Hydroxyheterocycloalkane-carbamoyl derivatives

Abstract

The present invention relates to X, Ar 1 , Ar 2 , L, n, m and R 1 The present invention relates to compounds of formula (I) as described herein, their preparation, pharma- ceutically acceptable salts, and their use as medicaments, pharmaceutical compositions comprising one or more compounds of formula (I), and their use, in particular as galectin-3 inhibitors. [Formula 1] TIFF2024506182000060.tif75156

Description

[Technical field]

[0001] The present invention relates to compounds of formula (I) that are galectin-3 inhibitors and their use in the prevention or treatment of diseases and disorders involving the binding of galectin-3 to its natural ligands. The invention also relates to related aspects including processes for the preparation of said compounds, pharmaceutical compositions comprising one or more compounds of formula (I) and their medical use as galectin-3 inhibitors. The compounds of formula (I) may inter alia be used as single agents or in combination with one or more therapeutic agents. [Background technology]

[0002] Galectins are a family of proteins defined based on a conserved β-galactoside-binding site found within their characteristic ∼130 amino acid (aa) carbohydrate recognition domain (CRD) (Barondes SH et al., Cell 1994;76,597-598). Genome sequences of human, mouse and rat have revealed the presence of at least 16 conserved galectins and galectin-like proteins in a mammalian genome (Leffler H. et al., Glycoconj. J. 2002,19,433-440). Three galectin subclasses have been identified so far: prototypical galectins, which contain a single carbohydrate recognition domain (CRD); tandem repeats of proline- and glycine-rich short stretches fused to the CRD; and tandem-repeat-type galectins, which have two distinct CRDs linked in tandem by a linker (Zhong X., Clin Exp Pharmacol Physiol. 2019;46:197-203). Galectins can bind bivalently or multivalently, e.g., crosslinking glycoconjugates on the cell surface to trigger cell signaling events. By this mechanism, galectins regulate a wide range of biological processes (Sundblad V. et al., Histol Histopathol 2011;26:247-265).

[0003] Galectin-3 (Gal-3), the only chimeric form of the galectin family, has a molecular mass of 32-35 kDa and consists of 250 amino acid residues in humans, a highly conserved CRD and an atypical N-terminal domain (ND). Galectin-3 is monomeric up to high concentrations (100 μM) but can aggregate with ligands at much lower concentrations, which is promoted by its N-terminal non-CRD region through an oligomerization mechanism that is not fully understood (Johannes, L. et al., Journal of Cell Science 2018;131, jcs208884).

[0004] Gal-3 is widely distributed in the body, but its expression level varies among different organs. Depending on its extracellular or intracellular localization, it can exhibit a wide range of biological functions, including immune regulation, host-pathogen interactions, angiogenesis, cell migration, wound healing, and apoptosis (Sundblad V. et al., Histol Histopathol 2011;26:247-265). Gal-3 is highly expressed in many human tumors and cell types such as myeloid cells, inflammatory cells (macrophages, mast cells, neutrophils, T cells, eosinophils, etc.), fibroblasts, and cardiomyocytes (Zhong X. et al., Clin Exp Pharmacol Physiol. 2019;46:197-203), indicating that Gal-3 is involved in the control of inflammatory and fibrotic processes (Henderson NC. et al., Immunological Reviews 2009;230:160-171; Sano H. et al., J Immunol. 2000;165(4):2156-64). Furthermore, the expression level of Gal-3 protein is upregulated in certain pathological conditions such as neoplasia and inflammation (Chiariotti L. et al., Glycoconjugate Journal 2004 19, 441-449; Farhad M. et al., OncoImmunology 2018, 7:6, e1434467).

[0005] asthma (Gao P. et al., Respir Res. 2013, 14:136; Rao SP et al., Front Med (Lausanne) 2017;4:68), rheumatoid arthritis, multiple sclerosis, diabetes, plaque psoriasis (Lacina L. et al., Folia Biol (Prague) 2006;52(1-2):10-5), atopic dermatitis (Saegusa J. et al., Am J Pathol. 2009, 174(3):922-31), endometriosis (Noel JC et al., Appl Immunohistochem Mol Morphol. 2011 19(3):253-7) or viral encephalitis (Liu FT et al., Ann N There is a large body of evidence supporting the functional involvement of Gal-3 in the pathogenesis of inflammatory / autoimmune diseases such as inflammatory bowel disease (Y Acad Sci. 2012;1253:80-91; Henderson NC et al., Immunol Rev. 2009;230(1):160-71; Li P et al., Cell 2016;167:973-984). Recently, Gal-3 has been implicated in the progression of chronic inflammation and fibrosis in organs, e.g., the liver (Henderson NC et al., PNAS 2006;103:5060-5065; Hsu DK et al., Int J Cancer. 1999;81(4):519-26), kidney (Henderson NC et al., Am. J. Pathol. 2008;172:288-298; Dang Z. et al., Transplantation. 2012;93(5):477-84), lung (Mackinnon AC et al., Am. J. Respir. Crit. Care Med 2012;185:537-546; Nishi Y. et al., Allergol Int. 2007;56(1):57-65), heart, (Thandavarayan RA et al., Biochem Pharmacol.2008, 75(9):1797-806;Sharma Gal-3 has been noted to play an important role in the nervous system (Burguillos MA et al., Cell Rep. 2015, 10(9):1626-1638) and corneal neovascularization (Chen WS. et al., Investigative Ophthalmology & Visual Science 2017, Vol. 58, 9-20). Furthermore, Gal-3 has been found to be involved in dermal thickening of keloid tissue (Arciniegas E. et al., The American Journal of dermatopathology 2019; 41(3):193-204) and systemic sclerosis (SSc), particularly in the dermal fibrosis and proliferative vasculopathy observed in such pathologies (Taniguchi T. et al., J Rheumatol. 2012, 39(3):539-44). Gal-3 was found to be upregulated in patients with chronic kidney disease (CKD)-associated renal failure, especially in those with diabetes. Interestingly, data from this patient population showed a correlation between Gal-3 upregulation in the glomeruli and the observed urinary protein excretion (Kikuchi Y. et al., Nephrol Dial Transplant. 2004, 19(3):602-7). In addition, a recent prospective study from 2018 showed that high plasma levels of Gal-3 increase the risk of developing concomitant CKD, especially in hypertensive populations (Rebholz et al., 2016). Gal-3 has been shown to be involved in atherosclerosis (Nachtigal M. et al., Am J Pathol. 1998;152(5):1199-208), coronary artery disease (Falcone C. et al., Int J Immunopathol Pharmacol 2011, 24(4):905-13), heart failure and thrombosis (Nachtigal M. et al., Am J Pathol.1998;152(5):1199-208;Gehlken C. et al., Heart Fail Clin.2018, 14(1):75-92;DeRoo EP. et al., Blood. 2015, 125(11):1813-21) and cardiovascular diseases (Zhong X. et al., Clin Exp Pharmacol Physiol. 2019, 46(3):197-203). Blood levels of Gal-3 are elevated in obese and diabetic patients and are associated with increased risk for micro- and macrovascular complications (such as heart failure, nephropathy / retinopathy, peripheral arterial disease, cerebrovascular events, or myocardial infarction) (Qi-hui-Jin et al., Chin Med J(Engl). 2013, 126(11):2109-15). Gal-3 has been shown to promote carcinogenesis, cancer progression and metastasis (Vuong L. et al., Cancer Res 2019(79)(7)1480-1492), function as a pro-tumor factor by acting within the microtumor environment and suppress immune surveillance (Ruvolo PP. et al., Biochim Biophys Acta. 2016 Mar, 1863(3):427-437; Farhad M. et al., Oncoimmunology 2018 Feb 20;7(6):e1434467). Among the cancers expressing high levels of Gal-3, lymphomas, carcinomas, non-small cell lung cancers, melanomas and neuroblastomas have been found, in addition to those involving the thyroid, central nervous system, tongue, breast, gastric lineage, head and neck squamous cells, pancreas, bladder, kidney, liver, parathyroid and salivary glands (Sciacchitano S. et al., Int J Mol Sci 2018 Jan 26, 19(2):379).

[0006] In addition, inhibition of Gal-3 has been shown to be effective in preventing COVID-19 (Caniglia JL et al., Peer J 2020, 8:e9392) and influenza H5N1 (Chen YJ et al., Am. J. Pathol. 2018, 188(4), 1031-1042), possibly due to its anti-inflammatory effects.

[0007] Recently, Gal-3 inhibitors have been shown to have positive effects when used in combination immunotherapy (Galectin Therapeutics. Press release, February 7, 2017) and in idiopathic pulmonary fibrosis (Galecto Biotech. Press release, March 10, 2017) and NASH cirrhosis (December 5, 2017). WO20180209276, WO2018209255 and WO20190890080 disclose compounds having binding affinity to galectin proteins for the treatment of systemic insulin resistance disorders. Thus, Gal-3 inhibitors, alone or in combination with other therapies, would be useful in the prevention or treatment of diseases or disorders such as organ fibrosis, cardiovascular diseases and disorders, acute and chronic kidney injury, liver diseases and disorders, interstitial lung diseases and disorders, eye diseases and disorders, cell proliferative disorders and cancer, inflammatory and autoimmune diseases and disorders, gastrointestinal diseases and disorders, pancreatic diseases and disorders, abnormal angiogenesis-related diseases and disorders, brain-related diseases and disorders, neuropathic pain and peripheral neuropathies, and / or transplant rejection.

[0008] Synthetic inhibitors of Gal-3 that are being explored as antifibrotic agents have been described in various publications and patent applications (see, e.g., WO2005113568, WO2005113569, WO2014067986, WO2016120403, US20140099319, WO2019067702, WO2019075045, WO2014078655, WO2020078807, WO2020078808, and WO2020210308).

[0009] The present invention provides novel compounds of formula (I) that are galectin-3 inhibitors. The compounds of the present invention may therefore be useful in the prevention or treatment of diseases and disorders in which modulation of the binding of Gal-3 to its natural carbohydrate ligands is required. Summary of the Invention

[0010] 1) In a first aspect, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof (the absolute configuration is as shown in each formula): [ka]

[0011] (In the formula, n and m each independently represent an integer of 1 or 2, and n+m is 2 or 3; X is O or NR 2 R 2 is hydrogen, C 1-3 -Alkyl (especially methyl or ethyl), -CO-H, -SO2-C 1-3 -Alkyl (especially SO2-CH3) or -CO-C 1-3 -alkyl (especially -CO-CH3); Ar 1 teeth, aryl (especially phenyl) substituted by 1, 2, 3, 4 or 5 substituents (especially substituted by 2 or 3 substituents), the substituents being halogen; methyl; cyano; methoxy; trifluoromethyl; trifluoromethoxy; and NR N11 R N12 (R N11 represents hydrogen, and R N12 is hydroxy-C 2-3 -alkyl or R N11 and R N12 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl selected from morpholin-4-yl, azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl, which 4- to 6-membered heterocyclyl is unsubstituted or substituted by one hydroxyl, in particular said substituents being independently selected from halogen or methyl, aryl (in particular phenyl); - a 5- or 6-membered heteroaryl which is independently unsubstituted or substituted by one or two substituents, said substituents being independently selected from halogen, methyl, cyano and methoxy; or - 9- or 10-membered heteroaryl, which is independently unsubstituted or substituted by one methyl; represents; R 1 teeth, - Hydroxy; - C 1-3 -alkoxy; - -O-CO-C 1-3 -alkyl; - -O-CH2-CH2-OH; or - -O-CH2-CO-R 1X (R 1X teeth, -- Hydroxy; --morpholin-4-yl; or -- -NR N21 R N22 (R N21 and R N22 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl selected from azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl, the 4- to 6-membered heterocyclyl containing one hydride. Replaced by Proxy. ); represents ); represents; [Such a substituent R 1 Especially C 1-3 -alkoxy (especially methoxy). L represents a direct bond, methylene or ethylene (especially a direct bond); Ar 2 teeth, - phenyl or 5- or 6-membered heteroaryl (especially phenyl), which phenyl or 5- or 6-membered heteroaryl is independently unsubstituted or substituted by 1, 2 or 3 substituents (especially substituted by 1 or 2 substituents), said substituents being selected from the group consisting of C 1-6 -Alkyl (especially methyl), C 3-6 -Cycloalkyl, -CH2-C 3-6 -Cycloalkyl, C 1-3 -fluoroalkyl, C 1-3-Fluoroalkoxy, C 1-3 - independently selected from alkoxy (especially methoxy), halogen, morpholin-4-yl, amino, ethynyl and cyano (especially C 1-6 -Alkyl (especially methyl), C 1-3 -alkoxy (especially methoxy), halogen and cyano), phenyl or 5- or 6-membered heteroaryl (especially phenyl); - a 9-membered bicyclic heteroaryl or a 10-membered bicyclic heteroaryl, wherein the 9- or 10-membered bicyclic heteroaryl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from methyl, methoxy, and halogen; or - Naphthyl; represents.)

