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Pyrazolopyrimidine Jak Inhibitor Compounds And (19) TZZ ¥Z_T (11) EP 2 348 860 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A01N 43/90 (2006.01) A61K 31/519 (2006.01) 27.05.2015 Bulletin 2015/22 C07D 487/04 (2006.01) A61P 35/00 (2006.01) (21) Application number: 09824234.0 (86) International application number: PCT/US2009/063014 (22) Date of filing: 02.11.2009 (87) International publication number: WO 2010/051549 (06.05.2010 Gazette 2010/18) (54) PYRAZOLOPYRIMIDINE JAK INHIBITOR COMPOUNDS AND METHODS PYRAZOLOPYRIMIDIN-JAK-HEMMER-VERBINDUNGEN UND ENTSPRECHENDE VERFAHREN COMPOSÉS INHIBITEURS DE JAK À LA PYRAZOLOPYRIMIDINE ET PROCÉDÉS (84) Designated Contracting States: • MAGNUSON, Steven R. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Dublin HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL California 94568 (US) PT RO SE SI SK SM TR • PASTOR, Richard Designated Extension States: San Francisco AL BA RS California 94102 (US) • RAWSON, Thomas E. (30) Priority: 31.10.2008 US 110497 Mountain View California 94043 (US) (43) Date of publication of application: • ZHOU, Aihe 03.08.2011 Bulletin 2011/31 San Jose California 95129 (US) (60) Divisional application: • ZHU, Bing-Yan 15163226.2 Palo Alto California 94303 (US) (73) Proprietor: Genentech, Inc. South San Francisco, CA 94080 (US) (74) Representative: Bailey, Sam Rogerson et al Mewburn Ellis LLP (72) Inventors: 33 Gutter Lane • BLANEY, Jeffrey London South San Francisco, California 94080 (US) EC2V 8AS (GB) • GIBBONS, Paul A. South San Francisco, California 94080 (US) (56) References cited: • HANAN, Emily WO-A1-2007/013673 WO-A2-2004/052315 South San Francisco, California 94080 (US) WO-A2-2008/004698 US-A1- 2007 082 902 • LYSSIKATOS, Joseph P. Piedmont Remarks: California 94611 (US) Thefile contains technical information submitted after the application was filed and not included in this specification Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 348 860 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 348 860 B1 Description FIELD OF THE INVENTION 5 [0001] Pyrazolopyrimidine compounds, inhibitors of JAK kinases, as well as compositions containing these compounds and methods of use including, but not limited to, in vitro, in situ and in vivo diagnosis or treatment of mammalian cells. BACKGROUND OF INVENTION 10 [0002] Cytokine pathways mediate a broad range of biological functions, including many aspects of inflammation and immunity. Janus kinases (JAK), including JAK1, JAK2, JAK3 and TYK2 are cytoplasmic protein kinases that associate with type I and type II cytokine receptors and regulate cytokine signal transduction. Cytokine engagement with cognate receptors triggers activation of receptor associated JAKs and this leads to JAK-mediated tyrosine phosphorylation of signal transducer and activator of transcription (STAT) proteins and ultimately transcriptional activation of specific gene 15 sets (Schindler et al., 2007, J Biol. Chem. 282: 20059-63). JAK1, JAK2 and TYK2 exhibit broad patterns of gene ex- pression, while JAK3 expression is limited to leukocytes. Cytokine receptors are typically functional as heterodimers, and as a result, more than one type of JAK kinase is usually associated with cytokine receptor complexes. The specific JAKs associated with different cytokine receptor complexes have been determined in many cases through genetic studies and corroborated by other experimental evidence. 20 [0003] JAK1 was initially identified in a screen for novel kinases (Wilks A.F., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:1603-1607). Genetic and biochemical studies have shown that JAK1 is functionally and physically associated with the type I interferon (e.g., IFNalpha), type II interferon (e.g., IFNgamma), IL-2 and IL-6 cytokine receptor complexes (Kisseleva et al., 2002, gene 285:1-24; Levy et al., 2005, Nat. Rev. Mol. Cell Biol. 3:651-662; O’Shea et al., 2002, Cell, 109 (suppl.): S121-S131). JAK1 knockout mice die perinatally due to defects in LIF receptor signaling (Kisseleva et al., 25 2002, gene 285:1-24; O’Shea et al., 2002, Cell, 109 (suppl.): S121-S131). Characterization oftissues derived from JAK1 knockout mice demonstrated critical roles for this kinase in the IFN, IL-10, IL-2/IL-4, and IL-6 pathways. A humanized monoclonal antibody targeting the IL-6 pathway (Tocilizumab) was recently approved by the European Commission for the treatment of moderate-to-severe rheumatoid arthritis (Scheinecker et al., 2009, Nat. Rev. Drug Discov. 