Alpha-D-galactoside inhibitors of galectins

Abstract

The present invention relates to a compound of the general formula (1). The compound of formula (1) is suitable for use in a method for treating a disorder relating to the binding of a galectin, such as galectin-3 to a ligand in a mammal, such as a human. Furthermore, the present invention concerns a method for treatment of a disorder relating to the binding of a galectin, such as galectin-3 to a ligand in a mammal, such as a human.

Claims

1. A D-galactopyranose compound of formula (1) ##STR00116## wherein the pyranose ring is -D-galactopyranose, A is selected from ##STR00117## wherein Het.sup.1 is selected from a pyridinyl, optionally substituted with a group selected from H, CN, Br, Cl, I, F, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, and SCH.sub.3 optionally substituted with a F; or a pyrimidyl, optionally substituted with a group selected from H, CN, Br, Cl, I, F, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, and SCH.sub.3 optionally substituted with a F; wherein R.sup.1-R.sup.5 are independently selected from a group consisting of H, CN, Br, Cl, I, F, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, and SCH.sub.3 optionally substituted with a F; X is selected from S, SO, and SO.sub.2; B.sup.1 is selected from a) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl substituted with a five or six membered heteroaromatic ring, optionally substituted with a substituent selected from CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.14CONH wherein R.sup.14 is selected from C.sub.1-3 alkyl and cyclopropyl; or a C.sub.1-6 alkyl substituted with a phenyl, optionally substituted with a substituent selected from CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.15CONH wherein R.sup.15 is selected from C.sub.1-3 alkyl and cyclopropyl; b) an aryl, optionally substituted with a group selected from a halogen; CN; COOH; CONR.sup.22R.sup.23, wherein R.sup.22 and R.sup.23 are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.28R.sup.29, wherein R.sup.28 and R.sup.29 are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.16CONH wherein R.sup.16 is selected from C.sub.1-3 alkyl and cyclopropyl; c) a C.sub.5-7 cycloalkyl, optionally substituted with a substituent selected from a halogen, CN, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.17CONH wherein R.sup.17 is selected from C.sub.1-3 alkyl and cyclopropyl; and d) a heterocycle, optionally substituted with a group selected from a halogen; CN; COOH; CONR.sup.24R.sup.25, wherein R.sup.24 and R.sup.25 are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.30R.sup.31, wherein R.sup.30 and R.sup.31 are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.18CONH wherein R.sup.18 is selected from C.sub.1-3 alkyl and cyclopropyl; e) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl; or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1, wherein A is selected from formula 2 wherein R.sup.1-R.sup.5 are independently selected from H, halogen, CN, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F.

3. The compound of claim 1, wherein A is selected from formula 2 wherein R.sup.1 and R.sup.5 are selected from H and R.sup.2-R.sup.4 are selected from F, Cl, Br, CN, CH.sub.3 and CF.sub.3.

4. The compound of claim 1, wherein A is selected from formula 2 wherein R.sup.1 and R.sup.5 are selected from H and R.sup.2 and R.sup.4 are selected from F and R.sup.3 is selected from Br, Cl, CN, CH.sub.3 and CF.sub.3.

5. The compound of claim 1, wherein A is selected from formula 2 wherein R.sup.1 and R.sup.5 are selected from H and R.sup.2 is selected from F, and R.sup.3-R.sup.4 are selected from Cl.

6. The compound of claim 1, wherein A is selected from formula 2 wherein R.sup.1, R.sup.2 and R.sup.5 are selected from H and R.sup.3 and R.sup.4 are selected from F and Cl.

7. The compound of claim 1, wherein A is selected from formula 3 wherein Het.sup.1 is a pyridinyl optionally substituted with a group selected from Br, F, and Cl.

8. The compound of claim 1, wherein A is selected from formula 3 wherein Het.sup.1 is a pyridinyl substituted with a group selected from F and Cl.

9. The compound of claim 1, wherein X is selected from S.

10. The compound of claim 1, wherein B.sup.1 is selected from an aryl, optionally substituted with a group selected from a halogen; CN; methyl optionally substituted with a F; OCH.sub.3 optionally substituted with a F; OCH.sub.2CH.sub.3 optionally substituted with a F; OH; R.sup.16CONH wherein R.sup.16 is selected from C.sub.1-3 alkyl and cyclopropyl; COOH; NR.sup.28R.sup.29, wherein R.sup.28 and R.sup.29 are independently selected from H, C.sub.1-3 alkyl and isopropyl; and CONH.sub.2.

11. The compound of claim 1, wherein B.sup.1 is selected from a phenyl or phenyl substituted with one, two or three substituents selected from halogen.

12. The compound of claim 1, wherein B.sup.1 is selected from a phenyl substituted with two substituents selected from halogen.

13. The compound of claim 1, wherein B.sup.1 is selected from a heterocycle, optionally substituted with a group selected from a halogen; CN; methyl optionally substituted with a F; OCH.sub.3 optionally substituted with a F; OCH.sub.2CH.sub.3 optionally substituted with a F; OH; CONH.sub.2; NR.sup.30R.sup.31, wherein R.sup.30 and R.sup.31 are independently selected from H, C.sub.1-3 alkyl and isopropyl; and R.sup.18CONH wherein R.sup.18 is selected from C.sub.1-3 alkyl and cyclopropyl.

14. The compound of claim 1, wherein B.sup.1 is selected from a pyridinyl substituted with a group selected from halogen and CN.

15. The compound of claim 1 selected from: 4-Bromo-5-cyano-2-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 4-Chloro-5-cyano-2-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 2-Chloro-4-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-2-cyano-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Bromo-6-cyano-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Bromo-2-cyano-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 4-Chloro-2-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Bromo-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-6-cyano-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Bromo-2-cyano-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Bromo-6-cyano-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-2-cyano-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-3-pyridyl 3-deoxy-3-[4-(4-cyano-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,5-difluoro-4-trifluoromethyl-phenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-3-pyridyl 3-deoxy-3-[4-(4-bromo-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,4-dichloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-3-pyridyl 3-deoxy-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 3,4-Dichlorophenyl 3-deoxy-3-[4-(5-fluoro-3-pyridyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; and 3,4-Dichlorophenyl 3-deoxy-3-[4-(5-chloro-3-pyridyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside.

16. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable additive.

17. A method for treating a disorder relating to the binding of a galectin-3 to a ligand in a mammal, comprising the administration of the therapeutically effective amount pharmaceutical composition according to claim 16 to a mammal in need of said treatment.

18. The compound for use according to claim 17, wherein said disorder is selected from the group consisting of inflammation; fibrosis; scarring; keloid formation; aberrant scar formation; surgical adhesions; septic shock; cancer; metastasising cancers; autoimmune diseases; metabolic disorders; heart disease; heart failure; pathological angiogenesis; and eye diseases; atherosclerosis; metabolic diseases; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, mesothelioma; liver disorders.

19. A method for treatment of a disorder relating to the binding of a galectin-3 to a ligand in a mammal, wherein a therapeutically effective amount of at least one compound according to claim 1 is administered to a mammal in need of said treatment.

20. The method of claim 19, wherein said disorder is selected from the group consisting of inflammation; fibrosis; scarring; keloid formation; aberrant scar formation; surgical adhesions; septic shock; cancer; metastasising cancers; autoimmune diseases; metabolic disorders; heart disease; heart failure; pathological angiogenesis; and eye diseases; atherosclerosis; metabolic diseases; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, mesothelioma; liver disorders.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The present compounds of formula (1) differ from prior art compounds in particular in that the pyranose ring is -D-galactopyranose. Moreover, the present compounds of formula (1) differ from prior art compounds in that they have high affinity due to specific substituents in the 1 and 3 position of the -D-galactopyranose. It is important to emphasize that the skilled person may expect same or similar activity of both alpha and beta anomers according to known literature, however, the present inventors have found that the present compounds of formula (1) possesses increased affinity to galectin-3 compared to corresponding beta anomers.

(2) In general the compounds of formula (1) are >10 fold better with respect to galectin-3 affinity compared to the corresponding beta-anomers.

(3) In a broad aspect the present invention relates to a D-galactopyranose compound of formula (1)

(4) ##STR00015##
wherein
the pyranose ring is -D-galactopyranose,
A is selected from

(5) ##STR00016##

(6) wherein Het.sup.1 is selected from a pyridinyl, optionally substituted with a group selected from H, CN, Br, Cl, I, F, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, and SCH.sub.3 optionally substituted with a F; or a pyrimidyl, optionally substituted with a group selected from H, CN, Br, Cl, I, F, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, and SCH.sub.3 optionally substituted with a F;

(7) wherein R.sup.1-R.sup.5 are independently selected from a group consisting of H, CN, Br, Cl, I, F, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, and SCH.sub.3 optionally substituted with a F;

(8) X is selected from S, SO, and SO.sub.2;

(9) B.sup.1 is selected from a) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl substituted with a five or six membered heteroaromatic ring, optionally substituted with a substituent selected from CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.14CONH wherein R.sup.14 is selected from C.sub.1-3 alkyl and cyclopropyl; or a C.sub.1-6 alkyl substituted with a phenyl, optionally substituted with a substituent selected from CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.15CONH wherein R.sup.15 is selected from C.sub.1-3 alkyl and cyclopropyl; b) an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from a halogen; CN; COOH; CONR.sup.22R.sup.23, wherein R.sup.22 and R.sup.23 are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.28R.sup.29, wherein R.sup.28 and R.sup.29 are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.16CONH wherein R.sup.16 is selected from C.sub.1-3 alkyl and cyclopropyl; c) a C.sub.5-7 cycloalkyl, optionally substituted with a substituent selected from a halogen, CN, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.17CONH wherein R.sup.17 is selected from C.sub.1-3 alkyl and cyclopropyl; and d) a heterocycle, such as heteroaryl or heterocycloalkyl, optionally substituted with a group selected from a halogen; CN; COOH; CONR.sup.24R.sup.25, wherein R.sup.24 and R.sup.25 are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.30R.sup.31, wherein R.sup.30 and R.sup.31 are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.18CONH wherein R.sup.18 is selected from C.sub.1-3 alkyl and cyclopropyl; e) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl; or

(10) a pharmaceutically acceptable salt or solvate thereof.

(11) In an embodiment A is selected from formula 2 wherein R.sup.1-R.sup.5 are independently selected from H, halogen, CN, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F. In a further embodiment A is selected from formula 2 wherein R.sup.1 and R.sup.5 are selected from H and R.sup.2-R.sup.4 are selected from halogen, CN, CH.sub.3 and CF.sub.3. In a further embodiment A is selected from formula 2 wherein R.sup.1 and R.sup.5 are selected from H and R.sup.2-R.sup.4 are selected from F, Cl, Br, CN, CH.sub.3 and CF.sub.3. In a still further embodiment A is selected from formula 2 wherein R.sup.1 and R.sup.5 are selected from H and R.sup.2 and R.sup.4 are selected from F and R.sup.3 is selected from Br, Cl, I, CN, CH.sub.3 and CF.sub.3. In a still further embodiment A is selected from formula 2 wherein R.sup.1 and R.sup.5 are selected from H and R.sup.2 and R.sup.4 are selected from F and R.sup.3 is selected from Br, Cl, CN, CH.sub.3 and CF.sub.3. In a further embodiment A is selected from formula 2 wherein R.sup.1 and R.sup.5 are selected from H and R.sup.2 is selected from F, and R.sup.3-R.sup.4 are selected from Cl. In a further embodiment A is selected from formula 2 wherein R.sup.1, R.sup.2 and R.sup.5 are selected from H and R.sup.3 and R.sup.4 are selected from halogen, such as F and Cl.

(12) In a further embodiment A is selected from formula 3 wherein Het.sup.1 is a pyridinyl optionally substituted with a group selected from halogen. In a still further embodiment A is selected from formula 3 wherein Het.sup.1 is an unsubstituted pyridinyl.

(13) In a further embodiment A is selected from formula 3 wherein Het.sup.1 is a pyridinyl optionally substituted with a group selected from Br, F, and Cl. In a still further embodiment A is selected from formula 3 wherein Het.sup.1 is a pyridinyl substituted with a group selected from F and Cl. In a further embodiment A is selected from formula 3 wherein Het.sup.1 is a pyridinyl substituted with one group selected from F and Cl.

(14) In a further embodiment X is selected from S.

(15) In a still further embodiment B.sup.1 is selected from an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from a halogen; CN; methyl optionally substituted with a F; OCH.sub.3 optionally substituted with a F; OCH.sub.2CH.sub.3 optionally substituted with a F; OH; R.sup.16CONH wherein R.sup.16 is selected from C.sub.1-3 alkyl and cyclopropyl; COOH; NR.sup.28R.sup.29, wherein R.sup.28 and R.sup.29 are independently selected from H, C.sub.1-3 alkyl and isopropyl; and CONH.sub.2. In a further embodiment B.sup.1 is selected from a phenyl or phenyl substituted with one, two or three substituents selected from halogen. In a further embodiment B.sup.1 is selected from an unsubstituted phenyl. In a still further embodiment B.sup.1 is selected from a phenyl substituted with two substituents selected from halogen, such as Cl.

(16) In a further embodiment B.sup.1 is selected from a heterocycle, such as heteroaryl or heterocycloalkyl, optionally substituted with a group selected from a halogen; CN; methyl optionally substituted with a F; OCH.sub.3 optionally substituted with a F; OCH.sub.2CH.sub.3 optionally substituted with a F; OH; CONH.sub.2; NR.sup.30R.sup.31, wherein R.sup.30 and R.sup.31 are independently selected from H, C.sub.1-3 alkyl and isopropyl; and R.sup.18CONH wherein R.sup.18 is selected from C.sub.1-3 alkyl and cyclopropyl. In a still further embodiment B.sup.1 is selected from a pyridinyl substituted with a group selected from halogen and CN, such as Cl, Br and CN. In a still further embodiment B.sup.1 is selected from a pyridinyl substituted with one, two or three substituents selected from halogen and CN, such as Cl, Br and CN. In a still further embodiment B.sup.1 is selected from a pyridinyl substituted with one or two substituents selected from halogen and CN, such as Cl, Br and CN.

(17) In a further embodiment the compound of the present invention is selected from: 4-Bromo-5-cyano-2-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 4-Chloro-5-cyano-2-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 2-Chloro-4-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-2-cyano-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Bromo-6-cyano-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Bromo-2-cyano-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 4-Chloro-2-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1l-yl]-1-thio--D-galactopyranoside; 5-Bromo-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-6-cyano-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Bromo-2-cyano-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Bromo-6-cyano-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-2-cyano-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-3-pyridyl 3-deoxy-3-[4-(4-cyano-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,5-difluoro-4-trifluoromethyl-phenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-3-pyridyl 3-deoxy-3-[4-(4-bromo-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,4-dichloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-3-pyridyl 3-deoxy-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 3,4-Dichlorophenyl 3-deoxy-3-[4-(5-fluoro-3-pyridyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; 5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside; and 3,4-Dichlorophenyl 3-deoxy-3-[4-(5-chloro-3-pyridyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside.

(18) In a further aspect the present invention relates to a compound of formula (1) of the present invention for use as a medicine.

(19) In a still further aspect the present invention relates to a pharmaceutical composition comprising a compound of formula (1) of the present invention and optionally a pharmaceutically acceptable additive, such as a carrier and/or excipient.

(20) In a further aspect the present invention relates to a compound of formula (1) of the present invention for use in a method for treating a disorder relating to the binding of a galectin-3 to a ligand in a mammal, such as a human. In an embodiment the disorder is selected from the group consisting of inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart; scarring; keloid formation; aberrant scar formation; surgical adhesions; septic shock; cancer, such as carcinomas, sarcomas, leukemias and lymphomas, such as T-cell lymphomas; metastasising cancers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; heart disease; heart failure; pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer; and eye diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases such as diabetes; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, mesothelioma; liver disorders, such as non-alcoholic steatohepatitis. A non-limiting group of cancers given as examples of cancers that may be treated, managed and/or prevented by administration of a compound of formula (1) include: colon carcinoma, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangcoendothelia sarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystandeocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioblastomas, neuronomas, craniopharingiomas, schwannomas, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroama, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemias and lymphomas, acute lymphocytic leukemia and acute myelocytic polycythemia vera, multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's Disease, non-Hodgkin's lymphomas, rectum cancer, urinary cancers, uterine cancers, oral cancers, skin cancers, stomach cancer, brain tumors, liver cancer, laryngeal cancer, esophageal cancer, mammary tumors, childhood-null acute lymphoid leukemia (ALL), thymic ALL, B-cell ALL, acute myeloid leukemia, myelomonocytoid leukemia, acute megakaryocytoid leukemia, Burkitt's lymphoma, acute myeloid leukemia, chronic myeloid leukemia, and T cell leukemia, small and large non-small cell lung carcinoma, acute granulocytic leukemia, germ cell tumors, endometrial cancer, gastric cancer, cancer of the head and neck, chronic lymphoid leukemia, hairy cell leukemia and thyroid cancer. Each of these disorders is considered a single embodiment and may be made the subject of a claim specifically to such disease or disorder.

