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Imidazo[1,2-A]Pyrazine Compounds for Treatment

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Imidazo[1,2-A]Pyrazine Compounds for Treatment (19) TZZ _¥_¥__T (11) EP 2 193 131 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 487/04 (2006.01) A61K 31/4985 (2006.01) 30.01.2013 Bulletin 2013/05 A61P 31/00 (2006.01) (21) Application number: 08787346.9 (86) International application number: PCT/EP2008/060896 (22) Date of filing: 20.08.2008 (87) International publication number: WO 2009/024585 (26.02.2009 Gazette 2009/09) (54) IMIDAZO[1,2-A]PYRAZINE COMPOUNDS FOR TREATMENT OF VIRAL INFECTIONS SUCH AS HEPATITIS IMIDAZO[1,2-A]PYRAZINVERBINDUNGEN ZUR BEHANDLUNG VON VIRUSINFEKTIONEN WIE HEPATITIS Composés d’imidazo[1,2-a]pyrazine pour le traitement d’infections virales comme l’hépatite (84) Designated Contracting States: • HARRIS, Clifford John AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Eynsford HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT Kent DA4 0AB (GB) RO SE SI SK TR (74) Representative: Nichol, Maria Zenarosa (30) Priority: 21.08.2007 GB 0716292 Galapagos NV Chesterford Research Park (43) Date of publication of application: Saffron Walden, Essex CB10 1XL (GB) 09.06.2010 Bulletin 2010/23 (56) References cited: (60) Divisional application: WO-A-02/060492 WO-A-2007/058942 12188861.4 WO-A-2008/030795 WO-A-2008/079460 US-A1- 2004 063 715 US-A1- 2004 220 189 (73) Proprietor: Biofocus DPI Limited US-A1- 2005 009 832 US-A1- 2007 105 864 Walden, Essex CB10 1XL (GB) • BONNET P A ET AL: "Synthesis and (72) Inventors: antibronchospastic activity of 8-alkoxy- and • MACLEOD, Angus 8-(alkylamino)imidazo(1,2-a)pyrazines" Saffron JOURNAL OF MEDICINAL CHEMISTRY, US Walden, Essex CB10 1XL (GB) AMERICAN CHEMICAL SOCIETY. • MITCHELL, Dale Robert WASHINGTON, vol. 35, no. 18, 1 January 1992 Saffron (1992-01-01), pages 3353-3358, XP002971280 Walden, Essex CB10 1XL (GB) ISSN: 0022-2623 • PALMER, Nicholas John Saffron Remarks: Walde, Essex CB10 1XL (GB) Thefile contains technical information submitted after • PARSY, Christophe Claude the application was filed and not included in this F-34830 Jacou (FR) specification • GOLDSMITH, Michael Daniel Saffron Walden, Essex CB10 1XL (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 2 193 131 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 193 131 B1 Description Field of the invention 5 [0001] The invention is directed to imidazopyrazine compounds and pharmaceutical compositions containing such compounds that are useful in treating infections by hepatitis C virus and other viruses. Background to the invention 10 [0002] The hepatitis C virus (HCV) is estimated to infect 170 million people worldwide and in many countries is the leading cause of chronic liver disease. Infection frequently leads to cirrhosis and hepatocellular carcinoma in long- term chronically infected patients. In most cases, clinical symptoms post-infection are mild or even subacute. Hence, many patients do not realize that they are infected until there is chronic liver damage 10-30 years after the initial infection. There are no vaccines or selective drugs currently available to treat HCV and the current standard therapies for HCV 15 treatment are based on antiviral therapies that are not effective for a large number of patients, and are also poorly tolerated. The current best standard of care utilizes pegylated alpha- interferon and ribavirin. In the most common gen- otypes, this therapy is effective in less than 50% of cases and is associated with side effects and relapse after treatment cessation. Thus, there is a clear unmet need for effective therapies for the treatment of HCV infection. [0003] HCV is an enveloped, positive-sense single-stranded RNA virus belonging to the Flaviviridae family. The 9.6 20 kb genome encodes for a single open reading frame, resulting in the translation of a single polyprotein of approximately 3,010 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. The flanking 5’ and 3’ untranslated regions of the viral RNA genome contain important cis-acting signals for the initiation of viral RNA replication and protein translation. The HCV life- cycle can be separated into the following phases: 1) attachment to the cell membrane and entry into the cytoplasm; 2) cyto- 25 plasmic release and uncoating of the viral genome; 3) IRES- mediated translation; 4) polyprotein processing by cellular and viral proteases; 5) RNA replication; 6) packaging and assembly; 7) release from the host cell. As the HCV life cycle depends on the activity of numerous viral enzymes, engineering of specific enzyme inhibitors is being pursued in a number of laboratories to block HCV replication. Current research is mainly directed towards inhibiting HCV by targeting the non-structural