Novel macrocyclic compounds, methods for preparing same and pharmaceutical compositions containing same

Abstract

Formula (I): TIFF2023515572000128.tif48161 [In the formula, Z, Y1, Y2, TIFF2023515572000129.tif18161 R1 to R7 are as defined in the specification. a compound represented by the formula: embedded image and its optical isomers and addition salts with pharmaceutically acceptable bases.

Description

[Technical Field]

[0001] The present invention relates to novel macrocyclic compounds, processes for their preparation and pharmaceutical compositions containing them.

[0002] The compounds of the present invention are novel and have very valuable pharmacological properties.

[0003] Background of the Invention Nuclear factor erythroid 2-related factor 2 (Nrf2), also known as nuclear factor erythroid 2-like 2, is a transcription factor encoded by the NFE2L2 gene in humans (Moi P, Chan K, Asunis I, Cao A, Kan YW 1994. Proceedings of the National Academy of Sciences of the United States of America. 91 (21): 9926-30). Nrf2 is a basic leucine zipper (bZIP) protein that regulates and coordinates the basal and stress-induced activation of a vast number of cytoprotective genes. Of particular importance in this regard is the transcription of components of the glutathione and thioredoxin antioxidant systems, as well as enzymes involved in phase I and phase II detoxification of exogenous and endogenous products, NADPH regeneration, and heme metabolism. Thus, Nrf2 represents a key regulator of cellular defense mechanisms against xenobiotics and oxidative stress (Vomund S, Schafer, A, Parnham MJ, Brune B, and von Knethen A Int J Mol Sci. 2017 Dec; 18(12): 2772; Bischof LJM, Isoude A, Kuijper1 Schimming JP, Wolters L, ter Braak B, Langenberg JP, Noort D, Beltman JB and van de Water B Archives of Toxicology (2019) 93:435-451).Equally important, Nrf2 is involved in and modulates important cellular processes, such as inflammation, autophagy, glucose and lipid metabolism, stem cell quiescence, and the unfolded protein response (reviewed in Yamamoto M, Kensler TW, Motohashi H (2018). Physiol Rev 98:1169-1203; Ahmed SMU, Luo L, Namani A, Wang XJ, Tang X Biochimica et Biophysica Acta 1863 (2017) 585-597; Hayes JD and Dinkova-Kostova AT, Trends in Biochemical Sciences, vol. 39, no. 4, pp. 199-218, 2014).

[0004] Because alterations in these fundamental physiological processes are closely associated with many diseases, the regulatory system of Nrf2 activity has proven to be an attractive drug target for many important medical indications, such as metabolic, cardiovascular, neurodegenerative, and autoimmune diseases (Cuadrado A, Rojo AI, Wells G, Hayes JD, Cousin SP, Rumsey WL, Tucks OC, Franklin S, Levonen AL, Kensler TW and Dinkova-Kostova AT Nature Reviews Drug Discovery 2019 volume 18, pages 295-317; Robledinos-Anton N, Fernandez-Gines R, Manda G, Cuadrado A. Oxid Med Cell Longev. 2019:9372182; Satta S, Mahmoud AM, Wilkinson FL, Alexander MY and White SJ. Oxidative Medicine and Cellular Longevity Volume 2017; Gao B., Doan A., (Reviewed in Hybertson BM Clin. Pharmacol. 2014;6:19-34).

[0005] Nrf2 is an important part of the evolutionarily conserved defense mechanism in mammals, and zebrafish, Drosophila, and C. elegans have been shown to possess similar anti-stress systems (reviewed in Fuse Y and Kobayashi M. Molecules. 2017 Mar;22(3):436). Nrf2 is ubiquitously and constitutively expressed in cells, ensuring their rapid protective response to oxidative, inflammatory, and metabolic stress. Nrf2 expression is tightly regulated, and under healthy / non-stress conditions, low Nrf2 levels provide basal expression of its target genes. Under these conditions, Nrf2 has a rapid turnover due to its constant degradation by the ubiquitin proteasome system (McMahon M, Thomas N, Itoh K, Yamamoto M, and Hayes JD, Journal of Biological Chemistry 2004 vol. 279, no. 30, pp. 31556-31567; Katoh Y, Iida K, Kang MI, Kobayashi A, Mizukami M, Tong KI, McMahon M, Hayes JD, Itoh K, Yamamoto M. Archives of Biochemistry and Biophysics, vol. 433, no. 2, pp. 342-350, 2005).

[0006] Degradation of Nrf2 is regulated through binding to the E3 ubiquitin ligase adaptor protein KEAP1 (Kelch-like ECH-associated protein 1). In the presence of oxidative and xenobiotic stress, Nrf2 degradation is blocked through the release of Keap1, allowing Nrf2 to accumulate and translocate into the nucleus, where it heterodimerizes with bZip proteins, such as small aponeurotic fibromatosis (MAF) K, G, and F, via the Neh1-containing CNC-bZip domain (Ma Q. Annual Review of Pharmacology and Toxicology, vol. 53, no. 1, pp. 401-426, 2013; Hayes JD and Dinkova-Kostova AT, Trends in Biochemical Sciences, vol. 39, no. 4, pp. 199-218, 2014). In humans, these heterodimers directly regulate the expression of approximately 250 genes that display regulatory enhancer sequences called antioxidant response elements (AREs). These genes are involved in and regulate multiple homeostatic functions, including redox homeostasis, detoxification, inflammation, proteostasis, and metabolism (Pajares M, Jimenez-Moreno N, Garcia-Yague AJ et al., Autophagy 2016, vol. 12, no. 10, pp. 1902-1916; Pajares M, Cuadrado A, and Rojo AI, Redox Biology 2017, vol. 11, pp. 543-553; Pajares M, Jimenez-Moreno N, Dias IHK et al., Redox Biology 2015, vol. 6, pp. 409-420; de la Vega MR, Dodson M, Gross C et al. Current Pharmacology Reports, vol. 2, no. 2, pp. 91-101, 2016).

[0007] KEAP1 has two distinct structural domains: the BTB (broad complex, tramtrack, and bric-a-brac) domain in the N-terminal region and the double glycine repeat (DGR; also called the Kelch domain) in the C-terminal region (Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, and Yamamoto M Genes Dev. 1999 Jan 1;13(1):76-86). The BTB domain contributes to KEAP1 homodimerization and its interaction with CUL3, whereas the Kelch domain mediates KEAP1 binding to Nrf2 by interacting with the Neh2 domain. In this KEAP1-Nrf2 interaction, two specific motifs in the Neh2 domain of Nrf2, i.e., DLG and ETGE, individually bind to the Kelch domain of the KEAP1 homodimer. The identification of two binding sites of KEAP1 homodimers to Nrf2 led to a proposed molecular mechanism for electrophilic stress sensing, described in detail by Tong et al. (Tong KI, Katoh Y, Kusunoki H, Itoh K, Tanaka T, Yamamoto M (2006) Mol Cell Biol 26:2887-2900; Tong KI, Padmanabhan B, Kobayashi A, Shang C, Hirotsu Y, Yokoyama S, Yamamoto M (2007). Mol Cell Biol 27:7511-7521. https: / / doi.org / 10.1128 / MCB.00753-072006) and reviewed by Yamamoto et al. (Yamamoto M, Kensler TW, Motohashi H (2018). Physiol Rev 98:1169-1203).

[0008] The intervening region (IVR) of KEAP1, located between the BTB and DGR / Kelch domains, is rich in reactive cysteine ​​(Cys) residues that function as stress sensors. 27 and 25 Cys residues were identified in the human and mouse KEAP1 proteins, respectively. Among these, Cys151 in the BTB domain and Cys273 / 288 in the IVR are the main sensor cysteine ​​residues (Dinkova-Kostova, AT, Holtzclaw, WD, Cole, RN, Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., and Talalay, P. (2002). Proc. Natl. Acad. Sci. USA 99, 11908-11913;Zhang, DD and Hannink, M. (2003) Mol. Cell. Biol. 23, 8137-8151;Saito, R., Suzuki, T., Hiramoto, K., Asami, S., Naganuma, E., Suda, H., Iso, T., Yamamoto, H., Morita, M., Baird, L., et al. (2016). Mol. Cell. Biol. 36,271-284; Suzuki T, Muramatsu A, Saito R, Iso T, Shibata T, Kuwata K, Kawaguchi SI, Iwawaki T, Adachi S, Suda H, Morita M, Uchida K, Baird L, Yamamoto M (2019) Cell Rep 28:746-758). The specificity of Keap1 cysteine ​​residues for various chemical inducers of Nrf2 was investigated using mutants of three major cysteine ​​residues, namely, Cys151, Cys273, and Cys288.These experiments have led to the classification of Nrf2 inducers into four classes: class I (Cys151-selective), class II (Cys288-selective), class III (Cys151 / Cys273 / Cys288-coselective), and class IV (Cys151 / Cys273 / Cys288-independent) (Saito, R., Suzuki, T., Hiramoto, K., Asami, S., Naganuma, E., Suda, H., Iso, T., Yamamoto, H., Morita, M., Baird, L., et al. (2016). Mol. Cell. Biol. 36, 271-284). The cysteine ​​codes for Keap1 modification sites by various electrophiles have recently been summarized (Unoki T, Akiyama M, Kumagai Y. Int J Mol Sci. 2020 Jan 15;21(2)). However, as exemplified by 15-deoxy-prostaglandin J2 (15d-PGJ2) and prostaglandin A2 (PGA2), it appears difficult to define the chemical properties of each class. Despite sharing similar structural features, 15d-PGJ2 and PGA2 belong to class II and class IV, respectively. Therefore, the complex properties of electrophiles, such as their structure and reactivity, may determine their interaction with specific Keap1-reactive cysteine ​​residues (Unoki T, Akiyama M, Kumagai Y. Int J Mol Sci. 2020 Jan 15;21(2)).

[0009] Nrf2 activators, or KEAP1 inhibitors (when their molecular target is KEAP1) (Magesh S., Chen Y. and Hu L. Medicinal Research Reviews, 2012 vol. 32, no. 4, pp. 687-726), can be classified as electrophiles, protein-protein interaction (PPI) inhibitors, and multi-target drugs.

[0010] Most pharmacological Nrf2 activators are electrophilic molecules that covalently modify one or more cysteine ​​residues present in the thiol-rich KEAP1 protein by oxidation or alkylation (Hur W., Gray NS Current Opinion in Chemical Biology. 2011;15(1):162-173; Satoh T., McKercher SR, Lipton SA Free Radical Biology & Medicine. 2013;65:645-657; Wilson AJ, Kerns JK, Callahan JF, Moody CJ Journal of Medicinal Chemistry. 2013;56(19):7463-7476). The only Nrf2 activators currently available commercially are dimethyl fumarate (BG-12 or Tecfidera) and diroximel fumarate (DRF) from Biogen. For relapsing-remitting multiple sclerosis (MS), dimethyl fumarate was approved in 2013, and DRF was approved in 2019 (Schimrigk S., Brune N., Hellwig K., et al. European Journal of Neurology. 2006;13(6):604-610; Gold R., Kappos L., Arnold DL, et al. The New England Journal of Medicine. 2012;367(12):1098-1107; Fox RJ, Miller DH, Phillips JT, et al. The New England Journal of Medicine. 2012;367(12):1087-1097; Xu Z., Zhang F., Sun F., Gu KF, Dong S., He D. Cochrane Database of Systematic Reviews. 2015;4; Mills EA, Ogrodnik MA, Plave A., Mao-Draayer Y. Frontiers in Neurology. 2018;9(5)).Previously, dimethyl fumarate was approved for the treatment of psoriasis (Hoxtermann S., Nuchel C., Altmeyer P. Dermatology. 1998;196 (2):223-230). Dimethyl fumarate-induced activation of Nrf2 in the central nervous system was described in an MS mouse model of experimental allergic encephalomyelitis (Linker RA, Lee DH, Ryan S., et al. Brain. 2011;134(3):678-692). In this model, dimethyl fumarate-dependent Nrf2 activation correlated with improved clinical course of MS, promoted axonal preservation, and enhanced astrocyte activation. These beneficial effects of dimethyl fumarate did not occur in Nrf2-null mice, thus indicating that dimethyl fumarate acts primarily by targeting the Nrf2 pathway. Dimethyl fumarate is largely converted to monomethyl fumarate (MMF) by intestinal esterases, and only a small portion of dimethyl fumarate is found in the blood bound to glutathione (Dibbert S., Clement B., Skak-Nielsen T., Mrowietz U., Rostami-Yazdi M. Archives of Dermatological Research. 2013;305(5):447-451). Because MMF is thought to be the active metabolite of dimethyl fumarate, several clinical trials are underway to evaluate the efficacy and safety of MMF.

[0011] Nrf2 activators that interact with cysteine ​​residues of Keap1 also inherently react with glutathione or thiols in proteins due to their electrophilicity.This is a slightly less expensive ice cream cone Please watch the video Keap1 and Nrf2. The PayPal Performance Index (PPI) is also available in the public domain Please share Nrf2 kit (Bertrand, HC , Schaap , M. , Baird , ND , Fowkes , C. , Kachi , H. , Dinkova , AT , and Wells , G. (2015;Davies, TG, Wixted, WE, Coyle, JE). Griffiths-Jones , C. , Hearn , R. , Norton , D. , Rich , S. J. , Richardson , G. , Willems , H. M. , Cottom , J.E. , Kou , J. G. , et al. http: / / dx.doi.org / 10.1037 / 0021-843X.108.3.391-4006; 26585;Yasuda, D., Nakajima, M., Yuasa, R., Obata, K., Ohe, T., Ichimura, M., Komatsu, M., Imamura, R., Kojima, H., Okabe, T., Nagano, T., and Mashino, T. (2016) Bioorg. Chem., 26, 5956–5959).

[0012] PPI inhibitors most likely interfere with the docking of Nrf2 to the Kelch propeller of KEAP1, offering greater selectivity than electrophilic compounds (Richardson BG, Jain AD, Speltz TE, Moore TW Bioorganic & Medicinal Chemistry Letters. 2015;25(11):2261-2268). Based on the X-ray crystal structure of KEAP1, small PPI inhibitors have been designed to prevent the binding of the DLG and ETGE motifs to KEAP1. The ETGE motif adopts a β-hairpin structure that docks to the Kelch propeller of KEAP1 through specific hydrophobic and electrostatic interactions (Padmanabhan B., Tong KI, Ohta T., et al. Molecular Cell. 2006;21(5):689-700; Lo SC, Li X., Henzl MT, Beamer LJ, Hannink M. The EMBO Journal. 2006;25(15):3605-3617).To date, no PPI inhibitors have entered clinical development; however, potent and selective PPI inhibitors of the KEAP1-Kelch-Nrf2 interaction have been described, and their activity was confirmed in in vitro and in vivo studies, respectively (Davies, TG, Wixted, WE, Coyle, JE, Griffiths-Jones, C., Hearn, K., McMenamin, R., Norton, D., Rich, SJ, Richardson, C., Saxty, G., Willems, HM, Woolford, AJ, Cottom, JE, Kou, JP, Yonchuk, JG, et al. (2016). J. Med. Chem. 59, 3991-4006; Jiang, ZY, Lu, M C., and You, QD (2016). J. Med. Chem. 59, 3991-4006). 10837-10858; Robledinos-Anton N, Fernandez-Gines R, Manda G, Cuadrado A. Oxid Med Cell Longev. 2019:9372182).

[0013] Another mechanism of KEAP1 inhibition is related to its interaction with the CUL3 / RBX1 complex, which is required for Nrf2 ubiquitination and degradation. Cys-151, located in the BTB domain, affects the interaction between KEAP1 and CUL3. The crystal structure of the BTB domain bound to the pentacyclic triterpenoid 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oate (bardoxolone, CDDO-Me, or RTA 402) indicates that adduct formation with Cys-151 disrupts the interaction between KEAP1 and CUL3 (Cleasby A., Yon J., Day PJ, et al. Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO. PLoS One. 2014;9 (6, article e98896); Iso T., Suzuki T., Baird L., Yamamoto M. Molecular and Cellular Biology. 2016;36(24): 3100-3112; Dayalan Naidu S., Muramatsu A., Saito R., et al. Scientific Reports. 2018;8(1):p. 8037). As a result, KEAP1 is locked into an Nrf2-binding conformation, thereby allowing newly expressed Nrf2 to avoid KEAP1-CUL3-mediated ubiquitination.

[0014] Bardoxolone has entered clinical trials for the treatment of advanced chronic kidney disease (CKD) and type 2 diabetes (Pergola PE, Raskin P, Toto RD, et al. The New England Journal of Medicine. 2011;365(4):327-336). Phase II clinical trials demonstrated long-term increases in glomerular filtration, but the compound was halted in Phase III due to cardiovascular safety concerns (Zhang DD Antioxidants & Redox Signaling. 2013;19(5):517-518. doi: 10.1089 / ars.2012.5118). A new Phase III clinical trial of bardoxolone in patients with diabetic kidney disease (AYAME study) was recently initiated by Kyowa Kirin to further define the safety and efficacy profile of CDDO-Me. Bardoxolone is currently in clinical trials for Alport syndrome (Phase II / III CARDINAL trial) and pulmonary hypertension (Phase III CATALYST trial). Additionally, Reata is developing bardoxolone for rare forms of CKD, including autosomal dominant polycystic kidney disease (ADPKD), immunoglobulin A nephropathy (IgAN), type 1 diabetic CKD (T1D CKD), and focal segmental glomerulosclerosis (FSGS). A second-generation derivative of bardoxolone, called omaveloxone (RTA-408), is undergoing clinical investigation in the MOXIe trial, a pivotal registry for Friedreich's ataxia (Lynch DR, Farmer J., Hauser L. et al. Annals of Clinical Translational Neurology. 2019;6(1):15-26; https: / / www.reatapharma.com / our-science / pipeline / ).

[0015] Several additional mechanisms have been proposed to explain the dissociation of Nrf2 from Keap1 under stress conditions: in addition to oxidation of cysteine ​​residues in Keap1 and targeting of DLG and ETGE binding sites, binding of p62 to Keap1 and phosphorylation of Nrf2 by GSK3 have been of particular interest.

[0016] p62, also known as sequestosome 1 (SQSTM1), is a ubiquitin-binding protein that targets protein aggregates for degradation via the autophagy pathway; p62 competes with Nrf2 for binding to Keap1, and binding of p62 to Keap1 leads to the degradation of Keap1 and consequent stabilization of Nrf2 (Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y, et al. Nat Cell Biol 2010; 12(3):213-23; Lau A, Wang XJ, Zhao F, Villeneuve NF, Wu T, Jiang T, et al. Mol Cell Biol 2010; 30(13):3275-85). The p62 gene promoter contains an ARE, which induces ARE-driven p62 gene transcription, creating an Nrf2-driven positive feedback loop (Jain A, Lamark T, Sjottem E, Larsen KB, Awuh JA, Overvatn A, et al. J Biol Chem 2010; 285(29):22576-91). Because p62 is a cargo receptor for selective autophagy, Keap1-Nrf2 has an intriguing functional interaction with autophagy (Towers CG, Fitzwalter BE, Regan D, Goodspeed A, Morgan MJ, Liu CW, et al. Dev Cell 2019. 23;50(6):690-703. doi: 10.1016 / j.devcel.2019.07.010).

[0017] Nrf2 stability is also regulated by glycogen synthase kinase (GSK)-3-mediated phosphorylation. GSK-3 phosphorylates the DSGIS motif located in the Neh6 domain of Nrf2, thereby creating a recognition site for the β-transducin repeat-containing E3 ubiquitin protein ligase (β-TrCP). This interaction targets Nrf2 for ubiquitin-dependent proteasomal degradation (Rada P1, Rojo AI, Chowdhry S, McMahon M, Hayes JD, Cuadrado A. Mol Cell Biol. (2011) Mar;31(6):1121-33). These data may suggest that GSK-3 inhibitors may have utility as Nrf2 activators.

[0018] In addition to dimethyl fumarate for the treatment of relapsing-remitting multiple sclerosis and psoriasis, respectively, the broad therapeutic potential of Nrf2 activators is supported by numerous studies.

[0019] The importance of Nrf2 in protecting against reactive electrophiles was first demonstrated using acetaminophen. Nrf2 knockout mice exhibited greater hepatotoxicity after acetaminophen exposure than WT mice, with elevated serum ALT levels and altered liver histology (Chan K, Han X, Kan Y. Proc Natl Acad Sci USA 2001;98:4611-4616; Enomoto A, Itoh K, Nagayoshi E, Haruta J, Kimura T, O'Connor T, Harada T, Yamamoto M. Toxicol Sci 2001;59:169-177).

[0020] Acetaminophen has also been shown to activate the nuclear translocation of Nrf2 at nontoxic doses, thereby demonstrating a role for Nrf2 in orchestrating an adaptive response that results in attenuation of acetaminophen toxicity (Goldring C, Kitteringham N, Elsby R, Randle L, Clement Y, Williams D, McMahon M, Hayes J, Itoh K, Yamamoto M, Park B. Hepatology 2004;39:1267-1276). This adaptive response results in increased de novo synthesis of GSH and increased conjugation and excretion of reactive acetaminophen metabolites. This observation was further confirmed using hepatocyte-specific conditional Keap1 knockout mice, a model in which the absence of inhibitory components of the Nrf2 signaling pathway leads to elevated and sustained nuclear accumulation of Nrf2. These conditional knockout mice were significantly more resistant to acetaminophen toxicity than WT mice due to higher levels of cytoprotective enzymes regulated by Nrf2 (Okawa H, Motohashi H, Kobayashi A, Aburatani H, Kensler T, Yamamoto M. Biochem Biophys Res Commun 2006;339:79-88).

[0021] Activation of Nrf2 signaling by KEAP1 gene knockdown suppressed the onset of diabetes, and when crossed with diabetic db / db mice, blood glucose levels were lowered due to improvements in both insulin secretion and insulin resistance. KEAP1 knockdown also prevented high-calorie diet-induced diabetes, and oral administration of the Nrf2 inducer CDDO-Im also attenuated diabetes in db / db mice. Interestingly, Nrf2 induction altered the expression of antioxidant, energy expenditure, and gluconeogenesis-related genes in metabolic tissues. Overall, these data suggest that the KEAP1-Nrf2 axis is an important target for preventing the onset of diabetes mellitus (Uruno A, Furusawa Y, Yagishita Y, Toshiaki Fukutomi T, Muramatsu H, Negishi T, Sugawara A, Kensler TW, Yamamotoa M. Molecular and Cellular Biology 2013; 2996-3010). Consistent with the data obtained in db / db mice, Xue et al. investigated the effects of Nrf2 ablation in ob / ob mice. Global ablation resulted in a reduction in white adipose tissue (WAT) mass but also in a more severe metabolic syndrome accompanied by worsening insulin resistance, hyperglycemia, and hypertriglyceridemia. Compared with wild-type mice, WAT from ob / ob mice expressed substantially higher levels of many genes related to antioxidant response, inflammation, adipogenesis, lipogenesis, glucose uptake, and lipid transport. Lack of Nrf2 in WAT resulted in reduced expression of most of these factors at the mRNA or protein level.These findings support a role for Nrf2 in regulating adipose development and function, where it controls the capacity for WAT expansion and insulin sensitivity, and maintains glucose and lipid homeostasis (Xue P, Hou Y, Chen Y, Yang B, Fu J, Zheng H, Yarborough K, Woods CG, Liu D, Yamamoto M, Zhang Q, Andersen ME, Pi J. Diabetes. 2013 Mar;62(3):845-54).

[0022] Recent data support a critical role for Nrf2 in β-cell survival and proliferation under stress conditions. Nrf2 induction is required for ChREBPα-mediated mitochondrial biogenesis and glucose-stimulated, ChREBPα-enhanced β-cell proliferation. Interestingly, overexpression of Nrf2 is sufficient to drive human β-cell proliferation in vitro, confirming the critical role of this pathway and its potential utility for therapeutic β-cell regeneration strategies (Kumar A, Katz LS, Schulz AM, Kim M, Honig LB, Li L, Davenport B, Homann D, Garcia-Ocana A, Herman MA, Haynes CM, Chipuk JE, Scott DK. Diabetes. 2018 Aug;67(8):1561-1575). Furthermore, Nrf2 activators, such as Oltipraz or dimethyl fumarate, protect isolated mouse β-cells from glucolipotoxicity by preserving mitochondrial function, glucose-dependent ROS turnover, and antagonizing glucolipotoxicity-induced inhibition of insulin release and apoptosis (Schultheis J, Beckmann D, Mulac D, Muller L, Esselen M, Dufer M. Oxid Med Cell Longev. 2019 Nov 11;2019:7518510).

[0023] The important role of Nrf2 in preventing the development of type 2 diabetes in humans is supported by the identification of the Nrf2 rs6721961 polymorphism, a variant of the Nrf2 gene in the upstream promoter region. In a Chinese cohort, this polymorphism was significantly associated with oxidative stress, antioxidant status, and the risk of newly diagnosed T2DM (Wang X, Chen H, Liu J, Ouyang Y, Wang D, Bao W and Liu L. Int J Mol Sci. 2015; 16(7): 16483-16496). SNP rs6721961 was first identified to be associated with risk of acute lung injury, an oxidative stress-mediated condition (Marzec JM, Christie JD, Reddy SP, Jedlicka AE, Vuong H., Lanken PN, Aplenc R., Yamamoto T., Yamamoto M., Cho H.-Y. FASEB J. 2007;21:2237-2246).

[0024] Activation of Nrf2 in a NOD mouse model of type 1 diabetes by knocking down Keap1 expression inhibited T cell infiltration within pancreatic islets, improved impaired insulin secretion, and prevented the development of diabetes mellitus. Notably, Nrf2 activation reduced both plasma interferon-γ (IFN-γ) levels and the number of IFN-γ-positive cells in pancreatic islets. This demonstrates that activation of Nrf2 signaling prevents the development of type 1 diabetes in NOD mice. Therefore, Nrf2 is considered a potential target for the prevention and treatment of type 1 diabetes (Yagishita Y. et al. J Endocrinol. : JOE-18-0355.R2. Published online 2019 Jan 1. doi: 10.1530 / JOE-18-0355).

[0025] Oxidative stress and inflammation are the most important pathogenic events in the development and progression of liver disease, and multiple studies have shown that activation or suppression of Nrf2 has a clear impact on the progression of liver disease (Xu D, Xu M, Jeong S, Qian Y, Wu H, Xia Q and Kong X. Front Pharmacol. 2018; 9: 1428). Nrf2 has been found to be a key regulator for preventing the development of NASH (Gupte AA, Lyon CJ, Hsueh WA (2013).. Curr. Diabetes Rep. 13 362-371. 10.1007 / s11892-013-0372-1), and conversely, loss or deletion of Nrf2 has been found to cause benign steatosis, which progresses to NASH and contributes to the worsening of the disease state (Chowdhry S., Nazmy MH, Meakin PJ, Dinkova-Kostova AT, Walsh SV, Tsujita T., et al. (2010). Free Radic. Biol. Med. 48 357-371;Wang C., Cui Y., Li C., Zhang Y., Xu S., Li X., et al. (2013). Lipids Health Dis. 12:165. 10.1186 / 1476-511X-12-165;Ramadori P., Drescher H., Erschfeld S., Fragoulis A., Kensler TW, Wruck CJ, et al. (2017). Oxid. Med. Cell. Longev. 2017:3420286). The development of NASH was also investigated in p62:Nrf2 double knockout (DKO) mice.DKO mice exhibited massive hepatomegaly and steatohepatitis, hyperphagia-induced obesity, coupled with insulin resistance and adipokine imbalance (Akiyama K, Warabi E, Okada K, Yanagawa T, Ishii T, Kose K, Tokushige K, Ishige K, Mizokami Y, Yamagata K, Onizawa K, Ariizumi SI, Yamamoto M, Shoda J. Exp Anim. 2018 May 10;67(2):201-218).

[0026] The protective role of Nrf2 in NASH was demonstrated by Sharma et al. using the Nrf2-activating small molecule TBE-31. Treatment with TBE31 reversed insulin resistance in high-fat, high-fructose-fed wild-type mice but not in Nrf2-null mice. Furthermore, TBE-31-treated mice showed a substantial reduction in hepatic steatosis and lipogenic gene expression, but increased hepatic expression of fatty acid oxidation and lipoprotein assembly genes. TBE-31 treatment also reduced ER stress, inflammatory gene expression, and markers of apoptosis, fibrosis, and oxidative stress in the livers of high-fat, high-fructose-fed wild-type mice. In comparison, TBE-31 did not reduce steatosis, ER stress, lipogenesis, inflammation, fibrosis, or oxidative stress in the livers of HFFr-fed Nrf2-null mice. The authors concluded that pharmacological activation of Nrf2 in already obese and insulin-resistant mice reversed insulin resistance, suppressed hepatic steatosis, and attenuated NASH and liver fibrosis. These effects were primarily due to inhibition of ER, inflammation, and oxidative stress (Sharma RS, Harrison DJ, Kisielewski D, Cassidy DM, McNeilly AD, Gallagher JR, Walsh SV, Honda T, McCrimmon RJ, Dinkova-Kostova AT, Ashford MLJ, Dillon JF, Hayes JD Cell Mol Gastroenterol Hepatol. 2017 Dec 13;5(3):367-398).

[0027] The hepatoprotective role of Nrf2 was also demonstrated in acute high-dose alcohol exposure using Nrf2-KO mice. Alcohol treatment substantially exacerbated liver and pancreatic damage and pancreatic β-cell damage in these animals (Sun J, Fu J, Zhong Y, Li L, Chen C, Wang X, Wang L, Hou Y, Wang H, Zhao R, Zhang X, Yamamoto M, Xu Y, Pi J. Food Chem Toxicol. 2018 Nov;121:495-503).

[0028] Nrf2 activators have potential utility in diseases / indications associated with increased oxidative stress and inflammation, impaired redox capacity, impaired detoxification and metabolic deregulation.

[0029] Based on Nrf2 knockout, KEAP1 knockout, genetic polymorphism, and compound-mediated Nrf2 activation studies, respectively, we have demonstrated the potential of Nrf2 in the treatment of type I diabetes and type II diabetes and related complications, such as diabetic cardiomyopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and diabetic wound healing; maternal diabetes; liver diseases, such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease, toxin-induced liver disease (e.g., acetaminophen-induced liver disease), alcoholic liver disease (ALD), cholestasis, primary sclerosing cholangitis (PSC), viral hepatitis, cirrhosis, primary cholangitis, and urinary tract infections. liver cirrhosis (PBC), end-stage liver disease, fibrosis; renal diseases, e.g., chronic kidney disease (CKD), acute kidney injury, contrast-induced nephropathy, autosomal dominant polycystic kidney disease (ADPKD), Alstrom syndrome and Alport syndrome, sepsis-induced acute kidney injury; renal disease or dysfunction seen during kidney transplantation, focal segmental glomerulosclerosis, IgA glomerulonephritis / nephropathy, fibrosis; lung diseases, e.g., pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, acute lung injury, lung infection, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary arterial hypertension, lung disease secondary to environmental exposure, chronic and acute asthma, acute respiratory distress syndrome; heart diseases, e.g., atherosclerosis, high blood pressure, heart failure, stroke, cardiomyopathy, coronary heart disease, myocardial ischemia; nerve damage, traumatic brain injury, depression, epilepsy, hepatic encephalopathy, Huntington's disease, Parkinson's disease, Alzheimer's disease, autism, Friedreich's ataxia, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, cerebral infarction, encephalopathy, nerve damage / injury, spinal cord injury; inflammatory diseases, e.g., inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis, arthritis, lupus nephritis; eye diseases, e.g., age-related macular degeneration (AMD), ocular neurodegenerative diseases, age-related macular degeneration Genital warts, cataracts, glaucoma, eye disorders, Fuchs endothelial corneal dystrophy (FECD), uveitis, optic neuropathy / ocular neurodegenerative diseases; colon cancer; autoimmune diseases; psoriasis, dermatitis / local effects of radiation, immunosuppression due to radiation exposure, preeclampsia, altitude sickness; wound healing; metabolic syndrome; mitochondrial myopathy; malaria; ferroptosis / iron overload; allergic contact dermatitis; alcoholism; amyloidosis; anemia; anxiety disorders; Asperger's syndrome; eczema; cerebral edema; cerebral ischemia; cerebrovascular disease; chronic fatigue syndrome; cognitive decline; dermatitis / radiation-induced dermatitis;Evidence is provided for indications including Duchenne muscular dystrophy; edema; encephalitis; male / female fertility; fracture healing; gastroesophageal reflux disease; hearing loss; influenza infection; intestinal barrier dysfunction; osteoarthritis; osteoporosis; radiation-induced injury; reflux-induced esophagitis; reperfusion injury (brain, heart, kidney, liver, retina); schizophrenia; seizures; Sjögren's syndrome; sickle cell disease; skin ulcers; vascular endothelial dysfunction; blood-brain barrier dysfunction; and Down syndrome.

[0030] WO 2015 / 092713 discloses bisaryl compounds as Nrf2 regulators.

[0031] The present invention relates in particular to compounds of formula (I): [ka] [In the formula, Z is -O-(CH2)n1-, -O-(CH2)n1-O-(CH2)n2, -O-(CH2)n1-S-(CH2)n2, O-(CH2)n1-S(O)-(CH2)n2, O-(CH2)n1-S(O2)-(CH 2)n2, -O-(CH2)n1-NR-(CH2)n2, -O-(CH2)n1-CHR'-(CH2)n2, -NR-(CH2)n1-, -NR-(CO)-(CH2)n1-, -O-(CH2)n1-Ar-(CH2 )n2, -O-(CH2)n1-Ar-O-(CH2)n2, -O-(CH2)n1-Ar-S-(CH2)n2, -O-(CH2)n1-Ar-S(O)-(CH2)n2, -O-(CH2)n1-Ar-S(O2)-( CH2)n2, -O-(CH2)n1-Ar-CHR'-(CH2)n2, -O-(CH2)n1-Ar-CH=CH-, O-Ar-NR-(CH2)n1, -(CH2)n1-NR-(CO)-(CH2)n2-, or Z is [ka] and Y1 is C or N; Y2 is O or NR'; [ka] and Ar is an optionally substituted aryl or heteroaryl group; R is a hydrogen atom, a linear or branched C1-C3 alkyl group, or an optionally substituted aryl group; R' is a hydrogen atom or a group selected from hydroxyl, optionally substituted aryl and alkoxy, or straight or branched C1-C3 alkyl optionally substituted with 1 to 3 halogen atoms; n1 and n2 are each an integer of 1 to 6, R1, R2, R4, R8, and R9 may be the same or different, and each represents a group selected from a hydrogen atom, halo, cyano, linear or branched C1-C3 alkyl optionally substituted with 1 to 3 halogen atoms, linear or branched C1-C3 alkoxy, or optionally substituted aryl; R3 is hydrogen or a linear or branched C1-C3 alkyl group optionally substituted with 1 to 3 halogen atoms; or R2 and R3 together with the atoms holding them form a ring, R5 and R6 are the same or different and each represents a hydrogen atom, a deuterium atom, a halogen atom, or a linear or branched C1-C3 alkyl group; R7 is a group selected from hydroxyl and NHR'7; wherein R'7 is a straight or branched chain C1-C6 alkyl group or an optionally substituted aryl or heteroaryl group. The present invention relates to a compound of the formula: Figure imgf000016_0001, its optical isomers and addition salts thereof with pharmaceutically acceptable bases.

[0032] The term "aryl group" means a phenyl, naphthyl or biphenyl group optionally substituted by one or more identical or different groups selected from halogen, hydroxy, amino, straight-chain or branched (C1-C6) alkyl optionally substituted by 1 to 3 halogen atoms, carboxy, cyano, straight-chain or branched (C1-C6) alkoxy optionally substituted by 1 to 3 halogen atoms, straight-chain or branched (C1-C6) aminoalkyl optionally N-substituted by one or two straight-chain or branched (C1-C6) alkyl groups, straight-chain or branched (C1-C6) alkylsulfanyl optionally substituted by 1 to 3 halogen atoms, straight-chain or branched (C1-C6) alkylsulfinyl optionally substituted by 1 to 3 halogen atoms, or straight-chain or branched (C1-C6) alkylsulfonyl optionally substituted by 1 to 3 halogen atoms.

[0033] "Heteroaryl group" means a monocyclic aromatic or bicyclic aromatic or partially aromatic group having 5 to 12 ring members and containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur. It is understood that heteroaryl may be optionally substituted with one or more identical or different groups selected from halogen, hydroxy, amino, cyano, straight or branched (C1-C6) alkyl optionally substituted with 1 to 3 halogen atoms, straight or branched (C1-C6) alkoxy optionally substituted with 1 to 3 halogen atoms, straight or branched (C1-C6) aminoalkyl optionally N-substituted with one or two straight or branched (C1-C6) alkyl groups, straight or branched (C1-C6) alkylsulfanyl optionally substituted with 1 to 3 halogen atoms, straight or branched (C1-C6) alkylsulfinyl optionally substituted with 1 to 3 halogen atoms, or straight or branched (C1-C6) alkylsulfonyl optionally substituted with 1 to 3 halogen atoms.

[0034] Among heteroaryl groups, mention may be made, without any intended limitation, of pyrrolyl, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl (also known as pyridyl), pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, dihydroisoindolyl, indazolyl, benzothienyl, benzofuranyl, and imidazopyridinyl.

[0035] Optical isomers are understood to be diastereoisomers and enantiomers.

[0036] Among the pharmaceutically acceptable bases, sodium hydroxide, potassium hydroxide, arginine, lysine, triethylamine, and tert-butylamine may be mentioned, without any intended limitation.

[0037] One aspect of the present invention is a compound of formula (IA), which is a particular case of compounds of formula (I): [ka] [In the formula, Z, Y1, Y2, and R1 to R9 are as defined in formula (I)] The present invention relates to a compound of the formula: Figure imgf000016_0001, its optical isomers and addition salts thereof with pharmaceutically acceptable bases.

[0038] Another aspect of the present invention is a compound of formula (IA1), which is a particular case of compounds of formula (I): [ka] [In the formula, R1 to R4, R8 to R9, Y1, and Y2 are as defined above. Z1 is a group selected from -(CH2)n1, -(CH2)n1-O-(CH2)n2, -(CH2)n1-S-(CH2)n2, -(CH2)n1-NR-(CH2)n2, -(CH2)n1-CHR'-(CH2)n2, -(CH2)n1-Ar1-(CH2)n2, -(CH2)n1-Ar1-O-(CH2)n2, -(CH2)n1-Ar1-S-(CH2)n2, -(CH2)n1-Ar1-CHR'-(CH2)n2, -Ar1-NR-(CH2)n1; Or Z1 is [ka] is] The present invention relates to a compound of the formula: Figure imgf000016_0001, its optical isomers and addition salts thereof with pharmaceutically acceptable bases.

[0039] Another aspect of the present invention is a compound of formula (IB), which is a particular case of compounds of formula (I): [ka] [wherein Z, Y1, Y2, and R1 to R7 are as defined above] The present invention relates to a compound of the formula: Figure imgf000016_0001, its optical isomers and addition salts thereof with pharmaceutically acceptable bases.

[0040] Another aspect of the present invention is a compound of formula (IC), which is a particular case of compounds of formula (I): [ka] [Wherein Z, Y1, Y2, R1 to R8 and R 10 is as defined above] The present invention relates to a compound of the formula: Figure imgf000016_0001, its optical isomers and addition salts thereof with pharmaceutically acceptable bases.

[0041] Another aspect of the present invention relates to compounds of formula (I) wherein Z is —O—(CH2)n1—, —O—(CH2)n1-O—(CH2)n2, or —O—(CH2)n1-S—(CH2)n2.

[0042] Another aspect of the present invention relates to compounds of formula (I) wherein Y 1 is C.

[0043] Another aspect of the present invention relates to compounds of formula (I) wherein Y2 is O or NCH3.

[0044] Another aspect of the present invention is a method for producing a semiconductor device comprising: [ka] That is, It relates to a compound of formula (I):

[0045] Another aspect of the present invention relates to compounds of formula (I) wherein R7 is hydroxyl.

[0046] Another aspect of the present invention is a compound of formula (II): [ka] wherein P1 is a protecting group for the acid functionality, e.g., alkyl, and P2 is a protecting group for the alcohol functionality. Starting from a compound represented by This is represented by formula (III): [ka] [In the formula, R1 to R3 and Y1 are as defined in formula (I)] to form a compound of formula (IV): [ka] [wherein R1 to R3, R8 to R9, Y1, Z1, and P1 to P2 are as defined above] gives a compound represented by This is expressed as formula (V): [ka] wherein R and Y are as defined in formula (I), and P is a protecting group for the alcohol functional group. to form a compound of formula (VI): [ka] [wherein R1 to R4, R8 to R9, Y1, Y2, Z1, and P1 to P3 are as defined above] gives a compound represented by This is deprotected to give the compound of formula (VII): [ka] [In the formula, R1 to R4, R8 to R9, Y1, Y2, Z1 and P1 are as defined above.] gives a compound represented by This is halogenated to give the compound of formula (VIII): [ka] wherein R1 to R4, R8 to R9, Y1, Y2, Z1 and P1 are as defined above, and X is a halogen atom, for example, Br or Cl. gives a compound represented by This is reacted with a base (e.g., Cs2CO3) to give the compound of formula (IX): [ka] to give a compound represented by This is deprotected by reaction with a base, for example LiOH, to give a compound of formula (IA1), the stereoisomers of which are optionally separated using chiral separation techniques. The present invention relates to a process for preparing compounds of formula (IA1), which are a particular case of compounds of formula (I).

[0047] The compounds of the present invention are Nrf2 activators.

[0048] Thus, the compounds of the present invention can be used to treat type I and type II diabetes and related complications, such as diabetic cardiomyopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and diabetic wound healing; maternal diabetes; liver diseases, such as non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease, toxin-induced liver disease (e.g., acetaminophen-induced liver disease), alcoholic liver disease (ALD), cholestasis, primary sclerosing cholangitis (PSC), viral hepatitis, cirrhosis, primary biliary cirrhosis (PBC), end-stage liver disease, fibrosis; kidney diseases, such as chronic kidney disease (CKD), ), acute kidney injury, contrast-induced nephropathy, autosomal dominant polycystic kidney disease (ADPKD), Alstrom syndrome and Alport syndrome, sepsis-induced acute kidney injury; renal disease or dysfunction seen during kidney transplantation, focal segmental glomerulosclerosis, IgA glomerulonephritis / nephropathy, fibrosis; lung diseases, e.g., pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, acute lung injury, lung infections, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary arterial hypertension, lung diseases secondary to environmental exposures, chronic and acute asthma, acute respiratory distress syndrome; heart diseases, e.g., atherosclerosis, hypertension, heart failure, stroke, stroke, and stroke. Neurological disorders, cardiomyopathy, coronary heart disease, myocardial ischemia; neurological damage, traumatic brain injury, depression, epilepsy, hepatic encephalopathy, Huntington's disease, Parkinson's disease, Alzheimer's disease, autism, Friedreich's ataxia, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, cerebral infarction, encephalopathy, neurological damage / injury, spinal cord injury; inflammatory diseases, e.g., inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis, arthritis, lupus nephritis; eye diseases, e.g., age-related macular degeneration (AMD), ocular neurodegenerative diseases, age-related macular degeneration, cataracts, glaucoma, eye disorders, Fuchs' endothelial corneal dystrophy (FECD), Uveitis, optic neuropathy / ocular neurodegenerative diseases; colon cancer; autoimmune diseases; psoriasis, dermatitis / local effects of radiation, immunosuppression due to radiation exposure, preeclampsia, altitude sickness; wound healing; metabolic syndrome; mitochondrial myopathy; malaria; ferroptosis / iron overload; allergic contact dermatitis; alcoholism; amyloidosis; anemia; anxiety; Asperger's syndrome; eczema; cerebral edema; cerebral ischemia; cerebrovascular disease; chronic fatigue syndrome; cognitive decline; dermatitis / radiation-induced dermatitis; Duchenne muscular dystrophy; edema; encephalitis; male / female fertility; fracture healing;It can be used to treat diseases associated with increased oxidative stress and inflammation, impaired redox capacity, impaired detoxification and metabolic deregulation, including gastroesophageal reflux disease, hearing loss, influenza infection, intestinal barrier dysfunction, osteoarthritis, osteoporosis, radiation-induced injury, reflux-induced esophagitis, reperfusion injury (brain, heart, kidney, liver, retina), schizophrenia, seizures, Sjogren's syndrome, sickle cell disease, skin ulcers, vascular endothelial dysfunction, blood-brain barrier dysfunction, and Down's syndrome.

