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11~) United States 112) Patent Application Publication 110) Pub. No. : US 2016/0002242 A1 HOELZEMANN et al. 143) Pub. Date: Jan. 7, 2016

154) IMIDAZOPYRIMIDINE DERIVATIVES Publication Classification

171) Applicant: MERCK PATENT GMBH, Darmstadt 151) Int. Cl. 1DE) C07D 473/32 12006.01) 261K31/52 12006.01) 172) Inventors: Guenter HOELZEMANN, 152) U.S. Cl. Seeheim- Jugenheim 1DE); Dieter CPC ...... C07D 473/32 12013.01);261K31/52 DORSCH, Ober-Ramstadt 1DE); 12013.01) Ansgar WEGENER, Heusenstamm 1DE); Oliver POESCHKE, Wiesbaden 1DE); Michael BUSCH, Darmstadt 157) ABSTRACT 1DE); Jeyaprakashnarayanan SEENISAMY, Bangalore 1IN) Compounds of the formula I 173) Assignee: Merck Patent GmbH, Darmstadt 1DE)

121) Appl. No. : 14/772, 430 H / 122) PCT Filed: Feb. 11,2014 N

PCT No. : PCT/EP2014/000371 N 186) N ) 371 1c)11), 12) Date: Sep. 3, 2015 in which X, R' and R have the meanings indicated in Claim 130) Foreign Application Priority Data 1, are inhibitors of GCN2, and can be employed, inter alia, for Mar. 5, 2013 1EP) ... 13001111.7 the treatment of cancer. US 2016/0002242 A1 Jan. 7, 2016

IMIDAZOPYRIMIDINE DERIVATIVES [0007] Several mechanistic studies discovered that immune escape has an important interface with metabolic BACKGROUND OF THE INVENTION alterations within the tumor microenvironment. Here impor- tant roles in mediating immune tolerance to antigens have [0001] The invention had the object of finding novel com- been associated to the catabolism ofthe essential amino acids pounds having valuable properties, in particular those which tryptophan and arginine, carried out by the enzymes can be used for the preparation of medicaments. indoleamine 2,3-dioxygenase (IDO) and arginase I (ARG), [0002] The present invention relates to compounds and to respectively (Bronte and Zanovello, 2005; Muller et al. , the use of compounds in which the inhibition, regulation 2005b; Muller and Prendergast, 2007; Munn and Mellor, and/or modulation of signal transduction by protein kinases, 2007; Popovic et al. , 2007). in particular immune-modulatory or stress response kinases, [000S] IDO is a single-chain oxidoreductase that catalyzes furthermore to pharmaceutical compositions which comprise the degradation of tryptophan to kynurenine. IDO is not these compounds, and to the use of the compounds for the responsible for catabolizing excess dietary tryptophan but to treatment of kinase-induced diseases. modulate tryptophan level in a local environment. Elevations [0003] Because protein kinases regulate nearly every cel- in tryptophan catabolism in cancer patients manifest in sig- lular process, including metabolism, cell proliferation, cell nificantly altered serum concentration of tryptophan or differentiation, and cell survival, they are attractive targets for catabolites and this was correlated to IDO which is commonly therapeutic intervention for various disease states. For elevated in tumors and draining lymph nodes. According to example, cell-cycle control, immune modulation, stress several publications IDO over-expression is associated with response and angiogenesis, in which protein kinases play a poor prognosis in cancer [Okamoto et al 2005; Brandacher et pivotal role are cellular processes associated with numerous al, 2006]. T cells appear to be preferentially sensitive to IDO disease conditions such as but not limited to cancer, inflam- activation, such that when starved for tryptophan they cannot matory diseases, neurodegenerative diseases, chronic infec- divide and as a result cannot become activated by an antigen tions, abnormal angiogenesis and diseases related thereto, presented to them. Munn and Mellor and their colleagues, atherosclerosis, macular degeneration, diabetes, obesity, and revealed that IDO modulates immunity by suppressing T-cell pain. activation and by creating peripheral tolerance to tumor anti- [0004] Compounds of formula I inhibit the stress response gens (Mellor and Munn, 2004). These mechanism encompass elF2 kinase EIF2AK4 called general control nonderepress- the subversion of immune cells recruited by the tumor cell to ible 2 (GCN2). its immediate microenvironment or to the tumor-draining [0005] Many strategies of cancer treatment of solid tumors lymph nodes Here the tumor antigens that were scavenged by focus on the surgically removal of the tumor mass as far as antigen-presenting cells are cross-presented to the adaptive immune system. In addition to being directly toleragenic, possible and the subsequent eradication of any residual tumor cells by radiotherapy and chemotherapy with cytotoxic mature DCs have the capacity to expand regulatory Tcells agents or inhibitors that target cancer cell pathways more (Tregs) [Moser 2003]. specifically. However, the success of such approach is limited [0009] 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 [0010] 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 [0006] 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 [0011] 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 autophosphory- 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 2016/0002242 A1 Jan. 7, 2016

diminishes the general Cap-dependent translation initiation ever IMT 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. In con- related target genes mainly by cap-independent initiation via trast, the combinatory treatment with IMT and a variety of the activating transcription factor 4 (ATF4). By expressing cytotoxic chemotherapeutic agents elicited regression of the respective stress response proteins, e.g. enzymes in the in established MMTV-neu/HER2 tumors, which responded amino acid metabolism, the cell tries to compensate the par- poorly to any single-agent therapy [Muller et al 2005a]. ticular cell stress [Wek et al. 2006]. If the stress persists, the Immunodepletion of CD4+ or CD8+ T cells from the mice same pathway will switch to promoting cell death via tran- before treatment abolished the combinatorial efficacy scription of the pro-apoptotic transcription factor, CCAAT/ observed in this model, confirming the expectation that IMT 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 IMT action was provided by the demonstration cells altering eIF2aphosphorylation and translational initia- that IMT 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. [0012] 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. metabolic homeostasis in tumor cells. [0018] Specifically, presenilinisanessential for7-secretase [0013] Over all the present biology makes an interference activity. Ohata et al. (2010) describe a role of GCN2-elF2u- with the ARG/IDO pathway attractive for braking up the ATF4 signaling in the regulation of 7-secretase activity in tumoral immune escape by adaptive mechanism. The inter- autophagy impaired cells: The impairment of the autophagy- ference of GCN2 function is here of particular interest as it is lysosomal system may cause amino acid imbalance in the cell a merging point of the two pathways, the IDO and ARG, as because autophagy is required for maintenance of amino acid well as it provides additional opportunities to impede with the level. The autophagy-lysosomal system is discussed as a vital tumor metabolism directly. modulator of 7-secretase activity through GCN2, leading to [0014] Several pathway inhibitors are already considered A[3 accumulation in autophagy deterioration, which may be a as immune modulators. These inhibitors address mainly the possible therapeutic target for reducing A[3 production. enzymatic function of the IDO or ARG proteins (Muller and 7-Secretase plays an important role in the development of Scherle, 2006). The application of the arginase inhibitor, Alzheimer disease (AD). 7-Secretase activity is enriched in N-hydroxy-nor-L-Arg blocks growth of s.c. 3LL lung carci- autophagic vacuoles and it augments amyloid-[3 (A[3) synthe- noma in mice [Rodriguez 2004]. The NO-donating aspirins sts. like NCX 4016 (2-(acetyloxy)-benzoic acid 3-(nitrooxym- [0019] Senile plaques are primarily composed of [3-amy- ethyl)phenyl ester) have been reported to interfere with the loid peptides (A[3) derived from amyloid precursor protein inhibitory enzymatic activities of myeloid cells. Orally (APP) that has undergone proteolytic processing by [3-secre- administered NO aspirin normalized the immune status of tase (BACE-I) and 7-secretase. O' Connor et al. (2008) found tumor-bearing hosts, increased the number and function of that BACE-I levels are translationally increased by phospho- tumor-antigen-specific T lymphocytes, and enhanced the pre- rylation of elF2u. ventive and therapeutic effectiveness of the antitumor immu- [0020] Inhibition of GCN2 under such disease conditions nity elicited by cancer vaccination (DeSanto 2005). that promote activation of7-secretase or induction ofBACE- I [0015] The substrate analogue I methyl-tryptophan (IMT) with consequence of accumulation of A[3 and plaque forma- and related molecules have been used widely to target IDO in tion in the brain would provide a valuable avenue to temper or the cancer context and other settings. Studies by Friberg et al. even stop the progression of neurodegenerative diseases. (2002) and Uyttenhove et al. (2003) demonstrated that IMT [0021] It was described that persistent, not acute, parasite can limit the growth of tumors over-expressing IDO. How- or viral infections are associated to the establishment of US 2016/0002242 A1 Jan. 7, 2016 3

immune privileged conditions of even immune competent increases BACEI levels and promotes amyloidogenesis. host towards the infectious organism or particles. This has Neuron, 60 (2008), pp. 988-1009 been associated to the local induction of IDO expression. [0031] 9. Dey, M., Cao, C., Sicheri, F. and T. E. Dever. Makala et al (J Infect Dis. 2011 Mar. I; 203(5):715-25)show Conserved Intermolecular Salt Bridge Required for Acti- that cutaneous Leishmania major infection stimulated vation of Protein Kinases PKR, GCN2, and PERK. JBC expression of the immune regulatory enzyme indoleamine 282(9): 6653, 2007. 2,3 dioxygenase (IDO) in local lymph nodes. Induced IDO [0032] 10. Dunn, G. P.; Old, L. J.; Schreiber, R. D. The attenuated the T cell stimulatory functions of dendritic cells immunobiology ofcancer immunosurveillance and immu- nomi- and suppressed local T cell responses to exogenous and noediting. Immunity 2004, 21, 137-148. nal parasite antigens. IDO ablation reduced local inflamma- [0033] 11.Fallarino, F. U. Grohmann, S.You, B. C. et al. tion and parasite burdens, as did pharmacologic inhibition of The combined effects fo tryptophan starvation and tryp- IDO in mice with established infections. de Souza Sales (Clin tophan catabolites down-regulate T cell receptor zeta- Exp Immunol. 2011 August; 165(2):251-63)corroborated the chain and induce a regulatory phenotype in na'ive T cells. J. role of indoleamine 2,3-dioxygenase in lepromatous leprosy Immuno1. 176:6752, 2006. immunosuppression. Boasso et al (Blood, 2007 Apr. 15; 109 (8):3351-9)foundthatHIVinhibits CD4+ T-cellproliferation [0034] 12. Friberg M, Jennings R, Alsarraj M, Dessureault S, Cantor A, Extermann M et al. (2002). Indoleamine 2,3- by inducing indoleamine 2,3-dioxygenase in plasmacytoid contributes to tumor cell evasion T cell- dendritic cells and that in vitro inhibition of IDO results in dioxygenase of mediated rejection. Int. J Cancer 101: 151-155 increased CD4(+) T-cell proliferative response in PBMCs from HIV-infected patients [0035] 13.Harding H P, Novoa I, Zhang Y, Zeng H, Wek R, [0022] Inhibitor drugs ofthe IDO/GCN2 pathway could be Schapira M, Ron D. Regulated translation initiation con- used to enhance host immunity to chronic and persistent trols stress-induced gene expression in mammalian cells. infections. Mol Cell. 2000 November; 6(5):1099-108. [0036] 14.Hou DY, Muller A J, Sharma M D, DuHadaway LITERATURE J, Banerjee T, Johnson M et al. (2007). Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoi- [0023] I.Aaltoma, S.H. P. K. Lipponen, andV. M. Kosma. , somers of I-methyl-tryptophan correlates with antitumor 2001. Inducible nitric oxide synthase (iNOS) expression responses. Cancer Res 67: 792-801. and its prognostic value in prostate cancer. Anticancer Res. 21:3101-3106. [0037] 15. Keskinege, A. , S. Elgun, and E.Yilmaz. 2001. Possible implications of arginase and diamine oxidase in [0024] 2. Brandacher, G.; Perathoner, A. ; Ladurner, R.; prostatic carcinoma. Cancer Detect. Prev. 25:76-79. Schneeberger, S.; Obrist, P.; Winkler, C.; Werner, E. R.; Werner-Felmayer, G.; Weiss, H. G.; Gobel, G.; Margreiter, [003S] 16.Mellor A L, Munn D H. (2004). IDO expression dendritic cells: tolerance and catabolism. R.; Konigsrainer, A. ; Fuchs, D.; Amberger, A. Prognostic by tryptophan value of indoleamine 2,3-dioxygenase expression in col- Nat Rev Immunol 4: 762-774. orectal cancer: effect on tumorinfiltrating T cells. Clin. [0039] 17.Mitsuda T, Hayakawa Y, Itoh M, Ohta K, Naka- Cancer Res. 2006, 12, 1144-1151. gawa T. ATF4 regulates gamma-secretase activity during [0025] 3. Bronte V, Zanovello P. (2005). Regulation of amino acid imbalance, Biochem Biophys Res Commun. immune responses by L-arginine metabolism. Nat Rev 2007 Jan. 19; 352(3):722-7. Immunol 5: 641-654. [0040] 18. Moser, M. Dendritic cells in immunity and tol- [0026] 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 [0041] 19. Muller, A. J. and P. A. Scherle. Targeting the alloreactive T cells in tumor-bearing mice. J. Immunol. mechanisms oftumoral immune tolerance with small-mol- 170:270-278. ecule inhibitors. Nat. Rev. Cancer. 6:613,2006. [0027] 5. Bronte, V., P. Serafini, A. Mazzoni, D. M. Segal, [0042] 20. Muller A J, Prendergast G C. (2007). Indoleam- and P. Zanovello. 2003b. L-arginine metabolism in ine 2,3-dioxygenase in immune suppression and cancer. myeloid cells controls T-lymphocyte functions. Trends Curr Cancer Drug Targets 7: 31-40. Immunol. 24:302-306 [0043] 21. Muller A J, DuHadaway J B, Sutanto-Ward E, [002S] 6. Carmela De Santo, Paolo Serafini, Ilaria Marigo, Donover P S, Prendergast G C. (2005a). Inhibition of Luigi Dolcetti, Manlio Bolla, Piero Del Soldato, Cecilia ) indoleamine 2,3-dioxygenase, an immunomodulatory tar- Melani, Cristiana Guiducci, Mario P. Colombo, Manuela get of the tumor suppressor gene Binl, potentiates cancer lezzi, Piero Musiani, Paola Zanovello, and Vincenzo chemotherapy. Nature Med 11:312-319. Bronte. Nitroaspirin corrects immune dysfunction in Muller A Malachowski W Prendergast tumor-bearing hosts and promotes tumor eradication by [0044] 22. J, P, G C. cancer vaccination. Proc Natl Acad Sci USA. 2005 Mar. (2005b). Indoleamine 2,3-dioxygenase in cancer: targeting 15; 102(11):4185-4190 pathological immune tolerance with small-molecule inhibitors. Expert Opin Ther Targets 9: 831-849. [0029] 7. Cederbaum, S. D., H. Yu, W. W. Grody, R. M. Kern, P. Yoo, and R. K. Iyer. 2004. Arginases I and II: do [0045] 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 [0030] 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- [0046] 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 2016/0002242 A1 Jan. 7, 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. [0047] 25. Okamoto, A. ; Nikaido, T.; Ochiai, K.; Takakura, [0061] 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, [0062] It has been found that the compounds according to 6030-6039. the invention and salts thereof have very valuable pharmaco- [0048] 26. Oyadomari S, Mori M. Roles of CHOP/ logical properties while being well tolerated. GADD153 in endoplasmic reticulum stress. Cell Death [0063] 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 [0049] 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. [0050] 28. Popovic P J, Zeh III H J, Ochoa J B. (2007). [0064] Compounds of formula I can also inhibit tyrosine Arginine and immunity. J Nutr 137: 1681S-1686S. kinases FMS (CSFIR), GSK3u, GSK31[3, FLT3 or FLT4 or combinations of these kinases, preferentially in addition to [0051] 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. [0065] 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 [0052] 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 progression. Blood. 109:1568,2007. also be found on cells from patients with chronic myelog- enous leukemia in lymphoid blast crisis. It has been reported [0053] 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 [0054] 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. [0066] reported of FLT3 inhibitors are effective in inducing apoptosis in cell [0055] 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). [0056] 34. Wang, J., M. Torbenson, Q. Wang, J.Y. Ro, and [0067] 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 [0057] 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 [0058] 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 [0059] 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. [0060] The synthesis of small compounds which specifi- [0068] Scott et al (Bioorg. Med Chem Let. (2008) 18 (17)p cally inhibit, regulate and/or modulate signal transduction by 4794) describe CSF-IR inhibitors for the treatment ofcancer. US 2016/0002242 A1 Jan. 7, 2016

CSF-IR is a member ofthe class III receptor tyrosine kinases. [0073] The compounds ofthe formula I can furthermore be Colony stimulatory factor I (CSF-I), also known as mac- used for the isolation and investigation of the activity or rophage/monocyte colony stimulatory factor (M-CSF), binds expression of GCN2, GSK3u, GS 3[3, FMS (CSFIR), FLT3 to CSF-IR, resulting in dimerization, autophosphorylation, or FLT4. In addition, they are particularly suitable for use in and activation of signal transduction. ) CSF-I/CSF-I R signal- diagnostic methods for diseases in connection with unregu- ing is essential for normal monocyte development. In cancer, lated or disturbed GCN2, FMS (CSFIR), GSK3u, GSK3[3, pro-tumorigenic macrophages have been identified and FLT3 or FLT4activity. The host or patient can belong to any linked to poor prognosis in breast, ovarian, and prostate can- mammalian species, for example a primate species, particu- cers. 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 [0074] 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 [0069] 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 [0075] 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 Flt-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 [0070] 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 [0076] 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. [0077] Measurement of the kinase activity is a technique [0071] 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), GSK3u, GSK3[3, 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 [0078] For the identification of kinase inhibitors, various combinations of these kinases. assay systems are available. In scintillation proximity assay [0072] 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 2016/0002242 A1 Jan. 7, 2016

gies are suitable as assay methods (Sills et al. , J. of Biomo- ~Het', NO~, CN, [C(R l~]~COOR, O[C(R l~]~COOR, lecular Screening, 2002, 191-214l. CON(R l~) NR COA NR SO~A SO~N(R l~) S(Ol A [0079] Other non-radioactive ELISA assay methods use COHet', O[C(R l~] Het', NHCOOA, NHCON(R l~, specific phospho-antibodies (phospho-ABsl. The phospho- NHCOO[C(R l~] N(R l~, NHCOO[C(R l~] Het', AB binds only the phosphorylated substrate. This binding can NHCONH[C(R l ] N(R l, NHCONH[C(R l ] Het', be detected by chemiluminescence using a second peroxi- OCONH[C(R l~] N(R l~, OCONH[C(R l~] Het', S(Ol- dase-conjugated anti-sheep antibody (Ross et al. , 2002, Bio- Het', CHO, COA, S and/or 0, chem. J.l. [0089] Het' denotes pyrazolyl, pyridyl, pyrazinyl, indolyl, dihydropyrrolyl, pyrrolidinyl, azetidinyl, oxetanyl, tet- PRIOR ART rahydroimidazolyl, dihydropyrazolyl, tetrahydropyra- zolyl, tetrahydrofuranyl, dihydropyridyl, tetrahydropy- [0080] Other bicyclic aromatic heterocycles are described ridyl, piperidinyl, morpholinyl, hexahydropyridazinyl, in WO 2005/012307 Al, WO 2006/045828 and in WO 2006/ hexahydropyrimidinyl, 3]dioxolanyl, tetrahydropyra- 075023 A2. [1, nyl or erazinyl, each ofwhich is unsub stituted or mono- [0081] Aminopurines are described in WO 2006/076595 pip Al. ordisubstitutedbyHal, A, [C(R l~] OR, O[C(R l~] OR, [C(R l~] N(R l~, [C(R l~] Het, NO~, CN, [C(R l~] ~COOR CON(R NR COA SUMMARY OF THE INVENTION 0[C(R l~]~COOR l~) NR'SO, A, SO,N(R'l„S(Ol A, COHet', O[C(R'l, ] N [0082] The inventionrelates to compounds of the formula I (R l~, O[C(R l~] Het, NHCOOA, NHCON(R l~, NHCOO[C(R l~] N(R l~, NHCOO[C(R l~]~Het, NHCONH[C(R l ] N(R l, NHCONH[C(R l ] Het, OCONH[C(R l~] N(R l~, OCONH[C(R l~] Het, S(Ol- R' Het, CHO, COA, S and/or 0, [0090] Het denotes pyrrolidinyl, azetidinyl, azoxetanyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydro- furanyl, piperidinyl, morpholinyl, tetrahydropyranyl or piperazinyl, each of which is unsubstituted or mono- or disubstituted by Hal, A, OA, CN, COOA, CON H~, S(Ol in which A, S(Ol Ar, COA and/or 0, denotes cycloalkyl with 3-7 C-atoms, which is [0083] X denotes H, CH3 or NH~, [0091] Cyc unsub stituted or mono substituted [0084] R' denotes Ar or Het, by NH~, [0092] A denotes unbranched or branched alkyl with 1-6 [0085] R denotes pyrazolyl, pyrrolidinyl or cyclopentyl, C-atoms, wherein one or two non-adjacent CH- and/or CH~- each of which is unsubstituted or monosubstituted by A, groups may be replaced by N-, 0- and/or S-atoms and Hal, [C(R l ] OR, O[C(R l ] OR, [C(R l ] N(R l, wherein I-7H-atoms may be replaced by F or Cl, [C(R'l,] Ar, [C(R'l,]~Het', CN, [C(R'l,]~COOR', Cyc, [0093] Hal denotes F, Cl, Br or I, CO[C(R l~] N(R l~, CO[C(R l~] Het', NR COA, NR'SO, A, SO,N(R'l„S(Ol A, COHet', O[C(R'l, ] N [0094] n denotes 0, I or 2, m denotes 2 or (R l~, O[C(R l~] Het', NHCOOA, NHCON(R l~, [0095] I, 3, NHCOO[C(R l~] N(R l~, NHCOO[C(R l~]~Het', [0096] p denotes 0, I, 2, 3 or 4, NHCONH[C(R l~] N(R l~, NHCONH[C(R l~] Het', and pharmaceutically usable solvates, salts, tautomers and OCONH[C(R l~] N(R l~, OCONH[C(R l~] Het' or stereoisomers thereof, including mixtures thereof in all ratios. C(0lR, [0097] The invention also relates to the optically active [0086] R denotes H or unbranched or branched alkyl with forms (stereoisomersl, the enantiomers, the racemates, the 1-4 C-atoms, diastereomers and the hydrates and solvates of these com- [0087] Ar denotes phenyl, which is unsub stituted or mono-, pounds. di- or trisubstituted by Hal, A, [C(R l~] OR, O[C(R l~] [0098] The invention also relates to the solvates of the salts ofthe compounds offormula I, e.g. the mono- or dihydrate of ( 'l~], ( 'l~, oI ( 'l~], ( 'l~, I ( 'l~] Het', NO&, CN, [C(R lz] COOR, O[C(R lz] COOR, the hydrochloride. CONH~) CONA CONA~) NR COA NR SO~A SO~N [0099] Moreover, the invention relates to pharmaceutically (R l~, S(Ol A, COHet', O[C(R l~] Het', NHCOOA, acceptable derivatives of compounds of formula I. NHCON(R l~) NHCOO[C(R l~] N(R l~) NHCOO[C [0100] The term solvates of the compounds is taken to (R l~] Het', NHCONH[C(R l~] N(R l~, NHCONH[C mean adductions of inert solvent molecules onto the com- (R l~] Het', OCONH[C(R l~] N(R l~, OCONH[C(R l~] pounds which form owing to their mutual attractive force. Het', S(Ol Het', CHO and/or COA, Solvates are, for example, mono- or dihydrates or alcohol- [00SS] Het denotes furyl, thienyl, pyrrolyl, imidazolyl, ates. pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, [0101] The term pharmaceutically acceptable derivatives is triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, taken to mean, for example, the salts of the compounds pyrazinyl, indolyl, isoindolyl, indolinyl, benzimidazolyl, according to the invention and also so-called prodrug com- indazolyl, quinolyl, isoquinolyl, benzoxazolyl, 1,3-benzo- pounds. dioxolyl, benzothiophenyl, benzo furanyl, imidazopyridyl, [0102] As used herein and unless otherwise indicated, the dihydroindolyl, quinoxalinyl, benzo[1, 2,5]thiadiazolyl or term "prodrug" means a derivative of a compound of formula furo[3, 2-b]pyrldyl, each of which is unsubstituted or I that can hydrolyze, oxidize, or otherwise react under bio- mono- or disubstituted by Hal, A, [C(R l~] OR, O[C(R l logical conditions (in vitro or in vivol to provide an active ', compound, particularly a compound formula ~],o I ( 'l~], ( 'l~, oI ( 'l~], ( 'l~, I ( 'l~] of I. Examples US 2016/0002242 A1 Jan. 7, 2016

of prodrugs include, but are not limited to, derivatives and [0111] Above and below, the radicals R' and R have the metabolites of a compound of formula I that include biohy- meanings indicated for the formula I, unless expressly stated drolyzable moieties such as biohydrolyzable amides, biohy- otherwise. drolyzable esters, biohydrolyzable carbamates, biohydrolyz- able carbonates, biohydrolyzable ureides, and [0112] A denotes alkyl, this is unbranched (linear) or biohydrolyzable phosphate analogues. In certain embodi- branched, and has I, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A ments, prodrugs of compounds with carboxyl functional preferably denotes methyl, furthermore ethyl, propyl, isopro- groups are the lower alkyl esters of the carboxylic acid. The pyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also carboxylate esters are conveniently formed by esteri fying any pentyl, I-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpro- of the carboxylic acid moieties present on the molecule. Pro- trifluoro pyl, l-ethylpropyl, hexyl, I-, 2-, 3- or 4-methylpentyl, 1,1-, drugs can typically be prepared using well-known methods, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, I- or 2-ethylbutyl, such as those described by Burger' s Medicinal Chemistry and l-ethyl-l-methylpropyl, l-ethyl-2-methylpropyl, 1,1,2- or Drug Discovery 6th ed. (Donald J.Abraham ed. , 2001, Wiley) 2,2-trimethylpropyl, furthermore preferably, for example, and Design and Application of Prodrugs (H. Bundgaard ed. , 1, 1985, Harwood Academic Publishers Gmfh). methy. [0103] The expression "effective amount" denotes the [0113] A very particularly preferably denotes alkyl having amount of a medicament or of a pharmaceutical active ingre- 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, dient which causes in a tissue, system, animal or human a I, propyl, sec-butyl, tert-butyl, biological or medical response which is sought or desired, for isopropyl, butyl, isobutyl, pentyl, hexyl, example, by a researcher or physician. trifluoromethyl, pentafluoroethyl or I,I,I -trifluoroethyl. [0104] In addition, the expression "therapeutically effec- Moreover, A denotes e.g. CH~OCH3, CH~CH~OH, tive amount" denotes an amount which, compared with a OCH, CH, NH„CH,NHCH, or NHCH, CH, . corresponding subject who has not received this amount, has with 3-7 C-atoms denotes the following consequence: [0114] Cycloalkyl preferably [0105] improved treatment, healing, prevention or elimina- cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclo- tion of a disease, syndrome, condition, complaint, disorder or heptyl. side-effects or also the reduction in the advance of a disease, [0115] R' preferably denotes Ar. complaint or disorder. [0106] The expression "therapeutically effective amount" [0116] R preferably denotes pyrazolyl, pyrrolidinyl or also encompasses the amounts which are effective for cyclopentyl, each of which is unsubstituted or monosubsti- increasing normal physiological function. tuted by A, [C(R'),] Ar, [C(R'),] Het', Cyc, [C(R'),] OR', [0107] The invention also relates to the use of mixtures of CO[C(R )~] N(R )~ or CO[C(R )~] Het'. the compounds of the formula I, for example mixtures oftwo diastereomers, for example in the ratio I:I, I:2, I:3, I:4, I:5, [0117] R preferably denotes H or alkyl having I, 2, 3 or 4 I:10,I:100or I:1000. C atoms, particularly preferably H or methyl. These are mixtures stere- [010S] particularly preferably of [011S] Ar denotes, for example, o-, m- or p-tolyl, o-, m- or oisomeric compounds. p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopro- [0109] "Tautomers" refers to isomeric forms of a com- pylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydrox- pound that are in equilibrium with each other. The concen- yphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, trations ofthe isomeric forms will depend on the environment m- or p-(N-methylamino)phenyl, o-, m- or p-(N-methylami- the compound is found in and may be different depending o-, m- or p-methoxyphenyl, o-, m- or upon, for example, whether the compound is a solid or is in an nocarbonyl)phenyl, m- m- organic or aqueous solution. p-ethoxyphenyl, o-, or p-ethoxycarbonyl-phenyl, o-, or [0110] The invention relates to the compounds of the for- p-(N, N-dimethylamino)phenyl, o-, m- or p-(N, N-dimethyl- mula I and salts thereof and to a process for the preparation of aminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl, compounds of the formula I and pharmaceutically usable o-, m- or p-(N, N-diethylamino)phenyl, o-, m- or p-fluorophe- salts, solvates, tautomers and stereoisomers thereof, charac- nyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, terised in that m- or p-(methylsulfonamido)phenyl, o-, m- or p-(methyl- a) wherein in formula I X denotes H, sul fonyl)phenyl, o-, m- or p-cyanophenyl, o-, m- or p-carbox- a compound of the formula II yphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-formylphenyl, o-, m- or p-acetylphenyl, o-, m- or p-amino- sulfonylphenyl, o-, m- or p-[2-(morpholin-4-yl)ethoxy]phe- nyl, o-, m- or p-[3-(N, N-diethylamino)propoxy]phenyl, fur- R' thermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- H / 4- 5- N N NH difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3, or 3, R~ dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4- N dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4- NHp chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5- chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N, N- in which R' and R have the meanings indicated in Claim 1, dimethylamino- or 3-nitro-4-N, N-dimethylamino-phenyl, is reacted with trimethyl- or triethylorthoformate 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-tri- or chlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3, 5- b) wherein in formula I X denotes NH~, dichlorophenyl, p-iodo-phenyl, 3,6-dichloro-4-aminophe- a compound of the formula II is reacted with CN Br nyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5- and/or difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, a base or acid ofthe formula I is converted into one of its salts. 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, US 2016/0002242 A1 Jan. 7, 2016