proteins NS3 (protease and helicase) and NS5B (polymerase). Without wishing to be bound by any 30 particular mechanism, it is believed that the compounds of the present invention target a host cell mechanism. [0004] Picornaviruses are responsible for a large number of human viral diseases. The genus enterovirus, cardiovirus, rhinovirus, aphtovirus and hepatovirus especially the polioviruses (Sb), coxsackieviruses (CV), human echoviruses, human enteroviruses, human rhinoviruses (HRV) and hanks viruses all belong to the picornaviridae family. The disease syndromes range from mild upper respiratory disease to fatal neurological or cardiac- based illnesses. Rhinoviruses are 35 estimated to cause approximately one-third of all upper respiratory tract viral infections. Examples of diseases caused by picornaviridae viral infections include, but are not limited to e.g. in humans aseptic meningitis, poliomyelitis, herpangina , pleurodynia (Bornholm disease), myositis, rhabdomyolysis, diabetes type 1, summer fever, encephalitis, febrile illness and myocarditis. In animals rhinoviruses and the foot and mouth disease viruses can be caused by such infections. [0005] Picornaviruses are non- enveloped single-stranded positive-sense RNA viruses. The viral RNA genome is pack- 40 aged in a capsid consisting of 60 repeating protomeric units, each one containing a copy of the four viral proteins VP1, VP2, VP3 and VP4. The structural organization of the viral capsid of several picornaviruses e.g. human rhinovirus 14 (HRV-14), poliovirus and coxsackievirus B3 has been elucidated by crystallization and resolution of the three- dimensional structure. [0006] Imidazopyrazines are known in the literature and have been reported to be effective treatments for various 45 disorders (e.g. WO 2008/059373 (acid pump antagonists), WO 2008/057512 (kinase inhibitors), WO 2004/074289 (gas- tric secretion inhibitors)). In particular, there are several reports of imidazopyrazines having a use in oncology by inhibitin g cyclin-dependent kinases (e.g. WO 2007/058942, WO 2007/056468 also published as US2007/105864 and WO 2004/026877 also published as US 2004/0063715). [0007] US 2007/105864 discloses imidazo[1,2-a]pyrazines which have a C/8-NH-benzyl group, but not a C/3-phenyl 50 group, or a C/3-phenyl group but not not a C8-NH-benzyl group for use in the treatment of viral infections. [0008] US 2004/0063715 and WO 2007/058942 disclose further imidazo[1,2-a]pyrazines for use in the treatment of viral infections. [0009] US 2004/0220189 and its continuation in part US 2005/009832 disclose imidazo[1,2-a]pyrazines useful in treating disorders related to abnormal protein kinase activity. 55 [0010] In Bonnet et al. J. Med. Chem. 35 (1992) pages 3353-3358 synthesis and antibroonchospastic activity of certain imidazo[1,2-a]pyrazines are disclosed. [0011] WO 2008/079460 discloses compounds that inhibit kinases involved in pathogen- host cell interactions that are associated with or cause pathogenic infections, including viral infections. 2 EP 2 193 131 B1 [0012] WO 2008/030795 discloses compounds that inhibit the catalityc activity of tyrosine kinases and are useful for treating proliferative diseases. [0013] Surprisingly, the imidazopyrazines disclosed here have little or no effect on cyclin- dependent kinases and more surprisingly are effective as antiviral agents against a number of different viruses that include but are not limited to HCV, 5 HRV, Sb and CVB. SUMMARY OF THE INVENTION [0014] The present disclosure and invention describes novel imidazopyrazine compounds, pharmaceutically accept- 10 able prodrugs, pharmaceutically active metabolites, pharmaceutically acceptable salts, and pharmaceutically acceptable solvates therof, which are useful in treating or preventing a viral infection, in particular a hepatitis C virus (HCV) infectio n, in a patient in need therof. [0015] In a first aspect the invention relates to a compound according to Formulae (VA) or (VB) 15 20 25 30 wherein R2, R4 and R5 are independently selected from H, Me and Et; 6a 8 R is SO2R ; 35 7a 8 R is selected from OH, OCH3, halogen, NH2, CH2-OH and NHCOR ; 7b each R is selected from OH, halogen, CN, NO2, C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, CF3, OCF3, 9 8 9 10 C1-C6 alkyl-OH, NHSO2R , NHCOR , and NR R ; 8 9 10 R is C1-C6 alkyl or NR R ; 9 10 R and R are each independently selected from H and C 1-C6 alkyl; and 40 c is 0 or 1; wherein substituted 1C-C6 alkoxy refers to OCF3, OCH2CF3, OCH2Ph, OCH2-cyclopropyl, OCH2CH2OH, or OCH2CH2NMe2. [0016] The present disclosure provides a method for treating a viral infection, said method comprising administering to the patient a therapeutically or prophylatically effective amount of an imidazopyrazine compound of the invention.
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