α-D-galactoside inhibitors of galectin

Abstract

The present invention relates to a compound of general formula (1), wherein the pyranose ring is α-D-galactopyranose, A is selected from, and the compound of structural formula (1) is suitable for use in a method for treating diseases associated with the binding of galectins (such as galectin-3) and mammalian (such as human) ligands. In addition, the present invention relates to a compound for treating diseases associated with the binding of galectins (such as galectin-3) and mammalian (such as human) ligands.

Description

[0001] This application is a divisional application of the application with the application number 201680007946.8, the application date of January 28, 2016, and the title of "α-D-galactoside inhibitors of galectin". Technical Field

[0002] The present invention relates to novel compounds, the use of said compounds as drugs, and the use of drugs for the production of drugs for treating inflammation, fibrosis, scarring, keloid formation, abnormal scar formation, surgical adhesions, septic shock, cancer, autoimmune diseases, metabolic disorders, heart diseases, heart failure, pathological angiogenesis, eye diseases, atherosclerosis, metabolic diseases, asthma and other interstitial lung diseases, and liver diseases in mammals. The present invention also relates to pharmaceutical compositions comprising said novel compounds. Background Art

[0003] Galectins are proteins with a characteristic carbohydrate recognition domain (CRD) (Barondes et al, 1994; Leffler et al, 2004). This is a tightly folded β-sandwich structure of approximately 130 amino acids (approximately 15 kDa) with the following two defining features: 1) a β-galactose binding site and 2) an approximately 7 amino acid sequence motif with sufficient similarity such that most of them (approximately six residues) constitute the β-galactose binding site. However, for tight binding to natural carbohydrates, it is required that the sites be located near the β-galactose binding site, and the different preferences of these sites confer different fine specificities of galectins for natural carbohydrates.

[0004] Recently completed genome sequencing of humans, mice, and rats has shown that there are approximately 15 galectins and galectin-like proteins in a mammalian genome, with slight differences between species (Leffler et al., 2004).

[0005] Galectin subunits can contain one or two CRDs in a single peptide chain. The first class (mono-CRD galectins) can occur as monomers or dimers (two types) in vertebrates. The most well-studied galectins to date are the dimeric galectin-1 and galectin-3, which is monomeric in solution but can aggregate and form multimers when encountering ligands (Leffler et al., 2004). These are the first galectins discovered and are very abundant in many tissues.

[0006] There are now over 3,500 publications on galectins in PubMed, and as described above, the majority of these are on galectin-1 (>900) and galectin-3 (>1,600). There is strong evidence for the role of galectins in, for example, inflammation and cancer, and recent special issues (Leffler (ed.), 2004b) have reviewed the progress made.

[0007] Galectins are synthesized as cytoplasmic proteins without a signal peptide on free ribosomes. Their N-termini are acetylated (a typical modification of cytoplasmic proteins), and they reside in the cytosol for a long time (atypical secreted proteins). From here, they can target the nucleus, specific cytosolic sites, or be secreted (induced or constitutive) via currently unknown non-classical (non-ER-Golgi) pathways, but possibly similar to the export of, for example, IL-1 (Leffler et al., 2004). They can also function in all these compartments; for galectin-3, conclusive evidence published in important journals supports its role in RNA splicing in the nucleus, inhibition of apoptosis in the cytosol, and multiple extracellular effects on cell signaling and adhesion (Leffler (ed.), 2004b). Galectin-7 and galectin-12 also function in the cytosol by enhancing apoptosis and regulating the cell cycle and differentiation in certain cells (reported by Hsu and Liu in Leffler (ed.), 2004b). Most galectins also function extracellularly by cross-linking glycoproteins (such as laminin, integrin, and IgE receptor), possibly forming supramolecular arrays (Brewer et al., 2002), and thereby possibly regulating cell adhesion and inducing intracellular signaling. In this context, molecular mechanisms underlying these galectin functions have been reported in recent years, involving the formation of microdomains (rafts) within the membrane (Dam et al., 2008; Garner et al., 2008), which in turn affect intracellular trafficking and cell surface presentation of glycoprotein receptors (Delacour et al., 2007; Lau et al., 2007; Lau et al., 2008). This has been demonstrated in cell culture, in knockout mutant mice (Blois et al., 2007; Gedronneau et al., 2008; Thijssen et al., 2007; Toscano et al., 2007; Saegusa et al., 2009), and in animals treated with galectins (Blois et al., 2007; Perone et al., 2009) or galectin inhibitors (John et al., 2003; Pienta et al., 1995; Glinsky et al., 1996).

[0008] Potential Therapeutic Uses of Galectin-3 Inhibitors

[0009] Galectin-3 is associated with multiple phenomena, and therefore, these inhibitors may have multiple uses. This is easily found due to the lack of specificity or lack of scientific attention. Therefore, it is useful to draw an analogy with aspirin and cyclooxygenase (COX-I and II). COX produces precursors of various prostaglandins and is thus involved in multiple biological mechanisms. Their inhibitors - aspirin and other NSAIDs (non-steroidal anti-inflammatory drugs), also have a wide variety of diverse effects. Nevertheless, these inhibitors are very useful in medicine and have several different specific applications.

[0010] So, if galectins are part of some basic biological regulatory mechanisms like COX (currently unknown), they are likely to be "naturally used" for different purposes in different situations. Like NSAIDs, galectin inhibitors are not expected to disrupt the whole system but are expected to tip the balance a bit.

[0011] Inhibiting inflammation

[0012] In null mutant mice, galectin-3 induces various effects on immune cells in cells at the site of inflammation (e.g., oxidative burst in neutrophils and chemotaxis in monocytes), and reduces the inflammatory response mainly in neutrophils and macrophages, indicating the pro-inflammatory role of galectin-3 (in Leffler (ed.), 2004b). Additionally, the inflammatory response increases in Mac-2BP (a galectin-3 ligand) knockout mice (Trahey et al., 1999). Importantly, recent studies have determined that galectin-3 is a key rate-limiting factor in macrophage M2 differentiation and myofibroblast activation, affecting the development of fibrosis (Mackinnon et al., 2008; Mackinnon et al., 2012).

[0013] Inflammation is a protective response of the body to invading organisms and tissue damage. However, if unbalanced, inflammation is often also destructive and is part of the pathology of many diseases. Because of this, there is great medical interest in the pharmacological regulation of inflammation. Galectin-3 inhibitors are expected to provide an important addition to the medical arsenal for such uses.

[0014] Treating fibrosis-related diseases

[0015] The idea that galectin-3 may play a role in fibrosis comes from in vitro studies of macrophage differentiation (Mackinnon et al., 2008) and in vivo studies of macrophage differentiation and myofibroblast activation (Mackinnon et al., 2012). Briefly, the hypothesis is as follows: Galectin-3 has been shown to prolong cell surface residence and thereby increase responsiveness of the TGF-β receptor (Partridge et al., 2004), which in turn regulates the differentiation of alternative macrophages into M2 macrophages and the activation of myofibroblasts.

[0016] Thus, since galectin-3 is a good candidate for an endogenous enhancer of TGF-β signaling and alternative macrophage differentiation and myofibroblast activation, galectin-3 inhibitors may be very useful in the treatment of fibrosis and adverse tissue remodeling.

[0017] Treatment of cancer

[0018] Numerous immunohistochemical studies have shown altered expression of certain galectins in cancer (vanden Brule et al. and Bidon et al. in Leffler (ed.), 2004b), and, now, for example, galectin-3 is an established histochemical marker for thyroid cancer. Direct evidence for the role of galectin-3 in cancer mainly comes from Raz et al, but also from mouse models established by others (in Leffler (ed.), 2004b). In paired tumor cell lines (with reduced or increased expression of galectin-3), inducing galectin-3 caused more tumors and metastases, while inhibiting galectin-3 caused fewer tumors and metastases. It has been proposed that galectin-3 promotes tumor growth due to anti-apoptosis, promotes angiogenesis or promotes metastasis by affecting cell adhesion. In addition, recent evidence suggests that galectin-3 plays a key role in the tumor microenvironment – reviewed by Ruvolo, 2015. It is thought that galectin-3 also regulates the interaction between tumor cells and immune cells, such as T-lymphocytes (T-cells), and it has been shown that inhibiting galectin-3 restores T-cell activity (Demotte et al. 2010, Kouo et al. 2015, Menero et al. 2015). From the above, it is obvious that inhibitors of galectin-3 may have valuable anti-cancer effects. In fact, it has been reported that carbohydrates that inhibit galectin-3 have anti-cancer effects, but this has not been proven. In our own study, a galectin-3 fragment containing the CRD inhibited breast cancer in a mouse model by acting as a dominant negative inhibitor (John et al., 2003). It has recently been shown that using small molecules to inhibit galectin-3 in cell assays and in vitro (Lin et al., 2009) and in vivo (Glinsky et al., 2009) assays indeed greatly enhances the sensitivity of tumor cells to radiation and standard pro-apoptotic drugs.

[0019] Galectin-1 is also often overexpressed in poorly differentiated cancer cells, and galectin-9 or its related galectins-4 and -8 can be induced in specific cancer types (Huflejt and Leffler, 2004; Leffler (ed.), 2004b). Galectin-1 induces apoptosis in activated T-cells and has significant immunosuppressive effects on autoimmune diseases in vivo (Rabinovich et al; and Pace et al. in Leffler (ed.), 2004b). Thus, the overexpression of these galectins in cancer can assist the tumor itself in defending against the T-cell response generated by the host.

[0020] Galectin-1 and galectin-3 null mutant mice were generated many years ago (Poirier, 2002). Under animal house conditions, these mice are healthy and apparently reproduce normally. However, recent studies have shown an atypical phenotype of galectin-3 null mutants in neutrophil and macrophage functions (as described above) and in bone formation, as well as an atypical phenotype of galectin-1 null mutants in nerve and muscle cell regeneration / differentiation (Leffler et al., 2004; Poirier, 2002; Watt in Leffler (ed.), 2004b).

[0021] Galectin-7 and galectin-9 null mutant mice have recently been generated and are also very healthy under animal house conditions, but have not been analyzed in detail. Differences in expression sites, specificities and other properties make it unlikely that different galectins can replace each other functionally. As can be observed under normal animal house conditions, what is seen in null mutant mice will indicate that galectins are not essential for basic life support functions. Instead, they may be normal function optimizers and / or be essential under stress conditions not present in the animal house. The lack of a strong effect of galectin inhibitors in null mutant mice may make them more favorable as drugs. If, as described above, galectin activity promotes pathological conditions and has less effect on normal conditions, then there will be fewer unwanted side effects caused by inhibiting them.

[0022] Treatment of angiogenesis

[0023] VEGF signaling through the vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) is the major angiogenic pathway. Published studies have shown that both galectin-1 and galectin-3 are important regulators of the VEGF / VEGFR-2 signaling pathway. Published studies have also shown that the galectin inhibitor TDX is expected to be effective in blocking pathological angiogenesis. (Chen 2012)

[0024] Well-known inhibitors

[0025] Natural ligands

[0026] Solid-phase binding assays and inhibition assays have identified a large number of saccharides and glycoconjugates with the ability to bind galectins (reviewed in Leffler, 2001 and Leffler et al., 2004). All galectins bind lactose with a Kd of 0.5 - 1 mM. The affinity for D-galactose is 50 - 100 times lower. The binding to N-acetyl lactosamine and related disaccharides is about the same as that for lactose, but for some galectins, their binding is worse, or at most 10-fold better. The best carbohydrate ligands for galectin-3 are those carrying a blood group A-determinant linked to a lactose or LacNAc-residue, and their binding is found to be at most about 50-fold better than that of lactose. Galectin-1 does not show a preference for these saccharides.

[0027] It has been proposed that larger saccharides of the poly-lactosamine type are preferred ligands for galectins. In solution, using glycopeptides carrying poly-lactosamine, evidence has been shown for galectin-3, but not for galectin-1 (Leffler and Barondes, 1986). Modified plant pectin polysaccharides have been reported to bind to galectin-3 (Pienta et al., 1995).

[0028] The above-mentioned natural saccharides identified as galectin-3 ligands are not suitable as active components of pharmaceutical compositions because they are sensitive to acidic hydrolysis in the stomach and to enzymatic degradation. In addition, natural saccharides are hydrophilic in nature and are not easily absorbed through the gastrointestinal tract after oral administration.

[0029] Galectin specificity

[0030] Studies on the specificity of the above-mentioned natural small-molecule saccharides in inhibiting galectins have shown that all galectins bind lactose, LacNAc, and related disaccharides, but galectin-3 binds much better to some longer saccharides (Leffler and Barondes, 1986). These longer saccharides are characterized by an additional sugar residue at the C-3 position of galactose that binds to an extended binding groove (e.g., in lactose or LacNAc). The different shapes of this binding groove between galectins indicate that the same extension does not bind equally well to different galectins.

[0031] Synthetic inhibitors

[0032] Sugars linked to amino acids with anticancer activity were first identified as natural compounds in serum, but synthetic analogs were later prepared (Glinsky et al., 1996). Among them, those with lactose or galactose linked to amino acids inhibited galectins, but their potency was only about the same as the corresponding underivatized sugars. Chemically modified forms of citrus pectin inhibited galectin-3 (Piatt and Raz, 1992) and showed antitumor activity in vivo (Pienta et al., 1995; Nangia-Makker et al., 2002).

[0033] Cluster molecules with no more than four lactose units showed strong multivalent binding to galectin-3, but not to galectin-1 and galectin-5 (Vrasidas et al., 2003). Cyclodextrin-like sugar cluster molecules with seven galactose, lactose, or N-acetyllactosamine residues also showed strong multivalent binding to galectin-3, but weaker binding to galectin-1 and galectin-7 (Andre et al., 2004).

[0034] Starburst dendrimers (Andre et al., 1999) and glycopolymers (Pohl et al., 1999; David et al., 2004) containing multivalent lactose residues have been described as inhibitors of galectin-3 with slightly improved potency compared to lactose. The aforementioned synthetic compounds have been identified as galectin-3 ligands, but are not easily absorbed from the gastrointestinal tract after oral administration due to their hydrophilic nature and are therefore not suitable as active ingredients of pharmaceutical compositions.

[0035] The above-mentioned natural oligosaccharides, glycocluster molecules, glycodendrimers and glycopolymers are too large and polar to be absorbed, and in some cases are large enough to produce an immune response in patients. In addition, they are sensitive to acidic and enzymatic hydrolysis in the stomach. Therefore, small synthetic molecules are needed.

[0036] To our knowledge, thiodigalactosides are synthetic and hydrolytically stable polar inhibitors that are almost as potent as N-acetyllactosamine (Leffler and Barondes, 1986). N-acetyllactosamine derivatives carrying aromatic amide or substituted benzyl ether at C-3' have been shown to be highly potent inhibitors of galectin-3 with unprecedentedly low IC50 values ​​of 4.8 μM, a 20-fold improvement over the natural N-acetyllactosamine disaccharide ( et al., 2002; et al., 2003b). Due to the presence of the arylamide group unit, the polarity of these derivatives is overall weaker, and thus they are more suitable as in vivo galectin inhibitors. Additionally, it has been demonstrated that C3-triazolyl galactosides are as effective inhibitors as the corresponding C3-amides of some galectins. Therefore, any appropriately constructed galactose C3-substituent can confer enhanced galectin affinity.

[0037] However, due to the presence of glycosidic bonds in the glycosyl units of galactose and N-acetyl lactosamine, C3-acylamino-derived compounds and C3-triazolyl-derived compounds are still sensitive to in vivo hydrolytic degradation, and although they are effective small molecule inhibitors of galectin-3, their affinity and stability still need to be further improved. Therefore, 3,3'-bisamide-derived or 3,3'-bistriazolyl-derived inhibitors based on thiodigalactosides have been developed (Cumpstey et al., 2005b; Cumpstey et al., 2008; Salameh et al., 2010; WO / 2005 / 113569 and US2007185041; WO / 2005 / 113568, US7,638,623B2), which do not have hydrolytic and enzymatic instability of O-glycosidic bonds. These inhibitors also exhibit excellent affinity for several galectins (Kd is reduced to the lower nM range).

[0038] Although 3,3'-derived thiodigalactosides exhibit high affinity for galectins, there are some drawbacks in their multi-step synthesis involving double inversion reactions to obtain 3-N-derived galactose structural units. Additionally, it has been demonstrated that the cyclohexane substitution of one galactose ring in thiodigalactosides mimics the galactose ring and thus provides galectin-1 and -3 inhibitors with efficiency close to that of bisamide- and bistriazolyl-thiodigalactoside derivatives (WO / 2010 / 126435). Substituting the D-galactopyranose unit with a substituted cyclohexane reduces polarity and most likely also reduces metabolic susceptibility, thereby improving drug properties.

[0039] Some early disclosed compounds have the following general formula:

[0040]

[0041] As described in WO / 2005 / 113568, and

[0042]

[0043] As described in WO / 2005 / 113569, where R 1 can be D-galactose.

[0044] The most recently published US20140099319 and WO2014067986 disclose a compound with the following general formula:

[0045]

[0046] Both meta-positions of the two benzene rings relative to the triazole ring contain fluorine (F). This compound has shown to be a promising candidate drug for pulmonary fibrosis, especially with very high selectivity for galectin-3 and high affinity.

[0047] "Bioorganic & Medicinal Chemistry" 19(2011) 3280 - 3287, "Inhibitory potential of chemical substitutions at bioinspired sites of beta-D-galactopyranose on neoglycoprotein / cell surface binding of two classes of medically relevant lectins" discloses certain beta-D-galactopyranosides with an affinity for galectin-3 in the same range or lower than lactose (Kd is approximately 91 uM). The corresponding alpha-anomers with an affinity for galectin-3 superior to lactose are not disclosed or mentioned. Summary of the Invention

[0048] The compounds of the present invention are novel alpha-D-galactopyranose compounds, which unexpectedly show very high affinity for galectin-3 and are considered effective new drug candidates. Some of these compounds have very good oral PK properties, such as low clearance rate and high bioavailability.

[0049] Broadly speaking, the present invention relates to a D-galactopyranose compound with the structural formula (1)

[0050]

[0051] In the formula:

[0052] The pyranose ring is alpha-D-galactopyranose,

[0053] A

[0054] Selected from

[0055]

[0056] wherein Het 1 is selected from a five - or six - membered heteroaryl ring, optionally substituted with the following groups: Br; F; Cl; CN; NR 19 R 20 , where R 19 and R 20 are independently selected from H, C 1-3 alkyl, cyclopropyl, isopropyl, -C(=O)-R 21 , where R 21 is selected from H and C 1-3 alkyl; C 1-3 alkyl (optionally substituted with F); cyclopropyl (optionally substituted with F); isopropyl (optionally substituted with F); O - cyclopropyl (optionally substituted with F); O - isopropyl (optionally substituted with F); and OC 1-3 alkyl (optionally substituted with F);

[0057] where R 1 -R 5 are independently selected from H, CN, NH2, F, methyl (optionally substituted with fluorine (F)), and OCH3 (optionally substituted with F);

[0058] where R 6 is selected from C 1-6 alkyl (optionally substituted with halogen), branched - chain C 3-6 alkyl, and C 3-7 cycloalkyl;

[0059] where R 7 is selected from a five - or six - membered heteroaryl ring and phenyl, the five - or six - membered heteroaryl ring is optionally substituted with a group selected from Br, F, Cl, methyl (optionally substituted with F), and OCH3 (optionally substituted with F), and the phenyl is optionally substituted with Br, F, Cl, methyl (optionally substituted with F), and OCH3 (optionally substituted with F);

[0060] where R 8 -R 12 are independently selected from H, F, methyl (optionally substituted with fluorine (F)), and OCH3 (optionally substituted with F);

[0061] where R 13 is a five - or six - membered heteroaryl ring or aryl, the five - or six - membered heteroaryl ring is optionally substituted with a group selected from H, OH, F, methyl (optionally substituted with fluorine (F)), and OCH3 (optionally substituted with F), and the aryl (such as phenyl or naphthyl) is optionally substituted with a group selected from H, OH, F, methyl (optionally substituted with fluorine (F)), and OCH3 (optionally substituted with F);

[0062] X is selected from S, SO, SO2, O, C=O, and CR 7 R 8 , where R 7 and R 8 are independently selected from hydrogen, OH or halogen (such as F, Cl, Br);

[0063] where R 27 is selected from C 1-6 alkyl, branched C 3-6 alkyl, C 1-6 alkoxy and branched C 3-6 alkoxy;

[0064] B is selected from a) C 1-6 alkyl or branched C 3-6 alkyl substituted by a five- or six-membered heteroaryl ring, and the five- or six-membered heteroaryl ring is optionally substituted by a substituent selected from CN, halogen (such as Cl, F, Br, I), methyl (optionally substituted by F), OCH3 (optionally substituted by F), OCH2CH3 (optionally substituted by F), OH and R 14 -CONH- (where R 14 is selected from C 1-3 alkyl and cyclopropyl); or C 1-6 alkyl substituted by phenyl, and phenyl is optionally substituted by the following substituents: CN, halogen (such as Cl, F, Br, I), methyl (optionally substituted by F), OCH 3( optionally substituted by F), OCH2CH3 (optionally substituted by F), OH, and R 15 -CONH-, where R 15 is selected from C 1-3 alkyl and cyclopropyl; b) aryl (such as phenyl or naphthyl), optionally substituted by the following groups: halogen (such as Cl, F, Br, I); CN; -COOH; -CONR 22 R 23 (where R 22 and R 23 are independently selected from H, C 1-3 alkyl, cyclopropyl and isopropyl); C 1-3 (optionally substituted by F); cyclopropyl (optionally substituted by F); isopropyl (optionally substituted by F); OC 1-3 alkyl (optionally substituted by F); O-cyclopropyl (optionally substituted by F); O-isopropyl (optionally substituted by F); NR 28 R 29 (where R 28 and R 29 are independently selected from H, C 1-3 alkyl and isopropyl); OH; and R 16 -CONH- (where R 16 is selected from C1-3 (alkyl and cyclopropyl); c) C 5-7 Cycloalkyl, optionally substituted by the following groups: halogen (such as Cl, F, Br, I), CN, methyl (optionally substituted by F), OCH3 (optionally substituted by F), OCH2CH3 (optionally substituted by F), OH, and R 17 -CONH- (wherein R 17 is selected from C 1-3 (alkyl and cyclopropyl); and d) heterocycle (such as heteroaryl or heterocycloalkyl), optionally substituted by the following groups: halogen (such as Cl, F, Br, I); CN; -COOH; -CONR 24 R 25 (wherein R 24 and R 25 are independently selected from H, C 1-3 (alkyl, cyclopropyl and isopropyl); C 1-3 alkyl (optionally substituted by F); cyclopropyl (optionally substituted by F); isopropyl (optionally substituted by F); OC 1-3 alkyl (optionally substituted by F); O-cyclopropyl (optionally substituted by F); O-isopropyl (optionally substituted by F); NR 30 R 31 (wherein R 30 and R 31 are independently selected from H, C 1-3 (alkyl and isopropyl); OH; and R 18 -CONH- (wherein R 18 is selected from C 1-3 (alkyl and cyclopropyl); e) C 1-6 alkyl or branched C 3-6 alkyl; or a pharmaceutically acceptable salt or solvate thereof.

[0065] On the other hand, the present invention relates to a D-galactopyranose compound of formula (1).

[0066] (1)

[0068] In the formula:

[0069] The pyranose ring is α-D-galactopyranose

[0070] A is selected from

[0071]

[0072] wherein Het 1 is selected from a five- or six-membered heteroaryl ring, optionally substituted by the following groups: Br; F; Cl; CN; NR 19 R 20 wherein R 19and R 20 are independently selected from H, C 1-3 alkyl, cyclopropyl, isopropyl, -C(=O)-R 21 , where R 21 is selected from H and C 1-3 alkyl; C 1-3 alkyl (optionally substituted with F); cyclopropyl (optionally substituted with F); isopropyl (optionally substituted with F); O-cyclopropyl (optionally substituted with F); O-isopropyl (optionally substituted with F); and OC 1-3 alkyl (optionally substituted with F);

[0073] where R 1 -R 5 is independently selected from H, CN, NH2, F, methyl (optionally substituted with fluorine (F)), and OCH3 (optionally substituted with F);

[0074] where R 6 is selected from C 1-6 alkyl, branched C 3-6 alkyl and C 3-7 cycloalkyl;

[0075] where R 7 is selected from a five- or six-membered heteroaryl ring and a phenyl group, the five- or six-membered heteroaryl ring is optionally substituted with Br, F, Cl, methyl (optionally substituted with F), and OCH3 (optionally substituted with F), and the phenyl group is optionally substituted with Br, F, Cl, methyl (optionally substituted with F), and OCH3 (optionally substituted with F);

[0076] where R 8 -R 12 is independently selected from H, F, methyl (optionally substituted with fluorine (F)), and OCH3 (optionally substituted with F);

[0077] where R 13 is a five- or six-membered heteroaryl ring or an aryl group, the five- or six-membered heteroaryl ring is optionally substituted with a group selected from H, OH, F, methyl (optionally substituted with fluorine (F)), and OCH3 (optionally substituted with F), and the aryl group (such as phenyl or naphthyl) is optionally substituted with a group selected from H, OH, F, methyl (optionally substituted with fluorine (F)), and OCH3 (optionally substituted with F);

[0078] X is selected from S, SO, SO2, O, C=O, and CR 7 R 8 , where R 7 and R 8 are independently selected from hydrogen, OH, or a halogen (such as F, Cl, Br);

[0079] B is selected from a) C substituted with a five- or six-membered heteroaryl ring 1-6alkyl or branched C 3-6 alkyl, a five- or six-membered heteroaryl ring optionally substituted with the following substituents: CN, halogen (such as Cl, F, Br, I), methyl (optionally substituted with F), OCH3 (optionally substituted with F), OCH2CH3 (optionally substituted with F), OH, and R 14 -CONH- (wherein R 14 is selected from C 1-3 alkyl and cyclopropyl); or C 1-6 alkyl substituted with phenyl, the phenyl optionally substituted with the following groups: CN, halogen (such as Cl, F, Br, I), methyl (optionally substituted with F), OCH 3( optionally substituted with F), OCH2CH3 (optionally substituted with F), OH, and R 15 -CONH-, wherein R 15 is selected from C 1-3 alkyl and cyclopropyl; b) aryl (such as phenyl or naphthyl), optionally substituted with substituents selected from halogen (such as Cl, F, Br, I); CN; -COOH; -CONR 22 R 23 (wherein R 22 and R 23 are independently selected from H, C 1-3 alkyl, cyclopropyl, and isopropyl); C 1-3 alkyl (optionally substituted with F); cyclopropyl (optionally substituted with F); isopropyl (optionally substituted with F); OC 1-3 alkyl (optionally substituted with F); O-cyclopropyl (optionally substituted with F); O-isopropyl (optionally substituted with F); OH; and R 16 -CONH- (wherein R 16 is selected from C 1-3 alkyl and cyclopropyl); c) C 5-7 cycloalkyl, optionally substituted with the following groups: halogen (such as Cl, F, Br, I), CN, methyl (optionally substituted with F), OCH3 (optionally substituted with F), OCH2CH3 (optionally substituted with F), OH, and R 17 -CONH- (wherein R 17 is selected from C 1-3 alkyl and cyclopropyl); and d) heterocycle (such as heteroaryl or heterocycloalkyl), optionally substituted with the following groups: halogen (such as Cl, F, Br, I); CN; -COOH; -CONR 24 R 25 (wherein R 24 and R 25 are independently selected from H, C 1-3 alkyl, cyclopropyl, and isopropyl); C 1-3 alkyl (optionally substituted with F); cyclopropyl (optionally substituted with F); isopropyl (optionally substituted with F); OC1-3 alkyl (optionally substituted by F); O-cyclopropyl (optionally substituted by F); O-isopropyl (optionally substituted by F); OH; and R 18 -CONH- (wherein R 18 is selected from C 1-3 alkyl and cyclopropyl); or a pharmaceutically acceptable salt or solvate thereof.

[0080] On the other hand, the present invention relates to a D-galactopyranose compound of formula (1).

[0081]

[0082] In the formula:

[0083] the pyranose ring is α-D-galactopyranose

[0084] A is selected from

[0085]

[0086] wherein Het 1 is selected from a five- or six-membered heteroaromatic ring, optionally substituted by a group selected from Br, F, Cl, methyl (optionally substituted by F), and OCH3 (optionally substituted by F);

[0087] wherein R 1 -R 5 is independently selected from H, CN, NH2, F, methyl (optionally substituted by fluorine (F)), and OCH3 (optionally substituted by F);

[0088] wherein R 6 is selected from C 1-6 alkyl, branched C 3-6 alkyl, and C 3-7 cycloalkyl;

[0089] wherein R 7 is selected from a five- or six-membered heteroaromatic ring and phenyl, the five- or six-membered heteroaromatic ring is optionally substituted by Br, F, Cl, methyl (optionally F-substituted), and OCH3 (optionally F-substituted), and the phenyl is optionally substituted by Br, F, Cl, methyl (optionally F-substituted), and OCH3 (optionally F-substituted);

[0090] wherein R 8 -R 12 is independently selected from H, F, methyl (optionally substituted by fluorine (F)), and OCH3 (optionally substituted by F);

[0091] wherein R 13is a five- or six-membered heteroaryl or aryl group, the five- or six-membered heteroaryl group is optionally substituted with a group selected from H, OH, F, methyl (optionally substituted with fluorine (F)), and OCH3 (optionally substituted with F), and the aryl group (such as phenyl or naphthyl) is optionally substituted with a group selected from H, OH, F, methyl (optionally substituted with fluorine (F)), and OCH3 (optionally substituted with F);

[0092] X is selected from S, SO, SO2, O, C=O, and CR 7 R 8 , where R 7 and R 8 are independently selected from hydrogen, OH, or halogen (such as F, Cl, Br);

[0093] B is selected from a) a five- or six-membered heteroaryl-substituted C 1-6 alkyl or branched C 3-6 alkyl, the five- or six-membered heteroaryl group is optionally substituted with a substituent selected from CN, halogen (such as Cl, F, Br, I), methyl (optionally substituted with F), OCH3 (optionally substituted with F), OCH2CH3 (optionally substituted with F), OH, and R 14 -CONH- (where R 14 is selected from C 1-3 alkyl and cyclopropyl); or a phenyl-substituted C 1-6 alkyl, the phenyl group is optionally substituted with the following groups: CN, halogen (such as Cl, F, Br, I), methyl (optionally substituted with F), OCH 3( optionally substituted with F), OCH2CH3 (optionally substituted with F), OH, and R 15 -CONH- substituents, where R 15 is selected from C 1-3 alkyl and cyclopropyl; b) an aryl group (such as phenyl or naphthyl), optionally substituted with the following groups: halogen (such as Cl, F, Br, I); methyl (optionally substituted with F); OCH 3( optionally substituted with F), OCH2CH3 (optionally substituted with F), OH; and R 16 -CONH- (where R 16 is selected from C 1-3 alkyl and cyclopropyl); c) C 5-7 cycloalkyl, optionally substituted with the following groups: CN, halogen (such as Cl, F, Br, I), methyl (optionally substituted with F), OCH3 (optionally substituted with F), OCH2CH3 (optionally substituted with F), OH, and R 17 -CONH- (where R 17 is selected from C 1-3(alkyl and cyclopropyl); and d) a heterocycle (such as heteroaryl or heterocycloalkyl), optionally substituted with the following groups: halogen (such as Cl, F, Br, I); methyl (optionally substituted with F), OCH3 (optionally substituted with F), OCH2CH3 (optionally substituted with F), OH; and R 18 -CONH-(wherein R 18 is selected from C 1-3 alkyl and cyclopropyl); or a pharmaceutically acceptable salt or solvate thereof.

[0094] In one embodiment of the present invention, A is selected from Structural Formula 2, wherein R 1 -R 5 are independently selected from H, F, methyl (optionally substituted with fluorine (F)), and OCH3 (optionally substituted with F).

[0095] In another embodiment of the present invention, A is selected from Structural Formula 2, wherein R 1 and R 5 are selected from H, and R 2 -R 4 is selected from F.

[0096] In another embodiment of the present invention, A is selected from Structural Formula 2, wherein R 2 and R 3 is F, R 1 , R 4 and R 5 are H, or wherein R 2 and R 4 are F, and R 1 , R 3 and R 5 are H, or wherein R 2 is F, and R 1 , R 3 -R 5 are H, or wherein R 2 and R 4 are F, R 3 is OCH3, and R 1 and R 5 are H.

[0097] In another embodiment of the present invention, A is selected from Structural Formula 2, wherein R 1 -R 5 are independently selected from H and F, provided that at least one of R 1 -R 5 is F. Preferably, 1 to 5 of R 1 -R 5 , such as 3 or 5, are independently selected from F.

[0098] In another embodiment of the present invention, A is selected from Structural Formula 3, wherein Het 1 is selected from a six-membered heteroaromatic ring, optionally substituted with Br, F, and Cl. Generally, Het 1 is selected from pyridyl groups substituted with F (such as 3F).

[0099] In another embodiment of the present invention, A is selected from Structural Formula 4, wherein R 6 is selected from C 1-6 alkyl and branched C 3-6 alkyl. Generally, R 6 is C 1-6 alkyl, such as CH3, CH2CH3, CH2CH2CH3, and isopropyl, for example CH3 or isopropyl.

[0100] In another embodiment of the present invention, A is selected from Structural Formula 4, wherein R 6 is selected from C 1-6 alkyl substituted with halogen (such as 1, 2, or 3 F), such as CH2CF3.

[0101] In another embodiment of the present invention, A is selected from Structural Formula 5, wherein R 7 is selected from phenyl, optionally substituted with Br, F, Cl, methyl (optionally substituted with F), and OCH3 (optionally substituted with F).

[0102] In another embodiment of the present invention, A is selected from Structural Formula 5, wherein R 7 is selected from phenyl substituted with Cl.

[0103] In another embodiment of the present invention, A is selected from Structural Formula 6, wherein R 8 -R 12 are independently selected from H and F. Generally, R 8 -R 12 are both H, or R 10 -R 11 are both F, and R 8 、R 9 and R 12 are H.

[0104] In another embodiment of the present invention, A is selected from Structural Formula 7, wherein R 13 is aryl (such as phenyl or naphthyl), optionally substituted with F. Generally, R 13 is phenyl, optionally substituted with 1, 2, or 3 F.

[0105] In another embodiment of the present invention, A is selected from Structural Formula 8, wherein R 27 is selected from C 1-6 alkyl, branched C 3-6 alkyl, C 1-6 alkoxy, and branched C3-6 Alkoxy. Generally, R 27 is selected from C 1-6 alkyl and C 1-6 alkoxy.

[0106] In another embodiment of the present invention, X is selected from S, SO, SO2 and O. Preferably, X is selected from S, SO and SO2. In another embodiment of the present invention, X is selected from S and SO2, such as S.

[0107] In another embodiment of the present invention, B is selected from C 1-6 alkyl substituted with phenyl, and the phenyl is optionally substituted with Br, F, Cl, methyl (optionally substituted with F) and OCH3 (optionally substituted with F).

[0108] In another embodiment of the present invention, B is selected from C 1-6 alkyl substituted with phenyl, such as benzyl or CH2-CH2-phenyl.

[0109] In another embodiment of the present invention, B is selected from C 1-6 alkyl substituted with phenyl, and the phenyl is substituted with Cl, for example, benzyl substituted with 1 or 2 Cl atoms, or -CH2-CH2-phenyl substituted with 1 Cl atom.

[0110] In another embodiment of the present invention, B is selected from C 1-6 alkyl.

[0111] In another embodiment of the present invention, B is selected from aryl (such as phenyl or naphthyl), optionally substituted with one or more of the following groups: halogen (such as Cl, F, Br, I), methyl (optionally substituted with F), OCH3 (optionally substituted with F), OCH2CH3 (optionally substituted with F), OH and R 16 -CONH-, where R 16 is selected from C 1-3 alkyl and cyclopropyl.

[0112] In another embodiment of the present invention, B is selected from aryl (such as phenyl or naphthyl), optionally substituted with one or more substituents selected from I, COOH and CONH2.

[0113] In another embodiment of the present invention, B is selected from aryl (such as phenyl or naphthyl), optionally substituted with one or more substituents selected from NR 28 R 29 (where R 28 and R 29 are independently selected from H, C 1-3 alkyl and isopropyl).

[0114] In another embodiment of the present invention, B is selected from aryl (such as phenyl or naphthyl), optionally substituted with one or more substituents selected from CN.

[0115] In another embodiment of the present invention, B is selected from unsubstituted phenyl.

[0116] In another embodiment of the present invention, B is selected from unsubstituted naphthyl.

[0117] In another embodiment of the present invention, B is selected from phenyl, wherein the phenyl is substituted with one, two or three substituents selected from Cl, F, Br, CN, methyl, OH, CF3, OCH2CH3, OCH3, OCF3, R 16 -CONH- (wherein R 16 is selected from C 1-3 alkyl, such as methyl). For example, phenyl substituted with two substituents selected from Cl, F, Br, CN. For example, phenyl substituted with three substituents selected from Cl, F and CN.

[0118] In another embodiment of the present invention, B is selected from phenyl, wherein the phenyl is substituted with one, two or three substituents selected from Cl, F, Br, I, CN, methyl, OH, CF3, OCH2CH3, OCH3, OCF3, COOH, CONH2, R 16 -CONH- (wherein R 16 is selected from C 1-3 alkyl, such as methyl). For example, phenyl substituted with one substituent selected from I, COOH and CONH2.

[0119] In another embodiment of the present invention, B is selected from heterocycles (such as heteroaryl or heterocycloalkyl), optionally substituted with one or more substituents selected from the following groups: halogen (such as Cl, F, Br, I); methyl (optionally substituted with F); OCH3 (optionally substituted with F); OCH2CH3 (optionally substituted with F); CONH2; OH; NR 30 R 31 (wherein R 30 and R 31 are independently selected from H, C 1-3 alkyl and isopropyl); and R 18 -CONH- (wherein R 18 is selected from C 1-3 alkyl and cyclopropyl).

[0120] In another embodiment of the present invention, B is selected from heterocycles (such as heteroaryl or heterocycloalkyl), optionally substituted with one or more substituents selected from the following groups: halogen (such as Cl, F, Br, I), methyl (optionally substituted with F), OCH3 (optionally substituted with F), OCH2CH3 (optionally substituted with F), OH; and R 18 -CONH-, where R 18 is selected from C 1-3 alkyl and cyclopropyl.

[0121] In another embodiment of the present invention, B is selected from heterocycles (such as heteroaryl or heterocycloalkyl), optionally substituted with one or more substituents selected from CONH2; OH; Cl; Br; and CF3.

[0122] In another embodiment of the present invention, B is selected from heterocycles (such as heteroaryl or heterocycloalkyl), optionally substituted with one or more substituents selected from CN.

