EA048291B1 - 2-HYDROXYCYCLOALKANE-1-CARBAMOYL DERIVATIVES - Google Patents

Description

The present invention relates to compounds of formula (I) which are galectin-3 inhibitors and their use for preventing/prophylaxis or treating diseases and disorders which are related to galectin-3 binding to 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) can be used in particular as single agents or in combination with one or more therapeutic agents.

Galectins are defined as a family of proteins based on the conserved β-galactoside-binding sites found in their characteristic ~130 amino acid (aa) carbohydrate recognition domains (CRDs) (Barondes SH et al., Cell 1994; 76, 597-598). The human, mouse, and rat genome sequences reveal the existence 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 subclasses of galectins have been identified: prototypic galectins containing a single carbohydrate recognition domain (CRD); chimeric galectin consisting of unusual tandem repeats of proline- and glycine-rich short regions fused to the CRD; and tandem repeat galectins, which contain two individual CRDs in tandem connected by a linker (Zhong X., Clin Exp Pharmacol Physiol. 2019; 46:197–203). Because galectins can bind either bivalently or multivalently, they can, for example, cross-link cell surface glycoconjugates, triggering cellular signaling events. Through this mechanism, galectins modulate a wide range of biological processes (Sundblad V. et al., Histol Histopathol 2011; 26: 247–265).

Galectin-3 (Gal-3), the only chimeric type in the galectin family, has a molecular weight of 32–35 kDa in humans and consists of 250 amino acid residues, 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, facilitated by its N-terminal non-CRD region through an oligomerization mechanism that is not yet fully understood (Johannes, L. et al., Journal of Cell Science 2018; 131, jcs208884).

Gal-3 is widely distributed in the body, but the expression level varies in different organs. Depending on its extracellular or intracellular localization, it can exhibit a wide range of biological functions, including immunomodulation, host-pathogen interactions, angiogenesis, cell migration, wound healing, and apoptosis (Sundblad V. et al., Histol Histopathol 2011; 26: 247-265). Gal-3 is highly expressed in many human tumors and cell types, such as myeloid cells, inflammatory cells (macrophages, mast cells, neutrophils, T cells, eosinophils, etc.), fibroblasts, and cardiomyocytes (Zhong X. et al., Clin Exp Pharmacol Physiol. 2019; 46:197–203), indicating that Gal-3 is involved in the 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 up-regulated in certain pathological conditions such as neoplasms and inflammation (Chiariotti L. et al., Glycoconjugate Journal 2004 19, 441-449; Farhad M. et al., Oncolmmunology 2018, 7:6, e1434467).

There are several lines of evidence supporting the functional involvement of Gal-3 in the development of inflammatory/autoimmune diseases such as 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 (Praha) 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 Y Acad Sci. 2012; 1253:80–91; Henderson NC, et al., Immunol Rev. 2009;230(l):160–71; Li P et al., ^I 2016; 167:973–984). Gal-3 has recently been found to be a key player in chronic inflammation and fibrogenesis 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(l):57–65), heart (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(l):57–65), and brain (Henderson NC et al. Am. J. Pathol. 2008; 172:288–298; Dang Z. et al. Transplantation. 2012; 93(5):477–84). (Thandavarayan RA et al. Biochem Pharmacol. 2008, 75(9): 1797-806; Sharma U. et al. Am J Physiol Heart Circ Physiol. 2008; 294(3):H1226-32), as well as the nervous system (Burguillos MA et al. Cell Rep. 2015, 10(9): 1626-1638), and corneal neovascularization (Chen WS. et al., Investigative Ophthalmology & Visual Science 2017, Vol. 58, 9-20). Furthermore, Gal-3 has been found to be associated with keloid-like skin lesions (Arciniegas E et al. The American Journal of dermatopathology 2019; 41(3): 193-204) and systemic sclerosis (SSc), particularly the cutaneous fibrosis and proliferative vasculopathy observed in this condition (Taniguchi T et al. J Rheumatol. 2012; 39(3):539-44). Gal-3 has been found to be up-regulated in patients with chronic kidney disease (CKD)-associated renal failure, and particularly in patients with diabetes. Interestingly, data from this patient population showed a correlation between Gal-3 upregulation in the glomerulus and the observed urinary protein excretion (Kikuchi Y. et al. Nephrol Dial Transplant. 2004, 19(3):602-7). Furthermore, a recent prospective study conducted since 2018 demonstrated that more

- 1 048291 High plasma Gal-3 levels are associated with an increased risk of developing CKD, particularly in the hypertensive population (Rebholz CM et al. Kidney Int. Jan 2018; 93(1): 252-259). Gal-3 is highly elevated in cardiovascular diseases (Zhong X. et al. Clin Exp Pharmacol Physiol. 2019, 46(3): 197–203), such as atherosclerosis (Nachtigal M. et al. Am J Pathol. 1998; 152(5): 1199–208), coronary heart 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). Blood Gal-3 concentrations are elevated in obese and diabetic patients and are associated with a higher risk of micro- and macrovascular complications (such as heart failure, nephropathy/retinopathy, peripheral arterial disease, cerebrovascular accident, or myocardial infarction) (Qi-hui-Jin et al. Chin Med J (Eng). 2013,126(11):2109-15). Gal-3 has been shown to influence tumorigenesis, cancer progression, and metastasis (Vuong L. et al., Cancer Res 2019 (79) (7) 1480-1492), and has been shown to play a role as a pro-tumor factor by acting within the tumor microenvironment to suppress immune surveillance (Ruvolo PP. et al. Biochim Biophys Acta. 2016 Mar,1863(3):427-437; Farhad M. et al. Oncoimmunology 2018 Feb 20;7(6):e1434467). Among the malignancies that express high levels of Gal-3, thyroid cancer, central nervous system cancer, tongue cancer, breast cancer, gastric cancer, squamous cell carcinoma of the head and neck, pancreatic cancer, bladder cancer, kidney cancer, liver cancer, parathyroid cancer, salivary gland cancer, as well as lymphoma, carcinoma, non-small cell lung cancer, melanoma, and neuroblastoma have been identified (Sciacchitano S, et al. Int J Mol Sci, 2018 Jan 26, 19(2):379).

In addition, Gal-3 inhibition has been suggested to be beneficial in the treatment of COVID-19 (Caniglia JL et al. PeerJ 2020, 8:e9392) and H5N1 influenza (Chen YJ et al. Am. J. Pathol. 2018, 188(4), 1031-1042), possibly due to its anti-inflammatory effects.

Recently, Gal-3 inhibitors have been shown to have beneficial 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), as well as in NASH cirrhosis (December 5, 2017). WO 20180209276, WO 2018209255 and WO 20190890080 disclose compounds having specific binding affinity to galectin proteins for the treatment of systemic insulin resistance disorders. Thus, Gal-3 inhibitors, alone or in combination with other therapies, may be useful in the prevention or treatment of diseases or disorders such as organ fibrosis, cardiovascular diseases and disorders, acute kidney injury and chronic kidney disease, liver diseases and disorders, interstitial lung diseases and disorders, eye diseases and disorders, cell proliferative diseases and malignancies, inflammatory and autoimmune diseases and disorders, gastrointestinal diseases and disorders, pancreatic diseases and disorders, diseases and disorders associated with abnormal angiogenesis, brain diseases and disorders, neuropathic pain and peripheral neuropathy, and/or transplant rejection.

Several publications and patent applications describe synthetic Gal-3 inhibitors that are being studied as antifibrotic agents (see, for example, WO2005113568, WO2005113569, WO2014067986, WO2016120403, US20140099319, WO2019067702, WO2019075045, WO2014078655, WO2020078807, and WO2020078808).

The present invention provides novel compounds of formula (I) which are inhibitors of galectin-3. The compounds of the present invention may thus be useful for the prevention/prophylaxis or treatment of diseases and disorders in which modulation of the binding of Gal-3 to its natural carbohydrate ligands is indicated.

1. In a first embodiment, the invention relates to a compound of formula (I)

Ag ¹

Formula (I), where n is an integer 1 or 2 (in particular, n is 1);

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Ar ¹ is aryl (especially phenyl) which is mono-, di-, tri-, tetra-, or pentasubstituted (especially mono-, di-, or trisubstituted), wherein the substituents are independently selected from halogen; methyl; cyano; methoxy; trifluoromethyl; trifluoromethoxy; NR ⁿ¹¹ R ⁿ¹² , where RN ¹¹ is hydrogen and R ⁿ¹² is hydroxy-C _2-3 -alkyl (especially 3-hydroxyprop-1-yl), or R ⁿ¹¹ and R ⁿ¹² together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl selected from morpholin-4-yl, azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl (especially morpholin-4yl), wherein said 4- to 6-membered heterocyclyl is unsubstituted or monosubstituted by hydroxy (especially selected from halogen, methyl, cyano and methoxy);

(wherein, in particular, at least one of said substituents is attached at the meta or para position of said phenyl; wherein, if present, such substituent at the para position is preferably selected from halogen, methyl, cyano and methoxy; and, if present, such substituent at the meta position is preferably halogen);

5- or 6-membered heteroaryl (especially thiazolyl), wherein said 5- or 6-membered heteroaryl is independently unsubstituted, mono- or disubstituted, wherein the substituents are independently selected from halogen, methyl, cyano and methoxy; or

9- or 10-membered heteroaryl (especially benzothiazolyl), wherein said 9- or 10-membered heteroaryl is independently unsubstituted or monosubstituted with methyl;

R ¹ is hydroxy;

C _1-3 -alkoxy (especially methoxy);

- O-CO-C _1-3 -alkyl;

- O-CH2-CH2-OH; or

- O-CH ₂ -CO-R ^1x , where R ^1x is

- hydroxy;

morpholin-4-yl; or

- NR ^N21 R ^N22 , where RN ²¹ and RN ²² together with the nitrogen atom to which they are attached form a 4-6-membered heterocyclyl selected from azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl, wherein said 4-6-membered heterocyclyl is monosubstituted with hydroxy;

L represents a direct bond, methylene, or ethylene (especially a direct bond or methylene); and

Ar ² is phenyl or a 5- or 6-membered heteroaryl (especially furanyl, thiophenyl, pyrrolyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl or pyrimidinyl), wherein said phenyl or 5- or 6-membered heteroaryl is independently unsubstituted or mono-, di- or trisubstituted (especially mono- or disubstituted), wherein the substituents are independently selected from C _1-6 -alkyl, C _3-6 cycloalkyl, -CH ₂ -C _3-6 -cycloalkyl, C _1-3 -fluoroalkyl, C _1-3 -fluoroalkoxy, C _1-3 -alkoxy, halogen, morpholin-4-yl, amino, ethynyl and cyano;

9-membered bicyclic heteroaryl (especially indolyl or benzothiophenyl, benzothiazolyl or benzoimidazolyl) or 10-membered bicyclic heteroaryl (especially quinolinyl or quinoxalinyl), wherein said 9- or 10-membered bicyclic heteroaryl is independently unsubstituted, mono- or disubstituted, wherein the substituents are independently selected from methyl, methoxy and halogen (especially fluoro, chlorine); or naphthyl.

The compounds of formula (I) contain five stereogenic or asymmetric centers which are located on the tetrahydropyran moiety and two stereogenic or asymmetric centers which are located on the cycloalkane moiety and which are in the absolute ^^-configuration as depicted for formula (I). In addition, the compounds of formula (I) may contain one further and possibly more stereogenic or asymmetric centers, such as one or more additional asymmetric carbon atoms. Thus, the compounds of formula (I) may be present as mixtures of stereoisomers or, preferably, as pure stereoisomers. Mixtures of stereoisomers may be separated by a method known to a person skilled in the art.

Where a particular compound (or generic structure) is designated as being in a certain absolute configuration, for example as the (R)- or (Z)-enantiomer, such designation is to be understood as referring to the corresponding compound (or generic structure) in enriched, in particular substantially pure enantiomeric form. Similarly, where a particular asymmetric centre in a compound is designated as being in the (R)- or (S)-configuration or as being in a certain relative configuration, such designation is to be understood as referring to the compound which is in enriched, in particular substantially pure form, with respect to the corresponding configuration of the said asymmetric centre. By analogy, two stereogenic centres, for example in a cyclic group, may be present in a certain relative configuration. Accordingly, cis- or trans-designations (or (R*,R*)

- 3 048 291 designations used, for example, for certain intermediates for the preparation of compounds of the present invention) are to be understood as referring to the corresponding stereoisomer of the corresponding relative configuration in enriched form, in particular in substantially pure form. Thus, for a given molecule or group, the designation (R*,R*), unless expressly stated otherwise, includes the corresponding (R.K)-enantiomer. (LA)-enantiomer. and any mixture of these two enantiomers, including the racemate.

The term enriched, when used in the context of stereoisomers, should be understood in the context of the present invention to mean that the corresponding stereoisomer is present in a ratio of at least 70:30, in particular at least 90:10 (i.e. with a purity of at least 70 wt.%, in particular at least 90 wt.%), relative to the corresponding other stereoisomer/set of corresponding other stereoisomers.

The term substantially pure, when used in the context of stereoisomers, is to be understood within the scope of the present invention to mean that the corresponding stereoisomer is present with a purity of at least 95% by weight, in particular at least 99% by weight, relative to the corresponding other stereoisomer/set of corresponding other stereoisomers.

The present invention also includes isotopically labeled, especially ² H (deuterium) labeled compounds of formula (I) according to embodiments 1) to 36), such compounds being identical to the compounds of formula (I) except that one or each of a plurality of atoms is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass normally found in nature. Isotopically labeled, especially ² H (deuterium) labeled compounds of formulae (I), (II) and (III) and their salts are included within the scope of the present invention. The replacement of hydrogen by the heavier isotope ² H (deuterium) may result in greater metabolic stability, resulting in, for example, an increased in-vivo half-life or a reduced dosage requirement, or may result in reduced inhibition of cytochrome P450 enzymes, resulting in, for example, an improved safety profile. In one embodiment of the invention, the compounds of formula (I) are not isotopically labeled, or they are labeled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labeled at all. Isotopically labeled compounds of formula (I) can be prepared in analogy to the processes described hereinafter, but using an appropriate isotopic variation of suitable reagents or starting materials.

In this patent application, the bond drawn as a dotted line shows the point of attachment of the radical depicted. For example, the radical depicted below

represents a 3-fluorophenyl group.

When the plural form is used for compounds, salts, pharmaceutical compositions, diseases, etc., it also means one single compound, salt, etc.

Any reference to compounds of formula (I) according to embodiments 1) to 20) should be understood as also referring to salts (and in particular pharmaceutically acceptable salts) of such compounds, as the case may be and as appropriate.

The term pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the compound of the invention and exhibit minimal undesirable toxic effects. Such salts include addition salts with inorganic or organic acids and/or bases, depending on the presence of basic and/or acidic groups in the compound of the invention. For reference, see, for example, Handbook of Pharmaceutical Salts. Properties, Selection and Use., P. Heinrich Stahl, Camille G. Wermuth (eds.), Wiley-VCH, 2008; and Pharmaceutical Salts and Co-crystals, Johan Wouters and Luc Quere (eds.), RSC Publishing, 2012.

The definitions provided in the present invention are intended to apply equally to compounds of formula (I) as defined in any of embodiments 1) to 18) and, mutatis mutandis, throughout the specification and claims, unless a definition otherwise expressly set forth provides a broader or narrower definition. It is expressly understood that a definition or preferred definition of a term defines and may replace the corresponding term independently of (and in combination with) any definition(s) or preferred definition(s) of any or all other terms as defined in the present invention.

In this patent application, the compounds are named using IUPAC nomenclature, but may also be named using trivial carbohydrate nomenclature. Thus, the fragment:

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may be named (2R,3R,4S,5R,6R)-3,5-gurugpoKCu-6-(rugpoKCUMeTua)-4-(4-(4-phenyl-1H-1,2,3-Tpua3o l-1-yl)tetrahydro-2H-pyran-2-carbonyl or, alternatively, 1,3-dideoxy-3-[4-phenyl-1H-1,2,3-triazol-1-yl]-6-galactopyranoside-1-carbonyl, wherein the absolute configuration of the carbon atom bearing the carbonyl group, which is the point of attachment to the rest of the molecule, corresponds to the (2R)-, respectively, beta-configuration. For example, the compound (2R,3R,4S,5R,6R)-5-hydroxy-N((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy^-((1-methyl-1H-pyrrol-2-yl)methyl)-4(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide should be understood as also belonging to 1,3-dideoxy-2-(')-methy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1-ide]-(\((1-methyl-1H-pyrrol-2-yl)methyl)^-((1S,2S )-2-hydroxycyclohexyl))-β -D-galactopyranose-1-carboxamide.

In cases where a substituent is indicated as optional, it is to be understood that such a substituent may be absent (i.e. the corresponding residue is unsubstituted in relation to such an optional substituent), in which case all positions having a free valence (to which such an optional substituent could be attached, such as, for example, ring carbon atoms and/or ring nitrogen atoms in an aromatic ring, which have a free valence) are substituted with hydrogen if necessary. Similarly, where the term optional is used in the context of (ring) heteroatom(s), the term means that either the corresponding optional heteroatom(s), or the like, is/are absent (i.e., the defined moiety does not contain heteroatom(s)/is a carbocycle/or the like), or the corresponding optional heteroatom(s), or the like, is/are present, as explicitly defined. Unless explicitly stated otherwise in the relevant embodiment or claims, the groups defined in the present invention are unsubstituted.

The term halogen means fluorine, chlorine or bromine, preferably fluorine or chlorine.

The term alkyl, used alone or in combination, refers to a saturated hydrocarbon group with a straight or branched chain containing from one to six carbon atoms. The term C _x-y alkyl (x and y are each an integer) refers to an alkyl group as defined above containing from x to y carbon atoms. For example, a C _1-6 alkyl group contains from one to six carbon atoms. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 3-methylbutyl, 2,2-dimethylpropyl and 3,3-dimethylbutyl. Preferred is methyl. To avoid misinterpretation, it should be noted that when a group is named, for example, propyl or butyl, n-propyl and n-butyl are meant. In the case of a substituent for Ar ² (being phenyl or a 5- or 6-membered heteroaryl) being Cl-6-alkyl, the term especially refers to methyl, ethyl or isopropyl; in particular, to methyl.

The term -C _x-y -alkylene-, used alone or in combination, refers to a divalently attached alkyl group as defined above, containing from x to y carbon atoms. The term -C _0-y -alkylene- refers to a direct bond, or to -(C _1-y )alkylene- as defined above. Preferably, the points of attachment of the -C _1-y -alkylene group correspond to a 1,1-diyl, or 1,2-diyl, or 1,3-diyl pattern. Preferably, the points of attachment of the -C _2-y -alkylene group correspond to a 1,2-diyl or 1,3-diyl pattern. When a C _{0 -alkylene} group is used in combination with another substituent, the term means that either said substituent is attached through the C ₁ -alkylene group to the rest of the molecule, or it is attached directly to the rest of the molecule (i.e., the C ₀ -alkylene group is a direct bond attaching said substituent to the rest of the molecule). An alkylene group -C ₂ H ₄ - (or ethylene) refers to -CH2-CH2-, unless explicitly stated otherwise.

The term alkenyl, used alone or in combination, refers to a straight or branched hydrocarbon chain containing from two to five carbon atoms and one carbon-carbon double bond. The term C _x-y alkenyl (x and y are each an integer) refers to an alkenyl group as defined above containing from x to y carbon atoms. For example, a C _2-5 alkenyl group contains from two to five carbon atoms.

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The term "fluoroalkyl," used alone or in combination, refers to an alkyl group as defined above, containing from one to three carbon atoms, in which one or more (and possibly all) of the hydrogen atoms have been replaced by fluorine. The term "C, _-y- fluoroalkyl" (x and y are each an integer) refers to a fluoroalkyl group as defined above, containing from x to y carbon atoms. For example, a C _1-3 -fluoroalkyl group contains from one to three carbon atoms, and in which one to seven hydrogen atoms have been replaced by fluorine. Representative examples of fluoroalkyl groups include trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. Trifluoromethyl is preferred.

The term fluoroalkoxy, used alone or in combination, refers to an alkoxy group as defined above containing from one to three carbon atoms in which one or more (and possibly all) of the hydrogen atoms have been replaced by fluorine. The term Cx _- y-fluoroalkoxy (x and y are each an integer) refers to a fluoroalkoxy group as defined above containing from x to y carbon atoms. For example, a _C1-3 -fluoroalkoxy group contains from one to three carbon atoms and has from one to seven hydrogen atoms replaced by fluorine. Representative examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.

The term cycloalkyl, used alone or in combination, refers especially to a saturated monocyclic or fused, bridged or spirobicyclic hydrocarbon ring containing from three to eight carbon atoms. The term Cx _- y-cycloalkyl (x and y are each an integer) refers to a cycloalkyl group as defined above containing from x to y carbon atoms. For example, a _C3-6 -cycloalkyl group contains from three to six carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cyclopropyl is preferred.

The term alkoxy, used alone or in combination, refers to an alkyl-O- group, wherein the alkyl group is as defined above. The term Cx _- y-alkoxy (x and y are each an integer) refers to an alkoxy group as defined above containing from x to y carbon atoms. Preferred are ethoxy and, in particular, methoxy. In case R ¹ is C1-3-alkoxy, the term refers in particular to methoxy. In case the substituent for Ar ² (being phenyl or 5- or 6-membered heteroaryl) is C1-3-alkoxy, the term refers in particular to methoxy.

The term heterocyclyl, used alone or in combination, and unless explicitly defined more broadly or more narrowly, refers to a saturated or unsaturated non-aromatic monocyclic hydrocarbon ring containing one or two ring heteroatoms independently selected from nitrogen, sulfur and oxygen (especially one oxygen atom, one sulfur atom, one nitrogen atom, two nitrogen atoms, two oxygen atoms, one nitrogen atom and one oxygen atom). The term Cx _-y -heterocyclyl refers to such a heterocycle containing from x to y ring atoms. Heterocyclyl groups are unsubstituted or substituted as explicitly defined.

The term aryl, used alone or in combination, means phenyl or naphthyl, preferably phenyl, wherein said aryl group is unsubstituted or substituted as expressly defined.

The term heteroaryl, used alone or in combination and unless explicitly defined more broadly or more narrowly, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing from one to a maximum of four heteroatoms each independently selected from oxygen, nitrogen and sulfur. Representative examples of such heteroaryl groups are 5-membered heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl; 6-membered heteroaryl groups such as pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl; and 8- to 10-membered bicyclic heteroaryl groups such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, 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 explicitly defined. In the case of the substituent Ar ² being a 5- or 6-membered heteroaryl, the term especially means furanyl, thiophenyl, pyrrolyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl or pyrimidinyl; in particular furan-2-yl, thiophen-2-yl, thiophen-3-yl, 1H-pyrrol-2-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-4-yl, isothiazol-5-yl, isoxazol-4-yl, 1H-pyrazol-3-yl, 1H-pyrazol-5-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl or pyrimidin-5-yl. In the case of the substituent Ar ² representing a 9-membered bicyclic heteroaryl, the term especially means indolyl; or, in addition thereto, benzothiophenyl, benzothiazolyl or benzoimidazolyl; in particular 1H-indol-2-yl; or, in addition, benzothiophen-6-yl, benzothiazol-6-yl, benzothiazol-5-yl or

- 6 048291 benzoimidazol-6-yl; wherein said 9-membered bicyclic heteroaryl is unsubstituted or substituted as explicitly defined; a particular example is 1-methyl-1H-indol-2-yl. In the case of the substituent Ar ² being a 10-membered bicyclic heteroaryl, the term especially means quinolinyl or quinoxalinyl; in particular quinolin-2-yl or quinoxalin-5-yl.

The term cyano refers to the -CN group.

When the word between is used to describe a range of numerical values, it is to be understood to mean that the endpoints of the stated range are expressly included within the range. For example: if a temperature range is described as between 40°C and 80°C, this means that the endpoints 40°C and 80°C are included in the range; or if a variable is defined as an integer between 1 and 4, this means that the variable represents the integer 1, 2, 3, or 4.

When not used with respect to temperatures, the term approximately preceding a numerical value X in the present invention refers to a range that extends from X minus 10% of X to X plus 10% of X, and preferably to a range that extends from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term approximately preceding a temperature Y in the present invention refers to a range that extends from a temperature Y minus 10°C to Y plus 10°C, and preferably to a range that extends from Y minus 5°C to Y plus 5°C. Furthermore, the term room temperature, as used in the present invention, refers to a temperature of approximately 25°C.

Additional embodiments of the invention are presented below.

2. The second embodiment relates to compounds according to embodiment 1), wherein Ar ¹ is phenyl which is mono-, di- or trisubstituted, wherein the substituents are independently selected from halogen, methyl, cyano and methoxy;

wherein at least one of said substituents is attached at the meta or para position of said phenyl, wherein, if present, the substituent at the para position is preferably selected from halogen, methyl, cyano and methoxy; and wherein, if present, the substituent at the meta position is preferably halogen.

3. Another embodiment relates to compounds according to embodiment 1), wherein Ar ¹ is phenyl which is mono-, di- or trisubstituted, wherein one of said substituents is attached at the meta position of said phenyl, wherein said substituent is halogen; and the remaining substituent(s), if present, is/are halogen (especially fluorine); or one of said substituents is attached at the para position of said phenyl, wherein said substituent is independently selected from methyl, cyano and methoxy; and the remaining substituent(s), if present, is/are halogen (especially fluorine).

4. Another embodiment relates to compounds according to embodiment 1), wherein Ar ¹ is a phenyl group of the structure

(Ag-0), where R ^o1 is hydrogen, fluorine, methyl, methoxy or trifluoromethyl;

R ^ml represents hydrogen or halogen;

Rp is hydrogen, halogen, methyl, cyano, 3-hydroxyprop-1-yl or morpholin-4-yl; and

R ^m2 represents hydrogen, halogen, methyl, methoxy or trifluoromethoxy.

5. Another embodiment relates to compounds according to embodiment 1), wherein Ar ¹ is a phenyl group of the structure

F (Ar-1), where Rm ² is hydrogen or fluorine; and

R ^p is independently halogen (especially fluorine or chlorine), methyl, cyano or methoxy (in particular R ^p is fluorine, chlorine, or methyl); or

R ^m2 is hydrogen or fluorine; and

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Rp is hydrogen.

6. Another embodiment relates to compounds according to embodiment 1), wherein Ar ¹ is a phenyl group of the structure

where R ^m2 is a halogen (especially fluorine); and

Rp is hydrogen, halogen (especially fluorine or chlorine), methyl, cyano, or methoxy (especially Rp is fluorine, chlorine, or methyl).

7. Another embodiment relates to compounds according to embodiment 1), wherein Ar ¹ is

A) in particular,

B)

C)

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where each of the groups A)-C) form a separate sub-variant of implementation; and where the group A) form another sub-variant of implementation.

8. Another embodiment relates to compounds according to any one of embodiments 1)-7), wherein R ¹ is hydroxy;

methoxy; or

-O-CH2-CO-R ^1X , where R ^1X is

-hydroxy;

morpholin-4-yl; or

9. Another embodiment relates to compounds according to any one of embodiments 1)-7), wherein R ¹ is hydroxy.

10. Another embodiment relates to compounds according to any one of embodiments 1)-7), wherein R ¹ is methoxy.

11. Another embodiment relates to compounds according to any one of embodiments 1)-10), wherein L is methylene.

12. Another embodiment relates to compounds according to any one of embodiments 1)-10), wherein L is a direct bond.

13. Another embodiment relates to compounds according to any one of embodiments 1) to 12), wherein Ar ² is phenyl which is unsubstituted, mono- or disubstituted, wherein the substituents are independently selected from C _1-4 -alkyl (especially methyl), C _1-3 -fluoroalkyl (especially trifluoromethyl), C _1-3 alkoxy (especially methoxy), halogen (especially fluorine or chlorine), ethynyl and cyano; or

5- or 6-membered heteroaryl (especially furanyl, thiophenyl, pyrrolyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl or pyrimidinyl), wherein said 5- or 6-membered heteroaryl is independently unsubstituted, mono- or disubstituted, wherein the substituents are independently selected from -alkyl (especially methyl), _-CH2 - _C3-6 -cycloalkyl (especially _{-CH2cyclopropyl} ), _-C1-3- fluoroalkyl (especially trifluoromethyl), _-C1-3 -alkoxy (especially methoxy), halogen (especially fluorine or chlorine), morpholin-4-yl and amino.

