4.06 (m, 2H), 3.79-3.62 (m, 2H), 3.32 (s, 3H), 3.00-2.81 dropwise. An orange precipitate develops. Then, still under (m, IH), 2.21 (bs, IH), 2.10-1.94 (m, 2H), 1.84 (ddd, J=13.2, cooling (2-5' C.), triethylamine (29.8 ml, 215 mmol) is added 8.9, 5.8 Hz, IH), 1.76 (m, IH), 1.68 (m, IH). tem- slowly. The reaction mixture is allowed to reach room [0631] In a reaction flask, (IR,3R)-3-13-[4-(2-methoxy- perature and stirred for 30 minutes. The reaction mixture is ethoxy)-phenyl]-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5- filtered with suction and the residue is washed well with THF. ylamino)-cyclopentanecarboxylic acid (1.55 g, 3.87 mmol), The filtrate is evaporated and the residue is triturated with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydro- tert-butyl methyl ether to afford (2-chloro-5-nitro-pyrimidin- chloride (1.50 g, 7.82 mmol) and I-hydroxybenzotriazole 4-yl)-[4-(2-methoxy-ethoxy)-phenyl]-amine as orange red hydrate (525 mg, 3.89 mmol) are dissolved in a 0.5M solution crystals; HPLC/MS 1.93 min (B), [M+H]325; of ammonia in dioxane (40 ml, 20.0 mmol ammonia). The reaction mixture is stirred for 16 hours at 60' C. It is then [0623] 'H NMR (400 MHz, DMSO-d~) 6 1036 (s, IH), evaporated and the residue is chromatographed on a silica gel 9.12 I 7.41 J=9.0 Hz, 7.01 J=9.0 Hz, (s, H), (d, 2H), (d, IH), column with dichloromethane/methanol as eluent to afford 438-3.96 3.87-3.56 332 3H). (m, 2H), (m, 2H), (s, (IR,3R)-3-13-[4-(2-Methoxy-ethoxy)-phenyl]-3H-[1, 2,3] [0624] To a solution of (2-chloro-5-nitro-pyrimidin-4-yl)- triazolo[4, 5-d]pyrimidin-5-ylamino )-cyclopentanecarboxy- [4-(2-methoxy-ethoxy)-phenyl]-amine (68.9 g, 212 mmol) in lic acid amide as light yellow solid; HPLC/MS 1.65 min (B), THF (710 ml) is added sponge-nickel-catalyst (pH-neutral, [M+H]398; THF-wet) and the mixture is hydrogenated at normal pressure [0632] 'H NMR (500 MHz, DMSO-d~, TFA-d, ) 6 9.28 (s, and room temperature for 40 hours. The reaction mixture is IH), 8.09 (bs, 2H), 732-6.93 (m, 2H), 437 (bs, IH), 432-4. filtered with suction. 08 (m, 2H), 3.79-3.68 (m, 2H), 3.36 (s, 3H), 2.87 (p, J=8.0 Hz, I 2.23-2.05 2H), 2.06-1.96 I 1.87 I 1.74 [0625] The filtrate is evaporated and dried under vacuum to H), (m, (m, H), (m, H), 2H). afford 2-chloro-N4-[4-(2-methoxy-ethoxy)-phenyl]-pyrimi- (m, dine-4, 5-diamine as brown solid; HPLC/MS 1.63 min (B), [0633] The following compounds are prepared analogously [M+H]295; [0626] 'H NMR (400 MHz, DMSO-d, ) 6 8.48 (s, IH), 7.59 (IS,3R)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo 5-d]pyrimidin-5-ylamino]-cyclopentanecarboxylic (s, IH), 7.53 (d, J=9.0 Hz, IH), 6.94 (d, J=9.0 Hz, IH), 5.17 [4, acid amide ("A136") (s, 2H), 4.20-3.97 (m, 2H), 3.80-3.50 (m, 2H), 3.31 (s, 3H). [0627] To a solution of 2-chloro-N4-[4-(2-methoxy- [0634] ethoxy)-phenyl]-pyrimidine-4, 5-diamine (57.0 g, 193 mmol) in acetonitrile (600 ml) is added butyl nitrite (30.8 g, 34.9 ml, 290 mmol). The solution is heated to 70' C. and stirred at this temperature for 3 hours. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is chromatographed on a silica gel column (I kg silica gel 60) with tert-butyl methyl ether as eluent. The N product containing fractions are combined and concentrated N under reduced pressure until a precipitate forms. The solid is N filtered off, washed with heptane and dried under vacuum to afford S-chloro-3-[4-(2-methoxy-ethoxy)-phenyl]-3H-[1, 2, 3]triazolo[4, 5-d]pyrimidine as light yellow crystals; HPLC/ [0635] HPLC/MS 1.73 min (B), [M+H]354; MS 2.63 min (C), [M+H]306; [0628] 'H NMR (400 MHz, DMSO-d~) 6 9.83 (s, IH), 7.94 (IS,3S)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo (d, J=9.1 Hz, 2H), 7.28 (d, J=9.0 Hz, 2H), 4.42-4.06 (m, 3H), [4,5-d]pyrimidin-5-ylamino]-cyclopentanecarboxylic 3.90-3.66 (m, 2H), 335 (s, 3H). acid amide ("A137") [0629] To a solution of 5-chloro-3-[4-(2-methoxy-ethoxy)- [0636] phenyl]-3H-[1, 2,3]triazolo[4, 5-d]pyrimidine (336 g, 11.0 mmol) in 2-methoxyethanol (50 ml) is added (IR,3R)-3- amino-cyclopentanecarboxylic acid hydrochloride (1.82 g, 11.0 mmol) and N-ethyldiisopropylamine (3.75 ml, 22. 1 mmol). The mixture is heated to 80' C. and stirred at this temperature for 90 minutes. The reaction mixture is cooled to room temperature and evaporated. The residue is chromato- on a silica column with dichloromethane/metha- N graphed gel rN nol as eluent to afford 3R)-3-13-[4-(2-Methoxy-ethoxy)- (IR, N r phenyl] -3H-[1,2,3]triazolo [4,5-d]pyrimi din-5-ylamino )- cyclopentanecarboxylic acid as beige amorphous solid; HPLC/MS 1.77 min (B), [M+H]399; [0637] HPLC/MS 1.70 min (B), [M+H]354; US 2016/0015712 A1 Jan. 21, 2016 60

(1S,3R)-3-[3-(4-pyrrolidin- 1 -yl-phenyl)-3H-[1, 2,3] (1S,3R)-3-[3-(2-methyl-benzoxazol-6-yl)-3H- [1,2,3] triazolo [4,5-d]pyrimi din-5-ylamino]-cyclopentan- triazo1o [4,5-d]pyrimi din-5-ylamino]-cyclopentan- ecarboxylic acid amide ("A138") ecarboxylic acid amide ("A141")

[0638] [0644]

N NHp NHp r~Ill Q H Q QN N rN N

~~N N [0645] HPLC/MS 2.20 min (C), [M+H]379;

[0639] HPLC/MS 1.91 min (B), [M+H]393; 4-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d] pyrimidin-5-ylamino]-butyramide ("A142") (1R,3R)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [0646] [4,5-d]pyrimidin-5-ylamino]-cyc lop entanecarboxylic acid ("A139")

[0640]

N )—; OH NHp

H ~~N N

N rN [0647] HPLC/MS 1.61 min (B), [M+H]328; N [064S] 'H NMR (400 MHz, DMSO-d~) 6 [ppm]=9. 22 (s, 1H), 8.19-7.89 (m, 3H), 7.29-7.14 (m, 3H), 6.72 (s, 1H), 3.85 (s, 3H), 3.44-3.27 (m, 2H), 2.19-2.09 (m, 2H), 1.88-1.73 (m, HPLC/MS 79 min [0641] 1. (B), [M+H]355; 2H);

(1R,3R)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo 4-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d] [4,5-d]pyrimidin-5-ylamino]-cyc lop entanecarboxylic pyrimidin-5-ylamino]-cyclohexanecarboxylic acid acid amide ("A140") amide ("A143")

[0642] [0649]

NHp

H

N N rN rN N r N

[0643] HPLC/MS 1.68 min (B), [M+H]354; [0650] HPLC/MS 1.71 min (B), [M+H]368; US 2016/0015712 A1 Jan. 21, 2016 61

3-[3-(4-methoxy-phenyl)-3H- [1,2,3]triazolo [4,5-d] (1R,3R)-3-[3-(2-methyl-benzothiazo1-6-yl)-3H-[1, 2, pyrimidin-5-ylamino]-butyramide ("A144") 3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cyclopentan- ecarboxylic acid amide ("A147") [0651] [0658]

N 0 HpN N

HzN

~~N N N N

~~N N [0652] HPLC/MS 2.22 min (C), [M+H]328;

(trans)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [0659] HPLC/MS 1.66 min (B), [M+H]395; [4,5-d]pyrimidin-5-ylamino]-cyclobutanecarboxylic acid amide ("A145") (trans)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5-d]pyrimi din-5-ylamino]-cyclohexanecarboxylic [0653] acid amide ("A148")

[0660]

H 0

NHp ~~N N ~~N N [0654] HPLC/MS 1.62 min (B), [M+H]340; 'H [0655] NMR (400 MHz, DMSO-d~) 6 [ppm]=9. 24 (s, [0661] HPLC/MS 2.36 min (C), [M+H]368; 1H), 8.45 (d, J=6.5, 1H), 8.00 (d, J=8.6, 2H), 7.28-7.13 (m, 3H), 6.75 (s, 1H), 4.46-4.35 (m, 1H), 3.86 (s, 3H), 3.02-2.89 (1S,3R)-3-[3-(4-ethoxy-phenyl)-3H-[1, 2,3]triazolo (m, 1H), 2.53-237 (m, 2H), 234-2.14 (m, 2H); [4,5-d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide ("A149") (1R,3R)-3-[3-(4-pyrrolidin- 1 -yl-phenyl)-3H-[1, 2,3] triazolo [4,5-d]pyrimi din-5-ylamino]-cyclopentan- [0662] ecarboxylic acid amide ("A146")

[0656]

HpN

N

~~N N ~H gg I N [0663] HPLC/MS 1.82 min [M+H]368; N (B), [0664] 'H NMR (400 MHz, DMSO-d~, TFA-d, 6 [ppm]9. ~~N ) N 24 (s, 1H), 7.98 (d, J=8.8 Hz, 2H), 7.11 (d, J=9.1 Hz, 2H), 4.40-4.25 (m, 1H), 4.08 (q, J=6.9 Hz, 2H), 2.77 (p, J=7.8 Hz, 1H), 2.17 (ddd, J=12.9, 8.5, 6.7 Hz, 1H), 1.98-1.67 (m, 5H), [0657] HPLC/MS 1.86 min (B), [M+H]393; 1 34 (t, J=7.0 Hz, 3H); US 2016/0015712 A1 Jan. 21, 2016 62

(1R,3R)-3-[3-(4-ethoxy-phenyl)-3H- [1,2,3]triazolo (1R,3R)-3-13-[4-(2-hydroxy-ethoxy)-phenyl]-3H-[1, [4,5-d]pyrimidin-5-ylamino]-cyc lop entanecarboxylic 2,3]triazolo[4, 5-d]pyrimidin-5-ylamino)-cyclopen- acid amide ("A150") tanecarboxylic acid amide ("A153")

[0665] [0672] O~OH H

N

~~N ~~N N N

[0666] HPLC/MS 1.75 min (B), [M+H]368; [0673] HPLC/MS 1.53 min (B), [M+H]384; [0667] 'H NMR (500 MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 34 8.08 J=8.5 736-7.03 4.59- (s, 1H), (d, Hz, 1H), (m, 2H), (1R,3R)-3-13-[3-fluoro-4-(3-oxo-morpholin-4-yl)- 437 (m, 1H), 4.15 J=7.0 Hz, 2H), 2.98 J=8.0 Hz, 1H), (q, (p, phenyl]-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5- 2.25 (dt, J=13.7, 7.4 Hz, 1H), 2.22-2.14 (m, 1H), 2.09 (dtd, )-cyclopentanecarboxylic acid amide J=11.7, 7.7, 4.3 Hz, 1H), 1.95 (ddd, J=13.5, 8.7, 5.2 Hz, 1H), ylamino O'A154") 1.87-1.68 (m, 2H), 1.42 (t, J=7.0 Hz, 3H); [0674] (1R,3R)-3-13-[4-((S)-3,3,3-trifluoro-2-hydroxy-pro- poxy)-phenyl]-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5- ylamino)-cyclopentanecarboxylic acid amide ("A151") [0668] 0 F PO N

NH2 OH N CFs N ~ ~~N „Q; N

N N [0675] HPLC/MS 1.54 min (B), [M+H]441; ~~N N (1R,3R)-3-13-[4-((R)-3,3,3-trifluoro-2-hydroxy- propoxy)-phenyl]-3H-[1, 2,3]triazolo[4, 5-d]pyrimi- [0669] HPLC/MS 1.71 min (B), [M+H]352; din-5-ylamino)-cyclopentanecarboxylic acid amide O'A155") (1R,3R)-3-[3-(3-fluoro-4-methoxy-phenyl)-3H-[1, 2, 3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cyclopentan- [0676] ecarboxylic acid amide ("A152")

[0670] HO F O~CF H

~~N ~~N N N

[0671] HPLC/MS 2.33 min (C), [M+H]372; [0677] HPLC/MS 1.70 min (B), [M+H]452; US 2016/0015712 A1 Jan. 21, 2016 63

(1R,3R]-3-[3-(2,3-dihydro-benzo [1,4]dioxin-6-yl]- (1R,3R]-3-(3-[1-(2-methoxy-ethyl]-1H-pyrazo1-4- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cy- yl] -3H- [1,2,3]triazolo [4,5-d]-pyrimidin-5-ylamino1- clopentanecarboxylic acid amide ("A156"] cyclopentanecarboxylic acid amide ("A159"]

[0678] [0684]

~~N ~~N N N

[0679] HPLC/MS 2.26 min (C], [M+H]382; [06S5] HPLC/MS 1.92 min (C], [M+H]372;

(1R,3R]-3-[3-(4-ethoxy-3-fluoro-phenyl]-3H-[1, 2,3] (1R,3R]-3-(3-[4-(2-pyrazol-1-yl-ethoxy]-phenyl]- 3H- triazolo [4,5-d]pyrimi din-5-ylamino]-cyclopentan- [1,2,3]triazolo [4,5-d]-pyrimidin-5-ylamino1- ecarboxylic acid amide ("A157"] cyclopentanecarboxylic acid amide ("A160"]

[0680] [06S6]

F

~H N N N

~~N ~~N N N

[06S7] HPLC/MS 1.65 min (B], [M+H]434; [06S1] HPLC/MS 1.79 min (B], [M+H]386; (1R,3R]-3-(3-[4-(3,3,3-trifluoro-2-hydroxy-2-tri f- (1R,3R]-3-[3-(3-fluoro-4-morpho lin-4-yl-phenyl]- luoromethyl-propoxy]-phenyl]-3H-[1, 2,3]triazolo[4, 3H-[1,2,3]triazolo[4, 5-d]-pyrimidin-5-ylamino]- 5-d]pyrimidin-5-yl amino)-cyclopentanecarboxylic cyclopentanecarboxylic acid amide ("A158 "] acid amide ("A161 "]

[0682] [0688]

0 . CFg N )», Q; H2N H ~ N N

~~N ~~N N N

[06S3] HPLC/MS 1.73 min (B], [M+H]427; [06S9] HPLC/MS 1.88 min (B], [M+H]520; US 2016/0015712 A1 Jan. 21, 2016 64

(1R,3R)-3-[3-(4-methoxy-3-methyl-phenyl)-3H-[1, 2, (trans)-3-13-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]- 3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cyclopentan- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino)-cy- ecarboxylic acid amide ("A162") clohexanecarboxylic acid amide ("A165") [0696] [0690]

H g/ NHp ~N

~~N N

~~N N [0697] HPLC/MS 1.54 min (B), [M+H]386;

[0691] HPLC/MS 1.75 min (B), [M+H]368; (1S,3R)-3-13-[4-(2-methoxy-ethoxy)-phenyl]-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5-ylamino)-cyclopen- tanecarboxylic acid amide ("A166") (1R,3R)-3-[3-(3,5-di fluor-4-methoxy-phenyl)-3H- [1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cyclo- [0698] pentanecarboxylic acid amide ("A163")

[0692]

HpN

N / ~~N N H N N [0699] HPLC/MS 1.72 min (B), [M+H]398; i 'H NMR MHz, DMSO-d~, TFA-d, 6 NHp N [0700] (500 ) [ppm]9. 28 (s, 1H), 8.05 (d, J=8.5 Hz, 2H), 7.22 (d, J=9.0 Hz, 2H), 4.33 ~~N (bs, 1H), 4.26-4.17 (m, 2H), 3.86-3.68 (m, 2H), 336 (s, 3H), N 2.78 (p, J=8.1 Hz, 1H), 2.26-2. 15 (m, 1H), 1.96 (ddt, J=15.5, 8.1, 4.4 Hz, 1H), 1.91-1.83 (m, 2H), 1.78 (td, J=14.4, 7.3 Hz, 2H); [0693] HPLC/MS 1.79 min (B), [M+H]390; (1R,3R)-3-13-[4-(2-methoxy-1-methoxymethyl- (1R,3R)-3-[3-(4-isopropoxy-phenyl)-3H-[1, 2,3]tria- ethoxy)-phenyl]-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin- zolo [4,5-d]pyrimidin-5-yl amino] -cyclopentanecar- 5-ylamino)-cyclopentanecarboxylic acid amide boxylic acid amide ("A164") ("A167")

[0694] [0701]

0 ( NH / NHp N g / ~~N N~~N N

[0702] HPLC/MS 1.68 min (B), [M+H]442; [0703] 'H NMR (400 MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 25 (s, 1H), 7.97 (d, J=8.7 Hz, 2H), 7.14 (d, J=8.9 Hz, 2H), 4.61 [0695] HPLC/MS 1.80 min (B), [M+H]382; (p, J=5.1 Hz, 1H), 435 (p, J=6.2 Hz, 1H), 3.52 (d, J=5.0 Hz, US 2016/0015712 A1 Jan. 21, 2016 65

4H], 3.24 (s, 6H], 2.89 (p, J=8.0 Hz, 1H], 2.22-2.02 (m, 2H], (1R,3R]-3-[[3-(6-fluoro-2-naphthyl]triazolo [4,5-d] 1.98 (td, J=8.5, 43 Hz, 1H], 1.85 (ddd, J=133, 8.6, 5.1 Hz, pyrimidin-5-yl] amino] cyclopentanecarboxamide 1H], 1.78-1.59 (m, 2H]; O'A169b"]

(1R,3R]-3-13-[4-(tetrahydro-pyran-4-yloxy]-phe- [0710] nyl]-3H-[1, 2,3]triazolo[4, 5-d]-pyrimidin-5- ylamino1-cyclopentanecarboxylic acid amide O'A168"] [0704]

~~N N 0 NH 0 (1R,3R]-3-[[3-(4-tert-butoxyphenyl]triazolo [4,5-d] HpN pyrimidin-5-yl] amino] cyclopentanecarboxamide ("A169c"]

N [0711] / N~~N HpN

[0705] HPLC/MS 1.72 min (B], [M+H]424; [0706] 'H NMR (500 MHz, DMSO-d~, TFA-d, ] 6 [ppm]9. 28 (s, 1H], 8.08 (bs, 2H], 7.25 (d, J=8.8 Hz, 2H], 4.70 (tt, J=8.5, 4.0 Hz, 1H], 437 (bs, 1H], 3.91 (dt, J=11.6, 4.4 Hz, N 2H], 3.54 (ddd, J=11.9, 9.4, 2.8 Hz, 2H], 2.87 J=8.0 Hz, (p, ~~N 1H], 2.25-1.95 (m, 5H], 1.88 (m, 1H], 1.81-1.59 (m, 4H]; N

(1R,3R]-3-13-[4-(2-ethoxy-ethoxy]-phenyl] -3H-[1,2, triazo1o 5-d]pyrimi din-5-ylamino)-cyclopentan- 3] [4, (1R,3R]-3-[[3-[4-(2-hydroxy- 1,1 -dimethyl-ethoxy] ecarboxylic acid amide ("A169"] phenyl]triazolo[4, 5-d]pyrimidin-5-yl]amino]cyclo- [0707] pentanecarboxamide ("A169d"] [0712]

N

N=N ~N N

[0708] HPLC/MS 1.66 min (B], [M+H]412; (1R,3R]-3-[[3-[4-[(3R]-tetrahydro furan-3-yl] ox- (1R,3R]-3-[(3-azulen-2-yltriazolo [4,5-d]pyrimidin- yphenyl]triazolo [4,5-d]pyrimi din-5-yl] amino] cyclo- 5-yl]amino]cyclopentanecarboxamide ("A169a"] pentanecarboxamide ("A169e"] [0709] [0713]

~~N N N=N US 2016/0015712 A1 Jan. 21, 2016 66

(IR,3R)-3-[[3-[4-[(3S)-tetrahydro furan-3-yl] oxyphe- -continued nyl]triazolo[4, 5-d]pyrimidin-5-yl]amino]cyclopen- tanecarboxamide ("A169f')

[0714] x HCl

NH2 DIPEA CHgOCH2CH2OH N 80' C. N 0 /y N N ~ / ~

N=N

EDCI, HOBt Bloxerle

Example 19

Synthesis of (IR,3R)-3-[3-(4-iodo-phenyl)-3H- [1,2, 3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cyclopentan- 0 ecarboxylic acid amide ("A170") H2N +/

[0715]

Cl

NEts Yj

3-5 C. Cl [0716] In a reaction flask, 2,4-dichloro-5-nitro-pyrimidine NO2 NH2 (7.76 g, 40.0 mmol) is dissolved in THF (40 ml) and the solution is cooled in an ice bath. Under stirring and external cooling (3-5' C.), a solution of 4-iodo-phenylamine (8.76 g, 40.0 mmol) in THF (20 ml) is added dropwise. Then, still under cooling (2-5' C.), a solution of triethylamine (5.54 ml, 40.0 mmol) in THF (20 ml) is added slowly. The reaction mixture is stirred for 30 minutes under ice cooling and then S C1 allowed to reach room temperature. The reaction mixture is EtOAc/EtOH filtered with suction and the residue is washed well with THF. Cl~ N NH 70' C. The filtrate is evaporated and the residue is treated with water. The solids are filtered off, washed with water and dried under Ti vacuum to afford (2-chloro-5-nitro-pyrlmidin-4-yl)-(4-iodo- as min NO2 phenyl)-amine yellow powder; HPLC/MS 2.13 (B), [M+H] 377. [0717] To a solution of (2-chloro-5-nitro-pyrimidin-4-yl)- (4-iodo-phenyl)-amine (11.4 g, 303 mmol) in a mixture of ethyl acetate (120 ml) and ethanol (60 ml) is added tin(II) chloride (17.2 g, 90.8 mmol) and the reaction mixture is stirred for 60 minutes at 70' C. The reaction mixture is cooled to room temperature, basified with saturated sodium carbon- b tyl ate solution, filtered over a pad of Celite and the residue is acetonitrile washed with ethyl acetate. The organic phase of the filtrate is 70' C. Cl ~ N NH separated, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclo- Yi N hexane/ethyl acetate as eluent to afford 2-chloro-N4-(4-iodo- NH2 phenyl)-pyrimidine-4, 5-diamine as brown solid; HPLC/MS 2.72 min (C), [M+H]347. US 2016/0015712 A1 Jan. 21, 2016 67

[071S] To a solution of 2-chloro-N4-(4-iodo-phenyl)-pyri- (IS,3R)-3-(3-benzo[1, 2,5]thiadiazo1-5-y1-3H-[1, 2,3] midine-4, 5-diamine (8.50 g, 24.5 mmol) in acetonitrile (110 triazo1o [4,5-d]pyrimi din-5-ylamino)-cyclopentan- ml) is added butyl nitrite (430 ml, 36.8 mmol). The solution ecarboxylic acid amide ("A172") is heated to 70' C. and stirred at this temperature for 90 minutes. The reaction mixture is cooled to room temperature. [0725] The solid is filtered off, washed with acetonitrile and 2-pro- panol and dried under vacuum to afford 5-chloro-3-(4-iodo- phenyl)-3H-[1, 2,3]trlazolo[4, 5-d]pyrimidine as brown pow- N der; HPLC/MS 3.14 min (C), [M+H]358. s [0719] To a solution of S-chloro-3-(4-iodo-phenyl)-3H-[1, / N 2,3]triazolo[4, 5-d]pyrimidine (1.79 g, 5.0 mmol) in 2-meth- oxyethanol (12.5 ml) is added (IR,3R)-3-amino-cyclopen- N tanecarboxylic acid hydrochloride (910mg, 5.50 mmol) and N-ethyldiisopropylamine (1.87 ml, 11.0 mmol). The mixture ~N is heated to 80' C. and stirred at this temperature for 3 hours. N The reaction mixture is cooled to room temperature and water is added. The resulting precipitate is filtered off, washed with HPLC/MS 2.43 min water and dried under vacuum to afford (IR,3R)-3-[3-(4- [0726] (C), [M+H]382; iodo-phenyl)-3H-[1, 2,3]trlazolo[4, 5-d]pyrimidin-5- ylamino]-cyclopentanecarboxylic acid as beige solid; HPLC/ (IR,3R)-3-[3-(6-methoxy-pyridin-3-yl)-3H-[1, 2,3] MS 2.82 min (C), [M+H]451. triazo1o [4,5-d]pyrimi din-5-ylamino]-cyclopentan- [0720] To a suspension of (IR,3R)-3-[3-(4-iodo-phenyl)- ecarboxylic acid amide ("A173") 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cyclopen- tanecarboxylic acid (2.26 g, 5.02 mmol) in THF (12 ml) are [0727] added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.93 g, 10.1 mmol), I-hydroxybenzotriazole hydrate (678 mg, 5.02 mmol) and a 0.5M solution of ammo- nia in dioxane (50.2 ml, 25.1 mmol ammonia). The reaction 0 mixture is stirred for 3 days at room temperature. It is then partitioned between dichloromethane and saturated sodium N hydrogen carbonate solution. The organic phase is dried over N sodium sulfate and evaporated. The residue is chromato- !/ NHp N graphed on a silica gel column with dichloromethane/metha- nol as eluent to afford (IR,3R)-3-[3-(4-iodo-phenyl)-3H-[1, ~~N 2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]- N cyclopentanecarboxylic acid amide as off-white crystals; HPLC/MS 2.61 min (C), [M+H]450; [072S] HPLC/MS 1.64 min (B), [M+H]355; [0721] 'H NMR (300 MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 'H NMR MHz, DMSO-d~) 6 25 27 (s, I H), 8.12 (d, J=8.4 Hz, 2H), 8.01 (d, J=8.8 Hz, 2H), 4.41 [0729] (400 [ppm]9. (s, 8.92 8.44-8.36 831-8.23 7.23 (bs, I H), 2.91 (p, J=7.9 Hz, I H), 2.43-1.97 (m, 3H), 1.96-1.59 IH), (s, IH), (m, IH), (m, IH), (m, 3H). (s, IH), 7.11 (d, J=9.0, IH), 6.70 (s, IH), 434-4.22 (m, IH), 3.95 (s, 3H), 2.78 (p, J=7.9, I H), 2.12-2.00 (m, 2H), 1.98-1.77 The following compounds are analo- [0722] prepared (m, 2H), 1.73-1.56 (m, 2H); gously:

