Discovery and Exploration of Monosaccharide Linked Dimers of Galectin-3 Inhibitors to Target Fibrosis

Discovery and Exploration of Monosaccharide Linked Dimers of Galectin-3 Inhibitors to Target Fibrosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Discovery and Exploration of Monosaccharide Linked Dimers of Galectin-3 Inhibitors to Target Fibrosis Jacob J. Swidorski, Brett R. Beno, Chunjian Liu, David S. Yoon, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2757730/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Jun, 2023 Read the published version in Medicinal Chemistry Research → Version 1 posted 4 You are reading this latest preprint version Abstract Galectin proteins have been targets of interest in numerous therapeutic areas for some time. Galectin-3 has been identified as a target of particular interest because of its unique structural characteristics and physiological profile. Recent literature indicates Gal-3 inhibition can decrease myofibroblast activation and procollagen expression with the potential to affect the progression of fibrosis in the lung, liver and kidney. Potential π-stacking interactions between one monosaccharide ligand bound to the carbohydrate recognition domain of a galectin-3 protein and a second ligand bound to a different galectin-3 protein molecule were observed in the extended crystalline lattice in an X-ray crystal structure obtained while studying the monosaccharide structure-activity relationship. The direct interaction between the ligands suggests a potential for dimeric galectin-3 inhibitors which bind to two galectin-3 molecules simultaneously. This work describes the exploration of dimers designed to further probe these observations and explore the potential of binding to dimeric or higher order multimeric galectin-3 assemblies. Figures Figure 1 Figure 2 Figure 3 Introduction Nonalcoholic fatty liver disease (NAFLD) has become a global concern as rates of obesity, type II diabetes and related metabolic diseases have increased and are inextricably linked to onset of the disease. Worldwide estimates in 2013 put the prevalence of NAFLD as high as one billion individuals currently living with the ailment [1]. In countries with a high prevalence of obesity and related disease, as many as a third of the population may be affected by NAFLD [1,2]. Further progression of liver disease in NAFLD patients can lead to the development of nonalcoholic steatohepatitis (NASH) which is more concerning as it is one of the principal causes of cirrhosis in US adults and can ultimately progress to hepatocellular carcinoma requiring a liver transplantation or result in liver-related mortality [2–4]. Because progression of NAFLD has thus far been difficult to predict, fibrosis has been the most impartial indicator of liver damage that will lead to severe disease [5,6]. Galectins are proteins that bind to conserved b-galactoside binding sites and have been studied for their numerous physiological functions in both the intra- and extra-cellular space [7–11]. Galectin-3 (Gal-3) has unique structure and function among the galectin family of proteins [12]. It is the only known chimera-type protein in the galectin family that is composed of an N-terminal non-lectin domain linked to a C-terminal carbohydrate recognition domain (CRD) [12–17]. Although Gal-3 is found predominantly as a monomer in solution, it can oligomerize to form disorganized, pentameric cross-linked complexes when interacting with multivalent carbohydrates [12,16]. It has been postulated that the ability for Gal-3 to organize in oligomeric forms and its ability to organize less structured cross-linked lattices compared to other galectins may account for differences in biological activity compared to other galectin proteins [12]. Extensive efforts have advanced the understanding of the roles that Gal-3 plays in the pathogenesis of various diseases [18–21]. Gal-3 is involved in numerous cellular and physiological processes such as apoptosis, cell adhesion and migration, angiogenesis, and inflammation [22]. Our group was especially interested in Gal-3’s function in the regulation of inflammation and its therapeutic potential to affect the onset and progression of fibrotic diseases. Numerous studies indicate that Gal-3 is involved in myofibroblast activation and procollagen expression. Increased Gal-3 expression is associated with the progression of fibrosis in multiple organs including liver, lung, kidneys and the heart [22,23]. In the liver, Gal-3 expression is increased in hepatic stellate cells and human tissues of cirrhosis patients [24]. In preclinical models, Gal-3 inhibitors demonstrate therapeutic efficacies in acute CCl 4 liver injury models as well as thioacetamide induced liver fibrosis models in vivo [24–27]. Several research groups have advanced molecules into clinical trials for the treatment of fibrosis. TD139 (GB0139) is a thiodigalactoside being studied in phase IIb as an inhaled treatment of idiopathic pulmonary fibrosis [28]. TD139 was shown to have high binding affinity for Gal-3 in the low nanomolar range. However, this compound lacked oral bioavailability because of its large size and high polarity [29]. Further exploration led to the discovery of monogalactoside GB1211, a smaller and less polar low-nanomolar human Gal-3 inhibitor, that has improved oral bioavailability and is currently being examined in phase IIa clinical studies [29]. Together, publications outlining target engagement, predictive in vivo models, and advancement of compounds in the clinic make Gal-3 an attractive therapeutic target. Results And Discussion During our effort to optimize the monosaccharide based Gal-3 series, crystal structure data aimed at guiding the structure-activity relationship (SAR) development provided several interesting observations [30]. An X-ray structure of 1 bound to the mouse galectin 3 protein (mGal-3) showed an apparent π-stacking interaction of the benzothiazole group extending from the anomeric 1,2,4-triazole of 1 with a benzothiazole on a second molecule of 1 (Fig. 1 ). Each of the two molecules of 1 were bound to a different mGal-3 protein molecule by key carbohydrate binding interactions in the CRD [30,31], while the two ligand molecules aligned in close proximity to one another in the extended crystalline lattice. The intermolecular π-stacking interactions between the ligand benzothiazoles may contribute to the stability of this particular crystalline form of the complex. Inter-ligand close contacts were also observed in the extended lattice of the X-ray crystal structure of human Gal-3 CRD bound to TD-139 (PDB ID: 7CXA) [32]. In another X-ray structure obtained from 2 bound to mGal-3 in the CRD, the close proximity of a carboxylic acid extending from the C2 position of the galactose core to the C2 carboxylic acid extension of a second molecule of 2 bound to a separate mGal-3 protein CRD was observed. The distance between oxygen atoms in the two carboxylic acid moieties was < 6 Å, suggesting the possibility of linking the two monosaccharide molecules as a bis-amide with a diamine of appropriate size. These observations led us to explore the possibility of developing a dimer that could bind to multiple Gal-3 proteins with the potential to further enhance binding affinity which is reported in the current paper. Compounds were tested in both human and mouse Gal-3 (hGal-3 and mGal-3) homogeneous time-resolved fluorescence (HTRF) binding assays using biotin-asialofetuin (B-ASF) as the ligand. Many of the compounds were also tested in a second HTRF assay using a fluorescein isothiocyanate (FITC) labeled small molecule substrate [33] as the ligand (F-ligand). Both assays could be used as tools to effectively rank order the binding affinities of the molecules being tested for inhibition of Gal-3. Since we intended to use in vivo mouse models for PK/PD and efficacy studies, mGal-3 measurements became a focus for improvement with the monomeric series of compounds. In the case of compounds containing the trifluorophenyl substituents extending from the 1,2,3-triazole, mGal-3 potency was substantially lower than hGal-3 (19 fold for 1 and 15 fold for 2 ). Several attachment points joining monosaccharide subunits were explored as possibilities to afford potent dimers based on the observed interactions in Fig. 1 . Previously reported, monosaccharides containing 1,2,3-triazoles in the b conformation at the anomeric position showed moderate hGal-3 potency of 256–306 nM in the HTRF assay [30], so an attachment was made between the 4 position of the anomeric 1,2,3-triazole spanning 3 or 5 carbons between the monosaccharide subunits ( 3 and 4 ). Interestingly, these compounds showed an hGal-3 IC 50 > 4 mM and mGal-3 IC 50 > 30 mM in the HTRF assays. The dramatic decrease of the Gal-3 IC 50 value can likely be explained by the disruption of an important interaction at Gly182 of the protein with the halogen attached to a phenyl substituent projecting from the 1,2,3-triazole previously described by Liu et al [30]. The benzothiazole π-stacking interaction observed with 1 likely does not disrupt the Gly182 interaction in the same manner since X-ray crystal structure data shows a similar interaction to the halogen bond can be made between the sulfur atom of the benzothiazole and the Gly182 of the Gal-3 protein [31]. Using a different approach to link the two monosaccharide subunits, an extension from the 1,2,3-triazole in one monosaccharide was linked to a C-2 alcohol of another monomer with an acetamide and a carbon spacer to provide 5 . With this linkage, the hGal-3 and mGal-3 potencies were only several fold lower than that of the monosaccharide which had an hGal-3 IC 50 = 19 nM and mGal-3 IC 50 = 126 nM in the HTRF assay [30]. The structure of 5 allows the monosaccharide subunit with the extension from C-2 to interact with the Gly182 while maintaining the ability to halogen bond with the protein, while the second monosaccharide subunit is unavailable to interact with Gly 182 since there is no longer an extension from the anomeric carbon able to access the same pocket. The observed potency, comparable to the single monosaccharide subunit, is consistent with this hypothesis. To further test the effect of the linkages between the two subunits, additional connections between monosaccharides focused on side chains extending from the C-2 alcohol of the carbohydrate core which could allow for the halogen bond to Gly 182 to be retained in each of the subunits. When comparing monosaccharide 6 to a symmetrical dimer made up of two monosaccharides linked through an acetamide spacer extending from the C-2 alcohol (examples 7–10 , Table 1 ), the hGal-3 IC 50 was improved in each instance compared to the monosaccharide. The largest improvement in hGal-3 potency was 55x in the HTRF assay for 10 with a 5 carbon linker. Furthermore, 10 showed 7-13x improvement in the mGal-3 HTRF and F-ligand assays respectively compared to the monosaccharide. Since modifications to the phenyl substituents on the C-3 1,2,3-triazoles were reported to improve Gal-3 potency in the monosaccharide subunits one of the more potent substitution patterns, the phenyl F,Cl,F, was incorporated into dimers with acetamide linkers with 2, 4, 5, 6 and 7 carbon unit spacers. The 2, 4 and 5 carbon linkers ( 11 – 13 ) showed similar potency in the hGal-3 HTRF and F-ligand as the F,F,F-substituted analogs. Linkers with 6 and 7 carbon spacers between the acetamides ( 14 and 15 ) showed lower Gal-3 inhibition in both the human and mouse assays than the shorter linkers of 11 – 13 providing the optimal length of the spacers between the acetamides of 2 to 5 carbons. Consistent with the reported monosaccharide SAR, The R 1 substitution pattern showed a modest improvement in the mGal-3 potency for linkers of 2, 4 and 5 carbons (4–5 fold) in the fluorescence assay. Incorporating the F,Cl,F substitution pattern on the C3 triazole phenyl group appendage in combination with the CF 3 on R 2 of the 1,2,4-triazole, examples 16 – 18 provided another modest improvement to the in vitro mGal-3 IC 50 . In addition to all 3 examples showing hGal-3 IC 50 of < 1 nM in the HTRF assay, the compounds showed a 41–94 fold improvement in the mGal-3 HTRF assay and 23–74 fold improvement in the F-ligand assay when compared to the monosaccharide 6 . Table 1. Inhibition of hGal-3 and mGal-3, and in vitro metabolic stability for selected compounds in human, rat and mouse. Example Linker length R 1 R 2 hGal-3 IC 50 HTRF / F-ligand (nM) mGal-3 IC 50 HTRF / F-Ligand (nM) Metstab a human/rat/mouse 6 monosaccharide F, F, F Cl 38.6 b / 76.4 c 1,160 ± 57 / 1,930 c 93/78/88 7 n = 2 F, F, F Cl NT / 3.9 b NT / 252 ± 162 89/92/88 8 n = 3 F, F, F Cl NT / 4.4 b NT / 311 ± 306 9 n = 4 F, F, F Cl NT / 5.5 ± 0.9 NT / 850 b 10 n = 5 F, F, F Cl 0.7 c / 0.8 b 171 ± 14.6 / 151 b 96/92/84 11 n = 2 F, Cl, F Cl 3.0 ± 1.4 / 2.8 ± 1.2 90.4 ± 39.5 / 36.6 ± 17.1 97/89/93 12 n = 4 F, Cl, F Cl 1.0 b / 6.3 ± 2.7 54.3 ± 29.0 /108 c 92/80/81 13 n = 5 F, Cl, F Cl 1.3 b / 4.6 b 80.1 ± 28.0 /105 c 14 n = 6 F, Cl, F Cl 5.9 b / 18.5 b 244 b / 877 c 100/88/87 15 n = 7 F, Cl, F Cl 10.1 b / 23.6 ± 13.3 717 b / 522 ± 216 91/87/98 16 n = 3 F, Cl, F CF 3 0.7 b / 2.3 ± 1.0 12.4 ± 1.4 / 26.2 ± 7.7 87/88/98 17 n = 4 F, Cl, F CF 3 0.8 b / 4.4 ± 1.1 12.8 ± 3.8 / 83.5 ± 65.5 100/93/99 18 n = 5 F, Cl, F CF 3 0.9 b / 4.4 ± 1.7 28 ± 10.5 / 66 ± 18.2 88/94/93 a In vitro metabolic stability was measured by incubating the ligand in human, rat and mouse liver microsomes and measuring the % remaining after a 10 minute incubation period. HTRF and F-Ligand assays are reported as mean IC 50 values ± SD from at least three experiments unless otherwise noted. b Value is the average of two experiments. c Value determined from one experiment. Because 10 showed a promising in vitro inhibition profile for both human and mouse, it was further profiled for advancement to in vivo studies. The in vitro permeability measured in the parallel artificial membrane permeability assay (PAMPA), a model for passive diffusion used to predict absorption [34], was 299 nm/sec at pH 5.5 and 376 nm/sec at pH 7.4, surprisingly high for a large, polar compound with a calculated topological polar surface (tPSA) calculation of 288 [35,36]. In vitro metabolic stability was measured by incubating 10 in human, rat, and mouse liver microsomes and measuring the % remaining after a 10 minute incubation period. Metabolism was generally low ranging from 84–92% across species. With encouraging in vitro results, 10 was advanced to in vivo mouse PK studies. The compound was dosed at 2 mg/kg IV and 10 mg/kg, PO and concentrations of the compound at multiple timepoints was acquired over a 24h period. While the parent monosaccharide had an AUC total of 4.1 mM*h with a single dose IV and 4.0 mM*h with a single dose administered orally, only a small fraction of the dimer 10 was orally bioavailable (0.02 mM*h, PO, F% = 0.3) compared to the monosaccharide 6 which had F% = 20. Table 2. Alternative C-2 linkers a In vitro metabolic stability was measured by incubating the ligand in human, rat and mouse liver microsomes and measuring the % remaining after a 10 minute incubation period. HTRF and F-Ligand assays are reported as mean IC 50 values ± SD from at least three experiments unless otherwise noted. b Value is the average of two experiments. c Value determined from one experiment. To improve the oral bioavailability for in vivo studies, alternative modifications to the linker were examined (Table 2 ). The acetamide linkages of 7–18 were substituted for ether linkages of similar length in 19–20 which lowered the tPSA from 288 to 230 Å 2 . Although the distance between the two linked monosaccharide units was similar with the all carbon spacers in 19–20 , HTRF assays for both the hGal-3 and mGal-3 showed a significant decrease in potency. When the linker was changed to a C-2 carbamate in 21 and 22 , in vitro hGal-3 potency was somewhat restored with the 4 carbon linker between the carbamates having an hGal-3 IC 50 = 19 nM and the 3 carbon linker having an hGal-3 IC 50 = 110 nM, however in both carbamate examples the mGal-3 IC 50 decreased to nearly 3 mM in the HTRF assay, a substantial loss of potency when compared to the original acetamide linkers. Finally, a tertiary amide 23 was explored which removed the H-bond donor characteristic of the initial secondary amides, however this changes only modestly decreased the tPSA to 270 Å 2 . Interestingly, in vitro hGal-3 and mGal-3 IC 50 was comparable to the secondary amides 11 with the same linker length. Unfortunately, attempts to measure the in vitro permeability using the PAMPA assay were not successful so 23 was not progressed further. To follow on this result, two cyclic tertiary amides were explored as linkers, the 1,4-diazepane 24 and the piperizine 25 . Both compounds showed tPSAs of 270 Å 2 , and IC 50 values in the mGal-3 and hGal-3 F-ligand assay were comparable to the secondary amides of similar length. In addition, 24 and 25 showed acceptable metabolic stability in the 10 minute incubation assay. However, attempts to measure in vitro permeability using the PAMPA assay were unsuccessful for both compounds, potentially because of limitations in aqueous solubility. The piperazine analog 25 was advanced into an in vivo mouse PK study to explore its potential as an orally dosed inhibitor of Gal-3. The compound was dosed at 10 mg/kg PO and 10 mg/kg SQ and concentrations of the compound at multiple timepoints were acquired over a 24 h period. When dosed orally, AUC total was only 0.035 mM*h, which was comparable to 10 . The previous in vivo PO results of 10 , in addition to a high tPSA and the difficulty measuring the in vitro permeability of 25 , led to an alternative attempt at SQ dosing, which did improve the AUC total to 2.23 mM*h. While exploring opportunities to link the two monosaccharide subunits together, attempts to further understand the binding pocket using binding models developed from X-ray crystal structures of monomeric subunits were explored, however attaining an X-ray crystal structure of one of the dimers was exceedingly arduous. After multiple attempts to crystallize the dimers in Table 1 came up empty, an X-ray crystal structure of 25 bound to the hGal-3 CRD was finally determined (Fig. 2 ). The X-ray crystal structure data clearly showed the two monosaccharide subunits interacting with two hGal-3 proteins in close proximity. One hGal-3 protein is shown in orange, while a second hGal-3 protein is shown in green and the dimeric ligand has organized in a symmetric, yet opposite orientation reaching into the binding pockets of each protein. When examining the binding of 25 to the hGal-3 protein closer (Fig. 3 ), it becomes apparent that the core CRD interactions of the saccharide are intact as well as the key interaction previously described with the anomeric substituent extending to reach Gly 182 [30]. Interestingly, there is a water molecule that bridges the carbonyl of the acetamide linker, a ligand1,2,3-triazole nitrogen atom, and the side-chain indole NH of Trp 181. This interaction may stabilize the bound conformation of the ligand and could account for the observed differences in IC 50 values between the ethers and the acetamides used to link the two halves of the dimer. In addition to the ligand-protein interactions mentioned above, several inter-chain hydrogen bonds are observed between residues in the A and B hGal-3 CRD chains in the complex including Asp239A/ASN179B, Val116A/Asn153B, and Lys233A/Val116B. These additional interactions likely contribute to the stability of the ternary hGal-3 CRD/dimeric inhibitor complex, and the difficulties obtaining X-ray crystal structures of hGal-3 CRD with other dimeric inhibitors may be due to reduced ability of those ternary complexes to form inter-chain hydrogen bonds as a result of ligand conformations incompatible with inter-chain protein-protein contacts. Size-exclusion chromatography combined with multi-angle light scattering (SEC-MALS) experiments were utilized to further understand the binding of the monomeric and dimeric Gal-3 inhibitors [37,38]. When observing the hGal-3 protein by itself, the molecular weight (MW) of the protein was 2.7 x 10 4 Da and showed a single peak in the SEC-MALS analysis. Combining the protein with monosaccharide 26 , the SEC-MALS analysis showed a single peak with a 2.65 x 10 4 Da MW, consistent with monomeric protein and no change in the oligomerization state. The same experiment was repeated using 10 and the hGal-3 protein, and the protein eluted two minutes earlier from the gel filtration column, consistent with an increase in hydrodynamic radius, and the observed MW increased to 3.6 x10 4 Da, consistent with a mixture of monomer and dimer. When combining 25 with the hGal-3 protein and performing the SEC-MALS analysis, similar to 10 , the peak eluted two minutes earlier and the MW of the major peak increased to 3.6 x10 4 Da. Both studies involving dimeric ligands showed a small shoulder that stretched back to the initial hGal-3 protein shift and had a molecular weight similar to the unbound protein. These observations were interpreted to indicate that the monomeric inhibitor 26 was bound to only one hGal-3 protein as expected, while both of the dimeric inhibitors, 10 and 25 , showed a different binding profile, one that was likely a mixture of monomeric and dimeric protein interactions based on the peak shift, increase in molecular weight and shoulder stretching back to the original hGal-3 protein peak. While the in vitro assay data, X-ray crystal structure of hGal-3 CRD with dimeric inhibitor 25 , and the SEC-MALS results are consistent with the binding of two hGal-3 CRD molecules to dimeric inhibitors in vitro, it is still unknown whether the improved potency achieved with dimeric inhibitors would result in improved in vivo activity. Conclusions The X-ray crystal structure analysis of monosaccharide Gal-3 inhibitors bound to the Gal-3 CRD revealed close inter-ligand contacts in the extended crystalline lattices. A set of dimeric compounds was designed to test if improvements in potency compared to the monosaccharide subunits could be achieved using a strategy linking two monosaccharide subunits bound to different Gal-3 CRD molecules. These experiments show that after optimization of linker position, length and atom composition, dimers can improve the potency in HTRF and F-ligand assays when compared to their monosaccharide subunits while maintaining in vitro permeability and metabolic stability. In an optimized case, 10 improved potency 55x in the hGal-3 and 7-13x in the mGal-3 assays respectively when compared to the monosaccharide. Lead compounds 10 and 25 were further examined in in vivo mouse PK studies. PO dosing showed a much lower oral bioavailability compared to the monosaccharide comparators. However, when adjusting to dosing the compound SQ at 10 mg/kg of 25 , AUC total improved from 0.035 mM*h (PO) to 2.23 mM*h SQ. Furthermore, an X-ray crystal structure of 25 bound to hGal3 protein was obtained and crystallography analysis showed the ligand bound to two distinct Gal-3 proteins with each monosaccharide unit occupying the CRD of a single protein. SEC-MALS analysis was consistent with the X-ray crystal structure as the molecular weight and retention time shifted with the introduction of both 10 and 25 with the hGal-3 protein, while combining monosaccharide 26 with the hGal-3 protein did not show a corresponding shift in retention time and molecular weight using the SEC-MALS analysis. Chemistry The formation of dimers 3 and 4 proceeded by first forming the C-3 1,2,3-triazole 29 using click chemistry to couple the silyl protected phenyl alkyne 27 and azide 28 (scheme 1 ) [39]. The p-methoxybenzylidine acetal group was cleaved to unmask the C-4, C-6-diol 30 by heating in AcOH and H 2 O, then the diol was acylated with acetyl chloride to give 31 , where the C-2, C-4, and C-6 alcohols were all protected with as acetates. Treatment of 31 with bromine gave the anomeric bromide 32 in the beta configuration which could then be displaced using sodium azide in DMF at 75°C to give the azide 33 in the anomeric position in the alpha configuration. Global removal of the acetate groups followed using sodium methoxide in MeOH to provide triol 34 which was then subjected to another click reaction, coupling the C-1 azide with alkyl diynes to give linkers 3 and 5 carbons in length between the newly formed triazoles delivering dimers 3 and 4 . Dimer 5 used a different method to link the two halves of the molecule, in this instance extending a linker from the anomeric 1,2,3-triazole to the C-2 alcohol (scheme 2 ). Synthesis of the first half of the molecule utilized the C-2 alcohol of 35 [30] as a handle to extend an acetate group using sodium hydride and ethyl bromoacetate, then hydrolyzed to the carboxylic acid 36 by treatment with sodium hydroxide, MeOH, and H 2 O. An amide was formed by treating the carboxylic acid 36 with HATU [40] and an alkynyl amine which extended an alkynyl handle from the C-2 position to give 37 . Click chemistry of the alkyne 37 with azide 38 [41] provided 5 which effectively linked the C-2 alcohol of one monosaccharide to the newly formed anomeric 1,2,3-triazole of a second monosaccharide through an acetamide and carbon spacer. Amide linkages for compounds 7 – 10 were formed by treating alcohol 39 [30] with sodium hydride followed by t- Bu-bromoacetate to form the t -butyl acetate 40 (Scheme 3 ). Treatment of 40 with TFA, followed by 1,3-diaminopropane effectively unmasked both the C4, C6-diol and the carboxylic acid groups to give 41 . Acetyl chloride was used to protect the C4, C6-diol as the diacetate 42 and the dimers were then formed using HATU and diamines of varied lengths to link the two halves of the molecule through newly formed amide bonds extending from the C-2 position of each half. Removal of the acetate protecting groups with sodium methoxide in MeOH gave the dimers 7 – 10 . Diamines linked through extended C-2 amides 11 – 18 and 23 – 25 were formed using a slightly different synthetic route (scheme 4 ). C-2 alcohols 43 [30] and 35 , which differ by the substitution pattern on the phenyl group attached to the anomeric 1,2,4-triazole, were treated with sodium hydride followed by ethyl bromoacetate to give the C-2 carboxylates which were hyrolyzed to the C-2 carboxylic acids 36 and 44 using aqueous sodium hydroxide and MeOH. Amide formation was accomplished using HATU and Et 3 N to provide the penultimate intermediates of 11 – 18 or T3P [42] and Et 3 N for 23 – 25 . Deprotection of the C4, C6-diol was accomplished in each instance by first heating the benzylidine acetals in aqueous AcOH at 70°C, followed by concentration and treatment with K 2 CO 3 in H 2 O and MeOH to give 11 – 18 and 23 – 25 . Dimers 19 and 20 joined through ether linkages from the C-2 position were formed by treatment of the C-2 alcohols 43 and 45 [30] with sodium hydride, followed by introduction of the diiodoalkane (scheme 5 ). Deprotection of the C-4 and C-6 alcohols was accomplished using aqueous AcOH at 70°C followed by concentration and treatment with K 2 CO 3 in H 2 O and MeOH to give dimers 19 and 20 . A one step formation of the carbamate linker to join the two monosaccharide units at the C-2 position was envisioned for 21 and 22 , however, in practice the carbamate formation wasn’t as cooperative as planned. The pyridyl carbonate was formed in situ by heating the C-2 alcohols 39 and 43 [30], dipyrin-2-yl carbonate and DMAP in CDCl 3 to 50°C. After cooling to rt, the diamino alkanes were introduced, however, a mixture of the dimer as a minor peak and the monomeric amino carbamate as a major peak were isolated along with C-2 alcohol starting materials. To convert additional monomeric material to the dimer product, a second addition of the pre-formed pyridyl carbonates 50 and 51 were necessary. After stirring the mixtures overnight after the addition of the pyridyl carbonate, the dimer products 52 and 53 formed as the major products. Isolation of carbamate 53 was complicated as purification using reverse phase conditions with an MeCN/ H 2 O /TFA mobile phase cleanly separated the dimer, however, upon concentrating, a portion of the benzylidine acetal group had fallen off, so the mixture of protected and deprotected alcohols were carried to the next step where the benzilidine acetal would be completely removed by heating the mixture in aqueous AcOH at 70°C, then treating with K 2 CO 3 in MeOH and H 2 O to give 21 . With the lessons learned from the complicated isolation of 53 , intermediate 52 was purified using normal phase flash chromatography to avoid the partial deprotection of the benzylidine acetal seen with the reverse phase conditions. Deprotection of the diol was accomplished by heating 52 in AcOH and H 2 O at 70°C followed by concentration and treatment with K 2 CO 3 , MeOH and H 2 O to give 22 . Experimental Section Materials. All reagents were purchased from commercial sources and used without further purification unless otherwise noted. All reactions involving air- or moisture-sensitive reagents were performed under an inert atmosphere. Proton and carbon magnetic resonance ( 1 H and 13 C NMR) spectra were recorded either on a Bruker Avance 400 or a JEOL Eclipse 500 spectrometer and are reported in ppm relative to the reference solvent of the sample in which they were run. HPLC and LCMS analyses were conducted using a Shimadzu LC10AS liquid chromatograph and an SPDUV-vis detector at 220 or 254 nm with MS detection performed with a Micromass Platform LC spectrometer. HPLC purity analyses were performed using the following conditions: Method A. Waters XBridge C18 2.1 mm x 50 mm, 1.7 mM particles with a solvent system where solvent A = 5% MeCN, 95% H 2 O, and 10 mM ammonium acetate and solvent B = 95% MeCN, 5% H 2 O, and 10 mM ammonium acetate, flow rate = 1 mL/min, and linear gradient from 0-100% B over 3 minutes at 50°C. Method B. Waters XBridge C18 2.1 mm x 50 mm, 1.7 mM particles with a solvent system where solvent A = 5% MeCN, 95% H 2 O, and 0.1% TFA and solvent B = 95% MeCN, 5% H 2 O, and 0.1% TFA, flow rate = 1 mL/min, and linear gradient from 0-100% B over 3 minutes at 50°C. All final compounds were tested using two HPLC methods and the lower of the two HPLC purities was reported. LCMS analyses were performed using the following conditions: Method 1: Xbridge BEH C18 4.6 mm × 50 mm column with solvent system where solvent A = 10% MeCN, 90% H 2 O, and 0.1% TFA and solvent B = 90% MeCN, 10% H 2 O, and 0.1% TFA, flow rate = 0.8 mL/min, and linear gradient from 2–98% B over 1.5 minutes at 50°C. Method 2: Waters XBridge C18 2.1 mm x 50 mm, 1.7 mM particles with a solvent system where solvent A = 5% MeCN, 95% H 2 O, and 0.1% TFA and solvent B = 95% MeCN, 5% H 2 O, and 0.1% TFA, flow rate = 1 mL/min, and linear gradient from 0-100% B over 3 minutes at 50°C. Synthesis (29) (2S,4aR,6S,7R,8S,8aR)-8-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(4-methoxyphenyl)-6-(phenylthio)hexahydropyrano[3,2-d][1,3]dioxin-7-yl acetate. To a flask containing 28 (0.75 g, 1.639 mmol) was added copper (II) sulfate pentahydrate (0.287 g, 1.148 mmol) and sodium ascorbate (0.325 g, 1.639 mmol). The mixture was diluted with DMF (20 mL) and H 2 O (6.7 mL), 27 was added and the mixture was stirred at rt. After 21.5 h, the mixture was filtered through a plug of celite which was washed with a DCM:MeOH mixture (4:1). The filtrate was partially concentrated under reduced pressure until solids formed. The solids were dissolved in EtOAc (100 mL), and the organic layer was washed with H 2 O (3 x 75 mL) followed by brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the product as an off white solid (1.0 g, 1.63 mmol, 100% yield) which was used with no additional purification in the next step. LCMS: m/e 612.3 (MH + ), 1.06 min (Method 1). 