NOVEL GALACTOSIDE INHIBITOR OF GALECTINS

Abstract

A D-galactopyranose compound of formula (1)

##STR00001## wherein the pyranose ring is α-D-galactopyranose, and these compounds are high affinity galectin-3 inhibitors. Also, pharmaceutical compositions including these compounds. Further, a method for treatment of a disorder relating to the binding of a galectin-3 to a ligand, such as inflammation, in a mammal, such as a human, wherein a therapeutically effective amount of at least one of these compounds is administered to a mammal in need of the treatment.

Claims

1.-19. (canceled)

20. A D-galactopyranose compound of formula (1) ##STR00205## wherein the pyranose ring is α-D-galactopyranose, A.sup.1 is R.sup.1—Z, Wherein Z is a five membered heterocycle having at least one heteroatom selected from O, S, and N, except 1,2,3-triazole and is attached to the α-D-galactopyranose; R.sup.1 is selected from a) an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.6aR.sup.7a, wherein R.sup.6a and R.sup.7a are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl, or R.sup.6a and R.sup.7a together with the nitrogen may form a heterocycloalkyl; 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.8aR.sup.9a, wherein R.sup.8a and R.sup.9a are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.10a—CONH— wherein R.sup.10a is selected from C.sub.1-3 alkyl and cyclopropyl; b) a heterocycle, such as heteroaryl or heterocycloalkyl, optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; —COOH; —CONR.sup.12aR.sup.13a, wherein R.sup.12a and R.sup.13a 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.14aR.sup.15a, wherein R.sup.14a and R.sup.15a are independently selected from H, C.sub.1-3 alkyl, cyclopropyl and isopropyl, C(═O)—R.sup.21a, wherein R.sup.21a is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16a—CONH— wherein R.sup.16a is selected from C.sub.1-3 alkyl and cyclopropyl; X is selected from S, SO, SO.sub.2, O, C═O, and CR.sup.2bR.sup.3b wherein R.sup.2b and R.sup.3b are independently selected from hydrogen, OH, or halogen; 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.4b—CONH— wherein R.sup.4b 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.5b—CONH— wherein R.sup.5b 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; a spiro heterocycle, such as N-(2-oxa)-6-azaspiro[3.3]heptanyl; C.sub.2-alkynyl; —COOH; —CONR.sup.6bR.sup.7b, wherein R.sup.6b and R.sup.7b are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl, or R.sup.6b and R.sup.7b together with the nitrogen may form a heterocycloalkyl; 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.8bR.sup.9b, wherein R.sup.8b and R.sup.9b are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; a heterocycle optionally substituted with a C.sub.1-3 alkyl optionally substituted with a OH; and R.sup.10b—CONH— wherein R.sup.10b 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, C.sub.2-alkynyl, 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.11b—CONH— wherein R.sup.11b 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; a spiro heterocycle, such as N-(2-oxa)-6-azaspiro[3.3]heptanyl; C.sub.2-alkynyl; CN; —COOH; —CONR.sup.12bR.sup.13b, wherein R.sup.12b and R.sup.13b 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.14bR.sup.15b, wherein R.sup.14b and R.sup.15b are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; a heterocycle optionally substituted with a C.sub.1-3 alkyl optionally substituted with a OH; and R.sup.16b—CONH— wherein R.sup.16b is selected from C.sub.1-3 alkyl and cyclopropyl; e) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl; f) C.sub.2-6 alkynyl; R.sup.50 is selected from the group consisting of a) H, b) OH, c) OC.sub.1-6 alkyl optionally substituted with one or more halogen, phenyl, phenyl substituted with one or more groups selected form OH and halogen, CN, OR.sup.17b, NR.sup.18bR.sup.19b, and CONH.sub.2, wherein R.sup.17b is selected from the group consisting of H, 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.20b—CONH— wherein R.sup.20b is selected from C.sub.1-3 alkyl and cyclopropyl, R.sup.18b is selected from the group consisting of H, 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.21b—CONH— wherein R.sup.21b is selected from C.sub.1-3 alkyl and cyclopropyl, and R.sup.19b is selected from the group consisting of H, 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.22b—CONH— wherein R.sup.22b is selected from C.sub.1-3 alkyl and cyclopropyl, d) branched OC.sub.3-6 alkyl optionally substituted with one or more halogen, CN, OR.sup.23b, NR.sup.24bR.sup.25b, and CONH.sub.2, wherein R.sup.23b is selected from the group consisting of H, 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.26b—CONH— wherein R.sup.26b is selected from C.sub.1-3 alkyl and cyclopropyl, R.sup.24b is selected from the group consisting of H, 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.27b—CONH— wherein R.sup.27b is selected from C.sub.1-3 alkyl and cyclopropyl, and R.sup.25b is selected from the group consisting of H, 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.28—CONH— wherein R.sup.28 is selected from C.sub.1-3 alkyl and cyclopropyl, and e) cyclic OC.sub.3-6 alkyl optionally substituted with one or more halogen, CN, OR.sup.29, NR.sup.30R.sup.31, and CONH.sub.2, wherein R.sup.29 is selected from the group consisting of H, 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.32—CONH— wherein R.sup.32 is selected from C.sub.1-3 alkyl and cyclopropyl, R.sup.30 is selected from the group consisting of H, 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.33—CONH— wherein R.sup.33 is selected from C.sub.1-3 alkyl and cyclopropyl, and R.sup.31 is selected from the group consisting of H, 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.34—CONH— wherein R.sup.34 is selected from C.sub.1-3 alkyl and cyclopropyl; or a pharmaceutically acceptable salt or solvate thereof.

21. The compound of claim 20 wherein Z is selected from 1,2,4-triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, dioxolyl, dithiolyl, thiazolyl, isothiazolyl, furanyl, thiophen, pyrrolyl, imidazolyl, or pyrazolyl.

22. The compound of claim 20 wherein Z is ##STR00206## wherein the asterix on the carbon is linked to R.sup.1 and the Asterix on the nitrogen is attached to the α-D-galactopyranose.

23. The compound of claim 20 wherein R.sup.1 is phenyl optionally substituted with a group selected from CN, OH, NH.sub.2, F, Br, Cl, I, methyl optionally substituted with a fluorine (F), and OCH.sub.3 optionally substituted with a F, and SCH.sub.3 optionally substituted with a F.

24. The compound of claim 20 wherein R.sup.1 is selected from a five or six membered heteroaromatic ring, optionally substituted with a group selected from Br; F; Cl; I; OH; CN; NR.sup.14aR.sup.15a, wherein R.sup.14a and R.sup.15a are independently selected from H, C.sub.1-3 alkyl, cyclopropyl and isopropyl, C(═O)—R.sup.21a, wherein R.sup.21a is selected from H and C.sub.1-3 alkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; iso-propyl, optionally substituted with a F; O-cyclopropyl optionally substituted with a F; O-isopropyl optionally substituted with a F; OC.sub.1-3 alkyl optionally substituted with a F; and SC.sub.1-3 alkyl optionally substituted with a F.

25. The compound of claim 24 wherein R.sup.1 is a pyridinyl, optionally substituted with a group selected from OH, NH.sub.2, 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.

26. The compound of claim 20 wherein R.sup.1 is a five or six membered heteroaromatic ring selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, and formulas 2 to 9, wherein the asterix * indicates the carbon atom of the heteroaromatic ring that is covalently attached to the Z substituent: ##STR00207## wherein R.sup.2 to R.sup.23 and R.sup.27 are independently selected from H; halogen; OH; CN; SH; S—C.sub.1-3 alkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; iso-propyl, optionally substituted with a F; O-cyclopropyl optionally substituted with a F; O-isopropyl optionally substituted with a F; OC.sub.1-3 alkyl optionally substituted with a F; NR.sup.24R.sup.25, wherein R.sup.24 is selected from H, and C.sub.1-3 alkyl, and R.sup.25 is selected from H, C.sub.1-3 alkyl, and COR.sup.26, wherein R.sup.26 is selected from H, and C.sub.1-3 alkyl.

27. The compound of claim 26 wherein R.sup.1 is selected from the group consisting of ##STR00208## wherein R.sup.2 is selected from the group consisting of OH, methyl and halogen, preferably F, Cl and Br; R.sup.3 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen; R.sup.4 is selected from the group consisting of OH, NH.sub.2 and halogen, preferably F, Cl, and Br; R.sup.5 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen.

28. The compound of claim 20 wherein X is selected from S, SO, SO.sub.2, and O.

29. The compound of claim 20 wherein B1 is selected from a heteroaryl, optionally substituted with a group selected from a halogen; CN; ethynyl; methyl optionally substituted with a F; and a heterocycle optionally substituted with a C.sub.1-3 alkyl optionally substituted with a OH.

30. The compound of claim 29 wherein B1 is selected from a pyridinyl, optionally substituted with a group selected from a Cl, Br, CN, methyl, CF.sub.3, azetidinyl; azetidinyl substituted with a CH.sub.2OH; pyridinyl, pyrimidinyl, oxazolyl, and thiazolyl.

31. The compound of claim 20 wherein B1 is selected from a phenyl, optionally substituted with a group selected from a halogen, CN, C.sub.1-3 alkyl, optionally substituted with a F, and CONR.sup.6bR.sup.7b, wherein R.sup.6b and R.sup.7b are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl, or R.sup.6b and R.sup.7b together with the nitrogen may form a heterocycloalkyl.

32. The compound of claim 20 wherein R.sup.50 is selected from H, OH, OC.sub.1-6 alkyl, C.sub.1-4 alkyl, C.sub.1-4 alkyl substituted with at least one from the group consisting of phenyl and phenyl substituted with one or more groups selected form OH and halogen.

33. The compound of claim 20 selected from the group consisting of: 3-Chlorophenyl 3-deoxy-3-[4-(3-fluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Ethynylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyanophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 2-(N-Azetidinyl-carbonyl)-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 2-(N-Azetidinyl-carbonyl)-5-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyanopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Chloro-2-methylpyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Bromo-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 2-Cyano-5-ethynylpyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(6-fluoropyridin-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(5-fluoropyridin-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(4-fluoropyridin-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(1H-1,2-pyrazol-3-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(1-methyl-1,2-pyrazol-3-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(1H-imidazol-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(oxazol-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(thiazol-4-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(thiazol-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyanophenyl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyanopyridin-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Ethynylpyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,3-imidazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-[3,3-bis(hydroxymethyl)azetidin-1-yl]pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[3-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-oxazol-2-yl]-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-thiazol-2-yl]-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-deoxy-3-[5-(3,4,5-trifluorophenyl)-1,3,4-oxadiazol-2-yl]-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyanophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, and 5-Chloro-2-cyanophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside; or a pharmaceutically salt or solvate thereof.

34. A pharmaceutical composition comprising the compound of claim 20 and optionally a pharmaceutically acceptable additive.

35. 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 20 is administered to a mammal in need of said treatment.

36. The method of claim 35, wherein said disorder is selected from the group consisting of inflammation; Inflammation induced thrombosis; Atopic dermatitis; Acute coronary syndrome; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart; local fibrosis such as Dupuytren's disease and Peyronie's disease; fibrotic complications of other therapies such as coronary stents, bile duct stents, cerebral artery stents, ureter stents; scleroderma; scarring; keloid formation; covid-19; acute lung injury; ARDS; viral pneumonitis, aberrant scar formation; surgical adhesions; septic shock; cancer, such as colorectal cancer, other gastrointestinal carcinomas such as pancreatic cancer, gastric cancer, biliary tract cancer, lung cancers, mesothelioma, female cancers like breast cancer, ovarian cancer, uterine cancer, cancer of the cervix uteri, cancer of the salpingx, cerebral cancers such as medulloblastomao, glioma, meningioma, sarcomas of the bones and muscles and other sarcomas, leukemias and lymphomas, such as T-cell lymphomas; transplant rejection; metastasising cancers; ageing; Dementia; Alzheimers; TGFbeta driven bone disease such as osteogenesis imperfecta; Pulmonary hypertension; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Rheumatoid lung; Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; viral infections such as influenza virus, HIV, Herpes virus, Coronaviruses, Hepatitis C; 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; diabetes; type I diabetes; type 2 diabetes; insulin resistens; obesity; Marfans syndrome; Loeys-Dietz syndrome; nephropathy; Diastolic HF; fibrotic lung complications of aPD1 and other CPI therapies; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, liver disorders, such as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease; uterine disease such as uterine fibroids and uterine or cervical fibrosis.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0184] The present compounds of formula (1) differ from prior art compounds particularly in that the pyranose ring is α-D-galactopyranose. It is important to emphasize that alpha and beta anomers are very different isomers and it is by no means considered to be obvious to the skilled person to expect same or similar activity of both anomers. Consequently, alpha and beta anomers do not in general posses the same activity, and this is common knowledge to the skilled person. The compounds of the present invention are novel α-D-galactopyranose compounds that unexpectedly have shown very high affinity and specificity for galectin-3 and are considered novel potent drug candidates. Some of the novel α-D-galactopyranose compounds have galectin-1 affinity and some both galectin-1 and galectin-3 affinity and, as such have a broader disease treatment profile compared to selective galectin-1 inhibitors.

[0185] In broad aspect the present invention concerns a D-galactopyranose compound of formula (1)

##STR00039##

wherein
the pyranose ring is α-D-galactopyranose, and A1, X, R.sup.50 and B1 are as defined above.

[0186] Preferably X is S.

[0187] Typically, Z is a pyrazolyl, preferably

##STR00040##

wherein the asterix on the carbon is linked to R.sup.1 and the Asterix on the nitrogen is attached to the α-D-galactopyranose and X is S.

[0188] In another embodiment Z is selected from the group consisting of imidazole, such as 1,3-imidazol-2-yl; oxazolyl, such as oxazol-2-yl; oxadiazolyl; thiazolyl, such as thiazol-2-yl.

[0189] In one preferred embodiment R.sup.1 is phenyl optionally substituted with a group selected from CN, OH, NH.sub.2, F, Br, Cl, I, methyl optionally substituted with a fluorine (F), and OCH.sub.3 optionally substituted with a F, and SCH.sub.3 optionally substituted with a F. Typically, R.sup.1 is phenyl substituted with one to three groups selected from F, Br, Cl, I, methyl.