[0012] In a subembodiment, the compound of formula (I) or, mutatis mutandis, the nitrogen linking the heterocycloalkane to the remainder of the molecule and the hydroxy substituent of the heterocycloalkane shown in each formula are in a trans configuration relative to each other. For the avoidance of doubt, the compound of formula (I) may in particular be a compound of formula (I) as shown in embodiment 3) below. S ), a compound of formula (I R ) or any mixture thereof.

[0013] 2) A second aspect of the invention relates to compounds of formula (I) according to embodiment 1), which are also compounds of formula (II), (III) or (IV) (with the absolute configuration as indicated in the respective formulas):

[0014] [ka]

[0015] (In each of formula (II), formula (III) and formula (IV), the group X, Ar 1 , Ar 2 , R1 and L are independently as defined in embodiment 1).

[0016] In a first subembodiment, the compound of embodiment 2) is one in which X is O; 1 , Ar 2 , R 1 and L is independently as defined in embodiment 1) of formula (II), (III) or (IV).

[0017] In a second subembodiment, the compound of embodiment 2) is such that X is NR 2 (R 2 is hydrogen, C 1-3 -Alkyl (especially methyl or ethyl), -CO-H, -SO2-C 1-3 -Alkyl (especially SO2-CH3), -CO-C 1-3 -alkyl (especially -CO-CH3); 1 , Ar 2 , R 1 and L is independently as defined in embodiment 1) of formula (II), (III) or (IV).

[0018] 3) The third aspect of the present invention relates to a compound represented by formula (I S ) according to embodiment 1), which is also a compound of formula (I) (with the absolute configurations being as indicated in the respective formulas):

[0019] [ka]

[0020] (In the formula, group X, Ar 1 , Ar 2 , R 1 , L, m and n are as defined in embodiment 1). In a particular embodiment, the formula (I S The compound of formula (II S ), formula (III S ) or formula (IV S ) (the absolute configurations are as shown in the respective formulas):

[0021] [ka]

[0022] (Formula (II S ), formula (III S ) or formula (IV S ) in each of the groups X, Ar 1 , Ar 2 , R 1 and L are independently as defined in embodiment 1).

[0023] In a first subembodiment, the compound of embodiment 3) is one in which X is O; 1 , Ar 2 , R 1 and L are independently as defined in embodiment 1), S ), (III S ) or (IV S ) compound.

[0024] In a second subembodiment, the compound of embodiment 3) is such that X is NR 2 (R 2 is hydrogen, C 1-3 -Alkyl (especially methyl or ethyl), -CO-H, -SO2-C 1-3 -Alkyl (especially SO2-CH3), -CO-C 1-3 -alkyl (especially -CO-CH3); 1 , Ar 2 , R 1 and L are independently as defined in embodiment 1), S ), (III S ) or (IV S ) compound.

[0025] 4) Another aspect of the present invention is a compound represented by the formula (I R ) according to embodiment 1), which is also a compound of formula (I) (with the absolute configurations being as indicated in the respective formulas):

[0026] [ka]

[0027] (In the formula, group X, Ar 1 , Ar 2 , R 1 In a particular embodiment, the formula (I R The compound of formula (II R ), formula (III R ) or formula (IV R ) (the absolute configurations are as shown in the respective formulas):

[0028] [ka]

[0029] (Formula (II R ), formula (III R ) or formula (IV R ) in each of the groups X, Ar 1 , Ar 2 , R 1 and L are independently as defined in embodiment 1).

[0030] In a first subembodiment, the compound of embodiment 4) is one in which X is O; 1 , Ar 2 , R 1 and L are independently as defined in embodiment 1), R ), (III R ) or (IV R ) compound.

[0031] In a second subembodiment, the compound of embodiment 4) is such that X is NR 2 (R 2 is hydrogen, C 1-3 -Alkyl (especially methyl or ethyl), -CO-H, -SO2-C 1-3 -Alkyl (especially SO2-CH3), -CO-C 1-3 -alkyl (especially -CO-CH3); 1, Ar 2 , R 1 and L are independently as defined in embodiment 1), R ), (III R ) or (IV R ) compound.

[0032] The compounds of formula (I) have five chiral or asymmetric centers located in the tetrahydropyran moiety with the absolute configuration as set out in formula (I). The compounds of formula (I) further have two chiral or asymmetric centers located in the heterocycloalkane moiety. In certain embodiments, the compounds of formula (I) or, mutatis mutandis, the nitrogen linking the heterocycloalkane to the remainder of the molecule and the hydroxy substituent of the heterocycloalkane as shown in each formula are in a relative trans configuration. For the avoidance of doubt, the compounds of formula (I) are particularly preferred as shown in embodiment 3). S ), a compound of formula (I R ) or any mixture thereof.

[0033] In addition, the compounds of formula (I) may contain one, and possibly more, chiral or asymmetric centers, such as one or more additional asymmetric carbon atoms. Thus, the compounds of formula (I) may exist as a mixture of stereoisomers or, preferably, as pure stereoisomers. Mixtures of stereoisomers may be separated by methods known to those skilled in the art.

[0034] A particular compound (or generic structure) may be, for example, an (R)- or (S)-enantiomer. When described as being in a particular absolute configuration, such description is understood to mean the respective compound (or generic structure) in enriched, particularly essentially pure, enantiomeric form. Similarly, when a particular asymmetric center of a compound is described as being in the (R)- or (S)-configuration, or in a particular relative configuration, such description is understood to mean said compound in enriched, particularly essentially pure form, with respect to each configuration of said asymmetric center. Similarly, two chiral centers, for example in a cyclic group, may be present in a particular relative configuration.

[0035] The term "enriched", when used in connection with stereoisomers, is understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least 70:30, in particular at least 90:10, with respect to the total of each other stereoisomer / each other stereoisomer (i.e. with a purity of at least 70% by weight, in particular at least 90% by weight).

[0036] The term "essentially pure", when used in relation to stereoisomers, is understood in the context of the present invention to mean that each stereoisomer is present in a purity of at least 95 percent by weight, in particular at least 99 percent by weight, with respect to each other stereoisomer / total of each other stereoisomer.

[0037] The present invention also relates to isotopically labeled, especially 2 H (deuterium)-labeled compounds of formula (I) according to embodiments 1) to 18), which are identical to compounds of formula (I) except that one or more atoms are respectively replaced by atoms having the same atomic number but an atomic mass different from that normally found in nature. Isotopically labeled, especially 2 H (deuterium)-labeled compounds of formula (I), (II), (III), (IV), (I s ), (II s ), (III s ), (IV s ), (I R ), (II R), (III R ), (IV R Compounds of formula (V) and (V) and their salts are included within the scope of the present invention. 2 Substitution with H (deuterium) can increase metabolic stability, for example, prolonging in-vivo half-life, or reducing the required dose, or reducing inhibition of cytochrome P450 enzymes, for example, improving safety profile. In one embodiment of the present invention, the compounds of formula (I) are not isotopically labeled, or they are labeled only with one or more deuterium atoms. In a subembodiment, the compounds of formula (I) are not isotopically labeled at all. Isotopically labeled compounds of formula (I) may be prepared in a similar manner to the method described below, except that appropriate isotopic species of suitable reagents or starting materials are used.

[0038] In this patent application, bonds drawn as dotted lines indicate the point of attachment of the depicted group. For example, the group

[0039] [ka]

[0040] is a 3-fluorophenyl group.

[0041] When the plural is used for a compound, a salt, a pharmaceutical composition, a disease, etc., it is understood to mean a singular compound, It is intended to mean salts and the like.

[0042] Any reference to compounds of formula (I) according to embodiments 1) to 18) will, where appropriate, be understood to also refer to salts (especially pharma- ceutically acceptable salts) of such compounds.

[0043] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesired toxicological effects. Such salts include inorganic or organic acid and / or base addition salts, depending on the presence of basic and / or acidic groups in the subject compound. For reference, see, for example, "Handbook of Pharmaceutical Salts. Properties, Selection and Use.", P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and "Pharmaceutical Salts and Co-crystals", Johan Wouters and Luc See Quere (Eds.), RSC Publishing, 2012.

[0044] The definitions described herein are the same as those of formulas (I), (II), (III), (IV ... s ), (II s ), (III s ), (IV s ), (I R ), (II R ), (III R ), (IV R (V) and (V) are applied uniformly throughout the specification and claims, unless a broader or narrower definition is given by a specific definition, and apply mutatis mutandis throughout the specification and claims. It is to be understood that any definition or preferred definition of a term may independently (and together) define and replace the respective term in any or all other terms or preferred definitions defined herein.

[0045] In this patent application, compounds are named using the IUPAC nomenclature system, but may also be named using the carbohydrate nomenclature system. Thus, the group:

[0046] [ka]

[0047] can be named (2R,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-phenyl-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carbonyl or, alternatively, 1,3-di-deoxy-3-[4-phenyl-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside-1-carbonyl, with the carbocation being the point of attachment to the remainder of the molecule. The absolute configuration of the carbon atom bearing the yl group is in the (2R)- or beta-configuration. For example, the compound (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide is understood to also be called: 1,3-di-deoxy-2-O-methyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-N-(3-chlorophenyl)-N-((3S,4R)-4-hydroxy-3-tetrahydrofuranyl)-beta-D-galacto-pyranose-1-carboxamide.

[0048] Whenever a substituent is described as optional, it is understood that such a substituent may be absent (i.e., the respective residue is unsubstituted with respect to such optional substituent), in which case all sites having a free valence (e.g., in an aromatic ring, to which such optional substituent may be attached, such as ring carbon atoms and / or ring nitrogen atoms having a free valence) are replaced with hydrogen, as the case may be. Similarly, when the term "optionally" is used in reference to (ring) heteroatoms, this term means that each optional heteroatom, etc. is absent (i.e., a group has no heteroatoms / is a carbocyclic ring / etc.) or that each optional heteroatom, etc. is present as expressly defined. Unless expressly defined otherwise in each embodiment or claim, the groups defined herein are unsubstituted.

[0049] The term "halogen" means fluorine, chlorine, bromine or iodine (especially fluorine, chlorine or bromine).

[0050] The term "alkyl", used alone or in combination, means a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. x-y The term "-alkyl" (x and y are each integers) refers to an alkyl group as defined above having x to y carbon atoms. For example, C 1-6 -Alkyl groups have 1 to 6 carbon atoms. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, 3-methyl-butyl, 2,2-dimethyl-propyl and 3,3-dimethyl-butyl. Methyl is preferred. For the avoidance of doubt, when a group is described as, for example, propyl or butyl, it is meant to be n-propyl or n-butyl, respectively. Ar 1 Or Ar 2 The substituent of "C 1-6 When referring to "-alkyl", the term specifically refers to methyl. 2 "C 1-6 When referring to "C-alkyl", the term specifically refers to methyl or ethyl. 1-3 The term "-alkyl" is "-SO2-C 1-3 -Alkyl" or "-CO-C 1-3 -alkyl" etc. 2 When used in reference to the substituent, the term specifically refers to methyl.

[0051] The term "fluoroalkyl", used alone or in combination, means an alkyl group as defined above having one to three carbon atoms in which one or more, and optionally all, hydrogen atoms have been replaced by fluorine. x-y The term "fluoroalkyl" (x and y are each integers) refers to a fluoroalkyl group as defined above having x to y carbon atoms. For example, C1-3 -Fluoroalkyl groups have 1 to 3 carbon atoms and 1 to 7 hydrogen atoms are replaced by fluorine.

[0052] The term "fluoroalkoxy", used alone or in combination, means an alkoxy group as defined above having 1 to 3 carbon atoms in which one or more (and in some cases all) hydrogen atoms have been replaced by fluorine. x-y The term "fluoroalkoxy" (x and y are each integers) refers to a fluoroalkoxy group as defined above having x to y carbon atoms. For example, 1-3 A -fluoroalkoxy group has 1 to 3 carbon atoms and 1 to 7 hydrogen atoms are replaced by fluorine.

[0053] The term "cycloalkyl", used alone or in combination, specifically refers to a saturated monocyclic, or a fused, bridged or spiro-bicyclic hydrocarbon ring having 3 to 8 carbon atoms. x-y The term "cycloalkyl" (x and y are each integers) refers to a cycloalkyl group as defined above having x to y carbon atoms. For example, C 3-6 -cycloalkyl groups have 3 to 6 carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0054] The term "alkoxy", used alone or in combination, means an alkyl-O- group, wherein the alkyl group is as previously defined. x-y The term "-alkoxy" (x and y are each integers) means an alkoxy group as defined above having x to y carbon atoms. Preferred is ethoxy and especially methoxy. R 1 "C 1-3 When referring to "-alkoxy", the term specifically refers to methoxy. 2 The substituent of "C 1-3When referring to "-alkoxy", the term specifically refers to methoxy.

