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(19) United States (12) Patent Application Publication (Io) Pub llIIlIlllIlIlIllIlIllIllIllIIlIlllIlIIllllIIlllIIlIlllIIlIlllllIIIlllIlIllIIIIIIIIIIIIIIII US 20160015712AI (19) United States (12) Patent Application Publication (Io) Pub. No. : US 2016/0015712 A1 DORSCH et al. (43) Pub. Date: Jan. 21, 2016 (54) TRIAZOLO [4,5-D]PYRIMIDINE Publication Classification DERIVATIVES (51) Int. Cl. (71) Applicant: MERCK PATENT GMBH, Darmstadt 261K31/519 (2006.01) (DE) 261K31/53 77 (2006.01) C07D 519/00 (2006.01) (72) Inventors: Dieter DORSCH, Ober-Ramstadt (DE); C07D 487/04 (2006.01) Guenter HOELZEMANN, (52) U.S. Cl. Seeheim- Jugenheim (DE); Michel CPC ............ 261K31/519 (2013.01); C07D 487/04 CALDERINI, Darmstadt (DE); Ansgar (2013.01);261K31/5377 (2013.01); C07D WEGENER, Heusenstamm (DE); 519/00 (2013.01) Oliver POESCHKE, Wiesbaden (DE) (57) ABSTRACT (73) Assignee: MERCK PATENT GMBH, Darmstadt (DE) Compounds of the formula I (21) Appl. No. : 14/772, 865 (22) PCT Filed: Feb. 10, 2014 H (86) PCT No. : PCT/EP2014/000361 II ) 371 (c)(I), NX N (2) Date: Sep. 4, 2015 (30) Foreign Application Priority Data in which R' and R have the meanings indicated in Claim 1, are inhibitors of GCN2, and can be employed, inter alia, for Mar. 5, 2013 (EP) ... 13001110.9 the treatment of cancer. US 2016/0015712 A1 Jan. 21, 2016 TRIAZOLO [4,5-D]PYRIMIDINE [0006] Several mechanistic studies discovered that DERIVATIVES immune escape has an important interface with metabolic alterations within the tumor microenvironment. Here impor- BACKGROUND OF THE INVENTION tant roles in mediating immune tolerance to antigens have been associated to the catabolism ofthe essential amino acids [0001] The invention had the object of finding novel com- tryptophan and arginine, carried out by the enzymes pounds having valuable properties, in particular those which indoleamine 2,3-dioxygenase (IDO) and arginase I (ARG), can be used for the medicaments. preparation of respectively (Bronte and Zanovello, 2005; Muller et al. , [0002] The present invention relates to compounds and to 2005b; Muller and Prendergast, 2007; Munn and Mellor, the use of compounds in which the inhibition, regulation 2007; Popovic et al. , 2007). IDO is a single-chain oxi- and/or modulation of signal transduction by protein kinases, doreductase that catalyzes the degradation of tryptophan to in particular immune-modulatory or stress response kinases, kynurenine. IDO is not responsible for catabolizing excess furthermore to pharmaceutical compositions which comprise dietary tryptophan but to modulate tryptophan level in a local these compounds, and to the use of the compounds for the environment. Elevations in tryptophan catabolism in cancer treatment of kinase-induced diseases. Because protein patients manifest in significantly altered serum concentration kinases regulate nearly every cellular process, including of tryptophan or catabolites and this was correlated to IDO metabolism, cell proliferation, cell differentiation, and cell which is commonly elevated in tumors and draining lymph survival, they are attractive targets for therapeutic interven- nodes. According to several publications IDO over-expres- tion for various disease states. For example, cell-cycle con- sion is associated with poor prognosis in cancer [Okamoto et trol, immune modulation, stress response and angiogenesis, al 2005; Brandacher et al, 2006]. T cells appear to be prefer- in which protein kinases play a pivotal role are cellular pro- entially sensitive to IDO activation, such that when starved cesses associated with numerous disease conditions such as for tryptophan they cannot divide and as a result cannot but not limited to cancer, inflammatory diseases, neurodegen- become activated by an antigen presented to them. Munn and erative diseases, chronic infections, abnormal angiogenesis Mellor and their colleagues, revealed that IDO modulates and diseases related thereto, atherosclerosis, macular degen- immunity by suppressing T-cell activation and by creating eration, diabetes, obesity, and pain. peripheral tolerance to tumor antigens (Mellor and Munn, [0003] Compounds of formula I inhibit the stress response 2004). These mechanism encompass the subversion of eIF2 kinase EIF2AK4 called general control nonderepress- immune cells recruited by the tumor cell to its immediate ible 2 (GCN2). microenvironment or to the tumor-draining lymph nodes Here the tumor antigens that were scavenged antigen- [0004] Many strategies of cancer treatment of solid tumors by cells are cross-presented to the immune focus on the surgically removal of the tumor mass as far as presenting adaptive system. In addition to being directly toleragenic, mature DCs possible and the subsequent eradication of any residual tumor have the capacity to expand regulatory Tcells (Tregs) [Moser