14. Another embodiment relates to compounds according to any one of embodiments 1)-12), wherein Ar ² is:

phenyl which is unsubstituted, mono- or disubstituted, wherein the substituents are independently selected from C _1-4 -alkyl (especially methyl), C _1-3 -fluoroalkyl (especially trifluoromethyl), C _1-3 alkoxy (especially methoxy), halogen (especially fluorine or chlorine) and cyano; or

5- or 6-membered heteroaryl (especially thiophenyl, pyrrolyl, isothiazolyl, pyrazolyl, pyridinyl or pyrimidinyl), wherein said 5- or 6-membered heteroaryl is independently unsubstituted, mono- or disubstituted, wherein the substituents are independently selected from C _1-4 -alkyl (especially methyl), -CH ₂ -C _3-6 -cycloalkyl (especially -CH ₂ -cyclopropyl), C _1-3 -fluoroalkyl (especially trifluoromethyl), C _1-3 -alkoxy (especially methoxy), halogen (especially fluorine or chlorine) and morpholin-4-yl.

15. Another embodiment relates to compounds according to any one of embodiments 1)-12), wherein Ar ² is:

phenyl which is mono- or disubstituted, wherein the substituents are independently selected from C _1-3 fluoroalkyl (especially trifluoromethyl) and halogen; or

5- or 6-membered heteroaryl (especially thiophenyl, pyrrolyl, pyrazolyl, pyridinyl or pyrimidinyl), wherein said 5- or 6-membered heteroaryl is independently mono- or disubstituted, wherein the substituents are independently selected from C 1-3 -alkyl (especially methyl) and C _1-3 -fluoroalkyl (especially trifluoromethyl).

16. Another embodiment relates to compounds according to any one of embodiments 1)-10), wherein the -L-Ar ² moiety is:

- 9 048291

A)

IN)

WITH)

D)

E)

- 10 048291

F)

G)

H)

where each of the groups A)-H) form a separate sub-variant of implementation; and where the other sub-variant of implementation belongs to groups A), B) and/or C).

17. Another embodiment relates to compounds according to any one of embodiments 1)-16), wherein n is the integer 1.

18. The invention thus relates to compounds of formula (I) as defined in embodiment 1), or to such compounds further limited by the characteristic features of any of embodiments 2) to 17), when considering their respective dependencies; to pharmaceutically acceptable salts thereof; and to the use of such compounds as further described below. In order to avoid misinterpretation, it should be noted in particular that the following embodiments relating to compounds of formula (I) are thus possible and contemplated and are hereby specifically disclosed in individualized form:

1, 2+1, 3 + 1, 4+1, 5+1, 6+1, 7+1, 8+1, 8+2+1, 8+3 + 1, 8+4+1, 8+ 5+1, 8+6+1, 8+7+1, 9+1, 9+2+1, 9+3 + 1, 9+4+1, 9+5+1, 9+6+1, 9+7+1, 10+1, 10+2+1, 10+3 + 1, 10+4+1, 10+5+1, 10+6+1, 10+7+ 1, 11 + 1, 11+2+1, 11+3 + 1, 11+4+1, 11+5+1, 11+6+1, 11+7+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+ 7+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+7+1, 11 + 10+1, 11+10+2+1, 11+10+3+1, 11+10+ 4+1, 11+10+5+1, 11+10+6+1, 11+10+7+1, 12+1, 12+2+1, 12+3 + 1, 12+4+1, 12+5+1, 12+6+1, 12+7+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+7+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+7+1, 12+10+1, 12+10+ 2+1, 12+10+3 + 1, 12+10+4+1, 12+10+5+1, 12+10+6+1, 12+10+7+1, 13 + 1, 13+2+1, 13+3+1, 13+4+1,

- 11 048291

13+5+1, 13+6+1, 13+7+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+7+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+7+1, 13 + 10+1, 13 + 10+ 2+1, 13 + 10+3 + 1, 13 + 10+4+1, 13 + 10+5+1, 13 + 10+6+1, 13+ 10+7+1, 13 + 11 + 1, 13 + 11+2+1, 13 + 11+3 + 1, 13 + 11+4+1, 13 + 11+5+1, 13 + 11+6+ 1, 13 + 11+7+1, 13 + 11+8+1, 13 + 11+8+2+1, 13 + 11+8+3 + 1, 13 + 11+8+4+1, 13 + 11+8+5+1, 13 + 11+8+6+1, 13 + 11+8+7+1, 13 + 11+9+1, 13+11+9+2+1, + 11+9+3 + 1, 13 + 11+9+4+1, 13 + 11+9+5+1, 13 + 11+9+6+1, 13 + 11+9+7+1, + 11 + 10+1, 13 + 11 + 10+2+1, 13 + 11 + 10 +3 + 1, 13+11 + 10+4+1, 13 + 11 + 10+5+1, 13 + 11 + 10+6+1, 13 + 11 + 10+7+1, 13 + 12+1, 13 + 12+2+1, 13 + 12+3 + 1, 13 + 12+4+1, 13 + 12+5+1, 13 + 12+6+1, 13 + 12+7+1, 13 + 12+8+1, 13+ 12+8+2+1, 13 + 12+8+3 + 1, 13 + 12+8+4+1, 13 + 12+8+5+1, 13 + 12+8+6+1, 13 + 12+8+7+1, 13 + 12+9+1, + 12+9+2+1, 13 + 12+9+3 + 1, 13 + 12+9+4+1, 13 + 12+9+5+1, 13 + 12+9+6+1, + 12+9+7+1, 13 + 12+10+1, 13 + 12+10+2+1, 13 + 12+10+3 + 1, 13 + 12+10+4+1, 13 + 12+10+5+1, 13 + 12+10+6+1, 13 + 12+10+7+1, 14+1, 14+2+1, 14+3 + 1, 14+4+1, 14+5+1, 14+ 6+1, 14+7+1, 14+8+1, 14+8+2+1, 14+8+3 + 1, 14+8+4+1, 14+8+5+1, 14+8+6+1, 14+8+7+1, 14+9+1, 14+9+2+1, 14+9+ 3 + 1, 14+9+4+1, 14+9+5+1, 14+9+6+1, 14+9+7+1, 14+10+1, 14+10+2+1, 14+10+3 + 1, 14+10+4+1, 14+10+5+1, 14+10+6+1, 14+10+7+1, 14+11 + 1, 14+11+ 2+1, 14+11+3 + 1, 14+11+4+1, 14+11+5+1, 14+11+6+1, 14+11+7+1, 14+11+8+1, 14+11+8+2+1, 14+11+8+3+1, 14+11+8+ 4+1, 14+11+8+5+1, 14+11+8+6+1, 14+11+8+7+1, 14+11+9+1, 14+11+9+2+1,

14+11+9+3+1, 14+11+9+4+1, 14+11+9+5+1, 14+11+9+6+1, 14+11+9+7+1,

14+11+10+1, 14+11+10+2+1, 14+11+10+3+1, 14+11+10+4+1, 14+11+10+5+1, 14+ 11 + 10+6+1, 14+11 + 10+7+1, 14+12+1, 14+12+2+1, 14+12+3 + 1, 14+12+4+1, 14+12+5+1, 14+12+6+1, 14+12+7+1, 14+ 12+8+1, 14+12+8+2+1, 14+12+8+3 + 1, 14+12+8+4+1, 14+12+8+5+1, 14+12+8+6+1, 14+12+8+7+1, 14+12+9+1,

14+12+9+2+1, 14+12+9+3+1, 14+12+9+4+1, 14+12+9+5+1, 14+12+9+6+1, 14+12+9+7+1, 14+12+10+1, 14+12+10+2+1, 14+12+10+3+1, 14+12+10+4+1, 14+12+10+5+1, 14+12+10+6+1, 14+12+10+7+1, 15+1, 15+2+1, 15+3 + 1, 15+4+1, 15+5+1, 15+6+1, 15+7+1, 15+8+1, 15+8+2+1, 15+8+3 + 1, 15+8+4+1, 15+8+5+1, 15+8+6+1, 15+8+7+1, 15+ 9+1, 15+9+2+1, 15+9+3 + 1, 15+9+4+1, 15+9+5+1, 15+9+6+1, 15+9+7+1, 15+10+1, 15+10+2+1, 15+10+3 + 1, 15+10+4+1, 15+10+ 5+1, 15+10+6+1, 15+10+7+1, 15+11 + 1, 15+11+2+1, 15+11+3+1, 15+11+4+1, 15+11+5+1, 15+11+6+1, 15+11+7+1, 15+11+8+1, 15+11+8+2+1, 15+11+8+3 + 1, 15+11+8+4+1, 15+11+8+5+1, 15+11+8+6+1, 15+11+8+7+1, 15+11+9+1, 15+11+9+2+1,

- 12 048291

15+11+9+3 + 1, 15+11+9+4+1, 15+11+9+5+1, 15+11+9+6+1, 15+11+9+7+1,

15+11 + 10+1, 15+11 + 10+2+1, 15+11 + 10+3 + 1, 15+11 + 10+4+1, 15+11 + 10+5+1, 15+ 11 + 10+6+1, 15+11 + 10+7+1, 15+12+1, 15+12+2+1, 15+12+3 + 1, 15+12+4+1, 15+12+5+1, 15+12+6+1, 15+12+7+1, 15+ 12+8+1, 15+12+8+2+1, 15+12+8+3 + 1, 15+12+8+4+1, 15+12+8+5+1, 15+12+8+6+1, 15+12+8+7+1, 15+12+9+1,

15+12+9+2+1, 15+12+9+3+1, 15+12+9+4+1, 15+12+9+5+1, 15+12+9+6+1, 15+12+9+7+1, 15+12+10+1, 15+12+10+2+1, 15+12+10+3+1, 15+12+10+4+1, 15+12+10+5+1, 15+12+10+6+1, 15+12+10+7+1, 16+1, 16+2+1, 16+3 + 1, 16+4+1, 16+5+1, 16+6+1, 16+7+1, 16+8+1, 16+8+2+1, 16+8+3 + 1, 16+8+4+1, 16+8+5+1, 16+8+6+1, 16+8+7+1, 16+ 9+1, 16+9+2+1, 16+9+3 + 1, 16+9+4+1, 16+9+5+1, 16+9+6+1, 16+9+7+1, 16+10+1, 16+10+2+1, 16+10+3 + 1, 16+10+4+1, 16+10+ 5+1, 16+10+6+1, 16+10+7+1, 17+1, 17+2+1, 17+3 + 1, 17+4+1, 17+5+1, 17+6+1, 17+7+1, 17+8+1, 17+8+2+1, 17+8+3 + 1, 17+8+4+1, 17+8+5+1, 17+8+6+1, 17+8+7+1, 17+9+1, 17+9+2+1, 17+9+3 + 1, 17+9+4+1, 17+9+5+1, 17+9+6+1, 17+9+7+1, 17+10+1, 17+10+2+1, 17+10+ 3 + 1, 17+10+4+1, 17+10+5+1, 17+10+6+1, 17+10+7+1, 17+11+1, 17+11+2+1, 17+11+3 + 1, 17+11+4+1, 17+11+5+1, 17+11+6+1, 17+11+7+1,

17+11+8+1, 17+11+8+2+1, 17+11+8+3 + 1, 17+11+8+4+1, 17+11+8+5+1, 17+ 11+8+6+1, 17+11+8+7+1, 17+11+9+1, 17+11+9+2+1, 17+11+9+3 + 1, 17+11+9+4+1, 17+11+9+5+1, 17+11+9+6+1, 17+11+9+7+1, 17+11 + 10+1,

17+11 + 10+2+1, 17+11 + 10+3+1, 17+11 + 10+4+1, 17+11 + 10+5+1, 17+11 + 10+6+1, 17+11 + 10+7+1, 17+12+1, 17+12+2+1, 17+12+3 + 1, 17+12+4+1, 17+12+5+1, 17+12+6+1, 17+12+7+1, 17+12+8+1, 17+ 12+8+2+1, 17+12+8+3+1, 17+12+8+4+1, 17+12+8+5+1, 17+12+8+6+1, 17+12+8+7+1, 17+12+9+1, 17+12+9+2+1,

17+12+9+3+1, 17+12+9+4+1, 17+12+9+5+1, 17+12+9+6+1, 17+12+9+7+1,

17+12+10+1, 17+12+10+2+1, 17+12+10+3+1, 17+12+10+4+1, 17+12+10+5+1, 17+ 12+10+6+1, 17+12+10+7+1, 17+13 + 1, 17+13+2+1, 17+13+3 + 1, 17+13+4+1, 17+13+5+1, 17+13+6+1, 17+13+7+1, 17+13 + 8+1, 17+ 13+8+2+1, 17+13+8+3 + 1, 17+13+8+4+1, 17+13+8+5+1, 17+13+8+6+1, 17+13+8+7+1, 17+13+9+1,

17+13+9+2+1, 17+13+9+3 + 1, 17+13+9+4+1, 17+13+9+5+1, 17+13+9+6+1, 17+13+9+7+1, 17+13 + 10+1, 17+13 + 10+2+1, 17+13 + 10+3 + 1, 17+13 + 10+4+1, 17+13 + 10+5+1, 17+13 + 10+6+1, 17+13 + 10+7+1, 17+13 + 11 + 1, 17+13 + 11+2+1, 17+13 + 11+3 + 1, 17+13 + 11+4+1, 17+13 + 11+5+1, 17+13 + 11+6+1, 17+13 + 11+7+1, 17+13 + 11+8+1, 17+13 + 11+8+2+ 1, 17+13 + 11+8+3 + 1, 17+13 + 11+8+4+1,

17+13 + 11+8+5+1, 17+13 + 11+8+6+1, 17+13 + 11+8+7+1, 17+13 + 11+9+1,

- 13 048291

17+13 + 11+9+2+1, 17+13 + 11+9+3+1, 17+13 + 11+9+4+1, 17+13 + 11+9+5+1, 17+ 13 + 11+9+6+1, 17+13 + 11+9+7+1, 17+13 + 11 + 10+1, 17+13 + 11 + 10+2+1, 17+13 + 11 + 10+3 + 1, 17+13 + 11 + 10+4+1, 17+13 + 11 + 10+5+ 1, 17+13 + 11 + 10+6+1, 17+13+11+10+7+1, 17+13+12+1, 17+13+12+2+1, 17+13+12+3+1, 17+13+12+4+1, 17+13 + 12+5+1, 17+ 13 + 12+6+1, 17+13 + 12+7+1, 17+13 + 12+8+1, 17+13 + 12+8+2+1, 17+13+12+8+3+1, 17+13+12+8+4+1, 17+13+12+8+5+1, 17+ 13+12+8+6+1, 17+13+12+8+7+1, 17+13+12+9+1, 17+13+12+9+2+1, 17+13+12+9+3+1, 17+13+12+9+4+1, 17+13+12+9+5+1, 17+13+12+9+6+1, 17+ 13+12+9+7+1, 17+13+12+10+1, 17+13+12+10+2+1, 17+13+12+10+3+1, 17+13+12+10+4+1, 17+13+12+10+5+1, 17+13+12+10+6+1, 17+ 13+12+10+7+1, 17+14+1, 17+14+2+1, 17+14+3 + 1, 17+14+4+1, 17+14+5+1, 17+14+6+1, 17+14+7+1, 17+14+8+1, 17+14+8+2+1, 17+14+8+3+ 1, 17+14+8+4+1, 17+14+8+5+1, 17+14+8+6+1, 17+14+8+7+1, 17+14+9+1, 17+14+9+2+1, 17+14+9+3 + 1, 17+14+9+4+1, 17+ 14+9+5+1, 17+14+9+6+1, 17+14+9+7+1, 17+14+10+1, 17+14+10+2+1, 17+14+10+3+1, 17+14+10+4+1, 17+14+10+5+1, 17+14+10+6+1, 17+14+10+7+1, 17+14+11+1, 17+14+11+2+1, 17+14+11+3+1, 17+14+11+4+1, 17+14+11+5+1, 17+14+11+6+1, 17+14+11+7+1, 17+14+11+8+1, 17+14+11+8+2+1, 17+14+11+8+3+1, 17+14+11+8+4+1, 17+14+11+8+5+1, 17+14+11+8+6+1, 17+14+11+8+7+1, 17+14+11+9+1, 17+14+11+9+2+1, 17+14+ 11+9+3+1, 17+14+11+9+4+1, 17+14+11+9+5+1, 17+14+11+9+6+1, 17+14+11+9+7+1, 17+14+11+10+1, 17+14+11+10+2+1, 17+14+ 11+10+3+1, 17+14+11+10+4+1, 17+14+11+10+5+1, 17+14+11+10+6+1, 17+14+11+10+7+1, 17+14+12+1, 17+14+12+2+1, 17+14+12+3+1, 17+14+12+4+1, 17+14+12+5+1, 17+14+12+6+1, 17+14+12+7+1, 17+14+12+8+1, 17+14+12+8+2+1, 17+14+12+8+3+1, 17+14+12+8+4+1, 17+14+ 12+8+5+1, 17+14+12+8+6+1, 17+14+12+8+7+1, 17+14+12+9+1, 17+14+12+9+2+1, 17+14+12+9+3+1, 17+14+12+9+4+1, 17+14+12+9+5+1, 17+ 14+12+9+6+1, 17+14+12+9+7+1, 17+14+12+10+1, 17+14+12+10+2+1, 17+14+12+10+3+1, 17+14+12+10+4+1, 17+14+12+10+5+1, 17+ 14+12+10+6+1, 17+14+12+10+7+1, 17+15+1, 17+15+2+1, 17+15+3 + 1, 17+15+4+1, 17+15+5+1, 17+15+6+1, 17+15+7+1, 17+15+8+1, 17+15+8+2+1, 17+15+8+3+1, 17+15+8+4+1, 17+15+8+5+1, 17+15+8+6+1, 17+15+8+7+1, 17+15+9+1, 17+15+9+2+1, 17+15+9+3+1, 17+ 15+9+4+1, 17+15+9+5+1, 17+15+9+6+1, 17+15+9+7+1, 17+15+10+1, 17+15+10+2+1, 17+15+10+3+1, 17+15+10+4+1, 17+15+10+5+1, 17+15+10+6+1, 17+15+10+7+1, 17+15+11+1,

- 14 048291

17+15+11+2+1, 17+15+11+3 + 1, 17+15+11+4+1, 17+15+11+5+1, 17+15+11+6+1, 17+15+11+7+1, 17+15+11+8+1, 17+15+11+8+2+1, 17+15+11+8+3 + 1, 17+15+11+8+4+1, 17+15+11+8+5+1, 17+15+11+8+6+1, 17+ 15+11+8+7+1, 17+15+11+9+1, 17+15+11+9+2+1, 17+15+11+9+3+1, 17+15+11+9+4+1, 17+15+11+9+5+1, 17+15+11+9+6+1, 17+15+11+9+7+1, 17+ 15+11+10+1, 17+15+11+10+2+1, 17+15+11+10+3+1, 17+15+11+10+4+1, 17+15+11+10+5+1, 17+15+11 + 10+6+1, 17+15+11 + 10+7+1.17+ 15+12+1, 17+15+12+2+1, 17+15+12+3 + 1 17+15+12+4+1, 17+15+12+5+1, 17+15+12+6+1, 17+15+12+7+1, 17+15+12+8+1, 17+15+12+8+2+ 1, 17+15+12+8+3+1, 17+15+12+8+4+1, 17+15+12+8+5+1, 17+15+12+8+6+1, 17+15+12+8+7+1, 17+15+12+9+1, 17+15+ 12+9+2+1, 17+15+12+9+3+1, 17+15+12+9+4+1, 17+15+12+9+5+1, 17+15+12+9+6+1, 17+15+12+9+7+1, 17+15+12+10+1, 17+15+12+10+2+1, 17+15+12+10+3+1, 17+15+ 12+10+4+1, 17+15+12+10+5+1, 17+15+12+10+6+1, 17+15+12+10+7+1, 17+16+1, 17+16+2+1, 17+16+3 + 1, 17+16+4+1, 17+16+5+1, 17+16+6+1, 17+16+7+1, 17+16+8+1, 17+16+8+2+1, 17+16+8+3+1, 17+16+8+4+1, 17+16+8+5+1, 17+16+8+6+1, 17+16+8+7+1, 17+16+9+1, 17+ 16+9+2+1, 17+16+9+3+1, 17+16+9+4+1, 17+16+9+5+1, 17+16+9+6+1, 17+16+9+7+1, 17+16+10+1, 17+16+10+2+1, 17+16+10+3+1, 17+ 16+10+4+1, 17+16+10+5+1, 17+16+10+6+1, 17+16+10+7+1.

In the above list, the numbers refer to embodiments according to their numbering provided above, while + indicates a dependency on another embodiment. The various individualized embodiments are separated by commas. In other words, 17+16+7+1, for example, refers to embodiment 17), dependent on embodiment 16), dependent on embodiment 7), dependent on embodiment 1), i.e. embodiment 17+16+7+1 corresponds to compounds of formula (I) according to embodiment 1), further limited to all the features of embodiments 7), 16) and 17).

19. Another embodiment relates to compounds of formula (I) according to embodiment 1), which are selected from the following compounds:

- 15 048291 (2R,3R,4S,5R,6R)-N-6eH3yl-3,5-dihydroKCH-N-(( l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-( 4-(3,4,5-trifluorophenyl)-1 Η-1,2,3-triazol-1-yl)tetrag hydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)^-(3-chlorobenzyl)-3,5-dihydroxy^-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-ethynylbenzyl)-3,5-dihydroxy-18R-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-18G-phenethyl-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(4-chlorobenzyl)-3,5-dihydroxy-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(2-chlorobenzyl)-3,5-dihydroxy-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-(2-(trifluoromethyl)benzyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-((3-chloropyridin-4-yl)methyl)-3,5-dihydroxy-N-((1 S,2S )-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((2-(τρπφτορ methyl)pyridin-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((4-(trifluoromethyl)pyridin-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-M-(2-(methyl trifluoro) benzyl)-4-(4-(3,4,5-tr iforophenyl )-1 H1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

- 16 048291 (2K,3K,48,5K,6K)-18H-(2-chlorobenzyl)-5-hydroxy-18H-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-3,5-dihydroxy-18H-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-18H-((3-(trifluoromethyl)pyridin-2-yl)methyl)-4-(4-(3,4,5-trifluorophen yl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-3,5-dihydroxy-18H-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-18H-((2-methyl-1H-imidazol-4-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-18H-((2-amino-4-chlorothiazol-5-yl)methyl)-3,5-dihydroxy-18H((1S,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-3,5-dihydroxy-18H-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-18H-(isoxazol-4-ylmethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-tria sol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-T4-((5-chlorofuran-2-yl)methyl)-3,5-dihydroxy-181-((18,28)2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-3,5-dihydroxy-18H-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-18H-(isothiazol-4-ylmethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-3,5-dihydroxy-18H-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-18H-((1-methyl-1H-imidazol-4-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-18H-((2-bromothiazol-4-yl)methyl)-3,5-dihydroxy-18H-((1 S,2S)2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-3,5-dihydroxy-18H-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-18H-((2-morpholinothiazol-5-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-N-((5-chlorothiophen-2-yl)methyl)-3,5-dihydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

- 17 048291 (2K,3K,48,5K,6K)-T\G-((5-chlorothiazol-2-yl)methyl)-3,5-dihydroxy-T\G-((1 S,2S)2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-3,5-dihydroKCH-N-(( l S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-Ν-((Ι -methyl-1 N-pyrazol-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-5-hydroxy-T4-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-]N-((3-(trifluoromethyl)pyridin-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-T4-((2-(trifluoromethyl)pyridin-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((4-(trifluorophenyl)pyrimidin-5-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-((4,6-dimethylpyrimidin-5-yl)methyl)-3,5-dihydroxy-N-((1 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((4-methylpyrimidin-5-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3 - methoxy-18G-((5 - methyl-1 N-imidazol-4-yl) methyl )-4-(4-(3,4,5-trifluoroenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-((4-chloroisothiazol-5-yl)methyl)-5-hydroxy-N-((1 S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-MeTOKCH-N-(( l -methyl-1 N-pyrazol-5-yl)methyl)-4-(4-(3,4,5-trifluorophen yl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-M-((3-methylthiophene-2 -yl)methyl )-4-(4-(3,4,5-trifluoro enyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

- 18 048291 (2R,3R,4S,5R,6R)-5-hydroxy-T4-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-T4-((1-methyl-1H-pyrrol-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-((3-chlorothiophen-2-yl)methyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-]H-((4-methylthiazol- 5-yl)methyl)-4-(4-(3,4,5-trifluorophenyl) )-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-18R-((1-methyl-1H-imidazol-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-]H-((2-methylthiophene- 3-yl)methyl)-4-(4-(3,4,5-trifluoro) enyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-T4-(2-methoxybenzyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(2,6-dimethylbenzyl)-5-hydroxy-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((1-methyl-1H-imidazol-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((1-methyl-1H-imidazol-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-5-hydroxy-2-(((lS,2S)-2-hydroxycyclohexyl)((l-methyl1H-pyrazol-5-yl)methyl)carbamoyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl acetate;

(2R,3R,4S,5R,6R)-N-((l-ethyl-lH-pyrazol-5-yl)methyl)-5-hydroxy-N-((l S,2S )-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

- 19 048291 (2R,3R,4S,5R,6R)-5-trimethylcyclohexyl-N-((l S, 2 S )-2-hydroxycyclohexyl)-6-(hydroxymethyl )-N-((1-isopropyl-1H-pyrazol-5-yl)methyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-((l-(cyclopropylmethyl)-lH-pyrazol-5-yl)methyl)-5-hydroxypropylmethyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-((1,3-dimethyl-1H-pyrazol-5-yl)methyl)-5-hydroxy-18R-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-18G-((1-methyl-1 N-indol-2-yl)methyl)-4-(4-(3,4,5-trifluorophen and k)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R,6R)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydrox and-2-((( 18,28)-2-hydroxycyclohexyl)((1-methyl-1H-pyrazol-5-yl)methyl)carbamo yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate;

(2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-2-(((18,28)-2-hydroxycyclohexyl)((1-methyl-1H-pyrazol-5-yl)methyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate;

(2R,3R,4S,5R,6R)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-2-(((18,28)-2-hydroxycyclohexyl)((1-methyl-1H-pyrazol-5-yl)methyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate;

(2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-2-(((18,28)-2-hydroxycyclohexyl)((1-methyl-1H-pyrazol-5-yl)methyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate;

(2R,3R,4S,5R,6R)-N-(3-chlorobenzyl)-5-hydroxy-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-2-(((18,28)-2-hydroxycyclohexyl)(2-(trifluoromethyl)benzyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate;

(2R,3R,4S,5R,6R)-5-hydroxy-2-(((1S,2S)-2-hydroxycyclohexyl)(2-(trifluoromethyl)benzyl)carbamoyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl acetate;

- 20 048291 (2R, 3R, 4S, 5R, 6R)-N-(3,4-difluorophenyl)-5-hydroxy-T4-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide; and (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide.

