EA048927B1 - HYDROXYHETEROCYCLOALKANECARBAMOYL 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 sequences of the human, mouse, and rat genomes 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). Moreover, 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., Oncoimmunology 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 S.P., 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 J.C., et al. Appl Immunohistochem Mol Morphol. 2011 19(3):253-7) or viral encephalitis (Liu F.T. et al., Ann N.Y. Acad Sci. 2012; 1253:80-91; Henderson N.C., et al., Immunol Rev. 2009; 230(l):160-71; Li P et al., Cell 2016; 167:973-984). Recently, Gal-3 has been found to be a key element in chronic inflammation and fibrogenesis in organs such as the liver (Henderson N.C. et al., PNAS 2006; 103: 5060–5065; Hsu D.K. et al. Int J Cancer. 1999, 81(4):519–26), kidney (Henderson N.C. et al., Am. J. Pathol. 2008; 172:288–298; Dang Z. et al. Transplantation. 2012, 93(5):477–84), lung (Mackinnon A.C. et al., Am. J. Respir. Crit. Care Med 2012, 185: 537–546; Nishi Y. et al. Allergol Int. 2007, 56(l):57–65), heart (Thandavarayan R.A. 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 M.A. et al. Cell Rep. 2015, 10(9): 1626–1638), and corneal neovascularization (Chen W.S. et al., Investigative Ophthalmology & Visual Science 2017, vol. 58, 920). 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 glomeruli and observed urinary protein excretion (Kikuchi Y. et al. Nephrol Dial Transplant. 2004, 19(3):602-7). Furthermore, a recent prospective study conducted in 2018 demonstrated

- 1 048927 It was found that higher 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): 252259). 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(l):75–92; DeRoo E.R. 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-huiJin et al. Chin Med J (Engl). 2013, 126(11):2109-15). Gal-3 has been implicated in 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(6):e1434467). Among the malignancies that express high levels of Gal-3, thyroid cancer, central nervous system cancer, tongue cancer, breast cancer, gastrointestinal 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 J.L. et al. PeerJ 2020, 8:e9392) and H5N1 influenza (Chen Y.J. et al. Am. J. Pathol. 2018, 188(4), 10311042), possibly due to its anti-inflammatory effects.

Recently, Gal-3 inhibitors have been shown to have beneficial effects 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). WO20180209276, WO2018209255 and WO20190890080 disclose compounds having binding affinity for galectin proteins for the treatment of systemic insulin resistance disorders. Thus, Gal-3 inhibitors, alone or in combination with other 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, WO2020078808, and WO2020210308).

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) (it should be understood that the absolute configuration is as shown in the corresponding formula):

Ar ²

HE

Formula (I),

- 2 048927 where n and m, each independently, represent the integer 1 or 2, provided that n+m equals 2 or 3;

X is O or NR ² ; where R ² is hydrogen, C ₁ . ₃ -alkyl (especially methyl or ethyl), -CO-H, -SO ₂ -C ₁ . ₃ -alkyl (especially SO2-CH3) or -CO-C ₁ . ₃ -alkyl (especially -CO-CH3);

Ar ¹ is aryl (especially phenyl) which is mono-, di-, tri-, tetra- or pentasubstituted (especially di- or trisubstituted), wherein the substituents are independently selected from halogen; methyl; cyano; methoxy; trifluoromethyl; trifluoromethoxy; and NR ⁿ¹¹ R ⁿ¹² , wherein R ^N11 is hydrogen and R ^N12 is hydroxy-C ₂ . ₃ -alkyl, or RN ¹¹ 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, wherein said 4- to 6-membered heterocyclyl is unsubstituted or monosubstituted by hydroxy (especially the substituents are independently selected from halogen or methyl);

5- or 6-membered heteroaryl, 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, wherein said 9- or 10-membered heteroaryl is independently unsubstituted or monosubstituted by methyl;

R ¹ is hydroxy; C ₁ . ₃ -alkoxy; -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 R ^N21 and R ^N22 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl selected from azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl, wherein said 4-6 membered heterocyclyl is monosubstituted by hydroxy;

[such substituent R ¹ is in particular C ₁ . ₃ -alkoxy (especially methoxy)] L is a direct bond, methylene or ethylene (in particular a direct bond); and

Ar ² is phenyl or a 5- or 6-membered heteroaryl (especially phenyl), 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 (especially methyl), C ₃ _ ₆ -cycloalkyl, -CH ₂ -C ₃ . ₆ -cycloalkyl, C ₁ . ₃ -fluoroalkyl, C ₁ . ₃ -fluoroalkoxy, C ₁ . ₃ -alkoxy (especially methoxy), halogen, morpholin-4-yl, amino, ethynyl and cyano (especially independently selected from C ₁ . ₆ -alkyl (especially methyl), C ₁ . ₃ -alkoxy (especially methoxy), halogen and cyano);

9-membered bicyclic heteroaryl or 10-membered bicyclic heteroaryl, 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.

In a sub-embodiment, said compounds of formula (I), or mutatis mutandis, compounds of formula (II), (III) or (IV) below, are such that the nitrogen linking the heterocycloalkane to the remainder of the molecule and the hydroxy substituent of said heterocycloalkane, as shown in the corresponding formula, are in the relative trans configuration. To avoid misinterpretation, it should be noted that compounds of formula (I _S ), as shown in embodiment 3) below, compounds of formula (IR), as shown in embodiment 4) below, or any mixture thereof.

2) The second aspect of the invention relates to compounds of formula (I) according to embodiment 1), wherein said compounds are also compounds of formula (II), formula (III) or formula (IV) (it being understood that the absolute configuration is as shown in the corresponding formula):

- 3 048927 wherein in each of formula (II), formula (III) or formula (IV), the groups X, Ar ¹ , Ar ² , R ¹ and L independently have the meanings as defined in embodiment 1).

In a first sub-embodiment, the compounds of embodiment 2) refer to compounds of formula (II), (III) or (IV), wherein X is O; and wherein the groups Ar ¹ , Ar ² , R ¹ and L independently have the meanings as defined in embodiment 1).

In a second sub-embodiment, the compounds of embodiment 2) refer to compounds of formula (II), (III) or (IV), wherein X is NR ² ; wherein R ² is hydrogen, C ₁ . ₃ -alkyl (especially methyl or ethyl), -CO-H, -SO ₂ -C ₁ . ₃ -alkyl (especially SO ₂ -CH ₃ ), -CO-C ₁ . ₃ -alkyl (especially -COCH ₃ ); and wherein the groups Ar ¹ , Ar ² , R ¹ and L independently have the meanings as defined in embodiment 1).

3) The third aspect of the invention relates to compounds of formula (I) according to embodiment 1), wherein said compounds are also compounds of formula (I _S ) (it being understood that the absolute configuration is as shown in the corresponding formula):

Formula (Is), wherein the groups X, Ar ¹ , Ar ² , R ¹ , L, m and n are as defined in embodiment 1). In a particular embodiment, said compounds of formula (IS) are also compounds of formula (IIS), formula (IIIS) or formula (IVS) (it being understood that the absolute configuration is as shown in the corresponding formula):

wherein in each of formula (IIS), formula (IIIS) or formula (IVS), the groups X, Ar ¹ , Ar ² , R ¹ and L independently have the meanings as defined in embodiment 1).

In a first sub-embodiment, the compounds of embodiment 3) refer to compounds of formula (II _S ), (III _S ) or (IV _S ), wherein X is O; and wherein the groups Ar ¹ , Ar ² , R ¹ and L independently have the meanings as defined in embodiment 1).

In a second sub-embodiment, the compounds of embodiment 3) refer to compounds of formula (II _S ), (II _S ) or (IV _S ), wherein X is NR ² ; wherein R ² is hydrogen, C ₁ . ₃ -alkyl (especially methyl or ethyl), -CO-H, -SO ₂ -C ₁ . ₃ -alkyl (especially SO ₂ -CH ₃ ), -CO-C ₁ . ₃ -alkyl (especially -COCH ₃ ); and wherein the groups Ar ¹ , Ar ² , R ¹ and L independently have the meanings as defined in embodiment 1).

4) Another aspect of the invention relates to compounds of formula (I) according to embodiment 1), wherein said compounds are also compounds of formula (IR) (it being understood that the absolute configuration is as shown in the corresponding formula):

- 4 048927

Formula ( _IR ), wherein the groups X, Ar ¹ , Ar ² , R ¹ , L, m and n are independently as defined in embodiment 1). In a particular embodiment, said compounds of formula (IR) are also compounds of formula (IIR), formula (IIIR) or formula (IVR) (it being understood that the absolute configuration is as shown in the corresponding formula):

wherein in each of formula (IIR), formula (IIIR) or formula (IVR), the groups X, Ar ¹ , Ar ² , R ¹ and L independently have the meanings as defined in embodiment 1).

In a first sub-embodiment, the compounds of embodiment 4) refer to compounds of formula (IIR), (IIIR) or (IVR), wherein X is O; and wherein the groups Ar ¹ , Ar ² , R ¹ and L independently have the meanings as defined in embodiment 1).

In a second sub-embodiment, the compounds of embodiment 4) refer to compounds of formula (IIR), (IIIR) or (IVR), wherein X is NR ² ; wherein R ² is hydrogen, C ₁ . ₃ -alkyl (especially methyl or ethyl), -CO-H, -SO ₂ -C ₁ . ₃ -alkyl (especially SO ₂ -CH ₃ ), -CO-C ₁ . ₃ -alkyl (especially -COCH ₃ ); and wherein the groups Ar ¹ , Ar ² , R ¹ and L independently have the meanings as defined in embodiment 1).

The compounds of formula (I) contain five stereogenic or asymmetric centers which are located on the tetrahydropyran moiety and which are in the absolute configuration depicted for formula (I). The compounds of formula (I) further contain two stereogenic or asymmetric centers which are located on the heterocycloalkane moiety. In a particular embodiment, said compounds of formula (I), or mutatis mutandis, compounds of formula (II), (III) or (IV), are such that the nitrogen linking the heterocycloalkane to the remainder of the molecule and the hydroxy substituent of said heterocycloalkane, as shown in the corresponding formula, are in the relative trans configuration. To avoid misinterpretation, it should be noted that the compounds of formula (I _S ), as shown in embodiment 3), compounds of formula (IR), as shown in embodiment 4), or any mixture thereof.

Furthermore, the compounds of formula (I) may contain one and possibly more stereogenic or asymmetric centers, such as one or more additional asymmetric carbon atoms. 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 particular absolute configuration, for example as the (R)- or (S)-enantiomer, such designation shall be understood as referring to the corresponding compound (or generic structure) in enriched, in particular substantially pure, enantiomeric form. Similarly, where

- 5 048927 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 shall be understood as referring to the compound being in an enriched, in particular substantially pure, form with respect to the corresponding configuration of said asymmetric centre. By analogy, two stereogenic centres, for example in a cyclic group, may be present in a certain relative configuration.

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 18), 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), (III), (IV), (Is), (II _s ), (IIIs), (IVs), (Ir), (IIr), (IIIr), (IVr) and (V), and their salts are included within the scope of the present invention. Substitution of hydrogen with 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 further herein, but using an appropriate isotopic variation of suitable reagents or starting materials.

In this patent application, the connection shown by the dotted line shows the point of attachment.

of the drawn radical. For example, the radical shown 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 18) 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 this application are intended to apply equally to compounds of formulae (I), (II), (III), (IV), (Is), (IIs), (IIIs), (IVs), (Ir), (IIr), (IIIr), (IVr) and (V), as defined in any of embodiments 1) to 17), and, mutatis mutandis, throughout the specification and claims, unless a definition otherwise expressly provided 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 this application.

- 6 048927

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

ABOUT

II

may be called (2R,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-phenyl-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carbonyl or, alternatively, 1,3-dideoxy-3-[4-phenyl-1H-1,2,3-triazol-1-yl]-b-O-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)-N-(3-chlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide should be understood as also belonging to 1,3-dideoxy-2-O-methyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-N-(3-chlorophenyl)-N-((3S,4R)-4-hydroxy-3-tetrahydrofuranyl)-beta-D-galactopyranose-1-carboxamide.

In cases where a substituent is indicated as optional, it is to be understood that such substituent may be absent (i.e. the corresponding residue is unsubstituted so far as such optional substituent is concerned), in which case all positions having a free valence (to which such 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, in case the term optional is used in the context of (ring(s)) heteroatom(s), the term means that either the corresponding optional heteroatom(s), etc., are(are) absent (i.e. the defined moiety does not contain heteroatom(s)/is a carbocycle/or the like) or the corresponding optional heteroatom(s), etc., are(are) present, as expressly stated. Unless explicitly stated otherwise in a relevant embodiment or claims, the groups defined in this application are unsubstituted.

The term halogen means fluorine, chlorine, bromine, or iodine (especially fluorine, chlorine, or bromine).

