(2-ACETAMIDYL)THIO-BETA-D-GALACTOPYRANOSIDE DERIVATIVES
20220306674 · 2022-09-29
Inventors
- Martin Bolli (Allschwil, CH)
- Daniel Bur (Therwil, CH)
- John Gatfield (Allschwil, CH)
- Corinna Grisostomi (Allschwil, CH)
- Lubos Remen (Allschwil, CH)
- Cornelia Zumbrunn (Allschwil, CH)
Cpc classification
A61P29/00
HUMAN NECESSITIES
A61P31/00
HUMAN NECESSITIES
A61K31/7056
HUMAN NECESSITIES
A61P35/00
HUMAN NECESSITIES
International classification
Abstract
The present invention relates to compounds of Formula (I)
##STR00001##
wherein Ar.sup.1, R.sup.1, R.sup.2a, R.sup.2b, and R.sup.3 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) ##STR00029## wherein R.sup.1 represents an amide group of the structure: ##STR00030## wherein R.sup.N11 represents —C.sub.1-6-alkyl; —CH.sub.2—CH.sub.2—O—C.sub.1-3-alkyl; —CH.sub.2—C.sub.1-3-fluoroalkyl; —-Co.sub.0-2-alkylene-C.sub.3-6-cycloalkyl, wherein said C.sub.3-6-cycloalkyl is unsubstituted or mono- or di-substituted with fluoro or methyl; —Co.sub.0-2-alkylene-C.sub.4-6-cycloalkyl wherein said C.sub.4-6-cycloalkyl contains one oxygen ring atom; —CH.sub.2—CH.sub.2-NR.sup.N21R.sup.N22, wherein R.sup.N21 and R.sup.N22 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl selected from azetidine-1-yl, pyrrolidine-1-yl, piperidine-1-yl, and morpholin-4-yl; or —C.sub.1-2-alkylene-R.sup.11, wherein R.sup.11 represents phenyl or 5- or 6-membered heteroaryl wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted or mono-substituted with methyl; phenyl or 5- or 6-membered heteroaryl wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted or mono-substituted with methyl;or ##STR00031## and R.sup.N12 represents hydrogen or C.sub.1-2-alkyl; or R.sup.N11 and R.sup.N12 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl selected from azetidine-1-yl, pyrrolidine-1-yl, and piperidine-1-yl, wherein said 4- to 6-membered heterocyclyl independently is unsubstituted, mono-, or di-substituted, wherein the substituents independently are methyl or fluoro; or R.sup.N11 and R.sup.N12 together with the nitrogen atom to which they are attached form morpholin-4-yl; or R.sup.N11 and R.sup.N12 together with the nitrogen atom to which they are attached to form a partially aromatic bicyclic ring consisting of a pyrrolidine-1-yl or a piperidine-1-yl, wherein said pyrrolidine or piperidine is fused to a phenyl ring; 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; R.sup.2a represents hydrogen; and R.sup.2b represents —C.sub.2-4-alkyl, —C.sub.0-1-alkylene-Ar.sup.2b, wherein Ar.sup.2b 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.2a and R.sup.2b both represent hydrogen, methyl, ethyl, or n-propyl; or R.sup.2a and R.sup.2b 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; 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.N2 wherein -L-represents —CO—, —SO.sub.2—, *—CO—NH—, *—CO—O—, or *—SO.sub.2—NH—, and RN2 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.2a and R.sup.2b together with the carbon atom to which they are attached form a spiro-bicyclic ring system of the structure (S.sup.2AB) ##STR00032## 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.3 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 (Is), ##STR00033## wherein the carbon atom to which the group R.sup.1 is attached is in the absolute configuration as drawn in Formula (Is); 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 ##STR00034## 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 R.sup.1 represents an amide group of the structure ##STR00035## wherein R.sup.N11 represents -C.sub.1-6-alkyl; —CH.sub.2C.sub.1-3-fluoroalkyl; cyclopropyl, cyclobutyl, —CH.sub.2-cyclopropyl, —CH.sub.2-cyclopentyl, —CH.sub.2-1-fluorocyclopentyl, or —CH.sub.2—CH.sub.2-cyclopropyl; —CH.sub.2-3,3-difluorocyclobutyl; —CH.sub.2-tetrahydro-2H-pyran-4-yl, or —CH.sub.2—CH.sub.2-tetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-4-yl, or oxetane-3-yl; benzyl; phenyl, or pyridinyl; or ##STR00036## and R.sup.N12 represents hydrogen or C.sub.1-2-alkyl; or R.sup.N11 and R.sup.N12 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl selected from azetidin-1-yl which is unsubstituted, or di-substituted in position 3 with fluoro; pyrrolidin-1-yl which is unsubstituted, or di-substituted in position 3 with fluoro; and piperidin-1-yl which is unsubstituted, or di-substituted in position 3 or 4 with fluoro; or R.sup.N11 and R.sup.N12 together with the nitrogen atom to which they are attached form morpholin-4-yl; or R.sup.N11 and R.sup.N12 together with the nitrogen atom to which they are attached form an indolin-1-yl ring; or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 1; wherein R.sup.1 represents an amide group of the structure ##STR00037## wherein represents -C.sub.1-6-alkyl; —CH.sub.2—CH.sub.2-O-C.sub.1-3-alkyl; —CH.sub.2-C.sub.1-3-fluoroalkyl; or cyclopropyl, cyclobutyl, —CH.sub.2-cyclopropyl, —CH.sub.2-cyclopentyl, —CH.sub.2-1-fluorocyclopentyl, or —CH.sub.2—CH.sub.2-cyclopropyl; and R.sup.N12 represents C.sub.1-2-alkyl; or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 1; wherein R.sup.2a represents hydrogen; and R.sup.2b represents -C.sub.2-4-alkyl; benzyl; phenyl which is unsubstituted, mono- or di-substituted with methyl; or 5-membered heteroaryl which is unsubstituted or mono-substituted with methyl; or R.sup.2a and R.sup.2b both represent methyl, ethyl, or n-propyl; or R.sup.2a and R.sup.2b 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 cycloalkyl 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; or 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-cyclopropyl, or —SO.sub.2—NH—C.sub.1-3-alkyl; azetidine-3,3-diyl, wherein the nitrogen of said azetidine is substituted with —CO—O—C.sub.1-3-alkyl; or R.sup.2a and R.sup.2b together with the carbon atom to which they are attached form a spiro-bicyclic ring system of the structure: ##STR00038## or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1; wherein R.sup.3 represents methoxy; or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 1 wherein said compound is: (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-isobutyl-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N, N, 3-trimethyl butanamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-3-hydroxy-N,3-dimethyl butanamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N, N-diethyl-3-hydroxy-3-methylbutanamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-3-methyl-1-((R)-2-methylazetidi n-1-yl)butan-1-one; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-3-methyl-1-((S)-2-methylazetidi n-1-yl)butan-1-one; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-3-methyl-1-(3-methylazetidi n-1-yl)butan-1-one; (S)-1-(azetidi n-1-yl)-2-(((2S, 3R,4S,5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorop henyl)-1 H-1 ,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-3-methyl butan-1-one; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxy-1-methylpiperidi n-4-yl)-N-isobutyl-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxy-1-methylpiperidi n-4-yl)-N-methylacetamide; (S)-N-benzyl-2-(((2S, 3R,4S,5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorop henyl)-1 H-1 ,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxy-1-methylpiperidi n-4-yl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxy-1-methylpiperidi n-4-yl)-1-(piperidi n-1-yl)ethan-1-one; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxy-1-methylpiperidi n-4-yl)-1-(indol i n-1-yl)ethan-1-one; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N, N-dimethylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N, N-diethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)acetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-1-((R)-2-methylazetidi n-1-yl)ethan-1-one; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-1-((S)-2-methyl azetidi n-1-yl)ethan-1-one; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-1-(3-methylazetidi n-1-yl)ethan-1-one; (S)-1-(azetidi n-1-yl)-2-(((2S, 3R,4S,5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorop henyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethan-1-one; (S)-N-benzyl-2-(((2S, 3R,4S,5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorop henyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-1-(piperidi n-1-yl)ethan-1-one; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-1-(indol i n-1-yl)ethan-1-one; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methyl-N-(thiophen-2-ylmethyl)acetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-1-(pyrroli di n-1-yl)ethan-1-one; (S)-N-(cyclopentylmethyl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-ypthio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methyl-N-((1-methyl-1 H-imidazol-4-yl)methyl)acetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methyl-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)acetamide; (S)-N-(2-cyclopropylethyl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-N-(cyclopropylmethyl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-ypthio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methyl-N-(2,2,2-trifluoroethyl)acetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(1-hydroxycyclohexyl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(1-hydroxycyclohexyl)-1-(piperidin-1-yl)ethan-1-one; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-ypthio)-2-(1-hydroxycyclohexyl)-N-methyl-N-(2,2,2-trifluoroethyl)acetamide; (S)-N-cyclobutyl-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(1-hydroxycyclohexyl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-(241 uoro-2-methylpropyl)-2-(1-hydroxycyclohexyl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(1-hydroxycyclohexyl)-N-methyl-N-(pyridi n-2-yl methyl)acetamide; (S)-2-(4,4-difl uoro-1-hydroxycyclohexyl)-2-(((2S, 3R,4S,5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N,N-dimethylacetamide; (S)-2-(4,4-difl uoro-1-hydroxycyclohexyl)-2-(((2S, 3R,4S,5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-N-methylacetamide; (S)-N-cyclobutyl-2-(4,4-difl uoro-1-hydroxycyclohexyl)-2-(((2S, 3R,4S, 5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorop henyl)-1 H-1,2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide; (S)-2-(4,4-difl uoro-1-hydroxycyclohexyl)-2-(((2S, 3R,4S,5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-ypthio)-1-(piperidin-1-yl)ethan-1-one; (S)-N-(cyclopropylmethyl)-2-(4,4-difl uoro-1-hydroxycyclohexyl)-2-(((2S, 3R,4S,5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorop henyl)-1 H-1,2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide; (S)-N-cyclopropyl-2-(4,4-difl uoro-1-hydroxycyclohexyl)-2-(((2S, 3R,4S, 5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorop henyl)-1 H-1,2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide; (S)-2-(4,4-difl uoro-1-hydroxycyclohexyl)-2-(((2S, 3R,4S,5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-(241 uoro-2-methylpropyl)-N-methylacetamide; (S)-2-(4,4-difl uoro-1-hydroxycyclohexyl)-2-(((2S, 3R,4S,5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-((1-fluorocyclopentyl)methyl)-N-methylacetamide; (S)-2-(4,4-difl uoro-1-hydroxycyclohexyl)-2-(((2S, 3R,4S,5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-(3,3-di methyl butyl)-N-methylacetamide; (S)-2-(4,4-difl uoro-1-hydroxycyclohexyl)-1-(4,4-difl uoropiperidi n-1-yl)-2-(((2S,3R,4S,5R,6R)-3,5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-triazol-1-yl)tetrahydro-2H-pyran-2-ypthio)ethan-1-one; (S)-2-(4,4-difl uoro-1-hydroxycyclohexyl)-1-(3,3-difl uoroazetidi n-1-yl)-2-(((2S,3R,4S,5R,6R)-3,5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)ethan-1-one; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(1-hydroxycyclopentyl)-N-methylacetamide; (S)-1-(azetidi n-1-yl)-2-(((2S, 3R,4S,5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorop henyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(1-hydroxycyclopentyl)ethan-1-one; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(1-hydroxycyclopentyl)-N-methyl-N-(2,2,2-trifluoroethyl)acetamide; (S)-N-cyclobutyl-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(1-hydroxycyclopentyl)-N-methyl acetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(1-hydroxycyclopentyl)-N-methyl-N-neopentylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(1-hydroxycyclobutyl)-N-methylacetamide; (S)-1-(azetidi n-1-yl)-2-(((2S, 3R,4S,5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorop henyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(1-hydroxycyclobutyl)ethan-1-one; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(1-hydroxycyclobutyl)-1-(piperidi n-1-yl)ethan-1-one; (S)-N-(cyclopropylmethyl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(1-hydroxycyclobutyl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(1-hydroxycyclobutyl)-N-methyl-N-(2,2,2-trifluoroethyl)acetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-(241 uoro-2-methylpropyl)-2-(1-hydroxycyclobutyl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(1-hydroxycyclobutyl)-N-methyl-N-neopentylacetamide; (S)-2-(3, 3-difl uoro-1-hydroxycyclobutyl)-2-(((2S,3R,4S, 5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-N-methylacetamide; (S)-1-(azetidi n-1-yl)-2-(3,3-difl uoro-1-hydroxycyclobutyl)-2-(((2S,3R,4S,5R,6R)-3,5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorop henyl)-1 H-1,2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)ethan-1-one; (S)-N-(cyclopropylmethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N,3-diethyl-3-hydroxy-N-methylpentanamide; (S)-N-(cyclopropylmethyl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-ethyl-3-hydroxy-N-methylpentanamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-ethyl-N-(2-fluoro-2-methylpropyl)-3-hydroxy-N-methylpentanamide; (S)-N-benzyl-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N,3-dimethylbutanamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-3-methyl-1-(piperidin-1-yl)butan-1-one; (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-3-methyl-1-(pyrrolidin-1-yl)butan-1-one; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N,3-dimethyl-N-((1-methyl-1 H-imidazol-4-yl)methyl)butanamide; (S)-N-(cyclopropylmethyl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N,3-dimethylbutanamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N,3-dimethyl-N-neopentylbutanamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N-(2-methoxyethyl)-N,3-dimethylbutanamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N,3-dimethyl-N-(2-morp holinoethyl)butanamide; (2S,3R)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-3-hydroxy-N-methylpentanamide; (2S,3S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-3-hydroxy-N-methylpentanamide; (2S,3R)-1-(azeti di n-1-yl)-2-(((2S,3R,4S, 5R,6R)-3,5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxypentan-1-one; (2S,3S)-1-(azetidi n-1-yl)-2-(((2S,3R,4S,5R,6R)-3,5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxypentan-1-one; (2S,3R)-N-(cyclopropylmethyl)-2-(((2S, 3R,4S,5R,6R)-3,5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N-methylpentanamide; (2S,3S)-N-(cyclopropyl methyl)-2-(((2S, 3R,4S,5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N-methylpentanamide; (2S,3R)-2-(((2S, 3R,4S,5R,6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorop henyl)-1 H-1,2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-3-hydroxy-N-methyl-4-phenyl butanamide; (2S,3S)-2-(((2S, 3R,4S, 5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-3-hydroxy-N-methyl-4-phenyl butanamide; (2S,3R)-1-(azeti di n-1-yl)-2-(((2S,3R,4S, 5R,6R)-3,5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-4-p henyl butan-1-one; (2S,3S)-1-(azetidi n-1-yl)-2-(((2S,3R,4S,5R,6R)-3,5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-4-p henyl butan-1-one; (2S,3R)-N-(cyclopropylmethyl)-2-(((2S, 3R,4S,5R,6R)-3,5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N-methyl-4-phenylbutanamide; (2S,3S)-N-(cyclopropyl methyl)-2-(((2S, 3R,4S,5R, 6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N-methyl-4-phenylbutanamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxy-1-(methylsulfonyl)piperidi n-4-yl)-N-methylacetamide; (S)-2-(1-(cyclopropylsulfonyl)-4-hydroxypiperidin-4-yl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-N-methylacetamide; Methyl 4-((S)-1-(((2S, 3R,4S,5R,6R)-3, 5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorop henyl)-1 H-1,2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(ethyl(methyl)ami no)-2-oxoethyl)-4-hydroxypi peridi ne-1-carboxylate; (2S,3R)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-3-hydroxy-N-methyl-3-(1-methyl-1 H-pyrazol-3-yl)propanamide; (2S,3S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-3-hydroxy-N-methyl-3-(1-methyl-1 H-pyrazol-3-yl)propanamide; (2S,3R)-1-1-(Azeti din-1-yl)-2-(((2S,3R,4S,5R,6R)-3,5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-3-(1-methyl-1 H-pyrazol-3-yl)propan-1-one; (2S,3S)-1-(Azetidin-1-yl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-3-(1-methyl-1 H-pyrazol-3-yl)propan-1-one; (2S,3R)-N-(cyclopropylmethyl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N-methyl-3-(1-methyl-1 H-pyrazol-3-yl)propanamide; (2S,3S)-N-(cyclopropylmethyl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N-methyl-3-(1-methyl-1 H-pyrazol-3-yl)propanamide; (S)-N-Cyclopropyl-4-(1-(((2S,3R,4S,5R,6R)-3,5-di hydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(ethyl(methyl)amino)-2-oxoethyl)-4-hydroxypiperidine-1-carboxamide; (S)-N-(Cyclopropylmethyl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-ypthio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)acetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methyl-N-(oxetan-3-yl)acetamide; (2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-6-(((S)-2-(ethyl(methyl)amino)-1-(3-hydroxy-1-(methoxycarbonyl)azetidin-3-yl)-2-oxoethypthio)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate; N-Cyclopropyl-44(S)-2-(ethyl(methyl)amino)-1-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-oxoethyl)-4-hydroxypiperidine-1-carboxamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-phenylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methyl-N-p henylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methyl-N-(pyridin-2-yl)acetamide; (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methyl-N-(pyridin-3-yl)acetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-ypthio)-N-methyl-N-(pyridin-2-yl)acetamide; (S)-N-Cyclobutyl-2-(((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)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)acetamide; (S)-N-Cyclobutyl-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-N-Cyclopropyl-2-(4,4-difluoro-1-hydroxycyclohexyl)-N-ethyl-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)acetamide; (S)-N-(Cyclopropylmethyl)-2-(4,4-difluoro-1-hydroxycyclohexyl)-N-ethyl-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)acetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-N-ethyl-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide; (S)-N-Benzyl-2-(4,4-difluoro-1-hydroxycyclohexyl)-N-ethyl-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)acetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-N-((3,3-difluorocyclobutyl)methyl)-N-ethyl-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)acetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-N-ethyl-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-(tetrahydro-2H-pyran-4-yl)acetamide; (S)-2-(((2S,3R,4S,5R,6R)-4-(4-(3,5-Difluorophenyl)-1 H-1, 2,3-triazol-1-yl)-3,5-di hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-N-Ethyl-2-(((2S,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1 H-1, 2,3-triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-4-(4-(3,5-Difluoro-4-methylphenyl)-1 H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-4-(4-(4-Chloro-3,5-difluorophenyl)-1 H-1, 2,3-triazol-1-yl)-3,5-di hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-4-(4-(4-Bromothiazol-2-yl)-1 H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-4-(4-(4-Bromo-3-fluorophenyl)-1 H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-4-(4-(3-Chloro-5-fluorophenyl)-1 H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-4-(4-(3-Chloro-4,5-difluorophenyl)-1 H-1, 2,3-triazol-1-yl)-3,5-di hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-4-(4-(3,4-Difluorophenyl)-1 H-1, 2, 3-triazol-1-yl)-3, 5-di hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-4-(4-(3,4-Dichloro-5-fluorophenyl)-1 H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-4-(4-(4-Bromo-3,5-difluorophenyl)-1 H-1, 2, 3-triazol-1-yl)-3, 5-di hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-2-(((2S,3R,4S,5R,6R)-4-(4-(3-Cyano-5-methylphenyl)-1 H-1,2, 3-triazol-1-yl)-3, 5-di hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-N-Ethyl-2-(((2S,3R,4S,5R,6R)-4-(4-(3-fluoro-5-methylphenyl)-1 H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide; (S)-N-Cyclopropyl-2-(4,4-difluoro-1-hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-4-(4-(6-fluoro-5-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-N-(2-fluoro-2-methylpropyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-1-(4,4-difl uoropi peridi n-1-yl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorop henyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)ethan-1-one; (S)-N-(Cyclopropylmethyl)-2-(4,4-difluoro-1-hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N, N-dimethylacetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-N-ethyl-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-tri azol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methyl-N-(2,2, 2-trifluoroethyl)acetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-isopropyl-N-methylacetamide; (S)-2-(4,4-Difl uoro-1-hydroxycyclohexyl)-N-(3, 3-dimethyl butyl)-2-(((2S,3R,4S, 5R, 6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorop henyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide; (S)-N-(2-Cyclopropylethyl)-2-(4,4-difluoro-1-hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-N-(3,3-difluorocyclobutyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methyl-N-(oxetan-3-yl)acetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)acetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-1-morp holi noethan-1-one; (S)-2-(4,4-Difl uoro-1-hydroxycyclohexyl)-1-(4,4-dimethylpiperidi n-1-yl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorop henyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)ethan-1-one; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-N-(4,4-dimethylcyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide; (S)-N-(Bicyclo[1.1.1]pentan-1-yl)-2-(4,4-difluoro-1-hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-(tetrahydro-2H-pyran-4-yl)acetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-(pentan-3-yl)acetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-isopropylacetamide; (S)-2-(4,4-Difl uoro-1-hydroxycyclohexyl)-N-(3, 3-dimethyl butyl)-2-(((2S,3R,4S, 5R, 6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorop henyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)acetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-N-(3,3-difluorocyclobutyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)acetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-(2, 2,2-trifluoroethyl)acetamide; (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-N-(4,4-dimethylcyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)acetamide; (S)-1-(4,4-Difl uoropiperi di n-1-yl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(6-hydroxyspiro[2.5]octan-6-yl)ethan-1-one; (S)-1-(4,4-Difluoropiperidin-1-yl)-2-(1-hydroxy-4,4-dimethylcyclohexyl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)ethan-1-one; (S)-1-(4,4-Difl uoropiperi di n-1-yl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(7-hydroxyspiro[3.5] nonan-7-yl)ethan-1-one; (S)-1-(4,4-Difl uoropiperi di n-1-yl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-ypthio)-2-(7-hydroxy-2-oxaspiro[3.5]nonan-7-yl)ethan-1-one; (S)-1-(4,4-Difl uoropiperi di n-1-yl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(8-hydroxyspiro[4.5]decan-8-yl)ethan-1-one; (S)-1-(4,4-Difl uoropiperi di n-1-yl)-2-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-ypthio)-2-(9-hydroxy-3-oxaspiro[5.5]undecan-9-yl)ethan-1-one; (S)-1-(4,4-Difl uoropiperi di n-1-yl)-2-((R)-4-hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((2S,3R,4S, 5R, 6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)ethan-1-one; (S)-1-(4,4-Difl uoropiperi di n-1-yl)-2-((S)-4-hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-(((2S,3R,4S, 5R, 6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)ethan-1-one; (2S)-2-(1,1-Difluoro-6-hydroxyspiro[2.5]octan-6-yl)-1-(4,4-difluoropiperidin-1-yl)-2-(((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)ethan-1-one; or (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-1-(4,4-difl uoropi peridi n-1-yl)-2-(((2S,3R,4S,5R, 6R)-3-ethoxy-5-hydroxy-6-(hydroxymethyl)-4-(4-(3,4, 5-trifluorop henyl)-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)ethan-1-one; or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound according to any one of 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 a meta-position of said phenyl and the substituent is halogen; or a pharmaceutically acceptable salt thereof.