[0055] The term "aryl", whether used alone or in combination, means phenyl or naphthyl, especially phenyl, which aryl groups are unsubstituted or substituted as expressly defined. The substituent Ar 1 Or Ar 2 In this regard, the term particularly denotes phenyl.

[0056] The term "heteroaryl", whether used alone or in combination, unless a broader or narrower definition is expressly indicated, refers to a 5-10 membered monocyclic or bicyclic aromatic ring having from 1 to up to 4 heteroatoms, each of which is independently selected from oxygen, nitrogen and sulfur. Representative examples of such heteroaryl groups are 5-membered heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.; 6-membered heteroaryl groups such as pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, etc.; and indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, and 8-10 membered bicyclic heteroaryl groups such as benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyridazinyl and imidazothiazolyl. The above heteroaryl groups are unsubstituted or substituted as expressly defined.

[0057] The substituent Ar representing "5- or 6-membered heteroaryl" 1With respect to the substituent Ar which represents a "5- or 6-membered heteroaryl", this term particularly refers to thiazolyl (especially 4-chlorothiazol-2-yl). 2 With respect to this term it is meant in particular furanyl, thiophenyl, pyrrolyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl or pyrimidinyl; said 5- or 6-membered heteroaryl being unsubstituted or substituted as expressly defined.

[0058] Substituent Ar representing "9- or 10-membered bicyclic heteroaryl" 1 With respect to the term, in particular, benzothiazolyl (especially 2-methylbenzo[d]thiazol-6-yl) is meant. 2 With respect to the term, in particular, indolyl, benzothiophenyl, benzothiazolyl or benzimidazolyl, in which the 9-membered bicyclic heteroaryl is unsubstituted or substituted as expressly defined. 2 With respect to the above, this term refers in particular to quinolinyl or quinoxalinyl; said 10-membered bicyclic heteroaryl being unsubstituted or substituted as expressly defined.

[0059] The term "cyano" refers to the group --CN.

[0060] Whenever the word "between" is used to describe a range of numerical values, it is intended that the endpoints of the stated range are expressly included in that range. This means, for example, that when a temperature range is described as being between 40° C. and 80° C., the endpoints 40° C. and 80° C. are included in the range; or, when a variable is defined as an integer between 1 and 4, it means that the variable is the integer 1, 2, 3, or 4.

[0061] When not used in reference to temperature, the term "about" placed before a numerical value "X" means in this application between 10% of XX and 10% of X+X, preferably between 5% of XX and 5% of X+X. In the specific case of temperatures, the term "about" placed before a temperature "Y" means in this application between a temperature Y-10°C and Y+10°C, preferably between Y-5°C and Y+5°C. Furthermore, the term "room temperature" as used herein means a temperature of about 25°C.

[0062] Further aspects of the invention are described below: 5) In another embodiment, Ar 1 represents phenyl, substituted by 1, 2, 3, 4 or 5 substituents (in particular substituted by 2 or 3 substituents), said substituents being independently selected from halogen; methyl; cyano; and methoxy;

[0063] 6) In another embodiment, Ar 1 represents phenyl, substituted by 2 or 3 substituents, said substituents being independently selected from halogen and methyl;

[0064] In a subembodiment, at least one of the substituents is attached to the meta or para position of the phenyl.

[0065] 7) In another embodiment, Ar 1 represents phenyl substituted with 2 or 3 substituents, said substituents being independently selected from halogen, methyl and cyano; at least one of the substituents is attached at the meta or para position of the phenyl; in particular, if a para-substituent is present, said para-substituent is halogen or methyl; In particular, if a meta-substituent is present, said meta-substituent is halogen; it relates to a compound according to any of embodiments 1) to 4).

[0066] 8) Another embodiment is Ar 1 represents phenyl substituted by 2 or 3 substituents independently selected from halogen; methyl; and cyano (in particular halogen or methyl); - if the phenyl is substituted by two substituents, at least one of the substituents is in the meta position and the substituent is in particular a halogen; the other substituent is in particular the other meta position or is in the para position; or - if the phenyl is substituted by three substituents, said substituents are Ar 1 forming a 2,3,4 or 3,4,5 substitution pattern relative to the point of attachment of, in particular the substituent at the para position is halogen or methyl and the remaining substituents are independently halogen (especially fluoro); ; relating to a compound according to any one of embodiments 1) to 4).

[0067] 9) In another embodiment, Ar 1 but,

[0068] [ka]

[0069] represents; relating to a compound according to any of embodiments 1) to 4).

[0070] In a subembodiment, Ar 1 stands in particular for a radical selected from group A) or B):

[0071] [ka]

[0072] Each of said groups A) and B) forms a specific subembodiment.

[0073] In another subembodiment, Ar 1 particularly represents a radical selected from group C), D) or E):

[0074] [ka]

[0075] Each of the groups C), D) and E) forms a specific subembodiment.

[0076] 10) In another aspect, R 1 represents methoxy; relates to compounds according to any one of embodiments 1) to 9).

[0077] 11) Another embodiment relates to compounds according to any one of embodiments 1) to 10), wherein L represents a direct bond.

[0078] 12) In another embodiment, Ar 2 is phenyl, unsubstituted or substituted by 1, 2 or 3 substituents (in particular substituted by 1 or 2 substituents), said substituents being 1-6 -Alkyl (especially methyl), C 1-3 -representing phenyl, independently selected from alkoxy (especially methoxy), halogen and cyano (especially where at least one of said substituents is in the meta position); relating to compounds according to any one of embodiments 1) to 11).

[0079] 13) In another embodiment, Ar 2 is phenyl and is substituted by 1 or 2 substituents, said substituents being C 1-4 -Alkyl (especially methyl), C 1-3 -representing phenyl, independently selected from alkoxy (especially methoxy), halogen and cyano (especially where at least one of said substituents is in the meta position); relating to compounds according to any one of embodiments 1) to 11).

[0080] 14) Another embodiment is Ar 2 is phenyl, - substituted by one substituent, said substituent being C 1-4 -Alkyl (especially methyl), C 1-3- selected from alkoxy (especially methoxy), halogen and cyano (especially where the substituents are in the meta position); or - substituted by two substituents, said substituents being C 1-4 -Alkyl (especially methyl), C 1-3 - independently selected from alkoxy (especially methoxy), halogen and cyano (especially where the substituents are in the meta position); represents phenyl; relates to compounds according to any one of embodiments 1) to 11).

[0081] 15) Another embodiment is the fragment L-Ar 2 but:

[0082] [ka]

[0083] represents; relating to a compound according to any one of embodiments 1) to 10).

[0084] 16) The present invention thus relates to compounds of formula (I) as defined in embodiment 1) or such compounds further defined by the features of any one of embodiments 2) to 15) according to their respective subdivisions; pharma- ceutically acceptable salts thereof; and uses of such compounds as further described below. For the avoidance of any doubt, the following embodiments in particular with respect to compounds of formula (I) are possible, contemplated and are specifically disclosed herein as individual forms: 2+1、3+1、4+1、5+1、5+2+1、5+3+1、5+4+1、6+1、6+2+1、6+3+1、6+4+1、7+1、7+2+1、7+3+1、7+4+1、8+1、8+2+1、8+3+1、8+4+1、9+1、9+2+1、9+3+1、9+4+1、10+1、10+2+1、10+3+1、10+4+1、10+5+1、10+5+2+1、10+5+3+1、10+5+4+1、10+6+1、10+6+2+1、10+6+3+1、10+6+4+1、10+7+1、10+7+2+1、10+7+3+1、10+7+4+1、10+8+1、10+8+2+1、10+8+3+1、10+8+4+1、10+9+1、10+9+2+1、10+9+3+1、10+9+4+1、11+1、11+2+1、11+3+1、11+4+1、11+5+1、11+5+2+1、11+5+3+1、11+5+4+1、11+6+1、11+6+2+1、11+6+3+1、11+6+4+1、11+7+1、11+7+2+1、11+7+3+1、11+7+4+1、11+8+1、11+8+2+1、11+8+3+1、11+8+4+1、11+9+1、11+9+2+1、11+9+3+1、11+9+4+1、11+10+1、11+10+2+1、11+10+3+1、11+10+4+1、11+10+5+1、11+10+5+2+1、11+10+5+3+1、11+10+5+4+1、11+10+6+1、11+10+6+2+1、11+10+6+3+1、11+10+6+4+1、11+10+7+1、11+10+7+2+1、11+10+7+3+1、11+10+7+4+1、11+10+8+1、11+10+8+2+1、11+10+8+3+1、11+10+8+4+1、11+10+9+1、11+10+9+2+1、11+10+9+3+1、11+10+9+4+1、12+1、12+2+1、12+3+1、12+4+1、12+5+1、12+5+2+1、12+5+3+1、12+5+4+1、12+6+1、12+6+2+1、12+6+3+1、12+6+4+1、12+7+1、12+7+2+1、12+7+3+1、12+7+4+1、12+8+1、12+8+2+1、12+8+3+1、12+8+4+1、12+9+1、12+9+2+1、12+9+3+1、12+9+4+1、12+10+1、12+10+2+1、12+10+3+1、12+10+4+1、12+10+5+1、12+10+5+2+1、12+10+5+3+1、12+10+5+4+1、12+10+6+1、12+10+6+2+1、12+10+6+3+1、12+10+6+4+1、12+10+7+1、12+10+7+2+1、12+10+7+3+1、12+10+7+4+1、12+10+8+1、12+10+8+2+1、12+10+8+3+1、12+10+8+4+1、12+10+9+1、12+10+9+2+1、12+10+9+3+1、12+10+9+4+1、12+11+1、12+11+2+1、12+11+3+1、12+11+4+1、12+11+5+1、12+11+5+2+1、12+11+5+3+1、12+11+5+4+1、12+11+6+1、12+11+6+2+1、12+11+6+3+1、12+11+6+4+1、12+11+7+1、12+11+7+2+1、12+11+7+3+1、12+11+7+4+1、12+11+8+1、12+11+8+2+1、12+11+8+3+1、12+11+8+4+1、12+11+9+1、12+11+9+2+1、12+11+9+3+1、12+11+9+4+1、12+11+10+1、12+11+10+2+1、12+11+10+3+1、12+11+10+4+1、12+11+10+5+1、12+11+10+5+2+1、12+11+10+5+3+1、12+11+10+5+4+1、12+11+10+6+1、12+11、 +10+6+2+1、12+11+10+6+3+1、12+11+10+6+4+1、12+11+10+7+1、12+11+10+7+2+1、12+11+10+7+3+1、12+11+10+7+4+1、12+11+10+8+1、12+11+10+8+2+1、12+11+10+8+3+1、12+11+10+8+4+1、12+11+10+9+1、12+11+10+9+2+1、12+11+10+9+3+1、12+11+10+9+4+1、 13+1、13+2+1、13+3+1、13+4+1、13+5+1、13+5+2+1、13+5+3+1、13+5+4+1、13+6+1、13+6+2+1、13+6+3+1、13+6+4+1、13+7+1、13+7+2+1、13+7+3+1、13+7+4+1、13+8+1、13+8+2+1、13+8+3+1、13+8+4+1、13+9+1、13+9+2+1、13+9+3+1、13+9+4+1、13+10+1、13+10+2+1、13+10+3+1、13+10+4+1、13+10+5+1、13+10+5+2+1、13+10+5+3+1、13+10+5+4+1、13+10+6+1、13+10+6+2+1、13+10+6+3+1、13+10+6+4+1、13+10+7+1、13+10+7+2+1、13+10+7+3+1、13+10+7+4+1、13+10+8+1、13+10+8+2+1、13+10+8+3+1、13+10+8+4+1、13+10+9+1、13+10+9+2+1、13+10+9+3+1、13+10+9+4+1、13+11+1、13+11+2+1、13+11+3+1、13+11+4+1、13+11+5+1、13+11+5+2+1、13+11+5+3+1、13+11+5+4+1、13+11+6+1、13+11+6+2+1、13+11+6+3+1、13+11+6+4+1、13+11+7+1、13+11+7+2+1、13+11+7+3+1、13+11+7+4+1、13+11+8+1、13+11+8+2+1、13+11+8+3+1、13+11+8+4+1、13+11+9+1、13+11+9+2+1、13+11+9+3+1、13+11+9+4+1、13+11+10+1、13+11+10+2+1、13+11+10+3+1、13+11+10+4+1、13+11+10+5+1、13+11+10+5+2+1、13+11+10+5+3+1、13+11+10+5+4+1、13+11+10+6+1、13+11+10+6+2+1、13+11+10+6+3+1、13+11+10+6+4+1、13+11+10+7+1、13+11+10+7+2+1、13+11+10+7+3+1、13+11+10+7+4+1、13+11+10+8+1、13+11+10+8+2+1、13+11+10+8+3+1、13+11+10+8+4+1、13+11+10+9+1、13+11+10+9+2+1、13+11+10+9+3+1、13+11+10+9+4+1、14+1、14+2+1、14+3+1、14+4+1、14+5+1、14+5+2+1、14+5+3+1、14+5+4+1、14+6+1、14+6+2+1、14+6+3+1、14+6+4+1、14+7+1、14+7+2+1、14+7+3+1、14+7+4+1、14+8+1、14+8+2+1、14+8+3+1、14+8+4+1、14+9+1、14+9+2+1、14+9+3+1、14+9+4+1、14+10+1、14+10+2+1、14+10+3+1、14+10+4+1、14+10+5+1、14+10+5+2+1、14+10+5+3+1、14+10+5+4+1、14+10+6+1、14+10+6+2+1、14+10+6+3+1、14+10+6+4+1、14+10+7+1、14+10+7+2+1、14+10+7+3+1、14+10+7+4+1、14+10+8+1、14+10+8+2+1、14+10+8+3+1、14+10+8+4+1、14+10+9+1、14+10+9+2+1、14+10+9+3+1、14+10+9+4+1、14+11+1、14+11+2+1、14+11+3+1、14+11+4+1、14+11+5+1、14+11+5+2+1、14+11+5+3+1、14+11+5+4+1、14+11+6+1、14+11+6+2+1、14+11+6+3+1、14+11+6+4+1、14+11+7+1、14+11+7+2+1、14+11+7+3+1、14+11+7+4+1、14+11+8+1、14+11+8+2+1、14+11+8+3+1、14+11+8+4+1、14、 +11+9+1、14+11+9+2+1、14+11+9+3+1、14+11+9+4+1、14+11+10+1、14+11+10+2+1、14+11+10+3+1、14+11+10+4+1、14+11+10+5+1、14+11+10+5+2+1、14+11+10+5+3+1、14+11+10+5+4+1、14+11+10+6+1、14+11+10+6+2+1、14+11+10+6+3+1、14+11+10+6+4+1、14+11+10+7+1、14+11+10+7+2+1、14+11+10+7+3+1、14+11+10+7+4+1、14+11+10+8+1、14+11+10+8+2+1、14+11+10+8+3+1、14+11+10+8+4+1、14+11+10+9+1、14+11+10+9+2+1、14+11+10+9+3+1、14+11+10+9+4+1、 15+1、15+2+1、15+3+1、15+4+1、15+5+1、15+5+2+1、15+5+3+1、15+5+4+1、15+6+1、15+6+2+1、15+6+3+1、15+6+4+1、15+7+1、15+7+2+1、15+7+3+1、15+7+4+1、15+8+1、15+8+2+1、15+8+3+1、15+8+4+1、15+9+1、15+9+2+1、15+9+3+1、15+9+4+1、15+10+1、15+10+2+1、15+10+3+1、15+10+4+1、15+10+5+1、15+10+5+2+1、15+10+5+3+1、15+10+5+4+1、15+10+6+1、15+10+6+2+1、15+10+6+3+1、15+10+6+4+1、15+10+7+1、15+10+7+2+1、15+10+7+3+1、15+10+7+4+1、15+10+8+1、15+10+8+2+1、15+10+8+3+1、15+10+8+4+1、15+10+9+1、15+10+9+2+1、15+10+9+3+1、15+10+9+4+1。

