Spiro derivatives of alpha-D-galactopyranoside

Abstract

The present invention is 1 , A, B and R 1 The present invention relates to compounds of formula (I), as described herein, their preparation, pharmaceutically acceptable salts thereof, 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] TIFF2023545046000063.tif70166

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 methods for preparing the 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 sequencing of humans, mice, and rats has revealed the presence of at least 16 conserved galectins and galectin-like proteins in a single mammalian genome (Leffler H. et al., Glycoconj. J. 2002, 19, 433-440). To date, three galectin subclasses have been identified: 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, for example, by cross-linking cell surface glycoconjugates, triggering cell signaling events. Through 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 exert diverse biological functions, including immunoregulation, 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, including 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), suggesting that Gal-3 is involved in the regulation 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, Gal-3 protein expression levels are 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 growing body of evidence supporting the functional involvement of Gal-3 in the progression 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 such as 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), and heart (Thandavarayan RA et al., Biochem Pharmacol.2008, 75(9):1797-806;Sharma It has been noted that it plays 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 implicated in skin thickening in 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 these conditions (Taniguchi T. et al., J Rheumatol. 2012;39(3):539-44). Gal-3 has also been found to be upregulated in patients with chronic kidney disease (CKD)-related renal failure, particularly in those with diabetes. Interestingly, data from this patient population showed a correlation between Gal-3 upregulation in glomeruli and the observed urinary protein excretion (Kikuchi Y. et al., Nephrol Dial Transplant. 2004;19(3):602-7). Additionally, a recent prospective study in 2018 showed that high plasma levels of Gal-3 are associated with an increased risk of developing CKD, especially in hypertensive populations (Rebholz CM. et al., Kidney Int. 2018 Jan;93(1):252-259). 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 is significantly elevated in cardiovascular diseases (Zhong X. et al. Clin Exp Pharmacol Physiol. 2019, 46(3):197-203). Circulating Gal-3 levels 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 tumor microenvironment, 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 cancers expressing high levels of Gal-3 have been found to involve the thyroid, central nervous system, tongue, breast, gastric, head and neck squamous cell, pancreas, bladder, kidney, liver, parathyroid, and salivary glands, as well as lymphoma, carcinoma, non-small cell lung cancer, melanoma, and neuroblastoma (Sciacchitano S. et al., Int J Mol Sci 2018 Jan 26, 19(2):379).

[0006] Furthermore, inhibition of Gal-3 has been shown to prevent the spread of 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), which may be 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 for galectin proteins for the treatment of systemic insulin resistance disorders. Thus, Gal-3 inhibitors, alone or in combination with other treatments, 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, and WO2020078808). WO2002057284, WO2005113569, and WO2014078655 disclose broad-spectrum beta-configured galectin inhibitors. WO2016120403, WO2020104335, WO2021001528, WO2021038068 and WO2021004940 disclose a broad range of alpha-D-galactoside inhibitors of galectins. Summary of the Invention

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

[0010] 1) In a first aspect, the present invention relates to a compound of formula (I):

[0011] [ka]

[0012] (In the formula, Ar 1 teeth, - aryl (especially phenyl) which is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents (especially substituted by 2 or 3 substituents), said substituents being independently selected from halogen, methyl, cyano, methoxy, trifluoromethyl and trifluoromethoxy; [In a subembodiment, the aryl is phenyl substituted with two or three substituents, at least one of which is attached at the meta or para position of the phenyl; in particular, if a para substituent is present, the para substituent is selected from halogen and methyl.] - 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, wherein the 9- or 10-membered heteroaryl is independently unsubstituted or substituted by one methyl; represents; R 1 teeth, - hydroxy; -C 1-4 -alkoxy (especially methoxy); - -O-CO-C 1-3 - alkyl; - O-CO-NH-R N11 (R N11 is hydrogen or C 1-3 -alkyl);- -O-CH2-C1-fluoroalkyl; or - -O-CH2-CO-R 1X (R 1X teeth, -- -hydroxy; -- C 1-3 -alkoxy (especially methoxy); --morpholin-4-yl; or -- -NR N21 R N22 (R N21 and R N22 each independently represents hydrogen or methyl; represents. ); represents;

[0013] [ka]

[0014] represents a spirocyclic fragment; Ring A is

[0015] [ka]

[0016] (wherein X represents nitrogen or oxygen, and n represents the integer 0 or 1 (particularly, X represents nitrogen and n represents the integer 0 or 1; or X represents oxygen and n represents the integer 0). When X represents nitrogen, the nitrogen is unsubstituted or substituted with one C 1-4 -substituted by alkyl (particularly, the nitrogen is unsubstituted); and

[0017] [ka]

[0018] (In the formula, R 2 is hydrogen or C 1-4 - represents alkyl (especially methyl); represents a heterocycloalkylene selected from: Ring B is -C 4-7 -cycloalkane-diyl, 4-7 -cycloalkane-diyl is unsubstituted or substituted by 1 or 2 substituents, said substituents being C 1-4 -Alkyl (especially methyl, isopropyl); C 1-3 -fluoroalkyl; C 1-4 -Alkoxy; Halogen (especially fluoro); Cyano; Oxo; Hydroxy; Hydroxy-C 1-4 -Alkyl (especially 2-hydroxy-prop-2-yl); hydroxyimino; morpho -4-yl; and -NH-R N11 (R N11 is C 1-6 -alkyl (especially isopropyl or pent-3-yl), C 2-4 -alkoxy, C 3-6 -cycloalkyl (especially cyclopropyl), C 2-3 -fluoroalkyl (especially 2,2-difluoroethyl or 2,2,2-trifluoroethyl), -CO-C 1-4 -Alkyl or -CO-C 1-4 -alkoxy. 4-7 -cycloalkane-diyl; - a 4- to 7-membered heterocycloalkane-diyl, which heterocycloalkane-diyl has one ring oxygen atom; or - 4- to 7-membered heterocycloalkane-diyl, wherein the heterocycloalkane-diyl has one ring nitrogen atom, and the ring nitrogen atom is unsubstituted or has one C 1-4 -Alkyl (especially methyl), -CO-C 1-4 -Alkyl, -SO2-C 1-4 -Alkyl, -CO-C 1-4-alkoxy or -CO-NH-C 1-4 -alkyl; said 4- to 7-membered heterocycloalkane-diyl does not bear any further substituent in addition to the substituent on the ring nitrogen atom or bears one further substituent on the ring carbon atom bonded to the ring nitrogen atom, and said substituent is oxo or -CO-OH; represents; or in addition, ring B is a bridged bicyclic C 6-9 - cycloalkane-diyl (in particular bicyclo[2,2,1]heptane-2,2-diyl or bicyclo[3,2,1]-octane-3,3-diyl); represents.)

[0019] In a subembodiment of embodiment 1), ring B is a bridged bicyclic C 6-9 -cycloalkane-diyl (in particular bicyclo[2,2,1]heptane-2,2-diyl or bicyclo[3,2,1]octane-3,3-diyl).

[0020] In another subembodiment of embodiment 1), ring B is a bridged bicyclic C 6-9 -cycloalkane-diyl is not.

[0021] The compound of formula (I) has five chiral or asymmetric centers located in the tetrahydropyran moiety, with the absolute configurations shown in formula (I). In addition, the compound of formula (I) may contain one, and possibly more, additional chiral or asymmetric centers, such as one or more additional asymmetric carbon atoms. Thus, the compound of formula (I) may exist as a mixture of stereoisomers or, preferably, as a pure stereoisomer. The mixture of stereoisomers may be separated by methods known to those skilled in the art.

[0022] When a particular compound (or generic structure) is described as being in a particular absolute configuration, e.g., the (R)- or (S)-enantiomer, such description is understood to refer to the respective compound (or generic structure) in enriched, especially 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 refer to the compound in enriched, especially essentially pure form with respect to each configuration of the asymmetric center.

[0023] Where a particular compound contains one or more chiral or asymmetric centers (in addition to the tetrahydropyran moiety), and one (or more) of such chiral or asymmetric centers is not expressly identified as (R)- or (S)-, it is intended that such chiral or asymmetric centers may independently be of either the (R)- or (S)-configuration. Such compound names are intended to encompass compounds in which such centers are in the (R)- or (S)-configuration, or any mixture of epimers about such centers. Similarly, where such chiral or asymmetric centers are described as being in the (RS)-configuration, When "R" is used, this means that such chiral or asymmetric center in the compound may be present in the (R)-configuration, the (S)-configuration, or any mixture of epimers about said center. When two or more such chiral or asymmetric centers are present in a molecule (either unspecified or in a specified (RS)-configuration), the order of absolute configurations is not intended to imply any definitive relative configurations for said two or more centers, unless expressly stated otherwise. Explicitly specified (R)- or (S)-configurations and unspecified or specified (RS)-configurations may coexist in the same molecule and shall be construed in accordance with the above description.

[0024] Ring B is "C 4-7 -cycloalkane-diyl, 4-7 -Cycloalkane-diyl substituted with 1 or 2 substituents 4-7 For a specific compound representing "-cycloalkane-diyl", the C4-7 If a chiral center of a -cycloalkane-diyl is not specifically identified, it means that such chiral center may be present in the (r,R)- or (s,S)-configuration or any mixture thereof. For example, the compound "tert-butyl (3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate" is a diastereoisomerically enriched, especially essentially pure, "tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate”, diastereomerically enriched, especially essentially pure, “tert-butyl ((5s,8S)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate" or any mixture of the diastereomers.

[0025] In this patent application, bonds drawn as dotted lines or interrupted by wavy lines indicate the point of attachment of the depicted group. For example, the group

[0026] [ka]

[0027] describes the 3,4,5-trifluorophenyl group.

[0028] The term "enriched", when used in connection with stereoisomers, means in the context of the present invention that each stereoisomer is present in a ratio of at least 70:30, in particular at least 90:10, relative to the total of each other stereoisomer / each other stereoisomer ( That is to say, it is understood to mean that it is present in a purity of at least 70% by weight, in particular at least 90% by weight.

[0029] The term "essentially pure", when used in connection with stereoisomers, is understood in the context of the present invention to mean that each stereoisomer is present in a purity of at least 95% by weight, in particular at least 99% by weight, with respect to each other stereoisomer / total of each other stereoisomer.

[0030] The present invention also provides isotopically labeled, especially 2 H (deuterium)-labeled compounds of formula (I) according to embodiments 1) to 17), 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 compounds, especially 2 H (deuterium) labeled compounds of formula (I) and salts thereof 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 the 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 similarly to the methods described below, except for using appropriate isotopic species of the appropriate reagents or starting materials.

[0031] When the plural is used for compounds, salts, pharmaceutical compositions, diseases, etc., it is intended to refer to the singular compound, salt, etc. as well.

[0032] Any reference to compounds of formula (I) according to embodiments 1) to 17) will be understood to also refer to salts (especially pharmaceutically acceptable salts) of such compounds, where appropriate.

[0033] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesired toxic 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. References include, 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.

[0034] The definitions set forth herein apply uniformly to compounds of formula (I) as defined in any one of embodiments 1) to 14) and apply mutatis mutandis throughout the specification and claims, unless a broader or narrower definition is given by a specific definition. It is to be understood that any definition or preferred definition of a term may independently (and together with) define and replace the respective term in any or all other terms or preferred definitions defined herein.

[0035] In this patent application, compounds are named using IUPAC nomenclature, but may also be named using carbohydrate nomenclature.

[0036] [ka]

[0037] can be named (2R,3R,4R,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-phenyl-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl, or alternatively 1,3-di-deoxy-3-[4-phenyl-1H-1,2,3-triazol-1-yl]-α-D-galactopyranosid-1-yl, where the absolute configuration of the carbon atom bearing the point of attachment to the rest of the molecule is (2R)-, or alpha. For example, the compound (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol is also understood to be: 1-(1,3-di-deoxy-2-O-methyl-3-[4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-α-D-galacto-pyranose)-1(1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-methane.

[0038] Whenever a substituent is described as optional, it is understood that such substituent may not be present (i.e., the respective residue is unsubstituted with respect to such optional substituent), in which case all valenced sites (e.g., in an aromatic ring, ring carbon atoms and / or ring nitrogen atoms with valences to which such optional substituents may be attached) are replaced with hydrogen, as appropriate. Similarly, when the term "optionally" is used in reference to (ring) heteroatoms, this term means that each optional heteroatom, etc. is absent (i.e., the group has no heteroatoms / is a carbocyclic ring / etc.) or that each optional heteroatom, etc. is present as explicitly defined. Unless expressly defined otherwise in each embodiment or claim, groups defined herein are unsubstituted.

[0039] The term "halogen" means fluorine, chlorine or bromine, preferably fluorine.

