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WO 2013/138665 Al 19 September 2013 (19.09.2013) P O P C T

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WO 2013/138665 Al 19 September 2013 (19.09.2013) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2013/138665 Al 19 September 2013 (19.09.2013) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07C 279/04 (2006.01) A61P 35/00 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/155 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2013/031733 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 14 March 2013 (14.03.2013) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, (25) Filing Language: English RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (26) Publication Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/61 1,967 16 March 2012 (16.03.2012) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: SANFORD-BURNHAM MEDICAL RE¬ GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, SEARCH INSTITUTE [US/US]; 10901 North Torrey UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, Pines Road, La Jaolla, CA 92037 (US). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (72) Inventors: STRONGIN, Alex; 10901 North Torrey Pines MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Road, La Jolla, CA 92037 (US). PELLECCHIA, Mauriz- TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, io; 10901 North Torrey Pines Road, La Jolla, CA 92037 ML, MR, NE, SN, TD, TG). (US). BARILE, Elisa; 10901 North Torrey Pines Road, La Jolla, CA 92037 (US). Published: (74) Agent: HOSTETLER, Michael, J., PH. D.; Wilson — with international search report (Art. 21(3)) Sonsini Goodrich & Rosati, 650 Page Mill Road, Palo Alto, CA 94304 (US). (54) Title: INHIBITORS OF FURIN AND OTHER PRO-PROTEIN CONVERTASES (57) Abstract: Disclosed herein are Furin/PC inhibitors for FIG. 13 inhibiting Furin and other Propprotein Convertases. Method of making the Furin/PC inhibitors, chemical and biological characterization of the Furin/PC inhibitors, and the use of the Furin/PC inhibitors to treat infectious diseases, cancers, and inflammatory/autoimmune disorders, are also disclosed. 96B22 96B23 Log (inhibitor] µ Μ 96B22 96B23 HillSlope 1.622 1.068 C50 0.003686 0.009096 INHIBITORS OF FURIN AND OTHER PRO-PROTEIN CONVERTASES CROSS-REFERENCE [0001] The present application claims benefit of U.S. Provisional Application No. 61/61 1,967, filed on March 16, 2012, which is incorporated herein by reference in its entirety. BACKGROUND [0002] Furin belongs to the subtilisin-like proprotein convertase family. Furin is a proprotein convertase that processes latent precursor proteins into their biologically active products. It is a calcium-dependent serine endoprotease that cleaves precursor proteins at their paired basic amino acid processing sites. Some of the Furin substrates are: proparathyroid hormone, transforming growth factor beta 1 precursor, prealbumin, pro-beta-secretase, membrane type-1 matrix metalloproteinase, beta subunit of pro-nerve growth factor and von Willebrand factor. SUMMARY OF THE DISCLOSURE [0003] Disclosed herein, in certain embodiments, are compounds having the general structure I or pharmaceutically acceptable salts thereof: A compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof: wherein Ri is alkyl, cycloalkyl, heteroalicyclyl, aryl, or heteroaryl; R2 is alkyl, cycloalkyl, or heteroalicyclyl; R3 is -Z-guanidine or -Z-C(NH 2)=NH, wherein Z is aryl or heteroaryl; R is -W-C(NH 2)=NR', wherein W is aryl, thiophenyl, furanyl, oxazolyl, pyrrolyl, or picolinyl; and wherein R' is hydrogen or hydroxyl; R is -U-guanidine, wherein U is alkyl, cycloalkyl, heteroalicyclyl, aryl, or heteroaryl; X= -CH2-, -CH2-CH2-, -CH2NHC(=0)-, -CH2CH2C(=0)NH-, or -CH2C(=0)NH-; Y is -C¾-,-S(=0) 2-, or -C(=0)-. In some embodiments of the compound of Formula I, R' is hydrogen. In some embodiments of the compound of Formula I, R' is hydroxyl. In some embodiments of the compound of Formula I, Ri is a Ci-C alkyl. In some embodiments of the compound of Formula I, Ri is methyl. In some embodiments of the compound of Formula I, R2 is a C -C alkyl. In some embodiments of the compound of Formula I, R2 is isopropyl. In some embodiments of the compound of Formula I, U is C C alkyl. In some embodiments of the compound of Formula I, U is -(CH 2)3-. In some embodiments of the compound