[0049] The compounds of the present invention are particularly useful in the treatment of type II diabetes and NASH.

[0050] The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) in combination with one or more inert, non-toxic pharmaceutically acceptable excipients or carriers.

[0051] Useful doses vary depending on the age and weight of the patient, the route of administration, the nature and severity of the disorder and any associated treatments, and range from 0.5 mg to 1000 mg per day in one or more administrations.

[0052] Among the pharmaceutical compositions of the invention, mention may be made, inter alia, of those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, nasal, rectal, lingual, ocular or respiratory administration, in particular tablets or dragees, sublingual tablets, gelatin capsules, capsules, suppositories, creams, ointments, skin gels, injectable or drinkable preparations, aerosols and eye or nasal drops.

[0053] According to one aspect of the invention, the pharmaceutical composition is a tablet for oral administration.

[0054] In addition to the compound of formula (I), the tablets of the present invention contain one or more excipients or carriers, such as diluents, lubricants, binders, disintegrants, absorbents, colorants, and sweeteners.

[0055] Examples of excipients or carriers include: Diluents include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerol, Lubricants: silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol, Binders include aluminum and magnesium silicates, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone, Disintegrants: agar, alginic acid and its sodium salt, effervescent mixture Examples include:

[0056] The content of the active ingredient represented by formula (I) in the tablet is preferably 5% by weight to 50% by weight.

[0057] According to one aspect of the present invention, the compounds of formula (I) of the present invention are administered in combination with one or more further active ingredients. The combination administration can be in the form of simultaneous or sequential co-administration of two or more separate pharmaceutical compositions each containing one of the active ingredients (loose combination) or in the form of a fixed combination of two or more active ingredients in the same pharmaceutical composition.

[0058] More specifically, the compounds of formula (I) and pharmaceutically acceptable salts thereof may be used in combination with one or more other active ingredients useful for the prevention or treatment of diabetes or NASH, including biguanides, sulfonylureas, DPP4 inhibitors, SGLT2 inhibitors, GLP1 agonists, dual GLP1-GCG or GLP1-GIP agonists, FXR agonists, PPAR modulators, thyroid hormone receptor agonists, FGF21 agonists, FGF19 agonists, DGAT2 inhibitors, ACC inhibitors or FAS inhibitors.

[0059] Abbreviation abs.:Anhydrous AcOH: acetic acid aq.: aqueous A taphos.PdCl2: Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) Cs2CO3: Cesium carbonate °C: Celsius DCM: dichloromethane DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone dia: diastereomer DIAD: Diisopropyl azodicarboxylate Dioxane: 1,4-dioxane DIPEA: Diisopropylethylamine, N-ethyl-N-(propan-2-yl)propan-2-amine DMEM: Dulbecco's modified Eagle's medium DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide E1: First eluting enantiomer E2: Second eluting enantiomer Et2O: Diethyl ether EtOAc: ethyl acetate EtOH: ethanol FBS: fetal bovine serum g: grams h: time HCl: Hydrochloric acid HCOOH: Formic acid HEC: Hydroxyethyl cellulose H2SO4: sulfuric acid HPLC: High-performance liquid chromatography HRMS: High resolution mass spectroscopy IPA: Propan-2-ol K2CO3: Potassium carbonate LC: liquid chromatography LC-MS: Liquid chromatography-mass spectroscopy LiOH: Lithium hydroxide M: Molar concentration MeOH: Methanol MeCN: acetonitrile mg: milligram MgSO4: Magnesium sulfate MHz: Megahertz min:minutes mL: milliliter mmol: millimolar MS: Mass spectroscopy MTBE: Methyl tert-butyl ether N2: Nitrogen gas NaCl: Sodium chloride NaH: sodium hydride NaOH: Sodium hydroxide NaHCO3: Sodium bicarbonate Na2SO4: Sodium sulfate NBS: N-bromosuccinimide NH4HCO3: Ammonium bicarbonate NH4Cl: Ammonium chloride NMR: nuclear magnetic resonance NMP: N-methylpyrrolidone Pd / C: Palladium activated carbon Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) PPh3: Triphenylphosphine quant.: quantitative yield rac: racemic RT: room temperature sat.: saturation tBuXPhos: 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl TEA: Triethylamine TFA: Trifluoroacetic acid THF: tetrahydrofuran wt%: weight%

[0060] General information IUPAC chemical names were generated using ACD / Labs 2018 2.2 (File version C60H41, Build 106041, 07 Dec 2018).

[0061] All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from commercial sources and used without further drying.

[0062] Normal phase silica gel (flash) chromatography was performed on an ISCO CombiFlash® Rf 200i equipped with pre-packed silica gel cartridges (RediSep® Rf Gold High Performance).

[0063] Microwave heating was performed in an Anton Parr MonoWave or CEM Discover® instrument.

[0064] Reverse-phase (preparative) HPLC purification was performed on a HANBON NP7000 liquid chromatography system equipped with a Gemini-NX® 5 μm C18, 250 mm × 50 mm i.d. column, using pure water, 5 mM NH4HCO3 aqueous solution, 5 mM HCOOH aqueous solution, or 5 mM TFA aqueous solution and MeCN as the eluent, unless otherwise noted, at a flow rate of 99.9 mL min -1 The flow rate was 100 s, and UV diode array detection (210-400 nm) was used.

[0065] Analytical LC-MS: Compounds of the present invention were characterized by high-performance liquid chromatography-mass spectroscopy (HPLC-MS) on an Agilent HP1200 equipped with an Agilent 6140 quadrupole LC / MS operating in positive or negative ion electrospray ionization mode. The molecular weight scan range was 100-1350. Parallel UV detection was performed at 210 nm and 254 nm. Samples were delivered as 1 mM solutions in ACN or THF-water (1:1) via 5 μL loop injection. LCMS analysis was performed on two instruments, one operated with a basic eluent and the other with an acidic eluent.

[0066] Basic LCMS: Gemini-NX, 3 μm, C18, 50 mm x 3.00 mm i.d. column, 23°C, flow rate 1 mL min -1, using 5 mM NH4HCO3 (solvent A) and acetonitrile (solvent B), with a gradient starting at 100% solvent A and ending at 100% solvent B over various / specified time periods.

[0067] Acidic LCMS: ZORBAX Eclipse XDB-C18, 1.8μm, 50mm x 4.6mm inner diameter column, 40℃, flow rate 1mL min -1 , using 0.02% v / v HCOOH in water (solvent A) and 0.02% v / v HCOOH in MeCN (solvent B), with a gradient starting at 100% solvent A and ending at 100% solvent B over various / specified time periods.

[0068] 1 H-NMR measurements were performed on a Bruker Avance III 500 MHz spectrometer and a Bruker Avance III 400 MHz spectrometer using DMSO-d6 (hexadeuterated dimethyl sulfoxide) or CDCl3 (deuterated chloroform) as the solvent. 1 H-NMR data are in the form of delta values ​​given in parts per million (ppm) using the residual peak of the solvent as an internal standard (2.50 ppm for DMSO-d6, 7.26 ppm for CDCl3). Splitting patterns are designated as follows: s (singlet), 2s (2× singlet), d (doublet), 2d (2× doublet), t (triplet), 2t (2× triplet), q (quartet), 2q (2× quartet), qn (quintet), sept (septet), m (multiplet), 2m (2× multiplet), brs (broad singlet), brd (broad doublet), brt (broad triplet). t), brq (broad quartet), brm (broad multiplet), vbrs (very broad singlet), dd (doublet of doublets), td (triplet of doublets), dt (doublet of triplets), dq (doublet of quartets), ddd (doublet of doublet of doublets), dm (doublet of multiplets), tm (triplet of multiplets), qm (quartet of multiplets).

[0069] HRMS was measured using a Shimadzu IT-TOF with an ion source temperature of 200°C, ESI + / -, and an ionization voltage (+ / -) of 4.5 kV. The minimum mass resolution was 10,000.

[0070] The final products or final intermediates were separated into pure enantiomers / diastereomers using chiral supercritical fluid chromatography (SFC) on a milligram scale using an SFC-PICLAB-PREP 200 instrument (Pic Solution) according to the following method.

[0071] The mobile phase is carbon dioxide as a supercritical fluid or a mixture of fluids (by adding a protic solvent, e.g., isocratic 35-45% IPA or EtOH / supercritical CO2). · Columns can be analyzed for chromatographic profiles, e.g. Whelk 01 RR 30 x 250 mm x 5 μm (particle size) or LUX (Phenomenex) 30mm x 150mm x 5μm (particle size) or Chiralpak IG 30×250mm×5μm (particle size) was selected according to. ·Temperature: 40℃ Detection: 230nm ·Flow rate: 120~150mL / min

[0072] The following examples illustrate the invention.

[0073] General Procedure 1 General Procedure 1 Step 1 To a solution of 1-fluoro-3-methyl-2-nitro-benzene (1 equiv., 64.5 mmol) in MeCN (2 mL / mmol, 101.3 g, 128.92 mL) was added amino alcohol (3 equiv., 193.5 mmol) at room temperature. The reaction mixture was heated to 70 °C and stirred overnight. After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was partitioned between water (250 mL) and EtOAc (200 mL). The separated organic layer was further washed with brine (150 mL). The combined aqueous layers were washed with EtOAc (100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the crude product, which was purified by normal-phase silica gel chromatography using heptane-EtOAc (e.g., 100:0 to 75:25) as eluent to give the title compound.

[0074] General Procedure 1 Step 2 To a solution of the product of General Procedure 1, Step 1 (1 equiv., 834 mmol) in AcOH (1.2 mL / mmol, 42 g, 40 mL) was added NBS (1 equiv., 6 g, 34 mmol) at room temperature. The reaction mixture was heated to 110° C. and stirred for 2 h. After completion of the reaction, the mixture was cooled to room temperature and quenched with ice-cold water (200 ml). The pH was set to 14 with NaOH solution. The mixture was stirred at room temperature for 10 min. The mixture was extracted with DCM (3×150 ml). The combined organic layers were washed with brine. The organic phase was dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound, which was used in the next step without further purification or purified by reverse-phase chromatography using water-MeCN as eluent.

[0075] General Procedure 1 Step 3 To a solution of the product of General Procedure 1, Step 2 (1 equiv., 35.1 mmol) or the appropriate aryl nitro compound in EtOH (25 mL / mmol, 692 g, 877 mL) and water (3 mL / mmol, 105 g, 105 mL), iron powder (15 equiv., 29.4 g, 526 mmol) and NH₄Cl (5 equiv., 9.38 g, 175 mmol) were added at room temperature. The reaction mixture was heated to 50 °C and stirred for 2 h. After completion of the reaction, the mixture was filtered through a pad of Celite, which was then washed with EtOH (2 × 100 mL). The solvent was evaporated under reduced pressure, and the evaporation residue was dissolved in DCM (100 mL). The solution was dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness to give the title compound, which was used in the next step without further purification.

[0076] General Procedure 1 Step 4 To a solution of the product of General Procedure 1, Step 3 (1 equiv., 32 mmol) in AcOH (0.3 mL / mmol, 10 g, 9.6 mL) and water (3 mL / mmol, 96 g, 96 mL) was added H2SO4 (0.3 mL / mmol, 18 g, 9.6 mL) at 0 °C. Sodium nitrite (1.5 equiv., 3.3 g, 48 mmol) was added portionwise, and the reaction mixture was stirred at 0 °C for 10 min. The resulting dark heterogeneous mixture was allowed to warm to room temperature and stirred for an additional 30 min. After completion of the reaction, the mixture was quenched with water (300 mL), and the pH was set to approximately 12 using concentrated NaOH solution. The mixture was extracted with DCM (3 × 70 mL). The organic layer was washed with brine (150 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to dryness to give a black oil, which was purified by normal phase silica gel chromatography with an eluent of DCM-EtOAc (100:0 to 70:30) to give the title compound.

[0077] General Procedure 1 Step 5 To a solution of the product of General Procedure 1, Step 4 (1 equiv., 22 mmol) in THF (10 mL / mmol, 200 g, 220 mL), water (5 mL / mmol, 110 g, 110 mL), and MeOH (2.5 mL / mmol, 44 g, 55 mL) was added LiOH (3 equiv., 1.6 g, 66 mmol) at room temperature, and the mixture was stirred for an additional 30 min. After completion of the reaction, the mixture was quenched with water (400 mL) and 2 M aqueous HCl (50 mL). The mixture was extracted with EtOAc (3 × 20 ml). The organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give an oil, which was purified by normal-phase silica gel chromatography using DCM-EtOH (100:0 to 80:20) as eluent to give the title compound.

[0078] General Procedure 1 Step 6 To a solution of the product of General Procedure 1, Step 5 (1 equiv., 10 mmol) in THF (7 mL / mmol, 63 g, 70 mL) was added NaH (1.2 equiv., 480 mg, 12 mmol, 60 wt % in mineral oil) at 0 °C. The mixture was allowed to warm to room temperature and stirred at this temperature for 30 min. The reaction mixture was cooled to 0 °C, 4-methoxy-benzyl chloride (1.2 equiv., 1.9 g, 12 mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was quenched with water (100 mL) and extracted with EtOAc (3 × 100 ml). The combined organic layers were washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give an orange oil, which was purified by normal-phase silica gel chromatography using heptane-EtOAc (100:0 to 75:25) as eluent to give the title compound.

[0079] General Procedure 1 Step 7 To a solution of the product of General Procedure 1, Step 6 (1 equiv., 7.1 mmol) in DMF (7 mL / mmol, 47.4 g, 50 mL), ethyl prop-2-enoate (2 equiv., 1.44 g, 1.56 mL, 14.2 mmol), DIPEA (3 equiv., 2.78 g, 3.75 mL, 21.5 mmol), tris-o-tolylphosphine (0.2 equiv., 0.44 g, 1.4 mmol), and palladium diacetate (0.1 equiv., 0.161 g, 0.71 mmol) were added at room temperature. The mixture was flushed with argon twice and heated at 100 °C overnight in a sealed Schlenk tube. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure to give a black oil, which was purified by normal phase silica gel chromatography using heptane-EtOAc (100:0 to 75:25) as eluent to give the title compound.

[0080] General Procedure 2 General Procedure 2 Step 1 To a solution of 1-fluoro-3-methyl-2-nitro-benzene (1 equiv., 1.93 mmol) in MeCN (2 mL / mmol, 101.3 g, 128.92 mL) was added O-benzyl-aminoalcohol (1.2 equiv., 2.32 mmol), followed by CsCO (2 equiv., 1.26 g, 3.87 mmol) or TEA (2 equiv., 3.87 mmol) at room temperature. The reaction mixture was heated to 70 °C and stirred at this temperature overnight. After completion of the reaction, the mixture was filtered, and the mother liquor was evaporated under reduced pressure. The crude product was purified by reverse-phase chromatography using a gradient elution of water-MeCN (95:5 to 0:100) to give the title compound.

[0081] General Procedure 2 Step 2 To a solution of the product of General Procedure 2, Step 1 (1 equiv., 22 mmol) in AcOH (26 mL) was added NBS (1.2 equiv., 4.6 g, 26 mmol) at room temperature. The reaction mixture was heated to 110° C. and stirred for 1.5 h. After completion of the reaction, the mixture was cooled to room temperature and quenched with ice-cold water (200 ml). The pH was adjusted to 14 using NaOH solution. The mixture was stirred at room temperature for 10 min. The mixture was extracted with DCM (3×150 ml). The combined organic layers were washed with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound, which was purified by reverse-phase chromatography using a gradient elution of water-MeCN (95:5 to 0:100) to give the title compound.

[0082] General Procedure 2 Step 3 To a solution of the product of General Procedure 2, Step 2 (1 equiv., 17 mmol) in EtOH (430 mL) (or IPA) and water (50 mL) was added iron powder (15 equiv., 14 g, 260 mmol) and NH4Cl (5.5 equiv., 5 g, 93.5 mmol) at room temperature. The reaction mixture was heated to 50 °C and stirred at this temperature overnight. After completion of the reaction, the mixture was filtered through a Celite pad and washed with EtOH (2 × 100 mL). The mother liquor was concentrated under reduced pressure. The crude product was purified by reverse-phase chromatography using a gradient elution of water-MeCN (95:5 to 0:100) to give the title compound.

[0083] General Procedure 2 Step 4 To a solution of the product of General Procedure 2, Step 3 (1 equiv., 13 mmol) in AcOH (30 mL) and water (30 mL) was added H2SO4 (8.9 g, 4.6 mL, 90 mmol) at 0 °C. Sodium nitrite (1.5 equiv., 3.3 g, 48 mmol) was added portionwise, and the reaction mixture was stirred at 0 °C for 10 min. The resulting dark heterogeneous mixture was allowed to warm to room temperature and stirred at this temperature for an additional 30 min. After completion of the reaction, the mixture was quenched with water (300 mL), and the pH was set to approximately 12 using 2 M aqueous NaOH. The mixture was extracted with DCM (3 × 70 ml). The combined organic layers were washed with brine (150 mL). The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the crude product, which was purified by normal-phase silica gel chromatography using DCM-EtOAc (100:0 to 95:5) as eluent to give the title compound.

[0084] General Procedure 2 Step 5 To a solution of the product of General Procedure 2, Step 4 (1 equiv., 2.91 mmol) in DMF (20 mL) was added ethyl prop-2-enoate (2.2 equiv., 642 g, 0.699 mL, 6.41 mmol), DIPEA (3 equiv., 1.13 g, 1.52 mL, 8.74 mmol), tris-o-tolylphosphine (0.2 equiv., 0.177 g, 0.583 mmol), and palladium acetate (0.1 equiv., 0.65 g, 0.291 mmol) at room temperature. The mixture was flushed with argon twice and heated in a sealed Schlenk tube at 100 °C overnight. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure. The crude product was purified by normal-phase silica gel chromatography using DCM-EtOH (100:0 to 95:5) as eluent to give the title compound.

[0085] General Procedure 3 The aryl bromide derivative (1 equiv., 10 mmol) was introduced into a round-bottom flask and dissolved in dioxane (5 mL / mmol, 50 mL). 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.1 equiv., 2.79 g, 11 mmol) and dry potassium acetate (3.5 equiv., 3.43 g, 35 mmol) were added at room temperature. The mixture was flushed with argon or nitrogen. Finally, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) catalyst (0.02 equiv., 146 mg, 0.2 mmol) was added, and the mixture was flushed again with argon or nitrogen and then heated at 75 °C overnight under an inert atmosphere. After completion of the reaction, the mixture was filtered through a Celite pad, and the mother liquor was evaporated to dryness under reduced pressure. The crude product was purified by normal phase silica gel chromatography using DCM-EtOAc (100:0 to 90:10) as eluent or by reverse phase chromatography using water-MeCN (95:5 to 0:100) as eluent to give the title compound.

[0086] General Procedure 4 General Procedure 4 Step 1 Paraformaldehyde (3 equiv., 12.8 mmol), magnesium dichloride (2 equiv., 0.812 mg, 8.5 mmol), and TEA (2 equiv., 1.18 mL, 8.5 mmol) were introduced into a round-bottom flask. The mixture was dissolved in THF (20 mL) and stirred at room temperature for 30 minutes. A substituted phenol (1 equiv., 4.3 mmol) was added, and the mixture was stirred at reflux temperature overnight. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with 1 M HCl solution (50 mL), followed by brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to give the crude product, which was purified by normal-phase silica gel chromatography using heptane-EtOAc as eluent to give the title compound.

[0087] General Procedure 4 Step 2 Chlorosulfonyl isocyanate (4 equiv., 13 g, 8.1 mL, 93 mmol) was introduced into a round-bottom flask at 0° C. HCOOH (4 equiv., 3.5 mL, 93 mmol) was added dropwise over 40 min at 0° C. The mixture was allowed to warm to room temperature over 30 min, and stirring at room temperature was continued for an additional 1 h. The mixture was cooled to 0° C., and the product of General Procedure 4, Step 1 (1 equiv., 23 mmol) dissolved in NMP (3.5 mL / mmol, 81 mL) was added dropwise over 10 min. The mixture was allowed to warm to room temperature and stirred at this temperature overnight. After completion of the reaction, the mixture was quenched with saturated aqueous NH4Cl (500 mL). The mixture was extracted with EtOAc (2×200 mL) and the combined organic layers were dried over anhydrous NaSO, filtered and concentrated to dryness to give the crude product, which was purified by normal phase silica gel chromatography using heptane-EtOAc (100:0 to 50:50) as eluent to give the title compound.

[0088] General Procedure 4 Step 3 To a cooled solution of the product of General Procedure 4, Step 2 (1 equiv., 22.4 mmol) in MeOH (8 mL / mmol, 179 mL) at −5° C., sodium borohydride (1.2 equiv., 1.02 g, 26.9 mmol) was added slowly over 20 min. The mixture was stirred at −5° C. for 1 h. After completion of the reaction, the mixture was allowed to warm to room temperature and concentrated to dryness to give the crude product, which was purified by normal-phase silica gel chromatography using DCM-EtOH (100:0 to 99:1) as eluent or by reverse-phase chromatography using a gradient elution of water-MeCN (95:5 to 0:100) to give the title compound.

[0089] General Step 5 General Procedure 5 Step 1 6-Bromo-3,4-dihydro-1,2λ in DCM (92 mL) 6To a stirred solution of ,3-benzoxathiazine 2,2-dioxide derivative (1 equivalent, 17 mmol), TEA (1.1 equivalent, 2.5 mL, 18 mmol), N,N-dimethylpyridin-4-amine (0.1 equivalent, 0.2 g, 1.7 mmol), and di-tert-butyl-dicarbonate (1.1 equivalent, 4 g, 18 mmol) were added at room temperature. The mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was extracted with 10 wt% aqueous citric acid solution (3 × 50 mL) and then with water (50 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound, which was used in the next step without further purification.

[0090] General Procedure 5 Step 2 General Procedure 5: The product of Step 1 (1 equiv., 16 mmol) was placed in a round-bottom flask and dissolved in dioxane (7.5 mL / mmol, 120 mL). 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.1 equiv., 4.6 g, 18 mmol) and dry potassium acetate (3.5 equiv., 5.6 g, 57 mmol) were added to the mixture at room temperature. The mixture was flushed with argon or nitrogen. Finally, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) catalyst (0.02 equiv., 160 mg, 0.33 mmol) was added, and the mixture was flushed again with argon or nitrogen. The mixture was then heated at 75 °C overnight under an inert atmosphere. The mixture was filtered through a Celite pad, and the mother liquor was concentrated to dryness under reduced pressure. The crude product was purified by normal phase silica gel chromatography with heptane-EtOAc (100:0 to 80:20) as eluent to give the title compound.

[0091] General Procedure 5 Step 3 To a stirred solution of the product of General Procedure 5, Step 2 (1 equiv., 11.5 mmol) in EtOH (15 mL / mmol, 73 mL) and water (7.5 mL / mmol, 37 mL), m-chloroperbenzoic acid (1 equiv., 2.84 g, 11.5 mmol) was added portionwise at room temperature. The mixture was stirred overnight at room temperature. After completion of the reaction, the mixture was quenched with saturated aqueous NaHCO3 (100 mL). The mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with saturated aqueous NaHCO3 (50 mL) and then with water (50 mL). The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the crude product, which was purified by normal-phase silica gel chromatography using heptane-EtOAc (100:0 to 50:50) as eluent to give the title compound.

[0092] General Procedure 5 Step 4 To a solution of the product of General Procedure 5, Step 3 (1 equiv., 9.2 mmol) in MeCN (58 mL) were added CsCO (2.4 equiv., 7.2 g, 22 mmol) and benzyl bromide (2.2 equiv., 3.4 g, 2.4 mL, 20 mmol), and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated under reduced pressure and then diluted with EtOAc (40 mL). The mixture was washed with brine (40 mL) and then water (40 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to dryness to give the crude product, which was used in the next step without further purification.

[0093] General Procedure 5 Step 5 To a solution of the product of General Procedure 5, Step 4 (1 equiv., 9.2 mmol) in DCM (75 mL) was added TFA (8 equiv., 8.4 g, 5.66 mL, 74 mmol) dropwise, and the mixture was stirred at room temperature overnight. The pH of the mixture was set to 9 using saturated aqueous NaHCO. The layers were separated, and the organic layer was extracted with brine (30 mL) and then water (30 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to dryness to give the crude product, which was purified by normal-phase silica gel chromatography using heptane-EtOAc (100:0 to 70:30) as eluent to give the title compound.

[0094] General Procedure 6 To a stirred solution of ethyl aryl(prop-2-enoate) derivative or ethyl heteroaryl(prop-2-enoate) derivative (1 equiv., 4.6 mmol) in dioxane (5–8 mL / mmol, 23 mL) and water (1–2.7 mL / mmol, 4.6 mL), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aryl derivative (1.5–2 equiv., 6.9 mmol) and TEA (1.5 equiv., 0.96 mL, 6.9 mmol) were added. The suspension was flushed with argon or nitrogen and degassed. Finally, chloro(1,5-cyclooctadiene)rhodium(I) dimer catalyst (0.05 equiv., 56 mg, 0.23 mmol) was added, and the mixture was heated at 80 °C for 4–16 h under an inert atmosphere. After completion of the reaction, the mixture was diluted with water (100 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL) and then dried over anhydrous NaSO. Filtration and concentration to dryness gave the crude product, which was purified by normal-phase silica gel chromatography using heptane-EtOAc (100:0 to 50:50) as eluent or by reverse-phase chromatography using a gradient elution of water-MeCN (95:5 to 0:100) to give the title compound.

[0095] General Procedure 7 To a stirred solution of the hydroxymethylphenyl derivative (1 equiv., 1.6 mmol) in THF (22 mL / mmol, 35 mL) was added a substituted benzoxathiazine 2,2-dioxide or 1,3-benzothiadiazine 2,2-dioxide derivative (1–2.5 equiv., 2.4 mmol) and PPh3 (2.2 equiv., 0.93 g, 3.5 mmol). The reaction mixture was cooled to 15 °C, and DIAD (2 equiv., 0.63 mL, 3.2 mmol) was added dropwise over 5 min. The mixture was allowed to warm to room temperature and stirred at this temperature overnight. After completion of the reaction, the mixture was concentrated to dryness and purified by normal-phase silica gel chromatography using an eluent of DCM-EtOAc (100:0 to 80:20) or by reverse-phase chromatography using a gradient elution of water-MeCN (95:5 to 0:100) to give the title compound.

[0096] General Procedure 8 Ethyl 3-[3-[(6-benzyloxy-2,2-dioxo-4H-1,2λ] 6 ,3-benzoxathiazin-3-yl)methyl]phenyl]-3-(4-methyl-1H-benzotriazol-5-yl)propanoate or ethyl 3-[3-[(6-benzyloxy-2,2-dioxo-1,4-dihydro-2,1,3-benzothiadiazin-3-yl)methyl]phenyl]-3-(4-methyl-1H-benzotriazol-5-yl)propanoate (1 equiv., 0.883 mmol), Pd / C catalyst (0.1 equiv., 0.0883 mmol), dioxane (3 mL), MeOH or EtOH (10 mL), and DCM (4 mL) were charged, and the autoclave was sealed, inertized, and charged with hydrogen (1-8 bar). After stirring at room temperature for 10-40 h, the reaction mixture was filtered through a Celite pad, and the volatiles of the filtrate were evaporated to give the title compound. The crude product was purified by normal phase silica gel chromatography or by reverse phase chromatography using a gradient elution of water-MeCN (95:5 to 0:100) to give the title compound.

[0097] General Procedure 9 N-Hydroxyalkyl ethyl 3-[3-[(6-hydroxy-2,2-dioxo-4H-1,2λ] in DCM (1 mL) 6 To a stirred solution of N-hydroxyalkyl ethyl 3-[3-[(6-hydroxy-2,2-dioxo-1,4-dihydro-2,1,3-benzothiadiazin-3-yl)methyl]phenyl]-3-(4-methyl-1H-benzotriazol-5-yl)propanoate or N-hydroxyalkyl ethyl 3-[3-[(6-hydroxy-2,2-dioxo-1,4-dihydro-2,1,3-benzothiadiazin-3-yl)methyl]phenyl]-3-(4-methyl-1H-benzotriazol-5-yl)propanoate (1 equiv., 0.122 mmol), carbon tetrabromide (7 equiv., 69 mg, 0.2074 mmol) and PPh3 (1.7 equiv., 54.4 mg, 0.2074 mmol) were added. After stirring at room temperature for 5–20 h, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by normal-phase silica gel chromatography using a gradient elution of hexanes-EtOAc to give the title compound.

[0098] General Procedure 10 N-Hydroxyalkyl ethyl 3-[3-[(6-hydroxy-2,2-dioxo-4H-1,2λ 6N-Hydroxyalkyl ethyl 3-[3-[(6-hydroxy-2,2-dioxo-1,4-dihydro-2,1,3-benzothiadiazin-3-yl)methyl]phenyl]-3-(4-methyl-1H-benzotriazol-5-yl)propanoate or N-hydroxyalkyl ethyl 3-[3-[(6-hydroxy-2,2-dioxo-1,4-dihydro-2,1,3-benzothiadiazin-3-yl)methyl]phenyl]-3-(4-methyl-1H-benzotriazol-5-yl)propanoate (1 equiv., 88.7 mmol) was dissolved in DCM (355 mL) under a N atmosphere. The solution was cooled to 0 °C, and thionyl chloride (1.2–4 equiv., 12.7 g, 7.77 mL, 106.5 mmol) was added dropwise under a N atmosphere. After stirring at 40 °C for 4 h, the reaction mixture was cooled to 0 °C. Water (155 mL) and saturated aqueous NaHCO (155 mL) were slowly added, and the layers were separated. The organic layer was washed with water, dried over MgSO4, and the solvent was removed under reduced pressure. The crude product was used without further purification or, if necessary, purified by normal-phase silica gel chromatography using a gradient elution of DCM-MeOH or hexane-EtOAc to give the title compound.

[0099] General Procedure 11 Chloro or bromoalkyl ethyl 3-[3-[(6-hydroxy-2,2-dioxo-4H-1,2λ]] in MeCN (16 mL) 6To a stirred solution of chloro or bromoalkyl ethyl 3-[3-[(6-hydroxy-2,2-dioxo-1,4-dihydro-2,1,3-benzothiadiazin-3-yl)methyl]phenyl]-3-(4-methyl-1H-benzotriazol-5-yl)propanoate or chloro or bromoalkyl ethyl 3-[3-[(6-hydroxy-2,2-dioxo-1,4-dihydro-2,1,3-benzothiadiazin-3-yl)methyl]phenyl]-3-(4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent, 0.055 mmol), CsCO (1–3 equivalents, 11 mg, 0.055 mmol) was added, and the mixture was stirred at room temperature to 80 °C for 4–36 hours. After completion of the reaction, water (10 mL) was added to the mixture, and MeCN was evaporated under reduced pressure. The residue was extracted with DCM (3 × 10 mL), and the combined organic layers were washed with water. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated to dryness to give the title compound, which was purified by normal-phase silica gel chromatography or by reverse-phase chromatography using a gradient elution of water-MeCN (95:5 to 0:100) to give the title compound.

[0100] General Procedure 12 To a solution of the macrocyclic ester (1 equiv., 0.067 mmol) in a mixture of THF (0.67 mL), MeOH or EtOH (0.17 mL), and water (0.34 mL) was added lithium hydroxide (3 equiv.-4 equiv., 4.8 mg, 0.20 mmol). The reaction mixture was stirred at room temperature to 80 °C for 2 to 30 h. After completion of the reaction, citric acid solution (10%) or 1 M aqueous HCl was added to the reaction mixture, and the neutralized mixture was extracted three times with DCM. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by preparative reverse-phase chromatography using a gradient elution of water-MeCN (95:5 to 0:100) to give the title compound.

[0101] Example 1 : [4,32-dimethyl-28,28-dioxo-22,27-dioxa-28λ 6 -Thia-1,14,15,16-tetraazahexacyclo[21.5.3.1 3,7 .1 9,13 .0 12,16 .0 26,30]tritriaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetic acid [ka]

[0102] Step A1: Preparation of 5-(3-methyl-2-nitroanilino)pentan-1-ol Using General Procedure 1, Step 1, starting with 1-fluoro-3-methyl-2-nitro-benzene (1 equiv., 10.0 g, 7.85 mL, 64.5 mmol) and 5-aminopentan-1-ol (3 equiv., 19.950 g, 21 mL, 193.5 mmol) as reactants, the title compound (12.6 g, 82% yield) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.26 (t, 1 H), 6.76 (d, 1 H), 6.54 (d, 1 H), 6.39 (t, 2 H), 4.34 (t, 1 H), 3.39 (q, 2 H), 3.16 (q, 2 H), 2.3 (s, 2 H), 1.55 (s, 2 H), 1.44 (m, 2 H), 1.34 (m, 2 H)

[0103] Step A2: Preparation of 5-(4-bromo-3-methyl-2-nitroanilino)pentyl acetate Using General Procedure 1, Step 2, starting with 5-(3-methyl-2-nitroanilino)pentan-1-ol (8 g, 34 mmol) as reactant, the title compound (12.6 g orange oil, quantitative) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.5 (d, 1 H), 6.72 (d, 1 H), 6.12 (tl, 1 H), 4 (t, 2 H), 3.15 (q, 2 H), 2.25 (s, 3 H), 2 (s, 3 H), 1.6-1.3 (m, 6H)

[0104] Step A3: Preparation of 5-(2-amino-4-bromo-3-methylanilino)pentyl acetate Using General Procedure 1, Step 3, starting with 5-(4-bromo-3-methyl-2-nitroanilino)pentyl acetate (12.6 g, 35.1 mmol) as reactant, the title compound was obtained (11.7 g orange solid, 91% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 6.7 (d, 1 H), 6.25 (d, 1 H), 5.8 (m, 3 H), 4 (t, 2 H), 3 (t, 2 H), 2.2 (s, 3 H), 2.01 (s, 3 H), 1.65-1.4 (m, 6 H)

[0105] Step A4: Preparation of 5-(5-bromo-4-methyl-1H-benzotriazol-1-yl)pentyl acetate Using General Procedure 1, Step 4, starting with 5-(2-amino-4-bromo-3-methylanilino)pentyl acetate (12 g, 32 mmol) as reactant, the title compound was obtained (7.5 g orange oil, 69% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.7 (2d, 2 H), 4.7 (t, 2 H), 3.97 (t, 2 H), 2.71 (s, 3 H), 1.99 (s, 3 H), 1.95 (m, 2 H), 1.6 (m, 2 H), 1.29 (m, 2 H)

[0106] Step A5: Preparation of 5-(5-bromo-4-methyl-1H-benzotriazol-1-yl)pentan-1-ol Using General Procedure 1, Step 5, starting with 5-(5-bromo-4-methyl-1H-benzotriazol-1-yl)pentyl acetate (7.5 g, 22 mmol) as reactant, the title compound (6.7 g orange oil, quantitative) was obtained. 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.7 (2d, 2 H), 4.7 (t, 2 H), 4.35 (m, 1 H), 3.35 (t, 2 H), 2.71 (s, 3 H), 1.9 (m, 2 H), 1.45 (m, 2 H), 1.28 (m, 2 H)

[0107] Step A6: Preparation of 5-bromo-1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4-methyl-1H-benzotriazole Using General Procedure 1, Step 6, starting with 5-(5-bromo-4-methyl-1H-benzotriazol-1-yl)pentan-1-ol (3.0 g, 10 mmol) as reactant, the title compound was obtained (3 g yellow oil, 72% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.7 (2d, 2 H), 7.15 (d, 2 H), 6.85 (d, 2 H), 4.7 (t, 2 H), 4.3 (s, 2 H), 3.75 (s, 3 H), 3.32 (t, 2 H), 2.71 (s, 3 H), 1.9 (m, 2 H), 1.52 (m, 2 H), 1.28 (m, 2 H)

[0108] Step A7: Preparation of ethyl (2E)-3-(1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate Using General Procedure 1, Step 7, and starting with 5-bromo-1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4-methyl-1H-benzotriazole (3 g, 7.1 mmol) as reactant, the title compound was obtained (3 g yellow solid, 91% yield). 1H-NMR (500 MHz, DMSO-d6) δ ppm: 8.03 (d, 1 H), 7.96 (d, 1 H), 7.73 (d, 1 H), 7.16 (d, 2 H), 6.86 (d, 2 H), 6.64 (d, 1 H), 4.7 (t, 2 H), 4.3 (s, 2 H), 4.22 (q, 2 H), 3.73 (s, 3 H), 3.33 (t, 2 H), 2.81 (s, 3 H), 1.9 (m, 2 H), 1.53 (m, 2 H), 1.28 (t, 3 H), 1.26 (m, 2 H)

[0109] Step C1: 6-(benzyloxy)-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-2,2-dione Using General Procedure 4, Step 2, starting with 5-(benzyloxy)-2-hydroxybenzaldehyde (1 eq, 5.3 g, 23 mmol) as reactant, the title compound was obtained (6.48 g yellow solid, 96% yield). 1 H-NMR (400 MHz, CDCl3) δ ppm: 8.6 (s, 1 H), 7.4 (m, 5 H), 7.35 (dd, 1 H), 7.3 (d, 1 H), 7.15 (d, 1 H), 5.1 (s, 2 H)

[0110] Step C2: 6-(benzyloxy)-3,4-dihydro-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-2,2-dione Using General Procedure 4, Step 3, 6-(benzyloxy)-2H-1,2λ as the reactant 6 Starting with ,3-benzoxathiazine-2,2-dione (1 equiv., 6.48 g, 22.4 mmol), the title compound was obtained (5.9 g, yellow solid, 90% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 8.4 (sl, 1 H), 7.45 (d, 2 H), 7.4 (t, 2 H), 7.3 (t, 1 H), 7 (m, m H), 5.1 (s, 2 H), 4.5 (s, 2 H)

[0111] Step 1: Preparation of ethyl 3-[3-(hydroxymethyl)-4-methylphenyl]-3-(1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using general procedure 6 and starting with (ethyl (2E)-3-(1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equivalent, 4 g, 4.6 mmol) and [2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (1.5 equivalents, 1.7 g, 6.9 mmol) as reactants, the title compound (0.96 g, 38% yield) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.48 (d, 1 H), 7.25 (d, 1 H), 7.18 (d, 2 H), 7.08 (dd, 1 H), 7 (d, 1 H), 6.88 (d, 2 H), 4.98 (t, 1 H), 4.82 (t, 1 H), 4.61 (t, 2 H), 4.4 (d, 2 H), 4.3 (s, 2 H), 3.92 (q, 2 H), 3.71 (s, 3 H), 3.3 (t, 2 H), 3.11 (2dd, 2 H), 2.75 (s, 3 H), 2.15 (s, 3 H), 1.88 (m, 2 H), 1.52 (m, 2 H), 1.28 (m, 2 H), 1 (t, 3 H);

[0112] Step 2: Ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6Preparation of 1-(1-(4-benzoxathiazin-3(4H)-yl)methyl}-4-methylphenyl)-3-(1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, the reactants were ethyl 3-[3-(hydroxymethyl)-4-methylphenyl]-3-(1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent, 0.96 g, 1.6 mmol) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6 Starting with ,3-benzoxathiazine-2,2-dione (1.5 equiv, 0.7 g, 2.4 mmol), the title compound was obtained (90% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 1.16 (m., 3 H) 1.21 - 1.29 (m, 1 H) 1.44 - 1.56 (m, 1 H) 1.78 - 1.89 (m, 1 H) 2.21 (s, 1 H) 2.76 (s, 1 H) 3.16 (dd, J=7.95, 4.77 Hz, 1 H) 3.26 - 3.29 (m, 1 H) 3.92 (q, J=7.09 Hz, 2 H) 4.21 (s, 2 H) 4.28 (s, 2 H) 4.42 (s, 2 H) 4.59 (t, J=6.91 Hz, 2H) 4.85 (t, J=7.95 Hz, 1 H) 5.10 (s, 2 H) 6.82 - 6.88 (m, 2 H) 6.94 (d, J=2.81 Hz, 1 H) 7.03 - 7.10 (m, 1 H) 7.10 - 7.17 (m, 4 H) 7.17 - 7.21 (m, 1 H) 7.22 (s, 1 H) 7.31 - 7.37 (m, 1 H) 7.37 - 7.43 (m, 2 H) 7.45 (s, 2 H) 7.48 (d, J=8.44 Hz, 2 H) 7.56 - 7.61 (m, 1 H)

[0113] Step 3: Ethyl 3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of {1-(5-hydroxypentyl)-4-methyl-1H-benzotriazol-5-yl}propanoate Using general procedure 8, ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ] was used as the reactant. 6 Starting from 1-(1-(4-benzoxathiazin-3(4H)-yl]methyl}-4-methylphenyl)-3-(1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equiv., 2 g, 1.4 mmol), the title compound (830 mg yellow oil, 90% yield) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.7 / 4.38 (2m, 2 H), 7.61 (d, 1 H), 7.5 (d, 1 H), 7.21 (d, 1 H), 7.2 (dd, 1 H), 7.12 (d, 1 H), 6.99 (d, 1 H), 6.8 (dd, 1 H), 6.6 (d, 1 H), 4.82 (t, 1 H), 4.61 (t, 2 H), 4.39 (s, 2 H), 4.29 (m, 2 H), 3.95 (q, 2 H), 3.31 (t, 2 H), 3.18 (m, 2 H), 2.75 (s, 3 H), 2.2 (s, 3 H), 1.88 (m, 2 H), 1.4 (m, 2 H), 1.25 (m, 2 H), 1 (t, 3 H)

[0114] Step 4: Ethyl 3-[1-(5-bromopentyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Starting from {1-(5-hydroxypentyl)-4-methyl-1H-benzotriazol-5-yl}propanoate (1 equiv., 0.8 g, 1.3 mmol), the title compound (710 mg white solid, 80% yield) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.7 (m, 1 H), 7.61 (d, 1 H), 7.5 (d, 1 H), 7.21 (d, 1 H), 7.2 (dd, 1 H), 7.12 (d, 1 H), 6.99 (d, 1 H), 6.8 (dd, 1 H), 6.6 (d, 1 H), 4.82 (t, 1 H), 4.65 (t, 2 H), 4.39 (s, 2 H), 4.29 (m, 2 H), 3.92 (q, 2 H), 3.45 (t, 2 H), 3.18 (m, 2 H), 2.75 (s, 3 H), 2.21 (s, 3 H), 1.9 (m, 2 H), 1.8 (m, 2 H), 1.35 (m, 2 H), 1 (t, 3 H)

[0115] Step 5: Ethyl [4,32-dimethyl-28,28-dioxo-22,27-dioxa-28λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[21.5.3.1 3,7 .1 9,13 .0 12,16 .0 26,30 Preparation of ]tritriaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(5-bromopentyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6Starting with {3-benzoxathiazin-3(4H)-yl)methyl}-4-methylphenyl}propanoate (1 equiv., 0.7 g, 0.99 mmol) gave the title compound (620 mg yellow oil, 93% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.65 (d, 1 H), 7.52 (d, 1 H), 7.5 (dd, 1 H), 7.3 (d, 1 H), 7.05 (d, 1 H), 6.9 (dd, 1 H), 6.78 (d, 1 H), 6.12 (d, 1 H), 4.8 (t, 1 H), 4.7 (t, 2 H), 4.2 / 3.9 (m, 2 H), 4.15 / 4 (m, 2 H), 3.9 (m, 2 H), 3.85 (m, 2 H), 3.07 (m, 2 H), 2.68 (s, 3 H), 2.35 (s, 3 H), 2 (m, 2 H), 1.75 (m, 2 H), 1.5 / 1.4 (m, 2H), 1 (t, 3H)

[0116] Step 6: Preparation of Example 1 Using general procedure 12, ethyl [4,32-dimethyl-28,28-dioxo-22,27-dioxa-28λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[21.5.3.1 3,7 .1 9,13 .0 12,16 .0 26,30 Starting from ]tritriaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetate (1 equiv., 0.62 g, 0.92 mmol), the title compound (291 mg white solid, 55% yield) was obtained.

