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WO 2017/059411 Al 6 April 2017 (06.04.2017) W P O P C T

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WO 2017/059411 Al 6 April 2017 (06.04.2017) W P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/059411 Al 6 April 2017 (06.04.2017) W P O P C T (51) International Patent Classification: (74) Agent: BAKER, C , Hunter; Wolf, Greenfield & Sacks, C08G 77/38 (2006.01) G02B 1/04 (2006.01) P.C., 600 Atlantic Avenue, Boston, MA 02210-2206 (US). C08G 77/20 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/US2016/055 136 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, (22) International Filing Date: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 3 October 2016 (03. 10.2016) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (25) Filing Language: English KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (26) Publication Language: English OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (30) Priority Data: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 62/236,077 1 October 201 5 (01. 10.2015) US TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant: MEMORIAL SLOAN-KETTERING CAN¬ CER CENTER [US/US]; 1275 York Avenue, New York, (84) Designated States (unless otherwise indicated, for every NY 10065 (US). kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (72) Inventors; and TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (71) Applicants : TAN, Derek, Shieh [US/US]; 345 East 73rd TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, St., Apt. 7c, New York, NY 10021 (US). EVANS, Chris¬ DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, topher, E.. SHARMA, Indrajeet. TONGE, Peter, James LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, [GB/GB]; 103 Gaywood Drive, Newbury, Berkshire, RG14 SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, 2PJ (GB). MATARLO, Joe, S.. GW, KM, ML, MR, NE, SN, TD, TG). [Continued on nextpage] (54) Title: INHIBITORS OF MENAQUINONE BIOSYNTHESIS (57) Abstract: Provided herein are compounds of Formula (I) and pharma ceuticals acceptable salts, solvates, hy drates, polymorphs, co-crystals, tau- Αγ ~ tomers, stereoisomers, and prodrugs / thereof. Also provided are pharmaceut ical compositions, kits, and methods in volving the inventive compounds for the treatment of an infectious disease o (e.g., bacterial infection (e.g., tubercu losis, methicillin- resistant Stap hy lo 7~~V X coccus aureus). Figure 1 w o 2017/059411 Al III 11 II II 11 I I 11 II III I II III II il II I II Published: INHIBITORS OF MENAQUINONE BIOSYNTHESIS RELATED APPLICATIONS [0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent application, U.S.S.N. 62/236,077, filed October 1, 2015, which is incorporated herein by reference. GOVERNMENT SUPPORT [0002] This invention was made with Government support under AI068038, GM100477, GM102864, GM073546 and CA008748 awarded by the National Institutes of Health. The Government has certain rights in the invention. BACKGROUND [0003] The spread of infections due to drug-resistant pathogenic bacteria, such as multi-drug- resistant and extensively-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus (MRSA), is a serious threat to the populations of both developing and developed countries. Approximately one-third of the world's population is infected with active or latent M. tuberculosis (see, e.g., Harper, Nat. Med. (2007) 13, 309-312; Nathan, Nat. Med. (2014), 20, 121-123; Keener, Nat. Med. (2014) 20, 976-978), and community-acquired MRSA is the cause of more than 7 million hospitalizations due to skin and soft tissue infections annually in the United States alone (see, e.g., McKenna, Nature (2012) 482, 23-25; Hersh et a , Arch. Intern. Med. (2008), 168, 1585-1591). There is a need for novel therapeutic agents to treat infections of pathogenic bacteria, particularly as new drug-resistant strains continue to emerge. SUMMARY [0004] Menaquinone, also known as Vitamin K2, is a lipid-soluble electron carrier used in the electron transport chain of cellular respiration. Menaquinone consists of a 2-methyl-l,4- naphthoquinone group attached to an isoprenoid side chain. The side chain typically consists of between 4 and 13 isoprene units {i.e., n = 4-13), and the length varies based on the biosynthetic pathway utilized to produce menaquinone in a particular species. For example, in M. tuberculosis the major vitamin K2 species is MK-9, menaquinone with nine isoprene units n = 9), whereas the major species synthesized by S. aureus is menaquinone with eight isoprenes (MK-8, n = 8). (menaquinone) [0005] Bacteria of the genus Mycobacterium, most Gram-positive bacteria, and some Gram- negative bacteria rely solely on menaquinone for electron transport, and this reliance extends