(IR,3R)-3-(3-benzo [1,2,5]thiadiazo1-5-yl-3H- [1,2,3] (IS,3R)-3-[3-(4-iodo-phenyl)-3H-[1, 2,3]triazolo[4, 5- triazo1o [4,5-d]pyrimi din-5-ylamino)-cyclopentan- d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid ecarboxylic acid amide ("A174") amide ("A171")

[0723] [0730] ~S NHp N .J..., QN N N ~N ~~N N N

[0724] HPLC/MS 1.94 min (B), [M+H]450; [0731] HPLC/MS 2.34 min (C), [M+H]382; US 2016/0015712 A1 Jan. 21, 2016 68

(1R,3R)-3-[3-(5-methoxy-pyridin-2-yl)-3H-[1, 2,3] (1R,3R)-3-[3-(5-ethoxy-pyri din-2-yl)-3H-[1, 2,3] triazolo [4,5-d]pyrimi din-5-ylamino]-cyclopentan- triazo1o [4,5-d]pyrimi din-5-ylamino]-cyclopentan- ecarboxylic acid amide ("A175") ecarboxylic acid amide ("A178")

[0732] [0738]

H H

~N N N N ~~N N

[0733] HPLC/MS 1.50 min (B), [M+H]355; [0739] HPLC/MS 2.06 min (C), [M+H]369; (1R,3R)-3-[3-(3-iodo-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cyclopentanecarboxylic (1R,3R)-3-[3-(6-ethoxy-pyri din-3-yl)-3H-[1, 2,3] acid amide ("A176") triazo1o [4,5-d]pyrimi din-5-ylamino]-cyclopentan- ecarboxylic acid amide ("A179") [0734] [0740]

N ~N NHp N N N

~~N N [0735] HPLC/MS 1.84 min (B), [M+H]450; 'H NMR (400 MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 28 (s, 1H), 8.77 (bs, 1H), 830 J=8.2 Hz, 1H), 7.84 J=8.0 Hz, OH), 7.42 J=8.1 (d, (d, (t, [0741] HPLC/MS 2.29 min (C), [M+H]369; Hz, 1H), 4.42 (bs, 1H), 2.96 (p, J=8.0 Hz, 1H), 2.22 (m, 2H), 2.15-1.91 (m, 2H), 1.90-1.65 (m, 2H); (1R,3R)-3-[3-(2-methyl-benzo furan-5-yl)-3H- [1,2,3] triazo1o [4,5-d]pyrimi din-5-ylamino]-cyclopentan- (1R,3R)-3-[3-(5-iodo-pyridin-2-yl)-3H-[1, 2,3]tria- ecarboxylic acid amide ("A180") zolo [4,5-d]pyrimidin-5-yl amino] -cyclopentanecar- boxylic acid amide ("A177") [0742] [0736]

H 0

N

~~N ~~N N N

[0737] HPLC/MS 2.19 min (C), [M+H]451; [0743] HPLC/MS 2.51 min (C), [M+H]378; US 2016/0015712 A1 Jan. 21, 2016 69

(1R,3R)-3-P-(2-methoxy-quinolin-6-yl)-3H- [1,2,3] (1R,3R)-3-P-(2-methyl-quinazo1 in-6-yl)-3H-[1, 2,3] triazolo [4,5-d]pyrimi din-5-ylamino]-cyclopentan- triazo1o [4,5-d]pyrimi din-5-ylamino]-cyclopentan- ecarboxylic acid amide ("A181") ecarboxylic acid amide ("A184")

[0744] [0750]

0

N N

HzN ~~N N N N

~~N [0751] HPLC/MS 1 37 min (B), [M+H]390; 'H NMR (500 N MHz, DMSO-d~) 6 [ppm]=9. 76 (s, 1H), 930 (s, 1H), 9.09- 9.04 (m, 1H), 8.92-8.83 (m, 1H), 8.41 (d, J=6.6, 1H), 8.18 (d, J=9.1, 1H), 734-7.25 (m, 1H), 6.83-6.73 (m, 1H), 4.46-4.37 [0745] HPLC/MS 2.50 min (C), [M+H]405; (m, 1H), 2.88-2.77 (m, 4H), 2.35-2.27 (m, 1H), 2.16-1.91 (m, 2H), 1.84-1.57 (m, 3H); (1R,3R)-3-13-[2-(2-ethoxy-ethoxy)-quinolin-6-yl]- 3H- 3]triazolo 5-d] -pyrimidin-5-ylamino )- [1,2, [4, (1R,3R)-3-P-(2-methyl-2H-indazol-6-yl)-3H- [1,2,3] ("A182") cyclopentanecarboxylic acid amide triazo1o [4,5-d]pyrimi din-5-ylamino]-cyclopentan- ecarboxylic acid amide ("A185") [0746] [0752]

N

N

N NHp ~~N N

/ N [0753] HPLC/MS 1.56 min (B), [M+H]378; 'H NMR (400 N MHz, DMSO-d~) 6 [ppm]=9. 31 (s, 1H), 8.55 (s, 1H), 8.48 (s, / 97 45 4.28 93 J=8.0 N~~N 1H), 7. (2H), 4. (s, 1H), (s, 3H), 2. (p, Hz, 1H), 2.25-2.10 (m, 2H), 2.10-1.91 (m, 2H), 1.86-1.70 (m, 2H); [0747] HPLC/MS 2.55 min (C), [M+H]463; (1R,3R)-3-P-(2-methyl-2H-indazol-5-yl)-3H- [1,2,3] triazo1o [4,5-d]pyrimi din-5-ylamino]-cyclopentan- 2-dimethyl-l H-benzimidazol-5-yl)- (1R,3R)-3-P-(1, ecarboxylic acid amide ("A186") 3H-[1,2,3]triazolo[4, 5-d]-pyrimidin-5-ylamino]- cyclopentanecarboxylic acid amide ("A183") [0754] N [0748]

N ~g NHp ~~N N

N [0755] HPLC/MS 1.56 min (B), [M+H]378; 'H NMR (500 MHz, DMSO-d~) 6 [ppm]=9. 29 (s, 1H), 8.60 (m, 2H), 8.07 ~~N N (bs, 1H), 7.87 (d, J=9.2 Hz, 1H), 4.59-430 (m, 1H), 4.26 (s, 3H), 2.87 (p, J=7.9 Hz, 1H), 230-2.15 (m, 1H), 2.10 (tt, J=11.8, 5.0 Hz, 1H), 2.01 (dq, J=11.0, 8.1 Hz, 1H), 1.84 (ddd, [0749] HPLC/MS 1.63 min (C), [M+H]392; J=13.6, 8.8, 5.6 Hz, 1H), 1.75 (dtd, J=183, 12.8, 7.0 Hz, 2H); US 2016/0015712 A1 Jan. 21, 2016 70

[1R,3R]-3-[[3-cinnolin-6-yltriazolo[4, 5-d]pyrimidin- [1R,3R]-3-[[3-[2-methylimidazo [1,2-a]pyridin-6-yl] 5-yl]amino]cyclopentanecarboxamide O'A186a"] triazo1o [4,5-d]pyrimi din-5-yl] amino] cyclopentan- ecarboxamide O'A186e"] [0756] [0760] N ' t["

N

~~N N ~~N N

3R]-3-[[3-[7-methoxy-3-quinolyl]triazolo[4, 5-d] [1R, [1R,3R]-3-[[3-[2-methyl-1H-indol-5-yl]triazolo [4,5- entanecarboxamide pyrimidin-5-yl] amino] cyclop d]pyrimidin-5-yl] amino] cyclopentanecarboxamide O'A186b "] O'A186P'] [0757] [0761] ")i ~~ ")/ ~: NH; N N ~ N N ~~N ~~N N N

[1R,3R]-3-[[3-[2-methylindolizin-7-yl]triazolo [4,5- [1R,3R]-3-[[3-[2-methylisoindo1-5-yl]triazolo [4,5-d] d]pyrimidin-5-yl] amino] cyclopentanecarboxamide pyrimidin-5-yl] amino] cyclopentanecarboxamide O'A186c "] O'A186g"] [0758] [0762] / /~

~~N ~~N N N

[1R,3R]-3-[[3-[2-methylindolizin-6-yl]triazolo [4,5- [1R,3R]-3-[[3-[7-methylindolizin-2-yl]triazolo [4,5- d]pyrimidin-5-yl] amino] cyclopentanecarboxamide d]pyrimidin-5-yl] amino] cyclopentanecarboxamide O'A186d"] O'A186h"] [0759] [0763]

H N N HpN / lj"

~~N ~~N N N US 2016/0015712 A1 Jan. 21, 2016 71

(1R,3R)-3-[[3-(1H-indazo1-5-yl)triazolo[4, 5-d]pyri- -continued midin-5-yl] amino] cyclop entanecarboxamide ("A186i")

[0764]

F INH CI EtOH/H10 H 55' N C. Cl ~ N NH N H ~ Yi N NO1 0 N

~~N N

N (1R,3R)-3-[[3-(2-methyl-3H-benzimidazo1-5-yl) triazolo [4,5-d]pyrimi din-5-yl] amino] cyclopentan- ecarboxamide ("A186j") E lyl acetoniu ile [0765] 80' C. Cl ~ N NH Yi

NH2

N

x HCl ~~N N

NH1 DIPEA Example 20 CHgOCH1CH1OH 80' C. Synthesis of (1R,3R)-3-[3-(2-methyl-quinolin-6-yl)- 3H-[1,2,3]triazolo[4, 5-d]-pyrimidin-5-ylamino]- Yj cyclopentanecarboxylic acid amide ("A187")

[0766]

N / N THE EDCI, HOB IttOXHtle Cl

NO1 NH1 Yj US 2016/0015712 A1 Jan. 21, 2016 72

-continued [0772] In a reaction flask, to (IR,3R)-3-P-(2-methyl- quino1 in-6-yl)-3H- [1,2,3]triazolo [4,5-d]pyrimi din-5- ylamino]-cyclopentanecarboxylic acid (845 mg, 2.17 mmol) are added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide HpN +/ hydrochloride (832 mg, 434 mmol), I -hydroxybenzotriazole hydrate (295 mg, 2.18 mmol) and a 0.5M solution of ammo- nia in dioxane (22 ml, 11 mmol ammonia). The resulting suspension is stirred for 18 hours at room temperature. The reaction mixture is concentrated and the residue is chromato- graphed on a silica gel column with dichloromethane/metha- nol as eluent to afford (IR,3R)-3-P-(2-methyl-quinolin-6- Vj' yl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]- cyclopentanecarboxylic acid amide as light orange amorphous solid; HPLC/MS 1.41 min (B), [M+H]389; 'H [0767] A solution of 2,4-dichloro-5-nitro-pyrimidine (11.5 [0773] NMR (400 MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. g, 593 mmol) in THF (25 ml) is cooled to O' C. To this 34 (m, 3H), 9.19-9.04 (m, IH), 8.51 (d, J=93 Hz, IH), 8.11 solution is added a solution of 6-amino-2-methyl-quinoline (d, J=8.7 Hz, IH), 4.56 (m, IH), 2.95 (p, J=8.0 Hz, IH), 2.40 (10.4 g, 65.9 mmol) in THF (95 ml) dropwise under stirring. (m, IH), 2.13 (m, 2H), 1.91-1.67 (m, 3H). The reaction mixture is allowed to reach room temperature. [0774] The following compounds are prepared analo- The precipitate that has formed is filtered off, washed with gously: water and dried under vacuum to afford (2-chloro-5-nitro- pyrimidin-4-yl)-(2-methyl-quinolin-6-yl)-amine hydrochlo- (IS,3R)-3-(3-quinolin-6-y1-3H-[1, 2,3]triazolo [4,5-d] ride as yellow crystals; HPLC/MS 1.42 min (A), [M+H]316; 'H pyrlmidin-5-ylamino)-cyclopentanecarboxylic acid NMR (400 MHz, DMSO-d~) 6 [ppm]10. 84 (s, IH), 9.24 ("A188") (s, IH), 8.94 (d, J=8.6 Hz, IH), 8.49-8.34 (m, 2H), 8.22 (dd, J=9. 2.4 7.91 J=8.6 2.96 1, Hz, IH), (d, Hz, IH), (s, 3H). [0775] [0768] To a suspension of (2-chloro-5-nitro-pyrimidin-4- yl)-(2-methyl-quinolin-6-yl)-amine hydrochloride (10.27 g, 29.2 mmol) in water (80 ml) are added ammonium chloride N OH (935 mg, 17.5 mmol) and ethanol (80 ml). The mixture is heated to 55' C. under stirring and then iron, particle size 10 m (8.15 g, 146 mmol) is added portionwise. The reaction ' mixture is stirred for 18 hours at 55' C. The reaction mixture '0 — is filtered and with filtrate 'z;, over Celite washed ethanol. The is evaporated and dried under vacuum to afford 2-chloro-N4- ~N (2-methyl-quinolin-6-yl)-pyrimidine-4, 5-diamine as yellow N solid which was used as such in the next step; HPLC/MS 1.26 min (B), [M+H]286. [0769] To a solution of crude 2-chloro-N4-(2-methyl- [0776] HPLC/MS 1.64 min (B), [M+H]376; quinolin-6-yl)-pyrimidine-4, 5-diamine (12.9 g, approx. 28 mmol) in acetonitrile (100ml) is added butyl nitrite (8.64 ml, (IS,3R)-3-(3-quinolin-6-y1-3H-[1, 2,3]triazolo [4,5-d] 70.2 mmol). The solution is heated to 80' C. and stirred at this pyrlmidin-5-ylamino)-cyclopentanecarboxylic acid temperature for 2 hours. The reaction mixture is cooled to amide ("A189") room temperature and concentrated under reduced pressure. The residue is chromatographed on a silica gel column with [0777] dichloromethane/methanol as eluent to afford 6-(5-chloro-[I, 2,3]triazolo[4, 5-d]pyrlmidin-3-yl)-2-methyl-quinoline as light yellow solid; HPLC/MS 1.61 min (B), [M+H]297; N 'H [0770] NMR (400 MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. N 93 (s, I H), 934 (d, J=8.6 Hz, IH), 9.12 (d, J=2.3 Hz, IH), 8.90 (dd, J=9.2, 23 Hz, IH), 8.59 (d, J=9.2 Hz, IH), 8.14 (d, J=8.6 Hz, IH), 3.04 (s, 3H). [0771] To a solution of 6-(5-chloro-[1, 2,3]triazolo[4, 5-d] NHp pyrimidin-3-yl)-2-methyl-quinoline (1.16 g, 4.0 mmol) in ~N 2-methoxyethanol (18 ml) is added (IR,3R)-3-amino-cyclo- N pentanecarboxylic acid hydrochloride (729 mg, 4.4 mmol) and N-ethyldiisopropylamine (1.36 ml, 8.0 mmol). The mix- HPLC/MS 1.55 min ture is heated to 80' C. and stirred at this temperature for 3 [0778] (B), [M+H]375; days. The reaction mixture is cooled to room temperature [0779] 'H NMR (400 MHz, DMSO-d~) 6 [ppm]=9. 29 (s, concentrated. The residue is chromatographed on a silica gel IH), 9.00 (dd, J=4.2, 1.7, IH), 8.86 (d, J=2.4, IH), 8.67-8.60 column with methanol/dichloromethane as eluent to afford (m, IH), 8.58-8.52 (m, IH), 8.38 (d, J=6.9, IH), 8.29 (d, (IR,3R)-3-P-(2-methyl-quinolin-6-yl)-3H-[1, 2,3]triazolo J=9.1, IH), 7.71-7.63 (m, IH), 739-730 (m, IH), 6.87-6.76 [4,5-d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid (m, IH), 439-4.28 (m, I H), 2.79-2.71 (m, IH), 2.29-2.19 (m, as light orange solid; HPLC/MS 1.52 min (B), [M+H]390. IH), 2.06-1.96 (m, IH), 1.90-1.73 (m, 4H); US 2016/0015712 A1 Jan. 21, 2016 73

(1R,3R)-3-(3-quinolin-6-y1-3H-[1, 2,3]triazolo[4, 5-d] (1S,3S)-3-P -(2-methyl-quinolin-6-yl)-3H- [1,2,3] pyrimidin-5-ylamino)-cyclopentanecarboxylic acid triazo1o [4,5-d]pyrimi din-5-ylamino]-cyclopentan- amide ("A190") ecarboxylic acid amide ("A193")

[0780] [0787]

.„„H ~~N N NHp

N [07S1] HPLC/MS 1.55 min (B), [M+H]375; ~~N [07S2] 'H NMR (400 MHz, DMSO-d~) 6 [ppm]=930 (s, N 1H), 9.03-8.93 (m, 2H), 8.68 (dd, J=9.2, 2.5, 1H), 8.60 (d, J=8.3, 1H), 836 (d, J=6.5, 1H), 8.28 (d, J=93, 1H), 7.70-7.62 (m, 1H), 734-7.21 (m, 1H), 6.80-6.66 (m, 1H), 4.47-433 (m, [07SS] HPLC/MS 1.44 min (B), [M+H]389; 1H), 2.89-2.77 (m, 1H), 232-L53 (m, 6H); (1S,3R)-3-P-(2- methyl-quinolin-6-yl)-3H-[1, 3]triazolo 5-d]pyrimidin- 2, [4, (1R,3R)-3-(3-[LS]naphthyridin-2-y1-3H-[1, 2,3]tria- 5-ylamino]-cyclopentanecarboxylic acid amide ("A191") zolo [4,5-d]pyrimidin-5-ylamino)-cyclopentanecar- boxylic acid amide ("A194")

N [0789] N

NHp ~N N

[07S3] HPLC/MS 1.47 min (B), [M+H]389; [07S4] 'H NMR (400 MHz, DMSO-d~, TFA-d, ) 6 [ppm] N =932 1H), 9.26 (m, 2H), 9.08 J=9.4 Hz, 1H), 8.51 (d, (s, (d, ~~N J=9.3 Hz, 1H), 8.11 (d, J=8.7 Hz, 1H), 4.48 (bs, 1H), 3.04 (s, N 3H), 2.87 (p, J=7.5 Hz, 1H), 2.28 (dt, J=133, 6.4 Hz, 1H), 1.91 (m, 5H); [0790] HPLC/MS 1.91 min (C), [M+H]376; (trans)-3-P-(2-methyl-quinolin-6-yl)-3H-[1, 2,3] [0791] (1R,3R)-3-P-(l-methyl-l H-indazol-5-yl)-3H-[1, triazolo [4,5-d]pyrimidin-5-yl amino] -cyclohexan- 2,3]triazolo [4,5-d]pyrimi din-5-ylamino]-cyclopentanecar- ecarboxylic acid amide ("A192") boxylic acid amide ("A195")

[0785]

N H H PN

NHp N NHp ~~N N ~~N N

[07S6] HPLC/MS 1.95 min (C), [M+H]403; [0792] HPLC/MS 1.52 min (B), [M+H]378; US 2016/0015712 A1 Jan. 21, 2016 74

(1R,3R)-3-[[3-(7-methyl-3-quinolyl)triazolo [4,5-d] (1R,3R)-3-[[3-(2-methyl-1-oxo-6-isoquinolyl)tria- pyrimidin-5-yl] amino] cyclop entanecarboxamide zo1o[4,5-d]pyrimi din-5-yl] amino] -cyclopentanecar- ("A195a") boxamide("A195b") [0794] [0793] N

~~N N

Example 21

N Synthesis of (1R,3R)-3-[3-(4-iodo-phenyl)-3H-[1, 2, 3]triazolo [4,5-d]pyrimi din-5-ylamino]-cyclopentano1 ~~N N ("A196")and (1S,3S)-3-[3-(4-iodo-phenyl)-3H-[1, 2, 3]triazolo [4,5-d]pyrimi din-5-ylamino]-cyclopentano1 O'A197") [0795]

HO

HO

DIPEA x HCl CHsOCH2CH2OH 80' C. Vj NH2 Vj

(racemic (racemic mixture) mixture)

chirat separation

HO HO US 2016/0015712 A1 Jan. 21, 2016 75

[0796] To a solution of S-chloro-3-(4-iodo-phenyl)-3H-[1, (trans)-3-(3-benzo [1,2,5]thiadiazo1-5-yl-3H- [1,2,3] 2,3]triazolo[4, 5-d]pyrimidine (2.36 g, 6.6 mmol) in 2-meth- triazolo [4,5-d]pyrlmidin-5-ylamino)-cyclopentanol oxyethanol (30 ml) is added trans-3-amino-cyclopentanol O'A200") hydrochloride (racemic mixture; 1.0 7.3 mmol) and N-eth- g, [0804] yldiisopropylamine (2.47 ml, 14.5 mmol). The mixture is heated to 80' C. and stirred at this temperature for 90minutes. N ~S The reaction mixture is cooled to room temperature and water is added. The resulting precipitate is filtered off, washed with water and dried under vacuum to afford (trans)-3-[3-(4-iodo- phenyl)-3H-[1, 2,3]trlazolo[4, 5-d]pyrimidin-5-ylamino]-cy- clopentanol (racemic mixture) as beige solid; HPLC/MS 1.94 N min (B), [M+H]423; [0797] 'H NMR (400 MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. ~~N N 26 (s, IH), 8.16-8.05 (m, 2H), 8.06-7.96 (m, 2H), 4.51 (bs, I H), 432 (tt, J=6.0, 3.2 Hz, I H), 2.24 (dt, J=12.6, 7.6 Hz, IH), 2.11-1.93 (m, 2H), 1.81 (dt, J=133, 6.6 Hz, IH), 1.61 (ddt, [OS05] HPLC/MS 2.40 min (C), [M+H]355; J=12.2, 8.1, 5.0 Hz, 2H). [079S] (trans)-3-[3-(4-Jodo-phenyl)-3H-[1, 2,3]triazolo[4, (IR,3R)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o 5-d]pyrimidin-5-ylamino]-cyclopentanol is separated by [4,5-d]pyrimidin-5-ylamino]-cyclohexanol O'A201") chiral chromatography on a chiral column with Lux-Amy- [0806] lose-2 as stationary phase and heptane/ethanol 8: 2 as mobile HO phase to afford two enantiomers. Both enantiomers are beige solids. LC/MS data and NMR data are identical to those ofthe racemic mixture. H [0799] The following compounds are prepared analo- gously:

(trans)-3-[3-(4-pyrrolidin- I -yl-phenyl)-3H-[1, 2,3] triazolo 5-d]pyrimidin-5-ylamino]-cyclopentanol ~~N [4, N O'A198")

[OSOO] [OS07] HPLC/MS 1.79 min (C), [M+H]341; 'H NMR (400 MHz, DMSO-d~, TFA-d, ) 6 [ppm]933 (s, IH), 8.09 (d, J=8.5 Hz, 2H), 7.24-7.16 (m, 2H), 431 (bs, I H), 4.05 (bs, IH), 3.88 (s, 3H), 1.92 (m, IH), 1.85-1.19 (m, 7H); (trans)-3-[3-(2- methyl-quinolin-6-yl)-3H-[1, 2,3]triazolo [4,5-d]pyrimidin- D:~, 5-ylamino]-cyclopentanol O'A202") N

~~N N

[OS01] HPLC/MS 1.91 min (B), [M+H]366; ~~N N (trans)-3-(3-(2-methyl-benzoxazol-6-yl)-3H-[1, 2,3] triazolo[4, 5-d]pyrimidin-5-ylamino cyclopentanol O'A199") [OSOS] HPLC/MS 1.48 min (B), [M+H]362;

[0802] (IR,3R)-3-(3-[4-(2-hydroxy-ethoxy)-phenyl]-3H-[1, 2,3]triazolo[4, 5-d]pyrlmidin-5-ylamino)-cyclopen- tanolK "A203") [0809] p~OH D:~, N N

~~N ~~N N N

[OS03] HPLC/MS 2.17 min (C), [M+H]352; [OS10] HPLC/MS 1.53 min (B), [M+H]357; US 2016/0015712 A1 Jan. 21, 2016 76

(1R,3R)-3-(3-quinolin-6-y1-3H-[1, 2,3]triazolo[4, 5-d] (trans)-3-[3-(4-ethoxy-phenyl)-3H-[1, 2,3]triazolo [4, pyrimidin-5-ylamino)-cyclopentanol ("A204") 5-d]pyrimidin-5-ylamino]-cyclopentanol ("A207")

[OS11] [OS17]

