CA3024320C - Novel cyclosporin derivatives and uses thereof - Google Patents

Abstract

(57) Abstract: A compound of the Formula (I) is disclosed: (I) or pharmaceutically acceptable salt thereof, wherein the symbols are as defined in the specification. Also described are a pharmaceutical composition comprising the same and a method for treating or preventing viral infections, inflammation, dry eye, central nervous disorders, cardiovascular diseases, cancer, obesity, diabetes, muscular dystrophy, lung, and liver, and kindey diseases, and hair loss using the same.

Description

84932431 NOVEL CYCLOSPORIN DERIVATIVES AND USES THEREOF Related Application

[0001] This application is related to U.S. Application Serial No. 13/840,088, filed March 15, 2013. This application claims priority to U.S. Provisional Application No. 62/337,377, filed May 17, 2016, to U.S. Provisional Application No. 62/339,464, filed May 20, 2016, and to U.S. Provisional Application No. 62/384,822, filed September 8, 2016. Field of the Invention

[0002] The invention relates to novel cyclosporine derivatives, their pharmaceutical compositions comprising the same, and methods for treating or preventing viral infections, inflammation, dry eye, central nervous disorders, liver, lung and kidney diseases, cardiovascular diseases, cancer, obesity, diabetes, muscular dystrophy, hair loss and so on. Background of the Invention

[0003] Cyclosporins in nature are poly-N-methyl, cyclic undecapeptides, isolated from fungi. Cyclosporin A has an immunosuppressive activity and has been used for almost 33 years to prevent rejection in kidney, heart and liver transplant recipients. It possesses anti¬ inflammatory properties and has been used for treating severe rheumatoid arthritis, severe psoriasis, Behget’s uveitis, and dry eye disease. In addition, it is useful for treating severe ulcerative colitis, Crohn’s disease, alopecia areata, aplastic anemia, HSV-1 stromal keratitis, systemic lupus erythematosus, and severe lupus nephritis. However, its strong immunosuppressive activity limits its applications in many diseases.

[0004] The anti-HIV activity of cyclosporin A was first discovered in 1986 and has been continually studied since then (Klatzmann, D., et al., 1986, CRAcad. Sci. Ill, 303(9):343-8; Wainberg, M. A., et al.,1988, Blood, 72, 1904-10; Luban, J., et al.,1993, Cell, 73, 1067- 1078). Its non-immunosuppressive derivative, NIM-811, was reported to have potent anti HIV activity due to its ability to inhibit cyclophilin A (Franke, E. K., et al.,1994, Nature, 372, 359- 362; Thali, M., et al., 1994,Nature, 372, 363-365; Gamble, T. R., et al., 1996, Cell, 87, 1157- 1159;RosenwirthB., et al., 1994, Antimicrob. Agents Chemother., 38, 1763-1772).

[0005] Cyclosporin A and its non-immunosuppressive derivatives, as such as NIM-811 (N-MeHe-4-Cyclosporin), Debio-025, SCY-635, EDP-494, DEP-546, NIM-258, CPI-431-32 (CRV431), and STG-175 and bind and inhibit cyclophilins, subsequent to prevent HCV RNA replication and protein synthesis. As a result, these compounds have an effective anti-HCV activity (Watashi, K., et al., 2007, Rev. Med. Virol., 17:245-252.37; Inoue, K., et al., 2001, -1 - Date reçue/Date Received 2023-10-0684932431 Nippon Rinsho., 59, 1326-30; Inoue, K., et al., 2003, J. Gastroenterol., 38, 567-72; Watashi, K., et al., 2003, Hepatology, 38, 1282-8; Gaither, L. A., et al., 2010, Virology, 397, 43-55; Rhodin, M. H. J., et al, 2016, EASL, Poster 250, and the news of the 34th Annual L. P. Morgan Healthcare, Conference Presentation on Jan. 13, 2016 at 11:00AM by Enanta Pharmaceutical. Inc. (www.enanta.com) (EDP-494); Baugh, J. M., et al, 2013, Antiviral Res. 100(2): 555-561 (EDP-546 included); Fu, J., et al, 2014, J. Med. Chern., 57, 8503-8516 (NIM-258); Gallay, P. A., et al, 2015, PLoS One 10(8):e0134707.doi: 10.1371/joumal.pone.0134707 (CPI-431- 32(CRV431)); Gallay, P. A., et al, 2016, PLoS One 11(4):eO152036. doi: 10.1371/joumal.pone.0152036 (STG-175)). NIM-811, Debio-025, and SCY-635 had been evaluated in clinical trials phase II and III against HCV, and EDP-494 phase I study is beginning in the first quarter of 2016 for resistance-associated variants of HCV.

[0006] NIM-811 and Debio-025 have a chemical structure similar to cyclosporine A and possess a poor pharmacokinetic profile. In addition, they are metabolized by P450 for inducing drug interactions (Lill, J., et al., 2000, Am J Health-Syst Pharm 57, 1579).

[0007] SCY-635 has an improved pharmacokinetic profile and low blood serum binding. In addition, it has a low potential for drug-drug interactions. SCY-635’s in vitro anti-HCV activity (ECso) was reported to be 0.10 pM (Hopkins, S. et al., 2010, Antimicrob. Agents Chemother.,54, 660-672). However, SCY-635 is not chemically stable, as it is easily converted to its diastereoisomer by epimerization. Its diasteroisomer is expected to have poor binding activity with cyclophilins, and as a result, its anti-viral activity in vivo may be affected (See, e.g., WO2012/009715, WO2012/021796, and WO2012/075494).

[0008] Cyclosporin A and its non-immunosuppressive derivatives were also found to possess anti-HBV activity through the inhibition of cyclophilins (Chokshi, S., et al., 2012, Gut 61:A11; Chokshi, S., et al., 2012, Poster Presentations, 47th Annual Meeting of the European Association for the Study of the Liver (EASL 2012), Barcelona, Spain; Chokshi, S., et al., 2011, Abstract 190 (Poster Presentations), 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011), Berlin, March 30-April 3; Tian, X. C., et al., 2010, J. Virol., 84, 3373-3381; Xia, W. L., et al., 2004, Hepatobiliary Pancreat Dis Int., 4, 18-22; Michael, J., et al., 2003, J. Virol., 77, 7713-7719).

[0009] Furthermore, cyclophilins were reported to regulate the life cycle and pathogenesis of several viruses, including severe acute respiratoiy syndrome coronavirus, vaccinia virus, and herpes simplex virus (Castro, A. P_, et al., 2003, J. Virol., 11, 9052-9068; Chen, Z., L., et al., 2005, J. Infect. Dis. 191(5):755-760; Arai, C., et al., Nihon Rinsho Meneki Gakkai Kaishi., -2- Date reçue/Date Received 2023-10-0684932431 35(1), 87-91; Labetoulle, M., 2012, JFr Ophtalmol., 35(4), 292-307; De Clercq, E., 2008, Expert Opin Emerg Drugs 13(3):393-416; Vahlne, A., 1992, Arch Virol., 122(l-2):61-75). Cyclosporin A and its non-immunosuppressive derivatives also possess such anti-viral activities.

[0010] N-MeVal-4-Cyclosporin (SDZ 220-384), another non-immunosuppressive cyclosporine derivative, was reported to have similar biological activities to that ofNIM-811 (Fliri, H., et al.,1993, Ann. N YAcadSci. 696, 47-53; Zenke, G., et al., 1993, Ann N Y Acad Sci. 23;685:330-5).

[0011] Hepatitis C virus (HCV) is a small (55-65 nm in size), enveloped, positive sense single strand RNA virus in the Flaviviridae family. HCV has a high rate of replication and an exceptionally high mutation rate. About 80% of people infected with HCV develop chronic, persistent infection. More than 4 million Americans have been infected with HCV and more than 200 million people are estimated to be infected chronically worldwide. About 35,000 new cases of hepatitis C are estimated to occur in the United States each year. HCV infection is responsible for about 50% of all chronic liver disease, 30% of all liver transplants, and 30% of all cirrhosis, end-stage liver disease, and liver cancer in the U.S. The peg-interferon and ribavirin combination is the standard treatment for chronic hepatitis C, but it has low efficacy against HCV infection. Recently, the FDA has approved Vertex’s Incivek (telaprevir) and Merck’s Victrelis (boceprevir) as an add-on to the current interferon/ribavirin therapy for treating HCV. Both drugs are HCV protease inhibitors that target the virus to prevent its replication. However, due to HCV’s fast mutation rate, drug resistance can be developed in a short period of time. Thus, there exists a need for an effective therapeutic for HCV treatment.

[0012] Hepatitis B virus (HBV) is a 42 nm partially double stranded DNA virus composed of a 27 nm nucleocapsid core (HBcAg) that is surrounded by an outer lipoprotein envelope containing the surface antigen (HBsAg). More than 2 billion people have been infected, and there are 350 million chronic carriers of the virus. The disease has caused epidemics in parts of Asia and Africa. Chronic hepatitis B will cause liver cirrhosis and liver cancer, a fatal disease with a very poor response to current chemotherapies. The infection is preventable by vaccination, and HBV load and replication can be reduced by current antiviral drugs, such as lamivudine (Epivir), adefovir (Hepsera), tenofovir (Viread), telbivudine (Tyzeka), entecavir (Baraclude), and the two immune system modulators interferon alpha-2a and PEGylated interferon alpha-2a (Pegasys). However, none of the available drugs can clear the infection. There remains a need for an effective therapeutic to treat HBV infection. Recently, NTCP has -3- Date reçue/Date Received 2023-10-0684932431 been identified as a HBV entry target (Yan, H., et al., 2012, eLife, l:e00049; Yan, H., et al., J. Virol., 88(6)3273-84; Watashi, K., 2014, Int. J. Mol. Sci., 15(2):2892-905; Yan, H., et al., 2015, Antiviral. Res., 121:24-30.); Cyclosporin A and its analogs inhibit HBV entry with the NTCP receptor (Nkongolo, S., et al., 2014, J. Hepatol., 60(4):723-31; Watashi, K., 2014, Hepatology, 59(5):1726-37.) Cyclosporin analogs, Alisporivir and STG-175, also inhibit cyclophilin in hepatocyte cell and reduce replication of HBV RNA and HBsAg production and secretion (Phillips, S., et al., Gastroenterology, 148(2):403-14; Gallay, P. A., et al., PloS One, ll(4):e0152036. Doi: 10.1371/joumal.pone.0152036.).

[0013] The non-immunosuppressive cyclosporin derivatives bind to cyclophilins, a family of host proteins that catalyze cis-trans peptidyl-prolyl isomerization in protein folding and regulation, which are crucial for the processing and maturation of the viral proteins for viral replication. HIV and HCV are viruses with a high mutation rate. All current anti-viral drugs target the virus itself; when the virus mutates, it leads to the development of drug resistance. Instead of directly targeting the virus, targeting host cofactors (cyclophilins) will be slow down the development of drug resistance due to a higher genetic barrier (Rosenwirth, B., et al.,1994, Antimicrob. Agents Chemother., 38, 1763-1772; Tang, H. L. et al., 2010, Viruses, 2, 1621- 1634; Hopkins, S. et al.,2010, Oral Presentation, Scynexis’s SCY-635 Demonstrates Impressive Barrier to Resistance in HCV Treatment, the 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010), Vienna, Austria, April 14-18). Cyclosporine derivatives affect a new target, cyclophilins, and therefore represent a new mechanism of action against viruses.

[0014] There are 19 cyclophilins in the human genome (Thapar, R., 2015, Biomolecules 5(2): 974-99.), but the functions of these cyclophilin isoforms are still unclear (Davis, T. L., et al., 2010, PLoS Biol. 8(7):el000439). Cyclophilin A, B, C, D, and other such isoforms play an important role in the pathophysiology of a number of serious diseases, such as cancer (Campa, MJ., et al., 2003, Cancer Res., 63(7), 1652-6; Li, M., et al., 2006, Cancer,106: 2284-94; Yang, H., et al., 2007, Biochem Biophys Res Commun., 361(3):763-7; Obchoei, S., et al., 2009, Med Sci Monit.,15(11), RA221-32; Andersson, Y., et al., 2009, Br J Cancer, 101, 1307-1315; Lee, J., 2Q1Q, Arch Pharm Res., 33(2), 181-7; Lee, J., et al., 2010, J Exp Clin Cancer Res., 29:97; Obchoei, S., 2011, Molecular Cancer, 10:102; Takahashi, M., et al., 2012, Oncol Rep., 27(1):198-203; Qian, Z., et al., 2010, BMC Cancer,12:442; Lee, J., 2010, Arch. Pharm. Res., 33(9):1401-9; Hamilton, G., 2014, Curr. Cancer Drug Target, 14(l):46-58; Zhu, D., et al., 2015, Nat. Med., 21(6):572-80; Lavin, P. T., et al., 2015, Curr. Mol. Pharmacol., 9(2): 148-64; Date reçue/Date Received 2023-10-0684932431 Seleh, T., et al., 2016, Nat. Chem. Biol., 12(2): 117-23), inflammations (the result of interactions between a secreted extracellular cyclophilin and CD-147, a surface protein; Yurchenko V., 2005, Immunology, 117(3):301-9; Yurchenko, V., 2010, Clin Exp Immunol., 160(3):305-17; Malesevic, M., 2010, Angew Chern Int Ed Engl., 49(1)1213-5), cardiovascular diseases (including vascular stenosis, atherosclerosis, abdominal aortic aneurysms, aortic rupture, cardiac hypertrophy, pulmonary arterial hypertension, myocarditis and myocardial fibrosis, and ischaemic heart diseases, liver, kidney, and lung fibrosis, protection and regeneration; Jin, Z. G., et al., 2000, Circ Res., 87(9)1789-96; Yurchenko, V., et al., 2005, Immunology, 117, 301-309; Suzuki, J., et al., 2006, Circ Res., 98(6)1811-7; Satoh, K., et al., 2008, Circulation., 117(24)13088-98; Nishihara, M., et al., 2008, J Mol Cell Cardiol., 44(2)1441-442; Satoh, K, et al., 2010, Circ J., 74(11)12249-56; Satoh, K., et al., 2010, Antioxid Redox Signal., 12(5)1675-82; Hausenloy, D. I, et al., 2012, Br J Pharmacol. 165(5)11235-45; Coppinger, J. A., et al., 2004, Blood, 103(6)12096-104; Satoh, K, et al., 2010, Antioxid Redox Signal., 1:12(5), 675-682; Nigro, P., et al., 2010, J Exp Med., 208(l):53-66; Wang, W. L., et al., 2011, Med Hypotheses, 77(5):734-8; Hattori, F., 2012, J Mol Cell Cardiol., 53(1):1-2; Seizer P., 2012, J Mol Cell Cardiol., 53(1):6-14; Naoumov, N. V., 2014, L. Hepatol., 61(5):1166-74), rheumatoid arthritis (Wells, G., et al., 2000, Cochrane Database Syst Rev., (2):CD001083; Kim, H., et al., 2005, Clin Immunol., 116(3):217-24; Yang, Y., Rheumatology (Oxford), 47(9):1299-310; Yurchenko, V., et al., 2006, Immunology, 117(3):301-9; Damsker, J. M., 2009, Immunology, 126(l):55-62; Wang, L., et al., 2010, J Clin Immunol.,30(l):24-33; Billich A., et al., 1997, J Exp Med., 185:975-80; De CeuninckF., et al., 2003, Arthritis Rheum.,48:2197-206), respiratory inflammation (Foda, H. D., et al., 2001, Am JRespir Cell Mol Biol., 25:717-24; Hasaneen, N. A., et al., FASEB J., 19:1507-9.Yurchenko, V., et al., 2006, Immunology,117(3):301-9; Gwinn, W. M., 2006, J Immunol., 177(7):4870-9; Onoue, S., 2009, J Control Release., 138(1):16-23; Balsley, M. A., et al., 2010, J Immunol., 185(12):7663-70; Balsley, M., et al., 2010, Am. J. Respir. Crit. Care Med., 181(1): A6821; Stemmy, E. J., et al., 2011, J. Asthma, 48(10):986-993; Stemmy, E. J., et al., 2011,^m J Respir Cell Mol Biol., 45(5):991-8; Amin, K., 2012, Respir Med., 106(l):9-14; Onoue, S., 2012, EurJPharm Biopharm., 80(l):54-60), lupus (Caccavo, D., et al., 1997, Arthritis & Rheumatism, 40(l):27-35; Dostal, C., et al., 1998, Lupus, 7(1):1 29-36; Tam, LS., et al., 1998, Q J Med., 91(8):573-580; Fu, LW., et al., 1998, Rheumatology 37 (2): 217-221; Hallegua, D., et al., 2009,Lupus, 9: 241-251), psoriasis (Ellis, C. N., 1991, N Engl J Med., 324, 277-284; Lebwohl, M., et al., 1998, J Am Acad Dermatol., 39(3):464-75; Rosmarin, DM., et al., 2010, J -5- Date reçue/Date Received 2023-10-0684932431 Am Acad Dermatol., 62(5):838-53), atopic dermatitis (Naeyaert, J. M., et al., 1999, Dermatology,198:145-152; Pacor, ML., et al., 2001, Recenti Prog Med., 92(6):390-l; Ricci, G., et al., 2009, Drugs, 69(3):297-306; Simon, D., 2011, Curr Probl Dermatol.,41:156-64), dry eye disease (Pflugfelder, S. C., 2004, J Ophthalmol., 137(2), 337-42; Kymionis, G. D., et al 2008, Clin Ophthalmol., 2, 829-836; Kunert, K. S., et al., 2002, Arch Ophthalmol., 120, 330-7; Yavuz, B., et al., 2012, Scientific World Journal. 2012:194848), severe Graves' ophthalmopathy (Prummel, M. F., 1989, A Engl J Med., 321(20), 1353-9), endogenous uveitis (Nussenblatt, R. B., et al., 1991, Am J Ophthalmol., 112(2), 138-46), Wegener's granulomatosis (Georganas, C., et al., 1996, Clin Rheumatol., 15(2), 189-92), vernal keratoconjutivitis (Pucci, N., et al., 2002, Ann Allergy Asthma Immunol., 89, 298-303), atopic keratoconjutivitis (Akpek, E. K., et al., 2004, Ophthalmology,111, 476-82), ligneous conjutivitis (Rubin, B. L, et al., 1991, Am J Ophthalmol.,112, 95-96), conjuctival linchen planus (Levell, N. J., et al., 1992, Br J Dermatol.,\T1,66-7), superior limbic keratoconjutivitis (Perry, H. D., et al., 2003, Ophthalmology,110, 1578-81), inflammatory bowel diseaseCrohn's Disease and Ulcerative Colitis (Sandborn, W. J., 1995, Inflamm Bowel Dis. 1:48-63; Shibolet, O., et al., 2005, Cochrane Database Syst Rev., (l):CD004277; Rufo, P. A., et al., 2006, Paediatr Drugs, 8(5):279-302; Reindl, W., et al., 2007, Gut., 56(7):1019; Hart, A. L., et al., 2010, Aliment Pharmacol Ther., 32(5):615-27; Cheifetz, A. S., et al., 2011, J Clin Gastroenterol.,45(2):107-12; Sharkey, L., 2011, J Crohns Colitis., 5(2):91-4; Fabro, M., et al., 2011, Curr Drug Targets., 12(10):1448-53; Van Assche, G., et al., 2011, Gut., 60(1):130-3), NSAID-induced enteropathy (LoGuidice, A., at al., 2010, Toxicol. Sci., 118, 276-285), and ischaemic brain diseases (Boulos, S., et al., 2007, Neurobiol Dis., 25:54-64).

[0015] Due to cyclophilin inhibition, cyclosporin derivatives also possess the following biological activities: anti-fungal (Kirkland, T. N., et al., 1983, Antimicrob Agents Chemother., 24(6): 921-924; Mody, C. H., et al., 1988,Infect Immun., 56(1): 7-12; Roilides, E., et al., 1994,Antimicrob Agents Chemother., 38(12): 2883-2888; Moussaïf, M., et al., 1997, Appl Environ Microbiol., 63(5):1739-43; Cruz, M. C., et al., 2000, Antimicrob Agents Chemother., 44(l):143-9), anti-malarial (Nickell, S. P., et al., 1982, Infect Immun., 37(3):1093-100; Murphy, J. R., et al, 1988, Antimicrob Agents Chemother., 32(4):462-6; Marin-Menéndez, A., et al., 2012, Mol Biochem Parasitol., 184(l):44-7), and anti-parasitic (including Leishmania donovani, Cryptosporidium parvum, Hymenolepis nana, Toxoplasma, Trypanosoma cruzi, and Schistosome; Chappell, L. H., et al., 1992, Parasitology, 105 Suppl:S25-40; Bell, A., et al., 1996, Gen Pharmacol., 27(6):963-71; Yau, W. L., et al., 2010, PLoSNegl Trop Dis., - 6 - Date reçue/Date Received 2023-10-0684932431 4(6):e729; Yurchenko, V., et al., 2008, Int J Parasitai., 38(6):633-9; Perkins, M. E., et al., 1998, Antimicrob Agents Chemother.,42(4):843-8; Matsuzawa, K., et al., 1998, Int J Parasitai.,28(4):579-88; Silverman, J. A., et al., 1997, Antimicrob Agents Chemother., 41(9):1859-66; Bùa, J., et al., 2008, Parasitology, 135(2):217-28; Bûa, J., et al., 2004, Bioorg Med Chem Lett., 14(18):4633-7; Bout, D. T, et al., 1984, J Trop MedHyg., 33(1):185-6; Bout, D., étal., 1986, Infect Immun., 52(3):823-7; Munro, G. H., et al., 1991, Parasitology, 102 Pt 1:57-63). In addition, cyclosporin derivatives can promote hair growth (Watanabe, S., et al., 1991, J Dermatol., (12):714-9; Paus R., et al., 1994, J Invest Dermatol., 103:2, 143-7; Hozumi, Y., et al., 1994, J Dermatol Sci., 7 Suppl:, S33-8; Takahashi, T., et al., 2001, Jinvest Dermatol.,117(3):605-ll; Taylor M., et al., 1993, J Invest Dermatol., 100:3, 237-9; GafterGvili, A., et al., 2004, Arch Dermatol Res., 296(6):265-9).

[0016] The research for Alzheimer’s disease indicated that Cyclophilin A is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration (Bell, R. D., et al., 2012, Nature, 485(7399):512-6; Bell, R. D., et al., 2009, Acta NeuropathoL,118(1):103-13).

[0017] Due to the function of extracellular cyclophilins, it is necessary to emphasize that the special target of a secreted extracellular cyclophilin using a cell-impermeable derivative of cyclosporine will be effective in reducing inflammation for diseases such as respiratory inflammation and cardiovascular diseases (Yurchenko V., 2005, Immunology, 117(3):301-9; Yurchenko, V., 2010, Clin Exp Immunol., 160(3):305-17; Malesevic, M., 2010, Angew Chern IntEdEngl.,49(l):213-5; Balsley, M. A., et al., 2010, J Immunol., 185(12):7663-70; Balsley, M., et al., 2010, Am. J. Respir. Crit. Care Med., 181(1): A6821; Satoh, K., et al., 2010, Cire J., 74(ll):2249-56; Bukrinsky, M., 2015, Biochim Biophys Acta, 1850(10): 2087-95). To target extracellular cyclophilin, MM284 had been discovered and tested for its anti-inflammatory property (Malesevic, M., et al., 2013, J. Med. Chern., 56, 7302-7311.). The further study for biliary atresia (BA) and other intrahepatic chronic disorders (lordanskaia, T., et al., 2015, Mol. Med., 21(1): 657-664.), for myocardial inflammation and reduction of cardiac fibrosis (Heinzmann, D., et al., 2015, PLoS One 10(8):e0124606. doi: 10.1371/joumal.pone. 0124606), study for reduction of TNF-alfa (Ditiatkovski, M., et al., 2015, J. Pharmacol. Exp. Ther., 353(3):490-5.) had been reported.

[0018] Cyclophilin D (CypD) is very important for mitochondrial related neuro and cardiovascular functions because it is an integral part of the mitochondrial permeability transition pore (mPTP). Unregulated opening of the mPTP can lead to mitochondrial swelling -7- Date reçue/Date Received 2023-10-0684932431 and cell death. Thus, the CypD-mediated mPTP is directly linked to a new pharmacologic treatment strategy for many neuro and cardiovascular diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS, aging, heart failure, traumatic brain injury, spinal cord injury, epilepticus, stroke, ischemia-reperfusion injury in the brain, heart, liver, lung, kidney, and particularly in myocardial infarction. The CypD-mediated mPTP is also linked to a new treatment strategy for cancer, obesity, diabetes, and muscular dystrophy, liver fibrosis, liver protection and regeneration (Henry-Mowatt, J., 2004, Oncogene, 23, 2850-60; Galluzzi, L., 2006, Oncogene, 25, 4812-4830; Hirai, K., et al., 2001, J Neurosci., 21, 3017- 3023; Friberg, H., et al., 2002, Biochimie, 84, 241-250; Waldmeier, P. C., et al., 2003, CunMed Chem.,10, 1485-506; Hansson, M. J., et al., 2004, J BioenergBiomembr., 36, 407-13; Sullivan, P. G., et al., 2005, J Neurosci Res., 79, 231-9; Baines, C. P., et al, 2005,Nature 434, 658-662; Shanmuganathan, S., et al, 2005, Am J Physiol Heart Circ Physiol., 289, H237- H242; McBride, H. M., et al., 2006, Curr Biol., 16, R551-560; Mandemakers, W., et al., 2007, J Cell Sci., 120, 1707-1716; Kroemer, G., et al., 2007, Physiol Rev., 87, 99-163; Ibarra, A., et al., 2007, Brain Res., 1149, 200-209; Michelakis, E. D., et al, 2008, Circulation,117, 2431- 2434; Du, H., et al, 2008, Nature Medicine, 14, 1097-1105; Piot C., et al., 2008, N Engl J Med., 359, 473-81; Hatton, J., et al., 2008, JNeurosurg., 109, 699-707; Tatsuta, T., et al., 2008, EMBOJ, 27, 306-314; Reutenauer, J., et al., 2008, Br J Pharmacol., 155, 574-84; Mazzeo, A. T., et al., 2009, Exp Neurol., 218, 363-370; Galluzzi, L., et al, 2009, Nature Rev Neurosci., 10, 481-494; Halestrap, A. P., et al., 2009, Biochim Biophys Acta., 1787, 1402-15; Arnett, A. L. H., et al., 2009, Curr. Opin. Genet. Dev., 19, 290-297; Tiepolo, T., et al., 2009, Br J Pharmacol.,157, 1045-1052; Wissing, E. R., et al., 2010, Neuromuscul Disord., 20, 753- 60; Halestrap, A. P., et al., 2010, Biochem Soc Trans., 38, 841-860; Cemak, I., et al., 2010, J Cereb Blood Flow Metab., 30, 255-66; Elrod, J. W., et al., 2010, J Clin Invest.,120, 3680- 3687; Duchen, M. R., et al., 2010, Essays Biochem., 47, 115-37; Schapira, A. H. V., et al., 2011, Parkinson's Disease, Volume 2011, 1-7 Article ID 159160; Osman, M. M., et al., 2011, Neuropeptides,45, 359-368; Devalaraja-Narashimha K., et al., 2011, FEBSLett.,585, 677-82; Fujimoto, K., et al., 2010, Proc Natl Acad Sci USA. 107, 10214-9; Irwin, W. A., et al., 2003, Nat Genet., 35, 267-271; Angelin, A., et al., 2007, Proc Natl Acad Sci U S A, 104, 991-6; Merlini, L., et al., 2008, Proc Natl Acad Sci USA,105, 5225-9; Millay, D. P., 2008, Nat Med., 14, 442-7; Malouitre, S., et al., 2009 Biochem. J., 425(1):137-48; Dear, J. W., et al., J. Immunol., 187(6):3347-52; Naoumov, N. V., 2014, L. Hepatol., 61(5):1166-74). Cyclosporine A and its derivatives can block CypD to prevent mitochondrial swelling and cell death, and -8- Date reçue/Date Received 2023-10-0684932431 therefore could be useful for treatment of the aforementioned diseases, for example, as a neuro and cardiovascular and liver protective agent or as a novel mitochondrial medicine.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Summary of the Invention

[0020] In one aspect, the present invention provides a compound of Formula (I): or pharmaceutically acceptable salt thereof, wherein: x is 0 or 1; Rs is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heteroaryl; wherein Rs is substituted by one or more Ri; provided that Rs-Ri is not n-butyl or (£)-but-2-enyl; R2 is ethyl, 1-hydroxyethyl, isopropyl or n-propyl; WisNRi,O, S,orCH2; R3 is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heteroaryl or substituted heteroaryl; wherein R3 is optionally substituted by one or more Ri; -9- Date reçue/Date Received 2023-10-06CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 each occurrence of Ri is independently H, halogen, aryl or substituted aryl, heteroaryl or substituted heteroaryl, ORa, SRa, NRaRb, -NRa(CH2)oORb, -N((CH2)oORa)((CH2)oORb) - C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)(Ci-C6 alkyl-RH), -OC(=O)(CH2)oORa, - C(=O)NRaRb, -NRaC(=O)Rb, -N(C(=O)Ra)(C(=O)Rb), -N(C(=O)(Ci-C6 alkyl-RH))(C(=O)(CiC6 alkyl-RH))> -N(C(=O)(Ci-C6 alkyl-RH))2, -NRaC(=O)(CH2)oORb, -NRaC(=O)(CH2)oORb, - N(C(=O)(CH2)oORb)2, -NRaC(=O)(CH2)oNRaRb, -NRa(CH2)oC(=O)ORb, - N((CH2)oC(=O)ORa)((CH2)oC(=O)ORb), -NRa(CH2)oC(=O)NRaRb, - N((CH2)oC(=O)NRaRb)((CH2)oC(=O)NRaRb),-NRa(CH2)oC(=O)NRa(CH2)oORb, - C(=O)N((CH2)oORb)2, -N((CH2)oC(=O)NRa(CH2)oORb)((CH2)oC(=O)NRa(CH2)oORb),- C(=O)NRa(CH2)oORb, -C(=O)NRa(CH2)oORb, -C(=O)NRa(CH2)oNRaRb, -N=CRa-NRaRb, - NRb-C( NH)-NRaRb, O(CH2)mORA, O(CH2)mCOORA, O(CH2)mCONRARB, O(CH2)mCONRA(CH2)mORA, O(CH2)mO(CH2)mORA, O(CH2)mNRARB, wherein said aryl or heteroaryl is optionally substituted by one or more groups which may be the same or different selected from the group consisting of halogen, hydroxy, (Ci-C6)alkyl, (CH2)pORa, (CH2)pNRaRb, (CH2)pC(=O)NRaRb and (CH2)pC(=O)ORa; each Rs is independently H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, or aryl or substituted aryl; each occurrence of Ra and Rb is independently: hydrogen; (Ci-C6)alkyl, optionally substituted by one or more groups Rd which may be the same or different; (C2-C6)alkenyl or (C2-C6)alkynyl; (C3-C7)cycloalkyl optionally substituted with (Ci-Ce)alkyl; - 10-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 phenyl or benzyl optionally substituted with from one to five groups which may be the same or different selected from halogen, -O(Ci-C6)alkyl, -C(=O)O(Ci-C6)alkyl, amino, alkylamino and dialkylamino; or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen; or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl; each occurrence of Rc is independently hydrogen or (Ci-Ce)alkyl; each occurrence of Rd is independently halogen, hydroxy, O(Ci-C4)alkyl, C(=O)(Ci- -l-l/ Z C4)alkyl, C(=O)O(Ci-C4)alkyl or \—/ wherein Z is CH2, O, S, NH, NCEh, NEt, Nisopropyl, N-isopropyl, N-neoPentyl, N-CH2CH2OH, or N-CEhCEEOMe; each occurrence of Rg is independently Ra, ORa, SRa, NRaRb, -(CH2)oRa, - (CH2)oC(=O)ORa, -(CH2)oC(=O)NRaRb, C(=O)ORa, OC(=O)Ra, NRaC(=O)Rb, NRaC(=O)(CH2)oORa, C(=O)O(CH2)oORa, C(=O)ORb, C(=O)NRaRb, C(=O)NRa(CH2)oORb, C(=O)N((CH2)oORa)((CH2)oORb), C(=O)N((CH2)oC(=O)ORa)((CH2)oC(=O)ORb), C(=O)N((CH2)oNRaRb)( (CH2)oNRaRb), C(=O)N((CH2)oOC(=O)(CH2)oORa)((CH2)oOC(=O)(CH2)oORb), C(=O)N((CH2)oNRaC(=O)(CH2)oORb)((CH2)oNRaC(=O)(CH2)oORb), o ^(CHzX, N^Z‘ -^(CH2)o N^Z' C(=O)NRa(CH2)oNRaRb, , , C(=O)NRa(CH2)oOC(=O)Rb, C(=O)NRa(CH2)oC(=O)ORb, C(=O)NRa(CH2)oC(=O)NRaRb, Ra O N^(CH2)0 C(=O)NRa(CH2)oOC(=O)(CH2)oORb, or ° o ; each occurrence of Rh is independently halogen; each occurrence Z’ is independently CH2, O, S, NRa, N(CH2)oORa, N(CH2)0NRaRb, N(CH2)oCOORa, N(CH2)oOC(=O)Ra, N(CH2)oCONRaRb, N(CH2)oNRaC(=O)Rb, or N(CH2)oOC(=O)(CH2)oORa; each occurrence of o is independently 0, 1,2, 3, 4, 5, or 6; - 11 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 each occurrence of p is independently an integer of 0, 1, 2, 3, 4, or 5; and each occurrence of m is independently an integer of 1, 2, 3, 4 or 5.

[0021] In certain specific embodiments, the compound disclosed herein has the structure of Formulae (II) or (III): (ID (Hi) or pharmaceutically acceptable salt thereof, wherein: x is 0 or 1; Y is H or ORs; wherein Rs is H or methyl; M’ and n’ are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; each occurrence of Ra and Rb’ is independently: hydrogen; (Ci-Ce)alkyl, optionally substituted by one or more groups Rd which may be the same or different; (C2-Ce)alkenyl or (C2-Ce)alkynyl; (C3-C7)cycloalkyl optionally substituted with (Ci-Ce)alkyl; phenyl or benzyl optionally substituted with from one to five groups which may be the same or different selected from halogen, -O(Ci-Ce)alkyl, -C(=O)O(Ci-C6)alkyl, amino, alkylamino and dialkylamino; or Ra’ and Rb’, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl; and - 12-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 each occurrence of Rd is independently halogen, hydroxy, O(Ci-C4)alkyl, C(=O)(Ci-C4)alkyl, W XZ C(=O)O(Ci-C4)alkyl or \—/ ; wherein Z is CH2, O, S, NH, NCH3, NEt, N-isopropyl, Nisopropyl, N-neoPentyl, N-CH2CH2OH, or N-CH2CH2OMe.

[0022] In certain specific embodiments, the compound disclosed herein has the structure of Formula (IV) or (V): (IV) (V) ; wherein x is 0 or 1; Y is H or OR5; wherein R5 is H or methyl; each occurrence of Rr is independently H, halogen, aryl or substituted aryl, heteroaryl or substituted heteroaryl, ORa, SRa, NRaRb, -NRa(CH2)oORb, -N((CH2)oORa)((CH2)oORb) -C(=O)Ra, -C(=O)ORa, - OC(=O)Ra, -OC(=O)(Ci-C6 alkyl-Ru), -OC(=O)(CH2)oORa, -C(=O)NRaRb, -NRaC(=O)Rb, - N(C(=O)Ra)(C(=O)Rb), -N(C(=O)(Ci-C6 alkyl-RH))(C(=O)(Ci-C6 alkyl-RH)), -N(C(=O)(Ci-C6 alkyl-RH))2, -NRaC(=O)(CH2)oORb, -NRaC(=O)(CH2)oORb, -N(C(=O)(CH2)oORb)2, - NRaC(=O)(CH2)oNRaRb, -NRa(CH2)oC(=O)ORb, -N((CH2)oC(=O)ORa)((CH2)oC(=O)ORb), - NRa(CH2)oC(=O)NRaRb, -N((CH2)oC(=O)NRaRb)((CH2)oC(=O)NRaRb),- NRa(CH2)oC(=O)NRa(CH2)oORb, -C(=O)N((CH2)oORb)2, - N((CH2)oC(=O)NRa(CH2)oORb)((CH2)oC(=O)NRa(CH2)oORb),-C(=O)NRa(CH2)oORb, - C(=O)NRa(CH2)oORb, -C(=O)NRa(CH2)oNRaRb, -N=CRa-NRaRb, -NRb-C(=NH)-NRaRb, O(CH2)mORA, O(CH2)mCOORA, O(CH2)mCONRARB, O(CH2)mCONRA(CH2)mORA, O(CH2)mO(CH2)mORA, O(CH2)mNRARB, O(CH2)mO(CH2)mNRaRb, NRc(CH2)mNRARB, optionally substituted by one or more groups which may be the same or different selected from - 13 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 the group consisting of halogen, hydroxy, (Ci-C6)alkyl, (CH2)pORa, (CH2)pNRaRb, (CH2)pC(=O)NRaRb and (CH2)pC(=O)ORa.

[0023] In certain specific embodiments, Ri is -NRaC(=O)Rb and Rr is ORa. Non-limiting examples of Rainclude H, Me, Et, Pr, Bu, and Pentyl. Non-limiting examples of Rb include H, Me, Et, Pr, Bu, and Pentyl. In certain specific embodiments, wherein Ri is -NHC(=O)Rb and Rr is OH; and Y is OH or H.

[0024] In certain specific embodiments, the compound disclosed herein has the structure of Formula (VI): wherein x is 0 or 1; W is CH2, O or S; Y is H or ORs; wherein R5 is H or methyl; m' and n’ are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each occurrence of Ri is independently H, halogen, aryl or substituted aryl, heteroaryl or substituted heteroaryl, ORa, SRa, NRaRb, -C(=O)Ra, -C(=O)ORa, - C(=O)NRaRb, -NRaC(=O)Rb, -NRaC(=O)(CH2)oRb, -NRaC(=O)(CH2)oORb, - NRaC(=O)(CH2)oNRaRb, or -C(=O)NRa(CH2)oRb.

[0025] In yet another aspect, the present invention provides a pharmaceutical composition comprising at least one compound as described herein and a pharmaceutically-acceptable carrier.

[0026] In a further aspect, the present invention provides a method for treating or preventing a viral infection in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein.

[0027] In another aspect, the present invention provides a method for treating or preventing hepatitis C virus infection in a mammalian species in need thereof, the method - 14-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein.

[0028] In yet another aspect, the present invention provides a method for inhibiting a cyclophilin in a subject in need thereof, which comprises administrating to said subject an effective cyclophilin-inhibiting amount of at least one compound as described herein.

[0029] In yet another aspect, the present invention provides a method for treating or preventing diseases that are mediated by cyclophilins in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein.

[0030] In yet another aspect, the present invention provides a method for treating or preventing diseases in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases are selected from inflammation, respiratory inflammation, rheumatoid arthritis, and dry eye.