20) In addition to the compounds listed in embodiment 19), the additional compounds according to embodiment 1) are selected from the following compounds:

(2R, 3R, 4S, 5R, 6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-2-(((18,28)-2-hydroxycyclohexyl)(2-(trifluoromethyl)benzyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate;

(2R,3R,4S,5R,6R)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-2-(((18,28)-2-hydroxycyclohexyl)(2-(trifluoromethyl)benzyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate;

(2R,3R,4S,5R,6R)-N-((6-φτop-3-methoxyquinoctalin-5-yl)methyl)-5-hydroxy-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-((3-chloroquinolin-2-yl)methyl)-5-hydroxy-N-((lS,2S)-2hydroxycyclohexyl)-6-(hydro Simyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-T4-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-1H-(2-(trifluoromethyl)benzyl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-T4-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-1H-(2-(trifluoromethyl)benzyl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-2-(((18,28)-2-hydroxycyclohexyl)(2-(trifluoromethyl)benzyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate;

- 21 048291 (2R, 3R, 4S, 5R, 6R)-4-(4-(4-6poM-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-3, 5-dihydroxy-T\R-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-T4-(2-(trifluoromethyl)benzyl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(4-6poM-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-18H-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-18H-(2-(trifluoromethyl)benzyl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R, 4S,5R,6R)-4-(4-(4-xnopTHa3on-2-Hn)-lH-1,2,3-triazol-1-yl)-3,5-dihydroxy-18G -((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-18G-(2-(trifluorometh yl)benzyl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazolyl-1-yl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-U((1S, 2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-18R-(3-methoxyphenyl)tetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-18N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3-φτop-2-methylphenyl)-lH -1,2,3-triazol-1 -yl)-5-hydroxy-18G-(( 1S, 2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3-chloro-5-cyanoφenyl)-4-(4-(5-φτop-2-meτocyphenyl)-l Н-1,2,3-triazol- 1-yl)-5-hydroxy-18G-((18.2 8)-2-hydroxycyclohexyl)-6-(hydrox and methyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-18N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-18R-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-N-((1 S, 2 S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-18N-(3-methoxyphenyl)tetrahydro-2H-pyran-2-carboxamide;

- 22 048291 (2R, 3R, 4S, 5R, 6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3,5-difluorophenyl)-1 Η-1,2, 3-triazole - 1-yl)-5-hydroxy-T4-(( 1S, 2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl l)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-N-(3-cyano-5-methylphenyl)-4-(4-(3,5-difluorophenyl)-1H-1,2, 3-triazol-1-yl)-5-hydroxy-T4-((1S, 28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-cyano-5-methoxyphenyl)-4-(4-(3,5-difluorophenyl)-1H1,2,3-triazol-1-yl)-5-hydroxy-18R-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-N-(3-chloro-5-methylphenyl)-4-(4-(3,5-difluorophenyl)-1H-1,2, 3-triazol-1-yl)-5-hydroxy-T4-((1S,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3-bromoφenyl)-4-(4-(3,5-diτopφenyl)-lH-1,2,3-triazo l-1-yl)-5 -hydroxy-18G-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-meth oxytetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3-chlorophenyl)-4-(4-(3,5-diτopτenyl)-lH-1,2,3-triazo l-1-yl)-5 -hydroxy-18G-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-meth oxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-cyanophenyl)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-18R-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-(methoxy-03)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3-chloro-5-cyanoφenyl)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3 -methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(5-chloro-2-methylphenyl)-5-hydroxy-N-((1 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3-chloro-4-φτopφenyl)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3 -methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3 -triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

- 23 048291 (2K,3K,48,5K,6K)^-(3-chloro-4-(trifluoromethyl)phenyl)-5-hydroxy-T\|-((1 S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-N-(3-bromo-4-fluorophenyl)-5-hydroxy-T4-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-T4-(benzo[c1]thiazol-6-yl)-5-hydroxy-181-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3 R,4S,5 R,6R)-5-hydroxy pokch-N-((1 S,2S)-2-hydroxy cyclohexyl)-6-(hydroxymethyl)-3-methoxy-N-(2-methylbenzo[c1]thiazol-6-yl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3-chloro-5-(τpiφτopmethyl)φenyl)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl) -3-methoxy-4-(4-(3,4,5-trifluoropheni l)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-5-chlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy -4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-tr iazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,4-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-4-chlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-5-rHflpoKCH-N-((lS,2S)-2-rHflpoKCHpHKfloreKCHfl)-6-(rHflpoK simethyl)-3-methoxy-M-phenyl-4-(4- (3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl )t etrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-5-rHflpoKCH-N-((lS,2S)-2-rHflpoKCHpHKfloreKCHfl)-6-(rHflpoK simethyl )-3-methoxy-N-(3-methoxyphenyl )-4-(4-(3,4,5-trifluorophenyl )-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

- 24 048291 (2K,3K,48,5K,6K)-1\|-(benzo[L]thiophen-6-yl)-5-hydroxy-T\|-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromophenyl)-5-hydroxy pokch-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-chloro-5-methoxyphenyl)-5-hydroxy-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1, 2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(5-chloro-2-φτopφenyl)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3 -methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3 -triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(2,5-dimethylbenzo[d]thiazol-6-yl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(2-chlorobenzo[d]thiazol-6-yl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-N-(3-cyano-5-methoxyphenyl)-5-hydroxy-18R-((1S, 2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H1, 2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(5-bromo-2-methylphenyl)-5-hydroxy-N-((1 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(4-chlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3-cyano-5-φτopφenyl)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3 -methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

- 25 048291 (2R,3R,4S,5R,6R)-N-(3-c]Topc])eHHn)-5-rHgpoKCH-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-18H-(3-cyanophenyl)-5-hydroxy-18H-((18,28)-2-hydroxycycl ox y l)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R, 3R,4S, 5 R,6R)-5-hydropokch-N-((1 S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-M-(3- (trifluoromethyl)phenyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1 ,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3,5-diτopφenyl)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy -4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-tr iazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-φτop-5-methoxyphenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-φτop-5-methylphenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3-bromo-5-φτopφenyl)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3 -methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3 -triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3-chloro-5-φτopφenyl)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3 -methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3 -triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-M-(l/-tol yl) -4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3 -triazol-1 -and l)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N-(2-methyl-1H-benzo[c1]imidazol-6-yl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(3-chloro-4,5-dichlorophenyl)-lH-l,2,3-triazol-l-yl)-N(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

- 26 048291 (2R,3R,4S,5R,6R)-4-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazole-1-methyl)-N(3,4-difluorophenyl)-5-hydroxy-T\R-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(benzo[d]τthiazol-6-yl)-4-(4-(3-chloro-4,5-difluorophenyl)-1 H-1,2, 3-triazol-1-yl)-5-hydroxy-18G-((1S, 2 8)-2-hydroxycyclohexyl)-6-(hydrox imethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-4-(4-(3-chloro-4,5-diφτopφenyl)-lH-l,2,3-τpiazol-l-yl)-N(3-chloro- 5-cyanophenyl)-5-hydroxy-18G-((18,28)-2-hydroxycyclohexyl)-6-(hydro xymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3-chloro-5-cyanoφenyl)-4-(4-(3-chloro-5-τopφenyl)-lH1,2,3-triazol-1-yl )-5-hydroxy-T4-((1S, 2 8)-2-hydroxycyclohexyl)-6-(hydroxyme ethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-lH-l,2,3-triazol-l-yl)-N-(3,4-difluorophenyl)-5-hydroxy-18Н-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-18H-(3-chloro-5-fluorophenyl)-5-hydroxy-18H-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-5-fluorophenyl)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-18N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3-chloro-5-fluorophenyl)-1H1,2,3-triazol-1-yl)-5-hydroxy-18R-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-N-(3-bromophenyl)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-18N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-lH-l,2,3-triazol-l-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-18Н-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,48,5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-U-(3-cyano-5-methylphenyl)-5-hydroxy-18R-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

- 27 048291 (2R,3R, 4S, 5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-1 Η-1,2,3-triazol-1-yl)-18G-(3 -ts yano-5-methoxyphenyl)-5-hydroxy-]H-((1 S,2S )-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-T4-(3-cyanophenyl)-5-hydroxy-18R-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-T4-(3-chlorophenyl)-5-hydroxy-18H-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(3-bromo-5-fluorophenyl)-lH-l,2,3-triazol-l-yl)-N-(3,5-dimethylphenyl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-18R-(3-chloro-5-cyanophenyl)-5-hydroxy-]N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-18R-(3-cyano-5-methylphenyl)-5-hydroxy-]N-((1 S, 2 S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-18H-(3-chloro-5-fluorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-18R-(3-cyanophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-18H-(3-chlorophenyl)-5-hydroxy-18H-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-18R-(3-cyano-5-methoxyphenyl)-5-hydroxy-]N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(4-bromo-3,5-dichlorophenyl)-lH-l,2,3-triazol-l-yl)-N(3,5-dichlorophenyl)-5-hydroKCH-N-((l S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

- 28 048291 (2R,3 R,4S, 5 R,6R)-4-(4-(4-6poM-3,5-difluorophenyl)-1 H-1,2,3-triazol-1-yl)-N(3,4-difluorophenyl)-5-hydroxy-N-((1 S, 2 S)-2-hydroxy cyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-T\G-(benzo[c1]thiazol-5-yl)-4-(4-(4-bromo-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-18G-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-4-(4-(4-6poM-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-18G(3-chloro-5-cyanophen yl)-5-hydroxy-M-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-4-(4-(4-6poM-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-18H(3-cyano-5-fluorophenyl)-5-hydroxyKCH-N-((l S,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-18G(3,5-dichlorophenyl)-5-hydroKCH-N-((l S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-18G(3-chloro-5-cyanophenyl)-5-hydroKCH-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-18G-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H1,2,3-triazol-1-yl)-5-hydroxypoKCH-N-((l S, 2 S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-I H-1,2,3-triazol-1-yl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-181-(3-bromo-5-fluorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-I H-1,2,3-triazol-1-yl)-5-hydroxy-N-((1 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R, 4S,5R,6R)-N-(3-cyano-5-fluorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1 H-1,2,3- triazol-1-yl)-5-hydroxy-M-((1S,2S)-2-hydroxycyclohexyl)-6-(hydr hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxypropyl KCH-N-((l S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

- 29 048291 (2R, 3R, 4S, 5R, 6R)-4-(4-(4-6poM-3-fluorophenyl)-1H-1,2,3-triazole-1-ιιπ)-N-(3,5dimethyl phenyl)-5-hydroxy-T4-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(4-bromo-3-fluorophenyl)-lH-l,2,3-triazol-l-yl)-N-(3,4-difluorophenyl)-5-hydroxy-N-((1 S,2S )-2-hydroxycyclohexyl )-6-(hydroxymethyl )-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(4-6poM-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-T4-(3-chloro-5-cyanophenyl)-5-hydroxy-]N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(3,4-dichloro-5-fluorophenyl)-lH-l,2,3-triazol-l-yl)-N(3,5-dichlorophenyl)-5-hydrochloride-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(3,4-dichloro-5-fluorophenyl)-lH-l,2,3-triazol-l-yl)-N(3,4-difluorophenyl)-5-hydroxy-N-((1 S, 2 S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(benzo[d]τthiazol-6-yl)-4-(4-(3,4-dichloro-5-φτopφenyl)-l Н-1,2, 3-triazol-1-yl)-5-hydroxy-T4-(( 1S,2 8)-2-hydroxycyclohexyl)-6-(hydrox and methyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3-chloro-5-cyanoφenyl)-4-(4-(3,4-dichloro-5-φτopφenyl)1Н-1,2,3-triazol- 1-yl)-5-hydroxy-T4-((1S,2 8)-2-hydroxycyclohexyl)-6-(hydro simethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3-φτop-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-]N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(2,3-diφτop-4-methylphenyl) - I Н-1,2,3- triazol-1 -yl)-5-hydroxy-]H-((1 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

2-(((2R,3R,4 S,5R,6R)-2-((3-chloro-5-cyanophenyl)((18,28)-2-hydroxycyclohexyl)carbamoyl)-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;

(2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-I H-1,2,3-triazol-1-yl)-5-hydroxy-N-((1 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-(2-morpholino-2-oxoethoxy)tetrahydro-2H-pyran-2-carboxamide;

- 30 048291 (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(4,5-difluoro-2-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-lH-l,2,3-triazol-l-yl)-N(3-chloro-5-cyanophenyl)-5-hydroKCH-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-4-(4-(4-6poM-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)^(3-cyano-5-fluorophenyl)-5-hydroxyKCH-N-(( l S, 28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-dichlorophenyl)-lH-l,2,3-triazol-l-yl)-N(3,5-dichlorophenyl)-5-hydroKCH-N-((l S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-lH-l,2,3-triazol-l-yl)-N(3-chloro-5-cyanophenyl)-5-hydroKCn-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-4-(4-(4-chloro-3-φτopφenyl)-lH-l,2,3-τpiazol-l-yl)-N-(3,5d their lorphen yl)-5-hydroxy-M-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl )-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3-φτop-4-(τpiφτopmethyl)φenyl)-1 Н-1,2,3- triazol-1 -yl)-5-hydroxy-M-((1 S,2S)-2-hydroxycyclohexyl )-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(4-cyano-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-4-(4-(4-chloro-2,5-diφτopφenyl)-lH-l,2,3-τpiazol-l-yl)-N(3-chloro- 5-cyanophenyl)-5-hydroKCH-N-(( l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-difluoro-5-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-18R-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3 R,4S,5 R,6R)-4-(4-(4-x chloro-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

- 31 048291 (2K,3K,48,5K,6K)-4-(4-(4-chloro-3-(trifluoromethoxy)phenyl)-1H-1,2,3-triazolI-yl)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxyKCH-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-N-(3-cyano-5-fluorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2, 3-triazol-1-yl)-5-hydroKCH-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-cyano-5-methoxyphenyl)-4-(4-(3,4-dichlorophenyl)-lH1,2,3-triazol-1-yl)-5-hydroxypoKCH-N-((l S, 2 S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-]N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3-fluoro-5-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(2-methylbenzo[c1]thiazol-6-yl)-1H1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(4-φτopnaτalin-l-yl)-lH-l,2, 3-triazol-1-yl )-5-hydroKCH-N-(( l 8.28)-2-hydroxycyclohexyl)-6-(hydroxymethyl l)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(4-xnopTHa3on-2-Hn)-l H-1,2,3-triazol-1-yl)-M-(2,3- difluorophenyl)-5-hydroKCH-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3 -methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-5-rHflpoKCH-N-((lS,2S)-2-rHflpoKCHpHiaioreKCHfl)-6-(rHflpoK simethyl)-3-MeTOKCH-N-(pyridin-2-yl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-5-rHflpoKCH-N-((lS,2S)-2-rHflpoKCHpHKfloreKCHfl)-6-(rHflpoK simethyl)-3-methoxy-N-!naphthalen-2-yl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-tria sol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

- 32 048291 (2R,3R,4S,5R,6R)-5-hydroxy-T\R-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N-(naphthali n-1-yl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(l,5-dimethyl-lH-pyrazol-3-yl)-5-hydroxy-N-((lS,2S)2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3-φτop-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-]N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3-chloro-5-cyanoφenyl)-4-(4-(4-chlorophenyl)-lH-l,2,3-τp iazol-1 -yl) -5-hyde poKCH-N-((l S,2S )-2-hydroxycyclohexyl)-6-(hydroxy methyl )-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-4-(4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(4-cyano-3-fluorophenyl)-lH-l,2,3-triazol-l-yl)-N-(3-cyano-5-methoxyphenyl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-4-(4-(4-cyano-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-cyano-5-methylphenyl)-5-hydroxy-]N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycycloheptyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycloheptyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxyclohexyl)-6-(hydroxymethyl)-3-(2-morpholino-2-oxoethoxy)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-(2-((8)-3-hydroxypyrrolidin-1-yl)-2-oxoethoxy)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

- 33 048291 (2R, 3R, 4S, 5R, 6R)-N-(3,5-dichlorophenethyl)-5-hydroxy-T\R-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-(2-(^)-3-hydroxypyrrolidin-1-yl)-2-oxoethoxy)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-(2-(4-hydroxypiperidin-1-yl)-2-oxoethoxy)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-3-(2-(3-hydroxyazethidine-1-yl)-2-okco3tokch)-N-((1 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(

4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

2-(((2R,3R,4S,5R,6R)-2-((3,5-dichlorophenyl)((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-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)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-3-(2-hydroxyethoxy)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-morpholine)

l)-1H-1,2,3-triazol-1-yl)-5-hydroxy-18R-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; and (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-dihydroxy-4-((3-hydroxypropyl)amino)phenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-18R-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide.

The compounds of formula (I) according to embodiments 1) to 20) and their pharmaceutically acceptable salts can be used as medicaments, for example in the form of pharmaceutical compositions for enteral (such as, in particular, oral, for example, in the form of a tablet or capsule) or parenteral administration (including topical application or inhalation).

The manufacture of pharmaceutical compositions can be carried out in a manner known to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st edition (2005), Part 5, Pharmaceutical Manufacturing [published by Lippincott Williams & Wilkins]) by introducing the described compounds of formula (I) or pharmaceutically acceptable salts thereof, optionally in combination with other therapeutically valuable substances, into a galenic dosage form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier substances and, if necessary, conventional pharmaceutical excipients.

The present invention also relates to a method for preventing/preventing or treating a disease or disorder referred to in the present invention, comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) according to embodiments 1) to 20). In a sub-embodiment of the invention, the amount administered is in the range of 1 mg to 1000 mg per day.

To avoid misinterpretation, it should be noted that where compounds are described as being useful for preventing/preventing or treating certain diseases, such compounds are also useful for use in the preparation of a medicament for preventing/preventing or treating said diseases. Likewise, such compounds are also useful for a method for preventing/preventing or treating such diseases, comprising administering to a subject (a mammal, in particular a human) in need thereof an effective amount of such a compound.

21. Another embodiment relates to compounds of formula (I) as defined in any one of embodiments 1) to 20), which are useful for the prevention/prophylaxis or treatment of diseases and disorders that are related to galectin-3 binding to nature

- 34 048291 ligands.

Such diseases and disorders that relate to the binding of Gal-3 to natural ligands are, in particular, diseases and disorders in which inhibition of the physiological activity of Gal-3 is beneficial, such as diseases in which the Gal-3 receptor is involved, is involved in the etiology or pathology of the disease, or is otherwise associated with at least one symptom of the disease.

Diseases or disorders that are related to the binding of galectin-3 to natural ligands may be defined as including, but not limited to:

fibrosis of organs, including:

all forms of pulmonary fibrosis/pulmonary fibrosis, including all forms of fibrosing interstitial lung diseases, especially idiopathic pulmonary fibrosis (alternatively called cryptogenic fibrosing alveolitis); pulmonary fibrosis secondary to a systemic inflammatory disease such as rheumatoid arthritis, scleroderma (systemic sclerosis, SSc), lupus (systemic lupus erythematosus, SLE), polymyositis, or mixed connective tissue disease (MCTD); pulmonary fibrosis secondary to sarcoidosis; iatrogenic pulmonary fibrosis, including radiation-induced fibrosis; silica-induced pulmonary fibrosis; asbestos-induced pulmonary fibrosis; and pleural fibrosis;

Renal fibrosis/kidney fibrosis, including renal fibrosis caused by/associated with chronic kidney disease (CKD), (acute or chronic) renal failure, tubulointerstitial nephritis and/or chronic nephropathies such as (primary) glomerulonephritis and glomerulonephritis secondary to systemic inflammatory diseases such as SLE or SSc, diabetes, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, renal allograft and Alport syndrome;

all forms of liver fibrosis/hepatic fibrosis (with or without portal hypertension), including cirrhosis, alcoholic liver fibrosis, nonalcoholic steatohepatitis, bile duct injury, primary biliary cirrhosis (also known as primary biliary cholangitis), infection- or virus-induced liver fibrosis (e.g., induced by chronic HCV infection), and autoimmune hepatitis;

all forms of cardiac fibrosis/cardiac fibrosis, including cardiac fibrosis/cardiac fibrosis associated with cardiovascular disease, heart failure, Fabry disease, CKD; diabetes, hypertension or hypercholesterolemia;

intestinal fibrosis, including intestinal fibrosis secondary to SSc and radiation-induced intestinal fibrosis;

cutaneous fibrosis including SSc and skin scars;

fibrosis of the head and neck, including radiation-induced fibrosis of the head and neck;

ocular fibrosis/corneal fibrosis, including scarring (eg, after laser in situ keratoplasty or trabeculectomy);

hypertrophic scars and keloids, including burn-induced or surgical hypertrophic scars and keloids;

fibrotic complications after organ transplantation (including corneal transplantation);

and other fibrosing diseases including endometriosis, spinal cord fibrosis, myelofibrosis, perivascular and arterial fibrosis; as well as scar tissue formation, Peyronie's disease, abdominal or intestinal adhesions, bladder fibrosis, nasal fibrosis, and fibroblast-mediated fibrosis;

(acute or chronic) liver diseases and disorders, including acute and chronic viral hepatitis; cirrhosis caused by/associated with arthritis and vasculitis; metabolic liver diseases caused by/associated with arthritis, myocarditis, diabetes or neurological symptoms; cholestatic diseases caused by/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, Sjogren's syndrome, panniculitis, alveolitis or alcoholic steatosis; Cirrhosis associated with dementia; Cirrhosis associated with peripheral neuropathy; Cirrhosis caused/associated with cancer of the oral cavity or esophagus; Non-alcoholic fatty liver disease (especially non-alcoholic steatohepatitis) caused/associated with obesity, metabolic syndrome or type 2 diabetes; Diseases of the blood vessels of the liver (including Budd-Chiari syndrome, portal vein thrombosis, sinusoidal obstruction syndrome); Acute and chronic liver failure (associated or not associated with portal hypertension); Liver hypofunction;

acute kidney injury and chronic kidney disease (CKD) [especially CKD stages

- 35 048291

1-5 as defined by the Kidney Disease International Consortium to Improve Global Outcomes (KDIGO) Guidelines], in particular CKD (in particular these stages) caused by/associated with heart disease (also called cardiorenal syndrome type 1 and type 2), or caused by/associated with hypertension, or caused by/associated with diabetes (also called diabetic kidney disease (DKD), including DKD associated with hypertension, where such diabetes is in particular type 1 or type 2 diabetes), or caused by/associated with inflammatory diseases and disorders (such as glomerulonephritis and glomerulonephritis secondary to systemic inflammatory diseases such as SLE or SSc, tubulointerstitial nephritis, vasculitis, sepsis, urinary tract infection), or caused by/associated with polycystic kidney disease, or caused by/associated with nephropathy due to obstruction of urine outflow (including stones, benign prostatic hyperplasia, prostate cancer, retroperitoneal pelvic tumor), or caused by/associated with symptoms associated with neurogenic bladder); as well as acute and chronic renal failure;

Cardiovascular diseases and disorders (including atherosclerosis caused by/associated with hypertension, hypercholesterolemia, diabetes, inflammation, obesity, advanced age; peripheral arterial disease caused by/associated with hypertension, hypercholesterolemia, diabetes, advanced age; deep vein thrombosis; pulmonary embolism caused by/associated with obesity or malignancy; aortic aneurysm and dissection caused by/associated with advanced age, hypertension, Marfan syndrome, congenital heart disease, inflammatory or infectious diseases; cerebrovascular disease caused by/associated with hypertension, atrial fibrillation, hypercholesterolemia, diabetes, advanced age; coronary heart disease caused by/associated with hypertension, hypercholesterolemia, diabetes, advanced age, or CKD (especially CKD stages 1-5 as defined by the International Consortium to Improve Kidney Disease Global Outcomes (KDIGO) Rules); rheumatic heart disease caused by/associated with bacterial infection; cardiac and vascular tumors; cardiomyopathy and arrhythmia; valvular heart disease (including calcified valve disease and degenerative aortic stenosis); inflammatory heart disease caused by/associated with infection, carditis, glomerulonephritis, malignancy; heart failure (HF) defined as including, in particular, congestive HF, including but not limited to 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 associated with/caused by chronic obstructive pulmonary disease; interstitial pneumonia associated with collagen vascular disease (including usual interstitial pneumonia) or pneumonia);

cell proliferative diseases and malignancies (including solid tumors, metastases from solid tumors, carcinomas, sarcomas, myeloma (and multiple myeloma), leukemia, lymphoma, mixed types of malignancies, vascular fibroma, Kaposi's sarcoma, chronic lymphocytic leukemia (CLL), spinal cord tumors, and invasive metastases from cancer cells);

Inflammatory and autoimmune diseases and disorders, including chronic and acute inflammatory and autoimmune diseases and disorders (in particular including sepsis, Q-strain rickettsiosis, asthma, rheumatoid arthritis, multiple sclerosis, SLE, SSc, polymyositis, plaque psoriasis (including psoriasis caused/associated with NASH), atopic dermatitis, inflammatory renal diseases/kidney diseases such as nephropathy (including diabetic nephropathy, glomerulonephritis, tubulointerstitial nephritis), inflammatory cardiac diseases/heart disease, inflammatory lung diseases/lung-related inflammatory diseases; inflammatory liver diseases/liver-related inflammatory 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 conditions; viral encephalitis; and COVID-19 and its sequelae);

gastrointestinal diseases and disorders (including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), gastritis and abnormal pancreatic secretion);

diseases and disorders of the pancreas (including pancreatitis, such as that associated with cystic fibrosis);

diseases and disorders associated with abnormal angiogenesis (including arterial occlusion);

diseases and disorders of the brain (including stroke and cerebral hemorrhage);

neuropathic pain and peripheral neuropathy;

- 36 048291 eye diseases and disorders (including dry eye disease (dry eye syndrome), age-related macular degeneration (AMD), diabetes-related disease (diabetic retinopathy), proliferative vitreoretinopathy (PVR), cicatricial pemphigoid and glaucoma (including glaucoma associated with increased intraocular pressure and ocular scars after glaucoma filtration surgery), and corneal angiogenesis/neovascularization); and graft rejection, including rejection of transplanted organs such as kidney, liver, heart, lung, pancreas, cornea and skin; graft-versus-host disease due to hematopoietic stem cell transplantation; chronic allograft rejection and chronic allograft vasculopathy; and the consequences of such graft rejection.

22. A further embodiment relates to compounds of formula (I) for use according to embodiment 21), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of organ fibrosis, including liver fibrosis/hepatic fibrosis, renal fibrosis/renal fibrosis, pulmonary fibrosis/pulmonary fibrosis, cardiac fibrosis/cardiac fibrosis, ocular fibrosis/corneal fibrosis, and skin fibrosis; as well as intestinal fibrosis, head and neck fibrosis, hypertrophic scars and keloids; and fibrotic complications following organ transplantation.

23. A further embodiment relates to compounds of formula (I) for use according to embodiment 21), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of cardiovascular diseases and disorders.

24. A further embodiment relates to compounds of formula (I) for use according to embodiment 21), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of acute kidney injury and chronic kidney disease (CKD).

25. A further embodiment relates to compounds of formula (I) for use according to embodiment 21), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of (acute or chronic) liver diseases and disorders.

26. A further embodiment relates to compounds of formula (I) for use according to embodiment 21), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of interstitial lung diseases and disorders.

27. A further embodiment relates to compounds of formula (I) for use according to embodiment 21), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of ocular diseases and disorders.

28. A further embodiment relates to compounds of formula (I) for use according to embodiment 21), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of cell proliferative diseases and malignancies.

29. A further embodiment relates to compounds of formula (I) for use according to embodiment 21), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of chronic or acute inflammatory and autoimmune diseases and disorders.

30. A further embodiment relates to compounds of formula (I) for use according to embodiment 21), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of diseases and disorders of the gastrointestinal tract.

31. A further embodiment relates to compounds of formula (I) for use according to embodiment 21), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of diseases and disorders of the pancreas.

32. A further embodiment relates to compounds of formula (I) for use according to embodiment 21), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of diseases and disorders associated with abnormal angiogenesis.

33. A further embodiment relates to compounds of formula (I) for use according to embodiment 21), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of diseases and disorders of the brain.

34. A further embodiment relates to compounds of formula (I) for use according to embodiment 21), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of neuropathic pain and peripheral neuropathy.

35. A further embodiment relates to compounds of formula (I) for use

- 37 048291 according to embodiment 21), wherein said compounds are intended for use in the treatment of transplant rejection.

Preparation of compounds of formula (I)

Compounds of formula (I) can be prepared by well-known literature methods, by the methods given below, by the methods given in the experimental section below, or by analogous methods. Optimum reaction conditions may vary depending on the particular reagents or solvents used, but such conditions can be determined by one skilled in the art using routine optimization techniques. In some cases, the order of the following reaction schemes and/or the steps of a particular reaction may be varied in order to facilitate the reaction or to avoid undesirable by-products. In the general reaction sequence set forth below, the integer n and the generic groups R ¹ , L, Ar ¹ and Ar ² are as defined for formula (I). Other abbreviations used in the present invention are explicitly defined or are as defined in the experimental section. In some cases, the generic groups R ¹ , L, Ar ¹ and Ar ² may be incompatible with the ensemble of other groups illustrated in the schemes below and will therefore require the use of protecting groups (Pg). The use of protecting groups is well known in the art (see, for example, Protective Groups in Organic Synthesis, TW Greene, PGM Wuts, Wiley-Interscience, 1999). For the purposes of the present discussion, it will be assumed that such protecting groups are in place when appropriate. In some cases, the final product may be further modified, for example, by manipulating substituents to yield a new final product. These manipulations may 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 also be converted into salts, especially pharmaceutically acceptable salts, by a method known per se.