[0123] In another embodiment of the present invention, B is selected from heterocycles (such as heteroaryl or heterocycloalkyl), optionally substituted with one to three (such as one or two) substituents selected from CONH2; OH; CN; Cl; Br; and CF3.

[0124] In another embodiment of the present invention, B is selected from unsubstituted pyridyl.

[0125] In another embodiment of the present invention, B is selected from pyridyl substituted with one to three (such as two) substituents selected from Cl, Br, CF3 and CN.

[0126] In another embodiment of the present invention, B is selected from pyridyl substituted with one to three (such as one or two) substituents selected from CONH2 and OH.

[0127] In another embodiment of the present invention, B is selected from pyridyl substituted with one to three (such as one) substituents selected from NR 30 R 31 (where R 30 and R 31 are independently selected from H, C 1-3 alkyl and isopropyl).

[0128] In another embodiment of the present invention, B is selected from pyridazinyl substituted with one to three (such as two) substituents selected from Cl, OH, OCH3 and CN.

[0129] In another embodiment of the present invention, B is selected from phenylthio substituted with one to three (such as one) substituents selected from halogen (such as Cl).

[0130] In another embodiment of the present invention, B is selected from C 5-7A cycloalkyl group, optionally substituted with one or more substituents selected from the following groups: halogen (such as Cl, F, Br, I), methyl (optionally substituted with F), OCH3 (optionally substituted with F), OCH2CH3 (optionally substituted with F), OH, and R 17 -CONH- (wherein R 17 is selected from C 1-3 alkyl and cyclopropyl).

[0131] In another embodiment of the present invention, B is selected from cyclohexyl, optionally substituted with one or more substituents selected from halogen.

[0132] In another embodiment of the present invention, B is cyclohexyl.

[0133] In another embodiment of the present invention, B is cyclohexyl substituted with one or two substituents (such as 2F) selected from halogen.

[0134] As described above, certain compounds of the present invention have high galectin-3 affinity and very good PK properties, with high oral bioavailability and are suitable for oral administration. The data provided herein support that at least the compounds of structural formula (1) of the present invention have very good PK properties and high galectin-3 affinity: wherein A is selected from structural formula 2, wherein R 1 -R 5 is independently selected from H, F, methyl (optionally substituted with F), and OCH3 (optionally substituted with F). Usually, R 1 -R 5 is selected from H, F, Br, and Cl. For example, R 2 -R 4 is selected from F, Br, and Cl, and R 1 and R 5 are H, or R 2 -R 5 both are selected from F, Br, and Cl; preferably, R 1 -R 5 is selected from H and F. For example, R 2 -R 5 is selected from F, and R 1 and R 5 are H, or R 1 -R 5 both are selected from F; wherein X is selected from S and SO2, and B is selected from phenyl, and the phenyl is substituted with one, two, or three of the following substituents: Cl, F, Br, methyl, OH, CN, CF3, OCH2CH3, OCH3, OCF3, R 16 -CONH-, wherein R 16 is selected from C 1-3An alkyl group, such as a methyl group; usually B is a phenyl group, and the phenyl group is substituted by 1 - 3 substituents selected from Cl, F, CN, and Br. For example, Cl is in the meta - position or para - position or at both positions, F is in the ortho - position, meta - position or para - position or at all three positions, CN is in the meta - position, or Br is in the meta - position or para - position or at both positions, or the ortho, meta, and para positions are substituted by 2 or 3 substituents selected from Cl, F, CN, and Br; or wherein B is selected from pyridyl and pyridazinyl, and is substituted by one, two, or three substituents selected from Cl, F, Br, OH, CN, CF3, OCH2CH3, OCH3, OCF3. Usually, B is selected from pyridyl and pyridazinyl, and its meta - position and para - position are substituted by two substituents selected from Cl, Br, OH, CN, CF3, OCH3.

[0135] In another embodiment of the present invention, the compound is selected from any one of Examples 1 - 42:

[0136] 3,4 - dimethylphenyl 3 - deoxy - 3 - [4 - (3,4,5 - trifluorophenyl)-1H - 1,2,3 - triazol - 1 - yl]-1 - thio - α - D - galactopyranoside,

[0137] 3 - bromophenyl 3 - deoxy - 3 - [4 - (3,4,5 - trifluorophenyl)-1H - 1,2,3 - triazol - 1 - yl]-1 - thio - α - D - galactopyranoside,

[0138] 3 - ethoxyphenyl 3 - deoxy - 3 - [4 - (3,4,5 - trifluorophenyl)-1H - 1,2,3 - triazol - 1 - yl]-1 - thio - α - D - galactopyranoside,

[0139] 4 - pyridyl 3 - deoxy - 3 - [4 - (3,4,5 - trifluorophenyl)-1H - 1,2,3 - triazol - 1 - yl]-1 - thio - α - D - galactopyranoside,

[0140] 2,4 - dichlorophenyl 3 - deoxy - 3 - [4 - (3,4,5 - trifluorophenyl)-1H - 1,2,3 - triazol - 1 - yl]-1 - thio - α - D - galactopyranoside,

[0141] 4 - acetanilidophenyl 3 - deoxy - 3 - [4 - (3,4,5 - trifluorophenyl)-1H - 1,2,3 - triazol - 1 - yl]-1 - thio - α - D - galactopyranoside,

[0142] 4 - methoxyphenyl 3 - deoxy - 3 - [4 - (3,4,5 - trifluorophenyl)-1H - 1,2,3 - triazol - 1 - yl]-1 - thio - α - D - galactopyranoside,

[0143] 2,3-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0144] 3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0145] Benzyl 3-deoxy-1–thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0146] 3-Methoxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0147] 2-Naphthyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0148] 3-Methylphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0149] 3-(Trifluoromethyl)phenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0150] 4-Bromophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0151] 3,5-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0152] 2,6-Dimethylphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0153] 1-Naphthyl 3-deoxy-1–thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0154] 3-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0155] 3-(trifluoromethoxy)phenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0156] 2-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0157] 3,4-dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside,

[0158] 4-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0159] 3,4-dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside sulfoxide,

[0160] 3,4-dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside sulfone,

[0161] 4-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside sulfoxide,

[0162] phenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0163] 3-chloro-4-fluorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0164] 4-tolyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0165] 4-Fluorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0166] 3-Trifluoromethoxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0167] Phenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside,

[0168] 3-Chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside,

[0169] 4-Chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside,

[0170] Cyclohexyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0171] 2,4,5-Trichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0172] 2,5-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0173] 3-Hydroxy-phenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0174] 3-Bromophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide,

[0175] 2-Ethoxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0176] 3,4-Dichlorophenyl 3-O-[(2-amino-(4-chlorophenyl)pyrimidin-6-yl)methylene]-1-thio-α-D-galactopyranoside, and

[0177] 3,4-Dichlorophenyl 3-deoxy-3-[4-(2,3,4,5,6-pentafluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide.

[0178] In another embodiment of the present invention, the compound is selected from any one of Examples 43-55:

[0179] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0180] 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0181] 3-Chloro-5-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0182] 3-Chloro-4-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0183] 3-Chloro-6-fluoro-4-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0184] 3-Bromo-4-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0185] 5-Bromo-6-trifluoromethyl-pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0186] 5-Chloro-6-cyano-pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0187] 5-chloro-6-cyano-pyridazin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0188] 3,4-dichlorophenyl 3-deoxy-3-[4-(2,3,4,5,6-pentafluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0189] 3,4-dichlorophenyl 3-deoxy-3-[4-(2,3,4,5,6-pentafluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfone,

[0190] 5-methoxy-6-cyano-pyridazin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, and

[0191] 5-hydroxy-6-cyano-pyridazin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside.

[0192] In another embodiment of the present invention, the compound is selected from any one of Examples 56 - 106:

[0193] 3-chloro-2,4-difluorophenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside,

[0194] 3,4-dichlorophenyl 3-deoxy-3-[4-(phenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0195] 3,5-dichloro-4-fluorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0196] 3,4-dichloro-6-fluorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0197] 3-bromo-4-fluorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0198] 3-chloro-4-(trifluoromethyl)phenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside,

[0199] 3,4,5-trichlorophenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside,

[0200] 5-chloro-2-fluorophenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside,

[0201] 5-bromo-2-fluorophenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside,

[0202] 5-chloro-2-methoxyphenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside,

[0203] 3-iodophenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside,

[0204] pyridinamide-5-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0205] 3-cyanophenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside,

[0206] 2-cyanopyridin-5-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0207] 4-chloro-2-thienyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0208] 3-carboxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0209] Benzamide-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0210] 3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0211] 3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0212] 3,4-Dichlorophenyl 3-deoxy-3-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0213] 3,3'-Difluoro-cyclohexyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0214] n-Butyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0215] 3,4-Dichlorophenyl 3-deoxy-3-[4-(3,5-difluoro-4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0216] 2-Hydroxy-pyridin-4-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0217] 2-Chloroethoxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0218] 4-Chloroethoxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0219] 2-Chlorobenzyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside,

[0220] 3,4-Dichlorobenzyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside,

[0221] 3-Chloroethoxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0222] 4-Chlorobenzyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside,

[0223] Propyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0224] 2-Aminopyridin-4-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0225] 5-Dimethylamino-naphthalen-2-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0226] Ethyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside,

[0227] S-5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide,

[0228] R-5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide,

[0229] 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfone,

[0230] S-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide,

[0231] R-chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide,

[0232] 5-dimethylamino-naphthalen-2-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfone,

[0233] 3,4-dichlorophenyl-3-deoxy-3-(3,4,5-trifluorobenzoylamino)-1-thio-α-D-galactopyranoside,

[0234] 3,4-dichlorophenyl 3-deoxy-3-[4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0235] 3,4-dichlorophenyl 3-deoxy-3-[4-(ethylaminocarbonyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0236] 3,4-dichlorophenyl 3-O-[(5,6-difluoro-2-oxo-3-chromenyl)methyl]-1-thio-α-D-galactopyranoside,

[0237] 5-dichloropyridin-3-yl 3-deoxy-3-[4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0238] 5-dichloropyridin-3-yl 3-deoxy-3-[4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0239] 3,4-dichlorophenyl 3-deoxy-3-[4-(propyl-carbonyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0240] 5-chloro-6-trifluoromethyl-pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0241] 5-chloro-2-trifluoromethyl-pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside,

[0242] 5-chloro-6-cyano-pyridin-3-yl 3-deoxy-3-[4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, and

[0243] 3-chloro-4-cyanophenyl 3-deoxy-3-[4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside.

[0244] On the other hand, the present invention relates to the use of a compound of formula (1) as a medicament.

[0245] On the other hand, the present invention relates to a pharmaceutical composition comprising any one of the aforementioned compounds and optionally a pharmaceutically acceptable additive such as a carrier and / or an excipient.

[0246] On the other hand, the present invention relates to the use of a compound of formula (1) of the present invention in mammals (such as humans) for the treatment of diseases related to the binding of galectin-3 and ligands. In another embodiment, the diseases are selected from inflammation; fibrosis (such as pulmonary fibrosis, liver fibrosis, renal fibrosis, ocular fibrosis, and skin and cardiac fibrosis); scarring; keloid formation; abnormal scar formation; surgical adhesions; septic shock; cancer (such as carcinoma, malignancy, leukemia, and lymphoma, such as T-cell lymphoma, metastatic carcinoma); autoimmune diseases (such as psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus); metabolic disorders; heart diseases; heart failure; pathological angiogenesis (such as ocular angiogenesis or diseases or symptoms related to ocular angiogenesis, such as neovascularization related to cancer); and ocular diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases (such as diabetes); asthma and other interstitial lung diseases (including Hermansky-Pudlak syndrome, mesothelioma); and liver diseases (such as non-alcoholic steatohepatitis).

[0247] On the other hand, the present invention relates to a method for treating a disease in a mammal (such as a human) associated with the binding of galectin-3 and a ligand, wherein a therapeutically effective dose of at least one compound of structural formula (1) of the present invention is administered to the mammal in need of such treatment. In another embodiment, the disease is selected from inflammation; fibrosis (such as pulmonary fibrosis, liver fibrosis, renal fibrosis, ocular fibrosis, and skin and cardiac fibrosis); scarring; keloid formation; abnormal scar formation; surgical adhesions; septic shock; cancer (such as carcinoma, malignancy, leukemia, and lymphoma, such as T-cell lymphoma, metastatic carcinoma); autoimmune diseases (such as psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus); metabolic disorders; heart disease; heart failure; pathological angiogenesis (such as ocular angiogenesis or diseases or symptoms related to ocular angiogenesis, such as neovascularization associated with cancer); and ocular diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases (such as diabetes); asthma and other interstitial lung diseases (including Hermansky-Pudlak syndrome, mesothelioma); and liver diseases (such as non-alcoholic steatohepatitis).

[0248] Another aspect of the present invention relates to a combination therapy of co-administering a compound of structural formula (1) of the present invention and a therapeutically active compound different from structural formula (1) (used interchangeably with "different therapeutically active compound"). One embodiment of the present invention relates to a combination of a compound of structural formula (1) and a different therapeutically active compound for treating a disease in a mammal associated with the binding of galectin-3 and a ligand. These diseases are disclosed as follows.

[0249] In one embodiment of the present invention, a therapeutically effective dose of at least one compound of formula (1) of the present invention is administered to a mammalian subject in need thereof together with a different therapeutically active compound. In another embodiment, the compound of formula (1) is used in combination with a different therapeutically active compound for treating mammalian subjects suffering from the following diseases: inflammation; fibrosis (such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis, ocular fibrosis, and dermal and cardiac fibrosis); scarring; keloid formation; abnormal scar formation; surgical adhesions; septic shock; cancer (such as carcinoma, malignancy, leukemia, and lymphoma, such as T-cell lymphoma, metastatic carcinoma); autoimmune diseases (such as psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus); metabolic disorders; heart disease; heart failure; pathological angiogenesis (such as ocular angiogenesis or diseases or conditions related to ocular angiogenesis, such as neovascularization associated with cancer); and ocular diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases (such as diabetes); asthma and other interstitial lung diseases (including Hermansky-Pudlak syndrome, mesothelioma); and liver diseases (such as non-alcoholic steatohepatitis).

[0250] Examples of cancers that can be treated, controlled, and / or prevented by administering a compound of formula (1) and different therapeutically active compounds are as follows, but are not limited to these cancers: colon cancer, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphosarcoma, lymphangioendothelioma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hidradenoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioblastoma, neurilemmoma, craniopharyngioma, Schwann cell tumor, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia and lymphoma, acute lymphocytic leukemia, acute myelogenous true polycythemia, multiple myeloma, Waldenström's macroglobulinemia, heavy chain disease, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's disease, non-Hodgkin lymphoma, rectal cancer, renal pelvic cancer, uterine cancer, oral cancer, skin cancer, gastric cancer, brain tumor, hepatocellular carcinoma, laryngeal cancer, esophageal cancer, breast tumor, childhood non-acute lymphoblastic leukemia (ALL), thymic ALL, B-cell ALL, acute myeloid leukemia, myelomonocytic leukemia, acute megakaryocytic leukemia, Burkitt lymphoma, acute myeloid leukemia, chronic myeloid leukemia, T-cell leukemia, small and large non-small cell lung cancer, acute granulocytic leukemia, germ cell tumor, endometrial cancer, gastric cancer, head and neck cancer, chronic lymphocytic leukemia, hairy cell leukemia, and thyroid cancer.

[0251] In some aspects of the invention, administering at least one compound of formula (1) of the invention and at least one other therapeutic agent exhibits a therapeutic synergistic effect. In some aspects of the method of the invention, compared to administering at least one compound of formula (1) of the invention or at least one other therapeutic agent alone, after administering at least one compound of formula (1) of the invention and at least one other therapeutic agent, the observed therapeutic effect indicators are improved.

[0252] Another aspect of the present invention relates to a combination therapy of administering the compound of structural formula (1) of the present invention together with an anti-fibrotic compound different from structural formula (1). In another embodiment, the anti-fibrotic compound is selected from the following anti-fibrotic compounds, but is not limited to pirfenidone, nintedanib, simtuzumab (GS-6624, AB0024), BG00011 (STX100), PRM-151, PRM-167, PEG-FGF21, BMS-986020, FG-3019, MN-001, IW001, SAR156597, GSK2126458, and PBI-4050.

[0253] Another aspect of the present invention relates to a combination therapy of administering the compound of structural formula (1) to a mammal in need thereof in combination with other conventional cancer treatments, such as chemotherapy or radiotherapy, or immunostimulatory substance treatment, gene therapy, antibody therapy, and dendritic cell therapy.

[0254] In one embodiment, the compound of structural formula (1) is administered in combination with at least one other therapeutic agent selected from anti-tumor chemotherapeutic agents. In another embodiment, the anti-tumor chemotherapeutic agent is selected from: all-trans retinoic acid, cobamamide (Actimide), azacitidine, azathioprine, bleomycin, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunomycin, docetaxel, doxifluridine, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarubicin, irinotecan, lenalidomide, folinic acid, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, thalidomide, temozolomide, teniposide, thioguanine, valrubicin, vinblastine, vincristine, vindesine, and vinorelbine. In one embodiment, the chemotherapeutic agent used in combination with the preparation of the present invention may itself be a combination of different chemotherapeutic agents. Suitable combinations include FOLFOX and IFL. FOLFOX is a combination comprising 5-fluorouracil (5-FU), folinic acid, and oxaliplatin. IFL treatment comprises irinotecan, 5-FU, and folinic acid.

[0255] In another embodiment of the present invention, other conventional cancer treatments include radiotherapy. In some embodiments, radiotherapy includes local tumor radiotherapy. In some embodiments, radiotherapy includes whole body radiotherapy.

[0256] In other embodiments of the present invention, other cancer treatment methods are selected from immunostimulatory substances such as cytokines and antibodies. The cytokines can be selected from the group consisting of, but not limited to: GM-CSF, IFN types, interleukin 21, interleukin 2, interleukin 12, and interleukin 15. The antibody is preferably an immunostimulatory antibody such as anti-CD40 or anti-CTLA-4 antibody. The immunostimulatory substance can also be a substance capable of eliminating immunosuppressive cells (such as regulatory T-cells) or factors, which can be, for example, an E3 ubiquitin ligase. E3 ubiquitin ligases (HECT, RING, and U-box proteins) are important molecular regulators of immune cell function, and they participate in regulating immune responses by targeting proteolytic destruction of specific inhibitory molecules during infection. Currently, several HECT and RING E3 proteins have been associated with the induction and maintenance of immune self-tolerance: c-Cbl, Cbl-b, GRAIL, Itch, and Nedd4, which negatively regulate T cell growth factor production and proliferation.

[0257] In some embodiments of the present invention, the compound of formula (1) is administered in combination with at least one other therapeutic agent selected from checkpoint inhibitors. In some embodiments of the present invention, the checkpoint inhibitor acts on one or more of the following targets (non-limiting): CEACAM1, galectin-9, TIM3, CD80, CTLA4, PD-1, PD-L1, HVEM, BTLA, CD160, VISTA, B7-H4, B7-2, CD155, CD226, TIGIT, CD96, LAG3, GITF, OX40, CD137, CD40, IDO, and TDO. These targets are well-known, and some of them are described in Melero et al., Nature Reviews Cancer (2015).

[0258] In some embodiments of the present invention, the compound of formula (1) is administered in combination with at least one other therapeutic agent selected from indoleamine-2,3-dioxygenase (IDO) inhibitors.

[0259] In some embodiments of the present invention, the compound of formula (1) is administered in combination with at least one other therapeutic agent selected from one or more inhibitors of the CTLA4 pathway. In some embodiments, the CTLA4 pathway inhibitor is selected from one or more anti-CTLA4 antibodies.

[0260] In some embodiments of the present invention, the compound of structural formula (1) is administered in combination with at least one other therapeutic agent selected from one or more inhibitors of the PD-1 / PD-L pathway. In some embodiments, one or more inhibitors of the PD-1 / PD-L pathway are selected from one or more anti-PD-1, PD-L1, and / or PD-L2 antibodies.

[0261] On the other hand, the present invention relates to a method for preparing a compound of structural formula III or a pharmaceutically acceptable salt or solvate thereof, comprising step a1;

[0262]

[0263] a1) In an inert solvent (such as DMF or acetonitrile), using a base (such as diisopropylethylamine), and catalyzed by Cul, reacting the compound of structural formula I (wherein X and B are as defined above for structural formula (1)) with the compound of structural formula II to obtain the compound of formula III.

[0264] On the other hand, the present invention relates to a method for preparing a compound of structural formula V or a pharmaceutically acceptable salt or solvate thereof, comprising step a2;

[0265]

[0266] a2) In an inert solvent, such as DMF or acetonitrile, using a base (such as diisopropylethylamine), and catalyzed by Cul, reacting I with IV, wherein P 1 is selected from C 1-5 alkyl, to obtain a compound, and treating the compound with an aliphatic base (such as R 6 -NH2) to obtain the compound of structural formula V.

[0267] On the other hand, the present invention relates to a method for preparing a compound of structural formula VII and / or VIII or a pharmaceutically acceptable salt or solvate thereof, comprising step a3;

[0268]

[0269] a3) In a solvent (such as acetic acid), or in a solution of 3-chloroperoxybenzoic acid in an inert solvent (such as dichloromethane), reacting the compound of structural formula VI with an oxidizing agent (such as hydrogen peroxide) to obtain the compound of structural formula VII and / or the compound of structural formula VIII.

[0270] On the other hand, the present invention relates to a method for preparing a compound of structural formula X (wherein R 7 is as defined above for structural formula (1)) or a pharmaceutically acceptable salt or solvate thereof, comprising step a4;

[0271]

[0272] a4) In an inert solvent (such as tetrahydrofuran), in the presence of potassium carbonate, react the compound of structural formula IX with guanidine hydrochloride to obtain the compound of structural formula X.

[0273] On the other hand, the present invention relates to a method for preparing a compound of structural formula XII or a pharmaceutically acceptable salt thereof or a solvate thereof, comprising step a5;

[0274]

[0275] a5) In methanol, react the compound of structural formula XI with a reagent (such as sodium methoxide) to obtain the compound of structural formula XII.

[0276] On the other hand, the present invention relates to a method for preparing a compound of structural formula XV or a pharmaceutically acceptable salt thereof or a solvate thereof, comprising step a6;

[0277]

[0278] a6) In the presence of a base (such as diisopropylethylamine (DIPEA)), in an inert solvent (such as DMF), using a reagent (such as HATU), react the compound of structural formula XIII with the compound of structural formula XIV to obtain the compound of formula XV.

[0279] On the other hand, the present invention relates to a method for preparing a compound of structural formula I (wherein X is oxygen or sulfur) or a pharmaceutically acceptable salt thereof or a solvate thereof, comprising steps a7 and a8;

[0280]

[0281] a7) In the presence of a Lewis acid (such as BF3·Et2O), in an inert solvent (such as dichloromethane or chloroform), react the compound XVI with a chlorinating agent (such as dichloromethyl methyl ether or PCl5) to obtain the compound of structural formula XVII.

[0282] a8) In the presence of a base (such as sodium hydride), in an inert solvent (such as DMF), react the compound of structural formula XVII with a nucleophile (such as B-XH), wherein X is sulfur or oxygen.

[0283] On the other hand, the present invention relates to a method for preparing a compound of structural formula I (wherein X is CH2) or a pharmaceutically acceptable salt thereof or a solvate thereof, comprising steps a9-a13;

[0284]

[0285] a9) Compound XVII can be prepared by the method described in Chem. Eur. J. 2009, 15, 2861 - 2873. It can react with a nucleophile (such as Grignard reagent B - MgBr) in an inert solvent (such as ether) to obtain a compound of structural formula XVIII.

[0286] a10) In the presence of a base (such as pyridine), using a reagent (such as (ClCH2O)2), the compound of structural formula XVIII can be converted into a compound of structural formula XIX.

[0287] a11) In the presence of a catalyst (such as palladium supported on carbon), in an inert solvent (such as methanol), using hydrogen, the compound of structural formula XIX can be converted into a compound of structural formula XX.

[0288] a12) Treated with dibutyltin oxide and then with benzyl bromide, the compound of structural formula XX can be selectively alkylated at the 3 - hydroxy position. Then, other protecting groups stable under conditions for removing the benzyl group, including acetoxy, silyl, and ortho - esters, can be used to protect the remaining hydroxyl groups. Then, in an inert solvent (such as DMF), in the presence of pyridine, using, for example, trifluoromethanesulfonic anhydride, and then using BU2NNO2, the benzyl group is selectively removed, and the free hydroxyl group at the 3 - position is converted to obtain compound XXI.

[0289] a13) In the presence of a base (such as pyridine), the compound of structural formula XXI can react with a reagent (such as tosyl chloride) to obtain a compound which, in an inert solvent (such as DMF), can react with sodium azide to obtain a compound of structural formula XXII.

[0290] On the other hand, the present invention relates to a method for preparing a compound of structural formula XXV (wherein X is as defined in the above structural formula (1)) or a pharmaceutically acceptable salt thereof or a solvate thereof, comprising steps a14 - 16;

[0291]

[0292] a14) The compound of structural formula XVIII can be treated with a halide - forming reagent (such as DAST (fluorine), PCl5 (chlorine), PBr5 (bromine)) to obtain compound XXIII, wherein W 1 is the corresponding halide F, Cl or Br, and W 2 is hydrogen.

[0293] Alternatively, XVIII can be treated with an oxidizing agent (such as PCC) to obtain compound XXIII, wherein W 1 and W 2are all connected to oxygen. This compound can be treated with a halide-forming reagent (such as DAST (fluorine), PCl5 (chlorine), PBr5 (bromine)) to obtain compound XXIII, where W 1 =W 2 , and is the corresponding halide F, Cl or Br.

[0294] a15) Treated with dibutyltin oxide and then with benzyl bromide, the compound of formula XXIII can be selectively alkylated at the 3-hydroxy position. Then, other protecting groups stable under conditions for removing benzyl, including acetoxy, silyl and orthoester, can be used to protect the remaining hydroxyl groups. Then, in an inert solvent (such as DMF), in the presence of pyridine, using, for example, trifluoromethanesulfonic anhydride, and then using BU2NNO2, the benzyl group is selectively removed, and the free hydroxyl group at the 3-position is transformed to obtain compound XXIV.

[0295] a16) In the presence of a base (such as pyridine), the compound of formula XXIV can react with a reagent (such as tosyl chloride) to obtain a compound which, in an inert solvent (such as DMF), can react with sodium azide to obtain the compound of formula XXV.

[0296] On the other hand, the present invention relates to a method for preparing a compound of formula XI (where R 8 , R 9 , R 10 , R 11 , R 12 , X and B are as defined in formula (1) above) or a pharmaceutically acceptable salt or solvate thereof, comprising step a17;

[0297]

[0298] a17) In the presence of tosyl azide, copper iodide, and triethylamine, in a solvent (such as THF), the compound of formula XXVII can react with the compound of formula XXVII to obtain the compound of formula XI, where R 12 is H.

[0299] On the other hand, the present invention relates to a method for preparing a compound of formula IX (where R 7 , X and B are as defined in formula (1) above) or a pharmaceutically acceptable salt or solvate thereof, comprising step a18;

[0300]

[0301] a18) In the presence of CuI, PdCl2(PPh3)2Cl2 and triethylamine, in an inert solvent (such as THF), the compound of formula XXVII can react with the structure of R7 React with a compound of -COCl to obtain a compound of structural formula IX.

[0302] On the other hand, the present invention relates to a method for preparing a compound of structural formula XXVII (wherein X is oxygen or sulfur, and B is as defined in the above structural formula (1)), or a pharmaceutically acceptable salt thereof or a solvate thereof, comprising steps a19 - a20;

[0303]

[0304] a19) Prepare a compound of structural formula XXV according to Farkas, I.; Szabo, I.F.; Bognar, R.; Anderle, D. Carbohydr. Res. 1976, 48, 136 - 138 or Ibatullin, F.M.; Selivanov, S.I.. Tetrahedron Letters 2002, 43, 9577 - 9580. In the presence of a base (such as sodium hydride) and in an inert solvent (such as DMF), react the compound of structural formula XXV with a nucleophile (such as B - XH), where X is sulfur or oxygen, to obtain a compound of structural formula XXVI.

[0305] a20) React the compound of structural formula XXVI with dibutyltin oxide in an inert solvent (such as methanol) to obtain a compound, which further reacts with 3 - bromopropyne in an inert solvent (such as tetrahydrofuran) in the presence of tetrabutylammonium iodide to obtain a compound of structural formula XXVII.

[0306] On the other hand, the present invention relates to a method for preparing a compound of structural formula II, comprising step a21:

[0307]

[0308] a21) Using a palladium catalyst (such as bis(triphenylphosphine)palladium(II) dichloride), copper(I) iodide, and a base (such as diisopropylethylamine), in an inert solvent (such as THF), react a compound of structural formula XXVIII (where P 1 is C 1-5 alkyl (such as methyl), and L is a leaving group (such as bromine)) with trimethylsilyl - acetylene to obtain a compound of structural formula II.

[0309] On the other hand, the present invention relates to a method for preparing a compound of structural formula XXIX, comprising step a22;

[0310] a22)

[0311]

[0312] In an inert solvent (such as DMF), using a base (such as sodium hydride), reacting a compound of structural formula XXIIX with a compound of structural formula B-L (where L is a leaving group (such as chlorine)) to obtain a compound of structural formula XXIX.

[0313] On the other hand, the present invention relates to a method for preparing a compound of formula XXIIX, comprising steps a23-a25);

[0314]

[0315] a23) In an inert solvent (such as DMF or acetonitrile), using a base (such as diisopropylethylamine), catalyzed by CuI, reacting a compound of structural formula XVI with a compound of structural formula II to obtain a compound of structural formula XXX.

[0316] a24) In the presence of a Lewis acid (such as BF3·Et2O), in an inert solvent (such as dichloromethane or chloroform), reacting compound XXX with a chlorinating agent (such as dichloromethyl methyl ether or PCl5) to obtain a compound of structural formula XXXI.

[0317] a25) Reacting the compound of structural formula XXXI with a sulfur-containing nucleophile (such as thioacetate), and then deprotecting using a base (such as sodium methoxide) to obtain a compound of structural formula XXIIX.

[0318] On the other hand, the present invention relates to a method for preparing a compound of structural formula XXXV, comprising steps a26-a28;

[0319]

[0320] a26) In an inert solvent (such as DMF), using a base (such as sodium hydride), reacting a compound of structural formula XXXII with an activated thioamide (such as dimethylcarbamoyl chloride) to obtain a compound of structural formula XXXIII.

[0321] a27) Heating the compound of structural formula XXXIII at a high temperature to form compound XXXIV.

[0322] a28) Reacting the compound of structural formula XXXIV with a base (such as potassium hydroxide) to obtain a compound of structural formula XXXV.

[0323] On the other hand, the present invention relates to a method for preparing a compound of structural formula XXXV, comprising steps a29-a30;

[0324]

[0325] a29) The compound of structural formula XXXVI is treated with sodium nitrite to form the corresponding diazo compound. This compound can further react with a sulfur source (such as potassium ethyl xanthate) to form compound XXXVII.

[0326] a30) The compound of structural formula XXXVII reacts with a base (such as potassium hydroxide) to obtain the compound of structural formula XXXV.

[0327] On the other hand, the present invention relates to a method for preparing a compound of structural formula XLI, comprising steps a31 - a34;

[0328]

[0329] a31) In an inert solvent (such as acetonitrile), optionally in the presence of a base (such as triethylamine), the compound of structural formula XXXVIII (where P 2 is C 1-6 alkyl) reacts with a diazotizing reagent (such as N-(4-azidosulfonylphenyl)acetamide) to obtain XXXIIX.

[0330] a32) The compound of structural formula XXXIIX reacts with triphenylphosphine and then with acetic acid to obtain the compound of structural formula XXXIX.

[0331] a33) In an alcohol (such as methanol), the compound of structural formula XXXIX reacts with an ammonia solution to obtain compound XL.

[0332] a34) The compound of structural formula XL reacts with a reagent (such as POCl3 or POBr3) to obtain the compound of structural formula XLI, where L is a halide (such as chlorine or bromine).

[0333] On the other hand, the present invention relates to a method for preparing a compound of structural formula XLIV, comprising steps a35 - a36;

[0334]

[0335] a35) In an inert solvent (such as DCM), using a base (such as diethylamine), the compound of structural formula XXIIX reacts with an α,β-unsaturated ketone (such as XLII) (referred to as conjugate addition) to form the compound of structural formula XLIII.

[0336] a36) Using a fluorination reagent (such as DAST), in an inert solvent (such as DCM), reacts with the compound of structural formula XLIII to form the compound of structural formula XLIV.

[0337] On the other hand, the present invention relates to a method for preparing a compound of structural formula XLVI, comprising step a37;

[0338]

[0339] a37) React with a compound of structural formula XLV in an inert solvent (such as CHCl3) using a Lewis acid (such as BF3·OEt2) to form a compound of structural formula XLVI.

[0340] On the other hand, the present invention relates to a method for preparing a compound of structural formula XL VIII, comprising step a38;

[0341]

[0342] a38) React a compound of structural formula XLVII with ammonium chloride in an inert solvent (such as DMF) using a reagent (such as HATU) and a base (such as TEA) to form a compound of structural formula XLVIII.

[0343] On the other hand, the present invention relates to a method for preparing a compound of structural formula XLIX, comprising step a39;

[0344]

[0345] a39) React a compound of structural formula XLIX with hydrogen in an inert solvent (such as methanol) using a reagent (such as Pd / C) to form a compound of structural formula L.

[0346] On the other hand, the present invention relates to a method for preparing a compound of structural formula LIII, comprising steps a40 - a41;

[0347]

[0348] a40) React a compound of structural formula LI with hydrogen in an inert solvent (such as methanol) using a reagent (such as Pd / C) to form a compound of structural formula LII. Optionally add DCM. An alternative method is to react the LI compound with triphenylphosphine in an inert solvent (such as DCM) to form the LII compound.

[0349] a41) React a compound of structural formula LII with a compound of structural formula R 13 -COOH in an inert solvent (such as DMF) using a coupling agent (such as HATU) to obtain a compound of structural formula LIII. Optionally add an organic base, such as diisopropyl ethylamine.

[0350] On the other hand, the present invention relates to a method for preparing a compound of structural formula LVII, comprising steps a42 - a44;

[0351]

[0352] a42) Using CuI, in an inert solvent (such as DMF or acetonitrile), using a base (such as diisopropylethylamine), reacting the compound of structural formula LIV with ethyl propionate to obtain the compound of structural formula LV.

[0353] a43) Reacting the compound of structural formula LV with a base (such as potassium hydroxide) to obtain the compound of structural formula LVI.

[0354] a44) Using a coupling agent (such as HATU), in an inert solvent (such as DMF), reacting the compound of structural formula LVI with the formula R 6 -NH2 compound. Reacting optionally in the presence of an organic base (such as diisopropylethylamine).

[0355] On the other hand, the present invention relates to a method for preparing a compound of structural formula LIX, comprising steps a45 - a47;

[0356]

[0357] a45) Using CuI, in an inert solvent (such as DMF or acetonitrile), using a base (such as diisopropylethylamine), reacting the compound of structural formula LI with the formula R 27 -CHOH-CC-H compound to obtain the compound of structural formula LVIII.

[0358] a46) In an inert solvent (such as DCM), reacting the compound of structural formula LVIII with an oxidizing agent (such as Dess-Martin periodinane) to obtain the compound of structural formula LIX.

[0359] On the other hand, the present invention relates to a method for preparing a compound of structural formula LXI, comprising step a47;

[0360]

[0361] a47) In an inert solvent (such as EtOAc), reacting the compound of structural formula LX with a reducing agent (such as SnCl2) to obtain the compound of structural formula LXI.

[0362] On the other hand, the present invention relates to a method for preparing a compound of structural formula LXIII, comprising step a48;

[0363]

[0364] a48) In the presence of a base (such as NaOH), in an inert solvent (such as DMF), reacting the compound of structural formula LXII with Na2S·10H2O to obtain the compound of structural formula LXIII.

[0365] On the other hand, the present invention relates to a method for preparing a compound of structural formula LXV, comprising step a49;

[0366]

[0367] a49) Reacting a compound of structural formula LXIV with triethylamine in methanol and water to obtain a compound of structural formula LXV.

[0368] On the other hand, the present invention relates to a method for preparing a compound of structural formula LXVII, comprising step a50;

[0369]

[0370] a50) Reacting a compound of structural formula LXVI with a reducing agent (such as triphenylphosphine) in an inert solvent (such as toluene) to obtain a compound of structural formula LXIII.

[0371] On the other hand, the present invention relates to a method for preparing a compound of structural formula LXVII, comprising step a51;

[0372]

[0373] a51) Reacting a compound of structural formula LXVII with a reducing agent (such as triphenylphosphine) in an inert solvent (such as toluene) to obtain a compound of structural formula LXVIII.

[0374] On the other hand, the present invention relates to a method for preparing a compound of structural formula LXX, comprising step a52;

[0375]

[0376] a52) Using a base (such as potassium carbonate), reacting a compound of structural formula LXIX with methyl iodide in an inert solvent (such as acetone) to obtain a compound of structural formula LXX.

[0377] On the other hand, the present invention relates to a method for preparing a compound of structural formula XXXVI, comprising step a53;

[0378]

[0379] a53) In the presence of ammonium chloride, reacting a compound of structural formula LXXI with a reducing agent (such as Fe) in a solvent mixture of ethanol and water to obtain a compound of structural formula XXXVI.

[0380] On the other hand, the present invention relates to a method for preparing a compound of structural formula LXXIV, comprising steps a54 - a55;

[0381]

[0382] a54) In an inert solvent (such as acetonitrile), in the presence of trimethylchlorosilane, react the compound of structural formula XXII with sodium iodide to obtain the compound of structural formula LXXIII.

[0383] a55) In a solvent (such as NMP), in the presence of a preheated mixture of CuI and potassium fluoride, react the compound of structural formula LXXII with trimethyl(trifluoromethyl)silane to obtain the compound of structural formula LXXIV. Detailed implementation mode

[0384] The compound of structural formula (1) of the present invention is different from the compounds of the prior art. In particular, its pyranose ring is α-D-galactopyranose.

[0385] The α-anomer and the β-anomer are two very different isomers. Obviously, for those skilled in the art, it is absolutely impossible to consider that these two isomers have the same or similar activities. It is very important to emphasize this point.

[0386] Therefore, the α-anomer and the β-anomer generally do not have the same activity, which is common sense for those skilled in the art. Generally, compared with the corresponding β-anomer, the compound of structural formula (1) has an improved affinity for galectin-3 by more than 10 times.

[0387] Broadly speaking, the present invention relates to D-galactopyranose compounds of structural formula (1).