[0117] The enantiopure products were obtained by chromatographic separation on a chiral column.

[0118] Example 1a (E1) HRMS C 30 H 32Calculated for N4O6S: 576.2042; [M+H] + Measured value: 577.2115 (δ=-0.1 ppm)

[0119] Example 1b (E2) HRMS C 30 H 32 Calculated for N4O6S: 576.2042; [M+H] + Measured value: 577.2113 (δ=-0.4 ppm) 1 H-NMR (400 MHz, DMSO-d6) δppm: 11.55 (m, 1 H), 7.62 (d, 1 H), 7.5 (d, 2 H), 7.29 (d, 1 H), 7.02 (d, 1 H), 6.9 (dd, 1 H), 6.72 (d, 1 H), 6.11 (d, 1 H), 4.8 (t, 1 H), 4.7 (t, 2 H), 4.2 / 3.9 (2d, 2 H), 4.11 / 4 (2d, 2 H), 3.9 / 3.8 (2m, 2 H), 2.92 (2dd, 2 H), 2.65 (s, 3 H), 2.31 (s, 3 H), 1.99 (m, 2 H), 1.72 (m, 2 H), 1.48 / 1.38 (2m, 2 H)

[0120] Example 2 : [4,30-dimethyl-26,26-dioxo-20,25-dioxa-26λ 6 -Thia-1,14,15,16-tetraazahexacyclo[19.5.3.1 3,7 .1 9,13 .0 12,16 .0 24,28 ]Hentriaconta-3(31),4,6,9(30),10,12,14,21,23,28-decaen-8-yl]acetic acid [ka]

[0121] Step A1: Preparation of N-[3-(benzyloxy)propyl]-3-methyl-2-nitroaniline Using General Procedure 2, Step 1, starting with 1-fluoro-3-methyl-2-nitro-benzene (1 eq, 1.93 mmol) and 3-benzyloxypropan-1-amine (1.2 eq, 383 mg, 2.32 mmol) as reactants, the title compound (375 mg, 64% yield) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.37-7.26 (m, 5 H), 7.26 (t, 1 H), 6.77 (d, 1 H), 6.55 (d, 1 H), 6.47 (t, 1 H), 4.47 (s, 2 H), 3.51 (t, 2 H), 2.29 (s, 2 H), 2.26 (q, 2 H), 1.83 (m, 2 H)

[0122] Step A2: Preparation of N-[3-(benzyloxy)propyl]-4-bromo-3-methyl-2-nitroaniline Using General Procedure 2, Step 2, starting with N-[3-(benzyloxy)propyl]-3-methyl-2-nitroaniline (6.5 g, 22 mmol) as reactant, the title compound (6.54 g, 80% yield) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.5 (d, 1 H), 7.3 (m, 5 H), 6.72 (d, 1 H), 6.18 (t), 4.45 (s, 2 H), 3.48 (t, 2 H), 3.22 (q, 2 H), 2.25 (s, 3 H), 1.8 (m, 2 H)

[0123] Process A3: N 1 Preparation of -[3-(benzyloxy)propyl]-4-bromo-3-methylbenzene-1,2-diamine Using General Procedure 2, Step 3, starting with N-[3-(benzyloxy)propyl]-4-bromo-3-methyl-2-nitroaniline (6.5 g, 17 mmol) as reactant, the title compound (5.4 g, 75% yield) was obtained. 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.39-7.24 (s, 5 H), 6.71 (d, 1 H), 6.26 (d, 1 H), 4.62-4.54 (m, 3 H), 4.48 (s, 2 H), 3.55 (t, 2 H), 3.08 (q, 2 H), 2.16 (s, 3 H), 1.86 (m, 2 H)

[0124] Step A4: Preparation of 1-[3-(benzyloxy)propyl]-5-bromo-4-methyl-1H-benzotriazole Using General Procedure 2, Step 4, N 1 Starting from -[3-(benzyloxy)propyl]-4-bromo-3-methylbenzene-1,2-diamine (5.4 g, 13 mmol), the title compound (1.09 g, 23% yield) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.68 / 7.65 (d, 2 H), 7.34-7.2 (m, 5 H), 4.78 (t, 2 H), 4.38 (s, 2 H), 3.41 (t, 2 H), 2.71 (s, 3 H), 2.18 (m, 2 H)

[0125] Step A5: Preparation of ethyl (2E)-3-{1-[3-(benzyloxy)propyl]-4-methyl-1H-benzotriazol-5-yl}prop-2-enoate Using General Procedure 2, Step 5, starting with 1-[3-(benzyloxy)propyl]-5-bromo-4-methyl-1H-benzotriazole (1.05 g, 2.91 mmol) as reactant, the title compound (1.18 g, 70% yield) was obtained. 1H-NMR (400 MHz, DMSO-d6) δ ppm: 1.28 (t, J=7.09 Hz, 2 H) 2.14 - 2.23 (m, 3 H) 3.41 (td, J=5.96, 3.00 Hz, 3 H) 4.22 (q, J=7.17 Hz, 2 H) 4.36 - 4.41 (m, 3 H) 4.78 (t, J=6.79 Hz, 3 H) 6.65 (d, J=15.77 Hz, 1 H) 7.28 (s, 7 H) 7.69 (d, J=8.80 Hz, 1 H) 7.95 - 7.97 (m, 1 H) 8.03 (d, J=15.89Hz, 1H)

[0126] Step 1: Preparation of ethyl 3-{1-[3-(benzyloxy)propyl]-4-methyl-1H-benzotriazol-5-yl}-3-[3-(hydroxymethyl)-4-methylphenyl]propanoate Using general procedure 6 and starting with ethyl (2E)-3-{1-[3-(benzyloxy)propyl]-4-methyl-1H-benzotriazol-5-yl}prop-2-enoate (1 equivalent) and [2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (1.5 equivalents) as reactants, the title compound was obtained (yellow oil, 44% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.55 (d, 1 H), 7.45 (d, 1 H), 7.25 (m, 6 H), 7.1 (dd, 1 H), 7.01 (d, 1 H), 4.81 (t, 1 H), 4.81 (t, 1 H), 4.7 (t, 2 H), 4.4 (d+s, 4 H), 3.92 (q, 2 H), 3.4 (t, 2 H), 3.12 (2dd, 2 H), 2.75 (s, 3 H), 2.15 (m+s, 5 H), 1 (t, 3 H)

[0127] Step 2: Ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6Preparation of 1-(3-benzoxathiazin-3(4H)-yl]methyl}-4-methylphenyl)-3-{1-[3-(benzyloxy)propyl]-4-methyl-1H-benzotriazol-5-yl}propanoate Using General Procedure 7, the reactants were ethyl 3-{1-[3-(benzyloxy)propyl]-4-methyl-1H-benzotriazol-5-yl}-3-[3-(hydroxymethyl)-4-methylphenyl]propanoate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6 Starting with ,3-benzoxathiazine-2,2-dione (1.5 equivalents), the title compound was obtained (94% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.09 Hz, 3 H) 2.13 (quint, J=6.36 Hz, 2 H) 2.22 (s, 3 H) 2.76 (s, 3 H) 3.17 (dd, J=8.01, 3.36 Hz, 2 H) 3.36 (t, J=6.05 Hz, 2 H) 3.92 (q, J=7.13 Hz, 2 H) 4.21 (s, 2 H) 4.37 (s, 2 H) 4.41 (s, 2 H) 4.68 (t, J=6.79 Hz, 2 H) 4.85 (t, J=8.01 Hz, 1 H) 5.10 (s, 2 H) 6.94 (d, J=2.81 Hz, 1 H) 7.03 - 7.09 (m, 1 H) 7.10 - 7.16 (m, 2 H) 7.16 - 7.31 (m, 7 H) 7.32 - 7.37 (m, 1 H) 7.37 - 7.43 (m, 1 H) 7.44 - 7.47 (m, 1 H) 7.48 (d, J=8.80 Hz, 1 H) 7.53 - 7.59 (m, 1 H)

[0128] Step 3: Ethyl 3-[1-(3-bromopropyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate Using general procedure 8, ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ] was used as the reactant. 6 ,3-benzoxathiazin-3(4H)-yl]methyl}-4-methylphenyl)-3-{1-[3-(benzyloxy)propyl]-4-methyl-1H-benzotriazol-5-yl}propanoate (1 equivalent), 6 ,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}-3-[1-(3-hydroxypropyl)-4-methyl-1H-benzotriazol-5-yl]propanoate (65% yield). The crude product was reacted using general procedure 9 to give the title compound (69% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.65 (s, 1 H), 7.62 (d, 1 H), 7.51 (d, 1 H), 7.2 (d, 1 H), 7.18 (dd, 1 H), 7.1 (d, 1 H), 7 (d, 1 H), 6.8 (dd, 1 H), 6.6 (d, 1 H), 4.85 (t, 1 H), 4.75 (t, 2 H), 4.38 (s, 2 H), 4.2 (m, 2 H), 3.92 (q, 2 H), 3.48 (t, 2 H), 3.18 (d, 2 H), 2.75 (s, 3 H), 2.42 (m, 2 H), 2.21 (s, 3 H), 1 (t, 3 H)

[0129] Step 4: Ethyl [4,30-dimethyl-26,26-dioxo-20,25-dioxa-26λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[19.5.3.1 3,7 .1 9,13 .0 12,16 .0 24,28Preparation of ]hentriaconta-3(31),4,6,9(30),10,12,14,21,23,28-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(3-bromopropyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate gave the title compound (96% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.54 (d, 1 H), 7.48 (dd, 1 H), 7.44 (d, 1 H), 7.28 (d, 1 H), 7.01 (d, 1 H), 6.85 (dd, 1 H), 6.47 (d, 1 H), 5.2 (d, 1 H), 4.87 (m, 2 H), 4.76 (t, 1 H), 4.36 / 3.64 (d, 2 H), 4.13 / 3.44 (d, 2 H), 4.01 / 3.7 (tt, 2 H), 3.91 (q, 2 H), 3.03 (d, 2 H), 2.63 (s, 3 H), 2.47 / 2.38 (m, 2 H), 2.32 (s, 3H), 1 (t, 3H)

[0130] Step 5: Preparation of Example 2 Using general procedure 12, ethyl [4,30-dimethyl-26,26-dioxo-20,25-dioxa-26λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[19.5.3.1 3,7 .1 9,13 .0 12,16 .0 24,28 Starting with ]hentriaconta-3(31),4,6,9(30),10,12,14,21,23,28-decaen-8-yl]acetate (1 equivalent), the title compound (white solid, 70% yield) was obtained as a racemate. HRMS C 28 H 28Calculated for N4O6S: 548.1730; [M+H] + Measured value: 549.1805 (δ=0.5 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (m, 1 H), 7.55 (d, 1 H), 7.45 (dd, 1 H), 7.4 (d, 1 H), 7.25 (d, 1 H), 7 (d, 1 H), 6.85 (dd, 1 H), 6.43 (d, 1 H), 5.22 (d, 1 H), 4.85 (m, 2 H), 4.75 (t, 1 H), 4.35 / 3.65 (m, 2 H), 4.15 / 3.45 (m, 2 H), 4 / 3.7 (m, 2 H), 2.95 (d, 2 H), 2.65 (s, 3 H), 2.4 (m, 2 H), 2.3 (s, 3 H)

[0131] Example 3 : [(2R,8R)-2,4,31-trimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid and [(2R,8S)-2,4,31-trimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0132] Step A1: Preparation of 4-(3-methyl-2-nitroanilino)butan-1-ol Using General Procedure 1 Step 1, starting with 1-fluoro-3-methyl-2-nitro-benzene (1 eq) and 4-aminobutan-1-ol (3 eq) as reactants, the title compound was obtained (44% yield). 1 H-NMR (400 MHz, DMSO-d6) δppm: 7.28 (t, 1 H), 6.78 (d, 1 H), 6.52 (d, 1 H), 6.4 (t, 1 H), 4.4 (t, 1 H), 3.41 (q, 2 H), 3.2 (q, 2 H), 2.3 (s, 3H), 1.58 (m, 2H), 1.48 (m, 2H)

[0133] Step A2: Preparation of 4-(4-bromo-3-methyl-2-nitroanilino)butyl acetate Using General Procedure 1, Step 2, starting with 4-(3-methyl-2-nitroanilino)butan-1-ol (1 equivalent) as reactant, the title compound was obtained (orange oil, 93% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.52 (d, 1 H), 6.72 (d, 1 H), 6.15 (t, 1 H), 4 (t, 2 H), 3.15 (q, 2 H), 2.25 (s, 3 H), 2 (s, 3 H), 1.55 (m, 4 H)

[0134] Step A3: Preparation of 4-(2-amino-4-bromo-3-methylanilino)butyl acetate Using General Procedure 1, Step 3, starting with 4-(4-bromo-3-methyl-2-nitroanilino)butyl acetate (1 equivalent) as reactant, the title compound was obtained (72% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 6.7 (d, 1 H), 6.25 (d, 1 H), 5.2-4.5 (ml, 3 H), 4.01 (t, 2 H), 3 (t, 2 H), 2.19 (s, 3 H), 2 (s, 3 H), 1.7-1.5 (m, 4H)

[0135] Step A4: Preparation of 4-(5-bromo-4-methyl-1H-benzotriazol-1-yl)butyl acetate Using General Procedure 1, Step 4, starting with 4-(2-amino-4-bromo-3-methylanilino)butyl acetate (1 equivalent) as reactant, the title compound was obtained (orange oil, 49% yield). HRMS C 13 H 16 Calculated for BrN3O2: 325.0426; [M+H] + Measured value: 326.0502 (δ=1.0 ppm)

[0136] Step A5: Preparation of 4-(5-bromo-4-methyl-1H-benzotriazol-1-yl)butan-1-ol Using General Procedure 1, Step 5, starting with 4-(5-bromo-4-methyl-1H-benzotriazol-1-yl)butyl acetate (1 equivalent) as reactant, the title compound was obtained (orange oil, 85% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.7 (m, 2 H), 4.75 (t, 2 H), 4.45 (t, 1 H), 3.45 (q, 2 H), 2.75 (s, 3 H), 1.95 (m, 2 H), 1.4 (m, 2 H)

[0137] Step A6: Preparation of 5-bromo-1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazole Using General Procedure 1, Step 6, starting with 4-(5-bromo-4-methyl-1H-benzotriazol-1-yl)butan-1-ol (1 equivalent) as reactant, the title compound was obtained (yellow oil, 74% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.68 (s, 2 H), 7.19 (d, 2 H), 6.88 (d, 2 H), 4.71 (t, 2 H), 4.32 (s, 2 H), 3.73 (s, 3 H), 3.39 (t, 2 H), 2.72 (s, 3 H), 1.95 (quint, 2 H), 1.48 (quint, 2 H)

[0138] Step A7: Preparation of ethyl (2E)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate Using General Procedure 1, Step 7, starting with 5-bromo-1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazole (1 equivalent) as reactant, the title compound was obtained (yellow solid, 74% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8.02 (d, 1 H), 7.95 (d, 1 H), 7.7 (d, 1 H), 7.19 (d, 2 H), 6.88 (d, 2 H), 6.65 (d, 1 H), 4.71 (t, 2 H), 4.32 (s, 2 H), 4.22 (q, 2 H), 3.73 (s, 3 H), 3.39 (t, 2 H), 2.81 (s, 3 H), 1.95 (m, 2 H), 1.49 (m, 2 H), 1.28 (t, 3 H)

[0139] Step 1: Preparation of ethyl 3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using general procedure 6 and starting with ethyl (2E)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equivalent) and (1S)-1-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1-ol (2 equivalents) as reactants, the title compound was obtained (yellow oil, 82% yield). 1 H-NMR (400 MHz, DMSO-d6) δppm: 0.99 (t, J=7.09 Hz, 3 H) 1.22 (dd, J=8.74, 6.42 Hz, 3 H) 1.42 - 1.53 (m, 2 H) 1.92 (quin, J=7.21 Hz, 2 H) 1.99 (s, 2 H) 2.19 (s, 3 H) 2.76 (d, J=3.79 Hz, 3 H) 3.09 - 3.16 (m, 2 H) 3.38 (t, J=6.30 Hz, 2 H) 3.73 (s, 3 H) 3.92 (q, J=7.09 Hz, 2 H) 4.32 (s, 2 H) 4.64 (t, J=6.91 Hz, 2 H) 4.83 (dt, J=7.64, 3.88 Hz, 2 H) 4.92 - 5.01 (m, 1 H) 6.83 - 6.90 (m, 2 H) 6.95 - 7.01 (m, 1 H) 7.02 - 7.08 (m, 1 H) 7.19 (d, J=8.56 Hz, 2 H) 7.40 (d, J=1.71 Hz, 1 H) 7.43 - 7.49 (m, 1 H) 7.55 - 7.60 (m, 1 H)

[0140] Step 2: Ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(4-(4-benzoxathiazin-3(4H)-yl]ethyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, the reactants were ethyl 3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6 Starting with ,3-benzoxathiazine-2,2-dione (1.5 equivalents), the title compound was obtained (69% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 0.93 - 1.01 (m, 3 H) 1.36 - 1.49 (m, 5 H) 1.83 - 1.94 (m, 2 H) 2.28 (s, 3 H) 2.77 (d, J=4.65 Hz, 3 H) 3.17 - 3.24 (m, 2 H) 3.32 - 3.38 (m, 2 H) 3.72 (s, 3 H) 3.88 - 3.95 (m, 2 H) 4.29 (d, J=2.69 Hz, 2 H) 4.37 - 4.46 (m, 1 H) 4.56 - 4.65 (m, 2 H) 4.82 - 4.91 (m, 1 H) 5.03 - 5.13 (m, 2 H) 5.27 (q, J=6.77 Hz, 1 H) 6.80 - 6.91 (m, 3 H) 6.95 - 7.07 (m, 2 H) 7.07 - 7.15 (m, 2 H) 7.18 (d, J=8.44 Hz, 2 H) 7.30 - 7.48 (m, 6 H)

[0141] Step 3: Ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate Using General Procedure 8, the reactant was ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6Starting from 1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained (79% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 1.00 (q, J=7.01 Hz, 3 H) 1.29 - 1.39 (m, 2 H) 1.39 - 1.46 (m, 3 H) 1.85 - 1.96 (m, 2 H) 2.28 (s, 3 H) 2.77 (s, 3 H) 3.22 (d, J=7.83 Hz, 2 H) 3.35 - 3.41 (m, 3 H) 3.94 (qd, J=7.11, 2.02 Hz, 2 H) 4.23 - 4.36 (m, 1 H) 4.37 (s, 1 H) 4.41 (t, J=5.14 Hz, 1 H) 4.65 (t, J=7.03 Hz, 2 H) 4.78 - 4.95 (m, 1 H) 5.26 (q, J=6.64 Hz, 1 H) 6.53 - 6.62 (m, 1 H) 6.69 - 6.76 (m, 1 H) 6.79 - 6.84 (m, 1 H) 6.88 - 6.94 (m, 1 H) 7.05 - 7.15 (m, 3 H) 7.47 (d, J=10.64 Hz, 1 H) 9.57 - 9.72 (m, 1 H)

[0142] Step 4: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ] 6Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate gave the title compound (colorless solid, 91% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.63 / 9.62 (2s, 1 H), 7.64 / 7.59 (4d, 2 H), 7.48 / 7.45 (2s, 1 H), 7.11 (m, 2 H), 6.91 (d, 1 H), 6.73 (m, 1 H), 6.6 / 6.56 (2d, 1 H), 5.26 (m, 1 H), 4.88 (m, 1 H), 4.69 (t, 2 H), 4.37 / 4.31 (s+m, 2 H), 3.94 (2q, 2 H), 3.54 (t, 2 H), 3.23 (dl, 2 H), 2.77 (s, 3 H), 2.28 (s, 3 H), 1.99 (quint, 2 H), 1.77 (quint, 2 H), 1.43 / 1.41 (2d, 3 H)

[0143] Step 5: Ethyl [(2R)-2,4,31-trimethyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate gave the title compound (white solid, 91% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 1.03 (td, J=7.09, 3.30 Hz, 9 H) 1.23 - 1.30 (m, 7 H) 1.33 - 1.94 (m, 12 H) 2.25 - 2.35 (m, 11 H) 2.67 (s, 6 H) 2.96 - 3.15 (m, 5 H) 3.34 - 3.53 (m, 9 H) 3.62 - 3.75 (m, 4 H) 3.88 - 3.98 (m, 5 H) 3.99 - 4.11 (m, 4 H) 4.70 - 4.85 (m, 10 H) 4.92 (t, J=7.95 Hz, 2 H) 5.18 - 5.31 (m, 2 H) 5.72 (d, J=2.81 Hz, 1 H) 5.89 (br. s., 1 H) 6.74 - 6.78 (m, 1 H) 6.88 - 6.98 (m, 2 H) 7.17 (s, 1 H) 7.31 (d, J=8.07 Hz, 1 H) 7.44 (d, J=7.58 Hz, 2 H) 7.75 (d, J=8.68 Hz, 1 H) 7.89 (d, J=8.68 Hz, 1 H)

[0144] The diastereomeric final intermediate was obtained by chromatographic separation on a chiral column.

[0145] Step 6: Preparation of Example 3 Using General Procedure 12, ethyl [(2R,8R)-2,4,31-trimethyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent) or ethyl [(2R,8S)-2,4,31-trimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.13,7 .1 9,13 .0 12,16 .0 25,29 Starting from ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent), the title compounds were obtained in yields ranging from 34% to 78%, respectively.

[0146] Example 3a (2R,8R) HRMS C 30 H 32 Calculated for N4O6S: 576.2042; [M+H] + Measured value: 577.2119 (δ=0.6 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.21 (m, 1 H), 7.7 (d, 1 H), 7.43 (d, 1 H), 7.3 (d, 1 H), 7.1 (d, 1 H), 6.9 (d, 1 H), 6.7 (m, 2 H), 5.89 (m, 1 H), 5.21 (q, 1 H), 4.9 (t, 1 H), 4.73 (m, 2 H), 4.05 / 3.48 (m, 2 H), 3.7 (m, 2 H), 3.25 / 2.89 (2dd, 2 H), 2.8 (s, 3 H), 2.3 (s, 3 H), 2.2 / 2 (2m, 2 H), 1.61 / 1.29 (2m, 2 H), 1.1 (d, 3 H)

[0147] Example 3b (2R,8S) HRMS C 30 H 32 Calculated for N4O6S: 576.2042; [M+H] + Measured value: 577.2118 (δ=0.5 ppm) 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.5-11.8 (m, 1 H), 7.88 (d, 1 H), 7.73 (d, 1 H), 7.43 (d, 1 H), 7.2 (d, 1 H), 7.11 (d, 1 H), 6.93 (d, 1 H), 6.78 (dd, 1 H), 5.69 (d, 1 H), 5.25 (q, 1 H), 4.82-4.67 (m, 2 H), 4.78 (t, 1 H), 4.01 / 3.4 (m, 2 H), 3.68 / 3.47 (m, 2 H), 3.19 / 2.99 (2dd, 2 H), 2.62 (s, 3 H), 2.29 (s, 3 H), 2.23-2 (2m, 2 H), 1.92-1.68 (2m, 2 H), 1.23 (d, 3 H)

[0148] Example 4 : [5-fluoro-31-methyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0149] Step 1: Preparation of ethyl 3-[3-fluoro-5-(hydroxymethyl)phenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using general procedure 6 and starting with ethyl (2E)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equivalent) and [3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (1.5 equivalents) as reactants, the title compound was obtained (yellow oil, 30% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.5 (d, 1 H), 7.2 (d, 2 H), 7.1-6.9 (m, 3 H), 6.88 (d, 2 H), 5.22 (t, 1 H), 4.85 (t, 1 H), 4.62 (t, 2 H), 4.41 (d, 2 H), 4.3 (s, 2 H), 3.95 (q, 2 H), 3.71 (s, 3 H), 3.39 (t, 2 H), 3.18 (m, 2 H), 2.78 (s, 3 H), 1.9 (m, 2 H), 1.5 (m, 2H), 1 (t, 3H)

[0150] Step 2: Ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(4-(4-benzoxathiazin-3(4H)-yl)methyl}-5-fluorophenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, reactants were ethyl 3-[3-fluoro-5-(hydroxymethyl)phenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6 Starting with ,3-benzoxathiazine-2,2-dione (1.1 equivalents), the title compound was obtained (64% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.48 (d, 1 H), 7.4-7.3 (m, 5 H), 7.2-7 (m, 3 H), 7.18 (d, 2 H), 7-6.9 (m, 3 H), 6.85 (d, 2 H), 5.05 (s, 2 H), 4.87 (t, 1 H), 4.62 (s+t, 4 H), 4.3 (s, 4 H), 3.92 (q, 2 H), 3.71 (s, 3 H), 3.38 (t, 2 H), 3.18 (d, 2 H), 2.78 (s, 3 H), 1.92 (m, 2 H), 1.5 (m, 2 H), 1 (t, 3 H)

[0151] Step 3: Ethyl 3-{3-fluoro-5-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl propanoate Using general procedure 8, ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ] was used as the reactant. 6 Starting from 1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained (96% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.6 / 4.4 (s+t, 2 H), 7.62 (d, 1 H), 7.5 (d, 1 H), 7.21 (d, 1 H), 7.1 (dd, 1 H), 7.02 (dd, 1 H), 6.81 (d, 1 H), 6.7 (dd, 1 H), 6.6 (d, 1 H), 4.85 (t, 1 H), 4.65 (t, 2 H), 4.52 (s, 2 H), 4.29 (s, 2 H), 3.95 (q, 2 H), 3.4 (q, 2 H), 3.2 (d, 2 H), 2.79 (s, 3 H), 1.9 (m, 2 H), 1.38 (m, 2 H), 1 (t, 3 H)

[0152] Step 4: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-fluoro-5-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]phenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-{3-fluoro-5-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Starting from {1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl}-phenyl}-3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]propanoate (1 equivalent), the title compound was obtained (66% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.6 (s, 1 H), 7.64 (d, 1 H), 7.51 (d, 1 H), 7.2 (t, 1 H), 7.13 / 7 (2dt, 2 H), 6.88 (d, 1 H), 6.7 (dd, 1 H), 6.59 (d, 1 H), 4.87 (t, 1 H), 4.69 (t, 2 H), 4.57 (s, 2 H), 4.29 (s, 2 H), 3.92 (q, 2 H), 3.52 (t, 2 H), 3.19 (d, 2 H), 2.78 (s, 3 H), 1.99 (m, 2 H), 1.78 (m, 2 H), 1 (t, 3 H)

[0153] Step 5: Ethyl [5-fluoro-31-methyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-fluoro-5-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)methyl]phenyl}propanoate gave the title compound (white solid, 72% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.59 (d, 1 H), 7.4 / 7.06 (2m, 2 H), 7.32 (d, 1 H), 6.91 (d, 1 H), 6.74 (m, 1 H), 6.69 (dd, 1 H), 6 (d, 1 H), 4.87-4.67 (m, 3 H), 4.15 / 4.05 (2dd, 4 H), 3.93 (m, 2 H), 3.67 / 3.37 (2m, 2 H), 3.27 / 3.11 (2m, 2 H), 2.75 (s, 3 H), 2.18 / 1.96 (2m, 2 H), 1.68 / 1.45 (2m, 2 H), 1.01 (t, 3 H)

[0154] Step 6: Preparation of Example 4 Using general procedure 12, ethyl [5-fluoro-31-methyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Starting from ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 98% yield). HRMS C 28 H 27 Calculated for FN4O6S: 566.1635; [M+H] + Measured value: 567.1710 (δ=0.3 ppm) 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.19 (m, 1 H), 7.59 (d, 1 H), 7.4 / 7.06 (2m, 2 H), 7.3 (d, 1 H), 6.91 (d, 1 H), 6.71 (m, 1 H), 6.69 (dd, 1 H), 6 (d, 1 H), 4.87-4.67 (m, 3 H), 4.14 / 4.04 (2dd, 4 H), 3.68 / 3.38 (2m, 2 H), 3.17 / 2.91 (2m, 2 H), 2.75 (s, 3 H), 2.19 / 1.97 (2m, 2 H), 1.69 / 1.46 (2m, 2H)

[0155] Example 5 : [5,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0156] Step B1: Preparation of [3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol Using general procedure 3 and starting with (3-bromo-5-methylphenyl)methanol (1 equivalent, 2.01 g, 10 mmol) as reactant, the title compound (1.13 g, 45% yield) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.44 / 7.35 / 7.23 (3tf, 3 H), 5.12 (t, 1 H), 4.46 (d, 2 H), 2.29 (s, 3 H), 1.28 (s, 12 H)

[0157] Step 1: Preparation of ethyl 3-[3-(hydroxymethyl)-5-methylphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using general procedure 6 and starting with ethyl (2E)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equivalent) and [3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (2 equivalents) as reactants, the title compound was obtained (68% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.58 (d, 1 H), 7.47 (d, 1 H), 7.2 (d, 2 H), 7.04 / 7 / 6.93 (3sl, 3 H), 6.87 (d, 2 H), 5.05 (t, 1 H), 4.82 (t, 1 H), 4.64 (t, 2 H), 4.39 (d, 2 H), 4.32 (s, 2 H), 3.92 (qd, 2 H), 3.73 (s, 3 H), 3.38 (t, 2 H), 3.13 (m, 2 H), 2.76 (s, 3 H), 2.23 (s, 3 H), 1.92 (m, 2 H), 1.48 (m, 2 H), 0.99 (t, 3 H)

[0158] Step 2: Ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(4-(4-benzoxathiazin-3(4H)-yl]methyl)-5-methylphenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, reactants were ethyl 3-[3-(hydroxymethyl)-5-methylphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ.6 Starting with 1.5 equivalents of 1,3-benzoxathiazine-2,2-dione, the title compound was obtained in 86% yield. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.57 (d, 1 H), 7.45-7.3 (m, 5 H), 7.45 (d, 1 H), 7.18 (d, 2 H), 7.14 / 7.07 / 6.98 (3tf, 3 H), 7.03 / 7 / 6.94 (dd+d+d, 3 H), 6.86 (d, 2 H), 5.05 (s, 2 H), 4.82 (t, 1 H), 4.63 (t, 2 H), 4.55 (s, 2 H), 4.31 (s, 2 H), 4.23 (s, 2 H), 3.92 (q, 2 H), 3.73 (s, 3 H), 3.36 (t, 2 H), 3.12 (d, 2 H), 2.76 (s, 3 H), 2.22 (s, 3 H), 1.91 (m, 2 H), 1.47 (m, 2 H), 0.98 (t, 3 H)

[0159] Step 3: Ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-5-methylphenyl}propanoate Using general procedure 8, ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ] was used as the reactant. 6 Starting from 1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained (99% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.63 (m, 1 H), 7.62 (d, 1 H), 7.47 (d, 1 H), 7.15 / 7.08 / 6.99 (3tf, 3 H), 6.91 (d, 1 H), 6.73 (dd, 1 H), 6.6 (d, 1 H), 4.83 (t, 1 H), 4.65 (t, 2 H), 4.5 / 4.22 (2s, 4 H), 3.94 (q, 2 H), 3.39 (t, 2 H), 3.14 (d, 2 H), 2.77 (s, 3 H), 2.24 (s, 3 H), 1.91 (m, 2 H), 1.37 (m, 2 H), 1 (t, 3 H)

[0160] Step 4: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-5-methylphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)methyl]-5-methylphenyl}propanoate gave the title compound (78% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.61 (m, 1 H), 7.63 (d, 1 H), 7.49 (d, 1 H), 7.14 / 7.07 / 6.98 (3tf, 3 H), 6.9 (d, 1 H), 6.73 (dd, 1 H), 6.59 (d, 1 H), 4.82 (t, 1 H), 4.69 (t, 2 H), 4.49 / 4.2 (2s, 4 H), 3.93 (q, 2 H), 3.54 (t, 2 H), 3.14 (d, 2 H), 2.76 (s, 3 H), 2.22 (s, 3 H), 1.99 (m, 2 H), 1.77 (m, 2 H), 0.99 (t, 3 H)

[0161] Step 5: Ethyl [5,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equivalent of 1,3-benzoxathiazin-3(4H)-yl)methyl]-5-methylphenyl}propanoate gave the title compound (98% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.35 (d, 1 H), 7.34 / 7.09 / 6.58 (3m, 3 H), 6.93 (d, 1 H), 6.73 (dd, 1 H), 5.98 (d, 1 H), 4.84-4.66 (2m, 3 H), 4.03 / 3.98 (2s, 4 H), 3.93 (m, 2 H), 3.68 / 3.45 (2m, 2 H), 3.21 / 3.09 (2m, 2 H), 2.71 (s, 3 H), 2.36 (s, 3 H), 2.19 / 1.99 (2m, 2 H), 1.68 / 1.48 (2m, 2 H), 1.01 (t, 3 H)

[0162] Step 6: Preparation of Example 5 Using general procedure 12, ethyl [5,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Starting from ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 50% yield). HRMS C 29 H 30 Calculated for N4O6S: 562.1886; [M+H] + Measured value: 563.1963 (δ=0.7 ppm) 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.15 (m, 1 H), 7.6 (d, 1 H), 7.34 / 7.09 / 6.57 (3sl, 3 H), 7.33 (d, 1 H), 6.94 (d, 1 H), 6.73 (dd, 1 H), 5.98 (d, 1 H), 4.85-4.67 (2m, 3 H), 4.03 / 3.98 (2s, 4 H), 3.68 / 3.45 (2m, 2 H), 3.11 / 2.97 (2m, 2 H), 2.71 (s, 3 H), 2.36 (s, 3 H), 2.19 / 1.99 (2m, 2 H), 1.71 / 1.47 (2m, 2 H)

[0163] Example 6 : [31-methyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0164] Step 1: Preparation of ethyl 3-[3-(hydroxymethyl)phenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using general procedure 6 and starting with ethyl (2E)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equivalent) and [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (2 equivalents) as reactants, the title compound was obtained (75% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.58 (d, 1 H), 7.48 (d, 1 H), 7.26-7.1 (m, 4 H), 7.2 (d, 2 H), 6.88 (d, 2 H), 5.09 (t, 1 H), 4.86 (t, 1 H), 4.64 (t, 2 H), 4.42 (d, 2 H), 4.32 (s, 2 H), 3.92 (q, 2 H), 3.73 (s, 3 H), 3.38 (t, 2 H), 3.18 / 3.13 (2dd, 2 H), 2.77 (s, 3 H), 1.92 (m, 2 H), 1.48 (m, 2 H), 0.99 (t, 3 H)

[0165] Step 2: Ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]phenyl}propanoate Using General Procedure 7, reactants were ethyl 3-[3-(hydroxymethyl)phenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6 Starting from 1.5 equivalents of ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ-benzoxathiazine-2,2-dione, 6 ,3-benzoxathiazin-3(4H)-yl]methyl}phenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate. The crude product was used without further purification using general procedure 8. The title compound was obtained (77% yield). 1H-NMR (400 MHz, DMSO-d6) δppm: 9.61 (m, 1 H), 7.61 (d, 1 H), 7.48 (d, 1 H), 7.36 (m, 1 H), 7.28-7.14 (m, 3 H), 6.89 (d, 1 H), 6.72 (dd, 1 H), 6.59 (d, 1 H), 4.86 (t, 1 H), 4.65 (t, 2 H), 4.51 / 4.26 (2s, 4 H), 4.41 (t, 2 H), 3.93 (q, 2 H), 3.38 (q, 2 H), 3.16 (d, 2 H), 2.76 (s, 3 H), 1.9 (m, 2 H), 1.37 (m, 2 H), 1 (t, 3 H)

[0166] Step 3: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]phenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting with 1 equivalent of 3-benzoxathiazin-3(4H)-yl)methyl]phenyl}propanoate gave the title compound (99% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.61 (m, 1 H), 7.61 (d, 1 H), 7.49 (d, 1 H), 7.25-7.14 (m, 3 H), 7.22 (m, 1 H), 6.89 (d, 1 H), 6.72 (dd, 1 H), 6.59 (d, 1 H), 4.88 (t, 1 H), 4.7 (t, 2 H), 4.5 / 4.26 (2s, 4 H), 3.91 (q, 2 H), 3.52 (t, 2 H), 3.16 (d, 2 H), 2.76 (s, 3 H), 2 (m, 2 H), 1.78 (m, 2 H), 1 (t, 3 H)

[0167] Step 4: Ethyl [31-methyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)methyl]phenyl}propanoate gave the title compound (78% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.5 (d, 1 H), 7.4 (t, 1 H), 7.31 (d, 1 H), 7.25 (d, 1 H), 6.95 (d, 1 H), 6.81 (sl, 1 H), 6.7 (dd, 1 H), 6 (d, 1 H), 4.8 / 4.71 (2m, 2 H), 4.8 (m, 1 H), 4.11 / 4 (2s, 4 H), 3.92 (q, 2 H), 3.7 / 3.4 (2m, 2 H), 3.2 / 3.1 (2dd, 2 H), 2.71 (s, 3H), 2.2 / 2 (2m, 2H), 1.7 / 1.5 (2m, 2H), 1 (t, 3H)

[0168] Step 5: Preparation of Example 6 Using general procedure 12, ethyl [31-methyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Starting from ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 21% yield). HRMS C 28 H 28 Calculated for N4O6S: 548.1730; [M+H] + Measured value: 549.1809 (δ=1.2 ppm) 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.58 (d, 1 H), 7.5 (d, 1 H), 7.41 (t, 1 H), 7.32 (d, 1 H), 7.26 (d, 1 H), 6.92 (d, 1 H), 6.8 (sl, 1 H), 6.72 (dd, 1 H), 5.98 (d, 1 H), 4.8 / 4.72 (2m, 2 H), 4.8 (m, 1 H), 4.1 (s, 2 H), 4 (s, 2 H), 3.68 / 3.4 (2m, 2 H), 3.12 / 3 (2dd, 2 H), 2.7 (s, 3H), 2.2 / 1.98 (2m, 2H), 1.7 / 1.48 (2m, 2 H)

[0169] Example 7 : [(8S)-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid and [(8R)-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0170] Step A1: Preparation of N-[4-(benzyloxy)butyl]-4-bromo-3-methyl-2-nitroaniline A mixture of 4-bromo-3-methyl-2-nitro-aniline (1 eq., 10 g, 43 mmol), NaOH (1.2 eq., 2.1 g, 52 mmol), and acetone (2 mL / mmol, 87 mL) was heated to 65° C. for 15 minutes. 4-Bromobutoxymethylbenzene (1.2 eq.) was added to the mixture over 5 minutes. The mixture was stirred at 65° C. for 72 hours. After completion of the reaction, the mixture was quenched with water (400 mL). The mixture was extracted with EtOAc (3×150 ml). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to dryness to give the crude product, which was purified by normal-phase silica gel chromatography using heptane-DCM (20:80) as eluent to give the title compound (6.5 g, orange oil, 38% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.5 (d, 1 H), 7.3 (m, 5 H), 6.7 (d, 1 H), 6.15 (t, 1 H), 4.4 (s, 2 H), 3.45 (t, 2 H), 3.1 (q, 2 H), 2.2 (s, 3 H), 1.6 (m, 4 H)

[0171] Process A2: N 1 Preparation of -[4-(benzyloxy)butyl]-4-bromo-3-methylbenzene-1,2-diamine To a solution of N-[4-(benzyloxy)butyl]-4-bromo-3-methyl-2-nitroaniline (1 equiv., 6.1 g, 16 mmol) in EtOH (4 mL / mmol, 62 mL) was added tin(II) dichloride dehydrate (4 equiv., 13 g, 62 mmol) at room temperature. The reaction mixture was heated to 70 °C and stirred at this temperature for 3 h. After completion of the reaction, 5 N aqueous NaOH (40 mL) was added, followed by EtOAc (160 mL). The mixture was filtered, and the mother liquor was separated. The organic layer was dried over anhydrous NaSO, filtered, and concentrated to dryness to give the crude product, which was purified by reverse-phase chromatography using water-MeCN as eluent (4 g, 71% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.35-7.25 (m, 5 H), 6.7 (d, 1 H), 6.22 (d, 1 H), 4.6 (s, 2 H), 4.52 (t, 1 H), 4.42 (s, 2 H), 3.49 (t, 2 H), 3 (q, 2 H), 2.15 (s, 3 H), 1.65 (m, 4 H)

[0172] Step A3: Preparation of 1-[4-(benzyloxy)butyl]-5-bromo-4-methyl-1H-benzotriazole Using General Procedure 2, Step 4, N 1 Starting with -[4-(benzyloxy)butyl]-4-bromo-3-methylbenzene-1,2-diamine (1 equivalent), the title compound was obtained (orange oil, 79% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.68 (s, 2 H), 7.3-7.2 (m, 5 H), 4.7 (t, 2 H), 4.4 (s, 2 H), 3.42 (t, 2 H), 2.7 (s, 3 H), 1.98 (m, 2 H), 1.5 (m, 2H)

[0173] Step A4: Preparation of ethyl (2E)-3-{1-[4-(benzyloxy)butyl]-4-methyl-1H-benzotriazol-5-yl}prop-2-enoate Using General Procedure 2, Step 5, starting with 1-[4-(benzyloxy)butyl]-5-bromo-4-methyl-1H-benzotriazole (1 equivalent) as reactant, the title compound was obtained (black oil, 96% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 8 (d, 1 H), 7.9 (d, 1 H), 7.7 (d, 1 H), 7.35-7.2 (m, 5 H), 6.65 (d, 1 H), 4.72 (t, 2 H), 4.4 (s, 2 H), 4.2 (q, 2 H), 3.45 (t, 2 H), 2.8 (s, 3 H), 1.95 (quint, 2 H), 1.52 (quint, 2 H), 1.3 (t, 3 H)

[0174] Step 1: Preparation of ethyl 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H-benzotriazol-5-yl}-3-[3-(hydroxymethyl)-4-methylphenyl]propanoate Using general procedure 6 and starting with ethyl (2E)-3-{1-[4-(benzyloxy)butyl]-4-methyl-1H-benzotriazol-5-yl}prop-2-enoate (1 equivalent) and [2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (1.5 equivalents) as reactants, the title compound was obtained (49% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.45 (d, 1 H), 7.35-7.2 (m, 6 H), 7.1 (dd, 1 H), 7.01 (d, 1 H), 4.99 (t, 1 H), 4.82 (t, 1 H), 4.65 (t, 2 H), 4.4 (d+s, 4 H), 3.91 (q, 2 H), 3.45 (t, 2 H), 3.15 (d, 2 H), 2.75 (s, 3 H), 2.15 (s, 3 H), 1.95 (m, 2 H), 1.5 (m, 2 H), 1 (t, 3H)

[0175] Step 2: Ethyl 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H-benzotriazol-5-yl}-3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6Preparation of ,3-benzoxathiazin-3(4H)-yl]methyl}-4-methylphenyl)propanoate Using General Procedure 7, the reactants were ethyl 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H-benzotriazol-5-yl}-3-[3-(hydroxymethyl)-4-methylphenyl]propanoate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6 Starting with ,3-benzoxathiazine-2,2-dione (2.2 equivalents), the title compound was obtained (60% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.58 (d, 1 H), 7.48 (d, 1 H), 7.45-7.2 (m, 13 H), 7.15 (d, 1 H), 7.05 (dd, 1 H), 6.95 (d, 1 H), 5.1 (s, 2 H), 4.85 (t, 1 H), 4.65 (t, 2 H), 4.45 / 4.4 (2s, 4 H), 4.22 (s, 2 H), 3.92 (q, 2 H), 3.42 (t, 2 H), 3.15 (m, 2 H), 2.75 (s, 3 H), 2.2 (s, 3 H), 1.92 (m, 2 H), 1.48 (m, 2 H), 1.2 (t, 3 H)

[0176] Step 3: Ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate Using general procedure 8, the reactant was ethyl 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H-benzotriazol-5-yl}-3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Starting with ,3-benzoxathiazin-3(4H)-yl]methyl}-4-methylphenyl)propanoate (1 equivalent) gave the title compound (white solid, quantitative). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.62 (d, 1 H), 7.5 (d, 1 H), 7.22 (s, 1 H), 7.2 (d, 1 H), 7.15 (d, 1 H), 7 (s, 1 H), 6.8 (dd, 1 H), 6.6 (d, 1 H), 4.85 (t, 1 H), 4.65 (t, 2 H), 4.4 (m, 1 H), 4.4 (s, 2 H), 4.2 (m, 2 H), 3.95 (q, 2 H), 3.38 (tl, 2 H), 3.15 (m, 2 H), 2.75 (s, 3 H), 2.32 (s, 3H), 1.9 (m, 2H), 1.35 (m, 2 H), 1 (t, 3 H)

[0177] Step 4: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate gave the title compound (73% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.68 (s, 1 H), 7.63 (d, 1 H), 7.52 (d, 1 H), 7.22 (d, 1 H), 7.2 (dd, 1 H), 7.13 (d, 1 H), 6.99 (d, 1 H), 6.79 (dd, 1 H), 6.6 (d, 1 H), 4.84 (t, 1 H), 4.69 (t, 2 H), 4.38 (s, 2 H), 4.2 (m, 2 H), 3.94 (q, 2 H), 3.54 (t, 2 H), 3.19 (m, 2 H), 2.76 (s, 3 H), 2.22 (s, 3 H), 1.99 (quint, 2 H), 1.77 (quint, 2 H), 1 (t, 3 H)

[0178] Step 5: Ethyl [4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate gave the title compound (white solid, 79% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.7 (d, 1 H), 7.5 (dd, 1 H), 7.45 (d, 1 H), 7.3 (d, 1 H), 7 (d, 1 H), 6.8 (dd, 1 H), 6.55 (d, 1 H), 5.85 (d, 1 H), 4.8 (m, 3 H), 4.1 / 3.95 (m, 2 H), 4 / 3.8 (m, 2 H), 3.9 (m, 2 H), 3.7 / 3.45 (m, 2 H), 3.15 / 3.08 (m, 2 H), 2.63 (s, 3 H), 2.31 (s, 3 H), 2.2 / 2 (m, 2 H), 1.8 / 1.6 (m, 2 H), 1.02 (t, 3 H)

[0179] Step 6: Preparation of Example 7 Using general procedure 12, ethyl [4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Starting from ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 93% yield).