~~N N ~~N N [OS1S] HPLC/MS 2.52 min (C), [M+H]341; 'H NMR (400 MHz, DMSO-d~, TFA-d, ) b [ppm]9. 28 (s, 1H), 8.05 (d, J=8.5 [OS12] HPLC/MS 1.54 min (B), [M+H]348; Hz, 2H), 7.18 (d, J=9.1 Hz, 2H), 4.50 (bs, 1H), 4.30 (tt, J=6.0, 3.2 Hz, 1H), 4.15 (q, J=6.9 Hz, 2H), 230-2.13 (m, 1H), 1.99 (m, 2H), 1.80 (dt, J=13.4, 6.7 Hz, 1H), 1.69-1.50 (m, 2H), (trans)-3- (3-[4-((S)-3,3,3-tri fluor-2-hydroxy-pro- 1.40 (t, J=7.0 Hz, 3H); poxy)-phenyl]-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5- ylamino )-cyclopentano1 ("A205") (1R,3R)-3-[3-(2-methyl-quinolin-6-yl)-3H-[1, 2,3] triazolo [4,5-d]pyrimidin-5-yl amino] -cyclopentano1 [OS13] C'A208")

[OS19] OH

CFg

N N ~~N N ~~N N

[OS14] HPLC/MS 1.73 min (B), [M+H]425; [OS20] HPLC/MS 1.48 min (B), [M+H]362; (trans)-3-[3-(6-ethoxy-pyri din-3-yl)-3H-[1, 2,3]tria- (trans)-3-[3-(2-methyl-quinazolin-6-yl)-3H-[1, 2,3] zolo 5-d]pyrimidin-5-ylamino] -cyclop entanol [4, triazolo [4,5-d]pyrimidin-5-yl amino] -cyclopentano1 C'A206") C'A209")

[OS15] [OS21] o~ Yl HO' N HO

N ~~N N ~~N N

HPLC/MS min 'H NMR [OS16] 1.76 (B), [M+H]342; (400 [OS22] HPLC/MS 1 33 min (B), [M+H]363; 'H NMR (400 MHz, DMSO-d~) b ppm=936-9. 20 (m, 1H), 8.93-8.76 (m, MHz, DMSO-d~) b ppm=9. 67-9.64 (m, 1H), 9.28 (s, 1H), 1H), 8.41-8.25 (m, 1H), 8.25-7.93 (m, 1H), 7.08 (d, J=8.9, 9.04-8.97 (m, 1H), 8.89-8.81 (m, 1H), 837-8.29 (m, 1H), 1H), 4.55-4.46 (m, 1H), 4.46-4.32 (m, 3H), 4.28-4.17 (m, 8.18 (d, J=9.1, 1H), 4.68-4.54 (m, 1H), 4.53-4.44 (m, 1H), 1H), 2.22-2.02 (m, 1H), 2.02-1.83 (m, 2H), 1.83-1.62 (m, 431-4.21 (m, 1H), 2.83 (s, 3H), 2.25-2.02 (m, 2H), 2.01-1.88 1H), 1.60-1.43 (m, 2H), 1 37 (t, J=7.0, 3H); (m, 1H), 1.82-1.69 (m, 1H), 1.67-1.45 (m, 2H); US 2016/0015712 A1 Jan. 21, 2016 77

(trans]-3-[3-(4-isopropoxy-phenyl]-3H-[1, 2,3]tria- -continued zolo [4,5-d]pyrimidin-5-ylamino] -cyclop entanol O'A210"] .) [OS23]

N~ N

HO'

NH2 N N

~~N N

[OS24] HPLC/MS 1.87 min (B], [M+H]355. Vj'

Example 22 [OS26] To a solution of (IR,3R]-3-[3-(4-iodo-phenyl]-3H- Synthesis of (IR,3R]-3-(3-(4-[1-(2-ethoxy-ethyl]- [1,2,3]triazolo [4,5-d]pyrimidin-5-ylamino]-cyclopentan- 1-(2- I H-pyrazol-4-yl]-phenyl)-3H- [1,2,3]trlazolo [4,5-d] ecarboxylic acid amide (314 mg, 0.70 mmol] and ethoxy-ethyl]-4-(4, 4,5,5-tetramethyl-[1, 2]dioxaborolan-2- pyrlmidin-5-ylamino]-cyclopentanecarboxylic acid 3, yl]-I H-pyrazole (242 mg, 0.91 mmol] in dioxane (2 ml] are ("A211 amide "] added water (0.2 ml] and potassium carbonate (290 mg, 2.10 mmol]. The mixture is flushed with nitrogen and heated to 80 [OS25] C. Dichloro[1, 1'-bis(diphenylphosphino]ferrocene]palla- dium(II] dichloromethane adduct (57 mg, 0.07 mmol] is added and the mixture is stirred in a closed reaction vial for 18 hours at 80' C. The reaction mixture is allowed to reach room temperature and treated with water. The resulting precipitate is filtered off, washed with water and dried under vacuum. It is chromatographed on a silica gel column with dichlo- NH2 romethane/methanol as eluent to afford (IR,3R]-3-(3-(4-[1- (2-ethoxy-ethyl]-I H-pyrazol-4-yl]-phenyl)-3H-[1, 2,3]tria- zolo [4,5-d]pyrimi din-5-ylamino]-cyc lop entanecarboxylic acid amide as beige solid; HPLC/MS 233 min (C], [M+H] 462; 'H NMR (500 MHz, DMSO-de, TEA-dt] ft [ppm]9. 30 (s, IH], 8.26 (m, 3H], 8.06 (s, IH], 7.90-7.84 (m, 2H], 4.50- N 4.42 (m, 1H], 436 (t, J=5.4 Hz, 2H], 3.82 (t, J=5.4 Hz, 2H], N 3.49 (q, J=7.0 Hz, 2H], 2.94 (p, J=8.0 Hz, IH], 2.28-2.12 (m, /y IH], 2.06 (dtd, J=11.2, 7.4, 6.8, 4.1 Hz, IH), 1.95 (ddd, N J=133,8.7, 4.2 Hz, IH], 1.79 (m, 2H], 1.12 (t, J=7.0 Hz, 3H]. [OS27] The following compounds are prepared analo- gously:

(IR,3R]-3-(3-(4-[I-(2-methoxy-ethyl]- I H-pyrazol- 4-yl]-phenyl)-3H-[1, 2,3]triazolo [4,5-d]pyrimidin-5- ) ylamino]-cyclopentanol ("A212"] . [OS2S] HO

N~ PdCl (dppO N '"NH K2COg dioxatte/water N 80' C. ~B / 0 / N=N

[OS29] HPLC/MS 1.67 min (B], [M+H]421; US 2016/0015712 A1 Jan. 21, 2016 78

(1R,3R)-3-(3-(4-[1-(2-pyrrolidin-l-yl-ethyl)-1H- [OS36] (1S,3R)-3-(3-(4-[1-(2-pyrrolidin-l-yl-ethyl)-1H- pyrazo1-4-yl]-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyri- pyrazol-4-yl]-phenyl )-3H-[1,2,3]triazolo[4, 5-d]pyrimidin- midin-5-ylamino)-cyclopentanol O'A213") 5-ylamino)-cyclopentanecarboxylic acid amide O'A216")

[OS30]

HO

"'~ 'NH Q

//

N / / N~N [OS37] HPLC/MS 1.81 min (C), [M+H]487;

[OS31] HPLC/MS 1.40 min (B), [M+H]460; (1R,3R)-3-(3-(4-[1-(2-cyano-ethyl)-1H-pyrazo1-4- yl] -phenyl )-3H-[1,2,3]triazolo [4,5-d]pyrimidin-5- 3-(4-(4-[5-(trans-3-hydroxy-cyclopentylamino)-[1, 2, ylamino)-cyclopentanecarboxylic acid amide 3]triazolo[4, 5-d]pyrimidin-3-yl]-phenyl )-pyrazol-1- O'A217") yl)-propionitrile O'A214") [OS38] [OS32]

HO ~ ~ 0 H N N ~ '"NH N

N ~N N

~~N N

[OS39] HPLC/MS 2.20 min (C), [M+H]443; [OS33] HPLC/MS 1.65 min (B), [M+H]416; (1R,3R)-3-(3-(4-[1-(2-methoxy-ethyl)-1H-pyrazol- N-(3-(4- [1-(2-pyrazol-1-yl-ethyl)-1H-pyrazo1-4-yl]- 4-yl]-phenyl )-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5- phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5-yl)- ylamino)-cyclopentanecarboxylic acid amide cyclohexane-1, 4-diamine O'A215") O'A218")

[OS34] [OS40]

H 0 N N —N N

i ~N N ~NI N N=N

[OS35] HPLC/MS 1.44 min (B), [M+H]470; [OS41] HPLC/MS 2.23 min (C), [M+H]448. US 2016/0015712 A1 Jan. 21, 2016 79

(1R,3R)-3-(3-(5-[1-(2-methoxy-ethyl)-1H-pyrazol- (1R,3R)-3-(3-(3-[1-(2-methoxy-ethyl)-1H-pyrazol- 4-yl]-pyri din-2-yl )-3H-[1,2,3]triazolo [4,5-d]pyrimi- 4-yl]-phenyl )-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5- din-5-ylamino)-cyclopentanecarboxylic acid amide ylamino)-cyclopentanecarboxylic acid amide O'A219") C'A222")

[OS42] [OS4S]

/ Q«"'~N N

N N 2 N ~N N ~~N N

[OS43] HPLC/MS 1.96 min (C), [M+H]449; [OS49] HPLC/MS 1.66 min (B), [M+H]448;

(1R,3R)-3-[3-(4- 1-[2-(5-methyl-[1, 2,4]oxadiazo1-3- ( 3R)-3-(3-(4-[1-(2-ethoxy-ethyl)-1H-pyrazol-4- yl)-ethyl]-1H-pyrazo1-4-yl)-phenyl)-3H-[1, 2,3]tria- (1R, yl]-3-fluoro-phenyl)-3H-[1, 3]triazolo[4, 5-d]pyri- zolo [4,5-d]pyrimidin-5-yl amino] -cyclopentanecar- 2, midin-5-ylamino)-cyclopentanecarboxylic acid boxylic acid amide ("A220") amide ("A223")

[OS44] [OS50]

N F p H

N N

N

[OS45] HPLC/MS 1.65 min (B), [M+H]500; [OS51] HPLC/MS 2.46 min (C), [M+H]480;

(1R,3R)-3-(3-(3-fluoro-4-[1-(2-methoxy-ethyl)-1H- (1R,3R)-3-(3-(6-[1-(2-methoxy-ethyl)-1H-pyrazol- pyrazo1-4-yl]-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyri- 4-yl]-pyri din-3-yl )-3H- [1,2,3]triazolo [4,5-d]pyrimi- midin-5-ylamino)-cyclopentanecarboxylic acid din-5-ylamino)-cyclopentanecarboxylic acid amide amide ("A221") C'A224")

[OS46] [OS52]

PH~N

N N ~N N

[OS47] HPLC/MS 2.35 min (C), [M+H]466; [OS53] HPLC/MS 2.07 min (C), [M+H]449; US 2016/0015712 A1 Jan. 21, 2016 80

(1R,3R)-3-(3-(4-[1-(2-ethoxy-ethyl)-1H-pyrazo1-4- (1R,3R)-3-(3-(3-fluoro-4-[1-(2-methoxy-ethyl)-1H- yl]-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5- pyrazo1-4-yl] -phenyl )-3H-[1,2,3]triazolo [4,5-d]pyri- ylamino)-cyclopentanecarboxylic acid (2-methoxy- midin-5-ylamtno)-cyclopentanol ("A228") ethyl)-amide ("A225") [OS60]

[OS54]

')„"Q „ o~ / J. N N / / / o N=N / [OS61] HPLC/MS 1.75 min (B), [M+H]439; N N (1R,3R)-3-(3-(6-[1-(2-ethoxy-ethyl)-1H-pyrazol-4- yl]-pyridin-3-yl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimi- [OS55] HPLC/MS 2.45 min (C), [M+H]520; 'H NMR (500 din-5-ylamino)-cyclopentanecarboxylic acid amide MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 31 (s, 1H), 8.27 (m, 3H), C'A229") [OS62] 8.06 (s, 1H), 7.87 (d, J=83 Hz, 2H), 4.46 (bs, 1H), 437 (t, J=5.3 Hz, 2H), 3.82 (t, J=53 Hz, 2H), 3.49 (q, J=7.0 Hz, 2H), 339 (t, J=5.6 Hz, 2H), 330 (t, J=5.6 Hz, 2H), 3.27 (s, 3H), o~ 2.93 (p, J=8.0 Hz, 1H), 2.19 (m, 2H), 2.04 (dt, J=11.8, 7.9 Hz, N 1H), 1.93 (ddd, J=13.5, 83, 4.9 Hz, 1H), 1.84-1.67 (m, 2H), 1.13 (t, J=7.0 Hz, 3H); i [OS56] (1R,3R)-3-(3-(4-[1-(2-ethoxy-ethyl)-1H-pyrazol- N 4-yl]-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5- N=N ylamino)-cyclopentanecarboxylic acid (2-hydroxy-ethyl)- amide ("A226") [OS63] HPLC/MS 2.18 min (C), [M+H]463;

/ ~N

N=N

[OS57] HPLC/MS 1.69 min (B), [M+H]506; (1R,3R)-3-(3-(4-[1-(2-methoxy-ethyl)-1H-pyrazol- 4-yl]-3-methyl-phenyl )-3H- [1,2,3]triazolo [4,5-d] pyrimidin-5-ylamino)-cyclopentanecarboxylic acid (1R,3R)-3-(3-(4-[1-(2-ethoxy-ethyl)-1H-pyrazo1-4- amide ("A230") yl]-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5- ylamino)-cyclopentanol ("A227") [OS64]

[OS5S]

/ ~N

N=N

[OS59] HPLC/MS 1.73 min (B), [M+H]435; 'H NMR (400 N=N MHz, DMSO-d~) 6 [ppm]=936-9. 19 (m, 1H), 8.27 (s, 1H), 8.24-8.14 (m, 2H), 8.14-8.04 (m, 1H), 8.00 (s, 1H), 7.89-7.77 (m, 2H), 4.64-4.49 (m, 1H), 4.48-4.36 (m, 1H), 434-4.18 (m, 3H), 3.78 (t, J=5.4, 2H), 3.45 (q, J=7.0, 2H), 2.25-2.06 (m, 1H), 2.02-1.86 (m, 2H), 1.85-1.66 (m, 1H), 1.63-1.44 (m, 2H), 1.08 (t, J=7.0, 3H); [OS65] HPLC/MS 1.70 min (B), [M+H]462; US 2016/0015712 A1 Jan. 21, 2016 81

(1R,3R)-3-(3-[4-(l-pyridin-3-ylmethy1-1H-pyrazol- (1R,3R)-3-(3-(4-[1-(2-hydroxy-2-methyl-propyl)- 4-yl)-phenyl]-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5- 1H-pyrazo1-4-yl]-phenyl)-3H-[1, 2,3]triazolo[4, 5-d] ylamino )-cyclopentanol ("A231") pyrimidin-5-ylamino)-cyclopentanecarboxylic acid amide ("A233") [OS66] [OS70]

N N N ~~OH

N=N N=N

[OS67] HPLC/MS 1.50 min (B), [M+H]454; HPLC/MS 2.17 min (C), [M+H]462;

(1R,3R)-3-(3-(4-[1-(2-hydroxy-2-methyl-propyl)- (trans)-3-(3-( 6-[1-(2-methoxy-ethyl)-1H-pyrazo1-4- 1H-pyrazo1-4-yl]-phenyl)-3H-[1, 2,3]triazolo[4, 5-d] yl]-pyridin-3-yl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimi- pyrimidin-5-ylamino)-cyclopentanol ("A232") din-5-ylamino)-cyclopentanol ("A234") [OS71] [OS68]

~~OH

N=N N=N

[OS72] HPLC/MS 1.62 min (B), [M+H]422; [OS69] HPLC/MS 1.86 min (A), [M+H]435; 'H NMR (400 3R)-3-(3-(4-[1-(2-methoxy-ethyl)-1H-pyrazol- MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 29 (s, 1H), 8.28 (d, J=0.8 (1R, Hz, 1H), 8.24 (d, J=8.5 Hz, 2H), 8.10 (d, J=0.8 Hz, 1H), 7.89 4-yl]-phenyl )-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5- (1-methyl- (d, J=8.7 Hz, 2H), 4.54 (bs, 1H), 4.33 (tt, J=5.8, 3.1 Hz, 1H), ylamino)-cyclopentanecarboxylic acid piperidin-4-ylmethyl)-amide ("A235") 4.15 (s, 2H), 2.25 (q, J=7.0, 6.6 Hz, 1H), 2.13-1.92 (m, 2H), 1.83 (dt, J=13.4, 6.6 Hz, 1H), 1.70-1.53 (m, 2H), 1.17 (s, 6H); [OS73]

N H ~/

N=N US 2016/0015712 A1 Jan. 21, 2016 82

[OS74] "A235" formate salt: HPLC/MS 1.49 min (B), (1R,3R)-3-(3-(5-[1-(2-cyano-ethyl)-1H-pyrazo1-4- [M+H] 559; 'H NMR (500 MHz, DMSO-d~) fI [ppm] =9.25 (s, yl]-pyridin-2-yl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimi- 1H), 830-8.18 (m, 3H), 8.16 (s, 1H), 7.99 (s, 1H), 7.88-7.75 din-5-ylamino)-cyclopentanecarboxylic acid amide (m, 3H), 4.52-4.32 (m, 1H), 430 (t, J=53, 2H), 3.74 (t, J=53, O'A239") 2H), 3.26 (s, 3H), 2.94 (t, J=6.3, 2H), 2.90-2.77 (m, 3H), [OSS1] 2.29-2.18 (m, 3H), 2.14-1.90 (m, 5H), 1.90-1.82 (m, 1H), 1.73-1.64 (m, 2H), 1.64-1.56 (m, 2H), L44-1 33 (m, 1H), 1.21-1.09 N (m, 2H); N~CN 2-[2-(4-(4-[5-((1R,3R)-3-hydroxy-cyclopenty- lamino)-[1, 2,3]triazolo [4,5-d]-pyrimidin-3-yl]-phe- nyl )-pyrazo1-1-yl)-ethyl] -2H-pyridazin-3-one +I O'A236") N=N [OS75] [OSS2] HPLC/MS 1.42 min (B), [M+H]444; H N (1R,3R)-3-[[3-(4-pyrimidin-5-ylphenyl)triazolo [4,5- N d]pyrimidin-5-yl] amino] cyclopentanecarboxamide O'A239a")

[OS83] N=N

[OS76] HPLC/MS 1.61 min (B), [M+H]485; N (1R,3R)-3-[3-(4-(1-[2-(6-oxo-6H-pyridazin-1-yl)- ethyl]-1H-pyrazo1-4-yl)-phenyl)-3H-[1, 2,3]triazolo [4,5-d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide O'A237") N=N [OS77] 0 H (1R,3R)-3-[[3-[4-(6-methyl-3-pyridyl)phenyl] tria- NHp zolo [4,5-d]pyrimidin-5-yl] amino] cyclopentanecar- boxamide O'A239b")

[OS84] N=N

[OS7S] HPLC/MS 1.60 min [M+H]512; 'H NMR (500 (B), N MHz, DMSO-d~, TFA-d, ) fI [ppm] 9.29 (s, 1H), 8.23 (m, 3H), 7.99 (s, 1H), 7.87-7.77 (m, 3H), 7.38 (dd, J=9.4, 3.8 Hz, 1H), 6.95 (dd, J=9.5, 1.6 Hz, 1H), 4.65-4.58 (m, 2H), 4.58-4.51 (m, N 2H), 4.41 (bs, 1H), 2.90 (p, J=8.0 Hz, 1H), 2.16 (m, 2H), 2.03 / (dtd, J=10.7, 7.2, 6.3, 4.0Hz, 1H), 1.92 (m, 1H), 1.78 (m, 2H); N=N

(1R,3R)-3-(3-(5-[1-(2-ethoxy-ethyl)-1H-pyrazol-4- yl]-pyridin-2-yl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimi- 3R)-3-[[3-[4-[1-[2-methoxy-1-(methoxymethyl) din-5-ylamino)-cyclopentanecarboxylic acid amide (1R, O'A238") ethyl]pyrazol-4-yl]phenyl]-triazolo [4,5-d]pyrimidin- 5-yl]amino]cyclopentanecarboxamide O'A239c") [OS79] [OS85] HpN H N HpN H N N 0 +I N=N N=N

[OSSO] HPLC/MS 1.50 min (B), [M+H]463; US 2016/0015712 A1 Jan. 21, 2016 83

(1R,3R)-3-[[3-[4-(5-methylpyrimi din-2-yl)phenyl] -continued triazolo [4,5-d]pyrimi din-5-yl] amino] cyclopentan- HOI ecarboxamide ("A239d")

[OSS6]

N H

N

N Vj' N /z N ~~N N

[OSS9] To a solution of (1R,3R)-3-[3-(4-ethoxy-phenyl)- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cyclopen- 3R)-3-[[3-[5-[1-(2-pyrazo1-1-ylethyl)pyrazo1-4- (1R, tanecarboxylic acid (184 mg, 0.50 mmol) in THF (2 ml) are yl]-2-pyridyl]triazolo[4, 5-d]pyrimidin-5-yl] amino] added 4-amino-2-methyl-butan-2-ol (103 mg, 1.00 mmol), cyclopentanecarboxamide ("A239e") N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydro- chloride (144 mg, 0.75 mmol) and 1-hydroxybenzotriazole [OS87] hydrate (76.5 mg, 0.50 mmol) The reaction mixture is stirred for 4 hours at room temperature. The reaction mixture is filtered. The filtrate is concentrated and the residue is chro- H2N ~ NQ matographed on a silica gel column with dichloromethane/ ~ N methanol as eluent to afford (1R,3R)-3-[3-(4-ethoxy-phe- nyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]- N cyclopentanecarboxylic acid (3-hydroxy-3-methyl-butyl)- amide as light yellow solid; HPLC/MS 1.80 min (B), [M+H] 454;

[OS90] 'H NMR (500 MHz, DMSO-d~, TFA-d, ) fI [ppm]9. 27 (s, 1H), 8.08 (bs, 2H), 7.28-7.03 (m, 2H), 437 (bs, 1H), Example 23 4.14 (q, J=7.0 Hz, 2H), 3.24-3.08 (m, 2H), 2.82 (p, J=8.0 Hz, 1H), 2.10 (m, 2H), 2.03-1.91 (m, 1H), 1.91-1.80 (m, 1H), J=7. Synthesis of (1R,3R)-3-[3-(4-ethoxy-phenyl)-3H-[1, 1.78-1.62 (m, 2H), 1.60-1.52 (m, 2H), 1.40 (t, 0 Hz, 3H), 2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cyclopen- 1.12 (s, 6H). tanecarboxylic acid (3-hydroxy-3-methyl-butyl)- [OS91] The following compounds are prepared analo- amide ("A240") gously:

[OSSS] 1(1R,3R)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]tria- zolo[4, 5-d]pyrimidin-5-ylamino]-cyclopentyl)-(4- methyl-piperazin-1-yl)-methanone ("A241")

[OS92] OH

Vj' N lr N HO ~N N EDCI HOH, THF

H2N [OS93] "A241" formate salt HPLC/MS 1.47 min (B), [M+H]437; US 2016/0015712 A1 Jan. 21, 2016 84

(1S,3R)-3-(3-quinolin-6-y1-3H-[1, 2,3]triazo1o [4,5-d] (1R,3R)-3-[3-(2-methyl-quinolin-6-yl)-3H-[1, 2,3] pyrimidin-5-ylamino)-cyclopentanecarboxylic acid triazo1o [4,5-d]pyrimi din-5-ylamino]-cyclopentan- [2-(4-methyl-piperazin-1-yl)-ethyl]-amide ("A242") ecarboxylic acid (2-hydroxy-ethyl)-amide ("A245")

[0894] [0900]

KAHN ~NH N

N / ~N~ I X N~~N

[0901] HPLC/MS 1.40 min (B), [M+H]433; 'H NMR (500 [0895] HPLC/MS 1.37 min (B), [M+H]501; MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 43 (d, J=8.7 Hz, 1H), 936 (s, 1H), 9.29 (s, 1H), 9.05 (d, J=9.0 Hz, 1H), 8.46 (d, (1R,3R)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo J=9.3 Hz, 1H), 8.09 (d, J=8.7 Hz, 1H), 4.53 (p, J=7.0 Hz, 1H), [4,5-d]pyrimidin-5-ylamino]-cyclo pentanecarboxy- 3.42 (t, J=6.0 Hz, 2H), 3.19 (t, J=6.1 Hz, 2H), 3.00 (s, 3H), lic acid dimethylamide ("A243") 2.89 (m 1H), 2.35 (m, 1H), 2.18-1.96 (m, 2H), 1.86-1.59 (m, 3H); [0896] (1R,3R)-3-[3-(2-methyl-quinolin-6-yl)-3H-[1, 2,3] triazo1o [4,5-d]pyrimi din-5-ylamino]-cyclopentan- ecarboxylic acid (2-methoxy-ethyl)-amide ("A246")

H [0902]

~~N N

[0897] HPLC/MS 1.81 min (B), [M+H]382; N I

(1R,3R)-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d]pyrimidin-5-ylamino]-cyc lop entanecarboxylic acid [2-(4-methyl-piperazin-1-yl)-ethyl]-amide [0903] HPLC/MS 1.50 min (B), [M+H]447; C'A244") (1R,3R)-3-[3-(4-ethoxy-phenyl)-3H-[1, 2,3]triazolo [0898] [4,5-d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid (2-hydroxy-ethyl)-amide ("A247")

[0904]

)""~N 0 NN" X, NH

NH N N N HO N

[0899] HPLC/MS 1.46 min (B), [M+H]480; [0905] HPLC/MS 1.73 min (B), [M+H]412; US 2016/0015712 A1 Jan. 21, 2016 85

(1R,3R]-3-[3-(4-ethoxy-phenyl]-3H- [1,2,3]triazolo [0913] (1R,3R]-3-[3-(4-ethoxy-phenyl]-3H-[1, 2,3]tria- [4,5-d]pyrimidin-5-ylamino]-cyc lop entanecarboxylic zolo[4, 5-d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid (2-methoxy-ethyl]-amide ("A248 "] acid (2-hydroxy-2-methyl-propyl]-methyl-amide ("A251 "] [0906]

0 NH

N N~N N~~N

[0907] HPLC/MS 1.85 min (B], [M+H]426; [0914] HPLC/MS 2.63 min (C], [M+H]454; (1R,3R]-3-[3-(4-ethoxy-phenyl]-3H- [1,2,3]triazolo 5-d]pyrimidin-5-ylamino]-cycloentanecarboxyic [4, (1R,3R]-3-[3-(2-methyl-quinolin-6-yl]-3H-[1, 2,3] acid (1-methyl-piperidin-4-ylmethyl]-amide "A249"] triazo1o [4,5-d]pyrimi din-5-ylamino]-cyclopentan- [0908] ecarboxylic acid (1-methyl-piperidin-4-ylmethyl]- amide ("A252"]

[0915]

N N / / N N

N~~N [0909] "A249" formate salt: [0910] HPLC/MS 2.02 min (C], [M+H]479; 'H NMR (500 MHz, DMSO-d~, TFA-d, 6 [ppm]9. 29 (s, 1H], 8.12 (s, 1H], ] [0916] "A252" formate salt HPLC/MS 134 min (B], 8.08 (bs, 2H], 7.18 (d, J=9.0 Hz, 2H], 4.42 (bs, 1H], 4.15 (q, [M+H]500; J=7.0 Hz, 2H], 3.52-3.41 (m, 2H], 3.21 (m, 1H], 3.10-2.99 (m, 2H], 2.91 (m, 3H], 2.77 (s, 3H], 2.15 (m, 2H], 2.03 (m, 1H], 1.96-1.81 (m, 3H], 1.81-1.62 (m, 4H], 1.41 (t, J=7.0 Hz, (1R,3R]-3-[3-(2-methyl-quinolin-6-yl]-3H-[1, 2,3] 3H]; triazo1o [4,5-d]pyrimi din-5-ylamino]-cyclopentan- ecarboxylic acid (3-hydroxy-3-methyl-butyl]-amide (1R,3R]-3-[3-(2-methyl-quinolin-6-yl]-3H-[1, 2,3] O'A253 "] triazolo [4,5-d]pyrimi din-5-ylamino]-cyclopentan- ecarboxylic acid [2-(4-methyl-piperazin-1-yl]-ethyl]- [0917] amide ("A250" [0911]

'p„. Q „ ~ +H 8 ~

N=N

[0912] "A250" formate HPLC/MS 1.40 min (B], [M+H] 516; [091S] HPLC/MS 1.55 min (B], [M+H]475; US 2016/0015712 A1 Jan. 21, 2016 86

(1R,3R)-3-[3-(2-methyl-quinolin-6-yl)-3H-[1, 2,3] -continued triazolo [4,5-d]pyrimi din-5-ylamino]-cyclopentan- ecarboxylic acid ((trans)-3-hydroxy-cyclopentyl)- amide ("A254")

[0919]

PdCl (dpppl N~ H N Kr CO1 dioxane/water 80' C.