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 Cx.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-dimethyl-propyl and 3,3-dimethylbutyl. Preferred is methyl. To avoid misinterpretation, it should be noted that when a group is called, for example, propyl or butyl, n-propyl and n-butyl are meant. When the substituent for Ar ¹ or Ar ² is C1.6-alkyl, the term especially refers to methyl. When R ² is _C1.6 -alkyl, the term especially refers to methyl or ethyl. When the term C _{1.3 -} alkyl is used in relation to a substituent R ² such as -SO ₂ -C _{1.3 -} alkyl or -CO-C _{1.3 -} alkyl, the term especially refers to methyl.

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 Cx.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 has from one to seven hydrogen atoms replaced by fluorine.

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

- 7 048927 (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 C ₁ . ₃ -fluoroalkoxy group contains from one to three carbon atoms and has from one to seven hydrogen atoms replaced by fluorine.

The term cycloalkyl, used alone or in combination, refers especially to a saturated monocyclic or fused, bridged or spiro-bicyclic hydrocarbon ring containing from three to eight carbon atoms. The term Cx-y-cycloalkyl (x and y each representing 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.

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 C _{1_3} -alkoxy, the term refers in particular to methoxy. In case the substituent for Ar is C _{1_3 -alkoxy} , the term refers in particular to methoxy.

The term aryl, used alone or in combination, means phenyl or naphthyl, especially phenyl, wherein said aryl group is unsubstituted or substituted as expressly stated. In the case of a substituent Ar ¹ or Ar ² representing aryl, the term especially means phenyl.

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 Ar ¹ being a 5- or 6-membered heteroaryl, the term especially means thiazolyl (especially 4-chlorothiazol-2-yl). In the case of Ar ² being a 5- or 6-membered heteroaryl, the term especially means furanyl, thiophenyl, pyrrolyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl or pyrimidinyl; wherein said 5- or 6-membered heteroaryl is unsubstituted or substituted as expressly defined.

In the case of Ar ¹ being a 9- or 10-membered bicyclic heteroaryl, the term especially means benzothiazolyl (especially 2-methylbenzo[d]thiazol-6-yl). In the case of Ar ² being a 9-membered bicyclic heteroaryl, the term especially means indolyl, benzothiophenyl, benzothiazolyl or benzoimidazolyl; wherein said 9-membered bicyclic heteroaryl is unsubstituted or substituted as explicitly defined. In the case of Ar ² being a 10-membered bicyclic heteroaryl, the term especially means quinolinyl or quinoxalinyl; wherein said 10-membered bicyclic heteroaryl is unsubstituted or substituted as explicitly defined.

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 this application refers to a range extending from X minus 10% of X to X plus 10% of X, and preferably to a range extending from X minus 5% of X to X plus 5% of X. In the special case of temperatures, the term approximately preceding a temperature Y in this application refers to a range extending from a temperature Y minus 10°C to Y plus 10°C, and preferably to a range extending from Y minus 5°C to Y plus 5°C. Furthermore, the term room temperature as used in this

- 8 048927 application, refers to a temperature of approximately 25°C.

Additional embodiments of the invention are presented below:

5) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar ¹ is phenyl which is mono-, di-, tri-, tetra- or pentasubstituted (especially di- or trisubstituted), wherein the substituents are independently selected from halogen; methyl; cyano; and methoxy.

6) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar ¹ is phenyl which is di- or trisubstituted, wherein the substituents are independently selected from halogen and methyl.

In a sub-embodiment, at least one of said substituents is attached at the meta or para position of said phenyl.

7) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar ¹ is phenyl which is di- or trisubstituted, wherein the substituents are independently selected from halogen, methyl and cyano; wherein at least one of said substituents is attached at the meta- or para-position of said phenyl;

wherein, first of all, said substituent at the para-position, if present, is halogen or methyl; and wherein, first of all, said substituent at the meta-position, if present, is halogen.

8) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar ¹ is phenyl which is di- or trisubstituted, wherein the substituents are independently selected from halogen; methyl; and cyano (especially halogen or methyl); wherein in case said phenyl is disubstituted, at least one of said substituents is in the meta position, said substituent being especially halogen; and the other substituent is especially in the other meta or in the para position; or in case said phenyl is trisubstituted, the substituents form a 2,3,4 or 3,4,5 substitution pattern about the point of attachment of Ar ¹ , wherein firstly the substituent in the para position is halogen or methyl, and the remaining substituents are independently halogen (especially fluorine).

9) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein Ar ¹ is

- 9 048927

In a sub-embodiment, Ar ¹ is, in particular, a group selected from groups A) or B):

where each of the specified groups A) and B) forms a separate sub-variant of implementation.

- 10 048927

In another sub-embodiment, Ar ¹ in particular represents a group selected from groups C), D) or E):

where each of the specified groups C), D) and E) forms a separate sub-variant of implementation.

10) Another embodiment relates to compounds according to any one of embodiments 1) to 9), wherein R ¹ is methoxy.

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

12) Another embodiment relates to compounds according to any one of embodiments 1) to 11), wherein Ar ² is phenyl which is unsubstituted, mono-, di- or trisubstituted (especially mono- or disubstituted), wherein the substituents are independently selected from C _1-6 -alkyl (especially methyl), C _1-3 -alkoxy (especially methoxy), halogen and cyano (wherein especially at least one of said substituents is in the meta position).

13) Another embodiment relates to compounds according to any one of embodiments 1) to 11), wherein Ar ² is phenyl which is mono or disubstituted, wherein the substituents are independently selected from C _1-4 -alkyl (especially methyl), C _1-3 -alkoxy (especially methoxy), halogen and cyano (wherein especially at least one of said substituents is in a meta position).

14) Another embodiment relates to compounds according to any one of embodiments 1) to 11), wherein Ar ² is phenyl which is monosubstituted, wherein the substituent is selected from C _1-4 alkyl (especially methyl), C _1-3 alkoxy (especially methoxy), halogen and cyano (wherein especially said substituent is in the meta position); or disubstituted, wherein the substituents are independently selected from C 1-4 alkyl (especially methyl), C ₃ alkoxy (especially methoxy), halogen and cyano (wherein especially said substituents are in the meta position).

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

- 11 048927

16) 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 15), 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 that in particular the following embodiments relating to compounds of formula (I) are thus possible and contemplated and are hereby specifically disclosed in individualized form:

2+1, 3 + 1, 4+1, 5+1, 5+2+1, 5+3 + 1, 5+4+1, 6+1, 6+2+1, 6+3 + 1, 6+4+1, 7+1,

7+2+1, 7+3 + 1, 7+4+1, 8+1, 8+2+1, 8+3 + 1, 8+4+1, 9+1, 9+2+1, 9+3+1, 9+4+1, 10+1,

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

12+11+10+5+3+1, 12+11+10+5+4+1, 12+11+10+6+1, 12+11+10+6+2+1,

12+11+10+6+3+1, 12+11+10+6+4+1, 12+11+10+7+1, 12+11+10+7+2+1,

12+11+10+7+3+1, 12+11+10+7+4+1, 12+11+10+8+1, 12+11+10+8+2+1,

12+11+10+8+3+1, 12+11+10+8+4+1, 12+11+10+9+1, 12+11+10+9+2+1,

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

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

- 12 048927 + 10+6+3 + 1, 13 + 10+6+4+1, 13 + 10+7+1, 13 + 10+7+2+1, 13+10+7+3 + 1, + 10+7+4+1, 13 + 10+8+1, 13 + 10+8+2+1, 13 + 10+8+3 + 1, 13 + 10+8+4+1, 13 + 10+9+1, 13 + 10+9+2+1, 13 + 10+9+3 + 1, 13 + 10+9+4+1, 13 + 11 + 1, 13 + 11+2+1, 13 + 11+3 + 1, 13+ 11+4+1, 13 + 11+5+1, 13 + 11+5+2+1, 13 + 11+5+3 + 1, 13+11+5+4+1, 13 + 11+6+1, 13 + 11+6+2+1, 13 + 11+6+3+1, 13 + 11+6+4+1, 13 + 11+7+1, 13+11+7+2+1, + 11+7+3 + 1, 13 + 11+7+4+1, 13 + 11+8+1, 13 + 11+8+2+1, 13+11+8+3 + 1, + 11+8+4+1, 13 + 11+9+1, 13 + 11+9+2+1, 13 + 11+9+3 + 1, 13+11+9+4+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+5+2+1, 13 + 11 + 10+5+3 + 1, 13 + 11 + 10+5+4+1, 13 + 11 + 10+6+1, + 11 + 10+6+2+1, 13 + 11 + 10+6+3 + 1, 13 + 11 + 10+6+4+1, 13 + 11 + 10+7+1, + 11 + 10+7+2+1, 13 + 11 + 10+7+3 + 1, 13 + 11 + 10+7+4+1, 13 + 11 + 10+8+1, + 11 + 10+8+2+1, 13 + 11 + 10+8+3+1, 13 + 11 + 10+8+4+1, 13 + 11 + 10+9+1, + 11 + 10+9+2+1, 13 + 11 + 10+9+3 + 1, 13 + 11 + 10+9+4+1, 14+1, 14+2+1, 14+3 + 1, 14+4+1, 14+5+1, 14+5+2+1, 14+5+3+1, 14+5+4+1, 14+6+1, 14+6+2+1, 14+6+3 + 1, 14+6+4+1, 14+7+1, 14+7+2+1, 14+7+3 + 1, 14+7+4+1, 14+8+1, 14+8+2+1, 14+8+3 + 1, 14+8+4+1, 14+9+1, 14+9+2+1, 14+9+3 + 1, 14+9+4+1, 14+10+1, 14+10+2+1, 14+10+3 + 1, 14+10+4+1, 14+10+5+1, 14+10+5+2+1, 14+10+5+3 + 1, 14+10+5+4+1, 14+10+6+1, 14+10+6+2+1, 14+10+6+3 + 1, 14+10+6+4+1, 14+10+7+1, 14+10+7+2+1, 14+10+7+3+1, 14+10+7+4+1, 14+10+8+1, 14+10+8+2+1, 14+10+8+3+1,

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

14+11+8+3+1, 14+11+8+4+1, 14+11+9+1, 14+11+9+2+1, 14+11+9+3+1,

14+11+9+4+1, 14+11+10+1, 14+11+10+2+1, 14+11+10+3+1, 14+11+10+4+1, 14+11+10+5+1, 14+11+10+5+2+1, 14+11+10+5+3+1, 14+11+10+5+4+1,

14+11+10+6+1, 14+11+10+6+2+1, 14+11+10+6+3+1, 14+11+10+6+4+1,

14+11+10+7+1, 14+11+10+7+2+1, 14+11+10+7+3+1, 14+11+10+7+4+1,

14+11+10+8+1, 14+11+10+8+2+1, 14+11+10+8+3+1, 14+11+10+8+4+1,

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

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, 11+9+4+1, for example, refers to embodiment 11), dependent on embodiment 9), dependent on embodiment 4), dependent on embodiment 1), i.e. embodiment 11+9+4+1 corresponds to compounds of formula (I) according to embodiment 1), further limited to all the features of embodiments 4), 9) and 11).

- 13 048927

17) A further aspect of the invention relates to compounds of formula (I) according to embodiment 1), which are also compounds of formula (V) (it being understood that the absolute configuration is as shown in the corresponding formula):

where X is O or NR ² ; where R ² is hydrogen, C _1-3 -alkyl (especially methyl or ethyl), -CO-H, -SO ₂ -C _1-3 -alkyl (especially SO ₂ -CH ₃ ) or -CO-C _1-3 -alkyl (especially CO-CH ₃ );

Ar ¹ is phenyl which is mono-, di-, tri-, tetra- or pentasubstituted (especially di- or trisubstituted), wherein the substituents are independently selected from halogen; methyl; cyano; and methoxy (especially independently selected from halogen and methyl);

[group Ar ¹ in particular is one of the groups listed in embodiment 9) or any of its sub-variants]

R ¹ is hydroxy;

C _1-3 -alkoxy;

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

- O-CH2-CH2-OH; or

- O-CH2-CO-OH;

[such substituent R ¹ is in particular C _1-3 -alkoxy (especially methoxy)] L is a direct bond or methylene (in particular a direct bond); and

Ar ² is phenyl, wherein said phenyl is unsubstituted, mono-, di- or trisubstituted (especially mono- or disubstituted), wherein the substituents are independently selected from methyl, methoxy, halogen and cyano; and wherein the features disclosed in embodiments 2) to 16) are intended to apply mutatis mutandis also to the compounds of formula (V) according to embodiment 17).