[0388]

[0389] (1) wherein

[0390] the pyranose ring is α-D-galactopyranose,

[0391] A is selected from

[0392]

[0393] wherein Het 1 is selected from a five- or six-membered heteroaryl ring, optionally substituted by the following groups: Br; F; Cl; CN; NR 19 R 20 (wherein R 19 and R 20 are independently selected from H, C 1-3 alkyl, cyclopropyl, isopropyl, -C(=O)-R 21 wherein R 21 is selected from H and C 1-3 alkyl); C 1-3Alkyl (optionally substituted by F); cyclopropyl (optionally substituted by F); isopropyl (optionally substituted by F); O-cyclopropyl (optionally substituted by F); O-isopropyl (optionally substituted by F); and OC 1-3 Alkyl (optionally substituted by F);

[0394] wherein R 1 -R 5 is independently selected from H, CN, NH2, F, methyl (optionally substituted by fluorine (F)), and OCH3 (optionally substituted by F);

[0395] wherein R 6 is selected from C 1-6 alkyl, optionally substituted by halogen, branched C 3-6 alkyl and C 3-7 cycloalkyl;

[0396] wherein R 7 is selected from a five- or six-membered heteroaryl ring and phenyl, the five- or six-membered heteroaryl ring being optionally substituted by Br, F, Cl, methyl (optionally substituted by F), and OCH3 (optionally substituted by F), and the phenyl being optionally substituted by Br, F, Cl, methyl (optionally substituted by F), and OCH3 (optionally substituted by F);

[0397] wherein R 8 -R 12 is independently selected from H, F, methyl (optionally substituted by fluorine (F)), and OCH3 (optionally substituted by F);

[0398] wherein R 13 is selected from a five- or six-membered heteroaryl ring or aryl (such as phenyl or naphthyl), the five- or six-membered heteroaryl ring being optionally substituted by H, OH, F, methyl (optionally substituted by fluorine (F)), and OCH3 (optionally substituted by F), and the aryl being optionally substituted by H, OH, F, methyl (optionally substituted by fluorine (F)), and OCH3 (optionally substituted by F);

[0399] X is selected from S, SO, SO2, O, C=O, and CR 7 R 8 wherein R 7 and R 8 are independently selected from hydrogen, OH, or halogen (such as F, Cl, Br);

[0400] wherein R 27 is selected from C 1-6 alkyl, branched C 3-6 alkyl, C 1-6 alkoxy, and branched C 3-6 alkoxy;

[0401] B is selected from a) C 1-6 alkyl or branched C3-6 An alkyl group, and a five- or six-membered heteroaryl ring is optionally substituted with the following groups: CN, halogen (such as Cl, F, Br, I), methyl (optionally substituted with F), OCH3 (optionally substituted with F), OCH2CH3 (optionally substituted with F), OH, and R 14 -CONH- (wherein R 14 is selected from C 1-3 alkyl and cyclopropyl); or a phenyl-substituted C 1-6 alkyl group, and the phenyl is optionally substituted with the following groups: CN, halogen (such as Cl, F, Br, I), methyl (optionally substituted with F), OCH 3( (optionally substituted with F), OCH2CH3 (optionally substituted with F), OH, and R 15 -CONH-, wherein R 15 is selected from C 1-3 alkyl and cyclopropyl; b) an aryl group (such as phenyl or naphthyl), optionally substituted with groups selected from halogen (such as Cl, F, Br, I); CN; -COOH; -CONR 22 R 23 (wherein R 22 and R 23 are independently selected from H, C 1-3 alkyl, cyclopropyl, and isopropyl); C 1-3 alkyl (optionally substituted with F); cyclopropyl (optionally substituted with F); isopropyl (optionally substituted with F); OC 1-3 alkyl (optionally substituted with F); O-cyclopropyl (optionally substituted with F); O-isopropyl (optionally substituted with F); NR 28 R 29 (wherein R 28 and R 29 are independently selected from H, C 1-3 alkyl, and isopropyl); OH; and R 16 -CONH- (wherein R 16 is selected from C 1-3 alkyl and cyclopropyl); c) a C 5-7 cycloalkyl group, optionally substituted with the following groups: halogen (such as Cl, F, Br, I), CN, methyl (optionally substituted with F), OCH3 (optionally substituted with F), OCH2CH3 (optionally substituted with F), OH, and R 17 -CONH-, wherein R 17 is selected from C 1-3 alkyl and cyclopropyl; and d) a heterocycle (such as heteroaryl or heterocycloalkyl), optionally substituted with the following groups: halogen (such as Cl, F, Br, I); CN; -COOH; -CONR 24 R 25 (wherein R 24 and R 25 are independently selected from H, C1-3 alkyl, cyclopropyl, and isopropyl); C 1-3 alkyl (optionally substituted with F); cyclopropyl (optionally substituted with F); isopropyl (optionally substituted with F); OC 1-3 alkyl (optionally substituted with F); O - cyclopropyl (optionally substituted with F); O - isopropyl (optionally substituted with F); NR 30 R 31 (wherein R 30 and R 31 are independently selected from H, C 1-3 alkyl, and isopropyl); OH; and R 18 -CONH-, wherein R 18 is selected from C 1-3 alkyl and cyclopropyl; e) C 1-6 alkyl or branched C 3-6 alkyl; or a pharmaceutically acceptable salt or solvate thereof.

[0402] Generally, compared with the corresponding β - anomer, the compounds of formula (1) have an improved affinity for galectin - 3 by 15 - 80 times.

[0403] A is selected from formula (2), wherein R 1 -R 5 are independently selected from H and F, provided that at least one of R 1 -R 5 is F, usually 2 or 3 Fs;

[0404] X is selected from S, SO, or SO2; and

[0405] B is selected from

[0406] i) phenyl, substituted with one, two, or three groups selected from the following groups: halogen; CN; -COOH; -CONR 22 R 23 (wherein R 22 and R 23 are independently selected from H, C 1-3 alkyl, cyclopropyl, and isopropyl); C 1-3 alkyl (optionally substituted with F); cyclopropyl (optionally substituted with F); isopropyl (optionally substituted with F); OC 1-3 alkyl (optionally substituted with F); O - cyclopropyl (optionally substituted with F); O - isopropyl (optionally substituted with F); NR 28 R 29 (wherein R 28 and R 29 are independently selected from H, C 1-3 alkyl, and isopropyl); OH; and R 16 -CONH- (wherein R 16 is selected from C1-3 alkyl and cyclopropyl); provided that the 3-position relative to X is substituted with an atom selected from Cl, Br, and I;

[0407] ii) pyridyl, substituted with one, two, or three groups selected from the following groups: halogen; CN; -COOH; -CONR 22 R 23 (wherein R 22 and R 23 are independently selected from H, C 1-3 alkyl, cyclopropyl, and isopropyl); C 1-3 alkyl (optionally substituted with F); cyclopropyl (optionally substituted with F); isopropyl (optionally substituted with F); OC 1-3 alkyl (optionally substituted with F); O-cyclopropyl (optionally substituted with F); O-isopropyl (optionally substituted with F); NR 28 R 29 (wherein R 28 and R 29 are independently selected from H, C 1-3 alkyl, and isopropyl); OH; and R 16 -CONH- (wherein R 16 is selected from C 1-3 alkyl and cyclopropyl); provided that the 3-position relative to X is substituted with an atom selected from Cl, BR, and I;

[0408] iii) pyridazinyl, substituted with one, two, or three groups selected from the following groups: halogen; CN; -COOH; -CONR 22 R 23 (wherein R 22 and R 23 are independently selected from H, C 1-3 alkyl, cyclopropyl, and isopropyl); C 1-3 alkyl (optionally substituted with F); cyclopropyl (optionally substituted with F); isopropyl (optionally substituted with F); OC 1-3 alkyl (optionally substituted with F); O-cyclopropyl (optionally substituted with F); O-isopropyl (optionally substituted with F); NR 28 R 29 (wherein R 28 and R 29 are independently selected from H, C 1-3 alkyl and isopropyl); OH; and R 16 -CONH- (wherein R 16 is selected from C 1-3 alkyl and cyclopropyl); provided that the 3-position relative to X is substituted with an atom selected from Cl, BR, and I;

[0409] In one embodiment, A is selected from the structural formula (2), wherein R1 -R 5 is independently selected from H, CN, NH2, F, methyl (optionally substituted with F), and OCH3 (optionally substituted with F). In another embodiment, R 1 is selected from H, CN, NH2, F, methyl (optionally substituted with F), and OCH3 (optionally substituted with F), such as H, CN, NH2, F, methyl, CF3, OCH3, and OCF3. In another embodiment, R 1 is selected from H and F. In another embodiment, R 2 is selected from H, CN, NH2, F, methyl (optionally substituted with F), and OCH3 (optionally substituted with F), such as H, CN, NH2, F, methyl, CF3, OCH3, and OCF3. In another embodiment, R 2 is selected from F.

[0410] In another embodiment, R 3 is selected from H, CN, NH2, F, methyl (optionally substituted with F), and OCH3 (optionally substituted with F), such as H, CN, NH2, F, methyl, CF3, OCH3, and OCF3. In another embodiment, R 3 is selected from H, OCH3, and F. In another embodiment, R 4 is selected from H, CN, NH2, F, methyl (optionally substituted with F), and OCH3 (optionally substituted with F), such as H, CN, NH2, F, methyl, CF3, OCH3, and OCF3. In another embodiment, R 4 is selected from H and F. In another embodiment, R 5 is selected from H, CN, NH2, F, methyl (optionally substituted with F), and OCH3 (optionally substituted with F), such as H, CN, NH2, F, methyl, CF3, OCH3, and OCF3. In another embodiment, R 5 is selected from H and F.

[0411] In another embodiment, A is selected from structural formula (3), wherein Het 1 is selected from a five- or six-membered heteroaryl ring, optionally substituted with a group selected from the following: Br; F; Cl; CN; NR 19 R 20 (wherein as R 19 and R 20 are independently selected from H, C 1-3 alkyl, cyclopropyl, isopropyl, -C(=O)-R 21 , wherein R 21 is selected from H and C 1-3 alkyl); methyl (optionally substituted with F), and OCH3 (optionally substituted with F). In another embodiment, A is selected from structural formula (3), wherein Het1 Selected from five - or six - membered heteroaromatic rings, optionally substituted with groups selected from the following: Br; F; Cl; methyl (optionally substituted with F) and OCH3 (optionally substituted with F). In another embodiment, Het 1 Selected from five - membered heteroaromatic rings. In another embodiment, Het 1 Selected from five - membered heteroaromatic rings substituted with groups selected from Br, F, Cl, methyl, CF3, OCH3 and OCF3.

[0412] In another embodiment, Het 1 Selected from six - membered heteroaromatic rings.

[0413] In another embodiment, Het 1 Selected from six - membered heteroaromatic rings substituted with groups selected from Br, F, Cl, methyl, CF3, OCH3 and OCF3. In another embodiment, Het 1 Selected from six - membered heteroaromatic rings substituted with groups selected from Br, F, Cl.

[0414] In another embodiment, Het 1 Selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, phenylthio and imidazolyl, optionally substituted with Br, F, Cl, methyl, CF3, OCH3 and OCF3. In another embodiment, Het 1 Selected from pyridyl substituted with Br, F, Cl. In another embodiment, Het 1 Selected from pyridyl substituted with F (such as one, two or three F, usually 3F).

[0415] In another embodiment, A is selected from structural formula (4), wherein R 6 Selected from C 1-6 alkyl, branched C 3-6 alkyl and C 3-7 cycloalkyl. In one embodiment, R 6 is C 1-6 alkyl, such as methyl or ethyl. In another embodiment, R 6 is cyclopropyl, cyclopentyl or cyclohexyl.

[0416] In another embodiment, A is selected from structural formula (4), wherein R 6 Selected from halogen - substituted C 1-6 alkyl. In another embodiment, R 6 is C 1-3 alkyl substituted with one, two or three halogens, such as one, two or three F, such as CH2CF3.

[0417] In another embodiment, A is selected from structural formula (5), wherein R7 Selected from a five- or six-membered heteroaromatic ring and a phenyl group, wherein the five- or six-membered heteroaromatic ring is optionally substituted with a group selected from the following: Br, F, Cl, methyl (optionally substituted with F), and OCH3 (optionally substituted with F), and the phenyl group is optionally substituted with a group selected from the following: Br, F, Cl, methyl (optionally substituted with F), and OCH3 (optionally substituted with F). In another embodiment, R 7 is selected from a five-membered heteroaromatic ring. In another embodiment, R 7 is selected from a five-membered heteroaromatic ring substituted with a group selected from Br, F, Cl, methyl, CF3, OCF3, and OCH3. In another embodiment, R 7 is selected from a six-membered heteroaromatic ring. In another embodiment, R 7 is selected from a six-membered heteroaromatic ring substituted with a group selected from Br, F, Cl, methyl, CF3, OCF3, and OCH3 (such as substituted with 1, 2, or 3 groups selected from Br, F, Cl, methyl, CF3, OCF3, and OCH3). In another embodiment, R 7 is selected from a phenyl group. In another embodiment, R 7 is selected from a phenyl group substituted with a group selected from Br, F, Cl, methyl, CF3, OCF3, and OCH3 (such as substituted with 1, 2, or 3 groups selected from Br, F, Cl, methyl, CF3, OCF3, and OCH3). In another embodiment, R 7 is selected from a phenyl group substituted with Cl.

[0418] In another embodiment, A is selected from the structural formula (6), wherein R 8 -R 12 independently is selected from H, F, methyl (optionally substituted with F), and OCH3 (optionally substituted with F). In another embodiment, R 8 -R 12 independently is selected from H, F. In another embodiment, R 8 -R 12 is H. In another embodiment, R 8 -R 12 independently is selected from H and F, provided that at least two of R 8 -R 12 are F. In another embodiment, R 10 -R 11 is F, and R 8 , R 9 and R 12 are H. In another embodiment, R 8 is selected from H, F, methyl (optionally substituted with F), and OCH3 (optionally substituted with F), for example, H, F, methyl, CF3, OCF3, and OCH3. In another embodiment, R 9Selected from H, F, methyl (optionally substituted by F), and OCH3 (optionally substituted by F), such as H, F, methyl, CF3, OCF3, and OCH3. In another embodiment, R 10 Selected from H, F, methyl (optionally substituted by F), and OCH3 (optionally substituted by F), such as H, F, methyl, CF3, OCF3, and OCH3. In another embodiment, R 11 Selected from H, F, methyl (optionally substituted by F), and OCH3 (optionally substituted by F), such as H, F, methyl, CF3, OCF3, and OCH3. In another embodiment, R 12 Selected from H, F, methyl (optionally substituted by F), and OCH3 (optionally substituted by F), such as H, F, methyl, CF3, OCF3, and OCH3, and is typically H or methyl.

[0419] In another embodiment, A is selected from the structural formula (7), wherein R 13 Selected from a five- or six-membered heteroaromatic ring or aryl (such as phenyl or naphthyl), wherein the five- or six-membered heteroaromatic ring is optionally substituted by a group selected from: H, OH, F, methyl (optionally substituted by F), and OCH3 (optionally substituted by F), and the aryl is optionally substituted by a group selected from: H, OH, F, methyl (optionally substituted by F), and OCH3 (optionally substituted by F). In another embodiment, R 13 is a five-membered heteroaromatic ring. In another embodiment, R 13 Selected from a five-membered heteroaromatic ring substituted by a group selected from H, OH, F, methyl, CF3, OCF3, and OCH3 (such as substituted by 1, 2, or 3 groups selected from OH, F, methyl, CF3, OCF3, and OCH3). In one embodiment, R 13 is a six-membered heteroaromatic ring. In one embodiment, R 13 Selected from a six-membered heteroaromatic ring substituted by a group selected from H, OH, F, methyl, CF3, OCF3, and OCH3 (such as substituted by 1, 2, or 3 groups selected from OH, F, methyl, CF3, OCF3, and OCH3). In another embodiment, R 13 is phenyl or naphthyl. In another embodiment, R 13 Selected from phenyl substituted by a group selected from H, OH, F, CF3, OCF3, and OCH3 (such as substituted by 1, 2, or 3 groups selected from OH, F, methyl, CF3, OCF3, and OCH3). In another embodiment, R 13 is phenyl substituted by F, for example, substituted by 1, 2, or 3 Fs. In another embodiment, R 13is a naphthyl group substituted with a group selected from H, OH, F, CF3, OCF3, and OCH3 (such as substituted with 1, 2, or 3 groups selected from OH, F, methyl, CF3, OCF3, and OCH3).

[0420] In another embodiment, A is selected from the structural formula (8), where R 27 is selected from C 1-6 alkyl, branched C 3-6 alkyl, C 1-6 alkoxy, and branched C 3-6 alkoxy. In another embodiment, R 27 is selected from C 1-6 alkyl, such as C 1-4 alkyl, for example, methyl, ethyl, propyl. In another embodiment, R 27 is selected from C 1-6 alkoxy, such as C 1-4 alkoxy, for example, methoxy, ethoxy, propoxy.

[0421] In another embodiment, X is selected from S, SO, SO2, O, C=O, and CR 7 R 8 where R 7 and R 8 are independently selected from hydrogen, OH, or halogen (such as F, Cl, Br); in another embodiment, X is selected from S. In another embodiment, X is selected from SO. In another embodiment, X is selected from SO2. In another embodiment, X is selected from O. In another embodiment, X is selected from C=O. In another embodiment, X is selected from CR 7 R 8 where R 7 and R 8 are independently selected from hydrogen, OH, F, Cl, and Br, for example, CH2, CHF, CHCl, CHBr, CHOH, CF2, CCl2, and CBr2.

[0422] In another embodiment, B is selected from a five- or six-membered heteroaryl ring-substituted C 1-6 alkyl or branched C 3-6 alkyl, where the five- or six-membered heteroaryl ring is optionally substituted with a group selected from the following: halogen (such as Cl, F, Br, I), CN, methyl (optionally substituted with F), OCH3 (optionally substituted with F), OCH2CH3 (optionally substituted with F), OH, and R 14 -CONH-, where R 14 is selected from C 1-3 alkyl and cyclopropyl. In another embodiment, B is selected from a five-membered heteroaryl ring-substituted C 1-6 alkyl. In another embodiment, B is selected from a five-membered heteroaryl ring-substituted C 3-6Branched alkyl. In another embodiment, B is selected from C alkyl substituted with a five-membered heteroaryl ring 1-6 wherein the five-membered heteroaryl ring is substituted with a group selected from: CN, Cl, F, Br, I, methyl (optionally substituted with F), OCH3 (optionally substituted with F), OCH2CH3 (optionally substituted with F), OH, and R 14 -CONH-, wherein R 14 is selected from C 1-3 alkyl and cyclopropyl. In another embodiment, B is selected from C alkyl substituted with a five-membered heteroaryl ring 1-6 wherein the five-membered heteroaryl ring is substituted with a group selected from: CN, Cl, F, Br, I, methyl, CF3, OCH3, OCF3, OCH2CH3, OCF2CF3, OH and R 14 -CONH-, wherein R 14 is selected from methyl. In another embodiment, B is selected from branched C alkyl substituted with a five-membered heteroaryl ring 3-6 wherein the five-membered heteroaryl ring is substituted with a group selected from: CN, Cl, F, Br, I, methyl (optionally substituted with F), OCH3 (optionally substituted with F), OCH2CH3 (optionally substituted with F), OH, and R 14 -CONH-, wherein R 14 is selected from C 1-3 alkyl and cyclopropyl. In another embodiment, B is selected from branched C alkyl substituted with a five-membered heteroaryl ring 3-6 wherein the five-membered heteroaryl ring is substituted with 1, 2 or 3 groups selected from: CN, Cl, F, Br, I, methyl, CF3, OCH3, OCF3, OCH2CH3, OCF2CF3, OH and R 14 -CONH-, wherein R 14 is selected from methyl. In another embodiment, B is selected from C alkyl substituted with a phenyl group 1-6 such as benzyl or CH2-CH2-phenyl. In another embodiment, B is selected from C alkyl substituted with a phenyl group 1-6 wherein the phenyl group is substituted with, for example, 1, 2 or 3 substituents selected from CN, Cl, F, Br, I, methyl, CF3, OCH3, OCF3, OCH2CH3, OCF2CF3, OH and R 15 -CONH- (wherein R 15 is selected from methyl). In another embodiment, B is selected from C alkyl substituted with a phenyl group 1-6An alkyl group, wherein the phenyl group is substituted with a group selected from the following: Cl, F, Br, methyl, CF3, OCH3, OCF3. For example, B is selected from benzyl substituted with one or two Cl atoms, or CH2CH2-phenyl substituted with one Cl atom. In another embodiment, B is selected from phenyl groups. In another embodiment, B is selected from naphthyl groups. In another embodiment, B is selected from naphthyl groups substituted with an NR 28 R 29 group, wherein R 28 and R 29 are independently selected from H and C 1-3 alkyl groups. In another embodiment, B is selected from naphthyl groups substituted with an NR 28 R 29 group, wherein R 28 and R 29 are independently selected from H and CH3. In another embodiment, B is selected from naphthyl groups substituted with an NR 28 R 29 group, wherein R 28 and R 29 are selected from CH3. In another embodiment, B is selected from phenyl groups, wherein the phenyl group is substituted with, for example, one, two or three groups selected from Cl, F, Br, I, methyl, CF3, OCH3, OCF3, OCH2CH3, OCF2CF3, OH and R 16 -CONH- (wherein R 16 is selected from methyl). In another embodiment, B is selected from phenyl groups, wherein the phenyl group is substituted with, for example, one, two or three groups selected from Cl, F, Br, I, CN, methyl, CF3, OCH3, OCF3, OCH2CH3, OCF2CF3, OH and R 16 -CONH- (wherein R 16 is selected from methyl). In another embodiment, B is selected from phenyl groups, wherein the phenyl group is substituted with, for example, one, two or three groups selected from COOH and CONH2. In another embodiment, B is selected from naphthyl groups, wherein the naphthyl group is substituted with, for example, one, two or three groups selected from Cl, F, Br, I, methyl, CF3, OCH3, OCF3, OCH2CH3, OCF2CF3, OH and R 16 -CONH- (wherein R 16 is selected from methyl). In another embodiment, B is selected from naphthyl groups. In another embodiment, B is selected from naphthyl groups substituted with an NR 28 R 29 group, wherein R 28 and R 29 are independently selected from H, C 1-3 alkyl groups and isopropyl groups, such as naphthyl groups substituted with N(CH3)2.

[0423] In another embodiment, B is selected from C 5-7 cycloalkyl groups such as cyclopentyl or cyclohexyl. In another embodiment, B is selected from cyclohexyl. In another embodiment, B is selected from C 5-7 cycloalkyl groups such as cyclohexyl, where C 5-7 the cycloalkyl group is substituted with, for example, 1, 2 or 3 groups selected from CN, Cl, F, Br, I, methyl, CF3, OCH3, OCF3, OCH2CH3, OCF2CF3, OH and R 17 -CONH- (where R 17 is selected from methyl). In another embodiment, B is selected from cyclohexyl substituted with halogen, such as one or more halogens, typically F.

[0424] In another embodiment of the present invention, B is selected from C 1-4 alkyl groups. Generally, B is selected from ethyl, propyl and butyl.

[0425] In another embodiment, B is selected from heterocyclic compounds such as heteroaryl or heterocycloalkyl. In another embodiment, B is selected from heteroaryl, and the heteroaryl is substituted with, for example, 1, 2 or 3 groups selected from Cl, F, Br, I, methyl, CF3, OCH3, OCF3, OCH2CH3, OCF2CF3, OH and R 18 -CONH- (where R 18 is selected from methyl). In another embodiment, B is selected from heteroaryl, and the heteroaryl is substituted with, for example, 1, 2 or 3 groups selected from Cl, F, Br, I, CN, methyl, CF3, OCH3, OCF3, OCH2CH3, OCF2CF3, OH and R 18 -CONH- (where R 18 is selected from methyl). In another embodiment, B is selected from heterocycloalkyl, and the heterocycloalkyl is substituted with, for example, 1, 2 or 3 groups selected from Cl, F, Br, I, methyl, CF3, OCH3, OCF3, OCH2CH3, OCF2CF3, OH and R 18 -CONH- groups, where R 18 is selected from methyl. In another embodiment, B is selected from heteroaryl, and the heteroaryl is substituted with, for example, 1, 2 or 3 groups selected from NR 30 R 31 where R 30 and R 31 are independently selected from H, C 1-3Alkyl and isopropyl. Generally, B is selected from pyridyl groups substituted by, for example, 1, 2 or 3 groups selected from NH2 (for example, 1 NH2). In another embodiment, B is selected from phenylthio groups substituted by a halogen, such as 1 Cl. In another embodiment, B is selected from pyridazinyl groups. In another embodiment, B is selected from pyridazinyl groups substituted by 1, 2 or 3 groups selected from OCH3, CN, OH and Cl.

[0426] On the other hand, the present invention relates to the use of the compound of formula (1) as a medicament.

[0427] On the other hand, the present invention relates to a pharmaceutical composition comprising the compound of formula (1) of the present invention and optionally a pharmaceutically acceptable additive, such as a carrier and / or an excipient.

[0428] On the other hand, the present invention relates to the use of a compound of formula (1) of the present invention for treating diseases in mammals (such as humans) associated with the binding of galectin-3 and ligands. In another embodiment, the diseases are selected from inflammation; fibrosis (such as pulmonary fibrosis, liver fibrosis, renal fibrosis, ocular fibrosis, and skin and cardiac fibrosis); scarring; keloid formation; abnormal scar formation; surgical adhesions; septic shock; cancer (such as carcinoma, malignancy, leukemia, and lymphoma, such as T-cell lymphoma, metastatic carcinoma); autoimmune diseases (such as psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus); metabolic disorders; heart disease; heart failure; pathological angiogenesis (such as ocular angiogenesis or diseases or symptoms related to ocular angiogenesis, such as neovascularization associated with cancer); and ocular diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases (such as diabetes); asthma and other interstitial lung diseases (including Hermansky-Pudlak syndrome, mesothelioma); and liver diseases (such as non-alcoholic steatohepatitis).Examples of cancers that can be treated, controlled, and / or prevented by administering a compound of formula (1) include, but are not limited to: colon cancer, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphosarcoma, lymphangioendothelioma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hidradenoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioblastoma, neuroma, craniopharyngioma, schwannoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia and lymphoma, acute lymphocytic leukemia, acute myelogenous leukemia, polycythemia vera, multiple myeloma, Waldenström's macroglobulinemia, heavy chain disease, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, rectal cancer, renal pelvic cancer, uterine cancer, oral cancer, skin cancer, gastric cancer, brain cancer, liver cancer, laryngeal cancer, esophageal cancer, breast tumor, childhood non-acute lymphoblastic leukemia (ALL), thymic ALL, B-cell ALL, acute myeloid leukemia, myelomonocytic leukemia, acute megakaryocytic leukemia, Burkitt's lymphoma, acute myeloid leukemia, chronic myeloid leukemia, T-cell leukemia, small and large non-small cell lung cancer, acute granulocytic leukemia, germ cell tumor, endometrial cancer, gastric cancer, head and neck cancer, chronic lymphocytic leukemia, hairy cell leukemia, and thyroid cancer. Each of these diseases is considered an example and can be the subject of claims directed to such diseases or conditions.

[0429] On the other hand, the present invention relates to a method for treating diseases in mammals (such as humans) related to the binding of galectin-3 and ligands, wherein a therapeutically effective dose of at least one compound of formula (1) of the present invention is administered to a mammal in need of such treatment. In another embodiment, the diseases are selected from inflammation; fibrosis (such as pulmonary fibrosis, liver fibrosis, renal fibrosis, ocular fibrosis, and skin and cardiac fibrosis); scarring; keloid formation; abnormal scar formation; surgical adhesions; septic shock; cancer (such as carcinoma, malignancy, leukemia, and lymphoma, such as T-cell lymphoma, metastatic carcinoma); autoimmune diseases (such as psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus); metabolic disorders; heart diseases; heart failure; pathological angiogenesis (such as ocular angiogenesis or diseases or symptoms related to ocular angiogenesis, such as neovascularization related to cancer); and ocular diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases (such as diabetes); asthma and other interstitial lung diseases (including Hermansky-Pudlak syndrome, mesothelioma); and liver diseases (such as non-alcoholic steatohepatitis). Each of these diseases is considered an embodiment and can be the subject of claims directed to such diseases or conditions.

[0430] Those skilled in the art will understand that it may be necessary to adjust or change the order of the steps in methods a1 to a55, and such changes in order are included in the description of the various aspects of the above methods and the method steps in the reaction scheme.

[0431] In addition, those skilled in the art will understand that the functional groups of the above methods and the intermediate compounds hereinafter may need to be protected by protecting groups.

[0432] Functional groups to be protected include hydroxyl, amino, and carboxylic acid. Suitable hydroxyl protecting groups include optionally substituted and / or unsaturated alkyl groups (such as methyl, allyl, benzyl, or tert-butyl), trialkylsilyl or diarylalkylsilyl groups (such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), AcO (acetoxy), TBS (tert-butyldimethylsilyl), TMS (trimethylsilyl), PMB (p-methoxybenzyl), and tetrahydropyranyl. Suitable carboxylic acid protecting groups include (C 1-6 )-alkyl esters or benzyl esters. Suitable amino protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, 2-(trimethylsilyl)-ethoxymethyl, or 2-trimethylsilylethoxycarbonyl (Teoc). Suitable S protecting groups include S-C(=N)NH2, TIPS.

[0433] The protection and deprotection of functional groups can be carried out before or after any of the reactions mentioned in the above methods.

[0434] In addition, those skilled in the art should understand that, in order to obtain the compounds of the present invention in an alternative manner, and in some cases in a more convenient manner, the above-mentioned method steps can be carried out in a different order, and / or the respective reactions can be carried out at different stages of the overall route (i.e., substituents can be added and / or chemical transformations can be carried out on different intermediates mentioned above, as well as specific reactions). In this way, protecting groups may no longer be required or protecting groups may have to be employed.

[0435] In another embodiment, the compound (1) is in free form. As used herein, the term "free form" refers to the compound of structural formula (1), which, depending on the substituents, can be in the form of an acid or a base, or a neutral compound. In addition, the free form does not have any acidic or basic salts. In one embodiment, the free form is an anhydride. In another embodiment, the free form is a solvate, such as a hydrate.

[0436] In another embodiment, the compound (1) is in crystalline form. Those skilled in the art can conduct experiments to discover polymorphs, which are included by the term "crystalline form" herein.

[0437] When the compounds and pharmaceutical compositions disclosed herein are used for the above-mentioned treatment, a therapeutically effective dose of at least one compound is administered to a mammal in need of such treatment.

[0438] The term "C 1-x alkyl" as used herein refers to an alkyl group containing 1 - x carbon atoms, such as C 1-5 or C 1-6 , such as methyl, ethyl, propyl, butyl, pentyl or hexyl.

[0439] The term "branched C 3-6 alkyl" as used herein refers to a branched alkyl group containing 3 - 6 carbon atoms, such as isopropyl, isobutyl, tert-butyl, isopentyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl.

[0440] The term "C 3-7 cycloalkyl" as used herein refers to a cycloalkyl group containing 3 - 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 1-methylcyclopropyl.

[0441] The term "C 5-7 cycloalkyl" as used herein refers to a cycloalkyl group containing 5 - 7 carbon atoms, such as cyclopentyl, cyclohexyl or cycloheptyl.

[0442] The term "Oxo" as used herein refers to a double-bonded oxygen atom, also represented as =O.

[0443] As used herein, the term "CN" refers to a nitrile group.

[0444] As used herein, the term "five- or six-membered heteroaromatic ring" refers to a five-membered heteroaromatic ring or a six-membered heteroaromatic ring. The five-membered heteroaromatic ring contains 5 ring atoms, where 1 to 4 of the ring atoms are heteroatoms selected from N, O, and S. The six-membered heteroaromatic ring contains 6 ring atoms, where 1 to 5 of the ring atoms are heteroatoms selected from N, O, and S. Examples include thiophene, furan, pyran, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, and pyridazine. When the heteroaromatic ring is a substituent, they are referred to as thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl. Also included are oxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, and pyridoneyl.

[0445] As used herein, the term "heterocycle, such as heteroaryl or heterocycloalkyl" refers to a heterocycle composed of one or more 3- to 7-membered ring systems, where the ring system contains one or more heteroatoms, and where the ring system is optionally aromatic. As used herein, the term "heteroaryl" refers to a monocyclic or bicyclic aromatic ring system containing one or more (e.g., 1-10, such as 1-6) heteroatoms selected from O, S, and N, including but not limited to oxazolyl, oxadiazolyl, thienyl, thiadiazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridoneyl, pyrimidinoneyl, quinolinyl, azaquinolyl, isoquinolinyl, azaisoquinolinyl, quinazolinyl, azaquinazolinyl, benzoxazolyl, azabenzoxazolyl, benzothiazolyl, or azabenzothiazolyl. As used herein, "heterocycloalkyl" refers to a monocyclic or bicyclic 3- to 7-membered aliphatic heterocycle containing one or more (e.g., 1-7, such as 1-5) heteroatoms selected from O, S, and N, including but not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, or piperidinoneyl.

[0446] As used herein, the term "treatment" refers to the management and care of a patient to combat a disease, such as an illness or symptom. The term is used to include all treatments provided for a given condition suffered by a patient, such as administering an active compound, alleviating symptoms or complications, delaying the progression of a disease, symptom, or condition, alleviating or reducing symptoms and complications, and / or curing or eliminating a disease, symptom, or condition, as well as preventing a disease, where prevention should be understood as the management and care of a patient to combat a disease, condition, or symptom, including administering an active compound to prevent the occurrence of symptoms or complications. Treatment can be carried out in an acute or chronic manner. The patient to be treated is preferably a mammal; particularly a human, but can also include animals such as dogs, cats, cows, sheep, and pigs.

[0447] As used herein, the "therapeutically effective dose" of the compound of structural formula (1) of the present invention refers to the dose required to sufficiently cure, relieve or partially inhibit the clinical manifestations of a given disease and its complications. The dose sufficient to achieve this is defined as the "therapeutically effective dose". The effective dose for each treatment will depend on the severity of the disease or injury and the weight and general condition of the patient. It should be understood that by using routine experiments, constructing a numerical matrix and testing different points in the matrix, the appropriate dose can be determined, and these methods are the general skills of a trained doctor or veterinarian.

[0448] On the other hand, the present invention relates to a pharmaceutical composition comprising a compound of structural formula (1) and optionally a pharmaceutically acceptable additive such as a carrier and / or an excipient.

[0449] As used herein, the term "pharmaceutically acceptable additive" includes carriers, excipients, diluents, adjuvants, pigments, flavors, preservatives, etc., but is not limited to these. These additives are the additives considered for use by those skilled in the art when formulating the compounds of the present invention to prepare pharmaceutical compositions.

[0450] The adjuvants, diluents, excipients and / or carriers that can be used in the compositions of the present invention must be pharmaceutically acceptable, which means that they are compatible with the compound of structural formula (1) and other components of the pharmaceutical composition, and are harmless to the patient. Preferably, the composition should not contain any materials that may cause adverse reactions such as allergic reactions. The adjuvants, diluents, excipients and carriers that can be used in the pharmaceutical compositions of the present invention are well-known to those skilled in the art.

[0451] As described above, in addition to the compounds disclosed herein, the compositions disclosed herein, particularly pharmaceutical compositions, may further comprise at least one pharmaceutically acceptable adjuvant, diluent, excipient and / or carrier. In some embodiments, the pharmaceutical composition comprises 1-99 wt% of the at least one pharmaceutically acceptable adjuvant, diluent, excipient and / or carrier and 1-99 wt% of the compound disclosed herein. The total content of the active ingredient and the pharmaceutically acceptable adjuvant, diluent, excipient and / or carrier does not exceed 100% of the weight of the composition, particularly the pharmaceutical composition.

[0452] In some embodiments, only one compound disclosed herein is used for the above-mentioned uses.

[0453] In some embodiments, two or more compounds disclosed herein are used in combination for the above-mentioned uses.

[0454] Compositions, especially pharmaceutical compositions, which comprise the compounds described herein, are suitable for oral, intravenous, topical, intraperitoneal, nasal, buccal, sublingual or subcutaneous administration, or for administration via the respiratory tract in the form of, for example, an aerosol or an air-suspended fine powder. Thus, the pharmaceutical compositions of the invention can be in the form of, for example, tablets, capsules, powders, nanoparticles, crystals, amorphous substances, solutions, transdermal patches or suppositories.

[0455] Other embodiments of the method are illustrated in the experimental section herein, and each embodiment consisting of each method and each starting material may be part of other embodiments.

[0456] Unless an embodiment is indicated to relate to certain aspects of the invention, the above embodiments should be considered to relate to any one of the aspects described herein (such as "treatment methods", "pharmaceutical compositions", "use of compounds as medicaments") and any one of the embodiments described herein.

[0457] All references cited herein, including publications, patent applications, and patents, are incorporated herein by reference as if each reference were individually and specifically incorporated by reference in its entirety.

[0458] All headings and subheadings used herein are for convenience only and should in no way be construed as limiting the invention.

[0459] Any combination of various possible variations of the above elements is included in the invention unless explicitly stated herein or clearly negated by the context.

[0460] Unless otherwise indicated herein or clearly negated by the context, in the context of describing the invention, the words "a" and "the" and similar indications shall be considered to include the singular and the plural.

[0461] The recitation of numerical ranges herein is merely a shorthand method for separately referring to each individual value falling within the range. Unless otherwise indicated, each individual value is included in the specification as if it were specifically recited herein. Unless otherwise stated, all exact numerical values provided herein represent corresponding approximations (e.g., all exact exemplary values are provided relative to a specific factor or metric and can be considered to also provide the corresponding approximate metric, modified by "about" if appropriate).

[0462] Unless otherwise indicated by the invention or clearly negated by the context, all methods described herein can be performed in any suitable order.

[0463] Unless otherwise stated, the use of any example and all examples, or of exemplary language (such as "such as") is merely for the purpose of better illustrating the present invention and does not limit the scope of the present invention. Unless explicitly stated, no word in the specification should be construed as indicating that any element is essential for the practice of the present invention.

[0464] The patent documents cited and incorporated herein are for convenience only and do not reflect any validity, patentability, and / or enforceability of these patent documents.

[0465] When referring to an element or elements, the use of words such as "comprising", "having", or "including" or "containing" to describe any aspect or embodiment of the present invention is intended to support that the similar aspects or examples of the present invention "consist of", "consist essentially of", or "substantially include" these specific elements or elements, unless otherwise stated or the context clearly negates (for example, when the present invention describes a composition as including a certain specific element, it should be understood that a composition consisting of this element is also described, unless otherwise stated or the context clearly negates). To the maximum extent permitted by applicable law, the present invention includes all modifications and equivalent forms of the subject matter or claims mentioned in each aspect herein.