HO ~B N 0 ~N N

[0920] HPLC/MS 1.41 min (B), [M+H]473;

(1R,3R)-3-[[3-(2-methyl-6-quinolyl)triazolo [4,5-d] pyrimidin-5-yl] amino]-N-(2-morpholino ethyl) cyclo- pentanecarboxamide ("A254a")

[0921]

N~ N 4N HCl in dtoxane

CHrClr/MCOH () NHr

0 Vj' N

HO Example 24

Synthesis of (1R,3R)-3-(3-(4-[1-(2-hydroxy-ethyl)- 1H-pyrazo1-4-yl]-phenyl)-3H-[1, 2,3]triazolo[4, 5-d] N~ N pyridimdin-5-ylamino)-cyclopentanecarboxylic acid amide (A"255")

[0922] NHr

NHr Vj'

N [0923] To a solution of (1R,3R)-3-[3-(4-iodo-phenyl)-3H- Vj' N [1,2,3]triazolo [4,5-d]pyrimidin-5-ylamino]-cyclopentan- Iz ecarboxylic acid amide 0.40 mmol) and 1-[2-(tet- N (179 mg, rahydro-pyran-2-yloxy)-ethyl]-4-(4, 4,5,5-tetramethyl-[1, 3, 2]dioxaborolan-2-yl)-1 H-pyrazole (168 mg, 0.52 mmol) in US 2016/0015712 A1 Jan. 21, 2016 87

dioxane (2 ml) are added water (0.2 ml) and potassium car- 2-(4-14-[5-((1R,3S)-3-amino-cyclopentylamino)-[I, bonate (1660 mg, 1.2 mmol). The mixture is flushed with 2,3]triazolo [4,5-d]pyrimidin-3-yl]-phenyl )-pyrazol- nitrogen and heated to 80 C. Dichloro [1,1'-bis(diphenylphos- I-yl)-ethanol ("A257") phino) ferrocene]-palladium(II) dichloromethane adduct (33 mg, 0.04 mmol) is added and the mixture is stirred in a closed [0929] reaction vial for 16 hours at 80' C. The reaction mixture is allowed to reach room temperature and partitioned between water and dichloromethane. The organic phase is dried over HpN sodium sulfate and evaporated. The residue is chromato- graphed on a silica gel column with dichloromethane/metha- nol as eluent to afford (IR,3R)-3-P-(4-11-[2-0.35 (tetrahy- "NH dro-pyran-2-yloxy)-ethyl]- IH-pyrazol-4-yl )-phenyl)-3H- [1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]- cyclopentanecarboxylic acid amide as beige solid; HPLC/MS 44 min 2. (C), [M+H]518. N [0924] To a solution of (IR,3R)-3-P-(4-11-[2-(tetrahydro- N=N/ pyran-2-yloxy)-ethyl]-I H-pyrazol-4-yl)-phenyl)-3H-[1, 2,3] triazolo [4,5-d]pyrimi din-5-ylamino]-cyclopentanecarboxy- lic acid amide (77.6 mg, 0.15 mmol) in dichloromethane (1.5 [0930] HPLC/MS 1.41 min (B), [M+H]406; ml) are added methanol (0.8 ml) and a 4 N solution of hydro- chloric acid in dioxane (275 pl) and the reaction mixture is H-pyrazo1-4- stirred for 60 minutes at 50' C. The solvent is evaporated and (IS,3R)-3-(3-14-[I -(2-hydroxy-ethyl)- I the residue is treated with saturated sodium hydrogen carbon- yl] -phenyl )-3H-[1,2,3]triazolo [4,5-d]pyrimidin-5- ate solution. The solids are filtered off, washed with water and ylamino)-cyclopentanecarboxylic acid amide dried under vacuum. The residue is chromatographed on a ("A258") silica gel column with dichloromethane/methanol as eluent to afford (IR,3R)-3-(3-14-[I-(2-hydroxy-ethyl)-IH-pyrazo1-4- [0931] yl]-phenyl)-3H-[1, 2,3]triazolo [4,5-d]pyrimidin-5- ylamino)-cyclopentanecarboxylic acid amide as white crys- tals; HPLC/MS 2.03 min (C), [M+H]434; [0925] 'H NMR (400 MHz, DMSO-d~, TFA-d, ) 6 [ppm]9. 29 (s, IH), 8.32 (s, IH), 8.25 (d, J=8.3 Hz, 2H), 8.08 (s, IH), 7.88 (d, J=8.6 Hz, 2H), 4.42 (bs, IH), 4.26 (t, J=5.5 Hz, 2H), 3.85 (t, J=5.5 Hz, 2H), 2.90 (p, J=7.9 Hz, IH), 2.18 (m, 2H), 2.09-1.98 (m, IH), 1.92 (m, IH), 1.86-1.64 (m, 2H). Q '"N [0926] The following compounds are prepared analo- gously:

2-(4-14-[5-(trans-4-amino-cyclohexyl amino)-[1, 2,3] ~~N triazolo [4,5-d]pyrimidin-3-yl]-phenyl )-pyrazo1- I- N yl)-ethanol ("A256") [0932] HPLC/MS 1.55 min [M+H]434; [0927] (B),

(IR,3R)-3-(3-14-[I -(2-hydroxy-ethyl)- I H-pyrazo1-4- yl] -phenyl )-3H-[1,2,3]triazolo [4,5-d]pyrimidin-5- ylamino)-cyclopentanol ("A259")

HpN [0933] '"NH ~OH N

N=N

[0928] HPLC/MS 1.35 min (B), [M+H]420; [0934] HPLC/MS 1.55 min (B), [M+H]407; US 2016/0015712 A1 Jan. 21, 2016 88

(1R,3R)-3-(3-(3-fluoro-4-[1-(2-hydroxy-ethyl)-1H- (1R,3R)-3-(3-(5-[1-(2-hydroxy-ethyl)-1H-pyrazo1-4- pyrazo1-4-yl]-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyri- yl]-pyridin-2-yl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimi- midin-5-ylamino)-cyclopentanecarboxylic acid din-5-ylamino)-cyclopentanecarboxylic acid amide amide ("A260") O'A261") [0937] [0935] N ~OH H N 0 N

N N ~N N N ~OH H 0 N N [0938] HPLC/MS L82 min (C), [M+H]435; Example 25 N F Synthesis of [3-(4-methoxy-phenyl)-3H-[1, 2,3]tria- ~N zolo[4, 5-d]pyrimidin-5-yl]-Ktrans)-3-methylsulfa- N nyl-cyclopentyl)-amine ("A262"), Ktrans)-3-meth- ane sul fonyl-cyc lop entyl)-[3-(4-methoxy-phenyl)- 3H-[1,2,3]triazolo [4,5-d]pyrimidin-5-yl]-amine ("A263") and ((cis)-3-methanesulfonyl-cyclopentyl)- [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazo1o [4,5-d] pyrimidin-5-yl]-amine ("A264") [0936] HPLC/MS 1.60 min (B), [M+H]452; [0939]

DIPEA CHsOCH2CH2OH 80' C. NH2 Yi

contains 30% cis-isomer

sodium perborate formic acid US 2016/0015712 A1 Jan. 21, 2016 89

[0940] "A262":HPLC/MS 2.11min (B],[M+H]356; trans- 930 (s, 1H], 831-8.17 (m, 3H], 8.00 (s, 1H], 7.82 (d, J=8.4 'H isomer: NMR (500 MHz, DMSO-d~, TFA-d, ] 6 [ppm]9. Hz, 2H], 4.67 (t, J=6.8 Hz, 2H], 4.46 (bs, 1H], 3.56 (t, J=6.8 27 (s, 1H], 8.06 (d, J=9.6 Hz, 2H], 7.19 (d, J=9.1 Hz, 1H], 4.31 Hz, 2H], 2.95 J=7.9 Hz, 1H], 2.21 (m, 2H], 2.06 (m, 1H], (bs, 1H], 3.87 (s, 3H], 3.18-2.96 (m, 1H], 2.51-1.51 (multip- (p, lets, 6], signals of the cis-isomer: 6 7.19 (d, J=93 Hz, 2H], 1.96 (m, 1H], 1.89-1.68 (m, 2H]. 4.43 (bs, 1H], 3.29 (p, J=6.9 Hz, 1H]; [0941] "A263" (trans-isomer]: HPLC/MS 1.77 min (B], trans-3-[3-(4-(1-[2-(1H-Tetrazol-5-yl]-ethyl]-1H- [M+H]389; 'H NMR (500 MHz, DMSO-d~, TFA-d, ] 6 [ppm] 9.26 (s, 1H], 8.05 (bs, 2H], 7.20 (d, J=8.7 Hz, 2H], 433 (bs, pyrazo1-4-yl)-phenyl]-3H-[1, 2,3]triazolo [4,5-d]pyri- 1H], 3.87 (s, 3H], 3.81-3.59 (m, 1H], 2.95 (s, 3H], 2.47 (m, midin-5-ylamino]-cyclopentanol ("A266"] 1H], 2.06 (m, 4H], 1.79 (m, 1H]; "A264" [0942] (cis-isomer]: HPLC/MS 1.79 min (B], [0946] [M+H]389; 'H NMR (500 MHz, DMSO-d~, TFA-d, ] 6 [ppm] 9.22 (s, 1H], 8.30-7.78 (m, 2H], 7.14 (d, J=8.9 Hz, 2H], 4.38 (bs, 1H], 3.82 (s, 3H], 3.77 (td, J=9.1, 4.6 Hz, 1H], 2.91 (s, 3H], 2.47-2.32 (m, 1H], 2.24-2. 12 (m, 1H], 2.11-2.04 (m, N 1H], 2.04-1.91 (m, 2H], 1.79 (m, 1H].

Example 26 H Synthesis of (1R,3R]-3-[3-(4-(1-[2-(1H-tetrazo1-5- yl]-ethyl] -1H-pyrazo1-4-yl1-phenyl]-3H- [1,2,3]tria- zolo [4,5-d]pyrimidin-5-yl amino] -cyclopentanecar- ("A265"] boxylic acid amide ~N [0943] N CN

is prepared similarly: HPLC/MS 1.77 min (B], [M+H]459. N~ N Example 27 0

H2N +l Synthesis of [3-(4-methoxy-phenyl]-3H-[1, 2,3]tria- zolo [4,5-d]pyrimidin-5-yl]-[(1R, 3S]-3-(5-methyl- oxazol-2-yl]-cyclopentyl]-amine ("A267"]

[0947]

Yj 0 OH Bu2Snp TMS ~ DMF/DME 150' C. N=N HOBt/ / NH HN DMF N~ N

N Yj /y N

~N N

N~ N H2N N CHsCN ~-(~ / 50' C.

[0944] TMSN3Mrimethylsilylazide [0945] "A265":dark purple solid; HPLC/MS 1.77 min (C], [M+H]486; 'H NMR (400 MHz, DMSO-d~, TFA-d, ] 6 [ppm] US 2016/0015712 A1 Jan. 21, 2016 90

-continued [0950] HPLC/MS 1.55 min (B), [M+H]434; 'H NMR (500 MHz, DMSO-de, TFA-d, ) 6 [ppm]8. 09 (m, 3H), 7.94 (s, 1H), 7.72 (d, J=8.6 Hz, 1H), 4.45 (p, J=6.9 Hz, 1H), 439 (t, J=6.5 Hz, 2H), 4.26 (tt, J=5.8, 3.1 Hz, 1H), 2.73 (t, J=6.5 Hz, 2H), 2.18 (m, 1H), 2.01 (ddd, J=12.9, 7.4, 3.0 Hz, 1H), 1.97-1.87 (m, 1H), 1.74 (ddd, J=13.4, 7.4, 5.9 Hz, 1H), 1.61-1.47 (m, 2H).

Example 29

Synthesis of ((R)-1-methanesulfonyl-pyrrolidin-3- yl)-(3-quinolin-6-yl-3H- [1,2,3]triazolo [4,5-d]pyrimi- Vj din-5-yl)-amine ("A269") [0951]

[0948] HPLC/MS 2.89 min (C), [M+H]392; 'H NMR (400 MHz, DMSO-de, TFA-d, ) 6 [ppm]9. 29 (s, 1H), 8.08 (bs, 2H), 28-7. J=8. N 7. 03 (m, 3H), 4.47 (bs, 1H), 3.88 (s, 3H), 3.55 (p, 4 C1 / Hz, 1H), 2.68-2.60 (m, 1H), 236 (d, J=1.3 Hz, 3H), 2.31-2.00 (m, 4H), 1.92 (d, J=8.6 Hz, 1H). H2N DIPEA Example 28 CH SO CI CH2C12

Synthesis of 3-(4-14-[5-(trans-3-hydroxy-cyclopen- tylamino)-[1, 2,3]triazolo[4, 5-d]pyrimidin-3-yl]-phe- nyl )-pyrazo1-1-yl)-prop ionamide ("A268") Vj [0949] /

CN /

N~ N Vj' OH H CO IH 0

MCOH/DMSO 80' C. [0952] HPLC/MS 1.63 min (B), [M+H]411; 'H NMR (400 MHz, DMSO-de, TFA-d, ) 6 [ppm]9. 47 (dd, J=5.4, 1.5 Hz, 1H), 9.44 (d, J=8.5 Hz, 1H), 936 (s, 1H), 932 (s, 1H), 9.16 (d, N J=9.6 Hz, 1H), 8.61 (d, J=9.3 Hz, 1H), 8.25 (dd, J=8.5, 5 3 Hz, Vj' 1H), 4.69 (bs, 1H), 3.83 (m, 1H), 3.58 (dt, J=9.9, 73 Hz, 1H), // N 3.53-336 (m, 2H), 2.94 (s, 3H), 237 (m, 1H), 2.20 (m, 1H).

((R)-1-Methane sul fonyl-pyrroli din-3-yl)-[3-(4-meth- NH2 oxy-phenyl)-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5- yl] -amine ("A269a") N~ [0953] N

OH 0 H

N N N ~N Yj // N N

is prepared analogously. US 2016/0015712 A1 Jan. 21, 2016 91

Example 30 -continued

Synthesis of (R)-3-[3-(4-methoxy-phenyl)-3H-[1, 2, 3]triazolo [4,5-d]pyrimidin-5-ylamino]-pyrrolidine-l- sulfonic acid amide ("A270") ~ [0954] TBTU HOB//NMM () DMF C1

H/N'

011OXRITO + NH/SO/NH/ 000' C. OH

Yj 0

H/N —S

N

4N HC1/ Yj 011OXRITO

[0955] HPLC/MS 1.71 min (B), [M+H]391; 'H NMR (400 MHz, DMSO-do) 6 [ppm]9. 22 (s, 1H), 8.04 (bs, 2H), 7.14 (d, J=8.7 Hz, 2H), 4.45 (bs, 1H), 3.81 (s, 3H), 3.52 (dd, J=10.4, 6.5 Hz, 1H), 3.34 (dt, J=9.8, 7.2 Hz, 1H), 3.21 (dt, J=9.8, 7.6 Hz, 1H), 3.16 (m, 1H), 2.22 (dq, J=13.9, 7.1 Hz, 1H), 2.02 (m, 1H).

Example 31

Synthesis of 1-((R)-3-(3-[4-(1-methyl-1H-pyrazol-4- yl)-phenyl] -3H- [1,2,3]triazolo [4,5-d]pyrimi din-5- N~ N ylamino )-pyrrolidin-1-yl)-4-piperazin-1-yl-butan-1- one ("A271")

[0956]

N~ / N C1 Yj H/N'

[0957] "A271" dihydrochloride: HPLC/MS 1 34 min (B), [M+H] 516; 1H NMR (400 MHz, DMSO-d6, d-TEA) 6 9.27 (s, 1H), 8.20 (s, 1H), 8.20-8.05 (m, 2H), 7.96 (s, 1H), 7.80 (d, Yj J=8.0 Hz, 2H), 4.51 (d, J=29.6 Hz, 2H), 3.55 (m, 13H), 2.40 (dt, J=13.9, 6.9 Hz, 2H), 2.27 (m, 1H), 2.13m, 2H), 2.01-1.86 (m, 2H). US 2016/0015712 A1 Jan. 21, 2016 92

Example 32 [0960] "A273": HPLC/MS 2.24 min (C), [M+H]352; 'H NMR DMSO-, TFA-di) ft 28 Synthesis of (1R,4S)-4-[3-(4-ethoxy-phenyl)-3H-[1, (500 MHz, [ppm]9. (s, 1H), 20-7. J=9. 2,3]triazolo 5-d]pyrimidin-5-yl amino] -cyclopent- 8. 85 (m, 2H), 7.21 (d, 0 Hz, 2H), 5.94 (m, 2H), 5.16 [4, J=8. 2-enecarboxylic acid amide ("A272") and (1S,4S)-4- (bs, 1H), 3.87 (s, 3H), 3.66 (ddd, 6, 43, 2.2 Hz, 1H), [3-(4-Methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d] 2.58-2.51 (m, 1H), 1.99 (ddd, J=13.2, 8.7, 4.6 Hz, 1H). pyrimidin-5-ylamino]-cyclopent-2-enecarboxylic Example 33 acid amide ("A273") Synthesis of (1R,3R)-3-13-[4-(2-methoxy-ethoxy)- [0958] phenyl]-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5- ylamino)-cyclopentanecarbonitrile ("A274") [0961]

NH3 Yj dtoxatle 0— 100' C.

N

N // N CH3OCH3CH3OH 80' C. NH3 L-tartrate salt N .j

MeOH

N N Vj' N // // N f N 0 'H HO HO I [0962] HPLC/MS 1.88 min (B), [M+H]380; NMR (400 MHz, DMSO-de, TFA-dt) ft [ppm] 9.28 (s, 1H), 8.08 (bs, 2H), 7.48-7.00 (m, 2H), 4.46 (bs, 1H), 433-4.09 (m, 2H), 3.87-3. 63 (m, 2H), 337 (s, 3H), 3.20 (p, J=7.7 Hz, 1H), 236-L99 (m, 4H), 1.99-1.69 (m, 2H). cis-3-[3-(4-Methoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5- d]pyrimidin-5-ylamino]-cyclopentanecarbonitrile ("A275") EDCl, HOBt 3 dioxatte/THE [0963] 0 H3N H3N I

N

~~N N

is prepared analogously; HPLC/MS 1.90 min (B), [M+H] [0959] "A272": HPLC/MS 235 min (C), [M+H]352; 'H 336; 'H NMR (500 MHz, DMSO-de, TFA-dt) ft [ppm]9. 31 NMR (500 MHz, DMSO-de, TFA-dt) ft [ppm]931 (s, 1H), (s, 1H), 8.07 (d, J=8.0 Hz, 2H), 7.18 (d, J=9.0 Hz, 2H), 4.38 8.07 (d, J=8.5 Hz, 2H), 7.20 (d, J=9.0 Hz, 2H), 5.97 (m, 2H), (bs, 1H), 3.88 (s, 3H), 3.02 (p, J=8.1 Hz, 1H), 2.56 (dt, J=13.1, 5.11 (bs, 1H), 3.88 (s, 3H), 3.49 (m, 1H), 2.56-2.48 (m, 1H), 7.8 Hz, 1H), 2.19-2.05 (m, 3H), 2.05-1.96 (m, 1H), 1.91 (m, 1.97 (dt, J=13.3, 5.2 Hz, 1H). 1H). US 2016/0015712 A1 Jan. 21, 2016 93

Example 34 Synthesis of (1R,3R)-3-[3-(4-hydroxy-phenyl)-3H- [1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cyclo- pentanecarboxylic acid amide ("A276"), (1R,3R)-3- (3-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-3H-[1, 2,3] triazolo[4, 5-d]pyrimidin-5-ylamino)- cyclopentanecarboxylic acid amide ("A277"), (1R, 3R)-3-(3-[4-(3-hydroxy- 1,1-dimethyl-prop oxy)- phenyl]-3H-[1, 2,3]triazolo [4,5-d]pyrimidin-5- ylamino)-cyclopentanecarboxylic acid amide ("A278") and (1R,3R)-3-(3-[4-(piperidin-4-yl- methoxy)-phenyl]-3H-[1, 2,3]triazolo [4,5-d]pyrimi- din-5-ylamino)-cyclopentanecarboxylic acid amide C'A279") [0964] 0

H2N +7

KOA B—Bl / PdCl2 (PPhs12 Yj DMF/80' C.

0 0 B H2N M

sodium p p THF/water Vj'

OK H2N M

/ PPhs/DIAD/THF H2N +7 Vj'

OH

PPhs/DIAD THF Yj

PPhs/DIAD OH 4N HCl in dioxane THF US 2016/0015712 A1 Jan. 21, 2016 94

-continued OH NH2

0 C1 H2N +8 H2N M H2N +8

/

Y~Q';; Y~Q'„'

[0965] "A276": HPLC/MS 1.98 min (C), [M+H]340; 'H -continued NMR (400 MHz, DMSO-de, TFA-dr) 6 [ppm]9. 41 (s, 1H), 7.93 (d, J=8.5 Hz, 2H), 7.07 (d, J=8.9 Hz, 2H), 4.46 (p, J=6.2 Hz, 1H), 3.00 (p, J=8.0 Hz, 1H), 233-2.15 (m, 2H), 2.10 (dtd, PN J=11.2, 7.4, 6.8, 4.1 Hz, 1H), 1.97 (ddd, J=13.7, 8.8, 5.1 Hz, 1H), 1.90-1.69 (m, 2H); [0966] "A277": HPLC/MS 1.66 min (C), [M+H]453; 'H NMR (500 MHz, DMSO-de, TFA-dr) 6 [ppm]9. 29 (s, 1H), 8.16 (d, J=8.4 Hz, 2H), 731 (d, J=9.0 Hz, 2H), 4.55-4.51 (m, 2H), 439 (bs, 1H), 4.12-3.98 (m, 2H), 3.87-3.75 (m, 2H), 3.70 (t, J=4.9 Hz, 2H), 3.63 (d, J=12.6 Hz, 2H), 3.31 (td, Burgess J=12.3, 3.7 Hz, 2H), 2.92 (p, J=8.0 Hz, 1H), 2.26-2.09 (m, R" 2H), 2.09-1.99 (m, 1H), 1.92 (m, 1H), 1.84-1.66 (m, 2H); [0967] "A278": HPLC/MS 2.20 min (C), [M+H]426; 'H THF NMR (500 MHz, DMSO-de, TFA-dr) 6 [ppm]930 (s, 1H), 100' C. 8.21-8.05 (m, 2H), 7.25 (d, J=8.9 Hz, 2H), 4.44 (bs, 1H), 3.73 (microwavel (t, J=73 Hz, 2H), 2.93 (p, J=8.0 Hz, 1H), 2.33-2.11 (m, 2H), 2.06 (qd, J=8.1, 4.5 Hz, 1H), 1.95 (t, J=73 Hz, 2H), 1.94-1.89 (m, 1H), 1.77 (m, 2H), 1 36 (s, 6H); [0968] "A279": HPLC/MS 1.78 min (C), [M+H]437; 'H NMR (500 MHz, DMSO-de) 6 [ppm]9. 30 (s, 1H), 8.11 (d, J=9.5 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H), 4.41 (bs, 1H), 4.01 (d, J=6.2 Hz, 2H), 3.40 (d, J=12.7 Hz, 2H), 3.04-2.89 (m, 3H), 2.18 (m, 3H), 2.11-1.97 (m, 3H), 1.92 (ddd, J=13.4, 9.3, 5.6 Hz, 1H), 1.76 (m, 2H), 1.68-1.50 (m, 2H).