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

(2K,3K,48,5K,6K)-X-(3-chlorophenyl)-5-hydroxy-6-(hydroxymethyl)-X-((38,4

K)-4-hydroxytetrahydrofuran-3-yl)-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)-X-(3-bromophenyl)-5-hydroxy-6-(hydroxymethyl)-X-((38,4

K)-4-hydroxytetrahydrofuran-3-yl)-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)-5-hydroxy-6-(hydroxymethyl)-X-((38,4K)-4-hydroxytetrahydrofuran-3-yl)-X-(3-iodophenyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,

3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

- 14 048927 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-lH-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

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

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

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

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

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

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

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

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

(2R, 3R, 4S, 5R, 6R)-4-(4-(4-6poM-2,3-difluorophenyl)-1H-1,2,3-triazole-1-Hn)-N(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S, 4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-4-(4-(4-6poM-2,3-difluorophenyl)-1H-1,2,3-triazole-1-πη)-N(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S, 4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

- 15 048927 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-dichloro-4-methylphenyl)-lH1,2,3-triazol-l-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3 R,4S, 5 R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1 H -1,2,3-triazol-l-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-X-((38,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-X-((3 S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(2,3-dichloro-4-methylphenyl)-lH1,2,3-triazol-l-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((38,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-dimethyl-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-X-((3 S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

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

(2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-X(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-X-((3 S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

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

(2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(4-chloro-3,5-diτopφenyl)1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-K-((3 S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

- 16 048927 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-X-((38,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrophenyl-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

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

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

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

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

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

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

(2K,3K,48,5K,6K)-X-(3-chloro-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)N-((3R,4S)-4-hydroxytetrahydropyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

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

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

- 17 048927 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)N-((3R,4S)-4-hydroxytetrahydropyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-cyano-5-methoxyphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((ЗR,4S)-4-hydroxytetrahydropyran-3-yl)-3-methoxy-4-(4-(3,4,5-triphenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

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

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

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

(2R, 3R, 4S, 5R, 6R)-4-(4-(4-6-poM-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-X(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R, 4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R, 3R, 4S, 5R, 6R)-4-(4-(4-6poM-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-X(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R, 4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-diφop-4-methylphenyl)-lH1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4 8)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,5-diφτop-4-methylphenyl)-lH -1,2,3-triazol-l-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4 8)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3,5-diφτop-4-methylphenyl)-1H-1,2,3-triazole-1 -yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,ЗR,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-diφtop-4-methylphenyl)-1H-1,2,3-triazole-1 -yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

- 18 048927 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(2,3-dimethylphenyl)-1H1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,48)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

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

(2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

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

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

(2nd, 3rd, 48, 5th, 6th)-N-(3-bromo-5-cyanophenyl)-4-(4-(4-chloro-3,5-difluorophenyl)1H-1,2,3-triazole-l-Hn)-5-rHflpoKCH-6-(rHflpoKCHMeTHn)-N-((3R, 4S)-4-rnflpoKCHTeTp ahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

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

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

(2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-tr iazol-l-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydro-2H-pyran-2-carboxamide;

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

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

- 19 048927 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,48)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)N-((3S,48)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

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

(2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-lH-l,2,3-triazol-l-yl)-N(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-X-((38,48)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(2,3-dichloro-4-methylphenyl)-1H1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-1H-((38,48)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-dimethyl-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-X-((38,48)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-X-((38,48)-4-hydroxypyrrolidin-3yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

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

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

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

(2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-dimethyl-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

- 20 048927 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((38,48)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

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

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

(2K,3K,48,5K,6K)^-((38,48)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)^-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-N-((38,48)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-((3S,4S)-l-acetyl-4-hydroxypyrrolide-3-yl)-N-(3-6p-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-((3S,4S)-l-acetyl-4-hydroxypyrrolide-3-yl)-N-(3-6p-5-methylphenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-H-((3K,4K)-1-acetyl-4-hydroxypyrrolidin-3-yl)-H-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

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

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

- 21 048927 (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrroledi n-3-yl)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-X-((3K,4K)-1-acetyl-4-hydroxypyrrolidin-3-yl)-X-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-X-((3K,4K)-1-acetyl-4-hydroxypyrrolidin-3-yl)-X-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-X-((3K,4K)-1-acetyl-4-hydroxypyrrolidin-3-yl)-X-(3-bromo-5-methylphenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-X-((38,48)-1-acetyl-4-hydroxypyrrolidin-3-yl)-X-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-X-((3K,4K)-1-acetyl-4-hydroxypyrrolidin-3-yl)-X-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-X-((38,48)-1-acetyl-4-hydroxypyrrolidin-3-yl)-X-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-X-((3K,4K)-1-acetyl-4-hydroxypyrrolidin-3-yl)-X-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-X-((38,48)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-X-(3,5-dichlorophenyl)-5-hydroxy6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

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

(2K,3K,48,5K,6K)-X-((38,48)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-X-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

- 22 048927 (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolide-3-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-H-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

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

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

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

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

(2R, 3R, 4S, 5R, 6R)-4-(4-(4-methyl-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-H(3,5-dichlorophenyl)-N-((3S, 4 S)-l-formyl-4-hydroxypyrrolide-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-dimethyl-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-N-((3S,4S)-l-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

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

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

(2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-dimethyl-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4R)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide;

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

- 23 048927 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-N-((3S,4S)-1-ethyl-4-hydroxy π yrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-N-((38,48)-4-hydroxy-1-(methylsulfonyl)pyrrolidin-3-yl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3B,48)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

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

(2C,ZC,48,5C,6C)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)X-((ZK,48)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

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

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((38,4B)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2C,ZC,48,5C,6C)-M-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)X-((38,4B)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((38,48)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)X-((38,48)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

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

- 24 048927 ('2R,3R,4S,5R,6R)-N-('3-bromo-5-methylphenyl)-5-hydroxy-6-('hydroxymethyl)N-((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3

8,48)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3

-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)X-((38,48)-3-hydroxypiperidin-4-yl)-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-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)X-((38,48)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2K,3K,48,5K,6K)-18G-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)X-((3K,4K)-3-hydroxypiperidin-4-yl)-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-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3

8,48)-4-hydroxypiperidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3

-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide;

(2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)X-((38,48)-4-hydroxypiperidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; and (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)N-((3R,4R)-4-hydroxypiperidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H

-1,2,3-tr iazol-1-yl)tetrahydro-2H-pyran-2-carboxamide.

The compounds of formula (I) according to embodiments 1) to 18) 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 ed. (2005), part 5, Pharmaceutical Manufacturing [published by Lippincott Williams & Wilkins]) by introducing the described compounds of formula (I) or their pharmaceutically acceptable salts, 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/prophylaxis or treating a disease or disorder mentioned herein, comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) according to embodiments 1) to 18). In a sub-embodiment of the invention, the amount administered is in the range between 1 mg and 1000 mg per day.

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

19) Another embodiment relates to compounds of formula (I) as defined in any one of embodiments 1) to 18), which are useful for the prevention/prophylaxis

- 25 048927 or treatment of diseases and disorders that are related to the binding of galectin-3 to natural ligands.

Such diseases and disorders that are related 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 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 1-5 as defined by the International Consortium for Improving Global Kidney Health Guidelines

- Kidney Disease Outcomes in Governance (KDIGO) [26 048927], in particular CKD (especially 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 urinary outflow obstruction (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 Kidney Disease Improving Global Outcomes (KDIGO) Rules); rheumatic heart disease caused/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/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 of cancer cells; in particular, said cell proliferative diseases and malignancies are cancers of the thyroid gland, central nervous system, tongue, breast, digestive system, squamous cell carcinoma of the head and neck, pancreas, bladder, kidney, liver, parathyroid, or salivary glands; or lymphoma; carcinoma, non-small cell lung cancer, melanoma, or neuroblastoma);

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);

- 27 048927 diseases and disorders of the brain (including stroke and cerebral hemorrhage);

neuropathic pain and peripheral neuropathy;

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 raised intraocular pressure and ocular scarring following 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 haematopoietic stem cell transplantation; chronic allograft rejection and chronic allograft vasculopathy; and the sequelae of such graft rejection.

20) A further embodiment relates to compounds of formula (I) for use according to embodiment 19), 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.

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

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

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

24) A further embodiment relates to compounds of formula (I) for use according to embodiment 19), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of interstitial lung diseases and disorders.

25) A further embodiment relates to compounds of formula (I) for use according to embodiment 19), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of ocular diseases and disorders.

26) A further embodiment relates to compounds of formula (I) for use according to embodiment 19), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of cell proliferative diseases and malignancies.

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

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

28) A further embodiment relates to compounds of formula (I) for use according to embodiment 19), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of diseases and disorders of the gastrointestinal tract.

29) A further embodiment relates to compounds of formula (I) for use according to embodiment 19), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of diseases and disorders of the pancreas.

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

31) A further embodiment relates to compounds of formula (I) for use according to embodiment 19), wherein said compounds are intended for use

- 28 048927 for the prevention/prophylaxis or treatment of diseases and disorders of the brain.

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

33) A further embodiment relates to compounds of formula (I) for use according to embodiment 19), wherein said compounds are intended for use in the treatment of transplant rejection.

Furthermore, any preferences and (sub-)embodiments given for the compounds of formula (I) (either for the compounds themselves, their salts, compositions containing these compounds or their salts, or for uses of these compounds or their salts, etc.) apply mutatis mutandis to the compounds of formulae (II), (III), (IV), (IS), (IIS), (IIIS), (IVS), (IR), (IIR), (IIIR), (IVR) and (V).

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 integers n and m, and the generic groups R ¹ , L, Ar ¹ , Ar ² , n and m are as defined for formula (I). Other abbreviations used in this application are explicitly defined or are as defined in the experimental section. In some cases, the generic groups R ¹ , L, Ar ¹ , Ar ² , n and m may be incompatible with the array 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 carried out using standard peptide coupling conditions, for example, 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 acetyl, trimethylsilyl (TMS), or tert-butyl dimethylsilyl (TBS), or benzyl, which are well known to those skilled in the art. The hydroxyl groups at positions 4 and 6 of structure 1 can be protected with cyclic protecting groups such as isopropylidene, benzylidene or bis-tert-butylsilyl groups. R is either a suitable protecting group (Pg) or the OR group corresponds to R (as defined for formula (I)). Compounds of structure 3 are then deprotected to give compounds of formula (I).

- 29 048927

In case Pg is an acyl protecting group, such a 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 K ₂ CO ₃ , NaOH, LiOH. In case such a 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, PtO ₂ , in methanol, EA, THF, etc. or a mixture thereof, or with BBr ₃ in a solvent such as DCM. In case such a 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 mild acidic conditions, such as in aqueous AcOH at temperatures between room temperature and reflux temperature. In the case where Pg is a cyclic protecting group such as isopropylidene, benzylidene and bis-tert-butylsilylene group, the cleavage can be carried out under acidic conditions using aqueous AcOH or TFA.

Compounds of structure 1 are prepared by hydrolysis of the nitrile function in structure 4 to the carboxylic acid using aqueous acidic (conc. HCl) or basic (NaOH) conditions at temperatures between 20 and 100 °C, followed by appropriate protection or modification of the free hydroxyl groups. Compound of structure 4 in turn is prepared, for example, by the reaction of compound of structure 5 with 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 ed., 2013, John Wiley & Sons), alternatively the reaction can be carried out in a commercial continuous flow 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 one 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 one skilled in the art (Carbohydrate Research 1994, 251, 33-67; Bioorg. Med. Chem. 2002, 10, 1911-2013).

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 reacting 3,6-dioxabicyclo[3.1.0]hexane, tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate, 1-(6-oxa-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one, 3,7-dioxabicyclo[4.1.0]heptane, or tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate with an amine.

For coupling with compounds of structure 1, compounds of structure 2 are used in racemic form or as resolved enantiomers. Diastereomers of structure 3 or formula I (after deprotection) are separated using techniques well known to those skilled in the art, such as chiral preparative HPLC using achiral or chiral stationary phases. Typically used achiral or chiral stationary phases for chiral preparative HPLC are such as a Waters XBridge C18, 10 µm OBD, 30x75 mm, or Daicel Chiralcel OZ-H (5 µm) column, Daicel ChiralCel OJ-H (5-10 µm) column, ChiralPak IC column (5 µm), ChiralPak ID column (5 µm), ChiralPak IG column (5 µm), ChiralPak IH column (5 µm), ChiralPak IE column (5

- 30 048927 µm), ChiralPak AS-H column (5 µm), AD-H column (5 µm) or IB column (5 µm), respectively.

Typical chiral HPLC conditions are an isocratic mixture of eluent A (CO ₂ ) and eluent B (DCM/MeOH, MeCN/MeOH, MeCN/EtOH, 0.1% Et ₂ NH in EtOH, MeOH, EtOH, iPrOH), at flow rates ranging from 0.8 to 160 mL/min). In some cases, enantiomerically pure forms of compounds of structure 2 are used for amide coupling reactions with compounds of structure 1 to afford pure enantiomers of compounds of structure 3 and formula I, respectively.

In cases where diastereomers have not been separated, IC ₅₀ values are measured for a mixture of diastereomers.

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, Redisep), by prep. TLC (TLC plates from Merck, silica gel 60 F ₂₅₄ ) or by preparative HPLC. Characterization of the compounds described in the invention was determined by ¹ H-NMR (Bruker Neo, 400 MHz Ultra ShieldTM or Broker Avance III HD, Ascend, 50o 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, spin-spin 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 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 = MeCN. 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 B (%) 5 5 95 95 5

Detection: UV at 210 nm.

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

B) Preparative LC-MS (I).

A Zorbax column (Zorbax Dr. Maisch, 5 μm, 30x75 mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% formic acid in water; solvent B = MeCN. The eluent flow rate was 75 ml/min, and the characteristics of the 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 3.0 6.0 6.7 Solvent A (%) 50 5 5 50 Solvent B (%) 50 95 95 50

C) Preparative LC-MS (II).

