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WO 2015/028850 Al 5 March 2015 (05.03.2015) 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 2015/028850 Al 5 March 2015 (05.03.2015) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C07D 519/00 (2006.01) A61P 39/00 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, C07D 487/04 (2006.01) A61P 35/00 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/5517 (2006.01) A61P 37/00 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR, A61K 47/48 (2006.01) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (21) International Application Number: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, PCT/IB2013/058229 SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (22) International Filing Date: TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, 2 September 2013 (02.09.2013) ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (71) Applicant: HANGZHOU DAC BIOTECH CO., LTD UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, [US/CN]; Room B2001-B2019, Building 2, No 452 Sixth TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Street, Hangzhou Economy Development Area, Hangzhou EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, City, Zhejiang 310018 (CN). MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (72) Inventor: ZHAO, Robert Yongxin; Room B2005, Build KM, ML, MR, NE, SN, TD, TG). ing 2, No. 452 Sixth Street, Hangzhou Economy Develop ment Area, Hangzhou City, Zhejiang 310018 (CN). Declarations under Rule 4.17 : — as to the identity of the inventor (Rule 4.1 7(Ϊ)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, [Continued on nextpage] (54) Title: NOVEL CYTOTOXIC AGENTS FOR CONJUGATION OF DRUGS TO CELL BINDING MOLECULE (57) Abstract: Provided are cytotoxic agents, pyrrolo[2,l-c][l,4]ben- zodiazepine (PBD) derivatives, their conjugates with a cell-binding agent, the preparation and the therapeutic uses in the targeted treat ment of cancers, autoimmune disorders, and infectious diseases. 00 © o o WO 2015/028850 Al llll II II 11III II — as to applicant's entitlement to apply for and be granted with amended claims (Art. 19(1)) a patent (Rule 4.1 7(H)) Published: NOVEL CYTOTOXIC AGENTS FOR CONJUGATION OF DRUGS TO CELL BINDING MOLECULE DECRIPTION FIELD OF THE INVENTION The present invention relates to novel cytotoxic agents, pyrrole [2,1- c][l,4]benzodiazepine (PBD) derivatives and their therapeutic use. These novel cytotoxic agents have therapeutic use as a result of delivering the pyrrolo[2,l-c][l,4]benzodiazepine (PBD) derivatives to a specific targeted cell population by chemically linking these derivatives to a cell binding agent. BACKGROUND OF THE INVENTION Since the successful launches of Brentuximab vedotin (Adcetris) and Trastuzumab emtansineo (Kadcyla), Antibody-drug conjugates (ADCs) have currently become a promising therapeutic modality for the clinical management of cancer. The new ADC compounds, which covalently incorporate the antitumor activity of a cytotoxic agent to a monoclonal antibody, have ability to deliver cytotoxic agents specifically to antigen-expressing tumor cells and then kill the tumor cells. The ADC platform includes a growing repertoire of cytotoxic agents, linker technologies, antibody properties, and conjugation methods. An important key factor in generating an optimal ADC is the cytotoxic agents. Pyrrolo[2,l-c][l,4]benzodiazepines (PBDs) are a well-known class of sequence- selective DNA-binding agents derived from various Streptomyces species. Well-known members of this include DC-81, tomaymycin, porothramycin B, prothracarcin, mazethramycin, porothramycin, prothracarcin, sibanomycin, neothramycin, chicamycin, abbemycin, sibiromycin and anthramycin (I. O'Neil et al. Tetrahedron Letters 2003, 44, 7809-7812 ; L. Cipolla, et al, Anti-Cancer Agents in Medicinal Chemistry, 2009, 9, 1-31; L, Hurley, J. Antibiot. 1977, 30, 349.; K. Schimizu, et al. J. Antibiot 1982, 35, 992.; J. Lown, et al. Biochem. Pharmacol. 1979, 28, 2017.; D. Thurston, et al. Chem. Rev. 1994, 94, 433; P. Molina, et al. Tetrahedron 1995, 51, 5617; A. Kamal, et al. Chem. Commun. 