[0180] Enantiopure final products or final intermediates were obtained by chromatographic separation on a chiral column.

[0181] Example 7a (8S) HRMS C 29 H 30 Calculated for N4O6S: 562.1886; [M+H] + Measured value: 563.1962 (δ=0.6 ppm)

[0182] Example 7b (8R) HRMS C 29 H 30Calculated for N4O6S: 562.1886; [M+H] + Measured value: 563.1962 (δ=0.6 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.12 (m, 1 H), 7.69 (d, 1 H), 7.49 (dd, 1 H), 7.41 (d, 1 H), 7.3 (d, 1 H), 7 (d, 1 H), 6.8 (dd, 1 H), 6.55 (d, 1 H), 5.85 (d, 1 H), 4.75 (m, 3 H), 4.11-3.92 (d, 2 H), 4-3.85 (d, 2 H), 3.62 / 3.4 (m, 2 H), 3.05 / 2.95 (dd, 2 H), 2.65 / 2.31 (s, 6 H), 2.2 / 2.08 (m, 2 H), 1.8 / 1.65 (m, 2 H)

[0183] Example 8 : [5-methoxy-31-methyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0184] Step 1: Preparation of ethyl 3-[3-(hydroxymethyl)-5-methoxyphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using general procedure 6 and starting with ethyl (2E)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equivalent) and [3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (1 equivalent) as reactants, the title compound was obtained (yellow oil, 30% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.59 (d, 1 H), 7.5 (d, 1 H), 7.2 (d, 2 H), 6.88 (d, 2 H), 6.3-6.15 (3sl, 3 H), 5.1 (t, 1 H), 4.81 (t, 1 H), 4.62 (t, 2 H), 4.4 (d, 2 H), 4.3 (s, 2 H), 3.95 (q, 2 H), 3.71 (s, 6 H), 3.39 (t, 2 H), 3.12 (m, 2 H), 2.75 (s, 3 H), 1.92 (m, 2 H), 1.5 (m, 2H), 1 (t, 3H)

[0185] Step 2: Ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(4-(4-benzoxathiazin-3(4H)-yl)methyl}-5-methoxyphenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, reactants were ethyl 3-[3-(hydroxymethyl)-5-methoxyphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6 Starting with ,3-benzoxathiazine-2,2-dione (1.1 equivalents), the title compound was obtained (88% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.72-7.3 (m, 5 H), 7.58 (d, 1 H), 7.48 (d, 1 H), 7.2 (d, 2 H), 7-6.9 (m, 3 H), 6.91 / 6.8 / 6.72 (3d, 3 H), 6.87 (d, 2 H), 5.05 (s, 2 H), 4.81 (t, 1 H), 4.62 (t, 2 H), 4.55 (s, 2 H), 4.3 / 4.23 (2s, 4 H), 3.91 (q, 2 H), 3.7 (2s, 6 H), 3.35 (t, 2 H), 3.12 (d, 2 H), 2.78 (s, 3 H), 1.9 (m, 2 H), 1.48 (m, 2 H), 1 (t, 3 H)

[0186] Step 3: Ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-5-methoxyphenyl}propanoate Using general procedure 8, ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ] was used as the reactant. 6 Starting from 1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained as a white solid (96% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.6 / 4.4 (s+t, 2 H), 7.6 (d, 1 H), 7.5 (d, 1 H), 6.91 (d, 1 H), 6.9 (d, 1 H), 6.8 / 6.72 / 6.6 (3sl, 3 H), 6.71 (dd, 1 H), 4.81 (t, 1 H), 4.62 (t, 2 H), 4.52 (s, 2 H), 4.21 (s, 2 H), 3.92 (q, 2 H), 3.7 (s, 3 H), 3.4 (q, 2 H), 3.17 (d, 2 H), 2.78 (s, 3 H), 1.9 (m, 2 H), 1.38 (m, 2 H), 1 (t, 3 H)

[0187] Step 4: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-5-methoxyphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)methyl]-5-methoxyphenyl}propanoate gave the title compound (white solid, 82% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.61 (m, 1 H), 7.64 (d, 1 H), 7.51 (d, 1 H), 6.91 / 6.81 (2sl, 2 H), 6.88 (d, 1 H), 6.73 (sl, 1 H), 6.71 (dd, 1 H), 6.58 (d, 1 H), 4.82 (t, 1 H), 4.69 (t, 2 H), 4.51 / 4.21 (2s, 4 H), 3.93 (q, 2 H), 3.69 (s, 3 H), 3.54 (t, 2 H), 3.15 (d, 2 H), 2.76 (s, 3 H), 1.99 (m, 2 H), 1.78 (m, 2H), 1 (t, 3H)

[0188] Step 5: Ethyl [5-methoxy-31-methyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting with 1 equivalent of 3-benzoxathiazin-3(4H)-yl)methyl]-5-methoxyphenyl}propanoate gave the title compound (95% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.33 (d, 1 H), 7.09 / 6.78 / 6.37 (3sl, 3 H), 6.93 (d, 1 H), 6.71 (dd, 1 H), 5.98 (d, 1 H), 4.85-4.67 (m, 3 H), 4.12-3.9 (2dd, 4 H), 3.94 (m, 2 H), 3.81 (s, 3 H), 3.52 / 3.42 (2m, 2 H), 3.2 / 3.08 (2dd, 2 H), 2.72 (s, 3 H), 2.19 / 1.98 (2m, 2H), 1.68 / 1.48 (2m, 2H), 1.02 (t, 3 H)

[0189] Step 6: Preparation of Example 8 Using general procedure 12, ethyl [5-methoxy-31-methyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Starting from ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 28% yield).

[0190] The enantiopure products were obtained by chromatographic separation on a chiral column.

[0191] Example 8a (E1) HRMS C 29 H 30 Calculated for N4O7S: 578.1835; [M+H] + Measured value: 579.1911 (δ=0.5 ppm)

[0192] Example 8b (E2) HRMS C 29 H 30Calculated for N4O7S: 578.1835; [M+H] + Measured value: 579.1912 (δ=0.7 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.15 (m, 1 H), 7.6 (d, 1 H), 7.31 (d, 1 H), 7.31 (2dd, 4 H), 7.1 / 6.8 / 6.38 (3sl, 3 H), 6.95 (d, 1 H), 6.71 (dd, 1 H), 5.98 (d, 1 H), 4.85-4.67 (m, 3 H), 3.81 (s, 3 H), 3.68 / 3.41 (2m, 2 H), 3.1 / 2.98 (2dd, 2 H), 2.71 (s, 3 H), 2.19 / 1.98 (2m, 2 H), 1.68 / 1.48 (2m, 2H)

[0193] Example 9 : [4-chloro-31-methyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0194] Step 1: Preparation of ethyl 3-[4-chloro-3-(hydroxymethyl)phenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using general procedure 6 and starting with ethyl (2E)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equivalent) and [2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (2 equivalents) as reactants, the title compound was obtained (yellow oil, 83% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.48 (d, 1 H), 7.47 (d, 1 H), 7.3 (d, 1 H), 7.22 (dd, 1 H), 7.19 (d, 2 H), 6.88 (d, 2 H), 5.3 (t, 1 H), 4.89 (t, 1 H), 4.63 (t, 2 H), 4.49 (d, 2 H), 4.3 (s, 2 H), 3.92 (q, 2 H), 3.71 (s, 3 H), 3.39 (t, 2 H), 3.17 (m, 2 H), 2.75 (s, 3 H), 1.91 (m, 2 H), 1.49 (m, 2 H), 1 (t, 3 H)

[0195] Step 2: Ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(4-(4-benzoxathiazin-3(4H)-yl)methyl}-4-chlorophenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, reactants were ethyl 3-[4-chloro-3-(hydroxymethyl)phenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6 Starting with 1.5 equivalents of 1,3-benzoxathiazine-2,2-dione, the title compound was obtained in 92% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.5-7.3 (m, 8 H), 7.49 (d, 1 H), 7.18 (d, 2 H), 7.09 (d, 1 H), 7.04 (dd, 1 H), 6.96 (d, 1 H), 6.86 (d, 2 H), 5.09 (s, 2 H), 4.89 (t, 1 H), 4.63 (t, 2 H), 4.56 / 4.34 (2s, 4 H), 4.3 (s, 2 H), 3.94 (q, 2 H), 3.72 (s, 3 H), 3.36 (t, 2 H), 3.2 (2ddd, 2 H), 2.77 (s, 3 H), 1.9 (m, 2 H), 1.46 (m, 2 H), 1 (t, 3 H)

[0196] Step 3: Ethyl 3-{4-chloro-3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Preparation of 1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl propanoate Using general procedure 8, ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ] was used as the reactant. 6 Starting from 1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained (77% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.68 (m, 1 H), 7.64 (d, 1 H), 7.51 (d, 1 H), 7.49 (d, 1 H), 7.39 (dd, 1 H), 7.31 (d, 1 H), 6.95 (d, 1 H), 6.77 (dd, 1 H), 6.63 (d, 1 H), 4.89 (t, 1 H), 4.66 (t, 2 H), 4.51 / 4.33 (2s, 4 H), 4.41 (t, 2 H), 3.95 (q, 2 H), 3.38 (q, 2 H), 3.23 / 3.17 (2dd, 2 H), 2.76 (s, 3 H), 1.91 (m, 2 H), 1.37 (m, 2 H), 1.01 (t, 3 H)

[0197] Step 4: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{4-chloro-3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]phenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-{4-chloro-3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from {1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl}-phenyl}-3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]propanoate (1 equivalent), the title compound was obtained (79% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.67 (s), 7.66 (d, 1 H), 7.53 (d, 1 H), 7.49 (d, 1 H), 7.39 (d, 1 H), 7.32 (dd, 1 H), 6.95 (d, 1 H), 6.77 (dd, 1 H), 6.62 (d, 1 H), 4.89 (t, 1 H), 4.7 (t, 2 H), 4.52 (s, 2 H), 4.33 (s, 2 H), 3.95 (q, d H), 3.55 (t, 2 H), 3.2 (m, 2 H), 2.77 (s, 3 H), 2 (m, 2 H), 1.78 (m, 2 H), 1.01 (t, 3 H)

[0198] Step 5: Ethyl [4-chloro-31-methyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{4-chloro-3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)methyl]phenyl}propanoate gave the title compound (97% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.69 (d, 1 H), 7.64 (dd, 1 H), 7.57 (d, 1 H), 7.45 (d, 1 H), 6.99 (d, 1 H), 6.8 (dd, 1 H), 6.8 (d, 1 H), 5.86 (d, 1 H), 4.82 (m, 2 H), 4.79 (m, 1 H), 4.24 / 4.05 (dd, 2 H), 4.01 / 3.84 (dd, 2 H), 3.93 (q, 2 H), 3.67 / 3.47 (2m, 2 H), 3.21 / 3.08 (2dd, 2 H), 2.63 (s, 3 H), 2.2 / 2.05 (2m, 2H), 1.8 / 1.64 (2m, 2H), 1 (t, 3H)

[0199] Step 6: Preparation of Example 9 Using general procedure 12, ethyl [4-chloro-31-methyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Starting from ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 56% yield).

[0200] The enantiopure products were obtained by chromatographic separation on a chiral column.

[0201] Example 9a (E1) HRMS C 28 H 27 Calculated for ClN4O6S: 582.1340; [M+H] + Measured value: 583.1418 (δ=0.9 ppm)

[0202] Example 9b (E2) HRMS C 28 H27 Calculated for ClN4O6S: 582.1340; [M+H] + Measured value: 583.1417 (δ=0.8 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.28 (m, 1 H), 7.69 (d, 1 H), 7.64 (dd, 1 H), 7.57 (d, 1 H), 7.44 (d, 1 H), 6.99 (d, 1 H), 6.79 (dd, 1 H), 6.78 (d, 1 H), 5.85 (d, 1 H), 4.84-4.7 (m, 1 H), 4.8 (t, 2 H), 4.23 / 4.05 (dd, 2 H), 4 / 3.83 (dd, 2 H), 3.67 / 3.45 (2m, 2 H), 3.09 / 2.96 (2dd, 2H), 2.63 (s, 3H), 2.2 / 2.08 (2m, 2H), 1.82 / 1.63 (2m, 2H)

[0203] Example 10 : [4-Methoxy-31-methyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0204] Step 1: Preparation of ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using general procedure 6 and starting with ethyl (2E)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equivalent) and [2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (1.4 equivalents) as reactants, the title compound was obtained (yellow oil, 68% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.45 (d, 1 H), 7.28 (d, 1 H), 7.2 (d, 2 H), 7.19 (dd, 1 H), 6.9 (d, 2 H), 6.82 (d, 1 H), 4.9 (t, 1 H), 4.82 (t, 1 H), 4.65 (t, 2 H), 4.41 (d, 2 H), 4.31 (s, 2 H), 3.92 (q, 2 H), 3.71 (2s, 6 H), 3.4 (t, 2 H), 3.12 (dd, 2 H), 2.78 (s, 3 H), 1.91 (m, 2 H), 1.5 (m, 2 H), 1 (t, 3 H)

[0205] Step 2: Ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(4-(4-benzoxathiazin-3(4H)-yl]methyl}-4-methoxyphenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, reactants 3-[3-(hydroxymethyl)-4-methoxyphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ were used. 6 Starting with ,3-benzoxathiazine-2,2-dione (1.1 equivalents), the title compound was obtained (79% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.49 (d, 1 H), 7.45-7.3 (m, 5 H), 7.28 (d, 1 H), 7.21 (dd, 1 H), 7.18 (d, 2 H), 7-6.9 (m, 3 H), 6.85 (d, 3 H), 5.08 (s, 2 H), 4.8 (t, 1 H), 4.65 (t, 2 H), 4.52 (s, 2 H), 4.31 (s, 2 H), 4.2 (s, 2 H), 3.92 (q, 2 H), 3.72 / 3.65 (2s, 6 H), 3.38 (t, 2 H), 3.12 (d, 2 H), 2.79 (s, 3 H), 1.9 (m, 2 H), 1.45 (m, 2 H), 1 (t, 3 H)

[0206] Step 3: Ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-4-methoxyphenyl}propanoate Using general procedure 8, ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ] was used as the reactant. 6 Starting from 1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained as a white solid (81% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.6 / 4.41 (s+t, 2 H), 7.65 (d, 1 H), 7.5 (d, 1 H), 7.28 (d, 1 H), 7.21 (dd, 1 H), 6.9 (d, 1 H), 6.87 (d, 1) H), 6.71 (dd, 1 H), 6.6 (d, 1 H), 4.82 (t, 1 H), 4.65 (t, 2 H), 4.5 (s, 2 H), 4.2 (s, 2 H), 3.95 (q, 2 H), 3.7 (s, 3 H), 3.4 (q, 2 H), 3.15 (d, 2 H), 2.75 (s, 3 H), 1.91 (m, 2 H), 1.38 (m, 2 H), 1.02 (t, 3 H)

[0207] Step 4: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-4-methoxyphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 4-benzoxathiazin-3(4H)-yl)methyl]-4-methoxyphenyl}propanoate gave the title compound (white solid, 69% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.6 (s, 1 H), 7.65 (d, 1 H), 7.51 (d, 1 H), 7.25 (d, 1 H), 7.22 (dd, 1 H), 6.9 (d, 1 H), 6.82 (d, 1 H), 6.71 (dd, 1 H), 6.59 (d, 1 H), 4.85 (t, 1 H), 4.7 (t, 2 H), 4.49 (s, 2 H), 4.21 (s, 2 H), 3.92 (q, 2 H), 3.7 (s, 3 H), 3.55 (t, 2 H), 3.15 (d, 2 H), 2.75 (s, 3 H), 2 (m, 2 H), 1.8 (m, 2 H), 1 (t, 3 H)

[0208] Step 5: Ethyl [4-methoxy-31-methyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 4-benzoxathiazin-3(4H)-yl)methyl]-4-methoxyphenyl}propanoate gave the title compound (70% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.69 (d, 1 H), 7.55 (dd, 1 H), 7.45 (d, 1 H), 7.09 (d, 1 H), 6.95 (d, 1 H), 6.78 (dd, 1 H), 6.59 (d, 1 H), 5.8 (d, 1 H), 4.78 (m, 3 H), 4.12 / 3.92 (2d, 2 H), 4.02 / 3.8 (2d, 2 H), 3.92 (q, 2 H), 3.81 (s, 3 H), 3.61 / 3.4 (2m, 2 H), 3.12 / 3.02 (2dd, 2H), 2.62 (s, 3H), 2.2 / 2.1 (2m, 2H), 1.8 / 1.62 (2m, 2H), 1.02 (t, 3H)

[0209] Step 6: Preparation of Example 10 Using general procedure 12, ethyl [4-methoxy-31-methyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Starting from ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 88% yield).

[0210] The enantiopure products were obtained by chromatographic separation on a chiral column.

[0211] Example 10a (E1) HRMS C 29 H 30 Calculated for N4O7S: 578.1835; [M+H] + Measured value: 579.1911 (δ=0.5 ppm)

[0212] Example 10b (E2) HRMS C 29 H30 Calculated for N4O7S: 578.1835; [M+H] + Measured value: 579.1911 (δ=0.5 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.15 (m, 1 H), 7.69 (d, 1 H), 7.55 (dd, 1 H), 7.41 (d, 1 H), 7.09 (d, 1 H), 6.95 (d, 1 H), 6.78 (dd, 1 H), 6.55 (d, 1 H), 5.79 (d, 1 H), 4.75 (m, 3 H), 4.12 / 3.92 (2d, 2 H), 4.02 / 3.8 (2d, 2 H), 3.8 (s, 3 H), 3.61 / 3.4 (2m, 2 H), 3.12 / 2.95 (2dd, 2H), 2.62 (s, 3H), 2.2 / 2.1 (2m, 2H), 1.8 / 1.62 (2m, 2H)

[0213] Example 11 : [4,33-dimethyl-29,29-dioxo-23,28-dioxa-29λ 6 -Thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid [ka]

[0214] Step A1: Preparation of N-[6-(benzyloxy)hexyl]-3-methyl-2-nitroaniline Using General Procedure 2, Step 1, starting with 1-fluoro-3-methyl-2-nitrobenzene (1 equivalent) and 6-benzyloxyhexan-1-amine (1.2 equivalents) as reactants, the title compound was obtained (53% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.35-7.2 (m, 6 H), 6.78 (d, 1 H), 6.52 (d, 1 H), 6.39 (t, 1 H), 4.42 (s, 2 H), 3.41 (t, 2 H), 3.15 (q, 2 H), 2.29 (s, 3 H), 1.55 (m, 4 H), 1.32 (m, 4 H)

[0215] Step A2: Preparation of N-[6-(benzyloxy)hexyl]-4-bromo-3-methyl-2-nitroaniline Using General Procedure 2, Step 2, starting with N-[6-(benzyloxy)hexyl]-3-methyl-2-nitroaniline (1 equivalent) as reactant, the title compound was obtained (99% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.5 (d, 1 H), 7.3 (m, 5 H), 6.7 (d, 1 H), 6.12 (t), 4.43 (s, 2 H), 3.4 (t, 2 H), 3.1 (q, 2 H), 2.25 (s, 3 H), 1.53 / 1.34 (2m, 8H)

[0216] Process A3: N 1 Preparation of -[6-(benzyloxy)hexyl]-4-bromo-3-methylbenzene-1,2-diamine Using General Procedure 2, Step 3, starting with N-[6-(benzyloxy)hexyl]-4-bromo-3-methyl-2-nitroaniline (1 equivalent, 25.3 mmol) as reactant, the title compound was obtained (67% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.3 (m, 5 H), 6.7 (d, 1 H), 6.23 (d, 1 H), 4.59 (sl, 2 H), 4.51 (t, 1 H), 4.44 (s, 2 H), 3.42 (t, 2 H), 2.96 (q, 2 H), 2.16 (s, 3 H), 1.56 (m, 4 H), 1.37 (m, 4 H)

[0217] Step A4: Preparation of 1-[6-(benzyloxy)hexyl]-5-bromo-4-methyl-1H-benzotriazole Using General Procedure 2, Step 4, N 1 Starting with -[6-(benzyloxy)hexyl]-4-bromo-3-methylbenzene-1,2-diamine (1 equivalent), the title compound was obtained (28% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.68 (2d, 2 H), 7.35-7.2 (m, 5 H), 4.68 (t, 2 H), 4.4 (s, 2 H), 3.39 (t, 2 H), 2.71 (s, 3 H), 1.9 (m, 2 H), 1.5 (m, 2 H), 1.32 (m, 2 H), 1.22 (m, 2 H)

[0218] Step A5: Preparation of ethyl (2E)-3-{1-[6-(benzyloxy)hexyl]-4-methyl-1H-benzotriazol-5-yl}prop-2-enoate Using General Procedure 2, Step 5, starting with 1-[6-(benzyloxy)hexyl]-5-bromo-4-methyl-1H-benzotriazole (1 equivalent) as reactant, the title compound was obtained (22% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8 (dJ=16Hz, 1 H), 7.91 (d, 1 H), 7.7 (d, 1 H), 7.32-7.22 (m, 5 H), 6.62 (d, 1 H), 4.69 (t, 2 H), 4.4 (s, 2 H), 4.2 (q, 2 H), 3.38 (t, 2 H), 2.8 (s, 3 H), 1.9 (m, 2 H), 1.5 (m, 2 H), 1.35-1.2 (m, 4 H), 1.28 (t, 3 H)

[0219] Step 1: Preparation of ethyl 3-{1-[6-(benzyloxy)hexyl]-4-methyl-1H-benzotriazol-5-yl}-3-[3-(hydroxymethyl)-4-methylphenyl]propanoate Using general procedure 6 and starting with ethyl (2E)-3-{1-[6-(benzyloxy)hexyl]-4-methyl-1H-benzotriazol-5-yl}prop-2-enoate (1 equivalent) and [2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (1.5 equivalents) as reactants, the title compound was obtained (14% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.45 (d, 1 H), 7.3 (s, 1 H), 7.3 (m, 5 H), 7.1 (d, 1 H), 7 (d, 1 H), 5 (t, 1 H), 4.85 (t, 1 H), 4.65 (t, 2 H), 4.4 (2s, 4 H), 3.95 (q, 2 H), 3.35 (t, 2 H), 3.15 (m, 2 H), 2.75 (s, 3 H), 2.15 (s, 3 H), 1.85 (m, 2 H), 1.5 (m, 2 H), 1.35-1.2 (m, 4 H), 1 (t, 3 H)

[0220] Step 2: Ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(3-benzoxathiazin-3(4H)-yl]methyl}-4-methylphenyl)-3-{1-[6-(benzyloxy)hexyl]-4-methyl-1H-benzotriazol-5-yl}propanoate Using General Procedure 7, the reactants were ethyl 3-{1-[6-(benzyloxy)hexyl]-4-methyl-1H-benzotriazol-5-yl}-3-[3-(hydroxymethyl)-4-methylphenyl]propanoate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6Starting with ,3-benzoxathiazine-2,2-dione (1.2 equivalents), the title compound was obtained (84% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.61-6.93 (m, 18 H), 5.1 (s, 2 H), 4.84 (t, 1 H), 4.58 (t, 2 H), 4.42 / 4.21 (s, 2 H), 4.42 / 4.21 (s, 2 H), 4.38 (s, 2 H), 3.92 (q, 2 H), 3.32 (m, 2 H), 3.16 (m, 2 H), 2.76 (s, 3 H), 2.21 (s, 3 H), 1.83 (m, 2 H), 1.45 (m, 2 H), 1.3 (m, 2 H), 1.19 (m, 2H), 0.97 (t, 3H)

[0221] Step 3: Ethyl 3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of {1-(6-hydroxyhexyl)-4-methyl-1H-benzotriazol-5-yl}propanoate Using general procedure 8, ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ] was used as the reactant. 6 Starting from ,3-benzoxathiazin-3(4H)-yl]methyl}-4-methylphenyl)-3-{1-[6-(benzyloxy)hexyl]-4-methyl-1H-benzotriazol-5-yl}propanoate (1 equivalent), the title compound was obtained (95% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.68 (m, 1 H), 7.61 (d, 1 H), 7.5 (d, 1 H), 7.21 (d, 1 H), 7.19 (dd, 1 H), 7.13 (d, 1 H), 6.99 (d, 1 H), 6.79 (dd, 1 H), 6.6 (d, 1 H), 4.84 (t, 1 H), 4.63 (t, 2 H), 4.38 (s, 2 H), 4.29 (t, 1 H), 4.2 (dd, 2 H), 3.94 (q, 2 H), 3.32 (m, 2 H), 3.17 (m, 2 H), 2.75 (s, 3 H), 2.22 (s, 3 H), 1.87 (m, 2 H), 1.38-1.15 (m, 6 H), 0.99 (t, 3 H)

[0222] Step 4: Ethyl 3-[1-(6-bromohexyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Starting from {1-(6-hydroxyhexyl)-4-methyl-1H-benzotriazol-5-yl}-3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}-3-[1-(6-hydroxyhexyl)-4-methyl-1H-benzotriazol-5-yl]propanoate (1 equivalent), the title compound was obtained (87% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.68 (m, 1 H), 7.61 (d, 1 H), 7.5 (d, 1 H), 7.21 (d, 1 H), 7.2 (dd, 1 H), 7.13 (d, 1 H), 6.99 (d, 1 H), 6.78 (dd, 1 H), 6.6 (d, 1 H), 4.84 (t, 1 H), 4.63 (t, 2 H), 4.38 (s, 2 H), 4.19 (dd, 2 H), 3.94 (q, 2 H), 3.46 (t, 2 H), 3.16 (dd, 2 H), 2.75 (s, 3 H), 2.22 (s, 3 H), 1.88 (m, 2 H), 1.74 (m, 2 H), 1.39 (m, 2 H), 1.24 (m, 2 H), 1 (t, 3 H)

[0223] Step 5: Ethyl [4,33-dimethyl-29,29-dioxo-23,28-dioxa-29λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 Preparation of ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(6-bromohexyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equivalent of 1,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate gave the title compound (88% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.64 (d, 1 H), 7.46 (d, 1 H), 7.4 (dd, 1 H), 7.21 (d, 1 H), 7.15 (d, 1 H), 7.07 (d, 1 H), 6.9 (dd, 1 H), 6.45 (d, 1 H), 4.81 (t, 1 H), 4.48 (t, 2 H), 4.4 / 4.11 (dd, 2 H), 4.23 / 4.03 (dd, 2 H), 3.89 (q, 2 H), 3.8 (m, 2 H), 3.07 (d, 2 H), 2.74 (s, 3 H), 2.31 (s, 3 H), 1.97 (m, 2 H), 1.7 (m, 2 H), 1.53 (m, 2 H), 1.32 (m, 2 H), 0.99 (t, 3 H)

[0224] Step 6: Preparation of Example 11 Using general procedure 12, ethyl [4,33-dimethyl-29,29-dioxo-23,28-dioxa-29λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 Starting with ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 62% yield).

[0225] The enantiopure products were obtained by chromatographic separation on a chiral column.

[0226] Example 11a (E1) HRMS C 31 H 34 Calculated for N4O6S: 590.2199; [M+H] + Measured value: 591.2274 (δ=0.4 ppm)

[0227] Example 11b (E2) HRMS C 31 H 34 Calculated for N4O6S: 590.2199; [M+H] + Measured value: 591.2274 (δ=0.4 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.13 (m, 1 H), 7.64 (d, 1 H), 7.45 (d, 1 H), 7.4 (dd, 1 H), 7.21 (d, 1 H), 7.13 (d, 1 H), 7.07 (d, 1 H), 6.9 (dd, 1 H), 6.43 (d, 1 H), 4.9 (t, 1 H), 4.66 (t, 2 H), 4.39 / 4.11 (dd, 2 H), 4.23 / 4.04 (dd, 2 H), 3.91-3.76 (m, 2 H), 2.96 (m, 2 H), 2.74 (s, 3 H), 2.31 (s, 3 H), 1.97 (m, 2 H), 1.7 (m, 2 H), 1.53 (m, 2 H), 1.32 (m, 2 H)

[0228] Example 12 : [31-methyl-27,27-dioxo-5-(trifluoromethyl)-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0229] Step B1: Preparation of [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl]methanol Using general procedure 3 and starting with [3-bromo-5-(trifluoromethyl)phenyl]methanol (1 equivalent, 2.5 g, 9.8 mmol) as reactant, the title compound (2.7 g, 91% yield) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.9 / 7.87 (m, 3 H), 5.4 (t, 1 H), 4.6 (d, 2 H), 1.3 (s, 12 H)

[0230] Step 1: Ethyl 3-[3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(4-(4-benzoxathiazin-3(4H)-yl)methyl)-5-(trifluoromethyl)phenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 6, starting with ethyl (2E)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equivalent) and [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl]methanol (1 equivalent), ethyl 3-[3-(hydroxymethyl)-5-(trifluoromethyl)phenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (colorless oil, 16% yield) was obtained. The crude product was purified using General Procedure 7 to afford 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6 ,3-benzoxathiazine-2,2-dione (1.1 equiv.) to give the title compound (85% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.68 (s, 1 H), 7.61 (d, 1 H), 7.6 (s, 1 H), 7.52 (s, 1 H), 7.5 (d, 1 H), 7.42-7.3 (m, 5 H), 7.19 (d, 2 H), 7-6.9 (m, 3 H), 6.88 (d, 2 H), 5.05 (s, 2 H), 4.95 (t, 1 H), 4.7 (t, 2 H), 4.62 (s, 2 H), 4.42 / 4.3 (2s, 4 H), 3.92 (q, 2 H), 3.71 (s, 3 H), 3.38 (t, 2 H), 3.21 (d, 2 H), 2.79 (s, 3 H), 1.9 (m, 2 H), 1.48 (m, 2 H), 1 (t, 3 H)

[0231] Step 2: Ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-5-(trifluoromethyl)phenyl}propanoate Using general procedure 8, the reactant was ethyl 3-[3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Starting from 1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl]propanoate (1 equivalent), the title compound was obtained as a white solid (89% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.59 (s), 7.67 (sl, 1 H), 7.65 (d, 1 H), 7.61 (sl, 1 H), 7.53 (sl, 1 H), 7.52 (d, 1 H), 6.8 (d, 1 H), 6.68 (dd, 1 H), 6.58 (d, 1 H), 4.95 (t, 1 H), 4.65 (t, 2 H), 4.63 (s, 2 H), 4.41 (t), 4.4 (s, 2 H), 3.95 (q, 2 H), 3.38 (q, 2 H), 3.23 (d, 2 H), 2.78 (s, 3 H), 1.91 (m, 2 H), 1.37 (m, 2H), 1.01 (t, 3H)

[0232] Step 3: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-5-(trifluoromethyl)phenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 5-(trifluoromethyl)phenyl, 3-benzoxathiazin-3(4H)-yl)methyl]-5-(trifluoromethyl)phenyl}propanoate gave the title compound (white solid, 50% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.6 (s, 1 H), 7.69 / 7.6 / 7.52 (3sl, 3 H), 7.69 (d, 1 H), 7.55 (d, 1 H), 6.8 (d, 1 H), 6.7 (dd, 1 H), 6.58 (d, 1 H), 4.98 (t, 1 H), 4.7 (t, 2 H), 4.6 (s, 2 H), 4.4 (s, 2 H), 3.92 (q, 2 H), 3.55 (t, 2 H), 3.22 (d, 2 H), 2.79 (s, 3 H), 2 (m, 2 H), 1.78 (m, 2H), 1.02 (t, 3H)

[0233] Step 4: Ethyl [31-methyl-27,27-dioxo-5-(trifluoromethyl)-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 5-(trifluoromethyl)phenyl, 3-benzoxathiazin-3(4H)-yl)methyl]-5-(trifluoromethyl)phenyl}propanoate gave the title compound (93% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.81 / 7.6 / 7.25 (3s, 3 H), 7.71 / 4.81 (2m, 2 H), 7.6 (d, 1 H), 7.35 (d, 1 H), 6.9 (d, 1 H), 6.69 (dd, 1 H), 6.02 (d, 1 H), 4.81 (t, 1 H), 4.28 (s, 2 H), 4.05 (m, 2 H), 3.95 (m, 2 H), 3.88 / 3.68 (2m, 2 H), 3.32 / 3.18 (2dd, 2 H), 2.78 (s, 3 H), 2.2 / 1.98 (2m, 2H), 1.68 / 1.45 (2m, 2H), 1 (t, 3H)

[0234] Step 5: Preparation of Example 12 Using General Procedure 12, the reactant was ethyl [31-methyl-27,27-dioxo-5-(trifluoromethyl)-21,26-dioxa-27λ]. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Starting from ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent), the title compound was obtained (white solid, quantitative).

[0235] The enantiopure products were obtained by chromatographic separation on a chiral column.

[0236] Example 12a (E1) HRMS C 29 H 27 Calculated for F3N4O6S: 616.1603; [M+H] + Measured value: 617.1677 (δ=0.1 ppm)

[0237] Example 12b (E2) HRMS C 29 H 27Calculated for F3N4O6S: 616.1603; [M+H] + Measured value: 617.1678 (δ=0.3 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.3 (m, 1 H), 7.84 / 7.58 / 7.23 (3s, 3 H), 7.6 (d, 1 H), 7.33 (d, 1 H), 6.89 (d, 1 H), 6.68 (dd, 1 H), 6.02 (d, 1 H), 4.89 (t, 1 H), 4.81 / 4.72 (2m, 2 H), 4.27 (s, 2 H), 4.06 (m, 2 H), 3.68 / 3.34 (2m, 2 H), 3.32 / 3.18 (2dd, 2 H), 2.78 (s, 3 H), 2.2 / 1.98 (2m, 2H), 1.69 / 1.45 (2m, 2 H)

[0238] Example 13 : [(2R,8R)-2,4,32-trimethyl-28,28-dioxo-19,22,27-trioxa-28λ 6 -Thia-1,14,15,16-tetraazahexacyclo[21.5.3.1 3,7 .1 9,13 .0 12,16 .0 26,30 ]tritriaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetic acid and [(2R,8S)-2,4,32-trimethyl-28,28-dioxo-19,22,27-trioxa-28λ 6 -Thia-1,14,15,16-tetraazahexacyclo[21.5.3.1 3,7 .1 9,13 .0 12,16 .0 26,30 ]tritriaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetic acid [ka]

[0239] Step A1: Preparation of 2-[2-(3-methyl-2-nitroanilino)ethoxy]ethan-1-ol Using General Procedure 1, Step 1, starting with 1-fluoro-3-methyl-2-nitrobenzene (1 equivalent) and 2-(2-aminoethoxy)ethan-1-ol (3 equivalents) as reactants, the title compound was obtained (24% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.28 (t, 1 H), 6.83 (d, 1 H), 6.58 (d, 1 H), 6.43 (t, 1 H), 4.59 (t, 1 H), 3.6 (t, 2 H), 3.5 (m, 2 H), 3.45 (m, 2 H), 3.34 (q, 2 H), 2.31 (s, 3 H)

[0240] Step A2: Preparation of 2-[2-(4-bromo-3-methyl-2-nitroanilino)ethoxy]ethan-1-ol Using General Procedure 1, Step 2, starting with 2-[2-(3-methyl-2-nitroanilino)ethoxy]ethan-1-ol (1 equivalent) as reactant, the title compound was obtained (67% yield). 1 H-NMR (400 MHz, DMSO-d6) δppm: 7.53 (d, 1 H), 6.8 (d, 1 H), 6.1 (t), 4.56 (t), 3.56 (t, 2 H), 3.5 (q, 2 H), 3.44 (t, 2 H), 3.3 (q, 2 H), 2.28 (s, 3H)

[0241] Step A3: Preparation of 2-[2-(2-amino-4-bromo-3-methylanilino)ethoxy]ethan-1-ol Using General Procedure 1, Step 3, starting with 2-[2-(4-bromo-3-methyl-2-nitroanilino)ethoxy]ethan-1-ol (1 equivalent) as reactant, the title compound was obtained (80% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 6.72 (d, 1 H), 6.3 (d, 1 H), 4.64-4.52 (m, 4 H), 3.6 (t, 2 H), 3.51 (m, 2 H), 3.46 (m, 2 H), 3.17 (m, 2 H), 2.16 (s, 3H)

[0242] Step A4: Preparation of 2-[2-(5-bromo-4-methyl-1H-benzotriazol-1-yl)ethoxy]ethan-1-ol Using General Procedure 1, Step 4, starting with 2-[2-(2-amino-4-bromo-3-methylanilino)ethoxy]ethan-1-ol (1 equivalent) as reactant, the title compound was obtained (yellow solid, 45% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.69 (d, 2 H), 4.87 (t, 2 H), 4.52 (m, 1 H), 3.9 (t, 2 H), 3.4-3.36 (m, 4 H), 2.72 (s, 3 H)

[0243] Step A5: Preparation of 1-{2-[2-(benzyloxy)ethoxy]ethyl}-5-bromo-4-methyl-1H-benzotriazole To a solution of 2-[2-(5-bromo-4-methyl-1H-benzotriazol-1-yl)ethoxy]ethan-1-ol (1 equiv., 4.1 g, 13 mmol) in DMF (7 mL / mmol, 92 mL) was added NaH (1.2 equiv., 630 mg, 16 mmol, 60 wt % in mineral oil) at 0° C. The mixture was allowed to warm to room temperature and stirred at this temperature for 30 minutes. The reaction mixture was cooled to 0° C. Benzyl bromide (1.2 equiv., 2.7 g, 1.9 mL, 16 mmol) was added and stirring was continued at room temperature overnight. The mixture was quenched with water (500 mL) and extracted with EtOAc (4×1000 ml), and the organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give a black oil, which was purified by normal phase silica gel chromatography using heptane-EtOAc (20:80) as eluent to give the title compound (3.65 g, 71% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.69 / 7.6 (dd, 2 H), 7.33-7.23 (m, 3 H), 7.16 (m, 2 H), 4.88 (t, 2 H), 4.31 (s, 2 H), 3.91 (t, 2 H), 3.53 / 3.43 (2m, 4H), 2.7 (s, 3H)

[0244] Step A6: Preparation of ethyl (2E)-3-(1-{2-[2-(benzyloxy)ethoxy]ethyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate Using General Procedure 1, Step 7, starting with 1-{2-[2-(benzyloxy)ethoxy]ethyl}-5-bromo-4-methyl-1H-benzotriazole (1 equivalent, 3.65 g, 9.35 mmol) as reactant, the title compound (1.7 g, 28% yield) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8 (d, 1 H), 7.87 (d, 1 H), 7.72 (d, 1 H), 7.32-7.15 (m, 5 H), 6.6 (d, 1 H), 4.88 (t, 2 H), 4.32 (s, 2 H), 4.23 (q, 2 H), 3.92 (t, 2 H), 3.54 / 3.45 (2m, 4 H), 2.79 (s, 3 H), 1.29 (t, 3 H)

[0245] Step 1: Preparation of ethyl 3-(1-{2-[2-(benzyloxy)ethoxy]ethyl}-4-methyl-1H-benzotriazol-5-yl)-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propanoate Using general procedure 6 and starting with ethyl (2E)-3-(1-{2-[2-(benzyloxy)ethoxy]ethyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equivalent) and (1S)-1-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1-ol (2 equivalents) as reactants, the title compound was obtained (44% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.61 (d, 1 H), 7.41 (d, 1 H), 7.4 (sl, 1 H), 7.32-7.18 (m, 5 H), 7.02 (dd, 1 H), 6.97 (d, 1 H), 4.98 / 4.97 (2d, 1 H), 4.85-4.78 (m, 4 H), 4.33 / 4.32 (2s, 2 H), 3.92 (q, 2 H), 3.89 (m, 2 H), 3.53 / 3.43 (2m, 4 H), 3.16-3.01 (m, 2 H), 2.75 (2s, 3 H), 2.18 (2s, 3 H), 1.22 / 1.2 (2d, 3 H), 1 (t, 3 H)

[0246] Step 2: Ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(2-benzoxathiazin-3(4H)-yl]ethyl)-4-methylphenyl)-3-(1-{2-[2-(benzyloxy)ethoxy]ethyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, the reactants were ethyl 3-(1-{2-[2-(benzyloxy)ethoxy]ethyl}-4-methyl-1H-benzotriazol-5-yl)-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propanoate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6 Starting with ,3-benzoxathiazine-2,2-dione (1.5 equivalents), the title compound was obtained (79% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.62 (d, 1 H), 7.5 (d, 1 H), 7.48-7 (m, 13 H), 7.1-6.96 (m, 2 H), 6.89 / 6.83 (2d, 1 H), 5.26 (m, 1 H), 5.08 (m, 2 H), 4.86 (m, 1 H), 4.78 (m, 2 H), 4.41 (s, 2 H), 4.28 (s, 2 H), 3.91 (q, 2 H), 3.88 (m, 2 H), 3.49 / 3.39 (2m, 4 H), 3.18 (m, 2 H), 2.76 (s, 3 H), 2.27 (s, 3 H), 1.4 (d, 3H), 0.98 (t, 3H)

[0247] Step 3: Ethyl 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(2-(2-hydroxyethoxy)ethyl)-4-methylphenyl)-3-{1-[2-(2-hydroxyethoxy)ethyl]-4-methyl-1H-benzotriazol-5-yl}propanoate Using General Procedure 8, the reactant was ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Starting from ,3-benzoxathiazin-3(4H)-yl]ethyl}-4-methylphenyl)-3-(1-{2-[2-(benzyloxy)ethoxy]ethyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained (white solid, 94% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.63 (m, 1 H), 7.65-7.53 (2dd, 2 H), 7.47 (m, 1 H), 7.14-7.08 (m, 2 H), 6.91 (2, 1 H), 6.76-6.7 (m, 1 H), 6.6 / 6.56 (2d, 1 H), 5.26 (q, 1 H), 4.88 (q, 1 H), 4.8 (t, 2 H), 4.37 / 4.31 (s+dd, 2 H), 3.95 (2q, 2 H), 3.89 (m, 2 H), 3.48-3.27 (m, 4 H), 3.22 (2d, 2 H), 2.77 (s, 3 H), 2.28 (s, 3 H), 1.43 / 1.41 (2d, 3 H), 1.02 / 1 (2t, 3 H)

[0248] Step 4: Ethyl 3-{1-[2-(2-bromoethoxy)ethyl]-4-methyl-1H-benzotriazol-5-yl}-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Starting from {1-[2-(2-hydroxyethoxy)ethyl]-4-methyl-1H-benzotriazol-5-yl}propanoate (1 equivalent), the title compound was obtained (71% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.64 (m, 1 H), 7.67-7.55 (2dd, 2 H), 7.47 (m, 1 H), 7.14-7.08 (m, 2 H), 6.91 (m, 1 H), 6.76-6.7 (m, 1 H), 6.6 / 6.56 (2d, 1 H), 5.26 (q, 1 H), 4.88 (q, 1 H), 4.83 (t, 2 H), 4.36 / 4.31 (s+dd, 2 H), 3.95 (2q, 2 H), 3.93 (m, 2 H), 3.66 (m, 2 H), 3.44 (t, 2 H), 3.3 / 3.22 (2d, 2 H), 2.77 (s, 3 H), 2.28 (s, 3 H), 1.43 / 1.41 (2d, 3 H), 1.02 / 1 (2t, 3 H)

[0249] Step 5: Ethyl [(2R)-2,4,32-trimethyl-28,28-dioxo-19,22,27-trioxa-28λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[21.5.3.1 3,7 .1 9,13 .0 12,16 .0 26,30 Preparation of ]tritriaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-{1-[2-(2-bromoethoxy)ethyl]-4-methyl-1H-benzotriazol-5-yl}-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate gave the title compound (99% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.72 / 7.65 (2d, 1 H), 7.52 / 6.91 (2s, 1 H), 7.52 / 7.16 (2d, 1 H), 7.45 / 7.09 (2d, 1 H), 7.28 / 6.98 (2d, 1 H), 6.93 / 6.88 (2d, 1 H), 6.8 / 6.75 (2d, 1 H), 6.36 / 5.99 (2sl, 1 H), 5.4 / 5.26 (2m, 1 H), 4.93 / 4.85 (2m, 1 H), 4.83 (m, 2 H), 4.71 / 4.17 / 3.81 (2m, 2H), 4.14-3.58 (m, 6 H), 4.03 / 3.93 (2q, 2 H), 3.23 / 2.96 (m+dd, 2 H), 2.81 / 2.8 (2s, 3 H), 2.33 / 2.29 (2s, 3 H), 1.53 / 1.42 (s+sl, 3 H), 1.17 / 1.02 (2m, 3H)

[0250] Step 6: Preparation of Example 13 Using General Procedure 12, ethyl [(2R)-2,4,32-trimethyl-28,28-dioxo-19,22,27-trioxa-28λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[21.5.3.1 3,7 .1 9,13 .0 12,16 .0 26,30 Starting with ]tritriaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 59% yield).