17. 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.
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
[0544] Reference Example 1
Example 2.53.203.
[0545] 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxv-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenv1)-1H-1,2,3-triazol-1-vhtetrahydro-2H-pyran-2-yhthio)-N-ethyl-N,3-dimethylbutanamide 1. (2R,3R,4S,5R, 65)-2-(Acetoxymethy0-641-(tert-butoxy)-3-methyl-1-oxobutan-2-yhthio)-4-(4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yhtetrahydro-2H-pyran-3,5-diyl diacetate
[0546] TBAB (0.073 g, 0.23 mmol, 0.25 eq) is added to a solution of Intermediate 3 (0.50 g, 0.9 mmol) and tert-butyl 3-methyl-2-sulfanylbutanoate (0.24 g, 1.27 mmol, 1.4 eq) in EA (10.0 mL). Aq. 1M Na.sub.2CO.sub.3is then added (2.0 mL) and the mixture is stirred at rt for 17 h. TBAB (1 spatula tip), tert-butyl 3-methyl-2-sulfanylbutanoate (5 drops) and aq. 1M Na.sub.2CO.sub.3 (1.0 mL) are added again. After 4 h of stirring at rt, the reaction mixture is diluted with EA (25.0 mL), followed by water (25.0 mL), and brine (25.0 mL). The phases are separated and the aq. layer is extracted with EA (50.0 mL). The combined organic phase is dried over Na.sub.2SO.sub.4, filtered and solvent removed in vacuo. The residue is purified by preparative HPLC/MS (I) to recover the title compound (0.2 g, 32%) as a beige solid, that is used without further purification. LC-MS (A): t.sub.R=1.16 min; [M-FH]+: 660.31.
[0547] 2. 2-(((2S,3R,4S,5R,6R)-3,5-Diacetoxy-6-(acetoxymethy0-4-(4-(3,4,5-trifluoropheny0-1H-1,2,3-triazol-1-yhtetrahydro-2H-pyran-2-yhthio)-3-methylbutanoic acid
[0548] To a solution of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-64(1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate (0.2 g, 0.3 mmol) in DCM (45.0 mL) is added TFA (0.38 mL, 5.0 mmol, 17 eq) at rt. The reaction mixture is stirred at rt for 72 h, then neutralized with aq. 1N NaOH, diluted with DCM and the layers are separated. The aq. layer is extracted with DCM (3x). The combined organic layer is dried over Na.sub.2SO.sub.4, filtered and solvent removed in vacuo to recover the title compound (0.17 g, 96%) as a beige powder, that is not further purified. LC-MS (A): t.sub.R=0.98 min; [M-FH]+: 604.28.
[0549] 3. (2R,3R,4S,5R,6S)-2-(Acetoxymethy0-641-(ethyl(methyl)amino)-3-methyl-1-oxobutan-2-yl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate
[0550] HATU (0.035 g, 0.087 mmol, 1.05 eq), followed by a solution of N-ethylmethylamine (97%, 0.015 mL, 0.17 mmol, 2.0 eq) and DIPEA (0.032 mL, 0.182 mmol, 2.2 eq) in DMF (2.0 mL) are added to a cooled (0° C.) solution of 2-(((2S, 3R,4S, 5R,6R)-3, 5-diacetoxy-6-(acetoxymethyl)-4-(4-(3, 4, 5-trifluorophenyl)-1H-1, 2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-methylbutanoic acid (0.05 g, 0.08 mmol) in DMF (2.0 mL). The reaction mixture is stirred at rt for 1.5 h, then it is partitioned between aq. 1N NaOH and DCM. The layers are separated, the aqueous layer is extracted with DCM, the combined organic layer is dried over Na.sub.2SO.sub.4, filtered and solvent removed in vacuo. The residue is purified by preparative HPLC/MS (I) to recover the title compound as a beige solid (0.044 g, 82%). LC-MS (A): t.sub.R=1.03 min;
[0551] [M +H]+: 645.15.
[0552] 4. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethy0-4-(4-(3,4,5-trifluoropheny0-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-N,3-dimethylbutanamide (Reference Example 1)
[0553] K.sub.2CO.sub.3 (0.002 g, 0.012 mmol, 0.2 eq) is added at rt to a solution of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-64(1-(ethyl(methyl)amino)-3-methyl-1-oxobutan-2-yl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyldiacetate (0.042 g, 0.06 mmol) in MeOH (20.0 mL). 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 recover the title compound as a beige solid (0.032 g, 94%). LC-MS (A): t.sub.R=0.085 min; [M-FH]+: 545.32.
Reference Example 2
Example 2.56.203S.
[0554] (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethy0-4-(4-(3,4,5-trifluoropheny0-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-N-methyl-2-(tetrahydro-2H-pyran-4-yOacetamide 1. Methyl 2-bromo-2-(tetrahydro-2H-pyran-4-yOacetate
[0555] Methyl 2-(tetrahydro-2H-pyran-4-yl)acetate (5.0 g, 31.6 mmol) is dissolved in THF (60.0 mL) and cooled to -75° C.
[0556] NaHMDS (1M in THF, 35.0 mL, 35.0 mmol, 1.1 eq) is added dropwise and the reaction mixture stirred for 30 min at −75° C. TMSCI (4.0mL, 31.6 mmol, 1.0 eq) is added dropwise and stirring is continued for 1 h at -75° C. NBS (5.62 g, 31.6 mmol, 1.0 eq) is added, the cooling bath is removed and the mixture is stirred at rt for 1 h. It is then diluted with EA, the layers are separated, the organic layer is washed with water, dried over Na.sub.2SO.sub.4, filtered and solvent removed under reduced pressure. The residue is purified by CC on silica gel eluting with (Hept:/EA 3/1) to give methyl 2-bromo-2-(tetrahydro-2H-pyran-4-yl)acetate (5.8 g, 78%). .sup.1H NMR (400 MHz, CDCI3) δ: 4.03 (d, J=9.3 Hz, 1H), 4.00 (m, 2H), 3.81 (s, 3H), 3.42 (m, 2H), 2.15 (m, 1H), 1.99 (m, 1H), 1.64 (m, 1H), 1.41 (m, 2H).
[0557] 2. Methyl 2-(acetylthio)-2-(tetrahydro-2H-pyran-4-yOacetate
[0558] To a solution of methyl 2-bromo-2-(tetrahydro-2H-pyran-4-yl)acetate (5.8 g, 24.5 mmol) in acetone (80.0 mL) is added potassium acetate (3.36 g, 29.5 mmol, 1.2 eq) at rt and stirring is continued for 1h at rt. The reaction mixture is filtered and the filtrate is diluted with EA, washed with brine. The layers are separated and the organic layer is washed with water, dried over Na.sub.2SO.sub.4, filtered and solvent removed under reduced pressure to yield the title compound, that is not further purified. LC-MS (C): t.sub.R=0.74 min; [M-FH]+: 233.19.
[0559] 3. Methyl 2-mercapto-2-(tetrahydro-2H-pyran-4-yOacetate
[0560] Sodium metal (0.20 g, 8.6 mmol) is dissolved in MeOH (100.0 mL), methyl 2-(acetylthio)-2-(tetrahydro-2H-pyran-4-yl)acetate (5.4 g, 23.2 mmol) is added and the reaction mixture is stirred at rt for 4 h.The reaction mixture is quenched with aq 10% citric acid, the layers are separated and the aq. layer is extracted with DCM (3x). The organic layer is washed with water, dried over Na.sub.2SO.sub.4, filtered and solvent removed under reduced pressure. The residue is purified by preparative HPLC/MS to yield methyl 2-mercapto-2-(tetrahydro-2H-pyran-4-yl)acetate (1.6 g, 36%). LC-MS (C): t.sub.R =0.70 min; [M-FH]+: 191.36.
[0561] 4. Methyl 2-(((2S,3R,4S,5R,6R)-3,5-bis(benzyloxy)-6-((benzyloxy)methy0-4-(4-(3,4,5-trifluoropheny0-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(tetrahydro-2H-pyran-4-yOacetate
[0562] To a solution of Intermediate 5 (3.05 g, 2.95 mmol) and methyl 2-mercapto-2-(tetrahydro-2H-pyran-4-yl)acetate (0.84 g, 4.43 mmol, 1.5 eq) in EA (65.0 mL) is added TBAB (0.24 g, 0.74 mmol, 0.25 eq), followed by aq. 1M Na.sub.2CO.sub.3 (15.0 mL) and the reaction mixture is stirred at rt for 30 min. 2-Mercapto-2-(tetrahydro-2H-pyran-4-yl)acetate (0.56 g, 3.0 mmol, 1.0 eq) is added again and stirring is continued at rt for 1 h. The reaction mixture is diluted with water (25.0 mL), the layers are separated and the aq. layer is extracted with EA (2x). The combined organic phase is dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to recover the crude product that is purified by CC on silica gel eluting with EA/Hept 50/50, to give the title compound (1.3 g, 55%). LC-MS (C): t.sub.R=1.36 min; [M-FH]+:804.47.
[0563] 5. 2-(((2S, 3R, 4S, 5R, 6R)-3,5-bis(Benzyloxy)-6-((benzyloxy)methy0-4-(4-(3,4,5-trifluoropheny0-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-2-yl)thio)-2-(tetrahydro-2H-pyran-4-yOacetic acid
[0564] To a solution of methyl 2-(((25,3R,45,5R,6R)-3,5-bis(benzyloxy)-6-((benzyloxy)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-111)tetrahydro-2H-pyran-211)thio)-2-(tetrahydro-2H-pyran-4-yl)acetate (1.3 g, 1.62 mmol) in THF (25.0 ml) and EtOH (15.0 mL) is added aq. 1M NaOH (15.0 mL) and it is stirred at rt for 1.5 h. The reaction mixture is quenched with aq. 1 M HCI (pH=5), the layers are separated and the aq. layer is extracted with EA (2x). The combined organic phase is dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to recover the crude that is purified by preparative HPLC/MS to yield the title compound (0.65 g, 51%). LC-MS (C): t.sub.R=1.29 min; [M-FH]+:790.21.
[0565] 6. 2-(((2S,3R,4S,5R,6R)-3,5-bis(Benzyloxy)-6-((benzyloxy)rnethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-N-rnethyl-2-(tetrahydro-2H-pyran-4-yOacetarnide 2-(((2S,3R,4S, 5R, 6R)-3,5-bis(Benzyloxy)-6-((benzyloxy)methyl)-4-(4-(3,4, 5-trifluorophenyl)-1H-1,2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (0.63 g, 0.8 mmol) is dissolved in DMF (15.0 ml) and the solution cooled to 0° C. DIPEA (0.27 mL, 0.755 mmol, 2.0 eq) is added followed by ethylmethylamine (0.14 mL, 1.6 mmol, 2.0 eq), then HATU (0.33 g, 0.84 mmol, 1.0 eq) and stirring is continued at rt for 1 h. The reaction mixture is diluted with water and a spatula of NaCI is added, the layers are separated, and the aq. layer is extracted with EA (2x). The combined organic phase is dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to recover the crude product that is purified by CC on silica gel eluting with EA/Hept 50/50 to 100/0 to give the title compound (0.6 g, 91%). LC-MS (C): t.sub.R=1.33 min; [M-FH]+:831.52.
[0566] 7. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-111)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-N-methyl-2-(tetrahydro-2H-pyran-4-yOacetamide
[0567] To a cooled (0° C.) solution of 2-(((2S,3R,4S,5R,6R)-3,5-bis(benzyloxy)-6-((benzyloxy)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-N-methyl-2-(tetrahydro-2H-pyran-4-yl)acetamide (0.55 g, 0.66 mmol) in DCM (20.0 mL) is added BBr.sub.3 (1M in DCM, 4.0 mL). The reaction mixture is stirred at 0° C. for 10 min, then quenched by the addition of ice-water. The layers are separated, and the aq. layer is extracted with DCM (2x). The combined organic phase is dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to recover the crude product that is purified by preparative HPLC/MS (I) to give the title compound (0.035 g, 9%). LC-MS (C): t.sub.R =0.72 min; [M-FH]+:562.21.
[0568] 8. (S)-2-(((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)-N-ethyl-N-rnethyl-2-(tetrahydro-2H-pyran-4-yOacetarnide (Reference Example 2).
[0569] Separation of the epimers of Example 2.56.203S. (0.035 g) by chiral preparative HPLC(I) yielded the title compound (0.004 g). LC-MS (C): t.sub.R=0.72 min; [M-FH]+:562.21. Chiral analytical HPLC (E): t.sub.R=2.36 min.
[0570] LC-MS and Gal-3 inhibition data from Reference Examples 1 and 2 are listed in Table 1 below. The LC-MS conditions used were LC-MS (A) for Reference Example 1 and LC-(MS (C) for Reference Example 2.
TABLE-US-00006 TABLE 1 t.sub.R [M + IC.sub.50 Example Name min H].sup.+ [uM] 2.53.203. 2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy- 0.79 519.14 7.8 Ref. 1 6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-2-yl)thio)-N- ethyl-N,3-dimethylbutanamide 2.56.203S. (S)-2-(((2S,3R,4S,5R,6R)-3,5- 0.74 562.21 6.86 Ref. 2 dihydroxy-6-(hydroxymethyl)-4-(4- (3,4,5-trifluorophenyl)-1H-1,2,3- triazol-1-yl)tetrahydro-2H-pyran- 2-yl)thio)-N-ethyl-N-methyl-2- (tetrahydro-2H-pyran-4-yl)acetamide
[0571] Preparation of the compounds of Structure 1 and Examples thereof Example 2.41.200.
[0572] 2-(((2S,3R,4S,5R, 6R)-3,5-Dihydroxv-6-(hydroxymethyl)-4-(4-(3,4,5-trif luorophenv1)-1 H-1, 23-triazol-1-vhtetra hydro-2H-pyran-2-yhthio)-2-(4-hydroxytetra hydro-2H-pyran-4-y0-N-isobutyl-N-methylacetam ide 1. 2-(((2S,3R,4S,5R,6R)-3,5-bis((4-Chlorobenzyhoxy)-64(4-chlorobenzyhoxy)methy0-4-(4-(3,4,5-trifluoropheny0-1H-1,2,3-triazol-1-yhtetrahydro-2H-pyran-2-yhthio)-N-isobutyl-N-methylacetamide
[0573] Intermediate 4 (0.60 g, 0.44 mmol) and N-isobutyl-2-mercapto-N-methylacetamide (Intermediate 6) (0.10 g, 0.44 mmol, 1.0 eq) are dissolved in EA (12.5 mL). TBAB (0.036 g, 0.11 mmol, 0.25 eq) in aq. 1M Na.sub.2CO.sub.3 (6.25 mL) is added and stirring is continued for 17 h. The reaction mixture is diluted with EA (25.0 mL), water (25.0 mL) and brine (25.0 mL), the phases are separated and the aq. layer is extracted with EA (50.0 mL). The combined organic phase is dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The material is purified by preparative HPLC/MS (I) to recover the title compound (0.064 g, 16%) as a beige solid. LC-MS (A): t.sub.R=1.30 min; [M-FH]+: 877.23.
[0574] 2. 2-(((2S,3R,4S,5R,6R)-3,5-bis((4-Chlorobenzyhoxy)-64(4-chlorobenzyhoxy)methyl)-4-(4-(3,4,5-trifluoropheny0-1 H-1,2,3-triazol-1-yhtetrahydro-2H-pyran-2-yhthio)-2-(4-hydroxytetra hydro-2H-pyran-4-y0-N-isobutyl-N-methylacetamide
[0575] To a cooled (-78° C.) solution of 2-(((2S,3R,4S,5R,6R)-3,5-bis((4-chlorobenzypoxy)-6-(((4-chlorobenzypoxy)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-isobutyl-N-methylacetamide (0.03 g, 0.03 mmol) and TMEDA (0.01 mL, 0.07 mmol, 2.2 eq) in THF (1.8 mL), is added dropwise LDA (1.0 M in THF/Hept/ethylbenzene, 0.07 mL, 0.07 mmol, 2.2 eq). The solution is stirred at -78° C. for 1h, tetrahydro-4H-pyran-4-one (0.004 mL, 0.004 mmol, 1.2 eq) is added at -78° C. After 1 h the reaction mixture is quenched at -78° C. with aq.
[0576] sat. NH.sub.4C.sub.1, warmed to rt and diluted with EA and toluene. The phases are separated, the organic phase is dried over Na.sub.2SO.sub.4, filtered and solvent removed in vacuo. The crude is purified by preparative HPLC/MS (I) to recover the title compound (0.022 g, 75%) as a beige solid. LC-MS (A): t.sub.R=1.31 min; [M-FH]+: 979.31.
[0577] 3. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trif luorophenyl)-1 H-1 ,2,3-triazol-111)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetra hydro-2H-pyran-4-yl)-N-isobutyl-N-methylacetarn ide (2.41.200.)
[0578] To a cooled (0° C.) solution of 2-(((2S,3R,4S,5R,6R)-3,5-bis((4-chlorobenzypoxy)-6-(((4-chlorobenzypoxy)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-ypthio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-isobutyl-N-methylacetamide (0.022 g, 0.023 mmol) in DCM (5.0 mL) is added BBr.sub.3 (1M in DCM, 0.14 mL, 6.0 eq). The reaction mixture is stirred at 0° C. for 2h, quenched with dropwise addition of water at 0° C. The mixture is extracted with DCM (2x), the layers are separated and the combined org. layer is washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude is purified by preparative HPLC/MS (I) to recover the title compound (0.003 g, 24%) as a beige powder. LC-MS (A): t.sub.R=0.79 min; [M-FH]+: 605.49.
Example 2.41.200R.
[0579] (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxv-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenv1)-1H-1,2,3-triazol-1-0)tetrahydro-2H-pyran-2-0)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-0)-N-isobutyl-N-methylacetamide (2.41.200R.)
[0580] Separation of the epimers of Example 2.41.200. (0.022 g) by chiral preparative HPLC (II) yielded the title compound (0.013 g) as a beige solid. Chiral analytical HPLC (F): t.sub.R=1.44 min; [M-FH]+: 605.41. .sup.1H NMR (400 MHz, MeOD) 5:
[0581] 8.6, (s, 1H), 7.65 (m, 2H), 4.9-4.82 (m, 2H), 4.24-4.13 (m, 3H), 3.91-3.83 (m, 1H), 3.82-3.73 (m, 6H), 3.35-3.18 (m, 2H), 3.29 (s, 2.5H), 2.97 (s, 0.5H), 1.92-2.13 (m, 2H), 1.83-1.73 (m, 1H), 1.67-1.55 (m, 1H), 1.6-0.92 (m, 6H).
Example 2.41.200S.
[0582] (S)-2-(((2S, 3R, 4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1 ,2,3-triazol-1-yl)tetra hydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetra hydro-2H-pyran-4-4-N-isobutyl-N-methylacetamide
[0583] Separation of the epimers of Example 2.41.200. (0.022 g) by chiral preparative HPLC (II) yielded Example 2.41.200S. (0.013 g) as a beige solid. Chiral analytical HPLC (F): t.sub.R=2.02 min; [M-FH]+: 605.41.
[0584] LC-MS and Gal-3 inhibition data of Example 2.41.200. are listed in Table 2 below. The LC-MS conditions used were LC-MS (A). Chiral HPLC (conditions and retention time) and inhibition data of the epimers R and S of Example 2.41.200. are also listed.
TABLE-US-00007 TABLE 2 t.sub.R Chiral t.sub.R chiral IC.sub.50 Example Name [min] [M + H].sup.+ HPLC [min] [uM] 2.41.200. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.79 605.41 0.06 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2- (4-hydroxytetrahydro-2H-pyran-4-yl)-N-isobutyl-N- methylacetamide 2.41.200R. (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.79 605.41 Chiralcel OJ-H 1.47 4.01 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 15% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2- 5 min run (4-hydroxytetrahydro-2H-pyran-4-yl)-N-isobutyl-N- methylacetamide 2.41.200S. (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.79 605.41 Chiralcel OJ-H 2.02 0.05 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 15% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2- 5 min run (4-hydroxytetrahydro-2H-pyran-4-yl)-N-isobutyl-N- methylacetamide
[0585] Example 2.31.201.
[0586] 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxv-6-(hydroxvmethvI)-4-(4-(3,4,5-trifluorochenv1)-1H-1,23-triazol-1-yl)tetrahvdro-2H-cyran-2-yl)thio)-3-hydroxv-N,N,3-trimethvlbutanamide 1. tert-Butyl 2-(((2S,3R, 4S,5R, 6R)-3,5-bis((4-Chlorobenzy0oxy)-64(4-chlorobenzy0oxy)m ethyl) -44443,4,5-trifluorophenyl)-1 H-1 ,2,3-triazol-1-Atetrahydro-2H-pyran-2.sub.11)thio)-3-hydroxy-3-rnethylbutanoate Intermediate 4 (1.6 g, 1.2 mmol) and tert-butyl 3-hydroxy-2-mercapto-3-methylbutanoate (Intermediate 7) (0.35 g, 1.7 mmol, 1.4 eq) are dissolved in EA (12.5 mL) and TBAB (0.89 g, 1.55 mmol, 0.25 eq) in aq. 1M Na.sub.2CO.sub.3 (6.2 mL) is added. The mixture is stirred for 17 h and diluted with EA (25.0 mL), water (25.0 mL) and brine (25.0 mL). The phases are separated and the aq. layer is extracted with EA (50.0 mL). The combined organic phase is dried over Na.sub.2SO.sub.4, filtered and solvent removed in vacuo . The residue is purified by preparative HPLC/MS(II) to recover the title compound as a beige solid (0.55 g, 49%). LC-MS (A): t.sub.R=1.33 min; [M-FH]+: 922.15.
[0587] 2.2-(((2S,3R,4S,5R,6R)-3,5-bis((4-Chlorobenzy0oxy)-64(4-chlorobenzyl)oxy)methyl)-4-(4-(3,4,5-trifluoropheny0-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-3-methylbutanoic acid TFA (0.23 mL, 3.0 mmol, 5.0 eq) is added at rt to a solution of tert-butyl 2-(((2S,3R,4S,5R,6R)-3,5-bis((4-chlorobenzypoxy)-6-(((4-chlorobenzypoxy)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-3-methylbutanoate (0.55 g, 0.6 mmol) in DCM (50.0 mL) and stirred at rt for 17 h. TFA (0.23 mL, 1.55 mmol, 5.0 eq) is added again and stirred at rt for additional 48 h. The mixture is carefully neutralized with aq.
[0588] 1M NaOH, diluted with DCM and the layers are separated. The aqueous layer is extracted with DCM (3x). The combined organic layer is dried over Na.sub.2SO.sub.4, filtered and solvent removed in vacuo to recover the crude title compound as a beige solid (0.48 g, 93%), that is used without further purification. LC-MS (A): t.sub.R=1.21 min; [M-FH]+: 868.10.
[0589] 3. 2-(((2S,3R,4S,5R,6R)-3,5-bis((4-Chlorobenzyl)oxy)-64(4-chlorobenzyl)oxy)methyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1 ,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N,N,3-trimethylbutanamide
[0590] To a solution of crude 2-(((2S,3R,4S,5R,6R)-3,5-bis((4-chlorobenzypoxy)-6-(((4-chlorobenzypoxy)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-3-methylbutanoic acid (0.8 g, 0.09 mmol) in DMF (1.0 mL) at rt are successively added EDC HCI (0.044 mg, 0.23 mmol, 2.5 eq), HOBT (0. 017 g, 0.11 mmol, 1.2 eq), 4-DMAP (0.003 g, 0.023 mmol, 0.25 eq), DIPEA (0.047 mL, 0.277 mmol, 3.0 eq) and dimethyl amine (0.008 g, 0.185 mmol, 2.0 eq). The reaction mixture is stirred at rt for 4 h, then dimethylamine (0.002 g, 0.0046 mmol, 0.5 eq), DIPEA (0.008 mL, 0.07 mmol, 0.5 eq), a spatula tip of each HOBT, EDC HCI and 4-DMAP are added again. After additional 2 h at rt the reaction mixture is partitioned between aq. 1N NaOH and EA, the layers are separated and the aqueous layer is extracted with EA. The combined organic layer is dried over Na.sub.2SO.sub.4, filtered and solvent removed in vacuo. The crude is purified by preparative HPLC/MS (I) to recover the title compound (0.018 g, 22%) as a beige solid. LC-MS (A): t.sub.R=1.25 min; [M-FH]+: 895.56.
[0591] 4. 2-(((2S, 3R, 4S, 5R, 6R)-3, 5-Di hydroxy-6-(hydroxymethy0-4-(4-(3,4,5-trif luorophenyl)-1 H-1, 2,3-triazol-111)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N,N,3-trimethylbutanamide (2.31.201.) To a cooled (0° C.) solution of 2-(((2S,3R,4S,5R,6R)-3,5-bis((4-chlorobenzypoxy)-6-(((4-chlorobenzypoxy)methyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N,N,3-trimethylbutanamide (0.018 g, 0.02 mmol) in DCM (2.0 mL) is added BBr.sub.3 solution (1M in DCM, 0.2 mL, 10.0 eq). The reaction mixture is stirred at 0° C. for 1.5 h, then quenched through dropwise addition of water at 0° C. The layers are separated, the aq. layer is extracted with DCM (2x), the combined org. layer is washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue is purified by preparative HPLC/MS (I) to recover the title compound as a beige powder (0.008 g, 73%). LC-MS (A): t.sub.R=0.67 min; [M-FH]+: 521.41.
Example 2.31.203R.
[0592] (R)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-3-hydroxy-N,3-dimethylbutanamide 0.31.203R.)
[0593] Example 2.31.203. is prepared as described for Example 2.31.201. Separation of the epimer of Example 2.31.203. (0.097 g) by chiral preparative HPLC (111) yielded the title compound (0.029 g) as a white powder. Chiral analytical
[0594] HPLC (G): t.sub.R=1.43 min.
Example 2.31.203S.
[0595] (S)-2-(((2S, 3R, 4S, 5R, 6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-triazol-1-Votetrahydro-2H-pyran-2-0)thio)-N-ethyl-3-hydroxy-N,3-dim ethylbutanamide
[0596] Separation of th. epimer of Example 2.31.203. (0.097 g) by chiral preparative HPLC (Ill) in analogy to Example 2.31.203R. yielded the title compound (0.047 g) as a white powder. Chiral analytical HPLC (G): t.sub.R=2.1 min.
[0597] Following examples are prepared starting from either Intermediate 4 or Intermediate 5 and Intermediate 7, according to the procedures described for Example 2.31.201. LC-MS and Gal-3 inhibition data are listed in Table 3 below. The LC-MS conditions used are 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 Chiral t.sub.R chiral IC.sub.50 Example Name [min] [M + H].sup.+ HPLC [min] [uM] 2.31.201. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.67 521.41 0.27 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-3-hydroxy-N,N,3-trimethylbutanamide 2.31.203. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.71 535.22 0.21 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-N-ethyl-3-hydroxy-N,3- dimethylbutanamide 2.31.203R. (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.73 535.05 Chiralpak IC 1.43 3.88 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- B: 35% EtOH 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- 5 min run yl)thio)-N-ethyl-3-hydroxy-N,3- dimethylbutanamide 2.31.203S. (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.72 535.05 Chiralpak IC 2.1 0.07 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- B: 35% EtOH 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- 5 min run yl)thio)-N-ethyl-3-hydroxy-N,3- dimethylbutanamide 2.31.202. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.75 549.17 0.16 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-N,N-diethyl-3-hydroxy-3- methylbutanamide 2.31.204. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.70 548.29 0.14 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-3-hydroxy-3-methyl-1-(2- methylazetidin-1-yl)butan-1-one 2.31.205R.* (R)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- 0.70 548.27 Chiralcel OJH 2.77 2.13 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- B: 10% EtOH 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- 5 min run yl)thio)-3-hydroxy-3-methyl-1-(3- methylazetidin-1-yl)butan-1-one 2.31.205S.* (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- 0.70 548.27 Chiralcel OJH 2.00 0.27 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- B: 10% EtOH 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- 5 min run yl)thio)-3-hydroxy-3-methyl-1-(3- methylazetidin-1-yl)butan-1-one 2.31.206. 1-(Azetidin-1-yl)-2-(((2S,3R,4S,5R,6R)-3,5- 0.66 533.39 0.20 dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-3- methylbutan-1-one *Epimers are separated during the purification on preparative HPLC/MS(I) or HPLC/MS(II).