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 = MeCN. 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 table below (a linear gradient was used between two consecutive time points):

- 31 048927

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

Detection 210 nm.

Abbreviations (in the context of this application).

ABTS 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid Ace acetyl, such as in AcOH = acetic acid water. water Vi butyl (as in wBuLi = n-butyl lithium) approx. approximately KK silica gel column chromatography END. concentrated DXM dichloromethane DIPEA A-ethyldiisopropylamine DMFA dimethylformamide DMSO dimethyl sulfoxide EA ethyl acetate equiv. (molar(s)) equivalent(s) Et ethyl EtOH ethanol _Et2O diethyl ether note example FH flash chromatography h hour(s) HOBt 1-hydroxybenzotriazole hydrate vzhh high performance liquid chromatography v.v. high vacuum LC liquid chromatography m molarity [mol l' ¹ ] Me methyl MeCN acetonitrile MeOH methanol

- 32 048927

ms mass spectroscopy min minute(s) n. normal concentration NaOH sodium hydroxide OP optical density v/n during the night

org. organic Pg protective group Ph phenyl PTSA i-toluenesulfonic acid

k.t. room temperature saturation saturated TVME i/p-butyl methyl ether TBS i/p-butyldimethylsilyl tBu ot/?eot-butyl = tertiary butyl TEA triethylamine Tf trifluoromethanesulfonate TFU trifluoroacetic acid THF tetrahydrofuran TMS trimethylsilyl TZR propylphosphonic anhydride U holding time

A. Obtaining precursors and intermediates.

Preparation of intermediate compounds of structure 1.

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

Intermediate 1. (3R,4S,5R,6R)-6-(Acetoxymethyl)-4-azidotetrahydro-2H-pyran2,3,5-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 from Carbohydrate Research 1994, 251, 33-67 and the references cited therein.

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

Intermediate 1 (10,000 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

- 33 048927 (400 mL), saturated with aqueous bicarbonate solution (100 mL) and TBME (300 mL). The aqueous phase was extracted once more with TBME (200 mL) and the organic phase was washed twice with water/brine (ca. 5:1) and brine, dried over MgSO ₄ . TBME was evaporated on a rotary vacuum evaporator at 20 °C. The crude intermediate was purified by filtration through SiO ₂ (150 mL cartridge, filled 3/4 full, DCM/TBME 10:1). The intermediate was used immediately in the next step.

1H NMR (500 MHz, DMSO) δ: 5.47 (dd, J1=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, Ji=3.2 Hz, J2=10.4 Hz, 1H), 4.15 (ddd, J1=0.8 Hz, J2=4.5 Hz, J3=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, 3H), 2.15 (m, 3H), 2.04 (s, 3H).

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

Intermediate 2 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. The finely divided Cu residues were filtered off and the filtrate was washed with _NH4Cl solution (semi-saturated) and brine, dried over _MgSO4 and concentrated. The residue was triturated with MeOH (ca. 100 mL), filtered and dried at i.v. to give the desired intermediate 3a as a beige solid.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ: 8.85 (s, 1H), 7.81-7.85 (m, 2H), 5.91 (m, 1H), 5.64 (dd, Ji=3.1 Hz, J2=11.0 Hz, 1H), 5.51 (dd, Ji=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=0.97 min; [M+N]+=497.21.

Intermediate 3 is further functionalized as shown in the scheme below:

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

Intermediate 3 (2800 mg, 5.64 mmol, 1 equiv) was suspended in HCl 25% (20.6 ml,

169 mmol, 30 equiv) and heated under reflux for 1.5 h. The solution was applied to a MCI® gel column (approx. 100 mL gel) under water. The column was eluted with water until neutral pH was reached (5 fractions of 40 mL). The compound was then eluted with _H2O /MeCN (3:1). 40 mL fractions were collected. The fractions containing the product were first concentrated in vacuo to remove MeCN and then lyophilized to give the title compound as a colorless solid.

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

1H NMR (500 MHz, DMSO-d ₆ ) δ: 12.88-12.90 (br, 1H), 8.79 (s, 1H), 7.86 (dd, Ji=6.8 Hz, J ₂ =9.1 Hz, 2H), 5.43-5.46 (m, 1H), 5.30 (d, J=6.2 Hz, 1H), 4.84 (dd, Ji=3.0 Hz, J2=10.8 Hz, 1H), 4.72 (d, J=0.5 Hz, 1H), 4.36 (t, J=10.0 Hz, 1H), 3.94 (dd, Ji=3.0 Hz, J2=6.0 Hz, 1H), 3.85 (d, J=9.4 Hz, 1H), 3.71 (t, J=6.5 Hz, 1H), 3.48-3.55 (m, 2H).

- 34 048927

Intermediate compound 5. Methyl (4aR,6R,7R,8R,8aR)-7-hydroxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d] [1,3]dioxin-6-carboxylate.

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

To a suspension of Intermediate 4 (14.2 g, 0.036 mol) in MeOH (60 mL) and THF (40 mL) was added 1 M _H2SO4 in MeOH (1.82 mL, 0.00182 mol) [freshly prepared by dissolving _H2SO4 9598% (0.136 mL ₎ in 2.5 mL MeOH _] . The mixture was stirred at rt over the weekend. K2CO3 (0.25 g, 0.0018 mol) was added, the mixture was filtered and the solvent was evaporated in vacuo. The crude intermediate was purified by filtration through _SiO2 (EA/MeOH 9:1). The crude product, a colourless solid, was used in the next step without purification.

LCMS (A): t _R =0.85 min; [M+N]+=403.87.

Step 2. Methyl (4aR,6R,7R,8R,8aR)-7-hydroxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-6-carboxylate.

To a mixture of the crude product from step 1 (15.5 g, 0.038 mmol) in THF (400 mL) and 2,2-dimethoxypropane (7.22 mL, 0.058 mmol) at rt was added PTSA (0.165 g, 0.001 mol). The reaction mixture was stirred at 75 °C for 1.5 h, during which time ca. 150 mL of solvent was distilled from the mixture. The mixture was allowed to cool to rt and partitioned between aq. sat. NaHCO ₃ and EA. The aq. layer was extracted again with EA. The combined org. layers were washed with water and brine, dried over MgSO ₄ , filtered and evaporated in vacuo. The crude product, a yellowish solid, was used in the next step without purification.

LCMS (A): t _R =0.88 min; [M+N] ⁺ =444.01.

Intermediate 6. Methyl (4aR,6R,7R,8R,8aR)-7-methoxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d] [1,3]dioxin-6-carboxylate.

To a solution of intermediate 5 (16.5 g, 0.037 mol) in DMF (180 mL) at 0 °C was added iodomethane (2.57 mL, 0.041 mol) followed by NaH (60% dispersion in mineral oil, 1.57 g, 0.041 mol). The mixture was allowed to warm to rt and stirred at rt for 4 h. The mixture was cooled to 0 °C, carefully quenched by adding water and extracted twice with EA. The combined organic layers were washed with water and brine, dried with MgSO ₄ , filtered and evaporated in vacuo. The crude product is purified by column chromatography (6 cm x 24 cm _SiO2 column; gradient: heptane/EA 2:1 to heptane/EA 1:1) to afford the desired product as a yellowish solid.

LCMS (A): t _R =0.98 min; [M+N]+=458.03.

Acid 1. (4aR,6R,7R,8R,8aR)-7-Methoxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol1-yl)hexahydropyrano[3,2-d][1,3]dioxin-6-carboxylic acid.

A mixture of Intermediate 6 (12.8 g, 0.028 mol) in THF/MeOH/ _H2O (3.2:1, 90 mL) and LiOH- _H2O (1.77 g, 0.042 mmol) was stirred at rt for 2 h. The mixture was diluted with water (100 mL) and THF/MeOH was evaporated. Additional water (100 mL) and citric acid (10% solution in water) were added until pH 3. The suspension was filtered, the solid was washed with water and the crude product, a colourless solid, was dried in i.v.

LCMS (A): t _R =0.87 min; [M+N]+=444.03.

Acids 2-6 are synthesized in analogy with acid 1, using the appropriate acetylene for a cycloaddition reaction with intermediate 2.

Acid Connection t _R [min] LC-MS A ms data m/z [M+H] ⁺ 2 (4aR, 6R, 7R, 8R, 8aR)-8-(4-(4-6poM-2,3-difluorophenyl)-1H-1,2,3-triazo l- 1-yl)-7methoxy-2,2-dimethylhexahydropyrano[3,2-b][1,3]dioxin-6-carboxylic acid 0.89 505.92 3 (4aR,6R,7R,8R,8aR)-8-(4-(3,5-difluoro-4-methylphenyl)-lH-l,2,3-triazol-l-yl)-7methoxy-2,2-dimethylhexahydropyrano[3,2-b][1,3]dioxin-6-carboxylic acid 0.88 440.08 4 (4aR,6R,7R,8R,8aR)-8-(4-(2,3-difluoro-4-methylphenyl)-lH-l,2,3-triazol-l-yl)-7methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-carboxylic acid 0.87 440.12 5 (4aR,6R,7R,8R,8aR)-8-(4-(4-chloro-3,5-difluorophenyl)-lH-l,2,3-triazol-l-yl)-7methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-carboxylic acid 0.90 460.01 6 (4aR, 6R, 7R, 8R, 8aR)-8-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazolyl-1-yl)-7-methoxy-2,2 -dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-carboxylic acid 0.90 457.98

Preparation of intermediate compounds of structure 2.

Prom. comp. 7 Amine 1

- 35 048927

Intermediate 7. 4-((3-Chlorophenyl)amino)tetrahydrofuran-3-ol.

Step 1. To a solution of 3,6-dioxabicyclo[3.1.0]hexane (400 mg, 4.55 mmol) and 3-chloroaniline (639 mg, 5.01 mmol) in toluene (4 mL) was added InCl ₃ (71 mg, 0.32 mmol) and the reaction mixture was stirred at 85° for 3 days. Water and EA were added at rt and the mixture was stirred for 30 min at rt. The aqueous phase was separated and extracted with EA. The combined org. layers were dried with MgSO ₄ , filtered and evaporated in vacuo. The crude product was purified by prep. LCMS MS (II) to give the title Intermediate 7 as a yellow oil.

LCMS (A): t _R =0.72 min; [M+N]+=214.06.

Amine 1. 4-((tert-Butyldimethylsilyl)oxy)-N-(3-chlorophenyl)tetrahydrofuran-3-amine.

Step 2. To a solution of intermediate 7 (250 mg, 1.41 mmol) and 2,6-lutidine (333 mg, 3.1 mmol) in DCM (10 mL) at 0 °C was added tert-butyldimethylsilyl trifluoromethanesulfonate (447 mg, 1.69 mmol), and the mixture was stirred at 0 °C for 1 h. Water was added, the mixture was quenched with sat. aq. NH4Cl and extracted twice with DCM. The org. layers were washed with brine. The combined org. layers were dried over _MgSO4 , filtered, and concentrated. The crude product was purified by CombiFlash FC (24 g RediSep column, 0-30% EA in heptane over 10 min) to afford amine 1 as a colorless oil. LCMS (A): t _R =1.21 min; [M+N]+=328.05.

The following amines 2-11 are prepared by analogy with amine 1 in 2 steps by coupling the corresponding aniline with 3,6-dioxabicyclo[3.1.0]hexane.

Amine Connection t _R [min] LC-MS A MS data m/z [M+H] ⁺ 2 H-(3-bromophenyl)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-3amine 1.22 371.97 3 4-((trv/l-butyldimethylsilyl)oxy)-C-(3-iodophenyl)tetrahydrofuran-3-a min 1.23 419.86 4 4-((tert-butyldimethylsilyl)oxy)-X-(3,5-dichlorophenyl)tetrahydrofuran-3-amine 1.26 361.97 5 3-((4-((da/>e»g-butyldimethylsilyl)oxy)tetrahydrofuran-3-yl)amino)-5-x lorbenzonitrile 1.21 352.97 6 4-(((3,5-dibromophenyl)tetrahydrofuran-3-amine)-((3,5-dibromophenyl)-dimethylsilyl)oxy)-1-(3,5-dibromophenyl)tetrahydrofuran-3-amine) 1.28 451.89 7 3-bromo-5-((4-((dareda-butyldimethylsil yl)ox and)tetrahydrofuran-3-yl)amino)benzonitrile 1.22 398.96 8 N-(3-bromo-5-methylphenyl)-4-((n-butyldimethylsilyl)oxy)tetrahydrofuran-3-amine 1.25 385.82 9 3-((4-((»г/>е»г-butyldimethylsilyl)oxy)tetrahydrofuran-3-yl)amino)-5-m ethoxybenzonitrile 1.16 349.07 10 3-((4-((da/>e"g-butyldimethylsilyl)oxy)tetrahydrofuran-3-yl)amino)-5-ethylbenzonitrile 1.19 333.11 11 3-((4-((yau?eta-butyldimethylsilyl)oxy)tetrahydrofuran-3-yl)amino)-5-fluorobenzonitrile 1.17 337.05

The following amines 12 and 13 are prepared analogously to amine 1 in 2 steps by coupling the appropriate aniline with tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate. The enantiomers are separated by chiral chromatography before silylation and used for the amide coupling reaction.