3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, [C(R'),]~Ar, [C(R'),]~Het', Cyc, [C(R'),]~OR', CO[C 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophe- (R )~]~N(R )~ or CO[C(R )~]~Het', nyl. [0137] R denotes H or unbranched or branched alkyl [0119] Ar furthermore preferably denotes phenyl, which is with 1-4 C-atoms, unsubstituted or mono-, di- or tri substituted by Hal, A, [C(R ) [0138] Ar denotes phenyl, which is unsubstituted or ~]~OR, O[C(R )~]~OR, [C(R )~]~Het', CONH~, CONA mono-, di- or trisubstituted by Hal, A, [C(R )~] OR, and/or CONA~. O[C(R )~]~OR, [C(R )~]~Het', CONH~, CONA and/or [0120] Het preferably denotes pyrazolyl, pyridyl, indolyl, CONA~, isoindolyl, indolinyl, quinolyl or isoquinolyl, each ofwhich is [0139] Het denotes pyrazolyl, pyridyl, indolyl, isoin- unsubstituted or mono- or disubstituted by A and/or O. dolyl, indolinyl, quinolyl or isoquinolyl, each of which [0121] Furthermore, Het preferably denotes pyrazolyl, is unsubstituted or mono- or disubstituted by A and/or pyridyl, indolyl, isoindolyl, quinolyl or isoquinolyl, each of 0, which is unsub stituted or mono- or di substituted by A, or Het [0140] Het' denotes pyrazolyl, pyridyl, pyrrolidinyl, denotes indolinyl, which is unsubstituted or mono- or disub- piperidinyl, morpholinyl, tetrahydropyranyl or piperazi- stituted by A and/or O. nyl, each of which is unsubstituted or mono- or disub- [0122] Het' preferably denotes pyrazolyl, pyridyl, pyrro- stituted by A and/or [C(R )~] Het, lidinyl, piperidinyl, morpholinyl, tetrahydropyranyl or piper- [0141] Het denotes pyrrolidinyl, piperidinyl, morpholi- azinyl, each of which is unsubstituted or mono- or disubsti- nyl or piperazinyl, each of which is unsubstituted or tuted by A and/or [C(R )~] Het, mono substituted by A, [0123] Het preferably denotes pyrrolidinyl, azetidinyl, [0142] A denotes unbranched or branched alkyl with 1-6 azoxetanyl, tetrahydroimidazolyl, tetrahydropyrazolyl, tet- C-atoms, wherein one or two non-adjacent CH- and/or rahydrofuranyl, piperidinyl, morpholinyl, tetrahydropyranyl CH~-groups may be replaced by N-, 0- and/or S-atoms or piperazinyl, each of which is unsubstituted or mono- or and wherein I-7H-atoms may be replaced by F or Cl, disubstituted by A. [0143] Hal denotes F, Cl, Br or I, [0124] Het furthermore preferably denotes pyrrolidinyl, [0144] n denotes 0, I or 2, piperidinyl, morpholinyl or piperazinyl, each of which is [0145] m denotes I, 2 or 3, unsubstituted or monosubstituted by A. [0146] p denotes 0, I, 2, 3 or 4 [0125] Het very particularly preferably denotes piperidi- and pharmaceutically acceptable salts, solvates, tautomers nyl. and stereoisomers thereof, including mixtures thereof in all [0126] Hal preferably denotes F, Cl or Br, but also I, par- ratios. ticularly preferably F or Cl. [0147] The compounds of the formula I and also the start- [0127] Throughout the invention, all radicals which occur ing materials for their preparation are, in addition, prepared more than once may be identical or different, i.e. are indepen- by methods known per se, as described in the literature (for dent of one another. example in the standard works, such as Houben-Weyl, Meth- [0128] The compounds of the formula I may have one or oden der organischen Chemic [Methods of Organic Chemis- more chiral centres and can therefore occur in various stere- try], Georg-Thieme-Verlag, Stuttgart), to be precise Use can oisomeric forms. The formula I encompasses all these forms. also be made here of variants known per se which are not [0129] Accordingly, the invention relates, in particular, to mentioned here in greater detail. the compounds of the formula I in which at least one of the [0148] The starting compounds of the formulae II are gen- said radicals has one of the preferred meanings indicated erally known. Ifthey are novel, however, they can be prepared above. Some preferred groups of compounds may be by methods known per se. expressed by the following sub-formulae Ia to Id, which [0149] Compounds of the formula I can preferably be conform to the formula I and in which the radicals not desig- obtained by reacting a compound of the formula II with nated in greater detail have the meaning indicated for the trimethyl- or triethylorthoformate or with CN Br. formula I, but in which [0150] The reaction is generally carried out under condi- [0130] in Ia R denotes pyrazolyl, pyrrolidinyl or cyclopen- tions known to the skilled artisan and which are known and tyl, each of which is unsubstituted or monosubstituted by suitable for the this reaction. A, [C(R'),] Ar, [C(R'),]~Het', Cyc, [C(R'),]~OR', CO[C [0151] Depending on the conditions used, the reaction time (R )~]~N(R )~ or CO[C(R )~]~Het', is between a few minutes and 14 days, the reaction tempera- [0131] in Ib Ar denotes phenyl, which is unsubstituted or ture is between about 0' and 140', normally between 20' and mono-, di- or trisubstituted by Hal, A, [C(R )~] OR, O[C 120', in particular between about 80' and about 110'. (R )~] OR, [C(R )~] Het', CONH~, CONA and/or Examples of suitable inert solvents are hydrocarbons, such as CONA~; hexane, petroleum ether, benzene, toluene or xylene; chlori- [0132] in Ic Het denotes pyrazolyl, pyridyl, indolyl, isoin- nated hydrocarbons, such as trichloroethylene, 1,2-dichloro- dolyl, indolinyl, quinolyl or isoquinolyl, each of which is ethane, carbon tetrachloride, chloroform or dichloromethane; unsub stituted or mono- or di substituted by A and/or 0; alcohols, such as methanol, ethanol, isopropanol, n-propanol, [0133] in Ic Het' denotes pyrazolyl, pyridyl, pyrrolidinyl, n-butanol or tert-butanol; ethers, such as diethyl ether, diiso- piperidinyl, morpholinyl, tetrahydropyranyl or piperazi- propyl ether, tetrahydrofuran (THF) or dioxane; glycol nyl, each of which is unsubstituted or mono- or disubsti- ethers, such as ethylene glycol monomethyl or monoethyl tuted by A and/or [C(R )~] Het; ether, ethylene glycol dimethyl ether (diglyme); ketones, [0134] in Id R' denotes Ar or Het, such as acetone or butanone; amides, such as acetamide, [0135] X denotes H, CH3 or NH~, dimethylacetamide or dimethylformamide (DMF); nitriles, [0136] R denotes pyrazolyl, pyrrolidinyl or cyclopentyl, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide each of which is unsubstituted or monosubstituted by A, (DMSO); carbon disulfide; carboxylic acids, such as formic US 2016/0002242 A1 Jan. 7, 2016

acid or acetic acid; nitro compounds, such as nitromethane or of such groups are the above-mentioned unsubstituted or nitrobenzene; esters, such as ethyl acetate, or mixtures of the substituted aryl, aralkyl or acyl groups, furthermore also alkyl said solvents. groups. The nature and size ofthe hydroxylprotecting groups [0152] Particular preference is given to acetonitril and are not crucial since they are removed again after the desired water. chemical reaction or reaction sequence; preference is given to [0153] Free amino groups can furthermore be acylated in a groups having 1-20, in particular 1-10, carbon atoms. conventional manner using an acid chloride or anhydride or Examples of hydroxylprotecting groups are, inter alia, tert- alkylated using an unsubstituted or substituted alkyl halide, butoxycarbonyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl, advantageously in an inert solvent, such as dichloromethane tert-butyl and acetyl, where benzyl and tert-butyl are particu- or THF, and/or in the presence of a base, such as triethylamine larly preferred. The COOH groups in aspartic acid and or pyridine, at temperatures between —60 and +30'. glutamic acid are preferably protected in the form of their [0154] The compounds ofthe formula I can furthermore be tert-butyl esters (for example Asp(OBut)). obtained liberating them from their functional derivatives by [0160] The compounds of the formula I are liberated from solvolysis, in particular hydrolysis, or hydrogenolysis. by by their functional derivatives~epending on the protecting [0155] Preferred starting materials for the solvolysis or group used for example using strong acids, advantageously hydrogenolysis are those which contain corresponding pro- using TFA or perchloric acid, but also using other strong tected amino and/or instead one or more hydroxyl groups of inorganic acids, such as hydrochloric acid or sulfuric acid, free amino and/or preferably those which hydroxyl groups, strong organic carboxylic acids, such as trichloroacetic acid, carry an aminoprotecting instead of an H atom bonded group or sulfonic acids, such as benzene- or p-toluenesulfonic acid. to an N for those which conform to the formula atom, example The presence of an additional inert solvent is possible, but is but contain an NHR' which R' is an aminopro- I, group (in not always necessary. Suitable inert solvents are preferably tecting for example BOC or instead of an NH~ group, CBZ) organic, for example carboxylic acids, such as acetic acid, group. ethers, such as tetrahydrofuran or dioxane, amides, such as [0156] Preference is furthermore given to starting materials DMF, halogenated hydrocarbons, such as dichloromethane, which carry a hydroxylprotecting group instead ofthe H atom furthermore also alcohols, such as methanol, ethanol or iso- of a hydroxyl group, for example those which conform to the and water. Mixtures of the above-mentioned sol- R" R" propanol, formula I, but contain an 0-phenyl group (in which is a vents are furthermore suitable. TFA is preferably used in hydroxylprotecting group) instead ofa hydroxyphenyl group. excess without addition of a further solvent, and perchloric [0157] It is also possible for a plurality of identical or acid is preferably used in the form of a mixture of acetic acid different protected amino and/or hydroxyl groups to be and 70% perchloric acid in the ratio 9:1.The reaction tem- present in the molecule ofthe starting material. Ifthe protect- peratures for the cleavage are advantageously between about ing groups present are different from one another, they can in 0 and about 50', preferably between 15 and 30' (room tem- many cases be cleaved off selectively. perature). [0158] The term "aminoprotecting group" is known in gen- The BOC, OBut, Pbf, Pmc and Mtr groups can, for eral terms and relates to groups which are suitable for pro- [0161] example, preferably be cleaved off using TFA in dichlo- tecting (blocking) an amino group against chemical reac- romethane or using approximately 3 to 5N HCI in dioxane at tions, but are easy to remove after the desired chemical 15-30', and the FMOC can be cleaved off using an reaction has been carried out elsewhere in the molecule. Typi- group approximately 5 to 50% solution of dimethylamine, diethy- cal of such groups are, in particular, unsubstituted or substi- lamine or piperidine in DMF at 15-30'. tuted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the aminoprotecting groups are removed after the desired reac- [0162] The trityl group is employed to protect the amino tion (or reaction sequence), their type and size are further- acids histidine, asparagine, glutamine and cysteine. They are more not crucial; however, preference is given to those having cleaved off, depending on the desired end product, using 1-20, in particular 1-8, carbon atoms. The term "acyl group" TFA/10% thiophenol, with the trityl group being cleaved off is to be understood in the broadest sense in connection with from all the said amino acids; on use of TFA/anisole or the present process. It includes acyl groups derived from TFA/thioanisole, only the trityl group of His, Asn and Gin is aliphatic, araliphatic, aromatic or heterocyclic carboxylic cleaved off, whereas it remains on the Cys side chain. acids or sulfonic acids, and, in particular, alkoxycarbonyl, The Pbf (pentamethylbenzofuranyl) is aryloxycarbonyl and especially aralkoxycarbonyl groups. [0163] group employed to protect Arg. It is cleaved off using, for example, Examples of such acyl groups are alkanoyl, such as acetyl, TFA in dichloromethane. propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyl, such as [0164] Hydrogenolytically removable protecting groups POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycar- (for example CBZ or benzyl) can be cleaved off, for example, bonyl, 2,2,2-trichloroethoxycarbonyl, BOC and 2-iodoet- by treatment with hydrogen in the presence of a catalyst (for hoxycarbonyl; aralkoxycarbonyl, such as CBZ ("carboben- example a noble-metal catalyst, such as palladium, advanta- zoxy"), 4-methoxybenzyloxycarbonyl and FMOC; and geously on a support, such as carbon). Suitable solvents here arylsulfonyl, such as Mtr, Pbf and Pmc. Preferred aminopro- are those indicated above, in particular, for example, alcohols, tecting groups are BOC and Mtr, furthermore CBZ, Fmoc, such as methanol or ethanol, or amides, such as DMF. The benzyl and acetyl. hydrogenolysis is generally carried out at temperatures [0159] The term "hydroxylprotecting group" is likewise between about 0 and 100' and pressures between about I and known in general terms and relates to groups which are suit- 200 bar, preferably at 20-30' and 1-10bar. Hydrogenolysis of able for protecting a hydroxyl group against chemical reac- the CBZ group succeeds well, for example, on 5 to 10%Pd/C tions, but are easy to remove after the desired chemical reac- in methanol or using ammonium formate (instead of hydro- tion has been carried out elsewhere in the molecule. Typical gen) on Pd/C in methanol/DMF at 20-30'. US 2016/0002242 A1 Jan. 7, 2016 10

Pharmaceutical Salts and Other Forms mine, diethylamine, 2-diethylaminoethanol, 2-dimethylami- noethanol, ethanolamine, ethylenediamine, [0165] The said compounds according to the invention can N-ethylmorpholine, N-ethylpiperidine, glucamine, glu- be used in their final non-salt form. On the other hand, the cosamine, histidine, hydrabamine, isopropylamine, present invention also encompasses the use of these com- lidocaine, lysine, meglumine, N-methyl-D-glucamine, mor- pounds in the form oftheir pharmaceutically acceptable salts, pholine, piperazine, piperidine, polyamine resins, procaine, which can be derived from various organic and inorganic purines, theobromine, triethanolamine, triethylamine, trim- acids and bases procedures known in the art. Pharmaceu- by ethylamine, tripropylamine and tris(hydroxymethyl)methy- tically acceptable salt forms of the compounds ofthe formula lamine (tromethamine), but this is not intended to represent a I are for the most part prepared conventional methods. If by restriction. the compound ofthe formula I contains a carboxyl group, one of its suitable salts can be formed by reacting the compound [0167] 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,-C4)alkyl halides, for example methyl, including potassium hydroxide, sodium hydroxide and ethyl, isopropyl and tert-butyl chloride, bromide and iodide; lithium hydroxide; alkaline earth metal hydroxides, such as di(C, -C4)alkyl sulfates, for example dimethyl, diethyl and barium hydroxide and calcium hydroxide; alkali metal alkox- diamyl sulfate; (C,o-C, s)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, -C4)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 [016S] The above-mentioned pharmaceutical salts which acceptable organic and inorganic acids, for example hydro- are preferred include acetate, trifluoroacetate, besylate, cit- gen halides, such as hydrogen chloride, hydrogen bromide or rate, fumarate, gluconate, hemisuccinate, hippurate, hydro- hydrogen iodide, other mineral acids and corresponding salts chloride, hydrobromide, isethionate, mandelate, meglumine, thereof, such as sulfate, nitrate or phosphate and the like, and nitrate, oleate, phosphonate, pivalate, sodium phosphate, alkyl- and monoarylsulfonates, such as ethanesulfonate, tolu- stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate enesulfonate and benzenesulfonate, and other organic acids and tromethamine, but this is not intended to represent a and corresponding salts thereof, such as acetate, trifluoroac- restriction. etate, tartrate, maleate, succinate, citrate, benzoate, salicy- [0169] Particular preference is given to hydrochloride, late, ascorbate and the like. Accordingly, pharmaceutically dihydrochloride, hydrobromide, maleate, mesylate, phos- acceptable acid-addition salts of the compounds of the for- phate, sulfate and succinate. mula I include the following: acetate, adipate, alginate, argin- [0170] The acid-addition salts of basic compounds of the ate, aspartate, benzoate, benzenesulfonate (besylate), bisul- formula I are prepared by bringing the free base form into fate, bisulfite, bromide, butyrate, camphorate, camphor- contact with a sufficient amount of the desired acid, causing sulfonate, caprylate, chloride, chlorobenzoate, citrate, the formation of the salt in a conventional manner. The free cyclopentanepropionate, digluconate, dihydrogenphosphate, base can be regenerated by bringing the salt form into contact dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, with a base and isolating the free base in a conventional galacterate (from mucic acid), galacturonate, gluco-hep- manner. The free base forms differ in a certain respect from tanoate, gluconate, glutamate, glycerophosphate, hemisucci- the corresponding salt forms thereof with respect to certain nate, hemi-sulfate, heptanoate, hexanoate, hippurate, hydro- physical properties, such as solubility in polar solvents; for chloride, hydrobromide, hydroiodide, the purposes of the invention, however, the salts otherwise 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, correspond to the respective free base forms thereof. lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, mono- [0171] As mentioned, the pharmaceutically acceptable hydrogenphosphate, 2-naphthalenesulfonate, nicotinate, base-addition salts of the compounds of the formula I are nitrate, oxalate, oleate, palmoate, pectinate, persulfate, phe- formed with metals or amines, such as alkali metals and nylacetate, 3-phenylpropionate, phosphate, phosphonate, alkaline earth metals or organic amines. Preferred metals are phthalate, but this does not represent a restriction. sodium, potassium, magnesium and calcium. Preferred [0166] Furthermore, the base salts of the compounds organic amines are N, N'-dibenzylethylenediamine, chlorop- according to the invention include aluminium, ammonium, rocaine, choline, diethanolamine, ethylenediamine, N-me- calcium, copper, iron(III), iron(II), lithium, magnesium, thyl-D-glucamine and procaine. manganese(III), manganese(II), potassium, sodium and zinc [0172] The base-addition salts of acidic compounds salts, but this is not intended to represent a restriction. Of the according to the invention are prepared by bringing the free above-mentioned salts, preference is given to ammonium; the acid form into contact with a sufficient amount of the desired alkali metal salts sodium and potassium, and the alkaline base, causing the formation of the salt in a conventional earth metal salts calcium and magnesium. Salts of the com- manner. The free acid can be regenerated by bringing the salt pounds of the formula I which are derived from pharmaceu- form into contact with an acid and isolating the free acid in a tically acceptable organic non-toxic bases include salts of conventional manner. The free acid forms differ in a certain primary, secondary and tertiary amines, substituted amines, respect from the corresponding salt forms thereof with also including naturally occurring substituted amines, cyclic respect to certain physical properties, such as solubility in amines, and basic ion exchanger resins, for example arginine, polar solvents; for the purposes ofthe invention, however, the betaine, caffeine, chloroprocaine, choline, N, N'-dibenzyleth- salts otherwise correspond to the respective free acid forms ylenediamine (benzathine), dicyclohexylamine, diethanola- thereof. US 2016/0002242 A1 Jan. 7, 2016

[0173] 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 of this type, the invention also 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 example, bitartrate, diacetate, difumarate, dime- Exchange of a heavier isotope usually results in a lowering of glumine, diphosphate, disodium and trihydrochloride, but 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 [0174] With regard to that stated above, it can be seen that bond breakage occurs in or in the vicinity of a saddle-point the expression "pharmaceutically acceptable salt" 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 [0177] 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- dative metabolism of this which in turn permits the [0175] There is furthermore intended that a compound of type, rational deuterated compounds the formula with the formula I includes isotope-labelled forms thereof. An design of of I improved stability through resistance to such oxidative meta- isotope-labelled form of a compound of the formula I is bolism. Significant improvements in the pharmacokinetic identical to this compound apart from the fact that one or profiles of compounds of the formula I are thereby obtained, more atoms of the compound have been replaced by an atom and can be expressed quantitatively in terms of increases in or atoms having an atomic mass or mass number which dif- the in vivo half-life concentration at maximum thera- fers from the atomic mass or mass number of the atom which (t/2), peutic effect area under the dose response curve usually occurs naturally. Exam-pies of isotopes which are (C ), and and in terms reduced clearance, dose and readily commercially available and which can be incorpo- (AUC), F; of materials costs. rated into a compound of the formula I by well-known meth- ods include isotopes of hydrogen, carbon, nitrogen, [0178] The following is intended to illustrate the above: a oxygen,' phos-phorus, fluo-rine and chlorine, for example H, H, C, compound ofthe formula I which has multiple potential sites ' ' ' ' ' C N 0 0 'P P S F and Cl, respectively. A of attack for oxidative metabolism, for example benzylic compound of the formula I, a prodrug, thereof or a pharma- hydrogen atoms and hydrogen atoms bonded to a nitrogen ceutically acceptable salt of either which contains one or atom, is prepared as a series of analogues in which various more of the above-mentioned isotopes and/or other iso-topes combinations of hydrogen atoms are replaced by deuterium of other atoms is intended to be part of the present invention. atoms, so that some, most or all ofthese hydrogen atoms have An isotope-labelled compound ofthe formula I can be used in been replaced by deuterium atoms. Half-life determinations a number of beneficial ways. For example, an isotope-la- enable favourable and accurate determination ofthe extent of belled compound of the formula I into which, for example, a the extent to which the improve-ment in resistance to oxida- radioisotope, such as H or ' C, has been incorporated is tive metabolism has improved. In this way, it is deter-mined suitable for medicament and/or substrate tissue distribution that the half-life of the parent compound can be extended by assays. These radioisotopes, i.e. tritium ( H) and carbon-14 up to 100% as the result of deuterium-hydrogen exchange of (' C), are particularly preferred owing to simple preparation this type. and excellent detectability. Incor-po-ra-tion of heavier iso- [0179] Deuterium-hydrogen exchange in a compound of topes, for example deuterium ( H), into a compound of the the formula I can also be used to achieve a favourable modi- formula I has therapeutic advantages owing to the higher fication of the metabolite spectrum of the starting compound metabolic stability ofthis isotope-labelled compound. Higher in order to diminish or eliminate undesired toxic metabolites. metabolic stability translates directly into an increased in vivo For example, if a toxic metabolite arises through oxidative half-life or lower dosages, which under most circumstances carbon-hydrogen (C H) bond cleavage, it can reasonably be would represent a preferred embodi-ment of the present assumed that the deuterated analogue will greatly diminish or invention. An isotope-labelled compound ofthe formula I can eliminate production of the unwanted metabolite, even if the usually be prepared by carrying out the procedures dis-closed particular oxidation is not a rate-determining step. Further in the synthesis schemes and the related description, in the information on the state of the art with respect to deuterium- example part and in the preparation part in the present text, hydrogen exchange may be found, for example in Hanzlik et replacing a non-isotope-labelled reactant by a readily avail- al. , J. Org. Chem. 55, 3992-3997, 1990, Reider et al. , J. Org. able isotope-labelled reactant. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, [0176] Deuterium ( H) can also be incorporated into a com- 1985, Gillette et al, Biochemistry 33(10) 2927-2937, 1994, pound of the formula I for the purpose in order to manipulate and Jarman et al. Carcinogenesis 16(4), 683-688, 1993. the oxidative metabolism of the compound by way of the [0180] The invention furthermore relates to medicaments primary kinetic isotope effect. The primary kinetic isotope comprising at least one compound of the formula I and/or US 2016/0002242 A1 Jan. 7, 2016 12

pharmaceutically acceptable salts, solvates, tautomers and and the like. The disintegrants include, without being stereoi somers thereof, including mixtures thereof in all ratios, restricted thereto, starch, methylcellulose, agar, bentonite, and optionally excipients and/or adjuvants. xanthan gum and the like. The tablets are formulated by, for [01S1] Pharmaceutical formulations can be administered in example, preparing a powder mixture, granulating or dry- the form of dosage units which comprise a predetermined 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 mg to I g, preferably I mg to 700 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, depending on the condition 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 of the patient, or pharmaceutical formulations can a dissolution retardant, such as, for example, paraffin, an be administered in the form of dosage units which comprise a 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 using a process which is generally known in the pharmaceu- alternative to granulation, the powder mixture can be run tical art. through a tabletting machine, giving lumps of non-uniform [01S2] 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- [01S3] Pharmaceutical formulations adapted for oral mer material and a gloss layer of wax may be present. Dyes administration can be administered as separate units, such as, can be added to these coatings in order to be able to differen- for example, capsules or tablets; powders or granules; solu- tiate between different dosage units. tions or suspensions in aqueous or non-aqueous liquids; [01S7] Oral liquids, such as, for example, solution, syrups edible foams or foam foods; or oil-in-water liquid emulsions and elixirs, can be prepared in the form ofdosage units so that or water-in-oil liquid emulsions. a given quantity comprises a pre-specified amount of the [01S4] Thus, for example, inthe case of oral administration compound. Syrups can be prepared by dissolving the com- in the form of a tablet or capsule, the active-ingredient com- pound in an aqueous solution with a suitable flavour, while ponent can be combined with an oral, non-toxic and pharma- elixirs are prepared using a non-toxic alcoholic vehicle. Sus- ceutically acceptable inert excipient, such as, for example, pensions can be formulated by dispersion ofthe compound in ethanol, glycerol, water and the like. Powders are prepared by a non-toxic vehicle. Solubilisers and emulsifiers, such as, for comminuting the compound to a suitable fine size and mixing example, ethoxylated isostearyl alcohols and polyoxyethyl- it with a pharmaceutical excipient comminuted in a similar ene sorbitol ethers, preservatives, flavour additives, such as, manner, such as, for example, an edible carbohydrate, such for example, peppermint oil or natural sweeteners or saccha- as, for example, starch or mannitol. A flavour, preservative, rin, or other artificial sweeteners and the like, can likewise be dispersant and dye may likewise be present. added. [01S5] Capsules are produced by preparing a powder mix- [01SS] The dosage unit formulations for oral administra- ture as described above and filling shaped gelatine shells tion can, if desired, be en-capsulated in microcapsules. The therewith. Glidants and lubricants, such as, for example, formulation can also be prepared in such a way that the highly disperse silicic acid, talc, magnesium stearate, calcium release is extended or retarded, such as, for example, by stearate or polyethylene glycol in solid form, can be added to coating or embedding of particulate material in polymers, the powder mixture before the filling operation. A disinte- wax and the like. grant or solubiliser, such as, for example, agar-agar, calcium [01S9] The compounds of the formula I and salts, solvates, carbonate or sodium carbonate, may likewise be added in tautomers and stereoisomers thereof can also be administered order to improve the availability of the medicament after the in the form of liposome delivery systems, such as, for capsule has been taken. example, small unilamellar vesic les, large uni lamellar [01S6] In addition, if desired or necessary, suitable binders, vesicles and multilamellar vesicles. Liposomes can be lubricants and disintegrants as well as dyes can likewise be formed from various phospholipids, such as, for example, incorporated into the mixture. Suitable binders include cholesterol, stearylamine or phosphatidylcholines. starch, gelatine, natural sugars, such as, for example, glucose [0190] The compounds of the formula I and the salts, sol- or beta-lactose, sweeteners made from maize, natural and vates, tautomers and stereoisomers thereof can also be deliv- synthetic rubber, such as, for example, acacia, tragacanth or ered using monoclonal antibodies as individual carriers to sodium alginate, carboxymethylcellulose, polyethylene gly- which the compound molecules are coupled. The compounds col, waxes, and the like. The lubricants used in these dosage can also be coupled to soluble polymers as targeted medica- forms include sodium oleate, sodium stearate, magnesium ment carriers. Such polymers may encompass polyvinylpyr- stearate, sodium benzoate, sodium acetate, sodium chloride rolidone, pyran copolymer, polyhydroxypropylmethacryla- US 2016/0002242 A1 Jan. 7, 2016 13

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 [0201] It goes without saying that, in addition to the above controlled release of a medicament, for example polylactic particularly mentioned constituents, the formulations may acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, also comprise other agents usual in the art with respect to the polyorthoesters, polyacetals, polydihydroxypyrans, polycy- particular type of formulation; thus, for example, formula- anoacrylates and crosslinked or amphipathic block copoly- tions which are suitable for oral administration may comprise mers of hydrogels. flavours. [0191] Pharmaceutical formulations adapted for transder- [0202] 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, [0192] 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, [0193] 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 [0194] Pharmaceutical formulations adapted for topical can be assumed that similar doses are suitable for the treat- application to the eye include eye drops, in which the active ment of other conditions mentioned above. ingredient is dissolved or suspended in a suitable carrier, in [0203] The disclosed compounds of the formula I can be particular an aqueous solvent. administered in combination with other known therapeutic [0195] Pharmaceutical formulations adapted for topical agents including agents for the treatment of RA (rheumatoid application in the mouth encompass lozenges, pastilles and arthritis). As used here, the term "agents for the treatment of mouthwashes. RA" relates to any agent which is administered to a patient [0196] Pharmaceutical formulations adapted for rectal with RA for the purposes of treating the RA. administration can be administered in the form of supposito- [0204] The medicaments below are preferably, but not ries or enemas. exclusively, combined with the compounds of the formula I: [0197] Pharmaceutical formulations adapted for nasal 1.NSAIDs (non-steroidal anti-inflammatory drugs) and anal- administration in which the carrier substance is a solid com- gesics prise a coarse powder having a particle size, for example, in 2. Glucocorticoids (low oral doses) the range 20-500 microns, which is administered in the man- 3. Conventional disease-modifying antirheumatic drugs ner in which snuff is taken, i.e. by rapid inhalation via the (DMARDs) nasal passages from a container containing the powder held [0205] Methotrexate close to the nose. Suitable formulations for administration as [0206] Leflunomide nasal spray or nose drops with a liquid as carrier substance [0207] Sulfasalazine encompass active-ingredient solutions in water or oil. [0208] Hydroxycloroquine [0198] Pharmaceutical formulations adapted for adminis- [0209] Azathioprine tration by inhalation encompass finely particulate dusts or [0210] Ciclosporin mists, which can be generated by various types ofpressurised [0211] Minocycline dispensers with aerosols, nebulisers or insuflIators. [0212] Gold [0199] Pharmaceutical formulations adapted for vaginal 4. Biologic response modifiers (BRMs)—&target molecules/ administration can be administered as pessaries, tampons, immune cells involved in the inflammatory process, and creams, gels, pastes, foams or spray formulations. include the following agents: [0200] Pharmaceutical formulations adapted for parenteral [0213] TNF inhibitors administration include aqueous and non-aqueous sterile [0214] etanercept (Enbrel) bacte- injection solutions comprising antioxidants, buffers, [0215] infliximab (Remicade) riostatics and solutes, means of which the formulation is by [0216] adalimumab (Humira) rendered isotonic with the blood ofthe recipient to be treated; [0217] B-cell-directed therapy and aqueous and non-aqueous sterile suspensions, which may rituximab comprise suspension media and thickeners. The formulations [0218] (Rituxan) can be administered in single-dose or multidose containers, [0219] T-cell/B-cell coactivation signal inhibitor for example sealed ampoules and vials, and stored in freeze- [0220] abatacept (Orencia) dried (lyophilised) state, so that only the addition ofthe sterile [0221] IL-I receptor antagonist carrier liquid, for example water for injection purposes, [0222] anakinra (Kineret) US 2016/0002242 A1 Jan. 7, 2016 14