[0251] Diastereomeric pure final products or final intermediates were obtained by chromatographic separation on a chiral column.

[0252] Example 13a (2R,8R) HRMS C 30 H 32 Calculated for N4O7S: 592.1992; [M+H] +Measured value: 593.2072 (δ=1.3 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 13.6-11 (m, 1 H), 7.64 (d, 1 H), 7.48 (dd, 1 H), 7.27 (d, 1 H), 7.11 (d, 1 H), 6.94 (d, 1 H), 6.88 (sl, 1 H), 6.8 (dd, 1 H), 6.01 (d, 1 H), 5.24 (q, 1 H), 4.92 (t, 1 H), 4.81 (t, 2 H), 4.14 / 3.78 (dd, 2 H), 4.1 / 4.04 (2m, 2 H), 3.99-3.63 (m, 4 H), 3.06 / 2.75 (2dd, 2 H), 2.79 (s, 3 H), 2.33 (s, 3 H), 1.15 (d, 3 H)

[0253] Example 13b (2R,8S) HRMS C 30 H 32 Calculated for N4O7S: 592.1992; [M+H] + Measured value: 593.2071 (δ=1.1 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 13.6-11 (m, 1 H), 7.71 (d, 1 H), 7.51 (d, 1 H), 7.49 (d, 1 H), 7.1 (dd, 1 H), 6.99 (d, 1 H), 6.89 (d, 1 H), 6.76 (dd, 1 H), 6.33 (d, 1 H), 5.37 (q, 1 H), 4.88-4.77 (m, 3 H), 4.64 / 4.13 (dd, 2 H), 3.96 (m, 2 H), 3.96-3.58 (m, 4 H), 3.08 (d, 2 H), 2.79 (s, 3 H), 2.28 (s, 3 H), 1.49 (d, 3H)

[0254] Preparation of the sodium salt: The compound of Example 13b (2.03 g) and sodium hydroxide (0.14 g) were suspended in water (235 mL) at 25° C. tert-Butanol (100 mL) was added to the suspension, and the reaction mixture was heated at 60° C. for at least 1 hour (until complete dissolution). The solution was then cooled to −20° C. for rapid solidification before a 96-hour lyophilization step. After isolation from the lyophilization vessel, [(2R,8S)-2,4,32-trimethyl-28,28-dioxo-19,22,27-trioxa-28λ] was obtained. 6 -Thia-1,14,15,16-tetraazahexacyclo[21.5.3.1 3,7 .1 9,13 .0 12,16 .0 26,30 Amorphous sodium salt of ]tritriaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetic acid (water content: 3.0%) (2.10 g) was obtained. IR: 2980~2860 cm -1 (CH2, CH3), 1574 cm -1 (COO - asym), 1492 cm -1 (C=C), 1391 cm -1 (COO - sym and SO2asym), 1200~1130 cm -1 (SO2sym, =COC asym and COC asym).

[0255] Example 14 : [4-fluoro-31-methyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0256] Step 1: Ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(4-(4-benzoxathiazin-3(4H)-yl]methyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 6, starting with ethyl (E)-3-[1-[4-[(4-methoxyphenyl)methoxy]butyl]-4-methyl-benzotriazol-5-yl]prop-2-enoate (1 equivalent) and [2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (1 equivalent) as reactants, ethyl 3-[4-fluoro-3-(hydroxymethyl)phenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (17% yield) was obtained. The crude product was purified using General Procedure 7 to afford 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6 ,3-benzoxathiazine-2,2-dione (1.1 equiv.) to afford the title compound (85% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.5-7.35 (m, 5 H), 7.49 (d, 1 H), 7.35 / 7.3 (m, 2 H), 7.2 (d, 2 H), 7.08 (t, 1 H), 7-6.95 (m, 3 H), 6.88 (d, 2 H), 5.08 (s, 2 H), 4.88 (t, 1 H), 4.65 (t, 2 H), 4.58 (s, 2 H), 4.31 (2s, 4 H), 3.92 (q, 2 H), 3.71 (s, 3 H), 3.38 (t, 2 H), 3.18 (d, 2 H), 2.79 (s, 3 H), 1.91 (m, 2 H), 1.48 (m, 2 H), 1 (t, 3 H)

[0257] Step 2: Ethyl 3-{4-fluoro-3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Preparation of 1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl propanoate Using general procedure 8, ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ] was used as the reactant. 6 Starting from 1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained as a white solid (77% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.4 / 4.4 (s+t, 2 H), 7.63 (d, 1 H), 7.5 (d, 1 H), 7.45 (dd, 1 H), 7.3 (m, 1 H), 7.1 (t, 1 H), 6.88 (d, 1 H), 6.71 (dd, 1 H), 6.61 (d, 1 H), 4.88 (t, 1 H), 4.67 (t, 2 H), 4.53 (s, 2 H), 4.3 (s, 2 H), 3.95 (q, 2 H), 3.4 (q, 2 H), 3.2 (d, 2 H), 2.78 (s, 3 H), 1.9 (m, 2 H), 1.38 (m, 2 H), 1.02 (t, 3 H)

[0258] Step 3: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{4-fluoro-3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]phenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-{4-fluoro-3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6Starting from {1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl}-phenyl}-3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]propanoate (1 equivalent), the title compound was obtained (31% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.6 (s, 1 H), 7.65 (d, 1 H), 7.51 (d, 1 H), 7.45 (dd, 1 H), 7.3 (m, 1 H), 7.1 (t, 1 H), 6.88 (d, 1 H), 6.71 (dd, 1 H), 6.6 (d, 1 H), 4.88 (t, 1 H), 4.7 (t, 2 H), 4.52 (s, 2 H), 4.31 (s, 2 H), 3.93 (q, 2 H), 3.55 (t, 2 H), 3.2 (d, 2 H), 2.79 (s, 3 H), 2 (m, 2 H), 1.8 (m, 2 H), 1 (t, 3 H)

[0259] Step 4: Ethyl [4-fluoro-31-methyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{4-fluoro-3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)methyl]phenyl}propanoate gave the title compound (white solid, 75% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.7 (d, 1 H), 7.61 (dd, 1 H), 7.45 (d, 1 H), 7.29 (t, 1 H), 6.98 (d, 1 H), 6.81 (dd, 1 H), 6.78 (dd, 1 H), 6.4 (d, 1 H), 4.85-4.7 (m, 3 H), 4.21 / 4.05 (2d, 2 H), 4.02 / 3.92 (2d, 2 H), 3.95 (q, 2 H), 3.68 / 3.42 (2m, 2 H), 3.2 / 3.1 (2dd, 2 H), 2.65 (s, 3H), 2.2 / 2.02 (2m, 2H), 1.8 / 1.65 (2m, 2H), 1.01 (t, 3H)

[0260] Step 5: Preparation of Example 14 Using general procedure 12, ethyl [4-fluoro-31-methyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Starting from ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 81% yield). HRMS C 28 H 27 Calculated for FN4O6S: 566.1635; [M+H] + Measured value: 567.1712 (δ=0.7 ppm) 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.3 (m, 1 H), 7.67 (d, 1 H), 7.63 (m, 1 H), 7.42 (d, 1 H), 7.27 (t, 1 H), 6.97 (d, 1 H), 6.76 (m, 1 H), 6.76 (m, 1 H), 5.88 (d, 1 H), 4.8 (t, 2 H), 4.77 (m, 1 H), 4.21 / 4.05 (dd, 2 H), 4.06 / 3.92 (dd, 2 H), 3.66 / 3.4 (2m, 2 H), 3.06 / 2.95 (2dd, 2H), 2.65 (s, 3H), 2.21 / 2.05 (2m, 2H), 1.79 / 1.59 (2m, 2H)

[0261] Example 15 : [4,24,31-trimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0262] Step C1: 6-bromo-8-methyl-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-2,2-dione Using General Procedure 4, Step 2, starting with 5-bromo-2-hydroxy-3-methylbenzaldehyde (1 eq, 3.65 g, 9.35 mmol) as reactant, the title compound (2.85 g, 30% yield) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.14 (sl, 1 H), 8.09 / 8.05 (dl+dd, 2 H), 2.33 (s, 3 H)

[0263] Step C2: 6-bromo-8-methyl-3,4-dihydro-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-2,2-dione Using General Procedure 4, Step 3, 6-bromo-8-methyl-2H-1,2λ as the reactant 6 Starting with ,3-benzoxathiazine-2,2-dione (1 equiv, 4.52 g, 16.37 mmol), the title compound (4.64 g, 99% yield) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8.59 (t, 1 H), 7.5 / 7.38 (2d, 2 H), 4.55 (sl, 2 H), 2.2 (s, 3 H)

[0264] Step C3: tert-butyl 6-bromo-8-methyl-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-3(4H)-carboxylate Using General Procedure 5, Step 1, 6-bromo-8-methyl-3,4-dihydro-2H-1,2λ as the reactant 6 Starting with ,3-benzoxathiazine-2,2-dione (1 equiv, 4.6 g, 16.539 mmol), the title compound (6.2 g, 99% yield) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.7 / 7.64 (2d, 2 H), 5.04 (s, 2 H), 2.27 (s, 3 H), 1.48 (s, 9 H)

[0265] Step C4: tert-butyl 8-methyl-2,2-dioxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-3(4H)-carboxylate Using General Procedure 5, Step 2, with tert-butyl 6-bromo-8-methyl-2,2-dioxo-2H-1,2λ as the reactant 6Starting with ,3-benzoxathiazine-3(4H)-carboxylate (1 equiv, 6.2 g, 16.39 mmol), the title compound (4.9 g, 70% yield) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.69 / 7.65 (2sl, 2 H), 5.06 (s, 2 H), 2.29 (s, 3 H), 1.48 (s, 9 H), 1.3 (s, 12 H)

[0266] Step C5: tert-butyl 6-hydroxy-8-methyl-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-3(4H)-carboxylate Using General Procedure 5, Step 3, with tert-butyl 8-methyl-2,2-dioxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2λ as the reactant 6 Starting with ,3-benzoxathiazine-3(4H)-carboxylate (1 equiv, 4.9 g, 11.52 mmol), the title compound (3.9 g, 97% yield) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.81 (m, 1 H), 6.74 / 6.7 (2d, 2 H), 4.9 (s, 2 H), 2.19 (s, 3 H), 1.48 (s, 9 H)

[0267] Step C6: tert-butyl 6-(benzyloxy)-8-methyl-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-3(4H)-carboxylate Using General Procedure 5, Step 4, with tert-butyl 6-hydroxy-8-methyl-2,2-dioxo-2H-1,2λ as the reactant 6 Starting with ,3-benzoxathiazine-3(4H)-carboxylate (1 equiv., 2.9 g, 9.19 mmol), the title compound (5 g, quantitative) was obtained. 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.46-7.29 (m, 5 H), 7.12 / 7.03 (2d, 2 H), 5.1 (s, 2 H), 4.97 (s, 2 H), 2.26 (s, 3 H), 1.48 (s, 9 H)

[0268] Step C7: 6-(benzyloxy)-8-methyl-3,4-dihydro-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-2,2-dione Using General Procedure 5, Step 5, and using tert-butyl 6-(benzyloxy)-8-methyl-2,2-dioxo-2H-1,2λ as the reactant 6 Starting with ,3-benzoxathiazine-3(4H)-carboxylate (1 equiv, 5.0 g, 12.33 mmol), the title compound (1.85 g, 65% yield) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8.37 (m, 1 H), 7.46-7.3 (m, 5 H), 6.92 / 6.79 (2d, 2 H), 5.06 (s, 2 H), 4.47 (s, 2 H), 2.16 (s, 3 H)

[0269] Step 1: Preparation of ethyl 3-[3-(hydroxymethyl)-4-methylphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using general procedure 6 and starting with ethyl (E)-3-[1-[4-[(4-methoxyphenyl)methoxy]butyl]-4-methyl-benzotriazol-5-yl]prop-2-enoate (1 equivalent) and [2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (2 equivalents) as reactants, the title compound was obtained (43% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.58 (d, 1 H), 7.45 (d, 1 H), 7.28 (d, 1 H), 7.2 (d, 2 H), 7.1 (dd, 1 H), 7.01 (d, 1 H), 6.88 (d, 2 H), 4.98 (t, 1 H), 4.82 (t, 1 H), 4.65 (t, 2 H), 4.4 (d, 2 H), 4.3 (s, 2 H), 3.91 (q, 2 H), 3.71 (s, 3 H), 3.4 (t, 2 H), 3.11 (dd, 2 H), 2.75 (s, 3 H), 2.15 (s, 3 H), 1.91 (m, 2 H), 1.48 (m, 2H), 1 (t, 3H)

[0270] Step 2: Ethyl 3-(3-{[6-(benzyloxy)-8-methyl-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(4-(4-benzoxathiazin-3(4H)-yl]methyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, reactants were ethyl 3-[3-(hydroxymethyl)-4-methylphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent) and 6-(benzyloxy)-8-methyl-3,4-dihydro-2H-1,2λ. 6 Starting with 1.5 equivalents of 1,3-benzoxathiazine-2,2-dione, the title compound was obtained in 88% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.56 (d, 1 H), 7.47 (d, 1 H), 7.46-7.31 (m, 5 H), 7.46-7.12 (m, 3 H), 7.19 (d, 2 H), 7 / 6.75 (2d, 2 H), 6.86 (d, 2 H), 5.08 (s, 2 H), 4.85 (t, 1 H), 4.6 (t, 2 H), 4.38 (s, 2 H), 4.23 (s, 2 H), 4.21 (s, 2 H), 3.92 (q, 2 H), 3.72 (s, 3 H), 3.35 (t, 2 H), 3.16 (m, 2 H), 2.76 (s, 3 H), 2.22 / 2.21 (2s, 6 H), 1.89 (m, 2 H), 1.44 (m, 2 H), 0.97 (t, 3 H)

[0271] Step 3: Ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methyl-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate Using general procedure 8, ethyl 3-(3-{[6-(benzyloxy)-8-methyl-2,2-dioxo-2H-1,2λ] was used as the reactant. 6 Starting from 1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained as a white solid (97% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.55 (m, 1 H), 7.61 (d, 1 H), 7.49 (d, 1 H), 7.22-7.11 (3m, 3 H), 6.68 / 6.42 (2d, 2 H), 4.84 (t, 1 H), 4.65 (t, 2 H), 4.34 (s, 2 H), 4.19 (dd, 2 H), 3.94 (q, 2 H), 3.38 (t, 2 H), 3.18 / 3.13 (2dd, 2 H), 2.75 (s, 3 H), 2.22 / 2.17 (2s, 6 H), 1.9 (m, 2 H), 1.36 (m, 2 H), 1 (t, 3 H)

[0272] Step 4: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methyl-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methyl-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 4-methylphenyl]-4-benzoxathiazin-3(4H)-yl)methyl}-4-methylphenyl propanoate gave the title compound (78% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.55 (s, 1 H), 7.65 (d, 1 H), 7.5 (d, 1 H), 7.2 (m, 2 H), 7.11 (d, 1 H), 6.7 / 6.41 (2d, 2 H), 4.85 (t, 1 H), 4.7 (t, 2 H), 4.38 (s, 2 H), 4.2 (m, 2 H), 3.95 (q, 2 H), 3.55 (t, 2 H), 3.18 (m, 2 H), 2.78 (s, 3 H), 2.22 / 2.18 (2s, 6 H), 1.98 (m, 2 H), 1.78 (m, 2 H), 1 (t, 3 H)

[0273] Step 5: Ethyl [4,24,31-trimethyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methyl-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate gave the title compound (quantitative). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.67 (d, 1 H), 7.47 (dd, 1 H), 7.43 (d, 1 H), 7.43 (d, 1 H), 6.71 (d, 1 H), 6.55 (d, 1 H), 5.67 (d, 1 H), 4.84-4.7 (m, 3 H), 4.13-3.79 (2dd, 4 H), 3.92 (q, 2 H), 3.63-3.43 (2m, 2 H), 3.17 / 3.04 (2dd, 2 H), 2.63 (s, 3 H), 2.33 (s, 3 H), 2.25-2 (m, 2 H), 2.11 (s, 3 H), 1.79 / 1.6 (2m, 2H), 1 (t, 3H)

[0274] Step 6: Preparation of Example 15 Using general procedure 12, ethyl [4,24,31-trimethyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Starting from ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 66% yield).

[0275] The enantiopure products were obtained by chromatographic separation on a chiral column.

[0276] Example 15a (E1) HRMS C 30 H 32 Calculated for N4O6S: 576.2042; [M+H] + Measured value: 577.2119 (δ=0.6 ppm)

[0277] Example 15b (E2) HRMS C 30 H 32Calculated for N4O6S: 576.2042; [M+H] + Measured value: 577.2117 (δ=0.3 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.14 (m, 1 H), 7.67 (d, 1 H), 7.49 (dd, 1 H), 7.42 (d, 1 H), 7.29 (d, 1 H), 6.71 (d, 1 H), 6.53 (d, 1 H), 5.66 (d, 1 H), 4.84-4.7 (m, 3 H), 4.13-3.79 (2dd, 4 H), 3.63-3.43 (2m, 2 H), 3.07 / 2.94 (2dd, 2 H), 2.63 (s, 3 H), 2.33 (s, 3 H), 2.19 / 2.08 (2m, 2H), 2.11 (s, 3H), 1.8 / 1.6 (2m, 2H)

[0278] Example 16 : [24-Methoxy-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0279] Step C1: 6-bromo-8-methoxy-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-2,2-dione Using General Procedure 4, Step 2, starting with 5-bromo-2-hydroxy-3-methoxy-benzaldehyde (1 equivalent) as reactant, the title compound was obtained (32% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.14 (s, 1 H), 7.83 / 7.79 (2d, 2 H), 3.98 (s, 3 H)

[0280] Step C2: 6-bromo-8-methoxy-3,4-dihydro-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-2,2-dione Using General Procedure 4, Step 3, 6-bromo-8-methoxy-2H-1,2λ as the reactant 6 Starting with 1 equiv. of 1,3-benzoxathiazine-2,2-dione, the title compound was obtained in 95% yield. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8.6 (sl, 1 H), 7.26 (d, 1 H), 7.1 (d, 1 H), 4.55 (s, 2 H), 3.85 (s, 3 H)

[0281] Step C3: tert-butyl 6-bromo-8-methoxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-3(4H)-carboxylate Using General Procedure 5, Step 1, 6-bromo-8-methoxy-3,4-dihydro-2H-1,2λ as the reactant 6 Starting with 1 equivalent of 1,3-benzoxathiazine-2,2-dione, the title compound was obtained in 88% yield. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.48 (s, 1 H), 7.4 (s, 1 H), 5.05 (s, 2 H), 3.9 (s, 3 H), 1.5 (s, 9 H)

[0282] Step C4: tert-butyl 8-methoxy-2,2-dioxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-3(4H)-carboxylate Using General Procedure 5, Step 2, with tert-butyl 6-bromo-8-methoxy-2,2-dioxo-2H-1,2λ as the reactant 6 Starting with ,3-benzoxathiazine-3(4H)-carboxylate (1 equivalent), the title compound was obtained (80% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.41 (d, 1 H), 7.31 (d, 1 H), 5.09 (s, 2 H), 3.9 (s, 3 H), 1.49 (s, 9 H), 1.3 (s, 12 H)

[0283] Step C5: tert-butyl 6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-3(4H)-carboxylate Using General Procedure 5, Step 3, with tert-butyl 8-methoxy-2,2-dioxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2λ as the reactant 6 Starting from ,3-benzoxathiazine-3(4H)-carboxylate (1 equivalent), the title compound was obtained (81% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.92 (m, 1 H), 6.52 (d, 1 H), 6.43 (d, 1 H), 4.9 (s, 2 H), 3.8 (s, 3 H), 1.48 (s, 9 H)

[0284] Step C6: tert-butyl 6-(benzyloxy)-8-methoxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-3(4H)-carboxylate Using General Procedure 5, Step 4, with tert-butyl 6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2λ as the reactant 6 Starting with ,3-benzoxathiazine-3(4H)-carboxylate (1 equivalent), the title compound was obtained (74% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.5-7.28 (m, 5 H), 6.83 (sl, 2 H), 5.12 (s, 2 H), 4.98 (s, 2 H), 3.86 (s, 3 H), 1.5 (s, 9 H)

[0285] Step C7: 6-(benzyloxy)-8-methoxy-3,4-dihydro-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-2,2-dione Using General Procedure 5, Step 5, tert-butyl 6-(benzyloxy)-8-methoxy-2,2-dioxo-2H-1,2λ as the reactant 6 Starting with ,3-benzoxathiazine-3(4H)-carboxylate (1 equivalent), the title compound was obtained (89% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8.4 (sl, 1 H), 7.48-7.3 (m, 5 H), 6.71 (d, 1 H), 6.5 (d, 1 H), 5.08 (s, 2 H), 4.49 (s, 2 H), 3.8 (s, 3 H)

[0286] Step 1: Ethyl 3-(3-{[6-(benzyloxy)-8-methoxy-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(4-(4-benzoxathiazin-3(4H)-yl]methyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, reactants were ethyl 3-[3-(hydroxymethyl)-4-methylphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent) and 6-(benzyloxy)-8-methoxy-3,4-dihydro-2H-1,2λ. 6Starting with ,3-benzoxathiazine-2,2-dione (1.2 equivalents), the title compound was obtained (yellow solid, 88% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.57 (d, 1 H), 7.48 (d, 2 H), 7.48 (d, 1 H), 7.4 (t, 2 H), 7.33 (t, 1 H), 7.22-7.1 (m, 5 H), 6.87 (d, 2 H), 6.8 (d, 1 H), 6.47 (d, 1 H), 5.09 (s, 2 H), 4.83 (t, 1 H), 4.6 (t, 2 H), 4.39 (s, 2 H), 4.29 (s, 2 H), 4.2 (s, 2 H), 3.9 (q, 2 H), 3.82 (s, 3 H), 3.7 (s, 3 H), 3.33 (t, 2 H), 3.18 (m, 2 H), 2.73 (s, 3 H), 2.2 (s, 3 H), 1.89 (m, 2 H), 1.42 (m, 2 H), 0.98 (t, 3 H)

[0287] Step 2: Ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate Using general procedure 8, the reactant was ethyl 3-(3-{[6-(benzyloxy)-8-methoxy-2,2-dioxo-2H-1,2λ 6 Starting from 1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained as a white solid (97% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.7 / 4.41 (s+t, 2 H), 7.61 (d, 1 H), 7.5 (d, 1 H), 7.2 (d+dd, 2 H), 7.15 (d, 1 H), 6.52 (d, 1 H), 6.15 (d, 1 H), 4.85 (t, 1 H), 4.68 (t, 2 H), 4.35 (s, 2 H), 4.2 (m, 2 H), 3.95 (q, 2 H), 3.8 (s, 3 H), 3.4 (q, 2 H), 3.18 (m, 2 H), 2.78 (s, 3 H), 2.22 (s, 3H), 1.9 (m, 2H), 1.39 (m, 2 H), 1 (t, 3 H)

[0288] Step 3: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate gave the title compound (yellow solid, 86% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.69 (s, 1 H), 7.62 (d, 1 H), 7.5 (d, 1 H), 7.2 (d, 1 H), 7.19 (dd, 1 H), 7.11 (d, 1 H), 6.5 (d, 1 H), 6.11 (d, 1 H), 4.82 (t, 1 H), 4.68 (t, 2 H), 4.32 (s, 2 H), 4.19 (m, 2 H), 3.91 (q, 2 H), 3.79 (s, 3 H), 3.51 (t, 2 H), 3.18 (m, 2 H), 2.73 (s, 3 H), 2.2 (s, 3 H), 1.99 (m, 2 H), 1.78 (m, 2H), 1 (t, 3H)

[0289] Step 4: Ethyl [24-methoxy-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate gave the title compound (white solid, 73% yield).

[0290] The enantiopure final intermediate was obtained by chromatographic separation on a chiral column. 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.69 (d, 1 H), 7.48 (dd, 1 H), 7.42 (d, 1 H), 7.29 (d, 1 H), 6.57 / 6.51 (2d, 2 H), 5.32 (d, 1 H), 4.79 (m, 3 H), 4.12 / 3.8 (2d, 2 H), 3.91 / 3.8 (2d, 2 H), 3.91 (q, 2 H), 3.74 (s, 3 H), 3.6 / 3.39 (m, 2 H), 3.14 / 3.03 (m, 2 H), 2.61 (s, 3 H), 2.3 (s, 3 H), 2.2 / 2.05 (m, 2 H), 1.8 / 1.6 (m, 2H), 1 (t, 3H)

[0291] Step 5: Preparation of Example 16 Using general procedure 12, ethyl [24-methoxy-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Starting from E1 (1 equivalent) or E2 (1 equivalent), the title compounds were obtained in yields ranging from 85% to 67%, respectively.

[0292] Example 16a (E1) HRMS C 30 H 32 Calculated for N4O7S: 592.1992; [M+H] + Measured value: 593.2070 (δ=0.9 ppm)

[0293] Example 16b (E2) HRMS C 30 H 32 Calculated for N4O7S: 592.1992; [M+H] + Found value: [M+H]+=593.2073 (δ=1.4 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (m, 1 H), 7.68 (d, 1 H), 7.49 (dd, 1 H), 7.41 (d, 1 H), 7.29 (d, 1 H), 5.31 (d, 1 H), 4.75 (m, 3 H), 4.11 / 3.92 (2d, 2 H), 3.98 / 3.8 (2d, 2 H), 3.73 (s, 3 H), 3.59 / 3.33 (2m, 2 H), 3.52 / 3.51 (2d, 2 H), 3.05 / 2.92 (2dd, 2 H), 2.6 (s, 3 H), 2.3 (s, 3 H), 2.19 / 2.07 (2m, 2 H), 1.8 / 1.6 (2m, 2H)

[0294] Example 17 : [24-fluoro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0295] Step C1: 6-bromo-8-fluoro-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-2,2-dione Using General Procedure 4, Step 2, starting with 5-bromo-3-fluoro-2-hydroxybenzaldehyde (1 equivalent) as reactant, the title compound was obtained in 25% yield. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.2 (s, 1 H), 8.3 (dd, 1 H), 8.1 (s, 1 H)

[0296] Step C2: 6-bromo-8-fluoro-3,4-dihydro-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-2,2-dione Using General Procedure 4, Step 3, 6-bromo-8-fluoro-2H-1,2λ as the reactant 6 Starting with 1 equiv. of 1,3-benzoxathiazine-2,2-dione, the title compound was obtained in 87% yield. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8.91 (sl, 1 H), 7.72 (dd, 1 H), 7.41 (tf, 1 H), 4.68 (s, 2 H)

[0297] Step C3: tert-butyl 6-bromo-8-fluoro-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-3(4H)-carboxylate Using General Procedure 5, Step 1, 6-bromo-8-fluoro-3,4-dihydro-2H-1,2λ as the reactant 6 Starting with 1 equiv. of 1,3-benzoxathiazine-2,2-dione, the title compound was obtained in 85% yield. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.88 (d, 1 H), 7.74 (s, 1 H), 5.18 (s, 2 H), 1.5 (s, 9 H)

[0298] Step C4: tert-butyl 8-fluoro-2,2-dioxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-3(4H)-carboxylate Using General Procedure 5, Step 2, with tert-butyl 6-bromo-8-fluoro-2,2-dioxo-2H-1,2λ as the reactant 6 Starting with ,3-benzoxathiazine-3(4H)-carboxylate (1 equivalent), the title compound was obtained (71% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.69 (s, 1 H), 7.57 (d, 1 H), 5.21 (s, 2 H), 1.49 (s, 9 H), 1.31 (s, 12 H)

[0299] Step C5: tert-butyl 8-fluoro-6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-3(4H)-carboxylate Using General Procedure 5, Step 3, with tert-butyl 8-fluoro-2,2-dioxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2λ as the reactant 6 Starting from ,3-benzoxathiazine-3(4H)-carboxylate (1 equivalent), the title compound was obtained (81% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 10.4 (m, 1 H), 6.79 (dd, 1 H), 6.78 (d, 1 H), 5.02 (s, 2 H), 1.49 (s, 9 H)

[0300] Step C6: 6-(benzyloxy)-8-fluoro-3,4-dihydro-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-2,2-dione Using General Procedure 5, Step 4, with tert-butyl 8-fluoro-6-hydroxy-2,2-dioxo-2H-1,2λ as the reactant 6 Starting from 1 equiv. of tert-butyl 6-(benzyloxy)-8-fluoro-2,2-dioxo-2H-1,2λ, 3-benzoxathiazine-3(4H)-carboxylate, 6 ,3-benzoxathiazine-3(4H)-carboxylate (yield 36%). The crude product was reacted using General Procedure 5, Step 5 to afford the title compound (yield 91%). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 8.7 (m, 1 H), 7.48-7.3 (m, 5 H), 7.1 (dd, 1 H), 6.8 (d, 1 H), 5.09 (s, 2 H), 4.58 (s, 2 H)

[0301] Step 1: Ethyl 3-(3-{[6-(benzyloxy)-8-fluoro-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(4-(4-benzoxathiazin-3(4H)-yl]methyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, reactants were ethyl 3-[3-(hydroxymethyl)-4-methylphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent) and 6-(benzyloxy)-8-fluoro-3,4-dihydro-2H-1,2λ. 6 Starting with 1 equiv. of 1,3-benzoxathiazine-2,2-dione, the title compound was obtained in 85% yield. 1H-NMR (400 MHz, DMSO-d6) δppm: 0.97 (t, J=7.09 Hz, 3 H) 1.39 - 1.51 (m, 2 H) 1.89 (quint, J=7.27 Hz, 2 H) 1.99 (s, 2 H) 2.22 (s, 3 H) 2.76 (s, 3 H) 3.16 (dd, J=8.07, 2.69 Hz, 2 H) 3.35 (t, J=6.30 Hz, 2 H) 3.72 (s, 3 H) 3.92 (q, J=7.05 Hz, 2 H) 4.24 - 4.32 (m, 4 H) 4.49 (s, 2 H) 4.60 (t, J=6.97 Hz, 2 H) 4.84 (t, J=8.07 Hz, 1 H) 5.11 (s, 2 H) 6.79 (s, 1 H) 6.82 - 6.89 (m, 2 H) 7.10 - 7.22 (m, 5 H) 7.24 (s, 1 H) 7.32 - 7.50 (m, 6 H) 7.53 - 7.59 (m, 1 H)

[0302] Step 2: Ethyl 3-{3-[(8-fluoro-6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of {1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl}propanoate Using general procedure 8, ethyl 3-(3-{[6-(benzyloxy)-8-fluoro-2,2-dioxo-2H-1,2λ] was used as the reactant. 6 Starting from 1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained as a white solid (97% yield). 1H-NMR (400 MHz, DMSO-d6) δppm: 10.1 / 4.4 (s+t, 2 H), 7.62 (d, 1 H), 7.5 (d, 1 H), 7.28 (d, 1 H), 7.2 (dd, 1 H), 7.15 (d, 1 H), 6.78 (dd, 1 H), 6.48 (d, 1 H), 4.85 (t, 1 H), 4.65 (t, 2 H), 4.49 (s, 2 H), 4.28 (m, 2 H), 3.95 (q, 2 H), 3.4 (q, 2 H), 3.18 (d, 2 H), 2.78 (s, 3 H), 2.22 (s, 3 H), 1.9 (m, 2 H), 1.38 (m, 2 H), 1 (t, 3 H)

[0303] Step 3: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(8-fluoro-6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-{3-[(8-fluoro-6-hydroxy-2,2-dioxo-2H-1,2λ 6 Starting from {1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl}-3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]propanoate (1 equivalent), the title compound was obtained as an off-white solid (65% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 10.1 (s, 1 H), 7.62 (d, 1 H), 7.5 (d, 1 H), 7.22 (d, 1 H), 7.19 (dd, 1 H), 7.12 (d, 1 H), 6.78 (d, 1 H), 6.45 (d, 1 H), 4.83 (t, 1 H), 4.69 (t, 2 H), 4.48 (s, 2 H), 4.26 (m, 2 H), 3.91 (q, 2 H), 3.51 (t, 2 H), 3.15 (m, 2 H), 2.73 (s, 3 H), 2.21 (s, 3 H), 2 (m, 2 H), 1.78 (m, 2 H), 1 (t, 3 H)

[0304] Step 4: Ethyl [24-fluoro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(8-fluoro-6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting with 1 equiv. of 4-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate gave the title compound (off-white solid, 74% yield).

[0305] The enantiopure final intermediate was obtained by chromatographic separation on a chiral column. 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.68 (d, 1 H), 7.49 (dd, 1 H), 7.41 (d, 1 H), 7.3 (d, 1 H), 6.9 (dd, 1 H), 6.6 (d, 1 H), 5.75 (d, 1 H), 4.79 (m, 3 H), 4.2 / 4.02 (2d, 2 H), 4.02 / 3.95 (2d, 2 H), 3.95 (q, 2 H), 3.7 / 3.5 (2m, 2 H), 3.18 / 3.05 (2dd, 2 H), 2.63 (s, 3 H), 2.32 (s, 3 H), 2.2 / 2.05 (2m, 2 H), 1.8 / 1.62 (2m, 2H), 1 (t, 3H)

[0306] Step 5: Preparation of Example 17 Using general procedure 12, ethyl [24-fluoro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Starting from E1 (1 equivalent) or E2 (1 equivalent), the title compounds were obtained in yields ranging from 65% to 99%, respectively.

[0307] Example 17a (E1) HRMS C 29 H 29 Calculated for FN4O6S: 580.1792; [M+H] + Measured value: 581.1871 (δ=1.1 ppm)

[0308] Example 17b (E2) HRMS C 29 H 29 Calculated for FN4O6S: 580.1792; [M+H] + Measured value: 581.1867 (δ=0.4 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.3 (m, 1 H), 7.55 (d, 1 H), 7.5 (dd, 1 H), 7.4 (d, 1 H), 7.3 (d, 1 H), 6.9 (dd, 1 H), 6.55 (d, 1 H), 5.7 (sl, 1 H), 4.8 (m, 3 H), 4.15 / 4 (2d, 2 H), 4 / 3.9 (2d, 2 H), 3.7 / 3.5 (2m, 2 H), 3 / 2.9 (2m, 2 H), 2.6 (s, 3 H), 2.3 (s, 3 H), 2.2 / 2.1 (2m, 2H), 1.8 / 1.6 (2m, 2H) 19 F-NMR (376 MHz, DMSO-d6) δ ppm: 133

[0309] Example 18 : [5-fluoro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0310] Step B1: Preparation of (5-bromo-3-fluoro-2-methylphenyl)methanol Lithium aluminum hydride (4 equiv., 3.07 g, 80.9 mmol) was placed in a round-bottom flask. After the addition of anhydrous THF (5 mL / mmol, 101 ml), the mixture was cooled to 0 °C. A solution of methyl 5-bromo-3-fluoro-2-methylbenzoate (5 g, 20.2 mmol) in anhydrous THF (5 mL / mmol, 101 mL) was added dropwise at 0 °C with continuous stirring. The reaction mixture was allowed to warm to room temperature and stirred at this temperature overnight. After completion of the reaction, the mixture was carefully quenched with water (150 mL), and 2 M aqueous NaOH solution (100 mL) was added. The mixture was concentrated to dryness, which was then purified by normal-phase silica gel chromatography using DCM-EtOH (90:10) as the eluent to give the title compound (1.8 g, 41% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.41 (d, 1 H), 7.35 (dd, 1 H), 5.35 (t, 1 H), 4.5 (d, 2 H), 2.1 (s, 3 H)

[0311] Step B2: Preparation of [3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol Using general procedure 3 and starting with (5-bromo-3-fluoro-2-methylphenyl)methanol (1 equivalent, 1.8 g, 8.2 mmol) as reactant, the title compound (2.5 g, 73% yield) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.55 (s, 1 H), 7.2 (d, 1 H), 5.2 (t, 1 H), 4.52 (d, 2 H), 2.18 (s, 3 H), 1.31 (s, 12 H)

[0312] Step 1: Preparation of ethyl 3-[3-fluoro-5-(hydroxymethyl)-4-methylphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using general procedure 6 and starting with ethyl (2E)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equivalent) and [3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (1.4 equivalents) as reactants, the title compound was obtained (32% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.5 (d, 1 H), 7.2 (d, 2 H), 7.12 (sl, 1 H), 7.05 (d, 1 H), 6.9 (d, 2 H), 5.1 (t, 1 H), 4.82 (t, 1 H), 4.65 (t, 2 H), 4.45 (d, 2 H), 4.32 (s, 2 H), 3.95 (q, 2 H), 3.72 (s, 3 H), 3.4 (t, 2 H), 3.15 (t, 2 H), 2.78 (s, 3 H), 2.08 (s, 3 H), 1.92 (m, 2 H), 1.5 (m, 2 H), 1 (t, 3 H)

[0313] Step 2: Ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(4-(4-benzoxathiazin-3(4H)-yl)methyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, reactants were ethyl 3-[3-fluoro-5-(hydroxymethyl)-4-methylphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6 Starting with ,3-benzoxathiazine-2,2-dione (1.1 equivalents), the title compound was obtained (91% yield). 1H-NMR (400 MHz, DMSO-d6) δppm: 7.6 / 7.5 (2d, 2 H), 7.45 (dl, 2 H), 7.4 (t, 2 H), 7.35 (tl, 1 H), 7.2 (d, 2 H), 7.1 (m, 3 H), 7.05 (dd, 1 H), 6.95 (d, 1 H), 6.85 (d, 2 H), 5.1 (s, 2 H), 4.85 (t, 1 H), 4.6 (t, 2 H), 4.45-4.25 (3s, 6 H), 3.95 (q, 2 H), 3.7 (s, 3 H), 3.35 (t, 2 H), 3.2 (m, 2 H), 2.8 (sl, 3 H), 2.1 (sl, 3 H), 1.9 (quint, 2 H), 1.45 (quint, 2 H), 1 (t, 3 H)

[0314] Step 3: Ethyl 3-{3-fluoro-5-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of {1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl}propanoate Using general procedure 8, ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ] was used as the reactant. 6 Starting from 1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained as a white solid (quantitative). 1H-NMR (400 MHz, DMSO-d6) δppm: 9.7 (s, 1 H), 7.6 (d, 1 H), 7.5 (d, 1 H), 7.15 (m, 2 H), 7 (d, 1 H), 6.8 (dd, 1 H), 6.6 (d, 1 H), 4.85 (t, 1 H), 4.65 (t, 2 H), 4.4 (m, 3 H), 4.25 (2d, 2 H), 3.9 (q, 2 H), 3.4 (q, 2 H), 3.2 (m, 2 H), 2.8 (s, 3 H), 2.1 (d, 3 H), 1.9 (quint, 2 H), 1.4 (quint, 2 H), 1 (t, 3 H)

[0315] Step 4: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-fluoro-5-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-{3-fluoro-5-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Starting from {1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl}-3-benzoxathiazin-3(4H)-yl)methyl}-4-methylphenyl}-3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]propanoate (1 equivalent), the title compound was obtained as a white solid (73% yield). 1H-NMR (400 MHz, DMSO-d6) δppm: 9.7 (s, 1 H), 7.65 / 7.5 (2d, 2 H), 7.15 (m, 2 H), 7 (d, 1 H), 6.8 (dd, 1 H), 6.6 (d, 1 H), 4.85 (t, 1 H), 4.7 (t, 2 H), 4.4 (2d, 2 H), 4.25 (2d, 2 H), 3.9 (q, 2 H), 3.5 (t, 2 H), 3.2 (m, 2 H), 2.75 (sl, 3 H), 2.1 (d, 3 H), 2 (m, 2 H), 1.8 (quint, 2 H), 1 (t, 3 H)

[0316] Step 5: Ethyl [5-fluoro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-fluoro-5-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate gave the title compound (96% yield).

[0317] The enantiopure final intermediate was obtained by chromatographic separation on a chiral column. 1H-NMR (400 MHz, DMSO-d6) δ ppm: 1.17 (t, J=7.15 Hz, 3 H) 1.58 (dt, J=13.63, 6.76 Hz, 1 H) 1.70 - 1.86 (m, 1 H) 2.20 - 2.27 (m, 3 H) 2.65 (s, 3 H) 3.05 (dd, J=15.83, 8.74 Hz, 1 H) 3.16 - 3.26 (m, 1 H) 3.43 - 3.57 (m, 1 H) 3.62 - 3.73 (m, 1 H) 3.83 - 4.00 (m, 7 H) 4.03 - 4.17 (m, 4 H) 4.63 - 4.89 (m, 4 H) 5.89 (d, J=2.81 Hz, 1 H) 6.45 (s, 1 H) 6.79 (dd, J=9.05, 2.93 Hz, 1 H) 6.97 - 7.01 (m, 1 H) 7.39 - 7.47 (m, 2 H) 7.68 (d, J=8.68Hz, 1H)

[0318] Step 6: Preparation of Example 18 Using general procedure 12, ethyl [5-fluoro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Starting from E1 (1 equivalent) or E2 (1 equivalent), the title compounds were obtained in 80% to 72% yields, respectively.

