Novel macrocyclic compounds, methods for their preparation and pharmaceutical compositions containing them

Abstract

Compounds of the formula (I), optical isomers thereof and addition salts thereof with pharmaceutically acceptable bases: wherein Z, Y1, Y2, (formula II), R1 to R7 are as defined in the description. Pharmaceutical.

Description

[0001] This invention relates to novel macrocyclic compounds, methods for their preparation, and pharmaceutical compositions containing them.

[0002] The compounds of this invention are novel and possess highly valuable pharmacological characteristics. Background of the Invention

[0004] Nuclear factor erythrocyte-associated factor 2 (Nrf2), also known as erythrocyte-derived nuclear factor 2-like protein 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 large number of cellular protection genes. Of particular importance in this regard are the transcription of components of the glutathione and thioredoxin antioxidant system, as well as enzymes involved in phase I and II detoxification of exogenous and endogenous products, NADPH regeneration, and heme metabolism. Therefore, Nrf2 represents a key regulator of cellular defense mechanisms against exogenous substances and oxidative stress (Vomund S, A, Parnham MJ, Brune B, and von Knethen A Int J Mol Sci. 2017 Dec;18(12):2772; Bischof LJ, 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). Also of importance, Nrf2 is involved in and regulates key 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).

[0005] Since alterations in these fundamental physiological processes are intimately linked to 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 (reviewed in Cuadrado A, Rojo AI, Wells G, Hayes JD, Cousin SP, Rumsey WL, ttucks OC, Franklin S, Levo nen A-L, Kensler TW and Dinkova-Kostova AT Nature Reviews Drug Discovery 2019 vol. 18, pages 295-317; Robledinos-Antón N, Fernández-Ginés 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 2017 vol; Gao B., Doan A., Hybertson B.M. Clin. Pharmacol. 2014; 6: 19-34).

[0006] Nrf2 is an important component of the evolutionarily conserved defense mechanism in mammals, and zebrafish, Drosophila and C. elegans have been shown to have similar anti-stress systems (reviewed by Fuse Y and Kobayashi M Molecules. 2017 Mar; 22(3): 436). Nrf2 is ubiquitous and constitutively expressed in cells, ensuring their rapid protective response to oxidative, inflammatory and metabolic stress. Nrf2 expression is tightly regulated, with low Nrf2 levels providing basal expression of its target genes under healthy / non-stressed conditions. Under these conditions, Nrf2 is constantly degraded by the ubiquitin proteasome system, so it is rapidly renewed (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).

[0007] Degradation of Nrf2 is regulated by binding to the adaptor protein KEAP1 (Kelch-like ECH-associated protein 1) of E3 ubiquitin ligases. In the presence of oxidative and exogenous substance stress, degradation of Nrf2 is blocked by release of Keap1, allowing Nrf2 to accumulate and translocate to the nucleus, where it forms heterodimers with bZip proteins such as small muscle tendon fibromatosis (MAF) K, G and F through Neh1 containing CNC-bZIP domains (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 present a regulatory enhancer sequence called antioxidant response element (ARE). These genes participate and regulate a variety of homeostatic functions, including redox homeostasis, detoxification, inflammation, protein homeostasis 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).

[0008] KEAP1 comprises two discrete domains, a BTB (Broad complex, Tramtrack and Bric-a-brac) domain in the N-terminal region and a double glycine repeat (DGR; also known as 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). While the BTB domain contributes to homodimerization of KEAP1 and its interaction with CUL3, the Kelch domain mediates the binding of KEAP1 to Nrf2 through interaction with the Neh2 domain. In this KEAP1-Nrf2 interaction, two specific motifs in the Neh2 domain of Nrf2, DLG and ETGE, bind to the Kelch domain of KEAP1 homodimer, respectively. The recognition of the dual-site binding of KEAP1 homodimer to Nrf2 led to the proposal of a molecular mechanism of electrophilic stress sensing, which is 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 in Yamamoto et al. (Yamamoto M, Kensler TW, Motohashi H (2018). Physiol Rev 98: 1169-1203).

[0009] The intervening region (IVR) of KEAP1, located between the BTB and DGR / Kelch domains, is rich in reactive cysteine (Cys) residues that can act as stress sensors. Twenty-seven and twenty-five Cys residues were identified in human and mouse KEAP1 proteins, respectively. Of these, Cys151 in the BTB domain and Cys273 / 288 in the IVR are the major sensor cysteine residues (Dinkova-Kostova, A. T., Holtzclaw, W. D., Cole, R. N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., and Talalay, P. (2002). Proc. Natl. Acad. Sci. USA 99, 11908-11913; Zhang, D. D., 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 by using mutants of the three major cysteine residues, Cys151, Cys273, and Cys288. These experiments classified Nrf2 inducers into four classes, Class I (Cys151-preferred), Class II (Cys288-preferred), Class III (Cys151 / Cys273 / Cys288 collaborative-preferred), 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 code of Keapl modification sites for various electrophiles was recently 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 challenging to define the chemical nature of each class. Despite having similar structural features, 15d-PGJ2 and PGA2 belong to class II and class IV, respectively. Therefore, complex features such as the structure and reactivity of the electrophile can determine the interaction with specific Keapl reactive cysteine residues (Unoki T, Akiyama M, Kumagai Y. Int J Mol Sci. 2020 Jan 15; 21(2)).

[0010] As their molecular target is KEAP1 (Magesh S., Chen Y. and Hu L. Medicinal Research Reviews, 2012 vol. 32, no. 4, pp. 687-726), Nrf2 activators or KEAP1 inhibitors can be classified as electrophiles, protein-protein interaction (PPI) inhibitors and multi-target drugs.

[0011] Most pharmacological Nrf2 activators are electrophilic molecules that covalently modify one or more cysteine residues in the KEAP1 protein that are rich in thiols through oxidation or alkylation (Hur W., Gray N.S. Current Opinion in Chemical Biology. 2011; 15(1): 162-173; Satoh T., McKercher S.R., Lipton S.A. Free Radical Biology & Medicine. 2013; 65: 645-657; Wilson A.J., Kerns J.K., Callahan J.F., Moody C.J. Journal of Medicinal Chemistry. 2013; 56(19): 7463-7476). The only marketed Nrf2 activators to date are dimethyl fumarate (BG-12 or Tecfidera) and fumaderm (DRF) from Biogen. Dimethyl fumarate was approved in 2013 and DRF in 2019 for relapsing-remitting multiple sclerosis (MS) (Schimrigk S., Brune N., Hellwig K. et al., European Journal of Neurology. 2006; 13(6): 604-610; Gold R., Kappos L., Arnold D.L. et al., The New England Journal of Medicine. 2012; 367(12): 1098-1107; Fox R.J., Miller D.H., Phillips J.T. et al., The New England Journal of Medicine. 2012; 367(12): 1087-1097; Xu Z., Zhang F., Sun F., Gu K.F., Dong S., He D. Cochrane Database of Systematic Reviews. 2015; 4; Mills E.A., Ogrodnik M.A., 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).Fumaric acid esters-induced activation of the central nervous system Nrf2 was described in a mouse model of experimental allergic encephalomyelitis, a model of MS (Linker R.A., Lee D.H., Ryan S. et al., Brain. 2011; 134(3): 678-692).

[0012] In this model, fumaric acid esters-dependent Nrf2 activation was associated with improvement of the clinical course of MS, preservation of axons and increased activation of astrocytes. These beneficial effects of fumaric acid esters did not occur in Nrf2-null mice, thus indicating that fumaric acid esters act mainly through the targeting of the Nrf2 pathway. Fumaric acid esters are mainly converted to monomethyl fumarate (MMF) by intestinal esterases, only a small fraction of fumaric acid dimethyl ester (Dibbert S., Clement B., Skak-Nielsen T., Mrowietz U., Rostami-Yazdi M. Archives of Dermatological Research. 2013; 305(5): 447-451) being found in blood bound to glutathione. Since MMF is considered the active metabolite of fumaric acid dimethyl ester, several clinical trials are ongoing to assess the efficacy and safety of MMF.

[0013] Nrf2 activators interact with the cysteine residues of Keapl by virtue of their inherent electrophilic nature and also react with glutathione or thiols in the protein. Since such thiol-reactive chemicals have the potential to cause electrophilic damage in cells, chemicals that directly inhibit the protein-protein interaction (PPI) of Keapl and Nrf2 are emerging as attractive new Nrf2 inducers (Bertrand, H. C, Schaap, M., Baird, L., Georgakopoulos, N. D., Fowkes, A., Thiollier, C, Kachi, H., Dinkova-Kostova, A. T., and Wells, G. (2015). J. Med. Chem. 58, 7186-7194; Davies, T. G., Wixted, W. E., Coyle, J. E., Griffiths-Jones, C, Hearn, K., McMenamin, R., Norton, D., Rich, S. J., Richardson, C, Saxty, G., Willems, H. M., Woolford, A. J., Cottom, J. E., Kou, J. P., Yonchuk, J. G., et al. (2016). J. Med. Chem. 59, 3991-4006; Jiang, Z. Y, Lu, M. C, and You, Q. D. (2016). J. Med. Chem. 59, 10837-10858; Lu, M. C, Ji, J. A., Jiang, Y. L., Chen, Z. Y, Yuan, Z. W., You, Q. D., and Jiang, Z. Y. (2016). Sci. Rep. 6, 26585; Yasuda, D., Nakajima, M., Yuasa, A., Obata, R., Takahashi, K., Ohe, T., Ichimura, Y., Komatsu, M., Yamamoto, M., Imamura, R., Kojima, H., Okabe, T., Nagano, T., and Mashino, T. (2016) Bioorg. Med. Chem. Lett. 26, 5956-5959).

[0014] PPI inhibitors interfere with the docking of Nrf2 to the Kelch propeller of KEAP1 and likely provide higher selectivity than electrophilic compounds (Richardson B.G., Jain A.D., Speltz T.E., Moore T.W. Bioorganic & Medicinal Chemistry Letters. 2015; 25(11): 2261-2268). Based on the X-ray crystal structure of KEAP1, small PPI inhibitors were designed to prevent the binding of the DLG and ETGE motifs to KEAP1. The ETGE motif adopts a beta-hairpin structure that docks to the Kelch propeller of KEAP1 through specific hydrophobic and electrostatic interactions (Padmanabhan B., Tong K.I., Ohta T. et al., Molecular Cell. 2006; 21(5): 689-700; Lo S.C., Li X., Henzl M.T., Beamer L.J., Hannink M. The EMBO Journal. 2006; 25(15): 3605-3617). To date, no PPI inhibitor has entered clinical development, however, potent and selective PPI inhibitors of the KEAP1 Kelch-Nrf2 interaction have been described and their activity was demonstrated in in vitro and in vivo studies, respectively (Davies, T.G., Wixted, W.E., Coyle, J.E., Griffiths-Jones, C., Hearn, K., McMenamin, R., Norton, D., Rich, S.J., Richardson, C., Saxty, G., Willems, H.M., Woolford, A.J., Cottom, J.E., Kou, J.P., Yonchuk, J.G. et al., (2016). J. Med. Chem. 59, 3991-4006; Jiang, ZY, Lu, M C. and You, Q.D. (2016). J. Med. Chem. 59, 10837-10858; Robledinos-Antón N, Fernández-Ginés R, Manda G, Cuadrado A. Oxid Med Cell Longev. 2019: 9372182).

[0015] Another mechanism of KEAP1 inhibition involves interaction with the CUL3 / RBX1 complex, which is necessary for Nrf2 ubiquitination and degradation. Cys-151, located in the BTB domain, influences KEAP1 interaction with CUL3. Crystal structures of the BTB domain in complex with the pentacyclic triterpenoid 2-cyano-3,12-dioxo-olean-1,9(l l)-dien-28-oic acid (Bardoxolone, CDDO-Me or RTA 402) indicate that adduct formation with Cys-151 disrupts the interaction between KEAP1 and CUL3 (Cleasby A., Yon J., Day P.J. 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 in the Nrf2 binding conformation and newly expressed Nrf2 escapes KEAP1-CUL3 mediated ubiquitination.

[0016] Bardoxolone entered clinical trials for the treatment of end-stage chronic kidney disease (CKD) and type 2 diabetes (Pergola P.E., Raskin P., Toto R.D., et al., The New England Journal of Medicine. 2011; 365(4): 327-336). Despite phase II clinical trials showing long-term increases in glomerular filtration, the compound was stopped in phase III due to cardiovascular safety concerns (Zhang D.D. Antioxidants & Redox Signaling. 2013; 19(5): 517-518. doi: 10.1089 / ars.2012.5118). Kyowa Kirin recently started a new phase III clinical trial of Bardoxolone in patients with diabetic nephropathy (AYAME study) to better define the safety and efficacy of CDDO-Me. Currently, Bardoxolone is also under clinical investigation for Alport syndrome (phase 2 / 3 CARDINAL trial) and pulmonary arterial hypertension (phase 3 CATALYST trial). In addition, Reata is developing Bardoxolone for rare forms of CKD, including autosomal dominant polycystic kidney disease (ADPKD), IgA nephropathy (IgAN), type 1 diabetes CKD (T1D CKD), and focal segmental glomerulosclerosis (FSGS). A second-generation derivative of Bardoxolone, called Omaveloxone (RTA-408), is under clinical investigation in the pivotal registration MOXIe trial for Friedreich’s ataxia (Lynch D.R., Farmer J., Hauser L., et al., Annals of Clinical Translational Neurology. 2019; 6(1): 15-26; https: / / www.reatapharma.com / our-science / pipeline / ).

[0017] Several additional mechanisms have been proposed to explain the dissociation of Nrf2 from Keap1 under stress conditions. In addition to the oxidation of cysteine residues of Keap1 and targeting of the DLG and ETGE binding sites, the binding of p62 to Keap1 and the phosphorylation of Nrf2 by GSK3 have also been of particular interest.

[0018] p62, also known as sequestosome 1 (SQSTM1), is a ubiquitin-binding protein that targets protein aggregates for degradation via the autophagic pathway. p62 competes with Nrf2 for binding to Keapl, and binding of p62 to Keapl results in degradation of Keapl 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, and creates an Nrf2-driven positive feedback loop by inducing ARE-driven p62 gene transcription (Jain A, Lamark T, Sjottem E, Larsen KB, Awuh JA, Overvatn A, et al., J Biol Chem 2010; 285(29):22576-91). As p62 is a cargo receptor for selective autophagy, Keapl-Nrf2 has an interesting 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).

[0019] The stability of Nrf2 is also regulated by phosphorylation mediated by glycogen synthase kinase (GSK)-3. GSK-3 phosphorylates the DSGIS motif located in the Neh6 domain of Nrf2, creating a recognition site for the beta-transducin repeat-containing E3 ubiquitin-protein ligase (beta- 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 can suggest that GSK-3 inhibitors can be used as Nrf2 activators.

[0020] In addition to dimethyl fumarate for the treatment of relapsing-remitting multiple sclerosis and psoriasis, respectively, a number of studies support the broad therapeutic potential of Nrf2 activators.

[0021] The importance of Nrf2 in protection against electrophilic agents was first demonstrated with acetaminophen. Following acetaminophen exposure, Nrf2 knockout mice exhibited greater hepatotoxicity compared to WT mice, as evidenced by increased serum ALT values and liver histological changes (Chan K, Han X, Kan Y. Proc Natl Acad Sci U S A 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).

[0022] Acetaminophen also was shown to activate nuclear translocation of Nrf2 at non-toxic doses, illustrating the role of Nrf2 in coordinating adaptive responses that result 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 resulted in increased de novo synthesis of glutathione and conjugation and excretion of reactive acetaminophen metabolites. This observation was further confirmed by the use of a liver cell-specific conditional Keap1 knockout mouse, in which the repressive elements of the Nrf2 signaling pathway are absent, resulting in 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 Nrf2-regulated cytoprotective enzymes (Okawa H, Motohashi H, Kobayashi A, Aburatani H, Kensler T, Yamamoto M. Biochem Biophys Res Commun 2006; 339: 79-88).

[0023] Activation of Nrf2 signaling by KEAP1 gene knockdown suppressed the onset of diabetes, and when crossed with diabetic db / db mice, blood glucose levels became lower by improving insulin secretion and insulin resistance. KEAP1 knockdown also prevented high-calorie diet-induced diabetes, and oral Nrf2 inducer CDDO-Im also alleviated diabetes in db / db mice. Interestingly, Nrf2 induction altered the expression of genes related to antioxidant, energy expenditure, and gluconeogenesis in metabolic tissues. Overall, these data suggest that the KEAP1-Nrf2 system is a key target for preventing the onset of diabetes (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). Based on the data obtained in db / db mice, Xue and colleagues investigated the effect of Nrf2 ablation on ob / ob mice. Global ablation resulted in a decrease in white adipose tissue (WAT) mass but led to a more severe metabolic syndrome, with exacerbated insulin resistance, hyperglycemia, and hypertriglyceridemia. WAT of ob / ob mice expressed significantly higher levels of many genes related to antioxidant response, inflammation, adipocyte genesis, adipogenesis, glucose uptake, and lipid transport compared with wild-type mice. Deletion of Nrf2 in WAT resulted in decreased 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, the ability to control WAT expansion and insulin sensitivity through Nrf2, and the maintenance of 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).

[0024] Recent data support a key role for Nrf2 in β-cell survival and proliferation under stress conditions. Induction of Nrf2 is required for ChREBPa-mediated mitochondrial biogenesis and glucose-stimulated and ChREBPa-enhanced β-cell proliferation. Interestingly, overexpression of Nrf2 was sufficient to drive human β-cell proliferation in vitro, confirming the key role of this pathway and its potential use in therapeutic β-cell regeneration strategies (Kumar A, Katz LS, Schulz AM, Kim M, Honig LB, Li L, Davenport B, Homann D, Garcia-Ovejero D, Sempere L, Sempere AF, Moresco EM, Tsukumo Y, Yamamoto M, Pi J, Andersen ME. Diabetes. 2013 Mar;62(3):855-65). A, Herman MA, Haynes CM, Chipuk JE, Scott DK. Diabetes. 2018 Aug;67(8): 1561-1575). In addition, Nrf2 activators such as Oltipraz or dimethyl fumarate protect isolated mouse beta cells from glucolipotoxicity by preserving mitochondrial function, glucose-dependent ROS shift, and inhibition of insulin release and apoptosis induced by glucolipotoxicity (Schultheis J, Beckmann D, Mulac D, Muller L, Esselen M, Dufer M. Oxid Med Cell Longev. 2019 Nov 11;2019:7518510).

[0025] The important role of Nrf2 in the prevention of the onset 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 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 initially identified as being associated with the risk of acute lung injury, an oxidative stress-mediated disease (Marzec J.M., Christie J.D., Reddy S.P., Jedlicka A.E., Vuong H., Lanken P.N., Aplenc R., Yamamoto T., Yamamoto M., Cho H.-Y. FASEB J. 2007; 21 :2237-2246).

[0026] Activation of Nrf2 by knockdown of Keap1 expression in a type 1 diabetes NOD mouse model inhibited T cell infiltration within the islets, improved impaired insulin secretion and prevented the development of diabetes. Notably, Nrf2 activation decreased plasma interferon-gamma (IFN-g) levels and the number of IFN-g positive cells in the islets, indicating that activation of Nrf2 signaling prevented the onset of type 1 diabetes in NOD mice. Thus, Nrf2 appears to be a potential target for the prevention and treatment of type 1 diabetes (Yagishita Y. et al., J Endocrinol.: JOE-18-0355.R2. Online publication 2019 Jan 1. doi: 10.1530 / JOE-18-0355).

[0027] Oxidative stress and inflammation are the most important pathogenic events in the development and progression of liver disease, and a number of studies have shown that activation or inhibition of Nrf2 significantly affects 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 in preventing the development of NASH (Gupte A.A., Lyon C.J., Hsueh W.A. (2013).. Curr. Diabetes Rep. 13 362-371. 10.1007 / s11892-013-0372-1), and conversely, a deficiency or absence of Nrf2 has been found to cause benign steatosis, which in turn develops into NASH and leads to a worsening of the disease state (Chowdhry S., Nazmy M.H., Meakin P.J., Dinkova-Kostova A.T., Walsh S.V., 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 T.W., Wruck C.J. et al., (2017). Oxid. Med. Cell. Longev. 2017: 3420286). The development of NASH has also been studied in p62:Nrf2 double knockout (DKO) mice. DKO mice exhibit severe hepatomegaly and steatohepatitis, obesity with insulin resistance and an imbalance of adipokines caused by excessive food intake (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).

[0028] Sharma and colleagues demonstrated the protective role of Nrf2 in NASH by using the Nrf2-activating small molecule TBE-31. TBE31 treatment reversed insulin resistance in high-fat high-fructose-fed wild-type mice, but not in Nrf2 deficient mice. In addition, TBE-31 treated mice had significantly reduced liver steatosis and expression of lipogenesis genes, while liver expression of fatty acid oxidation and lipoprotein assembly genes was increased. Furthermore, TBE-31 treatment reduced ER stress, expression of inflammatory genes, and markers of apoptosis, fibrosis, and oxidative stress in the liver of high-fat high-fructose-fed wild-type mice. In contrast, TBE-31 did not reduce steatosis, ER stress, lipogenesis, inflammation, fibrosis, or oxidative stress in the liver of HFFr-fed Nrf2 deficient mice. The authors concluded that pharmacological activation of Nrf2 in mice that have become obese and insulin resistant can reverse insulin resistance, suppress liver steatosis, and attenuate NASH and liver fibrosis. These effects are mainly attributed to the suppression 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).

[0029] The hepatoprotective role of Nrf2 after acute high-dose alcohol exposure was also demonstrated using Nrf2-KO mice. Alcohol treatment led to significantly worsened liver and pancreas injury in these animals, as well as pancreatic beta cell injury (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).

[0030] Nrf2 activators have potential use for diseases / indications associated with increased oxidative stress and inflammation, impaired redox potential, impaired detoxification, and metabolic dysregulation.

[0031] Based on Nrf2 knockout, KEAP1 knockout, genetic polymorphism, and compound-mediated Nrf2 activation studies, respectively, evidence is provided for diseases including Type I and Type II diabetes and related complications such as diabetic cardiomyopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and diabetic wound healing; gestational 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 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), and Alport syndrome, acute kidney injury caused by sepsis; kidney disease or dysfunction occurring during kidney transplantation, focal segmental glomerulosclerosis, IgA glomerulonephritis / nephropathy, fibrosis; lung diseases, such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, acute lung injury, lung infection, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary hypertension, environmental exposure secondary pulmonary disease, chronic and acute asthma, acute respiratory distress syndrome; heart diseases, such as atherosclerosis, hypertension, heart failure, stroke, cardiomyopathy, coronary heart disease, myocardial ischemia; neuronal injury, 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, neurons damaged / injured, spinal cord injury; inflammatory diseases, such as inflammatory bowel disease, ulcerative colitis, Crohn’s disease, pancreatitis, arthritis, lupus nephritis; eye diseases, such as age-related macular degeneration (AMD), ocular neurodegenerative disease, age-related macular degeneration, cataract, glaucoma, ocular injury, Fuchs endothelial corneal dystrophy (FECD), uveitis, optic neuropathy / ocular neurodegenerative disease; colon cancer; autoimmune diseases; psoriasis, dermatitis / radiation-induced local effects, immunosuppression caused by radiation exposure, preeclampsia, altitude sickness; wound healing; metabolic syndrome; mitochondrial myopathy; malaria; ferroptosis / iron overload; allergic contact dermatitis; alcohol dependence; amyloidosis; anemia; anxiety; Asperger’s syndrome; eczema; brain edema; cerebral ischemia; cerebrovascular disease; chronic fatigue syndrome; cognitive decline; dermatitis / radiation-induced dermatitis; Duchenne muscular dystrophy; edema; encephalitis; male / female fertility; fracture healing; gastroesophageal reflux disease; hearing loss; influenza infection; intestinal barrier dysfunction; osteoarthritis; osteoporosis; radiation-induced damage; reflux esophagitis; reperfusion injury (brain, heart, kidney, liver, retina); schizophrenia; seizure; Sjogren’s syndrome; sickle cell anemia; skin ulcers; vascular endothelial dysfunction; blood-brain barrier dysfunction; Down’s syndrome.

[0032] WO 2015 / 092713 discloses diaryl compounds as Nrf2 modulators.

[0033] The present application relates in particular to compounds of formula (I):

[0034]

[0035] wherein

[0036] Z is -0-(CH2)ni-, -0-(CH2)ni-0-(CH2)n2-, -0-(CH2)ni-S-(CH2)n2-, 0-(CH2)ni-S(O)-(CH2)n2, 0-(CH2)ni-S(O2)-(CH2)n2, -0-(CH2)ni-NR-(CH2)n2, -0-(CH2)ni-CHR'-(CH2)n2, -NR-(CH2)ni-, -NR-(CO)-(CH2)ni-, -0-(CH2)ni-Ar-(CH2)n2, -0-(CH2)ni-Ar-0-(CH2)n2, -0-(CH2)ni-Ar-S-(CH2)n2, -0-(CH2)ni-Ar-S(O)-(CH2)n2, -0-(CH2)ni-Ar-S(O2)-(CH2)n2, -0-(CH2)ni-Ar-CHR'-(CH2)n2, -0-(CH2)ni-Ar-CH=CH-, 0-Ar-NR-(CH2)ni, -(CH2)ni-NR-(CO)-(CH2)n2-

[0037] or Z is

[0038] Y1is C or N,

[0039] Y2is O or NR',

[0040]

[0041] Ar is an optionally substituted aryl or heteroaryl group,

[0042] R is a hydrogen atom, a linear or branched C1-C3 alkyl group or an optionally substituted aryl group,

[0043] R' is a hydrogen atom or a group selected from the list consisting of: a hydroxyl group, an optionally substituted aryl group and a linear or branched C1-C3 alkyl group optionally substituted with an alkoxy group or with 1 to 3 halogen atoms,

[0044] ni, n2are integers from 1 to 6,

[0045] R1, R2, R4, R8, R9, R 10 are the same or different and are each a hydrogen atom or a group selected from the list consisting of: a halogen, a cyano group, a linear or branched C1-C3 alkyl group optionally substituted with 1 to 3 halogen atoms, a linear or branched C1-C3 alkoxy group or an optionally substituted aryl group,

[0046] R3is a hydrogen or a linear or branched C1-C3 alkyl group optionally substituted with 1 to 3 halogen atoms,

[0047] R1, R2, R4, R8, R9, R10 the same or different and each is a hydrogen atom or a group selected from halogen, 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,

[0048] R3 is a hydrogen or a linear or branched C1-C3 alkyl optionally substituted with 1 to 3 halogen atoms,

[0049] or R2 and R3 form, together with the atom that bears them, a ring,

[0050] R5, R6 are the same or different and each is a hydrogen, deuterium or halogen atom or a linear or branched C1-C3 alkyl,

[0051] R7 is a group selected from hydroxyl and NHR’7,

[0052] wherein R’7 is a linear or branched C1-C6 alkyl or optionally substituted aryl or heteroaryl,

[0053] the optical isomers thereof and the addition salts thereof with a pharmaceutically acceptable base.

[0054] "aryl" means phenyl, naphthyl or biphenyl optionally substituted with one or more groups, the same or different, selected from halogen, hydroxyl, amino, linear or branched (C1-C6)-alkyl optionally substituted with 1-3 halogen atoms, carboxyl, cyano, linear or branched (C1-C6)-alkoxy optionally substituted with 1-3 halogen atoms, linear or branched (C1-C6)-aminoalkyl optionally N-substituted with one or two linear or branched (C1-C6)-alkyl groups, linear or branched (C1-C6)-alkylthio optionally substituted with 1-3 halogen atoms, linear or branched (C1-C6)-alkylsulfinyl optionally substituted with 1-3 halogen atoms or linear or branched (C1-C6)-alkylsulfonyl optionally substituted with 1-3 halogen atoms.

[0055] "Heteroaryl" means a monocyclic or bicyclic aromatic group having 5 to 12 ring members and containing one, two or three heteroatoms selected from oxygen, nitrogen and sulfur, it being understood that the heteroaryl group can optionally be substituted by one or more groups, identical or different, selected from halogen, hydroxyl, amino, cyano, linear or branched (Ci-C6)-alkyl optionally substituted with 1 to 3 halogen atoms, linear or branched (Ci-C6)-alkoxy optionally substituted with 1 to 3 halogen atoms, linear or branched (Ci-C6)-aminoalkyl optionally N-substituted with one or two linear or branched (Ci-C6)-alkyl groups, linear or branched (Ci-C6)-alkylthio optionally substituted with 1 to 3 halogen atoms, linear or branched (Ci-C6)-alkylsulfinyl optionally substituted with 1 to 3 halogen atoms or linear or branched (Ci-C6)-alkylsulfonyl optionally substituted with 1 to 3 halogen atoms.

[0056] Among the heteroaryls, one can mention, without implying any limitation, pyrrolyl, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, dihydroisoindolyl, indazolyl, benzothienyl, benzofuranyl, imidazopyridinyl.

[0057] Optical isomers are understood to mean diastereoisomers and enantiomers.

[0058] Among the pharmaceutically acceptable bases, one can mention, without implying any limitation, sodium hydroxide, potassium hydroxide, arginine, lysine, triethylamine and tert-butylamine.

[0059] One aspect of the application relates to compounds of formula (IA), a particular case of compounds of formula (I):

[0060]

[0061] in which Z, Y1, Y2, R1 to R9 are as defined in relation to formula (I), the optical isomers thereof and the addition salts thereof with a pharmaceutically acceptable base.

[0062] Another aspect of the application relates to compounds of formula (IA1), a particular case of compounds of formula (I):

[0063]

[0064] in which R1-R4, R8-R9, Y1, Y2 are as defined above and Z1 is a group selected from:

[0065] -(CH2)ni, -(CH2)ni-O-(CH2)n2, -(CH2)ni-S-(CH2)n2, -(CH2)ni-NR-(CH2)n2, -(CH2)ni-CHR'-(CH2)n2, -(CH2)ni-Ar1-(CH2)n2, -(CH2)ni-Ar1-O-(CH2)n2, -(CH2)ni-Ar1-S-(CH2)n2, -(CH2)ni-Ar1-CHR'-(CH2)n2, -Ar1-NR-(CH2)ni,

[0066] or Z1is

[0067] its optical isomers and the addition salts thereof with a pharmaceutically acceptable base.

[0068] Another aspect of the application relates to compounds of formula (IB), a particular case of compounds of formula (I):

[0069]

[0070] wherein Z, Y1, Y2, R1to R7are as defined above,

[0071] its optical isomers and the addition salts thereof with a pharmaceutically acceptable base.

[0072] Another aspect of the application relates to compounds of formula (IC), a particular case of compounds of formula (I):

[0073]

[0074] Z, Y1, Y2, R1to R8and R 10 as defined above,

[0075] its optical isomers and the addition salts thereof with a pharmaceutically acceptable base.

[0076] Another aspect of the application relates to compounds of formula (I) wherein Z is -O-(CH2)ni-, -O-(CH2)ni-O-(CH2)n2or -O-(CH2)ni-S-(CH2)n2.

[0077] Another aspect of the application relates to compounds of formula (I) wherein Y1is C.

[0078] Another aspect of the application relates to compounds of formula (I) wherein Y2is O or NCH3.

[0079] Another aspect of the application relates to compounds of formula (I) wherein is

[0080] Another aspect of the application relates to compounds of formula (I), wherein R7 is hydroxy.

[0081] Another aspect of the application relates to a process for preparing a compound of formula (IA1) (a particular case of a compound of formula (I)) starting from a compound of formula (II):

[0082]

[0083] wherein P1 is a protecting group of an acid function such as an alkyl group, P2 is a protecting group of an alcohol function,

[0084] said compound of formula (II) is reacted with a compound of formula (III):

[0085]

[0086] wherein R1-R3 and Y1 are as defined in relation to formula (I),

[0087] to give a compound of formula (IV):

[0088]

[0089] wherein R1-R3, R8-R9, Y1, Z1 and P1-P2 are as defined above,

[0090] said compound of formula (IV) is reacted with a compound of formula (V):

[0091]

[0092] wherein R4 and Y2 are as defined in relation to formula (I), P3 is a protecting group of an alcohol function,

[0093] to give a compound of formula (VI):

[0094]

[0095] wherein R1-R4, R8-R9, Y1, Y2, Z1 and P1-P3 are as defined above,

[0096] said compound of formula (VI) is deprotected to give a compound of formula (VII):

[0097]

[0098] wherein R1-R4, R8-R9, Y1, Y2, Z1 and P1 are as defined above,

[0099] said compound of formula (VII) is halogenated to give a compound of formula (VIII):

[0100]

[0101] wherein R1-R4, R8-R9, Y1, Y2, Z1and P1are as defined above, and X is a halogen atom such as Br or CI,

[0102] The compound of formula (VIII) is reacted with a base such as Cs2C03to give the compound of formula (IX):

[0103]

[0104] The compound of formula (IX) is deprotected by reaction with a base such as LiOH to give the compound of formula (IA1), which is separated into its stereoisomers if necessary, using chiral separation techniques.

[0105] The compounds of the application are Nrf2 activators.

[0106] They are therefore useful for the treatment of diseases associated with increased oxidative stress and inflammation, impaired redox potential, impaired detoxification and metabolic disorders, including: type I and type II diabetes and related complications such as diabetic cardiomyopathy, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy and diabetic wound healing; gestational 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), and Alport syndrome, acute kidney injury caused by sepsis; kidney disease or dysfunction occurring during kidney transplantation, focal segmental glomerulosclerosis, IgA glomerulonephritis / nephropathy, fibrosis; lung diseases, such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, acute lung injury, lung infection, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary hypertension, environmental exposure secondary pulmonary disease, chronic and acute asthma, acute respiratory distress syndrome; heart diseases, such as atherosclerosis, hypertension, heart failure, stroke, cardiomyopathy, coronary heart disease, myocardial ischemia; neuronal injury, 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, neurons damaged / injured, spinal cord injury; inflammatory diseases, such as inflammatory bowel disease, ulcerative colitis, Crohn’s disease, pancreatitis, arthritis, lupus nephritis; eye diseases, such as age-related macular degeneration (AMD), ocular neurodegenerative disease, age-related macular degeneration, cataract, glaucoma, ocular injury, Fuchs endothelial corneal dystrophy (FECD), uveitis, optic neuropathy / ocular neurodegenerative disease; colon cancer; autoimmune diseases; psoriasis, dermatitis / radiation-induced local effects, immunosuppression caused by radiation exposure, preeclampsia, altitude sickness; wound healing; metabolic syndrome; mitochondrial myopathy; malaria; ferroptosis / iron overload; allergic contact dermatitis; alcohol dependence; amyloidosis; anemia; anxiety; Asperger’s syndrome; eczema; brain edema; cerebral ischemia; cerebrovascular disease; chronic fatigue syndrome; cognitive impairment; dermatitis / radiation-induced dermatitis; Duchenne muscular dystrophy; edema; encephalitis; male / female fertility; fracture healing; gastroesophageal reflux disease; hearing loss; influenza infection; intestinal barrier dysfunction; osteoarthritis; osteoporosis; radiation-induced damage; reflux esophagitis; reperfusion injury (brain, heart, kidney, liver, retina); schizophrenia; seizures; Sjogren’s syndrome; sickle cell anemia; skin ulcers; vascular endothelial dysfunction; blood-brain barrier dysfunction; Down’s syndrome.

[0107] The compounds of the present application are particularly useful for the treatment of type II diabetes and NASH.

[0108] The present application also relates to pharmaceutical compositions comprising a compound of formula (I) together with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.

[0109] Useful dosages can vary from 0.5 mg to 1000 mg per day, depending on the age and weight of the patient, the potency of the compound, the nature and severity of the disease being treated, and any other relevant factors. Dosage is typically in the range of 0.5 mg to 1000 mg per day, administered in one or more dosages.

[0110] Among the pharmaceutical compositions according to the application, mention can more particularly be made of those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal or transcutaneous, nasal, rectal, translingual, ocular or respiratory administration, in particular tablets or dragees, sublingual tablets, gelatin capsules, capsules, suppositories, creams, ointments, dermal gels, injectable or drinkable formulations, aerosols and eye or nose drops.

[0111] According to one of the aspects of the application, the pharmaceutical composition is a tablet for oral administration.

[0112] In addition to the compound of formula (I), the tablet of the application also comprises one or more excipients or carriers, such as diluents, lubricants, binders, disintegrants, absorbents, colorants and sweeteners.

[0113] As examples of excipients or carriers, mention can be made of:

[0114] ♦ as diluents: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerol,

[0115] ♦ as lubricants: silicon dioxide, talc, stearic acid and its magnesium and calcium salts, polyethylene glycols,

[0116] ♦ as binders: aluminum and magnesium silicates, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone,

[0117] ♦ as disintegrants: agar agar, alginic acid and its sodium salt, effervescent mixtures.

[0118] The percentage of active ingredient of formula (I) in the tablet is preferably between 5% and 50% by weight.

[0119] According to one of the aspects of the application, the compound of formula (I) of the application is administered in combination with one or more additional active ingredients.

[0120] The combination administration can be in the form of simultaneous or sequential coadministration of two or more separate pharmaceutical compositions each containing one active ingredient (free combination), or in the form of a fixed combination administration of two or more active ingredients in the same pharmaceutical composition.

[0121] More particularly, the compound of formula (I) and its pharmaceutically acceptable salts can be used in combination with one or more other active ingredients useful for the prevention or treatment of diabetes or NASH, including biguanides, sulfonylureas, DPP 4 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.

[0122] Abbreviations

[0123] abs.: absolute

[0124] AcOH: acetic acid

[0125] aq.: aqueous

[0126] A ta phos. PdCI2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) dichloride

[0127] Cs2CO3: cesium carbonate

[0128] °C: degrees Celsius

[0129] DCM: dichloromethane

[0130] DDQ: 2,3-dichloro-5,6-dicyano-l,4-benzoquinone

[0131] dia: diastereoisomer

[0132] DIAD: diisopropyl azodicarboxylate

[0133] dioxane: 1,4-dioxane

[0134] DIPEA: diisopropylethylamine, N-ethyl-N-(propan-2-yl)propan-2-amine

[0135] DMEM: Dulbecco's modified Eagle's medium

[0136] DMF: N,N-dimethylformamide

[0137] DMSO: dimethyl sulfoxide

[0138] E1: first eluted enantiomer

[0139] E2: second eluted enantiomer

[0140] Et2O: diethyl ether

[0141] EtOAc: ethyl acetate

[0142] EtOH: ethanol

[0143] FBS: fetal bovine serum

[0144] g: gram

[0145] h: hour

[0146] HCI: hydrochloric acid

[0147] HCOOH: formic acid

[0148] HEC: hydroxyethylcellulose

[0149] H2SO4: sulfuric acid

[0150] HPLC: high-performance liquid chromatography

[0151] HRMS: high-resolution mass spectrometry

[0152] IPA: propan-2-ol

[0153] K2CO3: potassium carbonate

[0154] LC: liquid chromatography

[0155] LC-MS: liquid chromatography-mass spectrometry

[0156] LiOH: lithium hydroxide

[0157] M: molar

[0158] MeOH: methanol

[0159] MeCN: acetonitrile

[0160] mg: milligram

[0161] MgSO4: magnesium sulfate

[0162] MHz: megahertz

[0163] min: minute

[0164] mL: milliliter

[0165] mmol: millimole

[0166] MS: mass spectrometry

[0167] MTBE: methyl-tert-butyl ether

[0168] N2: nitrogen

[0169] NaCl: sodium chloride

[0170] NaH: sodium hydride

[0171] NaOH: sodium hydroxide

[0172] NaHCO3: sodium bicarbonate

[0173] Na2SO4: sodium sulfate

[0174] NBS: N-bromosuccinimide

[0175] NH4HCO3: ammonium bicarbonate

[0176] NH4Cl: ammonium chloride

[0177] NMR: nuclear magnetic resonance

[0178] NMP: N-methylpyrrolidone

[0179] Pd / C: palladium on activated carbon

[0180] Pd2(dba) 3: tris(dibenzylideneacetone)dipalladium(0)

[0181] PPh3: triphenylphosphine

[0182] quant.: quantitative yield

[0183] rac: racemic

[0184] RT: room temperature

[0185] sat.: saturated

[0186] tBuXPhos: 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

[0187] TEA: triethylamine

[0188] TFA: trifluoroacetic acid

[0189] THF: tetrahydrofuran

[0190] wt%: weight percent

[0191] General information

[0192] IUPAC chemical names were generated using ACD / Labs 2018 2.2 (file version C60H41, Build 106041, December 7, 2018).

[0193] All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from commercial sources and used without further drying.

[0194] Normal phase silica gel (flash) chromatography was performed on an ISCO CombiFlash Rf 200i, pre-packed silica gel column (Teledyne ISCO, Inc., 3134 Gold High Performance).

[0195] Microwave heating was performed in an Anton Parr MonoWave or CEM Mars microwave instrument.

[0196] Reverse phase (preparative) HPLC purification was performed on a HANBON NP7000 liquid chromatography system, equipped with a Phenomenex Gemini-NX 5u C18 5 μΜ C18, 250 mm x 50 mm i.d. column, run at 99.9 mL min -1 with UV diode array detection (210-400 nm) using pure water or 5 mM aqueous NH4HCO3, or 5 mM aqueous HCOOH, or 5 mM aqueous TFA and MeCN as eluents, unless otherwise stated.

[0197] Analytical LC-MS: Compounds of the application were characterised by high performance liquid chromatography-mass spectrometry (HPLC-MS) on an Agilent HP1200 and Agilent 6140 quadrupole LC / MS, operating in positive or negative electrospray ionisation mode. The molecular weight scan range was 100 to 1350. Parallel UV detection was performed at 210 nm and 254 nm. Samples were provided as 1 mM solutions in ACN or THF-water (1 :1) and were injected with a 5 μL loop. LC-MS analysis was performed on both instruments, one using basic eluents and the other using acidic eluents.

[0198] Basic LC-MS: Gemini-NX, 3 μm, C18, 50 mm x 3.00 mm i.d. column, run at 23 °C, flow rate of 1 mL min -1 using a gradient of 5 mM NH4HCO3(solvent A) and acetonitrile (solvent B) over varying / constant time, starting at 100% solvent A and ending at 100% solvent B.

[0199] Acidic LCMS: ZORBAX Eclipse XDB-C18, 1.8 μm, 50 mm x 4.6 mm i.d. column, run at 40 °C, flow rate of 1 mL min -1 using a gradient of 0.02% v / v aqueous HCOOH (solvent A) and 0.02% v / v HCOOH in MeCN (solvent B) over varying / constant time, starting at 100% solvent A and ending at 100% solvent B.