The compounds of formula (I) of the present invention can be prepared according to the general reaction sequence set out below. Only some of the possible synthetic routes leading to compounds of formula (I) are described.

Compounds of formula (I) are prepared by coupling a compound of structure 1, wherein R is either hydrogen, a suitable protecting group (Pg), or R ¹ (as defined for formula (I)) with a compound of structure 2 to yield a compound of structure 3. The coupling reaction is performed using standard peptide coupling conditions, such as using DCC, HOBT, or T3P in the presence of a base such as TEA or DIPEA, in a suitable solvent such as DCM or DMF, or mixtures thereof. Alternatively, POCl ₃ with pyridine as the base can be used. In structures 2 and 3, Pg is a suitable protecting group such as an acetyl, trimethylsilyl (TMS), or tert-butyldimethylsilyl (TBS) group, or a benzyl group, which are well known to those skilled in the art. The hydroxy groups at position 4 and 6 of structure 1 can be protected with cyclic protecting groups such as isopropylidenyl, benzylidenyl or bis-t-butylsilyl groups. R is either hydrogen, a suitable protecting group (Pg) or R ¹ (as defined for formula (I)). Compounds of structure 3 can then be deprotected to give compounds of formula (I).

In case Pg is an acyl protecting group, such protecting group can be cleaved under standard conditions, for example, with water or alcohol in the presence or absence of additional solvents such as THF, dioxane, etc. and in the presence of a base such as K2CO3, NaOH, LiOH. In case such protecting group is a benzyl group, the protecting group can be cleaved, for example, with hydrogen in the presence of a catalyst such as Pd/C, _PtO2 in methanol, EA, THF, etc., or a mixture thereof, or _BBr3 in a solvent such as DCM. In case such protecting group is TMS or TBS, the protecting group is cleaved using fluoride ions, for example, TBAF or HF in pyridine. Alternatively, silyl protecting groups are removed under slightly acidic conditions such as aqueous acetic acid at rt. to the reflux temperature. In the case where Pg is a cyclic protecting group such as iso- 38 048291 propylidenyl, benzylidenyl and bis-tert-butylsilyl lenyl groups, the cleavage can be carried out under acidic conditions using aqueous acetic acid or TFA.

Compounds of structure 1 are prepared by hydrolysis of the nitrile function in structure 4 to the carboxylic acid in aqueous acidic (conc. HCl) or basic (NaOH) conditions at temperatures between 20 and 100 °C, followed by suitable protection or modification of the free hydroxyl groups. Compounds of structure 4 in turn are prepared, for example, by the reaction of a compound of structure 5 with a compound of structure 6 in the presence of CuI and DIPEA in solvents such as THF or DMF (Click Chemistry in Glycoscience: New Development and Strategies, 1st edition, 2013, John Wiley & Sons), alternatively the reaction can be carried out in a commercially available continuous reactor (Vapourtec) using a copper coil in a solvent such as THF. Compounds of structure 6 are either commercially available or can be prepared according to methods known to those skilled in the art (Synthesis 2011, 22, 3604-3611). Compounds of structure 5 can be prepared from the corresponding gulofuranose derivatives using methods well known to those skilled in the art (Carbohydrate Research 1994, 251, 33-67; Bioorg. Med. Chem. 2002, 10, 1911-2013).

Structure 7

Compounds of structure 2 are prepared by protecting compounds of structure 7 with a suitable silyl protecting group under standard conditions. Compounds of structure 7 are prepared by functionalization of (1S,2S)-trans-2-aminocyclohexanol or (^^)-trans-2-aminocycloheptanol, for example, by reductive amination using a suitable carbonyl component and a reducing agent such as NaB(OAc) _3H or _NaCNBH3 , in a suitable solvent such as DCM, MeOH, THF, DMF, or mixtures thereof. Alternatively, compounds of structure 7 are prepared by the reaction of cyclohexene oxide or cycloheptene oxide with an amine. This reaction affords either racemic trans-amino alcohols or, when carried out with a suitable catalyst such as that described in Org. Lett. 2014, 16, 2798-2801, provides enantiomerically enriched derivatives. In the case where compounds of structure 7 are used in racemic form, diastereomers of structure 3 or formula 1 can be separated after coupling with compounds of structure 1 using methods that are well known to those skilled in the art, such as chiral preparative HPLC or column chromatography on SiO ₂ .

In cases where the compounds of formula (I) are obtained as mixtures of stereoisomers, the stereoisomers can be separated by preparative HPLC using achiral or chiral stationary phases such as a Waters XBridge C18, 10 μm OBD, 30x75 mm, or Daicel ChiralCel OJ-H (5-10 μm), Daicel ChiralPak IH (5 μm) or AS-H (5 μm) or IB (5 μm) column, respectively. Typical chiral HPLC conditions are an isocratic mixture of eluent A (CO ₂ ) and eluent B (DCM/MeOH, 0.1% Et ₂ NH in EtOH, MeOH, EtOH), at a flow rate of 0.8 to 160 mL/min).

Experimental section.

The following examples illustrate the invention but in no way limit its scope.

All temperatures are in °C. Commercially available starting materials were used as received without further purification. Unless otherwise stated, all reactions were performed under nitrogen or argon. Compounds were purified by flash chromatography on silica gel (Biotage), prep. TLC (TLC plates from Merck, silica gel 60 F ₂₅₄ ) or preparative HPLC. The compounds described in the invention were characterized by 1H NMR (Bruker Avance II, 400 MHz, Ultra ShieldTM or 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=quadruplet, quint=quintuplet, hex=hexet, hept=heptet, m=multiplet, br=broad, coupling constants are given in Hz); and/or by LCMS (retention time t _R is given in min; molecular weight obtained for the mass spectrum is given in g/mol), using a

- 39 048291 the conditions listed below.

Methods used to determine characteristics:

LC-MS retention time values were obtained using the following elution conditions:

A. LC-MS (A):

Column Zorbax RRHD SB-Aq, 1.8 µm, 2.1x50 mm, thermostatted 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 elution mixture composition as a function of time t from the start of elution are summarized in the table below (a linear gradient was used between two consecutive time points):___________________________________

t (min) 0 0.01 1.20 1.90 2.10 Solvent A (%) 95 95 5 5 95 Solvent in (%) 5 5 95 95 5

Detection: UV at 210 nm.

B. LC-MS (B):

The column was a Waters BEH C18, 1.8 μm, 1.2*50 mm, thermostatted at 40°C. The two elution solvents were as follows: solvent A = water +13 mM NH4OH; solvent B = acetonitrile. The eluent flow rate was 0.8 ml/min, and the characteristics of the elution mixture composition as a function of time t from the start of elution are summarized in the table below (a linear gradient was used between two consecutive time points):

t (min) 0 0.01 1.20 1.90 2.00 Solvent A (%) 95 95 5 5 95 Solvent in (%) 5 5 95 95 5

Detection: UV at 210 nm.

D. LC-MS (D):

The column was an Acquity UPLC CSH C18 1.7 μm, 2.1x50 mm from Waters, thermostatted at 60°C. The two elution solvents were as follows: solvent A = water + 0.05% formic acid; solvent B = acetonitrile. The eluent flow rate was 1 ml/min, and the characteristics of the elution mixture composition as a function of time t from the start of elution are summarized in the table below (a linear gradient was used between two consecutive time points):

t (min) 0 1.50 1.90 1.95 4.90 5.00 Solvent A (%) 98 5 5 98 98 50 Solvent in (%) 2 95 95 2 2 50

Detection: UV 214 nm.

E. LC-MS (E):

The column was Acquity UPLC CSH C18 1.7 μm, 2.1x50 mm from Waters, thermostatted at 60°C. The two elution solvents were as follows: solvent A = water + 0.05% formic acid; solvent B = acetonitrile + 0.045% formic acid. The eluent flow rate was 1 ml/min, and the characteristics of the elution mixture composition as a function of time t from the start of elution are summarized in the table below (a linear gradient was used between two consecutive time points):

t (min) 0 1.50 1.90 1.95 4.90 5.00 Solvent A (%) 98 5 5 98 98 50 Solvent in (%) 2 95 95 2 2 50

Detection: UV 214 nm

Preparative LC-MS purification steps were performed using the conditions described below.

C. Preparative LC-MS (I):

A Waters column (Waters XBridge C18, 10 μm OBD, 30x75 mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% of 25% NH4OH in water; solvent B = acetonitrile. The eluent flow rate was 75 ml/min, and the characteristics of the elution mixture composition as a function of time t from the start of elution are summarized in the tables below (a linear gradient was used between two successive time points):

- 40 048291

t (min) 0 0.01 4.0 6.0 6.2 6.6 Solvent A (%) 90 90 5 5 90 90 Solvent in (%) 10 10 95 95 10 10

Detection 210 nm.

Abbreviations (in the context of the present invention).

ABTS 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid AcSON acetic acid drive. water Vi butyl (as in nBuLi = n-butyllithium) approx. approximately KH silica gel column chromatography END. concentrated CSA 10-camphorsulfonic acid DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DXM dichloromethane DEAD diethyl azodicarboxylate DIPEA A-ethyldiisopropylamine DMAP 4-dimethyl aminopyridine DMFA dimethylformamide DMSO dimethyl sulfoxide EA ethyl acetate

- 41 048291

EDC HC1 hydrochloride X-(3-dimethylaminopropyl)-X'-ethylcarbodiimide EQ. (molar(s)) equivalent(s) Et ethyl EtOH ethanol _Et2O diethyl ether ΦΧ flash chromatography 4 watch) HATU hexafluorophosphate 3-oxide 1-[bis(dimethyl amino)methylene]-1H-1,2,3-triazole o[4,5-b]pyridinium Hept. heptane HOBt 1-hydroxybenzotriazole hydrate HPLC high performance liquid chromatography B.B. high vacuum LAH lithium aluminum hydride LDA lithium diisopropylamide LC liquid chromatography M molarity [mol l' ¹ ] Me methyl MeCN acetonitrile MeOH methanol MC mass spectroscopy min minute(s) H. normality NaOMe sodium methylate NaO/Bu ot/?eot(tertiary)-sodium butoxide on optical density b/h during the night

org. p-ABSA Pd(Ph ₃ ) ₄ PPh ₃ organic i-acetamidobenzenesulfonyl azide tetrakis(triphenylphosphine)andyl(0)triphenylphosphine Ph phenyl

- 42 048291

PTSA i-toluenesulfonic acid k.t. room temperature saturation saturated TVME ot/?eot-butyl methyl ether TBTU tetrafluoroborate O-benzotriazol-1-yl-Ν,Ν,Ν’ ,Ν’ -tetramethyluronium tBu /77/7C/77-BUTYL = tertiary butyl TEA triethylamine Tf trifluoromethanesulfonate TFU trifluoroacetic acid THF tetrahydrofuran TMS trimethylsilyl TZR propylphosphonic anhydride tR holding time

A - Obtaining precursors and intermediates.

The following precursors were obtained for the synthesis of the compounds:

Intermediate

Intermediate connection 2 connection 1 L _1

Ag ¹

Intermediate connection 3

Intermediate compound 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 was synthesized from (3aR,5S,6S,6Ar)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol following the literature procedures in Carbohydrate Research 1994, 251, 33-67 and the references cited therein.

Intermediate compound 2:

(2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-cyano-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1yl)tetrahydro-2H-pyran-3,5-diyl diacetate.

Intermediate 1 (10000 mg, 26.5 mmol, 1 equiv) was dissolved in nitromethane (4 vol) (40 mL) and trimethylsilyl cyanide 98% (10.2 mL, 79.6 mmol, 3 equiv) and boron trifluoride diethyl etherate (3.93 mL, 31.8 mmol, 1.2 equiv) were added portionwise over 30 min. The temperature was maintained below 35 °C using a water bath. The mixture was stirred at rt for 2 h. The mixture was partitioned between water (400 mL), saturated aq. bicarbonate (100 mL), and TBME (300 mL). The aq. phase was extracted once more with TBME (200 mL) and org. The phases were washed twice with water/brine (approx. 5:1) and brine, and dried over _MgSC4 . TBME was evaporated on a rotary vacuum evaporator at 20°C. The crude intermediate was purified by filtration on _SiO2 (150 ml cartridge filled 3/4 full with DCM/TBME 10:1). The intermediate was used immediately in the next step.

¹ H NMR (500 MHz, DMSO) δ: 5.47 (dd, J ¹ = 0.7 Hz, J2 = 3.2 Hz, 1H), 5.17 (t, J = 10.3 Hz, 1H), 5.04 (d, J = 10.1 Hz, 1H), 4.22 (dd, J ¹ = 3.2 Hz, J2 = 10.4 Hz, 1H), 4.15 (ddd, J ¹ = 0.8 Hz, J2 = 4.5 Hz, J ³ = 7.2 Hz, 1H), 4.03-4.08 (m, 1H), 3.97 (dd, J1 = 7.4 Hz, J ² = 11.7 Hz, 1H), 2.18 (s, 3 H), 2.15 (m, 3 H), 2.04 (s, 3 H)

Intermediate compound 3a:

(2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-cyano-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1yl)tetrahydro-2H-pyran-3,5-diyl diacetate.

Intermediate 2 was dissolved in DMF (80 mL) and 5-ethynyl-1,2,3-trifluorobenzene (312 mg, 21.2 mmol, 0.8 equiv), DIPEA (13.6 mL, 79.6 mmol, 3 equiv), and CuI (505 mg, 2.65 mmol, 0.1 equiv) were added under N2. The yellow mixture was stirred at rt for 1 h. An exothermic reaction was observed. The yellow solution was slowly poured onto water (800 mL) and stirred for 10 min. The beige precipitate was filtered off and the filtrate was discarded. The beige solid was washed with MeOH and then dissolved in EA (300 mL) and stirred for 10 min. Fine Cu residues are filtered off and the filtrate is washed with NH ₄ Cl solution (semi-saturated) and brine, dried over MgSO ₄ and concentrated. The residue is triturated with MeOH (approx. 100 ml), filtered

- 43 048291 is evaporated and dried in v.v. to give the desired intermediate compound 3a as a beige solid.

1H NMR (500 MHz, DMSO^) δ: 8.85 (s, 1H), 7.81-7.85 (m, 2H), 5.91 (m, 1H), 5.64 (dd, J1= 3.1 Hz, J2=11.0 Hz, 1H) , 5.51 (dd, J1=0.7 Hz, J2=3.0 Hz, 1H), 5.24 (d, J=9.9 Hz, 1H), 4.43-4.46 (m, 1H), 4.03-4.12 (m, 2H), 2.10 (s, 3H), 2.04 (m, 3H ), 1.94 (m, 3H). LCMS (A): tR=0.86 min; [M+N]+=577.28

Intermediate 3b:

(2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-cyano-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate.

Prepared in analogy to intermediate 3a using the appropriate alkyne derivative (commercially available). LCMS (A): t _R = 0.95 min; [M+H] ⁺ = 479.23.

Intermediate connection 3c:

(2R,3R,4R,5R,6S)-2-(acetoxymethyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-6-cyanotetrahydro-2H-pyran-3,5-diyl diacetate.

Prepared in analogy to intermediate 3a using the appropriate alkyne derivative (commercially available). LCMS (A): t _R = 1.00 min; [M+H] ⁺ = 513.28.

Intermediate connection 3d:

(2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-cyano-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)tetrahydro-2H-pyran-3,5-diyl diacetate.

Prepared in analogy to intermediate 3a using the appropriate alkyne derivative (commercially available). LCMS (A): t _R = 0.98 min; [M+H] ⁺ = 493.26

Intermediate connection 3e:

(2R,3R,4R,5R,6S)-2-(acetoxymethyl)-6-cyano-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro2H-pyran-3,5-diyl diacetate.

Prepared in analogy to intermediate 3a using the appropriate alkyne derivative (commercially available). LCMS (A): t _R = 0.91 min; [M+H] ⁺ = 461.18.

Intermediates 3 are further functionalized as shown in the scheme below.

Intermediate compound 4a:

(2R,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol- 1yl)tetrahydro-2H-pyran-2-carboxylic acid.

Intermediate 3a (2800 mg, 5.64 mmol, 1 equiv) was suspended in 25% HCl (20.6 mL, 169 mmol, 30 equiv) and heated at reflux for 1.5 h. The solution was applied to a MCI® silica gel column (approx. 100 mL silica gel) with water. The column was eluted with water until neutral pH (5 fractions of 40 mL). The compound was then eluted with H ₂ O/MeCN (3:1). 40 mL fractions were collected. The product-containing fractions were first concentrated in vacuo to remove MeCN and then freeze-dried to afford the title compound as a colorless solid.

LCMS (A): t _R =0.59 min; [M+N] ⁺ =390.22.

1H NMR (500 MHz, DMSO-4) δ: 12.88-12.90 (br, 1H), 8.79 (s, 1H), 7.86 (dd, J1=6.8 Hz, ^J2 =9.1 Hz, 2H), 5.43-5.46 (m, 1H), 5.30 (d, J=6.2 Hz, 1H), 4.84 (dd, J1=3.0 Hz, ^J2 =10.8 Hz, 1H), 4.72 (d, J=0.5 Hz, 1H), 4.36 (t,

- 44 048291

J=10.0 Hz, 1H), 3.94 (dd, J1=3.0 Hz J2 6.01Hz 1H), 3.85 (d, 3=9.4Hz 1H), 3.71 (t, 3=6.5Hz 1H), 3.48-3.55 (m , 2H)

Intermediate 4b:

(2R,3R,4S,5R,6R)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl )tetrahydro-2H-pyran-2-carboxylic acid.

Obtained by analogy with intermediate compound 4a. LCMS (A): t _R = 0.55 min; [M+H]+=371.90

Intermediate connection 4c:

(2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy- 6(hydroxymethyl)tetrahydro-2H-pyran-2-carboxylic acid.

Obtained by analogy with intermediate compound 4a. LCMS (A): t _R = 0.64 min; [M+H]+=406.20

Intermediate 4d:

(2R,3R,4S,5R,6R)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy- 6-(hydroxymethyl)tetrahydro-2H-pyran-2-carboxylic acid.

Obtained by analogy with intermediate compound 4a. LCMS (A): t _R = 0.61 min; [M+H]+=386.17

Intermediate connection 4e:

(2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro -2H-pyran-2-carboxylic acid.

Obtained by analogy with intermediate compound 4a. LCMS (A): t _R = 0.50 min; [M+H]+=354.11

Intermediate connection 5a:

(4Al^^^)-7-hydroxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3, 2D][1,3]dioxin-6-carboxylic acid.

Intermediate 4a (1780 mg, 4.57 mmol, 1 equiv) was dissolved in THF (80 mL) and 2,2-dimethoxypropane (1.17 mL, 9.14 mmol, 2 equiv) was added followed by PTSA monohydrate (16.1 mg, 0.0914 mmol, 0.02 equiv) at rt.

The mixture was heated to 75°C for 1.5 h and 20-25 ml of the solvent was distilled off using a Dean-Stark apparatus. The solution was cooled to rt and then diluted with EA and washed with 10% citric acid solution, water and brine. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to afford the title intermediate as a beige solid.

LCMS (A): tR=0.8 min; [M+N]+=430.20.

1H NMR (500 MHz, DMSO) δ: 12.85-13.10 (m, 1H), 8.67 (s, 1H), 7.88 (dd, J1= 9.1 Hz, J ² =6.8 Hz, 2H), 5.45-5.59 (m, 1H), 4.98 (dd, J1=10.7 Hz, J ² = 3.4 Hz, 1H), 4.32-4.38 (m, 2H), 4.01-4.03 (m, 1H), 3.94 (d, J=9.3 Hz, 1H), 3.71-3.76 (m, 2H), 1.32 (s, 3 H), 1.21 (s, 3 H)

Intermediate 5b:

(4Lr,6R,7R,8R,8Lr)-8-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-7-hydroxy-2,2-dimethylhexahydropyrano[ 3,2D][1,3]dioxin-6-carboxylic acid.

Obtained by analogy with intermediate compound 5a. LCMS (A): t _R = 0.76 min; [M+H]+=412.29

Intermediate connection 5c:

(4Λr,6R,7R,8R,8Λr)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-7-hydroxy-2, 2-dimethylhexahydropyrano[3,2D][1,3]dioxin-6-carboxylic acid.

Obtained by analogy with intermediate compound 5a. LCMS (A): t _R = 0.84 min; [M+H]+=446.24

Intermediate compound 5d:

(4Λr,6R,7R,8R,8Λr)-8-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-7-hydroxy-2, 2-dimethylhexahydropyrano[3,2D][1,3]dioxin-6-carboxylic acid.

Obtained by analogy with intermediate compound 5a. LCMS (A): t _R = 0.81 min; [M+H]+=426.27

Intermediate connection 5e:

(4Λr,6R,7R,8R,8Λr)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-hydroxy-2,2-dimethylhexahydropyrano[3, 2D][1,3]dioxin-6-carboxylic acid.

Obtained by analogy with intermediate compound 5a. LCMS (A): t _R = 0.72 min; [M+H]+=394.19

Intermediate compound 6a:

(4Λr,6R,7R,8R,8Λr)-7-methoxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2D][1,3]dioxin-6-carboxylic acid.

Step 1: methyl (4aK,6K7^8^8aK)-7-methoxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1yl )hexahydropyrano[3,2-d][1,3]dioxin-6-carboxylate.

A solution of intermediate 5a (3180 mg, 7.41 mmol, 1 equiv.) in DMF (dry) (14.8 mL) and THF (dry) (29.6 mL) was cooled to 0 °C and dimethyl sulfate* 99.8% (1.44 mL, 15.2 mmol, 2.05 equiv.) was added followed by NaH (55% dispersion in mineral oil) (622 mg, 15.6 mmol, 2.1 equiv.). The mixture was stirred at 0 °C for 30 min and then at rt for 3 h. The mixture was cooled to 0 °C again and quenched by adding saturated NH4Cl solution. The mixture was diluted with water and EA and the layers were separated. The org. layer was washed with water and brine, and the aq. layer was reextracted once with

- 45 048291 using EA. The combined org. layers were dried over magnesium sulfate, filtered and evaporated. The residue was precipitated from a mixture of TBME/Hept. and the colorless solid was filtered and washed with a small amount of TBME and dried in v.v. The desired methyl ester was isolated as a colorless solid.

LCMS (A): t _R =0.98 min; [M+N]+=458.22.

* Iodomethane can be used as a reagent, which will equally successfully provide the same product.

Stage 2:

(4aR,6R,7R,8R,8aR)-7-methoxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1yl)hexahydropyrano[3,2^][1,3]dioxin-6-carboxylic acid.

The intermediate from step 1 (1546 mg, 3.38 mmol, 1 equiv) was dissolved in a mixture of THF/MeOH/ _H2O 3:2:1 (34.1 mL) and lithium hydroxide monohydrate (217 mg, 5.07 mmol, 1.5 equiv) was added at rt.

The mixture was stirred at rt for 4 h. The mixture was diluted with water, acidified with 0.1 N HCl and extracted twice with EA. The org. layers were washed with brine, combined, dried over magnesium sulfate, filtered and concentrated. The residue was triturated with TME. The white solid was filtered and washed with TME and dried in i.v. to give the title intermediate as a colorless solid.

LCMS (A): t _R =0.87 min; [M+N]+=444.25.

Intermediate 6b:

(4Ag,6R,7R,8S,8Ag)-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)-7-((trimethylsilyl)oxy)hexahydropyrano[3,2^][1,3]dioxin-6-carboxylic acid.

To a solution of intermediate 5a (2000 mg, 4.66 mmol, 1 equiv) and 2,6-lutidine (0.192 ml, 1.63 mmol, 3.5 equiv) in dry DCM (5 ml) was added dropwise trimethylsilyl trifluoromethanesulfonate (0.255 ml, 1.4 mmol, 3 equiv) at 0 °C. The mixture was stirred at 0 °C for 4.5 h. 2,6-lutidine (1.09 ml, 9.32 mmol, 2 equiv) and trimethylsilyl trifluoromethanesulfonate (1.69 ml, 9.32 mmol, 2 equiv) were again added at 0 °C, and stirring was continued at 0 °C. 2,6-lutidine (1.09 mL, 9.32 mmol, 2 equiv) and trimethylsilyl trifluoromethanesulfonate (0.506 mL, 2.79 mmol, 0.6 equiv) were added again and stirring was continued for 1 h. The mixture was diluted with DCM and quenched with water at 0 °C. The layers were separated and the org. layer was washed once with water and brine. The org. layer was filtered through a phase separator and evaporated. The crude material was dried in i.v. and used without purification due to its instability.

Intermediate connection 6c:

(4Ar^^^,8Ar)-7-((tert-butyldimethylsilyl)oxy)-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H1,2,3-triazol-1-yl)hexahydropyrano[3,2^][1,3]dioxy n-6-carboxylic acid.

To a solution of intermediate 5a (50 mg, 0.116 mmol, 1 equiv) in dry DCM (1 mL) under N2 at 0 °C was added 2,6-lutidine (0.0274 mL, 0.233 mmol, 2 equiv), followed by tert-butyldimethylsilyl trifluoromethanesulfonate (0.03 mL, 0.128 mmol, 1.1 equiv). The orange solution was then stirred at 0 °C for 1.5 h. The mixture was stirred at rt. Tert-butyldimethylsilyl trifluoromethanesulfonate (0.0267 mL, 0.116 mmol, 1 equiv) and 2,6-lutidine (0.0271 mL, 0.233 mmol, 2 equiv) were added again at 0 °C and the mixture was stirred at 0 °C for 1 h. The mixture was quenched with 10% citric acid solution and extracted twice with DCM. The combined organic layers were dried using a phase separator and then concentrated under reduced pressure. The reaction mixture was dissolved in MeCN/water 1/1 (1 mL) and treated with HCOOH (0.5 mL). The suspension was stirred at rt for 1 h and then filtered. The solid was purified by PC using a CombiFlash (4 g _SiO2 column; gradient: Hept. to Hept./EA 1/2 over 15 min) to give the desired product as a colourless solid.

LCMS (A): t _R =1.07 min; [M+N]+=544.30.

Intermediate compound 6d:

(4Ar^^^,8Ar)-7-acetoxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2^][1,3]dioxin-6-carboxylic acid.

To a solution of intermediate 5a (500 mg, 1.16 mmol, 1 equiv) in DCM (11.6 mL) and TEA (0.648 mL, 4.66 mmol, 4 equiv) was added Ac ₂ O (0.22 mL, 2.33 mmol, 2 equiv), followed by DMAP (14.2 mg, 0.116 mmol, 0.1 equiv). The mixture was stirred at rt. The mixture was diluted with water and DCM. The pH was carefully adjusted to 5-6 with 10% citric acid solution and the layers were separated. The aq. layer was re-extracted once with DCM and the combined org. layers were dried over MgSO ₄ , filtered and evaporated. The residue was precipitated from a mixture of TBME/Hepta + a small amount of MeOH. The colorless solid was filtered and washed with TBME to give the title intermediate as a colorless solid.

LCMS (A): t _R =0.87 min; [M+N]+=472.11.

Intermediate connection 6e:

(4Ag,6R,7R,8S,8Ag)-7-acetoxy-8-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2,2-dimethylhexa

- 46 048291 hydropyrano[3.2d|[1.3|dioxin-6-carboxylic acid.

Prepared from 5b by analogy with intermediate 6d. LCMS (A): t _R = 0.83 min; [M+H|+=454.01

Intermediate compound 6f:

(4Ar.6K.7d^.8Alg)-7-acetoxy-8-(4-(4-chloro-.3.5-di(|)tor(|)enyl)-1H-1.2..3-triazol-1- yl)-2.2dimethylhexahydropyrano[3.2d|[1.3|dioxin-6-carboxylic acid.

Obtained from 5c by analogy with intermediate compound 6d. LCMS (A): t _R = 0.90 min; [M+H|+=487.96.

Intermediate compound 6g:

(4Λr.6R.7R.8S.8Ar)-7-acetoxy-8-(4-(3.5-difluoro-4-methylphenyl)-1H-1.2.3-triazol-1-yl)-2.2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-carboxylic acid.