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 antibody to TNF GCN2 pathway. In another embodiment this relates to con- Certolizumab pegol Anti-TNF agent with just the Fab ditions treatable or preventable by inhibition of a kinase or a 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 antibody that binds to the soluble an effective amount of a compound of formula (I) is an and membrane-expresses IL-6 amount that inhibits a kinase in a cell, such as, for example, in 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 cells 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99%, Ofatumumab Human monoclonal anti-CD20 compared to the activity ofthe kinase in an untreated cell. The IgGI antibody effective amount ofthe compound offormula (I),subject'for example Denosumab Fully humanized monoclonal in a pharmaceutical composition, may be at a level that will antibody that binds to and inhibits the receptor activator for nuclear exercise the desired effect; for example, about 0.005 mg/kg of factor-kB ligand a subject' s body weight to about 10mg/kg ofa s 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 inhibitors) Use Tolerogens (dnaJPl1 Immunotherapy based on T-cell tolerization [0231] The present compounds are suitable as pharmaceu- tical active ingredients for mammals, especially for humans, in the treatment of immune modulatory and stress response [0223] 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 ing of the individual components of the treatment. Combina- tumor cancers, cancers of the lymphatic or blood system, the tion products ofthis type employ the compounds according to pro li feration oftumour cells, pathological neovasculari sation the invention. (or angiogenesis) which promotes the growth of solid [0224] The invention furthermore relates to medicaments tumours, neurodegenerative diseases (Alzheimer, demyeli- comprising at least one compound of the formula I and/or nating core disorders multiple sclerosis and the like), immune pharmaceutically acceptable salts, solvates, tautomers and related disorders like arthritis, psoriasis, lupus, or other stereoi somers thereof, including mixtures thereof in all ratios, autoimmune diseases as well as chronic infections. and at least one further medicament active ingredient. [0232] The present invention encompasses the use of the [0225] The invention also relates to a set (kit) consisting of compounds of the formula I and/or physiologically accept- separate packs of able salts and solvates thereof for the preparation of a medi- [0226] (a) an effective amount of a compound of the cament for the treatment or prevention of cancer. Preferred formula I and/or pharmaceutically acceptable salts, sol- carcinomas for the treatment originate from the group cere- vates, tautomers and stereoisomers thereof, including bral carcinoma, urogenital tract carcinoma, carcinoma of the mixtures thereof in all ratios, and lymphatic system, stomach carcinoma, laryngeal carcinoma [0227] (b) an effective amount of a further medicament and lung carcinoma. A further group of preferred forms of active ingredient. cancer are monocytic leukaemia, lung adenocarcinoma, [0228] The set comprises suitable containers, such as small-cell lung carcinomas, pancreatic cancer, glioblasto- boxes, individual bottles, bags or ampoules. The set may, for mas, melanomas and breast carcinoma. A further group of example, comprise separate ampoules, each containing an preferred forms of cancer include, but is not limited to, cer- effective amount of a compound of the formula I and/or vical cancer, neuroblastoma, testicular cancer, macroglobu- pharmaceutically acceptable salts, solvates, tautomers and linemia and sarcomas. stereoi somers thereof, including mixtures thereof in all ratios, [0233] Also encompassed is the use of the compounds and an effective amount of a further medicament active ingre- according to Claim 1 according to the invention and/or physi- dient in dissolved or lyophilised form. ologically acceptable salts and solvates thereof for the prepa- [0229] "Treating" as used herein, means an alleviation, in ration of a medicament for the treatment or prevention of a whole or in part, of symptoms associated with a disorder or neurological disorder, particularly a neurodegenerative dis- disease, or slowing, or halting of further progression or wors- ease, for example a disease caused by axonal degeneration or ening ofthose symptoms, or prevention or prophylaxis of the by protein plaque deposition. Neurodegenerative diseases disease or disorder in a subject at risk for developing the include, for example, demyelinating core disorders, such as disease or disorder. multiple sclerosis, acute transverse myelitis, amyotrophic lat- [0230] The term "effective amount" in connection with a eral sclerosis, Creutzfeldt-Jakob disease or Alzheimer dis- compound of formula (I) can mean an amount capable of ease. alleviating, in whole or in part, symptoms associated with a [0234] Further encompassed is the use of the compounds disorder or disease, or slowing or halting further progression according to Claim 1 according to the invention and/or physi- or worsening of those symptoms, or preventing or providing ologically acceptable salts and solvates thereof for the prepa- prophylaxis for the disease or disorder in a subject having or ration of a medicament for the treatment of chronic infec- at risk for developing a disease disclosed herein, such as tions. Such a chronic infection could relate to parasites like inflammatory conditions, immunological conditions, cancer, leishmania to leprosy or to viral infection by HIV and the like. US 2016/0002242 A1 Jan. 7, 2016 15

[0235] Further encompassed is the use of the compounds salts, solvates, tautomers and stereoisomers thereof, includ- according to Claim 1 according to the invention and/or physi- ing mixtures thereof in all ratios, for the use for the inhibition ologically acceptable salts and solvates thereof for the prepa- of GCN2. ration of a medicament for the treatment or prevention of a [0243] The present invention specifically relates to com- disease in which angiogenesis is implicated. pounds of the formula I and pharmaceutically acceptable [0236] Such a disease in which angiogenesis is implicated salts, solvates, tautomers and stereoisomers thereof, includ- is an ocular disease, such as retinal vascularisation, diabetic ing mixtures thereof in all ratios, for the use for the treatment retinopathy, age-induced macular degeneration and the like. of neoplastic malignancies (solid tumor cancers, cancers of the lymphatic or blood system and the like), of neurodegen- [0237] The present invention encompasses the use of the erative diseases, immune related disorders like arthritis, pso- compounds of the formula I and/or physiologically accept- riasis, lupus, multiple sclerosis or other autoimmune diseases able salts and solvates thereof for the preparation of a medi- as well as chronic infections. cament for the treatment or prevention of immune related [0244] Especial preference is given to the use for the treat- disorder like ankylosing spondylitis, arthritis, aplastic ane- ment of a disease where the disease is a neoplastic malignan- mia, Behcet's disease, I diabetes mellitus, graft-versus- type cies. host disease, Graves' disease, autoimmune hemolytic ane- [0245] The neoplastic malignancies is preferably selected mia, Wegener's granulomatosis, hyper IgE syndrome, from the group of tumours of the lung, squamous epithelium, idiopathic thrombocytopenia purpura, rheumatoid arthritis, the bladder, the stomach, the kidneys, of head and neck, the Crohn's disease, multiple sclerosis, Myasthenia gravis, pso- oesophagus, the cervix, the thyroid, the intestine, the liver, the riasis, and lupus, among other autoimmune diseases. It might brain, the prostate, the urogenital tract, the lymphatic system, also be used treat organ rejection, bone marrow transplant the stomach and/or the larynx. rejection, non-myeloablative bone marrow transplant rejec- The neoplastic malignancies is furthermore prefer- tion, enhance bone marrow engraftment after non-myeloab- [0246] selected from the adenocarcinoma, small- lative conditioning regimens, and combinations thereof ably group lung cell lung carcinomas, pancreatic cancer, glioblastomas, colon [023S] Also encompassed is the use of the compounds of carcinoma and breast carcinoma. the formula I and/or acceptable salts and physiologically [0247] Preference is furthermore given to the use for the solvates thereof for the preparation of a medicament for the treatment of a neoplastic malignancies of the blood and treatment or prevention of a immune-modulatory or stress immune system, preferably for the treatment of a tumour response kinase-induced disease or a immune-modulatory or selected from the group of acute myeloid Ieukaemia, chronic stress response kinase-induced condition in a mammal, in myeloid leukaemia, acute lymphatic leukaemia and/or which to this method a effective amount a therapeutically of chronic lymphatic leukaemia. compound according to the invention is administered to a sick [024S] The present invention specifically relates to meth- mammal in need of such treatment. The therapeutic amount ods for treating or preventing an inflammatory condition, varies according to the specific disease and can be determined immunological condition, autoimmune condition, allergic by the person skilled in the art without undue effort. condition, rheumatic condition, thrombotic condition, can- [0239] The present invention also encompasses the use cer, infection, neurodegenerative disease, neuroinflammatory compounds of the formula I and/or physiologically accept- disease, cardiovascular disease or metabolic condition, com- salts and the medi- able solvates thereof for preparation of a prising administering to a subject in need thereof an effective cament for the treatment or prevention of retinal vascularisa- amount of a compound of formula I or a pharmaceutically tion. acceptable salt, tautomer, stereoisomer or solvate thereof. [0240] The expression "immune-modulatory or stress [0249] In another aspect provided herein are methods of response kinase-induced diseases or conditions" refers to inhibiting a kinase in a cell expressing said kinase, compris- pathological conditions that depend on the activity of one or ing contacting said cell with an effective amount of a com- more immune-modulatory or stress response kinases. pound of formula I or a pharmaceutically acceptable salt, immune-modulatory or stress response kinases either directly tautomer, stereoisomer or solvate thereof. In one embodiment or indirectly participate in the signal transduction pathways the kinase is GCN2 or mutants or isoforms thereof, or com- of a variety of cellular activities, including proliferation, binations of two or more thereof. adhesion and migration and differentiation. Diseases associ- [0250] Representative immunological conditions that com- ated with immune-modulatory or stress response kinase pounds of formula I are useful for treating or preventing activity include neoplastic malignancies (solid tumor can- include, but are not limited to, Behcet's syndrome, non-al- cers, cancers of the lymphatic or blood system and the like), lergy mast cell diseases (e.g., mastocytosis and treatment of of neurodegenerative diseases, immune related disorders like anaphylaxis), ankylosing spondylitis, osteoarthritis, rheuma- arthritis, psoriasis, lupus, multiple sclerosis or other autoim- toid arthritis (RA), multiple sclerosis, lupus, inflammatory mune diseases as well as chronic infections. bowel disease, ulcerative colitis, Crohn's disease, myasthenia Grave's [0241] The present invention specifically relates to com- gravis, disease, transplant rejection, humoral trans- pounds of the formula I and pharmaceutically acceptable plant rejection, non-humoral transplant rejection, cellular salts, solvates, tautomers and stereoisomers thereof, includ- transplant rejection, immune thrombocytopenic purpura immu- ing mixtures thereof in all ratios, (ITP), idiopathic thrombocytopenic purpura, diabetes, nological response to bacterial, parasitic, helminth infestation for the use for the treatment of diseases in which the inhibi- or viral infection, eczema, dermatitis, graft versus host dis- tion, regulation and/or modulation inhibition of GCN2 plays ease, Goodpasture's disease, hemolytic disease of the new- a role. born, autoimmune hemolytic anemia, anti-phospholipid syn- [0242] The present invention specifically relates to com- drome, ANCA-associated vasculitis, Churg-Strauss pounds of the formula I and pharmaceutically acceptable syndrome, Wegeners granulomatosus, pemphigus vulgaris, US 2016/0002242 A1 Jan. 7, 2016 16

serum sickness, mixed cryoglobulinemia, peripheral neur- [0257] 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. [0251] Representative autoimmune conditions that com- [025S] 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 vtdgaris, 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 another embodiment, provided herein are methods for the [0252] Representative allergic conditions that compounds treatment or prevention of Type II diabetes, Type I diabetes, of formula I are useful for treating or preventing include, but slow-onset Type I diabetes, diabetes insipidus (e.g., neuro- are not limited to, anaphylaxis, hay fever, allergic conjunc- genic diabetes insipidus, nephrogenic diabetes insipidus, dip- tivitis, allergic rhinitis, allergic asthma, atopic dermatitis, sogenic diabetes insipidus, or gestagenic diabetes insipidus), eczema, urticaria, mucosal disorders, tissue disorders and diabetes mellitus, gestational diabetes mellitus, certain gastrointestinal disorders. polycystic ovarian syndrome, maturity-onset diabetes, juvenile diabetes, [0253] Representative rheumatic conditions that com- insulin-dependant diabetes, non-insulin dependant diabetes, pounds of formula I are useful for treating or preventing malnutrition-related diabetes, ketosis-prone diabetes, pre- include, but are not limited to, rheumatoid arthritis, gout, diabetes (e.g., impaired glucose metabolism), cystic fibrosis ankylosing spondylitis, or osteoarthritis. related diabetes, hemochromatosis and ketosis-resistant dia- [0254] Representative inflammatory conditions that com- betes. pounds of formula I are useful for treating or preventing [0259] Representative neurodegenerative and neuroin- include, but are not limited to, non-ANCA (anti-neutrophil flammatory diseases that compounds of formula I are useful cytoplasmic autoantibody) vasculitis (e.g., wherein GCN2 for treating or preventing include, but are not limited to, function is associated with neutrophil adhesion, diapedesis Huntington's disease, Alzheimer's disease, viral (e.g., HIV) and/or activation), psoriasis, asthma, allergic rhinitis, allergic or bacterial-associated encephalitis and damage. conjunctivitis, chronic urticaria, hives, anaphylaxis, bronchi- [0260] In another embodiment, provided herein are meth- tis, chronic obstructive pulmonary disease, cystic fibrosis, ods for the treatment or prevention of fibrotic diseases and inflammatory bowel disease, irritable bowel syndrome, gout, disorders. In a particular embodiment, provided herein are Crohn's disease, mucous colitis, ulcerative colitis, allergy to methods for the treatment or prevention of idiopathic pulmo- intestinal antigens (such as gluten enteropathy), diabetes nary fibrosis, myelofibrosis, hepatic fibrosis, steatofibrosis (e.g., Type I diabetes and Type II diabetes) and obesity. In and steatohepatitis. some embodiments, the inflammatory condition is a derma- [0261] In another embodiment, provided herein are meth- tologic condition, such as, for example, psoriasis, urticaria, ods for the treatment or prevention ofdiseases associated with hives, eczema, scleroderma, or dermatitis. In other embodi- thrombotic events such as but not limited to atherosclerosis, ments, the inflammatory condition is an inflammatory pul- myocardial infarction and ischemic stroke. monary condition, such for example, asthma, bronchitis, as, [0262] The present invention specifically relates to com- chronic obstructive pulmonary disease or adult/ (COPD), pounds of the formula I and pharmaceutically acceptable acute respiratory distress syndrome In other (ARDS). salts, solvates, tautomers and stereoisomers thereof, includ- embodiments, the inflammatory condition is a gastrointesti- ing mixtures thereof in all ratios, for the use for the treatment nal condition, such for example, inflammatory bowel dis- as, and/or prevention of inflammatory conditions, immunologi- ease, ulcerative colitis, Crohn' s disease, idiopathic inflamma- cal conditions, autoimmune conditions, allergic conditions, tory bowel disease, irritable bowel syndrome, or spastic rheumatic conditions, thrombotic conditions, cancer, infec- colon. tions, neurodegenerative diseases, neuroinflammatory dis- [0255] Representative infections that compounds of for- eases, cardiovascular diseases, and metabolic conditions, the mula I are useful for treating or preventing include, but are not methods comprising administering to a subject in need limited to, bacterial, parasitic, prion, viral infections or hel- thereof an effective amount of a compound of claim 1. minth infestation. [0263] Moreover, the present invention specifically relates [0256] Representative cancers that compounds offormula I to compounds for the use for the treatment and/or prevention are useful for treating or preventing include, but are not lim- of cancer, where the cancer to be treated is a solid tumour or ited to, cancer of the head, neck, eye, mouth, throat, esopha- a tumour of the blood and immune system. gus, bronchus, larynx, pharynx, chest, bone, lung, colon, [0264] Moreover, the present invention specifically relates rectum, stomach, prostate, urinary bladder, uterine, cervix, to compounds, for the use for the treatment and/or prevention breast, ovaries, testicles or other reproductive organs, skin, of cancer, where the where the tumour originates from the thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, group of acute myeloid leukaemia, chronic myeloid leu- central nervous system, solid tumors and blood-borne kaemia, acute lymphatic leukaemia and/or chronic lymphatic tumors. leukaemia. US 2016/0002242 A1 Jan. 7, 2016 17

[0265] Moreover, the present invention specifically relates fene), oestrogen receptor downregulators (for example ful- to compounds, for the use for the treatment and/or prevention vestrant), antiandrogens (for example bicalutamide, fluta- ofcancer, where the solidtumour originates from the group of mide, nilutamide and cyproterone acetate), LHRH tumours of the epithelium, the bladder, the stomach, the kid- antagonists or LHRH agonists (for example goserelin, leu- neys, ofhead and neck, the esophagus, the cervix, the thyroid, prorelin and buserelin), progesterones (for example mege- the intestine, the liver, the brain, the prostate, the uro-genital strol acetate), aromatase inhibitors (for example as anastro- tract, the lymphatic system, the stomach, the larynx, the zole, letrozole, vorazole and exemestane) and inhibitors of bones, including chondosarcoma and Ewing sarcoma, germ Srt.-reductase, such as finasteride; cells, including embryonal tissue tumours, and/or the lung, (iii) agents which inhibit cancer cell invasion (for example from the group of monocytic leukaemia, lung adenocarci- metallo-proteinase inhibitors, like marimastat, and inhibitors noma, small-cell lung carcinomas, pancreatic cancer, glio- of urokinase plasminogen activator receptor function); blastomas, neurofibroma, angiosarcoma, breast carcinoma (iv) inhibitors of growth factor function, for example such and/or maligna melanoma. inhibitors include growth factor antibodies, growth factor Moreover, the invention relates [0266] present specifically receptor antibodies (for example the anti-erbb2 antibody tras- to for the use for the treatment and/or prevention of diseases tuzumab [Herceptin™]and the anti-erbbl antibody cetux- selected from the rheumatoid arthritis, group systemic lupus, imab [C225]), farnesyl transferase inhibitors, tyrosine kinase asthma, multiple sclerosis, osteoarthritis, ischemic injury, inhibitors and serine/threonine kinase inhibitors, for example cell arteritis, inflammatory bowel disease, diabetes, cys- giant inhibitors of the epidermal growth factor family (for example and transplant tic fibrosis, psoriasis, Sjogrens syndrom organ EGFR family tyrosine kinase inhibitors, such as rej ection. N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- [0267] Moreover, the present invention specifically relates morpholinopropoxy) quinazolin-4-amineis(2-methoxyethoxy) (gefitinib, to compounds for the use for the treatment and/or prevention AZD1839), of diseases selected from the group Alzheimer's disease, N-(3-ethynylphenyl)-6, 7-b quinazolin- Down's syndrome, hereditary cerebral hemorrhage with 4-amine (erlotinib, OSI-774) and 6-acrylamido- amyloidosis-Dutch Type, cerebral amyloid angiopathy, N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy) Creutzfeldt-Jakob disease, frontotemporal dementias, Hun- quinazolin-4-amine (CI 1033)),for example inhibitors of the tingon's disease, Parkinson's disease. platelet-derived growth factor family and for example inhibi- [0268] Moreover, the present invention specifically relates tors of the hepatocyte growth factor family; to compounds for the use for the treatment and/or prevention (v) antiangiogenic agents, such as those which inhibit the diseases selected from the leishmania, mycobacte- of group effects ofvascular endothelial growth factor, (for example the ria, including M. leprae, M. tuberculosis and/or M. avium, anti-vascular endothelial cell growth factor antibody bevaci- leisltmania, human immunodeficiency plasmodium, virus, zumab [Avastin™],compounds such as those disclosed in Epstein Barr virus, Herpes simplex virus, hepatitis C virus. published international patent applications WO 97/22596, [0269] The disclosed compounds of the formula I can be WO 97/30035, WO 97/32856 and WO 98/13354) and com- administered in combination with other known therapeutic pounds that work by other mechanisms (for example lino- agents, including anticancer agents. As used here, the term mide, inhibitors of integrin rtcv[33 function and angiostatin); "anticancer agent" relates to any agent which is administered (vi) vessel-damaging agents, such as combretastatin A4 and to a patient with cancer for the purposes oftreating the cancer. compounds disclosed in international patent applications WO The anti-cancer treatment defined herein be [0270] may 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO as a sole involve, in addition to the applied therapy or may 02/04434 and WO 02/08213; compound of the invention, conventional surgery or radio- antisense therapies, for example those which are directed therapy or chemotherapy. Such chemotherapy may include (vii) to the listed such as an anti-Ras one or more of the following categories of anti-tumour targets above, ISIS 2503, antisense; agents: for (I) antiproliferative/antineoplastic/DNA-damaging agents (viii) gene therapy approaches, including, example, and combinations thereof, as used in medical oncology, such approaches for re-placement of aberrant genes, such as aber- as alkylating agents (for example cis-platin, carboplatin, rant p53 or aberrant BRCAI or BRCA2, GDEPT (gene- cyclophosphamide, nitrogen mustard, melphalan, chloroam- directed enzyme pro-drug therapy) approaches, such as those bucil, busulphan and nitrosoureas); antimetabolites (for using cytosine deaminase, thymidine kinase or a bacterial example antifolates such as fluoropyrimidines like 5-fluorou- nitroreductase enzyme, and approaches for increasing patient racil and tegafur, raltitrexed, methotrexate, cytosine arabino- tolerance to chemotherapy or radiotherapy, such as multi- side, hydroxyurea and gemcitabine); antitumour antibiotics drug resistance gene therapy; and (for example anthracyclines, like adriamycin, bleomycin, (ix) immunotherapy approaches, including, for example, ex- doxorubicin, daunomycin, epirubicin, idarubicin, mitomy- vivo and in-vivo approaches for increasing the immunogenic- cin-C, dactinomycin and mithramycin); antimitotic agents ity of patient tumour cells, such as transfection with cytok- (for example vinca alkaloids, like vincristine, vinblastine, ines, such as interleukin 2, interleukin 4 or granulocyte- vindesine and vinorelbine, and taxoids, like taxol and taxo- macrophage colony stimulating factor, approaches for tere); topoisomerase inhibitors (for example epipodophyllo- decreasing T-cell anergy, approaches using trans fected toxins, like etoposide and teniposide, amsacrine, topotecan, immune cells, such as cytokine-transfected dendritic cells, irinotecan and camptothecin) and cell-differentiating agents approaches using cytokine-trans fected tumour cell lines, and (for example all-trans-retinoic acid, 13-cis-retinoic acid and approaches using anti-idiotypic antibodies. fenretinide); [0271] The medicaments from Table I below are prefer- (ii) cytostatic agents, such as antioestrogens (for example ably, but not exclusively, combined with the compounds of tamoxifen, toremifene, raloxifene, droloxifene and iodoxy- the formula I. US 2016/0002242 A1 Jan. 7, 2016 18

TABLE 1

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 (AnorMED) Spiroplatin Lob ap latin (Aeterna) Carboxyphthalatoplatinum Satraplatin (Johnson Tetrap latin Matthey) Ormiplatin BBR-3464 Iproplatin (Hoffmann-La Roche) SM-11355 (Sumitomo) AP-5280 (Access) Antimetab o lite s Azacytidine Tomudex Gemcitabine Trimetrexate Capecitabine Deoxyco formycin 5-fluorouraci Fludarabine Floxuridine Pentostatin 2-chlorodesoxyadenosine Raltitrexed 6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen) Cytarabine Clofarabine (Bioenvision) 2-fluorodesoxycytidine Irofulven (MGI Pharrna) Methotrexate DMDC (Hoffmann-La Idatrexate Roche) Ethynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan (SuperGen) inhibitors Epirubicin Exatecan mesylate Etoposide (Daiichi) Teniposide or Quinamed (ChemGenex) mitoxantrone Gimatecan (Sigma- Tau) Irinotecan (CPT-I I) Diflomotecan (Beaufour- 7-efltyi-10- Ipsen) hydroxycamptothecin TAS-103 (Taiho) Topotecan Elsamitrucin (Specuum) Dexrazoxanet J-107088 (Merck & Co) (Topo Target) BNP-1350 (BioNumerik) Pixantrone (Novuspharrna) CKD-602 (Chong Kun Rebeccamycin analogue Dang) (Exefixis) KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna) Antitumour Dactinomycin (Actinomycin Amonafide antibiotics D) Azonafide Doxorubicin (Adriamycin) Anthrapyrazole Deoxyrubicin Oxantrazole Valrubicin Losoxantrone Daunorubicin Bleomycin sulfate (Daunomycin) (Bienoxan) Epirubicin Bleomycinic acid Therarubicin Bleomycin A Idarubicin Bleomycin B Rubidazon Mitomycin C Plicamycinp MEN-10755 (Menarini) Porfiromycin GPX-100 (Gem Cyanomorpholinodoxorubicin Pharmaceuticais) Mitoxantron (Novantron) Antimitotic agents Paclitaxel SB 408075 Docetaxel (GiaxoSmifltKfine) Colchicine E7010 (Abbott) Vinblastine PG-TXL (Cefl Vincristine Therapeutics) Vinorelbine IDN 5109 (Bayer) Vindesine A 105972 (Abbott) Dolastatin 10 (NCI) A 204197 (Abbott) Rhizoxin (Fuj isawa) LU 223651 (BASF) Mivobulin (Warner- D 24851 (ASTA Medica) Lambert) ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4 (BMS) RPR 109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) Epothilone B (Novartis) ZD 6126 (AstraZeneca) T 900607 (Tuiarik) PEG-Paclitaxel (Enzon) US 2016/0002242 A1 Jan. 7, 2016 19

TABLE 1-continued

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 Immunomodulators Interferon Dexosome therapy (Anosysi Oncophage (Antigenicsi Pentrix (Australian Cancer GMK (Progenicsi Technologyi Adenocarcinoma vaccine JSF-154 (Trageni (Biomirai Cancer vaccine (Interce!!i CTP-37 (AVI BioPharmai Norelin (Biostari JRX-2 (Immuno-Rxi BLP-25 (Biomirai PEP-005 (Pepfin Biotech) MGV (Progenicsi Synchrovax vaccines (CTL P-A!eflun (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 US 2016/0002242 A1 Jan. 7, 2016 20

TABLE 1-continued

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 BioCtysti 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, 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, Wyeflti antibody, Wyeth Ayersti Exisulind (PDE-V inhibitor, PG2 (haematopoiesis Cell Pathways) promoter, Pharmagenesisi CP-461 (PDE-V inhibitor, Immunol ™ (triciosan Cell Pathways) moufltwash, Endo) AG-2037 (GART inhibitor, Triacetyluridine (uridine Pfizer) prodrug, Weflstati 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-3145 (apoptosis SRL-172 (T-cefl stimulant, promoter, Procyoni SR Phatmai Doranidazole (apoptosis TLK-286 (glutathione-S promoter, Poiai trans ferase inhibitor, Tefiki CHS-828 (cytotoxic agent, PT-100 (growth factor Leoi US 2016/0002242 A1 Jan. 7, 2016 21

TABLE I-continued

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) Evertifei Urocidin (apoptosis SDX-101 (apoptosis promoter, promoter, Bionichei Satmedixi Ro-31-7463 (apoptosis Ceflatonin (apoptosis promoter, promoter, La Roche) Chem Genexi Brostallicin (apoptosis promoter, Pharmaciai

[0272] The anti-cancer treatment defined above may be Anticancer Antibiotics applied as a monotherapy or may involve, in addition to the [02S3] such as bleomycin, dactinomycin, doxorubicin, epi- herein disclosed compounds of formula I, conventional sur- rubicin, idarubicin, levamisole, miltefosine, mitomycin C, gery or radiotherapy or medicinal therapy. Such medicinal romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, therapy, e.g. a chemotherapy or a targeted therapy, may daunurobicin, plicamycin; include one or more, but preferably one, of the following [02S4] aclarubicin, peplomycin, pirarubicin; anti-tumor agents: Hormones/Antagonists Alkylating Agents [02S5] such as abarelix, abiraterone, bicalutamide, buser- [0273] such as altretamine, bendamustine, busulfan, car- elin, calusterone, chlorotrianisene, degarelix, dexametha- mustine, chlorambucil, chlormethine, cyclophosphamide, sone, estradiol, fluocortolone fluoxymesterone, flutamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mito- melphalan, mitobronitol, mitolactol, nimustine, ranimustine, tane, nafarelin, nandrolone, nilutamide, octreotide, predniso- temozolomide, thiotepa, treosulfan, mechloretamine, carbo- lone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, quone; apaziquone, fotemustine, glufosfamide, palifosfa- trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, trofosfamide, uramustine, TH-302, mide, pipobroman, enzalutamide'; VAL-083; deslorelin, epitiostanol, orteronel, Aromatase Inhibitors Platinum Compounds [02S6] such as aminoglutethimide, anastrozole, exemes- [0274] such as carboplatin, cisplatin, eptaplatin, miri- tane, fadrozole, letrozole, testolactone; platine hydrate, oxaliplatin, lobaplatin, nedaplatin, picopl- [02S7] formestane; atin, satraplatin; [0275] lobaplatin, nedaplatin, picoplatin, satraplatin; Small Molecule Kinase Inhibitors DNA Altering Agents [02SS] such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sor- [0276] such as amrubicin, bisantrene, decitabine, mitox- afenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefi- antrone, procarbazine, trabectedin, clofarabine; tinib, axitinib; [0277] amsacrine, brostallicin, pixantrone, laromustine'; [02S9] afatinib, alisertib, dabrafenib, dacomitinib, dinaci- clib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, Topoisomerase Inhibitors linsitinib, masitinib, midostaurin, motesanib, neratinib, oran- [027S] such as etoposide, irinotecan, razoxane, sobuzox- tinib, perifosine, ponatinib, radotinib, rigosertib, tipifarnib, ane, teniposide, topotecan; amonafide, belotecan, elliptinium tivantinib, tivozanib, trametinib, pimasertib, brivanib alani- acetate, voreloxin; nate, cediranib, apatinib, cabozantinib S-malate', ibru- tinib', icotinib, buparlisib, cipatinib, cobimetinib', Microtubule Modifiers idelalisib', fedratinib', XL-647; such as cabazitaxel, docetaxel, eribulin, ixabepi- [0279] Photosensitizers lone, paclitaxel, vinblastine, vincristine, vinorelbine, vin- desine, vinflunine; [0290] such as methoxsalen; [02SO] fosbretabulin, tesetaxel; [0291] porfimer sodium, talaporfin, temoporfin;