[0466] The present invention will be further illustrated by the following examples. However, these examples should not be regarded as limiting the scope of protection of the present invention. The features disclosed in the foregoing description and the following examples may be independent features and any combination of these features, and may be materials in various forms for implementing the present invention.

[0467] Experimental methods

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487] Kd value evaluation

[0488] The fluorescence anisotropy assay was used to determine the affinity of the compounds of Examples 1-106 for galectin, where the compounds served as inhibitors of the interaction between galectin and a fluorescein-labeled sugar probe, as described in Sorme, P., Kahl-Knutsson, B., Huflejt, M., Nilsson, U. J., and Leffler H. (2004) Fluorescence polarization as an analytical tool to evaluate galectin-ligand interactions. Anal. Biochem. 334:36-47, (Sorme et al., 2004) and Monovalent interactions of Galectin-1 By Salomonsson, Emma; Larumbe, Amaia; Tejler, Johan; Tullberg, Erik; Rydberg, Hanna; Sundin, Anders; Khabut, Areej; Frejd, Torbjorn; Lobsanov, Yuri D.; Rini, James M.; et al, From Biochemistry (2010), 49(44), 9518-9532, (Salomonsson et al., 2010). This assay can also use the following probes that have a high affinity for galectin-3. With these probes, a low concentration of galectin-3 (50 nM) can be used to determine the high affinity between the compound and galectin-3. 100 nM albumin was included as a carrier to prevent protein loss at such a low galectin concentration.

[0489]

[0490] probe

[0491] PK experiment

[0492] We observed that certain compounds of Structural Formula 1 exhibited good in vitro PK properties, showing high oral bioavailability, low clearance, good half-life, and high Cmax in a mouse pharmacokinetic study at a concentration of 10 mg / kg. These characteristics are exemplified in the following table by 3,4-dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside of Example 9.

[0493]

[0494] General Methods for Synthetic Examples and Intermediates

[0495] Nuclear magnetic resonance (NMR) spectra were measured at 25 °C using a 400 MHz Varian or 500 MHz Bruker AVANCE III 500. Residual solvents were used as internal standards, and chemical shifts were reported in parts per million (δ). The multiplicities of the peaks were represented as follows: s, singlet; d, doublet; dd, double doublet; t, triplet; dt, double triplet; q, quartet; m, multiplet; br s, broad singlet.

[0496] LC-MS was obtained using an Agilent 1100 or Agilent 1200 HPLC connected to an Agilent MSD mass spectrometer, operating in the ES(+) ionization mode. Columns: Waters symmetry 2.1x 30mm C18, Chromolith RP-18 2x 50mm or XBridge C18 (4.6x 50mm, 3.5(μm) or SunFire C18 (4.6x 50mm, 3.5(μm). Solvent A: water + 0.1% TFA and Solvent B: acetonitrile + 0.1% TFA. Wavelength: 254 nM.

[0497] Preparative HPLC was performed on a Gilson system. A) Flow rate: 10 ml / min Column: kromasil 100-5-C18 column. Wavelength: 254 nM. Solvent A: water + 0.1% TFA and Solvent B: acetonitrile + 0.1% TFA. B) Performed on a Gilson 215. Flow rate: 25 ml / min Column: XBrige prep C18 10μm OBD (19x 250mm) column. Wavelength: 254 nM. Solvent A: water (10 mM ammonium bicarbonate) and Solvent B: acetonitrile.

[0498] Flash chromatography was performed on a Biotage SP1 automated system using a Biotage Snap KP-Sil 25g or 50g cartridge.

[0499] The following abbreviations were used:

[0500] EtOAc: Ethyl acetate

[0501] DIEA: N,N-Diisopropylethylamine

[0502] PE: Petroleum ether

[0503] NEt3: Triethylamine

[0504] DMF: N,N-Dimethylformamide

[0505] BF3·OEt2: Boron trifluoride diethyl etherate

[0506] ESI-MS: Electrospray ionization mass spectrometry

[0507] Calcd: Calculated

[0508] TFA: Trifluoroacetic acid

[0509] Rt: Room temperature

[0510] UV: Ultraviolet

[0511] PMA: Polymolybdic acid

[0512] DAST: Diethylaminosulfur trifluoride

[0513] TBDMS: tert-Butyldimethylsilyl

[0514] TBAF: Tetrabutylammonium fluoride

[0515] MTBE: Methyl tert-butyl ether

[0516] HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0517] Example 1

[0518] 3,4-Dimethylphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0519]

[0520] Dissolve 3,4-dimethylphenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside, i1, (46 mg, 0.10 mmol) in anhydrous acetonitrile (3 mL), and stir under N2 at room temperature. Add CuI (20 mg, 0.11 mmol), and after 5 minutes, add 3,4,5-trifluorophenylacetylene (0.028 mL, 0.21 mmol). After another 5 minutes, add DIEA (0.018 mL, 0.10 mmol), and stir the mixture at room temperature for 18 hours. Filter the mixture through a short silica gel column, elute with EtOAc, and concentrate. Dissolve the residue in methanolic NaOMe (20 mL, 0.05 M), and stir at room temperature. After 4 hours, add acetic acid (2 mL), and concentrate the mixture. Purify the crude product by preparative HPLC and lyophilize to obtain 28 mg (57%) of 3,4-dimethylphenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside. 1 1H NMR (400 MHz, methanol-d4) δ 8.53 (s, 1H), 7.70 - 7.61 (m, 2H), 7.40 (s, 1H), 7.33 (d, J = 1.1 Hz, 1H), 7.10 (d, J = 1.1 Hz, 1H), 5.66 (d, J = 5.3 Hz, 1H), 4.98 (dd, J = 11.4, 2.7 Hz, 1H), 4.88 (dd, J = 11.6, 5.3 Hz, 1H), 4.59 (t, J = 6.1 Hz, 1H), 4.20 (s, 1H), 3.71 (qd, J = IIA, 6.2 Hz, 2H), 2.26 (s, 6H). [C 22 H 23 F3N3O4](M + H) + The calculated ESI-MS m / z value of [C

[0521] Examples 2 - 16 were prepared from their corresponding intermediates i2 - i16 by a method similar to that of Example 1.

[0522] Example 2

[0523] 3-bromophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0524]

[0525] Yield 53%. 1HNMR (400 MHz, methanol-d4) δ 8.54 (s, 1H), 7.80 (s, 1H), 7.71 - 7.55 (m, 3H), 7.45 (d, J = 8.5 Hz, 1H), 7.25 (t, J = 7.9 Hz, 1H), 5.83 (d, J = 5.1 Hz, 1H), 4.98 (dd, J = 11.5, 2.6 Hz, 1H), 4.91 (dd, J = 11.4, 5.2 Hz, 1H), 4.51 (t, J = 6.1 Hz, 1H), 4.21 (d, J = 1.6 Hz, 1H), 3.72 (qd, J = 11A, 6.2 Hz, 2H). [C 20 H 18 BrF3N3O4S](M + H) + The calculated value of ESI-MS m / z for

[0526] Example 3

[0527] 3-Ethoxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0528]

[0529] Yield 78%. 1 HNMR (400 MHz, methanol-d4) δ 8.54 (s, 1H), 7.71 - 7.60 (m, 2H), 7.27 - 7.12 (m, 3H), 6.84 (d, J = 7.9 Hz, 1H), 5.78 (d, J = 5.2 Hz, 1H), 4.97 (dd, J-11.5, 2.7 Hz, 1H), 4.89 (dd, J = 11.5, 5.3 Hz, 1H), 4.56 (t, J = 6.1 Hz, 1H), 4.21 (d, J = 1.7 Hz, 1H), 4.05 (q, J = 7.0 Hz, 2H), 3.72 (qd, J = 11.3, 6.2 Hz, 2H), 1.39 (t, J = 7.0 Hz, 3H). [C 22 H 23 F3N3O5S] + (M + H) + The calculated value of ESI-MS m / z for

[0530] Example 4

[0531] 4-Pyridyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0532]

[0533] The yield was 73%. 1 HNMR (400 MHz, methanol-d4) δ 8.58 (s, 1H), 8.52 (d, J = 6.8 Hz, 2H), 8.07 (d, J = 6.8 Hz, 2H), 7.71 - 7.58 (m, 2H), 6.49 (bs, 1H), 5.06 (d, J = 1.4 Hz, 2H), 4.25 (t, J = 6.0 Hz, 1H), 4.20 (s, 1H), 3.72 (dd, J = 5.9, 2.5 Hz, 2H). [C 19 H 18 F3N4O4S] + (M + H) + The calculated value of ESI-MS m / z for

[0534] Example 5

[0535] 2,4-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0536]

[0537] The yield was 58%. 1 HNMR (400 MHz, methanol-d4) δ 8.55 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.69 - 7.59 (m, 2H), 7.51 (d, J = 2.1 Hz, 1H), 7.32 (dd, J = 8.5, 2.1 Hz, 1H), 5.99 (d, J = 5.3 Hz, 1H), 5.07 (dd, J = 11.4, 2.7 Hz, 1H), 4.96 (dd, J = 11.4, 5.4 Hz, 1H), 4.44 (t, J = 6.2 Hz, 1H), 4.22 (d, J = 1.7 Hz, 1H), 3.70 (dd, J = 11.4, 5.9 Hz, 1H), 3.61 (dd, J = 11.4, 6.4 Hz, 1H). [C 20 H 17 Cl2F3N3O4S] + (M + H) + The calculated value of ESI-MS m / z for

[0538] Example 6

[0539] 4-Acetylanilino 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0540]

[0541] Yield 36%. 1 HNMR(400MHz, methanol-d4) δ8.53(s,1H),7.64(dd,J=8.6,6.8Hz,2H),7.58-7.51(m,4H),5.69(d,J=5.2Hz,1H),4.98(dd,J=11.4,2.7Hz,1H),4.88(dd,J=11.5,5.3Hz,1H),4.58(t,J=6.1Hz,1H),4.21(d,.7=2.0Hz,1H),3.72(qd,J=11A,6.2Hz,2H),2.13(s,3H).[C 22 H 22 F3N4O5S] + (M+H) + The calculated value of ESI-MS m / z for

[0542] Example 7

[0543] 4-Methoxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0544]

[0545] Yield 49%. 1 HNMR(400MHz, methanol-d4) δ8.53(s,1H),7.70-7.60(m,2H),7.54(d,J=8.6Hz,2H),6.91(d,J=8.7Hz,2H),5.59(d,J=5.3Hz,1H),4.98(dd,J=11.4,2.8Hz,lH),4.88(d,J=5.4Hz,1H),4.61(t,J=6.1Hz,1H),4.21(d,.7=1.9Hz,1H),3.80(s,3H),3.72(qd,J=11.3,6.1Hz,2H).[C 21 H 21 F3N3O5S] + (M+H) + The calculated value of ESI-MS m / z for

[0546] Example 8

[0547] 2,3-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0548]

[0549] Yield: 33%. 1 HNMR(400MHz, methanol-d4) δ8.55(s,1H),7.75(d,J = 8.0Hz,1H),7.65(dd,J = 8.4,6.9Hz,2H),7.43(d,J = 8.0Hz,1H),7.28(t,J = 8.0Hz,1H),6.05(d,J = 5.4Hz,1H),5.08(dd,J = 11A,2.7Hz,1H),4.98(dd,J = 11A,5.3Hz,1H),4.43(t,J = 6.2Hz,1H),4.22(d,J = 2.2Hz,1H),3.70(dd,J = 11A,6.0Hz,1H),3.61(dd,J = 11.4,6.3Hz,1H).[C 20 H 17 Cl2F3N3O4S] + (M + H) + The calculated value of ESI-MS m / z for [C

[0550] Example 9

[0551] 3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0552]

[0553] Yield: 77%. 1 HNMR(400MHz, chloroform-d) δ8.13(s,1H),7.66(d,J = 2.1Hz,1H),7.48 - 7.35(m,4H),5.86(d,J = 5.3Hz,1H),4.91(dd,J = 11.0,5.3Hz,1H),4.73(dd,J = 11.0,2.5Hz,1H),4.63(s,1H),4.46(t,J = 4.0Hz,1H),4.14 - 4.00(m,2H).[C 20 H 16 Cl2F3N3O4S] + (M + H)+ Calculated ESI-MS m / z: 522.0; Found: 521.9.

[0554] Example 10

[0555] Benzyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0556]

[0557] Yield: 74%. 1 HNMR (400 MHz, chloroform-d) δ 7.95 (s, 1H), 7.31 - 7.09 (m, 7H), 5.45 (d, J = 5.1 Hz, 1H), 4.66 (dd, J = 11.0, 5.2 Hz, 1H), 4.59 (dd, J = 11.0, 2.5 Hz, 1H), 4.42 (d, J = 2.3 Hz, 1H), 4.24 (t, J = 4.4 Hz, 1H), 3.86 - 3.73 (m, 4H). ESI-MS m / z [C 21 H 20 F3N3O4S] + (M + H) + Calculated: 468.1; Found: 468.0.

[0558] Example 11

[0559] 3-Methoxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0560]

[0561] Yield: 69%. 1 HNMR (400 MHz, chloroform-d) δ 8.12 (s, 1H), 7.39 (dd, J = 8.1, 6.3 Hz, 2H), 7.30 - 7.23 (m, 1H), 7.16 - 7.07 (m, 2H), 6.92 - 6.84 (m, 1H), 5.87 (d, J = 5.2 Hz, 1H), 4.86 (dd, J = 11.1, 5.3 Hz, 1H), 4.73 (dd, J = 11.2, 2.4 Hz, 1H), 4.61 (d, J = 2.5 Hz, 1H), 4.51 (d, J = 4.0 Hz, 1H), 4.11 - 3.98 (m, 2H), 3.82 (s, 3H). [C 21 H 20 F3N3O5S] +(M+H) + Calculated ESI-MS m / z for (M+H): 484.1; Found: 484.1.

[0562] Example 12

[0563] 2-Naphthyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0564]

[0565] Yield: 56%. 1 HNMR (400 MHz, chloroform-d) δ 8.16 (s, 1H), 8.07 (s, 1H), 7.88 - 7.78 (m, 3H), 7.60 (d, J = 8.6 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.47 (d, J = 7.1 Hz, 2H), 5.96 (d, J = 5.2 Hz, 1H), 4.90 (dd, J = 11.2, 5.2 Hz, 1H), 4.79 (d, J = 11.3 Hz, 1H), 4.65 (s, 1H), 4.58 (s, 1H), 4.14 - 4.01 (m, 2H). [C 24 H 20 F3N3O4S] + (M+H) + Calculated ESI-MS m / z for (M+H): 504.1; Found: 504.0.

[0566] Example 13

[0567] 3-Methylphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0568]

[0569] Yield: 58%. 1 HNMR (400 MHz, chloroform-d) δ 8.11 (s, 1H), 7.43 - 7.31 (m, 4H), 7.24 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 5.83 (d, J = 5.1 Hz, 1H), 4.90 - 4.81 (m, 1H), 4.72 (dd, J = 11.1, 2.4 Hz, 1H), 4.61 (d, J = 1.9 Hz, 1H), 4.51 (t, J = 4.2 Hz, 1H), 4.08 - 4.01 (m, 2H), 2.36 (s, 3H). [C 21 H 20F3N3O4S] + (M+H) + The calculated value of ESI-MS m / z for (M+H): 468.1; measured value: 468.0.

[0570] Example 14

[0571] 3-(Trifluoromethyl)phenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0572]

[0573] Yield 65%. 1 HNMR(400MHz, methanol-d 4) δ8.55(d, J = 2.2Hz, 1H), 7.92 - 7.84(m, 2H), 7.64(ddd, J = 9.0, 6.6, 2.4Hz, 2H), 7.59(d, J = 8.2Hz, 1H), 7.53(td, J = 7.7, 2.2Hz, 1H), 5.88(dd, J = 5.3, 2.3Hz, 1H), 5.01(dt, J = 11.6, 2.6Hz, 1H), 4.98 - 4.89(m, 1H), 4.58 - 4.50(m, 1H), 4.23(s, 1H), 3.72(dddd, J = 26.3, 9.2, 6.2, 3.3Hz, 2H). [C 21 H 17 F6N3O4S] + (M+H) + The calculated value of ESI-MS m / z for (M+H): 522.1; measured value: 522.0.

[0574] Example 15

[0575] 4-Bromophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0576]

[0577] Yield 0.2%. 1 HNMR(400MHz, chloroform-d) δ8.14(s, 1H), 7.54 - 7.39(m, 6H), 5.83(d, J = 5.3Hz, 1H), 4.88(dd, J = 11.0, 5.2Hz, 1H), 4.73(dd, J = 11.0, 2.5Hz, 1H), 4.63(s, 1H), 4.49(d, J = 4.1Hz, 1H), 4.13 - 3.99(m, 2H). [C20 H 17 BrF3N3O4S] + (M+H) + Calculated ESI-MS m / z for (M+H): 532.0; Found: 532.0.

[0578] Example 16

[0579] 3,5-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0580]

[0581] Yield 14%. 1 1H NMR (400 MHz, chloroform-d) δ 8.09 (s, 1H), 7.37 (d, J = 1.7 Hz, 2H), 7.32 - 7.20 (m, 3H), 5.85 (d, J = 5.2 Hz, 1H), 4.90 (dd, J = 11.2, 5.2 Hz, 1H), 4.70 (d, J = 11.2 Hz, 1H), 4.56 (s, 1H), 4.40 (s, 1H), 4.03 - 3.97 (m, 2H). [C 20 H 17 BrF3N3O4S] + (M+H) + Calculated ESI-MS m / z for (M+H): 522.0; Found: 521.9.

[0582] Example 17

[0583] 2,6-Dimethylphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0584]

[0585] 2,4,6 - Tri - O - acetyl - 3 - azido - 1 - chloro - 3 - deoxy - β - D - galactopyranoside (123 mg, 0.35 mmol) was dissolved in anhydrous DMF (1 mL), and Cs2CO3 (184 mg, 0.56 mmol) was added. After 5 minutes, 2,6 - dimethylbenzenethiol (0.052 mL, 0.39 mmol) was added, and the mixture was heated to 50 °C. After 2 hours, it was cooled to room temperature, MeCN (2 mL) was added, and then CuI (34 mg, 0.18 mmol) was added. After 5 minutes, 3,4,5 - trifluorophenylacetylene (0.095 mL, 0.71 mmol) was added, and after 5 minutes, DIEA (0.092 mL, 0.53 mmol) was added. The mixture was stirred at room temperature for 18 hours. It was eluted with EtOAc, filtered through a short silica gel column, and concentrated. The residue was dissolved in methanolic NaOMe (10 mL, 0.05 M) and stirred at room temperature. After 4 hours, acetic acid (2 mL) was added, and the mixture was concentrated. The crude product was purified by preparative HPLC and lyophilized to give 24 mg (11%) of 2,6 - dimethylphenyl 3 - deoxy - 1 - thio - 3 - [4 - (3,4,5 - trifluorophenyl) - 1H - 1,2,3 - triazol - 1 - yl] - α - D - galactopyranoside. 1 1H NMR (400 MHz, methanol - d4) δ 8.53 (s, 1H), 7.84 - 7.58 (m, 2H), 7.14 (bs, 3H), 5.36 (d, J = 5.3 Hz, 1H), 5.03 (dd, J = 11.6, 2.6 Hz, 1H), 4.83 - 4.76 (m, 1H), 4.56 (t, J = 6.2 Hz, 1H), 4.24 (d, J = 1.4 Hz, 1H), 3.78 - 3.57 (m, 2H), 2.60 (s, 6H). [C 22 H 23 F3N3O4S] + (M + H) + The calculated value of ESI - MS m / z for [C

[0586] Examples 18 - 21 were prepared by a method similar to that of Example 17 using the corresponding thiols.

[0587] Example 18

[0588] 1 - naphthyl 3 - deoxy - 1 - thio - 3 - [4 - (3,4,5 - trifluorophenyl) - 1H - 1,2,3 - triazol - 1 - yl] - 1 - thio - α - D - galactopyranoside

[0589]

[0590] Yield 17%.1 HNMR (400 MHz, methanol-d4) δ 8.63 - 8.58 (m 1H), 8.56 (s, 1H), 7.99 - 7.82 (m, 3H), 7.76 - 7.50 (m, 4H), 7.47 (t, J = 7.7 Hz, 1H), 5.73 (d, J = 5.3 Hz, 1H), 5.13 (dd, J = 11.5, 2.8 Hz, 1H), 4.93 (dd, J = 11.5, 5.4 Hz, 1H), 4.69 (t, J = 6.2 Hz, lH), 4.27 (d, J = 2.0 Hz, 1H), 3.76 - 3.69 (m, 1H), 3.63 (dd, J = 11.3, 6.3 Hz, 1H). [C 24 H 21 F3N3O4S] +( M + H) + The calculated value of ESI-MS m / z for [C

[0591] Example 19

[0592] 3-Chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0593]

[0594] Yield 25%. 1 HNMR (400 MHz, chloroform-d) δ 8.10 (s, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.40 (dt, J = 7.2, 1.7 Hz, 1H), 7.35 - 7.22 (m, 4H), 5.85 (d, J = 5.2 Hz, 1H), 4.90 (dd, J = ll.l, 5.3 Hz, 1H), 4.73 (dd, J = 11.1, 2.5 Hz, 1H), 4.59 (d, J = 2.5 Hz, 1H), 4.46 (t, J = 4.3 Hz, 1H), 4.06 - 3.90 (m, 2H). [C 20 H 17 ClF3N3O4S] + (M + H) + The calculated value of ESI-MS m / z for [C

[0595] Example 20

[0596] 3-(Trifluoromethoxy)phenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0597]

[0598] The yield is 4%. 1 HNMR(400 MHz, chloroform-d) δ 8.15 (s, 1H), 7.55 - 7.36 (m, 5H), 7.21 (d, J = 8.7 Hz, 1H), 5.92 (d, J = 5.3 Hz, 1H), 4.91 (dd, J = 11.0, 5.1 Hz, 1H), 4.75 (q, J = 14A, 14.0 Hz, 1H), 4.64 (s, 1H), 4.50 - 4.45 (m, 1H), 4.14 - 4.00 (m, 2H). [C 21 H 17 F6N3O5S] + (M + H) + The calculated value of ESI-MS m / z for

[0599] Example 21

[0600] 2-Pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0601]

[0602] The yield is 4%. 1 HNMR(400 MHz, methanol-d4) δ 8.57 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 7.90 (dd, J = 8.9, 7.1 Hz, 1H), 7.78 (d, J = 1.1 Hz, 1H), 7.66 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H), 6.50 (s, 1H), 5.01 (t, J = 1.9 Hz, 2H), 4.35 (t, J = 6.2 Hz, 1H), 4.20 (s, 1H), 3.75 - 3.62 (m, 2H). [C 19 H 17 F3N4O4S] + (M + H) + The calculated value of ESI-MS m / z for

[0603] Examples 22 - 23 were prepared by a method similar to that of Example 1 through their corresponding intermediates i22 - i23;

[0604] Example 22

[0605] 1-O-(3,4-dichlorophenyl)-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[0606]

[0607] Yield 42%. 1 HNMR(400MHz, methanol-d4) δ8.59(s,1H),7.78-7.58(m,2H),7.53-7.40(m,2H),7.21(dd,J=8.9,2.7Hz,1H),5.69(d,J=3.6Hz,1H),5.27(dd,J=11.4,2.8Hz,1H),4.69(dd,J=11.4,3.6Hz,1H),4.21(d,J=2.0Hz,1H),4.11(t,J=6.1Hz,1H),3.72(d,J=6.1Hz,2H).[C 20 H 17 Cl2F3N3O5] + (M+H) + The calculated value of ESI-MS m / z for

[0608] Example 23

[0609] 4-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0610]

[0611] Yield 31%. 1 HNMR(400MHz, chloroform-d) δ8.12(s,1H),7.49(d,J=8.5Hz,2H),7.41(t,J=7.6Hz,2H),7.34(d,J=8.4Hz,2H),7.27(d,J=0.7Hz,2H),5.82(d,J=5.2Hz,1H),4.88(dd,J=11.1,5.2Hz,1H),4.73(dd,J=11.1,2.3Hz,1H),4.62(s,1H),4.48(t,J=4.4Hz,1H),4.11-3.97(m,2H).[C 20 H 17 ClF3N3O4S] + (M+H) + The calculated value of ESI-MS m / z for

[0612] By purifying the title compound, the product 4-chlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside was additionally isolated (yield 6%).

[0613] Example 24

[0614] 3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide

[0615]

[0616] Dissolve 3,4-dichlorophenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside (30 mg, 0.06 mmol) in acetic acid (4 ml). Add 27% aqueous hydrogen peroxide solution (0.20 ml). Heat the mixture to 45 °C. After 2 hours, dilute the mixture with water (2 ml) and purify it on an HPLC column. The title compound was isolated to give a white freeze-dried powder (20 mg, 65%).

[0617] 1 HNMR (400 MHz, chloroform-d) δ 8.14 (s, 1H), 7.86 (d, J = 1.9 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.44 (dd, J = 8.0, 6.4 Hz, 2H), 5.32 (d, J = 10.9 Hz, 1H), 5.08 (d, J = 4.7 Hz, 1H), 5.03 - 4.95 (m, 1H), 4.91 (s, 1H), 4.52 (t, J = 4.9 Hz, 1H), 4.10 (dd, J = 12.1, 5.4 Hz, 1H), 4.02 (dd, J = 12.0, 4.4 Hz, 1H). [C 20 H 16 Cl2F3N3O5S] + (M + H) + The calculated value of ESI-MS m / z for

[0618] Example 25

[0619] 3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfone

[0620]

[0621] The title compound (1 mg, 3%) was also isolated from the purification described in Example 24.

[0622] 1 HNMR (400 MHz, methanol-d4) δ 8.54 (s, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 8.5, 2.0 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.65 (dd, J = 8.5, 6.7 Hz, 2H), 5.74 (dd, J = 11.5, 2.7 Hz, 1H), 5.34 (d, J = 6.4 Hz, 1H), 5.13 (dd, J = 11.5, 6.4 Hz, 1H), 4.52 (t, J = 6.1 Hz, 1H), 4.28 (d, J = 2.6 Hz, 1H), 3.60 (qd, J = 11.6, 5.9 Hz, 2H). [C 20 H 16 Cl2F3N3O6S] + (M+H) + The calculated value of ESI-MS m / z for [C

[0623] Example 26

[0624] 4-Chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide

[0625]

[0626] 4-Chlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside (10 mg, 0.02 mmol) was dissolved in acetic acid (3 ml). Hydrogen peroxide (100 μl) was added. The mixture was stirred at 45 °C for 1 hour, then diluted with water and freeze-dried. The residue was dissolved in MeOH (10 ml), and 1 M sodium methoxide in methanol (1 ml) was added. After standing at room temperature overnight, the mixture was concentrated in vacuo and the residue was purified by HPLC. After freeze-drying, the product was isolated as a white fluffy powder (3 mg, 37%).

[0627] 1HNMR (400 MHz, methanol-d4) δ 8.54 (s, 1H), 7.91 - 7.81 (m, 2H), 7.69 - 7.59 (m, 4H), 5.52 (dd, J = 11.4, 2.8 Hz, 1H), 5.13 (dd, J = 11.3, 5.6 Hz, 1H), 4.92 (d, J = 5.5 Hz, 1H), 4.26 (d, J = 2.8 Hz, 1H), 4.08 (t, J = 6.1 Hz, 1H), 3.53 (dd, J = 11.4, 5.8 Hz, 1H), 3.41 (dd, J = 11.4, 6.4 Hz, 1H). [C 20 H 17 ClF3N3O5S] + (M + H) + The calculated value of ESI-MS m / z for

[0628] Example 27

[0629] Phenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0630]

[0631] To a solution of phenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (160 mg, α-anomer:β-anomer = 100:8, 0.38 mmol) in DMF was added trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (4) (170 mg, 0.74 mmol), copper(I) iodide (20 mg, 0.11 mmol) and triethylamine (0.26 mL, 1.85 mmol). The mixture was stirred at 100 °C for 1 h. Water (10 mL) was added and the mixture was filtered. The filtrate was diluted with DCM (40 mL) and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was dissolved in methanolic NaOMe (8 mL, pH = 9 - 10) and stirred at room temperature for 2 h. Neutralized with + resin, filtered and concentrated to give a slurry. The crude product was purified by preparative-HPLC and then chiral-HPLC to give 40 mg of the α-anomer product as a white solid.

[0632] Chiral-HPLC conditions: Instrument: SFC-80 (Thar, Waters), chromatographic column: IC 20*250 mm, 5 μm (Decial), column temperature: 35 °C, mobile phase: CO2 / methanol (0.1% NH4OH) = 65 / 35, flow rate: 80 g / min, back pressure: 100 bar, detection wavelength: 214 nm, cycle time: 4.2 min, sample solution: 60 mg of sample dissolved in 15 mL of methanol, injection volume: 5.0 mL.

[0633] 1 HNMR (400 MHz, methanol-d4) δ 8.57 (s, 1H), 7.67 (d, J = 6.5 Hz, 1H), 7.65 (d, J = 7.0 Hz, 1H), 7.63 - 7.61 (m, 2H), 7.36 - 7.30 (m, 3H), 5.77 (d, J = 5.5 Hz, 1H), 5.00 (dd, J = 11.5, 2.5 Hz, 1H), 4.91 (d, J = 5.0 Hz, 1H), 4.57 (t, J = 6.5 Hz, 1H), 4.21 (d, J = 1.5 Hz, 1H), 3.74 (dd, J = 11.5, 6.0 Hz, 1H), 3.67 (dd, J = 11.5, 6.5 Hz, 1H). [C 20 H 19 F3N3O4S] + (M + H) + The calculated value of ESI-MS m / z for [C

[0634] Example 28

[0635] 3-chloro-4-fluorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0636]

[0637] To a solution of 3-chloro-4-fluorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (210 mg, 0.44 mmol) in DMF (3 mL) was added trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (200 mg, 0.88 mmol), copper(I) iodide (30 mg, 0.13 mmol), and triethylamine (0.30 mL, 2.2 mmol). The mixture was stirred at 100 °C for 1 h. Water (10 mL) was added and the mixture was filtered. The filtrate was diluted with DCM (40 mL) and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was dissolved in methanolic NaOMe (8 mL, pH = 9 - 10) and stirred at room temperature for 2 h. Neutralized with H + resin, filtered, and concentrated to give a slurry. The crude product was purified by preparative-HPLC to give 120 mg of the α-anomer product as a white solid. 1 1H NMR (400 MHz, methanol-d4) δ 8.57 (s, 1H), 7.80 (dd, J = 7.5, 2.5 Hz, 1H), 7.68 (dd, J = 9.0, 6.5 Hz, 2H), 7.60 (m, 1H), 7.25 (t, J = 9.0 Hz, 1H), 5.78 (d, J = 5.5 Hz, 1H), 5.00 (dd, J = 11.5, 3.0 Hz, 1H), 4.93 (t, J = 5.5 Hz, 1H), 4.55 (t, J = 6.0 Hz, 1H), 4.22 (d, J = 1.5 Hz, 1H), 3.78 - 3.70 (m, 2H). [C 20 H 17 ClF4N3O4S] + (M + H) + Calculated for ESI-MS m / z of [C

[0638] Example 29

[0639] 4-Tolyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0640]

[0641] To a solution of 4-tolyl 2,4,6-tri-O-acetyl-3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside (85 mg, 0.14 mmol) in MeOH (5 mL) was added sodium methoxide solution (30%, 7.7 mg, 0.04 mmol), and the solution was stirred at room temperature for 1 hour. TLC (silica gel, PE:EtOAc = 1:1) analysis showed the total consumption of the starting material. After completion of the reaction, Dowex 50W×8 hydrogen form (100 - 200 mesh) exchange resin (pH = 7) was added, and the mixture was filtered. The filtrate was concentrated and purified by preparative-HPLC and freeze-dried to give 14 mg of the product as a white solid.

[0642] 1 H NMR (500 MHz, DMSO-d6) δ 8.79 (s, 1H), 7.87 - 7.83 (m, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 5.77 (brs, 1H), 5.67 (d, J = 5.5 Hz, 1H), 5.50 (brs, 1H), 4.79 (dd, J = 11.5 Hz, 3.0 Hz, 1H), 4.73 - 4.70 (m, 2H), 4.34 (t, J = 6.0 Hz, 1H), 4.03 (s, 1H), 3.54 (brs, 1H), 3.42 - 3.38 (m, 1H), 2.30 (s, 3H). [C 21 H 20 F3N3O4S] + (M+H) + The calculated ESI-MS m / z for

[0643] Example 30

[0644] 4-Fluorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0645]

[0646] To a solution of 4-fluorophenyl 2,4,6-tri-O-acetyl-3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside (150 mg, 0.25 mmol) in MeOH (5 mL) was added a solution of sodium methoxide (30%, 9 mg, 0.05 mmol), and the solution was stirred at room temperature for 1 hour. TLC (silica gel, PE:EtOAc = 3:1, UV, PMA) analysis showed the total consumption of the starting material. Dowex 50W×8 hydrogen form (100 - 200 mesh) exchange resin (pH = 7) was added, and the mixture was filtered. The solvent was removed to give a residue. Purification by flash column chromatography (silica gel, DCM:MeOH = 20:1) gave 58 mg of the product as a white solid.

[0647] 1 H NMR (500 MHz, DMSO-d6) δ 8.80 (s, 1H), 7.86 - 7.83 (m, 2H), 7.63 - 7.60 (m, 2H), 7.23 - 7.19 (m, 2H), 5.83 (s, 1H), 5.71 (d, J = 5.0 Hz, 1H), 5.51 (d, J = 6.0 Hz, 1H), 4.80 (dd, J = 11.5 Hz, 2.5 Hz, 1H), 4.75 - 4.71 (m, 2H), 4.33 (t, J = 6.0 Hz, 1H), 4.04 (s, 1H), 3.57 - 3.52 (m, 1H), 3.43 - 3.39 (m, 1H). [C 20 H 17 F4N3O4S] + (M + H) + The calculated ESI-MS m / z for

[0648] Example 31

[0649] 4-Trifluoromethoxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0650]

[0651] To a solution of 4-trifluoromethoxy(2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (150 mg, 0.23 mmol) in MeOH (5 mL) was added a solution of sodium methoxide (30%, 8 mg, 0.05 mmol), and the solution was stirred at room temperature for 1 hour. TLC (silica gel, PE:EtOAc = 3:1, UV, PMA) analysis showed the total consumption of the starting material. Dowex 50W×8 hydrogen form (100-200 mesh) exchange resin (pH = 7) was added, and the mixture was filtered. The solvent was removed to give a residue. The residue was purified by flash column chromatography (silica gel, DCM:MeOH = 20:1) to give 44 mg of the product as a white solid.

[0652] 1 H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.73 - 7.69 (m, 2H), 7.54 (d, J = 9.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 5.71 (dd, J = 8.5 Hz, 4.5 Hz, 2H), 5.38 (d, J = 6.0 Hz, 1H), 4.67 (dd, J = 11.5 Hz, 2.5 Hz, 1H), 4.62 - 4.60 (m, 2H), 4.15 (t, J = 6.5 Hz, 1H), 3.90 (dd, J = 6.0 Hz, 2.5 Hz, 1H), 3.43 - 3.38 (m, 1H), 3.25 - 3.30 (m, 1H). [C 21 H 17 F6N3O5S] + (M+H) + The calculated value of ESI-MS m / z for

[0653] Examples 32 - 38 were prepared by a method similar to Example 1 through the corresponding intermediates i32 - i38

[0654] Example 32

[0655] Phenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[0656]

[0657] Yield 70%. 1HNMR (400 MHz, methanol-d4) δ 8.59 (s, 1H), 7.66 (dd, J = 8.6, 6.8 Hz, 2H), 7.32 (t, J = 7.9 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.05 (t, J = 7.2 Hz, 1H), 5.67 (d, J = 3.6 Hz, 1H), 5.31 (dd, J = 11.4, 2.8 Hz, 1H), 4.68 (dd, J = 11.4, 3.6 Hz, 1H), 4.23 (d, J = 2.4 Hz, 1H), 4.18 (t, J = 6.2 Hz, 1H), 3.72 (dd, J = 6.1, 3.4 Hz, 2H). [C 20 H 19 F3N3O5] + (M + H) + The calculated value of ESI-MS m / z for [C

[0658] Example 33

[0659] 3-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[0660]

[0661] Yield 75%. 1 HNMR (400 MHz, methanol-d4) δ 8.59 (s, 1H), 7.70 - 7.63 (m, 2H), 7.34 - 7.27 (m, 2H), 7.20 (d, J = 8.5 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H), 5.69 (d, J = 3.6 Hz, 1H), 5.29 (dd, J = 11.5, 2.8 Hz, 1H), 4.69 (dd, J = 11A, 3.6 Hz, 1H), 4.23 - 4.20 (m, 1H), 4.14 (t, J = 6.1 Hz, 1H), 3.72 (d, J = 6.0 Hz, 2H). ESI-MS m / z [C 20 H 18 ClF3N3O5](M + H) + The calculated value: 472.1; the measured value: 472.0.

[0662] Example 34

[0663] 3-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[0664]

[0665] The yield is 60%. 1 HNMR(400 MHz, methanol-d4) δ 8.59 (s, 1H), 7.69 - 7.62 (m, 2H), 7.31 (d, J = 9.0 Hz, 2H), 7.23 (d, J = 9.0 Hz, 2H), 5.65 (d, J = 3.4 Hz, 1H), 5.29 (dd, J = 11.4, 2.6 Hz, 1H), 4.68 (dd, J = 11.4, 3.5 Hz, 1H), 4.22 (d, J = 1.3 Hz, 1H), 4.14 (t, J = 6.0 Hz, 1H), 3.72 (d, J = 6.1 Hz, 2H). [C 20 H 18 ClF3N3O5] + (M + H) + The calculated value of ESI-MS m / z for (M + H): 472.1; the measured value: 472.0.

[0666] Example 35

[0667] Cyclohexyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0668]

[0669] The yield is 99%. 1 HNMR(400 MHz, methanol-d4) δ 8.50 (s, 1H), 7.67 - 7.60 (m, 2H), 5.65 (d, J = 5.4 Hz, 1H), 4.91 (dd, J = 11A, 2.8 Hz, 1H), 4.79 (dd, J = 11A, 5.4 Hz, 1H), 4.43 (t, J = 6.1 Hz, 1H), 4.13 (s, 1H), 3.73 (d, J = 6.0 Hz, 2H), 2.96 (t, J = 10.0 Hz, 1H), 2.16 - 1.26 (m, 10H). [C 20 H 25 F3N3O4S] + (M + H) + The calculated value of ESI-MS m / z for (M + H): 460.2; the measured value: 460.0.