[0085] In the above list, the numbers refer to the embodiments according to the above numbers, and "+" indicates a dependency from another embodiment. The various embodiments are individually separated by commas. In other words, for example, "11+9+4+1" means embodiment 11) which is dependent on embodiment 9) which is dependent on embodiment 4) which is dependent on embodiment 1), i.e. embodiment "11+9+4+1" corresponds to a compound of formula (I) according to embodiment 1) further limited by all the features of embodiments 4), 9) and 11).

[0086] 17) A further aspect of the invention relates to compounds of formula (I) according to embodiment 1), which are also compounds of formula (V) (with the absolute configuration as indicated in the respective formula):

[0087] [ka]

[0088] (In the formula, X is O or NR 2 R 2 is hydrogen, C 1-3 -Alkyl (especially methyl or ethyl) -CO-H, -SO2-C 1-3 -Alkyl (especially SO2-CH3) or -CO-C 1-3 -alkyl (especially -CO-CH3); Ar 1 represents phenyl, substituted by 1, 2, 3, 4 or 5 substituents (particularly substituted by 2 or 3 substituents), said substituents being independently selected from halogen; methyl; cyano; and methoxy (particularly independently selected from halogen and methyl); [Ar 1 stands in particular for a radical as described in embodiment 9) or any of its subembodiments. R 1 teeth, - Hydroxy; - C 1-3 -alkoxy; - -O-CO-C 1-3 -alkyl; - -O-CH2-CH2-OH; or - -O-CH2-CO-OH; represents; [Such a substituent R 1 Especially C 1-3 -alkoxy (especially methoxy). L represents a direct bond or methylene (especially a direct bond); Ar 2 teeth, - phenyl, which is unsubstituted or substituted by 1, 2 or 3 substituents (in particular substituted by 1 or 2 substituents), said substituents being independently selected from methyl, methoxy, halogen and cyano; represents ); It is intended that the features disclosed in embodiments 2) to 16) also apply mutatis mutandis to compounds of formula (V) according to embodiment 17).

[0089] 18) Another embodiment relates to compounds of formula (I) according to embodiment 1), which are selected from the following compounds: (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-N-(3-iodophenyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- Carboxamides; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-methoxyphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-fluorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2- Carboxamides; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran -2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-N-(3-iodophenyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carbo oxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-methoxyphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-fluorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-yl Carboxamides; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide ; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-N-((3S,4S)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-N-((3S,4S)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-N-((3S,4S)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-N-((3S,4S)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-N-((3R,4R)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-N-((3R,4R)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4R)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-N-((3S,4S)-4-hydroxy-1-methylpyrrolidin-3-yl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-N-((3S,4S)-1-ethyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-N-((3S,4S)-4-hydroxy-1-(methylsulfonyl)pyrrolidin-3-yl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypiperidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypiperidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; and (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypiperidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide.

[0090] The compounds of formula (I) according to embodiments 1) to 18) and their pharma- ceutically acceptable salts can be used as medicaments, for example in the form of pharmaceutical compositions for enteral (such as, in particular orally, for example in the form of tablets or capsules) or parenteral (including topical application or inhalation) administration.

[0091] The preparation of pharmaceutical compositions can be carried out in a manner well known to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by combining the above-mentioned compounds of formula (I) or pharma- ceutical acceptable salts thereof, optionally with other therapeutically valuable substances, with suitable non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if necessary, with conventional pharmaceutical adjuvants, to form a pharmaceutical dosage form.

[0092] The present invention also relates to a method for the prevention or treatment of a disease or disorder described herein, comprising administering to a subject a pharma- ceutically effective amount of a compound of formula (I) according to embodiments 1) to 18). In a subembodiment of the invention, the dosage is comprised between 1 mg and 1000 mg per day.

[0093] For the avoidance of any doubt, where a compound is described as being useful for the prevention or treatment of a disease, such compound may likewise be used for the prevention or treatment of that disease. Similarly, such compounds are suitable for use in a method for the prevention or treatment of such diseases, comprising administering an effective amount of such compound to a subject (a mammal, particularly a human) in need thereof.

[0094] 19) Another embodiment relates to compounds of formula (I) as defined in any one of embodiments 1) to 18) useful for the prevention or treatment of diseases and disorders in which the binding of galectin-3 to its natural ligand is involved.

[0095] Such diseases and disorders in which binding of Gal-3 to its natural ligand is implicated are, in particular, diseases and disorders in which inhibition of the physiological activity of Gal-3 is beneficial, e.g., diseases in which the Gal-3 receptor is implicated and which are implicated in the etiology or pathology of the disease or which are otherwise implicated in at least one symptom of the disease.

[0096] Diseases or disorders in which the binding of galectin-3 to its natural ligands is implicated may be defined as including, in particular: - fibrosis of an organ: -- all forms of fibrotic interstitial lung disease, including in particular idiopathic pulmonary fibrosis (also known as cryptogenic fibrosing alveolitis); pulmonary fibrosis secondary to systemic inflammatory diseases such as rheumatoid arthritis, scleroderma (systemic sclerosis, SSc), lupus (systemic lupus erythematosus, SLE), polymyositis or mixed connective tissue disease (MCTD); pulmonary fibrosis secondary to sarcoidosis; iatrogenic pulmonary fibrosis, including radiation-induced fibrosis; silicosis-induced pulmonary fibrosis; asbestos-induced pulmonary fibrosis; and pleural fibrosis; -- renal / kidney fibrosis, including chronic kidney disease (CKD), renal failure (acute or chronic), tubulointerstitial nephritis and / or chronic nephropathy such as (primary) glomerulonephritis or glomerulonephritis secondary to systemic inflammatory diseases such as SLE and SSc, diabetes, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, renal transplantation and renal fibrosis due to / associated with Alport syndrome; -- all forms of liver / hepatic fibrosis (whether or not associated with portal hypertension), including cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis, bile duct injury, primary biliary cirrhosis (also known as primary biliary cholangitis), infectious or virally induced liver fibrosis (e.g. chronic HCV infection) and autoimmune hepatitis; -- Cardiovascular disease, heart failure, Fabry disease, CKD; all forms of heart / cardiac fibrosis, including cardiac fibrosis associated with diabetes, hypertension or hypercholesterolemia; --gut fibrosis, including gastrointestinal fibrosis secondary to SSc and radiation-induced gastrointestinal fibrosis; -- Skin fibrosis, including SSc and skin scarring; --Head and neck fibrosis, including radiation-induced head and neck fibrosis; -- ocular / corneal fibrosis, including scarring (e.g., sequelae of laser-assisted in situ keratomileusis or trabeculectomy); -- Hypertrophic scars and keloids, including burn-induced or surgical hypertrophic scars and keloids; -- fibrotic sequelae of organ transplants (including corneal transplants); -- and other fibrotic diseases, including endometriosis, spinal fibrosis, myelofibrosis, perivascular and arterial fibrosis; as well as scar tissue formation, Peyronie's disease, abdominal or intestinal adhesions, bladder fibrosis, nasal fibrosis and fibrosis mediated by fibroblasts; fibrosis of organs, including; - Liver diseases and disorders (acute or chronic) (acute and chronic viral hepatitis; cirrhosis due to / associated with arthritis and vasculitis; metabolic liver diseases due to / associated with arthritis, myocarditis, diabetes or neurological conditions; cholestatic diseases due to / associated with hyperlipidemia, inflammatory bowel disease (IBD) or ulcerative colitis) diseases);liver tumors;autoimmune hepatitis and cirrhosis caused by / associated with celiac disease, autoimmune hemolytic anemia, IBD, autoimmune thyroiditis, ulcerative colitis, diabetes, glomerulonephritis, pericarditis, autoimmune thyroiditis, hyperthyroidism, polymyositis, Sjögren's syndrome, panniculitis, alveolitis or alcoholic steatosis;cirrhosis associated with dementia;cirrhosis associated with peripheral neuropathy;cirrhosis caused by / associated with oral or esophageal cancer;non-alcoholic fatty liver disease (particularly non-alcoholic steatohepatitis) caused by / associated with obesity, metabolic syndrome or type 2 diabetes;hepatic vascular disorders (including Budd-Chiari syndrome, portal vein thrombosis, sinusoidal obstruction syndrome);acute and chronic liver failure (with or without portal hypertension);liver insufficiency; - acute kidney injury and chronic kidney disease (CKD) caused by / associated with heart disease (also called cardiorenal syndrome types 1 and 2), or caused by / associated with hypertension, or caused by / associated with diabetes (also called diabetic nephropathy (DKD) including DKD associated with hypertension), in particular diabetes mellitus type 1 or 2), or caused by / associated with inflammatory diseases and disorders (such as glomerulonephritis and glomerulonephritis secondary to systemic inflammatory diseases such as SLE or SSc, tubulointerstitial nephritis, vasculitis, sepsis, urinary tract infections), or caused by / associated with polycystic kidney disease, or caused by / associated with obstructive nephropathy (including stones, benign prostatic hyperplasia, prostate cancer, retroperitoneal pelvic tumors), or caused by / associated with neurogenic bladder disease-related symptoms) [in particular the Kidney Disease Improving Global stages 1 to 5 CKD as defined by the Kidney Disease Outcomes (KDIGO) Guidelines], especially (particularly) these stages of CKD; and acute and chronic renal failure; - Cardiovascular diseases and disorders (atherosclerosis caused / related to hypertension, hypercholesterolemia, diabetes, inflammation, obesity, elderly / age; peripheral arterial disease caused / related to hypertension, hypercholesterolemia, diabetes, elderly / age; deep vein thrombosis; pulmonary embolism caused / related to obesity or cancer; aortic aneurysm and dissection caused / related to elderly, hypertension, Marfan syndrome, congenital heart defects, inflammatory or infectious disorders; cerebrovascular disease caused / related to hypertension, atrial fibrillation, hypercholesterolemia, diabetes, elderly / age; hypertension, hypercholesterolemia, diabetes, elderly / age or CKD, in particular Kidney Disease Improving coronary heart disease due to / associated with CKD (stages 1-5 as defined by the Cardiovascular Outcomes Global Outcomes (KDIGO) Guidelines); rheumatic heart disease due to / associated with bacterial infection; cardiac and vascular tumors; cardiomyopathies and arrhythmias; valvular heart disease (including valvular calcification and degenerative aortic stenosis); inflammatory heart disease due to / associated with infection, carditis, glomerulonephritis, cancer; heart failure (HF) defined as including congestive HF, specifically including systolic HF / HF with reduced ejection fraction (HFrEF) and diastolic HF / HF with preserved ejection fraction (HFpEF); - Interstitial lung diseases and disorders (including smoking-related interstitial lung disease; interstitial lung disease due to / associated with chronic obstructive pulmonary disease; interstitial pneumonia (including ordinary interstitial pneumonia) associated with collagen vascular disease, or pneumonia); - cell proliferative disorders and cancers (including solid tumors, solid tumor metastases, carcinomas, sarcomas, myelomas (and multiple myelomas), leukemias, lymphomas, mixed cancers, angiofibromas, Kaposi's sarcoma, chronic lymphocytic leukemia (CLL), spinal tumors and invasive metastases of cancer cells; in particular, said cell proliferative disorders and cancers are cancers of the thyroid, central nervous system, tongue, breast, digestive system, head and neck squamous cell, pancreas, bladder, kidney, liver, parathyroid or salivary gland; or lymphomas, carcinomas, non-small cell lung cancer, melanoma or neuroblastoma); - Inflammatory and autoimmune diseases and disorders (chronic and acute inflammatory and autoimmune diseases and disorders, in particular sepsis, Q fever, asthma, rheumatoid arthritis, multiple sclerosis, SLE, SSc, polymyalgia, inflammatory renal / kidney diseases such as psoriasis, plaque psoriasis (including psoriasis caused / associated with NASH), atopic dermatitis, nephropathy (including diabetic nephropathy, glomerulonephritis, tubulointerstitial nephritis), inflammatory cardiac / heart diseases, inflammatory lung / lung-related diseases; inflammatory liver / liver-related diseases; diabetes (type 1 or type 2) and diabetes-related diseases such as diabetic vasculopathy, diabetic nephropathy, diabetic retinopathy, diabetic peripheral neuropathy or skin-related diseases; viral encephalitis; and COVID-19 and its sequelae; - Digestive diseases and disorders (including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), gastritis and abnormal pancreatic secretions); - Pancreatic diseases and disorders (including, for example, pancreatitis associated with cystic fibrosis); - Diseases and disorders associated with abnormal angiogenesis (including arterial occlusive disease); - Brain-related diseases and disorders (including stroke and cerebral hemorrhage); - Neuropathic pain and peripheral neuropathy; - Eye diseases and disorders (including dry eye, age-related macular degeneration (AMD), diabetes-related diseases (diabetic retinopathy), proliferative vitreous retinopathy (PVR), cicatricial pemphigoid and glaucoma (including ocular scarring after glaucoma filtration surgery and glaucoma associated with elevated intraocular pressure) and corneal angiogenesis / neovascularization); and - Transplant rejection (including rejection of transplanted organs such as kidney, liver, heart, lung, pancreas, cornea and skin; graft-versus-host disease resulting from hematopoietic stem cell transplantation; chronic allograft rejection and chronic allograft vasculopathy); and sequelae of such transplant rejection.