[0200] 1 H-NMR measurements were made using a Bruker Avance III 500 MHz spectrometer and a Bruker Avance III 400 MHz spectrometer, with DMSO-d6(six deuterated dimethyl sulfoxide) or CDC13(deuterated chloroform) as solvent. 1HNMR data is in the form of delta values given in parts per million (ppm) using the residual solvent peak (DMSO-d6 at 2.50 ppm, CDC13 at 7.26 ppm) as an internal standard. Splitting patterns are designated as: s (singlet), 2s (2 x singlet), d (doublet), 2d (2 x doublet), t (triplet), 2t (2 x triplet), q (quartet), 2q (2 x quartet), quint (quintet), sept (septet), m (multiplet), 2m (2 x multiplet), br s (broad singlet), br d (broad doublet), br t (broad triplet), br q (broad quartet), br m (broad multiplet), v br s (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).

[0201] HRMS was determined on a Shimadzu IT-TOF, ion source temperature 200 °C, ESI + / -, ionization voltage: (+-) 4.5 kV. Mass resolution minimum 10000.

[0202] The final product or final intermediate was separated into pure enantiomers / diastereomers on a milligram scale using chiral supercritical fluid chromatography (SFC) using a SFC-PICLAB-PREP 200 instrument (Pic Solution) by the following method:

[0203] • The mobile phase is carbon dioxide as supercritical fluid or mixed fluid (by adding a protic solvent, for example: isocratic 35-45% IPA or EtOH / supercritical CO2)

[0204] • The column was chosen according to the chromatogram, for example:

[0205] Whelk 01 RR 30 x 250 mm x 5 pm (particle size) or

[0206] LUX (Phenomenex) 30 mm x 150 mm x 5 pm (particle size) or

[0207] Chiralpak IG 30 x 250 mm x 5 pm (particle size)

[0208] • Temperature: 40 °C

[0209] • Detection: 230 nm

[0210] • Flow rate: 120-150 mL / min.

[0211] The following examples illustrate the application.

[0212] General procedure 1

[0213] General Method 1 Step 1

[0214] To a solution of 1-fluoro-3-methyl-2-nitro-benzene (1 eq., 64.5 mmol) in MeCN (2 mL / mmol, 101.3 g, 128.92 mL) was added the amino alcohol (3 eq., 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 250 mL water and 200 mL EtOAc. The separated organic layer was further washed with 150 mL brine. The combined aqueous layer was washed with 100 mL EtOAc. The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to dryness to get 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 get the title compound.

[0215] General Method 1 Step 2

[0216] To a solution of the product of General Method 1 Step 1 (1 eq., 834 mmol) in AcOH (1.2 mL / mmol, 42 g, 40 mL) was added NBS (1 eq., 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 200 ml ice water. The pH was adjusted to 14 with NaOH solution. The mixture was stirred at room temperature for 10 min. The mixture was extracted with 3x150 ml DCM. The combined organic layer was washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to dryness to get the title compound which was used directly in the next step without further purification or purified by reverse phase chromatography using water-MeCN as eluent.

[0217] General Method 1 Step 3

[0218] To a solution of the product of General Method 1, Step 2 (1 eq., 35.1 mmol) or appropriate aryl nitro compound in EtOH (25 mL / mmol, 692 g, 877 mL) and water (3 mL / mmol, 105 g, 105 mL) was added iron powder (15 eq., 29.4 g, 526 mmol) and NH4CI (5 eq., 9.38 g, 175 mmol) at room temperature. The reaction mixture was heated to 50 °C and stirred for 2 h. Upon completion of the reaction, the mixture was filtered through a pad of celite, then washed with 2 x 100 ml EtOH. The solvent was evaporated under reduced pressure, the evaporated residue was dissolved in 100 ml DCM. The solution was dried over anhydrous sodium sulfate, filtered, concentrated to dryness to give the title compound which was used directly in the next step without further purification.

[0219] General Method 1, Step 4

[0220] To a solution of the product of General Method 1, Step 3 (1 eq., 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 eq., 3.3 g, 48 mmol) was added portionwise and the reaction mixture was stirred at 0 °C for 10 min. The black heterogeneous mixture formed was allowed to warm to room temperature and stirring was continued for 30 min. Upon completion of the reaction, the mixture was quenched with 300 mL of water and the pH was adjusted to ~12 with a concentrated NaOH solution. The mixture was extracted with 3 x 70 ml DCM. The organic layer was washed with 150 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to dryness to give a black oil which was purified by normal phase silica gel chromatography using DCM-EtOAc (100:0 to 70:30) as eluent to give the title compound.

[0221] General Method 1, Step 5

[0222] To a solution of the product of General Method 1, Step 4 (1 eq., 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 eq., 1.6 g, 66 mmol) at room temperature and the mixture was stirred for another 30 min. Upon completion of the reaction, the mixture was quenched with 400 mL of water and 50 mL of 2M aqueous HC1. The mixture was extracted with 3 x 20 ml EtOAc. The organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered, 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.

[0223] General procedure 1 step 6

[0224] To a solution of the product of general procedure 1 step 5 (1 eq., 10 mmol) in THF (7 mL / mmol, 63 g, 70 mL) at 0 °C was added NaH (1.2 eq., 480 mg, 12 mmol, 60 wt% in mineral oil). 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 eq., 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 100 mL of water and extracted with 3x100 ml EtOAc. The combined organic layers were washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, 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.

[0225] General procedure 1 step 7

[0226] To a solution of the product of general procedure 1 step 6 (1 eq., 7.1 mmol) in DMF (7 mL / mmol, 47.4 g, 50 mL) at room temperature was added ethyl prop-2-enoate (2 eq., 1.44 g, 1.56 mL, 14.2 mmol), DIPEA (3 eq., 2.78 g, 3.75 ml, 21.5 mmol), tri-o-tolylphosphine (0.2 eq., 0.44 g, 1.4 mmol) and palladium diacetate (0.1 eq. 0.161 g, 0.71 mmol). The mixture was flushed twice with argon and heated at 100 °C in a closed Schlenk tube overnight. 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.

[0227] General procedure 2

[0228] General procedure 2 step 1

[0229] To a solution of 1-fluoro-3-methyl-2-nitro-benzene (1 eq., 1.93 mmol) in MeCN (2 mL / mmol, 101.3 g, 128.92 mL) was added at room temperature o-benzyl-glycinal (1.2 eq., 2.32 mmol) followed by Cs2CO3(2 eq., 1.26 g, 3.87 mmol) or TEA (2 eq., 3.87 mmol). 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 eluting with a water-MeCN gradient (95:5 to 0:100) to afford the title compound.

[0230] General method 2 step 2

[0231] To a solution of the product of general method 2 step 1 (1 eq., 22 mmol) in AcOH (26 mL) was added at room temperature NBS (1.2 eq., 4.6 g, 26 mmol). 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 the reaction was quenched with 200 ml ice water. The pH was adjusted to 14 with NaOH solution. The mixture was stirred at room temperature for 10 min. The mixture was extracted with 3x150 ml DCM. The combined organic layers were washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to afford the title compound which was purified by reverse phase chromatography eluting with a water-MeCN gradient (95:5 to 0:100) to afford the title compound.

[0232] General method 2 step 3

[0233] To a solution of the product of general method 2 step 2 (1 eq., 17 mmol) in EtOH (430 mL) (or IPA) and water (50 mL) was added at room temperature iron powder (15 eq., 14 g, 260 mmol) and NH4CI (5.5 eq., 5 g, 93.5 mmol). 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 pad of celite and washed with 2x100 ml EtOH. The mother liquor was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography eluting with a water-MeCN gradient (95:5 to 0:100) to afford the title compound.

[0234] General method 2 step 4

[0235] To a solution of the product of General Method 2, Step 3 (1 eq., 13 mmol) in AcOH (30 mL) and water (30 mL) at 0 °C was added H2SO4 (8.9 g, 4.6 mL, 90 mmol). Sodium nitrite (1.5 eq., 3.3 g, 48 mmol) was added in small portions and the reaction mixture was stirred at 0 °C for 10 minutes. The black heterogeneous mixture formed was allowed to warm to room temperature and stirring was continued at this temperature for 30 minutes. After the completion of the reaction, the mixture was quenched with 300 mL of water and the pH was adjusted to ~12 with 2 M aqueous NaOH solution. The mixture was extracted with 3 x 70 ml of DCM. The combined organic layers were washed with 150 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered, 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.

[0236] General Method 2, Step 5

[0237] To a solution of the product of General Method 2, Step 4 (1 eq., 2.91 mmol) in DMF (20 mL) at room temperature was added ethyl prop-2-enoate (2.2 eq., 642 g, 0.699 mL, 6.41 mmol), DIPEA (3 eq., 1.13 g, 1.52 ml, 8.74 mmol), tri-o-tolylphosphine (0.2 eq., 0.177 g, 0.583 mmol) and palladium acetate (0.1 eq. 0.65 g, 0.291 mmol). The mixture was flushed with argon twice and heated at 100 °C in a closed Schlenk tube overnight. After the 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.

[0238] General procedure 3

[0239] The aryl bromide derivative (1 eq., 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 eq., 2.79 g, 11 mmol) and dry potassium acetate (3.5 eq., 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(ll) catalyst (0.02 eq., 146 mg, 0.2 mmol) was added and the mixture was flushed again with argon or nitrogen and then heated at 75 °C under inert atmosphere overnight. After completion of the reaction, the mixture was filtered through a pad of celite and the mother liquor was evaporated to dryness under reduced pressure. The crude product was purified by normal phase silica gel chromatography with DCM-EtOAc (100:0 to 90:10) as eluent or by reverse phase chromatography with water-MeCN (95:5 to 0:100) as eluent to give the title compound.

[0240] General procedure 4

[0241] General method 4 step 1

[0242] Paraformaldehyde (3 eq., 12.8 mmol), magnesium dichloride (2 eq., 0.812 mg, 8.5 mmol) and TEA (2 eq., 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 min. The substituted phenol (1 eq., 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 50 mL EtOAc, washed with 50 mL 1 M HCI solution and then with 50 mL brine. The organic layer was dried over anhydrous MgS04, filtered, concentrated to give the crude product which was purified by normal phase silica gel chromatography with heptane-EtOAc as eluent to give the title compound.

[0243] General method 4 step 2

[0244] Chlorosulfonyl isocyanate (4 eq., 13 g, 8.1 mL, 93 mmol) was introduced into a round bottom flask at 0 °C. HCOOH (4 eq., 3.5 mL, 93 mmol) was added dropwise over 40 minutes at 0 °C. The mixture was allowed to warm to room temperature over 30 minutes and stirring was continued at room temperature for 1 hour. The mixture was cooled to 0 °C and the product of General Method 4, Step 1 (1 eq., 23 mmol) dissolved in NMP (3.5 mL / mmol, 81 mL) was added dropwise over 10 minutes. The mixture was allowed to warm to room temperature and stirring was continued at this temperature overnight. After completion of the reaction, the mixture was quenched with 500 mL of saturated aqueous NH4Cl solution. The mixture was extracted with 2 x 200 mL EtOAc, the combined organic layers were dried over anhydrous sodium sulfate, filtered, 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.

[0245] General Method 4, Step 3

[0246] To a cooled solution of the product of General Method 4, Step 2 (1 eq., 22.4 mmol) in MeOH (8 mL / mmol, 179 mL) was added sodium borohydride (1.2 eq., 1.02 g, 26.9 mmol) slowly over 20 minutes at -5 °C. The mixture was stirred at -5 °C for 1 hour. 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 eluting with a gradient of water-MeCN (95:5 to 0:100) to give the title compound.

[0247] General procedure 5

[0248] General Method 5, Step 1

[0249] To a stirred solution of 6-bromo-3,4-dihydro-l,2 6 ,3-oxathiazine 2,2-dioxide derivative (1 eq., 17 mmol) in DCM (92 mL) at room temperature was added TEA (1.1 eq., 2.5 mL, 18 mmol), N,N-dimethylpyridin-4-amine (0.1 eq., 0.2 g, 1.7 mmol) and di-tert-butyl dicarbonate (1.1 eq., 4 g, 18 mmol). The mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was extracted with 3 x 50 ml of 10 wt% aqueous citric acid solution and then with 50 ml of water. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to dryness to give the title compound which was used directly in the next step without further purification.

[0250] General Method 5, Step 2

[0251] The product of General Method 5, Step 1 (1 eq., 16 mmol) was introduced into a round bottom flask and dissolved in dioxane (7.5 mL / mmol, 120 mL). To the mixture was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (1.1 eq., 4.6 g, 18 mmol) and dry potassium acetate (3.5 eq., 5.6 g, 57 mmol) at room temperature. The mixture was flushed with argon or nitrogen. Finally, [1,1 '-bis(diphenylphosphino)ferrocene] palladium(II) dichloride catalyst (0.02 eq., 160 mg, 0.33 mmol) was added and the mixture was flushed again with argon or nitrogen. The mixture was heated at 75 °C under inert atmosphere overnight. The mixture was then filtered over a pad of celite and the mother liquor was concentrated to dryness under reduced pressure. The crude product was purified by normal phase silica gel chromatography using heptane-EtOAc (100:0 to 80:20) as eluent to afford the title compound.

[0252] General Method 5, Step 3

[0253] To a stirred solution of the product of General Method 5, Step 2 (1 eq., 11.5 mmol) in EtOH (15 mL / mmol, 73 mL) and water (7.5 mL / mmol, 37 mL) was added m-chloro-perbenzoic acid (1 eq., 2.84 g, 11.5 mmol) portionwise at room temperature. The mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was quenched with 100 mL of saturated aqueous NaHC03solution. The mixture was extracted with 3 x 50 ml EtOAc. The combined organic layers were washed with 50 mL of saturated aqueous NaHC03solution, then with 50 mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to dryness to afford the crude product which was purified by normal phase silica gel chromatography using heptane-EtOAc (100:0 to 50:50) as eluent to afford the title compound.

[0254] General Method 5, Step 4

[0255] To a solution of the product of General Method 5, Step 3 (1 eq., 9.2 mmol) in MeCN (58 mL) was added Cs2C03(2.4 eq., 7.2 g, 22 mmol) and benzyl bromide (2.2 eq., 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, then diluted with 40 ml EtOAc. The mixture was washed with 40 mL of brine, then with 40 mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to dryness to afford the crude product which was used directly in the next step without further purification.

[0256] General Procedure 5, step 5

[0257] To a solution of the product of General Procedure 5, step 4 (1 eq., 9.2 mmol) in DCM (75 mL) was added TFA (8 eq., 8.4 g, 5.66 mL, 74 mmol) dropwise and the mixture was stirred at room temperature overnight. The pH of the mixture was adjusted to 9 with saturated aqueous NaHC03solution. The layers were separated and the organic layer was extracted with 30 mL of brine, then 30 mL of water. The organic layer was dried over anhydrous sodium sulfate, 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.

[0258] General procedure 6

[0259] To a stirred solution of the aryl (or heteroaryl) (prop-2-enic acid ethyl ester) derivative (1 eq., 4.6 mmol) in dioxane (5-8 mL / mmol, 23 mL) and water (1-2.7 mL / mmol, 4.6 mL) was added [3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) aryl derivative (1.5-2 eq., 6.9 mmol) and TEA (1.5 eq., 0.96 mL, 6.9 mmol). The suspension was flushed with argon or nitrogen and degassed. Finally, chloro(l,5-cyclooctadiene)rhodium(I) dimer catalyst (0.05 eq., 56 mg, 0.23 mmol) was added and the mixture was heated at 80 °C under inert atmosphere for 4-16 hours. After completion of the reaction, the mixture was diluted with 100 mL of water, the layers were separated and the aqueous layer was extracted with 2 x 50 mL EtOAc. The combined organic layers were washed with 50 mL of brine, then dried over anhydrous Na2S04, 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, or by reverse phase chromatography eluting with a gradient of water-MeCN (95:5 to 0:100) to give the title compound.

[0260] General procedure 7

[0261] To a stirred solution of the hydroxymethyl phenyl derivative (1 eq., 1.6 mmol) in THF (22 mL / mmol, 35 mL) was added the substituted oxathiazine 2,2-dioxide or 1,3-benzothiadiazine 2,2-dioxide derivative (1-2.5 eq., 2.4 mmol) and PPh3(2.2 eq., 0.93 g, 3.5 mmol). The reaction mixture was cooled to 15 °C and DIAD (2 eq., 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 DCM-EtOAc (100:0 to 80:20) as eluent or by reverse phase chromatography eluting with a water-MeCN gradient (95:5 to 0:100) to give the title compound.

[0262] General procedure 8

[0263] To a stirred solution of the hydroxymethyl phenyl derivative (1 eq., 1.6 mmol) in THF (22 mL / mmol, 35 mL) was added the substituted oxathiazine 2,2-dioxide or 1,3-benzothiadiazine 2,2-dioxide derivative (1-2.5 eq., 2.4 mmol) and PPh3(2.2 eq., 0.93 g, 3.5 mmol). The reaction mixture was cooled to 15 °C and DIAD (2 eq., 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 DCM-EtOAc (100:0 to 80:20) as eluent or by reverse phase chromatography eluting with a water-MeCN gradient (95:5 to 0:100) to give the title compound. 6 ,3-oxathiazin-3-yl)methyl]phenyl]-3-(4-methyl-1H-benzotriazol-5-yl)propionic acid ethyl ester (1 eq., 0.883 mmol), Pd / C catalyst (0.1 eq., 0.0883 mmol), dioxane (3 mL), MeOH or EtOH (10 mL) and DCM (4 mL) 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 pad of celite and the volatiles evaporated from the filtrate to give the title compound. The crude product was purified by normal phase silica gel chromatography or reverse phase chromatography eluting with a water-MeCN gradient (95:5 to 0:100) to give the title compound.

[0264] General procedure 9

[0265] To a stirred solution of the hydroxymethyl phenyl derivative (1 eq., 1.6 mmol) in THF (22 mL / mmol, 35 mL) was added the substituted oxathiazine 2,2-dioxide or 1,3-benzothiadiazine 2,2-dioxide derivative (1-2.5 eq., 2.4 mmol) and PPh3(2.2 eq., 0.93 g, 3.5 mmol). The reaction mixture was cooled to 15 °C and DIAD (2 eq., 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 DCM-EtOAc (100:0 to 80:20) as eluent or by reverse phase chromatography eluting with a water-MeCN gradient (95:5 to 0:100) to give the title compound. 6To a solution of N-hydroxyalkyl 3-[3-[(6-hydroxy-2,2-dioxo-4H-l,2λ

[0266] General procedure 10

[0267] To a solution of N-hydroxyalkyl 3-[3-[(6-hydroxy-2,2-dioxo-4H-l,2λ 6 To a solution of N-hydroxyalkyl 3-[3-[(6-hydroxy-2,2-dioxo-4H-l,2λ

[0268] General procedure 11

[0269] To a solution of N-hydroxyalkyl 3-[3-[(6-hydroxy-2,2-dioxo-4H-l,2λ 6To a solution of ethyl 3-[3-[(6-hydroxy-2,2-dioxo-l,4-dihydro-2,l,3- benzothiadiazin-3-yl)methyl]phenyl]-3-(4-methyl-lH-benzotriazol-5-yl)propanoate (1 eq., 0.055 mmol) in MeCN (16 mL) was added Cs2CO3(1-3 eq., 11 mg, 0.055 mmol) and the mixture was stirred at room temperature to 80 °C for 4-36 hours. After the reaction was complete, water (10 mL) was added to the mixture and the MeCN was evaporated under reduced pressure. The residue was extracted with DCM (3 x 10 mL) and the combined organic layers were washed with water. The organic layer was dried over sodium sulfate, 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 eluting with a water-MeCN gradient (95:5 to 0:100) to give the title compound.

[0270] General procedure 12

[0271] To a solution of the macrocyclic ester (1 eq., 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 eq. - 4 eq., 4.8 mg, 0.20 mmol). The reaction mixture was stirred at room temperature to 80 °C for 2-30 hours. After the reaction was complete, a solution of citric acid (10%) or 1 M aqueous HC1 was added to the reaction mixture and the neutralized mixture was extracted with DCM three times. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative reverse phase chromatography eluting with a water-MeCN gradient (95:5 to 0:100) to give the title compound.

[0272] Example 1 : [4, 32-dimethyl-28, 28-dioxo-22, 27-dioxa-28 lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo[21.5.3.13 3,7 .1 9,13 .0 12,16 .0 26,30 ]tricosa-3(33), 4, 6, 9(32), 10, 12, 14, 23, 25, 30-decaen-8-yl] acetic acid

[0273]

[0274] Step Al: Preparation of 5-(3-methyl-2-nitroanilino)pentan-l-ol

[0275] General procedure 1 step 1 was applied using 1-fluoro-3-methyl-2-nitro-benzene (1 eq., 10.0 g, 7.85 mL, 64.5 mmol) and 5-aminopentan-1-ol (3 eq., 19.950 g, 21 mL, 193.5 mmol) as starting reagents to afford the title compound (12.6 g, 82% yield).

[0276] 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).

[0277] Step A2: Preparation of 5-(4-bromo-3-methyl-2-nitroanilino)pentyl acetate

[0278] General procedure 1 step 2 was applied using 5-(3-methyl-2-nitroanilino)pentan-1-ol (8 g, 34 mmol) as starting reagent to afford the title compound (12.6 g orange oil, quantitative).

[0279] 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, 6 H).

[0280] Step A3: Preparation of 5-(2-amino-4-bromo-3-methyl-anilino)pentyl acetate

[0281] General procedure 1 step 3 was applied using 5-(4-bromo-3-methyl-2-nitroanilino)pentyl acetate (12.6 g, 35.1 mmol) as starting reagent to afford the title compound (11.7 g orange solid, 91% yield).

[0282] 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).

[0283] Step A4: Preparation of 5-(5-bromo-4-methyl-1 H-benzotriazol-1 -yl)pentyl acetate

[0284] Using General Method 1 step 4 with 5-(2-amino-4-bromo-3-methyl- anilino)pentyl acetate (12 g, 32 mmol) as starting reagent, afforded the title compound (7.5 g orange oil, 69% yield).

[0285] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.7 (2d, 2H), 4.7 (t, 2H), 3.97 (t, 2H), 2.71 (s, 3H), 1.99 (s, 3H), 1.95 (m, 2H), 1.6 (m, 2H), 1.29 (m, 2H).

[0286] Step A5: Preparation of 5-(5-bromo-4-methyl-lH-benzotriazol-l- yl)pentan-l-ol

[0287] Using General Method 1 step 5 with 5-(5-bromo-4-methyl-lH- benzotriazol-l-yl)pentyl acetate (7.5 g, 22 mmol) as starting reagent, afforded the title compound (6.7 g orange oil, quantitative).

[0288] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.7 (2d, 2H), 4.7 (t, 2H), 4.35 (m, 1H), 3.35 (t, 2H), 2.71 (s, 3H), 1.9 (m, 2H), 1.45 (m, 2H), 1.28 (m, 2H).

[0289] Step A6: Preparation of 5-bromo-l-{5-[(4-methoxyphenyl)methoxy]pentyl}- 4-methyl-lH-benzotriazole

[0290] Using General Method 1 step 6 with 5-(5-bromo-4-methyl-lH- benzotriazol-l-yl)pentan-l-ol (3.0 g, 10 mmol) as starting reagent, afforded the title compound (3 g yellow oil, 72% yield).

[0291] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.7 (2d, 2H), 7.15 (d, 2H), 6.85 (d, 2H), 4.7 (t, 2H), 4.3 (s, 2H), 3.75 (s, 3H), 3.32 (t, 2H), 2.71 (s, 3H), 1.9 (m, 2H), 1.52 (m, 2H), 1.28 (m, 2H).

[0292] Step A7: Preparation of (2E)-3-(l-{5-[(4-methoxyphenyl)methoxy]pentyl}-4- methyl-lH-benzotriazol-5-yl)prop-2-enate

[0293] Using General Method 1 Step 7 with 5-bromo-l-{5-[(4-methoxyphenyl)methoxy]pentyl}- 4-methyl-lH-benzotriazole (3 g, 7.1 mmol) as starting reagent, afforded the title compound (3 g yellow solid, 91% yield).

[0294] 1 H-NMR (400 MHz, CDC13) δ ppm: 8.6 (s, 1H), 7.4 (m, 5H), 7.35 (dd, 1H), 7.3 (d, 1H), 7.15 (d, 1H), 5.1 (s, 2H).

[0295] Step Cl: Preparation of 6-(benzyloxy)-2H-l,2 6 ,3-oxathiazine-2,2-dione

[0296] Using General Method 4 Step 2 with 5-(benzyloxy)-2-hydroxybenzaldehyde (1 eq., 5.3 g, 23 mmol) as starting reagent, afforded the title compound (6.48 g yellow solid, 96% yield).

[0297] 1 H-NMR (400 MHz, CDC13) δ ppm: 8.6 (s, 1H), 7.4 (m, 5H), 7.35 (dd, 1H), 7.3 (d, 1H), 7.15 (d, 1H), 5.1 (s, 2H).

[0298] Step C2: Preparation of 6-(benzyloxy)-3,4-dihydro-2H-l,2 6 ,3-oxathiazine-2,2-dione

[0299] Using General Method 4 Step 3 with 6-(benzyloxy)-2H-l,2 6 ,3-oxathiazine-2,2-dione (1 eq., 6.48 g, 22.4 mmol) as starting reagent, afforded the title compound (5.9 g, yellow solid, 90% yield).

[0300] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 8.4 (sl, 1H), 7.45 (d, 2H), 7.4 (t, 2H), 7.3 (t, 1H), 7 (m, m H), 5.1 (s, 2H), 4.5 (s, 2H).

[0301] Step 1 : Preparation of 3-[3-(hydroxymethyl)-4-methylphenyl]-3-(1-{5-[(4- methoxyphenyl)methoxy]pentyl}-4-methyl-1 H-benzotriazol-5-yl)propanoic acid ethyl ester

[0302] General procedure 6 was applied using ((2E)-3-(1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4-methyl-1 H- benzotriazol-5-yl)prop-2-enoic acid ethyl ester (1 eq., 4 g, 4.6 mmol) and [2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (1.5 eq., 1.7 g, 6.9 mmol) as starting reagents to give the title compound (0.96 g, 38% yield).

[0303] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1H), 7.48 (d, 1H), 7.25 (d, 1H), 7.18 (d, 2H), 7.08 (dd, 1H), 7 (d, 1H), 6.88 (d, 2H), 4.98 (t, 1H), 4.82 (t, 1H), 4.61 (t, 2H), 4.4 (d, 2H), 4.3 (s, 2H), 3.92 (q, 2H), 3.71 (s, 3H), 3.3 (t, 2H), 3.11 (2dd, 2H), 2.75 (s, 3H), 2.15 (s, 3H), 1.88 (m, 2H), 1.52 (m, 2H), 1.28 (m, 2H), 1 (t, 3H).

[0304] Step 2: Preparation of 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl]methyl}-4-methylphenyl)-3-(1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4-methyl-1 H-benzotriazol-5-yl)propanoic acid ethyl ester

[0305] General procedure 7 was applied using 3-[3-(hydroxymethyl)-4-methylphenyl]-3-(1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4-methyl-1 H-benzotriazol-5-yl)propanoic acid ethyl ester (1 eq., 0.96 g, 1.6 mmol) and 6-(benzyloxy)-3,4-dihydro-2H-1,26 3-oxothiazolidine-2,2-dione (1.5 eq., 0.7 g, 2.4 mmol) as starting reagent to give the title compound (90% yield).

[0306] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 1.16 (m., 3H) 1.21-1.29 (m, 1H) 1.44-1.56 (m, 1H) 1.78-1.89 (m, 1H) 2.21 (s, 1H) 2.76 (s, 1H) 3.16 (dd, J=7.95, 4.77 Hz, 1H) 3.26-3.29 (m, 1H) 3.92 (q, J=7.09 Hz, 2H) 4.21 (s, 2H) 4.28 (s, 2H) 4.42 (s, 2H) 4.59 (t, J=6.91 Hz, 2H) 4.85 (t, J=7.95 Hz, 1H) 5.10 (s, 2H) 6.82-6.88 (m, 2H) 6.94 (d, J=2.81 Hz, 1H) 7.03-7.10 (m, 1H) 7.10-7.17 (m, 4H) 7.17-7.21 (m, 1H) 7.22 (s, 1H) 7.31-7.37 (m, 1H) 7.37-7.43 (m, 2H) 7.45 (s, 2H) 7.48 (d, J=8.44 Hz, 2H) 7.56-7.61 (m, 1H).

[0307] Step 3: 3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2 6 Preparation of 3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2

[0308] Using the general method 8, 3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2 6 Using the general method 8, 3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2

[0309] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.7 / 4.38 (2m, 2H), 7.61 (d, 1H), 7.5 (d, 1H), 7.21 (d, 1H), 7.2 (dd, 1H), 7.12 (d, 1H), 6.99 (d, 1H), 6.8 (dd, 1H), 6.6 (d, 1H), 4.82 (t, 1H), 4.61 (t, 2H), 4.39 (s, 2H), 4.29 (m, 2H), 3.95 (q, 2H), 3.31 (t, 2H), 3.18 (m, 2H), 2.75 (s, 3H), 2.2 (s, 3H), 1.88 (m, 2H), 1.4 (m, 2H), 1.25 (m, 2H), 1 (t, 3H).

[0310] Step 4: Preparation of ethyl 3-[1-(5-bromopentyl)-4-methyl-1H- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate

[0311] Using the general method 9, ethyl 3-[1-(5-bromopentyl)-4-methyl-1H- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate (1 eq., 0.8 g, 1.3 mmol) as starting reagent, afforded the title compound (710 mg white solid, 80% yield).

[0312] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.7 (m, 1H), 7.61 (d, 1H), 7.5 (d, 1H), 7.21 (d, 1H), 7.2 (dd, 1H), 7.12 (d, 1H), 6.99 (d, 1H), 6.8 (dd, 1H), 6.6 (d, 1H), 4.82 (t, 1H), 4.65 (t, 2H), 4.39 (s, 2H), 4.29 (m, 2H), 3.92 (q, 2H), 3.45 (t, 2H), 3.18 (m, 2H), 2.75 (s, 3H), 2.21 (s, 3H), 1.9 (m, 2H), 1.8 (m, 2H), 1.35 (m, 2H), 1 (t, 3H).

[0313] Step 5: Preparation of [4,32-dimethyl-28,28-dioxo-22,27-dioxa-28λ 6 -thia-1,14,15,16-tetraazahexacyclo[21.5.3.13,7 .1 9,13 .0 12,16 .0 26,30 ]triaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl] ethyl acetate

[0314] Using General Method 11, ethyl 3-[1-(5-bromopentyl)-4-methyl-1H- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2lambda 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propionate (1 eq., 0.7 g, 0.99 mmol) as starting reagent to give the title compound (620 mg yellow oil, 93% yield).

[0315] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.65 (d, 1H), 7.52 (d, 1H), 7.5 (dd, 1H), 7.3 (d, 1H), 7.05 (d, 1H), 6.9 (dd, 1H), 6.78 (d, 1H), 6.12 (d, 1H), 4.8 (t, 1H), 4.7 (t, 2H), 4.2 / 3.9 (m, 2H), 4.15 / 4 (m, 2H), 3.9 (m, 2H), 3.85 (m, 2H), 3.07 (m, 2H), 2.68 (s, 3H), 2.35 (s, 3H), 2 (m, 2H), 1.75 (m, 2H), 1.5 / 1.4 (m, 2H), 1 (t, 3H).

[0316] Step 6: Preparation of Example 1

[0317] Using General Method 12, [4,32-dimethyl-28,28-dioxo-22,27-dioxa-28lambda 6 -sulfur-1,14,15,16-tetraazahexacyclo[21.5.3.13 3,7 .1 9,13 .0 12,16 .0 26,30 ]triaconta-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl] ethyl acetate (1 eq., 0.62 g, 0.92 mmol) as starting reagent to give the title compound (291 mg white solid, 55% yield).

[0318] The enantiopure product was isolated by chiral column chromatography.

[0319] Example 1a (E1)

[0320] C 30 H 32 HRMS calcd for N4O6S: 576.2042; [M+H] found: 577.2115 (delta = -0.1 ppm). +

[0321] Example 1b (E2)

[0322] C 30 H 32 HRMS calcd for N4O6S: 576.2042; [M+H] found: 577.2113 (delta = -0.4 ppm). +

[0323] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 11.55 (m, 1H), 7.62 (d, 1H), 7.5 (d, 2H), 7.29 (d, 1H), 7.02 (d, 1H), 6.9 (dd, 1H), 6.72 (d, 1H), 6.11 (d, 1H), 4.8 (t, 1H), 4.7 (t, 2H), 4.2 / 3.9 (2d, 2H), 4.11 / 4 (2d, 2H), 3.9 / 3.8 (2m, 2H), 2.92 (2dd, 2H), 2.65 (s, 3H), 2.31 (s, 3H), 1.99 (m, 2H), 1.72 (m, 2H), 1.48 / 1.38 (2m, 2H).

[0324] Example 2 : [4,30-Dimethyl-26,26-dioxo-20,25-dioxa-26 lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [ 19.5.3.1 3,7 .1 9,13 .0 12,16 .0 24,28 ]triaconta-3(31),4,6,9(30),10,12,14,21,23,28-decaen-8-yl]acetic acid

[0325]

[0326] Step Al: Preparation of N-[3-(benzyloxy)propyl]-3-methyl-2-nitroaniline

[0327] ​​​​​​​​​Step 1 of General Method 2 using 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 starting reagents to give the title compound (375 mg, 64% yield).

[0328] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.37-7.26 (m, 5H), 7.26 (t, 1 H), 6.77 (d, 1 H), 6.55 (d, 1 H), 6.47 (t, 1 H), 4.47 (s, 2H), 3.51 (t, 2H), 2.29 (s, 2H), 2.26 (q, 2H), 1.83 (m, 2H)

[0329] Step A2: Preparation of N-[3-(benzyloxy)propyl]-4-bromo-3-methyl-2-nitroaniline

[0330] Step 2 of General Method 2 using N-[3-(benzyloxy)propyl]-3-methyl-2-nitroaniline (6.5 g, 22 mmol) as starting reagents to give the title compound (6.54 g, 80% yield).

[0331] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.5 (d, 1 H), 7.3 (m, 5H), 6.72 (d, 1 H), 6.18 (t), 4.45 (s, 2H), 3.48 (t, 2H), 3.22 (q, 2H), 2.25 (s, 3H), 1.8 (m, 2H).

[0332] Step A3: Preparation of N 1 -[3-(benzyloxy)propyl]-4-bromo-3-methylbenzene-1,2-diamine

[0333] Step 3 of General Method 2 using N-[3-(benzyloxy)propyl]-4-bromo-3-methyl-2-nitroaniline (6.5 g, 17 mmol) as starting reagents to give the title compound (5.4 g, 75% yield).

[0334] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.39-7.24 (s, 5H), 6.71 (d, 1 H), 6.26 (d, 1 H), 4.62-4.54 (m, 3H), 4.48 (s, 2H), 3.55 (t, 2H), 3.08 (q, 2H), 2.16 (s, 3H), 1.86 (m, 2H).

[0335] Step A4: Preparation of l-[3-(benzyloxy)propyl]-5-bromo-4-methyl-lH- benzotriazole

[0336] Using General Method 2, Step 4, with N 1 -[3-(benzyloxy)propyl]-4-bromo-3-methylbenzene-l,2-diamine (5.4 g, 13 mmol) as the starting reagent to give the title compound (1.09 g, 23% yield).

[0337] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.68 / 7.65 (d, 2H), 7.34-7.2 (m, 5H), 4.78 (t, 2H), 4.38 (s, 2H), 3.41 (t, 2H), 2.71 (s, 3H), 2.18 (m, 2H).

[0338] Step A5: Preparation of (2E)-3-{l-[3-(benzyloxy)propyl]-4-methyl-lH- benzotriazol-5-yl}prop-2-enoic acid ethyl ester

[0339] Using General Method 2, Step 5, with l-[3-(benzyloxy)propyl]-5-bromo-4- methyl-lH-benzotriazole (1.05 g, 2.91 mmol) as the starting reagent to give the title compound (1.18 g, 70% yield).

[0340] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 1.28 (t, J = 7.09 Hz, 2H) 2.14-2.23 (m, 3H) 3.41 (td, J = 5.96, 3.00 Hz, 3H) 4.22 (q, J = 7.17 Hz, 2H) 4.36-4.41 (m, 3H) 4.78 (t, J = 6.79 Hz, 3H) 6.65 (d, J = 15.77 Hz, 1H) 7.28 (s, 7H) 7.69 (d, J = 8.80 Hz, 1H) 7.95-7.97 (m, 1H) 8.03 (d, J = 15.89 Hz, 1H).

[0341] Step 1: Preparation of 3-{l-[3-(benzyloxy)propyl]-4-methyl-lH-benzotriazol-5-yl}- 3-[3-(hydroxymethyl)-4-methylphenyl]propionic acid ethyl ester

[0342] Using general method 6, 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-dioxaneborane-2-yl)phenyl]methanol (1.5 equivalent) as starting reagents, the title compound (yellow oil, 44% yield) was obtained.

[0343] 1 H-NMR(400MHz,DMSO-d6)δppm:7.55(d,1H),7.45(d,1H),7.25(m,6H),7.1(dd,1H),7.01(d,1H),4.81(t,1H),4.8 1(t,1H),4.7(t,2H),4.4(d+s,4H),3.92(q,2H),3.4(t,2H),3.12(2dd,2H),2.75(s,3H),2.15(m+s,5H),1(t,3H).

[0344] Step 2: 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of ethyl 3-oxathiazine-3(4H)-yl]methyl}-4-methylphenyl)-3-{1-[3-(benzyloxy)propyl]-4-methyl-1H-benzotriazol-5-yl}propionate

[0345] Using general method 7, ethyl 3-{1-[3-(benzyloxy)propyl]-4-methyl-1H-benzotriazol-5-yl}-3-[3-(hydroxymethyl)-4-methylphenyl]propionate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ 6 Using 3-oxathiazine-2,2-dione (1.5 equivalents) as the starting reagent, the title compound was obtained (94% yield).

[0346] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 0.98 (t, J = 7.09 Hz, 3H) 2.13 (quint, J = 6.36 Hz, 2H) 2.22 (s, 3H) 2.76 (s, 3H) 3.17 (dd, J = 8.01, 3.36 Hz, 2H) 3.36 (t, J = 6.05 Hz, 2H) 3.92 (q, J = 7.13 Hz, 2H) 4.21 (s, 2H) 4.37 (s, 2H) 4.41 (s, 2H) 4.68 (t, J = 6.79 Hz, 2H) 4.85 (t, J = 8.01 Hz, 1H) 5.10 (s, 2H) 6.94 (d, J = 2.81 Hz, 1H) 7.03 - 7.09 (m, 1H) 7.10 - 7.16 (m, 2H) 7.16 - 7.31 (m, 7H) 7.32 - 7.37 (m, 1H) 7.37 - 7.43 (m, 1H) 7.44 - 7.47 (m, 1H) 7.48 (d, J = 8.80 Hz, 1H) 7.53 - 7.59 (m, 1H).

[0347] Step 3: Preparation of 3-[l-(3-bromopropyl)-4-methyl-lH-benzotriazol-5-yl]-3-{3-[(6- hydroxy-2,2-dioxo-2H-l,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propionic acid ethyl ester

[0348] General Procedure 8 was employed using 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-l,2λ 6 ,3-oxathiazin-3(4H)-yl]methyl}-4-methylphenyl)-3-{l-[3-(benzyloxy)propyl]-4- methyl-lH-benzotriazol-5-yl}propionic acid ethyl ester (1 equiv) as the reactant to give 3-{3-[(6-hydroxy-2,2-dioxo-2H-l,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}-3-[l-(3-hydroxypropyl)-4-methyl- lH-benzotriazol-5-yl]propionic acid ethyl ester (65% yield). The crude product was reacted with General Procedure 9 to give the title compound (69% yield).

[0349] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.65 (s, 1H), 7.62 (d, 1H), 7.51 (d, 1H), 7.2 (d, 1H), 7.18 (dd, 1H), 7.1 (d, 1H), 7 (d, 1H), 6.8 (dd, 1H), 6.6 (d, 1H), 4.85 (t, 1H), 4.75 (t, 2H), 4.38 (s, 2H), 4.2 (m, 2H), 3.92 (q, 2H), 3.48 (t, 2H), 3.18 (d, 2H), 2.75 (s, 3H), 2.42 (m, 2H), 2.21 (s, 3H), 1 (t, 3H).

[0350] Step 4: Preparation of [4,30-dimethyl-26,26-dioxo-20,25-dioxa-26 6 - thia-1,14,15,16-tetraazahexacyclo[19.5.3.13 3,7 .1 9,13 .0 12,16 .0 24,28 ]triaconta-3(31),4,6,9(30),10,12,14,21,23,28-decaene-8-yl] ethyl acetate

[0351] Using general procedure 11, ethyl 3-[1-(3-bromopropyl)-4-methyl-1H- benzotriazole-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2 6 ,3-oxathiazine-3(4H)-yl)methyl]-4-methylphenyl}propionate (1 equiv) as starting reagent, afforded the title compound (96% yield).

[0352] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.54 (d, 1H), 7.48 (dd, 1H), 7.44 (d, 1H), 7.28 (d, 1H), 7.01 (d, 1H), 6.85 (dd, 1H), 6.47 (d, 1H), 5.2 (d, 1H), 4.87 (m, 2H), 4.76 (t, 1H), 4.36 / 3.64 (d, 2H), 4.13 / 3.44 (d, 2H), 4.01 / 3.7 (tt, 2H), 3.91 (q, 2H), 3.03 (d, 2H), 2.63 (s, 3H), 2.47 / 2.38 (m, 2H), 2.32 (s, 3H), 1 (t, 3H).

[0353] Step 5: Preparation of Example 2

[0354] General procedure 12 was applied with [4, 30-dimethyl-26, 26-dioxo-20, 25-dioxa- 26lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [19.5.3.1 3,7 .1 9,13 .0 12,16 .0 24,28 ] thirty one carbon-3(31), 4, 6, 9(30), 10, 12, 14, 21, 23, 28-decaene-8-yl] ethyl acetate (1 equiv) as starting reagent to give the title compound as racemic mixture (white solid, 70% yield). C 28 H 28 N4O6S. HRMS calculated for C32H35N4O6S: 548.1730; [M+H] + found: 549.1805 (delta = 0.5 ppm).

[0355] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (m, 1H), 7.55 (d, 1H), 7.45 (dd, 1H), 7.4 (d, 1H), 7.25 (d, 1H), 7 (d, 1H), 6.85 (dd, 1H), 6.43 (d, 1H), 5.22 (d, 1H), 4.85 (m, 2H), 4.75 (t, 1H), 4.35 / 3.65 (m, 2H), 4.15 / 3.45 (m, 2H), 4 / 3.7 (m, 2H), 2.95 (d, 2H), 2.65 (s, 3H), 2.4 (m, 2H), 2.3 (s, 3H).