[0670] Example 36

[0671] 2,4,5-Trichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0672]

[0673] The yield is 65%. 1 HNMR(400MHz, methanol-d4) δ 8.55(s, 1H), 7.96(s, 1H), 7.70 - 7.61(m, 3H), 6.03(d, J = 5.3Hz, 1H), 5.06(dd, J = 11.4, 2.3Hz, 1H), 4.98(dd, J = 11.4, 5.3Hz, 1H), 4.40(t, J = 6.0Hz, 1H), 4.22(s, 1H), 3.71(dd, J = 11.3, 5.7Hz, 1H), 3.64(dd, J = 11.4, 6.5Hz, 1H). [C 20 H 16 Cl3F3N3O4S] + (M + H) + The calculated value of ESI-MS m / z for [C

[0674] Example 37

[0675] 2,5-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0676]

[0677] The yield is 32%. 1 HNMR(400MHz, methanol-d4) δ 8.55(s, 1H), 7.81(q, J = 1.7Hz, 1H), 7.69 - 7.60(m, 2H), 7.42(dt, J = 8.5, 1.5Hz, 1H), 7.25(ddt, J = 8.7, 2.8, 1.5Hz, 1H), 6.03(d, J = 5.3Hz, 1H), 5.11 - 5.02(m, 1H), 4.98(ddt, J = 11.5, 5.4, 1.5Hz, 1H), 4.47 - 4.39(m, 1H), 4.23(q, J = 1.5Hz, 1H), 3.73(ddt, J = 11.4, 6.1, 1.5Hz, 1H), 3.63(ddt, J = 11.3, 6.4, 1.5Hz, 1H). [C 20 H 17 Cl2F3N3O4S] + (M + H) + The calculated value of ESI-MS m / z for [C

[0678] Example 38

[0679] 3-Hydroxy-phenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0680]

[0681] Yield 14%. 1 HNMR(400MHz, methanol-d4) δ8.53(s,1H),7.65(dd,J=8.6,6.6Hz,2H),7.14(t,J=7.9Hz,1H),7.09-7.02(m,2H),6.71(dt,J=7.9,1.6Hz,1H),5.78(d,J=5.2Hz,1H),4.97(dd,J=11.5,2.7Hz,1H),4.94-4.87(m,1H),4.54(t,J=6.3Hz,1H),4.21(d,J=2.7Hz,1H),3.73(qd,J=11.3,6.1Hz,2H).[C 20 H 18 F3N3O5S] + (M+H) + The calculated value of ESI-MS m / z for

[0682] Example 39

[0683] 3-Bromo-phenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide

[0684]

[0685] Dissolve 3-bromo-phenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1–thio-α-D-galactopyranoside (12 mg, 0.023 mmol) in CH2Cl2 (3 mL) and stir at room temperature. Add mCPBA (6.4 mg, 0.027 mmol) dissolved in CH2C12 (0.355 mL). After 3 hours, elute with EtOAc, filter the mixture through a short silica gel column, and concentrate. Purify by preparative HPLC and freeze-dry to obtain 11 mg (89%) of the sulfoxide.

[0686] 1HNMR (400 MHz, methanol-d4) δ 8.54 (s, 1H), 8.03 (s, 1H), 7.78 (dd, J = 21.7, 7.9 Hz, 2H), 7.70 - 7.61 (m, 2H), 7.52 (t, J = 7.9 Hz, 1H), 5.55 (dd, J = 11.2, 2.7 Hz, 1H), 5.13 (dd, J = 11.3, 5.6 Hz, 1H), 4.94 (d, J = 5.7 Hz, 1H), 4.28 (s, 1H), 4.16 (t, J = 6.1 Hz, 1H), 3.55 (dd, J = II A, 5.8 Hz, 1H), 3.46 (dd, J = 11.5, 6.4 Hz, 1H). [C 20 H 18 BrF3N3O5S] + (M + H) + The calculated value of ESI-MS m / z for

[0687] Example 40

[0688] 2-Ethoxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0689]

[0690] To a solution of 2-ethoxyphenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (80 mg, 0.18 mmol) in DMF (3 mL) was added trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (80 mg, 0.35 mmol), copper(I) iodide (10 mg, 0.05 mmol), and triethylamine (0.12 mL, 0.89 mmol). The mixture was stirred at 100 °C for 1 h. Water (10 mL) was added and the mixture was filtered through celite. The filtrate was diluted with DCM (40 mL) and washed with saturated NaCl solution. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was dissolved in sodium methoxide in methanol (8 mL, pH = 9 - 10) and stirred at 15 °C for 2 h. Neutralized with H + resin, filtered, and concentrated to give a syrup. The crude product was purified by preparative-HPLC to give 2-ethoxyphenyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl]-3-deoxy-1-thio-α-D-galactopyranoside as a white solid.

[0691] 1HNMR (400 MHz, methanol-d4) δ 8.50 (s, 1H), 7.64 (d, J = 7.0 Hz, 1H), 7.62 (d, J = 6.5 Hz, 1H), 7.28 - 7.26 (m, 4H), 7.20 - 7.18 (m, 1H), 5.62 (d, J = 5.5 Hz, 1H), 4.94 (dd, J = 11.0, 2.5 Hz, 1H), 4.83 (dd, J = 11.5, 5.5 Hz, 1H), 4.40 (t, J = 6.0 Hz, 1H), 4.30 (d, J = 2.5 Hz, 1H), 3.77 - 3.75 (m, 2H), 2.99 - 2.95 (m, 3H), 2.89 - 2.87 (m, 1H). [C 22 H 23 F3N3O4S] + (M + H) + The calculated value of ESI-MS m / z for

[0692] Example 41

[0693] 3,4-Dichlorophenyl 3-O-[(2-amino-(4-chlorophenyl)pyrimidin-6-yl)methylene]-1-thio-α-D-galactopyranoside

[0694]

[0695] To a solution of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-O-[(4-chlorophenyl)-4-oxo-2-butynyl]-1-thio-α-D-galactopyranoside (140 mg, 0.22 mmol) in tetrahydrofuran (10 mL) were added guanidine hydrochloride (52 mg, 0.54 mmol) and K2CO3 (90 mg, 0.65 mmol). The reaction vessel was purged with nitrogen three times. Then, the mixture was heated under reflux with stirring for 20 h. The reaction mixture was concentrated using a rotary evaporator. It was diluted with MeOH (10 mL) and concentrated again using a rotary evaporator. The residue was diluted with MeOH (5 mL) and filtered, and the filtrate was purified by preparative-HPLC to give 22 mg (18.1%) of 3,4-dichlorophenyl 3-O-[(2-amino-(4-chlorophenyl)pyrimidin-6-yl)methylene]-1-thio-α-D-galactopyranoside as a white solid.

[0696] 1HNMR (400 MHz, methanol-d4) δ 8.13 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 2.0 Hz, 1H), 7.56 - 7.42 (m, 5H), 5.74 (d, J = 5.6 Hz, 1H), 4.65 - 4.75 (dd, 2H), 4.42 - 4.48 (m, 1H), 4.33 - 4.22 (m, 2H), 3.76 (dd, J = 15.0, 6.1 Hz, 2H), 3.65 (dd, J = 10.1, 3.0 Hz, 1H). [C 23 H 23 Cl3F3N3O5S] + (M + H) + The calculated value of ESI-MS m / z for

[0697] Synthesis of intermediates i1 - i41

[0698] i1) 3,4-Dimethylphenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0699]

[0700] 2,4,6-Tri-O-acetyl-3-azido-1-chloro-3-deoxy-β-D-galactopyranoside was prepared from 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy-β-D-galactopyranoside according to the well-known literature method (Farkas et al, 1976). However, the obtained product was used without purification in the next step.

[0701]

[0702] Synthesized according to the known literature method (Ramos-Soriano et al., 2013). 3,4-Dimethylbenzenethiol (0.056 mL, 0.42 mmol) was dissolved in anhydrous DMF and stirred at room temperature. NaH (21 mg, 57-63%, 0.55 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, 3-azido-3-deoxy-β-D-galactopyranosyl chloride (73 mg, 0.21 mmol) dissolved in anhydrous DMF (1 mL) was added, and the resulting mixture was stirred at 55 °C for 1 hour and then at room temperature for 18 hours. The reaction mixture was diluted with EtOAc and washed 4 times with brine. The combined aqueous phase was extracted with EtOAc, and the combined organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography with a 7-75% EtOAc in petroleum ether solution to give 46 mg (49%) of 3,4-dimethylphenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside as an amorphous white solid. 1 H NMR (400 MHz, chloroform-d) δ 7.31 - 7.22 (m, 2H), 7.11 (d, J = 7.8 Hz, 1H), 5.93 (d, J = 5.5 Hz, 1H), 5.52 (d, J = 2.9 Hz, 1H), 5.31 (dd, J = 10.9, 5.5 Hz, 1H), 4.75 (t, J = 6.4 Hz, 1H), 4.15 (dd, J = 11.5, 5.6 Hz, 1H), 4.11 - 3.98 (m, 2H), 2.28 (s, 6H), 2.23 (s, 3H), 2.20 (s, 3H), 2.04 (s, 3H). [C 20 H 25 N3O7SNa] + (M + Na) + The calculated ESI-MS m / z value for [C

[0703] Intermediates i2 - i9, i11–i16 were prepared by a method similar to that of i1 from the corresponding aryl thiols.

[0704] i2) 3-Bromophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0705]

[0706] Yield 31%. 1HNMR (400 MHz, chloroform-d) δ 7.52 (s, 1H), 7.35 - 7.24 (m, 2H), 7.08 (t, J = 7.9 Hz, 1H), 5.90 (d, J = 5.5 Hz, 1H), 5.38 (d, J = 3.1 Hz, 1H), 5.19 (dd, J = 10.9, 5.5 Hz, 1H), 4.58 - 4.49 (m, 1H), 4.03 (dd, J = 11.6, 5.0 Hz, 1H), 3.97 - 3.81 (m, 2H), 2.08 (d, J = 8.3 Hz, 6H), 1.90 (s, 3H). [C 18 H 20 BrN3O7SNa] + (M+Na) + The calculated value of ESI-MS m / z for

[0707] i3) 3-Ethoxyphenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0708]

[0709] Yield: 29%. 1 H NMR (400 MHz, chloroform-d) δ 7.36 - 7.22 (m, 1H), 7.08 (d, J = 6.7 Hz, 2H), 6.91 - 6.84 (m, 1H), 6.05 (d, J = 5.5 Hz, 1H), 5.54 (d, J = 3.0 Hz, 1H), 5.35 (dd, J = 11.0, 5.5 Hz, 1H), 4.74 (t, J = 6.3 Hz, 1H), 4.19 (dd, J = 11.5, 5.3 Hz, 1H), 4.13 - 3.99 (m, 4H), 2.25 (s, 3H), 2.23 (s, 3H), 2.05 (s, 3H), 1.47 (t, J = 7.0 Hz, 3H). [C 20 H 25 N3O8SNa] + (M+Na) + The calculated value of ESI-MS m / z for

[0710] i4) 4-Pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0711]

[0712] Yield: 29%. 11H NMR (400 MHz, chloroform-d) δ 8.41 (d, J = 6.1 Hz, 2H), 7.31 - 7.24 (m, 2H), 6.20 (d, J = 5.6 Hz, 1H), 5.43 (d, J = 3.1 Hz, 1H), 5.29 (dd, J = 11.0, 5.6 Hz, 1H), 4.54 - 4.41 (m, 1H), 4.08 (dd, J = 11.6, 5.0 Hz, 1H), 4.00 - 3.87 (m, 2H), 2.13 (s, 3H), 2.12 (s, 3H), 1.82 (s, 3H). [C 17 H 21 N4O7S] + (M + H) + The calculated ESI-MS m / z value of [C

[0713] i5) 2,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0714]

[0715] Yield: 39%. 1 1H NMR (400 MHz, chloroform-d) δ 7.57 - 7.45 (m, 2H), 7.26 (dd, J = 8.4, 2.0 Hz, 1H), 6.07 (d, J = 5.5 Hz, 1H), 5.53 (d, J = 2.3 Hz, 1H), 5.35 (dd, J = 11.0, 5.5 Hz, 1H), 4.65 (t, J = 6.2 Hz, 1H), 4.21 - 3.96 (m, 3H), 2.24 (s, 3H), 2.20 (s, 3H), 2.01 (s, 3H). [C 18 H 19 Cl2N3O7SNa] + (M + Na) + The calculated ESI-MS m / z value of [C

[0716] i6) 4-acetanilido 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0717]

[0718] Yield: 56%. 11H NMR (400 MHz, chloroform-d) δ 7.51 - 7.38 (m, 4H), 5.86 (d, J = 5.5 Hz, 1H), 5.47 (d, J = 2.4 Hz, 1H), 5.25 (dd, J = 10.9, 5.5 Hz, 1H), 4.69 (t, J = 6.3 Hz, 1H), 4.15 - 4.06 (m, 1H), 4.04 - 3.93 (m, 2H), 2.19 (s, 3H), 2.17 (s, 3H), 2.15 (s, 3H), 2.02 (s, 3H). [C 20 H 24 [N4O8SNa] + (M + Na) + The calculated ESI-MS m / z value of [N4O8SNa](M + Na): 503.1; the measured value: 503.1.

[0719] i7) 4-Methoxyphenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0720]

[0721] Yield 52%. 1 1H NMR (400 MHz, chloroform-d) δ 7.28 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 8.7 Hz, 2H), 5.68 (d, J = 5.5 Hz, 1H), 5.37 (d, J = 2.6 Hz, 1H), 5.14 (dd, J = 10.9, 5.5 Hz, 1H), 4.61 (t, J = 6.3 Hz, 1H), 4.00 (dd, J = 11.5, 5.5 Hz, 1H), 3.95 - 3.83 (m, 2H), 3.69 (s, 3H), 2.09 (s, 3H), 2.04 (s, 3H), 1.92 (s, 3H). [C 19 H 23 [N3O8SNa] + (M + Na) + The calculated ESI-MS m / z value of [N3O8SNa](M + Na): 476.1; the measured value: 476.0.

[0722] i8) 2,3-Dichlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside glycoside

[0723]

[0724] Yield 29%. 11H NMR (400 MHz, chloroform-d) δ 7.28 (dd, J = 7.9, 1.2 Hz, 1H), 7.20 (dd, J = 8.0, 1.3 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 5.91 (d, J = 5.6 Hz, 1H), 5.31 (d, J = 3.2 Hz, 1H), 5.14 (dd, J = 11.0, 5.6 Hz, 1H), 4.42 (t, J = 6.3 Hz, 1H), 3.97 - 3.75 (m, 3H), 2.01 (s, 3H), 1.98 (s, 3H), 1.76 (s, 3H). [C 18 H 19 Cl2N3O7SNa] + (M+Na) + The calculated ESI-MS m / z for

[0725] i9) 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0726]

[0727] Yield 57%. [C 18 H 19 Cl2N3O7SNa] + (M+Na) + is 514.0; found 513.9.

[0728] i11) 3-methoxyphenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0729]

[0730] Yield 22%. m / z 19 H 23 N3NaO8S] + (M+Na) + The calculated ESI-MS for

[0731] i12) 2-naphthyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0732]

[0733] Yield 22%. [C 22 H 23 N3NaO7S]​​​+ (M+Na) + The calculated ESI-MS m / z value of (M+Na): 496.1; measured value: 496.1.

[0734] i13) 3-Methylphenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0735]

[0736] Yield 46%. [C 19 H 23 N3NaO7S] + (M+Na) + The calculated ESI-MS m / z value of (M+Na): 460.1; measured value: 460.1.

[0737] i14) 3-Trifluoromethylphenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0738]

[0739] Yield 19%. [C 19 H 20 F3N3NaO7S] + (M+Na) + The calculated ESI-MS m / z value of (M+Na): 514.1; measured value: 514.1.

[0740] i15) 4-Bromophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0741]

[0742] Yield 19%. [C 18 H 20 BrN3NaO7S] + (M+Na) + The calculated ESI-MS m / z value of (M+Na): 524.0; measured value: 524.1.

[0743] i16) 3,5-Dichlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0744]

[0745] Yield 15%. [C 18 H 23 C12N4O7S] +(M + NH4) + Calculated ESI-MS m / z for (M + NH4): 509.1; Found: 509.1.

[0746] i22) 3,4-Dichlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-α-D-galactopyranoside

[0747]

[0748] 1,2,4,6-Tetra-O-acetyl-3-azido-3-deoxy-β-D-galactopyranoside (155 mg, 0.42 mmol) was dissolved in 1,2-dichloroethane (5 mL), 3,4-dichlorophenol (131 mg, 0.80 mmol) was added, and then BF3-OEt2 (0.155 mL, 1.26 mmol) was added. The resulting mixture was heated to 60 °C. After 18 h, 3,4-dichlorophenol (138 mg, 0.85 mmol) and BF3-OEt2 (0.155 mL, 1.26 mmol) were added. After 72 h, the resulting mixture was cooled to room temperature, NEt3 (2 mL) was added, and the resulting mixture was concentrated. The residue was purified by flash chromatography using a 6 - 75% EtOAc in petroleum ether solution to give 95 mg (48%) of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-α-D-galactopyranoside as an amorphous white solid. 1 1H NMR (400 MHz, chloroform-d) δ 7.28 (d, J = 8.9 Hz, 1H), 7.15 (d, J = 2.8 Hz, 1H), 6.84 (dd, J = 8.9, 2.8 Hz, 1H), 5.62 (d, J = 3.5 Hz, 1H), 5.41 (d, J = 3.0 Hz, 1H), 5.11 (dd, J = 10.9, 3.5 Hz, 1H), 4.13 (dd, J = 10.8, 3.5 Hz, 2H), 4.03 (dd, J = 11.5, 5.2 Hz, 1H), 3.93 (dd, J = 11.4, 7.6 Hz, 1H), 2.10 (s, 3H), 2.07 (s, 3H), 1.90 (s, 3H). [C 18 H 19 Cl2N3O8Na] + (M + Na) + Calculated ESI-MS m / z for (M + Na): 498.0; Found: 498.0.

[0749] Intermediates i10 and i23 were prepared in a similar manner to i22 from the corresponding aryl thiols.

[0750] i10) Benzyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0751]

[0752] Yield 20%. [C 19 H 23 N3O7SNa] + (M+Na) + Calculated ESI-MS m / z for

[0753] i23) 4-Chlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0754]

[0755] Yield 34%. 1 H NMR (400 MHz, chloroform-d) δ 7.43 - 7.30 (m, 2H), 7.30 - 7.21 (m, 2H), 5.91 (d, J = 5.5 Hz, 1H), 5.45 (d, J = 2.7 Hz, 1H), 5.25 (ddd, J = 11.0, 5.5, 1.3 Hz, 1H), 4.61 (t, J = 6.0 Hz, 1H), 4.08 (ddd, J = 11.5, 5.2, 1.4 Hz, 1H), 4.03 - 3.90 (m, 2H), 2.16 (s, 3H), 2.13 (s, 3H), 1.96 (s, 3H). [C 18 H 20 ClN3O7SNa] + (M+Na) + Calculated ESI-MS m / z for

[0756] i27) Phenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0757] 2,4,6-tri-O-acetyl-3-azido-1-chloro-3-deoxy-β-D-galactopyranoside

[0758]

[0759] To a stirred suspension of 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy-β-D-galactopyranoside (1.0 g, 2.68 mmol) and PCl5 (610 mg, 2.93 mmol) in dry DCM (10 mL) was added BF3-Et2O (15 μL). After stirring for 20 minutes, TLC analysis showed complete disappearance of the starting material. The reaction mixture was diluted with DCM (50 mL), and then successively washed with ice-cold water, ice-cold saturated NaHCO3 solution (2 x 30 mL), and then again with ice-cold water, dried over anhydrous Na2SO4, and evaporated under reduced pressure to give 850 mg of crude 2,4,6-tri-O-acetyl-3-azido-1-chloro-3-deoxy-β-D-galactopyranoside as a white solid. 1 1H NMR (500 MHz, CDCl3) δ 5.48 (dd, J = 3.0, 1.0 Hz, 1H), 5.34 (dd, J = 10.0, 9.0 Hz, 1H), 5.24 (d, J = 8.5 Hz, 1H), 4.18 (dd, J = 11.0, 5.5 Hz, 1H), 4.10 (dd, J = 11.5, 6.5 Hz, 1H), 3.98 (m, 1H), 3.60 (dd, J = 10.0, 3.5 Hz, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 2.07 (s, 3H). [C 12 H 21 N4O8] + (M-Cl+OH+NH4) + ESI-MS m / z calculated for: 349.1; found: 349.1.

[0760]

[0761] At 0 °C, NaH (60 mg, 60% mineral oil solution, 1.67 mmol) was added to a stirred solution of benzenethiol (190 mg, 1.72 mmol) in dry DMF. The resulting mixture was stirred at room temperature for 30 minutes. Then, 2,4,6-tri-O-acetyl-3-azido-1-chloro-3-deoxy-β-D-galactopyranoside (200 mg, 0.57 mmol) was added. The resulting mixture was stirred at 50 °C for 10 hours and then at room temperature overnight. The solvent was removed, the resulting crude product was diluted with DCM, and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography (PE:EtOAc = 2:1) to give 160 mg of a product mixture as a white solid. [α-anomer:β-anomer = 100:8].

[0762] 11H NMR (α-anomer, 500 MHz, CDCl3) δ 7.46 - 7.44 (m, 2H), 7.33 - 7.29 (m, 3H), 5.97 (d, J = 6.0 Hz, 1H), 5.48 (d, J = 2.0 Hz, 1H), 5.28 (dd, J = 11.0, 5.5 Hz, 1H), 4.69 (t, J = 6.5 Hz, 1H), 4.11 (dd, J = 11.0, 6.5 Hz, 1H), 4.03 - 3.97 (m, 2H), 2.19 (s, 3H), 2.16 (s, 3H), 1.97 (s, 3H). [C 18 H 25 N4O7S] + (M + NH4) + The calculated value of ESI-MS m / z for

[0763] i28) 3-chloro-4-fluorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0764]

[0765] At 0 °C, NaH (60 mg, 60% mineral oil solution, 1.67 mmol) was added to a stirred solution of 3-chloro-4-fluorobenzenethiol (280 mg, 1.72 mmol) in dry DMF (4 mL). The resulting mixture was stirred at room temperature for 30 minutes. Then, 2,4,6-tri-O-acetyl-3-azido-1-chloro-3-deoxy-β-D-galactopyranoside (200 mg, 0.57 mmol) was added. The resulting mixture was stirred at 50 °C for 10 hours and then at room temperature overnight. Then, the solvent was removed, and the resulting crude product was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography (PE:EtOAc = 3:1) to give 210 mg of the α-anomer product as a white solid.

[0766] 11H NMR (500 MHz, CDCl3) δ 7.54 (dd, J = 6.5, 2.0 Hz, 1H), 7.33 (m, 1H), 7.10 (t, J = 9.0 Hz, 1H), 5.90 (d, J = 5.5 Hz, 1H), 5.48 (d, J = 2.0 Hz, 1H), 5.26 (dd, J = 11.5, 5.5 Hz, 1H), 4.64 (t, J = 6.0 Hz, 1H), 4.12 (dd, J = 12.0, 5.0 Hz, 1H), 4.02 (dd, J = 12.0, 8.0 Hz, 1H), 3.93 (dd, J = 11.0, 3.5 Hz, 1H), 2.20 (s, 3H), 2.16 (s, 3H), 2.03 (s, 3H). [C 18 H 23 ClFN4O7S] + (M + NH4) + The calculated value of ESI-MS m / z for

[0767] i29) 4-Tolyl 2,4,6-tri-O-acetyl-3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[0768] 4-Tolyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0769]

[0770] To a solution of 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy-β-D-galactopyranoside (200 mg, 0.54 mmol) in 1,2-dichloroethane (10 mL) was added boron trifluoride diethyl etherate (0.4 mL, 3.2 mmol), 3A molecular sieves, and 4-methylbenzenethiol (144 mg, 1.1 mmol), and the resulting solution was stirred at 60 °C for 17 h. TLC (silica gel, PE:EtOAc = 3:1, UV, PMA) analysis showed the total consumption of the starting material. The mixture was filtered, and the filtrate was poured onto saturated NaHCO3 (20 mL) and DCM (50 mL). The organic phase was washed with water (20 mL) and brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was removed to give a residue, which was purified by flash chromatography (silica gel, PE:EtOAc = 3:1) to give 70 mg of 4-tolyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside and 59 mg of the corresponding β-anomer byproduct as a white solid.

[0771] 1 1H NMR (α-isomer, 500 MHz, CDCl3) δ 7.34 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 7.5 Hz, 2H), 5.88 (d, J = 5.5 Hz, 1H), 5.47 (d, J = 2.5 Hz, 1H), 5.26 (dd, J = 6.0, 5.5 Hz, 1H), 4.70 (t, J = 6.0 Hz, 1H), 4.10 (dd, J = 11.5 Hz, 5.0 Hz, 1H), 4.02 - 3.96 (m, 2H), 2.33 (s, 3H), 2.19 (s, 3H), 2.15 (s, 3H), 2.00 (s, 3H). [C 19 H 23 N3O7S] + (M + NH4) + The calculated value of ESI-MS m / z for

[0772] 4-Tolyl 2,4,6-tri-O-acetyl-3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[0773]

[0774] To a dry DMF (5 mL) solution of 4-tolyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (70 mg, 0.16 mmol) were added N,N-diethylethylamine (0.11 mL, 0.8 mmol), copper(I) iodide (9.1 mg, 0.05 mmol), and trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (73 mg, 0.32 mmol), and the resulting solution was stirred at 100 °C for 1 h. The reaction mixture was poured onto water (50 mL) and filtered. The aqueous phase was extracted with ethyl acetate (2 x 50 mL), and the combined organic phases were washed with water (4 x 50 mL) and brine (100 mL) and dried over anhydrous sodium sulfate. The solvent was removed to give a residue, which was purified by flash chromatography (silica gel, PE:EtOAc = 3:1) to give 85 mg of the title compound as a white solid.

[0775] 11H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 7.44 (t, J = 7.0 Hz, 2H), 7.38 (d, J = 7.5 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 6.07 - 6.03 (m, 2H), 5.60 (dd, J = 3.5 Hz, 1.0 Hz, 1H), 5.27 - 5.23 (m, 1H), 4.93 (t, 6.5 Hz, 1H), 4.14 (dd, J = 11.5 Hz, 6.0 Hz, 1H), 4.06 (dd, J = 11.5 Hz, 7.50 Hz, 1H), 2.35 (s, 3H), 2.05 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H). [C 27 H 26 F3N3O7S] + (M + H) + The calculated value of ESI-MS m / z for

[0776] i30) 4-Fluorophenyl 2,4,6-tri-O-acetyl-3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[0777] 4-Fluorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0778]

[0779] To a dry DMF solution (5 mL) of 2,4,6-tri-O-acetyl-3-azido-1-chloro-3-deoxy-β-D-galactopyranoside (200 mg, 0.57 mmol) was added 4-fluorobenzenethiol (219 mg, 1.7 mmol) and sodium hydride (60% mineral oil solution, 68 mg, 1.7 mmol).

[0780] The resulting solution was stirred at 50 °C for 17 h. TLC (silica gel, PE:EtOAc = 3:1, UV, PMA) analysis showed total consumption of the starting material. The reaction mixture was poured onto water (50 mL) and EtOAc (50 mL). The organic phase was washed with water (2 x 50 mL) and brine (50 mL) and dried over anhydrous sodium sulfate. Removal of the solvent gave a residue, which was purified by flash chromatography (silica gel, PE:EtOAc = 3:1) to give 156 mg of 4-fluorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside as a white solid.

[0781] 1 1H NMR (500 MHz, CDCl3) δ 7.46 - 7.43 (m, 2H), 7.04 - 7.00 (m, 2H), 5.87 (d, J = 5.0 Hz, 1H), 5.48 (d, J = 2.5 Hz, 1H), 5.25 (dd, J = 11.5 Hz, 5.5 Hz, 1H), 4.67 (t, J = 6.0 Hz, 1H), 4.10 (dd, J = 11.0 Hz, 5.5 Hz, 1H), 4.03 - 3.95 (m, 2H), 2.20 (s, 3H), 2.16 (s, 3H), 2.01 (s, 3H). [C 18 H 20 [C + FN3O7S] + The calculated value of ESI-MS m / z for (M + NH4): 459.1; the measured value: 459.0.

[0782] 4-Fluorophenyl 2,4,6-tri-O-acetyl-3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[0783]

[0784] To a solution of 2-fluorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (156 mg) in DMF (10 mL) were added triethylamine (179 mg, 1.8 mmol), copper(I) iodide (20 mg, 0.11 mmol), and trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (161 mg, 0.71 mmol). The resulting solution was stirred at 100 °C for 1 h under N2. TLC (silica gel, PE:EtOAc = 3:1, UV, PMA) analysis showed the total consumption of the starting material. Water (50 mL) and EtOAc (50 mL) were added. The mixture was filtered, and the filtrate was extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with water (100 mL) and brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was removed to give a residue. The crude product was purified by flash column chromatography (silica gel, PE:EtOAc = 3:1) to give 150 mg of the product as a white solid.

[0785] 11H NMR (500 MHz, CDCl3) δ 7.77 (m, 1H), 7.51 - 7.42 (m, 4H), 7.07 - 7.04 (m, 2H), 6.07 - 6.02 (m, 2H), 5.60 (dd, J = 2.5 Hz, J = 1.0 Hz, 1H), 5.22 (dd, J = 10.5 Hz, 3.0 Hz, 1H), 4.90 (t, J = 7.0 Hz, 1H), 4.15 - 4.05 (m, 2H), 2.06 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H). [C 26 H 23 F4N3O7S] + (M + H) + The calculated value of ESI-MS m / z for

[0786] i31) 4-(Trifluoromethoxy)phenyl 2,4,6-tri-O-acetyl-3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[0787] Trifluoromethoxyphenyl (2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0788]

[0789] To a dry DMF solution (5 mL) of 2,4,6-tri-O-acetyl-3-azido-1-chloro-3-deoxy-β-D-galactopyranoside (200 mg, 0.57 mmol) was added 4-(trifluoromethoxy)benzenethiol (333 mg, 1.7 mmol) and sodium hydride (60% mineral oil solution, 68 mg, 1.7 mmol), and the solution was stirred at 50 °C for 17 h. TLC (silica gel, PE:EtOAc = 3:1, UV, PMA) analysis showed the total consumption of the starting material. The reaction mixture was poured onto water (50 mL) and EtOAc (50 mL). The organic phase was washed with water (2 x 50 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was removed to give a residue, which was purified by flash chromatography (silica gel, PE:EtOAc = 3:1) to give 117 mg of 4-(trifluoromethoxy)phenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside as a white solid.

[0790] 11H NMR (500 MHz, CDCl3) δ 7.50 - 7.47 (m, 2H), 7.17 - 7.16 (m, 2H), 5.97 (d, J = 6.0 Hz, 1H), 5.48 (d, J = 2.0 Hz, 1H), 5.28 (dd, J = 11.5, 6.0 Hz, 1H), 4.65 (t, J = 6.5 Hz, 1H), 4.13 - 4.10 (m, 1H), 4.03 - 3.95 (m, 2H), 2.19 (s, 3H), 2.17 (s, 3H), 1.97 (s, 3H). [C 19 H 20 F3N3O8S] + (M + NH4) + The calculated value of ESI-MS m / z for

[0791] 4-Trifluoromethoxyphenyl 2,4,6-tri-O-acetyl-3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[0792]

[0793] To a solution of 4-trifluoromethoxyphenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (117 mg, 0.23 mmol) in DMF (10 mL) were added N,N-diethylethylamine (117 mg, 1.1 mmol), copper(I) iodide (13 mg, 0.07 mmol), and trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (105 mg, 0.46 mmol). The resulting solution was stirred at 100 °C for 1 h under N2. TLC (silica gel, PE:EtOAc = 3:1, UV, PMA) analysis showed the total consumption of the starting material. Water (50 mL) and EtOAc (50 mL) were added. The resulting mixture was filtered, and the filtrate was extracted with ethyl acetate (2 x 50 mL). The organic phase was washed with water (20 mL) and brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was removed to give a residue. The crude product was purified by flash column chromatography (silica gel, PE:EtOAc = 3:1) to give 150 mg of 4-trifluoromethoxyphenyl 2,4,6-tri-O-acetyl-3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside as a white solid.

[0794] 11H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 7.55 - 7.52 (m, 2H), 7.45 - 7.42 (m, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.13 (d, J = 6.0 Hz, 1H), 6.08 (dd, J = 11.5 Hz, 5.5 Hz, 1H), 5.61 (d, J = 2.5 Hz, 1H), 5.23 (dd, J = 11.5 Hz, 3.0 Hz, 1H), 4.88 (t, J = 6.5 Hz, 1H), 4.17 - 4.06 (m, 2H), 2.06 (s, 3H), 1.98 (s, 3H), 1.97 (s, 3H). [C 27 H 23 F6N3O8S] + (M + H) + The calculated value of ESI-MS m / z for [C

[0795] Examples i32 - i34 were prepared by a method similar to that of i22 using the corresponding nucleophiles

[0796] i32) Phenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-α-D-galactopyranoside

[0797]

[0798] Yield: 37%. 1 1H NMR (400 MHz, chloroform-d) δ 7.32 (t, J = 8.0 Hz, 2H), 7.10 - 7.06 (m, 3H), 5.77 (d, J = 3.5 Hz, 1H), 5.51 (d, J = 2.9 Hz, 1H), 5.22 (dd, J = 10.9, 3.5 Hz, 1H), 4.36 - 4.25 (m, 2H), 4.14 (dd, J = 11.4, 5.7 Hz, 1H), 4.01 (dd, J = 11.4, 7.2 Hz, 1H), 2.19 (s, 3H), 2.16 (s, 3H), 1.95 (s, 3H). [C 18 H 21 N3O8Na] + (M + Na) + The calculated value of ESI-MS m / z for [C

[0799] i33) 3-Chlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-α-D-galactopyranoside

[0800]

[0801] Yield: 27%. 1 H NMR (400 MHz, chloroform-d) δ 7.31 - 7.23 (m, 1H), 7.22 - 7.14 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.99 (dd, J = 8.3, 1.4 Hz, 1H), 5.77 (d, J = 3.4 Hz, 1H), 5.56 - 5.50 (m, 1H), 5.24 (dd, J = 10.9, 3.5 Hz, 1H), 4.32 - 4.25 (m, 2H), 4.16 (dd, J = 11.4, 5.3 Hz, 1H), 4.06 (dd, J = 11.4, 7.6 Hz, 1H) 2.22 (s, 3H), 2.19 (s, 3H), 2.01 (s, 3H). [C 18 H 20 ClN3O8Na] + (M+Na) + The calculated value of ESI-MS m / z for

[0802] i34) 4-chlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-α-D-galactopyranoside

[0803]

[0804] Yield: 52%. 1 H NMR (400 MHz, chloroform-d) δ 7.28 (d, J = 9.0 Hz, 2H), 6.78 (d, J = 8.9 Hz, 2H), 5.73 (d, J = 3.5 Hz, 1H), 5.51 (d, J = 2.9 Hz, 1H), 5.21 (dd, J = 10.9, 3.5 Hz, 1H), 4.31 - 4.23 (m, 2H), 4.14 (dd, J = 11.4, 5.6 Hz, 1H), 4.02 (dd, J = 11.4, 7.3 Hz, 1H), 2.19 (s, 3H), 2.17 (s, 3H), 1.98 (s, 3H). [C 18 H 20 ClN3O8Na] + (M+Na) + The calculated value of ESI-MS m / z for

[0805] Examples i35 - i38 were prepared using a method similar to i1 with the corresponding nucleophiles.

[0806] i35) cyclohexyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-α-D-galactopyranoside

[0807]

[0808] The yield is 6%. 1 H NMR (400 MHz, chloroform-d) δ 5.82 (d, J = 5.6 Hz, 1H), 5.41 (d, J = 2.4 Hz, 1H), 5.18 (dd, J = 10.9, 5.6 Hz, 1H), 4.57 (t, J = 6.3 Hz, 1H), 4.12 (dd, J = 11.5, 5.5 Hz, 1H), 4.03 (dd, J = 11A, 7.3 Hz, 1H), 3.88 (dd, J = 10.9, 3.3 Hz, 1H), 2.83 - 2.73 (m, 1H), 2.15 (s, 3H), 2.14 (s, 3H), 2.05 (s, 3H), 2.03 - 1.23 (m, 10H). [C 18 H 27 N3O7SNa] + (M + Na) + The calculated value of ESI-MS m / z for [C

[0809] i36) 2,4,5-Trichlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-α-D-galactopyranoside

[0810]

[0811] The yield is 50%. 1 H NMR (400 MHz, chloroform-d) δ 7.66 (s, 1H), 7.53 (s, 1H), 6.06 (d, J = 5.6 Hz, 1H), 5.49 (d, J = 2.9 Hz, 1H), 5.31 (dd, J = 11.0, 5.6 Hz, 1H), 4.58 (dd, J = 7.3, 5.2 Hz, 1H), 4.11 (dd, J = 11.7, 4.9 Hz, 1H), 4.06 - 3.96 (m, 2H), 2.20 (s, 3H), 2.17 (s, 3H), 1.98 (s, 3H). [C 18 H 18 N3O7SNa] + (M + Na) + The calculated value of ESI-MS m / z for [C

[0812] i37) 2,5-Dichlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0813]

[0814] The yield is 40%.[C 18 H 19 Cl2N3O7SNa] + (M+Na) + The calculated ESI-MS m / z value of (M+Na): 514.0; the measured value: 513.9.

[0815] i38) 3-Hydroxyphenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0816]

[0817] It was not isolated but directly used in the next step.[C 18 H 21 N3NaO8S] + (M+Na) + The calculated ESI-MS m / z value of (M+Na): 462.1; the measured value: 462.1.