[0097] 20) A further embodiment relates to a compound of formula (I) for use according to embodiment 19), wherein the compound is for use in the prevention or treatment of organ fibrosis, including liver / hepatic fibrosis, renal / kidney fibrosis, lung / pulmonary fibrosis, heart / cardiac fibrosis, ocular / corneal fibrosis and skin fibrosis; and gastrointestinal fibrosis, head and neck fibrosis, hypertrophic scars and keloids; and fibrotic sequelae of organ transplantation.

[0098] 21) A further embodiment relates to compounds of formula (I) for use according to embodiment 19), wherein the compounds are for use in the prevention or treatment of cardiovascular diseases and disorders.

[0099] 22) A further embodiment relates to compounds of formula (I) for use according to embodiment 19), wherein the compounds are for use in the prevention or treatment of acute kidney injury and chronic kidney disease (CKD).

[0100] 23) A further embodiment relates to compounds of formula (I) for use according to embodiment 19), wherein the compounds are for use in the prevention or treatment of (acute or chronic) liver diseases and disorders.

[0101] 24) A further embodiment relates to a compound of formula (I) for use according to embodiment 19), wherein the compound is for use in the prevention or treatment of interstitial lung diseases and disorders.

[0102] 25) A further embodiment relates to a compound of formula (I) for use according to embodiment 19), wherein the compound is for use in the prevention or treatment of eye diseases and disorders.

[0103] 26) A further embodiment relates to compounds of formula (I) for use according to embodiment 19), wherein the compounds are for use in the prevention or treatment of cell proliferative disorders and cancer.

[0104] In particular, such cell proliferative disorders and cancers are cancers of the thyroid, central nervous system, tongue, breast, digestive system, head and neck squamous cell, pancreas, bladder, kidney, liver, parathyroid or salivary glands; or lymphoma; carcinoma, non-small cell lung cancer, melanoma or neuroblastoma.

[0105] 27) A further embodiment relates to compounds of formula (I) for use according to embodiment 19), wherein the compounds are for use in the prevention or treatment of chronic or acute inflammatory and autoimmune diseases and disorders.

[0106] 28) A further embodiment relates to compounds of formula (I) for use according to embodiment 19), wherein the compounds are for use in the prevention or treatment of digestive diseases and disorders.

[0107] 29) A further embodiment relates to a compound of formula (I) for use according to embodiment 19), wherein the compound is for use in the prevention or treatment of pancreatic diseases and disorders.

[0108] 30) A further embodiment relates to compounds of formula (I) for use according to embodiment 19), wherein the compounds are for use in the prevention or treatment of diseases and disorders associated with abnormal angiogenesis.

[0109] 31) A further embodiment relates to a compound of formula (I) for use according to embodiment 19), wherein the compound is for use in the prevention or treatment of brain-related diseases and disorders.

[0110] 32) A further embodiment relates to compounds of formula (I) for use according to embodiment 19), wherein the compounds are for use in the prevention or treatment of neuropathic pain and peripheral neuropathy.

[0111] 33) A further embodiment relates to a compound of formula (I) for use according to embodiment 19), wherein the compound is for use in the treatment of transplant rejection.

[0112] Furthermore, any preferences and (sub)embodiments expressed for a compound of formula (I) (whether for said compound itself, a salt thereof, a composition comprising said compound or a salt thereof or the use of said compound or a salt thereof, etc.) also apply mutatis mutandis to any compound of formula (II), (III), (IV), (I s ), (II s ), (III s ), (IV s ), (I R ), (II R ), (III R ), (IV R ) and (V).

[0113] Preparation of Compounds of Formula (I) Compounds of formula (I) can be prepared by well-known literature methods, by the methods described below, by the methods described in the experimental section below, or by analogous methods. Optimum reaction conditions will vary with the specific reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures. In some cases, the reaction schemes below and / or the order of carrying out the reaction steps may be modified to facilitate the reaction or to avoid undesired by-products. In the general reaction sequences outlined below, the integers n and m and the generic group, R 1 , L, Ar 1 , Ar 2 , n and m are as defined for formula (I). Other abbreviations used herein are either explicitly defined or as defined in the experimental section. In some cases, the generic group, R 1 , L, Ar 1 , Ar 2 , n and m may not be compatible with the preparation illustrated in the scheme below and the use of a protecting group (Pg) will be required. The use of protecting groups is well known in the art (see, for example, "Protective Groups in Organic Synthesis," TW Greene, PG M Huts, Wiley-Interscience, 1999). For this purpose, such protecting groups may be used. It is assumed that substituents have been introduced as necessary. In some cases, the final product may be further modified, for example by manipulating the substituents to give new final products. Such manipulations include, but are not limited to, reduction, oxidation, alkylation, acylation, hydrolysis and transition metal catalyzed cross-coupling reactions well known to those skilled in the art. The compounds obtained may be converted into salts, in particular pharma- ceutically acceptable salts, by methods known per se.

[0114] The compounds of formula (I) of the present invention may be prepared according to the general reaction sequences outlined below: Only a few of the synthetic possibilities which lead to compounds of formula (I) are described.

[0115] The compounds of formula (I) may be prepared by reacting R with H, a suitable protecting group (Pg) or R 1 The compound of Structure 1, which is: is coupled with the compound of Structure 2 to give Structure 3. The coupling reaction is carried out using standard peptide coupling conditions such as DCC, HOBT or T3P in a suitable solvent such as DCM or DMF or mixtures thereof in the presence of a base such as TEA or DIPEA. Alternatively, POCl3 can be used with pyridine as the base. In Structures 2 and 3, Pg is a suitable protecting group such as acetyl, trimethylsilyl (TMS) or tert-butyl dimethylsilyl (TBS) or benzyl, which are well known to those skilled in the art. The hydroxy groups at positions 4 and 6 of Structure 1 can be protected with cyclic protecting groups such as isopropylidene, benzylidene or bis-tert-butylsilyl groups. R is a suitable protecting group (Pg) or the group OR is R (as defined in formula (I)). 1 The compound of structure 3 is then deprotected to give the compound of formula (I).

[0116] [ka]

[0117] In the case where Pg represents an acyl protecting group, such protecting groups can be cleaved under standard conditions, for example with water or alcohols in the presence or absence of additional solvents such as THF, dioxane, and in the presence of bases such as K2CO3, NaOH, LiOH. In the case where such protecting groups represent benzyl groups, they can be cleaved, for example, with hydrogen in the presence of catalysts such as Pd / C, PtO2, in methanol, EA, THF, etc. or mixtures thereof, or with BBr3 in a solvent such as DCM. In the case where such protecting groups are TMS or TBS, they are cleaved with fluoride ions such as TBAF or HF in pyridine. Alternatively, silyl protecting groups are removed under mild acidic conditions, such as aqueous AcOH, at temperatures between rt and reflux. In the case where Pg represents a cyclic protecting group, such as isopropylidene, benzylidene and bis-tert-butylsilylene groups, the cleavage can be carried out under acidic conditions using aqueous AcOH or TFA.

[0118] [ka]

[0119] Compounds of structure 1 are prepared by hydrolysis of the nitrile functionality in structure 4 to a carboxylic acid using aqueous acidic (conc. HCl) or basic (NaOH) conditions at temperatures between 20 and 100° C., followed by appropriate protection or modification of the free hydroxyl group. Alternatively, structure 4 can be obtained by reacting compounds of structure 5 with compounds of structure 6 in the presence of CuI and DIPEA in a solvent such as THF or DMF (Click Chemistry in Glycoscience: New Development and Strategies, 1st Edition, 2013, John Wiley & Sons), or the reaction can be carried out in a commercially available continuous-flow reactor (Vapourtec) using a copper coil in a solvent such as THF. Compounds of structure 6 are commercially available or can be prepared according to procedures known to those skilled in the art (Synthesis 2011, 22, 3604-3611). Compounds of structure 5 can be prepared from the corresponding gulo furanose derivatives by methods well known to those skilled in the art (Carbohydrate Research 1994, 251, 33-67; Bioorg. Med. Chem. 2002, 10, 1911-2013).

[0120] Compounds of structure 2 can be obtained by protecting compounds of structure 7 with a suitable silyl-based protecting group under standard conditions. Compounds of structure 7 can be obtained by reaction of 3,6-dioxabicyclo[3.1.0]hexane, tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate, 1-(6-oxa-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one, 3,7-dioxabicyclo[4.1.0]heptane or tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate with an amine.

[0121] In coupling with the compound of structure 1, the compound of structure 2 is used as a racemate or as separated enantiomers. The diastereomers of structure 3 or formula I (after deprotection) are separated using techniques well known to those skilled in the art, such as chiral preparative HPLC, using achiral or chiral stationary phases. Commonly used achiral or chiral stationary phases for chiral preparative HPLC are, for example, Waters XBridge C18, 10 μm OBD, 30x75 mm or Daicel Chiralcel OZ-H (5 μm) columns, Daicel ChiralCel OJ-H (5-10 μm) columns, ChiralPak IC (5 μm) columns, ChiralPak ID (5 μm) columns, ChiralPak These are IG (5 μm) column, ChiralPak IH (5 μm) column, ChiralPak IE (5 μm) column, ChiralPak AS-H (5 μm), AD-H (5 μm) or IB (5 μm) column.

