(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 2017/191579 Al 09 November 2017 (09.11.2017) W !P O PCT (51) International Patent Classification: nomics, Inc., 10675 John Jay Hopkins Drive, San Diego, C07K 7/64 (2006.01) California 92121 (US). (21) International Application Number: (74) Agent: NOVARTIS AG; Lichtstrasse 35, 4056 Basel PCT/IB2017/052577 (CH). (22) International Filing Date: (81) Designated States (unless otherwise indicated, for every 03 May 2017 (03.05.2017) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, (25) Filing Language: English CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (26) Publication Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, (30) Priority Data: KW,KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 17 05 May 20 16 (05 .05 .2016) 62/332,1 US MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (71) Applicant: NOVARTIS AG [CH/CH]; Lichtstrasse 35, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 4056 Basel (CH). SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (72) Inventors: BURGER, Matthew T.; c/ Novartis Institutes for Biomedical Research, Inc., 250 Massachusetts Avenue, (84) Designated States (unless otherwise indicated, for every Cambridge, Massachusetts 02139 (US). JIN, Yunho; c/ kind of regional protection available): ARIPO (BW, GH, o Novartis Institute for Functional Genomics, Inc., 10675 GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, John Jay Hopkins Drive, San Diego, California 92121 (US). UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, UNO, Tetsuo; c/o Novartis Institute for Functional Ge TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (54) Title: AMATOXIN DERIVATIVES AND CONJUGATES THEREOF AS INHIBITORS OF RNA POLYMERASE -X- Vehicle - anti-Her2-HC-E1 52C-S375C-2(2.5 mg/kg) - anti-Her2-HC-E1 52C-S375C-6 (2.5 mg/kg) -∆ - anti-Her2-HC-E1 52C-S375C-1 (2.5 mg/kg) 1600 Έ LU tn + i 1200· E E i 800 400' TO ) (A) 16 24 32 48 Days Post Implant Figure 1 (57) Abstract: The invention disclosed herein relates to cytotoxic cyclic peptides of Formula (A), methods of inhibiting RNA poly- merase with such cyclic peptides, immunoconjugates comprising such cyclic peptides (i.e Antibody Drug Conjugates), pharmaceutical compositions comprising such cyclic peptides immunoconjugates, compositions comprising such cyclic peptides immunoconjugates with a therapeutic co-agent and methods of treatment using such cyclic peptides immunoconjugates. o [Continued on nextpage] WO 2017/191579 Al llll II II 11III I II I II II II I III I III II I II 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, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Declarations under Rule 4.17: — as to applicant's entitlement to apply for and be granted a patent (Rule 4.1 7(H)) Published: — with international search report (Art. 21(3)) — with sequence listing part of description (Rule 5.2(a)) AMATOXIN DERIVATIVES AND CONJUGATES THEREOF AS INHIBITORS OF RNA POLYMERASE F IELD OF THE INVENTION The invention relates to amatoxins and conjugates of amatoxins to a target-binding moiety, e.g. an antibody, and the use of such conjugates to treat cancer. BACKGROUND Amatoxins are cyclic peptides comprised of eight amino acid units which can be prepared synthetically, or can be isolated from a variety of mushroom species, such as Amanita phalloides (green death cap mushroom), Amanita bisporigera (destroying angel), Amanita ocreata (destroying angel), Amanita virosa (destroying angel), Amanita bisporigera (fool's mushroom), Lepiota brunneo-incamata (deadly dapperling), Conocybe filaris and Galerina marginata. There are currently ten known members of the Amatoxin Family: alpha-Amanitin , beta- Amanitin, gamma-Amanitin, epsilon-Amanitin, Amanullin, Amanullinic acid, Amaninamide, Amanin and Proamanullin. Different mushroom species contain varying amounts of different Amatoxin family members. Amatoxins are potent and selective inhibitors of RNA polymerase II, a vital enzyme in the synthesis of messenger RNA (m RNA), microRNA, and small nuclear RNA (snRNA) . By inhibiting the synthesis of mRNA, Amatoxins thereby stop cell metabolism by inhibiting transcription and protein biosynthesis, which results in cellular apoptosis. Consequently Amatoxins stop cell growth and proliferation. Alpha-amanitin, is known to be an extremely potent inhibitor of eukaryotic RNA polymerase II (EC2.7.7.6) and to a lesser degree, RNA polymerase II I, thereby inhibiting transcription and protein biosynthesis. Wieland ( 1 983) Int. J. Pept. Protein Res. 22(3) :257-276. Alpha-amanitin binds non-covalently to RNA polymerase II and dissociates slowly, making enzyme recovery unlikely. The use of antibody-drug