[0356] Example 3: [(2R, 8R)-2, 4, 31-trimethyl-27, 27-dioxo-21, 26-dioxa-27lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ] thirty two carbon-3(32), 4, 6, 9(31), 10, 12, 14, 22, 24, 29-decaene-8-yl] acetic acid and

[0357] [(2R, 8S)-2, 4, 31-trimethyl-27, 27-dioxo-21, 26-dioxa-27lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29Tricyclo[6.2.1.0]undeca-3(12),4,6,9(11),10,12,14-triene-8-carboxylic acid

[0358]

[0359] Step Al: Preparation of 4-(3-methyl-2-nitroanilino)butan-l-ol

[0360] Using General Method 1, Step 1, with 1-fluoro-3-methyl-2-nitro-benzene (1 equiv) and 4-aminobutan-l-ol (3 equiv) as starting reagents, afforded the title compound (44% yield).

[0361] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 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, 3 H), 1.58 (m, 2 H), 1.48 (m, 2 H).

[0362] Step A2: Preparation of 4-(4-bromo-3-methyl-2-nitroanilino)butyl acetate

[0363] Using General Method 1, Step 2, with 4-(3-methyl-2-nitroanilino)butan-l-ol (1 equiv) as starting reagent, afforded the title compound (orange oil, 93% yield).

[0364] 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).

[0365] Step A3: Preparation of 4-(2-amino-4-bromo-3-methyl-anilino)butyl acetate

[0366] Using General Method 1, Step 3, with 4-(4-bromo-3-methyl-2-nitroanilino)butyl acetate (1 equiv) as starting reagent, afforded the title compound (72% yield).

[0367] 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, 4 H).

[0368] Step A4: Preparation of 4-(5-bromo-4-methyl-lH-benzotriazol-l- yl)butyl acetate

[0369] Using General Method 1 Step 4, 4-(2-amino-4-bromo-3-methylphenylamino)butyl acetate (1 equiv) as the starting reagent, the title compound was obtained as an orange oil in 49% yield.

[0370] C 13 H 16 HRMS calcd for BrN3O2: 325.0426; [M+H] found: 326.0502 (delta = 1.0 ppm). + , found: 326.0502 (delta = 1.0 ppm).

[0371] Step A5: Preparation of 4-(5-bromo-4-methyl-lH-benzotriazol-l- yl)butan-l-ol

[0372] Using General Method 1 Step 5, 4-(5-bromo-4-methyl-lH-benzotriazol-l- yl)butyl acetate (1 equiv) as the starting reagent, the title compound was obtained as an orange oil in 85% yield.

[0373] 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).

[0374] Step A6: Preparation of 5-bromo-l-{4-[(4-methoxyphenyl)methoxy]butyl}-4- methyl-lH-benzotriazole

[0375] Using General Method 1 Step 6, 4-(5-bromo-4-methyl-lH-benzotriazol-l- yl)butan-l-ol (1 equiv) as the starting reagent, the title compound was obtained as a yellow oil in 74% yield.

[0376] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.68 (s, 2H), 7.19 (d, 2H), 6.88 (d, 2H), 4.71 (t, 2H), 4.32 (s, 2H), 3.73 (s, 3H), 3.39 (t, 2H), 2.72 (s, 3H), 1.95 (quint, 2H), 1.48 (quint, 2H).

[0377] Step A7: Preparation of (2E)-3-(l-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl- lH- benzotriazol-5-yl)prop-2-enate

[0378] Using General Method 1 Step 7 with 5-bromo-l-{4-[(4-methoxyphenyl)methoxy]butyl}- 4-methyl-lH-benzotriazole (1 equiv) as starting reagent, the title compound was obtained (yellow solid, 74% yield).

[0379] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.68 (s, 2H), 7.19 (d, 2H), 6.88 (d, 2H), 4.71 (t, 2H), 4.32 (s, 2H), 3.73 (s, 3H), 3.39 (t, 2H), 2.72 (s, 3H), 1.95 (quint, 2H), 1.48 (quint, 2H).

[0380] Step 1 : Preparation of (2E)-3-(l-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl- lH-benzotriazol-5-yl)-3-{3-[(lS)-l-hydroxyethyl]-4-methylphenyl}prop-2-enoic acid ethyl ester

[0381] Using General Method 6 with (2E)-3-(l-{4-[(4-methoxyphenyl)methoxy]butyl}-4- methyl-lH-benzotriazol-5-yl)prop-2-enate (1 equiv) and (lS)-l-[2-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]ethan-l-ol (2 equiv) as starting reagents, the title compound was obtained (yellow oil, 82% yield).

[0382] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 0.99 (t, J = 7.09 Hz, 3H) 1.22 (dd, J = 8.74, 6.42 Hz, 3H) 1.42 - 1.53 (m, 2H) 1.92 (quin, J = 7.21 Hz, 2H) 1.99 (s, 2H) 2.19 (s, 3H) 2.76 (d, J = 3.79 Hz, 3H) 3.09 - 3.16 (m, 2H) 3.38 (t, J = 6.30 Hz, 2H) 3.73 (s, 3H) 3.92 (q, J = 7.09 Hz, 2H) 4.32 (s, 2H) 4.64 (t, J = 6.91 Hz, 2H) 4.83 (dt, J = 7.64, 3.88 Hz, 2H) 4.92 - 5.01 (m, 1H) 6.83 - 6.90 (m, 2H) 6.95 - 7.01 (m, 1H) 7.02 - 7.08 (m, 1H) 7.19 (d, J = 8.56 Hz, 2H) 7.40 (d, J = 1.71 Hz, 1H) 7.43 - 7.49 (m, 1H) 7.55 - 7.60 (m, 1H).

[0383] Step 2: Preparation of 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2 6 ,3-oxathiazine-3(4H)-yl]ethyl}-4-methylphenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester

[0384] Using General Procedure 7, 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2 6 ,3-oxathiazine-2,2-dione (1.5 eq) as starting reagents, to give the title compound (69% yield).

[0385] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 0.93-1.01 (m, 3H) 1.36-1.49 (m, 5H) 1.83-1.94 (m, 2H) 2.28 (s, 3H) 2.77 (d, J=4.65 Hz, 3H) 3.17-3.24 (m, 2H) 3.32-3.38 (m, 2H) 3.72 (s, 3H) 3.88-3.95 (m, 2H) 4.29 (d, J=2.69 Hz, 2H) 4.37-4.46 (m, 1H) 4.56-4.65 (m, 2H) 4.82-4.91 (m, 1H) 5.03-5.13 (m, 2H) 5.27 (q, J=6.77 Hz, 1H) 6.80-6.91 (m, 3H) 6.95-7.07 (m, 2H) 7.07-7.15 (m, 2H) 7.18 (d, J=8.44 Hz, 2H) 7.30-7.48 (m, 6H).

[0386] Step 3: Preparation of 3-[l-(4-hydroxybutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(lR)-l-(6-hydroxy-2,2-dioxo-2H-l,2λ 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propionic acid ethyl ester

[0387] Using General Procedure 8, 3-(3-{(lR)-l-[6-(benzyloxy)-2,2-dioxo-2H-l,2λ 6 ,3-oxathiazin-3(4H)-yl]ethyl}-4-methylphenyl)-3-(l-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-lH-benzotriazol-5-yl)propionic acid ethyl ester (1 equiv) as starting reagent to give the title compound (79% yield).

[0388] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 1.00 (q, J = 7.01 Hz, 3H) 1.29 - 1.39 (m, 2H) 1.39 - 1.46 (m, 3H) 1.85 - 1.96 (m, 2H) 2.28 (s, 3H) 2.77 (s, 3H) 3.22 (d, J = 7.83 Hz, 2H) 3.35 - 3.41 (m, 3H) 3.94 (qd, J = 7.11, 2.02 Hz, 2H) 4.23 - 4.36 (m, 1H) 4.37 (s, 1H) 4.41 (t, J = 5.14 Hz, 1H) 4.65 (t, J = 7.03 Hz, 2H) 4.78 - 4.95 (m, 1H) 5.26 (q, J = 6.64 Hz, 1H) 6.53 - 6.62 (m, 1H) 6.69 - 6.76 (m, 1H) 6.79 - 6.84 (m, 1H) 6.88 - 6.94 (m, 1H) 7.05 - 7.15 (m, 3H) 7.47 (d, J = 10.64 Hz, 1H) 9.57 - 9.72 (m, 1H).

[0389] Step 4: Preparation of ethyl 3-[l-(4-bromobutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(lR)-l-(6-hydroxy-2,2-dioxo-2H-l,2 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propionate

[0390] Using General Procedure 9, ethyl 3-[l-(4-hydroxybutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(lR)-l-(6-hydroxy-2,2-dioxo-2H-l,2 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propionate (1 equiv) as starting reagent, afforded the title compound (colorless solid, 91% yield).

[0391] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.63 / 9.62 (2s, 1H), 7.64 / 7.59 (4d, 2H), 7.48 / 7.45 (2s, 1H), 7.11 (m, 2H), 6.91 (d, 1H), 6.73 (m, 1H), 6.6 / 6.56 (2d, 1H), 5.26 (m, 1H), 4.88 (m, 1H), 4.69 (t, 2H), 4.37 / 4.31 (s+m, 2H), 3.94 (2q, 2H), 3.54 (t, 2H), 3.23 (dl, 2H), 2.77 (s, 3H), 2.28 (s, 3H), 1.99 (quint, 2H), 1.77 (quint, 2H), 1.43 / 1.41 (2d, 3H).

[0392] Step 5: Preparation of [(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 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl] ethyl acetate

[0393] Using general procedure 11, ethyl [(2R)-2,4,31 -trimethyl-27,27-dioxo-21,26-dioxa- 27λ 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propionate (1 equiv) as starting reagent to give the title compound (white solid, 91% yield).

[0394] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 1.03 (td, J = 7.09, 3.30 Hz, 9H) 1.23 - 1.30 (m, 7H) 1.33 - 1.94 (m, 12H) 2.25 - 2.35 (m, 11H) 2.67 (s, 6H) 2.96 - 3.15 (m, 5H) 3.34 - 3.53 (m, 9H) 3.62 - 3.75 (m, 4H) 3.88 - 3.98 (m, 5H) 3.99 - 4.11 (m, 4H) 4.70 - 4.85 (m, 10H) 4.92 (t, J = 7.95 Hz, 2H) 5.18 - 5.31 (m, 2H) 5.72 (d, J = 2.81 Hz, 1H) 5.89 (br. s., 1H) 6.74 - 6.78 (m, 1H) 6.88 - 6.98 (m, 2H) 7.17 (s, 1H) 7.31 (d, J = 8.07 Hz, 1H) 7.44 (d, J = 7.58 Hz, 2H) 7.75 (d, J = 8.68 Hz, 1H) 7.89 (d, J = 8.68 Hz, 1H).

[0395] The diastereomerically pure final intermediates were isolated by chiral column chromatography.

[0396] Step 6: Preparation of Example 3

[0397] General Method 12 was used with [(2R,8R)-2,4,31 -trimethyl-27,27-dioxo-21,26-dioxa- 27λ 6 -sulfur-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]docosa-3(32),4,6,9(31 ),10,12,14,22,24,29-decaen-8-yl] acetate (1 equiv) or [(2R,8S)-2,4,31 -trimethyl-27,27-dioxo-21,26-dioxa-27λ 6 -sulfur-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12, 16 .0 25,29 ]docosa-3(32),4,6,9(31 ),10,12,14,22,24,29-decaen-8-yl] acetate (1 equiv) as starting reagents to give the title compounds (yield 34-78% respectively).

[0398] Example 3a (2R, 8R)

[0399] C 30 H 32 HRMS calculated for N4O6S: 576.2042; [M+H] found: 577.2119 (delta = 0.6 ppm). +

[0400] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.21 (m, 1H), 7.7 (d, 1H), 7.43 (d, 1H), 7.3 (d, 1H), 7.1 (d, 1H), 6.9 (d, 1H), 6.7 (m, 2H), 5.89 (m, 1H), 5.21 (q, 1H), 4.9 (t, 1H), 4.73 (m, 2H), 4.05 / 3.48 (m, 2H), 3.7 (m, 2H), 3.25 / 2.89 (2dd, 2H), 2.8 (s, 3H), 2.3 (s, 3H), 2.2 / 2 (2m, 2H), 1.61 / 1.29 (2m, 2H), 1.1 (d, 3H).

[0401] Example 3b (2R, 8S)

[0402] C 30 H 32 HRMS calculated for N4O6S: 576.2042; [M+H] found: 577.2118 (delta = 0.5 ppm). +

[0403] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.5-11.8 (m, 1H), 7.88 (d, 1H), 7.73 (d, 1H), 7.43 (d, 1H), 7.2 (d, 1H), 7.11 (d, 1H), 6.93 (d, 1H), 6.78 (dd, 1H), 5.69 (d, 1H), 5.25 (q, 1H), 4.82-4.67 (m, 2H), 4.78 (t, 1H), 4.01 / 3.4 (m, 2H), 3.68 / 3.47 (m, 2H), 3.19 / 2.99 (2dd, 2H), 2.62 (s, 3H), 2.29 (s, 3H), 2.23-2 (2m, 2H), 1.92-1.68 (2m, 2H), 1.23 (d, 3H).

[0404] Example 4: [5-Fluoro-31-methyl-27,27-dioxo-21,26-dioxa-27 lambda 6 -thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1​​9,13 .0 12,16 .0 25,29 ]triaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid

[0405]

[0406] 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

[0407] Using General Method 6, with ethyl (2E)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4- methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equiv) and [3-fluoro-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl]methanol (1.5 equiv) as starting reagents, the title compound was obtained (yellow oil, 30% yield).

[0408] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1H), 7.5 (d, 1H), 7.2 (d, 2H), 7.1-6.9 (m, 3H), 6.88 (d, 2H), 5.22 (t, 1H), 4.85 (t, 1H), 4.62 (t, 2H), 4.41 (d, 2H), 4.3 (s, 2H), 3.95 (q, 2H), 3.71 (s, 3H), 3.39 (t, 2H), 3.18 (m, 2H), 2.78 (s, 3H), 1.9 (m, 2H), 1.5 (m, 2H), 1 (t, 3H).

[0409] Step 2: Preparation of ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2 6 ,3-oxathiazine-3(4H)-yl]methyl}-5-fluorophenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}- 4-methyl-1H-benzotriazol-5-yl)propanoate

[0410] Using General Method 7, with ethyl 3-[3-fluoro-5-(hydroxymethyl)phenyl]-3-(1-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equiv) and 6- (benzyloxy)-3,4-dihydro-2H-1,2 6 ,3-oxathiazine-2,2-dione (1.1 equiv) as starting reagents, the title compound was obtained (64% yield).

[0411] 1 H-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).

[0412] Step 3: Preparation of 3-{3-fluoro-5-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]phenyl}-3-[1-(4-hydroxybutyl)-4-methyl-1H- benzotriazol-5-yl]propanoic acid ethyl ester

[0413] Using General Procedure 8, 3-{3-fluoro-5-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-5-fluorophenyl}-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoic acid ethyl ester (1 equiv) as starting reagent to give the title compound (96% yield).

[0414] 1 H-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).

[0415] Step 4: Preparation of 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-fluoro-5-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]phenyl}propanoic acid ethyl ester

[0416] Using General Procedure 9, ethyl 3-{3-fluoro-5-[(6-hydroxy-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl)methyl]phenyl}-3-[1 -(4-hydroxybutyl)-4-methyl- 1 H- benzotriazol-5-yl]propanoate (1 equiv) as starting reagent to give the title compound (66% yield).

[0417] 1 H-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, 2H), 6.88 (d, 1 H), 6.7 (dd, 1 H), 6.59 (d, 1 H), 4.87 (t, 1 H), 4.69 (t, 2H), 4.57 (s, 2H), 4.29 (s, 2H), 3.92 (q, 2H), 3.52 (t, 2H), 3.19 (d, 2H), 2.78 (s, 3H), 1.99 (m, 2H), 1.78 (m, 2H), 1 (t, 3H).

[0418] Step 5: Preparation of ethyl [5-fluoro-31 -methyl-27,27-dioxo-21,26-dioxa-27 6 thia-1,14,15,16-tetraazahexadecacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31 ),10,12,14,22,24,29-decaen-8-yl]acetate

[0419] Using General Procedure 11, ethyl 3-[1 -(4-bromobutyl)-4-methyl- 1 H- benzotriazol-5-yl]-3-{3-fluoro-5-[(6-hydroxy-2,2-dioxo-2H-1,2 6 oxathiazin-3(4H)-yl)methyl]phenyl}propanoate (1 equiv) as starting reagent to give the title compound (white solid, 72% yield).

[0420] 1H-NMR(400MHz,DMSO-d6)δppm:7.59(d,1H),7.4 / 7.06(2m,2H),7.32(d,1H),6.91(d,1H),6.74(m,1H),6.69(dd,1H),6(d,1H),4.87-4.67(m,3H ),4.15 / 4.05(2dd,4H),3.93(m,2H),3.67 / 3.37(2m,2H),3.27 / 3.11(2m ,2H),2.75(s,3H),2.18 / 1.96(2m,2H),1.68 / 1.45(2m,2H),1.01(t,3H)

[0421] Step 6: Preparation of Example 4

[0422] Using general method 12, [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 Starting with ethyl acetate (1 equivalent), the title compound was obtained (white solid, 98% yield).

[0423] C 28 H 27 HRMS calculated value of FN4O6S: 566.1635; [M+H] + Measured value: 567.1710 (δ=0.3ppm).

[0424] 1 H-NMR(400MHz,DMSO-d6)δppm:12.19(m,1H),7.59(d,1H),7.4 / 7.06(2m,2H),7.3(d,1H),6.91(d,1H),6.71(m,1H),6.69(dd,1H),6(d,1H ),4.87-4.67(m,3H),4.14 / 4.04(2dd,4H),3.68 / 3.38(2m,2H),3.17 / 2.91(2m,2H),2.75(s,3H),2.19 / 1.97(2m,2H),1.69 / 1.46(2m,2H).

[0425] Example 5 :[5,31-dimethyl-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 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaene-8-yl]acetic acid

[0426]

[0427] Step B1 : Preparation of [3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]methanol

[0428] General procedure 3 was applied using (3-bromo-5-methylphenyl)methanol (1 eq., 2.01 g, 10 mmol) as starting reagent to give the title compound (1.13 g, 45% yield).

[0429] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.44 / 7.35 / 7.23 (3tf, 3H), 5.12 (t, 1H), 4.46 (d, 2H), 2.29 (s, 3H), 1.28 (s, 12H).

[0430] Step 1 : Preparation of ethyl 3-[3-(hydroxymethyl)-5-methylphenyl]-3-(l-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-lH-benzotriazol-5-yl)propanoate

[0431] General procedure 6 was applied using ethyl (2E)-3-(l-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-lH-benzotriazol-5-yl)prop-2-enoate (1 eq.) and [3-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]methanol (2 eq.) as starting reagents to give the title compound (68% yield).

[0432] 1H-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 (3 s 1 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).

[0433] Step 2: Preparation of 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2 6 Step 2: Preparation of 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2

[0434] Using General Procedure 7, ethyl 3-[3-(hydroxymethyl)-5-methylphenyl]-3-(1-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-1 H-benzotriazole-5-yl)propanoate (1 equiv) and 6- (benzyloxy)-3,4-dihydro-2H-1,2 6 ,3-oxathiazine-2,2-dione (1.5 equiv) as the reagents gave the title compound (86% yield).

[0435] 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 (3 s 1 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).

[0436] Step 3: Preparation of ethyl 3-[1 -(4-hydroxybutyl)-4-methyl-1 H- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Step 4: Preparation of ethyl 3-[1 -(4-bromobutyl)-4-methyl-1 H- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ

[0437] Using General Procedure 8, ethyl 3-[1 -(4-hydroxybutyl)-4-methyl-1 H- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Step 4: Preparation of ethyl 3-[1 -(4-bromobutyl)-4-methyl-1 H- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ

[0438] 1 H-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, 3H), 6.91 (d, 1 H), 6.73 (dd, 1 H), 6.6 (d, 1 H), 4.83 (t, 1 H), 4.65 (t, 2H), 4.5 / 4.22 (2s, 4H), 3.94 (q, 2H), 3.39 (t, 2H), 3.14 (d, 2H), 2.77 (s, 3H), 2.24 (s, 3H), 1.91 (m, 2H), 1.37 (m, 2H), 1 (t, 3H).

[0439] Step 4: Preparation of ethyl 3-[1 -(4-bromobutyl)-4-methyl-1 H- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Step 4: Preparation of ethyl 3-[1 -(4-bromobutyl)-4-methyl-1 H- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ

[0440] Using General Procedure 9, ethyl 3-[1 -(4-hydroxybutyl)-4-methyl-1 H- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Step 4: Preparation of ethyl 3-[1 -(4-bromobutyl)-4-methyl-1 H- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ

[0441] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.61 (m, 1H), 7.63 (d, 1H), 7.49 (d, 1H), 7.14 / 7.07 / 6.98 (3tf, 3H), 6.9 (d, 1H), 6.73 (dd, 1H), 6.59 (d, 1H), 4.82 (t, 1H), 4.69 (t, 2H), 4.49 / 4.2 (2s, 4H), 3.93 (q, 2H), 3.54 (t, 2H), 3.14 (d, 2H), 2.76 (s, 3H), 2.22 (s, 3H), 1.99 (m, 2H), 1.77 (m, 2H), 0.99 (t, 3H).

[0442] Step 5: Preparation of [5, 31 -dimethyl-27, 27-dioxo-21, 26-dioxa-27 6 - thia- 1, 14, 15, 16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ethyl [5, 31 -dimethyl-27, 27-dioxo-21, 26-dioxa-27

[0443] Using general procedure 11, ethyl 3-[1 -(4-bromobutyl)-4-methyl- 1H- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H- 1,2 6 ,3-oxathiazin-3(4H)-yl)methyl]-5-methylphenyl}propanoate (1 equiv) as starting reagent, afforded the title compound (98% yield).

[0444] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1H), 7.35 (d, 1H), 7.34 / 7.09 / 6.58 (3m, 3H), 6.93 (d, 1H), 6.73 (dd, 1H), 5.98 (d, 1H), 4.84-4.66 (2m, 3H), 4.03 / 3.98 (2s, 4H), 3.93 (m, 2H), 3.68 / 3.45 (2m, 2H), 3.21 / 3.09 (2m, 2H), 2.71 (s, 3H), 2.36 (s, 3H), 2.19 / 1.99 (2m, 2H), 1.68 / 1.48 (2m, 2H), 1.01 (t, 3H).

[0445] Step 6: Preparation of Example 5

[0446] General Procedure 12 was used with [5,31 -dimethyl-27,27-dioxo-21,26-dioxa-27 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]triaconta-3(32),4,6,9(31 ),10,12,14,22,24,29-decaen-8-yl]acetic acid ethyl ester (1 equiv) as starting reagent to give the title compound (white solid, 50% yield).

[0447] C 29 H 30 HRMS calculated for C32H34N4O6S: 562.1886; [M+H] found: 563.1963 (delta = 0.7 ppm). + , found: 563.1963 (delta = 0.7 ppm).

[0448] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.15 (m, 1 H), 7.6 (d, 1 H), 7.34 / 7.09 / 6.57 (3 s 1 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 (2 m, 3 H), 4.03 / 3.98 (2 s, 4 H), 3.68 / 3.45 (2 m, 2 H), 3.11 / 2.97 (2 m, 2 H), 2.71 (s, 3 H), 2.36 (s, 3 H), 2.19 / 1.99 (2 m, 2 H), 1.71 / 1.47 (2 m, 2 H).

[0449] Example 6 :[31 -methyl-27,27-dioxo-21,26-dioxa-27 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]triaconta-3(32),4,6,9(31 ),10,12,14,22,24,29-decaen-8-yl]acetic acid

[0450]

[0451] Step 1 : Preparation of 3-[3-(hydroxymethyl)phenyl]-3-(1-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-1 H-benzotriazole-5-yl)propionic acid ethyl ester

[0452] The title compound was obtained using General Method 6 with (2E)-3-(1-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoic acid ethyl ester (1 equiv.) and [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (2 equiv.) as reagents (75% yield).

[0453] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.58 (d, 1H), 7.48 (d, 1H), 7.26-7.1 (m, 4H), 7.2 (d, 2H), 6.88 (d, 2H), 5.09 (t, 1H), 4.86 (t, 1H), 4.64 (t, 2H), 4.42 (d, 2H), 4.32 (s, 2H), 3.92 (q, 2H), 3.73 (s, 3H), 3.38 (t, 2H), 3.18 / 3.13 (2dd, 2H), 2.77 (s, 3H), 1.92 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H).

[0454] Step 2: Preparation of 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6- hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]phenyl}propionic acid ethyl ester

[0455] General Method 7 with 3-[3-(hydroxymethyl)phenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propionic acid ethyl ester (1 equiv.) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ 6 ,3-oxathiazine-2,2-dione (1.5 equiv.) as reagents to give 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl]methyl}phenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propionic acid ethyl ester. The crude product was used without purification using General Method 8. The title compound was obtained (77% yield).

[0456] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.61 (m, 1H), 7.61 (d, 1H), 7.48 (d, 1H), 7.36 (m, 1H), 7.28-7.14 (m, 3H), 6.89 (d, 1H), 6.72 (dd, 1H), 6.59 (d, 1H), 4.86 (t, 1H), 4.65 (t, 2H), 4.51 / 4.26 (2s, 4H), 4.41 (t, 2H), 3.93 (q, 2H), 3.38 (q, 2H), 3.16 (d, 2H), 2.76 (s, 3H), 1.9 (m, 2H), 1.37 (m, 2H), 1 (t, 3H).

[0457] Step 3: Preparation of 3-[l-(4-bromobutyl)-4-methyl-lH-benzotriazol-5-yl]-3-{3-[(6- hydroxy-2,2-dioxo-2H-l,2lambda 6 ,3-oxathiazin-3(4H)-yl)methyl]phenyl}propionic acid ethyl ester

[0458] General procedure 9 was applied using 3-[l-(4-hydroxybutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-l,2lambda 6 ,3-oxathiazin-3(4H)-yl)methyl]phenyl}propionic acid ethyl ester (1 equiv) as starting reagent to give the title compound (99% yield).

[0459] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.61 (m, 1H), 7.61 (d, 1H), 7.48 (d, 1H), 7.36 (m, 1H), 7.28-7.14 (m, 3H), 6.89 (d, 1H), 6.72 (dd, 1H), 6.59 (d, 1H), 4.86 (t, 1H), 4.65 (t, 2H), 4.51 / 4.26 (2s, 4H), 4.41 (t, 2H), 3.93 (q, 2H), 3.38 (q, 2H), 3.16 (d, 2H), 2.76 (s, 3H), 1.9 (m, 2H), 1.37 (m, 2H), 1 (t, 3H).

[0460] Step 4: Preparation of [31-methyl-27,27-dioxo-21,26-dioxa-27lambda 6 -sulfur-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29Preparation of [31 -methyl-27,27-dioxo-21,26-dioxa-27λ

[0461] Using General Method 11, ethyl [31 -methyl-27,27-dioxo-21,26-dioxa-27λ 6 ,3-oxathiazin-3(4H)-yl)methyl]phenyl}propanoate (1 equiv) as starting reagent to give the title compound (78% yield).

[0462] 1 H-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, 2H), 4.8 (m, 1 H), 4.11 / 4 (2s, 4H), 3.92 (q, 2H), 3.7 / 3.4 (2m, 2H), 3.2 / 3.1 (2dd, 2H), 2.71 (s, 3H), 2.2 / 2 (2m, 2H), 1.7 / 1.5 (2m, 2H), 1 (t, 3H)

[0463] Step 5: Preparation of Example 6

[0464] Using General Method 12, [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 ethyl [31 -methyl-27,27-dioxo-21,26-dioxa-27λ

[0465] C 28 H 28 N4O6S. HRMS calcd for: 548.1730; [M+H] + found: 549.1809 (δ = 1.2 ppm).

[0466] 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, 3 H), 2.2 / 1.98 (2m, 2 H), 1.7 / 1.48 (2m, 2 H).

[0467] 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 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid and

[0468] [(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 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid

[0469]

[0470] Step Al: Preparation of N-[4-(benzyloxy)butyl]-4-bromo-3-methyl-2-nitroaniline

[0471] 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 min. 4-Bromobutoxy methyl benzene (1.2 eq.) was added to the mixture over 5 min. The mixture was stirred at 65 °C for 72 h. After completion of the reaction, the mixture was quenched with 400 mL of water. The mixture was extracted with 3x150 ml EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to dryness to get the crude product which was purified by normal phase silica gel chromatography using heptane-DCM (20:80) as eluent to get the title compound (6.5 g, orange oil, 38% yield).

[0472] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.5 (d, 1H), 7.3 (m, 5H), 6.7 (d, 1H), 6.15 (t, 1H), 4.4 (s, 2H), 3.45 (t, 2H), 3.1 (q, 2H), 2.2 (s, 3H), 1.6 (m, 4H).

[0473] Step A2: N 1 Preparation of N-[4-(benzyloxy)butyl]-4-bromo-3-methylbenzene-1,2-diamine

[0474] To a solution of N-[4-(benzyloxy)butyl]-4-bromo-3-methyl-2-nitroaniline (1 eq., 6.1 g, 16 mmol) in EtOH (4 mL / mmol, 62 mL) was added tin (II) chloride dihydrate (4 eq., 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 160 ml EtOAc. The mixture was filtered and the mother liquor was separated. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to dryness to get the crude product which was purified by reverse phase chromatography using water-MeCN as eluent (4 g, 71% yield).

[0475] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.35-7.25 (m, 5H), 6.7 (d, 1H), 6.22 (d, 1H), 4.6 (s, 2H), 4.52 (t, 1H), 4.42 (s, 2H), 3.49 (t, 2H), 3 (q, 2H), 2.15 (s, 3H), 1.65 (m, 4H).

[0476] Step A3: Preparation of 3-[4-(benzyloxy)butyl]-5-bromo-4-methyl-1 H- benzotriazole

[0477] Using General Method 2, Step 4, with N 1 -[4-(benzyloxy)butyl]-4-bromo-3-methylbenzene-1,2-diamine (1 equiv) as the starting reagent to give the title compound (orange oil, 79% yield).

[0478] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.68 (s, 2H), 7.3-7.2 (m, 5H), 4.7 (t, 2H), 4.4 (s, 2H), 3.42 (t, 2H), 2.7 (s, 3H), 1.98 (m, 2H), 1.5 (m, 2H).

[0479] Step A4: Preparation of (2E)-3-{1-[4-(benzyloxy)butyl]-4-methyl-1 H- benzotriazol-5-yl}prop-2-en-1 -ol

[0480] Using General Method 2, Step 5, with 3-[4-(benzyloxy)butyl]-5-bromo-4- methyl-1 H-benzotriazole (1 equiv) as the starting reagent to give the title compound (black oil, 96% yield).

[0481] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.68 (s, 2H), 7.3-7.2 (m, 5H), 4.7 (t, 2H), 4.4 (s, 2H), 3.42 (t, 2H), 2.7 (s, 3H), 1.98 (m, 2H), 1.5 (m, 2H).

[0482] Step 1 : Preparation of (2E)-3-{1-[4-(benzyloxy)butyl]-4-methyl-1 H- benzotriazol-5-yl}-3-[3-(hydroxymethyl)-4-methylphenyl]prop-2-enoic acid ethyl ester

[0483] Using General Method 6, with (2E)-3-{1-[4-(benzyloxy)butyl]-4-methyl-1 H- benzotriazol-5-yl}prop-2-en-1 -ol (1 equiv) and [2-methyl-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl]methanol (1.5 equiv) as the reagents to give the title compound (49% yield).

[0484] 1H-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, 3 H).

[0485] Step 2: Preparation of 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H- benzotriazol-5-yl}-3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl]methyl}-4-methylphenyl}propionic acid ethyl ester

[0486] General Procedure 7 was used with 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H- benzotriazol-5-yl}-3-[3-(hydroxymethyl)-4-methylphenyl]propionic acid ethyl ester (1 equiv) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ 6 ,3-oxathiazine-2,2-dione (2.2 equiv) to give the title compound (60% yield).

[0487] 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).

[0488] Step 3: Preparation of 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3- [(6-hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propionic acid ethyl ester

[0489] Using General Method 8, ethyl 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H- benzotriazol-5-yl}-3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl]methyl}-4-methylphenyl)propanoate (1 equiv) as the starting reagent to give the title compound (white solid, quantitative).

[0490] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.62 (d, 1H), 7.5 (d, 1H), 7.22 (s, 1H), 7.2 (d, 1H), 7.15 (d, 1H), 7 (s, 1H), 6.8 (dd, 1H), 6.6 (d, 1H), 4.85 (t, 1H), 4.65 (t, 2H), 4.4 (m, 1H), 4.4 (s, 2H), 4.2 (m, 2H), 3.95 (q, 2H), 3.38 (tl, 2H), 3.15 (m, 2H), 2.75 (s, 3H), 2.32 (s, 3H), 1.9 (m, 2H), 1.35 (m, 2H), 1 (t, 3H).

[0491] Step 4: Preparation of ethyl 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3- [(6-hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate

[0492] Using General Method 9, ethyl 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3- [(6-hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate (1 equiv) as the starting reagent to give the title compound (73% yield).

[0493] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.68 (s, 1H), 7.63 (d, 1H), 7.52 (d, 1H), 7.22 (d, 1H), 7.2 (dd, 1H), 7.13 (d, 1H), 6.99 (d, 1H), 6.79 (dd, 1H), 6.6 (d, 1H), 4.84 (t, 1H), 4.69 (t, 2H), 4.38 (s, 2H), 4.2 (m, 2H), 3.94 (q, 2H), 3.54 (t, 2H), 3.19 (m, 2H), 2.76 (s, 3H), 2.22 (s, 3H), 1.99 (quint, 2H), 1.77 (quint, 2H), 1 (t, 3H).

[0494] Step 5: Preparation of [4,31 -dimethyl-27,27-dioxo-21,26-dioxa-27 6 - thia-1,14,15,16-tetraazahexacyclo[20.5.3.13 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31 ),10,12,14,22,24,29-decaen-8-yl]acetic acid ethyl ester

[0495] Using general procedure 11, ethyl 3-[1 -(4-bromobutyl)-4-methyl-1 H- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate (1 equiv) as starting reagent, afforded the title compound (white solid, 79% yield).

[0496] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.7 (d, 1H), 7.5 (dd, 1H), 7.45 (d, 1H), 7.3 (d, 1H), 7 (d, 1H), 6.8 (dd, 1H), 6.55 (d, 1H), 5.85 (d, 1H), 4.8 (m, 3H), 4.1 / 3.95 (m, 2H), 4 / 3.8 (m, 2H), 3.9 (m, 2H), 3.7 / 3.45 (m, 2H), 3.15 / 3.08 (m, 2H), 2.63 (s, 3H), 2.31 (s, 3H), 2.2 / 2 (m, 2H), 1.8 / 1.6 (m, 2H), 1.02 (t, 3H).

[0497] Step 6: Preparation of example 7

[0498] General procedure 12 was applied with [4,31 -dimethyl-27,27-dioxo-21,26-dioxa-27 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31 ),10,12,14,22,24,29-decaen-8-yl] ethyl acetate (1 equiv) as starting reagent to give the title compound (white solid, 93% yield).

[0499] The enantiomerically pure final product or final intermediate was obtained by separation on a chiral column.

[0500] Example 7a (8S)

[0501] C 29 H 30 HRMS calcd for N4O6S: 562.1886; [M+H] found: 563.1962 (delta = 0.6 ppm). +

[0502] Example 7b (8R)

[0503] C 29 H 30 HRMS calcd for N4O6S: 562.1886; [M+H] found: 563.1962 (delta = 0.6 ppm). +

[0504] 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, 3H), 4.11-3.92 (d, 2H), 4-3.85 (d, 2H), 3.62 / 3.4 (m, 2H), 3.05 / 2.95 (dd, 2H), 2.65 / 2.31 (s, 6H), 2.2 / 2.08 (m, 2H), 1.8 / 1.65 (m, 2H).

[0505] Example 8:[5-methoxy-31 -methyl-27,27-dioxo-21,26-dioxa-27 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1​​3,7 .1 9,13 .0 12,16 .0 25,29 ]triaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid

[0506]

[0507] Step 1: Preparation of ethyl 3-[3-(hydroxymethyl)-5-methoxyphenyl]-3-(1-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate

[0508] Using General Procedure 6, ethyl (2E)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4- methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equiv) and [3-methoxy-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (1 equiv) as starting reagents, afforded the title compound (yellow oil, 30% yield).

[0509] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.59 (d, 1H), 7.5 (d, 1H), 7.2 (d, 2H), 6.88 (d, 2H), 6.3-6.15 (3 sl, 3H), 5.1 (t, 1H), 4.81 (t, 1H), 4.62 (t, 2H), 4.4 (d, 2H), 4.3 (s, 2H), 3.95 (q, 2H), 3.71 (s, 6H), 3.39 (t, 2H), 3.12 (m, 2H), 2.75 (s, 3H), 1.92 (m, 2H), 1.5 (m, 2H), 1 (t, 3H).

[0510] Step 2: Preparation of ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl]methyl}-5-methoxyphenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate

[0511] Using General Procedure 7, ethyl 3-[3-(hydroxymethyl)-5-methoxyphenyl]-3-(1-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equiv) and 6-(benzyloxy)-3,4-dihydro-2H-1,2 6Using 3-oxathiazine-2,2-dione (1.1 equivalents) as the starting reagent, the title compound was obtained (88% yield).

[0512] 1 H-NMR(400MHz,DMSO-d6)δppm:7.72-7.3(m,5H),7.58(d,1H),7.48(d,1H),7. 2(d,2H),7-6.9(m,3H),6.91 / 6.8 / 6.72(3d,3H),6.87(d,2H),5.05(s,2H),4. 81(t,1H),4.62(t,2H),4.55(s,2H),4.3 / 4.23(2s,4H),3.91(q,2H),3.7(2s, 6H),3.35(t,2H),3.12(d,2H),2.78(s,3H),1.9(m,2H),1.48(m,2H),1(t,3H).

[0513] Step 3: 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Preparation of ethyl 3-oxathiazine-3(4H)-yl)methyl]-5-methoxyphenyl]propionate

[0514] Using general method 8, 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Starting with ethyl 3-oxathiazine-3(4H)-yl]methyl}-5-methoxyphenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propionate (1 equivalent), the title compound (white solid, 96% yield) was obtained.

[0515] 1 H-NMR(400MHz,DMSO-d6)δppm:9.6 / 4.4(s+t,2H),7.6(d,1H),7.5(d,1H),6.91(d,1H),6.9(d,1H),6.8 / 6.72 / 6.6(3sl,3H),6.71(dd,1H),4.81( t,1H),4.62(t,2H),4.52(s,2H),4.21(s,2H),3.92(q,2H),3.7(s,3H), 3.4(q,2H),3.17(d,2H),2.78(s,3H),1.9(m,2H),1.38(m,2H),1(t,3H).

[0516] Step 4: Preparation of ethyl 3-[l-(4-bromobutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-l,2l 6 oxathiazin-3(4H)-yl)methyl]-5-methoxyphenyl}propanoate

[0517] Using General Method 9, ethyl 3-[l-(4-bromobutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-l,2l 6 oxathiazin-3(4H)-yl)methyl]-5-methoxyphenyl}propanoate (1 equiv) as the starting reagent, afforded the title compound (white solid, 82% yield).

[0518] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.61 (m, 1H), 7.64 (d, 1H), 7.51 (d, 1H), 6.91 / 6.81 (2 s, 2H), 6.88 (d, 1H), 6.73 (s, 1H), 6.71 (dd, 1H), 6.58 (d, 1H), 4.82 (t, 1H), 4.69 (t, 2H), 4.51 / 4.21 (2 s, 4H), 3.93 (q, 2H), 3.69 (s, 3H), 3.54 (t, 2H), 3.15 (d, 2H), 2.76 (s, 3H), 1.99 (m, 2H), 1.78 (m, 2H), 1 (t, 3H).

[0519] Step 5: Preparation of ethyl [5-methoxy-31-methyl-27,27-dioxo-21,26-dioxa- 27l 6 thia-l,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 .0 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate

[0520] Using General Method 11, ethyl 3-[l-(4-bromobutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-l,2l 6 oxathiazin-3(4H)-yl)methyl]-5-methoxyphenyl}propanoate (1 equiv) as the starting reagent, afforded the title compound (95% yield).

[0521] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.33 (d, 1 H), 7.09 / 6.78 / 6.37 (3 s 1 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 (2 dd, 4 H), 3.94 (m, 2 H), 3.81 (s, 3 H), 3.52 / 3.42 (2 m, 2 H), 3.2 / 3.08 (2 dd, 2 H), 2.72 (s, 3 H), 2.19 / 1.98 (2 m, 2 H), 1.68 / 1.48 (2 m, 2 H), 1.02 (t, 3 H).

[0522] Step 6: Preparation of Example 8

[0523] Using the general method 12 with [5-methoxy-31-methyl-27,27-dioxo-21,26-dioxa-27 6 - thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl] acetate (1 equiv) as starting reagent to give the title compound (white solid, 28% yield).

[0524] The enantiopure product was obtained by separation on a chiral column.

[0525] Example 8a (E1)

[0526] C 29 H 30 HRMS calcd for N4O7S: 578.1835; [M+H] + found: 579.1911 (delta = 0.5 ppm).

[0527] Example 8b (E2)

[0528] C 29 H 30 HRMS calcd for N4O7S: 578.1835; [M+H] + found: 579.1912 (delta = 0.7 ppm).

[0529] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.15 (m, 1H), 7.6 (d, 1H), 7.31 (d, 1H), 7.31 (2dd, 4H), 7.1 / 6.8 / 6.38 (3sI, 3H), 6.95 (d, 1H), 6.71 (dd, 1H), 5.98 (d, 1H), 4.85-4.67 (m, 3H), 3.81 (s, 3H), 3.68 / 3.41 (2m, 2H), 3.1 / 2.98 (2dd, 2H), 2.71 (s, 3H), 2.19 / 1.98 (2m, 2H), 1.68 / 1.48 (2m, 2H).