[0040] 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. Typical examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl and pent-3-yl. 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. 2 "C 1-4 When referring to "-alkyl", the term specifically refers to methyl.

[0041] "Hydroxy-C 1-4 The term "-alkyl" refers to a C alkyl group as defined above, in which one hydrogen atom has been replaced with hydroxy. 1-4 -alkyl group. An example is 2-hydroxy-prop-2-yl.

[0042] "-C x-y The term "-alkylene-", used alone or in combination, refers to a bivalently bound alkyl group, as defined above, having x to y carbon atoms. 0-y The term "-alkylene-" refers to either a direct bond or the previously defined -(C 1-y ) alkylene-. Preferably, -C 1-y The points of attachment of the alkylene groups are in the 1,1-diyl or 1,2-diyl or 1,3-diyl configuration. 0-yWhen an -alkylene group is used in combination with another substituent, the term also applies when that substituent is C 1-y -alkylene group, or that is directly attached to the remainder of the molecule (i.e., a C0-alkylene group represents a direct bond attaching the substituent to the remainder of the molecule).

[0043] The term "fluoroalkyl," used alone or in combination, refers to an alkyl group, as defined above, having 1 to 4 carbon atoms, in which one or more (and in some cases all) hydrogen atoms have been replaced with 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, C 1-3 A -fluoroalkyl group has 1 to 3 carbon atoms in which 1 to 7 hydrogen atoms have been replaced by fluorine. Representative examples of fluoroalkyl groups include trifluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0044] 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, C 1-3 A fluoroalkoxy group has 1 to 3 carbon atoms, and 1 to 7 hydrogen atoms are replaced by fluorine atoms. Representative examples of the fluoroalkoxy group include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy. Preferred are C1-fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy.

[0045] The term "cycloalkyl," used alone or in combination, specifically refers to a saturated monocyclic hydrocarbon ring having from 3 to 7 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. Representative examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Said cycloalkyl groups are unsubstituted or substituted as expressly defined.

[0046] "-C x-y The term "-cycloalkylene-", used alone or in combination, refers to a doubly bonded cycloalkyl group as defined above having x to y carbon atoms. Preferably, the points of attachment of the doubly bonded cycloalkyl group are in a 1,1-diyl configuration. When ring B is "C 4-7 When referring to "-cycloalkane-diyl", this term in particular means cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl or cycloheptane-1,1-diyl. 4-7 -cycloalkane-diyl" is unsubstituted or substituted as expressly defined.

[0047] “Bridged Bicyclic C 6-9 The term "-cycloalkane-diyl" means a saturated bridged bicyclic hydrocarbon ring system having 6 to 9 carbon atoms. 6-9 When referring to "bicycloalkane-diyl", this term especially denotes bicyclo[2,2,1]heptane-2,2-diyl or bicyclo[3,2,1]octane-3,3-diyl.

[0048] 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. Representative examples of alkoxy groups are methoxy, ethoxy, isopropoxy, and tert-butoxy. 1-4 -alkoxy" 1 Examples are methoxy and ethoxy; most preferably methoxy.

[0049] The term "heterocycloalkyl," whether used alone or in combination, unless a broader or narrower definition is explicitly indicated, means a saturated or unsaturated non-aromatic monocyclic hydrocarbon ring having one or two ring heteroatoms independently selected from nitrogen, sulfur, and oxygen (particularly one oxygen atom, one sulfur atom, one nitrogen atom, two nitrogen atoms, two oxygen atoms, or one nitrogen atom and one oxygen atom). The term "x-y membered heterocycloalkyl" means such a heterocycle having a total of x to y ring atoms.

[0050] The term "heterocycloalkylene", whether used alone or in combination, refers to a heterocycloalkyl group as defined above bonded at two positions. For the avoidance of doubt, when a 4- to 7-membered heterocycloalkane-diyl is defined as having one ring heteroatom (such as one ring oxygen atom or one ring nitrogen atom), the 4- to 7-membered heterocycloalkane-diyl (as used for ring B, for example) shall have exactly that one ring heteroatom and no additional ring heteroatoms. When ring B represents a "4- to 7-membered heterocycloalkane-diyl", the heterocycloalkane-diyl shall be bivalently bonded to ring A via one ring carbon atom of the heterocycloalkane-diyl. An example of ring B representing a "4- to 7-membered heterocycloalkane-diyl having one ring oxygen atom" is tetrahydro-2H-pyran-4,4-diyl. Examples of Ring B representing "4- to 7-membered heterocycloalkane-diyl having one ring nitrogen atom" are piperidine-4,4-diyl or azepane-4,4-diyl. The heterocycloalkylene group is unsubstituted or substituted as explicitly defined.

[0051] Ring A is heterocycloalkylene

[0052] [ka]

[0053] When representing, the heterocycloalkylene particularly means the following structure:

[0054] [ka]

[0055] The term "aryl", used alone or in combination, means phenyl or naphthyl, preferably phenyl, which aryl groups are unsubstituted or substituted as expressly defined.

[0056] The term "heteroaryl," whether used alone or in combination, unless a broader or narrower definition is explicitly stated, refers to a 5- to 10-membered monocyclic or bicyclic aromatic ring having from 1 to 4 heteroatoms, each independently selected from oxygen, nitrogen, and sulfur. Representative examples of such heteroaryl groups include 5-membered heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl; 6-membered heteroaryl groups such as pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl; and indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, and the like. and 8-10 membered bicyclic heteroaryl groups such as benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, 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 term "heteroarylene," used alone or in combination, refers to a heteroaryl group, as defined above, attached at two positions.

[0058] The term "cyano" refers to the group --CN.

[0059] The term "oxo" refers to, for example, a carbonyl group -(CO)- (or a sulfonyl group -(S O2)-) preferably attached to a chain or ring carbon or sulfur atom.

[0060] Whenever the word "between" is used to describe a range of numerical values, 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 of 40°C and 80°C are included in the range; or, when a variable is defined as an integer between 1 and 4, the variable is meant to be the integer 1, 2, 3, or 4.

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

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

[0063] In a subembodiment, at least one of the substituents is attached at the meta or para position of the phenyl.

[0064] 3) Another embodiment is Ar 1 represents phenyl, substituted by 1, 2 or 3 substituents, said substituents being independently selected from halogen and methyl;

[0065] 4) Another embodiment is Ar 1represents phenyl substituted with two or three substituents independently selected from halogen and methyl; and at least one of said substituents is attached at the meta and / or para position of said phenyl.

[0066] 5) Another embodiment is Ar 1 but,

[0067] [ka]

[0068] It relates to compounds according to embodiment 1), which represent

[0069] 6) Another aspect is R 1 but, - hydroxy; -C 1-4 -alkoxy (especially methoxy); - -O-CO-C 1-3 - alkyl; - O-CO-NH-R N11 (R N11 is hydrogen or C 1-3 -alkyl);- -O-CH2-C1-fluoroalkyl; or - -O-CH2-CO-R 1X (R 1X teeth, -- -hydroxy; or -- C 1-3 -alkoxy (especially methoxy); represents. ); and relates to a compound according to any one of embodiments 1) to 5).

[0070] 7) Another aspect is R 1 represents methoxy; relates to compounds according to any one of embodiments 1) to 5).

[0071] 8) In another embodiment, ring A is

[0072] [ka]

[0073] wherein X represents nitrogen or oxygen, and n represents the integer 0 or 1 (particularly, X represents nitrogen and n represents the integer 0 or 1; or X represents oxygen and n represents the integer 0); when X represents nitrogen, the nitrogen is unsubstituted; and

[0074] [ka]

[0075] (In the formula, R 2 represents hydrogen or methyl; represents a heterocycloalkylene selected from: The compound according to any one of embodiments 1) to 7).

[0076] 9) Another embodiment is where ring A is heterocycloalkylene:

[0077] [ka]

[0078] and relates to a compound according to any one of embodiments 1) to 7).

[0079] 10) Another embodiment is where ring B is - Unsubstituted C 4-7 -cycloalkane-diyl; -C 4-7 -cycloalkane-diyl, 4-7 -cycloalkane-diyl is substituted by one substituent, and the substituent is C 1-4 -Alkyl (especially methyl, isopropyl); halogen (especially fluoro); cyano; oxo; hydroxy; hydroxy-C 1-4 -alkyl (especially 2-hydroxy-prop-2-yl); morpholin-4-yl; and -NH-R N11 (RN11 is C 1-6 -alkyl (especially isopropyl or pent-3-yl), C 2-4 -alkoxy, C 3-6 -cycloalkyl (especially cyclopropyl), C 2-3 -fluoroalkyl (especially 2,2-difluoroethyl or 2,2,2-trifluoroethyl), -CO-C 1-4 -Alkyl or -CO-C 1-4 -alkoxy. 4-7 -cycloalkane-diyl; -C 4-7 -cycloalkane-diyl, 4-7 -cycloalkane-diyl is substituted by two substituents, and the substituents are C 1-4 - independently selected from alkyl (especially methyl) and halogen (especially fluoro); 4-7 -cycloalkane-diyl; - a 4- to 7-membered heterocycloalkane-diyl, which heterocycloalkane-diyl has one ring oxygen atom; or - 4- to 7-membered heterocycloalkane-diyl, wherein the heterocycloalkane-diyl has one ring nitrogen atom, and the nitrogen atom is unsubstituted or has one C 1-4 -Alkyl (especially methyl), -CO-C 1-4 -Alkyl, -SO2-C 1-4 -Alkyl, -CO-C 1-4 -alkoxy or -CO-NH-C 1-4 -alkyl; said 4- to 7-membered heterocycloalkane-diyl does not bear any further substituents in addition to the substituent on the ring nitrogen atom or bears one further substituent on the ring carbon atom bonded to the ring nitrogen atom, and said substituent is oxo; and relates to a compound according to any one of embodiments 1) to 9).

[0080] 11) Another embodiment is where ring B is - Unsubstituted C4-7 - cycloalkane-diyl (in particular cyclohexane-1,1-diyl or cycloheptane-1,1-diyl); -C 4-7 -cycloalkane-diyl (especially cyclohexane-1,1-diyl), 4-7 -cycloalkane-diyl is substituted by one substituent, and the substituent is C 1-4 -Alkyl (especially methyl, isopropyl); cyano; hydroxy; hydroxy-C 1-4 -alkyl (especially 2-hydroxy-prop-2-yl); and -NH-R N11 (R N11 is C 1-6 -alkyl (especially isopropyl or pent-3-yl), C 2-4 -alkoxy, C 3-6 -cycloalkyl (especially cyclopropyl), C 2-3 -fluoroalkyl (especially 2,2-difluoroethyl or 2,2,2-trifluoroethyl), -CO-C 1-4 -Alkyl or -CO-C 1-4 -alkoxy. 4-7 -cycloalkane-diyl; -C 4-7 -cycloalkane-diyl (especially cyclohexane-1,1-diyl), 4-7 -cycloalkane-diyl is substituted by two substituents, and the substituents are C 1-4 - independently selected from alkyl (especially methyl) and halogen (especially fluoro); 4-7 -cycloalkane-diyl; - 4- to 7-membered heterocycloalkane-diyl, which has one ring oxygen atom (especially tetrahydropyran-4,4-diyl); or - 4- to 7-membered heterocycloalkane-diyl, which has one ring nitrogen atom (in particular piperidine-4,4-diyl or azepan-4,4-diyl), and which nitrogen atom is unsubstituted or has one C 1-4-Alkyl (especially methyl), -CO-C 1-4 -alkoxy or -CO-NH-C 1-4 -alkyl; the 4- to 7-membered heterocycloalkane-diyl does not carry any further substituents in addition to the substituents on the ring nitrogen atom, or the ring bonded to the ring nitrogen atom is 4-7 membered heterocycloalkane-diyl bearing one further substituent on a carbon atom, said substituent being oxo; and relates to a compound according to any one of embodiments 1) to 9).