8:273-274). [0004] Myeloproliferative disorders (MPD) originate in hematopoietic stem cells and primarily manifest in elevated 30 counts of mostly normal cells of the myeloid lineage. A primary distinction between Philadelphia-chromosome positive (Ph+) and Philadelphia-chromosome negative (Ph-) can be made. Ph+ MPD results in chronic myelogenous leukemia and is driven by a bcr-abl fusion protein that drives hematopoietic cell proliferation. Ph-MPD can be further subclassified into three distinct disorders by related varieties, namely polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). Dameshek, W., Blood 6(4):372-375 (1951). Patients with PV suffer from high counts of 35 red blood cells, whereas patients with ET have high levels of circulating platelets. If left untreated, both diseases can result in life-threatening thrombotic events. Patients with IMF experience fibrosis of the bone marrow with subsequent displacement of hematopoiesis into the spleen and liver. This primarily leads to splenomegaly, which is followed by anemia in later stages of the disease as hematopoiesis becomes non-productive. These patients have a poor prognosis, although under cetain conditions they can be cured by means of an allogeneic bone marrow transplant. There is no 40 known cure for Ph- MPD diseases. [0005] An activating mutation in the tyrosine kinase JAK2 is associated with PV, ET, IMF and other diseases. Virtually all patients with PV and about 50% patients with ET and IMF harbor this mutation. Morgan, K.J. and Gilliland, D.G., Ann. Rev. Med. 59:213-222 (2008). The mutation is an exchange from valine to phenylalanine at position 617 in the mature human JAK2 protein (V617F). Additional mutations in JAK2, commonly found in exon 12 and referred to as exon 12 45 mutations, also have an activating effect and can lead to MPD. Furthermore, a T875N mutation was associated with megakaryoblastic leukemia. Finally, JAK2 fusion proteins have been identified in acute leukemias. [0006] The V617F mutation functions to activate JAK2, which leads to MPD. In non-mutated form, JAK2 is linked to cytokine receptors (i.e. EPO-R, TPO-R and others) and only gets activated if the receptor itself is activated by stimulation with the cognate cytokine ligand. Hematopoiesis as a whole is then regulated through the availability of ligands. For to 50 elevated levels of red blood cells. By analogy, thrombopoietin (TPO) regulates platelet growth by binding to the TPO- R, which in turn also signals through JAK2. Thus, elevated levels of platelets can also result from aberrant JAK2 activation. [0007] Compounds are needed that inhibit JAK2, which would be beneficial to patients with JAK2 driven myeloprolif- erative disorders, as well as, other diseases that are responsive to the inhibition of JAK2. Such diseases include both diseases in which JAK2 is activated by mutation or amplificatio n, as well as, diseases in which JAK2 activation is a part 55 of the oncogenic cascade. Numerous tumor cell lines and tumor samples have high levels of phospho-STAT3, which is a JAK2 target gene. [0008] JAK3 associates exclusively with the gamma common cytokine receptor chain, which is present in the IL-2, IL- 4, IL-7, IL-9, IL-15 and IL-21 cytokine receptor complexes. JAK3 is critical for lymphoid cell development and proliferation 2 EP 2 348 860 B1 and mutations in JAK3 result in severe combined immunodeficiency (SCID) (O’Shea et al., 2002, Cell, 109 (suppl.): S121-S131). Based on its role in regulating lymphocytes, JAK3 and JAK3-mediated pathways have been targeted for immunosuppressive indications (e.g., transplantation rejection and rheumatoid arthritis) (Baslund et al., 2005, Arthritis & Rheumatism 52:2686-2692; Changelian et al., 2003, Science 302: 875-878). 5 [0009] TYK2 associates with the type I interferon (e.g., IFNalpha), IL-6, IL-10, IL-12 and IL-23 cytokine receptor complexes (Kisseleva et al., 2002, Gene 285:1-24; Watford, W.T. & O’Shea, J.J., 2006, Immunity 25:695-697). Consistent with this, primary cells derived from a TYK2 deficient human are defective in type I interferon, IL-6, IL-10, IL-12 and IL- 23 signaling. A fully human monoclonal antibody targeting the shared p40 subunit of the IL-12 and I1-23 cytokines (Ustekinumab) was recently approved by the European Commission for the treatment of moderate-to-severe plaque 10 psoriasis (Krueger et al., 2007, N. Engl. J. Med. 356:580-92; Reich et al., 2009, Nat. Rev. Drug Discov. 8:355-356). In addition,an antibody targeting theIL-12 and IL-23 pathwaysunderwent clinical trialsfor treating Crohn’sDisease (Mannon et al., 2004, N. Engl. J. Med. 351:2069-79). [0010] US 2007/0082902 A1 describes pyrazolo[1,5-a]pyrimidine compounds useful as inhibitors, regulators or mod- ulators of a range of protein kinases for use in the treatment of diseases such as cancer, inflammation, arthritis, viral 15 diseases, neurodegenerative diseases such as Alzheimer’s disease, cardiovascular diseases and fungal diseases. [0011] WO 2004/052315 A2 describes pyrazolopyrimidine compounds capable of inhibiting, modulating and/or regu- lating signal transduction of both receptor-type and non-receptor type tyrosine kinases.
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