1 H NMR (400 MHz, chloroform-d) δ 7.87 (s, 1H), 7.67–7.62 (m, 2H), 7.57–7.51 (m, 1H), 7.43–7.21 (m, 7H), 6.94–6.88 (m, 2H), 5.58 (dd, J = 10.8, 9.5 Hz, 1H), 5.42 (s, 1H), 5.16 (dd, J = 11.0, 3.1 Hz, 1H), 4.87 (d, J = 9.7 Hz, 1H), 4.47 (dd, J = 12.7, 1.4 Hz, 1H), 4.41 (dd, J = 3.1, 0.9 Hz, 1H), 4.08 (dd, J = 12.7, 1.7 Hz, 1H), 3.86 (s, 3H), 3.79 (d, J = 1.1 Hz, 1H), 1.93 (s, 3H). 19 F NMR (377 MHz, chloroform-d) δ -114.97 (s, 1F). (30) (2S,3R,4S,5R,6R)-4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-2-(phenylthio)tetrahydro-2H-pyran-3-yl acetate. To a flask containing 29 (1.13 g, 1.846 mmol, combined from two lots) was added AcOH (20 mL) and H 2 O (5 mL). The mixture was warmed to 60°C. After 2h, the mixture was cooled to rt and the solvent was concentrated under reduced pressure. The mixture was diluted with DCM and concentrated two additional times to give the crude product which was used in the next step with no additional purification. LCMS: m/e 494.2 (MH + ), 0.89 min (Method 1). (31) (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(phenylthio)tetrahydro-2H-pyran-3,5-diyl diacetate. To a suspension of the crude product, 30 , in dichloromethane (20 mL) was added pyridine (0.75 mL, 9.23 mmol) followed by DMAP (5.6 mg, 0.046 mmol) and acetyl chloride (0.40 mL, 5.54 mmol). The mixture is stirred at rt for 43 h then was concentrated under reduced pressure and was purified by flash chromatography using a 10–70% EtOAc in hexanes gradient and a 40g silica gel column. The fractions containing the product were combined and concentrated under reduced pressure to give the title product as a light-yellow solid (1.04 g, 1.80 mmol, 98% yield). LCMS: m/e 578.3 (MH + ), 0.99 min (Method 1). 1 H NMR (500 MHz, chloroform-d) δ 7.78 (s, 1H), 7.64–7.55 (m, 3H), 7.52–7.42 (m, 2H), 7.40–7.34 (m, 3H), 5.73 (t, J = 10.3 Hz, 1H), 5.58 (d, J = 3.0 Hz, 1H), 5.19 (dd, J = 11.0, 3.0 Hz, 1H), 4.89 (d, J = 9.6 Hz, 1H), 4.22–4.10 (m, 3H), 2.06 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H). 19 F NMR (471 MHz, chloroform-d) δ -114.50 (s, 1F). (32) (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-bromo-4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate. A solution of 31 (1.04 g, 1.80 mmol) in dichloromethane (20 mL) was cooled to 0°C and a solution of bromine (0.185 mL, 3.60 mmol) in dichloromethane (2 mL) was added slowly. The mixture was stirred at 0°C for 2h, then was diluted with sat. aq. sodium thiosulfate (50 mL) and was stirred until the red color had subsided. The mixture was extracted with dichloromethane (3 x 30 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 5–50% EtOAc in hexanes gradient and an 80g silica gel column. The fractions containing the product were combined and concentrated under reduced pressure to give the title product as an off-white solid (0.67 g, 1.22 mmol, 68% yield). LCMS: m/e 548.1, 550.1 (MH + ), 0.95 min (Method 1). 1 H NMR (400 MHz, chloroform-d) δ 7.81 (s, 1H), 7.63 (dd, J = 9.8, 1.9 Hz, 1H), 7.55–7.51 (m, 1H), 7.49–7.43 (m, 1H), 6.90 (d, J = 3.7 Hz, 1H), 5.82 (dd, J = 11.3, 3.9 Hz, 1H), 5.64 (dd, J = 2.9, 1.3 Hz, 1H), 5.33 (dd, J = 11.2, 3.1 Hz, 1H), 4.68–4.63 (m, 1H), 4.28–4.22 (m, 1H), 4.18–4.12 (m, 1H), 2.08 (s, 6H), 1.97 (s, 3H). 19 F NMR (377 MHz, chloroform-d) δ -114.48 (s, 1F). (33) (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-azido-4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate. To a solution of 32 (0.67 g, 1.221 mmol) in DMF (15 mL) was added sodium azide (0.238 g, 3.66 mmol) and the mixture was heated to 75 ° C. After 15h of heating, the mixture was cooled to rt, diluted with H 2 O (40 mL) and extracted with EtOAc (2 x 40 mL). The organic layers were washed with H 2 O 4 x 40 mL), then with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 20–60% EtOAc in hexanes gradient and an 80g silica gel column. The fractions containing the product were combined and concentrated under reduced pressure to give the title product as a white solid (0.54 g, 1.06 mmol, 87% yield). LCMS: m/e 511.3 (MH + ), 0.92 min (Method 1). 1 H NMR (400 MHz, chloroform-d) δ 7.81 (s, 1H), 7.61 (dd, J = 9.9, 1.8 Hz, 1H), 7.54–7.41 (m, 2H), 5.66 (dd, J = 11.4, 8.6 Hz, 1H), 5.60 (d, J = 3.1 Hz, 1H), 5.16 (dd, J = 11.4, 3.3 Hz, 1H), 4.82 (d, J = 8.4 Hz, 1H), 4.26–4.16 (m, 3H), 2.08 (s, 6H), 1.97 (s, 3H). 19 F NMR (377 MHz, chloroform-d) δ -114.41 (s, 1F). (34) (2R,3R,4S,5R,6R)-2-azido-4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol. To a suspension of 33 (0.54g, 1.06 mmol) in MeOH (20 mL) was added sodium methoxide (25% in MeOH) (0.024 mL, 0.106 mmol) and the mixture was stirred at rt. After 2h LC/MS showed the reaction was complete. To the mixture was added 0.25 mL of 1N HCl and it was concentrated under reduced pressure. The residue was diluted with H 2 O (25 mL) and extracted with EtOAc (3 x 25 mL). The organic layers were washed with brine and dried over magnesium sulfate filtered and concentrated under reduced pressure to give the title product as an off-white solid (0.365 g, 0.949 mmol, 89% yield). LCMS: m/e 385.2 (MH + ), 0.67 min (Method 1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.76 (s, 1H), 7.91 (dd, J = 10.7, 1.9 Hz, 1H), 7.78 (dd, J = 8.4, 1.5 Hz, 1H), 7.70–7.64 (m, 1H), 5.81 (d, J = 6.6 Hz, 1H), 5.40 (d, J = 6.4 Hz, 1H), 4.87 (dd, J = 10.9, 3.0 Hz, 1H), 4.78 (t, J = 5.6 Hz, 1H), 4.74 (d, J = 8.4 Hz, 1H), 4.13–4.04 (m, 1H), 3.92 (dd, J = 6.3, 3.0 Hz, 1H), 3.86 (t, J = 6.4 Hz, 1H), 3.60–3.49 (m, 2H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -115.85 (s, 1F). (3) (2R,2'R,3R,3'R,4S,4'S,5R,5'R,6R,6'R)-6,6'-(propane-1,3-diylbis(1H-1,2,3-triazole-4,1-diyl))bis(4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol). To a flask containing 34 (23 mg, 0.06 mmol) was added copper(II) sulfate pentahydrate (21 mg, 0.084 mmol) and sodium ascorbate (24 mg, 0.120 mmol). The mixture was diluted with DMF (0.5 mL) and H 2 O (0.167 mL). 1,6-heptadiyne (1M in THF) (0.030 mL, 0.030 mmol) was added and the mixture was stirred at rt for 5h. The mixture was filtered through a plug of glass wool to remove the solids and the filtrate was concentrated under a stream of nitrogen. The residue was diluted with DMF and was filtered through a plug of celite. The filtrate was purified by preparative HPLC using an XBridge C18, 200 mm x 19 mm, 5-µm particles column; mobile phase A: 5:95 MeCN: H 2 O with 10-mM ammonium acetate; mobile phase B: 95:5 MeCN: H 2 O with 10-mM ammonium acetate; gradient: a 0-minute hold at 20% B, 20–60% B over 20 minutes, then a 4-minute hold at 100% B; flow rate: 20 mL/min; column temperature: 25°C. Fraction collection was triggered by MS and UV signals. Fractions containing the product were combined and dried via centrifugal evaporation to give the title product (8.6 mg, 0.01 mmol, 33% yield) with a 98% HPLC purity. LCMS: m/e 861.03 (MH + ), 1.59 min (Method 2). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.78 (s, 2H), 8.14 (s, 2H), 7.89 (br d, J = 10.7 Hz, 2H), 7.76 (br d, J = 8.2 Hz, 2H), 7.72–7.66 (m, 2H), 5.83 (d, J = 8.9 Hz, 2H), 5.68 (d, J = 7.0 Hz, 2H), 5.50 (d, J = 6.7 Hz, 2H), 5.16–5.09 (m, 2H), 4.91–4.80 (m, 4H), 4.11–4.01 (m, 4H), 3.55 (br t, J = 5.8 Hz, 2H), 2.78 (br t, J = 7.3 Hz, 4H), 2.03 (quin, J = 7.1 Hz, 2H). Several protons in the aliphatic region near the H 2 O peak were obscured because of H 2 O suppression used while processing the NMR. 98.4% purity based on two HPLC methods. (4) (2R,2'R,3R,3'R,4S,4'S,5R,5'R,6R,6'R)-6,6'-(pentane-1,5-diylbis(1H-1,2,3-triazole-4,1-diyl))bis(4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol). To a flask containing 34 (26 mg, 0.068 mmol) was added copper (II) sulfate pentahydrate (24 mg, 0.095 mmol) and sodium ascorbate (27 mg, 0.135 mmol). The mixture was diluted with DMF (0.5 mL) and H 2 O (0.167 mL), 1,8-nonadiyne (1M in THF) (0.034 mL, 0.034 mmol) was added and the mixture was stirred at rt for 5h. The mixture was filtered through a plug of glass wool to remove the solids then was concentrated under a stream of nitrogen. The residue was diluted with H 2 O (1 mL) and was extracted with dichloromethane (3 x 1 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The aqueous layer was concentrated under a stream of nitrogen. The concentrated organic layer gave only 4mg of material, so the concentrated aqueous layer was diluted with DMF and was filtered through a plug of glass wool. The filtrate was combined with the organic extract and the mixture was filtered through a plug of celite then was purified by preparative HPLC using an XBridge C18, 200 mm x 19 mm, 5-µm particles column; mobile phase A: 5:95 MeCN: H 2 O with 10-mM ammonium acetate; mobile phase B: 95:5 MeCN: H 2 O with 10-mM ammonium acetate; gradient: a 0-minute hold at 20% B, 20–60% B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25°C. Fraction collection was triggered by MS signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title product (7.1 mg, 0.008 mmol, 24% yield) with 97% HPLC purity. LCMS: m/e 889.21 (MH + ), 1.66 min (Method 2). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.66 (s, 2H), 8.07 (s, 2H), 7.82 (br d, J = 9.8 Hz, 2H), 7.71 (br d, J = 8.5 Hz, 2H), 7.67–7.60 (m, 2H), 5.84 (br d, J = 7.3 Hz, 2H), 5.76 (d, J = 8.9 Hz, 2H), 5.67 (br d, J = 6.7 Hz, 2H), 5.11–5.02 (m, 2H), 4.85–4.74 (m, 2H), 4.09–3.74 (m, 7H), 3.53 (br s, 3H), 2.65 (br t, J = 7.5 Hz, 4H), 1.73–1.56 (m, 4H), 1.45–1.32 (m, 2H). 99.0% purity based on 2 HPLC runs. (36) 2-(((2S,4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)AcOH. A solution of 35 (0.291 g, 0.410 mmol) in THF (5 mL) was cooled to 0°C and sodium hydride (0.082 g, 2.051 mmol) was added. The mixture was stirred for 15 minutes and ethyl bromoacetate (0.183 mL, 1.641 mmol) was added. The mixture was allowed to warm to rt as the ice bath melted and after 17.5h, the reaction was carefully quenched with EtOH and the mixture was concentrated under reduced pressure. The residue was diluted with H 2 O (20 mL) and was extracted with EtOAc (2 x 30 mL). The organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 10–80% EtOAc in hexanes gradient and a 40g silica gel column. Fractions containing the product were combined and concentrated under reduced pressure to give the carboxylate product as an off-white foam (207 mg, 0.260 mmol, 63% yield). LCMS: m/e 795.4 (MH + ), 1.12 min (Method 1). 1 H NMR (400 MHz, chloroform-d) δ 8.18 (s, 1H), 7.80 (br d, J = 8.4 Hz, 2H), 7.65 (dd, J = 8.7, 1.0 Hz, 1H), 7.47–7.40 (m, 7H), 5.49 (s, 1H), 5.13 (dd, J = 10.6, 3.5 Hz, 1H), 4.86 (br t, J = 9.2 Hz, 1H), 4.41 (d, J = 3.1 Hz, 1H), 4.36 (d, J = 9.0 Hz, 1H), 4.33 (dd, J = 12.8, 1.1 Hz, 1H), 4.05 (dd, J = 12.7, 1.2 Hz, 1H), 4.01–3.84 (m, 3H), 3.67 (br d, J = 15.6 Hz, 1H), 3.58 (s, 1H), 2.45 (s, 3H), 1.11 (t, J = 7.2 Hz, 3H). To a suspension of the carboxylate (0.207 g, 0.260 mmol) in MeOH (5 mL) was added sodium methoxide (25% in MeOH) (0.030 mL, 0.130 mmol) and the mixture was stirred at rt. After 2h, the mixture was diluted with 1,4-dioxane (5 mL) and sodium hydroxide (1N) (1.301 mL, 1.301 mmol) was added. The mixture was stirred at rt for 2h, then was concentrated under reduced pressure, diluted with a solution of sat. aq. ammonium chloride and was extracted with EtOAc (3 x 30 mL). The organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title product (0.20 g, 0.26 mmol, 100% yield) as an off-white solid. LCMS: m/e 767.5 (MH + ), 1.02 min (Method 1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.59 (br s, 1H), 9.27 (s, 1H), 8.31–8.13 (m, 1H), 8.09–8.02 (m, 1H), 7.96 (br d, J = 8.4 Hz, 1H), 7.82 (br d, J = 8.4 Hz, 2H), 7.37 (s, 5H), 5.54 (s, 1H), 5.47 (br dd, J = 10.7, 3.0 Hz, 1H), 4.87 (br t, J = 9.1 Hz, 1H), 4.62 (br d, J = 9.2 Hz, 1H), 4.43 (br d, J = 2.9 Hz, 1H), 4.12–4.03 (m, 1H), 3.99–3.78 (m, 3H), 3.67–3.51 (m, 1H), 2.33 (s, 3H). (37) 2-(((2S,4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-N-(hex-5-yn-1-yl)acetamide. To a flask containing a solution of 36 (50 mg, 0.065 mmol) in DMF (1 mL) and triethylamine (0.036 mL, 0.261 mmol) was added hex-5-yn-1-amine (9.5 mg, 0.098 mmol) followed by HATU (49.5 mg, 0.130 mmol). The mixture was stirred at rt for 1.75 h, then was diluted with H 2 O (5 mL) and was extracted with EtOAc (3 x 5 mL). The organic layers were washed with H 2 O (3 x 10 mL), then with brine, dried over sodium sulfate filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a 10–70% EtOAc in hexanes gradient and a 24g silica gel column. The fractions containing the product were combined and concentrated under reduced pressure to give the title product (40 mg, 0.047 mmol, 72% yield) as a white solid. LCMS: m/e 846.5 (MH + ), 1.08 min (Method 1). 1 H NMR (400 MHz, Chloroform-d) δ 8.15 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.69–7.59 (m, 2H), 7.49–7.34 (m, 7H), 6.12–6.02 (m, 1H), 5.50 (s, 1H), 5.11 (dd, J = 10.5, 3.4 Hz, 1H), 4.80–4.68 (m, 1H), 4.41 (d, J = 2.9 Hz, 1H), 4.36 (br d, J = 8.8 Hz, 1H), 4.26 (br d, J = 12.8 Hz, 1H), 4.05 (d, J = 11.4 Hz, 1H), 3.94–3.84 (m, 1H), 3.57 (s, 1H), 3.43 (d, J = 14.5 Hz, 1H), 3.15–2.98 (m, 2H), 2.45 (s, 3H), 2.17 (td, J = 6.7, 2.6 Hz, 2H), 1.93 (t, J = 2.8 Hz, 1H), 1.53–1.40 (m, 4H). Preparation of 2-(((2S,4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-N-(4-(1-((2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-4-yl)butyl)acetamide : To a flask containing 37 (23 mg, 0.027 mmol) was added copper (II) sulfate pentahydrate (9.50 mg, 0.038 mmol) and sodium ascorbate (10.76 mg, 0.054 mmol) followed by 38 (12mg, 0.030 mmol). The mixture was diluted with DMF (0.5 mL) and H 2 O (0.167 mL) and was stirred at rt for 64h then was diluted with H 2 O (2 mL) and extracted with EtOAc (4 x 2 mL). The organic layers were washed with H 2 O (4 x 8 mL), then with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product (30 mg, 0.024 mmol, 89% yield) as an off-white solid which was used in the next step with no additional purification. LCMS: m/e 1250.9 (MH + ), 1.03 min (Method 1). (5) 2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(4-(1-((2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-4-yl)butyl)acetamide. To a vial containing the crude dimerized product (30 mg, 0.024 mmol) was added AcOH (0.5 mL) and H 2 O (0.167 mL). The vial was sealed and the mixture was heated to 70°C for 15.5h. The mixture was cooled to rt then was concentrated under a stream of nitrogen. K 2 CO 3 (35 mg) was added and the mixture was diluted with MeOH (0.5 mL) and H 2 O (0.25 mL). After stirring for 1h at rt, the mixture was diluted with 2 mL of H 2 O and extracted with dichloromethane (4 x 2 mL) followed by chloroform : MeOH (4 : 1, 2 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. Only 6 mg of crude material was isolated, so the aqueous layer was concentrated under a stream of nitrogen then was diluted with 1 mL of DMF and stirred for several minutes. The mixture was filtered through a plug of celite to remove the solids and filtrate was combined with the organic residue and was purified by preparative HPLC using an XBridge C18, 200 mm x 19 mm, 5-µm particles column; mobile phase A: 5:95 MeCN: H 2 O with 10-mM ammonium acetate; mobile phase B: 95:5 MeCN: H 2 O with 10-mM ammonium acetate; gradient: a 0-minute hold at 30% B, 30–70% B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25°C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title product (9.1 mg, 0.0078 mmol, 33% yield over 2 steps). LCMS: m/e 1160.2 (MH + ), 1.83 min (Method 2). Key 1 H NMR peaks: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.07–8.98 (m, 1H), 8.80–8.70 (m, 1H), 8.04–7.97 (m, 2H), 7.94–7.88 (m, 2H), 7.84–7.72 (m, 4H), 6.99–6.76 (m, 1H), 2.32 (s, 3H), 1.46–1.34 (m, 2H), 1.28–1.15 (m, 2H). 99.0% purity based on 2 HPLC runs. (40) Tert-butyl 2-(((2S,4aR,6S,7R,8R,8aR)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetate. A solution of 39 (0.536 g, 0.813 mmol) in THF (10 mL) was cooled to 0°C and sodium hydride (60% mineral oil dispersion) (0.098 g, 2.438 mmol) was added. The mixture was stirred for 15 minutes and tert-butyl bromoacetate (0.238 mL, 1.626 mmol) was added. The mixture was allowed to warm to rt as the ice bath melted and the mixture was stirred at rt for 24h. The mixture was carefully diluted with 20 mL of H 2 O and was extracted with EtOAc (3 x 20 mL). The organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a 10–50% EtOAc in hexanes gradient and a 40g silica gel column. The fractions containing the product were combined and concentrated under reduced pressure to give the title product as a white solid (0.494g, 0.64 mmol, 79% yield). LCMS: m/e 773.5 (MH + ), 1.14 min (Method 1). 1 H NMR (400 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.79–7.67 (m, 1H), 7.56–7.38 (m, 9H), 5.48 (s, 1H), 5.12 (dd, J = 10.5, 3.4 Hz, 1H), 4.91–4.76 (m, 1H), 4.47–4.39 (m, 2H), 4.34 (dd, J = 12.8, 1.1 Hz, 1H), 4.05 (dd, J = 12.8, 1.5 Hz, 1H), 3.89–3.76 (m, 1H), 3.65–3.55 (m, 2H), 2.46 (s, 3H), 1.28 (s, 9H). (41) 2-(((2S,3R,4S,5R,6R)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)AcOH. To a solution of tert-butyl ester 40 (0.494 g, 0.639 mmol) in dichloromethane (4 mL) was added TFA (2 ml, 26.0 mmol) and the mixture was stirred at rt for 38 h, then was concentrated under reduced pressure. The residue was treated with a solution of 1,3-diaminopropane (1M in THF) to decompose the anhydride that was apparent in the LC/MS and the mixture was stirred at rt for 66 h, then was diluted with several drops of MeOH and was purified by flash chromatography using a 0–15% MeOH in DCM gradient and a 40g silica gel column. Fractions containing the product were combined and concentrated under reduced pressure to give the title product as an off-white solid (0.09 g, 0.14 mmol, 22% yield). LCMS: m/e 629.3 (MH + ), 0.76 min (Method 1). 1 H NMR (400 MHz, chloroform-d) δ 8.24 (s, 1H), 7.60–7.45 (m, 5H), 4.89–4.76 (m, 2H), 4.69–4.60 (m, 1H), 4.36 (d, J = 2.0 Hz, 1H), 4.12–4.04 (m, 1H), 3.74–3.51 (m, 4H), 3.44 (d, J = 15.6 Hz, 1H), 2.49 (s, 3H). (42) 2-(((2S,3R,4R,5R,6R)-5-acetoxy-6-(acetoxymethyl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)AcOH. To a suspension of carboxylic acid 41 (0.089 g, 0.14 mmol) in dichloromethane (2 mL) was added pyridine (0.1 mL, 1.236 mmol), DMAP (0.864 mg, 7.07 µmol) and acetyl chloride (0.075 mL, 1.055 mmol). The mixture was stirred at rt for 63h, then was concentrated under reduced pressure. The residue was purified by flash chromatography using a 0–10% EtOAc in DCM gradient followed by 10% MeOH in DCM gradient. The fractions containing product were combined and concentrated under reduced pressure to give the title product as an off-white solid which was used in the next step with no additional purification. LCMS: m/e 713.4 (MH + ), 0.89 min (Method 1). (7) 2-(((2R,3S,4R,5S,6S)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)-N-(2-(2-(((2S,3R,4S,5R,6R)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)ethyl)acetamide. To a flask containing a solution of 42 (0.036 g, 0.050 mmol) in DMF (2 mL) and triethylamine (0.035 mL, 0.252 mmol) was added HATU (0.058 g, 0.151 mmol) followed by ethylenediamine (1M in DMF) (0.040 mL, 0.040 mmol). The mixture was stirred at rt for 24 h then was filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with TFA buffer. The fractions containing the product were concentrated under reduced pressure to give the dimer as a white solid (7 mg, 0.0048 mmol, 19% yield). LCMS: m/e 1452.0 (MH + ), 1.03 min (Method 1). To the dimer (0.007 g, 4.82 µmol) in MeOH (1 mL) was added sodium methoxide (25% solution in MeOH) (1.1 µl, 4.8 µmol). The mixture was stirred at rt for 16h. Three drops of 1N HCl was added and the mixture was concentrated under a stream of nitrogen. The mixture was diluted with DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with ammonium acetate buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the title product (2.7 mg, 0.0021 mmol, 42% yield). LCMS: m/e 1281.33 (MH + ), 1.84 min (Method 2). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.96 (s, 2H), 7.87–7.57 (m, 10H), 6.96 (br s, 2H), 5.50–5.34 (m, 2H), 5.08 (br d, J = 10.1 Hz, 2H), 4.80–4.55 (m, 4H), 4.40 (br d, J = 9.2 Hz, 2H), 4.10–3.31 (m, 8H), 2.70–2.58 (m, 4H), 2.27 (br s, 6H). 96.4% purity based on two HPLC methods. (8) 2-(((2R,3S,4R,5S,6S)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)-N-(3-(2-(((2S,3R,4S,5R,6R)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)propyl)acetamide. To a flask containing a solution of 42 (0.034 g, 0.048 mmol) in DMF (1 mL) and triethylamine (0.033 mL, 0.238 mmol) was added HATU (0.054 g, 0.143 mmol) followed by 1,3-diaminopropane (1M in DMF) (0.038 mL, 0.038 mmol). The mixture was stirred at rt for 24h, then was filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with TFA buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the dimerized product (7 mg, 0.0047 mmol, 20% yield) as a white solid. LCMS: m/e 1466.1 (MH + ), 1.03 min (Method 1). To a solution of the dimer (0.007 g, 4.7 µmol) in MeOH (1 mL) was added sodium methoxide (25% in MeOH) (1.1 µl, 4.78 µmol) and the mixture was stirred at rt for 16h. Three drops of 1N HCl was added and the mixture was concentrated under a stream of nitrogen. The mixture was diluted with DMF, filtered through a plug of glass wool and was purified using a C18 column and a H 2 O /MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title product (1.9 mg, 0.0015 mmol, 30% yield). LCMS: m/e 1295.86 (MH + ), 1.84 min (Method 2). 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.03–8.89 (m, 2H), 7.85–7.59 (m, 10H), 6.91–6.69 (m, 2H), 5.42 (br d, J = 5.8 Hz, 2H), 5.10 (br d, J = 13.4 Hz, 2H), 4.73 (br t, J = 9.8 Hz, 2H), 4.64–4.55 (m, 2H), 4.48–4.37 (m, 2H), 3.93–3.85 (m, 2H), 3.77 (br d, J = 15.0 Hz, 2H), 3.65–3.52 (m, 2H), 5.33–3.14 (m, 2H), 2.67–2.54 (m, 4H), 2.27 (s, 6H), 1.14–0.85 (m, 2H). 95.2% purity based on two HPLC methods. (9) 2-(((2R,3S,4R,5S,6S)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)-N-(4-(2-(((2S,3R,4S,5R,6R)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)butyl)acetamide. To a flask containing a solution of 42 (0.031 g, 0.043 mmol) in DMF (1 mL) and triethylamine (0.030 mL, 0.217 mmol) was added HATU (0.050 g, 0.130 mmol) followed by 1,4-diaminobutane (1M in DMF) (0.035 mL, 0.035 mmol). The mixture was stirred at rt for 24h, then was filtered through a plug of glass wool and was purified by prep HPLC using a C18 column and a H 2 O /MeCN gradient with TFA buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the dimerized product (7 mg, 0.0047 mmol, 22% yield) as a white solid. LCMS: m/e 1480.0 (MH + ), 1.02 min (Method 1). To a solution of the dimer (0.007 g, 4.7 µmol) in MeOH (0.5 mL) was added sodium methoxide (25% in MeOH) (1.3 µl, 5.55 µmol) and the mixture was stirred at rt for 16h at rt. Three drops of 1N HCl were added and the mixture was concentrated under a stream of nitrogen, diluted with DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title product (2.4 mg, 0.0018 mmol, 38% yield). LCMS: m/e 1309.09 (MH + ), 1.86 min (Method 2). Key 1 H NMR peaks: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.03 (s, 2H), 7.89–7.58 (m, 10H), 6.79–6.61 (m, 2H), 2.34 (s, 6H), 0.96 (br s, 4H). 97.6% purity based on two HPLC methods. (10) 2-(((2R,3S,4R,5S,6S)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)-N-(5-(2-(((2S,3R,4S,5R,6R)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)pentyl)acetamide. To a flask containing a solution of 42 (0.056 g, 0.078 mmol) in DMF (2 mL) and triethylamine (0.055 mL, 0.392 mmol) was added HATU (0.090 g, 0.235 mmol) followed by 1,5-diaminopentane (9.2 µl, 0.08 mmol). The mixture was stirred at rt for 45h, then was diluted with H 2 O (15 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with H 2 O (3 x 15 mL), then with brine and were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a 10–75% EtOAc in hexanes gradient and a 24g silica gel column. When the product did not elute, the solvent system was changed to a 0–10% MeOH in DCM gradient. The fractions containing the major product were combined and concentrated under reduced pressure to give the dimer (0.02 g, 0.013 mmol, 33% yield) as an off-white film. LCMS: m/e 1494.2 (MH + ), 1.02 min (Method 1). To a solution of the dimer (0.02 g, 0.013 mmol) in MeOH (1.0 mL) was added sodium methoxide (25% solution in MeOH) (3.0 ml, 0.013 mmol) and the mixture was stirred at rt. After 2.5 h of stirring at rt, 5 drops of 1N HCl were added and the mixture was concentrated under reduced pressure. The residue was diluted with DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with ammonium acetate buffer. Fractions containing the products were concentrated under reduced pressure to give the title product (10.2 mg, 0.0076 mmol, 58% yield). LCMS: m/e 1323.66 (MH + ), 1.85 min (Method 2). Key 1 H NMR peaks: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.96 (s, 2H), 7.84–7.62 (m, 10H), 6.62 (br s, 2H), 2.30 (s, 6H), 1.04–0.92 (m, 4H), 0.79 (br d, J = 6.4 Hz, 2H). 97.3% purity based on two HPLC methods. (44) 2-(((2S,4aR,6S,7R,8R,8aR)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)AcOH. A solution of 43b (0.442 g, 0.654 mmol) in THF (10 mL) was cooled to 0°C and sodium hydride (60% dispersion in mineral oil) (0.131 g, 3.27 mmol) was added. The mixture was stirred for 15 minutes and ethyl bromoacetate (0.291 mL, 2.62 mmol) was added. The mixture was warmed to rt as the ice bath melted and was stirred for 15.5 h. The reaction was carefully quenched with EtOH and the mixture was concentrated under reduced pressure. The residue was diluted with H 2 O (20 mL) and extracted with EtOAc (2 x 30 mL). The organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a 10–80% EtOAc in hexanes gradient and a 40g silica gel column. Fractions containing the product were combined and concentrated under reduced pressure to give the ethyl ester as an off-white solid (422 mg, 0.554 mmol, 85% yield). LCMS: m/e 761.3 (MH + ), 1.11 min (Method 1). 1 H NMR (400 MHz, chloroform-d) δ 8.17 (s, 1H), 7.68 (br d, J = 0.9 Hz, 1H), 7.54–7.38 (m, 9H), 5.49 (s, 1H), 5.15 (dd, J = 10.6, 3.5 Hz, 1H), 4.91–4.79 (m, 1H), 4.46–4.40 (m, 2H), 4.34 (dd, J = 12.8, 1.1 Hz, 1H), 4.05 (dd, J = 12.8, 1.5 Hz, 1H), 4.00–3.89 (m, 3H), 3.68 (br d, J = 15.8 Hz, 1H), 3.63 (s, 1H), 2.46 (s, 3H), 1.11 (t, J = 7.2 Hz, 3H). To a solution of the carboxylate (422 mg, 0.554 mmol) in MeOH (3 mL) and 1,4-dioxane (3 mL) was added 1N sodium hydroxide (2.77 mL, 2.77 mmol) and the mixture was stirred at rt. After 40 h of stirring the mixture at rt, it was concentrated under reduced pressure, diluted with sat. aq. Ammonium chloride (25 mL) and the solids that formed were collected by filtration and were washed with excess H 2 O and diethyl ether. The title product was isolated as a white solid (0.307 g, 0.418 mmol, 75% yield) LCMS: m/e 733.4 (MH + ), 1.01 min (Method 1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.34 (s, 1H), 8.36–8.21 (m, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.81–7.76 (m, 1H), 7.75–7.69 (m, 1H), 7.37 (s, 5H), 5.55 (s, 1H), 5.44 (dd, J = 10.9, 3.4 Hz, 1H), 4.88–4.76 (m, 1H), 4.57 (d, J = 9.2 Hz, 1H), 4.44 (d, J = 3.5 Hz, 1H), 4.11–3.98 (m, 2H), 3.87 (s, 1H), 3.71–3.51 (m, 1H), 3.47–3.35 (m, 1H), 2.34 (s, 3H). (11) 2-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(2-(2-(((2S,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)ethyl)acetamide. To a flask containing a solution of 44 (40 mg, 0.055 mmol) in DMF (1 mL) and triethylamine (0.038 mL, 0.273 mmol) was added ethane-1,2-diamine (1M in DMF) (0.027 mL, 0.027 mmol) followed by HATU (62.2 mg, 0.164 mmol). The mixture was stirred at rt for 40 h, then was diluted with 2 mL of H 2 O and was extracted with dichloromethane (3 x 2 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with TFA buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the dimer (0.023g, 0.0154 mmol, 56% yield) as a white solid. LCMS: m/e 1489.9 (MH + ), 1.19 min (Method 1). To a solution of the dimer (0.023 g, 0.015 mmol) in AcOH (0.5 mL) was added H 2 O (0.167 mL) and the mixture was heated to 70°C. After heating the mixture for 30 h, it was cooled to rt and was concentrated under a stream of nitrogen. To the residue was added 0.035 g of K 2 CO 3 and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H 2 O. The mixture was stirred at rt for 3 days, then was diluted with H 2 O (1 mL) and extracted with dichloromethane (3 x 1 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with ammonium acetate buffer. The fractions containing the product were combined and concentrated under reduced pressure to give the title product (6.8 mg, 0.0052, 35% yield). LCMS: m/e 1316.1 (MH + ), 1.93 min (Method 2). Key 1 H NMR peaks: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.94 (dd, J = 5.4, 2.5 Hz, 2H), 7.79–7.58 (m, 10H), 7.01 (br d, J = 1.3 Hz, 2H), 2.26 (s, 6H). 100% purity based on two HPLC methods. (12) 2-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(4-(2-(((2S,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)butyl)acetamide. To a flask containing a solution of 44 (40 mg, 0.055 mmol) in DMF (1 mL) and triethylamine (0.038 mL, 0.273 mmol) was added butane-1,4-diamine (1M in DMF) (0.027 mL, 0.027 mmol) followed by HATU (62.2 mg, 0.164 mmol). The mixture was stirred at rt for 64h, then was diluted with 2 mL of H 2 O and was extracted with dichloromethane (3 x 2 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-100% MeOH in dichloromethane gradient and a 24g silica gel column. Fractions containing the product were combined and concentrated under reduced pressure to give the dimer product (0.022 g, 0.0145, 53% yield) as an off-white solid. LCMS: m/e 1520.1 (MH + ), 1.18 min (Method 1). To a solution of the dimer (22 mg, 0.014 mmol) in AcOH (0.5 mL) was added H 2 O (0.167 mL) and the mixture was heated to 70°C. After 21 h of heating, the mixture was cooled to rt and was concentrated under a stream of nitrogen. To the residue was added 0.035g of K 2 CO 3 and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H 2 O. The mixture was stirred at rt for 20 h, then was diluted with H 2 O (1 mL) and extracted with dichloromethane (3 x 1 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with ammonium acetate buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the title product (9.8 mg, 0.0073 mmol, 52% yield). LCMS: m/e 1341.8 (MH + ), 1.94 min (Method 2). Key 1 H NMR peaks: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.03–8.88 (m, 2H), 7.81–7.61 (m, 10H), 6.86–6.60 (m, 2H), 2.27 (s, 6H), 0.87 (br s, 4H). 