(HETERO)ARYL-METHYL-THIO-BETA-D-GALACTOPYRANOSIDE DERIVATIVES

Abstract

The present invention relates to compounds of Formula (I)

##STR00001##

wherein Ar.sup.1, Ar.sup.2, R.sup.1a, R.sup.1b, and R.sup.2 are as described in the description, their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of Formula (I), and especially to their use as Galectin-3 inhibitors.

Claims

1. A compound of Formula (I) ##STR00023## wherein Ar.sup.1 represents aryl which is mono-, di-, tri-, tetra-, or penta-substituted, wherein the substituents are independently selected from halogen, methyl, cyano, and methoxy; or 5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl independently is unsubstituted, mono- or di-substituted, wherein the substituents are independently selected from halogen, methyl, cyano, and methoxy; Ar.sup.2 represents phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, mono-, di-, or tri-substituted wherein the substituents independently are C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, C.sub.1-3-fluoroalkyl, C.sub.1-3-fluoroalkoxy, halogen, hydroxy-C.sub.1-3-alkyl, or phenyl; or naphthyl; R.sup.1a represents hydrogen; and R.sup.1b represents —C.sub.2-4-alkyl; or —C.sub.0-1-alkylene-Ar.sup.1b, wherein Ar.sup.1b represents phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, mono- or di-substituted with methyl; or R.sup.1a and R.sup.1b both represent hydrogen, methyl, ethyl, or n-propyl; or R.sup.1a and R.sup.1b together with the carbon atom to which they are attached form a 3- to 6-membered ring selected from C.sub.3-6-cycloalkylene, wherein said C.sub.3-6-cycloalkylene independently is unsubstituted, mono-, or di-substituted, wherein the substituents independently are methyl or fluoro; tetrahydro-2H-pyran-4,4-diyl, which is unsubstituted, di-, or tetra-substituted with methyl; tetrahydro-2H-thiopyran-1,1-dioxide-4,4-diyl; or piperidine-4,4-diyl, pyrrolidine-3,3-diyl, or azetidine-3,3-diyl wherein the nitrogen of said piperidine, pyrrolidine or azetidine independently is unsubstituted, or substituted with —C.sub.1-3-alkyl, —C.sub.0-2-alkylene-C.sub.3-6-cycloalkyl, or -L-R.sup.N1 wherein -L- represents —CO—, —SO.sub.2—, *—CO—NH—, *—CO—O—, or *—SO.sub.2—NH—, and R.sup.N1 represents —C.sub.1-3-alkyl or —C.sub.0-2-alkylene-C.sub.3-6-cycloalkyl; wherein in the above groups the asterisks indicate the bond which is connected to the rest of the molecule; or R.sup.1a and R.sup.1b together with the carbon atom to which they are attached form a spiro-bicyclic ring system of the structure (S.sup.1AB) ##STR00024## wherein ring (A) represents a 3- to 6-membered non-aromatic carbocyclic ring, wherein said 3- to 6-membered non-aromatic carbocyclic ring optionally contains one ring oxygen atom and wherein said 3- to 6-membered non-aromatic carbocyclic ring is unsubstituted or di-substituted with fluoro; and R.sup.2 represents hydroxy or C.sub.1-3-alkoxy; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein said compound is a compound of Formula (I.sub.R), ##STR00025## wherein the carbon atom to which the group Ar.sup.2 is attached is in the absolute configuration as drawn in Formula (I.sub.R); or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1; wherein Ar.sup.1 represents phenyl which is mono-, di- or tri-substituted, wherein the substituents are independently selected from halogen, methyl, cyano, and methoxy; wherein at least one of said substituents is attached in a meta- or in para-position of said phenyl; or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1; wherein Ar.sup.1 represents a phenyl group of the structure ##STR00026## wherein R.sup.m2 represents halogen; and R.sup.p represents hydrogen, halogen, methyl, cyano, or methoxy; or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1; wherein Ar.sup.2 represents phenyl which is mono-, di-, or tri-substituted; wherein one substituent is attached in ortho-position with regard to the point of attachment of Ar.sup.2 to the rest of the molecule; wherein said substituent is C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, C.sub.1-3-fluoroalkyl, C.sub.1-3-fluoroalkoxy, halogen, hydroxy-C.sub.1-3-alkyl, or phenyl; and the other substituent(s), if present, is/are attached in meta- and/or para-position with regard to the point of attachment of Ar.sup.2 to the rest of the molecule; wherein the substituent(s) independently are C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, C.sub.1-3-fluoroalkyl, or halogen; or 5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl independently is mono-, di-, or tri-substituted; wherein one substituent is attached in ortho-position with regard to the point of attachment of Ar.sup.2 to the rest of the molecule; wherein said substituent is C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, or C.sub.1-3-fluoroalkyl; and the other substituent(s), if present, is/are independently C.sub.1-6-alkyl, C.sub.3-6-cycloalkyl, C.sub.1-3-fluoroalkyl, or halogen; or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1; wherein Ar.sup.2 represents ##STR00027## ##STR00028## or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1; wherein R.sup.1a represents hydrogen; and R.sup.1b represents —C.sub.2-4-alkyl; or phenyl which is unsubstituted, mono- or di-substituted with methyl; or R.sup.1a and R.sup.1b both represent methyl, ethyl, or n-propyl; or R.sup.1a and R.sup.1b together with the carbon atom to which they are attached form a 3- to 6-membered ring selected from C.sub.4-6-cycloalkylene, wherein said C.sub.4-6-cycloalkylene independently is unsubstituted, mono-, or di-substituted, wherein the substituents independently are methyl or fluoro; tetrahydro-2H-pyran-4,4-diyl; 2,2-dimethyltetrahydro-2H-pyran-4,4-diyl, or 2,2,6,6-tetramethyltetrahydro-2H-pyran-4,4-diyl; tetrahydro-2H-thiopyran-1,1-dioxide-4,4-diyl; piperidine-4,4-diyl, wherein the nitrogen of said piperidine is unsubstituted, or substituted with —C.sub.1-3-alkyl, —CO—C.sub.1-3-alkyl, —CO—O—C.sub.1-3-alkyl, —CO—NH-cyclopropyl, —SO.sub.2—C.sub.1-3-alkyl, —SO.sub.2-cyclopropyl, or —SO.sub.2—NH—C.sub.1-3-alkyl; or azetidine-3,3-diyl, wherein the nitrogen of said azetidine is unsubstituted, or substituted with —SO.sub.2—C.sub.1-3-alkyl, —CO—O—C.sub.1-3-alkyl, or —CO—NH-cyclopropyl; or R.sup.1a and R.sup.1b together with the carbon atom to which they are attached form a spiro-bicyclic ring system of the structure: ##STR00029## or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1; wherein R.sup.2 represents methoxy; or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 wherein said compound is: (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-1-phenylethyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-1-(2-Bromophenyl)-2-hydroxyethyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-1-(2-isopropylphenyl)ethyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1-(o-tolyl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-1-(2-Ethylphenyl)-2-hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1-(2-propylphenyl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-1-(2-isobutylphenyl)-2-methylpropyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1-(2-pentylphenyl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-1-([1,1′-Biphenyl]-2-yl)-2-hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-1-(2-Chlorophenyl)-2-hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1-(2-(trifluoromethyl)phenyl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-1-(2,3-Dichlorophenyl)-2-hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-1-(3-Fluoro-2-methylphenyl)-2-hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1-(naphthalen-1-yl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1-(2-methylpyridin-3-yl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1-(4-methylpyridin-3-yl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1-(3,5,6-trimethylpyrazin-2-yl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1-(4-methylisoxazol-3-yl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-1-(3,5-Dimethylisoxazol-4-yl)-2-hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-1-(2,5-Dimethylthiazol-4-yl)-2-hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1-(4-methylthiophen-3-yl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-2-Ethyl-2-hydroxy-1-(3-methylisoxazol-4-yl)butyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((1R,2R)-2-Hydroxy-1-(2-(trifluoromethyl)phenyl)butyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((1R,2S)-2-Hydroxy-1-(2-(trifluoromethyl)phenyl)butyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(3,3-Difluoro-1-hydroxycyclobutyl)(2-(trifluoromethyl)phenyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (3R,4R,5R,6R)-2-((R)-2-(1-Hydroxycyclobutyl)-2-(o-tolyl)ethyl)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(1-Hydroxy-3,3-dimethylcyclobutyl)(o-tolyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((1R)-(1-Hydroxy-3-methylcyclobutyl)(o-tolyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((1R)-((2R,3R)-1-Hydroxy-2,3-dimethylcyclobutyl)(o-tolyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((1R)-((2R,3S)-1-Hydroxy-2,3-dimethylcyclobutyl)(o-tolyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((1R)-((2S,3R)-1-Hydroxy-2,3-dimethylcyclobutyl)(o-tolyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((1R)-((2S,3S)-1-Hydroxy-2,3-dimethylcyclobutyl)(o-tolyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(1-Hydroxycyclopentyl)(o-tolyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(1-Hydroxycyclohexyl)(o-tolyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(4-Hydroxy-1-methylpiperidin-4-yl)(o-tolyl)methyl)thio)-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,6S)-2-(Hydroxymethyl)-6-(((R)-(4-hydroxytetrahydro-2H-pyran-4-yl)(2-(trifluoromethyl)phenyl)methyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(4-Hydroxy-2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)(2-(trifluoromethyl)phenyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)—((R)-4-Hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)(2-(trifluoromethyl)phenyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)—((S)-4-Hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)(2-(trifluoromethyl)phenyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(3,3-Difluoro-1-hydroxycyclobutyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(1-Hydroxycyclohexyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(1-Hydroxycyclohexyl)(3,5,6-trimethylpyrazin-2-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(1-Hydroxycyclohexyl)(4-methylisoxazol-3-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(4-methylisoxazol-3-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(2-isopropylphenyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3,5,6-trimethylpyrazin-2-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(2-Chlorophenyl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-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,6S)-2-(Hydroxymethyl)-6-(((R)-(4-hydroxytetrahydro-2H-pyran-4-yl)(3-(trifluoromethyl)pyridin-2-yl)methyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((R)-(4-hydroxytetrahydro-2H-pyran-4-yl)(3,5,6-trimethylpyrazin-2-yl)methyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(4-Hydroxy-1-methylpiperidin-4-yl)(2-(trifluoromethyl)phenyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(4-Hydroxy-1-methylpiperidin-4-yl)(3-(trifluoromethyl)pyridin-2-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(4-Hydroxy-1-methylpiperidin-4-yl)(3,5,6-trimethylpyrazin-2-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(1-Hydroxycyclopentyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-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,6S)-2-(Hydroxymethyl)-6-(((R)-(4-hydroxypiperidin-4-yl)(2-(trifluoromethyl)phenyl)methyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; 4-((R)-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2-(trifluoromethyl)phenyl)methyl)-4-hydroxy-N-methylpiperidine-1-sulfonamide; (2S,3R,4S,5R,6R)-2-(((R)-(4-Hydroxy-1-(methylsulfonyl)piperidin-4-yl)(2-(trifluoromethyl)phenyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; 1-(4-((R)-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2-(trifluoromethyl)phenyl)methyl)-4-hydroxypiperidin-1-yl)ethan-1-one; N-Cyclopropyl-4-((R)-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2-(trifluoromethyl)phenyl)methyl)-4-hydroxypiperidine-1-carboxamide; Methyl 4-((R)-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2-(trifluoromethyl)phenyl)methyl)-4-hydroxypiperidine-1-carboxylate; (2S,3R,4S,5R,6R)-4-(4-(3,5-Difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(((R)-2-hydroxy-2-methyl-1-(2-(trifluoromethyl)phenyl)propyl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1-(2-(trifluoromethyl)phenyl)propyl)thio)-6-(hydroxymethyl)-4-(4-(naphthalen-2-yl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; 4-(1-((2S,3R,4S,5R,6R)-3,5-Dihydroxy-2-(((R)-2-hydroxy-2-methyl-1-(2-(trifluoromethyl)phenyl)propyl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-2-fluorobenzonitrile; (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((R)-4-hydroxytetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-1-(2-isopropylphenyl)-2-methylpropyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-1-(2-Cyclopropylphenyl)-2-hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-1-(2-(2-hydroxyethyl)phenyl)-2-methylpropyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1-(2-(trifluoromethyl)pyridin-3-yl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-1-(2,5-Dimethyloxazol-4-yl)-2-hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((1R,2R)-2-Hydroxy-2-phenyl-1-(2-(trifluoromethyl)phenyl)ethyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((1R,2S)-2-Hydroxy-2-phenyl-1-(2-(trifluoromethyl)phenyl)ethyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((1R,2R)-2-Hydroxy-2-(o-tolyl)-1-(2-(trifluoromethyl)phenyl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((1R,2S)-2-Hydroxy-2-(o-tolyl)-1-(2-(trifluoromethyl)phenyl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(5-Cyclopropyl-3-methylisoxazol-4-yl)(1-hydroxycyclohexyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)—((R)-4-Hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)—((S)-4-Hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(2-(trifluoromethyl)phenyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(2,3-Dichlorophenyl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(2-Cyclopropylphenyl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyrazin-2-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(5-Cyclopropyl-4-ethylisoxazol-3-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(5-Cyclopropyl-4-isobutylisoxazol-3-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-isopropylpyridin-2-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(3-Chloropyrazin-2-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(3-Cyclopropylpyridin-2-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(4-methylpyridazin-3-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; 4-((R)-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(4-methylisoxazol-3-yl)methyl)-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide; 4-((R)-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(3-methylpyridin-2-yl)methyl)-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide; (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((R)-(4-hydroxytetrahydro-2H-pyran-4-yl)(3-methylpyridin-2-yl)methyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)-(3-Hydroxy-1-(methylsulfonyl)azetidin-3-yl)(2-(trifluoromethyl)phenyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; Methyl 3-((R)-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2-(trifluoromethyl)phenyl)methyl)-3-hydroxyazetidine-1-carboxylate; N-Cyclopropyl-3-((R)-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2-(trifluoromethyl)phenyl)methyl)-3-hydroxyazetidine-1-carboxamide; (2R,3R,4S,5R,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-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,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)thio)-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,6S)-6-(((R)-(1-Hydroxycyclohexyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)thio)-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,6S)-6-(((R)-(3-Chloropyridin-2-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-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,6S)-6-(((R)—((R)-4-Hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)(2-(trifluoromethyl)phenyl)methyl)thio)-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,6S)-6-(((R)—((S)-4-Hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)(2-(trifluoromethyl)phenyl)methyl)thio)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; 4-Hydroxy-4-((R)-(((2S,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)thio)(3-methylpyridin-2-yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide; (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((R)-(4-hydroxytetrahydro-2H-pyran-4-yl)(3-methylpyridin-2-yl)methyl)thio)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6S)-6-(((R)—((R)-4-Hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)thio)-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,6S)-6-(((R)—((S)-4-Hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)(o-tolyl)methyl)thio)-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,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-isopropylpyridin-2-yl)methyl)thio)-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,6S)-6-(((R)-(3-Cyclopropylpyridin-2-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-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,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(4-methylpyridazin-3-yl)methyl)thio)-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,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyrazin-2-yl)methyl)thio)-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,6S)-6-(((R)-(1-Hydroxycyclohexyl)(4-methylisoxazol-3-yl)methyl)thio)-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,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(2-isopropylphenyl)methyl)thio)-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,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(4-methylisoxazol-3-yl)methyl)thio)-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,6S)-6-(((R)-(2-Cyclopropylphenyl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-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,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(1,4-dimethyl-1H-pyrazol-5-yl)methyl)thio)-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,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(1-ethyl-4-methyl-1H-1,2,3-triazol-5-yl)methyl)thio)-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,6S)-6-(((R)-(4-Chloro-1-ethyl-1H-pyrazol-5-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-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,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(5-ethyl-4-methylisoxazol-3-yl)methyl)thio)-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,6S)-2-(Hydroxymethyl)-6-(((R)-(4-hydroxytetrahydro-2H-pyran-4-yl)(4-methylisoxazol-3-yl)methyl)thio)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; 4-Hydroxy-4-((R)-(((2S,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)thio)(4-methylisoxazol-3-yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide; (2R,3R,4S,5R,6S)-6-(((R)-(5-Cyclopropyl-3-methylisoxazol-4-yl)(1-hydroxycyclohexyl)methyl)thio)-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,6S)-6-(((R)-(5-Cyclopropyl-4-ethylisoxazol-3-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-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,6S)-6-(((R)-(5-Cyclopropyl-4-isobutylisoxazol-3-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-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,6S)-6-(((R)-(3-Chloropyrazin-2-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-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,6S)-6-(((R)-(4-Chloro-3-methylpyridin-2-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-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,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-ethylpyridin-2-yl)methyl)thio)-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,6S)-6-(((R)-(3,4-Dichloropyridin-2-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; (2S,3R,4S,5R,6R)-2-(((R)-(3,6-Dichloropyridin-2-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)—((R)-4-Hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)(3-methylpyridin-2-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol; (2S,3R,4S,5R,6R)-2-(((R)—((S)-4-Hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)(3-methylpyridin-2-yl)methyl)thio)-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,6S)-6-(((R)-(5-Cyclopropyl-4-methylisoxazol-3-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-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,6S)-6-((((R)-4,4-Difluoro-1-hydroxycyclohexyl)(4-ethyl-5-propylisoxazol-3-yl)methyl)thio)-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,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-methyl-4-(trifluoromethyl)pyridin-2-yl)methyl)thio)-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,6S)-6-(((R)-(3-Chloro-6-methylpyridin-2-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-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,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3,5,6-trimethylpyrazin-2-yl)methyl)thio)-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,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3,6-dimethylpyridin-2-yl)methyl)thio)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; 9-((R)-(((2S,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)thio)(3-methylpyridin-2-yl)methyl)-3-oxaspiro[5.5]undecan-9-ol; (2R,3R,4S,5R,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-5-ethoxy-2-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol; 1-(Cyclopropylsulfonyl)-4-((R)-(((2S,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)thio)(2-(trifluoromethyl)phenyl)methyl)piperidin-4-ol; 1-(4-Hydroxy-4-((R)-(((2S,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)thio)(2-(trifluoromethyl)phenyl)methyl)piperidin-1-yl)ethan-1-one; N-Cyclopropyl-4-hydroxy-4-((R)-(((2S,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)thio)(2-(trifluoromethyl)phenyl)methyl)piperidine-1-carboxamide; (2R,3R,4S,5R,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-4-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-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,6S)-4-(4-(4-Chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(((R)-(4,4-difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-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,6S)-4-(4-(4-Bromo-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(((R)-(4,4-difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6S)-4-(4-(3,4-Dichloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(((R)-(4,4-difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6S)-4-(4-(4-Bromo-3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(((R)-(4,4-difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6S)-4-(4-(4-Chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(((R)-(4,4-difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; (2R,3R,4S,5R,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; or (2R,3R,4S,5R,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-4-(4-(6-fluoro-5-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol; or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11-14. (canceled)

15. A method for the prophylaxis or treatment of fibrosis of organs; liver diseases and disorders; cardiovascular diseases and disorders; cell proliferative diseases and cancers; inflammatory and autoimmune diseases and disorders; gastrointestinal tract diseases and disorders; pancreatic diseases and disorders; abnormal angiogenesis-associated diseases and disorders; brain-associated diseases and disorders; neuropathic pain and peripheral neuropathy; ocular diseases and disorders; acute kidney injury and chronic kidney disease; interstitial lung diseases and disorders; or transplant rejection; comprising administering to a subject in a need thereof an effective amount of a compound according to claim 1, or of a pharmaceutically acceptable salt thereof.

16. A compound according to claim 3; wherein at least one of said substituents is attached in para-position of said phenyl and the substituent is selected from halogen, methyl, cyano, and methoxy; or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 3; wherein at least one of said substituents is attached in a meta-position of said phenyl and the substituent is halogen; or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound according to claim 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. A method for the prophylaxis or treatment of fibrosis of organs; liver diseases and disorders; cardiovascular diseases and disorders; cell proliferative diseases and cancers; inflammatory and autoimmune diseases and disorders; gastrointestinal tract diseases and disorders; pancreatic diseases and disorders; abnormal angiogenesis-associated diseases and disorders; brain-associated diseases and disorders; neuropathic pain and peripheral neuropathy; ocular diseases and disorders; acute kidney injury and chronic kidney disease; interstitial lung diseases and disorders; or transplant rejection; comprising administering to a subject in a need thereof an effective amount of a compound according to claim 9, or of a pharmaceutically acceptable salt thereof.

Description

PREPARATION OF THE REFERENCE EXAMPLES

Reference Example 1

(2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-((2-methoxy-1-phenylethyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol (2.30.100.OMe)

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

[0651] To a solution of Intermediate 3 (0.088 g, 0.15 mmol) in EA (1.65 mL) are added TBAB (0.012 g, 0.037 mmol, 0.25 eq), aq. 1M Na.sub.2CO.sub.3 (0.8 mL) and 2-methoxy-1-phenylethane-1-thiol (0.038 g, 0.225 mmol, 1.5 eq). The reaction mixture is stirred for 17 at rt, diluted with EA, followed by water and brine. The phases are separated and the aq. layer is extracted with EA (3×). The combined organic layer is dried over MgSO.sub.4, filtered and solvent removed in vacuo. The crude material is purified by preparative HPLC/MS (II) to yield the title compound as a white solid (0.019 g, 20%). LC-MS (A): t.sub.R=1.12 min; [M+H].sup.+: 638.03.

2. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-((2-methoxy-1-phenylethyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol (2.30.100.OMe)

[0652] (2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-6-((2-methoxy-1-phenylethyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate (0.019 g, 0.029 mmol) is dissolved in MeOH (1.4 mL) and NaOMe (0.003 g, 0.0588 mmol, 2.0 eq) is added. The reaction mixture is stirred at rt for 17 h. The mixture is neutralized with HCl 1N, concentrated in vacuo and purified by preparative HPLC/MS (I) to yield the titled compound as a white solid (0.01, 67%). LC-MS (A): t.sub.R=0.85 min; [M+H].sup.+: 512.26.

[0653] Following examples are prepared starting from a thiol and Intermediate 3, according to the procedures described for Reference Example 1. LC-MS and Gal-3 inhibition data are listed in Table 1 below. The LC-MS conditions used were LC-MS (A).

TABLE-US-00006 TABLE 1 t.sub.R IC.sub.50 Example Name [min] [M + H].sup.+ [uM] 2.30.100.OMe (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-((2-methoxy-1-phenylethyl)thio)-4- 0.85 512.26 2.90 Ref. 1 (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.55.100. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-((1-phenylethyl)thio)-4-(4-(3,4,5- 0.88 481.74 4.03 Ref. 2 trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.54.100. (2S,3R,4S,5R,6R)-2-((Cyclopropyl(phenyl)methyl)thio)-6-(hydroxymethyl)- 0.92 508.28 3.21 Ref. 3 4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5- diol

[0654] Preparation of the Compounds of Structure 1 and Examples Thereof

Example 2.30.100R

(2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-1-phenylethyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol

1. Ethyl (R)-2-((dimethylcarbamothioyl)thio)-2-phenylacetate

[0655] To a solution of S-ethylmandelate (1.0 g, 5.55 mmol) in toluene (50.0 mL) are added PPh.sub.3 (2.9 g, 11.1 mmol, 2.0 eq) and Ziram (1.2 g, 3.9 mmol, 0.7 eq). The suspension is cooled to 2-4° C., DEAD (40% in toluene, 5.05 mL, 11.1 mmol, 2.0 eq) is added dropwise and the reaction mixture stirred at rt over 17 h. The solvent is removed in vacuo and the crude product directly purified by column chromatography on silica gel eluting with (Hept/EA 4/1) to give ethyl (R)-2-((dimethylcarbamothioyl)thio)-2-phenylacetate as an oil (1.3 g, 81%). LC-MS (B): t.sub.R=1.04 min; [M+H].sup.+: 284.21.

2. (R)-2-Mercapto-2-phenylethan-1-ol

[0656] To a cooled solution (0°) of ethyl (R)-2-((dimethylcarbamothioyl)thio)-2-phenylacetatein (1.27 g, 4.48 mmol) in Et.sub.2O (50.0 mL) is added LAH (2M in THF, 4.5 mL, 8.96 mmol, 2.0 eq). The cooling bath is removed and the reaction mixture allowed to warm up to rt and heated to reflux for 1 h. The suspension is cooled to rt, carefully quenched with water and Et.sub.2O, the pH adjusted to 4 through addition of aq. 2M HCl. The phases are separated, the aq. phase is extracted with Et.sub.2O (2×), the combined organic layer is dried over MgSO.sub.4, filtered and solvent removed in vacuo. The crude is purified by preparative HPLC/MS(II) to yield (R)-2-mercapto-2-phenylethan-1-ol as an oil (0.4 g, 57%). LC-MS (B): t.sub.R=072 min; [M+H].sup.+: no mass seen. .sup.1H NMR (400 MHz, CDCl3) δ: 7.38 (m, 4H), 7.30-7.33 (m, 1H), 4.13 (q, J=7.3 Hz, 1H), 3.96 (dd, J.sub.1=6.5 Hz, J.sub.2=11.3 Hz, 1H), 3.84 (dd, J.sub.1=7.5 Hz, J.sub.2=11.0 Hz, 1H), 2.03 (s, 1H), 2.00 (d, J=7.5 Hz, 1H).

3. (2S,3R,4S,5R,6R)-4-(4-(3,4,5-Trifluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(((R)-2-hydroxy-1-phenylethyl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol (2.30.100R.)

[0657] To a solution of Intermediate 3 (0.8 g, 1.46 mmol) in EA (32.0 mL) are added TBAB (0.117 g, 0.364 mmol, 0.25 eq) and aq. 1M Na.sub.2CO.sub.3 (16.0 mL). The reaction mixture is stirred at rt for 16 h, diluted with EA, the layers are separated and the aqueous layer is extracted with EA. The combined organic layer is dried over MgSO.sub.4, and solvent removed in vacuo. Purification over preparative HPLC/MS(I) yielded the desired acetyl-protected thioglycoside as an oil (0.085 g, 9%). LC-MS (B): t.sub.R=1.03 min; [M+H].sup.+: 623.95.

[0658] The above thioglycoside is dissolved in 0.02M NaOMe solution in MeOH and stirred at rt over 2 h. The solvent is removed in vacuo and the residue purified by preparative HPLC/MS(I) to yield the title compound (0.0041 g, 6%) as a solid. LC-MS (B): t.sub.R=0.77 min; [M+H].sup.+: 498.17.

Example 1.30.101

(2S,3R,4S,5R,6R)-2-((1-(2-Bromophenyl)-2-hydroxyethyl)thio)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol

1. Ethyl 2-(2-bromophenyl)-2-diazoacetate

[0659] Ethyl-(2-bromophenyl)acetate (1.0 g, 4.11 mmol) and p-ABSA (1.28 g, 5.35 mmol, 1.3 eq) are dissolved in MeCN (20.0 mL) and the solution cooled to 0° C. DBU (0.77 mL, 5.35 mmol, 1.45 eq) is added, and stirring continued at 0° C. After 20 min the cooling bath is removed and the reaction mixture stirred at rt for 15 h. The mixture is diluted with DCM, and the organic phase washed with water, dried over MgSO.sub.4, filtered and the solvent removed in vacuo. The residue is purified by column chromatography on silica gel eluting with (Hept/EA 4/1) to give ethyl 2-(2-bromophenyl)-2-diazoacetate (1.0 g, 90%) as an oil. LC-MS (C): t.sub.R=1.09 min; [M+H].sup.+: no mass.

2. Ethyl-2-(2-bromophenyl)-2-hydroxyacetate

[0660] Ethyl 2-(2-bromophenyl)-2-diazoacetate (1.0 g, 3.72 mmol) is added to 0.5M HClO.sub.4 in dioxane/water=6/4. After 2 h at rt, the reaction mixture is poured over water and extracted with DCM (2×), the combined organic layer is dried over MgSO.sub.4, filtered and solvent removed in vacuo. The residue is purified by preparative HPLC/MS (II) to afford ethyl-2-(2-bromophenyl)-2-hydroxyacetate as an oil (0.69 g, 72%). LC-MS (C): t.sub.R=0.80 min; [M+H].sup.+: 258.90.

3. (2S,3R,4S,5R,6R)-2-((1-(2-Bromophenyl)-2-hydroxyethyl)thio)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol (1.30.101.)

[0661] The last three steps are performed according to the procedures described for Example 1.30.100R to afford the title compound (1.30.101.) as a solid (0.065 g). LC-MS (C): t.sub.R=0.74 min; [M+H].sup.+: 539.92.

Example 2.30.105

(2S,3R,4S,5R,6R)-2-((2-Hydroxy-1-(2-isopropylphenyl)ethyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol

1. Methyl 2-(2-bromophenyl)-2-hydroxyacetate

[0662] The title compound is prepared from methyl-(2-bromophenyl)acetate according to the procedures described in Example 1.30.101. (Step 1 & Step 2). LC-MS (C): t.sub.R=0.71 min; [M+H].sup.+: 244.86.

2. Methyl 2-acetoxy-2-(2-bromophenyl)acetate

[0663] Methyl 2-(2-bromophenyl)-2-hydroxyacetate (2.46 g, 10.0 mmol) is dissolved in pyridine (20.0 mL). Acetic anhydride (1.42 mL, 15.1 mmol, 1.5 eq) is added and the reaction mixture stirred at rt for 72 h. Removal of the solvent under vacuum yielded the title compound (2.99, >99%) that is not further purified. LC-MS (C): t.sub.R=0.93 min; [M+H].sup.+: 288.82.

3. Methyl 2-acetoxy-2-(2-(prop-1-en-2-yl)phenyl)acetate

[0664] Methyl 2-acetoxy-2-(2-bromophenyl)acetate (1.50 g, 5.22 mmol) and isopropenyl boronic acid pinacolester (1.55 mL, 7.84 mmol, 1.5 eq) are dissolved in dioxane (50.0 mL) and water (12.0 mL). K.sub.2CO.sub.3 and Pd(Ph.sub.3).sub.4 are added and the reaction mixture is heated at 100° C. for 17 h. The mixture is cooled to rt, diluted with EA, the layers are separated and the organic layer is washed with water, dried over MgSO.sub.4, filtered and solvent removed in vacuo. The residue is purified by column chromatography on silica gel eluting with (Hept/EA 4/1) to give methyl 2-acetoxy-2-(2-(prop-1-en-2-yl)phenyl)acetate (0.96 g, 74%). LC-MS (C) t.sub.R=1.0 min; [M+H].sup.+: 248.99.

4. Methyl 2-acetoxy-2-(2-isopropylphenyl)acetate

[0665] Methyl 2-acetoxy-2-(2-(prop-1-en-2-yl)phenyl)acetate (0.96 g, 3.87 mmol) is dissolved in THF. Palladium on charcoal is added, followed by MeOH and the reaction mixture is submitted to hydrogenation under 5 bar for 72 h. The suspension is filtered (glass microfiber filters) and the solvent removed undervacuum to yield the title compound (0.93, 96%), that is not further purified. LC-MS (C) t.sub.R=1.03 min; [M+H].sup.+: 250.08.

5. Methyl 2-hydroxy-2-(2-isopropylphenyl)acetate

[0666] Methyl 2-acetoxy-2-(2-isopropylphenyl)acetate is dissolved in 0.02M NaOMe in MeOH (20.0 mL) and stirred at rt for 1 h. The reaction mixture is poured over water and extracted with EA (2×). The combined organic layer is dried over MgSO.sub.4, filtered and solvent removed in vacuo to yield the title compound (0.71 g, 92%), that is not further purified. LC-MS (C) t.sub.R=0.83 min; [M+H].sup.+: no mass.

6. Methyl 2-bromo-2-(2-isopropylphenyl)acetate

[0667] To a solution of methyl 2-hydroxy-2-(2-isopropylphenyl)acetate (0.715 g, 3.43. mmol) in DCM (20.0 mL), is added pyridine (0.41 mL, 5.15 mmol, 1.5 eq) and SBr.sub.2 (0.332 mL, 4.29 mmol, 1.25 eq) and the reaction mixture stirred at rt for 16 h. The mixture is diluted with DCM and washed with water, the organic phase is dried over MgSO.sub.4, filtered and solvent removed in vacuo. The residue is purified by column chromatography on silica gel eluting with (Hept/EA 4/1) to give methyl 2-bromo-2-(2-isopropylphenyl)acetate (0.49 g, 53%). LC-MS (C) t.sub.R=0.63 min; [M+H].sup.+: 270.04.

7. Methyl 2-(acetylthio)-2-(2-isopropylphenyl)acetate

[0668] To a solution of methyl 2-bromo-2-(2-isopropylphenyl)acetate (0.49 g, 1.81 mmol) in acetone (10.0 mL) is added potassium thioacetate (0.41 g, 3.61 mmol, 2.0 eq) and the reaction mixture stirred at rt for 1 h. The mixture is filtered and diluted wth EA, washed with water and brine. The organic layer is dried over MgSO.sub.4, filtered and solvent removed in vacuo to give the title compound (0.63 g, >99%), that is not further purified. LC-MS (C) t.sub.R=1.10 min; [M+H].sup.+: 267.01.

8. 2-Mercapto-2-phenylethan-1-ol

[0669] Methyl 2-(acetylthio)-2-(2-isopropylphenyl)acetate (0.4 g, 1.5 mmol) is dissolved in THF (10.0 mL) and the solution is cooled to 0° C. LAH (2M solution in THF 1.5 mL, 3.0 mmol, 2.0 eq) is added dropwise. Upon ending the LAH addition, the cooling bath is removed and the reaction is allowed to reach rt, and it is stirred at rt for 1 h. The mixture is quenched with aq. 1M HCl and extracted with EA (2×). The combined organic layer is dried over MgSO.sub.4, filtered and solvent removed in vacuo and the crude is purified by preparative HPLC/MS (II) to give the title compound (0.174, 59%). LC-MS (C) t.sub.R=0.92 min; [M+H].sup.+: no mass.

9. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-1-(2-isopropylphenyl)ethyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol (2.30.105.)

[0670] Aq. 1M K.sub.2CO.sub.3 solution (5.0 mL)) is added at rt to a solution of (Intermediate 3) (0.20 g, 0.36 mmol) in EA (10.0 mL). The reaction mixture is stirred at rt for 52 h, diluted with EA, washed with water. The organic layer is dried over MgSO.sub.4, filtered and solvent removed in vacuo and the crude is purified by preparative HPLC/MS (I) to give the thioglycoside. LC-MS (A): t.sub.R=1.13 min; [M+H].sup.+: 666.00.

[0671] The above thioglycoside is dissolved in 0.01M NaOMe solution in MeOH and stirred at rt over 40 min. The solvent is removed in vacuo and the residue purified by preparative HPLC/MS(I) to yield the title compound (0.023 g, 12%). LC-MS (B): t.sub.R=0.89 min; [M+H].sup.+: 540.01.

[0672] LC-MS and Gal-3 inhibition data from Examples 2.30.100R. to Example 2.30.105. are listed in Table 2 below. The LC-MS conditions used were LC-MS (C).

TABLE-US-00007 TABLE 2 t.sub.R IC.sub.50 Example Name [min] [M + H].sup.+ [uM] 2.30.100R. (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-1-phenylethyl)thio)-6-(hydroxymethyl)-4- 0.77 498.17 0.8 (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 1.30.101. (2S,3R,4S,5R,6R)-2-((1-(2-Bromophenyl)-2-hydroxyethyl)thio)-4-(4-(3- 0.74 539.92 1.7 fluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5- diol 2.30.105. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-1-(2-isopropylphenyl) ethyl)thio)-6- 0.89 540.01 0.40 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-3,5-diol

Example 2.31.102

(2S,3R,4S,5R,6R)-2-((2-Hydroxy-2-methyl-1-(o-tolyl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol

1. (2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-6-((2-hydroxy-2-methyl-1-(o-tolyl)propyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate

[0673] To a solution of Intermediate 3 (0.15 g, 0.27 mmol) in EA (3.0 mL) are added TBAB (0.022 g, 0.068 mmol, 0.25 eq), aq. 1M Na.sub.2CO.sub.3 (2.0 mL) and Intermediate 5 (0.161 g, 0.41 mmol, 1.5 eq). The reaction mixture is stirred at rt for 72 h, diluted with EA, followed by water and brine. The phases are separated and the aq. layer is extracted with EA (3×). The combined organic layer is dried over MgSO.sub.4, filtered and solvent removed in vacuo to give a yellow oil. The crude material is purified by preparative HPLC/MS(I) to yield a colorless oil (0.066 g, 36%) as the title compound. LC-MS (A) t.sub.R=1.08 min; [M+H].sup.+: 666.03.

2. ((2S,3R,4S,5R,6R)-2-((2-Hydroxy-2-methyl-1-(o-tolyl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol (2.31.102.)

[0674] (2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-6-((2-hydroxy-2-methyl-1-(o-tolyl)propyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate (0.066 g, 0.10 mmol) is dissolved in MeOH (2.0 mL), NaOMe (0.5M in MeOH, 0.60 mL, 0.29 mmol, 3.0 eq) is added. The reaction mixture is stirred at rt over 17 h, the solvent removed in vacuo and the residue dissolved in MeCN, before being purified by preparative HPLC/MS(I) to give the title compound as a white solid (0.024 g, 44%). LC-MS (A) t.sub.R=0.86 min; [M+H].sup.+: 540.04.

Example 2.31.102R

(2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1-(o-tolyl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol

[0675] Separation of the epimers of Example 2.31.102. (0.02 g) by chiral preparative HPLC (III) yielded the title compound (0.09 g) as a white solid. Chiral analytical HPLC (J): t.sub.R=1.8 min.

Example 2.31.102S

(2S,3R,4S,5R,6R)-2-(((S)-2-Hydroxy-2-methyl-1-(o-tolyl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol

[0676] Separation of the epimers of Example 2.31.102. (0.02 g) by chiral preparative HPLC (III) yielded the title compound (0.05 g) as a white solid. Chiral analytical HPLC (J): t.sub.R=1.23 min.

Example 2.31.118R

(2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1-(2-(trifluoromethyl)pyridin-3-yl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol

[0677] The title compound is prepared from Intermediate 3 and Intermediate 6R according to the procedures described for Example 2.31.102. (Step 1. and Step 2.) as a white solid (0.145 g). LC-MS (A) t.sub.R=0.79 min; [M+H].sup.+: 595.05.

Example 2.31.118S

(2S,3R,4S,5R,6R)-2-(((S)-2-Hydroxy-2-methyl-1-(2-(trifluoromethyl)pyridin-3-yl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol

[0678] The title compound is prepared from Intermediate 3 and Intermediate 6S according to the procedures described for Example 2.31.102. (Step 1. and Step 2.) as a white solid (0.135 g). LC-MS (A) t.sub.R=0.8 min; [M+H].sup.+: 595.21.

[0679] Following examples are prepared starting from o-substituted benzyl bromides, the corresponding dimethyl or diethyl ketones and Intermediate 3, according to the procedures described for Example 2.31.102. LC-MS and Gal-3 inhibition data are listed in Table 3 below. The LC-MS conditions used were LC-MS (A). Chiral analytical HPLC (I) (conditions and retention time) and inhibition data of the epimers R and S of selected Examples are also listed.

TABLE-US-00008 TABLE 3 t.sub.R t.sub.R HPLC chiral IC.sub.50 Example Name [min] [M + H].sup.+ conditions [min] [uM] 2.31.102. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-2-methyl-1-(o- 0.86 540.04 0.17 tolyl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.31.102R. (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1-(o- 0.85 540.02 Chiralpak IB 1.8 0.12 tolyl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- B: 35% EtOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- 3 min run pyran-3,5-diol 2.31.102S. (2S,3R,4S,5R,6R)-2-(((S)-2-Hydroxy-2-methyl-1-(o- 0.87 540.03 Chiralpak IB 1.23 4.43 tolyl)propyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- B: 35% EtOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- 3 min run pyran-3,5-diol 2.31.100. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-2-methyl-1- 0.82 526.01 1.9 phenylpropyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.31.103. (2S,3R,4S,5R,6R)-2-((1-(2-Ethylphenyl)-2-hydroxy- 0.90 554.31 0.30 2-methylpropyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.31.104. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-2-methyl-1-(2- 0.93 568.03 0.17 propylphenyl) propyl)thio)-6-(hydroxymethyl)-4-(4- (3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3,5-diol 2.31.105. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-1-(2- 0.92 568.31 0.18 isopropylphenyl)-2-methylpropyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.31.105R. (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-1-(2- 0.93 568.26 Chiralpak IB 1.74 0.06 isopropylphenyl)-2-methylpropyl)thio)-6- B: 30% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.31.105S. (2S,3R,4S,5R,6R)-2-(((S)-2-Hydroxy-1-(2- 0.94 568.27 Chiralpak IB 1.33 8.3 isopropylphenyl)-2-methylpropyl)thio)-6- B: 30% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.31.106. (2S,3R,4S,5R,6R)-2-((1-(2-Cyclopropylphenyl)-2- 0.90 566.34 0.20 hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4- (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3,5-diol 2.31.106R. (2S,3R,4S,5R,6R)-2-(((R)-1-(2-cyclopropylphenyl)-2- 0.9 566.35 Chiralpak IB 2.3 0.14 hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4- B: 30% EtOH (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- 5 min run yl)tetrahydro-2H-pyran-3,5-diol 2.31.106S. (2S,3R,4S,5R,6R)-2-(((S)-1-(2-cyclopropylphenyl)-2- 0.91 566.36 Chiralpak IB 1.46 15.9 hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4- B: 30% EtOH (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- 5 min run yl)tetrahydro-2H-pyran-3,5-diol 2.31.107. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-1-(2- 0.96 582.02 0.26 isobutylphenyl)-2-methylpropyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.31.107R. (2S,3R,4S,5R,6R)-2-(((R)-2-hydroxy-1-(2- 0.96 582.01 Chiralpak IB 1.73 0.2 isobutylphenyl)-2-methylpropyl)thio)-6- B: 30% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.31.107S. (2S,3R,4S,5R,6R)-2-(((S)-2-hydroxy-1-(2- 0.98 582.03 Chiralpak IB 1.24 0.95 isobutylphenyl)-2-methylpropyl)thio)-6- B: 30% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.31.108. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-1-(2-(2- 0.78 570.19 0.38 hydroxyethyl)phenyl)-2-methylpropyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.31.108R. (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-1-(2-(2- 0.79 570.17 Chiralpak IB 3.89 0.27 hydroxyethyl)phenyl)-2-methylpropyl)thio)-6- B: 20% (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- MeOH, 0.1% 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol DEA 5 min run 2.31.108S. (2S,3R,4S,5R,6R)-2-(((S)-2-Hydroxy-1-(2-(2- 0.8 570.17 Chiralpak IB 3.25 8.1 hydroxyethyl)phenyl)-2-methylpropyl)thio)-6- B: 20% (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- MeOH 0.1% 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol DEA 5 min run 2.31.109. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-2-methyl-1-(2- 1.01 595.98 0.54 pentylphenyl) propyl)thio)-6-(hydroxymethyl)-4-(4- (3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3,5-diol 2.31.110. (2S,3R,4S,5R,6R)-2-((1-([1,1′-Biphenyl]-2-yl)-2- 0.96 602.07 0.18 hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4- (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3,5-diol 2.31.110R. (2S,3R,4S,5R,6R)-2-(((R)-1-([1,1′-Biphenyl]-2-yl)-2- 0.96 601.93 Chiralpak IB 1.92 0.22 hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4- B: 35% EtOH (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- 3 min run yl)tetrahydro-2H-pyran-3,5-diol 2.31.110S. (2S,3R,4S,5R,6R)-2-(((S)-1-([1,1′-Biphenyl]-2-yl)-2- 0.97 601.96 Chiralpak IB 1.25 4.9 hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4- B: 35% EtOH (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- 3 min run yl)tetrahydro-2H-pyran-3,5-diol 2.31.111. (2S,3R,4S,5R,6R)-2-((1-(2-Chlorophenyl)-2-hydroxy- 0.86 560.02 0.41 2-methylpropyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.31.111R. (2S,3R,4S,5R,6R)-2-(((R)-1-(2-Chlorophenyl)-2- 0.85 559.91 Chiralpak IB 3.36 0.38 hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4- B: 25% EtOH (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- 3 min run yl)tetrahydro-2H-pyran-3,5-diol 2.31.111S. (2S,3R,4S,5R,6R)-2-(((S)-1-(2-Chlorophenyl)-2- 0.86 559.89 Chiralpak IB 2.13 4.3 hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4- B: 25% EtOH (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- 3 min run yl)tetrahydro-2H-pyran-3,5-diol 2.31.112. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-2-methyl-1-(2- 0.89 593.69 0.25 (trifluoromethyl)phenyl)propyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.31.112R. (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1-(2- 0.89 594.12 Chiralpak IB 1.52 0.29 (trifluoromethyl)phenyl)propyl)thio)-6- B: 40% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.31.112S. (2S,3R,4S,5R,6R)-2-(((S)-2-Hydroxy-2-methyl-1-(2- 0.89 594.11 Chiralpak IB 1.09 7.07 (trifluoromethyl)phenyl)propyl)thio)-6- B: 40% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.31.113. (2S,3R,4S,5R,6R)-2-((1-(2,3-Dichlorophenyl)-2- 0.90 593.64 0.46 hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4- (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3,5-diol 2.31.114. (2S,3R,4S,5R,6R)-2-((1-(3-Fluoro-2-methylphenyl)- 0.87 557.99 0.13 2-hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4- (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3,5-diol 2.31.114R. (2S,3R,4S,5R,6R)-2-(((S)-1-(3-Fluoro-2- 0.87 557.98 Chiralpak IB 1.94 0.18 methylphenyl)-2-hydroxy-2-methylpropyl)thio)-6- B: 30% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.31.114S. (2S,3R,4S,5R,6R)-2-(((S)-1-(3-Fluoro-2- 0.88 557.96 Chiralpak IB 1.34 5.4 methylphenyl)-2-hydroxy-2-methylpropyl)thio)-6- B: 30% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.31.115. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-2-methyl-1- 0.89 576.2 0.18 (naphthalen-1-yl)propyl)thio)-6-(hydroxymethyl)-4-(4- (3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3,5-diol 2.31.115R. (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1- 0.89 576.26 Chiralpak IC 2.42 0.17 (naphthalen-1-yl)propyl)thio)-6-(hydroxymethyl)-4-(4- B: 25% EtOH (3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- 5 min run yl)tetrahydro-2H-pyran-3,5-diol 2.31.115S. (2S,3R,4S,5R,6R)-2-(((S)-2-Hydroxy-2-methyl-1- 0.91 576.25 Chiralpak IC 3.51 10.3 (naphthalen-1-yl)propyl)thio)-6-(hydroxymethyl)-4-(4- B: 25% EtOH (3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- 5 min run yl)tetrahydro-2H-pyran-3,5-diol 2.31.116. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-2-methyl-1-(2- 0.62 540.96 0.30 methylpyridin-3-yl)propyl)thio)-6-(hydroxymethyl)-4- (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3,5-diol 2.31.117. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-2-methyl-1-(4- 0.62 541.05 0.53 methylpyridin-3-yl)propyl)thio)-6-(hydroxymethyl)-4- (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3,5-diol 2.31.118R.* (2S,3R,4S,5R,6R)-2-(((R)-2-hydroxy-2-methyl-1-(2- 0.79 595.05 Chiralpak IB 2.53 0.21 (trifluoromethyl)pyridin-3-yl)propyl)thio)-6- B: 30% iPrOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.31.118S.* (2S,3R,4S,5R,6R)-2-(((S)-2-Hydroxy-2-methyl-1-(2- 0.8 595.21 Chiralpak IB 2.19 6.21 (trifluoromethyl)pyridin-3-yl)propyl)thio)-6- B: 30% iPrOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.31.119. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-2-methyl-1-(3,5,6- 0.75 570.06 0.23 trimethylpyrazin-2-yl)propyl)thio)-6-(hydroxymethyl)- 4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3,5-diol 2.31.119R. (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1- 0.76 570.34 Chiralpak IC 3.57 0.27 (3,5,6-trimethylpyrazin-2-yl)propyl)thio)-6- B: 25% (1/1) (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- MeCN/EtOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 5 min run 2.31.119S. (2S,3R,4S,5R,6R)-2-(((S)-2-Hydroxy-2-methyl-1- 0.75 570.35 Chiralpak IC 1.26 2.63 (3,5,6-trimethylpyrazin-2-yl)propyl)thio)-6- B: 25% (1/1) (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- MeCN/EtOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 5 min run 2.31.120. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-2-methyl-1-(4- 0.75 530.98 0.73 methylisoxazol-3-yl)propyl)thio)-6-(hydroxymethyl)-4- (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3,5-diol 2.31.120R. (2S,3R,4S,5R,6R)-2-(((R)-2-Hydroxy-2-methyl-1-(4- 0.75 531.00 Chiralpak ID 2.76 0.32 methylisoxazol-3-yl)propyl)thio)-6-(hydroxymethyl)-4- B: 35% (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- 2-ProOH yl)tetrahydro-2H-pyran-3,5-diol 5 min run 2.31.120S. (2S,3R,4S,5R,6R)-2-(((S)-2-Hydroxy-2-methyl-1-(4- 0.76 531.01 Chiralpak ID 1.67 12.4 methylisoxazol-3-yl)propyl)thio)-6-(hydroxymethyl)-4- B: 35% (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- 2-ProOH yl)tetrahydro-2H-pyran-3,5-diol 5 min run 2.31.121. (2S,3R,4S,5R,6R)-2-((1-(3,5-Dimethylisoxazol-4-yl)- 0.75 544.9 0.71 2-hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4- (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3,5-diol 2.31.122. (2S,3R,4S,5R,6R)-2-((1-(2,5-Dimethyloxazol-4-yl)-2- 0.72 545.05 0.88 hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4- (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3,5-diol 2.31.122R. (2S,3R,4S,5R,6R)-2-(((R)-1-(2,5-Dimethyloxazol-4- 0.73 545.09 Chiralpak IB 1.92 0.37 yl)-2-hydroxy-2-methylpropyl)thio)-6- B: 30% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.31.122S. (2S,3R,4S,5R,6R)-2-(((S)-1-(2,5-dimethyloxazol-4- 0.72 545.04 Chiralpak IB 1.27 4.12 yl)-2-hydroxy-2-methylpropyl)thio)-6- B: 30% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.31.123. (2S,3R,4S,5R,6R)-2-((1-(2,5-Dimethylthiazol-4-yl)-2- 0.71 562.02 0.55 hydroxy-2-methylpropyl)thio)-6-(hydroxymethyl)-4- (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3,5-diol 2.31.123R. (2S,3R,4S,5R,6R)-2-(((R)-1-(2,5-Dimethylthiazol-4- 0.71 562.05 Chiralcel 2.34 0.28 yl)-2-hydroxy-2-methylpropyl)thio)-6- OD-H (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 35% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 0.1% DEA 5 min run 2.31.123S. (2S,3R,4S,5R,6R)-2-(((S)-1-(2,5-Dimethylthiazol-4- 0.71 562.07 Chiralcel 1.24 4.7 yl)-2-hydroxy-2-methylpropyl)thio)-6- OD-H (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 35% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 0.1% DEA 5 min run 2.31.124. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-2-methyl-1-(4- 0.84 545.67 0.50 methylthiophen-3-yl)propyl)thio)-6-(hydroxymethyl)- 4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3,5-diol 2.32.120R.* (2S,3R,4S,5R,6R)-2-(((R)-2-Ethyl-2-hydroxy-1-(3- 0.84 559.24 Chiralpak IC 2.52 1.22 methylisoxazol-4-yl)butyl)thio)-6-(hydroxymethyl)-4- B: 25% (1/1) (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- MeCN/EtOH yl)tetrahydro-2H-pyran-3,5-diol 5 min run 2.32.120S.* (2S,3R,4S,5R,6R)-2-(((S)-2-Ethyl-2-hydroxy-1-(3- 0.84 559.24 Chiralpak IC 3.23 11.3 methylisoxazol-4-yl)butyl)thio)-6-(hydroxymethyl)-4- B: 25% (1/1) (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- MeCN/EtOH yl)tetrahydro-2H-pyran-3,5-diol 5 min run *Epimers are obtained from the chiral separation of the corresponding thioquinoline intermediates in analogy to the procedures described for Example 2.31.118R. and Example 2.31.118S..

[0680] Following examples are prepared starting from 1-(bromomethyl)-2-(trifluoromethyl)benzene, the corresponding aldehyde and Intermediate 3, according to the procedures described for 2.31.102. LC-MS and Gal-3 inhibition data are listed in Table 4 below. The LC-MS conditions used were LC-MS (A).

TABLE-US-00009 TABLE 4 t.sub.R IC.sub.50 Example Name [min] [M + H].sup.+ [uM] 2.60.112. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-1-(2-(trifluoromethyl)phenyl) butyl)thio)-6- 0.91 594.17 0.23 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-3,5-diol 2.61.112. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-2-phenyl-1-(2- 0.95 642.00 1.1 (trifluoromethyl)phenyl)ethyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.62.112. (2S,3R,4S,5R,6R)-2-((2-Hydroxy-2-(o-tolyl)-1-(2- 0.97 656.18 1.22 (trifluoromethyl)phenyl)ethyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol

Example 2.33.112

(2S,3R,4S,5R,6R)-2-(((3,3-Difluoro-1-hydroxycyclobutyl)(2-(trifluoromethyl)phenyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol

1. 2-((2-(Trifluoromethyl)benzyl)thio)quinoline

[0681] DBU (1.8 mL, 11.8 mmol, 1.0 eq) is added to a solution of 2-quinolinethiol (2.0 g, 11.8 mmol, 1.0 eq) in toluene (40.0 mL) at rt. The reaction mixture is stirred at rt for 30 min. 2-(Trifluoromethyl)benzyl bromide (2.8 g, 11.8 mmol) is added and the solution is stirred at rt for 48 h. The reaction mixture is concentrated under reduced pressure to give a yellow solid. Trituration from Hept yielded a solid, that is removed by filtration and the remaining Hept is concentrated in vacuo to give an orange solid as 2-((2-(trifluoromethyl)benzyl)thio)quinoline (3.61 g, 96%). LC-MS (A) t.sub.R=1.16 min; [M+H].sup.+: 320.08.

2. 3,3-Difluoro-1-((quinolin-2-ylthio)(2-(trifluoromethyl)phenyl)methyl)cyclobutan-1-ol

[0682] To a cooled (−78° C.) solution of 2-((2-(trifluoromethyl)benzyl)thio)quinoline (1.0 g, 3.1 mmol) in THF (30.0 mL) is added at −78° C. n-BuLi (1.6M in hexane, 4.7 mmol, 1.5 eq) and the reaction mixture is stirred at −78° C. for 60 min. 3,3-Difluoro-cyclobutanone (0.41 g, 3.7 mmol, 1.2 eq) in THF (15.0 mL) is added and the reaction mixture is allowed to warm to −50° C. for 2 h, then cooled down to −78° C. and n-BuLi (1.6 M in hexane, 3.0 mL, 4.68 mmol, 1.5 eq) is added again, followed by 3,3-difluoro-cyclobutanone (0.41 g, 3.76 mmol, 1.2 eq). The reaction mixture is allowed to warm to rt for 17 h, quenched with aq. sat. NH.sub.4Cl, extracted with EA, the layers are separated and the aqueous layer is extracted with EA (3×). The combined organic layer is washed with brine, dried over MgSO.sub.4, filtered and the solvent removed in vacuo to give a brown oil. The crude is purified by preparative HPLC-MS (I) to afford a brown solid as the title compound (0.23 g, 18%). LC-MS (A): t.sub.R=1.12 min; [M+H].sup.+: 426.1.

3. 3,3-Difluoro-1-(mercapto(2-(trifluoromethyl)phenyl)methyl)cyclobutan-1-ol

[0683] To a solution of 3,3-difluoro-1-((quinolin-2-ylthio)(2-(trifluoromethyl)phenyl)methyl) cyclobutan-1-ol (0.24 g, 0.55 mmol, 1.0 eq) in glacial acetic acid (10.0 mL) is added sodium cyanoborohydride (0.22 g, 3.33 mmol, 6.0 eq) and stirring is continued at rt for 17 h. The reaction mixture is quenched by the addition of water (5.0 mL) and is left stirring at rt for 1 h, diluted with DCM, the layers are separated and the aqueous layer is extracted with DCM. The combined organic layer is washed with brine, dried over MgSO.sub.4 and the solvent is removed in vacuo to give a yellow oil. The crude material is purified by Flash Master (Büchi, product added dry on isolute, 10 g column, 15 mL/min, 10 mL fractions, Hept/EA 100/0 to 1/1, Rf(Hept/EA 1/1)=0.38) to give 3,3-difluoro-1-(mercapto(2-(trifluoromethyl)phenyl)methyl)cyclobutan-1-ol as a yellow oil (0.13 g, 77%). LC-MS (A): t.sub.R=0.97 min; [M+H].sup.+: no mass visible.

4. (2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-6-(((3,3-difluoro-1-hydroxycyclobutyl)(2-(trifluoromethyl)phenyl)methyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate

[0684] To a solution of Intermediate 3 (0.20 g, 0.36 mmol) in EA (6.0 mL) is added 3,3-difluoro-1-(mercapto(2-(trifluoromethyl)phenyl)methyl)cyclobutan-1-ol (0.13 g, 0.43 mmol, 1.2 eq) and TBAB (0.03 g, 0.09 mmol, 0.25 eq), followed by aq 1M Na.sub.2CO.sub.3 (3.0 mL). The reaction mixture is stirred at rt over 72 h, then diluted with EA, followed by water and brine. The phases are separated and the aq. layer is extracted with EA (3×). The combined organic layer is dried over MgSO.sub.4, filtered and the solvent is removed in vacuo to give a brown oil, that is purified by preparative HPLC/MS (I) to afford the title compound as a beige oil (0.27 g, 96%). LC-MS (A): t.sub.R=1.12 min; [M+H].sup.+: 768.19.

5. (2S,3R,4S,5R,6R)-2-(((3,3-Difluoro-1-hydroxycyclobutyl)(2-(trifluoromethyl)phenyl) methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol (2.33.112.)

[0685] (2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-6-(((3,3-difluoro-1-hydroxycyclobutyl)(2-(trifluoromethyl)phenyl)methyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate (0.27 g, 0.35 mmol, 1.0 eq) is dissolved in MeOH (4.0 mL) and K.sub.2CO.sub.3 (0.09 g, 0.07 mmol, 0.2 eq) is added at rt. The reaction mixture is stirred at rt for 48 h, then diluted with MeCN, followed by water and the mixture is directly purified by preparative HPLC/MS (I) to give the title compound as a white solid (0.12 g, 52%). LC-MS (A): t.sub.R=0.94 min; [M+H].sup.+: 642.04.

Example 2.33.112R

(2S,3R,4S,5R,6R)-2-(((R)-(3,3-Difluoro-1-hydroxycyclobutyl)(2-(trifluoromethyl)phenyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol [1,3-di-deoxy-1-((3,3-difluoro-1-hydroxy-cyclobutan-1-yl)-(2-(trifluoromethyl)phenyl)methyl-(R)-thio)-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside]

[0686] Separation of the epimers of Example 2.33.112. (0.116 g) by chiral preparative HPLC (IV) yielded the title compound (0.038 g) as a white solid. Chiral analytical HPLC (K): t.sub.R=1.7 min.

Example 2.33.112S

(2S,3R,4S,5R,6R)-2-(((S)-(3,3-Difluoro-1-hydroxycyclobutyl)(2-(trifluoromethylphenyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol

[0687] Separation of the epimers of Example 2.33.112. (0.116 g) by chiral preparative HPLC (IV) yielded the title compound (0.041 g) as a white solid. Chiral analytical HPLC (K): t.sub.R=1.25 min.

[0688] Following examples are prepared starting from o-substituted benzyl bromides, the corresponding cyclic ketons and Intermediate 3 according to the procedures described for Example 2.33.112. LC-MS and Gal-3 inhibition data are listed in Table 5 below. The LC-MS conditions used were LC-MS (A). Chiral analytical HPLC (conditions and retention time) and inhibition data of the epimers R and S of selected Examples are also listed.

TABLE-US-00010 TABLE 5 t.sub.R t.sub.R HPLC chiral IC.sub.50 Example Name [min] [M + H].sup.+ conditions [min] [uM] 2.33.112. (2S,3R,4S,5R,6R)-2-(((3,3-Difluoro-1- 0.94 642.04 0.25 hydroxycyclobutyl)(2- (trifluoromethyl)phenyl)methyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.33.112R. (2S,3R,4S,5R,6R)-2-(((R)-(3,3-Difluoro-1- 0.94 642.04 Chiralpak IB 1.69 0.14 hydroxycyclobutyl)(2- B: 30% EtOH (trifluoromethyl)phenyl)methyl)thio)-6- 2.5 min run (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.33.112S. (2S,3R,4S,5R,6R)-2-(((S)-(3,3-Difluoro-1- 0.94 642.08 Chiralpak IB 1.24 11.3 hydroxycyclobutyl)(2- B: 30% EtOH (trifluoromethyl)phenyl)methyl)thio)-6- 2.5 min run (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.34.102. (2S,3R,4S,5R,6R)-2-(((1-Hydroxycyclobutyl)(o- 0.9 551.98 1.00 tolyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.35.102. (2S,3R,4S,5R,6R)-2-(((1-Hydroxy-3,3- 0.96 579.99 0.35 dimethylcyclobutyl)(o-tolyl)methyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.36.102. (2S,3R,4S,5R,6R)-2-(((1-Hydroxy-3- 0.91 565.96 0.46 methylcyclobutyl)(o-tolyl)methyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.36.102R. (2S,3R,4S,5R,6R)-2-(((1R)-(1-Hydroxy-3- 0.91 565.99 Chiralpak IB 2.44 0.44 methylcyclobutyl)(o-tolyl)methyl)thio)-6- B: 30% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 2.5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.36.102S. (2S,3R,4S,5R,6R)-2-(((1S)-(1-Hydroxy-3- 0.94 565.99 Chiralpak IB 1.44 7.2 methylcyclobutyl)(o-tolyl)methyl)thio)-6- B: 30% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 2.5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.37.102. (2S,3R,4S,5R,6R)-2-(((1-Hydroxy-2,3- 0.96 580 0.56 dimethylcyclobutyl)(o-tolyl)methyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.38.102. (2S,3R,4S,5R,6R)-2-(((1-Hydroxycyclopentyl)(o- 0.92 565.97 0.18 tolyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.38.102R. (2S,3R,4S,5R,6R)-2-(((R)-(1- 0.90 566.02 Chiralpak IB 2.18 0.11 Hydroxycyclopentyl)(o-tolyl)methyl)thio)-6- B: 30% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 4 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.38.102S. (2S,3R,4S,5R,6R)-2-(((S)-(1- 0.92 566.1 Chiralpak IB 1.65 2.75 Hydroxycyclopentyl)(o-tolyl)methyl)thio)-6- B: 30% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 4 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.39.128. (2S,3R,4S,5R,6R)-2-(((5-Cyclopropyl-3- 0.89 611.2 0.21 methylisoxazol-4-yl)(1- hydroxycyclohexyl)methyl)thio)-6-(hydroxymethyl)- 4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3,5-diol 2.39.128R. (2S,3R,4S,5R,6R)-2-(((R)-(5-Cyclopropyl-3- 0.88 611.2 Chiralcel 1.41 0.19 methylisoxazol-4-yl)(1- OJ-H hydroxycyclohexyl)methyl)thio)-6-(hydroxymethyl)- B: 15% (1/1) 4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- MeCN/EtOH yl)tetrahydro-2H-pyran-3,5-diol 3 min run 2.39.128S. (2S,3R,4S,5R,6R)-2-(((S)-(5-Cyclopropyl-3- 0.88 611.2 Chiralcel 1.28 3.21 methylisoxazol-4-yl)(1- OJ-H hydroxycyclohexyl)methyl)thio)-6-(hydroxymethyl)- B: 15% (1/1) 4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- MeCN/EtOH yl)tetrahydro-2H-pyran-3,5-diol 3 min run 2.39.102. (2S,3R,4S,5R,6R)-2-(((1-Hydroxycyclohexyl)(o- 0.96 579.99 0.09 tolyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.39.102R. (2S,3R,4S,5R,6R)-2-(((R)-(1- 0.95 580.01 Chiralpak IB 2.18 0.09 Hydroxycyclohexyl)(o-tolyl)methyl)thio)-6- B: 30% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 3 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.39.102S. (2S,3R,4S,5R,6R)-2-(((S)-(1- 0.97 579.99 Chiralpak IB 1.74 4.54 Hydroxycyclohexyl)(o-tolyl)methyl)thio)-6- B: 30% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 3 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.40.102. (2S,3R,4S,5R,6R)-2-(((4-Hydroxy-1- 0.69 594.92 0.09 methylpiperidin-4-yl)(o-tolyl)methyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.41.102. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-((4- 0.81 581.99 0.09 hydroxytetrahydro-2H-pyran-4-yl)(o- tolyl)methyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.41.102R. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((R)-4- 0.81 582.07 Chiralpak IF 2.42 0.04 hydroxytetrahydro-2H-pyran-4-yl)(o- B: 35% tolyl)methyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H- 2-ProOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 5 min run 2.41.102S. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((S)-4- 0.83 582.09 Chiralpak IF 1.61 7.36 hydroxytetrahydro-2H-pyran-4-yl)(o- B: 35% tolyl)methyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H- 2-ProOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 5 min run 2.42.102. (2S,3R,4S,5R,6R)-2-(((4-Hydroxy-2,2,6,6- 0.95 638.13 0.38 tetramethyltetrahydro-2H-pyran-4-yl)(2- (trifluoromethyl)phenyl)methyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.42.102R. (2S,3R,4S,5R,6R)-2-(((R)-(4-Hydroxy-2,2,6,6- 0.93 638.16 Chiralpak IA 1.91 0.09 tetramethyltetrahydro-2H-pyran-4-yl)(2- B: 3% EtOH (trifluoromethyl)phenyl)methyl)thio)-6- 5 min run (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.42.102S. (2S,3R,4S,5R,6R)-2-(((S)-(4-Hydroxy-2,2,6,6- 0.95 638.16 Chiralpak IA 1.53 7.82 tetramethyltetrahydro-2H-pyran-4-yl)(2- B: 3% EtOH (trifluoromethyl)phenyl)methyl)thio)-6- 5 min run (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.43.102. (2S,3R,4S,5R,6R)-2-(((4-Hydroxy-2,2- 0.89 610.12 0.12 dimethyltetrahydro-2H-pyran-4-yl)(2- (trifluoromethyl)phenyl)methyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.43.102RS. (2S,3R,4S,5R,6R)-2-(((R)-((S)-4-Hydroxy-2,2- 0.87 609.93 Chiralpak AD-H 2.39 0.04 dimethyltetrahydro-2H-pyran-4-yl)(2- B: 30% (trifluoromethyl)phenyl)methyl)thio)-6- 2-ProOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.43.102RR. (2S,3R,4S,5R,6R)-2-(((R)-((R)-4-Hydroxy-2,2- 0.86 609.92 Chiralpak AD-H 3.36 0.29 dimethyltetrahydro-2H-pyran-4-yl)(2- B: 30% (trifluoromethyl)phenyl)methyl)thio)-6- 2-ProOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.43.102SS. (2S,3R,4S,5R,6R)-2-(((S)-((S)-4-Hydroxy-2,2- 0.89 609.94 Chiralpak AD-H 1.85 3.92 dimethyltetrahydro-2H-pyran-4-yl)(2- B: 30% (trifluoromethyl)phenyl)methyl)thio)-6- 2-ProOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.43.102SR. (2S,3R,4S,5R,6R)-2-(((S)-((R)-4-Hydroxy-2,2- 0.88 609.87 Chiralpak AD-H 1.16 3.9 dimethyltetrahydro-2H-pyran-4-yl)(2- B: 30% (trifluoromethyl)phenyl)methyl)thio)-6- 2-ProOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.43.112RS. (2S,3R,4S,5R,6R)-2-(((R)-((S)-4-Hydroxy-2,2- 0.91 664.13 Chiralpak IA 1.21 0.13 dimethyltetrahydro-2H-pyran-4-yl)(o- B: 30% (1/1) tolyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- MeCN/EtOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- 5 min run pyran-3,5-diol 2.43.112RR. (2S,3R,4S,5R,6R)-2-(((R)-((R)-4-Hydroxy-2,2- 0.89 664.05 Chiralcel OJ-H 1.14 1.5 dimethyltetrahydro-2H-pyran-4-yl)(o- B: 20% (1/1) tolyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- MeCN/EtOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- 5 min run pyran-3,5-diol 2.43.112SR. (2S,3R,4S,5R,6R)-2-(((S)-((R)-4-Hydroxy-2,2- 0.92 664.13 Chiralpak IA 3.3 4.9 dimethyltetrahydro-2H-pyran-4-yl)(o- B: 30% (1/1) tolyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- MeCN/EtOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- 5 min run pyran-3,5-diol 2.43.112SS. (2S,3R,4S,5R,6R)-2-(((S)-((S)-4-Hydroxy-2,2- 0.9 664.05 Chiralcel OJ-H 1.95 7.3 dimethyltetrahydro-2H-pyran-4-yl)(o- B: 20% (1/1) tolyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- MeCN/EtOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- 5 min run pyran-3,5-diol 2.35.125. (2S,3R,4S,5R,6R)-2-(((3,3-Difluoro-1- 0.96 635.15 0.32 hydroxycyclobutyl)(3-(trifluoromethyl)pyridin-2- yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.35.125R. (2S,3R,4S,5R,6R)-2-(((R)-(3,3-Difluoro-1- 0.96 635.15 Chiralpak ID 1.03 0.1 hydroxycyclobutyl)(3-(trifluoromethyl)pyridin-2- B: 40% EtOH yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.35.125S. (2S,3R,4S,5R,6R)-2-(((S)-(3,3-Difluoro-1- 0.95 635.18 Chiralpak ID 1.39 3.0 hydroxycyclobutyl)(3-(trifluoromethyl)pyridin-2- B: 40% EtOH yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.39.125R.* (2S,3R,4S,5R,6R)-2-(((R)-(1- 0.94 635.33 Chiralpak ID 1.14 0.1 Hydroxycyclohexyl)(3-(trifluoromethyl)pyridin-2- B: 40% MeOH yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.39.125S.* (2S,3R,4S,5R,6R)-2-(((S)-(1- 0.93 635.32 Chiralpak ID 1.84 3.0 Hydroxycyclohexyl)(3-(trifluoromethyl)pyridin-2- B: 40% MeOH yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.39.119R.* (2S,3R,4S,5R,6R)-2-(((R)-(1- 0.86 610.28 Chiralpak IB 1.74 0.07 Hydroxycyclohexyl) (3,5,6-trimethylpyrazin-2- B: 35% MeOH yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.39.119S.* (2S,3R,4S,5R,6R)-2-(((S)-(1- 0.85 610.28 Chiralpak IB 1.3 3.96 Hydroxycyclohexyl) (3,5,6-trimethylpyrazin-2- B: 35% MeOH yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.39.120R.* (2S,3R,4S,5R,6R)-2-(((R)-(1- 0.85 571.16 Chiralpak IC 2.23 0.2 Hydroxycyclohexyl)(4-methylisoxazol-3- B: 30% MeOH yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.39.120S.* (2S,3R,4S,5R,6R)-2-(((S)-(1- Chiralpak IC 2.75 14.8 Hydroxycyclohexyl)(4-methylisoxazol-3- B: 30% MeOH yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.44.120R.* (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1- 0.86 607.32 Chiralpak AD-H 1.68 0.11 hydroxycyclohexyl)(4-methylisoxazol-3- B: 40% MeOH yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.44.120S.* (2S,3R,4S,5R,6R)-2-(((S)-(4,4-Difluoro-1- 0.86 607.32 Chiralpak AD-H 1.02 8.27 hydroxycyclohexyl)(4-methylisoxazol-3- B: 40% MeOH yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.44.105. (2S,3R,4S,5R,6R)-2-(((4,4-Difluoro-1- 1.01 644.3 0.14 hydroxycyclohexyl)(2-isopropylphenyl)methyl)thio)- 6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol [1,3-di-deoxy-1-((4,4-difluoro-1-hydroxy- cyclohexan-1-yl)-(2-(-isopropyl)phenyl)methyl- thio)-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl]-β-D-galactopyranoside] 2.44.105R. (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1- 1.00 644.2 Chiralpak AD-H 1.73 0.06 hydroxycyclohexyl)(2-isopropylphenyl)methyl)thio)- B: 35% EtOH 6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol [1,3-di-deoxy-1-((4,4-difluoro-1-hydroxy- cyclohexan-1-yl)-(2-(-isopropyl)phenyl)methyl-(R)- thio)-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl]-β-D-galactopyranoside] 2.44.105S. (2S,3R,4S,5R,6R)-2-(((S)-(4,4-Difluoro-1- 1.01 644.21 Chiralpak AD-H 1.1 0.95 hydroxycyclohexyl)(2-isopropylphenyl)methyl)thio)- B: 35% EtOH 6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.44.119R.* (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1- 0.88 646.19 Chiralpak ID 1.5 0.03 hydroxycyclohexyl)(3,5,6-trimethylpyrazin-2- B: 25% MeOH yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- 4 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.44.119S.* (2S,3R,4S,5R,6R)-2-(((S)-(4,4-Difluoro-1- 0.87 646.2 Chiralpak ID 1.86 0.7 hydroxycyclohexyl)(3,5,6-trimethylpyrazin-2- B: 25% MeOH yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- 4 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.44.125R.* (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1- 0.94 671.18 Chiralpak ID 1.18 0.05 hydroxycyclohexyl)(3-(trifluoromethyl)pyridin-2- B: 30% (1/1) yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- (MeCN/MeOH) trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- 3.5 min run pyran-3,5-diol 2.44.125S.* (2S,3R,4S,5R,6R)-2-(((S)-(4,4-Difluoro-1- 0.94 671.18 Chiralpak ID 1.64 0.82 hydroxycyclohexyl)(3-(trifluoromethyl)pyridin-2- B: 30% (1/1) yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- (MeCN/MeOH) trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- 3.5 min run pyran-3,5-diol 2.44.111R* (2S,3R,4S,5R,6R)-2-(((R)-(2-Chlorophenyl)(4,4- 0.94 636.17 Chiralpak IB 2.42 0.09 difluoro-1-hydroxycyclohexyl)methyl)thio)-6- B: 25% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 3.5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.44.111S * (2S,3R,4S,5R,6R)-2-(((S)-(2-Chlorophenyl)(4,4- 0.96 636.15 Chiralpak IB 2.17 18.4 difluoro-1-hydroxycyclohexyl)methyl)thio)-6- B: 25% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 3.5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.44.112. (2S,3R,4S,5R,6R)-2-(((4,4-Difluoro-1- 0.97 670.12 0.3 hydroxycyclohexyl)(2- (trifluoromethyl)phenyl)methyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.44.112R. (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1- 0.97 670.12 Chiralpak IG 1.33 0.08 hydroxycyclohexyl)(2- B: 35% (trifluoromethyl)phenyl)methyl)thio)-6- MeCN/EtOH/DEA (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- (50:50:0.1) 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 5 min run 2.44.112S. (2S,3R,4S,5R,6R)-2-(((S)-(4,4-Difluoro-1- Chiralpak IG 2.06 19.5 hydroxycyclohexyl)(2- B: 35% (trifluoromethyl)phenyl)methyl)thio)-6- MeCN/EtOH/DEA (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- (50:50:0.1) 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 5 min run 2.44.113. (2S,3R,4S,5R,6R)-2-(((2,3-Dichlorophenyl)(4,4- 670.07 0.98 0.36 difluoro-1-hydroxycyclohexyl)methyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.44.113R. (2S,3R,4S,5R,6R)-2-(((R)-(2,3-Dichlorophenyl)(4,4- 670.04 0.97 Chiralpak AY-H 1.23 0.80 difluoro-1-hydroxycyclohexyl)methyl)thio)-6- B: 30% (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- MeCN/2- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol PrOH/DEA 50:50:0.1 5 min run 2.44.113S. (2S,3R,4S,5R,6R)-2-(((S)-(2,3- 670.05 0.98 Chiralpak AY-H 1.30 57.5 Dichlorophenyl)(4,4-difluoro-1- B: 30% hydroxycyclohexyl)methyl)thio)-6-(hydroxymethyl)- MeCN/2- 4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- PrOH/DEA yl)tetrahydro-2H-pyran-3,5-diol 50:50:0.1 5 min run 2.44.106R.* (2S,3R,4S,5R,6R)-2-(((R)-(2- 641.87 0.97 Chiralpak IA 3.04 0.06 Cyclopropylphenyl)(4,4-difluoro-1- B: 30% (1/1) hydroxycyclohexyl)methyl)thio)-6-(hydroxymethyl)- MeCN/EtOH 4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- 5 min run yl)tetrahydro-2H-pyran-3,5-diol 2.44.106S.* (2S,3R,4S,5R,6R)-2-(((S)-(2- 641.88 0.98 Chiralpak IA 2.18 0.93 Cyclopropylphenyl)(4,4-difluoro-1- B: 30% (1/1) hydroxycyclohexyl)methyl)thio)-6-(hydroxymethyl)- MeCN/EtOH 4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- 5 min run yl)tetrahydro-2H-pyran-3,5-diol 2.41.112. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((4- 0.85 636.08 0.11 hydroxytetrahydro-2H-pyran-4-yl)(2- (trifluoromethyl)phenyl)methyl)thio)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.41.112R. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((R)-(4- 0.85 636.09 Chiralpak IG 1.57 0.08 hydroxytetrahydro-2H-pyran-4-yl)(2- B: 35% (trifluoromethyl)phenyl)methyl)thio)-4-(4-(3,4,5- 2-ProOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- 5 min run pyran-3,5-diol 2.41.112S. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((S)-(4- 0.86 636.08 Chiralpak IG 2.63 6 hydroxytetrahydro-2H-pyran-4-yl)(2- B: 35% (trifluoromethyl)phenyl)methyl)thio)-4-(4-(3,4,5- 2-ProOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- 5 min run pyran-3,5-diol 2.41.125. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((4- 0.82 636.95 0.25 hydroxytetrahydro-2H-pyran-4-yl)(3- (trifluoromethyl)pyridin-2-yl)methyl)thio)-4-(4- (3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3,5-diol 2.41.125R. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((R)-(4- 0.83 636.97 Chiralpak IF 1.55 0.03 hydroxytetrahydro-2H-pyran-4-yl)(3- B: 35% (1/1) (trifluoromethyl)pyridin-2-yl)methyl)thio)-4-(4- MeCN/EtOH (3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- 4 min run yl)tetrahydro-2H-pyran-3,5-diol 2.41.125S. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((S)-(4- 0.81 636.95 Chiralpak IF 2.48 1.83 hydroxytetrahydro-2H-pyran-4-yl)(3- B: 35% (1/1) (trifluoromethyl)pyridin-2-yl)methyl)thio)-4-(4- MeCN/EtOH (3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- 4 min run yl)tetrahydro-2H-pyran-3,5-diol 2.41.119. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((4- 0.74 611.90 0.16 hydroxytetrahydro-2H-pyran-4-yl)(3,5,6- trimethylpyrazin-2-yl)methyl)thio)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.41.119R. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((R)-(4- 0.75 612.13 Chiralpak IC 1.72 0.06 hydroxytetrahydro-2H-pyran-4-yl)(3,5,6- B: 35% (1/1) trimethylpyrazin-2-yl)methyl)thio)-4-(4-(3,4,5- MeCN/EtOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- 4 min run pyran-3,5-diol 2.41.119S. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((S)-(4- 0.74 612.13 Chiralpak IC 2.49 2.99 hydroxytetrahydro-2H-pyran-4-yl)(3,5,6- B: 35% (1/1) trimethylpyrazin-2-yl)methyl)thio)-4-(4-(3,4,5- MeCN/EtOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- 4 min run pyran-3,5-diol 2.40.112. (2S,3R,4S,5R,6R)-2-(((4-Hydroxy-1- 0.71 649.11 0.13 methylpiperidin-4-yl)(2- (trifluoromethyl)phenyl)methyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.40.112R. (2S,3R,4S,5R,6R)-2-(((R)-(4-Hydroxy-1- 0.72 648.99 Chiralpak ID 2.17 0.06 methylpiperidin-4-yl)(2- B: 30% (1/1/0.1) (trifluoromethyl)phenyl)methyl)thio)-6- (DCM/MeOH/ (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- DEA) 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 5 min run 2.40.112S. (2S,3R,4S,5R,6R)-2-(((S)-(4-Hydroxy-1- 0.70 649.02 Chiralpak ID 2.87 3.95 methylpiperidin-4-yl)(2- B: 30% (1/1/0.1) (trifluoromethyl)phenyl)methyl)thio)-6- (DCM/MeOH/ (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- DEA) 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 5 min run 2.40.125. (2S,3R,4S,5R,6R)-2-(((4-Hydroxy-1- 0.65 649.96 0.2 methylpiperidin-4-yl)(3-(trifluoromethyl)pyridin-2- yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.40.125R. (2S,3R,4S,5R,6R)-2-(((R)-(4-Hydroxy-1- 0.67 650.32 Chiralpak IB 2.61 0.02 methylpiperidin-4-yl)(3-(trifluoromethyl)pyridin-2- B: 35% yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- EtOH, 0.1% trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- DEA pyran-3,5-diol 5 min run 2.40.125S. (2S,3R,4S,5R,6R)-2-(((S)-(4-Hydroxy-1- 0.65 650.32 Chiralpak IB 1.94 3.65 methylpiperidin-4-yl)(3-(trifluoromethyl)pyridin-2- B: 35% yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- EtOH, 0.1% trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- DEA pyran-3,5-diol 5 min run *Epimers are obtained from the chiral separation of the corresponding thioquinoline intermediates according to the procedures described for Example 2.31.118R. and Example 2.31.118S..

Example 2.40.119

(2S,3R,4S,5R,6R)-2-(((4-Hydroxy-1-methylpiperidin-4-yl)(3,5,6-trimethylpyrazin-2-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol [1,3-di-deoxy-1-((1-methyl-4-hydroxy-piperidin-4-yl)-(3,5,6-trimethylpyrazin-2-yl)methyl-thio)-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside]

[0689] Example 2.40.119 is synthesized from Intermediate 3 and Intermediate 5.

1. (2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-6-(((4-hydroxy-1-methylpiperidin-4-yl)(3,5,6-trimethylpyrazin-2-yl)methyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate

[0690] To a solution of Intermediate 3 (0.80 g, 1.45 mmol) in EA (20.0 mL) are added Intermediate 5 (0.480 g, 1.71 mmol, 1.17 eq), TBAB (0.12 g, 0.36 mmol, 0.25 eq) and aq. 1M Na.sub.2CO.sub.3 (10.0 mL) at rt. The reaction mixture is stirred at rt for 48 h, diluted with EA, followed by water, then brine. The phases are separated and the aq. layer is extracted with EA (3×). The combined organic layer is dried over MgSO.sub.4, filtered and solvent removed in vacuo to give a beige solid, that is purified by preparative HPLC/MS(I) to give the title compound as a white solid (0.33 g, 30%). LC-MS (A): t.sub.R=0.82 min; [M+H].sup.+: 751.27.

2. (2S,3R,4S,5R,6R)-2-(((4-Hydroxy-1-methylpiperidin-4-yl)(3,5,6-trimethylpyrazin-2-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol (2.40.119.)

[0691] K.sub.2CO.sub.3 (0.012 g, 0.09 mmol, 0.2 eq) is added to a solution of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(((4-hydroxy-1-methylpiperidin-4-yl)(3,5,6-trimethylpyrazin-2-yl)methyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate (0.33 g, 0.44 mmol) in MeOH (3.0 mL) at rt. The reaction mixture is stirred at rt for 1 h, quenched by the addition of MeCN and water and the mixture is directly purified by preparative HPLC/MS(I) to yield the title compound as a white solid (0.21 g, 75%). LC-MS (A): t.sub.R=0.63 min; [M+H].sup.+: 625.06. .sup.1H NMR (400 MHz, MeOD) δ: 8.53 (s, 1H), 7.65 (dd, J.sub.1=7.6 Hz, J.sub.2=7.6 Hz, 2H), 4.79 (dd, J.sub.1=2.8 Hz, J.sub.2=10.7 Hz, 1H), 4.55 (s, 1H), 4.47 (d, J=9.4 Hz, 1H), 4.24 (t, J=10.0 Hz, 1H), 4.11 (d, J=2.6 Hz, 1H), 3.68 (m, 3H), 2.71 (d, J=11.5 Hz, 1H), 2.64 (s, 3H), 2.57-2.61 (m, 1H), 2.53 (s, 6H), 2.38-2.46 (m, 2H), 2.30 (s, 3H), 2.25 (bd, J=13.8 Hz, 1H), 1.85-1.94 (m, 1H), 1.71-1.81 (m, 1H), 1.45 (dd, J.sub.1=1.5 Hz, J.sub.2=13.7 Hz, 1H).

Example 2.40.119R

(2S,3R,4S,5R,6R)-2-(((R)-(4-Hydroxy-1-methylpiperidin-4-yl)(3,5,6-trimethylpyrazin-2-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol [1,3-di-deoxy-1-((1-methyl-4-hydroxy-piperidin-4-yl)-(3,5,6-trimethylpyrazin-2-yl)methyl-(R)-thio)-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside]

[0692] Separation of the epimers of Example 2.40.119. (0.017 g) by chiral preparative HPLC (V) yielded the title compound (0.006 g) as a white solid. Chiral analytical HPLC (L): t.sub.R=1.7 min.

Example 2.40.119S

(2S,3R,4S,5R,6R)-2-(((S)-(4-Hydroxy-1-methylpiperidin-4-yl)(3,5,6-trimethylpyrazin-2-yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol [1,3-di-deoxy-1-((1-methyl-4-hydroxy-piperidin-4-yl)-(3,5,6-trimethylpyrazin-2-yl)methyl-(S)-thio)-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside]

[0693] Separation of the epimers of Example 2.40.119. (0.017 g) by chiral preparative HPLC (V) yielded the title compound (0.006 g) as a white solid. Chiral analytical HPLC (L): t.sub.R=2.4 min.

[0694] Following examples are prepared starting from o-substituted bromomethyl heteroaryls, the corresponding cyclic ketons and Intermediate 3 according to the procedures described for Example 2.40.119. LC-MS and Gal-3 inhibition data are listed in Table 6 below. The LC-MS conditions used were LC-MS (A). Chiral analytical HPLC (I) (conditions and retention time) and inhibition data of the epimers R and S of selected Examples are also listed.

TABLE-US-00011 TABLE 6 t.sub.R t.sub.R HPLC chiral IC.sub.50 Example Name [min] [M + H].sup.+ conditions [min] [uM] 2.40.119. (2S,3R,4S,5R,6R)-2-(((4-Hydroxy-1- 0.65 625.07 0.10 methylpiperidin-4-yl) (3,5,6-trimethylpyrazin-2- yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-3,5-diol 2.40.119R. (2S,3R,4S,5R,6R)-2-(((R)-(4-Hydroxy-1- 0.64 625.07 Chiralpak IB 2.41 0.05 methylpiperidin-4-yl) (3,5,6-trimethylpyrazin-2- B: 25% yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- MeOH, 0.1% trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- DEA 2H-pyran-3,5-diol 5 min run 2.40.119S. (2S,3R,4S,5R,6R)-2-(((S)-(4-Hydroxy-1- 0.63 625.06 Chiralpak IB 1.9 3.04 methylpiperidin-4-yl) (3,5,6-trimethylpyrazin-2- B: 25% yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- MeOH, 0.1% trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- DEA 2H-pyran-3,5-diol 5 min run 2.38.125. (2S,3R,4S,5R,6R)-2-((1-Hydroxycyclopentyl)(3- 0.89 621.15 0.13 (trifluoromethyl)pyridin-2-yl)methyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.38.125R. (2S,3R,4S,5R,6R)-2-(((R)-(1- 0.91 621.16 Chiralpak IC 2.4 0.08 Hydroxycyclopentyl)(3-(trifluoromethyl)pyridin-2- B: 25% MeOH yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-3,5-diol 2.38.125S. (2S,3R,4S,5R,6R)-2-(((S)-(1- 0.90 621.17 Chiralpak IC 1.2 5.62 Hydroxycyclopentyl)(3-(trifluoromethyl)pyridin-2- B: 25% MeOH yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-3,5-diol 2.44.126. (2S,3R,4S,5R,6R)-2-(((4,4-Difluoro-1- 0.71 617.18 0.06 hydroxycyclohexyl)(3-methylpyridin-2- yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-3,5-diol 2.44.126R. (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1- 0.72 617.19 Chiralcel 1.97 0.04 hydroxycyclohexyl)(3-methylpyridin-2- OJ-H yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- B: 20% (1/1) trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- MeCN/EtOH 2H-pyran-3,5-diol 5 min run 2.44.126S. (2S,3R,4S,5R,6R)-2-(((S)-(4,4-Difluoro-1- 0.72 617.21 Chiralcel 1.42 3.35 hydroxycyclohexyl)(3-methylpyridin-2- OJ-H yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- B: 20% (1/1) trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- MeCN/EtOH 2H-pyran-3,5-diol 5 min run 2.44.129. (2S,3R,4S,5R,6R)-2-(((4,4-Difluoro-1- 0.83 618.19 0.09 hydroxycyclohexyl)(3-methylpyrazin-2- yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-3,5-diol 2.44.129R. (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1- 0.83 618.16 Chiracel 2.23 0.03 hydroxycyclohexyl)(3-methylpyrazin-2- OJ-H yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- B: 18% EtOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 3.5 min run 2H-pyran-3,5-diol 2.44.129S. (2S,3R,4S,5R,6R)-2-(((S)-(4,4-Difluoro-1- 0.83 618.16 Chiracel 1.53 1.48 hydroxycyclohexyl)(3-methylpyrazin-2- OJ-H yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- B: 18% EtOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 3.5 min run 2H-pyran-3,5-diol 2.44.130. (2S,3R,4S,5R,6R)-2-(((5-Cyclopropyl-4- 0.96 661.19 0.06 ethylisoxazol-3-yl)(4,4-difluoro-1- hydroxycyclohexyl)methyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.44.130R. (2S,3R,4S,5R,6R)-2-(((R)-(5-Cyclopropyl-4- 0.96 661.19 Chiracel 2.91 0.02 ethylisoxazol-3-yl)(4,4-difluoro-1- OJ-H hydroxycyclohexyl)methyl)thio)-6- B: 15% (1/1) (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- MeCN/MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 5 min run 2.44.130S. (2S,3R,4S,5R,6R)-2-(((S)-(5-Cyclopropyl-4- 0.96 661.19 Chiracel 1.92 1.85 ethylisoxazol-3-yl)(4,4-difluoro-1- OJ-H hydroxycyclohexyl)methyl)thio)-6- B: 15% (1/1) (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- MeCN/MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 5 min run 2.44.131. (2S,3R,4S,5R,6R)-2-(((5-Cyclopropyl-4- 1.02 690.11 0.11 isobutylisoxazol-3-yl)(4,4-difluoro-1- hydroxycyclohexyl)methyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.44.131 R. (2S,3R,4S,5R,6R)-2-(((R)-(5-Cyclopropyl-4- 1.01 689 Chiracel 1.98 0.05 isobutylisoxazol-3-yl)(4,4-difluoro-1- OJ-H hydroxycyclohexyl)methyl)thio)-6- B: 15% MeOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.44.131S. (2S,3R,4S,5R,6R)-2-(((S)-(5-Cyclopropyl-4- 1.02 688.99 Chiracel 1.35 9.74 isobutylisoxazol-3-yl)(4,4-difluoro-1- OJ-H hydroxycyclohexyl)methyl)thio)-6- B: 15% MeOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.44.132. (2S,3R,4S,5R,6R)-2-(((4,4-Difluoro-1- 0.77 645.21 0.1 hydroxycyclohexyl)(3-isopropylpyridin-2- yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-3,5-diol 2.44.132R. (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1- 0.77 645.21 Chiracel 1.85 0.05 hydroxycyclohexyl)(3-isopropylpyridin-2- OD-H yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- B: 30% (1/1) trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- MeCN/EtOH 2H-pyran-3,5-diol 5 min run 2.44.132S. (2S,3R,4S,5R,6R)-2-(((S)-(4,4-Difluoro-1- 0.78 645.21 Chiracel 1.29 2.27 hydroxycyclohexyl)(3-isopropylpyridin-2- OD-H yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- B: 30% (1/1) trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- MeCN/EtOH 2H-pyran-3,5-diol 1:1 5 min run 2.44.133. (2S,3R,4S,5R,6R)-2-(((3-Chloropyrazin-2-yl)(4,4- 0.85 638.14 0.04 difluoro-1-hydroxycyclohexyl)methyl)thio)-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.44.133R. (2S,3R,4S,5R,6R)-2-(((R)-(3-Chloropyrazin-2- 0.86 638.14 Regis (R,R) 2.2 0.02 yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)- Whelk-O1 6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 25% (1/1) 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol MeCN/EtOH 5 min run 2.44.133S. (2S,3R,4S,5R,6R)-2-(((S)-(3-Chloropyrazin-2- 0.86 638.15 Regis (R,R) 1.79 1.83 yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)- Whelk-O1 6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 25% (1/1) 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol MeCN/EtOH 1:1 5 min run 2.44.134. (2S,3R,4S,5R,6R)-2-(((3-Cyclopropylpyridin-2- 0.75 643.21 0.07 yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)- 6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.44.134R. (2S,3R,4S,5R,6R)-2-(((R)-(3-Cyclopropylpyridin- 0.75 643.21 Chiralpak ID 2.85 0.01 2-yl)(4,4-difluoro-1- B: 20% (1/1) hydroxycyclohexyl)methyl)thio)-6- MeCN/EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.44.134S. (2S,3R,4S,5R,6R)-2-(((S)-(3-Cyclopropylpyridin- 0.74 643.3 Chiralpak ID 3.55 0.7 2-yl)(4,4-difluoro-1- B: 20% (1/1) hydroxycyclohexyl)methyl)thio)-6- MeCN/EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 2.44.135. (2S,3R,4S,5R,6R)-2-(((4,4-Difluoro-1- 0.77 618.21 0.07 hydroxycyclohexyl)(4-methylpyridazin-3- yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-3,5-diol 2.44.135R. (2S,3R,4S,5R,6R)-2-(((R)-(4,4-Difluoro-1- 0.79 618.2 Chiralpak ID 1.63 0.04 hydroxycyclohexyl)(4-methylpyridazin-3- B: 35% (1/1) yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- MeCN/EtOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 5 min run 2H-pyran-3,5-diol 2.44.135S. (2S,3R,4S,5R,6R)-2-(((S)-(4,4-Difluoro-1- 0.77 618.22 Chiralpak ID 1.19 2.79 hydroxycyclohexyl)(4-methylpyridazin-3- B: 35% (1/1) yl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5- MeCN/EtOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 5 min run 2H-pyran-3,5-diol 2.66.120. 4-((((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.72 621.08 0.14 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(4- methylisoxazol-3-yl)methyl)-4-hydroxytetrahydro- 2H-thiopyran 1,1-dioxide 2.66.120R. 4-((R)-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.72 621.12 Chiracel 1.23 0.03 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- OJ-H 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(4- B: 20% EtOH methylisoxazol-3-yl)methyl)-4-hydroxytetrahydro- 5 min run 2H-thiopyran 1,1-dioxide 2.66.120S. 4-((S)-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.73 621.11 Chiracel 2.17 4.57 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- OJ-H 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(4- B: 20% EtOH methylisoxazol-3-yl)methyl)-4-hydroxytetrahydro- 5 min run 2H-thiopyran 1,1-dioxide 2.66.126R. 4-((R)-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.63 631.14 Chiracel 1.26 0.02 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- OJ-H 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(3- B: 20% EtOH methylpyridin-2-yl)methyl)-4-hydroxytetrahydro- 5 min run 2H-thiopyran 1,1-dioxide 2.66.126S. 4-((S)-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.62 631.16 Chiracel 1.99 2.0 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- OJ-H 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(3- B: 20% EtOH methylpyridin-2-yl)methyl)-4-hydroxytetrahydro- 5 min run 2H-thiopyran 1,1-dioxide 2.41.126. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((4- 0.6 583.2 0.08 hydroxytetrahydro-2H-pyran-4-yl)(3- methylpyridin-2-yl)methyl)thio)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-3,5-diol 2.41.126R. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((R)-(4- 0.61 583.19 Chiralpak IC 1.2 0.03 hydroxytetrahydro-2H-pyran-4-yl)(3- B: 50% (1/1) methylpyridin-2-yl)methyl)thio)-4-(4-(3,4,5- MeCN/EtOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 5 min run 2H-pyran-3,5-diol 2.41.126S. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((S)-(4- 0.6 583.2 Chiralpak IC 1.66 2.25 hydroxytetrahydro-2H-pyran-4-yl)(3- B: 50% (1/1) methylpyridin-2-yl)methyl)thio)-4-(4-(3,4,5- MeCN/EtOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 5 min run 2H-pyran-3,5-diol

Example 2.45.112

(2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((4-hydroxypiperidin-4-yl)(2-(trifluoromethyl)phenyl)methyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol

[0695] Intermediate 8 (0.023 g, 0.03 mmol) is dissolved in MeOH (1.0 mL) and K.sub.2CO.sub.3 (0.004 g, 0.03 mmol, 1.0 eq) is added. The reaction mixture is stirred at rt for 17 h. The crude material is directly purified by preparative HPLC/MS(I) to yield the title product as a white solid (0.003 g, 17%). LC-MS (A): t.sub.R=0.69 min; [M+H].sup.+: 635.3.

Example 2.46.112

(2S,3R,4S,5R,6R)-2-(((4-Hydroxy-1-(methylsulfonyl)piperidin-4-yl)(2-(trifluoromethyl)phenyl) methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol

1. (2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-6-(((4-hydroxy-1-(N-methylsulfamoyl)piperidin-4-yl)(2-(trifluoromethyl)phenyl)methyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate

[0696] Methylsulfamoyl chloride (0.007, 0.06 mmol, 1.0 eq) and DIPEA (0.03 mL, 0.17 mmol, 3.0 eq) are added to a solution of Intermediate 8 (0.044 g, 0.06 mmol) in DCM (2.0 mL) at rt. The reaction mixture is stirred at rt for 48 h, partitioned between DCM and water, the layers are separated, the aqueous layer is extracted with DCM (3×). The combined organic layer is dried over MgSO.sub.4, filtered and solvent removed in vacuo to give a colorless oil. The crude material is purified by preparative HPLC/MS(I) to give the title compound as a white solid (0.007 g, 14%). LC-MS (A): t.sub.R=1.05 min; [M+H].sup.+: 853.98.

2. 4-((((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2-(trifluoromethyl)phenyl)methyl)-4-hydroxy-N-methylpiperidine-1-sulfonamide (2.46.112.)

[0697] To a solution of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(((4-hydroxy-1-(N-methylsulfamoyl)piperidin-4-yl)(2-(trifluoromethyl)phenyl)methyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate (0.007 g, 0.008 mmol) in MeOH (1.0 mL) is added K.sub.2CO.sub.3 (0.002 g, 0.0002 mmol, 0.2 eq) at rt. The reaction mixture is stirred at rt for 17 h, diluted with MeCN, followed by water and the mixture is directly purified by preparative HPLC/MS(I). The title compound is obtained as a white solid (0.003 g, 52%). LC-MS (A): t.sub.R=0.86 min; [M+H].sup.+: 727.94.

Example 2.47.112

(2S,3R,4S,5R,6R)-2-(((4-Hydroxy-1-(methylsulfonyl)piperidin-4-yl)(2-(trifluoromethyl)phenyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol

[0698] Example 2.47.112. is synthesized from Intermediate 8 and methanesulfonyl chloride in analogy to Example 2.46.112. LC-MS (A): t.sub.R=0.86 min; [M+H].sup.+: 712.9.

Example 2.47.112R

(2S,3R,4S,5R,6R)-2-(((R)-(4-Hydroxy-1-(methylsulfonyl)piperidin-4-yl)(2-(trifluoromethyl)phenyl)methyl)thio)-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol [1,3-di-deoxy-1-((1-methylsulfonyl-4-hydroxy-piperidin-4-yl)-(2-(trifluoromethyl)phenyl)methyl-(R)-thio)-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-β-D-galactopyranoside]

[0699] Example 2.47.112R. is synthesized from Intermediate 8R and methanesulfonyl chloride in analogy to Example 2.47.112. LC-MS (A): t.sub.R=0.86 min; [M+H].sup.+: 713.19. .sup.1H NMR (400 MHz, MeOD) δ: 8.49 (s, 1H), 8.17 (d, J=7.9 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.64 (m, 3H), 7.46 (t, J=7.7 Hz, 1H), 4.71 (dd, J.sub.1=3.0 Hz, J.sub.2=10.5 Hz, 1H), 4.62 (s, 1H), 4.37 (d, J=9.5 Hz, 1H), 4.21 (t, J=10.3 Hz, 1H), 4.16 (d, J=2.8 Hz, 1H), 3.78-3.80 (m, 2H), 3.67 (t, J=6.3 Hz, 1H), 3.58-3.64 (m, 1H), 3.42-3.47 (m, 1H), 3.05 (td, J.sub.1=2.5 Hz, J.sub.2=12.5 Hz, 1H), 2.94 (td, J.sub.1=2.3 Hz, J.sub.2=12.0 Hz, 1H), 2.83 (s, 3H), 2.54 (dd, J.sub.1=2.5 Hz, J.sub.2=14.1 Hz, 1H), 1.2 (dd, J.sub.1=2.4 Hz, J.sub.2=13.7 Hz, 1H), 1.64-1.79 (m, 2H). Chiral analytical HPLC (L): t.sub.R=1.7 min.

Example 2.48.112

1-(4-((((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2-(trifluoromethyl)phenyl)methyl)-4-hydroxypiperidin-1-yl)ethan-1-one

[0700] Example 2.48.112. is obtained as a side-product during the preparation of Example 2.47.112. LC-MS (A): t.sub.R=0.84 min; [M+H].sup.+: 676.96.

Example 2.49.112R

N-Cyclopropyl-4-((R)-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2-(trifluoromethyl)phenyl)methyl)-4-hydroxypiperidine-1-carboxamide

[0701] Example 2.49.112R. is prepared from Intermediate 8R and isocyanato cyclopropane in analogy to Example 2.46.112. as a white powder. LC-MS (A): t.sub.R=0.89 min; [M+H].sup.+: 693.23. LC-MS (A): t.sub.R=0.84 min; [M+H].sup.+: 718.0. Chiral analytical HPLC (G): t.sub.R=1.84 min. .sup.1H NMR (400 MHz, MeOD) δ: 8.49 (s, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.70-7.59 (m, 4H), 7.44 (t, J=7.7 Hz, 1H), 4.70 (dd, J.sub.1=10.5 Hz, J.sub.2=3.0 Hz, 1H), 4.58 (s, 1H), 4.34 (d, J=9.5 Hz, 1H), 4.2 (t, J=10.0 Hz, 1H), 4.15 (d, J=2.8 Hz, 1H), 3.92-3.85 (m, 1H), 3.78-3.75 (m, 1H), 3.74-3.68 (m, 1H), 3.65 (t, J=3.65 Hz, 1H), 3.08 (td, J.sub.1=13.5 Hz, J.sub.2=3.0 Hz, 1H), 2.96 (td, J.sub.1=13.5 Hz, J.sub.2=3.0 Hz, 1H), 2.53 (m, 1H), 2.38 (dd, J.sub.1=13.6 Hz, J.sub.2=2.2 Hz, 1H), 1.55 (m, 2H), 1.06 (dd, J.sub.1=13.6 Hz, J.sub.2=2.1 Hz, 1H), 0.65 (m, 2H), 0.44 (m, 2H).

Example 2.50.112R

Methyl 4-((R)-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2-(trifluoromethyl)phenyl)methyl)-4-hydroxypiperidine-1-carboxylate

[0702] Example 2.50.112. is prepared from Intermediate 8R and methyl chloroformate in analogy to Example 2.46.112. as a white powder. LC-MS (A): t.sub.R=0.89 min; [M+H].sup.+: 693.23. .sup.1H NMR (400 MHz, MeOD) δ: 8.49 (s, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.62-7.66 (m, 3H), 7.46 (t, J=7.7 Hz, 1H), 4.70 (dd, J.sub.1=3.0 Hz, J.sub.2=10.5 Hz, 1H), 4.58 (s, 1H), 4.34 (d, J=9.5 Hz, 1H), 4.20 (t, J=10.1 Hz, 1H), 4.15 (d, J=2.8 Hz, 1H), 4.01 (bd, J=13.3 Hz, 1H), 3.85 (bd, J=13.8 Hz, 1H), 3.75-3.80 (m, 2H), 3.69 (s, 3H), 3.65 (t, J=6.3 Hz, 1H), 2.92-3.23 (m, 2H), 2.43 (d, J=13.8 Hz, 1H), 1.47-1.62 (m, 2H), 1.08 (d, J=14.0 Hz, 1H).

[0703] Following examples are prepared starting from Intermediate 8, Intermediate 8R or Intermediate 8A in analogy to the procedures described above. LC-MS and Gal-3 inhibition data are listed in Table 7 below. The LC-MS conditions used were LC-MS (A). Chiral analytical HPLC (I) (conditions and retention time) and inhibition data of the epimers R and S of selected Examples are also listed.

TABLE-US-00012 TABLE 7 t.sub.R t.sub.R HPLC chiral IC.sub.50 Example Name [min] [M + H].sup.+ conditions [min] [uM] 2.45.112. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)-6-(((4- 0.69 635.3 0.13 hydroxypiperidin-4-yl)(2- (trifluoromethyl)phenyl)methyl)thio)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3,5-diol 2.46.112. 4-((((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)- 0.86 727.94 0.05 4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-2-yl)thio)(2- (trifluoromethyl)phenyl)methyl)-4-hydroxy-N- methylpiperidine-1-sulfonamide 2.47.112. (2S,3R,4S,5R,6R)-2-(((4-Hydroxy-1- 0.86 712.9 0.07 (methylsulfonyl)piperidin-4-yl)(2- (trifluoromethyl)phenyl)methyl)thio)-6-(hydroxymethyl)-4- (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-3,5-diol 2.47.112R.* (2S,3R,4S,5R,6R)-2-(((R)-(4-Hydroxy-1- 0.86 713.19 Chiralpak IB 3.07 0.03 (methylsulfonyl)piperidin-4-yl)(2- B: 25% EtOH (trifluoromethyl)phenyl)methyl)thio)-6-(hydroxymethyl)-4- 5 min run (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-3,5-diol 2.47.112S.* (2S,3R,4S,5R,6R)-2-(((S)-(4-Hydroxy-1- 0.86 713.19 Chiralpak IB 2.62 2.82 (methylsulfonyl)piperidin-4-yl)(2- B: 25% EtOH (trifluoromethyl)phenyl)methyl)thio)-6-(hydroxymethyl)-4- 5 min run (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-3,5-diol 2.48.112. 1-(4-((((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.84 676.96 0.22 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3- triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2- (trifluoromethyl)phenyl)methyl)-4-hydroxypiperidin-1- yl)ethan-1-one 2.49.112R.* N-Cyclopropyl-4-((R)-(((2S,3R,4S,5R,6R)-3,5-dihydroxy- 0.84 718.0 Chiralpak IE 3.18 0.05 6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3- B: 45% (1/1) triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2- MeCN/EtOH (trifluoromethyl)phenyl)methyl)-4-hydroxypiperidine-1- 5 min run carboxamide 2.49.112S.* N-Cyclopropyl-4-((S)-(((2S,3R,4S,5R,6R)-3,5-dihydroxy- 0.84 718.0 Chiralpak IE 2.53 3.06 6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3- B: 45% (1/1) triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2- MeCN/EtOH (trifluoromethyl)phenyl)methyl)-4-hydroxypiperidine-1- 5 min run carboxamide 2.50.112R.* Methyl 4-((R)-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- 0.89 693.23 Chiralcel 1.7 0.08 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3- OD-H triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2- B: 30% (trifluoromethyl)phenyl)methyl)-4-hydroxypiperidine-1- MeOH carboxylate 3 min run 2.50.112S.* Methyl 4-((S)-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- 0.89 693.23 Chiralcel 2.2 7.7 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3- OD-H triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2- B: 30% (trifluoromethyl)phenyl)methyl)-4-hydroxypiperidine-1- MeOH carboxylate 3 min run 2..57.112. (2S,3R,4S,5R,6R)-2-(((3-Hydroxy-1- 0.85 685.12 0.22 (methylsulfonyl)azetidin-3-yl)(2- (trifluoromethyl)phenyl)methyl)thio)-6-(Hydroxymethyl)-4- (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-3,5-diol 2..57.112R. (2S,3R,4S,5R,6R)-2-(((R)-(3-Hydroxy-1- Chiralpak IB 1.6 0.17 (methylsulfonyl)azetidin-3-yl)(2- B: 35% (1/1) (trifluoromethyl)phenyl)methyl)thio)-6-(hydroxymethyl)-4- MeCN/EtOH (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 5 min run 2H-pyran-3,5-diol 2..57.112S. (2S,3R,4S,5R,6R)-2-(((S)-(3-Hydroxy-1- Chiralpak IB 1.21 5.8 (methylsulfonyl)azetidin-3-yl)(2- B: 35% (1/1) (trifluoromethyl)phenyl)methyl)thio)-6-(hydroxymethyl)-4- MeCN/EtOH (4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 5 min run 2H-pyran-3,5-diol 2..58.112. Methyl 3-((((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- 0.86 665.15 0.4 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3- triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2- (trifluoromethyl)phenyl)methyl)-3-hydroxyazetidine-1- carboxylate 2..59.11.2 N-Cyclopropyl-3-((((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- 0.81 690.05 0.29 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3- triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2- (trifluoromethyl)phenyl)methyl)-3-hydroxyazetidine-1- carboxamide *Epimers are obtained from Intermediate 8R and Intermediate 8S.

Example 3.31.112

(2S,3R,4S,5R,6R)-4-(4-(3,5-Difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-((2-hydroxy-2-methyl-1-(2-(trifluoromethyl)phenyl)propyl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol

1. (2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-6-((2-hydroxy-2-methyl-1-(2-(trifluoromethyl)phenyl)propyl)thio)tetrahydro-2H-pyran-3,5-diyl diacetate

[0704] The triazole synthesis is conducted on a commercial continuous-flow reactor (Vapourtec) using a copper coil (10.0 mL internal volume) and a back-pressure regulator (6.0 bar). Intermediate 9 (0.062 g, 0.11 mmol) is dissolved in THF (2.0 mL), followed by the addition of the 5-ethynyl-1,3-difluoro-2-methylbenzene (4.41 mg, 0.11 mmol, 1 eq) and DIPEA (0.056 mL, 0.33 mmol, 3.0 eq). The mixture is pumped at a flow rate of 0.4 mL/min through the coil, which is kept at a temperature of 90° C. The reactor outlet is collected and concentrated under reduced pressure on a GeneVac EZ-2 Elite (40° C., 0 mbar, overnight) to obtain the crude, that is purified by preparative HPLC/MS (I) to give the title compound (0.033 g, 42%). LC-MS (A): t.sub.R=1.1 min; [M+H].sup.+: 716.16.

2. (2S,3R,4S,5R,6R)-4-(4-(3,5-Difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(((R)-2-hydroxy-2-methyl-1-(2-(trifluoromethyl)phenyl)propyl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol (3.31.112.)

[0705] (2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-4-(4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-6-((2-hydroxy-2-methyl-1-(2-(trifluoromethyl)phenyl)propyl)thio)tetrahydro-2H-pyran-3,5-diyl diacetate (0.033 g, 0.0461 mmol) is dissolved in MeOH (2.0 mL) and K.sub.2CO.sub.3 (0.001 g, 0.009 mmol, 0.2 eq) is added at rt. The reaction mixture is stirred at rt for 2 h, quenched with MeCN, followed by water and the mixture is directly purified by preparative HPLC/MS(I) to yield a white solid (0.022 g, 82%) as the title compound. LC-MS (A): t.sub.R=0.9 min; [M+H].sup.+: 590.24.

Example 3.31.112R

(2S,3R,4S,5R,6R)-4-(4-(3,5-Difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(((R)-2-hydroxy-2-methyl-1-(2-(trifluoromethyl)phenyl)propyl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol

[0706] Separation of the epimers Example 3.31.112. (0.022 g) by chiral preparative HPLC (VI), followed by preparative HPLC/MS (I), yielded the title compound (0.006 g) as a white solid. Chiral analytical HPLC (M): t.sub.R=1.67 min. .sup.1H NMR (400 MHz, MeOD) δ: 8.45 (s, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 7.39-7.46 (m, 3H), 4.7-4.66 (m, 2H), 4.18-4.27 (m, 2H), 4.15 (d, J=2.8 Hz, 1H), 3.77 (m, 2H), 3.63 (t, J=6.4 Hz, 1H), 2.22 (s, 3H), 1.52 (s, 3H), 1.09 (s, 3H).

Example 3.31.112S

(2S,3R,4S,5R,6R)-4-(4-(3,5-Difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(((S)-2-hydroxy-2-methyl-1-(2-(trifluoromethyl)phenyl)propyl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol

[0707] Separation of the epimers Example 3.31.112. (0.022 g) by chiral preparative HPLC (VI), followed by preparative HPLC/MS (I), yielded the title compound (0.004 g) as a white solid. Chiral analytical HPLC (M): t.sub.R=1.34 min.

[0708] Following examples are prepared starting from Intermediate 9 and the corresponding alkyne, in analogy to Example 3.31.112. LC-MS and Gal-3 inhibition data are listed in Table 8 below. The LC-MS conditions used were LC-MS (A). Chiral analytical HPLC (I) (conditions and retention time) and inhibition data of the epimers R and S of selected Examples are also listed.

TABLE-US-00013 TABLE 8 t.sub.R t.sub.R HPLC chiral IC.sub.50 Example Name [min] [M + H].sup.+ conditions [min] [uM] 3.31.112. (2S,3R,4S,5R,6R)-4-(4-(3,5-Difluoro-4- 0.9 590.24 0.21 methylphenyl)-1H-1,2,3-triazol-1-yl)-2-((2- hydroxy-2-methyl-1-(2- (trifluoromethyl)phenyl)propyl)thio)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,5-diol 3.31.112R. (2S,3R,4S,5R,6R)-4-(4-(3,5-Difluoro-4- 0.9 590.28 Chiralpak IB 1.67 0.15 methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(((R)-2- B: 30% hydroxy-2-methyl-1-(2- MeOH, 0.1% (trifluoromethyl)phenyl)propyl)thio)-6- DEA (hydroxymethyl)tetrahydro-2H-pyran-3,5-diol 5 min run 3.31.112S. (2S,3R,4S,5R,6R)-4-(4-(3,5-Difluoro-4- 0.9 590.28 Chiralpak IB 1.34 4.85 methylphenyl)-1H-1,2,3-triazol-1-yl)-2-(((S)-2- B: 30% hydroxy-2-methyl-1-(2- MeOH, 0.1% (trifluoromethyl)phenyl)propyl)thio)-6- DEA (hydroxymethyl)tetrahydro-2H-pyran-3,5-diol 5 min run 4.31.112 (2S,3R,4S,5R,6R)-2-((2-Hydroxy-2-methyl-1- 0.89 590.27 2.24 (2-(trifluoromethyl)phenyl)propyl)thio)-6- (hydroxymethyl)-4-(4-(naphthalen-2-yl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diol 5.31.112. 4-(1-((2S,3R,4S,5R,6R)-3,5-Dihydroxy-2-((2- 0.85 583.24 1.5 hydroxy-2-methyl-1-(2- (trifluoromethyl)phenyl)propyl)thio)-6- (hydroxymethyl)tetrahydro-2H-pyran-4-yl)-1H- 1,2,3-triazol-4-yl)-2-fluorobenzonitrile

Example 2.44.126R.I

(2R,3R,4S,5R,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol [1,3-di-deoxy-1-((4,4-difluoro-1-hydroxy-cyclohexan-1-yl)-(3-(-methyl)pyridin-2-yl)methyl-(R)-thio)-2-O-methyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-b-D-galactopyranoside]

[0709] Example 2.44.126R.I. is synthesized from Example 2.44.126R. as described below.

1. (4aR,6S,7R,8R,8aR)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-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

[0710] A mixture of Example 2.44.126R. (0.26 g, 0.43 mmol), 2,2-dimethoxypropane (0.3 mL, 2.35 mmol, 5.5 eq), acetone (0.7 mL) and CSA (0.05 g, 0.21 mmol, 0.5 eq) in THF (4.0 mL) is heated at 60° C. for 6 h, then at rt for 15 h and again at 60° C. for 6 h. The reaction mixture is partitioned between EA and aq. sat. NaHCO.sub.3, the layers are separated and the aqueous layer is extracted with EA (3×). The combined organic layer is washed with brine, dried over MgSO.sub.4, filtered and the solvent removed in vacuo to give the title compound as a white solid (0.28 g, >99%), that is used without further purification. LC-MS (A): t.sub.R=0.88 min; [M+H].sup.+: 657.92.

2. 4,4-Difluoro-1-((R)-(((4aR,6S,7R,8S,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)thio)(3-methylpyridin-2-yl)methyl)cyclohexan-1-ol

[0711] To a stirred solution of (4aR,6S,7R,8R,8aR)-6-(((R)-(4,4-difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-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 (0.26 g, 0.4 mmol) in DMF (3.0 mL) is added MeI (0.05 mL, 0.8 mmol, 2.0 eq), followed after 5 min by CsCO.sub.3 (0.14 g, 0.4 mmol, 1.1 eq). The reaction mixture is stirred at rt for 48 h, partitioned between water and EA, the layers are separated and the aqueous layer is extracted with EA (3×). The combined organic layer is washed with brine, dried over MgSO.sub.4, filtered and solvent removed in vacuo to give a yellow oil. Purification by preparative HPLC/MS (I) yielded the title compound as a white solid (0.20 g, 74%). LC-MS (A): t.sub.R=0.95 min; [M+H].sup.+: 671.1.

3. (2R,3R,4S,5R,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol (2.44.126R.I.)

[0712] To a mixture of 4,4-difluoro-1-((R)-(((4aR,6S,7R,8S,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)thio)(3-methylpyridin-2-yl)methyl)cyclohexan-1-ol (0.20 g, 0.3 mmol) in water (2.0 mL) is added AcOH (2.0 mL), the resulting solution is stirred at 60° C. for 8 h, then at rt for 24 h. The reaction mixture is cooled to 0° C., quenched with (H.sub.2O/MeCN=1/1) (1.0 mL) and aq. NH.sub.4OH is added (until pH 5-6). The resulting solution is purified by preparative HPLC/MS(I) to give the title compound as a white solid (0.14 g, 76%). LC-MS (A): t.sub.R=0.79 min; [M+H].sup.+: 631.1. .sup.1H NMR (400 MHz, MeOD) δ: 8.63 (s, 1H), 8.42 (d, J=4.0 Hz, 1H), 7.63-7.70 (m, 3H), 7.26 (dd, J.sub.1=4.8 Hz, J.sub.2=7.8 Hz, 1H), 4.85 (dd, J.sub.1=2.9 Hz, J.sub.2=10.5 Hz, 1H), 4.65 (s, 1H), 4.47 (d, J=9.5 Hz, 1H), 4.06 (d, J=2.9 Hz, 1H), 3.95 (t, J=9.9 Hz, 1H), 3.88-3.64 (m, 7H) 3.15 (s, 3H), 2.48 (s, 3H), 2.24 (m, 1H), 1.85 (m, 1H), 1.72 (m, 1H), 1.25-1.20 (m, 1H)

[0713] Following 2-OMe-Gal inhibitors are prepared from the corresponding 2-OH-Gal inhibitors as single epimers or as mixture of epimers according to the procedures described for Example 2.44.126R.I. LC-MS, Gal-3 inhibition data are listed in Table 9 below. The LC-MS conditions used were LC-MS (A). Chiral analytical HPLC (I) (conditions and retention time) and inhibition data of the epimers R and S of selected Examples are also listed.

TABLE-US-00014 TABLE 9 HPLC t.sub.R IC.sub.50 Example Name t.sub.R [M + H].sup.+ conditions chiral [uM] 2.44.126R.I. (2R,3R,4S,5R,6S)-6-(((R)-(4,4- 0.79 631.24 ChiralCel 1.50 0.07 Difluoro-1-hydroxycyclohexyl)(3- OZ-H methylpyridin-2-yl)methyl)thio)-2- B: 40% (1/1) (hydroxymethyl)-5-methoxy-4-(4- MeCN/EtOH (3,4,5-trifluorophenyl)-1H-1,2,3- 5 min run triazol-1-yl)tetrahydro-2H-pyran-3-ol 2.44.125R.I. (2R,3R,4S,5R,6S)-6-(((R)-(4,4- 1.02 685.05 Chiralpak IB 1.89 0.06 Difluoro-1-hydroxycyclohexyl)(3- B: 20% (trifluoromethyl)pyridin-2- MeCN/EtOH/DEA yl)methyl)thio)-2-(hydroxymethyl)-5- 1/1/0.1 methoxy-4-(4-(3,4,5-trifluorophenyl)- 5 min run 1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3-ol 2.39.125R.I. (2R,3R,4S,5R,6S)-6-(((R)-(1- 1.03 649.07 Chiralpak IB 2.35 0.09 Hydroxycyclohexyl)(3- B: 25% (trifluoromethyl)pyridin-2- MeCN/EtOH/DEA yl)methyl)thio)-2-(hydroxymethyl)-5- 1/1/0.1 methoxy-4-(4-(3,4,5-trifluorophenyl)- 5 min run 1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3-ol 2.44.137.I. (2R,3R,4S,5R,6S)-6-(((3- 0.98 651.02 0.14 Chloropyridin-2-yl)(4,4-difluoro-1- hydroxycyclohexyl)methyl)thio)-2- (hydroxymethyl)-5-methoxy-4-(4- (3,4,5-trifluorophenyl)-1H-1,2,3- triazol-1-yl)tetrahydro-2H-pyran-3-ol 2.44.137R.I. (2R,3R,4S,5R,6S)-6-(((R)-(3- 0.99 651.05 Chiralpak IB 2.4 0.07 Chloropyridin-2-yl)(4,4-difluoro-1- B: 25% (1/1) hydroxycyclohexyl)methyl)thio)-2- MeCN/EtOH (hydroxymethyl)-5-methoxy-4-(4- 5 min run (3,4,5-trifluorophenyl)-1H-1,2,3- triazol-1-yl)tetrahydro-2H-pyran-3-ol 2.43.112RS.I (2R,3R,4S,5R,6S)-6-(((R)-((S)-4- 0.99 678.10 Chiralpak IB 1.45 0.14 Hydroxy-2,2-dimethyltetrahydro-2H- B: 25% (1/1) pyran-4-yl)(2- MeCN/EtOH (trifluoromethyl)phenyl)methyl)thio)-2- 5 min run (hydroxymethyl)-5-methoxy-4-(4- (3,4,5-trifluorophenyl)-1H-1,2,3- triazol-1-yl)tetrahydro-2H-pyran-3-ol 2.66.126R.I. 4-Hydroxy-4-((R)- 0.71 645.17 Chiralpak IB 2.46 0.06 (((2S,3R,4S,5R,6R)-5-hydroxy-6- B: 25% (hydroxymethyl)-3-methoxy-4-(4- MeCN/EtOH/DEA (3,4,5-trifluorophenyl)-1H-1,2,3- 1/1/0.1 triazol-1-yl)tetrahydro-2H-pyran-2- 5 min run yl)thio)(3-methylpyridin-2- yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide 2.41.126R.I. (2R,3R,4S,5R,6S)-2- 0.67 597.20 Chiralpak IH 2.4 0.06 (Hydroxymethyl)-6-(((R)-(4- B: 20% (1/1) hydroxytetrahydro-2H-pyran-4-yl)(3- MeCN/EtOH methylpyridin-2-yl)methyl)thio)-5- 5 min run methoxy-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3-ol 2.43.102RS.I. (2R,3R,4S,5R,6S)-6-(((R)-((S)-4- 0.96 624.22 Chiralpak IB 2.40 0.06 Hydroxy-2,2-dimethyltetrahydro-2H- B: 20% (1/1) pyran-4-yl)(o-tolyl)methyl)thio)-2- MeCN/EtOH (hydroxymethyl)-5-methoxy-4-(4- 5 min run (3,4,5-trifluorophenyl)-1H-1,2,3- triazol-1-yl)tetrahydro-2H-pyran-3-ol 2.44.132R.I. (2R,3R,4S,5R,6S)-6-(((R)-(4,4- 0.85 659.24 Chiralpak IB 1.85 0.12 Difluoro-1-hydroxycyclohexyl)(3- B: 20% isopropylpyridin-2-yl)methyl)thio)-2- MeCN/EtOH/DEA (hydroxymethyl)-5-methoxy-4-(4- 1/1/0.1 (3,4,5-trifluorophenyl)-1H-1,2,3- 5 min run triazol-1-yl)tetrahydro-2H-pyran-3-ol 2.44.134R.I. (2R,3R,4S,5R,6S)-6-(((R)-(3- 0.82 658.04 Chiralcel OZH 1.15 0.06 Cyclopropylpyridin-2-yl)(4,4-difluoro- B: 35% 1-hydroxycyclohexyl)methyl)thio)-2- MeCN/EtOH/DEA (hydroxymethyl)-5-methoxy-4-(4- (1/1/0.1) (3,4,5-trifluorophenyl)-1H-1,2,3- 4 min run triazol-1-yl)tetrahydro-2H-pyran-3-ol [1,3-di-deoxy-1-((4,4-difluoro-1- hydroxy-cyclohexan-1-yl)-(3-(- cyclopropyl)pyridin-2-yl)methyl-(R)- thio)-2-O-methyl-3-[4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl]- b-D-galactopyranoside] 2.44.135R.I. (2R,3R,4S,5R,6S)-6-(((R)-(4,4- 0.89 632.39 Chiralpak ID 2.45 0.07 Difluoro-1-hydroxycyclohexyl)(4- B: 35% (1/1) methylpyridazin-3-yl)methyl)thio)-2- MeCN/EtOH (hydroxymethyl)-5-methoxy-4-(4- 5 min run (3,4,5-trifluorophenyl)-1H-1,2,3- triazol-1-yl)tetrahydro-2H-pyran-3-ol 2.44.129R.I. (2R,3R,4S,5R,6S)-6-(((R)-(4,4- 0.93 632.16 Chiralpak IG 2.21 0.05 Difluoro-1-hydroxycyclohexyl)(3- B: 35% (1/1) methylpyrazin-2-yl)methyl)thio)-2- MeCN/MeOH (hydroxymethyl)-5-methoxy-4-(4- 5 min run (3,4,5-trifluorophenyl)-1H-1,2,3- triazol-1-yl)tetrahydro-2H-pyran-3-ol [1,3-di-deoxy-1-((4,4-difluoro-1- hydroxy-cyclohexan-1-yl)-(3-(- methyl)pyrazin-2-yl)methyl-(R)-thio)- 2-O-methyl-3-[4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl]- b-D-galactopyranoside]

Example 2.39.120R.I

(2R,3R,4S,5R,6S)-6-(((R)-(1-Hydroxycyclohexyl)(4-methylisoxazol-3-yl)methyl)thio)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol (2.39.120R.I.)

[0714] Example 2.39.120R.I. is synthesized from Example 2.39.120R. as described below.

1. (4aR,6S,7R,8R,8aR)-6-(((R)-(1-Hydroxycyclohexyl)(4-methylisoxazol-3-yl)methyl)thio)-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

[0715] A mixture of Example 2.39.120R. (0.14 g, 0.24 mmol), 2,2-dimethoxypropane (0.16 mL, 1.3 mmol, 5.5 eq), acetone (0.5 mL) and CSA (0.03 g, 0.12 mmol, 0.5 eq) in THF (1.5 mL) is heated at 50° C. for 2 h. The reaction mixture is partitioned between EA and sat.aq. NaHCO.sub.3, the layers are separated and the aqueous layer is extracted with EA (3×). The combined organic layer is washed with brine, dried over MgSO.sub.4, filtered and the solvent removed in vacuo to give a colorless oil, that is purified by preparative HPLC/MS (I) to give the title compound as a white solid (0.11 g, 76%). LC-MS (A): t.sub.R=1.03 min; [M+H].sup.+: 611.22.

2. 1-((R)-(((4aR,6S,7R,8S,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)thio)(4-methylisoxazol-3-yl)methyl)cyclohexan-1-ol

[0716] To a stirred solution of (4aR,6S,7R,8R,8aR)-6-(((R)-(1-hydroxycyclohexyl)(4-methylisoxazol-3-yl)methyl)thio)-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 (0.11 g, 0.18 mmol) in THF (2.0 mL) is added MeI (0.02 mL, 0.4 mmol, 2.0 eq) followed after 5 min by NaH (0.01 g, 0.2 mmol, 1.1 eq) and stirring is continued at rt for 2 h. The reaction mixture is partitioned between water and EA, the layers are separated and the aqueous layer is extracted with EA (3×). The combined organic layer is washed with brine, dried over MgSO.sub.4, filtered and solvent removed in vacuo to give a brown oil. Purification by preparative HPLC/MS(I) gave the title compound as a white solid (0.07 g, 63%). LC-MS (A): t.sub.R=1.10 min; [M+H].sup.+: 625.25

3. (2R,3R,4S,5R,6S)-6-(((R)-(1-Hydroxycyclohexyl)(4-methylisoxazol-3-yl)methyl)thio)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol (2.39.120R.I.)

[0717] To a mixture of 1-((R)-(((4aR,6S,7R,8S,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)thio)(4-methylisoxazol-3-yl)methyl)cyclohexan-1-ol (0.07 g, 0.11 mmol) in water (2.0 mL) is added AcOH (2.0 mL). The solution is stirred at 55° C. for 2.5 h, cooled (00), quenched with (H.sub.2O/MeCN 1/1, 1.0 mL) and aq. NH.sub.4OH is added (until pH 5-6) at 0° C. The resulting solution is purified by preparative HPLC/MS(I) to give the title compound as a white solid (0.05 g, 68%). .sup.1H NMR (400 MHz, MeOD) δ: 8.63 (s, 1H), 8.39 (s, 1H), 7.62-7.74 (m, 2H), 4.84 (dd, J=2.9 Hz, J=10.5 Hz, 1H), 4.52 (s, 1H), 4.32 (d, J=9.5 Hz, 1H), 4.09 (d, J=2.8 Hz, 1H), 4.01 (t, J=10.0 Hz, 1H), 3.83-3.68 (m, 2H), 3.64 (t, J=6.3 Hz, 1H), 3.23 (s, 3H), 2.21 (s, 3H), 1.87-2.03 (m, 1H), 1.5-1.8 (m, 8H), 1.28-1.38 (m, 1H). LC-MS (A): t.sub.R=0.94 min; [M+H].sup.+: 585.23.

Example 2.39.120S.I

(2R,3R,4S,5R,6S)-6-(((S)-(1-Hydroxycyclohexyl)(4-methylisoxazol-3-yl)methyl)thio)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol (2.39.120S.I.)

[0718] Example 2.39.120S.I. is synthesized from Example 2.39.120S. in analogy to Example 2.39.120R.I. as a white solid. LC-MS (A): t.sub.R=0.95 min; [M+H].sup.+: 585.2.

[0719] Following 2-OMe-Gal inhibitors are prepared from the corresponding 2-OMe-Gal inhibitors according to the procedures described for Example 2.39.120R.I. LC-MS and Gal-3 inhibition data are listed in Table 10 below. The LC-MS conditions used were LC-MS (A). Chiral analytical HPLC (I) (conditions and retention time) and inhibition data of the epimers R and S of selected Examples are also listed.

TABLE-US-00015 TABLE 10 HPLC t.sub.R IC.sub.50 Example Name t.sub.R [M + H].sup.+ conditions chiral [uM] 2.39.120R.I. (2R,3R,4S,5R,6S)-6-(((R)-(1- 0.94 585.23 Chiralpak IA 4.06 0.25 Hydroxycyclohexyl)(4-methylisoxazol- B: 30% (1/1) 3-yl)methyl)thio)-2-(hydroxymethyl)-5- MeCN/EtOH methoxy-4-(4-(3,4,5-trifluorophenyl)- 5 min run 1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3-ol 2.39.120S.I. (2R,3R,4S,5R,6S)-6-(((S)-(1- 0.95 585.2 Chiralpak IA 2.52 12.5 Hydroxycyclohexyl)(4-methylisoxazol- B: 30% (1/1) 3-yl)methyl)thio)-2-(hydroxymethyl)-5- MECN/EtOH methoxy-4-(4-(3,4,5-trifluorophenyl)- 5 min run 1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3-ol 2.44.105R.I. (2R,3R,4S,5R,6S)-6-(((R)-(4,4- 1.08 657.99 Chiralpak IF 3.84 0.32 Difluoro-1-hydroxycyclohexyl)(2- B: 15% (1/1) isopropylphenyl)methyl)thio)-2- MeCN/EtOH (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.105S.I. (2R,3R,4S,5R,6S)-6-(((S)-(4,4-Difluoro- 1.10 658 Chiralpak IF 3.28 70.5 1-hydroxycyclohexyl)(2- B: 15% (1/1) isopropylphenyl)methyl)thio)-2- MeCN/EtOH (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.120R.I. (2R,3R,4S,5R,6S)-6-(((R)-(4,4- 0.95 621.11 Chiralpak IB 1.46 0.21 Difluoro-1-hydroxycyclohexyl)(4- B: 25% (1/1) methylisoxazol-3-yl)methyl)thio)-2- MeCN/EtOH (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.106R.I. (2R,3R,4S,5R,6S)-6-(((R)-(2- 1.06 656.1 Chiralpak IB 1.58 0.18 Cyclopropylphenyl)(4,4-difluoro-1- B: 25% (1/1) hydroxycyclohexyl)methyl)thio)-2- MeCN/EtOH (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.136.I. (2R,3R,4S,5R,6S)-6-(((4,4-Difluoro-1- 0.92 634.11 0.42 hydroxycyclohexyl)(1,4-dimethyl-1H- pyrazol-5-yl)methyl)thio)-2- (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.136R.I. (2R,3R,4S,5R,6S)-6-(((R)-(4,4- 0.92 634.08 Chiralpak IG 2.56 0.26 Difluoro-1-hydroxycyclohexyl)(1,4- B: 35% (1/1) dimethyl-1H-pyrazol-5-yl)methyl)thio)- MeCN/EtOH 2-(hydroxymethyl)-5-methoxy-4-(4- 5 min run (3,4,5-trifluorophenyl)-1H-1,2,3-triazol- 1-yl)tetrahydro-2H-pyran-3-ol 2.44.136S.I. (2R,3R,4S,5R,6S)-6-(((S)-(4,4-Difluoro- 0.92 634.1 Chiralpak IG 1.23 15.6 1-hydroxycyclohexyl)(1,4-dimethyl-1H- B: 35% (1/1) pyrazol-5-yl)methyl)thio)-2- MeCN/EtOH (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.138.I. (2R,3R,4S,5R,6S)-6-(((4,4-Difluoro-1- 0.90 649.14 0.30 hydroxycyclohexyl)(1-ethyl-4-methyl- 1H-1,2,3-triazol-5-yl)methyl)thio)-2- (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.138R.I. (2R,3R,4S,5R,6S)-6-(((R)-(4,4- 0.91 649.09 Chiralpak IH 2.05 0.15 Difluoro-1-hydroxycyclohexyl)(1-ethyl- B: 25% (1/1) 4-methyl-1H-1,2,3-triazol-5- MeCN/EtOH yl)methyl)thio)-2-(hydroxymethyl)-5- 5 min run methoxy-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-3-ol 2.44.138S.I. (2R,3R,4S,5R,6S)-6-(((S)-(4,4-Difluoro- 0.90 649.10 Chiralpak IH 1.46 13.2 1-hydroxycyclohexyl)(1-ethyl-4-methyl- B: 25% (1/1) 1H-1,2,3-triazol-5-yl)methyl)thio)-2- MeCN/EtOH (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.139.I. (2R,3R,4S,5R,6S)-6-(((4-Chloro-1- 0.99 668.02 0.62 ethyl-1H-pyrazol-5-yl)(4,4-difluoro-1- hydroxycyclohexyl)methyl)thio)-2- (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.139R.I. (2R,3R,4S,5R,6S)-6-(((R)-(4-Chloro-1- 0.98 668.04 Chirakpak ID 3.063 0.32 ethyl-1H-pyrazol-5-yl)(4,4-difluoro-1- B: 20% (1/1) hydroxycyclohexyl)methyl)thio)-2- MeCN/2-ProOH (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.139S.I. (2R,3R,4S,5R,6S)-6-(((S)-(4-Chloro-1- 0.99 668.05 Chiralpak ID 2.1 37.9 ethyl-1H-pyrazol-5-yl)(4,4-difluoro-1- B: 20% (1/1) hydroxycyclohexyl)methyl)thio)-2- MeCN/2-ProOH (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- 1/1 trifluorophenyl)-1H-1,2,3-triazol-1- 5 min run yl)tetrahydro-2H-pyran-3-ol 2.44.140R.I. (2R,3R,4S,5R,6S)-6-(((R)-(4,4- 1.00 649.11 Chiralpak IB 1.37 0.12 Difluoro-1-hydroxycyclohexyl)(5-ethyl- B: 25% (1/1) 4-methylisoxazol-3-yl)methyl)thio)-2- MeCN/EtOH (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.41.120R.I. (2R,3R,4S,5R,6S)-2-(Hydroxymethyl)- 0.82 587.12 Chiralpak IB 1.81 0.19 6-(((R)-(4-hydroxytetrahydro-2H-pyran- B: 25% (1/1) 4-yl)(4-methylisoxazol-3- MeCN/EtOH yl)methyl)thio)-5-methoxy-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.66.120R.I. 4-Hydroxy-4-((R)-(((2S,3R,4S,5R,6R)- 0.81 635.15 Chiralpak IG 2.23 0.07 5-hydroxy-6-(hydroxymethyl)-3- B: 35% (1/1) methoxy-4-(4-(3,4,5-trifluorophenyl)- MeCN/EtOH 1H-1,2,3-triazol-1-yl)tetrahydro-2H- 5 min run pyran-2-yl)thio)(4-methylisoxazol-3- yl)methyl)tetrahydro-2H-thiopyran 1,1- dioxide 2.39.128R.I. (2R,3R,4S,5R,6S)-6-(((R)-(5- 0.98 626.09 Chiralpak IB 1.78 0.30 Cyclopropyl-3-methylisoxazol-4-yl)(1- B: 25% (1/1) hydroxycyclohexyl)methyl)thio)-2- MeCN/EtOH (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.130R.I. (2R,3R,4S,5R,6S)-6-(((R)-(5- 1.03 675.22 Chiralpak IB 2.12 0.06 Cyclopropyl-4-ethylisoxazol-3-yl)(4,4- B: 20% (1/1) difluoro-1- MeCN/EtOH hydroxycyclohexyl)methyl)thio)-2- 5 min run (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol [1,3-di- deoxy-1-((4,4-difluoro-1-hydroxy- cyclohexan-1-yl)-(5-(-cyclopropyl)-4-(- ethyl)isoxazol-3-yl)methyl-(R)-thio)-2- O-methyl-3-[4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl]-b-D- galactopyranoside] 2.44.131R.I. (2R,3R,4S,5R,6S)-6-(((R)-(5- 1.11 703.27 Chiralpak IH 1.83 0.13 Cyclopropyl-4-isobutylisoxazol-3- B: 20% (1/1) yl)(4,4-difluoro-1- MeCN/EtOH hydroxycyclohexyl)methyl)thio)-2- 5 min run (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.133.I. (2R,3R,4S,5R,6S)-6-(((3- 0.94 652.13 0.17 Chloropyrazin-2-yl)(4,4-difluoro-1- hydroxycyclohexyl)methyl)thio)-2- (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.133R.I. (2R,3R,4S,5R,6S)-6-(((R)-(3- 0.94 652.15 REGIS (R,R) 1.42 0.04 Chloropyrazin-2-yl)(4,4-difluoro-1- Whelk-O1 hydroxycyclohexyl)methyl)thio)-2- 35% EtOH (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- 2.5 min trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol [1,3-di- deoxy-1-((4,4-difluoro-1-hydroxy- cyclohexan-1-yl)-(3-(-chloro)pyrazin-2- yl)methyl-(R)-thio)-2-O-methyl-3-[4- (3,4,5-trifluorophenyl)-1H-1,2,3-triazol- 1-yl]-b-D-galactopyranoside] 2.44.133S.I. (2R,3R,4S,5R,6S)-6-(((S)-(3- 0.93 652.17 REGIS (R,R) 1.77 2.71 Chloropyrazin-2-yl)(4,4-difluoro-1- Whelk-O1 hydroxycyclohexyl)methyl)thio)-2- 35% EtOH (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- 2.5 min trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol

Example 2.44.141.I

(2R,3R,4S,5R,6S)-6-(((4-Chloro-3-methylpyridin-2-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol

[0720] Example 2.44.141.I. is prepared from 1-((4-chloro-3-methylpyridin-2-yl)(mercapto)methyl)-4,4-difluorocyclohexan-1-ol (prepared in analogy to Intermediate 7) and Intermediate 10 in analogy to Example 2.40.119. as a beige solid. LC-MS (A): t.sub.R=0.98 min; [M+H].sup.+: 665.16.

Example 2.44.141R.I

(2R,3R,4S,5R,6S)-6-(((R)-(4-Chloro-3-methylpyridin-2-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol

[0721] Separation of the epimers of Example 2.44.141.I. (0.026 g) by chiral preparative HPLC (VII) yielded the title compound (0.010 g) as a white solid. Chiral analytical HPLC (N): t.sub.R=1.9 min LC-MS (A): t.sub.R=0.98 min; [M+H].sup.+: 665.1.

Example 2.44.141 S.I

(2R,3R,4S,5R,6S)-6-(((S)-(4-Chloro-3-methylpyridin-2-yl)(4,4-difluoro-1-hydroxycyclohexyl)methyl)thio)-2-(hydroxymethyl)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol

[0722] Separation of the epimers of Example 2.44.141.I. (0.026 g) by chiral preparative HPLC (VII) yielded the title compound (0.008 g) as a white solid. Chiral analytical HPLC (N): t.sub.R=2.98 min LC-MS (A): t.sub.R=0.97 min; [M+H].sup.+: 665.11.

[0723] Following examples are prepared from Intermediate 10 and the corresponding mercapto alcohols (prepared in analogy to Intermediate 7) in analogy to Example 2.44.141.I. LC-MS and Gal-3 inhibition data are listed in Table 11 below. The LC-MS conditions used were LC-MS (A). Chiral analytical HPLC (I) (conditions and retention time) and inhibition data of the epimers R and S of selected Examples are also listed.

TABLE-US-00016 TABLE 11 HPLC t.sub.R IC.sub.50 Example Name t.sub.R [M + H].sup.+ conditions chiral [uM] 2.44.141.I. (2R,3R,4S,5R,6S)-6-(((4-Chloro-3- 0.98 665.16 0.15 methylpyridin-2-yl)(4,4-difluoro-1- hydroxycyclohexyl)methyl)thio)-2- (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.141R.I. (2R,3R,4S,5R,6S)-6-(((R)-(4-Chloro-3- 0.98 665.1 ChiralCel 1.88 0.07 methylpyridin-2-yl)(4,4-difluoro-1- OZ-H hydroxycyclohexyl)methyl)thio)-2- B: 30% (1/1) (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- MeCN/EtOH trifluorophenyl)-1H-1,2,3-triazol-1- 5 min run yl)tetrahydro-2H-pyran-3-ol 2.44.141S.I (2R,3R,4S,5R,6S)-6-(((S)-(4-Chloro-3- 0.97 665.11 ChiralCel 2.98 3.5 methylpyridin-2-yl)(4,4-difluoro-1- OZ-H hydroxycyclohexyl)methyl)thio)-2- B: 30% (1/1) (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- MeCN/EtOH trifluorophenyl)-1H-1,2,3-triazol-1- 5 min run yl)tetrahydro-2H-pyran-3-ol 2.44.142.I. (2R,3R,4S,5R,6S)-6-(((4,4-Difluoro-1- 0.82 645.42 0.05 hydroxycyclohexyl)(3-ethylpyridin-2- yl)methyl)thio)-2-(hydroxymethyl)-5- methoxy-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3- ol 2.44.142R.I. (2R,3R,4S,5R,6S)-6-(((R)-(4,4-Difluoro- 0.81 645.19 Chiralpak IC 2.32 0.03 1-hydroxycyclohexyl)(3-ethylpyridin-2- B: 20% (1/1) yl)methyl)thio)-2-(hydroxymethyl)-5- MeCN/EtOH methoxy-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3- ol [1,3-di-deoxy-1-((4,4-difluoro-1- hydroxy-cyclohexan-1-yl)-(3-(- ethyl)pyridin-2-yl)methyl-(R)-thio)-2-O- methyl-3-[4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl]-b-D- galactopyranoside] 2.44.142S.I. (2R,3R,4S,5R,6S)-6-(((S)-(4,4-Difluoro- 0.81 645.21 Chiralpak IC 3.32 8.11 1-hydroxycyclohexyl)(3-ethylpyridin-2- B: 20% (1/1) yl)methyl)thio)-2-(hydroxymethyl)-5- MeCN/EtOH methoxy-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3- ol 2.44.143.I. (2R,3R,4S,5R,6S)-6-(((3,4- 1.02 685.07 0.14 Dichloropyridin-2-yl)(4,4-difluoro-1- hydroxycyclohexyl)methyl)thio)-2- (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.143R.I. (2R,3R,4S,5R,6S)-6-(((S)-(3,4- 1.02 685.07 Chiralpak ID 1.23 0.07 Dichloropyridin-2-yl)(4,4-difluoro-1- B: 30% (1/1) hydroxycyclohexyl)methyl)thio)-2- MeCN/EtOH (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.143S.I. (2R,3R,4S,5R,6S)-6-(((S)-(3,4- 1.02 685.05 Chiralpak ID 1.65 9.97 Dichloropyridin-2-yl)(4,4-difluoro-1- B: 30% (1/1) hydroxycyclohexyl)methyl)thio)-2- MeCN/EtOH (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.144.I. (2R,3R,4S,5R,6S)-6-(((3,6- 1.03 685.07 0.25 Dichloropyridin-2-yl)(4,4-difluoro-1- hydroxycyclohexyl)methyl)thio)-2- (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.43.126.I. (2R,3R,4S,5R,6S)-6-(((4-Hydroxy-2,2- 0.71 626.01 0.16 dimethyltetrahydro-2H-pyran-4-yl)(3- methylpyridin-2-yl)methyl)thio)-2- (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.43.126RR.I. (2R,3R,4S,5R,6S)-6-(((R)-((R)-4- 0.72 625.93 Chiralpak IC 1.7 0.73 Hydroxy-2,2-dimethyltetrahydro-2H- B: 30% (1/1/0.1) pyran-4-yl)(3-methylpyridin-2- MeCN/2- yl)methyl)thio)-2-(hydroxymethyl)-5- PrOH/DEA methoxy-4-(4-(3,4,5-trifluorophenyl)-1H- 4 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3- ol 2.43.126RS.I. (2R,3R,4S,5R,6S)-6-(((R)-((S)-4- 0.73 626.04 Chiralpak IC 1.97 0.04 Hydroxy-2,2-dimethyltetrahydro-2H- B: 30% (1/1/0.1) pyran-4-yl)(3-methylpyridin-2- MeCN/2- yl)methyl)thio)-2-(hydroxymethyl)-5- PrOH/DEA methoxy-4-(4-(3,4,5-trifluorophenyl)-1H- 4 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3- ol 2.43.126SR.I. (2R,3R,4S,5R,6S)-6-(((S)-((R)-4- 0.72 625.97 Chiralpak IC 2.6 3.5 Hydroxy-2,2-dimethyltetrahydro-2H- B: 30% (1/1/0.1) pyran-4-yl)(3-methylpyridin-2- MeCN/2- yl)methyl)thio)-2-(hydroxymethyl)-5- PrOH/DEA methoxy-4-(4-(3,4,5-trifluorophenyl)-1H- 4 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3- ol 2.43.126SS.I. (2R,3R,4S,5R,6S)-6-(((S)-((S)-4- 0.72 625.96 Chiralpak IC 2.2 1.9 Hydroxy-2,2-dimethyltetrahydro-2H- B: 30% (1/1/0.1) pyran-4-yl)(3-methylpyridin-2- MeCN/2- yl)methyl)thio)-2-(hydroxymethyl)-5- PrOH/DEA methoxy-4-(4-(3,4,5-trifluorophenyl)-1H- 4 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3- ol 2.44.145.I. ((2R,3R,4S,5R,6S)-6-(((5-Cyclopropyl-4- 1.01 661.14 0.71 methylisoxazol-3-yl)(4,4-difluoro-1- hydroxycyclohexyl)methyl)thio)-2- (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.145R.I. (2R,3R,4S,5R,6S)-6-(((R)-(5- 1.04 661.09 Chiralpak IC 1.95 0.25 Cyclopropyl-4-methylisoxazol-3-yl)(4,4- B: 25% difluoro-1- MeOH hydroxycyclohexyl)methyl)thio)-2- 3 min run (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.145S.I. (2R,3R,4S,5R,6S)-6-(((S)-(5- 1.03 661.09 Chiralpak IC 1.45 11.2 Cyclopropyl-4-methylisoxazol-3-yl)(4,4- B: 25% difluoro-1- MeOH hydroxycyclohexyl)methyl)thio)-2- 3 min run (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.146.I. (2R,3R,4S,5R,6S)-6-(((4,4-Difluoro-1- 1.07 677.18 0.12 hydroxycyclohexyl)(4-ethyl-5- propylisoxazol-3-yl)methyl)thio)-2- (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.147.I. (2R,3R,4S,5R,6S)-6-(((4,4-Difluoro-1- 1.07 699.08 0.24 hydroxycyclohexyl)(3-methyl-4- (trifluoromethyl)pyridin-2-yl)methyl)thio)- 2-(hydroxymethyl)-5-methoxy-4-(4- (3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.147R.I. (2R,3R,4S,5R,6S)-6-(((R)-(4,4-Difluoro- 1.05 699.29 Chiralpak IB 2.15 0.19 1-hydroxycyclohexyl)(3-methyl-4- B: 15% (trifluoromethyl)pyridin-2-yl)methyl)thio)- EtOH/0.1% 2-(hydroxymethyl)-5-methoxy-4-(4- DEA (3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- 3.5 min run yl)tetrahydro-2H-pyran-3-ol 2.44.147S.I. (2R,3R,4S,5R,6S)-6-(((S)-(4,4-Difluoro- 1.05 699.28 Chiralpak IB 2.55 5.3 1-hydroxycyclohexyl)(3-methyl-4- B: 15% (trifluoromethyl)pyridin-2-yl)methyl)thio)- EtOH/0.1% 2-(hydroxymethyl)-5-methoxy-4-(4- DEA (3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1- 3.5 min run yl)tetrahydro-2H-pyran-3-ol 2.44.148R.I. (2R,3R,4S,5R,6S)-6-(((R)-(3-Chloro-6- 1.05 665.06 Chiralpak IC 1.8 0.24 methylpyridin-2-yl)(4,4-difluoro-1- B: 20% (1/1) hydroxycyclohexyl)methyl)thio)-2- EtOH/MeCN (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- 4 min run trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.148S.I. (2R,3R,4S,5R,6S)-6-(((S)-(3-Chloro-6- 1.05 665.03 Chiralpak IC 2.3 6.99 methylpyridin-2-yl)(4,4-difluoro-1- B: 20% (1/1) hydroxycyclohexyl)methyl)thio)-2- EtOH/MeCN (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- 4 min run trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.119.I. (2R,3R,4S,5R,6S)-6-(((4,4-Difluoro-1- 0.98 660.12 0.26 hydroxycyclohexyl)(3,5,6- trimethylpyrazin-2-yl)methyl)thio)-2- (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.119R.I. (2R,3R,4S,5R,6S)-6-(((R)-(4,4-Difluoro- 0.99 660.08 Chiralcel 1.1 0.09 1-hydroxycyclohexyl)(3,5,6- OJ-H trimethylpyrazin-2-yl)methyl)thio)-2- B: 50% (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- EtOH/0.1% trifluorophenyl)-1H-1,2,3-triazol-1- DEA yl)tetrahydro-2H-pyran-3-ol 3 min run 2.44.119S.I. (2R,3R,4S,5R,6S)-6-(((S)-(4,4-Difluoro- 0.98 660.11 Chiralcel 2.0 5.11 1-hydroxycyclohexyl)(3,5,6- OJ-H trimethylpyrazin-2-yl)methyl)thio)-2- B: 50% (hydroxymethyl)-5-methoxy-4-(4-(3,4,5- EtOH/0.1% trifluorophenyl)-1H-1,2,3-triazol-1- DEA yl)tetrahydro-2H-pyran-3-ol 3 min run 2.44.149.I. (2R,3R,4S,5R,6S)-6-(((4,4-Difluoro-1- 0.8 645.13 0.4 hydroxycyclohexyl)(3,6-dimethylpyridin- 2-yl)methyl)thio)-2-(hydroxymethyl)-5- methoxy-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3- ol 2.72.126.I 9-((((2S,3R,4S,5R,6R)-5-Hydroxy-6- 0.74 665.18 0.13 (hydroxymethyl)-3-methoxy-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-2-yl)thio)(3- methylpyridin-2-yl)methyl)-3- oxaspiro[5.5]undecan-9-ol

Example 2.44.126.II

(2R,3R,4S,5R,6S)-6-(((4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-5-ethoxy-2-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3-ol

[0724] Example 2.44.126.II. is prepared from 1-((4-chloro-3-methylpyridin-2-yl)(mercapto)methyl)-4,4-difluorocyclohexan-1-ol (prepared in analogy to Intermediate 7) and Intermediate 11 according to the procedures described for Example 2.40.119. as a beige solid. LC-MS (A): t.sub.R=0.81 min; [M+H].sup.+: 645.42.

[0725] LC-MS and Gal-3 inhibition data from Examples 2.44.126.II. are listed in Table 14 below. The LC-MS conditions used were LC-MS (A).

TABLE-US-00017 TABLE 12 HPLC t.sub.R IC.sub.50 Example Name t.sub.R [M + H].sup.+ conditions chiral [uM] 2.44.126.II. (2R,3R,4S,5R,6S)-6-(((4,4-Difluoro-1- 0.81 645.42 0.16 hydroxycyclohexyl)(3-methylpyridin-2- yl)methyl)thio)-5-ethoxy-2- (hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-3-ol 2.44.126R.II. (2R,3R,4S,5R,6S)-6-(((R)-(4,4-Difluoro- 0.81 645.13 Chiralpak IC 1.59 0.11 1-hydroxycyclohexyl)(3-methylpyridin-2- B: 20% yl)methyl)thio)-5-ethoxy-2- EtOH/0.1% (hydroxymethyl)-4-(4-(3,4,5- DEA trifluorophenyl)-1H-1,2,3-triazol-1- 4 min run yl)tetrahydro-2H-pyran-3-ol 2.44.126S.II. (2R,3R,4S,5R,6S)-6-(((S)-(4,4-Difluoro- 0.82 645.12 Chiralpak IC 2.03 0.98 1-hydroxycyclohexyl)(3-methylpyridin-2- B: 20% yl)methyl)thio)-5-ethoxy-2- EtOH/0.1% (hydroxymethyl)-4-(4-(3,4,5- DEA trifluorophenyl)-1H-1,2,3-triazol-1- 4 min run yl)tetrahydro-2H-pyran-3-ol

Example 2.51.112.I

1-(Cyclopropylsulfonyl)-4-((((2S,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)thio)(2-(trifluoromethyl)phenyl)methyl)piperidin-4-ol

1. 1-(Cyclopropylsulfonyl)-4-((((4aR,6S,7R,8S,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)thio)(2-(trifluoromethyl)phenyl)methyl)piperidin-4-ol

[0726] To a solution of Intermediate 12 (0.06 g, 0.087 mmol) in DCM (3.0 mL) at rt are added cyclopropylsulfonyl chloride (0.01 mL, 0.105 mmol, 1.2 eq) and DIPEA (33.9 uL, 0.26 mmol, 3.0 eq). The reaction mixture is stirred at rt for 15 h, partitioned between DCM and water, the layers are separated and the aqueous layer is extracted with DCM (3×). The combined organic layer is dried over MgSO4, filtered and solvent removed in vacuo to give a brown oil, that is purified by prep HPLC/MS (I) to yield the title compound (0.011 g, 16%) as a white solid. LC-MS (A): t.sub.R=1.11 min; [M+H].sup.+: 793.22.

2. 1-(Cyclopropylsulfonyl)-4-((((2S,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)thio)(2-(trifluoromethyl)phenyl)methyl)piperidin-4-ol (2.51.112.I.)

[0727] To a mixture of 1-(cyclopropylsulfonyl)-4-((((4aR,6S,7R,8S,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)thio)(2-(trifluoromethyl)phenyl)methyl)piperidin-4-ol (0.011 g, 0.014 mmol) in water is added AcOH (0.5 mL) and the solution is stirred at 60° C. for 2 h, then at rt over 15 h. A mixture water/MeCN 1/1 (1.0 mL) and NH.sub.4OH are added (until pH 5-6), while cooling (0° C.) and the solution is purified by prep HPLC/MS (I) to obtain a white solid (0.006 g). LC-MS (A): t.sub.R=0.98 min; [M+H].sup.+: 753.11.

Example 2.48.112.I

1-(4-Hydroxy-4-((((2S,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)thio)(2-(trifluoromethyl)phenyl)methyl)piperidin-1-yl)ethan-1-one

[0728] Example 2.48.112.I. is obtained as a side-product during the synthesis of Example 2.51.112.I. Step 1. and deprotected in analogy to Step 2. of the same Example as a white solid. LC-MS (A): t.sub.R=0.92 min; [M+H].sup.+: 691.12.

Example 2.49.112.I

(N-Cyclopropyl-4-hydroxy-4-((((2S,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)thio)(2-(trifluoromethyl)phenyl)methyl)piperidine-1-carboxamide

[0729] Example 2.49.112.I. is obtained from Intermediate 12 and isocyanato cyclopropane in analogy to Example 2.51.112.I. as a white solid. LC-MS (A): t.sub.R=0.91 min; [M+H].sup.+: 732.2.

[0730] LC-MS and Gal-3 inhibition data from Examples 2.51.112.I. to Example 2.49.112.I. are listed in Table 13 below. The LC-MS conditions used were LC-MS (A).

TABLE-US-00018 TABLE 13 IC.sub.50 Example Name t.sub.R [M + H].sup.+ [uM] 2.51.112.I. 1-(Cyclopropylsulfonyl)-4-((((2S,3R,4S,5R,6R)-5-hydroxy-6- 0.98 753.11 0.08 (hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2- (trifluoromethyl)phenyl)methyl)piperidin-4-ol 2.48.112.I. 1-(4-Hydroxy-4-((((2S,3R,4S,5R,6R)-5-hydroxy-6- 0.92 691.12 0.19 (hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2- (trifluoromethyl)phenyl)methyl)piperidin-1-yl)ethan-1-one 2.49.112.I. (N-Cyclopropyl-4-hydroxy-4-((((2S,3R,4S,5R,6R)-5-hydroxy-6- 0.91 732.2 0.21 (hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)(2- (trifluoromethyl)phenyl)methyl)piperidine-1-carboxamide

Example 16.44.126.I

(2R,3R,4S,5R,6S)-6-(((4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-4-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol

1. 4,4-Difluoro-1-(mercapto(3-methylpyridin-2-yl)methyl)cyclohexan-1-ol

[0731] 4,4-Difluoro-1-(mercapto(3-methylpyridin-2-yl)methyl)cyclohexan-1-ol is prepared from S-(tetrahydro-2H-pyran-2-yl) ethanethioate, 2-(bromomethyl)-3-methylpyridine and 4,4-difluorocyclohexan-1-one in analogy to Intermediate 7 as a yellow oil. LC-MS (A): t.sub.R=0.62 min; [M+H].sup.+: 273.91

2. (2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-4-azido-6-(((4,4-difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)tetrahydro-2H-pyran-3,5-diyl diacetate

[0732] (2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-4-azido-6-(((4,4-difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)tetrahydro-2H-pyran-3,5-diyl diacetate is prepared from 4,4-difluoro-1-(mercapto(3-methylpyridin-2-yl)methyl)cyclohexan-1-ol and Intermediate 2 in analogy to Intermediate 9 as a white powder. LC-MS (A): t.sub.R=0.81 min; [M+H].sup.+: 587.20.

3. (2S,3R,4S,5R,6R)-4-Azido-2-(((4,4-difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol

[0733] To a suspension of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-4-azido-6-(((4,4-difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)tetrahydro-2H-pyran-3,5-diyl diacetate (1.04 g, 1.77 mmol) in MeOH at rt (21.0 mL) is added NaOMe (0.14 g, 2.66 mmol, 1.5 eq). The mixture is stirred at rt for 15 h, neutralized with DOWEX 50WX2, filtered and solvent removed in vacuo to give the title compound as an orange oil (0.87 g, >99%), that is used without further purification. LC-MS (A): t.sub.R=0.48 min; [M+H].sup.+: 461.12.

4. (4aR,6S,7R,8R,8aR)-8-Azido-6-(((4,4-difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-ol

[0734] A solution of (2S,3R,4S,5R,6R)-4-azido-2-(((4,4-difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,5-diol (0.75 g, 1.62 mmol) in THF (11.5 mL) and acetone (11.5 mL) is treated with 2,2-dimethoxypropane (2.03 mL, 16.2 mmol, 10.0 eq) and p-TsOH H.sub.2O (0.04 g, 0.18 mmol, 0.1 eq) and stirred at 50° C. for 9 h. The reaction mixture is concentrated under reduced pressure, diluted with EA, washed with aq. sat. NaHCO.sub.3, dried over MgSO.sub.4, filtered and solvent removed in vacuo to give a white solid (0.72 g, 89%), that is used without further purification. LC-MS (A): t.sub.R=0.65-0.68 min: [M+H].sup.+: 501.16

5. 1-((((4aR,6S,7R,8S,8aR)-8-Azido-7-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)thio)(3-methylpyridin-2-yl)methyl)-4,4-difluorocyclohexan-1-ol

[0735] To a solution of (4aR,6S,7R,8R,8aR)-8-azido-6-(((4,4-difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-ol (0.57 g, 1.14 mmol) in DMF (12.0 mL) at rt is added MeI (0.43 mL, 6.87 mmol, 6.0 eq). After 5 min CsCO.sub.3 (1.23 g, 3.78 mmol, 3.3 eq) is added and the reaction mixture is stirred at rt for 15 h, then partitioned between water and EA. The layers are separated and the aq. layer is extracted with EA (3×). The combined organic layer is washed with brine, dried over MgSO.sub.4, filtered and solvent removed in vacuo to give a brown oil, that is purified by combi flash (ISCO system, product added dry on isolute, 12 g column, Hept/EA 100/0 to 20/80, Rf(Hept/EA 1/1)=0.33 & 0.42) to yield the title compound as a yellow oil (0.59 g, >99%). LC-MS (A): t.sub.R=0.76-0.78 min; [M+H].sup.+: 515.18

6. 1-((((4aR,6S,7R,8S,8aR)-8-(4-(3,4-Difluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)thio)(3-methylpyridin-2-yl)methyl)-4,4-difluorocyclohexan-1-ol

[0736] To a solution of 1-((((4aR,6S,7R,8S,8aR)-8-azido-7-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)thio)(3-methylpyridin-2-yl)methyl)-4,4-difluorocyclohexan-1-ol (0.058 g, 0.11 mmol) in DMF (1.0 mL) at rt are added 4-ethynyl-1,2-difluorobenzene (0.0202 mL, 0.16 mmol, 1.5 eq), CuI (0.07 g, 0.01 mmol, 0.1 eq)) and DIPEA (0.05 mL, 0.32 mmol, 3.0 eq). The reaction mixture is stirred at rt for 3 h, diluted with EA. The org. layer is washed with aq. sat. NH.sub.4Cl, brine, dried over MgSO.sub.4, filtered and solvent concentrated in vacuo to afford a beige solid. The crude material is purified by preparative prepHPLC/MS (I) to yield the title compound as a white solid (0.05 g, 77%). LC-MS (A): t.sub.R=0.92 min; [M+H].sup.+: 653.21

7. (2R,3R,4S,5R,6S)-6-(((4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-4-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol (16.44.126.I.)

[0737] To a mixture of 1-((((4aR,6S,7R,8S,8aR)-8-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)thio)(3-methylpyridin-2-yl)methyl)-4,4-difluorocyclohexan-1-ol (0.05 g, 0.08 mmol) in water (2.0 mL) is added AcOH (2.0 mL), the solution is heated at 80° C. for 15 h. The reaction mixture is cooled (00), quenched with (H.sub.2O/MeCN 1/1, 1.0 mL) and aq. NH.sub.4OH is added (until pH 5-6) at 0° C. The resulting solution is purified by preparative HPLC/MS(I) to give the title compound as a white solid (0.03 g, 64%). LC-MS (A): t.sub.R=0.75 min; [M+H].sup.+: 613.36.

Example 16.44.126R.I

(2R,3R,4S,5R,6S)-6-(((R)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-4-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol

[0738] Separation of the epimers of Example 16.44.126.I. (0.032 g) by chiral preparative HPLC (VIII) yielded the title compound (0.009 g) as a white solid. Chiral analytical HPLC (O): t.sub.R=1.4 min. LC-MS (A): t.sub.R=0.75 min: [M+H].sup.+: 613.13.

Example 16.44.126S.I

(2R,3R,4S,5R,6S)-6-(((S)-(4,4-Difluoro-1-hydroxycyclohexyl)(3-methylpyridin-2-yl)methyl)thio)-4-(4-(3,4-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-3-ol

[0739] Separation of the epimers of Example 16.44.126.I. (0.032 g) by chiral preparative HPLC (VIII) yielded the title compound (0.008 g) as a white solid. Chiral analytical HPLC (O): t.sub.R=2.0 min. LC-MS (A): t.sub.R=0.75 min; [M+H].sup.+: 613.13.

[0740] Following examples are prepared starting from 1-((((4aR,6S,7R,8S,8aR)-8-azido-7-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)thio)(3-methylpyridin-2-yl)methyl)-4,4-difluorocyclohexan-1-ol Example 16.44.126.I. Step 5. and the corresponding alkynes in analogy to Example 16.44.126.I. Step 6-7. LC-MS and Gal-3 inhibition data are listed in Table 14 below. The LC-MS conditions used were LC-MS (A). Chiral analytical HPLC (I) (conditions and retention time) and inhibition data of the epimers R and S of selected Examples are also listed.

TABLE-US-00019 TABLE 14 HPLC t.sub.R IC.sub.50 Example Name t.sub.R [M + H].sup.+ conditions chiral [uM] 16.44.126.I. (2R,3R,4S,5R,6S)-6-(((4,4-Difluoro-1- 0.75 613.36 0.09 hydroxycyclohexyl)(3-methylpyridin-2- yl)methyl)thio)-4-(4-(3,4-difluorophenyl)- 1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)- 5-methoxytetrahydro-2H-pyran-3-ol 16.44.126R.I. (2R,3R,4S,5R,6S)-6-(((R)-(4,4-Difluoro- 0.75 613.13 ChiralCel 1.42 0.08 1-hydroxycyclohexyl)(3-methylpyridin-2- OZ-H yl)methyl)thio)-4-(4-(3,4-difluorophenyl)- B: 40% (1/1) 1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)- MeCN/EtOH 5-methoxytetrahydro-2H-pyran-3-ol 5 min run 16.44.126S.I. (2R,3R,4S,5R,6S)-6-(((S)-(4,4-Difluoro- 0.75 613.13 ChiralCel 2.01 1.87 1-hydroxycyclohexyl)(3-methylpyridin-2- OZ-H yl)methyl)thio)-4-(4-(3,4-difluorophenyl)- B: 40(1/1) 1H-1,2,3-triazol-1-yl)-2-(hydroxymethyl)- MeCN/EtOH 5-methoxytetrahydro-2H-pyran-3-ol 5 min run 21.44.126.I. (2R,3R,4S,5R,6S)-6-(((4,4-Difluoro-1- 0.76 631.24 0.06 hydroxycyclohexyl)(3-methylpyridin-2- yl)methyl)thio)-2-(hydroxymethyl)-5- methoxy-4-(4-(2,3,4-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3- ol 22.44.126.I. (2R,3R,4S,5R,6S)-4-(4-(4-Chloro-2,3- 0.79 647.16 007 difluorophenyl)-1H-1,2,3-triazol-1-yl)-6- (((4,4-difluoro-1-hydroxycyclohexyl)(3- methylpyridin-2-yl)methyl)thio)-2- (hydroxymethyl)-5-methoxytetrahydro- 2H-pyran-3-ol 23.44.126.I. (2R,3R,4S,5R,6S)-6-(((4,4-Difluoro-1- 0.77 627.22 0.05 hydroxycyclohexyl)(3-methylpyridin-2- yl)methyl)thio)-4-(4-(2,3-difluoro-4- methylphenyl)-1H-1,2,3-triazol-1-yl)-2- (hydroxymethyl)-5-methoxytetrahydro- 2H-pyran-3-ol 18.44.126.I. (2R,3R,4S,5R,6S)-4-(4-(4-Bromo-3,5- 0.79 691.08 0.12 difluorophenyl)-1H-1,2,3-triazol-1-yl)-6- (((4,4-difluoro-1-hydroxycyclohexyl)(3- methylpyridin-2-yl)methyl)thio)-2- (hydroxymethyl)-5-methoxytetrahydro- 2H-pyran-3-ol 17.44.126.I. (2R,3R,4S,5R,6S)-4-(4-(3,4-Dichloro-5- 0.82 663.1 0.14 fluorophenyl)-1H-1,2,3-triazol-1-yl)-6- (((4,4-difluoro-1-hydroxycyclohexyl)(3- methylpyridin-2-yl)methyl)thio)-2- (hydroxymethyl)-5-methoxytetrahydro- 2H-pyran-3-ol 12.44.126.I. (2R,3R,4S,5R,6S)-4-(4-(4-Bromo-3- 0.78 675.08 0.19 fluorophenyl)-1H-1,2,3-triazol-1-yl)-6- (((4,4-difluoro-1-hydroxycyclohexyl)(3- methylpyridin-2-yl)methyl)thio)-2- (hydroxymethyl)-5-methoxytetrahydro- 2H-pyran-3-ol 11.44.126.I. (2R,3R,4S,5R,6S)-4-(4-(4-Chloro-3,5- 0.8 647.14 0.09 difluorophenyl)-1H-1,2,3-triazol-1-yl)-6- (((4,4-difluoro-1-hydroxycyclohexyl)(3- methylpyridin-2-yl)methyl)thio)-2- (hydroxymethyl)-5-methoxytetrahydro- 2H-pyran-3-ol 3.44.126R.I. (2R,3R,4S,5R,6S)-6-(((R)-(4,4-Difluoro- 0.79 627.15 Chiralpak IB 1.98 0.04 1-hydroxycyclohexyl)(3-methylpyridin-2- B: 20% yl)methyl)thio)-4-(4-(3,5-difluoro-4- MeOH, 0.1% methylphenyl)-1H-1,2,3-triazol-1-yl)-2- DEA (hydroxymethyl)-5-methoxytetrahydro- 5 min run 2H-pyran-3-ol 3.44.126S.I. (2R,3R,4S,5R,6S)-6-(((S)-(4,4-Difluoro- 0.8 627.14 Chiralpak IB 2.23 1.16 1-hydroxycyclohexyl)(3-methylpyridin-2- B: 20% yl)methyl)thio)-4-(4-(3,5-difluoro-4- MeOH, 0.1% methylphenyl)-1H-1,2,3-triazol-1-yl)-2- DEA (hydroxymethyl)-5-methoxytetrahydro- 5 min run 2H-pyran-3-ol 24.44.126.I. (2R,3R,4S,5R,6S)-6-(((4,4-Difluoro-1- 0.69 609.99 0.33 hydroxycyclohexyl)(3-methylpyridin-2- yl)methyl)thio)-4-(4-(6-fluoro-5- methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)- 2-(hydroxymethyl)-5-methoxytetrahydro- 2H-pyran-3-ol

[0741] Galectin-1 inhibition data are listed in Table 15 below. Inhibition data of the epimers R and S of selected Examples are also listed.

TABLE-US-00020 TABLE 15 IC.sub.50 IC.sub.50 IC.sub.50 IC.sub.50 Example [uM] Example [uM] Example [uM] Example [uM] 2.30.100.OMe 56.3 2.31.110. 0.4 2.31.120R. 1.8 2.37.102. 5.36 2.54.100. 61.2 2.31.110R. 0.28 2.31.120S. 61.3 2.38.102. 2.9 1.30.101. 5.77 2.31.110S. 16.7 2.31.121. 5.03 2.38.102R. 1.8 2.30.105. 1.73 2.31.111R. 3.19 2.31.122. 2.14 2.38.102S. 17 2.31.102. 2.14 2.31.111S. 30.9 2.31.122R 0.67 2.39.128. 1.11 2.31.102R. 1.42 2.31.112. 5.23 2.31.122S. 11.2 2.39.128R. 1.03 2.31.102S. 6.98 2.31.112R. 2.61 2.31.123. 1.74 2.39.128S. 23.2 2.31.100. 3.71 2.31.112S. 26.4 2.31.123R. 1.19 2.39.102. 1.6 2.31.103. 1.23 2.31.113. 3.75 2.31.123S. 29.4 2.39.102R. 1.14 2.31.104. 0.6 2.31.114. 2.27 2.31.124. 5.15 2.39.102S. 24 2.31.105. 0.3 2.31.114R. 7.24 2.32.120R. 2.83 2.40.102. 0.73 2.31.105R. 0.16 2.31.114S. 40.9 2.32.120S. 77.4 2.41.102. 1.61 2.31.105S. 65.1 2.31.115. 1.39 2.60.112. 3.5 2.41.102R. 0.21 2.31.106. 0.34 2.31.115R. 0.58 2.61.112. 7.88 2.41.102S. 65.4 2.31.106R. 0.21 2.31.115S. 47.9 2.62.112. 11.7 2.42.102. 18.5 2.31.106S. 65 2.31.116. 3.78 2.33.112. 1.8 2.42.102R. 6.4 2.31.107. 0.24 2.31.117. 4.95 2.33.112R. 0.67 2.42.102S. >100 2.31.107R. 0.3 2.31.118R. 0.64 2.33.112S. 21.7 2.43.102. 1.9 2.31.107S. 56.6 2.31.118S. 8.2 2.34.102. 11.0 2.43.102RS. 0.8 2.31.108. 21.2 2.31.119. 1.75 2.35.102. 6.22 2.43.102RR. 8.8 2.31.108R. 0.39 2.31.119R. 1.15 2.36.102. 13.2 2.43.102SS. 69.5 2.31.108S. 25.8 2.31.119S. 18.35 2.36.102R. 3.5 2.43.102SR. 55 2.31.109. 3.23 2.31.120. 3.0 2.36.102S. 54.2 2.43.112RS. 0.4 2.43.112RR. 6.8 2.44.113. 2.35 2.44.126. 0.06 2.66.126R. 0.17 2.43.112SR. 10.9 2.44.113R. 1.73 2.44.126R. 0.3 2.66.126S. 16.5 2.43.112SS. 19.4 2.44.113S. 56.8 2.44.126S. 26.5 2.41.126. 0.8 2.35.125. 1.46 2.44.106R. 0.02 2.44.129. 0.35 2.41.126R. 0.7 2.35.125R. 0.81 2.44.106S. 1.9 2.44.129R. 0.2 2.41.126S. 70.4 2.35.125S. 21.8 2.41.112. 0.9 2.44.129S. 6.3 2.45.112. 0.46 2.39.125R. 0.28 2.41.112R. 0.9 2.44.130. 0.13 2.46.112. 0.27 2.39.125S. 21.8 2.41.112S. 59.4 2.44.130R. 0.16 2.47.112R. 0.12 2.39.119R. 0.73 2.41.125. 5.7 2.44.130S. 5.65 2.47.112S. 17.5 2.39.119S. 18.9 2.41.125R. 0.13 2.44.131. 0.22 2.48.112. 0.75 2.39.120R. 0.61 2.41.125S. 7.47 2.44.131R. 0.09 2.49.112R. 0.16 2.39.120S. 70 2.41.119. 20 2.44.131S. 13.7 2.49.112S. 12.1 2.44.120R. 0.38 2.41.119R. 0.49 2.44.132. 0.16 2.50.112R. 0.37 2.44.120S. 22.6 2.41.119S. 19.9 2.44.132R. 0.05 2.50.112S. 15.8 2.44.105. 0.08 2.40.112. 0.42 2.44.132S. 4.7 2.57.112. 0.58 2.44.105R. 0.04 2.40.112R. 0.15 2.44.133. 0.45 2.57.112R. 1.2 2.44.105S. 0.52 2.40.112S. 21.7 2.44.133R. 0.16 2.57.112S. 76.5 2.44.119R. 0.23 2.40.125. 0.53 2.44.133S. 15.8 2.58.112. 1.47 2.44.119S. 7.21 2.40.125R. 0.04 2.44.134. 0.14 2.59.112. 1.28 2.44.125R. 0.2 2.40.125S. 11.2 2.44.134R. 0.05 3.31.112. 4.9 2.44.125S. 3.41 2.40.119. 0.27 2.44.134S. 2.7 3.31.112R. 2.84 2.44.111R. 1.06 2.40.119R. 0.11 2.44.135R. 0.22 3.31.112S. 54.2 2.44.111S. 47.5 2.40.119S. 10.8 2.44.135S. 5.43 4.31.112. 2.27 2.44.112. 0.95 2.38.125. 0.76 2.66.120. 0.33 5.31.112. 3.58 2.44.112R. 0.77 2.38.125R. 0.48 2.66.120R. 0.07 2.44.126R.I. 0.68 2.44.112S. 17.6 2.38.125S. 15.1 2.66.120S. 24.1 2.44.125R.I. 0.26 2.39.125R.I. 0.46 2.44.139S.I. >100 2.43.125SS.I. 12.6 21.44.126I. 0.38 2.44.137.I. 4.36 2.44.140R.I. 0.7 2.44.145.I. 1.26 22.44.126.I. 0.92 2.44.137R.I. 0.72 2.41.120R.I. 0.5 2.44.145R.I. 1.2 23.44.126.I. 0.55 2.43.112RS.I. 1.3 2.66.120R.I. 0.58 2.44.145S.I. 31 18.44.126.I. 3.47 2.66.126R.I. 0.09 2.39.128R.I. 2.36 2.44.146.I. 0.17 17.44.126.I. 1.68 2.41.126R.I. 0.8 2.44.130R.I. 0.16 2.44.147.I. 1.24 12.44.126.I. 3.24 2.43.102RS.I. 1.9 2.44.131R.I. 0.1 2.44.147R.I. 0.76 11.44.126.I. 2.43 2.44.132R.I. 0.1 2.44.133.I. 1.22 2.44.147S.I. 31.8 3.44.126R.I. 2.43 2.44.134R.I. 0.11 2.44.133R.I. 0.66 2.44.148R.I. 3.04 3.44.126S.I. 20 2.44.135R.I. 0.2 2.44.133S.I. 7.54 2.44.148S.I. 31 24.44.126.I 0.16 2.44.129R.I. 0.3 2.44.141.I. 0.86 2.44.119.I. 1.3 2.44.135. 0.45 2.39.120R.I. 0.56 2.44.141R.I. 0.35 2.44.119R.I. 0.45 2.39.120S.I. 27.3 2.44.105R.I. 0.15 2.44.141S.I. 10.5 2.44.119S.I. 28.6 2.44.105S.I. 53.3 2.44.142.I. 0.19 2.44.149.I. 2.8 2.44.120R.I. 0.61 2.44.142R.I. 0.1 2.72.126.I. 0.73 2.44.106R.I. 0.21 2.44.142S.I. 8.31 2.44.126.II. 1.32 2.44.136.I. 2.53 2.44.143.I. 0.85 2.44.126R.II. 0.87 2.44.136R.I. 1.9 2.44.143R.I. 0.86 2.44.126S.II. 24.3 2.44.136S.I. >100 2.44.143S.I. 9.77 2.51.112.I. 0.35 2.44.138.I. 0.84 2.44.144.I. 4.16 2.48.112.I. 0.4 2.44.138R.I. 0.4 2.43.125.I. 2.2 2.49.112.I. 0.49 2.44.138S.I. >100 2.43.125RR.I. 4.63 16.44.126.I. 0.73 2.44.139.I. 3.9 2.43.125RS.I. 0.7 16.44.126R.I. 0.57 2.44.139R.I. 0.54 2.43.125SR.I. 27.1 16.44.126S.I. 54.2

[0742] Biological Assay

[0743] Evaluation of Compound Inhibitory Activity (IC.sub.50)

[0744] The inhibitory activity of compounds is determined in competitive binding assays. This spectrophotometric assay measures the binding of biotinylated human Gal-3 (hGal-3) or human Gal-1 (hGal-1), respectively, to a microplate-adsorbed glycoprotein, asialofetuin (ASF) (Proc Natl Acad Sci USA. 2013 Mar. 26; 110(13):5052-7.).

[0745] 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) to which 1.2 μL of compound working dilutions are added and mixed.

[0746] Plates are incubated for 3 hours at 4° C., then washed with cold assay buffer (3×50 uL), incubated for 1 hour with 25 μL/well of a streptavidin-peroxidase solution (diluted in assay buffer to 80 ng/mL) at 4° C., followed by further washing steps with assay buffer (3×50 uL). Finally, 25 μL/well of ABTS substrate is added. OD (410 nm) is recorded after 30 to 45 min and IC.sub.50 values are calculated.

[0747] The calculated IC.sub.50 values may fluctuate depending on the daily assay performance. Fluctuations of this kind are known to those skilled in the art. IC.sub.50 values from several measurements are given as mean values.