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WO 2015/188120 Al 10 December 2015 (10.12.2015) P O P C T

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WO 2015/188120 Al 10 December 2015 (10.12.2015) 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 2015/188120 Al 10 December 2015 (10.12.2015) P O P C T (51) International Patent Classification: (74) Agents: CEPURITIS, Talivaldis et al; Olson & Cepurit- A61K 31/10 (2006.01) A61K 31/16 (2006.01) is, Ltd., 20 North Wacker Drive, 36th Floor, Chicago, Illinois 60606 (US). (21) International Application Number: PCT/US20 15/0345 16 (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, 5 June 2015 (05.06.2015) 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, 62/008,925 6 June 2014 (06.06.2014) 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: THE SCRIPPS RESEARCH INSTITUTE TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. [US/US]; 10550 North Torrey Pines Road, La Jolla, Cali fornia 92037 (US). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventors: DONG, Jiajia; 7693 Palmilla Drive, Apt. GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 23 11, San Diego, California 92122 (US). SHARPLESS, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, K. Barry; 7960 La Jota Way, La Jolla, California 92037 TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (US). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, [Continued on nextpage] (54) Title: SULFUR(VI) FLUORIDE COMPOUNDS AND METHODS FOR THE PREPARATION THEREOF (57) Abstract: This application describes a compound represented by Formula (I): (I) wherein: Y is a biologically active organic core group comprising one or more of an aryl group, a heteroaryl aryl group, a nonaromatic hydrocarbyl group, and a nonaromatic heterocyclic group, to which Z is covalently bonded; n is 1, 2, 3, 4 or 5; m is 1 or 2; Z is O, NR, or N ; X 1 is a covalent bond or -CH2CH2-, X2 is O or NR; and R comprises H or a substituted or ^substituted group selected from an aryl group, a heteroaryl aryl group, a nonaromatic hy drocarbyl group, and a nonaromatic heterocyclic group. Methods of preparing the compounds, methods of using the compounds, and pharmaceutical composi tions comprising the compounds are described as well. SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Published: GW, KM, ML, MR, NE, SN, TD, TG). SULFUR(VI) FLUORIDE COMPOUNDS AND METHODS FOR THE PREPARATION THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority benefit to U.S. Provisional Application No. 62/008,925, filed on June 6, 2014, which is incorporated herein by reference in its entirety. GOVERNMENT SUPPORT This invention was made with government support from National Institutes of Health, Grants No. U01NS058046 and EB015663, and National Science Foundation, Grant No. CHE 101 1796. The United States government has certain rights in this invention. FIELD OF THE INVENTION The present invention relates to sulfur(VI) fluoride compounds, including therapeutic compounds and compositions, as well as and methods of using and producing the compounds and compositions. BACKGROUND "Click" chemistry was introduced as a conceptual framework for functional molecular assembly a decade ago, emphasizing the importance of carbon-heteroatom linkages in joining modular building blocks (see H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. 2001, 123, 2056-2075; Angew. Chem. Int. Ed. 2001, 2040, 2004-2021). Taking inspiration from nature, click reactions were identified as processes that work under operationally simple, oxygen- and water-friendly conditions, and generate products in high yields with minimal requirements for product purification. Such reactions invariably have an unusual combination of strong thermodynamic driving forces and consistent, well-controlled reaction pathways. In tandem, these two features allow the use of widely varying substrates with great reliability. The azide-alkyne cycloaddition reaction (see R. Huisgen, Angew. Chem. 1963, 75, 604-637; Angew. Chem. Int. Ed. Engl. 1963, 1962, 1565-1598) is especially useful because of the unobtrusive nature of its participating functional groups and the ability to turn on their ligating ability (to different extents, and for different purposes) by Cu(I) catalysts (see (a) C. W. Tornoe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057-3062. (b) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. 