[0319] Example 18a (E1) HRMS C 29 H 29 Calculated for FN4O6S: 580.1792; [M+H] + Measured value: 581.1867 (δ=0.4 ppm)

[0320] Example 18b (E2) HRMS C 29 H 29 Calculated for FN4O6S: 580.1792; [M+H] + Measured value: 581.1866 (δ=0.2 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (m, 1 H), 7.7 (d, 1 H), 7.41 (2d, 2 H), 7 (d, 1 H), 6.8 (dd, 1 H), 6.45 (d, 1 H), 5.9 (d, 1 H), 4.79 (m, 3 H), 4.09 (m, 2 H), 3.91 (m, 2 H), 3.68 / 3.45 (2m, 2 H), 3.1 / 2.95 (2dd, 2 H), 2.65 (s, 3 H), 2.22 (s, 3 H), 2.2 / 2.05 (2m, 2 H), 1.8 / 1.6 (2m, 2H)

[0321] Example 19 : [(2R,8R)-2,4,33-trimethyl-29,29-dioxo-23,28-dioxa-29λ 6 -Thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid and [(2R,8S)-2,4,33-trimethyl-29,29-dioxo-23,28-dioxa-29λ 6 -Thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid [ka]

[0322] Step 1: Preparation of ethyl 3-{1-[6-(benzyloxy)hexyl]-4-methyl-1H-benzotriazol-5-yl}-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propanoate Using general procedure 6 and starting with ethyl (2E)-3-{1-[6-(benzyloxy)hexyl]-4-methyl-1H-benzotriazol-5-yl}prop-2-enoate (1 equivalent) and (1S)-1-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1-ol (2 equivalents) as reactants, the title compound was obtained (70% yield). 1 H-NMR (400 MHz, DMSO-d6) δppm: 7.59 (d, 1 H), 7.46 (d, 1 H), 7.4 (d, 1 H), 7.34-7.22 (br, 5 H), 6.99 (d, 1 H), 4.97 (d, 1 H), 4.82 (m, 1 H), 4.82 (m, 1 H), 4.62 (dd, 2 H), 4.4 (s, 2 H), 4.05 (dd, 1 H), 3.92 (q, 2 H), 3.36 (t, 2 H), 3.11 (m, 2 H), 2.75 (s, 3 H), 2.19 (s, 3 H), 1.87 (quint, 2 H), 1.48 (quint, 2 H), 1.32 (quint, 2 H), 1.22 (m, 3 H), 1.22 (m, 2 H), 0.99 (t, 3 H)

[0323] Step 2: Ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(3-benzoxathiazin-3(4H)-yl]ethyl)-4-methylphenyl)-3-{1-[6-(benzyloxy)hexyl]-4-methyl-1H-benzotriazol-5-yl}propanoate Using General Procedure 7, the reactants were ethyl 3-{1-[6-(benzyloxy)hexyl]-4-methyl-1H-benzotriazol-5-yl}-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propanoate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6 Starting with ,3-benzoxathiazine-2,2-dione (1.5 equivalents), the title compound was obtained (beige solid, 71% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 0.95 - 1.00 (m, 3 H) 1.23 - 1.36 (m, 3 H) 1.37 - 1.49 (m, 5 H) 1.83 (sxt, J=6.85 Hz, 2 H) 1.99 (s, 1 H) 2.28 (s, 3 H) 2.76 (d, J=3.67 Hz, 3 H) 3.14 - 3.26 (m, 2 H) 3.33 - 3.36 (m, 1 H) 3.86 - 3.97 (m, 2 H) 4.27 - 4.49 (m, 4 H) 4.59 (q, J=6.64 Hz, 2 H) 4.87 (td, J=7.98, 4.10 Hz, 1 H) 5.02 - 5.14 (m, 2 H) 5.27 (q, J=6.93 Hz, 1 H) 6.96 - 7.16 (m, 4 H) 7.24 - 7.48 (m, 11 H) 7.49 - 7.55 (m, 1 H) 7.57 - 7.63 (m, 1H)

[0324] Step 3: Ethyl 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of {1-(6-hydroxyhexyl)-4-methyl-1H-benzotriazol-5-yl)propanoate, 3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}-3-[1-(6-hydroxyhexyl)-4-methyl-1H-benzotriazol-5-yl]propanoate Using General Procedure 8, the reactant was ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6Starting from ,3-benzoxathiazin-3(4H)-yl]ethyl}-4-methylphenyl)-3-{1-[6-(benzyloxy)hexyl]-4-methyl-1H-benzotriazol-5-yl}propanoate (1 equivalent), the title compound was obtained (gray solid, 78% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.66 (m, 1 H), 7.63 / 7.56 (2dd, 2 H), 7.47 / 7.44 (2d, 1 H), 7.15-7.08 (m, 2 H), 6.92 / 6.9 (2d, 1 H), 6.72 (2dd, 1 H), 6.58 (2dd, 1 H), 5.26 (m, 1 H), 4.87 (m, 1 H), 4.63 (t, 2 H), 4.31 (m, 2 H), 3.94 (2d, 2 H), 3.32 (m, 2 H), 3.22 (d, 2 H), 2.76 (s, 3 H), 2.28 (s, 3 H), 1.87 (m, 2 H), 1.43 / 1.41 (2d, 3 H), 1.38-1.1 (m, 4 H), 1.33 (m, 2 H), 1 / 0.99 (2t, 3 H)

[0325] Step 4: Ethyl 3-[1-(6-bromohexyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Starting from {1-(6-hydroxyhexyl)-4-methyl-1H-benzotriazol-5-yl}-4-methylphenyl}-3-[1-(6-hydroxyhexyl)-4-methyl-1H-benzotriazol-5-yl]propanoate (1 equivalent), the title compound was obtained (84% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.61 / 9.6 (2s, 1 H), 7.62 (dd, 1 H), 7.58 (d, 1 H), 7.48 / 7.42 (2d, 1 H), 7.1 (m, 2 H), 6.91 (d, 1 H), 6.71 (m, 1 H), 6.6 / 6.53 (2d, 1 H), 5.26 (m, 1 H), 4.89 (m, 1 H), 4.62 (t, 2 H), 4.4-4.2 (m, 2 H), 3.92 (2d, 2 H), 3.46 (m, 2 H), 3.21 (d, 2 H), 2.77 (s, 3 H), 2.28 (s, 3 H), 1.88 (m, 2 H), 1.71 (m, 2 H), 1.4 (2d, 3 H), 1.38 (m, 2 H), 1.21 (m, 3 H), 1 (2t, 1 H)

[0326] Step 5: Ethyl [(2R)-2,4,33-trimethyl-29,29-dioxo-23,28-dioxa-29λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 Preparation of ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(6-bromohexyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate gave the title compound (81% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 1.00 (dt, J=11.62, 7.09 Hz, 12 H) 1.20 - 1.29 (m, 9 H) 1.29 - 1.76 (m, 25 H) 1.86 - 1.98 (m, 5 H) 2.30 (d, J=9.05 Hz, 10 H) 2.63 - 2.79 (m, 1 H) 2.97 (dd, J=15.77, 7.46 Hz, 1 H) 3.09 - 3.27 (m, 2 H) 3.64 - 3.76 (m, 1 H) 3.77 - 3.99 (m, 6 H) 4.00 - 4.10 (m, 1H) 4.18 (d, J=17.48 Hz, 1 H) 4.59 - 4.72 (m, 3 H) 4.86 (t, J=8.01 Hz, 1 H) 4.94 (t, J=7.95 Hz, 1 H) 5.24 - 5.42 (m, 3 H) 5.99 (d, J=2.81 Hz, 1 H) 6.40 (d, J=2.81 Hz, 1 H) 6.75 - 6.86 (m, 2 H) 6.93 - 7.04 (m, 3 H) 7.09 - 7.20 (m, 2 H) 7.29 (dd, J=12.41, 7.76 Hz, 2 H) 7.47 (d, J=7.58Hz, 1H) 7.55 (s, 1 H) 7.61 (d, J=8.80 Hz, 1 H) 7.66 (d, J=8.68 Hz, 1 H) 7.77 (d, J=8.93 Hz, 1 H)

[0327] Step 6: Preparation of Example 19 Using General Procedure 12, ethyl [(2R)-2,4,33-trimethyl-29,29-dioxo-23,28-dioxa-29λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 Starting with ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetate (1 equivalent), the title compound was obtained (white solid, 91% yield).

[0328] The diastereomeric pure products were obtained by chromatographic separation on a chiral column.

[0329] Example 19a (2R,8R) HRMS C 32 H 36 Calculated for N4O6S: 604.2356; [M+H] + Measured value: 605.2430 (δ=0.3 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (sl), 7.6 (d, 1 H), 7.48 (dd, 1 H), 7.3 (d, 1 H), 7.14 (d, 1 H), 7 (d, 1 H), 6.96 (d, 1 H), 6.78 (dd, 1 H), 6 (d, 1 H), 5.3 (q, 1 H), 4.92 (t, 1 H), 4.64 (m, 2 H), 4.04 / 3.83 (2d, 2 H), 3.7 (m, 2 H), 3.11 / 2.85 (2dd, 2 H), 2.82 (s, 3 H), 2.32 (s, 3 H), 2 (m, 2 H), 1.6 (m, 2 H), 1.4 (m, 2 H), 1.25 (m, 2 H), 1.25 (d, 3 H) 13 C-NMR (100 MHz, DMSO-d6) δ ppm: 131.6, 128.4, 128, 126.5, 119.5, 115.7, 111.4, 107.8, 68.4, 55.3, 47.8, 45, 41.6, 39.9, 29.5, 27.5, 25.7, 25.5, 18.7, 15.1, 13.6

[0330] Example 19b (2R,8S) HRMS C 32 H 36 Calculated for N4O6S: 604.2356; [M+H] + Measured value: 605.2431 (δ=0.4 ppm) 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.1 (sl), 7.75 (d, 1 H), 7.65 (d, 1 H), 7.52 (d, 1 H), 7.3 (dd, 1 H), 7.12 (d, 1 H), 7 (d, 1 H), 6.82 (dd, 1 H), 6.4 (d, 1 H), 5.34 (q, 1 H), 4.84 (t, 1 H), 4.67 (m, 2 H), 4.18 / 3.92 (2d, 2 H), 3.82 (t, 2 H), 3.15 / 3.05 (2dd, 2 H), 2.82 (s, 3 H), 2.3 (s, 3 H), 1.85 (m, 2 H), 1.7 (m, 2 H), 1.6-1.4 (m, 2 H), 1.5 (d, 3 H), 1.35 (m, 2 H) 13 C-NMR (100 MHz, DMSO-d6) δ ppm: 131.4, 129.9, 126.9, 125.2, 119.5, 116.1, 111.1, 107.9, 68.4, 55.4, 47.6, 45.4, 42.1, 40.9, 30, 28.2, 25.7, 24.8, 18.7, 15.7, 13.5

[0331] Example 20 : [(2R,8S)-2,4,32-trimethyl-28,28-dioxo-22,27-dioxa-28λ 6 -Thia-1,14,15,16-tetraazahexacyclo[21.5.3.1 3,7 .1 9,13 .0 12,16 .0 26,30 ]tritriaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetic acid and [(2R,8R)-2,4,32-trimethyl-28,28-dioxo-22,27-dioxa-28λ 6 -Thia-1,14,15,16-tetraazahexacyclo[21.5.3.1 3,7 .1 9,13 .0 12,16 .0 26,30]tritriaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetic acid [ka]

[0332] Step 1: Preparation of ethyl 3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}-3-(1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using general procedure 6 and starting with ethyl (2E)-3-(1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equivalent) and (1S)-1-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1-ol (2 equivalents) as reactants, the title compound was obtained (77% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.59 (d, 1 H), 7.45 (d, 1 H), 7.41 (d, 1 H), 7.18 (d, 2 H), 7.04 (dd, 1 H), 6.98 (d, 1 H), 6.87 (d, 2 H), 4.96 (d, 1 H), 4.82 (m, 1 H), 4.82 (m, 1 H), 4.62 (dd, 2 H), 4.31 (s, 2 H), 3.92 (q, 2 H), 3.73 (s, 3 H), 3.31 (m, 2 H), 3.15-3.09 (m, 2 H), 2.77 (s, 3 H), 2.19 (s, 3 H), 1.87 (m, 2 H), 1.51 (m, 2 H), 1.27 (m, 2 H), 1.23 / 1.21 (d, 3 H), 0.99 (t, 3 H)

[0333] Step 2: Ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6Preparation of 1-(1-benzoxathiazin-3(4H)-yl]ethyl}-4-methylphenyl)-3-(1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, reactants were ethyl 3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}-3-(1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6 Starting with ,3-benzoxathiazine-2,2-dione (1.5 equivalents), the title compound was obtained (64% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.51 (2d, 1 H), 7.5-6.8 (m, 15 H), 5.27 (q, 1 H), 5.09 (m, 2 H), 4.88 (m, 1 H), 4.59 (m, 2 H), 4.41 (m, 2 H), 4.29 (s, 2 H), 3.9 (q, 2 H), 3.71 (s, 3 H), 3.29 (m, 2 H), 3.2 (m, 2 H), 2.76 (2s, 3 H), 2.28 (s, 3 H), 1.82 (m, 2 H), 1.49 (m, 2 H), 1.4 (m, 3 H), 1.22 (m, 2H), 0.96 (m, 3H)

[0334] Step 3: Ethyl 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of {1-(5-hydroxypentyl)-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 8, the reactant was ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6Starting from 1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained as a gray solid (98% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.63 / 9.62 (2m, 3 H), 7.62 / 7.56 (2dd, 2 H), 7.47 / 7.45 (2sl, 1 H), 7.1 (m, 2 H), 6.92 / 6.9 (2d, 1 H), 6.73 (m, 1 H), 6.58 (2d, 1 H), 5.25 (m, 1 H), 4.88 (m, 1 H), 4.63 (t, 2 H), 4.32 (m, 2 H), 3.94 (m, 2 H), 3.32 (m, 2 H), 3.22 (m, 2 H), 2.77 (s, 3 H), 2.28 (s, 3 H), 1.88 (m, 2 H), 1.46-1.37 (m+d, 5 H), 1.24 (m, 2 H), 1 / 0.99 (2t, 3 H)

[0335] Step 4: Ethyl 3-[1-(5-bromopentyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Starting from {1-(5-hydroxypentyl)-4-methyl-1H-benzotriazol-5-yl}-4-methylphenyl}-3-[1-(5-hydroxypentyl)-4-methyl-1H-benzotriazol-5-yl]propanoate (1 equivalent), the title compound was obtained as a white solid (78% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.6 / 9.59 (2s, 1 H), 7.62 (2d, 1 H), 7.58 (d, 1 H), 7.48 / 7.42 (2d, 1 H), 7.1 (m, 2 H), 6.9 (d, 1 H), 6.71 (m, 1 H), 6.59 / 6.55 (2d, 1 H), 5.26 (m, 1 H), 4.88 (m, 1 H), 4.65 (t, 2 H), 4.4-4.25 (m, 2 H), 3.93 (q, 2 H), 3.48 (t, 2 H), 3.21 (m, 2 H), 2.77 (s, 3 H), 2.28 (s, 3 H), 1.9 (m, 2 H), 1.8 (m, 2 H), 1.41 (2d, 3 H), 1.32 (m, 2 H), 1 / 0.99 (2t, 3 H)

[0336] Step 5: Ethyl [(2R)-2,4,32-trimethyl-28,28-dioxo-22,27-dioxa-28λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[21.5.3.1 3,7 .1 9,13 .0 12,16 .0 26,30 Preparation of ]tritriaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(5-bromopentyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate gave the title compound (78% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 0.92 - 1.07 (m, 7 H) 1.27 - 1.53 (m, 9 H) 1.55 - 1.81 (m, 5 H) 1.85 - 1.98 (m, 3 H) 1.99 - 2.09 (m, 2 H) 2.23 - 2.36 (m, 7 H) 2.75 (s, 4 H) 2.80 (s, 3 H) 2.94 (dd, J=15.71, 7.52 Hz, 1 H) 3.10 (dd, J=16.08, 7.03 Hz, 2 H) 3.21 - 3.29 (m, 2 H) 3.57 - 3.78 (m, 3H) 3.80 - 3.98 (m, 8 H) 4.04 - 4.21 (m, 2 H) 4.56 - 4.76 (m, 4 H) 4.81 - 4.89 (m, 1 H) 4.95 (t, J=7.82 Hz, 1 H) 5.21 - 5.36 (m, 2 H) 5.99 (s, 2 H) 6.76 - 6.88 (m, 3 H) 6.91 - 6.99 (m, 2 H) 7.13 (dd, J=10.51, 8.19 Hz, 2 H) 7.24 - 7.38 (m, 3 H) 7.48 (d, J=7.95 Hz, 1 H) 7.60 - 7.71 (m, 2H) 7.84 (d, J=8.68 Hz, 1 H)

[0337] Step 6: Preparation of Example 20 Using General Procedure 12, ethyl [(2R)-2,4,32-trimethyl-28,28-dioxo-22,27-dioxa-28λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[21.5.3.1 3,7 .1 9,13 .0 12,16 .0 26,30 Starting with ]tritriaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 32% yield).

[0338] The diastereomeric pure products were obtained by chromatographic separation on a chiral column.

[0339] Example 20a (2R,8S) HRMS C 31 H 34 Calculated for N4O6S: 590.2199; [M+H] + Measured value: 591.2273 (δ=0.2 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.4-11.9 (m, 1 H), 7.62 (d, 1 H), 7.49 (dd, 1 H), 7.31 (d, 1 H), 7.09 (d, 1 H), 6.94 (d, 1 H), 6.84 (d, 1 H), 6.81 (dd, 1 H), 5.99 (d, 1 H), 5.28 (q, 1 H), 4.91 (m, 1 H), 4.75-4.6 (t, 2 H), 4.08 / 3.7 (m, 2 H), 3.89 / 3.7 (m, 2 H), 3.16 / 2.8 (2m, 2H), 2.8 (s, 3H), 2.32 (s, 3H), 2.1-1.85 (m, 2 H), 1.69 (m, 2 H), 1.55-1.23 (m, 2 H), 1.12 (d, 3 H)

[0340] Example 20b (2R,8R) HRMS C 31 H 34 Calculated for N4O6S: 590.2199; [M+H] + Measured value: 591.2274 (δ=0.4 ppm) 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.4-11.9 (m, 1 H), 7.81 (d, 1 H), 7.68 (d, 1 H), 7.37 (dd, 1 H), 7.29 (d, 1 H), 7.13 (d, 1 H), 6.98 (d, 1 H), 6.83 (dd, 1 H), 5.97 (d, 1 H), 5.3 (q, 1 H), 4.81 (m, 1 H), 4.7 (t, 2 H), 4.15 / 3.6 (m, 2 H), 3.85 (m, 2 H), 3.18 / 2.99 (2m, 2 H), 2.71 (s, 3 H), 2.29 (s, 3 H), 2.1-1.85 (m, 2 H), 1.8-1.55 (m, 2 H), 1.5-1.2 (m, 5 H)

[0341] Example 21 : [(2R,8S)-2,4,19,33-tetramethyl-29,29-dioxo-23,28-dioxa-29λ 6 -Thia-1,14,15,16,19-pentaazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid and [(2R,8R)-2,4,19,33-tetramethyl-29,29-dioxo-23,28-dioxa-29λ 6 -Thia-1,14,15,16,19-pentaazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid [ka] Step A1: Preparation of tert-butyl (2-{[3-(benzyloxy)propyl](methyl)amino}ethyl)carbamate To a solution of [(3-bromopropoxy)methyl]benzene (10 g, 43.6 mmol, 7.7 mL) in MeCN (3 mL / mmol, 131 mL), tert-butyl [2-(methylamino)ethyl]carbamate (1 eq., 7.61 g, 43.6 mmol) and K2CO3 (2 eq., 8.65 g, 87.3 mmol) were added at room temperature. The reaction mixture was heated to 50 °C and stirred for 2 h. After completion of the reaction, the mixture was diluted with EtOAc (500 ml) and extracted with water (500 ml) and then brine (500 ml). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the crude product as a colorless oil, which was used in the next step without further purification (14 g, 99% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.38-7.28 (m, 5 H), 6.58 (t, 1 H), 4.43 (s, 2 H), 3.45 (t, 2 H), 2.99 (q, 2 H), 2.38 (t, 2 H), 2.32 (t, 2 H), 2.13 (s, 3 H), 1.65 (quint, 2 H), 1.37 (s, 9 H)

[0342] Process A2: N 1 -[3-(benzyloxy)propyl]-N 1 Preparation of -methylethane-1,2-diamine To a solution of tert-butyl (2-{[3-(benzyloxy)propyl](methyl)amino}ethyl)carbamate (14 g, 43 mmol) in dioxane (5 mL / mmol, 220 mL), HCl (4 N in dioxane) (4 equivalents, 43 mL) was added at room temperature, and the reaction mixture was stirred overnight. After completion of the reaction, the volatiles were evaporated to dryness under reduced pressure. The crude product was partitioned between DCM (200 mL) and saturated aqueous NaHCO3 (300 ml). The layers were separated, and the aqueous layer was evaporated to dryness under reduced pressure. MeCN (50 ml) was added, then the solid was filtered off and washed with MeCN (2 × 20 ml). The mother liquor was concentrated to dryness to give the crude product as a yellow oil. The crude product was used without further purification (6.2 g, 62% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.38-7.23 (m, 5 H), 4.44 (s, 2 H), 3.45 (t, 2 H), 2.56 (t, 2 H), 2.36 (t, 2 H), 2.33 (t, 2 H), 2.1 (s, 3 H), 1.67 (quint, 2 H)

[0343] Process A3: N 1 -[3-(benzyloxy)propyl]-N 1 -methyl-N 2 Preparation of -(3-methyl-2-nitrophenyl)ethane-1,2-diamine Using General Procedure 2, Step 1, use 1-fluoro-3-methyl-2-nitro-benzene (1 equivalent) and crude N 1 -[3-(benzyloxy)propyl]-N 1 Starting with -methylethane-1,2-diamine (1.2 equivalents), the title compound was obtained (58% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.35-7.22 (m, 1 H), 7.35-7.22 (m, 5 H), 6.78 (d, 1 H), 6.61 (t, 1 H), 6.58 (d, 1 H), 4.41 (s, 2 H), 3.49 (t, 2 H), 3.2 (q, 2 H), 2.55 (t, 2 H), 2.41 (t, 2 H), 2.32 (s, 3 H), 2.19 (s, 3 H), 1.69 (quint, 2 H)

[0344] Process A4: N 1 Preparation of -(2-{[3-(benzyloxy)propyl](methyl)amino}ethyl)-4-bromo-3-methylbenzene-1,2-diamine General Procedure 2, Step 2, using N as reactant 1 -[3-(benzyloxy)propyl]-N 1 -methyl-N 2 Starting from -(3-methyl-2-nitrophenyl)ethane-1,2-diamine (1 equivalent), 1-[3-(benzyloxy)propyl]-N 2 -(4-bromo-3-methyl-2-nitrophenyl)-N 1 -methylethane-1,2-diamine (71% yield). The crude product was reacted using General Procedure 2, Step 3 to afford the title compound (76% yield). LC-MS C 20 H 28 Calculated for BrNO: 405; [M+H] + Actual value: 406 / 408

[0345] Step A5: Preparation of 3-(benzyloxy)-N-[2-(5-bromo-4-methyl-1H-benzotriazol-1-yl)ethyl]-N-methylpropan-1-amine Using General Procedure 2, Step 4, N 1 Starting with -(2-{[3-(benzyloxy)propyl](methyl)amino}ethyl)-4-bromo-3-methylbenzene-1,2-diamine (1 equivalent), the title compound was obtained (85% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8.19 (s, 1 H), 7.4 (2d, 2 H), 7.3 (t, 2 H), 7.25 (t, 1 H), 7.2 (d, 2 H), 4.3 (t, 2 H), 4.22 (s, 2 H), 3.18 (t, 2 H), 2.68 (t, 2 H), 2.55 (s, 3 H), 2.35 (t, 2 H), 2.2 (s, 3 H), 1.5 (m, 2 H)

[0346] Step A6: Preparation of ethyl (2E)-3-[1-(2-{[3-(benzyloxy)propyl](methyl)amino}ethyl)-4-methyl-1H-benzotriazol-5-yl]prop-2-enoate Using General Procedure 2, Step 5, starting with 3-(benzyloxy)-N-[2-(5-bromo-4-methyl-1H-benzotriazol-1-yl)ethyl]-N-methylpropan-1-amine (1 equivalent) as reactant, the title compound was obtained (93% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8 (d, 1 H), 7.91 (d, 1 H), 7.7 (d, 1 H), 7.3 (t, 2 H), 7.22 (t, 1 H), 7.19 (d, 2 H), 6.61 (d, 1 H), 4.77 (t, 2 H), 4.2 (q, 2 H), 4.18 (s, 2 H), 3.08 (t, 2 H), 2.82 (t, 2 H), 2.79 (s, 3 H), 2.31 (t, 2 H), 2.19 (s, 3 H), 1.42 (q, 2 H), 1.28 (t, 3 H)

[0347] Step 1: Preparation of ethyl 3-[1-(2-{[3-(benzyloxy)propyl](methyl)amino}ethyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propanoate Using general procedure 6 and starting with ethyl (2E)-3-[1-(2-{[3-(benzyloxy)propyl](methyl)amino}ethyl)-4-methyl-1H-benzotriazol-5-yl]prop-2-enoate (1 equivalent) and (1S)-1-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol (1 equivalent) as reactants, the title compound was obtained (33% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.59 (d, 1 H), 7.45 (d, 1 H), 7.41 (m, 1 H), 7.35 (d, 1 H), 7.31 (dd, 1 H), 7.22 (m, 2 H), 7.02 (m, 1 H), 6.97 (m, 2 H), 4.93 (d, 1 H), 4.82 (m, 1 H), 4.82 (m, 1 H), 4.7 (t, 2 H), 4.22 (s, 2 H), 3.91 (q, 2 H), 3.15 (m, 2 H), 3.15-3.05 (m, 2 H), 2.82 (t, 2 H), 2.75 (s, 3 H), 2.35 (t, 2 H), 2.19 (s, 3 H), 2.19 (s, 3 H), 1.47 (quint, 2 H), 1.21 (d, 3 H), 0.99 (t, 3 H)

[0348] Step 2: Ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(2-(3-benzoxathiazin-3(4H)-yl]ethyl)-4-methylphenyl)-3-[1-(2-{[3-(benzyloxy)propyl](methyl)amino}ethyl)-4-methyl-1H-benzotriazol-5-yl]propanoate Using General Procedure 7, reactants were ethyl 3-[1-[2-[3-benzyloxypropyl(methyl)amino]ethyl]-4-methyl-benzotriazol-5-yl]-3-[3-[(1S)-1-hydroxyethyl]-4-methyl-phenyl]propanoate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6 Starting with ,3-benzoxathiazine-2,2-dione (1.1 equivalents), the title compound was obtained (58% yield). LC-MS C 48 H 55 Calculated for N5O7S: 845; [M+H] + Actual value: 846

[0349] Step 3: Ethyl 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(2-((3-hydroxypropyl)methylamino)ethyl)-4-methylphenyl)-3-(1-(2-((3-hydroxypropyl)methylamino)ethyl)-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 8, the reactant was ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Starting from ,3-benzoxathiazin-3(4H)-yl]ethyl}-4-methylphenyl)-3-[1-(2-{[3-(benzyloxy)propyl](methyl)amino}ethyl)-4-methyl-1H-benzotriazol-5-yl]propanoate (1 equivalent), the title compound was obtained (yellow oil, 97% yield). LC-MS C 34 H 43 Calculated for N5O7S: 665; [M+H] + Actual value: 666

[0350] Step 4: Ethyl 3-(1-{2-[(3-bromopropyl)(methyl)amino]ethyl}-4-methyl-1H-benzotriazol-5-yl)-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Starting from 1-{2-[(3-hydroxypropyl)(methyl)amino]ethyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained as a white solid (20% yield). LC-MS C 34 H 42 Calculated for BrNOS: 727; [M+H] +Actual measurement: 728 / 730

[0351] Step 5: Ethyl [(2R)-2,4,19,33-tetramethyl-29,29-dioxo-23,28-dioxa-29λ] 6 -Thia-1,14,15,16,19-pentaazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 Preparation of ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetate Using general procedure 11, ethyl 3-(1-{2-[(3-bromopropyl)(methyl)amino]ethyl}-4-methyl-1H-benzotriazol-5-yl)-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ] as the reactant 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate gave the title compound (white solid, 99% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.74 / 7.63 (2d, 1 H), 7.73 / 7.48 (2d, 1 H), 7.58 (s, 1 H), 7.27 / 7.04 (2d, 1 H), 7.25 / 7.12 (d, 1 H), 7.01 / 6.93 (2d, 1 H), 6.84 / 6.73 (2d, 1 H), 6.37 / 5.81 (2sl, 1 H), 5.35 / 5.29 (2q, 1 H), 4.93 / 4.87 (2t, 1 H), 4.8 / 4.71 / 4.61 / 4.58 (4m, 2H), 4.24 / 4.02 / 3.98 / 3.87 (4d, 2 H), 3.91 (q, 2 H), 3.83 (m, 2 H), 3.34-3.13 / 3.02 (4dd, 2 H), 3.11 / 3.06 / 2.86 / 2.72 (4m, 2 H), 2.84 (2s, 3 H), 2.59-2.46 / 2.4 (2m, 2 H), 2.29 (s, 3 H), 2.19 / 2.13 (2sl, 3 H), 1.85 (m, 2 H), 1.52 / 1.27 (2d, 3 H), 1.01 (2d, 3 H)

[0352] Step 6: Preparation of Example 21 Using General Procedure 12, ethyl [(2R)-2,4,19,33-tetramethyl-29,29-dioxo-23,28-dioxa-29λ] was used as the reactant. 6 -Thia-1,14,15,16,19-pentaazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 Starting from ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 83% yield).

[0353] The diastereomeric pure products were obtained by chromatographic separation on a chiral column.

[0354] Example 21a (2R,8S) HRMS C32 H 37 Calculated for N5O6S: 619.2464; [M+H] + Measured value: 620.2538 (δ=0.1 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.05 (m, 1 H), 7.71 (m, 2 H), 7.55 (d, 1 H), 7.29 (dd, 1 H), 7.12 (d, 1 H), 7 (d, 1 H), 6.81 (dd, 1 H), 6.38 (d, 1 H), 5.35 (q, 1 H), 4.85 (t, 1 H), 4.78 / 4.58 (2m, 2 H), 4.21 / 3.95 (2d, 2 H), 3.82 (m, 2 H), 3.1 / 3 (2dd, 2 H), 3.05 / 2.7 (2m, 2 H), 2.81 (s, 3H), 2.55 (m, 2H), 2.3 (s, 3 H), 2.15 (s, 3 H), 1.82 (m, 2 H), 1.5 (d, 3 H)

[0355] Example 21b (2R,8R) HRMS C 32 H 37 Calculated for N5O6S: 619.2464; [M+H] + Measured value: 620.2576 (δ=6.2 ppm) 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.3 (m, 1 H), 7.65 / 7.22 (2d, 2 H), 7.5 (dd, 1 H), 7.22 (d, 1 H), 7 (d, 1 H), 6.95 (d, 1 H), 6.72 (dd, 1 H), 5.82 (d, 1 H), 5.3 (q, 1 H), 4.91 (t, 1 H), 4.7 / 4.6 (2m, 2 H), 4.02 / 3.85 (2d, 2 H), 3.48 / 3.32 (2m, 2 H), 3.1 (m, 2 H), 2.88 (m, 2 H), 2.81 (s, 3 H), 2.4 (t, 2 H), 2.3 (s, 3 H), 2.2 (s, 3 H), 1.68 (m, 2 H), 1.25 (d, 3 H)

[0356] Example 22 : [23-chloro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0357] Step C1: Preparation of 5-(benzyloxy)-4-chloro-2-hydroxybenzaldehyde Using General Procedure 4, Step 1, starting with 4-(benzyloxy)-3-chlorophenol (1 equivalent) as reactant, the title compound was obtained in 45% yield. 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 10.66 (s, 1 H), 10.22 (s, 1 H), 7.49-7.3 (m, 5 H), 7.38 (s, 1 H), 7.12 (s, 1 H), 5.16 (s, 2 H)

[0358] Step C2: 6-(benzyloxy)-7-chloro-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-2,2-dione Using General Procedure 4, Step 2, starting with 5-(benzyloxy)-4-chloro-2-hydroxybenzaldehyde (1 equivalent) as reactant, the title compound was obtained in 91% yield. 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 9.16 (s, 1 H), 7.93 (s, 1 H), 7.92 (s, 1 H), 7.53-7.34 (m, 5 H), 5.28 (s, 2 H)

[0359] Step C3: 6-(benzyloxy)-7-chloro-3,4-dihydro-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-2,2-dione Using General Procedure 4, Step 3, 6-(benzyloxy)-7-chloro-2H-1,2λ as the reactant 6 Starting with 1 equiv. of 1,3-benzoxathiazine-2,2-dione, the title compound was obtained (quantitative). 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 8.5 (br., 1 H), 7.47 (dm, 2 H), 7.41 (tm, 2 H), 7.35 (tm, 1 H), 7.34 (s, 1 H), 7.25 (s, 1 H), 5.17 (s, 2 H), 4.52 (s, 2H)

[0360] Step 1: Ethyl 3-(3-{[6-(benzyloxy)-7-chloro-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(4-(4-benzoxathiazin-3(4H)-yl]methyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, reactants were ethyl 3-[3-(hydroxymethyl)-4-methylphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent) and 6-(benzyloxy)-7-chloro-3,4-dihydro-2H-1,2λ. 6 Starting with ,3-benzoxathiazine-2,2-dione (1.4 eq.), the title compound was obtained (yellow oil, 50% yield). 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 7.57 (d, 1 H), 7.51-7.33 (m, 5 H), 7.48 (d, 1 H), 7.45 (s, 1 H), 7.26 (s, 1 H), 7.26 (d, 1 H), 7.19 (dd, 1 H), 7.18 (dm, 2 H), 7.13 (d, 1 H), 6.86 (dm, 2 H), 5.16 (s, 2 H), 4.85 (t, 1 H), 4.62 (t, 2 H), 4.49 / 4.44 (d+d, 2 H), 4.29 (s, 2 H), 4.27 / 4.21 (d+d, 2 H), 3.91 (q, 2 H), 3.72 (s, 3 H), 3.35 (t, 2 H), 3.2 / 3.16 (dd+dd, 2 H), 2.77 (s, 3 H), 2.2 (s, 3 H), 1.89 (m, 2 H), 1.45 (m, 2 H), 0.96 (t, 3 H)

[0361] Step 2: Ethyl 3-{3-[(7-chloro-6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of {1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl}propanoate Using general procedure 8, the reactant was ethyl 3-[3-[(6-benzyloxy-7-chloro-2,2-dioxo-4H-1,2λ 6Starting from]-3-[1-[4-[(4-methoxyphenyl)methoxy]butyl]-4-methyl-benzotriazol-5-yl]propanoate (1 equivalent), the title compound was obtained (yellow oil, 74% yield). 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 10.48 (brs, 1 H), 7.61 (d, 1 H), 7.51 (d, 1 H), 7.31 (s, 1 H), 7.27 (d, 1 H), 7.19 (dd, 1 H), 7.13 (d, 1 H), 6.85 (s, 1 H), 4.83 (t, 1 H), 4.64 (t, 2 H), 4.45 / 4.42 (d+d, 2 H), 4.43 (brs, 1 H), 4.25 / 4.2 (d+d, 2 H), 3.93 (q, 2 H), 3.37 (t, 2 H), 3.17 (d, 2 H), 2.76 (s, 3 H), 2.22 (s, 3 H), 1.9 (m, 2 H), 1.35 (m, 2 H), 0.99 (t, 3 H)

[0362] Step 3: Ethyl [23-chloro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 10, ethyl 3-{3-[(7-chloro-6-hydroxy-2,2-dioxo-2H-1,2λ] as the reactant 6,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}-3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]propanoate (1 equivalent), to prepare ethyl 3-[1-(4-chlorobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(7-chloro-6-hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate (yellow solid foam, quantitative), which was reacted in the next step without further purification using general procedure 11. The title compound (white solid) was obtained (yield 64%). 1 H-NMR (500 MHz, DMSO-d6) δppm: 7.68 (d, 1 H), 7.47 (dd, 1 H), 7.47 (d, 1 H), 7.35 (s, 1 H), 7.27 (d, 1 H), 6.67 (d, 1 H), 6.1 (s, 1 H), 4.85 / 4.74 (dm+dm, 2 H), 4.77 (t, 1 H), 4.27 / 3.9 (d+d, 2 H), 4 / 3.76 (d+d, 2 H), 3.92 (q, 2 H), 3.7 / 3.44 (m+m, 2 H), 3.13 / 3.06 (dd+dd, 2 H), 2.64 (s, 3 H), 2.31 (s, 3 H), 2.22 / 1.99 (m+m, 2 H), 1.82 / 1.62 (m+m, 2 H), 1.01 (t, 3 H)

[0363] Step 4: [23-chloro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid Using general procedure 12, ethyl [23-chloro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Starting from ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 94% yield).

[0364] The enantiopure products were obtained by chromatographic separation on a chiral column.

[0365] Example 22a (E1) HRMS C 29 H 29 Calculated for ClN4O6S: 596.1497; [M+H] + Measured value: 597.1564 (δ=-0.9 ppm)

[0366] Example 22b (E2) HRMS C 29 H 29 Calculated for ClN4O6S: 596.1497; [M+H] + Measured value: 597.1549 (δ=-3.4 ppm) 1H-NMR (500 MHz, DMSO-d6) δ ppm: 12.23 (brs, 1 H), 7.68 (d, 1 H), 7.48 (dd, 1 H), 7.46 (d, 1 H), 7.35 (s, 1 H), 7.27 (d, 1 H), 6.65 (d, 1 H), 6.09 (s, 1 H), 4.85 / 4.74 (m+m, 2 H), 4.75 (m, 1 H), 4.26 / 3.91 (d+d, 2 H), 4.01 / 3.77 (d+d, 2 H), 3.69 / 3.42 (m+m, 2 H), 3.02 / 2.96 (dd+dd, 2 H), 2.64 (s, 3 H), 2.31 (s, 3 H), 2.22 / 2.01 (m+m, 2 H), 1.83 / 1.63 (m+m, 2 H) 13 C-NMR (125 MHz, DMSO-d6) δ ppm: 131.3, 131.2, 128.7, 127.2, 120.1, 111.5, 107.9, 68.7, 52.1, 48.7, 48.1, 41.8, 40.9, 26.7, 25.5, 18.5, 13.4

[0367] Example 23 : [(2R,8R)-24-methoxy-2,4,31-trimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid and [(2R,8S)-24-Methoxy-2,4,31-trimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0368] Step 1: Ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-8-methoxy-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(4-(4-benzoxathiazin-3(4H)-yl]ethyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, reactants ethyl 3-{3-[(1R)-1-hydroxyethyl]-4-methylphenyl}-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent) and 6-(benzyloxy)-8-methoxy-3,4-dihydro-2H-1,2λ were used. 6 Starting with ,3-benzoxathiazine-2,2-dione (1.05 equivalents), the title compound was obtained (79% yield). 1H-NMR (400 MHz, DMSO-d6) δppm: 0.88 - 1.05 (m, 14 H) 1.13 - 1.30 (m, 10 H) 1.36 - 1.49 (m, 20 H) 1.82 - 1.94 (m, 9 H) 2.27 (s, 11 H) 2.74 - 2.81 (m, 11 H) 3.12 - 3.26 (m, 8 H) 3.34 (q, J=6.15 Hz, 8 H) 3.72 (s, 13 H) 3.81 (s, 11 H) 3.92 (q, J=7.09 Hz, 8 H) 4.23 - 4.36 (m, 11 H) 4.39 (s, 4H) 4.55 - 4.65 (m, 8 H) 4.87 (t, J=7.76 Hz, 4 H) 5.01 - 5.14 (m, 7 H) 5.21 - 5.30 (m, 3 H) 6.35 (d, J=2.57 Hz, 1 H) 6.42 (d, J=2.57 Hz, 1 H) 6.72 - 6.78 (m, 1 H) 6.86 (d, J=8.56 Hz, 2 H) 7.07 - 7.14 (m, 2 H) 7.17 (d, J=8.56 Hz, 2 H) 7.28 - 7.38 (m, 1 H) 7.38 - 7.44 (m, 3 H) 7.44 - 7.49 (m, 2 H) 7.49 - 7.55 (m, 1 H) 7.56 - 7.62 (m, 1 H)

[0369] Step 2: Ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2λ] 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate Using General Procedure 8, the reactant was ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-8-methoxy-2,2-dioxo-2H-1,2λ 6Starting from 1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained as a yellow solid (98% yield). 1 H-NMR (400 MHz, DMSO-d6) δppm: 0.92 - 1.06 (m, 6 H) 1.10 - 1.48 (m, 13 H) 1.90 (quin, J=7.18 Hz, 4 H) 2.27 (s, 5 H) 2.70 - 2.79 (m, 5 H) 3.22 (d, J=7.70 Hz, 3 H) 3.34 - 3.42 (m, 4 H) 3.77 (s, 5 H) 3.88 - 3.99 (m, 3 H) 4.27 (d, J=5.26 Hz, 1 H) 4.33 (d, J=2.32 Hz, 1 H) 4.37 - 4.46 (m, 1H) 4.65 (t, J=6.97 Hz, 2 H) 4.80 - 4.94 (m, 1 H) 5.24 (q, J=6.77 Hz, 1 H) 6.10 (d, J=2.45 Hz, 1 H) 6.15 (d, J=2.57 Hz, 1 H) 6.40 - 6.49 (m, 1 H) 6.76 - 6.84 (m, 1 H) 7.04 - 7.16 (m, 3 H) 7.45 (d, J=10.15 Hz, 1 H) 7.53 - 7.59 (m, 1 H) 7.59 - 7.66 (m, 1 H) 9.60 - 9.65 (m, 1 H)

[0370] Step 3: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2λ] 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2λ]. 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate gave the title compound (65% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 1.00 (q, J=6.89 Hz, 5 H) 1.35 - 1.46 (m, 3 H) 1.77 (quin, J=7.03 Hz, 3 H) 1.94 - 2.05 (m, 5 H) 2.27 (s, 4 H) 2.76 (s, 4 H) 3.22 (d, J=7.70 Hz, 3 H) 3.53 (t, J=6.66 Hz, 3 H) 3.76 (s, 4 H) 3.94 (qd, J=7.09, 2.32 Hz, 3 H) 4.23 - 4.37 (m, 2 H) 4.69 (t, J=6.79Hz, 3H) 4.81 - 4.94 (m, 2 H) 5.24 (d, J=6.72 Hz, 1 H) 6.03 - 6.18 (m, 2 H) 6.34 - 6.51 (m, 2 H) 6.96 - 7.22 (m, 3 H) 7.44 (d, J=11.37 Hz, 1 H) 7.52 - 7.68 (m, 3 H) 9.63 (d, J=5.14 Hz, 1 H)

[0371] Step 4: Ethyl [(2R)-24-methoxy-2,4,31-trimethyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate gave the title compound (white solid, 69% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 0.92 - 1.06 (m, 11 H) 1.11 (d, J=6.85 Hz, 4 H) 1.27 (d, J=6.85 Hz, 8 H) 1.54 - 1.92 (m, 8 H) 2.00 - 2.22 (m, 7 H) 2.23 - 2.36 (m, 13 H) 2.66 (s, 7 H) 2.81 (s, 4 H) 2.92 - 3.15 (m, 5 H) 3.33 - 3.50 (m, 7 H) 3.59 - 3.79 (m, 14 H) 3.83 - 4.00 (m, 10H) 4.64 - 4.99 (m, 11 H) 5.15 - 5.31 (m, 5 H) 5.37 (br. s., 1 H) 6.46 (dd, J=19.93, 2.45 Hz, 3 H) 6.73 (s, 1 H) 7.08 - 7.25 (m, 4 H) 7.30 (d, J=8.07 Hz, 1 H) 7.44 (d, J=7.70 Hz, 3 H) 7.68 (d, J=8.68 Hz, 1 H) 7.75 (d, J=8.80 Hz, 1 H) 7.89 (d, J=8.80 Hz, 1 H)

[0372] Step 5: Preparation of Example 23 Using General Procedure 12, ethyl [(2R)-24-methoxy-2,4,31-trimethyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29Starting from ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent), the title compound was obtained (72% yield).