Antimetabolites Antibodies [02S1] such as asparaginase, azacitidine, calcium levofo- [0292] such as alemtuzumab, besilesomab, brentuximab linate, capecitabine, cladribine, cytarabine, enocitabine, vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, floxuridine, fludarabine, fluorouracil, gemcitabine, mercap- panitumumab, rituximab, tositumomab, trastuzumab, beva- topurine, methotrexate, nelarabine, pemetrexed, pralatrexate, cizumab, pertuzumab '; azathioprine, thioguanine, carmo fur; [0293] catumaxomab, elotuzumab, epratuzumab, farletu- [02S2] doxifluridine, elacytarabine, raltitrexed, sapacitab- zumab, mogamulizumab, necitumumab, nimotuzumab, obi- ine, tegafur ', trimetrexate; nutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilo- US 2016/0002242 A1 Jan. 7, 2016 22

tumumab, siltuximab, tocilizumab, zalutumumab, NaHCOs (sodium bicarbonate), NaBH4 (sodium borohy- zanolimumab, matuzumab, dalotuzumab' ', onartuzumab' drlde), NMM (N-methyl morpholine), NMR (Nuclear Mag- 3, racotumomab', tabalumab', EMD-525797, nivolumab' netic Resonance), PyBOP (benzotriazole-I-yl-oxy-tris-pyr- s7 rolidino-phosphonium hexafluorophosphate), RT (room temperature), Rt (retention time), SPE (solid phase extrac- Cytokines tion), TBTU (2-(I -H-benzotriazole- l-yl)-1, 1,3,3-tetram- ethyluromium tetrafluoro borate), TEA (trlethylamine), TFA [0294] such as aldesleukin, interferon alfa, interferon (trlfluoroacetic THF TLC alfa2a, interferon alfa2b '; celmoleukin, tasonermin, acid), (tetrahydrofuran), (Thin Layer UV (Ultraviolet). teceleukin, oprelvekin', recombinant interferon beta-1 a; Chromatography), Description of the In Vitro Assays Drug Conjugates GCN2: Assay principle & conditions [0295] such as denileukin diftitox, ibritumomab tiuxetan, [0300] This assay can quantificate the activity of the serin iobenguane I123, prednimustine, trastuzumab emtansine, [0301] kinase GCN2 control non-derepressible-2). estramustine, gemtuzumab, ozogamicin, aflibercept; cintre- (general This kinase is involved in the stress metabolism dekin besudotox, edotreotide, inotuzumab ozogamicin, nap- [0302] of is activated starvation tumomab estafenatox, oportuzumab monatox, technetium cells. It upon (amino acid depletion). Its natural substrate is eIF2a initiation factor 2 (99mTc) arcitumomab', vintafolide'; (eukaryotic alpha subunit), a translation factor, which gets activated (phospho- Vaccines rylated) by GCN2 in case of an amino acid bottleneck in the cells. This in turn leads to a halt of the protein synthesis. [0296] such as sipuleucel; vitespen, emepepimut-S, Inhibition of GCN2 results in stopping this mechanism: The oncoVAX, rindopepimut, troVax, MGN-1601, MGN- cell can not stop protein production upon "starvation" stress. 1703; [0303] The assay is run in two steps: the enzymatic reaction and the detection step. In the first step GCN2 is incubated Miscellaneous with 10 pM ATP and 80 nM of the GFP-labelled substrate [0297] alitretinoin, bexarotene, bortezomib, everolimus, elF2alpha at room temperature. ibandronic acid, imiquimod, lenalidomide, lentinan, [0304] The enzymatic reaction is stopped by addition of metirosine, mifamurtide, pamidronic acid, pegaspargase, EDTA. The amount of phosphorylated elF2alpha is deter- pentostatin, sipuleucel', sizofiran, tamibarotene, temsiroli- mined by TR-FRET (Lanthascreen): A complex is formed mus, thalidomide, tretinoin, vismodegib, zoledronic acid, consisting of antibody and GFP labelled phospho-eIF2a, vorino stat; which allows a FRET upon exitation at 340 nm. [029S] celecoxib, cilengitide, entinostat, etanidazole, [0305] The GCN2-activity is directly proportional to the ganetespib, idronoxil, iniparib, ixazomib, lonidamine, ratio of fluorescence units at the emission wavelenghth 520 nimorazole, panobinostat, peretinoin, plitidepsin, pomalido- nm (phosphopeptide-sensitive wavelength=emission of mide, procodazol, ridaforolimus, tasquinimod, telotristat, GFP) to the units at 495 nm (reference wavelength=emission thymalfasin, tirapazamine, tosedostat, trabedersen, uben- of Terbium-chelate). imex, valspodar, gendicine, picibanil, reolysin, retaspimy- cin hydrochloride', trebananib ', virulizin, carfilzomib', Final Concentrations in the Enzymatic Reaction endostatin, immucothel, belinostat, MGN-1703; [0306] Hepes, pH 7.0 50 mM 'Prop. INN (Proposed international Nonproprietary Name) [0307] MgCI, 10 mM Rec. INN (Recommended International Nonproprietary Names) [030S] MnC12 5 mM USAN (United States Adopted Name) [0309] BSA 0.1% no INN. [0310] DMSO 1% [0299] The following abbreviations refer respectively to [0311] ATP 10 UM the definitions below: [0312] DTT 2 mM aq (aqueous), h (hour), g (gram), L (liter), mg (milligram), [0313] GFP-elF2a 80 nM (substrate) MHz (Megahertz), min. (minute), mm (millimeter), mmol [0314] GCN2 30 nM (enzyme) (millimole), mM (millimolar), m.p. (melting point), eq (equivalent), ml (milliliter), pl (microliter), ACN (acetoni- Assay Procedure trile), AcOH (acetic acid), CDCls (deuterated chloroform), 4 uL solution CDsOD (deuterated methanol), CHsCN (acetonitrile), c-hex [0315] enzyme (in assay buffer) 1.5 uL compound dilution buffer/63% (cyclohexane), DCC (dicyclohexyl carbodiimide), DCM [0316] (in cmpd DMSO) (dichloromethane), DIC (diisopropyl carbodiimide), DIEA Incubation 20 min at RT (diisopropylethyl-amine), DMF (dimethyl formamide), [0317] 4 uL substrate/ATP mix assay buffer) DMSO (dimethylsulfoxide), DMSO-de (deuterated dimeth- [031S] (in Incubation min at RT ylsulfoxide), EDC (I-(3-dimethyl-amino-propyl)-3-ethyl- [0319] 90 10 uL stop/detection mix (in antibody dilution carbodiimide), ESI (Electro-spray ionization), EtOAc (ethyl [0320] buffer) acetate), Et20 (diethyl ether), EtOH (ethanol), HATU (dim- [0321] Incubation 60 min at RT ethyl amino-([1, 2,3]triazo1o [4,5-b]pyridin-3-yloxy)-methyl- Readout Lanthascreen 340/495/520 ene]-dimethyl-ammonium hexafluorophosphate), HPLC [0322] (High Performance Liquid Chromatography), i-PrOH (2-pro- Cellular Assay for the Determination ofCompound Activities panol), K2COs (potassium carbonate), LC (Liquid Chroma- tography), MeOH (methanol), MgSO4 (magnesium sulfate), [0323] Human U2OS cells (2000 cells/well) are seeded into MS (mass spectrometry), MTBE (Methyl tert-butyl ether), 384-well plates and incubated for 20 hours. US 2016/0002242 A1 Jan. 7, 2016 23

[0324] The next day, the cells are treated with the test com- [0344] Eluent B:acetonitrile+0. 04% formic acid pounds and incubated for 2 hours. Then, tryptophanol, at a [0345] wavelength: 220 nm final concentration of 600 pM, is added to the cells and those are incubated for 30 minutes. [0346] mass spectroscopy: positive mode [0325] The analysis of cellular GCN2 activities is done by Above and below, all temperatures are indicated in ' immunocytochemistry. Briefly, cells are fixated on the well [0347] C. In the following examples, "conventional work-up" surfaces by formaldehyde and permeabilised with Triton X-100. The primary antibody (anti-phospho-eIF2alpha means: water is added if necessary, the pH is adjusted, if (Ser51, Cell Signalling Technology, ¹3398) is incubated on necessary, to values between 2 and 10, depending on the the treated cells for 20 hours, followed by a 60 minutes constitution of the end product, the mixture is extracted with incubation of the secondary antibody (anti-rabbit-IgG-Alexa ethyl acetate or dichloromethane, the phases are separated, 488; Molecular Probes ¹11008).The analysis and quantifi- the organic phase is dried over sodium sulfate and evaporated, cation of phosphorylated GCN2 is done by scanning the and the residue is purified by chromatography on silica gel plates in the Acumen Explorer system (TTPLabtech). The and/or by crystallisation. Rf values on silica gel; eluent: ethyl obtained data are normalised against the untreated control acetate/methanol 9:1. wells (DMSO only) and expressed as % effect values. The determination of values is done using the Graph Pad ICso by OVERVIEW SYNTHESIS OF Prism software. IMIDAZOPYRIMIDINES LCMS [0348] Method A

[0326] Method: A-0. 1%TFA in H~O, B-0.1%TFAinACN: OpN HpN Flow: 2.0 mL/min. Column: XBridge C8 (50x4.6 mm, 3.5 H N —N pm), +ve mode. DIAD, PPhs 10% P(1/C — / / Method B R2 OH H~, 14 psi, O' N N THF, C. RT [0327] A: 10 mM NH4HCOs in H~O, B:ACN; Flow Rate: NOp RT R2 R2 0.8 mL/min. [0328] Column: XBridge C8 (150x4.6) mm, 3.5 pm. [0329] 'H NMR: NHp [0330] Bruker 400 MHz NOp HPLC: Jl Method A C1 N C1

[0331] Method A: 0.1%TFA in H~O, B:0.1%TFA inACN: R1 Flow: 2.0 mL/min. Column: XBridge C8 (50x4.6 mm, 3.5 pm).

Method B NO2

[0332] MethOd A: 10 mM NH4HCOs in H~O, B: ACN; JL HpN Flow Rate: 0.8 mL/min. Column: XBridge C8 (150x4. mm, 6) C1 N NH 3.5 pm. / 1 D((s(. HPLC/MS Conditions A O' C. RT, 5 h [0333] column: Chromolith PerformanceROD RP-18e, 100x3 mm [0334] gradient: A:B=99:I to 0:100in 1.8 min R1 [0335] flow rate: 2.0 ml/min [0336] eluent A: water+0. 05% formic acid [0337] eluent B:acetonitrile+0. 04% formic acid [0338] wavelength: 220 nm [0339] mass spectroscopy: positive mode P()C ((0'/)

H~, 14 psi, HPLC/MS Conditions B 5 h RT [0340] column: Chromolith PerformanceROD RP-18e, 50x4.6 mm [0341] gradient: A:B=96:4to 0:100in 2.8 min [0342] flow rate: 2.40 ml/min R1 [0343] eluent A: water+0. 05% formic acid US 2016/0002242 A1 Jan. 7, 2016 24

-continued IH-pyrazol-I-yl)piperldine; yield: 38% (2.1 g, Pale Yellow R2 Solid); LCMS: (Method A) 210.1 (M+H). NHr - Step 2 'L,JL, NH Triethylordtoformate H I -(I -methylpiperi din-4-yl)- I H-pyrazo1-4-amine 100' C., 16 11 [0351]

OrN HrN R1 R2

/ N / N N 10% P(i'C

Hr/14 psi RT

N N

R1

Procedure: Example I [0352] I -methyl-4-(4-nitro-I H-pyrazol- I -yl)piperidine Synthesis of 9-(4-ethoxyphenyl)-N-(I-(I-methylpip- (2.1 g, 0.01 mol), was dissolved in methanol (20 mL) and eridin-4-yl)- IH-pyrazol-4-yl)-9H-purln-2-amine Pd/C (10%, 300 mg) was added and hydrogenated under C'AI") balloon Ha (14 psi) for 5 hr. After the completion of the reaction as evidenced by TLC, the reaction mixture was fil- Step I tered through Celite bed, washed with ethanol (10 mL). The filtrate was concentrated to get desired compound I-(I-me- I -methyl-4-(4-nitro-I H-pyrazol- I -yl)piperidine thylpiperidin-4-yl)-IH-pyrazol-4-amine; yield: 81% (1.5 g, yellow liquid); LCMS: (Method A) 181.1 (M+H). [0349] Step 3

OrN 2-chloro-N-(4-ethoxyphenyl)-5-nitropyrlmidin-4- amine H / N —N N DIAD, PPhs [0353]

—N OH NHr NOr N O' C. RT THF, NO2 1,4-dioxatte

Ai 2 11, O' C. RT C1 N C1 Procedure:

[0350] DIAD (6.32 mL, 0.026 mol) was added dropwise to a stirred solution of 4-nitro pyazole (3.23 g, 0.0286 mol), I-methylpiperidin-4-ol (3 g, 0.026 mol) and PPha (10.49 g, ~ 0.039 mol) in THE (50 mL) cooled to O' C. under Na atmo- )= sphere. The resulting solution was stirred at O' C. for 10 minutes then allowed to warm to room temperature and / stirred overnight. The mixture was diluted with hexane (80 mL) and EtOAc (20 mL) and then stirred vigorously. The mixture was filtered and the solid was washed with hexane. The combined filtrates were evaporated and the residue was purified by chromatography to afford I-methyl-4-(4-nitro- US 2016/0002242 A1 Jan. 7, 2016 25

Procedure: Step 5

[0354] To a solution of 4-dichloro-5-nitropyrimidine 5 2, (1. N4-(4-ethoxyphenyl)-N2-(I -(I -methylpiperi din-4- g, 0.0077 mol) in 1,4-dioxane (10 mL) at O' C. was added a yl)-IH-pyrazol-4-yl) pyrimidine-2, 4,5-triamine solution of (4-ethoxyphenyl) amine (037 g, 0.0077 mol)) in 1,4-dioxane (5 mL). The reaction was stirred for 2 h. After the [0357] completion of the reaction as evidenced by TLC, the reaction mixture was evaporated under reduced pressure and the resulting residue was purified by column chromatography to give the 2-chloro-N-(4-ethoxyphenyl)-5-nitropyrlmidin-4- N amine; yield: 66% (1.5 g, yellow solid); LCMS: (Method A) 295.0 (M+H).

Step 4

N -(4-ethoxyphenyl)-N -(I-(I-methylpiperldin-4- P4'C (10'/) I H-pyrazol-4-yl)-S-nitropyrlmidine-2, 4-diamine yl)- H1, 14 Psi, 5 h RT [0355]

NO2 H1N

C1 N NH / N DIPEA 1,4-dioxe11e O' C. RT, 5 h

N N

NO H N

N ~g —N~ N~

Procedure: Procedure: [0356] To a stirred solution of 2-chloro-N-(4-ethoxyphe- nyl)-5-nitropyrimidin-4-amine (1.5 g, 0.0053 mol) in 1,4- [035S] To a mixture of N -(4-ethoxyphenyl)-N -(I-(I-me- dioxane (10 mL) at O' C. was added a solution of 1-(1- thylpiperidin-4-yl)- IH-pyrazol-4-yl)-5-nitropyrimidine-2, 4- methylpiperidin-4-yl)-IH-pyrazol-4-amine (0.96 g, 0.0053 diamine (1.5 g, 0.0034 mol), in methanol (20 mL) was added mol), DIPEA (I mL, 0.016 mol) in 1,4-dioxane (2 mL) and Pd/C (10%,300 mg) and hydrogenated under H2 atmosphere allowed to stir for 5 h. After the completion of the reaction as for 5 h. After the completion of the reaction as evidenced by evidenced by TLC, the solvent was removed under reduced TLC, the reaction mixture was filtered through celite bed, pressure and the resulting residue was purified by column washed with ethanol (10mL). The filtrate was concentrated to chromatography to afford N -(4-ethoxyphenyl)-N -(1-(1- get desired compound N -(4-ethoxy-phenyl)-N -(I-(I-meth- methylpiperidin-4-yl)- IH-pyrazol-4-yl)-5-nitropyrimidine- ylpiperidin-4-yl)- I H-pyrazol-4-yl)pyrimidine-2, 4,5-tri- 2,4-diamine; yield: 65% (1.5 g, yellow solid); LCMS: amine; yield: 65% (0.9 g, pale yellow gummy solid); LCMS: (Method A) 439.0 (M+H). (Method A) 409.0 (M+H). US 2016/0002242 A1 Jan. 7, 2016 26

Step 6 [0362] HPLC: (Method A) RT, 2.69 min 94.8%, (Max), 92.6% (254 nm); 9-(4-ethoxyphenyl)-N-(1-(1-methylpiperi din-4-yl)- [0363] 'H NMR: (400 MHz, DMSO-de): ft [ppm] 9.62 (s, 1H-pyrazol-4-yl)-9H-purin-2-amine ("Al") 1H), 8.84 (s, 1H), 8.49 (s, 1H), 8.02 (s, 1H), 7.78 (d, J=8.5 Hz, [0359] 2H), 7.44 (s, 1H), 7.17 (d, J=8.7 Hz, 2H), 4.15-4.10 (m, 2H), 4.02-3.99 (m, 1H), 2.87-2.84 (m, 2H), 2.22 (s, 3H), 1.96-2.05 (m, 4H), 1.87-1.82 (m, 2H), 1 38 (t, J=6.9 Hz, 3H).

N Example 2

Synthesis of 9-(4-(2-methoxyethoxyl)phenyl)-N-(1- (1-methylpiperidin-4-yl)-1H-pyrazo1-4-yl)-9H-purin- 2-amine ("A2")

Step 1 Triethylordtoformate

100' C., 16 h 2-chloro-N-[4-(2-methoxyethoxyl)phenyl]-5-nitro- pyrimidin-4-amine

[0364]

NHr

Cl ~ N Cl 1,4-dioxatte O' C. RT, 2 h Yi

NO2

H

Cl ~' ~ ~ ~ ~o+

H NOr

Procedure: Procedure: [0360] To a stirred solution of N -(4-ethoxyphenyl)-N-2- (1-(1-methylpiperidin-4-yl)-1H-pyrazo1-4-yl)pyrimidine-2, [0365] To a stirred solution of 2,4-dichloro-5-nitropyrimi- 4,5-triamine (0.1 g, 0.000245 mol) was added trimethyl dine (0.25 0.013 mol) in 1,4-dioxane (10mL) at O' C. was 100' g, ortho formate (5 mL, 9.7 mol) and heated to C. After 16 added a solution of [4-(2-methoxy ethyl)phenyl]amine h the solvent was removed under reduced pressure and the (0.217 g, 0.0013 mol) in 1,4-dioxane (5 mL). The reaction resulting residue was purified by column chromatography to mixture was stirred for 2 h. After the completion of the reac- afford 9-(4-ethoxyphenyl)-N-(1-(1-methylpiperidin-4-yl)- tion as evidenced by TLC, the solvent was removed under 1H-pyrazol-4-yl)-9H-purin-2-amine; yield: 24% (25 mg, off reduced pressure and the resulted residue was purified by white solid); column chromatography afford 2-chloro-N-[4-(2-methoxy- [0361] LCMS: (Method A) 419.0 (M+H), RT 2.53 min, ethoxyl)phenyl]-5-nitropyrimidin-4-amine; yield: 40% (0.17 94.8% (Max), 92.9% (254 nm); g, yellow solid); LCMS: (Method A) 325.0 (M+H). US 2016/0002242 A1 Jan. 7, 2016 27

Step 2 N -(4-(2-methoxyethoxyl)phenyl)-N -(I-(I-meth- Q, ylpiperidin-4-yl)- I H-pyrazol-4-yl)-5-nitropyrimi- ~ dine-2, 4-diamine

[0366] H NO2

Procedure: [0367] To a stirred solution of 2-chloro-N-[4-(2-methoxy- ethoxyl)phenyl]-5-nitropyrlmidin-4-amine (0.17 g, 0.00052 mol) in 1,4-dioxane (10mL) at O' C. was added a solution of H-pyrazol-4-amine (obtained NH2 I -(I-methylpiperldin-4-yl)-I from example I step 2; 0.096 g, 0.00052 mol), DIPEA (0.1 mL, 0.00057 mol) in 1,4-dioxane (2.0 mL) and stirred for 12 h. After the completion of the reaction, the solvent was N~ DPPEA removed under reduced pres sure and the resulted residue was + N 1,4-diOXH22e purified by column chromatography to afford N -(4-(2-meth- oxyethoxyl)phenyl)-N -(I-(I-methylpiperidin-4-yl)-IH- pyrazol-4-yl)-5-nitro pyrimidine-2, 4-diamine); yield: 82% Cl~ N NH (0.20 g, pale yellow solid); LCMS: (Method A) 469.1 (M+H).

Yi N Step 3 N NO2 N -(4-(2-methoxyethoxy)phenyl)-N -(I-(I-meth- ylpiperidin-4-yl)- IH-pyrazol-4-yl)pyrimidine-2, 4,5- triamine [0368]

241C (20'I ) H, 244, 22 RT i~/

NO2

/ H N 2 / P/Q NH N

NH2 US 2016/0002242 A1 Jan. 7, 2016 28

[0369] A mixture ofN -(4-(2-methoxyethoxy)phenyl)-N- Procedure: (1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-nitropyri- midine-2, 4-diamine (0.2 g, 0.00042 mol), Pd/C (10%,25 mg) [0371] To a stirred solution of N -(4-(2-methoxyethoxyl) in methanol (20 mL) was hydrogenated for 2 h under H2 phenyl)-N -(1-(1-methyl piperidin-4-yl)-1H-pyrazol-4-yl) atmo sphere. After the completion ofthe reaction, the reaction pyrimidine-2, 4,5-triamine (0.1 g, 0.00022 mol) was added mixture was filtered through Celite bed, washed with ethanol trimethyl ortho formate (5 ml, 9.7 mol) and heated to 100' C. (10 mL). The filtrate was concentrated to get desired com- After 18 h, the solvent was removed under reduced pressure pound N -(4-(2-methoxyethoxy)phenyl)-N -(1-(1-meth- and the resulted residue was purified by column chromatog- ylpiperidin-4-yl)- 1pyrazo1-4-yl)pyrimidine-2, 4,5-triamine; raphy to afford 9-(4-(2-methoxy-ethoxy)phenyl)-N-(1-(1- yield: 54% (0.10 g, yellow liquid); LCMS: (MethodA) 439.1 methyl piperidin-4-yl)-1H-pyrazol-4-yl)-9H-purin-2-amine; (M+H). yield: 10% (10 mg, pale brown solid); LCMS: (Method A) 4493 (M+H), RT, 2.24 min, 91.1% (Max), 94.4% (254 nm); Step 4 [0372] HPLC: (Method A) RT 2.46 min 96.2% (Max), 96.4% (254 nm);

9-(4-(2-methoxyethoxy)phenyl)-N-(1-(1-methylpip- [0373] 'H NMR: (400 MHz, DMSO-de): 6 [ppm] 8.77 (s, eridin-4-yl)-1H-pyrazol-4-yl)-9H-purin-2-amine 1H), 8.37 (s, 1H), 8.09 (s, 1H), 7.75 (dd, J=2.2, 6.7 Hz, 2H), C'A2") 7.61 (s, 1H), 7.23 (d, J=8.9 Hz, 2H), 4.25-4.23 (m, 2H), 4.19-4.16 (m, 1H), 3.83-3.81 (m, 2H), 3.47 (s, 3H), 3.14-3.12 [0370] (m, 2H), 2.47-2.43 (m, 5H), 2.19-2.16 (m, 2H), 2.04-2.02 (m, 2H).

Example 3

Synthesis of 4-(2-Kl-(tetrahydro-2H-pyran-4-yl)- 1H-pyrazol-4-yl)amino)-9H-purin-9-yl)benzamide C'A3")

Step 1

Trie&yloWo- f 4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-Pyrazole 100' Co 16 11 Vj' [0374]

01N 01N

N / DIAD, PPh1 / N —OH N / H 0 OQ THF, O' C. RT

Procedure:

[0375] To a stirred solution of di-tert-butyl azodicarboxy- late (2.6 g, 11.5 mmol) in THF (5 mL) was added tetrahydro- pyran-4-ol (903 mg, 8.85 mmol), 4-nitro-1H-pyrazole (LO g, 8.85 mmol) and PPh3 (2.8 g, 10.62 mmol) in THF (35 mL) at RT for 16 h. After completion of the reaction the mixture was concentrated under reduced pressure to afford the crude prod- uct which was purified by column chromatography to afford N the product; yield: 91% (L59 g, white solid); [0376] 'H NMR: (400 MHz, DMSO-de): 6 [ppm] 2.04-1. 90 (m, 4H), 3.44-3.41 (m, 2H), 3.99-3.92 (m, 2H), 4.55-4.46 (m, 1H), 8.29 (s, 1H), 8.96 (s, 1H). US 2016/0002242 A1 Jan. 7, 2016 29

Step 2 Step 4 4-K5-nitro-2-((I -(tetrahydro-2H-pyran-4-yl)- I H- I -(tetrahydro-2H-pyran-4-yl)- IH-Pyrazol-4-amine Pyrazol-4-yl) amino)pyrlmidin-4-yl)amino)benza- [0377] mide 02N H2N [0382] 0 NH2 / / NH2 N 10% P41/C I E 444 RT 3 . DPPEA N 4 Cl ~ N NH 6h, RT Ti N 0 NO2 NH2 Procedure:

[037S] To a solution of 4-nitro-I-(tetrahydro-pyran-4-yl)- I H-pyrazole (1.59 g, 8.07 mmol) was added 10% Pd/C (300 mg) in ethanol (30 mL) and stirred for 16 h under H2 atmo- sphere. After the completion of the reaction, the reaction mixture was filtered through a Celite bed and the filtrate was concentrated to afford the product; yield: 98% (1.33 g, purple N colored solid); NO2 [0379] 'H NMR: (400 MHz, DMSO-d~): 6 [ppm] 1.76-1. 94 (m, 4H), 3.29-3.48 (m, 2H), 3.80 (s, 2H), 4.00-3.48 (m, 2H), 4.16-4.12 (m, IH), 6.90 (s, IH), 7.06 (s, IH). Procedure: Step 3 [03S3] To a stirred solution of 4-(2-chloro-5-nitropyrimi- din-4-yl)amino)-benzamide (03 0.0010 mol) in 1,4-diox- 4-K2-chloro-5-nitropyrlmidin-4-yl)amino)benzamide g, ane (10 mL) at O' C. was added a solution of I-(tetrahydro- 2H-pyran-4-yl)- IH-pyrazol-4-amine (0.17 g, 0.0010 mol) [0380] and DIPEA (0.5 mL, 0.003 mol) in 1,4-dioxane (2 mL). The NH2 reaction was stirred for 8 h. After the completion of the reaction, the solvent was removed under reduced pressure and Cl~ N Cl the resulting residue was purified by column chromatography to afford 4-(5-nitro-2-K I-(tetrahydro-2H-pyran-4-yl)-I H- Ti pyrazol-4-yl)amino)pyrimidin-4-yl)amino)benzamide; yield: 47% (0.2 g, yellow solid); LCMS: (Method A) 425. 1 NO2 (M+H).

H2N Step 5 Cl 4-((5-amino-2-K I -(tetrahydro-2H-pyran-4-yl)- I H- Pyrazol-4-yl) amino)pyrlmidin-4-yl)amino)benza- N+ N NH2 mide [0384] 0 NH2 H NO2

Procedure: PPT P4'C

[03S1] To a stirred solution of 2,4-dichloro-5-nitropyrimi- H2, 14 psi, RT dine (0.5 g, 0.0025 mol) in 1,4-dioxane (10mL) at O' C. was added a solution of 4-aminobenzamide (035 g, 0.0025 mol) in 1,4-dioxane (5 mL). The reaction was stirred for 2 h. After the completion ofthe reaction, the solvent was removed under reduced pressure and the resulted residue was purified by column chromatography to afford 4-K2-chloro-5-nitropyrl- midin-4-yl)amino)benzamide; yield: 41% (0.3 g, yellow solid); LCMS: (Method A) 294.0 (M+H). US 2016/0002242 A1 Jan. 7, 2016 30

-continued -continued 0 0 NHr

NHr

N —N

Yj

Procedure: [03S7] A solution of 4-((5-amino-2-((1-(tetrahydro-2H- pyran-4-yl)-1H-pyrazolyl)amino)pyrimidin-4-yl)amino) benzamide (0.1 g, 0.00025 mol) and trimethyl orthoformate (5 ml, 9.7 mol) were stirred at 100' C. for 12 h. After the completion of the reaction, the solvent was removed under Procedure: reduced pressure and the resulting residue was purified by column chromatography to afford 4-(2-((1-(tetrahydro-2H- [03S5] A mixture of 4-K5-nitro-2-((1-(tetrahydro-2H-py- pyran-4-yl)-1H-pyrazo1-4-yl) amino)-9H-purin-9-yl)-benza- ran-4-yl)-1H-pyrazo1-4-yl) amino)pyrimidin-4-yl)amino) mide; yield: 24'ro (25 mg, pale brown solid); [03SS] LCMS: (Method A) 405.2 (M+H), RT, 2.26 min, benzamide (0.2 g, 0.00047 mol), Pd/C (10'ro, 25 mg) in 97.3 lo (Max), 97.4 lo (254 nm); HPLC: (Method A) RT 2.22 CH3OH mL) was hydrogenated under atmosphere for (20 H2 min 98.0 ro (Max), 98.0ro (254 nm); 5 hr. After the completion of the reaction as evidenced by [03S9] 'H NMR: (400 MHz, DMSO-de): 6 [ppm] 9.67 (s, TLC, the reaction mixture was filtered through Celite, 1H), 8.88 (s, 1H), 8.67 (s, 1H), 8.14-8.12 (m, 3H), 8.06-8.01 7.54-7.52 4.32-4.28 3.98-3.95 washed with ethanol (10mL). The filtrate was concentrated to (m, 3H), (m, 2H), (m, 1H), (m, 2H), 3.47 (t, J=L96 Hz, 2H), 2.02-1.98 (m, 2H), 1.85-1.83 desired compound 4-K5-amino-2-((1-(tetrahydro-2H-py- get (m, 2H). ran-4-yl)-1H-pyrazo1-4-yl) amino)pyrimidin-4-yl)amino) Example 4 benzamide; yield: 54'ro (0.1 g, yellow liquid); LCMS: (Method 395.0 (M+H). A) Synthesis of N, 9-bis-(l-ethyl-l H-pyrazol-4-yl)-9H- purin-2-amine ("A4") Step 6 Step 1

4-(2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4- 1-ethyl-4-nitro-1H-pyrazole yl) amino)-9H-purin-9-yl)benzamide [0390] [0386] 01N 01N

0 NHr

K CO, 85' C.

Trime&yloWo- f 100' C., 12 11 Procedure:

Y~ [0391] To a stirred solution of 4-nitro-1H-pyrazole (2 g, 0.0176 mol) in CH3CN (50 mL) were added K2CO3 (4.88 g f 0.035 mol) and iodoethane (2.7 0.0176 mol). The resulting g, mixture was stirred at 85' C. for 5 h. After the completion of the reaction, the reaction mixture was filtered through a Celite bed, washed with methanol (10mL). The filtrate was concen- trated to afford 1-ethyl-4-nitro-1H-pyrazole; yield: 24'ro (L50 g, white solid); US 2016/0002242 A1 Jan. 7, 2016 31

[0392] 'H NMR: (400 MHz, DMSO-de): ft [ppm] 1.55 (t, pyrimidine-2, 4-diamine; yield: 45% (0.8 g, yellow solid); J=7.3 Hz, 3H), 4.22 (m, 2H), 8.07 (5, I H), 8.14 (s, IH). LCMS: (Method A) 344.0 (M+H).

Step 2 Step 4

I -ethyl- IH-pyrazol-4-amine N, N -bis(l-ethyl-lH-pyrazo1-4-yl)pyrimidine-2, 4,5- [0393] triamine NOr NHr [0398]

// 1 // i N —N N

10% P11/C Procedure: Hr, 14psi, RT

[0394] To a solution of I-ethyl-4-nitro-IH-pyrazole (2 g, 0.014 mol) was added 10%Pd/C (300mg) in ethanol (30mL) and stirred for 16 h under H2 atmosphere. After the comple- tion of the reaction, the reaction mixture was filtered through a Celite bed and the filtrate was concentrated to afford I -ethyl-I H-pyrazol-4-amine; yield: 81%(1.50 g, pale yellow liquid). [0395] 'H NMR: (400 MHz, DMSO-de): ft [ppm] 7.15 (5, IH), 7.02 (s, IH), 4.05-4.02 (m, 2H), 2.88 (br s, 2H), 1.43 (t, 3H, J=7.2 Hz).