Example 35

Synthesis of (1R,3R)-3-[3-(4-ethoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cyclopen- tanecarboxylic acid N'-acetyl-hydrazide ("A280") and [3-(4-ethoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5-d] pyrimidin-5-yl]-[(1R, 3R)-3-(5-methyl-[1, 3,4]oxadia- zol-2-yl)-cyclopentyl]-amine ("A281") Vj' [0969]

"A280": 'H 0 [0970] HPLC/MS 2.29 min (C), [M+H]425; NMR (500 MHz, DMSO-de, TFA-dr) 6 [ppm]9. 29 (s, 1H), HO ~7 8.27-7.95 (m, 2H), 7.19 (d, J=83 Hz, 2H), 4.43 (bs, 1H), 4.15 (q, J=7.0 Hz, 2H), 2.97 (p, J=7.9 Hz, 1H), 2.17 (m, 2H), 2.10-2.01 (m, 1H), 1.99-1.92 (m, 1H), 1.91 (s, 3H), 1.85-1.68 (m, 2H), 1.41 (t, J=7.0 Hz, 3H); [0971] "A281": HPLC/MS 2.73 min (C), [M+H]407; 'H NMR (400 MHz, DMSO-de, TFA-dr) 6 [ppm]9. 21 (s, 1H), 8.01 (d, J=8.4 Hz, 2H), 7.10 (d, J=9.0 Hz, 2H), 4.45 (bs, 1H), Yj 4.07 (q, J=6.9 Hz, 2H), 3.53 (p, J=7.8 Hz, 1H), 239 (s, 3H), 238-2.26 (m, 1H), 2.27-2.01 (m, 3H), 1.98-1.71 (m, 2H), 1 34 (t, J=7.0 Hz, 3H). US 2016/0015712 A1 Jan. 21, 2016 95

Example 36 Example 37

Synthesis of (1R,3R)-3-[3-(4-ethoxy-phenyl)-3H-[1, Synthesis of (R)-3-[3-(2-methyl-quino1 in-6-yl)-3H- 2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cyclopen- [1,2,3]triazolo [4,5-d]pyrimi din-5-ylamino]-pyrroli- tanecarboxylic acid hydrazide ("A282") and [(1R, dine-1-carboxylic acid amide ("A284") 3R)-3-(5-amino-[1, 3,4]oxadiazo1-2-yl)-cyclopentyl]- [3-(4-ethoxy-phenyl)-3H-[1, 2,3]triazolo [4,5-d] [0975] pyrimi din-5-yl] -amine ("A283")

[0972]

H N

HO +7 / 2-propertol M CNCO t CDI/DMSO 2. MeOH 3. NH2NH2 x OH/ 80' C. Vj' Vj'

0 N H Ng / / N BrCN KHCOg / MeOH

Yj

[0976] HPLC/MS 1 38 min (B), [M+H]390; 'H NMR (500 MHz, DMSO-de, TFA-dt) ft [ppm]9. 54-8.90 (m, 4H), 8.51 (d, J=9.3 Hz, 1H), 8.11 (d, J=8.6 Hz, 1H), 4.73 (bs, 1H), 3.88 (dd, J=l 1 3, 6.0 Hz, 1H), 3.68 (m, 1H), 3.65-3.49 (m, 2H), 3.05 (s, 3H), 2.42-2.29 (m, 1H), 2.29-2.17 (m, 1H).

(R)-3-[3-(4-Methoxy-phenyl)-3H-[1, 2,3]triazolo [4,5- d]pyrimidin-5-ylamino]-pyrrolidine-1-carboxylic Yj acid amide ("A285")

[0977] [0973] "A282": HPLC/MS 2.27 min (C), [M+H]383; 'H NMR (400 MHz, DMSO-de, TFA-dt) ft [ppm]9. 20 (s, 1H), 7.98 (d, J=83 Hz, 2H), 7.08 (d, J=9.0 Hz, 2H), 4.40 (bs, 1H), 4.05 (q, J=6.9 Hz, 2H), 2.95 (p, J=7.8 Hz, 1H), 2.09 (m, 3H), 1.90 (ddt, J=13.5, 9.0, 5.2 Hz, 1H), 1.73 (m, 2H), 1 32 (t, J=7.0 Hz, 3H); [0974] "A283": HPLC/MS 1.75 min (B), [M+H]408; 'H ~~N NMR (500 MHz, DMSO-de, TFA-dt) ft [ppm]9. 29 (s, 1H), N 8.07 (bs, 2H), 7.17 (d, J=9.1 Hz, 2H), 4.50 (bs, 1H), 4.14 (q, J=7.0 Hz, 2H), 3.57 (p, J=8.0 Hz, 1H), 236 (dt, J=143, 7.4 Hz, 1H), 232-2.25 (m, 1H), 2.23 (m, 2H), 1.97 (dq, J=12.0, is prepared analogously; HPLC/MS 1.62 min (B), [M+H] 7.5 Hz, 1H), 1.89 (m, 1H), 1.41 (t, J=7.0 Hz, 3H). 355. US 2016/0015712 A1 Jan. 21, 2016 96

Example 38 -continued

Synthesis of N-((1R,3R)-3-[3-(4-ethoxy-phenyl)- / 3H-[1,2,3]triazolo[4, 5-d]-pyrimidin-5-ylamino]- N cyclop entanecarbonyl )-methane sul fonamide O'A286") 4N HCl in dioxane [0978] X'X'

HO +/

/ / g N ~~N N DIPEA 2-methoxyedtanol 80' C. CDI/ Cl BDU NH3 S

2 / llrr N

Vj' Vj'

[09S1] HPLC/MS 1.91 min (B), [M+H]419; 'H NMR (500 MHz, DMSO-de) fI [ppm] 9.26 (s, 1H), 836 (d, J=6.0 Hz, 1H), [0979] HPLC/MS 2.64 min (C), [M+H]446; 'H NMR (500 8.04 (d, J=8.6 Hz, 2H), 8.01 (dd, J=3.8, 1.7 Hz, 1H), 7.42 (dd, MHz, DMSO-de, TEA-dt) fI [ppm]9. 30 (s, 1H), 8.10(bs, 2H), J=9.4, 3.8 Hz, 1H), 7.16 (d, J=9.0 Hz, 2H), 6.92 (d, J=9.1 Hz, 60-5. J=6. 7.19 (d, J=9.0 Hz, 2H), 4.40 (bs, 1H), 4.15 (q, J=7.0 Hz, 2H), 1H), 5. 48 (m, 1H), 4.51 (m, 1H), 4.13 (q, 9 Hz, 2H), 3.26 (s, 3H), 3.11-3.01 (m, 1H), 2.28 (m, 1H), 2.12 (m, 2H), 235-2.14 (m, 3H), 2.12-1.97 (m, 1H), 1.83 (m, 2H), 1 38 (t, 2.02-1.90 (m, 1H), 1.90-1.70 (m, 2H), 1.41 (t, J=7.0 Hz, 3H). J=7.0 Hz, 3H).

Example 40 Example 39 Synthesis of (trans)-3-[3-(4-methoxy-phenyl)-3H-[1, Synthesis of 2-((trans)-3-[3-(4-ethoxy-phenyl)-3H- 2,3]triazolo [4,5-d]pyrimidin-5-yl amino] -cyclope- [1,2,3]triazolo[4, 5-d]-pyrimidin-5-ylamino]-cyclo- ntanesulfon acid amide ("A288") pentyl )-2H-pyridazin-3-one ("A287") [0982] [0980]

HO HO

/ NEts PPhs + CHgSOaCI / CHaCIa / DIAD Vj' US 2016/0015712 A1 Jan. 21, 2016 97

-continued Example 41

Synthesis of (1R,3R)-3-(3-[4-(1-hydroxy-1-methyl- 0 ethyl)-phenyl]-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5- ylamino )-cyclopentanecarboxylic acid amide O'A289")

[0984]

THF 60' C. Yj 0 / 0 H2N +/

/ CeCls + CHgMgCl THF

Sr Vj

1. SO2Cl2/Ac20 HN N N 2. evaporate Y &en NHs 0 N OH N H2N +/

NH2 O=S/ Yj

acetone 60' C. [09S5] HPLC/MS 1.60 min (B), [M+H]382; 'H NMR (400 Vj' MHz, DMSO-de, TFA-dt) ft [ppm]9. 29 (s, 1H), 8.15 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.7 Hz, 2H), 4.44 (bs, 1H), 2.93 (p, J=8.0 Hz, 1H), 2.18 (m, 2H), 2.10-2.00 (m, 1H), 1.93 (ddd, J=133, 8.7, 5.2 Hz, 1H), 1.77 (m, 2H), 1.54 (s, 6H).

(trans)-3-(3-[4-(1-Hydroxy-1-methyl-ethyl)-phenyl]- NH2 O~ / 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino)-cy- /~ Sr clopentanol ("A290") [09S6]

H N Yj OH

N

'H ~~N [09S3] HPLC/MS 2.35 min (C), [M+H]390; NMR (500 N MHz, DMSO-de, TFA-dt) ft [ppm]9. 28 (s, 1H), 8.12 (bs, 2H), 7.20 (d, J=8.7 Hz, 2H), 4.45 (bs, 1H), 3.88 (s, 3H), 3.68 (tt, J=9.0, 6.6 Hz, 1H), 2.38 (dt, J=13.7, 6.8 Hz, 1H), 2.27-1.97 is prepared analogously: HPLC/MS 1.63 min (B), [M+H] (m, 4H), 1.89-1.68 (m, 1H). 355. US 2016/0015712 A1 Jan. 21, 2016 98

Example 42 Example 43

Synthesis of 1-1(1R,3R)-3-[3-(4-methoxy-phenyl)- Synthesis of 3-14-[5-((1R,3R)-3-carbamoyl-cyclo- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-cy- pentylamino)-[1, 2,3]triazolo[4, 5-d]pyrimidin-3-yl]- clopentyl)-pyrrolidin-2-one ("A291") phenoxy)-propionic acid methyl ester ("A292") and (1R,3R)-3-13-[4-(3-hydroxy-3-methyl-butoxy)-phe-

[0987] nyl]-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5-yl amino )- cyclopentanecarboxylic acid amide ("A293")

Cl [0989] HsN'

NEts THF

HO Cl N N NEts THF 3-5' C.

Cl NH2

CH2COs CHsCN H FR ~ THF Yj

Cl~ N NH

Ti N NO2

Vj'

b byl

acetonia ile 70' [09SS] HPLC/MS 1.80 min (B), [M+H]394; 'H NMR (400 C. MHz, DMSO-de) ft [ppm] 9.29 (s, 1H), 8.08 (d, J=8.6 Hz, 2H), 7.18 (d, J=9.1 Hz, 2H), 4.67 (p, J=8.2 Hz, 1H), 4.45 (bs, 1H), Cl~ N NH 3.88 (s, 3H), 3.43 (t, J=7.0 Hz, 2H), 2.32 (dd, J=8.7, 7.4 Hz, Ti 2H), 2.26-2.16 (m, 1H), 2.09 (dt, J=14.9, 7.9 Hz, 1H), 2.03- N 1.94 (m, 3H), 1.88 (ddd, J=13.5, 8.4, 5.0 Hz, 1H), 1.82-1.60 NH2 (m, 2H). US 2016/0015712 A1 Jan. 21, 2016 99

-continued -continued OH

0 H1N +7

x HCl

DIPEA CH1OCH1CH1OCH1 80' C. Yj Vj

[0990] "A292": HPLC/MS 1.75 min (B), [M+H]426; [0991] "A293": HPLC/MS 1.62 min (B), [M+H]426; 'H NMR (500 MHz, DMSO-de, TFA-d, ) 6 [ppm]930 (s, 1H), 8.09 (bs, 2H), 7.20 (d, J=9.0 Hz, 2H), 4.41 (bs, 1H), 4.23 (t, J=7.1 Hz, 2H), 2.91 (p, J=8.0 Hz, 1H), 2.16 (m, 1H), 2.09-1. 99 (m, 2H), 1.95 (t, J=7.1 Hz, 2H), 1.92-1.86 (m, 1H), 1.78 (m, 2H), 1.24 (s, 6H). [0992] The following compounds are prepared similarly:

(4-[5-((1R,3R]-3-carbamoyl-cyclopentyl amino]-[1, 2,3]triazolo [4,5-d]pyrimidin-3-yl]-phenoxy)-acetic acid methyl ester ("A294") ~H EDC1, HOBt [0993] 1tlOXRIle

~~N N

[0994] (1R,3R)-3-(3-[4-(2-hydroxy-2-methyl-propoxy)- phenyl]-3H-[1, 2,3]triazolo[4, 5-d]-pyrimidin-5-ylamino1- cyclopentanecarboxylic acid amide ("A295")

H1N +7 OH

CeCb THE

N

~~N Vj' N

[0995] HPLC/MS 1.55 min (B), [M+H]412. US 2016/0015712 A1 Jan. 21, 2016 100

Example 44 -continued

Synthesis of (1R,3R)-3-[3-(4-methane sul fonyl-phe- nyl)-3H- [1,2,3]triazolo [4,5-d]-pyrimidin-5-yl amino]- cyclopentanecarboxylic acid amide ("A296")

[0996] NHg

Cl EDC1, HOBt bttOXHtle Yi

NH1 s~

E p b AcOH/60' C. NH Yi N NO1 Vj' 0

[0997] HPLC/MS 1.50 min (B), [M+H]402; 'H NMR (500 MHz, DMSO-de) ft [ppm]9. 29 (s, 1H), 8.66 (bs, 2H), 8.24 (d, E Cl J=8.8 Hz, 2H), 4.45 (bs, 1H), 3.29 (s, 3H), 2.93 (p, J=8.0 Hz, EtOH/EtOAc 1H), 2.28 (m, 1H), 2.16 (m, 1H), 2.07 (m, 1H), 1.90 (ddd, Cl ~ N NH 70' C. J=13.5, 8.7, 53 Hz, 1H), 1.81 (m, 2H). Ti N Example 45 NO1 0 Synthesis of 3-[(1S,3R)-3-[[3-(4-methoxyphenyl) triazolo[4, 5-d]pyrimidin-5-yl]amino]cyclopentyl]- 4H-1, 2,4-oxadiazo1-5-one ("A297") and 3-(4-meth- oxy-phenyl)-N- [(1R,3S)-3-(5-methyl-1, 2,4- b lpl oxadiazol-3-yl)cyclopentyl]triazolo [4,5-d]pyrimidin- Hcetoniu ile 5-amine ("A298") 70' C. Cl N NH ~ Example 46 Yi N NH1 [0998]

N

x HCl

NH1 ~H OH«HCl DIPEA ~E lEOH CHgOCH1CH1OCHg 80' C. US 2016/0015712 A1 Jan. 21, 2016 101

-continued -continued H HO NHz N

N

0 a c=o NaBHsCN MeOH Yj Yj CICOOEt Aczp/AcOH / N

0

0 NH N 0 N N=N

Pharmacological Data Yg',' [1000]

TABLE 2

[0999] Synthesis of (1R,3R)-3-[[3-[4-(4-piperidyloxy) GCN2 inhibition phenyl]triazolo [4,5-d]pyrimidin-5-yl]amino]cyclopentan- of some re resentative com ounds of the formula I ecarboxamide ("A299") and (1R,3R)-3-[[3-[4-[(l-methyl-4- ICso GCN2 ICso GCN2 piperidyl)oxy]phenyl]triazolo[4, 5-d]pyrimidin-5-yl] amino] Compound (enzyme (cellular cyclopentanecarboxamide ("A300") No. assay) assay)

"A 1" "A2" A "A3" B y yy "A4" A "A5" according to "A6" example 18 A "A7" A "A8" A "A9" "AII3" A "Al I" C "A12" A "A13" B "A14" B "AI5" C "A16" A "A17" C "A18" B 0 "A19" C "A2I3" B "A21" A "A22" "A23" A "A24" A "A25" A "A26" A "A27" B "A28" A Yj "A29" A "A3I3" A "A31" B "A32" A US 2016/0015712 A1 Jan. 21, 2016 102

TABLE 2-continued TABLE 2-continued

GCN2 inhibition GCN2 inhibition of some re resentative com ounds of the formula I of some re resentative com ounds of the formula I

ICso GCN2 ICso GCN2 ICso GCN2 ICso GCN2 Compound (enzyme (cellular Compound (enzyme (cellular No. assay) assay) No. assay) assay) "A33" B "A103" "A34" A "A104" "A35" C "A105" "A36" "A106" "A37" "A107" "A38" "A108" A "A39" A "A109" A "A40" A "A110" A "A41" A "BI" A "A42" A "B2" "A43" B "B3" "A44" A "B4" "A45" A "B5" "A46" A "B6" B "A47" A "B7" A "A48" A "B8" "A49" A "B9" A "A50" B "B10" B "A51" A B "A111" A "A52" A B "A112" A "A53" A "A113" A "A54" A "A114" A "A55" A "AI I 5" A "A5 6" A "A116" A "A57" A "A117" A "A5 8" A "A118" A "A59" B "A119" A "A60" "A120" A B "A61" C "A121" A B "A62" B "A122" A B "A63" A "A123" A A "A64" A "A124" A B "A65" B "A125" A A "A66" C "A126" A "A67" B "A127" A B "A68" A "A128" A C "A69" B "A129" A B "A70" A "A130" A C "A71" A "A131" A C "A72" A "A132" A "A73" A "A133" A "A74" B "A134" A "A75" A "AI35" A "A76" A "A136" A "A77" C "A137" A "A78" B "A138" A "A79" A "A139" A "A80" "A140" A B "A81" "A141" A C "A82" A "A142" A "A83" A "A143" A "A84" "A144" A "A85" A "A 145" A "A86" A "A146" A "A87" B "A147" A "A88" B "A148" A "A89" B "A149" A "A90" A "AI50" A B "A91" B "AI5 I" A B "A92" B "A152" A B "A93" "AI53" A C "A94" A "A154" A "A95" A "AI55" A "A96" B "A15 6" A "A97" A "A157" A B "A98" A "A15 8" A C "A99" "A159" A "A100" "A160" A "A101" "A161" A "A102" "A162" A US 2016/0015712 A1 Jan. 21, 2016 103

TABLE 2-continued TABLE 2-continued

GCN2 inhibition GCN2 inhibition of some re resentative com ounds of the formula I of some re resentative corn ounds of the formula I

GCN2 GCN2 ICso ICso ICso GCN2 ICso GCN2 Compound (enzyme (cellular Compound (enzyme (cellular No. assay) assay) No. assay) assay) "A163" A "A233" A "A164" A "A234" "AI 65" B A "A235" "A166" A A B "A167" A B "A23 6" A C "A168" A B "A237" A "A169" "A23 8" "A170" A "A239" "A171" A "A240" A C "A172" A "A241" A B "A173" A "A242" A B "A174" A "A243" A B "AI75" A "A244" A A "A176" A "A245" A A "A177" A "A246" A B "A178" A "A247" A A "A179" A "A248" A B "A180" A "A249" A B "A181" A "A250" "A182" A A B "A183" A "A251" A C "A184" A B "A252" A B "AI 85" A C "A253" A A "A186" A B "A254" "A187" A A "A255" A B "A188" A "A25 6" A C "A189" A B "A257" A C "A190" A C "A25 8" A B "A191" A B "A259" "A192" A C A B "A193" A B "A260" A C "A194" A "A261" A "AI95" "A262" A "A196" "A263" A "A197" "A264" A "A198" A "A265" A "A199" A "A266" A "A200" A "A267" "A201" A A "A202" A B "A268" A "A203" A B "A269" A "A204" A B "A269a" A "A205" A C "A270" A "A206" A "A271" A "A207" A B "A272" A "A208" A B "A273" A C "A209" A "A274" "A210" A C A B "A211" A C "A275" A "A212" A B "A276" A C "A213" A B "A277" A C "A214" A B "A278" A B "A215" A C "A279" A "A216" A B "A280" A "A217" A "A281" A "A218" A "A282" "A219" B A "A220" A A "A283" A "A221" A B "A284" A "A222" A "A285" A "A223" A A "A286" A "A224" A C "A287" A "A225" A B "A288" A "A226" A B "A289" A "A227" A B "A290" "A228" A C A "A229" A "A291" A "A230" A "A292" A "A231" A "A232" A ICss.'&1 pM = A 1-5 pM = B 5-10 pM = C US 2016/0015712 A1 Jan. 21, 2016 104

TABLE 3 TABLE 3-continued

GSK3ct and GSK3P inhibition GSK3ct and GSK3P inhibition of some com ounds of the formula I of some com ounds of the formula I

ICso GSK3ct ICso GSK3 P ICso GSK3ct ICso GSK3 P Compound (enzyme (enzyme Compound (enzyme (enzyme No. assay) assay) No. assay) assay)

"A109" A "A184" "A111" A "AI85" "A112" A "A186" "A114" A "A187" "AI 15" A A "A188" "A118" A A "A189" A "A119" A B "A190" A "A120" A "A191" "A121" A B "A192" A A "A122" A B "A193" A A "A123" A "A194" A A "A124" A B "A195" "AI25" A B "A196" "A127" A "A197" "A128" "A198" A "A129" A "A199" A "A130" A "A200" A "A131" A "A201" "A132" A "A202" A "A133" A B "A203" A A "A134" A B "A204" A A "AI35" A A "A205" "A136" A A "A206" "A137" A A "A207" "A138" A "A208" "A139" "A209" A A "A140" A "A210" A A "A141" A "A211" A A "A142" A "A212" A A "A143" A "A213" A "A144" A "A214" A "A 1 45" A A "A215" A "A146" A A "A216" A "A147" A A "A217" A A "A148" A B "A218" A A "A149" "A219" A A "AI50" A A "A220" A A "AI 5 I" A A "A221" A A "AI52" A A "A222" A A "AI53" A A "A223" A A "A154" "A224" A A "AI55" A A "A225" A A "AI56" A A "A226" A A "AI57" A A "A227" A A "AI58" A A "A228" A A "AI59" A A "A229" A A "A160" A A "A230" A A "A161" "A231" "A162" "A232" A A "A163" "A233" A A "A164" "A234" "AI 65" "A235" "A166" "A23 6" "A167" "A237" "A168" "A23 8" "A169" "A239" "A170" "A240" A "A171" "A241" A "A172" A "A242" A "A173" A "A243" "A174" A "A244" A A "AI75" A "A245" A A "A176" A "A246" A A "A177" A A "A247" A A "A178" A A "A248" A A "A179" A A "A249" A A "A180" A A "A250" A A "A181" A A "A251" "A182" A A "A252" "A183" A A "A253" US 2016/0015712 A1 Jan. 21, 2016 105

TABLE 3-continued NazHPO4 12 HzO and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the GSK3ct and GSK3P inhibition solution is made up to I I and sterilised by irradiation. This of some com ounds of the formula I solution can be used in the form of eye drops.

ICso GSK3ct ICso GSK3 P Compound (enzyme (enzyme Example D No. assay) assay) Ointment "A264" "A266" [1005] 500 mg of an active ingredient of the formula I are "A266" mixed with 5 Vaseline under aseptic conditions. "A267" A 99. g of "A268" A "A269" A A Example E "A260" A A "A261" Tablets "A262" "A263" [1006] A mixture of I kg ofactive ingredient ofthe formula "A264" A I, 4 kg oflactose, 1.2 kg ofpotato starch, 0 2 kg oftalc and 0.1 "A266" A "A266" A kg of magnesium stearate is pressed in a conventional manner "A267" to give tablets in such a way that each tablet contains 10mg of "A268" active ingredient. "A269" "A269a" "A270" A Example F "A271" A "A272" Dragees "A273" A A "A274" A A [1007] Tablets are pressed analogously to Example E and "A276" subsequently coated in a conventional manner with a coating "A276" of sucrose, potato starch, talc, tragacanth and "A277" A A dye. "A278" A A "A279" A A Example G "A280" A A "A281" A A Capsules "A282" A A "A283" A B [1008] 2 kg of active ingredient of the formula I are intro- "A284" duced into hard in a conventional manner in "A286" A B gelatine capsules "A286" A A such a way that each capsule contains 20 mg of the active "A287" ingredient. "A288" A A "A289" A A "A290" Example H

ICss.'&1 pM =A 1-6 pM = B 6-10 pM = C Ampoules

[1001] The following examples relate to medicaments: [1009] A solution of I kg ofactive ingredient ofthe formula I in 60 I of bidistilled water is sterile filtered, transferred into Example A ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of Injection vials active ingredient. [1002] A solution of 100 g of an active ingredient of the 1. Compounds of the formula I formula I and 5 g of disodium hydrogenphosphate in 3 I of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred into injection vials, lyophi- lised under sterile conditions and sealed under sterile condi- Rt H tions. Each injection vial contains 5 mg of active ingredient.