(21) In a still further aspect the present invention relates to a method for treatment of a disorder relating to the binding of a galectin-3 to a ligand in a mammal, such as a human, wherein a therapeutically effective amount of at least one compound of formula (1) of the present invention is administered to a mammal in need of said treatment. In an embodiment the disorder is selected from the group consisting of inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart; scarring; keloid formation; aberrant scar formation; surgical adhesions; septic shock; cancer, such as carcinomas, sarcomas, leukemias and lymphomas, such as T-cell lymphomas; metastasising cancers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; heart disease; heart failure; pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer; and eye diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases such as diabetes; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, mesothelioma; liver disorders, such as non-alcoholic steatohepatitis. Each of these disorders are considered a single embodiment and may be made the subject of a claim specifically to such disease or disorder.

(22) The skilled person will understand that it may be necessary to adjust or change the order of steps in the processes a1 to a12, and such change of order is encompassed by the aspects of the process as described above in the reaction schemes and accompanying description of the process steps.

(23) Furthermore, the skilled person will understand that the processes described above and hereinafter the functional groups of intermediate compounds may need to be protected by protecting groups.

(24) Functional groups that it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include optionally substituted and/or unsaturated alkyl groups (e.g. methyl, allyl, benzyl or tert-butyl), trialkyl silyl or diarylalkylsilyl groups (e.g. t-butyldimethylsilyl, t-butyldipheylsilyl or trimethylsilyl), AcO(acetoxy), TBS(t-butyldimethylsilyl), TMS(trimethylsilyl), PMB (p-methoxybensyl), and tetrahydropyranyl. Suitable protecting groups for carboxylic acid include (C.sub.1-6)-alkyl or benzyl esters. Suitable protecting groups for amino include t-butyloxycarbonyl, benzyloxycarbonyl, 2-(trimethylsilyl)-ethoxy-methyl or 2-trimethylsilylethoxycarbonyl (Teoc). Suitable protecting groups for S include SC(N)NH.sub.2, TIPS.

(25) The protection and deprotection of functional groups may take place before or after any reaction in the above mentioned processes.

(26) Furthermore the skilled person will appreciate, that, in order to obtain compounds of the invention in an alternative, and on some occasions more convenient manner, the individual process steps mentioned hereinbefore may be performed in different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This may negate, or render necessary, the need for protecting groups.

(27) In a still further embodiment the compound (1) is on free form. On free form as used herein means a compound of formula (1), either an acid form or base form, or as a neutral compound, depending on the substitutents. The free form does not have any acid salt or base salt in addition. In one embodiment the free form is an anhydrate. In another embodiment the free form is a solvate, such as a hydrate.

(28) In a further embodiment the compound (1) is a crystalline form. The skilled person may carry out tests in order to find polymorphs, and such polymorphs are intended to be encompassed by the term crystalline form as used herein.

(29) When the compounds and pharmaceutical compositions herein disclosed are used for the above treatment, a therapeutically effective amount of at least one compound is administered to a mammal in need of said treatment.

(30) The term C.sub.1-x alkyl as used herein means an alkyl group containing 1-x carbon atoms, e.g. C.sub.1-5 or C.sub.1-6, such as methyl, ethyl, propyl, butyl, pentyl or hexyl.

(31) The term branched C.sub.3-6 alkyl as used herein means a branched alkyl group containing 3-6 carbon atoms, such as isopropyl, isobutyl, tert-butyl, isopentyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl.

(32) The term C.sub.3-7 cycloalkyl as used herein means a cyclic alkyl group containing 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 1-methylcyclopropyl.

(33) The term C.sub.5-7 cycloalkyl as used herein means a cyclic alkyl group containing 5-7 carbon atoms, such as cyclopentyl, cyclohexyl, or cycloheptyl.

(34) The term Oxo as used herein means an oxygen atom with double bonds, also indicated as O.

(35) The term CN as used herein means a nitril.

(36) The term a five or six membered heteroaromatic ring as used herein means one five membered heteroaromatic ring or one six membered heteroaromatic ring. The five membered heteroaromatic ring contains 5 ring atoms of which one to four are heteroatoms selected from N, O, and S. The six membered heteroaromatic ring contains 6 ring atoms of which one to five are heteroatoms selected from N, O and S. Examples include thiophene, furan, pyran, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine and pyridazine. When such heteroaromatic rings are substituents they are termed thiophenyl, furanyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl. Also included are oxazoyl, thiazoyl, thiadiazoly, oxadiazoyl, and pyridonyl.

(37) The term a heterocycle, such as heteroaryl or heterocycloalkyl as used herein means a heterocycle consisting of one or more 3-7 membered ring systems containing one or more heteroatoms and wherein such ring systems may optionally be aromatic. The term a heteroaryl as used herein means a mono or bicyclic aromatic ringsystem containing one or more heteroatoms, such as 1-10, e.g. 1-6, selected from O, S, and N, including but not limited to oxazolyl, oxadiazolyl, thiophenyl, thiadiazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridonyl, pyrimidonyl, quinolinyl, azaquionolyl, isoquinolinyl, azaisoquinolyl, quinazolinyl, azaquinazolinyl, bensozazoyl, azabensoxazoyl, bensothiazoyl, or azabensothiazoyl. The term a heterocycloalkyl as used herein means a mono or bicyclic 3-7 membered alifatic heterocycle containing one or more heteroatoms, such as 1-7, e.g. 1-5, selected from O, S, and N, including but not limited to piperidinyl, tetrahydropyranyl, tetrahydrothipyranyl, or piperidonyl.

(38) The term treatment and treating as used herein means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. The treatment may either be performed in an acute or in a chronic way. The patient to be treated is preferably a mammal; in particular, a human being, but it may also include animals, such as dogs, cats, cows, sheep and pigs.

(39) The term a therapeutically effective amount of a compound of formula (1) of the present invention as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as therapeutically effective amount. Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary.

(40) In a still further aspect the present invention relates to a pharmaceutical composition comprising the compound of formula (1) and optionally a pharmaceutically acceptable additive, such as a carrier or an excipient.

(41) As used herein pharmaceutically acceptable additive is intended without limitation to include carriers, excipients, diluents, adjuvant, colorings, aroma, preservatives etc. that the skilled person would consider using when formulating a compound of the present invention in order to make a pharmaceutical composition.

(42) The adjuvants, diluents, excipients and/or carriers that may be used in the composition of the invention must be pharmaceutically acceptable in the sense of being compatible with the compound of formula (1) and the other ingredients of the pharmaceutical composition, and not deleterious to the recipient thereof. It is preferred that the compositions shall not contain any material that may cause an adverse reaction, such as an allergic reaction. The adjuvants, diluents, excipients and carriers that may be used in the pharmaceutical composition of the invention are well known to a person skilled within the art.

(43) As mentioned above, the compositions and particularly pharmaceutical compositions as herein disclosed may, in addition to the compounds herein disclosed, further comprise at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier. In some embodiments, the pharmaceutical compositions comprise from 1 to 99 weight % of said at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier and from 1 to 99 weight % of a compound as herein disclosed.

(44) The combined amount of the active ingredient and of the pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier may not constitute more than 100% by weight of the composition, particularly the pharmaceutical composition.

(45) In some embodiments, only one compound as herein disclosed is used for the purposes discussed above.

(46) In some embodiments, two or more of the compounds as herein disclosed are used in combination for the purposes discussed above.

(47) The composition, particularly pharmaceutical composition comprising a compound set forth herein may be adapted for oral, intravenous, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via the respiratory tract in the form of, for example, an aerosol or an air-suspended fine powder. Therefore, the pharmaceutical composition may be in the form of, for example, tablets, capsules, powders, nanoparticles, crystals, amorphous substances, solutions, transdermal patches or suppositories.

(48) Further embodiments of the process are described in the experimental section herein, and each individual process as well as each starting material constitutes embodiments that may form part of embodiments.

(49) The above embodiments should be seen as referring to any one of the aspects (such as method for treatment, pharmaceutical composition, compound for use as a medicament, or compound for use in a method) described herein as well as any one of the embodiments described herein unless it is specified that an embodiment relates to a certain aspect or aspects of the present invention.

(50) All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

(51) All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

(52) Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

(53) The terms a and an and the and similar referents as used in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

(54) Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless other-wise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Unless otherwise stated, all exact values provided herein are representative of corresponding approximate values (e.g., all exact exemplary values provided with respect to a particular factor or measurement can be considered to also pro-vide a corresponding approximate measurement, modified by about, where appropriate).

(55) All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

(56) The use of any and all examples, or exemplary language (e.g., such as) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise indicated. No language in the specification should be construed as indicating any element is essential to the practice of the invention unless as much is explicitly stated.

(57) The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability and/or enforceability of such patent documents.

(58) The description herein of any aspect or embodiment of the invention using terms such as comprising, having, including or containing with reference to an element or elements is intended to provide support for a similar aspect or embodiment of the invention that consists of, consists essentially of, or substantially comprises that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context). This invention includes all modifications and equivalents of the subject matter recited in the aspects or claims presented herein to the maximum extent permitted by applicable law.

(59) The present invention is further illustrated by the following examples that, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realizing the invention indiverse forms thereof.

EXPERIMENTAL PROCEDURES

(60) Evaluation of Kd Values

(61) The affinity of Example 1-22 for galectins were determined by a fluorescence anisotropy assay where the compound was used as an inhibitor of the interaction between galectin and a fluorescein tagged saccharide probe as described Srme, P., Kahl-Knutsson, B., Huflejt, M., Nilsson, U. J., and Leffler H. (2004) Fluorescence polarization as an analytical tool to evaluate galectin-ligand interactions. Anal. Biochem. 334: 36-47, (Srme et al., 2004) and Monovalent interactions of Galectin-1 By Salomonsson, Emma; Larumbe, Amaia; Tejler, Johan; Tullberg, Erik; Rydberg, Hanna; Sundin, Anders; Khabut, Areej; Frejd, Torbjorn; Lobsanov, Yuri D.; Rini, James M.; et al, From Biochemistry (2010), 49(44), 9518-9532, (Salomonsson et al., 2010). The assay was also adapted to be able to measure the high affinity of compounds for galectin-3 by using the below probe constructed to have high affinity for galectin-3 which made it possible to use a low concentration of galectin-3 (50 nM). 100 nM albumin was included as a carrier to prevent protein loss at such low concentration of galectin.

(62) ##STR00017##

(63) TABLE-US-00001 Galectin- 3 (Kd Example IUPAC name Structure (M) 1 4-Bromo-5-cyano- 2-pyridyl 3-deoxy- 3-[4-(3,4,5- trifluorophenyl)- 1H-1,2,3-triazol-1- yl]-1-thio--D- galactopyranoside 0.027 2 4-Chloro-5-cyano- 2-pyridyl 3-deoxy- 3-[4-(3,4,5- trifluorophenyl)- 1H-1,2,3-triazol-1- yl]-1-thio--D- galactopyranoside 0.057 3 2-Chloro-4-pyridyl 3-deoxy-3-[4- (3,4,5- trifluorophenyl)- 1H-1,2,3-triazol-1- yl]-1-thio--D- galactopyranoside 0 0.086 4 5-Chloro-2-cyano- 3-pyridyl 3-deoxy- 3-[4-(3,4,5- trifluorophenyl)- 1H-1,2,3-triazol-1- yl]-1-thio--D- galactopyranoside 0.029 5 5-Bromo-6-cyano- 3-pyridyl 3-deoxy- 3-[4-(3,4,5- trifluorophenyl)- 1H-1,2,3-triazol-1- yl]-1-thio--D- galactopyranoside 0.022 6 5-Bromo-2-cyano- - 3-pyridyl 3-deoxy- 3-[4-(3,4,5- trifluorophenyl)- 1H-1,2,3-triazol-1- yl]-1-thio--D- galactopyranoside 0.022 7 4-Chloro-2-pyridyl 3-deoxy-3-[4- (3,4,5- trifluorophenyl)- 1H-1,2,3-triazol-1- yl]-1-thio--D- galactopyranoside 0.120 8 5-Bromo-3-pyrdyl 3-deoxy-3-[4-(4- chloro-3,5- difluorophenyl)-1H- 1,2,3-triazol-1-yl]- 1-thio--D- galactopyranoside 0.015 9 5-Chloro-3-pydyl 3-deoxy-3-[4-(4- chloro-3,5- difluorophenyl)-1H- 1,2,3-triazol-1-yl]- 1-thio--D- galactopyranoside 0.022 10 5-Chloro-6-cyano- 3-pyridyl 3-deoxy- 3-[4-(4-chloro-3,5- difluorophenyl)-1H- 1,2,3-triazol-1-yl]- 1-thio--D- galactopyranoside 0.018 11 5-Bromo-2-cyano- 3-pyridyl 3-deoxy- 3-[4-(4-chloro-3,5- difluorophenyl)-1H- 1,2,3-triazol-1-yl]- 1-thio--D- galactopyranoside 0.011 12 5-Bromo-6-cyano- 3-pyridyl 3-deoxy- 3-[4-(4-chloro-3,5- difluorophenyl)-1H- 1,2,3-triazol-1-yl]- 1-thio--D- galactopyranoside 0.016 13 5-Chloro-2-cyano- 3-pyridyl 3-deoxy- 3-[4-(4-chloro-3,5- difluorophenyl)-1H- 1,2,3-triazol-1-yl]- 1-thio--D- galactopyranoside 0 0.011 14 5-Chloro-3-pyridyl 3-deoxy-3-[4-(4- cyano-3,5- difluorophenyl)-1H- 1,2,3-triazol-1-yl]- 1-thio--D- galactopyranoside 0.18 15 5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,5- difluoro-4- trifluoromethyl- phenyl)-1H-1,2,3- triazol-1-yl]-1-thio- -D- galactopyranoside 0.097 16 5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,5- difluoro-4- methylphenyl)-1H- 1,2,3-triazol-1-yl]- 1-thio--D- galactopyranoside 0.018 17 5-Chloro-3-pyridyl 3-deoxy-3-[4-(4- bromo-3,5- difluorophenyl)-1H- 1,2,3-triazol-1-yl]- 1-thio--D- galactopyranoside 0.028 18 5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,4- dichloro-5- fluorophenyl)-1H- 1,2,3-triazol-1-yl]- 1-thio--D- galactopyranoside 0.027 19 5-Chloro-3-pyridyl 3-deoxy-3-[4-(4- chloro-3- fluorophenyl)-1H- 1,2,3-triazol-1-yl]- 1-thio--D- galactopyranoside 0.034 20 3,4-Dichlorophenyl 3-deoxy-3-[4-(5- fluoro-3-pyridyl)- 1H-1,2,3-triazol-1- yl]-1-thio--D- galactopyranoside 0.75 21 5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,4- dichlorophenyl)- 1H-1,2,3-triazol-1- yl]-1-thio--D- galactopyranoside 0.031 22 3,4-Dichlorophenyl 3-deoxy-3-[4-(5- chloro-3-pyridyl)- 1H-1,2,3-triazol-1- yl]-1-thio--D- galactopyranoside 0.694

(64) TABLE-US-00002 Example Galectin-1 (Kd (M) 1 2.6 7 6.9 12 7.0

Synthesis of Examples and Intermediates

(65) General Procedures:

(66) Nuclear Magnetic Resonance (NMR) spectra were recorded on a 400 MHz Bruker AVANCE III 500 instrument at 25 C. Chemical shifts are reported in ppm using the residual solvent as internal standard. Peak multiplicities are expressed as follow: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplet; q, quartet; m, multiplet; br s, broad singlet.