[0190] In another preferred embodiment R.sup.1 is

##STR00041##

[0191] wherein R.sup.2 is selected from the group consisting of OH, methyl and halogen, such as F, Cl and Br;

[0192] R.sup.3 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, such as methyl, and halogen. In one embodiment R.sup.2 is halogen, such as Cl and R.sup.3 is H.

[0193] In further preferred embodiment R.sup.1 is

##STR00042##

[0194] wherein

[0195] R.sup.4 is selected from the group consisting of OH, NH.sub.2 and halogen, such as F, Cl, and Br;

[0196] R.sup.5 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, such as methyl, and halogen. In one embodiment R.sup.4 is H or OH and R.sup.5 is H.

[0197] In further preferred embodiment R.sup.1 is imidazolyl. In another preferred embodiment R.sup.1 is oxadzolyl. In further preferred embodiment R.sup.1 is pyrazolyl, optionally substituted with a C.sub.1-3 alkyl, e.g. methyl. In a preferred embodiment B1 is a pyridinyl substituted with a group selected from a Cl; Br; C.sub.2-alkynyl; CN; methyl; CF.sub.3; pyridin; pyrimidin; oxazol; and thiazol.

[0198] In a further embodiment B1 is a pyridinyl substituted with a group selected from a Cl; Br; ethynyl; CN; methyl. In a still further embodiment B1 is a pyridinyl substituted with one or two selected from Cl; Br; ethynyl; CN; and methyl.

[0199] In a still further embodiment B1 is a phenyl substituted with a group selected from a halogen; and C.sub.1-3 alkyl, optionally substituted with a F.

[0200] In a further embodiment B1 is a phenyl substituted with a group selected from the group consisting of Cl, CN, and CONR.sup.6bR.sup.7b, wherein R.sup.6b and R.sup.7b together with the nitrogen may form a heterocycloalkyl. In a still further embodiment B1 is a phenyl substituted with one or two of Cl, CN, and CO-azetidinyl.

[0201] In a further embodiment R.sup.50 is selected from H, OH, C.sub.1-4 alkyl, such as methyl, ethyl, or isopropyl, C.sub.1-4 alkyl substituted with at least one from the group consisting of phenyl and phenyl substituted with one or more groups selected form OH and halogen.

[0202] In one embodiment R.sup.50 is OH. In another embodiment R.sup.50 is methoxy.

[0203] In a further embodiment the compound of formula (1) is selected from any one of: [0204] 3-Chlorophenyl 3-deoxy-3-[4-(3-fluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0205] 5-Chloropyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0206] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, and [0207] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside.

[0208] In a still further embodiment the compound of formula (1) is selected from any one of: [0209] 3-Chlorophenyl 3-deoxy-3-[4-(3-fluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0210] 5-Chloropyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0211] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0212] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0213] 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0214] 5-Bromopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0215] 5-Ethynylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0216] 5-Chloro-2-cyanophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0217] 2-(N-Azetidinyl-carbonyl)-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0218] 2-(N-Azetidinyl-carbonyl)-5-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0219] 5-Chloro-2-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0220] 5-Chloro-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0221] 5-Chloro-2-cyanopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0222] 5-Chloro-2-methylpyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0223] 5-Bromo-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0224] 2-Cyano-5-ethynylpyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0225] 5-Chloropyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0226] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(6-fluoropyridin-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0227] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(5-fluoropyridin-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0228] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(4-fluoropyridin-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0229] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(1H-1,2-pyrazol-3-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0230] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(1-methyl-1,2-pyrazol-3-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0231] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(1H-imidazol-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0232] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(oxazol-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0233] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(thiazol-4-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0234] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(thiazol-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0235] 5-Chloropyridin-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0236] 5-Bromopyridin-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0237] 5-Chloro-2-cyanophenyl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0238] 5-Chloro-2-cyanopyridin-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0239] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0240] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, [0241] 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, [0242] 5-Ethynylpyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, [0243] 5-Chloro-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, [0244] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,3-imidazol-1-yl]-1-thio-α-D-galactopyranoside, [0245] 5-Chloro-[3,3-bis(hydroxymethyl)azetidin-1-yl]pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0246] 5-Chloropyridin-3-yl 3-deoxy-3-[3-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0247] 5-Bromo-2-cyanopyridin-3-yl 3-[5-(4-chlorothiazol-2-yl)-1-methyl-1H-1,2-pyrazol-3-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0248] 3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-oxazol-2-yl]-1-thio-α-D-galactopyranoside, [0249] 3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-thiazol-2-yl]-1-thio-α-D-galactopyranoside, [0250] 3,4-Dichlorophenyl 3-deoxy-3-[5-(3,4,5-trifluorophenyl)-1,3,4-oxadiazol-2-yl]-1-thio-α-D-galactopyranoside, [0251] 3,4-Dichlorophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, [0252] 5-Chloro-2-cyanophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, [0253] 5-Chloro-2-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, and [0254] 5-Chloro-2-cyanophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside.

[0255] In a still further embodiment the compound of formula (1) is selected from any one of: [0256] 3-Chlorophenyl 3-deoxy-3-[4-(3-fluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0257] 5-Chloropyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0258] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0259] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0260] 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0261] 5-Bromopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0262] 5-Ethynylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0263] 5-Chloro-2-cyanophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0264] 2-(N-Azetidinyl-carbonyl)-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0265] 2-(N-Azetidinyl-carbonyl)-5-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0266] 5-Chloro-2-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0267] 5-Chloro-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0268] 5-Chloro-2-cyanopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0269] 5-Chloro-2-methylpyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0270] 5-Bromo-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0271] 2-Cyano-5-ethynylpyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0272] 5-Chloropyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0273] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(6-fluoropyridin-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0274] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(5-fluoropyridin-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0275] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(4-fluoropyridin-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0276] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(1H-1,2-pyrazol-3-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0277] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(1-methyl-1,2-pyrazol-3-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0278] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(1H-imidazol-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0279] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(oxazol-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0280] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(thiazol-4-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0281] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(thiazol-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0282] 5-Chloropyridin-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0283] 5-Bromopyridin-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0284] 5-Chloro-2-cyanophenyl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0285] 5-Chloro-2-cyanopyridin-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, [0286] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0287] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, [0288] 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, [0289] 5-Ethynylpyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, [0290] 5-Chloro-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, [0291] 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,3-imidazol-1-yl]-1-thio-α-D-galactopyranoside, [0292] 5-Chloro-[3,3-bis(hydroxymethyl)azetidin-1-yl]pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0293] 5-Chloropyridin-3-yl 3-deoxy-3-[3-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside, [0294] 3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-oxazol-2-yl]-1-thio-α-D-galactopyranoside, [0295] 3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-thiazol-2-yl]-1-thio-α-D-galactopyranoside, [0296] 3,4-Dichlorophenyl 3-deoxy-3-[5-(3,4,5-trifluorophenyl)-1,3,4-oxadiazol-2-yl]-1-thio-α-D-galactopyranoside, [0297] 3,4-Dichlorophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, [0298] 5-Chloro-2-cyanophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, [0299] 5-Chloro-2-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, and [0300] 5-Chloro-2-cyanophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside.

[0301] As explained in the experimental section some of the prepared compounds of formula 1 wherein Z is pyrazol, X is S, R.sup.1 is as defined above, R.sup.51 is a selection of R.sup.50 as defined above, and B1 is as defined above have high oral bioavailability and good CNS potential as evidenced by the data in the experimental section below.

[0302] In a particular aspect the present invention relates to a compound of formula 1A

##STR00043##

wherein

[0303] the pyranose ring is α-D-galactopyranose,

[0304] R.sup.1 is selected from a) an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.6aR.sup.7a, wherein R.sup.6a and R.sup.7a are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl, or R.sup.6a and R.sup.7a together with the nitrogen may form a heterocycloalkyl; 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.8aR.sup.9a, wherein R.sup.8a and R.sup.9a are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.10a—CONH— wherein R.sup.10a is selected from C.sub.1-3 alkyl and cyclopropyl; b) a heterocycle, such as heteroaryl or heterocycloalkyl, optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; —COOH; —CONR.sup.12aR.sup.13a wherein R.sup.12a and R.sup.13a 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.14aR.sup.15a, wherein R.sup.14a and R.sup.15a are independently selected from H, C.sub.1-3 alkyl, cyclopropyl and isopropyl, C(═O)—R.sup.21a, wherein R.sup.21a is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16a—CONH— wherein R.sup.16a is selected from C.sub.1-3 alkyl and cyclopropyl;

[0305] 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.4b—CONH— wherein R.sup.4b 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.5b—CONH— wherein R.sup.5b 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; C.sub.2-alkynyl; —COOH; —CONR.sup.6bR.sup.7b, wherein R.sup.6b and R.sup.7b are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl, or R.sup.6b and R.sup.7b together with the nitrogen may form a heterocycloalkyl; 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.8bR.sup.9b, wherein R.sup.8b and R.sup.9b are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; a heterocycle optionally substituted with a C.sub.1-3 alkyl optionally substituted with a OH; and R.sup.19b—CONH— wherein R.sup.19b 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, C.sub.2-alkynyl, 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.11b—CONH— wherein R.sup.11b 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; a spiro heterocycle, such as N-(2-oxa)-6-azaspiro[3.3]heptanyl; C.sub.2-alkynyl; CN; —COOH; —CONR.sup.12bR.sup.13b, wherein R.sup.12b and R.sup.13b 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.14bR.sup.15b, wherein R.sup.14b and R.sup.15b are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; a heterocycle optionally substituted with a C.sub.1-3 alkyl optionally substituted with a OH; and R.sup.16b—CONH— wherein R.sup.16b is selected from C.sub.1-3 alkyl and cyclopropyl; e) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl; f) C.sub.2-6 alkynyl;

[0306] R.sup.51 is selected from the group consisting of a1) OH and, a2) OC.sub.1-6 alkyl optionally substituted with one or more halogen, phenyl, phenyl substituted with one or more groups selected form OH and halogen, CN, OR.sup.17b, NR.sup.18bR.sup.19b, and CONH.sub.2, wherein R.sup.17b is selected from the group consisting of H, 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.29b—CONH— wherein R.sup.29b is selected from C.sub.1-3 alkyl and cyclopropyl, R.sup.18b is selected from the group consisting of H, 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.21b—CONH— wherein R.sup.21b is selected from C.sub.1-3 alkyl and cyclopropyl, and R.sup.19b is selected from the group consisting of H, 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.22b—CONH— wherein R.sup.22b is selected from C.sub.1-3 alkyl and cyclopropyl; or a pharmaceutically acceptable salt or solvate thereof.

[0307] In an embodiment of formula 1A R.sup.1 is selected from an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.6aR.sup.7a, wherein R.sup.6a and R.sup.7a are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl, or R.sup.6a and R.sup.7a together with the nitrogen may form a heterocycloalkyl; 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.8aR.sup.9a, wherein R.sup.8a and R.sup.9a are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.19a—CONH— wherein R.sup.10a is selected from C.sub.1-3 alkyl and cyclopropyl. In a further embodiment of formula 1A R.sup.1 is selected from a phenyl substituted with a group selected from a halogen. Typically, R.sup.1 is selected from a phenyl substituted with two or three halogens, such as Cl or F, preferably in the meta and/or para position on the phenyl. The halogens should not be in the ortho position on the phenyl.

[0308] In an embodiment of formula 1A B.sup.1 is selected from the group consisting of b) an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from a halogen; CN; C.sub.2-alkynyl; —COOH; —CONR.sup.6bR.sup.7b, wherein R.sup.6b and R.sup.7b are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl, or R.sup.6b and R.sup.7b together with the nitrogen may form a heterocycloalkyl; 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.8bR.sup.9b, wherein R.sup.8b and R.sup.9b are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; a heterocycle optionally substituted with a C.sub.1-3 alkyl optionally substituted with a OH; and R.sup.19b—CONH— wherein R.sup.10b 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; a spiro heterocycle, such as N-(2-oxa)-6-azaspiro[3.3]heptanyl; C.sub.2-alkynyl; CN; —COOH; —CONR.sup.12bR.sup.13b, wherein R.sup.12b and R.sup.13b 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.14bR.sup.15b, wherein R.sup.14b and R.sup.15b are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; a heterocycle optionally substituted with a C.sub.1-3 alkyl optionally substituted with a OH; and R.sup.16b—CONH— wherein R.sup.16b is selected from C.sub.1-3 alkyl and cyclopropyl. In a further embodiment of formula 1A B.sup.1 is selected from a phenyl substituted with one or two substituents selected from halogen and CN, such as Cl and CN. Typically, B.sup.1 is selected from a phenyl substituted with two substituents selected from Cl and CN, such as one Cl and one CN. In a still further embodiment of formula 1A B.sup.1 is selected from a pyridyl substituted with one or two substituents selected from one or more of halogen, CN and ethynyl. Typically, B.sup.1 is selected from a pyridyl substituted with one substituents selected from one or more of Br, Cl, CN and ethynyl. In another embodiment B.sup.1 is selected from a pyridyl substituted with two substituents selected from one or more of Br, Cl, CN and ethynyl.

[0309] In an embodiment of formula 1A R.sup.51 is selected from the group consisting of a1) OH and, a2) OC.sub.1-6 alkyl optionally substituted with one or more halogen, phenyl, phenyl substituted with one or more groups selected form OH and halogen, CN, OR.sup.17b, NR.sup.18bR.sup.19b, and CONH.sub.2, wherein R.sup.17b is selected from the group consisting of H, 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.20b—CONH— wherein R.sup.20b is selected from C.sub.1-3 alkyl and cyclopropyl, R.sup.18b is selected from the group consisting of H, 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.21b—CONH— wherein R.sup.21b is selected from C.sub.1-3 alkyl and cyclopropyl, and R.sup.19b is selected from the group consisting of H, 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.22b—CONH— wherein R.sup.22b is selected from C.sub.1-3 alkyl and cyclopropyl. In a further embodiment of formula 1A R.sup.51 is selected from OH and OC.sub.1-4 alkyl. Typically, R.sup.51 is selected from OH and OCH.sub.3.

[0310] The skilled person will understand that it may be necessary to adjust or change the order of steps in the processes a1 to a6, 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.

[0311] 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.

[0312] 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-trimethylsilylethoxycarbony 1 (Teoc). Suitable protecting groups for S include 5-C(═N)NH.sub.2, TIPS.

[0313] The protection and deprotection of functional groups may take place before or after any reaction in the above-mentioned processes.