Obtained from 5d by analogy with intermediate compound 6d. LCMS (A): t _R = 0.88 min; [M+H|+=468.09.

Intermediate compound 6h:

(4Λr.6R.7R.8S.8Ar)-7-acetoxy-8-(4-(3-fluorophenyl)-1H-1.2.3-triazol-1-yl)-2.2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-carboxylic acid.

Obtained from 5e by analogy with intermediate compound 6d. LCMS (A): t _R = 0.79 min; [M+H|+=436.04.

Intermediate compound 7a:

(2R,3R,4S,5R,6R)-3,5-diacetoxy-6-(acetoxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol- 1yl)tetrahydro-2H-pyran-2-carboxylic acid.

To a suspension of intermediate 4a (1500 mg, 3.85 mmol, 1 equiv.) in Ac ₂ O (2.04 mL, 21.2 mmol, 5.5 equiv.) was added 70% solution of perchloric acid in water (0.00831 mL, 0.0963 mmol, 0.025 equiv.) at 0 °C. The mixture was stirred at 0 °C for 5 min and then allowed to warm to rt. and stirred i.v. The mixture was cooled to 0 °C and diluted with water (50 mL) and THF (5 mL). The mixture was allowed to warm to rt. (26 °C, exothermic hydrolysis).

The mixture is cooled to 0-5°C and the precipitated product is filtered, washed with water and dried in v.v. v/n to obtain the product as a white solid.

LCMS (A): t _R =0.85 min; [M+N] ⁺ =516.13.

1H NMR (500 MHz. DMSO-D δ: 13.38 (d. 1H). 8.84 (s. 1H). 7.70-7.95 (m. 2H). 5.73 (dd. J ^! = 11.0 Hz. J ² = 9.5 Hz). Hz. 1H). 2.08 (s 5.67 (dd. J ¹ =11.1 Hz. J2 = 3.2 Hz). 5.42-5.45 (m. 1H). 4.37-4.42 (m. 1H). 4.36 (d. J = 9.5 Hz. 1H). 4.08 (dd. J ¹ = 11.5 Hz. J ² = 5.6 Hz. 1H) 4.04 (dd. J ¹ = 11.5 Hz. J ² = 7.0.3 N).

Intermediate compound 8a:

(^.4Ar.6y.7y.8y.8Ar)-7-hydroxy-2-(()enyl-8-(4-(3.4.5-tri(()tor(()enyl)-1H-1.2.3-triazol-1-yl)hexahydropyrano[3.2d|[1.3|dioxin-6-carboxylic acid.

Intermediate 4a (1 g, 2.57 mmol) was dissolved in MeCN (50 mL). Benzaldehyde dimethyl acetal (1 mL) was added followed by PTSA (0.035 g, 0.07 equiv). The mixture was stirred at rt for 16 h. The volatiles were removed under reduced pressure and the residue was partitioned between EA and saturated NH4Cl solution. The org. (azo) was dried over _MgSO4 and concentrated to give the title intermediate as a colourless solid.

LCMS (A): t _R =0.89 min; [M+N|+=478.17.

Ή NMR (500 MHz, DMSO-46) δ: 12.17-13.30 (m. 1H). 8.89 (s. 1H). 7.84 (dd. J ¹ =9.0 Hz. J ² =6.8 Hz. 2H). 7.32-7.36 (m. 4 H). 5.54 (s. 1H). 5.15 (dd. J ¹ =10.7 Hz. J ² =3.5 Hz. 1H). 4.45-4.52 (m. 2H). 4.08-4.16 (m. 2H). 4.02 (d. J=9.4 Hz. 1H). 3.93 (m. 1H).

Intermediate compound 9a:

(2S.4Ar.6R.7R.8S.8Λr)-7-acetoxy-2-phenyl-8-(4-(3.4.5-trifluorophenyl)-1H-1.2.3-triazol-1-yl)hexahydropyrano[3.2-d][1.3]dioxin-6-carboxylic acid.

Intermediate 8a (1.13 g, 2.37 mmol, 1 equiv) was dissolved in DCM (30 mL) and TEA (1.3 mL, 9.47 mmol, 4 equiv) and acetic anhydride (0.447 mL, 4.73 mmol, 2 equiv) were added. The mixture was stirred at rt i/n. A saturated solution of NH4Cl (20 mL) was added and the resulting mixture was stirred at rt for 10 min. The resulting precipitate is filtered and washed with DCM and water. The crude product, dried in w.v., still contains some salts. Therefore, the solid is washed with citric acid solution (10%) and water and dried again in w.v. LCMS (A): t _R = 0.94 min; [M+H|+=520.16.

Preparation of intermediates of structure 7 and structure 2 Intermediates of structure 7 are prepared by a) reductive amination of 2-aminocyclohexanol or

2-aminocycloheptanol with an aldehyde. b) alkylation reactions with an alkyl halide or c) epoxide ring opening reactions as shown below.

- 47 048291

Intermediate connection 10:

(^^)-2-((3-chlorobenzyl)amino)cyclohexan-1-ol.

To a solution of cis-2-aminocyclohexanol hydrochloride (100 mg, 0.868 mmol, 1 equiv.) in a 4/1 mixture of DCM/MeOH (2.5 mL) was added 3-chlorobenzaldehyde (0.109 mL, 0.955 mmol, 1.1 equiv.) at rt. To the resulting solution, sodium cyanoborohydride (68.9 mg, 1.04 mmol, 1.2 equiv.) was added at rt under nitrogen atmosphere, and the solution was stirred at rt for 4 h. Sodium cyanoborohydride (28.7 mg, 0.434 mmol, 0.5 equiv.) was added again at rt, and the mixture was stirred at rt overnight. The mixture was quenched with water and basified with 25% aq. NH4OH solution. The mixture was extracted twice with DCM and the combined organic layers were evaporated. The residue was redissolved in MeCN and basified with 25% aq. NH4OH solution. The product was purified by prep. LCMS (I). The product-containing fractions were freeze-dried to give the desired amino alcohol as a colorless solid.

LCMS (A): t _R =0.58 min; [M+N]+=240.25.

The following intermediates are prepared in a manner similar to that used for Intermediate 10:

Intermediate connection Connection t _R [min] (LC-MS) MS data m/z [M+H] ⁺ 11 (18,28)-2-((3-ethynylbenzyl)amino)cyclohexan-1-ol 0.58 (A) 230.33 12 (18,28)-2-(phenethylamino)cyclohexan-1-ol 0.56 (A) 220.38 13 (18,28)-2-((4-chlorobenzyl)amino)cyclohexan-1-ol 0.57 (A) 240.27 14 (18,28)-2-((2-chlorobenzyl)amino)cyclohexan-1-ol 0.56 (A) 240.28 15 (18,28)-2-((2-(trifluoromethyl)benzyl)amino)cyclohexane-1 -ol 0.6 (A) 274.01 16 (IS,28)-2-(((3-chloropyridin-4-yl)methyl)amino)cyclohexa n-1-ol 0.44 (A) 241.26 17 (IS, 2 8)-2-(((2-(trifluoromethyl)pyr idin-3-yl)methyl)amino)cyclohexan-1-ol 0.49 (A) 275.23 18 (IS, 2 8)-2-(((4-(trifluoromethyl)pyr idin-3-yl)methyl)amino)cyclohexan-1-ol 0.49 (A) 275.23 19 (IS,28)-2-(((3 -(trifluoromethyl)pyridin-2-yl)methyl)amino)cyclohexan-1-ol 0.55 (A) 275.24 20 (IS, 2 8)-2-(((2-methyl-1H-imidazo l-4-yl)methyl)amino)cyclohexan-1-ol 0.46 (B) 210.35 21 (IS, 2 8)-2-(((2-amino-4-chlorothiazo l-5-yl)methyl)amino)cyclohexan-1-ol 0.6 (B) 262.16 22 (18,28)-2-((isoxazol-4-ylmethyl)amino)cyclohexan-1-ol 0.53 (B) 197.36 23 (IS,28)-2-(((5-chlorofuran-2-yl)methyl)amino)cyclohexan1-ol 0.8 (B) 230.22 24 (18,28)-2-((isothiazol-4-ylmethyl)amino)cyclohexan-1-ol 0.57 (B) 213.17 25 (1S,28)-2-(((1-methyl-1H-imidazol-4-yl)methyl)amino)cyclohexan-1-ol 0.49 (B) 210.26 26 (1S, 28)-2-(((2-bromothiazo l-4-yl)methyl)amino)cyclohexan1-ol 0.71 (B) 291.13 27 (IS, 2 8)-2-(((2-morpholinothiazol-5-yl)methyl)amino)cyclohexan-1-ol 0.53 (B) 298.17 28 (1S,28)-2-(((5-chlorothiophen-2-yl)methyl)amino)cyclohexane -1-ol 0.91 (B) 246.12 29 (1S,28)-2-(((5-chlorothiazol-2-yl)methyl)amino)cyclohexan1-ol 0.77 (B) 247.12 30 (1S,28)-2-(((1-methyl-1H-pyr azol-3-yl)methyl)amino)cyclo hexan-1-ol 0.52 (B) 210.34

Preparation of compounds of structure 2 protected by a silyl protecting group:

Compounds of structure 7 can be further protected at the hydroxy group following the procedures below.

Intermediate connection 31:

(1S,2S)-N-(2-(trifluoromethyl)benzyl)-2-((trimethylsilyl)oxy)cyclohexane-1-amine

To a solution of intermediate 15 (556 mg, 2.03 mmol, 1 equiv) and 2,6-lutidine (0.479 mL, 4.07 mmol, 2 equiv) in dry DCM (10 mL) at 0 °C was added dropwise 99% trimethylsilyl trifluoromethanesulfonate (0.558 mL, 3.05 mmol, 1.5 equiv). The mixture was stirred at 0 °C for 5 min and then allowed to warm to rt. The mixture was quenched with water and extracted twice with DCM. The combined organic layers were dried using a phase separator and then concentrated under reduced pressure. The crude material was absorbed onto the isolate and purified by FC CombiFlash (12 g RediSep column, 0100% EA in hept. for 10 min) to give the title intermediate (545 mg) as a colourless oil.

LCMS (B): t _R =1.41 min; [M+N] ⁺ =346.23.

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Intermediate connection 32:

(1S,2S)-2-((tert-butyldimethylsilyl)oxy)-N-(2-(trifluoromethyl)benzyl)cyclohexane-1-amine.

To a solution of intermediate 15 (2000 mg, 7.32 mmol, 1 equiv) and 2,6-lutidine (1.7 mL, 14.6 mmol, 2 equiv) in dry DCM (80 mL) at 0 °C was added dropwise tert-butyldimethylsilyl trifluoromethanesulfonate (2.52 mL, 11 mmol, 1.5 equiv). The mixture was stirred at 0 °C for 5 min and then allowed to warm to rt. The mixture was quenched with water and extracted twice with DCM. The combined organic layers were dried using a phase separator and then concentrated under reduced pressure. The crude material was absorbed onto the isolate and purified by CombiFlash FC (40 g RediSep column, 0-100% EA in heptadeca for 10 min) to afford the title intermediate as a yellowish oil.

LCMS (A): t _R =0.96 min; [M+N]+=388.27.

The following intermediate compounds are prepared in a similar manner:

Intermediate connection Connection t _R [min] (LC-MS) MS data m/z [M+H] ⁺ 33 (18,28)-M-(2-chlorobenzyl)-2-((trimethylsilyl)oxy)cyclohexane-1-amine 1.37 (B) 312.31 34 (18.28)-2-((t-butyldimethylsilyl)oxy)-H-((3-(trifluoromethyl)pyridin-2-yl)methyl)cyclohexan-1-amine 0.96 (A) 389.28 35 (IS, 2 S)-N-((4,6-dimethoxypyrimidin-5-yl)methyl)-2-((trimethylsilyl)oxy)cyclohexan-1-amine 1.16 (B) 340.27 36 (18,28)-M-((4-methylpyrimidin-5-yl)methyl)-2-((trimethylsilyl)oxy)cyclohexan-1-amine 0.98 (B) 294.29 37 tert-butyl 4-((((18.28)-2-((pg/>et-butyldimethylsilyl)ok- c)cyclohexyl)amino)methyl)-5-methyl-1H-imidazole-1-carboxylate 0.98 (A) 424.43 38 (18,28)-2-((t/>-butyldimethylsilyl)oxy)-N-((4-chloroisothiazol-5-yl)methyl)cyclohexane-1-amine 0.87 (A) 361.22 39 (1 8.28)-2-((/"/n ^> /"-butyldimstilsilyl)oxy)-K-((3-methylthiophen-2-yl)methyl)cyclohexan-1-amine 0.93 (A) 340.30 40 (18.28)-2-((t-butyldimethylsilyl)oxy)-M-((1-methyl-1H-pyrrol-2-yl)methyl)cyclohexan-1-amine 0.92 (A) 323.37 41 (1 8.28)-2-((/»/n ^> /»-butyldimethylsilyl)oxy)-N-((3-chlorothio phen-2-yl)methyl)cyclohexane-1-amine 0.94 (A) 360.23 42 (IS, 2 S)-2-((t-butyldimethylsilyl)oxy)-M-((4-methylthiazol-5-yl)methyl)cyclohexane-1-amine 0.84 (A) 341.30 43 (1 8.28)-2-((/»/N ^> /»-butyldimethylsilyl)oxy)-N-((1-methyl-1H-imidazol-2yl)methyl)cyclohexane-1-amine 0.79 (A) 324.36 44 (IS, 2 S)-2-((t/>-butyldimethylsilyl)oxy)-N-((2-methylthiophen-3-yl)methyl)cyclohexane-1-amine 0.94 (A) 340.31 45 (18,28)-2-((t/>-butyldimethylsilyl)oxy)-N-(2-methoxybenzyl)cyclohexane-1-amine 0.96 (A) 350.22 46 (18,28)-2-((t/>-butyldimethylsilyl)oxy)-N-(2,6-dimethoxybenzyl)cyclohexane-1-amine 1.00 (A) 380.21 47 (1 8.28)-2-((/"/?с/"-butyldimstilsil yl)oxy)-K-((1-ethyl-111-pyrazo l-5 -yl)methyl)cyclohexan-1-amine 0.85 (A) 337.74 48 (1 8.28)-2-((/»/n ^> /»-butyldimethylsilyl)oxy)-N-((1-methylpropyl-111-pyrazol-5-yl)methyl)cyclohexane-1-amine 0.89 (A) 352.31 49 (1 8.28)-2-((/»/N ^> /»-butyldimethylsilyl)oxy)-N-((1 -(cyclopropylmethylsilyl)1H-pyrazol-5-yl)methyl)cyclohexane-1-amine 0.90 (A) 364.15 50 (1 8.28)-2-((/»/n ^> /»-butyldimethylsilyl)oxy)-N-((1.3-dimethyl-111-pyrazol-5-yl)methyl)cyclohexane-1-amine 0.85 (A) 338.02 51 (1 8.28)-2-((/»/n ^> /»-butyldimethylsilyl)oxy)-N-((1 -methyl-111-indol-2-i l)methyl)cyclohexane-1-amine 0.99 (A) 373.33 52 (18,28)-2-((t/>-butyldimethylsilyl)oxy)-N-(3-chlorobenzyl)cyclohexane-1-amine 0.95 (A) 353.96

Intermediate compound 53:

(1S,2S)-2-(((4-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)cyclohexan-1-ol.

Step 1: (4-(trifluoromethyl)pyrimidin-5-yl)methanol.

4-(Trifluoromethyl)pyrimidine-5-carboxylic acid (1000 mg, 5.21 mmol, 1 equiv) was dissolved in THF (26 mL, 26 mmol, 5 equiv) and cooled to -10 °C (dry ice bath). 4-Methylmorpholine (1.17 mL, 10.4 mmol, 2 equiv) was added at -15 to -10 °C, followed by ethyl chloroformate (0.77 mL, 7.81 mmol, 1.5 equiv) at an internal temperature of -20 to -10 °C. THF (10 mL) was added slowly, maintaining the internal temperature below -10 °C to improve stirring. The mixture was kept at -10 °C for 30 min. After 30 min, sodium borohydride (761 mg, 19.5 mmol, 3 equiv) was added at -10 °C and stirring at this temperature was continued for 5 min. The dry ice bath was then replaced by an ice bath and the mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with water (30 mL), acidified with 10% citric acid to pH 4-5 and then extracted with n-butanol (3x). The organic layers were combined, dried over MgSO ₄ , filtered and evaporated to give a crude orange oil which still contained some salts. The mixture was suspended in DCM and the salts were filtered off. The filtrate was concentrated and the residue was purified by PC CombiFlash (12 g RediSep column, 10-100% EA in hept.). The intermediate alcohol is isolated as a yellow oil.

LCMS (A): t _R =0.49 min; [M+N] ⁺ =220.3.

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Step 2: 4-(trifluoromethyl)pyrimidine-5-carbaldehyde.

The above alcohol (365 mg, 2.05 mmol, 1 equiv) was dissolved in DCM (15 mL) and activated manganese(II) oxide (3001 mg, 29.3 mmol, 14.32 equiv) was added at rt. The mixture was stirred at rt i/n. The mixture was filtered through a glass fiber filter and the filtrate was evaporated to give the title aldehyde as a yellow oil.

Stage 3:

(^^)-2-(((4-(trifluoromethyl)pyrimidin-5-yl)methyl)amino)cyclohexan-1-ol.

(^^)-2-Aminocyclohexanol (150 mg, 1.26 mmol, 1 equiv) and the above aldehyde (245 mg, 1.39 mmol, 1.1 equiv) were dissolved in a 4/1 mixture of DCM/MeOH (5 mL) and sodium cyanoborohydride (100 mg, 1.52 mmol, 1.2 equiv) was added portionwise at rt. The mixture was stirred at rt for 3 h. The mixture was diluted with DCM and carefully quenched with water. The mixture was basified with 25% NH4OH solution and the layers were separated (phase separator). The organic layer was concentrated and the crude product was purified by FC (CombiFlash, 4 g RediSep column, 0-10% MeOH in EA) to give the title intermediate as a yellow oil.

LCMS (A): t _R =0.46 min; [M+N]+=276.27

Intermediate connection 54:

rac-N-((1R*,2R*)-2-((tert-butyldimethylsilyl)oxy)-cyclohexyl)-3,4-difluoroaniline.

Step 1: rac-(^*^*)-2-((3,4-difluorophenyl)amino)cyclohexan-1-ol.

Cyclohexene oxide (0.258 ml, 2.5 mmol, 1 equiv) and 3,4-difluoroaniline (391 mg, 3 mmol, 1.2 equiv) were mixed with water (4 ml) and heated at 90°C v/n. The mixture was diluted with water and the EA and org. phase were dried over MgSO ₄ and concentrated. The product was purified by PC (Hepta/EA 4:1-1:1) to afford the desired amino alcohol as a brown oil.

LCMS (A): tR=0.71 min; [M+N]+=228.24.

Step 2: rac-N-((1R*,2R*)-2-((tert-butyldimethylsilyl)oxy)-cyclohexyl)-3,4-difluoroaniline

To a solution of the intermediate from step 1 (320 mg, 1.41 mmol, 1 equiv) and 2,6-lutidine (0.328 mL, 2.82 mmol, 2 equiv) in dry DCM (14.1 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (0.485 mL, 2.11 mmol, 1.5 equiv) dropwise at 0 °C over 5 min. The mixture was diluted with 10 mL of water. The layers were separated (phase separator) and the aq. phase was re-extracted twice with 5 mL of DCM. The org. layer was evaporated and dried i.v. v/n. The crude product was purified by FC (CombiFlash, 12 g RediSep column, 0-50% EA in hept.) to afford the target intermediate as an orange oil.

LCMS (A): tR=1.27 min; [M+N]+=342.00.

The following compounds are prepared by analogy with intermediate compound 54, steps 1 and 2.

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Intermediate connection Connection t _R [min] (LC-MS A) MS data m/z [M+H] ⁺ 55 />α!/-Ν-((1 K*,2K*)-2-((»г/>е»г-butyldimethylsilyl)oxy)cyclohexyl)-3-chloroaniline 1.30 340.17 56 />ag/-M-((1K*,2K*)-2-((t/>e"g-butyldimethylsilyl)oxy)cyclohexyl)-3,5-dichloroaniline 1.33 374.12 57 N-((l 8,28)-2-((t/>et-butyldimethylsilyl)oxy)cyclohexyl)-3-methoxyaniline 1.17 336.17 58 3-((( 18.28)-2-((t-butyldimethylsilyl)oxy)cyclohexyl)amino)-5-chlorobenzonitrile 1.27 365.15 59 3-bromo-5-(((18.28)-2-((t-butyldimethylsilyl)oxy)cyclohexyl)amino)benzonitrile 1.27 408.94 60 />ag/-3-(((1K,2K)-2-((t/>e"g-butyldimethylsilyl)oxy)cyclohexyl)amino)-5-methylbenzonitrile 1.26 345.2 61 3-((( 18.28)-2-((t-butyldimethylsilyl)oxy)cyclohexyl)amino)-5-methoxybenzonitrile 1.26 361.1 62 />ag/-M-((1K,2K)-2-((t/>e"g-butyldimethylsilyl)oxy)cyclohexyl)-3-chloro-5-methylaniline 1.30 353.92 63 3-6poM-N-((l 8.28)-2-((t-butyldimethylsilyl)oxy)cyclohexyl)aniline 1.31 358.64 64 />ag/-3-(((1K,2K)-2-((t/>e"g-butyldimethylsilyl)oxy)cyclohexyl)amino)benzonitrile 1.24 331.17 65 />α!/-Ν-((1 K,2 K)-2-((t/>e»r-butyldimethylsilyl)oxy)cyclohexyl)-5-chloro-2-methylaniline 1.32 354.13 66 />α!/-Ν-((1 K,2 K)-2-((t/>e»r-butyldimethylsilyl)oxy)cyclohexyl)-3-chloro-4-fluoroaniline 1.29 358.12 67 />α!/-Ν-((1 K,2 K)-2-((t/>e»r-butyldimethylsilyl)oxy)cyclohexyl)-3-chloro-4-(trifluoromethyl)aniline 1.32 408.09 68 />α!/-3-6ρθΜ-Ν-((1 K,2K)-2-((t/>e»r-butyldimethylsilyl)oxy)cyclohexyl)-4-fluoroaniline 1.28 402.06 69 />ag/-M-((1K,2K)-2-((t/>e"g-butyldimethylsilyl)oxy)cyclohexyl)benzo[<1]thiazo l-6-amine 1.25 363.13 70 />ag/-M-((1K,2K)-2-((t/>e»r-butyldimethylsilyl)oxy)cyclohexyl)-2-methylbenzo[<1]thiazol-6-amine 1.23 377.14 71 />α!/-Ν-((1 K,2 K)-2-((t/>e»r-butyldimethylsilyl)oxy)cyclohexyl)-3-chloro-5-(trifluoromethyl)aniline 1.31 408.13 72 />ag/-3-bromo-M-((1K,2K)-2-((t/>e"g-butyldimethylsilyl)oxy)cyclohexyl)-5-chloroaniline 1.33 420.01 73 />ag/-3,5-dibromo-M-((1 K,2K)-2-((»r/>e»r-butyldimethylsilyl)oxy)cyclohexyl)aniline 1.34 463.92 74 />α!/-Ν-((1 K,2 K)-2-((t/>e»r-butyldimethylsilyl)oxy)cyclohexyl)-3,4-dichloroaniline 1.32 374.06 75 />α!/-3-6ρθΜ-Ν-((1 K,2K)-2-((t/>e»g-butyldimethylsilyl)oxy)cyclohexyl)-4-chloroaniline 1.32 419.99

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76 />ag/-M-((1K,2K)-2-((t/>e"g-butyldimethylsilyl)oxy)cyclohexyl)aniline 1.12 306.18 77 N-((18,28)-2-((m/>e»r-butyldimethylsilyl)oxy)cyclohexyl)benzo[b]thiophene-6-amine 1.2 362.04 78 M-((18.28)-2-((m-butyldimethylsilyl)oxy)cyclohexyl)-3-chloro-5-methoxyaniline 1.29 369.81 79 N-((l 8.28)-2-((t-butyldimethylsilyl)oxy)cyclohexyl)-5-chloro-2-fluoroaniline 1.31 357.91 80 />ag/-M-((1K,2K)-2-((t/>e»r-butyldimethylsilyl)oxy)cyclohexyl)-2,5-dimethylbenzo[c1]thiazol-6-amine 1.25 391.18 81 /;"g/-K-((1I.2I)-2-((/"/;c/"-butyldimstilsilyl)oxy)cyclohexyl)-2-chlorobenzo[<1]thiazo l-6-amine 1.29 397.11 82 />α!/-5-6ρθΜ-Ν-((1 K,2K)-2-((t/>et-butyldimethylsilyl)oxy)cyclohexyl)-2-methylaniline 1.31 400.1 83 />α!/-Ν-((1 K,2K)-2-((t/>et-butyldimethylsilyl)oxy)cyclohexyl)-4-chloroaniline 1.27 340.07 84 />ag/-3-(((1K,2K)-2-((t/>e"g-butyldimethylsilyl)oxy)cyclohexyl)amino)-5-fluorobenzonitrile 1.24 349.18 85 />α!/-Ν-((1 K,2 K)-2-((t/>et-butyldimethylsilyl)oxy)cyclohexyl)-3-fluoroaniline 1.26 324.21 86 />α!/-Ν-((1 K,2 K)-2-((t/>et-butyldimethylsilyl)oxy)cyclohexyl)-3-(trifluoromethyl)aniline 1.29 374.2 87 />α!/-Ν-((1 K,2K)-2-((t/>et-butyldimethylsilyl)oxy)cyclohexyl)-3,5-difluoroaniline 1.27 342.15 88 />α!/-Ν-((1 K,2 K)-2-((t/>et-butyldimethylsilyl)oxy)cyclohexyl)-3-fluoro-5-methoxyaniline 1.25 353.95 89 />α!/-Ν-((1 K,2 K)-2-((t/>et-butyldimethylsilyl)oxy)cyclohexyl)-3-fluoro-5-methylaniline 1.28 337.95 90 3-6poM-N-((l K8.28)-2-((t-butyldimethylsilyl)oxy)cyclohexyl)-5-fluoroaniline 1.3 401.8 91 M-((1C8.28)-2-((t/>e"g-butyldimethylsilyl)oxy)cyclohexyl)-3-chloro-5-fluoroaniline 1.3 358.18 92 />ag/-M-((1K,2K)-2-((t/>et-butyldimethylsilyl)oxy)cyclohexyl)-3-methylaniline 1.12 320.25 93 />ag/-M-((1K,2K)-2-((t/>e»r-butyldimethylsilyl)oxy)cyclohexyl)-2-methyl-1H-benzo[c1]imidazol-6-amine 0.91 360.23 94 N-((l 8,28)-2-((t/>-butyldimethylsilyl)oxy)cyclohexyl)-2,3-difluoroaniline 1.26 342.14 95 M-((18.28)-2-((m-butyldimethylsilyl)oxy)cyclohexyl)-6-fluoro-3-methoxyquinoxalin-5-amine 0.98 420.18 96 M-((18.28)-2-((t/>e"g-butyldimethylsilyl)oxy)cyclohexyl)-3-chloroquinoline-2-amine 1.01 405.14 97 M-((18.28)-2-((t/>e"g-butyldimethylsilyl)oxy)cyclohexyl)pyr idin-2-amine 0.87 307.12 129 N-((l 8,28)-2-((t/>-butyldimethylsilyl)oxy)cyclohexyl)naphthalene-2-amine 1.28 356.13 130 M-((18.28)-2-((m-butyldimethylsilyl)oxy)cyclohexyl)naphthalene-1-amine 1.29 356.13 131 N-((18,28)-2-((m/>g-butyldimethylsilyl)oxy)cyclohexyl)-1,5-dimethyl-1H-pyrazol-3-amine 0.88 324.17 132 * />ag/-(1K,2K)-2-((t/>e"g-butyldimethylsilyl)oxy)-M-(3-chlorophenyl)cycloteptan-1-amine 1.36 353.82 133 * />ag/-(1K,2K)-2-(("g/>e"g-butyldimethylsilyl)oxy)-M-(3,5-dichlorophenyl)cycloteptan-1-amine 1.39 388.20

* derived from cycloheptene oxide.