Vos

Amine Connection t _R [min] LC-MS A MS data m/z [M+H] ⁺ 12* mpem-butyl (3 8,48)-3-((t/>-butyldimethylsilyl)oxy)-4-((3,5-dichlorophenyl)amino)pyrrolidine-1-carboxylate 1.32 461.08 13* t/>et-butyl (3S, 4 8)-3-((3 -bromo-5 -methylphenyl)amino)-4-((»r/>e»r-butyldimethyl-silyl)oxy)pyrrolidine-1-carboxylate 1.30 486.90

*May contain tert-butyldimethylsilyl (3S,4S)-3-((tert-butyldimethylsilyl)oxy)-4-((3,5-dichlorophenyl)amino)pyrrolidine-1-carboxylate as a by-product of hydroxyl group protection with TBSCl.

The following amines 14-17 are prepared analogously to amine 1 in 2 steps by coupling the corresponding aniline with 1-(6-oxa-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one. The enantiomers 16 are separated with

- 36 048927 by chiral chromatography before silylation and used for the amide coupling reaction, amines 14, 15 and 17 are used for the amide coupling as a racemate.

Amine Connection t _R [min] LC-MS A ms data m/z [M+H] ⁺ 14 1-(3-((tert-butyldimethylsilyl)oxy)-4-((3,5-dichlorophenyl)amino)pyrrolidone-1-yl)ethan-1-one 1.22 402.90 15 1-(3-((»г/>е»г-butyldimethylsilyl)oxy)-4-((3,5-dibromophenyl)amino)pyrrolide-1-yl)ethan-1-one 1.23 492.77 16 3-(((3 S,4S)-1-acetyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-3-yl)amino)-5-bromobenzonitrile 1.17 439.93 17 1-(3-((3-bromo-5-methylphenyl)amino)-4-((»у?е»г-butyldimethylsil yl )oxy)pyrrolidin-1-yl)ethan-1-one 1.22 428.92

The following amines 18-21 are prepared analogously to amine 1 in 2 steps by coupling the corresponding aniline with 3,7-dioxabicyclo[4.1.0]heptane. In these cases, the resulting amino alcohols are separated by chiral chromatography before silylation and used for the amide coupling reaction.

Amine Connection t _R [min] LC-MS A MS data m/z [M+H] ⁺ 18 (ЗК,48)-3-((т/>е»г-butyldimethylsilyl)oxy)-X-(3,5-dichlorophenyl)tetrahydro-2H-pyran-4-amine 0.85 262.04 19 (38,4K)-3-((t/>g-butyldimethylsilyl)oxy)-X-(3,5-dichlorophenyl)tetrahydro-2H-pyran-4-amine 0.85 262.04 20 (3 8.48 )-4-((/l/l'/l-butyldimethyl methyl)oxy)-X-(3,5-dichlorophenyl)tetrahydro-2H-pyran-3-amine 0.84 262.04 21 (ЗК,4К)-4-((т/>е»г-butyldimethylsilyl)oxy)-X-(3,5-dichlorophenyl)tetrahydro-2Н-pyran-3-amine 0.84 262.04

The following amines 22 - 25 are prepared analogously to amine 1 in 2 steps by coupling the appropriate aniline with tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate. In these cases, the resulting amino alcohols are separated by chiral chromatography before silylation and used for the amide coupling reaction.

Amine Connection t _R [min] LC-MS A MS data m/z [M+H] ⁺ 22 tert-butyl (3 8.48)-3-((and/>eng-butyldimethylsilyl)oxy)-4-((3,5-dichlorophenyl)amino)pi peridin-1-carboxylate 1.03 360.93 23 tert-butal (3 R,4R)-3-((tert-butyldimethylsilyl)oxo)-4-((3,5-dichlorophenyl)amino)piperidine-1-carboxylate 1.03 360.95 24 t-bottle (3 8,48)-4-((w/>e"g-butyldimethylsilyl)oxy)-3 -((3,5-dichlorophenyl)amino)pi peridin-1-carboxylate 1.01 360.95 25 tert-butyl (3R,4R)-4-((/and^>e»g-butyldimethylsilyl)oxide)-3-((3,5-dichlorophenyl)amino)piperidine-1-carboxylate 1.01 360.94

- 37 048927

B. Getting examples.

Example 1. (2R,3R,4S,5R,6R)-N-(3-Chlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro2H-pyran-2-carboxamide.

Step 1. (4aR,6R,7R,8R,8aR)-N-((3S,4R)-4-((tert-Butyldimethylsilyl)oxy)tetrahydrofuran-3-yl)N-(3-chlorophenyl)-7-methoxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-6-carboxamide.

To a mixture of acid 1 (50 mg; 0.113 mmol) and amine 1 (39 mg, 0.118 mmol) in DCM (4 mL) at rt was added phosphorus(V) oxychloride (1 M solution in pyridine, 0.14 mL, 0.135 mmol), and the mixture was stirred at rt for 24 h. Water was added, the mixture was quenched with sat. aq. NH ₄ Cl and extracted twice with DCM. The org. layers were washed with brine. The combined org. layers were dried over MgSO ₄ , filtered and concentrated. The crude product was purified by prep. LC-MS (I) to afford intermediate 8 (as a mixture of diastereomers).

LCMS (A): t _R =1.29/1.30 min; [M+N]+=753.10.

Step 2. (2R,3R,4S,5R,6R)-N-(3-Chlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro

2H-pyran-2-carboxamide.

To a solution of intermediate 8 (mixture of diastereomers) (74 mg, 0.98 mmol) in dioxane (1 mL) and water (0.5 mL) at 0 °C was added TFA (0.60 mL, 7.8 mmol), and the reaction mixture was stirred at rt for 21 h. The solvent was evaporated, MeCN was added, the mixture was basified with 25% aq. NH ₄ OH (until pH 11) and the product was purified by prep. LCMS (II) to give the title compound as a mixture of diastereomers, which were separated by chiral column chromatography to give example 1 and example 30.

Example 1: 1H NMR (500 MHz, DMSO-d ₆ ) δ: 9.00 (s, 1H), 7.88 (dd, J^9.0 Hz, J ₂ =6.8 Hz, 2H), 7.57 (m, 1H), 7.49-7.52 (m, 1H), 7.46 (s, 1H), 7.35-7.39 (m, 1H), 5.39 (d, J=4.9 Hz, 1H), 5.33 (d, J=6.0 Hz, 1H), 4.83 (d, J=9.2 Hz, 1H), 4.63-4.72 (m, 2H), 4.39 (dd, J1=9.1 Hz, J ₂ =10.6 Hz, 1H), 4.24 (m, 1H), 4.03 (dd, J1=7.1 Hz, J2=9.5 Hz, 1H), 3.76 (m, 1H), 3.64 (m, 2H), 3.50 (d, J=9.0 Hz, 1H), 3.38-3.46 (m, 3H), 3.17 (t, J=6.4 Hz, 1H), 3.07 (s, 3H).

LC-MS (A): t _R =0.85 min; [M+N]+=599.05.

Example 59. (2R,3R,4S,5R,6R)-N-(3,5-Dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1, 2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide.

Step 1. tert-Butyl (3S,4S)-3-((tert-butyldimethylsilyl)oxy)-4-((4aR,6R,7R,8R,8aR)-N-(3,5-dichlorophenyl)-7-methoxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-6-carboxamido)pyrrolidine-1-carboxylate.

To a mixture of Acid 1 (450 mg; 1.01 mmol) and Amine 12 (554 mg, 1.07 mmol) in DCM (35 mL) at rt was added phosphorus(V) oxychloride (1 M solution in pyridine, 1.22 mL, 1.22 mmol), and the mixture was stirred at rt for 24 h. Water was added, the mixture was quenched with sat. aq. NH ₄ Cl and extracted twice with DCM. The org. layers were washed with brine. The combined org. layers were dried over MgSO ₄ , filtered and concentrated. The crude product was purified by ISCO (24 g RediSep column, 0-80% EA in heptane over 15 min) to give intermediate 9 as a yellow foam.

LCMS (A): t _R =1.37 min; [M+N]+=886.09.

- 38 048927

The product may contain tert-butyldimethylsilyl (3S,4S)-3-((tert-butyldimethylsilyl)oxy)-4((4aR,6R,7R,8R,8aR)-N-(3,5-dichlorophenyl)-7-methoxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-6-carboxamido)pyrrolidine-1-carboxylate.

LCMS (A): t _R =1.42 min; [M+N]+=944.10.

Step 2. (2R,3R,4S,5R,6R)-N-(3,5-Dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide.

To a solution of intermediate 9 (486 mg, 0.51 mmol) in dioxane (10 mL) and water (5 mL) at 0 °C was added TFA (1.97 mL, 25.7 mmol), and the reaction mixture was stirred at rt for 2 weeks [additional TFA (0.5 mL) was added after 3 days and 1 week]. EA was added, the mixture was basified with 25% aq. NH4OH (until pH 9) and extracted twice with EA. The org. layers were washed with brine. The combined org. layers were dried over _MgSO4 , filtered, and concentrated. The crude product was purified by ISCO (12 g RediSep column, 0-30% 7 N _NH3 /MeOH in DCM) and prep. LC-MS (II) to give the final product as a colourless solid.

LCMS (A): t _R =0.71 min; [M+N] ⁺ =631.96.

Example 59: 1H NMR (500 MHz, DMSO) δ: 9.01 (s, 1H), 7.89 (dd, ^=9.0 Hz, J ₂ =6.8 Hz, 2H), 7.76 (t, J=1.8 Hz, 1H), 7.48 (s, 2H), 5.34 (d, J=6.0 Hz, 1H), 5.11 (d, J=5.1 Hz, 1H), 4.92 (dd, J1=10.7 Hz, J ₂ =2.9 Hz, 1H), 4.70 (m, 1H), 4.40 (dd, J1=9.0 Hz, J ₂ =10.7 Hz, 1H), 4.33 (m, 1H), 4.01 (m, 1Н), 3.79 (dd, J1=6.0 Hz, J2=2.8 Hz, 1H), 3.59 (d, J=9.0 Hz, 1H), 3.40-3.56 (m, 2H), 3.31 (m, 2H), 3.16 (dd, ^=8.3 Hz, J ₂ =11.3 Hz, 1H), 3.00-3.07 (m, 3H), 2.87 (dd, J1=6.6 Hz, J2=11.2 Hz, 1H), 2.80 (dd, J1=7.4 Hz, J2=11.4 Hz, 1H)

Example 72. (2R,3R,4S,5R,6R)-N-((3S,4S)-1-Acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1yl)tetrahydro-2H-pyran-2-carboxamide.

This product is obtained in 2 stages by analogy with example 1 from acid 1 and amine 15. Diastereomers are separated by chiral chromatography to obtain compounds of examples 72 and 79.

LCMS (A): t _R =0.84 min; [M+N]+=697.91.

Example 72. 100°C: 1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.82 (m, 1H), 7.77-7.83 (m, 2H), 7.49-7.51 (m, 1H), 7.31-7.42 (m, 1H), 7.17-7.28 (m, 1H), 5.17-5.29 (m, 1H), 4.96-5.02 (m, 1H), 4.64-4.82 (m, 2H), 4.42-4.49 (m, 1H), 4.33-4.42 (m, 1H), 4.13-4.29 (m, 1H), 3.84-3.93 (m, 1H+0.5H), 3.70-3.75 (m, 0.5 N), 3.33-3.65 (m, 5 N), 3.16-3.33 (m, 1H), 3.09 (s, 3H), 2.97 (m, 1H), 2.39 (s, 3H), 1.83 (s, 3H).

N-acetyl analogues can also be obtained by a 2-step method - peracetylation and O-deacetylation from the corresponding NH products, as shown for example 71.

Example 71. (2R,3R,4S,5R,6R)-N-((3S,4S)-1-Acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide.

Step 1. (2R,3R,4R,5R,6R)-6-(((3S,4S)-4-Acetoxy-1-acetylpyrrolidin-3-yl)(3,5-dichlorophenyl)carbamoyl)-2-(acetoxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl acetate.

To a solution of compound 59 (23 mg, 0.0364 mmol) in DCM (1.5 mL) at rt were added triethylamine (0.050 mL, 0.364 mmol), acetic anhydride (0.017 mL, 0.182 mmol) and DMAP (6.7 mg,

- 39 048927

0.054 mmol), and the mixture was stirred at rt for 15 min. The mixture was quenched with sat. aq. NH ₄ Cl and extracted twice with DCM. The org. layers were washed with brine. The combined org. layers were dried over MgSO ₄ , filtered and concentrated. Intermediate 11 was used in the next step without purification.

LCMS (A): t _R =1.07 min; [M+N]+=800.03.