[0122] Typical conditions for chiral HPLC are elution at a flow rate of 0.8-160 mL / min. The diastereomers were separated by isocratic mixture of eluent A (CO2) and eluent B (DCM / MeOH, MeCN / MeOH, MeCN / EtOH, 0.1% Et2NH in EtOH, MeOH, EtOH, iPrOH). In some cases, the enantiomerically pure form of the compound of structure 2 was used in an amide coupling with the compound of structure 1 to give the pure enantiomers of the compounds of structure 3 and formula I, respectively. In cases where the diastereomers were not separated, the IC 50 The values ​​are determined for mixtures of diastereomers.

[0123] Experimental section The following examples illustrate the invention but do not in any way limit its scope.

[0124] All temperatures are given in °C. Commercially available starting materials were used as received without further purification. All reactions were carried out under a nitrogen or argon atmosphere unless otherwise noted. Compounds were purified by flash chromatography on silica gel (Biotage, Redisep) or by preparative TLC (Merck TLC plates, Silica gel 60 F 254 ) or by preparative HPLC. The compounds described in this invention were 1 H-NMR (Bruker Neo, 400 MHz Ultra Shield™ or Bruker Avance III HD, Ascend 500 MHz); chemical shifts are given in ppm relative to the solvent used; multiplicities: s=singlet, d=doublet, t=triplet, q=quartet, quint=quintet, hex=sexlet, hept=septet, m=multiplet, br=broad; coupling constants are given in Hz.) and / or LC-MS (retention times t R are given in min; molecular weights obtained from mass spectrometry are given in g / mol.) using the conditions described below.

[0125] Qualitative analysis methods used LC-MS retention times were obtained using the following elution conditions: A) LC-MS(A): Zorbax RRHD SB-Aq, 1.8 μm, 2.1×50 mm column, thermostated at 40° C. The two elution solvents were: Solvent A=water+0.04% TFA; Solvent B=MeCN. The eluent flow rate was 0.8 mL / min and the characteristics of the proportion of the eluted mixture related to the time t from the start of the elution are summarized in the table below (a linear gradient is used between two successive time points):

[0126] [Table 1]

[0127] Purification by preparative LC-MS was carried out using the conditions described below.

[0128] B) Preparative LC-MS(I): A Zorbax column (Zorbax Dr. Maisch, 5 μm, 30×75 mm) was used. The two elution solvents were: Solvent A=water+0.5% formic acid in water; Solvent B=MeCN. The eluent flow rate was 75 mL / min and the characteristics of the proportions of the eluted mixture related to the time t from the start of the elution are summarized in the following table (a linear gradient is used between two successive time points):

[0129] [Table 2]

[0130] C) Preparative LC-MS(II): A Waters column (Waters XBridge C18, 10 μm OBD, 30×75 mm) was used. The two elution solvents were: Solvent A=water+0.5% of 25% NH4OH in water; Solvent B=MeCN. The eluent flow rate was 75 mL / min and the characteristics of the proportion of the eluted mixture related to the time t from the start of the elution are summarized in the following table (a linear gradient is used between two successive time points):

[0131] [Table 3]

[0132] Abbreviations (as used herein): ABTS 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid Ac AcOH = acetyl in acetic acid, etc. aq. aqueous solution Bu (in nBuLi = n-butyl lithium, etc.) Ca approx. CC Silica Column Chromatography Concentrated DCM Dichloromethane DIPEA N-Ethyldiisopropylamine DMF Dimethylformamide DMSO Dimethyl sulfoxide EA Ethyl acetate eq (mol) equivalent Et Ethyl EtOH Ethanol Et2O Diethyl ether Example: FC Flash Chromatography h time HOBt 1-Hydroxybenzotriazole hydrate HPLC High Performance Liquid Chromatography hv high vacuum LC Liquid Chromatography M Molar concentration [mol L -1 ] Me Methyl MeCN Acetonitrile MeOH Methanol MS mass spectrometry min. N normality NaOH Sodium hydroxide OD optical density o / n overnight org.organic Pg protecting group Ph Phenyl PTSA p-Toluenesulfonic acid rt room temperature sat. saturation TBME tert-Butyl methyl ether TBS tert-Butyldimethylsilyl tBu tert-butyl = tertiary butyl TEA Triethylamine Tf Trifluoromethanesulfonate TFA Trifluoroacetic acid THF Tetrahydrofuran TMS Trimethylsilyl T3P Propylphosphonic anhydride t R retention time

[0133] A. Preparation of precursors and intermediates Preparation of intermediates of structure 1 The following precursors were prepared for the synthesis of the compounds:

[0134] [ka]

[0135] Intermediate 1: (3R,4S,5R,6R)-6-(acetoxymethyl)-4-azidotetrahydro-2H-pyran-2,3,5-triyl triacetate (3R,4S,5R,6R)-6-(acetoxymethyl)-4-azidotetrahydro-2H-pyran-2,3,5-triyl triacetate is synthesized from (3aR,5S,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol according to the literature procedure from Ref: Carbohydrate Research 1994, 251, 33-67 and references cited therein.

[0136] Intermediate 2: (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-cyano-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate Intermediate 1 (10000 mg, 26.5 mmol, 1 eq) is dissolved in nitromethane (4 vol.) (40 mL) and trimethylsilyl cyanide 98% (10.2 mL, 79.6 mmol, 3 eq) and boron trifluoride diethyl etherate (3.93 mL, 31.8 mmol, 1.2 eq) are added in portions over 30 min. The temperature is kept below 35° C. with a water bath. The mixture is stirred at rt for 2 h. The mixture is partitioned between water (400 mL), saturated aqueous bicarbonate solution (100 mL) and TBME (300 mL). The aqueous phase is extracted once more with TBME (200 mL) and the organic phase is washed twice with water / brine (ca. 5:1) and brine and dried over MgSO4. TBME is evaporated on a Rotavap at 20° C. The crude intermediate is purified by filtration over SiO2 (150 mL cartridge 3 / 4 packed, DCM / TBME 10:1) and is used immediately in the next step.

[0137] 1 H NMR (500MHz, DMSO) δ:5.47(dd, J 1 = 0.7Hz, J 2 =3.2Hz, 1H), 5.17(t, J=10.3Hz, 1H), 5.04(d, J=10.1Hz, 1H), 4.22(dd, J 1 = 3.2Hz, J 2 =10.4Hz, 1H), 4.15(ddd, J 1 =0.8Hz, J 2 = 4.5Hz, J 3 =7.2Hz, 1H), 4.03-4.08(m, 1H), 3.97(dd, J 1 = 7.4Hz, J 2 =11.7Hz, 1H), 2.18(s, 3H), 2.15(m, 3H), 2.04(s, 3H) Intermediate 3: (2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-cyano-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate Intermediate 2 is dissolved in DMF (80 mL) and 5-ethynyl-1,2,3-trifluorobenzene (312 mg, 21.2 mmol, 0.8 eq), DIPEA (13.6 mL, 79.6 mmol, 3 eq) and CuI (505 mg, 2.65 mmol, 0.1 eq) are added under N2. The yellow mixture is stirred at rt for 1 h. Exotherm. The yellow solution is slowly poured into water (800 mL) and stirred for 10 min. The beige precipitate is filtered and the filtrate is discarded. The beige solid is washed with MeOH, then dissolved in EA (300 mL) and stirred for 10 min. The fine Cu residue is filtered and the filtrate is washed with NH4Cl solution (half saturated) and brine, dried over MgSO4 and concentrated. The residue is triturated with MeOH (ca 100 mL), filtered and dried under hv to give the desired intermediate 3a as a beige solid.

[0138] 1 H NMR (500MHz, DMSO-d6) δ:8.85(s, 1H), 7.81-7.85(m, 2H), 5.91(m, 1H), 5.64(dd, J1=3.1Hz, J2=11.0Hz, 1H), 5.51(dd, J1=0.7Hz, J2=3 .0Hz, 1H), 5.24(d, J=9.9Hz, 1H), 4.43-4.46(m, 1H), 4.03-4.12(m, 2H), 2.10(s, 3H), 2.04(m, 3H), 1.94(m, 3H). LCMS(A):t R =0.97min;[M+H] + =497.21 Intermediate 3 is further functionalized as shown in the scheme below.

[0139] [ka]

[0140] Intermediate 4: (2R,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxylic acid Intermediate 3 (2800 mg, 5.64 mmol, 1 eq) is suspended in HCl 25% (20.6 mL, 169 mmol, 30 eq) and heated under reflux for 1.5 h. The solution is poured onto an MCI® gel column (ca 100 mL gel) containing water. The column is eluted with water until neutral pH (5 fractions of 40 mL). The compound is then eluted with H2O / MeCN (3:1). Fractions of 40 mL are taken. The fractions containing the product are first concentrated under vacuum to remove MeCN and then lyophilized to give the title compound as a colorless solid. LCMS (A): t R =0.59min;[M+H] + =390.22 1 H NMR (500MHz, DMSO-d6) δ:12.88-12.90(br, 1H), 8.79(s, 1H), 7.86(dd, J 1 = 6.8Hz, J 2 =9.1Hz, 2H), 5.43-5.46(m, 1H), 5.30(d, J=6.2Hz, 1H), 4.84(dd, J 1 = 3.0Hz, J 2 =10.8Hz, 1H), 4.72(d, J=0.5Hz, 1H), 4.36(t, J=10.0Hz, 1H), 3.94(dd, J 1 = 3.0Hz, J 2 =6.0Hz, 1H), 3.85(d, J=9.4Hz, 1H), 3.71(t, J=6.5Hz, 1H), 3.48-3.55(m, 2H) Intermediate 5: Methyl (4aR,6R,7R,8R,8aR)-7-hydroxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate Step 1: Methyl (2R,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxylate To a suspension of intermediate 4 (14.2 g, 0.036 mol) in MeOH (60 ml) and THF (40 ml) is added 1M H2SO4 (1.82 ml, 0.00182 mol) in MeOH [freshly prepared by dissolving H2SO4 95-98% (0.136 ml) in 2.5 ml of MeOH]. The mixture is stirred at rt over the weekend. K2 CO3 (0.25 g, 0.0018 mol) is added, the mixture is filtered and the solvent is evaporated under vacuum. The crude intermediate is purified by filtration over SiO2 (EA / MeOH 9:1). The crude product - a colourless solid - is used in the next step without purification. LCMS (A):t R =0.85min;[M+H] + =403.87 Step 2: Methyl (4aR,6R,7R,8R,8aR)-7-hydroxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexa-hydropyrano[3,2-d][1,3]dioxine-6-carboxylate To a mixture of the crude product of step 1 (15.5 g, 0.038 mmol) and 2,2-dimethoxypropane (7.22 ml, 0.058 mmol) in THF (400 ml) is added PTSA (0.165 g, 0.001 mol) at rt. The reaction mixture is stirred at 75° C. for 1.5 h, during which time ca. 150 ml of solvent is distilled off from the mixture. The mixture is cooled to rt and partitioned between saturated aqueous NaHCO3 and EA. The aqueous layer is extracted once more with EA. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and evaporated under vacuum. The crude product—yellowish solid—is used in the next step without purification. LCMS (A): t R =0.88min;[M+H]+=444.01 Intermediate 6: Methyl (4aR,6R,7R,8R,8aR)-7-methoxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate To a solution of intermediate 5 (16.5 g, 0.037 mol) in DMF (180 ml) at 0° C., iodomethane (2.57 ml, 0.041 mol) is added followed by NaH (60% dispersion in mineral oil, 1.57 g, 0.041 mol). The mixture is allowed to warm to rt and stirred at rt for 4 h. The mixture is cooled to 0° C., carefully quenched by addition of water and extracted twice with EA. The organic layers are combined, washed with water and brine, dried over MgSO4, filtered and evaporated under vacuum. The crude product is purified by column chromatography (6 cm×24 cm SiO2 column; gradient: heptane / EA 2:1 to heptane / EA 1:1) to give the desired product as a yellowish solid. LCMS (A): t R =0.98min;[M+H] + =458.03 Acid 1: (4aR,6R,7R,8R,8aR)-7-Methoxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid A mixture of intermediate 6 (12.8 g, 0.028 mol) and LiOH.H2O (1.77 g, 0.042 mmol) in THF / MeOH / H2O (3.2:1, 90 ml) is stirred at rt for 2 h. The mixture is diluted with water (100 ml) and the THF / MeOH is evaporated. Further water (100 ml) and citric acid (10% in water) are added to reach pH 3. The suspension is filtered, the solid is washed with water and the crude product - a colourless solid - is dried under hv. LCMS (A):t R =0.87min;[M+H] + =444.03 Acids 2-6 are synthesized similarly to acid 1 using the corresponding acetylenes for cycloaddition with intermediate 2.