Intermediate 98: methyl (4Ar,6R,7R,8R,8Ar)-7-hydroxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2^][1,3]dioxin-6-carboxylate.

To a solution of intermediate 5a (120 mg, 0.279 mmol, 1 equiv.) in DMF (2.4 mL) was added NaH (60% dispersion in mineral oil, 11.3 mg, 0.282 mmol) at 0 °C. The reaction mixture was stirred for 0.5 h at rt. Dimethyl sulfate (0.029 mL, 0.307 mmol) was added and the reaction mixture was stirred for 1 h at rt. The mixture was cooled and quenched with water, extracted twice with ethyl acetate. The combined organic layers were washed with sat. aq. NaCl (10 mL), dried with MgSO ₄ and evaporated. The product was purified with CombiFlash, 24 g RediSep column, 0 - 100% ethyl acetate in hexane. The product is isolated as a colourless solid. LCMS (A): t _R = 0.88 min; [M+H]+=444.20.

Intermediate 99: methyl (4Ar,6R,7R,8R,8Ar)-7-(2-(tert-butoxy)-2-oxoethoxy)-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H1,2,3-triazol-1-yl)hexahydropyrano[3,2^][1,3]dioxy n-6-carboxylate.

To a solution of intermediate 98 (650 mg, 1.47 mmol, 1 equiv.) in DMF (15 mL) at rt were added tert-butyl bromoacetate (409 mg, 2.05 mmol) and NaH (60% dispersion in mineral oil, 78 mg, 2.05 mmol). The reaction mixture was stirred for 2.5 h at rt. The mixture was cooled and quenched with water, extracted twice with ethyl acetate. The combined org. layers were washed with sat. aq. NaCl (10 mL), dried with MgSO4 and evaporated. The product was purified by CombiFlash, 24 g RediSep column, 0-100% ethyl acetate in hexane. The product was isolated as a colorless solid. LCMS (A): t _R =1.05 min; [M+N] ⁺ =558.01.

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Intermediate connection 100a:

(4aK,6K,7K,8K,8aK)-7-(2-(tert-butoxy)-2-oxoethoxy)-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-III1,2,3-triazol-1-yl)hexahydropyrano[3,2^|[1,3|dioxy n-6-carboxylic acid.

To a solution of intermediate 99 (673 mg, 1.21 mmol, 1 equiv.) in THF, MeOH, H ₂ O (21 mL, 3:2:1) at 0 °C was added LiOH (44 mg, 1.81 mmol), and the mixture was stirred for 1 h. Additional LiOH (44 mg, 1.81 mmol) was added and the mixture was stirred for 0.5 h. 1 N aq. HCl was added to maintain pH 4, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with sat. aq. NaCl (10 mL), dried with MgSO ₄ and evaporated. The product was isolated as a colorless solid. LCMS (A): t _R = 0.96 min; [M+H]+ = 543.99.

Intermediate connection 100b:

(4Ar,6^7^8^8Ar)-7-(2-(tert-butoxy)-2-oxoethoxy)-8-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2.2-dimethylhexahydropyrano[.3.2^|[1..3|dioxin-6-carboxylic acid.

This compound is prepared in analogy to Intermediate 100a from the corresponding acid.

Intermediate 101: tert-Butyl

2-(((4Ar^^^,8Ar)-6-((III)-2-((tert-butyldimethylsilyl)oxy)-cyclohexyl)(3,5-dichlorophenyl)carbamoyl)-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2^][1,3]dioxin-7-yl)oxy) acetate.

The compound is prepared from Intermediate 100a and Intermediate 56 according to General Procedure B.

LCMS (A): tR=1.43 min; [M+N]+=899.17.

Intermediate 102: tert-butyl

2-(((2R,3R,4S,5R,6R)-2-((3,5-dichlorophenyl)((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-5-hydroxy6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetate.

To a solution of intermediate 101 (450 mg, 0.50 mmol) in 1,4-dioxane (24 mL) and water (12 mL) at 0 °C was added dropwise TFA (3.1 mL). The reaction mixture was stirred at rt for 16 h. A saturated aqueous solution of NaHCO ₃ was added to maintain pH 8, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of NaCl (10 mL), dried with MgSO ₄ and evaporated. The product was isolated as a yellowish oil. LCMS (A): t _R = 1.10 min; [M+H]+ = 745.19.

The following intermediate compounds are obtained by a 2-step procedure from the corresponding starting materials in analogy with acid 6a.

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Intermediate connection Connection t _R [min] (LC-MS A) MS data m/z [M+H] ⁺ 103a (4aR,6R,7R,8R,8aR)-8-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazolyl-1-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-<1][1,3]dioxin-6-carboxylic acid 0.89 460.09 103b methyl (4aR,6R,7R,8R,8aR)-8-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazo-l-1-yl)-7 -hydroxy-2,2-dimethylhexahydropyrano[3,2-b][1,3]dioxin-6-carboxylate 0.91 460.06 104a (4aR,6R,7R,8R,8aR)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazolyl-1-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-b][1,3]dioxin-6-carboxylic acid 0.90 460.01 104b (4aR,6R,7R,8R,8aR)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazolyl-1-yl)-7 -hydroxy-2,2-dimethylhexahydropyrano[3,2-b][1,3]dioxin-6-carboxylic acid 0.83 445.96 104s (4aR,6R,7R,8S,8aR)-7-acetoxy-8-(4-(4-chloro-3,5-diτopφenyl)-lH-l,2,3-τpiazol-1-yl)-2, 2-dimethylhexahydropyrano[3,2-b][1,3]dioxin-6-carboxylic acid 0.90 487.96 105a (4aR, 6R, 7R, 8R, 8aR)-8-(4-(4-bromo-3,5-difluorophenyl)-1H-1,2,3-triazolyl-1-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-b][1,3]dioxin-6-carboxylic acid 0.90 503.91 105b (4aR, 6R, 7R, 8R, 8aR)-8-(4-(4-bromo-3,5-difluorophenyl)-1H-1,2,3-triazolyl-1-yl)-7-hydroxy-2,2-dimethylhexahydropyrano[3,2-b][1,3]dioxin-6-carboxylic acid 0.83 491.85 106a (4aR,6R,7R,8R,8aR)-8-(4-(4-bromo-3-fluorophenyl)-lH-l,2,3-triazol-l-yl)-7methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-carboxylic acid 0.87 487.92 106b (4aR,6R,7R,8R,8aR)-8-(4-(4-bromo-3-fluorophenyl)-lH-l,2,3-triazol-l-yl)-7hydroxy-2,2-dimethylhexahydropyrano[3,2-c1][1,3]dioxin-6-carboxylic acid 0.80 473.91 107 (4aR,6R,7R,8R,8aR)-8-(4-(3-φτop-2-methylphenyl)-lH-l,2,3-triazol-l-yl)-7methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-carboxylic acid 0.83 421.91 108 (4aR,6R,7R,8R,8aR)-8-(4-(5-φτop-2-methoxyphenyl)-lH-l,2,3-triazol-l-yl)-7methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-carboxylic acid 0.81 437.75 109 (4aR,6R,7R,8R,8aR)-8-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazolyl-1-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-c1][1,3]dioxin-6-carboxylic acid 0.88 486.02 BY (4aR,6R,7R,8R,8aR)-8-(4-(3,4-difluorophenyl)-lH-l,2,3-triazol-l-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-c1][1,3]dioxin-6-carboxylic acid 0.81 425.99 111 (4aR,6R,7R,8R,8aR)-8-(4-(3-φτop-4-methylphenyl)-lH-l,2,3-triazol-l-yl)-7methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-carboxylic acid 0.83 421.97 112 (4aR,6R,7R,8R,8aR)-8-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazo l-1-yl)7-methoxy-2, 2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-carboxylic acid 0.87 440.12 113 (4aR,6R,7R,8R,8aR)-8-(4-(4,5-difluoro-2-methoxyphenyl)-lH-l,2,3-triazol-lyl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-b][1,3]dioxin-6-carboxylic acid 0.85 456.09 114 (4aR, 6R, 7R, 8R, 8aR)-8-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazolyl-1-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-b][1,3]dioxin-6-carboxylic acid 0.89 505.92 115 (4aR,6R,7R,8R,8aR)-8-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazolyl-1-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-b][1,3]dioxin-6-carboxylic acid 0.89 460.03 116 (4aR,6R,7R,8R,8aR)-8-(4-(4-chloro-3-fluorophenyl)-lH-l,2,3-triazol-l-yl)-7methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-carboxylic acid 0.86 441.86 117 (4aR,6R,7R,8R,8aR)-8-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-carboxylic acid 0.91 476.09 118 (4aR,6R,7R,8R,8aR)-8-(4-(4-cyano-3-fluorophenyl)-1H-1,2,3-triazolyl-1-yl)-7methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-carboxylic acid 0.82 433.02

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119 (4aR,6R,7R,8R,8aR)-8-(4-(4-chloro-2,5-difluorophenyl)-1H-1,2,3-triazolyl-1-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-<1][1,3]dioxin-6-carboxylic acid 0.88 460.06 120 (4aR,6R,7R,8R,8aR)-8-(4-(3,4-difluoro-5-methoxyphenyl)-lH-l,2,3-triazol-lyl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-c1][1,3]dioxin-6-carboxylic acid 0.86 456.08 121 (4aR,6R,7R,8R,8aR)-8-(4-(4-chloro-3-methoxyphenyl)-lH-l,2,3-triazol-l-yl)-7methoxy-2,2-dimethylhexahydropyrano[3,2-c1][1,3]dioxin-6-carboxylic acid 0.83 453.69 122 (4aR,6R,7R,8R,8aR)-8-(4-(4-chloro-3-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-c1][1,3]dioxin-6carboxylic acid 0.94 508.00 123 (4aR,6R,7R,8R,8aR)-8-(4-(3-φτop-5-methylphenyl)-lH-l,2,3-triazol-l-yl)-7methoxy-2,2-dimethylhexahydropyrano[3,2-c1][1,3]dioxin-6-carboxylic acid 0.83 422.00 124 (4aR.6R.7R.8R.8aR)-7-MCTOKCn-2.2-jnMCTn.i-8-(4-(2-MCTn.i6cH3o|d|Tna3O.i-6yl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-c1][1,3]dioxin-6-carboxylic acid 0.80 461.08 125 (4aR,6R,7R,8R,8aR)-8-(4-(4-fluoronaphthalen-l-yl)-lH-l,2,3-triazol-l-yl)-7methoxy-2,2-dimethylhexahydropyrano[3,2-c1][1,3]dioxin-6-carboxylic acid 0.87 458.01 126a (4aR,6R,7R,8R,8aR)-8-(4-(4-xnopTna3on-2-Hn)-lH-l,2,3-TpHa3on-l-Hn)-7methoxy-2,2-dimethylhexahydropyrano[3,2-c1][1,3]dioxin-6-carboxylic acid 0.73 430.98 126b (4aR,6R,7R,8R,8aR)-8-(4-(4-xnopTna3on-2-Hn)-lH-l,2,3-TpHa3on-l-Hn)-7hydroxy-2,2-dimethylhexahydropyrano[3,2-c1][1,3]dioxin-6-carboxylic acid 0.64 416.90 127 (4aR,6R,7R,8R,8aR)-8-(4-(4-chlorophenyl)-lH-l,2,3-triazol-l-yl)-7-methoxy-2, 2-dimethylhexahydropyrano[3,2-cG|[1,3]dioxin-6-carboxylic acid 0.84 424.02 128 (4aR,6R,7R,8R,8aR)-8-(4-(4-6pox^eHHn)-lH-l,2,3-TpHa3on-l-Hn)-7-MeTOKCH-2, 2-dimethylhexahydropyrano[3,2-c1][1,3]dioxin-6-carboxylic acid 0.86 469.54

B - Obtaining example connections.

General procedure A: Amide coupling using T3P.

To a solution of the acid component (1 equiv.) and the amine intermediate (1.1 equiv.) in DMF (5 mL/mmol) were added DIPEA (1.5 equiv.) and T3P (50% solution in EA, 1.5 equiv.), and the mixture was stirred at rt until complete conversion. After workup with water (EA/dil. HCl), the products were purified as described in the General Methods.

General Procedure B: Amide Coupling via _POCl3 /Pyridine To a solution of the acid component (1 equiv.) and the amine intermediate (1.2 equiv.) in DCM (10 mL/mmol) at 0 °C was added phosphorus(V) oxychloride (1 M solution in pyridine, 0.451 mL, 0.451 mmol, 1 equiv.) dropwise over 2-3 min. The mixture was stirred at 0 °C for 10 min and then allowed to warm slowly to rt. After completion of the reaction, the mixture was quenched with 10% citric acid and extracted twice with EA. The org. layers were washed with brine. The combined org. layers were dried over magnesium sulfate, filtered, and concentrated. The products were purified as described in the general methods.

General method C: removal of protection using water, AcOH solution.

The protected intermediate (acetal and/or silyl Pg) (1 equiv.) was heated under reflux in AcOH/H2O 1:1 (5 ml/mmol) until the reaction was complete. The products were purified as described in the general methods.

General Procedure D: Deprotection with CSA in MeOH.

CSA (0.1 equiv) was added to the isopropylidene-protected intermediate (1 equiv) in MeOH (5 mL/mmol) and heated at reflux until the reaction was complete. The products were purified as described in General Methods.

General procedure E: Removal of acetate protection with K2CO3 in MeOH.

K2CO3 (0.1 eq.) was added to the acetate-protected intermediate (1 eq.) in MeOH (5 mL/mmol) and stirred at rt until the reaction was complete. The products were purified as described in General Methods.

The example compounds listed in Table 1 below were prepared by using any of the above Methods A or B in combination with acids 1-9, 98-128 and amines 10-97, 129-133. The final compounds were prepared by deprotection using Methods C, D, or E.

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Table 1

Pr. Connection ίκ [min] (LCMS) MS data m/z [M+H] + 1 (2K,3K,48,5K,6K)-N-benzyl-3,5-dihydroxy-N-((18,28)-2-hydroxycyclohexyl)-6(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide 0.86 (A) 577.23 2 (2K,3K,48,5K,6K)-M-(3-chlorobenzyl)-3,5-dihydroxy-M-((18,28)-2-hydroxycyclohexyl) -6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2Hpyran-2-carboxamide 0.90 (A) 611.01 3 (2K,3K,48,5K,6K)-M-(3-ethynylbenzyl)-3,5-dihydroxy-M-((18,28)-2-hydroxycyclohexyl) -6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2Hpyran-2-carboxamide 0.89 (A) 601.22 4 (2R, 3R, 4 8,5R, 6R)-3,5-dihydroxy-M-(( 18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-M-phenethyl-4-(4-(3,4,5 -trifluorophenyl)-1H-1,2,3 -triazol-1 -yl)tetrahydro-2H-pyran2-carboxamide 0.89 (A) 591.26 5 (2R,3R,4S,5R,6R)-N-(4-xnop6eH3Hn)-3,5-flHrHflpoKCH-N-((18,2S)-2-rHflpoKCHiiHKnoreKCHn) -6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro-2Hpyran-2-carboxamide 0.90 (A) 611.03 6 (2R,3R,4S,5R,6R)-N-(2-xnop6eH3Hn)-3,5-flHrHflpoKCH-N-((18,2S)-2-rHflpoKCHiiHKnoreKCHn)-6-( Hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-k arboxamide 0.90 (A) 611.25

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7 (2R, 3 R, 4 8,5R,6R)-3,5-dihydroxy-N-(( 18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-(2-(trifluoromethyl)benzyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2 H-pyran-2-carboxamide 0.94 (A) 645.28 8 (2R,3R,4S,5R,6R)-N-((3-xnopnHpHflHH-4-Hn)MeTHn)-3,5-flHrHflpoKCH-N-((l 8,28)-2-hydroxycy clohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.76 (A) 612.22 9 (2R, 3 R, 4 8,5R,6R)-3,5-dihydroxy-N-(( 18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazo l-Gyl)tetrahydro-2H-pyran-2-carboxamide 0.85 (A) 646.10 10 (2R, 3 R, 4 8,5R,6R)-3,5-dihydroxy-N-(( 18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((4-(trifluoromethyl)pyridin-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazo l-Gyl)tetrahydro-2H-pyran-2-carboxamide 0.84 (A) 646.09 11 (2R,3R,4S,5R,6R)-5-rHflpoKCH-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-meth o kch-N-(2-(trifluoromethyl)benzyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazo l-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.00 (A) 659.32 12 (2R,3R,4S,5R,6R)-N-(2-xnop6eH3Hn)-5-rHflpoKCH-N-((18,2S)-2-rHflpoKCHHHKnoreKCHn)-6-(rHfloxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-Gyl)tetrahydro-2H-p irani-2-carboxamide 0.97 (A) 625.28 13 (2R, 3 R, 4 8,5R,6R)-3,5-dihydroxy-N-(( 18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((3-(trifluoromethyl)pyridin-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazo l- gil)tetrahydro-2H-pyran-2-carboxamide 0.89 (A) 646.08 14 (2R, 3 R, 4 8,5R,6R)-3,5-dihydroxy-N-(( 18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N -((2-methyl-1H-imidazol-4-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-gyl)tetrahydro-2H-pyran-2-carboxamide 0.61 (A) 582.10 15 (2R,3R,4S,5R,6R)-N-((2-aMHHO-4-xnopTHa3on-5-Hn)MeTHn)-3,5-flHrHflpoKCH-N-((18,2S)-2-rHflp oxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-Gyl)tet rahydro-2H-pyran-2-carboxamide 0.76 (A) 633.24 16 (2R, 3 R, 4 8,5R,6R)-3,5-dihydroxy-N-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-(isoxazol-4-ylmethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-gyl)tetrahydro-2H-p irani-2-carboxamide 0.75 (A) 568.28 17 (2R,ЗR,4S,5R,6R)-N-((5-chloropyran-2-yl)methyl)-3,5-dihydroxy-N-((lS,2S)-2-hydroxycyclic ohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-Gyl)tetrahydro-2H-pyran-2-carboxamide 0.88 (A) 601.26 18 (2R,3R,48,5R,6R)-3,5-dihydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-(isothiazol-4-ylmethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-gyl)tetrahydro-2H-p-iran-2-carboxamide 0.77 (A) 584.28 19 (2R,3R,48,5R,6R)-3,5-dihydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((Gmethyl-1H-imidazol-4-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-gyl)tetrahydro-2H-pyran-2-carboxamide 0.61 (A) 582.15 20 (2R,3R,4S,5R,6R)-N-((2-6poMTHa3on-4-Hn)MeTHn)-3,5-flHrHflpoKCH-N-((18,2S)-2-rHflpoKCHHHK logexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazo l-Gyl)tetrahydro2H-pyran-2-carboxamide 0.85 (A) 661.99 21 (2R, 3 R, 4 8,5R,6R)-3,5-dihydroxy-N-(( 18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N -((2-morpholinothiazol-5-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-Gyl)tetrag ydro-2H-pyran-2-carboxamide 0.67 (A) 669.36 22 (2R,3R,4S,5R,6R)-N-((5-chlorothiophen-2-yl)methyl)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazo l-gyl)tetrahydro2H-pyran-2-carboxamide 0.91 (A) 617.23 23 (2R,3R,4S,5R,6R)-N-((5-xnopTHa3on-2-Hn)MeTHn)-3,5-flHrHflpoKCH-N-((18,2S)-2-rHflpoKCHHHK logexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazo l-Gyl)tetrahydro2H-pyran-2-carboxamide 0.85 (A) 618.25 24 (2R,3R,48,5R,6R)-3,5-dihydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((Gmethyl-1H-pyrazol-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-gyl)tetrahydro-2H-pyran-2-carboxamide 0.76 (A) 582.09 25 (2R,3R,4S,5R,6R)-5-rHflpoKCH-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N-((3-(trifluoromethyl)pyridin-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-l-yl)tetrahydro-2H-pyran-2-carboxamide 0.95 (A) 660.33 26 (2R,3R,4S,5R,6R)-5-rHflpoKCH-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N-((2-(trifluoromethyl)pyridin-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-l-yl)tetrahydro-2H-pyran-2-carboxamide 0.92 (A) 660.36 27 (2R, 3 R, 4 8,5R,6R)-3,5-dihydroxy-N-(( 18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N -((4-(trifluoromethyl)pyrimidin-5-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1yl)tetrahydro-2H-pyran-2-carboxamide 0.84 (A) 647.37 28 (2R,3R,48,5R,6R)-N-((4,6-dimethoxypyrimidin-5-yl)methyl)-3,5-dihydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazo l-Nyl)tetrahydro-2H-pyran-2-carboxamide 0.82 (A) 639.4 29 (2R, 3 R, 4 8,5R,6R)-3,5-dihydroxy-N-(( 18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((4-methylpyrimidin-5-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetragidro-2H-pyran-2-carboxamide 0.72 (A) 593.37 30 (2R,3R,4S,5R,6R)-5-rHflpoKCH-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-meth 0.6 595.38

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okcii-N-((5-methyl-1 H-imidazol-4-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3 -triazol-1 yl)tetrahydro-2 H-pyran-2-carboxamide (A)8 31 (2K,3K,48,5K,6K)-M-((4-chloroisothiazol-5-yl)methyl)-5-hydroxy-M-((18,28)-2-hydroxycycle hexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.88 (A) 632.30 32 (2K,3K,48,5K,6K)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-meth okch-N-((1-methyl-1H-pyrazol-5-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro-2H-pyran-2-carboxamide [1,3-dideoxy-2-O-methyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-(N-((l-methyl-1H-pyrazol-5-yl)methyl)-N-((18,28)-2-hydroxycyclohexyl))-p-0-galactopyranose-1-carboxamide amide] 0.81 (A) 595.18 33 (2K,3K,48,5K,6K)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-meth okch-N-((3-methylthiophen-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tet rahydro-2H-pyran-2-carboxamide 0.95 (A) 611.36 34 (2K,3K,48,5K,6K)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N-((1-methyl-1H-pyrrol-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide [1,3-dideoxy-2-O-methyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-(N-((l-methyl-1H-pyrrol-2-yl)methyl)-N-((18,28)-2-hydroxycyclohexyl))-p-O-galactopyranose-1-carboxamide] 0.91 (A) 594.38 35 (2K,3K,48,5K,6K)-M-((3-chlorothiophen-2-yl)methyl)-5-hydroxy-M-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.96 (A) 631.31 36 (2H,3H,48,5H,6H)-5-hydroxy-KG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N-((4-methylthiazol-5-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.80 (A) 612.36 37 (2K,3K,48,5K,6K)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-meth okch-N-((1-methyl-1H-imidazol-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1yl)tetrahydro-2H-pyran-2-carboxamide 0.68 (A) 595.18 38 (2K,3K,48,5K,6K)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-meth okch-N-((2-methylthiophen-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tet rahydro-2H-pyran-2-carboxamide 0.96 (A) 611.37 39 (2K,3K,48,5K,6K)-5-hydroxy-M-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-meth oxy-M-(2-methoxybenzyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H -pyran-2-carboxamide 0.95 (A) 621.18 40 (2K,3K,48,5K,6K)-M-(2,6-dimethoxybenzyl)-5-hydroxy-M-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.96 (A) 651.19 41 (2K,3K,48,5K,6K)-3,5-dihydroxy-M-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-M-((1-methyl-1H-imidazol-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.63 (A) 581.24 42 (2K,3K,48,5K,6K)-5-hydroxy-2-(((18,28)-2-hydroxycyclohexyl)((1-methyl-1H-imidazol-2 -yl)methyl)carbamoyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl acetate 0.69 (A) 623.14 43 (2K,3K,48,5K,6K)-5-hydroxy-2-(((18,28)-2-hydroxycyclohexyl)((1-methyl-1H-pyrazol-5-and l)methyl)carbamoyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl acetate 0.80 (A) 623.14 44 (2K,3K,48,5K,6K)-M-((1-ethyl-1H-pyrazol-5-yl)methyl)-5-hydroxy-M-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.84 (A) 609.30 45 (2K,3K,48,5K,6K)-5-hydroxy-M-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-M-((1isopropyl-1H-pyrazol-5-yl)methyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.86 (A) 623.29 46 (2K,3K,48,5K,6K)-M-((1-(cyclopropylmethyl)-1H-pyrazol-5-yl)methyl)-5-hydroxy-M-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1, 2,3-triazo l-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.88 (A) 635.29 47 (2K,3K,48,5K,6K)-M-((1,3-dimethyl-1H-pyrazol-5-yl)methyl)-5-hydroxy-M-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.79 (A) 609.27 48 (2K,3K,48,5K,6K)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N-((1-methyl-1H-indol-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.99 (A) 644.29 49 (2R,3R,4 8,5R,6R)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-2-(((IS,28)-2hydroxycyclohexyl)((1-methyl-1H-pyrazol-5-yl)methyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate 0.77 (A) 605.16 50 (2R,3R,4 8,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-2-(((1 8,28)-2-hydroxycyclohexyl)((1-methyl-1H-pyrazol-5-yl)methyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate 0.83 (A) 639.14 51 (2R,3R,4S,5R,6R)-4-(4-(3,5-difluoro-4-methylphenyl)-lH-l,2,3-triazol-l-yl)-5-hydroxy-2-(((18,28)-2-hydroxycyclohexyl) ((1-methyl-1H-pyrazol-5-yl)methyl)carbamoyl)-6-(hydroxymethyl 0.81 (A) 619.22

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ethyl)tetrahydro-2H-pyran-3-yl acetate 52 (2R,3R,4 S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-2-(((18,28)-2-hydroxycyclohexyl)((1-methyl-1H-pyrazol-5-yl)methyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate 0.74 (A) 587.18 53 (2 R.3R.4 8.5 K.6K)-N-(3-hydroxypropyl 3-methyl ... 0.98 (A) 624.96 54 (2R,3R,4S,5R,6R)-4-(4-(3,5-difluoro-4-methylphenyl)-lH-l,2,3-triazol-l-yl)-5-hydroxy-2-(((18,2 8)-2-hydroxycyclohexyl) (2-(trifluoromethyl)benzyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate [1,3-dideoxy-2-O-acetyl-3-[4-(4-methyl-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-(KG-(3-t [(18,28)-2-hydroxycyclohexyl)-p-0-galactopyranose-1-carboxamide] 1.00 (A) 683.20 55 (2R,3R,4S,5R,6R)-5-hydroxy-2-(((1S,2S)-2-hydroxycyclohexyl)(2-(trifluoromethyl)benzyl)carbamoyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl acetate 0.99 (A) 687.02 56 (2R,3R,4S,5R,6R)-N-(3,4-difluorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2 H-pyran-2-carboxamide [1,3-dideoxy-2-O-methyl-3-[4-(3,4,5 -trifluorophenyl)-1H-1,2,3 -triazol-1 -yl]-(ЬР-(3,4-difluorophenyl)-1H-1,2,3 -triazol-1-yl]-(ЬР-(3,4-difluorophenyl)-1H-1,2,3 -triazol-1-yl)tetrahydro-2 H-pyran-2-carboxamide (1,3-dideoxy-2-O-methyl-3-[4-(3,4,5 -trifluorophenyl)-1H-1,2,3 -triazol-1-yl]-(ЬР-(3,4-difluorophenyl)-1H-1,2,3 -triazol-1-yl) ... [(rphenyl)-N-((18,28)-2-hydroxycyclohexyl))-p-0-galactopyranose-1-carboxamide] 0.96 (A) 612.99 Cc ыл. Прим. 57 (2R,3R,4S,5R,6R)-N-(3,4-difluorophenyl)-5-hydroxy-N-((lR,2R)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2 H-pyran-2-carboxamide 0.92 (A) 612.99 58 (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide [1,3-dideoxy-2-O-methyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-(N-(3-chlorophene ηπ)-N-((1 8,2 8)-2-hydroxycyclohexyl))-p-0-galactopyranose-1-carboxamide] 0.97 (A) 611.01 Ref. Ex. 59 (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-N-((lR,2R)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.94 (A) 611.02 60 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2Hpyran-2-carboxamide [1,3-dideoxy-2-O-methyl-3-[4-(3,4,5 -trifluorophenyl)-1H-1,2,3 -triazol-1 -yl]-(3,5-dichloro [(rphenyl)-N-((18,28)-2-hydroxycyclohexyl))-p-0-galactopyranose-1-carboxamide] 1.01 (A) 645.01 Ref. Ex. 61 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((lR,2R)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2 H-pyran-2-carboxamide 0.98 (A) 644.92 62 (2R,ЗR,4S,5R,6R)-4-(4-(3-φτopφenyl)-lH-l,2,3-τpiazol-l-yl)-5-hydroxy-2-(((lS,2S )-2-hydr oxycyclohexyl)(2-(trifluoromethyl)benzyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-p iran-3-yl acetate 1.10 (D) 651.50 63 (2R,ЗR,4S,5R,6R)-4-(4-(3,5-diτopφenyl)-lH-l,2,3-τpiazol-l-yl)-5-hydroxy-2-(((lS ,2S)-2hydr oxycyclohexyl)(2-(trifluoromethyl)benzyl)carbamoyl)-6-(hydroxymethyl)tetrahydro2H-pyran-3-yl acetate 1.13 (D) 669.50 64 (2R,3R,4S,5R,6R)-N-((6^Top-3-MeTOKCHXHHOKcanHH-5-Hn)MeTHn)-5-rmipoKCH-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.11 (E) 691.37 65 (2R,3R,4S,5R,6R)-N-((3-xnopxHHonHH-2-Hn)MeTHn)-5-rHflpoKCH-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.20 (D) 676.32 66 (2R,3R,4S,5R,6R)-4-(4-(3-chloro-4,5-difluorophenyl)-lH-l,2,3-triazol-l-yl)-3,5-dihydroxy-N -((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-KR-(2-(trifluoromethyl)benzyl)tetrahydro-2H-pyran-2-carboxamide 1.13 (D) 661.26 67 (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-lH-l,2,3-triazol-l-yl)-3,5-dihydroxy-N -((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-KR-(2-(trifluoromethyl)benzyl)tetrahydro-2H-pyran-2-carboxamide 1.14 (D) 661.50 68 (2R,ЗR,4S,5R,6R)-4-(4-(4-chloro-3,5-diτopphenyl)-lH-l,2,3-τpiazol-l-yl)-5-hydroxy-2- (((l 8,28)-2-hydroxycyclohexyl)(2-(trifluoromethyl)benzyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate 1.20 (E) 703.39 69 (2R,3R,4S,5R,6R)-4-(4-(4-bromo-3,5-difluorophenyl)-lH-l,2,3-triazol-l-yl)-3,5-dihydroxy-N -((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-(2-(trifluoromethyl)benzyl)tetrahydro-2H-pyran-2-carboxamide 1.14 (D) 706.60