(67) LC-MS spectra were acquired on an Agilent 1200 HPLC coupled with an Agilent MSD mass spectrometer operating in ES (+) ionization mode. Column: XBridge C18 (4.650 mm, 3.5 m) or SunFire C18 (4.650 mm, 3.5 m). Solvent A (0.1% TFA in water) and solvent B (Acetonitrile+0.1% TFA) or solvent A (10 mM Ammonium hydrogen carbonate in water) and solvent B (Acetonitrile). Wavelength: 254 nM. Preparative HPLC was performed on a Gilson 215. Flow: 25 mL/min Column: XBridge prep C18 10 m OBD (19250 mm) column. Wavelength: 254 nM. Solvent A (10 mM Ammonium hydrogen carbonate in water) and solvent B (Acetonitrile).

(68) The following abbreviations are used:

(69) Calcd: Calculated

(70) CH.sub.3CN: Acetonitrile

(71) DCM: Dichloromethane

(72) DIPEA: N,N-Diisopropylethylamine

(73) DMF: N,N-dimethylformamide

(74) ESI-MS: Electrospray ionization mass spectrometry

(75) EtOAc or EA: Ethylacetate

(76) HPLC: High performance liquid chromatography

(77) MeOH: Methanol

(78) MeOD-d4: Deuterated methanol

(79) MS: Mass spectroscopy

(80) MTBE: tert-butyl methyl ether

(81) NaOMe: Sodium methoxide

(82) NMR: Nuclear magnetic resonance

(83) PE: petroleum ether

(84) Prep: Preparative

(85) rt: Room temperature

(86) TBSOTf: tert-Butyldimethylsilyl trifluoromethanesulfonate

(87) TBME: tert-Butyl methyl ether

(88) TEA: Triethylamine

(89) TFA: trifluoroacetic acid

(90) TMS: Trimethyl silyl

(91) UV: Ultraviolet

Example 1-22 were Made from their Corresponding Intermediates i1-i22

Example 1

4-Bromo-5-cyano-2-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(92) ##STR00040##

(93) A solution of 4-Bromo-5-cyano-2-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (40 mg, 0.06 mmol) in MeOH/Et.sub.3N/H.sub.2O (5/3/1) (2 mL) was stirred at room temperature for 20 h.

(94) The reaction mixture was evaporated to dryness and the residue was purified by HPLC (on C-18 column using a gradient of CH.sub.3CN/10 mM NH.sub.4HCO.sub.3 from 0-42%) to afford the title compound as a white solid (5 mg).

(95) m/z calcd for [C.sub.20H.sub.15BrF.sub.3N.sub.5O.sub.4S].sup. [M+H].sup.+: 558.0; found: 558.0.

(96) .sup.1H NMR (400 MHz, MeOD) 8.58 (d, J=5.8 Hz, 2H), 8.14 (s, 1H), 7.68 (dd, J=8.7, 6.7 Hz, 2H), 6.46 (d, J=3.6 Hz, 1H), 5.08 (d, J=3.2 Hz, 2H), 4.27 (t, J=6.1 Hz, 1H), 4.23 (s, 1H), 3.72 (dd, J=6.0, 2.3 Hz, 2H).

Example 2

4-Chloro-5-cyano-2-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(97) ##STR00041##

(98) 4-Chloro-5-cyano-2-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (45 mg, 0.07 mmol) was dissolved in MeOH (4 mL). TEA (0.5 ml) and H.sub.2O (1 mL) was added. The mixture was stirred at rt for 2 hours. The mixture was concentrated in vacuum and the residue was purified on C-18 column using a gradient of CH.sub.3CN/10 mM NH.sub.4HCO.sub.3 from 0-42% to give the title compound 13 mg (36%).

(99) .sup.1H NMR (400 MHz, DMSO) 8.85 (s, 1H), 8.79 (s, 1H), 7.99 (s, 1H), 7.85 (dd, J=9.0, 6.7 Hz, 2H), 6.58 (d, J=5.2 Hz, 1H), 6.24 (d, J=5.0 Hz, 1H), 5.62 (d, J=6.3 Hz, 1H), 4.98-4.90 (m, 1H), 4.90-4.78 (m, 1H), 4.65 (t, J=5.5 Hz, 1H), 4.15-3.96 (m, 2H), 3.58-3.39 (m, 2H).

(100) ESI-MS m/z calcd for [C.sub.20H.sub.16ClF.sub.3N.sub.5O.sub.4S].sup.+ (M+H).sup.+: 514.1; found: 514.2.

Example 3

2-Chloro-4-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(101) ##STR00042##

(102) A solution of 2-Chloro-4-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (45 mg, 0.07 mmol) in MeOH/Et.sub.3N/H.sub.2O (2.5/1.5/0.5)(2 mL) was stirred at room temperature for 4 h. The mixture was evaporated to dryness. The crude product was purified by HPLC to afford product as a white solid 20 mg.

(103) m/z calcd for [C.sub.19H.sub.16ClF.sub.3N.sub.4O.sub.4S].sup.+[M+H].sup.+: 489.0; found: 489.0.

(104) .sup.1H NMR (400 MHz, MeOD) 8.59 (s, 1H), 8.20 (d, J=5.4 Hz, 1H), 7.75-7.61 (m, 3H), 7.54 (dd, J=5.4, 1.6 Hz, 1H), 6.26 (d, J=4.3 Hz, 1H), 5.04 (dd, J=11.3, 2.1 Hz, 1H), 5.00 (dd, J=11.4, 4.4 Hz, 1H), 4.35 (t, J=6.1 Hz, 1H), 4.20 (s, 1H), 3.81-3.64 (m, 2H).

Example 4

5-Chloro-2-cyano-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(105) ##STR00043##

(106) A solution of 5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1l-yl]-1-thio--D-galactopyranoside (10 mg, 0.015 mmol) in MeOH/Et.sub.3N/H.sub.2O (2.5/1.5/0.5) (1 mL) was stirred at room temperature with for 4 h. The mixture was evaporated to dryness. The crude product was purified by HPLC to afford the title compound as a white solid (6 mg, 75%).

(107) m/z calcd for [C.sub.20H.sub.15ClF.sub.3N.sub.5O.sub.4S].sup.+ [M+H].sup.+: 514.0; found: 514.0

(108) .sup.1H NMR (400 MHz, MeOD) 8.47 (d, J=1.8 Hz, 2H), 8.35 (d, J=2.1 Hz, 1H), 7.56 (dd, J=8.8, 6.6 Hz, 2H), 6.13 (d, J=5.1 Hz, 1H), 4.98 (dd, J=11.3, 2.7 Hz, 1H), 4.91 (dd, J=11.3, 5.2 Hz, 1H), 4.27 (dd, J=7.7, 4.3 Hz, 1H), 4.11 (d, J=1.9 Hz, 1H), 3.57 (d, J=6.0 Hz, 2H).

Example 5

5-Bromo-6-cyano-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(109) ##STR00044##

(110) A solution of 5-bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (20 mg, 0.03 mmol) in MeOH/Et.sub.3N/H.sub.2O (2.5/1.5/0.5) (2 mL) was stirred at room temperature for 4 h. The mixture was evaporated to dryness. The crude product was purified by HPLC to afford the product as a white solid. (10 mg, 60%)

(111) m/z calcd for [C.sub.20H.sub.15BrF.sub.3N.sub.5O.sub.4S].sup. [M+H].sup.+: 558.0; found: 558.0.

(112) .sup.1H NMR (400 MHz, MeOD) 8.66 (d, J=1.8 Hz, 1H), 8.46 (s, 1H), 8.37 (d, J=1.9 Hz, 1H), 7.55 (dd, J=8.7, 6.7 Hz, 2H), 6.09 (d, J=5.1 Hz, 1H), 4.95 (dd, J=11.4, 2.6 Hz, 1H), 4.88 (dd, J=11.4, 5.1 Hz, 1H), 4.25 (t, J=6.0 Hz, 1H), 4.09 (d, J=2.0 Hz, 1H), 3.60 (d, J=6.0 Hz, 2H).

Example 6

5-Bromo-2-cyano-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(113) ##STR00045##

(114) A solution of 5-Bromo-2-Cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (10 mg, 0.015 mmol) in MeOH/Et.sub.3N/H.sub.2O (2.5/1.5/0.5) (1 mL) was stirred at room temperature for 4 h. The mixture was evaporated to dryness. The crude product was purified by HPLC to afford the title compound as a white solid. (8.2 mg, 37%) m/z calcd for [C.sub.20H15BrF.sub.3N.sub.5O.sub.4S].sup. [M+H].sup.+: 558.0; found: 558.0.

(115) .sup.1H NMR (400 MHz, MeOD) 8.57 (d, J=2.0 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.47 (s, 1H), 7.56 (dd, J=8.8, 6.6 Hz, 2H), 6.12 (d, J=5.2 Hz, 1H), 4.98 (dd, J=11.3, 2.7 Hz, 1H), 4.91 (dd, J=11.3, 5.2 Hz, 1H), 4.27 (t, J=6.0 Hz, 1H), 4.11 (d, J=2.1 Hz, 1H), 3.59-3.54 (m, 2H).

Example 7

4-Chloro-2-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(116) ##STR00046##

(117) 4-Chloro-2-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (25 mg, 0.04 mmol) was dissolved in NaOCH.sub.3/methanol (0.05 M, 2 mL). Then the mixture was stirred at room temperature for 2 h. After completion, DOWEX 50wx8-200 Ion exchange resin was added (PH=7) and reaction mixture was filtered. The effluent was concentrated and the residue was purified by preparative HPLC to give the title compound (8 mg, 31%) as a white solid.

(118) .sup.1H NMR (400 MHz, MeOD) 8.57 (s, 1H), 8.38 (d, J=5.2 Hz, 1H), 7.70-7.65 (m, 3H), 7.28 (dd, J=5.6, 2.0 Hz, 2H), 6.56 (d, J=4.4 Hz, 1H), Hz, 2H), 4.90-5.02 (m, 2H), 4.35 (t, J=6.0 Hz, 1H), 4.21 (d, J=0.8 Hz, 1H), 3.90 (s, 1H), 3.73-3.67 (m, 2H).

(119) m/z calcd for [C.sub.19H.sub.16ClF.sub.3N.sub.4O.sub.4S].sup.+[M+H].sup.+: 489.0; found: 489.0.

Example 8

5-Bromo-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(120) ##STR00047##

(121) To a solution of 5-Bromo-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (40 mg, 0.06 mmol) in MeOH/Et.sub.3N/H.sub.2O (10/3/1) (2 mL) was stirred at room temperature for 20 h. The mixture was evaporated to dryness and the residue was purified by preparative HPLC to afford the title compound as a white solid. (20 mg, 61%).

(122) ESI-MS m/z calcd for [C.sub.19H.sub.16BrClF.sub.2N.sub.4O.sub.4S].sup.+[M+H].sup.+: 549.0; found: 549.0

(123) .sup.1H NMR (400 MHz, MeOD) 8.69 (d, J=1.8 Hz, 1H), 8.62 (s, 1H), 8.58 (d, J==2.1 Hz, 1H), 8.34 (t, J=2.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 2H), 5.93 (d, J=5.2 Hz, 1H), 5.05 (dd, J=11.4, 2.8 Hz, 1H), 4.96 (dd, J=11.4, 5.3 Hz, 1H), 4.51 (t, J=6.0 Hz, 1H), 4.22 (d, J=1.9 Hz, 1H), 3.80-3.64 (m, 2H).

Example 9

5-Chloro-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(124) ##STR00048##

(125) 5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (45 mg, 0.07 mmol) was dissolved in NaOCH.sub.3/methanol (0.05 M, 2 mL). The reaction mixture was stirred at room temperature with for 2 h. After completion, DOWEX 50wx8-200 Ion exchange resin was added (pH=7) and the mixture was filtered. The filtrate was concentrated to give a residue which was purified by preparative HPLC to give the title compound (22 mg, 62%) as a white solid.

(126) m/z calcd for [C.sub.19H.sub.16Cl.sub.2F.sub.2N.sub.4O.sub.4S].sup.+[M+H].sup.+: 505.0; found: 505.0.

(127) .sup.1H NMR (400 MHz, MeOD) 8.66 (d, J=1.9 Hz, 1H), 8.63 (s, 1H), 8.49 (d, J=2.2 Hz, 1H), 8.21 (t, J=2.1 Hz, 1H), 7.69 (d, J=8.0 Hz, 2H), 5.94 (d, J=5.2 Hz, 1H), 5.05 (dd, J=11.4, 2.7 Hz, 1H), 4.96 (dd, J=11.4, 5.2 Hz, 1H), 4.51 (t, J=6.2 Hz, 1H), 4.22 (d, J=1.8 Hz, 1H), 3.77-3.66 (m, 2H).

Example 10

5-Chloro-6-cyano-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(128) ##STR00049##

(129) A solution of 5-Chloro-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (80 mg, 0.12 mmol) in MeOH/Et.sub.3N/H.sub.2O (0.5/0.3/0.1) (0.9 mL) was stirred at room temperature for 4 h. The mixture was evaporated to dryness. The crude product was purified by preparative HPLC to afford product as a white solid. (17 mg, 26%).

(130) m/z calcd for [C.sub.20H.sub.15Cl.sub.2F.sub.2N.sub.5O.sub.4S].sup.+[M+H].sup.+: 530.0; found: 530.0.

(131) .sup.1H NMR (400 MHz, MeOD) 8.74 (d, J=1.9 Hz, 1H), 8.64 (s, 1H), 8.36 (d, J=1.9 Hz, 1H), 7.72-7.62 (m, 2H), 6.23 (d, J=5.2 Hz, 1H), 5.08 (dd, J=11.4, 2.7 Hz, 1H), 5.00 (dd, J=11.4, 5.2 Hz, 1H), 4.37 (t, J=6.0 Hz, 1H), 4.20 (d, J=1.8 Hz, 1H), 3.71 (d, J=6.0 Hz, 2H).

Example 11

5-Bromo-2-cyano-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(132) ##STR00050##

(133) A solution of 5-Bromo-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (20 mg, 0.015 mmol) in MeOH/Et.sub.3N/H.sub.2O (0.5/0.3/0.1) (0.9 mL) was stirred at room temperature with for 4 h. The mixture was evaporated to dryness. The crude product was purified by preparative HPLC to afford product as a white solid (7 mg, 43%).

(134) m/z calcd for [C.sub.20H.sub.15BrClF.sub.2N.sub.5O.sub.4S].sup.+[M+H]f: 574.0; found: 574.0.

(135) .sup.1H NMR (400 MHz, MeOD) 8.52 (d, J=2.0 Hz, 1H), 8.46 (s, 1H), 8.44 (d, J=2.0 Hz, 1H), 7.51 (d, J=7.9 Hz, 2H), 6.06 (d, J=5.2 Hz, 1H), 4.93 (dd, J=11.3, 2.8 Hz, 1H), 4.85 (dd, J=11.3, 5.2 Hz, 1H), 4.21 (t, J=6.0 Hz, 1H), 4.05 (d, J=2.0 Hz, 1H), 3.55-3.48 (m, 2H).

Example 12

5-Bromo-6-cyano-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(136) ##STR00051##

(137) A solution of 5-bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (80 mg, 0.11 mmol) in MeOH/Et.sub.3N/H.sub.2O (0.5/0.3/0.1) (0.9 mL) was stirred at room temperature for 4 h. The mixture was evaporated to dryness. The crude product was purified by preparative HPLC to afford the title compound as a white solid (15 mg, 22.9%).

(138) m/z calcd for [C.sub.20H.sub.15BrClF.sub.2N.sub.5O.sub.4S].sup.+[M+H].sup.+: 574.0; found: 574.0.

(139) .sup.1H NMR (400 MHz, MeOD) 8.78 (d, J=1.9 Hz, 1H), 8.63 (s, 1H), 8.50 (d, J=1.9 Hz, 1H), 7.69 (d, J=7.9 Hz, 2H), 6.21 (d, J=5.2 Hz, 1H), 5.07 (dd, J=11.4, 2.7 Hz, 1H), 5.00 (dd, J=11.4, 5.2 Hz, 1H), 4.37 (t, J=6.2 Hz, 1H), 4.20 (d, J=1.8 Hz, 1H), 3.71 (d, J=6.0 Hz, 2H).