[0031] In yet another aspect, the present invention provides a method for treating or preventing diseases in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases are selected from neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s Diseases, and ALS; traumatic brain injury; stroke; and ischemia-reperfusion injury in the brain, heart, and kindey.

[0032] In yet another aspect, the present invention provides a method for treating or preventing diseases in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases are selected from cardiovascular diseases, vascular stenosis, atherosclerosis, abdominal aortic aneurysms, cardiac hypertrophy, aortic rupture, pulmonary arterial hypertension, myocarditis and myocardial fibrosis, and ischaemic heart diseases.

[0033] In yet another aspect, the present invention provides a method for treating or preventing diseases or conditions in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases or conditions are selected from cancer; obesity; diabetes; muscular dystrophy; lung, and liver, and kindey diseases, and their protection; and hair loss.

[0034] In yet another aspect, the present invention provides a method for treating or preventing diseases or conditions in a mammalian species in need thereof, the method - 15 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases or conditions are selected from allergic conjunctivitis, atopic and vernal keratoconjunctivitis, atopic keratoconjunctivitis, anterior uveitis, Behcet's disease, blepharitis, chronic ocular surface inflammation caused by viral infection, corneal transplant rejection, corneal sensitivity impaired due to surgery on the cornea or other surface of the eye, meibomian gland disease, ptyregia, ocular symptoms of graft versus host disease, ocular allergy, ocular cicatricial pemphigoid, Steven Johnson syndrome, vernal keratoconjunctivitis, uveitis, herpes simplex keratitis, ocular rosacea, and Pinguecula. Detailed Description of the Invention Definitions

[0035] The following are definitions of terms used in the present specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated.

[0036] The terms “alkyl” and “alk” refer to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary “alkyl” groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. The term “(Ci-C4)alkyl” refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. The term “(Ci-Ce)alkyl” refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 6 carbon atoms, such as nhexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, 2,2-dimethylbutyl, in addition to those exemplified for “(Ci-C4)alkyl.” “Substituted alkyl” refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S( O)RC, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP( O)2Re, S( O)2NRbRc P( O)2NRbRc, C(=O)ORa, C( O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each - 16-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Ra is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In the aforementioned exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl can themselves be optionally substituted.

[0037] The term “alkenyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Examples of such groups include ethenyl or allyl. The term “C2-C6 alkenyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as ethylenyl, propenyl, 2-propenyl, (£)-but-2-enyl, (Z)-but- 2-enyl, 2-methy(£)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethy-but-2-enyl, (Z)-pent-2- enyl, (Æ)-pent-l-enyl, (Z)-hex-l-enyl, (£)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)- hex-l-enyl, (A)-hex-l-enyl, , (Z)-hex-3-enyl, (£)-hex-3-enyl, and (£)-hex-1,3-dienyl. “Substituted alkenyl” refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, PfO^ C(=O)ORa, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Ra is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted.

[0038] The term “alkynyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond. An exemplary of such groups includes ethynyl. The term “C2-Ce alkynyl” refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-l-ynyl, prop-2-ynyl, but-l-ynyl, but-2-ynyl, - 17-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 pent-l-ynyl, pent-2-ynyl, hex-l-ynyl, hex-2-ynyl, hex-3-ynyl. “Substituted alkynyl” refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORa, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Ra is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted.

[0039] The term “cycloalkyl” refers to a fully saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring. “C3-C7 cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. “Substituted cycloalkyl” refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Rc, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORd, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rjis independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted. Exemplary substituents also include spiro-attached or - 18-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 fused cylic substituents, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

[0040] The term “cycloalkenyl” refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Examples of such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. “Substituted cycloalkenyl” refers to a cycloalkenyl group substituted with one more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORa, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC(=O)NRbRc, NRdS(=O)2NRbRc, NRdP(=O)2NRbRc, NRbC(=O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Ra is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted. Exemplary substituents also include spiro-attached or fused cylic substituents, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

[0041] The term “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. When containing two or more aromatic rings (bicyclic, etc), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl, phenanthrenyl and the like). “Substituted aryl” refers to an aryl group substituted by one or more substituents, preferably 1 to 3 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such - 19-CA 03024320 2018-11-14 WO 2017/200984 PCT/US2017/032811 as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORa, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC(=O)ORe, NRdC( O)NRbRc, NRdS(=O)2NRbRc, NRdP( OhNRbRc, NRbC(= O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Ra is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents can themselves be optionally substituted. Exemplary substituents also include fused cylic groups, especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

[0042] The terms “heterocycle” and “heterocyclic” refer to fully saturated, or partially or fully unsaturated, including aromatic (i.e., “heteroaryl”) cyclic groups (for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 8 to 16 membered tricyclic ring systems) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. (The term “heteroarylium” refers to a heteroaryl group bearing a quaternary nitrogen atom and thus a positive charge.) The heterocyclic group may be attached to the remainder of the molecule at any heteroatom or carbon atom of the ring or ring system. Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, and the like. Exemplary bicyclic heterocyclic groups include indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzo[d][l,3]dioxolyl, 2,3- dihydrobenzo[b][l,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, -20-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, benzofiirazanyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), triazinylazepinyl, tetrahydroquinolinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like. [0043] “Substituted heterocycle” and “substituted heterocyclic” (such as “substituted heteroaryl”) refer to heterocycle or heterocyclic groups substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=O)Re, S(=O)2Re, P(=O)2Re, S(=O)2ORe, P(=O)2ORe, NRbRc, NRbS(=O)2Re, NRbP(=O)2Re, S(=O)2NRbRc, P(=O)2NRbRc, C(=O)ORa, C(=O)Ra, C(=O)NRbRc, OC(=O)Ra, OC(=O)NRbRc, NRbC( O)ORc, NRdC(=O)NRbRc, NRdS( O)2NRbRc, NRdP(O^ NRbC( O)Ra, or NRbP(=O)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substitutents can themselves be optionally substituted. Exemplary substituents also include spiro-attached or fused cylic substituents at any available point or points of attachment, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.

[0044] The term “alkylamino” refers to a group having the structure -NHR’, wherein R’ is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cyclolakyl, as defined herein. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, npropylamino, iso-propylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.

[0045] The term “dialkylamino” refers to a group having the structure -NRR’, wherein R and R’ are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, -21 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 cycloalkenyl or substituted cyclolalkenyl, aryl or substituted aryl, heterocylyl or substituted heterocyclyl, as defined herein. R and R’ may be the same or different in a dialkyamino moiety. Examples of dialkylamino groups include, but are not limited to, dimethylamino, methyl ethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(isopropyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like. In certain embodiments, R and R’ are linked to form a cyclic structure. The resulting cyclic structure may be aromatic or non-aromatic. Examples of cyclic diaminoalkyl groups include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,3,4-trianolyl, and tetrazolyl.

[0046] The terms “halogen” or “halo” refer to chlorine, bromine, fluorine or iodine.

[0047] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0048] The compounds of the present invention may form salts which are also within the scope of this invention. Reference to a compound of the present invention is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when a compound of the present invention contains both a basic moiety such as, but is not limited to, a pyridine or imidazole, and an acidic moiety such as, but is not limited to, a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation. Salts of a compound of the present invention may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0049] The compounds of the present invention which contain a basic moiety such as, but is not limited to, an amine or a pyridine or imidazole ring, may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonates), lactates, maleates, -22-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[0050] Compounds of the present invention which contain an acidic moiety, such but not limited to a carboxylic acid, may form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl) ethylenediamine), N-methyl-Dglucamines, N-methyl-D-glycamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quatemized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.

[0051] Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term “prodrug” as employed herein denotes a compound that, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the present invention, or a salt and/or solvate thereof. Solvates of the compounds of the present invention include, for example, hydrates.

[0052] Compounds of the present invention, and salts or solvates thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

[0053] All stereoisomers of the present compounds (for example, those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives -23 -84932431 or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.

[0021] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% pure (“substantially pure” compound I), which is then used or formulated as described herein. Such “substantially pure” compounds of the present invention are also contemplated herein as part of the present invention.

[0022] All configurational isomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds of the present invention embraces both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbon or heterocyclic rings.

[0023] Throughout the specifications, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0024] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75* Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999.

[0025] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cisand /rans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0026] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios are all contemplated by the present invention. Those of ordinary skill in the art Date reçue/Date Received 2023-10-06CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.

[0060] The present invention also includes isotopically labeled compounds, which are identical to the compounds disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, nC, 14C, 15N, 18O, 170, 31P, 32P, 35S, 18F, and 36C1, respectively. Compounds of the present invention, or an enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0061] If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0062] It will be appreciated that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term “substituted” whether preceded by the term “optionally” or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent -25 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 may be either the same or different at every position. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. Furthermore, this invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment, for example, of infectious diseases or proliferative disorders. The term “stable”, as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein. Compounds

[0063] The novel cyclosporin derivatives of the present invention are potent inhibitors of cyclophilins and are useful for inhibiting viruses such as HCV, HBV, and HIV.

[0064] In one aspect, the present invention provides a compound of Formula (I): œ or pharmaceutically acceptable salt thereof, wherein: x is 0 or 1; Rs is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heteroaryl; wherein Rs is substituted by one or more Ri; provided that Rs-Ri is not n-butyl or (£)-but-2-enyl; R2 is ethyl, 1-hydroxyethyl, isopropyl or n-propyl; W is O, S, or CH2; R3 is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heteroaryl or substituted heteroaryl; wherein R3 is optionally substituted by one or more Ri; -26-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 each occurrence of Ri is independently H, halogen, aryl or substituted aryl, heteroaryl or substituted heteroaryl, CN, ORa, SRa, NRaRb, -NRa(CH2)oORb, -N((CH2)oORa)((CH2)oORb) -C(=O)Ra, -C(=O)ORa, -OC(=O)Ra, -OC(=O)(Ci-C6 alkyl-RH), -OC(=O)(CH2)oORa, - C(=O)NRaRb, -NRaC(=O)Rb, -N(C(=O)Ra)(C(=O)Rb), -N(C(=O)(Ci-C6 alkyl-RH))(C(=O)(CiC6 alkyl-RH))> -N(C(=O)(Ci-C6 alkyl-RH))2, -NRaC(=O)(CH2)oORb, -NRaC(=O)(CH2)oORb, - N(C(=O)(CH2)oORb)2, -NRaC(=O)(CH2)oNRaRb, -NRa(CH2)oC(=O)ORb, - N((CH2)oC(=O)ORa)((CH2)oC(=O)ORb), -NRa(CH2)oC(=O)NRaRb, - N((CH2)oC(=O)NRaRb)((CH2)oC(=O)NRaRb),-NRa(CH2)oC(=O)NRa(CH2)oORb, - C(=O)N((CH2)oORb)2, -N((CH2)oC(=O)NRa(CH2)oORb)((CH2)oC(=O)NRa(CH2)oORb),- C(=O)NRa(CH2)oORb, -C(=O)NRa(CH2)oORb, -C(=O)NRa(CH2)oNRaRb, -N=CRa-NRaRb, - NRb-C( NH)-NRaRb, O(CH2)mORA, O(CH2)mCOORA, O(CH2)mCONRARB, O(CH2)mCONRA(CH2)mORA, O(CH2)mO(CH2)mORA, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRc(CH2)mNRARB, NRc(CH2)mNRc(CH2)mNRARB, said aryl or heteroaryl is optionally substituted by one or more groups which may be the same or different selected from the group consisting of halogen, hydroxy, (Ci-Ce)alkyl, (CH2)PORA, (CH2)pNRaRb, (CH2)pC(=O)NRaRb and (CH2)pC(=O)ORa; s i v V ~^oR5 *voR5 Rîis^-^, ^ORs, , = or T ; each Rs is independently H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, or aryl or substituted aryl; each occurrence of Ra and Rb is independently: hydrogen; (Ci-Ce)alkyl, optionally substituted by one or more groups Rd which may be the same or different; -27-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 (C2-C6)alkenyl or (C2-C6)alkynyl; (C3-C?)cycloalkyl optionally substituted with (Ci-C6)alkyl; phenyl or benzyl optionally substituted with from one to five groups which may be the same or different selected from halogen, -O(Ci-Ce)alkyl, -C(=O)O(Ci-C6)alkyl, amino, alkylamino and dialkylamino; or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different selected from nitrogen, sulfur and oxygen; or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl; each occurrence of Rc is independently hydrogen or (Ci-Câ)alkyl; each occurrence of Rd is independently halogen, hydroxy, O(Ci-C4)alkyl, C(=O)(Ci- -|-N^ Z C4)alkyl, C(=O)O(Ci-C4)alkyl or \ —/ wherein Z is CH2, O, S, NH, NCH3, NEt, Nisopropyl, N-isopropyl, N-neoPentyl, N-CH2CH2OH, or N-CH2CH2OMe; each occurrence of Rg is independently Ra, ORa, SRa, NRaRb, -(CH2)oRa, - (CH2)oC(=O)ORa, -(CH2)oC(=O)NRaRb, C(=O)ORa, OC(=O)Ra, NRaC(=O)Rb, NRaC(=O)(CH2)oORa, C(=O)O(CH2)oORa, C(=O)ORb, C(=O)NRaRb, C(=O)NRa(CH2)oORb, C(=O)N((CH2)oORa)((CH2)oORb), C(=O)N((CH2)oC(=O)ORa)((CH2)oC(=O)ORb), C(=O)N((CH2)oNRaRb)( (CH2)oNRaRb), C(=O)N((CH2)oOC(=O)(CH2)oORa)((CH2)oOC(=O)(CH2)oORb), C(=O)N((CH2)oNRaC(=O)(CH2)oORb)((CH2)oNRaC(=O)(CH2)oORb), o X^-(CH2)o JJ N/—\Z ^(CH2)o N \Z' C(=O)NRa(CH2)oNRaRb, , , C(=O)NRa(CH2)oOC(=O)Rb, C(=O)NRa(CH2)oC(=O)ORb, C(=O)NRa(CH2)oC(=O)NRaRb, Ra O /'if N ''(CHjJo T]-(Ra)o C(=O)NRa(CH2)oOC(=O)(CH2)oORb, or ° o ; each occurrence of Rh is independently halogen; -28-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 each occurrence Z’ is independently CH2, O, S, NRa, N(CH2)oORa, N(CH2)0NRaRb, N(CH2)oCOORa, N(CH2)oOC(=O)Ra, N(CH2)oCONRaRb, N(CH2)oNRaC(=O)Rb, or N(CH2)oOC(=0)(CH2)0ORa; each occurrence of o is independently 0, 1, 2, 3, 4, 5, or 6; each occurrence of p is independently an integer of 0, 1, 2, 3, 4, or 5; and each occurrence of m is independently an integer of 1, 2, 3, 4 or 5.

[0065] In some embodiments, x is 0. In other embodimetns, x is 1. In some embodiments, Rs is (Ci-Ci2)alkyl, (C2-Ci2)alkenyl, (C2-Ci2)alkynyl, (C3-Ci2)cycloalkyl, or phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (Ci-Ce)alkyl. In some embodiments, Rs is (CiCi2)alkyl. In yet other embodiments, Rs is (Ci-Ce) linear alkyl. In yet other embodiments, Rs is (C?-Ci2) linear alkyl. In yet other embodiments, Rs is (C4-Ce) linear alkyl. In yet other embodiments, Rs is (Ce-Cs) linear alkyl. In some specific embodiments, Rs is a -(CH2)3-nalkyl chain.

[0066] In some embodiments, Rs is (C2-Ci2)alkenyl. In yet other embodiments, Rs is (C2- Ce) linear alkenyl. In yet other embodiments, Rs is (C7-C12) linear alkenyl. In yet other embodiments, Rs is (C4-C6) linear alkenyl. In yet other embodiments, Rs is (Ce-Cs) linear alkenyl.

[0067] In some embodiments, Rs is (C2-Ci2)alkynyl. In yet other embodiments, Rs is (C2- Ce) linear alkynyl. In yet other embodiments, Rs is (C7-C12) linear alkynyl. In yet other embodiments, Rs is (C4-Ce) linear alkynyl. In yet other embodiments, Rs is (Ce-Cs) linear alkynyl.

[0068] In some embodiments, Ri is H. In yet other embodiments, Ri is halogen. In yet other embodiments, Ri is selected from the group consisting of H, ORa, SRa, NRaRb, - C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -NRaC(=O)Rb, -NRaC(=O)(CH2)oRb, - NRaC(=O)(CH2)oORb, -NRaC(=O)(CH2)oNRaRb, -C(=O)NRa(CH2)oRb, - C(=O)NRa(CH2)oORb, and -C(=O)NRa(CH2)oNRaRb. In other embodiments, Ri is selected from the group consisting of O(CH2)mORA, O(CH2)mO(CH2)mORA, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRc(CH2)mNRARB, andNRc(CH2)mNRc(CH2)mNRARB.

[0069] In certain specific embodiments, the compound disclosed herein has the structure of Formulae (II) or (III): -29-CA 03024320 2018-11-14 WO 2017/200984 (II) PCT/ÜS2017/032811 (Hl) or pharmaceutically acceptable salt thereof, wherein: x is 0 or 1; Y is H or ORs; wherein Rs is H or methyl; m’ and n’ are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; each occurrence of Ra and Rb is independently: hydrogen; (Ci-Ce)alkyl, optionally substituted by one or more groups Rd which may be the same or different; (C2-C6)alkenyl or (C2-C6)alkynyl; (C3-C7)cycloalkyl optionally substituted with (Ci-Ce)alkyl; phenyl or benzyl optionally substituted with from one to five groups which may be the same or different selected from halogen, -O(Ci-Ce)alkyl, -C(=O)O(Ci-C6)alkyl, amino, alkylamino and dialkylamino; or Ra’ and Rb% together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from the group consisting of alkyl, phenyl and benzyl; and each occurrence of Rd is independently halogen, hydroxy, O(Ci-C4)alkyl, C(=O)(Ci-C4)alkyl, -I-l/ \ C(=O)O(Ci-C4)alkyl or X—/ ; wherein Z is CH2, O, S, NH, NCH3, NEt, N-isopropyl, Nisopropyl, N-neoPentyl, N-CH2CH2OH, or N-CH2CH2OMe.

[0070] In certain specific embodiments, the compound disclosed herein has the structure of Formula (IV) or (V): -30-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 (IV) (V) ; wherein x is 0 or 1; Y is H or ORs; wherein Rs is H or methyl; each occurrence of Rr is independently H, halogen, aryl or substituted aryl, heteroaryl or substituted heteroaryl, ORa, SRa, NRaRb, -NRa(CH2)oORb, -N((CH2)oORa)((CH2)oORb) -C(=O)Ra, -C(=O)ORa, - OC(=O)Ra, -OC(=O)(Ci-C6 alkyl-Rh), -OC(=O)(CH2)oORa, -C(=O)NRaRb, -NRaC(=O)Rb, - N(C(=O)Ra)(C(=O)Rb), -N(C(=O)(Ci-C6 alkyl-RH))(C(=O)(Ci-C6 alkyl-RH)), -N(C(=O)(Ci-C6 alkyl-RH))2, -NRaC(=O)(CH2)oORb, -NRaC(=O)(CH2)oORb, -N(C(=O)(CH2)oORb)2, - NRaC(=O)(CH2)oNRaRb, -NRa(CH2)oC(=O)ORb, -N((CH2)oC(=O)ORa)((CH2)oC(=O)ORb), - NRa(CH2)oC(=O)NRaRb, -N((CH2)oC(=O)NRaRb)((CH2)oC(=O)NRaRb),- NRa(CH2)oC(=O)NRa(CH2)oORb, -C(=O)N((CH2)oORb)2, - N((CH2)oC(=O)NRa(CH2)oORb)((CH2)oC(=O)NRa(CH2)oORb),-C(=O)NRa(CH2)oORb,- C(=O)NRa(CH2)oORb, -C(=O)NRa(CH2)oNRaRb, -N=CRa-NRaRb, -NRb-C(=NH)-NRaRb, O(CH2)mORA, O(CH2)mCOORA, O(CH2)mCONRARB, O(CH2)mCONRA(CH2)mORA, O(CH2)mO(CH2)mORA, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRc(CH2)mNRARB, optionally substituted by one or more groups which may be the same or different selected from the group consisting of halogen, hydroxy, (Ci-Ce)alkyl, (CH2)pORa, (CH2)pNRaRb, (CH2)pC(=O)NRaRb and (CH2)PC(=O)ORA.

[0071] In certain specific embodiments, Ri’ is ORa, OCOCH2ORa, SRa, NHRa, N(Ra)2, or NHCOCH2ORa. In certain specific embodiments, Rr is OAc, OCOCH2C1, OCOCH2CH3, OCOCHMe2, OCOCMe3, OCOCH=CH2, NHCH2CH2OH, NHCH2CH2OMe, N(CH2CH2OH)2, N(CH2CH2OMe)2, NHCH2CHMe2, NHCH2CMe2, NHAc, NHCH2COOH, -31 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 NHCH2COOCH3, NMeCH2COOH, NMeCH2COOCH3, NHCH2CONH2, NHCH2CONHMe, NHCH2CONMe2, NHCH2CONHCH2CH2OH, NHCH2CONHCH2CH2OMe, NMeCH2CONH2, NMeCH2CONHMe, NMeCH2CONMe2, N(CH2COOH)2, N(CH2CONH2)2, N(CH2CONHMe)2, N(CH2CONMe2)2, N(CH2CONHCH2CH2OH)2, N(CH2CONHCH2CH2OMe)2, NHCOCH2C1, NHCOCH2CH3, NHCOCHMe2, NHCOCMe3, NHCOCH=CH2, N(COCH2C1)2, N(COCH2CH3)2, N(COCHMe2)2, N(COCMe3)2, or N(COCH=CH2)2.

[0072] In certain specific embodiments, Ra’ and Rb’ are each independently H, Me, Et, nPropyl, isoProyl, isoButyl, neoPentyl, cyclopentyl, cyclohexyl, CH2CH2OH, CH2CH2OMe, v -s. Kj J PPl II orPP LL ;wherein ZisCH2, O, S, NH, NCH3,NEt, N-isopropyl, Nisopropyl, N-neoPentyl, N-CH2CH2OH, or N-CH2CH2OMe. In certain specific embodiments, Ra’ and Rb’ are each Me. In certain specific embodiments, Ra’ and Rb’ are each Et.

[0073] In certain specific embodiments, the compound disclosed herein has the structure of Formula (VI): wherein x is 0 or 1; W is CH2, O or S; Y is H or OR5; wherein R5 is H or methyl; m’ and n’ are each independently 0, 1,2, 3, 4, 5, 6, 7, 8, 9, or 10; and each occurrence of Ri is independently H, halogen, aryl or substituted aryl, heteroaryl or substituted heteroaryl, ORa, SRa, NRaRb, -C(=O)Ra, -C(=O)ORa, - C(=O)NRaRb, -NRaC(=O)Rb, -NRaC(=O)(CH2)oRb, -NRaC( O)(CH2)oORb, - NRaC(=O)(CH2)oNRaRb, or -C(=O)NRa(CH2)oRb.

[0074] In certain specific embodiments, Ri is selected from the group consisting of H, ORa, SRa, NRaRb, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -NRaC(=O)Rb, - NRaC(=O)(CH2)oRb, -NRaC(=O)(CH2)oORb, -NRaC(=O)(CH2)oNRaRb, - -32-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 C(=O)NRa(CH2)oRb, -C(=O)NRa(CH2)oORb, and -C(=O)NRa(CH2)oNRaRb.

[0075] In certain specific embodiments, Ri is selected from the group consisting of O(CH2)mORA> O(CH2)mO(CH2)mORA, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRc(CH2)mNRARB, and NRc(CH2)mNRc(CH2)mNRARB.

[0076] In certain specific embodiments, Ri is selected from the group consisting of ORa, SRa, NRaRb, -C(=O)Ra, -C(=O)ORa, and -C(=O)NRaRb. In some specific embodiments, Ri is OH, OMe, OEt, O-isopropyl, O-isoButyl, O-neoPentyl, O-cyclopentyl, O-cyclohexyl, SH, SMe, S-isopropyl, S-isoButyl, S-neoPentyl, S-cyclopentyl, S-cyclohexyl, oh O r—y O r~“x O /—\ h , h , or h . In certain specific embodiments, Riis oh 5 NH, NCH3, NEt, N-isopropyl, N-isopropyl, N-neoPentyl, N-CH2CH2OH, or N-CH2CH2OMe. In some embodiments, Ra and Rb are described herein. In other embodiments, Ra and RB are each H, Me, Et, isoProyl, isoButyl, cyclopentyl, or cyclohexyl. In certain embodiments, Ri is hydroxyl. In certain other embodiments, Ri is C(=O)ORa.

[0077] In yet other embodiments, Ri is selected from the group consisting of H, OH, OMe, OEt, O-isoProyl, O-isoButyl, O-neoPentyl, O-cyclopentyl, O-cyclohexyl, OCH2CH2OH, OCH2CH2OCH3, OCH2COOH, OCH2COOCH3, OCH2CONH2, OCH2CONHMe, OCH2CONMe2, OCH2CONHCH2CH2OH, OCH2CONHCH2CH2OMe, OAc, OOCCH2C1, OOCCH2ORa, OOCCH2CH3, OOCCHMe2, OOCCMe3, and OC(=O)CCH=CH2.

[0078] In yet other embodiments, Ri is selected from the group consisting of:CA 03024320 2018-11-14 WO 2017/200984 PCT/US2017/032811 -34-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811

[0079] In yet other embodiments, Ri is SH, SMe, SEt, S-isoProyl, S-isoButyl, SneoPentyl, O-cyclopentyl, or S-cyclohexyl.

[0080] In yet other embodiments, Ri is selected from the group consisting of NH2, NHCH3, NHCH2CH3, NHCH2CHOH, NHCH2CH2OMe, NMe2, NEt2, NHCH2CHMe2, NHCH2CMe3, NHAc, NHCH2COOH, NHCH2COOCH3, NMeCH2COOH, NMeCH2COOCH3, NHCH2CONH2, NHCH2CONHMe, NHCH2CONMe2, NHCH2CONHCH2CH2OH, NHCH2CONHCH2CH2OMe, NMeCH2CONH2, NMeCH2CONHMe, NMeCH2CONMe2, N(CH2COOH)2, N(CH2CONH2)2, N(CH2CONHMe)2, N(CH2CONMe2)2, N(CH2CONHCH2CH2OH)2, N(CH2CONHCH2CH2OMe)2, NHCOCH2CI, NHCOCH2ORa, NHCOCH2CH3, NHCOCHMe2, NHCOCMe3, NHCOCH CH2, N(COCH2C1)2, N(COCH2ORa)2, N(COCH2CH3)2, N(COCHMe2)2, N(COCMe3)2, and N(COCH=CH2)2.

[0081] In yet other embodiments, Ri is , wherein Z is CH2, O, S, NH, NMe, NEt, N-isopropyl, N-neoPentyl, N-CH2CH2OH, NCH2CH2OCH3, NCH2CH2OCH3, NCH2COOH, NCH2COOMe, N-CH2CONH2, NCH2CONHMe, or NCH2CONMe2.

[0082] In yet other embodiments, Ri is selected from the group consisting of: wherein each occurrence Z’ is independently CH2, O, S, NRa, N(CH2)oORa, N(CH2)0NRaRb, -35-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 N(CH2)oCOORa, N(CH2)oOC(=O)Ra, N(CH2)oCONRaRb, N(CH2)oNRaC(=O)Rb, or N(CH2)oOC(=O)(CH2)oORa.

[0084] In yet other embodiments, Ri is -COOH, -COOMe, -COOEt, -CONH2, -CONHMe, - CONMe2, -CONHEt, -CONEt2, -COMICH2CH2OH, -CONHCH2CH2OMe, - CON(CH2CH2OH)2, -CON(CH2CH2OMe)2, or -CONMe2.

[0085] In yet other embodiments, Ri is selected from the group consisting of: -36-WO 2017/200984 CA 03024320 2018-11-14 PCT/US2017/032811 -37-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 ; wherein Z is CH2, O, S, NH, NCH3, NEt, N-isopropyl, N-isopropyl, N-neoPentyl, NCH2CH2OH, orN-CH2CH2OMe.

[0086] In yet other embodiments, Ri is !~V_/ or V_/~Rg in some embodiments, Rg is OH, OMe, OAc, NH2, NHMe, NHAc, NMe2, NEt2, NHCH2CMe3.

[0087] In yet other embodiments, Ri is selected from the group consisting of: O O Z\° O /\0 O Ra -^o K'Ra-hQA, 0 >A*N'WyN'R6 °

[0088] In yet other embodiments, Ri is ORa, OCOCH2ORA, SRa, NHRa, N(Ra)2, or NHCOCH2ORa.

[0089] In yet other embodiments, Ri is OAc, OCOCH2CI, OCOCH2CH3, OCOCHMe2, OCOCMe3, OCOCH=CH2, NHCH2CH2OH, NHCH2CH2OMe, N(CH2CH2OH)2, N(CH2CH2OMe)2, NHCH2CHMe2, NHCH2CMe2, NHAc, NHCH2COOH, NHCH2COOCH3, NMeCH2COOH, NMeCH2COOCH3, NHCH2CONH2, NHCH2CONHMe, NHCH2CONMe2, NHCH2CONHCH2CH2OH, NHCH2CONHCH2CH2OMe, NMeCH2CONH2, NMeCH2CONHMe, NMeCH2CONMe2, N(CH2COOH)2, N(CH2CONH2)2, N(CH2CONHMe)2, N(CH2CONMe2)2, N(CH2CONHCH2CH2OH)2, N(CH2CONHCH2CH2OMe)2, NHCOCH2C1, NHCOCH2CH3, NHCOCHMe2, NHCOCMe3, NHCOCH=CH2, N(COCH2C1)2, N(COCH2CH3)2, N(COCHMe2)2, N(COCMe3)2, or N(COCH=CH2)2.

[0090] In yet other embodiments, Ri is aryl or heteroaryl optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (CiC6)alkyl, (C3-C7)cycloalkyl, SRa, (CH2)pORa, (CH2)pNRaRb, (CH2)pC(=O)Ra, (CH2)pC(=O)NRaRb and (CH2)PC(=O)ORA; wherein p is 0, 1, 2, 3, 4, 5, 6; and each Rx \ -1-4 JL d-(Ry)t occurrence of Ra and Rb are defined herein. In some embodiments, Ri is 1 , wherein Rx isH, (Ci-C6)alkyl, or (C3-C?)cycloalkyl; Ry is H, (Ci-Ce)alkyl, (C3-C7)cycloalkyl, ORa, SRa, NRaRb, -C(=O)Ra, -C(=O)ORa, or -C(=O)NRaRb; and t is 1, 2, 3, or 4. In some embodiments, Rx is H or Me; and Ry is -C(=O)ORa or -C(=O)NRaRb. In some specific -38-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 NEt, N-isopropyl, N-isopropyl, N-neoPentyl, N-CH2CH2OH, or N-CH2CH2OMe.

[0091] In yet other embodiments, Ra and Rb are each independently H, Me, Et, isoProyl, isoButyl, neoPentyl, cyclopentyl, cyclohexyl, CH2CH2OH, CH2CH2OMe, or , wherein Z is CH2, O, S, NH, NCH3, NEt, N-isopropyl, N-isopropyl, N-neoPentyl, NCH2CH2OH, or N-CH2CH2OMe. In some embodiments, Ra and Rb are each independently H, Me, Et, isopropyl, isobutyl, cyclopentyl, or cyclohexyl. In some embodiments, each occurrence Ra and Rb is independently H or (Ci-C6)alkyl.

[0092] In some embodiments, R3 is H, (Ci-Ci2)alkyl, (C2-Ci2)alkenyl, (C2-Ci2)alkynyl, (C3-Ci2)cycloalkyl, or phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (Ci-C6)alkyl. In some embodiments, R3 is (Ci-Ci2)alkyl. In yet other embodiments, R3 is (Ci-Cg) linear alkyl. In yet other embodiments, R3 is (C7-C12) linear alkyl. In yet other embodiments, R3 is (C4-C6) linear alkyl. In yet other embodiments, R3 is (Ce-Cs) linear alkyl. In certain embodiments, R3 is (C7- Cio)alkyl. In certain other embodiments, R3 is (C?-C8)alkyl. In yet other embodiments, R3 is (C7-C10) linear alkyl. In yet other embodiments, R3 is (C7-C8) linear alkyl. In some specific embodiments, R3 is a -(CH2)3-u- alkyl chain.

[0093] In some embodiments, R3 is (C2-Ci2)alkenyl. In yet other embodiments, R3 is (C2- Ce) linear alkenyl. In yet other embodiments, R3 is (C7-C12) linear alkenyl. In yet other embodiments, R3 is (C4-C6) linear alkenyl. In yet other embodiments, R3 is (Cg-Cs) linear alkenyl.

[0094] In some embodiments, R3 is (C2-Ci2)alkynyl. In yet other embodiments, R3 is (C2- Cg) linear alkynyl. In yet other embodiments, R3 is (C7-Ci2) linear alkynyl. In yet other embodiments, R3 is (C4-C6) linear alkynyl. In yet other embodiments, R3 is (Ce-Cs) linear alkynyl. In any of the embodiments described herin, R3 may be 4-hydroxybutyl.

[0095] In certain embodiments, R2 is ethyl. In certain embodiments, R7 is or aX or5 . In certain embodiments, W is O or S. In certain embodiments described herin, W is S; x = 1; and R3 is 4-hydroxybutyl.

[0096] In certain embodiments, the compound of Formula I has the structure of Formulae (II’) through (VI’): -39-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 or pharmaceutically acceptable salt thereof, wherein: each x is 0 or 1; each W is independently O, S, or CH2, each occurrence of Ri is independently H, halogen, aryl, heteroaryl, ORa, SRa, NRaRb, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb. -NRaC(=0)Rb, -NRaC(=O)(CH2)oRb, -NRaC(=O)(CH2)oORb, -NRaC(=O)(CH2)oNRaRb, -C(=O)NRa(CH2)oRb, -N=CRa-NRaRb, -NRb-C(=NH)-NRaRb, -C(=O)NRa(CH2)oORb, -C(=O)NRa(CH2)oNRaRb, O(CH2)mORA, O(CH2)mO(CH2)mORA, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRc(CH2)mNRARB, or NRc(CH2)mNRc(CH2)mNRARB, wherein said aryl or heteroaryl is optionally substituted by one or more groups which may be the same or different selected from halogen, hydroxy, (CiC6)alkyl, (CH2)pORA, (CH2)pNRaRb, (CH2)pC(=O)NRaRb and (CH2)pC(=O)ORa; each R3 is independently (Ci-Ce)alkyl, (C?-Ci2)alkyl, (C2-Cô)alkenyl, (C7-Ci2)alkenyl, (C2- Ce)alkynyl, or (C?-Ci2)alkynyl, aryl, or heteroaryl all of which may be optionally substituted by one or more groups Ri which may be the same or different; each R5 is independently: -40-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 H; (Ci-C6)alkyl, optionally substituted by one or more groups Re, which may be the same or different; (C2-Ce)alkenyl, optionally substituted by one or more groups which may be the same or different and each selected from halogen, hydroxy, (Ci-Ce)alkyl, aryl (e.g., phenyl), (CH2)pORa, (CH2)mOH, (CH2)mO(CH2)mOH, (CH2)mNRARB, (CH2)mO(CH2)mNRARB, (CH2)pNRARB, (CH2)pNRc(CH2)mNRARB, (CH2)pNRc(CH2)mNRc(CH2)mNRARB, (CH2)PC(=O)NRARB, (CH2)pC(=O)ORa; (C2-Ce)alkynyl, optionally substituted by one or one or more groups which may be the same or different and each selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino; (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different and each selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino; phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different and each selected from halogen, hydroxy, (Ci-Ce)alkyl, (CH2)PORA, (CH2)PNRARB, (CH2)pC(=O)NRaRb, (CH2)pC(=O)ORa; each occurrence of Re is independently halogen, hydroxy, aryl (e.g., phenyl), S(Ci-Ce)alkyl, SRa, ORa, O(CH2)mORA, O(CH2)mO(CH2)mORA, C(=O)ORA, C(=O)NRARB, NRARB, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRc(CH2)mNRARB, or NRc(CH2)mNRc(CH2)mNRARB, wherein said aryl or phenyl is optionally substituted by one or more groups which may be the same or different and each selected from halogen, hydroxy, (Ci-C6)alkyl, (CH2)PORA, (CH2)PNRARB, (CH2)pC(=O)NRaRb and (CH2)PC(=O)ORA; each occurrence of RA and RB is independently: hydrogen; (Ci-Ce)alkyl, optionally substituted by one or more groups Rd which may be the same or different; (C2-Ce)alkenyl or (C2-Ce)alkynyl; -41 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 (C3-C7)cycloalkyl optionally substituted with (Ci-C6)alkyl; phenyl optionally substituted with from one to five groups which may be the same or different and each selected from halogen, -O(Ci-C6)alkyl, -C(=O)O(Ci-C6)alkyl, amino, alkylamino and dialkylamino; or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different and each selected from nitrogen, sulfur and oxygen; or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different and each selected from the group consisting of alkyl, phenyl and benzyl; or Ra and Rb, together with the nitrogen atom to which they are attached, form -N=CHNRfRf, -N=CMe-NRFRF’, or -NRfC(=NH)NRfRf; each occurrence of Rc is independently hydrogen or (Ci-Ce)alkyl; each occurrence of Rd is independently halogen, hydroxy, O(Ci-C4)alkyl, C(=O)(Ci-C4)alkyl, C(=O)O(Ci-C4)alkyl; each occurrence of RF and Rf is independently hydrogen, (Ci-Cô)alkyl, phenyl, benzyl, or RF and Rf, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different and each selected from the group consisting of alkyl, phenyl and benzyl; p is an integer of 0, 1, 2, 3, 4, 5, or 6; m’ isO, 1,2, 3, 4, 5,6, 7, 8 or 9; m is an integer of 1, 2, 3, 4, 5, or 6; and -42-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 n is an integer of 1, 2, 3, 4, 5 or 6.

[0097] In any of the embodiments described herein, x is 0 or 1. In any of the embodiments described herein, x may be 0. may be 1. In certain embodiments, W is O. other embodiments, W is CH2.

[0098] In certain embodiments, m’ is 1. In any of the embodfiemtns described herein, x In certain other embodiments, W is S. In yet In certain other embodiments, m’ is 2. In yet other embodiments, m’ is 3. In yet other embodiments, m’ is 4 or 5. In yet other embodiments, m’ is 6, 7, 8 or 9.

[0099] In certain embodiments, m is 1. In certain other embodiments, m is 2. In yet other embodiments, m is 3. In yet other embodiments, m is 4 or 5.