Step 3

N, N -bis(1-ethyl-IH-pyrazol-4-yl)-5-nitropyrlmi- dine-2, 4-diamine

[0396] Procedure: NHr [0399] A mixture of N, N -bis(1-ethyl-IH-pyrazol-4-yl)- Cl~ N Cl DIPEA S-nitropyrlmidine-2, 4-diamine (0.8 g, 0.0023 mol), Pd/C ~ I i Yi . Dioxatte, 8 h, RT (10%, 150 mg) in CHaOH (20 mL) was hydrogenated under N N H2 atmosphere for 5 hr. After the completion ofthe reaction as NOr evidenced by TLC, the reaction mixture was filtered through Celite, washed with ethanol (10 mL). The filtrate was con- centrated to afford N, N -bis(1-ethyl- IH-pyrazol-4-yl)pyri- midine-2, 4,5-triamine; yield: 83% (0.6 g, pale yellow liquid); LCMS: (Method A) 314.0 (M+H).

Step 5

N, 9-bi s(1-ethyl- I H-pyrazol-4-yl)-9H-purin-2-amine [0400]

N —N

Procedure: [0397] To a stirred solution of 2,4-dichloro-5-nitropyrimi- dine (I g, 0.0051 mol) in 1,4-dioxane (10 mL) at O' C. was added a solution of I-ethyl-IH-pyrazol-4-amine (0.288 g, Trime&yloWoformate and in 4-dioxane 0.010mol) DIPEA (2.7 mL, 0.015 mol) 1, (2 100' C., 16 11 mL). The reaction was stirred for 8 h. After the completion of the reaction, the solvent was removed under reduced pres sure and the resulting residue was purified by column chromatog- raphy to afford N, N -bis(1-ethyl-I H-pyrazol-4-yl)-5-nitro- US 2016/0002242 A1 Jan. 7, 2016 32

-continued Procedure:

[0405] To a stirred solution of 2,4-dichloro-5-nitropyrimi- dine (0.25 0.0013mol) in 1,4-dioxane (10mL) at O' C. was N —N N~ g, N added a solution of I-ethyl-IH-pyrazol-4-amine (0.14 g, 0.0013 mol) in 1,4-dioxane (5 mL). The reaction was stirred for 2 h. After the completion of the reaction, the solvent was removed under reduced pres sure and the resulted residue was N purified by column chromatography to afford 2-chloro-N-(I- Vj ethyl-I H-pyrazol-4-yl)-5-nitropyrlmidin-4-amine; yield: 57% (0.2 g, yellow solid): [0406] LCMS: (Method A) 269.0 (M+H).

Procedure: Step 2 [0401] A solution of N2, N4-bis(l-ethyl-lH-pyrazo1-4-yl) pyrimidine-2, 4,5-triamine (0.1 g, 0.00032 mol) and trimethyl N -(I-ethyl-IH-pyrazol-4-yl)-5-nitro-N -(I-(tetrahy- ortho formate (5 ml, 9.7 mol) were stirred at 100' C. for 16 h. dro-2H-pyran-4-yl)- I H-pyrazol-4-yl)pyrimidine-2, 4- After the completion ofthe reaction, the solvent was removed diamine under reduced pressure and the resulting residue was purified by column chromatography to afford N, 9-bis(1-ethyl-I H- [0407] pyrazol-4-yl)-9H-purin-2-amine; yield: 38% (40 mg, off- white solid); LCMS: (Method A) 324.0 (M+H), RT, 231 min, 9% 9% 99. (Max), 99. (254 nm); NHp [0402] HPLC: (Method A) RT 2.44 min 99.5% (Max), 99.2% (254 nm); 'H [0403] NMR: (400 MHz, DMSO-de): 6 [ppm] 9.55 (s, DIPEA I H), 8.82 (s, IH), 8.43 (s, I H), 8.02 (s, I H), 7.94 (s, IH), 7.52 Dioxane, (s, IH), 4.24 (q, J=7.2 Hz, 2H), 4.09 (q, J=7.2 Hz, 2H), 1.45 Cl N NH ~ 6h, RT (t, J=7.2 Hz, 3H), 1.36 (t, J=7.2 Hz, 3H). Yi

Example 5 NO2

Synthesis of 9-(I-ethyl-IH-pyrazol-4-yl)-N-(I-(tet- N —N rahydro-2H-pyran-4-yl)- I H-pyrazol-4-yl)-9H-purln- 2-amine ("A5")

H Step I

2-chloro-N-(I -ethyl-I H-pyrazol-4-yl)-5-nitropyrlmi- YQ din-4-amine

[0404]

NHp

Cl~ N Cl 1,4-doxane N Yi Procedure: N N 2 h, RT NOp [040S] To a stirred solution of 2-chloro-N-(I-ethyl-IH- pyrazol-4-yl)-5-nitro pyrimidin-4-amine (0.3 g, 0.0012 mol) in 1,4-dioxane (10 mL) at O' C. was added a solution of I-(tetrahydro-2H-pyran-4-yl)-IH-pyrazol-4-amine (0.22 g, 0.0012 mol) and DIPEA (0.2 mL, 0.002 mol) in 1,4-dioxane (2 mL). The reaction was stirred for 6 h. After the completion Cl~ N NH of the reaction, the solvent was removed under reduced pres- sure and the resulting residue was purified by column chro- ti to afford N -ethyl-I H-pyrazol-4-yl)-5-nitro- N matography -(I NOp N -(I-(tetrahydro-2H-pyran-4-yl)-IH-pyrazol-4-yl) pyrimidine-2, 4-diamine; yield: 42% (0.2 g, yellow solid); LCMS: (Method A) 400.0 (M+H). US 2016/0002242 A1 Jan. 7, 2016 33

Step 3 -continued

N -(1-ethyl-1H-pyrazol-4-yl)-N -(1-(tetrahydro-2H- pyran-4-yl)-1H-pyrazol-4-yl) pyrimidine-2, 4,5-tri- amine N —N N~ [0409] N

Yj

10% P(i'C

H2 14 psi, RT

Procedure:

[0412] A solution of N -(1-ethyl-1H-pyrazol-4-yl)-N -(1- (tetrahydro-2H-pyran-4-yl)-1H-pyrazo1-4-yl)pyrimidine-2, 4,5-triamine (0.1 g, 0.00027 mo1) and trimethyl ortho formate (5 ml, 9.7 mol) were stirred at 100' C. for 16 h. After the completion of the reaction, the solvent was removed under Y~Q reduced pressure and the resulting residue was purified by column chromatography to afford 9-(1-ethyl-1H-pyrazol-4- yl)-N-(1-(tetra hydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-9H- purin-2-amine; yield: 49% (50 mg, off-white solid); LCMS: (Method A) 380.0 (M+H), RT 231 min, 95.5% (Max), 95 3% (254 nm);

Procedure: [0413] HPLC: (Method A) RT, 2.50 min 95.6% (Max), 94.6% (254 nm);

[0410] A mixture ofN -(1-ethyl-1H-pyrazol-4-yl)-5-nitro- [0414] 'H NMR: (400 MHz, DMSO-de): ft [ppm] 9.58 (s, N -(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimi- 1H), 8.82 (s, 1H), 8.43 (d, J=7.2 Hz, 2H), 8.01 (d, J=2.4 Hz, dine-2, 4-diamine (0.2 g, 0.0005 mol), Pd/C (10%, 50 mg) in 2H), 7.54 (s, 1H), 4.34-4.30 (m, 1H), 4.24 (d, J=7.2 Hz, 2H), was hydrogenated under atmosphere for CH3OH (20 mL) H2 3.95-3.94 (m, 2H), 3.46-3.45 (m, 2H), 1.97-1.90 (m, 4H), 5 hr. After the completion the reaction as evidenced of by 1.45 (t, J=7.2 Hz, 3H). TLC, the reaction mixture was filtered through Celite, washed with ethanol (10mL). The filtrate was concentrated to get desired compound N -(1-ethyl-1H-pyrazol-4-yl)-N -(1- Example 6 (tetrahydro-2H-pyran-4-yl)-1H-pyrazo1-4-yl)pyrimidine-2, 5-triamine; yield: 54% 1 white liquid); 4, (0. g, gummy Synthesis of 9-(4-ethoxyphenyl)-8-methyl-N-(1-(1- LCMS: (Method A) 370.0 (M+H). methylpiperi din-4-yl)-1H-pyrazo1-4-yl)-9H-purin-2- amine ("A6") Step 4 [0415] 9-(1-ethyl-1H-pyrazo1-4-yl)-N-(1-(tetrahydro-2H- pyran-4-yl)-1H-Pyrazol-4-yl)-9H-purin-2-amine

[0411]

N —N CHsCOOH

86' C., 16 11 H

Trime&yl ohio formate Y~Q N 100' C., 16 11 NH2 US 2016/0002242 A1 Jan. 7, 2016 34

-continued -continued (. (.

N —N

HN N Yl z+NBB N

Procedure: Procedure:

[0416] A solution of (N -(4-ethoxyphenyl)-N -(1-(1-me- [0420] A solution of 9-(4-ethoxyphenyl)-8-methyl-N-(1- thylpiperidin-4-yl)-1H-pyrazo1-4-yl)pyrimidine-2, 4,5-tri- (1-methylpiperi din-4-yl)-1H-pyrazo1-4-yl)-9H-purin-2- amine 1 and (0. g, 0.00024 mol) glacial acetic acid (10ml, 9.7 amine (0.1 0.00024 mol) and cyanic bromide (0.026 85' g, g, mol) were stirred at C. for 16 h. After the completion of 0.00024 mmol) in MeCN (10 mL) and water (1 mL) were the reaction, the solvent was removed under reduced pres sure stirred at 85' C. for 16h. After the completion of the reaction, and the resulting residue was purified by column chromatog- the solvent was removed under reduced pressure and the to afford 9-(4-ethoxyphenyl)-8-methyl-N-(1-(1-meth- raphy resulting residue was purified by column chromatography to ylpiperidin-4-yl)-1H-pyrazo1-4-yl)-9H-purin-2-amine; afford 9-(4-ethoxyphenyl)-8-methyl-N-(1-(1-methylpiperi- yield: 49% (22 mg, pale yellow solid); LCMS: (Method A) din-4-yl)-1H-pyrazol-4-yl)-9H-purin-2-amine; yield: 6% (62 2 2.43 min, 6% 433. (M+H), RT, 96.2% (Max), 93. (254 nm); mg, pale brown solid); LCMS: (Method A) 434.2 (M+H), RT [0417] HPLC: (Method A) RT 2.45 min 95.5% (Max), 1.98 min, 96.3% (Max), 94.6% (254 nm); HPLC: (Method A) 93.0% (254 nm); RT 2.13 min 95.9% (Max), 95.0% (254 nm); 'H [0418] 'H NMR: (400 MHz, DMSO-d~): 6 [ppm] 9.42 (s, [0421] NMR: (400 MHz, DMSO-d~): 6 [ppm] 8.96 (s, 1H), 8.66 (s, 1H), 7.83 (s, 1H), 7.50 (d, J=8.6 Hz, 2H), 736 (s, 1H), 8.14 (s, 1H), 7.80 (s, 1H), 7.42 (d, J=8.8 Hz, 2H), 731 (s, 1H), 7.15 (d, J=8.8 Hz, 2H), 4.12-4.10 (m, 2H), 3.93-3.91 (m, 1H), 7.13 (d, J=8.8 Hz, 2H), 6.45 (s, 1H), 4.12 (q, J=6.9 Hz, 1H), 2.84-2.81 (m, 2H), 239 (s, 3H), 2.21 (s, 3H), 2.02-2.00 2H), 3.96-3.90 (m, 1H), 2.85-2.82 (m, 2H), 2.21 (s, 3H), (m, 2H), 1.91-1.88 (m, 2H), 1.74-1.72 (m, 2H), 1.50-1.49 (m, 2.03-2.00 (m, 2H), 1.91-1.88 (m, 2H), 1.88-1.74 (m, 2H), 3H). 1 39 (t, J=6.9 Hz, 3H).

Example 7 Example 8

Synthesis of 9-(4-ethoxyphenyl)-N2-(1-(1-methylpi- Synthesis of N, 9-bis(l-ethyl-lH-pyrazo1-4-yl)-9H- peridin-4-yl)-1H-pyrazo1-4-yl)-9H-purine-2, 8-di- purine-2, 8-diamine ("A8") amine ("A7") [0422] [0419] .J CN —B

85' C., 16 11

N

NHp US 2016/0002242 A1 Jan. 7, 2016 35

Procedure:

[0427] To a stirred solution of 2,4-dichloro-5-nitropyrimi- N~ dine (0.3 g, 0.00154 mol) in 1,4-dioxane (10mL) at O' C. was N added a solution of 6-amino-3, 3-dimethylindolin-2-one (03 g, 0.00154 mol) in 1,4-dioxane (5 mL). The reaction was stirred for 2 h. After the completion of the reaction, the sol- N vent was removed under reduced pressure and the resulted residue was purified by column chromatography to afford NHp Yj 6-((2-chloro-5-nitropyrimi din-4-yl) amino)-3, 3-dimethylin- N dolin-2-one; yield: 78% (0.4 g, yellow solid); LCMS: (Method A) 334.0 (M+H).

Procedure: Step 2

[0423] A solution of 9-(4-ethoxyphenyl)-8-methyl-N-(I- 6-K2-K I -ethyl- I H-Pyrazol-4-yl) amino)-5-nitropyri- (I-methylpiperi din-4-yl)- I H-pyrazol-4-yl)-9H-purln-2- midin-4-yl)amino)-3, 3-dimethylindolin-2-one amine (0.1 g, 0.00032 mol) and cyanic bromide (0.034 g, 0.00032 mmol) in MeCN (10 mL) and water (I mL) were stirred at 85' C. for 16h. After the completion ofthe reaction, [0428] the solvent was removed under reduced pressure and the resulting residue was purified by column chromatography to afford N2, 9-bis(l-ethyl-lH-pyrazo1-4-yl)-9H-purine-2, 8-di- amine; yield: 7% (73 mg, pale yellow solid); LCMS: (Method A) 339.0 (M+H), RT 1.93 min, 98.0% (Max), 97.8% (254 nm). [0424] HPLC: (Method A) RT 2.04 min 97.6% (Max), NHp 97.5% (254 nm); NO2 I DIPEA [0425] 'H NMR: (400 MHz, DMSO-de): 6 [ppm] 8.97 (s, ~ 3 . Dioxane, 6 h, RT IH), 8.17 (s, IH), 8.13 (s, IH), 7.80 (s, IH), 7.72 (s, IH), 7.37 N (s, IH), 5.00 (s, H), 4.20-4.18 (m, 2H), 4.02-4.01 (m, 2H), 1.44 (t, J=7.2 Hz, 3H), 1.31 (t, J=7.2 Hz, 3H).

Example 9 Cl

Synthesis of 6-(2-KI-ethyl-I H-pyrazol-4-yl)amino)- 9H-purin-9-yl)-3, 3-dimethylindolin-2-one ("A9") N

Step I /

N [0426] 6-((2-chloro-5-nitropyrimidin-4-yl)amino)-3, 3- dimethylindolin-2-one

Cl~ N Cl

Yi N NOp HpN Procedure:

[0429] To a stirred solution of 6-((2-chloro-5-nitropyrimi- 1,4-doxane 0 din-4-yl)amino)-3, 3-dimethylindolin-2-one (0.4 g, 0.0012 2 h, RT mol) in 1,4-dioxane (10mL) at O' C. was added a solution of -ethyl- IH-pyrazol-4-amine (0.133 g, 0.0012 mol) and DIPEA (0.5 mL, 0.003 mol) in 1,4-dioxane (2 mL). The reaction was stirred for 6 h. After the completion of the reaction, the solvent was removed under reduced pressure and

N the resulting residue was purified by column chromatography H H to afford 6-K2-KI-ethyl-I H-pyrazol-4-yl)amino)-5-nitropy- rlmidin-4-yl)amino)-3, 3-dimethylindolin-2-one; yield: 61% (03 g, yellow solid): LCMS: (Method A) 409.0 (M+H). US 2016/0002242 A1 Jan. 7, 2016 36

Step 3; 6-K5-amino-2-((1-ethyl-1H-Pyrazol-4-yl) Step 4 amino)pyrimi din-4-yl) amino)-3, 3-dimethylindolin- 2-one 6-(2-((1-ethyl-1H-Pyrazol-4-yl)amino)-9H-purin-9- yl)-3, 3-dimethylindolin-2-one [0430] [0432]

NOr

NHr 10% Pd/C

Hr, 14psi, RT Trime&yloWo formate 100' ~J C., to 12 h

N —N NHr /

Yj

Procedure:

[0433] A solution of 6-((5-amino-2-Kl-ethyl-1H-pyrazol- 4-yl) amino)-pyrimi din-4-ylamino)-3, 3-dimethyl indolin-2- one (0.15 g, 0.00039 mol) and trimethyl ortho formate (5 ml, 9.7 mol) were stirred at 100' C. for 12 h. After the completion of the reaction, the solvent was removed under reduced pres- Procedure: sure and the resulting residue was purified by column chro- matography to afford 6-(2-K 1-ethyl-1H-pyrazol-4-yl) [0431] A mixture of 6-K2-Kl-ethyl-1H-pyrazol-4-yl) amino)-9H-purin-9-yl)-3, 3-dimethylindolin-2-one; yield: amino)-5-nitro-pyrimidin-4-yl)amino)-3, 3-dimethylindolin- 23% (33 mg, white solid); LCMS: (Method A) 389.0 (M+H), 2-one (03 g, 0.00073 mol), Pd/C (10%, 70 mg) in CH3OH RT 2.74 min, 99.5% (Max), 99.5% (254 nm); (20 mL) was hydrogenated under H~ atmosphere for 5 hr. [0434] HPLC: (Method A) RT 2.76 min 993% (Max), After the completion ofthe reaction as evidenced by TLC, the 98.8% (254 nm); reaction mixture was filtered through Celite, washed with ethanol (10 mL). The filtrate was concentrated to get 6-((5- [0435] 'H NMR: (400 MHz, DMSO-de): ft [ppm] 10.66 (s, amino-2-((1-ethyl-1H-pyrazo1-4-yl) amino)pyrimidin-4-yl) 1H), 8.85 (s, 1H), 8.52 (s, 1H), 7.95 (s, 1H), 7.54 (d, J=7.9 Hz, amino)-3, 3-dimethylindolin-2-one; yield: 54% (0.15 g, 1H), 7.48 (s, 1H), 7.40 (d, J=7.8 Hz, 1H), 734 (d, J=7.5 Hz, brown liquid); LCMS: (Method A) 379.0 (M+H). 1H), 4.81-4.80 (m, 2H), 1.31 (s, 6H). US 2016/0002242 A1 Jan. 7, 2016 37

Example 10 Step 3

Synthesis of N-(I-(2-(1 H-pyrazol-I -yl)ethyl)- I H- N -(I-(2-(IH-pyrazol-I-yl)ethyl)-IH-pyrazol-4-yl)- pyrazol-4-yl)-9-(4-ethoxyphenyl)-9H-purln-2-amine N -(4-ethoxyphenyl)-5-nitropyrlmidine-2, 4-diamine O'AI0") Step I [0440]

I-(2-(1H-pyrazol-I -yl)ethyl)-4-nitro-I H-pyrazole NH2 [0436] 02N / DIPEA 02N / N / N / C1 N NH K CO, DMF H + Vi

QN H Br Ql 'yi'~: Procedure:

[0437] To a stirred solution of 4-nitro-IH-pyrazole (I g, NO2 O 0.0176 mol) in DMF (5 ml) was added K2CO3 (3.6 g 0.035 mol) and I-(2-bromoethyl)-I H-pyrazole (1.7 g, 0.0097 mol) were added. The mixture was stirred at 100' C. for 5 h. After the completion of the reaction, the solvent was evaporated and the residue was partitioned between DCM (20 mL) and H20 (20 mL), The organic layer was extracted dried using Na2SO4 and filtered. The filtrate was evaporated under Procedure: reduced pressure and the crude residue was purified by col- umn chromatography to afford I-(2-methoxy-4-nitrophe- [0441] To a stirred solution of 2-chloro-N-(4-ethoxyphe- nyl)-4-methyl-piperazine; yield: 81%(1.5 g, off-white solid); nyl)-5-nitro-pyrimidin-4-amine (0.25 g, 0.00085 mol) in 1,4- LCMS: (Method A) 208.0 (M+H). dioxane (10 mL) at O' C. was added a solution of 1-(2- pyrazol-I-yl-ethyl)-IH-pyrazol-4-ylamine (0.15 0.00085 Step 2 g, mol) and DIPEA (0.45 mL, 0.0025 mol) in 1,4-dioxane (2 I -(2-pyrazol- I-yl-ethyl)- I H-pyrazol-4-ylamine mL). The reaction was stirred for 8 h. After the completion of the reaction, the solvent was removed under reduced pressure [0438] and the resulting residue was purified by column chromatog- raphy to afford N -(I-(2-(IH-pyrazol-I-yl)ethyl)-IH-pyra- zol-4-yl)-N -(4-ethoxyphenyl)-5-nitropyrlmidine-2, 4-di- NQ NQ amine; yield: 54% (0.2 g, yellow solid); LCMS: (Method A) 4363 (M+H). 10% Pd/C

H2 14 psi, RT Step 4 N N N -(I-(241H-pyrazol- I -yl) ethyl)-1H-pyrazol-4-yl)- i / i / N -(4-ethoxyphenyl)pyrimidine-2, 4,5-trlamine

NO2 NH2 [0442] H H N Procedure: [0439] A mixture of I-(2-(IH-pyrazol-I-yl)ethyl)-4-nitro- Vj IH-pyrazole (1.5 g, 0.0072 mol), Pd/C (10%, 300 mg) in CH3OH (20 mL) was hydrogenated under H2 atmosphere for RT 5 hr. After the completion of the reaction as evidenced by TLC, the reaction mixture was filtered through Celite, washed with CH3OH (10 mL). The filtrate was concentrated to get desired compound I -(2-pyrazol-I -yl-ethyl)- IH-pyra- zol-4-ylamine; yield: 70% (0.9 g, yellow liquid); LCMS: (Method A) 178.0 (M+H). US 2016/0002242 A1 Jan. 7, 2016 38

-continued -continued

Yi f 2

4N f 4N

Procedure: Procedure: [0443] A mixture ofN -(1-(2-(1H-pyrazol-1-yl)ethyl)-1H- [0445] A solution of N -(1-(2-(1H-pyrazol-1-yl)ethyl)- pyrazol-4-yl)-N -(4-ethoxyphenyl)-5-nitropyrimidine-2, 4- 1H-pyrazol-4-yl)-N -(4-ethoxyphenyl)pyrimidine-2, 4,5-tri- amine 1 0.00024 mol) and trimethyl orthoformate ml, diamine (0.2 0.00046 mol), Pd/C (10%,75 in CH3OH (0. g, (5 g, mg) 9.7 mol) were stirred at 100' C. for 12 h. After the completion (20 mL) was hydrogenated under H~ atmosphere for 5 hr. of the reaction, the solvent was removed under reduced pres- After the completion ofthe reaction as evidenced by TLC, the sure and the resulting residue was purified by column chro- matography to afford N-(1-(2-(1H-pyrazol-1-yl)ethyl)-1H- reaction mixture was filtered through Celite, washed with pyrazol-4-yl)-9-(4-ethoxyphenyl)-9H-purin-2-amine; yield: ethanol (10mL). The filtrate was concentrated to get desired 25% (25 mg, off white solid); LCMS: (Method A) 416.2 RT 3.20 min, 97.7% 96.6% (254 compound N -(1-(2-(1H-pyrazol-1-yl)ethyl)-1H-pyrazol-4- (M+H), (Max), nm); [0446] HPLC: (Method A) RT 3.17 min 97.6% (Max), yl)-N -(4-ethoxyphenyl)pyrimidine-2, 4,5-triamine; yield: 96.5% (254 nm); 53%(0.1 g, yellow liquid); LCMS: (Method A) 406.0 (M+H). [0447] 'H NMR: (400 MHz, DMSO-de): ft [ppm] 9.57 (s, 1H), 8.83 (s, 1H), 8.50 (s, 1H), 7.76-7.72 (m, 2H), 7.67 (s, 1H), 7.54 (s, 1H), 7.41-7.40 (m, 2H), 7.19 (d, J=8.7 Hz, 2H), Step 5 6.12 (s, 1H), 4.50 (t, J=5.5 Hz, 2H), 4.44 (t, J=5.2 Hz, 2H), 4.13-4.10 (m, 2H), 1 38 (t, J=7.0 Hz, 3H). N-(1-(2-(1H-pyrazol-1-yl)ethyl)-1H-pyrazol-4-yl)-9- Example 11 (4-ethoxyphenyl)-9H-purin-2-amine Synthesis of 9-(4-ethoxyphenyl)-N-(1-(3-(piperidin- [0444] 4-yl)propyl)-1H-pyrazol-4-yl)-9H-purin-2-amine hydrochloride ("A11")

Step 1

tert-butyl 4-(3-(4-nitro-1H-pyrazol-1-yl)propyl)pip- eridine-1-carboxylate

0ime&yloWoformate [0448]

100' C., 12 h

OrN Yi i DIAD, PPhs THF, O' C. RT N H

Br US 2016/0002242 A1 Jan. 7, 2016 39

-continued Procedure: N N [0451] A mixture of tert-butyl 4-(3-(4-nitro-IH-pyrazol-I- yl)propyl)-piperidine-I-carboxylate (2.0 g, 0.0059 mol), Pd/C (10%, 300 in CH3OH (20 mL) was hydrogenated 02N mg) under H2 atmosphere for 5 hr. After the completion of the reaction as evidenced by TLC, the reaction mixture was fil- tered through Celite, washed with ethanol (10 mL). The fil- Procedure: trate was concentrated to get desired compound tert-butyl 4-(3-(4-amino-I H-pyrazol- I -yl)propyl)piperldine- I-car- [0449] DIAD (6.32 mL, 0.026 mol) was added dropwise to a stirred solution of 4-nitro-pyazole (I g, 0.0088 mol), boxylate; yield: 55% (I g, yellow liquid); LCMS: (Method A) (3-aminopropyl)-piperldine- I-carboxylic acid tert-butyl 309.0 (M+H). ester (2.9 g, 0.0088 mol) and PPh3 (3.5 g, 0.013 mol) in THE (50 mL) cooled to O' C. under N2 atmosphere. The resulting solution was stirred at O' C. for 10 minutes then allowed to Step 3 warm to room temperature and stirred overnight. The mixture was diluted with hexane and and (80 mL) EtOAc (20 mL) tert-butyl 4-(3-(4-K4-K4-ethoxyphenyl)amino)-5- then stirred vigorously. The mixture was filtered and the solid nitropyrimi din-2-yl) amino)-1H-pyrazol- I -yl)propyl) was washed with hexane. The combined filtrates were evapo- piperidine-I -carboxylate rated and the residue was purified by chromatography to afford tert-butyl 4-(3-(4-nitro-I H-pyrazol- I-yl)propyl)pip- [0452] eridine-I-carboxylate; yield: 67% (2.0 g, pale yellow solid); LCMS: (Method A) 339.0 (M+H).