Example 13

5-Chloro-2-cyano-3-pyridyl 3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(140) ##STR00052##

(141) To a solution of 5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (30 mg, 0.04 mmol) in MeOH/Et.sub.3N/H.sub.2O (0.5/0.3/0.1) (0.9 mL) was stirred at room temperature for 4 h. The mixture was evaporated to dryness.

(142) The crude product was purified by preparative HPLC to afford the title compound as a white solid (10 mg, 41%).

(143) m/z calcd for [C.sub.20H.sub.15Cl.sub.2F.sub.2N.sub.5O.sub.4S].sup.|[M+H].sup.|: 530.0; found: 530.0.

(144) .sup.1H NMR (400 MHz, MeOD) 8.46 (s, 1H), 8.41 (d, J=2.1 Hz, 1H), 8.29 (d, J=2.1 Hz, 1H), 7.51 (d, J=8.0 Hz, 2H), 6.08 (d, J=5.2 Hz, 1H), 4.93 (dd, J=11.3, 2.7 Hz, 1H), 4.86 (dd, J=11.3, 5.2 Hz, 1H), 4.21 (t, J=6.1 Hz, 1H), 4.05 (d, J=1.8 Hz, 1H), 3.51 (d, J=6.1 Hz, 2H).

Example 14

5-Chloro-3-pyridyl 3-deoxy-3-[4-(4-cyano-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(145) ##STR00053##

(146) A solution of 5-chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-cyano-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (42 mg, 0.07 mmol) in MeOH/Et.sub.3N/H.sub.2O (5/3/1) (1.8 mL) was stirred at room temperature for 20 h.

(147) The mixture was evaporated to dryness and the residue was purified by preparative HPLC to afford the title compound as a white solid (25 mg, 75%).

(148) m/z calcd for [C.sub.20H.sub.16ClF.sub.2N.sub.5O.sub.4S].sup. [M+H].sup.+: 497.0; found: 497.0.

(149) .sup.1H NMR (400 MHz, MeOD) 8.78 (s, 1H), 8.66 (d, J=1.9 Hz, 1H), 8.49 (d, J=2.2 Hz, 1H), 8.21 (t, J=2.1 Hz, 1H), 7.81 (d, J=8.9 Hz, 2H), 5.95 (d, J=5.3 Hz, 1H), 5.07 (dd, J=11.4, 2.8 Hz, 1H), 4.96 (dd, J=11.4, 5.3 Hz, 1H), 4.51 (t, J=6.1 Hz, 1H), 4.22 (d, J=1.9 Hz, 1H), 3.80-3.66 (m, 2H).

Example 15

5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,5-difluoro-4-trifluoromethyl-phenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(150) ##STR00054##

(151) A solution of 5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,5-difluoro-4-trifluoromethyl-phenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (33 mg, 0.05 mmol) in MeOH/Et.sub.3N/H.sub.2O (5/3/1) (1.8 mL) was stirred at room temperature for 20 h. The mixture was evaporated to dryness and the residue was purified by preparative HPLC to afford the title compound as a white solid (23 mg, 86%).

(152) m/z calcd for [C.sub.20H.sub.16ClF.sub.5N.sub.4O.sub.4S].sup. [M+H].sup.+: 539.0; found: 539.0.

(153) .sup.1H NMR (400 MHz, MeOD) 8.74 (s, 1H), 8.66 (d, J=1.8 Hz, 1H), 8.49 (d, J=2.2 Hz, 1H), 8.21 (t, J=2.1 Hz, 1H), 7.74 (d, J=10.9 Hz, 2H), 5.95 (d, J=5.3 Hz, 1H), 5.07 (dd, J=11.4, 2.8 Hz, 1H), 4.97 (dd, J=11.4, 5.3 Hz, 1H), 4.51 (t, J=6.0 Hz, 1H), 4.22 (d, J=1.9 Hz, 1H), 3.77-3.68 (m, 2H).

Example 16

5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(154) ##STR00055##

(155) A solution of 5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (50 mg, 0.10 mmol) in MeOH/Et.sub.3N/H.sub.2O (5/3/1) (1.8 mL) was stirred at room temperature for 20 h. The mixture was evaporated to dryness and the residue was purified by preparative HPLC to afford the title compound as a white solid (35 mg, 88.2%).

(156) m/z calcd for [C.sub.20H.sub.19ClF.sub.2N.sub.4O.sub.4S].sup. [M+H].sup.+: 485.0; found: 485.0.

(157) 1H NMR (400 MHz, MeOD) 8.48 (d, J=1.8 Hz, 1H), 8.36 (s, 1H), 8.31 (d, J=2.2 Hz, 1H), 8.03 (t, J=2.1 Hz, 1H), 7.33-7.22 (m, 2H), 5.77 (d, J=5.2 Hz, 1H), 4.86 (dd, J=11.4, 2.8 Hz, 1H), 4.79 (dd, J=11.4, 5.2 Hz, 1H), 4.33 (t, J=6.2 Hz, 1H), 4.04 (d, J=1.7 Hz, 1H), 3.61-3.48 (m, 2H).

Example 17

5-Chloro-3-pyridyl 3-deoxy-3-[4-(4-bromo-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(158) ##STR00056##

(159) A solution of 5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-bromo-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (65 mg, 0.10 mmol) in MeOH/Et.sub.3N/H.sub.2O (5/3/1) (1.8 mL) was stirred at room temperature for 20 h. The mixture was evaporated to dryness and the residue was purified by preparative HPLC to afford the title compound as a white solid (38 mg, 71.9%).

(160) m/z calcd for [C.sub.19H.sub.16BrClF.sub.2N.sub.4O.sub.4S].sup. [M+H].sup.+: 549.0; found: 549.0.

(161) .sup.1H NMR (400 MHz, MeOD) 8.66 (d, J=1.8 Hz, 1H), 8.64 (s, 1H), 8.49 (d, J=2.2 Hz, 1H), 8.21 (t, J=2.1 Hz, 1H), 7.65 (d, J=7.6 Hz, 2H), 5.95 (d, J=5.2 Hz, 1H), 5.05 (dd, J=11.4, 2.7 Hz, 1H), 4.96 (dd, J=11.4, 5.3 Hz, 1H), 4.51 (t, J=5.8 Hz, 1H), 4.22 (d, J=1.9 Hz, 1H), 3.78-3.66 (m, 2H).

Example 18

5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,4-dichloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(162) ##STR00057##

(163) 5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4-dichloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (30.0 mg, 0.046 mmol) was dissolved in water (1 ml), methanol (2 ml), TEA (0.5 ml). The mixture was stirred at rt for 5 h.

(164) Then the mixture was concentrated and purified by Prep-TLC eluted with DCM/MeOH (15/1) to give the title compound 15 mg (62.1%).

(165) 1H NMR (400 MHz, MeOD) 8.48 (d, J=1.8 Hz, 1H), 8.46 (s, 1H), 8.31 (d, J=2.2 Hz, 1H), 8.03 (t, J=2.0 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.61 (dd, J=9.7, 1.8 Hz, 1H), 5.77 (d, J=5.2 Hz, 1H), 4.87 (dd, J=11.4, 2.7 Hz, 1H), 4.79 (dd, J=11.4, 5.2 Hz, 1H), 4.33 (t, J=5.9 Hz, 1H), 4.04 (d, J=1.8 Hz, 1H), 3.59-3.48 (m, 2H).

(166) m/z calcd for [C19H16Cl3FN4O4S].sup. [M+H].sup.+: 521; found: 521.

Example 19

5-Chloro-3-pyridyl 3-deoxy-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(167) ##STR00058##

(168) A solution of 5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (60 mg, 0.10 mmol) in MeOH/Et.sub.3N/H.sub.2O (5/3/1) (1.8 mL) was stirred at room temperature for 20 h. The mixture was evaporated to dryness and the residue was purified by preparative HPLC to afford the title compound as a white solid. (18 mg, 37.8%).

(169) m/z calcd for [C.sub.19H.sub.17Cl.sub.2FN.sub.4O.sub.4S].sup. [M+H].sup.+: 487.0; found: 487.0.

(170) .sup.1H NMR (400 MHz, MeOD) 8.66 (d, J=1.9 Hz, 1H), 8.56 (s, 1H), 8.49 (d, J=2.2 Hz, 1H), 8.21 (t, J=2.1 Hz, 1H), 7.79 (dd, J=10.4, 1.9 Hz, 1H), 7.70 (dd, J=8.3, 1.3 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 5.95 (d, J=5.2 Hz, 1H), 5.05 (dd, J=11.4, 2.8 Hz, 1H), 4.97 (dd, J=11.4, 5.2 Hz, 2H), 4.51 (t, J=6.2 Hz, 1H), 4.22 (d, J=1.9 Hz, 1H), 3.78-3.68 (m, 2H).

Example 20

3,4-Dichlorophenyl 3-deoxy-3-[4-(5-fluoro-3-pyridyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(171) ##STR00059##

(172) 5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (45.0 mg, 0.073 mmol) was dissolved in water (1 ml), methanol (2 ml), TEA (0.5 ml). The mixture was stirred at rt for 5 h.

(173) Then the mixture was concentrated and purified by preparative-TLC eluted with DCM/MeOH (15/1) to give the title compound. 5 mg (14.0%). 1H NMR (400 MHz, MeOD) 8.95 (s, 1H), 8.70 (s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.18-8.10 (m, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.56 (dd, J=8.4, 2.0 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 5.88 (d, J=5.3 Hz, 1H), 5.04 (dd, J=11.4, 2.7 Hz, 1H), 4.96 (dd, J=11.5, 5.2 Hz, 1H), 4.52 (t, J=6.1 Hz, 1H), 4.23 (d, J=1.8 Hz, 1H), 3.81-3.68 (m, 2H).

(174) m/z calcd for [C19H17Cl2FN4O4S].sup.+[M+H].sup.+: 487, 489; found: 487, 489.

Example 21

5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(175) ##STR00060##

(176) A solution of 5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (50 mg, 0.08 mmol) in MeOH/Et.sub.3N/H.sub.2O (5/3/1) (1.8 mL) was stirred at room temperature for 20 h. The mixture was evaporated to dryness and the residue was purified by preparative HPLC to afford the title compound as a white solid (33 mg, 82.5%).

(177) m/z calcd for [C.sub.25H.sub.23Cl.sub.3N.sub.4O.sub.7S].sup. [M+H].sup.+: 503.0; found: 503.0.

(178) .sup.1H NMR (400 MHz, DMSO) 8.83 (s, 1H), 8.64 (d, J=1.8 Hz, 1H), 8.54 (d, J=2.2 Hz, 1H), 8.19 (t, J=2.1 Hz, 1H), 8.16 (d, J=1.9 Hz, 1H), 7.91 (dd, J=8.4, 2.0 Hz, 1H), 7.73 (d, 0.1=8.4 Hz, 1H), 6.00 (d, J=4.9 Hz, 1H), 5.95 (br, 1H), 5.56 (br, 1H), 4.85 (dd, J=11.3, 2.4 Hz, 1H), 4.79 (dd, J=11.3, 5.0 Hz, 1H), 4.77 (br, 1H), 4.26 (t, J=6.1 Hz, 1H), 4.03 (s, 1H), 3.47 (ddd, J=17.8, 10.9, 6.2 Hz, 2H).

Example 22

3,4-Dichlorophenyl 3-deoxy-3-[4-(5-chloro-3-pyridyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(179) ##STR00061##

(180) A solution of 3,4-Dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(5-chloro-3-pyridyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (50.0 mg, 0.08 mmol) was dissolved in water (1 mL), methanol (2 mL), TEA (0.5 mL). The mixture was stirred at rt for 5 h. Then the mixture was concentrated and purified by preparative TLC eluted with DCM/MeOH (15/1) to give the title compound. 25.0 mg (62.5%). 1H NMR (400 MHz, MeOD) 9.01 (d, J=1.8 Hz, 1H), 8.70 (s, 1H), 8.55 (d, J=2.3 Hz, 1H), 8.38 (t, J=2.1 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.56 (dd, J=8.4, 2.1 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 5.88 (d, J=5.2 Hz, 1H), 5.04 (dd, J=11.4, 2.8 Hz, 1H), 4.96 (dd, J=11.4, 5.2 Hz, 1H), 4.52 (t, J=6.2 Hz, 1H), 4.23 (d, J=1.8 Hz, 1H), 3.74 (qd, J=11.4, 6.1 Hz, 2H).

(181) m/z calcd for [C19H16Cl3FN4O4S].sup.+ [M+H].sup.+: 503, 505; found: 503, 505.

Intermediates i1-i20

i1) 4-Bromo-5-cyano-2-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

2,4,6-tri-O-acetyl-3-azido-1-chloro-3-deoxy--D-galactopyranoside

(182) ##STR00062##

(183) To a stirred suspension of 1,2,4,6-tetra-O-acetyl-3-azido-3-deoxy--D-galactopyranoside (5.0 g, 13.39 mmol), Phosphorus pentachloride (3.07 g, 14.7 mmol) in dry methylene chloride (50 mL), boron trifluoride dimethyl etherate (76.3 mg, 0.67 mmol) was added. After stirring for 30 min, the reaction mixture was diluted with DCM (120 mL2) and then washed with ice-cold water (60 mL3), saturated ice-cold NaHCO.sub.3 solution (250 mL), and again icecold water (30 mL2), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure. The residue was co-evaporated with toluene to give the title compound 4.510 g (96%) as a white solid.

(184) .sup.1H NMR (500 MHz, CDCl.sub.3) 5.48 (d, J=2.5 Hz, 1H), 5.38-5.28 (m, 1H), 5.24 (d, J=8.7 Hz, 1H), 4.18 (dd, J=11.6, 6.0 Hz, 1H), 4.10 (dd, J=11.6, 6.8 Hz, 1H), 4.02-3.94 (m, 1H), 3.61 (dd, J=10.3, 3.3 Hz, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 2.08 (s, 3H).

Acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(185) ##STR00063##

(186) To a solution of 2,4,6-tri-O-acetyl-3-azido-1-chloro-3-deoxy--D-galactopyranoside (1.6 g, 4.58 mmol) in DMF (20 mL) was added CH.sub.3COSK (1.05 g, 9.16 mmol) at room temperature for 20 h. Water (50 mL) and DCM (50 mL) were added. The aqueous phase was extracted with DCM (50 mL2), the combined organic phase was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=3/1) to obtain the desired product (900 mg, 50%).

(187) m/z calcd for [C.sub.14H.sub.19N.sub.3O.sub.8S].sup. [M+H].sup.+: 390.0; found: 390.0.

4-Bromo-5-cyano-2-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(188) ##STR00064##

(189) To a solution of acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (97 mg, 0.25 mmol) in DCM (5 mL) were added 4,6-dibromonicotinonitrile (130 mg, 0.5 mmol), Diethylamine (0.5 mL). The reaction was stirred at room temperature for 20 h. Water (50 mL) and DCM (50 mL) were added. The aqueous phase was extracted with DCM (50 mL2), the combined organic phases were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=3/1) to obtain the desired product. (45 mg, 34%)

(190) m/z calcd for [C.sub.18H.sub.18BrN.sub.5O.sub.7S].sup. [M+H].sup.+: 528.0; found: 528.0.

(191) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.50 (s, 1H), 7.78 (s, 1H), 6.35 (d, J=5.5 Hz, 1H), 5.50 (d, J=2.8 Hz, 1H), 5.36 (dd, J=11.0, 5.5 Hz, 1H), 4.44 (dd, J=7.6, 4.8 Hz, 1H), 4.18-4.09 (m, 2H), 4.01 (dd, J=11.1, 3.3 Hz, 1H), 2.20 (s, 3H), 2.19 (s, 3H), 1.96 (s, 3H). 4-Bromo-5-cyano-2-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(192) ##STR00065##

(193) To a solution of 4-bromo-5-cyano-2-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (45 mg, 0.08 mmol) in DMF (3 mL) were added TEA (0.07 mL), Copper(I)Iodide (5 mg, 0.03 mmol), CsF (20 mg, 0.13 mmol), 3,4,5-trifluorophenylacetylene (30 mg, 0.13 mmol). The reaction was stirred at room temperature for 20 h under a nitrogen atmosphere. Water (10 mL) and DCM (10 mL) were added. The aqueous phase was extracted with DCM (5 mL2), the combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue. which was purified by column chromatography (PE/EA=2/1) to obtain the desired product (40 mg, 43%).

(194) m/z calcd for [C.sub.26H.sub.21BrF.sub.3N.sub.5O.sub.7S].sup. [M+H].sup.+: 684.0; found: 684.0.

i2) 4-Chloro-5-cyano-2-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

4-Chloro-5-cyano-2-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(195) ##STR00066##

(196) Acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (400 mg, 1.03 mmol) and 4,6-dichloropyridine-3-carbonitrile (266.58 mg, 1.54 mmol) were dissolved in DMF (2 mL) and TEA (1 mL). Diethylamine (112.7 mg, 1.54 mmol) was added at 0 C. The mixture was stirred at 0 C. for 1 hour. EtOAc (100 mL) was added. The mixture was washed by 1 M NaHSO.sub.4 (50 mL), brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified on silica gel column using a gradient of EA/PE form 0-25% to give the title compound 200 mg (40%).

(197) ESI-MS m/z calcd for [C.sub.18H.sub.19ClN.sub.5O.sub.7S].sup.+ (M+H)+: 484.1; found: 484.1.

4-Chloro-5-cyano-2-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(198) ##STR00067##

(199) 4-Chloro-5-cyano-2-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (260 mg, 0.54 mmol), TEA (54 mg, 0.54 mmol) and trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (184 mg, 0.81 mmol) were dissolved in CH.sub.3CN (5 mL). CuI (30.7 mg, 0.16 mmol) and CsF (81.6 mg, 0.54 mmol) were added. The mixture was stirred at rt for 4 hours. Then the mixture was concentrated and the residue was purified on silica gel column using a gradient of EA/PE from 0-40% to give the title compound 60 mg (17%).

(200) ESI-MS m/z calcd for [C.sub.26H.sub.22ClF.sub.3N.sub.5O.sub.7S].sup.+ (M+H).sup.+: 640.1; found: 640.1.

i3) 2-Chloro-4-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

2-Chloro-4-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(201) ##STR00068##

(202) To a solution of acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (100 mg, 0.25 mmol) in DCM (5 mL) were added 2-chloro-4-fluoropyridine (50 mg, 0.38 mmol), Diethylamine (0.5 mL). The reaction was stirred at at room temperature with stirring for 20 h.

(203) Water (50 mL) and DCM (50 mL) were added. The aqueous phase was extracted with DCM (50 mL2), the combined organic phases were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=3/1) to obtain the product (50 mg).

(204) m/z calcd for [C17H19ClN.sub.4O.sub.7S].sup.+[M+H].sup.+: 459.0; found: 459.0.

2-Chloro-4-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(205) ##STR00069##

(206) To a mixture of 2-Chloro-4-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (50 mg, 0.11 mmol) in DMF (5 mL) were added TEA (0.2 mL), Copper(I)Iodide (6 mg, 0.03 mmol), CsF (25 mg, 0.16 mmol), trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (37 mg, 0.16 mmol). The reaction was stirred at room temperature for 20 h under a N.sub.2 atmosphere. Water (10 mL) and DCM (10 mL) were added. The aqueous phase was extracted with DCM (5 mL2), the combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=2/1) to obtain the product (45 mg)

(207) m/z calcd for [C.sub.25H.sub.22ClF.sub.3N.sub.4O.sub.7S].sup.+ [M+H].sup.+: 615.0; found: 615.0.

(208) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.21 (d, J=5.3 Hz, 1H), 7.71 (s, 1H), 7.37 (t, J=7.1 Hz, 3H), 7.21 (d, J=1.6 Hz, 1H), 6.36 (d, J=5.5 Hz, 1H), 6.09 (dd, J=11.8, 5.6 Hz, 1H), 5.54 (d, J=2.3 Hz, 1H), 5.13 (dd, J=11.7, 3.0 Hz, 1H), 4.71-4.62 (m, 1H), 4.06 (ddd, J=19.2, 11.6, 6.4 Hz, 2H), 2.02 (s, 3H), 1.89 (s, 3H), 1.86 (s, 3H).

i4) 5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside and

i5) 5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside and 5-Bromo-6-cyano-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(209) ##STR00070##

(210) To a solution of acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (100 mg, 0.25 mmol) in DCM (5 mL) were added 3-bromo-5-chloropicolinonitrile (80 mg, 0.38 mmol), Diethylamine (0.5 mL). The reaction was stirred at room temperature with for 20 h. Water (50 mL) and DCM (50 mL) were added. The aqueous phase was extracted with DCM (50 mL2), the combined organic phases were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=3/1) to obtain the title products as a mixture (50 mg).

5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(211) m/z calcd for [C.sub.18H.sub.18ClN.sub.5O.sub.7S].sup. [M+H].sup.+: 484.0; found: 484.0.

5-Bromo-6-cyano-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(212) m/z calcd for [C.sub.18H.sub.18BrN.sub.5O.sub.7S].sup. [M+H].sup.+: 528.0; found: 528.0.

5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (i4)

(213) ##STR00071##
and

5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (i5)

(214) ##STR00072##

(215) To a mixture of 5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside and 5-Bromo-6-cyano-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (50 mg) in DMF (5 mL) were added TEA (0.2 mL), Copper(I)Iodide (27 mg, 0.14 mmol), CsF (110 g, 0.70 mmol), trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane(160 mg, 0.07 mmol). The reaction was stirred at room temperature for 20 h under under a N.sub.2 atmosphere. Water (10 mL) and DCM (10 mL) were added. The aqueous phase was extracted with DCM (5 mL2), the combined organic phase was washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=2/1) to obtain the i4 (10 mg) and i5 (20 mg).

i4) 5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(216) m/z calcd for [C.sub.26H.sub.21ClF.sub.3N.sub.5O.sub.7S].sup.+ [M+H].sup.+: 640.0; found: 640.0.

(217) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.58 (d, J=2.1 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H), 7.85 (s, 1H), 7.44 (dd, J=7.8, 6.6 Hz, 2H), 6.29 (d, J=5.5 Hz, 1H), 6.16 (dd, J=11.6, 5.6 Hz, 1H), 5.65 (d, J=2.3 Hz, 1H), 5.22 (dd, J=11.6, 3.0 Hz, 1H), 4.88-4.77 (m, 1H), 4.22-4.03 (m, 2H), 2.06 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H).

i5) 5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(218) m/z calcd for [C.sub.26H.sub.21BrF.sub.3N.sub.5O.sub.7S].sup. [M+H].sup.+: 684.0; found: 684.0.

(219) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.67 (d, J=1.9 Hz, 1H), 8.16 (d, J=1.9 Hz, 1H), 7.78 (s, 1H), 7.50-7.38 (m, 2H), 6.34 (d, J=5.5 Hz, 1H), 6.16 (dd, J=11.7, 5.5 Hz, 1H), 5.62 (d, J=2.8 Hz, 1H), 4.83-4.64 (m, 1H), 4.24-3.98 (m, 2H), 2.09 (s, 3H), 2.01 (s, 3H), 1.98 (s, 3H).

i6) 5-Bromo-2-Cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

5-Bromo-2-Cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside and 5-Chloro-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(220) ##STR00073##

(221) To a solution of acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (100 mg, 0.25 mmol) in DCM (5 mL) were added 3-bromo-5-chloropicolinonitrile (80 mg, 0.38 mmol), Diethylamine (0.5 mL). The reaction was stirred at room temperature for 20 h. Water (50 mL) and DCM (50 mL) were added. The aqueous phase was extracted with DCM (50 mL2), the combined organic phases were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=3/1) to obtain a crude product mixture. (45 mg).

5-Bromo-2-Cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(222) m/z calcd for [C.sub.18H.sub.18BrN.sub.5O.sub.7S].sup. [M+H].sup.+: 528.0; found: 528.0.

5-Chloro-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(223) m/z calcd for [C.sub.18H.sub.18ClN.sub.5O.sub.7S].sup. [M+H].sup.+: 484.0; found: 484.0.

i6) 5-Bromo-2-Cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside and

5-Chloro-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(224) ##STR00074##

(225) To a mixture of 5-bromo-2-Cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside and 5-chloro-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (45 mg) in DMF (5 mL) were added TEA (0.2 mL), Copper(I)Iodide (27 mg, 0.14 mmol), CsF (110 g, 0.70 mmol), trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane(160 mg, 0.07 mmol). The reaction was stirred at room temperature for 20 h under N.sub.2. Water (10 mL) and DCM (10 mL) were added. The aqueous phase was extracted with DCM (5 mL2), the combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=2/1) to obtain the title products i6 (10 mg) and 5-Chloro-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside (18 mg).

i6) 5-Bromo-2-Cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(226) m/z calcd for [C.sub.26H.sub.21BrF.sub.3N.sub.5O.sub.7S].sup. [M+H].sup.+: 684.0; found: 684.0.

(227) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.63 (d, J=1.8 Hz, 1H), 8.16 (d, J=1.8 Hz, 1H), 7.79 (s, 1H), 7.43-7.34 (m, 2H), 6.24 (d, J=5.5 Hz, 1H), 6.11 (dd, J=11.6, 5.5 Hz, 1H), 5.58 (d, J=2.1 Hz, 1H), 5.14 (dd, J=11.6, 2.8 Hz, 1H), 4.80-4.73 (m, 1H), 4.15-3.97 (m, 10H), 2.00 (s, 3H), 1.95 (s, 6H).

5-Chloro-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(228) m/z calcd for [C.sub.26H.sub.21ClF.sub.3N.sub.5O.sub.7S].sup.+[M+H].sup.+: 640.0; found: 640.0.

(229) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.63 (d, J=1.9 Hz, 1H), 8.01 (d, J=1.9 Hz, 1H), 7.79 (s, 1H), 7.48-7.39 (m, 2H), 6.34 (d, J=5.5 Hz, 1H), 6.16 (dd, J=11.6, 5.6 Hz, 1H), 5.62 (d, J=2.3 Hz, 1H), 5.20 (dd, J=11.7, 3.0 Hz, 1H), 4.78-4.71 (m, 1H), 4.21-4.04 (m, 2H), 2.09 (s, 3H), 2.00 (s, 3H), 1.98 (s, 3H).

i7) 4-Chloro-2-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

O-4-chloropyridin-2-yl dimethylcarbamothioate

(230) ##STR00075##

(231) A solution of 4-chloropyridin-2-ol (1 g, 10 mmol) and 1,4-diazabicyclooctane (1.8 g, 16.02 mmol) in tetrahydrofuran (30 ml) was added N,N-dimethylcarbamothioyl chloride (1.3 g, 10.68 mmol). The reaction mixture was stirred at r.t over 16 h The reaction mixture was evaporated to dryness and the residue was purified by flash chromatography (PE:EA=10%-50%) to give the title compound 800 mg (54.6%).

(232) m/z calcd for [C.sub.8H.sub.9ClN.sub.2OS].sup.+ [M+H].sup.+: 217.0; found: 217.0.

S-[(5-chloro-3-pyridyl)] N,N-dimethylcarbamothioate

(233) ##STR00076##

(234) O-[(5-chloro-3-pyridyl)] N,N-dimethylcarbamothioate (600 mg, 2.8 mmol) was taken up to in phenoxybenzene (10 mL) and was added to 5 mL of refluxing phenoxybenzene. After 2 h the reaction mixture was cooled and filtered through 100 g SiO.sub.2 to remove the phenoxybenzene, subsequent elution with PE:EA=1:2 to give product 450 mg (72.6%) as yellow solid.

(235) m/z calcd for [C.sub.8H.sub.9ClN.sub.2OS].sup.+[M+H].sup.+: 217.0; found: 217.0.

4-chloropyridine-2-thiol

(236) ##STR00077##

(237) A solution of S-4-chloropyridin-2-yl dimethylcarbamothioate (450 mg, 1.8 mmol) and NaOH (300 mg, 7.5 mmol) in 20 mL ethanol/water=3:1, heated at 50 C. for 2 h. The mixture was concentrated to about 100 ml, EtOAc (50 mL) was added and the pH was adjusted to pH 6 with 2 M hydrochloric acid. The organic layer was dried over Na.sub.2SO.sub.4, concentrated and the residue was purified by flash chromatography (EA:PE=1:5 to 1:2, ISCO, 20 g, 30 ml/min, normal phase silica, uv254) to give product 100 mg (45%) as yellow oil.

(238) m/z calcd for [C.sub.5H.sub.4ClNS].sup. [MH].sup.: 144.0; found: 144.0.

4-Chloro-2-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(239) ##STR00078##

(240) Cs.sub.2CO.sub.3 (420 mg, 1.3 mmol) was suspended in DMF (5 mL) followed by addition of 4-chloropyridine-2-thiol (100 mg, 0.68 mmol). After 30 min, 2,4,6-tri-O-acetyl-3-azido-1-chloro-3-deoxy--D-galactopyranoside (200 mg, 0.6 mmol) was added. The mixture was stirred at r.t for 16 h. The mixture was diluted with DCM (50 mL), 0.5 M citric acid (50 mL) and water (50 mL). The organic phase was washed with water (50 mL) and concentrated. The residue was purified by column chromatography (PE:EA=3:1) to give product 30 mg (13%) as a white solid.

(241) m/z calcd for [C.sub.17H.sub.19ClN.sub.4O.sub.7S].sup.+[M+H].sup.+: 459.0; found: 459.0.

4-Chloro-2-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(242) ##STR00079##

(243) To a solution of 4-chloro-2-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (30 mg, 0.06 mmol) in MeCN (2 mL) was added trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (50 mg, 0.11 mmol), CsF (10 mg, 0.08 mmol), iodocopper (7 mg, 0.01 mmol). The reaction vessel was purged 3 times with nitrogen. The mixture was stirred at r.t for 16 h. The reaction was quenched with water (10 mL). The mixture was extracted with dichloromethane (10 mL3) and the combined organic phases were washed with brine (10 mL) and dried over Na.sub.2SO.sub.4, filtered, and concentrated to dryness in vacuo. The crude product was purified by flash chromatography (EA:PE=1:10 to 1:2, ISCO 12 g, 20 ml/min, normal phase silica, uv254) to give the title compound 25 mg (42%) as a yellow solid.

(244) m/z calcd for [C.sub.25H.sub.22ClF.sub.3N.sub.4O.sub.7S].sup.+[M+H].sup.+: 615.0; found: 615.0.

i8) 5-Bromo-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside O-[(5-bromo-3-pyridyl)] N,N-dimethylcarbamothioate

(245) ##STR00080##

(246) To a solution of 5-bromopyridin-3-ol (17.4 g, 0.10 mol) in DMF (0.15 L) was added sodium hydride (2.64 g, 0.11 mol, 96% in mineral oil) at 0 C., followed by stirring at 0 C. for 30 min. Dimethylthiocarbamoyl chloride (14.83 g, 0.12 mol) was added to the reaction mixture followed by stirring at room temperature over night. LC-MS analysis indicated formation of the target compound. The reaction mixture was quenched with water (100 mL) followed by extraction with EtOAc (100 mL3). The combined organic layers were washed with brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/PE=5%-40%, ISCO 120 g, 50 mL/min, normal phase silica gel, uv254) to afford the target compound (9.93 g, 36.5% yield) as yellow oil.

(247) ESI-MS m/z calcd for [C.sub.8H.sub.9BrN.sub.2OS].sup.+[M+H].sup.+: 261.0; found: 261.0

S-[(5-bromo-3-pyridyl)] N,N-dimethylcarbamothioate

(248) ##STR00081##

(249) O-[(5-bromo-3-pyridyl)] N,N-dimethylcarbamothioate (9.93 g, 0.04 mol) was dissolved in phenoxybenzene (100 mL). The mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature and directly purified by flash chromatography on a Biotage (EtOAc/PE=5%-50%, ISCO 120 g, 50 mL/min, normal phase silica gel, uv 254) to afford the target compound S-[(5-bromo-3-pyridyl)] N,N-dimethylcarbamothioate (4.63 g, 43.8% yield) as a yellow solid.

(250) ESI-MS m/z calcd for [C.sub.8H.sub.9BrN.sub.2OS].sup.+ [M+H].sup.+: 261.0; found: 261.0

3-bromo-5-methoxy-benzenethiol

(251) ##STR00082##

(252) S-(3-chloro-5-methoxy-phenyl) N,N-dimethylcarbamothioate (1.044 g, 4 mmol) and KOH (897.21 mg, 16 mmol) was taken up in in ethanol/water (40 mL, 3/1). The reaction mixture was heated at reflux for 2 h. LC-MS analysis indicated total consumption of the starting material. The mixture was concentrated followed by addition of 10% aq NaOH (30 mL). The reaction mixture was washed with ether (15 mL3). The aqueous layer was acidified with aq KHSO.sub.4 to adjust the pH 2, followed by extraction with EtOAc (20 mL5). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford crude product, which was used for next step directly without further purification.

(253) ESI-MS m/z calcd for [C.sub.8H.sub.4BrNS].sup. [MH].sup.: 188.9; found: 188.0.

5-Bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(254) ##STR00083##

(255) NaH (82.99 mg, 3.47 mmol) was added to a solution of 5-bromopyridine-3-thiol (658.67 mg, 3.47 mmol) in DMF (10 mL) at 0 C. The solution was stirred at rt for 30 min. Then 2,4,6-tri-O-acetyl-3-azido-1-chloro-3-deoxy--D-galactopyranoside (1.01 g, 2.89 mmol) was added. The reaction mixture was stirred at 50 C. for 2 h followed by cooling to room temperature. Water (50 mL) was added and the reaction mixture was extracted with EtOAc (15 mL3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford crude product, which was purified by biotage (EtOAc/PE=5-40%, ISCO 40 g, 30 mL/min, normal phase silica gel, uv 254) to afford the title compound (650 mg, 44.7% yield) as a white solid.

(256) ESI-MS m/z calcd for [C.sub.17H.sub.19BrN.sub.4O.sub.7S].sup.+[M+H].sup.+: 503.0; found: 503.0

5-Bromo-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(257) ##STR00084##

(258) To a solution of 5-bromo-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (50 mg, 0.10 mmol) in DMF (3 mL) were added TEA (0.10 mL), Copper(I)Iodide (6 mg, 0.03 mmol), CsF (23 mg, 0.15 mmol), ((4-chloro-3,5-difluorophenyl)ethynyl)trimethylsilane (37 mg, 0.15 mmol). The reaction was stirred at room temperature with for 20 h under N.sub.2. Water (10 mL) and DCM (10 mL) were added. The aqueous phase was extracted with DCM (5 mL2) and the combined organics were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=2/1) to obtain the desired product (40 mg, 59%).

(259) ESI-MS m/z calcd for [C.sub.25H.sub.22BrClF.sub.2N.sub.4O.sub.7S].sup.+[M+H].sup.+: 675.0; found: 675.0

i9) 5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

((4-chloro-3,5-difluorophenyl)ethynyl)trimethylsilane

(260) ##STR00085##

(261) To a solution of 5-bromo-2-chloro-1,3-difluorobenzene (1 g, 4.42 mmol) in CH.sub.3CN (20 mL) was added CuI (348 mg, 1.33 mmol), DIPEA (3.6 mL), Pd(PPh.sub.3).sub.2Cl.sub.2 (308 mg, 0.44 mmol). The mixture was heated under N.sub.2 at 50 C. for 20 h. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=10/1) to obtain product (400 mg, 37%).

(262) ESI-MS m/z calcd for [C.sub.11H.sub.11ClF.sub.2Si].sup.+[M+H].sup.+: 245.0; found: 245.0

i43) 5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

O-[(5-chloro-3-pyridyl)] N,N-dimethylcarbamothioate

(263) ##STR00086##

(264) To a solution of 5-chloropyridin-3-ol (10 g, 0.10 mol) in N,N-dimethylformamide (200 mL) was added NaH (1.90 g, 0.10 mol) at 0 C. The reaction mixture was stirred at 0 C. 30 minutes followed by addition of Dimethylthiocarbamoyl chloride (10.50 g, 0. 10 mol) followed by stirring at room temperature 20 h. The reaction was quenched with water (500 mL) and extracted with dichloromethane (500 mL3). The combined organics were washed with brine (400 mL3), dried over Na.sub.2SO.sub.4, filtered and the solvents where removed in vacuo. The crude product was purified by chromatography on a combiflash (EtOAc:PE=1:5) to give the title compound 6.2 g (28.7%) as brown oil.

(265) m/z calcd for [C.sub.8H.sub.9ClN.sub.2OS].sup.+[M+H].sup.+: 217.0; found: 217.0.

S-[(5-chloro-3-pyridyl)] N,N-dimethylcarbamothioate

(266) ##STR00087##

(267) O-[(5-chloro-3-pyridyl)] N,N-dimethylcarbamothioate (6.2 g, 28.7 mmol) was taken up to in phenoxybenzene (30 mL) and added to 5 mL of refluxing phenoxybenzene. After 2 h, the reaction mixture was cooled and passed through 200 g SiO.sub.2 to remove the phenoxybenzene, subsequent elution with PE:EtOAc=1:2 gave the title compound 4.5 g (73%) as yellow solid.

(268) m/z calcd for [C.sub.8H.sub.9ClN.sub.2OS].sup.+[M+H].sup.+: 217.0; found: 217.0.

5-chloropyridine-3-thiol

(269) ##STR00088##

(270) S-[(5-chloro-3-pyridyl)] N,N-dimethylcarbamothioate (3.5 g, 16.20 mmol) and NaOH (3.24 g, 81 mmol) was taken up into 160 mL ethanol/water=3:1 and heated at reflux for 2 h. The reaction mixture was concentrated to about 100 mL. EtOAc (300 mL) was added and the pH was adjusted to about 6 by addition of HCl (2M). The organic layer was isolated and dried over Na.sub.2SO.sub.4, concentrated, purified by chromatography on a combiflash (EtOAc:PE=1:5 to 1:2, ISCO, 40 g, 40 ml/min, normal phase silica, uv254) to give 5-chloropyridine-3-thiol 2.0 g (85%) as yellow oil.

(271) m/z calcd for [C.sub.5H.sub.4ClNS].sup. [MH].sup.: 144.0; found: 144.0.

5-Chloropyridin-3-yl 2,4,6-tri-O-Acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(272) ##STR00089##

(273) NaH (303.44 mg, 7.58 mmol) was suspended in DMF (25 mL). The 5-chloropyridine-3-thiol (1000 mg, 6.89 mmol) was added. After 30 min, the 3-azido-3-deoxy-2,4,6-tri-O-acetyl-1-chloro-3-D-galactopyranoside (1923.68 mg, 5.51 mmol) was added. The mixture was heated to 50 C. 3 h. The mixture was diluted with DCM (150 mL), 0.5M citric acid (150 mL) and water (150 mL). The organic phase was washed with water (100 mL) and concentrated. The residue was purified by column chromatography (PE:EtOAc=3:1) to give the title compound 900 mg (28.5%) as a white solid.

(274) m/z calcd for [C.sub.17H.sub.19ClN.sub.4O.sub.7S].sup.+ [M+H].sup.+: 459.0; found: 459.0.

5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(275) ##STR00090##

(276) To a solution of 5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (60 mg, 0.13 mmol) in N,N-dimethylformamide (6 mL) was added ((4-chloro-3,5-difluorophenyl)ethynyl)trimethylsilane (63 mg, 0.26 mmol), iodocopper (7 mg, 0.04 mmol). The reaction vessel was purged 3 times with nitrogen. The reaction was quenched with water (10 mL). The mixture was extracted with dichloromethane (10 mL3) and the combined organics were washed with brine (5 mL) and dried over Na.sub.2SO.sub.4, filtered, and concentrated to dryness. The crude product was purified by flash chromatography (EA:PE=1:10 to 1:2, ISCO 12 g, 20 ml/min, normal phase silica, uv254) to give the title compound 45 mg (56%) as a yellow solid.

(277) m/z calcd for [C.sub.25H.sub.22Cl.sub.2F.sub.2N.sub.4O.sub.7S].sup.+[M+H].sup.+: 631.0; found: 631.0.

i10) 5-Chloro-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside and

i11) 5-Bromo-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

5-Chloro-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside and

5-Bromo-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(278) ##STR00091##

(279) Acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (250 mg, 0.64 mmol) and 5-bromo-3-chloro-pyridine-2-carbonitrile (280 mg, 1.28 mmol) were dissolved in DMF (10 mL). Diethylamine (0.15 ml) was added. The reaction was stirred at room temperature with for 20 h. Water (50 mL) and DCM (50 mL) were added. The aqueous phase was extracted with DCM (50 mL2), the combined organic phases were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=3/1) to obtain the product (130 mg, 38%).

5-Chloro-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(280) m/z calcd for [C.sub.18H.sub.18ClN.sub.5O.sub.7S].sup. [M+H].sup.+: 484.0; found: 484.0.

5-Bromo-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(281) m/z calcd for [C.sub.18H18BrN.sub.5O.sub.7S].sup. [M+H].sup.+: 528.0; found: 528.0.

i10) 5-Chloro-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside and

i11) 5-Bromo-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(282) ##STR00092##

(283) To a mixture of 5-Chloro-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside and 5-Bromo-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (130 mg) in CH.sub.3CN (5 mL) were added DIEA (0.23 mL), Copper(I)Iodide (15 mg, 0.08 mmol), CsF (82 mg, 0.54 mmol), 2-(4-chloro-3,5-difluoro-phenyl)ethynyl-trimethyl-silane(132 mg, 0.54 mmol). The reaction was stirred at room temperature for 20 h under a N.sub.2 atmosphere. Water (10 mL) and DCM (10 mL) were added. The aqueous phase was extracted with DCM (5 mL2), the combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=2/1) to obtain the products i10 (80 mg) and i11 (20 mg).

i10) 5-Chloro-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(284) m/z calcd for [C.sub.26H.sub.21Cl.sub.2F.sub.2N.sub.5O.sub.7S].sup.+ [M+H].sup.+: 656.0; found: 656.0.

(285) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.63 (d, J=1.9 Hz, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.83 (s, 1H), 7.45 (t, J=6.3 Hz, 2H), 6.34 (d, J=5.5 Hz, 1H), 6.16 (dd, J=11.7, 5.6 Hz, 1H), 5.63 (d, J=2.3 Hz, 1H), 5.20 (dd, J=11.7, 3.1 Hz, 1H), 4.78-4.71 (m, 1H), 4.14 (tdd, J=12.8, 8.7, 4.4 Hz, 3H), 2.08 (s, 3H), 2.00 (s, 3H), 1.98 (s, 3H).

i11) 5-Bromo-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(286) m/z calcd for [C.sub.26H.sub.21BrClF.sub.2N.sub.5O.sub.7S]+[M+H].sup.+: 700.0; found: 700.0.

5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside and

5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(287) ##STR00093##

(288) Acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (250 mg, 0.64 mmol) and 3-bromo-5-chloro-pyridine-2-carbonitrile (280 mg, 1.28 mmol) were dissolved in DMF (10 mL). Diethylamine (0.15 ml) was added. The reaction was stirred at room temperature with stirring for 20 h. Water (50 mL) and DCM (50 mL) were added. The aqueous phase was extracted with DCM (50 mL2), the combined organic phases were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=3/1) to obtain the product mixture (150 mg, 48%).

5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(289) m/z calcd for [C.sub.18H.sub.18BrN.sub.5O.sub.7S].sup. [M+H].sup.+: 528.0; found: 528.0.

5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(290) m/z calcd for [C.sub.18H.sub.18ClN.sub.5O.sub.7S].sup. [M+H].sup.+: 484.0; found: 484.0.

i12) 5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside and

i13) 5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(291) ##STR00094##

(292) To a mixture of 5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside and 5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (150 mg) in CH.sub.3CN (5 mL) were added DIEA (0.25 mL), Copper(I)Iodide (16 mg, 0.08 mmol), CsF (86 mg, 0.57 mmol), 2-(4-chloro-3,5-difluoro-phenyl)ethynyl-trimethyl-silane (140 mg, 0.57 mmol). The reaction was stirred at room temperature with for 20 h under N.sub.2. Water (10 mL) and DCM (10 mL) were added. The aqueous phase was extracted with DCM (5 mL2), the combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=2/1) to obtain the products i12 (80 mg) and i13 (30 mg).

i12) 5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(293) m/z calcd for [C.sub.26H.sub.21BrClF.sub.2N.sub.5O.sub.7S].sup.+[M+H].sup.+: 700.0; found: 700.0.

(294) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.67 (d, J=2.0 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.83 (s, 1H), 7.45 (d, J=7.3 Hz, 2H), 6.34 (d, J=5.5 Hz, 1H), 6.16 (dd, J=11.7, 5.6 Hz, 1H), 5.63 (d, J=2.1 Hz, 1H), 5.20 (dd, J=11.7, 3.1 Hz, 1H), 4.84-4.56 (m, 1H), 4.13 (tdd, J=13.7, 11.8, 6.3 Hz, 4H), 2.08 (s, 3H), 2.01 (s, 3H), 1.98 (s, 3H).

i13) 5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(295) m/z calcd for [C.sub.26H.sub.21Cl.sub.2F.sub.2N.sub.5O.sub.7S].sup.+[M+H].sup.+: 656.0; found: 656.0.

i14) 5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-cyano-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside 2,6-Difluoro-4-(2-trimethylsilylethynyl)benzonitrile

(296) ##STR00095##

(297) To a solution of 4-bromo-2,6-difluoro-benzonitrile (500 mg, 2.29 mmol) in CH.sub.3CN (10 mL) was added CuI (131 mg, 0.69 mmol), DIPEA (2.0 mL), Pd(PPh.sub.3).sub.2Cl.sub.2 (161 mg, 0.23 mmol), ethynyl(trimethyl)silane (451 mg, 4.59 mmol). The mixture was heated under N.sub.2 at room temperature for 20 h. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=10/1) to obtain the title compound (100 mg, 19%).

(298) m/z calcd for [C.sub.12H.sub.11F.sub.2NSi] [M]: 235.0; found: 235.0; [M15]: 220.0; found: 220.0.

5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-cyano-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(299) ##STR00096##

(300) To a solution of 5-chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (50 mg, 0.11 mmol) in CH.sub.3CN (5 mL) was added 2,6-difluoro-4-(2-trimethylsilylethynyl)benzonitrile (100 mg, 0.42 mmol), iodocopper (6 mg, 0.03 mmol), CsF (33 mg, 0.22 mmol), DIEA (0.1 mL). The reaction vessel was purged 3 times with nitrogen. The reaction was concentrated to dryness. The crude product was purified by flash chromatography (EA:PE=1:10 to 1:2, ISCO 12 g, 25 ml/min, normal phase silica, uv254) to give product (42 mg, 62%).

(301) m/z calcd for [C.sub.26H.sub.22ClF.sub.2N.sub.5O.sub.7S].sup. [M+H].sup.+: 622.0; found: 622.0.

(302) 1H NMR (400 MHz, CDCl3) 8.57 (d, J=1.9 Hz, 1H), 8.54 (d, J=2.2 Hz, 1H), 7.95 (s, 1H), 7.88 (t, J=2.1 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 6.15 (d, J=5.5 Hz, 1H), 6.12 (dd, J=11.1, 5.6 Hz, 1H), 5.64-5.60 (m, 1H), 5.23 (dd, J=11.0, 3.1 Hz, 1H), 4.90-4.84 (m, 1H), 4.17-4.09 (m, 2H), 2.07 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H).

i15) 5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,5-difluoro-4-trifluoromethyl-phenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

2-(3,5-difluoro-4-trifluoromethyl-phenyl)ethynyl-trimethyl-silane

(303) ##STR00097##

(304) To a solution of 5-bromo-1,3-difluoro-2-(trifluoromethyl)benzene (500 mg, 1.92 mmol) in CH.sub.3CN (10 mL) was added CuI (109 mg, 0.57 mmol), DIPEA (1.6 mL), Pd(PPh.sub.3).sub.2Cl.sub.2 (54 mg, 0.07 mmol), ethynyl(trimethyl)silane (376 mg, 3.83 mmol). The mixture was heated under N.sub.2 at room temperature for 20 h. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=10/1) to obtain product (60 mg, 11%).

(305) m/z calcd for [C.sub.12H.sub.11F.sub.5Si] [M]: 278.0; found: 278.0; [M15]: 263.0; found: 263.0.

5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,5-difluoro-4-trifluoromethyl-phenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(306) ##STR00098##

(307) To a solution of 5-chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (50 mg, 0.11 mmol) in CH.sub.3CN (5 mL) was added 2-(3,5-difluoro-4-trifluoromethyl-phenyl)ethynyl-trimethyl-silane (60 mg, 0.22 mmol), CuI (6 mg, 0.03 mmol), CsF (33 mg, 0.22 mmol), DIEA (0.1 mL). The reaction vessel was purged 3 times with nitrogen. The reaction was concentrated to dryness. The crude product was purified by flash chromatography (EA:PE=1:10 to 1:2, ISCO 12 g, 25 ml/min, normal phase silica, uv254) to give the title compound (33 mg, 45%).

(308) m/z calcd for [C.sub.26H.sub.22ClF.sub.5N.sub.4O.sub.7S].sup. [M+H].sup.+: 665.0; found: 665.0.

(309) 1H NMR (400 MHz, CDCl3) 8.58 (d, J=1.9 Hz, 1H), 8.54 (d, J=2.2 Hz, 1H), 7.90 (s, 1H), 7.88 (t, J=2.1 Hz, 1H), 7.47 (d, J=10.1 Hz, 2H), 6.15 (d, J=5.6 Hz, 1H), 6.11 (dd, J=11.2, 5.6 Hz, 1H), 5.65-5.60 (m, 1H), 5.23 (dd, J=11.2, 3.1 Hz, 1H), 4.90-4.81 (m, 1H), 4.13 (ddd, J=19.4, 11.7, 6.3 Hz, 2H), 2.07 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H).

i16) 5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

2-(3,5-difluoro-4-methyl-phenyl)ethynyl-trimethyl-silane

(310) ##STR00099##

(311) To a solution of 5-bromo-1,3-difluoro-2-methyl-benzene (500 mg, 2.42 mmol) in DMF (2.5 mL) was added CuI (138 mg, 0.72 mmol), DIPEA (2.5 mL), Pd(PPh.sub.3).sub.2Cl.sub.2 (170 mg, 0.24 mmol), ethynyl(trimethyl)silane (474 mg, 4.83 mmol). The mixture was heated under N.sub.2 at 100 C. for 2 h. The mixture was cooled to room temperature and added 100-200 silica (5 g). The mixture was purified by column chromatography (PE/EA=10/1) to obtain the title compound (100 mg, 18.5%).

(312) m/z calcd for [C.sub.12H.sub.14F.sub.2Si] [M]: 224.0; found: 224.0; [M15]: 209.0; found: 209.0.

5-Chloro-3-pyridyl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(313) ##STR00100##

(314) To a solution of 5-chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (50 mg, 0.11 mmol) in CH.sub.3CN (5 mL) was added 2-(3,5-difluoro-4-methyl-phenyl)ethynyl-trimethyl-silane (100 mg, 0.45 mmol), iodocopper (6 mg, 0.03 mmol), CsF (33 mg, 0.22 mmol), DIEA (0.1 mL). The reaction vessel was purged 3 times with nitrogen. The reaction was concentrated to dryness. The crude product was purified by flash chromatography (EA:PE=1:10 to 1:2, ISCO 12 g, 25 ml/min, normal phase silica, uv254) to give the title compound (50 mg, 56%).

(315) m/z calcd for [C.sub.26H.sub.25ClF.sub.2N.sub.4O.sub.7S].sup. [M+H].sup.|: 611.0; found: 611.0.

(316) 1H NMR (400 MHz, CDCl3) 8.58 (d, J=1.9 Hz, 1H), 8.53 (d, J=2.2 Hz, 1H), 7.88 (t, J=2.1 Hz, 1H), 7.78 (s, 1H), 7.30 (d, J=7.6 Hz, 2H), 6.14 (d, J=5.6 Hz, 1H), 6.09 (dd, J=11.5, 5.6 Hz, 1H), 5.63 (d, J=2.2 Hz, 1H), 5.23 (dd, J=11.5, 3.1 Hz, 1H), 4.86 (dd, J=7.1, 5.1 Hz, 1H), 4.13 (ddd, J=19.4, 11.7, 6.3 Hz, 2H), 2.07 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H).

i117) 5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-bromo-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

2-(4-Bromo-3-fluoro-phenyl)ethynyl-trimethyl-silane

(317) ##STR00101##

(318) To a solution of 2-bromo-1,3-difluoro-5-iodo-benzene (500 mg, 1.57 mmol) in CH.sub.3CN (5 mL) was added CuI (90 mg, 0.47 mmol), DIPEA (1.3 mL), Pd(PPh.sub.3).sub.2Cl.sub.2 (110 mg, 0.16 mmol), ethynyl(trimethyl)silane (308 mg, 3.14 mmol). The mixture was stirred at room temperature under N.sub.2 for 20 h. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=10/1) to obtain the title compound (100 mg, 22.1%).

(319) m/z calcd for [C.sub.11H.sub.11BrF.sub.2Si] [M]: 287.0; found: 287.0; [M15]: 272.0; found: 272.0.

5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-bromo-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(320) ##STR00102##

(321) To a solution of 3-azido-3-deoxy-2,4,6-tri-O-acetyl-1-(5-chloropyridine-3-thiol-yl)--D-galactopyranoside (50 mg, 0.11 mmol) in CH.sub.3CN (5 mL) was added 2-(4-bromo-3,5-difluoro-phenyl)ethynyl-trimethyl-silane (100 mg, 0.35 mmol), CuI (6 mg, 0.03 mmol), DIEA (0.1 mL). The reaction vessel was purged 3 times with nitrogen. The reaction was concentrated to dryness. The crude product was purified by flash chromatography (EA:PE=1:10 to 1:2, ISCO 12 g, 25 ml/min, normal phase silica, uv254) to give the title compound (65 mg, 88.3%).

(322) m/z calcd for [C.sub.25H.sub.22BrClF.sub.2N.sub.4O.sub.7S].sup.+[M+H].sup.+: 675.0; found: 675.0.

(323) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.57 (d, J=1.9 Hz, 1H), 8.53 (d, J=2.2 Hz, 1H), 7.88 (t, J=2.1 Hz, 1H), 7.84 (s, 1H), 7.42 (d, J=7.1 Hz, 2H), 6.15 (d, J=5.6 Hz, 1H), 6.10 (dd, J=11.4, 5.6 Hz, 1H), 5.63 (d, J=2.0 Hz, 1H), 5.23 (dd, J=11.4, 3.1 Hz, 1H), 4.87 (dd, J=7.1, 5.4 Hz, 1H), 4.25-4.03 (m, 2H), 2.07 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H).

i18) 5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4-dichloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

4-bromo-2-chloro-6-fluoro-aniline

(324) ##STR00103##

(325) NCS (1.4 g, 10.5 mmol) was added portionwise to a mixture of 4-bromo-2-fluoro-aniline (2 g, 10.5 mmol) in acetonitrile (20 ml). The mixture was stirred at reflux for 2 hours, cooled and poured in a mixture of water and K.sub.2CO.sub.3 10%. The mixture was extracted with DCM. The organic layer was dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent:PE/ethyl acetate 80/20) to give the title compound 1.50 g (63.5%). 1H NMR (400 MHz, CDCl3) 7.21 (t, J=1.9 Hz, 1H), 7.09 (dd, J=10.0, 2.1 Hz, 1H), 4.36-3.92 (br, 2H).

5-bromo-1,2-dichloro-3-fluoro-benzene

(326) ##STR00104##

(327) To a stirred suspension of dichlorocopper (1.4 g, 10.7 mmol) and tert-butyl nitrite (1.38 g, 13.4 mmol) in acetonitrile (10 ml), heated at 60 C., was added a solution of 4-bromo-2-chloro-6-fluoro-aniline (1.20 g, 5.35 mmol) in acetonitrile (10 mL) dropwise over 50 minutes. After stirring at 60 C. for 1 hour, the mixture was poured into 20% hydrochloric acid (50 ml) and extracted with ether (2*30 ml). The crude product was purified by flash chromatography on silica gel eluding with hexane to provide the title compound 1.10 g (84.4%).

(328) 1H NMR (400 MHz, CDCl3) 7.38 (t, J=1.9 Hz, 1H), 7.21-7.17 (m, 1H).

((3,4-dichloro-5-fluorophenyl)ethynyl)trimethylsilane

(329) ##STR00105##

(330) To a solution of 5-bromo-1,2-dichloro-3-fluorobenzene (0.5 g, 2.05 mmol), Copper(I)Iodide (117 mg, 0.615 mmol), and Bis(Triphenylphosphine)palladium(II) chloride (224 mg, 0.308 mmol) Diisopropylamine (2075 mg, 20.5 mmol) in N,N-dimethylformamide (5 mL) was added ethynyl(trimethyl)silane (403 mg, 4.10 mmol). The mixture was stirred at 80 C. overnight under nitrogen atmosphere. After removal of the solvent under reduce pressure, the residue was purified by column with Hexane as the mobile-phase to give the title compound 180 mg (33.6%).

(331) 1H NMR (400 MHz, CDCl3) 7.30 (t, J=1.7 Hz, 1H), 7.08 (dt, J=9.4, 4.7 Hz, 1H), 0.18 (s, 9H).

5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4-dichloro-5-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(332) ##STR00106##

(333) A mixture of 5-chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (50 mg, 0.109 mmol) and 2-(3,4-dichloro-5-fluoro-phenyl)ethynyl-trimethyl-silane (57 mg, 0.218 mmol) were dissolved in CH.sub.3CN (5 mL). Then CsF (33.1 mg, 0.218 mmol), and DIEA (0.0560 mL, 0.327 mmol) were added. The mixture was stirred at rt for 5 min. CuI (6.23 mg, 0.0327 mmol) was added. The mixture was stirred at rt over night. Then the mixture was concentrated and purified by column chromatography (SiO.sub.2/PE/EA 2:1=1:1) to give the title compound 30.0 mg (42.5%).

(334) m/z calcd for [C25H22Cl3FN4O7S]+[M+H]+: 647; found: 647.

i19) 5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

2-(4-chloro-3-fluoro-phenyl)ethynyl-trimethyl-silane

(335) ##STR00107##

(336) To a solution of 4-bromo-1-chloro-2-fluoro-benzene (500 mg, 2.39 mmol) in CH.sub.3CN (5 mL) was added CuI (136 mg, 0.72 mmol), DIPEA (2.0 mL), Pd(PPh.sub.3).sub.2Cl.sub.2 (168 mg, 0.24 mmol), ethynyl(trimethyl)silane (469, 4.77 mmol). The mixture was heated under N.sub.2 at 50 C. for 20 h. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=10/1) to give the title compound (150 mg, 28%).

(337) m/z calcd for [C.sub.11H.sub.12ClFSi] [M]: 226.0; found: 226.0; [M15]: 211.0; found: 211.0.

5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(338) ##STR00108##

(339) To a solution of 5-chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (50 mg, 0.11 mmol) in CH.sub.3CN (5 mL) was added 2-(3,5-difluoro-4-methyl-phenyl)ethynyl-trimethyl-silane (150 mg, 0.66 mmol), iodocopper (6 mg, 0.03 mmol), CsF (33 mg, 0.22 mmol), DIEA (0.1 mL). The reaction vessel was purged 3 times with nitrogen. The reaction was concentrated to dryness. The crude product was purified by flash chromatography (EA:PE=1:10 to 1:2, ISCO 12 g, 25 ml/min, normal phase silica, U254) to give the title compound (60 mg, 90%).

(340) m/z calcd for [C.sub.25H.sub.23Cl.sub.2FN.sub.4O.sub.7S].sup. [M+H].sup.+: 613.0; found: 613.0.

(341) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.57 (d, J=1.9 Hz, 1H), 8.53 (d, J=2.2 Hz, 1H), 7.88 (t, J=2.1 Hz, 1H), 7.80 (s, 1H), 7.63 (dd, J=9.9, 1.8 Hz, 1H), 7.55-7.50 (m, 1H), 7.49-7.41 (m, 1H), 6.14 (d, J=5.5 Hz, 1H), 6.10 (dd, J=11.4, 5.5 Hz, 1H), 5.63 (d, J=2.1 Hz, 1H), 5.23 (dd, J=11.4, 3.1 Hz, 1H), 4.90-4.84 (m, 1H), 4.13 (ddd, J=19.4, 11.7, 6.3 Hz, 2H), 2.07 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H).

i20) 5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

3-fluoro-5-((trimethylsilyl)ethynyl)pyridine

(342) ##STR00109##

(343) To a solution of 3-bromo-5-fluoropyridine (0.5 g, 2.84 mmol), Copper(I)Iodide (81.2 mg, 0.426 mmol), and Bis(Triphenylphosphine)palladium (II) chloride (311 mg, 0.426 mmol) in Diisopropylamine (5750 mg, 56.8 mmol) was added ethynyl(trimethyl)silane (419 mg, 4.26 mmol). The mixture was stirred at 80 C. overnight under nitrogen atmosphere. After removal of the solvent under reduced pressure, the residue was purified by flash chromatography using hexane as the mobile-phase to give the title compound. 150 mg (27.3%)

(344) 1H NMR (400 MHz, CDCl3) 8.42 (s, 1H), 8.33 (d, J=2.8 Hz, 1H), 7.39 (ddd, J=9.0, 2.7, 1.6 Hz, 1H), 0.20 (s, 9H).

3,4-Dichlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside

(345) ##STR00110##

(346) To a solution of 3,4-dichlorobenzenethiol (4.61 g, 0.03 mol) in N,N-dimethylformamide (0.05 L) was added NaH (0.53 g, 0.02 mol). The mixture was stirred at room temperature for 30 min. 2,4,6-Tri-O-acetyl-3-azido-1-chloro-3-deoxy--D-galactopyranoside (4.5 g, 0.01 mol) in DMF (10 mL) was added and the reaction mixture was stirred at 50 C. for 20 h. The mixture was diluted with DCM (100 mL), 0.5 M citric acid (50 mL) and water (50 mL). The organic phase was isolated and washed with water (100 mL2) and concentrated. The residue was purified by column chromatography (SiO.sub.2/PE:EA=3:1) to give the title compound 5.1 g (81%) as a white solid. m/z calcd for [C.sub.18H.sub.19Cl.sub.2N.sub.3O.sub.7S].sup.+[M+NH.sub.4].sup.+:509.0; found: 509.0.

5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(347) ##STR00111##

(348) A mixture of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (50 mg, 0.102 mmol) and 2-(5-fluoro-3-pyridyl)ethynyl-trimethyl-silane (85 mg, 0.406 mol) were dissolved in CH.sub.3CN (5 ml). Then CsF (30.9 mg, 0.203 mmol), and DIEA (0.174 ml, 1.02 mmol) were added. The mixture was stirred at rt for 5 min. Copper(I)Iodide (5.80 mg, 0.0305 mmol) was added. The mixture was stirred at r.t over night. Then the mixture was concentrated and purified by column chromatography (SiO.sub.2/PE/EA 2:1=1:1) to give the the compound. 45.0 mg (72.2%).

(349) 1H NMR (400 MHz, CDCl3) 8.78 (s, 1H), 8.46 (d, J=2.7 Hz, 1H), 7.98-7.94 (m, 1H), 7.91 (s, 1H), 7.62 (d, J=2.1 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.34 (dd, J=8.4, 2.1 Hz, 1H), 6.15 (d, J=5.6 Hz, 1H), 6.10 (dd, J=11.4, 5.6 Hz, 1H), 5.62 (d, J=2.2 Hz, 1H), 5.23 (dd, J=11.4, 3.1 Hz, 1H), 4.84 (t, J=6.3 Hz, 1H), 4.12 (ddd, J=19.1, 11.6, 6.4 Hz, 2H), 2.08 (s, 3H), 2.01 (s, 3H), 1.98 (s, 3H).

i21) 5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

2-(3,4-dichlorophenyl)ethynyl-trimethyl-silane

(350) ##STR00112##

(351) To a solution of 4-bromo-1,2-dichloro-benzene (500 mg, 2.21 mmol) in CH.sub.3CN (5 mL) was added CuI (126 mg, 0.66 mmol), DIPEA (2.0 mL), Pd(PPh.sub.3).sub.2Cl.sub.2 (155 mg, 0.22 mmol), ethynyl(trimethyl)silane (435, 4.43 mmol). The mixture was heated under N.sub.2 at 50 C. for 20 h. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=10/1) to give the title compound (130 mg, 24.1%).

(352) m/z calcd for [C.sub.11H.sub.12Cl.sub.2Si] [M]: 242.0; found: 242.0; [M15]: 227.0; found: 227.0.

5-Chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4-dichlorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(353) ##STR00113##

(354) To a solution of 5-chloro-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (50 mg, 0.11 mmol) in CH.sub.3CN (5 mL) was added 2-(3,4-dichlorophenyl)ethynyl-trimethyl-silane(130 mg, 0.53 mmol), CuI (6 mg, 0.03 mmol), CsF (33 mg, 0.22 mmol), DIEA (0.1 mL). The reaction vessel was purged 3 times with nitrogen. The reaction was concentrated to dryness. The crude product was purified by flash chromatography (EA:PE=1:10 to 1:2, ISCO 12 g, 25 ml/min, normal phase silica, uv254) to give the title compound (50 mg, 73%).

(355) m/z calcd for [C.sub.25H.sub.23Cl.sub.3N.sub.4O.sub.7S].sup. [M+H].sup.+: 629.0; found: 629.0.

(356) 1H NMR (400 MHz, CDCl3) 8.58 (d, J=1.9 Hz, 1H), 8.53 (d, J=2.2 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.88 (t, J=2.1 Hz, 1H), 7.82 (s, 1H), 7.64 (dd, J=8.3, 2.0 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 6.15 (d, J=5.6 Hz, 1H), 6.10 (dd, J=11.4, 5.6 Hz, 1H), 5.63 (d, J=2.1 Hz, 1H), 5.23 (dd, J=11.4, 3.1 Hz, 1H), 4.89-4.84 (m, 1H), 4.21-4.05 (m, 2H), 2.07 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H).

i22) 3,4-Dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(5-chloro-3-pyridyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

3-Chloro-5-((trimethylsilyl)ethynyl)pyridine

(357) ##STR00114##

(358) To a solution of 3-bromo-5-chloropyridine (0.5 g, 2.60 mmol), Copper(I)Iodide (74.2 mg, 0.390 mmol), and Bis(Triphenylphosphine)palladium (II) chloride (284 mg, 0.39 mmol) in Diisopropylamine (15 mL) was added ethynyl(trimethyl)silane (383 mg, 3.90 mmol). The mixture was stirred at 80 C. overnight under nitrogen atmosphere. The solvents were removed under reduced pressure and the residue was purified by column chromatography with hexane as the mobile-phase to give the title compound 230 mg (42.2%).

(359) 1H NMR (400 MHz, CDCl3) 8.48 (d, J=1.7 Hz, 1H), 8.42 (d, J=2.3 Hz, 1H), 7.68-7.66 (m, 1H), 0.19 (s, 9H).

3,4-Dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(5-chloro-3-pyridyl)-1H-1,2,3-triazol-1-yl]-1-thio--D-galactopyranoside

(360) ##STR00115##

(361) 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio--D-galactopyranoside (50 mg, 0.102 mmol) and 2-(5-chloro-3-pyridyl)ethynyl-trimethyl-silane (85 mg, 0.44 mmol) were dissolved in CH.sub.3CN (5 ml). Then CsF (30.9 mg, 0.203 mmol), and DIEA (0.174 ml, 1.02 mmol) were added. The mixture was stirred at rt for 5 min. Copper(I)Iodide (5.80 mg, 0.0305 mmol) was added. The mixture was stirred at rt over night. Then the mixture was concentrated and purified by column chromatography (SiO.sub.2/PE/EA 2:1=1:1) to give the title compound. 45.0 mg (70.3%).

(362) 1H NMR (400 MHz, CDCl3) 8.77 (d, J=1.8 Hz, 1H), 8.48 (d, J=2.3 Hz, 1H), 8.15 (t, J=2.1 Hz, 1H), 7.84 (s, 1H), 7.55 (d, J=2.1 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.27 (dd, J=8.4, 2.1 Hz, 1H), 6.08 (d, J=5.6 Hz, 1H), 6.03 (dd, J=11.4, 5.6 Hz, 1H), 5.55 (d, J=2.1 Hz, 1H), 5.16 (dd, J=11.4, 3.1 Hz, 1H), 4.77 (t, J=6.3 Hz, 1H), 4.14-3.94 (m, 2H), 2.01 (s, 3H), 1.94 (s, 3H), 1.91 (s, 3H).

REFERENCES

(363) Aits S, Kricker J, Liu B, Ellegaard A M, Hmlist S, Tvingsholm S, Corcelle-Termeau E, Hgh S, Farkas T, Holm Jonassen A, Gromova I, Mortensen M, Jttel M. (2015) Sensitive detection of lysosomal membrane permeabilization by lysosomal galectin puncta assay Autophagy. 2015; 11(8):1408-24. Almkvist, J., Fldt, J., Dahlgren, C., Leffler, H., and Karlsson, A. (2001) Lipopolysaccharide-induced gelatinase granule mobilization primes neutrophils for activation by galectin-3 and f-Met-Leu-Phe. Infect. Immun. Vol. 69: 832-837. Arthur C M, Baruffi M D, Cummings R D, Stowell S R. (2015) Evolving mechanistic insights into galectin functions. Methods Mol Biol. 1207:1-35. Blanchard H, Yu X, Collins P M, Burn-Erdene K. (2014) Galectin-3 inhibitors: a patent review (2008-present). Expert Opin Ther Pat. 2014 October; 24(10):1053-65. Blidner A G, Mndez-Huergo S P, Cagnoni A J, Rabinovich G A. (2015) Re-wiring regulatory cell networks in immunity by galectin-glycan interactions. FEBS Lett. 2015 Sep. 6. pii: S0014-5793(15)00807-8. Chen, W.-S., Leffler H., Nilsson, U. J., Panjwani, N. (2012). Targeting Galectin-1 and Galectin-3 Attenuates VEGF-A-induced Angiogenesis; Mol. Biol. Cell (suppl), Abstract No. 2695. Clare D K, Magescas J, Piolot T, Dumoux M, Vesque C, Pichard E, Dang T, Duvauchelle B, Poirier F, Delacour D. (2014) Basal foot MTOC organizes pillar MTs required for coordination of beating cilia. Nat Commun. 5:4888. Cumpstey, I., Carlsson, S., Leffler, H. and Nilsson, U. J. (2005) Synthesis of a phenyl thio--D-galactopyranoside library from 1,5-difluoro-2,4-dinitrobenzene: discovery of efficient and selective monosaccharide inhibitors of galectin-7. Org. Biomol. Chem. 3: 1922-1932. Cumpstey, I., Sundin, A., Leffler, H. and Nilsson, U. J. (2005) C.sub.2-Symmetrical thiodigalactoside bis-benzamido derivatives as high-affinity inhibitors of galectin-3: Efficient lectin inhibition through double arginine-arene interactions. Angew. Chem. Int. Ed. 44: 5110-5112. Cumpstey, I., Salomonsson, E., Sundin, A., Leffler, H. and Nilsson, U. J. (2008) Double affinity amplification of galectin-ligand interactions through arginine-arene interactions: Synthetic, thermodynamic, and computational studies with aromatic diamido-thiodigalactosides. Chem. Eur. J. 14: 4233-4245. Delaine, T., Cumpstey, I., Ingrassia, L., Le Mercier, M., Okechukwu, P., Leffler, H., Kiss, R., and Nilsson, U. J. (2008). Galectin-Inhibitory Thiodigalactoside Ester Derivatives Have Anti-Migratory Effects in Cultured Lung and Prostate Cancer Cells. J Med Chem 51; 8109-8114. Demotte, N., Wieers, G., van der Smissen, P., Moser, M., Schmidt, C., Thielemans, K., et al., (2010). Cancer Res. 70; 7476-7488. Ebrahim A H, Alalawi Z, Mirandola L, Rakhshanda R, Dahlbeck S, Nguyen D, Jenkins M1, Grizzi F, Cobos E, Figueroa J A, Chiriva-Internati M (2014) Galectins in cancer: carcinogenesis, diagnosis and therapy. Ann Transl Med. 2014 September; 2(9):88. Elola M T, Blidner A G, Ferragut F, Bracalente C, Rabinovich G A. (2015) Assembly, organization and regulation of cell-surface receptors by lectin-glycan complexes. Biochem J. 2015 Jul. 1; 469(1):1-16. Farkas, I.; Szab, I. F.; Bognar, R.; Anderle, D. Carbohydr. Res. 1976, 48, 136-138. Funasaka T, Raz A, Nangia-Makker P. (2014) Nuclear transport of galectin-3 and its therapeutic implications. Semin Cancer Biol. 2014 August; 27:30-8. Gigure, D.; Bonin, M.-A.; Cloutier, P.; Patnam, R.; St-Pierre, C.; Sato, S.; Roy, R. Bioorganic & Medicinal Chemistry 2008, 16, 7811-7823. Gigure, D.; Andr, S.; Bonin, M.-A.; Bellefleur, M.-A.; Provencal, A.; Cloutier, P.; Pucci, B.; Roy, R.; Gabius, H.-J. Bioorganic & Medicinal Chemistry 2011, 19, 3280-3287 Giguere, D., Patnam, R., Bellefleur, M.-A., St.-Pierre, C., Sato, S., and Roy, R. (2006). Carbohydrate triazoles and isoxazoles as inhibitors of galectins-1 and -3. Chem Commun: 2379-2381. Glinsky, G. V., Price, J. E., Glinsky, V. V., Mossine, V. V., Kiriakova, G., and Metcalf, J. B. (1996). Cancer Res 56: 5319-5324. Synthetic Galectin-3 Inhibitor Increases Metastatic Cancer Cell Sensitivity to Taxol-Induced Apoptosis In Vitro and In Vivo. Neoplasia 11; 901-909. Huflejt, M. E. and Leffler, H. (2004) Galectin-4 in normal tissues and cancer. Glycoconj. J. 20: 247-255. Ingrassia et al. (2006) A Lactosylated Steroid Contributes in Vivo Therapeutic Benefits in Experimental Models of Mouse Lymphoma and Human Glioblastoma. J. Med. CHem. 49: 1800-1807. John, C. M., Leffler, H., Kahl-Knutsson, B., Svensson, I., and Jarvis, G. A. (2003) Truncated Galectin-3 Inhibits Tumor Growth and Metastasis in Orthotopic Nude Mouse Model of Human Breast Cancer. Clin. Cancer Res. 9: 2374-2383. Kouo, T., Huang, L., Pucsek, A. B., Cao, M., Solt, S., Armstrong, T., Jaffee, E. (2015) Cancer Immonol. Res. 3: 412-23 Leffler, H. and Barondes, S. H. (1986) Specificity of binding of three soluble rat lung lectins to substituted and unsubstituted mammalian beta-galactosides. J. Biol. Chem. 261:10119-10126. Leffler, H. Galectins Structure and FunctionA Synopsis in Mammalian Carbohydrate Recognition Systems (Crocker, P. ed.) Springer Verlag, Heidelberg, 2001 pp. 57-83. Leffler, H., Carlsson, S., Hedlund, M., Qian, Y. and Poirier, F. (2004) Introduction to galectins. Glycoconj. J. 19: 433-440. Lepur A, Salomonsson E, Nilsson U J, Leffler H. (2012) Ligand induced galectin-3 protein self-association. J Biol Chem. 2012 Jun. 22; 287(26):21751-6. Li L C, Li J, Gao J. (2014) Functions of galectin-3 and its role in fibrotic diseases. J Pharmacol Exp Ther. 2014 November; 351(2):336-43. MacKinnon, A. C., Farnworth, S. L., Henderson, N. C., Hodkinson, P. S., Kipari, T., Leffler, H., Nilsson, U. J., Haslett, C., Hughes, J., and Sethi T. (2008). Regulation of alternative macrophage activation by Galectin-3. J. Immun. 180; 2650-2658. Mackinnon, A., Gibbons, M., Farnworth, S., Leffler, H., Nilsson, U. J., Delaine, T., Simpson, A., Forbes, S., Hirani, N., Gauldie, J., and Sethi T. (2012). Regulation of TGF-1 driven lung fibrosis by Galectin-3. Am. J. Resp. Crit. Care Med., in press. Massa, S. M., Cooper, D. N. W., Leffler, H., Barondes, S. H. (1993) L-29, an endogenous lectin, binds to glycoconjugate ligands with positive cooperativity. Biochemistry 32: 260-267. Melero, I., Berman, D. M., Aznar, M. A., Korman, A. J., Gracia, J. L. P., Haanen, J. (2015) Nature Reviews Cancer, 15: 457-472 Partridge, E. A., Le Roy, C., Di Guglielmo, G. M., Pawling, J., Cheung, P., Granovsky, M., Nabi, I. R., Wrana, J. L., and Dennis, J. W. (2004). Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis. Science 306: 120-124. Pienta, K. J., Naik, H., Akhtar, A., Yamazaki, K., Reploge, T. S., Lehr, J., Donat, T. L., Tait, L., Hogan, V., and Raz, A. (1995). Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. J Natl Cancer Inst 87, 348-353. Ramos-Soriano, J.; Niss, U.; Angulo, J.; Angulo, M.; Moreno-Vargas, A. J.; Carmona, A. T.; Ohlson, S.; Robina, I. Chem. Eur. J. 2013, 19, 17989-18003. Ruvolo, P. P. Biochim. Biophys Acta. Molecular cell research (2015) E-pub ahead of print, title: Galectin-3 as a guardian of the tumor microenvironment, published on-line 8 Apr. 2015: [http://www.sciencedirect.com/science/article/pii/S0167488915002700], Salameh, B. A., Leffler, H. and Nilsson, U. J. (2005) Bioorg. Med. Chem. Lett. 15: 3344-3346. Salameh, B. A., Cumpstey, I., Sundin, A., Leffler, H., and Nilsson, U. J. (2010). 1H-1,2,3-Triazol-1-yl thiodigalactoside derivatives as high affinity galectin-3 inhibitors. Bioorg Med Chem 18: 5367-5378. Salomonsson, E., Larumbe, A., Tejler, J., Tullberg, E., Rydberg, H., Sundin, A., Khabut, A., Frejd, T., Lobsanov, Y. D., Rini, J. M., Nilsson, U. J., and Leffler, H (2010). Monovalent interactions of galectin-1. Biochemistry 49: 9518-9532. Srme, P., Qian, Y., Nyholm, P.-G., Leffler, H., Nilsson, U. J. (2002) Low micromolar inhibitors of galectin-3 based on 3-derivatization of N-acetyllactosamine. ChemBioChem 3:183-189. Srme, P., Kahl-Knutsson, B., Wellmar, U., Nilsson, U. J., and Leffler H. (2003a) Fluorescence polarization to study galectin-ligand interactions. Meth. Enzymol. 362: 504-512. Srme, P., Kahl-Knutsson, B., Wellmar, U., Magnusson, B.-G., Lefflcr H., and Nilsson, U. J. (2003b) Design and synthesis of galectin inhibitors. Meth. Enzymol. 363: 157-169. Srme, P., Kahl-Knutsson, B., Huflejt, M., Nilsson, U. J., and Leffler H. (2004) Fluorescence polarization as an analytical tool to evaluate galectin-ligand interactions. Anal. Biochem. 334: 36-47. Thijssen V L, Heusschen R, Caers J, Griffloen A W. (2015) Galectin expression in cancer diagnosis and prognosis: A systematic review. Biochim Biophys Acta. 2015 April; 1855(2):235-47. Toscano, M. A., Bianco, G. A., Ilarregui, J. M., Croci, D. O., Correale, J., Hernandez, J. D., Zwirner, N. W., Poirier, F., Riley, E. M., Baum, L. G., et al. (2007). Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death. Nat Immunol 8: 825-834. Viguier M, Advedissian T, Delacour D, Poirier F, Deshayes F. (2014) Galectins in epithelial functions. Tissue Barriers. 2014 May 6; 2:e29103.