[0141] [Table 4]

[0142] Preparation of intermediates of structure 2

[0143] [ka]

[0144] Intermediate 7: 4-((3-chlorophenyl)amino)tetrahydrofuran-3-ol Step 1: To a solution of 3,6-dioxabicyclo[3.1.0]hexane (400 mg, 4.55 mmol) and 3-chloroaniline (639 mg, 5.01 mmol) in toluene (4 ml) is added InCl3 (71 mg, 0.32 mmol) and the reaction mixture is stirred at 85° for 3 days. Water and EA are added at rt and the mixture is stirred at rt for 30 min. The aqueous phase is separated and extracted with EA. The organic layers are combined, dried over MgSO4, filtered and evaporated in vacuo. The crude product is purified by prep. LC-MS MS (II) to give the title intermediate 7 as a yellow oil. LCMS (A):t R =0.72min;[M+H] + =214.06 Amine 1: 4-((tert-butyldimethylsilyl)oxy)-N-(3-chlorophenyl)tetrahydrofuran-3-amine Step 2: To a solution of intermediate 7 (250 mg, 1.41 mmol) and 2,6-lutidine (333 mg, 3.1 mmol) in DCM (10 ml) at 0° C., tert-butyldimethylsilyl trifluoromethanesulfonate (447 mg, 1.69 mmol) is added and the mixture is stirred at 0° C. for 1 h. Water is added and the mixture is quenched with saturated aqueous NH4Cl. and extracted twice with DCM. The organic layers are washed with brine. The combined organic layers are dried over MgSO4, filtered and concentrated. The crude is purified by FC CombiFlash (24 g RediSep column, 0-30% EA in heptane within 10 min) to give the amine 1 as a colorless oil. LCMS (A):t R =1.21min;[M+H] + =328.05 Amines 2-11 below are prepared in two steps, similar to amine 1, by coupling of the corresponding anilines with 3,6-dioxabicyclo[3.1.0]hexane.

[0145] [Table 5]

[0146] Amines 12 and 13 below are prepared in two steps similar to amine 1 by coupling of the corresponding anilines with tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate. The enantiomers are separated by chiral chromatography, then silylated and used in the amide coupling.

[0147] [ka]

[0148] [Table 6]

[0149] Amines 14-17 below are prepared in two steps similar to amine 1 by coupling of the corresponding anilines with 1-(6-oxa-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one. The enantiomers of 16 are separated by chiral chromatography and then silylated and used in the amide coupling, while amines 14, 15 and 17 are used as racemates in the amide coupling.

[0150] [ka]

[0151] [Table 7]

[0152] Amines 18-21 below are prepared in two steps by coupling of the corresponding anilines with 3,7-dioxabicyclo[4.1.0]heptane, similar to amine 1. In these cases, the resulting amino alcohols are separated by chiral chromatography, then silylated and used for amide coupling.

[0153] [ka]

[0154] [Table 8]

[0155] Amines 22-25 below are prepared in two steps by coupling of the corresponding anilines with tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate, similar to amine 1. In these cases, the resulting amino alcohols are separated by chiral chromatography, then silylated and used for amide coupling.

[0156] [ka]

[0157] [Table 9]

[0158] B. Preparation of Examples

[0159] [ka]

[0160] Example 1: (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide Step 1: (4aR,6R,7R,8R,8aR)-N-((3S,4R)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-3-yl)-N-(3-chlorophenyl)-7-methoxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide To a mixture of acid 1 (50 mg; 0.113 mmol) and amine 1 (39 mg, 0.118 mmol) in DCM (4 ml) at rt is added phosphorus(V) oxychloride (1 M solution in pyridine, 0.14 mL, 0.135 mmol) and the mixture is stirred at rt for 24 h. Water is added and the mixture is quenched with saturated aqueous NH4Cl and extracted twice with DCM. The organic layer is washed with brine. The combined organic layers are dried over MgSO4, filtered and concentrated. The crude is purified by prep. LC-MS (I) to give intermediate 8 (as a mixture of diastereomers). LCMS (A): t R =1.29 / 1.30min;[M+H] + =753.10.

[0161] Step 2: (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide To a solution of intermediate 8 (mixture of diastereomers) (74 mg, 0.98 mmol) in dioxane (1 ml) and water (0.5 ml) at 0° C., TFA (0.60 ml, 7.8 mmol) is added and the reaction mixture is stirred at rt for 21 h. The solvent is evaporated, MeCN is added, the mixture is basified with 25% aqueous NH4OH (until pH 11) and the product is purified by prep. LCMS (II) to give the final compounds as a mixture of diastereomers, which are separated by chiral column chromatography to give Example 1 and Example 30.

[0162] Example 1: 1 H NMR (500MHz, DMSO) δ:9.00(s, 1H), 7.88(dd, J1=9.0Hz, J2=6.8Hz, 2H), 7.57(m, 1H), 7.49-7.52(m, 1H), 7.46(s, 1H), 7 .35-7.39(m, 1H), 5.39(d, J=4.9Hz, 1H), 5.33(d, J=6.0Hz, 1H), 4.83(d, J=9.2Hz, 1H), 4.63-4.72( m, 2H), 4.39(dd, J1=9.1Hz, J2=10.6Hz, 1H), 4.24(m, 1H), 4.03(dd, J1=7.1Hz, J2=9.5Hz, 1H), 3.76 (m, 1H), 3.64(m, 2H), 3.50(d, J=9.0Hz, 1H), 3.38-3.46(m, 3H), 3.17(t, J=6.4Hz, 1H), 3.07(s, 3H).

[0163] LC-MS(A):t R =0.85min;[M+H] + =599.05

[0164] [ka]

[0165] Example 59: (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide Step 1: To a mixture of tert-butyl (3S,4S)-3-((tert-butyldimethylsilyl)oxy)-4-((4aR,6R,7R,8R,8aR)-N-(3,5-dichlorophenyl)-7-methoxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide)pyrrolidine-1-carboxylate acid 1 (450 mg; 1.01 mmol) and amine 12 (554 mg, 1.07 mmol) in DCM (35 ml) at rt, phosphorus(V) oxychloride (1 M solution in pyridine, 1.22 ml, 1.22 mmol) is added and the mixture is stirred at rt for 24 h. Water is added and the mixture is quenched with saturated aqueous NH4Cl and extracted twice with DCM. The organic layers are washed with brine. The combined organic layers are dried over MgSO4, filtered and concentrated. Crude The material is purified by ISCO (24 g RediSep column, 0-80% EA in heptane within 15 min) to give intermediate 9 as a yellow foam. LCMS (A): R =1.37min;[M+H] + =886.09.

[0166] The product may contain tert-butyldimethylsilyl (3S,4S)-3-((tert-butyldimethylsilyl)oxy)-4-((4aR,6R,7R,8R,8aR)-N-(3,5-dichlorophenyl)-7-methoxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide)pyrrolidine-1-carboxylate. LCMS(A):t R=1.42min;[M+H] + =944.10 Step 2: (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide To a solution of intermediate 9 (486 mg, 0.51 mmol) in dioxane (10 ml) and water (5 ml) at 0° C., TFA (1.97 ml, 25.7 mmol) is added and the reaction mixture is stirred at rt for 2 weeks [additional TFA (0.5 ml) is added after 3 days and 1 week.]. EA is added and the mixture is basified with 25% aqueous NH4OH (until pH 9) and extracted twice with EA. The organic layer is washed with brine. The combined organic layers are dried over MgSO4, filtered and concentrated. The crude is purified by ISCO (12 g RediSep column, 0-30% 7N NH3 / MeOH in DCM) and prep. LC-MS (II) to give the final product as a colorless solid. LCMS (A):t R =0.71min;[M+H] + =631.96 Example 59: 1H NMR (500MHz, DMSO) δ:9.01(s, 1H), 7.89(dd, J1=9.0Hz, J2=6.8Hz, 2H), 7.76(t, J=1.8Hz, 1H), 7.48(s, 2H), 5.34(d, J=6.0Hz, 1H), 5.11( d, J=5.1Hz, 1H), 4.92(dd, J1=10.7Hz, J2=2.9Hz, 1H), 4.70(m, 1H), 4.40(dd, J1=9.0Hz, J2=10.7Hz, 1H), 4.33(m, 1H), 4.01(m, 1H), 3.79(dd, J1=6.0Hz, J2=2.8Hz, 1H), 3.59(d, J=9.0Hz, 1H), 3.40-3.56(m, 2H), 3.31(m, 2H), 3.16(dd, J1= 8.3Hz, J2=11.3Hz, 1H), 3.00-3.07(m, 3H), 2.87(dd, J1=6.6Hz, J2=11.2Hz, 1H), 2.80(dd, J1=7.4Hz, J2=11.4Hz, 1H).

[0167] [ka]

[0168] Example 72: (2R,3R,4S,5R,6R)—N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide This product is prepared in two steps from acid 1 and amine 15, analogous to Example 1. The diastereomers are separated by chiral chromatography to give Examples 72 and 79. LCMS (A): R =0.84min;[M+H] + =697.91 Example 72: 100°C: 1H NMR (400MHz, DMSO) δ:8.82(m, 1H), 7.77-7.83(m, 2H), 7.49-7.51(m, 1H), 7.31-7.42(m, 1H), 7.17-7.28(m , 1H), 5.17-5.29(m, 1H), 4.96-5.02(m, 1H), 4.64-4.82(m, 2H), 4.42-4.49(m, 1H), 4.3 3-4.42(m, 1H), 4.13-4.29(m, 1H), 3.84-3.93(m, 1H+0.5H), 3.70-3.75(m, 0.5H), 3.33 -3.65(m, 5H), 3.16-3.33(m, 1H), 3.09(s, 3H), 2.97(m, 1H), 2.39(s, 3H), 1.83(s, 3H).

[0169] The N-acetyl analog can also be prepared by a two-step procedure - peracetylation and O-deacetylation of the corresponding NH product as shown in Example 71.

[0170] Example 71: (2R,3R,4S,5R,6R)—N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide Step 1: (2R,3R,4R,5R,6R)-6-(((3S,4S)-4-acetoxy-1-acetylpyrrolidin-3-yl)(3,5-dichlorophenyl)carbamoyl)-2-(acetoxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl acetate To a solution of compound 59 (23 mg, 0.0364 mmol) in DCM (1.5 ml) at rt, triethylamine (0.050 ml, 0.364 mmol), acetic anhydride (0.017 ml, 0.182 mmol) and DMAP (6.7 mg, 0.054 mmol) are added and the mixture is stirred at rt for 15 min. The mixture is quenched with saturated aqueous NH4Cl solution and extracted twice with DCM. The organic layer is washed with brine. The combined organic layers are dried over MgSO4, filtered and concentrated. Intermediate 11 is used in the next step without purification. LCMS (A): t R =1.07min;[M+H] + =800.03 Step 2: (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide To a solution of intermediate 11 (27 mg, 0.0337 mmol) in MeOH (1.5 ml) is added a solution of NaOMe in MeOH (1.26 ml; prepared by dissolving 0.25 mg NaOMe in 1 ml MeOH) at rt and the mixture is stirred for 3 h. The mixture is quenched with saturated aqueous NH4Cl and extracted twice with ethyl acetate. The organic layer is washed with brine. The combined organic layers are dried over MgSO4, filtered and concentrated. The crude is purified by prep. LC-MS (II) to give the final product as a colorless solid. LCMS (A): t R =0.85min;[M+H] + =673.86.