[0818] i40) 2-Phenylethyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0819]

[0820] At 0 °C, 2-phenylethylsulfuric acid (220 mg, 1.59 mmol) and BF3·Et2O (0.4 mL, 3.24 mmol) were added to a stirred suspension of 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy-β-D-galactopyranoside (200 mg, 0.54 mmol) in dry CH2Cl2 (5 mL). The resulting mixture was stirred at 15 °C overnight. After dilution with CH2Cl2 (40 mL), the mixture was washed with saturated NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (PE:EtOAc = 3:1) to give 81 mg of 2-phenylethyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside as a white solid. 11H NMR (500 MHz, CDCl3) δ 7.31 - 7.17 (m, 5H), 5.75 (d, J = 6.0 Hz, 1H), 5.41 (d, J = 2.5 Hz, 1H), 5.21 (dd, J = 11.0, 5.5 Hz, 1H), 4.49 (t, J = 6.0 Hz, 1H), 4.12 (dd, J = 11.0, 5.0 Hz, 1H), 4.03 (dd, J = 11.5, 7.5 Hz, 1H), 3.66 (dd, J = 11.0, 4.0 Hz, 1H), 2.92 - 2.74 (m, 4H), 2.17 (s, 3H), 2.16 (s, 3H), 2.13 (s, 3H). [C 20 H 25 N3NaO7S] + (M + Na) + The calculated ESI-MS m / z value of [C

[0821] i41) 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-O-[(4-chlorophenyl)-4-oxo-2-butynyl]-1-thio-α-D-galactopyranoside

[0822] 1,2,3,4,6-penta-O-acetyl-β-D-galactopyranoside

[0823]

[0824] A suspension of anhydrous sodium acetate (13.7 g, 16.7 mmol) and acetic anhydride (20 mL) was refluxed for 5 minutes. After adding D-(+)-galactose (3.0 g, 16.7 mmol), refluxing was continued for 30 minutes. The hot solution was poured onto ice water (300 mL), and the resulting mixture was extracted with DCM (3 x 150 mL). It was dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. Then, the crude product was recrystallized from hexane / EtOAc (2:1) to give 4.2 g (64.6%) of 1,2,3,4,6-penta-O-acetyl-β-D-galactopyranoside as a white solid.

[0825] 1 1H NMR (500 MHz, CDCl3) δ 5.70 (d, J = 8.3 Hz, 1H), 5.43 (d, J = 2.6 Hz, 1H), 5.34 (dd, J = 10.4, 8.4 Hz, 1H), 5.08 (dd, J = 10.4, 3.4 Hz, 1H), 2.17 (s, 3H), 2.13 (s, 3H), 2.08 - 1.98 (m, 9H).

[0826] 1-Chloro-2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside

[0827]

[0828] To a stirred suspension of 1,2,3,4,6-penta-O-acetyl-β-D-galactopyranoside (2.3 g, 5.9 mmol) and PCl5 (1.35 g, 6.5 mmol) in dry CH2Cl2 (20 mL) was added BF3Et2O (34 mg, 0.29 mmol). After stirring for 30 minutes, the reaction mixture was diluted with CH2Cl2 (120 mL), then washed with ice-cold water (60 mL), ice-cold saturated NaHCO3 solution (2 x 50 mL), and again with ice-cold water (2 x 30 mL), dried over anhydrous Na2SO4, and evaporated under reduced pressure. The residue was co-evaporated with toluene to give 2.1 g (97.2%) of 1-chloro-2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside as a colorless oil.

[0829] 1 1H NMR (500 MHz, CDCl3) δ 5.42 (ddd, J = 19.0, 6.7, 4.9 Hz, 2H), 5.33 - 5.23 (m, 1H), 5.02 (dd, J = 10.2, 3.4 Hz, 1H), 4.17 (d, J = 6.5 Hz, 2H), 4.06 - 3.97 (m, 1H), 2.19 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H).

[0830] 3,4-Dichlorophenyl 2,3,4,6-tetra-O-acetyl-1-thio-α-D-galactopyranoside

[0831]

[0832] Suspend NaH (60% mineral oil solution, 338 mg, 14.7 mmol) in DMF (20 mL). Add 3,4-dichlorobenzenethiol (2.9 g, 16.3 mmol). After 30 minutes, add 1-chloro-2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside (3.0 g, 8.2 mmol). Heat the resulting mixture to 50 °C and keep it for 20 hours. Dilute the mixture with CH2Cl2 (100 mL), citric acid (0.5 M, 20 ml) and water (20 mL). Wash the organic phase with water (3 x 30 mL) and concentrate. Purify the crude product by silica gel column chromatography (PE:EtOAc = 3:1) to obtain 2.7 g (66%) of 3,4-dichlorophenyl 2,3,4,6-tetra-O-acetyl-1-thio-α-D-galactopyranoside as a white solid.

[0833] 1 H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 2.1 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.32 (d, 1H), 5.99 (d, J = 5.6 Hz, 1H), 5.50 (d, J = 2.4 Hz, 1H), 5.35 (dd, J = 11.0, 5.6 Hz, 1H), 5.25 (dd, J = 11.0, 3.3 Hz, 1H), 4.67 (t, J = 6.2 Hz, 1H), 4.13 - 4.04 (m, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H).

[0834] 3,4-dichloro-phenyl 1-thio-α-D-galactopyranoside

[0835]

[0836] Add NaOMe (29 mg, 0.53 mmol) to a methanol (30 ml) solution of 3,4-dichlorophenyl 2,3,4,6-tetra-O-acetyl-1-thio-α-D-galactopyranoside (2.7 g, 5.3 mmol). Stir the resulting solution at room temperature for 5 hours. After completion, neutralize the resulting mixture (pH = 7) with DOWEX 50w x 8 - 200 ion exchange resin and filter. Concentrate the filtrate to obtain a residue. Crystallize the product from CH2Cl2 (80 mL) to obtain 1.7 g (94%) of 3,4-dichloro-phenyl-1-thio-α-D-galactopyranoside as a white solid. [C 12 H 18 C12NO5S] + (M+NH4) +Calculated ESI-MS m / z value: 358.0; measured value: 358.0.

[0837] 3,4-Dichlorophenyl 3-O-propargyl-1-thio-α-D-galactopyranoside

[0838]

[0839] To a dry methanol (30 ml) solution of 3,4-dichlorophenyl 1-thio-α-D-galactopyranoside (1.2 g, 3.5 mmol) was added dibutyl(tin) oxide (1.0 g, 4.2 mmol). The resulting mixture was refluxed at 70 °C for 6 h. The reaction mixture became transparent. The solvent was evaporated and dried in vacuo. 1,4-Dioxane (50 mL), tetrabutylammonium iodide (1.3 g, 3.5 mmol) and methyl 2-bromoacetate (4.2 g, 35.2 mmol) were added and the reaction was carried out on the mixture, heating was continued at 105 °C for 1 night. The mixture was concentrated and purified by combiflash (EtOAc:PE = 4:1, ISCO 40 g, 40 ml / min, normal phase silica gel, uv254) to give 520 mg (39%) of 3,4-dichlorophenyl 3-O-propargyl-1-thio-α-D-galactopyranoside as a white solid. 1 HNMR (500 MHz, DMSO-d6) δ 7.75 (d, J = 2.1 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.45 (dd, J = 8.4, 2.1 Hz, 1H), 5.69 (d, J = 5.5 Hz, 1H), 5.54 (d, J = 4.7 Hz, 1H), 4.80 (d, J = 5.3 Hz, 1H), 4.65 (t, J = 5.6 Hz, 1H), 4.31 (qd, J = 16.0, 2.4 Hz, 2H), 4.15 (dt, J = 10.1, 5.1 Hz, 1H), 4.07 - 3.91 (m, 2H), 3.62 - 3.40 (m, 3H), 3.40 - 3.27 (m, 2H).

[0840] 3,4-Dichlorophenyl 2,4,6-tri-O-acetyl-3-O-propargyl-1-thio-α-D-galactopyranoside

[0841]

[0842] To a solution of 3,4-dichlorophenyl 3-O-propargyl-1-thio-α-D-galactopyranoside (520 mg, 1.37 mmol) in anhydrous pyridine (10 mL) was added acetic anhydride (1.4 g, 13.7 mmol) dropwise. The reaction mixture was stirred at 10 °C for 20 h under nitrogen. The resulting mixture was concentrated under reduced pressure and the residue was co-evaporated with toluene. The residue was purified by silica gel column chromatography (PE:EtOAc = 2:1) to give 530 mg (76.5%) of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-O-propargyl-1-thio-α-D-galactopyranoside as a yellow oil. [C 21 H 26 C12NO8S] + (M+NH4) + The calculated ESI-MS m / z for

[0843] 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-O-[(4-chlorophenyl)-4-oxo-2-butynyl]-1-thio-α-D-galactopyranoside

[0844]

[0845] To a solution of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-O-[(4-chlorophenyl)-4-oxo-2-butynyl]-1-thio-α-D-galactopyranoside (200 mg, 0.4 mmol) in tetrahydrofuran (15 mL) were added benzoyl chloride (69 mg, 0.4 mmol), copper(I) iodide (15 mg, 0.08 mmol), and PdCl2(PPh3)2Cl2 (29 mg, 0.04 mmol). The resulting mixture was purged with N2 three times. Then, the mixture was stirred at 10 °C for 20 min. Et3N (40 mg, 0.4 mmol) was added to the reaction by syringe. Then, the mixture was stirred at 10 °C for an additional 20 h. The reaction was quenched with water (20 mL), extracted with dichloromethane (3 x 50 mL), and the aqueous phase was removed. The extract was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by combiflash (EtOAc:PE = 1:20 to 1:5, ISCO, 40 g, 40 ml / min, normal phase, silica gel, uv 254) to give 160 mg (62.8%) of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl

[0846] -3-O-[(4-chlorophenyl)-4-oxo-2-butynyl]-1-thio-α-D-galactopyranoside as a yellow oil.

[0847] [C 28 H 29 C13NO9S] + (M + NH4) + The calculated ESI-MS m / z value of (M + NH4): 660.1; measured value: 660.0.

[0848] Examples 42 - 53 were prepared using intermediates i42 - i53.

[0849] Example 42

[0850] 3,4 - Dichlorophenyl 3 - deoxy - 3 - [4 - (2,3,4,5,6 - pentafluorophenyl)-1H - 1,2,3 - triazol - 1 - yl]-α - D - galactopyranosyl sulfoxide

[0851]

[0852] Dissolve 3,4 - dichlorophenyl 3 - deoxy - 3 - [4 - (2,3,4,5,6 - pentafluorophenyl)-1H - 1,2,3 - triazol - 1 - yl]-1 - thio - α - D - galactopyranoside (60 mg) of Example 52 in CH2Cl2 (30 mL), and cool with an ice / water bath. Dissolve meta - chloroperbenzoic acid (30 mg) in CH2Cl2 (5 mL), and add it to the first solution. Remove the cold water bath. Stir the mixture for 30 minutes. Add 30 mL of water and 5 mL of saturated aqueous NaHCO3. Separate the mixture, and concentrate the organic phase in vacuo. Purify the residue by HPLC. Freeze - dry to obtain 14 mg of the title compound as a white solid. 1 H NMR (400 MHz, methanol - d4) δ 8.48 (s, 1H), 8.03 (t, J = 1.1 Hz, 1H), 7.76 (d, J = 1.1 Hz, 2H), 5.64 (dd, J = 11.2, 2.8 Hz, 1H), 5.15 (dd, J = 11.2, 5.6 Hz, 1H), 4.95 (d, J = 5.6 Hz, 1H), 4.32 - 4.27 (m, 1H), 4.17 (t, J = 6.0 Hz, 1H), 3.61 - 3.45 (m, 2H). [C 20 H 15 Cl2F5N3O5S] + (M + H) + The calculated ESI-MS m / z value of (M + H): 574.00; measured value: 573.95.

[0853] Example 43

[0854] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0855]

[0856] 5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside i43 (450 mg, 0.73 mmol) was dissolved in sodium methoxide / methanol (0.05 M, 20 mL). The reaction mixture was stirred at room temperature for 2 h, then DOWEX 50wx 8-200 ion exchange resin was added to neutralize (pH 7). The reaction mixture was filtered and the filtrate was concentrated to give a crude product, which was purified by preparative HPLC. An appropriate amount of the product was combined and freeze-dried to give the title compound as a white solid (220 mg, 61.80%).

[0857] 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.50 (d, J = 2 Hz, 1H), 8.39 (d, J = 2 Hz, 1H), 8.05 (t, 1H), 7.73 - 7.69 (m, 2H), 5.84 (dd, J = 12.8, 4.8 Hz, 2H), 5.40 (d, J = 6.4 Hz, 1H), 4.73 - 4.70 (m, 1H), 4.61 (dt, J = 11.2, 5.3 Hz, 2H), 4.12 (t, J = 6.0 Hz, 1H), 3.90 (s, 1H), 3.37 (dd, J = 11.2, 5.6 Hz, 1H), 3.36 - 3.26 (m, 1H). [C 19 H 16 ClF3N4O4S][M + H] + Calculated m / z for [C

[0858] Example 44

[0859] 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0860]

[0861] Dissolve 5-bromo-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (910 mg) in MeOH (10.0 mL), and then add sodium methoxide (7.46 mg, 0.14 mmol). Stir the resulting mixture at room temperature for 1 h, acidify to pH 5 - 6 using dowex 50wx8 hydrogen form resin. Filter the reaction mixture, wash with MeOH (20 mL), concentrate in vacuo to give the crude product, and purify the crude product by preparative-HPLC to give the title compound (445 mg, 60.5% yield).

[0862] 1 H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 8.65 (dd, J = 24.1, 1.7 Hz, 2H), 8.39 - 8.23 (m, 1H), 7.96 - 7.74 (m, 2H), 6.09 - 5.90 (m, 2H), 5.55 (d, J = 6.3 Hz, 1H), 4.91 - 4.80 (m, 1H), 4.80 - 4.67 (m, 2H), 4.27 (t, J = 6.1 Hz, 1H), 4.04 (d, J = 3.7 Hz, 1H), 3.61 - 3.48 (m, 1H), 3.47 - 3.38 (m, 2H). [C 19 H 16 BrF3N4O4S] + (M + H) + The calculated value of ESI-MS m / z for

[0863] Example 45

[0864] 3-chloro-5-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0865]

[0866] Add TEA (6.6 mL) to a solution of 3-chloro-5-cyanophenyl-2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside i45 (120.00 mg, 47.48 mmol) in methanol (11 mL) and water (2.2 mL). After completion, evaporate the reaction mixture to dryness, and purify the residue by preparative HPLC to give the title compound as a white solid (20 mg, 15%).

[0867] 1 1H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 8.05 - 7.95 (m, 2H), 7.95 - 7.91 (m, 1H), 7.91 - 7.77 (m, 2H), 6.10 (d, J = 5.1 Hz, 1H), 5.97 (d, J = 4.8 Hz, 1H), 5.55 (d, J = 6.3 Hz, 1H), 4.87 - 4.69 (m, 3H), 4.24 - 4.16 (m, 1H), 4.05 - 4.00 (m, 1H), 3.55 - 3.48 (m, 1H), 3.44 - 3.38 (m, 1H).

[0868] [C 21 H 16 ClF3N4O4S] + (M + H) + Calculated m / z for: 513.0; Found: 513.0.

[0869] Example 46

[0870] 3 - Chloro - 4 - cyanophenyl 3 - deoxy - 3 - [4 - (3,4,5 - trifluorophenyl)-1H - 1,2,3 - triazol - 1 - yl]-1 - thio - α - D - galactopyranoside

[0871]

[0872] 3 - Chloro - 4 - cyanophenyl 2,4,6 - tri - O - acetyl - 3 - azido - 3 - deoxy - 1 - thio - α - D - galactopyranoside i46 (98 mg, 0.20 mmol) was dissolved in acetonitrile (5 mL) and stirred under argon at room temperature. Copper(I) iodide (43 mg, 0.23 mmol) was added. After 5 minutes, 1,2,3 - trifluoro - 5 - [2 - (trimethylsilyl)ethynyl]benzene (0.085 mL, 0.41 mmol) was added. After another 5 minutes, DIEA (0.040 mL, 0.23 mmol) was added and the mixture was heated to 70 °C. After 2.5 h, the reaction mixture was washed with EtOAc, filtered through a short silica gel column, and then concentrated. The residue was dissolved in methanolic sodium methoxide (0.05 M, 30 mL) and stirred at room temperature. After 18 h, acetic acid (2 mL) was added and the resulting mixture was concentrated. The crude product was purified by preparative HPLC and lyophilized to give 46 mg (44%) of the title compound. 1HNMR (400 MHz, methanol-d4) δ 8.55 (s, 1H), 7.85 (s, 1H), 7.74 - 7.61 (m, 4H), 6.11 (d, J = 4.8 Hz, 1H), 5.05 - 4.94 (m, 2H), 4.38 (t, J = 6.0 Hz, 1H), 4.20 (s, 1H), 3.77 - 3.66 (m, 2H). [C 22 H 16 ClF3N4O4S] + (M + H) + The calculated ESI-MS m / z value of

[0873] Example 47

[0874] 3-chloro-6-fluoro-4-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0875]

[0876] At 0 °C, triethylamine (3 mL) and H2O (1 mL) were added to a stirred solution of 3-chloro-6-fluoro-4-cyanophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside i47 (150 mg, 0.23 mmol) in MeOH (5 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give 20 mg of the title compound.

[0877] 1 H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 8.11 - 8.03 (m, 2H), 7.92 - 7.78 (m, 2H), 6.29 (d, J = 5.5 Hz, 1H), 6.19 - 6.09 (m, 1H), 5.69 - 5.51 (m, 1H), 4.95 - 4.88 (m, 1H), 4.86 - 4.77 (m, 1H), 4.73 - 4.60 (m, 1H), 4.13 - 3.95 (m, 2H), 3.52 - 3.43 (m, 2H).

[0878] [C 21 H 16 ClF4N4O4S] +( M + H) + The calculated ESI-MS m / z value of

[0879] Example 48

[0880] 3-Bromo-4-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0881]

[0882] Dissolve 3-bromo-4-cyanophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (100 mg) in MeOH (4 mL). Add TEA (2.4 mL) and H2O (0.8 mL). Stir the mixture overnight at room temperature, then purify by preparative HPLC to obtain 20 mg (24.5%) of the title compound as a white solid.

[0883] 1 H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 8.03 (d, J = 1.6 Hz, 1H), 7.94 - 7.80 (m, 3H), 7.69 (dd, J = 8.3, 1.6 Hz, 1H), 6.20 (d, J = 5.0 Hz, 1H), 6.00 (d, J = 4.6 Hz, 1H), 5.58 (d, J = 6.3 Hz, 1H), 4.92 - 4.72 (m, 2H), 4.69 (t, J = 5.6 Hz, 1H), 4.14 (t, J = 6.3 Hz, 1H), 4.02 (d, J = 4.4 Hz, 1H), 3.59 - 3.50 (m, 1H), 3.43 - 3.37 (m, 2H).

[0884] [C 21 H 17 BrF3N4O4S] + (M + H) + The calculated value of ESI-MS m / z for

[0885] Example 49

[0886] 5-Bromo-6-trifluoromethyl-pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0887]

[0888] At room temperature, sodium methoxide (0.67 mg, 0.01 mmol) was added to a solution of 5-bromo-6-trifluoromethyl-pyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside i49 (90 mg, 0.12 mmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified to pH 5 - 6 using dowex 50wx8 hydrogen form resin. The solution was filtered and washed with MeOH (20 mL), then concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give the title compound (12.77 mg, 17% yield).

[0889] 1 H NMR (400 MHz, MeOD) δ 8.65 (d, J = 1.8 Hz, 1H), 8.46 (s, 1H), 8.43 - 8.38 (m, 1H), 7.69 - 7.46 (m, 2H), 6.03 (d, J = 5.1 Hz, 1H), 5.00 - 4.85 (m, 2H), 4.31 (t, J = 6.1 Hz, 1H), 4.10 (d, J = 1.8 Hz, 1H), 3.68 - 3.54 (m, 2H).

[0890] [C 20 H 15 BrF6N4O4S](M + H) + The calculated value of ESI-MS m / z for is 600.0; the measured value is 601.0..

[0891] Example 50

[0892] 5-chloro-6-cyano-pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0893]

[0894] TEA (0.3 mL) was added to a solution of 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside i50 (12.00 mg, 0.02 mmol) in methanol (0.5 mL) and water (0.1 mL). After the reaction was completed, the reaction mixture was evaporated to dryness, and the residue was purified by preparative HPLC to give the title compound (1.27 mg).

[0895] [C 20 H15 ClF3N5O4S] + [M+H] + Calculated m / z for [M+H]: 514.0; Found: 514.0.

[0896] 1 H NMR (400 MHz, MeOD) δ 8.62 (d, J = 2 Hz, 1H), 8.46 (s, 1H), 8.40 (d, J = 2 Hz, 1H), 7.56 (m, 2H), 6.11 (d, J = 1.2 Hz, 1H), 4.95 (dd, J = 11.6, 2.8 Hz, 1H), 4.88 (dd, J = 11.2, 5.2 Hz, 1H), 4.25 (t, J = 12, 6 Hz, 1H), 4.08 (d, J = 1.6 Hz, 1H), 3.60 (d, J = 6 Hz, 2H).

[0897] Example 51

[0898] 5-Chloro-6-cyano-pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0899]

[0900] To a solution of acetyl chloride (0.5 ml) in methanol was added 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside i51 (15 mg). The reaction mixture was stirred at room temperature for 4 h. Purification by preparative-TLC (DCM / MeOH = 15 / 1) gave 0.95 mg of the title compound.

[0901] [C 19 H 14 ClF3N6O4S] + [M+H] + Calculated m / z for [M+H]: 515.0; Found: 515.0.

[0902] 1 H NMR (400 MHz, MeOD) δ 8.60 (s, 1H), 8.30 (s, 1H), 7.68 (dd, J = 8.8, 6.8 Hz, 2H), 7.56 (d, J = 4 Hz, 1H), 5.11 (d,.7 = 3.6 Hz, 2H), 4.20 (m, 2H), 3.71 (m, 2H).

[0903] Example 52

[0904] 3,4-Dichlorophenyl 3-deoxy-1-thio-3-[4-(2,3,4,5,6-pentafluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[0905]

[0906] Dissolve 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (214 mg) in MeCN (10 mL). Add copper(I) iodide (15 mg) and pentafluorophenylacetylene (0.130 mL), and degas the resulting mixture (nitrogen). After 5 minutes, add DIEA (0.300 mL), and stir the resulting mixture overnight. Filter the reaction mixture through a small silica plug and concentrate in vacuo. Suspend the residue in MeOH (40 mL). Add 1 M sodium methoxide in MeOH (1 mL) solution. Stir for 2 hours at room temperature, add acetic acid (1 mL), and concentrate the resulting mixture in vacuo. Dissolve the residue in a small amount of MeCN / water, filter, and purify by HPLC (C 18 / H2O:MeCN:0.1% TFA). Lyophilize to give the title compound (174 mg) as a white powder. 1 H NMR (400 MHz, methanol-d4) δ 8.49 (d, J = 1.6 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.57 - 7.44( m , 2H), 5.85 (d, J = 5.3 Hz, 1H), 5.06 (dd, J = 11.4, 2.8 Hz, 1H), 4.93 (dd, J = 11.4, 5.4 Hz, 1H), 4.50 (t, J = 6.0 Hz, 1H), 4.23 (s, 1H), 3.79 - 3.64 (m, 2H). [C 20 H 15 Cl2F5N3O4S] + (M + H) + The calculated value of ESI-MS m / z for

[0907] Example 53

[0908] 3,4-Dichlorophenyl 3-deoxy-3-[4-(2,3,4,5,6-pentafluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactosyl sulfone

[0909]

[0910] After purification by HPLC, 7 mg of the title compound of Example 42 was isolated.

[0911] 1 1H NMR (400 MHz, methanol-d4) δ 8.50 (s, 1H), 8.03 (t, J = 8.4, 2.1 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 5.82 (dd, J = 11.4, 2.8 Hz, 1H), 5.34 (d, J = 6.4 Hz, 1H), 5.15 (dd, J = 11.5, 6.4 Hz, 1H), 4.53 (t, J = 6.0 Hz, 1H), 4.31 (s, 1H), 3.60 (qd, J = 11.5, 6.0 Hz, 2H).

[0912] [C 20 H 15 Cl2F5N3O6S] + (M+H) + The calculated value of ESI-MS m / z for [C

[0913] Example 54

[0914] 5-Methoxy-6-cyano-pyridazin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0915]

[0916] After purification by the preparation-TLC (DCM / MeOH = 15 / 1) of Example 51, 0.5 mg of the title compound was isolated. [C 20 H 17 F3N6O5S] + [M+H] + The calculated value of m / z for [C

[0917] 1 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.56 (dd, J = 8.8, 6.8 Hz, 2H), 7.49 (s, 1H), 6.32 (d, J = 4 Hz, 1H), 4.95 (m, 2H), 4.14 (m, 1H), 4.08 (m, 4H), 3.59 (d, J = 6 Hz, 1H).

[0918] Example 55

[0919] 5-Hydroxy-6-cyano-pyridazin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0920]

[0921] To a methanol solution of acetyl chloride (2 ml) was added 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside i50 (40 mg). The reaction was stirred at room temperature for 4 h. The reaction mixture was concentrated and purified by preparative HPLC to give 7 mg of the title compound.

[0922] [C 19 H 15 F3N6O5S] + [M+H] + Calculated m / z for

[0923] 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.68 (dd, J = 8.8, 6.4 Hz, 2H), 7.28 (s, 1H), 6.35 (d, J = 4 Hz, 1H), 7.50 (d, J = 4 Hz, 2H), 4.27 (t, J = 12.4, 6 Hz, 1H), 4.22 (s, 1H), 3.75 - 3.73 (m, 2H).

[0924] Synthesis of intermediates i43 - i51

[0925] i43) 5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0926] O-[(5-Chloro-3-pyridinyl)] N,N-dimethylcarbamothioate

[0927]

[0928] At 0 °C, NaH (1.90 g, 0.10 mol) was added to a solution of 5-chloropyridin-3-ol (10 g, 0.10 mol) in N,N-dimethylformamide (200 mL). The reaction mixture was stirred at 0 °C for 30 minutes, then dimethylthiocarbamoyl chloride (10.50 g, 0.10 mol) was added, and then the mixture was stirred at room temperature for 20 hours. The reaction was quenched with water (500 mL) and extracted with dichloromethane (500 mL × 3). The combined organic phases were washed with brine (400 mL × 3), dried over Na2SO4, filtered, and the solvent was removed in vacuo. The crude product was purified by chromatography on combiflash (EtOAc:PE = 1:5) to give 6.2 g (28.7%) of O-[(5-chloro-3-pyridinyl)]N,N-dimethylcarbamothioate as a brown oil. [C8H9ClN2OS] + [M+H] + Calculated m / z for: 217.0; Found: 217.0.

[0929] S-[(5-chloro-3-pyridinyl)]N,N-dimethylcarbamothioate

[0930]

[0931] O-[(5-chloro-3-pyridinyl)]N,N-dimethylcarbamothioate (6.2 g, 28.7 mmol) was dissolved in diphenyl ether (30 mL) and added to 5 mL of refluxing diphenyl ether. After 2 hours, the reaction mixture was cooled, passed through 200 g of SiO2 to remove diphenyl ether, and then eluted with PE:EtOAc = 1:2 to give S-[(5-chloro-3-pyridinyl)]N,N-dimethylcarbamothioate as a yellow solid. [C8H9ClN2OS] + [M+H] + Calculated m / z for: Found: 217.0.

[0932] 5-chloropyridine-3-thiol

[0933]

[0934] Dissolve S-[(5-chloro-3-pyridyl)] N,N-dimethylthiocarbamate (3.5 g, 16.20 mmol) and NaOH (3.24 g, 81 mmol) in 160 mL of ethanol / water = 3:1, and reflux for 2 hours. Concentrate the reaction mixture to approximately 100 mL. Add EtOAc (300 mL), and adjust the pH to approximately 6 with HCl (2 M). Separate the organic layer, dry over Na2SO4, concentrate, and purify by chromatography using combiflash (EtOAc:PE = 1:5 to 1:2, ISCO, 40 g, 40 ml / min, normal-phase silica gel, uv254) to obtain 2.0 g (85%) of 5-chloropyridine-3-thiol as a yellow oil. [C5H4ClNS] - [M-H] - Calculated m / z for

[0935] 5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0936]

[0937] Suspend NaH (303.44 mg, 7.58 mmol) in DMF (25 mL). Add 5-chloropyridine-3-thiol (1000 mg, 6.89 mmol). After 30 minutes, add 3-azido-3-deoxy 2,4,6-tri-O-acetyl-1-chloro-β-D-galactopyranoside (1923.68 mg, 5.51 mmol). Heat the mixture to 50 °C and maintain for 3 hours. Dilute the mixture with DCM (150 mL), 0.5 M citric acid (150 mL), and water (150 mL). Wash the organic phase with water (100 mL) and concentrate. Purify the residue by column chromatography (PE:EtOAc = 3:1) to obtain 900 mg (28.52%) of the title compound as a white solid. [C 17 H 19 ClN4O7S] + [M+H] + Calculated m / z for

[0938] 1,3-dideoxy-2,4,6-tri-O-acetyl-1-(5-chloropyridin-3-yl-thio)-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[0939]

[0940] To a solution of 5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (600 mg, 1.30 mmol) in N,N-dimethylformamide (16 mL) was added trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (597.00 mg, 2.62 mmol) and copper(I) iodide (74.70 mg, 0.4 mmol). The reaction vessel was purged with nitrogen three times. After the reaction was completed, the reaction was quenched with water (100 mL), and the reaction mixture was extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with brine (50 mL × 1), dried over Na2SO4, filtered, and the solvent was evaporated in vacuo. The crude product was purified by combiflash (EtOAc:PE = 1:10 - 1:2, ISCO 40 g, 40 ml / min, normal phase silica gel, UV254) to give 450 mg (56%) of the title compound as a yellow solid. [C 25 H 22 ClF3N4O7S] + [M+H] + Calculated m / z for: 615.0; Found: 615.0.

[0941] i44) 5-Bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0942] O-[(5-Bromo-3-pyridinyl)] N,N-dimethylcarbamothioate

[0943]

[0944] At 0 °C, sodium hydride (2.64 g, 0.11 mol, 96% mineral oil solution) was added to a solution of 5-bromopyridin-3-ol (17.4 g, 0.10 mol) in DMF (0.15 L), and then the mixture was stirred at 0 °C for 30 minutes. Dimethylthiocarbamoyl chloride (14.83 g, 0.12 mol) was added to the reaction mixture, and then the mixture was stirred overnight at room temperature. LC-MS analysis showed the formation of the target compound. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography on Biotage (EtOAc / PE = 5% - 40%, ISCO 120 g, 50 mL / min, normal-phase silica gel, uv254) to give the target compound O-[(5-bromo-3-pyridyl)] N,N-dimethylthiocarbamate (9.93 g, 36.5% yield) as a yellow oil. [C8H9BrN2OS] + [M+H] + The calculated ESI-MS m / z value of

[0945] S-[(5-bromo-3-pyridyl)] N,N-dimethylthiocarbamate

[0946]

[0947] O-[(5-bromo-3-pyridyl)] N,N-dimethylthiocarbamate (9.93 g, 0.04 mol) was dissolved in diphenyl ether (100 mL). The mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and purified directly by flash chromatography on Biotage (EtOAc / PE = 5% - 50%, ISCO 120 g, 50 mL / min, normal-phase silica gel, uv 254) to give the target compound S-[(5-bromo-3-pyridyl)] N,N-dimethylthiocarbamate (4.63 g, 43.76% yield) as a yellow solid. [C8H9BrN2OS] + [M+H] + The calculated ESI-MS m / z value of

[0948] 3-bromo-5-methoxy-benzenethiol

[0949]

[0950] S-[(3-chloro-5-methoxyphenyl)]N,N-dimethylthiocarbamate (1.044 g, 4 mmol) and KOH (897.21 mg, 16 mmol) were dissolved in ethanol / water (40 mL, 3 / 1). The reaction mixture was heated under reflux for 2 h. LC-MS analysis showed total consumption of the starting material. The mixture was concentrated and then 10% aqueous NaOH (30 mL) was added. The reaction mixture was washed with diethyl ether (15 mL × 3). The aqueous layer was acidified with aqueous KHSO4 to adjust the pH to ~2 and then extracted with EtOAc (20 mL × 5). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product, which was used directly in the next step without purification. [C5H4BrNS] - (M-H) - The calculated ESI-MS m / z for [C5H4BrNS](M-H): 188.9; found: 188.0.

[0951] 5-Bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0952]

[0953] At 0 °C, NaH (82.99 mg, 3.47 mmol) was added to a solution of 5-bromopyridine-3-thiol (658.67 mg, 3.47 mmol) in DMF (10 mL). The resulting solution was stirred at room temperature for 30 min. Then, 2,4,6-tri-O-acetyl-3-azido-1-chloro-3-deoxy-β-D-galactopyranoside (1.01 g, 2.89 mmol) was added. The reaction mixture was stirred at 50 °C for 2 h and then cooled to room temperature. Water (50 mL) was added and the reaction mixture was extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product. The crude product was purified by biotage (EtOAc / PE = 5% - 40%, ISCO 40 g, 30 mL / min, normal-phase silica gel, uv 254) to give the title compound as a white solid (650 mg, 44.7% yield). [C 17 H 19 BrN4O7S] + (M+H) + The calculated ESI-MS m / z for [C5H4BrNS](M+H): 503.0; found: 503.0

[0954] 5-Bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0955]

[0956] To a solution of 5-bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (650 mg, 1.29 mmol) in DMF (16 mL) was added trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (442.22 mg, 1.94 mmol), copper(I) iodide (73.78 mg, 0.39 mmol), CsF (294.26 mg, 1.94 mmol) and N,N-diethylethylamine (653.39 mg, 6.46 mmol). The reaction vessel was purged with nitrogen three times. The reaction mixture was stirred at room temperature for 2 h. The mixture was filtered and washed with EtOAc (50 mL), and the filtrate was concentrated in vacuo to give the crude product of the title compound, which was used directly in the next step without further purification.

[0957] [C 17 H 19 BrN4O7S] + (M+H) + The calculated ESI-MS m / z for

[0958] i45) 3-Chloro-5-cyanophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0959] O-3-Chloro-5-cyanophenyl dimethylthiocarbamate

[0960]

[0961] To a solution of 3-chloro-5-hydroxybenzonitrile (2.5 g, 16.28 mmol) in DMF (25 mL) cooled to 0 °C was added sodium hydride (0.43 g, 17.91 mmol), followed by addition of dimethylthiocarbamyl chloride (2.21 g, 17.91 mmol). The reaction mixture was stirred at room temperature for 20 h, then water (50 mL) was added, and then it was extracted with DCM (100 mL×2). The combined organic phases were washed with brine, dried over Na2SO4, and evaporated to dryness to give the crude product. Purification by silica gel (PE / EtOAc = 10 / 1) gave 2.5 g (63.80%) of the target compound as a white solid.

[0962] S-3-chloro-5-cyanophenyl dimethylthiocarbamate

[0963]

[0964] A solution of O-(3-chloro-5-cyanophenyl) N,N-dimethylthiocarbamate (2.50 g, 10.39 mmol) in phenyl ether (20 mL) was stirred at 280 °C for 2 h. TLC analysis indicated total consumption of the SM. The reaction mixture was cooled to room temperature and purified by silica gel chromatography to give the product as a solid (2.20 g, 88%).

[0965] 3-chloro-5-mercaptobenzonitrile

[0966]

[0967] To a solution of S-(3-chloro-5-cyanophenyl) N,N-dimethylthiocarbamate (300 mg, 1.25 mmol) in methanol (15 mL) was added 2 M NaOH (8 mL). The reaction was stirred at 70 °C for 2 h. TLC analysis indicated total consumption of the SM. Water (30 mL) and DCM (30 mL) were added. Phase separation was carried out, and the aqueous phase was further extracted with DCM (50 mL×2). The combined organic phases were washed with brine, dried over Na2SO4, and then the solvent was removed in vacuo. The crude product was used immediately in the next step.

[0968] 3-chloro-5-cyanophenyl-2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0969]

[0970] To a solution of 3-chloro-5-mercapto-benzonitrile (212 mg, 3 mmol) in DMF (15 mL) was added NaH (22.99 mg, 1.00 mmol). After stirring for 0.5 h, 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranoside (218.53 mg, 0.62 mmol) was added and the resulting reaction mixture was maintained at 50 °C and stirred for 2 h. TLC analysis indicated total consumption of the SM. 10% Aqueous citric acid solution (30 mL) and DCM (30 mL) were added and phase separation was carried out. The aqueous phase was further extracted with DCM (50 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4 and the solvent was removed in vacuo. The crude product was purified by flash column chromatography to give 120 mg (20%) of the title compound as a white oil.

[0971] 3-chloro-5-cyanophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0972]

[0973] To a solution of 3-azido-1,3-dideoxy-2,4,6-tri-O-acetyl-1-(3-chloro-5-cyanophenyl-thio)-α-D-galactopyranoside (120 mg, 0.25 mmol) in DMF (3 mL) were added TEA (125.73 mg, 1.24 mmol), copper(I) iodide (14.20 mg, 0.07 mmol), trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (113.46 mg, 0.50 mmol). The reaction mixture was stirred at 100 °C for 2 h. Water (80 mL) and DCM (80 mL) were added and phase separation was carried out. The aqueous phase was extracted with DCM (10 mL × 2), the combined organic phases were washed with water (20 mL) and brine (20 mL) and dried over anhydrous sodium sulfate and the solvent was removed in vacuo. The crude material was purified by column chromatography (PE / EtOAc = 2 / 1) to give the title compound (100 mg, 45%).

[0974] i46) 3-chloro-4-cyanophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0975]

[0976] 3-Chloro-4-cyanobenzenethiol (196 mg, 1.16 mmol) was dissolved in DMF (2 mL), and then NaH (58 - 62%, 50 mg, 1.30 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, and then a stirred solution of 2,4,6-tri-O-acetyl-3-azido-1-chloro-3-deoxy-β-D-galactopyranoside (280 mg, 0.80 mmol) in DMF (2 mL) was added. The resulting mixture was heated to 55 °C and maintained for 100 h. EtOAc was added, and the organic phase was washed with brine 4 times. The aqueous phase was extracted with EtOAc once, and the combined organic phases were dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography (SiO2, petroleum ether solution of 0 - 60% EtOAc) to give 98 mg of the title compound as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 7.61 - 7.55 (m, 2H), 7.40 (dd, J = 8.3, 1.6 Hz, 1H), 6.15 (d, J = 5.5 Hz, 1H), 5.50 - 5.46 (m, 1H), 5.30 (dd, J = 11.0, 5.6 Hz, 1H), 4.55 - 4.50 (m, 1H), 4.13 (dd, J = 11.6, 4.9 Hz, 1H), 4.01 (dd, J = 11.6, 7.7 Hz, 1H), 3.94 (dd, J = 11.0, 3.2 Hz, 1H), 2.17 (s, 6H), 1.94 (s, 3H). [C 19 H 19 ClN4O7SNa] + (M+Na) + The calculated ESI-MS m / z for

[0977] i47) 3-chloro-6-fluoro-4-cyanophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0978] S-5-chloro-4-cyano-2-fluorophenyl O-ethyl dithiocarbonate

[0979]

[0980] 4-Amino-2-chloro-5-fluoro-benzonitrile (2.0 g, 11.73 mmol) was dissolved in 20 ml of HCl at 0 °C. Then, an aqueous solution of NaNO2 (810 mg, 11.73 mmol) was slowly added. The reaction mixture was stirred at 0 °C until the material was dissolved. The reaction mixture was filtered and slowly added to an aqueous solution (15 mL) of potassium ethyl xanthate (5.64 g, 35.18 mmol) at 50 °C. The reaction mixture was stirred at 70 °C for 2 hours and then extracted with EtOAc (100 mL * 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 3.0 g of a crude product for the next step. [C 10 H8ClFNOS2] + (M+H) + The calculated value of ESI-MS m / z for

[0981] 2-Chloro-5-fluoro-4-mercaptobenzonitrile

[0982]

[0983] O-Ethyl (5-chloro-4-cyano-2-fluoro-phenyl) thiolthiocarbonate (1.0 g, 3.63 mmol) was dissolved in 20 mL of ethanol and heated to 85 °C. KOH (0.41 g, 7.25 mmol) was slowly added and then stirred at 85 °C for 2 hours. After cooling to room temperature, the reaction mixture was acidified to pH = 4 with HCl (1 M) and then extracted with ethyl acetate EtOAc (50 mL * 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 1.0 g of a crude product of the title compound, which was used in the next step.

