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Pyrimidine Derivatives Useful As Protein Kinase Inhibitors

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Pyrimidine Derivatives Useful As Protein Kinase Inhibitors (19) TZZ _ __T (11) EP 2 124 951 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/506 (2006.01) A61K 31/551 (2006.01) 21.05.2014 Bulletin 2014/21 A61P 3/00 (2006.01) A61P 5/00 (2006.01) A61P 9/00 (2006.01) A61P 11/06 (2006.01) (2006.01) (2006.01) (21) Application number: 07867948.7 A61P 19/00 A61P 25/00 A61P 25/28 (2006.01) A61P 29/00 (2006.01) A61P 35/00 (2006.01) A61P 37/00 (2006.01) (22) Date of filing: 21.12.2007 A61P 37/08 (2006.01) A61P 43/00 (2006.01) C07D 471/04 (2006.01) (86) International application number: PCT/US2007/026190 (87) International publication number: WO 2008/079346 (03.07.2008 Gazette 2008/27) (54) 5-CYAN0-4- (PYRROLO[2, 3B]PYRIDINE-3-YL) -PYRIMIDINE DERIVATIVES USEFUL AS PROTEIN KINASE INHIBITORS 5-CYAN0-4- (PYRROLO [2, 3B]PYRIDINE-3-L)-PYRIMIDINDERIVATE ALS PROTEINKINASEHEMMER DÉRIVÉS DE 5-CYAN0-4- (PYRROLO[2, 3B]PYRIDINE-3-YL) -PYRIMIDINE UTILES EN TANT QU’INHIBITEURS DE LA PROTÉINE KINASE (84) Designated Contracting States: • PINDER, Joanne Louise AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Oxfordshire OX14 4RY (GB) HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE • RUTHERFORD, Alistair Peter SI SK TR Oxfordshire OX14 4RY (GB) • DURRANT, Steven (30) Priority: 21.12.2006 US 876307 P Oxfordshire OX14 4RY (GB) 06.04.2007 US 922291 P • BRENCHLEY, Guy 03.07.2007 US 947707 P Oxfordshire OX14 4RY (GB) 19.11.2007 US 989014 P • CHARRIER, Jean Damien Oxfordshire OX14 4RY (GB) (43) Date of publication of application: • O’DONNELL, Michael 02.12.2009 Bulletin 2009/49 Oxfordshire OX14 4RY (GB) (73) Proprietor: Vertex Pharmaceuticals Inc. (74) Representative: Cohausz & Florack Boston, MA 02210 (US) Patent- und Rechtsanwälte Partnerschaftsgesellschaft (72) Inventors: Bleichstraße 14 •MORTIMORE,Michael 40211 Düsseldorf (DE) Oxfordshire OX14 4RY (GB) • YOUNG, Stephen Clinton (56) References cited: Oxfordshire OX14 4RY (GB) WO-A-2005/095400 WO-A-2006/124863 • EVERITT, Simon Robert Lorrie WO-A-2008/005457 Oxfordshire OX14 4RY (GB) • KNEGTEL, Ronald Oxfordshire OX14 4RY (GB) 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 2 124 951 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 124 951 B1 • ALEXEI S KARPOV ET AL: "Concise Synthesis • BETTAYEB, K ET AL.: "Meriolins, a New Class of of Meridianins by Carbonylative Alkynylation and Cell Death-Inducing Kinase Inhibitors with a Four-Component Pyrimidine Synthesis" Enhanced Selectivity for Cyclin-Dependent ANGEWANDTE CHEMIE. INTERNATIONAL Kinases" CANCER RESEARCH, vol. 67, no. 17, 1 EDITION, WILEY VCH VERLAG, WEINHEIM, DE, September 2007 (2007-09-01), pages 8325-8334, vol. 44, 2005, pages 6951-6956, XP002452552 XP002476437 ISSN: 1433-7851 2 EP 2 124 951 B1 Description TECHNICAL FIELD OF THE INVENTION 5 [0001] The present invention relates to compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention. Methods of using the composi- tions in the treatment of various disorders and processes for preparing the compounds for use of the invention are also described herein. 10 BACKGROUND OF THE INVENTION [0002] The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and other biomolecules associated with diseases. One important class of enzymes that has been the subject of intensive study is protein kinases. 15 Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell (see Hardie, G. et al., The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA: 1995). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, 20 protein-serine/threonine, lipids etc). Sequence motifs have been identified that generally correspond to each of these kinase families (see, e.g., Hanks, S.K., Hunter, T., FASEB J., 1995, 9, 576-596; Knighton et al., Science, 1991, 253, 407-414; Hiles et al, Cell, 1992, 70, 419-429; Kunz et al, Cell, 1993, 73, 585-596; Garcia-Bustos et. al., EMBO J.. 1994, 13, 2352-2361). [0003] In general, protein kinases mediate intracellular signaling by effecting a phosphoryl transfer from a nucleoside 25 triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environ- mental and chemical stress signals (e.g., shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H2O2), cy- tokines (e.g., interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-a), and growth factors (e.g., granulocyte macro- 30 phage-colony stimulating factor (GM-CSF), and fibroblast growth factor (FGF)). An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of tran- scription factors, muscle contraction, glucose metabolism, control of protein synthesis, survival and regulation of the cell cycle. [0004] Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events 35 as described above. These diseases include, but are not limited to, cancer, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, allergies and asthma, Alzheimer’s disease and hormone related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents. [0005] The Polo-like kinases (PLK) belong to a family of serine/threonine kinases that are highly conserved across 40 the species, ranging from yeast to man (reviewed in Lowery, D.M. et al., Oncogene, 2005, 24; 248-259). The PLK kinases have multiple roles in cell cycle, including control of entry into and progression through mitosis. [0006] PLK1 is the best characterized of the PLK family members. PLK1 is widely expressed and is most abundant in tissues with a high mitotic index. Protein levels of PLK1 rise and peak in mitosis (Hamanaka, R. et al., J. Biol. Chem., 1995, 270, 21086-21091). The reported substrates of PLK1 are all molecules that are known to regulate entry and 45 progression through mitosis, and include CDC25C, cyclin B, p53, APC, BRCA2 and the proteasome. PLK1 is upregulated in multiple cancer types and the expression levels correlate with severity of disease (Macmillan, JC et al., Ann. Surg. Oncol., 2001, 8, 729-740). PLK1 is an oncogene and can transform NIH-3T3 cells (Smith, M.R. et al., Biochem. Biophys. Res. Commun .,1997, 234, 397-405). Depletion or inhibition of PLK1 by siRNA, antisense, microinjection of antibodies, or transfection of a dominant negative construct of PLK1 into cells, reduces proliferation and viability of tumour cells in 50 vitro (Guan, R. et al., Cancer Res., 2005, 65, 2698-2704; Liu, X. et al., Proc. Nat’l. Acad. Sci. USA, 2003, 100, 5789-5794; Fan, Y. et al., World J. Gastroenterol., 2005, 11, 4596-4599; Lane, H.A. et al., J. Cell Biol 1996, 135, 1701-1713; Wada, M. et al., Biochem. Biophys. Res. Commun., 2007, 357(2): 353-359; Rizki, A. et al., Cancer Res., 2007, 67 (23): 11106-11100). Tumour cells that have been depleted of PLK1 have activated spindle checkpoints and defects in spindle formation, chromosome alignment and separation and cytokinesis. Loss in viability has been reported to be the result 55 of an induction of apoptosis. In contrast, normal cells have been reported to maintain viability on depletion of PLK1. In vivo knock down of PLK1 by siRNA or the use of dominant negative constructs leads to growth inhibition or regression of tumours in xenograft models. [0007] PLK2 is mainly expressed during the G1 phase of the cell cycle and is localized to the centrosome in interphase 3 EP 2 124 951 B1 cells. PLK2 knockout mice develop normally, are fertile and have normal survival rates, but are around 20% smaller than wild type mice. Cells from knockout animals progress through the cell cycle more slowly than in normal mice (Ma, S. et al., Mol. Cell Biol., 2003, 23, 6936-6943). Depletion of PLK2 by siRNA or transfection of kinase inactive mutants into cells blocks centriole duplication. Downregulation of PLK2 also sensitizes tumour cells to taxol and promotes mitotic 5 catastrophe, in part by suppression of the p53 response (Bums, T.F. et al., Mol. Cell Biol., 2003, 23, 5556-5571). [0008] PLK3 is expressed throughout the cell cycle and increases from G1 to mitosis. Expression is upregulated in highly proliferating ovarian tumours and breast cancer and is associated with a worse prognosis (Weichert, W. et al., Br. J. Cancer, 2004, 90, 815-821; Weichert, W et al., Virchows. Arch., 2005, 446, 442-450). In addition to regulation of mitosis, PLK3 is believed to be involved in Golgi fragmentation during the cell cycle and in the DNA-damage response.
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