[0314] 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.

[0315] 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.

[0316] In a further embodiment the compound of formula (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.

[0317] 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.

[0318] 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.

[0319] The term “C.sub.2-alkynyl” as used herein means a —CCH group. Wherein the two carbon atoms are connected with a triple bond.

[0320] 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.

[0321] 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.

[0322] 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.

[0323] The term “Oxo” as used herein means an oxygen atom with double bonds, also indicated as ═O.

[0324] The term “CN” as used herein means a nitril.

[0325] 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, isooxazole, 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.

[0326] 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.

[0327] 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.

[0328] 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.

[0329] 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.

[0330] 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.

[0331] 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.

[0332] 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% by weight of said at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier and from 1 to 99% by weight of a compound as herein disclosed. 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.

[0333] In some embodiments, only one compound as herein disclosed is used for the purposes discussed above.

[0334] In some embodiments, two or more of the compounds as herein disclosed are used in combination for the purposes discussed above.

[0335] 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.

[0336] 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.

[0337] 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.

[0338] 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.

[0339] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0340] 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.

[0341] 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.

[0342] 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 otherwise 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).

[0343] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[0344] 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.

[0345] 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.

[0346] The term “and/or” as used herein is intended to mean both alternatives as well as each of the alternatives individually. For instance, the expression “xxx and/or yyy” means “xxx and yyy”; “xxx”; or “yyy”, all three alternatives are subject to individual embodiments.

[0347] 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.

[0348] 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 (Evaluation of Kd Values)

[0349] The affinity of Example 1-45 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 Sörme, 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, (Sorme 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).

TABLE-US-00001 Galectin-1 Galectin-3 Example Name structure Kd (μM) Kd (μM) 1 3-Chlorophenyl 3- deoxy-3-[4-(3- fluorophenyl)-1H- 1,2-pyrazol-1-yl]-1- thio-α-D- galactopyranoside [00044] 19.9 0.27 2 5-Chloropyridin-3- yl 3-[4-(4-chloro- 3,5- difluorophenyl)- 1H-1,2-pyrazol-1- yl]-3-deoxy-1-thio- α-D- galactopyranoside [00045] 27.6 0.020 3 5-Chloropyridin-3- yl 3-deoxy-3-[4- (3,4,5- trifluorophenyl)- 1H-1,2-pyrazol-1- yl]-1-thio-α-D- galactopyranoside [00046] 12.8 0.028 4 5-Chloropyridin-3- yl 3-deoxy-3-[4- (3,5-difluoro-4- methylphenyl)-1H- 1,2-pyrazol-1-yl]-1- thio-α-D- galactopyranoside [00047] 43 0.009 5 5-Bromopyridin-3- yl 3-deoxy-3-[4- (3,4,5- trifluorophenyl)- 1H-1,2-pyrazol-1- yl]-1-thio-α-D- galactopyranoside [00048] 14.8 0.025 6 5-Bromopyridin-3- yl 3-[4-(4-chloro- 3,5- difluorophenyl)- 1H-1,2-pyrazol-1- yl]-3-deoxy-1-thio- α-D- galactopyranoside [00049] 23 0.016 7 5-Ethynylpyridin- 3-yl 3-[4-(4-chloro- 3,5- difluorophenyl)- 1H-1,2-pyrazol-1- yl]-3-deoxy-1-thio- α-D- galactopyranoside [00050] 30 0.014 8 5-Chloro-2- cyanophenyl 3-[4- (4-chloro-3,5- difluorophenyl)- 1H-1,2-pyrazol-1- yl]-3-deoxy-1-thio- α-D- galactopyranoside [00051] 48 0.020 9 2-(N-Azetidinyl- carbonyl)-5- chlorophenyl 3-[4- (4-chloro-3,5- difluorophenyl)- 1H-1,2-pyrazol-1- yl]-3-deoxy-1-thio- α-D- galactopyranoside [00052] 19.2 0.012 10 2-(N-Azetidinyl- carbonyl)-5- chlorophenyl 3- deoxy-3-[4-(3,4,5- trifluorophenyl)- 1H-1,2-pyrazol-1- yl]-1-thio-α-D- galactopyranoside [00053] 6.8 0.015 11 5-Chloro-2- cyanophenyl 3- deoxy-3-[4-(3,4,5- trifluorophenyl)- 1H-1,2-pyrazol-1- yl]-1-thio-α-D- galactopyranoside [00054] 9.8 0.024 12 5-Chloro-2- cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5- trifluorophenyl)- 1H-1,2-pyrazol-1- yl]-1-thio-α-D- galactopyranoside [00055] 8.2 0.021 13 5-Chloro-2- cyanopyridin-3-yl 3-[4-(4-chloro-3,5- difluorophenyl)- 1H-1,2-pyrazol-1- yl]-3-deoxy-1-thio- α-D- galactopyranoside [00056] 34 0.014 14 5-Chloro-2- methylpyridin-3-yl 3-deoxy-3-[4-(3,4,5- trifluorophenyl)- 1H-1,2-pyrazol-1- yl]-1-thio-α-D- galactopyranoside [00057] 51 0.080 15 5-Bromo-2- cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5- trifluorophenyl)- 1H-1,2-pyrazol-1- yl]-1-thio-α-D- galactopyranoside [00058] 4.8 0.011 16 2-Cyano-5- ethynylpyridin-3-yl 3-deoxy-3-[4-(3,4,5- trifluorophenyl)- 1H-1,2-pyrazol-1- yl]-1-thio-α-D- galactopyranoside [00059] 12.7 0.021 17 5-Chloropyridin-3- yl 3-[4-(4-chloro-3- fluorophenyl)-1H- 1,2-pyrazol-1-yl]-3- deoxy-1-thio-α-D- galactopyranoside [00060] 19.7 0.029 18 5-Chloropyridin-3- yl 3-deoxy-3-[4-(6- fluoropyridin-2-yl)- 1H-1,2-pyrazol-1- yl]-1-thio-α-D- galactopyranoside [00061] 12.3 0.69 19 5-Chloropyridin-3- yl 3-deoxy-3-[4-(5- fluoropyridin-2-yl)- 1H-1,2-pyrazol-1- yl]-1-thio-α-D- galactopyranoside [00062] 4.1 1.6 20 5-Chloropyridin-3- yl 3-deoxy-3-[4-(4- fluoropyridin-2-yl)- 1H-1,2-pyrazol-1- yl]-1-thio-α-D- galactopyranoside [00063] 10.2 0.63 21 5-Chloropyridin-3- yl 3-deoxy-3-[4- (1H-1,2-pyrazol-3- yl)-1H-1,2-pyrazol- 1-yl]-1-thio-α-D- galactopyranoside [00064] 8.9 12.7 22 5-Chloropyridin-3- yl 3-deoxy-3-[4-(1- methyl-1,2-pyrazol- 3-yl)-1H-1,2- pyrazol-1-yl]-1- thio-α-D- galactopyranoside [00065] 14.7 9.6 23 5-Chloropyridin-3- yl 3-deoxy-3-[4- (1H-imidazol-2-yl)- 1H-1,2-pyrazol-1- yl]-1-thio-α-D- galactopyranoside [00066] 3.4 9 24 5-Chloropyridin-3- yl 3-deoxy-3-[4- (oxazol-2-yl)-1H- 1,2-pyrazol-1-yl]-1- thio-α-D- galactopyranoside [00067] 6.1 10.3 25 5-Chloropyridin-3- yl 3-deoxy-3-[4- (thiazol-4-yl)-1H- 1,2-pyrazol-1-yl]-1- thio-α-D- galactopyranoside [00068] 1.3 9.6 26 5-Chloropyridin-3- yl 3-deoxy-3-[4- (thiazol-2-yl)-1H- 1,2-pyrazol-1-yl]-1- thio-α-D- galactopyranoside [00069] 2.3 9.9 27 5-Chloropyridin-3- yl 3-[4-(4- chlorothiazol-2-yl)- 1H-1,2-pyrazol-1- yl]-3-deoxy-1-thio- α-D- galactopyranoside [00070] 0.59 1.5 28 5-Bromopyridin-3- yl 3-[4-(4- chlorothiazol-2-yl)- 1H-1,2-pyrazol-1- yl]-3-deoxy-1-thio- α-D- galactopyranoside [00071] 0.52 1.2 29 5-Chloro-2- cyanophenyl 3-[4- (4-chlorothiazol-2- yl)-1H-1,2-pyrazol- 1-yl]-3-deoxy-1- thio-α-D- galactopyranoside [00072] 0.49 1.5 30 5-Chloro-2- cyanopyridin-3-yl 3-[4-(4- chlorothiazol-2-yl)- 1H-1,2-pyrazol-1- yl]-3-deoxy-1-thio- α-D- galactopyranoside [00073] 0.51 1.1 31 5-Chloropyridin-3- yl 3-deoxy-3-[4-(2- hydroxythiazol-4- yl)-1H-1,2-pyrazol- 1-yl]-1-thio-α-D- galactopyranoside [00074] 0.14 3.4 32 5-Chloropyridin-3- yl 3-deoxy-3-[4- (3,4,5- trifluorophenyl)- 1H-1,2-pyrazol-1- yl]-2-O-methyl-1- thio-α-D- galactopyranoside [00075] 6.7 0.017 33 5-Bromopyridin-3- yl 3-deoxy-3-[4- (3,4,5- trifluorophenyl)- 1H-1,2-pyrazol-1- yl]-2-O-methyl-1- thio-α-D- galactopyranoside [00076] 3.6 0.022 34 5-Ethynylpyridin- 3-yl 3-deoxy-3-[4- (3,4,5- trifluorophenyl)- 1H-1,2-pyrazol-1- yl]-2-O-methyl-1- thio-α-D- galactopyranoside [00077] 16.5 0.023 35 5-Chloro-2- cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5- trifluorophenyl)- 1H-1,2-pyrazol-1- yl]-2-O-methyl-1- thio-α-D- galactopyranoside [00078] 3.1 0.014 36 5-Chloropyridin-3- yl 3-deoxy-3-[4- (3,4,5- trifluorophenyl)- 1H-1,3-imidazol-1- yl]-1-thio-α-D- galactopyranoside [00079] 12.7 0.067 37 5-Chloro-[3,3- bis(hydroxymethyl) azetidin-1- yl]pyridin-3-yl 3- deoxy-3-[4-(3,4,5- trifluorophenyl)- 1H-1,2-pyrazol-1- yl]-1-thio-α-D- galactopyranoside [00080] 5.1 0.013 38 5-Chloropyridin-3- yl 3-deoxy-3-[3- (3,4,5- trifluorophenyl)- 1H-1,2-pyrazol-1- yl]-2-O-methyl-1- thio-α-D- galactopyranoside [00081] 51 0.45 39 3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4,5- trifluorophenyl)- oxazol-2-yl]-1-thio- α-D- galactopyranoside [00082] >100 0.3 40 3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4,5- trifluorophenyl)- thiazol-2-yl]-1-thio- α-D- galactopyranoside [00083] >100 2 41 3,4-Dichlorophenyl 3-deoxy-3-[5-(3,4,5- trifluorophenyl)- 1,3,4-oxadiazol-2- yl]-1-thio-α-D- galactopyranoside [00084] >100 1.2 42 3,4-Dichlorophenyl 3-deoxy-3-[4-(2- hydroxythiazol-4- yl)-1H-1,2-pyrazol- 1-yl]-2-O-methyl-1- thio-α-D- galactopyranoside [00085] 0.18 63 43 3,4-Dichlorophenyl 3-[4-(2- aminothiazol-4-yl)- 1H-1,2-pyrazol-1- yl]-3-deoxy-2-O- methyl-1-thio-α-D- galactopyranoside [00086] 2.1 11 44 5-Chloro-2- cyanophenyl 3-[4- (4-chloro-3,5- difluorophenyl)- 1H-1,2-pyrazol-1- yl]-3-deoxy-2-O- methyl-1-thio-α-D- galactopyranoside [00087] 50 0.04 45 5-Chloro-2- cyanophenyl 3- deoxy-3-[4-(3,4,5- trifluorophenyl)- 1H-1,2-pyrazol-1- yl]-2-O-methyl-1- thio-α-D- galactopyranoside [00088] 8.5 0.03
A group of the compounds in table above have potential to have good uptake over the intestine and good systemic and even CNS bioavailability upon oral treatment. These compounds are considered potential human drug candidates within CNS as treatment for e.g. neurodegenerative disorders such as dementia and Azheimers.

TABLE-US-00002 MDCK-MDR1 MDCK-MDR1 A > B A > B Example Papp(10{circumflex over ( )} − 6 cm/s) Papp(10{circumflex over ( )} − 6 cm/s) 2 25 50 3 14 39 6 18 52 12 12 51 15 12 53 17 28 49 32 30 33 33 34 23 34 35 37 35 23 35
Some of the potential CNS available compounds above, examples 2, 3, 6, 12, 15, 17, 32, 33, 34 and 35 were shown to have low or no efflux and high uptake in an in vitro cell model (see Hellinger, E.; Veszelka, S.; Toth, A. E.; Walter, F.; Kittel, A.; Bakk, M. L.; Tihanyi, K.; Hada, V.; Nakagawa, S.; Duy, T. D. H.; Niwa, M.; Deli, M. A.; Vastag, M. Comparison of Brain Capillary Endothelial Cell-Based and Epithelial (MDCK-MDR1, Caco-2, and VB-Caco-2) Cell-Based Surrogate Blood-Brain Barrier Penetration Models. Eur J Pharm Biopharm 2012, 82 (2), 340-351.) of passage over Blood Brain Barrier (BBB) predicting availability for these compounds in the CNS.

[0350] In vivo mouse pharmacokinetic experiment for example 35 Dosing example 35 IV 1 mg/kg and PO 10 mg/kg results in excellent systemic bioavailability, FIG. 1. In addition, good exposure in brain is observed, FIG. 2. The ratio between exposure of example 35 in brain compared to plasma is determined to AUC.sub.brain/AUC.sub.plasma=0.19 after oral administration. (AUC=area under the curve)

Synthesis of Examples and Intermediates

General Experimental:

[0351] Nuclear Magnetic Resonance (NMR) spectra were recorded on a Varian instrument at 400 MHz or a 500 MHz Bruker Avance Neo 500 instrument, at 25° C.

