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WO 2016/069949 Al FIG. 6B

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WO 2016/069949 Al FIG. 6B (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 2016/069949 Al 6 May 2016 (06.05.2016) W P O P CT (51) International Patent Classification: (74) Agents: MILLER, Carin, R. et al; Thomas | Horstemeyer A61K 31/4545 (2006.01) C07D 471/04 (2006.01) LLP, 400 Interstate North Parkway, SE, Suite 1500, At lanta, GA 30339 (US). (21) International Application Number: PCT/US2015/058157 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 29 October 2015 (29.10.201 5) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (25) Filing Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (26) Publication Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (30) Priority Data: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 62/069,874 29 October 20 14 (29. 10.20 14) US PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (71) Applicant: VIRGINIA TECH INTELLECTUAL TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. PROPERTIES, INC. [US/US]; 2200 Kraft Drive, Suite 1050, Blacksburg, VA 24060 (US). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventors: CARLIER, Paul, R.; 2200 Kraft Drive, Suite GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 1050, Blacksburg, VA 24060 (US). CASSERA, Maria, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, Belen; 2200 Kraft Drive, Suite 1050, Blacksburg, VA TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 24060 (US). MERINO, Emilio, Fernando; 2200 Kraft DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Drive, Suite 1050, Blacksburg, VA 24060 (US). YAO, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Zhong-Ke; 2200 Kraft Drive, Suite 1050, Blacksburg, VA SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, 24060 (US). GHAVAMI, Maryam; 2200 Kraft Drive, GW, KM, ML, MR, NE, SN, TD, TG). Suite 1050, Blacksburg, VA 24060 (US). [Continued on nextpage] (54) Title: COMPOSITIONS AND FORMULATIONS OF METHYLERTHRITOL PHOSPHATE PATHWAY INHIBITORS AND USES THEREOF (57) Abstract: Described herein are com · pounds and formulations thereof that can in 0 hibit the methylerythritol phosphate pathway (MEP). Also described herein are methods of T making and uses of the compounds and for -XL... mulations thereof described herein. e 0 · \ ø [F. 80] F. 80 F. 80 FIG. 6B wo 2016/069949 Al III III II II III III I II II II II III! Ill II I II Declarations under Rule 4.17: Published: — as to applicant's entitlement to apply for and be granted — with international search report (Art. 21(3)) a patent (Rule 4.1 7(H)) — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.17(Hi)) COMPOSITIONS AND FORMULATIONS OF METHYLERTHRITOL PHOSPHATE PATHWAY INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Serial No. 62/069,874 filed on October 29, 2014, having the title "Novel Methylerthritol Phosphate Pathway Inhibitors", the entirety of which is incorporated herein by reference. STATEMENT REGARDING FEDERALY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant numbers AI082581 and A 0881 9 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND With over 200 million cases worldwide and accounting for about one-half million deaths, primarily in children under the age of 5 and pregnant women, malaria remains a serious global health threat. Although therapeutics for malaria infection exist, the causative protozoan parasites are becoming resistant to many of the current front-line therapies. As such, there exists an immediate need for improved treatments and preventatives for malaria. SUMMARY Provided herein are compositions and pharmaceutical formulations thereof where the composition can have a structure according to Formula 209: where R can be H , COOCH 3, COOEt, COOH, CONH2, CONHCH 3, a CONHd_ 6alkyl, CONH(CH) _5(CH3)2, CON(C6H ), CONHNHCH3, CON(CH3)2, or CH2OH, where R2 can be H or a C -Ce alkyl, where R3 can be H , a C1-C6 alkyl group, a benzyl, COCH3,or a diketopiperazine formed between N2 and R i , where X 2-Xi 5 can each be independently selected from the group of: H and a halogen, where R4 can have a structure according to Formula 210 or 2 11 Formula 210 