Step 2

tert-butyl 4-(3-(4-amino-I H-pyrazol-I-yl)propyl) piperidine-I -carboxylate

[0450]

NO2 Cl ~ N NH Ti N NO2 N —N PD'P PEPC PN H2 14psi RT

NH2

H2N / N h N ~N N DPPEA Dioxane, 6 h, RT US 2016/0002242 A1 Jan. 7, 2016 40

-continued -continued

f Yi f Yi

Procedure: [0455] A mixture of tert-butyl 4-(3-(4-K4-K4-ethoxyphe- Procedure: nyl) amino)-5-nitro pyrimi din-2-yl) amino)-1H-pyrazol- I -yl) [0453] To a stirred solution of N2-(I-(2-(1 H-pyrazol-I-yl) propyl)piperidine- I -carboxylate (0.2 g, 0.00035 mol), Pd/C ethyl)- IH-pyrazol-4-yl)-N4-(4-ethoxyphenyl)-5-nitropyri- (10%,75 mg) in CH3OH (20mL) was hydrogenated under H2 midine-2, 4-diamine (0.4 g, 0.0015 mol) in 1,4-dioxane (10 atmosphere for 5 hr. After the completion of the reaction as mL) at O' C. was added a solution oftert-butyl 4-(3-(4-amino- evidenced by TLC, the reaction mixture was filtered through I H-pyrazol- I-yl)propyl)piperldine-I -carboxylate (0.51 g, 0.00016mol) and DIPEA (0.8 mL, 0.004 mol) in 1,4-dioxane Celite, washed with methanol (10 mL). The filtrate was con- (2 mL). The reaction was stirred for 8 h. After the completion centrated to get desired compound tert-butyl 4-(3-(4-((5- of the reaction, the solvent was removed under reduced pres- amino-4-((4-ethoxyphenyl) amino)pyrlmidin-2-yl)amino)- sure and the resulting residue was purified by column chro- I H-pyrazol-I -yl) propyl)piperidine-I -carboxylate; yield: matography to afford tert-butyl 4-(3-(4-K4-K4-ethoxyphe- 40% (75 mg, yellow liquid); LCMS: (Method A) 537.2 nyl) amino)-5-nitropyrimi din-2-yl) amino)-1H-pyrazol- I -yl) (M+H). propyl)piperidine-I-carboxylate; yield: 47% (0.2 g, yellow solid); LCMS: (Method A) 425. 1 (M+H). Step 5 Step 4 tert-butyl 4-(3-(4-K5-amino-4-((4-ethoxyphenyl) tert-butyl 4-(3-(4-K9-(4-ethoxyphenyl)-9H-purin-2- amino)pyrimidin-2-yl)amino)- I H-pyrazol-I -yl)pro- yl)amino)-IH-pyrazol-I-yl) propyl)piperldine-I- pyl)piperldine-I -carboxylate carboxylate [0454] [0456]

Trime&yloWo formate 1D'/ P41C 100' C., 12 11 f Yi Hr 14 psi RT f Yi US 2016/0002242 A1 Jan. 7, 2016 41

-continued rated with diethyl ether to afford 9-(4-ethoxyphenyl)-N-(1- (3-(pip eridin-4-yl)propyl)-1H-pyrazol-4-yl)-9H-purin-2- amine hydrochloride; yield: 16% (10 mg, off-white solid); LCMS: (Method 4473 RT 2.82 min, N [0460] A) (M+H), 93.5% (Max), 913% (254 nm); [0461] HPLC: (Method A) RT 3.21 min 93.6% (Max), N 91.0% (254 nm);

gN [0462] 'H NMR: (400 MHz, DMSO-d~): 6 [ppm] 9.61 (s, 1H), 8.84 (s, 1H), 8.49 (s, 1H), 7.90 (s, 1H), 7.77 (d, J=8.8 Hz, 2H), 7.48 (s, 1H), 7.16 (d, J=8.8 Hz, 2H), 4.11-4.10 (m, 2H), 4.01 (t, J=6.9 Hz, 2H), 2.94-2.91 (m, 2H), 2.46-2.43 (m, 2H), Procedure: 1.74-1.71 (m, 2H), 1.56-1.53 (m, 2H), 1 37 (t, J=6.9 Hz, 3H), 1.27-1.26 (m, 2H), 1.00-0.99 (m, 2H). [0457] A solution of tert-butyl 4-(3-(4-((5-amino-4-((4- ethoxyphenyl)amino) pyrimidin-2-yl)amino)-1H-pyrazol-1- 12 yl)propyl)piperidine-1-carboxylate (0.15 g, 0.00027 mol) Example and trimethyl orthoformate (5 mL, 9.7 mol) were stirred at 100' C. for 12 h. After the completion of the reaction, the Synthesis of 9-(4-chloro-3-fluorophenyl)-N-(1-(tet- solvent was removed under reduced pressure and the result- rahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-9H-pu- ing residue was purified by column chromatography to afford rine-2-amine ("A12") tert-butyl 4-(3-(4-((9-(4-ethoxyphenyl)-9H-purin-2-yl) amino)-1H-pyrazol-1-yl)propyl)piperidine-1-carboxylate; yield: 40% (0.075 mg, yellow Liquid); LCMS: (Method A) Step 1 547.2 (M+H). 2-chloro-N-(4-chloro-3-fluorophenyl)-5-nitropyrimi- Step 6 din-4-amine

9-(4-ethoxyphenyl)-N-(1-(3-(piperidin-4-yl)propyl)- [0463] 1H-Pyrazol-4-yl)-9H-purin-2-amine hydrochloride [0458] NHp

Vi

NOp F 0 N N C1 C1

N qNHp

Cl~ N NH

Yi CIH N N N NOp HN

Procedure:

[0464] To a stirred solution of 2,4-dichloro-5-nitropyrimi- dine (0.4 g, 0.0020 mol) in 1,4-dioxane (10mL) at O' C. was added a solution 2-chloro-N-(4-chloro-3-fluorophenyl)-5- Procedure: of nitropyrimidin-4-amine (03 g, 0.0020 mol) in 1,4-dioxane (5 [0459] To a stirred solution of tert-butyl 4-(3-(4-((9-(4- mL). The reaction was stirred for 2 h. After the completion of ethoxyphenyl)-9H-purin-2-yl) amino)-1H-pyrazo1-1-yl)pro- the reaction, the solvent was removed under reduced pressure pyl)piperidine-1-carboxylate (75 mg, 0.0018 mol) in DCM and the resulted residue was purified by column chromatog- (10mL) was cooled to O' C. then 5 mL of HC1 in 1,4 dioxane raphy to afford 2-chloro-N-(4-chloro-3-fluorophenyl)-5-ni- added to the reaction mixture kept for 2 h at room tempera- tropyrimidin-4-amine; yield: 50% (0.3 g, yellow solid); ture, then solvent was removed under reduced pressure, tritu- LCMS: (Method A) 303.0 (M+H). US 2016/0002242 A1 Jan. 7, 2016 42

Step 2 -continued Cl N -(4-chloro-3-fluorophenyl)-5-nitro-N -(I-(tetrahy- dro-2H-pyran-4-yl)- I H-pyrazol-4-yl)pyrimidine-2, 4- diamine [0465] Cl

F NHr

DIPEA Yi N~ N Cl~ N NH

Ti

NO2

Cl

N~/ Procedure:

A mixture ofN -(4-chloro-3-fluorophenyl)-5-nitro- H [0468] N -(I-(tetrahydro-2H-pyran-4-yl)-IH-pyrazol-4-yl)pyrimi- NOr dine-2, 4-diamine (0.25 g, 0.00057 mol), Pd/C (10%, 75 mg) in CH3OH (20 mL) was hydrogenated under H~ atmosphere for 5 hr. After the completion of the reaction as evidenced Procedure: by TLC, the reaction mixture was filtered through Celite, [0466] To a stirred solution of 2-chloro-N-(4-chloro-3- fluorophenyl)-5-nitropyrlmidin-4-amine (03 g, 0.00099 washed with ethanol (10mL). The filtrate was concentrated to O' mol) in 1,4-dioxane (10mL) at C. was added a solution of get desired compound N -(4-chloro-3-fluoro-phenyl)-N -(I- I-(tetrahydro-2H-pyran-4-yl)-I H-pyrazol-4-amine (0.162 g, (tetrahydro-2H-pyran-4-yl)- I H-pyrazol-4yl)pyrimidine-2, 4, 0.00099 mol) and DIPEA (0.5 mL, 0.003 mol) in 1,4-dioxane (2 mL). The reaction was stirred for 5 h. After the completion 5-triamine; yield: 65% (0.15 g, colorless gummy liquid); of the reaction, the solvent was removed under reduced pres- LCMS: (Method A) 404.0 (M+H). sure and the resulting residue was purified by column chro- matography to afford N -(4-chloro-3-fluorophenyl)-5-nitro- N -(I-(tetrahydro-2H-pyran-4-yl)-IH-pyrazol-4-yl) Step 4 pyrimidine-2, 4-diamine; yield: 58% (0.25 g, yellow solid); LCMS: (Method A) 434.0 (M+H). 9-(4-chloro-3-fluorophenyl)-N-(I -(tetrahydro-2H- Step 3 pyran-4-yl)- I H-pyrazol-4-yl)-9H-purine-2-amine

N -(4-chloro-3-fluorophenyl)-N -(I-(tetrahydro-2H- [0469] pyran-4-yl)- I H-pyrazol-4-yl)pyrimidine-2, 4,5-tri- amine [0467] Cl Cl

H Trime&ylottho formate H 10% PIC 100' C., 12 11 Hr 14 psi, RT Yi g Yi+ f o2 US 2016/0002242 A1 Jan. 7, 2016 43

-continued

C1

N —N

Procedure:

[0474] To a stirred solution of 4-nitro-I H-pyrazole (1.5 g, Yj 13.27 mmol), tert-butyl 4-hydroxypiperidine-I -carboxylate (2.67 g, 13.27 mmol) and PPh3 (5.22 g, 19.90 mmol) in THE (30mL) at O' C. under N2 atmo sphere was added DIAD (3.92 mL, 19.90 mmol). The resulting solution was stirred at O' C. Procedure: for 10 minutes then allowed to warm to RT and stirred over- night. After the completion of the reaction, the reaction mix- [0470] A solution of N -(4-chloro-3-fluorophenyl)-N -(I- ture was diluted with hexane (80 mL) and EtOAc (20 mL) and (tetrahydro-2H-pyran-4-yl)- I H-pyrazol-4-yl)pyrimidine-2, then stirred vigorously. The mixture was filtered and the solid 4,5-triamine (0.15 g, 0.00037 mol) and trimethyl orthofor- washed with hexane (20 mL). The combined filtrates were mate (5 ml, 9.7 mol) was stirred at 100' C. for 12 h. After the evaporated and the residue was purified by chromatography completion of the reaction, the solvent was removed under to afford tert-butyl 4-(4-nitropyrazol- I-yl)piperldine- I-car- reduced pressure and the resulting residue was purified by boxylate; yield: 92% (3.63 g, pale yellow solid); column chromatography to afford 9-(4-chloro-3-fluorophe- [0475] 'HNMR: (400MHz, DMSO-do): 6 [ppm] 1.42 (9H, nyl)-N-(I -(tetrahydro-2H-pyran-4-yl)- IH-pyrazol-4-yl)- s), 1.84-1.79 (2H, m), 2.05-2.01 (2H, m), 2.97-2.87 (2H, m). 9H-purin-2-amine; yield: 46% off-white (70 mg, solid); 4.47-4.40 (IH, m), 8.28 (IH, s), 8.95 (IH, s). LCMS: (Method A) 414.2 (M+H), RT 3.47 min, 97.7% (Max), 97.9% (254 nm); Step 2 [0471] HPLC: (Method A) RT 3.46 min 98.1% (Max), 97.8% (254 nm); tert-butyl 4-(4-amino-I H-pyrazol-I-yl)piperldine-I- [0472] 'H NMR: (400 MHz, DMSO-do): 6 [ppm] 9.68 (s, carboxylate IH), 8.88 (s, IH), 8.66 (s, IH), 8.20-8.18 (m, IH), 8.00 (s, IH), 7.87 (s, 2H), 7.53 (s, IH), 435-430 (m, IH), 3.96-3.94 [0476] (m, 2H), 3.46-3.42 (m, 2H), 1.99-1.97 (m, 2H), 1.90-1.85 (m, 2H). N

Example 13 02N N Synthesis of N-(I-(I-(2-methoxyethyl)piperidin-4- yl)- I H-pyrazol-4-yl)-9-(4-methoxyphenyl)-9H-pu- N N —boc rin-2-amine ("A13") H2N

Step I

Procedure: tert-butyl 4-(4-nitro-I H-pyrazol-I-yl)piperldine-I- carboxylate [0477] tert-butyl 4-(4-nitropyrazol- I -yl)piperldine- I-car- boxylate (3.63 12.25 mmol), was dissolved in CH3OH (20 [0473] g, mL) and Pd/C (10%, 300 mg) was added and hydrogenated under H2 (14psi) atmosphere for 18h. After the completion of the reaction as evidenced by TLC, the reaction mixture was 02N filtered through Celite bed, washed with ethanol (10mL). The DIAD, PPhs filtrate was concentrated to afford tert-butyl 4-(4-aminopyra- zol-I-yl)piperidine-I-carboxylate; 1 / N yield: 64% (2. g, pale N boc —N OH yellow liquid); H [0478] 'H NMR: (400 MHz, DMSO-do): 6 [ppm] 1.41 (s, THF, O' C. RT 9H), 1.74-1.65 (m, 2H), 1.92-1.89 (m, 2H), 2.93-2.81 (m, 2H), 3.75 (s, 2H), 3.99-3.92 (m, 2H), 4.16-4.09 (m, I H), 6.91 (s, IH), 7.06 (s, IH). US 2016/0002242 A1 Jan. 7, 2016 44

Step 3 -continued

2-chloro-N-(4-methoxyphenyl)-5-nitropyrlmidin-4- amine pN~ NQ [0479]

NHp

C1 N C1 1,4-dioxane 2h, RT

NOp

C1 N

Procedure: H NOp [04S2] To a stirred solution of 2-chloro-N-(4-methoxyphe- nyl)-5-nitro-pyrimidin-4-amine (0.5 g, 0.00178 mol) in 1,4- dioxane (10 mL) at O' C. was added a solution of tert-butyl 4-(4-amino- IH-pyrazol-I -yl)piperidine-I -carboxylate (0.5 Procedure: g, 0.00178mol), DIPEA (0.9 mL, 0.0050 mol) in 1,4-dioxane (5 mL). The reaction was stirred for 6 h. The solvent was [04SO] To a stirred solution of 2,4-dichloro-5-nitropyrimi- removed under reduced pressure and the resulting residue dine (0.3 0.00155 mol) in 1,4-dioxane (10mL) at O' C. was g, was purified by column chromatography to give 4-(4-[4-(4- added a solution of (4-methoxyphenyl)amine (0.19 g, methoxy-phenyl amino)-5-nitro-pyrimi din-2-ylamino]-pyra- 0.00155 mol) in 4-dioxane The reaction was stirred 1, (5 mL). zol-I-yl)-piperidine-I-carboxylic acid tert-butyl ester; yield: for 2 h. After the completion of the reaction, the solvent was 20% (0.35 g, yellow solid); LCMS: (Method A) 511.2 removed under reduced pres sure and the resulted residue was (M+H). purified by column chromatography to afford 2-chloro-N-(4- methoxyphenyl)-5-nitro-pyrlmidin-4-amine; yield: 58% 5 (0.25 g, yellow solid); LCMS: (Method A) 281.0 (M+H). Step

Step 4 4-(4-[5-amino-4-(4-methoxy-phenyl amino)-pyrimi- din-2-ylamino]-pyrazol-I -yl )-piperidine-I -carboxy- lic acid tert-butyl ester 4-(4-[4-(4-methoxy-phenylamino)-5-nitro-pyrlmi- din-2-yl -carboxy- amino] -pyrazo1- I -yl )-pip eridine- I [0483] lic acid tert-butyl ester

[0481]

/ H N ~ 10% Pd/C i/ Q/ i N H 14t, RT

NOp

Cl~ N NH N

Ti o+

NO2 US 2016/0002242 A1 Jan. 7, 2016 45

-continued p— Procedure: [04S6] A solution of 4-14-[5-amino-4-(4-methoxy-pheny-

lamino)-pyrimidin-2-yl amino] -pyrazo1-1-yl )-pip eri dine-1- carboxylic acid tert-butyl ester (03 g, 0.00062 mol) and tri- methyl ortho formate (5 mL) was stirred at 100' C. for 18 h. H After the completion ofthe reaction as evidenced by TLC, the solvent was removed under reduced pressure and the resulted residue was purified by column chromatography to 4-14-[9- (4-methoxy-phenyl)-9H-purin-2-ylamino]-pyrazo1-1-yl )-pi-

peridine-1-carboxylic acid tert-butyl ester; yield: 66% (0.2 g, off-white solid); LCMS: (Method A) 4913 (M+H). Procedure: [04S4] 4-14-[4-(4-Methoxy-phenylamino)-5-nitro-pyrimi- din-2-ylamino]-pyrazol-1-yl)-piperidine-1-carboxylic acid Step 7 tert-butyl ester (035 g, 0.00068 mol), was dissolved in CH3OH (20 mL) and Pd/C (10%, 300 mg) was added and 9-(4-methoxyphenyl)-N-(1-(piperidin-4-yl)-1H-pyra- hydrogenated under H2 (14psi) atmosphere for 16h. After the zol-4-yl)-9H-purin-2-amine hydrochloride completion of the reaction as evidenced by TLC, the reaction mixture was filtered through Celite bed, washed with ethanol (10 mL). The filtrate was concentrated to afford 4-14-[5- [0487] amino-4-(4-methoxy-phenyl amino)-pyrimidin-2-ylamino]- pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester; N— yield: 92% (03 g, yellow liquid); LCMS: (Method A) 481.0 I (M+H).

Step 6 0 NQ g~N ~Q 4-14-[9-(4-methoxy-phenyl)-9H-purin-2-yl amino]- go 2h pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ~ HC1/ ester 1hoXRIle [0485]

100' C., 18 h

Trime&yl ohio formate

N H NHr 0

N —N US 2016/0002242 A1 Jan. 7, 2016 46

-continued solvent was evaporated and the residue was partitioned CIH between DCM (20 mL) and H20 (20 mL). The organic layer was extracted dried using Na2SO4 and filtered. The filtrate was evaporated under reduced pressure and the crude residue ~N was purified by column chromatography to afford N-(1-(1- N (2-methoxyethyl)piperidin-4-yl)-1H-pyrazo1-4-yl)-9-(4- methoxyphenyl)-9H-purin-2-amine; yield: 88% (0.15 g, pale yellow solid); LCMS: (Method A) 449.2 (M+H), RT 2.45 min, 94.8% (Max), 94.9% (254 nm); HPLC: (Method A) RT. 2.64 min 94.8%, (Max), 93.8% (254 nm); [0491] 'H NMR: (400 MHz, DMSO-d~): 6 [ppm] 9.60 (s, 1H), 8.84 (s, 1H), 8.49 (s, 1H), 8.01 (s, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.45 (s, 1H), 7.18 (d, J=8.9 Hz, 2H), 4.04-3.98 (m, 1H), 3.85 (s, 3H), 3.45 (t, J=5.8 Hz, 2H), 3.25 (s, 3H), 2.97-2.94 Procedure: (m, 2H), 2.50-2.49 (m, 2H), 2.16-2.10 (m, 2H), 1.99-1.96 (m, 2H), 1.81-1.79 (m, 2H). [04SS] To a stirred solution of tert-butyl 4-(4-((9-(4-meth- amino)-1H-pyrazo1-1-yl)piperi- oxyphenyl)-9H-purin-2-yl) Example 14 dine-1-carboxylate (0.2 g, 0.0004 mole) in a mixture of dichloromethane at O' C. was added 4M HC1 in (10 mL)) Synthesis of 9-(4-ethoxy-phenyl)-N -[1-(2-pyrazol- dioxane and stirred at 2 The solid which had (5 mL) for h. 1-yl-ethyl)-1H-pyrazol-4-yl]-9H-purine-2, 8-diamine formed was filtered off, washed with Et20 and dried to afford O'A14") the HC1 salt of 9-(4-methoxyphenyl)-N-(1-(piperidin-4-yl)- 1H-pyrazol-4-yl)-9H-purin-2-amine hydrochloride; yield: [0492] 88% (0.15 g, white solid); LCMS: (Method A) 391 3 (M+H).

Step 8

N-(1-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyra- zol-4-yl]-9-(4-methoxyphenyl]-9H-purin-2-amine [0489]

CIH CN — N~ +/ 8 N —N NH2 16h, RT

0 Yj K2COg, DMF 4N

/ N N —N ~ I

HN N Yl z+NH, Procedure: N [0490] To a stirred solution of 9-(4-methoxyphenyl)-N-(1- (piperidin-4-yl)-1H-pyrazol-4-yl)-9H-purin-2-amine hydro- [0493] To a stirred solution of N -(4-ethoxy-phenyl)-N- chloride (0.15 g, 0.00038 mol) in DMF (5 ml) was added [1-(2-pyrazo1-l-yl-ethyl)-1H-pyrazo1-4-yl]-pyrimidine-2, 4, K2CO3 (0.160g, 0.0011 mo1) and 1-bromo-2-methoxyethane 5-triamine (0.1 g, 0.00024 mol) was added cyanogen bromide (0.1 mL, 0.00076 mol) were added. The mixture was stirred at (0.034 g, 0.00024 mmol) in MeCN (10mL) and H20 (1 mL) 100' C. for 4 h. After the completion of the reaction, the and stirred for 16h at RT.After the completion ofthe reaction, US 2016/0002242 A1 Jan. 7, 2016 47

the reaction mixture was then diluted with EtOAc (50 mL) Step 2 and extracted with saturated NaHCO3 (3x25 mL) and brine (25 mL). The organic layer was separated and dried over N -(I-(I-methylpiperidin-4-yl)-IH-pyrazol-4-yl)-5- Na2SO4 filtered and evaporated. The crude residue was puri- nitro-N4-(quinolin-6-yl)-pyrimidine-2, 4-diamine fied by column chromatography to give 9-(4-ethoxy-phenyl)- N -[I -(2-pyrazol- I -yl-ethyl)- I H-pyrazo1-4-yl]-9H-purine- [0497] 2,8-diamine; yield: 20% (20 mg, pale yellow solid); LCMS: (Method A) 431.2 (M+H), RT 2.64 min, 95.5% (Max), 94.9% (254 nm); HPLC: (Method A) RT 2.64 min 94.8%, (Max), NO1 93.6% (254 nm); N

[0494] 'H NMR: (400 MHz, DMSO-d~): 6 [ppm] 8.93 (s, C1 N NH I H), 8.12 (s, IH), 7.56 (s, IH), 7.43-739 (m, 5H), 7.12-7.10 (m, 2H), 6.44 (s, 2H), 6.14 (s, I H), 4.47-4.44 (m, 2H), 436- 432 (m, 2H), 4.11-4.09 (m, 2H), 137-135 (m, 3H).

Example 15

N Synthesis of N-(I-(I-methylpiperldin-4-yl)-IH-pyra- zol-4-yl)-9-(quinolin-6-yl)-9H-purin-2-amine O'A15")

H1N Step I

N-(2-chloro-5-nitropyrlmidin-4-yl)quinolin-6-amine i N N [0495] D ?PEA EA-E NO2 O'C. RT, 5 11 N A. C1 N C1 NH1

NO1

H N N N y NO1 / H N~ H N ~ ~ ~

C1

Procedure:

Procedure: [0498] To a stirred solution of N-(2-chloro-5-nitropyrimi- din-4-yl)quinolin-6-amine (0.5 g, 0.00166 mol) in 1,4-diox- [0496] To a stirred solution of 2,4-dichloro-5-nitropyrimi- ane (10 mL) at O' C. was added a solution of I-(I-methylpi- dine (I g, 0.00515 mol) in 1,4-dioxane (10 mL) at O' C. was peridin-4-yl)-IH-pyrazol-4-amine (0.32 g, 0.00182 mol), added a solution of quinolin-6-amine (0.81 g, 0.00567 mol)) DIPEA (0.6 mL, 0.003 mol) in 1,4-dioxane (2 mL) and in 1,4-dioxane (5 mL). The reaction was stirred for 2 h. After allowed to stir for 5 h. After the completion of the reaction as the completion of the reaction as evidenced by TLC, the evidenced by TLC, the solvent was removed under reduced reaction mixture was evaporated under reduced pressure and pressure and the resulting residue was purified by column the resulting residue was purified by column chromatography chromatography to afford N2-(I-(I-methylpiperldin-4-yl)- to give the N-(2-chloro-5-nitropyrimidin-4-yl)-quinolin-6- I H-pyrazol-4-yl)-5-nitro-N4-(quinolin-6-yl)pyrimidine-2, 4- amine; yield: 32% (0.5 g, yellow solid); LCMS: (Method A) diamine; yield: 67% (0.5 g, yellow solid); LCMS: (Method A) 302.0 (M+H). 446.2 (M+H). US 2016/0002242 A1 Jan. 7, 2016 48

Step 3 -continued

N -(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)- N4-(quinolin-6-yl)pyrimidine-2, 4,5-triamine [0499]

NO2

N N Ql H NH P44C (10'/) N H, 444 H ShRT

Procedure: N [0502] To a stirred solution of N2-(1-(1-methylpiperidin- 4-yl)-1H-pyrazo1-4-yl)-N4-(quinolin-6-yl)pyrimidine-2, 4,5- NH2 triamine (0.2 g, 0.00045 mol) was added triethyl orthofor- mate (5 mL, 0.0072 mol) and heated to 100%.After 16 h the N solvent was removed under reduced pressure and the result- ~H ing residue was purified by column chromatography to afford N-(1-(1-methylpiperi din-4-yl)-1H-pyrazo1-4-yl)-9-(quino- H lin-6-yl)-9H-purin-2-amine; yield: 24% (47 mg, off white solid); LCMS: (Method A) 426.2 (M+H), RT 1.72 min, 96.3% (Max), 95.5% (254 nm); HPLC: (Method A) RT 1.76 min, 92.9%, (Max), 94.6% (254 nm). N [0503] 'H NMR 400 MHz, DMSO-d~: 6 [ppm] 9.68 (s, 1H), 9.01 (dd, J=1.5, 4.1 Hz, 1H), 8.90 (s, 1H), 8.73 (s, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.51 (d, J=7.9 Hz, 1H), 833 (d, J=23 J=2.4 Procedure: Hz, 1H), 831 (d, Hz, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.66 (dd, J=4.2, 83 Hz, 1H), 7.52 (s, 1H), 3.99 (s, 1H), [0500] To a mixture of N -(1-(1-methylpiperidin-4-yl)- 2.85-2.83 (m, 2H), 2.26 (s, 3H), 2.14-2.12 (m, 2H), 1.95-1.92 1H-pyrazo1-4-yl)-5-nitro-N4-(quinolin-6-yl)pyrimidine-2, 4- (m, 2H), 1.84-1.82 (m, 2H). diamine (0.5 g, 0.00112mol), in CH3OH (20 mL) was added Pd/C (10%,300 mg) and hydrogenated under H2 atmosphere Example 16 for 5 h. After the completion of the reaction as evidenced by TLC, the reaction mixture was filtered through Celite bed, washed with CH3OH (10 mL). The filtrate was concentrated Synthesis of 9-(4-methoxyphenyl)-N-(1-(1-methylpi- to get desired compound N2-(1-(1-methylpiperidin-4-yl)- peridin-4-yl)-1H-pyrazol-4-yl)-9H-purin-2-amine 1H-pyrazo1-4-yl)-N4-(quinolin-6-yl)pyrimidine-2, 4,5-tri- O'A16") amine; yield: 64% (0.3 g, pale brown gummy solid); LCMS: (Method A) 416.3 (M+H). Step 1

Step 4 N -(4-methoxyphenyl)-N -(1-(1-methylpiperidin-4- N-(1-(1-methylpiperidin-4-yl)-1H-pyrazo1-4-yl)-9- yl)-1H-pyrazo1-4-yl)-S-nitropyrimidine-2, 4-diamine (quinolin-6-yl)-9H-purin-2-amine [0504] [0501]

NO2 N N NH2 Ai C1 N NH N gl / NH N~N H

N US 2016/0002242 A1 Jan. 7, 2016 49

-continued -continued HrN

NHr / N

DtPEA H 1,A-E O' C. RT, 5 11 N

NOr

H N N y Procedure: / [0507] To a mixture of N4-(4-methoxyphenyl)-N2-(1-(1- N~ H methylpiperidin-4-yl)- I H-pyrazol-4-yl)-5-nitropyrimidine- 2,4-diamine (0.5 g, 0.0011 mol), in CH3OH (20 mL) was added Pd/C (10%, 150mg) and hydrogenated under H2 atmo- sphere for 5 h. After the completion of the reaction as evi- denced by TLC, the reaction mixture was filtered through celite bed, washed with CH3OH (10 mL). The filtrate was concentrated to get desired compound N4-(4-methoxy phe- Procedure: nyl)-N2-(I -(I -methylpiperi din-4-yl)- I H-pyrazol-4-yl)pyri- midine-2, 4,5-triamine; yield: 69% (03 g, pale brown gummy [0505] To a stirred solution of 2-chloro-N-(4-methoxyphe- solid); LCMS: (Method A) 395.0 (M+H). nyl)-5-nitro-pyrlmidin-4-amine 5 0.0053 mol) in 4- (1. g, 1, Step 3 dioxane (10 mL) at O' C. was added a solution of 1-(1- methylpiperidin-4-yl)-IH-pyrazol-4-amine (036 g, 0.002 9-(4-methoxyphenyl)-N-(I -(I -methylpiperidin-4-yl)- mol), DIPEA (0.7 mL, 0.004 mol) in 1,4-dioxane (2 mL) and I H-pyrazol-4-yl)-9H-purin-2-amine allowed to stir for 5 h. After the completion of the reaction as [050S] evidenced by TLC, the solvent was removed under reduced pressure and the resulting residue was purified by column chromatography to afford N -(4-methoxyphenyl)-N -(1-(1- methylpiperidin-4-yl)- IH-pyrazol-4-yl)-5-nitropyrimidine- 2,4-diamine; yield: 59% (0.5 g, yellow solid); LCMS: (Method A) 425.2 (M+H). Trie&yloWo- Step 2 E 100' C., 16 11 N4-(4-methoxyphenyl)-N2-(I -(I -methylpiperidin-4- yl)- I H-pyrazol-4-yl)Pyrimidine-2, 4,5-triamine HrN [0506] Q N +N— NOr

r' r i N MN

Hr, 14 psi 5 11 RT Procedure: [0509] To a stirred solution of N4-(4-methoxyphenyl)-N2- (1-(1-methylpiperidin-4-yl)- IH-pyrazol-4-yl)pyrimidine-2, US 2016/0002242 A1 Jan. 7, 2016 50

4,5-triamine (0.25 g, 0.00076 mol) was added triethyl ortho- Step 2 formate (5 mL, 9.7 mol) and heated to 100' C. After 16 h the solvent was removed under reduced pressure and the result- tert-butyl (4-(4-amino-IH-pyrazol-I-yl)cyclohexyl) ing residue was purified by column chromatography to afford carbamate 9-(4-methoxyphenyl)-N-(I -(I-methylpiperl din-4-yl)- I H- pyrazol-4-yl)-9H-purin-2-amine; yield: 49'zo (122 mg, off [0513] white solid); LCMS: (Method A) 405 3 (M+H), RT 2.29 min, 95.9 io (Max), 95.4 io (254 nm); HPLC: (Method A) RT 2.27 N min 98.5'zo, (Max), 983'zo (254 nm); 10'/0 Pd/C N ~HB0O H1 14 Psi, RT [0510] 'H NMR: 400 MHz, DMSO-de: 6 [ppm] 9.61 (s, 01N I H), 8.84 (s, I H), 8.49 (s, I H), 8.02 (s, I H), 7.80 (d, J=8.8 Hz, N 2H), 7.45 (s, I H), 7.18 (d, J=8.9 Hz, 2H), 7.45 (s, IH), 7.18 (d, N N —NHBOC J=8.9 Hz, 2H), 4.05-3.97 (m, I H), 3.86 (s, 3H), 2.84-2.82 (m, 2H), 2.20 (s, 3H), 2.06-2.00 (m, 4H), 1.88-1.81 (m, 2H). H1N

Example 17 Procedure: Synthesis of N-(I -(4-aminocyclohexyl)- IH-pyrazol- 4-yl)-9-(4-ethoxyphenyl)-9H-purin-2-amine hydro- [0514] tert-butyl (4-(4-nitro-I H-pyrazol-I-yl)cyclohexyl) chloride ("A17") carbamate (I g, 0.0032 mol), was dissolved in CH3OH (20 mL) and Pd/C (10'zo, 300 mg) was added and hydrogenated under balloon H2 (14 psi) for 5 h. After the completion of the Step I reaction as evidenced by TLC, the reaction mixture was fil- tered through Celite bed and washed with CH3OH (10 mL). tert-butyl (4-(4-nitro-IH-pyrazol-I-yl)cyclohexyl) The filtrate was concentrated to get desired compound tert- carbamate butyl (4-(4-amino-I H-pyrazol- I -yl)cyclohexyl)carbamate; yield: 51'zo (0.5 g, yellow liquid); LCMS: (Method A) 281.1 [0511] (M+H).

Step 3 H N —N DIAD, PPh1 tert-butyl (4-(4-((4-((4-ethoxyphenyl)amino)-5-nitro- pyrimi din-2-yl) amino)-1H-pyrazol- I -yl)cyclohexyl) carbamate NHBOC OH NO1 [0515] THF, O' C. RT

NO2 N

N C1 N NH N NHBOC

01N

Procedure:

[0512] DIAD (2.3 mL, 0.0132 mol) was added dropwise to a stirred solution of 4-nitro pyazole (1.0 g, 0.0088 mol), H1N trans-4-Boc-amino-cyclohexanol (2.09 g, 0.00972 mol) and PPh3 (3.47 g, 0.0132 mol) in THE (50 mL) cooled to O' C. / under N2 atmosphere. The resulting solution was stirred at 0' N C. for 10minutes, then allowed to warm to room temperature and stirred overnight. The mixture was diluted with hexane D(EEA (80 mL) and EtOAc (20 mL) and then stirred vigorously. The 4-dioxa((e mixture was filtered and the solid was washed with hexane. 1, O'C. RT, 5 h The combined filtrates were evaporated and the residue was purified by chromatography to afford I-methyl-4-(4-nitro- IH-pyrazol-I-yl)piperldine; yield: 36'zo (I g, pale yellow NHBOC solid); LCMS: (Method A) 311.0 (M+H). US 2016/0002242 A1 Jan. 7, 2016 51

-continued -continued BOCNH NO2 BOCNH

H N N g NH2 N / ~ N~ H gl / H ( (

Procedure: Procedure: [0516] To a stirred solution of 2-chloro-N-(4-ethoxyphe- [0518] To a mixture of tert-butyl (4-(4-K4-K4-ethoxyphe- nyl)-5-nitro-pyrlmidin-4-amine (0.5 g, 0.0018 mol) in 1,4- nyl) amino)-5-nitropyrlmidin-2-yl)amino)- I H-pyrazol- I -yl) dioxane (10 mL) at O' C. was added a solution of tert-butyl cyclohexyl)carbamate (0.5 g, 0.00092 mol), in CH3OH (20 (4-(4-amino-I H-pyrazol- I -yl)cyclohexyl)-carbamate (0.51 mL) was added Pd/C (10%,300 mg) and hydrogenated under g, 0.0018 mol), DIPEA (0.63 mL, 0.036 mol) in 1,4-dioxane H2 atmosphere for 5 h. After the completion ofthe reaction as (2 mL) and allowed to stir for 5 h. After the completion of the evidenced by TLC, the reaction mixture was filtered through reaction as evidenced by TLC, the solvent was removed under celite bed, washed with CH3OH (10 mL). The filtrate was reduced pressure and the resulting residue was purified by concentrated to get desired compound tert-butyl (4-(4-((5- column chromatography to afford tert-butyl (4-(4-((4-((4- amino-4-((4-ethoxyphenyl) amino)pyrlmidin-2-yl)amino)- ethoxyphenyl)amino)-5-nitro pyrimidin-2-yl)amino)-I H- IH-pyrazol-I-yl)cyclohexyl)carbamate; yield: 66% (03 g, pyrazol-I-yl)-cyclohexyl)carbamate; yield: 51% (0.5 g, yel- pale brown gummy solid); LCMS: (Method A) 509.2 (M+H). low solid); LCMS: (Method A) 539.2 (M+H).