to all species of bacteria growing under anaerobic conditions (see, e.g., Collins et al. , J. Gen. Microbiol. (1979) 110, 127-136; Nahaie et al. J. Gen. Microbiol. (1984) 130, 2427-2437; Hiratsuka et al. Science (2008) 321, 1670-1673). The reliance of certain pathogens on menaquinone for cellular respiration thus makes menaquinone biosynthesis a target for treatments of infectious disease. Such treatments would extend to latent infections (e.g., nonreplicating M. tuberculosis), since the latent pathogen must still respire. Since humans and other hosts lack the menaquinone biosynethetic pathway, treatments that target this pathway should by highly selective for the pathogen over the host. Menaquinone is synthesized by bacteria from chorismate via a biosynthetic pathway involving at least nine distinct enzymes, including MenA, MenB, MenC, MenD, MenE, MenF, MenH, Menl, and UbiE. [0006] MenE, also known as o-succinylbenzoate-CoA synthetase, is an acyl-CoA synthetase that shares similarity with several families of adenylate-forming enyzmes. These families include acyl-CoA synthetases, aryl-CoA synthetases, firefly luciferases, and the adenylation domains of non-ribosomal peptide synthetases (NRPSs), and have been grouped into a proposed superfamily of ANL enzymes (ANL stands for Acyl-CoA synthetases, NRPS adenylation domains, and Luciferase enzymes) (see, e.g., Gulick, ACS Chem. Biol. (2009) 62, 347-352). Members of these families catalyze two partial reactions, the initial adenylation of a carboxylate to form an acyl-AMP intermediate, and the subsequent coupling of the acyl group to a nucleophile (e.g., CoA) with release of an adenylate (e.g., AMP) (see, e.g., Gulick,). MenE catalyzes adenylation of o-succinylbenzoate with ATP, and the subsequent ligation of CoA to o-succinylbenzoate with release of AMP. Figure 1 shows the menaquinone biosynthetic pathway including the steps catalyzed by MenE. [0007] MenE inhibitors have been described by Tan, Tonge, and co-workers in Lu et al. Bioorg. Med. Chem. Lett. (2008) 18, 5963-5966, Lu et al. ChemBioChem (2012) 13, 129-136, and Matarlo et al. Biochemistry (2015) 54, 6514-6524, each of which is incorporated herein by reference. Inhibitors of MenE have also been previously described by Mesecar and co workers (see Tian et al. Biochemistry (2008) 47, 12434-12447). [0008] Compounds of the present invention may be capable of inhibiting ligases and adenylate-forming enzymes. In certain embodiments, the compounds of the invention are capable of inhibiting o-succinylbenzoate synthetase (MenE). In certain embodiments, the compounds of the invention are capable of inhibiting MenA, MenB, MenC, MenD, MenF, MenH, MenI, and/or UbiE. The compounds provided are analogs of the MenE intermediate o-succinylbenzoate-adensosinemonophosphate (OSB-AMP). In certain embodiments, the analogs comprise a linker (e.g., a sulfonyl moiety) that mimics the phosphate between the o- succinylbenzoate and adenosine moieties in OSB-AMP. [0009] Compounds of the present invention are of Formula (I): wherein, in certain embodiments, the o-benzoate moiety of OSB-AMP is replaced with group Y. Group Y comprises either an aryl or bicyclic moiety as shown below: [0010] In certain embodiments, a compound provided comprises a sulfamide linker, sulfamate linker, or vinylsulfonamide linker, as shown below: [0011] In certain embodiments, a provided compound is of Formula (III), (IV), or (V): (HI), [0012] Pharmaceutical compositions of the compounds are also provided, in addition to methods of preventing and/or treating an infectious disease using the compound or compositions thereof. The infectious disease may be a bacterial infection. The methods provided may be for treatment of an infection with a Gram-positive and/or Gram-negative bacteria, such as a Staphylococcus, Bacillus, or Escherichia bacteria. The methods may be for treatment of a mycobacterial infection, such as tuberculosis. The pharmaceutical compositions and methods may be useful in the treatment of drug-resistant tuberculosis infections or drug-resistant Staphylococcus aureus infections {e.g., MRSA, VRSA). [0013] The invention also provides methods useful for inhibiting ligases and adenylate- forming enzymes {e.g., o-succinylbenzoate-CoA synthetase (MenE)) or inhibiting menaquinone biosynthesis in an infectious microorganism by contacting the microorganism with a compound provided herein. Additionally provided are methods for inhibiting o- succinylbenzoate-CoA synthetase (MenE) or inhibiting menaquinone biosynthesis in an infectious microorganism in a subject by administering to the subject a compound provided herein. [0014] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, Figures, and Claims.
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