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70 (2R,3R,4 8,5R,6R)-4-(4-(4-6poM-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-M-((1 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-M-(2-(trifluoromethyl)benzyl)tetrahydro2H-pyran-2-carboxamide 1.11 (D) 688.36 71 (2R,3R,4S,5R,6R)-4-(4-(4-xnopTHa3on-2-Hn)-lH-l,2,3-TpHa3on-l-Hn)-3,5-flHrHflpoKCH-N- ((18.2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-KG-(2-(trifluoromethyl)benzyl)tetrahydro-2Hpyran-2-carboxamide 0.96 (E) 632.28 72 (2R,3R,4 8,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazolyl-1-yl)-5-hydro kch-N-((1 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.16 (E) 610.18 73 (2R,3R,4S,5R,6R)-4-(4-(3-φtopphenyl)-lH-l,2,3-triazol-l-yl)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-KR-(3-methoxyphenyl)tetrahydro-2H-pyran2-carboxamide 1.03 (E) 571.30 74 (2R,3R,4 8,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-KG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-p-iran-2-carboxamide [1,3-dideoxy-2-O-methyl-3-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-(N-(3-chloro-5-cyanophenyl)-N-((18,2 8)-2-hydroxycyclohexyl))-p-0-galactopyranose-1-carboxamide] 1.06 (E) 600.27 75 (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3-φτρ-2-methylphenyl)-lH-l,2,3-triazol-1-yl)-5-hydroxy-KH-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.09 (E) 614.28 76 (2R,3R,4 8,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(5-fluoro-2-methoxyphenyl)-1H-1,2,3-triazolyl-1-yl)-5-hydroxy-KG-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.09 (E) 630.20 77 (2R,3R,4 8,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-KG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-p-iran-2-carboxamide 1.08 (E) 644.51 78 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-dichlorophenyl)-lH-l,2,3-triazol-l-yl)-5-hydroxy-KG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-p-iran-2-carboxamide 1.21 (E) 628.05 79 (2R,3R,4S,5R,6R)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-N-((1S,2S)-2hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-K-(3-methoxyphenyl)tetrahydro-2H-pyran-2-carboxamide [1,3-dideoxy-2-O-methyl-3-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-(N-(3-methoxyphenyl)-N-((18,28)-2-hydroxycyclohexyl))-p-0-galactopyranose-1-carboxamide] 1.08 (E) 589.24 80 (2R,3R,4 8,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-KG-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2 H-pyran-2-carboxamide 1.11 (E) 618.28 81 (2R,3R,4 8,5R,6R)-N-(3-cyano-5-methylphenyl)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazolyl-1-yl)-5-hydroxy-KG-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.09 (E) 598.30 82 (2R, 3 R, 4 S, 5R,6R)-N-(3-cyano-5-methoxyphenyl)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazo-1yl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.08 (E) 614.30 83 (2R,3R,4 8,5R,6R)-N-(3-chloro-5-methylphenyl)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-N-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2 H-pyran-2-carboxamide 1.19 (E) 607.30 84 (2R,3R,4S,5R,6R)-N-(3-bromophenyl)-4-(4-(3,5-difluorophenyl)-lH-l,2,3-triazol-l-yl)-5-hydrokch-N-((1 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.15 (E) 639.00 85 (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-4-(4-(3,5-difluorophenyl)-lH-l,2,3-triazol-l-yl)-5-hydrokch-N-((1 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran -2-carboxamide 1.13 (E) 593.20 86 (2R,3R,4S,5R,6R)-N-(3-cyanophenyl)-4-(4-(3,5-difluorophenyl)-lH-l,2,3-triazol-l-yl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyr n-2-carboxamide 1.04 (D) 584.40 87 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-(methoxy-6 ₃ )-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.24 (E) 648.20 88 (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.11 (E) 636.10 89 (2R,3R,4S,5R,6R)-N-(5-chloro-2-methylphenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.22 (E) 625.33 90 (2R,3R,4S,5R,6R)-N-(3-chloro-4-fluorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.19 (E) 629.26 91 (2R,ЗR,4S,5R,6R)-N-(3-chloro-4-(τpiφτopmethyl)φenyl)-5-hydroxy-N-((lS,2S)-2-hydroxy clohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl) tetrahydro-2H-pyran-2- carboxamide 1.26 (D) 679.22

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92 (2K,3K,48,5K,6K)-M-(3-bromo-4-fluorophenyl)-5-hydroxy-M-((18,28)-2-hydroxycyclohexyl)6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.19 (E) 675.11 93 (2R,3R,4S,5R,6R)-N-(6eH3o[d]THa3on-6-iin)-5-riiflpoKCii-N-((18,2S)-2-riiflpoKCimiiKnoreKCiM)6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.05 (D) 634.33 94 (2R,3R,4S,5R,6R)-5-riiflpoKCii-N-((lS,2S)-2-riiflpoKCimiiKnoreKCiin)-6-(riiflpoKCHMeTiin)-3-MeT o kch-N-(2-methylbenzo[d]thiazol-6-yl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tet rahydro-2H-pyran-2-carboxamide 1.09 (E) 648.27 95 (2R,ЗR,4S,5R,6R)-N-(3-chloro-5-(τpiφτopmethyl)φenyl)-5-hydroxy-N-((lS,2S)-2-hydroxy clohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl) tetrahydro-2H-pyran-2- carboxamide 1.26 (E) 679.31 96 (2R,3R,4S,5R,6R)-N-(3-bromo-5-chlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.25 (E) 690.67 97 (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2 H-pyran-2-carboxamide 1.27 (E) 735.05 98 (2R,3R,4S,5R,6R)-N-(3,4-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2Hpyran-2-carboxamide 1.23 (E) 645.79 99 (2R,3R,4S,5R,6R)-N-(3-bromo-4-chlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.24 (E) 691.16 100 (2R,3R,4S,5R,6R)-5-rHflpoKCH-N-((18,2S)-2-rHflpoKCHiiHKnoreKCHn)-6-(rHflpoKCHMeTHn)-3-MeT oxy-N-phenyl-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.04 (E) 577.20 101 (2R,3R,4S,5R,6R)-5-rHflpoKCH-N-((18,2S)-2-rHflpoKCHiiHKnoreKCHn)-6-(rHflpoKCHMeTHn)-3-MeT okch-N-(3-methoxyphenyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2Hpyran-2-carboxamide 1.12 (E) 607.31 102 (2R,3R,4S,5R,6R)-N-(benzo[b]thiophen-6-yl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.18 (E) 633.25 103 (2R,3R,4S,5R,6R)-N-(3-bromophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.17 (D) 657.14 104 (2R,3R,4S,5R,6R)-N-(3-chloro-5-methoxyphenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.19 (E) 641.20 105 (2R,3R,4S,5R,6R)-N-(5-chloro-2-fluorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.17 (E) 629.27 106 (2R,3R,4S,5R,6R)-N-(2,5-flHMeTHn6eH3o[d]THa3on-6-Hn)-5-rHflpoKCH-N-((18,2S)-2-rHflpoKCHiiH clohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl) tetrahydro-2H-pyran-2-carboxamide 1.10 (E) 662.24 107 (2R,3R,4S,5R,6R)-N-(2-xnop6eH3o[d]THa3on-6-Hn)-5-rHflpoKCH-N-((18,2S)-2-rHflpoKCHiiHKnore xyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.18 (E) 668.10 108 (2R,3R,4S,5R,6R)-N-(3-cyano-5-methoxyphenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetragidro-2H-pyran-2-carboxamide 1.10 (E) 632.31 109 (2R,3R,4S,5R,6R)-N-(5-bromo-2-methylphenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.23 (E) 671.15 111 (2R,3R,4S,5R,6R)-N-(4-chlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.18 (D) 611.40 112 (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.15 (E) 681.00 113 (2R,3R,4S,5R,6R)-N-(3-cyano-5-fluorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.10 (E) 620.23 114 (2R,3R,4S,5R,6R)-N-(3-fluorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.11 (E) 595.20 115 (2R,3R,4S,5R,6R)-N-(3-cyanophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-p-iran-2-carboxamide 1.07 (E) 602.24 (2R,3R,4S,5R,6R)-5-rHflpoKCH-N-((18,2S)-2-rHflpoKCHiiHKnoreKCHn)-6-(rHflpoKCHMeTHn)-3-MeT

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116 okcii-N-(3-(trifluoromethyl)phenyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.19 (E) 645.20 117 (2K,3K,48,5K,6K)-M-(3,5-difluorophenyl)-5-hydroxy-M-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2 H-pyran-2-carboxamide 1.15 (D) 613.40 118 (2K,3K,48,5K,6K)-N-(3-fluoro-5-methoxyphenyl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.16 (D) 625.40 119 (2K,3K,48,5K,6K)-M-(3-fluoro-5-methylphenyl)-5-hydroxy-M-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.17 (E) 609.28 120 (2K,3K,48,5K,6K)-M-(3-bromo-5-fluorophenyl)-5-hydroxy-M-((18,28)-2-hydroxycyclohexyl)6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.21 (D) 675.40 121 (2K,3K,48,5K,6K)-M-(3-chloro-5-fluorophenyl)-5-hydroxy-M-((18,28)-2-hydroxycyclohexyl)6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.20 (D) 629.40 122 (2R,3R,4S,5R,6R)-5-rHflpoKCH-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-meth okch-N-(a/-to lyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.15 (E) 591.20 123 (2R,3R,4S,5R,6R)-5-rHflpoKCH-N-((l 8,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-meth o kch-N-(2-methyl-1H-benzo[<1]imidazol-6-yl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.72 (D) 631.40 129 (2R,3R,48,5R,6R)-4-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophen yl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.28 (E) 663.18 130 (2R,3R,48,5R,6R)-4-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,4-difluorophenyl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.19 (D) 629.29 131 (2R,3R,4 8,5R,6R)-N-(6eH3o[d]THa3on-6-nn)-4-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazo l -1-yl)-5-hydroxy-N-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.09 (E) 650.12 132 (2R,3R,48,5R,6R)-4-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.19 (E) 653.29 133 (2R,ЗR,4S,5R,6R)-N-(3-chloro-5-cyanoφenyl)-4-(4-(3-chloro-5-τopφenyl)-lH-l,2,3-τpiazol-l yl)-5-hydroxy-M-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydr o-2H-pyran-2-carboxamide 1.17 (E) 634.83 134 (2R,ЗR,4S,5R,6R)-4-(4-(3-chloro-5-φτopφenyl)-lH-l,2,3-τpiazol-l-yl)-N-(3,4-diφτopφenyl )5-hydroxy-M-((18.2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.17 (E) 611.27 135 (2R,3R,48,5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-lH-l,2,3-triazol-l-yl)-N-(3-cyano-5-fluorophen yl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.13 (E) 618.40 136 (2R,ЗR,4S,5R,6R)-N-(3-bromo-5-φτopφenyl)-4-(4-(3-chloro-5-φτopφenyl)-lH-l,2,3-τpiazol-l yl)-5-hydroxy-M-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydr o-2H-pyran-2-carboxamide 1.22 (E) 673.22 137 (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3-chloro-5-fluorophenyl)-lH-l,2,3-triazolyl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.18 (E) 680.16 138 (2R,3R,4 8,5R,6R)-N-(3-bromophenyl)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazolyl-1-yl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.21 (E) 655.26 139 (2R,3R,4S,5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-lH-l,2,3-triazol-l-yl)-N-(3,5-dichlorophenyl)5-hydroxy-N-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2 H-pyran-2-carboxamide 1.27 (E) 643.20 140 (2R,3R,4S,5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-lH-l,2,3-triazol-l-yl)-N-(3-cyano-5-methylphenyl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.14 (D) 614.29 141 (2R,3R,48,5R,6R)-4-(4-(3-chloro-5-φtopphenyl)-lH-l,2,3-triazol-l-yl)-N-(3-cyano-5-methoxyphenyl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.14 (D) 630.32 142 (2R,3R,4S,5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-lH-l,2,3-triazol-l-yl)-N-(3-cyanophenyl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-p-iran-2-carboxamide 1.10 (D) 600.25 143 (2R,3R,4S,5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-lH-l,2,3-triazol-l-yl)-N-(3-chlorophenyl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.20 (E) 609.20 144 (2R,3R,4S,5R,6R)-4-(4-(3-bromo-5-φtopphenyl)-lH-l,2,3-triazol-l-yl)-N-(3,5-dichlorophenyl)5-hydroxy-N-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2 1.28 689.18

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N-pyran-2-carboxamide (D) 145 (2R,3R,4 8,5R,6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophen yl)-5-hydroxy-kG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.19 (D) 680.22 146 (2R,3R,4 8,5R,6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-cyano-5-methylphenyl)-5-hydroxy-kG-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.16 (E) 659.47 147 (2R,3R,48,5R,6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-fluorophen yl)-5-hydroxy-kG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.24 (D) 673.30 148 (2R,3R,48,5R,6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-cyanophenyl)-5-hydroxy-kG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-p-iran-2-carboxamide 1.11 (D) 646.16 149 (2R,3R,48,5R,6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chlorophenyl)-5-hydroxy-kG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.21 (D) 655.26 150 (2R,3R,48,5R,6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-cyano-5-methoxyphenyl)-5-hydroxy-kG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.15 (E) 676.18 151 (2R,3R,4 8,5R,6R)-4-(4-(4-6poM-3,5-difluorophenyl)-1H-1,2,3-triazole-1-ηπ)-Ν-(3,5-dichlorophen yl)-5-hydroxy-kG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.29 (E) 707.06 152 (2R,ЗR,4S,5R,6R)-4-(4-(4-bromo-3,5-diφτopφenyl)-lH-l,2,3-τpiazol-l-yl)-N-(3,4 -diφτopφen yl)-5-hydroxy-kG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.20 (D) 675.11 153 (2R,ЗR,4S,5R,6R)-N-(benzo[d]τthiazol-5-yl)-4-(4-(4-bromo-3,5-diφτopφenyl)-lH-l,2,3 -τpiazol -1 -yl)-5-hydroxy-kg-(( 18.2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.10 (E) 695.90 154 (2R,3R,4 8,5R,6R)-4-(4-(4-6poM-3,5-difluorophenyl)-1H-1,2,3-triazole-1-ηπ)-Ν-(3-chloro-5-cyanophenyl)-5-hydroxy-kG-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.21 (E) 698.24 155 (2R,3R,4 8,5R,6R)-4-(4-(4-6poM-3,5-difluorophenyl)-1H-1,2,3-triazole-1-ηπ)-Ν-(3-cyano-5-fluoro pphenyl)-5-hydroxy-kG-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.16 (E) 681.66 156 (2R,ЗR,4S,5R,6R)-4-(4-(4-chloro-3,5-diφτopφenyl)-lH-l,2,3-τpiazol-l-yl)-N-(3,5 -dichlorophene yl)-5-hydroxy-kG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.29 (E) 662.30 157 (2R,3R,48,5R,6R)-4-(4-(4-xnop-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-kG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.19 (D) 652.98 158 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-lH-l,2,3-triazol-l-yl)-5-hydroxy-kG-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.26 (D) 642.43 159 (2R,ЗR,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3,5-diφτop-4-methylphenyl)-lH-l,2,3-τpia zol-1-yl)-5-hydroxy-kg-((18.2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.16 (E) 632.22 160 (2R,3R,4 8,5R,6R)-N-(3-bromo-5-fluorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-kG-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.23 (D) 671.40 161 (2R,ЗR,4S,5R,6R)-N-(3-cyano-5-φτopφenyl)-4-(4-(3,5-diφτop-4-methylphenyl)-lH-l,2,3-τpia zol-1-yl)-5-hydroxy-kg-((18.2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.12 (E) 616.36 162 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-lH-l,2,3-triazol-l-yl)-5-hydroxy-kg-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-p-iran-2-carboxamide 1.19 (D) 627.30 163 (2R,3R,4S,5R,6R)-4-(4-(4-bromo-3-fluorophenyl)-lH-l,2,3-triazol-l-yl)-N-(3,5-dichlorophenyl)5-hydroxy-kG-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2 H-pyran-2-carboxamide 1.25 (E) 689.10 164 (2R,3R,4S,5R,6R)-4-(4-(4-bromo-3-fluorophenyl)-lH-l,2,3-triazol-l-yl)-N-(3,4-difluorophenyl)5-hydroxy-kG-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2 H-pyran-2-carboxamide 1.16 (D) 657.21 165 (2R,3R,4 8,5R,6R)-4-(4-(4-6poM-3-fluorophenyl)-1H-1,2,3-triazole-1-ηπ)-Ν-(3-chloro-5-cyanophen yl)-5-hydroxy-kG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.16 (E) 680.27 166 (2R,3R,48,5R,6R)-4-(4-(3,4-dichloro-5-fluorophenyl)-1H-1,2,3-triazo l-1-yl)-N-(3,5-dichlorophen yl)-5-hydroxy-kG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.34 (E) 679.13 167 (2R,ЗR,4S,5R,6R)-4-(4-(3,4-dichloro-5-τopφenyl)-lH-l,2,3-τpiazol-l-yl)-N-(3,4 -diφτopφen yl)-5-hydroxy-kG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.24 (D) 646.27

- 63 048291

168 (2R,3R,4 8,5R,6R)-N-(6en3O [<1]thiazol-6-yl)-4-(4-(3,4-dichloro-5-fluorophenyl)-1H-1,2 ,3-triazo l -1-yl)-5-hydroxy-M-(( 18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.14 (E) 667.44 169 (2R,3R,4 8,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3,4-dichloro-5-fluorophenyl)-1H-1,2,3-triazolyl-1-yl)-5-hydroxy-KG-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.24 (E) 669.18 170 (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3-φτop-4-methylphenyl)-lH-l,2,3-triazol-1-yl)-5-hydroxy-KH-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.11 (E) 614.32 171 (2R,ЗR,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(2,3-diφτop-4-methylphenyl)-lH-l,2,3-τpia zol-1-yl)-5-hydroxy-KG-((18.2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.14 (E) 632.25 172 2-(((2R,3R,4S,5R,6R)-2-((3-chloro-5-cyanophenyl)((lS,2S)-2-hydroxycyclohecosil)carbamoyl )-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tet radihydro-2H-pyran- 3-yl)hydroxy)acetic acid 1.00 (D) 677.30 173 (2R,ЗR,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(2,3-diφτop-4-methylphenyl)-lH-l,2,3-τpia zol-1-yl)-5-hydroxy-KG-((18.2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-(2-morpho-li no-2-oxoethoxy)tetrahydro-2H-pyran-2-carboxamide 1.03 (E) 745.43 174 (2R,3R,48,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(4,5-difluoro-2-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-KH-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.13 (E) 648.40 175 (2R,3R,4 8,5R,6R)-4-(4-(4-6poM-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-KR-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.19 (E) 698.20 176 (2R,3R,4 8,5R,6R)-4-(4-(4-6poM-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-cyano-5-fluoro pphenyl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.15 (E) 682.27 177 (2R,3R,4 8,5R,6R)-4-(4-(4-6poM-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophen yl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.28 (E) 706.84 178 (2R,3R,48,5R,6R)-4-(4-(4-xnop-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.18 (E) 652.26 179 (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3-fluorophenyl)-lH-l,2,3-triazol-l-yl)-N-(3,5-dichlorophenyl)5-hydroxy-N-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2 H-pyran-2-carboxamide 1.24 (E) 645.06 180 (2R,ЗR,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3-φτop-4-(τpiφτopmethyl)φenyl)-lH-l,2,3-τpi azol-1-yl)-5-hydroxy-M-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.28 (E) 677.80 181 (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(4-cyano-3-fluorophenyl)-lH-l,2,3-triazol-1-yl)-5-hydroxy-N-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.07 (D) 625.33 182 (2R,3R,48,5R,6R)-4-(4-(4-xnop-2,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.18 (E) 653.02 183 (2R,3R,4 8,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-difluoro-5-methoxyphenyl)-1H-1,2,3-triazolyl-1-yl)-5-hydroxy-N-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.21 (E) 657.90 184 (2R,3R,48,5R,6R)-4-(4-(4-xnop-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.11 (E) 646.90 185 (2R,3R,48,5R,6R)-4-(4-(4-xnop-3-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro p-5-cyanophenyl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.26 (D) 700.30 186 (2R,3R,4 8,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-N-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2 H-pyran-2-carboxamide 1.20 (E) 651.88 187 (2R,3R,4 8,5R,6R)-N-(3-cyano-5-fluorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazole-Nyl)-5-hydroxy-N-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2 H-pyran-2-carboxamide 1.16 (E) 634.33 188 (2R,3R,4S,5R,6R)-N-(3-cyano-5-methoxyphenyl)-4-(4-(3,4-dichlorophenyl)-lH-l,2,3-triazolyl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.16 (D) 646.93 189 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-lH-l,2,3-triazol-l-yl)-5-hydroxy-N-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 1.30 (D) 661.30 190 (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3-φτρ-5-methylphenyl)-lH-l,2,3-triazol-1-yl)-5-hydroxy-N-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.92 (D) 614.40 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((lS,2S)-2-hydroxycyclohexyl)-6-(g

- 64 048291

191 hydroxymethyl)-3-methoxy-4-(4-(2-methylbenzo[<1]thiazol-6-yl)-1H-1,2,3-triazol-1-yl)tetrag hidro-2H-pyran-2-carboxamide 1.11 (E) 664.00 192 (2R, 3R, 4 S, 5R, 6R)-N-(3,5-dichlorophenyl)-4-(4-(4-fluoronaphthalen- 1-yl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-KG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2 H-pyran-2-carboxamide 1.25 (E) 661.00 193 (2R,3R,4S,5R,6R)-4-(4-(4-chlorothiazol-2-yl)-lH-l,2,3-triazol-l-yl)-N-(2,3-dimethylphenyl)-5hydroxy-KR-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2Hpyran-2-carboxamide 0.97 (E) 600.10 194 (2R,3R,4S,5R,6R)-5-rHflpoKCH-N-((18,2S)-2-rHflpoKCHnHKnoreKCHn)-6-(rHflpoKCHMeTHn)-3-MeT oxy-N-(pyridin-2-yl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.01 (E) 578.20 197 (2R,3R,4S,5R,6R)-5-rHflpoKCH-N-((18,2S)-2-rHflpoKCHnHKnoreKCHn)-6-(rHflpoKCHMeTHn)-3-MeT oxy-N-(naphthalen-2-yl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-p iran-2-carboxamide 1.00 (A) 627.15 198 (2R,3R,4S,5R,6R)-5-rHflpoKCH-N-((18,2S)-2-rHflpoKCHnHKnoreKCHn)-6-(rHflpoKCHMeTHn)-3-MeT oxy-N-(naphthalen-1-yl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-p iran-2-carboxamide 0.99 (A) 627.14 199 (2 R.3 R.4S.5 R.6R)-N-( 1.5-dnmstnl-1 N-pyrazol-Z-nl)-5-g11droxn-M-(( 1 8.2 8)-2-g11dro1<C11tsnl ohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2 -carboxamide 0.88 (A) 595.14 200 (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3-φτop-4-methylphenyl)-lH-l,2,3-triazol-1-yl)-5-hydroxy-KH-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.96 (A) 657.91 201 (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(4-chlorophenyl)-lH-l,2,3-triazol-l-yl)-5-hydroxy-KG-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-p irani-2-carboxamide 0.92 (A) 616.02 202 (2R,3R,4S,5R,6R)-4-(4-(4-bromophenyl)-lH-l,2,3-triazol-l-yl)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-KH-((18,28)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-p-iran-2-carboxamide 0.95 (A) 661.95 205 (2R,3R,4S,5R,6R)-4-(4-(4-cyano-3-fluorophenyl)-lH-l,2,3-triazol-l-yl)-N-(3-cyano-5-methoxyphenyl)-5-hydroxy-KH-((18,2 8)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.91 (A) 620.99 206 (2R,ЗR,4S,5R,6R)-4-(4-(4-cyano-3-φτopphenyl)-lH-l,2,3-τpiazol-l-yl)-N-(3-cyano-5 -methylenyl)-5-hydroxy-KG-((1S, 2 S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.91 (A) 605.00 207 (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycycloheptyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide 1.00 (A) 625.08 208 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycycloheptyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2 H-pyran-2-carboxamide 1.04 (A) 659.00

Example 195:

2-(((2R,3R,4S,5R,6R)-2-((3,5-dichlorophenyl)((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-5-hydroxy6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetic acid.

To a solution of intermediate 102 (373 mg, 0.5 mmol, 1 equiv.) in DCM (3 mL) at rt was added 2 M TFA (1.20 mL), and the reaction mixture was stirred at rt for 3 h. The solvent was evaporated. The product was isolated as the TFA salt. LCMS (A): t _R = 0.90 min; [M+H]+ = 689.18.

Example 196:

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-3-(2-hydroxyethoxy)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide

To a solution of Example 195 (54 mg, 0.067 mmol, 1 equiv.) in THF (3 mL) at 0 °C was added 2 _{M BH3Me2S} in THF (0.14 mL, 4.2 equiv.), and the reaction mixture was stirred at rt for 24 h. MeOH (1 mL) and sat. aq. NH4O (15 mL) were added, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with sat. aq. NaCl (10 mL) and evaporated. The product was purified by LC-MS (I). The product was isolated as a colorless solid. LCMS (A): t _R = 0.90 min; [M+H] ⁺ = 689.17.

Example 124:

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-(2-morpholino-2-oxoethoxy)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide.

To a solution of Example 195 (50 mg, 0.049 mmol, 1 equiv) in DMF (1 mL) at rt were added HATU (0.040 mL, 2 equiv), morpholine (9 µL, 2 equiv) and DIPEA (42 µL, 5 equiv) and the reaction mixture was stirred at rt for 0.5 h. The reaction mixture was purified by LC-MS (I). The product was isolated as a colourless solid. LCMS (A): t _R = 0.95 min; [M+H]+ = 757.99.