[0373] The enantiopure products were obtained by chromatographic separation on a chiral column.

[0374] Example 23a (2R,8R) HRMS C 31 H 34 Calculated for N4O7S: 606.2148; [M+H] + Measured value: 607.2223 (δ=0.3 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12 (sl, 1 H), 7.69 (d, 1 H), 7.44 (dd, 1 H), 7.39 (d, 1 H), 7.09 (d, 1 H), 6.72 (d, 1 H), 6.42 (d, 1 H), 5.38 (dl, 1 H), 5.21 (q, 1 H), 4.89 (t, 1 H), 4.76 (m, 2 H), 4.02 / 3.4 (2*d, 2 H), 3.7 (m, 2 H), 3.7 (s, 3 H), 3.28 / 2.87 (dd, 2 H), 2.81 (s, 3 H), 2.31 (s, 3 H), 2.2 / 2 (m, 2 H), 1.61 / 1.28 (m, 2H), 1.11 (d, 3H)

[0375] Example 23b (2R,8S) HRMS C 31 H 34 Calculated for N4O7S: 606.2148; [M+H] + Measured value: 607.2224 (δ=0.5 ppm) 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (sl, 1 H), 7.88 / 7.74 (d, 2 H), 7.44 (dd, 1 H), 7.2 (d, 1 H), 7.11 (d, 1 H), 6.49 (d, 1 H), 5.23 (q, 1 H), 5.19 (d, 1 H), 4.8-4.67 (m, 1 H), 4.8-4.67 (m, 2 H), 3.99 / 3.36 (d, 2 H), 3.73 (s, 3 H), 3.63 / 3.41 (m, 2 H), 3.28 / 2.96 (dd, 2 H), 2.64 (s, 3H), 2.29 (s, 3H), 2.18 / 2.09 (m, 2 H), 1.87 / 1.74 (m, 2 H), 1.27 (d, 3 H)

[0376] Example 24 : [(2R,8S)-18-(2-methoxyethyl)-2,4,31-trimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid and [(2R,8R)-18-(2-methoxyethyl)-2,4,31-trimethyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0377] Step A1: Preparation of 2-[2-(benzyloxy)ethyl]-4-methoxybutanenitrile To a solution of 4-methoxybutanenitrile (6.88 g, 69.4 mmol) in anhydrous THF (1 mL / mmol, 70 mL) was added lithium trimethyl-N-(trimethylsilyl)silane aminide (1.2 equiv., 1 M in THF, 83.3 mL, 83.3 mmol) dropwise at −78 °C with continuous stirring. [(2-iodoethoxy)methyl]benzene (1.2 equiv., 21.8 g, 83.3 mmol) dissolved in THF (35 mL) was added dropwise at −78 °C. The reaction mixture was allowed to warm to room temperature and stirred overnight. After completion of the reaction, the mixture was quenched with water. EtOAc (200 mL) was added and the layers were separated. The organic layer was washed with brine (150 mL) and dried over anhydrous Na2SO4. Filtration and concentration to dryness gave the crude product, which was purified by normal phase silica gel chromatography with heptane-EtOAc (100:0 to 70:30) as eluent to give the title compound (8.1 g, 50% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.4-7.25 (m, 5 H), 4.5 (s, 2 H), 3.55 (m, 2 H), 3.45 (m, 2 H), 3.25 (s, 3 H), 2.95 (m, 1 H), 1.9-1.7 (m, 4 H)

[0378] Step A2: Preparation of 2-[2-(benzyloxy)ethyl]-4-methoxybutan-1-amine Lithium aluminum hydride (1 equivalent, 1.3 g, 35 mmol) was placed in a round-bottom flask. After the addition of anhydrous THF (70 ml), the mixture was cooled to 10° C. A solution of 2-[2-(benzyloxy)ethyl]-4-methoxybutanenitrile (8.1 g, 35 mmol) in anhydrous THF (70 mL) was added dropwise at 10° C. with continuous stirring over 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for an additional 3 hours. After completion of the reaction, the mixture was cooled to 10° C. and quenched with aqueous NaSO solution. The mixture was stirred at room temperature overnight and filtered. The filter cake was washed with THF. The mother liquor was concentrated to dryness to give the title compound (8.3 g, 96% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.39-7.22 (m, 5 H), 4.44 (s, 2 H), 3.45 (t, 2 H), 3.32 (t, 2 H), 3.19 (s, 3 H), 2.46 (d, 2 H), 1.68-1.37 (m, 5 H), 1.44-1.14 (m, 2 H)

[0379] Step A3: Preparation of N-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-3-methyl-2-nitroaniline Using General Procedure 2 Step 1, starting with 1-fluoro-3-methyl-2-nitro-benzene (1 equivalent) and 2-[2-(benzyloxy)ethyl]-4-methoxybutan-1-amine (1.2 equivalents) as reactants, the title compound was obtained (50% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.3 (m, 5 H), 7.2 (t, 1 H), 6.75 (d, 1 H), 6.5 (d+t, 2 H), 4.45 (s, 2 H), 3.5 (m, 2 H), 3.4 (m, 2 H), 3.2 (s, 3 H), 3.15 (m, 2 H), 2.3 (s, 3 H), 1.9 (sept., 1 H), 1.55 (m, 4 H)

[0380] Step A4: Preparation of N-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-4-bromo-3-methyl-2-nitroaniline Using General Procedure 2, Step 2, starting with N-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-3-methyl-2-nitroaniline (1 equivalent) as reactant, the title compound was obtained (62% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.42 (d, 1 H), 7.31 (t, 2 H), 7.28 (d+t, 3 H), 6.7 (d, 1 H), 6.2 (t), 4.43 (s, 2 H), 3.5 (m, 2 H), 3.35 (m, 2 H), 3.2 (s, 3 H), 3.1 (m, 2 H), 2.25 (s, 3 H), 1.88 (m, 1 H), 1.64-1.42 (m, 4 H)

[0381] Process A5: N 1 Preparation of -{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-4-bromo-3-methylbenzene-1,2-diamine Using General Procedure 2, Step 3, starting with N-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-4-bromo-3-methyl-2-nitroaniline (1 equivalent) as reactant, the title compound (quantitative) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.3 (m, 5 H), 6.69 (d, 1 H), 6.25 (d, 1 H), 4.68 (m, 3 H), 4.45 (s, 2 H), 3.5 (m, 2 H), 3.4 (m, 2 H), 3.2 (s, 3 H), 2.98 (d, 2 H), 2.19 (s, 3 H), 1.9 (m, 1 H), 1.75-1.5 (m, 4 H)

[0382] Step A6: Preparation of 1-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-5-bromo-4-methyl-1H-benzotriazole Using General Procedure 2, Step 4, N 1 Starting with -{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-4-bromo-3-methylbenzene-1,2-diamine (1 equivalent), the title compound was obtained (78% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.69 (d, 1 H), 7.6 (d, 1 H), 7.35-7.2 (m, 5 H), 4.68 (d, 2 H), 4.39 (m, 2 H), 3.48 (m, 2 H), 3.35 (m, 2 H), 3.18 (s, 3 H), 2.71 (s, 3 H), 2.3 (m, 1 H), 1.6-1.4 (m, 4 H)

[0383] Step A7: Preparation of ethyl (2E)-3-(1-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate Using General Procedure 2, Step 5, starting with 1-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-5-bromo-4-methyl-1H-benzotriazole (1 equivalent) as reactant, the title compound was obtained (34% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8.02 (d, 1 H), 7.95 (d, 1 H), 7.65 (d, 1 H), 7.35-7.2 (m, 5 H), 6.65 (d, 1 H), 4.68 (d, 2 H), 4.4 (s, 2 H), 4.22 (q, 2 H), 3.49 (m, 2 H), 3.35 (m, 2 H), 3.19 (s, 3 H), 2.8 (s, 3 H), 2.3 (m, 1 H), 1.6-1.4 (m, 4 H), 1.3 (t, 3 H)

[0384] Step 1: Preparation of ethyl 3-(1-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-4-methyl-1H-benzotriazol-5-yl)-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propanoate Using general procedure 6 and starting with ethyl (2E)-3-(1-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equivalent) and (1S)-1-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1-ol (1.2 equivalents) as reactants, the title compound was obtained (83% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.5 (d, 1 H), 7.45 (2d, 1 H), 7.4 (d, 1 H), 7.32-7.2 (m, 5 H), 7.05 (2dd, 1 H), 6.98 (2d, 1 H), 4.99 (2d, 1 H), 4.81 (m, 2 H), 4.6 (d, 2 H), 4.4 (s, 2 H), 3.92 (q, 2 H), 3.48 (2t, 2 H), 3.3 (m, 2 H), 3.12 (s, 3 H), 3.1 (m, 2 H), 2.78 (s, 3 H), 2.28 (m, 1 H), 2.19 (s, 3 H), 1.6-1.4 (m, 4 H), 1.22 (2d, 3 H), 1 (t, 3 H)

[0385] Step 2: Ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(2-benzoxathiazin-3(4H)-yl]ethyl)-4-methylphenyl)-3-(1-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, the reactants were ethyl 3-(1-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-4-methyl-1H-benzotriazol-5-yl)-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propanoate (1 equivalent) and 6-(benzyloxy)-8-methoxy-3,4-dihydro-2H-1,2λ. 6 Starting with ,3-benzoxathiazine-2,2-dione (1.1 equivalents), the title compound was obtained (59% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6-7.2 (m, 15 H), 7.12-6.95 (m, 2 H), 6.9 / 6.85 (2d, 1 H), 5.28 (m, 1 H), 5.1 (2s, 2 H), 4.9 (m, 1 H), 4.6 (d, 2 H), 4.45-4.3 (m, 4 H), 3.9 (q, 2 H), 3.45 (m, 2 H), 3.3 / 3.2 (2m, 5 H), 3.1 (m, 2 H), 2.8 / 2.3 (s, 6 H), 2.28 (m, 1 H), 1.5 (m, 4 H), 1.4 (d, 3 H), 1.22 (t, 3 H)

[0386] Step 3: Preparation of ethyl 3-[3-[(1R)-1-(6-hydroxy-2,2-dioxo-4H-1,2λ6,3-benzoxathiazin-3-yl)ethyl]-4-methyl-phenyl]-3-[1-[2-(2-hydroxyethyl)-4-methoxy-butyl]-4-methyl-benzotriazol-5-yl]propanoate Using General Procedure 8, the reactant was ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Starting from 1-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained (81% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.6 / 4.35 (s+t, 2 H), 7.6 (m, 2 H), 7.5 (d, 1 H), 7.12 (m, 2 H), 6.91 (d, 1 H), 6.75 (dd, 1 H), 6.6 / 6.55 (2d, 1 H), 5.25 (q, 1 H), 4.9 (m, 1 H), 4.6 (d, 2 H), 4.35 (m, 2 H), 3.92 (q, 2 H), 3.45 (m, 4 H), 3.21 (d, 2 H), 3.12 (s, 3 H), 2.8 (s, 3 H), 2.3 (s, 3 H), 2.25 (m, 1 H), 1.5-1.3 (m, 4 H), 1.45 (d, 3 H), 1.2 (t, 3 H)

[0387] Step 4: Ethyl 3-{1-[2-(2-bromoethyl)-4-methoxybutyl]-4-methyl-1H-benzotriazol-5-yl}-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate Using general procedure 9 and starting with ethyl 3-[3-[(1R)-1-(6-hydroxy-2,2-dioxo-4H-1,2λ6,3-benzoxathiazin-3-yl)ethyl]-4-methyl-phenyl]-3-[1-[2-(2-hydroxyethyl)-4-methoxy-butyl]-4-methyl-benzotriazol-5-yl]propanoate (1 equivalent) as reactant, the title compound was obtained (39% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.6 (s, 1 H), 7.6 (d, 1 H), 7.55 (d, 1 H), 7.45 (2d, 1 H), 7.11 (m, 2 H), 6.9 (d, 1 H), 6.71 (dd, 1 H), 6.59 (2d, 1 H), 5.28 (q, 1 H), 4.9 (m, 1 H), 4.61 (d, 2 H), 4.4-4.3 (m, 2 H), 3.92 (q, 2 H), 3.58 (m, 2 H), 3.3 (m, 2 H), 3.21 (d, 2 H), 3.15 (s, 3H), 2.78 (s, 3H), 2.3 (m, 1 H), 2.28 (s, 3 H), 1.9-1.7 (2m, 2 H), 1.5 (m, 2 H), 1.4 (d, 3 H), 1 (2t, 3 H)

[0388] Step 5: Preparation of Example 24 Using general procedure 11, the reactant was ethyl 3-{1-[2-(2-bromoethyl)-4-methoxybutyl]-4-methyl-1H-benzotriazol-5-yl}-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate (1 equivalent), to prepare ethyl [(2R)-18-(2-methoxyethyl)-2,4,31-trimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (white solid, 57% yield). The crude product was reacted using general procedure 12 to give the title compound (quantitative).

[0389] The diastereomeric pure products were obtained by chromatographic separation on a chiral column.

[0390] Example 24a (2R,8S dia 1) HRMS C 33 H 38 Calculated for N4O7S: 634.246; [M+H] + Actual value: 635.2534 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (ml, 1 H), 7.79 (d, 1 H), 7.61 (d, 1 H), 7.45 (dd, 1 H), 7.22 (d, 1 H), 7.02 (d, 1 H), 6.9 (d, 1 H), 6.7 (dd, 1 H), 5.4 (d, 1 H), 5.22 (q, 1 H), 4.79 (dd, 1 H), 4.75 / 4.6 (2dd, 2 H), 4.12 / 3.4 (2d, 2 H), 3.58 (m, 3 H), 3.3 (s, 3 H), 3.2-3 (m, 2 H), 2.9 (dd, 1 H), 2.6 (s, 3 H), 2.3 (s, 3 H), 1.9-1.7 (m, 5 H), 1.2 (d, 3 H)

[0391] Example 24b (2R,8S dia 2) HRMS C 33 H 38 Calculated for N4O7S: 634.246; [M+H] + Actual value: 635.2534 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (ml, 1 H), 7.89 (d, 1 H), 7.78 (d, 1 H), 7.45 (dd, 1 H), 7.21 (d, 1 H), 7.04 (d, 1 H), 6.95 (d, 1 H), 6.75 (dd, 1 H), 5.4 (d, 1 H), 5.25 (q, 1 H), 4.79 (dd, 1 H), 4.61 / 4.55 (2dd, 2 H), 4.05 / 3.35 (2d, 2 H), 3.55 (t, 2 H), 3.45 (m, 1 H), 3.3 (m, 4 H), 3.1 / 2.9 (2m, 2 H), 2.6 (s, 3 H), 2.3 (s, 3 H), 1.9 - 1.7 (m, 5 H), 1.2 (d, 3 H)

[0392] Example 24c (2R,8R dia 1) HRMS C 33 H 38 Calculated value of C + Measured value: 635.2536 (δ = 0.3 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.49 (dd, 1 H), 7.28 (d, 1 H), 7.2 (d, 1 H), 6.9 (d, 1 H), 6.89 (d, 1 H), 6.7 (dd, 1 H), 5.6 (d, 1 H), 5.26 (q, 1 H), 4.9 (dd, 1 H), 4.7 / 4.6 (2dd, 2 H), 4.1 / 3.55 (2d, 2 H), 3.6 - 3.35 (m, 4 H), 3.3 (s, 3 H), 3.2 / 2.88 (2m, 2 H), 2.8 (s, 3 H), 2.3 (s, 3 H), 1.8 (m, 3 H), 1.68 / 1.5 (2m, 2 H), 1.2 (d, 3 H)

[0393] Example 24d (2R,8R dia 2) HRMS C 33 H 38Calculated for N4O7S: 634.246; [M+H] + Measured value: 635.2535 (δ=0.2 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.7 (d, 1 H), 7.49 (dd, 1 H), 7.31 (d, 1 H), 7.09 (d, 1 H), 6.91 (d, 1 H), 6.82 (d, 1 H), 6.7 (dd, 1 H), 5.65 (d, 1 H), 5.26 (q, 1 H), 4.95 (t, 1 H), 4.6 (m, 2 H), 4.05 / 3.6 (2d, 2 H), 3.6-3.35 (m, 4 H), 3.23 (s, 3 H), 3.15 / 2.82 (2m, 2 H), 2.8 (s, 3 H), 2.32 (s, 3 H), 1.88 / 1.78 (2m, 2H), 1.7 (m, 3H), 1.1 (d, 3H)

[0394] Example 25 : [23-Methoxy-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0395] Step C1: Preparation of 5-(benzyloxy)-2-hydroxy-4-methoxybenzaldehyde Using General Procedure 4, Step 1, starting with 4-(benzyloxy)-3-methoxyphenol (1 equivalent) as reactant, the title compound was obtained in 55% yield. 1H-NMR (500 MHz, DMSO-d6) δ ppm: 10.71 (s, 1 H), 10.02 (s, 1 H), 7.46-7.29 (m, 5 H), 7.24 (s, 1 H), 6.58 (s, 1 H), 5.03 (s, 2 H), 3.84 (s, 3 H)

[0396] Step C2: 6-(benzyloxy)-7-methoxy-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-2,2-dione Using General Procedure 4, Step 2, starting with 5-(benzyloxy)-2-hydroxy-4-methoxy-benzaldehyde (1 equivalent) as reactant, the title compound was obtained (67% yield). 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 8.96 (s, 1 H), 7.64 (s, 1 H), 7.5-7.33 (m, 5 H), 7.26 (s, 1 H), 5.14 (s, 2 H), 3.95 (s, 3 H)

[0397] Step C3: 6-(benzyloxy)-7-methoxy-3,4-dihydro-2H-1,2λ 6 Preparation of ,3-benzoxathiazine-2,2-dione Using General Procedure 4, Step 3, 6-(benzyloxy)-7-methoxy-2H-1,2λ as the reactant 6 Starting with ,3-benzoxathiazine-2,2-dione (1 equivalent) gave the title compound (white solid, 98% yield). 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 8.4 (t, 1 H), 7.52-7.29 (m, 5 H), 6.98 (s, 1 H), 6.76 (s, 1 H), 5.04 (s, 2 H), 4.42 (d, 2 H), 3.76 (s, 3 H)

[0398] Step 1: Ethyl 3-(3-{[6-(benzyloxy)-7-methoxy-2,2-dioxo-2H-1,2λ6 Preparation of 1-(4-(4-benzoxathiazin-3(4H)-yl]methyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, reactants were ethyl 3-[3-(hydroxymethyl)-4-methylphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent) and 6-(benzyloxy)-7-methoxy-3,4-dihydro-2H-1,2λ. 6 Starting with ,3-benzoxathiazine-2,2-dione (1.2 equivalents), the title compound was obtained (white solid, 74% yield). 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 7.57 (d, 1 H), 7.48 (d, 1 H), 7.48-7.31 (m, 5 H), 7.22 (d, 1 H), 7.19 (dd, 1 H), 7.18 (m, 2 H), 7.13 (d, 1 H), 6.99 (s, 1 H), 6.88 (s, 1 H), 6.86 (m, 2 H), 5.03 (s, 2 H), 4.85 (t, 1 H), 4.62 (t, 2 H), 4.38 / 4.34 (d+d, 2 H), 4.29 (s, 2 H), 4.22 / 4.18 (d+d, 2 H), 3.91 (q, 2 H), 3.8 (s, 3 H), 3.72 (s, 3 H), 3.35 (t, 2 H), 3.19 / 3.16 (dd+dd, 2 H), 2.76 (s, 3 H), 2.2 (s, 3 H), 1.89 (m, 2 H), 1.44 (m, 2 H), 0.97 (t, 3 H)

[0399] Step 2: Ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-7-methoxy-2,2-dioxo-2H-1,2λ 6Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate Using general procedure 8, the reactant was ethyl 3-(3-{[6-(benzyloxy)-7-methoxy-2,2-dioxo-2H-1,2λ 6 Starting from 1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound (quantitative) was obtained. 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 9.26 (s, 1 H), 7.61 (d, 1 H), 7.5 (d, 1 H), 7.2 (s, 1 H), 7.19 (dd, 1 H), 7.13 (d, 1 H), 6.8 (s, 1 H), 6.6 (s, 1 H), 4.83 (t, 1 H), 4.65 (t, 2 H), 4.63 (t, 1 H), 4.3 (s, 2 H), 4.19 / 4.16 (d+d, 2 H), 3.93 (q, 2 H), 3.79 (s, 3 H), 3.37 (m, 2 H), 3.18 / 3.14 (dd+dd, 2 H), 2.75 (s, 3 H), 2.21 (s, 3 H), 1.9 (m, 2 H), 1.35 (m, 2 H), 1 (t, 3 H)

[0400] Step 3: Ethyl 3-[1-(4-chlorobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-7-methoxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate hydrochloride Using general procedure 10, the reactant was ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-7-methoxy-2,2-dioxo-2H-1,2λ] 6Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate gave the title compound (quantitative). 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 9.26 (s, 1 H), 7.63 (d, 1 H), 7.52 (d, 1 H), 7.2 (m, 1 H), 7.2 (m, 1 H), 7.13 (d, 1 H), 6.8 (s, 1 H), 6.59 (s, 1 H), 4.83 (t, 1 H), 4.69 (t, 2 H), 4.3 (s, 2 H), 4.19 / 4.15 (d+d, 2 H), 3.93 (q, 2 H), 3.79 (s, 3 H), 3.64 (t, 2 H), 3.19 / 3.15 (dd+dd, 2 H), 2.75 (s, 3 H), 2.21 (s, 3 H), 1.99 (m, 2 H), 1.68 (m, 2 H), 0.99 (t, 3 H)

[0401] Step 4: Ethyl [23-methoxy-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-chlorobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-7-methoxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1,3-benzoxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate hydrochloride (1 equivalent) gave the title compound (white solid, 34% yield). 1H-NMR (500 MHz, DMSO-d6) δ ppm: 7.69 (d, 1 H), 7.47 (dd, 1 H), 7.46 (d, 1 H), 7.28 (d, 1 H), 6.75 (s, 1 H), 6.56 (d, 1 H), 5.77 (s, 1 H), 4.82 / 4.75 (m+m, 2 H), 4.78 (dd, 1 H), 4.18 / 3.87 (d+d, 2 H), 3.93 (q, 2 H), 3.93 / 3.69 (d+d, 2 H), 3.72 (s, 3 H), 3.56 / 3.3 (m+m, 2 H), 3.14 / 3.06 (dd+dd, 2 H), 2.61 (s, 3 H), 2.32 (s, 3 H), 2.2 / 2.02 (m+m, 2 H), 1.78 / 1.61 (m+m, 2 H), 1.01 (t, 3 H)

[0402] Step 5: Preparation of Example 25 Using general procedure 12, ethyl [23-methoxy-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Starting from ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 86% yield).

[0403] The enantiopure products were obtained by chromatographic separation on a chiral column.

[0404] Example 25a (E1, optical purity: 99.9%) HRMS C 30 H 32 Calculated for N4O7S: 592.1992; [M+H] + Measured value: 593.2048 (δ=-2.8 ppm)

[0405] Example 25b (E2, optical purity about 99.4%) HRMS C 30 H 32 Calculated for N4O7S: 592.1992; [M+H] + Measured value: 593.2047 (δ=-2.9 ppm) 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 12.54 (br., 1 H), 7.68 (d, 1 H), 7.48 (brd., 1 H), 7.45 (d, 1 H), 7.27 (d, 1 H), 6.74 (s, 1 H), 6.53 (brs., 1 H), 5.75 (s, 1 H), 4.81 / 4.74 (m+m, 2 H), 4.75 (m, 1 H), 4.16 / 3.87 (d+d, 2 H), 3.93 / 3.69 (d+d, 2 H), 3.72 (s, 3 H), 3.55 / 3.28 (m+m, 2 H), 2.99 / 2.92 (dd+dd, 2 H), 2.6 (s, 3 H), 2.32 (s, 3 H), 2.2 / 2.03 (m+m, 2 H), 1.78 / 1.61 (m+m, 2 H) 13 C-NMR (125 MHz, DMSO-d6) δ ppm: 173.3, 131.3, 131.3, 128.8, 127.3, 110.8, 107.9, 102.9, 68.3, 56.3, 51.9, 48.4, 48.2, 42, 41.3, 27, 25.6, 18.5, 13.4

[0406] Example 26 : [(2R,8S)-2,4,33-trimethyl-29,29-dioxo-20,23,28-trioxa-29λ 6 -Thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid and [(2R,8R)-2,4,33-trimethyl-29,29-dioxo-20,23,28-trioxa-29λ 6 -Thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid [ka]

[0407] Step A1: Preparation of N-{3-[2-(benzyloxy)ethoxy]propyl}-3-methyl-2-nitroaniline Using General Procedure 2, Step 1, starting with 1-fluoro-3-methyl-2-nitrobenzene (1 equivalent) and 3-[2-(benzyloxy)ethoxy]propan-1-amine hydrochloride (1.2 equivalents) as reactants, the title compound was obtained (85% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.38-7.27 (m, 5 H), 7.24 (dd, 1 H), 6.77 (d, 1 H), 6.54 (d, 1 H), 6.48 (t, 1 H), 4.49 (s, 2 H), 3.58 (m, 4 H), 3.5 (t, 2 H), 3.23 (q, 2 H), 2.3 (s, 3 H), 1.8 (quint, 2 H)

[0408] Step A2: Preparation of N-{3-[2-(benzyloxy)ethoxy]propyl}-4-bromo-3-methyl-2-nitroaniline Using General Procedure 2, Step 2, starting with N-{3-[2-(benzyloxy)ethoxy]propyl}-3-methyl-2-nitroaniline (1 equivalent) as reactant, the title compound was obtained (99% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.49 (d, 1 H), 7.38-7.25 (m, 5 H), 6.72 (d, 1 H), 6.18 (t, 1 H), 4.49 (s, 2 H), 3.6-3.5 (m, 4 H), 3.48 (t, 2 H), 3.2 (q, 2 H), 2.25 (s, 3 H), 1.77 (quint, 2 H)

[0409] Process A3: N 1 Preparation of -{3-[2-(benzyloxy)ethoxy]propyl}-4-bromo-3-methylbenzene-1,2-diamine Using General Procedure 2, Step 3, starting with N-{3-[2-(benzyloxy)ethoxy]propyl}-4-bromo-3-methyl-2-nitroaniline (1 equivalent) as reactant, the title compound (quantitative) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.37-7.24 (m, 5 H), 6.71 (d, 1 H), 6.27 (d, 1 H), 4.9-4.5 (m, 3 H), 4.49 (s, 2 H), 3.56 (m, 4 H), 3.52 (t, 2 H), 3.06 (t, 2 H), 2.16 (s, 3 H), 1.82 (m, 2 H)

[0410] Step A4: Preparation of 1-{3-[2-(benzyloxy)ethoxy]propyl}-5-bromo-4-methyl-1H-benzotriazole Using General Procedure 2, Step 4, N 1 Starting with -{3-[2-(benzyloxy)ethoxy]propyl}-4-bromo-3-methylbenzene-1,2-diamine (1 equivalent), the title compound was obtained (42% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 2.13 (quint, J=6.39 Hz, 2 H) 2.71 (s, 3 H) 3.35 (t, J=6.05 Hz, 2 H) 3.41 - 3.58 (m, 6 H) 4.43 - 4.47 (m, 3 H) 4.74 (t, J=6.72 Hz, 2 H) 7.20 - 7.37 (m, 9 H) 7.55 - 7.68 (m, 3 H)

[0411] Step A5: Preparation of ethyl (2E)-3-(1-{3-[2-(benzyloxy)ethoxy]propyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate Using General Procedure 2, Step 5, starting with 1-{3-[2-(benzyloxy)ethoxy]propyl}-5-bromo-4-methyl-1H-benzotriazole (1 equivalent) as reactant, the title compound was obtained (98% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8.01 (d, 1 H), 7.89 (d, 1 H), 7.69 (d, 1 H), 7.38-7.25 (m+m, 5 H), 6.61 (d, 1 H), 4.74 (t, 2 H), 4.47 (s, 2 H), 4.22 (q, 2 H), 3.54-3.47 (m+m, 4 H), 3.37 (t, 2 H), 2.8 (s, 3 H), 2.23 (quint, 2 H), 1.29 (t, 3 H)

[0412] Step 1: Preparation of ethyl 3-(1-{3-[2-(benzyloxy)ethoxy]propyl}-4-methyl-1H-benzotriazol-5-yl)-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propanoate Using general procedure 6 and starting with ethyl (2E)-3-(1-{3-[2-(benzyloxy)ethoxy]propyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equivalent) and (1S)-1-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1-ol (1 equivalent) as reactants, the title compound was obtained (59% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.56 (d, 1 H), 7.41 (d, 1 H), 7.39 (m, 1 H), 7.35-7.22 (m, 5 H), 7.02 (dd, 1 H), 6.99 (d, 1 H), 4.97 (m, 1 H), 4.82 (m, 1 H), 4.82 (m, 1 H), 4.68 (t, 2 H), 4.46 (s, 2 H), 3.92 (q, 2 H), 3.52 / 3.49 (m, 4 H), 3.35 (t, 2 H), 3.14-3.07 (m, 2 H), 2.75 (s, 3H), 2.19 (s, 3H), 2.1 (quint, 2 H), 1.21 (d, 3 H), 1 (t, 3 H)

[0413] Step 2: Ethyl 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(3-benzoxathiazin-3(4H)-yl)ethyl)-4-methylphenyl}-3-{1-[3-(2-hydroxyethoxy)propyl]-4-methyl-1H-benzotriazol-5-yl}propanoate Using General Procedure 7, the reactants were ethyl 3-(1-{3-[2-(benzyloxy)ethoxy]propyl}-4-methyl-1H-benzotriazol-5-yl)-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propanoate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6Starting from 1.1 equivalents of ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ]-benzoxathiazine-2,2-dione, 6 ,3-benzoxathiazin-3(4H)-yl]ethyl}-4-methylphenyl)-3-(1-{3-[2-(benzyloxy)ethoxy]propyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (orange oil, 84% yield). The crude product was reacted using general procedure 8 to give the title compound (white solid, 87% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.62 (m, 1 H), 7.64-7.54 (m, 2 H), 7.47 / 7.47 (2sl, 1 H), 7.14-7.08 (m, 2 H), 6.92 / 6.9 (2d, 1 H), 6.76-6.7 (m, 1 H), 6.57 (2d, 1 H), 5.25 (m, 1 H), 4.88 (q, 1 H), 4.7 (t, 2 H), 4.57 (m, 1 H), 4.36 / 4.31 (s+dd, 2 H), 3.95 (2d, 2 H), 3.47 (m, 2 H), 3.39-3.28 (m, 4 H), 3.22 (m, 2 H), 2.77 (s, 3 H), 2.28 (s, 3 H), 2.1 (m, 2 H), 1.43 / 1.41 (2d, 3 H), 1.01 / 1 (2t, 3 H)

[0414] Step 3: Ethyl 3-{1-[3-(2-bromoethoxy)propyl]-4-methyl-1H-benzotriazol-5-yl}-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6Starting from {1-[3-(2-hydroxyethoxy)propyl]-4-methyl-1H-benzotriazol-5-yl}propanoate (1 equivalent), the title compound was obtained as a white solid (60% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.55 (s, 1 H), 7.7-7.5 (2d, 2 H), 7.49 (2d, 1 H), 7.11 (m, 2 H), 6.91 (d, 1 H), 6.71 (2dd, 1 H), 6.48 (2d, 1 H), 5.28 (m, 1 H), 4.9 (m, 1 H), 4.7 (t, 2 H), 4.4-4.3 (m, 2 H), 3.95 (q, 2 H), 3.68 (t, 2 H), 3.55 (t, 2 H), 3.41 (t, 2 H), 3.21 (d, 2 H), 2.79 (s, 3 H), 2.3 (s, 3 H), 2.12 (m, 2H), 1.45 (2d, 3H), 1.02 (2t, 3H)

[0415] Step 4: Ethyl [(2R)-2,4,33-trimethyl-29,29-dioxo-20,23,28-trioxa-29λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 Preparation of ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetate Using general procedure 11, ethyl 3-{1-[3-(2-bromoethoxy)propyl]-4-methyl-1H-benzotriazol-5-yl}-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ] was used as the reactant. 6 Starting with 1 equiv. of 3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate gave the title compound (white solid, quantitative). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 1.01 (td, J=7.09, 4.16 Hz, 6 H) 1.18 (d, J=6.85 Hz, 2 H) 1.55 (d, J=6.85 Hz, 3 H) 2.18 (d, J=5.38 Hz, 3 H) 2.26 - 2.36 (m, 6 H) 2.79 (s, 2 H) 2.85 (s, 3 H) 2.95 (dd, J=15.77, 8.31 Hz, 1 H) 3.14 - 3.26 (m, 3 H) 3.39 - 3.54 (m, 3 H) 3.55 - 3.61 (m, 1 H) 3.61 - 3.73 (m, 2 H) 3.74 - 3.85 (m, 2 H) 3.87 - 3.98 (m, 5 H) 4.01 (d, J=6.60 Hz, 1 H) 4.08 (t, J=4.71 Hz, 2 H) 4.19 (d, J=17.73 Hz, 1 H) 4.35 (d, J=17.61 Hz, 1 H) 4.53 - 4.82 (m, 4 H) 4.83 - 4.96 (m, 2 H) 5.23 - 5.31 (m, 1 H) 5.33 - 5.42 (m, 1 H) 6.25 (d, J=2.81 Hz, 1 H) 6.50 (d, J=2.81Hz, 1 H) 6.78 - 6.94 (m, 2 H) 6.96 - 7.04 (m, 2 H) 7.10 (dd, J=19.38, 8.25 Hz, 2 H) 7.17 - 7.25 (m, 2 H) 7.42 (d, J=6.48 Hz, 1 H) 7.54 - 7.65 (m, 4H)

[0416] Step 5: Preparation of Example 26 Using General Procedure 12, ethyl [(2R)-2,4,33-trimethyl-29,29-dioxo-20,23,28-trioxa-29λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31Starting from ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 85% yield).

[0417] The diastereomeric pure products were obtained by chromatographic separation on a chiral column.

[0418] Example 26a (2R,8S) HRMS C 31 H 34 Calculated for N4O7S: 606.2148; [M+H] + Measured value: 607.2223 (δ=0.3 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.1 (sl, 1 H), 7.62 / 7.59 (d, 2 H), 7.59 (d, 1 H), 7.19 (dd, 1 H), 7.08 (d, 1 H), 7.01 (d, 1 H), 6.91 (dd, 1 H), 6.49 (d, 1 H), 5.37 (q, 1 H), 4.87 (t, 1 H), 4.77 / 4.67 (m, 2 H), 4.33 / 3.95 (d, 2 H), 4.08 (t, 2 H), 3.79 / 3.66 (m, 2 H), 3.49 (m, 2 H), 3.11 (m, 2 H), 2.83 (s, 3 H), 2.29 (s, 3H), 2.19 (m, 2H), 1.54 (d, 3H)

[0419] Example 26b (2R,8R) HRMS C 31 H 34 Calculated for N4O7S: 606.2148; [M+H] + Measured value: 607.2223 (δ=0.3 ppm) 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.11 (sl, 1 H), 7.61 (d, 1 H), 7.43 (dd, 1 H), 7.23 (d, 1 H), 7.11 (d, 1 H), 6.99 (d, 1 H), 6.88 (d, 1 H), 6.85 (dd, 1 H), 6.24 (d, 1 H), 5.28 (q, 1 H), 4.9 (t, 1 H), 4.75 / 4.61 (m, 2 H), 4.16 / 3.96 (d, 2 H), 3.91 / 3.83 (m, 2 H), 3.71 / 3.59 (m, 2 H), 3.59 / 3.5 (m, 2 H), 3.11 / 2.84 (dd, 2 H), 2.8 (s, 3 H), 2.3 (s, 3 H), 2.29 / 2.18 (m, 2 H), 1.19 (d, 3 H)

[0420] Example 27 : [(2R,8R)-2,4,33-trimethyl-29,29-dioxo-19,23,28-trioxa-29λ 6 -Thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid and [(2R,8S)-2,4,33-trimethyl-29,29-dioxo-19,23,28-trioxa-29λ 6 -Thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid [ka]

[0421] Step A1: Preparation of tert-butyl {2-[3-(benzyloxy)propoxy]ethyl}carbamate To a solution of 3-(benzyloxy)propyl 4-methylbenzene-1-sulfonate (41 g, 130 mmol) in toluene (2 mL / mmol, 260 mL) was added tetrabutylammonium hydrogensulfate (0.1 equivalent, 4.3 g, 13 mmol), tert-butyl(2-hydroxyethyl)carbamate (1 equivalent, 21 g, 130 mmol), and 50 wt% aqueous NaOH (9 equivalents, 92 g, 1.2 mol). The mixture was heated at 85 °C for 16 h. After completion of the reaction, the mixture was diluted with EtOAc (1 L). The mixture was washed with saturated aqueous NH4Cl (2 L), and the layers were separated. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the crude product, which was purified by reverse-phase chromatography using a water-MeCN elution system to give the title compound (19.6 g, yellow oil, 47% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.38-7.24 (m, 5 H), 6.73 (t, 1 H), 4.44 (s, 2 H), 3.49 (t, 2 H), 3.44 (t, 2 H), 3.33 (t, 2 H), 3.04 (q, 2 H), 1.76 (quint, 2 H), 1.38 (s, 9 H)

[0422] Step A2: Preparation of 2-[3-(benzyloxy)propoxy]ethan-1-amine hydrochloride To a solution of tert-butyl {2-[3-(benzyloxy)propoxy]ethyl}carbamate (19.6 g, 59.5 mmol) in dioxane (5 mL / mmol, 298 mL) was added HCl (4 N in dioxane) (4 equivalents, 59.5 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure. The crude product was used as the HCl salt (15.6 g, quantitative) without further purification. 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.98 (s, 3 H), 7.4-7.36 (m, 5 H), 4.46 (s, 2 H), 3.56 (t, 2 H), 3.5 (t, 2 H), 3.5 (t, 2 H), 2.93 (t, 2 H), 1.81 (quint, 2 H)

[0423] Step A3: Preparation of N-{2-[3-(benzyloxy)propoxy]ethyl}-3-methyl-2-nitroaniline Using General Procedure 2, Step 1, starting with 1-fluoro-3-methyl-2-nitrobenzene (1 equivalent) and 2-[3-(benzyloxy)propoxy]ethan-1-amine hydrochloride (1.2 equivalents) as reactants, the title compound was obtained (93% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.38-7.24 (m, 5 H), 7.27 (m, 1 H), 6.82 (d, 1 H), 6.59 (d, 1 H), 6.46 (t, 1 H), 4.42 (s, 2 H), 3.57 (t, 2 H), 3.52-3.47 (m, 4 H), 3.33 (dt, 2 H), 2.31 (s, 3 H), 1.79 (quint, 2 H)

[0424] Step A4: Preparation of N-{2-[3-(benzyloxy)propoxy]ethyl}-4-bromo-3-methyl-2-nitroaniline Using General Procedure 2, Step 2, starting with N-{2-[3-(benzyloxy)propoxy]ethyl}-3-methyl-2-nitroaniline (1 equivalent) as reactant, the title compound was obtained (58% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.54 (d, 1 H), 7.38-7.23 (m, 5 H), 6.8 (d, 1 H), 6.09 (t, 1 H), 4.42 (s, 2 H), 3.51 (t, 2 H), 3.47 (m, 4 H), 3.3 (q, 2 H), 2.38 (s, 3 H), 1.77 (quint, 2 H)

[0425] Process A5: N 1 Preparation of -{2-[3-(benzyloxy)propoxy]ethyl}-4-bromo-3-methylbenzene-1,2-diamine Using General Procedure 2, Step 3, starting with N-{2-[3-(benzyloxy)propoxy]ethyl}-4-bromo-3-methyl-2-nitroaniline (1 equivalent) as reactant, the title compound (quantitative) was obtained. 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.38-7.23 (m, 5 H), 6.71 (d, 1 H), 6.29 (d, 1 H), 4.6 (sl, 3 H), 4.42 (s, 2 H), 3.56 / 3.5 (m, 2 H), 3.56 / 3.5 (m, 4 H), 3.16 (t, 2 H), 2.17 (s, 3 H), 1.79 (quint, 2 H)

[0426] Step A6: Preparation of ethyl (2E)-3-(1-{2-[3-(benzyloxy)propoxy]ethyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate Using General Procedure 2, Step 4, N 1 Starting from -{2-[3-(benzyloxy)propoxy]ethyl}-4-bromo-3-methylbenzene-1,2-diamine (1 equivalent), 1-{2-[3-(benzyloxy)propoxy]ethyl}-5-bromo-4-methyl-1H-benzotriazole (29% yield) was obtained. The crude product was reacted using General Procedure 2, Step 5 to give the title compound (91% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 8.01 (d, 1 H), 7.92 (d, 1 H), 7.69 (d, 1 H), 7.3 (t, 2 H), 7.25 (t, 1 H), 7.2 (d, 2 H), 6.62 (d, 1 H), 4.85 (t, 2 H), 4.22 (s, 2 H), 4.21 (q, 2 H), 3.82 (t, 2 H), 3.4 (t, 2 H), 3.21 (t, 2 H), 2.79 (s, 3 H), 1.6 (quint, 2 H), 1.28 (t, 3 H)

[0427] Step 1: Preparation of ethyl 3-(1-{2-[3-(benzyloxy)propoxy]ethyl}-4-methyl-1H-benzotriazol-5-yl)-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propanoate Using general procedure 6 and starting with ethyl (2E)-3-(1-{2-[3-(benzyloxy)propoxy]ethyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equivalent) and (1S)-1-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1-ol (1 equivalent) as reactants, the title compound was obtained (48% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.58 (d, 1 H), 7.44 (d, 1 H), 7.4 (d, 1 H), 7.31 (t, 2 H), 7.24 (t, 1 H), 7.21 (d, 2 H), 7.03 (dd, 1 H), 6.97 (d, 1 H), 4.83 (m, 1 H), 4.83 (m, 1 H), 4.8 (m, 2 H), 4.25 (s, 2 H), 3.97 (d, 1 H), 3.92 (q, 2 H), 3.82 (t, 2 H), 3.4 (t, 2 H), 3.25 (m, 2 H), 3.15-3.05 (m, 2 H), 2.76 (s, 3 H), 2.18 (s, 3 H), 1.61 (quint, 2 H), 1.21 (d, 3 H), 1 (t, 3 H)

[0428] Step 2: Ethyl 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(2-(3-benzoxathiazin-3(4H)-yl)ethyl)-4-methylphenyl)-3-{1-[2-(3-hydroxypropoxy)ethyl]-4-methyl-1H-benzotriazol-5-yl}propanoate Using General Procedure 7, the reactants were ethyl 3-(1-{2-[3-(benzyloxy)propoxy]ethyl}-4-methyl-1H-benzotriazol-5-yl)-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propanoate (1.1 equivalents) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ. 6 Starting from 1.1 equivalents of ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ]-benzoxathiazine-2,2-dione, 6,3-benzoxathiazin-3(4H)-yl]ethyl}-4-methylphenyl)-3-(1-{2-[3-(benzyloxy)propoxy]ethyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (yellow oil, 86% yield). The crude product was reacted using general procedure 8 to give the title compound (yellow oil, 83% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.62 (2m, 2 H), 7.65-7.42 (m, 2 H), 7.47 / 7.45 (2sl, 1 H), 7.14-7.07 (m, 2 H), 6.92 / 6.9 (2d, 1 H), 6.75-6.7 (m, 1 H), 6.58 (2d, 1 H), 5.25 (q, 1 H), 4.87 (q, 1 H), 4.8 (t, 2 H), 4.36 / 4.32 (2s, 2 H), 4.31-4.24 (m, 1 H), 3.94 (2q, 2 H), 3.82 (m, 2 H), 3.39 (2t, 2 H), 3.29 (q, 2 H), 3.22 (m, 2 H), 2.76 (s, 3 H), 2.27 (s, 3 H), 1.5 (m, 2 H), 1.43 / 1.41 (2d, 3 H), 1.01 / 1 (2t, 3 H)

[0429] Step 3: Ethyl 3-{1-[2-(3-bromopropoxy)ethyl]-4-methyl-1H-benzotriazol-5-yl}-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6Starting from {1-[2-(3-hydroxypropoxy)ethyl]-4-methyl-1H-benzotriazol-5-yl}propanoate (1 equivalent), the title compound was obtained as a white solid (49% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.55 (s, 1 H), 7.7-7.55 (2d, 2 H), 7.49 (2d, 1 H), 7.1 (m, 2 H), 6.9 (d, 1 H), 6.71 (2, 1 H), 6.6 (2d, 1 H), 5.25 (m, 1 H), 4.9 (m, 1 H), 4.81 (t, 2 H), 4.4-4.25 (m, 2 H), 3.95 (m, 2 H), 3.85 (t, 2 H), 3.41 (t, 2 H), 3.3 (t, 2 H), 3.21 (d, 2 H), 2.76 (s, 3 H), 2.3 (s, 3 H), 1.85 (m, 2H), 1.45 (2d, 3H), 1.02 (2t, 3H)

[0430] Step 4: Ethyl [(2R)-2,4,33-trimethyl-29,29-dioxo-19,23,28-trioxa-29λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 Preparation of ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-{1-[2-(3-bromopropoxy)ethyl]-4-methyl-1H-benzotriazol-5-yl}-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate gave the title compound (white solid, 83% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 1.00 (td, J=7.09, 5.50 Hz, 5 H) 1.24 (d, J=6.85 Hz, 2 H) 1.52 (d, J=6.85 Hz, 3 H) 1.77 - 1.86 (m, 1 H) 1.92 (dt, J=12.90, 6.39 Hz, 2 H) 2.30 (d, J=1.59 Hz, 5 H) 2.79 (s, 2 H) 2.85 (s, 3 H) 2.92 - 3.27 (m, 4 H) 3.44 - 3.66 (m, 5 H) 3.81 - 3.88 (m, 3 H) 3.92 - 4.01 (m, 3 H) 4.01 - 4.16 (m, 2 H) 4.34 (d, J=17.85 Hz, 1 H) 4.70 - 4.82 (m, 2 H) 4.82 - 4.96 (m, 3 H) 5.28 (d, J=7.09 Hz, 1 H) 5.35 (q, J=6.64 Hz, 1 H) 6.00 (d, J=2.81 Hz, 1 H) 6.44 (d, J=2.81 Hz, 1 H) 6.71 - 6.85 (m, 2 H) 6.91 - 7.02 (m, 2 H) 7.11 (d, J=7.82 Hz, 1 H) 7.19 - 7.31 (m, 2 H) 7.48 (d, J=6.85 Hz, 1 H) 7.57 (s, 1 H) 7.58 - 7.69 (m, 3 H)

[0431] Step 5: Preparation of Example 27 Using General Procedure 12, ethyl [(2R)-2,4,33-trimethyl-29,29-dioxo-19,23,28-trioxa-29λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 Starting from ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 97% yield).