Example B N II X N Suppositories

[1003] A mixture of 20 g of an active ingredient of the in which formula I with 100 g of soya lecithin and 1400 g of cocoa R' butter is melted, poured into moulds and allowed to cool. denotes Ar or Het, 1-7 C-at- Each suppository contains 20 mg of active ingredient. R denotes unbranched or branched alkyl with oms, wherein two adjacent carbon atoms may form a Example C double or triple bond and which can be mono-, di-, tri-, tetra- or pentasubstituted by Hal and/or which can be Solution mono- or disubstituted by OR, N(R )z, Het', CN, [1004] A solution is prepared from I g of an active ingre- COOR OCOOR CONHz) CONHA CONAz) dient of the formula I, 938 g of NaHzPO4 2 HzO, 28.48 g of NR COA, NR SOzA, SOzN(R )z, S(O) A, COHet', US 2016/0015712 A1 Jan. 21, 2016 106

0[C(R )~] N(R )~, 0[C(R )~] Het', NHCOOA, zothiazolyl or furoP, 2-b]pyridyl, each of which is NHCON(R )~) NHCOO[C(R )~] N(R )~) NHCOO[C unsubstituted or mono- or disubstituted by Hal, A, Het', NHCONH[C(R NHCONH[C ', ', (R )~] )~] N(R )~, [ ( ').],0 o[ ( ').],0 I ( ').l, ( ')., o[ (R )~] Het', OCONH[C(R )~] N(R )~, OCONH[C (R )~]~N(R )~, [C(R )~]~Het', NO~, CN, [C(R )~] (R )~] Het' and/or COA, COOR, 0[C(R )2] COOR, CON(R )2, NR COA, or NR'SO, A, SO,N(R )„S(0)A, COHet', 0[C(R'),] denotes cycloalkyl with 3-7 C-atoms or cyclopentenyl, Het', NHCOOA, NHCON(R )~, NHCOO[C(R )~] N each of which can be mono-, di-, tri-, tetra- or penta- (R )~, NHCOO[C(R )~] Het', NHCONH[C(R )~] N substituted by A and/or Hal and/or which can be (R )~, NHCONH[C(R )~] Het', OCONH[C(R )~] N mono- or disubstituted by [C(R )~] OR, 0[C(R )~] (R )~, OCONH[C(R )~] Het', S(0) Het', CHO, COA, S and/or ( ')z], ( ')r, OI ( ')z], ( ')z, I ( ')z] 0, ~Ar, [C(R )~]~Het', 0[C(R )~]~Het', CN, [C(R )~] Het' denotes pyrazolyl, pyridazinyl, pyridinyl, oxazolyl, ~COOR 0[C(R )~]~COOR CONH~) CONHA isoxazoyl, oxadiazolyl, pyrazinyl, indolyl, dihydropyr- CONA~) [C(R )~]~NR COA CONR SO~A rolyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahydroimi- NR SO~A, SO~N(R )~, S(0) A, COHet', 0[C(R )~] dazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahy- N(R )~) [C(R )~]~NR CODA [C(R )~] dro furanyl, dihydropyridyl, tetrahydropyridyl, NR COOCH2Ph, NR CON(R )2, NHCOO[C(R )2] piperidinyl, morpholinyl, hexahydropyridazinyl, N(R )~, NHCOO[C(R )~] Het', NHCONH[C(R ) hexahydropyrimidinyl, [1,3]dioxolanyl, tetrahydropy- ~] N(R )~, NHCONH[C(R )~] Het', OCONH[C ranyl or piperazinyl, each of which is unsubstituted or (R )~] N(R )~, OCONH[C(R )~] Het', CONH mono- or disubstituted by Hal, A, [C(R )~] OR, 0[C (CH~) Het, CONR NR COA, CONR N(R )~, (R)]OR, [C(R)] N(R), [C(R)]Het, NO, CONHCyc, COA, S, NR and/or 0, [C(R )~]~CN, [C(R )~]~COOR, 0[C(R )~]~COOR, or [C(R )~]~CON(R )~) NR COA NR SO~A SO~N(R ) denotes piperidinyl, tetrahydropyranyl, pyrrolidinyl, S(0) A, COHet', 0[C(R'),] N(R')„0[C(R'),] azetidinyl, thiolanyl, oxetanyl, 3-aza-bicycloP. 1.0] Het, NHCOOA, NHCON(R )~, NHCOO[C(R )~] N hexyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, (R )~, NHCOO[C(R )~] Het, NHCONH[C(R )~] N 4,5,6,7-tetrahydro-lH-indazo1-5-yl, 4,5,6,7-tetrahy- (R )~, NHCONH[C(R )~] Het, OCONH[C(R )~] N dro- 1H-indazol-6-yl, tetrahydropyrazolyl, tetrahy- (R )~, OCONH[C(R )~] Het, S(0) Het, CHO, COA, drofuranyl or hexahydropyridazinyl, each of which S and/or 0, can be mono-, di-, tri-, tetra- or pentasubstituted by A Het denotes pyrazolyl, oxadiazolyl, pyridinyl, triazolyl, and/or Hal and/or which can be mono- or disubsti- tetrazolyl, pyridazinyl, pyrrolidinyl, azetidinyl, azoxeta- tuted by [C(R )~] OR, 0[C(R )~] OR, [C(R )~] N nyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahy- (R )~, [C(R )~] Ar, [C(R )~] Het', [C(R )~] Het, dro furanyl, piperidinyl, morpholinyl, tetrahydropyranyl CN [C(R )~]~COOR CO[C(R )~]~N(R )~) CO[C or piperazinyl, each of which is unsubstituted or mono- (R )~] Het', CO[C(R )~] Het, NR COA, or disubstituted by Hal, A, OA, CN, COOA, CONH~, NR'SO, A, SO,N(R')„S(0) A, COHet', 0[C(R'),] S(0) A, S(0) Ar, COA and/or 0, N(R Het', NHCOOA, NHCON(R )~, 0[C(R )~] ) Het denotes pyrazolyl, pyridinyl, pyrimidinyl or pyrazi- NHCOO[C(R N(R NHCOO[C(R )~] )~) )~] nyl, each of which is unsubstituted or mono- or disub- Het', NHCONH[C(R )~] N(R )~, NHCONH[C stituted by Hal, A, [C(R )~] OR, 0[C(R )~] OR, (R )~] Het', OCONH[C(R )~] N(R )~, OCONH[C [C(R )~] N(R )~, [C(R )~]~Het, NO~, CN, [C(R )~] (R )~] Het', C(0)R, S, NR and/or 0, ~COOR 0[C(R )~]~COOR CON(R )~) NR COA R denotes H or unbranched or branched alkyl with 1-6 NR'SO, A, SO,N(R')„S(0) A, COHet', 0[C(R'),] N C-atoms, (R )~, 0[C(R )~] Het, NHCOOA, NHCON(R )~, unsubsti- Ar denotes phenyl or naphthyl, each of which is NHCOO[C(R )~] N(R )~, NHCOO[C(R )~] Het, tuted or mono-, di- or trisubstituted by Hal, A, [C(R )~] NHCONH[C(R N(R NHCONH[C(R Het, ', ', ) ] ), ) ] ,o o[ ( ').],0 [ ( ').l, ( ')., o[ ( ').l, OCONH[C(R ) ] N(R ), OCONH[C(R ) ] Het, (R )~, [C(R )~] Het', [C(R )~] Het, NO~, CN, [C(R ) S(0) Het, CHO, COA, S and/or 0, CON(R NR COA ~]~COOR 0[C(R )~]~COOR )~) Cyc cycloalkyl with 3-7 C-atoms, which can be mono- or NR'SO, A, SO,N(R')„S(0) A, COHet', 0[C(R'), ] di substituted by OH, Het', NHCOOA, NHCON(R )~, NHCOO[C(R )~] N Ph denotes phenyl, iR )~, NHCOO[C(R )~] Het', NHCONH[C(R )~] N (R )~, NHCONH[C(R )~] Het', OCONH[C(R )~] N A denotes unbranched or branched alkyl with 1-10 C-at- (R )~, OCONH[C(R )~] Het', S(0) Het', CHO and/or oms, wherein one, two or three non-adjacent CH- and/or COA, CH~-groups may be replaced by N-, 0- and/or S-atoms or denotes azulenyl, and wherein 1-7H-atoms may be replaced by OH, F Het denotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, and/or Cl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, Hal denotes F, Cl, Br or I, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, n denotes 0, 1 or 2, indolyl, isoindolyl, benzimidazolyl, indazolyl, indoliz- m denotes 1, 2 or 3, inyl, cinnolinyl, quinolyl, isoquinolyl, benzoxazolyl, 1,3-benzodioxolyl, benzothiophenyl, benzofuranyl, p denotes 0, 1, 2, 3 or 4, imidazopyridyl, dihydroindolyl, quinoxalinyl, imidazo and pharmaceutically acceptable solvates, salts, tautomers [1,2-a]pyridinyl, benzo[1, 2,5]thiadiazolyl, naphthyridi- and stereoisomers thereof, including mixtures thereof in nyl, 2,3-dihydro-benzo [1,4]dioxinyl, quinazolinyl, ben- all ratios. US 2016/0015712 A1 Jan. 21, 2016 107

2. Compounds according to claim 1 in which 6. Compounds according to claim 1 in which R' R denotes unbranched or branched alkyl with 1-7 C-at- denotes Ar or Het, 1-7 C-at- oms, wherein two adjacent carbon atoms may form a R denotes unbranched or branched alkyl with double or triple bond and which can be mono-, di-, tri-, oms, wherein two adjacent carbon atoms may form a double or triple bond and which can be mono-, di-, tri-, tetra- or pentasubstituted by Hal and/or which can be tetra- or pentasubstituted by Hal and/or which can be mono- or disubstituted by CN, CONH~, CONHA, mono- or disubstituted by CN, CONH~, CONHA, CONA~ and/orO[C(R )~] N(R )~, CONA~ and/or 0[C(R )~] N(R )~ or or denotes cycloalkyl with 3-7 C-atoms or cyclopentenyl, denotes cycloalkyl with 3-7 C-atoms or cyclopentenyl, each of which can be mono-, di-, tri-, tetra- or penta- each of which can be mono-, di-, tri-, tetra- or penta- substituted by A and/or Hal and/or which can be substituted by A and/or Hal and/or which can be mono- or disubstituted by [C(R )~] OR, S(0) A, mono- or disubstituted by [C(R )~] OR, S(0) A, [C(R )~]~N(R )~, [C(R )~]~Ar, [C(R )~]~Het', [C(R )~]~N(R )~, [C(R )~]~Ar, [C(R )~]~Het', [C(R )~]~COOR, [C(R )~]~NR COOA, CN, [C(R )~]~COOR, [C(R )~]~NR COOA, CN, CONR SO~A SO~N(R )~) CONH~) CONHA CONR SO~A SO~N(R )~) CONH~) CONHA CONA~, CONH(CH~) Het, [C(R )~] Het', CONA~, CONH(CH~) Het, [C(R )~] Het', COHet', CONR NR COA, CONR N(R )~, CONH- COHet', CONR NR COA, CONR N(R )~, CONH- Cyc and/or [C(R )~] NR COOCH~Ph, Cyc and/or [C(R )~] NR COOCH~Ph, or or denotes piperidinyl, tetrahydropyranyl, pyrrolidinyl, denotes piperidinyl, tetrahydropyranyl, pyrrolidinyl, azetidinyl, thiolanyl, oxetanyl, 3-aza-bicycloP. 1.0] azetidinyl, thiolanyl, oxetanyl, 3-aza-bicycloP. 1.0] hexyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, hexyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, 4,5,6,7-tetrahydro-H-indazo1-5-yl, 4,5,6,7-tetrahy- 4,5,6,7-tetrahydro-lH-indazo1-5-yl, 4,5,6,7-tetrahy- dro-1H-indazol-6-yl, tetrahydropyrazolyl, tetrahy- dro-1H-indazol-6-yl, tetrahydropyrazolyl, tetrahy- drofuranyl or hexahydropyridazinyl, each of which drofuranyl or hexahydropyridazinyl, each of which can be mono-, di-, tri-, tetra- or pentasubstituted by A can be mono-, di-, tri-, tetra- or pentasubstituted by A and/or Hal and/or which can be mono- or disubsti- and/or Hal and/or which can be mono- or disubsti- tuted by [C(R )~] Het', [C(R )~] Het, [C(R )~] tuted by [C(R )z] Het', [C(R )z] Het, [C(R )z] ~COOR SO~N(R )~) S(0) A CO[C(R )~]~N(R )~) o. ( , (o). , oI ( ').1, ( ')., ). CO[C(R )~] Het', CO[C(R )~] Het, C(0)R, and/or CO[C(R )~] Het', CO[C(R )~] Het, C(0)R, and/or 0, 0, R denotes H or unbranched or branched alkyl with 1-6 and pharmaceutically acceptable solvates, salts, tautomers C-atoms, and stereoisomers thereof, including mixtures thereof in Ar denotes phenyl or naphthyl, each of which is unsubsti- all ratios. tuted or mono-, di- or trisubstituted by Hal, A, [C(R )~] 3. Compounds according to claim 1 in which OR, O[C(R )~] COOR, S(0) A, [C(R )~] Het', 0[C Het' Ar denotes phenyl or naphthyl, each of which is unsubsti- (R )~] and/or [C(R )~] Het, or denotes azulenyl, tuted or mono-, di- or trisubstituted by Hal, A, [C(R )~] ~OR, 0[C(R )~]~COOR, S(0) A, [C(R )~]~Het', 0[C Het denotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, (R )~] Het' and/or [C(R )~] Het, or denotes azulenyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, and pharmaceutically acceptable solvates, salts, tautomers indolyl, isoindolyl, benzimidazolyl, indazolyl, indoliz- and stereoisomers thereof, including mixtures thereof in inyl, cinnolinyl, quinolyl, isoquinolyl, benzoxazolyl, all ratios. 1,3-benzodioxolyl, benzothiophenyl, benzofuranyl, 4. Compounds according to claim 1 in which imidazopyridyl, dihydroindolyl, quinoxalinyl, imidazo Het' denotes pyrazolyl, pyridazinyl, oxazolyl, isoxazoyl, [1,2-a]pyridinyl, benzo[1, 2,5]thiadiazolyl, naphthyridi- oxadiazolyl, tetrahydro-pyranyl, tetrahydrofuranyl, nyl, 2,3-dihydro-benzo [1,4]dioxinyl, quinazolinyl, ben- dihydropyrrolyl, pyrrolidinyl, azetidinyl, oxetanyl, tet- zothiazolyl or furoP, 2-b]pyridyl, each of which is rahydroimidazolyl, piperidinyl, morpholinyl or piper- unsubstituted or mono- or disubstituted by A, Hal, azinyl, each of which is unsubstituted or mono- or dis- [C(R )~]~Het', 0 and/or [C(R )~]~OR, ubstituted by A, [C(R )~] Het, [C(R )~] CN, [C(R )~] Het' denotes pyrazolyl, pyridazinyl, oxazolyl, isoxazoyl, ~N(R')„[C(R'),]~CON(R')„[C(R'),]~OR' and/or oxadiazolyl, tetrahydro-pyranyl, tetrahydrofuranyl, 0, dihydropyrrolyl, pyrrolidinyl, azetidinyl, oxetanyl, tet- and pharmaceutically acceptable solvates, salts, tautomers rahydroimidazolyl, piperidinyl, morpholinyl or piper- and stereoisomers thereof, including mixtures thereof in azinyl, each of which is unsubstituted or mono- or dis- all ratios. ubstitutedby A, [C(R )~] Het, [C(R )~] CN, [C(R )~] ~N(R')„[C(R'),]~CON(R')„[C(R'),]~OR' and/or 5. Compounds according to claim 1 in which 0, Het denotes pyrazolyl, pyridinyl, pyrimidinyl or pyrazi- Het denotes pyrazolyl, oxadiazolyl, pyridinyl, triazolyl, nyl, each of which is unsubstituted or mono- or disub- tetrazolyl, pyridazinyl, pyrrolidinyl, azetidinyl, azoxeta- stituted by A, [C(R )~] Het and/or [C(R )~] OR, nyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahy- and pharmaceutically acceptable solvates, salts, tautomers dro furanyl, piperidinyl, morpholinyl, tetrahydropyranyl and stereoisomers thereof, including mixtures thereof in or piperazinyl, each of which is unsubstituted or mono- all ratios. substituted by A and/or 0, US 2016/0015712 A1 Jan. 21, 2016 108

Het denotes pyrazolyl, pyridinyl, pyrimidinyl or pyrazi- Hal denotes F, Cl, Br or I, nyl, each of which is unsubstituted or mono- or disub- n denotes 0, 1 or 2, stituted by A, [C(R )z] Het and/or [C(R )z] OR, Ph denotes phenyl, m denotes 1, 2 or 3, with 3-7 C-atoms, which mono- Cyc cycloalkyl can be or p denotes 0, 1, 2, 3 or 4, disubstituted by OH, and pharmaceutically acceptable so]vates, salts, tautomers A denotes unbranched or branched alkyl with 1-10 C-at- and stereoisomers thereof, including mixtures thereof in oms, wherein one, two or three non-adjacent CH- and/or all ratios. CHz-groups may be replaced by N-, 0- and/or S-atoms and wherein 1-7H-atoms may be replaced by OH, F 7. Compounds according to claim 1, selected from the and/or Cl, group

No. Name

[3-(4-ethoxy-phenyl]-3H-[1, 2,3]triazoto[4, 5-d]pyrimidin-5-yt]-prop-2-ynyt- amine "A2" Is op ropy t- [3-(4-me&oxy-phenyl]-3 H- [1,2,3]triazo to [4,5-d]- pyrimidin-5-yt]-amine "A3" [3-(4-me&oxy-phenyl]-3H-[1, 2,3]triazoto[4, 5-d]pyrimidin-5-yt]- ttetrahydro-pyran-4-yl)-amine "A4" cyc1op ropy 1-[3-(4-methoxy-phenyl)-3 H- [1,2,3]triazo1o [4,5-d]— pyrimidin-5-yt]-amine "A5" [3-(4-me&oxy-phenyl]-3H-[1, 2,3]triazoto[4, 5-d]pyrimidin-5-yt]- oxetan-3-yl-amine "A6" trans-4-[3-(4-me&oxy-phenyl]-3H-[1, 2,3]triazolo [4,5-d]pyrimidin- 5-ytamino]-cyctohexanot "A7" tert-butyl-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]- pyrimidin-5-yt]-amine "A8" N-tl, l-dioxothiotan-3-yt]-3-(4-me&oxyphenytitriazoto [4,5-d]-pyrimidin- 5-amine - "A9" [3-(4-me&oxy-phenyl]-3 H- [1,2,3]triazo to [4,5-d]pyrimi din-5-yt] (I- propyl-cyclopropyl]-amine "A10" trans-3-[3-(4-me&oxy-phenyl]-3H-[1, 2,3]triazolo [4,5-d]pyrimidin- 5-yt amino]-cyclopentanol "AI I" (4-[3-(4-Methoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5- ylamino]-cyclohexyl)-methanol "A12" cyctopentyt-[3-(4-me&oxy-phenyl]-3H-[1, 2,3]triazoto[4, 5-d]- pyrimidin-5-yt]-amine "A13" [3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5-yl] —[3- (4-methyl-piperazin- I -yl)-propyl]-amine "A14" [3-(4-me&oxy-phenyl]-3H-[1, 2,3]triazoto[4, 5-d]pyrimidin-5-yt]- methyl-amine "AI5" [3-(4-me&oxy-phenyl]-3H-[1, 2,3]triazoto[4, 5-d]pyrimidin-5-yt]- (1,2,2,6,6-pentamethyl-piperidin-4-yl)-amine "A16" ethyl-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5-yl]— amine "A17" [3-(4-me&oxy-phenyl]-3H-[1, 2,3]triazoto[4, 5-d]pyrimidin-5-yt]- (2,2,6,6-tetramethyl-piperidin-4-yl)-amine - "A18" [3-(4-me&oxy-phenyl]-3 H- [1,2,3]triazo to [4,5-d]pyrimi din-5-yt] (I- methyl-piperidin-4-yl)-amine - "A19" [3-(4-me&oxy-phenyl]-3 H- [1,2,3]triazo to [4,5-d]pyrimi din-5-yt] (3- methyl-3-aza-bicyclo[3. 1.0]hex-6-yl)-amine "A20" 4-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5- ylamino]-I -methyl-pyrrolidin-2-one "A21" cyctobutyt-[3-(4-me&oxy-phenyl]-3H-[1, 2,3]triazoto[4, 5-d]- pyrimidin-5-yt]-amine "A22" [2-(4-chtoro-phenyl]-cyctopropyt]-[3-(4-me&oxy-phenyl]-3 H- [1,2,3]triazoto [4,5-d]pyrimi din-5-yt]-amine "A23" [3-(4-me&oxy-phenyl]-3H-[1, 2,3]triazoto[4, 5-d]pyrimidin-5-yt]- (4,5,6,7-tetrahydro-l H-indazot-5-yti-amine "A24" trans-3-[3-(4-me&oxy-phenyl]-3H-[1, 2,3]triazolo [4,5-d]pyrimidin- 5-ytamino]-cyctobutanot "A25" cis-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5- ylamino]-cyclobutano1 "A26" cis-4-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5- ylamino]-cyclohexano1 "A27" cis-3-[3-(4-methoxy-phenyl)-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5- ylamino]-cyclopentanol "A28" [3-(4-me&oxy-phenyl]-3H-[1, 2,3]triazoto[4, 5-d]pyrimidin-5-yt]- (Si-tetrahydro-furan-3-yt-amine "A29" trans-3-[3-(4-bromo-phenyl]-3H-[1, 2,3]triazolo[4, 5-d]pyrimidin-5- ylamino]-cyclopentanol US 2016/0015712 A1 Jan. 21, 2016 109

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No. Name

"A30" (cis-3-[3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5- ylamino]-cyclobutyl)-carbamic acid tert-butyl ester "A31" cis-N-[3-(4-me&oxy-phenyl i-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5- yl]-cyclobutane-l, 3-diamine "A32" (trans-3- [3-(4-methoxy-phenyli-3H- [1,2,3]triazolo [4,5-d]pyrimidin- 5-ylamino]-cyclobutyl)-carbamic acid tert-butyl ester "A33" (4-[3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5- ylamino]-cyclohexylme&yl)-carbamic acid tert-butyl ester "A34" 4-[3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5- ylamino]-pip eridine- 1-carboxylic acid tert-butyl ester "A35" (trans-3- [3-(4-methoxy-phenyli-3H- [1,2,3]triazolo [4,5-d]pyrimidin- 5-ylamino]-cyclopentyl)-carbamic acid tert-butyl ester "A36" 3-[3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5- ylamino]-azetidine- 1-carboxylic acid tert-butyl ester "A37" (3-aza-bicycle[3. 1.0]hex-6-yli-[3-(4-me&oxy-phenyli-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-yl]-amine "A38" trans-N-[3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin- S-yl]-cyclobutane-l, 3-diamine "A39" (4-aminome&yhcyclohexyli-[3-(4-me&oxy-phenyli-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-yl]-amine "A40" [3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]- piperidin-4-yl-amine "A41" trans-N-[3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin- S-yl]-cyclopentane-l, 3-diamine "A42" 1-(3-[3-(4-methoxy-phenyl i-3H- [1,2,3]triazo 1o[4,5-d]pyrimi din-5- ylam inc] -pip eri din- 1 -yl )-e&anone "A43" [3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]- piperidin-3-yl-amine trans-N-[3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin- 5-yl]-cyclohexane-1, 4-diamine "A45" cis-N-[3-(4-me&oxy-phenyl i-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5- yl]-cyclohexane-1, 4-diamine "A48" 2-dim ethyl amino-1-(4- [3-(4-methoxy-phenyl i-3H- [1,2,3]triazo lo- [4,5-d]pyrimidin-5-ylamino]-piperidin-l-yl)-e&anone "A49" 3-dim ethyl amino-1-(4- [3-(4-methoxy-phenyl i-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino]-piperidin-l-yl)-propan-l-one "A50" [3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]-[2- (4-me&yhpiperazin-1-yli-ethyl]-amine "A51" trans-3-(3-[4-(1-me&yhtH-pyrazoh4-yli-phenyl]-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino)-cyclopentanol "A52" N-(3-(4-[1-(2-me&oxy-e&yli-1H-pyrazob4-yl]-phenyl)-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-yli-cyclohexane-1, 4-diamine "A53" N-[3-(4-iodo-phenyli-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5-yl]- cyclohexane-1, 4-diamine "A54" N-(3-[4-(l-e&yhlH-pyrazoh4-yli-phenyl]-3H-[1,ifluorome&yhcyclopentano 2,3]uiazolo[4, 5- d]pyrimidin-5-yl)-(transi-cyclohexane-l, 4-diamine "A57" trans-3-(3-(4-[1-(2-hydroxy-e&yli-1H-pyrazoh4-yl]-phenyl)-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylaminoi-cyclopentanol "A58" (1S,3Ri N-[3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-yl]-cyclopentane-l, 3-diamine "A59" (1R,3Si N-[3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-yl]-cyclopentane-l, 3-diamine "A60" ((1R,3Si-3-[3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimi din-5-y lamino] -cyclop entyl )-(4-me&ybp iperazin- 1-yli- methanone "A61" [3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]-(3- pyrrolidin-1-yhpropyli-amine "A62" 2-dim ethyl amino-1-(3- [3-(4-methoxy-phenyl i-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino]-azetidin-l-yl)-e&anone "A63" 3-dim ethyl amino-1-(3- [3-(4-methoxy-phenyl i-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino]-azetidin-l-yl)-propan-l- one "A64" N- [3-(4-morpho 1in-4-yl-phenyl i-3H- [1,2,3]triazo 1o [4,5-d]pyrimidin- 5-yl]-cyclohexane-1, 4-diamine "A65" (Ri-3- [3-(4-me&oxy-phenyl i-3H- [1,2,3]triazo 1o [4,5-d]pyrimi din-5- ylamino]-pyrrolidine- 1-carboxylic acid tert-butyl ester "A66" (Si-3-[3-(4-me&oxy-phenyli-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5- ylamino]-pyrrolidine- 1-carboxylic acid tert-butyl ester "A67" Mans-3- [3-(4-me&oxy-phenyli-3H- [1,2,3]triazolo [4,5-d]pyrimidin- 5-ylam inc] - 1-0 "A69" [3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]- (Ri-pyrrolidin-3-yhamine "A70" (Ri-1-(4-[5-((transi-4-amino-cyclohexylaminoi-[1, 2,3]triazolo [4,5- d]pyrimidin-3-yl]-phenyl)-pyrrolidin-3-ol US 2016/0015712 A1 Jan. 21, 2016 110