Step 5 Step 4

tert-butyl (4-(4-K9-(4-ethoxyphenyl)-9H-purln-2-yl) tert-butyl (4-(4-((5-amino-4-K4-ethoxyphenyl) amino)- I H-pyrazol-I -yl)-cyclohexyl)carbamate amino)pyrlmidin-2-yl)amino)- I H-pyrazol- I -yl) cy- clohexyl) carbamate [0519]

[0517]

BOCNH

BOCNH NH2

NO2 N / ~ N gl

H uie&ylortho- N f

100' C., 16 h P4'C (10'/) H, 14 r 5 h RT ( US 2016/0002242 A1 Jan. 7, 2016 52

-continued Procedure: BOCNH [0522] A stirred solution of tert-butyl (4-(4-K9-(4-ethox- yphenyl)-9H-purin-2-yl)amino)-1H-pyrazol-1-yl) cyclo- hexyl)carbamate (160 mg, 0.00030 mol) in DCM (10 mL) was cooled to O' C., then 5 mL of HC1 in 1,4 dioxane added to the reaction mixture and kept for 2 h at room temperature, x) then solvent was removed under reduced pressure, triturated with diethyl ether to afford N-(1-(4-aminocyclohexyl)-1H- pyrazol-4-yl)-9-(4-ethoxyphenyl)-9H-purin-2-amine hydro- N chloride; yield: 85% (120 mg, off white solid); LCMS: (Method A) 419.3 (M+H), RT 2.65 min, 98.1%(Max), 97.9% (254 nm); HPLC: (Method A) RT 2.66 min 97.7%, (Max), 96.5% (254 nm); [0523] 'H NMR: 400 MHz, DMSO-de: ft [ppm] 9.68 (s, 1H), 8.87 (s, 1H), 8.54 (s, 1H), 8.02 (s, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.55 (s, 1H), 7.15 (d, J=8.9 Hz, 2H), 4.20 (s, 1H), 4.12-4.10 (m, 2H), 2.23-2.21 (m, 2H), 1.09-1.85 (m, 4H), 1.78-1.67 (m, 2H), 1 37 (t, J=6.9 Hz, 3H). Example 18 Procedure: Synthesis of [9-(4-methoxy-phenyl)-9H-purin-2-yl]- [0520] To a stirred solution of tert-butyl (4-(4-((5-amino- (1H-pyrazol-4-yl)-amine ("A18") 4-((4-ethoxy-phenyl)amino)pyrimi din-2-yl) amino)-1H- Step 1 pyrazol-1-yl)cyclohexyl)carbamate (0.3 g, 0.00058 mol) was 4-[4-(4-methoxy-phenylamino)-5-nitro-pyrimidin-2- added triethyl orthoformate (5 mL, 9.7 mol) and heated to ylamino]-pyrazole-1-carboxylic acid tert-butyl ester 100' C. After 16 h the solvent was removed under reduced [0524] pressure and the resulting residue was purified by column chromatography to afford tert-butyl (4-(4-((9-(4-ethoxyphe- nyl)-9H-purin-2-yl) amino)-1H-pyrazo1-1-yl)-cyclohexyl) carbamate; yield: 53% (160 mg, off white solid); LCMS: (Method A) 519.2 (M+H). N C1 N NH N r Step 6 / N ~O N-(1-(4-amino cyclohexyl)-1H-pyrazo1-4-yl)-9-(4- ~ N' NH 2 ethoxyphenyl)-9H-purin-2-amine hydrochloride 0 [0521] BOCNH NH2

H N N y 0ie&yloWo formate

100' 11 / C., 16 N~ H ( CIH H2N US 2016/0002242 A1 Jan. 7, 2016 53

-continued -continued

NH

0

Procedure: Procedure: 2-chloro-5-nitro-pyrimidin-4-yl)-(4-methoxy-phe- [0525] [0527] To a mixture of 4-[4-(4-methoxy-phenylamino)-5- nyl)-amine (223.20 mg; 0.80 mmol; 1.00 eq.) and 4-amino- nitro-pyrimidin-2-ylamino]-pyrazole-1-carboxylic acid tert- ester in and THF pyrazole-1-carboxylic acid tert-butyl ester (160.27 mg; 0.87 butyl (0.278 g, 0.00065 mol) CH3OH (5 mL) (5 mL) was added Pd/C (5%, 300 mg) and the mixture was mmol; 1.10 eq. were weighed into a reaction vial. Then, ) hydrogenated under H2 atmosphere for 5 h. After the comple- N-ethyldiisopropylamine (148.76 pl; 0.87 mmol; 1.10 eq.) tion of the reaction as evidenced by HPLC, the reaction mix- and 1,4-dioxane (2 mL) were added. The reaction mixture ture was filtered through celite bed, washed with CH3OH (10 mL). The filtrate was concentrated to get desired compound was stirred at room temperature for six hours. Water was 4-[5-amino-4-(4-methoxy-phenyl-amino)-pyrimi din-2- added to the reaction mixture. The precipitate was filtered off, ylamino]-pyrazole-1-carboxylic acid tert-butyl ester; yield: 245 of crystals HPLC/MS conditions A: washed with water and dried under vacuum to give 4-[4-(4- mg grey (95%); 398.2 (M+H), RT 1.436 min. methoxy-phenylamino)-5-nitro-pyrimidin-2-ylamino]-pyra- zole-1-carboxylic acid tert-butyl ester; yield: 286 mg of Step 3 orange crystals (84%); HPLC/MS conditions B: 428.2 4- [9-(4-Methoxy-phenyl)-9H-purin-2-yl amino]- (M+H), RT 2.443 min. pyrazole-1-carboxylic acid tert-butyl ester

Step 2 [0528]

4-[5-Amino-4-(4-methoxy-phenylamino)-pyrimidin- 2-ylamino]-pyrazole-1-carboxylic acid tert-butyl ester

Trie&ylo&o formate [0526] 100' C., 16 11 'p.+Yi+

N —N /

0 US 2016/0002242 A1 Jan. 7, 2016 54

Procedure: Example 19

4-[5-amino-4-(4-methoxy-phenylamino)-pyrimi- [0529] Synthesis of [9-(4-methoxy-phenyl)-9H-purin-2-yl]- din-2-ylamino]-pyrazole-1-carboxylic acid tert-butyl ester (1-methyl-1H-pyrazol-3-yl)-amine ("A19") (39.74 mg; 0.10 mmol; 1.00 eq.) was weighed into a reaction vial. Then, diethoxymethoxy-ethane (0.95 ml) is added. Finally, the reaction mixture was stirred at 100' C. for 16 h. Step 1 The reaction mixture was concentrated and purified via chro- matography using dichloromethane/methanol: 95/5; yield: N4-(4-methoxy-phenyl)-N2-(1-methyl-1H-pyrazol- 64 mg of white material (95%); 3-yl)-5-nitro-pyrimidine-2, 4-diamine [0530] HPLC/MS conditions A: 408.2 (M+H), RT 1.799 min. [0533]

Step 4

[9-(4-methoxy-phenyl)-9H-purin-2-yl]-(1H-pyrazol- 4-yl)-amine ~N [0531] + X NHz Cl ~ N NH Ti N ~O ~ N'

/ 0 X.~'Vi'

0 —/Yi

0

Procedure: Procedure:

[0532] 4-[9-(4-Methoxy-phenyl)-9H-purin-2-ylamino]- [0534] (2-chloro-5-nitro-pyrimidin-4-yl)-(4-methoxy- pyrazole-1-carboxylic acid tert-butyl ester (60.00 mg; 0.15 phenyl)-amine (561 33 mg; 2.00 mmol; 1.00 eq.) was dis- mmol; 1.00 eq.) was dissolved in 1,4-dioxane (3 mL). Then, solved in 1,4-dioxane (4 mL). Then, 1-methyl-1H-pyrazol-3- HC1 in dioxane (288.00 pl; 9.40 mmol; 63.83 eq.) was added. ylamine (220.27 mg; 2.20 mmol; 1.10 eq.) and The reaction mixture was stirred at room temperature for two N-ethyldiisopropylamine (374.13 pl; 2.20 mmol; 1.10 eq.) days. An extraction was performed with DCM and sodium were added. The reaction was stirred at room temperature for hydroxide. The organic phase was dried with Na~SO4, con- 14 h. Water was added to the reaction mixture. The precipitate centrated and evaporated under vacuum; ield: 45 mg of yel- was filtered off, washed with water and dried under vacuum to low material (99%); HPLC/MS conditions A: 308.2 (M+H), give N4-(4-methoxy-phenyl)-N2-(1-methyl-1H-pyrazol-3- RT 1.448 min; 'H NMR: (400 MHz, DMSO-d~) 6 [ppm] 9.50 yl)-5-nitro-pyrimidine-2, 4-diamine; yield: 598 mg of yellow (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H), 7.78 (m, 4H), 7.17 (d, 2H), crystals (88%); HPLC/MS conditions B: 342. 1 (M+H), RT 3.86 (s, 3H). 2.086 min. US 2016/0002242 A1 Jan. 7, 2016 55

Step 2 ture was concentrated and dried under vacuum; yield: 145 mg of beige material; HPLC/MS conditions A: LCMS: 322.2 N4-(4-methoxy-phenyl)-N2-(1-methyl-1H-pyrazol- (M+H), RT 1.559 min; 'H NMR: (400 MHz, DMSO-de) ft 3-yl)-pyrimidine-2, 4,5-triamine [ppm] 9.76 (s, 1H), 8.86 (s, 1H), 8.52 (s, 1H), 7.84-7.74 (m, 52 J=2.2 20-7.10 6.58 J=2.2 [0535] 2H), 7. (d, Hz, 1H), 7. (m, 2H), (d, Hz, 1H), 3.85 (s, 3H), 3.74 (s, 3H).

Example 20

Synthesis of [9-(4-methoxy-phenyl)-9H-purin-2-yl]- — Vj' (1-phenyl-1H-pyrazol-4-yl)-amine ("A20")

+ Step 1 0 H H N N N N4-(4-methoxy-phenyl)-5-nitro-N2-(1-phenyl-1H- pyrazo1-4-yl)-Pyrimidine-2, 4-diamine

NH2

Procedure: [0536] To a mixture ofN4-(4-methoxy-phenyl)-N2-(1-me- thyl- 1H-pyrazol-3-yl)-5-nitro-pyrimidine-2, 4-diamine (0.6 g, 0.00018 mop in THE (10 mL) was added Pd/C (5%, 200 mg) and the mixture was hydrogenated under H2 atmosphere + for 19h. After the completion of the reaction as evidenced by Cl N NH HPLC, the reaction mixture was filtered through celite bed, ~ washed with CH3OH (10 mL). The filtrate was concentrated Yi to get desired compound N4-(4-methoxy-phenyl)-N2-(1-me- N ~O ~ N' thyl-lH-pyrazo1-3-yl)-pyrimidine-2, 4,5-triamine; yield: 560 mg of brown material; HPLC/MS conditions A: 312.2 0 (M+H), RT 1.324 min.

Step 3

[9-(4-methoxy-phenyl)-9H-purin-2-yl] -(1-methyl- 1H-pyrazol-3-yl)-amine [0537]

H H N N N N methylotutofotmate —N 0 N 100 C., 14h Y ~ NH2 (

0 0

Procedure:

[0540] (2-chloro-5-nitro-pyrimidin-4-yl)-(4-methoxy- phenyl)-amine (561 33 mg; 2.00 mmol; 1.00 eq.) and 1-phe- nyl-1H-pyrazol-4-ylamine (350.21 mg; 2.20 mmol; 1.10 eq.) were weighed into a reaction vial. Then, N-ethyldiisopropy- lamine (374.13 2.20 mmol; 1.10 eq. and 1,4-dioxane Procedure: pl; ) (6 mL) were added. The reaction mixture was stirred at room [0538] N4-(4-methoxy-phenyl)-N2-(1-methyl-1H-pyra- temperature for 14 h. Water was added to the reaction mix- zo1-3-yl)-pyrimidine-2, 4,5-triamine (155.67 mg; 0.50 mmol; ture. The precipitate was filtered off, washed with water and 1.00 eq.) was weighed into a reaction vial. Then, dried under vacuum to give the desired compound; yield: 857 diethoxymethoxy-ethane (4.8 mL) was added. The reaction mg of yellow solid; HPLC/MS conditions B: LCMS: 404. 1 mixture was stirred at 100' C. overnight. The reaction mix- (M+H), RT 2.499 min. US 2016/0002242 A1 Jan. 7, 2016 56

Step 2 -continued N4-(4-methoxy-phenyl)-N2-(1-phenyl-1H-pyrazol- / 4-yl)-pyrimidine-2, 4,5-triamine 0 [0541] N —N

Yj

V~' Procedure: ~ [0544] N4-(4-methoxy-phenyl)-N2-(1-phenyl-1H-pyra- zo1-4-yl)-pyrimidine-2, 5-triamine (302 0.81 mmol; 0 4, mg; 1.00 eq.) were weighed into a reaction vial. Then, diethoxymethoxy-ethane (7.70 ml) was added. The reaction mixture was stirred at 100' C. for 5 hours and 48 h at 80' C. The reaction mixture was concentrated and purified by chro- matography using dichloromethan/methanol: 95/5; yield: 140 mg of white solid (45%); HPLC/MS conditions A: 384.2 (M+H), RT 1.896 min; 'H NMR: (400 MHz, DMSO-de) ft [ppm] 9.83 (s, 1H), 8.91 (s, 1H), 8.63 (s, 1H), 8.52 (s, 1H), ' 7.84 (d, J=8.7 Hz, 2H), 7.78 (s, 1H), 7.68 (d, J=8.1 Hz, 2H), ~ Y~ 7.49 (m, 2H), 7.33-7.26 (m, 1H), 7.22 (d, J=8.7 Hz, 2H), 3.88 (s, 3H). f 2 [0545] HPLC/MS conditions C for examples 21-31: [0546] column: Chromolith PerformanceROD RP-18e, Procedure: 100x3 mm [0547] gradient: A:B=99:1to 0:100in 3.5 min [0542] To a mixture N4-(4-methoxy-phenyl)-5-nitro-N2- (1-phenyl-1 H-pyrazol-4-yl)-pyrimidine-2, 4-diamine (0.1 g, [0548] flow rate: 2.0 ml/min 0.00025 mol) in THE (10mL) was added Pd/C (5%, 200 mg) [0549] eluent A: water+0. 05% formic acid and the mixture was hydrogenated under H2 atmosphere for [0550] Eluent B:acetonitrile+0. 04% formic acid 15 h. After the completion of the reaction as evidenced by HPLC, the reaction mixture was filtered through celite bed, [0551] wavelength: 220 nm washed with CH3OH (10 mL). The filtrate was concentrated [0552] mass spectroscopy: positive mode to get desired compound N4-(4-methoxy-phenyl)-N2-(1- phenyl- 1H-pyrazol-4-yl)-pyrimidine-2, 4,5-triamine; yield: Example 21 93 mg of green solid; HPLC/MS conditions A: 374.2 (M+H), RT. 1.447 min. Synthesis of (1-methyl-1H-pyrazol-4-yl)-(9-[4-(1- Step 3 methyl-1H-pyrazo1-4-yl)-phenyl] -9H-purin-2-yl )- amine ("A21") [9-(4-methoxy-phenyl)-9H-purin-2-yl] -(1-phenyl- 1H-pyrazol-4-yl)-amine [0553] [0543] / N —N / Cl ~ N Cl

0ie&ylottho formate Yi N H 100' C. for 5 h NO2 80' C. for 48 h Qii —. Yi+ 7 NH2 US 2016/0002242 A1 Jan. 7, 2016 57

-continued / N —N / N —N N 3 /

~H

Cl ~ N NH Yi

NO2 is prepared analogously; LC/MS (method A) 3.38 min, / [M+H] 423. N —N Example 22 / Synthesis of (1-methyl-1H-pyrazol-4-yl)-(9-[4-(1- piperi din-4-yl-1H-pyrazo1-4-yl)-phenyl]-9H-purin-2- yl)-amine ("A23") N —N [0556]

HN N NH

NO2 / Cl N —N / + /

N —N HC(OH) NO2

HN N NH

NH2 N~ / N

N —N / N —N N —N

Yj ~H

[0554] The synthesis is performed analogously to previous examples (1,2,3,4,5); LC/MS (method A) 2.66 min, [M+H] Cl N NH 372. ~ Ti [0555] The compound N-(2, 3-dihydroxy-propyl)-4-[2-(1- N ethyl-1H-pyrazol-4-ylamino)-purin-9-yl]-benzamide NO2 C'A22") US 2016/0002242 A1 Jan. 7, 2016 58

-continued

N~ N

N —N N —N

N —N Yj

HN N NH

[0557] The synthesis is performed analogously to previous ~0 O examples (1, 2, 3, 4, 5); "A23" trifluoracetate: LC/MS (method A) 2.25 min, [M+H] 441.

Example 23

Synthesis of N2-(1-methyl-1H-pyrazol-4-yl)-9- [4-(1- N —N methyl-1H-pyrazol-4-yl)-phenyl]-9H-purine-2, 8- diamine ("A24") HO(OE) [0558]

N —N

HN N NH

N N —N

BrCN

HN N NH

NH2 N~ N

N~ N

HN N Yl N Yj [0559] The reaction is performed analogously to example 7; LC/MS (method A) 2.16 min, [M+H] 387. US 2016/0002242 A1 Jan. 7, 2016 59

[0560] The compound 4-[8-amino-2-(1-ethyl-1H-pyrazol- 4-ylamino)-purin-9-yl]-N-(2-hydroxy-ethyl)-benzamide O'A25")

N N N~ N

HCFF

N —N

HN N Yl N

is prepared analogously; LC/MS (method A) 2.87 min, [M+H] 458.

N~ Example 24 N

Synthesis of N2-(1-methyl-1H-pyrazol-4-yl)-9-[4-(1- piperidin-4-yl-1H-pyrazol-4-yl)-phenyl]-9H-purine- N —N 2,8-diamine ("A26")

[0561]

HN N

—F|FT, Yl y) N

[0562] The reaction is performed analogously to example 7; LC/MS (method A) 1.83 min, [M+H] 456.

Example 25

N —N Synthesis of (trans)-3- [9-(3-fluoro-4-iodo-phenyl)- 9H-purin-2-ylamino]-cyclopentanol ("A27") BTCN [0563] N —N

Cl N Cl HN N NH ~ ~F Yi THF N 2-10' C. NOp NHp NHp US 2016/0002242 A1 Jan. 7, 2016 60

-continued solids are filtered off and washed with THF. The filtrate is I evaporated and triturated with water. The solids are filtered off, washed with water and dried under vacuum to afford (2-chloro-5-nitro-pyrlmidin-4-yl)-(3-fluoro-4-iodo-phenyl)- amine; HPLC/MS 3.13 min (C), [M+H] 395. S C1 [0565] To a solution of (2-chloro-5-nitro-pyrimidin-4-yl)- EtOAc/EtOH (3-fluoro-4-iodo-phenyl)-amine (1533 g, 38.9 mmol) in a Cl~ N NH mixture ofethyl acetate (200 ml) and ethanol (50 ml) is added tin(II)chloride (11.1 g, 583 mmol) and the reaction mixture is Ti stirred for 90 minutes at 70' C. The reaction mixture is cooled with saturated sodium carbon- NO2 to room temperature, basified ate solution, filtered over a pad of Celite and the residue is washed with ethyl acetate. The organic phase of the filtrate is separated, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclo- hexane/ethyl acetate as eluent to afford 2-chloro-N4-(3- fluoro-4-iodo-phenyl)-pyrimidine-4, 5-diamine as orange solid; HPLC/MS 2.78 min (C), [M+H] 365. [0566] A solution of 2-chloro-N4-(3-fluoro-4-iodo-phe- nyl)-pyrimidine-4, 5-diamine (2.60 7.13 mmol) in triethyl HC(OH ) g, orthoformate (70 ml) is heated to 100' C. and stirred at this 100' C. temperature for 18 hours. The reaction mixture is evaporated C1 N NH ~ in vacuo and the residue is crystallized from ethyl acetate to Ti afford 2-chloro-9-(3-fluoro-4-iodo-phenyl)-9H-purine as N beige crystals; HPLC/MS 2.77 min (C), [M+H] 375. 'H NMR NHp (500 MHz, DMSO-d6) ft 9.23 (s, I H), 9.09 (s, I H), 8.15 (dd, J=8.5, 7.1 Hz, IH), 7.93 (dd, J=9.2, 2.4 Hz, IH), 7.65 (ddd, J=8.5, 2.4, 0.6 Hz, IH). [0567] To a solution of 2-chloro-9-(3-fluoro-4-iodo-phe- nyl)-9H-purine 16 3.08 mmol) in 2-methoxyethanol HO (1. g, (40 ml) are added trans-3-amino-cyclopentanol hydrochloride (466 mg, 330mmol) and N-ethyldiisopropylamine (1.05 ml, 6.17 mmol). The mixture is heated to 120' C. and stirred at this temperature for 30 hours. The reaction mixture is cooled F x HCl to room temperature and evaporated. The residue is chro- NHp matographed on a silica gel column with ethyl acetate/metha- DIPEA nol as eluent to afford trans-3-[9-(3-fluoro-4-iodo-phenyl)- CHgOCHpCHpOH 9H-purin-2-ylamino]-cyclopentanol as beige solid; HPLC/ 120' C. MS 2.33 min (C), [M+H] 440; 'H NMR (400 MHz, DMSO- Yi ') dc) ft [ppm] 8.72 (s, IH), 8.59 (s, IH), 8.08 (dd, J=9.8, 2.4 Hz, IH), 8.04 (dd, J=8.5, 7.2 Hz, IH), 7.75 (d, J=83 Hz, IH), 7.29 (bs, IH), 4.45 (d, J=3.8 Hz, IH), 436 (bs, IH), 4.21 (dq, J=6.1, 3.1 Hz, IH), 2.19-2.04 (m, IH), 1.90 (m, 2H), 1.71 (dt, J=133, 6.6 Hz, IH), 1.49 (m, 2H). [0568] The compound (trans)-3-[9-(4-ethoxy-phenyl)-9H- HO purin-2-ylamino]-cyclopentanol ("A28")

F (. N HO Vj'

[0564] To a stirred solution of 2,4-dichloro-5-nitro-pyrimi- dine (7.56 g, 39.0 mmol) in THF (150ml) is added a solution Yi of 3-fluoro-4-iodo-aniline (9.24 g, 39.0 mmol) in THF (150 ml) dropwise and under external cooling with ice. Then, still under cooling, triethylamine (5.40 ml, 39.0 mmol) is added slowly. The reaction mixture is stirred for 30 minutes at 2-10' is prepared analogously; HPLC/MS 2.07 min (B), [M+H] C. and then it is allowed to reach room temperature. The 340. US 2016/0002242 A1 Jan. 7, 2016 61

Example 26 mixture is allowed to reach room temperature and evaporated. The residue is chromatographed on a silica gel column with Synthesis of (trans)-3-(9-13-fluoro-4-[I-(2-methoxy- dichloromethane/methanol as eluent to afford trans-3-(9-(3- ethyl)- I H-pyrazol-4-yl]-phenyl )-9H-purln-2- fluoro-4-[1-(2-methoxy-ethyl)-1H-pyrazo1-4-yl]-phenyl )- ylamino)-cyclopentanol ("A29") 9H-purln-2-ylamino)-cyclopentanol as beige powder; HPLC/MS 2.06 min [M+H] 438; 'H NMR (500 MHz, [0569] (C), DMSO-de, TEA-dt): ft [ppm] 9.12 (s, IH), 9.06 (s, IH), 8.26 (s, IH), 8.05 (s, IH), 8.01 (t, J=8.5 Hz, IH), 7.95 (d, J=12.2 Hz, IH), 7.83 (d, J=8.5 Hz, IH), 4.43 J=7.4 Hz, IH), 4.37 HO (p, (t, J=53 Hz, 2H), 430 (dp, J=5.9, 2.9 Hz, IH), 3.77 (t, J=53 F Hz, 2H), 3.29 (s, 3H), 233-2.20 (m, IH), 2.04 (ddd, J=13.5, 7.6, 3.0 Hz, IH), 2.01-1.92 (m, IH), 1.83 (ddd, J=13.2, 7.2, 5.9 Hz, IH), 1.68-1.51 (m, 2H). [0571] The compound (trans)-3-19-[4-(I -Methyl-I H- pyrazol-4-yl)-phenyl]-9H-purin-2-ylamino )-cyclopentanol Yi ("A30")

OH

N~ N PdCl 222222

KaCOg dioxatte/water ~B 100' C. 0

is prepared analogously; HPLC/MS 1.66 min (A), [M+H] 376.

Example 27

Synthesis of (IR,3R)-3-[9-(3-fluoro-4-iodo-phenyl)- 9H-purin-2-ylamino]-cyclopentanecarboxylic acid N~ N amide ("A31")

[0572] HO

F

F

Yi [0570] To a solution of trans-3-[9-(3-fluoro-4-iodo-phe- nyl)-9H-purln-2-ylamino]-cyclopentanol (176 mg, 0.40 0 1-(2-methoxy-ethyl)-4-(4, 5-tetramethyl-[1, mmol), 4,5, 3,2] OH DIPEA dioxaborolan-2-yl)-IH-pyrazole (131 mg, 0.52 mmol) in CH OCH CH OH dioxane ml) are added water 7 ml) and potassium car- (7 (0. 2212' C. bonate (166 mg, 1.20 mmol). The mixture is flushed with 80' nitrogen and heated to C. Dichloro[1, 1'-bis(di-phe- x HCl nylphosphino) ferrocene]palladium(II) dichloromethane adduct (33 mg, 0.04 mmol) is added and the mixture is stirred NHa in a closed reaction vial for two hours at 100' C. The reaction US 2016/0002242 A1 Jan. 7, 2016 62

-continued [0575] The following compounds are prepared analo- gously: OH [0576] (IR,3R)-3-[9-(4-ethoxy-phenyl)-9H-purln-2- ylamino]-cyclopentanecarboxylic acid amide ("A32") F ~H EDC1, HOBt THF H2N M Yi

Vj NH2

F [0577] HPLC/MS 1.55 min (A), [M+H] 385; [0578] (IR,3R)-3-[9-(4-iodo-phenyl)-9H-purin-2- N ylamino]-cyclopentanecarboxylic acid amide ("A33") Vj'

H2N M [0573] To a solution of 2-chloro-9-(3-fluoro-4-iodo-phe- nyl)-9H-purine (1.12 g, 3.00 mmol) in 2-methoxyethanol (40 ml) are added (IR,3R)-3-amino-cyclopentanecarboxylic acid hydrochloride (488 mg, 3.00 mmol) and N-ethyldiisopropy- lamine (1.07 ml, 63 mmol). The mixture is heated to 120' C. and stirred at this temperature for 40 hours. The reaction mixture is cooled to room temperature and evaporated. The Vj residue is chromatographed on a silica gel column with ethyl acetate/methanol as eluent to afford (IR,3R)-3-[9-(3-fluoro- 4-iodo-phenyl)-9H-purin-2-ylamino]-cyclopentanecarboxy- lic acid as dark brown solid; HPLC/MS 2.45 min (C), [M+H] [0579] HPLC/MS 1.62 min (A), [M+H] 449; 468. [0580] (IR,3R)-3-19-[4-(2-methoxy-ethoxy)-phenyl]-9H- [0574] To a solution of (IR,3R)-3-[9-(3-fluoro-4-iodo- purin-2-ylamino)-cyclopentanecarboxylic acid amide phenyl)-9H-purln-2-ylamino]-cyclopentanecarboxylic acid ("A34") (406 mg, 0.87 mmol) in THF (10 ml) are added N-(3-dim- ethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (334 mg, 1.74 mmol), I-hydroxybenzotriazole hydrate (235 mg, 1.74 mmol) and ammonia as a 0.5 M solution in dioxane (8.9 ml, 4.4 mmol). The reaction mixture is stirred for 16 hours at room temperature. It is then evaporated and parti- tioned between ethyl acetate and saturated sodium hydrogen 0 carbonate solution. The organic phase is dried over sodium H2N +7 sulfate and evaporated. The residue is chromatographed on a silica gel column with dichloromethane/methanol as eluent to afford (IR,3R)-3-[9-(3-fluoro-4-iodo-phenyl)-9H-purin-2- ylamino]-cyclopentanecarboxylic acid amide as brown pow- der; HPLC/MS 2.25 min (C), [M+H] 467; 'H NMR (400 MHz, DMSO-d~) 6 [ppm] 8.74 (s, IH), 8.62 (s, IH), 8.08 (dd, J=9.8, 2.4 Hz, IH), 8.04 (dd, J=8.6, 7.2 Hz, IH), 7.79 (d, Yi J=5.6 Hz, IH), 7.34 (s, IH), 7.21 (s, IH), 6.68 (s, IH), 4.26 (s, IH), 2.77 (p, J=8.0 Hz, IH), 2.04 (m, 2H), 1.92 (td, J=83, 4.5 Hz, IH), 1.78 (ddd, J=13.4, 8.7, 5 3 Hz, IH), 1.73-1.53 (m, 2H). [0581] HPLC/MS 1.45 min (A), [M+H] 397. US 2016/0002242 A1 Jan. 7, 2016 63

Example 28 is flushed with nitrogen and heated to 80' C. Dichloro[1, 1'- bis(diphenylphosphino) ferrocene]palladium(II) dichlo- Synthesis of (IR,3R)-3-(9-13-fluoro-4-[1-(2-meth- romethane adduct (20 mg, 0.02 mmol) is added and the mix- oxy-ethyl)- I H-pyrazo1-4-yl]-phenyl )-9H-purin-2- ture is stirred in a closed reaction vial for three hours at 100' ylamino)-cyclopentanecarboxylic acid amide C. The reaction mixture is allowed to reach room temperature ("A35") and evaporated. The residue is chromatographed on a silica [0582] gel column with dichloromethane/methanol as eluent to afford (IR,3R)-3-(9-13-fluoro-4-[1-(2-methoxy-ethyl)-1 H- pyrazol-4-yl]-phenyl )-9H-purln-2-ylamino)-cyclopentan- ecarboxylic acid amide as brown powder; HPLC/MS 2.01 NH2 min (C), [M+H] 465; 'H NMR (500 MHz, DMSO-de) ft [ppm] 8.74 (s, IH), 8.62 (s, IH), 8.22 (d, J=1.9 Hz, I H), 8.05 F (d, J=12.7 Hz, IH), 8.00 (s, IH), 7.91 (m, 2H), 731 (s, IH), 7.21 (s, IH), 6.66 (s, IH), 433 (t, J=5.4 Hz, 2H), 4.28 (s, IH), 3.74 (t, J=53 Hz, 2H), 3.26 (s, 3H), 2.78 (p, J=8.0 Hz, IH), 2.04 (m, 2H), 1.93 (dtd, J=11.9, 7.8, 4.5 Hz, IH), 1.87-1.77 N Vj' (m, IH), 1.73-1.56 (m, 2H). [05S4] The following compound is prepared analogously: [05S5] (IR,3R)-3-(9-14-[1-(2-ethoxy-ethyl)-1 H-pyrazol- 4-yl]-phenyl )-9H-purln-2-ylamino)-cyclopentanecar- boxylic acid amide ("A36")

N~ N N PdCj Pddpp 0 K2COg H2N +j dioxatte/water ~B 100' C. 0

Yj

[05S6] HPLC/MS 1.55 min (A), [M+H] 461.