[0432] The diastereomeric pure products were obtained by chromatographic separation on a chiral column.

[0433] Example 27a (2R,8R) HRMS C 31 H 34 Calculated for N4O7S: 606.2148; [M+H] + Measured value: 607.2224 (δ=0.5 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (sl, 1 H), 7.6 (d, 1 H), 7.49 (dd, 1 H), 7.26 (d, 1 H), 7.19 (d, 1 H), 7 (d, 1 H), 6.95 (d, 1 H), 6.76 (dd, 1 H), 6.01 (d, 1 H), 5.28 (q, 1 H), 4.9 (t, 1 H), 4.78 (m, 2 H), 4.11 / 3.9 (d, 2 H), 4 (m, 2 H), 3.6 (m, 2 H), 3.55 (m, 2 H), 3.08 / 2.85 (dd, 2 H), 2.79 (s, 3 H), 2.3 (s, 3 H), 1.83 (m, 2 H), 1.23 (d, 3 H)

[0434] Example 27b (2R,8S) HRMS C 31 H 34 Calculated for N4O7S: 606.2148; [M+H] + Measured value: 607.2222 (δ=0.2 ppm) 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.1 (sl, 1 H), 7.64 (d, 1 H), 7.59 (d, 1 H), 7.55 (d, 1 H), 7.23 (dd, 1 H), 7.11 (d, 1 H), 6.99 (d, 1 H), 6.81 (dd, 1 H), 6.43 (d, 1 H), 5.33 (q, 1 H), 4.85 / 4.76 (m, 2 H), 4.85 (t, 1 H), 4.32 / 4.01 (d, 2 H), 4-3.97 (m, 2 H), 3.86 (m, 2 H), 3.61 / 3.52 (m, 2 H), 3.07 (m, 2 H), 2.83 (s, 3 H), 2.3 (s, 3 H), 1.91 (m, 2 H), 1.5 (d, 3 H)

[0435] Examples 28a and 28b : [(2R,8R)-4-Methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid and [(2R,8S)-4-Methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0436] Step 1: Preparation of ethyl 3-{3-[(1S)-1-hydroxyethyl]-4-methoxyphenyl}-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using general procedure 6 and starting with ethyl (2E)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equivalent) and (1S)-1-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1-ol (1.5 equivalents) as reactants, the title compound was obtained (65% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.58 (2d, 1 H), 7.45 (2d, 1 H), 7.37 (d, 1 H), 7.2 (d, 2 H), 7.13 (2dd, 1 H), 6.87 (d, 2 H), 6.82 (d, 1 H), 4.91 (m, 1 H), 4.89 (d, 1 H), 4.82 (m, 1 H), 4.64 (m, 2 H), 4.32 (s, 2 H), 3.92 (q, 2 H), 3.73 / 3.72 (2s, 6 H), 3.38 (t, 2 H), 3.11 (m, 2 H), 2.76 / 2.75 (2s, 3 H), 1.92 (m, 2 H), 1.48 (m, 2 H), 1.22-1.15 (2d, 3 H), 0.99 (t, 3 H)

[0437] Step 2: Ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(4-benzoxathiazin-3(4H)-yl]ethyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using General Procedure 7, reactants ethyl 3-{3-[(1S)-1-hydroxyethyl]-4-methoxyphenyl}-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ were used. 6 Starting with ,3-benzoxathiazine-2,2-dione (1.1 equivalents), the title compound was obtained (66% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.5 (2d, 1 H), 7.45-7.3 (m, 6 H), 7.2 (d, 2 H), 7.1 (dd, 1 H), 6.9 (m, 4 H), 6.75 (m, 2 H), 5.39 (m, 1 H), 5 (m, 2 H), 4.8 (m, 1 H), 4.6 (2t, 2 H), 4.55 (m, 2 H), 4.3 (s, 2 H), 3.91 (q, 2 H), 3.71 / 3.65 (2s, 6 H), 3.48 (m, 2 H), 3.18 (d, 2 H), 2.79 (s, 3 H), 1.91 (m, 2 H), 1.5 (m, 2 H), 1.45 (2d, 3 H), 1 (t, 3 H)

[0438] Step 3: Ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methoxyphenyl}propanoate Using General Procedure 8, the reactant was ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6Starting from 1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained as an off-white solid (83% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 1.01 (td, J=7.09, 3.79 Hz, 3 H) 1.21 (dd, J=13.69, 5.99 Hz, 1 H) 1.31 - 1.39 (m, 2 H) 1.42 (t, J=6.42 Hz, 3 H) 1.91 (quint, J=7.31 Hz, 2 H) 2.76 (d, J=3.67 Hz, 3 H) 3.09 - 3.21 (m, 2 H) 3.38 (t, J=5.93 Hz, 2 H) 3.67 (s, 3 H) 3.70 (s, 1 H) 3.94 (q, J=7.09Hz, 2H) 4.34 - 4.57 (m, 3 H) 4.65 (t, J=6.97 Hz, 2 H) 4.83 (q, J=7.62 Hz, 1 H) 5.37 (quint, J=6.79 Hz, 1 H) 6.51 (dd, J=13.14, 2.75 Hz, 1 H) 6.64 (dd, J=8.99, 2.75 Hz, 1 H) 6.73 - 6.85 (m, 3 H) 7.08 (d, J=8.19 Hz, 1 H) 7.13 (dd, J=8.56, 2.08 Hz, 1 H) 7.42 (dd, J=9.35, 2.02 Hz, 1 H) 7.53 (t, J=9.11 Hz, 1 H) 7.59 - 7.67 (m, 1 H) 9.54 (br. s., 1 H)

[0439] Step 4: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methoxyphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 4-methoxyphenyl]-4-benzoxathiazin-3(4H)-yl)ethyl}-4-methoxyphenyl propanoate gave the title compound (73% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 1.00 (td, J=7.09, 3.79 Hz, 3 H) 1.42 (t, J=6.66 Hz, 3 H) 1.71 - 1.83 (m, 2 H) 1.94 - 2.05 (m, 2 H) 2.70 - 2.79 (m, 3 H) 3.08 - 3.25 (m, 2 H) 3.53 (t, J=6.66 Hz, 2 H) 3.62 - 3.70 (m, 3 H) 3.94 (q, J=7.13 Hz, 2 H) 4.34 - 4.57 (m, 2 H) 4.69 (t, J=6.85Hz, 2H) 4.83 (q, J=7.83 Hz, 1 H) 5.31 - 5.42 (m, 1 H) 6.51 (dd, J=11.37, 2.81 Hz, 1 H) 6.64 (dd, J=8.93, 2.81 Hz, 1 H) 6.62 - 6.68 (m, 1 H) 6.74 - 6.84 (m, 2 H) 7.13 (dd, J=8.50, 2.02 Hz, 1 H) 7.42 (dd, J=10.03, 2.08 Hz, 1 H) 7.55 (t, J=8.74 Hz, 1 H) 7.61 - 7.68 (m, 1 H) 9.52 (d, J=5.01Hz, 1H)

[0440] Step 5: Ethyl [(2R)-4-methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)ethyl]-4-methoxyphenyl}propanoate gave the title compound (white solid, 73% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 1.02 (td, J=7.09, 2.81 Hz, 6 H) 1.12 - 1.22 (m, 5 H) 1.22 - 1.29 (m, 4 H) 1.31 (d, J=7.21 Hz, 3 H) 1.40 (d, J=7.46 Hz, 1 H) 1.48 - 1.61 (m, 1 H) 1.62 - 1.88 (m, 2 H) 2.00 - 2.28 (m, 4 H) 2.63 - 2.90 (m, 6 H) 3.09 (td, J=15.62, 7.89 Hz, 2 H) 3.24 - 3.37 (m, 10 H) 3.46 (td, J=9.54, 6.11 Hz, 1 H) 3.53 - 3.69 (m, 3 H) 3.70 - 3.80 (m, 7 H) 3.88 - 3.98 (m, 5 H) 4.05 - 4.15 (m, 1 H) 4.68 - 4.97 (m, 6 H) 5.43 (dq, J=17.93, 7.19 Hz, 2 H) 5.62 (d, J=2.57 Hz, 1 H) 5.75 (d, J=2.81 Hz, 1 H) 6.62 - 6.72 (m, 2 H) 6.80 - 6.94 (m, 4 H) 6.99 (d, J=8.56 Hz, 1 H) 7.20 - 7.29 (m, 2 H) 7.42 (dd, J=8.44, 1.96 Hz, 1 H) 7.50 (dd, J=8.56, 1.83 Hz, 1 H) 7.67 (d, J=8.68 Hz, 1 H) 7.74 - 7.81 (m, 1 H) 7.83 - 7.89 (m, 1H)

[0441] Step 6: Preparation of Examples 28a and 28b Using General Procedure 12, ethyl [(2R)-4-methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29Starting from ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 77% yield).

[0442] The diastereomeric pure products were obtained by chromatographic separation on a chiral column.

[0443] Example 28a (2R,8R) HRMS C 30 H 32 Calculated for N4O7S: 592.1992; [M+H] + Measured value: 593.2067 (δ=0.4 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.5-11.8 (m, 1 H), 7.67 (d, 1 H), 7.5 (dd, 1 H), 7.19 (d, 1 H), 7 (d, 1 H), 6.83 (d, 1 H), 6.8 (d, 1 H), 6.65 (dd, 1 H), 5.63 (d, 1 H), 5.4 (q, 1 H), 4.87 (dd, 1 H), 4.72 (m, 2 H), 4 / 3.71 (AM, 2 H), 3.76 (s, 3 H), 3.6 / 3.32 (2m, 2 H), 3.2 / 2.9 (2dd, 2H), 2.81 (s, 3H), 2.2 / 2.01 (2m, 2H), 1.7 / 1.4 (2m, 2H), 1.17 (d, 3H)

[0444] Example 28b (2R,8S) HRMS C 30 H 32 Calculated for N4O7S: 592.1992; [M+H] + Measured value: 593.2066 (δ=0.3 ppm) 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.3-11.6 (m, 1 H), 7.92 (dd, 1 H), 7.82 (d, 1 H), 7.77 (d, 1 H), 7.18 (d, 1 H), 6.9 (d, 1 H), 6.88 (d, 1) H), 6.69 (dd, 1 H), 5.7 (d, 1 H), 5.42 (q, 1 H), 4.75 (m, 3 H), 4.08 / 3.69 (AM, 2 H), 3.72 (s, 3 H), 3.62 / 3.45 (2m, 2 H), 3.2 / 2.99 (2dd, 2H), 2.68 (s, 3H), 2.2 / 2.1 (2m, 2 H), 1.8 / 1.59 (2m, 2H), 1.29 (d, 3H)

[0445] Examples 28c and 28d : [(2S,8R)-4-Methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid and [(2S,8S)-4-Methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0446] Step 1: Preparation of ethyl 3-{3-[(1R)-1-hydroxyethyl]-4-methoxyphenyl}-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using general procedure 6 and starting with ethyl (2E)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equivalent) and (1R)-1-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1-ol (1.1 equivalents) as reactants, the title compound was obtained (81% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (2d, 1 H), 7.45 (2d, 1 H), 7.35 (d, 1 H), 7.2 (d, 2 H), 7.12 (dd, 1 H), 6.88 (d, 2 H), 6.81 (d, 1 H), 4.9 (d, 1 H), 4.9 (m, 1 H), 4.8 (m, 1 H), 4.65 (t, 2 H), 4.32 (s, 2 H), 3.91 (q, 2 H), 3.71 (2s, 6 H), 3.4 (t, 2 H), 3.1 (2d, 2 H), 2.79 (2s, 3 H), 1.92 (m, 2 H), 1.48 (m, 2 H), 1.2 (2d, 3 H), 1 (t, 3 H)

[0447] Step 2: Ethyl 3-(3-{(1S)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of 1-(4-benzoxathiazin-3(4H)-yl]ethyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate Using general procedure 7, starting with ethyl 3-{3-[(1R)-1-hydroxyethyl]-4-methoxyphenyl}-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent) and 6-benzyloxy-3,4-dihydro-1,2λ6,3-benzoxathiazine 2,2-dioxide (1.1 equivalents) as reactants, the title compound was obtained (60% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.5 (2d, 1 H), 7.45-7.3 (m, 6 H), 7.2 (d, 2 H), 7.11 (dd, 1 H), 6.9 (m, 2 H), 6.88 (d, 2 H), 6.78 (m, 2 H), 5.39 (m, 1 H), 5.05 (m, 2 H), 4.81 (m, 1 H), 4.65-4.5 (m, 2 H), 4.61 (2t, 2 H), 4.3 (s, 2 H), 3.92 (q, 2 H), 3.71 / 3.65 (2s, 6 H), 3.38 (m, 2 H), 3.15 (m, 2 H), 2.78 (s, 3 H), 1.9 (m, 2 H), 1.48 (m+d, 5 H), 0.99 (t, 3 H)

[0448] Step 3: Ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1S)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methoxyphenyl}propanoate Using general procedure 8, the reactant was ethyl 3-(3-{(1S)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6Starting from 1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equivalent), the title compound was obtained (70% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 0.95 - 1.03 (m, 3 H) 1.30 - 1.47 (m, 5 H) 1.85 - 1.97 (m, 2 H) 2.76 (d, J=3.55 Hz, 3 H) 3.18 (d, J=8.19 Hz, 2 H) 3.34 - 3.42 (m, 2 H) 3.67 (s, 3 H) 3.94 (q, J=7.13 Hz, 2 H) 4.33 (t, J=5.07 Hz, 1 H) 4.37 - 4.58 (m, 3 H) 4.65 (t, J=6.97 Hz, 2 H) 4.83 (q, J=7.87 Hz, 1 H) 5.32 - 5.42 (m, 1 H) 6.51 (dd, J=13.20, 2.81 Hz, 1 H) 6.64 (dd, J=8.86, 2.75 Hz, 1 H) 6.76 (d, J=1.59 Hz, 1 H) 6.79 - 6.84 (m, 2 H) 7.08 (d, J=8.31 ​​Hz, 1 H) 7.13 (dd, J=8.56, 2.08 Hz, 1 H) 7.42 (dd, J=9.05, 1.96 Hz, 1 H) 7.53 (t, J=9.17 Hz, 1 H) 7.60 - 7.65 (m, 1 H) 9.51 (s, 1H) 9.52 (s, 1 H)

[0449] Step 4: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1S)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methoxyphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1S)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting with 1 equiv. of 3-benzoxathiazin-3(4H)-yl)ethyl]-4-methoxyphenyl}propanoate gave the title compound (white solid, quantitative). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 1.00 (td, J=7.09, 3.79 Hz, 3 H) 1.42 (t, J=6.66 Hz, 3 H) 1.71 - 1.82 (m, 2 H) 1.92 - 2.06 (m, 2 H) 2.76 (d, J=3.91 Hz, 3 H) 3.10 - 3.25 (m, 2 H) 3.53 (t, J=6.66 Hz, 2 H) 3.67 (d, J=1.10 Hz, 3 H) 3.94 (q, J=7.13 Hz, 2 H) 4.35 - 4.60 (m, 2 H) 4.69 (t, J=6.85 Hz, 2 H) 4.83 (q, J=7.83 Hz, 1 H) 5.36 (quin, J=6.94 Hz, 1 H) 6.51 (dd, J=11.37, 2.81 Hz, 1 H) 6.64 (dd, J=8.93, 2.81 Hz, 1 H) 6.76 (s, 1 H) 6.78 (s, 1 H) 6.81 (dd, J=8.68, 2.93 Hz, 1 H) 7.13 (dd, J=8.50, 2.02 Hz, 1 H) 7.42 (dd, J=10.03, 2.08 Hz, 1 H) 7.55 (t, J=8.74 Hz, 1 H) 7.61 - 7.69 (m, 1H) 9.52 (d, J=5.01 Hz, 1 H)

[0450] Step 5: Ethyl [(2S)-4-methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .012,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1S)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 4-benzoxathiazin-3(4H)-yl)ethyl]-4-methoxyphenyl}propanoate gave the title compound (white solid, 60% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 0.98 - 1.07 (m, 6 H) 1.15 - 1.20 (m, 4 H) 1.31 (d, J=7.21 Hz, 3 H) 1.40 (d, J=7.46 Hz, 1 H) 1.48 - 1.61 (m, 1 H) 1.62 - 1.75 (m, 1 H) 1.75 - 1.87 (m, 1 H) 2.00 - 2.14 (m, 2 H) 2.14 - 2.28 (m, 2 H) 2.70 (s, 3 H) 2.84 (s, 2 H) 3.09 (td, J=15.62, 7.89Hz, 2H) 3.32 - 3.38 (m, 1 H) 3.46 (td, J=9.54, 6.11 Hz, 1 H) 3.54 - 3.77 (m, 9 H) 3.87 - 3.98 (m, 5 H) 3.98 - 4.02 (m, 1 H) 4.05 - 4.14 (m, 1 H) 4.66 - 4.83 (m, 5 H) 4.89 (t, J=7.89 Hz, 1 H) 5.43 (dq, J=17.93, 7.19 Hz, 2 H) 5.62 (d, J=2.57 Hz, 1 H) 5.75 (d, J=2.81 Hz, 1 H) 6.62 - 6.72 (m, 2H) 6.81 - 6.93 (m, 4 H) 6.99 (d, J=8.56 Hz, 1 H) 7.19 - 7.26 (m, 2 H) 7.42 (dd, J=8.44, 1.96 Hz, 1 H) 7.50 (dd, J=8.56, 1.83 Hz, 1 H) 7.67 (d, J=8.68 Hz, 1 H) 7.74 - 7.80 (m, 1 H) 7.83 - 7.89 (m, 1 H)

[0451] Step 6: Preparation of Examples 28c and 28d Using General Procedure 12, ethyl [(2S)-4-methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .012,16 .0 25,29 Starting from ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 89% yield).

[0452] The diastereomeric pure products were obtained by chromatographic separation on a chiral column.

[0453] Example 28c (2S,8R) HRMS C 30 H 32 Calculated for N4O7S: 592.1992; [M+H] + Measured value: 593.2065 (δ=0.1 ppm)

[0454] Example 28d (2S,8S) HRMS C 30 H 32 Calculated for N4O7S: 592.1992; [M+H] + Measured value: 593.2070 (δ=0.9 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.3-11.6 (m, 1 H), 7.92 (dd, 1 H), 7.82 (d, 1 H), 7.77 (d, 1 H), 7.18 (d, 1 H), 6.9 (d, 1 H), 6.88 (d, 1) H), 6.69 (dd, 1 H), 5.7 (d, 1 H), 5.42 (q, 1 H), 4.75 (m, 3 H), 4.08 / 3.69 (AM, 2 H), 3.72 (s, 3 H), 3.62 / 3.45 (m, 2 H), 3.2 / 2.99 (dd, 2 H), 2.68 (s, 3 H), 2.2 / 2.1 (m, 2 H), 1.8 / 1.59 (m, 2H), 1.29 (d, 3H)

[0455] Example 29 : [(2R,8R)-2,4,24,31-tetramethyl-27,27-dioxo-21,26-dioxa-27λ6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid and [(2R,8S)-2,4,24,31-tetramethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0456] Step 1: Preparation of ethyl 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H-benzotriazol-5-yl}-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propanoate Using general procedure 6 and starting with ethyl (E)-3-[1-(4-benzyloxybutyl)-4-methyl-benzotriazol-5-yl]prop-2-enoate (1 equivalent) and (1S)-1-[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol (1.2 equivalents) as reactants, the title compound was obtained (50% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.58 / 7.46 (2dd, 1 H), 7.41 (d, 1 H), 7.35-7.22 (m, 5 H), 7.06 (dd, 1 H), 6.98 (d, 1 H), 4.97 / 4.96 (2d, 1 H), 4.83 (m, 1 H), 4.83 (m, 1 H), 4.65 (t, 2 H), 4.4 (s, 2 H), 3.92 (q, 2 H), 3.42 (t, 2 H), 3.12 (m, 2 H), 2.77 / 2.76 (2s, 3 H), 2.19 (s, 3 H), 1.94 (m, 2 H), 1.5 (m, 2 H), 1.23 / 1.21 (2d, 3H), 1 (t, 3H)

[0457] Step 2: Ethyl 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H-benzotriazol-5-yl}-3-(3-{(1R)-1-[6-(benzyloxy)-8-methyl-2,2-dioxo-2H-1,2λ) 6 Preparation of ,3-benzoxathiazin-3(4H)-yl]ethyl}-4-methylphenyl)propanoate Using General Procedure 7, the reactants were ethyl 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H-benzotriazol-5-yl}-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propanoate (1 equivalent) and 6-(benzyloxy)-8-methyl-3,4-dihydro-2H-1,2λ. 6 Starting with ,3-benzoxathiazine-2,2-dione (1.1 equivalents), the title compound was obtained (68% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 0.90 - 1.03 (m, 6 H) 1.41 (d, J=6.97 Hz, 5 H) 1.43 - 1.53 (m, 4 H) 1.81 - 1.98 (m, 4 H) 2.13 - 2.20 (m, 6 H) 2.28 (s, 6 H) 2.73 - 2.80 (m, 6 H) 3.11 - 3.25 (m, 4 H) 3.34 - 3.44 (m, 4 H) 3.92 (q, J=7.05 Hz, 4 H) 4.25 - 4.37 (m, 2 H) 4.39 (d, J=3.67 Hz, 5 H) 4.55 - 4.66 (m, 4 H) 4.81 - 4.91 (m, 2 H) 4.99 - 5.11 (m, 4 H) 5.26 (q, J=6.93 Hz, 2 H) 6.63 (d, J=2.81 Hz, 1 H) 6.69 (d, J=2.81 Hz, 1 H) 6.89 - 6.97 (m, 2 H) 7.06 - 7.15 (m, 4 H) 7.20 - 7.37 (m, 12 H) 7.37 - 7.48 (m, 10 H) 7.51 - 7.56 (m, 2 H) 7.56 - 7.61 (m, 2 H)

[0458] Step 3: Ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-8-methyl-2,2-dioxo-2H-1,2λ] 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate Using general procedure 8, the reactant was ethyl 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H-benzotriazol-5-yl}-3-(3-{(1R)-1-[6-(benzyloxy)-8-methyl-2,2-dioxo-2H-1,2λ). 6 Starting from ,3-benzoxathiazin-3(4H)-yl]ethyl}-4-methylphenyl)propanoate (1 equivalent) gave the title compound (63% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.5 / 4.4 (s+t, 2 H), 7.61 (2d, 1 H), 7.58 (2d, 1 H), 7.45 (2d, 1 H), 7.11 (m, 2 H), 6.61 (2d, 1 H), 6.41 / 6.39 (2d, 1 H), 5.25 (m, 1 H), 4.9 (m, 1 H), 4.65 (t, 2 H), 4.35 / 4.29 (2m, 2 H), 3.95 (q, 2 H), 3.4 (q, 2 H), 3.21 (d, 2 H), 2.79 (s, 3 H), 2.3 (s, 3 H), 2.11 (2s, 3 H), 1.91 (m, 2 H), 1.45 (2d, 3 H), 1.38 (m, 2 H), 1.01 (2t, 3 H)

[0459] Step 4: Ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-8-methyl-2,2-dioxo-2H-1,2λ] 6 Preparation of ,3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate Using General Procedure 9, the reactant was ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-8-methyl-2,2-dioxo-2H-1,2λ]. 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate gave the title compound (white solid, 77% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.5 (s, 1 H), 7.62 (d, 1 H), 7.59 (d, 1 H), 7.48 / 7.41 (d, 1 H), 7.1 (m, 2 H), 6.61 (d, 1 H), 6.4 / 6.39 (d, 1 H), 5.24 (m, 1 H), 4.88 (m, 1 H), 4.69 (t, 2 H), 4.31 / 4.28 (m, 2 H), 3.92 (q, 2 H), 3.52 (q, 2 H), 3.21 (d, 2 H), 2.79 (s, 3 H), 2.28 (s, 3 H), 2.1 (s, 2 H), 2 (m, 2 H), 1.78 (d, 3 H), 1.41 (m, 2 H), 1 (t, 3 H)

[0460] Step 5: Ethyl [(2R)-2,4,24,31-tetramethyl-27,27-dioxo-21,26-dioxa-27λ] 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate Using general procedure 11, the reactant was ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-8-methyl-2,2-dioxo-2H-1,2λ] 6 Starting from 1 equiv. of 3-benzoxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate gave the title compound (white solid, 61% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 0.97 - 1.13 (m, 4 H) 1.21 - 1.32 (m, 2 H) 1.53 - 1.76 (m, 1 H) 1.77 - 1.89 (m, 1 H) 2.03 - 2.10 (m, 3 H) 2.12 - 2.25 (m, 1 H) 2.31 (d, J=11.86 Hz, 3 H) 2.66 (s, 2 H) 2.72 - 2.80 (m, 1 H) 2.81 (s, 1 H) 2.95 - 3.15 (m, 1 H) 3.34 - 3.51 (m, 2 H) 3.67 (td, J=9.75, 5.32 Hz, 1 H) 3.88 - 4.01 (m, 3 H) 4.62 - 4.85 (m, 3 H) 4.92 (t, J=7.76 Hz, 1 H) 5.24 (dq, J=13.89, 6.82 Hz, 1 H) 5.53 (d, J=2.93 Hz, 1 H) 5.69 (br. s., 1 H) 6.56 - 6.76 (m, 1 H) 7.08 - 7.24 (m, 2 H) 7.30 (d, J=7.95 Hz, 1 H) 7.44 (d, J=7.70 Hz, 1 H) 7.68 (d, J=8.80 Hz, 1 H) 7.74 (d, J=8.68 Hz, 1 H) 7.88 (d, J=8.68 Hz, 1 H)

[0461] Step 6: Preparation of Example 29 Using General Procedure 12, ethyl [(2R)-2,4,24,31-tetramethyl-27,27-dioxo-21,26-dioxa-27λ] was used as the reactant. 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Starting from ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equivalent) gave the title compound (white solid, 73% yield).

[0462] The diastereomeric pure products were obtained by chromatographic separation on a chiral column.

[0463] Example 29a (2R,8R) HRMS C 31 H 34 Calculated for N4O6S: 590.2199; [M+H] + Measured value: 591.2273 (δ=0.2 ppm) 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.25 (m, 1 H), 7.7 (d, 1 H), 7.48 (dd, 1 H), 7.3 (d, 1 H), 7.1 (d, 1 H), 6.72 (d, 1 H), 6.61 (d, 1 H), 5.7 (sl, 1 H), 5.21 (q, 1 H), 4.9 (t, 1 H), 4.75 (m, 2 H), 4.02 / 3.48 (2d, 2 H), 3.75 / 3.7 (2m, 2 H), 3.28 / 2.9 (2dd, 2 H), 2.8 (s, 3 H), 2.31 (s, 3H), 2.2 / 2.02 (2m, 2H), 2.08 (s, 3H), 1.61 / 1.28 (2m, 2H), 1.11 (d, 3H)

[0464] Example 29b (2R,8S) HRMS C 31 H 34 Calculated for N4O6S: 590.2199; [M+H] + Measured value: 591.2273 (δ=0.2 ppm) 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (m, 1 H), 7.89 (d, 1 H), 7.72 (d, 1 H), 7.48 (dd, 1 H), 7.2 (d, 1 H), 7.11 (d, 1 H), 6.69 (d, 1 H), 5.51 (d, 1 H), 5.28 (q, 1 H), 4.8-4.7 (2m, 2 H), 4.8 (t, 1 H), 4 / 3.4 (2d, 2 H), 3.65 / 3.47 (2m, 2 H), 3.2 / 2.99 (2dd, 2 H), 2.69 (s, 3 H), 2.3 (s, 3 H), 2.18 / 2.1 (2m, 2 H), 2.1 (s, 3H), 1.82 / 1.71 (2m, 2H), 1.11 (d, 3H)

[0465] Example 30 : [5-Methoxy-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -Thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid [ka]

[0466] Step B1: Preparation of methyl 5-bromo-3-methoxy-2-methylbenzoate Methyl 5-bromo-3-hydroxy-2-methylbenzoate (1.0 equiv., 26.0 g, 106.1 mmol) was dissolved in DMF (300 mL), and then methyl iodide (4 equiv., 26.5 mL, 60.2 g, 424.5 mmol) and CsCO (4 equiv., 137.9 g, 424.5 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was poured into ice water and extracted with EtOAc. After separation, the organic phase was dried over MgSO and concentrated under reduced pressure. The crude product was purified by normal-phase silica gel chromatography using an eluent of heptane-EtOAc to give the title compound (pale yellow solid, 19.1 g, 69% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.44 (s, 1 H), 7.34 (s, 1 H), 3.88 (s, 3 H), 3.83 (s, 3 H), 2.25 (s, 3 H)

[0467] Step B2: Preparation of (5-bromo-3-methoxy-2-methylphenyl)methanol Methyl 5-bromo-3-methoxy-2-methylbenzoate (1 equiv., 19.0 g, 73 mmol) was dissolved in THF (200 mL) and the solution was cooled to 0 °C. Lithium tetrahydridoaluminate (1.2 equiv., 44 mL, 2 M solution in THF) was added over 30 minutes under a N atmosphere. The mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl, extracted with EtOAc, and the organic phase was separated, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by normal-phase silica gel chromatography using an eluent of heptane-EtOAc to give the title compound (yellow solid, 14.7 g, 87% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.16 (s, 1 H), 7.03 (s, 1 H), 5.23 (t, 1 H), 4.46 (d, 2 H), 3.34 (s, 3 H), 2.00 (s, 3 H)

[0468] Step B3: Preparation of [3-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol Using general procedure 3 and starting with (5-bromo-3-methoxy-2-methylphenyl)methanol (1 eq, 14.6 g, 63 mmol) as reactant gave the title compound (12.53 g, 71% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.37 (sl, 1 H), 7.06 (sl, 1 H), 5.04 (t, 1 H), 4.47 (d, 2 H), 3.79 (s, 3 H), 2.09 (s, 3 H), 1.29 (s, 12 H)

[0469] Step 1: Preparation of ethyl 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H-benzotriazol-5-yl}-3-[3-(hydroxymethyl)-5-methoxy-4-methylphenyl]propanoate Using general procedure 6 and starting with ethyl (2E)-3-{1-[4-(benzyloxy)butyl]-4-methyl-1H-benzotriaz...

Claims

1. Formula (I): 【Chemistry 102】 [In the formula, Z, -O- (Cyph) ２ )n １ -、-O-(EH ２ )n １ -O-(CH) ２ )n ２ ,-O-(EH ２ )n １ -S-(CH) ２ )n ２ ,O-(EH ２ )n １ -S(O)-(CH ２ )n ２ ,O-(EH ２ )n １ -S(O ２ )-(CH ２ )n ２ ,-O-(EH ２ )n １ -NR-(CH ２ )n ２ ,-O-(EH ２ )n １ -EHR'-(E ２ )n ２ ,-NR-(CH ２ )n １ -、-NR-(CO)-(CH ２ )n １ -、-O-(EH ２ )n １ -Ar-(EH) ２ )n ２ ,-O-(EH ２ )n １ -AMO-(EH ２ )n ２ ,-O-(EH ２ )n １ -AME-S-(EH ２ )n ２ ,-O-(EH ２ )n １ -Ar-S(O)-(CH ２ )n ２ ,-O-(EH ２ )n １ -Ar-S(O ２ )-(CH ２ )n ２ ,-O-(EH ２ )n １ -Ar-CHRR'-(CH ２ )n ２ ,-O-(EH ２ )n １ -Ar-CH=CH-、O-Ar-NR-(CH ２ )n １ ,-(EH ２ )n １ -NR-(A)-(CH ２ )n ２ - Or Z is 【Chemistry 103】 and Y １ is a hydrogen atom, R １ , R ２ , Y ３ a carbon atom bonded to R ３ C or N bonded to a carbon atom bonded to Y ２ is O or NR′, 【Chemistry 104】 and Ar is an optionally substituted aryl or heteroaryl group; R is a hydrogen atom, a straight or branched chain C １ ~C ３ is an alkyl group or an optionally substituted aryl group, R' is a straight or branched chain C alkyl group optionally substituted with a hydrogen atom or hydroxyl, optionally substituted aryl and alkoxy, or 1 to 3 halogen atoms. １ ~C ３ alkyl, n １ , n ２ is an integer from 1 to 6, R １ , R ２ , R ４ , R ８ , R ９ , R １０ are the same or different, and each is a straight-chain or branched C optionally substituted with a hydrogen atom, halo, cyano, or 1 to 3 halogen atoms. １ ~C ３ Alkyl, straight or branched chain C １ ~C ３ is a group selected from alkoxy or optionally substituted aryl, R ３ is a straight or branched chain C optionally substituted with hydrogen or 1 to 3 halogen atoms １ ~C ３ is an alkyl group, or R ２ and R ３ form a ring with the atoms that hold them together, R ５ , R ６ are the same or different and each represents a hydrogen atom, a deuterium atom, a halogen atom, or a straight-chain or branched-chain C １ ~C ３ is an alkyl group, R ７ is hydroxyl and NHR' ７ is a group selected from Here, R' ７ is a straight or branched chain C １ ~C ６ is an alkyl group or an optionally substituted aryl or heteroaryl group. and its optical isomers and addition salts with pharmaceutically acceptable bases.

2. Formula (IA): 【Chemistry 105】 [In the formula, Z, Y １ , Y ２ , R １ ~R ９ is as defined in claim 1.

2. The compound according to claim 1, which is represented by: [0023] its optical isomers and addition salts thereof with pharmaceutically acceptable bases.

3. Formula (IA) １ ): 【Chemistry 106】 [In the formula, R １ ~R ４ , R ８ ~R ９ , Y １ , Y ２ is as defined in claim 1, Z １ is -(CH ２ ) n １ , -(CH ２ ) n １ -O-(CH ２ ) n ２ , -(CH ２ ) n １ -S-(CH ２ ) n ２ , -(CH ２ ) n １ -NR-(CH ２ ) n ２ , -(CH ２ ) n １ -CHR'-(CH ２ ) n ２ , -(CH ２ ) n １ -Ar １ - (CH ２ ) n ２ , -(CH ２ ) n １ -Ar １ -O-(CH ２ ) n ２ , -(CH ２ ) n １ -Ar １ -S-(CH ２ ) n ２ , -(CH ２ ) n １ -Ar １ -CHR'-(CH ２ ) n ２ , -Ar １ -NR-(CH ２ ) n １ is a group selected from or Z １ teeth, 【Chemistry 107】 is wherein R, R'n 1 and n 2 are as defined in claim 1, and Ar 1 is a phenylene group.

3. The compound according to claim 2, which is represented by the formula: [0023] its optical isomers and addition salts thereof with pharmaceutically acceptable bases.

4. Formula (IB): 【Chemistry 108】 [In the formula, Z, Y １ , Y ２ , R １ ~R ７ is as defined in claim 1.

2. The compound according to claim 1, which is represented by: [0023] its optical isomers and addition salts thereof with pharmaceutically acceptable bases.

5. Formula (IC): 【Chemistry 109】 [In the formula, Z, Y １ , Y ２ , R １ ~R ８ and R １０ is as defined in claim 1.

2. The compound according to claim 1, which is represented by: [0023] its optical isomers and addition salts thereof with pharmaceutically acceptable bases.

6. Z is —O—(CH ２ ) n １ -, -O-(CH ２ ) n １ -O-(CH ２ ) n ２ or -O-(CH ２ ) n １ -S-(CH ２ ) n ２ 6. A compound of formula (I) according to any one of claims 1, 2, 4 or 5, wherein:

7. Y １ is a hydrogen atom, R １ , R ２ , Y ３ a carbon atom bonded to R ３ The compound of any one of claims 1 to 6, wherein C is bonded to a carbon atom bonded to

8. Y ２ is O or NCH ３ The compound of formula (I) according to any one of claims 1 to 7, wherein

9. the below described: [4,32-dimethyl-28,28-dioxo-22,27-dioxa-28λ ６ -thia-1,14,15,16-tetraazahexacyclo[21.5.3.1 ３，７ .1 ９，１３ .0 １２，１６ .0 ２６，３０ ]tritriaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetic acid, its optical isomers and addition salts thereof with pharmaceutically acceptable bases, [2,4,31-trimethyl-27,27-dioxo-21,26-dioxa-27λ ６ -thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 ３，７ .1 ９，１３ .0 １２，１６ .0 ２５，２９ ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and addition salts thereof with pharmaceutically acceptable bases, [4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ ６ -thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 ３，７ .1 ９，１３ .0 １２，１６ .0 ２５，２９ ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and addition salts thereof with pharmaceutically acceptable bases, [4-chloro-31-methyl-27,27-dioxo-21,26-dioxa-27λ ６ -thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 ３，７ .1 ９，１３ .0 １２，１６ .0 ２５，２９ ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and addition salts thereof with pharmaceutically acceptable bases, [4-methoxy-31-methyl-27,27-dioxo-21,26-dioxa-27λ ６ -thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 ３，７ .1 ９，１３ .0 １２，１６ .0 ２５，２９ ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and addition salts thereof with pharmaceutically acceptable bases, [4,33-dimethyl-29,29-dioxo-23,28-dioxa-29λ ６ -thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 ３，７ .1 ９，１３ .0 １２，１６ .0 ２７，３１ ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid, its optical isomers and addition salts thereof with pharmaceutically acceptable bases, [2,4,32-trimethyl-28,28-dioxo-19,22,27-trioxa-28λ ６ -thia-1,14,15,16-tetraazahexacyclo[21.5.3.1 ３，７ .1 ９，１３ .0 １２，１６ .0 ２６，３０ ]tritriaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetic acid, its optical isomers and addition salts thereof with pharmaceutically acceptable bases, [2,4,33-trimethyl-29,29-dioxo-23,28-dioxa-29λ ６ -thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 ３，７ .1 ９，１３ .0 １２，１６ .0 ２７，３１ ]tetratriaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid, its optical isomers and addition salts thereof with pharmaceutically acceptable bases, [23-chloro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ ６ -thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 ３，７ .1 ９，１３ .0 １２，１６ .0 ２５，２９ ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and addition salts thereof with pharmaceutically acceptable bases, [23-methoxy-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ ６ -thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 ３，７ .1 ９，１３ .0 １２，１６ .0 ２５，２９ ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and addition salts thereof with pharmaceutically acceptable bases, [23-fluoro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ ６ -thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 ３，７ .1 ９，１３ .0 １２，１６ .0 ２５，２９ ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and addition salts thereof with pharmaceutically acceptable bases, [4,26,31-trimethyl-27,27-dioxo-21-oxa-27λ ６ -thia-1,14,15,16,26-pentaazahexacyclo[20.5.3.1 ３，７ .1 ９，１３ .0 １２，１６ .0 ２５，２９ ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and addition salts thereof with pharmaceutically acceptable bases, [4,32-dimethyl-28,28-dioxo-22,27-dioxa-19,28λ ６ -dithia-1,14,15,16-tetraazahexacyclo[21.5.3.1 ３，７ .1 ９，１３ .0 １２，１６ .0 ２６，３０ ]tritriaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetic acid, its optical isomers and addition salts thereof with pharmaceutically acceptable bases, [30-chloro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ ６ -thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 ３，７ .1 ９，１３ .0 １２，１６ .0 ２５，２９ ]dotriaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and addition salts thereof with pharmaceutically acceptable bases, [4,32-dimethyl-28,28-dioxo-19,22,27-trioxa-28λ ６ -thia-1,14,15,16-tetraazahexacyclo[21.5.3.1 ３，７ .1 ９，１３ .0 １２，１６ .0 ２６，３０ ]tritriaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetic acid, its optical isomers and addition salts thereof with pharmaceutically acceptable bases 2. The compound of formula (I) according to claim 1, selected from:

10. A composition comprising a compound according to any one of claims 1 to 9 in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers. Pharmaceutical compositions.

11. 11. The pharmaceutical composition according to claim 10, further comprising one or more further active ingredients.

12. A compound according to any one of claims 1 to 9 for use as an Nrf2 activator.

13. 12. A pharmaceutical composition according to claim 10 or 11 for use in the treatment of diseases associated with increased oxidative stress and inflammation, impaired redox capacity, impaired detoxification or metabolic deregulation.

14. 12. The pharmaceutical composition according to claim 10 or 11, for use in the treatment of type II diabetes, non-alcoholic steatohepatitis, autosomal dominant polycystic kidney disease, acute kidney injury, Alport syndrome or Alström syndrome.

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