of Formula I, X is -CH2-. In some embodiments of the compound of Formula I, R3 is -Z-guanidine. In some embodiments of the compound of Formula I, Z is In some embodiments of the compound of Formula I, X is -CH2- and R3 In some embodiments of the compound of Formula I, Y is -CH 2-. In some embodiments of the compound of Formula I, R is -F, -CF3, -OCF3, -OCH3, or alkyl; and n is 0, 1, or 2. In a refinement, R7 is -F. In a further refinement, n is 1. In [0004] Further disclosed herein, in certain embodiments, are compounds of Formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof: wherein: is alkyl, cycloalkyl, or heteroalicyclyl; R2 is -U-guanidine, wherein U is alkyl, cycloalkyl, heteroalicyclyl, aryl, or heteroaryl; Y is -CONH-, -S0 2NH-, -0-, -CH2-, -S-, -S02-, or -COS0 2NH-; Z is -CONH-, -S0 2NH-, -0-, -CH2-, -S-, -S0 2-, or -COS0 2NH-; R3 and R4 are each independently -F, -CF3, -OCF3, -OCH3, or alkyl; a and b are each independently 0, 1, or 2; and m and n are each independently 0, 1, 2, or 3. In some embodiments of the compound of Formula II, R is C C alkyl. In some embodiments of the compound of Formula II, R is isopropyl. In some embodiments of the compound of Formula II, U is Ci-C6 alkyl. In some embodiments of the compound of Formula II, U is -(CH 2) -. In some embodiments of the compound of Formula II, Y is -CONH-. In some embodiments of the compound of Formula II, Z is -S0 2NH-. In some embodiments of the compound of Formula II, m is 1 and n is 1. In some embodiments of the compound of Formula II, a and b are 0. In some embodiments, the compound of Formula [0005] Also disclosed herein, in certain embodiments, are pharmaceutical compositions comprising a Furin/PC inhibitor disclosed herein. [0006] Additionally disclosed herein, in certain embodiments, are methods of treating an infectious disease in a subject in need of such treatment. In some embodiments, the methods comprise administering a therapeutically effective amount of a Furin/PC inhibitor disclosed herein. In some embodiments, the infection disease is associated with influenza virus, human immunodeficiency virus 1, Ebola, measles, cytomegalovirus, and flaviviruses (Dengue, Yellow fever, West Nile, Japanese encephalitis and multiple additional related flaviviruses) and parasitic nemarodes. In some embodiments, the Furin/PC inhibitor neutralizes an esotoxin selected from the group consisting of anthrax toxin, pseudomonas exotoxin A, Shiga toxin, diphtheria toxin, tetanus and botulism neurotoxins, and combinations thereof. In some embodiments, the Furin/PC inhibitor neutralizes virulence of bacteria carrying the esotoxin. [0007] Further disclosed herein, in certain embodiments, are methods of treating a cancer in a subject in need thereof. In some embodiments, the methods comprise administering a therapeutically effective amount of a Furin/PC inhibitor disclosed herein. In some embodiments, the cancer is skin tumors, head and neck squamous cell carcinomas, astrocytoma, lung non-small cell carcinoma, or metastasis of colorectal cancer. [0008] Also disclosed herein, in certain embodiments, are methods of treating an autoimmune or inflammatory disease, disorder or condition in a subject in need thereof. In some embodiments, the methods comprise administering a therapeutically effective amount of a Furin/PC inhibitor disclosed herein. In some embodiments, the autoimmune or inflammatory disease is atherosclerosis, arthritis, or Alzheimer's Disease. BRIEF DESCRIPTION OF THE DRAWINGS [0009] The technical features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which: [00010] FIG. 1 exemplifies the HPLC profile of Compound A; [0001 1] FIG. 2 exemplifies the MS profile of Compound A 2; [00012] FIG. 3 exemplifies the 1H NMR spectrum of Compound A in DMSO-d6; [00013] FIG. 4 exemplifies the HPLC profile Compound B; [00014] FIG. 5 exemplifies the 1H NMR spectrum of Compound B in deuterated PBS; [00015] FIG. 6 exemplifies the MS (MALDI) profile of Compound D; [00016] FIG. 7 exemplifies the HPLC profile of Compound D; [00017] FIG. 8 exemplifies the 1H NMR spectrum of Compound D in deuterated PBS; [00018] FIG. 9 exemplifies the HPLC profile of Compound E. [00019] FIG. 10 exemplifies the MS profile of Compound E; [00020] FIG. 11 exemplifies 1H NMR spectrum of Compound E in DMSO-d6; [00021] FIG.
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