[0081] 12) In another embodiment, ring B is - cyclohexane-1,1-diyl or cycloheptane-1,1-diyl; - cyclohexane-1,1-diyl, substituted by one substituent, said substituent being C 1-4 -Alkyl (especially methyl, isopropyl); cyano; hydroxy; hydroxy-C 1-4 -alkyl (especially 2-hydroxy-prop-2-yl); and -NH-R N11 (R N11 is cyclopropyl, C 2-3 -fluoroalkyl (especially 2,2-difluoroethyl or 2,2,2-trifluoroethyl), -CO-C 1-4 -Alkyl or -CO-C 1-4 -alkoxy; - cyclohexane-1,1-diyl, substituted by two substituents, the substituents being C 1-4 - cyclohexane-1,1-diyl selected from alkyl (especially methyl) and halogen (especially fluoro); - tetrahydropyran-4,4-diyl; - piperidine-4,4-diyl, wherein the nitrogen atom of said piperidine-4,4-diyl is a -CO-C 1-4 -alkoxy or -CO-NH-C 1-4-alkyl; said piperidine-4,4-diyl bearing no further substituents in addition to those on the ring nitrogen atoms; or - azepan-4,4-diyl, in which the nitrogen atom is unsubstituted or has one C 1-4 -Alkyl (especially methyl) or -CO-C 1-4 -alkoxy; said azepane-4,4-diyl either does not carry any further substituents in addition to the substituent on the ring nitrogen atom or carries one further substituent on the ring carbon atom attached to the ring nitrogen atom, said substituent being oxo; and relates to a compound according to any one of embodiments 1) to 9).

[0082] 13) Another embodiment is where ring B is - cyclohexane-1,1-diyl; - cyclohexane-1,1-diyl substituted by one substituent, said substituent being cyano; hydroxy-C 1-4 -alkyl (especially 2-hydroxy-prop-2-yl); and -NH-R N11 (R N11 is -CO-C 1-4 -Alkyl or -CO-C 1-4 -alkoxy; - cyclohexane-1,1-diyl substituted by two fluoro groups; or - tetrahydropyran-4,4-diyl; and relates to a compound according to any one of embodiments 1) to 9).

[0083] 14) Another aspect is

[0084] [ka]

[0085] represents a spiro ring fragment selected from the group consisting of: With respect to compounds according to one of the following:

[0086] [ka]

[0087] [ka]

[0088] Or, in addition to the above,

[0089] [ka]

[0090] Each of the above groups A) to E) represents a particular subembodiment, and further the above groups A) to D) form a particular subembodiment.

[0091] 15) Accordingly, the present invention relates to compounds of formula (I) as defined in aspect 1), or such compounds further defined by the features of any one of aspects 2) to 14), according to their respective subdivisions; pharmaceutically acceptable salts thereof; and uses of such compounds as further described below. For the avoidance of any doubt, compounds of formula (I) With respect to the above, the following embodiments are specifically possible, contemplated, and specifically disclosed herein as individual embodiments: 1、2+1、3+1、4+1、5+1、6+1、6+2+1、6+3+1、6+4+1、6+5+1、7+1、7+2+1、7+3+1、7+4+1、7+5+1、8+1、8+2+1、8+3+1、8+4+1、8+5+1、8+6+1、8+6+2+1、8+6+3+1、8+6+4+1、8+6+5+1、8+7+1、8+7+2+1、8+7+3+1、8+7+4+1、8+7+5+1、9+1、9+2+1、9+3+1、9+4+1、9+5+1、9+6+1、9+6+2+1、9+6+3+1、9+6+4+1、9+6+5+1、9+7+1、9+7+2+1、9+7+3+1、9+7+4+1、9+7+5+1、10+1、10+2+1、10+3+1、10+4+1、10+5+1、10+6+1、10+6+2+1、10+6+3+1、10+6+4+1、10+6+5+1、10+7+1、10+7+2+1、10+7+3+1、10+7+4+1、10+7+5+1、10+8+1、10+8+2+1、10+8+3+1、10+8+4+1、10+8+5+1、10+8+6+1、10+8+6+2+1、10+8+6+3+1、10+8+6+4+1、10+8+6+5+1、10+8+7+1、10+8+7+2+1、10+8+7+3+1、10+8+7+4+1、10+8+7+5+1、10+9+1、10+9+2+1、10+9+3+1、10+9+4+1、10+9+5+1、10+9+6+1、10+9+6+2+1、10+9+6+3+1、10+9+6+4+1、10+9+6+5+1、10+9+7+1、10+9+7+2+1、10+9+7+3+1、10+9+7+4+1、10+9+7+5+1、11+1、11+2+1、11+3+1、11+4+1、11+5+1、11+6+1、11+6+2+1、11+6+3+1、11+6+4+1、11+6+5+1、11+7+1、11+7+2+1、11+7+3+1、11+7+4+1、11+7+5+1、11+8+1、11+8+2+1、11+8+3+1、11+8+4+1、11+8+5+1、11+8+6+1、11+8+6+2+1、11+8+6+3+1、11+8+6+4+1、11+8+6+5+1、11+8+7+1、11+8+7+2+1、11+8+7+3+1、11+8+7+4+1、11+8+7+5+1、11+9+1、11+9+2+1、11+9+3+1、11+9+4+1、11+9+5+1、11+9+6+1、11+9+6+2+1、11+9+6+3+1、11+9+6+4+1、11+9+6+5+1、11+9+7+1、11+9+7+2+1、11+9+7+3+1、11+9+7+4+1、11+9+7+5+1、12+1、12+2+1、12+3+1、12+4+1、12+5+1、12+6+1、12+6+2+1、12+6+3+1、12+6+4+1、12+6+5+1、12+7+1、12+7+2+1、12+7+3+1、12+7+4+1、12+7+5+1、12+8+1、12+8+2+1、12+8+3+1、12+8+4+1、12+8+5+1、12+8+6+1、12+8+6+2+1、12+8+6+3+1、12+8+6+4+1、12+8+6+5+1、12+8+7+1、12+8+7+2+1、12+8+7+3+1、12+8+7+4+1、12+8+7+5+1、12+9+1、12+9+2+1、12+9+3+1、12+9+4+1、12+9+5+1、12+9+6+1、12+9+6+2+1、12+9+6+3+1、12+9+6+4+1、12+9+6+5+1、12+9+7+1、12+9+7+2+1、12+9+7+3+1、12+9+7+4+1、12+9+7+5+1、13+1、13+2+1、13+3+1、13+4+1、13+5+1、13+6+1、13+6+2+1、13+6+3+1、13+6+4+1、13+6+5+1、13+7+1、13+7+2+1、13+7+3+1、13+7+4+1、13+7+5+1、13+8+1、13+8+2+1、13+8+3+1、13+8+4+1、13+8+5+1、13+8+6+1、13+8+6+2+1、13+8+6+3+1、13+8+6+4+1、13+8+6+5+1、13+8+7+1、13+8+7+2+1、13+8+7+3+1、13+8+7+4+1、13+8+7+5+1、13+9+1、13+9+2+1、13+9+3+1、13+9+4+1、13+9+5+1、13+9+6+1、13+9+6+2+1、13+9+6+3+1、13+9+6+4+1、13+9+6+5+1、13+9+7+1、13+9+7+2+1、13、 +9+7+3+1, 13+9+7+4+1, 13+9+7+5+1, 14+1, 14+2+1, 14+3+1, 14+4+1, 14+5+1, 14+6+1, 14+6+2+1, 14+6+3+1, 14+6+4+1, 14+6+5+1, 14+7+1, 14+7+2+1, 14+7+3+1, 14+7+4+1, 14+7+5+1.

[0092] In the above list, the numbers refer to the embodiments corresponding to the number, and "+" indicates a dependency from another embodiment. The various embodiments are individually separated by commas. In other words, for example, "10+9+4+1" means embodiment 10) which is dependent on embodiment 9) which is dependent on embodiment 4) which is dependent on embodiment 1), i.e. embodiment "10+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 10).

[0093] 16) Another embodiment relates to compounds of formula (I) according to embodiment 1), which are selected from the following compounds: (2R,3R,4S,5R,6R)-2-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate; (2R,3R,4R,5R,6R)-2-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol; (2R,3R,4S,5R,6R)-2-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate; (2R,3R,4R,5R,6R)-2-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol; (2R,3R,4R,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; tert-butyl (3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5 -Methoxytetrahydro-2H-pyran-3-ol; tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.6]undec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (5s,8S)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; tert-butyl ((5s,8S)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; tert-butyl ((5s,8S)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; tert-butyl ((5s,8S)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; 3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; 3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; 3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6- (hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-(((5r,8R)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-(((5s,8S)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-((8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol; (5s,8S)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (5s,8S)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (5s,8S)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-(((5r,8R)-8-(2-hydroxypropan-2-yl)-1-oxa-2- Azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-(((5s,8S)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-(((5s,8S)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol; 3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-one; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-(2,2-difluoroethoxy)-2-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; Methyl 2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetate;(2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-ethoxy-2-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; 2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)-N-methylacetamide; 2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)-1-morpholinoethan-1-one; Methyl 2-(((2R,3R,4S,5R,6R)-2-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetate; (2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl carbamate; (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-6-(((5r,8R)-8-((2,2-difluoroethyl)amino)-1-oxa-2-azaspiro[4.5]deca -2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; tert-Butyl (RS)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.6]undec-2-ene-8-carboxylate; (RS)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.6]undec-2-en-9-one; (RS)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-8-methyl-1-oxa-2,8-diazaspiro[4.6]undec-2-en-9-one; (5RS,8S)-7-(tert-butoxycarbonyl)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene-8-carboxylic acid; 3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-ol; (5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-ol; N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide; N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide; N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide; N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide; ethyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; ethyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; ethyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; (2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-(((5r,8R)-8-(isopropylamino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((8-((2,2-difluoroethyl)amino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((8-(cyclopropylamino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-2-(hydroxymethyl)-5-methoxy-6-((8-((2,2,2-trifluoroethyl)amino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-(((5r,8R)-8-((2,2-difluoroethyl)amino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-(((5r,8R)-8-(cyclopropylamino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; 2-(((2R,3R,4S,5R,6R)-2-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetic acid; 2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methyl)methyl)- (ethylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetic acid; 2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetic acid; (2R,3R,4S,5R,6R)-6-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; N-(tert-butyl)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxamide; 1-(3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl)ethan-1-one; tert-Butyl 3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate; 3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-3-azaspiro[4.5]decan-2-one; 3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1,8-dioxa-3-azaspiro[4.5]decan-2-one; 3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1,3-diazaspiro[4.5]decan-2-one; 2-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-2,4-diazaspiro[5.5]undecan-3-one; (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxy-6-((2-methyl-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)tetrahydro-2H-pyran-3-ol; and (2R,3R,4S,5R,6R)-6-((1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol.

[0094] 17) In addition to the compounds described in embodiment 16), further compounds of formula (I) according to embodiment 1) are selected from the following compounds: (2R,3R,4S,5R,6R)-6-((4'H-spiro[bicyclo[2.2.1]heptane-2,5'-isoxazol]-3'-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; and (2R,3R,4S,5R,6R)-6-((4'H-spiro[bicyclo[3.2.1]octane-3,5'-isoxazol]-3'-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol.

[0095] The compounds of formula (I) according to embodiments 1) to 17) and their pharmaceutically 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.

[0096] Pharmaceutical compositions can be produced in a manner well known to anyone 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 compounds of formula (I) or pharmaceutically acceptable salts thereof, optionally with other therapeutically valuable substances, with suitable non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if necessary, conventional pharmaceutical adjuvants, to form a pharmaceutical dosage form.

[0097] 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 pharmaceutically effective amount of a compound of formula (I) according to embodiments 1) to 17). In a subembodiment of the invention, the dosage is comprised between 1 mg and 1000 mg per day.

[0098] For the avoidance of any doubt, where a compound is described as being useful for the prevention or treatment of a disease, such compound is also suitable for use in the manufacture of a medicament for the prevention or treatment of that disease, as well as in a method for the prevention or treatment of such disease, which comprises administering an effective amount of such compound to a subject (mammal, particularly a human) in need thereof.

[0099] 18) Another aspect relates to compounds of formula (I) as defined in any one of aspects 1) to 17), useful for the prevention or treatment of diseases and disorders in which the binding of galectin-3 to its natural ligand is involved.

[0100] Such diseases and disorders involving the binding of Gal-3 to its natural ligand are particularly those in which inhibition of the physiological activity of Gal-3 is beneficial, e.g., diseases in which the Gal-3 receptor is involved 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.

[0101] Diseases and disorders in which the binding of galectin-3 to its natural ligands is involved may be defined as including, inter alia: - fibrosis of an organ, characterized in that: All forms of fibrosing interstitial lung disease, especially idiopathic pulmonary fibrosis (also called cryptogenic fibrosing alveolitis); rheumatoid arthritis, scleroderma (systemic sclerosis, SSc), lupus (systemic lupus erythematosus), All forms of lung / pulmonary fibrosis, including pulmonary fibrosis secondary to systemic inflammatory diseases such as pulmonary fibrosis (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), (acute or chronic) renal failure, tubulointerstitial nephritis, and / or chronic nephropathy such as (primary) glomerulonephritis and glomerulonephritis secondary to systemic inflammatory diseases such as SLE and SSc, diabetes, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, renal transplantation, and renal fibrosis caused by / 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; --Gastrointestinal 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; and scar tissue formation, Peyronie's disease, abdominal or intestinal adhesions, bladder fibrosis, nasal fibrosis and fibroblast-mediated fibrosis; 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) 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 vasculopathy (including Budd-Chiari syndrome, portal vein thrombosis, sinusoidal obstruction syndrome); acute and chronic liver failure (whether or not associated with portal hypertension); hepatic dysfunction; - resulting from / associated with heart disease (also called cardiorenal syndrome types 1 and 2), or - resulting from / associated with hypertension, or - resulting from / associated with diabetes (also called diabetic nephropathy (DKD) including DKD associated with hypertension), where such diabetes is in particular type 1 or 2 diabetes), or - resulting from / associated with inflammatory diseases and disorders (such as glomerulonephritis and systemic inflammatory diseases such as SLE or SSc, tubulointerstitial nephritis, vasculitis, sepsis, glomerulonephritis secondary to urinary tract infection), or - resulting from / associated with polycystic kidney disease (such as stones, benign prostatic hyperplasia, prostate cancer, retroperitoneal pelvic tumors), Acute kidney injury and chronic kidney disease (CKD) caused by or associated with obstructive nephropathy (including urethral stenosis, urinary tract infection, urinary tract cancer, urinary tract infection ... - Cardiovascular diseases and disorders (e.g., atherosclerosis caused by / related to hypertension, hypercholesterolemia, diabetes, inflammation, obesity, elderly / age; peripheral arterial disease caused by / related to hypertension, hypercholesterolemia, diabetes, elderly / age; deep vein thrombosis; pulmonary embolism caused by / related to obesity or cancer; aortic aneurysm and dissection caused by / related to elderly, hypertension, Marfan syndrome, congenital heart defects, inflammatory or infectious disorders; cerebrovascular disease caused by / related to hypertension, atrial fibrillation, hypercholesterolemia, diabetes, elderly / age; hypertension, hypercholesterolemia, diabetes, elderly / age or CKD, in particular Kidney Disease Improving Coronary heart disease caused by / associated with CKD (stages 1-5 as defined by the Kingsley International Global Outcomes (KDIGO) Guidelines); rheumatic heart disease caused by / associated with bacterial infection; cardiac and vascular tumors; cardiomyopathies and arrhythmias; valvular heart disease (including cardiac valve calcification and degenerative aortic stenosis); inflammatory heart disease caused by / associated with infection, carditis, glomerulonephritis, and cancer; heart failure (HF), specifically defined as including congestive HF, including, inter alia, 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 caused by / associated with chronic obstructive pulmonary disease; interstitial pneumonia (including ordinary interstitial pneumonia) or pneumonia associated with collagen vascular disease); - Cell proliferative disorders and cancers (including solid tumors, solid tumor metastases, carcinomas, sarcomas, myeloma (and multiple myeloma), leukemia, lymphoma, mixed cancers, angiofibroma, Kaposi's sarcoma, chronic lymphocytic leukemia (CLL), spinal tumors and invasive metastases of cancer cells); - inflammatory and autoimmune diseases and disorders (including chronic and acute inflammatory and autoimmune diseases and disorders, in particular sepsis, Q fever, asthma, rheumatoid arthritis, multiple sclerosis, SLE, SSc, polymyositis, plaque psoriasis (including psoriasis caused by / associated with NASH), atopic dermatitis, inflammatory renal / kidney diseases such as 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 secretion); - 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; - Ocular diseases and disorders (including dry eye (xerophthalmia), age-related macular degeneration (AMD), diabetes-related diseases (diabetic retinopathy), proliferative vitreoretinopathy (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.

[0102] 19) A further embodiment relates to a compound of formula (I) for use according to embodiment 18), 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.

[0103] 20) A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein the compounds are for use in the prevention or treatment of cardiovascular diseases and disorders.

[0104] 21) A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein the compounds are for use in the prevention or treatment of acute kidney injury and chronic kidney disease (CKD).

[0105] 22) A further embodiment relates to compounds of formula (I) for use according to embodiment 18), in which the compounds are for use in the prevention or treatment of (acute or chronic) liver diseases and disorders.

[0106] 23) A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein the compounds are for use in the prevention or treatment of interstitial lung diseases and disorders.

[0107] 24) A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein the compounds are for use in the prevention or treatment of eye diseases and disorders.

[0108] 25) A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein the compounds are for use in the prevention or treatment of cell proliferative disorders and cancer.

[0109] 26) A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein the compounds are for use in the prevention or treatment of chronic or acute inflammatory and autoimmune diseases and disorders.

[0110] 27) A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein the compounds are for use in the prevention or treatment of digestive diseases and disorders.

[0111] 28) A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein the compounds are for use in the prevention or treatment of pancreatic diseases and disorders.

[0112] 29) A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein the compounds are for use in the prevention or treatment of diseases and disorders associated with abnormal angiogenesis.

[0113] 30) A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein the compounds are for use in the prevention or treatment of brain-related diseases and disorders.

[0114] 31) A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein the compounds are for use in the prevention or treatment of neuropathic pain and peripheral neuropathy.

[0115] 32) A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein the compounds are for use in the treatment of transplant rejection.

[0116] Preparation of Compounds of Formula (I) Compounds of formula (I) can be prepared by well-known literature methods, by the following methods, by methods described in the experimental section below, or by analogous methods. Optimum reaction conditions may vary with the specific reactants or solvents used; 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 unwanted reaction products. In the general reaction sequences outlined below, the generic group, R 1 , A, B and Ar 1 is 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 , A, B and Ar 1 may not be compatible with the preparation illustrated in the scheme below and would require the use of a protecting group (Pg). The use of protecting groups is well known in the art (see, for example, "Protective Groups in Organic Synthesis," T.W. Greene, P.G.M. Buts, Wiley-Interscience, 1999). For this purpose, it is assumed that such protecting groups have been introduced as necessary. Optionally, the final product may be further modified, for example, by manipulating substituents to obtain new final products. Such manipulations include, but are not limited to, reduction, oxidation, alkylation, acylation, hydrolysis, and transition metal-catalyzed cross-coupling reactions, which are well known to those skilled in the art. The resulting compounds may be converted into salts, in particular pharmaceutically acceptable salts, by methods known per se.

[0117] The compounds of formula (I) of the present invention can be prepared according to the general reaction sequences outlined below: Only a few of the synthetic possibilities leading to compounds of formula (I) are described.

[0118] [ka]

[0119] Compounds of formula (I) can be prepared by reacting R with R as defined in formula (I), where R is hydrogen; a suitable protecting group such as acetyl, trimethylsilyl, TBDMS, or the like; 1 The compound is prepared by deprotecting a compound of structure I, which represents:

[0120] Compounds of structure 1 (structure 1a) in which ring A represents a 3,5,5-trisubstituted isoxazoline are synthesized by 1,3-dipolar cycloaddition of nitrile oxides with exocyclic alkenes of structure 2 as shown below: Oximes such as these are precursors to nitrile oxides, which are oxidized in situ (e.g., with N-chlorosuccinimide) and then removed with a base such as lutidine, NEt3, or DIPEA in a suitable solvent such as DCM or DMF at temperatures ranging from rt to 50°C. If ring B contains a substituent, a mixture of diastereomers is formed during the cycloaddition. These isomers can be separated by silica gel chromatography or HPLC using various solvent mixtures and gradients, as described in the experimental section.

[0121] [ka]

[0122] Compounds of structure 1 (structure 1b) in which ring A represents a 3,5,5-trisubstituted oxazolidinone can be prepared by ring opening of exocyclic epoxides of structure 4 with amines of structure 5, followed by cyclization with carbonic acid derivatives such as CDI or phosgene.

[0123] [ka]

[0124] Compounds of structure 1 (structure 1c) in which ring A represents a 5- or 6-membered cyclic urea can be prepared by reductive amination of compounds of structure 6 with amines of structure 5, followed by cyclization with a strong base such as NaH, KOtBu, or other strong non-nucleophilic base, as shown in the scheme below.

[0125] [ka]

[0126] Compounds of structure 1 (structure 1d) in which ring A represents a 5- or 6-membered cyclic amidine can be prepared by reductive amination of compounds of structure 6 with amines of structure 5, followed by deprotection and cyclization of the resulting diamine with an orthoformate or orthoacetate or derivatives thereof, as shown in the scheme below.

[0127] [ka]

[0128] Experimental section The following examples illustrate the present invention but do not in any way limit its scope.

[0129] All temperatures are given in °C. Commercially available starting materials were used as received without further purification. Unless otherwise noted, all reactions were carried out under a nitrogen or argon atmosphere. Compounds were purified by flash chromatography on silica gel (Biotage) or by preparative TLC (Merck TLC plates, Silica gel 60 F 254 ) or by preparative HPLC. The compounds described in this invention were 1H-NMR (400 MHz or 500 MHz Bruker; chemical shifts are given in ppm relative to the solvent used; multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, hex = sextet, hept = septet, m = multiplet, br = broadband; 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.

[0130] Qualitative analysis methods used: LC-MS retention times were obtained using the following elution conditions: LC-MS(A): Zorbax RRHD SB-Aq, 1.8 μm, 2.1×50 mm column thermostated at 40° C. The two elution solvents were as follows: Solvent A = water + 0.04% TFA; Solvent B = acetonitrile. The eluent flow rate was 0.8 mL / min and the characteristics of the proportions of the elution mixture in relation to the time t from the start of the elution are summarized in the table below (a linear gradient is used between two consecutive time points):

[0131] [Table 1]

[0132] Purification by preparative LC-MS was carried out using the conditions described below.

[0133] Preparative LC-MS(I): A Waters column (Waters XBridge C18, 10 μm OBD, 30×75 mm) was used. The two elution solvents were as follows: Solvent A = water + 0.5% of 25% aqueous NH4OH; Solvent B = acetonitrile. The eluent flow rate was 75 mL / min and the characteristics of the proportion of the eluted mixture in relation to the time t from the start of the elution are summarized in the table below (a linear gradient is used between two consecutive time points):

[0134] [Table 2]

[0135] Preparative LC-MS(II): A Waters column (Waters XBridge C18, 10 μm OBD, 30×75 mm) was used. The two elution solvents were as follows: Solvent A = water + HCOOH 0.5%; Solvent B = acetonitrile. 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 table below (a linear gradient is used between two consecutive time points):

[0136] [Table 3]

[0137] Preparative LC-MS(III): A Waters column (Zorbax SB-AQ 30x75 mm, 5 μm) was used. The two elution solvents were as follows: solvent A = water + HCOOH 0.5%; solvent B = acetonitrile. The eluent flow rate was 75 mL / min and the characteristics of the proportion of the eluted mixture in relation to the time t from the start of the elution are summarized in the table below (a linear gradient is used between two consecutive time points):

[0138] [Table 4]

[0139] Chiral preparative HPLC method used: The epimers were separated by preparative chiral column chromatography using the conditions described below.

[0140] Chiral Preparative HPLC(I): A ChiralPack OZ-H, 5 μm, 30 × 250 mm column was used, and the column was thermostated at 40 °C. The two elution solvents were as follows: Solvent A = CO2; Solvent B = ACN / EtOH 1:1. The eluent flow rate was 160 mL / min. Elution was performed with 60% Solvent A and 40% Solvent B. Injection V = 1.0 mL, 10 mg / mL MeOH. Wavelength 247 nm. (Examples 2.02 / 2.03).

[0141] Chiral Preparative HPLC (II): A ChiralPack OJ-H column, 30x250 mm, was used, and the column was thermostated at 40°C. The two elution solvents were as follows: Solvent A = CO2; Solvent B = ACN / MeOH 1:1. The eluent flow rate was 160 mL / min. Elution was performed with 85% Solvent A and 15% Solvent B. Injection V = 2 mL, 10 mg / mL MeOH. Wavelength 245 nm. (Examples 1.62 / 1.63, 1.64 / 1.65).

[0142] Chiral Preparative HPLC (III): A ChiralPack IC, 5 μm, 30 × 250 mm column was used, and the column was thermostated at 40 °C. The two elution solvents were as follows: Solvent A = CO2; Solvent B = ACN / EtOH / DEA 50:50:0.1. The eluent flow rate was 160 mL / min. Elution was performed with 60% solvent A and 40% solvent B. Injection V = 1.2 mL, 11 mg / mL EtOH / ACN 1:1. (Examples 2.20 / 2.21, 2.22 / 2.23).