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

To a solution of intermediate 11 (27 mg, 0.0337 mmol) in MeOH (1.5 mL) was added a solution of NaOMe in MeOH (1.26 mL; prepared in-house by dissolving 0.25 mg NaOMe in 1 mL MeOH) at rt, and the mixture was stirred for 3 h. The mixture was quenched with sat. aq. _NH4Cl and extracted twice with ethyl acetate. The org. layers were washed with brine. The combined org. layers were dried over MgSO4, filtered and concentrated. The crude product was purified by prep. LC-MS (II) to give the final product as a colorless solid LCMS (A): t _R = 0.85 min; [M+H]+ = 673.86.

Example 90. (2R,3R,4S,5R,6R)-N-(3-Bromo-5-methylphenyl)-N-((3S,4S)-1-formyl-4-hydroxypyrrolidin-3yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide.

To a solution of the compound of Example 61 (35 mg, 0.053 mmol) in ethyl formate (0.44 mL, 5.33 mmol) was added triethylamine (0.008 mL, 0.053 mmol), and the reaction mixture was stirred at 50 °C for 4 h in a sealed tube. The solvent was evaporated and the mixture was purified by prep. LC-MS (II) to give the final product as a colorless solid.

LCMS (A): t _R =0.84 min; [M+N]+=683.83.

Example 90. 100°C ¹ H NMR (400 MHz, DMSO) δ: 8.82 (s, 1H), 8.00 (brs, 1H), 7.78-7.82 (m, 2H), 7.50 (s, 1H), 7.37 (m, 1H), 7.23 (s, 1H), 5.22-5.37 (m, 1H), 4.97-5.03 (m, 1H), 4.74-4.79 (m, 1H), 4.59-4.65 (m, 1H), 4.45 (m, 1H), 4.34-4.41 (m, 1H), 4.18-4.28 (m, 1H), 3.50-4.0 (m, 6H), 3.34-3.49 (m, 1H), 3.19-3.32 (m, 1H), 3.09 (s, 3H), 3.01-3.05 (m, 1H), 2.39 (s, 3H).

connection 12

Example 99. (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-3hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide.

This product is obtained in 2 stages by analogy with example 1 from acid 1 and amine 18.

LCMS (A): t _R =0.93 min; [M+N]+=646.97.

Example 99: 1H NMR (500 MHz, DMSO) δ: 9.00 (s, 1H), 7.89 (dd, J1=6.8 Hz, J ₂ =9.1 Hz, 2H), 7.78 (t, J=1.9 Hz, 1H), 7.55 (s, 1H), 7.38 (s, 1H), 5.33 (d, J=6.0 Hz, 1H), 5.10 (d, J=5.7 Hz, 1H), 4.90 (dd, J1=10.8 Hz, J ₂ =2.9 Hz, 1H), 4.68 (t, J=5.6 Hz, 1H), 4.31-4.41 (m, 2H), 3.76-3.81 (m, 4H), 3.55 (d, J=9.0 Hz, 1H), 3.45 (t, J=6.1 Hz, 2H), 3.31-3.36 (m, 1H), 3.28 (t, J=6.7 Hz, 1H), 3.21 (m, 1H), 3.07 (s, 3H), 1.71-1.84 (m, 2H).

- 40 048927

Example 105

Example 105. (2R,3R,4S,5R,6R)-N-(3,5-Dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-III-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide.

This product is obtained in 2 stages by analogy with example 1 from acid 1 and amine 20.

LCMS (A): t _R =0.93 min; [M+N]+=647.00.

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

Example 109 Example 113

Example 109. (2R,3R,4S,5R,6R)-N-(3,5-Dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-3hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide.

This product is obtained in 2 stages by analogy with example 1 from acid 1 and amine 22.

LCMS (A): t _R =0.71 min; [M+N]+=645.90.

Example 109: ¹ H NMR (500 MHz, DMSO) δ: 9.00 (s, 1H), 7.89 (dd, Ji=9.1 Hz, J ₂ =6.8 Hz, 2H), 7.77 (t, J=1.9 Hz, 1H), 7.57 (s, 1H), 7.27-7.34 (m, 1H), 5.33 (d, J=6.0 Hz, 1H), 4.88 (dd, J1=2.9 Hz, J ₂ =10.8 Hz, 1H), 4.85 (d, J=5.4 Hz, 1H), 4.68 (t, J=5.4 Hz, 1H), 4.38 (dd, J1=10.7 Hz, J ₂ =9.0 Hz, 1H), 4.24-4.33 (m, 1H), 3.79 (dd, J1=6.1 Hz, J ₂ =3.0 Hz, 1H), 3.52-3.55 (m, 1H), 3.45 (m, 2H), 3.23-3.28 (m, 1H), 3.06 (s, 3H), 2.87-3.03 (m, 2H), 2.78-2.87 (m, 1H), 2.37-2.43 (m, 1H), 2.22-2.27 (m, 1H), 1.67-1.81 (m, 1H), 1.31-1.54 (m, 1H).

Example 113. (2R,3R,4S,5R,6R)-N-(3,5-Dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4hydroxypiperidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide.

This product is obtained in 2 stages by analogy with example 1 from acid 1 and amine 24.

LCMS (A): t _R =0.70 min; [M+N]+=645.90.

Example 113: 1H NMR (500 MHz, DMSO) δ: 9.00 (s, 1H), 7.89 (dd, J1=6.8 Hz, J ₂ =9.1 Hz, 2H), 7.75 (t, J=1.9 Hz, 1H), 7.58 (s, 1H), 7.31-7.35 (m, 1H), 5.33 (d, J=6.0 Hz, 1H), 4.88 (dd, Ji=2.9 Hz, J ₂ =10.8 Hz, 1H), 4.85 (d, J=5.6 Hz, 1H), 4.69 (t, J=5.5 Hz, 1H), 4.39 (dd, J1=10.7 Hz, J ₂ =9.0 Hz, 1H), 4.11-4.19 (m, 1H), 3.79 (dd, Ji=6.0 Hz, J ₂ =3.0 Hz, 1H), 3.52 (d, J=8.9 Hz, 1H), 3.45 (t, J=6.0 Hz, 2H), 3.26 (t, J=6.6 Hz, 1H), 3.10-3.21 (m, 1H), 3.07 (s, 3H), 2.96-2.99 (m, 1H), 2.78 (dd, J1=10.9 Hz, J ₂ =1.3 Hz, 1H), 2.43-2.49 (m, 1H), 2.20-2.30 (m, 1H), 1.80-1.83 (m, 1H), 1.32-1.39 (m, 1H).

The following compounds are prepared in analogy with Example 1 from the corresponding acids and amines, or as described for the mentioned Examples 59, 71, 72, 90, 99, 105, 109 or 113.

- 41 048927

Table 1

Example Connection t _R [min] LC-MS (A) MS data m/z [M+H] ⁺ 1 (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxy-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-tri azol-1-yl]-N-(3-chlorophenyl)-N-((ЗS,4R)-4-hydroxy-3-tetrahydrofuranyl)-beta-O-galactopyranose-1-carboxamide 0.85 599.05 2 (2R,3R,4 S,5R,6R)-N-(3-bromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((ЗS,4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.86 642.96 3 (2K,3K,48,5K,6K)-5-hydroxy-6-(hydroxymethyl)-N-((3 8,4K)-4-hydroxytetrahydrofuran-3-yl)-N-(3-iodophenyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-k arboxamide 0.86 690.75 4 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyrrolidone-2-carboxamide 0.89 633.98 5 (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2Hpyran-2-carboxamide 0.85 624.07 6 (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.91 722.84 7 (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2Hpyran-2-carboxamide 0.86 669.58 8 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2Hpyran-2-carboxamide 0.89 656.98 9 (2R,3R,4S,5R,6R)-N-(3-cyano-5-methoxyphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.83 620.08 10 (2R, 3R, 4 S, 5R, 6R)-N-(3-cyano-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S, 4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2 H-pyran-2-carboxamide 0.83 604.10 11 (2R,3R,4S,5R,6R)-N-(3-cyano-5-fluorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2Hpyran-2-carboxamide 0.83 608.06 12 (2R, 3R, 4 S, 5R, 6R)-4-(4-(4-bromo-2,3-difluorophenyl)-lH-l, 2,3-triazolyl-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3 S, 4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.92 694.88 13 (2R, 3R, 4 S, 5R, 6R)-4-(4-(4-bromo-2,3-difluorophenyl)-lH-l, 2,3-triazolyl-1-yl)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl) N-((ЗS, 4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxytetrahydropyran o-2H-pyran-2-carboxamide 0.88 729.85 14 (2R, 3R, 4 S, 5R, 6R)-4-(4-(4-bromo-2,3-difluorophenyl)-lH-l, 2,3-triazolyl-1-yl)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)N-((3S, 4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxytetrahydropyran o-2H-pyran-2-carboxamide 0.92 718.82

- 42 048927

15 (2R, 3R, 4 S, 5R, 6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methyl phenyl)-1 H-1,2,3-triazolyl-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S, 4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxytetrahydro-2 H-pyran-2-carboxamide 0.91 629.02 16 (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,5-diφτop-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-( (3S,4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.92 718.79 17 (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3,5-diφτop-4-m ethylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3 S,4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxytetrahyde rho-2H-pyran-2-carboxamide 0.87 665.96 18 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-diφτop-4-ethylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl) -N-((3S,4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxytetrahyde rho-2H-pyran-2-carboxamide 0.90 654.95 19 (2R, 3R, 4 S, 5R, 6R)-N-(3,5-dichlorophenyl)-4-(4-(2,3-difluoro-4-methyl phenyl)- 1H-1,2,3 -triazo l- 1-yl)-5 -hydroxy-6-(hydroxymethyl) -N-((3S, 4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxytetrahydro-2 H-pyran-2-carboxamide 0.88 629.14 20 (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanoφenyl)-4-(4-(2,3-diφτop-4-m ethylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl) -N-((3S,4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxytetrahyde rho-2H-pyran-2-carboxamide 0.85 666.11 21 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-diφτop-4-ethylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl) -N-((3S,4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxytetrahyde rho-2H-pyran-2-carboxamide 0.88 655.09 22 (2R, 3R, 4 S, 5R, 6R)-4-(4-(4-chloro-3,5-difluorophenyl)-lH-1,2,3-triazolyl-1-ηπ)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3 S, 4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.92 649.06 23 (2R, 3R, 4 S,5R,6R)-4-(4-(4-chloro-3,5-diφτopφenyl)-lH-1,2,3-triazo l-1-yl)-M-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-M-(( 3S,4R)-4-hydroxytetrahydropyran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.93 738.97 24 (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(4-chloro-3,5-diφτ orphenyl)-1H-1,2,3-triazo l-1-yl)-5-hydroxy-6-(hydroxymethyl)N-((3S,4R)-4-hydroxyhydropyran-3-yl)-3-methohydroxy-2H-pyran-2-carboxamide 0.88 685.67 25 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(4-chloro-3,5-diφτ orphenyl)-1H-1,2,3-triazo l-1-yl)-5-hydroxy-6-(hydroxymethyl)N-((3S,4R)-4-hydroxyhydropyran-3-yl)-3-methohydroxy-2H-pyran-2-carboxamide 0.91 675.05 26 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-l H-1,2,3 -triazolyl-1-yl)-5 -hydroxy-6-(hydroxymethyl)-I-((3 8,4R)-4 -hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran2-carboxamide 0.92 648.93 27 (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,4-dichlorophenyl)-l H-l,2,3-TpHa3on-l-Hn)-5-rHflpoKCH-6-(rHflpoKCHMeTHn)-N-((3S,4R)-4 -hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran2-carboxamide 0.94 736.79 28 (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazolyl-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3 S,4 R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.89 683.92 29 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3 8,4 R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.92 672.92 30 (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydropyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.84 599.04

-43 048927

31 (2R,3R,4S,5R,6R)-N-(3-bromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3H,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.85 643.02 32 (2H,3H,48,5H,6H)-5-hydroxy-6-(hydroxymethyl)-N-((3H,48)-4-hydroxytetrahydrofuran-3-yl)-N-(3-iodophenyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-k arboxamide 0.85 690.74 33 (2H,3H,48,5H,6H)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3H,48)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyr n-2-carboxamide 0.88 632.97 34 (2H,3H,48,5H,6H)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3H,48)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2Hpyran-2-carboxamide 0.85 624.03 35 (2H,3H,48,5H,6H)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3H,48)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.91 722.85 36 (2H,3H,48,5H,6H)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydropyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2Hpyran-2-carboxamide 0.85 669.47 37 (2H,3H,48,5H,6H)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3H,48)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2Hpyran-2-carboxamide 0.88 658.97 38 (2H,3H,48,5H,6H)-N-(3-cyano-5-methoxyphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3H,48)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro2H-pyran-2-carboxamide 0.82 620.07 39 (2R,3R,48,5H,6H)-N-(3-cyano-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3H,48)-4-hydroxytetrahydrofuran-3-yl)-3-methox and-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2 H-pyran-2-carboxamide 0.83 604.08 40 (2H,3H,48,5H,6H)-N-(3-cyano-5-fluorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydropyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2Hpyran-2-carboxamide 0.82 608.07 41 (2R,3R,48,5H,6H)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazolyl-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3 R,4 S)-4-hydroxytetrahydrofuran-3-yl)-3-methox tetrahydro-2H-pyran-2-carboxamide 0.91 694.87 42 (2R,3R,48,5H,6H)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazolyl-1-yl)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)N-((3H,48)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.88 729.85 43 (2R,3R,48,5H,6H)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazolyl-1-yl)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)N-((3H,48)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.91 718.82 44 (2R, 3R, 4 S, 5R, 6R)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methyl phenyl)- 1H-1,2,3 -triazo l- 1-yl)-5 -hydroxy-6-(hydroxymethyl) -N-((3H,48)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2 H-pyran-2-carboxamide 0.90 629.08 45 (2H,3H,48,5H,6H)-N-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methyl phenyl)-1H-1,2,3-triazo-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3H,48)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2 H-pyran-2-carboxamide 0.91 718.83 46 (2H,3H,48,5H,6H)-N-(3-bromo-5-cyanophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3H,48)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.87 663.97