[0598] Following examples are prepared starting from Intermediate 4 or Intermediate 5 and either Intermediate 8 or Intermediate 9, according to the procedures described for Example 2.31.201. LC-MS and Gal-3 inhibition data are listed in Table 4 below. The LC-MS conditions used are 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-00009 TABLE 4 t.sub.R Chiral t.sub.R chiral IC.sub.50 Example Name [min] [M + H].sup.+ HPLC [min] [uM] 2.40.200. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.61 589.81 0.08 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(4-hydroxy-1-methylpiperidin-4-yl)-N-isobutyl- N-methylacetamide 2.40.203. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.68 618.04 0.08 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- N-ethyl-2-(4-hydroxy-1-methylpiperidin-4-yl)-N- methylacetamide 2.40.207. N-Benzyl-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy- 0.71 652.01 0.09 6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-2-(4-hydroxy-1-methylpiperidin-4-yl)-N- methylacetamide 2.40.208. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.66 616.03 0.03 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(4-hydroxy-1-methylpiperidin-4-yl)-1- (piperidin-1-yl)ethan-1-one 2.40.209. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.71 649.91 0.12 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(4-hydroxy-1-methylpiperidin-4-yl)-1-(indolin- 1-yl)ethan-1-one 2.41.201. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.66 563.36 0.18 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N,N- dimethylacetamide 2.41.201R. (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.66 563.36 Chiralcel OJ-H 1.26 4.1 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 20% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 3 min run 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N,N- dimethylacetamide 2.41.201S. (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.66 563.36 Chiralcel OJ-H 1.65 0.06 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 20% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 3 min run 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N,N- dimethylacetamide 2.41.202. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.75 590.93 0.05 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- N,N-diethyl-2-(4-hydroxytetrahydro-2H-pyran-4- yl)acetamide 2.41.204. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.69 589.33 0.21 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-1-(2- methylazetidin-1-yl)ethan-1-one 2.41.205R.* (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.69 589.34 Chiralpak IB 3.2 1.00 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 25% (1/1) 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- MeCN/EtOH 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-1-(3- 5 min run methylazetidin-1-yl)ethan-1-one 2.41.205S.* (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.7 589.34 Chiralpak IB 2.83 0.12 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 25% (1/1) 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- MeCN/EtOH 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-1-(3- 5 min run methylazetidin-1-yl)ethan-1-one 2.41.206. 1-(Azetidin-1-yl)-2-(((2S,3R,4S,5R,6R)-3,5- 0.65 575.35 0.26 dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H- pyran-4-yl)ethan-1-one 2.41.207. N-Benzyl-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy- 0.82 639.1 0.07 6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)- N-methylacetamide 2.41.207R. (R)-N-Benzyl-2-(((2S,3R,4S,5R,6R)-3,5- 0.82 639.1 Chiralpak ID 2.71 8.23 dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- B: 35% 2ProOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 5 min run 2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H- pyran-4-yl)-N-methylacetamide 2.41.207S. (S)-Benzyl-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy- 0.82 639.1 Chiralpak ID 3.47 0.04 6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- B: 35% 2ProOH 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- 5 min run yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)- N-methylacetamide 2.41.208. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.75 603.16 0.09 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-1- (piperidin-1-yl)ethan-1-one 2.41.208R. (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.75 603.16 Chiralcel OJ-H 1.07 1.65 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 25% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-1- (piperidin-1-yl)ethan-1-one 2.41.208S. (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.75 603.16 Chiralcel OJ-H 1.67 0.02 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 25% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-1- (piperidin-1-yl)ethan-1-one 2.41.209. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.83 636.98 0.15 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-1- (indolin-1-yl)ethan-1-one 2.41.209R. (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.83 636.98 Chiralpak ID 1.26 1.31 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 45% EtOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-1- (indolin-1-yl)ethan-1-one 2.41.209S. (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.83 636.98 Chiralpak ID 1.75 0.1 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 45% EtOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-1- (indolin-1-yl)ethan-1-one 2.41.210. 2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- 0.81 645.06 0.44 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N- methyl-N-(thiophen-2-ylmethyl)acetamide 2.41.211. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.69 589.11 0.13 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-1- (pyrrolidin-1-yl)ethan-1-one 2.41.212. (R)-N-(cyclopentylmethyl)-2- 0.85 631.03 0.08 (((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-(4-hydroxytetrahydro-2H-pyran-4-yl)-N- methylacetamide 2.41.212R. (S)-N-(cyclopentylmethyl)-2- 0.85 631.03 Chiralcel OJ-H 1.76 6.35 (((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- B: 15% MeOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N- methylacetamide 2.41.212S. (S)-N-Cyclopentylmethyl)-2-(((2S,3R,4S,5R,6R)- 0.85 631.03 Chiralcel OJ-H 2.75 0.01 3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- B: 15% MeOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 5 min run 2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H- pyran-4-yl)-N-methylacetamide 2.41.213. 2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- 0.72 647.01 0.08 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N- methyl-N-((tetrahydro-2H-pyran-4- yl)methyl)acetamide 2.41.214. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.76 661.03 0.03 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)- N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide 2.41.215. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.6 643.02 0.06 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N- methyl-N-((1-methyl-1H-imidazol-4- yl)methyl)acetamide 2.41.216. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.75 661 0.06 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N- methyl-N-(2-(tetrahydro-2H-pyran-4- yl)ethyl)acetamide 2.41.216R. (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.75 661 Chiralcel OJ-H 1.89 1.53 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 15% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N- methyl-N-(2-(tetrahydro-2H-pyran-4- yl)ethyl)acetamide 2.41.216S. (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.75 661 Chiralcel OJ-H 3.5 0.02 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 15% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N- methyl-N-(2-(tetrahydro-2H-pyran-4- yl)ethyl)acetamide 2.41.217. N-(2-Cyclopropylethyl)-2-(((2S,3R,4S,5R,6R)- 0.8 617.01 0.06 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-(4-hydroxytetrahydro-2H- pyran-4-yl)-N-methylacetamide 2.41.218. N-(Cyclopropylmethyl)-2-(((2S,3R,4S,5R,6R)- 0.76 603.02 0.8 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-(4-hydroxytetrahydro-2H- pyran-4-yl)-N-methylacetamide 2.41.218R. (R)-N-(Cyclopropylmethyl)-2- 0.76 603.02 Chiralcel OJ-H 1.7 2.25 (((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- B: 15% MeOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N- methylacetamide 2.41.218S. (S)-N-(Cyclopropylmethyl)-2- 0.76 603.02 Chiralcel OJ-H 2.81 0.02 (((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- B: 15% MeOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N- methylacetamide *Epimers are separated during the purification on preparative HPLC/MS(I) or HPLC/MS(II).
[0599] Example 2.41.203.
[0600] 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxv-6-(hydroxymethyl)-4-(4-(3,4,5-trif luorochenv1)-1 H-1, 23-triazol-1-v1)tetra hydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide 1. (2R, 3R, 4S, 5R, 6S)-2-(Acetoxymethyl)-642-(tert-butoxy)-1-(4-hydroxytetra hydro-2H-pyra n-4-yl)-2-oxoethyl)thio)-4-(4-(3, 4, 5-trifluorophenyl)-1 H-1 , 2, 3-triazol-1-yl)tetra hydro-2H-pyra n-3, 5-diyl diacetate TBAB (0. 22 g, 0.681 mmol, 0.25 eq) is added to a solution of Intermediate 3 (1.5 g, 2.73 mmol) and tert-butyl 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-mercaptoacetate (Intermediate 8) (0. 95 g 1.4 eq) in EA (35.0 mL) followed by aq. 1M Na.sub.2CO.sub.3 (8.0 mL). The mixture is stirred at rt for 17 h, diluted with EA (25.0 mL), water (25.0 mL) and brine (25.0 mL). The phases are separated and the aq. layer is extracted with EA (50.0 mL). The combined organic phase is dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue is purified by Flash Master (ISCO; compound linked on isolute and eluted with EA/Hept 0/100 to 70/30) to recover the title compound as a beige powder (1.8 g, 91%). LC-MS (A): t.sub.R=1.04-1.05 min; [M-FH]+: 717.92.
[0601] 2. 2-(((2S, 3R, 4S, 5R, 6R)-3, 5-Diacetoxy-6-(acetoxym ethy0-4-(4-(3, 4, 5-tri f luorophenyl)-1 H-1 , 2, 3-triazol-111)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yOacetic acid To a solution of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-64(2-(tert-butoxy)-1-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-oxoethypthio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate (3.8 g, 4.32 mmol) in DCM (80.0 mL) is added TFA (4.9 mL, 17.0 eq) at rt. The reaction mixture is stirred at rt for 17 h, carefully quenched by the addition of aq. 2N NaOH (until pH=7), diluted with DCM and the layers separated. The aqueous layer is extracted with EA (3x). The combined organic layer is dried over Na.sub.2SO.sub.4, filtered and solvent removed in vacuo to recover the title compound as a beige powder (3.8 g, >99%), that is used without further purification. LC-MS (A): t.sub.R =0.86 min; [M-FH]+: 662.29.
[0602] 3. (2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-642-(ethyl(methyl)amino)-1-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-oxoethyl)thio)-4-(4-(3,4,5-trifluoropheny0-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate 2-(((2S,3R,4S,5R,6R)-3,5-Diacetoxy-6-(acetoxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)acetic acid (4.0 g, 6.0 mmol) is dissolved in DMF (40.0 mL). HATU (2.53 g, 6.32 mmol, 1.05 eq) followed by a solution of N-ethylmethylamine (0.8 mL, 9.03 mmol, 1.5 eq) and DIPEA (1.8 mL, 10.2 mmol, 1.7 eq) in DMF (10.0 mL) are added. The reaction mixture is stirred at rt for 17 h, then partitioned between EA and water. The organic phase is washed with water and the combined aq. phase is extracted with EA. The combined organic phase is dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to recover the crude that is purified by Flash Master (ISCO, Column 80 g, compound linked on isolute and eluted with EA/Hept 35/65 to 100/0. The title compound is obtained as a beige powder (2.28 g, 54%). LC-MS (A): t.sub.R=0.96 min; [M-FH]+: 703.16.
[0603] 4. 2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trif luorophenyl)-1 H-1,2,3-triazol-111)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide (2.41.203.)
[0604] To a solution of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((2-(ethyl(methyl)amino)-1-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-oxoethypthio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate (0.72 g, 1.02 mmol) in MeOH (10.0 mL) is added K.sub.2CO.sub.3 (0.028 g, 0.2 eq) at rt. The reaction mixture is stirred at rt, diluted with MeCN and water and directly purified by preparative HPLC/MS(I) to recover the title compound as a beige powder (0.5 g, 85%). LC-MS (A): t.sub.R=0.71 min; [M-FH]+: 577.98.
Example 2.41.203R.
[0605] (R)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxv-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenv1)-1 H-1 ,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-0)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-0)-N-methylacetamide
[0606] Separation of the epimers of Example 2.41.203. (2.77 g) by chiral preparative HPLC/MS (IV) yielded the title compound (0.88 g) as a white powder. Chiral analytical HPLC (H): t.sub.R=1.53 min; [M-FH]+: 605.41. .sup.1H NMR (400 MHz, MeOD) δ: 8.53 (s, 0.4H), 8.51 (s, 0.6H), 7.65 (m, 2H), 4.87 (m, 1H), 4.82 (d, J1=9.5 Hz, 1.0 H), 4.2 (t, 10.5 Hz, 1H), 4.16 (s, 1H), 4.4 (d, J=2.5 Hz, 1H), 3.95-3.71 (m, 7H), 3.55-3.4 (m, 2H), 3.28 (s, 1.8H), 2.7 (s, 1.2H), 2.13-1.92 (m, 2H), 1.83-1.73 (m, 1H), 1.62-1.55 (m, 1H), 1.3 (t, J=7.0 Hz, 1.3 H), 1.15 (t, J=7.0 Hz, 1.8 H).
Example 2.41.203S.
[0607] (S)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-triazol-1-votetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4.sub.11)-N-methylacetarnide [1 ,3-di-deoxy-1-((N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide)-(S)-thio)-3-[4-(3,4,5-trif luoropheny0-1 H-1, 2,3-triazol-1-yl]-D-qalactopyranoside] Separation of the epimers of Example 2.41.203. (2.77 g) by chiral preparative HPLC/MS (IV) yielded the title compound (0.163 g) as a white powder. Chiral analytical HPLC (H): t.sub.R=2.4 min; [M-FH]+: 605.41. .sup.1H NMR (400 MHz, MeOD) δ: 8.58 (s, 0.6H), 8.56 (s, 0.4H), 7.65 (m, 2H), 4.9-4.85 (m, 1H), 4.78 (d, J=9.5 Hz, 0.5H), 4.74 (d, J=9.3 Hz, 0.5H), 4.25 (t, 10.5 Hz, 1H), 4.21 (s, 0.5H), 4.16 (s, 0.5H), 4.13 (m, 1H), 3.85-3.71 (m, 7H), 3.6-3.4 (m, 2H), 3.25 (s, 1.8H), 3.0 (s, 1.2H), 2.13-1.92 (m, 2H), 1.83-1.73 (m, 1H), 1.62-1.55 (m, 1H), 1.3 (t, J=7.3 Hz, 1.3 H), 1.14 (t, J =7.0 Hz, 1.8 H).
[0608] Following examples are prepared starting from tert-butyl sulfanyl acetate, the corresponding cyclic ketones (Intermediate 8, 9, and analogous) and Intermediate 3, according to the procedures described for Example 2.41.201. LC-MS and Gal-3 inhibition data are listed in Table 5 below. The LC-MS conditions used are 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-00010 TABLE 5 t.sub.R Chiral t.sub.R chiral IC.sub.50 Example Name [min] [M + H].sup.+ HPLC [min] [uM] 2.41.203. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.7 577.05 0.09 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)- N-methylacetamide 2.41.203R. (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.7 577.05 Chiralcel OJ-H 1.53 4.43 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 15% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)- N-methylacetamide 2.41.203S. (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.7 577.05 Chiralcel OJ-H 2.4 0.03 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 15% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)- N-methylacetamide 2.41.219. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.78 631.16 0.11 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N- methyl-N-(2,2,2-trifluoroethyl)acetamide 2.41.236. N-(Cyclopropylmethyl)-2-(((2S,3R,4S,5R,6R)- 0.8 618.1 4.47 3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-2-yl)thio)-N-ethyl-2-(4- hydroxytetrahydro-2H-pyran-4-yl)acetamide 2.41.235. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.66 605.4 0.06 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N- methyl-N-(oxetan-3-yl)acetamide 2.41.235R. (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- Chiracel OJ-H 1.71 2.4 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 20% (1/1) 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- ACN/EtOH 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N- 5 min run methyl-N-(oxetan-3-yl)acetamide 2.41.235S. (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- Chiracel OJ-H 1.26 0.04 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 20% (1/1) 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- ACN/EtOH 2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N- 5 min run methyl-N-(oxetan-3-yl)acetamide 2.39.203. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.81 575.3 0.07 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- N-ethyl-2-(1-hydroxycyclohexyl)-N- methylacetamide 2.39.208. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.87 601.3 0.02 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(1-hydroxycyclohexyl)-1-(piperidin-1-yl)ethan- 1-one 2.39.219R.* (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.89 629.20 Chiralpak IB 1.4 0.27 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 30% EtOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run 2-(1-hydroxycyclohexyl)-N-methyl-N-(2,2,2- trifluoroethyl)acetamide 2.39.219S.* (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.89 629.20 Chiralpak IB 1.7 0.06 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 30% EtOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run 2-(1-hydroxycyclohexyl)-N-methyl-N-(2,2,2- trifluoroethyl)acetamide 2.39.220. N-Cyclobutyl-2-(((2S,3R,4S,5R,6R)-3,5- 0.88 601.28 0.01 dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-2-yl)thio)-2-(1-hydroxycyclohexyl)-N- methylacetamide 2.39.222. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.90 621.29 0.05 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- N-(2-fluoro-2-methylpropyl)-2-(1- hydroxycyclohexyl)-N-methylacetamide 2.39.222R. (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.90 621.29 Chiralpak ID 1.91 10.2 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 25% EtOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run N-(2-fluoro-2-methylpropyl)-2-(1- hydroxycyclohexyl)-N-methylacetamide 2.39.222S. (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.90 621.29 Chiralpak ID 2.3 0.02 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 25% EtOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run N-(2-fluoro-2-methylpropyl)-2-(1- hydroxycyclohexyl)-N-methylacetamide [1,3-di- deoxy-1-((N-(3-fluoro-3-methylbutyl)-2-(1- hydroxycyclohexyl)-N-methylacetamide)-(S)- thio)-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3- triazol-1-yl]-β-D-galactopyranoside] 2.39.224R.* (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.80 680.22 Chiralpak ID 2.97 1.4 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 40% MeCN/ 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-ProOH (1/1) 2-(1-hydroxycyclohexyl)-N-methyl-N-(pyridin-2- 5 min run ylmethyl)acetamide 2.39.224S.* (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.80 680.22 Chiralpak ID 2.46 0.06 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 40% MeCN/ 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-ProOH (1/1) 2-(1-hydroxycyclohexyl)-N-methyl-N-(pyridin-2- 5 min run ylmethyl)acetamide [1,3-di-deoxy-1-((2-(1- hydroxycyclohexyl)-N-methyl-N-(pyridin-2-yl- methyl)acetamide)-(S)-thio)-3-[4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl]-β-D- galactopyranoside] 2.44.201. 2-(4,4-Difluoro-1-hydroxycyclohexyl)-2- 0.81 596.99 0.10 (((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)- N,N-dimethylacetamide 2.44.201R. 2-(4,4-Difluoro-1-hydroxycyclohexyl)-2- 0.81 596.99 Chiralpak AD-H 0.96 1.33 (((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- B: 50% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- N,N-dimethylacetamide 2.44.201S. 2-(4,4-Difluoro-1-hydroxycyclohexyl)-2- 0.81 596.99 Chiralpak AD-H 1.52 0.04 (((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- B: 50% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- N,N-dimethylacetamide 2.44.203. 