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No. Name

"A71" 1-(4-[5-((transi-4-amino-cyclohexylaminoi- [1,2,3]triazolo [4,5-d]- pyrimidin-3-yl]-phenyl)-pyrrolidin-2-one "A72" trans-2-(4-[3-(4-mefltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclohexyl)-efltanol "A73" cis-2-(4- [3-(4-mefltoxy-phenyli-3H- [1,2,3]triazolo [4,5-d]pyrimidin- 5-ylamino]-cyclohexyl)-efltanol "A74" [2-(2-amino-efltoxyi-ethyl]- [3-(4-mefltoxy-phenyl i-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-yl]-amine "A75" N-[3-(4-fluoro-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]- (transi-cyclohexane-l, 4-diamine "A76" [3-(3-amino-propoxyi-propyl] —[3-(4-methoxy-phenyli-3 H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-yl]-amine "A77" [3-(4-mefltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]- (Si-pyrrolidin-3-ybamine "A78" [3-(4-mefltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]-[l- (2-morpholin-4-yhefltyli-pip eridin-4-yl]-amine "A79" (1S,3Ri-3-[3-(4-mefltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid "A81" (1R,3Si-3-[3-(4-mefltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid "A82" [3-(4-mefltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]- (3,4,5,6-tetrahydro-2H-[1, 4']bipyridinyh4-yli-amine "A83" 2-dimefltylamino-1-((Ri-3-[3-(4-mefltoxy-phenyli-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino]-pyrrolidin-l-yl)- ethanone "A84" [2-(5-fluoro-1H-indoh3-yli-efltyl]-(3-[4-(2-mefltoxy-efltoxyi- phenyl] -3H- [1,2,3]triazo 1o [4,5-d]pyrimi din-5-y1 )-am inc "A85" 3-dimefltylamino-1-((Ri-3-[3-(4-mefltoxy-phenyli-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino]-pyrrolidin-l-yl)-propan- 1-one "A86" [3-(4-mefltoxy-phenyli-3H-[1, 2,3]tflazolo[4, 5-d]pyrimidin-5-yl]-[l- (2-pyrrolidin-1-yhefltyli-piperidin-4-yl]-amine "A87" 4-[3-(4-mefltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5- ylamino]-piperidin-2-one "A88" [3-(4-mefltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]- ((Si-1-pyridin-4-yhpyrrolidin-3-yli-amine "A89" ((1R,3Si-3-[3-(4-mefltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5- d]pyrimidin-5-ylamino]-cyclopentyl)-carbamic acid benzyl ester "A90" l-((Ri-3-[3-(4-mefltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-pyrrolidin-1-yl)-2-pyrazoht-yhefltanone "A91" 2-dimefltylamino-1-((Si-3-[3-(4-mefltoxy-phenyli-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino]-pyrrolidin-l-yl)- ethanone "A92" 3-dimefltylamino-1-((Si-3-[3-(4-mefltoxy-phenyli-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino]-pyrrolidin-l-yl)-propan- 1-one "A93" l-((Si-3-[3-(4-mefltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-pyrrolidin-1-yl)-2-pyrazoht-yhefltanone "A94" trans-3-(3-[5-(1-mefltyhtH-pyrazoh4-yli-pyridin-2-yl]-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino)-cyclopentanol "A95" trans-N-(3-[4-(2-morpholin-4-yhefltoxyi-phenyl]-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-yl)-cyclohexane-1, 4-diamine "A96" trans-N- [3-(5-morpho lin-4-yl-pyri din-2-yli-3H- [1,2,3]triazolo [4,5- d]pyrimidin-5-yl]-cyclohexane-1, 4-diamine "A97" ((1S,3Ri-3- [3-(4-mefltoxy-phenyl i-3H- [1,2,3]u iazo to [4,5- d]pyrimidin-5-ylamino]-cyclopentyl)-(4-mefltyhpiperazin-1-yli- methanone "A98" [3-(4-mefltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]- (Ri-tetrahydro-furan-3-yhamine "A99" 0ans-3- [3-(5-methoxy-pyridin-2-yli-3 H- [1,2,3]triazolo [4,5- d]pyrimidin-5-ylamino]-cyclopentanol "A100" N-(3-quinolin-6-yh3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yli- cyclohexane-1, 4-diamine "A101" (1S,3Ri-3-[3-(4-iodo-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5- ylamino]-cyclopentanecarboxylic acid "A102" (transi-3-(3-quinolin-6-yh3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5- ylaminoi-cyclopentanol "A103" (Si-3-[3-(4-mefltoxy-phenyli-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5- ylamino]-pip eridine- 1-carboxylic acid tert-butyl ester "A104" [3-(4-mefltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]-(l- mefltyhpiperidin-3-yli-amine US 2016/0015712 A1 Jan. 21, 2016

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No. Name

"A105" (Ri-3- [3-(4-me&oxy-phenyl i-3H- [1,2,3]triazo 1o [4,5-d]pyrimi din-5- ylamino]-pip eridine- 1-carboxylic acid tert-butyl ester "A106" trans-l-(4-[3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclohexyl)-pip eridin-4-ol "A107" cis-1-(4- [3-(4-me&oxy-phenyli-3H- [1,2,3]triazolo [4,5-d]pyrimidin- 5-ylamino]-cyclohexyl)-piperidin-4-ol "A108" (cisi-N-[3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin- 5-yl]-N', Nudimethyl-cyclopentane-1, 3-diamine "A109" [3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]- ((Ri-1-pyridin-4-yhpyrrolidin-3-yli-amine "A110" (1S,3 Si-3- [3-(4-me&oxy-phenyl i-3H- [1,2,3]triazo1o [4,5- d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid methyl ester "A111" ((1S,3Si-3-[3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5- d]pyrimidin-5-ylamino]-cyclopentyl)-me&snot "A112" ((1S,3Ri-3- [3-(4-me&oxy-phenyl i-3H- [1,2,3]u iazo le [4,5- d]pyrimidin-5-ylamino]-cyclopentyl)-me&snot "A113" (1R,3Ri-3- [3-(4-me&oxy-phenyli-3H- [1,2,3]triazolo [4,5- d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid methyl ester "A114" ((1R,3Ri-3- [3-(4-methoxy-phenyli-3H- [1,2,3]triazolo [4,5- d]pyrimidin-5-ylamino]-cyclopentyl)-me&snot "Atter" [3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]- [(Ri-1-(1-me&yhtH-pyrazoh4-yli-pyrrolidin-3-yl]-amine "A116" (3-[4-(l-me&yhlH-pyrazoh4-yli-phenyl]-3H-[1, 2,3]uiazolo[4, 5- d]pyrimidin-5-yl)-(Ri-pyrrolidin-3-yhamine "A117" ((ciai-3-[3-(4-me&oxy-phenyli-3H- [1,2,3]triazolo [4,5-d]pyrimidin- 5-ylamino]-cyclopentylme&yl)-carbamic acid tert-butyl ester "A118" (1S,3Ri-N3-(3-[4-(l-me&yhlH-pyrazoh4-yli-phenyl]-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-yl)-cyclopentane-l, 3-diamine "A119" (1S,3Ri-N3-(3-quinolin-6-yh3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5- yli-cyclopentane-l, 3-diamine "A120" (1R,3Ri-N3- [3-(4-methoxy-phenyli-3H- [1,2,3]triazolo [4,5- d]pyrimidin-5-yl]-cyclopentane-1, 3-diamine "A121" (1S,3Ri-N3-(3-(4-[t-(2-methoxy-e&yli-tH-pyrazoh4-yl]-phenyl)- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-yli-cyclopentane-l, 3-diamine "A122" ((1R,3Si-3-aminome&yhcyclopentyli-[3-(4-me&oxy-phenyli-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-yl]-amine "A123" (1R,3Ri N-(3-(4-[1-(2-me&oxy-ethyli-1H-pyrazoh4-yl]-phenyl)- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-yli-cyclopentane-l, 3-diamine "A124" (1R,3Ri N-[3-(2-methybquinolin-6-yli-3H-[1, 2,3]uiazolo[4, 5- 3-diamine d]pyrimidin-5-yl]-cyclopentane-1, amino "A125" (1R,3Ri N-(3-(4-[1-(2-3&oxy-ethyli-1H-pyrazoh4-yl]-phenyl)-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-yli-cyclopentane-1, 3-diamine "A126" [3-(2-methyl-quinolin-6-yli-3H-[1, 2,3]triazolo [4,5-d]pyrimidin-5- yl]-(Ri-pyrrolidin-3-yl-amine "A127" N-(3-[4-(tetrahydro-pyran-4-yloxyi-phenyl]-3H-[1, 2,3]uiazolo[4, 5- d]pyrimidin-5-yl)-trans-cyclohexane-l, 4-diamine "A128" (Si-l-(4-[5-(4-amino-cyclohexylaminoi-[1, 2,3]uiazolo[4, 5- d]pyrimidin-3-yl]-phenyl)-pyrrolidin-3-ol "A129" N-(3-[4-(l-me&yhlH-pyrazoh4-yli-phenyl]-3H-[1, 2,3]uiazolo[4, 5- d]pyrimidin-5-yl)-trans-cyclohexane-l, 4-diamine "A130" 3-dime&ylamino- 1-((Ri-3-(3-[4-(t -me&yh 1H-pyrazoh4-yli- phenyl] -3H- [1,2,3]triazo 1o [4,5-d]pyrimi din-5-y1 )-pyrro lidin- 1-yli-propan-1-one "A131" 3-(4-me&yhpiperazin-1-yli-1-((Ri-3-(3-[4-(1-me&yhtH-pyrazol-4- yli-phenyl]-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5-ylamino)- pyrrolidin-1-yli-propan-1-one "A132" l-((Ri-3-[3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5- d]pyrimi din-5-y lamino]-pyrro 1 i din- 1-yl )-3-(4-me&yh pip erazin- 1- yli-prop an- 1-one - "A133" 3-(4-me&yh pip erazin- 1-yli- 1 [(Ri-3-(3-quin olin-6-yh3 H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylaminoi-pyrrolidin-1-yl]-propan- 1-one "A134" 3-(4-me&yh pip erazin- 1-yli- 1-((Ri-3-[3-(2-me&yh quino lin-6-yli- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino]-pyrrolidin-l-yl)- propan-1-one "A135" (1R,3Ri-3-(3-[4-(2-me&oxy-e&oxyi-phenyl]-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino)-cyclopentanecarboxylic acid amide "A136" (1S,3Ri-3- [3-(4-me&oxy-phenyl i-3H- [1,2,3]u iazo le [4,5- d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A137" (1S,3 Si-3- [3-(4-me&oxy-phenyl i-3H- [1,2,3]triazo1o [4,5- d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A138" (1S,3Ri-3-[3-(4-pyrrolidin-l-yhphenyli-3H-[1, 2,3]uiazolo[4, 5- d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide US 2016/0015712 A1 Jan. 21, 2016 112

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No. Name

"A139" (1R,3Ri-3- [3-(4-mefltoxy-phenyli-3H- [1,2,3]triazolo [4,5- d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid "A140" (1R,3Ri-3- [3-(4-mefltoxy-phenyli-3H- [1,2,3]triazolo [4,5- d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A141" (1S,3Ri-3-[3-(2-mefltyhbenzoxazoh6-yli-3H-[1, 2,3]triazolo[4, 5- d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A142" 4-[3-(4-mefltoxy-phenyli-3H-[1, 2,3]fldazolo[4, 5-d]pyrimidin-5- ylamino]-butyramide "A143" 4-[3-(4-mefltoxy-phenyli-3H-[1, 2,3]fldazolo[4, 5-d]pyrimidin-5- ylamino]-cyclohexanecarboxylic acid amide "A144" 3-[3-(4-mefltoxy-phenyli-3H-[1, 2,3]fldazolo[4, 5-d]pyrimidin-5- ylamino]-butyramide "A145" (trans i-3-[3-(4-methoxy-phenyl i-3H- [1,2,3]triazo1o [4,5- d]pyrimidin-5-ylamino]-cyclobutanecarboxylic acid amide "A146" (1R,3Ri-3- [3-(4-pyrro 1 i din-1-yhphenyli-3 H- [1,2,3]triazo 1o[4,5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A147" (1R,3Ri-3-[3-(2-mefltyhbenzofluazoh6-yli-3H-[1, 2,3]fldazolo[4, 5- d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A148" (transi-3-[3-(4-methoxy-phenyli-3H-[1, 2,3]triazolo[4, 5-d]— pyrimidin-5-ylamino]-cyclohexanecarboxylic acid amide "A149" (1S,3Ri-3- [3-(4-efltoxy-phenyl i-3H- [1,2,3]tri azo 1o [4,5-d]pyrimidin- 5-ylamino]-cyclopentanecarboxylic acid amide "A150" (1R,3Ri-3-[3-(4-efltoxy-phenyli-3H-[1, 2,3]fldazolo[4, 5-d]pyrimidin- 5-ylamino]-cyclopentanecarboxylic acid amide "A151" (1R,3Ri-3-(3-[4-((Si-3,3,3-fldfluoro-2-hydroxy-propoxyi-phenyl]- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino)- cyclopentanecarboxylic acid amide "A152" (1R,3Ri-3-[3-(3-fluoro-4-mefltoxy-phenyli-3H-[1, 2,3]fldazolo[4, 5- d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A153" (1R,3Ri-3-(3-[4-(2-hydroxy-efltoxyi-phenyl]-3H-[1, 2,3]fldazolo- [4,5-d]pyrimidin-5-ylamino)-cyclopentanecarboxylic acid amide "A154" (1R,3Ri-3-(3-[3-fluoro-4-(3-oxo-morpholin-4-yli-phenyl]-3H- [1,2,3]fldazolo [4,5-d]pyrimidin-5-ylamino )-cyclopentanecarboxylic acid amide "A155" (1R,3Ri-3-(3-[4-((Ri-3,3,34 flfluoro-2-hydroxy-prop oxyi-phenyl]- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino)- cyclopentanecarboxylic acid amide "A156" (1R,3Ri-3-[3-(2,3-dihydro-benzoyl, 4]dioxin-6-yli-3H-[1, 2,3]- uiazolo[4, 5-d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid altllde "A157" (1R,3Ri-3- [3-(4-efltoxy-3-fluoro-phenyl i-3H- [1,2,3]triazo 1o[4,5- d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A158" (1R,3Ri-3-[3-(3-fluoro-4-morpholin-4-yhphenyli-3H- [1,2,3]fldazolo [4,5-d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A159" (1R,3Ri-3-(3-[l-(2-mefltoxy-efltyli-lH-pyrazoh4-yl]-3H- [1,2,3]fldazolo [4,5-d]pyrimidin-5-ylamino )-cyclopentanecarboxylic acid amide "A160" (1R,3Ri-3-(3-[4-(2-pyrazoh1-yhefltoxyi-phenyl]-3H- [1,2,3]fldazolo [4,5-d]pyrimidin-5-ylamino )-cyclopentanecarboxylic acid amide "A161" (1R,3Ri-3-(3-[4-(3,3,3-fldfluoro-2-hydroxy-2-fldfluoromefltyh propoxyi-phenyl]-3H-[1, 2,3]fldazolo[4, 5-d]pyrimidin-5-ylamino)- cyclopentanecarboxylic acid amide "A162" (1R,3Ri-3-[3-(4-mefltoxy-3-mefltyhphenyli-3H-[1, 2,3]fldazolo[4, 5- d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A163" (1R,3Ri-3-[3-(3,5-difluoro-4-methoxy-phenyli-3H-[1, 2,3]triazolo- [4,5-d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A164" (1R,3Ri-3- [3-(4-isopropoxy-phenyli-3H- [1,2,3]triazolo [4,5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A165" (transi-3-(3-[l-(2-mefltoxy-efltyli-lH-pyrazoh4-yl]-3H-[1, 2,3]- triazolo [4,5-d]pyrimidin-5-ylamino)-cyclohexanecarboxylic acid altllde "A166" (1S,3Ri-3-(3-[4-(2-methoxy-ethoxyi-phenyl]-3H-[1, 2,3]— triazolo [4,5-d]pyrimidin-5-ylamino)-cyclopentanecarboxylic acid altllde "A167" (1R,3Ri-3-(3-[4-(2-mefltoxy-1-mefltoxymethybefltoxyi-phenyl]- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino)- cyclopentanecarboxylic acid amide "A168" (1R,3Ri-3-(3-[4-(tetrahydro-pyran-4-yloxyi-phenyl]-3H- [1,2,3]fldazolo [4,5-d]pyrimidin-5-ylamino )-cyclopentanecarboxylic acid amide "A169" (1R,3Ri-3-(3-[4-(2-efltoxy-efltoxyi-phenyl]-3H-[1, 2,3]fldazolo[4, 5- d]pyrimidin-5-ylamino)-cyclopentanecarboxylic acid amide US 2016/0015712 A1 Jan. 21, 2016 113

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No. Name

"A169a" (1R,3Ri-3-[(3-azulen-2-ylfldazolo[4, 5-d]pyrimidin-5-yli- amino] cyclopentanecarboxamide "A169b" (1R,3Ri-3-[[3-(6-fluoro-2-naphfltyliuiazolo[4, 5-d]pyrimidin-5- yl] amino]cyclopentanecarboxamide "A169c" (1R,3Ri-3- [[3-(4-tert-butoxyphenylitriazolo [4,5-d]pyrimi din-5- yl] amino]cyclopentanecarboxamide "A169d" (1R,3Ri-3-[[3-[4-(2-hydroxy-1, 1-dimethyl-ethoxyiphenyl]— triazolo [4,5-d]pyrimidin-5-yl]amino]cyclopentanecarboxamide "A169e" (1R,3Ri-3-[[3-[4-[(3Ri-tetrahydrofuran-3-yl]oxyphenyl]- triazolo [4,5-d]pyrimidin-5-yl]amino]cyclopentanecarboxamide ' "A169f (1R,3Ri-3- [[3-[4-[(3S)-tetrahydro furan-3-yl] oxypheny1]triazo 1o[4,5- d]pyrimi din-5-yl] amino] cyclo pentane carboxami de "A170" (1R,3Ri-3- [3-(44odo-phenyl i-3H- [1,2,3]triazo 1o[4,5-d]pyrimi din-5- ylamino]-cyclopentanecarboxylic acid amide "A171" (1S,3Ri-3-[3-(4-iodo-phenyli-3H-[1, 2,3]fldazolo[4, 5-d]pyrimidin-5- ylamino]-cyclopentanecarboxylic acid amide "A172" (1S,3Ri-3-(3-benzoyl, 2,5]fluadiazoh5-yh3H-[1, 2,3]fldazolo[4, 5- d]pyrimidin-5-ylaminoi-cyclopentanecarboxylic acid amide "A173" (1R,3Ri-3- [3-(6-methoxy-pyridin-3-yli-3 H- [1,2,3]triazolo [4,5-d]— pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A174" (1R,3Ri-3-(3-benzoyl, 2,5]fluadiazoh5-yh3H-[1, 2,3]fldazolo[4, 5- d]pyrimidin-5-ylaminoi-cyclopentanecarboxylic acid amide "A175" (1R,3Ri-3- [3-(5-methoxy-pyridin-2-yli-3 H- [1,2,3]triazolo [4,5-d]— pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A176" (1R,3Ri-3- [3-(34odo-phenyli-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5- ylamino]-cyclopentanecarboxylic acid amide "A177" (1R,3Ri-3-[3-(5-iodo-pyridin-2-yli-3H-[1, 2,3]fldazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A178" (1R,3Ri-3- [3-(5-efltoxy-pyri din-2-yli-3 H- [1,2,3]triazo 1o[4,5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A179" (1R,3Ri-3- [3-(6-efltoxy-pyri din-3-yli-3 H- [1,2,3]triazo 1o[4,5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A180" (1R,3Ri-3-[3-(2-mefltyhbenzofuran-5-yli-3H-[1, 2,3]fldazolo[4, 5- d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A181" (1R,3Ri-3- [3-(2-methoxy-quinolin-6-yli-3H- [1,2,3]triazolo [4,5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A182" (1R,3Ri-3-(3-[2-(2-efltoxy-efltoxyi-quinolin-6-yl]-3H- [1,2,3]fldazolo [4,5-d]pyrimidin-5-ylamino )-cyclopentanecarboxylic acid amide

"A183" (1R,3Ri-3- [3-(1,2-dimethyl-1H-benz imidazo N 5-yli-3 H- [1,2,3]fldazolo [4,5-d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A184" (1R,3Ri-3-[3-(2-mefltyhquinazolin-6-yli-3H-[1, 2,3]fldazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A185" (1R,3Ri-3- [3-(2-methyl-2 H-indazo1-6-yli-3 H- [1,2,3]triazo1o [4,5-d]— pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A186" (1R,3Ri-3- [3-(2-methyl-2H-indazoh5-yli-3 H- [1,2,3]triazolo [4,5- d]pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A186a" (1R,3Ri-3- [(3-c inn olin-6-yltriazo 1o [4,5-d]pyrimi din-5-yli- amino] cyclopentanecarboxamide "A186b" (1R,3Ri-3-[[3-(7-mefltoxy-3-quinolylifldazolo[4, 5-d]pyrimidin-5- yl] amino]cyclopentanecarboxamide "A186c" (1R,3Ri-3-[[3-(2-mefltylindolizin-7-ylifldazolo [4,5-d]pyrimidin-5- yl] amino]cyclopentanecarboxamide "A186d" (1R,3Ri-3-[[3-(2-mefltylindolizin-6-ylitriazolo [4,5-d]pyrimidin-5- yl] amino]cyclopentanecarboxamide "A186e" (1R,3Ri-3-[[3-(2-mefltylimidazo[1, 2-a]pyridin-6-yliuiazolo[4, 5-d]- pyrimidin-5-yl]amino] cyclopentanecarboxamide "A186f' (1R,3Ri-3-[[3-(2-mefltyhlH-indoh5-ylitriazolo[4, 5-d]pyrimidin-5- yl] amino]cyclopentanecarboxamide "A1868" (1R,3Ri-3-[[3-(2-mefltylisoindoh5-ylitriazolo[4, 5-d]pyrimidin-5- yl] amino]cyclopentanecarboxamide "A18611" (1R,3Ri-3-[[3-(7-mefltylindolizin-2-ylifldazolo [4,5-d]pyrimidin-5- yl] amino]cyclopentanecarboxamide "A186i" (1R,3Ri-3-[[3-(tH-indazoh5-ylitriazolo [4,5-d]pyrimidin-5- yl] amino]cyclopentanecarboxamide "A186j" (1R,3Ri-3-[[3-(2-mefltyh3H-benzimidazoh5-ylifldazolo[4, 5- d]pyrimi din-5-yl] amino] cyclo pentane carboxami de "A187" (1R,3Ri-3-[3-(2-mefltyhquinolin-6-yli-3H-[1, 2,3]fldazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A188" (1S,3Ri-3-(3-quinolin-6-yh3H-[1, 2,3]fldazolo[4, 5-d]pyrimidin-5- ylaminoi-cyclopentanecarboxylic acid "A189" (1S,3Ri-3-(3-quinolin-6-yh3H-[1, 2,3]fldazolo[4, 5-d]pyrimidin-5- ylaminoi-cyclopentanecarboxylic acid amide US 2016/0015712 A1 Jan. 21, 2016 114

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No. Name

"A190" (1R,3R]-3-(3-quinolin-6-yh3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5- ylamino)-cyclopentanecarboxylic acid amide "A191" (1S,3R]-3-[3-(2-me&yhquinolin-6-yl]-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A192" (trans]-3-[3-(2-me&yhquinolin-6-yl]-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclohexanecarboxylic acid amide "A193" (1S,3S)-3-[3-(2-me&yhquinolin-6-yli-3H- [1,2,3]triazolo [4,5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide

"A194" (1R,3R)-3-(3-[1,5]nap hthyri din-2-yl-3 H- [1,2,3]triazo 1o[4,5-d]- pyrimidin-5-ylaminoi-cyclopentanecarboxylic acid amide "A195" (1R,3R)-3-[3-(1-methyl-1 H-indaz oh 5-yl)-3 H- [1,2,3]triazo1o [4,5-d]— pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A195a" (1R,3R)-3-[[3-(7-me&yh 3-quino lyl) triazo1o [4,5-d]pyri mid in-5- yl] amino]cyclopentanecarboxamide "A195b" (1R,3R]-3-[[3-(2-me&yhl-oxo-6-isoquinolyliuiazolo[4, 5- d]pyrimi din-5-yl] amino] cyclo pentane carboxami de "A196" (1R,3R)-3-[3-(44odo-phenyl)-3 H- [1,2,3]triazo 1o[4,5-d]pyrimi din-5- ylamino]-cyclopentanol "A197" (1S,3S]-3-[3-(4-iodo-phenyl]-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5- ylamino]-cyclopentanol "A198" (trans]-3-[3-(4-pyrrolidin-l-yhphenyl]-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentano1 "A199" (trans]-3-[3-(2-me&yhbenzoxazoh6-yl]-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentano1 "A200" (trans]-3-(3-benzo [1,2,5]thiadiazoh5-yl-3H- [1,2,3]triazolo [4,5-d]- pyrimidin-5-ylaminoi-cyclopentanol "A201" (1R,3R)-3-[3-(4-me&oxy-phenyl]-3H- [1,2,3]triazolo [4,5-d]- pyrimidin-5-ylamino]-cyclohexanol "A202" (trans]-3-[3-(2-me&yhquinolin-6-yl]-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentano1 "A203" (1R,3R]-3-(3-[4-(2-hydroxy-e&oxyi-phenyl]-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino)-cyclopentanol "A204" (1R,3R]-3-(3-quinolin-6-yh3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5- ylamino)-cyclopentanol "A205" (trans]-3-(3-[4-((S]-3,3,3-trifluoro-2-hydroxy-propoxyi-phenyl]-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino)-cyclopentanol "A206" (trans]-3-[3-(6-epoxy-pyridin-3-yl)-3H-[1, 2,3]triazolo[4, 5-d]— pyrimidin-5-ylamino]-cyclopentano1 "A207" (trans]-3-[3-(4-epoxy-phenyl]-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin- 5-ylamino]-cyclopentanol "A208" (1R,3R]-3-[3-(2-me&yhquinolin-6-yl]-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentano1 "A209" (trans]-3-[3-(2-me&yhquinazolin-6-yl]-3H-[1, 2,3]triazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentano1 "A210" (trans]-3-[3-(4-isopropoxy-phenyl]-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentano1 "A211" (1R,3R]-3-(3-(4-[l-(2-epoxy-e&yli-lH-pyrazoh4-yl]-phenyl)-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylaminoi-cyclopentanecarboxylic acid amide "A212" (1R,3R]-3-(3-(4-[t-(2-me&oxy-e&yli-tH-pyrazol-4-yl]-phenyl)- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylaminoi-cyclopentanol "A213" (1R,3R]-3-(3-(4-[t-(2-pyrrolidin-l-yl-ethyl)-1H-pyrazol-4-yl]- phenyl)-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-ylaminoi- cyclopentanol "A214" 3-(4-(4- [5-(trans-3-hydroxy-cyclopentylaminoi- [1,2,3]u iazole [4,5- d]pyrimidin-3-yl]-phenyl)-pyrazo1-1-yl)-propionitrile "A215" N-(3-(4-[1-(2-pyrazoh 1-yhe&yli-1H-pyrazol-4-yl]-phenyl)-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-yli-cyclohexane-1, 4-diamine "A216" (1S,3R]-3-(3-(4-[t-(2-pyrrolidin-t-yhe&yli-tH-pyrazoh4-yl]- phenyl)-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-ylaminoi- cyclopentanecarboxylic acid amide "A217" (1R,3R]-3-(3-(4-[l-(2-cyano-e&yli-lH-pyrazob4-yl]-phenyl)-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylaminoi-cyclopentanecarboxylic acid amide "A218" (1R,3R]-3-(3-(4-[t-(2-me&oxy-e&yli-tH-pyrazol-4-yl]-phenyl)- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylaminoi- cyclopentanecarboxylic acid amide "A219" (1R,3R]-3-(3-(5-[l-(2-me&oxy-e&yli-lH-pyrazol-4-yl]-pyridin-2- yl)-3H- [1,2,3]u iazole [4,5-d]pyrimidin-5-ylaminoi- cyclopentanecarboxylic acid amide US 2016/0015712 A1 Jan. 21, 2016 115