- 44 048927

47 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-diφτop-4-ethylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl) -N-((3R,4S)-4-hydroxytetrahydropyran-3-yl)-3-methoxytetrahyde rho-2H-pyran-2-carboxamide 0.90 654.94 48 (2R, 3R, 4 S, 5R, 6R)-N-(3,5-dichlorophenyl)-4-(4-(2,3-difluoro-4-methyl phenyl)- 1H-1,2,3 -triazo l- 1-yl)-5 -hydroxy-6-(hydroxymethyl)-N-((3R,48)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2 H-pyran-2-carboxamide 0.88 629.19 49 (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanoφenyl)-4-(4-(2,3-diφτop-4-m ethylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl) -M-((3K,48)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahyde rho-2H-pyran-2-carboxamide 0.84 664.10 50 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-diφτop-4-ethylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl) -N-((3R,4S)-4-hydroxytetrahydropyran-3-yl)-3-methoxytetrahyde rho-2H-pyran-2-carboxamide 0.87 655.11 51 (2R, 3R, 4 S, 5R, 6R)-4-(4-(4-chloro-3,5-difluorophenyl)-lH-1,2,3-triazolyl-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3 R, 4S)-4-hydroxytetrahydropyran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.91 651.07 52 (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-diφτopφenyl)-lH-1,2,3-triazo l-1-yl)-M-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-M-(( ZYa,48)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.92 738.96 53 (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(4-chloro-3,5-diφτ or phenyl)-1H-1,2,3-triazo l-1-yl)-5-hydroxy-6-(hydroxymethyl)N-((3R,4S)-4-hydroxyhydropyran-3-yl)-3-methohydroxy-2H-pyran-2-carboxamide 0.87 685.63 54 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(4-chloro-3,5-diφτ or phenyl)-1H-1,2,3-triazo l-1-yl)-5-hydroxy-6-(hydroxymethyl)N-((3R,4S)-4-hydroxyhydropyran-3-yl)-3-methohydroxy-2H-pyran-2-carboxamide 0.90 675.06 55 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-l H-1,2,3-triazo l-1-yl)-5-THflpoKCH-6-(rHflpoKCHMeTHn)-N-((3R,4 S)-4 -hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran2-carboxamide 0.92 648.93 56 (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,4-dichlorophenyl)-l H-1,2,3-triazolyl-1-yl)-5-THflpoKCH-6-(rHflpoKCHMeTHn)-N-((3R,4 S)-4 -hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran2-carboxamide 0.93 736.78 57 (2H,3K,48,5K,6K)-K-(3-bromo-5-cyanophenyl)-4-(4-(3,4-dichlorophenyl)-lH-l,2,3-TpHa3on-l-Hn)-5-THflpoKCH-6-(rHflpoKCHMeTHn)-N-((3R,4 8)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.88 683.90 58 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,4-dichlorophenyl)-lH-l,2,3-TpHa3on-l-Hn)-5-THflpoKCH-6-(rHflpoKCHMeTHn)-N-((3R,4 8)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.91 672.92 59 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-X-((38,48)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-k arboxamide 1,3-dideoxy-2-O-methyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-X-(3,5-dichlorophenyl ... (3-yl)-beta-0-galactopyranose-1-carboxamide 0.71 631.96 60 (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((38,48)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyr n-2-carboxamide 0.70 666.86 61 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((38,48)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyr n-2-carboxamide 0.72 655.83

- 45 048927

62 (2R, 3R, 4 S, 5R, 6R)-4-(4-(4-bromo-2,3-difluorophenyl)-lH-l, 2,3-triazo l-1-ηπ)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3 S, 48)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyr n-2-carboxamide 0.73 693.45 63 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazolyl-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((38,48)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.71 627.81 64 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-diφτop-4-m ethylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3 S,4S)-4-hydroxypyrrolidine-3 -yl)-3-methoxytetrahydro-2 H-pyran-2-carboxamide 0.70 651.96 65 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-l H-1,2,3-triazolyl-1-yl)-5-hydroxy-6-(hydroxymethyl)-X-((3 8,48)-4 -hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.74 647.73 66 (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl THn)-N-((3R,4R)-4-rHflpoKCHnnppolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide 0.71 631.98 67 (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxy CHMeTHn)-N-((3R,4R)-4-THflpoKCHnHpponnflHH-3-Hn)-3-MeTOKCH-4-(4 -(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyr n-2-carboxamide 0.70 666.86 68 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxy CHMeTHn)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyr n-2-carboxamide 0.72 655.85 69 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-diφτop-4-m ethylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3 R,4R)-4-hydroxypyrrolidine-3 -yl)-3-methoxytetrahydro-2 H-pyran-2-carboxamide 0.70 653.94 70 a mixture of two diastereomers: (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-diφτop-4-m ethylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3 S,4S)-4-hydroxypyrrho lidin-3-yl)-3-methoxytetrahydro-2 H-pyran-2-carboxamide (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-diφτop-4-m ethylphenyl)-1H-1,2,3-triazo l- 1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.72 653.84 71 (2R,3R,4S,5R,6R)-N-((3S,4S)-l-aiieTHn-4-rHflpoKCHnHpponHflHH-3-H π)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro-2Hpyran-2-carboxamide 0.85 673.86 72 (2R,3R,4S,5R,6R)-N-((3S,4S)-l-aiieTHn-4-rHflpoKCHnHpponHflHH-3-H π)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.84 697.91 73 (2R,3R,4S,5R,6R)-N-((3S,4S)-l-aiieTHn-4-rHflpoKCHnHpponHflHH-3-H l)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-X-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.98 734.27 74 (2R,3R,4S,5R,6R)-N-((3S,4S)-l-aiieTHn-4-rHflpoKCHnHpponHflHH-3-H l)-X-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.98 758.26 75 (2R,3R,4S,5R,6R)-N-((3S,4S)-l-aiieTHn-4-rHflpoKCHnHpponHflHH-3-H l)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H1,2,3-triazolyl-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.85 693.96 76 (2R,3R,4S,5R,6R)-N-((3S,4S)-l-aiieTHn-4-rHflpoKCHnHpponHflHH-3-H π)-N-(3-bromo-5-methylphenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazolyl-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.87 715.86

- 46 048927

77 (2R,3 R,4 S,5 R,6R)-N-((3 R,4R)-1-acetyl-4-hydroxypyrrolidine-3-and n)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5 -trifluorophenyl)-1H-1,2,3 -triazo l-1 -yl)tetrahydro-2Hpyran-2-carboxamide 0.84 673.85 78 (2R,3R,4S,5R,6R)-N-((3R,4R)-l-aHeTHn-4-rHflpoKCHnHpponHflHH-3-H π)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.82 710.84 79 (2R,3R,4S,5R,6R)-N-((3R,4R)-l-aHeTHn-4-THflpoKCHnHpponHflHH-3-H π)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.83 697.93 80 (2R,3R,4S,5R,6R)-N-((3R,4R)-l-aHeTHn-4-THflpoKCHnHpponHflHH-3-H l)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-X-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.98 734.24 81 (2R,3R,4S,5R,6R)-N-((3R,4R)-l-aHeTHn-4-THflpoKCHnHpponHflHH-3-H l)-N-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methox tetrahydro-2H-pyran-2-carboxamide 0.98 758.26 82 (2R,3R,4S,5R,6R)-N-((3R,4R)-l-aHeTHn-4-THflpoKCHnHpponHflHH-3-H π)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H1,2,3-triazo-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.83 693.97 83 (2R,3R,4S,5R,6R)-N-((3R,4R)-l-aHeTHn-4-THflpoKCHnHpponHflHH-3-H π)-N-(3-bromo-5-methylphenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazo-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.86 715.88 84 mixture of two diastereomers: (2R,3R,4S,5R,6R)-N-((3S,4S)-l-acetyl-4-hydroxypyrrolidine-3-and l)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2Hpyran-2-carboxamide (2R,3R,4S,5R,6R)-N-((3R,4R)-l-aHeTHn-4-THflpoKCHnHpponHflHH-3-H π)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy -4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro-2Hpyran-2-carboxamide 0.85 763.73 85 mixture of two diastereomers: (2R, 3R, 4 S, 5R, 6R)-N-((3S, 4 S)-l-acetyl-4-hydroxypyrrolidine-3-i l)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methox tetrahydro-2H-pyran-2-carboxamide (2R, 3 R, 4 S, 5R, 6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidine-3-i l)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazo (l-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methox tetrahydro-2H-pyran-2-carboxamide 0.85 669.83 86 mixture of two diastereomers: (2R, 3R, 4 S, 5R, 6R)-N-((3S, 4 S)-l-acetyl-4-hydroxypyrrolidine-3-i l)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-X-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide (2R,3R,4S,5R,6R)-N-((3R,4R)-l-aHeTHn-4-rHflpoKCHnHpponHflHH-3-H l)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-X-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro -2H-pyran-2-carboxamide 0.87 689.82 87 mixture of two diastereomers: (2R, 3R, 4 S, 5R, 6R)-N-((3S, 4 S)-l-acetyl-4-hydroxypyrrolidine-3-and l)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-X-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide (2R,3R,4S,5R,6R)-N-((3R,4R)-l-aHeTHn-4-rHflpoKCHnHpponHflHH-3-H l)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.88 779.73

- 47 048927

88 mixture of two diastereomers: (2R,3R,4S,5R,6R)-N-((3S,4S)-l-acetyl-4-hydroxypyrrolidine-3-i l)-N-(3,5-dichlorophenyl)-4-(4-(3,4-Dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide (2H,3H,4S,5H,6H)-N-((3H,4H)-1-acetyl-4-hydroxypyrrolidine-3-i l)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.86 689.79 89 (2H,3H,48,5H,6H)-N-(3-bromo-5-cyanophenyl)-N-((3 8,48)-1-formyl4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.84 696.84 90 (2H,3H,48,5H,6H)-N-(3-bromo-5-methylphenyl)-N-((3 8,48)-1-formyl4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.84 683.83 91 (2R,3R,48,5H,6H)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazolyl-1-yl)-N-(3,5-dichlorophenyl)-N-((38,4S)-l-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.87 721.73 92 (2H,3H,48,5H,6H)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-N-((38,48)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxyethylamine-2H-pyran-2-carboxamide 0.83 679.81 93 (2R,3R,48,5H,6H)-N-(3-bromo-5-cyanophenyl)-N-((3H,4H)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.81 696.88 94 (2R,3R,48,5H,6H)-N-(3-bromo-5-methylphenyl)-X-((3H,4H)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.84 685.83 95 (2H,3H,48,5H,6H)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-X-((3H,4H)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide 0.83 679.87 96 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-N-((3S,4S)-4-hydroxy-1-methylpyrrolidin-3-yl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.73 671.96 97 (2H,3H,48,5H,6H)-N-(3-bromo-5-methylphenyl)-N-((38,48)-1-ethyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methyl-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.75 684.01 98 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-N-((3S,4S)-4-hydroxy-1-(methylsulfonyl)pyrrolidin-3-yl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.90 735.95 99 (2H,3H,48.5H,6H)-M-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-3-rnflpoKCHTeTparnflpo-2H-nnpaH-4-nn)-3-methoxy -4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro-2Hpyran-2-carboxamide 1,3-dideoxy-2-O-methyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-tri-azol-1-yl]-N-(3,5-dichlorophenyl)-M-((3H, 4 S)-3-hydroxytetrahydro -2H-pyran-4-yl)-beta-0-galactopyranose-1-carboxamide 0.93 646.97 100 (2H,3H,48,5H,6H)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-X-((3H,48)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.89 637.92 101 (2H,3H,48,5H,6H)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxycnMeTnn)-N-((3R,4S)-3-rnflpoKCHTeTparn ₄ po-2H-nnpaH-4-nn)-3-MeT oxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.89 682.01

- 48 048927

102 (2K,3K,48,5K,6K)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3K,48)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.93 671.00 103 (2K,3K,48,5K,6K)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl τηπ)-N-((3 8,4K)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2Hpyran-2-carboxamide 0.91 646.96 104 (2K,3K,48,5K,6K)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-X-((38,4K)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.90 671.00 105 (2K,3K,48,5K,6K)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl τηπ)-N-((3 S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy4-(4-(3,4,5 -trifluorophenyl)-1H-1,2,3 -triazolyl-1 -yl)tetrahydro-2Hpyran-2-carboxamide 0.93 647.00 106 (2K,3K,48,5K,6K)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-X-((38,48)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro -2H-pyran-2-carboxamide 0.92 671.00 107 (2K,3K,48,5K,6K)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-X-((3K,4K)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2Hpyran-2-carboxamide 0.91 646.97 108 (2K,3K,48,5K,6K)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3B.,4B.)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.90 670.97 109 (2K,3K,48,5K,6K)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((38,48)-3-hydroxypiperidin-4-yl)-3-methoxy-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-(3,5-dichlorophenyl)-X-((38,48)-3-hydroxypiperidin-4-yl)-beta-O-galactopyranose-1-carboxamide 0.71 645.90 BY (2E,3E,48,5E,6E)-X-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((38,48)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.70 680.97 111 (2K,3K,48,5K,6K)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3 S,4S)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.71 669.63 112 (2K,3K,48,5K,6K)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3B.,4B.)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyr n-2-carboxamide 0.71 669.65 113 (2K,3K,48,5K,6K)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-X-((38,48)-4-hydroxypiperidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.70 645.90 114 (2K,3K,48,5K,6K)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((38,48)-4-hydroxypiperidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide 0.72 669.66 115 (2K,3K,48,5K,6K)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3B.,4B.)-4-hydroxypiperidin-3-yl)-3-methoxy-4-(4(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyr n-2-carboxamide 0.71 669.61

II. Biological analyses.

Determination of inhibitory activity of compounds (IC50).

