USOO892.1361 B2 (12) United States Patent (10) Patent No.: US 8,921,361 B2 Cmiljanovic et al. (45) Date of Patent: Dec. 30, 2014 (54) TRIAZINE, PYRIMIDINE AND PYRIDINE 409/04 (2013.01); C07D 413/04 (2013.01); ANALOGS AND THEIR USEAS C07D 413/14 (2013.01); C07D 417/04 THERAPEUTICAGENTS AND DAGNOSTIC (2013.01); C07D 417/14 (2013.01); C07D PROBES 491/048 (2013.01); C07D491/147 (2013.01); C07D 495/04 (2013.01); C07D 495/14 (2013.01); C07D498/04 (2013.01); C07D (75) Inventors: Vladimir Cmiljanovic, Basel (CH): 513/04 (2013.01); C07D 519/00 (2013.01) Natasa Cmiljanovic, Basel (CH); Bernd USPC .......................................... 514/232.2:544/83 Giese, Fribourg (CH); Matthias (58) Field of Classification Search Wymann, Bern (CH) None See application file for complete search history. (73) Assignee: University of Basel, Basel (CH) (56) References Cited (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S. PATENT DOCUMENTS U.S.C. 154(b) by 60 days. 5,489,591 A * 2/1996 Kobayashi et al. ........... 514,245 (21) Appl. No.: 13/128,436 7,173,029 B2 2/2007 Hayakawa et al. 8,217,036 B2 * 7/2012 Venkatesan et al. ....... 514,232.2 (22) PCT Filed: Nov. 10, 2009 2010 OO69629 A1 3/2010 Shimma et al. (86). PCT No.: PCT/B2O09/OOT404 FOREIGN PATENT DOCUMENTS EP 1864 665 A1 12/2007 S371 (c)(1), WO 2005/028444 A1 3, 2005 (2), (4) Date: Jul. 1, 2011 WO 2007 1271.75 A2 11/2007 WO 2008/O18426 A1 2, 2008 (87) PCT Pub. No.: WO2010/052569 WO 2009/093981 A1 T 2009 WO 2009/143313 A1 11, 2009 PCT Pub. Date: May 14, 2010 WO 2009/143317 A1 11, 2009 (65) Prior Publication Data OTHER PUBLICATIONS US 2011/0275762 A1 Nov. 10, 2011 Menicagli R. et al: “2-Alkyl-4,6-dialkylamino-1,3,5-triazines via Grignard Alkylation of Cyanuric Chloride: An Aged Reaction Revis (30) Foreign Application Priority Data ited' in: Tetrahedron, Elsevier Science Publishers, vol. 56, No. 49, Dec. 1, 2000, pp. 9705-9711. Nov. 10, 2008 (GB) ................................... O821219.3 Matsuno T et al: “Synthesis and Antitumor Activity of Benzimidazolyl-1,3,5-Triazine and Benzimidazolylpyrimidine (51) Int. Cl. Derivatives' in: Chemical and Pharmaceutical Bulletin, Pharmaceu CO7D40 L/04 (2006.01) tical Society of Japan, vol. 48, No. 11, Nov. 1, 2000, pp. 1778-1781. CO7D 403/04 (2006.01) A 6LX3/5.375 (2006.01) * cited by examiner CO7D 2.5L/8 (2006.01) CO7D 40/12 (2006.01) Primary Examiner — Alicia L Otton CO7D 403/2 (2006.01) (74) Attorney, Agent, or Firm — Joyce Von Natzmer, Agris CO7D 403/4 (2006.01) & von Natzmer LLP CO7D 405/04 (2006.01) CO7D 405/4 (2006.01) (57) ABSTRACT CO7D 409/04 (2006.01) The invention relates to novel therapeutic agents and diag CO7D 413/04 (2006.01) nostic probes. The invention also relates to phosphoinositide CO7D 413/4 (2006.01) 3-kinase (PI3K) and mammalian target of rapamycin CO7D 417/04 (2006.01) (mTOR) inhibitor triazine-, pyrimidine- and pyridine-based CO7D 417/4 (2006.01) compounds Formula (I), their stereoisomers, geometric iso CO7D 49/048 (2006.01) mers, tautomers, Solvates, metabolites, N-oxide derivatives, CO7D 49/47 (2006.01) pharmaceutically acceptable salts, and prodrugs thereof.com CO7D 495/04 (2006.01) positions of the new compounds; either alone or in combina CO7D 495/4 (2006.01) tion with at least one additional therapeutic agent, with a CO7D 49.8/04 (2006.01) pharmaceutically acceptable carrier; and uses of the new CO7D 53/04 (2006.01) compounds, either alone or in combination with at least one C07D 519/00 (2006.01) additional therapeutic agent, for treating disorders mediated (52) U.S. Cl. by lipid kinases. Methods of using compounds of Formula CPC ............ C07D401/04 (2013.01); C07D 251/18 (I) for in vitro, in situ, and in vivo diagnosis, prevention or (2013.01); C07D401/12 (2013.01); C07D treatment of such disorders in mammalian cells, or associated 403/04 (2013.01); C07D 403/12 (2013.01); pathological conditions, are disclosed. (Formula I) C07D 403/14 (2013.01); C07D405/04 (2013.01); C07D405/14 (2013.01); C07D 16 Claims, No Drawings US 8,921,361 B2 1. 2 TRIAZINE, PYRIMIDINE AND PYRIDINE years, the connection between cancer and PI3K has been ANALOGS AND THEIR USEAS further substantiated Cully et al., Nat. Rev., Cancer 6:184 THERAPEUTICAGENTS AND DAGNOSTIC 192 (2006); Wymannet al., Curr. Opin. Cell Biol. 17:141-149 PROBES (2005); Vivanco et al., Nat. Rev., Cancer 2:489-501 (2002). PI3Ks have since been recognized to modulate a wide range This is the U.S. national stage of International application of cellular activities, and to be central to the growth and PCT/IB2009/007.404, filed Nov. 10, 2009 designating the metabolic control. Genetically modified mice targeting the United States and claims priority to GB 0821219.3, filed Nov. PI3K pathway, and the elucidation of human hereditary dis 10, 2008. ease like Cowden's syndrome, tuberous Sclerosis, ataxia 10 telangiectasia, X-linked myotubular myopathy and Charcot FIELD OF THE INVENTION Marie-Tooth neuropathy, have provided further insight