[0352] Chemical shifts are reported in ppm (d) 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. LC-MS were acquired on an Agilent 1100 HPLC coupled with an Agilent MSD mass spectrometer operating in ES (+) ionization mode. Column Waters symmetry 2.1×30 mm C18 or Chromolith RP-18 2×50 mm Solvent A water+0.1% TFA and solvent B Acetonitrile+0.1% TFA. Wavelength 254 nm.

[0353] Preparative HPLC were acquired on a Gilson system. Flow: 15 ml/min Column: kromasil 100-5-C18 column Wavelength: 220 nm. Solvent A water+0.1% TFA and solvent B Acetonitrile+0.1% TFA.

[0354] The following abbreviations are used

aq: aqueous

Calcd: Calculated

CH.SUB.3.CN: Acetonitrile

CuI: Copper Iodide

DCM: Dichloromethane

DIPEA: Diisopropylethylamine

DMF: N,N-dimethylformamide

[0355] ESI-MS: Electrospray ionization mass spectrometry

Et.SUB.3.N: Triethylamine

EtOAc: Ethylacetate

[0356] h: hour(s)
HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
HPLC: High performance liquid chromatography

LC: Liquid Chromatography

MeCN: Acetonitrile

[0357] mL: milliliter

MeOH: Methanol

[0358] MeOD: Deuterated methanol
min millimeter
mM millimolar
MS: Mass spectroscopy
nm: nanometer

NaI: Sodium Iodide

[0359] NaOMe: Sodium methoxide

N.SUB.2.: Nitrogen gas

[0360] NMR: Nuclear magnetic resonance
Pd(dppf)Cl.sub.2: [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
PE: petroleum ether
pH: acidity

Prep: Preparative

[0361] rt: Room temperature
TBAF: Tetrabutylammonium fluoride
TFA: trifluoroacetic acid

THF: Tetrahydrofuran

UV: Ultraviolet

[0362] Å: Ångstrom

[0363] The below example 1-45 where made from their respective intermediates 1-44

Example 1

3-Chlorophenyl 3-deoxy-3-[4-(3-fluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0364] ##STR00089##

[0365] A solution of 3-chlorophenyl 3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside (30 mg, 0.069 mmol), (3-fluorophenyl)boronic acid (19 mg, 0.14 mmol), K.sub.2CO.sub.3 (38 mg, 0.28 mmol) and Pd(dppf)Cl.sub.2 (7.6 mg, 0.010 mmol) in dioxane/water (1 mL, 2:1) was stirred 3 h at 60° C. The mixture was concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (5 mg, 16%). ESI-MS m/z calcd for [C.sub.21H.sub.20ClFN.sub.2O.sub.4S] [M+H].sup.+: 451.1; found: 450.7. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.17 (s, 1H), 7.92 (s, 1H), 7.64 (s, 1H), 7.55-7.51 (m, 1H), 7.42-7.27 (m, 5H), 6.93 (t, J=7.8 Hz, 1H), 5.81 (d, J=5.4 Hz, 1H), 4.89-4.86 (m, 1H), 4.57 (dd, J=11.4, 2.7 Hz, 1H), 4.47 (t, J=6.1 Hz, 1H), 4.21 (d, J=1.9 Hz, 1H), 3.75 (dd, J=11.4, 5.8 Hz, 1H), 3.65 (dd, J=11.4, 6.6 Hz, 1H).

Example 2

5-Chloropyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside

[0366] ##STR00090##

[0367] A solution of 5-chloropyridin-3-yl 3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside (49 mg, 0.11 mmol), (4-chloro-3,5-difluorophenyl)boronic acid (43 mg, 0.22 mmol), K.sub.2CO.sub.3 (78 mg, 0.56 mg) and Pd(dppf)Cl.sub.2 (12 mg, 0.017 mmol) was dissolved in 1,4-dioxane/water (1 mL, 2:1) and stirred 4 h at 90° C. The mixture was partitioned between EtOAc and water and the organic phase was dried and concentrated. Purification of the residue by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) afforded the title compound (5 mg, 9%). ESI-MS m/z calcd for [C.sub.20H.sub.17Cl.sub.2F.sub.2N.sub.3O.sub.4S] [M+H].sup.+: 504.0; found: 503.8. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.64 (d, J=1.7 Hz, 1H), 8.47 (d, J=2.1 Hz, 1H), 8.24 (s, 1H), 8.20 (t, J=2.0 Hz, 1H), 7.97 (s, 1H), 7.38 (d, J=8.3 Hz, 2H), 5.91 (d, J=5.4 Hz, 1H), 4.91-4.86 (m, 1H), 4.61 (dd, J=11.3, 2.7 Hz, 1H), 4.43 (t, J=6.1 Hz, 1H), 4.19 (d, J=2.1 Hz, 1H), 3.76-3.65 (m, 2H).

Example 3

5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0368] ##STR00091##

[0369] Pd(dppf)Cl.sub.2 (18 mg, 0.024 mmol) was added to 5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside (90 mg, 0.16 mmol), (3,4,5-trifluorophenyl)boronic acid (56 mg, 0.32 mmol) and K.sub.2CO.sub.3 (177 mg, 1.28 mmol) in degassed water/dioxane (1:2, 1.5 mL). The mixture was stirred under argon for 3 h at 90° C. before it was cooled to ambient temperature. NaOH (3 M, 0.5 mL) was added and the mixture was stirred for 1 h. The mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic phase was dried, concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1 TFA) to afford the title compound (24 mg, 31%). ESI-MS m/z calcd for [C.sub.20H.sub.17ClF.sub.3N.sub.3O.sub.4S] [M+H].sup.+: 488.1; found: 488.1. .sup.1H NMR (400 MHz, Methanol-d4) δ 8.64 (d, J=1.6 Hz, 1H), 8.48 (d, J=2.1 Hz, 1H), 8.21 (t, J=1.8 Hz, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.42-7.30 (m, 2H), 5.91 (d, J=5.4 Hz, 1H), 4.92-4.86 (m, 1H), 4.60 (dd, J=11.3, 2.6 Hz, 1H), 4.43 (t, J=6.0 Hz, 1H), 4.22-4.12 (m, 1H), 3.78-3.64 (m, 2H).

Example 4

5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0370] ##STR00092##

[0371] Pd(dppf)Cl.sub.2 (16 mg, 0.021 mmol) was added to 5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside (80 mg, 0.14 mmol), 2-(3,5-difluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (59 mg, 0.23 mmol) and K.sub.2CO.sub.3 (157 mg, 1.14 mmol) in degassed water/dioxane (1:2, 1.5 mL). The mixture was stirred under argon for 3 h at 90° C. before it was cooled to ambient temperature. NaOH (3 M, 0.5 mL) was added and the mixture was stirred for 1 h. The mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic phase was dried, concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (34 mg, 49%). ESI-MS m/z calcd for [C.sub.21H.sub.20ClF.sub.2N.sub.3O.sub.4S] [M+H].sup.+: 484.1; found: 484.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.64 (s, 1H), 8.47 (d, J=1.9 Hz, 1H), 8.20 (t, J=2.1 Hz, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.16 (d, J=8.0 Hz, 2H), 5.91 (d, J=5.3 Hz, 1H), 4.92-4.85 (m, 1H), 4.59 (dd, J=11.3, 2.5 Hz, 1H), 4.43 (t, J=6.0 Hz, 1H), 4.22-4.16 (m, 1H), 3.77-3.64 (m, 2H), 2.17 (s, 3H).

Example 5

5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0372] ##STR00093##

[0373] A nitrogen purged solution of 1,2,4,6-tetra-O-acetyl-3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-β-D-galactopyranoside (250 mg, 0.52 mmol), (3,4,5-trifluorophenyl)boronic acid (184 mg, 1.05 mmol), K.sub.2CO.sub.3 (434 mg, 3.14 mmol) and Pd(dppf)Cl.sub.2 (58 mg, 0.079 mmol) in water/dioxane (1:2, 4 mL) was heated 20 min at 110° C. in a microwave reactor. The mixture was partitioned between EtOAc and water and the organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc). The obtained material and PCl.sub.5 (52 mg, 0.25 mmol) were dissolved in DCM (1.5 mL) and BF.sub.3OEt.sub.2 (0.031 mL, 0.25 mmol) was added. The mixture was stirred 3 h at rt before it was diluted with DCM and washed with water and saturated aq NaHCO.sub.3, dried and evaporated. The residue was dissolved with 5-bromopyridine-3-thiol (37 mg, 0.19 mmol) in DMF (1 mL). K.sub.2CO.sub.3 (53 mg, 0.39 mmol) was added and the mixture was stirred 18 h at rt. The mixture was diluted with EtOAc and washed with water and brine, the organic phase was dried and evaporated. The residue was stirred 1 h at rt in NaOMe (0.1 mL, 1M) and MeOH (1 mL). The reaction was quenched with acetic acid, concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (12 mg, 4%). ESI-MS m/z calcd for [C.sub.20H.sub.17BrF.sub.3N.sub.3O.sub.4S] [M+H].sup.+: 532.0; found: 531.7. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.68 (d, J=1.7 Hz, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.33 (t, J=1.9 Hz, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.37 (dd, J=9.1, 6.5 Hz, 2H), 5.89 (d, J=5.4 Hz, 1H), 4.90-4.86 (m, 1H), 4.59 (dd, J=11.3, 2.7 Hz, 1H), 4.43 (t, J=5.8 Hz, 1H), 4.19 (d, J=2.1 Hz, 1H), 3.74-3.67 (m, 2H).

Example 6

5-Bromopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside

[0374] ##STR00094##

[0375] A solution of 2,4,6-tri-O-acetyl-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D-galactopyranosyl chloride (195 mg, 0.34 mmol), 5-bromopyridine-3-thiol (94 mg, 0.45 mmol) and Cs.sub.2CO.sub.3 (220 mg, 0.67 mmol) in DMF (2.0 mL) was stirred 20 h at rt. The mixture was partitioned between EtOAc and brine, the organic phase was dried, evaporated and the residue was purified by chromatography (SiO.sub.2, PE/EtOAc). The obtained material was stirred 2 h at rt in MeOH (2.0 mL) and NaOMe (1 M, 1.0 mL). The reaction was neutralized with acetic acid (0.1 mL), evaporated, and the residue was purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (49 mg, 26%). ESI-MS m/z calcd for [C.sub.20H.sub.17BrClF.sub.2N.sub.3O.sub.4S] [M+H].sup.+: 548.0; found: 547.8. .sup.1H NMR (400 MHz, Methanol-d4) δ 8.68 (d, J=1.9 Hz, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.34 (t, J=2.0 Hz, 1H), 8.24 (d, J=0.6 Hz, 1H), 7.97 (d, J=0.6 Hz, 1H), 7.42-7.35 (m, 2H), 5.90 (d, J=5.4 Hz, 1H), 4.88 (dd, J=11.4, 5.4 Hz, 1H), 4.60 (dd, J=11.3, 2.8 Hz, 1H), 4.43 (t, J=6.3 Hz, 1H), 4.19 (d, J=1.7 Hz, 1H), 3.73 (dd, J=11.6, 5.3 Hz, 1H), 3.69 (dd, J=11.6, 6.9 Hz, 1H).

Example 7

5-Ethynylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside

[0376] ##STR00095##

[0377] 5-Bromopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (25 mg, 0.045 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (3.3 mg, 0.0045 mmol), CuI (1.0 mg, 0.0045 mol) were weighed into a flask and evacuated then flushed with nitrogen. THF (1.5 mL) and trimethylsilylacetylene (40 μL, 0.29 mmol) followed by Et.sub.3N (0.2 mL) were added. The mixture was bubbled with nitrogen and then stirred 19 h at 50° C. The mixture was purified by passing through a silica column eluting with EtOAc, evaporated, and the residue was stirred 10 min at rt in THF (1.0 mL) and TBAF (1.0 mL, 1M in THF, 1.0 mmol). The mixture was partitioned between water and EtOAc and the organic phase was evaporated, and the residue was purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1 TFA) to afford the title compound (11 mg, 49%). ESI-MS m/z calcd for [C.sub.22H.sub.18ClF.sub.2N.sub.3O.sub.4S] [M+H].sup.+: 494.1; found: 493.9. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.83 (bs, 1H), 8.68 (bs, 1H), 8.25 (s, 1H), 8.22 (s, 1H), 7.97 (s, 1H), 7.39 (d, J=8.3 Hz, 2H), 5.90 (d, J=5.3 Hz, 1H), 4.88 (dd, J=11.3, 5.3 Hz, 1H), 4.61 (dd, J=11.3, 2.5 Hz, 1H), 4.44 (t, J=5.7 Hz, 1H), 4.20 (d, J=1.8 Hz, 1H), 3.87 (s, 1H), 3.72 (dd, J=11.5, 5.3 Hz, 1H), 3.68 (dd, J=11.5, 6.8 Hz, 1H).

Example 8

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

[0378] ##STR00096##

[0379] A solution of 2,4,6-tri-O-acetyl-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D-galactopyranosyl chloride (200 mg, 0.34 mmol), 4-chloro-2-sulfanylbenzonitrile (221 mg, 1.04 mmol) and Cs.sub.2CO.sub.3 (549 mg, 1.69 mmol) in DMF (2.0 mL) was stirred 40 h at 40° C. The mixture was partitioned between EtOAc and brine, the organic phase was dried and evaporated. The residue was stirred 18 h in pyridine (2.0 mL) and acetic anhydride (1.0 mL) before being concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc). The obtained material was stirred 3.5 h at rt in MeOH (4.0 mL) and NaOMe (1 M, 1.0 mL). The reaction was neutralized with acetic acid (0.1 mL), evaporated, and the residue was purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (14 mg, 19%). ESI-MS m/z calcd for [C.sub.22H.sub.17Cl.sub.2F.sub.2N.sub.3O.sub.4S] [M+H].sup.+: 528.0; found: 527.8. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.25 (s, 1H), 7.97 (s, 2H), 7.72 (d, J=8.4 Hz, 1H), 7.45 (dd, J=8.3, 2.0 Hz, 1H), 7.39 (d, J=8.3 Hz, 2H), 6.11 (d, J=5.4 Hz, 1H), 4.92 (dd, J=11.3, 5.4 Hz, 1H), 4.65 (dd, J=11.3, 2.7 Hz, 1H), 4.37 (t, J=6.2 Hz, 1H), 4.22 (d, J=2.0 Hz, 1H), 3.71 (dd, J=11.5, 5.6 Hz, 1H), 3.64 (dd, J=11.5, 6.7 Hz, 1H).

Example 9

2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside

[0380] ##STR00097##

[0381] Pd(dppf)Cl.sub.2 (23 mg, 0.03 mmol), (4-chloro-3,5-difluorophenyl)boronic acid (61 mg, 0.30 mmol) and K.sub.2CO.sub.3 (104 mg, 0.75 mmol) were weighed into a vial and flushed with nitrogen. A solution of 2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside (78 mg, 0.15 mmol) in dioxane (2.0 mL) followed by water (0.5 mL) were added to the vial and degassed with nitrogen. The mixture was stirred 16 h at 80° C. and then partitioned between EtOAc and brine. The organic phase was evaporated, and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1 TFA) to afford the title compound (4.3 g, 5%). ESI-MS m/z calcd for [C.sub.25H.sub.23Cl.sub.2F.sub.2N.sub.3O.sub.5S] [M+H].sup.+: 586.1; found: 586.0. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.24 (s, 1H), 7.96 (s, 1H), 7.87 (d, J=1.9 Hz, 1H), 7.39 (m, 3H), 7.31 (d, J=8.2 Hz, 1H), 5.90 (d, J=5.4 Hz, 1H), 4.86 (dd, J=11.4, 5.4 Hz, 1H), 4.59 (dd, J=11.4, 2.7 Hz, 1H), 4.42 (t, J=6.1 Hz, 1H), 4.24-4.17 (m, 3H), 4.03 (t, J=7.7 Hz, 2H), 3.74 (dd, J=11.5, 5.5 Hz, 1H), 3.68 (dd, J=11.4, 6.7 Hz, 1H), 2.34 (p, J=7.7 Hz, 2H).

Example 10

2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0382] ##STR00098##

[0383] Pd(dppf)Cl.sub.2 (20 mg, 0.026 mmol), (3,4,5-trifluorophenyl)boronic acid (47 mg, 0.26 mmol) and K.sub.2CO.sub.3 (90 mg, 0.65 mmol) were weighed into a vial and flushed with nitrogen. A solution of 2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside (67 mg, 0.13 mmol) in dioxane (1.5 mL) followed by water (0.75 mL) were added to the vial and degassed with nitrogen. The mixture was stirred 18 h at 80° C. and was then partitioned between EtOAc and brine. The organic phase was evaporated, and the residue purified by chromatography (SiO.sub.2, PE/EtOAc). The product was further purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1 TFA) to afford the title compound (7.8 g, 11%). ESI-MS m/z calcd for [C.sub.25H.sub.23ClF.sub.3N.sub.3O.sub.5S] [M+H].sup.+: 570.1; found: 570.0. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.19 (s, 1H), 7.92 (s, 1H), 7.87 (d, J=1.9 Hz, 1H), 7.42-7.33 (m, 3H), 7.31 (d, J=8.2 Hz, 1H), 5.90 (d, J=5.4 Hz, 1H), 4.87 (dd, J=11.2, 5.4 Hz, 1H), 4.58 (dd, J=11.4, 2.7 Hz, 1H), 4.42 (t, J=6.2 Hz, 1H), 4.24-4.16 (m, 3H), 4.03 (t, J=7.7 Hz, 2H), 3.74 (dd, J=11.5, 5.6 Hz, 1H), 3.68 (dd, J=11.4, 6.7 Hz, 1H), 2.34 (p, J=7.7 Hz, 2H).

Example 11

5-Chloro-2-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0384] ##STR00099##

[0385] A nitrogen purged solution of 1,2,4,6-tetra-0-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-O-D-galactopyranoside (500 mg, 0.95 mmol), K.sub.2CO.sub.3 (659 mg, 4.77 mmol), (3,4,5-trifluorophenyl)boronic acid (252 mg, 1.43 mmol) and Pd(dppf)Cl.sub.2 (105 mg, 0.14 mmol) in water/dioxane (1:2, 4.5 mL) was heated 1 h at 60° C. The mixture was partitioned between EtOAc and water and the organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc). The obtained material and PCl.sub.5 (206 mg, 0.99 mmol) were dissolved in DCM (8 mL) and BF.sub.3OEt.sub.2 (0.12 mL, 0.99 mmol) was added. The mixture was stirred 5 h at rt before it was diluted with DCM and washed with water and saturated aq NaHCO.sub.3, dried and evaporated. The residue was dissolved with 4-chloro-2-sulfanylbenzonitrile (161 mg, 0.95 mmol) in DMF (4 mL). K.sub.2CO.sub.3 (210 mg, 1.52 mmol) was added and the mixture was stirred 18 h at rt. The mixture was diluted with EtOAc and washed with water and brine, the organic phase was dried and evaporated. The residue was stirred 30 min at rt in NaOMe (0.5 mL, 1M) and MeOH (5 mL). The reaction was concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (31 mg, 6%). ESI-MS m/z calcd for [C.sub.22H.sub.17ClF.sub.3N.sub.3O.sub.4S] [M+H].sup.+: 512.1; found: 512.3. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.23-8.21 (m, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.94 (d, J=0.7 Hz, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.47 (dd, J=8.4, 2.0 Hz, 1H), 7.39 (dd, J=9.3, 6.5 Hz, 2H), 6.13 (d, J=5.4 Hz, 1H), 4.93 (dd, J=11.3, 5.4 Hz, 1H), 4.66 (dd, J=11.3, 2.8 Hz, 1H), 4.38 (t, J=6.3 Hz, 1H), 4.25-4.23 (m, 1H), 3.72 (dd, J=11.5, 5.6 Hz, 1H), 3.66 (dd, J=11.5, 6.7 Hz, 1H).

Example 12

5-Chloro-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0386] ##STR00100##

[0387] A nitrogen purged solution of 2-bromo-5-chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (60.0 mg, 0.11 mmol), zinc cyanide (12.4 mg, 0.11 mmol), 1,1′-bis(diphenylphosphino)ferrocene (4.8 mg, 0.0085 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.8 mg, 0.0085 mmol) and Zn (3.5 mg, 0.053 mmol) in DMF (1 mL) was stirred 2 h at 100° C. The mixture was diluted with EtOAc, washed with water and brine. The organic phase was dried, concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) yielded the title compound (6 mg, 11%). ESI-MS m/z calcd for [C.sub.21H.sub.16ClF.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 513.1; found: 512.8, .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.55 (d, J=2.1 Hz, 1H), 8.43 (d, J=2.1 Hz, 1H), 8.20 (s, 1H), 7.92 (s, 1H), 7.40-7.33 (m, 2H), 6.21 (d, J=5.3 Hz, 1H), 4.93 (dd, J=11.3, 5.3 Hz, 1H), 4.66 (d, J=11.2 Hz, 1H), 4.31 (s, 1H), 4.20 (s, 1H), 3.68 (s, 1H), 3.66 (d, J=2.1 Hz, 1H).

Example 13

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

[0388] ##STR00101##

[0389] A nitrogen purged solution of 2-bromo-5-chloropyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (50 mg, 0.086 mmol), zinc cyanide (15.1 mg, 0.13 mmol), Zn (2.8 mg, 0.043 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.9 mg, 0.0069 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (3.9 mg, 0.0069 mmol) in DMF (2 mL) was stirred 20 h at 90° C. The mixture was diluted with EtOAc, washed with water and brine. The organic phase was dried, concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) yielded the title compound as a white solid (2.9 mg, 6%). ESI-MS m/z calcd for [C.sub.21H.sub.17Cl.sub.2F.sub.2N.sub.4O.sub.4S] [M+H].sup.+: 529.0; found: 528.7. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.57 (d, J=2.1 Hz, 1H), 8.45 (d, J=2.1 Hz, 1H), 8.28 (s, 1H), 7.99 (s, 1H), 7.41 (d, J=8.3 Hz, 2H), 6.23 (d, J=5.3 Hz, 1H), 4.95 (dd, J=11.3, 5.4 Hz, 1H), 4.69 (dd, J=11.3, 2.7 Hz, 1H), 4.33 (t, J=6.0 Hz, 1H), 4.22 (s, 1H), 3.74-3.64 (m, 2H).

Example 14

5-Chloro-2-methylpyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0390] ##STR00102##

[0391] A nitrogen purged solution of 5-chloro-2-methylpyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-1-thio-α-D-galactopyranoside (200 mg, 50% purity, 0.33 mmol), (3,4,5-trifluorophenyl)boronic acid (85.9 mg, 0.49 mmol), K.sub.2CO.sub.3 (225 mg, 1.63 mmol) and Pd(dppf)Cl.sub.2 (35.7 mg, 0.049 mmol) in dioxane (4 mL) and water (2 mL) was stirred 6 h at 60° C. The mixture was concentrated, and the residue dissolved in MeOH (10 mL) and NaOMe (1 mL, 1 M). After stirring 1 h at rt the reaction was quenched with acetic acid (0.1 mL). The mixture was concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (6 mg, 4%) as a white solid. ESI-MS m/z calcd for [C.sub.22H.sub.20F.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 493.1; found: 492.9. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.43 (s, 1H), 8.23-8.18 (m, 2H), 7.94 (s, 1H), 7.42-7.35 (m, 2H), 6.11 (d, J=5.4 Hz, 1H), 4.93 (dd, J=11.3, 5.4 Hz, 1H), 4.68 (dd, J=11.3, 2.7 Hz, 1H), 4.39 (t, J=6.1 Hz, 1H), 4.23 (d, J=2.1 Hz, 1H), 3.74-3.63 (m, 2H), 2.46 (s, 3H).

Example 15

5-Bromo-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0392] ##STR00103##

[0393] A solution of 5-bromo-2-cyanopyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (453 mg, 0.66 mmol) in MeOH (12 mL), Et.sub.3N (3 mL) and water (1 mL) was stirred 16 h at rt. The mixture was partitioned between EtOAc and water, the organic phase was dried and evaporated. The residue was recrystallized from EtOAc/PE (6 mL, 2:1) and the crystals were filtered off to afford the title compound (167 mg, 45%). The filtrate was concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1 TFA) to afford the title compound (97 mg, 26%). ESI-MS m/z calcd for [C.sub.21H.sub.16BrF.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 557.0; found: 557.0. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.67 (d, J=2.0 Hz, 1H), 8.60 (d, J=2.0 Hz, 1H), 8.22 (s, 1H), 7.95 (d, J=0.6 Hz, 1H), 7.39 (dd, J=9.3, 6.5 Hz, 2H), 6.21 (d, J=5.4 Hz, 1H), 4.95 (dd, J=11.3, 5.4 Hz, 1H), 4.68 (dd, J=11.3, 2.7 Hz, 1H), 4.33 (t, J=6.1 Hz, 1H), 4.22 (d, J=1.8 Hz, 1H), 3.74-3.65 (m, 2H).

Example 16

2-Cyano-5-ethynylpyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0394] ##STR00104##

[0395] To a nitrogen purged solution of 5-bromo-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (100 mg, 0.18 mmol), bis(triphenylphosphine)palladium(II) chloride (6.3 mg, 0.0090 mmol) and CuI (1.7 mg, 0.0090 mmol) in THF (2.0 mL) trimethylsilylacetylene (35 μL, 0.25 mmol) was added followed by DIPEA (44 μL, 0.25 mmol). The mixture was stirred 20 h at 50° C., cooled to rt and TBAF (0.3 mL, 1 M in THF, 0.3 mmol) was added and the mixture was stirred 10 min at rt. The mixture was partitioned between EtOAc and water and the organic phase was dried and evaporated. The residue was purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (39 mg, 43%). ESI-MS m/z calcd for [C.sub.23H.sub.17F.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 503.1; found: 503.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.62 (d, J=1.8 Hz, 1H), 8.42 (d, J=1.8 Hz, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.39 (dd, J=9.1, 6.6 Hz, 2H), 6.20 (d, J=5.4 Hz, 1H), 4.94 (dd, J=11.3, 5.4 Hz, 1H), 4.68 (dd, J=11.3, 2.7 Hz, 1H), 4.34 (t, J=6.1 Hz, 1H), 4.23 (d, J=2.0 Hz, 1H), 4.15 (s, 1H), 3.70 (dd, J=11.6, 5.2 Hz, 1H), 3.65 (dd, J=11.6, 6.9 Hz, 1H).

Example 17

5-Chloropyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside

[0396] ##STR00105##

[0397] 4-Bromo-1-chloro-2-fluorobenzene (13 μL, 0.10 mmol), 5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (45 mg, 0.052 mmol) and tetrakis(triphenylphosphine)palladium(0) (6.0 mg, 0.0052 mmol) were dissolved in a degassed mixture of toluene (0.5 mL), EtOH (0.1 mL) and aq Na.sub.2CO.sub.3 (52 μL, 2 M) and the resulting mixture was refluxed for 6 h. The mixture was concentrated, dissolved in MeOH (1.0 mL), Et.sub.3N (0.15 mL) and water (0.05 mL) and stirred 21 h at rt. The mixture was concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (3 mg, 12%). ESI-MS m/z calcd for [C.sub.20H.sub.18Cl.sub.2FN.sub.3O.sub.4S] [M+H].sup.+: 486.0; found: 486.4. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.64 (d, J=1.9 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H), 8.23-8.15 (m, 2H), 7.93 (s, 1H), 7.49 (dd, J=10.6, 1.7 Hz, 1H), 7.46-7.42 (m, 1H), 7.40 (dd, J=8.4, 1.7 Hz, 1H), 5.91 (d, J=5.4 Hz, 1H), 4.92-4.85 (m, 1H), 4.60 (dd, J=11.4, 2.7 Hz, 1H), 4.43 (t, J=6.0 Hz, 1H), 4.20 (d, J=2.5 Hz, 1H), 3.77-3.69 (m, 2H).

Example 18

5-Chloropyridin-3-yl 3-deoxy-3-[4-(6-fluoropyridin-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0398] ##STR00106##

[0399] 5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-α-D-galactopyranoside (97 mg, 0.11 mmol), (6-fluoro-2-pyridyl)boronic acid (31 mg, 0.22 mmol) and Pd(dppf)Cl.sub.2 (8.2 mg, 0.011 mmol) were dissolved in a degassed mixture of dioxane (1.0 mL), water (0.5 mL) and aq Na.sub.2CO.sub.3 (278 μL, 2 M). The mixture was stirred 17 h at 60° C. The mixture was filtered through celite, concentrated and the residue was dissolved in MeOH (1.0 mL), Et.sub.3N (0.15 mL) and water (0.05 mL) and stirred 5 h at rt. The mixture was filtered, concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1 TFA) to afford the title compound (10 mg, 20%). ESI-MS m/z calcd for [C.sub.19H.sub.18ClFN.sub.4O.sub.4S] [M+H].sup.+: 453.1; found: 453.5. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.66 (d, J=1.9 Hz, 1H), 8.49 (d, J=2.2 Hz, 1H), 8.38 (s, 1H), 8.23 (t, J=2.0 Hz, 1H), 8.11 (s, 1H), 7.91 (q, J=8.1 Hz, 1H), 7.58 (dd, J=7.5, 2.3 Hz, 1H), 6.85 (dd, J=8.1, 2.2 Hz, 1H), 5.94 (d, J=5.4 Hz, 1H), 4.91 (dd, J=11.4, 5.4 Hz, 1H), 4.65 (dd, J=11.3, 2.8 Hz, 1H), 4.45 (t, J=6.1 Hz, 1H), 4.22 (d, J=1.9 Hz, 1H), 3.77-3.69 (m, 2H).

Example 19

5-Chloropyridin-3-yl 3-deoxy-3-[4-(5-fluoropyridin-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0400] ##STR00107##

[0401] 5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (100 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol) and 2-bromo-5-fluoro-pyridine (87 mg, 0.49 mmol) were dissolved in a degassed mixture of toluene (1.0 mL), EtOH (0.2 mL) and aq Na.sub.2CO.sub.3 (246 μL, 2 M) and the mixture was refluxed for 2 h. The mixture was cooled to rt and the organic phase was separated. The aqueous phase was extracted with EtOAc (2×1 mL) and the combined organic phases were dried and concentrated. The residue was dissolved in MeOH (1.0 mL), Et.sub.3N (0.15 mL) and water (0.05 mL) and stirred 17 h at 50° C. The mixture was filtered, concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (33 mg, 44%). ESI-MS m/z calcd for [C.sub.19H.sub.18ClFN.sub.4O.sub.4S] [M+H].sup.+: 453.1; found: 453.0. .sup.1H NMR (400 MHz, Methanol-d4) δ 8.64 (s, 1H), 8.50-8.45 (m, 1H), 8.44 (d, J=2.2 Hz, 1H), 8.36 (s, 1H), 8.20 (s, 1H), 8.08 (s, 1H), 7.80 (dd, J=8.8, 4.4 Hz, 1H), 7.70 (td, J=8.5, 2.7 Hz, 1H), 5.92 (d, J=5.3 Hz, 1H), 4.94-4.87 (m, 1H), 4.64 (dd, J=11.3, 2.4 Hz, 1H), 4.44 (t, J=5.9 Hz, 1H), 4.25-4.17 (m, 1H), 3.77-3.64 (m, 2H).

Example 20

5-Chloropyridin-3-yl 3-deoxy-3-[4-(4-fluoropyridin-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0402] ##STR00108##

[0403] 5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (45 mg, 0.052 mmol), tetrakis(triphenylphosphine)palladium(0) (6.0 mg, 0.0052 mmol) and 2-bromo-4-fluoro-pyridine (35 μL, 0.33 mmol) were dissolved in a degassed mixture of toluene (1.0 mL), EtOH (0.2 mL) and aq Na.sub.2CO.sub.3 (167 μL, 3 M) and the mixture was refluxed for 20 h. The mixture was concentrated, dissolved in MeOH (1.0 mL), Et.sub.3N (0.15 mL) and water (0.05 mL) and stirred 24 h at rt. The mixture was concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (16 mg, 32%). ESI-MS m/z calcd for [C.sub.19H.sub.18ClFN.sub.4O.sub.4S] [M+H].sup.+: 453.1; found: 453.5. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.64 (d, J=1.5 Hz, 1H), 8.59 (t, J=6.8 Hz, 1H), 8.55 (s, 1H), 8.47 (d, J=2.1 Hz, 1H), 8.20 (s, 1H), 8.19 (t, J=2.0 Hz, 1H), 7.81 (dd, J=9.7, 2.3 Hz, 1H), 7.34-7.26 (m, 1H), 5.91 (d, J=5.3 Hz, 1H), 4.90 (dd, J=11.3, 5.4 Hz, 1H), 4.68 (dd, J=11.3, 2.7 Hz, 1H), 4.45 (t, J=6.0 Hz, 1H), 4.22 (d, J=2.2 Hz, 1H), 3.77-3.66 (m, 2H).

Example 21

5-Chloropyridin-3-yl 3-deoxy-3-[4-(1H-1,2-pyrazol-3-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0404] ##STR00109##

[0405] 5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-α-D-galactopyranoside (97 mg, 0.11 mmol), 1H-pyrazol-3-ylboronic acid (25 mg, 0.22 mmol) and Pd(dppf)Cl.sub.2 (8.2 mg, 0.011 mmol) were dissolved in a degassed mixture of dioxane (1.0 mL), water (0.5 mL) and aq Na.sub.2CO.sub.3 (278 μL, 2 M). The mixture was stirred 17.5 h at 60° C. More 1H-pyrazol-3-ylboronic acid (25 mg, 0.22 mmol) was added and the mixture was stirred 23 h at 80° C. The mixture was concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA). Further purification by chromatography (SiO.sub.2, EtOAc/MeOH) afforded the title compound (7 mg, 15%). ESI-MS m/z calcd for [C.sub.17H.sub.18ClN.sub.5O.sub.4S] [M+H].sup.+: 424.1; found: 424.5. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.65 (d, J=1.9 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H), 8.20 (t, J=2.1 Hz, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.67 (s, 1H), 6.50 (s, 1H), 5.91 (d, J=5.4 Hz, 1H), 4.92-4.87 (m, 1H), 4.62 (dd, J=11.7, 1.9 Hz, 1H), 4.46 (t, J=6.0 Hz, 1H), 4.22 (d, J=2.0 Hz, 1H), 3.74 (dd, J=11.6, 5.3 Hz, 1H), 3.71 (dd, J=11.6, 6.9 Hz, 1H).

Example 22

5-Chloropyridin-3-yl 3-deoxy-3-[4-(1-methyl-1,2-pyrazol-3-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0406] ##STR00110##

[0407] 5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (97 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (12.9 mg, 0.011 mmol) and 3-bromo-1-methylpyrazole (22.6 μL, 0.22 mmol) were dissolved in a degassed mixture of toluene (1.0 mL), EtOH (0.2 mL) and aq Na.sub.2CO.sub.3 (111 μL, 2 M) and the mixture was refluxed for 23 h. The mixture was concentrated, dissolved in MeOH (1.0 mL), Et.sub.3N (0.15 mL) and water (0.05 mL) and stirred 23 h at rt. The mixture was concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1 TFA) to afford the title compound (7.8 mg, 16%). ESI-MS m/z calcd for [C.sub.18H.sub.20ClN.sub.5O.sub.4S] [M+H].sup.+: 438.1; found: 438.5. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.66 (d, J=1.9 Hz, 1H), 8.49 (d, J=2.2 Hz, 1H), 8.22 (t, J=2.1 Hz, 1H), 8.12 (s, 1H), 7.89-7.82 (m, 1H), 7.60 (d, J=2.2 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 5.92 (d, J=5.3 Hz, 1H), 4.91-4.87 (m, 1H), 4.62 (dd, J=11.3, 2.7 Hz, 1H), 4.45 (t, J=6.1 Hz, 1H), 4.25-4.17 (m, 1H), 3.92 (s, 3H), 3.76-3.67 (m, 2H).

Example 23

5-Chloropyridin-3-yl 3-deoxy-3-[4-(1H-imidazol-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0408] ##STR00111##

[0409] 5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (97 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (12.9 mg, 0.011 mmol) and 2-bromo-1H-imidazole (32.7 mg, 0.22 mmol) were dissolved in a degassed mixture of toluene (1.0 mL), EtOH (0.2 mL) and aq Na.sub.2CO.sub.3 (111 μL, 2 M) and the mixture was refluxed for 23 h. The mixture was concentrated, dissolved in MeOH (1.0 mL), Et.sub.3N (0.15 mL) and water (0.05 mL) and stirred 23 h at rt. The mixture was concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (16 mg, 34%). ESI-MS m/z calcd for [C.sub.17H.sub.18ClN.sub.5O.sub.4S] [M+H].sup.+: 424.1; found: 424.5. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.65 (d, J=1.8 Hz, 1H), 8.53 (s, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.20 (t, J=2.1 Hz, 1H), 8.16-8.10 (m, 1H), 7.53 (s, 2H), 5.93 (d, J=5.3 Hz, 1H), 4.93-4.87 (m, 1H), 4.75 (dd, J=11.4, 2.8 Hz, 1H), 4.47 (t, J=6.0 Hz, 1H), 4.28-4.22 (m, 1H), 3.75 (dd, J=11.6, 5.4 Hz, 1H), 3.71 (dd, J=11.6, 6.9 Hz, 1H).

Example 24

5-Chloropyridin-3-yl 3-deoxy-3-[4-(oxazol-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0410] ##STR00112##

[0411] 5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (97 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (12.9 mg, 0.011 mmol) and 2-bromooxazole (32.9 mg, 0.22 mmol) were dissolved in a degassed mixture of toluene (1.0 mL), EtOH (0.2 mL) and aq Na.sub.2CO.sub.3 (111 μL, 2 M) and the mixture was refluxed for 23 h. The mixture was concentrated, dissolved in MeOH (1.0 mL), Et.sub.3N (0.15 mL) and water (0.05 mL) and stirred 23 h at rt. The mixture was concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA). Further purification by chromatography (SiO.sub.2, EtOAc/MeOH) afforded the title compound (15.8 mg, 33%). ESI-MS m/z calcd for [C.sub.17H.sub.17ClN.sub.4O.sub.5S] [M+H].sup.+: 425.1; found: 425.5. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.63 (d, J=1.8 Hz, 1H), 8.46 (d, J=2.2 Hz, 1H), 8.36 (s, 1H), 8.18 (t, J=2.1 Hz, 1H), 8.04 (s, 1H), 7.88 (s, 1H), 7.21 (s, 1H), 5.90 (d, J=5.3 Hz, 1H), 4.91-4.86 (m, 1H), 4.66 (dd, J=11.4, 2.8 Hz, 1H), 4.43 (t, J=6.2 Hz, 1H), 4.20 (d, J=1.9 Hz, 1H), 3.75-3.64 (m, 2H).

Example 25

5-Chloropyridin-3-yl 3-deoxy-3-[4-(thiazol-4-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0412] ##STR00113##

[0413] 5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (45 mg, 0.052 mmol), tetrakis(triphenylphosphine)palladium(0) (6.0 mg, 0.0052 mmol) and 4-bromothiazole (9.2 μL, 0.10 mmol) were dissolved in a degassed mixture of toluene (0.5 mL), EtOH (0.1 mL) and aq Na.sub.2CO.sub.3 (52 μL, 2 M) and the mixture was refluxed for 6 h. The mixture was concentrated, dissolved in MeOH (1.0 mL), Et.sub.3N (0.15 mL) and water (0.05 mL) and stirred overnight at rt. The mixture was concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1 TFA) to afford the title compound (6.0 mg, 26%). ESI-MS m/z calcd for [C.sub.17H.sub.17ClN.sub.4O.sub.4S.sub.2] [M+H].sup.+: 441.0; found: 441.5. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 9.06 (d, J=2.0 Hz, 1H), 8.66 (d, J=1.8 Hz, 1H), 8.49 (d, J=2.1 Hz, 1H), 8.26 (s, 1H), 8.23 (t, J=2.1 Hz, 1H), 8.03-7.97 (m, 1H), 7.66 (d, J=2.0 Hz, 1H), 5.93 (d, J=5.4 Hz, 1H), 4.93-4.88 (m, 1H), 4.64 (dd, J=11.3, 2.7 Hz, 1H), 4.45 (t, J=6.1 Hz, 1H), 4.25-4.20 (m, 1H), 3.77-3.68 (m, 2H).

Example 26

5-Chloropyridin-3-yl 3-deoxy-3-[4-(thiazol-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0414] ##STR00114##

[0415] 5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (45 mg, 0.052 mmol), tetrakis(triphenylphosphine)palladium(0) (6.0 mg, 0.0052 mmol) and 2-bromothiazole (9.2 μL, 0.10 mmol) were dissolved in a degassed mixture of toluene (0.5 mL), EtOH (0.1 mL) and aq Na.sub.2CO.sub.3 (52 μL, 2 M) and the mixture was refluxed for 6 h. The mixture was concentrated, dissolved in MeOH (1.0 mL), Et.sub.3N (0.15 mL) and water (0.05 mL) and stirred overnight at rt. The mixture was concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (7.0 mg, 31%). ESI-MS m/z calcd for [C.sub.17H.sub.17ClN.sub.4O.sub.4S.sub.2] [M+H].sup.+: 441.0; found: 441.0. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.66 (d, J=1.9 Hz, 1H), 8.49 (d, J=2.2 Hz, 1H), 8.38 (s, 1H), 8.22 (t, J=2.1 Hz, 1H), 8.05 (d, J=0.6 Hz, 1H), 7.81 (d, J=3.4 Hz, 1H), 7.54 (d, J=3.4 Hz, 1H), 5.93 (d, J=5.4 Hz, 1H), 4.94-4.88 (m, 1H), 4.67 (dd, J=11.4, 2.8 Hz, 1H), 4.45 (t, J=6.3 Hz, 1H), 4.23 (d, J=1.8 Hz, 1H), 3.74 (dd, J=11.7, 5.4 Hz, 1H), 3.71 (dd, J=11.6, 7.0 Hz, 1H).

Example 27

5-Chloropyridin-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside

[0416] ##STR00115##

[0417] 5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (45 mg, 0.052 mmol), tetrakis(triphenylphosphine)palladium(0) (6.0 mg, 0.0052 mmol) and 2-bromo-4-chlorothiazole (21 mg, 0.10 mmol) were dissolved in a degassed mixture of toluene (0.5 mL), EtOH (0.1 mL) and aq Na.sub.2CO.sub.3 (52 μL, 2 M) and the mixture was refluxed for 16 h. The mixture was concentrated, dissolved in MeOH (1.0 mL), Et.sub.3N (0.15 mL) and water (0.05 mL) and stirred 3 h at rt. The mixture was concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (11 mg, 45%). ESI-MS m/z calcd for [C.sub.17H.sub.16Cl.sub.2N.sub.4O.sub.4S.sub.2] [M+H].sup.+: 475.0; found: 474.7. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.63 (d, J=1.9 Hz, 1H), 8.46 (d, J=2.2 Hz, 1H), 8.35 (s, 1H), 8.18 (t, J=2.1 Hz, 1H), 8.02 (s, 1H), 7.30 (s, 1H), 5.90 (d, J=5.4 Hz, 1H), 4.91-4.85 (m, 1H), 4.64 (dd, J=11.3, 2.8 Hz, 1H), 4.43 (t, J=5.9 Hz, 1H), 4.20 (d, J=1.8 Hz, 1H), 3.72 (dd, J=11.6, 5.3 Hz, 1H), 3.68 (dd, J=11.6, 6.9 Hz, 1H).

Example 28

5-Bromopyridin-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside

[0418] ##STR00116##

[0419] 5-Bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (189 mg, 0.29 mmol), tetrakis(triphenylphosphine)palladium(0) (33 mg, 0.029 mmol) and 2-bromo-4-chlorothiazole (115 mg, 0.58 mmol) were dissolved in a degassed mixture of toluene (2.0 mL), EtOH (0.4 mL) and aq Na.sub.2CO.sub.3 (217 μL, 2 M) and the mixture was refluxed for 19 h. The mixture was diluted with water (10 mL), filtered and extracted with EtOAc (2×10 mL). The combined organic phases were concentrated, and the residue was stirred 2 h at rt in MeOH (2 mL) and NaOMe (0.1 mL, 1 M). The reaction was quenched with acetic acid, concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1 TFA) to afford the title compound (16 mg, 10%). ESI-MS m/z calcd for [C.sub.17H.sub.16BrClN.sub.4O.sub.4S.sub.2] [M+H].sup.+: 519.0; found: 518.8. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.69 (d, J=1.7 Hz, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.37 (s, 1H), 8.33 (t, J=1.9 Hz, 1H), 8.03 (s, 1H), 7.32 (s, 1H), 5.90 (d, J=5.4 Hz, 1H), 4.93-4.88 (m, 1H), 4.66 (dd, J=11.4, 2.7 Hz, 1H), 4.45 (t, J=6.2 Hz, 1H), 4.22 (d, J=2.0 Hz, 1H), 3.74 (dd, J=11.6, 5.3 Hz, 1H), 3.70 (dd, J=11.5, 6.9 Hz, 1H).

Example 29

5-Chloro-2-cyanophenyl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside

[0420] ##STR00117##

[0421] 5-Chloro-2-cyanophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (92 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol) and 2-bromo-4-chlorothiazole (58 mg, 0.29 mmol) were dissolved in a degassed mixture of toluene (1.0 mL) and aq Na.sub.2CO.sub.3 (109 μL, 2 M) and the mixture was refluxed for 22 h. The mixture was diluted with water (2 mL), filtered and extracted with EtOAc (2×5 mL). The combined organic phases were concentrated, and the residue was stirred 1 h at rt in MeOH (1 mL) and NaOMe (15 μL, 1 M). The reaction was quenched with acetic acid, concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (12 mg, 13%). ESI-MS m/z calcd for [C.sub.19H.sub.16Cl.sub.2N.sub.4O.sub.4S.sub.2] [M+H].sup.+: 499.0; found: 498.7. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.38 (d, J=0.5 Hz, 1H), 8.04 (d, J=0.7 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.48 (dd, J=8.4, 2.0 Hz, 1H), 7.32 (s, 1H), 6.13 (d, J=5.4 Hz, 1H), 4.94 (dd, J=11.4, 5.4 Hz, 1H), 4.71 (dd, J=11.4, 2.8 Hz, 1H), 4.39 (t, J=6.3 Hz, 1H), 4.27-4.22 (m, 1H), 3.72 (dd, J=11.5, 5.6 Hz, 1H), 3.65 (dd, J=11.5, 6.7 Hz, 1H).

Example 30

5-Chloro-2-cyanopyridin-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside

[0422] ##STR00118##

[0423] 5-Chloro-2-cyanopyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (23 mg, 0.036 mmol), tetrakis(triphenylphosphine)palladium(0) (4.2 mg, 0.0036 mmol) and 2-bromo-4-chlorothiazole (14 mg, 0.073 mmol) were dissolved in a degassed mixture of toluene (0.25 mL), EtOH (0.05 mL) and aq Na.sub.2CO.sub.3 (27 μL, 2 M) and the mixture was refluxed for 10 h. The mixture was concentrated, dissolved in MeOH (1.0 mL), Et.sub.3N (0.15 mL) and water (0.05 mL) and stirred 1 h at rt. The mixture was concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (2.5 mg, 14%). ESI-MS m/z calcd for [C.sub.18H.sub.18Cl.sub.2N.sub.5O.sub.4S.sub.2] [M+H].sup.+: 500.0; found: 499.8. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.57 (d, J=2.1 Hz, 1H), 8.46 (d, J=2.1 Hz, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 7.32 (s, 1H), 6.23 (d, J=5.4 Hz, 1H), 4.95 (dd, J=11.3, 5.4 Hz, 1H), 4.73 (dd, J=11.3, 2.8 Hz, 1H), 4.33 (t, J=6.2 Hz, 1H), 4.23 (d, J=2.0 Hz, 1H), 3.71-3.66 (m, 2H).

Example 31

5-Chloropyridin-3-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0424] ##STR00119##

[0425] A solution of 5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-benzyloxythiazol-4-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (77 mg, 0.11 mmol) and palladium on carbon (10 mg, 0.094 mmol) in MeOH (1.0 mL) was subjected to hydrogen gas (1 atm). The mixture was heated 2 h at 50° C., cooled to rt and filtered. NaOMe (0.2 mL, 1 M) was added to the filtrate that was stirred 100 min at rt. Acetic acid (50 μL) was added and the mixture was concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (11 mg, 21%). ESI-MS m/z calcd for [C.sub.17H.sub.17ClN.sub.4O.sub.5S.sub.2] [M+H].sup.+: 457.0; found: 457.0. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.62 (s, 1H), 8.45 (s, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.82 (s, 1H), 6.34 (s, 1H), 5.89 (d, J=5.3 Hz, 1H), 4.85-4.78 (m, 1H), 4.59 (dd, J=11.3, 2.4 Hz, 1H), 4.42 (t, J=6.0 Hz, 1H), 4.22-4.12 (m, 1H), 3.77-3.63 (m, 2H).

Example 32

5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside

[0426] ##STR00120##

[0427] A solution of 5-chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranos ide (183 mg, 0.38 mmol), benzaldehyde dimethylacetal (114 μL, 0.75 mmol) and p-toluenesulfonic acid monohydrate (30 mg, 0.14 mmol) in MeCN (2.0 mL) was stirred 72 h at rt. More benzaldehyde dimethylacetal (114 μL, 0.75 mmol) and p-toluenesulfonic acid monohydrate (30 mg, 0.14 mmol) was added and the mixture was stirred 1 h at rt. Et.sub.3N (100 μL, 0.73 mmol) followed by water and PE were added, the precipitate was isolated by filtration. The obtained solid was partitioned between EtOAc and saturated aq NaHCO.sub.3, and the organic phase was evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc). The obtained material and NaH (60% in oil, 16 mg, 0.4 mmol) were stirred 5 min in DMF (2.0 mL) before iodomethane (17 μL, 0.27 mmol) was added. After stirring 30 min at rt water was added and the precipitate was isolated and triturated in MeOH. The obtained material was stirred 30 min at rt in 80% aq TFA (2.0 mL). Ice and PE were added, and the supernatant was decanted off. The residue was partitioned between EtOAc and water where pH was adjusted to approximately 7 using NaOH (1 M). The organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc). The product was triturated in PE/EtOAc (1:1) to afford the title compound (54 mg, 29%). ESI-MS m/z calcd for [C.sub.21H.sub.19ClF.sub.3N.sub.3O.sub.4S] [M+H].sup.+: 502.1; found: 502.1. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.64 (d, J=1.9 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H), 8.21 (s, 1H), 8.20 (t, J=2.1 Hz, 1H), 7.91 (s, 1H), 7.42-7.33 (m, 2H), 6.23 (d, J=5.1 Hz, 1H), 4.62 (dd, J=11.3, 2.7 Hz, 1H), 4.55 (dd, J=11.3, 5.2 Hz, 1H), 4.41 (t, J=6.2 Hz, 1H), 4.17 (d, J=1.8 Hz, 1H), 3.72 (dd, J=11.6, 5.3 Hz, 1H), 3.68 (dd, J=11.6, 6.9 Hz, 1H), 3.38 (s, 3H).

Example 33

5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside

[0428] ##STR00121##

[0429] A solution of 5-bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (305 mg, 0.57 mmol), benzaldehyde dimethylacetal (182 μL, 1.2 mmol) and p-toluenesulfonic acid monohydrate (30 mg, 0.14 mmol) in MeCN (4.0 mL) was stirred 20 h at rt. Et.sub.3N (100 μL, 0.73 mmol) followed by water (2.0 mL) were added, the precipitate was isolated by filtration and the filter cake was washed with water and PE. The obtained solid and NaH (60% in oil, 30 mg, 0.71 mmol) were stirred 5 min in DMF (4.0 mL) before iodomethane (30 μL, 0.47 mmol) was added. After stirring 30 min at rt water was added and the precipitate was isolated by filtration. The precipitate was recrystallized in EtOAc/PE (1:2) and the crystals were isolated. The crystals were stirred 30 min at rt in 80% aq TFA (2.0 mL). Ice and PE were added, and the supernatant was decanted off. The residue was partitioned between EtOAc and water where pH was adjusted to approximately 7 using NaOH (1 M). The organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the title compound (124 mg, 40%). ESI-MS m/z calcd for [C.sub.21H.sub.19BrF.sub.3N.sub.3O.sub.4S] [M+H].sup.+: 546.0; found: 546.0. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.68 (d, J=1.8 Hz, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.34 (t, J=2.0 Hz, 1H), 8.21 (s, 1H), 7.91 (s, 1H), 7.38 (m, 2H), 6.21 (d, J=5.1 Hz, 1H), 4.62 (dd, J=11.3, 2.5 Hz, 1H), 4.54 (dd, J=11.3, 5.1 Hz, 1H), 4.41 (t, J=6.0 Hz, 1H), 4.17 (s, 1H), 3.75-3.63 (m, 2H), 3.38 (s, 3H).

Example 34

5-Ethynylpyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside

[0430] ##STR00122##

[0431] A solution of 5-bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (90 mg, 0.17 mmol) in THF (2.0 mL) was added to a mixture of CuI (2.0 mg, 0.0086 mmol) and bis(triphenylphosphine)palladium(II) chloride (6.3 mg, 0.0086 mmol) under nitrogen. DIPEA (41 μL, 0.23 mmol) followed by trimethylsilylacetylene (38 μL, 0.25 mmol) were added and the mixture was stirred 48 h at 50° C. The mixture was purified by chromatography (SiO.sub.2, PE/EtOAc) and then triturated from PE/EtOAc (1:1). The obtained material was stirred 45 min in THF (2.0 mL) and TBAF (1.0 mL, 1 M in THF, 1.0 mmol). The mixture was partitioned between EtOAc, water and NaOH (1 mL, 1 M). The organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the title compound (23 mg, 28%). ESI-MS m/z calcd for [C.sub.23H.sub.20F.sub.3N.sub.3O.sub.4S] [M+H].sup.+: 492.1; found: 492.1. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.69 (d, J=2.1 Hz, 1H), 8.54 (d, J=1.9 Hz, 1H), 8.21 (s, 1H), 8.19 (t, J=2.0 Hz, 1H), 7.91 (s, 1H), 7.43-7.34 (m, 2H), 6.19 (d, J=5.2 Hz, 1H), 4.62 (dd, J=11.3, 2.7 Hz, 1H), 4.54 (dd, J=11.3, 5.2 Hz, 1H), 4.42 (t, J=6.2 Hz, 1H), 4.18 (d, J=1.8 Hz, 1H), 3.71 (dd, J=11.5, 5.4 Hz, 1H), 3.66 (dd, J=11.5, 6.8 Hz, 1H), 3.38 (s, 3H).

Example 35

5-Chloro-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside

[0432] ##STR00123##

[0433] A nitrogen purged solution of 2-bromo-5-chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (124 mg, 0.21 mmol), 1,1′-bis(diphenylphosphino)ferrocene (9.6 mg, 0.017 mmol), zinc cyanide (25.1 mg, 0.21 mmol), tris(dibenzylideneacetone)dipalladium(0) (7.8 mg, 0.0085 mmol) and Zn (7.0 mg, 0.11 mmol) in DMF (2.77 mL) was stirred 1 h at 100° C. More zinc cyanide (25.1 mg, 0.21 mmol), Zn (7.0 mg, 0.11 mmol), 1,1′-bis(diphenylphosphino)ferrocene (9.6 mg, 0.017 mmol) and tris(dibenzylideneacetone)dipalladium(0) (7.8 mg, 0.0085 mmol) were added and the mixture was stirred 30 min at 100° C. The mixture was cooled to rt, diluted with EtOAc (30 mL), washed with water (5×30 mL) and brine (30 mL). The organic phase was dried, concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to yield the title compound (22 mg, 20%). ESI-MS m/z calcd for [C.sub.22H.sub.18ClF.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 527.1; found: 526.8, .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.59 (d, J=2.1 Hz, 1H), 8.46 (d, J=2.1 Hz, 1H), 8.23 (s, 1H), 7.92 (s, 1H), 7.43-7.34 (m, 2H), 6.48 (d, J=5.1 Hz, 1H), 4.67 (dd, J=11.2, 2.6 Hz, 1H), 4.61 (dd, J=11.2, 5.1 Hz, 1H), 4.33 (t, J=6.0 Hz, 1H), 4.18 (d, J=1.9 Hz, 1H), 3.68 (d, J=6.0 Hz, 2H), 3.43 (s, 3H).