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 and mixed.

The plates are incubated for 3 h at 4°C, then washed with cold assay buffer (3x50 µl) and incubated for 1 h with 25 µl/well of streptavidin-peroxidase solution (diluted

- 49 048927 (in assay buffer to 80 ng/ml) at 4°C followed by additional washing steps with assay buffer (3x50 µl). Finally, 25 µl/well of ABTS substrate are added. After 30-45 min, the OD (410 nm) is recorded and the IC ₅₀ values are calculated.

The calculated IC ₅₀ values may fluctuate depending on the day of the analysis. Such fluctuations are known to those skilled in the art. IC ₅₀ values from several measurements are given as average values.

Table 2

Activity against hGal-3 (IC ₅₀ in nM)

Example Gal-3 1C ₅₀ [nM] Example Gal-3 1C ₅₀ [nM] Example Gal-3 1C ₅₀ [nM] Example Gal-3 1C ₅₀ [nM] 1 102 2 80 3 56 4 72 5 69 6 53 7 83 8 77 9 101 10 136 AND 124 12 47 13 15 14 46 15 38 16 61 17 66 18 69 19 40 20 31 21 35 22 50 23 55 24 73 25 31 26 162 27 89 28 115 29 153 30 235 31 103 32 130 33 104 34 102 35 84 36 67 37 186 38 FROM 39 69 40 145 41 63 42 37 43 33 44 81 45 59 46 81 47 72 48 29 49 18 50 34 51 73 52 86 53 46 54 89 55 164 56 222 57 151 58 175 59 23 60 51 61 26 62 12 63 24 64 25 65 54 66 182 67 129 68 222 69 38 70 56 71 36 72 26 73 23 74 27 75 22 76 37 77 80 78 71 79 76 80 31 81 40 82 45 83 67 84 70 85 327 86 64 87 36 88 71 89 38 90 20 91 20 92 19 93 80 94 86 95 40 96 51 97 24 98 29 99 16 100 16 101 14 102 14 103 299 104 256 105 18 106 13 107 217 108 315 109 12 110 17 111 14 112 184 113 13 114 9 115 196

- 50 048927

Table 3

Activity against hGal-1 (IC ₅₀ in nM)

Example Gal-1 1C ₅₀ [nM] Example Gal-1 1C ₅₀ [nM] Example Gal-1 1C ₅₀ [nM] Example Gal-1 1C ₅₀ [nM] 1 2427 2 1680 3 2713 4 1298 5 801 6 689 7 956 8 1412 9 1475 10 1453 11 1723 12 807 13 593 14 1944 15 1934 16 2281 17 1415 18 3638 19 1355 20 1121 21 1758 22 2012 23 2492 24 1414 25 3061 26 788 27 950 28 308 29 1259 30 3870 31 3268 32 3887 33 1612 34 1195 35 2478 36 836 37 2477 38 1648 39 1458 40 1363 41 999 42 1030 43 3266 44 2524 45 2537 46 1419 47 6187 48 1451 49 1165 50 3280 51 3250 52 3506 53 2417 54 7387 55 982 56 1468 57 791 58 1563 59 148 60 456 61 235 62 167 63 226 64 218 65 93 66 1496 67 1828 68 1928 69 1229 70 1798 71 349 72 756 73 422 74 778 75 1040 76 1046 77 1280 78 1347 79 1866 80 973 81 2085 82 3016 83 1993 84 1210 85 13400 86 1780 87 1860 88 657 89 587 90 893 91 357 92 491 93 776 94 2289 95 1085 96 670 97 288 98 1160 99 73 100 147 101 109 102 311 103 2530 104 21300 105 147 106 314 107 1638 108 5030 109 49 BY 51 111 76 112 1170 113 31 114 40 115 1240

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

Claims (16)

1. Compound of formula (I) Ag ¹ Formula (I), - 51 048927 where n and m, each independently, represent the integer 1 or 2, provided that n+m equals 2 or 3; X is O or ^NR2 ; where ^R2 is hydrogen, _{C1.3 -} alkyl, -CO-H, -SO2-C1.3-alkyl or -CO- _Cl.3 -alkyl; Ar ¹ is phenyl which is mono-, di-, tri-, tetra- or pentasubstituted, wherein the substituents are independently selected from halogen; methyl; cyano; methoxy; trifluoromethyl; trifluoromethoxy; and NR ⁿ¹¹ R ⁿ¹² , wherein R ^N11 is hydrogen and R ^N12 is hydroxy-C ₂ . ₃ -alkyl, or R ^N11 and R ^N12 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl selected from morpholin-4-yl, azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl, wherein said 4- to 6-membered heterocyclyl is unsubstituted or monosubstituted by hydroxy; 5- or 6-membered heteroaryl containing from one to a maximum of four heteroatoms each independently selected from oxygen, nitrogen and sulfur, 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 containing from one to a maximum of four heteroatoms each independently selected from oxygen, nitrogen and sulfur, wherein said 9- or 10-membered heteroaryl is independently unsubstituted or monosubstituted by methyl; R ¹ is hydroxy; C ₁ . ₃ -alkoxy; - O-CO-Cl. 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 R ^N21 and R ⁿ²² together with the nitrogen atom to which they are attached form a 4-6-membered heterocyclyl selected from azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl, wherein said 4-6-membered heterocyclyl is monosubstituted by hydroxy; L is a direct bond, methylene or ethylene; and Ar ² is phenyl or a 5- or 6-membered heteroaryl containing one to a maximum of four heteroatoms each independently selected from oxygen, nitrogen and sulfur, wherein said phenyl or 5- or _{6-membered heteroaryl is independently unsubstituted or mono-, di- or trisubstituted; 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; A 9-membered bicyclic heteroaryl or a 10-membered bicyclic heteroaryl containing from one to a maximum of four heteroatoms each independently selected from oxygen, nitrogen and sulfur, 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 of formula (I) according to claim 1, wherein said compound is also a compound of formula (IS) or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 1 or 2, wherein Ar ¹ is phenyl which is di- or trisubstituted, wherein the substituents are independently selected from halogen, methyl and cyano; wherein at least one of said substituents is attached at the meta- or para-position of said phenyl; or a pharmaceutically acceptable salt thereof. - 52 048927 4. The compound according to claim 1 or 2, wherein Ar ¹ is or a pharmaceutically acceptable salt thereof. 5. A compound according to any one of claims 1 to 4, wherein R ¹ is methoxy; or a pharmaceutically acceptable salt thereof. 6. A compound according to any one of claims 1 to 5, wherein L is a direct bond; or a pharmaceutically acceptable salt thereof. 7. A compound according to any one of claims 1 to 6, wherein Ar ² is phenyl which is mono or disubstituted, wherein the substituents are independently selected from C ₁ . ₄ -alkyl, C ₁ . ₃ -alkoxy, halogen and cyano; or a pharmaceutically acceptable salt thereof. 8. A compound according to any one of claims 1 to 5, wherein the fragment -L-Ar ² is N or N or a pharmaceutically acceptable salt thereof. - 53 048927 9. The compound of claim 1, wherein said compound is (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-N(3-iodophenyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-methoxyphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-fluorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-bromo-5-cyanophenyl)5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-ul)-N-(3-bromo-5-methylphenyl)5-hydroxy -6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2Hpyran-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-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro2H-pyran-2-carboxamide; - 54 048927 (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dibromophenyl)-5hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-ul)5-hydroxy -6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-III-1,2,3-triazol-1-yl)-5-hydroxy6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,4-dichlorophenyl)-N-1,2,3-triazol-1-yl)-5-hydroxy6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3,4-dichlorophenyl)-N-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,4-dichlorophenyl)-III-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-chlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-N(3-iodophenyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-methoxyphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-cyano-5-fluorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-bromo-5-cyanophenyl)5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2Hpyran-2-carboxamide; - 55 048927 (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3-bromo-5-methylphenyl)5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2Hpyran-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-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro2H-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-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dibromophenyl)-5hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-III-1,2,3-triazol-1-yl)-5-hydroxy6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dibromophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-4-(4-(3,4-dichlorophenyl)-III-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,4-dichlorophenyl)-III-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-3-methoxytetrahydro-2H-pyran2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2carboxamide; - 56 048927 (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypyrrolidin-3-yl)-3-methoxytetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-5hydroxy-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-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-bromo-2,3-difluorophenyl)N-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-4-(4(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-4-(4(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-cyanophenyl)-5hydroxy-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-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-5hydroxy-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-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dibromophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-4-(4(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3-bromo-5-methylphenyl)-4-(4(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro2H-pyran-2-carboxamide; - 57 048927 (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-III-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-chloro-3,5-difluorophenyl)N-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-chloro-3,5-difluorophenyl)N-1,2,3-triazol-1-yl)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazole-1-yl)-N-(3,5-dibromophenyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3S,4S)-1-αacetyl-4-hydroxypyrroludin-3-yl)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-((3R,4R)-1-acetyl-4-hydroxypyrrolidin-3-yl)-N-(3,5-dichlorophenyl)-4-(4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-N-((3S,4S)-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-N-((3S,4S)-1-formyl-4-hydroxypyrrolidin-3-yl)-5hydroxy-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)-4-(4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-N-(3,5-dichlorophenyl)-N((3S,4S)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-N-((3S,4S)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-N-((3R,4R)-1-formyl-4-hydroxypyrrolidin-3-yl)-5hydroxy-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-methylphenyl)-N-((3R,4R)-1-formyl-4-hydroxypyrrolidin-3-yl)-5hydroxy-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-methylphenyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)-N-((3R,4R)-1-formyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-N-((3S,4S)-4-hydroxy-1-methylpyrrolidin3-yl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-N-((3S,4S)-1-ethyl-4-hydroxypyrrolidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-N-((3S,4S)-4-hydroxy-1-(methylsulfonyl)pyrrolidin-3-yl)-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran2-carboxamide; - 58 048927 (2R,3R,4S,5R,6R)-N-(3-chloro-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-III-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxytetrahydro-2H-pyran-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-cyanophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide; (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypiperidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypiperidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2carboxamide or (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5-hydroxy-6-(hydroxymethyl)-N-((3R,4R)-4-hydroxypiperidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1 -yl)tetrahydro-2H-pyran-2carboxamide; or a pharmaceutically acceptable salt thereof. 10. The compound of claim 1, which is (2R,3R,4S,5R,6R)-N-(3-bromo-5-methylphenyl)-5hydroxy-6-(hydroxymethyl)-N-((3S,4S)-4-hydroxypiperidin-3-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-carboxamide; or a pharmaceutically acceptable salt thereof. 11. The compound of claim 1, which is (2R,3R,4S,5R,6R)-N-(3,5-dichlorophenyl)-5-hydroxy-6(hydroxymethyl)-N-((3S,4S)-3-hydroxypiperidin-4-yl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol1-yl)tetrahydro-2H-pyran-2-carboxamide; or a pharmaceutically acceptable salt thereof. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 13. Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof as a medicinal product. 14. The use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of organ fibrosis; liver diseases and disorders; acute kidney injury and chronic kidney disease; cardiovascular diseases and disorders; interstitial - 59 048927 lung 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; eye diseases and disorders or transplant rejection. 15. The use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention or treatment of organ fibrosis; liver diseases and disorders; acute kidney injury and chronic kidney disease; cardiovascular diseases and disorders; interstitial lung 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; eye diseases and disorders or transplant rejection. 16. A method for the prevention or treatment of organ fibrosis; liver diseases and disorders; acute kidney injury and chronic kidney disease; cardiovascular diseases and disorders; interstitial diseases and disorders of the lungs; 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; ocular diseases and disorders; or transplant rejection; comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof.