EA048269B1 - SPIRO DERIVATIVES OF ALPHA-D-GALACTOPYRANOSIDES - Google Patents

Description

The present invention relates to compounds of formula (I) which are galectin-3 inhibitors and their use for preventing/prophylaxis or treating diseases and disorders which are related to galectin-3 binding to natural ligands. The invention also relates to related aspects including methods for preparing the compounds, pharmaceutical compositions comprising one or more compounds of formula (I) and their medical use as galectin-3 inhibitors. The compounds of formula (I) can be used in particular as single agents or in combination with one or more therapeutic agents.

Galectins are defined as a family of proteins based on the conserved β-galactoside-binding sites found in their characteristic ~130 amino acid (aa) carbohydrate recognition domains (CRDs) (Barondes SH et al., Cell 1994; 76, 597-598). The human, mouse, and rat genome sequences reveal the existence of at least 16 conserved galectins and galectin-like proteins in a single mammalian genome (Leffler H et al., Glycoconj. J. 2002, 19, 433-440). To date, three subclasses of galectins have been identified: prototypic galectins containing a single carbohydrate recognition domain (CRD); chimeric galectin consisting of unusual tandem repeats of proline- and glycine-rich short regions fused to the CRD; and tandem repeat galectins, which contain two individual CRDs in tandem connected by a linker (Zhong X., Clin Exp Pharmacol Physiol. 2019; 46:197–203). Because galectins can bind either bivalently or multivalently, they can, for example, cross-link cell surface glycoconjugates, triggering cellular signaling events. Through this mechanism, galectins modulate a wide range of biological processes (Sundblad V. et al., Histol Histopathol 2011; 26: 247–265).

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

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

There are several lines of evidence supporting the functional involvement of Gal-3 in the development of inflammatory/autoimmune diseases such as asthma (Gao P, et al. Respir Res. 2013; 14:136; Rao SP, et al. Front Med (Lausanne) 2017; 4:68), rheumatoid arthritis, multiple sclerosis, diabetes, plaque psoriasis (Lacina L, et al. Folia Biol (Praha) 2006; 52(1-2): 10-5), atopic dermatitis (Saegusa J, et al. Am J Pathol. 2009; 174(3):922-31), endometriosis (Noel JC, et al. Appl Immunohistochem Mol Morphol. 2011 19(3):253-7), or viral encephalitis (Liu FT et al., Ann N Y Acad Sci. 2012; 1253:8091; Henderson NC, et al., Immunol Rev. 2009;230(l):160–71; Li P et al., Cell 2016; 167:973–984). Gal-3 has recently been found to be a key player in chronic inflammation and fibrogenesis in organs such as the liver (Henderson NC et al. PNAS 2006; 103: 5060–5065; Hsu DK et al. Int J Cancer. 1999, 81(4):519–26), kidney (Henderson NC et al. Am. J. Pathol. 2008; 172:288–298; Dang Z. et al. Transplantation. 2012, 93(5):477–84), lung (Mackinnon AC et al. Am. J. Respir. Crit. Care Med 2012, 185: 537–546; Nishi Y. et al. Allergol Int. 2007, 56(1):57–65), heart (Henderson NC et al. Am. J. Pathol. 2008; 172:288–298; Dang Z. et al. Transplantation. 2012, 93(5):477–84), lung (Mackinnon AC et al. Am. J. Respir. Crit. Care Med 2012, 185: 537–546; Nishi Y. et al. Allergol Int. 2007, 56(1):57–65), and breast (Henderson NC et al. Am. J. Pathol. 2008; 172:288–298; Dang Z. et al. Transplantation. 2012, 93(5):477–84). (Thandavarayan RA et al. Biochem Pharmacol. 2008, 75(9): 1797–806; Sharma U. et al. Am J Physiol Heart Circ Physiol. 2008; 294(3):H1226–32), as well as the nervous system (Burguillos MA et al. Cell Rep. 2015, 10(9): 1626–1638), and corneal neovascularization (Chen WS et al., Investigative Ophthalmology & Visual Science 2017, vol. 58, 9–20). Furthermore, Gal-3 has been found to be associated with keloid-like skin lesions (Arciniegas E et al. The American Journal of dermatopathology 2019; 41(3): 193-204) and systemic sclerosis (SSc), particularly the cutaneous fibrosis and proliferative vasculopathy observed in this condition (Taniguchi T et al. J Rheumatol. 2012; 39(3):539-44). Gal-3 has been found to be up-regulated in patients with chronic kidney disease (CKD)-associated renal failure, and particularly in patients with diabetes. Interestingly, data from this patient population showed a correlation between Gal-3 upregulation in the glomerulus and the observed urinary protein excretion (Kikuchi Y. et al. Nephrol Dial Transplant. 2004, 19(3):602-7). Furthermore, a recent prospective study conducted since 2018 demonstrated that more

- 1 048269 High plasma Gal-3 levels are associated with an increased risk of developing CKD, particularly in the hypertensive population (Rebholz CM et al. Kidney Int. Jan 2018; 93(1): 252-259). Gal-3 is highly elevated in cardiovascular diseases (Zhong X. et al. Clin Exp Pharmacol Physiol. 2019, 46(3): 197–203), such as atherosclerosis (Nachtigal M. et al. Am J Pathol. 1998; 152(5): 1199–208), coronary heart disease (Falcone C. et al. Int J Immunopathol Pharmacol 2011, 24(4):905–13), heart failure, and thrombosis (Nachtigal M. et al., Am J Pathol. 1998; 152(5): 1199–208; Gehlken C. et al., Heart Fail Clin. 2018, 14(1):75–92; DeRoo EP. et al., Blood. 2015, 125(11): 1813-21). Blood Gal-3 concentrations are elevated in obese and diabetic patients and are associated with a higher risk of micro- and macrovascular complications (such as heart failure, nephropathy/retinopathy, peripheral arterial disease, cerebrovascular accident, or myocardial infarction) (Qi-hui-Jin et al. Chin Med J (Eng). 2013,126(11):2109-15). Gal-3 has been 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;7(6):e1434467). Among the malignancies that express high levels of Gal-3, thyroid cancer, central nervous system cancer, tongue cancer, breast cancer, gastric cancer, squamous cell carcinoma of the head and neck, pancreatic cancer, bladder cancer, kidney cancer, liver cancer, parathyroid cancer, salivary gland cancer, as well as lymphoma, carcinoma, non-small cell lung cancer, melanoma, and neuroblastoma have been identified (Sciacchitano S, et al. Int J Mol Sci. 2018 Jan 26;19(2):379).

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

Recently, Gal-3 inhibitors have been shown to have beneficial effects when used in combination immunotherapy (Galectin Therapeutics. Press Release, February 7, 2017) and in idiopathic pulmonary fibrosis (Galecto Biotech. Press Release, March 10, 2017), as well as in NASH cirrhosis (December 5, 2017). WO 20180209276, WO 2018209255 and WO 2019089080 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 and WO2020078808). WO2002057284, WO2005113569 and WO2014078655 disclose a broad spectrum of generic galectin inhibitors in the beta configuration. WO 2016120403, WO 2020104335, WO 2021001528, WO 2021038068 and WO 2021004940 disclose a broad generic spectrum of alpha-D-galactoside galectin inhibitors.

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

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

Ag ¹

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

- 2 048269

[in a sub-embodiment, said aryl is phenyl which is di- or tri-substituted, wherein at least one of said substituents is attached at the meta- or para-position of said phenyl; wherein, in particular, such substituent at the para-position, if present, is selected from halogen and 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;

Ci-4-alkoxy (especially methoxy);

- O-CO-C ₁ - ₃ -alkyl;

- O-CO-NH-R ^N11 , where R ^N11 is hydrogen or C ₁ . ₃ -alkyl;

- O-CH ₂ -C ₁ -fluoroalkyl; or

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

-hydroxy;

C ₁ _ ₃ -alkoxy (especially methoxy);

morpholin-4-yl; or _{- NR} N21 _R N22 _, where R ^N21 and R ^N22 are both independently hydrogen or methyl; and is a spirocyclic moiety, where:

ring A is a heterocycloalkylene selected from

wherein X is nitrogen or oxygen and n is an integer of 0 or 1 (in particular, X is nitrogen and n is an integer of 0 or 1; or X is oxygen and n is an integer of 0); and wherein in case X is nitrogen, said nitrogen is unsubstituted or monosubstituted by C _{1 .4} -alkyl (in particular, said nitrogen is unsubstituted);

ζ ^N -' , where R ² is hydrogen or C ₁ . ₄ -alkyl (especially methyl); and ring B is C ₄ _7-cycloalkanediyl, wherein said C ₄ _7-cycloalkanediyl is unsubstituted, mono- or disubstituted, wherein the substituents are independently selected from C ₁ . ₄ -alkyl (especially methyl, isopropyl); C _1-3 -fluoroalkyl; C ₁ . ₄ -alkoxy; halogen (especially fluorine); cyano; oxo; hydroxy; hydroxy-C ₁ _ ₄ -alkyl (especially 2-hydroxyprop-2-yl); hydroxyimino; morpholin-4yl; and -NH-RN ¹¹ , where R ^N11 is C ₁ . ₆ -alkyl (especially isopropyl or pent-3-yl), C _2-4 alkoxy, C ₃ . ₆ -cycloalkyl (especially cyclopropyl), C ₂ . _3- fluoroalkyl (especially _{2,2-difluoroethyl or 2,2,2-trifluoroethyl), -CO-C 1 . 4-alkyl or -CO-C 1 . 4 - αalkoxy} ;

4- to 7-membered heterocycloalkanediyl, wherein said heterocycloalkanediyl contains one ring oxygen atom; or

4- to 7-membered heterocycloalkanediyl, wherein said heterocycloalkanediyl contains one ring nitrogen atom, wherein said ring nitrogen atom is unsubstituted or monosubstituted by _{C 1.4} -alkyl (especially methyl), -CO-C _{1.4 -alkyl} , -SO ₂ -C _1.4 -alkyl, _{-CO-C 1.4 -alkoxy or} CO-NH-C _1.4 -alkyl; and wherein said 4- to ₇ -membered heterocycloalkanediyl bears no further substituent in addition to said substituent on the ring nitrogen atom, or bears one further substituent on a ring carbon atom that is attached to said ring nitrogen atom, wherein said substituent is oxo or -CO-OH;

or, in addition, ring B is a bridged bicyclic C ₆ . ₉ -cycloalkanediyl (especially bicyclo[2,2,1]heptane-2,2-diyl or bicyclo[3,2,1]-octane-3,3-diyl).

In a sub-variant of embodiment 1), ring B is a bridged bicyclic C ₆ . ₉ -cycloalkanediyl (especially bicyclo[2,2,1]heptane-2,2-diyl or bicyclo[3,2,1]-octane-3,3-diyl).

- 3 048269

In another sub-variant of embodiment 1), ring B differs from the bridged bicyclic C ₆ . ₉ -cycloalkanediyl.

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). In addition, the compounds of formula (I) may contain one and possibly more additional stereogenic or asymmetric centers, such as one or more additional asymmetric carbon atoms. Thus, the compounds of formula (I) may be present as mixtures of stereoisomers or, preferably, as pure stereoisomers. Mixtures of stereoisomers may be separated by a method known to a person skilled in the art.

Where a particular compound (or generic structure) is designated as being in a certain absolute configuration, for example as the (R)- or (S)-enantiomer, such designation is to be understood as referring to the corresponding compound (or generic structure) in enriched, in particular substantially pure, enantiomeric form. Similarly, where a particular asymmetric centre in a compound is designated as being in the (R)- or (S)-configuration or as being in a certain relative configuration, such designation is to be understood as referring to the compound which is in enriched, in particular substantially pure, form with respect to the corresponding configuration of the said asymmetric centre.

Where an individual compound contains (in addition to the tetrahydropyran moiety) one or more stereogenic or asymmetric centers, wherein said one or more of said stereogenic or asymmetric centers is(are) not explicitly designated as (R)- or (S)-, it is to be understood that said stereogenic or asymmetric center(s) may independently be in the (R)- or (S)-configuration. Such a name of a compound is intended to cover a compound in which such a center is in the (R)- or (S)-configuration, or any mixture of epimers about such a center. Similarly, where such a stereogenic or asymmetric center is designated as being in the (RS)-configuration, this means that such stereogenic or asymmetric center in such compound may be present in the (R)-configuration, in the (S)-configuration, or in a form corresponding to any mixture of epimers about such center. Where two or more such stereogenic or asymmetric centers (with undesignated or designated (RS)-configuration) are present in one molecule, it is to be understood that, unless expressly stated otherwise, the order in which the absolute configuration is indicated does not indicate any particular relative configuration with respect to the two or more centers. It is to be understood that explicitly designated (R)- or (S)-configuration(s) and undesignated or designated (RS)-configuration(s) may coexist in the same molecule and should be interpreted accordingly.

In the case of certain compounds in which ring B is a _C4-7 -cycloalkanediyl, wherein said _C4-7 -cycloalkanediyl is mono- or disubstituted, the stereogenic centers on said _C4-7 -cycloalkanediyl are not specifically designated, meaning that such stereogenic centers may be present in the (r,R)- or (s,S)-configuration, or in the form corresponding to any mixture thereof. For example, the compound tert-butyl (3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspyro[4.5]dec-2en-8-yl)carbamate encompasses diastereoisomerically enriched, in particular substantially pure, tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate, diastereoisomerically enriched, in particular, substantially pure, tert-butyl ((5s,8S)-3(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate, or any mixture of said diastereomers.

In this patent application, a bond drawn with a dotted line or interrupted by a wavy line indicates the point of attachment of the radical drawn. For example, the radicals drawn below describe a 3,4,5-trifluorophenyl group.

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.

- 4 048269 rheoisomer/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, in particular ² H (deuterium) labeled compounds of formula (I) according to embodiments 1) to 17), 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, in particular ² H (deuterium) labeled compounds of formula (I) and their salts are included within the scope of the present invention. The replacement of hydrogen by the heavier isotope ² H (deuterium) may result in greater metabolic stability, resulting in, for example, an increased in-vivo half-life or a reduced dosage requirement, or may result in reduced inhibition of cytochrome P450 enzymes, resulting in, for example, an improved safety profile. In one embodiment of the invention, the compounds of formula (I) are not isotopically labeled, or they are labeled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labeled at all. Isotopically labeled compounds of formula (I) can be prepared in analogy to the processes described hereinafter, but using an appropriate isotopic variation of suitable reagents or starting materials.

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 17) should be understood as also referring to salts (and in particular pharmaceutically acceptable salts) of such compounds, as the case may be and as appropriate.

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

The definitions provided in the present invention are intended to apply equally to compounds of formula (I) as defined in any of embodiments 1) to 14) 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 the present invention.

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

may be named (2R,3R,4R,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-phenyl-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl or, alternatively, 1,3-dideoxy-3-[4-phenyl-1H-1,2,3-triazol-1-yl]-α-D-galactopyranoside-1-yl, wherein the absolute configuration of the carbon atom bearing the point of attachment to the rest of the molecule corresponds to the designation (2R)-, respectively, alpha. For example, the compound (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol should be understood as also belonging to 1-(1,3-dideoxy-2-O-methyl-3-[4-(3-chloro-4,5-difluorophenyl)1H-1,2,3-triazol-1-yl]-α-D-galactopyranose)-1-(1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-methane.

- 5 048269

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

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

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 each represent 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 and pent-3-yl. To avoid misinterpretation, it should be noted that when a group is called, for example, propyl or butyl, n-propyl, respectively, n-butyl is meant. In case R ² is C ₁ . ₄ -alkyl, the term especially refers to methyl.

The term hydroxy-C1.4-alkyl refers to a _C1.4 -alkyl group as defined above in which one hydrogen atom has been replaced by hydroxy. An example is 2-hydroxyprop-2yl.

The term -Cx.y-alkylene-, used alone or in combination, refers to a divalently attached alkyl group as defined above, containing from x to y carbon atoms. The term -C ₀ . _y -alkylene- refers to a direct bond or to -(C ₁ . _y )alkylene- as defined above. Preferably, the points of attachment of the -C ₁ . _y -alkylene group correspond to a 1,1-diyl or 1,2-diyl or 1,3-diyl scheme. In case the C ₀ . _y -alkyleneα group is used in combination with another substituent, the term means that either said substituent is attached through the C ₁ . _y -alkylene group to the rest of the molecule, or it is attached directly to the rest of the molecule (i.e. the Co-alkylene group is a direct bond attaching said substituent to the rest of the molecule).

The term fluoroalkyl, used alone or in combination, refers to an alkyl group as defined above, containing from one to four 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 _{C1_3-} fluoroalkyl group contains from one to three carbon atoms, and in which one to seven hydrogen atoms have been replaced by fluorine. Representative examples of fluoroalkyl groups include trifluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

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 are replaced by fluorine. The term Cx.y-fluoroalkoxy (x and y are each an integer) refers to a fluoroalkoxy group as defined above containing from x to y carbon atoms. For example, a _C1-3- fluoroalkoxy group contains from one to three carbon atoms and has from one to seven hydrogen atoms replaced by fluorine. Representative examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred are _C1- fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy.

The term cycloalkyl, used alone or in combination, refers in particular to a saturated monocyclic hydrocarbon ring containing from three to seven carbon atoms. The term Cx.y-cycloalkyl (x and y each represent 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. Representative examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Said cycloalkyl groups are unsubstituted or substituted as expressly defined.

The term -Cx.y-cycloalkylene-, used alone or in combination, refers to a divalently attached cycloalkyl group as defined above, containing from x to y carbon atoms. Preferably, the points of attachment of any divalently attached

- 6 048269 cycloalkyl groups correspond to the 1,1-diyl scheme. In case the ring B is C _4-7 -cycloalkanediyl, the term in particular refers to cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl or cycloheptane-1,1-diyl. Said C _4-7 -cycloalkanediyl is unsubstituted or substituted as explicitly defined.

The term bridged bicyclic C _6-9 -cycloalkanediyl refers to a saturated bridged bicyclic hydrocarbon ring system containing six to nine carbon atoms. In case ring B is a bridged bicyclic C _6-9 -cycloalkanediyl, the term refers in particular to bicyclo[2,2,1]heptane-2,2-diyl or bicyclo[3,2,1]-octane-3,3-diyl.

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. Representative examples of alkoxy groups are methoxy, ethoxy, isopropoxy and tert-butoxy. Examples of R ¹ representing C _1-4 -alkoxy are methoxy and ethoxy; methoxy is most preferred.

The term heterocycloalkyl, used alone or in combination, and unless explicitly defined more broadly or more narrowly, refers to a saturated or unsaturated non-aromatic monocyclic hydrocarbon ring containing one or two ring heteroatoms independently selected from nitrogen, sulfur and oxygen (especially one oxygen atom, one sulfur atom, one nitrogen atom, two nitrogen atoms, two oxygen atoms, or one nitrogen atom and one oxygen atom). The term x-y-membered heterocycloalkyl refers to said heterocycle containing a total of x to y ring atoms.

The term heterocycloalkylene, used alone or in combination, refers to a divalently attached heterocycloalkyl group as defined above. To avoid misinterpretation, it should be noted that in the event that a certain 4- to 7-membered heterocycloalkanediyl is defined as containing one ring heteroatom (such as one ring oxygen atom or one ring nitrogen atom), it should be understood that such 4- to 7-membered heterocycloalkanediyl (e.g. used as ring B) contains exactly the specified one ring heteroatom and does not contain additional ring heteroatoms. In the event that ring B is a 4- to 7-membered heterocycloalkanediyl, it should be understood that such heterocycloalkanediyl is divalently attached to ring A through one ring carbon atom of said heterocycloalkanediyl. An example of a ring B that is a 4- to 7-membered heterocycloalkanediyl containing one ring oxygen atom is tetrahydro-2H-pyran-4,4-diyl. Examples of ring B, which is a 4- to 7-membered heterocycloalkanediyl containing one ring nitrogen atom, are piperidine-4,4-diyl or azepan-4,4-diyl. Said heterocycloalkylene group is unsubstituted or substituted as explicitly stated.

Lk _z N--In case the ring A is a heterocycloalkylene '' said heterocycloalkylene, in particular, refers to the following structures:

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

The term heteroaryl, used alone or in combination and unless explicitly defined more broadly or more narrowly, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing from one to a maximum of four heteroatoms each independently selected from oxygen, nitrogen and sulfur. Representative examples of such heteroaryl groups are 5-membered heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl; 6-membered heteroaryl groups such as pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl; and 8- to 10-membered bicyclic heteroaryl groups such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyridazinyl and imidazothiazolyl. The above heteroaryl groups are unsubstituted or substituted as explicitly defined.

- 7 048269

The term heteroarylene, used alone or in combination, refers to a divalently attached heteroaryl group as defined above.

The term cyano refers to the -CN group.

The term oxo refers to a =O group that is preferably attached to a carbon or sulfur atom present in a chain or ring, such as in the carbonyl group -(CO)- (or sulfonyl group -(SO2)-).

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 and 80°C, this means that the endpoints 40 and 80°C are included in the range; or if a variable is defined as an integer between 1 and 4, this means that the variable represents the integer 1, 2, 3, or 4.

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

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

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

3. Another embodiment relates to compounds according to embodiment 1), wherein Ar ¹ is phenyl which is mono-, di- or trisubstituted, wherein the substituents are independently selected from halogen and methyl.

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

5. Another embodiment relates to compounds according to embodiment 1), wherein Ar ¹ is ^F or

6. Another embodiment relates to compounds according to any one of embodiments 1) to 5), wherein R ¹ is hydroxy;

C _1-4 -alkoxy (especially methoxy);

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

- O-CO-NH-RN ¹¹ , where RN ¹¹ is hydrogen or C _1-3 -alkyl;

- O- _CH2 -C1-fluoroalkyl; or

- O-CH ₂ -CO-R ^1X , where R ^1X is

-hydroxy; or

C _1-3 -alkoxy (especially methoxy).

7. Another embodiment relates to compounds according to any one of embodiments 1) to 5), wherein R1 is methoxy.

- 8 048269

8. Another embodiment relates to compounds according to any one of embodiments 1) to 7), wherein ring A is a heterocycloalkylene selected from

where X is nitrogen or oxygen, and n is an integer 0 or 1 (in particular, X is nitrogen and n is an integer 0 or 1; or X is oxygen and n is an integer 0); where in the case where X is nitrogen, said nitrogen is unsubstituted;

/N— and '' where R ² is hydrogen or methyl.

9. Another embodiment relates to connections according to any of the embodiments

implementation 1) - 7), where ring A is heterocycloalkylene: '

10. Another embodiment relates to compounds according to any one of embodiments 1) to 9), wherein ring B is unsubstituted _C4.7 -cycloalkanediyl;

_C4.7 -cycloalkanediyl, wherein said _{C4_7 -} cycloalkanediyl is monosubstituted, wherein the substituents are independently selected from _{C1.4 -} alkyl (especially methyl, isopropyl); halogen (especially fluorine); cyano; oxo; hydroxy; hydroxy- _{C1_4-} alkyl (especially 2-hydroxyprop-2-yl); morpholin4-yl; and -NH- ^Rn11 , where ^RN11 is N-alkyl (especially isopropyl or pent-3-yl), C24-alkoxy, C3-6-cycloalkyl (especially cyclopropyl), _{C2.3 -} fluoroalkyl (especially 2,2-difluoroethyl or 2,2,2-trifluoroethyl), -CO- _{C1.4 -alkyl} or -CO- _C1 . ₄ -alkoxy;

C _{4_7 -} cycloalkanediyl, wherein said C _{4_7 -} cycloalkanediyl is disubstituted, wherein the substituents are independently selected from _{C 1.4} -alkyl (especially methyl) and halogen (especially fluorine);

4- to 7-membered heterocycloalkanediyl, wherein said heterocycloalkanediyl contains one ring oxygen atom; or

4- to ₇ -membered heterocycloalkanediyl, wherein said heterocycloalkanediyl contains one ring nitrogen atom, wherein said nitrogen atom is unsubstituted or monosubstituted by C1.4-alkyl (especially methyl), -CO- _{C1.4 -} alkyl, -SO2 _{- C1.4 -} alkyl, -CO- _{C1.4 -} αalkoxy or -CO-NH-C1.4alkyl; and wherein said 4- to 7-membered heterocycloalkanediyl bears no further substituent in addition to said substituent on the ring nitrogen atom, or bears one further substituent on a ring carbon atom that is attached to said ring nitrogen atom, wherein said substituent is oxo.

11. Another embodiment relates to compounds according to any one of embodiments 1) to 9), wherein ring B is unsubstituted _{C4_7 -} cycloalkanediyl (especially cyclohexane-1,1-diyl or cycloheptane-1,1-diyl);

C _{4_7} -cycloalkanediyl (especially cyclohexane-1,1-diyl), wherein said C _{4_7} -cycloalkanediyl is monosubstituted, wherein the substituents are independently selected from _{C 1_4} -alkyl (especially methyl, isopropyl ₎ ; cyano; hydroxy; hydroxy-C _{1_4} -alkyl (especially 2-hydroxyprop-2-yl); and -NH-RN ¹¹ , wherein RN ¹¹ is _{C 1_6 -alkyl (} especially isopropyl or pent-3-yl), C _{2_4} -alkoxy, C _{3_6} cycloalkyl (especially cyclopropyl), C _{2_3 -fluoroalkyl} (especially 2,2 _- difluoroethyl or 2,2,2-trifluoroethyl), -CO-C _{1_4} -alkyl or -CO _- C _{1_4} -alkyl. ₄ -alkoxy;

C _{4_7 -} cycloalkanediyl (especially cyclohexane-1,1-diyl), wherein said C _{4_7 -} cycloalkanediyl is disubstituted, wherein the substituents are independently selected from _{C 1.4} -alkyl (especially methyl) and halogen (especially fluorine);

4-7 membered heterocycloalkanediyl, wherein said heterocycloalkanediyl contains one ring oxygen atom (especially tetrahydropyran-4,4-diyl); or

4- to 7-membered heterocycloalkanediyl, wherein said heterocycloalkanediyl contains one ring nitrogen atom (especially piperidine-4,4-diyl or azepan-4,4-diyl), wherein said nitrogen atom is unsubstituted or monosubstituted by C ₁ . ₄ -alkyl (especially methyl), -CO-C 1-4 alkoxy or -CO-NH-C ₁ . ₄ -alkyl; and wherein said 4- to 7-membered heterocycloalkanediyl does not carry additional

- 9 048269 additional substituent in addition to the said substituent on the ring nitrogen atom, or bears one additional substituent on the ring carbon atom that is attached to the said ring nitrogen atom, wherein the said substituent is oxo.

12. Another embodiment relates to compounds according to any one of embodiments 1) to 9), wherein ring B is cyclohexane-1,1-diyl or cycloheptane-1,1-diyl;

cyclohexane-1,1-diyl which is monosubstituted, wherein the substituents are selected from _{C1_4} alkyl (especially methyl, isopropyl); cyano; hydroxy; hydroxy- _{C1_4} -alkyl (especially 2-hydroxyprop-2-yl); and -NH-R ⁿ¹¹ , where R ^N11 is cyclopropyl, C ₂ . ₃ -fluoroalkyl (especially 2,2-difluoroethyl or 2,2,2-trifluoroethyl), -CO-C ₁ . ₄ -alkyl or -CO-C ₁ . ₄ -alkoxy;

cyclohexane-1,1-diyl which is disubstituted wherein the substituents are selected from C ₁ . ₄ -alkyl (especially methyl) and halogen (especially fluorine);

tetrahydropyran-4,4-diyl;

piperidine-4,4-diyl, wherein the nitrogen atom of said piperidine-4,4-diyl is monosubstituted by -CO-C _{1.4 -alkoxy} or -CO-NH-C _{1.4 -alkyl} ; and wherein said piperidine-4,4-diyl does not carry an additional substituent in addition to said substituent on the ring nitrogen atom; or azepane-4,4-diyl, wherein the nitrogen atom of said azepane-4,4-diyl is unsubstituted or monosubstituted by _{C 1.4} -alkyl (especially methyl) or -CO-C _{1.4 -alkoxy} ; and wherein said azepan-4,4-diyl bears no additional substituent in addition to said substituent on a ring nitrogen atom, or bears one additional substituent on a ring carbon atom that is attached to said ring nitrogen atom, wherein said substituent is oxo.

13. Another embodiment relates to compounds according to any one of embodiments 1) to 9), wherein ring B is cyclohexane-1,1-diyl;

cyclohexane-1,1-diyl, which is monosubstituted, wherein the substituents are selected from cyano;

hydroxy- _{C1_4} -alkyl (especially 2-hydroxyprop-2-yl); and

-NH-RN ¹¹ , where RN ¹¹ is -CO-C ₁ . ₄ -alkyl or -CO-C ₁ . ₄ -alkoxy;

cyclohexane-1,1-diyl, which is disubstituted by fluorine; or tetrahydropyran-4,4-diyl.

14. Another embodiment relates to compounds according to any one of embodiments 1) to 7), wherein

A) is a spirocyclic fragment selected from the following groups:

- 10 048269

IN)

WITH)

D)

or, in addition to those listed above, E)

' OR / \ where each of the above groups A) - E) represents a separate sub-variant of implementation, and where, in addition, the above groups A) - D) form a separate sub-variant of implementation.

15. 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 14), when considering their respective dependencies; to pharmaceutically acceptable salts thereof; and to the use of such compounds as further described below. In order to avoid misinterpretation, it should be noted in particular that the following embodiments

- 11 048269 embodiments relating to compounds of formula (I) are thus possible and implied and are hereby specifically disclosed in individualized form:

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

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

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, 10+9+4+1, for example, refers to embodiment 10), dependent on embodiment 9), dependent on embodiment 4), dependent on embodiment 1), i.e. embodiment 10+9+4+1 corresponds to compounds of formula (I) according to embodiment 1), further limited to all the features of embodiments 4), 9) and 10).

16. Another embodiment relates to compounds of formula (I) according to the embodiment

- 12 048269 volume of implementation 1), which are selected from the following compounds:

(2K,3K,48,5K,6K)-2-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(

2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-3-yl acetate;

(2K,3K,4K,5K,6K)-2-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol;

(2K,3K,48,5K,6K)-2-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate;

(2K,3K,4K,5K,6K)-2-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl )-4-(4- (2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetr ahydro-2H-pyran-3,5-diol;

(2K,3K,4K,5K,6K)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-6-(hydroxymethyl)-4-(4 -(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol;

(2K,3K,48.5K,6K)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy- 4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro -2H-pyran-3-ol;

- 13 048269 t/?eot-butyl (3-(((2K,3K,48.5K,6K)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4, 5-thrift orphenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azac pyro[4.5]dec-2-en-8-yl )carbamate;

(2K,3K,48.5K,6K)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy- 4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;

(2K,3K,48.5K,6K)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3difluoro-4 -methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;

t/?eot-butyl ((5g,8K)-3-(((2K,3K,48,5K,6K)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oke a-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;

(2K,3K,48.5K,6K)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-br ohm- 2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrag hydro-2H-pyran-3-ol;

(2K,3K,48,5K,6K)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;

(2K,3K,48.5K,6K)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3-ft op- 4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahyde rho-2H-pyran-3-ol;

(2K,3K,48.5K,6K)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3,5difluoro-4 -methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetra ahydro-2H-pyran-3-ol;

(2K,3K,48,5K,6K)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;

(2K,3K,48.5K,6K)-6-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl )-4-(4- (2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-m ethoxytetrahydro-2H-pyran-3-ol;

- 14 048269 (2K,3K,48,5K,6K)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;

(2K,3K,48,5K,6K)-6-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydroxy-2H-pyran-3-ol;

(2K,3K,48,5K,6K)-6-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;

(2K,3K,48,5K,6K)-6-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol;

(2K,3K,48.5K,6K)-6-((1-oxa-2-azaspiro[4.6]undec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy- 4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahyde rho-2H-pyran-3-ol;

(58,88)-3-(((2K,3K,48,5K,6K)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;

(5g,8K)-3-(((2K,3K,48,5K,6K)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;

ot/?et-butyl ((5g,8K)-3-(((2K,3K,48,5K,6K)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oke a-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;

ot/?et-butyl ((58,88)-3-(((2R,3R,48,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oke a-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;

from/?eot-butyl ((5g,8K)-3-(((2K,3K,48.5K,6K)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1, 2,3-triazol1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl) -1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;

- 15 048269 t/?eot-butyl ((5s,8S)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(2,3-diτop-4-methylphenyl)-lH-l,2,3-τpiazol1- yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl) -1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;

t/?eot-butyl ((5r,8R)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(4-chloro-2,3-diφτopφenyl)-lH-l,2,3-τpiazol- lyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1 -oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;

t/?eot-butyl ((5 s, 8S)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1 ,2,3-triazol-1yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1 -oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;

3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;

3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;

3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;

(2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-(((5r,8R)-8-(2-hydroxypropylpropan-2-yl)1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;

(2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-(((5s,8S)-8-(2-hydroxypropylpropan-2-yl)1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;

(2R, 3R, 4S, 5R, 6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-((8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol;

(5s,8S)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(2,3-diτop-4-methylphenyl)-lH-l,2,3-τpia gold- 1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)me til)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;

- 16 048269 (5r,8R)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(2,3-diφτop-4-methylphenyl)-lH-l,2,3- τpia zol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8 -carbonitrile;

(5s,8S)-3-(((2R,ЗR,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methyloxy-4-(4(2 ,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1 -oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;

(5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;

(5 s, 8 S)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-x^op-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;

(5g, 8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile;

(2R,ЗR,4S,5R,6R)-4-(4-(2,3-diφτop-4-methylphenyl)-lH-1,2,3-triazol-1-yl)-2 -(hydroxymethyl)-6-(((5r,8R)-8-(2-hydroxypropan-2-yl)-l-oca-2-azacipo[4.5]d ec-2-en-3-yl)methyl) -5-methoxytetrahydro-2H-pyran-3-ol;

(2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-(((55,88)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol;

(2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-(((58,88)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol;

3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-one;

(2R,ЗR,4S,5R,6R)-6-((l-oca-2-azacpipo[4.5]dec-2-en-3-yl)methyl)-5-(2,2-diφ torethoxy)- 2-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3 -triazol-1-yl) tetrahydro-2H-pyran-3-ol;

methyl

2-(((2R,3R,4S,5R,6R)-2-((l-oκca-2-azacpipo[4.5]dec-2-en-3-yl)methyl)-5-hydroxy6-(hydroxymethyl) -4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol- 1-yl)tetrahydro2H-pyran-3-yl)oxy)acetate;

- 17 048269 (2R,ЗR,4S,5R,6R)-6-((l-oca-2-azacpipo[4.5]dec-2-en-3-yl)methyl)-5-ethoxy2-(hydroxymethyl)- 4-(4-(3,4,5-trifluorophenyl)-1 Η-1,2,3-triazol-1-yl)tetrahydro2H-pyran-3-ol;

2-(((2R,3R,4S,5R,6R)-2-((l-oxa-2-aza-cyano[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetradiro-2H-pyran-3-yl)oxy)-X-methylacetamide;

2-(((2R,3R,4S,5R,6R)-2-((l-octa-2-aza-cyano[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetradiro-2H-pyran-3-yl)oxy)-1-morpholinoethan-1-one; methyl

2-(((2R,ЗR,4S,5R,6R)-2-((8,8-diτop-l-oca-2-azacipo[4.5]dec-2-en-3-yl)methyl )4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxy methyl)tetrahydro-2H-pyran-3-yl)oxy)acetate;

(2R,3R,4S,5R,6R)-2-((l-OKca-2-a3acnnpo[4.5 ]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl carbamate;

(2R, 3R, 4S, 5R, 6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-6 -(((5r,8R)-8-((2,2-diφτopethyl)amino)-l-oca-2-azacpipo[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl) -5-methoxytetrahydro-2H-pyran-3-ol;

ot/?eot-butyl (RS)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-dimethyl-4-methylphenyl)-lH-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1oxa-2,8-diazaspiro[4.6]undec-2-ene-8-carboxylate;

(RS)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(2,3-diφτop-4-methylphenyl)-lH-1,2,3-triazo l-1- yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl l)-1-oxa-2,8-diazaspiro[4.6]undec-2-en-9-one;

(RS)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(2,3-diφτop-4-methylphenyl)-lH-1,2,3-triazo l-1- yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl l)-8-methyl-1-oxa-2,8-diazaspiro[4.6]undec-2-en-9-one;

(5RS,8S)-7-(/w/?e/w-6yTOKCHKap6oHHfl)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-xflop-2,3difluorophenyl) -1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxyte etrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,7-diazaspiro[4.4]non-2-en-8-carboxylic acid;

- 18 048269

3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-ol;

(5r,8R)-3-(((2R,ЗR,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methyloxy-4-(4(3 ,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1 -oxa-2-azaspiro[4.5]dec-2-en-8-ol;

N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide;

X-((5g,8K)-3-(((2K,3K,48.5K,6K)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3- t riazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl )methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide;

X-((5g,8K)-3-(((2K,3K,48,5K,6K)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide;

N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide;

ethyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-lH-l,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;

ethyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oke a-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;

ethyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-diφτopφenyl)-lH-l,2,3-τpiazole -lyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1 -oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate;

(2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-(((5r,8R)-8-(isopropylamino)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;

- 19 048269 (2R,ЗR,4S,5R,6R)-6-((8-((2,2-diφτopethyl)amino)-l-oca-2-azacipo[4.5]dec2-en-3-yl)methyl)- 2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 Η-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;

(2R,ЗR,4S,5R,6R)-6-((8-(cycloπpoπlamino)-l-oca-2-azapipo[4.5]dec-2-ene -3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-t riazol-1 -yl)tetrahydro- 2H-pyran-3-ol;

(2R,3R,4S,5R,6R)-2-(hydroxymethyl)-5-methoxy-6-((8-((2,2,2-trifluoroethyl)amino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;

(2R,ЗR,4S,5R,6R)-6-(((5r,8R)-8-((2,2-diτopethyl)amino)-l-oca-2-azac[4.5] dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1 - yl)tetrahydro-2H-pyran-3-ol;

(2R,ЗR,4S,5R,6R)-6-(((5r,8R)-8-(cycloπpopylamino)-l-oca-2-azacopipo[4.5]dec-2-en-3-yl)methyl) -2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol;

2-(((2R,3R,4S,5R,6R)-2-((l,8-dioca-2-azacipo[4.5]dec-2-en-3-yl)methyl)-4(4-( 2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxyme til)tetrahydro-2H-pyran-3-yl)oxy)acetic acid;

2-(((2R,ЗR,4S,5R,6R)-2-((l-oca-2-azac[4.5]dec-2-en-3-yl)methyl)-4-(4-(2 ,3-difluoro-4-methylphenyl)-1H-1,2,3-triazole-1 -yl)-5-hydroxy-6-(hydroxymethyl)t etrahydro-2H-pyran-3 -yl)oxy)acetic acid;

2-(((2R,3R,4S,5R,6R)-2-((l-octa-2-aza-pipo[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetradiro-2H-pyran-3-yl)oxy)acetic acid;

(2R,ЗR,4S,5R,6R)-6-((8,8-diφτop-l-oca-2-azapipo[4.5]dec-2-en-3-yl)methyl )-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-m ethoxytetrahydro-2H-pyran-3 -ol;

^-(tre m-butyl)-3-(((2R, 3 R, 4 S, 5 R, 6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxamide;

l-(3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oke a-2,8-diazaspiro[4.5]dec-2-en-8-yl)ethan-1-one;

- 20 048269 t/?eot-butyl

3-(((2R,ЗR,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-metoxy-4-(4-(3,4,5-τpiφτ orphenyl)-1Н-1, 2,3-triazole- 1-yl)tetrahydro-2H-pyran-2-yl)methyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate;

3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1oxa-3-azaspiro[4.5]decan-2-one;

3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-and L)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1,8-dioxa-3-azaspiro[4.5]decan-2-one;

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

2-(((2R, 3R, 4 S, 5R, 6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazole-pyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-2,4-diazaspiro[5.5]undecan-3-one;

(2R, 3R, 4S, 5R, 6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2

-(hydroxymethyl)-5-methoxy-6-((2-methyl-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)tetrahydro-2H-pyran-3-ol; and (2R,ЗR,4S,5R,6R)-6-((l,3-diazapypo[4.5]dec-l-en-3-yl)methyl)-4-(4-(2,3-diφ tor -4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahyde rho-2H-pyran-3-ol.

17) In addition to the compounds listed in the embodiment

16), additional compounds of Formula (I) according to embodiment 1) are selected from the following compounds:

(2R,3R,4S,5R,6N)-6-((4'H-spiro[bicyclo[2.2.1]heptan-2,5'-isoxazol]-3'-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; and (2R,3R,4S,5N,6N)-6-((4'H-spiro[bicyclo[3.2.1]octane-3,5'-isoxazol]-3'-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)

-5-methoxytetrahydro-2H-pyran-3-ol.

The compounds of formula (I) according to embodiments 1) to 17) and their pharmaceutically acceptable salts can be used as medicaments, for example in the form of pharmaceutical compositions for enteral (such as, in particular, oral, for example, in the form of a tablet or capsule) or parenteral administration (including topical application or inhalation).

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

The present invention also relates to a method for preventing/prophylaxis or treating a disease or disorder referred to in the present invention, comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) according to embodiments 1) to 17). In a sub-embodiment of the invention, the amount administered is in the range of 1 to 1000 mg per day.

- 21 048269

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

18. Another embodiment relates to compounds of formula (I) as defined in any of embodiments 1) to 17), which are useful for the prevention/prophylaxis 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 by/associated with cancer of the oral cavity or esophagus; Non-alcoholic fatty liver disease (especially non-alcoholic steatohepatitis) caused by/associated with obesity, metabolic syndrome, or type 2 diabetes; liver vascular diseases (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 to Improve Kidney Disease Global Outcomes (KDIGO) Rules], in particular CKD (in particular these stages) caused by/associated with heart disease (also called cardiorenal syndrome type 1 and type 2), or caused by/associated with hypertension, or caused by/associated with diabetes (also called diabetic kidney disease (DKD), including DKD associated with hypertension), where such diabetes is especially 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, infection urinary tract), or caused by/associated with polycystic kidney disease, or caused by/associated with nephropathy due to obstruction of urine outflow (including stones, benign prostatic hyperplasia, prostate cancer, retroperitoneal tumor of the pelvis), or caused by/associated with symptoms associated with neurogenic bladder); as well as acute and chronic renal failure;

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

interstitial lung diseases and disorders (including smoking-related interstitial lung disease; interstitial lung disease associated with/caused by chronic obstructive pulmonary disease; interstitial pneumonia associated with collagen vascular disease (including usual interstitial pneumonia) or pneumonia);

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

Inflammatory and autoimmune diseases and disorders, including chronic and acute inflammatory and autoimmune diseases and disorders (in particular including sepsis, Q-strain rickettsiosis, asthma, rheumatoid arthritis, multiple sclerosis, SLE, SSc, polymyositis, plaque psoriasis (including psoriasis caused/associated with NASH), atopic dermatitis, inflammatory renal diseases/kidney diseases such as nephropathy (including diabetic nephropathy, glomerulonephritis, tubulointerstitial nephritis), inflammatory cardiac diseases/heart disease, inflammatory lung diseases/lung-related inflammatory diseases; inflammatory liver diseases/liver-related inflammatory diseases; diabetes (type 1 or type 2) and diabetes-related diseases such as diabetic vasculopathy, diabetic nephropathy, diabetic retinopathy, diabetic peripheral neuropathy or skin-related conditions; viral encephalitis; and COVID-19 and its sequelae);

diseases and disorders of the gastrointestinal tract (including irritable bowel syndrome)

- 23 048269 (IBS), inflammatory bowel disease (IBD), gastritis and abnormal pancreatic secretion);

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

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

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

neuropathic pain and peripheral neuropathy;

eye diseases and disorders (including dry eye disease (syrup), age-related macular degeneration (AMD), diabetes-related disease (diabetic retinopathy), proliferative vitreoretinopathy (PVR), cicatricial pemphigoid and glaucoma (including glaucoma associated with increased intraocular pressure and ocular 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.

19. A further embodiment relates to compounds of formula (I) for use according to embodiment 18), 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.

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

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

22. A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of (acute or chronic) liver diseases and disorders.

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

24. A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of ocular diseases and disorders.

25. A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of cell proliferative diseases and malignancies.

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

27. A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of diseases and disorders of the gastrointestinal tract.

28. A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of diseases and disorders of the pancreas.

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

- 24 048269

30. A further embodiment relates to compounds of formula (I) for use according to embodiment 18), wherein said compounds are intended for use in the prevention/prophylaxis or treatment of diseases and disorders of the brain.

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

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

Preparation of compounds of formula (I).

Compounds of formula (I) can be prepared by well-known literature methods, by the methods given below, by the methods given in the experimental section below, or by analogous methods. Optimum reaction conditions may vary depending on the particular reagents or solvents used, but such conditions can be determined by one skilled in the art using routine optimization techniques. In some cases, the order of the following reaction schemes and/or the steps of a particular reaction may be varied in order to facilitate the reaction or to avoid undesirable reaction products. In the general reaction sequence set forth below, the generic groups R ¹ , A, B and Ar ¹ are as defined for formula (I). Other abbreviations used in the present invention are explicitly defined or are as defined in the experimental section. In some cases, the generic groups R ¹ , A, B and Ar ¹ may be incompatible with the ensemble of other groups illustrated in the schemes below and will therefore require the use of protecting groups (Pg). The use of protecting groups is well known in the art (see, for example, Protective Groups in Organic Synthesis, TW Greene, PGM Wuts, Wiley-Interscience, 1999). For the purposes of the present discussion, it will be assumed that such protecting groups are in place when appropriate. In some cases, the final product may be further modified, for example, by manipulating substituents to yield a new final product. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, hydrolysis, and transition metal catalyzed cross-coupling reactions, which are well known to those skilled in the art. The resulting compounds may also be converted into salts, especially pharmaceutically acceptable salts, by a method known per se.

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

Structure 1

Compounds of formula (I) are prepared by deprotecting a compound of structure 1 in which R is hydrogen, a suitable protecting group such as acetyl, trimethylsilyl, TBDMS, or R ¹ as defined for formula (I).

Compounds of structure 1, in which ring A is a 3,5,5-trisubstituted isoxazoline (structure 1a), are synthesized as shown below by the 1,3-dipolar cycloaddition of nitrile oxides with exocyclic alkenes of structure 2. The nitrile oxide precursors are oximes such as compounds of structure 3, which are oxidized in situ (e.g., with N-chlorosuccinimide) followed by elimination with a base such as lutidine, NEt ₃ , or DIPEA in a suitable solvent such as DCM or DMF at temperatures in the range from rt to 50 °C. If ring B is substituted, the cycloaddition produces mixtures of diastereomers. These isomers can be separated by silica gel chromatography using various solvent mixtures and gradients, or by HPLC as described in the Experimental Section.

- 25 048269

Compounds of structure 1, in which ring A is a 3,5,5-trisubstituted oxazolidinone (structure 1b), can be prepared by opening the exocyclic epoxide of structure 4 with an amine of structure 5, followed by cyclization with a carbonic acid derivative such as CDI or phosgene.

Structure 1b Structure 4 Structure 5 (oxazolidinone)

Compounds of structure 1, in which ring A is a cyclic 5- or 6-membered urea (structure 1c), can be prepared by reductive amination of a compound of structure 6 with an amine of structure 5 followed by cyclization using a strong base such as NaH, KOtBu, or other non-nucleophilic strong bases, as shown in the scheme below.

Structure 1c Structure 6 Structure 5 (cyclic urea)

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

R ₂

Structure Id (cyclic Structure 6 Structure 5 amidines or guanidines)

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 carried out under nitrogen or argon. Compounds were purified by flash chromatography on silica gel (Biotage), by prep. TLC (TLC plates from Merck, silica gel 60 F ₂₅₄ ), or by preparative HPLC. The compounds described in the invention were characterized by ¹ H-NMR (400 MHz or 500 MHz Bruker; chemical shifts are given in ppm relative to the solvent used; multiplicities: s=singlet, 6=doublet, t=triplet, q=quadruplet, quint=quintuplet, hex=hexet, hept=heptet, m=multiplet, br=broad, coupling constants are given in Hz) and/or by LCMS (retention time t _R is given in min; molecular weight obtained for the mass spectrum is given in g/mol) using the conditions listed below.

- 26 048269

Methods used to determine characteristics.

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

LC-MS (A).

Column Zorbax RRHD SB-Aq, 1.8 μm, 2.1x50 mm, thermostatted at 40°C. The two elution solvents were as follows: solvent A = water + 0.04% TFA; solvent B = acetonitrile. The eluent flow rate was 0.8 ml/min, and the characteristics of the composition of the elution mixture 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.

Preparative LC-MS (I).

A Waters column (Waters XBridge Cl8, 10 μm OBD, 30x75 mm) was used. The two elution solvents were as follows: solvent A = water + 0.5% solution of 25% NH ₄ OH in water; solvent B = acetonitrile. The eluent flow rate was 75 ml/min, and the characteristics of the composition of the eluting mixture as a function of time t from the start of elution are summarized in the table below (a linear gradient was used between two successive time points): _________________

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.

Preparative LC-MS (II):

A Waters column (Waters XBridge Cl8, 10 μm OBD, 30x75 mm) was used. The two elution solvents were as follows: solvent A = water + HCOOH 0.5%; solvent B = acetonitrile. The eluent flow rate was 75 ml/min, and the characteristics of the 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 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.

Preparative LC-MS (III).

A Waters column (Zorbax SB-AQ 30x75 mm 5 μm) was used. The two elution solvents were as follows: solvent A = water + HCOOH 0.5%; solvent B = acetonitrile. The eluent flow rate was 75 ml/min, and the characteristics of the composition of the eluting mixture 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 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.

Chiral preparative HPLC methods used.

Separation of epimers was accomplished by preparative chiral column chromatography using the conditions described below.

Chiral preparative HPLC (I).

A ChiralPack OZ-H column, 5 μm, 30x250 mm, thermostatted at 40°C was used. The two elution solvents were as follows: solvent A = CO ₂ ; solvent B = ACN/EtOH 1:1. The eluent flow rate was 160 ml/min. Elution was performed using 60% solvent A and 40% solvent B. The injected volume V = 1.0 ml, 10 mg/ml MeOH. Wavelength 247 nm. (examples 2.02/2.03).

Chiral preparative HPLC (II).

A ChiralPack OJ-H column, 30x250 mm, thermostatted at 40°C was used. The two elution solvents were as follows: solvent A = CO ₂ ; solvent B = ACN/MeOH 1:1. The elution

-27 048269 The eluent flow rate was 160 ml/min. Elution was performed using 85% solvent A and 15% solvent B. The injected volume V=2 ml, 10 mg/ml MeOH. Wavelength 245 nm. (examples 1.62/1.63, 1.64/1.65).

Chiral preparative HPLC (III).

A ChiralPack IC column, 5 μm, 30x250 mm, thermostatted at 40°C was used. The two elution solvents were as follows: solvent A= _CO2 ; solvent B=ACN/EtOH/DEA 50:50:0.1. The eluent flow rate was 160 mL/min. Elution was performed using 60% solvent A and 40% solvent B. The injected volume V=1.2 mL, 11 mg/mL EtOH/ACN 1:1. (examples 2.20/2.21, 2.22/2.23).

Chiral preparative HPLC (IV).

A ChiralPack IF column, 5 μm, 30x250 mm, thermostatted at 40°C was used. The two elution solvents were as follows: solvent A=CO2; solvent B=ACN/EtOH 50:50. The eluent flow rate was 160 ml/min. Elution was performed using 60% solvent A and 40% solvent B. The injected volume V=1 ml, 11.2 mg/ml EtOH/ACN 1:1. (examples 1.44/145 (acetal-protected)).

Chiral preparative HPLC (V).

A ChiralPack IE column, 5 μm, 30x250 mm, thermostatted at 40°C was used. The two elution solvents were as follows: solvent A=CO2; solvent B=ACN/MeOH 50:50. The eluent flow rate was 160 ml/min. Elution was performed using 55% solvent A and 45% solvent B. The injected volume V=3 ml, 10 mg/ml MeOH/ACN 1:1. (examples 1.15/1.16, 1.52/1.53, 1.61)

Chiral preparative HPLC (VI).

A ChiralPack OD-H column, 30x250 mm, thermostatted at 40°C was used. The two elution solvents were as follows: solvent A=CO2; solvent B=ACN/MeOH 1:1. The eluent flow rate was 160 ml/min. Elution was performed using 70% solvent A and 30% solvent B. The injected volume V=1 ml, 10 mg/ml MeOH. (examples 1.56/1.57, 1.58/1.59, 1.60/1.61)

Chiral preparative HPLC (VII).

A ChiralCell OJ-H column, 30x250 mm, thermostatted at 40°C was used. The two elution solvents were as follows: solvent A=CO2; solvent B=ACN/MeOH 1:1. The eluent flow rate was 160 ml/min. Elution was performed using 70% solvent A and 30% solvent B. The injected volume V=1 ml, 10 mg/ml MeOH. (examples 1.27/1.28, 1.33/1.34)

NMR.

¹ H-NMR spectra were recorded on a Bruker Avance II, 400 MHz Ultra ShieldTM or Brooker Avance III HD, Ascend 500 MHz; chemical shifts are given in ppm relative to the solvent used; multiplicities: s=singlet, d=doublet, t=triplet, q=quadruplet, quint=quintuplet, hex=hextet, hept=heptet, m=multiplet, br=broad, coupling constants are given in Hz).

Abbreviations (in the context of the present invention). Ac - acetyl, Ac2O - acetic anhydride, AcOH - acetic acid, aq. - aqueous, BF ₃ OEt2 - boron trifluoride diethyl etherate, Boc - tert-butoxycarbonyl, Bu - butyl (such as in nBuLi = n-butyl lithium), CC - column chromatography on silica gel, CDI - 1,1-carbonyldiimidazole, conc. - concentrated, DCM - dichloromethane, dil. - diluted, DIPEA - N-ethyldiisopropylamine, DMAP - 4-dimethylaminopyridine, DMF - dimethylformamide, DMSO - dimethyl sulfoxide, EA - ethyl acetate, EDC HCl - hydrochloride,

N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, equiv. - (molar(s)) equivalent(s), note - example, Et - ethyl, EtOH - ethanol, Et2O - diethyl ether,

- 28 048269

FC - flash chromatography, h - hour(s), HATU - 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, hept - heptane,

HOBt - 1-hydroxybenzotriazole hydrate,

HPLC - high performance liquid chromatography, M - molarity [mol-L ¹ ], Me - methyl, MeCN - acetonitrile, MeOH - methanol, Ms - methanesulfonyl, MS - mass spectroscopy, min. - minute(s), n. - normality, NaOAc - sodium acetate, NaOMe - sodium methoxide, NaOtBu - sodium tert (tertiary)-butoxide, NEt ₃ - triethylamine, v.n. - overnight, org. - organic, Pg - protecting group, Ph - phenyl, PTSA - p-toluenesulfonic acid, rt. - room temperature, sat. - saturated,

TBAF - tetra-n-butylammonium fluoride, TBME tert-butyl methyl ether, TBSCl - tert-butyldimethylsilyl chloride, TBTU - O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate, tBu tert-butyl - tertiary butyl, TFU - trifluoroacetic acid, THF - tetrahydrofuran, TMEDA - tetramethylethylenediamine, TMSCl - trimethylsilyl chloride, T3P - propylphosphonic anhydride, t _R - retention time.

A - Obtaining precursors and intermediates.

Intermediate connection 1 Intermediate connection 2 Intermediate connection 3

Intermediate connection 1.

(3R,4S,5R,6R)-6-(Acetoxymethyl)-4-azidotetrahydro-2H-pyran-2,3,5-triyl triacetate.

(3R,4S,5R,6R)-6-(Acetoxymethyl)-4-azidotetrahydro-2H-pyran-2,3,5-triyl triacetate was synthesized from (3aR,5S,6S,6aR)-5-(1-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol6-ol following the literature procedures from Carbohydrate Research 1994, 251, 33-67, and the references cited therein.

Intermediate connection 2.

(2K,3K,4K,5K,6K)-2-(Acetoxymethyl)-6-allyl-4-azidotetrahydro-2H-pyran-3,5-diyl diacetate.

A solution of intermediate 1 (10 g, 26.8 mmol, 1 equiv) in MeCN (100 mL) was cooled to 0 °C and allyltrimethylsilane 98% (13 mL, 80.4 mmol, 3 equiv) and, dropwise, trimethylsilyl trifluoromethanesulfonate 99% (2.45 mL, 13.4 mmol, 0.5 equiv) were added (without heat evolution). The ice bath was removed and the mixture was stirred at rt for 72 h. The mixture was poured onto saturated NaHCO ₃ solution and extracted with TBME. The organic phase was washed with brine, dried over MgSO ₄ and concentrated. The crude material was purified by filtration through SiO ₂ (DCM/TBME 9:1) to give the specified

- 29 048269 the title intermediate (as a 9:1 mixture of alpha/beta isomers) as a colourless oil, which was used in the next step without further purification.

Major isomer: ¹ H NMR (500 MHz, DMSO) δ: 5.70-5.78 (m, 2H), 5.31 (dd, J ¹ = 1.6 Hz, J2 = 3.4 Hz, 1H), 5.06-5.14 (m, 2H), 4.98-5.04 (m, 1H), 4.39 (dd, J ¹ 3.4 Hz, J ² = 10.6 Hz, 1H), 4.15 (m, 1H), 3.91-4.09 (m, 4H), 2.56-2.65 (m, 1H), 2.22-2.28 (m, 1H), 2.11 (s, 3H), 2.09 (s, 3H), 1.99 (s, 3H).

Intermediate compound 3 a.

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

To a solution of intermediate 2 (15 g, 42.5 mmol, 1 equiv) in DMF (160 mL) were added 5-ethynyl-1,2,3-trifluorobenzene (9950 mg, 63.7 mmol, 1.5 equiv), copper(I) iodide (809 mg, 4.25 mmol, 0.1 equiv) and Net ₃ (17.8 mL, 127 mmol, 3 equiv) and stirred at rt overnight. The mixture was diluted with EA and diluted HCl. The organic phase was washed with water and brine, dried over MgSO ₄ and concentrated. The crude material was crystallized from EA (20 mL) and TBME (200 mL) to afford the desired pure alpha-isomer as a colorless solid.

LCMS (A): t _R =1.02 min; [M+N]+=512.15.

¹ H NMR (500 MHz, DMSO-de) δ: 8.78 (s, 1H), 7.83-7.88 (m, 2H), 5.75-5.84 (m, 1H), 5.70-5.74 (m, 2H), 5.36 (s, 1H), 5.18-5.21 (m, 1H), 5.10-5.14 (m, 1H), 4.41 (m, 1H), 4.35 (m, 1H), 4.00-4.04 (m, 1H), 3.94 (dd, J ¹ 7.1 Hz, J ² =11.3 Hz, 1H), 2.84-2.91 (m, 1H), 2.30-2.35 (m, 1H), 2.02 (s, 3H), 1.98 (s, 3H), 1.86 (s, 3H).

Intermediate connection 4a.

(2R,3R,4R,5R,6R)-2-Allyl-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol.

To a solution of intermediate 3a (12 g, 23.5 mmol, 1 equiv) in methanol (240 mL) was added K2CO3 (324 mg, 2.35 mmol, 0.1 equiv). The reaction mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo to give a beige foam. The crude compound was purified by PC (DCM/MeOH 9:1) to give the desired product as a colorless solid.

LCMS (A): t _R = 0.7 min; [M+H] ⁺ =385.76 ^1H NMR (500 MHz, DMSO-de) δ: 8.72 (s, 1H), 7.82-7.87 (m, 2H), 5.88 (m, 1H), 5.26 (d, J=5.7 Hz, 1H), 5.14-5.19 (m, 2H), 5.05-5.07 (m, 1H), 4.90 (dd, J ¹ 2.9 Hz, J ² =11.4 Hz, 1H), 4.58 (t, J = 5.5 Hz, 1H), 4.52 (m, 1H), 4.02 (m, 1H), 3.93 (dd, J ¹ = 2.6 Hz, J ² =6.4 Hz, 1H), 3.78 (t, J=6.2 Hz, 1H), 3.49 (m, 1H), 3.42 (m, 1H), 2.68-2.75 (m, 1H), 2.33-2.38 (m, 1H).

Intermediate connection 5a.

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

A solution of intermediate 4a (15 g, 38.9 mmol, 1 equiv) in THF (180 mL) was treated with 2,2-dimethoxypropane (19.1 mL, 156 mmol, 4 equiv) and PTSA monohydrate (0.378 g, 1.95 mmol, 0.05 equiv) and the light yellow solution was stirred at rt. The mixture was diluted with EA and the org. layer was washed with saturated NaHCO ₃ solution, water and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title intermediate as a colourless solid.

LCMS (A): t _R =0.93 min; [M+N] ⁺ =426.13

Ή NMR (500 MHz, DMSO-d _e ) δ: 8.72 (s, 0 H), 8.58-8.64 (m, 1H), 7.80-7.94 (m, 2H), 5.81-5.90 (m, 1H), 5.33- 5.38 (m, 1H), 5.11-5.20 (m, 1H), 5.00-5.11 (m, 2H), 4.41-4.52 (m, 1H), 4.26-4.31 (m, 1H), 4.12 (ddd, J ¹ =11.5 Hz, J ² =5.7 Hz, J ³ =3.2 Hz, 1H), 4.01 (dd, J ¹ =12.7 Hz, J2=2.0 Hz, 1H), 3.66-3.71 (m, 1H), 3.57-3.65 (m, 1H), 2.64-2.72 (m, 1H), 2.34-2.41 (m, 1H), 1.32 (s, 3H), 1.20 (s, 3H).

Intermediate connection 6a.

1-((4aR,6R,7R,8R,8aR)-e-Allyl-7-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole.

To a solution of intermediate 5a (7.3 g, 17.2 mmol, 1 equiv.) in dry THF (50 mL) cooled to 0°C was added dimethyl sulfate (2 mL, 20.6 mmol, 1.2 equiv.) followed by portionwise addition of NaH [55% dispersion in paraffin] (824 mg, 20.6 mmol, 1.2 equiv.). The mixture was stirred at 0°C for 3 h. The mixture was quenched with saturated NH4Cl solution and extracted twice with TBME. The combined organic layers were washed with brine, dried over _MgSO4 , filtered, and concentrated at

- 30 048269 under reduced pressure to obtain a colorless solid.

LCMS (A): t _R =1.03 min; [M+N]+=440.22.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ: 8.71 (s, 1H), 7.68-7.98 (m, 2H), 5.70-5.97 (m, 1H), 5.14-5.21 (m, 2H), 5.09 (m, 1H), 4.48 (ddd, ^=3.5 Hz, J ² =5.5 Hz, J ³ =11.4 Hz, 1H), 4.30 (d, J=2.9 Hz, 1H), 4.22 (dd, ^=5.7 Hz, J ² =11.5 Hz, 1H), 3.93-4.10 (m, 1H), 3.56-3.74 (m, 2H), 3.21 (s, 3H), 2.70-2.78 (m, 1H), 2.20-2.31 (m, 1H), 1.32 (s, 3H), 1.20 (s, 3H).

Intermediate compound 6b.

(4aR,6R,7R,8S,8aR)-6-Allyl-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl )hexahydropyrano[3,2-d][1,3]dioxin-7-yl acetate.

Intermediate 5a (725 mg, 1.7 mmol, 1 equiv) was dissolved in DCM (10 mL) and Ac2O (0.193 mL, 2.05 mmol, 1.2 equiv), DIPEA (0.438 mL, 2.56 mmol, 1.5 equiv), and DMAP (10.4 mg, 0.0852 mmol, 0.05 equiv) were added. The mixture was stirred at rt for 1 h. The mixture was partitioned between EA and _NaHCO3 solution. The organic phase was washed with saturated _NH4Cl solution and brine, dried over _MgSO4 , and concentrated. Purification with FQ (hept./EA 2:1, 1:1, 1:2) gives the title intermediate as a colourless foam.

LCMS (A): t _R =1.04 min; [M+N]+=467.98.

Ή NMR (500 MHz, DMSO-d ₆ ) δ: 8.63 (s, 1H), 7.89 (m, 2H), 5.81 (m, 1H), 5.59 (dd, J1=5.7 Hz, J ² =11.4 Hz, 1H), 5.47 (dd, J1=3.2 Hz, J ² =11.4 Hz, 1H), 5.19 (dd, J1=1.9 Hz, J2=17.2 Hz, 1H), 5.09 (m, 1H), 4.36-4.41 (m, 2H), 4.03-4.06 (m, 1H), 3.76 (d, J=1.0 Hz, 1H), 3.66 (dd, J1=1.7 Hz, J2=12.8 Hz, 1H), 2.80 (m, 1H), 2.28-2.33 (m, 1H), 1.84 (s, 3H), 1.38 (s, 3H), 1.25 (s, 3H).

Intermediate connection 6c.

((2R,3R,4R,5R,6R)-3-Acetoxy-6-α-allyl-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1yl)tetrahydro-2H-pyran-2-yl)methyl acetate.

Stage 1.

(2R,3R,4S,5R,6R)-6-Allyl-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol.

To a mixture of Intermediate 6a (3050 mg, 6.94 mmol, 1 equiv.) in water (15 mL) was added acetic acid (30 mL), and the suspension was stirred at 55 °C for 3 h. The solution was concentrated under reduced pressure and the residue was dried under high vacuum v.n. The crude material (light yellow solid) was used in the next step without further purification.

Stage 2.

To a solution of the intermediate from step 1 (3340 mg, 8.36 mmol, 1 equiv) and _Et3N (6.99 mL, 50.2 mmol, 6 equiv) in DCM (40 mL) at 0 °C under N2 was added _Ac2O (2.42 mL, 25.1 mmol, 3 equiv) and the solution was stirred at rt. Water was added and the mixture was extracted with DCM. The organic layer was dried over MgSO4 and then concentrated under reduced pressure to give the title intermediate as a colorless solid.

LCMS (A): t _R =1.03 min; [M+N]+=484.20.

Intermediate connection 6d.

1-((4aR,6R,7R,8S,8aR)-6-Allyl-7-((tert-butyldimethylsilyl)oxy)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)-4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole.

Intermediate 5a (2000 mg, 4.7 mmol, 1 equiv) was dissolved in dry DCM (30 mL) and the solution was cooled to 0 °C. 2,6-lutidine (1.1 mL, 9.4 mmol, 2 equiv) was added under N2 followed by dropwise addition of tert-butyldimethylsilyl trifluoromethanesulfonate (1.32 mL, 5.64 mmol, 1.2 equiv) over 5 min. The yellowish solution was stirred at 0 °C for 30 min and at rt overnight. The mixture was quenched with water and the two layers were separated. The org. layer was dried using a phase separator and then concentrated under reduced pressure to give an off-white foam, which was used without further purification.

LCMS (A): t _R =1.23 min; [M+N]+=540.22

Intermediate connection 7a.

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

Intermediate 6a (4270 mg, 9.72 mmol, 1 equiv) was suspended in 1,4-dioxane (50 mL) and

- 31 048269 water (15 mL). 2,6-lutidine (1.24 mL, 10.6 mmol, 3 equiv.) and sodium periodate (6235 mg, 29.2 mmol, 3 equiv.) were added, followed by potassium osmate dihydrate (15 mg, 0.0408 mmol, 0.0042 equiv.). The suspension was stirred vigorously at room temperature. The mixture was diluted with water and EA, and the pH was carefully adjusted to 2-3 with 1 N HCl. The two layers were separated and the organic layer was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The crude material was purified by PC using a CombiFlash (40 g _SiO2 column; gradient: 0-100% EA in hept.) to give the desired aldehyde as a colorless solid.

LCMS (A): t _R =0.91 min; [M+N]+=442.12.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ: 9.72 (m, 1H), 8.73 (s, 1H), 7.87 (dd, J1=9.0 Hz, J ² =6.8 Hz, 2H), 5.1-5.18 (m, 2H), 4.24-4.30 (m, 2H), 4.01-4.04 (m, 1H), 3.57-3.69 (m, 2H), 3.32 (s), 3.20 (s, 3H), 2.98 (ddd, J1=16.2 Hz, J ² =9.2 Hz, J ³ =3.0 Hz, 1H), 2.83 (ddd, J1=16.2 Hz, J ² =5.0 Hz, J ³ =1.4 Hz, 1H), 1.18-1.33 (m, 6 H).

Intermediate compound 7b.

(4aR,6R,7R,8S,8aR)-2,2-Dumethyl-6-(2-oxoethyl)-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole -1yl)hexahydropyrano[3,2-d][1,3]dioxin-7-yl acetate.

Prepared by analogy with intermediate 7a, starting from intermediate 6b. LCMS (A): t _R = 0.92 min; [M+H]+= 469.96

Intermediate connection 7c.

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

Obtained by analogy with intermediate compound 7a, starting from intermediate compound 3a. LCMS (A): t _R = 0.93 min; [M+H]+ = 514.10

Intermediate connection 7d.

2-((4aR,6R,7R,8S,8aR)-7-((Tert-butyldimethylsilyl)oxy)-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-6-yl)acetaldehyde.

Obtained by analogy with intermediate compound 7a, starting from intermediate compound 6d. LCMS (A): t _R = 1.16 min; [M+H]+= 542.18.

Intermediate connection 8a.

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

Intermediate 7a (1390 mg, 3.15 mmol, 1 equiv), hydroxylamine HCl (328 mg, 4.72 mmol, 1.5 equiv), and NaOAc (775 mg, 9.45 mmol, 3 equiv) were charged into a flask and suspended in EtOH (5 mL) and H2O (5 mL). THF (10 mL) was added and the mixture was stirred at rt for 1.5 h. The mixture was partitioned between EA and water. The org. layer was washed with brine, dried over _MgSO4 , and concentrated under reduced pressure. The crude material was triturated in TBME and hept. 3/1 (20 mL), sonicated, and the off-white crystals were filtered and dried under high vacuum.

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

Intermediate compound 8b.

(4aR,6R,7R,8S,8aR)-6-(-2-(Hydroxyimino)ethyl)-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2 ,3triazol-1 -yl)hexahydropyrano[3,2-d] [1,3]dioxin-7 -yl acetate.

Obtained in analogy with intermediate compound 8a, starting from intermediate compound 7b. LCMS (A): t _R = 0.90 min; [M+H]+=485.18.

Intermediate connection 8c.

(2R,3R,4R,5R,6R)-2-(Acetoxymethyl)-6-(-2-(hydroxyimino)ethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-

1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate.

Obtained by analogy with intermediate compound 8a, starting from intermediate compound 7c. LCMS (A): t _R = 0.89 min; [M+H]+=529.05.

Intermediate connection 8d.

2-((4aR,6R,7R,8S,8aR)-7-((tert-butyldimethylsilyl)oxy)-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-6-yl)acetaldehyde oxime.

Prepared in analogy with intermediate 8a, starting from intermediate 7d. LCMS (A): t _R = 1.11 min; [M+H]+= 558.19

- 32 048269

Intermediate connection 9.

(2R,3R,4R,5R,6R)-2-(Acetoxymethyl)-6-(propa-1,2-dien-1-yl)-4-(214-triaza-1,2-dien-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate.

Intermediate 1 (3733 mg, 10 mmol, 1 equiv) was dissolved in MeCN (20 mL) and cooled to 3 °C. Trimethyl(propargyl)silane (3.73 mL, 25 mmol, 2.5 equiv) was added followed by dropwise addition of BF ₃ OEt ₂ (3.7 mL, 30 mmol, 3 equiv) and trimethylsilyl trifluoromethanesulfonate (3.66 mL, 20 mmol, 2 equiv). The mixture was stirred at 0 °C for 1.5 h and at rt for 1 h. The mixture was partitioned between TBME and saturated NaHCO ₃ solution. The organic phase was washed with brine, dried over MgSO ₄ and concentrated. The crude product was purified by PC (heptane/EA 2:1) to afford the desired allene intermediate as a yellowish oil.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ: 5.56 (q, J=6.7 Hz, 1H), 5.35 (d, J=2.2 Hz, 1H), 4.98-5.05 (m, 3H), 4.74 (m, 1H), 4.35 (dd, J1=3.3 Hz, J2=11.2 Hz, 1H), 4.20-4.23 (m, 1H), 4.00-4.03 (m, 1H), 3.90 (dd, J1=7.0 Hz, J ² =11.4 Hz, 1 H), 2.12 (s, 3H), 2.09 (s, 3H), 2.00-2.02 (m, 4H).

Intermediate connection 10a.

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

The title compound is prepared by analogy with intermediate compound 3a, starting from intermediate compound 9.

LCMS (a): tR=1.02 min; [M+N]+=510.24.

1H NMR (500 MHz, DMSO-d ₆ ) δ: 8.81 (s, 1H), 7.82-7.86 (m, 2H), 5.80 (q, J=6.8 Hz, 1H), 5.65-5.72 (m, 2H), 5.40 (d, J=1.5 Hz, 1H), 5.06 (dd, J1=6.6 Hz, J2=2.3 Hz, 2H), 4.96-4.99 (m, 1H), 4.50 (t, J=6.3 Hz, 1H), 4.01 (m, 2H), 2.00-2.04 (m, 6 H), 1.87 (s, 3H).

Intermediate connection 11a.

1-((4aR,6R,7R,8R,8aR)-7-methoxy-2,2-dimethyl-6-(propa-1,2-dien-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-8-yl)-4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole.

The title intermediate is prepared starting from Intermediate 10a and following the procedures for the preparation of intermediates 4a, 5a and 6a.

LCMS (A): t _R =1.02 min; [M+N] ⁺ =438.21

1H NMR (500 MHz, DMSO-d ₆ ) δ: 8.71 (s, 1H), 7.87 (dd, J1=6.8 Hz, J ² =9.0 Hz, 2H), 5.75 (m, 1H), 5.13 (dd, J1=3.3 Hz, J ² =11.4 Hz, 1H), 5.07 (m, 1H), 4.98 (m, 2H), 4.34-4.34 (m, 1H), 4.26 (dd, J1=5.6 Hz, J ² =11.5 Hz, 1H), 4.04 (dd, J1=2.0 Hz, J2=12.9 Hz, 1H), 3.82 (d, J=0.7 Hz, 1H), 3.68 (dd, J1=1.5 Hz, J2=12.9 Hz, 1H), 3.22 (s, 3H), 1.32 (s, 3H), 1.21 (s, 3H).

Intermediate connection 12a.

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

Intermediate 11a (1000 mg, 2.29 mmol, 1 equiv) was dissolved in DCM/MeOH 4:1 (60 mL) and cooled to -70 °C. Ozone was bubbled through the solution until the KI solution in the scrubber turned brown (~60 min). Excess _O3 was removed by bubbling N2 through the solution for 10 min. At -78 °C, _NaBH4 (86.5 mg, 2.29 mmol, 1 equiv) was added, the dry ice bath was removed and the mixture was allowed to warm to rt over 1 h. The mixture was then carefully quenched with water (25 mL), the layers were separated, the organic layer was dried over _MgSO4 and concentrated under reduced pressure.

The crude solid was purified by FC using a CombiFlash (24 g _SiO2 column; gradient from hept/EA 2/1 to 100% EA over 20 min) to give the title intermediate as a colourless solid.

- 33 048269

LCMS (A): t _R =0.84 min; [M+N]+=430.29.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ: 8.69 (s, 1H), 7.86 (m, 2H), 5.29 (dd, J ¹ =11.4 Hz, J ² =3.4 Hz, 1H), 4.80 (t, J=5.5 Hz, 1H), 4.34 (m, 2H), 4.24 (dd, T=11.4 Hz, J ² =6.1 Hz, 1H), 3.96-4.07 (m, 2H), 3.91 (s, 1H), 3.71 (dd, T=12.7 Hz, J ² =1.4 Hz, 1H), 3.63 (ddd, T=12.3 Hz, J2=5.8 Hz, J ³ =2.9 Hz, 1H), 3.23 (s, 3H), 1.32 (s, 3H), 1.20 (s, 3H).

Intermediate connection 13a.

((4aR,6R,7R,8R,8aR)-7-Methoxy-2,2-dimethyl-8-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)hexahydropyrano[3,2-d][1,3]dioxin-6-yl)methyl methanesulfonate.

Intermediate 12a (400 mg, 0.932 mmol, 1 equiv) was dissolved in DCM (8 mL) and cooled to 0 °C. At this temperature, MsCl (0.0736 mL, 0.932 mmol, 1 equiv) and DIPEA (0.191 mL, 1.12 mmol, 1.2 equiv) were added and the mixture was stirred at 0 °C for 30 min. Additional MsCl (0.0144 mL, 0.186 mmol, 0.2 equiv) was added and the mixture was stirred at 0 °C for another 30 min. The mixture was diluted with DCM and washed with water. The organic layer was dried on a phase separator and concentrated under reduced pressure. The crude foam was purified by PC using a CombiFlash (12 g _SiO2 column; gradient hept. to hept./EA 1/2 over 16 min) to afford the title intermediate as a colorless solid.

LCMS (A): t _R =0.96 min; [M+N]+=508.14.

1H NMR (500 MHz, DMSO-d6) δ: 8.72-8.74 (m, 1H), 7.83-7.90 (m, 2H), 5.18-5.27 (m, 1H), 4.89-4.98 (m, 1H), 4.75-4.84 (m, 1H), 4.27-4.37 (m, 3H), 4.06-4.09 (m, 1H), 3.83 (s, 1H), 3.73 (dd, ^=12.9 Hz, J ² =1.5 Hz, 1H), 3.26 (d, J=6.1 Hz, 6 H), 1.34 (s, 3H), 1.22 (s, 3H).

Intermediate connection 14a.

1-((4aR,6R,7R,8R,8aR)-6-(azidomethyl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)-4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazole.

To a solution of intermediate 13a (409 mg, 0.806 mmol, 1 equiv.) in dry DMF (10 mL) under N ₂ was added sodium azide (62.9 mg, 0.967 mmol, 1.2 equiv.). The reaction mixture was heated at 70 °C for 5 h. The temperature was raised to 80 °C and the mixture was stirred at this temperature until the reaction was complete. The mixture was allowed to cool to rt, diluted with EA and water, and the layers were separated. The aq. layer was extracted again with EA. The combined org. layers were washed twice with water, brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude colourless solid was purified by FC using a CombiFlash (12 g _SiO2 column; gradient: hept. to hept./EA 1/1 over 17 min) to give the title intermediate as a colourless solid.

LCMS (A): t _R =1.01 min; [M+N]+=455.19.

¹ H NMR (500 MHz, DMSO) δ: 8.68-8.74 (m, 1H), 7.82-7.91 (m, 2H), 5.13-5.23 (m, 1H), 4.67-4.74 (m, 1H), 4.27-4.33 (m, 2H), 4.17-4.25 (m, 1H), 4.05-4.12 (m, 1H), 3.78-3.86 (m, 1H), 3.66-3.74 (m, 1H), 3.23-3.26 (m, 1H), 3.22 (s, 3H), 1.34 (s, 3H), 1.23 (s, 3H).

Intermediate connection 15a.

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

To a solution of intermediate 14a (500 mg, 1.1 mmol, 1 equiv.) in THF (7.5 mL) were added _PPh3 (583 mg, 2.2 mmol, 2 equiv.) and water (1.5 mL). The resulting mixture was then heated under N2 at 60 °C for 3 h. The mixture was diluted with EA and then extracted with 10% citric acid (3 times) until all the amine was removed from the org. phase. The combined aq. layers were extracted once more with EA and then basified with saturated aq. _NaHCO3 . The basic aq. layer was extracted twice with EA. The combined org. layers were dried over _MgSO4 , filtered and concentrated under reduced pressure. The material was used as such.

LCMS (A): t _R =0.72 min; [M+N]+=429.09

1H NMR (500 MHz, DMSO) δ: 8.42-8.90 (m, 1H), 7.77-7.89 (m, 2H), 5.09 (dd, ^=11.4 Hz, J ² =3.4 Hz, 1H), 4.27-4.31 (m, 2H), 4.23 (m, 1H), 3.99-4.03 (m, 1H), 3.74 (dd, J ¹ =1.5 Hz, J2=12.8 Hz, 1H), 3.68 (s, 1H), 3.21 (s, 3H), 3.11 (dd, T=13.8 Hz, J ² =10.5 Hz, 1H), 2.67 (dd, T=13.8 Hz, J ² =3.4 Hz, 1H), 1.32 (s, 3H).

All further analogues of intermediates 3–15 with different Ar ¹ substituents were obtained by analogy with the methods described above, starting from known or commercially available substituted arylacetylenes.

More specifically, the following most important analogues of intermediates 6, 8, 14 and 15 were prepared and used in the synthesis of the final examples:

- 34 048269

Intermediate connection Connection t _R [min] (LC-MS method A) MS data m/z [M+H] ⁺ be l-((4aR,6R,7R,8R,8aR)-6-allyl-7-methoxy-2,2-dimethylhexahydropyrano[3,2-c!][1,3]dioxin-8-yl)-4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol 1.04 436.23 6f l-((4aR,6R,7R,8R,8aR)-6-allyl-7-methoxy-2,2-dimethylhexahydropyrano[3,2-c!][1,3]dioxin-8-yl)-4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazole 1.06 456.16 6g ((2R,ЗR,4R,5R,6R)-3-acetoxy-6-allyl-4-(4-(3,5-diφτop-4-methoylphenyl)-1H-1,2,3-triazo l- 1-yl)-5-methoxytetrahydro-2H-pyran-2-yl)methyl acetate 1.03 480.16 6h ((2R,3R,4R,5R,6R)-3-acetoxy-6-allyl-4-(4-(4-chloro-3,5-diφτo rphenyl)-1H-1,2,3-triazo l- 1-yl)-5-methoxytetrahydro-2H-pyr an-2-yl)methyl acetate 1.05 500.07 6i l-((4aR,6R,7R,8R,8aR)-6-allyl-7-methoxy-2,2-dimethylhexahydropyrano[3,2-c!][1,3]dioxin-8-yl)-4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazole 1.00 418.25 6j l-((4aR,6R,7R,8R,8aR)-6-allyl-7-methoxy-2,2-dimethylhexahydropyrano[3,2-c!][1,3]dioxin-8-yl)-4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol 1.06 436.25 6k l-((4aR,6R,7R,8R,8aR)-6-allyl-7-methoxy-2,2-dimethylhexahydropyrano[3,2-c!][1,3]dioxin-8-yl)-4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazole 1.08 456.17 61 l-((4aR,6R,7R,8R,8aR)-6-allyl-7-methoxy-2,2-dimethylhexahydropyrano[3,2-c!][1,3]dioxin-8-yl)-4-(4-bromo-2,3-difluorophenyl)-1H-1,2,3-triazole 1.06 500.10 6m l-((4aR,6R,7R,8R,8aR)-6-allyl-7-methoxy-2,2-dimethylhexahydropyrano[3,2-c!][1,3]dioxin-8-yl)-4-(4-chloro-3-fluorophenyl)-1 H-1,2,3-triazole 1.02 438.16 6n l-((4aR,6R,7R,8R,8aR)-6-allyl-7-methoxy-2,2-dimethylhexahydropyrano[3,2-c!][1,3]dioxin-8-yl)-4-(2,3,4-trifluorophenyl)-1 H-1,2,3-triazole 1.02 440.20 6o (4aR,6R,7R,8S,8aR)-6-allyl-8-(4-(2,3-diτop-4-methylphenyl)1Н-1,2,3-triazo l-1-yl)-2, 2-dimethylhexahydropyrano[3,2-c1][1,3]dioxin-7-yl acetate 1.05 464.20 6p l-((4aR,6R,7R,8R,8aR)-6-allyl-7-methoxy-2,2-dimethylhexahydropyrano[3,2-c!][1,3]dioxin-8-yl)-4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazole 1.05 456.21 6q l-((4aR,6R,7R,8R,8aR)-6-allyl-7-methoxy-2,2-dimethylhexahydropyrano[3,2-c!][1,3]dioxin-8-yl)-4-(2,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol 1.04 436.21 6r 4-( 1 -((4aI.6YuI.81C8aI)-6-allyl-7-mstoxy-2.2-dimstilgsx ahydropyrano[3,2-c1][1,3]dioxin-8-yl)-1H-1,2 ,3-triazol-4-yl)-2,6-difluorobenzonitrile 1.03 447.22 6s 4-( 1 -((4aI.6YuI.81C8aI)-6-allyl-7-mstoxy-2.2-dimstilgsx ahydropyrano[3,2-c1][1,3]dioxin-8-yl)-1H-1,2 ,3-triazol-4-yl)-2,3-difluorobenzonitrile 1.03 452.24 61 l-((4aR,6R,7R,8R,8aR)-6-allyl-7-methoxy-2,2-dimethylhexahydropyrano[3,2-c!][1,3]dioxin-8-yl)-4-(2,3-difluoro-4-methoxyphenyl)-1H-1,2,3-triazol 1.01 452.24 8e ((2K,3K,4K,5K,6K)-3-acetoxy-6-(2-(hydroxyimino)ethyl)-5-methyloxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-yl)methyl acetate 0.89 501.16

- 35 048269

8f ((2R,3R,4R,5R,6R)-3-acetoxy-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazolyl-1-yl)-6-(2-(hydroxyimino)ethyl)-5-methox tetrahydro-2H-pyran-2-yl)methyl acetate 0.89 497.11 8g ((2R,ЗR,4R,5R,6R)-3-acetoxy-4-(4-(4-chloro-3,5-diφτopφenyl)1H-1,2,3-triazo l-1-yl)-6 -(2-(hydroxyimino)ethyl)-5-methoxyte etrahydro-2H-pyran-2-yl)methyl acetate 0.91 517.01 8h oxime 2-((4aR, 6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazole-1 -yl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)acetaldehyde 0.81 421.12 8i oxime 2-((4aR,6R,7R,8R,8aR)-8-(4-(4-chloro-3-φτopφenyl)-lH-l,2,3-τp iazol-1 -yl)-7-methoxy- 2,2-dimethylhexahydropyrano[3,2-d][1, 3]dioxin-6-yl)acetaldehyde 0.88 455.07 8j oxime 2-((4aR,6R,7R,8R,8aR)-8-(4-(3,5-difluorophenyl)-lH-l,2,3-triazol-l-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-d][l,3]d ioxin-6-yl)acetaldehyde 0.85 439.10 8k oxime 2-((4aR,6R,7R,8R,8aR)-8-(4-(4-6poM-3-fluorophenyl)-1H-1,2,3-tr iazol-1 -yl)-7-methoxy- 2,2-dimethylhexahydropyrano[3,2-d][1, 3]dioxin-6-yl)acetaldehyde 0.89 500.99 81 oxime 2-((4aR,6R,7R,8R,8aR)-8-(4-(3,5-difluoro-4-methylphenyl)-lH-l, 2,3-triazol-1-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3, 2 -d] [ 1,3 ] dioxin-6 -yl)acetaldehyde 0.89 453.18 8m oxime 2-((4aR,6R,7R,8R,8aR)-8-(4-(3-φτop-4-methylphenyl)-lH-l,2,3-τ riazo l-1-yl)-7-methoxy -2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)acetaldehyde 0.86 435.18 8n oxime 2-((4aR,6R,7R,8R,8aR)-8-(4-(4-chloro-2,3-diτopφenyl)-lH-l,2, 3-triazol-1-yl)-7-methoxy -2,2-dimethylhexahydropyrano[3,2d][1,3]dioxin-6-yl)acetaldehyde 0.93 473.19 8o oxime 2-((4aR,6R,7R,8R,8aR)-8-(4-(4-6poM-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2d][1,3]dioxin-6-yl)acetaldehyde 0.93 519.14 8p oxime 2-((4aR,6R,7R,8R,8aR)-8-(4-(4-chloro-3,5-diτopφenyl)-lH-l,2, 3-triazol-1-yl)-7-methoxy -2,2-dimethylhexahydropyrano[3,2d][1,3]dioxin-6-yl)acetaldehyde 0.92 473.12 8q oxime 2-((4aR,6R,7R,8R,8aR)-8-(4-(2,3-difluoro-4-methylphenyl)-lH-l, 2,3-triazol-1-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3, 2 -d] [ 1,3 ] dioxin-6 -yl)acetaldehyde 0.89 453.19 8r oxime 2-((4aR,6R,7R,8R,8aR)-8-(4-(3-chloro-5-τopφenyl)-lH-1,2,3-tr iazol-1 -yl)-7-methoxy- 2,2-dimethylhexahydropyrano[3,2-d][1, 3]dioxin-6-yl)acetaldehyde 0.89 455.19 8s (4aR,6R,7R,8S,8aR)-8-(4-(2,3-diτop-4-methylphenyl)-lH-1,2,3triazol-1-yl)-6-(2-(hydroxyimino) ethyl)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl acetate 0.91 481.21 8t oxime 2-((4aI.6YuI.8I.8aI)-7-mstoxy-2.2-dimstil-8-(4-(2.3.4-triτopφenyl)-lH-l,2,3-τpiazol-l-yl)hexahydropyrano [3,2-d][l, 3]dioxin-6-yl)acetaldehyde 0.88 457.19 8u oxime 2-((4aR, 6R,7R,8R,8aR)-8-(4-(3-chloro-4,5-difluorophenyl)-1H-1,2, 3-triazolyl-1-yl)-7-methoxy-2,2-dimethylhexahydropyrano [3,2- 0.92 473.18

-36048269

d] [1,3] dioxin-6-yl)acetaldehyde 8v oxime 2-((4aK,6K,7K,8K,8aK)-8-(4-(2,5-difluoro-4-methylphenyl)-1H-1, 2,3-triazol-1-yl)-7-methoxy -2,2-dimethylhexahydropyrano[3, 2-d][1,3]dioxin-6-yl)acetaldehyde 0.89 453.23 14s 1-((4aK,6K,7K,8K,8aK)-6-(azidomethyl)-7-methoxy-2,2-dimethyl hexahydropyrano[3,2L][1,3]dioxin-8-yl)-4- (4-chloro-2,3-diforphenyl)-1H-1,2,3-triazole 1.06 471.17 15b ((4aK,6K,7K,8K,8aK)-8-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3 -triazo l-l-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-d ][1,3]dioxin-6-yl)methanamine 0.70 425.31 15s ((4aR, 6R,7R,8R, 8aI)-8-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3 triazol-1 -yl)-7-metho xy-2 ,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)methanamine 0.71 445.18

B - Getting examples.

General procedure A. Cycloaddition reaction of nitrile oxides with alkenes.

A solution of the oxime intermediate (1 equiv.) and NCS (1.5 equiv.) in DMF (5 mL/mmol) was stirred at rt until complete conversion to the hydroxymoyl chloride. The alkene (1-3 equiv.) and DIPEA or 2,6-lutidine (3 equiv.) were added and the mixture was stirred at rt or 50 °C until complete conversion of the intermediate. The products were isolated after aqueous workup (dil. HCl/EA) and purified as described in the general methods.

General method B. Removal of protection using an aqueous solution of AcOH.

The protected intermediate (acetal and/or silyl Pg) (1 equiv.) was heated under reflux in AcOH/ _H2O 1:1 (5 ml/mmol) until the reaction was complete. The products were purified as described in the general methods.

General procedure C. Removal of acetate protection using K2CO3 in MeOH.

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

General technique D. Removing BOC protection using TFU.

TFA (10-20 equiv) was added to a solution of the Boc-protected intermediate (1 equiv) in DCM (5 mL/mmol). The mixture was stirred at rt until the conversion was complete. The volatiles were removed under reduced pressure and the residue was partitioned between DCM and dilute NH4OH solution. The organic phase was dried over _MgSO4 and concentrated in vacuo. If necessary, the product was further purified as described in the general methods.

General method E. Removing Boc protection using HCl.

A solution of the Boc-protected amine (1 equiv.) in dioxane (5 ml/mmol) was treated with a solution of HCl in dioxane (4 M, 10-20 equiv.) and the resulting mixture was stirred at rt until the reaction was complete. The volatiles were removed under reduced pressure and the crude product was isolated by trituration with TBME.

General procedure F. Schotten-Baumann acylation reaction.

The acyl chloride or anhydride (1.2 equiv) was added at 0°C to a biphasic mixture of the amine (1 equiv) in DCM (5 ml/mmol) and saturated _NaHCO3 (5 ml/mmol) with vigorous stirring. The mixture was further stirred at rt until the conversion was complete. The phases were separated and the organic phase was dried over _MgSO4 and concentrated. The product was purified as described in the general methods.

General Procedure G. Derivatization with Sulfonyl Chlorides, Chloroformates or Isocyanates.

An electrophile (sulfonyl chloride, chloroformate, or isocyanate, 1.1 equiv) was added to a mixture of the starting amine (1 equiv, either as the free base or as TFA or HCl salt) in DCM (5 mL/mmol) and a base ( _NEt3 or DIPEA, 5 equiv) at 0°C or rt. The mixture was stirred at rt until the reaction was complete. The product was purified as described in the General Methods.

General method N. Reductive amination.

A mixture of the intermediate amine (1 equiv.) and aldehyde BB or ketone (1-2 equiv.) in DCM was treated with NaBH(OAc) ₃ (3 equiv.) and the mixture was stirred at rt until the conversion was complete. After workup with aqueous medium (DCM/dil. _NH4OH ), the target products were isolated as described in the general methods.

General method I. Saponification.

The ester (1 eq.) in THF/H2O 1:1 or THF/MeOH/H2O 3:2:1 (1 mL/mmol) and LiOH.H2O (1.5-3 eq.) was stirred at rt until the reaction was complete. After aqueous workup (EA/H2O), the product was purified as described in the general methods.

General procedure J. Wittig olefination reaction.

To a suspension of 98% methyltriphenylphosphonium bromide (1.05 equiv.) in dry Et2O (1.5 ml/mmol) under N2 at 0°C was added dropwise a 1.6 M solution of n-butyl lithium in hexanes (1.05 equiv.) over 15 min, maintaining the temperature below 5°C.

- 37 048269

The resulting suspension was stirred at rt for 1 h. Then a solution of the ketone (1 eq.) in dry Et2O (1 mL/mmol) was added dropwise over 15 min. The resulting suspension was stirred at rt until the reaction was complete. The mixture was carefully quenched with water (2 drops), _Et2O (1.5 mL/mmol) was added and the suspension was filtered and washed with _Et2O . The filtrate was concentrated under reduced pressure and the residue was stored in the freezer.

General Method K. Reduction of a Ketone with _NaBH4 . The ketone (1 equiv.) was dissolved in EtOH (11 ml/mmol) and THF (6 ml/mmol) and cooled to 0°C. _NaBH4 (2 equiv.) was added and the mixture was stirred at 0°C until the reaction was complete. The mixture was diluted with EA and water and acidified by adding 1 N HCl. The phases were separated and the organic phase was washed with water and brine, dried over _MgSO4 and concentrated. The product was purified as described in the General Methods.

General Method L. Epoxide Ring Opening with Amines. A solution of epoxide (1.1 equiv.) and amine (1 equiv.) in MeOH (10 mL/mmol) was heated under reflux in a sealed tube until the reaction was complete. The mixture was concentrated in vacuo and purified as described in the General Methods.

General method M. Cyclization with triphosgene.

A solution of triphosgene (1 equiv.) in DCM (5 mL/mmol) was added to a solution of the amino alcohol (1 equiv.) and DIPEA (10 equiv.) in DCM (10 mL/mmol) at rt. The mixture was stirred at rt until the reaction was complete. After aqueous workup (DCM/sat. NaHCO3), the compound was purified as described in the general methods.

In or With BUT,

Intermediate connection 8

Examples 1.01 - 1.82 listed in Table 1 below were prepared starting from intermediate 8 using General Procedure A to the appropriate exocyclic methylene derivative (either commercially available or prepared from the appropriate cyclic ketone via a Wittig olefination reaction (General Procedure J), followed by deprotection according to General Procedure C or D. The diastereomers were separated by chiral preparative chromatography using the appropriate method indicated above.

- 38 048269

Table 1

Note. Connection t _R [min] (LC-MS method A) MS data m/z [M+H] + 1.01 (2K,3Ya,48,5K,6K)-2-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3 -difluoro-4-methylphenyl)-1H-1,2,3-triazo-1-yl)-5-hydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-3-yl acetate 0.81 537.23 1.02 (2K,3Ya,4K,5K,6K)-2-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol 0.69 495.21 1.03 (2R,ЗR,4S,5R,6R)-2-((8,8-diφτop-l-oca-2-azacpipo[4.5]dec-2-en-3-yl)methyl)-4 -(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate 0.93 571.26 1.04 (2R,3R,4R,5R,6R)-2-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazo-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol 0.83 529.24 1.05 (2R,3R,4R,5R,6R)-2-((l-OKca-2-a3acnnpo[4.5]flep-2-eH-3-Hn)MeTHn)-6-(rHflpoKCH methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 0.81 497.16 1.06 tert-butyl 3-(((2R,3R,4S,5R,6R)-5-rnflpoKCH-6-(rHflpoKCHMeTHn)-3-MeTOKCH-4-(4-(3,4,5-TpH fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2, 8-diazaspiro[4.5]dec-2-ene-8-carboxylate 0.94 612.00 1.07 (2R,3R,4S,5R,6R)-6-((l-OKca-2,8-flHa3acnHpo[4.5]flep-2-eH-3-Hn)MeTHn)-2-(rHflpo oxymethyl)-5-methoxy-4-(4-(3,4,5 -trifluorophenyl)-1H-1,2,3 -triazo l-1-yl)tetrahydro-2H-pyran-3-ol 0.64 512.16 1.08 (2R,3R,4S,5R,6R)-6-((l-OKca-2-a3acnnpo[4.5]fle4-2-eH-3-nn)MeTnn)-2-(rnflpoKCHM ethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro2H-pyran-3-ol 0.92 511.18 1.09 (2R,3R,4S,5R,6R)-6-((l-OKca-2-a3acnHpo[4.4]HOH-2-eH-3-Hn)MeTHn)-2-(rHflpoKCH methyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol 0.88 497.19 1.10 (2R,3R,4S,5R,6R)-6-((5-OKca-6-a3acnHpo[3.4]oKT-6-eH-7-Hn)MeTHn)-2-(rHflpoKCHMethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro2H-pyran-3-ol 0.85 483.13 1.11 tert-butyl (3-(((2R,3R,4S,5R,6R)-5-rnflpoKCH-6-(rHflpoKCHMeTHn)-3-MeTOKCH-4-(4-(3,4,5-TpH fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2 azaspiro[4.5]dec-2-en-8-yl)carbamate (mixture of epimers) 0.93 626.27 1.12 (2R,3R,4S,5R,6R)-6-((l-OKca-2-a ₃ acnHpo[4.5]fle4-2-eH-3-Hn)MeTHn)-4-(4-(4-xnop3 -fluorophenyl)-1H-1,2,3-triazo l-1 -yl)-2-(hydroxymethyl)-5 -methoxytetra ahydro2H-pyran-3-ol 0.92 509.24 1.13 (2R,3R,4S,5R,6R)-6-((l-OKca-2-a ₃ acnHpo[4.5]flen-2-eH-3-Hn)MeTHn)-2-(rHflpoKCHMethyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro2H-pyran-3-ol 0.91 511.26 1.14 (2R,ЗR,4S,5R,6R)-6-((l-okca-2-a ₃ acπipo[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3 -diφ tor-4 -methylphenyl)-1H-1,2,3-triazo l-1-yl)-2-(hydroxymethyl)-5 -methoxytetrahydro-2H-pyran-3-ol 0.92 507.31 1.15 tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-rnflpoKCH-6-(rHflpoKCHMeTHn)-3-MeTOKCH-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate (resolution of Example 1.11 compound) 0.93 626.24

- 39 048269

1.16 tert-butyl ((55.88)-3-(((2K,3K,48.5K,6K)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate (separation of compound of Example 1.11) 0.94 626.29 1.17 (2R,3R,48,5R,6R)-6-((l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-bromo2,3-difluorophenyl)-1H-1,2,3-triazo l-pyr)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol 0.96 573.08 1.18 (2R,3R,4S,5R,6R)-6-((l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-chloro3,5-difluorophenyl)-1H-1,2,3-triazo l-pyr)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol 0.96 527.20 1.19 (2R,3R,4S,5R,6R)-6-((l-OKca-2-a3acnHpo[4.5]fleii-2-eH-3-Hn)MeTHn)-4-(4-(3-xnop5-fluorophenyl)-1H-1,2,3-triazo l-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro 2H-pyran-3-ol 0.94 509.24 1.20 (2R,ЗR,4S,5R,6R)-6-((l-oκca-2-azacpipo[4.5]dec-2-en-3-yl)methyl)-4-(4-(3-φτop4-methylphenyl )-1H-1,2,3-triazo l-1-yl)-2-(hydroxymethyl)-5-methoxytetra ag idr o-2H-pyran-3 -o l 0.91 489.32 1.21 (2R,ЗR,4S,5R,6R)-6-((l-oca-2-azac[4.5]dec-2-en-3-yl)methyl)-4-(4-(3,5-diφ tor-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrag hydro-2H-pyran-3-ol 0.94 507.25 1.22 (2R, 3R, 4 S,5R, 6R)-6-((l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-chloro2, 3-difluorophenyl)-1H-1,2,3-triazo l-1-yl)-2-(hydroxymethyl)-5-methoxytetragi dro-2H-pyran-3-ol 0.96 527.15 1.23 (2R,3R,4S,5R,6R)-6-((l,8-flHOKca-2-a3acnnpo[4.5]fleii-2-eH-3-Hn)MeTHn)-2-(rHflpo oxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro-2H-pyran-3-ol 0.79 513.20 1.24 (2R,ЗR,4S,5R,6R)-6-((8,8-diφτop-l-oca-2-azacpipo[4.5]dec-2-en-3-yl)methyl)-2 -(hydroxymethyl) -5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazo l-1-yl) tetrahydro-2H-pyran-3-ol 0.92 547.21 1.25 (2R,3R,4S,5R,6R)-2-(rHflpoKCHMeTHn)-6-((8-H3onponHn-l-OKca-2-a3acnHpo[4.5]fle c-2-en-3-yl)methyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-l)tetrahydro-2H -pyran-3-ol (mixture of epimers) 1.05 553.27 1.26 (2R,ЗR,4S,5R,6R)-6-((8,8-diφτop-l-oca-2-azapipo[4.5]dec-2-en-3-yl)methyl)-4 -(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-meoxytetrahydro-2H-pyran-3-ol 0.93 543.25 1.27 (2R,3R,4S,5R,6R)-2-(rnflpoKCHMeTHn)-6-(((5r,8R)-8-H3onponHn-l-OKca-2-a3acnHp o[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-tria sol-1-yl)tetrahydro-2H-pyran-3-ol (resolution of Example 1.25) 1.04 553.27 1.28 (2R,3R,4S,5R,6R)-2-(rHflpoKCHMeTHn)-6-(((5s,8S)-8-H3onponHn-l-OKca-2-a3acnHp o[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-tria sol-1-yl)tetrahydro-2H-pyran-3-ol (resolution of Example 1.25) 1.05 553.27 1.29 (2R,3R,4S,5R,6R)-6-((8,8-flHMeTHn-l-OKca-2-a3acnHpo[4.5]fleii-2-eH-3-Hn)MeTHn)2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol 1.00 539.25 1.30 (2R,3R,4S,5R,6R)-2-(rnflpoKCHMeTHn)-5-MeTOKCH-6-((8-MeTHn-l-OKca-2-a3acnHpo[ 4.5]dec-2-en-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tet rahydro-2H-pyran-3-ol (mixture of epimers) 0.97 526.26 1.31 (2R,3R,4S,5R,6R)-6-((l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3-chloro4,5-difluorophenyl)-1H-1,2,3-triazolyl-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol [1-(1,3-dideoxy-2-O-methyl-3-[4-(3-chloro-4,5-difluorophenyl)-1H-1,2,3-triazolyl-1-yl]-a-D-galactopyranose)-1(1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-methane] 0.96 527.22 1.32 (2R,3R,4 S, 5R, 6R)-6-((7,7-dimethyl-1-oxa-2-azaspiro[4.4]non-2-en-3-yl)methyl)2-(hydroxymethyl) -5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl )tetrahydro-2H-pyran-3-ol (mixture of epimers) 0.98 525.24 1.33 (2R,3R,4S,5R,6R)-2-(rnflpoKCHMeTHn)-5-MeTOKCH-6-(((5r,8R)-8-MeTHn-l-OKca-2-a3 aspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1 -yl)tetrahydro-2H-pyran-3-ol (resolution of Example 1.30) 0.97 525.25 1.34 (2R,3R,4S,5R,6R)-2-(rnflpoKcnMeTnn)-5-MeTOKcn-6-(((5s,8S)-8-MeTnn-l-OKca-2-a3 aspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1 -yl)tetrahydro-2H-pyran-3-ol (resolution of Example 1.30) 0.97 525.25 1.35 (2R,3R,4S,5R,6R)-6-((l,8-flHOKca-2-a3acnnpo[4.5]fleii-2-eH-3-Hn)MeTHn)-2-(rHflpo oxymethyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro-2H-pyran-3-ol 0.77 513.22

-40048269

1.36 (2R,3 R, 4 S,5 R,6R )-6-((1,8-dioxa-2-azaspiro[4.5 ]dec-2-en-3-yl )methyl l )-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazolyl-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol 0.79 509.22 1.37 (2R,3R,4S,5R,6R)-6-((l,8-flHOKca-2-a3acnnpo[4.5]fleii-2-eH-3-Hn)MeTHn)-4-(4-(4-x lor-2,3-difluorophenyl)- 1H-1,2,3 -triazo l-1 -yl)-2-(hydroxymethyl)-5-methoxyethyl rahydro-2H-pyran-3-ol 0.81 529.18 1.38 (2R,3R,4S,5R,6R)-6-((l-OKca-2-a3acnnpo[4.6]yHfleii-2-eH-3-Hn)MeTHn)-2-(rHflpoKC imethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3 -ol 0.95 525.25 1.39 (5s,8S)-3-(((2R,3R,4S,5R,6R)-5-rHflpoKCH-6-(rnflpoKCHMeTHn)-3-MeTOKCH-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1oxa-2-azaspiro)4.51dec-2-ene-8-carbonitrile 0.85 536.19 1.40 (5r,8R)-3-(((2R,3R,4S,5R,6R)-5-rHflpoKCH-6-(rnflpoKCHMeTHn)-3-MeTOKCH-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile [1-(1,3-dideoxy-2-O-methyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl] -a-0-galactopyranose)-1-(trans-8-cyano-1-oxa-2-azaspiro [4.5]dec-2-en-3-yl)methane] 0.86 536.22 1.41 tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-THflpoKCH-6-(rHflpoKCHMeTHn)-3-MeTOKCH-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate (resolution of Example 1.50) 0.92 626.30 1.42 tert-butyl ((5s,8S)-3-(((2R,3R,4S,5R,6R)-5-THflpoKCH-6-(rHflpoKCHMeTHn)-3-MeTOKCH-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate (resolution of Example 1.50) 0.93 626.33 1.43 tert-butyl ((5r,8R)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(2,3-diτop-4-methylphenyl)-lH-l,2,3-τpiazol -1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetra ag hydro-2H-pyran-2-yl)me til)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl) carbamate (separation of Example 1.51) 0.93 622.32 1.44 tert-butyl ((5s,8S)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(2,3-diτop-4-methylphenyl)-lH-l,2,3-τpiazol -1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetra ag hydro-2H-pyran-2-yl)me til)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate (separation of Example 1.51) 0.94 622.33 1.45 tert-butyl ((5r,8R)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-lH-l,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl l)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate (resolution of Example 1.49) 0.95 642.26 1.46 tert-butyl ((5s,8S)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-lH-l,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl l)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate (resolution of Example 1.49) 0.96 642.29 1.47 (2R,ЗR,4S,5R,6R)-6-((l-oca-2-azac[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,5-diφ tor-4-methylphenyl)-1H-1,2,3-triazo l-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol 0.92 507.28 1.48 (2R,3R,4S,5R,6R)-2-(rnflpoKCHMeTHn)-6-((8-(2-rHflpoKCHnponaH-2-Hn)-l-OKca-2-a-zaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol (mixture of epimers) 0.83 569.24 1.49 3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-diτopphenyl)-lH-l,2,3-τpiazol-l-yl)-5hydroxy- 6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oke a-2-azaspiro[4.5]dec-2-ene-8-carbonitrile (mixture of epimers) 0.88 552.05 1.50 3-(((2R,3R,4S,5R,6R)-5-rHflpoKcn-6-(rHflpoKCHMeTHn)-3-MeTOKCH-4-(4-(2,3,4-TpH fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2azaspiro[4.5]dec-2-ene-8-carbonitrile (mixture of epimers) 0.84 536.22 1.51 3-(((2R,3R, 4 S, 5R, 6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazo l-1-yl)- 5 -hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-ok ca-2-azaspiro)4.51dec-2-ene-8-carbonitrile (mixture of epimers) 0.84 532.10

-41 048269

1.52 (2K,3K,48,5K,6K)-2-(hydroxymethyl)-6-(((5g,8K)-8-(2-hydroxypropan-2-yl)-1oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol (separation of compound Example 1.48) 0.83 569.25 1.53 (2K,3K,48,5K,6B.)-2-(hydroxymethyl)-6-(((55,88)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol (separation of Example 1.48 compound) 0.84 569.24 1.54 (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazolyl-1-yl)-2-(hydroxymethyl)-6-((8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol (mixture of epimers) 0.85 565.09 1.55 (2R,3R,4 S,5R,6R)-4-(4-(4-xnop-2,3-difluorophenyl)-1H-1,2,3-triazolyl-1-yl)-2-(hydroxymethyl)-6-((8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol (mixture of epimers) 0.88 585.19 1.56 (5s,8S)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(2,3-diτop-4-methylphenyl)-lH-l,2,3-triazol - 1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)meth yl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile 0.86 532.24 1.57 (5r,8R)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-lH-l,2,3-triazole-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile 0.86 532.23 1.58 (5s,8S)-3-(((2R,3R,4S,5R,6R)-5-rHflpoKCH-6-(rHflpoKCHMeTHn)-3-MeTOKCH-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile 0.84 536.22 1.59 (5r,8R)-3-(((2R,3R,4S,5R,6R)-5-rHflpoKCH-6-(rnflpoKCHMeTHn)-3-MeTOKCH-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile 0.85 536.22 1.60 (5s,8S)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(4-chloro-2,3-diτopφenyl)-lH-l,2,3-τpiazol1-yl )-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl) methyl l)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile 0.88 552.16 1.61 (5r,8R)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(4-chloro-2,3-diφτopφenyl)-lH-l,2,3-τpiazol1-yl )-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl) methyl l)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile 0.88 552.17 1.62 (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazolyl-1-yl)-2-(hydroxymethyl)-6-(((5R,8R)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]de-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol 0.84 565.09 1.63 (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazolyl-1-yl)-2-(hydroxymethyl)-6-(((55,88)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]de c-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol 0.85 565.15 1.64 (2R,3R,4 S,5R,6R)-4-(4-(4-xnop-2,3-difluorophenyl)-1H-1,2,3-triazo l-1-yl)-2-(hy flpoKCHMeTHn)-6-(((5r,8R)-8-(2-rHflpoKCHnponaH-2-Hn)-l-OKca-2-a3acnHpo[4.5]fleii -2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol 0.87 585.17 1.65 (2R,3R,4 S,5R,6R)-4-(4-(4-xnop-2,3-difluorophenyl)-1H-1,2,3-triazolyl-1-yl)-2-(hydroxymethyl)-6-(((55,88)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol 0.88 585.16 1.66 3-(((2R,3R,4S,5R,6R)-5-rnflpoKCH-6-(rHflpoKCHMeTHn)-3-MeTOKCH-4-(4-(3,4,5-TpH fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2azaspiro[4.5]dec-2-en-8-one 0.8 525.19 1.67 (2R,ЗR,4S,5R,6R)-6-((l-oca-2-azac[4.5]dec-2-en-3-yl)methyl)-5-(2,2-diφτo rethoxy)-2-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl) tetrahydro-2H-pyran-3-ol 0.96 562.03 1.68 methyl 2-(((2R,3R,4S,5R,6R)-2-((l-OKca-2-a3acnnpo[4.5]fleii-2-eH-3-Hn)MeTHn)-5-rHflpoK si-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetate 0.93 569.22 1.69 (2R,3R,4S,5R,6R)-6-((l-OKca-2-a3acnHpo[4.5]fleii-2-eH-3-Hn)MeTHn)-5-3TOKCH-2-(r-hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2 H-pyran-3-ol 0.96 525.25 1.70 2-(((2R,3R,4S,5R,6R)-2-((l-OKca-2-a3acnHpo[4.5]flei(-2-eH-3-Hn)MeTHn)-5-rHflpoK si-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetragidro-2H-pyran-3-yl)oxy)-N-methylacetamide 0.84 568.21 1.71 2-(((2R,3R,4S,5R,6R)-2-((l-OKca-2-a3acnHpo[4.5]fleii-2-eH-3-Hn)MeTHn)-5-rHflpoK si-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetragidro-2H-pyran-3-yl)oxy)-1-morpholinoethan-1-one 0.84 624.28

- 42 048269

1.72 methyl 2-(((2R,ЗR,4S,5R,6R)-2-((8,8-diφτop-l-oca-2-azapipo[4.5]dec-2-en-3-yl)meth l)- 4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3 -triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetate 0.92 601.24 1.73 (2K,3K,48,5K,6Ya)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6 -(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl carbamate 0.82 540.22 1.74 (2R,3R,4 S,5R,6R)-4-(4-(2,3-difluoro-4-methyl phenyl)-1H-1,2,3-triazolyl-1-yl)-6-(((5r,8R)-8-((2,2-difluoroethyl)amino)-l-oxa-2-azacpipo[4.5]dec-2-en-3-yl)methyl)2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol 0.65 586.23 1.75 tert-butyl (RS)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(2,3-diφτop-4-methylphenyl)-lH-l,2,3-τpiazol-lyl)- 5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl) -1-oxa-2,8-diazaspiro[4.6]undec-2-ene-8-carboxylate (mixture of epimers) [1-(1,3-dideoxy-2-O-methyl-3-[4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol -1-i l]-α-D-galactopyr anose)-1(8-(t/>egi-butoxycarbonyl)-1-oxa-2,8-diazaspiro[4,6]undec-2-en-3-yl)-methane] 0.97 622.27 1.76 (RS)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-lH-l,2,3-triazol-lyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl) -1-oxa-2,8-diazaspiro[4.6]undec-2-en-9-one (mixture of epimers) 0.71 536.25 1.77 (K8)-3-(((2K,3K,48.5K,6K)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1yl)- 5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl) -8-methyl-1-oxa-2,8-diazaspiro[4.6]undec-2-en-9-one (mixture of epimers) 0.74 550.0 1.78 (5K8,88)-7-(t/>-butoxycarbonyl)-3-(((2K,3K,48,5K,6K)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene-8-carboxylic acid (mixture of epimers) 0.85 657.92 1.79 tert-butyl (RS)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(4-chloro-2,3-diτopφenyl)-lH-l,2,3-τpiazol-l-i l)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)1-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxylate (mixture epimers) 0.93 614.14 1.80 tert-butyl 7-(((2R,ЗR,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-lH-l,2,3-triazol-l-yl)-5hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-5-ox a-2,6-diazaspiro[3,4]oct-6-ene-2-carboxylate 0.93 600.08 1.81 (2R,3R,4S,5R,6R)-6-((4'H-cnnpo[6HiiHMO[2.2.1]heptan-2,5'-isoxazol]-3'-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol 0.95 519.51 1.82 (2R, 3R,4 S,5R,6R)-6-((4'H-cnHpo [bicyclo[3.2.1]octane-3,5'-isoxazol]-3'-yl)methyl)-4- (4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)- 5-methoxytetra ag hydro-2H-pyran-3-o l 0.97 533.13

The following examples (Table 2) were prepared starting from oxime intermediates 8 and exocyclic alkenes using general procedure A, followed by deprotection (procedure B, C, D, E, or I) and further derivatization following procedures F, G, H, or K. Final deprotection (if required) was performed according to procedures B or C.

Table 2

Note. Connection t _R [min] (LC-MS method A) MS data m/z [M+H] + 2.01 3-(((2R,3R,4S,5R,6R)-5-rHflpoKCH-6-(rHflpoKCHMeTHn)-3-MeTOKCH-4-(4-(3,4,5-Tp-fluorophenyl)-1H-1,2,3-triazo-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oke a-2-azaspiro[4.5]dec-2-en-8-ol (mixture of epimers) 0.76 527.21 2.02 (5s,8S)-3-(((2R,3R,4S,5R,6R)-5-rHflpoKCH-6-(rHflpoKCHMeTHn)-3-MeTOKCH-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl )-1-oxa-2-azaspiro[4.5]dec-2-en-8-ol (resolution of Example 2.01 compound) 0.76 527.2

- 43 048269

2.03 (5g,8K)-3-(((2K,3K,48,5K,6K)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-ol (separation of Example 2.01 compound) 0.76 527.2 2.04 M-((5g,8K)-3-(((2K,3K,48,5K,6B.)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide 0.771 568.2 2.05 N-((5s, 8 S)-3-(((2R,3R, 4 S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide 0.78 568.21 2.06 N-((5r,8R)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(2,3-diφτop-4-methylφenyl)-lH-l,2,3- τp iazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2 -yl)methyl)-1-oxa-2-azaspiro)4.51dec-2-en-8-yl)acetamide 0.76 564.27 2.07 N-((5r,8R)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(4-chloro-2,3-diφτopφenyl)-lH-l,2,3- τpi azo l-Pyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide 0.79 584.22 2.08 N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-rHflpoKCH-6-(rHflpoKCHMeTHn)-3-MeTOKCH-4-( 4-(2,3,4 -trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro-2H-pyran-2-yl)me til)-1-oxa-2-azaspiro)4.51dec-2-en-8-yl)acetamide 0.75 568.26 2.09 ethyl ((5r,8R)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(2,3-diτop-4-methylphenyl)-lH-l,2,3-τpiazo l-1 -yl)-5 -hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-i l)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate 0.87 594.27 2.10 ethyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-rHflpoKCH-6-(rHflpoKCHMeTHn)-3-MeTOKCH-4-(4(2,3,4-trifluorophenyl)-1H-1,2,3-triazo l-1-yl)tetrahydro-2H-pyran-2-yl)methyl l)-1-oxa-2-azaspiro(4.5]dec-2-en-8-yl)carbamate 0.85 598.03 2.11 ethyl ((5r,8R)-3-(((2R,ЗR,4S,5R,6R)-4-(4-(4-chloro-2,3-diφτopφenyl)-lH-l,2,3-τpiazol -1 -yl)-5 -hydroxy-6-(hydroxymethyl)-3-methoxytetra ag hydro-2H-pyran-2-yl) Methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate 0.89 614.02 2.12 (2R,3R,4S,5R,6R)-2-(rHflpoKCHMeTHn)-6-(((5r,8R)-8-(H3onponHnaMHHo)-l-OKca2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-! H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol 0.67 568.24 2.13 (2R,3R,4S,5R,6R)-2-(rHflpoKCHMeTHn)-6-(((5s,8S)-8-(H3onponHnaMHHo)-l-OKca2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-! H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol 0.68 568.24 2.14 (2R,3R,4S,5R,6R)-2-(rHflpoKCHMeTHn)-5-MeTOKCH-6-((8-(neHTaH-3-HnaMHHo)-l-o xa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3triazol-1-yl)tetrahydro-2H-pyran-3-ol (mixture of epimers) 0.73 596.26 2.15 (2R,3R,4 S,5R,6R)-6-((8-((2,2-difluoroethyl)amino)-l-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol (mixture of epimers) 0.66 590.2 2.16 (2R,3R,4 S,5R,6R)-6-((8-(uhmopropylamino)-1-oxa-2-azaspiro[4.5]dec-2-en3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol (mixture of epimers) 0.67 566.22 2.17 (2R,3R,4S,5R,6R)-2-(hydroxymethyl)-5-methoxy-6-((8-((2,2,2-trifluoroethyl)amino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol (mixture of epimers) 0.68 608.19 2.18 oxime 3-(((2R,3R,4S,5R,6R)-5-rnflpoKCH-6-(rHflpoKCHMeTHn)-3-MeTOKCH-4-(4-(3,4,5-Tp iforophenyl)-1H-1, 2,3-triazo l-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oke a-2-azaspiro(4.51dec-2-en-8-one (mixture of E/Z isomers) 0.77 540.17 2.19 (2R, 3 R, 4 S, 5R, 6R)-2-(hydroxymethyl)-5-methoxy-6-((8-morpholino-1-oxa-2-az aspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol -1-yl)tetrahydro-2H-pyran-3-ol (mixture of epimers) 0.66 596.27 2.20 (2R,ЗR,4S,5R,6R)-6-(((5r,8R)-8-((2,2-diτopethyl)amino)-l-oca-2-azac[4. 5]dec-2 -en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophen yl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol (separation of Example 2.15) 0.84 590.10 2.21 (2R,3R,4S,5R,6R)-6-(((5S,8S)-8-((2,2-difluoroethyl)amino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophen yl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol (resolution of Example 2.15) 0.86 590.11

- 44 048269

2.22 (2K,3K,48,5K,6K)-6-(((5g,8B.)-8-(cyclopropylamino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol (separation of compound Example 2.16) 0.67 566.22 2.23 (2R,3R,4S,5R,6R)-6-(((5S,8S)-8-(cyclopropylamino)-1-oxa-2-azaspiro[4.5]de-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol (resolution of Example 2.16) 0.67 566.22 2.24 2-(((2R,3R,4S,5R,6R)-2-((l,8-flHOKca-2-a3acnnpo[4.5]fleii-2-eH-3-Hn)MeTHn)-4-( 4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxy methyl)tetrahydro-2H-pyran-3-yl)oxy)acetic acid 0.69 553.2 2.25 2-(((2R,3R,4S,5R,6R)-2-((l-OKca-2-a3acnnpo[4.5]fleii-2-eH-3-Hn)MeTHn)-4-(4-(2, 3-difluoro-4-methylphenyl)-1H-1,2,3-triazo l-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetic acid 0.81 551.23 2.26 2-(((2R,3R,4S,5R,6R)-2-((l-OKca-2-a3acnnpo[4.5]fleii-2-eH-3-Hn)MeTHn)-5-rHflpo oxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tet rahydro-2H-pyran-3-yl)oxy)acetic acid 0.82 555.19 2.27 (2R,ЗR,4S,5R,6R)-6-((8,8-diφτop-l-oca-2-azacpipo[4.5]dec-2-en-3-yl)methyl) -4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)- 5-methoxytetrahydro-2H-pyran-3-ol 0.82 587.24 2.28 N-(m/>ew2-6yTHn)-3-(((2R,3R,4S,5R,6R)-5-rHflpoKCH-6-(rHflpoKCHMeTHn)-3-methyl si-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2yl)methyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxamide 0.86 611.19 2.29 (2R,3R,4S,5R,6R)-2-(rHflpoKCHMeTHn)-5-MeTOKCH-6-((8-MeTHn-l-OKca-2,8-flHa3a spiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol1-yl)tetrahydro-2H-pyran-3-ol 0.65 526.21 2.30 !-(3-(((2R,3R,4S,5R,6R)-5-rHflpoKCH-6-(rHflpoKCHMeTHn)-3-MeTOKCH-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl)ethan-1-one 0.76 554.18 2.31 (2R,3R,4S,5R,6R)-2-(hydroxymethyl)-5-methoxy-6-((8-(methylsulfonyl)-l-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazolyl-1-yl)tetrahydro-2H-pyran-3-ol 0.81 590.10

The examples in Table 3 were prepared starting from amines (intermediates 15) and epoxides according to General Procedures L and M, followed by deprotection (General Procedure B or C).

Table 3

Note. Connection t _R [min] (LC-MS method A) MS data m/z [M+H] + 3.01 t/>et-butyl 3-(((2R,3R,4S,5R,6R)-5-rnflpoKCH-6-(rHflpoKCHMeTHn)-3-MeTOKCH-4-(4-(3,4,5-T rifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-2-o xo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate 0.92 628.23 3.02 3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-lH-l,2,3-triazol-l-i l)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl l)-1-oxa-3-azaspiro[4.5]decan-2-one [1-(1,3-dideoxy-2-O-methyl-3-[4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-tria sol-1-yl]-a-P-galactopyranose)-1(1-oxa-3-azaspiro[4.5]decan-2-one-yl)-methane] 0.90 523.25 3.03 3-(((2R,ЗR,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-lH-l,2,3-triazol-l-i l)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl l)-1,8-dioxa-3-azaspiro[4.5]decan-2-one 0.76 525.23

Example 4.01.

3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-Difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1,3-diazaspiro[4.5]decan-2-one.

Stage 1. tert-Butyl (1-(((((4aR,6R,7R,8R,8aR)-8-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1ul)-7 -methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)methyl)amino)methyl)cyclohexyl)carbamate.

Intermediate 15b (300 mg, 0.707 mmol, 1 equiv) was dissolved in DCM/MeOH 4:1 (12 mL) and 1-(Boc-amino)-1-formylcyclohexane (338 mg, 1.41 mmol, 2 equiv), sodium triacetoxyborohydride 97% (237 mg, 1.06 mmol, 1.5 equiv) and AcOH (0.0404 mL, 0.707 mmol, 1 equiv) were added under N2 at rt. The mixture was stirred at rt until complete conversion. The title intermediate was isolated after aqueous workup (DCM/sat. NaHCO ₃ ) and silica gel column chromatography (0-15% MeOH in DCM) as a colorless solid. LCMS (A): t _R = 0.92 min; [M+H]+ = 636.32

Stage 2. The title compound.

The above intermediate (50 mg) was dissolved in DMF (0.7 mL) and treated with NaH (55% dispersion in mineral oil, 2 equiv) at 0 °C. The mixture was stirred at rt for 48 h, partitioned between EA and water. The org. phase was dried over MgSO ₄ and concentrated. The isolated intermediate was deprotected following General Method B. LCMS (A): t _R = 0.86 min; [M+H]+ = 522.22.

- 45 048269

Example 4.02.

2-(((2R,3R,4S,5R,6R)-4-(4-(4-Chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-2,4-diazaspiro[5.5]undecan-3-one.

The title compound was prepared in analogy to Example 4.01, steps 1 and 2, starting from intermediate 15c and tert-butyl ((1-formylcyclohexyl)methyl)carbamate (CAS 147603556-9). LCMS (A): t _R = 0.91 min; [M+H]+ = 556.18.

Example 4.03.

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

Stage 1.

(2R,3R,4S,5R,6R)-6-((((1-Aminocyclohexyl)methyl)amino)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)1H-1,2 ,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol.

The intermediate from Example 4.01, step 1 (200 mg, 0.315 mmol, 1 equiv) was dissolved in DCM (3 mL) at rt and 4 M HCl in dioxane (3 mL) was added. The white suspension was stirred at rt. Water was added and the aq. phase was basified with 32% NaOH solution, extracted with DCM (3x), dried over MgSO ₄ , filtered and concentrated to dryness and dried under high vacuum to give the title intermediate as a colourless gum which was used without purification. LCMS (A): t _R = 0.59 min; [M+H]+ = 496.28.

Stage 2.

(2R,3R,4S,5R,6R)-6-((((1-Aminocyclohexyl)methyl)amino)methyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-(2 ,3-difluoro-4-methylphenyl)-1H-1,2,3-triazole-1 -yl)-5-methoxytetrahydro-2H-pyran-3-ol.

To a solution of the above intermediate (130 mg) and _NEt3 (0.022 mL, 0.157 mmol, 0.6 equiv) in dry DCM (3 mL) was added TBSCl (excess) at 0 °C under nitrogen. The mixture was stirred at rt for 3 days. Water was added and the product was extracted with DCM. Chromatography on _SiO2 (0-20% MeOH in DCM (+0.5% NH4OH) afforded the title intermediate as a colorless solid. LCMS (A): t _R = 0.83 min; [M+H] ⁺ = 610.13

Stage 3.

(2R,3R,4S,5R,6R)-2-(((Tert-methylsilyl)oxy)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-methoxy-6-((2-methyl-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)tetrahydro-2H-pyran-3-ol.

The intermediate compound from step 2 (60 mg) was dissolved in dioxane (1 ml) and triethyl orthoacetate (2 equiv.) was added. The mixture was heated under reflux for 1.5 h. The mixture was concentrated in vacuo and dried under high vacuum. LCMS (A): t _R = 0.98 min; [M+H] ⁺ = 634.28

Stage 4. The title compound.

The intermediate from step 3 was dissolved in THF (2 mL) and TBAF (1 M in THF, 1.2 equiv) was added. The mixture was stirred at rt for 1 h, diluted with water and extracted with EA and DCM. The combined org. extracts were dried and concentrated, and purified by prep. HPLC (prep. LC-MS III). LCMS (A): t _R = 0.75 min; [M+H] ⁺ = 520.24

Example 4.03.

(2R,3R,4S,5R,6R)-6-((1,3-Diazaspiro[4.5]dec-1-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol.

This example is prepared in analogy to example 4.03, steps 3 and 4, using triethyl orthoformate instead of triethyl orthoacetate. LCMS (A): t _R = 0.74 min; [M+H] ⁺ = 506.21

II. Biological analyses.

Determination of inhibitory activity of compounds (IC ₅₀ ).

The inhibitory activity of the compounds is determined in competitive binding assays. This spectrophotometric assay measures the binding of biotinylated human Gal-3 (hGal-3) or human Gal-1 (hGal-1), respectively, to a microplate-adsorbed glycoprotein, asialofetuin (ASF) (Proc Natl Acad Sci USA. 2013 Mar 26; 110(13):5052-7.). Alternatively, and preferably, a version of human Gal-1 in which all six cysteines have been replaced with serines can be used.

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

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

- 46 048269 are given as average values.

Table 4

Activity against hGal-3 (IC50 in μM)

Note. Gal-3 1C ₅₀ Note. Gal-3 1C ₅₀ Note. Gal-3 1C ₅₀ Note. Gal-3 1C ₅₀ 1.01 0.061 1.02 0.084 1.03 0.079 1.04 0.17 1.05 0.28 1.06 0.34 1.07 0.32 1.08 0.24 1.09 0.95 1.10 0.62 1.11 0.069 1.12 0.31 1.13 0.14 1.14 0.078 1.15 0.035 1.16 0.34 1.17 0.16 1.18 0.18 1.19 0.68 1.20 0.12 1.21 0.11 1.22 0.076 1.23 0.76 1.24 0.45 1.25 1.3 1.26 0.11 1.27 1.1 1.28 2.0 1.29 0.44 1.30 0.50 1.31 0.26 1.32 0.34 1.33 0.33 1.34 0.52 1.35 0.11 1.36 0.064 1.37 0.12 1.38 0.16 1.39 0.26 1.40 0.089 1.41 0.012 1.42 0.132 1.43 0.015 1.44 0.10 1.45 0.010 1.46 0.060 1.47 0.43 1.48 0.49 1.49 0.11 1.50 0.16 1.51 0.10 1.52 0.26 1.53 0.27 1.54 0.20 1.55 0.40 1.56 0.12 1.57 0.041 1.58 0.11 1.59 0.13 1.60 0.090 1.61 0.049 1.62 0.19 1.63 0.18 1.64 0.49 1.65 0.12 1.66 0.25 1.67 0.23 1.68 0.22 1.69 0.30 1.70 0.24 1.71 0.20 1.72 0.14 1.73 0.11 1.74 0.12 1.75 0.16 1.76 0.11 1.77 0.10 1.78 0.27 1.79 0.49 1.80 0.31 1.81 0.06 1.82 0.05 2.01 0.25 2.02 0.70 2.03 0.19 2.04 0.061 2.05 0.45 2.06 0.071 2.07 0.062 2.08 0.052 2.09 0.017 2.10 0.020 2.11 0.019 2.12 0.22 2.13 0.55 2.14 0.39 2.15 0.28 2.16 0.24 2.17 0.21 2.18 0.32 2.19 0.39 2.20 0.11 2.21 0.38 2.22 0.14 2.23 0.59 2.24 0.080 2.25 0.037 2.26 0.090 2.27 0.081 2.28 0.14 2.29 0.38 2.30 0.28 2.31 0.53 3.01 0.12 3.02 0.036 3.03 0.090 4.01 0.046 4.02 0.074 4.03 0.074 4.04 0.081

- 47 048269

Table 5

Activity against hGal-1 IC ₅₀ (μM)

Note. Gal-1 1C ₅₀ Note. Gal-1 1C ₅₀ Note. Gal-1 1C ₅₀ Note. Gal-1 1C ₅₀ 1.01 4.2 1.02 5.2 1.03 >100 1.04 10.4 1.05 2.2 1.06 4.2 1.07 5.7 1.08 1.9 1.09 2.7 1.10 2.2 1.11 1.5 1.12 1.1 1.13 0.52 1.14 2.1 1.15 1.1 1.16 2.3 1.17 6.0 1.18 10.3 1.19 4.2 1.20 5.3 1.21 11.4 1.22 3.7 1.23 3.5 1.24 4.9 1.25 11.1 1.26 4.0 1.27 18.8 1.28 6.9 1.29 2.2 1.30 3.1 1.31 0.97 1.32 3.4 1.33 3.7 1.34 2.5 1.35 1.4 1.36 3.8 1.37 4.6 1.38 6.4 1.39 7.1 1.40 2.0 1.41 0.30 1.42 0.85 1.43 1.24 1.44 4.9 1.45 0.80 1.46 1.8 1.47 2.2 1.48 2.6 1.49 1.2 1.50 0.57 1.51 1.9 1.52 2.8 1.53 1.2 1.54 5.4 1.55 4.4 1.56 3.6 1.57 0.53 1.58 0.64 1.59 0.22 1.60 1.6 1.61 0.46 1.62 4.6 1.63 3.4 1.64 2.4 1.65 2.7 1.66 2.7 1.67 2.9 1.68 3.7 1.69 3.1 1.70 5.1 1.71 2.9 1.72 5.6 1.73 6.5 1.74 2.4 1.75 8.2 1.76 2.7 1.77 4.8 1.78 12.0 1.79 4.8 1.80 7.2 1.81 2.37 1.82 1.95 2.01 2.2 2.02 5.1 2.03 2.0 2.04 0.81 2.05 3.6 2.06 0.34 2.07 0.91 2.08 0.31 2.09 0.64 2.10 0.32 2.11 0.34 2.12 2.4 2.13 7.0 2.14 2.6 2.15 7.2 2.16 2.4 2.17 1.4 2.18 2.9 2.19 1.7 2.20 1.8 2.21 1.6 2.22 1.3 2.23 1.6 2.24 6.7 2.25 3.7 2.26 3.5 2.27 11.5 2.28 1.7 2.29 4.8 2.30 2.8 2.31 3.5 3.01 2.7 3.02 1.4 3.03 2.3 4.01 1.3 4.02 0.4 4.03 1.7 4.04 1.3

Claims (15)

1. Compound of formula (I) Formula (I), wherein Ar ¹ is aryl, which is phenyl or naphthyl, and is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted, wherein the substituents are independently selected from halogen, methyl, cyano, methoxy, trifluoromethyl and trifluoromethoxy; 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 _1-4 -alkoxy; - O-CO-C _1-3 -alkyl; O-CO-NH-RN ¹¹ , where RN ¹¹ is hydrogen or C _1-3 -alkyl; - O-CH ₂ -C ₁ -fluoroalkyl; or - O-CH2-CO-R ^1X , where R ^1X is -hydroxy; C _1-3 -alkoxy; morpholin-4-yl; or - NR ^N21 RN ²² , where RN ²¹ and RN ²² are both independently hydrogen or methyl; and is a spirocyclic moiety, where: ring A is a heterocycloalkylene selected from where X is nitrogen or oxygen and n is an integer of 0 or 1; and where in case X is nitrogen, said nitrogen is unsubstituted or monosubstituted by C _1-4 -alkyl; Ζ ^Ν -'' where R ² is hydrogen or C _1-4 -alkyl; and ring B is C _4-7 -cycloalkanediyl, wherein said C _4-7- cycloalkanediyl is unsubstituted, mono- or disubstituted, wherein the substituents are independently selected from C _1-4 -alkyl; C _1-3 -fluoroalkyl; C _1-4 -alkoxy; halogen; cyano; oxo; hydroxy; hydroxy-C _1-4 -alkyl; hydroxyimino; morpholin-4-yl; and -NH-RN ¹¹ , wherein RN ¹¹ is C _1-6 -alkyl, C _2-4 -alkoxy, C _3-6 -cycloalkyl, C _2-3 -fluoroalkyl, -CO-C _1-4 -alkyl or -CO-C _1-4 alkoxy; 4-7-membered heterocycloalkanediyl, wherein said heterocycloalkanediyl contains one ring oxygen atom; 4-7 membered heterocycloalkanediyl, wherein said heterocycloalkanediyl contains one ring - 49 048269 _a ring nitrogen atom, wherein said ring nitrogen atom is unsubstituted or monosubstituted by _{C 1.4} -alkyl, -CO _- C _1.4 -alkyl, -SO ₂ -C _1.4 -alkyl, -CO-C _1.4 -alkoxy, or -CO-NH-C _1.4 -alkyl; and wherein said 4- to ₇ -membered heterocycloalkanediyl bears no additional substituent in addition to said substituent on the ring nitrogen atom, or bears one additional substituent on a ring carbon atom that is attached to said ring nitrogen atom, wherein said substituent is oxo or -CO _{-OH; or a bridged bicyclic C 6.9 -cycloalkanediyl} ; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein Ar ¹ is phenyl which is di- or trisubstituted, wherein the substituents are independently selected from halogen, methyl, cyano, methoxy, trifluoromethyl and trifluoromethoxy; or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, wherein Ar ¹ is phenyl which is di- or trisubstituted, wherein the substituents are independently selected from halogen and methyl; wherein at least one of said substituents is attached at the meta- and/or para-position of said phenyl; or a pharmaceutically acceptable salt thereof. 4. A compound according to any one of claims 1 to 3, wherein R ¹ is methoxy; or a pharmaceutically acceptable salt thereof 5. A compound according to any one of claims 1 to 4, wherein ring A is a heterocycloalkylene selected from where X is nitrogen or oxygen and n is an integer 0 or 1; and where in the case where X is nitrogen, said nitrogen is unsubstituted; and '' where R ² is hydrogen or methyl; or a pharmaceutically acceptable salt thereof. 6. A compound according to any one of claims 1 to 5, wherein ring B is unsubstituted C _{4_7 -} cycloalkanediyl; C _{4_7 -} cycloalkanediyl, wherein said C _{4_7 -} cycloalkanediyl is monosubstituted, wherein the substituents are independently selected from C _{1_4} - _alkyl ; cyano; hydroxy; hydroxy-C _{1_4} -alkyl; and -NH-R ⁿ¹¹ , wherein R ^N11 is C _{1_6-} alkyl, C _{2_4 -} alkoxy, C _{3_6 -} cycloalkyl, C _{2_3 -} fluoroalkyl, -CO-C _{1_4 -} alkyl or -CO-Calkoxy; C _{4_7 -} cycloalkanediyl, wherein said C _{4_7 -} cycloalkanediyl is disubstituted, wherein the substituents are independently selected from C _{1.4 -} alkyl and halogen; 4- to 7-membered heterocycloalkanediyl, wherein said heterocycloalkanediyl contains one ring oxygen atom; or 4- to 7-membered heterocycloalkanediyl, wherein said heterocycloalkanediyl contains one ring nitrogen atom, wherein said nitrogen atom is unsubstituted or monosubstituted by _{C 1.4} -alkyl, -CO-C _{1.4 -alkoxy} or -CO-NH-C _1.4 -alkyl; and wherein said 4- to ₇ -membered heterocycloalkanediyl bears no additional substituent in addition to said substituent on the ring nitrogen atom, or bears one additional substituent on a ring carbon atom that is attached to said ring nitrogen atom, wherein said substituent is oxo; or a pharmaceutically acceptable salt thereof. 7. A compound according to any one of claims 1 to 5, wherein ring B is cyclohexane-1,1-diyl or cycloheptane-1,1-diyl; cyclohexane-1,1-diyl which is monosubstituted, wherein the substituents are selected from _{C1_4} alkyl; cyano; hydroxy; hydroxy- _{C1_4} -alkyl; and -NH-RN ¹¹ , wherein RN ¹¹ is cyclopropyl, C ₂ . ₃ -fluoroalkyl, -CO-C ₁ . ₄ -alkyl or -CO-C ₁ . ₄ -alkoxy; cyclohexane-1,1-diyl which is disubstituted wherein the substituents are selected from C _{1 .4} -alkyl and halogen; tetrahydropyran-4,4-diyl; piperidin-4,4-diyl, wherein the nitrogen atom of said piperidin-4,4-diyl is monosubstituted by -CO-C ₁ . ₄ -alkoxy or -CO-NH-C ₁ . ₄ -alkyl; and wherein said piperidine-4,4-diyl does not bear an additional substituent in addition to said substituent on the ring nitrogen atom; or - 50 048269 azepane-4,4-diyl, wherein the nitrogen atom of said azepane-4,4-diyl is unsubstituted or monosubstituted by C _1-4 -alkyl or -CO- _C1-4 -alkoxy; and wherein said azepane-4,4-diyl does not bear an additional substituent in addition to the said substituent on the ring nitrogen atom, or bears one additional substituent on the ring carbon atom that is attached to the said ring nitrogen atom, wherein the said substituent is oxo; or a pharmaceutically acceptable salt thereof. 8. A compound according to any one of claims 1 to 5, wherein ring B is cyclohexane-1,1-diyl; cyclohexane-1,1-diyl which is monosubstituted, wherein the substituents are selected from cyano; hydroxy-C _1-4 -alkyl; and -NH-RN ¹¹ , wherein RN ¹¹ is -CO-C _1-4 -alkyl or -CO-C _1-4 -alkoxy; cyclohexane-1,1-diyl which is disubstituted by fluorine; or tetrahydropyran-4,4-diyl; or a pharmaceutically acceptable salt thereof. 9. A connection according to any one of paragraphs 1-4, where A) is a spirocyclic fragment selected from the following groups: IN) WITH) D) - 51 048269 E) / or ' \ or its pharmaceutically acceptable salt. 10. The compound of claim 1, wherein said compound is: (2R,3R,4S,5R,6R)-2-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate; (2R,3R,4R,5R,6R)-2-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol; (2R,3R,4S,5R,6R)-2-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl acetate; (2R,3R,4R,5R,6R)-2-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol; (2R,3R,4R,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; tert-butyl (3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8yl)carbamate; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-bromo-2,3-difluorophenyl)1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-chloro-3,5-difluorophenyl)1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3-fluoro-4-methylphenyl)-1H1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3,5-difluoro-4-methylphenyl)1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-chloro-2,3-difluorophenyl)1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4- (2,3-diphtho p-4methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3-chloro-4,5-difluorophenyl)1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1,8-dioxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.6]undec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (5s,8S)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8yl)carbamate; tert-butyl ((5s,8S)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8yl)carbamate; - 52 048269 tert-butyl ((5R,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; tert-butyl ((5s,8S)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; tert-butyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; tert-butyl ((5s,8S)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; 3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; 3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; 3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-(((5r,8R)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran3-ol; (2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-(((5s,8S)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran3-ol; (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6-((8(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3ol; (5s,8S)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (5s,8S)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (5s,8S)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile; (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6(((5r,8R)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro2H-pyran-3-ol; (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6(((5s,8S)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro2H-pyran-3-ol; (2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-6(((5s,8S)-8-(2-hydroxypropan-2-yl)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-methoxytetrahydro-2H-pyran-3-ol; 3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-one; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-(2,2-difluoroethoxy)-2-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; methyl 2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetate; (2R,3R,4S,5R,6R)-6-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-ethoxy-2-(hydroxymethyl)-4-(4(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; 2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)4-(4-(3,4,5-trifluorophenyl)-N-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)-N-methylacetamide; - 53 048269 2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)-1-morpholinoethane-1 one; methyl 2-(((2R,3R,4S,5R,6R)-2-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetate; (2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)-4(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ylcarbamate; (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-6-(((5r,8R)-8-((2,2-difluoroethyl)amino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; tert-Butyl (RS)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.6]undec-2-ene-8-carboxylate; (RS)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.6]undec-2-en-9-one; (RS)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-8-methyl-1-oxa-2,8-diazaspiro[4.6]undec2-en-9-one; (5RS,8S)-7-(tert-butoxycarbonyl)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene-8-carboxylic acid; 3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-ol; (5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-ol; N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide; N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3- trazol-1-ul)-5-hydroxy-6-( hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide; N-((5R,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-pyrazol-1-yl)-5-hydroxy6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8yl)acetamide; N-((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)acetamide; ethyl ((5R,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8yl)carbamate; ethyl ((5r,8R)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(2,3,4-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8yl)carbamate; ethyl ((5R,8R)-3-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl)carbamate; (2R,3R,4S,5R,6R)-2-(hydroxymethyl)-6-(((5r,8R)-8-(isopropylamino)-1-oxa-2-azaspiro[4.5]dec-2en-3-yl)methyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((8-((2,2-difluoroethyl)amino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-((8-(cyclopropylamino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-2-(hydroxymethyl)-5-methoxy-6-((8-((2,2,2-trifluoroethyl)amino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-(((5r,8R)-8-((2,2-difluoroethyl)amino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-III-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6R)-6-(((5r,8R)-8-(cyclopropylamino)-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl) -2(g idroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; 2-(((2R,3R,4S,5R,6R)-2-((1,8-dioxα-2-αzaspuro[4.5]dec-2-en-3-yl)methyl)-4-(4- (2,3-difluoro-4-methyl phenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetic - 54 048269 acid; 2-(((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetic acid; 2-((2R,3R,4S,5R,6R)-2-((1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-5-hydroxy-6-(hydroxymethyl)4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-yl)oxy)acetic acid; (2R,3R,4S,5R,6R)-6-((8,8-difluoro-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)methyl)-4-(4- (2,3-difluoro-4methylphenyl)-1H-1,2,3-triazole-1 -yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; N-(tert-butyl)-3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-N-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8carboxamide; 1-(3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl)ethan-1-one; tert-butyl 3-(((2R,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate; 3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1-oxa-3-azaspiro[4.5]decan-2-one; 3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1,8-dioxa-3-azaspiro[4.5]decan-2-one; 3-(((2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-1,3-diazaspiro[4.5]decan-2-one; 2-(((2R,3R,4S,5R,6R)-4-(4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-yl)methyl)-2,4-diazaspiro[5.5]undecan-3-one; (2R,3R,4S,5R,6R)-4-(4-(2,3-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxy-6-((2-methyl-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)tetrahydro-2H-pyran-3-ol; or (2R,3R,4S,5R,6R)-6-((1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-4-(4-(2,3-difluoro-4-methylphenyl)-1H1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 12. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof as a medicinal product. 13. The use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of organ fibrosis; liver diseases and disorders; cardiovascular 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; acute kidney injury and chronic kidney disease; interstitial lung diseases and disorders; or transplant rejection. 14. The use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention or treatment of organ fibrosis; liver diseases and disorders; cardiovascular 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; acute kidney injury and chronic kidney disease; interstitial lung diseases and disorders; or transplant rejection. - 55 048269 15. A method for the prevention or treatment of organ fibrosis; liver diseases and disorders; cardiovascular 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; acute kidney injury and chronic kidney disease; interstitial lung 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 to 10, or a pharmaceutically acceptable salt thereof.