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WO 2014/176636 A9 6 November 2014 (06.11.2014) P O P C T

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WO 2014/176636 A9 6 November 2014 (06.11.2014) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) CORRECTED VERSION (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/176636 A9 6 November 2014 (06.11.2014) P O P C T (51) International Patent C I 1/40 Moira Street, Adamstown, New South Wales 2289 C07C 279/02 (2006.01) C07C 275/68 (2006.01) (AU). C07C 241/04 (2006.01) A61K 31/4045 (2006.01) (74) Agent: WRAYS; 56 Ord Street, West Perth, Western Aus C07C 281/08 (2006.01) A61K 31/155 (2006.01) tralia 6005 (AU). C07C 337/08 (2006.01) A61K 31/4192 (2006.01) C07C 281/18 (2006.01) A61K 31/341 (2006.01) (81) Designated States (unless otherwise indicated, for every C07C 249/14 (2006.01) A61K 31/381 (2006.01) kind of national protection available): AE, AG, AL, AM, C07D 407/12 (2006.01) A61K 31/498 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C07D 403/12 (2006.01) A61K 31/44 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, C07D 409/12 (2006.01) A61K 31/12 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, C07D 401/12 (2006.01) A61P 31/04 (2006.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/AU20 14/000483 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 1 May 2014 (01 .05.2014) TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 20139015 16 1 May 2013 (01.05.2013) AU UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (71) Applicant: NEOCULI PTY LTD [AU/AU]; 4/25-37 EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, Huntingdale Road, Burwood, Victoria 3125 (AU). MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (72) Inventors; and TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (71) Applicants : PAGE, Stephen [AU/AU]; 55 Campbell Street, Newtown, New South Wales 2042 (AU). GARG, Published: Sanjay [NZ/AU]; University of South Australia, City East — with international search report (Art. 21(3)) Campus, Frome Road, Adelaide, South Australia 5001 (AU). KEENAN, Martine [AU/AU]; Epichem Pty Ltd, (48) Date of publication of this corrected version: Murdoch University Campus, 70 South Street, Murdoch, 18 December 2014 Western Australia 6150 (AU). MCCLUSKEY, Adam [AU/AU]; 405 Warners Bay Road, Charlestown, New (15) Information about Correction: South Wales 2290 (AU). STEVENS, Andrew [AU/AU]; see Notice of 18 December 2014 < (54) Title: COMPOUNDS AND METHODS OF TREATING INFECTIONS o (57) Abstract: The invention provides compounds of Formula (I), and methods of treating or preventing a bacterial infection in a subject using a compound of Formula (I). The invention also provides the use of a compound of Formula (I) in the manufacture of a medicament for the treatment of a bacterial infection in a subject. The invention further provides a medical device when used in a method of treating or preventing a bacterial infection in a subject and to a medical device comprising the composition of the inven tion. COMPOUNDS AND METHODS OF TREATING INFECTIONS TECHNICAL FIELD [0001] This invention relates to compounds of Formula !, methods of treating or preventing a bacteria! infection i a subject using a compound of Formula , the use of a compound of Formula i in the manufacture of a medicament for the treatment of a bacteria! infection in a subject, and medical devices when used in a method of treating or preventing a bacterial infection in a subject. BACKGROUND ART GG2 ] A marked increase i prevalence of multi-drug resistance in disease-causing Gram- positive (G V ) (Staphylococcus a , Ent&rococcus spp. and Streptococcus p and Gram negative G~ve) pathogens {Escherichia iil , Eni&robacier spp., Salmonella spp., Acin&tobact&r a nii Klebsiella pneumoniae and Ps r as aeruginosa) has coincided w t an unprecedented global decline in investment in new anti-infective drugs. There are few currently registered alternatives for multidrug resistant (MDR) bacteria! infections, forcing clinicians to consider older generation drugs such as o stin with narrow spectrum and considerable potential for toxic side-effects. addition, there are fewer novel classes of n fe tive therapeutics moving through the drug development pipeline. [0003 Since the year 2000, a period of almost S years, only 5 novel mode of action (MOA) antibacterial agents have been approved by the US FDA - ine o id (an oxazoiidinone) in 2000, daptomycin (a ipopeptid in 2003, retapa n (a p orn il n in 200 , fidax cin (a macro i tia u icin) in 20 , and b daqui ine (a diarylq in i n ) in 2012. Notably, none of these agents has