[0100] In certain embodiments, p is 0. In certain other embodiments, p is 1. In yet other embodiments, m is 2. In yet other embodiments, m is 3, 4 or 5. o 0 ^^'Ra r 9 /\ 7

[0101] In certain embodiments, R3 is ' 'n , H , Rb , Rb , / \n I mH nh rb , or rb rb . In certain embodiments, R3 is H, methyl, ethyl, n-propyl, ipropyl, n-butyl, i-butyl, t-butyl, CHiCMes, phenyl, CHi-phenyl, V^'°'^s‘oh - , —~-'OH, v/1

[0102] In certain embodiments, R3 is -(CHi^NRaRb, wherein n is an integer of 2, 3, 4, 5 or 6, or integer of 7, 8, 9, 10, 11 or 12; and wherein each occurrence of Ra and Rb is independently hydrogen; (Ci-C4)alkyl, optionally substituted by one or more groups Rd which may be the same or different, in which each occurrence of Rd is independently halogen, hydroxy, O(Ci-C4)alkyl, C(=O)(Ci-C4)alkyl, C(=O)O(Ci-C4)alkyl; or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from (Ci-C4)alkyl, phenyl and benzyl.

[0103] In certain embodiments, R3 is -(CHz^NRaRb, wherein n is an integer of 2, 3, 4, 5 or 6, or integer of 7, 8, 9, 10, 11 or 12; and wherein Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from nitrogen, oxygen and sulfur and may be optionally substituted by from one to -43 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 four groups which may be the same or different selected from (Ci-C4)alkyl, phenyl and benzyl.

[0104] In certain embodiments, n is 2. In certain other embodiments, n is 3. In yet other embodiments, n is 4, 5, or 6. In yet other embodiments, n is 7 or 8. In yet other embodiments, n is 9 or 10. In yet other embodiments, n is 11 or 12.

[0105] In certain embodiments, R3 is -(CH2)iiNRaRb, wherein n is an integer of 7, 8, 9, 10, 11 or 12; and wherein each occurrence of Ra and Rb is independently hydrogen; (Ci-C4)alkyl, optionally substituted by one or more groups Rd which may be the same or different, in which each occurrence of Rd is independently halogen, hydroxy, O(Ci-C4)alkyl, C(=O)(Ci-C4)alkyl, C(=O)O(Ci-C4)alkyl; or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different selected from (Ci-C4)alkyl, phenyl and benzyl.

[0106] In certain embodiments, n is 7. In certain other embodiments, n is 8. In yet other embodiments, n is 9, 10, 11 or 12.

[0107] In certain embodiments, R3 is 2-aminoethyl, 2-aminopropyl, 3-aminopropyl, 2-monoalkylaminoethyl, 2-monoalkylaminopropyl, 3-monoalkylaminopropyl, 2-dialkylaminoethyl, 2-dialkylaminopropyl, or 3-dialkylaminopropyl, wherein said alkyl is (Ci-C4)alkyl.

[0108] In certain embodiments, R3 is 2-aminoethyl, 2-aminopropyl, 3-aminopropyl, 2-monoalkylaminoethyl, 2-monoalkylaminopropyl, 3-monoalkylaminopropyl, 2-dialkylaminoethyl, 2-dialkylaminopropyl, or 3-dialkylaminopropyl, wherein said alkyl is (Ci-C4)alkyl, wherein R3 is dimethylaminoethyl, diethylaminoethyl, methylethylaminoethyl, methyl-iso-butylaminoethyl, ethyl-iso-butylaminoethyl, methyl-tert-butylaminoethyl, or ethyltert-butylaminoethyl. N^(CH2)m(C1-C4)alkoxy ^^,N»(C1-C4)phenyl or benzyl in which n is an integer of 2 -44-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 3, 4, 5, or 6, and m is an integer of 2, 3, or 4. In certain embodiments, n is 2. In certain other embodiments, n is 3. In yet other embodiments, n is 4, or 5, or 6. In certain embodiments, m is 2. In certain other embodiments, m is 3. In certain other embodiments, m is 4. Incertain embodiments, n is 7. In certain other embodiments, n is 8. In yet other embodiments, n is 9, 10, 11 or 12.

[0110] In certain embodiments, Rs is H, (Ci-Ce)alkyl, (C2-C6)alkenyl, phenyl, benzyl, CH2-S-(Ci-C6)alky, CH2-O-(Ci-C6)alkyl, (C2-C6)ORa, (Ci-C6)-monoalkyl amine, (Ci-C6)- dialkyl amine, or (Ci-Ce)-cyclic amine, in which said phenyl or benzyl is optionally substituted by one to three substitutents selected from (Ci-C4)alkyl, (Ci-C4)alkoxy, and halogen; and Ra is H, (Ci-Ce)alkyl, phenyl, CH2-phenyl, (Ci-Ce)alkylOH, (CH2)pO(CH2)mOH, (CH2)pO(CH2)mO(CH2)mOH, (Ci-C6)alkylO(Ci-C4)alkyl, (CH2)pO(CH2)mO(Ci-C4)alkyl, or (CH2)pO(CH2)mO(CH2)mO(Ci-C4)alkyl; p is an integer of 0, 1, 2, 3, 4, or 5; and m is an integer of 1,2, 3, 4 or 5.

[0111] In certain embodiments, Rs is H. In certain other embodiments, Rs is methyl. In yet other embodiments, Rs is CH2-S-(Ci-C6)alky, e g., CH2-S-CH3. In yet other embodiments, Rs is CH2-O-(Ci-C6)alkyl, e.g., CH2-O-CH2-CH3. In yet other embodiments, Rs is (C2- C6)alkenyl, e.g., CH2-CH=CH2. In yet other embodiments, Rs is benzyl. In yet other embodiments, Rs is (C2-C6)OH. In yet other embodiments, Rs is (Ci-C6)-monoalkyl amine, e g., CH2-NH-Me. In yet other embodiments, Rs is (Ci-Cô)-dialkyl amine, e.g., CH2-CH2- N(Et)2. In yet other embodiments, Rs is (Ci-C6)-cyclic amine, e g., CH2-CH2-morpholine.

[0112] In certain embodiments, each occurrence Ra and Rb is independently H, (CiCe)alkyl, phenyl, CH2-phenyl, (Ci-Ce)alkylOH, (CH2)pO(CH2)mOH, or (CH2)pO(CH2)mO(CH2)mOH, (Ci-C6)alkylO(Ci-C4)alkyl, (CH2)pO(CH2)mO(Ci-C4)alkyl, or (CH2)pO(CH2)mO(CH2)mO(Ci-C4)alkyl. In certain other embodiments, Ra and Rb, together with the nitrogen atom to which they are attached, form a heterocycle selected from in which Re is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH2CMe3, Ph, CH2Ph, CH2CH2OH, or CH2CH2O(Ci-C4)alkyl.

[0113] In another aspect, the present invention provides a compound of Formulae (Ila)- (Vla): -45 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 or a pharmaceutically acceptable salt thereof, wherein: each x is 0 or 1; each W is independently O, S, or CH2; each occurrence of Ri is independently H, halogen, aryl, heteroaryl, ORa, SRa, NRaRb, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -NRaC(=O)Rb, -NRaC(=O)(CH2)oRb, -NRaC(=O)(CH2)oORb, -NRaC(=O)(CH2)oNRaRb, -C(=O)NRa(CH2)oRb, -C(=O)NRa(CH2)oORb, -C(=O)NRa(CH2)oNRaRb, O(CH2)mORA, O(CH2)mO(CH2)mORA, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB,NRc(CH2)mNRARB, or NRc(CH2)mNRc(CH2)mNRARB, wherein said aryl or heteroaryl is optionally substituted by one or more groups which may be the same or different and each selected from halogen, hydroxy, (Ci-C6)alkyl, (CH2)pORa, (CH2)pNRaRb, (CH2)pC(=O)NRaRb and (CH2)PC(=O)ORA; each Rs is independently: H; (Ci-C6)alkyl, optionally substituted by one or more groups Re which may be the same or different; -46-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 (C2-Ce)alkenyl, optionally substituted by one or more groups which may be the same or different and each selected from halogen, hydroxy, (Ci-C6)alkyl, aryl (e.g., phenyl), (CH2)pORa, O(CH2)mOH, O(CH2)mO(CH2)mOH, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, (CH2)PNRARB, (CH2)pNRc(CH2)mNRARB, (CH2)pNRc(CH2)mNRc(CH2)mNRARB, (CH2)PC(=O)NRARB, (CH2)PC(=O)ORA; (C2-C6)alkynyl, optionally substituted by one or one or more groups which may be the same or different and each selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino; (C3-C7)cycloalkyl, optionally substituted by one or more groups which may be the same or different and each selected from halogen, hydroxy, amino, monoalkylamino and dialkylamino; phenyl or CH2-phenyl, optionally substituted by one or more groups which may be the same or different and each selected from halogen, hydroxy, (Ci-C6)alkyl, (CH2)PORA, (CH2)pNRARB, (CH2)PC(=O)NRARB, (CH2)pC(=O)ORa; each occurrence of Re is independently halogen, hydroxy, aryl (e.g., phenyl), S(Ci-Ce)alkyl, SRA, ORa, O(CH2)mORA, O(CH2)mO(CH2)mORA, C(=O)ORA, C(=O)NRARB, NRARB, O(CH2)mNRARB, O(CH2)mO(CH2)mNRARB, NRc(CH2)mNRARB, or NRc(CH2)mNRc(CH2)mNRARB, wherein said aryl or phenyl is optionally substituted by one or more groups which may be the same or different and each selected from halogen, hydroxy, (Ci-C6)alkyl, (CH2)PORA, (CH2)PNRARB, (CH2)pC(=O)NRaRb and (CH2)PC(=O)ORA; each occurrence of RA and RB is independently: hydrogen; (Ci-Ce)alkyl, optionally substituted by one or more groups Rd which may be the same or different; (C2-Ce)alkenyl or (C2-Cô)alkynyl; (C3-C7)cycloalkyl optionally substituted with (Ci-Ce)alkyl; -47-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 phenyl optionally substituted with from one to five groups which may be the same or different and each selected from halogen, -O(Ci-Cô)alkyl, -C(=O)O(Ci-C6)alkyl, amino, alkylamino and dialkylamino; or a heterocyclic ring which may be saturated or unsaturated containing five or six ring atoms and from one to three heteroatoms which may be the same or different and each selected from nitrogen, sulfur and oxygen; or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain another heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to four groups which may be the same or different and each selected from the group consisting of alkyl, phenyl and benzyl; each occurrence of Rc is independently hydrogen or (Ci-GOalkyl; each occurrence of Rd is independently halogen, hydroxy, O(Ci-C4)alkyl, C(=O)(Ci-C4)alkyl, C(=O)O(Ci-C4)alkyl; each p is independently an integer of 0, 1, 2, 3, 4, or 5; m’ is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; each of m and n is independently an integer of 1, 2, 3, 4 or 5; q is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11.

[0114] In certain embodiments, q is 1. In certain other embodiments, q is 2. In certain other embodiments, n is independently an integer of 6, 7, 8, 9, 10 or 11.

[0115] In certain embodiments, W is S. In certain other embodiments, W is O.

[0116] In certain embodiments, Ri is hydrogen. In certain other embodiments, Ri is (CiC6)alkyl. In certain embodiments, R3 is (Ci-Ce)alkyl. In certain other embodiments, R3 is NRcCH2(CH2)pNRaRb.

[0117] In certain embodiments, Rs is H, (Ci-Ce)alkyl, (C2-Cô)alkenyl, phenyl, benzyl, CH2-S-(Ci-C6)alkyl, CH2-O-(Ci-C6)alkyl, (C2-C6)ORa, (Ci-C6)-monoalkyl amine, (Ci-C6)- dialkyl amine, or (Ci-Cô)-cyclic amine, in which said phenyl or benzyl is optionally substituted by one to three substituents selected from (Ci-C4)alkyl, (Ci-C4)alkoxy, and halogen; and Ra is H, (Ci-C6)alkyl, phenyl, CH2-phenyl, (Ci-C6)alkylOH, (CH2)PO(CH2)mOH, -48-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 (CH2)pO(CH2)mO(CH2)mOH, (Ci-C6)alkylO(Ci-C4)alkyl, (CH2)pO(CH2)mO(Ci-C4)alkyl, or (CH2)pO(CH2)mO(CH2)mO(Ci-C4)alkyl; p is an integer of 0, 1, 2, 3, 4, or 5; and m is an integer of 1,2, 3, 4 or 5.

[0118] In certain other embodiments, Rs is H, (Ci-C4)alkyl, (C2-C4)alkenyl, phenyl, benzyl, CH2-S-(Ci-C4)alkyl, CH2-O-(Ci-C4)alkyl, (CH2)2OH, or (CH2)2O(Ci-C4)alkyl. In certain embodiments, Rs is H. In certain other embodiments, Rs is methyl.

[0119] In certain embodiments, each occurrence Ra and Rb is independently H, (CiCe)alkyl, phenyl, CH2-phenyl, (Ci-C6)alkylOH, (CH2)pO(CH2)mOH, or (CH2)pO(CH2)mO(CH2)mOH, (Ci-C6)alkylO(Ci-C4)alkyl, (CH2)pO(CH2)mO(Ci-C4)alkyl, or (CH2)PO(CH2)mO(CH2)mO(Ci-C4)alkyl. In certain other embodiments, each occurrence Ra and Rb is independently H or (Ci-Ce)alkyl. In yet other embodiments, Ra and Rb, together with the nitrogen atom to which they are attached, form a heterocycle selected from R< in which Rc is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH2CMe3, Ph, CH2Ph, or CH2CH2OH and CH2CH2ORd.

[0120] In certain embodiments, the compounds are selected from the group consisting of: Z = OH, OMe, OEt, OCH2CMe3, OCH2CH2OH, OCH2CH2OMe, OCH2CH2OEt, OAc, OCOCH2OH, OCOCH2OMe, OCOCH2OEt, OPh, OPh-3-OMe, OPh-4-OMe, OCH2Ph, OCH2Ph-3-OMe, OCH2Ph-4- OMe, NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, NHAc, NHCOCH2OH, NHCOCH2OMe, NHCH2COOH, NHCH2COOMe, NHCH2COOEt, N(CH2COOH)2, N(CH2COOMe)2, N(CH2COOEt)2 Z = OH, OMe, OEt, OCH2CMe3, OCH2CH2OH, OCH2CH2OMe,NH2, NHMe, NMe2, NHEt, NEt2, NHCH2CH2OH, N(CH2CH2OH)2, NHCH2CH2OMe, N(CH2CH2OMe)2, -49-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Z = CH2, O, S, NH, NMe, NEt, NCH2CMe3, NCH2CH2OH, NCH2CH2OMe, NCH2CH2OEt, NCH2CH2OCH2CMe3, NAc, NCOCH2OH, NCOCH2OMe, NCOCH2OEt Z = OH, OMe, NH2, NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, N(CH2CMe3)2, NHCH2CH2OH, N(CH2CH2OH)2, NHCH2CH2OMe, N(CH2CH2OMe)2, NHCH2CH2OEt, N(CH2CH2OEt)2, NHCH2CH2OCH2CMe3, N(CH2CH2OCH2CMe3)2, NHAc, NHCOCH2OH, NHCOCH2OMe, COOH, COOMe, COOEt, CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHCH2CH2OH, CONHCH2CH2OMe, CONH(i-Propyl), CON(i-Propyl)2 Z = OH, OMe, NH2> NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, N(CH2CMe3)2> NHCH2CH2OH, N(CH2CH2OH)2, NHCH2CH2OMe, N(CH2CH2OMe)2, NHCH2CH2OEt, N(CH2CH2OEt)2, NHCH2CH2OCH2CMe3, N(CH2CH2OCH2CMe3)2, NHAc, NHCOCH2OH, NHCOCH2OMe, COOH, COOMe, COOEt, CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHCH2CH2OH, CONHCH2CH2OMe, CONH(i-Propyl), CON(i-Propyl)2 Z = CH2, O, S, NH, NMe, NEt, NCH2CMe3, NCH2CH2OH, NCH2CH2OMe, NCH2CH2OEt, NCH?CH?OCH2CMe3, NAc, NCOCH2OH, NCOCH2OMe, NCOCH2OEt Z = CH2, O, S, NH, NMe, NEt, NCH2CMe3, NCH2CH2OH, NCH2CH2OMe, NCH2CH2OEt, NCH2CH2OCH2CMe3, NAc, NCOCH2OH, NCOCH2OMe, NCOCH2OEt - 50-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Z = CH2, O, S, NH, NMe, NEt, NCH2CMe3, NCH2CH2OH, NCH2CH2OMe, NCH2CH2OEt, NCH2CH2OCH2CMe3, NAc, NCOCH2OH, NCOCH2OMe, NCOCH2OEt Z = OH, OMe, NH2, NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, N(CH2CMe3)2, NHCH2CH2OH, N(CH2CH2OH)2, NHCH2CH2OMe, N(CH2CH2OMe)2, NHCH2CH2OEt, N(CH2CH2OEt)2, NHCH2CH2OCH2CMe3, N(CH2CH2OCH2CMe3)2, NHAc, NHCOCH2OH, NHCOCH2OMe, COOH, COOMe, COOEt, CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHCH2CH2OH, CONHCH2CH2OMe, CONH(i-Propyl), CON(i-Propyl)2 Z = OH, OMe, NH2, NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, N(CH2CMe3)2, NHCH2CH2OH, N(CH2CH2OH)2, NHCH2CH2OMe, N(CH2CH2OMe)2, NHCH2CH2OEt, N(CH2CH2OEt)2, NHCH2CH2OCH2CMe3, N(CH2CH2OCH2CMe3)2, NHAc, NHCOCH2OH, NHCOCH2OMe, COOH, COOMe, COOEt, CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHCH2CH2OH, CONHCH2CH2OMe, CONH(i-Propyl), CON(i-Propyl)2 Z = OH, OMe, NH2, NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, N(CH2CMe3)2, NHCH2CH2OH, N(CH2CH2OH)2, NHCH2CH2OMe, N(CH2CH2OMe)2, NHCH2CH2OEt, N(CH2CH2OEt)2, NHCH2CH2OCH2CMe3, N(CH2CH2OCH2CMe3)2, NHAc, NHCOCH2OH, NHCOCH2OMe, COOH, COOMe, COOEt, CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHCH2CH2OH, CONHCH2CH2OMe, CONH(i-Propyl), CON(i-Propyl)2 Z = OH, OMe, NH2, NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, N(CH2CMe3)2, NHCH2CH2OH, N(CH2CH2OH)2, NHCH2CH2OMe, N(CH2CH2OMe)2, NHCH2CH2OEt, N(CH2CH2OEt)2, NHCH2CH2OCH2CMe3, N(CH2CH2OCH2CMe3)2, NHAc, NHCOCH2OH, NHCOCH2OMe, COOH, COOMe, COOEt, CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHCH2CH2OH, CONHCH2CH2OMe, CONH(i-Propyl), CON(i-Propyl)2 - 51 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Z = CH2, O, S, NH, NMe, NEt, NCH2CMe3, NCH2CH2OH, NCH2CH2OMe, NCH2CH2OEt, NCH2CH2OCH2CMe3, NAc, NCOCH2OH, NCOCH2OMe, NCOCH2OEt Z = OH, OMe, NH2, NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, N(CH2CMe3)2, NHCH2CH2OH, N(CH2CH2OH)2, NHCH2CH2OMe, N(CH2CH2OMe)2, NHCH2CH2OEt, N(CH2CH2OEt)2, NHCH2CH2OCH2CMe3, N(CH2CH2OCH2CMe3)2, NHAc, NHCOCH2OH, NHCOCH2OMe, COOH, COOMe, COOEt, CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHCH2CH2OH, CONHCH2CH2OMe, CONH(i-Propyl), CON(i-Propyl)2 Z = OH, OMe, NH2, NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, N(CH2CMe3)2, NHCH2CH2OH, N(CH2CH2OH)2, NHCH2CH2OMe, N(CH2CH2OMe)2, NHCH2CH2OEt, N(CH2CH2OEt)2, NHCH2CH2OCH2CMe3, N(CH2CH2OCH2CMe3)2, NHAc, NHCOCH2OH, NHCOCH2OMe, COOH, COOMe, COOEt, CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHCH2CH2OH, CONHCH2CH2OMe, CONH(i-Propyl), CON(i-Propyl)2 Z = OH, OMe, NH2, NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, N(CH2CMe3)2, NHCH2CH2OH, N(CH2CH2OH)2, NHCH2CH2OMe, N(CH2CH2OMe)2, NHCH2CH2OEt, N(CH2CH2OEt)2, NHCH2CH2OCH2CMe3, N(CH2CH2OCH2CMe3)2, NHAc, NHCOCH2OH, NHCOCH2OMe, COOH, COOMe, COOEt, CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHCH2CH2OH, CONHCH2CH2OMe, CONH(i-Propyl), CON(î-Propyl)2 Z = OH, OMe, NH2, NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, N(CH2CMe3)2, NHCH2CH2OH, N(CH2CH2OH)2, NHCH2CH2OMe, N(CH2CH2OMe)2, NHCH2CH2OEt, N(CH2CH2OEt)2, NHCH2CH2OCH2CMe3, N(CH2CH2OCH2CMe3)2, NHAc, NHCOCH2OH, NHCOCH2OMe, COOH, COOMe, COOEt, CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHCH2CH2OH, CONHCH2CH2OMe, CONH(î-Propyl), CON(i-Propyl)2 - 52-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Z = OH, OMe, NH2, NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, N(CH2CMe3)2, NHCH2CH2OH, N(CH2CH2OH)2, NHCH2CH2OMe, N(CH2CH2OMe)2, NHCH2CH2OEt, N(CH2CH2OEt)2, NHCH2CH2OCH2CMe3, N(CH2CH2OCH2CMe3)2, NHAc, NHCOCH2OH, NHCOCH2OMe, COOH, COOMe, COOEt, CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHCH2CH2OH, CONHCH2CH2OMe, CONH(i-Propyl), CON(i-Propyl)2 Z = OH, OMe, NH2, NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, N(CH2CMe3)2, NHCH2CH2OH, N(CH2CH2OH)2, NHCH2CH2OMe, N(CH2CH2OMe)2, NHCH2CH2OEt, N(CH2CH2OEt)2, NHCH2CH2OCH2CMe3, N(CH2CH2OCH2CMe3)2, NHAc, NHCOCH2OH, NHCOCH2OMe, COOH, COOMe, COOEt, CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHCH2CH2OH, CONHCH2CH2OMe, CONH(i-Propyl), CON(i-Propyl)2 and, wherein x is 0 or 1; m is 2, 3, 4, 5, 6, 7, or 8; Y is H, OH or OMe; W is O or S; and each Ra is independently selected from the group consisting of the moieties shown in Table 1; Table 1 Ra ^OH o ’V1' o o o O H o H o o o H O o o (^NH O o O J 1 o o !V*C-OH X" o o o o o o O 1 O 1 - 53 -CA 03024320 2018-11-14 WO 2017/200984 PCT/US2017/032811 o o 1 ^-Vo'X o 1 o Yx^Ox^N^ kxNH k^N^ k^Nx^OH O 0 O\ o o O 1 ^°^o" o ^VoZy y^°x^N^ k^° yx^sn y>zsx y^s. 1 y^N^ ^Xz^xZ ys/i^ yx^Nx^ H H I yx^N^^zk^ yx^N^xÀ^ y^Nx.xx. H U I H Ix Y/N^X y^N^Yx = H 1^ .^N^K V H 1^ ^J< ^Jx yx^N^ \/ r^° yx^iCZ^ ^C^Nx^C ykxN^z* \/ r^s X.O <"S 0° ^X/Nx/ y\zN\z* 1 N yxN^ yx^N^J Y'N^yC 1 |X^N^X^O^ yxxN^ o 1H 1 H o ? H Xy o ^V \/ H o o ^-nA^OH 1H o 1H o lH O I N-^Xx°'sXAX 1H ° 1 ^N\zOvX 1H u fl 1H \/ ° O yx—kOH O yxxko-^ O yx^kQx\ o Vx-^oxxy' o ^xA^ o VX*'^^ O yx^AN^ H O ît^n^ H O yx^JkNx i O yx^J^y^x O y-Ax^ H 1 o yx^xk^-^ o Vx^A^^ O yx^ANxx^ kxNH O yx^AN^x^ kxN*K -54-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 O l O yxXNY k .N^^zk^ O k^N^xK^ 'V^xX^qh VxX^oh ^ZS\X'‘Q‘*'\ V^^o-Y< O o Y^x^qA >IH^X o°=^ o .^X/SqA^OH O Y^xx^q-^ —°x O 5yX/^oA/O>/ O I O I O. Y^o NxX* ^-""xX^q-^xxNI^^NH xX1 Nx/1 y-NZX^OH yx^Q^xxn ^xXXqXX^N î^x*X^O''^ \/ ° 1 sX \/ o^N-> f^° o^y Î^^X^n^X-X H V^^SH ^xz^ ^*^xx^s‘*zsx VX-'X'Y V^-^sYC 1 1 5^X^n^x S^X^n^ S^^s^xx zx,^ V'XX^n'^ H %'X*X^--J'x -VxX^N'''xX • 1 H 1 ^xX^n* H ‘ H• 1 1 *—o Vx^N^ k^O 'V^N^ ^✓S .•^xX^n^i k^Nx X^ xH <^O ^^X^N^X| ^S k^N^X k^N^zk^ V^-^n^Y k^N^X^ I ^^xX^N^X| k^N.^ I k^Ns^x k^Ns^Xk kzN^oZ O H O ^AxXX^jJk» H O H ^,1 H O -V^rXoH 1H O ^X/XN'zkxX'O tH O ^Xxz- |sj-‘Jk^O\X 1H HCA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 zx JL ° J< 1 ।H V^-n-L-o^AJI ° Xïl 1H k^N^J^ yx/yOH o yXX-yO^ O yXXXyO^X o y^xx^o^Àx o yx^^yO^JC o ys/yNH2 o H ^X^X o H yXx^yN^ O l ys/yNs O yxyiM o H l^x y\/\|-NxJC o yx/yO O ys/yO o T 0 rk rk b yx^xx^N>^J o yX/y1^ ' o yXxXyN^X1 o y\zxzOH ^°H 5ÿkzX/OH ^4xx^OH ^Z\/OH yx/xz^s. \/ ° o H X^°rNV \/ ° o H O 1 yx^x^N^J yXs/XzOx/ !fSZ °'J\ yx^xxO-xx*^ J^V o yxz^xxO^x o O Ÿ'^zOyXn O >î'~^^'oY^o-x O ys/"— o y^ZX/OY^Q^XZ O 1 o 1 ° yx/x^A/^^ k^o yx/\z°xx'XNxy k^NH y'szs^x^N Jj^^XX^O^xx^ —N ^(xyOH O \/ K 1 yLx^x^N^xxC ^4xx2^n o y<XXXyN^ O \/ H ykx^XxN^x o yLxx^N^J \/ 1 kzO \/ f^o ykx*x^N^x* k^N^xx? i4^yox o yLxx^Nx. o °5O8 5X-x^-'°y^'o—y' ^C^Oy-N^ o 'xX >^x^x^O^x O O \/ ° O yxxx^sH yxxx^s^ y^xxXs^s^x' jÿXxX^^sX^X Y^z^3 —L yxx-^N^ 1 -56“CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 H। ^xx'^y' yxx^xj/ ^kxXx^ ^X^X^N^x H I Ys/Xx^x/k YxOxJx YXsXXxNxz**X H l1 X*» V .nJ< H 1 YXXX^N^^JX =- H। .i _✓ X—7 H | *^o Y^xX^lCx^ r^° yXXNA y^z^zN^X X YXz^sxNx^ X'H f^N^' ŸX/XN^ ^Xx^XxNvx^ I^n^XkC O yXxN^ \/ O yXXN^ \/ O < y ^O îXsX^XxN^ O |^N^—°^ H o •Jkx^Y v H o = H Z 1 ^Y O x—7 H o H Y^-x>y^oh o H YxxXxNy^o^ o H y^^Ny^o^ o H Vx^NyVy Ha Y'X'X^NY^°^Yx o ' H o jX*^XxNx^X o ^X/xAoh o Y^xJkQ/ O ^X-xX^Aq^X o o i^XX^-^ o Y^^—^Nh2 o H o ,\XZX^NX H o Y^XxAn^ O O h | o O Y\Z\Â^ o Yx^xAn-X] k^NH o Yxxx^Anx^ k^N^ o k^N^^x O ^xxAn^ . kzNsJ\ o Yxx'^^n'^ । k^N^/X ^X/X^-Qn ^XXX^OH —^OH YX*XXx*‘^qx' Y^x-^^xx^ YXxX^X^qXXjZ^ K YXxX^^qA, j O A^ O VS^V^O^OH o .y^sz^xx-^oA^0^ o ^xx^qA^o^ V'xx'\x^O'^O^-k yx^^Q-Xo^Jc -57-CA 03024320 2018-11-14 WO 2017/200984 PCT/US2017/032811 OFOb Nf^O j^NH Nxx^ ^n^OH [^N^Xx°^ >2^\X^X^qX\^N J ïX^XX^N^x^x H | ^A^X^-qA^OH \/ ° sX^^^^^^x \/ ° \ / O \/ ° .. —oo^Y YN^°H O ^^^sX^'XX****'Q^^XX o4IZ "SX*^C ko ^■^X^x^X^x^gj-] ^X^/\ZXg/\ ^■'■Xx'Xx^s'y'' Sj^x^^s—Y VXx^— H Vx^x/^NX H | YX^x/^nH^XZ |^ H | ^rxx\x^N-^x' H | ^X^XX^N^Xx" h r^ y^^nY ^'*^XX*%Xx*^ VXx S,X^Ï|^^| VX/XZ*N-X| k^O k^S Vx/x/^-X] L NH VX/X/^n^ k^N ^C^xX^ k^xX^ ^X/S/^nKO H . O V^x^yjA H = O Sfx/x^NA H sX-^Xx^n-K H O V^s^nA^oh H O H O ^\ZX^N H ° 1 H ° 1 H ° 1^1 Yxx^n^O^AJ H \/ ° YXYA^oJk VXx^^o^Xx V JL^ U Hn^x yO sY V x^ xx JL ? h ^x VXx^xX^o^xx y^oH O V î H o sX^^^^y014 o iX-'^Xx-'y0^ O ^X^Xx^y ys^v^yOH O VX^Xx-yO^ O JY\ZX/^oxzk O Vxzxzy°>X o VXx^^xX^yNH2 O H ^xX^^^yNx O H Î^Xx'^X^yN^x O O O H 1^ yX/X/yN^/\ O ^-x^xx^X^ynC/^ O ^'x^xx^^xx^nC^ O ( *NH ,^a./XXYn^ o ys/xzyN J o -58“CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 V^xz^xx^x^n^J o Vs—X/X^N^ O 1 ^XzX/X^N^/l O ' Yx/xx^oh i^^zX/x/^ ^X/\ZXzOH ,^^\/XzOH ^XzXzX^^x ^X/XzX^x/L ^-X^xX^x^O^Jc^ o o o ^sxx°y^oh o ^^X^Xx°Y^OX o >î'Vs/^oy/xo/\ o O 1 ^ZX/X^°Y^O'^Z O 1 o op V^^X-*'0'*^Nk^O VX^XX^^OXz^Nk^NH ^Xj o 0/ ^X/XXx0-^N^n-^oh o 0 o ^XzXzXzSx ^Xx*,X>z-^^ ^x/\/Xxs ^^X/X/Sxx^X ^X^/Xz^xzN^ ^X^XX^Xx^x^ XH ^X^x^X^Nx^ H I N^x*x H I :yxzX/\>x/x H I ^s/X/XN ^X/XX/ = HN^x^X I ^X^X/Xx V7 Nxx^X 1 ^X/X^ZX^sZ^ o ^•Xz^Xx^xx 1^0 yXXxXzNxx^ ^s ^X/XxX^N^ I^NH |XXN-^X ^X/SZX1^ ^X/XXz^ ' ^X.zXX^X^N^x' ' 0 o/ yx^x/x^Y' ।H o « H Vo 5'1111 Z-I °=\ H *x—^V o H ^X^zX^N^X^oH O H o H o H 5^\ZS/\zH Ny^o^kC -V— o ' O 1 z-x 0o \/ H 1 VXX/Xz^^\ °=( o0ZT o0IZr yCxzx^^zX \/ H I , or a pharmaceutically acceptable salt thereof. - 59-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811

[0121] In another aspect, a compound having the following formula is described, Z = OH, OMe, OEt, OCH2CMe3, OCH2CH2OH, OCH2CH2OMe, OCH2CH2OEt, OAc, OCOCH2OH, OCOCH2OMe, OCOCH2OEt, OPh, OPh-3-OMe, OPh-4-OMe, OCH2Ph, OCH2Ph-3-OMe, OCH2Ph-4- OMe, NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, NHAc, NHCOCH2OH, NHCOCH2OMe, NHCH2COOH, NHCH2COOMe, NHCH2COOEt, N(CH2COOH)2, N(CH2COOMe)2, N(CH2COOEt)2 wherein x is 1; m is 2, 3, 4, 5, 6, 7, or 8; Y is H, OH or OMe; W is O or S; and each Ra is , or a pharmaceutically acceptable salt thereof.

[0122] In another aspect, a compound having the following formula is described, Z = OH, OMe, OEt, OCH2CMe3, OCH2CH2OH, OCH2CH2OMe, OCH2CH2OEt, OAc, OCOCH2OH, OCOCH2OMe, OCOCH2OEt, OPh, OPh-3-OMe, OPh-4-OMe, OCH2Ph, OCH2Ph-3-OMe, OCH2Ph-4- OMe, NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, NHAc, NHCOCH2OH, NHCOCH2OMe, NHCH2COOH, NHCH2COOMe, NHCH2COOEt, N(CH2COOH)2, N(CH2COOMe)2, N(CH2COOEt)2 wherein x is 1; m is 2, 3, 4, 5, 6, 7, or 8; Y is H, OH or OMe; W is O or S; and each Ra is OH , or a pharmaceutically acceptable salt thereof

[0123] In another aspect, a compound having the following formula is described, Z = OH, OMe, OEt, OCH2CMe3, OCH2CH2OH, OCH2CH2OMe, OCH2CH2OEt, OAc, OCOCH2OH, OCOCH2OMe, OCOCH2OEt, OPh, OPh-3-OMe, OPh-4-OMe, OCH2Ph, OCH2Ph-3-OMe, OCH2Ph-4- OMe, NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, NHAc, NHCOCH2OH, NHCOCH2OMe, NHCH2COOH, NHCH2COOMe, NHCH2COOEt, N(CH2COOH)2, N(CH2COOMe)2, N(CH2COOEt)2 wherein x is 1; m is 2, 3, 4, 5, 6, 7, or 8; Y is H, OH or OMe; W is O or S; and each Ra is ;ora pharmaceutically acceptable salt thereof. -60-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811

[0124] In another aspect, a compound having the following formula is described, Z = OH, OMe, OEt, OCH2CMe3, OCH2CH2OH, OCH2CH2OMe, OCH2CH2OEt, OAc, OCOCH2OH, OCOCH2OMe, OCOCH2OEt, OPh, OPh-3-OMe, OPh-4-OMe, OCH2Ph, OCH2Ph-3-OMe, OCH2Ph-4- OMe, NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, NHAc, NHCOCH2OH, NHCOCH2OMe, NHCH2COOH, NHCH2COOMe, NHCH2COOEt, N(CH2COOH)2, N(CH2COOMe)2, N(CH2COOEt)2 wherein x is 1; m is 2, 3, 4, 5, 6, 7, or 8; Y is H, OH or OMe; W is O or S; and each Ra is OH , or a pharmaceutically acceptable salt thereof.

[0125] In another aspect, a compound having the following formula is described, Z = OH, OMe, OEt, OCH2CMe3, OCH2CH2OH, OCH2CH2OMe, OCH2CH2OEt, OAc, OCOCH2OH, OCOCH2OMe, OCOCH2OEt, OPh OPh-3-OMe, OPh-4-OMe, OCH2Ph, OCH2Ph-3-OMe, OCH2Ph-4- OMe, NHMe, NMe2, NHEt, NEt2, NHCH2CMe3, NHAc, NHCOCH2OH, NHCOCH2OMe, NHCH2COOH, NHCH2COOMe, NHCH2COOEt, N(CH2COOH)2> N(CH2COOMe)2, N(CH2COOEt)2 wherein x is 1; m is 2, 3, 4, 5, 6, 7, or 8; Y is H, OH or OMe; W is O or S; and each Ra is , or a pharmaceutically acceptable salt thereof

[0126] In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound described herein and a pharmaceutically-acceptable carrier or diluent.

[0127] In a further aspect, the present invention provides a method for treating or preventing a viral infection in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound described herein. In certain embodiments, the viral infection is HIV infection. In certain other embodiments, the viral infection is HBV infection. In yet other embodiments, the viral infection is HCV infection. In yet other embodiments, the viral infection is influenza A virus infection, severe acute respiratory syndrome coronavirus infection or vaccinia virus infection.

[0128] In another aspect, the present invention provides a method for treating or preventing hepatitis C virus infection in a mammalian species in need thereof, the method -61 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 comprising administering to the mammalian species a therapeutically effective amount of at least one compound described herein.

[0129] In yet another aspect, the present invention provides a method for inhibiting a cyclophilin in a subject in need thereof, which comprises administrating to said subject an effective cyclophilin-inhibiting amount of at least one compound as described herein.

[0130] In yet another aspect, the present invention provides a method for treating or preventing diseases that are mediated by cyclophilins in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein.

[0131] In yet another aspect, the present invention provides a method for treating or preventing diseases in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases are selected from inflammation, respiratory inflammation, rheumatoid arthritis, and dry eye.

[0132] In yet another aspect, the present invention provides a method for treating or preventing diseases in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases are selected from neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s Diseases, and ALS; traumatic brain injury; stroke; and ischemia-reperfusion injury in the brain, heart, and kidney.

[0133] In yet another aspect, the present invention provides a method for treating or preventing diseases in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases are selected from cardiovascular diseases, vascular stenosis, atherosclerosis, abdominal aortic aneurysms, cardiac hypertrophy, aortic rupture, pulmonary arterial hypertension, myocarditis and myocardial fibrosis, and ischaemic heart diseases.

[0134] In yet another aspect, the present invention provides a method for treating or preventing diseases or conditions in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases or conditions are selected from cancer; obesity; diabetes; muscular dystrophy; lung, and liver, and kidney diseases, and their protection; and hair loss.

[0135] In yet another aspect, the present invention provides a method for treating or preventing diseases or conditions in a mammalian species in need thereof, the method -62-84932431 comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein, wherein the diseases or conditions are selected from allergic conjunctivitis, atopic and vernal keratoconjunctivitis, atopic keratoconjunctivitis, anterior uveitis, Behcet's disease, blepharitis, chronic ocular surface inflammation caused by viral infection, comeal transplant rejection, comeal sensitivity impaired due to surgery on the cornea or other surface of the eye, meibomian gland disease, ptyregia, ocular symptoms of graft versus host disease, ocular allergy, ocular cicatricial pemphigoid, Steven Johnson syndrome, vernal keratoconjunctivitis, uveitis, herpes simplex keratitis, ocular rosacea, and Pinguecula. Methods of Preparation

[0027] In certain embodiments, the compound of formulae (I) can be prepared by the modification of cyclosporine A at position 1 of MeBmt, a similar method was used as described by US Patent No. 9,200,038 B2 and US Patent Application No. 2013/0190223 Al which is referenced, for the synthesis of the intermediate 3, 4, and 5. The cyclosporin A is treated with ClAczO and DMAP in Pyridine, subsequent cleavage the double bond by OsÛ4 and NaIÛ4 in dioxane give the corresponding aldehyde 2, and through the wittig olefination reaction and NaBH4 reduction the amine 4 are produced, and then coupling with AcOH give amide 5, following its hydrolysis yield its free hydroxyl of amide 6. The a-Methylene group on the Sarcosine at the position 3 of cyclosporine is introduced, by a similar method, described by WO2012/051194A1 and US Patent Application No. 2013/0210704 Al to have its important intermediate 7, when sulfur nucleophile is used for 1, 4-Michael Addition on the methylene group, the methylene sulfur side chain with S-conformation can be formed on the sarcosine of position 3 as novel cyclosporine derivatives. For example: Scheme 1 -63- Date reçue/Date Received 2023-10-0684932431

[0028] Other compounds disclosed herein may be prepared by using method similar to the method disclosed in Scheme 1, and/or method including any modification or variant thereof known to one of ordinary skill in the art.

[0029] Recently, we published our research on STG-175 (Gallay, P. A., et al, 2016,PLoS One ll(4):e0152036. doi: 10.1371/joumal.pone.0152036).The side of CH2-S-CH2CH2CH2CH2OH on positon 3 of Sarcosine of cyclosporine has been proved for high cyclophilin binding (EC50 0.6 nM for cyclophilin A) and with high anti-HCV activity (EC50 11.5-38.9 nM for multi-genotype HCV GTla to 4a).By comparison with Sofosbuvir, when its viral replication rebound, STG-175 still clears cells from HCV since no viral replication rebound is observed after cessation of drug treatment. Even at the drug dose is less than 2.5 times to Sofosbuvir. In addition, it presents a higher barrier to resistance than other cyclophilin inhibitors or direct anti-viral agents (DAAs), No cross-resistance is observed with DAAs. Therefore, by this discovery we would believe that could be possible to make even better derivatives by the modification position 1 of MeBmt and with the side of CH2-SCH2CH2CH2CH2OH on positon 3 of Sarcosine of cyclosporine as novel cyclosporine derivatives. Pharmaceutical Compositions

[0030] This invention also provides a pharmaceutical composition comprising at least one of the compounds as described herein or a pharmaceutically-acceptable salt or solvate thereof, and a pharmaceutically-acceptable carrier.

[0031] The phrase “pharmaceutically-acceptable carrier” as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository - 64 - Date reçue/Date Received 2023-10-06CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as butylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0141] As set out above, certain embodiments of the present pharmaceutical agents may be provided in the form of pharmaceutically-acceptable salts. The term “pharmaceuticallyacceptable salt”, in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al., (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).

[0142] The pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from nontoxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, butionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.

[0143] In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases. The term “pharmaceutically-acceptable salts” in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine. Representative -65-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra)

[0144] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polybutylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0145] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient, which can be combined with a carrier material to produce a single dosage form, will vary depending upon the host being treated and the particular mode of administration. The amount of active ingredient, which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of 100%, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.

[0146] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0147] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.

[0148] In solid dosage forms of the invention for oral administration (capsules, tablets pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or -66-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and polyethylene oxide¬ polybutylene oxide copolymer; absorbents, such as kaolin and bentonite clay; lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0149] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxybutylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface¬ active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0150] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxybutylmethyl cellulose in varying butortions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples are embedding compositions, which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients. -67-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811

[0151] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Additionally, cyclodextrins, e.g., hydroxybutyl-.beta.-cyclodextrin, may be used to solubilize compounds.

[0152] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0153] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0154] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active pharmaceutical agents of the invention.

[0155] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be apbutriate.

[0156] Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or butellants which may be required.

[0157] The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, -68-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0158] Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary butellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and butane.

[0159] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving, or dispersing the pharmaceutical agents in the buffer medium. Absorption enhancers can also be used to increase the flux of the pharmaceutical agents of the invention across the skin. The rate of such flux can be controlled, by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0160] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

[0161] Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0162] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. One strategy for depot injections includes the use of polyethylene oxide-polybutylene oxide copolymers wherein the vehicle is fluid at room temperature and solidifies at body temperature.

[0163] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly -69-84932431 (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping flie drug in liposomes or microemulsions, which are compatible with body tissue.

[0032] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0033] The compounds and pharmaceutical compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures)to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, the compound of the present invention may be administered concurrently with another anti-HCV agent), or they may achieve different effects (e.g., control of any adverse effects).

[0034] The compounds of the invention may be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means. The compounds may be usedto treat arthritic conditions in mammals (i.e., humans, livestock, and domestic animals), birds, lizards, and any other organism, which can tolerate the compounds.

[0035] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such containers) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. Equivalents

[0036] The representative examples which follow are intended to help illustrate die invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the frill contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are referenced to help -70- Date reçue/Date Received 2023-10-06CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 illustrate the state of the art. The following examples contain important additional information, exemplification and guidance which can be adapted to the practice of this invention in its various embodiments and equivalents thereof Examples Example 1 la-Methvlene-Sarl-3-cvclosDorin Exact Mass: 1231.85 Exact Mass: 1213.84 MW: 1232.66 MW: 1214.65

[0169] To a solution of [a-hydroxymethyl-Sar]-3-cyclosporin (246 mg, 0.20 mmol) in tetrahydrofuran (15 ml) were added sodium hydride (120 mg 60% in mineral oil, 3 mmol) and diethyl chlorophosphate (412 mg, 2.40 mmol). The resulting mixture was stirred at room temperature overnight. After the starting material disappeared, methanol (10 ml) and potassium tert-butoxide (33 mg, 26.00 mmol) were added. The mixture was stirred at room temperature for three hours and the solvents were removed under reduced pressure. The residue was dissolved in dichloromethane (50 ml). The dichloromethane layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography using dichloromethane/methanol as eluent to give 205 mg of product [Molecular formula: CesHniNuOn; Exact Mass: 1213.84; MS (m/z): 1214.59 (M+l)+; HPLC RT: 17.47 min. (C8 reverse phase column: 250mm; acetonitrile/water (0.05% trifluoroacetic acid), operation temperature: 64 °C; Detector: 210 nm]. Examples 2 r(3R,4R)-3-Hvdroxv-4-methvl-6-(4-methoxvcarbonvlbenzvn-N-MeNlel-l-r(SH4- hvdroxvbutvlthio)methvl-Sar]-3-cvclosporin -71 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [3-Acetyl-MeBmt]-l-cyclosporin Exact Mass: 1243.85 MW: 1244.67

[0170] To a dried flask under nitrogen were added cyclosporine (12.00 g, 9.98 mmol), N,Ndimethylaminopyridine (0.12 g, 0.10 mmol), anhydrous pyridine (120 ml) and acetic anhydride (54 ml, 0.54 mol). After stirred at room temperature overnight, the mixture was poured into ice¬ water (600 ml) and stirred until the ice was melted. Ethyl acetate (100 ml) was added and the mixture was separated. The ethyl acetate layer was washed with 1.0 N hydrochloric acid solution (100 ml x 2), saturated sodium bicarbonate solution (100 ml), brine (100 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 11.40 g of pure [3-acetyl-MeBmt]-l-cyclosporin [Molecular Formula: CmHuiNuOu; Exact Mass: 1243.85; MS (m/z): 1244.53 (M+l)+, 1266.70 (M+Na)+; HPLC RT: 18.02 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [(3R, 4R)-3-Acetyloxy-4-methyl-6-oxo-N-MeNle]-l-cyclosporin Exact Mass: 1231.82 MW: 1232.62

[0171] To a solution of [3-acetyl-MeBmt]-l-cyclosporin (10.00 g, 8.04 mmol) in dioxane (200 ml) were added water (20 ml), osmium(VIII) oxide solution (15.74 mM, 51 ml, 0.80 mmol) and sodium metaperiodate (6.88 g, 32.16 mmol). The reaction mixture was stirred at room temperature for five hours. Ethyl acetate (100 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 5.10 g of pure [(3R, 4R)-3-acetyloxy-4-methyl-6-oxoN-MeNle]-l-cyclosporin [Molecular Formula: C62H109N11O14; Exact Mass: 1231.82; MS (m/z): -72-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 1232.75 (M+l)+, 1254.77 (M+Na)+; HPLC RT: 15.74 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. |(3R, 4R)-3-Acetyloxy-4-methyl-6-(4-methoxycarbonylphenyl)methylene-N-MeNle]-lcyclosporin C27H24BrO2P+ Exact Mass: 490.07 MW: 491.36 C27H23O2P Exact Mass: 410.14 MW: 410.45

[0172] To a solution of (4-methoxycarbonylbenzyl)triphenylphosphonium bromide (4.00 g, 8.14 mmol) in anhydrous tetrahydrofuran (120 ml) under nitrogen were added sodium bis(trimethylsilyl)amide (1.0 M in THF, 10 ml, 10.00 mmol). The reaction mixture was stirred at room temperature for one hour and cooled to -40 °C. A solution of [(3R,4R)-3-acetyloxy-4- methyl-6-oxo-N-MeNle]-l-cyclosporin (5.00 g, 4.05 mmol) in anhydrous tetrahydrofuran (25 ml) was added. The mixture was stirred for another two hours at -30 °C and saturated ammonium chloride solution (20 ml) was added to quench the reaction. Most of tetrahydrofuran was evaporated under reduced pressure. Ethyl acetate (150 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 2.00 g of pure [(3R,4R)-3-acetyloxy-4-methyl-6-(4- methoxycarbonylphenyl)methylene-N-MeNle]-l-cyclosporin [Molecular Formula: C71H117N11O15; Exact Mass: 1363.87; MS (m/z): 1364.61 (M+ 1 T, HPLC RT: 17.89 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [(3R, 4R)-3-Acetyloxy-4-methyl-6-(4-methoxycarbonylbenzyl)-N-MeNle]-l-cyclosporin -73 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Exact Mass: 1363.87 MW: 1364.78 Exact Mass: 1365.89 MW: 1366.80

[0173] To a solution of [(3R,4R)-3-acetyloxy-4-methyl-6-(4- methoxycarbonylphenyl)methylene-N-MeNle]-l-cyclosporin (2.00 g, 1.46 mmol) in methanol (50 ml), palladium (10 wt% on carbon, 20 mg) and acetic acid (5 drops) were added. The mixture was stirred at room temperature under hydrogen for two hours. The mixture was filtered and the filtrate was evaporated under reduced pressure to give crude [(3R,4R)-3- acetyloxy-4-methyl-6-(4-methoxycarbonybenzyl)-N-MeNle]-1-cyclosporin [Molecular Formula: C71H119N11O15; Exact Mass: 1365.89; MS (m/z): 1366.73 (M+l ) ; HPLC RT: 18.02 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [(3R, 4R)-3-Hydroxy-4-methyl-6-(4-carboxybenzyl)-N-MeNle]-l-cyclosporin [0174] [(3R,4R)-3-Acetyloxy-4-methyl-6-(4-methoxycarbonylbenzyl)-N-MeNle]-lcyclosporin (0.25 g, 0.18 mmol) was dissolved in methanol (4 ml). Water (2 ml) and tétraméthylammonium hydroxide pentahydrate (70 mg) were added. The mixture was stirred at room temperature overnight. Then most of the methanol was evaporated. The PH of mixture was adjusted to 5 with acetic acid. Ethyl acetate (50 ml) and brine (10 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give crude product [(3R, 4R)-3-hydroxy-4-methyl-6-(4- carboxybenzyl)-N-MeNle]-l-cyclosporin [Molecular Formula: CôsHusNhOm; Exact Mass: 1309.86; MS (m/z): 1310.61 (M+l)+; HPLC RT: 14.36 min. (C8 reverse phase column: 250 -74-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [(3R, 4R)-3-Hydroxy-4-methyl-6-(4-carboxybenzyl)-N-MeNle]-l-[a-methylene-Sar]-3- cyclosporin Exact Mass: 1309.86 Exact Mass: 1321.86 MW: 1310.73 MW: 1322.74 [0175] n-Butyllithium (2.65 M, 7.7 ml, 20.41 mmol) was added to a solution of diisopropylamine (2.05 g, 20.30 mmol) in tetrahydrofuran (50 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for one hour, a solution of [(3R,4R)-3-hydroxy-4- methyl-6-(4-carboxybenzyl)-N-MeNle]-l-cyclosporin (2.40 g, 1.20 mmol) in tetrahydrofuran (10 ml) was added. The mixture was stirred at -78 °C for three hours. After carbon dioxide gas was bubbled into the reaction mixture for 15 minutes, the mixture was stirred at -78 °C for another hour. Then the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature to let unreacted carbon dioxide come out. The mixture was cooled to -78 °C again and chloromethyl chloroformate (3.00 ml) was added. The mixture was stirred and allowed to warm to room temperature overnight. Brine (5 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (80 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give 1.50 g of crude product [(3R, 4R)-3-hydroxy-4-methyl-6-(4-carboxybenzyl)-N-MeNle]-l-[amethylene-Sar]-3-cyclosporin [Molecular Formula: C69H115N11O14; Exact Mass: 1321.86; MS (m/z): 1322.55 (M+l)+; HPLC RT: 16.13 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [(3R, 4R)-3-Hydroxy-4-methyl-6-(4-methoxycarbonylbenzyl)-N-MeNle]-l-[(x-methyleneSar]-3-cyclosporin -75-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811

[0176] To a solution of [(3R, 4R)-3-hydroxy-4-methyl-6-(4-carboxybenzyl)-N-MeNle]-l- [a-methylene-Sar]-3-cyclosporin(1.32 g, 1.00 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (0.38 g, 2.75 mmol) and iodomethane (0.50 g, 3.52 mmol). The mixture was stirred at room temperature for three hours. Ethyl acetate (100 ml) and water (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 1.60 g of pure [(3R,4R)-3-hydroxy-4-methyl-6-(4- methoxycarbonylbenzyl)-N-MeNle]-l-[a-methylene-Sar]-3-cyclosporin [Molecular Formula: C70H117N11O14; Exact Mass: 1335.88; MS (m/z): 1336.64 (M+lf; HPLC RT: 18.03 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [(3R, 4R)-3-Hydroxy-4-methyl-6-(4-methoxycarbonylbenzyl)-N-MeNle]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin Exact Mass: 1335.88 Exact Mass: 1441.92 MW: 1336.77 MW: 1442.95

[0177] To a solution of [(3R, 4R)-3-hydroxy-4-methyl-6-(4-methoxycarbonylbenzyl)-NMeNle]-l-[oc-methylene-Sar]-3-cyclosporin (0.60 g, 0.45 mmol) in methanol (25 ml) were added 4-mercapto-l-butanol (0.45 g, 4.25 mmol) and lithium hydroxide (0.10 g, 4.25 mmol). The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (60 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and -76-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give pure [(3R,4R)-3-hydroxy-4-methyl-6-(4- methoxycarbonylbenzyl)-N-MeNle]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C74H127N11O15S; Exact Mass: 1441.92; MS (m/z): 1422.65 (M+l)+; HPLC RT: 16.79 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Examples 3 K3R,4R)-3-Hvdroxv-4-methvl-6-(4-carboxvbenzvn-N-MeNlel-l-r(SH4- hvdroxvbutvlthio)methyl-Sar]-3-cvclosporin Exact Mass: 1441.92 Exact Mass: 1427.91 MW: 1442.95 MW: 1428.93

[0178] To a solution of [(3R,4R)-3-hydroxy-4-methyl-6-(4-methoxycarbonylbenzyl)-NMeNle]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin (85 mg, 0.06 mmol) in methanol (5 ml) was added a solution of lithium hydroxide (15 mg) in water (5 ml). The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. The PH of the mixture was adjusted to 6 with 1.0 N hydrochloric acid. Ethyl acetate (60 ml) and brine (10 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified to give pure [(3R,4R)-3-hydroxy-4-methyl-6-(4- carboxybenzyl)-N-MeNle]-l-[(S)-(4-hydroxybutylthio) methyl-Sar]-3-cyclosporin [Molecular Formula: C73H125N11O15S; Exact Mass: 1427.91; MS (m/z): 1428.63 (M+l)+; HPLC RT: 14.37 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 4 K3R, 4R)-3-Hvdroxv-4-methvl-6-(3-amino)benzvl-N-MeNlel-l-[(SW4- hvdroxvbutvlthio)methvl-Sar]-3-cvclosporin (3-Nitrobenzyl)triphenylphosphonium bromide -77-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Ph3P Toluene C7H6BrNO2 C18H15P Exact Mass: 214.96 Exact Mass: 262.09 MW: 216.03 MW: 262.29 C25H21BrNO2P+ Exact Mass: 477.05 MW: 478.33 [0179] 3-Nitrobenzyl bromide (5.00 g, 23.15 mmol) and triphenylphosphine (6.06 g, 23.15 mmol) were added to toluene (60 ml). The mixture was stirred and heated to reflux overnight. After cooled to room temperature, the precipitate was filtered off, washed with toluene and hexane and dried in vacuum to give 10.50 g product [Molecular Formula: CzsHziBrNChP; Exact Mass: 477.05; MS (m/z): 398.45 (M+1)+-Br]. [(3R, 4R)-3-Acetyloxy-4-methyl-6-(3-nitro-phenylmethylene)-N-MeNle]-l-cyclosporin NaHMDS C25H21BrNO2P+ Exact Mass: 477.05 C25H20NO2P Exact Mass: 397.12 MW: 478.33 Exact Mass: 1231.82 MW: 1232.62

[0180] To a solution of (3-nitrobenzyl)triphenylphosphonium bromide (2.40 g, 5.03 mmol) in anhydrous tetrahydrofuran (90 ml) under nitrogen was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 6 ml, 6.00 mmol). The reaction mixture was stirred at room temperature for one hour and cooled to -40 °C. A solution of [(3R, 4R)-3-aceyloxy-4-methyl-6-oxo-N-MeNle]-lcyclosporin (3.69 g, 3.00 mmol) in anhydrous tetrahydrofuran (25 ml) was added. The mixture was stirred another two hours at -30 °C. Then saturated ammonium chloride solution (20 ml) was added to quench the reaction. Most of tetrahydrofuran was evaporated under reduced pressure. Ethyl acetate (150 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 1.60 g of pure [(3R,4R)-3- aceyloxy-4-methyl-6-(3-nitro-phenylmethylene)N-MeNle]-l-cyclosporin [Molecular Formula: C69H114N12O15; Exact Mass: 1350.85; MS (m/z): 1351.52 (M+l)+], -78-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [(3R, 4R)-3-Acetyloxy-4-methyl-6-(3-amino)benzyl-N-MeNle]-l-cyclosporin

[0181] To a solution of [(3R,4R)-3-acetyloxy-4-methyl-6-(3-nitro-phenylmethylene)-N-MeNle]- 1-cyclosporin (3.00 g, 2.22 mmol) in methanol (50 ml) under nitrogen was added nickel (II) chloride hexahydrate (0.19 g, 0.81 mmol). The reaction mixture was put into ice-water bath. Sodium borohydride (1.80 g, 47.33 mmol) was added in four batches in two hours. After the mixture was stirred for another two hours at 0°C, water (10 ml) was added. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (50 ml) and saturated sodium bicarbonate solution (50 ml) were added and the mixture was separated. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in methanol (30 ml). Palladium (10 wt% on carbon, 20 mg) and acetic acid (5 drops) were added. The mixture was stirred at room temperature under hydrogen for two hours. The mixture was filtered and the filtrate was evaporated under reduced pressure to give crude [(3R,4R)-3-acetyloxy-4-methyl-6-(3-amino)benzyl-N-MeNle]-l-cyclosporin [Molecular Formula: C69H118N12O13; Exact Mass: 1322.89; MS (m/z): 1323.73 (M+l)+]_ [(3R, 4R)-3-Hydroxy-4-methyl-6-(3-amino)benzyl-N-MeNle]-l-cyclosporin Exact Mass: 1322.89 MW: 1323.77 [0182] [(3R,4R)-3-Acetyloxy-4-methyl-6-(3-amino)benzyl-N-MeNle]-l-cyclosporin (2.60 g, 1.56 mmol) was dissolved in methanol (70 ml). Water (35 ml) and tétraméthylammonium hydroxide pentahydrate (2.00 g, 11.01 mmol) were added. The mixture was stirred at room temperature for eight hours. Then most of the methanol was evaporated. Ethyl acetate (100 ml) -79-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 and brine (100 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 1.90 g of pure [(3R,4R)-3-hydroxy-4- methyl-6-(3-aminophenyl)methyl-N-MeNle]-l-cyclosporin [Molecular Formula: CôîHi16N12O12; Exact Mass: 1280.88; MS (m/z): 1281.64 (M+l)+], [(3R, 4R)-3-Hydroxy-4-methyl-6-(3-(tert-butoxycarbonyl)amino)benzyl-N-MeNle]-lcyclosporin [0183] [(3R,4R)-3-Hydroxy-4-methyl-6-(3-amino)benzyl-N-MeNle]-l-cyclosporin(0.80 g, 0.62 mmol) was dissolved in tetrahydrofuran (30 ml). Di-tert-butyldicarbonate (0.37 g, 1.70 mmol) was added. The mixture was stirred at room temperature for two days. Most of tetrahydrofuran was evaporated under reduced pressure. Ethyl acetate (30 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography to give 750 mg of pure [(3R,4R)-3-hydroxy-4-methyl-6-(3-(tert-butoxycarbonyl)amino)benzyl-N-MeNle]-l-cyclosporin [Molecular Formula: C72H124N12O14; Exact Mass: 1380.94; MS (m/z): 1381.65 (M+l)+], [(3R, 4R)-3-Hydroxy-4-methyl-6-(3-(tert-butoxycarbonyl)amino)benzyI-N-MeNle]-l-[amethylene-Sar]-3-cyclosporin - 80-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [0184] n-Butyllithium (2.6.5M, 2.70 ml, 7.16 mmol) was added to a solution of diisopropylamine (0.71 g, 7.15 mmol) in tetrahydrofuran (50 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for an hour, a solution of [(3R,4R)-3-hydroxy-4-methyl-6-(3-(tertbutoxycarbonyl)amino)benzyl-N-MeNle]-l-cyclosporin (0.90 g, 0.65 mmol) in tetrahydrofuran (2 ml) was added. The mixture was stirred at -78 °C for three hours. After carbon dioxide gas was bubbled into the reaction mixture for 15 minutes, the mixture was stirred at —78 °C for another hour. Then the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature to let unreacted carbon dioxide come out. The mixture was cooled to -78 °C and chloromethyl chloroformate (1.20 ml) was added. The mixture was stirred and allowed to warm to room temperature overnight. Brine (5 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 0.45 g of pure [(3R,4R)-3-hydroxy-4-methyl-6-(3-(tertbutoxycarbonyl)amino)benzyl-N-MeNle]-1-[a-methylene-Sar]-3-cyclosporin [Molecular Formula: C73H124N12O14; Exact Mass: 1392.94; MS (m/z): 1393.88 (M+l)+], [(3R, 4R)-3-Hydroxy-4-methyl-6-(3-amino)benzyl-N-MeNle]-l-[a-methylene-Sar]-3- cyclosporin [0185] [(3R,4R)-3-Hydroxy-4-methyl-6-(3-(tert-butoxycarbonyl)amino)benzyl-N-MeNle]-l- [a-methylene-Sar]-3-cyclosporin (0.80 g, 0.57 mmol) was dissolved in dichloromethane (15 ml) and put into ice-water bath. Trifluoroacetic acid (7 ml) was added. The mixture was stirred at room temperature for one hour. Another dichloromethane (50 ml) was added. The mixture was washed with brine (30 ml) and saturated sodium bicarbonate solution (30 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 0.20 g of pure [(3R,4R)-3-hydroxy-4- - 81 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 methyl-6-(3-amino) benzyl-N-MeNle]-l-[oc-methylene-Sar]-3-cyclosporin [Molecular Formula: C68H116N12O12; Exact Mass: 1292.88; MS (m/z): 1293.68 (M+l)+], |(3R, 4R)-3-Hydroxy-4-methyl-6-(3-amino)benzyl-N-MeNle]-l-[(S)-(4- hydroxybutyIthio)methyl-Sar]-cyclosporin Exact Mass: 1292.88 Exact Mass: 1398.93 MW: 1293.75 MW: 1399.93

[0186] To a solution of [(3R,4R)-3-hydroxy-4-methyl-6-(3-amino) benzyl-N-MeNle]-l-[amethylene-Sar]-3-cyclosporin (0.20 g, 0.15 mmol) in methanol (10 ml) were added 4-mercapto- 1-butanol (0.07 g, 0.66 mmol) and lithium hydroxide (19 mg, 0.79 mmol). The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (30 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give pure [(3R,4R)-3-hydroxy-4-methyl-6-(3-amino)benzyl-N-MeNle]-l-[(S)-(4-hydroxy butylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C72H126N12O13S; Exact Mass: 1398.93; MS (m/z): 1399.62 (M+l)+; HPLC RT: 11.33 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 5 |(3R, 4R)-3-Hydroxv-4-methvl-6-(3-(N.,N-diisoDropvlamino)carbonvl)benzvl-N-MeNlel- 1-1(S)-(4-hydroxybutylthiolmethyl-Sarl-3-cyclosnorin (3-Methoxycarbonylbenzyl)triphenylphosphonium bromide C9H9BrO2 Exact Mass: 227.98 MW: 229.07 Cl8H15P Exact Mass: 262.09 MW: 262.29 C27H24BrO2P+ Exact Mass: 490.07 MW: 491.36 - 82-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811

[0187] Methyl (3-bromomethyl)benzoate (6.00 g, 26.20 mmol) and triphenylphosphine (6.86 g, 26.18 mmol) were added to toluene (60 ml). The mixture was stirred and heated to reflux overnight. After cooled to room temperature, the precipitate was filtered off, washed with toluene and hexane and dried in vacuum to give 11.05 g product. [Molecular Formula: C27H24BrO2P; Exact Mass: 490.07; MS (m/z): 411.25 (M+1)+-Br], [(3R, 4R)-3-Acetyloxy-4-methyl-6-(3-methoxycarbonylphenyl)methylene-N-MeNle]-lcyclosporin NaHMDS C27H24BrO2P+ Exact Mass: 490.07 MW: 491.36 C27H23O2P Exact Mass: 410.14 MW: 410.45 MW: 1232.62 Exact Mass: 1363.87 MW: 1364.78

[0188] To a mixture of (3-methoxycarbonylbenzyl)triphenylphosphonium bromide (4.00 g, 8.14 mmol) in anhydrous tetrahydrofuran (120 ml) under nitrogen were added sodium bis(trimethylsilyl)amide (1.0 M in THF, 10 ml, 10.00 mmol). The reaction mixture was stirred at room temperature for one hour and cooled to -40 °C. A solution of [(3R,4R)-3-acetyloxy-4- methyl-6-oxo-N-MeNle]-l-cyclosporin (5.00 g, 4.05 mmol) in anhydrous tetrahydrofuran (25 ml) was added. The mixture was stirred another two hours at -30 °C. Then saturated ammonium chloride solution (20 ml) was added to quench the reaction. Most of tetrahydrofuran was evaporated under reduced pressure. Ethyl acetate (150 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 2.00 g of pure [(3R,4R)-3-acetyloxy-4-methyl-6-(3-methoxycarbonylphenyl)methylene-NMeNle]-l-cyclosporin [Molecular Formula: C71H117N11O15; Exact Mass: 1363.87; MS (m/z): 1364.61 (M+l)+], [(3R, 4R)-3-Acetyloxy-4-methyl-6-(3-methoxycarbonyl)benzyl-N-MeNle]-l-cycIosporin - 83 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Exact Mass: 1363.87 MW: 1364.78

[0189] To a solution of [(3R,4R)-3-acetyloxy-4-methyl-6-(3-methoxycarbonylphenyl) methylene-N-MeNle]-l-cyclosporin (2.00 g, 1.46 mmol) in methanol (50 ml) were added palladium (10 wt% on carbon, 20 mg) and acetic acid (5 drops). The mixture was stirred at room temperature under hydrogen for two hours. The mixture was filtered and the filtrate was evaporated under reduced pressure to give crude [(3R,4R)-3-acetyloxy-4-methyl-6-(3- methoxycarbonyl)benzyl-N-MeNle]-l-cyclosporin [Molecular Formula: C71H119N11O15; Exact Mass: 1365.89; MS (m/z): 1366.73 (M+l) ]. [(3R, 4R)-3-Hydroxy-4-methyl-6-(3-carboxy)benzyl-N-MeNle]-l-cyclosporin MW: 1364.78 [0190] [(3R,4R)-3-Acetyloxy-4-methyl-6-(3-methoxycarbonyl)benzyl-N-MeNle]-lcyclosporin (0.25 g, 0.18 mmol) was dissolved in methanol (4 ml). Water (2 ml) and tétraméthylammonium hydroxide pentahydrate (70 mg) were added. The mixture was stirred at room temperature overnight. Then most of the methanol was evaporated. The PH of the mixture was adjusted to 6 with acetic acid. Ethyl acetate (50 ml) and brine (10 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was used for next step without further purification. [(3R, 4R)-3-hydroxy-4-methyl-6-(3-carboxy)benzyl-N-MeNle]-l-cyclosporin [Molecular Formula: CôsHiisNhOm; Exact Mass: 1309.86; MS (m/z): 1310.61 (M+l)+], - 84-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [(3R, 4R)-3-Hydroxy-4-methyl-6-(3-methoxycarbonyl)benzyl-N-MeNle]-l-cyclosporin

[0191] To the solution of [(3R,4R)-3-hydroxy-4-methyl-6-(3-carboxy)benzyl-N-MeNle]-lcyclosporin(1.80 g, 1.37 mmol) in N,N-dimethylformamide (25 ml) were added potassium carbonate (0.38 g, 2.75 mmol) and iodomethane (0.50 g, 3.52 mmol). The mixture was stirred at room temperature for three hours. Ethyl acetate (100 ml) and water (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 1.60 g of pure [(3R, 4R)-3-hydroxy-4-methyl-6-(3-methoxycarbonyl)benzyl-N-MeNle]-lcyclosporin [Molecular Formula: C69H117N11O14; Exact Mass: 1323.88; MS (m/z): 1324.64 (M+l)+], [(3R, 4R)-3-Hydroxy-4-methyl-6-((3-N,N-diisopropylaminocarbonyl))benzyl-N-MeNle]-l- [oc-methylene-Sar]-3-cyclosporiii [0192] n-Butyllithium (2.65 M, 5 ml, 13.33 mmol) was added to a solution of diisopropylamine (1.37 g, 13.30 mmol) in tetrahydrofuran (50 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for one hour, a solution of [(3R,4R)-3-hydroxy-4-methyl-6-(3- methoxycarbonyl)benzyl-N-MeNle]-l-cyclosporin (1.60 g, 1.20 mmol) in tetrahydrofuran (5 ml) was added. The mixture was stirred at -78 °C for three hours. After carbon dioxide gas was bubbled into the reaction mixture for 15 minutes, the mixture was stirred at -78 °C for another hour. Then the cooling bath was removed and the reaction mixture was allowed to warm up to - 85 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 room temperature to let unreacted carbon dioxide come out. The mixture was cooled to -78 °C and chloromethyl chloroformate (2.00 ml) was added. The mixture was stirred and allowed to warm to room temperature overnight. Brine (5 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 0.60 g of pure [(3R, 4R)-3-hydroxy-4-methyl-6-(3-(N,Ndiisopropylamino)carbonyl)benzyl-N-MeNle]-l-[a-methylene-Sar]-3-cyclosporin [Molecular Formula: C75H128N12O13; Exact Mass: 1404.97; MS (m/z): 1405.67 (M+l)+], [(3R, 4R)-3-Hydroxy-4-methyl-6-(3-(N,N-diisopropylamino)carbonyl)benzyl-N-MeNle]- l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin

[0193] To a solution of [(3R,4R)-3-hydroxy-4-methyl-6-(3-(N,N-diisopropyamino) carbonyl)benzyl-N-MeNle]-l-[a-methylene-Sar]-3-cyclosporin (0.60 g, 0.43 mmol) in methanol (25 ml) were added 4-mercapto-l-butanol (0.45 g, 4.25 mmol) and lithium hydroxide (0.10 g, 4.25 mmol). The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (60 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give pure [(3R, 4R)-3-hydroxy-4-methyl-6-(3-(N,Ndiisopropyamino)carbonyl)benzyl-N-MeNle]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- cyclosporin [Molecular Formula: C79H138N12O14S; Exact Mass: 1511.02; MS (m/z): 1511.70 (M+l)+; HPLC RT: 17.00 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 6 K3R, 4R)-3-Hvdroxv-4-methyl-6-(3-carboxv)benzyl-N-MeNle]-l-[(S)-(4- hvdroxvbutvlthio)methvl-Sar]-3-cyclosDorin - 86-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [(3R, 4R)-3-Hydroxy-4-methyl-6-(3-carboxy)benzyl-N-MeNle]-l-[<x-methylene-Sar]-3- cyclosporin [0194] n-Butyllithium (2.65 M, 7.7 ml, 20.41 mmol) was added to a solution of diisopropylamine (2.05 g, 20.30 mmol) in tetrahydrofuran (50 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for one hour, a solution of [(3R,4R)-3-hydroxy-4-methyl-6-(3- carboxy)benzyl-N-MeNle]-l-cyclosporin (2.40 g, 1.20 mmol) in tetrahydrofuran (10 ml) was added. The mixture was stirred at -78 °C for three hours. After carbon dioxide gas was bubbled into the reaction mixture for 15 minutes, the mixture was stirred at -78 °C for another hour. Then the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature to let unreacted carbon dioxide come out. The mixture was cooled to -78 °C and chloromethyl chloroformate (3.00 ml) was added. The mixture was stirred and allowed to warm to room temperature overnight. Brine (5 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (80 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give 1.50 g of crude product [(3R, 4R)-3-hydroxy-4- methyl-6-(3-carboxy)benzyl-N-MeNle]-l-[oc-methylene-Sar]-3-cyclosporin [Molecular Formula: C69H115N11O14; Exact Mass: 1321.86; MS (m/z): 1322.45 (M+l)+], [(3R, 4R)-3-Hydroxy-4-methyl-6-(3-methoxycarbonyl)benzyI-N-MeNle]-l-[a-methyleneSar]-3-cyclosporin - 87-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811

[0195] To the solution of [(3R, 4R)-3-hydroxy-4-methyl-6-(3-carboxy)benzyl-N-MeNle]-l-[ocmethylene-Sar]-3-cyclosporin(l.32 g, 1.00 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (0.38 g, 2.75 mmol) and iodomethane (0.50 g, 3.52 mmol). The mixture was stirred at room temperature for three hours. Ethyl acetate (100 ml) and water (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 1.60 g of pure [(3R,4R)-3-hydroxy-4-methyl-6-(3- methoxycarbonyl)benzyl-N-MeNle]-l-[a-methylene-Sar]-3-cyclosporin [Molecular Formula: C70H117N11O14; Exact Mass: 1335.88; MS (m/z): 1336.64 (M+l)+], [(3R, 4R)-3-Hydroxy-4-methyl-6-(3-methoxycarbonyI)benzyl-N-MeNle]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin Exact Mass: 1335.88 Exact Mass: 1441.92 MW: 1336.77 MW: 1442.95

[0196] To a solution of [(3R,4R)-3-hydroxy-4-methyl-6-(3-methoxycarbonyl)benzyl-NMeNle]-l-[oc-methylene-Sar]-3-cyclosporin (0.60 g, 0.45 mmol) in methanol (25 ml) were added 4-mercapto-l-butanol (0.45 g, 4.25 mmol) and lithium hydroxide (0.10 g, 4.25 mmol). The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (60 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give pure [(3R,4R)-3-hydroxy-4-methyl-6-(3- methoxycarbonyl)benzyl-N-MeNle]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C74H127N11O15S; Exact Mass: 1441.92; MS (m/z): 1422.65 (M+l) ]. Examples 7 |(3R.4R)-3-Hvdroxv-4-methvl-6-(3-carboxv)benzvl-N-MeNlel-l-USH4- hvdroxvbutvlthio)methvl-Sar]-3-cvclosporin -88-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 MW: 1442.95 MW: 1428.93

[0197] To a solution of [(3R,4R)-3-hydroxy-4-methyl-6-(3-methoxycarbonyl)benzyl-NMeNle]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin (85 mg, 0.06 mmol) in methanol (5 ml) was added a solution of lithium hydroxide (15 mg) in water (5 ml). The mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. The PH of aqueous mixture was adjusted to 6 with 1.0 N hydrochloric acid. Ethyl acetate (60 ml) and brine (10 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified to give pure [(3R,4R)-3-hydroxy-4-methyl-6-(3-carboxy)benzyl-N-MeNle]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C73H125N11O15S; Exact Mass: 1427.91; MS (m/z): 1428.63 (M+l)+; HPLC RT: 14.37 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Examples 8 K3R, 4R)-3-Hvdroxv-4-methvl-6-(2-hvdroxvethvl)-N-MeNle]-l-r(S)-(4- hvdroxvbutvlthio)methvl-Sarl-3-cvclosDorin [(3R, 4R)-3-Acetyloxy-4-methyl-(6-methoxycarbonylmethylene)-N-MeNIe]-l-cyclosporin o Exact Mass: 1231.82 Exact Mass: 1287.84 MW: 1232.62 MW: 1288.68

[0198] To a solution of methoxycarbonylmethylenetriphenylphosphorane (6.20 g, 18.54 mmol) in anhydrous tetrahydrofuran (100 ml) under nitrogen was added [(3R,4R)-3- acetyloxy-4-methyl-6-oxo-N-MeNle]-l-cyclosporin (4.10 g, 3.33 mmol). The mixture was - 89-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 stirred and heated to reflux for six hours. Then saturated ammonium chloride solution (20 ml) was added to quench the reaction. Most of tetrahydrofuran was evaporated under reduced pressure. Ethyl acetate (150 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 3.60 g of pure [(3R,4R)-3-acetyloxy-4-methyl-(6-methoxycarbonylmethylene)-N-MeNle]-1-cyclosporin [Molecular Formula: CesHnsNnOis; Exact Mass: 1287.84; MS (m/z): 1288.61 (MM ) ; HPLC RT: 16.43 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [(3R, 4R)-3-Acetyloxy-4-methyl-6-(methoxycarbonylmethyl)-N-MeNle]-l-cyclosporin

[0199] To a solution of [(3R,4R)-3-acetyloxy-4-methyl-6-(methoxycarbonylmethylene)- N-MeNle]-l-cyclosporin (3.80 g, 2.95 mmol) in methanol (100 ml) were added palladium (10 wt% on carbon, 250 mg) and acetic acid (5 drops). The mixture was stirred at room temperature under hydrogen for eight hours. The mixture was filtered and the filtrate was evaporated under reduced pressure to give crude [(3R,4R)-3-acetyloxy-4-methyl-6- (methoxycarbonymethyl)-N-MeNle]-l-cyclosporin [Molecular Formula: CesHnsNnOis; Exact Mass: 1289.86; MS (m/z): 1290.59 (M+l)+; HPLC RT: 16.50 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [(3R, 4R)-3-Hydroxy-4-methyl-6-(2-hydroxyethyl)-N-MeNle]-l-cyclosporiii -90-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811

[0200] To a solution of [(3R,4R)-3-acetyloxy-4-methyl-6-(methoxycarbonymethyl)-NMeNle]-l-cyclosporin (3.50 g, 2.71 mmol) in methanol (100 ml) was added cessium chloride (5.00 g, 29.78 mmol). Then sodium borohydride (10.00 g, 262.95 mmol) was added portions in 30 minutes. After the mixture was stirred for another eight hours at room temperature, most of the methanol was evaporated under reduced pressure. Ethyl acetate (150 ml) and saturated sodium bicarbonate solution (150 ml) were added and the mixture was separated. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 2.85 g of [(3R,4R)-3-hydroxy-4-methyl-6-(2-hydroxyethyl)-N-MeNle]-l-cyclosporin [Molecular Formula: C62H113N11O13; Exact Mass: 1219.85; MS (m/z): 1220.68 (M+l)+; HPLC RT: 15.80 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [(3R, 4R)-3-Hydroxy-4-methyl-6-(2-hydroxyethyl)-N-MeNle]-l-[a-methylene-Sar]-3- cyclosporin [0201] n-Butyllithium (2.65 M, 9.60 ml, 25.30 mmol) was added to a solution of diisopropylamine (2.56 g, 25.30 mmol) in tetrahydrofuran (80 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for one hour, a solution of [(3R,4R)-3-hydroxy-4- methyl-6-(2-hydroxyethyl)-N-MeNle]-l-cyclosporin (2.85 g, 2.30 mmol) in tetrahydrofuran (15 ml) was added. The mixture was stirred at -78 °C for three hours. After carbon dioxide -91 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 gas was bubbled into the reaction mixture for 15 minutes, the mixture was stirred at -78 °C for another hour. Then the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature to let unreacted carbon dioxide come out. The mixture was cooled to -78 °C and chloromethyl chloroformate (3.00 ml) was added. The mixture was stirred and allowed to warm to room temperature overnight. Brine (5 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (80 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 1.0 g of product [(3R,4R)-3-hydroxy-4- methyl-6-(2-hydroxyethyl)-N-MeNle]-l-[a.-methylene-Sar]-3-cyclosporin [Molecular Formula: C63H113N11O13; Exact Mass: 1231.85; MS (m/z): 1232.55 (M+l)+ ; HPLC RT: 15.14 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. |(3R, 4R)-3-Hydroxy-4-methyl-6-(2-hydroxyethyl)-N-MeNle]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin Exact Mass: 1231.85 Exact Mass: 1337.90 MW: 1232.66 MW: 1338.84

[0202] To a solution of [(3R,4R)-3-hydroxy-4-methyl-6-(2-hydroxyethyl)-N-MeNle]-l- [a-methylene-Sar]-3-cyclosporin (0.60 g, 0.45 mmol) in methanol (50 ml) were added 4- mercapto-1-butanol (0.45 g, 4.25 mmol) and lithium hydroxide (0.10 g, 4.25 mmol). The reaction mixture was stirred at room temperature for overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (60 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give pure [(3R,4R)-3-hydroxy-4-methyl-6-(2-hydroxyethyl)- N-MeNle]-l-[(S)-(4hydroxybutylthio) methyl-Sar]-3-cyclosporin [Molecular Formula: C67H123N11O14S; Exact Mass: 1337.90; MS (m/z): 1338.74 (M+l)+; HPLC RT: 12.98 min. -92-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 9 [8-(2-Acetamidoethyl)-6.,7-dihvdro-MeBmt]-l-[(R)-2-methoxvmethvl-Sar]-3-cvclosporin (3-Cyanopropyl)triphenylphosphonium bromide Ph3P Toluene ®Br NC^^x^xPPhs C4H6BrN Exact Mass: 146.97 MW: 148.00 Cl8H15P Exact Mass: 262.09 MW: 262.29 C22H21BrNP Exact Mass: 409.06 MW: 410.29 [0203] 4-Bromobutyronitrile (10 ml, 0.10 mol) and triphenylphosphine (36.23 g, 0.10 mol) were added to toluene (200 ml). The mixture was stirred and heated to reflux overnight. After cooled to room temperature, the precipitate was filtered off, washed with toluene and hexane and dried in vacuum to give 26.60 g product. [Molecular Formula: C22H2iNP+; Exact Mass: 330.14; MS (m/z): 330.23 (M)+]_ [8-Cyanomethyl-3-acetyl-MeBmt]-l-cyclosporin ©Br © NC PPh3 t-BuONa NC^xx^PPh3 C22H21BrNP Exact Mass: 409.06 MW: 410.29 ®22H20NP Exact Mass: 329.13 MW: 329.38

[0204] To a dried flask were added (3-cyanopropyl)triphenylphosphonium bromide (7.98 g, 19.50 mmol) and anhydrous tetrahydrofuran (60 ml) under nitrogen. The reaction mixture was put into an ice-water bath and sodium tert-butoxide (2.19 g, 22.75 mmol) was added. After the mixture was stirred for two hours, a solution of [(3R, 4R)-3-acetyloxy-4-methyl-6-oxo-N-MeNle]-lcyclosporin (4.00 g, 3.25 mmol) in anhydrous tetrahydrofuran (20 ml) was added. The mixture was stirred another five hours at 0 °C. Then saturated ammonium chloride solution (20 ml) was added to quench the reaction. Most of tetrahydrofuran was evaporated under reduced pressure. Ethyl acetate (100 ml) and brine (100 ml) were added and the mixture was separated. The organic -93 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 2.00 g of pure [8-cyanomethyl- 3-acetyl-MeBmt]-l-cyclosporin [Molecular Formula: C66H114N12O13; Exact Mass: 1282.86; MS (m/z): 1283.51 (M+l)+, 1305.73 (M+Na)+; HPLC RT: 16.50 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-Cyanomethyl-MeBmt]-l-cyclosporin Exact Mass: 1282.86 MW: 1283.71 [0205] [8-Cyanomethyl-3-acetyl-MeBmt]-l-cyclosporin (2.00 g, 1.56 mmol) was dissolved in methanol (20 ml). Water (10 ml) and tétraméthylammonium hydroxide pentahydrate (0.85 g, 4.68 mmol) were added. The mixture was stirred at room temperature for two hours. Then most of the methanol was evaporated. Ethyl acetate (100 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 1.70 g of pure [8-cyanomethyl-MeBmt]-l-cyclosporin [Molecular Formula: C64H112N12O12; Exact Mass: 1240.85; MS (m/z): 1241.54 (M+l)+, 1263.73 (M+Na)+; HPLC RT: 14.80 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Aminoethyl)-6,7-dihydro-MeBmt]-l-cyclosporin MW: 1247.72

[0206] To a solution of [8-cyanomethyl-MeBmt]-l-cyclosporin (2.00 g, 1.61 mmol) in methanol (50 ml) under nitrogen was added nickel (II) chloride hexahydrate (0.19 g, 0.81 mmol). -94-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 The reaction mixture was put into ice-water bath. Sodium borohydride (3.05 g, 80.50 mmol) was added in four batches in two hours. After the mixture was stirred for another two hours at 0 °C, water (10 ml) was added. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (50 ml) and saturated sodium bicarbonate solution (50 ml) were added and the mixture was separated. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in methanol (30 ml). Palladium (10 wt% on carbon, 20 mg) and acetic acid (5 drops) were added. The mixture was stirred at room temperature under hydrogen for two hours. The mixture was filtered and the filtrate was evaporated under reduced pressure to give crude [8-(2-aminoethyl)-6,7-dihydroMeBmt]-l-cyclosporin [Molecular Formula: C64H118N12O12; Exact Mass: 1246.90; MS (m/z): 1247.69 (M+l)+; HPLC RT: 11.13 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-cyclosporin Exact Mass: 1246.90 MW: 1247.72 Exact Mass: 1346.95 MW: 1347.84 [0207] [8-(2-Aminoethyl)-6,7-dihydro-MeBmt]-l-cyclosporin (crude, 1.61 mmol) was dissolved in tetrahydrofuran (20 ml). Saturated sodium bicarbonate solution (20 ml) and di-tertbutyldicarbonate (0.39 g, 1.77 mmol) were added. The mixture was stirred at room temperature for two hours. Most of tetrahydrofuran was evaporated under reduced pressure. Ethyl acetate (30 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 2.00 g of pure [8-(2-(tertbutoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-cyclosporin [Molecular Formula: C69H126N12O14; Exact Mass: 1346.95; MS (m/z): 1347.54 (M+l)+, 1369.78 (M+Na)+; HPLC RT: 17.08 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-2-methoxycarbonylSar]-3-cyclosporin -95-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Exact Mass: 1404.96 MW: 1405.87 [0208] n-Butyllithium (2.20 M, 3.38 ml, 7.42 mmol) was added to a solution of diisopropylamine (1.06 ml, 7.42 mmol) in tetrahydrofuran (20 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for an hour, a solution of [8-(2-(tertbutoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-cyclosporin (1.00 g, 0.74 mmol) in tetrahydrofuran (10 ml) was added over ten minutes. The mixture was stirred at -78 °C for two hours. After carbon dioxide gas was bubbled into the reaction mixture for 20 minutes, the mixture was stirred at -78 °C for another hour. Then the cooling bath was removed and the reaction mixture was allowed to warm up to 0 °C slowly. Most of tetrahydrofuran was removed under vacuum at room temperature. The residue was quenched by the addition of saturated citric acid solution and the pH of the aqueous layer was adjusted to 3~4 with 1 N hydrochloric acid and the precipitated oil was extracted with ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (100 ml x 3). The combined ethyl acetate layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 0.50 g of [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-2-carboxy-Sar]-3- cyclosporin [Molecular Formula: C70H126N12O16; Exact Mass: 1390.94; MS (m/z): 1391.60 (M+l)+; HPLC RT: 15.57 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [0209] [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-2-carboxy-Sar]-3- cyclosporin (0.50 g, 0.36 mmol) was dissolved in acetone (10 ml). lodomethane (0.03 ml, 0.54 mmol) and potassium carbonate (0.08 g, 0.54 mmol) were added. The mixture was stirred at room temperature for two hours. Most of acetone was evaporated under reduced pressure. Then ethyl acetate (40 ml) and water (40 ml) were added and the mixture was separated. The ethyl -96-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 acetate layer was dried over magnesium sulfate and evaporated under reduced pressure to give 0.51 g of crude [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-2- methoxycarbonyl-Sar]-3-cyclosporin [Molecular Formula: C71H128N12O16; Exact Mass: 1404.96; MS (m/z): 1405.64 (M+l)+, 1427.86 (M+Na)+; HPLC RT: 16.65 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-2-hydroxymethylSar]-3-cyclosporin MW: 1405.87 Exact Mass: 1376.96 MW: 1377.86 [0210] [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-2-methoxy carbonyl-Sar]-3-cyclosporin (0.51 g, 0.36 mmol) was dissolved in tetrahydrofuran (10 ml). Sodium borohydride (0.68 g, 18.00 mmol) and cesium chloride (0.49 g, 1.51 mmol) were added. The mixture was stirred at room temperature and methanol (10 ml) was added dropwise in one hour. The mixture was stirred for another two hours. Most of solvents were evaporated under reduced pressure. Then ethyl acetate (40 ml) and water (40 ml) were added and the mixture was separated. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure to give 0.50 g of crude [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydroMeBmt]-l-[(R)-2-hydroxymethyl-Sar]-3-cyclosporin [Molecular Formula: C70H128N12O15; Exact Mass: 1376.96; MS (m/z): 1377.71 (M+l)+, 1388.85 (M+Na)+; HPLC RT: 16.49 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. |8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt|-l-|(R)-2-hydroxymethyl-Sar|-3-cyclosporin -97-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Exact Mass: 1318.92 MW: 1319.78 [0211] [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-2-hydroxy methyl-Sar]-3-cyclosporin(0.50 g, 0.36 mmol) was dissolved in dichloromethane (10 ml) and put into ice-water bath. Trifluoroacetic acid (5 ml) was added. The mixture was stirred at room temperature for one hour. Another dichloromethane (20 ml) was added. The mixture was washed with brine (30 ml), saturated sodium bicarbonate solution (30 ml) and dried over magnesium sulfate and evaporated under reduced pressure to give crude [8-(2-aminoethyl)-6,7- dihydro-MeBmt]-l-[(R)-2-hydroxymethyl-Sar]-3-cyclosporin [Molecular Formula: C65H120N12O13; Exact Mass: 1276.91; MS (m/z): 1277.75 (M+l)+; HPLC RT: 9.13 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. The crude [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-l- [(R)-2-hydroxymethyl-Sar]-3-cyclosporin was dissolved in dichloromethane (10 ml). Acetic acid (0.12 ml, 2.20 mmol), HBTU (0.41 g, 1.08 mmol), 1-hydroxybenzotriazole (0.15 g, 1.08 mmol) and pyridine (0.50 ml) were added. The mixture was stirred at room temperature for two hours. Then dichloromethane (30 ml) and brine (50 ml) were added and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 27 mg of pure [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(R)-2-hydroxymethyl-Sar]-3- cyclosporin [Molecular Formula: C67H122N12O14; Exact Mass: 1318.92; MS (m/z): 1319.72 (M+l)+, 1341.91 (M+Na)+; HPLC RT: 14.12 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(R)-2-methoxymethyl-Sar]-3-cyclosporin - 98 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 ch3i NaOH n-Bu4NBr Benzene Water MW: 1319.78 MW: 1333.81 [0212] [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(R)-2-hydroxymethyl-Sar]-3- cyclosporin (0.20 g, 0.15 mmol) was dissolved in benzene (10 ml). lodomethane (0.21 g, 1.52 mmol), tetra-n-butylammonium bromide (0.49 g, 1.52 mmol), sodium hydroxide (1.00 g, 2.50 mmol) and water (2 ml) were added. The mixture was stirred at room temperature overnight. Then ethyl acetate (50 ml) and brine (50 ml) were added and separated. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 60 mg of pure [8-(2- acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(R)-2-methoxymethyl-Sar]-3-cyclosporin [Molecular Formula: CesHmNuOu; Exact Mass: 1332.94; MS (m/z): 1333.69 (M+l)+, 1355.86 (M+Na)+; HPLC RT: 16.18 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Examples 10 [8-f2-Acetamidoethyl)-6.,7-dihvdro-MeBmt]-l-[fS)-f4-hvdroxvbutvlthio)methvl-Sar]-3- cvclosporin [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[a-methylene-Sar]-3- cyclosporin MW: 1347.84 MW: 1359.85 [0213] n-Butyllithium (2.20 M, 6.75 ml, 14.85 mmol) was added to a solution of diisopropylamine (2.11 ml, 14.85 mmol) in tetrahydrofuran (40 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for an hour, a solution of [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro- -99-CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 MeBmt]-l-cyclosporin (2.00 g, 1.48 mmol) in tetrahydrofuran (15 ml) was added over ten minutes. The mixture was stirred at -78 °C for two hours. After carbon dioxide gas was bubbled into the reaction mixture for 30 minutes, the mixture was stirred at -78 °C for another hour. Then the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature to let unreacted carbon dioxide come out. The mixture was cooled to -78 °C and chloromethyl chloroformate (1.32 ml, 14.85 mmol) was added. The mixture was stirred and allowed to warm to room temperature overnight. Brine (5 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 0.60 g of pure [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydroMeBmt]-l-[a-methylene-Sar]-3-cyclosporin [Molecular Formula: C70H126N12O14; Exact Mass: 1358.95; MS (m/z): 1359.59 (M+l)+, 1381.81 (M+Na)+; HPLC RT: 18.44 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[a-methylene-Sar]-3-cyclosporin [0214] [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[a-methylene-Sar]-3- cyclosporin (0.60 g, 0.44 mmol) was dissolved in dichloromethane (10 ml) and put into ice-water bath. Trifluoroacetic acid (5 ml) was added. The mixture was stirred at room temperature for one hour. Another dichloromethane (20 ml) was added. The mixture was washed with brine (30 ml), saturated sodium bicarbonate solution (30 ml) and dried over magnesium sulfate and evaporated under reduced pressure to give crude [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-l-[oi-methylene- - 100 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Sar]-3-cyclosporin [Molecular Formula: CesHnsNnOu; Exact Mass: 1258.90; MS (m/z): 1259.77 (M+l)+, 1281.84 (M+Na)+; HPLC RT: 13.00 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. The crude [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-l-[a-methylene-Sar]-3-cyclosporin was dissolved in dichloromethane (10 ml). Acetic acid (0.12 ml, 2.20 mmol), HBTU (0.50 g, 1.32 mmol), 1-hydroxybenzotriazole (0.18 g, 1.32 mmol) and pyridine (1 ml) were added. The mixture was stirred at room temperature for one hour. Then dichloromethane (30 ml) and brine (50 ml) were added and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 0.30 g of pure [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]- l-[oc-methylene-Sar]-3-cyclosporin [Molecular Formula: C67H120N12O13; Exact Mass: 1300.91; MS (m/z): 1301.66 (M+l)+, 1323.92 (M+Na)+; HPLC RT: 17.41 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- cyclosporin Exact Mass: 1300.91 Exact Mass: 1406.96 MW: 1301.77 MW: 1407.95

[0215] To a solution of [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-l-[a.-methylene-Sar]- 3-cyclosporin (0.30 g, 0.23 mmol) in methanol (10 ml) were added 4-mercapto-l-butanol (0.14 ml, 1.38 mmol) and lithium hydroxide (0.06 g, 2.31 mmol). The reaction mixture was stirred at room temperature for five hours. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (30 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone from 90/10 to 75/25) to give 14 mg of pure [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- cyclosporin [Molecular Formula: C71H130N12O14S; Exact Mass: 1406.95; MS (m/z): 1407.70 - 101 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 (M+l)+, 1429.89 (M+Na)+; HPLC RT: 15.02 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 11 [8-(2-Hvdroxvethvl)-6,7-dihvdro-MeBmt]-l-r(S)-(4-hvdroxvbutvlthio)methvl-Sar]-3- cyclosporin (4-Ethoxy-4-oxobutyl)triphenylphosphonium bromide CgHnBrO2 Exact Mass: 193.99 MW: 195.06 Ph3P Toluene C18H15P Exact Mass: 262.09 MW: 262.29 ^oA^^,ppn3 n ® C24H2§BrO2P Exact Mass: 456.09 MW: 457.35

[0216] Ethyl 4-bromobutyrate (14.40 ml, 0.10 mol) and triphenylphosphine (26.29 g, 0.10 mol) were added to toluene (200 ml). The mixture was stirred and heated to reflux for twenty four hours. After cooled to room temperature, the mixture was stirred at room temperature for a weekend. The precipitate was filtered off, washed with toluene and hexane and dried in vacuum to give 20.0 g product [Molecular Formula: C24H26O2P*; Exact Mass: 377.17; MS (m/z): 377.20 (M)+], [8-(2-Ethoxy-2-oxoethyl)-3-acetyl-MeBmt]-l-cyclosporin o ©Br © ,PPh3 t-BuONa C24H26B^O2P Exact Mass: 456.09 MW: 457.35 ^24^25^2^ Exact Mass: 376.16 MW: 376.44

[0217] To a dried flask were added (4-ethoxy-4-oxobutyl)triphenylphosphonium bromide (8.88 g, 19.48 mmol) and anhydrous tetrahydrofuran (60 ml) under nitrogen. The reaction mixture was put into an ice-water bath and sodium tert-butoxide (2.18 g, 22.74 mmol) was added. After the mixture was stirred for two hours, a solution of [(3R,4R)-3-aceyloxy-4-methyl-6-oxo-N-MeNle]- 1-cyclosporin (4.00 g, 3.25 mmol) in anhydrous tetrahydrofuran (20 ml) was added. The mixture was stirred another 5 hours at 0°C. Most of tetrahydrofuran was evaporated under reduced - 102 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 pressure. Dichloromethane (100 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 2.82 g of [8-(2- ethoxy-2-oxoethyl)-3-acetyl-MeBmt]-l-cyclosporin [Molecular Formula: CesHngNuOis; Exact Mass: 1329.89; MS (m/z): 1330.51 (M+l)+, 1352.69 (M+Na)+; HPLCRT: 17.72 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Hydroxyethyl)-MeBmt]-l-cyclosporin [0218] [8-(2-Ethoxy-2-oxoethyl)-3-acetyl-MeBmt]-l-cyclosporin (2.82 g, 2.12 mmol) was dissolved in tetrahydrofuran (40 ml). Sodium borohydride (8.02 g, 212.04 mmol) and cesium chloride (3.56 g, 21.20 mmol) were added. The mixture was stirred at room temperature and methanol (40 ml) was added dropwise in two hours. The mixture was stirred for another three hours. Most of solvents were evaporated under reduced pressure. Then ethyl acetate (100 ml) and water (100 ml) were added and the mixture was separated. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 2.70 g of [8-(2-hydroxyethyl)-MeBmt]-lcyclosporin [Molecular Formula: C64H115N11O13; Exact Mass: 1245.87; MS (m/z): 1246.56 (M+l)+, 1413.96 (M+Na)+; HPLC RT: 14.15 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Hydroxyethyl)-6,7-dihydro-MeBmt]-l-cyclosporin - 103 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Exact Mass: 1245.87 MW: 1246.69 MW: 1248.70 [0219] [8-(2-hydroxyethyl)-MeBmt]-l-cyclosporin (2.70 g, 2.17 mmol) was dissolved in methanol (50 ml). Palladium (10 wt% on carbon, 50 mg) and acetic acid (6 drops) were added. The mixture was stirred at room temperature overnight under hydrogen. The mixture was filtered and the filtrate was evaporated under reduced pressure to give 1.50 g of crude [8-(2- hydroxyethyl)-6,7-dihydro-MeBmt]-l-cyclosporin [Molecular Formula: C64H117N11O13; Exact Mass: 1247.88; MS (m/z): 1248.66 (M+l)+, 1270.77 (M+Na)+; HPLC RT: 14.32 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Hydroxyethyl)-6,7-dihydro-MeBmt]-l-[a-methyIene-Sar]-3-cycIosporin [0220] n-Butyllithium (2.65 M, 5.00 ml, 13.23 mmol) was added to a solution of diisopropylamine (1.87 ml, 13.23 mmol) in tetrahydrofuran (40 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for an hour, a solution of [8-(2-hydroxyethyl)-6,7- dihydro-MeBmt]-l-cyclosporin (1.50 g, 1.20 mmol) in tetrahydrofuran (15 ml) was added over ten minutes. The mixture was stirred at -78 °C for two hours. After carbon dioxide gas was bubbled into the reaction mixture for 30 minutes, the mixture was stirred at -78 °C for another hour. Then the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature to let unreacted carbon dioxide come out. The mixture was cooled to -78 °C and chloromethyl chloroformate (1.07 ml, 12.03 mmol) was added. The mixture was stirred and allowed to warm to room temperature overnight. Brine (5 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine - 104 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 0.50 g of pure [8-(2-hydroxyethyl)-6,7-dihydro-MeBmt]-l-[ocmethylene-Sar]-3-cyclosporin [Molecular Formula: C65H117N11O13; Exact Mass: 1259.88; MS (m/z): 1260.61 (M+l)+, 1282.78 (M+Na)+; HPLC RT: 16.09 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Hydroxyethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- cyclosporin

[0221] To a solution of [8-(2-hydroxyethyl)-6,7-dihydro-MeBmt]-l-[a-methylene-Sar]-3- cyclosporin (0.50 g, 0.40 mmol) in methanol (10 ml) were added 4-mercapto-l-butanol (0.25 ml, 2.38 mmol) and lithium hydroxide (0.10 g, 4.00 mmol). The reaction mixture was stirred at room temperature for four hours. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (30 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 80 mg of pure [8-(2-hydroxyethyl)- 6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C69H127N11O14S; Exact Mass: 1365.93; MS (m/z): 1366.64 (M+l)+, 1388.84 (M+Na)+; HPLC RT: 13.94 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 12 [8-(2-(2-Ethoxv-2-oxoethvl)amino)ethvl-6,7-dihydro-MeBmf|-l-KS)-(4- hvdroxvbutvlthio)methyl-Sarl-3-cvclosDorin (12a) and [8-(2-bis(2-ethoxy-2- - 105 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 oxoethvl)ainiiio)ethvl-6.7-dihvdix)-MeBmtl- l-l(S)-(4-hvdroxvbiitvltliio)methvl-Sar|-3- cyclosporin (12b) [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin

[0222] To a solution of [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[amethylene-Sar]-3-cyclosporin (0.25 g, 0.18 mmol) in methanol (15 ml) were added 4-mercapto- 1-butanol (0.12 ml, 1.10 mmol) and lithium hydroxide (0.04 g, 1.84 mmol). The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (30 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone from 90/10 to 75/25) to give 100 mg of pure [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C74H136N12O15S; Exact Mass: 1465.00; MS (m/z): 1465.53 (M+l)+, 1487.84 (M+Na)+; HPLC RT: 16.77 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- cyclosporin [0223] [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutyl thio)methyl -Sar]-3-cyclosporin (0.10 g, 0.07 mmol) was dissolved in dichloromethane (8 ml) and - 106 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 put into ice-water bath. Trifluoroacetic acid (4 ml) was added. The mixture was stirred at 0 °C for two hours. Another dichloromethane (10 ml) was added. The mixture was washed with brine (30 ml), saturated sodium bicarbonate solution (30 ml), dried over magnesium sulfate and evaporated under reduced pressure to give crude [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C69H128N12O13S; Exact Mass: 1364.94; MS (m/z): 1365.75 (M+l)+; HPLC RT: 10.57 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-(2-Ethoxy-2-oxoethyl)amino)ethyl-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyI-Sar|-3-cyclosporin (12a) and [8-(2-bis(2-ethoxy-2- oxoethyl)amino)ethyl-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- cyclosporin (12b) MW: 1538.09

[0224] Crude [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-l -[(S)-(4-hydroxybutylthio)methyl-Sar]- 3-cyclosporin from last step was dissolved in dichloromethane (10 ml). Ethyl bromoacetate (48 mg, 0.34 mmol), and triethylamine (0.50 ml) were added. The mixture was stirred and heated to reflux for three hours. Then dichloromethane (30 ml) and brine (50 ml) were added and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 10 mg of [8-(2-((2-ethoxy-2-oxoethyl)amino)ethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C73H134N12O15S; Exact Mass: 1450.98; MS (m/z): 1451.70 (M+l)+, 1473.87 (M+Na)+; HPLC RT: 12.23 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; - 107 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 detector: 210 nm)] and 30 mg of [8-(2-(bis(2-ethoxy-2-oxoethyl)amino)ethyl)-6,7-dihydroMeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C77H140N12O17S; Exact Mass: 1537.02; MS (m/z): 1337.70 (M+l)+, 1559.90 (M+Na)+; HPLC RT: 14.42 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 13 |8-(2-(Carboxvnietlivl)amiiio)ethvl-6,7-dihvdro-MeBmtl-l -KSM4- hvdroxvbutvlthio)methyl-Sar|-3-cvclosDorin [0225] [8-(2-(2-Ethoxy-2-oxoethyl)amino)ethyl-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutyl thio)methyl-Sar]-3-cyclosporin (10 mg, 6.9 MO"3 mmol) was dissolved in methanol (3 ml). Lithium hydroxide (2 mg, 0.08 mmol) and water (3 ml) were added. The mixture was stirred at room temperature for one hour. Then most of the methanol was evaporated under reduced pressure. Ethyl acetate (10 ml) and brine (10 ml) were added and the PH of the aqueous layer was adjusted to 3 by adding hydrochloric acid solution (1.0 N). After separated, the ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography to give [8-(2-((carboxymethyl)amino)ethyl)-6,7-dihydro-MeBmt]-l- [(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C71H130N12O15S; Exact Mass: 1422.95; MS (m/z): 1423.59 (MH); 1445.84 (M+Na)+; HPLC RT: 10.41 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)] Example 14 |8-(2-Bis(carboxvmetlivl)amino)ethvl-6.7-dihydro-MeBmt|-l-|(S)-(4- hvdroxvbutvlthio)methvl-Sar1-3-cvclosporin - 108 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Exact Mass: 1537.02 Exact Mass: 1480.96 MW: 1538.09 MW: 1481.99 [0226] [8-(2-Bis(2-ethoxy-2-oxoethyl)amino)ethyl-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio) methyl-Sar]-3-cyclosporin (30 mg, 0.02 mmol) was dissolved in methanol (3 ml). Lithium hydroxide (6 mg, 0.23 mmol) and water (3 ml) were added. The mixture was stirred at room temperature for one hour. Then most of the methanol was evaporated under reduced pressure. Ethyl acetate (10 ml) and brine (10 ml) were added and the PH of the aqueous layer was adjusted to 3 by adding hydrochloric acid solution (1.0 N). After separated, the ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography to give [8-(2-(bis(carboxymethyl)amino)ethyl)-6,7-dihydroMeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C73H132N12O17S; Exact Mass: 1480.96; MS (m/z): 1481.70 (M+l)+, 1503.87 (M+Na)+; HPLC RT: 9.88 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)] = Example 15 [8-(2-(4-(Methoxvcarbonvl)benzvl)amino)ethyl-6,7-dihvdro-MeBmt1-l-[(S)-(4- [0227] [8-(2-Aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]- 3-cyclosporin (0.50 g, 0.37 mmol) was dissolved in dichloromethane (50 ml). 4-Methyl 4- formylbenzoate (0.08 g, 0.46 mmol), tétraméthylammonium triacetoxyborohydride (0.12 g, 0.46 mmol) and acetic acid (5 drops) were added. The mixture was stirred at room temperature - 109 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 for one hour. Then dichloromethane (30 ml) and saturated sodium bicarbonate solution (50 ml) were added and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 140 mg of [8-(2-(4- (methoxycarbonyl)benzyl)amino)ethyl-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C78H136N12O15S; Exact Mass: 1513.00; MS (m/z): 1513.77 (M+l) , 1535.80 (M+Na)+; HPLC RT: 13.40 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 16 18-(2-(4-Carboxvbenzvl)amino)ethvl)-6,7-dihvdro-MeBmt]-l-iïS)-(4- hvdroxvbutvlthio)methvl-Sarl-3-cvclosporin Molecular Weight 1514.08 Molecular Weight: 1500.05 [0228] [8-(2-(4-(Methoxycarbonyl)benzyl)amino)ethyl-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxy butylthio)methyl-Sar]-3-cyclosporin (0.14 g, 0.09 mmol) was dissolved in methanol (5 ml). Lithium hydroxide (0.01 g, 0.40 mmol) and water (5 ml) were added. The mixture was stirred at room temperature for two hours. Then most of the methanol was evaporated under reduced pressure. Ethyl acetate (10 ml) and brine (10 ml) were added and the PEI of the aqueous layer was adjusted to 3 by adding hydrochloric acid solution (1.00 N). After separated, the ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography to give [8-(2-(4- carboxybenzyl)amino)ethyl-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- cyclosporin [Molecular Formula: C77H134N12O15S; Exact Mass: 1498.98; MS (m/z): 1499.62 (M+l)+, 1521.77 (M+Na)+; HPLC RT: 11.76 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. - 110 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Example 17 [8-(2-(4-(Dimethvlcarbamovh)benzvhamino)ethyl-6.,7-dihvdro-MeBmt]-l-r(S)-(4- hvdroxvbutyIthio)methyl-Sar]-3-cyclosporin Molecular Weight: 1500.05 Molecular Weight: 1527.12 [0229] [8-(2-(4-Carboxybenzyl)amino)ethyl-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin (0.13 g, 0.09 mmol) was dissolved in dichloromethane (10 ml). Dimethylamine hydrochloride (0.04, 0.45 mmol), HBTU (0.10 g, 0.27 mmol), 1-hydroxybenzotriazole (0.04 g, 0.27 mmol) and triethylamine (0.5 ml) were added. The mixture was stirred at room temperature for two hours. Then dichloromethane (30 ml) and brine (50 ml) were added and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography to give [8-(2-(4-(dimethylcarbamoyl))benzyl)amino)ethyl-6,7-dihydroMeBmt]-1-[(S)-(4-hydroxybutylthio) methyl-Sar]-3-cyclosporin [Molecular Formula: C79H139N13O14S; Exact Mass: 1526.03; MS (m/z): 1526.72 (M+l)+, 1548.84 (M+Na)+; HPLC RT: 11.90 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 18 [8-(2-Bis(4-(methoxvcarbonvhbenzvl)aminoï)ethyl-6.,7-dihvdro-MeBmtl-l-[(SM4- hvdroxvbutvIthio)methvl-Sar]-3-cyclosporin - Ill -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [0230] [8-(2-Aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]- 3-cyclosporin (0.50 g, 0.37 mmol) was dissolved in dichloromethane (50 ml). 4-Methyl 4- formylbenzoate (0.30 g, 1.83 mmol), tétraméthylammonium triacetoxyborohydride (0.48 g, 1.83 mmol) and acetic acid (10 drops) were added. The mixture was stirred at room temperature for one hour. Then dichloromethane (30 ml) and saturated sodium bicarbonate solution (50 ml) were added and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 174 mg of [8-(2-bis(4- (methoxycarbonyl)benzyl)amino))ethyl-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C87H144N12O17S; Exact Mass: 1661.05; MS (m/z): 1661.66 (M+l)+, 1684.06 (M+Na)+; HPLC RT: 15.32 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 19 [8-(2-(Bis(4-carboxvbenzvl)amino)ethyl)-6.,7-dihvdro-MeBmt|-l-[(SM4- hvdroxvbutvlthio)methvl-Sar]-3-cvclosDorin [0231] [8-(2-Bis(4-(methoxycarbonyl)benzyl)amino))ethyl-6,7-dihydro-MeBmt]-l-[(S)- (4-hydroxybutylthio)methyl-Sar]-3-cyclosporin (174 mg, 0.10 mmol) was dissolved in methanol (5 ml). Lithium hydroxide (12 mg, 0.46 mmol) and water (5 ml) were added. The mixture was stirred at room temperature for two hours. Then most of the methanol was evaporated under reduced pressure. Ethyl acetate (10 ml) and brine (10 ml) were added and the PH of the aqueous layer was adjusted to 3 by adding hydrochloric acid solution (1.00 N). After separated, the ethyl acetate layer was dried over magnesium sulfate and evaporated to give 100 mg of [8-(2-(bis(4-carboxybenzyl)amino)ethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C85H140N12O17S; Exact Mass: 1633.02; MS (m/z): 1633.56 (M+1) , 1655.68 (M+Na)+; HPLC RT: 11.64 min. (C8 - 112 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 20 [8-(2-Bis(4-(dimethylcarbamoyl))benzyl)amino)ethyl-6.,7-dihvdro-MeBmt]-l-[(S)-(4- hvdroxvbutvlthio)methyl-Sarl-3-cvclosporin Exact Mass: 1633.02 MW: 1634.18 Exact Mass: 1687.11 MW: 1688.32 [0232] [8-(2-(Bis(4-carboxybenzyl)amino)ethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio) methyl-Sar]-3-cyclosporin (0.10 g, 0.06 mmol) was dissolved in dichloromethane (10 ml). Dimethylamine hydrochloride (0.03, 0.37 mmol), HBTU (0.12 g, 0.31 mmol), 1-hydroxybenzotriazole (0.04 g, 0.31 mmol) and triethylamine (0.5 ml) were added. The mixture was stirred at room temperature for two hours. Then dichloromethane (30 ml) and brine (50 ml) were added and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography to give [8-(2-(Bis(4-(dimethylcarbamoyl))benzyl)amino)ethyl)-6,7-dihydroMeBmt]-l-[(S)-(4-hydroxybutyl thio)methyl-Sar]-3-cyclosporin [Molecular Formula: C89H150N14O15S; Exact Mass: 1687.11; MS (m/z): 1687.73 (M+l)+, 1709.88 (M+Na)+; HPLC RT: 12.44 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 21 [8-(2-(3-Carboxvbenzamido)ethyl)-6.,7-dihvdro-MeBmtl-l-[(Sy-(4- hvdroxvbutvlthio)methyl-Sarl-3-cvclosporin - 113 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 o o CygH^N^O-igS Exact Mass: 1526.98 MW: 1528.06 [0233] [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- cyclosporin (0.19 g, 0.14 mmol) was dissolved in dichloromethane (8 ml). Isophthalic acid (0.07 g, 0.41 mmol), HBTU (0.16 g, 0.41 mmol), 1-hydroxybenzotriazole (0.06 g, 0.41 mmol) and Nethyldiisopropylamine (0.50 ml) were added. The mixture was stirred at room temperature for two hours. Then dichloromethane (50 ml) and brine (50 ml) were added. The PH of the aqueous layer was adjusted to 4 by adding hydrochloric acid solution (1.0 N). After the mixture was separated, the dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure to give crude [8-(2-(3-carboxybenzamido)ethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C77H132N12O16S; Exact Mass: 1512.96; MS (m/z): 1513.66 (M+l)+, 1535.80 (M+Na)+; HPLC RT: 14.15 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)].

[0234] Crude [8-(2-(3-carboxybenzamido)ethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutyl thio)methyl-Sar]-3-cyclosporin was dissolved in acetone (10 ml). lodomethane (0.06 g, 0.41mmol) and potassium carbonate (0.06 g, 0.41 mmol) were added. The mixture was stirred at room temperature for two hours. Then most of solvent was evaporated. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column (hexane/acetone) to give 44 mg of [8-(2-(3-(methoxycarbonyl)benzamido)ethyl)-6,7-dihydroMeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin. [Molecular Formula: C78H134N12O16S; Exact Mass: 1526.98; MS (m/z): 1527.62 (M+l)+, 1549.81 (M+Na)+; HPLC - 114 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 RT: 16.08 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 22 [8-(2-(3-Carboxvbenzamido)ethvl)-6,7-dihydro-MeBmtl-l-[(S)-(4- hvdroxvbutvlthio)methvl-Sar|-3-cvclosDorin Exact Mass: 1526.98 MW: 1528.06 [0235] [8-(2-(3-(Methoxycarbonyl)benzamido)ethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxy butylthio) methyl-Sar]-3-cyclosporin (44 mg, 0.03 mmol) was dissolved in methanol (3 ml). Lithium hydroxide (20 mg, 0.83 mmol) and water (3 ml) were added. The mixture was stirred at room temperature for two hours. Then most of the methanol was evaporated under reduced pressure. Ethyl acetate (10 ml) and brine (10 ml) were added and the PH of the aqueous layer was adjusted to 4 by adding hydrochloric acid solution (1.0 N). After the mixture separated, the ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (C8 reverse phase column) to give 16 mg of [8-(2-(3- carboxybenzamido)ethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- cyclosporin [Molecular Formula: C77H132N12O16S; Exact Mass: 1512.96; MS (m/z): 1513.66 (M+l)+, 1535.80 (M+Na)+; HPLC RT: 14.15 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 23 r8-(2-(4-(Methoxvcarbonvl)benzamido)ethvl)-6.,7-dihvdro-MeBmtl-l-[(SM4- hydroxybutvlthio)methyl-Sarl-3-cvclosDorin - 115 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Exact Mass: 1364.94 MW: 1365.91 O Exact Mass: 1526.98 MW: 1528.06 [0236] [8-(2-Aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]- 3-cyclosporin (0.60 g, 0.44 mmol) was dissolved in dichloromethane (30 ml). Methyl hydrogen terephthalate (0.24 g, 1.32 mmol), HBTU (0.52 g, 1.32 mmol), 1- hydroxybenzotriazole (0.16 g, 1.32 mmol) and N,N-diisopropylethylamine (3.0 ml) were added. The mixture was stirred at room temperature for two hours. Then dichloromethane (100 ml) and brine (100 ml) were added and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography to give 0.34 g of [8-(2-(4-(methoxycarbonyl)benzamido)ethyl)-6,7-dihydroMeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C78H134N12O16S; Exact Mass: 1526.98; MS (m/z): 1527.69 (M+l)+, 1549.95 (M+Na)+; HPLC RT: 16.08 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 24 r8-(2-f4-Carboxvbenzamido)ethvl)-6.,7-dihvdro-MeBmtl-l-r(S)-(4- hvdroxvbutvlthio)methvl-Sarl-3-cvclosDorin Exact Mass: 1526.98 MW: 1528.06 Exact Mass: 1512.96 MW: 1514.03 [0237] [8-(2-(4-(Methoxycarbonyl)benzamido)ethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio) methyl-Sar]-3-cyclosporin (0.34 mg, 0.24 mmol) was dissolved in methanol (5 ml). Lithium hydroxide (20 mg, 0.83 mmol) and water (5 ml) were added. The mixture was stirred at room temperature for two hours. Then most of the methanol was - 116 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 evaporated under reduced pressure. Ethyl acetate (20 ml) and brine (20 ml) were added and the PH of the aqueous layer was adjusted to 3 by adding hydrochloric acid solution (1.00 N). After separated, the ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (Cl8 reverse phase column) to give 0.22 g of [8-(2-(4-carboxybenzamido)ethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C77H132N12O16S; Exact Mass: 1512.96; MS (m/z): 1513.66 (M+l) , 1535.80 (M+Na)+; HPLC RT: 13.98 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. C79H137[ Exact Mass: 1540.01 MW: 1541.10 C77Hl32 Exact Mass: 1512.96 MW: 1514.03 Example 25 [8-(2-(4-(Dimethvlcarbamovl)benzamido)ethyl)-6,7-dihvdro-MeBmt]-l-[(S)-(4- hvdroxvbutvlthio)methyl-Sarl-3-cvclosporin [0238] [8-(2-(4-Carboxybenzamido)ethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin (0.22 g, 0.15 mmol) was dissolvedin dichloromethane (5 ml). Dimethylamine hydrochloride (0.04, 0.49 mmol), HBTU (0.17 g, 0.45 mmol), 1-hydroxybenzotriazole (0.06 g, 0.45 mmol) and pyridine (0.5 ml) were added. The mixture was stirred at room temperature overnight. Then dichloromethane was evaporated under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography to give [8-(2-(4-(dimethylcarbamoyl) benzamido)ethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C79H137N13O15S; Exact Mass: 1540.01; MS (m/z): 1540.89 (M+l)+, 1563.06 (M+Na)+; HPLC RT: 14.54 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. - 117 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Example 26 |8-(2-(2-Hydroxyacetamidolethvl)-6,7-dihvdro-MeBm11-1-|(S)-(4- hvdroxvbutylthio)methyl-Sar]-3-cvclosporin MW: 1365.91 MW: 1423.95 [0239] [8-(2-Aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]- 3-cyclosporin (0.26 g, 0.19 mmol) was dissolved in dichloromethane (20 ml). Glycolic acid (0.04 g, 0.53 mmol), HBTU (0.22 g, 0.58 mmol), 1-hydroxybenzotriazole (0.08 g, 0.58 mmol) and pyridine (1.00 ml) were added. The mixture was stirred at room temperature for two hours. Then dichloromethane (30 ml) and brine (50 ml) were added and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give pure [8-(2-(2-hydroxyacetamido)ethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C71H130N12O15S; Exact Mass: 1422.95; MS (m/z): 1423.80 (M+l)+, 1445.95 (M+Na)+; HPLC RT: 12.73 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 27 |8-(2-Acetamidoethvl)-6,7-dihvdro-MeBmt|-1-|(RM4-acetoxvbutoxv)methvl-Sar|-3- cyclosporin (26a) - 118 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [0240] [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(R)-hydroxymethyl-Sar]-3- cyclosporin (0.14 g, 0.11 mmol) was dissolved in benzene (10 ml). 4-Bromobutyl acetate (0.21 g, 1.06 mmol), tetra-n-butylammonium bromide (0.34 g, 1.06 mmol), tétraméthylammonium hydroxide pentahydrate (0.19 g, 1.06 mmol) and sodium hydroxide solution (2.0 ml, 45%) were added. The mixture was stirred at 50 °C overnight. Then ethyl acetate (50 ml) and brine (50 ml) were added and separated. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 50 mg of pure [8-(2-acetamidoethyl)- 6,7-dihydro-MeBmt]-l-[(R)-(4-acetoxybutoxy)methyl-Sar]-3-cyclosporin [Molecular Formula: C73H132N12O16; Exact Mass: 1432.99; MS (m/z): 1433.73 (M+l)+, 1455.99 (M+Na)+; HPLC RT: 17.43 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 28 [8-(2-Acetamidoethvl)-6,7-dihvdro-MeBmt]-l-[(R)-(4-hvdroxvbutoxv)methyl-Sar]-3- cvclosporin MW: 1433.93 Exact Mass: 1390.98 MW: 1391.89 [0241] [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(4-acetoxybutoxy)methyl-Sar]- 3-cyclosporin (50 mg, 0.03 mmol) was dissolved in methanol (5 ml). Lithium hydroxide (20 mg, 0.83 mmol) and water (5 ml) were added. The mixture was stirred at room temperature for two hours. Then most of the methanol was evaporated under reduced pressure. Ethyl acetate (20 ml) and brine (30 ml) were added and the PH of the aqueous layer was adjusted to 3 by adding hydrochloric acid solution (1.00 N). After separated, the ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by Cl8 reverse phase chromatography to give 15 mg of [8-(2-acetamidoethyl)-6,7-dihydroMeBmt]-l-[(R)-(4-hydroxybutoxy)methyl-Sar]-3-cyclosporin [Molecular Formula: C7iHi3oNi20i5; Exact Mass: 1390.98; MS (m/z): 1391.80 (M+lf, 1413.98 (M+Na)+; HPLC - 119 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 RT: 15.50 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 29 [8-(3-AcetamidoDroDvl)-6.,7-dihvdro-MeBmt]-l-[(S)-(3-(N-morpholino)DroDvlthio)methvlSar]-3-cvclosDorin (4-Cyanobutyl)triphenylphosphonium bromide NC Br C6H8BrN Exact Mass: 160.98 MW: 162.03 Ph3P Toluene c18h15p Exact Mass: 262.09 MW: 262.29 0Br © PPh3 C23H23BrNP Exact Mass: 423.08 MW: 424.32 [0242] 5-Bromovaleronitrile (1.62 g, 10.00 mmol) and triphenylphosphine (2.62 g, 10.00 mmol) were added to toluene (20 ml). The mixture was stirred and heated to reflux overnight. After cooled to room temperature, the precipitate was filtered off, washed with toluene and hexane and dried in vacuum to give 3.00 g product. [Molecular Formula: CisHzsBrNP; Exact Mass: 423.08; MS (m/z): 344.28 (M-Br)+], [8-(2-Cyanoethyl)-3-acetyl-MeBmt]-l-cyclosporin ©Br © NaHMDS Nc^^^pph3 ' C23H23BrNP Exact Mass: 423.08 MW: 424.32 NC^^X^PPh3 C23H22NP Exact Mass: 343.15 MW: 343.41 O Exact Mass: 1231.82 MW: 1232.62

[0243] To a solution of (4-cyanobutyl)triphenylphosphonium bromide (6.40 g, 15.08 mmol) in anhydrous tetrahydrofuran (180 ml) under nitrogen was added sodium bis(trimethylsilyl)amide (2.0 M in THF, 11.2 ml, 22.40 mmol). The reaction mixture was stirred at room temperature for one hour and cooled to -30 °C. A solution of [(3R, 4R)-3-acetyloxy-4-methyl-6-oxo-N-MeNle]- l-cyclosporin(8.20 g, 6.65 mmol) in anhydrous tetrahydrofuran (25 ml) was added. The mixture was stirred another two hours at -30 °C. Then saturated ammonium chloride solution (20 ml) was added to quench the reaction. Most of tetrahydrofuran was evaporated under reduced pressure. - 120 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Ethyl acetate (250 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 5.60 g of pure [8-(2-cyanoethyl)- 3-acetyl-MeBmt]-l-cyclosporin [Molecular Formula: C67H116N12O13; Exact Mass: 1296.88; MS (m/z): 1297.57 (M+l)+], [8-(2-Cyanoethyl)-MeBmt]-l-cyclosporin MW: 1297.74 Exact Mass: 1254.87 MW: 1255.70 [0244] [8-(2-Cyanoethyl)-3-acetyl-MeBmt]-l-cyclosporin (5.00 g, 3.86 mmol) was dissolved methanol (100 ml). Water (50 ml) and tétraméthylammonium hydroxide pentahydrate (4.40 g, 24.22 mmol) were added. The mixture was stirred at room temperature overnight. Then most of the methanol was evaporated. Ethyl acetate (250 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 3.60 g of pure [8-(2-cyanoethyl)-MeBmt]-l-cyclosporin [Molecular Formula: C65H114N12O12; Exact Mass: 1254.87; MS (m/z): 1255.51 (M+l)+; HPLC RT: 14.90 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(3-Aminopropyl)-6,7-dihydro-MeBmt]-l-cyclosporin Exact Mass: 1254.87 MW: 1255.70 Exact Mass: 1260.91 MW: 1261.75

[0245] To a solution of [8-(2-cyanoethyl)-MeBmt]-l-cyclosporin (2.40 g, 1.91 mmol) in methanol (120 ml) under nitrogen was added nickel(II) chloride hexahydrate (0.38 g, 1.62 mmol). Sodium borohydride (2.00 g, 52.63 mmol) was added in four batches in 30 minutes. - 121 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 After the mixture was stirred for another hour, most of the methanol was evaporated under reduced pressure. Ethyl acetate (100 ml) and saturated sodium bicarbonate solution (50 ml) were added and the mixture was separated. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in methanol (30 ml). Palladium (10 wt% on carbon, 150 mg) and acetic acid (5 drops) were added. The mixture was stirred at room temperature under hydrogen for four hours. The mixture was filtered and the filtrate was evaporated under reduced pressure to give crude [8-(3- aminopropyl)-6,7-dihydro-MeBmt]-l-cyclosporin [Molecular Formula: C65H120N12O12; Exact Mass: 1260.90; MS (m/z): 1261.69 (M+l)+; HPLC RT: 11.23 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(3-Acetamidopropyl)-6,7-dihydro-MeBmt]-l-cyclosporin MW 1261.75 MW: 1303.78

[0246] To a solution of [8-(3-aminopropyl)-6,7-dihydro-MeBmt]-l-cyclosporin (2.40 g, 1.90 mmol) and acetic acid (240 mg, 60 mmol) in dichloromethane (100 ml) were added diisopropylethyl amine (386 mg, 1.99 mmol) and HATU (1.20 g, 3.15 mmol). After stirred at room temperature for two hours, the reaction mixture was washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 2.00 g of pure [8-(3-acetamidopropyl)-6,7-dihydro-MeBmt]-l-cyclosporin [Molecular Formula: C67H122N12O13; Exact Mass: 1302.93; MS (m/z): 1303.63(M+l)+. HPLC RT: 13.74 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. - 122 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [8-(3-Acetamidopropyl)-6,7-dihydro-MeBmt]-l-[a-methylene-Sar]-3-cyclosporiii Exact Mass: 1302.93 Exact Mass: 1314.93 MW: 1303.78 MW: 1315.80 [0247] n-Butyllithium (2.65 M, 12 ml, 31.80 mmol) was added to a solution of diisopropylamine (3.23 g, 32 mmol)in tetrahydrofuran (100 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for one hour, a solution of [8-(3-acetamidopropyl)-6,7-dihydro-MeBmt]-l-cyclosporin (3.80 g, 2.92 mmol) in tetrahydrofuran (15 ml) was added over ten minutes. The mixture was stirred at -78 °C for three hours. After carbon dioxide gas was bubbled into the reaction mixture for 30 minutes, the mixture was stirred at -78 °C for another hour. Then the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature to let unreacted carbon dioxide come out. The mixture was cooled to -78 °C and chloromethyl chloroformate (3.70 ml) was added. The mixture was stirred and allowed to warm to room temperature overnight. Brine (20 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 1.20 g of pure [8- (3-acetamidopropyl)-6,7-dihydro-MeBmt]-l-[a-methylene-Sar]-3-cyclosporin [Molecular Formula: C68H122N12O13; Exact Mass: 1314.93; MS (m/z): 1315.61 (M+l)+; HPLC RT: 16.44 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(3-Acetamidopropyl)-6,7-dihydro-MeBmt]-l-[(S)-(3-(N-morpholino)propylthio)methylSar]-3-cyclosporin - 123 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Exact Mass: 1314.93 Exact Mass: 1476.01 MW: 1315.80 MW: 1477.06

[0248] To a solution of [8-(3-acetamidopropyl)-6,7-dihydro-MeBmt]-l-[(S)-(a-methylene-Sar]- 3-cyclosporin (0.50 g, 0.38 mmol) in methanol (60 ml) were added 3-morpholinopropanethiol (0.48 g, 3.00 mmol) and lithium hydroxide (92 mg, 3.83 mmol). The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (80 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 130 mg of pure [8-(3- acetamidopropyl)-6,7-dihydro-MeBmt]-l-[(S)-(3-(N-morpholino)propylthio)methyl-Sar]-3- cyclosporin [Molecular Formula: C75H137N13O14S; Exact Mass: 1476.01; MS (m/z): 1476.82 (M+l)+; HPLC RT: 12.61 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 30 |8-(3-Acetaiiiidopror)vl)-6.7-(lihvdro-MeBmtl- l-l(S)-(4-hvdroxvbutvlthio)iiiethvl-Sar|-3- cyclosporin

[0249] To a solution of [8-(3-acetamidopropyl)-6,7-dihydro-MeBmt]-l-[(S)-(a.-methyleneSar]-3-cyclosporin (0.50 g, 0.38 mmol) in methanol (60 ml) were added 4-mercapto-l-butanol (0.28 g, 2.64 mmol) and lithium hydroxide (92 mg, 3.83 mmol). The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (80 ml) and brine (30 ml) were added and the mixture was separated. - 124 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 115 mg of pure [8-(3-acetamidopropyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- cyclosporin [Molecular Formula: C72H132N12O14S; Exact Mass: 1420.97; MS (m/z): 1421.80 (M+l)+; HPLC RT: 15.49 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 31 [8-(3-(4-Carboxybenzamido)DroDvl)-6.,7-dihvdro-MeBmtl-l-iïS)-(4- hvdroxvbutvIthio)methvl-Sar]-3-cyclosporin [8-(3-(4-Methoxycarbonylbenzamido)propyl)-6,7-dihydro-MeBmt]-l-cyclosporin

[0250] To a solution of [8-(3-aminopropyl)-6,7-dihydro-MeBmt]-l-cyclosporin (4.00 g, 3.17 mmol) and methyl hydrogen terephthalate (0.85 g, 4.72 mmol) in dichloromethane (100 ml) were added diisopropylethyl amine (770 mg, 5.96 mmol) and HATU (2.40 g, 6.30 mmol). The reaction mixture was stirred at room temperature for two hours and then washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 2.00 g of pure [8-(3-(4- methoxycarbonylbenzamido)propyl)-6,7-dihydro-MeBmt]-1-cyclosporin [Molecular Formula: C74H126N12O15; Exact Mass: 1422.95; MS (m/z): 1423.70(M+l) . HPLC RT: 16.74 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(3-(4-Carboxybenzamido)propyl)-6,7-dihydro-MeBmt]-l-cyclosporin - 125 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811

[0251] To a solution of [8-(3-(4-methoxycarbonylbenzamido)propyl)-6,7-dihydroMeBmt]-l-cyclosporin (2.40 g, 1.68 mmol) in methanol (80 ml) and water (20 ml) was added lithium hydroxide (0.28 g, 11.66 mmol). The reaction mixture was stirred at room temperature for two hours and evaporated under reduced pressure. Ethyl acetate (10 ml) and brine (10 ml) were added and the PH of the aqueous layer was adjusted to 5 by adding hydrochloric acid solution (1.00 N). After separated, the ethyl acetate layer was dried over magnesium sulfate and evaporated to give 2.3 g of [8-(3-(4-carboxybenzamido)propyl)-6,7-dihydro-MeBmt]-lcyclosporin. [Molecular Formula: C73H124N12O15; Exact Mass: 1408.93; MS (m/z): 1409.70(M+l)+. HPLC RT: 14.93 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(3-(4-Carboxybenzamido)propyl)-6,7-dihydro-MeBmt]-l-[cx-methylene-Sar]-3- cyclosporin [0252] n-Butyllithium (2.65 M, 7.6 ml, 20.14 mmol) was added to a solution of diisopropylamine (2.02 g, 20.00 mmol) in tetrahydrofuran (120 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for one hour, a solution of [8-(3-(4- carboxybenzamido)propyl)-6,7-dihydro-MeBmt]-l-cyclosporin (2.10 g, 1.49 mmol) in tetrahydrofuran (15 ml) was added over ten minutes. The mixture was stirred at -78 °C for three hours. After carbon dioxide gas was bubbled into the reaction mixture for 30 minutes, - 126 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 the mixture was stirred at -78 °C for another hour. Then the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature to let unreacted carbon dioxide come out. The mixture was cooled to -78 °C and chloromethyl chloroformate (2.20 ml) was added. The mixture was stirred and allowed to warm to room temperature overnight. Brine (20 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography to give 1.20 g of pure [8-(3-(4- carboxybenzamido)propyl)-6,7-dihydro-MeBmt]-l-[a-methylene-Sar]-3-cyclosporin [Molecular Formula: C74H124N12O15; Exact Mass: 1420.93; MS (m/z): 1421.61 (M+l)+; HPLC RT: 16.56 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(3-(4-Carboxybenzamido)propyI)-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporiii

[0253] To a solution of [8-(3-(4-carboxybenzamido)propyl)-6,7-dihydro-MeBmt]-l-[amethylene-Sar]-3-cyclosporin (0.50 g, 0.35 mmol) in methanol (30 ml) were added 4- mercapto-1-butanol (0.28 g, 2.64 mmol) and lithium hydroxide (92 mg, 3.83 mmol). The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (80 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 115 mg of pure [8-(3-(4-carboxybenzamido)propyl)-6,7- dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio) methyl-Sar]-3-cyclosporin [Molecular Formula: C78H134N12O16S; Exact Mass: 1526.98; MS (m/z): 1527.84 (M+l)+; HPLC RT: 14.80 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. - 127 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Example 32 |8-(3-(4-(Diethylcarbamovlbcnzamido)DroDvü-6.,7-dihvdro-MeBmtl-l-l(SM4- hvdroxvbutyIthio)methyl-Sar]-3-cyclosporin Exact Mass: 1526.98 Exact Mass: 1582.05 MW: 1528.06 MW: 1583.18

[0254] To a solution of [8-(3-(4-carboxybenzamido)propyl)-6,7-dihydro-MeBmt]-l-[(S)- (4-hydroxybutylthio)methyl-Sar]-3-cyclosporin (0.10 g, 0.07 mmol) and diethylamine (15 mg, 0.21 mmol) in dichloromethane (10 ml) were added diisopropylethyl amine (25 mg, 0.19 mmol), HOBT (29 mg, 0.19 mmol) and HBTU (73 mg, 0.19 mmol). After stirred at room temperature for two hours, the reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 42 mg of pure [8-(3-(4-diethylcarbamoybenzamido)propyl)-6,7-dihydro-MeBmt]-l—[(S)-(4- hydroxybutylthio) methyl-Sar]-3-cyclosporin [Molecular Formula: C82H143N13O15S; Exact Mass: 1582.05; MS (m/z): 1582.70(M+l)+. HPLC RT: 16.08 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 33 [8-(3-(3-MethoxvcarbonyIbenzamido)proDvl)-6.,7-dihvdro-MeBmtl-l-[(S)-(4- hvdroxvbutylthio)methyl-Sarl-3-cyclosporin [8-(3-(3-Methoxycarbonylbenzamido)propyl)-6,7-dihydro-MeBmt]-l-cyclosporin - 128 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811

[0255] To a solution of [8-(3-aminopropyl)-6,7-dihydro-MeBmt]-l-cyclosporin (4.33 g, 3.43 mmol) and methyl hydrogen isophthalate (0.92 g, 5.11 mmol) in dichloromethane (100 ml) were added diisopropylethyl amine (770 mg, 5.96 mmol) and HATU (2.40 g, 6.30 mmol). The reaction mixture was stirred at room temperature for two hours and then washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 2.00 g of pure [8-(3-(3- methoxycarbonylbenzamido)propyl)-6,7-dihydro-MeBmt]-1-cyclosporin [Molecular Formula: C74H126N12O15; Exact Mass: 1422.95; MS (m/z): 1423.70(M+l)+. HPLC RT: 16.82 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(3-(3-Carboxybenzamido)propyl)-6,7-dihydro-MeBmt]-l-cyclosporin

[0256] To a solution of [8-(3-(3-methoxycarbonylbenzamido)propyl)-6,7-dihydroMeBmt]-l-cyclosporin (2.50 g, 1.76 mmol) in methanol (80 ml) were added water (20 ml) and lithium hydroxide (0.28 g, 11.66 mmol). The reaction mixture was stirred at room temperature for two hours and evaporated under reduced pressure. Ethyl acetate (10 ml) and brine (10 ml) were added and the PH of the aqueous layer was adjusted to 5 by adding hydrochloric acid solution (1.00 N). After separated, the ethyl acetate layer was dried over magnesium sulfate and evaporated to give 2.1 g of [8-(3-(3-carboxybenzamido)propyl)-6,7-dihydro-MeBmt]-lcyclosporin. [Molecular Formula: C73H124N12015; Exact Mass: 1408.93; MS (m/z): - 129 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 1409.70(M+l)+. HPLC RT: 15.11 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(3-(3-Methoxycarbonylbenzamido)propyl)-6,7-dihydro-MeBmt]-l-[a-methylene-Sar]-3- cyclosporin [0257] n-Butyllithium (2.65 M, 7.9 ml, 20.94 mmol) was added to a solution of diisopropylamine (2.12 g, 21.00 mmol) in tetrahydrofuran (120 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for one hour, a solution of [8-(3-(3- carboxybenzamido)propyl)-6,7-dihydro-MeBmt]-l-cyclosporin (2.10 g, 1.49 mmol) in tetrahydrofuran (15 ml) was added over ten minutes. The mixture was stirred at -78 °C for three hours. After carbon dioxide gas was bubbled into the reaction mixture for 30 minutes, the mixture was stirred at -78 °C for another hour. Then the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature to let unreacted carbon dioxide come out. The mixture was cooled to -78 °C and chloromethyl chloroformate (2.20 ml) was added. The mixture was stirred and allowed to warm to room temperature overnight. Methanol (20 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 1.20 g of pure [8-(3-(3-methoxycarbonylbenzamido)propyl)-6,7-dihydro-MeBmt]-l-[a-methylene-Sar]-3- cyclosporin [Molecular Formula: C75H126N12O15; Exact Mass: 1434.95; MS (m/z): 1435.61 (M+l)+; HPLC RT: 18.26 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(3-(3-MethoxycarbonyIbenzamido)propyl)-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin - 130 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 MW: 1435.90 MW: 1542.09

[0258] To a solution of [8-(3-(3-methoxycarbonylbenzamido)propyl)-6,7-dihydroMeBmt]-l-[a-methylene-Sar]-3-cyclosporin (0.62 g, 0.43 mmol) in methanol (30 ml) were added 4-mercapto-l-butanol (0.28 g, 2.64 mmol) and lithium hydroxide (103 mg, 4.29 mmol). The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (80 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 115 mg of pure [8-(3-(3- methoxycarbonylbenzamido)propyl)-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C79H136N12O16S; Exact Mass: 1540.99; MS (m/z): 1541.84 (M+l)+; HPLC RT: 16.83 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 34 [8-(3-(3-Carboxvlbenzamido)propvl)-6.,7-dihvdro-MeBmt|-1-1(S)-(4- hvdroxvbutvlthio)methyl-Sar|-3-cvclosDorin Exact Mass: 1540.99 MW: 1542.09 MW: 1528.06

[0259] To a solution of [8-(3-(3-methoxycarbonylbenzamido)propyl)-6,7-dihydroMeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin (0.20 g, 0.13 mmol) in methanol (8 ml) were added water (3 ml) and lithium hydroxide (15 mg, 0.63 mmol). The - 131 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 reaction mixture was stirred at room temperature for eight hours and evaporated under reduced pressure. Ethyl acetate (10 ml) and brine (10 ml) were added and the PH of the aqueous layer was adjusted to 5 by adding hydrochloric acid solution (1.00 N). After separated, the ethyl acetate layer was dried over magnesium sulfate and evaporated to give [8-(3-(3- carboxylbenzamido)propyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- cyclosporin [Molecular Formula: C78H134N12O16S; Exact Mass: 1526.98; MS (m/z): 1527.84 (M+l)+; HPLC RT: 14.99 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 35 [8-14-Acetamidobutyl)-6.,7-dihvdro-MeBmt1-l-KS)-(4-hvdroxvbutvlthio)methvl-Sar1-3- cyclosporin (5-Cyanopentyl)triphenylphosphonium bromide NC^-x^^Br + Ph3P Toluene ©Br © NC PPh3 CgH10BrN C18H15P Exact Mass: 175.00 Exact Mass: 262.09 MW: 176.06 MW: 262.29 C24H26BrNP+ Exact Mass: 437.09 MW: 438.35 [0260] 6-Bromohexanenitrile (10.00 g, 56.80 mmol) and triphenylphosphine (14.90 g, 56.80 mmol) were dissolved in toluene (100 ml). The mixture was stirred and heated to reflux for three days. After cooled to room temperature, most of toluene was decanted. The residue was dried in vacuum for six hours. Then hexane (160 ml) was added and the mixture was stirred for a weekend at room temperature. The precipitate was filtered off and dried in vacuum to give 21.0 g product. [Molecular Formula: C24H25NP; Exact Mass: 358.17; MS (m/z): 358.20 (M)+], [8-(3-Cyanopropyl)-3-acetyl-MeBmt]-l-cyclosporin NC. ©Br © ,PPh3 t-BuONa C24H25BrNP+ Exact Mass: 437.09 MW: 438.35 c24h24np Exact Mass: 357.16 MW: 357.44 - 132 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Exact Mass: 1231.82 Exact Mass: 1310.89 MW: 1232.62 MW: 1311.76

[0261] To a dried flask were added (5-cyanopentyl)triphenylphosphonium bromide (14.00 g, 32.04 mmol) and anhydrous tetrahydrofuran (50 ml) under nitrogen. The reaction mixture was put into an ice-water bath and sodium tert-butoxide (4.30 g, 44.84 mmol) was added. After the mixture was stirred for three hours, a solution of [(3R,4R)-3-acetyloxy-4-methyl-6-oxo-N-MeNle]-lcyclosporin (7.90 g, 6.40 mmol) in anhydrous tetrahydrofuran (20 ml) was added. The mixture was stirred another three hours at 0°C. Then saturated ammonium chloride solution (20 ml) was added to quench the reaction. Most of tetrahydrofuran was evaporated under reduced pressure. Ethyl acetate (100 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 7.19 g of [8-(3-cyanopropyl)-3- acetyl-MeBmt]-l-cyclosporin [Molecular Formula: CôsHi18N12O13; Exact Mass: 1310.89; MS (m/z): 1311.58 (M+l)+, 1333.74 (M+Na)+; HPLC RT: 17.19 min.(C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(3-Cyanopropyl)-MeBmt]-l-cyclosporin Exact Mass: 1310.89 MW: 1311.76 [0262] [8-(3-Cyanopropyl)-3-acetyl-MeBmt]-l-cyclosporin (7.19 g, 5.48 mmol) was dissolved methanol (40 ml). Water (20 ml) and tétraméthylammonium hydroxide pentahydrate (2.98 g, 16.45 mmol) were added. The mixture was stirred at room temperature for two hours. Then most of the methanol was evaporated. Ethyl acetate (100 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under - 133 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 4.50 g of pure [8-(3-cyanopropyl)-MeBmt]-l-cyclosporin [Molecular Formula: C66H116N12O12; Exact Mass: 1268.88; MS (m/z): 1269.62 (M+l)+, 1291.76 (M+Na)+; HPLC RT: 15.78 min.(C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(4-Aminobutyl)-6, 7-dihydro-MeBmt]-l-cyclosporin Exact Mass: 1274.93 MW: 1275.77

[0263] To a solution of [8-(3-cyanopropyl)-MeBmt]-l-cyclosporin (4.50 g, 3.63 mmol) in methanol (60 ml) under nitrogen was added nickel (II) chloride hexahydrate (0.43 g, 1.81 mmol). The reaction mixture was put into ice-water bath. Sodium borohydride (7.04 g, 181.33 mmol) was added in four batches in two hours. After the mixture was stirred for another two hours at 0°C, water (10 ml) was added. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (120 ml) and saturated sodium bicarbonate solution (120 ml) were added and the mixture was separated. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in methanol (60 ml). Palladium (10 wt% on carbon, 50 mg) and acetic acid (6 drops) were added. The mixture was stirred at room temperature under hydrogen overnight. The mixture was filtered and the filtrate was evaporated under reduced pressure to give crude 4.63 g of 8-(4-aminobutyl)-6,7-dihydroMeBmt]-l-cyclosporin [Molecular Formula: C66H122N12O12; Exact Mass: 1274.93; MS (m/z): 1275.71 (M+l)+; HPLC RT: 11.95 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. - 134 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [8-(4-(tert-Butoxycarbonyl)aminobutyl)-6,7-dihydro-MeBmt]-l-cyclosporin MW: 1275.77 Exact Mass: 1374.98 MW: 1375.89 [0264] [8-(4-Aminobutyl)-6,7-dihydro-MeBmt]-l-cyclosporin (4.63 g, 3.63 mmol) was dissolved in tetrahydrofuran (50 ml). Saturated sodium bicarbonate solution (25 ml) and di-tertbutyldicarbonate were (0.87 g, 3.99 mmol) were added. The mixture was stirred at room temperature for two hours. Most of tetrahydrofuran was evaporated under reduced pressure. Ethyl acetate (30 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 3.00 g of pure [8-(4-(tertbutoxycarbonyl)aminobutyl)-6,7-dihydro-MeBmt]-1-cyclosporin [Molecular Formula: C71H130N12O14; Exact Mass: 1374.98; MS (m/z): 1375.64 (M+l)+, 1397.85 (M+Na)+; HPLC RT: 17.81 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(4-(tert-Butoxycarbonyl)aminobutyl)-6,7-dihydro-MeBmt]-l-[a-methylene-Sar]-3- cyclosporin Exact Mass: 1386.98 MW: 1387.90 [0265] n-Butyllithium (2.65 M, 8.23 ml, 21.82 mmol) was added to a solution of diisopropylamine (3.09 ml, 21.82 mmol) in tetrahydrofuran (60 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for an hour, a solution of[8-(4-(tert-butoxycarbonyl)aminobutyl)-6,7-dihydroMeBmt]-l-cyclosporin (3.00 g, 2.18 mmol) in tetrahydrofuran (20 ml) was added over ten minutes. The mixture was stirred at -78 °C for two hours. After carbon dioxide gas was bubbled into the reaction mixture for 30 minutes, the mixture was stirred at -78 °C for another hour. Then - 135 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature to let unreacted carbon dioxide come out. The mixture was cooled to -78 °C and chloromethyl chloroformate (1.93 ml, 21.82 mmol) was added. The mixture was stirred and allowed to warm to room temperature overnight. Brine (10 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 0.40 g of pure [8-(4-(tert-butoxycarbonyl)aminobutyl)-6,7-dihydroMeBmt]-l-[a-methylene-Sar]-3-cyclosporin [Molecular Formula: C72H130N12O14; Exact Mass: 1386.98; MS (m/z): 1387.61 (M+l)+, 1409.80 (M+Na)+; HPLC RT: 19.01 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(4-(tert-Butoxycarbonyl)aminobutyl)-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin

[0266] To a solution of [8-(4-(tert-butoxycarbonyl)aminobutyl)-6,7-dihydro-MeBmt]-l- [a-methylene-Sar]-3-cyclosporin (0.40 g, 0.29 mmol) in methanol (15 ml) were added 4- mercapto-1-butanol (0.18 ml, 1.73 mmol) and lithium hydroxide (0.07 g, 2.88 mmol). The reaction mixture was stirred at room temperature for seven hours. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone from 90/10 to 75/25) to give 200 mg of pure [8-(4-(tertbutoxycarbonyl)aminobutyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- cyclosporin [Molecular Formula: C76H140N12O15S; Exact Mass: 1493.03; MS (m/z): 1493.63 (M+l)+, 1515.88 (M+Na)+; HPLC RT: 17.65 min.(C8 reverse phase column: 250 mm; - 136 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(4-Acetamidobutyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- cyclosporin C73H134N12°14S Exact Mass: 1434.99 MW: 1436.01 [0267] [8-(4-(tert-Butoxycarbonyl)aminobutyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutyl thio)methyl-Sar]-3-cyclosporin (0.20 g, 0.16 mmol) was dissolved in dichloromethane (15 ml) and put into ice-water bath. Trifluoroacetic acid (5 ml) was added. The mixture was stirred at 0 °C for one hour. Another dichloromethane (20 ml) was added. The mixture was washed with brine (30 ml), saturated sodium bicarbonate solution (30 ml) and dried over magnesium sulfate and evaporated under reduced pressure to give crude [8-(4-aminobutyl)-6,7-dihydro-MeBmt]-l-[(S)- (4-hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C71H32N12O13S; Exact Mass: 1392.98; MS (m/z): 1393.80 (M+l)+; HPLC RT: 11.38 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. The crude [8-(4-aminobutyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutyl thio)methyl-Sar]-3-cyclosporin was dissolved in dichloromethane (15 ml). Acetic acid (48 mg, 0.80 mmol), HBTU (0.18 g, 0.48 mmol), 1-hydroxybenzotriazole (0.06 g, 0.48 mmol) and pyridine 0.50 ml) were added. The mixture was stirred at room temperature for two hours. Then dichloromethane (30 ml) and brine (50 ml) were added and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 27 mg of [8-(4-acetamidobutyl)- 6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin [Molecular Formula: C73H134N12O14S; Exact Mass: 1434.99; MS (m/z): 1435.69 (M+l)+, 1457.87 (M+Na)+; - 137 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 HPLC RT: 16.01 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Example 36 [8-(2-Acetamidoethyl)-6, 7-dihvdro-MeBmt]-l-r(S)-(4-hvdroxybutylthio)methyl-Sar|-3- IÏY-hvdroxy)-N-MeLeul-4-cvclosporin [3-Chloroacetyl-MeBmt]-l-[(Y-hydroxy)-N-MeLeu]-4-cyclosporin Exact Mass: 1217.84 Exact Mass: 1294.82 MW: 1218.63 MW: 1296.12

[0268] To a solution of [(y-hydroxy)-N-MeLeu]-4-cyclosporin (12.17 g, 1.00 mmol) in N,Ndimethylformamide (300 ml) were added N,N-dimethylaminopyridine (0.12 g, 0.10 mmol), anhydrous pyridine (16.00 g, 0.20 mol) and chloroacetic anhydride (72.05 g, 0.54 mol) at -35 °C. The reaction mixture was stirred at room temperature overnight. The mixture was poured into 800 ml ice-water and stirred until the ice was melted. Ethyl acetate (500 ml) was added and the mixture was separated. The ethyl acetate layer was washed with water (100 ml), saturated sodium bicarbonate solution (100 ml), brine (100 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 9.40 g of pure [3-chloroacetyl-MeBmt]-l-[(Y-hydroxy)-N-MeLeu]-4-cyclosporin [Molecular Formula: CmHibCINuOm; Exact Mass: 1294.82; MS (m/z): 1295.50 (MH)]. [0269] [(Y-Hydroxy)-N-MeLeu]-4-cyclosporin was prepared by Sebekia benihana biotransformation according to a method described by Kuhnt M. et al., 1996, Microbial Biotransformation Products of Cyclosporin A, J. Antibiotics, 49 (8), 781. - 138 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [(3R, 4R)-3-Chloroacetyloxy-4-methyl-6-oxo-N-MeNle]-l-[(Y-hydroxy)-N-MeLeu]-4- cyclosporin Exact Mass: 1294.82 Exact Mass: 1282.78 Molecular Weight: 1296.12 Molecular Weight: 1284.07

[0270] To a solution of [3-chloroacetyl-MeBmt]-l-[(y-hydroxy)-N-MeLeu]-4-cyclosporin (9.50 g, 7.34 mmol) in dioxane (125 ml) were added water (100 ml), osmium(VIII) oxide solution (0.4% in water, 35 ml) and sodium metaperiodate (6.60 g, 30.90 mmol). The reaction mixture was stirred at room temperature for five hours. Ethyl acetate (100 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 5.00 g of pure [(3R,4R)-3-chloroacetyloxy-4-methyl-6-oxo-N-MeNle]-l-[(Y-hydroxy)-N-MeLeu]-4- cyclosporin [Molecular Formula: C62H109CIN11O15; Exact Mass: 1282.78; MS (m/z): 1283.47 (M+l)+; HPLC RT: 14.74 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [3-Chloroacetyl-8-cyanomethyl-MeBmt]-l-[(Y-hydroxy)-N-MeLeu]-4-cyclosporin MW: 1284.07 MW: 1335.16

[0271] To a solution of (3-cyanopropyl)triphenylphosphonium bromide (3.07 g, 7.48 mmol) in anhydrous tetrahydrofuran (120 ml) under nitrogen was added sodium bis(trimethylsilyl)amide (1.00 M in tetrahydrofuran, 14 ml, 14.00 mmol). The reaction mixture was stirred at room temperature for one hour and cooled to -30 °C. A solution of [(3R, 4R)-3-chloroaceyloxy-4- methyl-6-oxo-N-MeNle]-l-[(Y-hydroxy)-N-MeLeu]-4-cyclosporin (4.80 g, 3.74 mmol) in anhydrous tetrahydrofuran (15 ml) was added. The mixture was stirred another two hours at -30 - 139 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 °C. Then saturated ammonium chloride solution (20 ml) was added to quench the reaction. Most of tetrahydrofuran was evaporated under reduced pressure. Ethyl acetate (100 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 2.00 g of pure [3-chloroacetyl-8-cyanomethyl-MeBmt]-l- [(y-hydroxy)-N-MeLeu]-4-cyclosporin [Molecular Formula: C66H114CIN12O14; Exact Mass: 1333.83; MS (m/z): 1334.56 (M+l)+], [3-Acetyl-8-(2-aminoethyl)-6,7-dihydro-MeBmt]-l-[(y-hydroxy)-N-MeLeu]-4-cyclosporin MW: 1335.16

[0272] To a solution of [3-chloroacetyl-8-cyanomethyl-MeBmt]-l-[(y-hydroxy)-NMeLeu]-4-cyclosporin (0.85 g, 0.63 mmol) in methanol (100 ml) were added nickel (II) chloride hexahydrate (0.19 g, 0.81 mmol). Then sodium borohydride (0.38 g, 10.00 mmol) was added portions in 30 minutes. After the mixture was stirred for another hour at room temperature, most of the methanol was evaporated under reduced pressure. Ethyl acetate (50 ml) and saturated sodium bicarbonate solution (50 ml) were added and the mixture was separated. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 0.61 g of [3-acetyl-8-(2-aminoethyl)-6,7-dihydro-MeBmt]-l-[(y-hydroxy)-N-MeLeu]-4-cyclosporin [Molecular Formula: CôôHuoNuOm; Exact Mass: 1304.90; MS (m/z): 1305.68 (M+l)+; HPLC RT: 12.80 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-AcetamidoethyI)-3-acetyl-6,7-dihydro-MeBmt]-l-[(y-hydroxy)-N-MeLeu]-4- cyclosporin - 140 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 MW: 1305.76

[0273] To a solution of [3-acetyl-8-(2-aminoethyl)-6,7-dihydro-MeBmt]-l-[(y-hydroxy)- N-MeLeu]-4-cyclosporin (0.80 g, 0.61 mmol) and acetic acid (0.11 g, 1.83 mmol) in dichloromethane (60 ml) were added diisopropylethylamine (0.25 g, 1.93 mmol) and HATU (0.70 g, 1.83 mmol). The reaction mixture was stirred at room temperature for three hours and then washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 0.55 g of pure [8-(2-acetamidoethyl)-3-acetyl-6,7-dihydroMeBmt]-l-[(y-hydroxy)-N-MeLeu]-4-cyclosporin [Molecular Formula: C68H122N12O15; Exact Mass: 1346.92; MS (m/z): 1347.63 (M+l)+; HPLC RT: 13.74 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(y-hydroxy)-N-MeLeu]-4-cyclosporin Exact Mass: 1346.92 Exact Mass: 1304.90 MW: 1347.79 MW: 1305.76 [0274] [8-(2-Acetamidoethyl)-3-acetyl-6,7-dihydro-MeBmt]-1-[(y-hydroxy)-N-MeLeu]- 4-cyclosporin (0.50 g, 0.37 mmol) was dissolved in methanol (50 ml). Tétraméthylammonium hydroxide pentahydrate (0.22 g, 1.21 mmol) was added. The mixture was stirred at room temperature for two days. Then most of the methanol was evaporated. Ethyl acetate (100 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 0.22 g of [8-(2-acetamidoethyl)-6,7- - 141 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 dihydro-MeBmt]-l-[(y-hydroxy)-N-MeLeu]-4-cyclosporin [Molecular Formula: C66H120N12O14; Exact Mass: 1304.90; MS (m/z): 1305.72 (M H )L HPLC RT: 12.80 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[a-methylene-Sar]-3-[(Y-hydroxy)-NMeLeu]-4-cyclosporin o o Exact Mass: 1304.90 Exact Mass: 1316.90 MW: 1305.76 MW: 1317.77 [0275] n-Butyllithium (2.65 M, 5.3 ml, 14.04 mmol) was added to a solution of diisopropylamine (2.11 ml, 14.85 mmol) in tetrahydrofuran (50 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for an hour, a solution of [8-(2-acetamidoethyl)-6,7- dihydro-MeBmt]-l-[(y-hydroxy)-N-MeLeu]-4-cyclosporin (1.60 g, 1.23 mmol) in tetrahydrofuran (6 ml) was added over ten minutes. The mixture was stirred at —78 °C for three hours. After carbon dioxide gas was bubbled into the reaction mixture for 30 minutes, the mixture was stirred at -78 °C for another hour. Then the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature to let unreacted carbon dioxide come out. The mixture was cooled to -78 °C and chloromethyl chloroformate (1.32 ml, 14.85 mmol) was added. The mixture was stirred and allowed to warm to room temperature overnight. Brine (5 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 0.50 g of pure [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-l-[a-methylene-Sar]-3-[(y-hydroxy)-N-MeLeu]- 4-cyclosporin [Molecular Formula: C67H120N12O14; Exact Mass: 1316.90; MS (m/z): 1317.66 (M+l)+; HPLC RT: 14.32 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. - 142 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- [(Y-hydroxy)-N-MeLeu]-4-cyclosporin

[0276] To a solution of [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-l-[a-methylene-Sar]- 3-[(Y-hydroxy)-N-MeLeu]-4-cyclosporin (0.30 g, 0.23 mmol) in methanol (20 ml) were added 4-mercapto-1-butanol (0.14 ml, 1.38 mmol) and lithium hydroxide (54 mg, 2.31 mmol). The reaction mixture was stirred at room temperature for five hours. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (30 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 120 mg of pure [8-(2-acetamidoethyl)-6,7-dihydroMeBmt]-l-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-[(y-hydroxy)-N-MeLeu]-4-cyclosporin [Molecular Formula: C71H130N12O15S; Exact Mass: 1422.95; MS (m/z): 1423.74 (M+l)+; HPLC RT: 11.98 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Examples 37 [8-(3-Acetamidopropvl)-6,7-dihvdro-MeBmtl-l-[(RW3-hvdroxvpropyl)thio-Sarl-3- cyclosporin /-A ° —e y—S-SK + X ' Ô C7H7KO2S2 Exact Mass: 225.95 MMW: 226.35 Br^^xOH C3H7BrO Exact Mass: 137.97 MW: 138.99 EtOH C10H14O3S2 Exact Mass: 246.04 MW: 246.34 [0277] p-Toluenethiosulfonic acid potassium salt (4.5 g, 19.91 mmol) and 3-bromo-lpropanol (2.8 g, 20.29 mmol) were added to ethanol (50 ml). The reaction mixture was stirred and heated to reflux for four hours. Most of ethanol was evaporated under reduced pressure. The residue was mixed with ethyl acetate (100 ml). The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated to give 14.79 g of crude S-(3- hydroxypropyl) 4-methylbenzenesulfonothioate. - 143 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 S-(3-((Tetrahydro-2H-pyran-2-yl)oxy)propyl) 4-methylbenzenesulfonothioate C10H14O3S2 C15H22O4S2 Exact Mass: 246.04 Exact Mass: 330.10 MW: 246.34 MW: 330.46

[0278] S-(3-hydroxypropyl) 4-methylbenzenesulfonothioate (7.20 g, 29.26 mmol) was dissolved in dichloromethane (100 ml). 3,4-Dihydro-2H-pyran (3.00 g, 35.66 mmol) and ptoluenesulfonic acid monohydrate (1.00 g, 5.26 mmol) were added. The mixture was stirred at room temperature overnight. The dichloromethane was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography to give 6.50 g of pure S-(3-((tetrahydro-2H-pyran-2- yl)oxy)propyl) 4-methylbenzenesulfonothioate. [Molecular Formula: C15H22O4S2; Exact Mass: 330.10; MS (m/z): 330.95 (M+l)+. [8-(3-Aminopropyl)-6,7-dihydro-MeBmt]-l-[(R)-(3-((tetrahydro-2H-pyran-2- yl)oxy)propyl)thio-Sar]-3-cyclosporin Exact Mass: 1346.95 Exact Mass: 1434.99 MW: 1347.84 Molecular Weight: 1436.01 [0279] n-Butyllithium (2.60 M, 6.40 ml, 16.64 mmol) was added to a solution of diisopropylamine (2.32 ml, 16.33 mmol) in tetrahydrofuran (50 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for an hour, a solution of [8-(3-(aminopropyl)-6,7- dihydro-MeBmt]-l-cyclosporin (1.50 g, 1.11 mmol) in tetrahydrofuran (15 ml) was added over ten minutes. The mixture was stirred at -78 °C for two hours. S-(3-((Tetrahydro-2Hpyran-2-yl)oxy)propyl) 4-methylbenzenesulfonothioate (2.70 g, 8.18 mmol) in tetrahydrofuran (10 ml) was added and the mixture was stirred at -78 °C for another two hours. Then the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature and stirred for another two hours. Saturated ammonium chloride solution (20 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 0.38 g of [8- - 144 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 (3-aminopropyl)-6,7-dihydro-MeBmt]-l-[(R)-( 3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)thioSar]-3-cyclosporin [Molecular Formula: C73H134N12O14S; Exact Mass: 1434.99; MS (m/z): 1435.70 (M+l)+; HPLC RT: 14.93 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(3-Acetamidopropyl)-6,7-dihydro-MeBmt]-l-[(R)-(3-((tetrahydro-2H-pyran-2- yl)oxy)propyl)thio-Sar]-3-cyclosporin

[0280] To a solution of [8-(3-aminopropyl)-6,7-dihydro-MeBmt]-l-[(R)-(3-((tetrahydro- 2H-pyran-2-yl)oxy)propyl)thio-Sar]-3-cyclosporin (0.50 g, 0.35 mmol) and acetic acid (50 mg, 0.83 mmol) in dichloromethane (50 ml) were added diisopropylethylamine (90 mg, 0.70 mmol), HOBT (85 mg, 0.56 mmol) and HBTU (237 mg, 0.63 mmol). The reaction mixture was stirred at room temperature for two hours and then washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 142 mg of pure [8-(3-acetamidopropyl)-6,7-dihydro-MeBmt]-l-[(R)-(3-((tetrahydro-2Hpyran-2-yl)oxy)propyl)thio-Sar]-3-cyclosporin [Molecular Formula: C75H135N12O15S; Exact Mass: 1477.00; MS (m/z): 1477.65(M+1)+. HPLC RT: 18.17min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(3-Acetamidopropyl)-6,7-dihydro-MeBmt]-l-[(R)-(3-hydroxypropyl)thio-Sar]-3- cyclosporin - 145 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Molecular Weight: 1478.04 Molecular Weight: 1393.92

[0281] To a solution of [8-(3-acetamidopropyl)-6,7-dihydro-MeBmt]-l-[(R)-(3- ((tetrahydro-2H-pyran-2-yl)oxy)propyl)thio-Sar]-3-cyclosporin (0.14 g, 0.09 mmol) in methanol (15 ml) was added Dowex-50WX4 (200 mg). The reaction mixture was stirred at room temperature for four hours and then filtered. Most the methanol was evaporated under reduced pressure and the residue was purified by chromatography (dichloromethane/methanol) to give 48 mg of pure [8-(3-acetamidopropyl)-6,7-dihydro-MeBmt]-l-[(R)-(3- hydroxypropyl)thio-Sar]-3-cyclosporin [Molecular Formula: C70H128N12O14S; Exact Mass: 1392.94; MS (m/z): 1393.66(M+1)+. HPLC RT: 15.38min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Examples 36 [8-(2-Acetamidoethyl)-6.,7-dihvdro-MeBmt]-l-[(R)-(4-hvdroxvbutvhthio-Sarl-3- cyclosporin 4-(Tosylthio)butyl benzoate —^^-S-SK + ° C4H9CIO C7H7KO2S2 Exact Mass: 108.03 Exact Mass: 225.95 MW' 108 57 MMW: 226.35 EtOH C11H16O3S2 Exact Mass: 260.05 MW: 260.37 Chemical Formula: C1sH2o04S2 Exact Mass: 364.08 Molecular Weight: 364.47

[0282] P-Toluenethiosulfonic acid potassium salt (20.00 g, 88.36 mmol) and 4-chloro-lbutanol (9.60 g, 88.36 mmol) were added to ethanol (160 ml). The reaction mixture was stirred and heated to reflux for four hours. Most of ethanol was evaporated under reduced pressure. The residue was mixed with ethyl acetate (100 ml). The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated to give 14.79 g of crude S- (4-hydroxybutyl) 4-methylbenzenesulfonothioate. - 146 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811

[0283] S-(4-Hydroxybutyl) 4-methylbenzenesulfonothioate (14.79 g, 56.90 mmol) was dissolved in acetone (60ml). Benzoic anhydride (25.74, 113.80 mmol), 4- (dimethylamino)pyridine (1.39 g, 11.38 mmol) and pyridine (30 ml) were added. The mixture was stirred at room temperature overnight. Most of acetone and pyridine were evaporated under reduced pressure. Ethyl acetate (100 ml) was added. The ethyl acetate layer was washed with hydrochloric acid solution (1.00 N), brine, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 3.30 g of pure 4-(tosylthio)butyl benzoate [Molecular Formula: C18H20O4S2; Exact Mass: 364.08; MS (m/z): 364.57 (M+l)+; HPLC RT: 19.44 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-(tert-Butoxvcarbonvl)aminoethvl)-6.,7-dihvdro-MeBmtl-l-r(RW4- (benzovloxv)butvhthio-Sar]-3-cvclosporin [0284] n-Butyllithium (2.60 M, 6.28 ml, 16.33 mmol) was added to a solution of diisopropylamine (2.32 ml, 16.33 mmol) in tetrahydrofuran (50 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for an hour, a solution of [8-(2-(tertbutoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-cyclosporin (2.20 g, 1.63 mmol) in tetrahydrofuran (15 ml) was added over ten minutes. The mixture was stirred at -78 °C for two hours. 4-(Tosylthio)butyl benzoate (3.56 g, 9.78 mmol) in tetrahydrofuran (10 ml) was added and the mixture was stirred at -78 °C for another two hours. Then the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature and stirred for another two hours. Saturated ammonium chloride solution (20 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give 0.38 g of crude [8-(2-(tertbutoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(4-(benzoyloxy)butyl)thio-Sar]-3- cyclosporin [Molecular Formula: CsoHbsN^OiôS; Exact Mass: 1555.01; MS (m/z): 1555.72 - 147 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 (M+l)+; HPLC RT: 19.21 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(4-hydroxybutyl)thioSar]-3-cyclosporin MW: 1556.11 [0285] [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-1-[(R)-(4- (benzoyloxy)butyl)thio-Sar]-3-cyclosporin from prior step was dissolved in methanol (10 ml). Lithium hydroxide (2.00 g, 83.33 mmol) and water (10 ml) were added. The mixture was stirred at room temperature for two hours. Then most of the methanol was evaporated under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and separated. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 0.38 g of pure [8-(2-(tertbutoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(4-hydroxybutyl)thio-Sar]-3- cyclosporin [Molecular Formula: C73H134N12O15S; Exact Mass: 1450.98; MS (m/z): 1451.68 (M+l)+, 1473.79 (M+Na)+; HPLC RT: 17.06 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-AminoethyI)-6,7-dihydro-MeBmt]-l-[(R)-(4-hydroxybutyl)thio-Sar]-3-cyclosporin Molecular Weight 1452.00 Exact Mass: 1350.93 Molecular Weight: 1351.89 [0286] [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(4- hydroxybutyl)thio-Sar]-3-cyclosporin (0.38 g, 0.26 mmol) was dissolved in dichloromethane - 148 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 (12 ml) and put into ice-water bath. Trifluoroacetic acid (4 ml) was added. The mixture was stirred at 0 °C for three hours. Another dichloromethane (50 ml) was added. The mixture was washed with brine (50 ml), saturated sodium bicarbonate solution (50 ml) and dried over magnesium sulfate and evaporated under reduced pressure to give crude [8-(2-aminoethyl)- 6,7-dihydro-MeBmt]-l-[(R)-(4-hydroxybutyl)thio-Sar]-3-cyclosporin [Molecular Formula: C68H126N12O13S; Exact Mass: 1350.93; MS (m/z): 1351.67 (M+l)+; HPLC RT: 10.72 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(4-hydroxybutyl)tliio-Sar]-3- cyclosporin Exact Mass: 1350.93 Molecular Weight: 1351.89

[0287] Crude [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(4-hydroxybutyl)thio-Sar]-3- cyclosporin was dissolved dichloromethane (15 ml). Acetic acid (0.08 g, 1.33 mmol), HBTU (0.30 g, 0.79 mmol), 1-hydroxybenzotriazole (0.11 g, 0.79 mmol) and diisopropylethylamine (0.50 ml) were added. The mixture was stirred at room temperature for two hours. Then most of solvent was evaporated under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and separated. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 25 mg of pure [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(4- hydroxybutyl)thio-Sar]-3-cyclosporin [Molecular Formula: C70H129N12O14S; Exact Mass: 1392.94; MS (m/z): 1393.98 (M+l f, 1415.92 (M+Naf; HPLC RT: 15.09 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Examples 39 [8-(2-Acetamidoethyl)-6.,7-dihvdro-MeBmt]-l-r(R)-(5-hvdroxvDentvl)thio-Sarl-3- cyclosporin 5-(Tosylthio)pentyl benzoate - 149 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 CgHnCIO EtOH C7H7KO2S2 Exact Mass: 122.05 Exact Mass: 225.95 MW: 122.59 MMW: 226.35 C12H18O3S2 Exact Mass: 274.07 MW: 274.39 C19H22O4S2 Exact Mass: 378.10 Molecular Weight: 378.50

[0288] P-Toluenethiosulfonic acid potassium salt (11.80 g, 47.71 mmol) and 5-chloro-lpentanol (5.84 g, 47.71 mmol) were added to ethanol (100 ml). The reaction mixture was stirred and heated to reflux overnight. Most of ethanol was evaporated under reduced pressure. The residue was mixed with ethyl acetate (100 ml). The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated to give 9.16 g of crude S-(5- hydroxypentyl) 4-methylbenzenesulfonothioate.

[0289] S-(5-Hydroxypentyl) 4-methylbenzenesulfonothioate (9.16 g, 33.42 mmol) was dissolved in acetone (60ml). Benzoic anhydride (15.12, 66.83 mmol), 4- (dimethylamino)pyridine (0.82 g, 6.71 mmol) and pyridine (30 ml) were added. The mixture was stirred at room temperature overnight. Most of acetone and pyridine were evaporated under reduced pressure. Ethyl acetate (100 ml) was added. The ethyl acetate layer was washed with hydrochloric acid solution (1.00 N), brine, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 7.78 g of pure 5-(tosylthio)pentyl benzoate [Molecular Formula: C19H22O4S2; Exact Mass: 378.10; MS (m/z): 378.57 (M+l) ; HPLC RT: 20.24 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(5- (benzoyloxy)pentyl)thio-Sar]-3-cyclosporin Exact Mass: 1346.95 Exact Mass:i569.02 MW: 1347.84 MW: 1570.14 [0290] n-Butyllithium (2.65 M, 6.16 ml, 16.33 mmol) was added to a solution of diisopropylamine (2.32 ml, 16.33 mmol) in tetrahydrofuran (50 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for an hour, a solution of [8-(2-(tertbutoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-cyclosporin (2.20 g, 1.63 mmol) in - 150 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 tetrahydrofuran (15 ml) was added over ten minutes. The mixture was stirred at -78 °C for two hours. 5-(Tosylthio)pentyl benzoate (3.71 g, 9.80 mmol) in tetrahydrofuran (10 ml) was added and the mixture was stirred at -78 °C for another two hours. Then the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature and stirred for another two hours. Saturated ammonium chloride solution (20 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (80 ml) and brine (80 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give 0.38 g of crude [8-(2-(tertbutoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(5-(benzoyloxy)pentyl)thio-Sar]-3- cyclosporin [Molecular Formula: CsiHuoNnOieS; Exact Mass: 1569.02; MS (m/z): 1569.73 (M+l)+; HPLC RT: 19.56 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(5- hydroxypentyl)thio-Sar]-3-cyclosporin [0291] [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(5- (benzoyloxy)pentyl)thio -Sar]-3-cyclosporin from prior step was dissolved in methanol (25 ml). Lithium hydroxide (1.25 g, 52.08 mmol) and water (25 ml) were added. The mixture was stirred at room temperature for two hours. Then most of the methanol was evaporated under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and separated. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 0.22 g of pure [8-(2-(tertbutoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(5-hydroxypentyl)thio-Sar]-3- cyclosporin [Molecular Formula: C74H136N12O15S; Exact Mass: 1465.00; MS (m/z): 1465.68 (M+l)+, 1487.79 (M+Na)+; HPLC RT: 17.44 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(5-hydroxypentyl)thio-Sar]-3-cycIosporin - 151 -CA 03024320 2018-11-14 WO 2017/200984 Exact Mass: 1465.00 Molecular Weight: 1466.03 PCT/ÜS2017/032811 Exact Mass: 1364.94 Molecular Weight: 1365.91 [0292] [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(5- hydroxypentyl)thio-Sar]-3-cyclosporin (0.22 g, 0.15 mmol) was dissolved in dichloromethane (6 ml) and put into ice-water bath. Trifluoroacetic acid (2 ml) was added. The mixture was stirred at 0 °C for three hours. Another dichloromethane (50 ml) was added. The dichloromethane layer was washed with brine (50 ml), saturated sodium bicarbonate solution (50 ml) and dried over magnesium sulfate and evaporated under reduced pressure to give crude [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(5-hydroxypentyl)thio-Sar]-3- cyclosporin [Molecular Formula: C69H128N12O13S; Exact Mass: 1364.94; MS (m/z): 1365.67 (M+l)+; HPLC RT: 11.53 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(5-hydroxypentyl)thio-Sar]-3- cyclosporin o Exact Mass: 1406.96 Molecular Weight: 1407.95

[0293] Crude [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(5-hydroxypentyl)thio-Sar]- 3-cyclosporin was dissolved dichloromethane (15 ml). Acetic acid (0.05 g, 0.83 mmol), HBTU (0.17 g, 0.45mmol), 1-hydroxybenzotriazole (0.06 g, 0.45 mmol) and pyridine (0.50 ml) were added. The mixture was stirred at room temperature for three hours. Then most of solvent was evaporated under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and separated. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 12 mg of pure [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(5-hydroxypentyl)thio-Sar]- - 152 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 3-cyclosporin [Molecular Formula: C71H130N12O14S; Exact Mass: 1406.96; MS (m/z): 1407.77 (M+l)+, 1429.96 (M+Na)+; HPLC RT: 15.72 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Examples 40 [8-(2-Acetamidoethyl)-6.,7-dihvdro-MeBmt]-l-[(R)-(6-hvdroxvhexvl)thio-Sar]-3- cvclosporin 6-(Tosylthio)hexyl benzoate — S-SK + Cl^^ ^-^OH — ° c6h13cio C7H7KO2S2 Exact Mass: 136.07 Exact Mass: 225.95 MW: 136.62 EtOH MMW: 226.35 C2oH2404S2 Exact Mass: 392.11 Molecular Weight: 392.53 C13H20O3S2 Exact Mass: 288.09 MW: 288.42

[0294] P-Toluenethiosulfonic acid potassium sait (18.00 g, 79.52 mmol) and 6-chloro-lhexanol (10.86 g, 79.52 mmol) were added to ethanol (160 ml). The reaction mixture was stirred and heated to reflux for five hours. Most of ethanol was evaporated under reduced pressure. The residue was mixed with ethyl acetate (200 ml). The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated to give 15.33 g of crude S- (6-hydroxyhexyl) 4-methylbenzenesulfonothioate.

[0295] S-(6-Hydroxyhexyl) 4-methylbenzenesulfonothioate (15.33 g, 53.23 mmol) was dissolved in acetone (60ml). Benzoic anhydride (24.08, 106.46 mmol), 4- (dimethylamino)pyridine (1.30 g, 10.65 mmol) and pyridine (30 ml) were added. The mixture was stirred at room temperature overnight. Most of acetone and pyridine were evaporated under reduced pressure. Ethyl acetate (100 ml) was added. The ethyl acetate layer was washed with hydrochloric acid solution (1.00 N), brine, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 5.41 g of pure 6-(tosylthio)hexyl benzoate [Molecular Formula: C20H24O4S2; Exact Mass: 392.11; MS (m/z): 392.57 (M+l)+; HPLC RT: 20.86 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(6- (benzoyloxy)hexyl)thio-Sar]-3-cyclosporin - 153 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Exact Mass: 1346.95 Exact Mass: 1583.04 MW: 1347.84 MW: 1584.17 [0296] n-Butyllithium (2.60 M, 6.28 ml, 16.33 mmol) was added to a solution of diisopropylamine (2.32 ml, 16.33 mmol) in tetrahydrofuran (50 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for an hour, a solution of [8-(2-(tertbutoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-cyclosporin (2.20 g, 1.63 mmol) in tetrahydrofuran (15 ml) was added over ten minutes. The mixture was stirred at -78 °C for two hours. 6-(Tosylthio)hexyl benzoate (3.83 g, 9.78 mmol) in tetrahydrofuran (10 ml) was added and the mixture was stirred at -78 °C for another two hours. Then the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature and stirred for another two hours. Saturated ammonium chloride solution (20 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give crude [8-(2-(tertbutoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(6-(benzoyloxy)hexyl)thio-Sar]-3- cyclosporin [Molecular Formula: C82H142N12O16S; Exact Mass: 1583.04; MS (m/z): 1583.75(M+1)+; HPLC RT: 19.27 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-(tert-Butoxycarbonyl)aminoethyI)-6,7-dihydro-MeBmt]-l-[(R)-(6-hydroxyhexyl)tliioSar]-3-cyclosporin Exact Mass: 1479.01 Molecular Weight: 1480.06 Exact Mass: 1583.04 MW: 1584.17 [0297] [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-1-[(R)-(6- (benzoyloxy)hexyl)thio-Sar]-3-cyclosporin was dissolved in methanol (10 ml). Lithium hydroxide (1.25 g, 52.08 mmol) and water (10 ml) were added. The mixture was stirred at - 154 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 room temperature for two hours. Then most of the methanol was evaporated under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and separated. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 0.34 g of pure [8-(2-(tertbutoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(6-hydroxyhexyl)thio-Sar]-3- cyclosporin [Molecular Formula: C75H138N12O15S; Exact Mass: 1479.01; MS (m/z): 1479.86 (M+l)+, 1501.80 (M+Na)+; HPLC RT: 17.86 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(6-hydroxyhexyl)thio-Sar]-3-cyclosporin Exact Mass: 1378.96 Molecular Weight: 1379.94 [0298] [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(6- hydroxyhexyl)thio-Sar]-3-cyclosporin (0.34 g, 0.15 mmol) was dissolved in dichloromethane (15 ml) and put into ice-water bath. Trifluoroacetic acid (5 ml) was added. The mixture was stirred at 0 °C for three hours. Another dichloromethane (50 ml) was added. The dichloromethane layer was washed with brine (50 ml), saturated sodium bicarbonate solution (50 ml) and dried over magnesium sulfate and evaporated under reduced pressure to give 0.14 g of crude [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(6-hydroxyhexyl)thio-Sar]-3- cyclosporin [Molecular Formula: C70H130N12O13S; Exact Mass: 1378.96; MS (m/z): 1379.67 (M+l)+; HPLC RT: 12.45 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(6-hydroxyhexyI)thio-Sar]-3- cyclosporin - 155 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 Exact Mass: 1378.96 Molecular Weight: 1379.94 o Exact Mass: 1420.97 Molecular Weight: 1421.98

[0299] Crude [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(6-hydroxyhexyl)thio-Sar]- 3-cyclosporin dissolved dichloromethane (15 ml). Acetic acid (0.14 g, 2.43 mmol), HBTU (0.55 g, 1.46 mmol), 1-hydroxybenzotriazole (0.20 g, 1.46 mmol) and pyridine (1.0 ml) were added. The mixture was stirred at room temperature overnight. Then most of solvent was evaporated under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and separated. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 14 mg of pure [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(R)-(6-hydroxyhexyl)thio-Sar]-3- cyclosporin [Molecular Formula: C72H132N12O14S; Exact Mass: 1420.97; MS (m/z): 1422.08 (M+l)+, 1443.93 (M+Na)+; HPLC RT: 16.23 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Examples 41 [8-(2-Acetamidoethvh-6/7-dihvdro-MeBmtl-l-[(S)-((4-hvdroxv-2-methylbutan-2- vl)thio)methyI-Sar]-3-cvclosporin 3-Methyl-3-mercaptobutyricic acid C5H10°3 S HjN^NHj HCI Exact Mass: 118.06 MW: 118.13 CsH12N2O2S Exact Mass: 176.06 MW: 176.23 LiOH MeOH/H2O C5H10O2S Exact Mass: 134.04 MW: 134.19 [0300] 3-Hydroxy-3-methylbutyric acid (10.00 g, 84.65 mmol), hydrochloric acid (36%, 30 ml) and thiourea (7.08 g, 93.12 mmol) were mixed and heated to reflux for twenty four hours. Then the mixture was evaporated under reduced pressure. Methanol (10 ml) and a solution of lithium hydroxide (6.09 g, 253.95 mmol) in water (10 ml) were added. The mixture was stirred and heated to reflux overnight. After cooled to room temperature, the mixture was filtered. The filtrate was evaporated under reduced pressure to give crude product. - 156 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-((l-carboxy-2- methylpropan-2-yl)thio)methyl-Sar]-3-cyclosporiii Exact Mass: 1358.95 Exact Mass: 1492.99 MW: 1359.85 MW: 1494.04

[0301] To a solution of [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l- [a-methylene-Sar]-3-cyclosporin (1.00 g, 0.74 mmol) in methanol (10 ml) were added 3- methyl-3-mercaptobutyricic acid (0.30 g, 2.20 mmol) and lithium hydroxide (0.18 g, 7.36 mmol). The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and the PH of the aqueous layer was adjusted to 3 by adding hydrochloric acid solution (1.0 N). The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure to give crude [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)- ((l-carboxy-2-methylpropan-2-yl)thio)methyl-Sar]-3-cyclosporin [Molecular Formula: C75H136N12O16S; Exact Mass: 1492.99; MS (m/z): 1493.63 (M+l)+, 1515.88 (M+Na)+], |8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt|-l-|(S)-((4-methoxy-2-mcthyl- 4-oxobutan-2-yl)thio)methyl-Sar]-3-cyclosporin Cz6H138N12Ol6S Exact Mass: 1507.01 MW: 1508.07

[0302] Crude [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-((lcarboxy-2-methylpropan-2-yl)thio)methyl-Sar]-3-cyclosporin was dissolved in acetone (10 ml). lodomethane (0.14 ml, 2.22 mmol) and potassium carbonate (0.31 g, 2.22 mmol) were added. The mixture was stirred at room temperature for two hours. Most of acetone was evaporated under reduced pressure. Then ethyl acetate (50 ml) and water (50 ml) were added and the mixture was separated. The ethyl acetate layer was dried over magnesium sulfate and - 157 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 evaporated under reduced pressure The residue was purified by chromatography (hexane/acetone) to give 0.16 g of pure [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydroMeBmt]-l-[(S)-((4-methoxy-2-methyl-4-oxobutan-2-yl)thio)methyl-Sar]-3-cyclosporin [Molecular Formula: CTôHnsNuOiôS; Exact Mass: 1507.01; MS (m/z): 1507.65 (M+l)+, 1529.95 (M+Na)+; HPLC RT: 18.34 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-((4-methoxy-2-methyl-4-oxobutan-2- yl)thio)methyI-Sar|-3-cyclosporin [0303] [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4-methoxy- 2-methyl-4-oxobutan-2-ylthio)methyl-Sar]-3-cyclosporin (0.16 g, 0.11 mmol) was dissolved in dichloromethane (6 ml) and put into ice-water bath. Trifluoroacetic acid (2 ml) was added. The mixture was stirred at 0 °C for three hours. Another dichloromethane (20 ml) was added. The mixture was washed with brine (30 ml), saturated sodium bicarbonate solution (30 ml) and dried over magnesium sulfate and evaporated under reduced pressure to give crude [8-(2- aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-((4-methoxy-2-methyl-4-oxobutan-2-yl)thio)methylSar]-3-cyclosporin. Molecular Formula: C71H130N12O14S; Exact Mass: 1406.96; MS (m/z): 1407.65 (M+l)+; HPLC RT: 13.66 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(S)-((4-methoxy-2-methyI-4-oxobutan-2- yl)thio)methyl-Sar]-3-cyclosporin - 158 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 MW: 1407.95 O C73H132N12°15S Exact Mass: 1448.97 MW: 1449.99

[0304] Crude [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-((4-methoxy-2-methyl-4- oxobutan-2-yl)thio)methyl-Sar]-3-cyclosporin was dissolved dichloromethane (10 ml). Acetic acid (0.03 ml, 20.53 mmol), HBTU (0.12 g, 0.32 mmol), 1-hydroxybenzotriazole (0.04 g, 0.32 mmol) and pyridine (0.50 ml) were added. The mixture was stirred at room temperature for two hours. Then dichloromethane (30 ml) and brine (50 ml) were added and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure to give crude [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(S)-((4-methoxy-2- methyl-4-oxobutan-2-yl)thio)methyl-Sar]-3-cyclosporin [Molecular Formula: C73H132N12O15S; Exact Mass: 1448.97; MS (m/z): 1449.72 (M+l)+, 1471.91 (M+Na)+; HPLC RT: 17.19 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Acetamidoethyl)-6,7-dihydro-MeBint]-l-[(S)-((4-hydroxy-2-methylbutan-2- yl)thio)methyl-Sar]-3-cyclosporin

[0305] Crude [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(S)-((4-methoxy-2-methyl-4- oxobutan-2-yl)thio)methyl-Sar]-3-cyclosporin was dissolved in tetrahydrofuran (10 ml). Sodium borohydride (0.50 g, 12.88 mmol) and cesium chloride (0.10 g, 0.59 mmol) were added. The mixture was stirred at room temperature and methanol (10 ml) was added dropwise over two hours. Then the mixture was stirred overnight. Most of solvents were evaporated under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and - 159 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 the mixture was separated. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 34 mg of pure [8-(2-acetamidoethyl)-6,7-dihydroMeBmt]-l-[(S)-((4-hydroxy-2-methylbutan-2-yl)thio)methyl-Sar]-3-cyclosporin [Molecular Formula: C72H132N12O14S; Exact Mass: 1420.97; MS (m/z): 1421.87(M+1)+, 1444.00 (M+Na)+; HPLC RT: 15.67 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Examples 42 [8-(2-Acetamidoethvl)-6.,7-dihvdro-MeBmt]-l-[(S)-((5-hvdroxv-2-methvIpentan-2- vl)thio)methyl-Sar]-3-cvclosporin 4-Mercapto-4-methylpentanoic acid MeO 1. MeMgCI 2. H2O CgHioOs Exact Mass: 130.06 MW: 130.14 C7K14O3 Exact Mass: 146.09 MW: 146.19 O C8H16N2O2S Exact Mass: 204.09 MW: 204.29 LiOH MeOH/H2O C6H12O2S Exact Mass: 148.06 MW: 148.22

[0306] Methyl levulinate (10.00 g, 76.84 mmol) was dissolved in anhydrous tetrahydrofuran (50 ml) under nitrogen. The mixture was put into a dry ice-acetone bath and methylmagnesium chloride (3.00 M, 25.6 ml, 76.84 mmol) was added slowly. The mixture was stirred at -78 °C for two hours and allowed to warm to room temperature overnight. Saturated ammonium chloride solution (20 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 8.13 g of pure methyl 4-hydroxy-4-methylpentanoate [Molecular Formula: C7H14O3; Exact Mass: 146.09; MS (m/z): 146.64 (M+l)+],

[0307] Methyl 4-hydroxy-4-methylpentanoate (8.13 g, 55.70 mmol), hydrochloric acid (36%, 25 ml) and thiourea (4.66 g, 61.27 mmol) were mixed and heated to reflux for twenty four hours. Then the mixture was evaporated under reduced pressure. Methanol (10 ml) and a solution of lithium hydroxide (4.01 g, 167.09 mmol) in water (10 ml) were added. The mixture was stirred and heated to reflux overnight. After cooled to room temperature, the mixture was filtered. The filtrate was evaporated under reduced pressure to give crude product. [8-(2-(tert-BiitoxycarbonyI)aminoethyI)-6,7-dihydro-MeBmt]-l-[(S)-((4-carboxy-2- methylbutan-2-yl)thio)methyl-Sar]-3-cyclosporin - 160 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 MW: 1359.85 MW: 1508.07

[0308] To a solution of [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-1- [a-methylene-Sar]-3-cyclosporin (1.91 g, 1.41 mmol) in methanol (20 ml) were added 4- mercapto-4-methylpentanoic acid (0.62 g, 4.22 mmol) and lithium hydroxide (0.20 g, 8.43 mmol). The reaction mixture was stirred at room temperature for two days. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (100 ml) and brine (100 ml) were added and the PH of the aqueous layer was adjusted to 3 by adding hydrochloric acid solution (1.00 N). After separated, the ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure to give crude [8-(2-(tert-butoxycarbonyl)aminoethyl)- 6,7-dihydro-MeBmt]-l-[(S)-((4-carboxy-2-methylbutan-2-yl)thio)methyl-Sar]-3-cyclosporin [Molecular Formula: C-ôHBxNnOiôS; Exact Mass: 1507.01; MS (m/z): 1507.65 (M+l)+, 1529.95 (M+Na)+], [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-((5-methoxy-2-methyl- 5-oxopentan-2-yl)thio)methyl-Sar]-3-cyclosporin Exact Mass: 1507.01 Exact Mass: 1521.02 MW: 1508.07 MW: 1522.10

[0309] Crude [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-((4- carboxy-2-methyl butan-2-yl)thio)methyl-Sar]-3-cyclosporin was dissolved in acetone (20 ml). lodomethane (0.56 ml, 8.88 mmol) and potassium carbonate (1.24 g, 8.88 mmol) were added. The mixture was stirred at room temperature for a weekend. Most of acetone was evaporated under reduced pressure. Then ethyl acetate (50 ml) and water (50 ml) were added and the mixture was separated. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure The residue was purified by chromatography (hexane/acetone) to give 0.45 g of pure [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro- - 161 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 MeBmt]-l-[(S)-((5-methoxy-2-methyl-5-oxopentan-2-yl)thio)methyl-Sar]-3-cyclosporin [Molecular Formula: C77H140N12O16S; Exact Mass: 1521.02; MS (m/z): 1521.61 (M+ If, 1543.72 (M+Na)+; HPLC RT: 18.31 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-((5-methoxy-2-methyl-5-oxopentan-2- yl)thio) methyl-Sar]-3-cyclosporin MW: 1522.10 MW: 1421.98 [0310] [8-(2-(tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-1-[(S)-((5-methoxy- 2-methyl-5-oxopentan-2-yl)thio)methyl-Sar]-3-cyclosporin (0.45 g, 0.30 mmol) was dissolved in dichloromethane (15 ml) and put into ice-water bath. Trifluoroacetic acid (5 ml) was added. The mixture was stirred at 0 °C for two hours. Another dichloromethane (50 ml) was added. The mixture was washed with brine (50 ml), saturated sodium bicarbonate solution (50 ml) and dried over magnesium sulfate and evaporated under reduced pressure to give crude [8-(2- aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-((5-methoxy-2-methyl-5-oxopentan-2-yl)thio) methyl-Sar]-3-cyclosporin [Molecular Formula: C72H132N12O14S; Exact Mass: 1420.97; MS (m/z): 1421.67 (M+l)+; HPLC RT: 12.97 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(S)-((5-methoxy-2-methyI-5-oxopentan-2- yl)thio)methyl-Sar]-3-cyclosporin - 162 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811

[0311] Crude [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-l-[(S)-((5-methoxy-2-methyl-5- oxopentan-2-yl)thio)methyl-Sar]-3-cyclosporin was dissolved dichloromethane (15 ml). Acetic acid (0.09 g, 1.48 mmol), HBTU (0.34 g, 0.89 mmol), 1-hydroxybenzotriazole (0.12 g, 0.89 mmol) and triethylamine (0.50 ml) were added. The mixture was stirred at room temperature for two hours. Then dichloromethane (50 ml) and brine (50 ml) were added and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 0.20 mg of pure [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(S)-((5-methoxy-2-methyl-5- oxopentan-2-yl)thio)methyl-Sar]-3-cyclosporin [Molecular Formula: C74H134N12O15S; Exact Mass: 1462.98; MS (m/z): 1463.74 (M+l)+, 1485.81 (M+Na)+; HPLC RT: 17.11 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(S)-((5-hydroxy-2-methyIpentan-2- yl)thio)methyl-Sar]-3-cyclosporin [0312] [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(S)-((5-methoxy-2-methyl-5- oxopentan-2-yl) thio)methyl-Sar]-3-cyclosporin (0.20 g, 0.14 mmol) was dissolved in tetrahydrofuran (10 ml). Sodium borohydride (1.00 g, 64.40 mmol) and cesium chloride (0.20 g, 0.59 mmol) were added. The mixture was stirred at room temperature and methanol (10 ml) was added dropwise over two hours. Then the mixture was stirred overnight. Most of solvents - 163 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 were evaporated under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 34 mg of pure [8-(2-acetamidoethyl)-6,7-dihydroMeBmt]-l-[(S)-((5-hydroxy-2-methylpentan-2-yl)thio)methyl-Sar]-3-cyclosporin [Molecular Formula: C73H134N12O14S; Exact Mass: 1434.99; MS (m/z): 1435.86 (M+l)+, 1457.87 (M+Na)+; HPLC RT: 17.03 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Reference Example 1 [8-(2-Acetamidoethyl)-6.,7-dihvdro-MeBmt|-l-[(R)-2-methvl-Sar|-3-cvclosDorin (CPI- 431-32(CRV431)) [(R)-2-Methyl-Sar]-3-cyclosporin Exact Mass: 1201.84 Exact Mass: 1215.86 MW: 1202.64 MW: 1216.66 [0313] n-Butyllithium (2.20 M, 75.60 ml, 166.39 mmol) was added to a solution of diisopropylamine (23.60 ml, 166.39 mmol) in tetrahydrofuran (150 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for an hour, a solution of cyclosporine (20.00 g, 16.64 mmol) in tetrahydrofuran (50 ml) was added over ten minutes. The mixture was stirred at -78 °C for two hours. After iodomethane (10.36 ml, 166.39 mmol) was added, the mixture was stirred at -78 °C for another two hours and allowed to warm to room temperature overnight. Brine (20 ml) was added to quench the reaction. Most of tetrahydrofuran was removed under reduced pressure. Ethyl acetate (100 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 5.49 g of [(R)-2-methyl-Sar]-3-cyclosporin [Molecular Formula: C63H113N11O12; Exact Mass: 1215.86; MS (m/z): 1216.63 (M+l)+, 1238.79 (M+Na)+; HPLC RT: 17.53 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. - 164 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [3-Acetyl-MeBmt]-l-[(R)-2-methyl-Sar]-3-cyclosporin Exact Mass: 1257.87 MW: 1258.70

[0314] To a dried flask under nitrogen were added [(R)-2-methyl-Sar]-3-cyclosporin (5.49 g, 4.52 mmol), N,N-dimethylaminopyridine (0.06 g, 0.45 mmol), anhydrous pyridine (60 ml) and acetic anhydride (28.21 ml, 299.00 mol). The reaction mixture was stirred overnight at room temperature. The mixture was poured into ice-water (300 ml) and stirred until the ice was melted. Ethyl acetate (100 ml) was added and the mixture was separated. The ethyl acetate layer was washed with 1 N hydrochloric acid solution (50 ml x 2), saturated sodium bicarbonate solution (50 ml), brine (50 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone/methanol) to give 4.67 g of [3-acetylMeBmt]-l-[(R)-2-methyl-Sar]-3-cyclosporin [Molecular Formula: C65H115N11O13; Exact Mass: 1257.87; MS (m/z): 1258.54 (M+l)+, 1280.71 (M+Na)+; HPLC RT: 19.31 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. |(3R, 4R)-3-Acetyloxy-4-methyl-6-oxo-N-MeNle]-l-[(R)-2-methyl-Sar]-3-cyclosporin Exact Mass: 1257.87 MW: 1258.70

[0315] To a solution of [3-acetyl-MeBmt]-l-[(R)-2-methyl-Sar]-3-cyclosporin (4.67 g, 3.71 mmol) in dioxane (100 ml) were added water (20 ml), osmium(VIII) oxide solution (15.74 mM, 23.50 ml, 0.37 mmol) and sodium metaperiodate (3.18g, 14.85 mmol). The reaction mixture was stirred at room temperature for five hours. Ethyl acetate (100 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone) to give 4.10 g of [(3R, 4R)-3-acetyloxy-4- - 165 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 methyl-6-oxo-N-MeNle]-l-[(R)-2-methyl-Sar]-3-cyclosporin [Molecular Formula: C63H111N11O14; Exact Mass: 1245.83 ; MS (m/z): 1246.54 (M+l)+, 1268.71 (M+Na)+; HPLCRT: 17.27 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-Cyanomethyl-3-acetyl-MeBmt]-l-[(R)-2-methyl-Sar]-3-cyclosporin ©Br t-BuONa NC^^PPPj C22H21BrNP Exact Mass: 409.06 MW: 410.29 C22H20NP Exact Mass: 329.13 MW: 329.38

[0316] To a dried flask were added (3-cyanopropyl)triphenylphosphonium bromide (7.98 g, 19.50 mmol) and anhydrous tetrahydrofuran (60 ml) under nitrogen. The reaction mixture was put into an ice-water bath and sodium tert-butoxide (2.19 g, 22.75 mmol) was added. After the mixture was stirred for two hours, a solution of [(3R, 4R)-3-acetyloxy-4-methyl-6-oxo-N-MeNle]-l-[(R)- 2-methyl-Sar]-3-cyclosporin (4.10 g, 3.29 mmol) in anhydrous tetrahydrofuran (20 ml) was added. The mixture was stirred another five hours at 0°C. Then saturated ammonium chloride solution (20 ml) was added to quench the reaction. Most of tetrahydrofuran was evaporated under reduced pressure. Ethyl acetate (100 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 2.00 g of pure [8-cyanomethyl-3-acetyl-MeBmt]-l-[(R)-2-methyl-Sar]-3-cyclosporin [Molecular Formula: Cô-HhôNhOb; Exact Mass: 1296.88; MS (m/z): 1297.55 (M+l)+, 1319.787 (M+Na)+; HPLC RT: 17.56 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. - 166 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [8-(2-Aminoethyl)-3-acetyl-6,7-dihydro-MeBmt]-l-[(R)-2-methyl-Sar]-3-cyclosporin

[0317] To a solution of [8-cyanomethyl-3-acetyl-MeBmt]-l-[(R)-2-methyl-Sar]-3- cyclosporin (2.00 g, 1.54 mmol) in methanol (50 ml) under nitrogen was added nickel (II) chloride hexahydrate (0.04 g, 0.15 mmol).The reaction mixture was put into ice-water bath. Sodium borohydride (3.05 g, 80.50 mmol) was added in four batches in two hours. After the mixture was stirred for another two hours at 0°C, water (10 ml) was added. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (50 ml) and saturated sodium bicarbonate solution (50 ml) were added and the mixture was separated. The organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in methanol (30 ml). Palladium (10 wt% on carbon, 20 mg) and acetic acid (5 drops) were added. The mixture was stirred at room temperature under hydrogen for two hours. Then the mixture was filtered and the filtrate was evaporated under reduced pressure to give 2.20 g of crude [8-(2-aminoethyl)-3-acetyl-6,7-dihydro-MeBmt]-l-[(R)-2-methyl-Sar]-3-cyclosporin [Molecular Formula: C67H122N12O13; Exact Mass: 1302.93; MS (m/z): 1303.75 (M+l)+; HPLC RT: 14.72 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-2-methyl-Sar]-3-cycIosporin Exact Mass: 1302.93 MW: 1303.78 Exact Mass: 1260.91 MW: 1261.75 [0318] [8-(2-Aminoethyl)-3-acetyl-6,7-dihydro-MeBmt]-l-[(R)-2-methyl-Sar]-3-cyclosporin (1.60 g, 1.24 mmol) was dissolved in methanol (20 ml). Water (10 ml) and tétraméthylammonium hydroxide pentahydrate (0.67 g, 3.72 mmol) were added. The mixture was stirred at room - 167 -84932431 temperature for two hours. Then most of the methanol was evaporated. Ethyl acetate (100 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 1.20 g of pure [8-(2-aminoethyl)-6,7- dihydro-MeBmt]-l-[(R)-2-methyl-Sar]-3-cyclosporin [Molecular Formula: C65H120N12O12; Exact Mass: 1260.91; MS (m/z): 1261.72 (M+l)+; HPLC RT: 12.11 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(R)-2-methyl-Sar]-3-cyclosporin o Exact Mass: 1260.91 Exact Mass: 1302.93 MW: 1261.75 MW: 1303.78 [0037] [8-(2-Aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-2-methyl-Sar]-3-cyclosporin (0.60 g, 0.48 mmol) was dissolved in dichloromethane (25 ml). Acetic acid (0.14 ml, 2.38 mmol), HBTU (0.54 g, 1.43 mmol), 1-hydroxybenzotriazole (0.19 g, 1.43 mmol) and pyridine (1.00 ml) were added. The mixture was stirred at room temperature for three hours. Then dichloromethane (30 ml) and brine (50 ml) were added and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 0.11 g of pure [8-(2-acetamidoethyl)-6,7- dihydro-MeBmt]-l-[(R)-2-methyl-Sar]-3-cyclosporin [Molecular Formula: C67H122N12O13; Exact Mass: 1302.93; MS (m/z): 1303.66 (M+l)+, 1325.86 (M+Na)+; HPLC RT: 16.56 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. This product was prepared using a method analogous to the procedure described in US Patent No. 9,200,038 B2 and US 2013/0190223 Al. Reference Example 2 [8-(2-Acetamidoethyl)-6,7-dihvdro-MeBmt1-l-cvclosDorin - 168 - Date reçue/Date Received 2023-10-06CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [0320] [8-(2-Aminoethyl)-6,7-dihydro-MeBmt]-l-cyclosporin (0.50 g, 0.40 mmol) was dissolved dichloromethane (20 ml). Acetic acid (0.11 ml, 2.00 mmol), HBTU (0.46 g, 1.20 mmol), 1-hydroxybenzotriazole (0.16 g, 1.20 mmol) and pyridine (0.50 ml) were added. The mixture was stirred at room temperature for one hour. Then dichloromethane (30 ml) and brine (50 ml) were added and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol) to give 0.20 g of pure [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]- 1-cyclosporin [Molecular Formula: C66H120N12O13; Exact Mass: 1288.91; MS (m/z): 1289.96 (M+l)+, 1311.82 (M+Na)+; HPLC RT: 14.92 min. (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. Reference Example 3 [a-Methvlene-Sar]-3-cvclosporin [a-Methoxycarbonyl-Sar]-3-cyclosporin Mol. Wt.: 1246.64 Mol. Wt.: 1260.67 [0321] [a-Carboxy-sar]-3-cyclosporin (5.00 g, 4.01 mmol) was dissolved in N,Ndimethylformamide (30 ml). lodomethane (2.85 g, 20.10 mmol) and potassium carbonate (1.38 g, 10.00 mmol) were added. The mixture was stirred at room temperature for two hours. Then ethyl acetate (60 ml) and water (60 ml) were added and the mixture was separated. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 5.32 g of crude product, which was directly used for the next step - 169 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 without purification (yield: ~ 100%) [Molecular Formula: CôÆibNuOu; Exact Mass: 1259.85; MS (m/z): 1260.7 (M+l)+, 1282.7 (M+Na)+], [(R)-a-Hydroxymethyl-Sar]-3-cyclosporin Exact Mass: 1259.85 Exact Mass: 1231.85 Mol. Wt.: 1260.67 Mol. Wt: 1232.66 [0322] [a-Methoxycarbonyl-Sar]-3-cyclosporin (2.00 g, 1.59 mmol) was dissolved in tetrahydrofuran (30 ml). Cesium chloride (1.33 g, 7.90 mmol) and sodium borohydride (0.60 g, 15.89 mmol) were added. Then methanol (30 ml) was added dropwise to the mixture over two hours. After addition, the mixture was stirred at room temperature overnight. Most of solvent was then evaporated under reduced pressure. Ethyl acetate (50 ml) and water (50 ml) were added. The ethyl acetate layer was separated and washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 1.99 g of crude product, which was purified by on silica gel column with dichloromethane/methanol (from 100:0 to 95:5) to give 1.50 g of pure product (yield: 76%) [Molecular Formula: C63H113N11O13; Exact Mass: 1231.85; MS (m/z): 1232.7 (M+l)+, 1254.7 (M+Na)+], [a-Methylmethanesulfonate-Sar]-3-cyclosporin Mol. Wt.: 1310.75

[0323] To a solution of [a-hydroxymethyl-Sar]-3-cyclosporin (30 mg, 0.024 mmol) in dichloromethane (2 ml) at 0 °C were added triethylamine (52.8 pl, 0.38 mmol) and methanesulfonyl chloride (23 mg, 0.20 mmol). After stirred at room temperature for two hours, the mixture was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 33 mg of crude product, which was directly used in next step reaction without further purification [Molecular Formula: C64H115N11O15S; Exact Mass: 1309.83; MS (m/z): 1310.7 (M+l)+]. - 170 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [a-Chloromethyl-Sar]-3-cyclosporin Mol. Wt: 1232.66 Mol. Wt: 1251.10

[0324] To a solution of [a-hydroxymethyl-Sar]-3-cyclosporin (30 mg, 0.024 mmol) in dichloromethane (2 ml) at 0 °C were added triethylamine (52.8 pL, 0.384 mmol, 16 equivalents) and methanesulfonyl chloride (23 mg, 0.20 mmol). After stirred at room temperature overnight, the mixture was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 30 mg of crude product, which was directly used in next step reaction without further purification [Molecular Formula: C63H112CIN11O12; Exact Mass: 1249.82; MS (m/z): 1250.7 (M+l)+, 1272.9 (M+Na)+], [a-Methylene-Sar]-3-cyclosporin Method 1 Exact Mass: 1309.83 Mol. Wt.: 1310.75 Mol. Wt.: 1214.65

[0325] To a solution of either [a-methanesulfonatemethyl-Sar]-3-cyclosporin (33 mg, 0.025 mmol) or [a-chloromethyl-Sar]-3-cyclosporin (30 mg, 0.025 mmol) in tetrahydrofuran (3 ml) was added sodium hydride (15.3 mg, 60% in oil, 0.38 mmol, 10 equivalents) at 0 °C. The mixture was stirred at 0 °C for one hour and then warmed up to room temperature for 30 minutes. After removal of solvent, the residue was dissolved in dichloromethane (20 ml). The dichloromethane layer was washed with 1 N hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using dichloromethylene/methanol (20/1) to give 16 mg of product (yield: 54%) [Molecular Formula: C63H111N11O12; Exact Mass: 1213.84; MS (m/z): 1214.7 (M+l)+, 1236.7 (M+Na)+; TLC Rf: 0.55 (ethyl acetate/methanol = - 171 -84932431 20/1); HPLC RT: 7.0 min (C8 reverse phase column: 150 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. [a-Methylene-Sar]-3-cyclosporin Method 2 [0038] [a-Methylene-Sar]-3-cyclosporin can also be prepared using a method analogous to the procedure described in WO2012/051194A1. Reference Example 4 [a-Methylene-Sar1-3-[(Y-hvdroxv)-NMeLeul-4-cvclosporin [a-Methoxycarbonyl-Sar]-3-[(Y-hydroxy)-NMeLeu]-4-cyclosporin Mol. Wt: 1276.67

[0039] To a solution of LDA (2.0 M in tetrahydrofuran, 23 ml, 46 mmol) in tetrahydrofuran (80 ml) at -78 °C under nitrogen, [(y-hydroxy)-N-MeLeu]-4-cyclosporin (4.40 g, 3.61 mmol) in tetrahydrofuran (15 ml) was added over 3 min. After the mixture was stirred at -78 °C for 3 hours, carbon dioxide gas was bubbled into the reaction mixture for 1 hour. Then the mixture was allowed to warm to room temperature slowly and kept stirring for 3 hours. Most of tetrahydrofuran was evaporated. Dichloromethane (100 ml) and water (50 ml) were added. The - 172- Date reçue/Date Received 2023-10-06CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 PH of the mixture was adjusted to around 5 by adding aqueous citric acid solution. The mixture was separated and the organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 3.20 g of crude product as acid, which was used for next step without purification [Molecular Formula: CesHiuNnOis; Exact Mass: 1261.83; MS (m/z): 1262.49 (M+l)+], To a mixture of [a-carboxy-Sar]-3-[(y-hydroxy)-N-MeLeu]-4- cyclosporin (3.20 g 2.53 mmol) and potassium carbonate (1.30 g, 9.40 mmol) in N,Ndimethylformamide (20 ml) was added iodomethane (1.80 g, 12.70 mmol). The mixture was stirred overnight at room temperature. Dichloromethane (80 ml) and water (50 ml) were added and the mixture was separated. The dichloromethane layer was washed with water (25 ml) and brine (25 ml), dried over magnesium sulfate and evaporated under reduced pressure to give crude 3.00 g of product [Molecular Formula: C64H113N11O15; Exact Mass: 1275.84; MS (m/z): 1276.75 (M+l)+], [0328] [(y-Hydroxy)-N-MeLeu]-4-cyclosporin was prepared by Sebekia benihana biotransformation according to a method described by Kuhnt M. et al., 1996, Microbial Biotransformation Products of Cyclosporin A, J. Antibiotics, 49 (8), 781. [(R)-a-Hydroxymethyl-Sar]-3-[(y-hydroxy)-NMeLeu]-4-cyclosporin Mol. Wt: 1276.67 Mol. Wt.: 1248.66

[0329] To a suspension of [a-methoxycarbonyl-Sar]-3-[(y-hydroxy)-N-MeLeu]-4- cyclosporin (3.00 g, 2.35 mmol) and lithium chloride (1.50 g, 35.30 mmol) in methanol (100 ml) was added sodium borohydride (2.50 g, 66.10 mmol) in portions. The mixture was stirred overnight at room temperature. Most of solvent was evaporated under reduced pressure. Dichloromethane (80 ml) and water (50 ml) were added and the mixture was separated. The dichloromethane layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane/methanol = 96/4) to give 1.30 g of product [Molecular Formula: C63H113N11O14; Exact Mass: 1247.85; MS (m/z): 1248.48 (M+l)+; 'H NMR spectrum (600 MHz, CDCh, S in ppm): 0.68 (d, J = 5.4Hz, 3H), 0.80-1.00 (m, 30H), 1.07 (d, J = 6.0Hz, 3H), 1.16- 1.29 (m, 10H), 1.32 (d, J = 7.2Hz, 3H), 1.39-1.46 (m, 2H), 1.59-1.63 (m, 6H), 1.68-1.83 (m, 7H), 2.02-2.11 (m, 4H), 2.31-2.33 (m, 1H), 2.37-2.42 (m, 2H), 2.67 (s, 6H), 3.09 (s, 3H), 3.19 - 173 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 (s, 3H), 3.20 (s, 3H), 3.22 (s, 3H), 3.47 (s, 3H), 3.72-3.75 (m, 1H), 3.82 (br, 1H), 3.97-3.99 (m, 1H), 4.07-4.10 (m, 1H), 4.50-4.52 (m, 1H), 4.65-4.67 (t, J = 8.4 Hz, 1H), 4.79-4.81 (m, 1H), 4.90-4.95 (m, 2H), 5.00 -5.05 (m, 2H), 5.09 (d, J = 10.8Hz, 1H), 5.30-5.35 (m, 2H), 5.46 (d, J = 6.0Hz, 1H), 5.52-5.53 (m, 1H), 5.66-5.68 (m, 1H), 7.12 (d, J = 7.8Hz, 1H), 7.47 (d, J = 8.4Hz, 1H), 7.60 (d, J = 7.2Hz, 1H), 7.87-7.89 (d, J = 9.6Hz, 1H)]. [a-Methylene-Sar]-3-[(y-hydroxy)-NMeLeu]-4-cyclosporin Method 1 Mol. Wt: 1248.66 Mol. Wt.: 1230.65

[0330] To a solution of [a-hydroxymethyl-Sar]-3-[(y-hydroxy)-NMeLeu]-4-cyclosporin (0.25 g, 0.20 mmol) in dichloromethane (10 mL) at room temperature were added triethylamine (0.33 mL, d 0.726, 2.40 mmol) and triethylamine hydrochloride (95.6 mg, 1.00 mmol), followed by adding p-toluenesulfonyl chloride (0.23 g, 1.20 mmol) under stirring. The mixture was stirred at room temperature overnight. Then the reaction mixture was washed with brine, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The reaction mixture of [a-chloromethyl-Sar]-3-[(y-hydroxy)-NMeLeu]-4-cyclosporin [Molecular formula: C63H112CIN11O13; Exact Mass: 1265.81; MS (m/z): 1266.32 (M+l)+, 1288.43 (M+Na)+] and [ap-toluenesulfonylmethyl-Sar]-3-[(y-hydroxy)-NMeLeu]-4-cyclosporin [Molecular formula: C70H119N11O16S; Exact Mass: 1401.856; MS (m/z): 1402.34 (M+l)+, 1424.62 (M+Na)+] was directly used in next step reaction without further purification. To a solution of the above mixture in tetrahydrofuran (20 ml) was added sodium hydride (320 mg, 60% in oil, 8 mmol) at 0 °C. The mixture was stirred at 0 °C for one hour and then warmed up to room temperature for 30 minutes. The reaction was quenched with a saturated ammonia chloride solution. After removing tetrahydrofuran, the crude product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate/methanol (20/1) to give 45 mg of product (yield: 18 %) [Molecular formula: C63H111N11O13; Exact Mass: 1229.84; MS (m/z): 1230.6 (M+l)+, 1252.82 (M+Na)+; TLC Rf: 0.50 (ethyl acetate/methanol = 10/1); HPLC RT: 15.38 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm); ’H NMR spectrum (600 - 174 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 MHz, CDCh, 5 in ppm): 0.72 (d, J = 5.4Hz, 3H), 0.84-1.00 (m, 30H), 1.17-1.26 (m, 15H), 1.34 (d, J = 6.0 Hz, 3H), 1.44 -1.47 (m, 2H), 1.59-1.62 (m, 6H), 1.69-1.76 (m, 4H), 1.94-1.99 (m, 1H), 2.09-2.13 (m, 3H), 2.34-2.37 (m, 3H), 2.65(s, 3H), 2.67 (s, 3H), 3.09 (s, 3H)), 3.10 (s, 3H), 3.19 (s, 3H), 3.44 (s, 3H), 3.46 (s, 3H), 3.80 (m, 1H), 3.91 (m, 1H), 4.47-4.50 (m, 1H), 4.68- 4.71(t, J = 9.0Hz, 1H), 4.78-4.81 (m, 1H), 4.98-5.02 (m, 2H), 5.06-5.11 (m, 3H), 5.24 (s, 1H), 5.32 (m, 2H), 5.41-5.43 (m, 2H), 5.64-5.66 (m, 1H), 7.11 (d, J = 7.2Hz, 1H), 7.49 (d, J = 7.2Hz, 1H), 7.74 (d, J = 8.4Hz, 1H), 7.84 (d, J = 9.6Hz, 1H)]. [a-Methylene-Sar]-3-[(y-hydroxy)-NMeLeu]-4-cyclosporin Method 2 Mol. Wt: 1248.66 Mol. Wt.: 1230.65 [0331] [(R)-a-Hydroxymethyl-Sar]-3-[(Y-hydroxy)-NMeLeu]-4-cyclosporin (crude, 2.00 g), carbon tetrabromide (2.66 g, 8.02 mmol) and triphenylphosphine (2.11 g, 8.02 mmol) were dissolved in dichloromethane (30 ml). The mixture was stirred under nitrogen at room temperature for two hours. Then the mixture was added into a suspension of sodium hydride (60% dispersion in mineral oil) (0.77 g, 19.25 mmol) in tetrahydrofuran (30 ml) under nitrogen at 0 °C. The mixture was stirred at 0 °C for one hour. Most of solvents then were evaporated under reduced pressure. The residue was treated with water (10 ml) slowly at 0 °C. Ethyl acetate (30 ml) and water (30 ml) were added and the mixture was separated. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane/acetone from 90/10 to 70/30) to give 0.68 g product of [a-methylene-Sar]-3-[(y-hydroxy)-NMeLeu]-4-cyclosporin [Molecular Formula: CgiHuiNuOb; Exact Mass: 1229.84; MS (m/z): 1230.50 (M+l)+, 1252.68 (M+Na)+; TLC Rf: 0.50 (ethyl acetate/methanol = 10/1); HPLC RT: 15.36 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. - 175 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [a-Methylene-Sar]-3-[(Y-hydroxy)-NMeLeu]-4-cyclosporin Method 3 Exact Mass: 1247.85 Exact Mass: 1229.84 Mol. Wt: 1248.66 Mol. Wt: 1230.65

[0332] To a solution of [(R)-a-hydroxymethyl-Sar]-3-[(y-hydroxy)-NMeLeu]-4- cyclosporin (0.25 g, 0.20 mmol) in methylene chloride (10 mL) was added dropwise 1-chloroN,N,2-trimethyl-l-propenylamine (131 pl, d 1.01, 1.0 mmol) at 0 °C under nitrogen atmosphere. After stirred for 30 minutes at 0 °C, the mixture was allowed to warm to room temperature and stirred for another hour. The reaction mixture was washed with sodium bicarbonate solution, brine, dried over magnesium sulfate and evaporated under reduced pressure. The crude product containing [a-chloromethyl-Sar]-3-[(y-hydroxy)-NMeLeu]-4-cyclosporin [Molecular formula: C63H112CIN11O13; Exact Mass: 1265.81; MS (m/z): 1266.32 (M+l)+, 1288.43 (M+Na)+] was used in next step reaction without further purification. To a solution of the above crude product in tetrahydrofuran (20 ml) was added sodium hydride (320 mg, 60% in oil, 8 mmol) at 0 °C under stirring. The mixture was stirred at 0 °C for one hour and then warmed up to room temperature for another 30 minutes. The reaction was then quenched with a saturated ammonia chloride solution. After removing tetrahydrofuran, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate/methanol (20/1) to give 33 mg of product (yield: 13 %) [Molecular formula: C63H111N11O13; Exact Mass: 1229.84; MS (m/z): 1230.45(M+l)+, 1252.65 (M+Na)+; TLC Re 0.50 (ethyl acetate/methanol = 10/1); HPLC RT: 15.36 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. - 176 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [a-Methylene-Sar]-3-[(Y-hydroxy)-NMeLeu]-4-cyclosporin Method 4 Cb3hiuniiOi3 Exact Mass: 1229.84 Mol. Wt: 1230.65 [0333] n-Butyllithium (2.2 M, 49.30 ml, 108.46 mmol) was added into a solution of diisopropylamine (15.39 ml, 108.46 mmol) in tetrahydrofuran (150 ml) at -78 °C under nitrogen. After the reaction mixture was stirred for an hour, a solution of [(y-hydroxy)-NMeLeu]-4- cyclosporin (12.00 g, 9.86 mmol) in tetrahydrofuran (30 ml) was added over 10 min. The stirring was continued at -78 °C for two hours. Carbon dioxide gas was bubbled through the reaction mixture for two hour and the mixture was stirred at -78 °C for another hour. Then the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature slowly with bubbling out of unreacted carbon dioxide. The mixture was cooled to about 0-5 °C by ice bath and chloromethyl chloroformate (13.98 g, 108.46 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. Water (30 ml) was added to quench the reaction. Most of solvent was then evaporated under reduced pressure. Ethyl acetate (100 ml) and water (80 ml) were added. The ethyl acetate layer was separated and washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography with hexane/acetone (from 90:10 to 70:30) as eluent to give 4.74 g of pure product of [a-Methylene-Sar]-3-[(y-hydroxy)-NMeLeu]-4-cyclosporin* [Molecular Formula: CmHihNuOb; Exact Mass: 1229.84; MS (m/z): 1230.39 (M+l)\ 152.59 (M+Na)': TLC Re 0.50 (ethyl acetate/methanol = 10/1); HPLC RT: 15.38 min (C8 reverse phase column: 250 mm; acetonitrile/water (0.05% trifluoroacetic acid); operation temperature: 64 °C; detector: 210 nm)]. This [a-Methylene-Sar]-3-[(y-hydroxy)-NMeLeu]-4-cyclosporin prepared using a method analogous to the procedure described in WO2012/051194A1. - 177 -84932431 Example 43 Anti HCV Activity of Cyclosporin Derivatives

[0040] Anti-HCV activity of cyclosporine derivatives were evaluated in the HCV subgenomic replicon assay. The assay use the cell line ET (luc-ubi-neo/ET), which is a Huh7 human hepatoma cell line harboring an HCV replicon with a stable luciferase (Luc) reporter. HCV RNA replication was assessed by quantifying HCV replicon-derived luciferase activity. The antiviral activity of cyclosporine analogs were evaluated after drug treatment to derive ECso and EC90 values by using the luciferase end point (Krieger, N., et al., 2001, J. Virol. 75, 4614-4624; Pietschmann, T., et al., 2002, J. Virol. 76, 4008-4021). Cytotoxicity was assessed in parallel. Table 2. Testing results of certain representative compounds Compound Antiviral activity Cyclosporine A * [N-MeHe]-4-cyclosporin (SDZ-NIM-811) [N-MeVal]-4-cyclosporin (SDZ 220-384) ** (R)-2-(N,N-Dimethylamino)ethylthio-Sar]-3-[(y-hydroxy)-N-MeLeu]-4- cyclosporin (SCY-635) *** [D-N-MeAla]-3-[N-EtVal]-4-cyclosporin (Alisporivir, Debio-025) **** (R)-2-(N,N-Diethylamino)ethylthio-Sar]-3-[N-MeIle]-4-cyclosporin **** (S)-2-(N,N-Diethylamino)ethylthio-Sar]-3-[N-MeIle]-4-cyclosporin No activity [8-(2-Acetamidoethyl)aminoethyl)-6,7-dihydro-MeBmt]-1-[(R)-2-methylSar]-3-cyclosporin (CPI-431-32(CRV431)) **** [8-(2-Acetamidoethyl)-6, 7-dihydro-MeBmt]-l-cyclosporin **** [8-(2-Acetamidoethyl)-6, 7-dihydro-MeBmt]-l-[(R)-Methyl]-3- cyclosporin **** [8-(2-Acetamidoethyl)-6, 7-dihydro-MeBmt]-l-[(y-hydroxy)-NMeLeu]-4-cyclosporin **** [8-(2-Acetamidoethyl)-6, 7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-[(y-hydroxy)-N-MeLeu]-4-cyclosporin **** [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(R)-hydroxymethyl-Sar]- 3-cyclosporin **** [8-(2-Acetamidoethyl)-6, 7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin **** Antiviral activity: ****IC5o < 35 nM; ***35 nM < IC50 < 90 nM; **90 nM < IC50 < 250 nM; * 250 nM < IC50 < 450 nM; No activity > 1500 nM. Example 44 Cyclophilin A and D (CyPA & CyPD) PPIase Inhibition Assay

[0041] Inhibition of CyPA isomerase activity was assessed using the a-chymotrypsin-coupled assay adapted to a 96-well plate format. Human recombinant CypA (Atgen) was dissolved to 10 - 178 - Date reçue/Date Received 2023-10-06CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 nM in isomerase buffer (50 mM Hepes, 100 mM NaCl, 1 mg/ml bovine serum albumin, 1 mg/ml a-chymotrypsin; pH 8). Succinyl-AAPF-pNA peptide substrate (Sigma) was dissolved to 3.2 mM in dried LiCl/trifluoroethanol. Each test compound was prepared at 10 concentrations in DMSO, and then diluted into CypA-isomerase buffer to 0.05-1000 nM (reaction mix). All solutions were equilibrated, and reactions conducted at 5°C. Reactions were initiated by mixing 95 pL reaction mix with 5 pL peptide preloaded in multiple wells of 96-well plates and measuring OD405 nm in each well at 6-sec intervals for 6 min using a BMG Polarstar Galaxy plate reader. Data were fitted with Graphpad Prism 6.0 to obtain first-order rate constants. Enzyme catalyzed rate constants were calculated by subtracting the rate constant from uncatalyzed reactions (no CypA), and the catalytic rate constants plotted as a function of inhibitor concentration to obtain IC50s (see Gallay et al., 2015, PLOS ONE). Table 3. ECso based on PPIase Inhibition of Cyclophilin A (CyPA) for certain representative compounds Compound PPIase Inhibition of CyPA Cyclosporine A * (R)-2-(N,N-Dimethylamino)ethylthio-Sar]-3-[(y-hydroxy)-N-MeLeu]-4- cyclosporin (SCY-635) ** [D-N-MeAla]-3-[N-EtVal]-4-cyclosporin (Alisporivir, Debio-025) *** [8-(2-Acetamidoethyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-2-methylSar]-3-cyclosporin (CPI-431-32(CRV431)) 4< 4c 4c [(S)-(4-Hydroxylbutylthio)methyl-Sar]-3-[(y-hydroxy)-N-MeLeu]-4- cyclosporin *** [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin *** CyPA PPIase inhibition activity: *** IC50 < 4.0 nM; **4.0 nM < IC50 < 10.0 nM; * 10.0 nM < IC50 < 20.0 nM. Table 4. ECso based on PPIase Inhibition of Cyclophilin D (CyPD) for certain representative compounds Compound PPIase Inhibition of CyPD ECso (nM) Cyclosporine A 4c (R)-2-(N,N-Dimethylamino)ethylthio-Sar]-3-[(y-hydroxy)-N-MeLeu]-4- cyclosporin (SCY-635) 4c 4c [D-N-MeAla]-3-[N-EtVal]-4-cyclosporin (Alisporivir, Debio-025) *** [8-(2-Acetamidoethyl)aminoethyl)-6,7-dihydro-MeBmt]-l-[(R)-2-methylSar]-3-cyclosporin (CPI-431-32(CRV431)) *** - 179 -CA 03024320 2018-11-14 WO 2017/200984 PCT/ÜS2017/032811 [(S)-(4-Hydroxylbutylthio)methyl-Sar]-3-[(y-hydroxy)-N-MeLeu]-4- cyclosporin *** [8-(2-Acetamidoethyl)-6,7-dihydro-MeBmt]-l-[(S)-(4- hydroxybutylthio)methyl-Sar]-3-cyclosporin *** CyPD PPIase inhibition activity: *** IC50 < 4.0 nM; **4.0 nM < IC50 < 10.0 nM; * 10.0 nM < IC50 < 20.0 nM. - 180 -

Claims (26)

1. 84932431 CLAIMS: 1. A compound having the structure of wherein Zi is NHAc, NHCOCH2D, NHCOCHD2, or NHCOCD3; xis 1; m’ is 4; Y is Hot OH; Wis S; and Rajs —0H or a pharmaceutically acceptable salt thereof.
2. 2. The compound of claim 1, wherein Ra is ,
3. 3. The compound of claim 1, wherein Ra is 0 , o , or 0 .
4. 4. The compound of claim 1, wherein Ra is
5. 5. The compound of claim 3, wherein Ra is 0 .
6. 6. The compound of claim 3, wherein Ra is ° .
7. 7. The compound of claim 3, wherein Ra is ° . - 181 - Date reçue/Date Received 2023-10-06 84932431
8. 8. The compound of claim 3, wherein Ra is ° .
9. 9. The compound of claim 3, wherein Ra is o .
10. 10. The compound of claim 1, wherein Zi is NHAc.
11. 11. The compound of claim 11, wherein Ra is
12. 12. The compound of claim 11, wherein Ra is 0 , ° , ° ,
13. 13. The compound of claim 1, wherein the compound is - 182- Date reçue/Date Received 2023-10-06 84932431
14. 14. The compound of claim 1, wherein the compound is
15. 15. The compound of claim 1, wherein the compound is [(8-(2-acetamidoethyl)-6,7-dihydroMeBmt]-1-((S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin.
16. 16. A pharmaceutical composition comprising at least one compound according to any one of claims 1-15 and a pharmaceutically-acceptable carrier or diluent.
17. 17. A compound of any one of claims 1-15 for use in treating or preventing a viral infection in a mammalian species in need thereof.
18. 18. A compound of any one of claims 1-15 for use in treating or preventing hepatitis C virus infection in a mammalian species in need thereof.
19. 19. A compound of any one of claims 1-15 for use in treating or preventing hepatitis B virus infection in a mammalian species in need thereof.
20. 20. A compound of any one of claims 1-15 for use in treating or preventing HIV infection in a mammalian species in need thereof.
21. 21. A compound of any one of claims 1-15 for use in inhibiting a cyclophilin in a subject in need thereof.
22. 22. A compound of any one of claims 1-15 for use in treating or preventing diseases that are mediated by cyclophilins in a mammalian species in need thereof.
23. 23. A compound of any one of claims 1-15 for use in preventing diseases in a mammalian species in need thereof, wherein the diseases are selected from inflammation, respiratory inflammation, rheumatoid arthritis, and dry eye. - 183 - Date reçue/Date Received 2023-10-06 84932431
24. 24. A compound of any one of claims 1-15 for use in treating or preventing diseases in a mammalian species in need thereof, wherein the diseases are selected from Alzheimer’s disease, Parkinson’s disease, Huntington’s Diseases, ALS, traumatic brain injury, stroke, and ischemia-reperfusion injury in the brain, heart, kidney, and myocardial infarction.
25. 25. A compound of any one of claims 1-15 for use in treating or preventing diseases in a mammalian species in need thereof, wherein the diseases are selected from cardiovascular diseases, vascular stenosis, atherosclerosis, abdominal aortic aneurysms, cardiac hypertrophy, aortic rupture, pulmonary arterial hypertension, myocarditis and myocardial fibrosis, and ischaemic heart diseases.
26. 26. A compound of any one of claims 1-15 for use in treating or preventing diseases or conditions in a mammalian species in need thereof, wherein the diseases or conditions are selected from cancer, obesity, diabetes, muscular dystrophy, lung diseases, liver diseases, kidney diseases, and hair loss. - 184 - Date reçue/Date Received 2023-10-06