The following compounds are prepared by analogy with Example 124 from the compound of Example 195 and the corresponding amine.

Example 125:

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)-2-oxoethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide.

LCMS (A): t _R =0.86 min; [M+N] ⁺ =758.19.

Example 126:

- 65 048291 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6(hydroxymethyl)-3-(2-((C)-3-hydroxypyrrolidin-1-yl)-2-oxoethoxy)-4-(4-(3.4.5-trifluorophenyl)-1H1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide.

LCMS (A): t _R =0.86 min; [M+N]+=758.18.

Example 127:

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6(hydroxymethyl)-3-(2-(4-hydroxypiperidin-1-yl)-2-oxoethoxy)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide.

Stage 1:

(2R,3R,4S,5R,6R)-3-(2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-oxoethoxy)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide was prepared from the compound of Example 195 and 4-((tert-butyldimethylsilyl)oxy)piperidine according to the procedure described for Example 124.

LCMS (A): t _R =1.23 min; [M+N]+=886.36.

Step 2: To a solution of the above silyl ether (28 mg, 0.032 mmol) in dioxane (3 mL) and water (1.45 mL) was added TFA (0.4 mL) and the reaction mixture was stirred at rt for 1.5 h. Ethyl acetate (10 mL) and sat. aq. _NaHCO3 (15 mL) were added to maintain pH 8, the aqueous phase was separated and extracted twice with ethyl acetate. The combined organic layers were evaporated. The product was purified by LC-MS (I). The product was isolated as a colorless solid. LCMS (A): t _R = 0.88 min; [M+H]+ = 772.17.

Example 128:

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-3-(2-(3-hydroxyazetidin-1-yl)-2-oxoethoxy)N-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1yl)tetrahydro-2H-pyran-2-carboxamide.

This compound is obtained by a 2-step method similar to example 127. LCMS (A): t _R = 0.85 min; [M+H]+ = 744.09.

Example 203:

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-morpholinophenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-N((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2carboxamide

Step 1: To a solution of intermediate 6a (0.100 mg, 0.226 mmol, 1 equiv.), K ₂ CO ₃ (0.156 mg, 1.13 mmol) in DMSO (4 mL) at rt was added morpholine (0.100 mL, 1.13 mmol) and the reaction mixture was stirred at 130 °C for 40 h. Morpholine (0.100 mL) was added and the mixture was stirred for 5 days. Ethyl acetate and saturated aqueous NH4Cl were added to maintain pH 6-7, the aqueous phase was separated and extracted twice with ethyl acetate. The combined organic layers were evaporated. The product was purified by LC-MS (I). The product was isolated as a colorless solid. LCMS (A): t _R = 0.86 min; [M+H] ⁺ =511.03.

Step 2: Amide coupling of the acid from step 1 with amine 56 is performed according to procedure B.

LCMS (A): t _R =1.42 min; [M+N]+=866.09.

Step 3: The product from Step 2 is deprotected according to the procedure described for Example 127, Step 2.

LCMS (A): t _R =1.00 min; [M+N]+=712.03.

Example 204:

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-((3-hydroxypropyl)amino)phenyl)-1H1,2,3-triazol-1-yl)-5-hydroxy-Na((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide.

Example 204 is prepared in analogy to Example 203, using azetidine instead of morpholine in step 1.

LCMS (A): t _R =0.93 min; [M+N]+=700.01.

II. Biological analyses.

Determination of inhibitory activity of compounds (IC ₅₀ )

The inhibitory activity of compounds is determined in competitive binding assays. This spectrophotometric assay measures the binding of biotinylated human Gal-3 (hGal-3) or human Gal-1 (hGal-1), respectively, to a microplate-adsorbed glycoprotein, asialofetuin (ASF) (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 have been replaced with serines can be used.

Briefly, compounds are serially diluted in DMSO (working dilutions). ASF-coated 384-well plates are supplemented with 22.8 µl/well of biotinylated hGal-3 or hGal-1 in assay buffer (i.e., 300-1000 ng/ml biotinylated hGal-3 or hGal-1), and 1.2 µl of compound working dilutions are added to the mixture and mixed.

- 66 048291

The plates are incubated for 3 h at 4°C, then washed with cold assay buffer (3 x 50 µl) and incubated for 1 h with 25 µl/well of streptavidin-peroxidase solution (diluted in assay buffer to 80 ng/ml) at 4°C followed by additional washing steps with assay buffer (3 x 50 µl). Finally, 25 µl/well of ABTS substrate are added. After 30-45 min, the OD (410 nm) is recorded and the IC50 values are calculated.

The calculated IC50 values may fluctuate depending on the day of the assay. Such fluctuations are known to those skilled in the art. IC50 values from several measurements are given as average values.

Table 2

Activity against hGal-3 (IC ₅₀ in μM)

Example Gal-3 1C ₅ o [μM] Example Gal-3 IC50 [μM] Example Gal-3 IC50 [μM] Example Gal-3 IC50 [μM] 1 0.154 2 0.301 3 0.471 4 0.677 5 0.174 6 0.071 7 0.057 8 0.169 9 0.147 10 0.122 11 0.055 12 0.052 13 0.255 14 0.564 15 0.419 16 0.476 17 0.281 18 0.179 19 0.403 20 0.352 21 0.112 22 0.167 23 0.403 24 0.294 25 0.280 26 0.159 27 0.264 28 0.165 29 0.232 30 0.575 31 0.311 32 0.122 33 0.127 34 0.069 35 0.210 36 0.231 37 0.337 38 0.207 39 0.224 40 0.199 41 0.464 42 0.212 43 0.076 44 0.179 45 0.421 46 0.160 47 0.151 48 0.344 49 0.129 50 0.053 51 0.058 52 0.191 53 0.868 54 0.020 55 0.031 56 0.042 Ref. Note 57 1.37 58 0.021 Ref. Note 59 0.679 60 0.016 Ref. Note 61 0.511 62 0.141 63 0.138 64 0.123 65 0.196 66 0.095 67 0.042 68 0.044 69 0.084 70 0.090 71 0.143 72 0.031 73 0.069 74 0.044 75 0.050 76 0.042 77 0.037 78 0.026 79 0.062 80 0.025 81 0.073 82 0.017 83 0.026 84 0.025 85 0.035 86 0.111 87 0.007 88 0.013 89 0.010 90 0.026 91 0.147 92 0.018 93 0.020 94 0.031 95 0.016 96 0.014 97 0.013 98 0.033 99 0.032 100 0.073 101 0.036 102 0.043 103 0.025 104 0.019 105 0.014 106 0.056 107 0.317 108 0.024 109 0.017 111 0.158 112 0.008 113 0.018 114 0.049 115 0.025 116 0.026 117 0.038 118 0.026 119 0.030 120 0.021 121 0.019 122 0.043 123 0.085 124 0.012 125 0.009 126 0.016 127 0.012 128 0.013 129 0.032 130 0.053 131 0.034 132 0.013

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133 0.022 134 0.063 135 0.052 136 0.025 137 0.024 138 0.043 139 0.027 140 0.033 141 0.056 142 0.077 143 0.024 144 0.061 145 0.018 146 0.050 147 0.071 148 0.081 149 0.085 150 0.062 151 0.037 152 0.062 153 0.025 154 0.023 155 0.024 156 0.014 157 0.019 158 0.015 159 0.012 160 0.011 161 0.025 162 0.032 163 0.018 164 0.058 165 0.034 166 0.022 167 0.064 168 0.025 169 0.014 170 0.018 171 0.012 172 0.011 173 0.009 174 0.040 175 0.013 176 0.015 177 0.013 178 0.026 179 0.010 180 0.011 181 0.029 182 0.035 183 0.009 184 0.029 185 0.232 186 0.017 187 0.037 188 0.044 189 0.011 190 0.017 191 0.041 192 0.021 193 0.143 194 0.011 195 0.009 196 0.021 197 0.097 198 0.117 199 0.321 200 0.008 201 0.020 202 0.021 203 0.024 204 0.021 205 0.087 206 0.126 207 0.049 208 0.062

Table 3

Activity against hGal-1 (IC50 in μM)

Example Gal-1 1C ₅₀ [μM] Example Gal-1 1C ₅₀ [μM] Example Gal-1 1C ₅₀ [μM] Example Gal-1 IC50 |μM| 1 6.495 2 22.8 3 >100 4 >100 5 18.2 6 1.920 7 1.235 8 2.49 9 1.64 10 1.69 11 0.497 12 0.497 13 7.25 14 40.6 15 3.181 16 28.3 17 23.1 18 11.6 19 37.6 20 11.7 21 10.7 22 86.6 23 22.7 24 25.9 25 4.92 26 0.338 27 3.20 28 3.97 29 4.405 30 10.4 31 1.48 32 0.905 33 0.962 34 0.863 35 1.63 36 1.03 37 5.77 38 1.68 39 2.96 40 4.67 41 12.350 42 34.5 43 2.67 44 0.974 45 1.43 46 0.497 47 1.04 48 2.24 49 1.94 50 7.58 51 11.2 52 1.60 53 10.8 54 2.66 55 0.828 56 0.417 Ref. Note 57 13.2 58 0.729 Ref. Note 59 6.65 60 0.665 Ref. Note 61 6.41 62 0.939 63 1.020 64 0.980 65 6.770 66 0.534 67 0.610 68 1.170 69 2.570 70 0.615 71 1.310 72 0.058 73 1.545 74 0.161 75 0.259 76 0.901 77 0.140 78 0.192 79 2.110 80 0.383

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81 1.320 82 1.160 83 2.320 84 1.900 85 1.690 86 1.850 87 0.173 88 0.157 89 0.076 90 0.358 91 1.540 92 0.340 93 0.163 94 0.254 95 0.398 96 0.403 97 0.266 98 0.169 99 0.377 100 18.630 101 0.800 102 1.240 103 0.238 104 1.185 105 0.136 106 0.143 107 1.200 108 1.575 109 0.100 111 4.220 112 0.150 113 0.520 114 2.010 115 1.000 116 1.950 117 0.978 118 1.480 119 1.830 120 0.422 121 0.449 122 4.750 123 5.880 124 0.226 125 0.134 126 0.134 127 0.181 128 0.177 129 0.141 130 0.924 131 0.224 132 0.140 133 0.184 134 0.761 135 0.270 136 0.323 137 0.318 138 0.935 139 0.860 140 0.671 141 1.560 142 1.670 143 1.410 144 0.726 145 0.218 146 0.751 147 0.530 148 0.343 149 0.707 150 0.671 151 1.130 152 3.140 153 1.079 154 0.957 155 1.505 156 1.380 157 0.709 158 0.798 159 0.528 160 1.765 161 2.170 162 0.134 163 1.275 164 1.940 165 0.792 166 1.340 167 1.240 168 0.672 169 0.333 170 0.569 171 0.238 172 0.421 173 0.5089 174 0.750 175 0.386 176 0.682 177 0.852 178 0.123 179 0.591 180 1.200 181 0.618 182 0.267 183 0.516 184 0.282 185 1.370 186 0.210 187 0.359 188 1.120 189 0.257 190 0.239 191 1.140 192 1.140 193 0.605 194 2.740 195 0.096 196 0.161 197 6.830 198 >100 199 18.000 200 0.158 201 0.242 202 0.341 203 0.678 204 0.273 205 1.820 206 1.340 207 1.790 208 0.586

Claims (14)

1. Compound of formula (I) where n is an integer 1 or 2; Ar ¹ is aryl which is mono-, di-, tri-, tetra- or pentasubstituted, wherein the substituents are independently selected from halogen; methyl; cyano; methoxy; trifluoromethyl; trifluoromethoxy; NR ⁿ¹¹ R ⁿ¹² , wherein R ^N11 is hydrogen and RN ¹² is hydroxy-C ₂ .3-alkyl, or RN ¹¹ and RN ¹² together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl selected from morpholin-4-yl, azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl, wherein said 4- to 6-membered heterocyclyl is unsubstituted or monosubstituted with hydroxy; R ¹ is hydroxy; C1.3-alkoxy; -O-CO-C ₁ . ₃ -alkyl; - 69 048291 - O-CH2-CH2-OH; or - O-CH2-CO-R ^1X , where R ^1X is - hydroxy; morpholin-4-yl; or - NRN ²¹ RN ²² , where RN ²¹ and RN ²² together with the nitrogen atom to which they are attached form a 4-6-membered heterocyclyl selected from azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl, wherein said 4-6-membered heterocyclyl is monosubstituted with hydroxy; L represents a direct bond, methylene, or ethylene; and Ar ² is phenyl or a 5- or 6-membered heteroaryl selected from furanyl, thiophenyl, pyrrolyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl and pyrimidinyl, wherein said phenyl or 5- or 6-membered heteroaryl is independently unsubstituted or mono-, di- or trisubstituted; wherein the substituents are independently selected from _C1-6 alkyl, _C3-6 cycloalkyl, -CH _{2 -C3-6} cycloalkyl, _C1-3 fluoroalkyl, _C1-3 fluoroalkoxy, _C1-3 alkoxy, halogen, morpholin-4-yl, amino, ethynyl and cyano; A 9-membered bicyclic heteroaryl selected from indolyl, benzothiophenyl, benzothiazolyl and benzoimidazolyl; or a 10-membered bicyclic heteroaryl selected from quinolinyl and quinoxalinyl, wherein said 9- or 10-membered bicyclic heteroaryl is independently unsubstituted, mono- or disubstituted, wherein the substituents are independently selected from methyl, methoxy and halogen; or naphthyl; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1; wherein Ar ¹ is phenyl which is mono-, di- or trisubstituted, wherein the substituents are independently selected from halogen, methyl, cyano and methoxy; wherein at least one of said substituents is attached at the meta or para position of said phenyl, wherein, if present, the substituent at the para position is preferably selected from halogen, methyl, cyano and methoxy; and wherein, if present, the substituent at the meta position is preferably halogen; or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1; wherein Ar ¹ is a phenyl group of the structure (Ag-1), wherein R ^m2 is a halogen; and Rp represents hydrogen, halogen, methyl, cyano or methoxy; or a pharmaceutically acceptable salt thereof. 4. A compound according to any one of claims 1 to 3; wherein R ¹ is methoxy; or a pharmaceutically acceptable salt thereof. 5. A compound according to any one of paragraphs 1-4; wherein L represents a direct bond; or a pharmaceutically acceptable salt thereof. 6. A compound according to any one of claims 1 to 5; wherein Ar ² is phenyl which is unsubstituted, mono- or disubstituted, wherein the substituents are independently selected from C _1-4 -alkyl, C _1-3 -fluoroalkyl, C _1-3 -alkoxy, halogen, ethynyl and cyano; or 5- or 6-membered heteroaryl selected from furanyl, thiophenyl, pyrrolyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl and pyrimidinyl, wherein said 5- or 6-membered heteroaryl is independently unsubstituted, mono- or disubstituted, wherein the substituents are independently selected from C _1-4 -alkyl, -CH ₂ -C _3-6 -cycloalkyl, C _1-3 -fluoroalkyl, C _1-3 -alkoxy, halogen, morpholin-4-yl and amino; or a pharmaceutically acceptable salt thereof. 7. A compound according to any one of claims 1-5; wherein Ar ² is phenyl which is mono- or disubstituted, wherein the substituents are independently selected from C _1-3 fluoroalkyl and halogen; or 5- or 6-membered heteroaryl selected from furanyl, thiophenyl, pyrrolyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl and pyrimidinyl, wherein said 5- or 6-membered heteroaryl is independently mono- or disubstituted, wherein the substituents are independently selected from C 1-3 -alkyl and C _1-3 -fluoroalkyl; or a pharmaceutically acceptable salt thereof. 8. A compound according to any one of paragraphs 1-4; wherein the fragment -L-Ar ² is: - 70 048291 - 71 048291 or its pharmaceutically acceptable salt. - 72 048291 9. A compound according to any one of paragraphs 1-8; where n is the integer 1; or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 1, wherein said compound is: (2R,3R,4S,5R,6R)-N-benzyl3,5-dihydroxy-N-((3,4,5-trifluorophenyl)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chlorobenzyl)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-1-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-ethynylbenzyl)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-1-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-phenethyl-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(4-chlorobenzyl)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-1-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(2-chlorobenzyl)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-1-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-(2-(trifluoromethyl)benzyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3-chloropyridin-4-yl)methyl)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((2(trifluoromethyl)pyridin-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((4(trifluoromethyl)pyridin-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N(2-(trifluoromethyl)benzyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(2-chlorobenzyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-1-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((3(trifluoromethyl)pyridin-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((2-methyl-1H-imidazol-4-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-((2-amino-4-chlorothiazol-5-yl)methyl)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl )-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-(isoxazol-4-ylmethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((5-chlorofuran-2-yl)methyl)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-(isothiazol-4-ylmethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((1-methyl-1H-imidazol-4-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-((2-bromothiazol-4-yl)methyl)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((2-morpholinothiazol-5-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-((5-chlorothiophen-2-yl)methyl)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((5-chlorothiazol-2-yl)methyl)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl) -6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxy - 73 048291 samid; (2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((1-methyl-1H-p irazol-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N((3-(trifluoromethyl)pyridin-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N((2-(trifluoromethyl)pyridin-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((4(1-fluoromethyl)pyrimidin-5-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((4,6-dimethoxypyrimidin-5-yl)methyl)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((4methylpyrimidin-5-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N((5-methyl-1H-imidazol-4-yl)methyl)-4-(4-(3,4,5-1-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((4-chloroisothiazol-5-yl)methyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N((1-methyl-1H-pyrazol-5-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N((3-methyl thiophen-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N((1-methyl-1H-pyrrol-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran2-carboxamide; (2R,3R,4S,5R,6R)-N-((3-chlorothiophen-2-yl)methyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6(hydroxy Simyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N((4-methyl thiazol-5-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N((1-methyl-1H-imidazol-2-yl)methyl)-4-(4-(3,4,5-1-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N((2-methyl thiophen-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N(2-methoxybenzyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(2,6-dimethoxybenzyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((1methyl-1H-im idazol-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran2-carboxamide; (2R,3R,4S,5R,6R)-3,5-dihydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((1methyl-1H-imidazol-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-2-(((1S,2S)-2-hydroxycyclohexyl)((1-methyl-1H-pyrazol-5-yl)methyl)carbamoyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-3-yl acetate; (2R,3R,4S,5R,6R)-N-((1-ethyl-1H-pyrazol-5-yl)methyl)-5-hydroxy-N-((1S,2S)-2 - 74 048291 hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-N-((1-isopropyl-1H-pyrazol-5-yl)methyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((1-(cyclopropylmethyl)-1H-pyrαzol-5-yl)methyl)-5-hydroxy-N-((1S,2S)-2hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((1,3-dimethyl-1H-pyrαzol-5-yl)methyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N((1-methyl-1H-indol-2-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-2-(((1S,2S)-2-hydroxycyclohexyl)((1-methyl-1H-pyrazol-5-yl)methyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3 yl acetate; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-2-(((1S,2S)-2hydroxycyclohexyl)((1-methyl-1H-pyrazol-5-yl)methyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2Hpyran-3-yl acetate; (2R,3R,4S,5R,6R)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-Ίriazol-1-yl)-5-hydroxy-2- (((1S,2S)-2hydr oxycyclohexyl)((1-methyl-1H-pyrazol-5-yl)methyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2Hpyran-3-yl acetate; (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triαzol-1-yl)-5-hydroxy-2-(((1S,2S)-2-hydroxycyclohexyl)((1-methyl-1H-pyrazol-5-yl)methyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate; (2R,3R,4S,5R,6R)-N-(3-chlorobenzyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-1-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-Ίriazol-1-yl)-5-hydroxy-2- (((1S,2S)-2hydroxycyclohexyl)(2-(trifluoromethyl)benzyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate; (2R,3R,4S,5R,6R)-5-hydroxy-2-(((1S,2S)-2-hydroxycyclohexyl)(2-(trifluoromethyl)benzyl)carbamoyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl acetate; (2R,3R,4S,5R,6R)-N-(3,4-difluorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-1-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triαzol-1-yl)-5-hydroxy-2-(((1S,2S)-2-hydroxycyclohexyl)(2-(trifluoromethyl)benzyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate; (2R,3R,4S,5R,6R)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-2-(((1S,2S)-2-hydroxycyclohexyl)(2-(trifluoromethyl)benzyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate; (2R,3R,4S,5R,6R)-N-((6-fluoro-3-methoxyquinoxalin-5-yl)methyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3-chloroquinolin-2-yl)methyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-N-((1S,2S)2-hydroxycyclohexyl)-6-(hydroxymethyl)-H-(2-(trifluoromethyl)benzyl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-N-((1S,2S)2-hydroxycyclohexyl)-6-(hydroxymethyl)-H-(2-(trifluoromethyl)benzyl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-2-(((1S,2S)-2hydroxycyclohexyl)(2-(trifluoromethyl)benzyl)carbamoyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate; - 75 048291 (2R,3R,4S,5R,6R)-4-(4-(4-bromo-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-N((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-H-(2-(trifluoromethyl)benzyl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-N-((1S,2S)-2hydroxycyclohexyl)-6-(hydroxymethyl)-H-(2-(tri((fluoromethyl)benzyl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chlorothiazol-2-yl)-1H-1,2,3-Ίriazol-1-yl)-3,5-dihydroxy-N- ((1S,2S)-2hydr oxycyclohexyl)-6-(hydroxymethyl)-H-(2-(tri(((()tormethyl)benzyl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-N((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N-(3-methoxyphenyl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxyN-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3-fluoro-2-methylphenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(5-fluoro-2-methoxyphenyl)-1H-1,2,3-triazol-1-yl)5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxyN-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxyN-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-H-(3-methoxyphenyl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-methylphenyl)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-methoxyphenyl)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-methylphenyl)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromophenyl)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-N((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-N((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyanophenyl)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-N((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-(methoxy-3)-4-(4-(3,4,5-trifluorophenyl)-III-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(5-chloro-2-methylphenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-4-fluorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-4-(trifluoromethyl)phenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-4-fluorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2 - 76 048291 carboxamide; (2R,3R,4S,5R,6R)-N-(benzo[d]thiazol-6-yl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N(2-methylbenzo[thiazol-6-yl)-4-(4-C3,4,5-tri((methyl)enyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-(trifluoromethyl)phenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-chlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-1riazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,4-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-4-chlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-Nphenyl-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N(3-methoxyphenyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(benzo[b]thiophen-6-yl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-1-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-methoxyphenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(5-chloro-2-fluorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(2,5-dimethylbenzo[d]thiazol-6-yl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(2-chlorobenzo[d]thiazol-6-yl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-methoxyphenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(5-bromo-2-methylphenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(4-chlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-fluorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-fluorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyanophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N - 77 048291 (3-(trifluoromethyl)phenyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-difluorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-fluoro-5-methoxyphenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-fluoro-5-methylphenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-fluorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-fluorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N(m-tolyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N(2-methyl-1H-benzo[imidazol-6-yl)-4-(4-(3.4.5-tri(|)tor(|)enyl)-1H-1.2.3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,4-difluorophenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(benzo[d]thiazol-6-yl)-4-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophenyl)5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,4-difluorophenyl)-5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-cyano-5-fluorophenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-fluorophenyl)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromophenyl)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxyH-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-cyano-5-methylphenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-cyano-5-methoxyphenyl)5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-cyanophenyl)-5-hydroxyH-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; - 78 048291 (2R,3R,4S,5R,6R)-4-(4-(3-chloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chlorophenyl)-5-hydroxyN-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrafluoro-2H-pyran-2-carboxymethyl; (2R,3R,4S,5R,6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-cyano-5-methylphenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-fluorophenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-cyanophenyl)-5-hydroxyH-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chlorophenyl)-5-hydroxyH-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3-bromo-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-cyano-5-methoxyphenyl)5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,4-difluorophenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(benzo[d]thiazol-5-yl)-4-(4-(4-bromo-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophenyl)5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-cyano-5-fluorophenyl)5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophenyl)5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-fluorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-fluorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxyH-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,4-difluorophenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; - 79 048291 (2R,3R,4S,5R,6R)-4-(4-(4-bromo-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3,4-dichloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(3,4-dichloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,4-difluorophenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(benzo[d]thiazol-6-yl)-4-(4-(3,4-dichloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3,4-dichloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2carboxamide; 2-(((2R,3R,4S,5R,6R)-2-((3-chloro-5-cyanophenyl)((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-4-(4(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran3-yl)oxy)acetic acid; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-N-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-(2-morpholino-2-oxoethoxy)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(4,5-difluoro-2-methoxyphenyl)-1H-1,2,3-Ίriazol-1yl)-5-hydroxy-N-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-Ίriazol-1-yl)-N-(3-chloro-5-cyanophenyl)5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-Ίriazol-1-yl)-N-(3-cyano-5-fluorophenyl)5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-Ίriazol-1-yl)-N-(3,5-dichlorophenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazole-1-yl)-N-(3-chloro-5-cyanophenyl)5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3-fluoro-4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(4-cyano-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophenyl)5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-difluoro-5-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H - 80 048291 pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-fluorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-methoxyphenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triαzol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxyN-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(3-fluoro-5-methylphenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(2-methylbenzothiazol-6-yl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(4-fluoronaphthalen-1-yl)-1H-1,2,3-triαzol-1-yl)-5-hydroxypropyl POkcu-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chlorothiazol-2-yl)-1H-1,2,3-triαzol-1-yl)-N-(2,3-difluorophenyl)-5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N(pyridin-2-yl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N(naphthalen-2-yl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxy-N(naphthalen-1-yl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-4-(4-(4-chlorophenyl)-1H-1,2,3-triαzol-1-yl)-5-hydroxyN-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-chloro-5-cyanophenyl)-5-hydroxyN-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-cyano-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-cyano-5-methoxyphenyl)5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-cyano-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-cyano-5-methylphenyl)-5hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycycloheptyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycycloheptyl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-(2-morpholino-2-oxoethoxy)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-(2-(^)-3-hydroxypyrrolidin-1-yl)-2-oxoethoxy)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-(2-(^)-3-hydroxypyrrolidin-1-yl)-2-oxoethoxy)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-(2-(4-hydroxypiperidin-1-yl)-2-oxoethoxy)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole-1 - 81 048291 yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-3-(2-(3-hydroxyazetidin-1-yl)-2-oxoethoxy)H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-4-(4-(.3.4.5-trifluorophenyl)-1H-1.2..3-triazol-1yl)tetrahydro-2H-pyran-2-carboxamide; 2-(((2R,3R,4S,5R,6R)-2-((3,5-dichlorophenyl)((1S,2S)-2-hydroxycyclohexyl)carbamoyl)-5-hydroxy6-(hydroxymethyl)-4-(4-(3,4,5-1-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetic acid; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-3-(2-hydroxyethoxy)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-morpholinophenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-H-((^^)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-.3-methoxytetrahydro-2H-pyran-2carboxamide; or (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-((3-hydroxypropyl)amino)phenyl)-1H1,2,3-triazol-1-yl)-5-hydroxy-N-((1S,2S)-2-hydroxycyclohexyl)-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 12. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, as a medicinal product having galectin-3 inhibitor activity. 13. The use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of diseases and disorders in which modulation of the binding of galectin-3 (Gal-3) to its natural carbohydrate ligands is indicated, wherein the diseases and disorders are selected from organ fibrosis; liver diseases and disorders; cardiovascular diseases and disorders; cell proliferative diseases and malignancies; inflammatory and autoimmune diseases and disorders; urinary tract diseases and disorders; stroke; neuropathic pain and peripheral neuropathy; eye diseases and disorders; acute kidney injury and chronic kidney disease; or transplant rejection. 14. The use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention or treatment of diseases and disorders in which modulation of the binding of galectin-3 (Gal-3) to its natural carbohydrate ligands is indicated, wherein the diseases and disorders are selected from organ fibrosis; liver diseases and disorders; cardiovascular diseases and disorders; cell proliferative diseases and malignancies; inflammatory and autoimmune diseases and disorders; stroke; neuropathic pain and peripheral neuropathy; eye diseases and disorders; acute kidney injury and chronic kidney disease; or transplant rejection.