[0530] Example 9 : [4-chloro-31-methyl-27,27-dioxo-21,26-dioxa-27 lambda 6 - thia- 1, 14, 15, 16-tetraazahexadecacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid

[0531]

[0532] Step 1: Preparation of ethyl 3-[4-chloro-3-(hydroxymethyl)phenyl]-3-(l-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-lH-benzotriazol-5-yl)propanoate

[0533] Using General Procedure 6, with ethyl (2E)-3-(l-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-lH- benzotriazol-5-yl)prop-2-enoate (1 equiv) and [2-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]methanol (2 equiv) as starting reagents, the title compound was obtained (yellow oil, 83% yield).

[0534] 1H-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).

[0535] Step 2: Preparation of 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2 6 Step 3: Preparation of 3-{4-chloro-3-[(6-hydroxy-2,2-dioxo-2H-1,2

[0536] Using General Procedure 7, ethyl 3-[4-chloro-3-(hydroxymethyl)phenyl]-3-(1-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-1 H-benzotriazole-5-yl)propanoate (1 equiv) and 6- (benzyloxy)-3,4-dihydro-2H-1,2 6 ,3-oxathiazine-2,2-dione (1.5 equiv) as starting reagents to give the title compound (92% yield).

[0537] 1 H-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 (2 s, 4 H), 4.3 (s, 2 H), 3.94 (q, 2 H), 3.72 (s, 3 H), 3.36 (t, 2 H), 3.2 (2 ddd, 2 H), 2.77 (s, 3 H), 1.9 (m, 2 H), 1.46 (m, 2 H), 1 (t, 3 H).

[0538] Step 3: Preparation of 3-{4-chloro-3-[(6-hydroxy-2,2-dioxo-2H-1,2 6Preparation of Ethyl 3-{4-chloro-3-[(6-hydroxy-2,2-dioxo-2H-1,2

[0539] Using General Method 8, ethyl 3-{4-chloro-3-[(6-hydroxy-2,2-dioxo-2H-1,2 6 Using General Method 8, ethyl 3-{4-chloro-3-[(6-hydroxy-2,2-dioxo-2H-1,2

[0540] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.68 (m, 1H), 7.64 (d, 1H), 7.51 (d, 1H), 7.49 (d, 1H), 7.39 (dd, 1H), 7.31 (d, 1H), 6.95 (d, 1H), 6.77 (dd, 1H), 6.63 (d, 1H), 4.89 (t, 1H), 4.66 (t, 2H), 4.51 / 4.33 (2s, 4H), 4.41 (t, 2H), 3.95 (q, 2H), 3.38 (q, 2H), 3.23 / 3.17 (2dd, 2H), 2.76 (s, 3H), 1.91 (m, 2H), 1.37 (m, 2H), 1.01 (t, 3H).

[0541] Step 4: Ethyl 3-{4-chloro-3-[(6-hydroxy-2,2-dioxo-2H-1,2 6 Preparation of Ethyl 3-{4-chloro-3-[(6-hydroxy-2,2-dioxo-2H-1,2

[0542] Using General Method 9, ethyl 3-{4-chloro-3-[(6-hydroxy-2,2-dioxo-2H-1,2 6 Using General Method 8, ethyl 3-{4-chloro-3-[(6-hydroxy-2,2-dioxo-2H-1,2

[0543] 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).

[0544] Step 5: Preparation of [4-chloro-31-methyl-27,27-dioxo-21,26-dioxa-27 6 - thia-1,14,15,16-tetraazahexacyclo[20.5.3.13 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl] ethyl acetate

[0545] Using general procedure 11, ethyl 3-[1-(4-bromobutyl)-4-methyl-1 H- benzotriazol-5-yl]-3-{4-chloro-3-[(6-hydroxy-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl)methyl]phenyl}propanoate (1 equiv) as starting reagent, afforded the title compound (97% yield).

[0546] 1 H-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 (2 m, 2 H), 3.21 / 3.08 (2 dd, 2 H), 2.63 (s, 3 H), 2.2 / 2.05 (2 m, 2 H), 1.8 / 1.64 (2 m, 2 H), 1 (t, 3 H).

[0547] Step 6: Preparation of Example 9

[0548] General procedure 12 was applied with [4-chloro-31 -methyl-27,27-dioxo-21,26-dioxa- 27lambda*6*-phthalazidin-1 -yl]acetic acid ethyl ester (1 equiv) as starting reagent to give the title compound (white solid, 56% yield). 6 - thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31 ),10,12,14,22,24,29-decaene-8-yl]acetic acid ethyl ester (1 equiv) as starting reagent to give the title compound (white solid, 56% yield).

[0549] The enantiopure product was obtained by separation on a chiral column.

[0550] Example 9a (E1)

[0551] C 28 H 27 HRMS calcd for CI N4O6S: 582.1340; [M+H] found: 583.1418 (delta = 0.9 ppm). +

[0552] Example 9b (E2)

[0553] C 28 H 27 HRMS calcd for CI N4O6S: 582.1340; [M+H] found: 583.1417 (delta = 0.8 ppm). +

[0554] 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 (2 m, 2 H), 3.09 / 2.96 (2 dd, 2 H), 2.63 (s, 3 H), 2.2 / 2.08 (2 m, 2 H), 1.82 / 1.63 (2 m, 2 H).

[0555] Example 10 :[4-chloro-31 -methyl-27,27-dioxo-21,26-dioxa- 27lambda*6*-phthalazidin-1 -yl]acetic acid ethyl ester (1 equiv) as starting reagent to give the title compound (white solid, 56% yield). 6 ​​- Thia- 1, 14, 15, 16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]triaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaene-8-yl]acetic acid

[0556]

[0557] Step 1: Preparation of ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-3-(l-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-lH-benzotriazol-5-yl)propanoate

[0558] Using General Procedure 6, with ethyl (2E)-3-(l-{4-[(4-methoxyphenyl)methoxy]butyl}-4- methyl-lH-benzotriazol-5-yl)prop-2-enoate (1 equiv) and [2-methoxy-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl]methanol (1.4 equiv) as starting reagents, the title compound was obtained (yellow oil, 68% yield).

[0559] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1H), 7.45 (d, 1H), 7.28 (d, 1H), 7.2 (d, 2H), 7.19 (dd, 1H), 6.9 (d, 2H), 6.82 (d, 1H), 4.9 (t, 1H), 4.82 (t, 1H), 4.65 (t, 2H), 4.41 (d, 2H), 4.31 (s, 2H), 3.92 (q, 2H), 3.71 (2s, 6H), 3.4 (t, 2H), 3.12 (dd, 2H), 2.78 (s, 3H), 1.91 (m, 2H), 1.5 (m, 2H), 1 (t, 3H).

[0560] Step 2: Preparation of ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-l,2 6 ,3-oxathiazin-3(4H)-yl]methyl}-4-methoxyphenyl)-3-(l-{4-[(4-methoxyphenyl)methoxy]butyl}- 4-methyl-lH-benzotriazol-5-yl)propanoate

[0561] General Procedure 7 was used with 3-[3-(hydroxymethyl)-4- methoxyphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H- benzotriazol-5-yl)propanoic acid (1 equiv.) and 6-(benzyloxy)-3,4-dihydro- 2H-1,2λ 6 ,3-oxathiazine-2,2-dione (1.1 eq.) as starting reagents to give the title compound (79% yield).

[0562] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1H), 7.49 (d, 1H), 7.45-7.3 (m, 5H), 7.28 (d, 1H), 7.21 (dd, 1H), 7.18 (d, 2H), 7-6.9 (m, 3H), 6.85 (d, 3H), 5.08 (s, 2H), 4.8 (t, 1H), 4.65 (t, 2H), 4.52 (s, 2H), 4.31 (s, 2H), 4.2 (s, 2H), 3.92 (q, 2H), 3.72 / 3.65 (2s, 6H), 3.38 (t, 2H), 3.12 (d, 2H), 2.79 (s, 3H), 1.9 (m, 2H), 1.45 (m, 2H), 1 (t, 3H).

[0563] Step 3: Preparation of ethyl 3-[1 -(4-hydroxybutyl)-4-methyl-1 H- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methoxyphenyl}propanoate

[0564] General Procedure 8 was used with ethyl 3-(3-{[6-(benzyloxy)-2,2-dioxo- 2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl]methyl}-4-methoxyphenyl)-3-(1-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-1 H-benzotriazol-5-yl)propanoate (1 equiv.) as starting reagents to give the title compound (white solid, 81 % yield).

[0565] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.6 / 4.41 (s+t, 2H), 7.65 (d, 1H), 7.5 (d, 1H), 7.28 (d, 1H), 7.21 (dd, 1H), 6.9 (d, 1H), 6.87 (d, 1H), 6.71 (dd, 1H), 6.6 (d, 1H), 4.82 (t, 1H), 4.65 (t, 2H), 4.5 (s, 2H), 4.2 (s, 2H), 3.95 (q, 2H), 3.7 (s, 3H), 3.4 (q, 2H), 3.15 (d, 2H), 2.75 (s, 3H), 1.91 (m, 2H), 1.38 (m, 2H), 1.02 (t, 3H).

[0566] Step 4: Preparation of ethyl 3-[1-(4-bromobutyl)-4-methyl-1H- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methoxyphenyl}propanoate

[0567] General procedure 9 was applied using ethyl 3-[1-(4-hydroxybutyl)-4-methyl- 1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methoxyphenyl}propanoate (1 equiv) as starting reagent to give the title compound (white solid, 69% yield).

[0568] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.6 (s, 1H), 7.65 (d, 1H), 7.51 (d, 1H), 7.25 (d, 1H), 7.22 (dd, 1H), 6.9 (d, 1H), 6.82 (d, 1H), 6.71 (dd, 1H), 6.59 (d, 1H), 4.85 (t, 1H), 4.7 (t, 2H), 4.49 (s, 2H), 4.21 (s, 2H), 3.92 (q, 2H), 3.7 (s, 3H), 3.55 (t, 2H), 3.15 (d, 2H), 2.75 (s, 3H), 2 (m, 2H), 1.8 (m, 2H), 1 (t, 3H).

[0569] Step 5: Preparation of [4-methoxy-31-methyl-27,27-dioxo-21,26-dioxa-27λ 6 -sulfur-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16.0 25,29 ] Preparation of [3-(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl] ethyl acetate

[0570] Using General Method 11, with 3-[1-(4-bromobutyl)-4-methyl-1H- benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methoxyphenyl}propionic acid ethyl ester (1 equiv) as starting reagent to give the title compound (70% yield).

[0571] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.69 (d, 1H), 7.55 (dd, 1H), 7.45 (d, 1H), 7.09 (d, 1H), 6.95 (d, 1H), 6.78 (dd, 1H), 6.59 (d, 1H), 5.8 (d, 1H), 4.78 (m, 3H), 4.12 / 3.92 (2d, 2H), 4.02 / 3.8 (2d, 2H), 3.92 (q, 2H), 3.81 (s, 3H), 3.61 / 3.4 (2m, 2H), 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).

[0572] Step 6: Preparation of Example 10

[0573] Using General Method 12, with [4-methoxy-31-methyl-27,27-dioxo-21,26-dioxa- 27λ 6 -sulfur-1,14,15,16-tetraazahexacyclo[20.5.3.13 3,7 .1 9,13 .0 12,16 .0 25,29 ] Preparation of [3-(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl] ethyl acetate (1 equiv) as starting reagent to give the title compound (white solid, 88% yield).

[0574] The enantiopure product was obtained by chiral column chromatography separation.

[0575] Example 10a (E1)

[0576] C 29 H 30 HRMS calculated for N4O7S: 578.1835; [M+H]+ HRMS calculated for N4O7S: 578.1835; [M+H] found: 579.1911 (delta = 0.5 ppm).

[0577] Example 10b (E2)

[0578] C 29 H 30 HRMS calculated for N4O7S: 578.1835; [M+H] found: 579.1911 (delta = 0.5 ppm). + HRMS calculated for N4O7S: 578.1835; [M+H] found: 579.1911 (delta = 0.5 ppm).

[0579] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.15 (m, 1H), 7.69 (d, 1H), 7.55 (dd, 1H), 7.41 (d, 1H), 7.09 (d, 1H), 6.95 (d, 1H), 6.78 (dd, 1H), 6.55 (d, 1H), 5.79 (d, 1H), 4.75 (m, 3H), 4.12 / 3.92 (2d, 2H), 4.02 / 3.8 (2d, 2H), 3.8 (s, 3H), 3.61 / 3.4 (2m, 2H), 3.12 / 2.95 (2dd, 2H), 2.62 (s, 3H), 2.2 / 2.1 (2m, 2H), 1.8 / 1.62 (2m, 2H).

[0580] Example 11 : [4, 33-dimethyl-29, 29-dioxo-23, 28-dioxa-29 lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ] tridecacora-3(34), 4, 6, 9(33), 10, 12, 14, 24, 26, 31-decaene-8-yl] acetic acid

[0581]

[0582] Step Al: Preparation of N-[6-(benzyloxy)hexyl]-3-methyl-2-nitroaniline

[0583] The title compound was obtained (53% yield) using General Method 2, step 1 with 1-fluoro-3-methyl-2-nitrobenzene (1 equiv) and 6-benzyloxyhexan-1-amine (1.2 equiv) as starting reagents.

[0584] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.35-7.2 (m, 6H), 6.78 (d, 1H), 6.52 (d, 1H), 6.39 (t, 1H), 4.42 (s, 2H), 3.41 (t, 2H), 3.15 (q, 2H), 2.29 (s, 3H), 1.55 (m, 4H), 1.32 (m, 4H).

[0585] Step A2: Preparation of N-[6-(benzyloxy)hexyl]-4-bromo-3-methyl-2-nitroaniline

[0586] General method 2 step 2 was applied using N-[6-(benzyloxy)hexyl]-3-methyl-2-nitroaniline (1 eq.) as starting reagent to give the title compound (99% yield).

[0587] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.5 (d, 1H), 7.3 (m, 5H), 6.7 (d, 1H), 6.12 (t), 4.43 (s, 2H), 3.4 (t, 2H), 3.1 (q, 2H), 2.25 (s, 3H), 1.53 / 1.34 (2m, 8H).

[0588] Step A3: Preparation of N 1 -[6-(benzyloxy)hexyl]-4-bromo-3-methylbenzene-1,2-diamine

[0589] General method 2 step 3 was applied using N-[6-(benzyloxy)hexyl]-4-bromo-3-methyl-2-nitroaniline (1 eq., 25.3 mmol) as starting reagent to give the title compound (67% yield).

[0590] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.3 (m, 5H), 6.7 (d, 1H), 6.23 (d, 1H), 4.59 (sl, 2H), 4.51 (t, 1H), 4.44 (s, 2H), 3.42 (t, 2H), 2.96 (q, 2H), 2.16 (s, 3H), 1.56 (m, 4H), 1.37 (m, 4H).

[0591] Step A4: Preparation of 1-[6-(benzyloxy)hexyl]-5-bromo-4-methyl-1H-benzotriazole

[0592] General method 2 step 4 was applied using N 1 -[6-(benzyloxy)hexyl]-4-bromo-3-methylbenzene-1,2-diamine (1 eq.) as starting reagent to give the title compound (28% yield).

[0593] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.68 (2 d, 2H), 7.35-7.2 (m, 5H), 4.68 (t, 2H), 4.4 (s, 2H), 3.39 (t, 2H), 2.71 (s, 3H), 1.9 (m, 2H), 1.5 (m, 2H), 1.32 (m, 2H), 1.22 (m, 2H).

[0594] Step A5: Preparation of (2E)-3-{1-[6-(benzyloxy)hexyl]-4-methyl-1H- benzotriazol-5-yl}prop-2-enoic acid ethyl ester

[0595] Using General Method 2, Step 5, with 1-[6-(benzyloxy)hexyl]-5-bromo-4- methyl-1H-benzotriazole (1 equiv) as the starting reagent, the title compound was obtained (22% yield).

[0596] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.68 (2 d, 2H), 7.35-7.2 (m, 5H), 4.68 (t, 2H), 4.4 (s, 2H), 3.39 (t, 2H), 2.71 (s, 3H), 1.9 (m, 2H), 1.5 (m, 2H), 1.32 (m, 2H), 1.22 (m, 2H).

[0597] Step 1: Preparation of (2E)-3-{1-[6-(benzyloxy)hexyl]-4-methyl-1H- benzotriazol-5-yl}-3-[3-(hydroxymethyl)-4-methylphenyl]propionic acid ethyl ester

[0598] Using General Method 6, with (2E)-3-{1-[6-(benzyloxy)hexyl]-4-methyl-1H- benzotriazol-5-yl}prop-2-enoic acid ethyl ester (1 equiv) and [2-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (1.5 equiv) as the starting reagents, the title compound was obtained (14% yield).

[0599] 1H-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 (2 s, 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).

[0600] Step 2: Preparation of 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl]methyl}-4-methylphenyl)-3-{1-[6-(benzyloxy)hexyl]-4- methyl-1 H-benzotriazole-5-yl}propionic acid ethyl ester

[0601] Using General Procedure 7, 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-2,2-dione (1.2 eq) as starting reagents, to give the title compound (84% yield).

[0602] 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 (2 s, 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).

[0603] Step 3: Preparation of 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}-3-{1-[6-(benzyloxy)hexyl]-4- methyl-1 H-benzotriazole-5-yl}propionic acid ethyl ester

[0604] Using General Method 8, ethyl 3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}-3-{1 -[6-(benzyloxy)hexyl]-4- methyl-1 H-benzotriazol-5-yl}propanoate (1 equiv) as the starting reagent to give the title compound (95% yield).

[0605] 1 H-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).

[0606] Step 4: Preparation of ethyl 3-[1 -(6-bromohexyl)-4-methyl-1 H-benzotriazol-5-yl]-3-{3- [(6-hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate

[0607] Using General Method 9, ethyl 3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}-3-{1 -(6-hydroxyhexyl)-4-methyl- 1 H-benzotriazol-5-yl}propanoate (1 equiv) as the starting reagent to give the title compound (87% yield).

[0608] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.68 (m, 1H), 7.61 (d, 1H), 7.5 (d, 1H), 7.21 (d, 1H), 7.2 (dd, 1H), 7.13 (d, 1H), 6.99 (d, 1H), 6.78 (dd, 1H), 6.6 (d, 1H), 4.84 (t, 1H), 4.63 (t, 2H), 4.38 (s, 2H), 4.19 (dd, 2H), 3.94 (q, 2H), 3.46 (t, 2H), 3.16 (dd, 2H), 2.75 (s, 3H), 2.22 (s, 3H), 1.88 (m, 2H), 1.74 (m, 2H), 1.39 (m, 2H), 1.24 (m, 2H), 1 (t, 3H).

[0609] Step 5: [4, 33-dimethyl-29, 29-dioxo-23, 28-dioxo-29 lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 Preparation of ethyl [3-(34), 4, 6, 9(33), 10, 12, 14, 24, 26, 31-decaen-8-yl]acetate

[0610] Using general procedure 11, ethyl 3-[1-(6-bromohexyl)-4-methyl-1H- benzotriazole-5-yl]-3-{3-[(6-hydroxy-2, 2-dioxo-2H-1, 2 lambda 6 , 3-oxathiazine-3(4H)-yl)methyl]-4-methylphenyl}propanoate (1 equiv) as starting reagent, to give the title compound (88% yield).

[0611] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.64 (d, 1H), 7.46 (d, 1H), 7.4 (dd, 1H), 7.21 (d, 1H), 7.15 (d, 1H), 7.07 (d, 1H), 6.9 (dd, 1H), 6.45 (d, 1H), 4.81 (t, 1H), 4.48 (t, 2H), 4.4 / 4.11 (dd, 2H), 4.23 / 4.03 (dd, 2H), 3.89 (q, 2H), 3.8 (m, 2H), 3.07 (d, 2H), 2.74 (s, 3H), 2.31 (s, 3H), 1.97 (m, 2H), 1.7 (m, 2H), 1.53 (m, 2H), 1.32 (m, 2H), 0.99 (t, 3H).

[0612] Step 6: Preparation of Example 11

[0613] General procedure 12 was used with [4,33-dimethyl-29,29-dioxo-23,28-dioxa-29lambda 6 - thia-1,14,15,16-tetraazahexacyclo[22.5.3.13 3,7 .1 9,13 .0 12,16 .0 27,31 ]tricosa-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl] ethyl acetate (1 equiv) as starting reagent to give the title compound (white solid, 62% yield).

[0614] The enantiopure product was obtained by separation on a chiral column.

[0615] Example 11a (E1)

[0616] C 31 H 34 HRMS calcd for N4O6S: 590.2199; [M+H] found: 591.2274 (delta = 0.4 ppm). +

[0617] Example 11b (E2)

[0618] C 31 H 34 HRMS calcd for N4O6S: 590.2199; [M+H] found: 591.2274 (delta = 0.4 ppm). +

[0619] 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).

[0620] Example 12 ​​: [31 -methyl- 27,27-dioxo-5-(trifluoromethyl)-21,26-dioxa-27 lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31 ),10,12,14,22,24,29-decaen-8-yl]acetic acid

[0621]

[0622] Step B1 : Preparation of [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)phenyl]methanol

[0623] General procedure 3 was applied using [3-bromo-5-(trifluoromethyl)phenyl]methanol (1 eq., 2.5 g, 9.8 mmol) as starting reagent to give the title compound (2.7 g, 91 % yield).

[0624] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.9 / 7.87 (m, 3H), 5.4 (t, 1 H), 4.6 (d, 2H), 1.3 (s, 12H).

[0625] Step 1 : Preparation of 3-[3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2 lambda 6 ,3-oxathiazine-3(4H)-yl]methyl}-5-(trifluoromethyl)phenyl]-3-(1 -{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-1 H-benzotriazol-5-yl)propanoic acid ethyl ester

[0626] General procedure 6 was applied using (2E)-3-(1 -{4-[(4-methoxyphenyl)methoxy]butyl}- 4-methyl-1 H-benzotriazol-5-yl)prop-2-enoic acid ethyl ester (1 eq.) and [3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl]methanol (1 eq.) as starting reagents to give 3-[3-(hydroxymethyl)-5-(trifluoromethyl)phenyl]-3-(1 -{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-1 H-benzotriazol-5-yl)propanoic acid ethyl ester (colorless oil, 16% yield). The crude was reacted with 6-(benzyloxy)-3,4-dihydro- 2H-1,2 lambda 6 ,3-oxathiazine-2,2-dione (1.1 eq.) using general procedure 7 to give the title compound (85% yield).

[0627] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.68 (s, 1H), 7.61 (d, 1H), 7.6 (s, 1H), 7.52 (s, 1H), 7.5 (d, 1H), 7.42-7.3 (m, 5H), 7.19 (d, 2H), 7-6.9 (m, 3H), 6.88 (d, 2H), 5.05 (s, 2H), 4.95 (t, 1H), 4.7 (t, 2H), 4.62 (s, 2H), 4.42 / 4.3 (2s, 4H), 3.92 (q, 2H), 3.71 (s, 3H), 3.38 (t, 2H), 3.21 (d, 2H), 2.79 (s, 3H), 1.9 (m, 2H), 1.48 (m, 2H), 1 (t, 3H).

[0628] Step 2: 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2- dioxo-2H-1,2 lambda 6 Preparation of ethyl 3-[3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2 lambda

[0629] Using General Method 8, ethyl 3-[3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2 lambda 6 Preparation of ethyl 3-[3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2 lambda

[0630] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.59 (s), 7.67 (sl, 1H), 7.65 (d, 1H), 7.61 (sl, 1H), 7.53 (sl, 1H), 7.52 (d, 1H), 6.8 (d, 1H), 6.68 (dd, 1H), 6.58 (d, 1H), 4.95 (t, 1H), 4.65 (t, 2H), 4.63 (s, 2H), 4.41 (t), 4.4 (s, 2H), 3.95 (q, 2H), 3.38 (q, 2H), 3.23 (d, 2H), 2.78 (s, 3H), 1.91 (m, 2H), 1.37 (m, 2H), 1.01 (t, 3H).

[0631] Step 3: 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Preparation of ethyl 3-oxathiazine-3(4H)-yl)methyl]-5-(trifluoromethyl)phenyl]propionate

[0632] Using general method 9, 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Ethyl 3-oxathiazine-3(4H)-yl)methyl]-5-(trifluoromethyl)phenyl}propionate (1 equivalent) was used as the starting agent to give the title compound (white solid, 50% yield).

[0633] 1 H-NMR(400MHz,DMSO-d6)δppm:9.6(s,1H),7.69 / 7.6 / 7.52(3sl,3H),7.69(d,1H),7.55(d,1H),6.8(d,1H),6.7(dd,1H),6.58(d,1H),4 .98(t,1H),4.7(t,2H),4.6(s,2H),4.4(s,2H),3.92(q,2H),3.55(t,2H),3.22(d,2H),2.79(s,3H),2(m,2H),1.78(m,2H),1.02(t,3H).

[0634] Step 4: [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 ethyl acetate of 32-deca-3(32),4,6,9(31),10,12,14,22,24,29-deca-en-8-yl]

[0635] Using general method 11, 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Ethyl 3-oxathiazine-3(4H)-yl)methyl]-5-(trifluoromethyl)phenyl}propionate (1 equivalent) was used as the starting agent to give the title compound (93% yield).

[0636] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.81 / 7.6 / 7.25 (3s, 3H), 7.71 / 4.81 (2m, 2H), 7.6 (d, 1H), 7.35 (d, 1H), 6.9 (d, 1H), 6.69 (dd, 1H), 6.02 (d, 1H), 4.81 (t, 1H), 4.28 (s, 2H), 4.05 (m, 2H), 3.95 (m, 2H), 3.88 / 3.68 (2m, 2H), 3.32 / 3.18 (2dd, 2H), 2.78 (s, 3H), 2.2 / 1.98 (2m, 2H), 1.68 / 1.45 (2m, 2H), 1 (t, 3H).

[0637] Step 5: Preparation of Example 12

[0638] Using the general method 12 with [31-methyl-27,27-dioxo-5-(trifluoromethyl)-21,26-dioxa-27 6 - thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 equiv) as starting reagent to give the title compound (white solid, quantitative).

[0639] The enantiopure product was obtained by separation on a chiral column.

[0640] Example 12a (E1)

[0641] C 29 H 27 HRMS calcd for F3N4O6S: 616.1603; [M+H] + found: 617.1677 (delta = 0.1 ppm).

[0642] Example 12b (E2)

[0643] C 29 H 27 HRMS calcd for F3N4O6S: 616.1603; [M+H] + found: 617.1678 (delta = 0.3 ppm).

[0644] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.3 (m, 1H), 7.84 / 7.58 / 7.23 (3s, 3H), 7.6 (d, 1H), 7.33 (d, 1H), 6.89 (d, 1H), 6.68 (dd, 1H), 6.02 (d, 1H), 4.89 (t, 1H), 4.81 / 4.72 (2m, 2H), 4.27 (s, 2H), 4.06 (m, 2H), 3.68 / 3.34 (2m, 2H), 3.32 / 3.18 (2dd, 2H), 2.78 (s, 3H), 2.2 / 1.98 (2m, 2H), 1.69 / 1.45 (2m, 2H).

[0645] Example 13 [(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 and

[0646] [(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

[0647]

[0648] Step Al: Preparation of 2-[2-(3-methyl-2-nitroanilino)ethoxy]ethan-l-ol

[0649] General Method 1, Step 1 was applied using 1-fluoro-3-methyl-2-nitrobenzene (1 equiv.) and 2-(2-aminoethoxy)ethan-l-ol (3 equiv.) as starting reagents to give the title compound (24% yield).

[0650] 1H-NMR(400MHz,DMSO-d6)δppm:7.28(t,1H),6.83(d,1H),6.58(d,1H),6.43(t,1 H),4.59(t,1H),3.6(t,2H),3.5(m,2H),3.45(m,2H),3.34(q,2H),2.31(s,3H).

[0651] Step A2: Preparation of 2-[2-(4-bromo-3-methyl-2-nitrophenylamino)ethoxy]ethanol-1-ol

[0652] Using the general method, step 2, with 2-[2-(3-methyl-2-nitrophenylamino)ethoxy]ethanol-1-ol (1 equivalent) as the starting agent, the title compound was obtained (67% yield).

[0653] 1 H-NMR (400MHz, DMSO-d6) δppm: 7.53 (d, 1H), 6.8 (d, 1H), 6.1 (t), 4.56 (t), 3.56 (t, 2H), 3.5 (q, 2H), 3.44 (t, 2H), 3.3 (q, 2H), 2.28 (s, 3H).

[0654] Step A3: Preparation of 2-[2-(2-amino-4-bromo-3-methylphenylamino)ethoxy]ethane-1-ol

[0655] Using the general method, step 3, with 2-[2-(4-bromo-3-methyl-2-nitrophenylamino)ethoxy]ethane-1-ol (1 equivalent) as the starting agent, the title compound was obtained (80% yield).

[0656] 1 H-NMR (400MHz, DMSO-d6) δppm: 6.72 (d, 1H), 6.3 (d, 1H), 4.64-4.52 (m, 4H), 3.6 (t, 2H), 3.51 (m, 2H), 3.46 (m, 2H), 3.17 (m, 2H), 2.16 (s, 3H).

[0657] Step A4: Preparation of 2-[2-(5-bromo-4-methyl-1H-benzotriazol-1-yl)ethoxy] ethylene-1-ol

[0658] Using the general method, step 4, with 2-[2-(2-amino-4-bromo-3-methylphenylamino)ethoxy]ethane-1-ol (1 equivalent) as the starting agent, the title compound (yellow solid, 45% yield) was obtained.

[0659] 1H-NMR (400MHz, DMSO-d6) δppm: 7.69 (d, 2H), 4.87 (t, 2H), 4.52 (m, 1H), 3.9 (t, 2H), 3.4-3.36 (m, 4H), 2.72 (s, 3H).

[0660] Step A5: Preparation of 1-{2-[2-(benzyloxy)ethoxy]ethyl}-5-bromo-4-methyl-1H-benzotriazole

[0661] To a solution of 2-[2-(5-bromo-4-methyl-1H-benzotriazol-1-yl)ethoxy]ethane-1-ol (1 eq., 4.1 g, 13 mmol) in DMF (7 mL / mmol, 92 mL), NaH (1.2 eq., 630 mg, 16 mmol, 60 wt% mineral oil solution) was added at 0 °C. The mixture was heated to room temperature and stirred at that temperature for 30 min. The reaction mixture was cooled to 0 °C. Benzyl bromide (1.2 eq., 2.7 g, 1.9 mL, 16 mmol) was added and stirring continued at room temperature. The mixture was quenched with 500 mL of water, extracted with 4 x 1000 mL EtOAc, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, 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).

[0662] 1 H-NMR(400MHz,DMSO-d6)δppm:7.69 / 7.6(dd,2H),7.33-7.23(m,3H),7.16(m ,2H),4.88(t,2H),4.31(s,2H),3.91(t,2H),3.53 / 3.43(2m,4H),2.7(s,3H).

[0663] Step A6: Preparation of ethyl (2E)-3-(1-{2-[2-(benzyloxy)ethoxy]ethyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate

[0664] Using the general method, step 7, with 1-{2-[2-(benzyloxy)ethoxy]ethyl}-5-bromo-4-methyl-1H-benzotriazole (1 eq., 3.65 g, 9.35 mmol) as the starting reagent, the title compound (1.7 g, 28% yield) was obtained.

[0665] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 8 (d, 1H), 7.87 (d, 1H), 7.72 (d, 1H), 7.32-7.15 (m, 5H), 6.6 (d, 1H), 4.88 (t, 2H), 4.32 (s, 2H), 4.23 (q, 2H), 3.92 (t, 2H), 3.54 / 3.45 (2m, 4H), 2.79 (s, 3H), 1.29 (t, 3H).

[0666] Step 1: Preparation of ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2

[0667] Using General Procedure 6, with ethyl (2E)-3-(1-{2-[2-(benzyloxy)ethoxy]ethyl}-4- methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equiv) and (1S)-1-[2-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1-ol (2 equiv) as starting reagents, the title compound was obtained (44% yield).

[0668] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.61 (d, 1H), 7.41 (d, 1H), 7.4 (sl, 1H), 7.32-7.18 (m, 5H), 7.02 (dd, 1H), 6.97 (d, 1H), 4.98 / 4.97 (2d, 1H), 4.85-4.78 (m, 4H), 4.33 / 4.32 (2s, 2H), 3.92 (q, 2H), 3.89 (m, 2H), 3.53 / 3.43 (2m, 4H), 3.16-3.01 (m, 2H), 2.75 (2s, 3H), 2.18 (2s, 3H), 1.22 / 1.2 (2d, 3H), 1 (t, 3H).

[0669] Step 2: Preparation of ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl]ethyl}-4-methylphenyl)-3-(1-{2-[2-(benzyloxy)ethoxy]ethyl}-4- methyl-1H-benzotriazol-5-yl)propanoate

[0670] General Procedure 7 was used with ethyl 3-(1-{2-[2-(benzyloxy)ethoxy]ethyl}-4- methyl-1H-benzotriazol-5-yl)-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propanoate (1 equiv) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ 6 ,3-oxathiazine-2,2-dione (1.5 equiv) as starting reagents to give the title compound (79% yield).

[0671] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.62 (d, 1H), 7.5 (d, 1H), 7.48-7 (m, 13H), 7.1-6.96 (m, 2H), 6.89 / 6.83 (2d, 1H), 5.26 (m, 1H), 5.08 (m, 2H), 4.86 (m, 1H), 4.78 (m, 2H), 4.41 (s, 2H), 4.28 (s, 2H), 3.91 (q, 2H), 3.88 (m, 2H), 3.49 / 3.39 (2m, 4H), 3.18 (m, 2H), 2.76 (s, 3H), 2.27 (s, 3H), 1.4 (d, 3H), 0.98 (t, 3H).

[0672] Step 3: Preparation of ethyl 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}-3-{1-[2-(2-hydroxyethoxy)ethyl]-4- methyl-1H-benzotriazol-5-yl}propanoate

[0673] General Procedure 8 was used with ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl]ethyl}-4-methylphenyl)-3-(1-{2-[2-(benzyloxy)ethoxy]ethyl}-4- methyl-1H-benzotriazol-5-yl)propanoate (1 equiv) as starting reagents to give the title compound (white solid, 94% yield).

[0674] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.63 (m, 1H), 7.65-7.53 (2dd, 2H), 7.47 (m, 1H), 7.14-7.08 (m, 2H), 6.91 (2, 1H), 6.76-6.7 (m, 1H), 6.6 / 6.56 (2d, 1H), 5.26 (q, 1H), 4.88 (q, 1H), 4.8 (t, 2H), 4.37 / 4.31 (s+dd, 2H), 3.95 (2q, 2H), 3.89 (m, 2H), 3.48-3.27 (m, 4H), 3.22 (2d, 2H), 2.77 (s, 3H), 2.28 (s, 3H), 1.43 / 1.41 (2d, 3H), 1.02 / 1 (2t, 3H).

[0675] Step 4: Preparation of 3-{1-[2-(2-bromoethoxy)ethyl]-4-methyl-1H- benzotriazol-5-yl}-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propionic acid ethyl ester

[0676] Using General Procedure 9, with 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}-3-{1-[2-(2-hydroxyethoxy)ethyl]-4- methyl-1H-benzotriazol-5-yl}propionic acid ethyl ester (1 equiv) as starting reagent, the title compound was obtained (71% yield).

[0677] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.63 (m, 1H), 7.65-7.53 (2dd, 2H), 7.47 (m, 1H), 7.14-7.08 (m, 2H), 6.91 (2, 1H), 6.76-6.7 (m, 1H), 6.6 / 6.56 (2d, 1H), 5.26 (q, 1H), 4.88 (q, 1H), 4.8 (t, 2H), 4.37 / 4.31 (s+dd, 2H), 3.95 (2q, 2H), 3.89 (m, 2H), 3.48-3.27 (m, 4H), 3.22 (2d, 2H), 2.77 (s, 3H), 2.28 (s, 3H), 1.43 / 1.41 (2d, 3H), 1.02 / 1 (2t, 3H).

[0678] Step 5: Preparation of [(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 ]tricosa-3(33),4,6,9(32), 10, 12, 14, 23, 25, 30-decaene-8-yl] ethyl acetate

[0679] Using General Method 11, 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

[0680] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.72 / 7.65 (2d, 1H), 7.52 / 6.91 (2s, 1H), 7.52 / 7.16 (2d, 1H), 7.45 / 7.09 (2d, 1H), 7.28 / 6.98 (2d, 1H), 6.93 / 6.88 (2d, 1H), 6.8 / 6.75 (2d, 1H), 6.36 / 5.99 (2sl, 1H), 5.4 / 5.26 (2m, 1H), 4.93 / 4.85 (2m, 1H), 4.83 (m, 2H), 4.71 / 4.17 / 3.81 (2m, 2H), 4.14-3.58 (m, 6H), 4.03 / 3.93 (2q, 2H), 3.23 / 2.96 (m+dd, 2H), 2.81 / 2.8 (2s, 3H), 2.33 / 2.29 (2s, 3H), 1.53 / 1.42 (s+sl, 3H), 1.17 / 1.02 (2m, 3H).

[0681] Step 6: Preparation of Example 13

[0682] Using General Method 12, 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 26,30Ethyl [tricosa-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetate (1 eq) as starting reagent to give the title compound (white solid, 59% yield).

[0683] The final product or final intermediate is obtained diastereomerically pure by separation on a chiral column.

[0684] Example 13a (2R, 8R)

[0685] C 30 H 32 HRMS calculated for N4O7S: 592.1992; [M+H] found: 593.2072 (delta = 1.3 ppm) + , found: 593.2071 (delta = 1.1 ppm).

[0686] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 13.6-11 (m, 1H), 7.64 (d, 1H), 7.48 (dd, 1H), 7.27 (d, 1H), 7.11 (d, 1H), 6.94 (d, 1H), 6.88 (sl, 1H), 6.8 (dd, 1H), 6.01 (d, 1H), 5.24 (q, 1H), 4.92 (t, 1H), 4.81 (t, 2H), 4.14 / 3.78 (dd, 2H), 4.1 / 4.04 (2m, 2H), 3.99-3.63 (m, 4H), 3.06 / 2.75 (2dd, 2H), 2.79 (s, 3H), 2.33 (s, 3H), 1.15 (d, 3H).

[0687] Example 13b (2R, 8S)

[0688] C 30 H 32 HRMS calculated for N4O7S: 592.1992; [M+H] found: 593.2072 (delta = 1.3 ppm) + , found: 593.2071 (delta = 1.1 ppm).

[0689] 1H-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, 3 H).

[0690] Preparation of the sodium salt:

[0691] 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, then freeze-dried for 96 hours. 2.10 g of amorphous sodium salt of [(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 ]tricosa-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl] acetate (water content: 3.0%).

[0692] IR: 2980 to 2860 cm -1 (CH2, CH3), 1574 cm -1 (COO - asym), 1492 cm -1 (C=C), 1391 cm -1 (COO - sym and SO2 asym), 1200 to 1130 cm -1 (SO2 sym, =C-O-C asym and C-O-C asym).

[0693] Example 14 : [4-fluoro-31 -methyl-27,27-dioxo-21,26-dioxa-27λ 6- Thia- 1, 14, 15, 16-tetraazahexadecacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]triaconta-3(32),4,6,9(31), 10,12,14,22,24,29-decaene-8-yl]acetic acid

[0694]

[0695] Step 1 : Preparation of 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazine-3(4H)-yl]methyl}-4-fluorophenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1 H- benzotriazole-5-yl)propanoic acid ethyl ester

[0696] Using General Procedure 6, (E)-3-[1-[4-[(4-methoxyphenyl)methoxy]butyl]-4-methyl- benzotriazole-5-yl]prop-2-enoic acid ethyl ester (1 equiv) and [2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]methanol (1 equiv) as starting reagents gave 3-[4-fluoro-3-(hydroxymethyl)phenyl]- 3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1 H-benzotriazole-5-yl)propanoic acid ethyl ester (17% yield). The crude product was reacted with 6-(benzyloxy)-3,4-dihydro-2H-1,2λ 6 ,3-oxathiazine-2,2-dione (1.1 equiv) using General Procedure 7 to give the title compound (85% yield).

[0697] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.5-7.35 (m, 5H), 7.49 (d, 1 H), 7.35 / 7.3 (m, 2H), 7.2 (d, 2H), 7.08 (t, 1 H), 7-6.95 (m, 3H), 6.88 (d, 2H), 5.08 (s, 2H), 4.88 (t, 1 H), 4.65 (t, 2H), 4.58 (s, 2H), 4.31 (2s, 4H), 3.92 (q, 2H), 3.71 (s, 3H), 3.38 (t, 2H), 3.18 (d, 2H), 2.79 (s, 3H), 1.91 (m, 2H), 1.48 (m, 2H), 1 (t, 3H).

[0698] Step 2: Preparation of 3-{4-fluoro-3-[(6-hydroxy-2,2-dioxo-2H-1,2λ6 Preparation of ethyl 3-{4-fluoro-3-[(6-hydroxy-2,2-dioxo-2H-1,2

[0699] Using General Method 8, ethyl 3-{4-fluoro-3-[(6-hydroxy-2,2-dioxo-2H-1,2 6 Using General Method 8, ethyl 3-{4-fluoro-3-[(6-hydroxy-2,2-dioxo-2H-1,2

[0700] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.4 / 4.4 (s+t, 2H), 7.63 (d, 1H), 7.5 (d, 1H), 7.45 (dd, 1H), 7.3 (m, 1H), 7.1 (t, 1H), 6.88 (d, 1H), 6.71 (dd, 1H), 6.61 (d, 1H), 4.88 (t, 1H), 4.67 (t, 2H), 4.53 (s, 2H), 4.3 (s, 2H), 3.95 (q, 2H), 3.4 (q, 2H), 3.2 (d, 2H), 2.78 (s, 3H), 1.9 (m, 2H), 1.38 (m, 2H), 1.02 (t, 3H).

[0701] Step 3: Ethyl 3-{4-fluoro-3-[(6-hydroxy-2,2-dioxo-2H-1,2 6 Preparation of ethyl 3-{4-fluoro-3-[(6-hydroxy-2,2-dioxo-2H-1,2

[0702] Using General Method 9, ethyl 3-{4-fluoro-3-[(6-hydroxy-2,2-dioxo-2H-1,2 6 Using General Method 8, ethyl 3-{4-fluoro-3-[(6-hydroxy-2,2-dioxo-2H-1,2

[0703] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.6 (s, 1H), 7.65 (d, 1H), 7.51 (d, 1H), 7.45 (dd, 1H), 7.3 (m, 1H), 7.1 (t, 1H), 6.88 (d, 1H), 6.71 (dd, 1H), 6.6 (d, 1H), 4.88 (t, 1H), 4.7 (t, 2H), 4.52 (s, 2H), 4.31 (s, 2H), 3.93 (q, 2H), 3.55 (t, 2H), 3.2 (d, 2H), 2.79 (s, 3H), 2 (m, 2H), 1.8 (m, 2H), 1 (t, 3H).

[0704] Step 4: Preparation of [4-fluoro-31-methyl-27,27-dioxo-21,26-dioxa-27 6 - thia-1,14,15,16-tetraazahexacyclo[20.5.3.13 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl] ethyl acetate

[0705] General Procedure 11 was employed using ethyl 3-[1-(4-bromobutyl)-4-methyl-1H- benzotriazole-5-yl]-3-{4-fluoro-3-[(6-hydroxy-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl)methyl]phenyl}propanoate (1 equiv) as the starting reagent to give the title compound (white solid, 75% yield).

[0706] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.7 (d, 1H), 7.61 (dd, 1H), 7.45 (d, 1H), 7.29 (t, 1H), 6.98 (d, 1H), 6.81 (dd, 1H), 6.78 (dd, 1H), 6.4 (d, 1H), 4.85-4.7 (m, 3H), 4.21 / 4.05 (2d, 2H), 4.02 / 3.92 (2d, 2H), 3.95 (q, 2H), 3.68 / 3.42 (2m, 2H), 3.2 / 3.1 (2dd, 2H), 2.65 (s, 3H), 2.2 / 2.02 (2m, 2H), 1.8 / 1.65 (2m, 2H), 1.01 (t, 3H).

[0707] Step 5: Preparation of Example 14

[0708] General procedure 12 was applied using [4-fluoro-31-methyl-27,27-dioxo-21,26-dioxa- 27lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid ethyl ester (1 eq) as starting reagent to give the title compound (white solid, 81% yield).

[0709] C 28 H 27 HRMS calculated for FN4O6S: 566.1635; [M+H] found: 567.1712 (delta = 0.7 ppm). + , found: 567.1712 (delta = 0.7 ppm).

[0710] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.3 (m, 1H), 7.67 (d, 1H), 7.63 (m, 1H), 7.42 (d, 1H), 7.27 (t, 1H), 6.97 (d, 1H), 6.76 (m, 1H), 6.76 (m, 1H), 5.88 (d, 1H), 4.8 (t, 2H), 4.77 (m, 1H), 4.21 / 4.05 (dd, 2H), 4.06 / 3.92 (dd, 2H), 3.66 / 3.4 (2m, 2H), 3.06 / 2.95 (2dd, 2H), 2.65 (s, 3H), 2.21 / 2.05 (2m, 2H), 1.79 / 1.59 (2m, 2H).

[0711] Example 15 : [4,24,31 -trimethyl-27,27-dioxo-21,26-dioxa-27lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid

[0712]

[0713] Step C1 : Preparation of 6-bromo-8-methyl-2H-1,2lambda 6 ,3-oxathiazine-2,2-dione

[0714] Using General Procedure 4 Step 2 with 5-bromo-2-hydroxy-3-methylbenzaldehyde (1 eq., 3.65 g, 9.35 mmol) as the starting reagent to obtain the title compound (2.85 g, 30% yield).

[0715] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.14 (s, 1H), 8.09 / 8.05 (dl+dd, 2H), 2.33 (s, 3H).

[0716] Step C2: Preparation of 6-bromo-8-methyl-3,4-dihydro-2H-1,2 6 oxathiazine-2,2-dione

[0717] Using General Procedure 4 Step 3 with 6-bromo-8-methyl-2H-1,2 6 oxathiazine-2,2-dione (1 eq., 4.52 g, 16.37 mmol) as the starting reagent to obtain the title compound (4.64 g, 99% yield).

[0718] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8.59 (t, 1H), 7.5 / 7.38 (2d, 2H), 4.55 (s, 2H), 2.2 (s, 3H).

[0719] Step C3: Preparation of tert-butyl 6-bromo-8-methyl-2,2-dioxo-2H-1,2 6 oxathiazine-3(4H)-carboxylate

[0720] Using General Procedure 5 Step 1 with 6-bromo-8-methyl-3,4-dihydro-2H-1,2 6 oxathiazine-2,2-dione (1 eq., 4.6 g, 16.539 mmol) as the starting reagent to obtain the title compound (6.2 g, 99% yield).

[0721] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.7 / 7.64 (2d, 2H), 5.04 (s, 2H), 2.27 (s, 3H), 1.48 (s, 9H).

[0722] Step C4: Preparation of tert-butyl 8-methyl-2,2-dioxo-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2H-1,2 6 oxathiazine-3(4H)-carboxylate

[0723] Using the general method, step 2 of 5, 6-bromo-8-methyl-2,2-dioxo-2H-1,2λ 6 Starting with tert-butyl 3-oxathiazine-3(4H)-carboxylate (1 eq., 6.2 g, 16.39 mmol), the title compound (4.9 g, 70% yield) was obtained.

[0724] 1 H-NMR (400MHz, DMSO-d6) δppm: 7.69 / 7.65 (2sl, 2H), 5.06 (s, 2H), 2.29 (s, 3H), 1.48 (s, 9H), 1.3 (s, 12H).

[0725] Step C5: 6-hydroxy-8-methyl-2,2-dioxo-2H-1,2λ 6 Preparation of tert-butyl 3-oxathiazine-3(4H)-formate

[0726] Using the general method, step 3 of 5, 8-methyl-2,2-dioxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2H-1,2λ 6 Starting with tert-butyl 3-oxathiazide-3(4H)-carboxylate (1 eq., 4.9 g, 11.52 mmol), the title compound (3.9 g, 97% yield) was obtained.

[0727] 1 H-NMR (400MHz, DMSO-d6) δppm: 9.81 (m, 1H), 6.74 / 6.7 (2d, 2H), 4.9 (s, 2H), 2.19 (s, 3H), 1.48 (s, 9H).

[0728] Step C6: 6-(benzyloxy)-8-methyl-2,2-dioxo-2H-1,2λ 6 Preparation of tert-butyl 3-oxathiazine-3(4H)-formate

[0729] Using the general method, step 4 of step 5, 6-hydroxy-8-methyl-2,2-dioxo-2H-1,2λ 6 Using tert-butyl 3-oxathiazide-3(4H)-carboxylate (1 eq., 2.9 g, 9.19 mmol) as the starting reagent, the title compound (5 g, quantitative) was obtained.

[0730] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.46-7.29 (m, 5H), 7.12 / 7.03 (2d, 2H), 5.1 (s, 2H), 4.97 (s, 2H), 2.26 (s, 3H), 1.48 (s, 9H).

[0731] Step C7: Preparation of 6-(benzyloxy)-8-methyl-3,4-dihydro-2H-1,2 6 l,2laxa-oxazothiazine-2,2-dione

[0732] General Method 5, Step 5 was used to prepare the title compound (1.85 g, 65% yield) using 6-(benzyloxy)-8-methyl-2,2-dioxo-2H-l,2laxa-oxazothiazine-3(4H)-carboxylic acid tert-butyl ester (1 eq., 5.0 g, 12.33 mmol) as the starting reagent. 6

[0733] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8.37 (m, 1H), 7.46-7.3 (m, 5H), 6.92 / 6.79 (2d, 2H), 5.06 (s, 2H), 4.47 (s, 2H), 2.16 (s, 3H).

[0734] Step 1: Preparation of ethyl 3-[3-(hydroxymethyl)-4-methylphenyl]-3-(l-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-lH-benzotriazol-5-yl)propanoate

[0735] General Method 6 was used to prepare the title compound (43% yield) using ethyl (E)-3-[l-[4-[(4-methoxyphenyl)methoxy]butyl]-4-methyl-benzotriazol-5-yl]prop-2-enoate (1 eq.) and [2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]methanol (2 eq.) as the starting reagents.

[0736] 1 ​H-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, 2 H), 1 (t, 3 H).

[0737] Step 2: Preparation of 3-(3-{[6-(benzyloxy)-8-methyl-2,2-dioxo-2H-1,2 6 Step 2: Preparation of 3-(3-{[6-(benzyloxy)-8-methyl-2,2-dioxo-2H-1,2

[0738] General Procedure 7 was used with 3-[3-(hydroxymethyl)-4-methylphenyl]-3-(1-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-1 H-benzotriazole-5-yl)propanoic acid ethyl ester (1 equiv) and 6-(benzyloxy)-8-methyl-3,4-dihydro-2H-1,2 6

[0739] 1 H-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, 2 H), 1 (t, 3 H).

[0740] ​Step 3: Preparation of ethyl 3-[l-(4-hydroxybutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methyl-2,2-dioxo-2H-l,2λ 6 Step 4: Preparation of ethyl 3-[l-(4-bromobutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methyl-2,2-dioxo-2H-l,2λ

[0741] General Procedure 8 was employed using ethyl 3-[l-(4-hydroxybutyl)-4- methyl-lH-benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methyl-2,2-dioxo-2H-l,2λ 6 Step 4: Preparation of ethyl 3-[l-(4-bromobutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methyl-2,2-dioxo-2H-l,2λ

[0742] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.55 (m, 1H), 7.61 (d, 1H), 7.49 (d, 1H), 7.22-7.11 (3m, 3H), 6.68 / 6.42 (2d, 2H), 4.84 (t, 1H), 4.65 (t, 2H), 4.34 (s, 2H), 4.19 (dd, 2H), 3.94 (q, 2H), 3.38 (t, 2H), 3.18 / 3.13 (2dd, 2H), 2.75 (s, 3H), 2.22 / 2.17 (2s, 6H), 1.9 (m, 2H), 1.36 (m, 2H), 1 (t, 3H).

[0743] Step 4: Preparation of ethyl 3-[l-(4-bromobutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methyl-2,2-dioxo-2H-l,2λ 6 Step 4: Preparation of ethyl 3-[l-(4-bromobutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methyl-2,2-dioxo-2H-l,2λ

[0744] General Procedure 9 was employed using ethyl 3-[l-(4-hydroxybutyl)-4- methyl-lH-benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methyl-2,2-dioxo-2H-l,2λ 6 Step 4: Preparation of ethyl 3-[l-(4-bromobutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methyl-2,2-dioxo-2H-l,2λ

[0745] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.55 (s, 1H), 7.65 (d, 1H), 7.5 (d, 1H), 7.2 (m, 2H), 7.11 (d, 1H), 6.7 / 6.41 (2d, 2H), 4.85 (t, 1H), 4.7 (t, 2H), 4.38 (s, 2H), 4.2 (m, 2H), 3.95 (q, 2H), 3.55 (t, 2H), 3.18 (m, 2H), 2.78 (s, 3H), 2.22 / 2.18 (2s, 6H), 1.98 (m, 2H), 1.78 (m, 2H), 1 (t, 3H).

[0746] Step 5: Preparation of [4, 24, 31 -trimethyl-27, 27-dioxo-21, 26-dioxa-27 6 - thia- 1, 14, 15, 16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl] ethyl acetate

[0747] Using general procedure 11, ethyl 3-[1-(4-bromobutyl)-4-methyl-1H- benzotriazole-5-yl]-3-{3-[(6-hydroxy-8-methyl-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propionate (1 equiv) as starting reagent, to give the title compound (quantitative).

[0748] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.67 (d, 1H), 7.47 (dd, 1H), 7.43 (d, 1H), 7.43 (d, 1H), 6.71 (d, 1H), 6.55 (d, 1H), 5.67 (d, 1H), 4.84-4.7 (m, 3H), 4.13-3.79 (2dd, 4H), 3.92 (q, 2H), 3.63-3.43 (2m, 2H), 3.17 / 3.04 (2dd, 2H), 2.63 (s, 3H), 2.33 (s, 3H), 2.25-2 (m, 2H), 2.11 (s, 3H), 1.79 / 1.6 (2m, 2H), 1 (t, 3H).

[0749] Step 6: Preparation of Example 15

[0750] General procedure 12 was applied using [4, 24, 31 -trimethyl-27, 27-dioxo-21, 26-dioxa- 27lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl] ethyl acetate (1 equiv) as starting reagent to give the title compound (white solid, 66% yield).

[0751] The enantiopure product was obtained by separation on a chiral column.

[0752] Example 15a (E1)

[0753] C 30 H 32 HRMS calculated for N4O6S: 576.2042; [M+H] found: 577.2119 (delta = 0.6 ppm). +

[0754] Example 15b (E2)

[0755] C 30 H 32 HRMS calculated for N4O6S: 576.2042; [M+H] found: 577.2117 (delta = 0.3 ppm). +

[0756] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.14 (m, 1H), 7.67 (d, 1H), 7.49 (dd, 1H), 7.42 (d, 1H), 7.29 (d, 1H), 6.71 (d, 1H), 6.53 (d, 1H), 5.66 (d, 1H), 4.84-4.7 (m, 3H), 4.13-3.79 (2dd, 4H), 3.63-3.43 (2m, 2H), 3.07 / 2.94 (2dd, 2H), 2.63 (s, 3H), 2.33 (s, 3H), 2.19 / 2.08 (2m, 2H), 2.11 (s, 3H), 1.8 / 1.6 (2m, 2H).

[0757] Example 16 :[24-methoxy-4, 31 -dimethyl-27, 27-dioxo-21, 26-dioxa- 27lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1​​3,7 .1 9,13 .0 12,16 .0 25,29 [32,4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid

[0758]

[0759] Step C1: 6-Bromo-8-methoxy-2H-1,2λ 6 Preparation of 3-oxathiazine-2,2-dione

[0760] Using the general method, step 2, with 5-bromo-2-hydroxy-3-methoxy-benzaldehyde (1 equivalent) as the starting reagent, the title compound was obtained (32% yield).

[0761] 1 H-NMR (400MHz, DMSO-d6) δppm: 9.14 (s, 1H), 7.83 / 7.79 (2d, 2H), 3.98 (s, 3H).

[0762] Step C2: 6-Bromo-8-methoxy-3,4-dihydro-2H-1,2λ 6 Preparation of 3-oxathiazine-2,2-dione

[0763] Using the general method, step 3 of 4, 6-bromo-8-methoxy-2H-1,2λ 6 Using 3-oxathiazine-2,2-dione (1 equivalent) as the starting reagent, the title compound was obtained (95% yield).

[0764] 1 H-NMR (400MHz, DMSO-d6) δppm: 8.6 (sl, 1H), 7.26 (d, 1H), 7.1 (d, 1H), 4.55 (s, 2H), 3.85 (s, 3H).

[0765] Step C3: 6-Bromo-8-methoxy-2,2-dioxo-2H-1,2λ 6 Preparation of tert-butyl 3-oxathiazine-3(4H)-formate

[0766] Using the general method, step 5, step 1, 6-bromo-8-methoxy-3,4-dihydro-2H-1,2λ 6 Using 3-oxathiazine-2,2-dione (1 equivalent) as the starting reagent, the title compound was obtained (88% yield).

[0767] 1H-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).

[0768] Step C4: Preparation of 8-methoxy-2,2-dioxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 2H-1,2 6 Step C4: Preparation of tert-butyl 6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2

[0769] Step C4: Preparation of tert-butyl 6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2 6 Step C4: Preparation of tert-butyl 6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2

[0770] 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).

[0771] Step C4: Preparation of tert-butyl 6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2 6 Step C4: Preparation of tert-butyl 6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2

[0772] Step C4: Preparation of tert-butyl 6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2 6 Step C4: Preparation of tert-butyl 6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2

[0773] 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).

[0774] Step C4: Preparation of tert-butyl 6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2 6 Step C4: Preparation of tert-butyl 6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2

[0775] Step C4: Preparation of tert-butyl 6-hydroxy-8-methoxy-2,2-dioxo-2H-1,2 6tert-Butyl 3-oxothiazolidine-2,2-dicarboxylate (1 equiv) as starting reagent to give the title compound (89% yield).

[0776] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.5-7.28 (m, 5H), 6.83 (sl, 2H), 5.12 (s, 2H), 4.98 (s, 2H), 3.86 (s, 3H), 1.5 (s, 9H).

[0777] Step C7: 6-(benzyloxy)-8-methoxy-3,4-dihydro-2H-1,2 6 Preparation of 3-oxothiazolidine-2,2-dicarboxylic acid

[0778] General method 5 step 5 was used with 6-(benzyloxy)-8-methoxy-2,2-dioxo-2H-1,2 6 tert-Butyl 3-oxothiazolidine-2,2-dicarboxylate (1 equiv) as starting reagent to give the title compound (89% yield).

[0779] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8.4 (sl, 1H), 7.48-7.3 (m, 5H), 6.71 (d, 1H), 6.5 (d, 1H), 5.08 (s, 2H), 4.49 (s, 2H), 3.8 (s, 3H).

[0780] Step 1 : 3-(3-{[6-(benzyloxy)-8-methoxy-2,2-dioxo-2H-1,2 6 Preparation of 3-oxothiazolidine-2,2-dicarboxylic acid

[0781] General method 7 was used with ethyl 3-[3-(hydroxymethyl)-4-methylphenyl]-3-(1-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-1 H-benzotriazole-5-yl)propanoate (1 equiv) and 6- (benzyloxy)-8-methoxy-3,4-dihydro-2H-1,2 6 tert-Butyl 3-oxothiazolidine-2,2-dicarboxylate (1 equiv) as starting reagent to give the title compound (89% yield).

[0782] 1H-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).

[0783] Step 2: Preparation of 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6- hydroxy-8-methoxy-2,2-dioxo-2H-1,2λ 6 Step 2: Preparation of 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6- hydroxy-8-methoxy-2,2-dioxo-2H-1,2λ

[0784] General Procedure 8 was employed using 3-(3-{[6-(benzyloxy)-8-methoxy-2,2-dioxo- 2H-1,2λ 6 Step 2: Preparation of 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6- hydroxy-8-methoxy-2,2-dioxo-2H-1,2λ

[0785] 1 H-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, 3 H), 1.9 (m, 2 H), 1.39 (m, 2 H), 1 (t, 3 H).

[0786] Step 3: Preparation of ethyl 3-[l-(4-bromobutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methoxy-2,2-dioxo-2H-l,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate

[0787] Using General Method 9, ethyl 3-[l-(4-bromobutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methoxy-2,2-dioxo-2H-l,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate (1 equiv) as the starting reagent, afforded the title compound (yellow solid, 86% yield).

[0788] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.69 (s, 1H), 7.62 (d, 1H), 7.5 (d, 1H), 7.2 (d, 1H), 7.19 (dd, 1H), 7.11 (d, 1H), 6.5 (d, 1H), 6.11 (d, 1H), 4.82 (t, 1H), 4.68 (t, 2H), 4.32 (s, 2H), 4.19 (m, 2H), 3.91 (q, 2H), 3.79 (s, 3H), 3.51 (t, 2H), 3.18 (m, 2H), 2.73 (s, 3H), 2.2 (s, 3H), 1.99 (m, 2H), 1.78 (m, 2H), 1 (t, 3H).

[0789] Step 4: Preparation of ethyl [24-methoxy-4,31-dimethyl-27,27-dioxo-21,26-dioxa- 27λ 6 -sulfur-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 .0 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate

[0790] Using General Method 11, ethyl 3-[l-(4-bromobutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(6-hydroxy-8-methoxy-2,2-dioxo-2H-l,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate (1 equiv) as the starting reagent, afforded the title compound (white solid, 73% yield).

[0791] The enantiomerically pure final intermediates were obtained by separation on chiral column chromatography.

[0792] 1 H-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, 2 H), 1 (t, 3 H).

[0793] Step 5: Preparation of Example 16

[0794] Using the general method 12, with [24-methoxy-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27lambda 6 - thia-1,14,15,16-tetraazahexadecacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl] acetate E1 (1 equiv) or E2 (1 equiv) as starting reagent, the title compounds were obtained (yield 85%-67% respectively).

[0795] Example 16a (E1)

[0796] C 30 H 32 HRMS calcd for N4O7S: 592.1992; [M+H] + found: 593.2070 (delta = 0.9 ppm).

[0797] Example 16b (E2)

[0798] C 30 H 32 HRMS calcd for N4O7S: 592.1992; [M+H] + found: [M+H]+ = 593.2073 (delta = 1.4 ppm).

[0799] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (m, 1H), 7.68 (d, 1H), 7.49 (dd, 1H), 7.41 (d, 1H), 7.29 (d, 1H), 5.31 (d, 1H), 4.75 (m, 3H), 4.11 / 3.92 (2d, 2H), 3.98 / 3.8 (2d, 2H), 3.73 (s, 3H), 3.59 / 3.33 (2m, 2H), 3.52 / 3.51 (2d, 2H), 3.05 / 2.92 (2dd, 2H), 2.6 (s, 3H), 2.3 (s, 3H), 2.19 / 2.07 (2m, 2H), 1.8 / 1.6 (2m, 2H).

[0800] Example 17 : [24-Fluoro-4, 31 -dimethyl-27, 27-dioxo-21, 26-dioxa-27 lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocosa-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl] acetic acid

[0801]

[0802] Step C1 : Preparation of 6-bromo-8-fluoro-2H- 1,2 6 oxathiazine-2,2-dione

[0803] General method 4 step 2 was applied using 5-bromo-3-fluoro-2-hydroxybenzaldehyde (1 equiv.) as starting reagent to give the title compound (25% yield).

[0804] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.2 (s, 1H), 8.3 (dd, 1H), 8.1 (s, 1H).

[0805] Step C2: Preparation of 6-bromo-8-fluoro-3,4-dihydro-2H- 1,2 6 oxathiazine-2,2-dione

[0806] General method 4 step 3 was applied using 6-bromo-8-fluoro-2H- 1,2 6 oxathiazine-2,2-dione (1 equiv.) as starting reagent to give the title compound (87% yield).

[0807] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 8.91 (sl, 1H), 7.72 (dd, 1H), 7.41 (tf, 1H), 4.68 (s, 2H).

[0808] Step C3: Preparation of 6-bromo-8-fluoro-2,2-dioxo-2H-1,2 6 ,3-oxathiazine-3(4H)-carboxylic acid tert-butyl ester

[0809] Using General Method 5, Step 1, with 6-bromo-8-fluoro-3,4-dihydro-2H-1,2 6 ,3-oxathiazine-2,2-dione (1 equiv) as starting reagent, to give the title compound (85% yield).

[0810] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.88 (d, 1H), 7.74 (s, 1H), 5.18 (s, 2H), 1.5 (s, 9H).

[0811] Step C4: Preparation of 8-fluoro-2,2-dioxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 2H-1,2 6 ,3-oxathiazine-3(4H)-carboxylic acid tert-butyl ester

[0812] Using General Method 5, Step 2, with 6-bromo-8-fluoro-2,2-dioxo-2H-1,2 6 ,3-oxathiazine-3(4H)-carboxylic acid tert-butyl ester (1 equiv) as starting reagent, to give the title compound (71 % yield).

[0813] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.69 (s, 1H), 7.57 (d, 1H), 5.21 (s, 2H), 1.49 (s, 9H), 1.31 (s, 12H).

[0814] Step C5: Preparation of 8-fluoro-6-hydroxy-2,2-dioxo-2H-1,2 6 ,3-oxathiazine-3(4H)-carboxylic acid tert-butyl ester

[0815] Using General Method 5, Step 3, with 8-fluoro-2,2-dioxo-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2H-1,2 6 ,3-oxathiazine-3(4H)-carboxylic acid tert-butyl ester (1 equiv) as starting reagent, to give the title compound (81 % yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 10.4 (m, 1H), 6.79 (dd, 1H), 6.78 (d, 1H), 5.02 (s, 2H), 1.49 (s, 9H).

[0816] Step C6: Preparation of 6-(benzyloxy)-8-fluoro-3,4-dihydro-2H-1,2 6 ,3-oxathiazine-2,2-dione

[0817] General Procedure 5, Step 4 using 8-fluoro-6-hydroxy-2,2-dioxo-2H-1,2 6 ,3-oxathiazine-3(4H)-carboxylic acid tert-butyl ester (1 eq) as the reactant to give 6-(benzyloxy)-8-fluoro-2,2-dioxo-2H-1,2 6 ,3-oxathiazine-3(4H)-carboxylic acid tert-butyl ester (36% yield). The crude was reacted with General Procedure 5, Step 5 to give the title compound (91% yield).

[0818] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8.7 (m, 1H), 7.48-7.3 (m, 5H), 7.1 (dd, 1H), 6.8 (d, 1H), 5.09 (s, 2H), 4.58 (s, 2H).

[0819] Step 1: Preparation of 3-(3-{[6-(benzyloxy)-8-fluoro-2,2-dioxo-2H-1,2 6 ,3-oxathiazine-3(4H)-yl]methyl}-4-methylphenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazole-5-yl)propanoic acid ethyl ester

[0820] General Procedure 7 using 3-[3-(hydroxymethyl)-4-methylphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazole-5-yl)propanoic acid ethyl ester (1 eq) and 6-(benzyloxy)-8-fluoro-3,4-dihydro-2H-1,2 6 ,3-oxathiazine-2,2-dione (1 eq) as the starting reagent to give the title compound (85% yield).

[0821] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 0.97 (t, J = 7.09 Hz, 3H) 1.39-1.51 (m, 2H) 1.89 (quint, J = 7.27 Hz, 2H) 1.99 (s, 2H) 2.22 (s, 3H) 2.76 (s, 3H) 3.16 (dd, J = 8.07, 2.69 Hz, 2H) 3.35 (t, J = 6.30 Hz, 2H) 3.72 (s, 3H) 3.92 (q, J = 7.05 Hz, 2H) 4.24-4.32 (m, 4H) 4.49 (s, 2H) 4.60 (t, J = 6.97 Hz, 2H) 4.84 (t, J = 8.07 Hz, 1H) 5.11 (s, 2H) 6.79 (s, 1H) 6.82-6.89 (m, 2H) 7.10-7.22 (m, 5H) 7.24 (s, 1H) 7.32-7.50 (m, 6H) 7.53-7.59 (m, 1H).

[0822] Step 2: Preparation of 3-{3-[(8-fluoro-6-hydroxy-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}-3-[1-(4-hydroxybutyl)-4- methyl-1H-benzotriazol-5-yl]propanoic acid ethyl ester

[0823] Using General Procedure 8, 3-{3-[(8-fluoro-6-hydroxy-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}-3-[1-(4-hydroxybutyl)-4- methyl-1H-benzotriazol-5-yl]propanoic acid ethyl ester (1 equiv) as starting reagent to give the title compound (white solid, 97% yield).

[0824] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 10.1 / 4.4 (s+t, 2H), 7.62 (d, 1H), 7.5 (d, 1H), 7.28 (d, 1H), 7.2 (dd, 1H), 7.15 (d, 1H), 6.78 (dd, 1H), 6.48 (d, 1H), 4.85 (t, 1H), 4.65 (t, 2H), 4.49 (s, 2H), 4.28 (m, 2H), 3.95 (q, 2H), 3.4 (q, 2H), 3.18 (d, 2H), 2.78 (s, 3H), 2.22 (s, 3H), 1.9 (m, 2H), 1.38 (m, 2H), 1 (t, 3H).

[0825] Step 3: Preparation of ethyl 3-[l-(4-bromobutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(8-fluoro-6-hydroxy-2,2-dioxo-2H-l,2l 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate

[0826] Using General Procedure 9, ethyl 3-[l-(4-bromobutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(8-fluoro-6-hydroxy-2,2-dioxo-2H-l,2l 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate (1 equiv) as the starting reagent, afforded the title compound (off-white solid, 65% yield).

[0827] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 10.1 (s, 1H), 7.62 (d, 1H), 7.5 (d, 1H), 7.22 (d, 1H), 7.19 (dd, 1H), 7.12 (d, 1H), 6.78 (d, 1H), 6.45 (d, 1H), 4.83 (t, 1H), 4.69 (t, 2H), 4.48 (s, 2H), 4.26 (m, 2H), 3.91 (q, 2H), 3.51 (t, 2H), 3.15 (m, 2H), 2.73 (s, 3H), 2.21 (s, 3H), 2 (m, 2H), 1.78 (m, 2H), 1 (t, 3H).

[0828] Step 4: Preparation of ethyl [24-fluoro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27l 6 -thia-l,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 .3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate

[0829] Using General Procedure 11, ethyl 3-[l-(4-bromobutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(8-fluoro-6-hydroxy-2,2-dioxo-2H-l,2l 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate (1 equiv) as the starting reagent, afforded the title compound (off-white solid, 65% yield).

[0830] The enantiomerically pure final intermediates were obtained by separation on a chiral column.

[0831] 1 H-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, 2 H), 1 (t, 3 H).

[0832] Step 5: Preparation of Example 17

[0833] Using the general method 12, with [24-fluoro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27 6 -thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate E1 (1 equiv) or E2 (1 equiv) as starting reagent, to give the title compounds (yield 65-99% respectively).

[0834] Example 17a (E1)

[0835] C 29 H 29 HRMS calcd for C32H39FN4O6S: 580.1792; [M+H] + found: 581.1871 (delta = 1.1 ppm).

[0836] Example 17b (E2)

[0837] C 29 H 29 HRMS calcd for C32H39FN4O6S: 580.1792; [M+H] + found: 581.1867 (delta = 0.4 ppm).

[0838] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.3 (m, 1H), 7.55 (d, 1H), 7.5 (dd, 1H), 7.4 (d, 1H), 7.3 (d, 1H), 6.9 (dd, 1H), 6.55 (d, 1H), 5.7 (sl, 1H), 4.8 (m, 3H), 4.15 / 4 (2d, 2H), 4 / 3.9 (2d, 2H), 3.7 / 3.5 (2m, 2H), 3 / 2.9 (2m, 2H), 2.6 (s, 3H), 2.3 (s, 3H), 2.2 / 2.1 (2m, 2H), 1.8 / 1.6 (2m, 2H).

[0839] 19 F-NMR (376 MHz, DMSO-d6) δ ppm: 133.

[0840] Example 18 :[5-Fluoro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27 6 -thia-1,14,15,16-tetraazahexacyclo[20.5.3.13 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid

[0841]

[0842] Step B1 : Preparation of (5-bromo-3-fluoro-2-methylphenyl)methanol

[0843] Lithium aluminum hydride (4 eq., 3.07 g, 80.9 mmol) was placed in a round bottom flask. Anhydrous THF (5 mL / mmol, 101 ml) was added and 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 while stirring was continued. 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 150 mL of water and 100 mL of 2M aqueous NaOH solution was added. The mixture was concentrated to dryness and then purified by normal phase silica gel chromatography using DCM-EtOH (90:10) as eluent to give the title compound (1.8 g, 41% yield).

[0844] 1H-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)

[0845] Step B2: Preparation of [3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methanol

[0846] General procedure 3 was applied using (5-bromo-3-fluoro-2-methylphenyl)methanol (1 eq., 1.8 g, 8.2 mmol) as starting reagent to give the title compound (2.5 g, 73% yield).

[0847] 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).

[0848] Step 1 : Preparation of 3-[3-fluoro-5-(hydroxymethyl)-4-methylphenyl]-3-(1 -{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-1 H-benzotriazol-5-yl)propanoic acid ethyl ester

[0849] General procedure 6 was applied using (2E)-3-(1 -{4-[(4-methoxyphenyl)methoxy]butyl}-4- methyl-1 H-benzotriazol-5-yl)prop-2-enoic acid ethyl ester (1 eq.) and [3-fluoro-2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (1.4 eq.) as starting reagents to give the title compound (32% yield).

[0850] 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).

[0851] Step 2: 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Preparation of ethyl 3-oxathiazine-3(4H)-yl]methyl}-5-fluoro-4-methylphenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propionate

[0852] Using general method 7, ethyl 3-[3-fluoro-5-(hydroxymethyl)-4-methylphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propionate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ 6 Using 3-oxathiazine-2,2-dione (1.1 equivalents) as the starting reagent, the title compound was obtained (91% yield).

[0853] 1 H-NMR(400MHz,DMSO-d6)δppm:7.6 / 7.5(2d,2H),7.45(dl,2H),7.4(t,2H),7.35(t l,1H),7.2(d,2H),7.1(m,3H),7.05(dd,1H),6.95(d,1H),6.85(d,2H),5.1(s,2H), 4.85(t,1H),4.6(t,2H),4.45-4.25(3s,6H),3.95(q,2H),3.7(s,3H),3.35(t,2H) ,3.2(m,2H),2.8(sl,3H),2.1(sl,3H),1.9(quint,2H),1.45(quint,2H),1(t,3H).

[0854] Step 3: 3-{3-fluoro-5-[(6-hydroxy-2,2-dioxo-2H-1,2λ]} 6 Preparation of ethyl 3-oxathiazine-3(4H)-yl)methyl]-4-methylphenyl}-3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]propionate

[0855] Using general method 8, 3-(3-{[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Using ethyl 3-oxathiazine-3(4H)-yl]methyl}-5-fluoro-4-methylphenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propionate (1 equivalent) as the starting agent, the title compound (white solid, quantitative) was obtained.

[0856] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.7 (s, 1H), 7.6 (d, 1H), 7.5 (d, 1H), 7.15 (m, 2H), 7 (d, 1H), 6.8 (dd, 1H), 6.6 (d, 1H), 4.85 (t, 1H), 4.65 (t, 2H), 4.4 (m, 3H), 4.25 (2d, 2H), 3.9 (q, 2H), 3.4 (q, 2H), 3.2 (m, 2H), 2.8 (s, 3H), 2.1 (d, 3H), 1.9 (quint, 2H), 1.4 (quint, 2H), 1 (t, 3H).

[0857] Step 4: Preparation of ethyl 3-[1-(4-bromobutyl)-4-methyl-1H- benzotriazol-5-yl]-3-{3-fluoro-5-[(6-hydroxy-2,2-dioxo-2H-1,2 6 oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate

[0858] Using General Procedure 9, ethyl 3-[1-(4-bromobutyl)-4-methyl-1H- benzotriazol-5-yl]-3-{3-fluoro-5-[(6-hydroxy-2,2-dioxo-2H-1,2 6 oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate (1 equiv) as starting reagent to give the title compound (white solid, 73% yield).

[0859] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.7 (s, 1H), 7.65 / 7.5 (2d, 2H), 7.15 (m, 2H), 7 (d, 1H), 6.8 (dd, 1H), 6.6 (d, 1H), 4.85 (t, 1H), 4.7 (t, 2H), 4.4 (2d, 2H), 4.25 (2d, 2H), 3.9 (q, 2H), 3.5 (t, 2H), 3.2 (m, 2H), 2.75 (sl, 3H), 2.1 (d, 3H), 2 (m, 2H), 1.8 (quint, 2H), 1 (t, 3H).

[0860] Step 5: Preparation of [5-fluoro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27 6 lambda 3,7 - thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 9,13 .1 12,16 .0 25,29Preparation of [3-(32),4,6,9(31),10,12,14,22,24,29-decaEne-8-yl] ethyl acetate

[0861] Using General Method 11, ethyl [3-[1-(4-bromobutyl)-4-methyl-1H- benzotriazol-5-yl]-3-{3-fluoro-5-[(6-hydroxy-2,2-dioxo-2H-1,2lambda 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate (1 equiv) as starting reagent to give the title compound (96% yield).

[0862] The enantiomerically pure final intermediate was isolated by chiral column chromatography.

[0863] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 1.17 (t, J = 7.15 Hz, 3H) 1.58 (dt, J = 13.63, 6.76 Hz, 1H) 1.70 - 1.86 (m, 1H) 2.20 - 2.27 (m, 3H) 2.65 (s, 3H) 3.05 (dd, J = 15.83, 8.74 Hz, 1H) 3.16 - 3.26 (m, 1H) 3.43 - 3.57 (m, 1H) 3.62 - 3.73 (m, 1H) 3.83 - 4.00 (m, 7H) 4.03 - 4.17 (m, 4H) 4.63 - 4.89 (m, 4H) 5.89 (d, J = 2.81 Hz, 1H) 6.45 (s, 1H) 6.79 (dd, J = 9.05, 2.93 Hz, 1H) 6.97 - 7.01 (m, 1H) 7.39 - 7.47 (m, 2H) 7.68 (d, J = 8.68 Hz, 1H).

[0864] Step 6: Preparation of Example 18

[0865] Using General Method 12, [5-fluoro-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27lambda 6 -thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]triaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaEne-8-yl] ethyl acetate E1 (1 equiv) or E2 (1 equiv) as reaction reagent to give the title compound (80% - 72% yield, respectively).

[0866] Example 18a (E1)

[0867] C 29 H 29 HRMS calculated for FN4O6S: 580.1792; [M+H] found: 581.1867 (delta = 0.4 ppm). +

[0868] Example 18b (E2)

[0869] C 29 H 29 HRMS calculated for FN4O6S: 580.1792; [M+H] found: 581.1866 (delta = 0.2 ppm). +

[0870] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (m, 1H), 7.7 (d, 1H), 7.41 (2d, 2H), 7 (d, 1H), 6.8 (dd, 1H), 6.45 (d, 1H), 5.9 (d, 1H), 4.79 (m, 3H), 4.09 (m, 2H), 3.91 (m, 2H), 3.68 / 3.45 (2m, 2H), 3.1 / 2.95 (2dd, 2H), 2.65 (s, 3H), 2.22 (s, 3H), 2.2 / 2.05 (2m, 2H), 1.8 / 1.6 (2m, 2H).

[0871] Example 19 [(2R,8R)-2,4,33-trimethyl-29,29-dioxo-23,28-dioxa-29lambda 6 -thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]tracosa-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid and

[0872] [(2R,8S)-2,4,33-trimethyl-29,29-dioxo-23,28-dioxa-29lambda 6 -thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]tracosa-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid

[0873] ​​

[0874] Step 1: Preparation of 3-{1-[6-(benzyloxy)hexyl]-4-methyl-1H- benzotriazol-5-yl}-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propionic acid ethyl ester

[0875] General Procedure 6 was employed using (2E)-3-{1-[6-(benzyloxy)hexyl]-4- methyl-1H-benzotriazol-5-yl}prop-2-enoic acid ethyl ester (1 equiv) and (1S)-1-[2- methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1-ol (2 equiv) as starting reagents to give the title compound (70% yield).

[0876] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.59 (d, 1H), 7.46 (d, 1H), 7.4 (d, 1H), 7.34-7.22 (br, 5H), 6.99 (d, 1H), 4.97 (d, 1H), 4.82 (m, 1H), 4.82 (m, 1H), 4.62 (dd, 2H), 4.4 (s, 2H), 4.05 (dd, 1H), 3.92 (q, 2H), 3.36 (t, 2H), 3.11 (m, 2H), 2.75 (s, 3H), 2.19 (s, 3H), 1.87 (quint, 2H), 1.48 (quint, 2H), 1.32 (quint, 2H), 1.22 (m, 3H), 1.22 (m, 2H), 0.99 (t, 3H).

[0877] Step 2: Preparation of 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl]ethyl}-4-methylphenyl)-3-{1-[6-(benzyloxy)hexyl]-4- methyl-1H-benzotriazol-5-yl}propionic acid ethyl ester

[0878] General Procedure 7 was employed using 3-{1-[6-(benzyloxy)hexyl]-4-methyl- 1H-benzotriazol-5-yl}-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propionic acid ethyl ester (1 equiv) and 6-(benzyloxy)-3,4-dihydro-2H-1,2 6 ,3-oxathiazine-2,2-dione (1.5 equiv) as starting reagents to give the title compound (beige solid, 71% yield).

[0879] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 0.95-1.00 (m, 3H) 1.23-1.36 (m, 3H) 1.37-1.49 (m, 5H) 1.83 (sxt, J = 6.85 Hz, 2H) 1.99 (s, 1H) 2.28 (s, 3H) 2.76 (d, J = 3.67 Hz, 3H) 3.14-3.26 (m, 2H) 3.33-3.36 (m, 1H) 3.86-3.97 (m, 2H) 4.27-4.49 (m, 4H) 4.59 (q, J = 6.64 Hz, 2H) 4.87 (td, J = 7.98, 4.10 Hz, 1H) 5.02-5.14 (m, 2H) 5.27 (q, J = 6.93 Hz, 1H) 6.96-7.16 (m, 4H) 7.24-7.48 (m, 11H) 7.49-7.55 (m, 1H) 7.57-7.63 (m, 1H).

[0880] Step 3: Preparation of 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}-3-[1-(6-hydroxyhexyl)-4- methyl-1H-benzotriazol-5-yl]propanoic acid ethyl ester

[0881] Using General Procedure 8, 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}-3-[1-(6-hydroxyhexyl)-4- methyl-1H-benzotriazol-5-yl]propanoic acid ethyl ester (1 equiv) as starting reagent to give the title compound (yellow solid, 78% yield).

[0882] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.66 (m, 1H), 7.63 / 7.56 (2dd, 2H), 7.47 / 7.44 (2d, 1H), 7.15-7.08 (m, 2H), 6.92 / 6.9 (2d, 1H), 6.72 (2dd, 1H), 6.58 (2dd, 1H), 5.26 (m, 1H), 4.87 (m, 1H), 4.63 (t, 2H), 4.31 (m, 2H), 3.94 (2d, 2H), 3.32 (m, 2H), 3.22 (d, 2H), 2.76 (s, 3H), 2.28 (s, 3H), 1.87 (m, 2H), 1.43 / 1.41 (2d, 3H), 1.38-1.1 (m, 4H), 1.33 (m, 2H), 1 / 0.99 (2t, 3H).

[0883] Step 4: Preparation of ethyl 3-[1 -(6-bromohexyl)-4-methyl-1 H- benzotriazol-5-yl]-3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate

[0884] Using General Method 9, ethyl 3-[1 -(6-bromohexyl)-4-methyl-1 H- benzotriazol-5-yl]-3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate (1 equiv) as starting reagent, afforded the title compound (84% yield).

[0885] 1 H-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, 2H), 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, 2H), 4.4-4.2 (m, 2H), 3.92 (2d, 2H), 3.46 (m, 2H), 3.21 (d, 2H), 2.77 (s, 3H), 2.28 (s, 3H), 1.88 (m, 2H), 1.71 (m, 2H), 1.4 (2d, 3H), 1.38 (m, 2H), 1.21 (m, 3H), 1 (2t, 1 H).

[0886] Step 5: Preparation of ethyl [(2R)-2,4,33-trimethyl-29,29-dioxo-23,28-dioxa-29 6 - thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]tricosa-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetate

[0887] Using General Method 11, ethyl 3-[1 -(6-bromohexyl)-4-methyl-1 H- benzotriazol-5-yl]-3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2 6Ethyl [(2R)-2,4,33-trimethyl-29,29-dioxo-23,28-dioxa-29lambda

[0888] 1 H-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, 1 H) 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 = 7.58 Hz, 1 H) 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).

[0889] Step 6: Preparation of Example 19

[0890] Using the general method 12, ethyl [(2R)-2,4,33-trimethyl-29,29-dioxo-23,28-dioxa-29lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]tracosa-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetate (1 equiv) as starting reagent to give the title compound (white solid, 91% yield).