2002, 114, 2708-271 1; Angew. Chem. Int. Ed. 2002, 2141, 2596-2599.), installing strain in the alkyne component (see (a) G. Wittig, A. Krebs, Chem. Ber. Reel. 1961, 94, 3260-3275. (b) N . J. Agard, J. A. Prescher, C. R. Bertozzi, J. Am. Chem. Soc. 2004, 126, 15046-15047), or holding them in close spatial proximity (see (a) W. G. Lewis, L. G. Green, F. Grynszpan, Z. Radic, R. P. Carlier, P. Taylor, M. G. Finn, K. B. Sharpless, Angew. Chem. 2002, 114, 1095-1099; Angew. Chem. Int. Ed. 2002, 1041, 1053-1057. (b) H. D. Agnew, R. D. Rhode, S. W. Millward, A. Nag, W. S. Yeo, J. E. Hein, S. M. Pitram, A. A. Tariq, V. M. Burns, R. J. Krom, V. V. Fokin, K. B. Sharpless, J. R. Heith, Angew. Chem. 2009, 121, 5044-5048; Angew. Chem. Int. Ed. 2009, 5048, 4944-4948). Thus, this click reaction emerged by finding ways to induce two functional groups to react with each other that otherwise have very little propensity to react with anything, in spite of their highly energetic nature. In contrast, most other click reactions find a useful window of activity by moderating the properties of at least one highly reactive partner. There is an ongoing need for new click chemistry methods, particularly for the preparation of biologically active materials with useful and uncommon functional groups and pharmacophores. The compounds and methods described herein address these needs. SUMMARY A new aspect of "click" chemistry - dubbed Sulfonyl Fluoride Exchange (SuFEx) - is described herein. SuFEx is made possible by the interplay between the unique hydrogen- bonding requirements of the fluoride ion and the thermodynamic and kinetic properties of fluoride bonds to sulfur(VI) and silicon centers. Click reactions rarely involve acid-base chemistry, because acid-base reactions generally exhibit low selectivity; however, SuFEx transformations are an exception. The special nature of the fluoride ion makes this possible, + requiring guidance by "H " or "R3S 1 " under strict spatial and kinetic constraints. SuFEx chemistry uses interfacial (aqueous/organic) and homogeneous conditions to advantage. The muted polarity of the S0 2 group allows the properties of the molecules built with S0 2 linkages to be influenced to a great degree by the motifs being connected. The resulting sulfonyl/sulfate connector toolbox is also powerfully enhanced by another click reaction, the conjugate (Michael) addition of nucleophiles to the special electrophile ethenesulfonyl fluoride (also known as ethylenesulfonyl fluoride). The compounds descried herein are analogs of biologically active materials such as drugs, other therapeutic agents, herbicides, pesticides, antimicrobial agents, veterinary medical agents, and the like, which include at least one -Z-X1-(S)(X )F group, as described below, generally in place of an -OH, -NH2 or -NHR substituent of the drug or therapeutic agent. In some cases, the -Z-X1-(S)(X )F substituent of the analog replaces another group on the drug, therapeutic or other biologically active agent, such as a -CF3, -OCF3, -OMe, -OEt, or halogen (e.g., CI or Br) substituent, or a hydrogen on a carbon of the drug or therapeutic agent. In some embodiments, a biologically active compound described herein is represented by Formula (I): (I) Y Z X — S(0)(X2)F ) m n wherein: Y is a biologically active organic core group comprising one or more unsubstituted or substituted moiety selected from an aryl group, a heteroaryl aryl group, a nonaromatic hydrocarbyl group, and a nonaromatic heterocyclic group, to which each Z independently is covalently bonded; n is 1, 2, 3, 4 or 5; each Z independently is O, NR, or N; when Z is O, m is 1, X1 is a covalent bond, and the Z is covalently bonded to an aryl or a heteroaryl moiety of Y; 1 when Z is NR, m is 1, X is a covalent bond or CH2CH2, and the Z is covalently bonded to a nonaromatic hydrocarbyl, a nonaromatic heterocyclic, an aryl, or a heteroaryl moiety of Y; 1 when Z is N, either (a) m is 2, X is CH2CH2 and the Z is covalently bonded to a nonaromatic hydrocarbyl, a nonaromatic heterocyclic, an aryl, or a heteroaryl moiety of Y; or 1 (b) m is 1, X is a covalent bond or CH2CH2, and the Z is a nitrogen in an aromatic or non aromatic heterocyclic ring portion of core group Y; each X2 independently is O or NR; and each R independently comprises H or a substituted or unsubstituted group selected from an aryl group, a heteroaryl aryl group, a nonaromatic hydrocarbyl group, and a nonaromatic heterocyclic group.
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