[0143] Chiral Preparative HPLC (IV): A ChiralPack IF, 5 μm, 30 × 250 mm column was used, and the column was thermostated at 40 °C. The two elution solvents were as follows: Solvent A = CO2; Solvent B = ACN / EtOH 50:50. The eluent flow rate was 160 mL / min. Elution was performed with 60% Solvent A and 40% Solvent B. Injection V = 1 mL, 11.2 mg / mL EtOH / ACN 1:1 (Example 1.44 / 145 (acetal protected)).

[0144] Chiral Preparative HPLC(V): A ChiralPack IE, 5 μm, 30 × 250 mm column was used, and the column was thermostated at 40 °C. The two elution solvents were as follows: Solvent A = CO2; Solvent B = ACN / MeOH 50:50. The eluent flow rate was 160 mL / min. Elution was performed with 55% solvent A and 45% solvent B. Injection V = 3 mL, 10 mg / mL MeOH / ACN 1:1 (Examples 1.15 / 1.16, 1.52 / 1.53, 1.61).

[0145] Chiral Preparative HPLC (VI): A ChiralPack OD-H, 30x250 mm, was used, and the column was thermostated at 40°C. The two elution solvents were as follows: Solvent A = CO2; Solvent B = ACN / MeOH 1:1. The eluent flow rate was 160 mL / min. Elution was performed with 70% Solvent A and 30% Solvent B. Injection V = 1 mL, 10 mg / mL MeOH. (Examples 1.56 / 1.57, 1.58 / 1.59, 1.60 / 1.61).

[0146] Chiral Preparative HPLC (VII): A ChiralCell OJ-H column, 30x250 mm, was used and the column was thermostated at 40°C. The two elution solvents were as follows: Solvent A = CO2; Solvent B = ACN / MeOH 1:1. The eluent flow rate was 160 mL / min. Elution was performed with 70% solvent A and 30% solvent B. Injection V = 1 mL, 10 mg / mL MeOH (Examples 1.27 / 1.28, 1.33 / 1.34).

[0147] NMR: 1H-NMR spectra are recorded on a Bruker Avance II, 400 MHz Ultra Shield™ or a Brooker 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 = sextet, hept = septet, m = multiplet, br = broad; coupling constants are given in Hz.

[0148] Abbreviations (as used herein): Ac Acetyl Ac2O acetic anhydride AcOH acetic acid aq. aqueous solution BF3OEt2 Boron trifluoride diethyl ether Boc tert-butoxycarbonyl Bu (as in nBuLi = n-butyllithium) CC silica column chromatography CDI 1,1-carbonyldiimidazole Concentrated DCM dichloromethane dil. Dilution DIPEA N-Ethyldiisopropylamine DMAP 4-dimethylaminopyridine DMF Dimethylformamide DMSO dimethyl sulfoxide EA Ethyl acetate EDC HCl N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride eq (mol) equivalent Example: Example Et Ethyl EtOH ethanol Et2O diethyl ether FC flash chromatography h time HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate Heptane HOBt 1-Hydroxybenzotriazole Hydrate HPLC High Performance Liquid Chromatography M Molar concentration [mol L -1 ] Me methyl MeCN acetonitrile MeOH Methanol Ms methanesulfonyl MS mass spectrometry min. N normality NaOAc Sodium Acetate NaOMe Sodium methoxide NaOtBu Sodium tert.(tertiary)butoxide NEt3 Triethylamine o / n overnight org.organic Pg protecting group Ph Phenyl PTSA p-toluenesulfonic acid rt room temperature sat. saturation TBAF Tetra-n-butylammonium fluoride TBME tert-butyl methyl ether TBSCI tert-butyldimethylchlorosilane TBTU O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate tBu tert-butyl = tertiary butyl TFA trifluoroacetic acid THF tetrahydrofuran TMEDA Tetramethylethylenediamine TMSCl Chlorotrimethylsilane T3P Propylphosphonic Anhydride t R retention time

[0149] A. Preparation of precursors and intermediates

[0150] [ka]

[0151] 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-(l-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.

[0152] Intermediate 2: (2R,3R,4R,5R,6R)-2-(acetoxymethyl)-6-allyl-4-azidotetrahydro-2H-pyran-3,5-diyl diacetate A solution of intermediate 1 (10 g, 26.8 mmol, 1 eq) in MeCN (100 mL) is cooled to 0 °C, and allyltrimethylsilane 98% (13 mL, 80.4 mmol, 3 eq) and trimethylsilyl trifluoromethanesulfonate 99% (2.45 mL, 13.4 mmol, 0.5 eq) are added dropwise (non-exothermic). The ice bath is removed, and the mixture is stirred at rt for 72 h. The mixture is poured into saturated NaHCO solution and extracted with TBME. The organic phase is washed with brine, dried over MgSO, and concentrated. The crude product is purified by filtration through SiO (DCM / TBME 9:1) to afford the title intermediate (as a 9:1 mixture of alpha / beta isomers) as a colorless oil, which is used in the next step without further purification.

[0153] Major isomer: 1H NMR (500MHz, DMSO) δ:5.70-5.78(m, 2H), 5.31(dd, J 1 =1.6Hz, J 2 =3.4Hz, 1H), 5.06-5.14(m, 2H), 4.98-5.04(m, 1H), 4.39(dd, J 1 =3.4Hz, J 2 =10.6Hz, 1H), 4.15(m, 1H), 3.91-4.09(m, 4H), 2.56-2.65(m, 1H), 2.22-2.28(m, 1H), 2.11(s, 3H), 2.09(s, 3H), 1.99(s, 3H).

[0154] Intermediate 3a: (2R,3R,4R,5R,6R)-2-(acetoxymethyl)-6-allyl-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate To a solution of intermediate 2 (15 g, 42.5 mmol, 1 eq) in DMF (160 mL) are added 5-ethynyl-1,2,3-trifluorobenzene (9950 mg, 63.7 mmol, 1.5 eq), copper(I) iodide (809 mg, 4.25 mmol, 0.1 eq) and NEt3 (17.8 mL, 127 mmol, 3 eq) and stirred at rt overnight. The mixture is diluted with EA and dil.HCl. The organic phase is washed with water and brine, dried over MgSO4 and concentrated. The crude product is crystallized from EA (20 mL) and TBME (200 mL) to give the desired pure alpha isomer as a colorless solid. LCMS (A): t R = 1.02 min; [M+H] + =512.15.

[0155] 1 H NMR (500MHz, DMSO-d6) δ:8.78(s, 1H), 7.83-7.88(m, 2H), 5.75-5.84(m, 1H), 5.70-5.74(m, 2H), 5.36(s, 1H), 5.1 8-5.21(m, 1H), 5.10-5.14(m, 1H), 4.41(m, 1H), 4.35(m, 1H), 4.00-4.04(m, 1H), 3.94(dd, J 1=7.1Hz, J 2 =11.3Hz, 1H), 2.84-2.91(m, 1H), 2.30-2.35(m, 1H), 2.02(s, 3H), 1.98(s, 3H), 1.86(s, 3H)

[0156] [ka]

[0157] Intermediate 4a: (2R,3R,4R,5R,6R)-2-allyl-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol To a solution of intermediate 3a (12 g, 23.5 mmol, 1 eq) in methanol (240 mL) is added K2CO3 (324 mg, 2.35 mmol, 0.1 eq). The reaction mixture is stirred at rt for 2 h. The mixture is concentrated in vacuo to give a beige foam. The crude compound is purified by FC (DCM / MeOH 9:1) to give the desired product as a colorless solid. LCMS (A): R =0.7min;[M+H] + =385.76 1 H NMR (500MHz, DMSO-d6) δ:8.72(s, 1H), 7.82-7.87(m, 2H), 5.88(m, 1H), 5.26(d, J=5.7Hz, 1H), 5.14-5.19(m, 2H), 5.05-5.07(m, 1H), 4.90(dd, J 1 =2.9Hz, J 2 =11.4Hz, 1H), 4.58(t, J=5.5Hz, 1H), 4.52(m, 1H), 4.02(m, 1H), 3.93(dd, J 1 =2.6Hz, J 2 =6.4Hz, 1H), 3.78(t, J=6.2Hz, 1H), 3.49(m, 1H), 3.42(m, 1H), 2.68-2.75(m, 1H), 2.33-2.38(m, 1H).

[0158] Intermediate 5a: (4aR,6R,7R,8R,8aR)-6-allyl-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-7-ol A solution of intermediate 4a (15 g, 38.9 mmol, 1 eq) in THF (180 mL) is treated with 2,2-dimethoxypropane (19.1 mL, 156 mmol, 4 eq) and PTSA monohydrate (0.378 g, 1.95 mmol, 0.05 eq) and the light yellow solution is stirred overnight at rt. The mixture is diluted with EA and the organic layer is washed with sat. NaHCO3 solution, water and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the title intermediate as a colorless solid. LCMS (A): t R =0.93 min; [M+H] + =426.13 1 H NMR (500MHz, DMSO-d6) δ:8.72(s, 0H), 8.58-8.64(m, 1H), 7.80-7.94(m, 2H), 5.81-5.90(m, 1H), 5.33-5.38(m, 1H) ), 5.11-5.20(m, 1H), 5.00-5.11(m, 2H), 4.41-4.52(m, 1H), 4.26-4.31(m, 1H), 4.12(ddd, J 1 =11.5Hz, J 2 =5.7Hz, J 3 =3.2Hz, 1H), 4.01(dd, J 1 =12.7Hz, J 2 =2.0Hz, 1H), 3.66-3.71(m, 1H), 3.57-3.65(m, 1H), 2.64-2.72(m, 1H), 2.34-2.41(m, 1H), 1.32(s, 3H), 1.20(s, 3H).

[0159] Intermediate 6a: 1-((4aR,6R,7R,8R,8aR)-6-allyl-7-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8- To a solution of (3,4,5-trifluorophenyl)-4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole intermediate 5a (7.3 g, 17.2 mmol, 1 eq) in dry THF (50 mL) cooled to 0 °C, dimethyl sulfate (2 mL, 20.6 mmol, 1.2 eq) was added, followed by portionwise addition of NaH [55% dispersion in paraffin] (824 mg, 20.6 mmol, 1.2 eq). The mixture was stirred at 0 °C for 3 h. The mixture was quenched with sat. NH4Cl and extracted twice with TBME. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give a colorless solid. LCMS (A): t R = 1.03 min; [M+H] + =440.22 1 H NMR (500MHz, DMSO-d6) δ:8.71(s, 1H), 7.68-7.98(m, 2H), 5.70-5.97(m, 1H), 5.14-5.21(m, 2H), 5.09(m, 1H), 4.48(ddd, J 1 =3.5Hz, J 2 =5.5Hz, J 3 =11.4Hz, 1H), 4.30(d, J=2.9Hz, 1H), 4.22(dd, J 1 =5.7Hz, J 2 =11.5Hz, 1H), 3.93-4.10(m, 1H), 3.56-3.74(m, 2H), 3.21(s, 3H), 2.70-2.78(m, 1H), 2.20-2.31(m, 1H), 1.32(s, 3H), 1.20(s, 3H).

[0160] Intermediate 6b: (4aR,6R,7R,8S,8aR)-6-allyl-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-7-yl acetate Intermediate 5a (725 mg, 1.7 mmol, 1 eq) is dissolved in DCM (10 mL) and Ac2O (0.193 mL, 2.05 mmol, 1.2 eq), DIPEA (0.438 mL, 2.56 mmol, 1.5 eq) and DMAP (10.4 mg, 0.0852 mmol, 0.05 eq) are added. The mixture is stirred at rt for 1 h. The mixture is partitioned between EA and NaHCO3 solution. The organic phase is washed with sat. NH4Cl and brine, dried over MgSO4 and concentrated. Purification by FC (hept / EA 2:1, 1:1, 1:2) gives the title intermediate as a colorless foam. LCMS (A): t R =1.04min;[M+H]+=467.98 1 H NMR (500MHz, DMSO-d6) δ:8.63(s, 1H), 7.89(m, 2H), 5.81(m, 1H), 5.59(dd, J 1 =5.7Hz, J 2 =11.4Hz, 1H), 5.47(dd, J 1 =3.2Hz, J 2 =11.4Hz, 1H), 5.19(dd, J 1 =1.9Hz, J 2 =17.2Hz, 1H), 5.09(m, 1H), 4.36-4.41(m, 2H), 4.03-4.06(m, 1H), 3.76(d, J=1.0Hz, 1H), 3.66(dd, J 1 =1.7Hz, J 2 =12.8Hz, 1H), 2.80(m, 1H), 2.28-2.33(m, 1H), 1.84(s, 3H), 1.38(s, 3H), 1.25(s, 3H).