Example 29 N~ N Synthesis of (IR,3R)-3-[9-(2-methyl-quino1 in-6-yl)- 9H-purin-2-ylamino]-cyclopentanecarboxylic acid NH2 amide ("A37")

[0587]

N

[05S3] To a solution of (IR,3R)-3-[9-(3-fluoro-4-iodo- phenyl)-9H-purln-2-ylamino]-cyclopentanecarboxylic acid C1 amide (117 mg, 0.25 mmol), 1-(2-methoxy-ethyl)-4-(4, 4,5, S-tetramethyl-[1, 3,2]dioxaborolan-2-yl)-IH-pyrazole (80.7 NO2 NH2 mg, 032 mmol) in dioxane (5 ml) are added water (0.5 ml) and potassium carbonate (103 mg, 0.74 mmol). The mixture US 2016/0002242 A1 Jan. 7, 2016 64

-continued -continued 0 HOW N H2N ~/ / /

x HCl NH2 EtNHPr12 BloxHrlc Yj Cl ~ N NH Yi N NO2 [05SS] A solution of 2,4-dichloro-5-nitro-pyrimidine (11.5 g, 593 mmol) in THF (25 ml) is cooled to O' C. To this solution is added a solution of 6-amino-2-methyl-quinoline in THF (95 ml) dropwise under stirring. The reaction mixture is allowed to reach room temperature. The precipitate that has formed is filtered off, washed with water and dried under vacuum to afford (2-chloro-5-nitro-pyrlmidin-4-yl)-(2-me- N thyl-quinolin-6-yl)-amine hydrochloride as yellow crystals; HO +/ HPLC/MS 1.42 min (A), [M+H] 316; 'H NMR (400 MHz, ~H DMSO-dc) ft [ppm] 10.84 (s, IH), 9.24 (s, IH), 8.94 (d, J=8.6 EDC1, HOBt Hz, I H), 8.49-8.34 (m, 2H), 8.22 (dd, J=9.1,2.4 Hz, I H), 7.91 THE (d, J=8.6 Hz, IH), 2.96 (s, 3H). [0589] To a solution of (2-chloro-5-nitro-pyrimidin-4-yl)- HN N NH (2-methyl-quinolin-6-yl)-amine hydrochloride (1.41 g, 4.01 mmol) in dioxane (20 ml) are added (IR,3R)-3-amino-cyclo- N pentanecarboxylic acid hydrochloride (700 mg, 4.23 mmol) NO2 and N-ethyldiisopropylamine (2.0 ml, 11.8 mmol) and the mixture is stirred for 18 hours at ambient temperature. The reaction mixture is evaporated and the residue is chromato- graphed on a silica gel column with dichloromethane/metha- nol as eluent to afford (IR,3R)-3-[4-(2-methyl-quinolin-6- ylamino)-5-nitro-pyrlmidin-2-ylamino]- N cyclopentanecarboxylic acid as yellow solid; HPLC/MS 1.52 'H H2N +7 min (A), [M+H] 409; NMR (400 MHz, DMSO-dc) ft [ppm] 10.84 (s, IH), 9.24 (s, IH), 8.94 (d, J=8.6 Hz, IH), 8.49-834 (m, 2H), 8.22 (dd, J=9.1,2.4 Hz, IH), 7.91 (d, J=8.6 SnC12 Hz, IH), 2.96 (s, 3H). EtOAc EtOH [0590] To a suspension of (IR,3R)-3-[4-(2-methyl-quino- 70' C. Iin-6-ylamino)-5-nitro-pyrlmidin-2-ylamino]-cyclopentan- HN N NH ecarboxylic acid (355 mg, 0.87 mmol) in THF (9 ml) are added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (332 mg, 1.73 mmol), I -hydroxybenzotriazole NO2 hydrate (117mg, 0.87 mmol) and ammonia as a 0.5M solu- tion in dioxane (9.0 ml, 4.5 mmol). The reaction mixture is stirred for 16 hours at room temperature. It is then evaporated and the residue is chromatographed on a silica gel column with dichloromethane/methanol as eluent to afford (IR,3R)- 0 3-[4-(2-methyl-quinolin-6-ylamino)-5-nitro-pyrlmidin-2- N ylamino]-cyclopentanecarboxylic acid amide as yellow H2N +7 solid; HPLC/MS 139min (A), [M+H] 408. [0591] To a suspension of (IR,3R)-3-[4-(2-methyl-quino-

HC(OH ) Iin-6-ylamino)-5-nitro-pyrlmidin-2-ylamino]-cyclopentan- 100' C. ecarboxylic acid amide (399 mg, 0.98 mmol) in a mixture of ethyl acetate (4.5 ml) and ethanol (1.5 ml) is added tin(II)- HN N NH chloride (555 mg, 2.93 mmol) and the reaction mixture is stirred for 16hours at 70' C. The reaction mixture is cooled to room temperature, basified with saturated sodium carbonate solution, filtered over a Celite and the residue is NH2 pad of washed with ethyl acetate and water. The organic phase ofthe filtrate is separated, dried over sodium sulfate and evaporated US 2016/0002242 A1 Jan. 7, 2016 65

to afford (1R,3R)-3-[5-amino-4-(2-methyl-quinolin-6- 7.53 (d, J=8.5 Hz, 1H), 7.25 (m, 2H), 6.68 (s, 1H), 430 (bs, ylamino)-pyrimidin-2-ylamino]-cyclopentanecarboxylic 1H), 2.79 (p, J=8.2 Hz, 1H), 2.70 (s, 3H), 2.18-1.99 (m, 2H), acid amide as orange brown solid; HPLC/MS 1.15 min (A), 1.98-1.87 (m, 1H), 1.86-1.75 (m, 1H), 1.74-1.56 (m, 2H). [M+H] 378. [0592] A solution of (1R,3R)-3-[5-amino-4-(2-methyl- Example 30 quinolin-6-yl amino)-pyrimidin-2-ylamino]-cyclopentan- ecarboxylic acid amide (109 mg, 0.29 mmol) in triethyl Synthesis of (9-(4-[1-(2-methoxy-ethyl)-1H-pyra- orthoformate (3 ml) is heated to 100' C. and stirred at this zo1-4-yl]-phenyl )-9H-purin-2-yl)-(R)-pyrrolidin-3- temperature for 16 hours. The reaction mixture is evaporated yl-amine ("A38") and 1-[(R)-3-(9-(4-[1-(2-methoxy- in vacuo and the residue is chromatographed on a silica gel ethyl)-1H-pyrazol-4-yl]-phenyl )-9H-purin-2- column with dichloromethane/methanol as beige solid; ylamino)-pyrro1idin-1-yl]-3-(4-methyl-piperazin-1- 'H HPLC/MS 1.29 min (A), [M+H] 388; NMR (400 MHz, yl)-propan-1-one ("A39") DMSO-de) ft [ppm] 8.77 (s, 1H), 8.66 (s, 1H), 8.56 (s, 1H), 834 (d, J=8.5 Hz, 1H), 830 (s, 1H), 8.11 (d, J=9.0 Hz, 1H), [0593]

N

NEts ~H EtNHPrlr 2-medtoxyedtano1 Cl Cl N NH

NOr NHr N NOr

SnClr HC(0Etb EtOAc 100' C. HN N NH EtOH HN N NH 70' C.

NOr NHr

0 0 ~ a / 0/ ~N Pd(dpp0 KrCOg 80' C. Yj dioxane/water US 2016/0002242 A1 Jan. 7, 2016 66

-continued

N~ N~ N N

Cl

HC 1/di oxane H ~ OH dichloro- TBTU methane 4-methyl-morphine DMF

Yj Yj

"A38"

N~ N

Vj'

"A39"

[0594] "A38":grey solid; HPLC/MS 1.33 min (A), [M+H] 405;

[0595] "A39":colourless amorphous solid; HPLC/MS 1 34 min (A), [M+H] 559.

Example 31

H HN —N Synthesis of (1R,3R)-3-[9-(4-ethoxy-phenyl)-8-me- THF thyl-9H-purin-2-ylamino]-cyclobentanecarboxylic Cl ~ N NH acid amide ("A40") Yi N [0596] NO2 I

CH C(OH) NEts 80' C. Cl~ N NH 2 days 2-10 Cl C. Ti N NO2 NH2 NH2 US 2016/0002242 A1 Jan. 7, 2016 67

-continued TABLE 2-continued 0 GCN2 inhibition of some representative OH com ounds of the formula I

ICso ICso ICso ICso GCN2 GCN2 GCN2 GCN2 x HCI Compound (enzyme (cellular Compound (enzyme (cellular No. assay) assay) No. assay) assay) NHz "A24" "A34" B DIPEA "A26" "A36" A CHsOCHzCHzOH "A26" "A36" A "A27" "A37" 160' C. A "A28" "A38" C "A29" "A39" B "A30" "A40"

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

[0598] The compounds shown in Table 2 are particularly ~H preferred compounds according to the invention. EDC1, HOB [0599] The following examples relate to medicaments: THE Example A

Injection vials

A solution of 100 of an active ingredient of the 0 [0600] g 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- tions. Each injection vial contains 5 mg of active ingredient.

Example B

Suppositories

[0601] A mixture of 20 g of an active ingredient of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and allowed to cool. light beige solid; HPLC/MS 1.49 min (A), [M+H] 381. Each suppository contains 20 mg of active ingredient. Pharmacological Data Example C [0597] Solution TABLE 2 [0602] A solution is prepared from I g of an active ingre- GCN2 inhibition of some representative dient of the formula I, 938 g of NaHzPO4. 2 HzO, 28.48 g of com ounds of the formula I 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 ICso ICso ICso ICso solution is made up to I I and sterilised by irradiation. This GCN2 GCN2 GCN2 GCN2 Compound (enzyme (cellular Compound (enzyme (cellular solution can be used in the form of eye drops. No. assay) assay) No. assay) assay) Example D "A 1" A "Al I" A "A2" A "A12" A "A3" A "A13" A Ointment "A4" A "A14" C "As" A "AI6" B [0603] 500 mg of an active ingredient of the formula I are "A6" B "A16" A mixed with 99.5 g of Vaseline under aseptic conditions. "A7" A "A17" A "A8" C "A18" A "A9" A "A19" B Example E "A10" A "A20" C "A21" A "A31" B Tablets "A22" B "A32" B "A23" A "A33" B [0604] A mixture of I kg ofactive ingredient ofthe formula I, 4 kg oflactose, 1.2 kg ofpotato starch, 0 2 kg oftalc and 0.1 US 2016/0002242 A1 Jan. 7, 2016 68

kg ofmagnesium stearate is pressed in a conventional manner NR'SO, A, SO,N(R')„S(O)A, COHet', O[C(R'),] to give tablets in such a way that each tablet contains 10mg of Het', NHCOOA, NHCON(R )~, NHCOO[C(R )~] active ingredient. N(R ), NHCOO[C(R )~] Het', NHCONH[C(R ) ~] N(R )~, NHCONH[C(R )~] Het', OCONH[C Example F (R )~] N(R )~, OCONH[C(R )~] Het', S(O) Het', CHOand/orCOA, Dragees Het denotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, [0605] Tablets are pressed analogously to Example E and oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, subsequently coated in a conventional manner with a coating tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, of sucrose, potato starch, talc, tragacanth and dye. indolyl, isoindolyl, indolinyl, benzimidazolyl, inda- zolyl, quinolyl, isoquinolyl, benzoxazolyl, 1,3-ben- Example G zodioxolyl, benzothiophenyl, benzofuranyl, imida- zopyridyl, dihydroindolyl, quinoxalinyl, benzo[1, 2, Capsules 5]thiadiazolyl or furo[3, 2-b]pyrldyl, each of which is unsubstituted or mono- or disubstituted Hal, [0606] 2 kg of active ingredient of the formula I are intro- by A, duced into hard gelatine capsules in a conventional manner in [C(R ))]~OR, O[C(R )~]~OR, [C(R )~]~N(R )), O[C(R N(R [C(R Het', NO~, CN, [C(R such a way that each capsule contains 20 of the active )~] )~, )~] ) mg CON(R ingredient. ~]~COOR, O[C(R )~]~COOR, )), NR COA, NR SO~A, SO~N(R )~, S(O) A, COHet, O[C(R Het', NHCOOA, NHCON(R Example H )~] )~, NHCOO[C(R )~] N(R )~, NHCOO[C(R )~]~-Het, NHCONH[C(R N(R NHCONH[C(R Ampoules )~] )~) )~] Het', OCONH[C(R )~] N(R )~, OCONH[C(R )~] [0607] Asolutionof1 kgofactiveingredientoftheformula Het', S(O) Het', CHO, COA, S and/or 0, I in 60 I of bidistilled water is sterile filtered, transferred into Het' ampoules, lyophilised under sterile conditions and sealed denotes pyrazolyl, pyridyl, pyrazinyl, indolyl, dihydro- under sterile conditions. Each ampoule contains 10 mg of pyrrolyl, pyrrolidinyl, azetidinyl, oxetanyl, tetrahy- active ingredient. droimidazolyl, dihydropyrazolyl, tetrahydropyra- tetrahydro 1. Compounds of the formula I zolyl, furanyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, morpholinyl, hexahy- dropyridazinyl, hexahydropyrimidinyl, [1,3]dioxola- nyl, tetrahydropyranyl or piperazinyl, each of which R' is unsubstituted or mono- or disubstituted by Hal, A, [C(R )2] OR, O[C(R )2] OR, [C(R ) ] N(R ), [C(R )~]~Het, NO~, CN, [C(R )~]~COOR, O[C(R ) 2] COOR, CON(R ), NR COA, NR SO2A, SO2N (R )~, S(O) A, COHet, O[C(R )~] N(R )~, O[C(R ) ~] Het, NHCOOA, NHCON(R )~, NHCOO[C(R ) ~] N(R )~, NHCOO[C(R )~] Het, NHCONH[C in which (R )~] N(R )~, NHCONH[C(R ) ] Het, OCONH X [C(R )~] N(R )~, OCONH[C(R (~] Het, S(O) and/or denotes H, CH3 or NH~, Het, CHO, COA, S 0, R' Het denotes pyrrolidinyl, azetidinyl, azoxetanyl, tetrahy- denotes Ar or Het, droimidazolyl, tetrahydropyrazolyl, tetrahydrofura- R nyl, piperidinyl, morpholinyl, tetrahydropyranyl or denotes pyrazolyl, pyrrolidinyl or cyclopentyl, each of piperazinyl, each of which is unsubstituted or mono- which is unsubstituted or monosubstituted by A, Hal, or disubstituted by Hal, A, OA, CN, COOA, CON H~, ( ')~],o ', OI ( ')~] o ', [ ( ')~], ( ')~, S(O) A, S(O) Ar, COA and/or 0, [C(R )~] Ar, [C(R )~] Het, CN, [C(R )~] COOR, Cyc Cyc, CO[C(R'),]~N(R')„CO[C(R),]~Het', denotes cycloalkyl with 3-7 C-atoms, which is unsub- NR COA, NR SO~A, SO~N(R )~, S(O) A, COHet', stituted or monosubstituted by NH~, O[C(R )~] N(R )~, O[C(R )~] Het', NHCOOA, A NHCON(R )~) NHCOO[C(R )~] N(R )~) NHCOO denotes unbranched or branched alkyl with 1-6C-atoms, [C(R )~] -Het', NHCONH[C(R )~] N(R )~, wherein one or two non-adjacent CH- and/or CH~- N-, 0- and/or S-atoms and NHCONH[C(R )~] Het', OCONH[C(R )~] N(R )~, groups may be replaced by wherein I-7H-atoms be replaced F or OCONH[C(R )~] Het' or C(O)R, may by Cl, R Hal denotes F, Cl, Br or I, denotes H or unbranched or branched alkyl with 1-4 n C-atoms, denotes 0, I or 2, Ar m denotes phenyl, which is unsubstituted or mono-, di- or denotes I, 2 or 3, trisubstituted by Hal, A, [C(R )~] OR, O[C(R )~] p denotes 0, I, 2, 3 or 4,

( ')~], ( ')r, OI ( ')~], ( ')~, I ( ')~] and pharmaceutically acceptable solvates, salts, tau- ~Het', NO~, CN, [C(R )~]~COOR, O[C(R )~] tomers and stereoisomers thereof, including mixtures ~COOR CONH~) CONA CONA~) NR COA thereof in all ratios. US 2016/0002242 A1 Jan. 7, 2016 69

2. Compounds according to claim 1 in which Het R denotes pyrrolidinyl, piperidinyl, morpholinyl or piper- denotes pyrazolyl, pyrrolidinyl or cyclopentyl, each of azinyl, each of which is unsubstituted or monosubsti- which is unsubstituted or monosubstituted by A, tuted by A, [C[R')z] Ar, [C[R')z]~Het', Cyc, [C[R')z]~OR', A CO[CD )z]~N[R )z or CO[CD )z]~Het', denotes unbranched or branched alkyl with 1-6C-atoms, and pharmaceutically acceptable solvates, salts, tautomers wherein one or two non-adjacent CH- and/or CHz- and stereoisomers thereof, including mixtures thereof in groups may be replaced by N-, 0- and/or S-atoms and all ratios. wherein 1-7H-atoms may be replaced by F or Cl, 3. Compounds according to claim 1 in which Hal Ar denotes F, Cl, Br or I, denotes phenyl, which is unsubstituted or mono-, di- or n trisubstituted by Hal, A, [C[R OR, O[C[R )z] )z] denotes 0, 1 or 2, Het', CONHz, CONA and/or OR, [C[R )z] m CONAz, denotes 2 or and pharmaceutically acceptable solvates, salts, tau- 1, 3, tomers and stereoisomers thereof, including mixtures p denotes 0, 1, 2, 3 or 4, thereof in all ratios. and pharmaceutically acceptable solvates, salts, tau- 4. Compounds according to claim 1 in which tomers and stereoisomers thereof, including mixtures Het thereof in all ratios. denotes pyrazolyl, pyridyl, indolyl, isoindolyl, indoli- 7. Compounds according to claim 1, selected from the nyl, quinolyl or isoquinolyl, each of which is unsub- group stituted or mono- or disubstituted by A and/or 0, and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in No. Name all ratios. "Al" 9-(4-ethoxyphenyll-N-(1-(1-medtylpiperidin-4-yll-1H-pyrazoh 5. Compounds according to claim 1 in which 4-ylb9H-purin-2-amine "A2" 9-(4-(2-medtoxyedtoxylphenyll-N-(N(gmedtylpiperidin-4-yll- Het' 1H-pyrazol-4-ylb9H-purin-2-amine denotes pyrazolyl, pyridyl, pyrrolidinyl, piperidinyl, "A3" 4-(2-((N(tetrahydro-2H-pyran-4-yll-1H-pyrazoh4-yllaminob morpholinyl, tetrahydropyranyl or piperazinyl, each 9H-purin-9-yllbenzamide "A4" N, 9-bis-(l-edtyb1 H-pyrazol-4-ylb9H-purin-2-amine o which is unsub stituted or mono- or di substituted f by "A6" 9-(1-ethyhtH-pyrazob4-yll-N-(N(tetrahydro-2H-pyran-4-yll- A and/or [C[R )z] Het, 1H-pyrazol-4-ylb9H-purin-2-amine and pharmaceutically acceptable solvates, salts, tau- "A6" 9-(4-ethoxyphenyll-8-medtyhN-(1-(Nmedtylpiperidin-4-yll-1H- tomers and stereoisomers thereof, including mixtures pyrazol-4-ylb9H-purin-2-amine "A7" 9-(4-ethoxyphenyll-N2-(N(gmedtylpiperidin-4-yll-1H-pyrazoh thereof in all ratios. 4-ylb9H-purine-2, 8-diamine 6. Compounds according to claim 1 in which "A8" N, 9-bis (1-ethyl-1H-pyrazol-4-ylb9H-purine-2, 8-diamine X "A9" 6-(2-((1-edtyh 1H-pyrazol-4-yl)aminob9H-purin-9-ylb3, 3- dimethylindolin-2-one denotes H, CHs or NHz, "A10" N-(N(2-(1H-pyrazohgylledtyll-1H-pyrazoh4-yll-9-(4- R' ethoxyphenylb9H-purin-2-amine "A11" 9-(4-ethoxyphenyll-N-(1-(3-(piperidin-4-yllpropyll-1H-pyrazoh denotes Ar or Het, 4-ylb9H-purin-2-amine R "A12" 9-(4-chloro-3-fluorophenyll-N-(N(tetrahydro-2H-pyran-4-yll- denotes pyrazolyl, pyrrolidinyl or cyclopentyl, each of 1H-pyrazol-4-ylb9H-purine-2-amine "A13" N-(N(N(2-methoxyedtyllpiperidin-4-yll-1H-pyrazoh4-yll-9-(4- which is unsubstituted or monosubstituted by A, methoxyphenylb9H-purin-2-amine [C[R')z] Ar, [C[R')z]~Het', Cyc, [C[R')z]~OR', "A14" 9-(4-ethoxy-phenyll-N qt-(2-pyrazoht-yhedtyll-1H-pyrazob4- CO[CD )z]~N[R )z or CO[CD )z]~Het', yll-9H-purine-2, 8-diamine R "A16" N-(N(gmethylpiperidin-4-yll-1H-pyrazoh4-yll-9-(quinolin-6- ylb9H-purin-2-amine denotes H or unbranched or branched alkyl with 1-4 "A16" 9-(4-medtoxyphenyll-N-(1-(Nmedtylpiperidin-4-yll-1H- C-atoms, pyrazol-4-ylb9H-purin-2-amine "A17" Ar N-(N(4-aminocyclohexyll-1H-pyrazoh4-yll-9-(4- ethoxyphenylb9H-purin-2-amine denotes phenyl, which is unsubstituted or mono-, di- or "A18" [9-(4-medtoxy-phenyll-9H-purin-2-ylb(1H-pyrazob4-yll-amine trisubstituted by Hal, A, [C[R )z] OR, O[C[R )z] "A19" [9-(4-medtoxy-phenyll-9H-purin-2-ylb(t-medtyhtH-pyrazoh3- OR, [C[R )z] Het', CONHz, CONA and/or ylbamine "A20" [9-(4-medtoxy-phenyll-9H-purin-2-ylb(t-phenyh1H-pyrazoh4- CONAz, ylbamine Het "A21" (1-medtyhtH-pyrazoh4-yll-(944-(NmedtyhtH-pyrazoh4-yll- denotes pyrazolyl, pyridyl, indolyl, isoindolyl, indoli- phenylF9H-purin-2-yl)-amine "A22" N-(2, 3-dihydroxy-propyl1-442-(l-edtyh 1H-pyrazol-4-ylaminob quinolyl or isoquinolyl, each of which is unsub- nyl, purin-9-yll-benzamide stituted or mono- or disubstituted by A and/or 0, "A23" (1-medtyhtH-pyrazoh4-yll-(944-(Npiperidin-4-yhtH-pyrazob Het' 4-ylbphenyll-9H-purin-2-yl)-amine "A24" N2-(1-medtyhtH-pyrazoh4-yll-944-(1-medtyhtH-pyrazoh4- denotes pyrrolidinyl, piperidinyl, pyrazolyl, pyridyl, ylbphenyll-9H-purine-2, 8-diamine morpholinyl, tetrahydropyranyl or piperazinyl, each "A26" 448-amino-2-(Nedtyh 1H-pyrazoh4-ylaminol-purin-9-ylFN-(2- ofwhich is unsub stituted or mono- or di substituted by hydroxy-ethylbbenzamide A and/or [C[R )z] Het, US 2016/0002242 A1 Jan. 7, 2016 70

-continued tures thereof in all ratios, and optionally an pharmaceutically acceptable carrier, excipient or vehicle. No. Name 10. Compounds of the formula I and pharmaceutically acceptable salts, solvates, tautomers and stereoisomers "A26" N2-(1-mefltyhtH-pyrazoh4-yli-9-[4-(1-piperidin-4-yhtH- thereof, including mixtures thereof in all ratios, for the use for pyrazoh4-yli-phenylb9H-purine-2, 8-diamine "A27" (transi-3-[9-(3-fluoro-44odo-phenyli-9H-purin-2-ylaminob the treatment and/or prevention of inflammatory conditions, cyclopentanol immunological conditions, autoimmune conditions, allergic "A28" (transi-3-[9-(4-efltoxy-phenyli-9H-purin-2-ylaminob conditions, rheumatic conditions, thrombotic conditions, cyclopentanol cancer, infections, neurodegenerative diseases, neuroinflam- "A29" (transi-3-(9-(3-fluoro-4-[1-(2-methoxy-efltyli-1H-pyrazoh4-ylb matory diseases, cardiovascular diseases, and metabolic con- phenyl)-9H-purin-2-ylaminoi-cyclopentanol "A30" (transi-3-(9-[4-(1-mefltyhtH-pyrazoh4-yli-phenylb9H-purin-2- ditions, the methods comprising administering to a subject in ylamino )-cyclopentanol need thereof an effective amount of a compound of claim 1. "A31" (1R,3Ri-3-[9-(3-fluoro-4-iodo-phenyli-9H-purin-2-ylaminob 11.Compounds according to claim 10 for the use for the cyclopentanecarboxylic acid amide treatment and/or prevention of cancer, "A32" (1R,3Ri-3-[9-(4-efltoxy-phenyli-9H-purin-2-ylaminob cyclopentanecarboxylic acid amide where the cancer to be treated is a solid tumour or a tumour "A33" (1R,3Ri-3-[9-(4-iodo-phenyli-9H-purin-2-ylaminob of the blood and immune system. cyclopentanecarboxylic acid amide 12. Compounds according to claim 11, where the solid "A34" (1R,3Ri-3-(9-[4-(2-mefltoxy-efltoxyi-phenylb9H-purin-2- tumour originates from the group of tumours of the epithe- ylamino)-cyclopentanecarboxylic acid amide "A36" (1R,3Ri-3-(9-(3-fluoro-4-[l-(2-mefltoxy-efltyli-lH-pyrazol-4- lium, the bladder, the stomach, the kidneys, ofhead and neck, ylbphenyl)-9H-purin-2-ylaminoi-cyclopentanecarboxylic acid the esophagus, the cervix, the thyroid, the intestine, the liver, atrtlde the brain, the prostate, the uro-genital tract, the lymphatic "A36" (1R,3Ri-3-(9-(4-[l-(2-efltoxy-efltyli-lH-pyrazoh4-ylbphenyl)- system, the stomach, the larynx, the bones, including chon- 9H-purin-2-ylaminoi-cyclopentanecarboxylic acid amide "A37" (1R,3Ri-3-[9-(2-methyl-quinolin-6-yli-9H-purin-2-ylaminob dosarcoma and Ewing sarcoma, germ cells, including cyclopentanecarboxylic acid amide embryonal tissue tumours, and/or the lung, from the group of "A38" monocytic leukaemia, lung adenocarcinoma, small-cell lung "A39" "A40" carcinomas, pancreatic cancer, glioblastomas, neurofibroma, angiosarcoma, breast carcinoma and/or maligna melanoma. 13. Compounds according to claim 10 for the use for the and pharmaceutically acceptable solvates, salts, tautomers treatment and/or prevention of diseases selected from the and stereoisomers thereof, including mixtures thereof in all group rheumatoid arthritis, systemic lupus, asthma, multiple ratios. sclerosis, osteoarthritis, ischemic injury, giant cell arteritis, S.Process for the preparation of compounds of the formula inflammatory bowel disease, diabetes, cystic fibrosis, psoria- I according to claim 1 and pharmaceutically acceptable salts, sis, Sjogrens syndrom and transplant organ rejection. solvates, tautomers and stereoisomers thereof, characterised 14. Compounds according to claim 10 for the use for the in that treatment and/or prevention of diseases selected from the a) wherein in formula I X denotes H, group Alzheimer's disease, Down's syndrome, hereditary a compound of the formula II cerebral hemorrhage with amyloidosis-Dutch Type, cerebral amyloid angiopathy, Creutzfeldt-Jakob disease, frontotem- poral dementias, Huntingon's disease, Parkinson's disease. 15. Compounds according to claim 10 for the use for the R' treatment and/or prevention of diseases selected from the H / N N NH group leishmania, mycobacteria, including M. /eprae, M. Rz tuberculosis and/or M. avium, /eis/zmania, plasmodium, human immunodeficiency virus, Epstein Barr virus, Herpes N simplex virus, hepatitis C virus. NHz 16.Medicaments comprising at least one compound ofthe formula I ofclaim 1 and/or pharmaceutically acceptable salts, in which R' and R have the meanings indicated in claim 1, solvates and stereoisomers thereof, including mixtures is reacted with trimethyl- or triethylorthoformate thereof in all ratios, and at least one further medicament active or ingredient. b) wherein in formula I X denotes NHz 17. Set (kit) consisting of separate packs of a compound of the formula II is reacted with CN Br (a) an effective amount of a compound of the formula I of and/or claim 1 and/or pharmaceutically acceptable salts, sol- mix- a base or acid of the formula I is converted into one of its vates, salts and stereoisomers thereof, including salts. tures thereof in all ratios, and an effective amount a further medicament active 9. Medicaments comprising at least one compound of the (b) of ingredient. formula I ofclaim 1 and/or pharmaceutic ally acceptable salts, solvates, tautomers and stereoisomers thereof, including mix-