Formula 2 11 where X 1- X 5 can each be independently selected from the group of H , a halogen, a C C6 alkyl, a C 6 alkoxy, NHCH3, and C(Xi 6)3 where X 6 can be a halogen, where X can be C or N , where X 0 can be selected from the group of O, S, and NXn , where X can be selected from the group of: H , a halogen, a C C6 alkyl, a C 6 alkoxy, NHCH3, and C(Xi 6)3, where X 6 can be a halogen and where X7-X9 can each be independently selected from the group of: H , a halogen, a C C6 alkyl, a C 6 alkoxy, NHCH3, and C(Xi 6)3 where X 6 can be a halogen. In some embodiments, the compound does not have a structure according to Formula 60 The composition can have (1R,3S) configuration. The compound can have an R4 of Formula 210. The halogens specifed in composition can be each independently selected from F, CI, Br, and I. In some embodiments, X and X3 are each can each be a halogen. The halogen can be independently selected from F, CI, Br, and I. In other embodiments, X and X3 can each be independently selected from a halogen and a C C alkyl. The halogen can be independently selected from F, CI, Br, and I and the C C alkyl is a methyl. In some embodiments, R can be COOH or CONHCH 3. The compositions can, in some embodiments, inhibit an enzyme of the methylerythritol phosphate pathway. The compositions can, in some embodiments, be toxic to to an organism of the genus Plasmodium. In some embodiments, the toxicity at 5 µΜ of compound is completely eliminated by supplementation with an amount of isopentenyl diphosphate (IPP). In further embodiments, the toxicity at 5 µΜ of compsition is completely eliminated by supplementation with an amount of IPP. In some embodiments, the composition can be according to Formula 70, 74, 75, 80, 90, 126, 127, 128, 129, 131 , 133, 138, or 140. In some embodiments, the composition can be according to Formula 74, 80, 90, 126, 127, 128, 129, 133, 138, or 140. In some embodiments, the composition can have an IC50 for growth inhibition of the organisim of about 880 nM or less. In some embodiments, the composition can have an IC 50 for growth inhibition of the organisim of about 650 nM or less. The pharmaceutial formulations thereof can include a pharmaceutically acceptable carrier. Also provided herein are methods of administering a composition or pharmaceutical formulation thereof to a subject in need thereof where the composition can have a structure according to Formula 209: I Formula 209 where R can be H , COOCH3, COOEt, COOH, CONH2, CONHCH3, a CONHd-ealkyl, CONH(CH) _5(CH3)2, CON(C6Hn), CONHNHCH3, CON(CH3)2, or CH2OH, where R2 can be H or a C alkyl, where R3 can be H , a C1-C6 alkyl group, a benzyl, COCH3,or a diketopiperazine formed between N2 and R , where X 2 -Xis can each be independently selected from the group of: H and a halogen, where R4 can have a structure according to Formula 210 or 2 11 Formula 210 Formula 2 11 where X1-X5 can each be independently selected from the group of H , a halogen, a C C 6 alkyl, a C 6 alkoxy, NHCH 3 , and C(Xi 6 )3 where X 6 can be a halogen, where X can be C or N , where X |0 can be selected from the group of O, S, and NXn , where X can be selected from the group of: H , a halogen, a C C6 alkyl, a C 6 alkoxy, NHCH3, and C(Xi 6 )3, where X 6 can be a halogen, and where X 7-X can each be independently selected from the group of: H , a halogen, a C C6 alkyl, a C 6 alkoxy, NHCH3, and C(Xi 6 ) 3 where X 6 can be a halogen. In some embodiments, the compound does not have a structure according to Formula 60 The pharmaceutial formulations thereof can include a pharmaceutically acceptable carrier. The subject can be infected with or can be suspected of being infected with a methylerythritol phosphate (MEP) pathway obligate organism. The composition or pharmaceutical formulation can be administered prophylactically to prevent infection by a methylerythritol phosphate (MEP) pathway obligate organism. The organisim can be a species of the genus Plasmodium, Toxoplasma, Mycobacterium, Baccillus, Vibrio, Clostriduium, Helicobacter, Campylobacter, Chlamydia, Brucella, Eimeria, Klebsiella, Acinetobacter, Pseudomonas, or Neisseria. The organisim can be P.
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