[0161] Intermediate 6c: ((2R,3R,4R,5R,6R)-3-acetoxy-6-allyl-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl acetate Step 1: (2R,3R,4S,5R,6R)-6-allyl-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol To a mixture of intermediate 6a (3050 mg, 6.94 mmol, 1 eq) in water (15 mL) was added acetic acid (30 mL) and the suspension was stirred at 55 °C for 3 h. The solution was concentrated under reduced pressure and the residue was dried overnight under vacuum. The crude product (light yellow solid) was used in the next step without further purification.

[0162] Step 2: To a solution of the intermediate from step 1 (3340 mg, 8.36 mmol, 1 eq) and EtN (6.99 mL, 50.2 mmol, 6 eq) in DCM (40 mL) at 0 °C under N is added AcO (2.42 mL, 25.1 mmol, 3 eq) and the solution is stirred overnight at rt. Water is added and the mixture is extracted with DCM. The organic layer is dried over MgSO and then concentrated under reduced pressure to give the title intermediate as a colorless solid. LCMS (A): R = 1.03 min; [M+H]+ = 484.20.

[0163] Intermediate 6d: 1-((4aR,6R,7R,8S,8aR)-6-allyl-7-((tert-butyldimethylsilyl)oxy)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)-4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole Intermediate 5a (2000 mg, 4.7 mmol, 1 eq) is dissolved in dry DCM (30 mL) and the solution is cooled to 0 °C. Under N2, 2,6-lutidine (1.1 mL, 9.4 mmol, 2 eq) is added, followed by dropwise addition of tert-butyldimethylsilyl trifluoromethanesulfonate (1.32 mL, 5.64 mmol, 1.2 eq) within 5 min. The yellowish solution is stirred at 0 °C for 30 min and at rt overnight. The mixture is quenched with water and the two layers are separated. The organic layer is dried using a phase separator and then concentrated under reduced pressure to give an off-white foam, which is used without further purification. LCMS (A): t R = 1.23 min; [M+H]+ = 540.22.

[0164] [ka]

[0165] Intermediate 7a: 2-((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]dioxin-6-yl)acetaldehyde Intermediate 6a (4270 mg, 9.72 mmol, 1 eq) is suspended in 1,4-dioxane (50 mL) and water (15 mL). 2,6-Lutidine (1.24 mL, 10.6 mmol, 3 eq) and sodium periodate (6235 mg, 29.2 mmol, 3 eq) are added, followed by potassium osmate dihydrate (15 mg, 0.0408 mmol, 0.0042 eq). The suspension is vigorously stirred overnight at room temperature. The mixture is diluted with water and EA and carefully adjusted to pH 2-3 with HCl (1N). The two layers are separated, and the organic layer is washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude product is purified by FC using a CombiFlash (40 g SiO2 column; gradient: 0-100% EA in hept) to give the desired aldehyde as a colorless solid. LCMS(A):t R =0.91 min; [M+H] + =442.12 1 H NMR (500MHz, DMSO-d6) δ:9.72(m, 1H), 8.73(s, 1H), 7.87(dd, J 1 =9.0Hz, J 2 =6.8Hz, 2H), 5.11-5.18(m, 2H), 4.24-4.30(m, 2H), 4.01-4.04(m , 1H), 3.57-3.69(m, 2H), 3.32(s), 3.20(s, 3H), 2.98(ddd, J 1 =16.2Hz, J 2 =9.2Hz, J 3 =3.0Hz, 1H), 2.83(ddd, J 1 =16.2Hz, J 2 =5.0Hz, J 3=1.4Hz, 1H), 1.18-1.33(m, 6H).

[0166] Intermediate 7b: (4aR,6R,7R,8S,8aR)-2,2-dimethyl-6-(2-oxoethyl)-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-7-yl acetate Prepared similarly to intermediate 7a starting from intermediate 6b. LCMS(A):t R =0.92 min; [M+H] + =469.96.

[0167] Intermediate 7c: (2R,3R,4R,5R,6R)-2-(acetoxymethyl)-6-(2-oxoethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate Prepared in the same manner as intermediate 7a, starting from intermediate 3a. LCMS(A):t R =0.93 min; [M+H] + =514.10.

[0168] Intermediate 7d: 2-((4aR,6R,7R,8S,8aR)-7-((tert-butyldimethylsilyl)oxy)-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-6-yl)acetaldehyde Prepared in the same manner as intermediate 7a, starting from intermediate 6d. LCMS(A):t R = 1.16 min; [M+H] + =542.18.

[0169] Intermediate 8a: -2-((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]dioxin-6-yl)acetaldehyde oxime Intermediate 7a (1390 mg, 3.15 mmol, 1 eq), hydroxylamine HCl (328 mg, 4.72 mmol, 1.5 eq), and NaOAc (775 mg, 9.45 mmol, 3 eq) were placed in a flask and suspended in EtOH (5 mL) and HO (5 mL). THF (10 mL) was added, and the mixture was stirred at rt for 1.5 h. The mixture was partitioned between EA and water. The organic layer was washed with brine, dried over MgSO, and concentrated under reduced pressure. The crude product was triturated with TBME and hept 3 / 1 (20 mL), sonicated, and the off-white crystals were filtered and dried under vacuum.

[0170] The desired oxime (E / Z mixture) is isolated as an off-white solid. LCMS (A): R =0.88min;[M+H] + =457.16.

[0171] Intermediate 8b: (4aR,6R,7R,8S,8aR)-6-(2-(hydroxyimino)ethyl)-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-7-yl acetate Prepared in the same manner as intermediate 8a, starting from intermediate 7b. LCMS(A):t R =0.90min;[M+H] + =485.18.

[0172] Intermediate 8c: (2R,3R,4R,5R,6R)-2-(acetoxymethyl)-6-(2-(hydroxyimino)ethyl)-4-(4-(3,4,5-trifluorophenyl) )-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate Prepared in the same manner as intermediate 8a, starting from intermediate 7c. LCMS(A):t R =0.89 min; [M+H] + =529.05.

[0173] Intermediate 8d: 2-((4aR,6R,7R,8S,8aR)-7-((tert-butyldimethylsilyl)oxy)-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-6-yl)acetaldehyde oxime Prepared in the same manner as intermediate 8a, starting from intermediate 7d. LCMS(A):t R = 1.11 min; [M+H] + =558.19.

[0174] [ka]

[0175] Intermediate 9: (2R,3R,4R,5R,6R)-2-(acetoxymethyl)-6-(propa-1,2-dien-1-yl)-4-(214-triaza-1,2-dien-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate Intermediate 1 (3733 mg, 10 mmol, 1 eq) is dissolved in MeCN (20 mL) and cooled to 3 °C. Trimethyl(propargyl)silane (3.73 mL, 25 mmol, 2.5 eq) is added, followed by dropwise addition of BF3Oet2 (3.7 mL, 30 mmol, 3 eq) and trimethylsilyl trifluoromethanesulfonate (3.66 mL, 20 mmol, 2 eq). The mixture is stirred at 0 °C for 1.5 h and at rt for 1 h. The mixture is partitioned between TBME and sat. NaHCO3. The organic phase is washed with brine, dried over MgSO4, and concentrated. The crude product is purified by FC (hept / EA 2:1) to give the desired allene intermediate as a yellowish oil.

[0176] 1H NMR (500MHz, DMSO-D6) δ:5.56(q, J=6.7Hz, 1H), 5.35(d, J=2.2Hz, 1H), 4.98-5.05(m, 3H), 4.74(m, 1H), 4.35(dd, J 1 =3.3Hz, J 2 =11.2Hz, 1H), 4.20-4.23(m, 1H), 4.00-4.03(m, 1H), 3.90(dd , J 1 =7.0Hz, J 2 =11.4Hz, 1H), 2.12(s, 3H), 2.09(s, 3H), 2.00-2.02(m, 4H).

[0177] Intermediate 10a: (2R,3R,4R,5R,6R)-2-(acetoxymethyl)-6-(propa-1,2-dien-1-yl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate The title compound is prepared analogously to intermediate 3a, starting from intermediate 9. LCMS (A): R = 1.02 min; [M+H] + =510.24 1 H NMR (500MHz, DMSO-d6) δ:8.81(s, 1H), 7.82-7.86(m, 2H), 5.80(q, J=6.8Hz, 1H), 5.65-5.72(m, 2H), 5.40(d, J=1.5Hz, 1H), 5.06(dd, J 1 =6.6Hz, J 2 =2.3Hz, 2H), 4.96-4.99(m, 1H), 4.50(t, J=6.3Hz, 1H), 4.01(m, 2H), 2.00-2.04(m, 6H), 1.87(s, 3H).

[0178] Intermediate 11a: 1-((4aR,6R,7R,8R,8aR)-7-methoxy-2,2-dimethyl-6-(propa-1,2-dien-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-8-yl)-4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole The title intermediate is prepared by following the preparation of intermediates 4a, 5a and 6a, starting from intermediate 10a. LCMS(A): R = 1.02 min; [M+H] + =438.21 1 H NMR (500MHz, DMSO-d6) δ:8.71(s, 1H), 7.87(dd, J 1 =6.8Hz, J 2 =9.0Hz, 2H), 5.75(m, 1H), 5.13(dd, J 1 =3.3Hz, J 2 =11.4Hz, 1H), 5.07(m, 1H), 4.98(m, 2H), 4.34-4.34(m, 1H), 4.26(dd, J 1 =5.6Hz, J 2 =11.5Hz, 1H), 4.04(dd, J 1 =2.0Hz, J 2 =12.9Hz, 1H), 3.82(d, J=0.7Hz, 1H), 3.68(dd, J 1 =1.5Hz, J 2 =12.9Hz, 1H), 3.22(s, 3H), 1.32(s, 3H), 1.21(s, 3H).

[0179] Intermediate 12a: ((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]dioxin-6-yl)methanol Intermediate 11a (1000 mg, 2.29 mmol, 1 eq) was dissolved in 4:1 DCM / MeOH (60 mL) and cooled to -70 °C. Ozone was bubbled through the solution until the KI solution in the scrubber turned brown (~60 min). Excess O was purged by bubbling N for 10 min. NaBH (86.5 mg, 2.29 mmol, 1 eq) was added at -78 °C, the dry ice bath was removed, and the mixture was allowed to warm to rt within 1 h. The mixture was then carefully quenched with water (25 mL), the layers were separated, and the organic layer was dried over MgSO and concentrated under reduced pressure.

[0180] The crude solid is purified by FC using CombiFlash (24 g SiO2 column; gradient from hept / EA 2 / 1 to 100% EA in 20 min) to give the title intermediate as a colorless solid. LCMS (A): R =0.84 min; [M+H] + =430.29 1 H NMR (500MHz, DMSO-d6) δ:8.69(s, 1H), 7.86(m, 2H), 5.29(dd, J 1 =11.4Hz, J 2 =3.4Hz, 1H), 4.80(t, J=5.5Hz, 1H), 4.34(m, 2H), 4.24(dd, J 1 =1 1.4Hz, J 2 =6.1Hz, 1H), 3.96-4.07(m, 2H), 3.91(s, 1H), 3.71(dd, J 1 =12.7Hz, J 2 =1.4Hz, 1H), 3.63(ddd, J 1 =12.3Hz, J 2 =5.8Hz, J 3 =2.9Hz, 1H), 3.23(s, 3H), 1.32(s, 3H), 1.20(s, 3H).

[0181] Intermediate 13a: ((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]dioxin-6-yl)methyl methanesulfonate Intermediate 12a (400 mg, 0.932 mmol, 1 eq) is dissolved in DCM (8 mL) and cooled to 0 °C. At this temperature, MsCl (0.0736 mL, 0.932 mmol, 1 eq) and DIPEA (0.191 mL, 1.12 mmol, 1.2 eq) are added and the mixture is stirred at 0 °C for 30 min. MsCl (0.0144 mL, 0.186 mmol, 0.2 eq) is further added and the mixture is stirred at 0 °C for another 30 min. The mixture is diluted with DCM and washed with water. The organic layer is dried on a phase separator and concentrated under reduced pressure. The crude foam is purified by FC using CombiFlash (12 g SiO column; gradient from hept to hept / EA 1 / 2 in 16 min) to give the desired intermediate as a colorless solid. LCMS (A): t R =0.96 min; [M+H] + =508.14 1 H NMR (500MHz, DMSO-d6) δ:8.72-8.74(m, 1H), 7.83-7.90(m, 2H), 5.18-5.27(m, 1H), 4.89-4.98(m, 1H), 4 .75-4.84(m, 1H), 4.27-4.37(m, 3H), 4.06-4.09(m, 1H), 3.83(s, 1H), 3.73(dd, J 1 =12.9Hz, J 2 =1.5Hz, 1H), 3.26(d, J=6.1Hz, 6H), 1.34(s, 3H), 1.22(s, 3H).