[0891] The diastereomeric pure products were separated by chiral column chromatography.

[0892] Example 19a (2R, 8R)

[0893] C 32 H 36 HRMS calculated for N4O6S: 604.2356; [M+H] + , found: 605.2430 (delta = 0.3 ppm).

[0894] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (sl), 7.6 (d, 1H), 7.48 (dd, 1H), 7.3 (d, 1H), 7.14 (d, 1H), 7 (d, 1H), 6.96 (d, 1H), 6.78 (dd, 1H), 6 (d, 1H), 5.3 (q, 1H), 4.92 (t, 1H), 4.64 (m, 2H), 4.04 / 3.83 (2d, 2H), 3.7 (m, 2H), 3.11 / 2.85 (2dd, 2H), 2.82 (s, 3H), 2.32 (s, 3H), 2 (m, 2H), 1.6 (m, 2H), 1.4 (m, 2H), 1.25 (m, 2H), 1.25 (d, 3H).

[0895] 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.

[0896] Example 19b (2R, 8S)

[0897] C 32 H 36 HRMS calculated for N4O6S: 604.2356; [M+H] + , found: 605.2431 (delta = 0.4 ppm).

[0898] 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).

[0899] 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.

[0900] 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 ]tricosa-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetic acid and

[0901] [(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 ]tricosa-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetic acid

[0902]

[0903] Step 1 : Preparation of 3-{3-[(1 S)-1 -hydroxyethyl]-4-methylphenyl}-3-(1-{5-[(4- methoxyphenyl)methoxy]pentyl}-4-methyl-1 H-benzotriazol-5-yl)propanoic acid ethyl ester

[0904] Using General Method 6, with (2E)-3-(1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4- methyl-1 H-benzotriazol-5-yl)prop-2-enoic acid ethyl ester (1 equiv) and (1 S)-1 -[2- methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1 -ol (2 equiv) as starting reagents, the title compound was obtained (77% yield).

[0905] 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, 2H), 7.04 (dd, 1 H), 6.98 (d, 1 H), 6.87 (d, 2H), 4.96 (d, 1 H), 4.82 (m, 1 H), 4.82 (m, 1 H), 4.62 (dd, 2H), 4.31 (s, 2H), 3.92 (q, 2H), 3.73 (s, 3H), 3.31 (m, 2H), 3.15-3.09 (m, 2H), 2.77 (s, 3H), 2.19 (s, 3H), 1.87 (m, 2H), 1.51 (m, 2H), 1.27 (m, 2H), 1.23 / 1.21 (d, 3H), 0.99 (t, 3H).

[0906] Step 2: Preparation of 3-(3-{(1 R)-1 -[6-(benzyloxy)-2,2-dioxo-2H-1,2 6 3-oxothiazin-3(4H)-yl]ethyl}-4-methylphenyl)-3-(1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4- methyl-1 H-benzotriazol-5-yl)propanoic acid ethyl ester

[0907] Using General Method 7, with 3-{3-[(1 S)-1 -hydroxyethyl]-4-methylphenyl}-3-(1-{5-[(4- methoxyphenyl)methoxy]pentyl}-4-methyl-1 H-benzotriazol-5-yl)propanoic acid ethyl ester (1 equiv) and 6-(benzyloxy)-3,4-dihydro-2H-1,2 6 3-oxothiazin-2,2-dione (1.5 equiv) as starting reagents, the title compound was obtained (64% yield).

[0908] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1H), 7.51 (2d, 1H), 7.5-6.8 (m, 15H), 5.27 (q, 1H), 5.09 (m, 2H), 4.88 (m, 1H), 4.59 (m, 2H), 4.41 (m, 2H), 4.29 (s, 2H), 3.9 (q, 2H), 3.71 (s, 3H), 3.29 (m, 2H), 3.2 (m, 2H), 2.76 (2s, 3H), 2.28 (s, 3H), 1.82 (m, 2H), 1.49 (m, 2H), 1.4 (m, 3H), 1.22 (m, 2H), 0.96 (m, 3H).

[0909] Step 3: 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2 6 Preparation of ethyl 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2

[0910] Using General Method 8, ethyl 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2 6 oxathiazin-3(4H)-yl]ethyl}-4-methylphenyl)-3-(1-{5-[(4-methoxyphenyl)methoxy]pentyl}-4- methyl-1H-benzotriazol-5-yl)propanoate (1 equiv) as the starting reagent to give the title compound (grey solid, 98% yield).

[0911] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.63 / 9.62 (2m, 3H), 7.62 / 7.56 (2dd, 2H), 7.47 / 7.45 (2sl, 1H), 7.1 (m, 2H), 6.92 / 6.9 (2d, 1H), 6.73 (m, 1H), 6.58 (2d, 1H), 5.25 (m, 1H), 4.88 (m, 1H), 4.63 (t, 2H), 4.32 (m, 2H), 3.94 (m, 2H), 3.32 (m, 2H), 3.22 (m, 2H), 2.77 (s, 3H), 2.28 (s, 3H), 1.88 (m, 2H), 1.46-1.37 (m+d, 5H), 1.24 (m, 2H), 1 / 0.99 (2t, 3H).

[0912] Step 4: 3-[1-(5-bromopentyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-2,2- dioxo-2H-1,26 Preparation of ethyl 3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2

[0913] Using General Method 9, ethyl 3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2 6 Using General Method 9, ethyl 3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2

[0914] 1 H-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, 2H), 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, 2H), 4.4-4.25 (m, 2H), 3.93 (q, 2H), 3.48 (t, 2H), 3.21 (m, 2H), 2.77 (s, 3H), 2.28 (s, 3H), 1.9 (m, 2H), 1.8 (m, 2H), 1.41 (2d, 3H), 1.32 (m, 2H), 1 / 0.99 (2t, 3H).

[0915] Step 5: Preparation of ethyl [(2R)-2,4,32-trimethyl-28,28-dioxo-22,27-dioxa-28 6 - thia-1,14,15,16-tetraazahexacyclo[21.5.3.1 3,7 .1 9,13 .0 12,16 .0 26,30 Step 5: Preparation of ethyl [(2R)-2,4,32-trimethyl-28,28-dioxo-22,27-dioxa-28

[0916] Using General Method 11, ethyl 3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2 6 Using General Method 9, ethyl 3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2

[0917] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 0.92-1.07 (m, 7H) 1.27-1.53 (m, 9H) 1.55-1.81 (m, 5H) 1.85-1.98 (m, 3H) 1.99-2.09 (m, 2H) 2.23-2.36 (m, 7H) 2.75 (s, 4H) 2.80 (s, 3H) 2.94 (dd, J=15.71, 7.52 Hz, 1H) 3.10 (dd, J=16.08, 7.03 Hz, 2H) 3.21-3.29 (m, 2H) 3.57-3.78 (m, 3H) 3.80-3.98 (m, 8H) 4.04-4.21 (m, 2H) 4.56-4.76 (m, 4H) 4.81-4.89 (m, 1H) 4.95 (t, J=7.82 Hz, 1H) 5.21-5.36 (m, 2H) 5.99 (s, 2H) 6.76-6.88 (m, 3H) 6.91-6.99 (m, 2H) 7.13 (dd, J=10.51, 8.19 Hz, 2H) 7.24-7.38 (m, 3H) 7.48 (d, J=7.95 Hz, 1H) 7.60-7.71 (m, 2H) 7.84 (d, J=8.68 Hz, 1H).

[0918] Step 6: Preparation of Example 20

[0919] Using the general method 12, with [(2R)-2,4,32-trimethyl-28,28-dioxo-22,27-dioxa-28 lambda 6 - thia-1,14,15,16-tetraazahexacyclo[21.5.3.13 3,7 .1 9,13 .0 12,16 .0 26,30 ]tricosa-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetic acid ethyl ester (1 eq) as starting reagent to give the title compound (white solid, 32% yield).

[0920] The diastereomerically pure products were isolated by chiral column chromatography.

[0921] Example 20a (2R, 8S)

[0922] C 31 H 34 HRMS calculated for C42H56N4O6S: 790.4191 ; [M+H] found: 791.4268 (delta = 0.2 ppm). + , found: 791.4268 (delta = 0.2 ppm).

[0923] 1H-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 (2 m, 2 H), 2.8 (s, 3 H), 2.32 (s, 3 H), 2.1-1.85 (m, 2 H), 1.69 (m, 2 H), 1.55-1.23 (m, 2 H), 1.12 (d, 3 H).

[0924] Example 20b (2R, 8R)

[0925] C 31 H 34 N4O6S. HRMS calculated for 590.2199; [M+H] found: 591.2274 (delta = 0.4 ppm). +

[0926] 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 (2 m, 2 H), 2.8 (s, 3 H), 2.32 (s, 3 H), 2.1-1.85 (m, 2 H), 1.69 (m, 2 H), 1.55-1.23 (m, 2 H), 1.12 (d, 3 H).

[0927] Example 21 [(2R,8S)-2,4,19,33-tetramethyl-29,29-dioxo-23,28-dioxa-29lambda 6 -thia-1,14,15,16,19-pentaazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 .0]tricosa-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid and

[0928] [(2R,8R)-2,4,19,33-tetramethyl-29,29-dioxo-23,28-dioxa-29lambda 6 - thia- 1, 14, 15, 16, 19-pentaazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]tricarba-3(34),4,6,9(33), 10, 12, 14, 24, 26, 31-decaen-8-yl] acetic acid

[0929]

[0930] Step Al: Preparation of tert-butyl (2-{[3-(benzyloxy)propyl](methyl)amino}ethyl)carbamate

[0931] To a solution of [(3-bromopropoxy)methyl]benzene (10 g, 43.6 mmol, 7.7 mL) in MeCN (3 mL / mmol, 131 mL) was added tert-butyl [2-(methylamino)ethyl]carbamate (1 eq., 7.61 g, 43.6 mmol) and K2CO3 (2 eq., 8.65 g, 87.3 mmol) 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 500 ml EtOAc, extracted with 500 ml water, then 500 ml brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to dryness to get the crude product as colorless oil which was used directly for the next step without further purification (14 g, 99% yield).

[0932] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.38-7.28 (m, 5H), 6.58 (t, 1H), 4.43 (s, 2H), 3.45 (t, 2H), 2.99 (q, 2H), 2.38 (t, 2H), 2.32 (t, 2H), 2.13 (s, 3H), 1.65 (quint, 2H), 1.37 (s, 9H).

[0933] Step A2: Preparation of N 1 -[3-(benzyloxy)propyl]-N 1 -methyl ethane-1,2-diamine

[0934] 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) was added HCl (4N in dioxane) (4 eq., 43 mL) 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 was partitioned between 200 mL of DCM and 300 ml of saturated aqueous NaHC03solution. The layers were separated and the aqueous layer was evaporated to dryness under reduced pressure. 50 ml of MeCN was added, then the solid was filtered off and washed with 2x20 ml of MeCN. The mother liquor was concentrated to dryness to give the crude product as a yellow oil. The crude product was used without purification (6.2 g, 62% yield).

[0935] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.38-7.23 (m, 5H), 4.44 (s, 2H), 3.45 (t, 2H), 2.56 (t, 2H), 2.36 (t, 2H), 2.33 (t, 2H), 2.1 (s, 3H), 1.67 (quint, 2H).

[0936] Step A3: N 1 -[3-(benzyloxy)propyl]-N 1 -methyl-N 2 Preparation of (3-methyl-2-nitrophenyl)ethane-1,2-diamine

[0937] Using the general method 2 step 1 with 1-fluoro-3-methyl-2-nitro-benzene (1 eq.) and N 1 -[3-(benzyloxy)propyl]-N 1 -methyl ethane-1,2-diamine crude (1.2 eq.) as starting reagent to give the title compound (58% yield).

[0938] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.35-7.22 (m, 1H), 7.35-7.22 (m, 5H), 6.78 (d, 1H), 6.61 (t, 1H), 6.58 (d, 1H), 4.41 (s, 2H), 3.49 (t, 2H), 3.2 (q, 2H), 2.55 (t, 2H), 2.41 (t, 2H), 2.32 (s, 3H), 2.19 (s, 3H), 1.69 (quint, 2H).

[0939] Step A4: N 1 Preparation of (2-{[3-(benzyloxy)propyl](methyl)amino}ethyl)-4-bromo-3-methylbenzene-1,2-diamine

[0940] Using General Method 2, Step 2, N 1 -[3-(benzyloxy)propyl]-N 1 -methyl-N 2 -(3-methyl-2-nitrophenyl)ethane-1,2-diamine (1 equiv) as the reacting reagent to give N 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 with General Method 2, Step 3 to give the title compound (76% yield). C 20 H 28 LC-MS calculated for BrN3O: 405; [M+H] found: 406 / 408. + , found: 406 / 408.

[0941] Step A5: Preparation of 3-(benzyloxy)-N-[2-(5-bromo-4-methyl-1 H- benzotriazol-1 -yl)ethyl]-N-methylpropan-1 -amine

[0942] Using General Method 2, Step 4, N 1 -(2-{[3-(benzyloxy)propyl](methyl)amino}ethyl)-4-bromo-3-methylbenzene-1,2- diamine (1 equiv) as the starting reagent to give the title compound (85% yield).

[0943] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8.19 (s, 1 H), 7.4 (2d, 2H), 7.3 (t, 2H), 7.25 (t, 1 H), 7.2 (d, 2H), 4.3 (t, 2H), 4.22 (s, 2H), 3.18 (t, 2H), 2.68 (t, 2H), 2.55 (s, 3H), 2.35 (t, 2H), 2.2 (s, 3H), 1.5 (m, 2H).

[0944] Step A6: Preparation of (2E)-3-[1 -(2-{[3-(benzyloxy)propyl](methyl)amino}ethyl)- 4-methyl-1 H-benzotriazol-5-yl]prop-2-enoic acid ethyl ester

[0945] Using General Method 2, Step 5, 3-(benzyloxy)-N-[2-(5-bromo-4-methyl-1 H- benzotriazol-1 -yl)ethyl]-N-methylpropan-1 -amine (1 equiv) as the starting reagent to give the title compound (93% yield).

[0946] 1H-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).

[0947] Step 1: Preparation of 3-[1-(2-{[3-(benzyloxy)propyl](methyl)amino}ethyl)-4- methyl-1H-benzotriazol-5-yl]-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propionic acid ethyl ester

[0948] Using General Procedure 6, (2E)-3-[1-(2-{[3-(benzyloxy)propyl](methyl)amino}ethyl)-4- methyl-1H-benzotriazol-5-yl]prop-2-enoic acid ethyl ester (1 equiv) and (1S)-1-[2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol (1 equiv) as starting reagents, afforded the title compound (33% yield).

[0949] 1 H-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).

[0950] Step 2: Preparation of 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2 6 3-oxothiazin-3(4H)-yl]ethyl}-4-methylphenyl)-3-[1-(2-{[3-(benzyloxy)propyl](methyl)amino}ethyl)-4-methyl-1H-benzotriazol-5-yl]propionic acid ethyl ester

[0951] Using general method 7, ethyl 3-[1-[2-[3-benzyloxypropyl(methyl)amino]ethyl]-4-methyl-benzotriazol-5-yl]-3-[3-[(1S)-1-hydroxyethyl]-4-methyl-phenyl]propionate (1 equivalent) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ 6 Using 3-oxathiazine-2,2-dione (1.1 equivalents) as the starting agent, the title compound was obtained (58% yield).

[0952] C 48 H 55 LC-MS calculated value of N5O7S: 845; [M+H] + , Measured value: 846.

[0953] Step 3: 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ethyl 3-oxathiazine-3(4H)-yl)ethyl]-4-methylphenyl}-3-(1-{2-[(3-hydroxypropyl)(methyl)amino]ethyl}-4-methyl-1H-benzotriazol-5-yl)propionate

[0954] Using general method 8, 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2λ 6 Starting with ethyl 3-oxathiazine-3(4H)-yl]ethyl}-4-methylphenyl)-3-[1-(2-{[3-(benzyloxy)propyl](methyl)amino}ethyl)-4-methyl-1H-benzotriazol-5-yl]propionate (1 equivalent), the title compound (yellow oil, 97% yield) was obtained.

[0955] C 34 H 43 LC-MS calculated value of N5O7S: 665; [M+H] + , Measured value: 666.

[0956] Step 4: 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 ethyl 3-oxathiazine-3(4H)-yl)ethyl]-4-methylphenyl]propionate

[0957] Using general method 9, 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ] 6LC-MS calculated for C42H53BrN5O6S: 727; [M+H] found: 728 / 730.

[0958] C 34 H 42 LC-MS calculated for C42H53BrN5O6S: 727; [M+H] found: 728 / 730. + LC-MS calculated for C42H53BrN5O6S: 727; [M+H] found: 728 / 730.

[0959] Step 5: Preparation of [(2R)-2,4,19,33-tetramethyl-29,29-dioxo-23,28-dioxa-29λ 6 -sulfur-1,14,15,16,19-pentaazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 Step 5: Preparation of [(2R)-2,4,19,33-tetramethyl-29,29-dioxo-23,28-dioxa-29λ

[0960] Using General Procedure 11 with 3-(1-{2-[(3-bromopropyl)(methyl)amino]ethyl}-4- methyl-1 H-benzotriazole-5-yl)-3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2λ 6 LC-MS calculated for C42H53BrN5O6S: 727; [M+H] found: 728 / 730.

[0961] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.74 / 7.63 (2d, 1H), 7.73 / 7.48 (2d, 1H), 7.58 (s, 1H), 7.27 / 7.04 (2d, 1H), 7.25 / 7.12 (d, 1H), 7.01 / 6.93 (2d, 1H), 6.84 / 6.73 (2d, 1H), 6.37 / 5.81 (2sl, 1H), 5.35 / 5.29 (2q, 1H), 4.93 / 4.87 (2t, 1H), 4.8 / 4.71 / 4.61 / 4.58 (4m, 2H), 4.24 / 4.02 / 3.98 / 3.87 (4d, 2H), 3.91 (q, 2H), 3.83 (m, 2H), 3.34-3.13 / 3.02 (4dd, 2H), 3.11 / 3.06 / 2.86 / 2.72 (4m, 2H), 2.84 (2s, 3H), 2.59-2.46 / 2.4 (2m, 2H), 2.29 (s, 3H), 2.19 / 2.13 (2sl, 3H), 1.85 (m, 2H), 1.52 / 1.27 (2d, 3H), 1.01 (2d, 3H).

[0962] Step 6: Preparation of Example 21

[0963] General Method 12 was used with [(2R)-2,4,19,33-tetramethyl-29,29-dioxo-23,28-dioxa-29 lambda 6 - thia- 1, 14, 15, 16, 19-pentazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]tracosa-3(34),4,6,9(33), 10,12,14,24,26,31-decaen-8-yl] ethanoate (1 equiv) as starting reagent to give the title compound (white solid, 83% yield).

[0964] The diastereomerically pure products were isolated by chiral column chromatography.

[0965] Example 21a (2R, 8S)

[0966] C 32 H 37 HRMS calcd for C34H45N5O6S: 619.2464; [M+H] + found: 620.2538 (delta = 0.1 ppm).

[0967] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.05 (m, 1H), 7.71 (m, 2H), 7.55 (d, 1H), 7.29 (dd, 1H), 7.12 (d, 1H), 7 (d, 1H), 6.81 (dd, 1H), 6.38 (d, 1H), 5.35 (q, 1H), 4.85 (t, 1H), 4.78 / 4.58 (2m, 2H), 4.21 / 3.95 (2d, 2H), 3.82 (m, 2H), 3.1 / 3 (2dd, 2H), 3.05 / 2.7 (2m, 2H), 2.81 (s, 3H), 2.55 (m, 2H), 2.3 (s, 3H), 2.15 (s, 3H), 1.82 (m, 2H), 1.5 (d, 3H).

[0968] Example 21b (2R, 8R)

[0969] C 32 H 37 HRMS calcd for N5O6S: 619.2464; [M+H] found: 620.2576 (delta = 6.2 ppm). +

[0970] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.3 (m, 1H), 7.65 / 7.22 (2d, 2H), 7.5 (dd, 1H), 7.22 (d, 1H), 7 (d, 1H), 6.95 (d, 1H), 6.72 (dd, 1H), 5.82 (d, 1H), 5.3 (q, 1H), 4.91 (t, 1H), 4.7 / 4.6 (2m, 2H), 4.02 / 3.85 (2d, 2H), 3.48 / 3.32 (2m, 2H), 3.1 (m, 2H), 2.88 (m, 2H), 2.81 (s, 3H), 2.4 (t, 2H), 2.3 (s, 3H), 2.2 (s, 3H), 1.68 (m, 2H), 1.25 (d, 3H).

[0971] Example 22 : 23-chloro-4, 31-dimethyl-27, 27-dioxo-21, 26-dioxa-27 lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ] tridocos-3(32), 4, 6, 9(31), 10, 12, 14, 22, 24, 29-decaen-8-yl] acetic acid

[0972] ​

[0973] Step Cl: Preparation of 5-(benzyloxy)-4-chloro-2-hydroxybenzaldehyde

[0974] General Procedure 4, Step 1 using 4-(benzyloxy)-3-chlorophenol (1 equiv) as the starting reagent to give the title compound (45% yield).

[0975] 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 10.66 (s, 1H), 10.22 (s, 1H), 7.49-7.3 (m, 5H), 7.38 (s, 1H), 7.12 (s, 1H), 5.16 (s, 2H).

[0976] Step C2: Preparation of 6-(benzyloxy)-7-chloro-2H-1,2 6 oxathiazine-2,2-dione

[0977] General Procedure 4, Step 2 using 5-(benzyloxy)-4-chloro-2-hydroxybenzaldehyde (1 equiv) as the starting reagent to give the title compound (91% yield).

[0978] 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 9.16 (s, 1H), 7.93 (s, 1H), 7.92 (s, 1H), 7.53-7.34 (m, 5H), 5.28 (s, 2H).

[0979] Step C3: Preparation of 6-(benzyloxy)-7-chloro-3,4-dihydro-2H-1,2 6 oxathiazine-2,2-dione

[0980] General Procedure 4, Step 3 using 6-(benzyloxy)-7-chloro-2H-1,2 6 oxathiazine-2,2-dione (1 equiv) as the starting reagent to give the title compound (quantitative).

[0981] 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 8.5 (br., 1H), 7.47 (dm, 2H), 7.41 (tm, 2H), 7.35 (tm, 1H), 7.34 (s, 1H), 7.25 (s, 1H), 5.17 (s, 2H), 4.52 (s, 2H).

[0982] Step 1 : 3-(3-{[6-(benzyloxy)-7-chloro-2,2-dioxo-2H-1,2 6Preparation of ethyl 3-oxathiazine-3(4H)-yl]methyl}-4-methylphenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propionate

[0983] Using general method 7, ethyl 3-[3-(hydroxymethyl)-4-methylphenyl]-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propionate (1 equivalent) and 6-(benzyloxy)-7-chloro-3,4-dihydro-2H-1,2λ 6 Using 3-oxathiazine-2,2-dione (1.4 equivalents) as the starting agent, the title compound (yellow oil, 50% yield) was obtained.

[0984] 1 H-NMR(500MHz,DMSO-d6)δppm:7.57(d,1H),7.51-7.33(m,5H),7.48(d,1H),7.45(s,1H),7.26(s, 1H),7.26(d,1H),7.19(dd,1H),7.18(dm,2H),7.13(d,1H),6.86(dm,2H),5.16(s,2H),4.85(t,1H) ,4.62(t,2H),4.49 / 4.44(d+d,2H),4.29(s,2H),4.27 / 4.21(d+d,2H),3.91(q,2H),3.72(s,3H),3 .35(t,2H),3.2 / 3.16(dd+dd,2H),2.77(s,3H),2.2(s,3H),1.89(m,2H),1.45(m,2H),0.96(t,3H).

[0985] Step 2: 3-{3-[(7-chloro-6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ethyl 3-oxathiazine-3(4H)-yl)methyl]-4-methylphenyl}-3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]propionate

[0986] Using general method 8, 3-[3-[(6-benzyloxy-7-chloro-2,2-dioxo-4H-1,2λ] 6 Ethyl 3-oxathiazine-3-yl)methyl]-4-methyl-phenyl]-3-[1-[4-[(4-methoxyphenyl)methoxy]butyl]-4-methyl-benzotriazol-5-yl]propionate (1 equivalent) was used as the starting agent to give the title compound (yellow oil, 74% yield).

[0987] 1H-NMR (500 MHz, DMSO-d6) δ ppm: 10.48 (br s, 1H), 7.61 (d, 1H), 7.51 (d, 1H), 7.31 (s, 1H), 7.27 (d, 1H), 7.19 (dd, 1H), 7.13 (d, 1H), 6.85 (s, 1H), 4.83 (t, 1H), 4.64 (t, 2H), 4.45 / 4.42 (d+d, 2H), 4.43 (br s, 1H), 4.25 / 4.2 (d+d, 2H), 3.93 (q, 2H), 3.37 (t, 2H), 3.17 (d, 2H), 2.76 (s, 3H), 2.22 (s, 3H), 1.9 (m, 2H), 1.35 (m, 2H), 0.99 (t, 3H).

[0988] Step 3: [23-Chloro-4, 31-dimethyl-27, 27-dioxo-21, 26-dioxa-27 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of ethyl [23-chloro-4, 31-dimethyl-27, 27-dioxo-21, 26-dioxa-27

[0989] Using General Method 10, ethyl 3-{3-[(7-chloro-6-hydroxy-2,2-dioxo-2H- 1,2 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1

[0990] 1H-NMR (500 MHz, DMSO-d6) δ ppm: 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).

[0991] Step 4: Preparation of [23-chloro-4, 31-dimethyl-27, 27-dioxo-21, 26-dioxa-27 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 .0 6 ] tridocos-3(32), 4, 6, 9(31), 10, 12, 14, 22, 24, 29-decaen-8-yl] acetic acid

[0992] Using the general method 12, [23-chloro-4, 31-dimethyl-27, 27-dioxo-21, 26-dioxa-27 3,7 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 9,13 .1 12,16 .0 25,29 ] tridocos-3(32), 4, 6, 9(31), 10, 12, 14, 22, 24, 29-decaen-8-yl] acetic acid ethyl ester (1 equiv) as starting reagent to give the title compound (white solid, 94% yield).

[0993] The enantiopure product was obtained by chiral column chromatography separation.

[0994] Example 22a (E1)

[0995] C 29 H 29 HRMS calcd for C26H32CIN4O6S: 596.1497; [M+H] found: 597.1564 (delta = -0.9 ppm). + Example 22b (E2) ​

[0996] C 29 H 29 HRMS calcd for C26H26N4O6S: 596.1497; [M+H] found: 597.1549 (delta = -3.4 ppm) + , found: 597.1549 (delta = -3.4 ppm) 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 12.23 (br s, 1H), 7.68 (d, 1H), 7.48 (dd, 1H), 7.46 (d, 1H), 7.35 (s, 1H), 7.27 (d, 1H), 6.65 (d, 1H), 6.09 (s, 1H), 4.85 / 4.74 (m+m, 2H), 4.75 (m, 1H), 4.26 / 3.91 (d+d, 2H), 4.01 / 3.77 (d+d, 2H), 3.69 / 3.42 (m+m, 2H), 3.02 / 2.96 (dd+dd, 2H), 2.64 (s, 3H), 2.31 (s, 3H), 2.22 / 2.01 (m+m, 2H), 1.83 / 1.63 (m+m, 2H).

[0997] 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.

[0998] 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 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid and

[0999] [(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 25,29Tridcaco-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid

[1000]

[1001] Step 1: 3-(3-{(1R)-1-[6-(benzyloxy)-8-methoxy-2,2-dioxo-2H-1,2 6 Preparation of ethyl 3-(3-{(1R)-1-hydroxyethyl}-4-methylphenyl)-3-(1-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate

[1002] Using General Procedure 7, ethyl 3-(3-{(1R)-1-hydroxyethyl}-4-methylphenyl)-3-(1-{4- [(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propanoate (1 equiv) and 6-(benzyloxy)-8-methoxy-3,4-dihydro-2H-1,2 6 ,3-oxathiazine-2,2-dione (1.05 equiv) as starting reagents gave the title compound (79% yield).

[1003] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 0.88-1.05 (m, 14H) 1.13-1.30 (m, 10H) 1.36-1.49 (m, 20H) 1.82-1.94 (m, 9H) 2.27 (s, 11H) 2.74-2.81 (m, 11H) 3.12-3.26 (m, 8H) 3.34 (q, J=6.15 Hz, 8H) 3.72 (s, 13H) 3.81 (s, 11H) 3.92 (q, J=7.09 Hz, 8H) 4.23-4.36 (m, 11H) 4.39 (s, 4H) 4.55-4.65 (m, 8H) 4.87 (t, J=7.76 Hz, 4H) 5.01-5.14 (m, 7H) 5.21-5.30 (m, 3H) 6.35 (d, J=2.57 Hz, 1H) 6.42 (d, J=2.57 Hz, 1H) 6.72-6.78 (m, 1H) 6.86 (d, J=8.56 Hz, 2H) 7.07-7.14 (m, 2H) 7.17 (d, J=8.56 Hz, 2H) 7.28-7.38 (m, 1H) 7.38-7.44 (m, 3H) 7.44-7.49 (m, 2H) 7.49-7.55 (m, 1H) 7.56-7.62 (m, 1H).

[1004] Step 2: Preparation of ethyl 3-[l-(4-hydroxybutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(lR)-l-(6-hydroxy-8-methoxy-2,2-dioxo-2H-l,2 6 ,3-oxathiazin-3(4H)-yl]ethyl]-4-methylphenyl}propanoate

[1005] Using General Procedure 8, ethyl 3-[l-(4-hydroxybutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(lR)-l-(6-hydroxy-8-methoxy-2,2-dioxo-2H-l,2 6 ,3-oxathiazin-3(4H)-yl]ethyl]-4-methylphenyl}propanoate (1 equiv) as the starting reagent to give the title compound (yellow solid, 98% yield).

[1006] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 0.92-1.06 (m, 6H) 1.10-1.48 (m, 13H) 1.90 (quin, J=7.18 Hz, 4H) 2.27 (s, 5H) 2.70-2.79 (m, 5H) 3.22 (d, J=7.70 Hz, 3H) 3.34-3.42 (m, 4H) 3.77 (s, 5H) 3.88-3.99 (m, 3H) 4.27 (d, J=5.26 Hz, IH) 4.33 (d, J=2.32 Hz, IH) 4.37-4.46 (m, IH) 4.65 (t, J=6.97 Hz, 2H) 4.80-4.94 (m, IH) 5.24 (q, J=6.77 Hz, IH) 6.10 (d, J=2.45 Hz, IH) 6.15 (d, J=2.57 Hz, IH) 6.40-6.49 (m, IH) 6.76-6.84 (m, IH) 7.04-7.16 (m, 3H) 7.45 (d, J=10.15 Hz, IH) 7.53-7.59 (m, IH) 7.59-7.66 (m, IH) 9.60-9.65 (m, IH).

[1007] Step 3: Preparation of ethyl 3-[l-(4-bromobutyl)-4-methyl-lH- benzotriazol-5-yl]-3-{3-[(lR)-l-(6-hydroxy-8-methoxy-2,2-dioxo-2H-l,2 6 ,3-oxathiazin-3(4H)-yl]ethyl]-4-methylphenyl}propanoate

[1008] Using General Method 9, ethyl [(2R)-24-methoxy-2,4,31-trimethyl-27,27-dioxo- 21,26-dioxa-27λ 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate (1 equiv) as the starting reagent to give the title compound (65% yield).

[1009] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 1.00 (q, J = 6.89 Hz, 5H) 1.35 - 1.46 (m, 3H) 1.77 (quin, J = 7.03 Hz, 3H) 1.94 - 2.05 (m, 5H) 2.27 (s, 4H) 2.76 (s, 4H) 3.22 (d, J = 7.70 Hz, 3H) 3.53 (t, J = 6.66 Hz, 3H) 3.76 (s, 4H) 3.94 (qd, J = 7.09, 2.32 Hz, 3H) 4.23 - 4.37 (m, 2H) 4.69 (t, J = 6.79 Hz, 3H) 4.81 - 4.94 (m, 2H) 5.24 (d, J = 6.72 Hz, 1H) 6.03 - 6.18 (m, 2H) 6.34 - 6.51 (m, 2H) 6.96 - 7.22 (m, 3H) 7.44 (d, J = 11.37 Hz, 1H) 7.52 - 7.68 (m, 3H) 9.63 (d, J = 5.14 Hz, 1H).

[1010] Step 4: Preparation of 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 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate

[1011] Using General Method 11, ethyl [(2R)-24-methoxy-2,4,31-trimethyl-27,27-dioxo- 21,26-dioxa-27λ 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate (1 equiv) as the starting reagent to give the title compound (white solid, 69% yield).

[1012] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 0.92-1.06 (m, 11H) 1.11 (d, J=6.85 Hz, 4H) 1.27 (d, J=6.85 Hz, 8H) 1.54-1.92 (m, 8H) 2.00-2.22 (m, 7H) 2.23-2.36 (m, 13H) 2.66 (s, 7H) 2.81 (s, 4H) 2.92-3.15 (m, 5H) 3.33-3.50 (m, 7H) 3.59-3.79 (m, 14H) 3.83-4.00 (m, 10H) 4.64-4.99 (m, 11H) 5.15-5.31 (m, 5H) 5.37 (br. s., 1H) 6.46 (dd, J=19.93, 2.45 Hz, 3H) 6.73 (s, 1H) 7.08-7.25 (m, 4H) 7.30 (d, J=8.07 Hz, 1H) 7.44 (d, J=7.70 Hz, 3H) 7.68 (d, J=8.68 Hz, 1H) 7.75 (d, J=8.80 Hz, 1H) 7.89 (d, J=8.80 Hz, 1H).

[1013] Step 5: Preparation of Example 23

[1014] Using the general method 12, with [(2R)-24-methoxy-2,4,31-trimethyl-27,27-dioxo-21,26-dioxa-27lambda 6 - thia-1,14,15,16-tetraazahexacyclo[20.5.3.13 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (1 eq) as starting reagent to give the title compound (72% yield).

[1015] The enantiopure product was obtained by chiral column chromatography separation.

[1016] Example 23a (2R, 8R)

[1017] C 31 H 34 HRMS calculated for N4O7S: 606.2148; [M+H] found: 607.2223 (delta = 0.3 ppm). +

[1018] 1 ​H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (s, 1H), 7.88 / 7.74 (d, 2H), 7.44 (dd, 1H), 7.2 (d, 1H), 7.11 (d, 1H), 6.49 (d, 1H), 5.23 (q, 1H), 5.19 (d, 1H), 4.8-4.67 (m, 1H), 4.8-4.67 (m, 2H), 3.99 / 3.36 (d, 2H), 3.73 (s, 3H), 3.63 / 3.41 (m, 2H), 3.28 / 2.96 (dd, 2H), 2.64 (s, 3H), 2.29 (s, 3H), 2.18 / 2.09 (m, 2H), 1.87 / 1.74 (m, 2H), 1.27 (d, 3H).

[1019] Example 23b (2R, 8S)

[1020] C 31 H 34 HRMS calcd for N4O7S: 606.2148; [M+H] found: 607.2224 (delta = 0.5 ppm). +

[1021] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (s, 1H), 7.88 / 7.74 (d, 2H), 7.44 (dd, 1H), 7.2 (d, 1H), 7.11 (d, 1H), 6.49 (d, 1H), 5.23 (q, 1H), 5.19 (d, 1H), 4.8-4.67 (m, 1H), 4.8-4.67 (m, 2H), 3.99 / 3.36 (d, 2H), 3.73 (s, 3H), 3.63 / 3.41 (m, 2H), 3.28 / 2.96 (dd, 2H), 2.64 (s, 3H), 2.29 (s, 3H), 2.18 / 2.09 (m, 2H), 1.87 / 1.74 (m, 2H), 1.27 (d, 3H).

[1022] Example 24 [(2R,8S)-18-(2-methoxyethyl)-2,4,31-trimethyl-27,27-dioxo-21,26-dioxa-27 6 thia-1,14,15,16-tetraazahexacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid and ​

[1023] [(2R,8R)-18-(2-methoxyethyl)-2,4,31-trimethyl-27,27-dioxo-21,26-dioxa-27lambda 6 - thia- 1, 14, 15, 16-tetraazahexadecahydrocyclophane 3,7 .1 9,13 .0 12,16 .0 25,29 ]trideca-3(32),4,6,9(31), 10,12,14,22,24,29-decaene-8-yl] acetic acid

[1024]

[1025] Step Al: Preparation of 2-[2-(benzyloxy)ethyl]-4-methoxybutyronitrile

[1026] To a solution of 4-methoxybutyronitrile (6.88 g, 69.4 mmol) in dry THF (1 mL / mmol, 70 mL) at -78°C was added dropwise lithium bis(trimethylsilyl)amide (1.2 eq., 1 M in THF, 83.3 mL, 83.3 mmol) while stirring was continued. To this was added dropwise [(2-iodoethoxy)methyl]benzene (1.2 eq., 21.8 g, 83.3 mmol) dissolved in 35 mL of THF 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. 200 mL of EtOAc was added and the layers were separated. The organic layer was washed with 150 mL of brine and dried over anhydrous sodium sulfate. Filtration and concentration to dryness gave 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 (8.1 g, 50% yield). 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.4-7.25 (m, 5H), 4.5 (s, 2H), 3.55 (m, 2H), 3.45 (m, 2H), 3.25 (s, 3H), 2.95 (m, 1H), 1.9-1.7 (m, 4H).

[1027] Step Al: Preparation of 2-[2-(benzyloxy)ethyl]-4-methoxybutyronitrile

[1028] Lithium aluminum hydride (1 eq., 1.3 g, 35 mmol) was placed in a round bottom flask. After addition of anhydrous THF (70 ml) the mixture was cooled to 10°C. A solution of 2-[2-(benzyloxy)ethyl]-4-methoxybutyronitrile (8.1 g, 35 mmol) in anhydrous THF (70 mL) was added dropwise at 10°C while stirring was continued for 15 minutes. The reaction mixture was allowed to warm to room temperature and stirring was continued at this temperature for 3 hours. After completion of the reaction the mixture was cooled to 10°C and quenched with an aqueous solution of Na2SO4. 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).

[1029] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.39-7.22 (m, 5H), 4.44 (s, 2H), 3.45 (t, 2H), 3.32 (t, 2H), 3.19 (s, 3H), 2.46 (d, 2H), 1.68-1.37 (m, 5H), 1.44-1.14 (m, 2H).

[1030] Step A3: Preparation of N-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-3-methyl-2-nitroaniline

[1031] Using General Method 2, Step 1, with 1-fluoro-3-methyl-2-nitro-benzene (1 eq.) and 2-[2-(benzyloxy)ethyl]-4-methoxybutan-1 -amine (1.2 eq.) as starting reagents, the title compound was obtained (50% yield).

[1032] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.39-7.22 (m, 5H), 4.44 (s, 2H), 3.45 (t, 2H), 3.32 (t, 2H), 3.19 (s, 3H), 2.46 (d, 2H), 1.68-1.37 (m, 5H), 1.44-1.14 (m, 2H).

[1033] Step A4: Preparation of N-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-4-bromo-3-methyl-2-nitroaniline

[1034] Using General Method 2, Step 2, with N-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-3-methyl-2-nitroaniline (1 eq.) as starting reagent, the title compound was obtained (62% yield).

[1035] 1H-NMR(400MHz,DMSO-d6)δppm:7.42(d,1H),7.31(t,2H),7.28(d+t,3H),6.7(d,1H),6.2(t),4.43(s ,2H),3.5(m,2H),3.35(m,2H),3.2(s,3H),3.1(m,2H),2.25(s,3H),1.88(m,1H),1.64-1.42(m,4H).

[1036] Step A5:N 1 Preparation of 2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-4-bromo-3-methylphenyl-1,2-diamine

[1037] Using the general method, step 3, with N-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-4-bromo-3-methyl-2-nitroaniline (1 equivalent) as the starting reagent, the title compound was obtained (quantitatively).

[1038] 1 H-NMR(400MHz,DMSO-d6)δppm:7.3(m,5H),6.69(d,1H),6.25(d,1H),4.68(m,3H),4.45(s,2H ),3.5(m,2H),3.4(m,2H),3.2(s,3H),2.98(d,2H),2.19(s,3H),1.9(m,1H),1.75-1.5(m,4H).

[1039] Step A6: Preparation of 1-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-5-bromo-4-methyl-1H-benzotriazole

[1040] Using the general method, step 4, with N 1 Using 2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-4-bromo-3-methylphenyl-1,2-diamine (1 equivalent) as the starting agent, the title compound was obtained (78% yield).

[1041] 1 H-NMR(400MHz,DMSO-d6)δppm:7.69(d,1H),7.6(d,1H),7.35-7.2(m,5H),4.68(d,2H),4.3 9(m,2H),3.48(m,2H),3.35(m,2H),3.18(s,3H),2.71(s,3H),2.3(m,1H),1.6-1.4(m,4H).

[1042] Step A7: Preparation of (2E)-3-(l-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-4- methyl-lH-benzotriazol-5-yl)prop-2-enate

[1043] Using General Procedure 2, Step 5, with l-{2-[2-(benzyloxy)ethyl]-4- methoxybutyl}-5-bromo-4-methyl-lH-benzotriazole (1 equiv) as the starting reagent, the title compound was obtained (34% yield).

[1044] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8.02 (d, 1H), 7.95 (d, 1H), 7.65 (d, 1H), 7.35-7.2 (m, 5H), 6.65 (d, 1H), 4.68 (d, 2H), 4.4 (s, 2H), 4.22 (q, 2H), 3.49 (m, 2H), 3.35 (m, 2H), 3.19 (s, 3H), 2.8 (s, 3H), 2.3 (m, 1H), 1.6-1.4 (m, 4H), 1.3 (t, 3H).

[1045] Step 1: Preparation of (2E)-3-(l-{2-[2-(benzyloxy)ethyl]-4-methoxybutyl}-4- methyl-lH-benzotriazol-5-yl)-3-{3-[(lS)-l-hydroxyethyl]-4-methylphenyl}propyl acetate

[1046] Using General Procedure 6, with (2E)-3-(l-{2-[2-(benzyloxy)ethyl]-4- methoxybutyl}-4-methyl-lH-benzotriazol-5-yl)prop-2-enate (1 equiv) and (lS)-l-[2- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]ethan-l-ol (1.2 equiv) as the starting reagents, the title compound was obtained (83% yield).

[1047] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8.02 (d, 1H), 7.95 (d, 1H), 7.65 (d, 1H), 7.35-7.2 (m, 5H), 6.65 (d, 1H), 4.68 (d, 2H), 4.4 (s, 2H), 4.22 (q, 2H), 3.49 (m, 2H), 3.35 (m, 2H), 3.19 (s, 3H), 2.8 (s, 3H), 2.3 (m, 1H), 1.6-1.4 (m, 4H), 1.3 (t, 3H).

[1048] Step 2: Preparation of 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2 6 Step 3: Preparation of 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2

[1049] Using General Method 7, ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2 6 ,3-oxathiazine-2,2-dione (1.1 eq) as starting reagents to give the title compound (59% yield).

[1050] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6-7.2 (m, 15H), 7.12-6.95 (m, 2H), 6.9 / 6.85 (2d, 1H), 5.28 (m, 1H), 5.1 (2s, 2H), 4.9 (m, 1H), 4.6 (d, 2H), 4.45-4.3 (m, 4H), 3.9 (q, 2H), 3.45 (m, 2H), 3.3 / 3.2 (2m, 5H), 3.1 (m, 2H), 2.8 / 2.3 (s, 6H), 2.28 (m, 1H), 1.5 (m, 4H), 1.4 (d, 3H), 1.22 (t, 3H).

[1051] Step 3: Preparation of 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2

[1052] Using General Method 8, ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2 6 ,3-oxathiazine-2,2-dione (1.1 eq) as starting reagents to give the title compound (59% yield).

[1053] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.6 / 4.35 (s+t, 2H), 7.6 (m, 2H), 7.5 (d, 1H), 7.12 (m, 2H), 6.91 (d, 1H), 6.75 (dd, 1H), 6.6 / 6.55 (2d, 1H), 5.25 (q, 1H), 4.9 (m, 1H), 4.6 (d, 2H), 4.35 (m, 2H), 3.92 (q, 2H), 3.45 (m, 4H), 3.21 (d, 2H), 3.12 (s, 3H), 2.8 (s, 3H), 2.3 (s, 3H), 2.25 (m, 1H), 1.5-1.3 (m, 4H), 1.45 (d, 3H), 1.2 (t, 3H).

[1054] Step 4: Preparation of 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-oxothiazin-3(4H)-yl)ethyl]-4-methylphenyl}propionic acid ethyl ester

[1055] Using General Procedure 9, 3-[3-[(1R)-1-(6-hydroxy-2,2-dioxo-4H-1,2λ6,3- oxothiazin-3-yl)ethyl]-4-methyl-phenyl]-3-[1-[2-(2-hydroxyethyl)-4-methoxy- butyl]-4-methyl-benzotriazol-5-yl]propionic acid ethyl ester (1 equiv) as starting reagent, the title compound was obtained (39% yield).

[1056] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.6 (s, 1H), 7.6 (d, 1H), 7.55 (d, 1H), 7.45 (2d, 1H), 7.11 (m, 2H), 6.9 (d, 1H), 6.71 (dd, 1H), 6.59 (2d, 1H), 5.28 (q, 1H), 4.9 (m, 1H), 4.61 (d, 2H), 4.4-4.3 (m, 2H), 3.92 (q, 2H), 3.58 (m, 2H), 3.3 (m, 2H), 3.21 (d, 2H), 3.15 (s, 3H), 2.78 (s, 3H), 2.3 (m, 1H), 2.28 (s, 3H), 1.9-1.7 (2m, 2H), 1.5 (m, 2H), 1.4 (d, 3H), 1 (2t, 3H).

[1057] Step 5: Preparation of Example 24

[1058] General Procedure 11 was used with ethyl 3-{1-[2-(2-bromoethyl)-4- methoxybutyl]-4-methyl-1H-benzotriazol-5-yl}-3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo- 2H-1,2lambda 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate (1 equiv) as the reagent to give [(2R)-18-(2-methoxyethyl)-2,4,31-trimethyl-27,27-dioxo-21,26-dioxa- 27lambda 6 -thia-1,14,15,16-tetraazahexadecacyclo[20.5.3.1 3,7 .1 9,13 .0 12 ,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetate (white solid, 57% yield). The crude was reacted with General Procedure 12 to give the title compound (quantitative).

[1059] The diastereomerically pure products were isolated by chiral column chromatography.

[1060] Example 24a (2R, 8S dia 1)

[1061] C 33 H 38 HRMS calcd for C34H42N4O7S: 634.246; [M+H] found: 635.2534. + , real value: 635.2534.

[1062] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (m, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.45 (dd, 1H), 7.22 (d, 1H), 7.02 (d, 1H), 6.9 (d, 1H), 6.7 (dd, 1H), 5.4 (d, 1H), 5.22 (q, 1H), 4.79 (dd, 1H), 4.75 / 4.6 (2dd, 2H), 4.12 / 3.4 (2d, 2H), 3.58 (m, 3H), 3.3 (s, 3H), 3.2-3 (m, 2H), 2.9 (dd, 1H), 2.6 (s, 3H), 2.3 (s, 3H), 1.9-1.7 (m, 5H), 1.2 (d, 3H).

[1063] Example 24b (2R, 8S dia 2)

[1064] C 33 H 38HRMS calculated for N4O7S: 634.246; [M+H] + found: 635.2534.

[1065] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (m, 1H), 7.89 (d, 1H), 7.78 (d, 1H), 7.45 (dd, 1H), 7.21 (d, 1H), 7.04 (d, 1H), 6.95 (d, 1H), 6.75 (dd, 1H), 5.4 (d, 1H), 5.25 (q, 1H), 4.79 (dd, 1H), 4.61 / 4.55 (2dd, 2H), 4.05 / 3.35 (2d, 2H), 3.55 (t, 2H), 3.45 (m, 1H), 3.3 (m, 4H), 3.1 / 2.9 (2m, 2H), 2.6 (s, 3H), 2.3 (s, 3H), 1.9-1.7 (m, 5H), 1.2 (d, 3H).

[1066] Example 24c (2R, 8R dia 1)

[1067] C 33 H 38 HRMS calculated for N4O7S: 634.246; [M+H] + found: 635.2536 (delta = 0.3 ppm).

[1068] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1H), 7.49 (dd, 1H), 7.28 (d, 1H), 7.2 (d, 1H), 6.9 (d, 1H), 6.89 (d, 1H), 6.7 (dd, 1H), 5.6 (d, 1H), 5.26 (q, 1H), 4.9 (dd, 1H), 4.7 / 4.6 (2dd, 2H), 4.1 / 3.55 (2d, 2H), 3.6-3.35 (m, 4H), 3.3 (s, 3H), 3.2 / 2.88 (2m, 2H), 2.8 (s, 3H), 2.3 (s, 3H), 1.8 (m, 3H), 1.68 / 1.5 (2m, 2H), 1.2 (d, 3H).

[1069] Example 24d (2R, 8R dia 2)

[1070] C 33 H 38 HRMS calculated for N4O7S: 634.246; [M+H] + found: 635.2535 (delta = 0.2 ppm).

[1071] 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, 2 H), 1.7 (m, 3 H), 1.1 (d, 3 H).

[1072] Example 25 :[23-methoxy-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid

[1073]

[1074] Step C1 : Preparation of 5-(benzyloxy)-2-hydroxy-4-methoxybenzaldehyde

[1075] General procedure 4 step 1 was applied using 4-(benzyloxy)-3-methoxyphenol (1 equiv.) as starting reagent to give the title compound (55% yield).

[1076] 1 H-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).

[1077] Step C2: Preparation of 6-(benzyloxy)-7-methoxy-2H-1,2 6 ,3-oxathiazine-2,2-dione

[1078] Using General Procedure 4, step 2, with 5-(benzyloxy)-2-hydroxy-4- methoxy-benzaldehyde (1 equiv) as starting reagent, afforded the title compound (67% yield).

[1079] 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 8.96 (s, 1H), 7.64 (s, 1H), 7.5-7.33 (m, 5H), 7.26 (s, 1H), 5.14 (s, 2H), 3.95 (s, 3H).

[1080] Step C3: Preparation of 6-(benzyloxy)-7-methoxy-3,4-dihydro-2H-1,2 6 oxathiazine-2,2-dione

[1081] Using General Procedure 4, step 3, with 6-(benzyloxy)-7-methoxy-2H-1,2 6 oxathiazine-2,2-dione (1 equiv) as starting reagent, afforded the title compound (white solid, 98% yield).

[1082] 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 8.4 (t, 1H), 7.52-7.29 (m, 5H), 6.98 (s, 1H), 6.76 (s, 1H), 5.04 (s, 2H), 4.42 (d, 2H), 3.76 (s, 3H).

[1083] Step 1 : Preparation of 3-(3-{[6-(benzyloxy)-7-methoxy-2,2-dioxo-2H-1,2 6 oxathiazine-3(4H)-yl]methyl}-4-methylphenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazole-5-yl)propanoic acid ethyl ester

[1084] Using General Procedure 7, with 3-[3-(hydroxymethyl)-4-methylphenyl]-3-(1-{4- [(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazole-5-yl)propanoic acid ethyl ester (1 equiv) and 6-(benzyloxy)-7-methoxy-3,4-dihydro-2H-1,2 6 oxathiazine-2,2-dione (1.2 equiv) as starting reagents, afforded the title compound (white solid, 74% yield).

[1085] 1H-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).

[1086] Step 2: 3-[1-(4-Hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-7- methoxy-2,2-dioxo-2H-1,2λ

[1087] -2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propionic acid ethyl ester

[1088] Using General Procedure 8, 3-(3-{[6-(benzyloxy)-7-methoxy-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl]methyl}-4-methylphenyl)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5-yl)propionic acid ethyl ester (1 equiv) as starting reagent to give the title compound (quantitative).

[1089] 1H-NMR (500 MHz, DMSO-d6) δ ppm: 9.26 (s, 1H), 7.61 (d, 1H), 7.5 (d, 1H), 7.2 (s, 1H), 7.19 (dd, 1H), 7.13 (d, 1H), 6.8 (s, 1H), 6.6 (s, 1H), 4.83 (t, 1H), 4.65 (t, 2H), 4.63 (t, 1H), 4.3 (s, 2H), 4.19 / 4.16 (d+d, 2H), 3.93 (q, 2H), 3.79 (s, 3H), 3.37 (m, 2H), 3.18 / 3.14 (dd+dd, 2H), 2.75 (s, 3H), 2.21 (s, 3H), 1.9 (m, 2H), 1.35 (m, 2H), 1 (t, 3H).

[1090] Step 3: Preparation of 3-[l-(4-chlorobutyl)-4-methyl-lH-benzotriazol-5-yl]-3-{3-[(6- hydroxy-7-methoxy-2,2-dioxo-2H-l,2lambda 6 Step 4: Preparation of ethyl 3-[l-(4-chlorobutyl)-4-methyl-lH-benzotriazol-5-yl]-3-{3-[(6- hydroxy-7-methoxy-2,2-dioxo-2H-l,2lambda

[1091] Step 4: Preparation of ethyl 3-[l-(4-chlorobutyl)-4-methyl-lH-benzotriazol-5-yl]-3-{3-[(6- hydroxy-7-methoxy-2,2-dioxo-2H-l,2lambda 6 Step 4: Preparation of ethyl 3-[l-(4-chlorobutyl)-4-methyl-lH-benzotriazol-5-yl]-3-{3-[(6- hydroxy-7-methoxy-2,2-dioxo-2H-l,2lambda

[1092] 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 9.26 (s, 1H), 7.63 (d, 1H), 7.52 (d, 1H), 7.2 (m, 1H), 7.2 (m, 1H), 7.13 (d, 1H), 6.8 (s, 1H), 6.59 (s, 1H), 4.83 (t, 1H), 4.69 (t, 2H), 4.3 (s, 2H), 4.19 / 4.15 (d+d, 2H), 3.93 (q, 2H), 3.79 (s, 3H), 3.64 (t, 2H), 3.19 / 3.15 (dd+dd, 2H), 2.75 (s, 3H), 2.21 (s, 3H), 1.99 (m, 2H), 1.68 (m, 2H), 0.99 (t, 3H).

[1093] Step 4: Preparation of ethyl 3-[l-(4-chlorobutyl)-4-methyl-lH-benzotriazol-5-yl]-3-{3-[(6- hydroxy-7-methoxy-2,2-dioxo-2H-l,2lambda 6- Thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of [23-methoxy-4, 31-dimethyl-27, 27-dioxo-21, 26-dioxa-27lambda

[1094] Using General Method 11, ethyl [3-[1-(4-chlorobutyl)-4-methyl-1H- benzotriazol-5-yl]-3-{3-[(6-hydroxy-7-methoxy-2, 2-dioxo-2H-1, 2lambda 6 , 3-oxathiazin-3(4H)-yl)methyl]-4-methylphenyl}propanoate hydrochloride (1 equiv) as starting reagent to give the title compound (white solid, 34% yield).

[1095] 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 7.69 (d, 1H), 7.47 (dd, 1H), 7.46 (d, 1H), 7.28 (d, 1H), 6.75 (s, 1H), 6.56 (d, 1H), 5.77 (s, 1H), 4.82 / 4.75 (m+m, 2H), 4.78 (dd, 1H), 4.18 / 3.87 (d+d, 2H), 3.93 (q, 2H), 3.93 / 3.69 (d+d, 2H), 3.72 (s, 3H), 3.56 / 3.3 (m+m, 2H), 3.14 / 3.06 (dd+dd, 2H), 2.61 (s, 3H), 2.32 (s, 3H), 2.2 / 2.02 (m+m, 2H), 1.78 / 1.61 (m+m, 2H), 1.01 (t, 3H).

[1096] Step 5: Preparation of Example 25

[1097] Using General Method 12, ethyl [23-methoxy-4, 31-dimethyl-27, 27-dioxo-21, 26-dioxa-27lambda 6 - Thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 (1 equiv) as starting reagent to give the title compound (white solid, 86% yield).

[1098] The enantiopure product was obtained by chiral column chromatography separation.

[1099] Example 25a (E1, optical purity: 99.9%)

[1100] C 30 H 32 HRMS calcd for N4O7S: 592.1992; [M+H] + found: 593.2048 (delta = -2.8 ppm).

[1101] Example 25b (E2, optical purity ~ 99.4%)

[1102] C 30 H 32 HRMS calcd for N4O7S: 592.1992; [M+H] + found: 593.2047 (delta = -2.9 ppm).

[1103] 1 H-NMR (500 MHz, DMSO-d6) δ ppm: 12.54 (br., 1H), 7.68 (d, 1H), 7.48 (br d., 1H), 7.45 (d, 1H), 7.27 (d, 1H), 6.74 (s, 1H), 6.53 (br s., 1H), 5.75 (s, 1H), 4.81 / 4.74 (m+m, 2H), 4.75 (m, 1H), 4.16 / 3.87 (d+d, 2H), 3.93 / 3.69 (d+d, 2H), 3.72 (s, 3H), 3.55 / 3.28 (m+m, 2H), 2.99 / 2.92 (dd+dd, 2H), 2.6 (s, 3H), 2.32 (s, 3H), 2.2 / 2.03 (m+m, 2H), 1.78 / 1.61 (m+m, 2H).

[1104] 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.

[1105] Example 26 : [(2R, 8S)-2, 4, 33-trimethyl-29, 29-dioxo-20, 23, 28-trioxa-29 lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31[thirty-four-carb-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl] acetic acid and

[1106] [(2R,8R)-2,4,33-trimethyl-29,29-dioxo-20,23,28-trioxa-29lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]thirty-four-carb-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl] acetic acid

[1107]

[1108] Step Al: Preparation of N-{3-[2-(benzyloxy)ethoxy]propyl}-3-methyl-2-nitroaniline

[1109] Using General Method 2, Step 1, with 1-fluoro-3-methyl-2-nitrobenzene (1 eq) and 3-[2-(benzyloxy)ethoxy]propyl-1-amine hydrochloride (1.2 eq) as starting reagents, the title compound was obtained (85% yield).

[1110] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.38-7.27 (m, 5H), 7.24 (dd, 1H), 6.77 (d, 1H), 6.54 (d, 1H), 6.48 (t, 1H), 4.49 (s, 2H), 3.58 (m, 4H), 3.5 (t, 2H), 3.23 (q, 2H), 2.3 (s, 3H), 1.8 (quint, 2H).

[1111] Step A2: Preparation of N-{3-[2-(benzyloxy)ethoxy]propyl}-4-bromo-3-methyl-2-nitroaniline

[1112] Using General Method 2, Step 2, with N-{3-[2-(benzyloxy)ethoxy]propyl}-3-methyl-2-nitroaniline (1 eq) as starting reagent, the title compound was obtained (99% yield).

[1113] 1H-NMR(400MHz,DMSO-d6)δppm:7.49(d,1H),7.38-7.25(m,5H),6.72(d,1H),6.18(t,1H ),4.49(s,2H),3.6-3.5(m,4H),3.48(t,2H),3.2(q,2H),2.25(s,3H),1.77(quint,2H).

[1114] Step A3:N 1 Preparation of 3-[2-(benzyloxy)ethoxy]propyl}-4-bromo-3-methylphenyl-1,2-diamine

[1115] Using the general method, step 3, with N-{3-[2-(benzyloxy)ethoxy]propyl}-4-bromo-3-methyl-2-nitroaniline (1 equivalent) as the starting reagent, the title compound was obtained (quantitatively).

[1116] 1 H-NMR(400MHz,DMSO-d6)δppm:7.37-7.24(m,5H),6.71(d,1H),6.27(d,1H),4.9-4.5( m,3H),4.49(s,2H),3.56(m,4H),3.52(t,2H),3.06(t,2H),2.16(s,3H),1.82(m,2H).

[1117] Step A4: Preparation of 1-{3-[2-(benzyloxy)ethoxy]propyl}-5-bromo-4-methyl-1H-benzotriazole

[1118] Using the general method, step 4, with N 1 Using 3-[2-(benzyloxy)ethoxy]propyl}-4-bromo-3-methylphenyl-1,2-diamine (1 equivalent) as the starting agent, the title compound was obtained (42% yield).

[1119] 1 H-NMR (400MHz, DMSO-d6) δppm: 2.13 (quint, J = 6.39Hz, 2H) 2.71 (s, 3H) 3.35 (t, J = 6.05Hz, 2H) 3 .41-3.58(m,6H)4.43-4.47(m,3H)4.74(t,J=6.72Hz,2H)7.20-7.37(m,9H)7.55-7.68(m,3H).

[1120] Step A5: Preparation of ethyl (2E)-3-(1-{3-[2-(benzyloxy)ethoxy]propyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate

[1121] Using General Procedure 2, Step 5, with 1-{3-[2-(benzyloxy)ethoxy]propyl}-5- bromo-4-methyl-1H-benzotriazole (1 equiv) as the starting reagent, the title compound was obtained (98% yield).

[1122] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 8.01 (d, 1H), 7.89 (d, 1H), 7.69 (d, 1H), 7.38-7.25 (m+m, 5H), 6.61 (d, 1H), 4.74 (t, 2H), 4.47 (s, 2H), 4.22 (q, 2H), 3.54-3.47 (m+m, 4H), 3.37 (t, 2H), 2.8 (s, 3H), 2.23 (quint, 2H), 1.29 (t, 3H).

[1123] Step 1: Preparation of 3-(1-{3-[2-(benzyloxy)ethoxy]propyl}-4-methyl-1H- benzotriazol-5-yl)-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propionic acid ethyl ester

[1124] Using General Procedure 6, with (2E)-3-(1-{3-[2-(benzyloxy)ethoxy]propyl}-4- methyl-1H-benzotriazol-5-yl)prop-2-enoic acid ethyl ester (1 equiv) and (1S)-1-[2- methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1-ol (1 equiv) as the starting reagents, the title compound was obtained (59% yield).

[1125] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.56 (d, 1H), 7.41 (d, 1H), 7.39 (m, 1H), 7.35-7.22 (m, 5H), 7.02 (dd, 1H), 6.99 (d, 1H), 4.97 (m, 1H), 4.82 (m, 1H), 4.82 (m, 1H), 4.68 (t, 2H), 4.46 (s, 2H), 3.92 (q, 2H), 3.52 / 3.49 (m, 4H), 3.35 (t, 2H), 3.14-3.07 (m, 2H), 2.75 (s, 3H), 2.19 (s, 3H), 2.1 (quint, 2H), 1.21 (d, 3H), 1 (t, 3H).

[1126] Step 2: 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2 6Preparation of ethyl 3-{3-[(1 S)-1 -(6-hydroxy-2,2-dioxo-2H-1,2

[1127] Using General Method 7, ethyl 3-{3-[(1 S)-1 -(6-hydroxy-2,2-dioxo-2H-1,2 6 Using General Method 7, ethyl 3-{3-[(1 S)-1 -(6-hydroxy-2,2-dioxo-2H-1,2 6 Using General Method 7, ethyl 3-{3-[(1 S)-1 -(6-hydroxy-2,2-dioxo-2H-1,2

[1128] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.62 (m, 1 H), 7.64-7.54 (m, 2H), 7.47 / 7.47 (2 s, 1 H), 7.14-7.08 (m, 2H), 6.92 / 6.9 (2 d, 1 H), 6.76-6.7 (m, 1 H), 6.57 (2 d, 1 H), 5.25 (m, 1 H), 4.88 (q, 1 H), 4.7 (t, 2H), 4.57 (m, 1 H), 4.36 / 4.31 (s+dd, 2H), 3.95 (2 d, 2H), 3.47 (m, 2H), 3.39-3.28 (m, 4H), 3.22 (m, 2H), 2.77 (s, 3H), 2.28 (s, 3H), 2.1 (m, 2H), 1.43 / 1.41 (2 d, 3H), 1.01 / 1 (2 t, 3H).

[1129] Step 3: Ethyl 3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2 6 Preparation of ethyl 3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2

[1130] Using General Method 9, ethyl 3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2 6Ethyl 3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2λ

[1131] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.55 (s, 1 H), 7.7-7.5 (2d, 2H), 7.49 (2d, 1 H), 7.1 1 (m, 2H), 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, 2H), 4.4-4.3 (m, 2H), 3.95 (q, 2H), 3.68 (t, 2H), 3.55 (t, 2H), 3.41 (t, 2H), 3.21 (d, 2H), 2.79 (s, 3H), 2.3 (s, 3H), 2.12 (m, 2H), 1.45 (2d, 3H), 1.02 (2t, 3H).

[1132] Step 4: Preparation of [(2R)-2,4,33-trimethyl-29,29-dioxo-20,23,28-trioxa-29 6 - thia-1,14,15,16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 Step 4: Preparation of ethyl [(2R)-2,4,33-trimethyl-29,29-dioxo-20,23,28-trioxa-29

[1133] Using General Method 1 1, ethyl 3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Ethyl 3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2λ

[1134] 1H-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 = 2.81 Hz, 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, 4 H)

[1135] Step 5: Preparation of Example 26

[1136] Using the general method 12, with [(2R)-2,4,33-trimethyl-29,29-dioxo-20,23,28- trioxa-29 lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]tracosa-3(34),4,6,9(33), 10,12,14,24,26,31-decaen-8-yl] acetate (1 eq) as starting reagent to give the title compound (white solid, 85% yield).

[1137] The diastereomeric pure products were separated by chiral column chromatography.

[1138] Example 26a (2R, 8S)

[1139] C 31 H 34HRMS calculated for N4O7S: 606.2148; [M+H] + found: 607.2223 (delta = 0.3 ppm).

[1140] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.1 (sl, 1H), 7.62 / 7.59 (d, 2H), 7.59 (d, 1H), 7.19 (dd, 1H), 7.08 (d, 1H), 7.01 (d, 1H), 6.91 (dd, 1H), 6.49 (d, 1H), 5.37 (q, 1H), 4.87 (t, 1H), 4.77 / 4.67 (m, 2H), 4.33 / 3.95 (d, 2H), 4.08 (t, 2H), 3.79 / 3.66 (m, 2H), 3.49 (m, 2H), 3.11 (m, 2H), 2.83 (s, 3H), 2.29 (s, 3H), 2.19 (m, 2H), 1.54 (d, 3H).

[1141] Example 26b (2R, 8R)

[1142] C 31 H 34 HRMS calculated for N4O7S: 606.2148; [M+H] + found: 607.2223 (delta = 0.3 ppm).

[1143] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.1 (sl, 1H), 7.62 / 7.59 (d, 2H), 7.59 (d, 1H), 7.19 (dd, 1H), 7.08 (d, 1H), 7.01 (d, 1H), 6.91 (dd, 1H), 6.49 (d, 1H), 5.37 (q, 1H), 4.87 (t, 1H), 4.77 / 4.67 (m, 2H), 4.33 / 3.95 (d, 2H), 4.08 (t, 2H), 3.79 / 3.66 (m, 2H), 3.49 (m, 2H), 3.11 (m, 2H), 2.83 (s, 3H), 2.29 (s, 3H), 2.19 (m, 2H), 1.54 (d, 3H).

[1144] Example 27 : [(2R,8R)-2,4,33-trimethyl-29,29-dioxo-19,23,28-trioxa-29 lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [22.5.3.13,7 .1 9,13 .0 12,16 .0 27,31 ]triaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid and

[1145] [(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 ]triaconta-3(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid

[1146]

[1147] Step Al: Preparation of tert-butyl {2-[3-(benzyloxy)propoxy]ethyl}carbamate

[1148] To a solution of 3-(benzyloxy)propyl 4-methylbenzene-l-sulfonate (41 g, 130 mmol) in toluene (2 mL / mmol, 260 mL) was added tetrabutylammonium hydrogen sulfate (0.1 eq., 4.3 g, 13 mmol), tert-butyl (2-hydroxyethyl)carbamate (1 eq., 21 g, 130 mmol) and 50 wt% aqueous NaOH (9 eq., 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 1 L EtOAc. The mixture was washed with 2 L saturated aqueous NH4Cl solution, the layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the crude product which was purified by reverse phase chromatography eluting with water-MeCN to give the title compound (19.6 g, yellow oil, 47% yield).

[1149] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.38-7.24 (m, 5H), 6.73 (t, 1H), 4.44 (s, 2H), 3.49 (t, 2H), 3.44 (t, 2H), 3.33 (t, 2H), 3.04 (q, 2H), 1.76 (quint, 2H), 1.38 (s, 9H).

[1150] Step A2: Preparation of 2-[3-(benzyloxy)propoxy]ethan-l-amine hydrochloride

[1151] 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 eq., 59.5 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated to dryness under reduced pressure. The crude product was used as such in the form of HCl salt without purification (15.6 g, quantitative).

[1152] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.98 (s, 3H), 7.4-7.36 (m, 5H), 4.46 (s, 2H), 3.56 (t, 2H), 3.5 (t, 2H), 3.5 (t, 2H), 2.93 (t, 2H), 1.81 (quint, 2H).

[1153] Step A3: Preparation of N-{2-[3-(benzyloxy)propoxy]ethyl}-3-methyl-2-nitroaniline

[1154] Using General Method 2 Step 1 with 1-fluoro-3-methyl-2-nitrobenzene (1 equiv.) and 2-[3-(benzyloxy)propoxy]ethan-1-amine hydrochloride (1.2 equiv.) as starting reagents, the title compound was obtained (93% yield).

[1155] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.38-7.24 (m, 5H), 7.27 (m, 1H), 6.82 (d, 1H), 6.59 (d, 1H), 6.46 (t, 1H), 4.42 (s, 2H), 3.57 (t, 2H), 3.52-3.47 (m, 4H), 3.33 (dt, 2H), 2.31 (s, 3H), 1.79 (quint, 2H).

[1156] Step A4: Preparation of N-{2-[3-(benzyloxy)propoxy]ethyl}-4-bromo-3-methyl-2-nitroaniline

[1157] Using General Method 2 Step 2 with N-{2-[3-(benzyloxy)propoxy]ethyl}-3-methyl-2-nitroaniline (1 equiv.) as starting reagent, the title compound was obtained (58% yield).

[1158] 1H-NMR(400MHz,DMSO-d6)δppm:7.54(d,1H),7.38-7.23(m,5H),6.8(d,1H),6.09(t,1 H),4.42(s,2H),3.51(t,2H),3.47(m,4H),3.3(q,2H),2.38(s,3H),1.77(quint,2H).

[1159] Step A5:N 1 Preparation of 2-[3-(benzyloxy)propoxy]ethyl}-4-bromo-3-methylphenyl-1,2-diamine

[1160] Using the general method, step 3, with N-{2-[3-(benzyloxy)propoxy]ethyl}-4-bromo-3-methyl-2-nitroaniline (1 equivalent) as the starting reagent, the title compound was obtained (quantitatively).

[1161] 1 H-NMR(400MHz,DMSO-d6)δppm:7.38-7.23(m,5H),6.71(d,1H),6.29(d,1H),4.6(sl,3H),4 .42(s,2H),3.56 / 3.5(m,2H),3.56 / 3.5(m,4H),3.16(t,2H),2.17(s,3H),1.79(quint,2H).

[1162] Step A6: Preparation of ethyl (2E)-3-(1-{2-[3-(benzyloxy)propoxy]ethyl}-4-methyl-1H-benzotriazol-5-yl)prop-2-enoate

[1163] Using the general method, step 4, with N 1 Using 1-{2-[3-(benzyloxy)propoxy]ethyl}-4-bromo-3-methylphenyl-1,2-diamine (1 equivalent) as a reactant, 1-{2-[3-(benzyloxy)propoxy]ethyl}-5-bromo-4-methyl-1H-benzotriazole (29% yield) was given. The crude product was reacted using general method 2, step 5 to give the title compound (91% yield).

[1164] 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).

[1165] Step 1: Preparation of 3-(1-{2-[3-(benzyloxy)propoxy]ethyl}-4-methyl-1H- benzotriazol-5-yl)-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propionic acid ethyl ester

[1166] Using General Procedure 6, (2E)-3-(1-{2-[3-(benzyloxy)propoxy]ethyl}-4-methyl- 1H-benzotriazol-5-yl)prop-2-enoic acid ethyl ester (1 equiv) and (1S)-1-[2-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1 -ol (1 equiv) as starting reagents, afforded the title compound (48% yield).

[1167] 1 H-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).

[1168] Step 2: Preparation of 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}-3-{1-[2-(3-hydroxypropoxy)ethyl]- 4-methyl-1H-benzotriazol-5-yl}propionic acid ethyl ester

[1169] General Procedure 7 was used with 3-(1-{2-[3-(benzyloxy)propoxy]ethyl}-4- methyl-1H-benzotriazol-5-yl)-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propionic acid ethyl ester (1.1 eq) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ 6 ,3-oxathiazine-2,2-dione (1.1 eq) as starting reagents to give 3-(3-{(1R)-1-[6- (benzyloxy)-2,2-dioxo-2H-1,2λ 6 ,3-oxathiazin-3(4H)-yl]ethyl}-4-methylphenyl)-3-(1-{2-[3-(benzyloxy)propoxy]ethyl}- 4-methyl-1H-benzotriazol-5-yl)propionic acid ethyl ester (yellow oil, 86% yield). The crude was reacted with General Procedure 8 to give the title compound (yellow oil, 83% yield).

[1170] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.62 (2m, 2H), 7.65-7.42 (m, 2H), 7.47 / 7.45 (2sl, 1H), 7.14-7.07 (m, 2H), 6.92 / 6.9 (2d, 1H), 6.75-6.7 (m, 1H), 6.58 (2d, 1H), 5.25 (q, 1H), 4.87 (q, 1H), 4.8 (t, 2H), 4.36 / 4.32 (2s, 2H), 4.31-4.24 (m, 1H), 3.94 (2q, 2H), 3.82 (m, 2H), 3.39 (2t, 2H), 3.29 (q, 2H), 3.22 (m, 2H), 2.76 (s, 3H), 2.27 (s, 3H), 1.5 (m, 2H), 1.43 / 1.41 (2d, 3H), 1.01 / 1 (2t, 3H).

[1171] Step 3: Preparation of 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 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propionic acid ethyl ester

[1172] General Procedure 9 was used with 3-{3-[(1R)-1-(6-hydroxy-2,2-dioxo-2H-1,2λ 6Ethyl 3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2λ

[1173] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.55 (s, 1 H), 7.7-7.55 (2d, 2H), 7.49 (2d, 1 H), 7.1 (m, 2H), 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, 2H), 4.4-4.25 (m, 2H), 3.95 (m, 2H), 3.85 (t, 2H), 3.41 (t, 2H), 3.3 (t, 2H), 3.21 (d, 2H), 2.76 (s, 3H), 2.3 (s, 3H), 1.85 (m, 2H), 1.45 (2d, 3H), 1.02 (2t, 3H).

[1174] Step 4: Preparation of [(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 Step 4: Preparation of ethyl [(2R)-2,4,33-trimethyl-29,29-dioxo-19,23,28-trioxa-29λ

[1175] General Method 11 was used with 3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Ethyl 3-{3-[(1 R)-1 -(6-hydroxy-2,2-dioxo-2H-1,2λ

[1176] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 1.00 (td, J = 7.09, 5.50 Hz, 5H) 1.24 (d, J = 6.85 Hz, 2H) 1.52 (d, J = 6.85 Hz, 3H) 1.77 - 1.86 (m, 1H) 1.92 (dt, J = 12.90, 6.39 Hz, 2H) 2.30 (d, J = 1.59 Hz, 5H) 2.79 (s, 2H) 2.85 (s, 3H) 2.92 - 3.27 (m, 4H) 3.44 - 3.66 (m, 5H) 3.81 - 3.88 (m, 3H) 3.92 - 4.01 (m, 3H) 4.01 - 4.16 (m, 2H) 4.34 (d, J = 17.85 Hz, 1H) 4.70 - 4.82 (m, 2H) 4.82 - 4.96 (m, 3H) 5.28 (d, J = 7.09 Hz, 1H) 5.35 (q, J = 6.64 Hz, 1H) 6.00 (d, J = 2.81 Hz, 1H) 6.44 (d, J = 2.81 Hz, 1H) 6.71 - 6.85 (m, 2H) 6.91 - 7.02 (m, 2H) 7.11 (d, J = 7.82 Hz, 1H) 7.19 - 7.31 (m, 2H) 7.48 (d, J = 6.85 Hz, 1H) 7.57 (s, 1H) 7.58 - 7.69 (m, 3H).

[1177] Step 5: Preparation of Example 27

[1178] Using the general method 12, with [(2R)-2,4,33-trimethyl-29,29-dioxo-19,23,28- trioxa-29lambda 6 - thia- 1, 14, 15, 16-tetraazahexacyclo[22.5.3.1 3,7 .1 9,13 .0 12,16 .0 27,31 ]tracosa-3(34),4,6,9(33), 10,12,14,24,26,31-decaen-8-yl] ethyl acetate (1 eq) as starting reagent to give the title compound (white solid, 97% yield).

[1179] The diastereomeric pure products were separated by chiral column chromatography.

[1180] Example 27a (2R, 8R)

[1181] C 31 H 34 HRMS calculated for C42H52N4O7S: 606.2148; [M+H] found: 607.2224 (delta = 0.5 ppm). + , found: 607.2224 (delta = 0.5 ppm).

[1182] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (sl, 1H), 7.6 (d, 1H), 7.49 (dd, 1H), 7.26 (d, 1H), 7.19 (d, 1H), 7 (d, 1H), 6.95 (d, 1H), 6.76 (dd, 1H), 6.01 (d, 1H), 5.28 (q, 1H), 4.9 (t, 1H), 4.78 (m, 2H), 4.11 / 3.9 (d, 2H), 4 (m, 2H), 3.6 (m, 2H), 3.55 (m, 2H), 3.08 / 2.85 (dd, 2H), 2.79 (s, 3H), 2.3 (s, 3H), 1.83 (m, 2H), 1.23 (d, 3H).

[1183] Example 27b (2R, 8S)

[1184] C 31 H 34 HRMS calcd for N4O7S: 606.2148; [M+H] found: 607.2222 (delta = 0.2 ppm). +

[1185] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.1 (sl, 1H), 7.64 (d, 1H), 7.59 (d, 1H), 7.55 (d, 1H), 7.23 (dd, 1H), 7.11 (d, 1H), 6.99 (d, 1H), 6.81 (dd, 1H), 6.43 (d, 1H), 5.33 (q, 1H), 4.85 / 4.76 (m, 2H), 4.85 (t, 1H), 4.32 / 4.01 (d, 2H), 4-3.97 (m, 2H), 3.86 (m, 2H), 3.61 / 3.52 (m, 2H), 3.07 (m, 2H), 2.83 (s, 3H), 2.3 (s, 3H), 1.91 (m, 2H), 1.5 (d, 3H).

[1186] Example 28a and 28b [(2R,8R)-4-methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27λ 6 thia-1,14,15,16-tetraazahexadecacyclo[20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 .0decyl] acetic acid and

[1187] [(2R,8S)-4-methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27lambda 6 - thia- 1, 14, 15, 16-tetraazahexadec- 20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid

[1188]

[1189] 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

[1190] Using General Procedure 6, with ethyl (2E)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4- methyl-1H-benzotriazol-5-yl)prop-2-enoate (1 equiv) and (1S)-1-[2-methoxy-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethan-1 -ol (1.5 equiv) as starting reagents, the title compound was obtained (65% yield).

[1191] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.58 (2d, 1H), 7.45 (2d, 1H), 7.37 (d, 1H), 7.2 (d, 2H), 7.13 (2dd, 1H), 6.87 (d, 2H), 6.82 (d, 1H), 4.91 (m, 1H), 4.89 (d, 1H), 4.82 (m, 1H), 4.64 (m, 2H), 4.32 (s, 2H), 3.92 (q, 2H), 3.73 / 3.72 (2s, 6H), 3.38 (t, 2H), 3.11 (m, 2H), 2.76 / 2.75 (2s, 3H), 1.92 (m, 2H), 1.48 (m, 2H), 1.22-1.15 (2d, 3H), 0.99 (t, 3H).

[1192] Step 2: Preparation of ethyl 3-(3-{(1R)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2lambda 6Preparation of ethyl 3-[l-(4-hydroxybutyl)-4-methyl-lH-benzotriazol-5-yl]-3-{3-[(lR)-l-(6- hydroxy-2,2-dioxo-2H-l,2l

[1193] Using General Method 7, ethyl 3-{3-[(lS)-l-hydroxyethyl]-4-methoxyphenyl}-3-(l-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-lH-benzotriazol-5-yl)propanoate (1 equiv) and 6- (benzyloxy)-3,4-dihydro-2H-l,2l 6 Using General Method 7, ethyl 3-{3-[(lS)-l-hydroxyethyl]-4-methoxyphenyl}-3-(l-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-lH-benzotriazol-5-yl)propanoate (1 equiv) and 6- (benzyloxy)-3,4-dihydro-2H-l,2l

[1194] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1H), 7.5 (2d, 1H), 7.45-7.3 (m, 6H), 7.2 (d, 2H), 7.1 (dd, 1H), 6.9 (m, 4H), 6.75 (m, 2H), 5.39 (m, 1H), 5 (m, 2H), 4.8 (m, 1H), 4.6 (2t, 2H), 4.55 (m, 2H), 4.3 (s, 2H), 3.91 (q, 2H), 3.71 / 3.65 (2s, 6H), 3.48 (m, 2H), 3.18 (d, 2H), 2.79 (s, 3H), 1.91 (m, 2H), 1.5 (m, 2H), 1.45 (2d, 3H), 1 (t, 3H).

[1195] Step 3: Preparation of ethyl 3-[l-(4-hydroxybutyl)-4-methyl-lH-benzotriazol-5-yl]-3-{3-[(lR)-l-(6- hydroxy-2,2-dioxo-2H-l,2l 6 Using General Method 7, ethyl 3-{3-[(lS)-l-hydroxyethyl]-4-methoxyphenyl}-3-(l-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-lH-benzotriazol-5-yl)propanoate (1 equiv) and 6- (benzyloxy)-3,4-dihydro-2H-l,2l

[1196] Using General Method 8, ethyl 3-(3-{(lR)-l-[6-(benzyloxy)-2,2-dioxo-2H-l,2l 6 Using General Method 7, ethyl 3-{3-[(lS)-l-hydroxyethyl]-4-methoxyphenyl}-3-(l-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-lH-benzotriazol-5-yl)propanoate (1 equiv) and 6- (benzyloxy)-3,4-dihydro-2H-l,2l

[1197] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 1.01 (td, J = 7.09, 3.79 Hz, 3H) 1.21 (dd, J = 13.69, 5.99 Hz, IH) 1.31 - 1.39 (m, 2H) 1.42 (t, J = 6.42 Hz, 3H) 1.91 (quint, J = 7.31 Hz, 2H) 2.76 (d, J = 3.67 Hz, 3H) 3.09 - 3.21 (m, 2H) 3.38 (t, J = 5.93 Hz, 2H) 3.67 (s, 3H) 3.70 (s, IH) 3.94 (q, J = 7.09 Hz, 2H) 4.34 - 4.57 (m, 3H) 4.65 (t, J = 6.97 Hz, 2H) 4.83 (q, J = 7.62 Hz, IH) 5.37 (quint, J = 6.79 Hz, IH) 6.51 (dd, J = 13.14, 2.75 Hz, IH) 6.64 (dd, J = 8.99, 2.75 Hz, IH) 6.73 - 6.85 (m, 3H) 7.08 (d, J = 8.19 Hz, IH) 7.13 (dd, J = 8.56, 2.08 Hz, IH) 7.42 (dd, J = 9.35, 2.02 Hz, IH) 7.53 (t, J = 9.11 Hz, IH) 7.59 - 7.67 (m, IH) 9.54 (br. s., IH).

[1198] Step 4: Preparation of 3-[l-(4-bromobutyl)-4-methyl-lH-benzotriazol-5-yl]-3-{3-[(lR)-l-(6- hydroxy-2,2-dioxo-2H-l,2λ 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methoxyphenyl}propionic acid ethyl ester

[1199] Using General Procedure 9, 3-[l-(4-hydroxybutyl)-4-methyl-lH-benzotriazol-5-yl]-3-{3-[(lR)-l-(6- hydroxy-2,2-dioxo-2H-l,2λ 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methoxyphenyl}propionic acid ethyl ester (1 equiv) as starting reagent to give the title compound (73% yield).

[1200] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 1.00 (td, J = 7.09, 3.79 Hz, 3H) 1.42 (t, J = 6.66 Hz, 3H) 1.71 - 1.83 (m, 2H) 1.94 - 2.05 (m, 2H) 2.70 - 2.79 (m, 3H) 3.08 - 3.25 (m, 2H) 3.53 (t, J = 6.66 Hz, 2H) 3.62 - 3.70 (m, 3H) 3.94 (q, J = 7.13 Hz, 2H) 4.34 - 4.57 (m, 2H) 4.69 (t, J = 6.85 Hz, 2H) 4.83 (q, J = 7.83 Hz, IH) 5.31 - 5.42 (m, IH) 6.51 (dd, J = 11.37, 2.81 Hz, IH) 6.64 (dd, J = 8.93, 2.81 Hz, IH) 6.62 - 6.68 (m, IH) 6.74 - 6.84 (m, 2H) 7.13 (dd, J = 8.50, 2.02 Hz, IH) 7.42 (dd, J = 10.03, 2.08 Hz, IH) 7.55 (t, J = 8.74 Hz, IH) 7.61 - 7.68 (m, IH) 9.52 (d, J = 5.01 Hz, IH).

[1201] Step 5: Preparation of [(2R)-4-methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl] ethyl acetate

[1202] Using General Procedure 11, ethyl [(2R)-4-methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27 6 thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1

[1203] 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, 1 H).

[1204] Step 6: Preparation of Example 28a and 28b

[1205] General Procedure 12 was employed using [(2R)-4-methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27 6 - thia-1,14,15,16-tetraazahexacyclo[20.5.3.13 3,7 .10 9,13 .0 12,16 .0 25,29 .0 ethyl [32-(2R)-4-methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27

[1206] The diastereomeric pure products were separated by chiral column chromatography.

[1207] Example 28a (2R, 8R)

[1208] C 30 H 32HRMS calculated for N4O7S: 592.1992; [M+H] found: 593.2067 (delta = 0.4 ppm). + HRMS calculated for N4O7S: 592.1992; [M+H] found: 593.2066 (delta = 0.3 ppm).

[1209] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.5-11.8 (m, 1H), 7.67 (d, 1H), 7.5 (dd, 1H), 7.19 (d, 1H), 7 (d, 1H), 6.83 (d, 1H), 6.8 (d, 1H), 6.65 (dd, 1H), 5.63 (d, 1H), 5.4 (q, 1H), 4.87 (dd, 1H), 4.72 (m, 2H), 4 / 3.71 (AM, 2H), 3.76 (s, 3H), 3.6 / 3.32 (2m, 2H), 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).

[1210] Example 28b (2R, 8S)

[1211] C 30 H 32 HRMS calculated for N4O7S: 592.1992; [M+H] found: 593.2066 (delta = 0.3 ppm). + HRMS calculated for N4O7S: 592.1992; [M+H] found: 593.2066 (delta = 0.3 ppm).

[1212] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.5-11.8 (m, 1H), 7.67 (d, 1H), 7.5 (dd, 1H), 7.19 (d, 1H), 7 (d, 1H), 6.83 (d, 1H), 6.8 (d, 1H), 6.65 (dd, 1H), 5.63 (d, 1H), 5.4 (q, 1H), 4.87 (dd, 1H), 4.72 (m, 2H), 4 / 3.71 (AM, 2H), 3.76 (s, 3H), 3.6 / 3.32 (2m, 2H), 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).

[1213] Example 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 .012,16 .0 25,29 ]tricosa-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid and

[1214] [(2S,8S)-4-methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27lambda 6 -thia-1,14,15,16-tetraazahexadecacyclo[20.5.3.13 3,7 .1 9,13 .0 12,16 .0 25,29 ]tricosa-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid

[1215]

[1216] 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

[1217] The title compound was obtained (81% yield) using General Procedure 6 with ethyl (2E)-3-(1-{4-[(4-methoxyphenyl)methoxy]butyl}-4-methyl-1H-benzotriazol-5- yl)prop-2-enoate (1 equiv) and (1R)-1-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]ethan-1-ol (1.1 equiv) as starting reagents.

[1218] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (2d, 1H), 7.45 (2d, 1H), 7.35 (d, 1H), 7.2 (d, 2H), 7.12 (dd, 1H), 6.88 (d, 2H), 6.81 (d, 1H), 4.9 (d, 1H), 4.9 (m, 1H), 4.8 (m, 1H), 4.65 (t, 2H), 4.32 (s, 2H), 3.91 (q, 2H), 3.71 (2s, 6H), 3.4 (t, 2H), 3.1 (2d, 2H), 2.79 (2s, 3H), 1.92 (m, 2H), 1.48 (m, 2H), 1.2 (2d, 3H), 1 (t, 3H).

[1219] Step 2: Preparation of 3-(3-{(1S)-1-[6-(benzyloxy)-2,2-dioxo-2H-1,2lambda 6Preparation of ethyl 3-[1 -(4-hydroxybutyl)-4-methyl-1 H-benzotriazol-5-yl]-3-{3-[(1 S)-1 -(6- hydroxy-2,2-dioxo-2H-1,2λ

[1220] Using General Method 7, ethyl 3-{3-[(1 R)-1 -hydroxyethyl]-4-methoxyphenyl}-3-(1-{4-[(4- methoxyphenyl)methoxy]butyl}-4-methyl-1 H-benzotriazol-5-yl)propanoate (1 equiv) and 6- benzyloxy-3,4-dihydro-1,2λ6,3-oxathiazine 2,2-dioxide (1.1 eq.) as starting reagents, afforded the title compound (60% yield).

[1221] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.6 (d, 1 H), 7.5 (2d, 1 H), 7.45-7.3 (m, 6H), 7.2 (d, 2H), 7.1 1 (dd, 1 H), 6.9 (m, 2H), 6.88 (d, 2H), 6.78 (m, 2H), 5.39 (m, 1 H), 5.05 (m, 2H), 4.81 (m, 1 H), 4.65-4.5 (m, 2H), 4.61 (2t, 2H), 4.3 (s, 2H), 3.92 (q, 2H), 3.71 / 3.65 (2s, 6H), 3.38 (m, 2H), 3.15 (m, 2H), 2.78 (s, 3H), 1.9 (m, 2H), 1.48 (m+d, 5H), 0.99 (t, 3H).

[1222] Step 3: 3-[1 -(4-hydroxybutyl)-4-methyl-1 H-benzotriazol-5-yl]-3-{3-[(1 S)-1 -(6-hydroxy-2,2- dioxo-2H-1,2λ 6 Preparation of ethyl 3-{3-[(1 S)-1 -(6-hydroxy-2,2-dioxo-2H-1,2λ

[1223] Using General Method 8, ethyl 3-{3-[(1 S)-1 -(6-hydroxy-2,2-dioxo-2H-1,2λ 6 Preparation of ethyl 3-{3-[(1 S)-1 -(6-hydroxy-2,2-dioxo-2H-1,2λ

[1224] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 0.95-1.03 (m, 3H) 1.30-1.47 (m, 5H) 1.85-1.97 (m, 2H) 2.76 (d, J=3.55 Hz, 3H) 3.18 (d, J=8.19 Hz, 2H) 3.34-3.42 (m, 2H) 3.67 (s, 3H) 3.94 (q, J=7.13 Hz, 2H) 4.33 (t, J=5.07 Hz, 1H) 4.37-4.58 (m, 3H) 4.65 (t, J=6.97 Hz, 2H) 4.83 (q, J=7.87 Hz, 1H) 5.32-5.42 (m, 1H) 6.51 (dd, J=13.20, 2.81 Hz, 1H) 6.64 (dd, J=8.86, 2.75 Hz, 1H) 6.76 (d, J=1.59 Hz, 1H) 6.79-6.84 (m, 2H) 7.08 (d, J=8.31 Hz, 1H) 7.13 (dd, J=8.56, 2.08 Hz, 1H) 7.42 (dd, J=9.05, 1.96 Hz, 1H) 7.53 (t, J=9.17 Hz, 1H) 7.60-7.65 (m, 1H) 9.51 (s, 1H) 9.52 (s, 1H).

[1225] Step 4: Preparation of 3-[l-(4-bromobutyl)-4-methyl-lH-benzotriazol-5-yl]-3-{3-[(lS)-l-(6- hydroxy-2,2-dioxo-2H-l,2λ 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methoxyphenyl}propionic acid ethyl ester

[1226] Using General Procedure 9, 3-[l-(4-hydroxybutyl)-4-methyl-lH-benzotriazol-5-yl]-3-{3-[(lS)-l-(6- hydroxy-2,2-dioxo-2H-l,2λ 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methoxyphenyl}propionic acid ethyl ester (1 equiv) as starting reagent to give the title compound (white solid, quantitative).

[1227] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 1.00 (td, J = 7.09, 3.79 Hz, 3H) 1.42 (t, J = 6.66 Hz, 3H) 1.71 - 1.82 (m, 2H) 1.92 - 2.06 (m, 2H) 2.76 (d, J = 3.91 Hz, 3H) 3.10 - 3.25 (m, 2H) 3.53 (t, J = 6.66 Hz, 2H) 3.67 (d, J = 1.10 Hz, 3H) 3.94 (q, J = 7.13 Hz, 2H) 4.35 - 4.60 (m, 2H) 4.69 (t, J = 6.85 Hz, 2H) 4.83 (q, J = 7.83 Hz, 1H) 5.36 (quin, J = 6.94 Hz, 1H) 6.51 (dd, J = 11.37, 2.81 Hz, 1H) 6.64 (dd, J = 8.93, 2.81 Hz, 1H) 6.76 (s, 1H) 6.78 (s, 1H) 6.81 (dd, J = 8.68, 2.93 Hz, 1H) 7.13 (dd, J = 8.50, 2.02 Hz, 1H) 7.42 (dd, J = 10.03, 2.08 Hz, 1H) 7.55 (t, J = 8.74 Hz, 1H) 7.61 - 7.69 (m, 1H) 9.52 (d, J = 5.01 Hz, 1H).

[1228] Step 5: Preparation of [(2S)-4-methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl] ethyl acetate

[1229] Using General Procedure 11, ethyl [(2S)-4-methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methoxyphenyl}propionate (1 equiv) as starting reagent to give the title compound (white solid, 60% yield).

[1230] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 0.98-1.07 (m, 6H) 1.15-1.20 (m, 4H) 1.31 (d, J=7.21 Hz, 3H) 1.40 (d, J=7.46 Hz, 1H) 1.48-1.61 (m, 1H) 1.62-1.75 (m, 1H) 1.75-1.87 (m, 1H) 2.00-2.14 (m, 2H) 2.14-2.28 (m, 2H) 2.70 (s, 3H) 2.84 (s, 2H) 3.09 (td, J=15.62, 7.89 Hz, 2H) 3.32-3.38 (m, 1H) 3.46 (td, J=9.54, 6.11 Hz, 1H) 3.54-3.77 (m, 9H) 3.87-3.98 (m, 5H) 3.98-4.02 (m, 1H) 4.05-4.14 (m, 1H) 4.66-4.83 (m, 5H) 4.89 (t, J=7.89 Hz, 1H) 5.43 (dq, J=17.93, 7.19 Hz, 2H) 5.62 (d, J=2.57 Hz, 1H) 5.75 (d, J=2.81 Hz, 1H) 6.62-6.72 (m, 2H) 6.81-6.93 (m, 4H) 6.99 (d, J=8.56 Hz, 1H) 7.19-7.26 (m, 2H) 7.42 (dd, J=8.44, 1.96 Hz, 1H) 7.50 (dd, J=8.56, 1.83 Hz, 1H) 7.67 (d, J=8.68 Hz, 1H) 7.74-7.80 (m, 1H) 7.83-7.89 (m, 1H).

[1231] Step 6: Preparation of Example 28c and 28d

[1232] General Method 12 was used with [(2S)-4-methoxy-2,31-dimethyl-27,27-dioxo-21,26-dioxa-27 6 - thia- 1, 14, 15, 16-tetraazahexacyclo [20.5.3.1 3,7 .1 9,13 .0 12,16 .0 25,29 .0 ethyl 32-acetate (1 equiv) as starting reagent to give the title compound (white solid, 89% yield).

[1233] The diastereomerically pure products were isolated by chiral column chromatography.

[1234] Example 28c (2S, 8R)

[1235] C30 H 32 HRMS calculated for N4O7S: 592.1992; [M+H] found: 593.2065 (delta = 0.1 ppm). +

[1236] Example 28d (2S, 8S)

[1237] C 30 H 32 HRMS calculated for N4O7S: 592.1992; [M+H] found: 593.2070 (delta = 0.9 ppm). +

[1238] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.3-11.6 (m, 1H), 7.92 (dd, 1H), 7.82 (d, 1H), 7.77 (d, 1H), 7.18 (d, 1H), 6.9 (d, 1H), 6.88 (d, 1H), 6.69 (dd, 1H), 5.7 (d, 1H), 5.42 (q, 1H), 4.75 (m, 3H), 4.08 / 3.69 (AM, 2H), 3.72 (s, 3H), 3.62 / 3.45 (m, 2H), 3.2 / 2.99 (dd, 2H), 2.68 (s, 3H), 2.2 / 2.1 (m, 2H), 1.8 / 1.59 (m, 2H), 1.29 (d, 3H).

[1239] Example 29 [(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 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid and

[1240] [(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 ​​Tricyclo[7.3.1.0]trideca-2,4,6,9(12),10,12,14-trien-8-yl]acetic acid

[1241]

[1242] Step 1: Preparation of ethyl 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H- benzotriazol-5-yl}-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propanoate

[1243] Using General Procedure 6, ethyl (E)-3-[1-(4-benzyloxybutyl)-4-methyl- benzotriazol-5-yl]prop-2-enoate (1 equiv) and (1S)-1-[2-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol (1.2 equiv) as starting reagents, afforded the title compound (50% yield).

[1244] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.58 / 7.46 (2dd, 1H), 7.41 (d, 1H), 7.35-7.22 (m, 5H), 7.06 (dd, 1H), 6.98 (d, 1H), 4.97 / 4.96 (2d, 1H), 4.83 (m, 1H), 4.83 (m, 1H), 4.65 (t, 2H), 4.4 (s, 2H), 3.92 (q, 2H), 3.42 (t, 2H), 3.12 (m, 2H), 2.77 / 2.76 (2s, 3H), 2.19 (s, 3H), 1.94 (m, 2H), 1.5 (m, 2H), 1.23 / 1.21 (2d, 3H), 1 (t, 3H).

[1245] Step 2: Preparation of ethyl 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H- benzotriazol-5-yl}-3-(3-{(1R)-1-[6-(benzyloxy)-8-methyl-2,2-dioxo-2H-1,2 6 lambda

[1246] Using General Procedure 7, ethyl 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H- benzotriazol-5-yl}-3-{3-[(1S)-1-hydroxyethyl]-4-methylphenyl}propanoate (1 equiv) and 6-(benzyloxy)-8-methyl-3,4-dihydro-2H-1,2 6 lambda

[1247] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 0.90-1.03 (m, 6H) 1.41 (d, J=6.97 Hz, 5H) 1.43-1.53 (m, 4H) 1.81-1.98 (m, 4H) 2.13-2.20 (m, 6H) 2.28 (s, 6H) 2.73-2.80 (m, 6H) 3.11-3.25 (m, 4H) 3.34-3.44 (m, 4H) 3.92 (q, J=7.05 Hz, 4H) 4.25-4.37 (m, 2H) 4.39 (d, J=3.67 Hz, 5H)

[1248] 4.55-4.66 (m, 4H) 4.81-4.91 (m, 2H) 4.99-5.11 (m, 4H) 5.26 (q, J=6.93 Hz, 2H) 6.63 (d, J=2.81 Hz, 1H) 6.69 (d, J=2.81 Hz, 1H) 6.89-6.97 (m, 2H) 7.06-7.15 (m, 4H) 7.20-7.37 (m, 12H) 7.37-7.48 (m, 10H) 7.51-7.56 (m, 2H) 7.56-7.61 (m, 2H).

[1249] Step 3: Preparation of 3-[l-(4-hydroxybutyl)-4-methyl-lH-benzotriazol-5-yl]-3-{3-[(lR)-l-(6-hydroxy-8-methyl-2,2-dioxo-2H-l,2 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propionic acid ethyl ester

[1250] Using General Method 8, 3-{l-[4-(benzyloxy)butyl]-4-methyl-lH-benzotriazol-5-yl}-3-(3-{(lR)-l-[6-(benzyloxy)-8-methyl-2,2-dioxo-2H-l,2 6 ,3-oxathiazin-3(4H)-yl]ethyl}-4-methylphenyl)propionic acid ethyl ester (1 equiv) as starting reagent to give the title compound (63% yield).

[1251] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.5 / 4.4 (s+t, 2H), 7.61 (2d, 1H), 7.58 (2d, 1H), 7.45 (2d, 1H), 7.11 (m, 2H), 6.61 (2d, 1H), 6.41 / 6.39 (2d, 1H), 5.25 (m, 1H), 4.9 (m, 1H), 4.65 (t, 2H), 4.35 / 4.29 (2m, 2H), 3.95 (q, 2H), 3.4 (q, 2H), 3.21 (d, 2H), 2.79 (s, 3H), 2.3 (s, 3H), 2.11 (2s, 3H), 1.91 (m, 2H), 1.45 (2d, 3H), 1.38 (m, 2H), 1.01 (2t, 3H).

[1252] Step 4: Preparation of ethyl 3-[1-(4-bromobutyl)-4-methyl-1H- benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-8-methyl-2,2-dioxo-2H-1,2 6 Step 5: Preparation of ethyl 3-[1-(4-bromobutyl)-4-methyl-1H- benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-8-methyl-2,2-dioxo-2H-1,2

[1253] Step 5: Preparation of ethyl 3-[1-(4-bromobutyl)-4-methyl-1H- benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-8-methyl-2,2-dioxo-2H-1,2 6 Step 5: Preparation of ethyl 3-[1-(4-bromobutyl)-4-methyl-1H- benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-8-methyl-2,2-dioxo-2H-1,2

[1254] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.5 (s, 1H), 7.62 (d, 1H), 7.59 (d, 1H), 7.48 / 7.41 (d, 1H), 7.1 (m, 2H), 6.61 (d, 1H), 6.4 / 6.39 (d, 1H), 5.24 (m, 1H), 4.88 (m, 1H), 4.69 (t, 2H), 4.31 / 4.28 (m, 2H), 3.92 (q, 2H), 3.52 (q, 2H), 3.21 (d, 2H), 2.79 (s, 3H), 2.28 (s, 3H), 2.1 (s, 2H), 2 (m, 2H), 1.78 (d, 3H), 1.41 (m, 2H), 1 (t, 3H).

[1255] Step 5: Preparation of ethyl 3-[1-(4-bromobutyl)-4-methyl-1H- benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-8-methyl-2,2-dioxo-2H-1,2 6thia-1, 14, 15, 16-tetraazahexacyclo[20.5.3.13 3,7 .1 9,13 .0 12,16 .0 25,29 Preparation of [3-(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl] ethyl acetate

[1256] Using General Method 11, ethyl 3-[1-(4-bromobutyl)-4-methyl-1H- benzotriazol-5-yl]-3-{3-[(1R)-1-(6-hydroxy-8-methyl-2,2-dioxo-2H-1,2lambda 6 ,3-oxathiazin-3(4H)-yl)ethyl]-4-methylphenyl}propanoate (1 equiv) as starting reagent to give the title compound (white solid, 61% yield).

[1257] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 0.97-1.13 (m, 4H) 1.21-1.32 (m, 2H) 1.53-1.76 (m, 1H) 1.77-1.89 (m, 1H) 2.03-2.10 (m, 3H) 2.12-2.25 (m, 1H) 2.31 (d, J=11.86 Hz, 3H) 2.66 (s, 2H) 2.72-2.80 (m, 1H) 2.81 (s, 1H) 2.95-3.15 (m, 1H) 3.34-3.51 (m, 2H) 3.67 (td, J=9.75, 5.32 Hz, 1H) 3.88-4.01 (m, 3H) 4.62-4.85 (m, 3H) 4.92 (t, J=7.76 Hz, 1H) 5.24 (dq, J=13.89, 6.82 Hz, 1H) 5.53 (d, J=2.93 Hz, 1H) 5.69 (br. s., 1H) 6.56-6.76 (m, 1H) 7.08-7.24 (m, 2H) 7.30 (d, J=7.95 Hz, 1H) 7.44 (d, J=7.70 Hz, 1H) 7.68 (d, J=8.80 Hz, 1H) 7.74 (d, J=8.68 Hz, 1H) 7.88 (d, J=8.68 Hz, 1H).

[1258] Step 6: Preparation of Example 29

[1259] Using General Method 12, [(2R)-2,4,24,31-tetramethyl-27,27-dioxo-21,26-dioxa-27lambda 6 thia-1, 14, 15, 16-tetraazahexacyclo[20.5.3.13 3,7 .19,13 .0 12,16 .0 25,29 ]triaconta-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl] ethyl acetate (1 eq) as starting reagent to give the title compound (white solid, 73% yield).

[1260] The diastereomeric pure products were isolated by chiral column chromatography.

[1261] Example 29a (2R, 8R)

[1262] C 31 H 34 HRMS calcd for N4O6S: 590.2199; [M+H] + found: 591.2273 (delta = 0.2 ppm).

[1263] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 12.25 (m, 1H), 7.7 (d, 1H), 7.48 (dd, 1H), 7.3 (d, 1H), 7.1 (d, 1H), 6.72 (d, 1H), 6.61 (d, 1H), 5.7 (sl, 1H), 5.21 (q, 1H), 4.9 (t, 1H), 4.75 (m, 2H), 4.02 / 3.48 (2d, 2H), 3.75 / 3.7 (2m, 2H), 3.28 / 2.9 (2dd, 2H), 2.8 (s, 3H), 2.31 (s, 3H), 2.2 / 2.02 (2m, 2H), 2.08 (s, 3H), 1.61 / 1.28 (2m, 2H), 1.11 (d, 3H).

[1264] Example 29b (2R, 8S)

[1265] C 31 H 34 HRMS calcd for N4O6S: 590.2199; [M+H] + found: 591.2273 (delta = 0.2 ppm).

[1266] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (m, 1H), 7.89 (d, 1H), 7.72 (d, 1H), 7.48 (dd, 1H), 7.2 (d, 1H), 7.11 (d, 1H), 6.69 (d, 1H), 5.51 (d, 1H), 5.28 (q, 1H), 4.8-4.7 (2m, 2H), 4.8 (t, 1H), 4 / 3.4 (2d, 2H), 3.65 / 3.47 (2m, 2H), 3.2 / 2.99 (2dd, 2H), 2.69 (s, 3H), 2.3 (s, 3H), 2.18 / 2.1 (2m, 2H), 2.1 (s, 3H), 1.82 / 1.71 (2m, 2H), 1.11 (d, 3H).

[1267] Example 30 : [5-methoxy-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27 6 - thia-1,14,15,16-tetraazahexacyclo[20.5.3.13 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocosa-3(32),4,6,9(31),10,12,14,22,24,29-decaene-8-yl]acetic acid

[1268]

[1269] Step B1 : Preparation of methyl 5-bromo-3-methoxy-2-methylbenzoate

[1270] Methyl 5-bromo-3-hydroxy-2-methylbenzoate (1.0 eq., 26.0 g, 106.1 mmol) was dissolved in DMF (300 mL) and then iodomethane (4 eq., 26.5 mL, 60.2 g, 424.5 mmol) and Cs2C03(4 eq., 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 magnesium sulfate and concentrated under reduced pressure. The crude product was purified by normal phase silica gel chromatography eluting with heptane-EtOAc to give the title compound (pale yellow solid, 19.1 g, 69% yield).

[1271] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.44 (s, 1H), 7.34 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 2.25 (s, 3H).

[1272] Step B2: Preparation of (5-bromo-3-methoxy-2-methylphenyl)methanol

[1273] Methyl 5-bromo-3-methoxy-2-methylbenzoate (1 eq., 19.0 g, 73 mmol) was dissolved in THF (200 mL) and the solution was cooled to 0 °C. Lithium aluminum hydride (1.2 eq., 44 mL, 2 M in THF) was added over 30 minutes under N2atmosphere. 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 NH4C1 solution, extracted with EtOAc and the organic phase was separated, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by normal phase silica gel chromatography eluting with heptane-EtOAc to give the title compound (yellow solid, 14.7 g, 87% yield).

[1274] 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).

[1275] Step B3: Preparation of [3-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methanol

[1276] The general procedure 3 was applied using (5-bromo-3-methoxy-2-methylphenyl)methanol (1 eq., 14.6 g., 63 mmol) as the reagent to give the title compound (12.53 g, 71% yield).

[1277] 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).

[1278] Step 1 : Preparation of ethyl 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H- benzotriazol-5-yl}-3-[3-(hydroxymethyl)-5-methoxy-4-methylphenyl]propanoate

[1279] General procedure 6 was used with (2E)-3-{1-[4-(benzyloxy)butyl]-4-methyl-1H- benzotriazol-5-yl}prop-2-enoic acid ethyl ester (1 equiv.) and [3-methoxy-2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (1.15 equiv.) as starting reagents to give the title compound (76% yield).

[1280] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 7.59 (d, 1 H), 7.49 (d, 1 H), 7.35-7.2 (m, 5H), 6.89 (d, 2H), 4.95 (t, 1 H), 4.82 (t, 1 H), 4.67 (t, 2H), 4.41 (s, 2H), 4.4 (d, 2H), 3.91 (q, 2H), 3.75 (s, 3H), 3.45 (t, 2H), 3.15 (d, 2H), 2.8 (s, 3H), 2 (s, 3H), 1.95 (m, 2H), 1.5 (m, 2H), 1 (t, 3H).

[1281] Step 2: Preparation of 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H-benzotriazol-5-yl}-3-(3-{[6- (benzyloxy)-2,2-dioxo-2H-1,2λ 6 ,3-oxazothiazin-3(4H)-yl]methyl}-5-methoxy-4-methylphenyl)propionic acid ethyl ester

[1282] General procedure 7 was used with 3-{1-[4-(benzyloxy)butyl]-4-methyl-1H-benzotriazol-5-yl}- 3-[3-(hydroxymethyl)-5-methoxy-4-methylphenyl]propionic acid ethyl ester (1 equiv.) and 6-(benzyloxy)-3,4-dihydro-2H-1,2λ 6 ,3-oxazothiazine-2,2-dione (1.1 equiv.) as starting reagents to give the title compound (87% yield).

[1283] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.59 (d, 1 H), 7.54 (d, 1 H), 7.49-7.2 (m, 10 H), 7.11 (d, 1 H), 7.08 (dd, 1 H), 6.96 (d, 1 H), 6.9 (d, 1 H), 6.8 (d, 1 H), 5.1 (s, 2 H), 4.87 (t, 1 H), 4.61 (t, 2 H), 4.39 (s, 4 H), 4.19 (m, 2 H), 3.92 (q, 2 H), 3.74 (s, 3 H), 3.39 (t, 2 H), 3.19 (d, 2 H), 2.79 (s, 3 H), 2.03 (s, 3 H), 1.9 (m, 2 H), 1.48 (m, 2 H), 0.99 (t, 3 H).

[1284] Step 3: Preparation of 3-[1 -(4-hydroxybutyl)-4-methyl-1 H-benzotriazol-5-yl]-3-{3-[(6- hydroxy-2,2-dioxo-2H-1,2λ 6 Step 4: Preparation of ethyl 3-{1 -[4-(benzyloxy)butyl]-4-methyl-1 H-benzotriazol-5-yl}-3-(3-{[6- (benzyloxy)-2,2-dioxo-2H-1,2λ

[1285] Step 4: Preparation of ethyl 3-{1 -[4-(benzyloxy)butyl]-4-methyl-1 H-benzotriazol-5-yl}-3-(3-{[6- (benzyloxy)-2,2-dioxo-2H-1,2λ 6 Step 4: Preparation of ethyl 3-{1 -[4-(benzyloxy)butyl]-4-methyl-1 H-benzotriazol-5-yl}-3-(3-{[6- (benzyloxy)-2,2-dioxo-2H-1,2λ

[1286] 1 H-NMR (400 MHz, DMSO-d6) δ ppm: 9.7 / 4.85 (s+t, 2 H), 7.6 (d, 1 H), 7.52 (d, 1 H), 7 (d, 1 H), 6.95 (d, 1 H), 6.8 (m, 2 H), 6.59 (d, 1 H), 4.65 (t, 2 H), 4.41 (m, 1 H), 4.31 (s, 2 H), 4.18 (m, 2 H), 3.95 (q, 2 H), 3.78 (s, 3 H), 3.4 (t, 2 H), 3.2 (d, 2 H), 2.8 (s, 3 H), 2.05 (s, 3 H), 1.91 (m, 2 H), 1.38 (m, 2 H), 1 (t, 3 H).

[1287] Step 4: Preparation of ethyl 3-{1 -[4-(benzyloxy)butyl]-4-methyl-1 H-benzotriazol-5-yl}-3-(3-{[6- (benzyloxy)-2,2-dioxo-2H-1,2λ 6Preparation of ethyl 3-oxathiazine-3(4H)-yl)methyl]-5-methoxy-4-methylphenyl]propionate

[1288] Using general method 9, 3-[1-(4-hydroxybutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Ethyl 3-oxathiazine-3(4H)-yl)methyl]-5-methoxy-4-methylphenyl]propionate (1 equivalent) was used as the starting agent to give the title compound (white solid, 86% yield).

[1289] 1 H-NMR(400MHz,DMSO-d6)δppm:9.67(s,1H),7.63(d,1H),7.56(d,1H),6.98 (d,1H),6.95(d,1H),6.78(m,2H),6.57(d,1H),4.84(t,1H),4.69(t,2H),4 .33(s,2H),4.2 / 4.12(2d,2H),3.94(q,2H),3.75(s,3H),3.53(t,2H),3.19 (d,2H),2.78(s,3H),2.05(s,3H),2(quint,2H),1.77(quint,2H),1(t,3H).

[1290] Step 5: [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 Preparation of ethyl acetate of 32-deca-3(32),4,6,9(31),10,12,14,22,24,29-deca-en-8-yl]

[1291] Using general method 11, 3-[1-(4-bromobutyl)-4-methyl-1H-benzotriazol-5-yl]-3-{3-[(6-hydroxy-2,2-dioxo-2H-1,2λ] 6 Using ethyl 3-oxathiazine-3(4H)-yl)methyl]-5-methoxy-4-methylphenyl]propionate (1 equivalent) as the starting reagent, the title compound was obtained (quantitatively).

[1292] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.67 (d, 1 H), 7.45 (d, 1 H), 7.23 (s, 1 H), 6.98 (d, 1 H), 6.79 (dd, 1 H), 6.12 (d, 1 H), 5.81 (d, 1 H), 4.83-4.74 (m, 3 H), 4.16-3.78 (m, 6 H), 3.9 (s, 3 H), 3.64 / 3.4 (dt, 2 H), 3.21 / 3.07 (dd, 2 H), 2.64 (s, 3 H), 2.24-2.03 (m, 2 H), 2.14 (s, 3 H), 1.82 / 1.65 (m, 2 H), 1.02 (t, 3 H).

[1293] Step 6: Preparation of Example 30

[1294] Using the general method 12 with [5-methoxy-4,31-dimethyl-27,27-dioxo-21,26-dioxa-27 6 - thia-1,14,15,16-tetraazahexacyclo[20.5.3.13 3,7 .1 9,13 .0 12,16 .0 25,29 ]tridocos-3(32),4,6,9(31),10,12,14,22,24,29-decaen-8-yl] acetate (1 eq) as starting reagent to give the title compound (white solid, 66% yield).

[1295] The enantiopure product was obtained by separation on a chiral column.

[1296] Example 30a (E1)

[1297] C 30 H 32 HRMS calcd for N4O7S: 592.1992; [M+H] + found: 593.2069 (delta = 0.8 ppm).

[1298] Example 30b (E2)

[1299] C 30 H 32 HRMS calcd for N4O7S: 592.1992; [M+H] + found: 593.2066 (delta = 0.3 ppm).

[1300] 1H-NMR (400 MHz, DMSO-d6) δ ppm: 12.2 (m, 1H), 7.7 (d, 1H), 7.45 (d, 1H), 7.25 (d, 1H), 7 (d, 1H), 6.8 (dd, 1H), 6.11 (d, 1H), 5.8 (d, 1H), 4.8 (m, 3H), 4.12 / 3.82 (d, 2H), 4.03 / 3.85 (d, 2H), 3.9 (s, 3H), 3.65 / 3.4 (m, 2H), 3.1 / 2.98 (dd, 2H), 2.62 (s, 3H), 2.21 / 2.1 (m, 2H), 2.18 (s, 3H), 1.88 / 1.68 (m, 2H).

[1301] Example 31 [(2S, 8S)-4-methoxy-2, 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 ]tricosa-3(33), 4, 6, 9(32), 10, 12, 14, 23, 25, 30-decaen-8-yl] acetic acid,

[1302] [(2R, 8S)-4-methoxy-2, 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 ]tricosa-3(33), 4, 6, 9(32), 10, 12, 14, 23, 25, 30-decaen-8-yl] acetic acid,

[1303] [(2S, 8R)-4-methoxy-2, 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 ]tricosa-3(33), 4, 6, 9(32), 10, 12, 14, 23, 25, 30-decaen-8-yl] acetic acid and

[1304] [(2R, 8R)-4-methoxy-2, 32-dimethyl-28, 28-dioxo-22, 27-dioxa-28λ6 - Thia- 1, 14, 15, 16-tetraazahexacyclo[21.5.3.1 3,7 .1 9,13 .0 12,16 .0 26,30 ]tricosa-3(33),4,6,9(32),10,12,14,23,25,30-decaene-8-yl]acetic acid

[1305]

[1306] Step Al: Preparation of {[(5-iodopentyl)oxy]methyl}benzene

[1307] To a solution of 5-(benzyloxy)pentan-1-ol (1 eq., 1.15 kg, 5.92 mol) in DCM (8 L) was added PPh3 (1.3 eq., 2.02 kg, 7.70 mol) and imidazole (1.3 eq., 524 g, 7.70 mol) at 15 °C. Iodine (1.3 eq., 1.95 kg, 7.70 mol) was added portionwise to the mixture at 0-15 °C. The mixture was stirred at 15 °C for 0.5 h. Upon completion of the reaction, the mixture was quenched with saturated aqueous Na2S03 solution (5 L). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was slowly cooled to 0 °C. The precipitate formed was filtered off, the filter cake was washed with MTBE (2 x 1.3 L) and the filtrate was concentrated under reduced pressure. The residue was purified by normal phase silica gel chromatography eluting with petroleum ether / EtOAc 0 to 50:1 to give the title compound (pale yellow oil, 1.45 kg, 81% yield).

[1308] 1 H-NMR (400 MHz, CDC13) δ ppm: 7.27-7.37 (m, 5H), 4.52 (m, 2H), 3.49 (t, J = 6.4 Hz, 2H), 3.20 (t, J = 7.2 Hz, 2H), 1.84-1.88 (m, 2H), 1.64-1.67 (m, 2H), 1.49-1.53 (m, 2H).

[1309] Step A2: Preparation of N-[5-(benzyloxy)pentyl]-4-bromo-3-methyl-2-nitroaniline

[1310] To a solution of 4-bromo-3-methyl-2-nitro-aniline (1 eq., 25 g, 108 mmol) and {[(5-iodopentyl)oxy]methyl}benzene (1.5 eq., 49.4 g, 162 mmol) in DMF (250 mL) was added potassium tert-butoxide (1.5 eq., 18.2 g, 162 mmol) in portions at 0-5 °C and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into H2O (520 mL) and extracted with MTBE (3 x 90 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by normal phase silica gel chromatography eluting with petroleum ether / EtOAc 0 to 7:1 to give the title compound (red oil, 26.46 g, 65 mmol, 60% yield).

[1311] 1 H-NMR (400 MHz, CDC13) δ ppm: 7.46 (d, J = 9.2 Hz, 1H), 7.33-7.36 (m, 5H), 6.54 (d, J = 9.2 Hz, 1H), 5.72 (s, 1H), 4.51 (s, 2H), 3.49 (t, J = 6.4 Hz, 2H), 3.13-3.18 (m, 2H), 2.45 (s, 3H), 1.64-1.71 (m, 4H), 1.44-1.52 (m, 2H).

[1312] Step A3: N 1 Preparation of N-[5-(benzyloxy)pentyl]-4-bromo-3-methylbenzene-1,2-diamine

[1313] To a solution of N-[5-(benzyloxy)pentyl]-4-bromo-3-methyl-2-nitrobenzenamine (1 eq., 316 g, 776 mmol) in EtOH (1.9 L) and water (950 mL) was added NH4CI (10 eq., 415 g, 7.76 mol). The mixture was heated to 70 °C and then iron (5 eq., 217 g, 3.88 mol) was added in small portions and the mixture was heated at 80 °C for 1 hour. The reaction mixture was cooled to 50 °C, diatomaceous earth was added and stirring was continued for 10 minutes. The reaction mixture was filtered through diatomaceous earth. The filter cake was washed with hot EtOAc (2 x 2.5 L, 50 °C) and the filtrate was concentrated under reduced pressure. The aqueous layer was extracted with EtOAc (3 x 1.3 L), the organic layers were washed with brine (3 x 0.5 L), dried over sodium sulfate a...

Claims

1. Compounds of formula (I): in Z is -O-(CH2)n1-, -O-(CH2)n1-O-(CH2)n2, -O-(CH2)n1-S-(CH2)n2, -O-(CH2)n1-NR-(CH 2)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-CH R'-(CH2)n2, -O-(CH2)n1-Ar-CH=CH-, O-Ar-NR-(CH2)n1, -(CH2)n1-NR-(CO)-(CH2)n2- Or Z is Y1 is C, Y2 is either O or NR'. yes Ar is a divalent phenylene. R is a hydrogen atom, a straight-chain or branched C1-C3 alkyl or phenyl group. R' is a hydrogen atom or a group selected from the following: hydroxyl, phenyl optionally substituted with a straight-chain or branched (C1-C6)-alkyl group substituted with 1 to 3 halogen atoms, and straight-chain or branched C1-C3 alkyl optionally substituted with a C1-C3 alkoxy group or substituted with 1 to 3 halogen atoms, where n1 and n2 are integers from 1 to 6. R1, R2, R4, R8, R9, R 10 They may be the same or different, and each is a hydrogen atom or a group selected from the following: halogen, cyano, a straight-chain or branched C1-C3 alkyl group optionally substituted with 1 to 3 halogen atoms, a straight-chain or branched C1-C3 alkoxy group or phenyl group, where R3 is hydrogen or a straight-chain or branched C1-C3 alkyl group optionally substituted with 1 to 3 halogen atoms. R5 and R6 may be the same or different, and each is a C1-C3 alkyl group, either with hydrogen, deuterium, or halogen atoms, or with straight or branched chains. R7 is a group selected from hydroxyl and NHR'7. Where R'7 is a straight-chain or branched C1-C6 alkyl, pyridinyl, or pyrimidinyl group. Its optical isomers and their addition salts with pharmaceutically acceptable bases.

2. The compound having formula (IA) according to claim 1: Wherein Z, Y1, Y2, R1 to R9 are as defined in claim 1. Its optical isomers and their addition salts with pharmaceutically acceptable bases.

3. The compound having formula (IA1) according to claim 2: Wherein R1-R4, R8-R9, Y1, and Y2 are as defined in claim 1, and Z1 is a group selected from the following: -(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 Ar1 is a divalent phenylene. R, R', n1, and n2 are as defined in claim 1. Its optical isomers and their addition salts with pharmaceutically acceptable bases.

4. The compound having formula (IB) according to claim 1: Wherein Z, Y1, Y2, R1 to R7 are as defined in claim 1. Its optical isomers and their addition salts with pharmaceutically acceptable bases.

5. The compound having formula (IC) according to claim 1: Among them, Z, Y1, Y2, R1 to R8 and R 10 As defined in claim 1, its optical isomer and its addition salt with a pharmaceutically acceptable base.

6. A compound of formula (I) according to any one of claims 1, 2, 4 or 5, wherein Z is -O-(CH2)n1-, -O-(CH2)n1-O-(CH2)n2 or -O-(CH2)n1-S-(CH2)n2.

7. The compound of formula (I) according to any one of claims 1, 2, 4 or 5, wherein Y2 is O or NCH3.

8. The compound of formula (I) according to claim 1, wherein the compound is selected from: [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 [Tridecano-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetic acid, its optical isomers and their addition salts 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 [32,4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and their addition salts 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 [32,4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and their addition salts 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 [32,4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and their addition salts 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 [32,4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and their addition salts 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 [34-(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid, its optical isomers and their addition salts 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 [Tridecano-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetic acid, its optical isomers and their addition salts 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 [34-(34),4,6,9(33),10,12,14,24,26,31-decaen-8-yl]acetic acid, its optical isomers and their addition salts 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 [32,4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and their addition salts 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 [32,4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and their addition salts 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 [32,4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and their addition salts with pharmaceutically acceptable bases, [4,26,31-trimethyl-27,27-dioxo-21-oxa-27λ] 6 -Thia-1,14,15,16,26-pentaazahexacyclic[20.5.3.1] 3,7 .1 9,13 .0 12,16 .0 25,29 [32,4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and their addition salts 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 [Tridecano-3(33),4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetic acid, its optical isomers and their addition salts 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 [32,4,6,9(31),10,12,14,22,24,29-decaen-8-yl]acetic acid, its optical isomers and their addition salts 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 [33,4,6,9(32),10,12,14,23,25,30-decaen-8-yl]acetic acid, its optical isomers and their addition salts with pharmaceutically acceptable bases.

9. A method for preparing a compound of formula (IA1) according to claim 3, starting from a compound of formula (II). Where P1 is the protecting group for the acid functional group and P2 is the protecting group for the alcohol functional group. The compound of formula (II) reacts with the compound of formula (III): Wherein R1-R3 and Y1 are as defined in claim 1. Compounds with formula (IV): R1-R3, R8-R9, Y1, Z1, and P1-P2 are defined as above. React the compound of formula (IV) with the compound of formula (V): Wherein R4 and Y2 are as defined in claim 1, and P3 is a protecting group for the alcohol functional group, resulting in a compound of formula (VI): R1-R4, R8-R9, Y1, Y2, Z1, and P1-P3 are defined as above. Deprotecting the compound of formula (VI) yields the compound of formula (VII): R1-R4, R8-R9, Y1, Y2, Z1, and P1 are defined as above. Halogenating the compound of formula (VII) yields the compound of formula (VIII): R1-R4, R8-R9, Y1, Y2, Z1, and P1 are defined as above, and X is a halogen atom. Reacting the compound of formula (VIII) with a base yields the compound of formula (IX): The compound of formula (IX) is deprotected by a base reaction to obtain the compound of formula (IA1), and its stereoisomers are separated by chiral separation techniques if necessary.

10. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 8 and one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.

11. The pharmaceutical composition according to claim 10, characterized in that... It also contains one or more other active ingredients.

12. Use of the compound according to any one of claims 1 to 8 in the preparation of a medicament for treating diseases associated with increased oxidative stress and inflammation, impaired redox potential, impaired detoxification, or metabolic disorders.

13. The compound according to any one of claims 1 to 8 in the preparation of a treatment for type II diabetes, non-alcoholic steatohepatitis, autosomal dominant polycystic kidney disease, acute kidney injury, Alport syndrome, or Use in medications for syndromes.

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