2-(4,4-Difluoro-1-hydroxycyclohexyl)-2- 0.81 575.3 0.06 (((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)- N-ethyl-N-methylacetamide 2.44.206R.* (R)-N-Cyclobutyl-2-(4,4-difluoro-1- 0.79 609.23 Chiralcel OJH 1.6 0.44 hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-3,5- B: 15% MeOH dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-2-yl)thio)-N-methylacetamide 2.44.206S.* (S)-N-Cyclobutyl-2-(4,4-difluoro-1- 0.79 609.23 Chiralcel OJH 2.34 0.04 hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-3,5- B: 15% MeOH dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-2-yl)thio)-N-methylacetamide 2.44.208. 2-(4,4-Difluoro-1-hydroxycyclohexyl)-2- 0.87 601.3 0.07 (((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)- 1-(piperidin-1-yl)ethan-1-one 2.44.208R. (R)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-2- 0.87 601.3 Chiralpak AD-H 2.1 3.36 (((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- B: 45% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 3 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 1-(piperidin-1-yl)ethan-1-one 2.44.208S. (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-2- 0.87 601.3 Chiralpak AD-H 1.2 0.02 (((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- B: 45% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 3 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 1-(piperidin-1-yl)ethan-1-one 2.44.218. N-(Cyclopropylmethyl)-2-(4,4-difluoro-1- 0.89 637.33 0.02 hydroxycyclohexyl)-2-(((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)-N-methylacetamide 2.44.218R. (R)-N-(Cyclopropylmethyl)-2-(4,4-difluoro-1- 0.89 637.33 Chiralcel OJ-H 1.52 1.15 hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-3,5- B: 15% MeOH dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-2-yl)thio)-N-methylacetamide 2.44.218S. (S)-N-(Cyclopropylmethyl)-2-(4,4-difluoro-1- 0.89 637.33 Chiralcel OJ-H 2.19 0.05 hydroxycyclohexyl)-2-(((2S,3R,4S,5R,6R)-3,5- B: 15% MeOH dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-2-yl)thio)-N-methylacetamide 2.44.221. N-Cyclopropyl-2-(4,4-difluoro-1- 0.86 623.17 0.03 hydroxycyclohexyl)-2-(((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)-N-methylacetamide 2.44.222. 2-(4,4-Difluoro-1-hydroxycyclohexyl)-2- 0.90 621.29 0.13 (((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)- N-(2-fluoro-2-methylpropyl)-N-methylacetamide 2.44.223. 2-(4,4-Difluoro-1-hydroxycyclohexyl)-2- 0.95 683.33 0.05 (((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)- N-((1-fluorocyclopentyl)methyl)-N- methylacetamide 2.44.223R. 2-(4,4-Difluoro-1-hydroxycyclohexyl)-2- 0.95 683.33 Chiralpak AD-H 1.99 3.57 (((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- B: 30% 2ProOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- N-((1-fluorocyclopentyl)methyl)-N- methylacetamide 2.44.223S. (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-2- 0.95 683.33 Chiralpak AD-H 3.04 0.07 (((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- B: 30% 2-ProOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- N-((1-fluorocyclopentyl)methyl)-N- methylacetamide 2.44.225. 2-(4,4-Difluoro-1-hydroxycyclohexyl)-2- 0.98 667.28 0.07 (((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)- N-(3,3-dimethylbutyl)-N-methylacetamide 2.44.226. 2-(4,4-Difluoro-1-hydroxycyclohexyl)-1-(4,4- 0.90 673.23 0.09 difluoropiperidin-1-yl)-2-(((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)ethan-1-one 2.44.227R.* (R)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-1-(3,3- 0.84 646.01 Chiralcel OJH 1.16 1.05 difluoroazetidin-1-yl)-2-(((2S,3R,4S,5R,6R)-3,5- B: 18% (1/1) dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- ACN/EtOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 3 min run 2H-pyran-2-yl)thio)ethan-1-one 2.44.227S.* (S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-1-(3,3- 0.84 646.01 Chiralcel OJH 1.93 0.10 difluoroazetidin-1-yl)-2-(((2S,3R,4S,5R,6R)-3,5- B: 18% (1/1) dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- ACN/EtOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 3 min run 2H-pyran-2-yl)thio)ethan-1-one 2.38.203. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.77 561.31 0.43 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- N-ethyl-2-(1-hydroxycyclopentyl)-N- methylacetamide 2.38.206. 1-(Azetidin-1-yl)-2-(((2S,3R,4S,5R,6R)-3,5- 0.71 559.23 0.23 dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-2-yl)thio)-2-(1- hydroxycyclopentyl)ethan-1-one 2.38.219. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.86 615.18 0.04 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(1-hydroxycyclopentyl)-N-methyl-N-(2,2,2- trifluoroethyl)acetamide 2.38.220. N-Cyclobutyl-2-(((2S,3R,4S,5R,6R)-3,5- 0.85 587.28 0.03 dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-2-yl)thio)-2-(1-hydroxycyclopentyl)-N- methylacetamide 2.38.228. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.90 603.32 0.15 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(1-hydroxycyclopentyl)-N-methyl-N- neopentylacetamide 2.34.203. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.73 547.22 0.40 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- N-ethyl-2-(1-hydroxycyclobutyl)-N- methylacetamide 2.34.203R. (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.73 547.22 Chiralcel OJ-H 1.37 3.58 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 15% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2.5 min run N-ethyl-2-(1-hydroxycyclobutyl)-N- methylacetamide 2.34.203S. (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.73 547.22 Chiralcel OJ-H 1.71 0.12 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 15% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2.5 min run N-ethyl-2-(1-hydroxycyclobutyl)-N- methylacetamide 2.34.206. 1-(Azetidin-1-yl)-2-(((2S,3R,4S,5R,6R)-3,5- 0.70 545.2 1.20 dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-2-yl)thio)-2-(1- hydroxycyclobutyl)ethan-1-one 2.34.206R. (R)-1-(Azetidin-1-yl)-2-(((2S,3R,4S,5R,6R)-3,5- 0.70 545.2 Chiralcel OJ-H 1.57 1.8 dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- B: 15% MeOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 5 min run 2H-pyran-2-yl)thio)-2-(1- hydroxycyclobutyl)ethan-1-one 2.34.206S. (S)-1-(Azetidin-1-yl)-2-(((2S,3R,4S,5R,6R)-3,5- 0.70 545.2 Chiralcel OJ-H 2.07 0.34 dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- B: 15% MeOH trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 5 min run 2H-pyran-2-yl)thio)-2-(1- hydroxycyclobutyl)ethan-1-one 2.34.208. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.81 573.25 0.38 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(1-hydroxycyclobutyl)-1-(piperidin-1-yl)ethan- 1-one 2.34.208R. (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.81 573.25 Chiralcel OJ-H 1.54 3.24 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 15% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run 2-(1-hydroxycyclobutyl)-1-(piperidin-1-yl)ethan- 1-one 2.34.208S. (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.81 573.25 Chiralcel OJ-H 2.05 0.14 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 15% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run 2-(1-hydroxycyclobutyl)-1-(piperidin-1-yl)ethan- 1-one 2.34.218. N-(Cyclopropylmethyl)-2-(((2S,3R,4S,5R,6R)- 0.81 573.24 0.31 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-(1-hydroxycyclobutyl)-N- methylacetamide 2.34.218R. (R)-N-(Cyclopropylmethyl)-2- 0.81 573.24 Chiralpak IB 6.08 (((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- B: 30% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(1-hydroxycyclobutyl)-N-methylacetamide 2.34.218S. (S)-N-(Cyclopropylmethyl)-2- 0.81 573.24 Chiralpak IB 0.06 (((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- B: 30% EtOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(1-hydroxycyclobutyl)-N-methylacetamide [1,3-di-deoxy-1-((2-(3,3-difluoro-1- hydroxycyclobutyl)-N-ethyl-N- methylacetamide)-(S)-thio)-3-[4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl]-β-D- galactopyranoside] 2.34.219. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.84 601.18 0.26 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(1-hydroxycyclobutyl)-N-methyl-N-(2,2,2- trifluoroethyl)acetamide 2.34.219R. (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.84 601.18 Chiralcel OJ-H 1.23 7.84 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 15% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run 2-(1-hydroxycyclobutyl)-N-methyl-N-(2,2,2- trifluoroethyl)acetamide 2.34.219S. (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.84 601.18 Chiralcel OJ-H 1.64 0.11 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 15% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run 2-(1-hydroxycyclobutyl)-N-methyl-N-(2,2,2- trifluoroethyl)acetamide 2.34.222. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.83 593.24 0.41 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- N-(2-fluoro-2-methylpropyl)-2-(1- hydroxycyclobutyl)-N-methylacetamide 2.34.222R. (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.83 593.24 Chiralcel OJ-H 2.56 8.61 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 10% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run N-(2-fluoro-2-methylpropyl)-2-(1- hydroxycyclobutyl)-N-methylacetamide 2.34.222S. (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.83 593.24 Chiralcel OJ-H 3.56 0.09 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 10% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run N-(2-fluoro-2-methylpropyl)-2-(1- hydroxycyclobutyl)-N-methylacetamide 2.34.228. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.88 589.27 0.31 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 2-(1-hydroxycyclobutyl)-N-methyl-N- neopentylacetamide 2.34.228R. (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.88 589.27 Chiralcel OJ-H 1.23 5.9 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 15% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run 2-(1-hydroxycyclobutyl)-N-methyl-N- neopentylacetamide 2.34.228S. (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.88 589.27 Chiralcel OJ-H 1.59 0.12 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- B: 15% MeOH 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- 5 min run 2-(1-hydroxycyclobutyl)-N-methyl-N- neopentylacetamide 2.33.203R.* (R)-2-(3,3-Difluoro-1-hydroxycyclobutyl)-2- 0.79 583.26 Chiralpak ID 1.5 1.45 (((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- B: 30% 2-PrOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- N-ethyl-N-methylacetamide 2.33.203S.* (S)-2-(3,3-Difluoro-1-hydroxycyclobutyl)-2- 0.79 583.26 Chiralpak ID 2.27 0.05 (((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- B: 30% 2-PrOH (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)- N-ethyl-N-methylacetamide 2.33.206. 1-(Azetidin-1-yl)-2-(3,3-difluoro-1- 0.76 581.2 0.58 hydroxycyclobutyl)-2-(((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)ethan-1-one 2.33.218R.* (R)-N-(Cyclopropylmethyl)-2-(3,3-difluoro-1- 0.85 609.21 Chiralcel OJ-H 1.61 0.44 hydroxycyclobutyl)-2-(((2S,3R,4S,5R,6R)-3,5- B: 30% 2-PrOH dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-2-yl)thio)-N-methylacetamide 2.33.218S.* (S)-N-(Cyclopropylmethyl)-2-(3,3-difluoro-1- 0.85 609.21 Chiralcel OJ-H 2.62 0.04 hydroxycyclobutyl)-2-(((2S,3R,4S,5R,6R)-3,5- B: 30% 2-PrOH dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-2-yl)thio)-N-methylacetamide *Epimers are separated during the purification on preparative HPLC/MS(I) or HPLC/MS(II).
[0609] Following examples are prepared starting from tert-butyl sulfanyl acetate, the corresponding ketones (Intermediate 7 and analogous) and Intermediate 3, according to the procedures described for Example 2.41.201. LC-MS and Gal-3 inhibition data are listed in Table 6 below. The LC-MS conditions used are 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 Chiral t.sub.R chiral IC.sub.50 Example Name [min] [M + H].sup.+ HPLC [min] [uM] 2.32.203. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.82 563.25 0.49 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-N,3-diethyl-3-hydroxy-N- methylpentanamide 2.32.203R. (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.82 563.25 Chiralcel OJ-H 2.51 4.55 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- B: 10% MeOH 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- 5 min run yl)thio)-N,3-diethyl-3-hydroxy-N- methylpentanamide 2.32.203S. (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.82 563.25 Chiralcel OJ-H 3.07 0.24 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- B: 10% MeOH 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- 5 min run yl)thio)-N,3-diethyl-3-hydroxy-N- methylpentanamide 2.32.218. N-(Cyclopropylmethyl)-2- 0.87 589.31 0.71 (((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-ethyl-3-hydroxy-N- methylpentanamide 2.32.222. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.88 609.27 0.36 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-3-ethyl-N-(2-fluoro-2-methylpropyl)- 3-hydroxy-N-methylpentanamide 2.31.207. N-Benzyl-2-(((2S,3R,4S,5R,6R)-3,5- 0.83 597.21 0.06 dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy- N,3-dimethylbutanamide 2.31.208. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.77 561.05 0.07 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-3-hydroxy-3-methyl-1-(piperidin-1- yl)butan-1-one 2.31.211R.* (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.71 547.21 Chiralpak IB 1.76 0.31 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- B: 30% (1/1) 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- MeCN/EtOH yl)thio)-3-hydroxy-3-methyl-1-(pyrrolidin-1- 5 min run yl)butan-1-one 2.31.211S* (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.71 547.21 Chiralpak IB 2.2 0.08 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- B: 30% (1/1) 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- MeCN/EtOH yl)thio)-3-hydroxy-3-methyl-1-(pyrrolidin-1- 5 min run yl)butan-1-one 2.31.215. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.61 601.21 0.19 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-3-hydroxy-N,3-dimethyl-N-((1- methyl-1H-imidazol-4-yl)methyl)butanamide 2.31.218. N-(Cyclopropylmethyl)-2- 0.78 561.05 0.03 (((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-hydroxy-N,3-dimethylbutanamide 2.31.228. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.84 577.08 0.67 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-3-hydroxy-N,3-dimethyl-N- neopentylbutanamide 2.31.229. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.72 565.03 0.11 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-3-hydroxy-N-(2-methoxyethyl)-N,3- dimethylbutanamide 2.31.230. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.61 620.06 0.11 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-3-hydroxy-N,3-dimethyl-N-(2- morpholinoethyl)butanamide *Epimers are separated during the purification on preparative HPLC/MS(I) or HPLC/MS(II).
[0610] Following examples have been prepared starting from tert-butyl sulfanyl acetate, the corresponding aldehydes and Intermediate 3, according to the procedures described for Example 2.41.201. LC-MS and Gal-3 inhibition data are listed in Table 7 below. The LC-MS conditions used are LC-MS (A).
TABLE-US-00012 TABLE 7 t.sub.R [M + IC.sub.50 Example Name [min] H].sup.+ [uM] 2.60.203. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- 0.72 535.21 0.17 trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-3- hydroxy-N-methylpentanamide 2.60.206. 1-(Azetidin-1-yl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4- 0.68 533.12 0.50 (3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3- hydroxypentan-1-one 2.60.218. N-(Cyclopropylmethyl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- 0.78 561.27 0.12 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-2-yl)thio)-3-hydroxy-N-methylpentanamide 2.64.203. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- 0.84 598.02 0.22 trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-3- hydroxy-N-methyl-4-phenylbutanamide 2.64.206. 1-(Azetidin-1-yl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4- 0.79 595.22 0.71 (3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3- hydroxy-4-phenylbutan-1-one 2.64.218. N-(Cyclopropylmethyl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- 0.89 623.24 0.11 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-2-yl)thio)-3-hydroxy-N-methyl-4-phenylbutanamide 2.65.203. 2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- 0.68 587.26 0.65 trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-3- hydroxy-N-methyl-3-(1-methyl-1H-pyrazol-3-yl)propanamide 2.65.206. 1-(Azetidin-1-yl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-(4- 0.66 585.23 1.04 (3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3- hydroxy-3-(1-methyl-1H-pyrazol-3-yl)propan-1-one 2.65.218. N-(cyclopropylmethyl)-2-(((2S,3R,4S,5R,6R)-3,5-dihydroxy-6- 0.74 613.32 0.69 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-2-yl)thio)-3-hydroxy-N-methyl-3-(1-methyl-1H-pyrazol-3- yl)propanamide
Example 2.47.203.
[0611] 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxv-6-(hydroxvmethvI)-4-(4-(3,4,5-trif luorochenvI)-1 H-1, 23-triazol-1-v1)tetrahvdro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxy-1-(m ethylsulfonyOpiperidin-4-yl)-N-methylacetamide (2R, 3R, 4S,5R,6S)-2-(Acetoxymethyl)-642-(ethyl(methyl)amino)-1-(4-hydroxy-1-(methylsulfonyOpiperidin-4-yl)-2-oxoethyl)thio)-4-(4-(3,4,5-trif luoropheny0-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate
[0612] To a solution of Intermediate 10 (0.06 g, 0.1 mmol) in DCM (3.0 mL) at rt are added methanesulfonyl chloride (0.007 mL, 1.2 eq) and DIPEA (0.041 mL, 0.17 mmol, 3.0 eq). The reaction mixture is stirred at rt for 2 h, then partitioned between DCM and water. The layers are separated, the aqueous layer is extracted with DCM (3x). The combined organic layer is dried over Na.sub.2SO.sub.4, filtered and solvent removed in vacuo to give a colorless oil. The crude is purified by preparative HPLC/MS (II) to recover the title compound as a white powder (0.06 g, 92%). LC-MS (A): t.sub.R=0.97 min; [M-FH]+: 780.18.
[0613] 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5-trifluoropheny0-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxy-1-(methylsulfonyOpiperidin-4-yl)-N-methylacetamide (2.47203.)
[0614] K.sub.2O0.sub.3 (0.001 g, 0.2 eq) is added to a solution of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-64(2-(ethyl(methyl)amino)-1-(4-hydroxy-1-(methylsulfonyl)piperidin-4-yl)-2-oxoethypthio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyldiacetate (0.03 g, 0.04 mmol) in MeOH (1.5 mL) at rt. The reaction mixture is stirred at rt over 17 h, then partitioned between MeCN and water. The mixture is directly purified by preparative HPLC/MS(II) to recover the title compound as a beige powder (0.024 g, 97%). LC-MS (A): t.sub.R=0.74 min; [M-FH]+: 653.97. .sup.1H NMR (400 MHz, MeOD) 5: 8. 56 (m, 1H), 7.65 (m, 2H), 4.9-4.75 (m, 2H), 4.28-4.16 (m, 2H), 4.13 (m, 1H), 3.9-3.71 (m, 3H), 3.65-3.55 (m, 3H), 3.55-3.45 (m, 1H), 3.28 (s, 0.8H), 3.24 (s, 1.2H), 3.15-3.05 (m, 1H), 3.0 (s, 0.5H), 2.97 (s, 0.5H), 2.86 (s, 3H), 2.35-2.23 (m, 1H), 2.4-1.9 (m, 1H), 1.82-1.7 (m, 2H), 1.3 (m, 1.3 H), 1.15 (m, 1.8 H).
Example 2.47.203R.
[0615] (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxv-6-(hydroxvmethvI)-4-(4-(3,4,5-trifluorochenv1)-1H-1,2,3-triazol-1-v1)1efrahvdro-2H-ovran-2-vnthio)-N-ethyl-2-(4-hydroxv-1-(methvIsulfonv1)oioeridin-4-0)-N-methvlacetamide
[0616] Separation of the epimers of Example 2.47.203. (0.024 g) by chiral preparative HPLC (V) yielded the title compound (0.008 g) as a beige powder. Chiral analytical HPLC (J): t.sub.R=2.66 min.
[0617] Example 2.47.203S. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethy0-4-(4-(3,4,5-trifluoropheny0-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxy-1-(methylsulfonyOpiperidin-4-yl)-N-methylacetamide
[0618] Separation of the epimers of Example 2.47.203. (0.024 g) by chiral preparative HPLC (V) yielded the title compound (0.008 g) as a beige powder. Chiral analytical HPLC (J): t.sub.R=3.52 min.
[0619] Following examples have been prepared starting from Intermediate 10, Intermediate 10AR, Intermediate 10AS,
[0620] Intermediate101 and the corresponding sulfonylchlorides, carbamoyl chloride and isocyanate in analogy to Example 2.47.203. LC-MS and Gal-3 inhibition data are listed in Table 8 below. The LC-MS conditions used are 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 Chiral t.sub.R chiral IC.sub.50 Example Name [min] [M + H].sup.+ HPLC [min] [uM] 2.47.203. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.74 653.97 0.03 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-N-ethyl-2-(4-hydroxy-1- (methylsulfonyl)piperidin-4-yl)-N- methylacetamide 2.47.203R. (R)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.74 653.97 Chiralpak IH 2.69 6.77 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- B: 20% MeCN/ 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- EtOH (1/1) yl)thio)-N-ethyl-2-(4-hydroxy-1- 5 min run (methylsulfonyl)piperidin-4-yl)-N- methylacetamide 2.47.203S. (S)-2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6- 0.74 653.97 Chiralpak IH 3.52 0.01 (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)- B: 20% MeCN/ 1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2- EtOH (1/1) yl)thio)-N-ethyl-2-(4-hydroxy-1- 5 min run (methylsulfonyl)piperidin-4-yl)-N- methylacetamide 2.51.203. 2-(1-(Cyclopropylsulfonyl)-4-hydroxypiperidin- 0.78 680.19 0.03 4-yl)-2-(((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)-N-ethyl-N-methylacetamide 2.51.203R. (R)-2-(1-(Cyclopropylsulfonyl)-4- 0.78 680.19 Chiralcel OJ-H 1.31 4.96 hydroxypiperidin-4-yl)-2-(((2S,3R,4S,5R,6R)- B: 25% MeOH 3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-N- methylacetamide 2.51.203S. (S)-2-(1-(Cyclopropylsulfonyl)-4- 0.78 680.19 Chiralcel OJ-H 2.14 0.02 hydroxypiperidin-4-yl)-2-(((2S,3R,4S,5R,6R)- B: 25% MeOH 3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- 5 min run trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-N- methylacetamide [1,3-di-deoxy-1-((2-(1- (cyclopropylsulfonyl)-4-hydroxypiperidin-4-yl)- N-ethyl-N-methylacetamide)-(S)-thio)-3-[4- (3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-β- D-galactopyranoside] 2.49.203. N-Cyclopropyl-4-(1-(((2S,3R,4S,5R,6R)-3,5- 0.71 659.25 0.05 dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-2-yl)thio)-2- (ethyl(methyl)amino)-2-oxoethyl)-4- hydroxypiperidine-1-carboxamide 2.49.203R. (R)-N-Cyclopropyl-4-(1-(((2S,3R,4S,5R,6R)- 0.71 659.25 Chiralcel OJ-H 1.57 2.65 3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- B: 15% MeOH trifluorophenyl)-1H-1,2,3-triazol-1- 5 min run yl)tetrahydro-2H-pyran-2-yl)thio)-2- (ethyl(methyl)amino)-2-oxoethyl)-4- hydroxypiperidine-1-carboxamide 2.49.203S. (S)-N-Cyclopropyl-4-(1-(((2S,3R,4S,5R,6R)- 0.71 659.25 Chiralcel OJ-H 2.04 0.04 3,5-dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- B: 15% MeOH trifluorophenyl)-1H-1,2,3-triazol-1- 5 min run yl)tetrahydro-2H-pyran-2-yl)thio)-2- (ethyl(methyl)amino)-2-oxoethyl)-4- hydroxypiperidine-1-carboxamide 2.50.203. Methyl 4-(1-(((2S,3R,4S,5R,6R)-3,5- 0.76 634.26 0.07 dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-2-yl)thio)-2- (ethyl(methyl)amino)-2-oxoethyl)-4- hydroxypiperidine-1-carboxylate 2.50.203R. (R)-Methyl 4-(1-(((2S,3R,4S,5R,6R)-3,5- 0.76 634.26 Chiralcel OJ-H 1.14 4.45 dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- B: 15% MeOH trifluorophenyl)-1H-1,2,3-triazol-1- 5 min run yl)tetrahydro-2H-pyran-2-yl)thio)-2- (ethyl(methyl)amino)-2-oxoethyl)-4- hydroxypiperidine-1-carboxylate 2.50.203S. (S)-Methyl 4-(1-(((2S,3R,4S,5R,6R)-3,5- 0.76 634.26 Chiralcel OJ-H 1.98 0.04 dihydroxy-6-(hydroxymethyl)-4-(4-(3,4,5- B: 15% MeOH trifluorophenyl)-1H-1,2,3-triazol-1- 5 min run yl)tetrahydro-2H-pyran-2-yl)thio)-2- (ethyl(methyl)amino)-2-oxoethyl)-4- hydroxypiperidine-1-carboxylate 2.58.203R. (2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-6-(((R)- 0.71 606.23 Chiralpak IC 3.1 0.45 2-(ethyl(methyl)amino)-1-(3-hydroxy-1- B: 35% (1/1) (methoxycarbonyl)azetidin-3-yl)-2- MeCN/EtOH oxoethyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate 2.58.203S. (2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-6-(((S)- 0.71 606.19 Chiralpak IC 2.13 0.03 2-(ethyl(methyl)amino)-1-(3-hydroxy-1- B: 35% (1/1) (methoxycarbonyl)azetidin-3-yl)-2- MeCN/EtOH oxoethyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H- 5 min run 1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate 2.49.226.I. N-Cyclopropyl-4-(2-(ethyl(methyl)amino)-1- 0.87 735.16 0.1 (((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-oxoethyl)- 4-hydroxypiperidine-1-carboxamide 2.49.226R.I. N-Cyclopropyl-4-((R)-2-(ethyl(methyl)amino)- Chiralpak IB 2.8 1.74 1-(((2S,3R,4S,5R,6R)-5-hydroxy-6- B: 25% (1/1) (hydroxymethyl)-3-methoxy-4-(4-(3,4,5- MeCN/EtOH trifluorophenyl)-1H-1,2,3-triazol-1- 5 min run yl)tetrahydro-2H-pyran-2-yl)thio)-2-oxoethyl)- 4-hydroxypiperidine-1-carboxamide 2.49.226S.I. N-Cyclopropyl-4-((S)-2-(ethyl(methyl)amino)- Chiralpak IB 2.33 0.06 1-(((2S,3R,4S,5R,6R)-5-hydroxy-6- B: 25% (1/1) (hydroxymethyl)-3-methoxy-4-(4-(3,4,5- MeCN/EtOH trifluorophenyl)-1H-1,2,3-triazol-1- 5 min run yl)tetrahydro-2H-pyran-2-yl)thio)-2-oxoethyl)- 4-hydroxypiperidine-1-carboxamide
[0621] Example 2.41.232.
[0622] 2R,3R,4S,5R,6S)-2-(AcetoxvmethvI)-642-(ethvl(phenvI)amino)-1-(4-hvdroxvtetrahvdro-2H-pvran-4-v1)-2-oxoethyl)thio)-4-(4-(3,4,5-trifluorophenv1)-1 H-1, 2,3-triazol-1-yl)tetra hydro-2H-pvran-3,5-divl diacetate 1. N-Ethyl-N-phenyl-2-((tetrahydro-2H-pyran-2-yl)thio)acetamide N-Ethyl-N-phenyl-2-((tetrahydro-2H-pyran-2-yl)thio)acetamide is prepared from 3,4-dihydro-2H-pyran, ethyl thioglycolate, N-ethyl aniline and tetrahydro-4H-pyran-4-one according to the procedures described for Intermediate 12 as a beige oil. LC-MS (A): t.sub.R=0.81; [M-FH]+: 296.15.
[0623] 2. (2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-642-(ethyl(pheny0amino)-1-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-oxoethyl)thio)-4-(4-(3,4,5-trifluoropheny0-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate To a solution of N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-mercapto-N-phenylacetamide (0.09 g, 0.3 mmol) in aq. 10% Na.sub.2CO.sub.3 (2.0 mL) is added TBAHS (0.62 g, 1.78 mmol, 6.0 eq). To this mixture is added Intermediate 3 (0.22 g, 1.2 mmol, 1.2 eq in EA (4.0 mL) and the mixture is stirred at rt for 15 h, diluted with EA (25.0 mL), water (25.0 mL), and brine (25.0 mL). The phases are separated and the aq. layer is extracted with EA (50.0 mL). The combined organic phase is dried over Na.sub.2SO.sub.4, filtered and solvent removed in vacuo. The residue is purified by preparative HPLC/MS (I) to recover the title compound as a beige powder. (0.06 g, 24%). LC-MS (A): t.sub.R=1.05 min; [M-FH]+: 765.17.
[0624] 3. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy-6-(hydroxymethy0-4-(4-(3,4,5-trifluoropheny0-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-phenylacetamide (2.41.232.)
[0625] K.sub.2O0.sub.3 (0.002 g, 0.014 mmol, 0.2 eq) is added at rt to a solution of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((2-(ethyl(phenyl)amino)-1-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-oxoethypthio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyldiacetate (0.055 g, 0.07 mmol) in MeOH (2.0 mL). The reaction mixture is stirred at rt for 15 h, quenched with MeCN, followed by water and the mixture is directly purified by preparative HPLC/MS (I) to recover the title compound as a beige solid (0.040 g, 87%). LC-MS (A): t.sub.R=0.83 min; [M-FH]+:
[0626] 639.15..sup.1H NMR (400 MHz, MeOD) 6: 8.51-8.62 (m, 1 H), 7.39-7.73 (m, 7 H), 4.75-4.82 (m, 1 H), 4.55-4.68 (m, 0 H), 4.33-4.41 (m, 1 H), 4.05-4.27 (m, 2 H), 3.83-4.00 (m, 1 H), 3.65-3.80 (m, 6 H), 3.55-3.65 (m, 1 H), 3.40-3.54 (m, 2 H), 1.48-2.21 (m, 4 H), 1.08-1.26 (m, 3 H).
[0627] Following aryl/heteroaryl amides have been prepared starting from the corresponding 2-mercapto acetamides (prepared in analogy to Intermediate 12) and Intermediate 2 or Intermediate 14 in analogy to Example 2.41.232. LC-MS and Gal-3 inhibition data are listed in Table 9 below. The LC-MS conditions used are LC-MS (A). Chiral HPLC (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] 2.41.232. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy- 0.83 639.15 0.09 6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-2-yl)thio)-N- ethyl-2-(4-hydroxytetrahydro-2H- pyran-4-yl)-N-phenylacetamide 2.41.231. 2-(((2S,3R,4S,5R,6R)-3,5-Dihydroxy- 0.79 625.06 0.11 6-(hydroxymethyl)-4-(4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1- yl)tetrahydro-2H-pyran-2-yl)thio)-2- (4-hydroxytetrahydro-2H-pyran-4-yl)- N-methyl-N-phenylacetamide 2.41.231R. (R)-2-(((2S,3R,4S,5R,6R)-3,5- 0.80 625.93 Chiralpak ID 3.26 3.44 Dihydroxy-6-(hydroxymethyl)-4-(4- B: 25% (1/1) (3,4,5-trifluorophenyl)-1H-1,2,3- MeCN/EtOH triazol-1-yl)tetrahydro-2H-pyran-2- 5 min run yl)thio)-2-(4-hydroxytetrahydro-2H- pyran-4-yl)-N-methyl-N- phenylacetamide 2.41.231S. (S)-2-(((2S,3R,4S,5R,6R)-3,5- 0.81 625.91 Chiralpak ID 4.03 0.07 Dihydroxy-6-(hydroxymethyl)-4-(4- B: 25% (1/1) (3,4,5-trifluorophenyl)-1H-1,2,3- MeCN/EtOH triazol-1-yl)tetrahydro-2H-pyran-2- 5 min run yl)thio)-2-(4-hydroxytetrahydro-2H- pyran-4-yl)-N-methyl-N- phenylacetamide 2.41.233R. (R)-2-(((2S,3R,4S,5R,6R)-3,5- 0.71 625.98 Chiralcel OZ-H 3.86 8.5 Dihydroxy-6-(hydroxymethyl)-4-(4- B: 40% (1/1) (3,4,5-trifluorophenyl)-1H-1,2,3- MeCN/EtOH triazol-1-yl)tetrahydro-2H-pyran-2- 5 min run yl)thio)-2-(4-hydroxytetrahydro-2H- pyran-4-yl)-N-methyl-N-(pyridin-2- yl)acetamide 2.41.233S. (S)-2-(((2S,3R,4S,5R,6R)-3,5- 0.72 625.97 Chiralcel OZ-H 2.27 0.04 Dihydroxy-6-(hydroxymethyl)-4-(4- B: 40% (1/1) (3,4,5-trifluorophenyl)-1H-1,2,3- MeCN/EtOH triazol-1-yl)tetrahydro-2H-pyran-2- 5 min run yl)thio)-2-(4-hydroxytetrahydro-2H- pyran-4-yl)-N-methyl-N-(pyridin-2- yl)acetamide 2.41.234R (R)-2-(((2S,3R,4S,5R,6R)-3,5- 0.64 625.98 Chiralpak IH 1.67 7.8 Dihydroxy-6-(hydroxymethyl)-4-(4- B: 25% (1/1) (3,4,5-trifluorophenyl)-1H-1,2,3- MeCN/EtOH triazol-1-yl)tetrahydro-2H-pyran-2- 5 min run yl)thio)-2-(4-hydroxytetrahydro-2H- pyran-4-yl)-N-methyl-N-(pyridin-3- yl)acetamide 2.41.234S. (S)-2-(((2S,3R,4S,5R,6R)-3,5- 0.65 625.98 Chiralpak IH 3.8 0.1 Dihydroxy-6-(hydroxymethyl)-4-(4- B: 25% (1/1) (3,4,5-trifluorophenyl)-1H-1,2,3- MeCN/EtOH triazol-1-yl)tetrahydro-2H-pyran-2- 5 min run yl)thio)-2-(4-hydroxytetrahydro-2H- pyran-4-yl)-N-methyl-N-(pyridin-3- yl)acetamide 2.41.233R.I. (R)-2-(4,4-Difluoro-1- 0.94 674.18 Chiralpak IE 2.14 7.24 hydroxycyclohexyl)-2- B: 30% (1/1) (((2S,3R,4S,5R,6R)-5-hydroxy-6- MeCN/2-PrOH (hydroxymethyl)-3-methoxy-4-(4- 5 min run (3,4,5-trifluorophenyl)-1H-1,2,3- triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-N-methyl-N-(pyridin-2- yl)acetamide 2.41.233S.I. (S)-2-(4,4-Difluoro-1- 0.94 674.21 Chiralpak IE 1.69 0.05 hydroxycyclohexyl)-2- B: 30% (1/1) (((2S,3R,4S,5R,6R)-5-hydroxy-6- MeCN/2-PrOH (hydroxymethyl)-3-methoxy-4-(4- 5 min run (3,4,5-trifluorophenyl)-1H-1,2,3- triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-N-methyl-N-(pyridin-2- yl)acetamide [1,3-di-deoxy-1-((2- (4,4-difluoro-1-hydroxycyclohexyl)-N- methyl-N-(pyridin-2-yl)acetamide)- (S)-thio)-2-O-methyl-3-[4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl]- b-D-galactopyranoside]
[0628] Following examples are prepared starting from the corresponding 2-mercapto acetamides (prepared in analogy to Intermediate 12) and Intermediate 2 or Intermediate 14 in analogy to Example 2.41.232. LC-MS and Gal-3 inhibition data are listed in Table 10 below. The LC-MS conditions used are LC-MS (A). Chiral HPLC (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] 2.41.237. N-Cyclobutyl-2-(((2S,3R,4S,5R,6R)- 0.80 617.21 0.03 3,5-dihydroxy-6-(hydroxymethyl)-4- (4-(3,4,5-trifluorophenyl)-1H-1,2,3- triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-N-ethyl-2-(4- hydroxytetrahydro-2H-pyran-4- yl)acetamide 2.41.220. N-Cyclobutyl-2-(((2S,3R,4S,5R,6R)- 0.77 603.19 0.05 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-(4-hydroxytetrahydro-2H- pyran-4-yl)-N-methylacetamide 2.44.238.I. N-Cyclopropyl-2-(4,4-difluoro-1- 0.99 651.22 0.04 hydroxycyclohexyl)-N-ethyl-2- (((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)acetamide 2.44.238R.I. (R)-N-Cyclopropyl-2-(4,4-difluoro-1- 1.0 651.13 Chiralcel OZ-H 1.89 1.0 hydroxycyclohexyl)-N-ethyl-2- B: 35% (1/1) (((2S,3R,4S,5R,6R)-5-hydroxy-6- MeCN/EtOH (hydroxymethyl)-3-methoxy-4-(4- 5 min run (3,4,5-trifluorophenyl)-1H-1,2,3- triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)acetamide 2.44.238S.I. (S)-N-Cyclopropyl-2-(4,4-difluoro-1- 1.0 651.14 Chiralcel OZ-H 2.68 0.02 hydroxycyclohexyl)-N-ethyl-2- B: 35% (1/1) (((2S,3R,4S,5R,6R)-5-hydroxy-6- MeCN/EtOH (hydroxymethyl)-3-methoxy-4-(4- 5 min run (3,4,5-trifluorophenyl)-1H-1,2,3- triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)acetamide [1,3-di-deoxy-1-((2- (4,4-difluoro-1-hydroxycyclohexyl)- (N-(cyclopropyl))-N-ethylacetamide)- (S)-thio)-2-O-methyl-3-[4-(3,4,5- trifluorophenyl)-1H-1,2,3-triazol-1-yl]- b-D-galactopyranoside] 2.44.239.I. N-(Cyclopropylmethyl)-2-(4,4- 1.00 665.16 0.04 difluoro-1-hydroxycyclohexyl)-N- ethyl-2-(((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)acetamide 2.44.214.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 0.96 710 0.03 N-ethyl-2-(((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)-N-((tetrahydro-2H- pyran-4-yl)methyl)acetamide 2.44.240.I. N-Benzyl-2-(4,4-difluoro-1- 1.04 701.17 0.04 hydroxycyclohexyl)-N-ethyl-2- (((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)acetamide 2.44.256.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 1.05 715.13 0.05 N-((3,3-difluorocyclobutyl)methyl)-N- ethyl-2-(((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)acetamide 2.44.257.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 0.97 695.14 0.07 N-ethyl-2-(((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)-N-(tetrahydro-2H- pyran-4-yl)acetamide
Example 10.41.203.
[0629] 2-(((2S, 3R, 4S, 5R, 6R)-4-(4-(3,5-Dif luorophenvh-1 H-1,2,3-triazol-1-0)-3,5-dihydroxv-6-(hvdroxvmethvhtetrahvdro-2H-Pyran-2-vhthio)-N-ethyl-2-(4-hvdroxvtetrahvdro-2H-pyran-4-0)-N-methvlacetamide 1. (2R,3R,4S,5R,6S)-2-(Acetoxymethy0-4-(4-(3,5-difluoropheny0-1 H-1, 2,3-triazol-1-y0-642-(ethyl(methyl)amino)-1-(4-hydroxytetrahydro-2H-pyran-4-y0-2-oxoethyl)thio)tetrahydro-2H-pyran-3,5-diyl diacetate
[0630] To a solution of Intermediate 13 (0.05 g, 0.10 mmol) in DMF (2.0 mL) are added 1-ethynyl-3,5-difluorobenzene (0.02 g, 0.15 mmol, 1.5 eq), Cul (0.006 g, 0.03 mmol, 0.3 eq) and DIPEA (0.05 mL, 0.30 mmol, 3.0 eq). The reaction mixture is stirred at 43° C. for 1 h, then cooled to rt, diluted with EA and filtered. The org. layer is washed with aq. sat. NH.sub.4CI, brine, dried over Na2SO4, filtered and solvent removed in vacuo. The resulting crude is purified by preparative HPLC/MS (I) to give the title compound as a beige solid (0.06 g, 90%). LC-MS (A): t.sub.R=0.93 min; [M-FH]+: 685.18.
[0631] 2. 2-(((2S,3R,4S,5R,6R)-4-(4-(3,5-Difluoropheny0-1H-1,2,3-triazol-1-y0-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(4-hydroxytetrahydro-2H-pyran-4-y0-N-methylacetamide (10.41.203.) To a solution of 2R,3R,4S,5R,6S)-2-(acetoxymethyl)-4-(4-(3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-6-((2-(ethyl(methypamino)-1-(4-hydroxytetrahydro-2H-pyran-4-yl)-2-oxoethypthio)tetrahydro-2H-pyran-3,5-diyldiacetate (0.06 g, 0.09 mmol, 1.0 eq) in MeOH (3.0 mL) is added K.sub.2CO.sub.3 (0.003 g, 0.02 mmol, 0.2 eq). The reaction mixture is stirred at rt for 3 h, acetonitrile is added, followed by water and the mixture is directly purified by preparative HPLC/MS (I) to give the title product as a beige solid (0.05 g, 91%). LC-MS (A): t.sub.R=0.67 min; [M-FH]+: 559.22.
[0632] Following examples are prepared starting from Intermediate 13 or a close analogue and the corresponding alkynes according to the procedures described for Example 10.41.203. LC-MS and Gal-3 inhibition data are listed in Table 11 below. The LC-MS conditions used are LC-MS (A). Chiral HPLC (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] 10.41.203. 2-(((2S,3R,4S,5R,6R)-4-(4-(3,5- 0.67 559.22 0.10 Difluorophenyl)-1H-1,2,3-triazol-1-yl)- 3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2- yl)thio)-N-ethyl-2-(4-hydroxytetrahydro- 2H-pyran-4-yl)-N-methylacetamide 1.41.203. N-Ethyl-2-(((2S,3R,4S,5R,6R)-4-(4-(3- 0.63 541.15 0.13 fluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5- dihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-2-yl)thio)-2-(4- hydroxytetrahydro-2H-pyran-4-yl)-N- methylacetamide 3.41.203. 2-(((2S,3R,4S,5R,6R)-4-(4-(3,5-Difluoro- 0.72 573.22 0.04 4-methylphenyl)-1H-1,2,3-triazol-1-yl)- 3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2- yl)thio)-N-ethyl-2-(4-hydroxytetrahydro- 2H-pyran-4-yl)-N-methylacetamide 11.41.203. 2-(((2S,3R,4S,5R,6R)-4-(4-(4-Chloro- 0.74 593.17 0.03 3,5-difluorophenyl)-1H-1,2,3-triazol-1- yl)-3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2- yl)thio)-N-ethyl-2-(4-hydroxytetrahydro- 2H-pyran-4-yl)-N-methylacetamide 14.41.203. 2-(((2S,3R,4S,5R,6R)-4-(4-(4- 0.63 610.07 0.15 Bromothiazol-2-yl)-1H-1,2,3-triazol-1-yl)- 3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2- yl)thio)-N-ethyl-2-(4-hydroxytetrahydro- 2H-pyran-4-yl)-N-methylacetamide 12.41.203. 2-(((2S,3R,4S,5R,6R)-4-(4-(4-Bromo-3- 0.72 621.17 0.04 fluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5- dihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-2-yl)thio)-N-ethyl-2-(4- hydroxytetrahydro-2H-pyran-4-yl)-N- methylacetamide 13.41.203. 2-(((2S,3R,4S,5R,6R)-4-(4-(3-Chloro-5- 0.71 575.33 0.08 fluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5- dihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-2-yl)thio)-N-ethyl-2-(4- hydroxytetrahydro-2H-pyran-4-yl)-N- methylacetamide 15.41.203. 2-(((2S,3R,4S,5R,6R)-4-(4-(3-Chloro- 0.73 593.33 0.06 4,5-difluorophenyl)-1H-1,2,3-triazol-1- yl)-3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2- yl)thio)-N-ethyl-2-(4-hydroxytetrahydro- 2H-pyran-4-yl)-N-methylacetamide 16.41.203. 2-(((2S,3R,4S,5R,6R)-4-(4-(3,4- 0.67 559.21 0.06 Difluorophenyl)-1H-1,2,3-triazol-1-yl)- 3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2- yl)thio)-N-ethyl-2-(4-hydroxytetrahydro- 2H-pyran-4-yl)-N-methylacetamide 17.41.203. 2-(((2S,3R,4S,5R,6R)-4-(4-(3,4- 0.77 609.17 0.04 Dichloro-5-fluorophenyl)-1H-1,2,3- triazol-1-yl)-3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2- yl)thio)-N-ethyl-2-(4-hydroxytetrahydro- 2H-pyran-4-yl)-N-methylacetamide 18.41.203. 2-(((2S,3R,4S,5R,6R)-4-(4-(4-Bromo- 0.74 639.04 0.04 3,5-difluorophenyl)-1H-1,2,3-triazol-1- yl)-3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2- yl)thio)-N-ethyl-2-(4-hydroxytetrahydro- 2H-pyran-4-yl)-N-methylacetamide 19.41.203. 2-(((2S,3R,4S,5R,6R)-4-(4-(3-Cyano-5- 0.67 562.28 0.15 methylphenyl)-1H-1,2,3-triazol-1-yl)-3,5- dihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-2-yl)thio)-N-ethyl-2-(4- hydroxytetrahydro-2H-pyran-4-yl)-N- methylacetamide 20.41.203. N-ethyl-2-(((2S,3R,4S,5R,6R)-4-(4-(3- 0.69 555.25 0.06 Fluoro-5-methylphenyl)-1H-1,2,3-triazol- 1-yl)-3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2- yl)thio)-2-(4-hydroxytetrahydro-2H- pyran-4-yl)-N-methylacetamide 21.44.221R*. (R)-N-Cyclopropyl-2-(4,4-difluoro-1- 0.77 602.18 0.23 hydroxycyclohexyl)-2- (((2S,3R,4S,5R,6R)-4-(4-(6-fluoro-5- methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)- 3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2- yl)thio)-N-methylacetamide 21.44.221S*. (S)-N-Cyclopropyl-2-(4,4-difluoro-1- 0.78 602.17 0.05 hydroxycyclohexyl)-2- (((2S,3R,4S,5R,6R)-4-(4-(6-fluoro-5- methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl)- 3,5-dihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2- yl)thio)-N-methylacetamide *Epimers are separated during the purification on preparative HPLC/MS(I).
Example 2.44.222.1.
[0633] 2-(4, 4-D if luoro-1-hydroxycyclohexyl)-N-(24 luoro-2-m ethylpropy0-24(2S, 3R, 4S, 5R, 6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trif luorophenv0-1 H-1, 2, 3-tri azol-1-yl)tetra hydro-2H-pyran-2-yl)thio)-N-methylacetamide 1. tert-Butyl 2-(4,4-difluoro-1-hydroxycyclohexy0-2-mercaptoacetate tert-Butyl 2-(4,4-difluoro-1-hydroxycyclohexyl)-2-mercaptoacetate is synthesized from tert-butyl 2-sulfanylacetate and 4,4-difluorocyclohexan-1-one as a white solid in analogy to Intermediate 7. LC-MS(A) t.sub.R=0.94 min, [M-FH]+: 283.17.
[0634] 2. tert-Butyl 2-(((2S,3R,4S,5R,6R)-5-acetoxy-6-(acetoxymethy0-3-methoxy-4-(4-(3,4,5-trifluoropheny0-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4,4-difluoro-1-hydroxycyclohexy0acetate To a solution of tert-butyl 2-(4,4-difluoro-1-hydroxycyclohexyl)-2-mercaptoacetate (0.12 g, 0.43 mmol,) in aq.10% Na.sub.2CO.sub.3 (4.0 mL) is added TBAHS (0.89 g, 2.55 mmol, 6.0 eq), followed by a solution of Intermediate 14 (0.63 g, 0.50 mmol, 1.2 eq) in EA (10.0 mL). The reaction mixture is stirred at rt for 2 h, diluted with EA, water and brine and the phases are separated. The aq. layer is extracted with EA, the combined organic phase is dried over Na.sub.2SO.sub.4, filtered and solvent removed in vacuo to give a solid. Purification by preparative HPLC/MS (II) yielded the expected product as a white solid (0.22 g, 71%). LC-MS(A) t.sub.R=1.13 min, [M-FH]+: 724.21.
[0635] 3. 2-(((2S, 3R, 4S, 5R, 6R)-5-Acetoxy-6-(acetoxym ethy0-3-m ethoxy-4-(4-(3, 4, 5-tri f luoropheny0-1 H-1, 2, 3-tri azol-1- yl)tetrahydro-2H-pyra n-2-yOthi 0)-244, 4-di f 1 uoro-1-hydroxycyclohexyl) acetic acid To a solution of tert-butyl 2-(((2S,3R,4S,5R,6R)-5-acetoxy-6-(acetoxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4,4-difluoro-1-hydroxycyclohexyl)acetate (0.22 g, 0.30 mmol) in DCM (8.0 mL) is added TFA (0.39 mL, 5.11 mmol, 17.0 eq), the reaction mixture is stirred at rt for 20 h. The mixture is neutralized with aq. 2M NaOH, diluted with DCM and the layers are separated. The aqueous layer is extracted with
[0636] DCM (3x) and the combined organic layer is dried over Na.sub.2SO.sub.4, filtered and solvent removed in vacuo to recover the title product as a beige powder (0.14 g, 68%), that is not further purified. LC-MS(A) t.sub.R=0.97 min, [M-FH]+: 668.15.
[0637] 4. ((2R,3R,4S,5R,6S)-3-Acetoxy-641-(4,4-difluoro-1-hydroxycyclohexy0-242-fluoro-2-methylpropy0(methy0amino)-2-oxoethyl)thio)-5-methoxy-4-(4-(3,4,5-trifluoropheny0-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yOrnethyl acetate
[0638] To a solution of 2-(((2S,3R,4S,5R,6R)-5-acetoxy-6-(acetoxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4,4-difluoro-1-hydroxycyclohexyl)acetic acid (0.45 g, 0.58 mmol) in DMF (20.0 mL) is added HATU (0.25 g, 0.616 mmol, 1.05 eq), followed by a solution of 2-fluoro-N,2-dimethylpropan-1-amine HCI salt (0.1 g, 0.7 mmol, 1.2 eq) and DIPEA (0.27 mL, 1.58 mmol, 2.7 eq) in DMF (2.0 mL). The mixture is stirred at rt for 72 h, filtered and directly purified by preparative HPLC/MS (I) to give the title compound as a beige solid (0.14 g, 32%). LC-MS(A) t.sub.R=1.10 min, [M-FH]+: 755.23.
[0639] 5. 2-(4,4-Difluoro-1-hydroxycyclohexy0-N-(2-fluoro-2-methylpropy0-202S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluoropheny0-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide (2.44.222.1.)
[0640] To a solution of ((2R,3R,4S,5R,6S)-3-acetoxy-6-((1-(4,4-difluoro-1-hydroxycyclohexyl)-2-((2-fluoro-2-methylpropyl)(methypamino)-2-oxoethypthio)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl acetate (0.142 g, 0.094 mmol) in MeOH (7.0 mL) is added K.sub.2O0.sub.3 (0.003 g, 0.02 mmol, 0.2 eq). After 2 h stirring at rt, the reaction mixture is diluted with MeCN, followed by water and directly purified by preparative HPLC/MS (I) to give the title compound as a beige solid (0.055 g, 88%). LC-MS(A) t.sub.R=0.99 min, [M-FH]+: 671.42.
Example 2.44.222R. I.
[0641] (R)-2-(4, 4-Di f luoro-1-hydroxycyclohexy0-N-(24 luoro-2-methylpropy0-24(2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide 11,3-di-deoxy-14(2-(4,4-difluoro-1-hydroxycyclohexyl)-(N-(3-fluoro-3-methylbutyl)-N-methylacetamide)-(R)-thio)-2-0-methyl-3-14-(3,4,5-trifluorophenyl)-1 H-1 ,2,3-triazol-1-yO-b-D-dalactopyranosidel Separation of the epimers of Example 2.44.222.1. (0.055 g) by chiral preparative HPLC (VI) yielded the title compound (0.024 g) as a white solid. Chiral analytical HPLC (K): t.sub.R=1.62 min.
Example 2.44.222S. I.
[0642] S)-2-(4, 4-Difluoro-1-hydroxycyclohexyl)-N-(2-fluoro-2-m ethylpropyl)-24(2S,3R, 4S, 5R, 6R)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-4-(4-(3,4,5-trifluoropheny0-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide [1,3-di-deoxy-142-(4,4-difluoro-1-hydroxycyclohexyl)-(N-(3-fluoro-3-methylbutyl)-N-methylacetamide)-(S)-thio)-2-O-methyl-3-[4-(3,4,5-trifluorophenyl)-1 H-1,2,3-triazol-1-yl]b-D-dalactopyranoside]
[0643] Separation of the epimers of Example 2.44.222.1. (0.055 g) by chiral preparative HPLC (VI) yielded the title compound (0.016 g) as a white solid. Chiral analytical HPLC (K): t.sub.R=2.24 min. .sup.1H NMR (400 MHz, MeOD) δ: 8.68 (s, 0.8H), 8.66 (s, 0.2H), 7.68 (m, 2H), 4.95 (dd, Ji=10.8 Hz, J2=3.3 Hz, 1H),), 4.85 (d, J=9.5 Hz, 1H), 4.3 (s, 1H), 4.1 (d, J=2.3 Hz, 1H), 4.0-3.93 (m, 1H), 3.85-3.6 (m, 5H), 3.7 (s, 0.8H), 3.5 (s, 2.3H), 3.55 (s, 3H) 2.4-1.7 (m, 8H), 1.5-1. 3 (m, 6H).
[0644] Following examples are prepared starting from 2-(((25,3R,45,5R,6R)-5-acetoxy-6-(acetoxymethyl)-3-methoxy-4-(4-(3, 4,5-trifluorophenyl)-1H-1,2, 3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(4, 4-difluoro-1-hydroxycyclohexyl)acetic acid (Example 2.44.222.1. Step 3.) and the corresponding secondary and primary amines according to the procedures described for Example 2.44.222.1. LC-MS and Gal-3 inhibition data are listed in Table 12 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-00017 TABLE 12 HPLC t.sub.R IC.sub.50 Example Name t.sub.R [M + H].sup.+ conditions chiral [uM] 2.44.222.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 0.99 671.25 0.05 N-(2-fluoro-2-methylpropyl)-2- (((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)-N- methylacetamide 2.44.222R.I. (R)-2-(4,4-Difluoro-1- 1.00 671.15 Chiralcel OZ-H 1.6 7.9 hydroxycyclohexyl)-N-(2-fluoro-2- B: 30% (1/1) methylpropyl)-2-(((2S,3R,4S,5R,6R)- MeCN/EtOH 5-hydroxy-6-(hydroxymethyl)-3- 5 min run methoxy-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-2-yl)thio)-N-methylacetamide 2.44.222S.I. (S)-2-(4,4-Difluoro-1- 1.01 671.14 Chiralcel OZ-H 2.24 0.01 hydroxycyclohexyl)-N-(2-fluoro-2- B: 30% (1/1) methylpropyl)-2-(((2S,3R,4S,5R,6R)- MeCN/EtOH 5-hydroxy-6-(hydroxymethyl)-3- 5 min run methoxy-4-(4-(3,4,5-trifluorophenyl)- 1H-1,2,3-triazol-1-yl)tetrahydro-2H- pyran-2-yl)thio)-N-methylacetamide 2.44.226R.I. (R)-2-(4,4-difluoro-1- 1.0 687.11 Chiralpak IC 2.2 0.89 hydroxycyclohexyl)-1-(4,4- B: 15% (1/1) difluoropiperidin-1-yl)-2- MeCN/EtOH (((2S,3R,4S,5R,6R)-5-hydroxy-6- 5 min run (hydroxymethyl)-3-methoxy-4-(4- (3,4,5-trifluorophenyl)-1H-1,2,3-triazol- 1-yl)tetrahydro-2H-pyran-2- yl)thio)ethan-1-one 2.44.226S.I. (S)-2-(4,4-difluoro-1- 1.0 687.1 Chiralpak IC 2.9 0.05 hydroxycyclohexyl)-1-(4,4- B: 15% (1/1) difluoropiperidin-1-yl)-2- MeCN/EtOH (((2S,3R,4S,5R,6R)-5-hydroxy-6- 5 min run (hydroxymethyl)-3-methoxy-4-(4- (3,4,5-trifluorophenyl)-1H-1,2,3-triazol- 1-yl)tetrahydro-2H-pyran-2- yl)thio)ethan-1-one 2.44.218.I. N-(Cyclopropylmethyl)-2-(4,4-difluoro- 0.97 651.27 0.03 1-hydroxycyclohexyl)-2- (((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)-N- methylacetamide 2.44.201.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 0.89 611.27 0.06 2-(((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)- N,N-dimethylacetamide 2.44.203.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 0.92 625.28 0.04 N-ethyl-2-(((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)-N-methylacetamide 2.44.241.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 0.99 679.15 0.18 2-(((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)-N- methyl-N-(2,2,2- trifluoroethyl)acetamide 2.44.242.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 0.96 639.22 0.08 2-(((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)-N- isopropyl-N-methylacetamide 2.44.225.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 1.06 681.26 0.10 N-(3,3-dimethylbutyl)-2- (((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)-N- methylacetamide 2.44.217.I. N-(2-Cyclopropylethyl)-2-(4,4-difluoro- 1.01 665.22 0.05 1-hydroxycyclohexyl)-2- (((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)-N- methylacetamide 2.44.237.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 0.99 687.22 0.09 N-(3,3-difluorocyclobutyl)-2- (((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)-N- methylacetamide 2.44.243.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 0.88 653.21 0.11 2-(((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)-N- methyl-N-(oxetan-3-yl)acetamide 2.44.213.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 0.92 681.24 0.07 2-(((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)-N- methyl-N-(tetrahydro-2H-pyran-4- yl)acetamide 2.44.244.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 0.89 653.22 0.07 2-(((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)-1- morpholinoethan-1-one 2.44.245.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 1.03 679.31 0.09 1-(4,4-dimethylpiperidin-1-yl)-2- (((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)ethan-1-one 2.44.246.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 1.09 707.03 0.32 N-(4,4-dimethylcyclohexyl)-2- (((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)-N- methylacetamide 2.44.247.I. N-(Bicyclo[1.1.1]pentan-1-yl)-2-(4,4- 1.02 663.19 0.05 difluoro-1-hydroxycyclohexyl)-2- (((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)-N- methylacetamide 2.44.248.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 0.91 597.98 0.49 2-(((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)-N- methylacetamide 2.44.249.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 0.89 667.14 0.08 2-(((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)-N- (tetrahydro-2H-pyran-4-yl)acetamide 2.44.250.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 1.0 653.16 0.05 2-(((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)-N- (pentan-3-yl)acetamide 2.44.251.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 0.94 625.14 0.09 2-(((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)-N- isopropylacetamide 2.44.252.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 1.04 667.16 0.32 N-(3,3-dimethylbuty1)-2- (((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)acetamide 2.44.253.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 0.96 673.12 0.16 N-(3,3-difluorocyclobutyl)-2- (((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)acetamide 2.44.254.I. 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 0.96 665.09 0.13 2-(((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)-N- (2,2,2-trifluoroethyl)acetamide 2.44.255.I 2-(4,4-Difluoro-1-hydroxycyclohexyl)- 1.07 693.95 0.39 N-(4,4-dimethylcyclohexyl)-2- (((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)acetamide
Example 2.67.226.1.
[0645] 1-(4,4-Difluoropiperidin-1-0-24(2S,3R,4S,5R,6R)-5-hydroxv-6-(hydroxymethyl)-3-methoxv-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-v0tetrahydro-2H-pyran-2-v0thio)-2-(6-hydroxvspirof2.57octan-6-v0ethan-1-one 1. 1-(4,4-Difluoropiperidin-1-y0-2-(6-hydroxyspiro[2.5]octan-6-y0-2-mercaptoethan-1-one 1-(4,4-Difluoropiperidin-1-yl)-2-(6-hydroxyspiro[2.5]octan-6-yl)-2-mercaptoethan-1-one is synthesized from 3,4-dihydro-2H-pyran, ethyl 2-mercaptoacetate, 4,4-difluoropiperidine and spiro[2.5]octan-6-one as a beige solid according to the procedure described for the synthesis of Intermediate 12. LC-MS(A) t.sub.R =0.95 min, [M-FH]+: 320.15
[0646] 2. ((2R,3R,4S,5R,6S)-3-Acetoxy-642-(4,4-difluoropiperidin-1-y0-1-(6-hydroxyspiro[2.5]octan-6-y0-2-oxoethyl)thio)-5-methoxy-4-(4-(3,4,5-trifluoropheny0-1 H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yOrnethyl acetate ((2R,3R,4S,5R,6S)-3-Acetoxy-6-((2-(4,4-difluoropiperidin-1-yl)-1-(6-hydroxyspiro[2.5]octan-6-yl)-2-oxoethypthio)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl acetate is prepared from Step 1. of this experiment, 1-(4,4-difluoropiperidin-1-yl)-2-(6-hydroxyspiro[2.5]octan-6-yl)-2-mercaptoethan-1-one, and Intermediate 14 as a beige solid according to the procedure described for the synthesis of Intermediate 13. LC-MS(A) t.sub.R=1.13 min, [M-FH]+: 761.26
[0647] 3. 1-(4,4-Difluoropiperidin-1-yl)-202S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethy0-3-methoxy-4-(4-(3,4,5-trifluoropheny0-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(6-hydroxyspiro[2.5]octan-6-yOethan-1-one (2.67.226.1.)
[0648] To a solution of ((2R,3R,4S,5R,6S)-3-acetoxy-64(2-(4,4-difluoropiperidin-1-yl)-1-(6-hydroxyspiro[2.5]octan-6-yl)-2-oxoethypthio)-5-methoxy-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)methyl acetate (0.05 g, 0.07 mmol, 1.0 eq) in MeOH (3.0 mL) is added K.sub.2O0.sub.3 (0.002 g, 0.01 mmol, 0.2 eq) at rt. The reaction mixture is stirred at rt for 90 min, then diluted with MeCN, followed by water. The mixture is directly purified by preparative HPLC/MS(I) to yield the title compound as a beige solid (0.04 g, 79%). LC-MS(A) t.sub.R=1.02 min, [M-FH]+: 677.19.
[0649] Following examples have been prepared starting from 1-(4,4-difluoropiperidin-1-yl)-2-((tetrahydro-2H-pyran-2-yl)thio)ethan-1-one (synthesized in analogy to Intermediate 12, Step 1.-3.), the corresponding ketones and Intermediate 14 in analogy to Example 2.67.226.1. LC-MS and Gal-3 inhibition data are listed in Table 13 below.
[0650] The LC-MS conditions used are LC-MS (A). Chiral HPLC (conditions and retention time) and inhibition data of the epimers R and S of selected Examples are also listed.
TABLE-US-00018 TABLE 13 HPLC t.sub.R IC.sub.50 Example Name t.sub.R [M + H].sup.+ conditions chiral [uM] 2.67.226.I. 1-(4,4-Difluoropiperidin-1-yl)-2- 1.02 677.19 0.12 (((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-(6-hydroxyspiro[2.5]octan- 6-yl)ethan-1-one 2.68.226.I. 1-(4,4-Difluoropiperidin-1-yl)-2-(1- 1.04 679.23 0.10 hydroxy-4,4-dimethylcyclohexyl)-2- (((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)ethan-1-one 2.69.226R.I.* (R)-1-(4,4-Difluoropiperidin-1-yl)-2- 1.05 691.25 Chiralpak ID 1.94 0.57 (((2S,3R,4S,5R,6R)-5-hydroxy-6- B: 25% (1/1) (hydroxymethyl)-3-methoxy-4-(4- MeCN/MeOH (3,4,5-trifluorophenyl)-1H-1,2,3- 5 min run triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-2-(7-hydroxyspiro[3.5]nonan- 7-yl)ethan-1-one 2.69.226S.I.* (S)-1-(4,4-Difluoropiperidin-1-yl)-2- 1.06 691.26 Chiralpak ID 2.2 0.12 (((2S,3R,4S,5R,6R)-5-hydroxy-6- B: 25% (1/1) (hydroxymethyl)-3-methoxy-4-(4- MeCN/MeOH (3,4,5-trifluorophenyl)-1H-1,2,3- 5 min run triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-2-(7-hydroxyspiro[3.5]nonan- 7-yl)ethan-1-one 2.70.226.I. 1-(4,4-Difluoropiperidin-1-yl)-2- 0.91 694.06 0.11 (((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-(7-hydroxy-2- oxaspiro[3.5]nonan-7-yl)ethan-1-one 2.71.226R.I.* (R)-1-(4,4-Difluoropiperidin-1-yl)-2- 1.07 705.27 Chiralpak IA 2.02 0.67 (((2S,3R,4S,5R,6R)-5-hydroxy-6- B: 30% (1/1) (hydroxymethyl)-3-methoxy-4-(4- MeCN/EtOH (3,4,5-trifluorophenyl)-1H-1,2,3- 5 min run triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-2-(8-hydroxyspiro[4.5]decan- 8-yl)ethan-1-one 2.71.226S.I.* (S)-1-(4,4-Difluoropiperidin-1-yl)-2- 1.08 705.28 Chiralpak IA 2.27 0.1 (((2S,3R,4S,5R,6R)-5-hydroxy-6- B: 30% (1/1) (hydroxymethyl)-3-methoxy-4-(4- MeCN/EtOH (3,4,5-trifluorophenyl)-1H-1,2,3- 5 min run triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-2-(8-hydroxyspiro[4.5]decan- 8-yl)ethan-1-one 2.72.226.I. 1-(4,4-Difluoropiperidin-1-yl)-2- 0.96 721.51 0.06 (((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-(9-hydroxy-3- oxaspiro[5.5]undecan-9-yl)ethan-1- one 2.72.226R.I.* (R)-1-(4,4-Difluoropiperidin-1-yl)-2- 0.96 721.17 Chiralcel OZH 1.48 14.9 (((2S,3R,4S,5R,6R)-5-hydroxy-6- B: 45% (1/1) (hydroxymethyl)-3-methoxy-4-(4- MeCN/MeOH (3,4,5-trifluorophenyl)-1H-1,2,3- 5 min run triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-2-(9-hydroxy-3- oxaspiro[5.5]undecan-9-yl)ethan-1- one 2.72.226S.I.* (S)-1-(4,4-Difluoropiperidin-1-yl)-2- 0.97 721.15 Chiralcel OZH 2.23 0.04 (((2S,3R,4S,5R,6R)-5-hydroxy-6- B: 45% (1/1) (hydroxymethyl)-3-methoxy-4-(4- MeCN/MeOH (3,4,5-trifluorophenyl)-1H-1,2,3- 5 min run triazol-1-yl)tetrahydro-2H-pyran-2- yl)thio)-2-(9-hydroxy-3- oxaspiro[5.5]undecan-9-yl)ethan-1- one 2.43.226.I. 1-(4,4-Difluoropiperidin-1-yl)-2-(4- 1.0 713.43 0.25 hydroxy-2,2-dimethyltetrahydro-2H- pyran-4-yl)-2-(((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)ethan-1-one 2.73.226.I. 2-(1,1-Difluoro-6- 0.92- 681.18 0.10 hydroxyspiro[2.5]octan-6-yl)-1-(4,4- 0.94 difluoropiperidin-1-yl)-2- (((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)ethan-1-one *Epimers are separated during the purification on preparative HPLC/MS(I) or HPLC/MS(II).
Example 2.44.226.11.
[0651] 2-(4,4-Difluoro-1-hydroxycyclohexv1)-1-(4,4-dif luoropiperidin-1-0-2-(((2S,3R, 4S, 5R, 6R)-3-ethoxy-5-hydroxy-6- (hydroxymethyl)-4-(4-(3,4,5-trifluorophenyl)-1 H-1, 2,3-triazol-1-Atetrahydro-2H-pyran-211)thio)ethan-1-one
[0652] Example 2.44.226.11. is prepared from 2-(4,4-difluoro-1-hydroxycyclohexyl)-1-(4,4-difluoropiperidin-1-yl)-2-mercaptoethan-1-one (prepared in analogy to Intermediate 11) and Intermediate 15 in analogy to Example 2.67.226.1. as a beige solid. LC-MS (A): t.sub.R=1.0 min; [MEI-1]': 701.21.
[0653] LC-MS and Gal-3 inhibition data of Example 2.44.226.11. are listed in Table 14 below. The LC-MS conditions used are LC-MS (A).
TABLE-US-00019 TABLE 14 [M + IC.sub.50 Example Name t.sub.R H].sup.+ [uM] 2.44.226.II. 2-(4,4-Difluoro-1- 1.00 701.21 0.1 hydroxycyclohexyl)-1-(4,4- difluoropiperidin-1-yl)-2- (((2S,3R,4S,5R,6R)-3-ethoxy- 5-hydroxy-6-(hydroxymethyl)- 4-(4-(3,4,5-trifluorophenyl)-1H- 1,2,3-triazol-1-yl)tetrahydro- 2H-pyran-2-yl)thio)ethan-1-one
[0654] Galectin-1 enzyme inhibition data are listed in Table 15 below. Inhibition data of the epimers R and S of selected
[0655] 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] 2.53.203. 35.9 2.31.204. 2.8 2.41.201. 1.8 2.41.207R. 51.5 2.56.203S. 36 2.31.205R. 20.0 2.41.201R. >100 2.41.207S. 0.9 2.41.200. 0.26 2.31.205S. 0.82 2.41.201S. 0.21 2.41.208. 0.22 2.41.200R. 10.9 2.31.206. 1.4 2.41.202. 0.11 2.41.208R. 32.3 2.41.200S. 0.11 2.40.200. 0.19 2.41.204. 0.95 2.41.208S. 0.8 2.31.201. 1.92 2.40.203. 0.16 2.41.205R. 4.9 2.41.209. 0.31 2.31.203. 0.88 2.40.207. 0.59 2.41.205S. 0.55 2.41.209S. 0.17 2.31.203S. 0.24 2.40.208. 0.05 2.41.206. 1.5 2.41.210. 1.12 2.31.202. 2.77 2.40.209. 0.23 2.41.207. 0.072 2.41.211. 0.33 2.41.212. 0.2 2.39.220. 8.79 2.44.227R. 5.13 2.34.222S. 0.11 2.41.212R. 79.8 2.39.222. 0.12 2.44.227S. 0.23 2.34.228. 0.16 2.41.212S. 0.08 2.39.222R. 38.1 2.38.203. 1.13 2.34.228R. 22.6 2.41.213. 0.2 2.39.222S. 0.09 2.38.206. 0.77 2.34.228S. 0.09 2.41.214. 0.12 2.39.224R. 2.82 2.38.219. 0.11 2.33.203R. 4.2 2.41.215. 0.37 2.39.224S. 0.07 2.38.220. 0.02 2.33.203S. 0.11 2.41.216. 0.38 2.44.201. 0.23 2.38.228. 0.17 2.33.206. 1.71 2.41.216S. 0.11 2.44.201R. 1.71 2.34.203. 0.64 2.33.218R. 0.58 2.41.217. 0.22 2.44.201S. 0.18 2.34.203R. 28.3 2.33.218S. 0.06 2.41.218. 0.19 2.44.203. 0.14 2.34.203S. 0.17 2.32.203. 1.89 2.41.218R. 19.03 2.44.206R. 1.48 2.34.206. 2.71 2.32.203R. 30.8 2.41.218S. 0.05 2.44.206S. 0.19 2.34.206R. 6.91 2.32.203S. 0.73 2.41.203. 0.42 2.44.208. 0.21 2.34.206S. 0.62 2.32.218. 1.13 2.41.203R. >39.8 2.44.208S. 0.03 2.34.208. 0.52 2.32.222. 2.06 2.41.203S. 0.067 2.44.218. 0.03 2.34.208R. 11.5 2.31.207. 0.57 2.41.219. 0.21 2.44.218R. 1.9 2.34.208S. 0.14 2.31.208. 0.03 2.41.236. 9.9 2.44.218S. 0.04 2.34.218. 0.22 2.31.211R 2.15 2.41.235. 0.09 2.44.221. 0.06 2.34.218R. 20.9 2.31.211S. 0.53 2.41.235R. 6.54 2.44.222. 0.35 2.34.218S. 0.07 2.31.215. 1.68 2.41.235S. 0.09 2.44.223. 0.12 2.34.219. 0.64 2.31.218. 0.22 2.39.203. 0.17 2.44.223R. 13.44 2.34.219R. 33.6 2.31.228. 1.65 2.39.208. 0.07 2.44.223S. 0.08 2.34.219S. 0.12 2.31.229. 0.8 2.39.219R. 0.55 2.44.225. 0.15 2.34.222. 0.22 2.31.230. 1.25 2.39.219S. 0.1 2.44.226. 0.11 2.34.222R. 46 2.60.203. 1.02 2.60.206. 3.4 2.49.226S.I. 1.7 11.41.203. 0.32 2.44.238.I. 0.06 2.60.218 0.2 2.41.232. 0.06 14.41.203. 0.03 2.44.243.I. 0.17 2.64.203 1.46 2.41.231. 0.08 12.41.203. 0.36 2.44.213.I. 0.15 2.64.206. 5.94 2.41.231R. 8.26 13.41.203. 0.13 2.44.244.I. 0.1 2.64.218. 0.34 2.41.231S. 0.05 15.41.203. 0.08 2.44.245.I. 0.21 2.65.203. 3.05 2.41.233R. 9.8 16.41.203. 0.13 2.44.246.I. 1.2 2.65.206. 7.29 2.41.233S. 0.03 17.41.203. 0.14 2.44.247.I. 0.03 2.65.218. 3.07 2.41.234R 10.9 18.41.203. 0.35 2.44.248.I. 0.73 2.47.203. 0.11 2.41.234S. 0.1 19.41.203. 0.15 2.44.249.I. 0.36 2.47.203R. 33.9 2.41.233R.I. 7.1 20.41.203. 0.18 2.44.250.I. 0.27 2.47.203S. 0.03 2.41.233S.I. 0.03 21.44.221R. 0.22 2.44.251.I. 0.19 2.51.203. 0.07 2.41.237. 0.02 21.44.221S. 0.07 2.44.252.I. 0.83 2.51.203R. 7.5 2.41.220. 0.03 2.44.222.I. 0.22 2.44.253.I. 0.67 2.51.203S. 0.03 2.44.238.I. 011 2.44.222R.I. 8.78 2.44.254.I. 0.3 2.49.203. 0.07 2.44.238R.I. >100 2.44.222S.I. 0.07 2.44.255.I. 0.83 2.49.203R. 4.43 2.44.238S.I. 0.03 2.44.226R.I. 5.73 2.67.226.I. 0.17 2.49.203S. 0.06 2.44.239.I. 0.02 2.44.226S.I. 0.07 2.68.226.I. 0.19 2.50.203. 0.1 2.44.214.I. 0.02 2.44.218.I. 0.08 2.69.226R.I. 1.64 2.50.203R. 10.5 2.44.240.I. 0.28 2.44.201.I. 0.25 2.69.226S.I. 0.27 2.50.203S. 0.06 2.44.256.I. 0.13 2.44.203.I. 0.12 2.70.226.I. 0.2 2.58.203R. 1.18 2.44.257.I. 0.18 2.44.241.I. 0.65 2.71.226R.I. 1.1 2.58.203S. 0.1 10.41.203. 0.27 2.44.242.I. 0.11 2.71.226S.I. 0.27 2.49.226.I. 0.18 1.41.203. 0.16 2.44.225.I. 0.12 2.72.226.I. 0.12 2.49.226R.I. 0.08 3.41.203. 0.68 2.44.217.I. 0.11 2.72.226R.I. 39.6 2.72.226S.I. 0.1 2.43.226.I. 0.46 2.73.226.I. 0.15 2.44.226.II. 0.1
[0656] Biological Assay
[0657] Evaluation of compound inhibitory activity (IC.sub.50)
[0658] 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 U S A. 2013 Mar 26;110(13):5052-7.).
[0659] Briefly, compounds are serially diluted in DMSO (working dilutions). ASF-coated 384we11 plates are supplemented with 22.8 pL/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.
[0660] Plates are incubated for 3 hours at 4° C., then washed with cold assay buffer (3×50uL), 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 (3×50uL). Finally, 25 μL/well of ABTS substrate is added. OD (410nm) is recorded after 30 to 45min and IC.sub.50 values are calculated.
[0661] 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.