[0182] Intermediate 14a: 1-((4aR,6R,7R,8R,8aR)-6-(azidomethyl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)-4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole To a solution of intermediate 13a (409 mg, 0.806 mmol, 1 eq) in dry DMF (10 mL) under N2 is added sodium azide (62.9 mg, 0.967 mmol, 1.2 eq). The reaction mixture is heated at 70 °C for 5 h. The temperature is raised to 80 °C and the mixture is stirred at this temperature until the reaction is complete. The mixture is cooled to rt, diluted with EA and water and the layers are separated. The aqueous layer is extracted once more with EA. The combined organic layers are washed twice with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude colorless solid is purified by FC using CombiFlash (12 g SiO2 column; gradient from hept to hept / EA 1 / 1 in 17 min) to give the desired intermediate as a colorless solid. LCMS (A): t R = 1.01 min; [M+H] + =455.19 1 H NMR (500MHz, DMSO) δ:8.68-8.74(m, 1H), 7.82-7.91(m, 2H), 5.13-5.23(m, 1H), 4.67-4.74(m, 1H), 4.27-4.33(m, 2H), 4.17-4.25(m, 1H) , 4.05-4.12(m, 1H), 3.78-3.86(m, 1H), 3.66-3.74(m, 1H), 3.23-3.26(m, 1H), 3.22(s, 3H), 1.34(s, 3H), 1.23(s, 3H).

[0183] Intermediate 15a: ((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]dioxin-6-yl)methanamine To a solution of intermediate 14a (500 mg, 1.1 mmol, 1 eq) in THF (7.5 mL) is added PPh3 (583 mg, 2.2 mmol, 2 eq) and water (1.5 mL). The resulting mixture is then heated at 60°C under N2 for 3 h. The mixture is diluted with EA and then extracted with 10% citric acid (3 times) until all amine has been removed from the organic phase. The combined aqueous layers are extracted once more with EA and then basified with aq. sat. NaHCO3. The basic aqueous layer is extracted twice with EA. The combined organic layers are dried over MgSO4, filtered and concentrated under reduced pressure. Used as is. LCMS (A): t R =0.72 min; [M+H] + =429.09 1 H NMR (500MHz, DMSO) δ:8.42-8.90(m, 1H), 7.77-7.89(m, 2H), 5.09(dd, J 1 =11.4Hz, J 2 =3.4Hz, 1H), 4.27-4.31(m, 2H), 4.23(m, 1H), 3.99-4.03(m, 1H), 3.74(dd, J 1 =1.5Hz, J 2 =12.8Hz, 1H), 3.68(s, 1H), 3.21(s, 3H), 3.11(dd, J 1 =13.8Hz, J 2 =10.5Hz, 1H), 2.67(dd, J 1 =13.8Hz, J 2 =3.4Hz, 1H), 1.32(s, 3H).

[0184] Different Ar 1 All further analogs of intermediates 3-15 bearing - substituents were prepared similarly to the above procedures starting from known or commercially available substituted arylacetylenes.

[0185] Namely, the following most important analogs of intermediates 6, 8, 14 and 15 were prepared and used in the synthesis of the final examples:

[0186] [Table 5]

[0187] [Table 6]

[0188] [Table 7]

[0189] [Table 8]

[0190] B. Preparation of Examples General Procedure A: Cycloaddition of nitrile oxides with alkenes: A solution of the oxime intermediate (1 eq) and NCS (1.5 eq) in DMF (5 mL / mmol) is stirred at rt until complete conversion to the hydroximoyl chloride. Alkene (1-3 eq) and DIPEA or 2,6-lutidine (3 eq) are added, and the mixture is stirred at rt or 50 °C until complete conversion of the intermediate. After aqueous workup (dil.HCl / EA), the product is isolated and purified as described in the general method.

[0191] General Procedure B: Deprotection with aq. AcOH The protected intermediate (acetal and / or silyl Pg) (1 eq) is added until the reaction is complete. and refluxed in AcOH / H2O 1:1 (5 mL / mmol). The product is purified as described in the general method.

[0192] General Procedure C: Acetate Deprotection with K2CO3 in MeOH K2CO3 (0.1 eq) is added to the acetate protected intermediate (1 eq) in MeOH (5 mL / mmol) and stirred at rt until the reaction is complete. The product is purified as described in the general method.

[0193] General Procedure D: Boc Deprotection with TFA TFA (10-20 eq) is added to a solution of the Boc-protected intermediate (1 eq) in DCM (5 ml / mmol). The mixture is stirred at rt until complete conversion. Volatiles are removed under reduced pressure and the residue is partitioned between DCM and dil.NH4OH solution. The organic phase is dried over MgSO4 and concentrated in vacuo. If necessary, the product is further purified as described in the general method.

[0194] General Procedure E: Boc Deprotection with HCl A solution of the Boc-protected amine (1 eq) in dioxane (5 ml / mmol) is treated with a solution of HCl in dioxane (4 M, 10-20 eq), and the resulting mixture is stirred at rt until the reaction is complete. Volatiles are removed under reduced pressure, and the crude product is isolated by trituration with TBME.

[0195] General Procedure F: Schotten Baumann Acylation Acyl chloride or anhydride (1.2 eq) is added at 0° C. to a two-phase mixture of amine (1 eq) in DCM (5 ml / mmol) and saturated NaHCO solution (5 ml / mmol) under vigorous stirring. The mixture is further stirred at rt until complete conversion. The phases are separated and the organic phase is dried over MgSO and concentrated. The product is purified as described in the general method.

[0196] General Procedure G: Derivatization with sulfonyl chlorides, chloroformates, or isocyanates An electrophile (sulfonyl chloride, chloroformate, or isocyanate, 1.1 eq) is added to a mixture of the starting amine (1 eq free base, or as TFA or HCl salt) and base (NEt or DIPEA, 5 eq) in DCM (5 ml / mmol) at 0° C. or rt. The mixture is stirred at rt until the reaction is complete. The product is purified as described in the general method.

[0197] General Procedure H: Reductive Amination A mixture of the amine intermediate (1 eq) and either the aldehyde BB or the ketone (1-2 eq) in DCM is treated with NaBH(OAc) (3 eq) and the mixture is stirred at rt until complete conversion. After aqueous workup (DCM / dil.NHOH), the desired product is isolated as described in the general method.

[0198] General Procedure I: Saponification Ester (1 eq) in THF / H2O 1:1 or THF / MeOH / H2O 3:2:1 (1 mL / mmol) and LiOH . H2O (1.5-3 eq) is stirred at rt until the reaction is complete. After aqueous workup (EA / H2O), the product is purified as described in the general method.

[0199] General Procedure J: Wittig Olefination Methyltriphenylphosphonium bromide 98% (1.05 eq) in dry Et2O (1. To a suspension in 1.5 mL / mmol of n-butyllithium in hexane under N2 at 0 °C is added dropwise within 15 min, keeping the temperature below 5 °C. The resulting suspension is stirred at rt for 1 h. Then, a solution of the ketone (1 eq) in dry Et2O (1 mL / mmol) is added dropwise within 15 min. The resulting suspension is stirred at rt until the reaction is complete. The mixture is carefully quenched with water (2 drops), Et2O (1.5 mL / mmol) is added, and the suspension is filtered and washed with Et2O. The filtrate is concentrated under reduced pressure, and the residue is stored in the freezer.

[0200] General Procedure K: Reduction of Ketones with NaBH4 The ketone (1 eq) is dissolved in EtOH (11 mL / mmol) and THF (6 mL / mmol) and cooled to 0 °C. NaBH (2 eq) is added and the mixture is stirred at 0 °C until the reaction is completely converted. The mixture is diluted with EA and water and acidified by adding 1N HCl. The phases are separated and the organic phase is washed with water and brine, dried over MgSO and concentrated. The product is purified as described in the general method.

[0201] General Procedure L: Ring-opening of epoxides with amines A solution of epoxide (1.1 eq) and amine (1 eq) in MeOH (10 ml / mmol) is heated under reflux in a sealed vial until the reaction is complete. The mixture is concentrated in vacuo and purified as described in the general method.

[0202] General Procedure M: Cyclization with Triphosgene A solution of triphosgene (1 eq) in DCM (5 ml / mmol) is added at rt to a solution of aminoalcohol (1 eq) and DIPEA (10 eq) in DCM (10 ml / mmol). The reaction mixture is stirred at rt until the reaction is complete. After aqueous workup (DCM / sat NaHCO), the compound is purified as described in the general method.

[0203] [ka]

[0204] The compounds of Examples 1.01 to 1.82 listed in Table 1 below are prepared starting from intermediate 8 by applying general procedure A to the appropriate exocyclic methylene derivative (commercially available or prepared from the corresponding cyclic ketone by Wittig olefination (general procedure J)), followed by deprotection according to general procedure C or D. The diastereomers are separated by chiral preparative chromatography using the appropriate method described above.

[0205] [Table 9]

[0206] [Table 10]

[0207] [Table 11]

[0208] [Table 12]

[0209] [Table 13]

[0210] [Table 14]

[0211] [Table 15]

[0212] [Table 16]

[0213] [Table 17]

[0214] [Table 18]

[0215] [Table 19]

[0216] The following examples (Table 2) are prepared starting from oxime intermediate 8 and exocyclic alkene by applying general procedure A, followed by deprotection (procedure B, C, D, E or I) and subsequent derivatization according to procedure F, G, H or K. Final deprotection (if necessary) is carried out according to procedure B or C.

[0217] [Table 20]

[0218] [Table 21]

[0219] [Table 22]

[0220] [Table 23]

[0221] The examples in Table 3 are prepared by starting from an amine (Intermediate 15) and an epoxide and following general procedures L and M, followed by deprotection (General Procedure B or C).

[0222] [Table 24]

[0223] Example 4.01: 3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1,3-diazaspiro[4.5]decan-2-one

[0224] Step 1: tert-butyl (1-(((((4aR,6R,7R,8R,8aR)-8-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)methyl)amino)methyl)cyclohexyl)carbamate Intermediate 15b (300 mg, 0.707 mmol, 1 eq) is dissolved in DCM / MeOH 4:1 (12 mL) and 1-(Boc-amino)-1-formylcyclohexane (338 mg, 1.41 mmol, 2 eq), sodium triacetoxyborohydride 97% (237 mg, 1.06 mmol, 1.5 eq) and AcOH (0.0404 mL, 0.707 mmol, 1 eq) are added at rt under N. The mixture is stirred at rt until complete conversion. After aqueous workup (DCM / sat NaHCO) and silica gel column chromatography (0-15% MeOH in DCM), the title intermediate is isolated as a colorless solid. LCMS (A): t R =0.92 min; [M+H] + =636.32.

[0225] Step 2: Title Compound The above intermediate (50 mg) is dissolved in DMF (0.7 ml) and treated with NaH (55% dispersion in mineral oil, 2 eq) at 0° C. The mixture is stirred at rt for 48 h and partitioned between EA and water. The organic phase is dried over MgSO4 and concentrated. The isolated intermediate is deprotected according to general procedure B. LCMS (A): t R =0.86 min; [M+H] + =522.22.