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No. Name

"A220" (1R,3Ri-3-[3-(4-(l-[2-(5-mefltyl-[1, 2,4]oxadiazoh3-yli-efltyl]-lH- pyrazoh4-yl)-phenyli-3H-[1, 2,3]fldazolo[4, 5-d]pyrimidin-5- ylamino]-cyclopentanecarboxylic acid amide "A221" (1R,3Ri-3-(3-(3-fluoro-4-[l-(2-mefltoxy-efltyli-lH-pyrazoh4-yl]- phenyl)-3H-[1, 2,3]fldazolo[4, 5-d]pyrimidin-5-ylaminoi- cyclopentanecarboxylic acid amide "A222" (1R,3Ri-3-(3-(3-[l-(2-mefltoxy-efltyli-lH-pyrazoh4-yl]-phenyl)- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylaminoi- cyclopentanecarboxylic acid amide "A223" (1R,3Ri-3-(3-(4-[t-(2-efltoxy-efltyli-tH-pyrazoh4-yl]-3-fluoro- phenyl)-3H-[1, 2,3]fldazolo[4, 5-d]pyrimidin-5-ylaminoi- cyclopentanecarboxylic acid amide "A224" (1R,3Ri-3-(3-(6-[l-(2-mefltoxy-efltyli-lH-pyrazoh4-yl]-pyridin-3- yl)-3H-[1, 2,3]fldazolo [4,5-d]pyrimidin-5-ylaminoi- cyclopentanecarboxylic acid amide "A225" (1R,3Ri-3-(3-(4-[l-(2-efltoxy-efltyli-lH-pyrazoh4-yl]-phenyl)-3H- [1,2,3]fldazolo [4,5-d]pyrimidin-5-ylaminoi-cyclopentanecarboxylic acid (2-mefltoxy-efltyli-amide "A226" (1R,3Ri-3-(3-(4-[l-(2-efltoxy-efltyli-lH-pyrazoh4-yl]-phenyl)-3H- [1,2,3]fldazolo [4,5-d]pyrimidin-5-ylaminoi-cyclopentanecarboxylic acid (2-hydroxy-efltyli-amide "A227" (1R,3Ri-3-(3-(4-[l-(2-efltoxy-efltyli-lH-pyrazoh4-yl]-phenyl)-3H- [1,2,3]fldazolo [4,5-d]pyrimidin-5-ylaminoi-cyclopentanol "A228" (1R,3Ri-3-(3-(3-fluoro-4-[l-(2-mefltoxy-efltyli-lH-pyrazoh4-yl]- phenyl)-3H-[1, 2,3]fldazolo[4, 5-d]pyrimidin-5-ylaminoi- cyclopentanol "A229" (1R,3Ri-3-(3-(6-[l-(2-efltoxy-efltyli-lH-pyrazoh4-yl]-pyridin-3- yl)-3H-[1, 2,3]fldazolo [4,5-d]pyrimidin-5-ylaminoi- cyclopentanecarboxylic acid amide "A230" (1R,3Ri-3-(3-(4-[t-(2-mefltoxy-efltyli-tH-pyrazoh4-yl]-3-mefltyh phenyl)-3H-[1, 2,3]fldazolo[4, 5-d]pyrimidin-5-ylaminoi- cyclopentanecarboxylic acid amide "A231" (1R,3Ri-3-(3-[4-(l-pyridin-3-ylmefltyhlH-pyrazoh4-yli-phenyl]- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylamino)-cyclopentanol "A232" (1R,3Ri-3-(3-(4-[t-(2-hydroxy-2-methyhpropyli-tH-pyrazoh4-yl]- phenyl)-3H-[1, 2,3]fldazolo[4, 5-d]pyrimidin-5-ylaminoi- cyclopentanol "A233" (1R,3Ri-3-(3-(4-[t-(2-hydroxy-2-methyhpropyli-tH-pyrazoh4-yl]- phenyl)-3H-[1, 2,3]fldazolo[4, 5-d]pyrimidin-5-ylaminoi- cyclopentanecarboxylic acid amide "A234" (transi-3-(3-(6- [1-(2-mefltoxy-efltyli-1H-pyrazoh4-yl]-pyridin-3- yl)-3H-[1, 2,3]fldazolo [4,5-d]pyrimidin-5-ylaminoi-cyclopentanol "A235" (1R,3Ri-3-(3-(4-[l-(2-mefltoxy-efltyli-tH-pyrazoh4-yl]-phenyl)- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylaminoi-cyclopentane- carboxylic acid (1-mefltyhpiperidin-4-ylmefltyli-amide "A23 6" 2- [2-(4-(4-[5-((lR,3Ri-3-hydroxy-cyclopentylaminoi- [1,2,3]fldazolo[4, 5-d]pyrimidin-3-yl]-phenyl)-pyrazoh1-yli-efltyl]- 2H-pyridazin-3-one "A237" (1R,3Ri-3-[3-(4-(l-[2-(6-oxo-6H-pyridazin-l-yli-efltyl]-lH- pyrazoh4-yl)-phenyli-3H-[1, 2,3]fldazolo[4, 5-d]pyrimidin-5- ylamino]-cyclopentanecarboxylic acid amide "A23 8" (1R,3Ri-3-(3-(5-[l-(2-efltoxy-efltyli-lH-pyrazoh4-yl]-pyridin-2- yl)-3H-[1, 2,3]fldazolo [4,5-d]pyrimidin-5-ylaminoi- cyclopentanecarboxylic acid amide "A239" (1R,3Ri-3-(3-(5-[l-(2-cyano-efltyli-lH-pyrazob4-yl]-pyridin-2-yl)- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylaminoi- cyclopentanecarboxylic acid amide "A239a" (1R,3Ri-3-[[3-(4-pyrimidin-5-ylphenylifldazolo[4, 5-d]pyrimidin-5- yl] amino]cyclopentanecarboxamide "A239b" (1R,3Ri-3- [[3-[4-(6-mefltyh3-pyridyliphenyl]triazolo [4,5- d]pyrimi din-5-yl] amino] cyclo pentane carboxami de "A239c" - (1R,3Ri-3 [[3-[4-[1 [2-methoxy- 1 -(meth oxym ethyl i ethyl]pyrazo1-4- yl]phenyl]triazolo [4,5-d]pyrimidin-5- yl] amino]cyclopentanecarboxamide "A239d" (1R,3Ri-3- [[3-[4-(5-mefltylpyrimidin-2-yli phenyl] triazo 1o[4,5- d]pyrimi din-5-yl] amino] cyclo pentane carboxami de "A240" (1R,3Ri-3-[3-(4-efltoxy-phenyli-3H-[1, 2,3]fldazolo[4, 5-d]pyrimidin- 5-ylamino]-cyclopentanecarboxylic acid (3-hydroxy-3-mefltyh butyl)-amide "A241" ((1R,3Ri-3- [3-(4-methoxy-phenyli-3H- [1,2,3]triazolo [4,5- d]pyrimidin-5-ylamino]-cyclopentyl)-(4-mefltyhpiperazin-1-yli- methanone US 2016/0015712 A1 Jan. 21, 2016 116

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No. Name

"A242" (1S,3Ri-3-(3-quinolin-6-yh3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5- ylaminoi-cyclopentanecarboxylic acid [2-(4-mefltyhpiperazin-1-yli- ethyl]-amide "A243" (1R,3Ri-3- [3-(4-mefltoxy-phenyli-3H- [1,2,3]triazolo [4,5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid dimethylamide "A244" (1R,3Ri-3- [3-(4-mefltoxy-phenyli-3H- [1,2,3]triazolo [4,5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid [2-(4-mefltyh piperazin-1-yli-efltyl]-amide "A245" (1R,3Ri-3-[3-(2-mefltyhquinolin-6-yli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid (2-hydroxy- efltyli-amide "A246" (1R,3Ri-3-[3-(2-mefltyhquinolin-6-yli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid (2-mefltoxy- efltyli-amide "A247" (1R,3Ri-3-[3-(4-efltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin- 5-ylamino]-cyclopentanecarboxylic acid (2-hydroxy-efltyli-amide "A248" (1R,3Ri-3-[3-(4-efltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin- 5-ylamino]-cyclopentanecarboxylic acid (2-mefltoxy-efltyli-amide "A249" (1R,3Ri-3-[3-(4-efltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin- 5-ylamino]-cyclopentanecarboxylic acid (1-mefltyhpiperidin-4- ylmefltyli-amide "A250" (1R,3Ri-3-[3-(2-mefltyhquinolin-6-yli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid [2-(4-mefltyh piperazin-1-yli-efltyl]-amide "A251" (1R,3Ri-3-[3-(4-efltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin- 5-ylamino]-cyclopentanecarboxylic acid (2-hydroxy-2-mefltyh propyli-mefltyhamide "A252" (1R,3Ri-3-[3-(2-mefltyhquinolin-6-yli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid (1-mefltyh piperidin-4-ylmefltyli-amide "A253" (1R,3Ri-3-[3-(2-mefltyhquinolin-6-yli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid (3-hydroxy-3- mefltyhbutyli-amide "A254" (1R,3Ri-3-[3-(2-mefltyhquinolin-6-yli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid ((transi-3- hydroxy-cyclopentyli-amide "A254a" (1R,3Ri-3- [[3-(2-mefltyh 6-quino lylitriazolo [4,5-d]pyri mid in-5- yl] amino]-N-(2-morpholinoethylicyclopentanecarboxamide "A255" (1R,3Ri-3-(3-(4-[t-(2-hydroxy-efltyli-tH-pyrazoh4-yl]-phenyl)- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylaminoi- cyclopentanecarboxylic acid amide "A25 6" 2-(4-(4-[5-(trans-4-amino-cyclohexylaminoi-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-3-yl]-phenyl)-pyrazobt-yli-ethanol "A257" 2-(4-(4-[5-((1R,3Si-3-amino-cyclopentylaminoi-[1, 2,3]triazolo[4, 5- d]pyrimidin-3-yl]-phenyl)-pyrazoht-yli-efltanol "A25 8" (1S,3Ri-3-(3-(4-[t-(2-hydroxy-efltyli-tH-pyrazoh4-yl]-phenyl)- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylaminoi- cyclopentanecarboxylic acid amide "A259" (1R,3Ri-3-(3-(4-[t-(2-hydroxy-efltyli-tH-pyrazoh4-yl]-phenyl)- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-ylaminoi-cyclopentanol "A260" (1R,3Ri-3-(3-(3-fluoro-4- [1-(2-hydroxy-efltyli-1H-pyrazoh4-yl]- phenyl)-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-ylaminoi- cyclopentanecarboxylic acid amide "A261" (1R,3Ri-3-(3-(5-[t-(2-hydroxy-efltyli-tH-pyrazoh4-yl]-pyridin-2- yl)-3H- [1,2,3]u iazole [4,5-d]pyrimidin-5-ylaminoi- cyclopentanecarboxylic acid amide "A262" [3-(4-mefltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]- ((transi-3-mefltylsulfanyhcyclopentyli-amine "A263" ((trans i-3-mefltanesulfonyl-cyclopentyli-[3-(4-mefltoxy-phenyli-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-yl]-amine "A264" ((cisi-3-mefltanesulfonybcyclopentyli-[3-(4-mefltoxy-phenyli-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-yl]-amine "A265" (1R,3Ri-3-[3-(4-(l-[2-(lH-tetrazoh5-yli-efltyl]-lH-pyrazoh4-yl)- phenyl)-3 H- [1,2,3]triazo 1o [4,5-d]pyrimi din-5-y1 amino]— cyclopentanecarboxylic acid amide "A266" trans-3-[3-(4-(1-[2-(1H-Tetrazoh5-yli-efltyl]-1H-pyrazoh4-yl)- phenyl)-3 H- [1,2,3]triazo 1o [4,5-d]pyrimi din-5-y1 amino]— cyclopentanol "A267" [3-(4-mefltoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]- [(1R,3Si-3-(5-mefltyhoxazoh2-yli-cyclopentyl]-amine "A268" 3-(4-(4- [5-(trans-3-hydroxy-cyclopentylaminoi- [1,2,3]u iazole [4,5- d]pyrimidin-3-yl]-phenyl)-pyrazoht-yli-propionamide "A269" ((Ri-1-mefltanesulfonyl-pyrrolidin-3-yli-(3-quinolin-6-yl-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-yli-amine US 2016/0015712 A1 Jan. 21, 2016 117

-continued

No. Name

"A269a" ((Ri- 1-Methanesulfonyl-pyrrolidin-3-yli- [3-(4-methoxy-phenyli- 3H-[1,2,3]triazolo[4, 5-d]pyrimidin-5-yl]-amine "A270" (Ri-3- [3-(4-me&oxy-phenyl i-3H- [1,2,3]triazo 1o [4,5-d]pyrimi din-5- ylamino]-pyrrolidine- 1-sulfonic acid amide "A271" 1-((Ri-3-(3-[4-(1-me&yhtH-pyrazoh4-yli-phenyl]-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino)-pyrrolidin-t-yli-4- piperazin-1-yl-butan-1-one "A272" (1R,4Si-4- [3-(4-epoxy-phenyl i-3H- [1,2,3]tri azo 1o [4,5-d]pyrimidin- 5-ylamino]-cyclopent-2-enecarboxylic acid amide "A273" (1S,4Si-4-[3-(4-Me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopent-2-enecarboxylic acid amide "A274" (1R,3Ri-3-(3-[4-(2-me&oxy-e&oxyi-phenyl]-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino)- cyclopentanecarbonitrile "A275" cis-3- [3-(4-Me&oxy-phenyli-3H- [1,2,3]triazolo [4,5-d]pyrimidin-5- ylamino]-cyclopentanecarbonitrile "A276" (1R,3Ri-3- [3-(4-hydroxy-phenyli-3H- [1,2,3]triazolo [4,5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A277" (1R,3Ri-3-(3-[4-(2-morpholin-4-yhe&oxyi-phenyl]-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino)-cyclopentanecarboxylic acid amide "A278" (1R,3Ri-3-(3-[4-(3-hydroxy-l, l-dime&yhpropoxyi-phenyl]-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino)-cyclopentanecarboxylic acid amide "A279" (1R,3Ri-3-(3-[4-(piperidin-4-ylme&oxyi-phenyl]-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino)-cyclopentanecarboxylic acid amide "A280" (1R,3Ri-3-[3-(4-epoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin- 5-ylamino]-cyclopentanecarboxylic acid Nuacetyl-hydrazide "A281" [3-(4-epoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]- [(1R,3Ri-3-(5-methyl-[1, 3,4]oxadiazoh2-yli-cyclopentyl]-amine "A282" (1R,3Ri-3-[3-(4-epoxy-phenyli-3H-[1, 2,3]kiazolo[4, 5-d]pyrimidin- 5-ylamino]-cyclopentanecarboxylic acid hydrazide "A283" [(1R,3Ri-3-(5-amino-[1, 3,4]oxadiazoh2-yli-cyclopentyl]-[3-(4- epoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]pyrimidin-5-yl]-amine "A284" (Ri-3-[3-(2-me&yhquinolin-6-yli-3H-[1, 2,3]triazolo[4, 5-d]- pyrimidin-5-ylamino]-pyrrolidine-1-carboxylic acid amide

"A285" (Ri-3- [3-(4-Me&oxy-phenyl i-3H- [1,2,3]0iazo le [4,5-d]pyri mid in-5- ylamino]-pyrrolidine- 1-carboxylic acid amide "A286" N-((lR, 3Ri-3-[3-(4-epoxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentanecarbonyl)-me&anesul fonamide "A287" 2-((transi-3- [3-(4-ethoxy-phenyli-3H- [1,2,3]triazolo [4,5-d]- pyrimidin-5-ylamino]-cyclopentyl)-2H-pyridazin-3-one "A288" (transi-3-[3-(4-methoxy-phenyli-3H-[1, 2,3]triazolo[4, 5-d]— pyrimidin-5-ylamino]-cyclopentanesulfonic acid amide "A289" (1R,3Ri-3-(3-[4-(l-hydroxy-l-me&yhe&yli-phenyl]-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino)-cyclopentanecarboxylic acid amide "A290" (transi-3-(3- [4-(t -Hydroxy- 1-me&yhe&yli-phenyl]-3 H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino)-cyclopentanol "A291" l-((lR, 3Ri-3-[3-(4-me&oxy-phenyli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentyl)-pyrrolidin-2-one "A292" 3-(4-[5-((lR,3Ri-3-carbamoyhcyclopentylaminoi- [1,2,3]uiazolo[4, 5-d]pyrimidin-3-yl]-phenoxy)-propionic acid methyl ester "A293" (1R,3Ri-3-(3-[4-(3-hydroxy-3-me&yhbutoxyi-phenyl]-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino)-cyclopentanecarboxylic acid amide "A294" (4-[5-((lR,3Ri-3-carbamoybcyclopentylaminoi-[1, 2,3]uiazolo[4, 5- d]pyrimidin-3-yl]-phenoxy)-acetic acid methyl ester "A295" (1R,3Ri-3-(3-[4-(2-hydroxy-2-me&yhpropoxyi-phenyl]-3H- [1,2,3]uiazolo[4, 5-d]pyrimidin-5-ylamino)-cyclopentanecarboxylic acid amide "A296" (1R,3Ri-3-[3-(4-me&anesulfonybphenyli-3H-[1, 2,3]uiazolo[4, 5-d]- pyrimidin-5-ylamino]-cyclopentanecarboxylic acid amide "A297" 3-[(1S,3Ri-3- [[3-(4-meth oxyphenylitriazo 1o [4,5-d]pyrimi din-5- yl]amino]cyclopentyl]-4H-1, 2,4-oxadiazoh5-one "A298" 3-(4-me&oxyphenyli-N-[(1R, 3Si-3-(5-methyl-1, 2,4-oxadiazol-3- ylicyclopentyl]uiazolo[4, 5-d]pyrimidin-5-amine "A299" (1R,3Ri-3- [[3-[4-(4-pip eridyloxyiphenyl]triazolo [4,5-d]pyrimidin- 5-yl] amino] cyclopentanecarboxamide "A300" (1R,3Ri-3- [[3-[4-[t1-methyl-4-piperidylioxy]phenyl]triazolo [4,5-d]- pyrimidin-5-yl]amino] cyclopentanecarboxamide US 2016/0015712 A1 Jan. 21, 2016

and pharmaceutically acceptable solvates, salts, tautomers 14. A method according to claim 10 for the treatment and stereoisomers thereof, including mixtures thereof in all and/or prevention of diseases selected from the group Alzhe- ratios. imer's disease, Down's syndrome, hereditary cerebral hem- S.Process for the preparation of compounds of the formula orrhage with amyloidosis-Dutch Type, cerebral amyloid I according to claim 1 and pharmaceutically acceptable salts, angiopathy, Creutzfeldt-Jakob disease, frontotemporal solvates, tautomers and stereoisomers thereof, characterised dementias, Huntington's disease, Parkinson's disease. in that 15. A method according to claim 10 for the treatment a compound of the formula II and/or prevention of diseases selected from the group /eish- mania, mycobacteria, including M. /eprae, M. tuberculosis and/or M. avium, /eishmania, plasmodium, human immuno- deficiency virus, Epstein Barr virus, Herpes simplex virus, R' hepatitis C virus. 16.Medicaments comprising at least one compound ofthe formula I ofclaim 1 and/or pharmaceutically acceptable salts, Yj solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient. R' in which has the meanings indicated in claim 1, 17. Set (kit) consisting of separate packs of is reacted with a compound of the formula III (a) an effective amount of a compound of the formula I of R NHz HI claim 1 and/or pharmaceutically acceptable salts, sol- in which R has the meaning indicated in claim 1 vates, salts and stereoisomers thereof, including mix- and/or tures thereof in all ratios, a base or acid of the formula I is converted into one of its and salts. (b) an effective amount of a further medicament active 9. Medicaments comprising at least one compound of the ingredient. formula I and/or pharmaceutically acceptable salts, solvates, 1S. Compounds according to claim 1, selected from the tautomers and stereoisomers thereof, including mixtures group thereof in all ratios, and optionally an pharmaceutically acceptable carrier, excipient or vehicle. 10.A method comprising using the compounds of claim 1 No. Name of the formula I and pharmaceutically acceptable salts, sol- "B1" vates, tautomers and stereoisomers thereof, including mix- (I-meflryi-IH-pyrazoi-4-yimeflryii-(3-quinolin-6-yi-3H- [1,2,3]niazoio[4, 6-d]pyrimidin-6-yii-amine tures in all the treatment and/or prevention thereof ratios, for "B2" 3,3-dimeflry1-6-(6-[(6-meflryi-pyrazin-2-yimeflryii-aminob of inflammatory conditions, immunological conditions, [1,2,3lniazolo[4, 6-d]pyrimidin-3-yl)-1, 3-dihydro-indol-2-one autoimmune conditions, allergic conditions, rheumatic con- "B3" (3-[4-(2-meflroxy-eflroxyi-phenyIP3H-[1, 2,3]rflazoio[4, 6-db ditions, thrombotic conditions, cancer, infections, neurode- pyrimidin-6-yi)-(6-meflryi-pyrazin-2-yimeflryii-amine "B4" [3-(4-chioro-3-fluoro-phenyii-3H-[1, 2,3]niazoio[4, 6- neuroinflammatory cardiovas- generative diseases, diseases, d]pyrimidin-6-yib(I-meflryi-I H-pyrazoi-4-yimeflryii-amine cular diseases, and metabolic conditions, the methods "B6" (6-meflryi-pyrazin-2-yimeflryii-(3-quinoxalin-6-yi-3H- comprising administering to a subject in need thereof an [1,2,3]niazoio[4, 6-d]pyrimidin-6-yii-amine "B6" effective amount of a compound of claim 1. (3-[4-(2-meflroxy-eflroxyi-phenyIP3H-[1, 2,3]rflazoio[4, 6-db pyrimidin-6-yi)-(I-meflryi-I H-pyrazoi-4-yimeflryii-amine A method according to claim 10 for the treatment 11. "B7" [3-(4-eflroxy-phenyii-3H-[1, 2,3]niazoio[4, 6-d]pyrimidin- and/or prevention of cancer, 6-yIP [2-(I-meflryi- IH-pyrazo I-4-yi i-eflryIP amine where the cancer to be treated is a solid tumour or a tumour "B8" 2-(3,4-difluoro-phenyii-2-[3-(6-meflroxy-pyridin-3-yii-3H- of the blood and immune system. [1,2,3lniazolo[4, 6-d]pyrimidin-6-ylaminobeflranol "B9" [3-(4-eflroxy-phenyii-3H-[1, 2,3]niazoio[4, 6-d]pyrimidin- 12. A method according to claim where the solid 11, 6-yIP [2-(IH-pyrazoi-4-yi i-eflryi b amine tumour originates from the group of tumours of the epithe- "B10" [3-(4-meflroxy-phenyii-3H-[1, 2,3]niazoio[4, 6-d]pyrimidin-6-yib lium, the bladder, the stomach, the kidneys, ofhead and neck, pheneflryi-amine "B11" the esophagus, the cervix, the thyroid, the intestine, the liver, benzyi-[3-(4-meflroxy-phenyii-3H-[1, 2,3]niazoio[4, 6- d]pyrimidin-6-yibamine the brain, the prostate, the uro-genital tract, the lymphatic "A46" 3-(4-(6-[3-(4-nine-pyrazoi-I-yii-propyiaminob system, the stomach, the larynx, the bones, including chon- [1,2,3]niazoio[4, 6-d]pyrimidin-3-yi)-phenoxyi-propionic acid dosarcoma and Ewing sarcoma, germ cells, including "A47" 3-(4-(6-[3-(4-amino-pyrazoi-I-yii-propyiaminob embryonal tissue tumours, and/or the lung, from the group of [1,2,3]niazoio[4, 6-d]pyrimidin-3-yi)-phenoxyi-propionic acid "A68" (3-[4-(2-meflroxy-eflroxyi-phenyIP3H-[1, 3]rflazoio[4, 6-db small-cell 2, monocytic leukaemia, lung adenocarcinoma, lung pyrimidin-6-yi)-(3-pyridin-2-yi-propyii-amine carcinomas, pancreatic cancer, glioblastomas, neurofibroma, "A80" (3-[4-(2-meflroxy-eflroxyi-phenyIP3H-[1, 2,3]rflazoio[4, 6-db angiosarcoma, breast carcinoma and/or maligna melanoma. pyrimi din-6-yi )-[3-(4-meflroxy-phenyl i-prop yI herniae 13. A method according to claim 10 for the treatment and/or prevention of diseases selected from the group rheu- and pharmaceutically acceptable solvates, salts, tautomers matoid arthritis, systemic lupus, asthma, multiple sclerosis, and stereoisomers thereof, including mixtures thereof in osteoarthritis, ischemic injury, giant cell arteritis, inflamma- all ratios. tory bowel disease, diabetes, cystic fibrosis, psoriasis, Sjog- rens syndrom and transplant organ rejection.