[0984] 3-Chloro-6-fluoro-4-cyanophenyl-2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0985]

[0986] To a stirred solution of 2-chloro-5-fluoro-4-mercapto-benzonitrile (400 mg, 2.13 mmol) in DMF (5 mL) was added NaH (49 mg, 2.13 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 30 minutes and then 2,4,6-tri-O-acetyl-3-azido-1-chloro-3-deoxy-β-D-galactopyranoside (1.1 g, 3.41 mmol) was added. The reaction mixture was stirred at 50 °C for 1 h and then the solvent was removed in vacuo. The resulting crude product was diluted with CH2Cl2 and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and the solvent was removed in vacuo. The crude product was purified by column chromatography (PE:EtOAc = 3:1) to give the title compound (130 mg, white solid).

[0987] 3-chloro-6-fluoro-4-cyanophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0988]

[0989] 3-chloro-6-fluoro-4-cyanophenyl-2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (130 mg, 0.26 mmol), trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (120 mg, 0.52 mmol), copper(I) iodide (15 mg, 0.08 mmol) and triethylamine (131 mg, 1.3 mmol) were added to a flask. DMF (3 mL) was added. The resulting mixture was stirred at 100 °C for 1 h under N2 protection. Then, the mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography to give 160 mg of the title compound. [C 27 H 22 ClF4N4O7S] + (M+H) + The calculated ESI-MS m / z for

[0990] i48) 3-bromo-4-cyanophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0991] 2-bromo-4-mercaptobenzonitrile

[0992]

[0993] Dissolve 2-bromo-4-fluoro-benzonitrile (2 g, 10 mmol) in DMF (5 mL). Add Na2S·10H2O (2.58 g, 10 mmol). Stir the mixture at room temperature for 1 hour. Then, add 1 M NaOH (100 mL). Extract the mixture with DCM (100 mL * 2). Then, acidify the aqueous phase to pH = 2 with 6 M HCl. Extract the mixture with DCM (200 mL * 2). Wash the organic phase with brine, dry over Na2SO4, filter, and concentrate. The crude product is used in the next step without further purification.

[0994] 3-Bromo-4-cyanophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[0995]

[0996] Add NaH (60%, 168.72 mg, 4.4 mmol) and 2-bromo-4-mercapto-benzonitrile (1 g of crude product) to a flask. Add DMF (5 mL) under N2 protection at 0 °C. Stir the reaction mixture at 0 °C for 15 minutes. Then, add 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (700 mg, 2 mmol) to the reaction mixture. Stir the reaction at room temperature for 2 hours. Add EtOAc (200 ml). Wash the mixture with water (100 mL) and brine (100 mL), dry over Na2SO4, filter, and concentrate in vacuo. Purify the residue by silica gel column chromatography to obtain 240 mg (22.7%) of the title compound. [C 19 H 19 BrN4NaO7S] + (M+Na) + Calculated ESI-MS m / z for [C

[0997] 3-Bromo-4-cyanophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0998]

[0999] 2,4,6 - Tri - O - acetyl - 1 - (3 - bromo - 4 - cyanophenylthio)-3 - azido - 1,3 - dideoxy - α - D - galactopyranoside (240 mg, 0.46 mmol), 2 - (3,5 - difluoro - 4 - methoxyphenyl)ethynyl - trimethyl - silane (328.12 mg, 1.37 mmol), copper(I) iodide (26 mg, 0.14 mmol) and triethylamine (230.26 mg, 2.28 mmol) were dissolved in DMF (5 mL). The resulting mixture was stirred at 100 °C for 1 h. EtOAc (200 ml) was added. The mixture was filtered, washed with water (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography. 220 mg (70.7%) of the title compound was obtained.

[1000] [C 27 H 23 BrF3N4O7S] + (M + H) + The calculated value of ESI - MS m / z for

[1001] 5 - bromo - 6 - trifluoromethyl - pyridin - 3 - yl 2,4,6 - tri - O - acetyl - 3 - azido - 3 - deoxy - 1 - thio - α - D - galactopyranoside

[1002]

[1003] At 0 °C, NaH (15.59 mg, 0.65 mmol) was added to a solution of 5 - bromo - 6 - (trifluoromethyl)pyridine - 3 - thiol (140 mg, 0.54 mmol) in DMF (10 mL). The resulting solution was stirred at room temperature for 30 min. Then, 2,4,6 - tri - O - acetyl - 3 - azido - 1 - chloro - 3 - deoxy - β - D - galactopyranoside (189.73 mg, 0.54 mmol) was added to the resulting mixture. The reaction was stirred at 50 °C for 2 h. The mixture was cooled to room temperature, water (20 mL) was added, and then it was extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography on biotage (EtOAc / PE = 5% - 40%, ISCO 20 g, 15 mL / min, normal - phase silica gel, uv 254) to give the crude product 3 - azido - 1,3 - dideoxy - 2,4,6 - tri - O - acetyl - 1 - (3 - chloro - 2 - trifluoromethylpyridin - 5 - yl - thio)-α - D - galactopyranoside (70 mg, 22.58% yield). [C 18 H 18 BrF3N4O7S](M + H)+ Calculated ESI-MS m / z for + : 570.0; Found: 571.0.

[1004] 5-Bromo-6-(trifluoromethyl)pyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1005]

[1006] 5-Bromo-6-(trifluoromethyl)pyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (70 mg, 0.12 mmol), trimethyl((3,4,5-trifluorophenyl)ethynyl)silane (27.97 mg, 0.12 mmol), CuI (7.0 mg, 0.04 mmol) and Et3N (18.60 mg, 0.18 mmol) were dissolved in DMF (10 mL), and the resulting mixture was stirred at 50 °C for 2 h. Then, the solvent was removed in vacuo to give the crude product (90 mg, >100% yield). The crude product was used in the next step without further purification. [C 26 H 21 BrF6N4O7S] + (M+H) + Calculated ESI-MS m / z for + : 726.0; Found: 727.0.

[1007] i50) 5-Chloro-6-cyano-pyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1008] 3-Chloro-5-mercaptopyridinecarbonitrile

[1009]

[1010] To a solution of 3,5-dichloropyridine-2-carbonitrile (50 mg, 0.29 mmol) in DMF (2 mL) was added Na2S (33.83 mg, 0.43 mmol). After the reaction was completed, NaHSO4 (aqueous solution) was added to the mixture to adjust the pH to 4 - 5, and then DCM (10 mL) was added. The organic phase was washed with water (10 mL) and brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was removed to give the desired product (30 mg, crude product).

[1011] [C6H3ClN2S] - [M-H]- Calculated m / z: 169.0; Found: 169.0.

[1012] 5-Chloro-6-cyano-pyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside

[1013]

[1014] At 0 °C, NaH (3.94 mg, 0.17 mmol) was added to a solution of 3-chloro-5-mercapto-pyridine-2-carbonitrile (30 mg, 0.17 mmol) in DMF (3 mL). After 10 minutes, 2,4,6-tri-O-acetyl-3-azido-1-chloro-3-deoxy-β-D-galactopyranoside (40 mg, 0.11 mmol) was added. The reaction mixture was stirred at room temperature for 4 h. Water (20 mL) and DCM (10 mL) were added. The aqueous phase was extracted with DCM (10 mL × 2), and the combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by flash chromatography (petroleum ether / EtOAc = 3 / 1) to give the title compound (20 mg, 36.14%). [C 18 H 18 C1N5O7S] + [M+H] + Calculated m / z: 484.0; Found: 484.0.

[1015] 5-Chloro-6-cyano-pyridin-3-yl-2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1016]

[1017] To a solution of 3-azido-1,3-dideoxy-2,4,6-tri-O-acetyl-1-(3-chloro-5-cyanopyridin-5-yl-thio)-α-D-galactopyranoside (20 mg, 0.04 mmol) in DMF (3 mL) were added TEA (20.91 mg, 0.21 mmol), copper(I) iodide (2.36 mg, 0.01 mmol), CsF (9.42 mg, 0.06 mmol), trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (14.15 mg, 0.06 mmol). The reaction was stirred for 2 h at N2 and room temperature. Water (80 mL) and DCM (80 mL) were added. The aqueous phase was extracted with DCM (10 mL * 2), and the combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, and then the solvent was removed in vacuo. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give the title compound (12 mg, 45.36%). [C 26 H 21 C1F3N5O7S] + [M+H] + Calculated m / z for [C1F3N5O7S][M+H]: 640.0; Found: 640.0

[1018] i51) 5-Hydroxy-6-cyano-pyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1019] Diethyl 2-azido-3-oxoglutarate

[1020]

[1021] At 0 °C, N-(4-azidosulfonylphenyl)acetamide (5.9 g, 24.73 mmol) was added portionwise to a mixture of diethyl 3-oxoglutarate (5 g, 24.73 mmol) and TEA (3.8 ml) in CH3CN (100 ml). The reaction was stirred at room temperature for 1 h and then filtered. The filter was washed with 1:1 hexane:ether, and the filtrate was stirred in an ice bath for 30 min to form a precipitate. The precipitate was filtered and the filter was washed with 1:1 hexane:ether. The filtrate was collected and the solvent was removed in vacuo to give the title compound as a yellow oil (5.5 g, 97.47%). [C9H 12 N2O5] + [M-N2] + Calculated m / z for [C9H4N2O5][M-N2]: 200.0; Found: 200.0.

[1022] Ethyl 4,6-dihydroxypyridazine-3-carboxylate

[1023]

[1024] A mixture of diethyl 2-azido-3-oxopentanedioate (1 g, 4.38 mmol) and PPh3 (1.15 g, 4.38 mmol) in diethyl ether (50 mL) was stirred at room temperature for 48 h. The diethyl ether was removed in vacuo, and HOAc (50 mL) and water (5 mL) were added to the residue. The resulting mixture was refluxed for 10 h under N2. The solvent was removed in vacuo to dryness. The residue was purified by column chromatography (DCM / MeOH = 10 / 1) to give the desired product (2.1 g, 47%). [C7H8N2O4] + [M+H] + Calculated m / z for

[1025] 4,6-Dihydroxypyridazine-3-carboxamide

[1026]

[1027] A solution of ethyl 4,6-dihydroxypyridazine-3-carboxylate (2.1 g, 11.40 mmol) in NH3–MeOH (40 mL) was kept at room temperature and stirred for 20 h under N2. The solvent was removed in vacuo, and the residue was used directly in the next step. [C5H5N3O3] + [M+H] + Calculated m / z for

[1028] 4,6-Dichloropyridazine-3-carbonitrile

[1029]

[1030] A solution of 4,6-dihydroxypyridazine-3-carboxamide (800 mg, 5.16 mmol) in POCl3 (10 mL) was stirred at 100 °C for 3 h under N2. The reaction mixture was poured into ice water and extracted with DCM (40 mL × 2). The combined organic phases were washed with brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was removed to give a residue. The residue was purified by column chromatography (PE / EtOAc = 10 / 1) to give 4,6-dichloropyridazine-3-carbonitrile (280 mg). [C5HCl2N3] + [M+H] + Calculated m / z for

[1031] 1,2,4,6-Tetra-O-acetyl-1-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside

[1032]

[1033] To a solution of 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy-β-D-galactopyranoside (2.00 g, 5.36 mmol) in DMF (20 mL) were added TEA (2.71 g, 26.80 mmol), copper(I) iodide (306.16 mg, 1.61 mmol), and trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (1.83 g, 8.04 mmol). The reaction was stirred for 2 h under N2 at 100 °C. Water (80 mL) and DCM (80 mL) were added. The aqueous phase was extracted with DCM (10 mL * 2), and the combined organic phases were washed with water (20 mL) and brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was removed to give a residue. The residue was purified by column chromatography (PE / EtOAc = 2 / 1) to give the title compound (2 g, 71%).

[1034] 2,4,6-Tri-O-acetyl-1-chloro-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside

[1035]

[1036] To a stirred suspension of 1,2,4,6-tetra-O-acetyl-1-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside (2.00 g, 3.78 mmol) and PCl5 (1.56 g, 7.56 mmol) in dry DCM (20 mL) was added BF3·Et2O (2 mL). After stirring for 2 h, TLC analysis showed complete disappearance of the starting material. The reaction mixture was diluted with DCM (50 mL) and then successively washed with ice-cold water, ice-cold saturated NaHCO3 solution (2 x 50 mL), and then again with ice-cold water, dried over anhydrous Na2SO4, and evaporated under reduced pressure to give 1 g of a crude product as a white solid. The crude product was used directly in the next step.

[1037] Acetyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1038]

[1039] To a solution of 2,4,6-tri-O-acetyl-1-chloro-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside (1.00 g, 1.98 mmol) in DMF (10 mL) was added potassium thioacetate. The reaction mixture was stirred at room temperature for 20 h. Water (40 mL) and DCM (40 mL) were added. The aqueous phase was extracted with DCM (40 mL × 2), and the combined organic phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by flash column chromatography (PE / EtOAc = 3 / 2) to give the title compound (450 mg, 42%).

[1040] 2,4,6-Tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1041]

[1042] Under N2, a solution of 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (200 mg, 0.36 mmol) in DCM / methanol (30 mL) was cooled to 0 °C. Then, sodium methanethiolate (25.68 mg, 0.36 mmol) was added. The reaction mixture was stirred at 0 °C for 30 min. The pH was adjusted to 5 - 6 with 0.3 M aqueous HCl. The organic layer was washed with water (60 mL) and brine (60 mL), and dried over anhydrous sodium sulfate. The solvent was removed to give the crude product (160 mg).

[1043] [C 20 H 20 F3N3O7S] + [M + H] + The calculated m / z value for [C

[1044] H

[1045]

[1046] F3N3O7S] + [M + H] + is 504.0; found 504.0.

[1044] 5-Hydroxy-6-cyano-pyridazin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1045]

[1046] Under N2 and ice bath conditions, 4,6-dichloropyridazine-3-carbonitrile (82.96 mg, 0.48 mmol) was added to a solution of 1,3-dideoxy-2,4,6-tri-O-acetyl-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside (160 mg, 0.32 mmol) in DMF (20 mL). Then, NaH (10.96 mg, 0.48 mmol) was added. The resulting mixture was stirred at room temperature for 4 hours. Water (40 mL) and DCM (20 mL) were added. The aqueous phase was extracted with DCM (20 mL * 2), and the combined organic phases were washed with water (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, and the solvent was removed under vacuum. The crude product was purified by column chromatography (PE / EtOAc = 2 / 1) to obtain the desired product (42 mg, 20%). [C 25 H 20 ClF3N6O7S] + [M+H] + Calculated m / z value: 641.0; Measured value: 641.0.

[1047] Example 56

[1048] 3-chloro-2,4-dichlorophenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[1049]

[1050] Dissolve 3-chloro-2,4-difluoro-benzenethiol (110 mg) in DMF (1 mL). Add sodium hydride (54 mg, approximately 60% mineral oil solution), and then dissolve 2,4,6-tri-O-acetyl-3-azido-1-chloro-3-deoxy-β-D-galactopyranoside (135 mg) in DMF (2 mL). Heat the mixture to 50 °C and maintain for 1 hour, then stir overnight at room temperature. Separate it with Et2O (100 mL) and water (3 x 150 mL). Purify the organic phase by flash chromatography (SiO2, 5 - 95% EtOAc - heptane solution). Obtain the intermediate thioglycoside as an oil (96 mg). Add copper(I) iodide (10 mg), 3,4,5-trifluorophenylacetylene (0.080 mL), and DIEA (0.200 mL), and stir the resulting mixture at room temperature for 2.5 hours. Concentrate the mixture in vacuo. Dissolve / suspend the residue in EtOAc (5 mL) and filter through a short silica gel column. Remove the solvent in vacuo and dissolve the residue in MeOH (20 mL). Add 1 M sodium methoxide dissolved in MeOH (2 mL), and let the resulting mixture stand overnight at room temperature. Concentrate the mixture in vacuo, dissolve the residue in a small amount of MeCN / water, filter, and purify by HPLC (C 18 / H2O:MeCN:0.1% TFA). Lyophilize to obtain the product as a white powder (63 mg). 1 1H NMR (400 MHz, methanol-d4) δ 8.54 (s, 1H), 7.74 - 7.58 (m, 3H), 7.14 (td, J = 8.7, 1.8 Hz, 1H), 5.88 (d, J = 5.4 Hz, 1H), 5.07 (dd, J = 11.3, 2.8 Hz, 1H), 4.92 (dd, J = 11.3, 5.4 Hz, 1H), 4.44 (t, J = 6.2 Hz, 1H), 4.22 (d, J = 2.8 Hz, 1H), 3.66 (dd, J = 11.4, 5.9 Hz, 1H), 3.55 (dd, J = II A, 6.4 Hz, 1H). [C 20 H 16 ClF5N3O4S] + (M + H) + Calculated ESI-MS m / z for [C

[1051] Example 57

[1052] 3,4-dichlorophenyl 3-deoxy-3-[4-(phenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1053]

[1054] To a stirred solution of 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(phenyl)]-1-thio-α-D-galactopyranoside (100 mg) in MeOH (5 mL) was added NaOMe (9 mg). The resulting mixture was stirred at room temperature for 2 h. Then, the mixture was purified by reverse-phase chromatography to give 40 mg (50.8%) of 3,4-dichlorophenyl 3-deoxy-3-[4-(phenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside. 1 H NMR (400 MHz, DMSO) δ 8.58 (s, 1H), 7.92 - 7.86 (m, 2H), 7.84 (d, J = 2.1 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.53 (dd, J = 8.4, 2.1 Hz, 1H), 7.45 (t, J = 1.1 Hz, 2H), 7.33 (t, J = 1.4 Hz, 1H), 5.89 (dd, J = 19.3, 4.3 Hz, 2H), 5.48 (d, J = 6.5 Hz, 1H), 4.87 - 4.75 (m, 2H), 4.71 (t, J = 5.6 Hz, 1H), 4.25 (t, J = 6.1 Hz, 1H), 4.04 (d, J = 6.4 Hz, 1H), 3.60 - 3.50 (m, 1H), 3.48 - 3.37 (m, 1H). [C 20 H 20 Cl2N3O4S] + (M + H) + ESI-MS m / z calculated for: 468.1; found: 468.0.

[1055] Example 58

[1056] 3,5-Dichloro-4-fluorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1057]

[1058] Add 3,5-dichloro-4-fluorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (50 mg, 0.1 mmol), trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (43.87 mg, 0.2 mmol), copper(I) iodide (6 mg, 0.03 mmol) and triethylamine (49 mg, 0.48 mmol) to a flask. Add DMF (2.5 mL). Stir the resulting mixture at 50 °C for 1 h under N2 protection. LCMS indicated the formation of the target product and no SM residue. Filter and concentrate the mixture in vacuo to obtain the crude intermediate. Dissolve the crude intermediate in MeOH (5 mL) and cool to 0 °C, then add sodium methoxide (5.0 mg, 0.09 mmol). Stir the resulting mixture at room temperature for 30 min. LCMS indicated the formation of the target product and no SM residue. Then, acidify the mixture using dowex 50wx8 hydrogen form ion exchange resin to pH = 5 - 6. Filter and concentrate the solution to obtain the crude product. Purify the crude product by preparative-HPLC to obtain the title compound (40 mg).

[1059] 1 H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.53 (d, J = 6.1 Hz, 2H), 7.49 - 7.40 (m, 2H), 5.83 (d, J = 5.3 Hz, 1H), 4.97 - 4.86 (m, 1H), 4.74 - 4.67 (m, 1H), 4.66 - 4.59 (m, 1H), 4.49 - 4.42 (m, 1H), 4.42 - 4.31 (m, 1H), 4.06 (tt, J = 12.2, 5.9 Hz, 2H). [C 20 H 15 Cl2F4N3O4S] + (M + H) + The calculated value of ESI-MS m / z for

[1060] Example 59

[1061] 3,4-dichloro-6-fluorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1062]

[1063] At 0 °C, sodium methoxide (4 mg, 0.07 mmol) was added to a stirred solution of 3,4-dichloro-6-fluorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside in MeOH (5 mL). The mixture was stirred at room temperature for 1 hour. LCMS indicated no SM. The mixture was acidified with dowex 50wx8 hydrogen ion resin to pH = 5 - 6. The solution was filtered and concentrated to give the crude product. The crude product was purified by preparative-HPLC to give the title compound (50 mg). 1 H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 7.99 (d, J = 7.1 Hz, 1H), 7.97 - 7.82 (m, 2H), 7.77 (d, J = 9.0 Hz, 1H), 6.14 - 5.96 (m, 2H), 5.53 (d, J = 6.3 Hz, 1H), 4.89 (dd, J = 11.3, 2.7 Hz, 1H), 4.81 - 4.72 (m, 1H), 4.67 (t, J = 5.5 Hz, 1H), 4.18 (t, J = 6.3 Hz, 1H), 4.07 - 4.00 (m, 1H), 3.55 - 3.42 (m, 1H), 3.42 - 3.34 (m, 1H). [C 20 H 15 Cl2F4N3O4S] + (M + H) + The calculated value of ESI-MS m / z for

[1064] Example 60

[1065] 3-bromo-4-fluorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1066]

[1067] To a solution of 3-bromo-4-fluorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (250 mg, 0.37 mmol) in methanol (10 mL) was added sodium methoxide (6.79 mg, 0.13 mol). The reaction was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness. The crude product was purified by preparative HPLC to give 3-bromo-4-fluorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside as a white solid (40 mg, 36.15%).

[1068] 1 H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 8.10 - 7.73 (m, 3H), 7.72 - 7.54 (m, 1H), 7.38 (t, J = 8.7 Hz, 1H), 5.99 - 5.71 (m, 2H), 5.52 (d, J = 6.3 Hz, 1H), 4.84 - 4.69 (m, 2H), 4.30 (t, J = 6.0 Hz, 1H), 4.03 (d, J = 4.2 Hz, 1H), 3.63 - 3.50 (m, 1H), 3.50 - 3.38 (m, 1H).

[1069] [C 20 H 16 BrF4N3O4S] + [M + H] + The calculated m / z value: 550.0; found: 550.0.

[1070] Example 61

[1071] 3-chloro-4-(trifluoromethyl)phenyl 3-deoxy 1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[1072]

[1073] Dissolve 3-chloro-4-(trifluoromethyl)phenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (32 mg) in MeCN (5 mL) and stir under argon at room temperature. Add copper(I) iodide (20 mg), and after 5 minutes, add 1,2,3-trifluoro-5-[2-(trimethylsilyl)ethynyl]benzene (0.026 mL). After 5 minutes, add DIEA (0.011 mL) and heat the mixture to 70 °C. After 5 hours, wash the reaction mixture with EtOAc, filter through a short silica gel column, and then concentrate in vacuo. Dissolve the crude product in methanolic NaOMe (0.05 M, 10 mL) and stir at room temperature. After 18 hours, add acetic acid (2 mL) and concentrate the resulting mixture in vacuo. Purify the crude product by preparative HPLC (C 18 / H2O:MeCN:0.1% TFA) and lyophilize to give 10 mg of 3-chloro-4-(trifluoromethyl)phenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside. 1H NMR (400 MHz, methanol-d4) δ 8.55 (s, 1H), 7.84 (s, 1H), 7.74 - 7.61 (m, 4H), 6.05 (d, J = 5.0 Hz, 1H), 4.98 (qd, J = 11.4, 3.7 Hz, 2H), 4.43 (t, J = 6.1 Hz, 1H), 4.20 (s, 1H), 3.71 (tt, J = 11.4, 6.3 Hz, 2H). [C 21 H 17 ClF3N3O4S] + (M+H) + Calculated ESI-MS m / z for [C

[1074] Example 62

[1075] 3,4,5-Trichlorophenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[1076]

[1077] Dissolve 3,4,5-trichlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (64 mg) in MeCN (5 mL) and stir under argon at room temperature. Add copper(I) iodide (18 mg), and after 5 minutes, add 1,2,3-trifluoro-5-[2-(trimethylsilyl)ethynyl]benzene (0.051 mL). After 5 minutes, add DIEA (0.022 mL) and heat the mixture to 70 °C. After 2 hours, add 1,2,3-trifluoro-5-[2-(trimethylsilyl)ethynyl]benzene (0.051 mL) and lower the temperature to 50 °C. After 16 hours, wash the reaction mixture with EtOAc, filter through a short silica gel column, and then concentrate in vacuo. Dissolve the crude product in methanolic NaOMe (0.05 M, 20 mL) and stir at room temperature. After 2.5 hours, add acetic acid (2 mL) and concentrate the resulting mixture in vacuo. Purify the crude product by preparative HPLC (C 18 / H2O:MeCN:0.1% TFA) and lyophilize to give 43 mg (64%) of 3,4,5-trichlorophenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside. 1 1H NMR (400 MHz, methanol-d4) δ 8.54 (s, 1H), 7.76 (s, 2H), 7.69 - 7.60 (m, 2H), 5.92 (d, J = 4.9 Hz, 1H), 5.03 - 4.89 (m, 2H), 4.46 (t, J = 6.0 Hz, 1H), 4.20 (s, 1H), 3.79 - 3.65 (m, 2H). [C 20 H 16 Cl3F3N3O4S] + (M+H) + ESI-MS m / z calculated for: 556.0; found: 556.0.

[1078] Example 63

[1079] 5-Chloro-2-fluorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1080]

[1081] 5-Chloro-2-fluorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (87 mg) was dissolved in MeCN (6 mL) and stirred under nitrogen at room temperature. Copper(I) iodide (13 mg) was added, and after 5 minutes, 1,2,3-trifluoro-5-[2-(trimethylsilyl)ethynyl]benzene (0.080 mL) was added. After 5 minutes, DIEA (0.035 mL) was added and the mixture was stirred at room temperature. After 18 hours, the mixture was heated to 70 °C. After 6 hours, the reaction mixture was washed with EtOAc, filtered through a short silica gel column, and then concentrated in vacuo. The crude product was dissolved in methanolic NaOMe (0.05 M, 20 mL) and stirred at room temperature. After 18 hours, acetic acid (2 mL) was added and the resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (C 18 / H2O:MeCN:0.1% TFA) and lyophilized to give 71 mg of 5-chloro-2-fluorophenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside. 1 1H NMR (400 MHz, methanol-d4) δ 8.55 (s, 1H), 7.73 (d, J = 6.1 Hz, 1H), 7.65 (t, J = 12 Hz, 2H), 7.39 - 7.29 (m, 1H), 7.15 (t, J = 8.8 Hz, 1H), 5.95 (d, J = 5.3 Hz, 1H), 5.06 (d, J = 11.4 Hz, 1H), 4.94 (dd, J = 11.2, 5.2 Hz, 1H), 4.44 (t, J = 6.0 Hz, 1H), 4.23 (s, 1H), 3.68 (dd, J = 11.1, 6.2 Hz, 1H), 3.57 (dd, J = 11.2, 6.2 Hz, 1H). 13 13C NMR (101 MHz, methanol-d4) δ 163.6, 154.1, 151.7, 141.7, 139.3, 135.3, 130.6, 130.5, 123.6, 123.0, 118.1, 117.8, 110.9, 110.7, 89.6, 73.2, 69.5, 66.7, 65.4, 61.8. [C 20 H 17 ClF4N3O4S] + (M + H) + ESI-MS m / z calculated for: 506.1; found: 506.0.

[1082] Example 64

[1083] 5-Bromo-2-fluorophenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[1084]

[1085] To a solution of 5-bromo-2-fluorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (170 mg, 0.25 mmol) in methanol (10 mL) was added sodium methoxide (6.79 mg, 0.13 mmol). The reaction was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness. The crude product was purified by preparative HPLC to give 5-bromo-2-fluorophenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside as a white solid (50 mg, 36.15%). 1 1H NMR (400 MHz, MeOD) δ 8.57 (s, 1H), 7.89 (dd, J = 6.4, 2.4 Hz, 1H), 7.72 - 7.63 (m, 2H), 7.58 - 7.46 (m, 1H), 7.12 (t, J = 8.9 Hz, 1H), 5.95 (d, J = 5.4 Hz, 1H), 5.16 - 5.02 (m, 1H), 4.98 - 4.93 (m, 1H), 4.46 (t, J = 6.1 Hz, 1H), 4.23 (d, J = 2.0 Hz, 1H), 3.79 - 3.64 (m, 1H), 3.64 - 3.54 (m, 1H). [C 20 H 16 BrF4N3O4S] + [M + H] + The calculated m / z value: 550.0; found: 550.0.

[1086] Example 65

[1087] 5-Chloro-2-methoxyphenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[1088]

[1089] Dissolve 5-chloro-2-methoxyphenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (59 mg) in MeCN (5 mL) and stir under nitrogen at room temperature. Add copper(I) iodide (13 mg), and after 5 minutes, add 3,4,5-trifluorophenylacetylene (0.040 mL). After another 5 minutes, add DIEA (0.022 mL) and stir the mixture at room temperature. After 18 hours, wash the reaction mixture with EtOAc, filter through a short silica gel column, and then concentrate in vacuo. Dissolve the crude product in methanolic NaOMe (0.05 M, 20 mL) and stir at room temperature. After 5.5 hours, add acetic acid (2 mL) and concentrate the resulting mixture in vacuo. Purify the crude product by preparative HPLC (C 18 / H2O:MeCN:0.1% TFA) and lyophilize to give 31 mg of 5-chloro-2-methoxyphenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside. 1 1H NMR (400 MHz, methanol–d4) δ 8.54 (s, 1H), 7.70 - 7.58 (m, 3H), 7.27 (dd, J = 8.8, 2.5 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 5.96 (d, J = 5.4 Hz, 1H), 5.07 (dd, J = 11.3, 2.8 Hz, 1H), 4.92 (dd, J = 11.4, 5.4 Hz, 1H), 4.45 (t, J = 6.2 Hz, 1H), 4.22 (d, J = 2.1 Hz, 1H), 3.89 (s, 3H), 3.68 (dd, J = 11.1, 6.6 Hz, 1H), 3.54 (dd, J = 11.2, 6.0 Hz, 1H). 13 13C NMR (101 MHz, methanol–d4) δ 159.1, 133.8, 129.4, 126.7, 124.6, 123.0, 113.2, 110.9, 110.7, 88.4, 72.9, 69.5, 66.8, 65.5, 61.7, 56.7. [C 21 H 20 ClF3N3O5S] + (M + H) + The calculated ESI-MS m / z for

[1090] Example 66

[1091] 1-iodophenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1092]

[1093] Dissolve 3-iodophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (50 mg) in MeCN (10 mL). Add copper(I) iodide (5 mg) and 3,4,5-pentafluorophenylacetylene (0.100 mL), and degas the resulting mixture (nitrogen). Add cesium fluoride (21 mg), and after 5 minutes, add DIEA (0.200 mL). Stir the resulting mixture for 4 hours. Then, filter through a short silica gel column and concentrate in vacuo. Suspend the residue in MeOH (40 mL). Add a 1 M solution of sodium methoxide in MeOH (1 mL). Stir at room temperature for 2 hours, add acetic acid (1 mL), and concentrate the resulting mixture in vacuo. Dissolve the residue in a small amount of MeCN / water, filter, and purify by HPLC (C 18 / H2O:MeCN:0.1% TFA). Lyophilize to obtain the title compound (38 mg) as a white powder. 1 1H NMR (400 MHz, methanol-d4) δ 8.54 (s, 1H), 7.98 (t, J = 1.6 Hz, 1H), 7.71 - 7.58 (m, 3H), 7.10 (t, J = 7.9 Hz, 1H), 5.80 (d, J = 5.2 Hz, 1H), 4.98 (dd, J = 11.4, 2.8 Hz, 1H), 4.91 (dd, J = 11.4, 5.1 Hz, 1H), 4.52 (t, J = 6.2 Hz, 1H), 4.21 (d, J = 2.7 Hz, 1H), 3.72 (qd, J = 11.4, 6.1 Hz, 2H). [C 20 H 18 F3IN3O4S] + (M + H) + Calculated ESI-MS m / z for [C

[1094] Example 67

[1095] Pyridinecarboxamido-5-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1096]

[1097] A solution of 2-cyano-pyridin-5-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (1.2 g, 1.98 mmol) in i-MeOH / Et3N / H2O (10 / 3 / 3) (20 mL) was kept at room temperature with stirring for 4 days. The mixture was evaporated to dryness. The residue was triturated with ether and filtered. The reaction mixture was purified by preparative HPLC to give pyridinecarboxamide-5-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (20 mg, 1.87%).

[1098] [C 20 H 18 F3N5O5S] + [M+H] + Calculated m / z for

[1099] 1 H NMR (400 MHz, MeOD) δ 8.78 (d, J = 1.8 Hz, 1H), 8.59 (s, 1H), 8.21 (dd, J = 8.2, 2.2 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.68 (dd, J = 8.8, 6.7 Hz, 2H), 6.02 (d, J = 5.2 Hz, 1H), 5.06 (dd, J = 11A, 2.7 Hz, 1H), 4.97 (dd, J = 11A, 5.3 Hz, 1H), 4.49 (dt, J = 6.0 Hz, 1H), 4.22 (d, 1H), 3.77 - 3.66 (m, 2H).

[1100] Example 68

[1101] 3-Cyanophenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[1102]

[1103] 3-Cyanophenyl 2,4,6-tri-O-acetyl-3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside (72 mg) was dissolved in sodium methoxide NaOMe (0.05 M, 10 mL), and the solution was stirred at room temperature. After 2 h, acetic acid (2 mL) was added and the resulting mixture was concentrated in vacuo. By preparative HPLC (C 18The crude product was purified by (H2O:MeCN:0.1% TFA), and then (Xterra / 25 mM NH3 in H2O:MeCN solution) was used, followed by lyophilization to obtain 15 mg of 3-cyanophenyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside. 1 HNMR (400 MHz, methanol-d4) δ 8.55 (s, 1H), 7.99 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.70 - 7.60 (m, 3H), 7.51 (t, J = 7.9 Hz, 1H), 5.91 (d, J = 5.2 Hz, 1H), 5.01 (dd, J = 11.4, 2.5 Hz, 1H), 4.93 (dd, J = 11.4, 5.2 Hz, 1H), 4.50 (t, J = 6.0 Hz, 1H), 4.20 (s, 1H), 3.8 - 3.3 (m, 2H). [C 21 H 17 F3N4O4S] + (M + H) + The calculated ESI-MS m / z value of [C

[1104] Example 69

[1105] 2-Cyanopyridin-5-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1106]

[1107] A solution of 2-cyanopyridin-5-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (1.2 g, 1.98 mmol) in i-PrOH / Et3N / H2O (10 / 3 / 3) (20 mL) was stirred at room temperature for 4 days. The reaction mixture was evaporated to dryness. The residue was triturated with ether and filtered to obtain 2-cyanopyridin-5-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside as a white solid (600 mg, 63.26%). [C 20 H 16 F3N5O4S] + [M + H] + The m / z calculated value: 480.0; found value: 480.0. 11H NMR (400 MHz, MeOD) δ 8.83 (d, J = 1.9 Hz, 1H), 8.58 (s, 1H), 8.22 (dd, J = 8.2, 2.3 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.67 (dt, J = 11.4, 5.7 Hz, 2H), 6.15 (d, J = 5.1 Hz, 1H), 5.07 (dd, J = 11.4, 2.7 Hz, 1H), 4.99 (dd, J = 11.4, 5.2 Hz, 1H), 4.40 (t, J = 6.0 Hz, 1H), 4.21 (d, J = 1.8 Hz, 1H), 3.75 - 3.65 (m, 2H).

[1108] Example 70

[1109] 4-Chloro-2-thienyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1110]

[1111] At room temperature, sodium methoxide (0.53 mg, 0.01 mmol) was added to a solution of 4-chloro-2-thienyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (61 mg, 0.10 mmol) in MeOH (5.0 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified with dowex 50wx8 hydrogen form resin to pH = 5 - 6. The solution was filtered, washed with MeOH (50 mL), and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give 4-chloro-2-thienyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (6.64 mg, 13.7% yield).

[1112] 1 1H NMR (400 MHz, MeOD) δ 8.56 (s, 1H), 7.67 (dd, J = 8.9, 6.6 Hz, 2H), 7.41 (d, J = 1.2 Hz, 1H), 7.27 (d, J = 1.2 Hz, 1H), 5.65 (d, J = 5.2 Hz, 1H), 4.98 (dt, J = 13.6, 6.8 Hz, 2H), 4.94 - 4.91 (m, 2H), 4.55 (t, J = 5.9 Hz, 1H), 4.24 (d, J = 1.6 Hz, 1H), 3.77 (qd, J = 11.3, 6.2 Hz, 2H). [C18 H 15 ClF3N3O4S2] + (M + H) + The calculated ESI-MS m / z value of (M + H): 493.0; measured value: 494.0.

[1113] Example 71

[1114] 3-Carboxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1115]

[1116] A solution of (methyl 1-benzoate)-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (30 mg, 0.05 mmol) in NH4OH (2 mL) was stirred at room temperature for 20 hours. The crude product was purified by preparative HPLC to obtain 3-carboxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (10 mg, 42.7%).

[1117] 1 H NMR (400 MHz, MeOD) δ 8.46 (s, 1H), 8.13 (s, 1H), 7.85 (d, J = 1.1 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.70 - 7.46 (m, 2H), 7.36 (t, J = 1.1 Hz, 1H), 5.75 (d, J = 5.3 Hz, 1H), 4.95 - 4.82 (m, 2H), 4.45 (t, J = 6.3 Hz, 1H), 4.13 (s, 1H), 3.83 - 3.45 (m, 2H).

[1118] [C 21 H 18 F3N3O6S] + [M + H] + The calculated m / z value of [M + H]: 498.0; measured value: 498.0.