100% purity based on two HPLC methods. (13) 2-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(5-(2-(((2S,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)pentyl)acetamide. To a flask containing a solution of 44 (0.04 g, 0.055 mmol) in DMF (1 mL) and triethylamine (0.038 mL, 0.273 mmol) was added 1,5-diaminopentane (1M in DMF) (0.027 mL, 0.027 mmol) followed by HATU (0.062 g, 0.164 mmol). The mixture was stirred at rt for 64 h, then was diluted with 2 mL of H 2 O and was extracted with dichloromethane (3 x 2 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with TFA buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the dimer product (0.024 g, 0.0156 mmol, 57% yield) as a white solid. LCMS: m/e 1535.3 (MH + ), 1.27 min (Method 1). A solution of the dimer (24 mg, 0.016 mmol) in AcOH (0.5 mL) and H 2 O (0.167 mL) was heated to 70°C. After heating the mixture for 67 h, it was cooled to rt and concentrated under a stream of nitrogen. To the residue was added 0.035 g of K 2 CO 3 and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H 2 O. The mixture was stirred at rt for 66 h then was diluted with H 2 O (1 mL) and extracted with dichloromethane (3 x 1 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was diluted with DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with ammonium acetate buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the title product (6.5 mg, 0.0048 mmol, 30% yield). LCMS: m/e 1357.9 (MH + ), 1.96 min (Method 2). Key 1 H NMR peaks: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.01–8.93 (m, 2H), 7.81–7.62 (m, 10H), 6.76–6.58 (m, 2H), 2.29 (s, 6H), 0.99 − 0.87 (m, 4H), 0.80 − 0.69 (m, 2H). 100% purity based on two HPLC methods. (14) 2-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(6-(2-(((2S,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)hexyl)acetamide. To a flask containing a solution of 44 (0.04 g, 0.055 mmol) in DMF (1 mL) and triethylamine (0.038 mL, 0.273 mmol) was added hexane-1,6-diamine (1M in DMF) (0.027 mL, 0.027 mmol) followed by HATU (0.062 g, 0.164 mmol). The mixture was stirred at rt for 64 h, then was diluted with 2 mL of H 2 O and was extracted with dichloromethane (3 x 2 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with TFA buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the dimer product (0.027 g, 0.017 mmol, 62% yield) as a white solid. LCMS: m/e 1546.0 (MH + ), 1.19 min (Method 1). To a solution of the dimer (27 mg, 0.017 mmol) in AcOH (0.5 mL) was added H 2 O (0.167 mL) and the mixture was heated to 70°C. After 19 h of heating, the mixture was cooled to rt and was concentrated under a stream of nitrogen. To the residue was added 0.035 g of K 2 CO 3 0.5 mL of MeOH and 0.25 mL of H 2 O. After stirring the mixture for 20 h at rt, it was diluted with H 2 O (1 mL) and extracted with dichloromethane (2 x 1 mL) then with chloroform : MeOH (4 : 1, 2 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title product (10.1 mg, 0.0074 mmol, 43% yield). LCMS: m/e 1369.96 (MH + ), 2.06 min (Method 2). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.98 (s, 2H), 7.84–7.61 (m, 10H), 6.62 (br d, J = 4.9 Hz, 2H), 5.46 (d, J = 6.1 Hz, 2H), 5.12 (dd, J = 11.0, 2.4 Hz, 2H), 4.80–4.63 (m, 4H), 4.42 (br d, J = 9.5 Hz, 2H), 3.90 (br d, J = 2.7 Hz, 2H), 3.78–2.58 (m, 10H), 2.30 (s, 6H), 0.96 (br s, 4H), 0.79 (br s, 4H). 100% purity based on two HPLC methods. (15) 2-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(7-(2-(((2S,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)heptyl)acetamide. To a flask containing a solution of 44 (0.04 g, 0.055 mmol) in DMF (2 mL) and triethylamine (0.038 mL, 0.273 mmol) was added heptane-1,7-diamine (1M in DMF) (0.027 mL, 0.027 mmol) followed by HATU (0.062 g, 0.164 mmol). The mixture was stirred at rt for 64h, then was diluted with 2 mL of H 2 O and was extracted with dichloromethane (3 x 2 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with TFA buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the dimer product (0.027 g, 0.017 mmol, 62% yield) as a white solid. LCMS: m/e 1559.9 (MH + ), 1.20 min (Method 1). To a solution of the dimer (27 mg, 0.017 mmol) in AcOH (0.5 mL) was added H 2 O (0.167 mL) and the mixture was heated to 70°C. After 19h, the mixture was cooled to rt and was concentrated under a stream of nitrogen. To the residue was added 0.035g of K 2 CO 3 and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H 2 O and was stirred at rt for 20 h. The mixture was diluted with H 2 O (1 mL) and extracted with dichloromethane (2 x 1 mL) then with chloroform : MeOH (4:1, 2 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with ammonium acetate buffer. The fractions containing the product were concentrated under reduced pressure to give the title product (16.2 mg, 0.0117 mmol, 69% yield). LCMS: m/e 1382.89 (MH + ), 2.14 min (Method 2). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.98 (s, 2H), 7.83–7.60 (m, 10H), 6.61 (br d, J = 3.7 Hz, 2H), 5.46 (d, J = 6.1 Hz, 2H), 5.12 (dd, J = 10.7, 2.7 Hz, 2H), 4.83–4.63 (m, 4H), 4.42 (d, J = 9.5 Hz, 2H), 3.91 (dd, J = 5.5, 2.7 Hz, 2H), 3.75–2.59 (m, 10H), 2.30 (s, 6H), 0.98 (br s, 4H), 0.83 (br s, 6H). 100% purity based on two HPLC methods. (16) 2-(((2R,3S,4R,5S,6S)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(3-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)propyl)acetamide. To a flask containing a solution of 36 (0.035 g, 0.046 mmol) in DMF (1 mL) and triethylamine (0.032 mL, 0.228 mmol) was added 1,3-diaminopropane (1M in DMF) (0.023 mL, 0.023 mmol) followed by HATU (0.052 g, 0.137 mmol). The mixture was stirred at rt for 43h, then was diluted with 2 mL of H 2 O and was extracted with dichloromethane (3 x 2 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with TFA buffer. Fractions containing the product were concentrated under reduced pressure. The dimerized product (25 mg, 0.016 mmol, 70% yield) was isolated as a white film. LCMS: m/e 1573.6 (MH + ), 1.19 min (Method 1). To a solution of the dimer (25 mg, 0.016 mmol) was added AcOH (0.5 mL) and H 2 O (0.167 mL) and the mixture was heated to 70°C. After heating the mixture for 17.5h, it was cooled to rt and concentrated under a stream of nitrogen. To the residue was added 0.035g of K 2 CO 3 and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H 2 O and was stirred at rt overnight for 17h. The mixture was diluted with H 2 O (1 mL) and extracted with a mixture of dichloromethane : chloroform : MeOH (1 : 1 : 0.25, 3 x 2.25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool and purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title compound (13.0 mg, 0.0093 mmol, 59% yield). LCMS: m/e 1396.8 (MH + ), 2.03 min (Method 2). Key 1 H NMR peaks: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.93 (s, 2H), 7.98–7.65 (m, 10H), 6.99–6.74 (m, 2H), 2.24 (s, 6H), 1.06–0.90 (m, 2H). 100% purity based on two HPLC methods. (17) 2-(((2R,3S,4R,5S,6S)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(4-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)butyl)acetamide. To a flask containing a solution of 36 (0.026 g, 0.034 mmol) in DMF (1 mL) and triethylamine (0.024 mL, 0.169 mmol) was added 1,4-diaminobutane (1M in DMF) (0.017 mL, 0.017 mmol) followed by HATU (0.039 g, 0.102 mmol). The mixture was stirred at rt for 43 h then was diluted with 2 mL of H 2 O and was extracted with dichloromethane (3 x 2 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with TFA buffer. Fractions containing the product were concentrated under reduced pressure. The dimerized compound (24 mg, 0.015 mmol, 88% yield) was isolated as an off-white solid. LCMS: m/e 1573.6 (MH + ), 1.19 min (Method 1). To a solution of the dimer (24 mg, 0.015 mmol) was added AcOH (0.5 mL) and H 2 O (0.167 mL) and the mixture was heated to 70°C. After 17.5 h of heating, the mixture was cooled to rt and concentrated under a stream of nitrogen. To the residue was added 0.035g of K 2 CO 3 and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H 2 O. The mixture was stirred for 5 h at rt, then was diluted with H 2 O (1 mL) and extracted with dichloromethane (3 x 1 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF and purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with TFA buffer. Fractions containing the product were concentrated under reduced pressure to give the title product (13.0 mg, 0.0092 mmol, 61% yield). LCMS: m/e 1409.19 (MH + ), 1.97 min (Method 2). Key 1 H NMR peaks: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.02 (s, 2H), 7.99–7.94 (m, 2H), 7.92–7.84 (m, 4H), 7.77 (d, J = 8.2 Hz, 4H), 6.72–6.54 (m, 2H), 2.27 (s, 6H), 0.90 (br s, 4H). 100% purity based on two HPLC methods. (18) 2-(((2R,3S,4R,5S,6S)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(5-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)pentyl)acetamide. To a flask containing a solution of 36 (37 mg, 0.048 mmol) in DMF (1 mL) and triethylamine (0.034 mL, 0.241 mmol) was added 1,5-diaminopentane (0.024 mL, 0.024 mmol) followed by HATU (55.0 mg, 0.145 mmol). The mixture was stirred at rt for 43h, then was diluted with 2 mL of H 2 O and was extracted with dichloromethane (3 x 2 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF and was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with TFA buffer. Fractions containing the product were combined and concentrated under reduced pressure. The dimer product (29 mg, 0.018 mmol, 75% yield) was isolated as a white solid. LCMS: m/e 1602.2 (MH + ), 1.19 min (Method 1). To a solution of the dimer (29 mg, 0.018 mmol) was added AcOH (0.5 mL) and H 2 O (0.167 mL) and the mixture was heated to 70°C. After 17.5 h of heating, the mixture was cooled to rt and concentrated under a stream of nitrogen. To the residue was added 0.035g of K 2 CO 3 and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H 2 O and was stirred at rt for 5h. The mixture was diluted with H 2 O (1 mL) and extracted with dichloromethane (3 x 1 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title product (15.3 mg, 0.011 mmol, 61% yield). LCMS: m/e 1423.11 (MH + ), 2.08 min (Method 2). Key 1 H NMR peaks: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.94 (s, 2H), 7.95 (d, J = 8.9 Hz, 2H), 7.91–7.80 (m, 4H), 7.72 (d, J = 8.2 Hz, 4H), 6.73–6.51 (m, 2H), 2.28 (s, 6H), 0.93 (quin, J = 7.2 Hz, 4H), 0.74 (quin, J = 7.1 Hz, 2H). 100% purity based on two HPLC methods. (23) 2-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(2-(2-(((2S,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-methylacetamido)ethyl)-N-methylacetamide. To a vial containing carboxylic acid 44 (0.168 g, 0.229 mmol) was added DMF (2 mL), TEA (0.128 mL, 0.916 mmol), N 1 ,N 2 -dimethylethane-1,2-diamine (0.092 mL, 0.092 mmol) and 1-propanephosphonic anhydride (T3P, 50% in EtOAc) (0.340 mL, 0.572 mmol). The mixture was stirred at rt for 17 h then an additional 0.046 mL of the N 1 ,N 2 -dimethylethane-1,2-diamine was added and the mixture was stirred at rt for an additional 24h. An additional 0.092 mL of N 1 ,N 2 -dimethylethane-1,2-diamine was added and the mixture was stirred at rt for an additional 24h. The mixture was diluted with H 2 O (10 mL) and was extracted with EtOAc (2 x 10 mL). The organic layers were washed with H 2 O (3 x 10 mL), then with brine and were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-100% EtOAc in dichloromethane gradient. The fractions containing the dimerized product were combined and concentrated under reduced pressure to give the product (0.095 g, 0.0625 mmol, 55% yield) as an off-white solid. LCMS: m/e 1521.4 (MH + ), 1.21 min (Method 1). To a flask containing the dimer (0.09 g, 0.059 mmol) was added AcOH (1 mL) and H 2 O (0.33 mL) and the mixture was heated to 70°C. After 19.5h of heating, the mixture was cooled to rt and was concentrated under reduced pressure. The residue was diluted with DCM and concentrated two additional times. The residue was dilute with 1 mL of MeOH and 0.5 mL of H 2 O and 0.07 g of K 2 CO 3 was added then it was stirred at rt for 5h, concentrated under reduced pressure, diluted with DMF and filtered through a plug of glass wool to remove the solids. The filtrate was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with ammonium acetate buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the title product (46.6 mg, 0.035 mmol, 59% yield). LCMS: m/e 1341.18 (MH + ), 2.08 min (Method 2). Key 1 H NMR peaks: 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.11–8.95 (m, 2H), 7.97–7.44 (m, 10H), 2.85 (s, 3H), 2.69 (s, 3H), 2.32–2.17 (m, 6H). 98.0% purity based on two HPLC methods. (24) 2-(((2R,4aS,6R,7S,8S,8aS)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-(4-(2-(((2S,4aR,6S,7R,8R,8aR)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetyl)-1,4-diazepan-1-yl)ethan-1-one. To a flask containing carboxylic acid 44 (0.05 g, 0.068 mmol) was added DMF (1 mL), TEA (0.038 mL, 0.273 mmol), homopiperazine (1M in DMF) (0.034 mL, 0.034 mmol) and 1-propanephosphonic anhydride (T3P, 50% in EtOAc) (0.101 mL, 0.170 mmol). The mixture was stirred at rt for 19 h then was diluted with H 2 O (10 mL) and was extracted with EtOAc (3 x 10 mL). The organic layers were washed with H 2 O (3 x 20 mL), then with brine and were dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give the crude dimerized product (0.048 g, 0.031 mmol, 91% yield) as an off-white solid. LCMS: m/e 1533.5 (MH + ), 1.21 min (Method 1). To a flask containing the crude dimer (0.048 g, 0.031 mmol) was added AcOH (1 mL) and H 2 O (0.33 mL). The mixture was heated to 70°C for 15h, then was cooled to rt and concentrated under reduced pressure. The residue was diluted with 2 mL of MeOH and 0.5 mL of H 2 O and 0.07g of K 2 CO 3 was added. The mixture was stirred at rt overnight, then was concentrated under reduced pressure. The residue was diluted with DMF and filtered through a plug of glass wool to remove the solids. The filtrate was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title product (15.1 mg, 0.0111 mmol, 36% yield). LCMS: m/e 1353.16 (MH + ), 2.04 min (Method 2). 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.09–8.94 (m, 2H), 7.94–7.60 (m, 12H), 5.44–5.35 (m, 2H), 5.18–5.08 (m, 2H), 4.78–4.58 (m, 4H), 4.41–4.26 (m, 2H), 3.91–3.80 (m, 2H), 3.64 (br d, J = 6.1 Hz, 2H), 2.50 (s, 14H), 2.31–2.22 (m, 6H), 1.26–1.02 (m, 2H). 100% purity based on two HPLC methods. (25) 2-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-1-(4-(2-(((2S,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetyl)piperazin-1-yl)ethan-1-one. To a vial containing carboxylic acid 44 (0.125 g, 0.170 mmol) was added DMF (2 mL), TEA (0.095 mL, 0.681 mmol), piperazine (0.5M in DMF:THF, 1:1) (0.136 mL, 0.068 mmol) and 1-propanephosphonic anhydride (T3P, 50% in EtOAc) (0.253 mL, 0.426 mmol). The mixture was stirred at rt for 17 h then was diluted with H 2 O (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layers was washed with H 2 O (3 x 20 mL) then with brine and were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude dimerized product was used in the next step with no additional purification. LCMS: m/e 1517.6 (MH + ), 1.18 min (Method 1). To a flask the crude dimer (129 mg, 0.085 mmol) was added AcOH (2 mL) and H 2 O (0.667 mL). The mixture was heated to 70°C for 18h, then was cooled to rt and concentrated under reduced pressure. The residue was diluted with 5 mL of MeOH, 2.5 mL of H 2 O and 0.07g of K 2 CO 3 was added. The mixture was stirred at rt for 24h, then was concentrated under reduced pressure. The residue was diluted with DMF, filtered through a plug of glass wool and the filtrate was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title product (46.1 mg, 0.034 mmol, 40% yield over two steps). LCMS: m/e 1339.3 (MH + ), 2.02 min (Method 2). Key 1 H NMR peaks. 1 H NMR (600 MHz, DMSO-d6) δ 9.07 (br s, 2H), 7.90–7.79 (m, 6H), 7.77 (d, J = 8.6 Hz, 2H), 7.73 (dd, J = 8.6, 2.2 Hz, 2H), 5.43 (d, J = 6.0 Hz, 2H), 5.19 (br d, J = 10.3 Hz, 2H), 4.85–4.69 (m, 2H), 4.65 (t, J = 5.5 Hz, 2H), 4.42 (br d, J = 7.9 Hz, 2H), 4.22–4.05 (m, 1H), 3.90 (br s, 2H), 3.81 (br s, 3H), 3.70 (t, J = 6.5 Hz, 2H), 3.47–3.37 (m, 4H), 2.32 (br s, 6H). 13 C NMR (126 MHz, DMSO-d 6 ) δ 166.5, 160.4, 159.9, 159.9, 158.0, 157.9, 154.4, 144.0, 135.3, 132.7, 132.3, 132.1, 130.4, 123.5, 109.5, 109.3, 107.4, 79.4, 71.6, 71.4, 68.0, 65.8, 60.2, 14.0. HRMS (m/z) calculated for [M + H] + ion species C 54 H 48 Cl 6 F 4 N 14 O 10 : 1339.1818; found 1339.1802. 100% purity based on two HPLC methods. (19) (2R,3R,4S,5R,6S)-4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-((10-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)decyl)oxy)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol. A solution of C-2 alcohol 45 in THF (2 mL) was cooled to 0°C and sodium hydride (60% mineral oil dispersion) (13.07 mg, 0.327 mmol) was added. The mixture was stirred for 15 minutes and a solution of 1,10-diiododecane (1M in THF) (0.033 mL, 0.033 mmol) was added. The mixture was stirred at 0°C and was allowed to warm to rt as the ice bath melted and warmed. After stirring the mixture for 6 days, it was carefully diluted with H 2 O (10 mL) and extracted with dichloromethane (3 x 10 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product (37 mg, 0.025 mmol, 77% yield) was used in the next step with no additional purification. LCMS: m/e 1453.9 (MH + ), 1.31 min (Method 1). To a vial containing the crude ether linked dimer (37 mg, 0.025 mmol) was added AcOH (0.5 mL) and H 2 O (0.167 mL). The mixture was heated to 70°C for 26 h then was concentrated under a stream of nitrogen. To the residue was added 35 mg of K 2 CO 3 and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H 2 O then was stirred at rt for 2h. The mixture was diluted with H2O (1 mL) and extracted with dichloromethane (3 x 1 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF and was purified by preparative HPLC using a C18 column and a H 2 O/MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title compound (8.1 mg, 0.0063 mmol, 25% yield). LCMS: m/e 1277.0 (MH + ), 2.65 min (Method 2). Key 1 H NMR peaks. 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.91 (br s, 2H), 7.86 (br d, J = 10.4 Hz, 2H), 7.79–7.48 (m, 10H), 2.30 (s, 6H), 0.81 (br d, J = 5.0 Hz, 4H), 0.65 − 0.41 (m, 12H). 93.8% purity based on two HPLC methods. (20) Preparation of (2R,3R,4S,5R,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-((8-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)octyl)oxy)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol. A solution of 43 (50 mg, 0.074 mmol) in THF (2 mL) was cooled to 0°C and a sodium hydride (60% mineral oil dispersion) (0.370 mL, 0.370 mmol) was added. The mixture was stirred for 15 minutes and a solution of 1,8-diiodooctane (0.044 mL, 0.044 mmol) was added. The mixture was stirred at 0°C and was allowed to warm to rt as the ice bath melted and warmed. After stirring for 7 days, the solvent had evaporated. An additional 1 mL of THF was added followed by 1,8-diiodooctane (0.044 mL, 0.044 mmol). After 4 additional days of stirring, the mixture was again diluted with 1 mL of THF and additional 1,8-diiodooctane (0.044 mL, 0.044 mmol) was added. After 3 days of stirring, the mixture was diluted with H 2 O (10 mL) and was extracted with EtOAc (3 x 10 mL). The organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture of products, which included a peak with the m/z of the expected product, was used in the next step with no additional purification. LCMS: m/e 1462.3 (MH + ), 1.29 min (Method 1). To a flask containing the crude mixture above was added AcOH (0.5 mL) and H 2 O (0.167 mL). The mixture was heated to 70°C for 16h. The mixture was cooled to rt then was concentrated under reduced pressure. To the residue was added K 2 CO 3 (35 mg) and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H 2 O. The mixture was stirred at rt for 4h, then was diluted with H 2 O (2 mL) and was extracted with dichloromethane (3 x 3 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF and purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with ammonium acetate buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the title product (3.7 mg, 0.0029 mmol, 8% yield over 2 steps). LCMS: m/e 1283.09 (MH + ), 2.63 min (Method 2). Key 1 H NMR peaks. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.05 (s, 2H), 7.87–7.70 (m, 8H), 7.68–7.47 (m, 2H), 2.34 (s, 6H), 0.81 − 0.68 (m, 4H), 0.58 − 0.37 (m, 8H). 97.5% purity based on two HPLC methods. (49) (2S,4aR,6S,7R,8S,8aR)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl (3-aminopropyl)carbamate. To a solution of C-2 alohol 43 (0.063 g, 0.093 mmol) in d-chloroform (2 mL) was added DMAP (1.1 mg, 9.32 µmol) followed by dipyridin-2-yl carbonate (0.101 g, 0.466 mmol). The mixture was heated to 50°C for 2 h then was cooled to rt. To the mixture was added propane-1,3-diamine (0.078 mL, 0.932 mmol) and it was stirred at rt for 4h. The mixture diluted with sat. aq. ammonium chloride and was extracted with dichloromethane (3 x 10 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a mixture of products which included a peak with the m/z of the title compound. The crude product was used in the next step with no additional purification. LCMS: m/e 777.3 (MH + ), 0.84 min (Method 1). (51) (2S,4aR,6S,7R,8S,8aR)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl pyridin-2-yl carbonate. To a solution of C-2 alcohol 43 (0.05 g, 0.074 mmol) in d-chloroform (3 mL) was added DMAP (0.9 mg, 7.40 µmol) followed by dipyridin-2-yl carbonate (0.080 g, 0.370 mmol). The mixture was heated to 50°C for 2 h then was cooled to rt, diluted with sat. aq. ammonium chloride and was extracted with dichloromethane (3 x 10 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title product. The crude product was used in the next step with no additional purification. (53) (2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl ((2S,4aR,6S,7R,8S,8aR)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl) propane-1,3-diyldicarbamate. To a flask containing the crude 49 (0.072 g, 0.093 mmol) and 51 (0.059 g, 0.074 mmol) in d-chloroform (3 mL) was added DMAP (0.9 mg, 7.40 µmol) and the mixture was stirred at rt. After 18h, the mixture was diluted with H 2 O (3 mL) and was extracted with dichloromethane (3 x 3 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool and was purified by prep HPLC using a C18 column and an MeCN/ H 2 O gradient. The fractions containing the product were combined and concentrated under reduced pressure to give a mixture of products (54 mg) including the title compound. LCMS: m/e 1479.5 (MH + ), 1.22 min (Method 1). (21) (2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl ((2S,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl) propane-1,3-diyldicarbamate. A solution of 53 (54 mg) in AcOH (0.5 mL) and H 2 O (0.167 mL) was heated to 70°C. After 15.5h, the mixture was cooled to rt and was concentrated under a stream of nitrogen. To the residue was added 0.035g of K 2 CO 3 , 0.5 mL of MeOH and 0.25 mL of H 2 O and the mixture was stirred at rt. After stirring the mixture at rt for 1h, it was further diluted with 1 mL of MeOH and was heated to 50°C. After 1 h of heating, the mixture was cooled to rt and was stirred overnight. The mixture was then heated to 50°C for 2 h, then was cooled to rt and was concentrated under a steam of nitrogen. The residue was diluted with DMF, filtered through a plug of glass wool to remove the solids and was purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with ammonium acetate buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the title product (29.0 mg, 0.022 mmol, 24% yield over 3 steps). LCMS: m/e 1299.2 (MH + ), 2.09 min (Method 2). Key 1 H NMR peaks: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.57 (br s, 2H), 7.79–7.50 (m, 10H), 2.14 (s, 6H), 0.94 (br s, 2H). 100% purity based on two HPLC methods. (48) (2S,4aR,6S,7R,8S,8aR)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-7-yl (4-aminobutyl)carbamate. To a solution of 39 (28 mg, 0.042 mmol) in d-chloroform (2 mL) was added DMAP (0.5 mg, 4.25 µmol) followed by dipyridin-2-yl carbonate (45.9 mg, 0.212 mmol). The mixture was heated to 50°C for 3h, then 1,4-diaminobutane (0.043 mL, 0.425 mmol) was added and the mixture was stirred at rt. After stirring the mixture for 22h, it was diluted with H 2 O (3 mL) and extracted with dichloromethane (3 x 3 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. LC/MS showed a mixture of products including the m/z of the expected product. The crude product was used in the next step with no additional purification. LCMS: m/e 773.8 (MH + ), 0.83 min (Method 1). (50) (2S,4aR,6S,7R,8S,8aR)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-7-yl pyridin-2-yl carbonate. To a solution of 39 (28 mg, 0.042 mmol) in d-chloroform (2 mL) was added DMAP (0.5 mg, 4.25 µmol) followed by dipyridin-2-yl carbonate (45.9 mg, 0.212 mmol). The mixture was heated to 50°C for 2.5 h then was cooled to rt. The mixture was diluted with sat. aq. ammonium chloride and was extracted with dichloromethane (3 x 10 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used in the next step with no additional purification. (52) (2S,4aR,6S,7R,8S,8aR)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-7-yl ((2S,6R,7S,8R)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-7-yl) butane-1,4-diyldicarbamate. To a flask containing the crude 50 (32.8 mg, 0.042 mmol) was added a solution of the crude mixture containing 48 (32.5 mg, 0.042 mmol) in d-chloroform (2 mL) followed by DMAP (0.26 mg, 2.100 µmol). The mixture was stirred at rt for 18h, then was diluted with H 2 O and extracted with dichloromethane (3 x 10 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a 0–50% EtOAc in DCM gradient and a 24g silica gel column. Fractions containing the product were combined and concentrated under reduced pressure to give the title product (24 mg, 0.016 mmol, 38% yield) as an off-white solid. LCMS: m/e 1460.3 (MH + ), 1.19 min (Method 1). (22) (2R,3S,4R,5S,6S)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl ((2S,3R,4S,5R,6R)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl) butane-1,4-diyldicarbamate. To a solution of dimer 52 (0.024 g, 0.016 mmol) was added AcOH (0.5 mL) and H 2 O (0.167 mL) and the mixture was heated to 70°C for 20.5 h. The mixture was cooled to rt and concentrated under a stream of nitrogen. To the residue was added 0.035g of K 2 CO 3 and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H 2 O. The mixture was stirred at rt for 3h, then was concentrated under a stream of nitrogen, diluted with DMF, filtered through a plug of glass wool and purified by preparative HPLC using a C18 column and a H 2 O /MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title product (8.2 mg, 0.0064 mmol, 40% yield). LCMS: m/e 1281.04 (MH + ), 1.91 min (Method 2). Key 1 H NMR peaks: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.49 (br s, 2H), 7.75–7.55 (m, 10H), 2.18 (s, 6H), 0.75 (br s, 4H). 98.8% purity based on two HPLC methods. In Vitro Human and Mouse Gal-3 HTRF Assays. The assays were performed in 384 white Opti plates in three replicates. From the original stocks, 2.5× working stock concentrations of His-tagged recombinant h or mGal-3 and that of B-ASF were prepared. From the working stock, 20 µL of 15 nM His-tagged h or mGal-3 and B-ASF were added to the plates. In negative control wells, one of the binding partners (B-ASF) was replaced with 20 µL of assay buffer. A concentration range of 50× working stocks was prepared for compounds in 100% DMSO. An aliquot of 1 µL compound working stocks was added to each well. The compound was preincubated with 20 µL of h or mGal-3 for 30 min. After adding 20 µL of B-ASF and incubation for additional 1 h, Terbium-labeled anti-His antibody (5 µL/well, 1.0 nM final concentration) was added and incubated for 30 min. Then, streptavidin (2.5 µL/well, 20 nM final concentration) was added and incubated for 1 h. All incubations were conducted at room temperature with gentle shaking at approx. 250 − 300 rpm. The assay plate was read using the homogeneous time-resolved fluorescence screen protocol (excitation wavelength = 340 nm and emission wavelength = 615 nm/665 nm) on an EnVision 2104 multilabel reader. IC 50 values were calculated using Toolset and Curve Master. The F-ligand assay was run in a similar manner using either 384 well or 1536 well plates and fluorescein-conjugated saccharide probe 9 [33] at a final concentration of 79.8 nM prepared from 9.6 µL of the ligand in 4000 µL of buffer. X-ray Crystallography. The protein expression and purification and compound crystallization procedures for the X-ray co-crystal structures have previously been described [32]. PAMPA Assay [43]. Compounds and controls are utilized as 10 mM stocks in 100% DMSO. Compounds are diluted 1:100 in pH 7.4 or 5.5 donor-well buffer (pION, catalogue no. 110151), providing a 100 µM assay solution in 1% DMSO. Compounds diluted in a donorwell buffer were transferred to Whatman Unifilter plates and filtered prior to 200 µL being dispensed into the donor wells of the assay plates (pION, catalogue no. 110163). The PAMPA membrane was formed by pipetting 4 µL of the lipid solution (pION, catalogue no. 110169) onto the filter plate (VWR CAT #13503). The membrane was then covered with 200 µL of acceptor-well buffer at pH 7.4 (pION, catalogue no. 110139). The PAMPA-assay plate (donor and acceptor sides) was combined and allowed to incubate at room temperature for 4 h. The plate was then disassembled, and spectrophotometer plates (VWR, catalogue no. 655801) were filled (150 µL/well). The donor, acceptor, reference, and blank plates were read in a SpectraMax UV plate reader. Data were captured by the pION software, which analyzed the spectra and generated Pc values. The control compounds in this assay are as follows (mean ± SD): ketoprofen (pH 5.5, Pc 34.2 ± 3.1 cm − 6 /s; pH 7.4, Pc 1.1 ± 0.3 cm − 6 / s), metoprolol (pH 5.5, Pc 10.2 ± 1.1 cm − 6 /s; pH 7.4, Pc 83.5 ± 4.7 cm − 6 /s), and ranitidine (pH 5.5, Pc 0 ± 0 cm − 6 /s; pH 7.4, Pc 0.2 ± 0.1 cm − 6 /s). Metabolic Stability in Liver Microsomes [44]. The metabolic stability (Metstab) assay evaluates cytochrome P450 (CYP)-mediated metabolism of test compounds in vitro using human and rat microsomes after a 10 min incubation. The incubation was automated on a Biomek FX automation workstation (Beckman Coulter, Fullerton, CA, USA). Each compound was incubated in duplicate in the respective species at a concentration of 0.5 µM. Compounds were received as 3.5 mM solutions in DMSO and were diluted with CH3CN to 50 µM before being added to the prewarmed (37°C) microsomal suspension (1 mg/mL) prepared in 100 mM sodium phosphate, pH 7.4, and 6.6 mM MgCl2. The reaction was initiated by adding 17 µL of prewarmed 5 mM NADPH in 100 mM sodium phosphate, pH 7.4, into 153 µL of reaction mix. The concentration of DMSO in the incubation mixture was 0.014%. Reaction components were mixed well, and 75 µL was transferred into 150 µL of quench solution at 0 min time point (t0) and again at the 10 min incubation time point (t10). Quenched mixtures were centrifuged at 1500 rpm in an Allegra X-12 centrifuge (Beckman Coulter) for 15 min, and 90 µL of the supernatant was then transferred to a separate 96-well plate for analysis. The metabolism rate was determined based on the parent compound disappearance over time, as measured by LC − MS/MS. SEC-MALS Method. Isocratic separations were performed on a GE Healthcare Superdex 200 Increase 10/300 GL column (10 mm X 300 mm), connected to Shimadzu Prominence UFLC in buffer containing HBS, pH 7.4 (Cytiva), with 0.02% Na azide added and 0.1 mm filtered running at a flow rate of 0.75 mL/min. Data were obtained from three online detectors connected in series: A Shimadzu Prominence dual wavelength UV/vis spectrophotometer followed by a Wyatt Technologies DAWN multi-angle laser light scattering detector then a Wyatt Optilab interferometric refractometer. Data were collected and analyzed using ASTRA 8 (Wyatt) and LabSolutions Lite (Shimadzu) software. Pharmacokinetic Studies in Mice. The pharmacokinetic studies were conducted at Syngene International Ltd., Biocon-Bristol Myers Squibs Research Center, Bangalore, India, which is a CPCSEA- (Committee for the Purpose of Control and Supervision on Experiments on Animals) and AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care)-approved facility. Study protocols were approved by Institutional Animal Ethics Journal of Medicinal Chemistry pubs.acs.org/jmc Article https://doi.org/10.1021/acs.jmedchem.2c00517 J. Med. Chem. 2022, 65, 11084 − 11099 11096 Committee (IAEC). The study protocol was previously described [43]. Abbreviations NAFLD Nonalcoholic fatty liver disease NASH Nonalcoholic steatohepatitis Gal-3 Galectin-3 CRD Carbohydrate recognition domain SAR Structure-activity relationship HTRF Homogeneous time-resolved fluorescence B-ASF Biotin-asialofetuin FITC Fluorescein isothiocyanate PK/PD Pharmacokinetic/pharmacodynamic PAMPA Parallel artificial membrane permeability assay tPSA Topological polar surface IV Intravenous PO Per os, orally administered UAC total Total area under the plasma concentration time-curve F% Oral bioavailability PK Pharmacokinetic SQ Subcutaneous SEC-MALS Size-exclusion chromatography combined with multi-angle light scattering MW Molecular weight Declarations The authors declare no competing interests References Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013;10:686-90. http://dx.doi.org/10.1038/nrgastro.2013.171. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73-84. https://doi.org/10.1002/hep.28431 . Stepanova M, Rafiq N, Makhlouf H, Agrawal R, Kaur I, Younoszai Z, McCullough, A, Goodman Z, Younossi, ZM. Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD). Digest Dis Sci. 2013;58:3017-23. https://doi.org/10.1007/s10620-013-2743-5 . Perumpail BJ, Khan MA, Yoo, ER, Cholankeril G, Kim D, Ahmed A. Clinical epidemiology and disease burden of nonalcoholic fatty liver disease. World J Gastroentero. 2017;23:8263-76. http://dx.doi.org/10.3748/wjg.v23.i47.8263 . Adams LA, Sanderson S, Lindor KD, Angulo, P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005;42:132-38. https://doi.org/10.1016/j.jhep.2004.09.012 Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. (2009). Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol. 2009;51:371-379. https://doi.org/10.1016/j.jhep.2009.03.019 . Barondes SH, Castronovo V, Cooper DN, Cummings RD, Drickamer K, Feizi T, Gitt MA, Hirabayashi J, Hughes C, Kasai K. Galectins: a family of animal beta-galactoside-binding lectins. Cell. 1994;76:597-98. https://doi.org/10.1016/0092-8674(94)90498-7. Leffler H, Carlsson S, Hedlund M, Qian Y, Poirier F. Introduction to galectins. Glycoconj J. 2002;19:433-40. https://doi.org/10.1023/B:GLYC.0000014072.34840.04 . Boscher C, Dennis JW, Nabi IR. Glycosylation, galectins and cellular signaling. Curr Opin Cell Biol. 2011;23:383-92. https://doi.org/10.1016/j.ceb.2011.05.001. Johannes L, Jacob R, Leffler H. Galectins at a glance.J. Cell Sci. 2018; 131 :1-9. https://doi:10.1242/jcs.208884. Yang RY, Rabinovich GA, Liu FT. Galectins: structure, function and therapeutic potential. Expert Rev Mol Med. 2008;10:e17. https://doi.org/10.1017/S1462399408000719. Ahmad N, Gabius HJ, André S, Kaltner H, Sabesan S, Roy R, Liu B, Macaluso F, Brewer CF. Gal-3 precipitates as a pentamer with synthetic multivalent carbohydrates and forms heterogeneous cross-linked complexes. J Biol Chem. 2004;279:10841-47. https://doi.org/10.1074/jbc.M312834200. Herrmann J, Turck WC, Atchison RE, Huflejt ME, Poulter M, Gitt MA, Burlingame AL, Barondes SH, Leffler H. Primary structure of the soluble lactose binding lectin L-29 from rat and dog and interaction of its noncollagenous proline-, glycine-, tyrosine-rich sequence with bacterial and tissue collagenase. J Biol Chem. 1993;268:26704-11. Liu FT. 1993. S-type mammalian lectins in allergic inflammation. Immunol Today. 1993;14:486-90. https://doi.org/10.1016/0167-5699(93)90263-K. Liu FT. Galectins: a new family of regulators of inflammation. clinical immunology 2000;97:79-88. https://doi.org/10.1006/clim.2000.4912. Modenutti CP, Capurro JIB, Di Lella S, Martí MA. The structural biology of galectin-ligand recognition: current advances in modeling tools, protein engineering, and inhibitor design. Front Chem. 2019;7:823. https://doi.org/10.3389/fchem.2019.00823. Berbís MA, André S, Cañada FJ, Pipkorn R, Ippel H, Mayo KH, Kübler D, Gabius HJ, Jiménez-Barbero J. Peptides derived from human Gal-3 N-terminal tail interact with its carbohydrate recognition domain in a phosphorylation-dependent manner. Biochem Biophys Res Commun. 2014;443:126-31. https://doi.org/10.1016/j.bbrc.2013.11.063 . Sciacchitano S, Lavra L, Morgante A, Ulivieri A, Magi F, De Francesco GP, Bellotti C, Salehi LB, Ricci A. Gal-3: one molecule for an alphabet of diseases, from A to Z. Int J Mol Sci. 2018;26;19:379-438. https://doi.org/10.1016/j.bbrc.2013.11.063. Klyosov AA, Traber PG. Galectins and disease implications for targeted therapeutics. ACS Symposium Series eBooks; ACS Washington, DC, December 18, 2012. https://doi.org/ https://pubs.acs.org/doi/pdf/10.1021/bk-2012-1115.ch001. https://doi.org/10.1023/B:GLYC.0000014072.34840.04 Blanchard H, Yu X, Collins PM, Bum-Erdene K. Galectin-3 inhibitors: a patent review (2008-present). Expert Opin Ther Pat. 2014;24:1053-65. https://doi.org/10.1517/13543776.2014.947961. Sethi A, Sanam S, Alvala R, Alvala M. An updated patent review of galectin-1 and galectin-3 inhibitors and their potential therapeutic applications (2016-present). Expert Opin Ther Pat. 2021;31:709-21. https://doi.org/10.1080/13543776.2021.1903430. Li LC, Li J, Gao J. Functions of Gal-3 and its role in fibrotic diseases. J Pharmacol Exp Ther. 2014;351:336-43. https://doi.org/10.1124/jpet.114.218370. Slack RJ, Mills R, Mackinnon AC. The therapeutic potential of Gal-3 inhibition in fibrotic disease. Int J Biochem Cell Biol. 2021;130:105881. https://doi.org/10.1016/j.biocel.2020.105881. Maeda N, Kawada N, Seki S, Arakawa T, Ikeda K, Iwao H, Okuyama H, Hirabayashi J, Kasai K, Yoshizato K. Stimulation of proliferation of rat hepatic stellate cells by galectin-1 and Gal-3 through different intracellular signaling pathways. J Biol Chem. 2003;278:18938-44. https://doi.org/10.1074/jbc.M209673200. Henderson NC, Mackinnon AC, Farnworth SL, Sethi T. Gal-3 regulates myofibroblast activation and hepatic fibrosis. PNAS. 2006; 103: 5060-65. https://doi.org/10.1073/pnas.0511167103 de Oliveira SA, de Freitas Souza BS, Sá Barreto EP, Kaneto CM, Neto HA, Azevedo, CM, Guimarães ET, de Freitas LA, Ribeiro-Dos-Santos R, Soares MB. Reduction of Gal-3 expression and liver fibrosis after cell therapy in a mouse model of cirrhosis. Cytotherapy. 2012;14:339-49. https://doi.org/10.3109/14653249.2011.637668 Traber PG, Chou H, Zomer E, Hong F, Klyosov A, Fiel MI, Friedman SL. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PLoS One. 2013;8:e75361. https://doi.org/10.1371/journal.pone.0075361. Hirani N, MacKinnon AC, Nicol L, Ford P, Schambye H, Pedersen A, Nilsson UJ, Leffler H, Sethi T, Tantawi S, Gravelle L, Slack RJ, Mills R, Karmakar U, Humphries D, Zetterberg F, Keeling L, Paul L, Molyneaux PL, Li F, Funston W, Forrest IA, Simpson AJ, Gibbons MA, Maher TM. Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis. Eur Respir J. 2021;57:2002559. https://doi.org/10.1183/13993003.02559-2020. Erratum in: Eur Respir J. 2022 Apr 14;59: PMID: 33214209; PMCID: PMC8156151. Zetterberg FR, MacKinnon A, Brimert T, Gravelle L, Johnsson RE, Kahl-Knutson B, Leffler H, Nilsson UJ, Pedersen A, Peterson K, Roper JA, Schambye H, Slack RJ, Tantawi S. Discovery and optimization of the first highly effective and orally available galectin-3 inhibitors for treatment of fibrotic disease. J Med Chem. 2022;65:12626-38. https://doi.org/10.1021/acs.jmedchem.2c00660. Liu C, Jalagam PR, Feng J, Wang W, Raja T, Sura MR, Manepalli RKVLP, Aliphedi BR, Medavarapu S, Nair SK, Muthalagu V, Natesan R, Gupta A, Beno B, Panda M, Ghosh K, Shukla JK, Sale H, Haldar P, Kalidindi N, Shah D, Patel D, Mathur A, Ellsworth BA, Cheng D, Regueiro-Ren A. Identification of monosaccharide derivatives as potent, selective, and orally bioavailable inhibitors of human and mouse Gal-3. J Med Chem. 2022;65:11084-99. https://doi.org/10.1021/acs.jmedchem.2c00517. Liu C, Wang W, Feng J, Beno Brett, Raja T, Swidorski J, Manepalli R, Vetrichelvan M, Jalagam P, Prasada; Nair S, Gupta A, Panda M, Ghosh K, Shukla JK, Sale H, Shah D, Gautam S, Patel D, Mathur A, Ellsworth B, Cheng D, Dong; Regueiro-Ren A. Identification of benzothiazole derived monosaccharides as potent, selective, and orally bioavailable inhibitors of human and mouse galectin-3. J Med Chem. Submitted March 8, 2023. Kumar A, Paul M, Panda M, Jayaram S, Kalidindi N, Sale S, Vetrichelvan M, Gupta A, Mathur A, Beno B, Regueiro-Ren A, Cheng D, Ramarao M, Ghosh K. Molecular mechanism of interspecies differences in the binding affinity of TD139 to galectin-3. Glycobiology 2021;31:1390-1400. https://doi.org/10.1093/glycob/cwab072. Sörme P, Kahl-Knutsson B, Huflejt M, Nilsson UJ, Leffler H. Fluorescence polarization as an analytical tool to evaluate galectin–ligand interactions. Anal Biochem. 2004;334:36-47. https://doi.org/10.1016/j.ab.2004.06.042. Fluorescein-conjugated saccharide probe 9 was used for the F-ligand assay reported. Kansy M, Senner F, Gubernator, K. Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes. J Med Chem. 1998;41:1007-1010. https://doi.org/10.1021/jm970530e. Ertl P, Rohde B, Selzer P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug rransport properties. J Med Chem. 2000;43:3714-17. https://doi.org/10.1021/jm000942e. tPSA calculations were calculated using PerkinElmer ChemDraw Professional version 20.1.0.110. Sahin E, Roberts CJ. Size-exclusion chromatography with multi-angle light scattering for elucidating protein aggregation mechanisms. Methods Mol Biol. 2012;899:403-23. https://doi.org/10.1007/978-1-61779-921-1_25. Some D, Amartely H, Tsadok A, Lebendiker M. Characterization of proteins by size-exclusion chromatography coupled to multi-angle light scattering (SEC-MALS). J Vis Exp. 2019;148. https://doi.org:/10.3791/59615. Kolb HC, Sharpless BK. The growing impact of click chemistry on drug discovery. Drug Discov Today 2003;8:1128-37. https://doi.org/10.1016/S1359-6446(03)02933-7. Dourtoglou V, Gross B. O-Benzotriazolyl-N,N,N’,N’-tetramethyluronium hexafluorophosphate as a coupling reagent for the sythesis of peptides of biological interest. Synthesis 1984;7:572-4. https://doi.org/10.1055/s-1984-30895. Azide 38 can be prepared using the same method described in scheme 1 for azide 34 only starting with different substitution on the phenyl group of the alkyne. Wissmann H, Kleiner H-J. New peptide synthesis. Angew Chem, Int Ed Engl. 1980;19:133-4. https://doi.org/10.1002/anie.198001331. Xu L, Hartz RA, Beno BR, Ghosh K, Shukla JK, Kumar A, Patel D, Kalidindi N, Lemos N, Gautam SS, Kumar A, Ellsworth BA, Shah D, Sale H, Cheng D, and Regueiro-Ren A. Synthesis, structure-activity relationships, and in vivo evaluation of novel tetrahydropyran-based thiodisaccharide mimics as Gal-3 inhibitors. J Med Chem. 2021;64:6634-55. https://doi.org/10.1021/acs.jmedchem.0c02001. Kieltyka K, Zhang J, Li S, Vath M, Baglieri C, Ferraro C, Zvyaga TA, Drexler DM, Weller HN, Shou WZ. A high throughput bioanalytical platform using automated infusion for tandem mass spectrometric method optimization and its application in a metabolic stability screen. Rapid Commun Mass Spectrom. 2009;23:1579-91. https://doi.org/10.1002/rcm.4037. Schemes Schemes 1 to 6 are available in the Supplementary Files section Supplementary Files Schemes.docx UnnumberedFigure1.png Unnumbered image in the Introduction section. UnnumberedFigure2.png Unnumbered image in the Results and Discussion section. UnnumberedFigure3.png Unnumbered image in the Results and Discussion section. Cite Share Download PDF Status: Published Journal Publication published 08 Jun, 2023 Read the published version in Medicinal Chemistry Research → Version 1 posted Reviewers agreed at journal 10 Apr, 2023 Reviewers invited by journal 08 Apr, 2023 Editor assigned by journal 31 Mar, 2023 First submitted to journal 30 Mar, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2757730","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":190174617,"identity":"886f441b-5814-4167-b764-3342cd0db431","order_by":0,"name":"Jacob J. 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Green ribbon represents one Gal-3 protein bound to green inhibitor molecule \u003cstrong\u003e1\u003c/strong\u003e while orange ribbon representing a second Gal-3 protein is in close proximity as it is bound to a second molecule of \u003cstrong\u003e1\u003c/strong\u003ein orange. The two benzothiazole moieties of \u003cstrong\u003e1\u003c/strong\u003e appear to associate through p-stacking (blue dashed lines) and the interaction may contribute to the stability of this crystalline form. At the right, an X-ray crystal structure (PDB ID: 8ILU) shows a distance of 5.8 Å between a carboxylic acid extension from the C2 position of one molecule of \u003cstrong\u003e2\u003c/strong\u003e to the carboxylic acid extension from the C2 position of a second molecule of \u003cstrong\u003e2\u003c/strong\u003e with an unobstructed path between the two moieties. Each molecule of \u003cstrong\u003e2\u003c/strong\u003e is bound to a distinct Gal-3 protein represented by the green and orange ribbons. Images created with the PyMOL Molecular Graphics System, Version 2.4 Schrödinger, LLC\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2757730/v1/12729549c5e67a02854f03aa.png"},{"id":35604299,"identity":"dd2cef1c-6bd1-4956-a64c-5957045a7f52","added_by":"auto","created_at":"2023-04-11 18:36:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1306329,"visible":true,"origin":"","legend":"\u003cp\u003eThe X-ray crystal structure of \u003cstrong\u003e25\u003c/strong\u003ebound to two hGal-3 proteins (PDB ID: 8ITX)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-2757730/v1/36af9dfdb4745907d95bb25e.png"},{"id":35604831,"identity":"77192ed2-8194-4e93-a445-78b5408aa591","added_by":"auto","created_at":"2023-04-11 18:44:27","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":477343,"visible":true,"origin":"","legend":"\u003cp\u003eAn expanded view of the X-ray crystal structure of \u003cstrong\u003e25\u003c/strong\u003e bound to two hGal-3 proteins with key binding residues labeled (PDB ID: 8ITX)\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-2757730/v1/c4f843ffd2a8e1e68a9e5647.png"},{"id":44730711,"identity":"e6104145-193e-44b4-bea8-fe51d1dfd30b","added_by":"auto","created_at":"2023-10-16 21:33:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4856818,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2757730/v1/24168132-6992-46ba-add6-c7e49cbef2fb.pdf"},{"id":35604301,"identity":"f38b7b3f-ad45-4e4b-98e5-085b39ddec11","added_by":"auto","created_at":"2023-04-11 18:36:28","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":442132,"visible":true,"origin":"","legend":"","description":"","filename":"Schemes.docx","url":"https://assets-eu.researchsquare.com/files/rs-2757730/v1/84f9b17914bc8a55e1f443e1.docx"},{"id":35604303,"identity":"4d9848f0-0796-472d-9e2c-1315e279e5a5","added_by":"auto","created_at":"2023-04-11 18:36:28","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":22471,"visible":true,"origin":"","legend":"\u003cp\u003eUnnumbered image in the Introduction section.\u003c/p\u003e","description":"","filename":"UnnumberedFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-2757730/v1/1a40c96c694a554ec31845b3.png"},{"id":35604297,"identity":"d8576e6f-d81f-4ff7-aa29-8f303e6d2795","added_by":"auto","created_at":"2023-04-11 18:36:27","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":39956,"visible":true,"origin":"","legend":"\u003cp\u003eUnnumbered image in the Results and Discussion section.\u003c/p\u003e","description":"","filename":"UnnumberedFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-2757730/v1/79023b5dd844456956f6e289.png"},{"id":35604302,"identity":"af85c7d7-ccde-4630-9a74-39faa7654270","added_by":"auto","created_at":"2023-04-11 18:36:28","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":17089,"visible":true,"origin":"","legend":"\u003cp\u003eUnnumbered image in the Results and Discussion section.\u003c/p\u003e","description":"","filename":"UnnumberedFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-2757730/v1/09b6c05f0e4be0c2ff58a2dd.png"}],"financialInterests":"","formattedTitle":"Discovery and Exploration of Monosaccharide Linked Dimers of Galectin-3 Inhibitors to Target Fibrosis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNonalcoholic fatty liver disease (NAFLD) has become a global concern as rates of obesity, type II diabetes and related metabolic diseases have increased and are inextricably linked to onset of the disease. Worldwide estimates in 2013 put the prevalence of NAFLD as high as one billion individuals currently living with the ailment [1]. In countries with a high prevalence of obesity and related disease, as many as a third of the population may be affected by NAFLD [1,2]. Further progression of liver disease in NAFLD patients can lead to the development of nonalcoholic steatohepatitis (NASH) which is more concerning as it is one of the principal causes of cirrhosis in US adults and can ultimately progress to hepatocellular carcinoma requiring a liver transplantation or result in liver-related mortality [2\u0026ndash;4]. Because progression of NAFLD has thus far been difficult to predict, fibrosis has been the most impartial indicator of liver damage that will lead to severe disease [5,6].\u003c/p\u003e\n\u003cp\u003eGalectins are proteins that bind to conserved b-galactoside binding sites and have been studied for their numerous physiological functions in both the intra- and extra-cellular space [7\u0026ndash;11]. Galectin-3 (Gal-3) has unique structure and function among the galectin family of proteins [12]. It is the only known chimera-type protein in the galectin family that is composed of an N-terminal non-lectin domain linked to a C-terminal carbohydrate recognition domain (CRD) [12\u0026ndash;17]. Although Gal-3 is found predominantly as a monomer in solution, it can oligomerize to form disorganized, pentameric cross-linked complexes when interacting with multivalent carbohydrates [12,16]. It has been postulated that the ability for Gal-3 to organize in oligomeric forms and its ability to organize less structured cross-linked lattices compared to other galectins may account for differences in biological activity compared to other galectin proteins [12].\u003c/p\u003e\n\u003cp\u003eExtensive efforts have advanced the understanding of the roles that Gal-3 plays in the pathogenesis of various diseases [18\u0026ndash;21]. Gal-3 is involved in numerous cellular and physiological processes such as apoptosis, cell adhesion and migration, angiogenesis, and inflammation [22]. Our group was especially interested in Gal-3\u0026rsquo;s function in the regulation of inflammation and its therapeutic potential to affect the onset and progression of fibrotic diseases. Numerous studies indicate that Gal-3 is involved in myofibroblast activation and procollagen expression. Increased Gal-3 expression is associated with the progression of fibrosis in multiple organs including liver, lung, kidneys and the heart [22,23]. In the liver, Gal-3 expression is increased in hepatic stellate cells and human tissues of cirrhosis patients [24]. In preclinical models, Gal-3 inhibitors demonstrate therapeutic efficacies in acute CCl\u003csub\u003e4\u003c/sub\u003e liver injury models as well as thioacetamide induced liver fibrosis models in vivo [24\u0026ndash;27].\u003c/p\u003e\n\u003cp\u003eSeveral research groups have advanced molecules into clinical trials for the treatment of fibrosis. TD139 (GB0139) is a thiodigalactoside being studied in phase IIb as an inhaled treatment of idiopathic pulmonary fibrosis [28]. TD139 was shown to have high binding affinity for Gal-3 in the low nanomolar range. However, this compound lacked oral bioavailability because of its large size and high polarity [29]. Further exploration led to the discovery of monogalactoside GB1211, a smaller and less polar low-nanomolar human Gal-3 inhibitor, that has improved oral bioavailability and is currently being examined in phase IIa clinical studies [29]. Together, publications outlining target engagement, predictive in vivo models, and advancement of compounds in the clinic make Gal-3 an attractive therapeutic target.\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\" width=\"470\" height=\"152\"\u003e\u003c/p\u003e"},{"header":"Results And Discussion","content":"\u003cp\u003eDuring our effort to optimize the monosaccharide based Gal-3 series, crystal structure data aimed at guiding the structure-activity relationship (SAR) development provided several interesting observations [30]. An X-ray structure of \u003cstrong\u003e1\u003c/strong\u003e bound to the mouse galectin 3 protein (mGal-3) showed an apparent \u0026pi;-stacking interaction of the benzothiazole group extending from the anomeric 1,2,4-triazole of \u003cstrong\u003e1\u003c/strong\u003e with a benzothiazole on a second molecule of \u003cstrong\u003e1\u003c/strong\u003e (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Each of the two molecules of \u003cstrong\u003e1\u003c/strong\u003e were bound to a different mGal-3 protein molecule by key carbohydrate binding interactions in the CRD [30,31], while the two ligand molecules aligned in close proximity to one another in the extended crystalline lattice. The intermolecular \u0026pi;-stacking interactions between the ligand benzothiazoles may contribute to the stability of this particular crystalline form of the complex. Inter-ligand close contacts were also observed in the extended lattice of the X-ray crystal structure of human Gal-3 CRD bound to TD-139 (PDB ID: 7CXA) [32]. In another X-ray structure obtained from \u003cstrong\u003e2\u003c/strong\u003e bound to mGal-3 in the CRD, the close proximity of a carboxylic acid extending from the C2 position of the galactose core to the C2 carboxylic acid extension of a second molecule of \u003cstrong\u003e2\u003c/strong\u003e bound to a separate mGal-3 protein CRD was observed. The distance between oxygen atoms in the two carboxylic acid moieties was \u0026lt;\u0026thinsp;6 \u0026Aring;, suggesting the possibility of linking the two monosaccharide molecules as a bis-amide with a diamine of appropriate size. These observations led us to explore the possibility of developing a dimer that could bind to multiple Gal-3 proteins with the potential to further enhance binding affinity which is reported in the current paper.\u003c/p\u003e\n\u003cp\u003eCompounds were tested in both human and mouse Gal-3 (hGal-3 and mGal-3) homogeneous time-resolved fluorescence (HTRF) binding assays using biotin-asialofetuin (B-ASF) as the ligand. Many of the compounds were also tested in a second HTRF assay using a fluorescein isothiocyanate (FITC) labeled small molecule substrate [33] as the ligand (F-ligand). Both assays could be used as tools to effectively rank order the binding affinities of the molecules being tested for inhibition of Gal-3. Since we intended to use in vivo mouse models for PK/PD and efficacy studies, mGal-3 measurements became a focus for improvement with the monomeric series of compounds. In the case of compounds containing the trifluorophenyl substituents extending from the 1,2,3-triazole, mGal-3 potency was substantially lower than hGal-3 (19 fold for \u003cstrong\u003e1\u003c/strong\u003e and 15 fold for \u003cstrong\u003e2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eSeveral attachment points joining monosaccharide subunits were explored as possibilities to afford potent dimers based on the observed interactions in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Previously reported, monosaccharides containing 1,2,3-triazoles in the b conformation at the anomeric position showed moderate hGal-3 potency of 256\u0026ndash;306 nM in the HTRF assay [30], so an attachment was made between the 4 position of the anomeric 1,2,3-triazole spanning 3 or 5 carbons between the monosaccharide subunits (\u003cstrong\u003e3\u003c/strong\u003e and \u003cstrong\u003e4\u003c/strong\u003e). Interestingly, these compounds showed an hGal-3 IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;4 mM and mGal-3 IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;30 mM in the HTRF assays. The dramatic decrease of the Gal-3 IC\u003csub\u003e50\u003c/sub\u003e value can likely be explained by the disruption of an important interaction at Gly182 of the protein with the halogen attached to a phenyl substituent projecting from the 1,2,3-triazole previously described by Liu et al [30]. The benzothiazole \u0026pi;-stacking interaction observed with \u003cstrong\u003e1\u003c/strong\u003e likely does not disrupt the Gly182 interaction in the same manner since X-ray crystal structure data shows a similar interaction to the halogen bond can be made between the sulfur atom of the benzothiazole and the Gly182 of the Gal-3 protein [31].\u003c/p\u003e\n\u003cp\u003eUsing a different approach to link the two monosaccharide subunits, an extension from the 1,2,3-triazole in one monosaccharide was linked to a C-2 alcohol of another monomer with an acetamide and a carbon spacer to provide \u003cstrong\u003e5\u003c/strong\u003e. With this linkage, the hGal-3 and mGal-3 potencies were only several fold lower than that of the monosaccharide which had an hGal-3 IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;19 nM and mGal-3 IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;126 nM in the HTRF assay [30]. The structure of \u003cstrong\u003e5\u003c/strong\u003e allows the monosaccharide subunit with the extension from C-2 to interact with the Gly182 while maintaining the ability to halogen bond with the protein, while the second monosaccharide subunit is unavailable to interact with Gly 182 since there is no longer an extension from the anomeric carbon able to access the same pocket. The observed potency, comparable to the single monosaccharide subunit, is consistent with this hypothesis.\u003c/p\u003e\n\u003cp\u003eTo further test the effect of the linkages between the two subunits, additional connections between monosaccharides focused on side chains extending from the C-2 alcohol of the carbohydrate core which could allow for the halogen bond to Gly 182 to be retained in each of the subunits. When comparing monosaccharide \u003cstrong\u003e6\u003c/strong\u003e to a symmetrical dimer made up of two monosaccharides linked through an acetamide spacer extending from the C-2 alcohol (examples \u003cstrong\u003e7\u0026ndash;10\u003c/strong\u003e, Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e), the hGal-3 IC\u003csub\u003e50\u003c/sub\u003e was improved in each instance compared to the monosaccharide. The largest improvement in hGal-3 potency was 55x in the HTRF assay for \u003cstrong\u003e10\u003c/strong\u003e with a 5 carbon linker. Furthermore, \u003cstrong\u003e10\u003c/strong\u003e showed 7-13x improvement in the mGal-3 HTRF and F-ligand assays respectively compared to the monosaccharide. Since modifications to the phenyl substituents on the C-3 1,2,3-triazoles were reported to improve Gal-3 potency in the monosaccharide subunits one of the more potent substitution patterns, the phenyl F,Cl,F, was incorporated into dimers with acetamide linkers with 2, 4, 5, 6 and 7 carbon unit spacers. The 2, 4 and 5 carbon linkers (\u003cstrong\u003e11\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e13\u003c/strong\u003e) showed similar potency in the hGal-3 HTRF and F-ligand as the F,F,F-substituted analogs. Linkers with 6 and 7 carbon spacers between the acetamides (\u003cstrong\u003e14\u003c/strong\u003e and \u003cstrong\u003e15\u003c/strong\u003e) showed lower Gal-3 inhibition in both the human and mouse assays than the shorter linkers of \u003cstrong\u003e11\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e13\u003c/strong\u003e providing the optimal length of the spacers between the acetamides of 2 to 5 carbons. Consistent with the reported monosaccharide SAR, The R\u003csup\u003e1\u003c/sup\u003e substitution pattern showed a modest improvement in the mGal-3 potency for linkers of 2, 4 and 5 carbons (4\u0026ndash;5 fold) in the fluorescence assay. Incorporating the F,Cl,F substitution pattern on the C3 triazole phenyl group appendage in combination with the CF\u003csub\u003e3\u003c/sub\u003e on R\u003csup\u003e2\u003c/sup\u003e of the 1,2,4-triazole, examples \u003cstrong\u003e16\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e18\u003c/strong\u003e provided another modest improvement to the in vitro mGal-3 IC\u003csub\u003e50\u003c/sub\u003e. In addition to all 3 examples showing hGal-3 IC\u003csub\u003e50\u003c/sub\u003e of \u0026lt;\u0026thinsp;1 nM in the HTRF assay, the compounds showed a 41\u0026ndash;94 fold improvement in the mGal-3 HTRF assay and 23\u0026ndash;74 fold improvement in the F-ligand assay when compared to the monosaccharide \u003cstrong\u003e6\u003c/strong\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv\u003e\u003cstrong\u003eTable 1. Inhibition of hGal-3 and mGal-3, and in vitro metabolic stability for selected compounds in human, rat and mouse.\u003c/strong\u003e\u003c/div\u003e\n \u003ctable border=\"1\" id=\"Taba\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eExample\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLinker length\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eR\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ehGal-3 IC\u003csub\u003e50\u003c/sub\u003e HTRF / F-ligand (nM)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003emGal-3 IC\u003csub\u003e50\u003c/sub\u003e\u003c/p\u003e\n \u003cp\u003eHTRF / F-Ligand (nM)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMetstab\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003ehuman/rat/mouse\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emonosaccharide\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF, F, F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38.6\u003csup\u003eb\u003c/sup\u003e / 76.4\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,160\u0026thinsp;\u0026plusmn;\u0026thinsp;57 / 1,930\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e93/78/88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e7\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF, F, F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNT / 3.9\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNT / 252\u0026thinsp;\u0026plusmn;\u0026thinsp;162\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e89/92/88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF, F, F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNT / 4.4\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNT / 311\u0026thinsp;\u0026plusmn;\u0026thinsp;306\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF, F, F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNT / 5.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNT / 850\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e10\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF, F, F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.7\u003csup\u003ec\u003c/sup\u003e / 0.8\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e171\u0026thinsp;\u0026plusmn;\u0026thinsp;14.6 / 151\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96/92/84\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF, Cl, F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4 / 2.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90.4\u0026thinsp;\u0026plusmn;\u0026thinsp;39.5 / 36.6\u0026thinsp;\u0026plusmn;\u0026thinsp;17.