IP Library › Granted Patent US 12,410,208

Granted Patent B2

US 12,410,208 · App. 17/633,941 · Granted Sep 9, 2025

(2-acetamidyl)thio-beta-D-galactopyranoside derivatives

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)

Assignee: IDORSIA PHARMACEUTICALS LTD

C07H19/056

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 12,410,208
App. No.: 17/633,941
Granted: Sep 9, 2025
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention relates to compounds of Formula (I) wherein Ar 1 , R 1 , R 2a , R 2b , and R 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 (260)

1. A compound of Formula (I)

wherein

R 1 represents

an amide group of the structure:

wherein

R N11 represents

—C 1-6 -alkyl;

—CH 2 —CH 2 —O—C 1-3 -alkyl;

—CH 2 —C 1-3 -fluoroalkyl;

—C 0-2 -alkylene-C 3-6 -cycloalkyl, wherein said C 3-6 -cycloalkyl is unsubstituted or mono- or di-substituted with fluoro or methyl;

—C 0-2 -alkylene-C 4-6 -cycloalkyl wherein said C 4-6 -cycloalkyl contains one oxygen ring atom;

—CH 2 —CH 2 —NR N21 R N22 , wherein R N21 and R 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 1-2 -alkylene-R 11 , wherein R 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

and R N12 represents hydrogen or C 1-2 -alkyl;

or R N11 and R N12 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl selected from 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 N11 and R N12 together with the nitrogen atom to which they are attached form morpholin-4-yl;

or R N11 and R 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 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 2a represents hydrogen; and R 2b represents

—C 2-4 -alkyl,

—C 0-1 -alkylene-Ar 2b , wherein Ar 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 2a and R 2b both represent hydrogen, methyl, ethyl, or n-propyl;

or R 2a and R 2b together with the carbon atom to which they are attached form a 3- to 6-membered ring selected from

C 3-6 -cycloalkylene, wherein said C 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 1-3 -alkyl, —C 0-2 -alkylene-C 3-6 -cycloalkyl, or -L-R N2 wherein

-L- represents —CO—, —SO 2 —, *—CO—NH—, *—CO—O—, or *—SO 2 —NH—, and

R N2 represents —C 1-3 -alkyl or —C 0-2 -alkylene-C 3-6 -cycloalkyl;

wherein in the above groups the asterisks indicate the bond which is connected to the rest of the molecule; or

R 2a and R 2b together with the carbon atom to which they are attached form a spiro-bicyclic ring system of the structure (S 2AB )

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 3 represents hydroxy or C 1-3 -alkoxy;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein said compound is a compound of Formula (I S ),

wherein the carbon atom to which the group R 1 is attached is in the absolute configuration as drawn in Formula (I S );

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 ; wherein Ar 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 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.

5. 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.

6. A compound according to claim 1 ; wherein Ar 1 represents a phenyl group of the structure

wherein

R m2 represents halogen; and

R p represents hydrogen, halogen, methyl, cyano, or methoxy;

or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 ; wherein R 1 represents an amide group of the structure

wherein

R N11 represents

—C 1-6 -alkyl;

—CH 2 —C 1-3 -fluoroalkyl;

cyclopropyl, cyclobutyl, —CH 2 -cyclopropyl, —CH 2 -cyclopentyl, —CH 2 -1-fluorocyclopentyl, or —CH 2 —CH 2 -cyclopropyl;

—CH 2 -tetrahydro-2H-pyran-4-yl, or —CH 2 —CH 2 -tetrahydro-2H-pyran-4-yl;

tetrahydro-2H-pyran-4-yl, or oxetane-3-yl;

benzyl;

phenyl, or pyridinyl; or

and R N12 represents hydrogen or C 1-2 -alkyl;

or R N11 and R N12 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl selected from 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 N11 and R N12 together with the nitrogen atom to which they are attached form morpholin-4-yl;

or R N11 and R N12 together with the nitrogen atom to which they are attached form an indolin-1-yl ring;

or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 ; wherein R 1 represents an amide group of the structure

wherein

R N11 represents

—C 1-6 -alkyl;

—CH 2 —CH 2 —O—C 1-3 -alkyl;

—CH 2 —C 1-3 -fluoroalkyl; or

cyclopropyl, cyclobutyl, —CH 2 -cyclopropyl, —CH 2 -cyclopentyl, —CH 2 -1-fluorocyclopentyl, or —CH 2 —CH 2 -cyclopropyl;

and R N12 represents C 1-2 -alkyl;

or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 ; wherein

R 2a represents hydrogen; and R 2b represents

—C 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 2a and R 2b both represent methyl, ethyl, or n-propyl;

or R 2a and R 2b together with the carbon atom to which they are attached form a 3- to 6-membered ring selected from

C 4-6 -cycloalkylene, wherein said C 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 1-3 -alkyl, —CO—C 1-3 -alkyl, —CO—O—C 1-3 -alkyl, —CO—NH-cyclopropyl, —SO 2 —C 1-3 -alkyl, —SO 2 -cyclopropyl, or —SO 2 —NH—C 1-3 -alkyl;

azetidine-3,3-diyl, wherein the nitrogen of said azetidine is substituted with —CO—O—C 1-3 -alkyl; or

R 2a and R 2b together with the carbon atom to which they are attached form a spiro-bicyclic ring system of the structure:

or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 1 ; wherein R 3 represents methoxy;

or a pharmaceutically acceptable salt thereof.

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

12. A method for the treatment of an indication mediated by galectin-3 selected from fibrosis of organs; neuropathic pain; insulin resistance disorders, and cancer wherein the cancer is treated in combination with immunotherapy, 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.

13. A compound, wherein said compound is:

(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)-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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N,N,3-trimethylbutanamide;

(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-3-hydroxy-N,3-dimethylbutanamide;

(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,N-diethyl-3-hydroxy-3-methylbutanamide;

(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)-3-hydroxy-3-methyl-1-((R)-2-methylazetidin-1-yl) butan-1-one;

(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)-3-hydroxy-3-methyl-1-(3-methylazetidin-1-yl) butan-1-one;

(S)-1-(azetidin-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)-3-hydroxy-3-methylbutan-1-one;

(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)-2-(4-hydroxy-1-methylpiperidin-4-yl)-N-isobutyl-N-methylacetamide;

(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-2-(4-hydroxy-1-methylpiperidin-4-yl)-N-methylacetamide;

(S)—N-benzyl-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)-2-(4-hydroxy-1-methylpiperidin-4-yl)-N-methylacetamide;

(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)-2-(4-hydroxy-1-methylpiperidin-4-yl)-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)-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;

(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)-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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N,N-diethyl-2-(4-hydroxytetrahydro-2H-pyran-4-yl)acetamide;

(S)-1-(azetidin-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)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethan-1-one;

(S)—N-(cyclopentylmethyl)-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)-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-methylacetamide;

(S)—N-(2-cyclopropylethyl)-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)-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)-1H-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)-1H-1,2,3-triazol-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)-1H-1,2,3-triazol-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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-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)-1H-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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-(2-fluoro-2-methylpropyl)-2-(1-hydroxycyclohexyl)-N-methylacetamide;

(S)-2-(4,4-difluoro-1-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,N-dimethylacetamide;

(S)-2-(4,4-difluoro-1-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-ethyl-N-methylacetamide;

(S)—N-cyclobutyl-2-(4,4-difluoro-1-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;

(S)—N-(cyclopropylmethyl)-2-(4,4-difluoro-1-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;

(S)—N-cyclopropyl-2-(4,4-difluoro-1-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;

(S)-2-(4,4-difluoro-1-hydroxycyclohexyl)-1-(4,4-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;

(S)-2-(4,4-difluoro-1-hydroxycyclohexyl)-1-(3,3-difluoroazetidin-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;

(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-2-(1-hydroxycyclopentyl)-N-methylacetamide;

(S)-1-(azetidin-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)-2-(1-hydroxycyclopentyl)ethan-1-one;

(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)-2-(1-hydroxycyclopentyl)-N-methylacetamide;

(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)-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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-ethyl-2-(1-hydroxycyclobutyl)-N-methylacetamide;

(S)-1-(azetidin-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)-2-(1-hydroxycyclobutyl)ethan-1-one;

(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)-2-(1-hydroxycyclobutyl)-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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-2-(1-hydroxycyclobutyl)-N-methyl-N-neopentylacetamide;

(S)-2-(3,3-difluoro-1-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)-N-ethyl-N-methylacetamide;

(S)-1-(azetidin-1-yl)-2-(3,3-difluoro-1-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;

(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)-1H-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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N,3-diethyl-3-hydroxy-N-methylpentanamide;

(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)-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)-1H-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)-1H-1,2,3-triazol-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)-1H-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)-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;

(S)—N-(cyclopropylmethyl)-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)-3-hydroxy-N,3-dimethylbutanamide;

(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)-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)-1H-1,2,3-triazol-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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-N,3-dimethyl-N-(2-morpholinoethyl) butanamide;

(2S,3R)-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-3-hydroxy-N-methylpentanamide;

(2S,3S)-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-3-hydroxy-N-methylpentanamide;

(2S,3R)-1-(azetidin-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)-3-hydroxypentan-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)-1H-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-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-methylpentanamide;

(2S,3S)—N-(cyclopropylmethyl)-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)-3-hydroxy-N-methylpentanamide;

(2S,3R)-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-3-hydroxy-N-methyl-4-phenylbutanamide;

(2S,3S)-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-3-hydroxy-N-methyl-4-phenylbutanamide;

(2S,3R)-1-(azetidin-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)-3-hydroxy-4-phenylbutan-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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-3-hydroxy-4-phenylbutan-1-one;

(2S,3R)—N-(cyclopropylmethyl)-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)-3-hydroxy-N-methyl-4-phenylbutanamide;

(2S,3S)—N-(cyclopropylmethyl)-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)-3-hydroxy-N-methyl-4-phenylbutanamide;

(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)-1H-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-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;

(2S,3R)-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-3-hydroxy-N-methyl-3-(1-methyl-1H-pyrazol-3-yl) propanamide;

(2S,3S)-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-3-hydroxy-N-methyl-3-(1-methyl-1H-pyrazol-3-yl) propanamide;

(2S,3R)-1-1-(Azetidin-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)-3-hydroxy-3-(1-methyl-1H-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)-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;

(S)—N-Cyclopropyl-4-(1-(((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-(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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-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)-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;

(2R,3R,4S,5R,6S)-2-(Acetoxymethyl)-6-(((S)-2-(ethyl(methyl)amino)-1-(3-hydroxy-1-(methoxycarbonyl) azetidin-3-yl)-2-oxoethyl)thio)-4-(4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,5-diyl diacetate;

N-Cyclopropyl-4-((S)-2-(ethyl(methyl)amino)-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;

(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-2-(4-hydroxytetrahydro-2H-pyran-4-yl)-N-phenylacetamide;

(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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-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)-1H-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)-1H-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)-1H-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)-1H-1,2,3-triazol-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)-1H-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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)acetamide;

(S)-2-(((2S,3R,4S,5R,6R)-4-(4-(3,5-Difluorophenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-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)-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;

(S)-2-(((2S,3R,4S,5R,6R)-4-(4-(3,5-Difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-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)-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;

(S)-2-(((2S,3R,4S,5R,6R)-4-(4-(4-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;

(S)-2-(((2S,3R,4S,5R,6R)-4-(4-(4-Bromo-3-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;

(S)-2-(((2S,3R,4S,5R,6R)-4-(4-(3-Chloro-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;

(S)-2-(((2S,3R,4S,5R,6R)-4-(4-(3-Chloro-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;

(S)-2-(((2S,3R,4S,5R,6R)-4-(4-(3,4-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;

(S)-2-(((2S,3R,4S,5R,6R)-4-(4-(3,4-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;

(S)-2-(((2S,3R,4S,5R,6R)-4-(4-(4-Bromo-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;

(S)-2-(((2S,3R,4S,5R,6R)-4-(4-(3-Cyano-5-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;

(S)—N-Ethyl-2-(((2S,3R,4S,5R,6R)-4-(4-(3-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;

(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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide;

(S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-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;

(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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide;

(S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-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;

(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)-1H-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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide;

(S)-2-(4,4-Difluoro-1-hydroxycyclohexyl)-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;

(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)-1H-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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio)-N-methylacetamide;

(S)-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)-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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio) ethan-1-one;

(S)-1-(4,4-Difluoropiperidin-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)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-2-yl)thio) ethan-1-one;

(S)-1-(4,4-Difluoropiperidin-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)-1H-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-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;

or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound according to claim 13 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. A method for the treatment of an indication mediated by galectin-3 selected from fibrosis of organs; neuropathic pain; insulin resistance disorders, and cancer wherein the cancer is treated in combination with immunotherapy, comprising administering to a subject in a need thereof an effective amount of a compound according to claim 13 , or of a pharmaceutically acceptable salt thereof.

Assignments (2)

PATENT SECURITY AGREEMENT Recorded Jun 25, 2026

From: IDORSIA PHARMACEUTICALS LTD

To: BIOPHARMA CREDIT PLC, AS COLLATERAL AGENT

Reel/Frame 076038/0461 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 26, 2022

From: BOLLI, MARTIN; BUR, DANIEL; GATFIELD, JOHN; GRISOSTOMI, CORINNA; REMEN, LUBOS; ZUMBRUNN, CORNELIA

To: IDORSIA PHARMACEUTICALS LTD

Reel/Frame 060313/0939 →

Continuity (1)

Related Publication 20220306674A1 · Sep 29, 2022

References Cited (107)

US 20140099319A1 · Traber · 2014 [cited by applicant]

US 20230295182A1 · Bolli et al. · 2023 [cited by applicant]

US 20230348442A1 · Bolli et al. · 2023 [cited by applicant]

US 20240109930A1 · Bolli et al. · 2024 [cited by applicant]

US 20240124427A1 · Bolli et al. · 2024 [cited by applicant]

WO WO02057284A1 · 2002 [cited by applicant]

WO WO2005113568A1 · 2005 [cited by applicant]

WO WO2005113569A1 · 2005 [cited by applicant]

WO WO2014067986A1 · 2014 [cited by applicant]

WO WO2014078655A1 · 2014 [cited by applicant]

WO WO2016120403A1 · 2016 [cited by applicant]

WO WO2017007689A1 · 2017 [cited by applicant]

WO WO2018011094A1 · 2018 [cited by applicant]

WO WO2018209255A1 · 2018 [cited by applicant]

WO WO2018209276A1 · 2018 [cited by applicant]

WO WO2019067702A1 · 2019 [cited by applicant]

WO WO2019067702A9 · 2019 [cited by applicant]

WO WO2019075045A1 · 2019 [cited by applicant]

WO WO2019089080A1 · 2019 [cited by applicant]

WO WO2020078807A1 · 2020 [cited by applicant]

WO WO2020078808A1 · 2020 [cited by applicant]

WO WO2020104335A1 · 2020 [cited by applicant]

WO WO2020210308A1 · 2020 [cited by applicant]

WO WO2021001528A1 · 2021 [cited by applicant]

WO WO2021004940A1 · 2021 [cited by applicant]

WO WO2021028336A1 · 2021 [cited by applicant]

WO WO2021028570A1 · 2021 [cited by applicant]

WO WO2021038068A1 · 2021 [cited by applicant]

WO WO2022073969A1 · 2022 [cited by applicant]

WO WO2022090544A1 · 2022 [cited by applicant]

WO WO2022171594A1 · 2022 [cited by applicant]

WO WO2022184755A1 · 2022 [cited by applicant]

Blanchard et al., “Galectin-3 inhibitors: a patent review (2008-present)” Expert Opin Ther Patents vol. 24 No. 10 pp. 1053-1065, DOI:10.1517/13543776.2014.947961 (Year: 2014). [cited by examiner]

Rose et al., “Prediction and Prevention of Autoimmune Disease in the 21st Century: A Review and Preview” vol. 183 No. 5 pp. 403-406, DOI: 10.1093/aje/kwv292 (Year: 2016). [cited by examiner]

Marcel Verweij, “Preventative Medicine Between Obligation and Aspiration”, published by Springer-Science and Business Media, DOI:10.1007/978-94-015-9365-6, pp. 25-48 (Year: 2000). [cited by examiner]

Penny et al., “The challenges for cancer chemoprevention” Chem Soc Rev vol. 44, pp. 8836-8847, DOI: 10.1039/c5cs00705d (Year: 2015). [cited by examiner]

Li et al., “Functions of Galectin-3 and Its Role in Fibrotic Diseases” The Journal of Pharmacology and Experimental Therapeutics vol. 351, pp. 336-343, DOI:10.1124/jpet.114.218370 (Year: 2014). [cited by examiner]

Traber et al., “Therapy of Experimental NASH and Fibrosis with Galectin Inhibitors” PLOS One vol. 8 issue 12 pp. 1-12, DOI:doi: 10.1371/journal.pone.0083481 (Year: 2013). [cited by examiner]

Ma et al., “Galectin-3 Inhibition Is Associated with Neuropathic Pain Attenuation after Peripheral Nerve Injury” PLOS One vol. 11 No. 2 e0148792, doi: 10.1371/journal.pone.0148792 (Year: 2016). [cited by examiner]

U.S. Appl. No. 17/633,895, filed Feb. 8, 2022 (371(c) Date), Bolli et al. [cited by applicant]

U.S. Appl. No. 17/634,512, filed Feb. 10, 2022 (371(c) Date), Bolli et al. [cited by applicant]

U.S. Appl. No. 17/638,799, filed Feb. 25, 2022 (371(c) Date), Bolli et al. [cited by applicant]

Arciniegas, E. et al., “Galectin-1 and Galectin-3 and Their Potential Binding Partners in the Dermal Thickening of Keloid Tissues,” The American Journal of Dermatopathology, 2019, 41 (3), 193-204. [cited by applicant]

Barondes, S. et al., “Galectins: A Family of Animal β-Galactoside-Binding Lectins,” Cell, 1994, 76, 597-598. [cited by applicant]

Burguillos, M. et al., “Macroglia-Secreted Galectin-3 Acts as a Toll-like Receptor 4 Ligand and Contributes to Microglial Activation,” Cell Reports, 2015, 10, 1626-1638. [cited by applicant]

Caldararu, O. et al., “Are crystallographic β-factors suitable for calculating protein conformational entropy?,” Physical Chemistry Chemical Physics, 2019, 21, 18149-18160. [cited by applicant]

Caniglia, J. et al., “A potential role for Galectin-3 inhibitors in the treatment of COVID-19,” PeerJ, 2020, 8:e9392, 10 pages, doi: 10.7717/peerj.9392. [cited by applicant]

Chasse, T. et al., “Dendritic encapsulation-roles of cores and branches,” Tetrahedron, 2003, 59, 3853-3861. [cited by applicant]

Chen, W-S. et al., “Galectin-3 Inhibition by a Small-Molecule Inhibitor Reduces Both Pathological Corneal Neovascularization and Fibrosis,” Investigative Ophthalmology & Visual Science, 2017, 58 (1), 9-20. [cited by applicant]

Chen, Y-J. et al., “Galectin-3 Enhances Avian H5N1 Influenza A Virus-Induced Pulmonary Inflammation by Promoting NLRP3 Inflammasome Activation,” The American Journal of Pathology, 2018, 188 (4), 1031-1042. [cited by applicant]

Chiariotti, L. et al., “Galectin genes: Regulation of expression,” Glycoconjugate Journal, 2004, 19, 441-449. [cited by applicant]

Dang, Z. et al., “Tubular Atrophy and Interstitial Fibrosis After Renal Transplantation Is Dependent on Galectin-3,” Transplantation, 2012, 93 (5), 477-484. [cited by applicant]

Deroo, E. et al., “The role of galectin-3 and galectin-3-binding protein in venous thrombosis,” Blood, 2015, 125 (11), 1813-1821. [cited by applicant]

Falcone, C. et al., “Galectin-3 Plasma Levels and Coronary Artery Disease: A New Possible Biomarker of Acute Coronary Syndrome,” International Journal of Immunopathology and Pharmacology, 2011, 24 (4), 905-913. [cited by applicant]

Farhad, M. et al., “The role of Galectin-3 in modulating tumor growth and immunosuppression within the tumor microenvironment,” OncoImmunology, 2018, 7 (6), e 1434467, 8 pages, https://doi.org/10.1080/2162402X.2018.1434… [cited by applicant]

Galectin Therapeutics, “Combination Immunotherapy with Galectin-3 Inhibitor GR-MD-02 Enhances Effects in Pre-clinical Models and Early Results of Phase 1 Clinical Trials,” Press Release, dated 2017, 3 pages. [cited by applicant]

Galectin Therapeutics, “Galectin Therapeutics Announces Results from Phase 2b NASH-CX Trial,” Bloomberg, Press Release, dated 2017, 5 pages. [cited by applicant]

Galecto Biotech, “Galecto Biotech's Lead Molecule TD139 is Safe, Well Tolerated, with Direct Target Engagement and Biomarker Effects in a Clinical Phase Ib/IIa trial in IPF Patients,” Press Release, dated 2017, 4 pages. [cited by applicant]

Gao, P. et al., “Galectin-3: its role in asthma and potential as an anti-inflammatory target,” Respiratory Research, 2013, 14:136, 9 pages, doi:10.1186/1465-9921-14-136. [cited by applicant]

Gehlken, C. et al., “Galectin-3 in Heart Failure: An Update of the Last 3 Years,” Heart Failure Clinics, 2018, 14, 75-92. [cited by applicant]

Giguère, D. et al., “Carbohydrate triazoles and isoxazoles as inhibitors of galectins-1 and -3,” Chemical Communications, 2006, 2379-2381. [cited by applicant]

Greene, T. et al., Eds., Protective Groups in Organic Synthesis, Wiley-Interscience, 1999. [cited by applicant]

Guha, P. et al., “Cod glycopeptide with picomolar affinity to galectin-3 suppresses T-cell apoptosis and prostate cancer metastasis,” Proceedings of the National Academy of Sciences, 2013, 110 (13), 5052-5057. [cited by applicant]

Henderson, N. et al., “Galectin-3 regulates myofibroblast activation and hepatic fibrosis,” Proceedings of the National Academy of Sciences, 2006, 103 (13), 5060-5065. [cited by applicant]

Henderson, N. et al., “Galectin-3 Expression and Secretion Links Macrophages to the Promotion of Renal Fibrosis,” The American Journal of Pathology, 2008, 172 (2), 288-298. [cited by applicant]

Henderson, N. et al., “The regulation of inflammation by galectin-3,” Immunological Reviews, 2009, 230, 160-171. [cited by applicant]

Hsu, D. et al., “Galectin-3 Expression is Induced in Cirrhotic Liver and Hepatocellular Carcinoma,” International Journal of Cancer, 1999, 81, 519-526. [cited by applicant]

Jin, Q-h. et al., “Serum galectin-3: a risk factor for vascular complications in type 2 diabetes mellitus,” Chinese Medical Journal, 2013, 126 (11), 2109-2115. [cited by applicant]

Johannes, L. et al., “Galectins at a glance,” Journal of Cell Science, 2018, 131, jcs208884, 9 pages, doi:10.1242/jcs.208884. [cited by applicant]

Kikuchi, Y. et al., “Galectin-3-positive call infiltration in human diabetic nephropathy,” Nephrology Dialysis Transplantation, 2004, 19 (3), 602-607. [cited by applicant]

Lacina, L. et al., “Glycophenotype of Psoriatic Skin,” Folia Biologica (Praha), 2006, 52, 10-15. [cited by applicant]

Ladouceur, S et al., “One-Pot Click Synthesis of 1N-Alkyl-4-aryl-1,2,3-triazoles from Protected Arylalkynes and Alkyl Bromides,” Synthesis, 2011, 22, 3604-3611. [cited by applicant]

Leffler, H. et al., “Introduction to galectins,” Glycoconjugate Journal, 2004, 19, 433-440. [cited by applicant]

Li, P. et al., “Hematopoietic-derived Galectin-3 Causes Cellular and Systemic Insulin Resistance,” HHS Public Access, Author manuscript, available in PMC 2017, 22 pages, face of article states: Published in final edited… [cited by applicant]

Liu, F-T. et al., “Galectins in acute and chronic inflammation,” Annals of the New York Academy of Sciences, 2012, 1253, 80-91. [cited by applicant]

Lowary, T. et al., “Recognition of synthetic O-methyl, epimeric, and amino analogues of the acceptor α-L-Fuc p-(1→2)-β-D-Gal p-OR by the blood-group A and B gene-specified glycosyltransferases,” Carbohydrate Research, 1… [cited by applicant]

MacKinnon, A. et al., “Regulation of Transforming Growth Factor-β1-driven Lung Fibrosis by Galectin-3,” American Journal of Respiratory and Critical Care Medicine, 2012, 185 (5), 537-546. [cited by applicant]

Nachtigal, M. et al., “Galectin-3 Expression in Human Atherosclerotic Lesions,” American Journal of Pathology, 1998, 152 (5), 1199-1208. [cited by applicant]

Nishi, Y. et al., “Role of Galectin-3 in Human Pulmonary Fibrosis,” Allergology International, 2007, 56 (1), 57-65. [cited by applicant]

Noël, J-C. et al., “Galectin-3 is Overexpressed in Various Forms of Endometriosis,” Appllied Immunohistochemistry & Molecular Morphology, 2011, 19 (3), 253-257. [cited by applicant]

Rao, S. et al., “Regulation of Eosinophil Recruitment and Activation by Galectins in Allergic Asthma,” Frontiers in Medicine, 2017, 4:68, 12 pages, doi:10.3389/fmed.2017.00068. [cited by applicant]

Rebholz, C. et al., “Plasma galectin-3 levels are associated with the risk of incident chronic kidney disease,” Kidney International, 2018, 93, 252-259. [cited by applicant]

Remington, The Science and Practice of Pharmacy, 21st Edition, 2005, Part 5, “Pharmaceutical Manufacturing,” published by Lippincott Williams & Wilkins. [cited by applicant]

Ruvolo, P., “Galectin 3 as a guardian of the tumor microenvironment,” Biochimica et Biophysica Acta, 2016, 1863, 427-437. [cited by applicant]

Saegusa J. et al., “Galectin-3 Is Critical for the Development of the Allergic Inflammatory Response in a Mouse Model of Atopic Dermatitis,” The American Journal of Pathology, 2009, 174 (3), 922-931. [cited by applicant]

Sano, H. et al., “Human Galectin-3 Is a Novel Chemoattractant for Monocytes and Macrophages,” The Journal of Immunology, 2000, 165 (4), 2156-2164. [cited by applicant]

Sciacchitano, S. et al., “Galectin-3: One Molecule for an Alphabet of Diseases, from A to Z,” International Journal of Molecular Sciences, 2018, 19, 379, 59 pages, doi:10.3390/ijms9020379. [cited by applicant]

Sharma, U. et al., “Novel anti-inflammatory mechanisms of N-Acetyl-Ser-Asp-Lys-Pro in hypertension-induced target organ damage,” HHS Public Access, Author manuscript, available in PMC 2019, 17 pages, face of article sta… [cited by applicant]

Stahl, P. et al., Eds., Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Wiley-VCH, 2008. [cited by applicant]

Sundblad, V. et al., “Regulated expression of galectin-3, a multifunctional glycan-binding protein, in haematopoietic and non-haematopoietic tissues,” Histology and Histopathology, 2011, 26, 247-265. [cited by applicant]

Tanaka, K. et al., “Dianions of Ethyl a-Mercaptoacetate and Ethyl α-Mercaptopropionate: A New Method for an Efficient Synthesis of α, β-Unsaturated Esters from Carbonyl Compounds,” Chemistry Letters, 1977, 471-474. [cited by applicant]

Taniguchi, T. et al., “Serum Levels of Galectin-3: Possible Association with Fibrosis, Aberrant Angiogenesis, and Immune Activation in Patients with Systemic Sclerosis,” Journal of Rheumatology, 2012, 39 (3), 539-544. [cited by applicant]

Thandavarayan, R. et al., “14-3-3 protein regulates Ask1 signaling and protects against diabetic cardiomyopathy,” Biochemical Pharmacology, 2008, 75, 1797-1806. [cited by applicant]

Verteramo, M. et al., “Interplay between Conformational Entropy and Solvation Entropy in Protein-Ligand Binding,” Journal of the American Chemical Society, 2019, 141, 2012-2026. [cited by applicant]

Vuong, L. et al., “An Orally Active Galectin-3 Antagonist Inhibits Lung Adenocarcinoma Growth and Augments Response to PD-L1 Blockade,” Cancer Research, 2019, 79 (7), 1480-1492. [cited by applicant]

Watanabe, H. et al., “Bulky Thiols and Their Coordination Compounds. An Improvement of the Removal Method of Tetrahydropyranyl Group from Thiols and Its Application for Ligand Syntheses,” Chemistry Letters, 1996, 999-10… [cited by applicant]

Witczak, Z. et al., Eds., Click Chemistry in Glycoscience: New Developments and Strategies, 2013, John Wiley & Sons, Inc., Hoboken, New Jersey. [cited by applicant]

Wouters, J. et al., Eds., Pharmaceutical Salts and Co-crystals, RSC Publishing, 2012. [cited by applicant]

Zhong, X. et al., “The role of galectin-3 in heart failure and cardiovascular disease,” Clinical and Experimental Pharmacology and Physiology, 2019, 46, 197-203. [cited by applicant]

De Oliveira, F. et al., “Galectin-3 in autoimmunity and autoimmune diseases,” Experimental Biology and Medicine, 2015, 240, 1019-1028. [cited by applicant]

Park, A-M. et al., “Galectin-3 Plays an Important Role in Innate Immunity to Gastric Infection by [cited by applicant]

Suárez-Fuentetaja, N. et al., “Circulating Galectin-3 Following Heart Transplant: Long-term Dynamics and Prognostic Value,” Revista Española de Cardiología, 2019, 72 (11), 899-906. [cited by applicant]

Tao, C-C. et al., “Galectin-3 promotes Aβ oligomerization and Aβ toxicity in a mouse model of Alzheimer's disease,” Cell Death & Differentiation, 2020, 27, 192-209. [cited by applicant]

U.S. Appl. No. 18/248,007, filed Apr. 5, 2023 (371(c) Date), Bolli et al. [cited by applicant]

U.S. Appl. No. 18/251,273, filed May 1, 2023 (371(c) Date), Bolli et al. [cited by applicant]

U.S. Appl. No. 18/264,751, filed Aug. 8, 2023 (371(c) Date), Bolli et al. [cited by applicant]

U.S. Appl. No. 18/548,833, filed Sep. 1, 2023 (371(c) Date), Bolli et al. [cited by applicant]