in the cellular and systemic role of phosphoinositide signaling. The invention relates to new therapeutic agents and diag Deregulation of phosphoinositide levels, and in particular the nostic probes, including pharmaceutically acceptable salts, product of class I PI3Ks, PtdIns(3,4,5)P3, is involved in the prodrugs and metabolites thereof, which are useful for modu 15 pathogenesis of cancer, chronic inflammation, allergy, meta lating protein or enzyme activity for modulating cellular bolic disease, diabetes and cardiovascular problems. activities such as signal transduction, proliferation, differen PI3Ks are a family of enzymes, which phosphorylate the tiation, programmed cell death, migration and cytokine secre 3'-OH position of the inositol ring of phosphoinositides. They tion. More specifically the invention provides compounds have been divided into three classes on the basis of structural which inhibit, regulate, detect and/or modulate kinase activ features and in vitro lipid substrate specificity (Marone et al. ity, in particular phosphoinositide 3-kinase (PI3K), mamma Biochimica et Biophysica Acta 1784:159-185 (2008). Class lian target of rapamycin (mTOR), DNA-PK and ATM kinase I PI3Ks form heterodimers, which consist of one of the four inhibitor compounds, their pharmaceutically acceptable closely related ~110kDa catalytic Subunits, and an associated salts, and prodrugs thereof compositions of the new com regulatory Subunit belonging to two distinct families. In vitro pounds, either alone or in combination with at least one 25 they are capable to convert PtdIns to PtdIns-3-P, PtdIns-4-P to additional therapeutic agent, with a pharmaceutically accept PtdIns(3,4)P2, and PtdIns(4,5)P2 to PtdIns(3,4,5)P3, but the able carrier, and uses of the new compounds, either alone or in vivo substrate is PtdIns(4,5)P2 Cantley et al., Science in combination with at least one additional therapeutic agent, 2.96:1655-1657 (2002). Class I PI3Ks are activated by a large in the prophylaxis or treatment of a number of diseases, in variety of cell-surface receptors, comprising growth factor particular, those characterized by the abnormal activity of 30 receptors as well as G protein-coupled receptors. serine/threonine kinases, receptor tyrosine kinases and lipid Class II PI3Ks are capable to phosphorylate PtdIns and kinases. The invention also relates to methods of using the PtdIns-4-P in vitro, but their relevant in vivo substrates are compounds for in vitro, in situ, and in vivo diagnosis, assay still under investigation. This class of large (170-200 kDa) development or treatment of mammalian cells, or associated enzymes has three members, all characterized by a C-termi pathological conditions. 35 nal C2 homology domain. No adaptor molecules for class II PI3Ks have been identified so far. Class III PI3Ks are solely BACKGROUND OF THE INVENTION able to phosphorylate PtdIns, and thus generate only PtdIns 3-P. The single member of this class is Vps34, of which the S. Protein kinases participate in the signaling events which cerevisiae Vps34p (vacuolar protein Sorting mutant 34 pro control the activation, growth, differentiation, Survival and 40 tein) is the prototype, and has been shown to play an essential migration of cells in response to extracellular mediators or role in trafficking of newly synthesized proteins from the stimuli including growth factors, cytokines or chemokines. In Golgi to the yeast vacuole, an organelle equivalent to lysos general, these kinases are classified in two groups, those that omes in mammals Schu et al., Science 260:88-91 (1993). preferentially phosphorylate tyrosine residues and those that Phosphoinositide 4-kinases (PI4Ks) phosphorylate the preferentially phosphorylate serine and/or threonine resi 45 4'-OH position of the inositol ring of PtdIns, and thereby dues. The tyrosine kinases include membrane-spanning generate PtdIns-4-P. This lipid can then be further phospho growth factor receptors, for example the epidermal growth rylated by PtdIns-4-P 5-kinases to generate PtdIns(4,5)P2. factor receptor (EGFR) and cytosolic non-receptor kinases which is the main source for phospholipase C and PI3K including Src family kinases, the Syk family kinases and the signaling at the plasma membrane. Four PI4Ks isoforms are Tec family kinases. 50 known: PI4KIIC. and B, and PI4KIIIC. and B. The PI4KIIIs are Inappropriately high protein kinase activity is involved in most closely related to PI3Ks. many diseases including cancer, metabolic diseases, immu The class of PI3K-related proteins, referred to as class IV nological diseases and inflammatory disorders. This can be PI3Ks, consists of high molecular weight enzymes with a caused either directly or indirectly by the failure of control catalytic core similar to PI3Ks and PI4Ks and include the mechanisms due to mutation, overexpression or inappropri 55 target of rapamycin (mTOR, also known as FRAP), DNA ate activation of the enzyme.