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97/89/93\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF, Cl, F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.0\u003csup\u003eb\u003c/sup\u003e / 6.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54.3\u0026thinsp;\u0026plusmn;\u0026thinsp;29.0 /108\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e92/80/81\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e13\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF, Cl, F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.3\u003csup\u003eb\u003c/sup\u003e / 4.6\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e80.1\u0026thinsp;\u0026plusmn;\u0026thinsp;28.0 /105\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e14\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF, Cl, F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.9\u003csup\u003eb\u003c/sup\u003e / 18.5\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e244\u003csup\u003eb\u003c/sup\u003e / 877\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100/88/87\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e15\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF, Cl, F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.1\u003csup\u003eb\u003c/sup\u003e / 23.6\u0026thinsp;\u0026plusmn;\u0026thinsp;13.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e717\u003csup\u003eb\u003c/sup\u003e / 522\u0026thinsp;\u0026plusmn;\u0026thinsp;216\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e91/87/98\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e16\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF, Cl, F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCF\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.7\u003csup\u003eb\u003c/sup\u003e/ 2.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4 / 26.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e87/88/98\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e17\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF, Cl, F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCF\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.8\u003csup\u003eb\u003c/sup\u003e / 4.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8 / 83.5\u0026thinsp;\u0026plusmn;\u0026thinsp;65.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e100/93/99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF, Cl, F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCF\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.9\u003csup\u003eb\u003c/sup\u003e / 4.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28\u0026thinsp;\u0026plusmn;\u0026thinsp;10.5 / 66\u0026thinsp;\u0026plusmn;\u0026thinsp;18.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88/94/93\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eIn vitro metabolic stability was measured by incubating the ligand in human, rat and mouse liver microsomes and measuring the % remaining after a 10 minute incubation period. HTRF and F-Ligand assays are reported as mean IC\u003csub\u003e50\u003c/sub\u003e values\u0026thinsp;\u0026plusmn;\u0026thinsp;SD from at least three experiments unless otherwise noted. \u003csup\u003eb\u003c/sup\u003eValue is the average of two experiments. \u003csup\u003ec\u003c/sup\u003eValue determined from one experiment.\u003c/p\u003e\n\u003cp\u003eBecause \u003cstrong\u003e10\u003c/strong\u003e showed a promising in vitro inhibition profile for both human and mouse, it was further profiled for advancement to in vivo studies. The in vitro permeability measured in the parallel artificial membrane permeability assay (PAMPA), a model for passive diffusion used to predict absorption [34], was 299 nm/sec at pH 5.5 and 376 nm/sec at pH 7.4, surprisingly high for a large, polar compound with a calculated topological polar surface (tPSA) calculation of 288 [35,36]. In vitro metabolic stability was measured by incubating \u003cstrong\u003e10\u003c/strong\u003e in human, rat, and mouse liver microsomes and measuring the % remaining after a 10 minute incubation period. Metabolism was generally low ranging from 84\u0026ndash;92% across species. With encouraging in vitro results, \u003cstrong\u003e10\u003c/strong\u003e was advanced to in vivo mouse PK studies. The compound was dosed at 2 mg/kg IV and 10 mg/kg, PO and concentrations of the compound at multiple timepoints was acquired over a 24h period. While the parent monosaccharide had an AUC\u003csub\u003etotal\u003c/sub\u003e of 4.1 mM*h with a single dose IV and 4.0 mM*h with a single dose administered orally, only a small fraction of the dimer \u003cstrong\u003e10\u003c/strong\u003e was orally bioavailable (0.02 mM*h, PO, F% = 0.3) compared to the monosaccharide \u003cstrong\u003e6\u003c/strong\u003e which had F% = 20.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Alternative C-2 linkers\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\" width=\"805\" height=\"702\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eIn vitro metabolic stability was measured by incubating the ligand in human, rat and mouse liver microsomes and measuring the % remaining after a 10 minute incubation period. HTRF and F-Ligand assays are reported as mean IC\u003csub\u003e50\u003c/sub\u003e values\u0026thinsp;\u0026plusmn;\u0026thinsp;SD from at least three experiments unless otherwise noted. \u003csup\u003eb\u003c/sup\u003eValue is the average of two experiments. \u003csup\u003ec\u003c/sup\u003eValue determined from one experiment.\u003c/p\u003e\n\u003cp\u003eTo improve the oral bioavailability for in vivo studies, alternative modifications to the linker were examined (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The acetamide linkages of \u003cstrong\u003e7\u0026ndash;18\u003c/strong\u003e were substituted for ether linkages of similar length in \u003cstrong\u003e19\u0026ndash;20\u003c/strong\u003e which lowered the tPSA from 288 to 230 \u0026Aring;\u003csup\u003e2\u003c/sup\u003e. Although the distance between the two linked monosaccharide units was similar with the all carbon spacers in \u003cstrong\u003e19\u0026ndash;20\u003c/strong\u003e, HTRF assays for both the hGal-3 and mGal-3 showed a significant decrease in potency. When the linker was changed to a C-2 carbamate in \u003cstrong\u003e21\u003c/strong\u003e and \u003cstrong\u003e22\u003c/strong\u003e, in vitro hGal-3 potency was somewhat restored with the 4 carbon linker between the carbamates having an hGal-3 IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;19 nM and the 3 carbon linker having an hGal-3 IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;110 nM, however in both carbamate examples the mGal-3 IC\u003csub\u003e50\u003c/sub\u003e decreased to nearly 3 mM in the HTRF assay, a substantial loss of potency when compared to the original acetamide linkers. Finally, a tertiary amide \u003cstrong\u003e23\u003c/strong\u003e was explored which removed the H-bond donor characteristic of the initial secondary amides, however this changes only modestly decreased the tPSA to 270 \u0026Aring;\u003csup\u003e2\u003c/sup\u003e. Interestingly, in vitro hGal-3 and mGal-3 IC\u003csub\u003e50\u003c/sub\u003e was comparable to the secondary amides \u003cstrong\u003e11\u003c/strong\u003e with the same linker length. Unfortunately, attempts to measure the in vitro permeability using the PAMPA assay were not successful so \u003cstrong\u003e23\u003c/strong\u003e was not progressed further. To follow on this result, two cyclic tertiary amides were explored as linkers, the 1,4-diazepane \u003cstrong\u003e24\u003c/strong\u003e and the piperizine \u003cstrong\u003e25\u003c/strong\u003e. Both compounds showed tPSAs of 270 \u0026Aring;\u003csup\u003e2\u003c/sup\u003e, and IC\u003csub\u003e50\u003c/sub\u003e values in the mGal-3 and hGal-3 F-ligand assay were comparable to the secondary amides of similar length. In addition, \u003cstrong\u003e24\u003c/strong\u003e and \u003cstrong\u003e25\u003c/strong\u003e showed acceptable metabolic stability in the 10 minute incubation assay. However, attempts to measure in vitro permeability using the PAMPA assay were unsuccessful for both compounds, potentially because of limitations in aqueous solubility. The piperazine analog \u003cstrong\u003e25\u003c/strong\u003e was advanced into an in vivo mouse PK study to explore its potential as an orally dosed inhibitor of Gal-3. The compound was dosed at 10 mg/kg PO and 10 mg/kg SQ and concentrations of the compound at multiple timepoints were acquired over a 24 h period. When dosed orally, AUC\u003csub\u003etotal\u003c/sub\u003e was only 0.035 mM*h, which was comparable to \u003cstrong\u003e10\u003c/strong\u003e. The previous in vivo PO results of \u003cstrong\u003e10\u003c/strong\u003e, in addition to a high tPSA and the difficulty measuring the in vitro permeability of \u003cstrong\u003e25\u003c/strong\u003e, led to an alternative attempt at SQ dosing, which did improve the AUC\u003csub\u003etotal\u003c/sub\u003e to 2.23 mM*h.\u003c/p\u003e\n\u003cp\u003eWhile exploring opportunities to link the two monosaccharide subunits together, attempts to further understand the binding pocket using binding models developed from X-ray crystal structures of monomeric subunits were explored, however attaining an X-ray crystal structure of one of the dimers was exceedingly arduous. After multiple attempts to crystallize the dimers in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e came up empty, an X-ray crystal structure of \u003cstrong\u003e25\u003c/strong\u003e bound to the hGal-3 CRD was finally determined (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The X-ray crystal structure data clearly showed the two monosaccharide subunits interacting with two hGal-3 proteins in close proximity. One hGal-3 protein is shown in orange, while a second hGal-3 protein is shown in green and the dimeric ligand has organized in a symmetric, yet opposite orientation reaching into the binding pockets of each protein. When examining the binding of \u003cstrong\u003e25\u003c/strong\u003e to the hGal-3 protein closer (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e), it becomes apparent that the core CRD interactions of the saccharide are intact as well as the key interaction previously described with the anomeric substituent extending to reach Gly 182 [30]. Interestingly, there is a water molecule that bridges the carbonyl of the acetamide linker, a ligand1,2,3-triazole nitrogen atom, and the side-chain indole NH of Trp 181. This interaction may stabilize the bound conformation of the ligand and could account for the observed differences in IC\u003csub\u003e50\u003c/sub\u003e values between the ethers and the acetamides used to link the two halves of the dimer. In addition to the ligand-protein interactions mentioned above, several inter-chain hydrogen bonds are observed between residues in the A and B hGal-3 CRD chains in the complex including Asp239A/ASN179B, Val116A/Asn153B, and Lys233A/Val116B. These additional interactions likely contribute to the stability of the ternary hGal-3 CRD/dimeric inhibitor complex, and the difficulties obtaining X-ray crystal structures of hGal-3 CRD with other dimeric inhibitors may be due to reduced ability of those ternary complexes to form inter-chain hydrogen bonds as a result of ligand conformations incompatible with inter-chain protein-protein contacts.\u003c/p\u003e\n\u003cp\u003eSize-exclusion chromatography combined with multi-angle light scattering (SEC-MALS) experiments were utilized to further understand the binding of the monomeric and dimeric Gal-3 inhibitors [37,38]. When observing the hGal-3 protein by itself, the molecular weight (MW) of the protein was 2.7 x 10\u003csup\u003e4\u003c/sup\u003e Da and showed a single peak in the SEC-MALS analysis. Combining the protein with monosaccharide \u003cstrong\u003e26\u003c/strong\u003e, the SEC-MALS analysis showed a single peak with a 2.65 x 10\u003csup\u003e4\u003c/sup\u003e Da MW, consistent with monomeric protein and no change in the oligomerization state. The same experiment was repeated using \u003cstrong\u003e10\u003c/strong\u003e and the hGal-3 protein, and the protein eluted two minutes earlier from the gel filtration column, consistent with an increase in hydrodynamic radius, and the observed MW increased to 3.6 x10\u003csup\u003e4\u003c/sup\u003e Da, consistent with a mixture of monomer and dimer. When combining \u003cstrong\u003e25\u003c/strong\u003e with the hGal-3 protein and performing the SEC-MALS analysis, similar to \u003cstrong\u003e10\u003c/strong\u003e, the peak eluted two minutes earlier and the MW of the major peak increased to 3.6 x10\u003csup\u003e4\u003c/sup\u003e Da. Both studies involving dimeric ligands showed a small shoulder that stretched back to the initial hGal-3 protein shift and had a molecular weight similar to the unbound protein.\u003c/p\u003e\n\u003cp\u003eThese observations were interpreted to indicate that the monomeric inhibitor \u003cstrong\u003e26\u003c/strong\u003e was bound to only one hGal-3 protein as expected, while both of the dimeric inhibitors, \u003cstrong\u003e10\u003c/strong\u003e and \u003cstrong\u003e25\u003c/strong\u003e, showed a different binding profile, one that was likely a mixture of monomeric and dimeric protein interactions based on the peak shift, increase in molecular weight and shoulder stretching back to the original hGal-3 protein peak. While the in vitro assay data, X-ray crystal structure of hGal-3 CRD with dimeric inhibitor \u003cstrong\u003e25\u003c/strong\u003e, and the SEC-MALS results are consistent with the binding of two hGal-3 CRD molecules to dimeric inhibitors in vitro, it is still unknown whether the improved potency achieved with dimeric inhibitors would result in improved in vivo activity.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe X-ray crystal structure analysis of monosaccharide Gal-3 inhibitors bound to the Gal-3 CRD revealed close inter-ligand contacts in the extended crystalline lattices. A set of dimeric compounds was designed to test if improvements in potency compared to the monosaccharide subunits could be achieved using a strategy linking two monosaccharide subunits bound to different Gal-3 CRD molecules. These experiments show that after optimization of linker position, length and atom composition, dimers can improve the potency in HTRF and F-ligand assays when compared to their monosaccharide subunits while maintaining in vitro permeability and metabolic stability. In an optimized case, \u003cb\u003e10\u003c/b\u003e improved potency 55x in the hGal-3 and 7-13x in the mGal-3 assays respectively when compared to the monosaccharide. Lead compounds \u003cb\u003e10\u003c/b\u003e and \u003cb\u003e25\u003c/b\u003e were further examined in in vivo mouse PK studies. PO dosing showed a much lower oral bioavailability compared to the monosaccharide comparators. However, when adjusting to dosing the compound SQ at 10 mg/kg of \u003cb\u003e25\u003c/b\u003e, AUC\u003csub\u003etotal\u003c/sub\u003e improved from 0.035 mM*h (PO) to 2.23 mM*h SQ. Furthermore, an X-ray crystal structure of \u003cb\u003e25\u003c/b\u003e bound to hGal3 protein was obtained and crystallography analysis showed the ligand bound to two distinct Gal-3 proteins with each monosaccharide unit occupying the CRD of a single protein. SEC-MALS analysis was consistent with the X-ray crystal structure as the molecular weight and retention time shifted with the introduction of both \u003cb\u003e10\u003c/b\u003e and \u003cb\u003e25\u003c/b\u003e with the hGal-3 protein, while combining monosaccharide \u003cb\u003e26\u003c/b\u003e with the hGal-3 protein did not show a corresponding shift in retention time and molecular weight using the SEC-MALS analysis.\u003c/p\u003e"},{"header":"Chemistry","content":"\u003cp\u003eThe formation of dimers \u003cstrong\u003e3\u003c/strong\u003e and \u003cstrong\u003e4\u003c/strong\u003e proceeded by first forming the C-3 1,2,3-triazole \u003cstrong\u003e29\u003c/strong\u003e using click chemistry to couple the silyl protected phenyl alkyne \u003cstrong\u003e27\u003c/strong\u003e and azide \u003cstrong\u003e28\u003c/strong\u003e (scheme \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e) [39]. The p-methoxybenzylidine acetal group was cleaved to unmask the C-4, C-6-diol \u003cstrong\u003e30\u003c/strong\u003e by heating in AcOH and H\u003csub\u003e2\u003c/sub\u003eO, then the diol was acylated with acetyl chloride to give \u003cstrong\u003e31\u003c/strong\u003e, where the C-2, C-4, and C-6 alcohols were all protected with as acetates. Treatment of \u003cstrong\u003e31\u003c/strong\u003e with bromine gave the anomeric bromide \u003cstrong\u003e32\u003c/strong\u003e in the beta configuration which could then be displaced using sodium azide in DMF at 75\u0026deg;C to give the azide \u003cstrong\u003e33\u003c/strong\u003e in the anomeric position in the alpha configuration. Global removal of the acetate groups followed using sodium methoxide in MeOH to provide triol \u003cstrong\u003e34\u003c/strong\u003e which was then subjected to another click reaction, coupling the C-1 azide with alkyl diynes to give linkers 3 and 5 carbons in length between the newly formed triazoles delivering dimers \u003cstrong\u003e3\u003c/strong\u003e and \u003cstrong\u003e4\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eDimer \u003cstrong\u003e5\u003c/strong\u003e used a different method to link the two halves of the molecule, in this instance extending a linker from the anomeric 1,2,3-triazole to the C-2 alcohol (scheme \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Synthesis of the first half of the molecule utilized the C-2 alcohol of \u003cstrong\u003e35\u003c/strong\u003e [30] as a handle to extend an acetate group using sodium hydride and ethyl bromoacetate, then hydrolyzed to the carboxylic acid \u003cstrong\u003e36\u003c/strong\u003e by treatment with sodium hydroxide, MeOH, and H\u003csub\u003e2\u003c/sub\u003eO. An amide was formed by treating the carboxylic acid \u003cstrong\u003e36\u003c/strong\u003e with HATU [40] and an alkynyl amine which extended an alkynyl handle from the C-2 position to give \u003cstrong\u003e37\u003c/strong\u003e. Click chemistry of the alkyne \u003cstrong\u003e37\u003c/strong\u003e with azide \u003cstrong\u003e38\u003c/strong\u003e [41] provided \u003cstrong\u003e5\u003c/strong\u003e which effectively linked the C-2 alcohol of one monosaccharide to the newly formed anomeric 1,2,3-triazole of a second monosaccharide through an acetamide and carbon spacer.\u003c/p\u003e\n\u003cp\u003eAmide linkages for compounds \u003cstrong\u003e7\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e10\u003c/strong\u003e were formed by treating alcohol \u003cstrong\u003e39\u003c/strong\u003e [30] with sodium hydride followed by \u003cem\u003et-\u003c/em\u003eBu-bromoacetate to form the \u003cem\u003et\u003c/em\u003e-butyl acetate \u003cstrong\u003e40\u003c/strong\u003e (Scheme \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Treatment of \u003cstrong\u003e40\u003c/strong\u003e with TFA, followed by 1,3-diaminopropane effectively unmasked both the C4, C6-diol and the carboxylic acid groups to give \u003cstrong\u003e41\u003c/strong\u003e. Acetyl chloride was used to protect the C4, C6-diol as the diacetate \u003cstrong\u003e42\u003c/strong\u003e and the dimers were then formed using HATU and diamines of varied lengths to link the two halves of the molecule through newly formed amide bonds extending from the C-2 position of each half. Removal of the acetate protecting groups with sodium methoxide in MeOH gave the dimers \u003cstrong\u003e7\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e10\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eDiamines linked through extended C-2 amides \u003cstrong\u003e11\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e18\u003c/strong\u003e and \u003cstrong\u003e23\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e25\u003c/strong\u003e were formed using a slightly different synthetic route (scheme \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). C-2 alcohols \u003cstrong\u003e43\u003c/strong\u003e [30] and \u003cstrong\u003e35\u003c/strong\u003e, which differ by the substitution pattern on the phenyl group attached to the anomeric 1,2,4-triazole, were treated with sodium hydride followed by ethyl bromoacetate to give the C-2 carboxylates which were hyrolyzed to the C-2 carboxylic acids \u003cstrong\u003e36\u003c/strong\u003e and \u003cstrong\u003e44\u003c/strong\u003e using aqueous sodium hydroxide and MeOH. Amide formation was accomplished using HATU and Et\u003csub\u003e3\u003c/sub\u003eN to provide the penultimate intermediates of \u003cstrong\u003e11\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e18\u003c/strong\u003e or T3P [42] and Et\u003csub\u003e3\u003c/sub\u003eN for \u003cstrong\u003e23\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e25\u003c/strong\u003e. Deprotection of the C4, C6-diol was accomplished in each instance by first heating the benzylidine acetals in aqueous AcOH at 70\u0026deg;C, followed by concentration and treatment with K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e in H\u003csub\u003e2\u003c/sub\u003eO and MeOH to give \u003cstrong\u003e11\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e18\u003c/strong\u003e and \u003cstrong\u003e23\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e25\u003c/strong\u003e. Dimers \u003cstrong\u003e19\u003c/strong\u003e and \u003cstrong\u003e20\u003c/strong\u003e joined through ether linkages from the C-2 position were formed by treatment of the C-2 alcohols \u003cstrong\u003e43\u003c/strong\u003e and \u003cstrong\u003e45\u003c/strong\u003e [30] with sodium hydride, followed by introduction of the diiodoalkane (scheme \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e). Deprotection of the C-4 and C-6 alcohols was accomplished using aqueous AcOH at 70\u0026deg;C followed by concentration and treatment with K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e in H\u003csub\u003e2\u003c/sub\u003eO and MeOH to give dimers \u003cstrong\u003e19\u003c/strong\u003e and \u003cstrong\u003e20\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eA one step formation of the carbamate linker to join the two monosaccharide units at the C-2 position was envisioned for \u003cstrong\u003e21\u003c/strong\u003e and \u003cstrong\u003e22\u003c/strong\u003e, however, in practice the carbamate formation wasn\u0026rsquo;t as cooperative as planned. The pyridyl carbonate was formed in situ by heating the C-2 alcohols \u003cstrong\u003e39\u003c/strong\u003e and \u003cstrong\u003e43\u003c/strong\u003e [30], dipyrin-2-yl carbonate and DMAP in CDCl\u003csub\u003e3\u003c/sub\u003e to 50\u0026deg;C. After cooling to rt, the diamino alkanes were introduced, however, a mixture of the dimer as a minor peak and the monomeric amino carbamate as a major peak were isolated along with C-2 alcohol starting materials. To convert additional monomeric material to the dimer product, a second addition of the pre-formed pyridyl carbonates \u003cstrong\u003e50\u003c/strong\u003e and \u003cstrong\u003e51\u003c/strong\u003e were necessary. After stirring the mixtures overnight after the addition of the pyridyl carbonate, the dimer products \u003cstrong\u003e52\u003c/strong\u003e and \u003cstrong\u003e53\u003c/strong\u003e formed as the major products. Isolation of carbamate \u003cstrong\u003e53\u003c/strong\u003e was complicated as purification using reverse phase conditions with an MeCN/ H\u003csub\u003e2\u003c/sub\u003eO /TFA mobile phase cleanly separated the dimer, however, upon concentrating, a portion of the benzylidine acetal group had fallen off, so the mixture of protected and deprotected alcohols were carried to the next step where the benzilidine acetal would be completely removed by heating the mixture in aqueous AcOH at 70\u0026deg;C, then treating with K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e in MeOH and H\u003csub\u003e2\u003c/sub\u003eO to give \u003cstrong\u003e21\u003c/strong\u003e. With the lessons learned from the complicated isolation of \u003cstrong\u003e53\u003c/strong\u003e, intermediate \u003cstrong\u003e52\u003c/strong\u003e was purified using normal phase flash chromatography to avoid the partial deprotection of the benzylidine acetal seen with the reverse phase conditions. Deprotection of the diol was accomplished by heating \u003cstrong\u003e52\u003c/strong\u003e in AcOH and H\u003csub\u003e2\u003c/sub\u003eO at 70\u0026deg;C followed by concentration and treatment with K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e, MeOH and H\u003csub\u003e2\u003c/sub\u003eO to give \u003cstrong\u003e22\u003c/strong\u003e.\u003c/p\u003e"},{"header":"Experimental Section","content":"\u003cp\u003e \u003cb\u003eMaterials.\u003c/b\u003e All reagents were purchased from commercial sources and used without further purification unless otherwise noted. All reactions involving air- or moisture-sensitive reagents were performed under an inert atmosphere. Proton and carbon magnetic resonance (\u003csup\u003e1\u003c/sup\u003eH and \u003csup\u003e13\u003c/sup\u003eC NMR) spectra were recorded either on a Bruker Avance 400 or a JEOL Eclipse 500 spectrometer and are reported in ppm relative to the reference solvent of the sample in which they were run. HPLC and LCMS analyses were conducted using a Shimadzu LC10AS liquid chromatograph and an SPDUV-vis detector at 220 or 254 nm with MS detection performed with a Micromass Platform LC spectrometer. HPLC purity analyses were performed using the following conditions: Method A. Waters XBridge C18 2.1 mm x 50 mm, 1.7 mM particles with a solvent system where solvent A\u0026thinsp;=\u0026thinsp;5% MeCN, 95% H\u003csub\u003e2\u003c/sub\u003eO, and 10 mM ammonium acetate and solvent B\u0026thinsp;=\u0026thinsp;95% MeCN, 5% H\u003csub\u003e2\u003c/sub\u003eO, and 10 mM ammonium acetate, flow rate\u0026thinsp;=\u0026thinsp;1 mL/min, and linear gradient from 0-100% B over 3 minutes at 50\u0026deg;C. Method B. Waters XBridge C18 2.1 mm x 50 mm, 1.7 mM particles with a solvent system where solvent A\u0026thinsp;=\u0026thinsp;5% MeCN, 95% H\u003csub\u003e2\u003c/sub\u003eO, and 0.1% TFA and solvent B\u0026thinsp;=\u0026thinsp;95% MeCN, 5% H\u003csub\u003e2\u003c/sub\u003eO, and 0.1% TFA, flow rate\u0026thinsp;=\u0026thinsp;1 mL/min, and linear gradient from 0-100% B over 3 minutes at 50\u0026deg;C. All final compounds were tested using two HPLC methods and the lower of the two HPLC purities was reported. LCMS analyses were performed using the following conditions: Method 1: Xbridge BEH C18 4.6 mm \u0026times; 50 mm column with solvent system where solvent A\u0026thinsp;=\u0026thinsp;10% MeCN, 90% H\u003csub\u003e2\u003c/sub\u003eO, and 0.1% TFA and solvent B\u0026thinsp;=\u0026thinsp;90% MeCN, 10% H\u003csub\u003e2\u003c/sub\u003eO, and 0.1% TFA, flow rate\u0026thinsp;=\u0026thinsp;0.8 mL/min, and linear gradient from 2\u0026ndash;98% B over 1.5 minutes at 50\u0026deg;C. Method 2: Waters XBridge C18 2.1 mm x 50 mm, 1.7 mM particles with a solvent system where solvent A\u0026thinsp;=\u0026thinsp;5% MeCN, 95% H\u003csub\u003e2\u003c/sub\u003eO, and 0.1% TFA and solvent B\u0026thinsp;=\u0026thinsp;95% MeCN, 5% H\u003csub\u003e2\u003c/sub\u003eO, and 0.1% TFA, flow rate\u0026thinsp;=\u0026thinsp;1 mL/min, and linear gradient from 0-100% B over 3 minutes at 50\u0026deg;C.\u003c/p\u003e\n\u003ch3\u003eSynthesis\u003c/h3\u003e\n\u003cp\u003e \u003cb\u003e(29) (2S,4aR,6S,7R,8S,8aR)-8-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(4-methoxyphenyl)-6-(phenylthio)hexahydropyrano[3,2-d][1,3]dioxin-7-yl acetate.\u003c/b\u003e To a flask containing \u003cb\u003e28\u003c/b\u003e (0.75 g, 1.639 mmol) was added copper (II) sulfate pentahydrate (0.287 g, 1.148 mmol) and sodium ascorbate (0.325 g, 1.639 mmol). The mixture was diluted with DMF (20 mL) and H\u003csub\u003e2\u003c/sub\u003eO (6.7 mL), \u003cb\u003e27\u003c/b\u003e was added and the mixture was stirred at rt. After 21.5 h, the mixture was filtered through a plug of celite which was washed with a DCM:MeOH mixture (4:1). The filtrate was partially concentrated under reduced pressure until solids formed. The solids were dissolved in EtOAc (100 mL), and the organic layer was washed with H\u003csub\u003e2\u003c/sub\u003eO (3 x 75 mL) followed by brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the product as an off white solid (1.0 g, 1.63 mmol, 100% yield) which was used with no additional purification in the next step. LCMS: m/e 612.3 (MH\u003csup\u003e+\u003c/sup\u003e), 1.06 min (Method 1). \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, chloroform-d) δ 7.87 (s, 1H), 7.67\u0026ndash;7.62 (m, 2H), 7.57\u0026ndash;7.51 (m, 1H), 7.43\u0026ndash;7.21 (m, 7H), 6.94\u0026ndash;6.88 (m, 2H), 5.58 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.8, 9.5 Hz, 1H), 5.42 (s, 1H), 5.16 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11.0, 3.1 Hz, 1H), 4.87 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.7 Hz, 1H), 4.47 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12.7, 1.4 Hz, 1H), 4.41 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.1, 0.9 Hz, 1H), 4.08 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12.7, 1.7 Hz, 1H), 3.86 (s, 3H), 3.79 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.1 Hz, 1H), 1.93 (s, 3H). \u003csup\u003e19\u003c/sup\u003eF NMR (377 MHz, chloroform-d) δ -114.97 (s, 1F).\u003c/p\u003e \u003cp\u003e \u003cb\u003e(30) (2S,3R,4S,5R,6R)-4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-2-(phenylthio)tetrahydro-2H-pyran-3-yl acetate.\u003c/b\u003e To a flask containing \u003cb\u003e29\u003c/b\u003e (1.13 g, 1.846 mmol, combined from two lots) was added AcOH (20 mL) and H\u003csub\u003e2\u003c/sub\u003eO (5 mL). The mixture was warmed to 60\u0026deg;C. After 2h, the mixture was cooled to rt and the solvent was concentrated under reduced pressure. The mixture was diluted with DCM and concentrated two additional times to give the crude product which was used in the next step with no additional purification. LCMS: m/e 494.2 (MH\u003csup\u003e+\u003c/sup\u003e), 0.89 min (Method 1).\u003c/p\u003e \u003cp\u003e \u003cb\u003e(31) (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(phenylthio)tetrahydro-2H-pyran-3,5-diyl diacetate.\u003c/b\u003e To a suspension of the crude product, \u003cb\u003e30\u003c/b\u003e, in dichloromethane (20 mL) was added pyridine (0.75 mL, 9.23 mmol) followed by DMAP (5.6 mg, 0.046 mmol) and acetyl chloride (0.40 mL, 5.54 mmol). The mixture is stirred at rt for 43 h then was concentrated under reduced pressure and was purified by flash chromatography using a 10\u0026ndash;70% EtOAc in hexanes gradient and a 40g silica gel column. The fractions containing the product were combined and concentrated under reduced pressure to give the title product as a light-yellow solid (1.04 g, 1.80 mmol, 98% yield). LCMS: m/e 578.3 (MH\u003csup\u003e+\u003c/sup\u003e), 0.99 min (Method 1). \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, chloroform-d) δ 7.78 (s, 1H), 7.64\u0026ndash;7.55 (m, 3H), 7.52\u0026ndash;7.42 (m, 2H), 7.40\u0026ndash;7.34 (m, 3H), 5.73 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.3 Hz, 1H), 5.58 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.0 Hz, 1H), 5.19 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11.0, 3.0 Hz, 1H), 4.89 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.6 Hz, 1H), 4.22\u0026ndash;4.10 (m, 3H), 2.06 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H). \u003csup\u003e19\u003c/sup\u003eF NMR (471 MHz, chloroform-d) δ -114.50 (s, 1F).