[0226] Example 4.02: 2-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-2,4-diazaspiro[5.5]undecan-3-one The title compound is prepared analogously to Example 4.01, steps 1 and 2, starting from intermediate 15c and tert-butyl ((1-formylcyclohexyl)methyl)carbamate (CAS 1476035-56-9). LCMS (A): R =0.91 min; [M+H] + =556.18

[0227] Example 4.03: (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxy-6-((2-methyl-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)tetrahydro-2H-pyran-3-ol

[0228] Step 1: (2R,3R,4S,5R,6R)-6-((((1-aminocyclohexyl)methyl)amino)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol The intermediate of Example 4.01, Step 1 (200 mg, 0.315 mmol, 1 eq) is dissolved in DCM (3 mL) at rt and 4 M HCl in dioxane (3 mL) is added. The white suspension is stirred at rt. Water is added and the aqueous phase is basified with 32% NaOH solution, extracted with DCM (3x), dried over MgSO4, filtered, concentrated to dryness and dried under HV to give the title intermediate as a colorless resin, which is used without purification. LCMS (A): t R =0.59 min; [M+H] + =496.28

[0229] Step 2: (2R,3R,4S,5R,6R)-6-((((1-aminocyclohexyl)methyl)amino)methyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-methoxytetrahydro-2H-pyran-3-ol To a solution of the above intermediate (130 mg) and NEt3 (0.022 mL, 0.157 mmol, 0.6 eq) in dry DCM (3 mL) is added TBSCl (excess) at 0 °C under nitrogen. The mixture is stirred at rt for 3 days. Water is added and the product is extracted with DCM. Chromatography on SiO2 (0-20% MeOH in DCM (+0.5% NH4OH)) affords the title intermediate as a colorless solid. LCMS (A):R =0.83 min; [M+H] + =610.13

[0230] Step 3: (2R,3R,4S,5R,6R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-methoxy-6-((2-methyl-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)tetrahydro-2H-pyran-3-ol The intermediate from step 2 (60 mg) is dissolved in dioxane (1 ml) and triethyl orthoacetate (2 eq) is added. The mixture is heated under reflux for 1.5 h. The mixture is concentrated in vacuo and Dry under vacuum. LCMS(A): R =0.98 min; [M+H] + =634.28

[0231] Step 4: Title Compound The intermediate from step 3 is dissolved in THF (2 ml) and TBAF (1 M in THF, 1.2 eq) is added. The mixture is stirred at rt for 1 h, diluted with water and extracted with EA and DCM. The combined organic extracts are dried, concentrated and purified by prep HPLC (prep LC-MS III). LCMS (A): t R =0.75min;[M+H] + =520.24

[0232] Example 4.03: (2R,3R,4S,5R,6R)-6-((1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol This example is prepared analogously to Example 4.03, steps 3 and 4, using triethyl orthoformate instead of triethyl orthoacetate. LCMS (A): R =0.74 min; [M+H] + =506.21

[0233] II. Biological Testing Inhibitory activity of the compound (IC 50 ) evaluation The inhibitory activity of the compounds is determined in a competitive binding assay. 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 to 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.

[0234] Briefly, compounds are serially diluted in DMSO (test diluent). To an ASF-coated 384-well plate, 22.8 μL / well of biotin-labeled hGal-3 or hGal-1 in assay buffer (i.e., 300-1000 ng / ml biotin-labeled hGal-3 or hGal-1) is added, followed by 1.2 L of compound test diluent and mixing.

[0235] The plate is incubated at 4°C for 3 hours, then washed with cold assay buffer (3 x 50 μl), and incubated with 25 μL / well of streptavidin-peroxidase solution (diluted to 80 ng / ml in assay buffer) for 1 hour at 4°C, followed by another wash with assay buffer (3 x 50 μl). Finally, 25 μL / well of ABTS substrate is added. After 30-45 minutes, the OD (410 nm) is recorded and the IC is calculated. 50 Calculate the value.

[0236] 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.

[0237] [Table 25]

[0238] Table 26

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: 【Chemical 1】 (In the formula, Ar １ teeth, aryl, which is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents, said substituents being independently selected from halogen, methyl, cyano, methoxy, trifluoromethyl and trifluoromethoxy; a 5- or 6-membered heteroaryl, which is independently unsubstituted or substituted with 1 or 2 substituents 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 １－４ -alkoxy; - -O-CO-C １－３ - alkyl; -O-CO-NH-R Ｎ１１ (R Ｎ１１ is hydrogen or C １－３ - represents alkyl; - -O-CH ２ -C １ -fluoroalkyl; Or, - -O-CH ２ -CO-R １Ｘ (R １Ｘ は、 -- -hydroxy; -- C １－３ -alkoxy; --morpholin-4-yl; Or, -- --NR Ｎ２１ R Ｎ２２ (R Ｎ２１ and R Ｎ２２ each independently represents hydrogen or methyl; represents.) represents; 【Chemistry 2】 represents a spiro ring fragment; Ring A is 【Chemistry 3】 wherein X represents nitrogen or oxygen, and n represents an integer of 0 or 1; when X represents nitrogen, the nitrogen is unsubstituted or substituted with one C １－４ -substituted by alkyl; and 【Chemistry 4】 (In the formula, R ２ is hydrogen or C １－４ -represents alkyl; represents a heterocycloalkylene selected from: Ring B is - C ４－７ -cycloalkane-diyl, ４－７ -cycloalkane-diyl is unsubstituted or substituted by 1 or 2 substituents, said substituents being C １－４ - alkyl; C １－３ -fluoroalkyl; C １－４ -alkoxy; halogen; cyano; oxo; hydroxy; hydroxy-C １－４ -alkyl; hydroxyimino; morpholin-4-yl; and -NH-R Ｎ１１ (R Ｎ１１ is C １－６ -Alkyl, C ２－４ -alkoxy, C ３－６ -cycloalkyl, C ２－３ -fluoroalkyl, -CO-C １－４ -Alkyl or -CO-C １－４ -alkoxy; ４－７ -cycloalkane-diyl; - 4- to 7-membered heterocycloalkane-diyl, which heterocycloalkane-diyl has one ring oxygen atom; - 4-7 membered heterocycloalkane-diyl, which has one ring nitrogen atom, and which ring nitrogen atom is unsubstituted or has one C １－４ -Alkyl, -CO-C １－４ -Alkyl, -SO ２ -C １－４ -Alkyl, -CO-C １－４ -alkoxy or -CO-NH-C １－４ -alkyl; said 4- to 7-membered heterocycloalkane-diyl either does not carry any further substituents in addition to the substituent on the ring nitrogen atom or carries one further substituent on the ring carbon atom bonded to the ring nitrogen atom, said substituent being oxo or -CO-OH; or - Bridged bicyclic C ６－９ -cycloalkane-diyl; represents.).

2. Ar １ represents phenyl substituted by two or three substituents, said substituents being independently selected from halogen, methyl, cyano, methoxy, trifluoromethyl and trifluoromethoxy; or a pharmaceutically acceptable salt thereof.

3. Ar １ represents phenyl substituted with two or three substituents independently selected from halogen and methyl, at least one of which is attached at the meta and / or para position of said phenyl; or a pharmaceutically acceptable salt thereof.

4. R １ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: represents methoxy.

5. Ring A is 【Chemistry 5】 wherein X represents nitrogen or oxygen, and n represents the integer 0 or 1; when X represents nitrogen, the nitrogen is unsubstituted; and 【Chemistry 6】 (In the formula, R ２ represents hydrogen or methyl; represents a heterocycloalkylene selected from: The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

6. Ring B is - unsubstituted C ４－７ -cycloalkane-diyl; - C ４－７ -cycloalkane-diyl, ４－７ -cycloalkane-diyl is substituted by one substituent, said substituent being C １－４ -Alkyl; Cyano; Hydroxy; Hydroxy-C １－４ -alkyl; and -NH-R Ｎ１１ (R Ｎ１１ is C １－６ -Alkyl, C ２－４ -alkoxy, C ３－６ -cycloalkyl, C ２－３ -fluoroalkyl, -CO-C １－４ -Alkyl or -CO-C １－４ -alkoxy; ４－７ -cycloalkane-diyl; - C ４－７ -cycloalkane-diyl, ４－７ -cycloalkane-diyl is substituted by two substituents, and the substituents are C １－４ - independently selected from alkyl and halogen; ４－７ -cycloalkane-diyl; a 4- to 7-membered heterocycloalkane-diyl, which heterocycloalkane-diyl has one ring oxygen atom; or 4- to 7-membered heterocycloalkane-diyl, which has one ring nitrogen atom, and which nitrogen atom is unsubstituted or has one C １－４ -Alkyl, -CO-C １－４ -alkoxy or -CO-NH-C １－４ -alkyl; said 4- to 7-membered heterocycloalkane-diyl either does not carry any further substituents in addition to the substituent on the ring nitrogen atom or carries one further substituent on the ring carbon atom bonded to the ring nitrogen atom, and said substituent is oxo; The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which represents:

7. Ring B is cyclohexane-1,1-diyl or cycloheptane-1,1-diyl; cyclohexane-1,1-diyl substituted by one substituent, said substituent being C １－４ -Alkyl; Cyano; Hydroxy; Hydroxy-C １－４ -alkyl; and -NH-R Ｎ１１ (R Ｎ１１ is cyclopropyl, C ２－３ -fluoroalkyl, -CO-C １－４ -Alkyl or -CO-C １－４ -alkoxy; cyclohexane-1,1-diyl, substituted by two substituents, the substituents being C １－４ - cyclohexane-1,1-diyl selected from alkyl and halogen; tetrahydropyran-4,4-diyl; - piperidine-4,4-diyl, wherein the nitrogen atom of the piperidine-4,4-diyl is a -CO-C １－４ -alkoxy or -CO-NH-C １－４ -alkyl; said piperidine-4,4-diyl carrying no further substituents in addition to those on the ring nitrogen atoms; Or, azepan-4,4-diyl, in which the nitrogen atom is unsubstituted or has one C １－４ -Alkyl or -CO-C １－４ -alkoxy; said azepane-4,4-diyl either carries no further substituents in addition to the substituent on the ring nitrogen atom or carries one further substituent on the ring carbon atom attached to the ring nitrogen atom, said substituent being oxo; The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which represents:

8. Ring B is cyclohexane-1,1-diyl; cyclohexane-1,1-diyl substituted by one substituent, said substituent being cyano; hydroxy-C １－４ -alkyl; and -NH-R Ｎ１１ (R Ｎ１１ is -CO-C １－４ -Alkyl or -CO-C １－４ -alkoxy; - cyclohexane-1,1-diyl substituted by two fluoro groups; Or, tetrahydropyran-4,4-diyl; The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which represents:

9. 【Chemical 7】 represents a spiro ring fragment selected from the group consisting of: 【Chemistry 8】 【Chemistry 9】

10. The compound is (2R,3R,4S,5R,6R)-2-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate; (2R,3R,4R,5R,6R)-2-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol; (2R,3R,4S,5R,6R)-2-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate; (2R,3R,4R,5R,6R)-2-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol; (2R,3R,4R,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; tert-butyl (3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.6]undec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (5s,8S)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; tert-butyl ((5s,8S)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; tert-Butyl ((5s,8S)-3-(((2R,3R,4S,5R,6R)-4 -(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; tert-butyl ((5s,8S)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; 3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; 3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; 3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-(((5r,8R)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-(((5s,8S)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-((8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol; (5s,8S)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbo Nitriles; (5s,8S)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (5s,8S)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-(((5r,8R)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-(((5s,8S)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-(((5s,8S)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol; 3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-one; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-(2,2-difluoroethoxy)-2-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; Methyl 2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetate; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-ethoxy-2-(hydroxymethyl)-4-( 4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; 2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)-N-methylacetamide; 2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)-1-morpholinoethan-1-one; Methyl 2-(((2R,3R,4S,5R,6R)-2-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetate; (2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl carbamate; (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-6-(((5r,8R)-8-((2,2-difluoroethyl)amino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; tert-butyl (RS)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.6]undec-2-ene-8-carboxylate; (RS)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.6]undec-2-en-9-one; (RS)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-8-methyl-1-oxa-2,8-diazaspiro[4.6]undec-2-en-9-one; (5RS,8S)-7-(tert-butoxycarbonyl)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene-8-carboxylic acid; 3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-ol; (5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-ol; N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide; N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide; N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide; N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide; ethyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; ethyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; ethyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; (2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-(((5r,8R)-8-(isopropylamino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((8-((2,2-difluoroethyl)amino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((8-(cyclopropylamino)-1-oxo sa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-2-(hydroxymethyl)-5-methoxy-6-((8-((2,2,2-trifluoroethyl)amino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-(((5r,8R)-8-((2,2-difluoroethyl)amino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-(((5r,8R)-8-(cyclopropylamino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; 2-(((2R,3R,4S,5R,6R)-2-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetic acid; 2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetic acid; 2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetic acid; (2R,3R,4S,5R,6R)-6-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; N-(tert-butyl)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxamide; 1-(3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl)ethan-1-one; tert-butyl 3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate; 3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methyl (ethylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-3-azaspiro[4.5]decan-2-one; 3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1,8-dioxa-3-azaspiro[4.5]decan-2-one; 3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1,3-diazaspiro[4.5]decan-2-one; 2-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-2,4-diazaspiro[5.5]undecan-3-one; (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxy-6-((2-methyl-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)tetrahydro-2H-pyran-3-ol; Or, (2R,3R,4S,5R,6R)-6-((1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; 2. The compound of claim 1, wherein:

11. A pharmaceutical composition comprising the compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

12. A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

13. A drug for the prevention or treatment of organ fibrosis; liver diseases and disorders; cardiovascular diseases and disorders; cell proliferative disorders and cancers; 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; acute kidney injury and chronic kidney disease; interstitial lung diseases and disorders; or transplant rejection, comprising as an active ingredient a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

14. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of organ fibrosis; liver diseases and disorders; cardiovascular 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; acute kidney injury and chronic kidney disease; interstitial lung diseases and disorders; or transplant rejection.

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