slghficianf activity against gram negative bacteria. No novel MOA antibacterial agents were approved in 20 and to date in 2014 only tedizoiid and daibavancin, both analogs of classes, have been recommended for approval in the US. While there ar mor than 300 anti-infective medicines in various stages of development, th large majority of these medicines are previously approved antibacterial compounds or their derivatives that are undergoing studies for new indications. [0004] Furthermore, the prevalence of muStldrug-resistance in a ma -specifi pathogens together with greater regulation of th registration and usage of antimicrobials in animals, has caused veterinarians to become increasingly reliant on the traditional classes of antimicrobial agents. The risk of transfer of I DR zoonotic organisms from animals to humans has also led t calls for further restrictions on the usage som¾ recently registered ani ib fe i drugs such as the fluoroquinolones and the third and fourth generation cephalosporins. RECTIFIED SHEET Rule 91) JSA/AU Epidemiology of antibacterial resistance development in pathogens of humans and animals }5| Much of the evolution n resistance development Is driven by changes in the epidemiology of key D organisms. Once only restricted to human hospitals and aged care facilities, mefhieiliin resistant Staphylococcus aureus RSA) strains are now being isolated from the community in alarming proportions. Furthermore, community-acquired R A strains a more k y to carry the Pant n Vaia ine l uk cidin PVL) toxin, a virulence factor linked t skin and soft tissue lesions as well a a rapid, fulminating, necrotizing pneumonia with significant associated mortality. Recently RSA strains have become host-adapted in several key animal species including livestock, horses and companion animals and regular cases of man-to nima and animal~to~human transfer are being documented. This has important consequences for strain transmission and public health. A recent survey of 51 Australian veterinarians for MRSA nasal carriage found that a remarkable 21.4% of equin veterinarians S positive compared to 4.9% of s all animal veterinarians 0.9% of veterinarians with little animal contact These ecological shifts of RSA together with the emergence of resistance to new drugs developed specifically tor IVIRSA such as linezotid, confirm that new MRSA nt -infe ti es are urgently needed. Furthermore, hospitals that use vancomycin for treating RSA then have to contend with outbreaks of vanc my in-res lant enterocoeci VRE infections in their patients, once again with limited alternative antimicrobial choices. [0006] The global emergence and spread within the community of highly virulent MDR Gram- negative (G-ve) bacteria such as E coil 02Sb:ST131 confirms that bacterial pathogens can simultaneously evolve both virulence and resistance determinants. Echoing recent MRSA epidemiology. E cols G25b ST , a major of urinary tract and bloodstream infections in humans, has now been isolated from extraintestinal infections in companion animals, and poultry. The increasing significance of E. c 25 :ST 1 and other MDR Enf oba tari aceae with combined resistance to fluoroquinolones and extended spectrum -iac s and car penems is another worrying trend, especially considering there have been fe recent breakthroughs in tne development of G-ve spectrum nt infect s apart from incremental advances in the c rbape e family. |0007] The World Health Organisation has identified antibiotic resistance as one of the three ajor future threats to global health, A recent report from the US Centers for Disease Control and Prevention (CDC) estimated that " n the United States, more than two miilion peopl sickened ©very year with antibiotic-resistant infections, with at least 23,000 dying as a result* The extra medical costs, in the USA aloha, associated with treating and managing a single case of antibiotic-resistant infection are estimated to b between US$18,588 and US$2 , 88 per year resulting in an overall direct cost to the US health system of over US$20 billion annually. I addition, the cost tp US households in terms of lost productivity is estimated at over US$35 RECTIFIED SHEET {Rule 9 1} SA A U billion p r annum. Twenty five thousand patients i the European Union (EU) still die annually from infection with D bacteria despite many EU countries having world's best practice hospital surveillance and infection control strategies, The EU costs fr o health care n d lost productivity associated with MDR infections are estimated to be at least €15 billion per year.
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