cells by radiotherapy and chemotherapy with cytotoxic agents or inhibitors that target cancer cell pathways more 2003]. specifically. However, the success of such approach is limited [0007] Beside tryptophan catabolism the conversion of and often does not persist. This is mainly due to the narrow arginine is increased in a tumor-conditioned microenviron- therapeutic window for such cytotoxic agents (specificity and ment, and numerous reports indicate a role for the activation side effects) and to the capability ofcancer calls to adapt to the ofarginases during tumor growth and development. In tumor- selective pressure applied by cytotoxic or other inhibitory infiltrating myeloid cells, arginine is converted by arginase I agents. The survival of a small number of tumor (stem) cells (ARGI), arginase II (ARG2) to urea and ornithine and oxi- that acquired resistance to the initial treatment can be sufft- dized by the inducible form of nitric oxide synthase (NOS2) cient to seed the regrowth of a tumor. These relapses are in to citrulline and nitric oxide (NO). most cases more difficult to treat compared to that of the [000S] Increased ARG activity is frequently observed in initial tumors. As a consequence the more successful target- patients with colon, breast, lung, and prostate cancer [Ceder- ing of tumor cells may require targeting multiple survival and baum 2004] correlating with the over-expression of ARG and escape mechanism of tumor cells in parallel (Muller & NOS found in prostate cancers [Keskinege et al. 2001, Aal- Prendegast 2007). toma et al. 2001, Wang et al. 2003]. It was shown that ARG [0005] Development of malignancies is accompanied by a activity in infiltrating macrophages impairs antigen-specific major roll up of the cellular physiology. During this process T cell responses and the expression of the CD3 receptor. several qualities are acquired by the cancer cells that are basis Moreover the cumulative activity ofARG and NOS in tumor for immortalization or insensitivity to growth inhibitory sig- associated myeloid cells can generate inhibitory signals to nals. In addition the tumor cells also modify the interaction antigen-specific T lymphocytes that eventually lead to apop- with the microenvironment and beyond. The latter area tosis [Bronte 2003 a; 2003b]. includes the strategies of tumor cells to escape from the [0009] Both, the IDO and the ARG related mechanism immunological surveillance (Muller & Prendegast 2007). merge at the point of sensing the depleted concentration ofthe The immune surveillance limits malignant growth but also respective amino acid concentration. During amino acid dep- provides a selective pressure triggering the evolution of rivation, the eIF2 kinase EIF2AK4 called general control mechanisms for evading the immune response as reviewed by nonderepressible 2 (GCN2) is interacting with the intracellu- [Dunn et al. 2004]. Essentially it has been frequently lar accumulating deacylated tRNA. As a consequence the observed that ablation of T cell immunity is sufficient to GCN2 is assumed to change from an auto-inhibited to an increase tumor incidence [Shankaran et al. 2001] and it is active conformation and further activate by auto-phosphory- believed that immune escape is affecting tumor dormancy lation. Then the only known substrate protein eIF2a becomes versus progression, promoting invasion and metastasis and phosphorylated and as a consequence the complex for trans- negatively impacts on therapeutic response. lation initiation is inhibited [Harding et al. 2000,]. This US 2016/0015712 A1 Jan. 21, 2016 diminishes the general Cap-dependent translation initiation ever I MT was unable to elicit tumor regression in several and by this the corresponding protein production. On the tumor models, suggesting only modest antitumor efficacy other hand this induces the specific expression of stress when IDO inhibition was applied as a monotherapy. related target genes mainly by cap-independent initiation via [0015] In contrast, the combinatory treatment with I MT the activating transcription factor 4 (ATF4). By expressing and a variety of cytotoxic chemotherapeutic agents elicited the respective stress response proteins, e.g. enzymes in the in regression of established MMTV-neu/HER2 tumors, which amino acid metabolism, the cell tries to compensate the par- responded poorly to any single-agent therapy [Muller et al ticular cell stress [Wek et al. 2006]. If the stress persists, the 2005a]. Immunodepletion of CD4+ or CD8+ T cells from the same pathway will switch to promoting cell death via tran- mice before treatment abolished the combinatorial efficacy scription of the pro-apoptotic transcription factor, CCAAT/ observed in this model, confirming the expectation that I MT enhancer-binding protein homologous protein
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