[1119] Example 72

[1120] Benzamide-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1121]

[1122] To a solution of 3-carboxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (4.00 mg, 0.01 mmol) in DMF (1 mL) were added NH4Cl (4.30 mg, 0.08 mmol), HATU (6.11 mg, 0.02 mmol), and TEA (8.14 mg, 0.08 mmol). The reaction mixture was stirred at room temperature for 20 h. The crude product was purified by preparative-HPLC to give benzamide-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (1.42 mg, 35.57%).

[1123] 1 H NMR (400 MHz, MeOD) δ 8.46 (s, 1H), 8.02 (s, 1H), 7.70 (d, J = 7.9 Hz, 2H), 7.67 (t, J = 22.8 Hz, 2H), 7.56 (dd, J = 8.7, 6.8 Hz, 1H), 7.56 (dd, J = 8.7, 6.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 5.75 (d, J = 5.2 Hz, 1H), 4.92 (dd, J = 11.4, 2.8 Hz, 1H), 4.83 (d, J = 5.3 Hz, 1H), 4.48 (t, J = 5.9 Hz, 1H), 4.11 (d,.7 = 1.9 Hz, 1H), 3.77 - 3.52 (m, 2H). [C 21 H 19 F3N4O5S] + [M+H] + Calculated m / z for

[1124] Example 73

[1125] 3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1126]

[1127] To a solution of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (400 mg, 0.63 mmol) in methanol (10 ml) was added a solution of sodium methoxide (30%, 5 mg), and the mixture was stirred at room temperature for 2 h. LC-MS analysis showed total consumption of the starting material. After completion of the reaction, DOWEX 50wx8-200 ion exchange resin (pH = 7) was added, and the reaction mixture was filtered. The filtrate was concentrated and purified by combiflash (EtOAc:PE = 1:20 - 1:5, ISCO 40 g, 40 ml / min, normal-phase silica gel, uv254) to give 55 mg of the target compound as a white solid.

[1128] 1 1H NMR (500 MHz, DMSO) δ 7.99 - 7.95 (m, 1H), 7.85 (s, 1H), 7.79 - 7.75 (m, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.54 - 7.52 (m, 2H), 5.94 (dd, J = 20.4, 3.5 Hz, 2H), 5.50 (d, J = 6.7 Hz, 1H), 4.81 - 4.75 (m, 3H), 4.27 (t, J = 5.9 Hz, 1H), 4.06 (d, J = 5.5 Hz, 1H), 3.50 - 3.48 (m, 1H), 3.37 - 3.33 (m, 1H).

[1129] [C 20 H 17 Cl2F2N3O4S] + (M + H) + The calculated value of ESI-MS m / z for

[1130] Example 74

[1131] 3,4-dichlorophenyl 3-deoxy-3-[4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1132]

[1133] At 0 °C, sodium methoxide (4 mg, 0.07 mmol) was added to a stirred solution of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4–difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (160 mg, 0.25 mmol) in MeOH (5 mL). The resulting mixture was stirred at room temperature for 0.5 h. LCMS indicated the formation of the target product and no residual SM. The mixture was concentrated and the residue was purified by preparative HPLC to give 50 mg of the title compound.

[1134] 1H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.53 (dd, J = 8.4, 2.1 Hz, 1H), 7.21 (t, J = 9.4 Hz, 1H), 5.91 (dd, J = 13.4, 4.6 Hz, 2H), 5.52 (d, J = 6.3 Hz, 1H), 4.88 - 4.67 (m, 3H), 4.25 (t, J = 6.3 Hz, 1H), 4.03 (d, J = 4.8 Hz, 1H), 3.58 - 3.51 (m, 1H), 3.47 - 3.38 (m, 2H).

[1135] [C 20 H 18 Cl2F2N3O4S] + (M+H) + The calculated ESI-MS m / z for

[1136] Example 75

[1137] 3,4-Dichlorophenyl 3-deoxy-3-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1138]

[1139] To a stirred solution of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (140 mg) in MeOH (5 mL) was added NaOMe (12.35 mg). The resulting mixture was stirred at room temperature for 2 h. Then, the mixture was purified by reverse phase chromatography to give 50 mg (45%) of the title compound.

[1140] 1H NMR (400 MHz, DMSO) δ 8.72 (s, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.83 - 7.66 (m, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.59 - 7.47 (m, 2H), 7.16 (td, J = 8.4, 2.1 Hz, 1H), 6.04 - 5.82 (m, 2H), 5.50 (d, J = 6.4 Hz, 1H), 4.80 (s, 2H), 4.72 (t, J = 5.6 Hz, 1H), 4.25 (t, J = 6.2 Hz, 1H), 4.03 (d, J = 6.6 Hz, 1H), 3.64 - 3.50 (m, 1H), 3.46 - 3.38 (m, 1H). [C 20 H 19 Cl2FN3O4S] + (M + H) + The calculated value of ESI-MS m / z for

[1141] Example 76

[1142] 3,3'-Difluoro-cyclohexyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1143]

[1144] To a solution of 3,3'-difluoro-cyclohexyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (10.00 mg, 0.01 mmol) in methanol (0.5 mL) and water (0.1 mL) was added TEA (0.3 mL). The reaction mixture was evaporated to dryness and the residue was purified by preparative-HPLC to give the title compound (1 mg).

[1145] 1 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.66 (dd, J = 8.8, 6.4 Hz, 2H), 5.72 (d, J = 2.8 Hz, 1H), 4.85 - 4.81 (m, 1H), 4.42 (t, J = 6.8 Hz, 1H), 4.14 (d, J = 2 Hz, 1H), 3.75 (d, J = 6.4 Hz, 1H), 3.09 - 3.07 (m, 1H), 2.52 (m, 1H), 4.12 (t, J = 6.0 Hz, 1H), 2.17 - 1.39 (m, 8H).

[1146] [C20 H 22 F5N3O4S] + [M+H] + Calculated m / z for [M+H]: 496.0; Found: 496.0.

[1147] Example 77

[1148] n-Butyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1149]

[1150] At room temperature, sodium methoxide (2.7 mg, 0.05 mmol) was added to a solution of n-butyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (300 mg, 0.54 mmol) in MeOH (5.0 mL). The resulting mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 5 - 6 using dowex 50wx8 hydrogen ion resin. The solution was filtered and concentrated in vacuo to give the crude product. The crude product was purified by preparative-HPLC to give the title compound (163.6 mg, 70% yield).

[1151] 1 H NMR (400 MHz, MeOD) δ 8.36 (s, 1H), 7.58 - 7.42 (m, 2H), 5.42 (d, J = 5.4 Hz, 1H), 4.79 (dd, J = 11.3, 2.8 Hz, 1H), 4.66 (dd, J = 11.3, 5.4 Hz, 1H), 4.25 (t, J = 6.1 Hz, 1H), 3.97 (d, J = 2.1 Hz, 1H), 3.59 (d, J = 6.1 Hz, 2H), 2.53 (dtd, J = 20.2, 12.8, 7.5 Hz, 2H), 1.60 - 1.45 (m, 2H), 1.40 - 1.27 (m, 2H), 0.81 (t, J = 7.4 Hz, 3H).

[1152] [C 18 H 22 F3N3O4S] + (M+H) + Calculated ESI-MS m / z for [M+H]: 433.1; Found: 434.2.

[1153] Example 78

[1154] 3,4-Dichlorophenyl 3-deoxy-3-[4-(3,5-difluoro-4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1155]

[1156] To a stirred solution of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,5-difluoro-4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (150 mg) in MeOH (5 mL) was added NaOMe (12.35 mg). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was neutralized with H + resin, filtered and concentrated to give the product as a slurry. The crude product was purified by preparative HPLC to give the title compound (50 mg, 45% yield).

[1157] 1 1H NMR (400 MHz, DMSO) δ 8.73 (s, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.74 - 7.47 (m, 4H), 5.90 (dd, J = 15.5, 4.5 Hz, 2H), 5.51 (d, J = 6.4 Hz, 1H), 4.90 - 4.64 (m, 3H), 4.25 (t, J = 6.1 Hz, 1H), 4.02 (d, J = 4.8 Hz, 1H), 3.96 (s, 3H), 3.60 - 3.50 (m, 1H), 3.48 - 3.37 (m, 1H).

[1158] [C 21 H 19 Cl2F2N3O5S] +( M + H) + The calculated value of ESI-MS m / z for

[1159] Example 79

[1160] 2-Hydroxy-pyridin-4-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1161]

[1162] Dissolve 2-hydroxy-pyridin-4-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (100 mg) in MeOH (10 mL). Add NaOMe (0.05 g). Stir the resulting mixture at room temperature for 30 minutes. Concentrate the reaction mixture and purify the residue by preparative HPLC to obtain 20 mg (28%) of the title compound.

[1163] 1 H NMR (400 MHz, DMSO) δ 11.39 (s, 1H), 8.80 (s, 1H), 7.84 (dd, J = 9.0, 6.8 Hz, 2H), 7.27 (d, J = 6.9 Hz, 1H), 6.43 (d, J = 1.7 Hz, 1H), 6.23 (dd, J = 7.0, 1.8 Hz, 1H), 6.07 (d, J = 2.6 Hz, 1H), 5.91 (s, 1H), 5.56 (s, 1H), 4.78 (s, 2H), 4.71 (s, 1H), 4.13 (t, J = 6.4 Hz, 1H), 4.02 (s, 1H), 3.65 - 3.50 (m, 1H), 3.49 - 3.38 (m, 1H). [C 19 H 18 F3N4O5S] + (M + H) + The calculated value of ESI-MS m / z for

[1164] Example 80

[1165] 2-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1166]

[1167] Dissolve 2-chlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (100 mg, 0.16 mmol) in MeOH (12 mL). Add NaOMe (8.5 mg, 0.16 mmol). Stir the resulting mixture at room temperature for 16 hours. Then, concentrate the mixture and purify the residue by a 0 - 52% acetonitrile / 0.01 M NH4HCO3 gradient reverse-phase column to obtain 30 mg (37%) of the title compound. 11H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 7.84 (dd, J = 9.0, 6.8 Hz, 2H), 7.44 (dd, J = 1.1, 1.5 Hz, 2H), 7.34 - 7.16 (m, 2H), 5.60 (d, J = 5.2 Hz, 2H), 5.43 (d, J = 6.1 Hz, 1H), 4.77 - 4.69 (m, 2H), 4.69 - 4.52 (m, 1H), 4.16 (t, J = 6.2 Hz, 1H), 4.05 - 3.94 (m, 1H), 3.67 - 3.39 (m, 2H), 3.04 (t, J = 1.1 Hz, 2H), 2.93 - 2.70 (m, 2H). [C 22 H 22 ClF3N3O4S] + (M + H) + The calculated value of ESI-MS m / z for

[1168] Example 81

[1169] 4-Chloroethoxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1170]

[1171] 4-Chloroethoxyphenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (100 mg, 0.16 mmol) was dissolved in MeOH (12 mL). NaOMe (8.5 mg, 0.16 mmol) was added. The resulting mixture was stirred at room temperature for 16 h. Then, the mixture was concentrated and the residue was purified on a C18 column to give 30 mg (37.3%) of the title compound as a white solid.

[1172] 1 1H NMR (400 MHz, DMSO) δ 8.75 (s, 1H), 7.83 (dd, J = 9.0, 6.8 Hz, 2H), 7.45 - 7.20 (m, 4H), 5.57 (d, J = 5.2 Hz, 2H), 5.43 (s, 1H), 4.87 - 4.72 (m, 2H), 4.72 - 4.60 (m, 1H), 4.14 (t, J = 6.2 Hz, 1H), 3.96 (s, 1H), 3.65 - 3.43 (m, 2H), 2.96 - 2.71 (m, 4H).

[1173] [C 22H 22 ClF3N3O4S] + (M+H) + Calculated ESI-MS m / z for 22 ClF3N3O4S][(M+H): 516.1; Found: 516.1

[1174] Example 82

[1175] 2-Chlorobenzyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[1176]

[1177] 2-Chlorobenzyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (132 mg) was dissolved in MeCN (10 mL). Cuprous iodide (I) (5 mg) and 3,4,5-trifluorophenylacetylene (0.100 mL) were added, and the resulting mixture was degassed (nitrogen). After 5 minutes, DIEA (0.200 mL) was added and the resulting mixture was stirred overnight. Then, the mixture was filtered through a small plug of silica gel and concentrated in vacuo. The residue was suspended in MeOH (40 mL). A solution of 1 M sodium methoxide in MeOH (1 mL) was added. The mixture was stirred at room temperature for 2 hours, acetic acid (1 mL) was added, and the resulting mixture was concentrated in vacuo. The residue was dissolved in a small amount of MeCN / water, filtered, and purified by HPLC (C 18 / H2O:MeCN:0.1% TFA). Lyophilization gave the title compound (123 mg) as a white powder. 1 H NMR (400 MHz, methanol-d4) δ 8.49 (s, 1H), 7.61 (dd, J = 8.6, 6.6 Hz, 2H), 7.52 (dd, J = 6.4, 2.9 Hz, 1H), 7.40 (dd, J = 6.5, 2.8 Hz, 1H), 7.31 - 7.20 (m, 2H), 5.50 (d, J = 5.4 Hz, 1H), 4.97 (dd, J = 11.3, 2.8 Hz, 1H), 4.82 (dd, J = 11.3, 5.5 Hz, 1H), 4.46 (t, J = 6.1 Hz, 1H), 4.17 (d, J = 2.8 Hz, 1H), 4.03 - 3.90 (m, 2H), 3.77 (d, J = 6.1 Hz, 2H). [C 21 H 20 ClF3N3O4S] + (M+H) + Calculated ESI-MS m / z for 20 ClF3N3O4S][(M+H): 502.07; Found: 502.10.

[1178] Example 83

[1179] 3,4-Dichlorobenzyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[1180]

[1181] Dissolve 3,4-dichlorobenzyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (123 mg) in MeCN (10 mL). Add copper(I) iodide (10 mg) and 3,4,5-trifluorophenylacetylene (0.100 mL), and degas the resulting mixture (nitrogen). After 5 minutes, add DIEA (0.200 mL) and stir the resulting mixture overnight. Then, filter the mixture through a small silica plug and concentrate in vacuo. Suspend the residue in MeOH (40 mL). Add a 1 M solution of sodium methoxide in MeOH (1 mL). After stirring at room temperature for 2 hours, add acetic acid (1 mL) and concentrate the resulting mixture in vacuo. Dissolve the residue in a small amount of MeCN / water, filter, and purify by HPLC (C 18 / H2O:MeCN:0.1% TFA). Lyophilize to give the title compound (84 mg) as a white powder. 1 1H NMR (400 MHz, methanol–d4) δ 8.49 (s, 1H), 7.68 - 7.57 (m, 3H), 7.46 (d, J = 8.2 Hz, 1H), 7.36 (dd, J = 8.3, 1.9 Hz, 1H), 5.36 (d, J = 5.5 Hz, 1H), 4.97 (dd, J = 11.3, 2.9 Hz, 1H), 4.80 (dd, J = 11.3, 5.5 Hz, 1H), 4.41 (t, J = 6.1 Hz, 1H), 4.15 (d, J = 2.8 Hz, 1H), 3.91 - 3.83 (m, 1H), 3.83 - 3.71 (m, 3H). [C 21 1H 19 Cl2F3N3O4S] + (M+H) + Calculated ESI-MS m / z for

[1182] Example 84

[1183] 3-Chloroethoxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1184]

[1185] 3-Chloroethoxyphenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (120 mg, 0.19 mmol) was dissolved in MeOH (12 mL). NaOMe (10.1 mg, 0.19 mmol) was added. The resulting mixture was stirred at room temperature for 16 h. Then, the mixture was concentrated and the residue was purified by a 0 - 52% acetonitrile / 0.01 M NH4HCO3 gradient C18 column to afford 33 mg (34.2%) of the title compound as a white solid.

[1186] 1 H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 7.84 (dd, J = 9.0, 6.8 Hz, 2H), 7.39 - 7.23 (m, 4H), 5.58 (t, J = 5.7 Hz, 2H), 5.42 (d, J = 6.4 Hz, 1H), 4.81 - 4.70 (m, 2H), 4.70 - 4.60 (m, 1H), 4.15 (t, J = 6.1 Hz, 1H), 3.96 (dd, J = 6.1, 2.5 Hz, 1H), 3.64 - 3.45 (m, 2H), 3.01 - 2.71 (m, 4H).

[1187] [C 22 H 22 ClF3N3O4S] + (M + H) + The calculated ESI-MS m / z for

[1188] Example 85

[1189] 4-Chlorobenzyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside

[1190]

[1191] Dissolve 4-chlorobenzyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (98 mg) in MeCN (10 mL). Add copper(I) iodide (5 mg) and 3,4,5-trifluorophenylacetylene (0.100 mL), and degas the resulting mixture (nitrogen). After 5 minutes, add DIEA (0.200 mL), and stir the resulting mixture overnight. Then, filter the mixture through a small silica plug and concentrate in vacuo. Suspend the residue in MeOH (40 mL). Add 1 M sodium methoxide in MeOH (1 mL) solution. After stirring for 2 hours at room temperature, add acetic acid (1 mL), and concentrate the resulting mixture in vacuo. Dissolve the residue in a small amount of MeCN / water, filter, and purify by HPLC (C 18 / H2O:MeCN:0.1% TFA). Lyophilize to give the title compound (85 mg) as a white powder. 1 1H NMR (400 MHz, methanol-d4) δ 8.48 (s, 1H), 7.62 (dd, J = 8.5, 6.7 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.35 - 7.27 (m, 2H), 5.38 (d, J = 5.4 Hz, 1H), 4.97 (dd, J = 11.4, 2.9 Hz, 1H), 4.80 (dd, J = 11.3, 5.6 Hz, 1H), 4.43 (t, J = 6.0 Hz, 1H), 4.15 (d, J = 2.9 Hz, 1H), 3.92 - 3.83 (m, 1H), 3.82 - 3.72 (m, 3H). [C 21 H 20 ClF3N3O4S] + (M + H) + ESI-MS m / z calculated for: 502.07; found: 502.10.

[1192] Example 86

[1193] Propyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1194]

[1195] At room temperature, MeONa (1.08 mg, 0.02 mmol) was added to a solution of propyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (100 mg, 0.18 mmol) in MeOH (5.0 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was acidified to pH 5 - 6 using dowex 50wx8 hydrogen form resin. The solution was filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give the title compound (68.7 mg, 91% yield).

[1196] 1 H NMR (400 MHz, MeOD) δ 8.36 (s, 1H), 7.49 (dd, J = 8.8, 6.7 Hz, 2H), 5.42 (d, J = 5.4 Hz, 1H), 4.79 (dd, J = 11.3, 2.9 Hz, 1H), 4.66 (dd, J = 11.3, 5.4 Hz, 1H), 4.25 (t, J = 6.0 Hz, 1H), 3.97 (d, J = 2.3 Hz, 1H), 3.59 (d, J = 6.1 Hz, 2H), 2.50 (dtd, J = 20.3, 12.9, 7.5 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H). ESI-MS m / z 17 H 20 [C + (M + H) + Calculated for

[1197] Example 87

[1198] 2-Aminopyridin-4-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1199]

[1200] At room temperature, sodium methoxide (3.37 mg, 0.06 mmol) was added to a solution of 2-amino-4-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (124 mg, 0.21 mmol) in MeOH (5.0 mL). The mixture was stirred at room temperature for 1 hour. The mixture was acidified to pH 5 - 6 using dowex 50wx8 hydrogen form resin. The solution was filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give the title compound (4.95 mg, 5.06% yield).

[1201] 1 H NMR (400 MHz, MeOD) δ 8.46 (s, 1H), 7.64 (d, J = 5.5 Hz, 1H), 7.56 (dd, J = 8.9, 6.7 Hz, 2H), 6.73 (s, 1H), 6.66 (dd, J = 5.8, 1.6 Hz, 1H), 6.00 (d, J = 4.4 Hz, 1H), 4.91 - 4.82 (m, 2H), 4.29 (t, J = 6.1 Hz, 1H), 4.09 (d, J = 2.4 Hz, 1H), 3.69 - 3.58 (m, 2H).

[1202] [C 19 H 18 F3N5O4S] + (M + H) + The calculated ESI-MS m / z for

[1203] Example 88

[1204] 5-(Dimethylamino)-naphthalen-2-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1205]

[1206] TEA (0.3 ml) was added to a solution of 5-(dimethylamino)-naphthalen-2-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (50 mg, 0.07 mol) in MeOH / H2O (0.6 mL). The reaction was stirred at room temperature for 2 hours. The solvent was evaporated. The residue was purified by preparative HPLC to give the desired product.

[1207] 11H NMR (400 MHz, MeOD) δ 8.41 (s, 1H), 8.01 (d, J = 8.9 Hz, 1H), 7.94 (d, J = 1.7 Hz, 1H), 7.58 - 7.43 (m, 3H), 7.33 (d, J = 8.2 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 6.9 Hz, 1H), 5.74 (d, J = 5.3 Hz, 1H), 4.89 (dd, J = 11.4, 2.8 Hz, 1H), 4.81 - 4.76 (m, 1H), 4.48 (t, J = 6.2 Hz, 1H), 4.07 (d, J = 2.0 Hz, 1H), 3.68 - 3.43 (m, 2H), 2.71 (s, 6H).

[1208] [C 26 H 25 F3N4O4S] + [M + H] + Calculated m / z for

[1209] Example 89

[1210] Ethyl 3 - deoxy - 1 - thio - 3 - [4 - (3,4,5 - trifluorophenyl)-1H - 1,2,3 - triazol - 1 - yl]-α - D - galactopyranoside

[1211]

[1212] Ethyl 2,4,6 - tri - O - acetyl - 3 - azido - 3 - deoxy - 1 - thio - α - D - galactopyranoside (43 mg) was dissolved in MeCN (5 mL) and stirred under nitrogen at room temperature. Copper(I) iodide (9 mg) was added and after 5 minutes, 1,2,3 - trifluoro - 5 - [2 - (trimethylsilyl)ethynyl]benzene (0.050 mL) was added. After another 5 minutes, DIEA (0.020 mL) was added and the reaction mixture was heated to 45 °C. After 2 hours, it was heated to 80 °C and maintained for 70 minutes, then cooled to 30 °C. After three days, the reaction mixture was filtered through a short silica gel column eluting with EtOAc and then concentrated in vacuo. The crude product was dissolved in sodium methoxide in methanol (0.05 M, 20 mL) and stirred at room temperature. After 100 minutes, acetic acid (2 mL) was added and the resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (C 18 / H2O:MeCN:0.1% TFA) and lyophilized to give 42 mg of ethyl 3 - deoxy - 1 - thio - 3 - [4 - (3,4,5 - trifluorophenyl)-1H - 1,2,3 - triazol - 1 - yl]-α - D - galactopyranoside. 1H NMR (400 MHz, methanol-d4) δ 8.50 (s, 1H), 7.72-7.58 (m, 2H), 5.61 (d, J = 5.4 Hz, 1H), 4.94 (dd, J = 11.3, 2.3 Hz, 1H), 4.85-4.77 (m, 1H), 4.40 (t, J = 6.0 Hz, 1H), 4.13 (s, 1H), 3.74 (d, J = 6.1 Hz, 2H), 2.80-2.59 (m, 2H), 1.34 (t, J = 1A Hz, 3H). 13 C NMR (101 MHz, methanol-d4) δ 123.0, 110.9, 110.6, 86.9, 72.5, 69.8, 66.6, 65.6, 62.4, 24.5, 15.2. [C 16 H 19 F3N3O4S] + (M+H) + ESI-MS m / z calcd: 406.1; found: 406.1.

[1213] Example 90

[1214] 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide, isomer 1

[1215]

[1216] To a mixture of 5-bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside sulfoxide (145 mg, 0.21 mmol) in MeOH (10 mL) was added NaOMe (2.32 mg, 0.04 mmol). Then stirred at room temperature for 1 hour. The mixture was acidified with dowex 50wx8 H resin to pH = 5-6. The solution was filtered, washed with MeOH (20 mL), and concentrated in vacuo to obtain a crude product. The crude product was purified by trituration with CH2Cl2 and Et2O to give 1,3-dideoxy-1-(5-bromopyridin-3-yl-thio)-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside (69.41 mg, 58.86% yield). The chirality of the stereocenter at the * sulfur atom was not determined.

[1217] 11H NMR (400 MHz, MeOD) δ 8.93 (d, J = 1.8 Hz, 1H), 8.85 (d, J = 2.1 Hz, 1H), 8.56 (s, 1H), 8.50 (t, J = 1.9 Hz, 1H), 7.79 - 7.51 (m, 1H), 5.61 (dd, J = 11.1, 2.6 Hz, 1H), 5.18 (dd, J = 11.0, 5.6 Hz, 1H), 5.09 (d, J = 5.6 Hz, 1H), 4.27 (d, J = 2.3 Hz, 1H), 4.21 (t, J = 5.9 Hz, 1H), 3.64 - 3.46 (m, 1H). [C 16 H 19 F3N3O4S] + (M + H) + The calculated value of ESI-MS m / z for

[1218] Example 91

[1219] 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-2H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide, isomer 2

[1220]

[1221] To a mixture of 5-bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside sulfoxide isomer 2 (40 mg, 0.06 mmol) in MeOH (5 mL) was added NaOMe (0.64 mg, 0.01 mmol). The mixture was then stirred at room temperature for 1 hour. The mixture was acidified to pH = 5 - 6 using dowex 50wx8 hydrogen form resin. The solution was filtered and washed with MeOH (20 mL), then concentrated in vacuo to give the crude product. The crude product was purified by trituration with CH2Cl2 and Et2O to give the title compound (3.32 mg, 10.21% yield). The chirality of the stereocenter at the sulfur atom marked with * was not determined.

[1222] 1HNMR (400 MHz, MeOD) δ 8.84 (dd, J = 13.6, 1.9 Hz, 1H), 8.62 (s, 1H), 8.49 (t, J = 2.0 Hz, 1H), 7.69 (dd, J = 8.8, 6.6 Hz, 1H), 5.77 (dd, J = 11.2, 2.7 Hz, 1H), 5.24 (dd, J = 11.3, 6.6 Hz, 1H), 5.02 (t, J = 6.0 Hz, 1H), 4.95 (d, J = 6.5 Hz, 1H), 4.26 (s, 1H), 3.56 (s, 1H), 3.56 - 3.50 (m, 1H).

[1223] [C 19 H 16 BrF3N4O5S] + (M + H) + The calculated value of ESI-MS m / z for

[1224] Example 92

[1225] 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfone

[1226]

[1227] At room temperature, 5-bromo-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (9 mg) was dissolved / suspended in CH2Cl2 (3 mL), and m-chloroperoxybenzoic acid (4.6 mg) dissolved in CH2Cl2 (0.460 mL) was added. After 20 h, more m-chloroperoxybenzoic acid (8.4 mg) dissolved in CH2Cl2 (0.840 mL) was added. After 4 h, the temperature was raised to 30 °C and maintained for 20 h. MeCN (1 mL) was added, then H2O2 (27%, 0.5 mL) was added, and the resulting mixture was stirred for 6.5 h. It was eluted with 15% MeOH in EtOAc, the mixture was filtered through a short silica gel column, and concentrated in vacuo. The crude product was purified by preparative HPLC (C 18 / H2O:MeCN:0.1% TFA), freeze-dried to give 3 mg of the title compound. 11H NMR (400 MHz, methanol-d4) δ 9.07 (s, 1H), 8.97 (s, 1H), 8.56 (d, J = 9.3 Hz, 2H), 7.70 - 7.61 (m, 2H), 5.73 (d, J = 11.5 Hz, 1H), 5.43 (d, J = 6.4 Hz, 1H), 5.15 (dd, J = 11.4, 6.5 Hz, 1H), 4.55 (s, 1H), 4.28 (s, 1H), 3.62 (d, J = 6.2 Hz, 2H). 13 13C NMR (101 MHz, methanol-d4) δ 156.3, 148.9, 140.9, 122.8, 121.9, 110.9, 93.8, 78.1, 69.2, 66.2, 64.1, 62.3. [C 19 H 17 BrF3N4O6S] + (M + H) + The calculated value of ESI-MS m / z for

[1228] Example 93

[1229] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide, isomer 1

[1230]

[1231] A solution of 5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide isomer 1 (18 mg, 0.03 mmol) in MeOH / Et3N / H2O (5 / 3 / 1) (0.5 mL) was stirred at room temperature for 4 h. The mixture was evaporated to dryness, and the residue was triturated with ether, filtered to give the title compound as a white solid (5 mg, 34.72%). The chirality of the sulfur atom stereocenter was not determined. 11H NMR (400 MHz, MeOD) δ 8.79 (d, J = 1.7 Hz, 1H), 8.76 (d, J = 2.3 Hz, 1H), 8.62 (s, 1H), 8.36 (t, J = 2.0 Hz, 1H), 7.69 (dd, J = 8.8, 6.6 Hz, 2H), 5.77 (dd, J = 11.3, 2.7 Hz, 1H), 5.24 (dd, J = 11.3, 6.6 Hz, 1H), 5.02 (t, J = 5.9 Hz, 1H), 4.96 (d, J = 6.6 Hz, 1H), 4.26 (d, 1H), 3.60 - 3.47 (m, 2H). [C 19 H 16 ClF3N4O5S] + [M + H] + Calculated m / z for [M + H]: 505.0; Found: 505.0.

[1232] Example 94

[1233] 5 - Chloro - 3 - pyridyl 3 - deoxy - 3 - [4 - (3,4,5 - trifluorophenyl)-1H - 1,2,3 - triazol - 1 - yl]-α - D - galactopyranosyl sulfoxide, isomer 2

[1234]

[1235] A solution of 5 - chloro - 3 - pyridyl 2,4,6 - tri - O - acetyl - 3 - deoxy - 3 - [4 - (3,4,5 - trifluorophenyl)-1H - 1,2,3 - triazol - 1 - yl]-α - D - galactopyranosyl sulfoxide isomer 2 (100 mg, 0.16 mmol) in MeOH / Et3N / H2O (5 / 3 / 1) (2 mL) was stirred at room temperature for 4 h. The mixture was evaporated to dryness and the residue was triturated with ether, filtered to give the title compound as a white solid (47 mg, 59%). The chirality of the sulfur atom stereocenter was not determined.

[1236] 1 1H NMR (400 MHz, MeOD) δ 8.73 (d, J = 1.8 Hz, 1H), 8.58 (d, J = 2.2 Hz, 1H), 8.39 (s, 1H), 8.20 (t, J = 2.0 Hz, 1H), 7.50 (dd, J = 8.8, 6.7 Hz, 2H), 5.44 (dd, J = 11.1, 2.8 Hz, 1H), 5.01 (dd, J = 11.1, 5.6 Hz, 1H), 4.92 (d, J = 5.6 Hz, 1H), 4.10 (d, J = 2.0 Hz, 1H), 4.03 (t, J = 5.8 Hz, 1H), 3.39 (qd, J = 11.6, 5.9 Hz, 2H). [C 19 H16 ClF3N4O5S] + [M+H] + Calculated m / z for [M+H]: 505.0; Found: 505.0.

[1237] Example 95

[1238] 5-Dimethylamino-naphthalen-2-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfone

[1239]

[1240] To a solution of 5-dimethylamino-naphthalen-2-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (20 mg, 0.03 mmol) in MeOH / H2O (0.5 mL) was added TEA (0.3 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was purified by preparative-HPLC to give the title compound (6 mg).

[1241] 1 1H NMR (400 MHz, MeOD) δ 8.58 (s, 2H), 8.45 (d, J = 9.0 Hz, 1H), 7.99 (dd, J = 9.0, 1.8 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.73 - 7.63 (m, 2H), 7.59 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 7.3 Hz, 1H), 5.87 (dd, J = 11.5, 2.8 Hz, 1H), 5.36 (d, J = 6.3 Hz, 1H), 5.20 - 5.11 (m, 1H), 4.65 (t, J = 6.1 Hz, 1H), 4.33 (d, J = 1.8 Hz, 1H), 3.62 - 3.56 (m, 1H), 3.53 - 3.46 (m, 1H), 2.92 (s, 6H). [C 26 1H 25 F3N4O6S] + [M+H] + Calculated m / z for [M+H]: 578.0; Found: 578.0

[1242] Example 96

[1243] 3,4-Dichlorophenyl 3-deoxy-3-(3,4,5-trifluorobenzamido)-1-thio-α-D-galactopyranoside

[1244]

[1245] At 0 °C, sodium methoxide (13 mg, 0.37 mmol) was added to a stirred solution of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-(4-(3,4,5-trifluorobenzamido)-1-thio-α-D-galactopyranoside (50 mg, 0.08 mmol) in MeOH (2 mL) and DCM (0.5 mL). The resulting mixture was stirred at room temperature for 2 h. The pH was adjusted to 7 using 2 M HCl. The resulting mixture was concentrated and the residue was purified by reverse phase column chromatography. The title compound (18 mg, 45% yield) was obtained. 1 H NMR (400 MHz, DMSO) δ 8.52 - 8.39 (m, 1H), 7.96 - 7.84 (m, 2H), 7.79 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 8.4, 2.1 Hz, 1H), 5.81 (d, J = 5.3 Hz, 1H), 5.40 (d, J = 4.4 Hz, 1H), 5.14 (d, J = 5.4 Hz, 1H), 4.64 (t, J = 5.7 Hz, 1H), 4.38 - 4.26 (m, 1H), 4.14 - 3.95 (m, 2H), 3.92 - 3.87 (m, 1H), 3.60 - 3.47 (m, 1H), 3.36 (s, 1H). [C 19 H 17 Cl2F3NO5S] + (M + H) + ESI-MS m / z calculated for [C

[1246] Example 97

[1247] 3,4-Dichlorophenyl 3-deoxy-3-[4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1248]

[1249] 3,4-Dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-(4-(3,4,5-ethoxycarbonyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (117 mg, 0.20 mmol) was dissolved in EtOH (10 mL). TEA (200 mg) and water (1 mL) were added. The resulting mixture was stirred at 90 °C for 48 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give 22 mg of the title compound.

[1250] 11H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 8.5, 2.0 Hz, 1H), 5.97 - 5.83 (m, 2H), 5.45 (d, J = 6.8 Hz, 1H), 4.90 - 4.78 (m, 2H), 4.74 (t, J = 5.6 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 4.24 (t, J = 6.2 Hz, 1H), 4.01 (d, J = 6.2 Hz, 1H), 3.60 - 3.49 (m, 1H), 3.44 - 3.36 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H).

[1251] [C 17 H 20 Cl2N3O6S] + (M + H) + The calculated value of ESI-MS m / z for

[1252] Example 98

[1253] 3,4-Dichlorophenyl 3-deoxy-3-[4-(ethylaminocarbonyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[1254]

[1255] 3,4-Dichlorophenyl 3-deoxy-3-[4-(carboxy)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (80 mg, 0.18 mmol) and 2,2,2-trifluoroethylamine (36 mg, 0.37 mmol) were dissolved in DMF (2 mL). HATU (140 mg, 0.37 mmol) and N-ethyl-N-isopropyl-propan-2-amine (120 mg, 0.92 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours and then purified by preparative HPLC to obtain 40 mg of the title compound.

[1256] 1 1H NMR (400 MHz, DMSO) δ 9.18 (t, 1H), 8.58 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.66 - 7.45 (m, 2H), 5.89 (d, J = 5.0 Hz, 2H), 5.56 - 5.38 (m, 1H), 4.93 - 4.68 (m, 2H), 4.24 (t, J = 6.2 Hz, 1H), 4.15 - 3.90 (m, 3H), 3.58 - 3.44 (m, 2H). [C17 H 18 Cl2F3N4O5S] + (M+H) + Calculated ESI-MS m / z for (M+H): 517.0; Found: 517.0.

[1257] Example 99

[1258] 3,4-Dichlorophenyl 3-O-[(5,6-difluoro-2-oxo-3-chromenyl)methyl]-1-thio-α-D-galactopyranoside

[1259]

[1260] To a solution of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-O-propynyl-1-thio-α-...

Claims

1. Use of a compound of formula (1), a D-galactopyranose compound, in the preparation of a medicament for the treatment of diseases related to galectin-3 and ligand binding in mammals, wherein: the pyranose ring is α-D-galactopyranose, A is selected from wherein R 1 -R 5 is independently selected from H, F, and OCH3 optionally substituted with F; X is selected from S, SO, SO2, O; B is selected from a) phenyl or naphthyl, optionally substituted by the following groups: halogen; CN; methyl optionally substituted by F; OCH3 optionally substituted by F; OCH2CH3 optionally substituted by F; OH; -COOH; NR 28 R 29 , where R 28 and R 29 are independently selected from H and C 1-3 alkyl; and -CONH2; and b) pyridyl, thienyl or pyridazinyl, optionally substituted by a group selected from Cl, Br, CF3, OCH3, OH, NH2, CONH2 and CN; or a pharmaceutically acceptable salt thereof.

2. The use according to claim 1, wherein A is selected from Structural Formula 2, wherein R 1 and R 5 are selected from H and R 2 -R 4 is selected from F, or wherein R 1 -R 5 are both F, or wherein R 2 and R 3 are F and R 1 、R 4 and R 5 are H, or wherein R 2 and R 4 are F and R 1 、R 3 and R 5 are H, or wherein R 2 is F and R 1 and R 3 -R 5 is H, or wherein R 2 and R 4 are F, R 3 is OCH3, and R 1 and R 5 are H.

3. The use according to claim 1, wherein X is selected from S, SO and SO2.

4. Use according to claim 1, wherein B is selected from naphthyl, optionally substituted by NR 28 R 29 wherein R 28 and R 29 are independently selected from H and C 1-3 alkyl.

5. The use according to claim 1, wherein B is selected from phenyl or phenyl substituted with one, two or three substituents selected from Cl, F, Br, I, CN, methyl, OH, CF3, OCH2CH3, OCH3, OCF3, COOH and CONH2.

6. Use of a compound in the preparation of a medicament for the treatment of diseases related to galectin-3 and ligand binding in mammals, wherein the compound is selected from 4-acetanilido-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, benzyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 2-naphthyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 1-naphthyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3,4-dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfone, 4-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide, cyclohexyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 2-ethoxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3,4-dichlorophenyl 3-deoxy-3-[4-(2,3,4,5,6-pentafluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide, 5-chloro-6-cyano-pyridazin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-methoxy-6-cyano-pyridazin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Hydroxy-6-cyano-pyridazin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, Pyridinecarboxamide-5-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 4-Chloro-2-thienyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3,3'-Difluoro-cyclohexyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, n-Butyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 2-Chloroethoxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 4-Chloroethoxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 2-Chlorobenzyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside, 3,4-Dichlorobenzyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside, 3-Chloroethoxyphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 4-Chlorobenzyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside, Propyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-dimethylamino-naphthalen-2-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, Ethyl 3-deoxy-1-thio-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside, S-5-bromo-pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside, R-5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfone, S-5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide, R-5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfoxide, 5-(Dimethylamino)-naphthalen-2-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosyl sulfone.

Images