1996, 385; A. Kamal, et al. Tetrahedron Lett. 1996, 37, 6803). These agents exert their antitumor antibiotics activity by the formation of a covalent adduct in the minor groove of a DNA with preference of a three base pairs of Pu-G-Pu (where Pu = purine; G = guanine) sequences, wherein their ( Ί 1-position is electrophilic, enabling the molecules to alkylate the N l group of a guanine in the minor groove of DNA (Thurston, D. Molecular Aspects of Anticancer Drug- DNA Interactions; The Macmillan Press Ltd.: London, UK, 1993, pp 54-88, D. Antonow and D. Thurston, Chem. Rev. 201 , 111, 2815-2864; P. Dervan, Science 1989, 232, 464.; L, Hurley, J. Med. Chem. 1989, 32, 2027.; D. Thurston, Chem. Br. 1990, 26, 767). Moreover, PBDs have potential not only as antitumor agents but also as gene regulators and probes of DNA structure (Hurley, L. J. Med. Chem. (1989), 32: 2027-2033). Thurston and co-workers reported the first C8/C 8'-linked PBD dimer (DSB-120) in which two DC-81 subunits are joined through their aromatic A-ring at phenol positions by an inert propyldioxy linkage (D. Thurston, et al., J. Org. Chem. 1996, 61, 8141). These C8/C8'- diether-linked PBD dimers exhibit higher DNA binding affinity, a least twice compared to the monomer DC-81. The three carbon space ((n=3) C8/C8' -linked PBD dimer analog (DSB- 120) covalently bind to a 5'-Pu-GATC-Py sequence by crosslinking opposite-strand guanines separately by 2 base pairs, span six DNA base pairs ( l man, K. et al .1. Am. Chem. Soc.(2009), 131(38), 13756-13766; Martin, C. et al Biochemistry (2005), 44(11), 4135-4147). The more extended PBD dimer (n = 5) can span an extra base pair and cross-link the 5'-Pu- GA(T/A)TC-Py sequence (S. Hopton and A. Thompson, Biochemistry 2011, 50(21), 4720- 4732, M. Smellie, et al, Biochemistry 2003, 42(27), 8232-8239; Gregson, S. et al J. Med. Chem. (2004), 47(5), 1161-1174). Among the C8/C8'-linked dimmers, the one with five carbon chain showed the highest cytotoxicities n most of the tested cell lines (Thurston, D. et al, J. Org. Chem. 1996, 61, 8141; Kamal, A. et al., Curr. Med. Chem. - Anti-cancer Agents, 2002, 2, 215-254, Gregson, S . et al J. Med. Chem. (2004), 47(5), 1161-1 174). Since the introduction of C8/C8'-linked PBD dimer, a number of structurally modified PBD dimers have been synthesized and evaluated for their biological activity, particularly for their DNA binding ability and antitumor activity (see US patents 8,383,618; 8,372,831; 8,217,167; 8,318,726; 8,153,627; 7,754,694; 7,741,319; 7,704,924; 7,612,062; 7,608,615; 7,557,099; 7,528,128; 7,528,126; 7,476,664; 7,465,724; 7,429,658; 7,407,951; 7,312,210; 7,265,105; 7,189,710; 7,183,054; 7,173,026; 7,067,51 1; 7,056,913; 7,049,311; 7,015,215; 6,979,684; 6,951,853; 6,939,869; 6,884,799; 6,800,622; 6,683,073; 6,660,856; 6,562,806; 6,362,331; Seifert, .1. et al. Org. Biomol. Chem. (2012), 10(34), 6850-6860; Rahman, Ket al .1. Antimicro. Chem. (2012), 67(7), 1683-1696. Hartley, J. et al Cancer Research (2010), 70(17), 6849-6858; Hartley, J. et al Invest. New Drugs (2012), 30(3), 950-958; Howard, P. et al WO 2011130613; Hartley, J. et al Expert Opin. Invest. Drugs (2011), 20(6), 733-744; Howard, P. et al Bioorg. Med. Chem. Lett. (2009), 19(22), 6463-6466; Cipolla, L. et al Anti-Cancer Agents Med. Chem. (2009), 9(1), 1-31; Tiberghien, Ar. Bioorg. Med. Chem. Lett. (2008), 18(6), 2073- 2077; Purnell, B. et al Bioorg. Med. Chem. Lett. (2006), 16(21), 5677-5681; Kamal, A. Bioorg. Med. Chem. (2006), 14(2), 385-394; Howard, P. et al WO 2005085259; Kumar, R. et al Eur. .1. Med. Chem. (2005), 40(7), 641-654; Kamal. A. et al Bioorg. Med. Chem. (2004), 12(20), 5427-5436; Wilkinson, G. Invest. New Drugs (2004), 22(3), 231-240; Kumar, R. et al Mini-Reviews Med. ( 'hem. (2003), 3(4), 323-339; Gregson, S. al Bioorg. Med. ' hem. Lett. (2001), 11(21), 2859-2862; Reddy, B. et al Anti-Cancer Drag Design (2000), 15(3), 225-238; Damayanthi, Y. et al J Org ( "hem 1999, 64, 290-292). Some structures of these dimers are shown in the Table 1. Interestingly, only the PBD dimers which have flexible linkers between two PBD subunits to form none distorting interstrand cross-links within the minor groove of DNA hav been shown significantly increased the potency comparing to the PBD monomer. So far, a number of these compounds have been selected for preclinical studies but unfortunately most of them did not proceed beyond that stage mainly because of problems related to poor bioavailability.
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