[0171] [ka]

[0172] Example 90: (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-N-((3S,4S)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide To a solution of Example 61 (35 mg, 0.053 mmol) in ethyl formate (0.44 ml, 5.33 mmol) is added triethylamine (0.008 ml, 0.053 mmol) and the reaction mixture is stirred in a sealed tube at 50° C. for 4 h. The solvent is evaporated and the mixture is purified by prep. LC-MS (II) to give the final product as a colorless solid. LCMS (A): t R =0.84min;[M+H] + =683.83 Example 90: 100°C 1 H NMR (400MHz, DMSO) δ:8.82(s, 1H), 8.00(brs, 1H), 7.78-7.82(m, 2H), 7.50(s, 1H), 7.37(m, 1H), 7. 23(s, 1H), 5.22-5.37(m, 1H), 4.97-5.03(m, 1H), 4.74-4.79(m, 1H), 4.59-4.65( m, 1H), 4.45(m, 1H), 4.34-4.41(m, 1H), 4.18-4.28(m, 1H), 3.50-4.0(m, 6H), 3. 34-3.49(m, 1H), 3.19-3.32(m, 1H), 3.09(s, 3H), 3.01-3.05(m, 1H), 2.39(s, 3H)

[0173] [ka]

[0174] Example 99: (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide This product is prepared in two steps from acid 1 and amine 18, analogous to Example 1. LCMS (A): R =0.93min;[M+H] + =646.97 Example 99: 1 H NMR (500MHz, DMSO) δ:9.00(s, 1H), 7.89(dd, J1=6.8Hz, J2=9.1Hz, 2H), 7.78(t, J=1.9Hz, 1H), 7.55(s, 1H), 7.38( s, 1H), 5.33 (d, J=6.0Hz, 1H), 5.10 (d, J=5.7Hz, 1H), 4.90 (dd, J1=10.8Hz, J2=2.9Hz, 1H), 4.68 (t, J=5.6Hz, 1H), 4.31-4.41(m, 2H), 3.76-3.81(m, 4H), 3.55(d, J=9.0Hz, 1H), 3.45(t, J=6.1 Hz, 2H), 3.31-3.36(m, 1H), 3.28(t, J=6.7Hz, 1H), 3.21(m, 1H), 3.07(s, 3H), 1.71-1.84(m, 2H)

[0175] [ka]

[0176] Example 105: (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide This product is prepared in two steps from acid 1 and amine 20 analogously to Example 1. LCMS (A): R =0.93min;[M+H] + =647.00.

[0177] Example 105: 1 H NMR (500MHz, DMSO) δ:9.00(s, 1H), 7.89(dd, J1=6.8Hz, J2=9.1Hz, 2H), 7.76(m, 1H), 7.59(s, 1H), 7.31-7.39(m, 1H), 5.32(d, J=6.0Hz, 1H), 5.04( d, J=5.8Hz, 1H), 4.89(dd, J1=10.8Hz, J2=2.9Hz, 1H), 4.68(t, J=5.6Hz, 1H), 4.39(dd, J1=10.7Hz, J2=9.0Hz, 1H), 4.23(td, J1 =10.4Hz, J2=4.4Hz, 1H), 3.85(dd, J1=4.7Hz, J2=11.0Hz, 1H), 3.74-3.79(m, 2H), 3.53(d, J=9.0Hz, 1H), 3.45(t, J=6.0Hz, 2H) , 3.32-3.36(m, 1H), 3.25-3.30(m, 2H), 3.20(td, J1=1.4Hz, J2=12.1Hz, 1H), 3.07(s, 3H), 1.84-1.87(m, 1H), 1.42-1.61(m, 1H)

[0178] [ka]

[0179] Example 109: (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide This product is prepared in two steps from acid 1 and amine 22 analogously to Example 1. LCMS (A): R =0.71min;[M+H] +=645.90 Example 109: 1 H NMR (500MHz, DMSO) δ:9.00(s, 1H), 7.89(dd, J1=9.1Hz, J2=6.8Hz, 2H), 7.77(t, J=1.9Hz, 1H), 7.57(s, 1H), 7.27-7.34(m, 1H), 5.33(d, J=6. 0Hz, 1H), 4.88(dd, J1=2.9Hz, J2=10.8Hz, 1H), 4.85(d, J=5.4Hz, 1H), 4.68(t, J=5.4Hz, 1H), 4.38(dd, J1=10.7Hz, J2=9.0 Hz, 1H), 4.24-4.33(m, 1H), 3.79(dd, J1=6.1Hz, J2=3.0Hz, 1H), 3.52-3.55(m, 1H), 3.45(m, 2H), 3.23-3.28(m, 1H), 3.06( s, 3H), 2.87-3.03(m, 2H), 2.78-2.87(m, 1H), 2.37-2.43(m, 1H), 2.22-2.27(m, 1H), 1.67-1.81(m, 1H), 1.31-1.54(m, 1H) Example 113: (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypiperidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide This product is prepared in two steps from acid 1 and amine 24 analogously to Example 1. LCMS (A): R =0.70min;[M+H] + =645.90 Example 113: 1H NMR (500MHz, DMSO) δ:9.00(s, 1H), 7.89(dd, J1=6.8Hz, J2=9.1Hz, 2H), 7.75(t, J=1.9Hz, 1H), 7.58(s, 1H), 7.31-7.35(m, 1H), 5.33(d, J=6.0Hz, 1H), 4.88 (dd, J1=2.9Hz, J2=10.8Hz, 1H), 4.85(d, J=5.6Hz, 1H), 4.69(t, J=5.5Hz, 1H), 4.39(dd, J1=10.7Hz, J2=9.0Hz, 1H), 4.11-4.19(m, 1H), 3.79(dd, J1=6.0Hz, J2=3.0Hz, 1H), 3.52(d, J=8.9Hz, 1H), 3.45(t, J=6.0Hz, 2H), 3.26(t, J=6.6Hz, 1H), 3.10-3.21(m, 1H), 3.07(s, 3H) ), 2.96-2.99(m, 1H), 2.78(dd, J1=10.9Hz, J2=1.3Hz, 1H), 2.43-2.49(m, 1H), 2.20-2.30(m, 1H), 1.80-1.83(m, 1H), 1.32-1.39(m, 1H) The following compounds are prepared from the corresponding acids and amines analogously to Example 1 or as described in Reference Examples 59, 71, 72, 90, 99, 105, 109 or 113.

[0180] [Table 10]

[0181] [Table 11]

[0182] [Table 12]

[0183] [Table 13]

[0184] [Table 14]

[0185] [Table 15]

[0186] [Table 16]

[0187] [Table 17]

[0188] [Table 18]

[0189] [Table 19]

[0190] [Table 20]

[0191] [Table 21]

[0192] [Table 22]

[0193] [Table 23]

[0194] II. Biological Testing Inhibitory activity of the compound (IC 50 ) Evaluation The inhibitory activity of the compounds is determined in a competitive binding test. This spectrophotometric assay measures the binding of biotin-labeled human Gal-3 (hGal-3) or human Gal-1 (hGal-1), respectively, to the glycoprotein asialofetuin (ASF) adsorbed on microplates (Proc Natl Acad Sci USA. 2013 Mar 26;110(13):5052-7). Alternatively and preferably, a version of human Gal-1 in which all six cysteines are replaced by serine may be used.

[0195] Briefly, compounds are serially diluted in DMSO (Test Diluent). To an ASF-coated 384-well plate, add 22.8 μL / well of biotinylated hGal-3 or hGal-1 in assay buffer (i.e., 300-1000 ng / ml biotinylated hGal-3 or hGal-1) and add 1.2 μL of compound test diluent and mix.

[0196] Plates are incubated for 3 h at 4 °C, then washed with cold assay buffer (3x50 μl), incubated with 25 μL / well of streptavidin-peroxidase solution (diluted to 80 ng / mL in assay buffer) for 1 h at 4 °C, then washed further with assay buffer (3x50 μL). Finally, 25 μL / well of ABTS substrate is added. OD (410 nm) is recorded after 30-45 min and IC 50 Value Calculate.

[0197] Calculated IC 50 Values ​​may vary with each day's assay run. This type of variation is known to those skilled in the art. IC values ​​obtained from several measurements 50 Values ​​are reported as average values.

[0198] [Table 24]

[0199] [Table 25]

[0200] The compounds of the present invention may be further characterized for their general pharmacokinetic and pharmacological properties using conventional assay methods well known in the art; for example, for their bioavailability in different species (such as rats or dogs) (including aspects such as solubility, permeability, metabolic stability, absorption); or for their properties related to drug safety and / or toxicological properties, for example, cytochrome P450 enzyme inhibition and time-dependent inhibition, pregnane X receptor (PXR) activation, glutathione binding or phototoxic behavior using conventional assay methods well known in the art.

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, n and m each independently represent an integer of 1 or 2, and n+m is 2 or 3; X is O or NR ２ Represents; R ２ is hydrogen, C １－３ -Alkyl, -CO-H, -SO ２ -C １－３ -Alkyl or -CO-C １－３ - represents alkyl; Ar １ teeth, aryl, substituted by 1, 2, 3, 4 or 5 substituents, the substituents being selected from the group consisting of halogen; methyl; cyano; methoxy; trifluoromethyl; trifluoromethoxy; and NR Ｎ１１ R Ｎ１２ (R Ｎ１１ represents hydrogen, and R Ｎ１２ is hydroxy-C ２－３ -alkyl or R Ｎ１１ and R Ｎ１２ together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl selected from morpholin-4-yl, azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl, which 4- to 6-membered heterocyclyl is unsubstituted or substituted with one hydroxy; - a 5- or 6-membered heteroaryl, which is independently unsubstituted or substituted with 1 or 2 substituents, said substituents being independently selected from halogen, methyl, cyano and methoxy; or - 9- or 10-membered heteroaryl, which 9- or 10-membered heteroaryl is independently unsubstituted or substituted by one methyl; represents; R １ teeth, - hydroxy; - C １－３ -alkoxy; - -O-CO-C １－３ - alkyl; - -O-CH ２ -CH ２ -OH; Or, - -O-CH ２ -CO-R １Ｘ (R １Ｘ は、 -- hydroxy; --morpholin-4-yl; Or, -- -NR Ｎ２１ R Ｎ２２ (R Ｎ２１ and R Ｎ２２ together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl selected from azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl, said 4-6 membered heterocyclyl being substituted by one hydroxy; ) ; represents; L represents a direct bond, methylene or ethylene; Ar ２ teeth, - phenyl or 5- or 6-membered heteroaryl, which is independently unsubstituted or substituted by 1, 2 or 3 substituents; １－６ -Alkyl, C ３－６ -cycloalkyl, -CH ２ -C ３－６ -Cycloalkyl, C １－３ -fluoroalkyl, C １－３ -fluoroalkoxy, C １－３ - phenyl or 5- or 6-membered heteroaryl independently selected from alkoxy, halogen, morpholin-4-yl, amino, ethynyl and cyano; a 9-membered bicyclic heteroaryl or a 10-membered bicyclic heteroaryl, which 9- or 10-membered bicyclic heteroaryl is independently unsubstituted or substituted with 1 or 2 substituents independently selected from methyl, methoxy and halogen; or - naphthyl; represents.)

2. Formula (I Ｓ ) compounds of formula (I) according to claim 1 or a pharma- ceutically acceptable salt thereof: 【Chemistry 2】 。

3. Ar １ represents phenyl substituted with two or three substituents independently selected from halogen, methyl and cyano; at least one of said substituents is attached at the meta or para position of said phenyl; or a pharma- ceutically acceptable salt thereof, as claimed in claim 1 or 2.

4. Ar １ but, 【Chemistry 3】 3. The compound according to claim 1 or 2, which represents:

5. R １ A compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein: represents methoxy.

6. 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein L represents a direct bond.

7. Ar ２ is phenyl and is substituted by 1 or 2 substituents, said substituents being C １－４ -Alkyl, C １－３ -phenyl, independently selected from alkoxy, halogen and cyano; or a pharma- ceutically acceptable salt thereof.

8. Fragment L-Ar ２ but: 【Chemistry 4】 The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof.

9. The compound is (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-N-(3-iodophenyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide D; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-methoxyphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-fluorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran -2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-yl Carboxamides; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-N-(3-iodophenyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carbo oxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-methoxyphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-fluorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran -2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran -2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxylate Samid; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-N-((3S,4S)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-N-((3S,4S)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-N-((3S,4S)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-N-((3S,4S)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-N-((3R,4R)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-N-((3R,4R)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4R)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-N-((3S,4S)-4-hydroxy-1-methylpyrrolidin-3-yl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-N-((3S,4S)-1-ethyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-N-((3S,4S)-4-hydroxy-1-(methylsulfonyl)pyrrolidin-3-yl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypiperidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypiperidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; Or, (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypiperidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; 2. The compound of claim 1, wherein:

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof; and a pharma- ceutically acceptable carrier.

11. A compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, for use as a medicament.

12. A method for treating organ fibrosis; liver disease and disorders; acute kidney injury and chronic kidney disease; cardiovascular disease and and disorders; interstitial lung diseases and disorders; cell proliferative disorders and cancer; inflammatory and autoimmune diseases and disorders; gastrointestinal diseases and disorders; pancreatic diseases and disorders; abnormal angiogenesis-related diseases and disorders; brain-related diseases and disorders; neuropathic pain and peripheral neuropathies; eye diseases and disorders; or for the prevention or treatment of transplant rejection.

13. Use of a compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of organ fibrosis; liver diseases and disorders; acute and chronic kidney injury; cardiovascular diseases and disorders; interstitial lung diseases and disorders; cell proliferative disorders and cancer; inflammatory and autoimmune diseases and disorders; gastrointestinal diseases and disorders; pancreatic diseases and disorders; abnormal angiogenesis-related diseases and disorders; brain-related diseases and disorders; neuropathic pain and peripheral neuropathies; eye diseases and disorders; or transplant rejection.

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