\u003c/p\u003e \u003cp\u003e \u003cb\u003e(32) (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-bromo-4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate.\u003c/b\u003e A solution of \u003cb\u003e31\u003c/b\u003e (1.04 g, 1.80 mmol) in dichloromethane (20 mL) was cooled to 0\u0026deg;C and a solution of bromine (0.185 mL, 3.60 mmol) in dichloromethane (2 mL) was added slowly. The mixture was stirred at 0\u0026deg;C for 2h, then was diluted with sat. aq. sodium thiosulfate (50 mL) and was stirred until the red color had subsided. The mixture was extracted with dichloromethane (3 x 30 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 5\u0026ndash;50% EtOAc in hexanes gradient and an 80g silica gel column. The fractions containing the product were combined and concentrated under reduced pressure to give the title product as an off-white solid (0.67 g, 1.22 mmol, 68% yield). LCMS: m/e 548.1, 550.1 (MH\u003csup\u003e+\u003c/sup\u003e), 0.95 min (Method 1). \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, chloroform-d) δ 7.81 (s, 1H), 7.63 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.8, 1.9 Hz, 1H), 7.55\u0026ndash;7.51 (m, 1H), 7.49\u0026ndash;7.43 (m, 1H), 6.90 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.7 Hz, 1H), 5.82 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11.3, 3.9 Hz, 1H), 5.64 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.9, 1.3 Hz, 1H), 5.33 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11.2, 3.1 Hz, 1H), 4.68\u0026ndash;4.63 (m, 1H), 4.28\u0026ndash;4.22 (m, 1H), 4.18\u0026ndash;4.12 (m, 1H), 2.08 (s, 6H), 1.97 (s, 3H). \u003csup\u003e19\u003c/sup\u003eF NMR (377 MHz, chloroform-d) δ -114.48 (s, 1F).\u003c/p\u003e \u003cp\u003e \u003cb\u003e(33) (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-azido-4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate.\u003c/b\u003e To a solution of \u003cb\u003e32\u003c/b\u003e (0.67 g, 1.221 mmol) in DMF (15 mL) was added sodium azide (0.238 g, 3.66 mmol) and the mixture was heated to 75 \u0026deg; C. After 15h of heating, the mixture was cooled to rt, diluted with H\u003csub\u003e2\u003c/sub\u003eO (40 mL) and extracted with EtOAc (2 x 40 mL). The organic layers were washed with H\u003csub\u003e2\u003c/sub\u003eO 4 x 40 mL), then with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 20\u0026ndash;60% EtOAc in hexanes gradient and an 80g silica gel column. The fractions containing the product were combined and concentrated under reduced pressure to give the title product as a white solid (0.54 g, 1.06 mmol, 87% yield). LCMS: m/e 511.3 (MH\u003csup\u003e+\u003c/sup\u003e), 0.92 min (Method 1). \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, chloroform-d) δ 7.81 (s, 1H), 7.61 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.9, 1.8 Hz, 1H), 7.54\u0026ndash;7.41 (m, 2H), 5.66 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11.4, 8.6 Hz, 1H), 5.60 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.1 Hz, 1H), 5.16 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11.4, 3.3 Hz, 1H), 4.82 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 1H), 4.26\u0026ndash;4.16 (m, 3H), 2.08 (s, 6H), 1.97 (s, 3H). \u003csup\u003e19\u003c/sup\u003eF NMR (377 MHz, chloroform-d) δ -114.41 (s, 1F).\u003c/p\u003e \u003cp\u003e \u003cb\u003e(34) (2R,3R,4S,5R,6R)-2-azido-4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol.\u003c/b\u003e To a suspension of \u003cb\u003e33\u003c/b\u003e (0.54g, 1.06 mmol) in MeOH (20 mL) was added sodium methoxide (25% in MeOH) (0.024 mL, 0.106 mmol) and the mixture was stirred at rt. After 2h LC/MS showed the reaction was complete. To the mixture was added 0.25 mL of 1N HCl and it was concentrated under reduced pressure. The residue was diluted with H\u003csub\u003e2\u003c/sub\u003eO (25 mL) and extracted with EtOAc (3 x 25 mL). The organic layers were washed with brine and dried over magnesium sulfate filtered and concentrated under reduced pressure to give the title product as an off-white solid (0.365 g, 0.949 mmol, 89% yield). LCMS: m/e 385.2 (MH\u003csup\u003e+\u003c/sup\u003e), 0.67 min (Method 1). \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 8.76 (s, 1H), 7.91 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.7, 1.9 Hz, 1H), 7.78 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4, 1.5 Hz, 1H), 7.70\u0026ndash;7.64 (m, 1H), 5.81 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.6 Hz, 1H), 5.40 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.4 Hz, 1H), 4.87 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.9, 3.0 Hz, 1H), 4.78 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.6 Hz, 1H), 4.74 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 1H), 4.13\u0026ndash;4.04 (m, 1H), 3.92 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.3, 3.0 Hz, 1H), 3.86 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.4 Hz, 1H), 3.60\u0026ndash;3.49 (m, 2H). \u003csup\u003e19\u003c/sup\u003eF NMR (377 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ -115.85 (s, 1F).\u003c/p\u003e \u003cp\u003e \u003cb\u003e(3) (2R,2'R,3R,3'R,4S,4'S,5R,5'R,6R,6'R)-6,6'-(propane-1,3-diylbis(1H-1,2,3-triazole-4,1-diyl))bis(4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol).\u003c/b\u003e To a flask containing \u003cb\u003e34\u003c/b\u003e (23 mg, 0.06 mmol) was added copper(II) sulfate pentahydrate (21 mg, 0.084 mmol) and sodium ascorbate (24 mg, 0.120 mmol). The mixture was diluted with DMF (0.5 mL) and H\u003csub\u003e2\u003c/sub\u003eO (0.167 mL). 1,6-heptadiyne (1M in THF) (0.030 mL, 0.030 mmol) was added and the mixture was stirred at rt for 5h. The mixture was filtered through a plug of glass wool to remove the solids and the filtrate was concentrated under a stream of nitrogen. The residue was diluted with DMF and was filtered through a plug of celite. The filtrate was purified by preparative HPLC using an XBridge C18, 200 mm x 19 mm, 5-\u0026micro;m particles column; mobile phase A: 5:95 MeCN: H\u003csub\u003e2\u003c/sub\u003eO with 10-mM ammonium acetate; mobile phase B: 95:5 MeCN: H\u003csub\u003e2\u003c/sub\u003eO with 10-mM ammonium acetate; gradient: a 0-minute hold at 20% B, 20\u0026ndash;60% B over 20 minutes, then a 4-minute hold at 100% B; flow rate: 20 mL/min; column temperature: 25\u0026deg;C. Fraction collection was triggered by MS and UV signals. Fractions containing the product were combined and dried via centrifugal evaporation to give the title product (8.6 mg, 0.01 mmol, 33% yield) with a 98% HPLC purity. LCMS: m/e 861.03 (MH\u003csup\u003e+\u003c/sup\u003e), 1.59 min (Method 2). \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 8.78 (s, 2H), 8.14 (s, 2H), 7.89 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.7 Hz, 2H), 7.76 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 2H), 7.72\u0026ndash;7.66 (m, 2H), 5.83 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.9 Hz, 2H), 5.68 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.0 Hz, 2H), 5.50 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.7 Hz, 2H), 5.16\u0026ndash;5.09 (m, 2H), 4.91\u0026ndash;4.80 (m, 4H), 4.11\u0026ndash;4.01 (m, 4H), 3.55 (br t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.8 Hz, 2H), 2.78 (br t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.3 Hz, 4H), 2.03 (quin, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.1 Hz, 2H). Several protons in the aliphatic region near the H\u003csub\u003e2\u003c/sub\u003eO peak were obscured because of H\u003csub\u003e2\u003c/sub\u003eO suppression used while processing the NMR. 98.4% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(4) (2R,2'R,3R,3'R,4S,4'S,5R,5'R,6R,6'R)-6,6'-(pentane-1,5-diylbis(1H-1,2,3-triazole-4,1-diyl))bis(4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol).\u003c/b\u003e To a flask containing \u003cb\u003e34\u003c/b\u003e (26 mg, 0.068 mmol) was added copper (II) sulfate pentahydrate (24 mg, 0.095 mmol) and sodium ascorbate (27 mg, 0.135 mmol). The mixture was diluted with DMF (0.5 mL) and H\u003csub\u003e2\u003c/sub\u003eO (0.167 mL), 1,8-nonadiyne (1M in THF) (0.034 mL, 0.034 mmol) was added and the mixture was stirred at rt for 5h. The mixture was filtered through a plug of glass wool to remove the solids then was concentrated under a stream of nitrogen. The residue was diluted with H\u003csub\u003e2\u003c/sub\u003eO (1 mL) and was extracted with dichloromethane (3 x 1 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The aqueous layer was concentrated under a stream of nitrogen. The concentrated organic layer gave only 4mg of material, so the concentrated aqueous layer was diluted with DMF and was filtered through a plug of glass wool. The filtrate was combined with the organic extract and the mixture was filtered through a plug of celite then was purified by preparative HPLC using an XBridge C18, 200 mm x 19 mm, 5-\u0026micro;m particles column; mobile phase A: 5:95 MeCN: H\u003csub\u003e2\u003c/sub\u003eO with 10-mM ammonium acetate; mobile phase B: 95:5 MeCN: H\u003csub\u003e2\u003c/sub\u003eO with 10-mM ammonium acetate; gradient: a 0-minute hold at 20% B, 20\u0026ndash;60% B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25\u0026deg;C. Fraction collection was triggered by MS signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title product (7.1 mg, 0.008 mmol, 24% yield) with 97% HPLC purity. LCMS: m/e 889.21 (MH\u003csup\u003e+\u003c/sup\u003e), 1.66 min (Method 2). \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 8.66 (s, 2H), 8.07 (s, 2H), 7.82 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.8 Hz, 2H), 7.71 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.5 Hz, 2H), 7.67\u0026ndash;7.60 (m, 2H), 5.84 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.3 Hz, 2H), 5.76 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.9 Hz, 2H), 5.67 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.7 Hz, 2H), 5.11\u0026ndash;5.02 (m, 2H), 4.85\u0026ndash;4.74 (m, 2H), 4.09\u0026ndash;3.74 (m, 7H), 3.53 (br s, 3H), 2.65 (br t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.5 Hz, 4H), 1.73\u0026ndash;1.56 (m, 4H), 1.45\u0026ndash;1.32 (m, 2H). 99.0% purity based on 2 HPLC runs.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(36) 2-(((2S,4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)AcOH.\u003c/b\u003e A solution of \u003cb\u003e35\u003c/b\u003e (0.291 g, 0.410 mmol) in THF (5 mL) was cooled to 0\u0026deg;C and sodium hydride (0.082 g, 2.051 mmol) was added. The mixture was stirred for 15 minutes and ethyl bromoacetate (0.183 mL, 1.641 mmol) was added. The mixture was allowed to warm to rt as the ice bath melted and after 17.5h, the reaction was carefully quenched with EtOH and the mixture was concentrated under reduced pressure. The residue was diluted with H\u003csub\u003e2\u003c/sub\u003eO (20 mL) and was extracted with EtOAc (2 x 30 mL). The organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 10\u0026ndash;80% EtOAc in hexanes gradient and a 40g silica gel column. Fractions containing the product were combined and concentrated under reduced pressure to give the carboxylate product as an off-white foam (207 mg, 0.260 mmol, 63% yield). LCMS: m/e 795.4 (MH\u003csup\u003e+\u003c/sup\u003e), 1.12 min (Method 1). \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, chloroform-d) δ 8.18 (s, 1H), 7.80 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 2H), 7.65 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.7, 1.0 Hz, 1H), 7.47\u0026ndash;7.40 (m, 7H), 5.49 (s, 1H), 5.13 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.6, 3.5 Hz, 1H), 4.86 (br t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.2 Hz, 1H), 4.41 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.1 Hz, 1H), 4.36 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.0 Hz, 1H), 4.33 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12.8, 1.1 Hz, 1H), 4.05 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12.7, 1.2 Hz, 1H), 4.01\u0026ndash;3.84 (m, 3H), 3.67 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;15.6 Hz, 1H), 3.58 (s, 1H), 2.45 (s, 3H), 1.11 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.2 Hz, 3H). To a suspension of the carboxylate (0.207 g, 0.260 mmol) in MeOH (5 mL) was added sodium methoxide (25% in MeOH) (0.030 mL, 0.130 mmol) and the mixture was stirred at rt. After 2h, the mixture was diluted with 1,4-dioxane (5 mL) and sodium hydroxide (1N) (1.301 mL, 1.301 mmol) was added. The mixture was stirred at rt for 2h, then was concentrated under reduced pressure, diluted with a solution of sat. aq. ammonium chloride and was extracted with EtOAc (3 x 30 mL). The organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title product (0.20 g, 0.26 mmol, 100% yield) as an off-white solid. LCMS: m/e 767.5 (MH\u003csup\u003e+\u003c/sup\u003e), 1.02 min (Method 1). \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, \u003cem\u003eDMSO-d\u003c/em\u003e\u003csub\u003e\u003cem\u003e6\u003c/em\u003e\u003c/sub\u003e) δ 12.59 (br s, 1H), 9.27 (s, 1H), 8.31\u0026ndash;8.13 (m, 1H), 8.09\u0026ndash;8.02 (m, 1H), 7.96 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 1H), 7.82 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.4 Hz, 2H), 7.37 (s, 5H), 5.54 (s, 1H), 5.47 (br dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.7, 3.0 Hz, 1H), 4.87 (br t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.1 Hz, 1H), 4.62 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.2 Hz, 1H), 4.43 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.9 Hz, 1H), 4.12\u0026ndash;4.03 (m, 1H), 3.99\u0026ndash;3.78 (m, 3H), 3.67\u0026ndash;3.51 (m, 1H), 2.33 (s, 3H).\u003c/p\u003e \u003cp\u003e \u003cb\u003e(37) 2-(((2S,4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-N-(hex-5-yn-1-yl)acetamide.\u003c/b\u003e To a flask containing a solution of \u003cb\u003e36\u003c/b\u003e (50 mg, 0.065 mmol) in DMF (1 mL) and triethylamine (0.036 mL, 0.261 mmol) was added hex-5-yn-1-amine (9.5 mg, 0.098 mmol) followed by HATU (49.5 mg, 0.130 mmol). The mixture was stirred at rt for 1.75 h, then was diluted with H\u003csub\u003e2\u003c/sub\u003eO (5 mL) and was extracted with EtOAc (3 x 5 mL). The organic layers were washed with H\u003csub\u003e2\u003c/sub\u003eO (3 x 10 mL), then with brine, dried over sodium sulfate filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a 10\u0026ndash;70% EtOAc in hexanes gradient and a 24g silica gel column. The fractions containing the product were combined and concentrated under reduced pressure to give the title product (40 mg, 0.047 mmol, 72% yield) as a white solid. LCMS: m/e 846.5 (MH\u003csup\u003e+\u003c/sup\u003e), 1.08 min (Method 1). \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, Chloroform-d) δ 8.15 (s, 1H), 7.79 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.6 Hz, 1H), 7.69\u0026ndash;7.59 (m, 2H), 7.49\u0026ndash;7.34 (m, 7H), 6.12\u0026ndash;6.02 (m, 1H), 5.50 (s, 1H), 5.11 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.5, 3.4 Hz, 1H), 4.80\u0026ndash;4.68 (m, 1H), 4.41 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.9 Hz, 1H), 4.36 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.8 Hz, 1H), 4.26 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12.8 Hz, 1H), 4.05 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11.4 Hz, 1H), 3.94\u0026ndash;3.84 (m, 1H), 3.57 (s, 1H), 3.43 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14.5 Hz, 1H), 3.15\u0026ndash;2.98 (m, 2H), 2.45 (s, 3H), 2.17 (td, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.7, 2.6 Hz, 2H), 1.93 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.8 Hz, 1H), 1.53\u0026ndash;1.40 (m, 4H).\u003c/p\u003e \u003cp\u003e \u003cb\u003ePreparation of 2-(((2S,4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-N-(4-(1-((2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-4-yl)butyl)acetamide\u003c/b\u003e: To a flask containing \u003cb\u003e37\u003c/b\u003e (23 mg, 0.027 mmol) was added copper (II) sulfate pentahydrate (9.50 mg, 0.038 mmol) and sodium ascorbate (10.76 mg, 0.054 mmol) followed by \u003cb\u003e38\u003c/b\u003e (12mg, 0.030 mmol). The mixture was diluted with DMF (0.5 mL) and H\u003csub\u003e2\u003c/sub\u003eO (0.167 mL) and was stirred at rt for 64h then was diluted with H\u003csub\u003e2\u003c/sub\u003eO (2 mL) and extracted with EtOAc (4 x 2 mL). The organic layers were washed with H\u003csub\u003e2\u003c/sub\u003eO (4 x 8 mL), then with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product (30 mg, 0.024 mmol, 89% yield) as an off-white solid which was used in the next step with no additional purification. LCMS: m/e 1250.9 (MH\u003csup\u003e+\u003c/sup\u003e), 1.03 min (Method 1).\u003c/p\u003e \u003cp\u003e \u003cb\u003e(5) 2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(4-(1-((2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-4-yl)butyl)acetamide.\u003c/b\u003e To a vial containing the crude dimerized product (30 mg, 0.024 mmol) was added AcOH (0.5 mL) and H\u003csub\u003e2\u003c/sub\u003eO (0.167 mL). The vial was sealed and the mixture was heated to 70\u0026deg;C for 15.5h. The mixture was cooled to rt then was concentrated under a stream of nitrogen. K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e (35 mg) was added and the mixture was diluted with MeOH (0.5 mL) and H\u003csub\u003e2\u003c/sub\u003eO (0.25 mL). After stirring for 1h at rt, the mixture was diluted with 2 mL of H\u003csub\u003e2\u003c/sub\u003eO and extracted with dichloromethane (4 x 2 mL) followed by chloroform : MeOH (4 : 1, 2 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. Only 6 mg of crude material was isolated, so the aqueous layer was concentrated under a stream of nitrogen then was diluted with 1 mL of DMF and stirred for several minutes. The mixture was filtered through a plug of celite to remove the solids and filtrate was combined with the organic residue and was purified by preparative HPLC using an XBridge C18, 200 mm x 19 mm, 5-\u0026micro;m particles column; mobile phase A: 5:95 MeCN: H\u003csub\u003e2\u003c/sub\u003eO with 10-mM ammonium acetate; mobile phase B: 95:5 MeCN: H\u003csub\u003e2\u003c/sub\u003eO with 10-mM ammonium acetate; gradient: a 0-minute hold at 30% B, 30\u0026ndash;70% B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25\u0026deg;C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title product (9.1 mg, 0.0078 mmol, 33% yield over 2 steps). LCMS: m/e 1160.2 (MH\u003csup\u003e+\u003c/sup\u003e), 1.83 min (Method 2). Key \u003csup\u003e1\u003c/sup\u003eH NMR peaks: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 9.07\u0026ndash;8.98 (m, 1H), 8.80\u0026ndash;8.70 (m, 1H), 8.04\u0026ndash;7.97 (m, 2H), 7.94\u0026ndash;7.88 (m, 2H), 7.84\u0026ndash;7.72 (m, 4H), 6.99\u0026ndash;6.76 (m, 1H), 2.32 (s, 3H), 1.46\u0026ndash;1.34 (m, 2H), 1.28\u0026ndash;1.15 (m, 2H). 99.0% purity based on 2 HPLC runs.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(40) Tert-butyl 2-(((2S,4aR,6S,7R,8R,8aR)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetate.\u003c/b\u003e A solution of \u003cb\u003e39\u003c/b\u003e (0.536 g, 0.813 mmol) in THF (10 mL) was cooled to 0\u0026deg;C and sodium hydride (60% mineral oil dispersion) (0.098 g, 2.438 mmol) was added. The mixture was stirred for 15 minutes and tert-butyl bromoacetate (0.238 mL, 1.626 mmol) was added. The mixture was allowed to warm to rt as the ice bath melted and the mixture was stirred at rt for 24h. The mixture was carefully diluted with 20 mL of H\u003csub\u003e2\u003c/sub\u003eO and was extracted with EtOAc (3 x 20 mL). The organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a 10\u0026ndash;50% EtOAc in hexanes gradient and a 40g silica gel column. The fractions containing the product were combined and concentrated under reduced pressure to give the title product as a white solid (0.494g, 0.64 mmol, 79% yield). LCMS: m/e 773.5 (MH\u003csup\u003e+\u003c/sup\u003e), 1.14 min (Method 1). \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.79\u0026ndash;7.67 (m, 1H), 7.56\u0026ndash;7.38 (m, 9H), 5.48 (s, 1H), 5.12 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.5, 3.4 Hz, 1H), 4.91\u0026ndash;4.76 (m, 1H), 4.47\u0026ndash;4.39 (m, 2H), 4.34 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12.8, 1.1 Hz, 1H), 4.05 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12.8, 1.5 Hz, 1H), 3.89\u0026ndash;3.76 (m, 1H), 3.65\u0026ndash;3.55 (m, 2H), 2.46 (s, 3H), 1.28 (s, 9H).\u003c/p\u003e \u003cp\u003e \u003cb\u003e(41) 2-(((2S,3R,4S,5R,6R)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)AcOH.\u003c/b\u003e To a solution of tert-butyl ester \u003cb\u003e40\u003c/b\u003e (0.494 g, 0.639 mmol) in dichloromethane (4 mL) was added TFA (2 ml, 26.0 mmol) and the mixture was stirred at rt for 38 h, then was concentrated under reduced pressure. The residue was treated with a solution of 1,3-diaminopropane (1M in THF) to decompose the anhydride that was apparent in the LC/MS and the mixture was stirred at rt for 66 h, then was diluted with several drops of MeOH and was purified by flash chromatography using a 0\u0026ndash;15% MeOH in DCM gradient and a 40g silica gel column. Fractions containing the product were combined and concentrated under reduced pressure to give the title product as an off-white solid (0.09 g, 0.14 mmol, 22% yield). LCMS: m/e 629.3 (MH\u003csup\u003e+\u003c/sup\u003e), 0.76 min (Method 1). \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, chloroform-d) δ 8.24 (s, 1H), 7.60\u0026ndash;7.45 (m, 5H), 4.89\u0026ndash;4.76 (m, 2H), 4.69\u0026ndash;4.60 (m, 1H), 4.36 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.0 Hz, 1H), 4.12\u0026ndash;4.04 (m, 1H), 3.74\u0026ndash;3.51 (m, 4H), 3.44 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;15.6 Hz, 1H), 2.49 (s, 3H).\u003c/p\u003e \u003cp\u003e \u003cb\u003e(42) 2-(((2S,3R,4R,5R,6R)-5-acetoxy-6-(acetoxymethyl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)AcOH.\u003c/b\u003e To a suspension of carboxylic acid \u003cb\u003e41\u003c/b\u003e (0.089 g, 0.14 mmol) in dichloromethane (2 mL) was added pyridine (0.1 mL, 1.236 mmol), DMAP (0.864 mg, 7.07 \u0026micro;mol) and acetyl chloride (0.075 mL, 1.055 mmol). The mixture was stirred at rt for 63h, then was concentrated under reduced pressure. The residue was purified by flash chromatography using a 0\u0026ndash;10% EtOAc in DCM gradient followed by 10% MeOH in DCM gradient. The fractions containing product were combined and concentrated under reduced pressure to give the title product as an off-white solid which was used in the next step with no additional purification. LCMS: m/e 713.4 (MH\u003csup\u003e+\u003c/sup\u003e), 0.89 min (Method 1).\u003c/p\u003e \u003cp\u003e \u003cb\u003e(7) 2-(((2R,3S,4R,5S,6S)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)-N-(2-(2-(((2S,3R,4S,5R,6R)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)ethyl)acetamide.\u003c/b\u003e To a flask containing a solution of \u003cb\u003e42\u003c/b\u003e (0.036 g, 0.050 mmol) in DMF (2 mL) and triethylamine (0.035 mL, 0.252 mmol) was added HATU (0.058 g, 0.151 mmol) followed by ethylenediamine (1M in DMF) (0.040 mL, 0.040 mmol). The mixture was stirred at rt for 24 h then was filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with TFA buffer. The fractions containing the product were concentrated under reduced pressure to give the dimer as a white solid (7 mg, 0.0048 mmol, 19% yield). LCMS: m/e 1452.0 (MH\u003csup\u003e+\u003c/sup\u003e), 1.03 min (Method 1). To the dimer (0.007 g, 4.82 \u0026micro;mol) in MeOH (1 mL) was added sodium methoxide (25% solution in MeOH) (1.1 \u0026micro;l, 4.8 \u0026micro;mol). The mixture was stirred at rt for 16h. Three drops of 1N HCl was added and the mixture was concentrated under a stream of nitrogen. The mixture was diluted with DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with ammonium acetate buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the title product (2.7 mg, 0.0021 mmol, 42% yield). LCMS: m/e 1281.33 (MH\u003csup\u003e+\u003c/sup\u003e), 1.84 min (Method 2). \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 8.96 (s, 2H), 7.87\u0026ndash;7.57 (m, 10H), 6.96 (br s, 2H), 5.50\u0026ndash;5.34 (m, 2H), 5.08 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.1 Hz, 2H), 4.80\u0026ndash;4.55 (m, 4H), 4.40 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.2 Hz, 2H), 4.10\u0026ndash;3.31 (m, 8H), 2.70\u0026ndash;2.58 (m, 4H), 2.27 (br s, 6H). 96.4% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(8) 2-(((2R,3S,4R,5S,6S)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)-N-(3-(2-(((2S,3R,4S,5R,6R)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)propyl)acetamide.\u003c/b\u003e To a flask containing a solution of \u003cb\u003e42\u003c/b\u003e (0.034 g, 0.048 mmol) in DMF (1 mL) and triethylamine (0.033 mL, 0.238 mmol) was added HATU (0.054 g, 0.143 mmol) followed by 1,3-diaminopropane (1M in DMF) (0.038 mL, 0.038 mmol). The mixture was stirred at rt for 24h, then was filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with TFA buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the dimerized product (7 mg, 0.0047 mmol, 20% yield) as a white solid. LCMS: m/e 1466.1 (MH\u003csup\u003e+\u003c/sup\u003e), 1.03 min (Method 1). To a solution of the dimer (0.007 g, 4.7 \u0026micro;mol) in MeOH (1 mL) was added sodium methoxide (25% in MeOH) (1.1 \u0026micro;l, 4.78 \u0026micro;mol) and the mixture was stirred at rt for 16h. Three drops of 1N HCl was added and the mixture was concentrated under a stream of nitrogen. The mixture was diluted with DMF, filtered through a plug of glass wool and was purified using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title product (1.9 mg, 0.0015 mmol, 30% yield). LCMS: m/e 1295.86 (MH\u003csup\u003e+\u003c/sup\u003e), 1.84 min (Method 2). \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 9.03\u0026ndash;8.89 (m, 2H), 7.85\u0026ndash;7.59 (m, 10H), 6.91\u0026ndash;6.69 (m, 2H), 5.42 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.8 Hz, 2H), 5.10 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;13.4 Hz, 2H), 4.73 (br t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.8 Hz, 2H), 4.64\u0026ndash;4.55 (m, 2H), 4.48\u0026ndash;4.37 (m, 2H), 3.93\u0026ndash;3.85 (m, 2H), 3.77 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;15.0 Hz, 2H), 3.65\u0026ndash;3.52 (m, 2H), 5.33\u0026ndash;3.14 (m, 2H), 2.67\u0026ndash;2.54 (m, 4H), 2.27 (s, 6H), 1.14\u0026ndash;0.85 (m, 2H). 95.2% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(9) 2-(((2R,3S,4R,5S,6S)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)-N-(4-(2-(((2S,3R,4S,5R,6R)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)butyl)acetamide.\u003c/b\u003e To a flask containing a solution of \u003cb\u003e42\u003c/b\u003e (0.031 g, 0.043 mmol) in DMF (1 mL) and triethylamine (0.030 mL, 0.217 mmol) was added HATU (0.050 g, 0.130 mmol) followed by 1,4-diaminobutane (1M in DMF) (0.035 mL, 0.035 mmol). The mixture was stirred at rt for 24h, then was filtered through a plug of glass wool and was purified by prep HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with TFA buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the dimerized product (7 mg, 0.0047 mmol, 22% yield) as a white solid. LCMS: m/e 1480.0 (MH\u003csup\u003e+\u003c/sup\u003e), 1.02 min (Method 1). To a solution of the dimer (0.007 g, 4.7 \u0026micro;mol) in MeOH (0.5 mL) was added sodium methoxide (25% in MeOH) (1.3 \u0026micro;l, 5.55 \u0026micro;mol) and the mixture was stirred at rt for 16h at rt. Three drops of 1N HCl were added and the mixture was concentrated under a stream of nitrogen, diluted with DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title product (2.4 mg, 0.0018 mmol, 38% yield). LCMS: m/e 1309.09 (MH\u003csup\u003e+\u003c/sup\u003e), 1.86 min (Method 2). Key \u003csup\u003e1\u003c/sup\u003eH NMR peaks: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 9.03 (s, 2H), 7.89\u0026ndash;7.58 (m, 10H), 6.79\u0026ndash;6.61 (m, 2H), 2.34 (s, 6H), 0.96 (br s, 4H). 97.6% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(10) 2-(((2R,3S,4R,5S,6S)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)-N-(5-(2-(((2S,3R,4S,5R,6R)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)pentyl)acetamide.\u003c/b\u003e To a flask containing a solution of \u003cb\u003e42\u003c/b\u003e (0.056 g, 0.078 mmol) in DMF (2 mL) and triethylamine (0.055 mL, 0.392 mmol) was added HATU (0.090 g, 0.235 mmol) followed by 1,5-diaminopentane (9.2 \u0026micro;l, 0.08 mmol). The mixture was stirred at rt for 45h, then was diluted with H\u003csub\u003e2\u003c/sub\u003eO (15 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with H\u003csub\u003e2\u003c/sub\u003eO (3 x 15 mL), then with brine and were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a 10\u0026ndash;75% EtOAc in hexanes gradient and a 24g silica gel column. When the product did not elute, the solvent system was changed to a 0\u0026ndash;10% MeOH in DCM gradient. The fractions containing the major product were combined and concentrated under reduced pressure to give the dimer (0.02 g, 0.013 mmol, 33% yield) as an off-white film. LCMS: m/e 1494.2 (MH\u003csup\u003e+\u003c/sup\u003e), 1.02 min (Method 1). To a solution of the dimer (0.02 g, 0.013 mmol) in MeOH (1.0 mL) was added sodium methoxide (25% solution in MeOH) (3.0 ml, 0.013 mmol) and the mixture was stirred at rt. After 2.5 h of stirring at rt, 5 drops of 1N HCl were added and the mixture was concentrated under reduced pressure. The residue was diluted with DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with ammonium acetate buffer. Fractions containing the products were concentrated under reduced pressure to give the title product (10.2 mg, 0.0076 mmol, 58% yield). LCMS: m/e 1323.66 (MH\u003csup\u003e+\u003c/sup\u003e), 1.85 min (Method 2). Key \u003csup\u003e1\u003c/sup\u003eH NMR peaks: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 8.96 (s, 2H), 7.84\u0026ndash;7.62 (m, 10H), 6.62 (br s, 2H), 2.30 (s, 6H), 1.04\u0026ndash;0.92 (m, 4H), 0.79 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.4 Hz, 2H). 97.3% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(44) 2-(((2S,4aR,6S,7R,8R,8aR)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)AcOH.\u003c/b\u003e A solution of \u003cb\u003e43b\u003c/b\u003e (0.442 g, 0.654 mmol) in THF (10 mL) was cooled to 0\u0026deg;C and sodium hydride (60% dispersion in mineral oil) (0.131 g, 3.27 mmol) was added. The mixture was stirred for 15 minutes and ethyl bromoacetate (0.291 mL, 2.62 mmol) was added. The mixture was warmed to rt as the ice bath melted and was stirred for 15.5 h. The reaction was carefully quenched with EtOH and the mixture was concentrated under reduced pressure. The residue was diluted with H\u003csub\u003e2\u003c/sub\u003eO (20 mL) and extracted with EtOAc (2 x 30 mL). The organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a 10\u0026ndash;80% EtOAc in hexanes gradient and a 40g silica gel column. Fractions containing the product were combined and concentrated under reduced pressure to give the ethyl ester as an off-white solid (422 mg, 0.554 mmol, 85% yield). LCMS: m/e 761.3 (MH\u003csup\u003e+\u003c/sup\u003e), 1.11 min (Method 1). \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, chloroform-d) δ 8.17 (s, 1H), 7.68 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.9 Hz, 1H), 7.54\u0026ndash;7.38 (m, 9H), 5.49 (s, 1H), 5.15 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.6, 3.5 Hz, 1H), 4.91\u0026ndash;4.79 (m, 1H), 4.46\u0026ndash;4.40 (m, 2H), 4.34 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12.8, 1.1 Hz, 1H), 4.05 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12.8, 1.5 Hz, 1H), 4.00\u0026ndash;3.89 (m, 3H), 3.68 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;15.8 Hz, 1H), 3.63 (s, 1H), 2.46 (s, 3H), 1.11 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.2 Hz, 3H). To a solution of the carboxylate (422 mg, 0.554 mmol) in MeOH (3 mL) and 1,4-dioxane (3 mL) was added 1N sodium hydroxide (2.77 mL, 2.77 mmol) and the mixture was stirred at rt. After 40 h of stirring the mixture at rt, it was concentrated under reduced pressure, diluted with sat. aq. Ammonium chloride (25 mL) and the solids that formed were collected by filtration and were washed with excess H\u003csub\u003e2\u003c/sub\u003eO and diethyl ether. The title product was isolated as a white solid (0.307 g, 0.418 mmol, 75% yield) LCMS: m/e 733.4 (MH\u003csup\u003e+\u003c/sup\u003e), 1.01 min (Method 1). \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 9.34 (s, 1H), 8.36\u0026ndash;8.21 (m, 1H), 7.84 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.1 Hz, 2H), 7.81\u0026ndash;7.76 (m, 1H), 7.75\u0026ndash;7.69 (m, 1H), 7.37 (s, 5H), 5.55 (s, 1H), 5.44 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.9, 3.4 Hz, 1H), 4.88\u0026ndash;4.76 (m, 1H), 4.57 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.2 Hz, 1H), 4.44 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.5 Hz, 1H), 4.11\u0026ndash;3.98 (m, 2H), 3.87 (s, 1H), 3.71\u0026ndash;3.51 (m, 1H), 3.47\u0026ndash;3.35 (m, 1H), 2.34 (s, 3H).\u003c/p\u003e \u003cp\u003e \u003cb\u003e(11) 2-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(2-(2-(((2S,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)ethyl)acetamide.\u003c/b\u003e To a flask containing a solution of \u003cb\u003e44\u003c/b\u003e (40 mg, 0.055 mmol) in DMF (1 mL) and triethylamine (0.038 mL, 0.273 mmol) was added ethane-1,2-diamine (1M in DMF) (0.027 mL, 0.027 mmol) followed by HATU (62.2 mg, 0.164 mmol). The mixture was stirred at rt for 40 h, then was diluted with 2 mL of H\u003csub\u003e2\u003c/sub\u003eO and was extracted with dichloromethane (3 x 2 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with TFA buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the dimer (0.023g, 0.0154 mmol, 56% yield) as a white solid. LCMS: m/e 1489.9 (MH\u003csup\u003e+\u003c/sup\u003e), 1.19 min (Method 1). To a solution of the dimer (0.023 g, 0.015 mmol) in AcOH (0.5 mL) was added H\u003csub\u003e2\u003c/sub\u003eO (0.167 mL) and the mixture was heated to 70\u0026deg;C. After heating the mixture for 30 h, it was cooled to rt and was concentrated under a stream of nitrogen. To the residue was added 0.035 g of K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H\u003csub\u003e2\u003c/sub\u003eO. The mixture was stirred at rt for 3 days, then was diluted with H\u003csub\u003e2\u003c/sub\u003eO (1 mL) and extracted with dichloromethane (3 x 1 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with ammonium acetate buffer. The fractions containing the product were combined and concentrated under reduced pressure to give the title product (6.8 mg, 0.0052, 35% yield). LCMS: m/e 1316.1 (MH\u003csup\u003e+\u003c/sup\u003e), 1.93 min (Method 2). Key \u003csup\u003e1\u003c/sup\u003eH NMR peaks: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 8.94 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.4, 2.5 Hz, 2H), 7.79\u0026ndash;7.58 (m, 10H), 7.01 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.3 Hz, 2H), 2.26 (s, 6H). 100% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(12) 2-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(4-(2-(((2S,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)butyl)acetamide.\u003c/b\u003e To a flask containing a solution of \u003cb\u003e44\u003c/b\u003e (40 mg, 0.055 mmol) in DMF (1 mL) and triethylamine (0.038 mL, 0.273 mmol) was added butane-1,4-diamine (1M in DMF) (0.027 mL, 0.027 mmol) followed by HATU (62.2 mg, 0.164 mmol). The mixture was stirred at rt for 64h, then was diluted with 2 mL of H\u003csub\u003e2\u003c/sub\u003eO and was extracted with dichloromethane (3 x 2 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-100% MeOH in dichloromethane gradient and a 24g silica gel column. Fractions containing the product were combined and concentrated under reduced pressure to give the dimer product (0.022 g, 0.0145, 53% yield) as an off-white solid. LCMS: m/e 1520.1 (MH\u003csup\u003e+\u003c/sup\u003e), 1.18 min (Method 1). To a solution of the dimer (22 mg, 0.014 mmol) in AcOH (0.5 mL) was added H\u003csub\u003e2\u003c/sub\u003eO (0.167 mL) and the mixture was heated to 70\u0026deg;C. After 21 h of heating, the mixture was cooled to rt and was concentrated under a stream of nitrogen. To the residue was added 0.035g of K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H\u003csub\u003e2\u003c/sub\u003eO. The mixture was stirred at rt for 20 h, then was diluted with H\u003csub\u003e2\u003c/sub\u003eO (1 mL) and extracted with dichloromethane (3 x 1 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with ammonium acetate buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the title product (9.8 mg, 0.0073 mmol, 52% yield). LCMS: m/e 1341.8 (MH\u003csup\u003e+\u003c/sup\u003e), 1.94 min (Method 2). Key \u003csup\u003e1\u003c/sup\u003eH NMR peaks: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 9.03\u0026ndash;8.88 (m, 2H), 7.81\u0026ndash;7.61 (m, 10H), 6.86\u0026ndash;6.60 (m, 2H), 2.27 (s, 6H), 0.87 (br s, 4H). 100% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(13) 2-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(5-(2-(((2S,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)pentyl)acetamide.\u003c/b\u003e To a flask containing a solution of \u003cb\u003e44\u003c/b\u003e (0.04 g, 0.055 mmol) in DMF (1 mL) and triethylamine (0.038 mL, 0.273 mmol) was added 1,5-diaminopentane (1M in DMF) (0.027 mL, 0.027 mmol) followed by HATU (0.062 g, 0.164 mmol). The mixture was stirred at rt for 64 h, then was diluted with 2 mL of H\u003csub\u003e2\u003c/sub\u003eO and was extracted with dichloromethane (3 x 2 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with TFA buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the dimer product (0.024 g, 0.0156 mmol, 57% yield) as a white solid. LCMS: m/e 1535.3 (MH\u003csup\u003e+\u003c/sup\u003e), 1.27 min (Method 1). A solution of the dimer (24 mg, 0.016 mmol) in AcOH (0.5 mL) and H\u003csub\u003e2\u003c/sub\u003eO (0.167 mL) was heated to 70\u0026deg;C. After heating the mixture for 67 h, it was cooled to rt and concentrated under a stream of nitrogen. To the residue was added 0.035 g of K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H\u003csub\u003e2\u003c/sub\u003eO. The mixture was stirred at rt for 66 h then was diluted with H\u003csub\u003e2\u003c/sub\u003eO (1 mL) and extracted with dichloromethane (3 x 1 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was diluted with DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with ammonium acetate buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the title product (6.5 mg, 0.0048 mmol, 30% yield). LCMS: m/e 1357.9 (MH\u003csup\u003e+\u003c/sup\u003e), 1.96 min (Method 2). Key \u003csup\u003e1\u003c/sup\u003eH NMR peaks: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 9.01\u0026ndash;8.93 (m, 2H), 7.81\u0026ndash;7.62 (m, 10H), 6.76\u0026ndash;6.58 (m, 2H), 2.29 (s, 6H), 0.99\u0026thinsp;\u0026minus;\u0026thinsp;0.87 (m, 4H), 0.80\u0026thinsp;\u0026minus;\u0026thinsp;0.69 (m, 2H). 100% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(14) 2-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(6-(2-(((2S,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)hexyl)acetamide.\u003c/b\u003e To a flask containing a solution of \u003cb\u003e44\u003c/b\u003e (0.04 g, 0.055 mmol) in DMF (1 mL) and triethylamine (0.038 mL, 0.273 mmol) was added hexane-1,6-diamine (1M in DMF) (0.027 mL, 0.027 mmol) followed by HATU (0.062 g, 0.164 mmol). The mixture was stirred at rt for 64 h, then was diluted with 2 mL of H\u003csub\u003e2\u003c/sub\u003eO and was extracted with dichloromethane (3 x 2 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with TFA buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the dimer product (0.027 g, 0.017 mmol, 62% yield) as a white solid. LCMS: m/e 1546.0 (MH\u003csup\u003e+\u003c/sup\u003e), 1.19 min (Method 1). To a solution of the dimer (27 mg, 0.017 mmol) in AcOH (0.5 mL) was added H\u003csub\u003e2\u003c/sub\u003eO (0.167 mL) and the mixture was heated to 70\u0026deg;C. After 19 h of heating, the mixture was cooled to rt and was concentrated under a stream of nitrogen. To the residue was added 0.035 g of K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e 0.5 mL of MeOH and 0.25 mL of H\u003csub\u003e2\u003c/sub\u003eO. After stirring the mixture for 20 h at rt, it was diluted with H\u003csub\u003e2\u003c/sub\u003eO (1 mL) and extracted with dichloromethane (2 x 1 mL) then with chloroform : MeOH (4 : 1, 2 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title product (10.1 mg, 0.0074 mmol, 43% yield). LCMS: m/e 1369.96 (MH\u003csup\u003e+\u003c/sup\u003e), 2.06 min (Method 2). \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 8.98 (s, 2H), 7.84\u0026ndash;7.61 (m, 10H), 6.62 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.9 Hz, 2H), 5.46 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.1 Hz, 2H), 5.12 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11.0, 2.4 Hz, 2H), 4.80\u0026ndash;4.63 (m, 4H), 4.42 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.5 Hz, 2H), 3.90 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.7 Hz, 2H), 3.78\u0026ndash;2.58 (m, 10H), 2.30 (s, 6H), 0.96 (br s, 4H), 0.79 (br s, 4H). 100% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(15) 2-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(7-(2-(((2S,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)heptyl)acetamide.\u003c/b\u003e To a flask containing a solution of \u003cb\u003e44\u003c/b\u003e (0.04 g, 0.055 mmol) in DMF (2 mL) and triethylamine (0.038 mL, 0.273 mmol) was added heptane-1,7-diamine (1M in DMF) (0.027 mL, 0.027 mmol) followed by HATU (0.062 g, 0.164 mmol). The mixture was stirred at rt for 64h, then was diluted with 2 mL of H\u003csub\u003e2\u003c/sub\u003eO and was extracted with dichloromethane (3 x 2 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with TFA buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the dimer product (0.027 g, 0.017 mmol, 62% yield) as a white solid. LCMS: m/e 1559.9 (MH\u003csup\u003e+\u003c/sup\u003e), 1.20 min (Method 1). To a solution of the dimer (27 mg, 0.017 mmol) in AcOH (0.5 mL) was added H\u003csub\u003e2\u003c/sub\u003eO (0.167 mL) and the mixture was heated to 70\u0026deg;C. After 19h, the mixture was cooled to rt and was concentrated under a stream of nitrogen. To the residue was added 0.035g of K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H\u003csub\u003e2\u003c/sub\u003eO and was stirred at rt for 20 h. The mixture was diluted with H\u003csub\u003e2\u003c/sub\u003eO (1 mL) and extracted with dichloromethane (2 x 1 mL) then with chloroform : MeOH (4:1, 2 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with ammonium acetate buffer. The fractions containing the product were concentrated under reduced pressure to give the title product (16.2 mg, 0.0117 mmol, 69% yield). LCMS: m/e 1382.89 (MH\u003csup\u003e+\u003c/sup\u003e), 2.14 min (Method 2). \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 8.98 (s, 2H), 7.83\u0026ndash;7.60 (m, 10H), 6.61 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3.7 Hz, 2H), 5.46 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.1 Hz, 2H), 5.12 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.7, 2.7 Hz, 2H), 4.83\u0026ndash;4.63 (m, 4H), 4.42 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9.5 Hz, 2H), 3.91 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.5, 2.7 Hz, 2H), 3.75\u0026ndash;2.59 (m, 10H), 2.30 (s, 6H), 0.98 (br s, 4H), 0.83 (br s, 6H). 100% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(16) 2-(((2R,3S,4R,5S,6S)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(3-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)propyl)acetamide.\u003c/b\u003e To a flask containing a solution of \u003cb\u003e36\u003c/b\u003e (0.035 g, 0.046 mmol) in DMF (1 mL) and triethylamine (0.032 mL, 0.228 mmol) was added 1,3-diaminopropane (1M in DMF) (0.023 mL, 0.023 mmol) followed by HATU (0.052 g, 0.137 mmol). The mixture was stirred at rt for 43h, then was diluted with 2 mL of H\u003csub\u003e2\u003c/sub\u003eO and was extracted with dichloromethane (3 x 2 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with TFA buffer. Fractions containing the product were concentrated under reduced pressure. The dimerized product (25 mg, 0.016 mmol, 70% yield) was isolated as a white film. LCMS: m/e 1573.6 (MH\u003csup\u003e+\u003c/sup\u003e), 1.19 min (Method 1). To a solution of the dimer (25 mg, 0.016 mmol) was added AcOH (0.5 mL) and H\u003csub\u003e2\u003c/sub\u003eO (0.167 mL) and the mixture was heated to 70\u0026deg;C. After heating the mixture for 17.5h, it was cooled to rt and concentrated under a stream of nitrogen. To the residue was added 0.035g of K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H\u003csub\u003e2\u003c/sub\u003eO and was stirred at rt overnight for 17h. The mixture was diluted with H\u003csub\u003e2\u003c/sub\u003eO (1 mL) and extracted with a mixture of dichloromethane : chloroform : MeOH (1 : 1 : 0.25, 3 x 2.25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool and purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title compound (13.0 mg, 0.0093 mmol, 59% yield). LCMS: m/e 1396.8 (MH\u003csup\u003e+\u003c/sup\u003e), 2.03 min (Method 2). Key \u003csup\u003e1\u003c/sup\u003eH NMR peaks: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 8.93 (s, 2H), 7.98\u0026ndash;7.65 (m, 10H), 6.99\u0026ndash;6.74 (m, 2H), 2.24 (s, 6H), 1.06\u0026ndash;0.90 (m, 2H). 100% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(17) 2-(((2R,3S,4R,5S,6S)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(4-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)butyl)acetamide.\u003c/b\u003e To a flask containing a solution of \u003cb\u003e36\u003c/b\u003e (0.026 g, 0.034 mmol) in DMF (1 mL) and triethylamine (0.024 mL, 0.169 mmol) was added 1,4-diaminobutane (1M in DMF) (0.017 mL, 0.017 mmol) followed by HATU (0.039 g, 0.102 mmol). The mixture was stirred at rt for 43 h then was diluted with 2 mL of H\u003csub\u003e2\u003c/sub\u003eO and was extracted with dichloromethane (3 x 2 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with TFA buffer. Fractions containing the product were concentrated under reduced pressure. The dimerized compound (24 mg, 0.015 mmol, 88% yield) was isolated as an off-white solid. LCMS: m/e 1573.6 (MH\u003csup\u003e+\u003c/sup\u003e), 1.19 min (Method 1). To a solution of the dimer (24 mg, 0.015 mmol) was added AcOH (0.5 mL) and H\u003csub\u003e2\u003c/sub\u003eO (0.167 mL) and the mixture was heated to 70\u0026deg;C. After 17.5 h of heating, the mixture was cooled to rt and concentrated under a stream of nitrogen. To the residue was added 0.035g of K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H\u003csub\u003e2\u003c/sub\u003eO. The mixture was stirred for 5 h at rt, then was diluted with H\u003csub\u003e2\u003c/sub\u003eO (1 mL) and extracted with dichloromethane (3 x 1 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF and purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with TFA buffer. Fractions containing the product were concentrated under reduced pressure to give the title product (13.0 mg, 0.0092 mmol, 61% yield). LCMS: m/e 1409.19 (MH\u003csup\u003e+\u003c/sup\u003e), 1.97 min (Method 2). Key \u003csup\u003e1\u003c/sup\u003eH NMR peaks: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 9.02 (s, 2H), 7.99\u0026ndash;7.94 (m, 2H), 7.92\u0026ndash;7.84 (m, 4H), 7.77 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 4H), 6.72\u0026ndash;6.54 (m, 2H), 2.27 (s, 6H), 0.90 (br s, 4H). 100% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(18) 2-(((2R,3S,4R,5S,6S)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(5-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)pentyl)acetamide.\u003c/b\u003e To a flask containing a solution of \u003cb\u003e36\u003c/b\u003e (37 mg, 0.048 mmol) in DMF (1 mL) and triethylamine (0.034 mL, 0.241 mmol) was added 1,5-diaminopentane (0.024 mL, 0.024 mmol) followed by HATU (55.0 mg, 0.145 mmol). The mixture was stirred at rt for 43h, then was diluted with 2 mL of H\u003csub\u003e2\u003c/sub\u003eO and was extracted with dichloromethane (3 x 2 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF and was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with TFA buffer. Fractions containing the product were combined and concentrated under reduced pressure. The dimer product (29 mg, 0.018 mmol, 75% yield) was isolated as a white solid. LCMS: m/e 1602.2 (MH\u003csup\u003e+\u003c/sup\u003e), 1.19 min (Method 1). To a solution of the dimer (29 mg, 0.018 mmol) was added AcOH (0.5 mL) and H\u003csub\u003e2\u003c/sub\u003eO (0.167 mL) and the mixture was heated to 70\u0026deg;C. After 17.5 h of heating, the mixture was cooled to rt and concentrated under a stream of nitrogen. To the residue was added 0.035g of K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H\u003csub\u003e2\u003c/sub\u003eO and was stirred at rt for 5h. The mixture was diluted with H\u003csub\u003e2\u003c/sub\u003eO (1 mL) and extracted with dichloromethane (3 x 1 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool and was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title product (15.3 mg, 0.011 mmol, 61% yield). LCMS: m/e 1423.11 (MH\u003csup\u003e+\u003c/sup\u003e), 2.08 min (Method 2). Key \u003csup\u003e1\u003c/sup\u003eH NMR peaks: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 8.94 (s, 2H), 7.95 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.9 Hz, 2H), 7.91\u0026ndash;7.80 (m, 4H), 7.72 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.2 Hz, 4H), 6.73\u0026ndash;6.51 (m, 2H), 2.28 (s, 6H), 0.93 (quin, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.2 Hz, 4H), 0.74 (quin, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.1 Hz, 2H). 100% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(23) 2-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(2-(2-(((2S,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-methylacetamido)ethyl)-N-methylacetamide.\u003c/b\u003e To a vial containing carboxylic acid \u003cb\u003e44\u003c/b\u003e (0.168 g, 0.229 mmol) was added DMF (2 mL), TEA (0.128 mL, 0.916 mmol), N\u003csup\u003e1\u003c/sup\u003e,N\u003csup\u003e2\u003c/sup\u003e-dimethylethane-1,2-diamine (0.092 mL, 0.092 mmol) and 1-propanephosphonic anhydride (T3P, 50% in EtOAc) (0.340 mL, 0.572 mmol). The mixture was stirred at rt for 17 h then an additional 0.046 mL of the N\u003csup\u003e1\u003c/sup\u003e,N\u003csup\u003e2\u003c/sup\u003e-dimethylethane-1,2-diamine was added and the mixture was stirred at rt for an additional 24h. An additional 0.092 mL of N\u003csup\u003e1\u003c/sup\u003e,N\u003csup\u003e2\u003c/sup\u003e-dimethylethane-1,2-diamine was added and the mixture was stirred at rt for an additional 24h. The mixture was diluted with H\u003csub\u003e2\u003c/sub\u003eO (10 mL) and was extracted with EtOAc (2 x 10 mL). The organic layers were washed with H\u003csub\u003e2\u003c/sub\u003eO (3 x 10 mL), then with brine and were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a 0-100% EtOAc in dichloromethane gradient. The fractions containing the dimerized product were combined and concentrated under reduced pressure to give the product (0.095 g, 0.0625 mmol, 55% yield) as an off-white solid. LCMS: m/e 1521.4 (MH\u003csup\u003e+\u003c/sup\u003e), 1.21 min (Method 1). To a flask containing the dimer (0.09 g, 0.059 mmol) was added AcOH (1 mL) and H\u003csub\u003e2\u003c/sub\u003eO (0.33 mL) and the mixture was heated to 70\u0026deg;C. After 19.5h of heating, the mixture was cooled to rt and was concentrated under reduced pressure. The residue was diluted with DCM and concentrated two additional times. The residue was dilute with 1 mL of MeOH and 0.5 mL of H\u003csub\u003e2\u003c/sub\u003eO and 0.07 g of K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e was added then it was stirred at rt for 5h, concentrated under reduced pressure, diluted with DMF and filtered through a plug of glass wool to remove the solids. The filtrate was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with ammonium acetate buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the title product (46.6 mg, 0.035 mmol, 59% yield). LCMS: m/e 1341.18 (MH\u003csup\u003e+\u003c/sup\u003e), 2.08 min (Method 2). Key \u003csup\u003e1\u003c/sup\u003eH NMR peaks: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 9.11\u0026ndash;8.95 (m, 2H), 7.97\u0026ndash;7.44 (m, 10H), 2.85 (s, 3H), 2.69 (s, 3H), 2.32\u0026ndash;2.17 (m, 6H). 98.0% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(24) 2-(((2R,4aS,6R,7S,8S,8aS)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-(4-(2-(((2S,4aR,6S,7R,8R,8aR)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetyl)-1,4-diazepan-1-yl)ethan-1-one.\u003c/b\u003e To a flask containing carboxylic acid \u003cb\u003e44\u003c/b\u003e (0.05 g, 0.068 mmol) was added DMF (1 mL), TEA (0.038 mL, 0.273 mmol), homopiperazine (1M in DMF) (0.034 mL, 0.034 mmol) and 1-propanephosphonic anhydride (T3P, 50% in EtOAc) (0.101 mL, 0.170 mmol). The mixture was stirred at rt for 19 h then was diluted with H\u003csub\u003e2\u003c/sub\u003eO (10 mL) and was extracted with EtOAc (3 x 10 mL). The organic layers were washed with H\u003csub\u003e2\u003c/sub\u003eO (3 x 20 mL), then with brine and were dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give the crude dimerized product (0.048 g, 0.031 mmol, 91% yield) as an off-white solid. LCMS: m/e 1533.5 (MH\u003csup\u003e+\u003c/sup\u003e), 1.21 min (Method 1). To a flask containing the crude dimer (0.048 g, 0.031 mmol) was added AcOH (1 mL) and H\u003csub\u003e2\u003c/sub\u003eO (0.33 mL). The mixture was heated to 70\u0026deg;C for 15h, then was cooled to rt and concentrated under reduced pressure. The residue was diluted with 2 mL of MeOH and 0.5 mL of H\u003csub\u003e2\u003c/sub\u003eO and 0.07g of K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e was added. The mixture was stirred at rt overnight, then was concentrated under reduced pressure. The residue was diluted with DMF and filtered through a plug of glass wool to remove the solids. The filtrate was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title product (15.1 mg, 0.0111 mmol, 36% yield). LCMS: m/e 1353.16 (MH\u003csup\u003e+\u003c/sup\u003e), 2.04 min (Method 2). \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 9.09\u0026ndash;8.94 (m, 2H), 7.94\u0026ndash;7.60 (m, 12H), 5.44\u0026ndash;5.35 (m, 2H), 5.18\u0026ndash;5.08 (m, 2H), 4.78\u0026ndash;4.58 (m, 4H), 4.41\u0026ndash;4.26 (m, 2H), 3.91\u0026ndash;3.80 (m, 2H), 3.64 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.1 Hz, 2H), 2.50 (s, 14H), 2.31\u0026ndash;2.22 (m, 6H), 1.26\u0026ndash;1.02 (m, 2H). 100% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(25) 2-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-1-(4-(2-(((2S,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetyl)piperazin-1-yl)ethan-1-one.\u003c/b\u003e To a vial containing carboxylic acid \u003cb\u003e44\u003c/b\u003e (0.125 g, 0.170 mmol) was added DMF (2 mL), TEA (0.095 mL, 0.681 mmol), piperazine (0.5M in DMF:THF, 1:1) (0.136 mL, 0.068 mmol) and 1-propanephosphonic anhydride (T3P, 50% in EtOAc) (0.253 mL, 0.426 mmol). The mixture was stirred at rt for 17 h then was diluted with H\u003csub\u003e2\u003c/sub\u003eO (20 mL) and extracted with EtOAc (2 x 20 mL). The organic layers was washed with H\u003csub\u003e2\u003c/sub\u003eO (3 x 20 mL) then with brine and were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude dimerized product was used in the next step with no additional purification. LCMS: m/e 1517.6 (MH\u003csup\u003e+\u003c/sup\u003e), 1.18 min (Method 1). To a flask the crude dimer (129 mg, 0.085 mmol) was added AcOH (2 mL) and H\u003csub\u003e2\u003c/sub\u003eO (0.667 mL). The mixture was heated to 70\u0026deg;C for 18h, then was cooled to rt and concentrated under reduced pressure. The residue was diluted with 5 mL of MeOH, 2.5 mL of H\u003csub\u003e2\u003c/sub\u003eO and 0.07g of K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e was added. The mixture was stirred at rt for 24h, then was concentrated under reduced pressure. The residue was diluted with DMF, filtered through a plug of glass wool and the filtrate was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title product (46.1 mg, 0.034 mmol, 40% yield over two steps). LCMS: m/e 1339.3 (MH\u003csup\u003e+\u003c/sup\u003e), 2.02 min (Method 2). Key \u003csup\u003e1\u003c/sup\u003eH NMR peaks. \u003csup\u003e1\u003c/sup\u003eH NMR (600 MHz, DMSO-d6) δ 9.07 (br s, 2H), 7.90\u0026ndash;7.79 (m, 6H), 7.77 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.6 Hz, 2H), 7.73 (dd, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.6, 2.2 Hz, 2H), 5.43 (d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.0 Hz, 2H), 5.19 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.3 Hz, 2H), 4.85\u0026ndash;4.69 (m, 2H), 4.65 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.5 Hz, 2H), 4.42 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.9 Hz, 2H), 4.22\u0026ndash;4.05 (m, 1H), 3.90 (br s, 2H), 3.81 (br s, 3H), 3.70 (t, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6.5 Hz, 2H), 3.47\u0026ndash;3.37 (m, 4H), 2.32 (br s, 6H). \u003csup\u003e13\u003c/sup\u003eC NMR (126 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 166.5, 160.4, 159.9, 159.9, 158.0, 157.9, 154.4, 144.0, 135.3, 132.7, 132.3, 132.1, 130.4, 123.5, 109.5, 109.3, 107.4, 79.4, 71.6, 71.4, 68.0, 65.8, 60.2, 14.0. HRMS (m/z) calculated for [M\u0026thinsp;+\u0026thinsp;H]\u0026thinsp;+\u0026thinsp;ion species C\u003csub\u003e54\u003c/sub\u003eH\u003csub\u003e48\u003c/sub\u003eCl\u003csub\u003e6\u003c/sub\u003eF\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e14\u003c/sub\u003eO\u003csub\u003e10\u003c/sub\u003e: 1339.1818; found 1339.1802. 100% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(19) (2R,3R,4S,5R,6S)-4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-((10-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)decyl)oxy)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol.\u003c/b\u003e A solution of C-2 alcohol \u003cb\u003e45\u003c/b\u003e in THF (2 mL) was cooled to 0\u0026deg;C and sodium hydride (60% mineral oil dispersion) (13.07 mg, 0.327 mmol) was added. The mixture was stirred for 15 minutes and a solution of 1,10-diiododecane (1M in THF) (0.033 mL, 0.033 mmol) was added. The mixture was stirred at 0\u0026deg;C and was allowed to warm to rt as the ice bath melted and warmed. After stirring the mixture for 6 days, it was carefully diluted with H\u003csub\u003e2\u003c/sub\u003eO (10 mL) and extracted with dichloromethane (3 x 10 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product (37 mg, 0.025 mmol, 77% yield) was used in the next step with no additional purification. LCMS: m/e 1453.9 (MH\u003csup\u003e+\u003c/sup\u003e), 1.31 min (Method 1). To a vial containing the crude ether linked dimer (37 mg, 0.025 mmol) was added AcOH (0.5 mL) and H\u003csub\u003e2\u003c/sub\u003eO (0.167 mL). The mixture was heated to 70\u0026deg;C for 26 h then was concentrated under a stream of nitrogen. To the residue was added 35 mg of K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H\u003csub\u003e2\u003c/sub\u003eO then was stirred at rt for 2h. The mixture was diluted with H2O (1 mL) and extracted with dichloromethane (3 x 1 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF and was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO/MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title compound (8.1 mg, 0.0063 mmol, 25% yield). LCMS: m/e 1277.0 (MH\u003csup\u003e+\u003c/sup\u003e), 2.65 min (Method 2). Key \u003csup\u003e1\u003c/sup\u003eH NMR peaks. \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 8.91 (br s, 2H), 7.86 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10.4 Hz, 2H), 7.79\u0026ndash;7.48 (m, 10H), 2.30 (s, 6H), 0.81 (br d, \u003cem\u003eJ\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.0 Hz, 4H), 0.65\u0026thinsp;\u0026minus;\u0026thinsp;0.41 (m, 12H). 93.8% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(20) Preparation of (2R,3R,4S,5R,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-((8-(((2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)octyl)oxy)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol.\u003c/b\u003e A solution of \u003cb\u003e43\u003c/b\u003e (50 mg, 0.074 mmol) in THF (2 mL) was cooled to 0\u0026deg;C and a sodium hydride (60% mineral oil dispersion) (0.370 mL, 0.370 mmol) was added. The mixture was stirred for 15 minutes and a solution of 1,8-diiodooctane (0.044 mL, 0.044 mmol) was added. The mixture was stirred at 0\u0026deg;C and was allowed to warm to rt as the ice bath melted and warmed. After stirring for 7 days, the solvent had evaporated. An additional 1 mL of THF was added followed by 1,8-diiodooctane (0.044 mL, 0.044 mmol). After 4 additional days of stirring, the mixture was again diluted with 1 mL of THF and additional 1,8-diiodooctane (0.044 mL, 0.044 mmol) was added. After 3 days of stirring, the mixture was diluted with H\u003csub\u003e2\u003c/sub\u003eO (10 mL) and was extracted with EtOAc (3 x 10 mL). The organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture of products, which included a peak with the m/z of the expected product, was used in the next step with no additional purification. LCMS: m/e 1462.3 (MH\u003csup\u003e+\u003c/sup\u003e), 1.29 min (Method 1). To a flask containing the crude mixture above was added AcOH (0.5 mL) and H\u003csub\u003e2\u003c/sub\u003eO (0.167 mL). The mixture was heated to 70\u0026deg;C for 16h. The mixture was cooled to rt then was concentrated under reduced pressure. To the residue was added K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e (35 mg) and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H\u003csub\u003e2\u003c/sub\u003eO. The mixture was stirred at rt for 4h, then was diluted with H\u003csub\u003e2\u003c/sub\u003eO (2 mL) and was extracted with dichloromethane (3 x 3 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF and purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with ammonium acetate buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the title product (3.7 mg, 0.0029 mmol, 8% yield over 2 steps). LCMS: m/e 1283.09 (MH\u003csup\u003e+\u003c/sup\u003e), 2.63 min (Method 2). Key \u003csup\u003e1\u003c/sup\u003eH NMR peaks. \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 9.05 (s, 2H), 7.87\u0026ndash;7.70 (m, 8H), 7.68\u0026ndash;7.47 (m, 2H), 2.34 (s, 6H), 0.81\u0026thinsp;\u0026minus;\u0026thinsp;0.68 (m, 4H), 0.58\u0026thinsp;\u0026minus;\u0026thinsp;0.37 (m, 8H). 97.5% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(49) (2S,4aR,6S,7R,8S,8aR)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl (3-aminopropyl)carbamate.\u003c/b\u003e To a solution of C-2 alohol \u003cb\u003e43\u003c/b\u003e (0.063 g, 0.093 mmol) in d-chloroform (2 mL) was added DMAP (1.1 mg, 9.32 \u0026micro;mol) followed by dipyridin-2-yl carbonate (0.101 g, 0.466 mmol). The mixture was heated to 50\u0026deg;C for 2 h then was cooled to rt. To the mixture was added propane-1,3-diamine (0.078 mL, 0.932 mmol) and it was stirred at rt for 4h. The mixture diluted with sat. aq. ammonium chloride and was extracted with dichloromethane (3 x 10 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a mixture of products which included a peak with the m/z of the title compound. The crude product was used in the next step with no additional purification. LCMS: m/e 777.3 (MH\u003csup\u003e+\u003c/sup\u003e), 0.84 min (Method 1).\u003c/p\u003e \u003cp\u003e \u003cb\u003e(51) (2S,4aR,6S,7R,8S,8aR)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl pyridin-2-yl carbonate.\u003c/b\u003e To a solution of C-2 alcohol \u003cb\u003e43\u003c/b\u003e (0.05 g, 0.074 mmol) in d-chloroform (3 mL) was added DMAP (0.9 mg, 7.40 \u0026micro;mol) followed by dipyridin-2-yl carbonate (0.080 g, 0.370 mmol). The mixture was heated to 50\u0026deg;C for 2 h then was cooled to rt, diluted with sat. aq. ammonium chloride and was extracted with dichloromethane (3 x 10 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title product. The crude product was used in the next step with no additional purification.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(53) (2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl ((2S,4aR,6S,7R,8S,8aR)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl) propane-1,3-diyldicarbamate.\u003c/b\u003e To a flask containing the crude \u003cb\u003e49\u003c/b\u003e (0.072 g, 0.093 mmol) and \u003cb\u003e51\u003c/b\u003e (0.059 g, 0.074 mmol) in d-chloroform (3 mL) was added DMAP (0.9 mg, 7.40 \u0026micro;mol) and the mixture was stirred at rt. After 18h, the mixture was diluted with H\u003csub\u003e2\u003c/sub\u003eO (3 mL) and was extracted with dichloromethane (3 x 3 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool and was purified by prep HPLC using a C18 column and an MeCN/ H\u003csub\u003e2\u003c/sub\u003eO gradient. The fractions containing the product were combined and concentrated under reduced pressure to give a mixture of products (54 mg) including the title compound. LCMS: m/e 1479.5 (MH\u003csup\u003e+\u003c/sup\u003e), 1.22 min (Method 1).\u003c/p\u003e \u003cp\u003e \u003cb\u003e(21) (2R,3S,4R,5S,6S)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl ((2S,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl) propane-1,3-diyldicarbamate.\u003c/b\u003e A solution of \u003cb\u003e53\u003c/b\u003e (54 mg) in AcOH (0.5 mL) and H\u003csub\u003e2\u003c/sub\u003eO (0.167 mL) was heated to 70\u0026deg;C. After 15.5h, the mixture was cooled to rt and was concentrated under a stream of nitrogen. To the residue was added 0.035g of K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e, 0.5 mL of MeOH and 0.25 mL of H\u003csub\u003e2\u003c/sub\u003eO and the mixture was stirred at rt. After stirring the mixture at rt for 1h, it was further diluted with 1 mL of MeOH and was heated to 50\u0026deg;C. After 1 h of heating, the mixture was cooled to rt and was stirred overnight. The mixture was then heated to 50\u0026deg;C for 2 h, then was cooled to rt and was concentrated under a steam of nitrogen. The residue was diluted with DMF, filtered through a plug of glass wool to remove the solids and was purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with ammonium acetate buffer. Fractions containing the product were combined and concentrated under reduced pressure to give the title product (29.0 mg, 0.022 mmol, 24% yield over 3 steps). LCMS: m/e 1299.2 (MH\u003csup\u003e+\u003c/sup\u003e), 2.09 min (Method 2). Key \u003csup\u003e1\u003c/sup\u003eH NMR peaks: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 8.57 (br s, 2H), 7.79\u0026ndash;7.50 (m, 10H), 2.14 (s, 6H), 0.94 (br s, 2H). 100% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(48) (2S,4aR,6S,7R,8S,8aR)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-7-yl (4-aminobutyl)carbamate.\u003c/b\u003e To a solution of \u003cb\u003e39\u003c/b\u003e (28 mg, 0.042 mmol) in d-chloroform (2 mL) was added DMAP (0.5 mg, 4.25 \u0026micro;mol) followed by dipyridin-2-yl carbonate (45.9 mg, 0.212 mmol). The mixture was heated to 50\u0026deg;C for 3h, then 1,4-diaminobutane (0.043 mL, 0.425 mmol) was added and the mixture was stirred at rt. After stirring the mixture for 22h, it was diluted with H\u003csub\u003e2\u003c/sub\u003eO (3 mL) and extracted with dichloromethane (3 x 3 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. LC/MS showed a mixture of products including the m/z of the expected product. The crude product was used in the next step with no additional purification. LCMS: m/e 773.8 (MH\u003csup\u003e+\u003c/sup\u003e), 0.83 min (Method 1).\u003c/p\u003e \u003cp\u003e \u003cb\u003e(50) (2S,4aR,6S,7R,8S,8aR)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-7-yl pyridin-2-yl carbonate.\u003c/b\u003e To a solution of \u003cb\u003e39\u003c/b\u003e (28 mg, 0.042 mmol) in d-chloroform (2 mL) was added DMAP (0.5 mg, 4.25 \u0026micro;mol) followed by dipyridin-2-yl carbonate (45.9 mg, 0.212 mmol). The mixture was heated to 50\u0026deg;C for 2.5 h then was cooled to rt. The mixture was diluted with sat. aq. ammonium chloride and was extracted with dichloromethane (3 x 10 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used in the next step with no additional purification.\u003c/p\u003e \u003cp\u003e \u003cb\u003e(52) (2S,4aR,6S,7R,8S,8aR)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-7-yl ((2S,6R,7S,8R)-6-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-phenyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-7-yl) butane-1,4-diyldicarbamate.\u003c/b\u003e To a flask containing the crude \u003cb\u003e50\u003c/b\u003e (32.8 mg, 0.042 mmol) was added a solution of the crude mixture containing \u003cb\u003e48\u003c/b\u003e (32.5 mg, 0.042 mmol) in d-chloroform (2 mL) followed by DMAP (0.26 mg, 2.100 \u0026micro;mol). The mixture was stirred at rt for 18h, then was diluted with H\u003csub\u003e2\u003c/sub\u003eO and extracted with dichloromethane (3 x 10 mL). The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a 0\u0026ndash;50% EtOAc in DCM gradient and a 24g silica gel column. Fractions containing the product were combined and concentrated under reduced pressure to give the title product (24 mg, 0.016 mmol, 38% yield) as an off-white solid. LCMS: m/e 1460.3 (MH\u003csup\u003e+\u003c/sup\u003e), 1.19 min (Method 1).\u003c/p\u003e \u003cp\u003e \u003cb\u003e(22) (2R,3S,4R,5S,6S)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl ((2S,3R,4S,5R,6R)-2-(1-(2,5-dichlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl) butane-1,4-diyldicarbamate.\u003c/b\u003e To a solution of dimer \u003cb\u003e52\u003c/b\u003e (0.024 g, 0.016 mmol) was added AcOH (0.5 mL) and H\u003csub\u003e2\u003c/sub\u003eO (0.167 mL) and the mixture was heated to 70\u0026deg;C for 20.5 h. The mixture was cooled to rt and concentrated under a stream of nitrogen. To the residue was added 0.035g of K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e and the mixture was diluted with 0.5 mL of MeOH and 0.25 mL of H\u003csub\u003e2\u003c/sub\u003eO. The mixture was stirred at rt for 3h, then was concentrated under a stream of nitrogen, diluted with DMF, filtered through a plug of glass wool and purified by preparative HPLC using a C18 column and a H\u003csub\u003e2\u003c/sub\u003eO /MeCN gradient with ammonium acetate buffer. Fractions containing the product were concentrated under reduced pressure to give the title product (8.2 mg, 0.0064 mmol, 40% yield). LCMS: m/e 1281.04 (MH\u003csup\u003e+\u003c/sup\u003e), 1.91 min (Method 2). Key \u003csup\u003e1\u003c/sup\u003eH NMR peaks: \u003csup\u003e1\u003c/sup\u003eH NMR (500 MHz, DMSO-d\u003csub\u003e6\u003c/sub\u003e) δ 8.49 (br s, 2H), 7.75\u0026ndash;7.55 (m, 10H), 2.18 (s, 6H), 0.75 (br s, 4H). 98.8% purity based on two HPLC methods.\u003c/p\u003e \u003cp\u003e \u003cb\u003eIn Vitro Human and Mouse Gal-3 HTRF Assays.\u003c/b\u003e The assays were performed in 384 white Opti plates in three replicates. From the original stocks, 2.5\u0026times; working stock concentrations of His-tagged recombinant h or mGal-3 and that of B-ASF were prepared. From the working stock, 20 \u0026micro;L of 15 nM His-tagged h or mGal-3 and B-ASF were added to the plates. In negative control wells, one of the binding partners (B-ASF) was replaced with 20 \u0026micro;L of assay buffer. A concentration range of 50\u0026times; working stocks was prepared for compounds in 100% DMSO. An aliquot of 1 \u0026micro;L compound working stocks was added to each well. The compound was preincubated with 20 \u0026micro;L of h or mGal-3 for 30 min. After adding 20 \u0026micro;L of B-ASF and incubation for additional 1 h, Terbium-labeled anti-His antibody (5 \u0026micro;L/well, 1.0 nM final concentration) was added and incubated for 30 min. Then, streptavidin (2.5 \u0026micro;L/well, 20 nM final concentration) was added and incubated for 1 h. All incubations were conducted at room temperature with gentle shaking at approx. 250\u0026thinsp;\u0026minus;\u0026thinsp;300 rpm. The assay plate was read using the homogeneous time-resolved fluorescence screen protocol (excitation wavelength\u0026thinsp;=\u0026thinsp;340 nm and emission wavelength\u0026thinsp;=\u0026thinsp;615 nm/665 nm) on an EnVision 2104 multilabel reader. IC\u003csub\u003e50\u003c/sub\u003e values were calculated using Toolset and Curve Master. The F-ligand assay was run in a similar manner using either 384 well or 1536 well plates and fluorescein-conjugated saccharide probe 9 [33] at a final concentration of 79.8 nM prepared from 9.6 \u0026micro;L of the ligand in 4000 \u0026micro;L of buffer.\u003c/p\u003e \u003cp\u003e \u003cb\u003eX-ray Crystallography.\u003c/b\u003e The protein expression and purification and compound crystallization procedures for the X-ray co-crystal structures have previously been described [32].\u003c/p\u003e \u003cp\u003e \u003cb\u003ePAMPA Assay\u003c/b\u003e [43]. Compounds and controls are utilized as 10 mM stocks in 100% DMSO. Compounds are diluted 1:100 in pH 7.4 or 5.5 donor-well buffer (pION, catalogue no. 110151), providing a 100 \u0026micro;M assay solution in 1% DMSO. Compounds diluted in a donorwell buffer were transferred to Whatman Unifilter plates and filtered prior to 200 \u0026micro;L being dispensed into the donor wells of the assay plates (pION, catalogue no. 110163). The PAMPA membrane was formed by pipetting 4 \u0026micro;L of the lipid solution (pION, catalogue no. 110169) onto the filter plate (VWR CAT #13503). The membrane was then covered with 200 \u0026micro;L of acceptor-well buffer at pH 7.4 (pION, catalogue no. 110139). The PAMPA-assay plate (donor and acceptor sides) was combined and allowed to incubate at room temperature for 4 h. The plate was then disassembled, and spectrophotometer plates (VWR, catalogue no. 655801) were filled (150 \u0026micro;L/well). The donor, acceptor, reference, and blank plates were read in a SpectraMax UV plate reader. Data were captured by the pION software, which analyzed the spectra and generated Pc values. The control compounds in this assay are as follows (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD): ketoprofen (pH 5.5, Pc 34.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1 cm\u0026thinsp;\u0026minus;\u0026thinsp;6 /s; pH 7.4, Pc 1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3 cm\u0026thinsp;\u0026minus;\u0026thinsp;6 / s), metoprolol (pH 5.5, Pc 10.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1 cm\u0026thinsp;\u0026minus;\u0026thinsp;6 /s; pH 7.4, Pc 83.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7 cm\u0026thinsp;\u0026minus;\u0026thinsp;6 /s), and ranitidine (pH 5.5, Pc 0\u0026thinsp;\u0026plusmn;\u0026thinsp;0 cm\u0026thinsp;\u0026minus;\u0026thinsp;6 /s; pH 7.4, Pc 0.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1 cm\u0026thinsp;\u0026minus;\u0026thinsp;6 /s).\u003c/p\u003e \u003cp\u003e \u003cb\u003eMetabolic Stability in Liver Microsomes\u003c/b\u003e [44]. The metabolic stability (Metstab) assay evaluates cytochrome P450 (CYP)-mediated metabolism of test compounds in vitro using human and rat microsomes after a 10 min incubation. The incubation was automated on a Biomek FX automation workstation (Beckman Coulter, Fullerton, CA, USA). Each compound was incubated in duplicate in the respective species at a concentration of 0.5 \u0026micro;M. Compounds were received as 3.5 mM solutions in DMSO and were diluted with CH3CN to 50 \u0026micro;M before being added to the prewarmed (37\u0026deg;C) microsomal suspension (1 mg/mL) prepared in 100 mM sodium phosphate, pH 7.4, and 6.6 mM MgCl2. The reaction was initiated by adding 17 \u0026micro;L of prewarmed 5 mM NADPH in 100 mM sodium phosphate, pH 7.4, into 153 \u0026micro;L of reaction mix. The concentration of DMSO in the incubation mixture was 0.014%. Reaction components were mixed well, and 75 \u0026micro;L was transferred into 150 \u0026micro;L of quench solution at 0 min time point (t0) and again at the 10 min incubation time point (t10). Quenched mixtures were centrifuged at 1500 rpm in an Allegra X-12 centrifuge (Beckman Coulter) for 15 min, and 90 \u0026micro;L of the supernatant was then transferred to a separate 96-well plate for analysis. The metabolism rate was determined based on the parent compound disappearance over time, as measured by LC\u0026thinsp;\u0026minus;\u0026thinsp;MS/MS.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSEC-MALS Method.\u003c/b\u003e Isocratic separations were performed on a GE Healthcare Superdex 200 Increase 10/300 GL column (10 mm X 300 mm), connected to Shimadzu Prominence UFLC in buffer containing HBS, pH 7.4 (Cytiva), with 0.02% Na azide added and 0.1 mm filtered running at a flow rate of 0.75 mL/min. Data were obtained from three online detectors connected in series: A Shimadzu Prominence dual wavelength UV/vis spectrophotometer followed by a Wyatt Technologies DAWN multi-angle laser light scattering detector then a Wyatt Optilab interferometric refractometer. Data were collected and analyzed using ASTRA 8 (Wyatt) and LabSolutions Lite (Shimadzu) software.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePharmacokinetic Studies in Mice.\u003c/b\u003e The pharmacokinetic studies were conducted at Syngene International Ltd., Biocon-Bristol Myers Squibs Research Center, Bangalore, India, which is a CPCSEA- (Committee for the Purpose of Control and Supervision on Experiments on Animals) and AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care)-approved facility. Study protocols were approved by Institutional Animal Ethics Journal of Medicinal Chemistry pubs.acs.org/jmc Article \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1021/acs.jmedchem.2c00517\u003c/span\u003e\u003cspan address=\"10.1021/acs.jmedchem.2c00517\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e J. Med. Chem. 2022, 65, 11084\u0026thinsp;\u0026minus;\u0026thinsp;11099 11096 Committee (IAEC). The study protocol was previously described [43].\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNAFLD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNonalcoholic fatty liver disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNASH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNonalcoholic steatohepatitis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGal-3\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGalectin-3\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCarbohydrate recognition domain\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSAR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStructure-activity relationship\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHTRF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHomogeneous time-resolved fluorescence\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eB-ASF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBiotin-asialofetuin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFITC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFluorescein isothiocyanate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePK/PD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePharmacokinetic/pharmacodynamic\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePAMPA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eParallel artificial membrane permeability assay\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003etPSA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTopological polar surface\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntravenous\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePer os, orally administered\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUAC\u003csub\u003etotal\u003c/sub\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTotal area under the plasma concentration time-curve\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eF%\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOral bioavailability\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePK\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePharmacokinetic\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSQ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSubcutaneous\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSEC-MALS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSize-exclusion chromatography combined with multi-angle light scattering\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMW\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMolecular weight\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e "},{"header":"Declarations","content":"\u003cp\u003eThe authors declare no competing interests\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLoomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013;10:686-90. http://dx.doi.org/10.1038/nrgastro.2013.171.\u003c/li\u003e\n\u003cli\u003eYounossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73-84. https://doi.org/10.1002/hep.28431\u003cu\u003e.\u003c/u\u003e\u003c/li\u003e\n\u003cli\u003eStepanova M, Rafiq N, Makhlouf H, Agrawal R, Kaur I, Younoszai Z, McCullough, A, Goodman Z, Younossi, ZM. Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD). Digest Dis Sci. 2013;58:3017-23. https://doi.org/10.1007/s10620-013-2743-5\u003cu\u003e.\u003c/u\u003e\u003c/li\u003e\n\u003cli\u003ePerumpail BJ, Khan MA, Yoo, ER, Cholankeril G, Kim D, Ahmed A. Clinical epidemiology and disease burden of nonalcoholic fatty liver disease. World J Gastroentero. 2017;23:8263-76. http://dx.doi.org/10.3748/wjg.v23.i47.8263\u003cu\u003e.\u003c/u\u003e\u003c/li\u003e\n\u003cli\u003eAdams LA, Sanderson S, Lindor KD, Angulo, P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005;42:132-38. https://doi.org/10.1016/j.jhep.2004.09.012\u003c/li\u003e\n\u003cli\u003eArgo CK, Northup PG, Al-Osaimi AM, Caldwell SH. (2009). Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol. 2009;51:371-379. https://doi.org/10.1016/j.jhep.2009.03.019\u003cu\u003e.\u003c/u\u003e\u003c/li\u003e\n\u003cli\u003eBarondes SH, Castronovo V, Cooper DN, Cummings RD, Drickamer K, Feizi T, Gitt MA, Hirabayashi J, Hughes C, Kasai K. Galectins: a family of animal beta-galactoside-binding lectins. Cell. 1994;76:597-98. https://doi.org/10.1016/0092-8674(94)90498-7.\u003c/li\u003e\n\u003cli\u003eLeffler H, Carlsson S, Hedlund M, Qian Y, Poirier F. Introduction to galectins. Glycoconj J. 2002;19:433-40. https://doi.org/10.1023/B:GLYC.0000014072.34840.04\u003cu\u003e.\u003c/u\u003e\u003c/li\u003e\n\u003cli\u003eBoscher C, Dennis JW, Nabi IR. Glycosylation, galectins and cellular signaling. Curr Opin Cell Biol.\u003cem\u003e \u003c/em\u003e2011;23:383-92. https://doi.org/10.1016/j.ceb.2011.05.001.\u003c/li\u003e\n\u003cli\u003eJohannes L, Jacob R, Leffler H. Galectins at a glance.J. Cell Sci. 2018;\u003cem\u003e131\u003c/em\u003e:1-9. https://doi:10.1242/jcs.208884.\u003c/li\u003e\n\u003cli\u003eYang RY, Rabinovich GA, Liu FT. Galectins: structure, function and therapeutic potential. 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Gal-3: one molecule for an alphabet of diseases, from A to Z. Int J Mol Sci. 2018;26;19:379-438. https://doi.org/10.1016/j.bbrc.2013.11.063.\u003c/li\u003e\n\u003cli\u003eKlyosov AA, Traber PG. Galectins and disease implications for targeted therapeutics. ACS Symposium Series eBooks; ACS Washington, DC, December 18, 2012. https://doi.org/ https://pubs.acs.org/doi/pdf/10.1021/bk-2012-1115.ch001. https://doi.org/10.1023/B:GLYC.0000014072.34840.04\u003c/li\u003e\n\u003cli\u003eBlanchard H, Yu X, Collins PM, Bum-Erdene K. Galectin-3 inhibitors: a patent review (2008-present). Expert Opin Ther Pat. 2014;24:1053-65. https://doi.org/10.1517/13543776.2014.947961.\u003c/li\u003e\n\u003cli\u003eSethi A, Sanam S, Alvala R, Alvala M. An updated patent review of galectin-1 and galectin-3 inhibitors and their potential therapeutic applications (2016-present). Expert Opin Ther Pat. 2021;31:709-21. https://doi.org/10.1080/13543776.2021.1903430.\u003c/li\u003e\n\u003cli\u003eLi LC, Li J, Gao J. Functions of Gal-3 and its role in fibrotic diseases. J Pharmacol Exp Ther. 2014;351:336-43. https://doi.org/10.1124/jpet.114.218370.\u003c/li\u003e\n\u003cli\u003eSlack RJ, Mills R, Mackinnon AC. The therapeutic potential of Gal-3 inhibition in fibrotic disease. Int J Biochem Cell Biol. 2021;130:105881. https://doi.org/10.1016/j.biocel.2020.105881.\u003c/li\u003e\n\u003cli\u003eMaeda N, Kawada N, Seki S, Arakawa T, Ikeda K, Iwao H, Okuyama H, Hirabayashi J, Kasai K, Yoshizato K. Stimulation of proliferation of rat hepatic stellate cells by galectin-1 and Gal-3 through different intracellular signaling pathways. J Biol Chem. 2003;278:18938-44. https://doi.org/10.1074/jbc.M209673200.\u003c/li\u003e\n\u003cli\u003eHenderson NC, Mackinnon AC, Farnworth SL, Sethi T. Gal-3 regulates myofibroblast activation and hepatic fibrosis. PNAS. 2006;\u003cem\u003e103:\u003c/em\u003e5060-65. https://doi.org/10.1073/pnas.0511167103\u003c/li\u003e\n\u003cli\u003ede Oliveira SA, de Freitas Souza BS, S\u0026aacute; Barreto EP, Kaneto CM, Neto HA, Azevedo, CM, Guimar\u0026atilde;es ET, de Freitas LA, Ribeiro-Dos-Santos R, Soares MB. Reduction of Gal-3 expression and liver fibrosis after cell therapy in a mouse model of cirrhosis. Cytotherapy. 2012;14:339-49. https://doi.org/10.3109/14653249.2011.637668\u003c/li\u003e\n\u003cli\u003eTraber PG, Chou H, Zomer E, Hong F, Klyosov A, Fiel MI, Friedman SL. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PLoS One. 2013;8:e75361. https://doi.org/10.1371/journal.pone.0075361.\u003c/li\u003e\n\u003cli\u003eHirani N, MacKinnon AC, Nicol L, Ford P, Schambye H, Pedersen A, Nilsson UJ, Leffler H, Sethi T, Tantawi S, Gravelle L, Slack RJ, Mills R, Karmakar U, Humphries D, Zetterberg F, Keeling L, Paul L, Molyneaux PL, Li F, Funston W, Forrest IA, Simpson AJ, Gibbons MA, Maher TM. Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis. Eur Respir J. 2021;57:2002559. https://doi.org/10.1183/13993003.02559-2020. Erratum in: Eur Respir J. 2022 Apr 14;59: PMID: 33214209; PMCID: PMC8156151.\u003c/li\u003e\n\u003cli\u003eZetterberg FR, MacKinnon A, Brimert T, Gravelle L, Johnsson RE, Kahl-Knutson B, Leffler H, Nilsson UJ, Pedersen A, Peterson K, Roper JA, Schambye H, Slack RJ, Tantawi S. Discovery and optimization of the first highly effective and orally available galectin-3 inhibitors for treatment of fibrotic disease. J Med Chem. 2022;65:12626-38. https://doi.org/10.1021/acs.jmedchem.2c00660.\u003c/li\u003e\n\u003cli\u003eLiu C, Jalagam PR, Feng J, Wang W, Raja T, Sura MR, Manepalli RKVLP, Aliphedi BR, Medavarapu S, Nair SK, Muthalagu V, Natesan R, Gupta A, Beno B, Panda M, Ghosh K, Shukla JK, Sale H, Haldar P, Kalidindi N, Shah D, Patel D, Mathur A, Ellsworth BA, Cheng D, Regueiro-Ren A. Identification of monosaccharide derivatives as potent, selective, and orally bioavailable inhibitors of human and mouse Gal-3. J Med Chem. 2022;65:11084-99. https://doi.org/10.1021/acs.jmedchem.2c00517.\u003c/li\u003e\n\u003cli\u003eLiu C, Wang W, Feng J, Beno Brett, Raja T, Swidorski J, Manepalli R, Vetrichelvan M, Jalagam P, Prasada; Nair S, Gupta A, Panda M, Ghosh K, Shukla JK, Sale H, Shah D, Gautam S, Patel D, Mathur A, Ellsworth B, Cheng D, Dong; Regueiro-Ren A. Identification of benzothiazole derived monosaccharides as potent, selective, and orally bioavailable inhibitors of human and mouse galectin-3. J Med Chem. Submitted March 8, 2023.\u003c/li\u003e\n\u003cli\u003eKumar A, Paul M, Panda M, Jayaram S, Kalidindi N, Sale S, Vetrichelvan M, Gupta A, Mathur A, Beno B, Regueiro-Ren A, Cheng D, Ramarao M, Ghosh K. Molecular mechanism of interspecies differences in the binding affinity of TD139 to galectin-3. Glycobiology 2021;31:1390-1400. https://doi.org/10.1093/glycob/cwab072.\u003c/li\u003e\n\u003cli\u003eS\u0026ouml;rme P, Kahl-Knutsson B, Huflejt M, Nilsson UJ, Leffler H. Fluorescence polarization as an analytical tool to evaluate galectin\u0026ndash;ligand interactions. Anal Biochem. 2004;334:36-47. https://doi.org/10.1016/j.ab.2004.06.042. Fluorescein-conjugated saccharide probe 9 was used for the F-ligand assay reported.\u003c/li\u003e\n\u003cli\u003eKansy M, Senner F, Gubernator, K. Physicochemical high throughput screening:\u0026thinsp; parallel artificial membrane permeation assay in the description of passive absorption processes. J Med Chem. 1998;41:1007-1010. https://doi.org/10.1021/jm970530e.\u003c/li\u003e\n\u003cli\u003eErtl P, Rohde B, Selzer P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug rransport properties. J Med Chem. 2000;43:3714-17. https://doi.org/10.1021/jm000942e.\u003c/li\u003e\n\u003cli\u003etPSA calculations were calculated using PerkinElmer ChemDraw Professional version 20.1.0.110.\u003c/li\u003e\n\u003cli\u003eSahin E, Roberts CJ. Size-exclusion chromatography with multi-angle light scattering for elucidating protein aggregation mechanisms. Methods Mol Biol. 2012;899:403-23. https://doi.org/10.1007/978-1-61779-921-1_25.\u003c/li\u003e\n\u003cli\u003eSome D, Amartely H, Tsadok A, Lebendiker M. Characterization of proteins by size-exclusion chromatography coupled to multi-angle light scattering (SEC-MALS). J Vis Exp. 2019;148. https://doi.org:/10.3791/59615.\u003c/li\u003e\n\u003cli\u003eKolb HC, Sharpless BK. The growing impact of click chemistry on drug discovery. Drug Discov Today 2003;8:1128-37. https://doi.org/10.1016/S1359-6446(03)02933-7.\u003c/li\u003e\n\u003cli\u003eDourtoglou V, Gross B. O-Benzotriazolyl-N,N,N\u0026rsquo;,N\u0026rsquo;-tetramethyluronium hexafluorophosphate as a coupling reagent for the sythesis of peptides of biological interest. Synthesis 1984;7:572-4. https://doi.org/10.1055/s-1984-30895.\u003c/li\u003e\n\u003cli\u003eAzide \u003cstrong\u003e38 \u003c/strong\u003ecan be prepared using the same method described in scheme 1 for azide \u003cstrong\u003e34 \u003c/strong\u003eonly starting with different substitution on the phenyl group of the alkyne.\u003c/li\u003e\n\u003cli\u003eWissmann H, Kleiner H-J. New peptide synthesis. Angew Chem, Int Ed Engl. 1980;19:133-4. https://doi.org/10.1002/anie.198001331.\u003c/li\u003e\n\u003cli\u003eXu L, Hartz RA, Beno BR, Ghosh K, Shukla JK, Kumar A, Patel D, Kalidindi N, Lemos N, Gautam SS, Kumar A, Ellsworth BA, Shah D, Sale H, Cheng D, and Regueiro-Ren A. Synthesis, structure-activity relationships, and in vivo evaluation of novel tetrahydropyran-based thiodisaccharide mimics as Gal-3 inhibitors. J Med Chem. 2021;64:6634-55. https://doi.org/10.1021/acs.jmedchem.0c02001.\u003c/li\u003e\n\u003cli\u003eKieltyka K, Zhang J, Li S, Vath M, Baglieri C, Ferraro C, Zvyaga TA, Drexler DM, Weller HN, Shou WZ. A high throughput bioanalytical platform using automated infusion for tandem mass spectrometric method optimization and its application in a metabolic stability screen. Rapid Commun Mass Spectrom. 2009;23:1579-91. https://doi.org/10.1002/rcm.4037.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Schemes","content":"\u003cp\u003eSchemes 1 to 6 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"medicinal-chemistry-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mcre","sideBox":"Learn more about [Medicinal Chemistry Research](https://www.springer.com/journal/44)","snPcode":"44","submissionUrl":"https://submission.nature.com/new-submission/44/3","title":"Medicinal Chemistry Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-2757730/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2757730/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGalectin proteins have been targets of interest in numerous therapeutic areas for some time. Galectin-3 has been identified as a target of particular interest because of its unique structural characteristics and physiological profile. Recent literature indicates Gal-3 inhibition can decrease myofibroblast activation and procollagen expression with the potential to affect the progression of fibrosis in the lung, liver and kidney. Potential π-stacking interactions between one monosaccharide ligand bound to the carbohydrate recognition domain of a galectin-3 protein and a second ligand bound to a different galectin-3 protein molecule were observed in the extended crystalline lattice in an X-ray crystal structure obtained while studying the monosaccharide structure-activity relationship. The direct interaction between the ligands suggests a potential for dimeric galectin-3 inhibitors which bind to two galectin-3 molecules simultaneously. This work describes the exploration of dimers designed to further probe these observations and explore the potential of binding to dimeric or higher order multimeric galectin-3 assemblies.\u003c/p\u003e","manuscriptTitle":"Discovery and Exploration of Monosaccharide Linked Dimers of Galectin-3 Inhibitors to Target Fibrosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-04-11 18:36:22","doi":"10.21203/rs.3.rs-2757730/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2023-04-10T14:42:00+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-04-08T11:29:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-03-31T10:51:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"Medicinal Chemistry Research","date":"2023-03-30T12:58:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"medicinal-chemistry-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mcre","sideBox":"Learn more about [Medicinal Chemistry Research](https://www.springer.com/journal/44)","snPcode":"44","submissionUrl":"https://submission.nature.com/new-submission/44/3","title":"Medicinal Chemistry Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"09ee56d5-7a49-49fc-a2a2-dcc975e95172","owner":[],"postedDate":"April 11th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T21:17:44+00:00","versionOfRecord":{"articleIdentity":"rs-2757730","link":"https://doi.org/10.1007/s00044-023-03087-x","journal":{"identity":"medicinal-chemistry-research","isVorOnly":false,"title":"Medicinal Chemistry Research"},"publishedOn":"2023-06-08 21:07:58","publishedOnDateReadable":"June 8th, 2023"},"versionCreatedAt":"2023-04-11 18:36:22","video":"","vorDoi":"10.1007/s00044-023-03087-x","vorDoiUrl":"https://doi.org/10.1007/s00044-023-03087-x","workflowStages":[]},"version":"v1","identity":"rs-2757730","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2757730","identity":"rs-2757730","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}