conjugates (ADCs) for the targeted delivery of cell proliferation inhibitors and/or cytotoxic agents to specific cells has been the focus of significant research. Antibody-Drug Conjugate, Methods in Molecular Biology, Vol. 1045, Editor L . Ducry, Humana Press (201 3). ADCs include an antibody selected for its ability to bind to a cell targeted for therapeutic intervention, linked to a drug selected for its cytostatic or cytotoxic activity. Binding of the antibody to the targeted cell thereby delivers the drug to the site where its therapeutic effect is needed. Many antibodies that recognize and selectively bind to targeted cells, like cancer cells, have been disclosed for use in ADCs, and many methods for attaching payload (drug) compounds such as cytotoxins to antibodies have also been described. In spite of the extensive work on ADCs, though, only a few classes of cell proliferation inhibitors have been used extensively as ADC payloads. Even though the first ADC approved for use in humans in the U.S. was launched in 2000 (and later withdrawn from the market), a decade later only a few chemical classes of drug compounds (maytansinoids, auristatins, calicheamycins and duocarmycins) had reached clinical trials as payloads for ADCs. Antibody-Drug Conjugates: the Next Generation of Moving Parts, A . Lash, Start-Up , Dec. 201 1, 1-6. The use of amatoxins as cytotoxic moieties in ADC's for tumour therapy was explored in 1981 (Davis & Preston , Science 1981 , 2 13 , 1385-1 388) by coupling an anti-Thy 1.2 antibody to alpha-amanitin using a linker attached to the 7' position of the indole ring via diazotation . Morris & Venton (Morris & Venton, Int. J. Peptide Protein Res. 1983, 2 1 4 19-430) also demonstrated that substitution at the 7' position resulted in a derivative which maintained cytotoxic activity. Patent application EP 1 859 8 1 1 A 1 (published November 28, 2007) described the direct conjugation (i.e. without a linker structure) of albumin or a monoclonal antibody (HEA1 25, OKT3, or PA-1) to the gamma C-atom of amatoxin amino acid 1 of beta-amanitin. The inhibitory effect of these conjugates on the proliferation of breast cancer cells (MCF-7), Burkitt's lymphoma cells (Raji), and Tlymphoma cells (Jurkat) was shown . The use of linkers was suggested, however no such constructs were exemplified and no details regarding linker attachment sites on Amatoxins were provided. Patent applications WO 201 0/1 15629 and WO 201 0/1 15630 (both published October 14 , 201 0) describe conjugates, where antibodies, such as antiEpCAM antibodies such as humanized antibody huHEA1 25, are coupled to amatoxins via (i) the gamma C-atom of amatoxin amino acid 1, (ii) the 6' C-atom of amatoxin amino acid 4 , or (iii) via the delta C-atom of amatoxin amino acid 3 , in each case either directly or via a linker between the antibody and the amatoxins. The inhibitory effects of these conjugates on the proliferation of breast cancer cells (cell line MCF-7), pancreatic carcinoma (cell line Capan-1 ) , colon cancer (cell line Colo205) and cholangiocarcinoma (cell line OZ) were shown. Patent applications WO 201 2/1 19787 (published September 13 , 201 2) describes conjugating a target-binding moiety via a linker attached to the amatoxin indole nitrogen. The cytotoxic activity of such conjugates on a HER2-positive tumor cell line in vitro was disclosed. Patent applications WO 201 4/043403 (published March 20, 201 4) describes conjugating a target-binding moiety via a linker attached to the 7' position of the amatoxin indole. The cytotoxic activity of such conjugates on Herceptin and lgG1 in MDA-MB-468 cells was disclosed. Also, the cytotoxic activity of such conjugates on Herceptin in PC3, HCC-1 954 and MDA-MB-46 cells was disclosed. In view of the toxicity of amatoxins, particularly for liver cells, it is important that ADC's comprising a linked amatoxin remain highly stable in plasma prior to the release of the amatoxin after internalization into the target cells. In this regard, improvements of the conjugate stability may have drastic consequences for the therapeutic window and the safety of the amatoxin conjugates for therapeutic approaches. Thus, given the widely acknowledged value of ADCs as therapeutics for treating cancer, there remains a need for the stable delivery of potent RNA polymerase inhibitors to the target cells prior to internalization of the RNA polymerase inhibitors. SUMMARY OF THE INVENTION The invention provided herein includes cytotoxic cyclic peptides of formula (I), which are analogs of alpha-amanitin and beta-amanitin, and methods of using such cytotoxic cyclic peptides as the drug component of an antibody-drug conjugate (ADC).