Example 36

5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,3-imidazol-1-yl]-1-thio-α-D-galactopyranoside

[0434] ##STR00124##

[0435] A solution of N-[p-tolylsulfonyl-(3,4,5-trifluorophenyl)methyl]formamide (54 mg, 0.16 mmol) in 1,2-dimethoxyethane (4.5 mL) was cooled to −10° C. To the solution phosphorus(V) oxychloride (36 μL, 0.39 mmol) was added followed by dropwise addition of Et.sub.3N (0.11 mL, 0.79 mmol) in 1,2-dimethoxyethane (0.5 mL). The mixture reached rt in 1 h and was then stirred 2 h additionally at rt. The mixture was partitioned between water and EtOAc. The organic phase was washed with saturated aq NaHCO.sub.3, dried and evaporated to afford crude 1,2,3-trifluoro-5-[isocyano(p-tolylsulfonyl)methyl]benzene. A solution of 5-chloropyridin-3-yl 3-amino-3-deoxy-1-thio-α-D-galactopyranoside (40 mg, 0.13 mmol), 2-oxoacetic acid (8.7 mg, 0.012 mmol) and K.sub.2CO.sub.3 (90 mg, 0.65 mmol) in DMF (0.6 mL) was stirred 2 h at rt. Afterwhich the crude 1,2,3-trifluoro-5-[isocyano(p-tolylsulfonyl)methyl]benzene dissolved in DMF (0.1 mL) was added and the resulting mixture was stirred 19 h at rt. The mixture was partitioned between water and EtOAc, the organic phase was dried and evaporated. The residue was purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to yield the title compound as a TFA salt (13 mg, 17%). ESI-MS m/z calcd for [C.sub.20H.sub.17ClF.sub.3N.sub.3O.sub.4S] [M+H].sup.+: 488.1; found: 488.1, .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 9.00 (s, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 7.59 (dd, J=8.3, 6.5 Hz, 2H), 5.94 (d, J=5.3 Hz, 1H), 4.86-4.83 (m, 1H), 4.74 (dd, J=11.3, 2.8 Hz, 1H), 4.45 (t, J=6.2 Hz, 1H), 4.23 (d, J=2.0 Hz, 1H), 3.78-3.70 (m, 2H).

Example 37

5-Chloro-[3,3-bis(hydroxymethyl)azetidin-1-yl]pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0436] ##STR00125##

[0437] To a nitrogen purged solution of 5-chloro-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside (42 mg, 0.079 mmol), Pd(dppf)Cl.sub.2 (9.5 mg, 0.013 mmol) and K.sub.2CO.sub.3 (45 mg, 0.32 mmol) in dioxane (1.5 mL) and water (0.75 mL) (3,4,5-trifluorophenyl)boronic acid (24 mg, 0.13 mmol) was added and the mixture was stirred 18 h at 80° C. The mixture was filtered through silica, evaporated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (1.1 mg, 2%). ESI-MS m/z calcd for [C.sub.25H.sub.26ClF.sub.3N.sub.4O.sub.6S] [M+H].sup.+: 586.1; found: 586.0. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.17 (s, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.80 (s, 1H), 7.41-7.29 (m, 2H), 5.63 (d, J=5.2 Hz, 1H), 4.58 (d, J=9.3 Hz, 1H), 4.41 (t, J=6.2 Hz, 1H), 4.19 (s, 1H), 4.10 (d, J=8.6 Hz, 3H), 3.99 (d, J=8.8 Hz, 2H), 3.74 (s, 4H), 3.73-3.54 (m, 2H).

Example 38

5-Chloropyridin-3-yl 3-deoxy-3-[3-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside

[0438] ##STR00126##

[0439] A nitrogen purged solution of 5-chloropyridin-3-yl 3-deoxy-3-(3-iodo-1H-1,2-pyrazol-1-yl)-2-O-methyl-1-thio-α-D-galactopyranoside (20 mg, 0.040 mmol), (3,4,5-trifluorophenyl)boronic acid (11 mg, 0.060 mmol), Pd(dppf)Cl.sub.2 (4.4 mg, 0.0060 mmol) and K.sub.2CO.sub.3 (28 mg, 0.20 mmol) in dioxane (0.5 mL) and water (0.25 mL) was stirred 1 h at 60° C. The mixture was partitioned between EtOAc and water. The organic phase was dried, evaporated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (12 g, 60%). ESI-MS m/z calcd for [C.sub.21H.sub.19ClF.sub.3N.sub.3O.sub.4S] [M+H].sup.+: 502.1; found: 502.1. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.66 (d, J=1.9 Hz, 1H), 8.49 (d, J=2.2 Hz, 1H), 8.24 (t, J=2.1 Hz, 1H), 7.82 (d, J=2.5 Hz, 1H), 7.61-7.54 (m, 2H), 6.73 (d, J=2.5 Hz, 1H), 6.24 (d, J=5.3 Hz, 1H), 4.65 (dd, J=11.3, 2.8 Hz, 1H), 4.54 (dd, J=11.3, 5.3 Hz, 1H), 4.41 (t, J=6.1 Hz, 1H), 4.21 (d, J=2.2 Hz, 1H), 3.75-3.66 (m, 2H), 3.37 (s, 3H).

Example 39

3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-oxazol-2-yl]-1-thio-α-D-galactopyranoside

[0440] ##STR00127##

[0441] A solution of 3,4-dichlorophenyl 2,4-di-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-oxazol-2-yl]-1-thio-α-D-galactopyranoside (40 mg, 0.066 mmol) in MeOH (10 mL), Et.sub.3N (0.184 mL) and water (0.5 mL) was stirred overnight at rt. The mixture was filtered and purified by prep HPLC (MeCN/H.sub.2O (10 mmol/L NH.sub.4HCO.sub.3), X-Select10 μm 19*250 mm, 20 mL/min, UV 254) to afford the title compound (17 mg, 50%). ESI-MS m/z calcd for [C.sub.21H.sub.16Cl.sub.2F.sub.3NO.sub.5S] [M+H].sup.+: 522.0; found: 522.0. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.36 (s, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.64-7.57 (m, 2H), 7.57-7.51 (m, 1H), 7.51-7.45 (m, 1H), 5.80 (d, J=5.2 Hz, 1H), 4.93-4.90 (m, 1H), 4.41 (t, J=6.4 Hz, 1H), 4.26-4.22 (m, 1H), 3.78-3.62 (m, 2H), 3.44 (dd, J=11.6, 2.8 Hz, 1H).

Example 40

3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-thiazol-2-yl]-1-thio-α-D-galactopyranoside

[0442] ##STR00128##

[0443] A solution of 3,4-dichlorophenyl 2,4-di-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-thiazol-2-yl]-1-thio-α-D-galactopyranoside (15 mg, 0.024 mmol) in MeOH (5 mL), Et.sub.3N (0.10 mL) and water (0.5 mL) was stirred overnight at rt. The mixture was filtered and the filtrate was purified by prep HPLC (MeCN/H.sub.2O (10 mmol/L NH.sub.4HCO.sub.3), X-Select10 μm 19*250 mm, 20 mL/min, UV 254) to afford the title compound (2.5 mg, 19%). ESI-MS m/z calcd for [C.sub.21H.sub.16Cl.sub.2F.sub.3NO.sub.4S.sub.2] [M+H].sup.+: 538.0; found: 538.0. .sup.1H NMR (400 MHz, Methanol-d4) δ 7.90 (s, 1H), 7.81-7.70 (m, 3H), 7.54-7.42 (m, 2H), 5.76 (d, J=5.2 Hz, 1H), 4.66 (dd, J=11.6, 5.2 Hz, 1H), 4.42 (t, J=6.0 Hz, 1H), 4.26 (s, 1H), 3.77-3.65 (m, 2H), 3.61 (dd, J=11.6, 2.4 Hz, 1H).

Example 41

3,4-Dichlorophenyl 3-deoxy-3-[5-(3,4,5-trifluorophenyl)-1,3,4-oxadiazol-2-yl]-1-thio-α-D-galactopyranoside

[0444] ##STR00129##

[0445] A solution of 3,4-dichlorophenyl 2,4-di-O-acetyl-3-deoxy-3-[(3,4,5-trifluorophenyl)-1,3,4-oxadiazol-2-yl]-1-thio-D-galactopyranoside (19 mg, 0.031 mmol) in MeOH (1 mL), Et.sub.3N (0.5 mL) and water (0.25 mL) was stirred overnight at rt. The mixture was filtered and purified by prep HPLC (MeCN/H.sub.2O (10 mmol/L NH.sub.4HCO.sub.3), X-Select10 μm 19*250 mm, 20 mL/min, UV 254). The product was further purified by preparative-SFC to afford the title compound (3.4 mg, 21%). ESI-MS m/z calcd for [C.sub.20H.sub.15Cl.sub.2F.sub.3N.sub.2O.sub.5S] [M+H].sup.+: 523.0; found: 523.0. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.89-7.86 (m, 2H), 7.78 (d, J=2.0 Hz, 1H), 7.53-7.47 (m, 2H), 5.80 (d, J=5.2 Hz, 1H), 4.61 (s, 1H), 4.41 (t, J=6.0 Hz, 1H), 4.24 (s, 1H), 3.74-3.61 (m, 3H).

Example 42

3,4-Dichlorophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside

[0446] ##STR00130##

[0447] A solution of 3,4-dichlorophenyl 3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-2-O-methyl-1-thio-α-D-galactopyranoside (100 mg, 0.19 mmol), 2-(2-benzyloxythiazol-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (112 mg, 0.28 mmol), and K.sub.2CO.sub.3 (130 mg, 0.94 mmol) in dioxane (1.5 mL) and water (0.75 mL) was degassed with nitrogen before Pd(dppf)Cl.sub.2 (28 mg, 0.038 mmol) was added and the mixture stirred 1 h at 60° C. The mixture was partitioned between EtOAc and brine. The organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc). The obtained material was stirred 1 h in DCM (1.0 mL) and TFA (150 μL) at rt. The mixture was partitioned between EtOAc and saturated aq NaHCO.sub.3. The organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the title compound (28 mg, 29%). ESI-MS m/z calcd for [C.sub.19H.sub.19Cl.sub.2N.sub.3O.sub.5S.sub.2] [M+H].sup.+: 504.0; found: 504.0. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.07 (s, 1H), 7.82-7.81 (m, 1H), 7.80 (d, J=2.1 Hz, 1H), 7.53 (dd, J=8.4, 2.1 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 6.35 (s, 1H), 6.13 (d, J=5.2 Hz, 1H), 4.58 (m, 1H), 4.47 (dd, J=11.3, 5.3 Hz, 1H), 4.40 (t, J=6.2 Hz, 1H), 4.16 (d, J=1.9 Hz, 1H), 3.72 (dd, J=11.5, 5.5 Hz, 1H), 3.66 (dd, J=11.5, 6.7 Hz, 1H), 3.36 (s, 3H).

Example 43

3,4-Dichlorophenyl 3-[4-(2-aminothiazol-4-yl)-1H-1,2-pyrazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside

[0448] ##STR00131##

[0449] To an argon degassed solution of 3,4-dichlorophenyl 3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-1-thio-α-D-galactopyranos ide (39 mg, 0.073 mmol), [2-(tert-butoxycarbonylamino)thiazol-4-yl]boronic acid (18 mg, 0.073 mmol), tris(dibenzylideneacetone)dipalladium(0) (6.6 mg, 0.0073 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (8.2 mg, 0.015 mmol) in dioxane (0.5 mL) K.sub.2CO.sub.3 (72.5 μL, 2 M, 0.15 mmol) and water (0.18 mL) were added and the mixture stirred 1 h at 60° C. The mixture was diluted with water and extracted trice with EtOAc. The organic phases were dried, evaporated and dissolved in DCM (1.0 mL) and TFA (1.0 mL). The mixture was stirred 1 h in at rt before being concentrated. The residue was purified by reverse phase chromatography (C.sub.18, H.sub.2O/MeCN/0.1 TFA) to afford the title compound (1.8 mg, 5%). ESI-MS m/z calcd for [C.sub.19H.sub.20Cl.sub.2N.sub.4O.sub.4S.sub.2] [M+H].sup.+: 503.0; found: 502.8. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.18 (s, 1H), 7.89 (s, 1H), 7.82 (d, J=2.1 Hz, 1H), 7.55 (dd, J=8.4, 2.1 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 6.82 (s, 1H), 6.15 (d, J=5.3 Hz, 1H), 4.63 (dd, J=11.3, 2.8 Hz, 1H), 4.50 (dd, J=11.3, 5.3 Hz, 1H), 4.43 (t, J=6.2 Hz, 1H), 4.20 (d, J=2.0 Hz, 1H), 3.74 (dd, J=11.5, 5.6 Hz, 1H), 3.69 (dd, J=11.5, 6.7 Hz, 1H), 3.38 (s, 3H).

Example 44

5-Chloro-2-cyanophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside

[0450] ##STR00132##

[0451] Pd(dppf)Cl.sub.2 (6 mg, 0.0082 mmol), (4-chloro-3,5-difluorophenyl)boronic acid (15 mg, 0.076 mmol), 5-chloro-2-cyanophenyl 4,6-O-benzylidene-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-2-O-methyl-1-thio-α-D-galactopyranoside (31 mg, 0.050 mmol) and K.sub.2CO.sub.3 (35 mg, 0.25 mmol) were weighed into a vial and flushed with nitrogen. Dioxane (2.0 mL) followed by water (1.0 mL) were added to the vial and degassed with nitrogen. The mixture was stirred 2 h at 60° C. and was then partitioned between EtOAc and brine. The organic phase was evaporated, and the residue purified by filtration through silica using EtOAc/DCM. The obtained material was stirred 20 min at rt in TFA/water (0.5 mL, 4:1). The mixture was neutralized with NaOH (1 M) and extracted twice with EtOAc. The combined organic phases were dried, evaporated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1 TFA). The product was further purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the title compound (6.0 mg, 22%). ESI-MS m/z calcd for [C.sub.23H.sub.19Cl.sub.2F.sub.2N.sub.3O.sub.4S] [M+H].sup.+: 542.0; found: 542.0. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.28 (s, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.96 (d, J=0.6 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.49 (dd, J=8.4, 2.0 Hz, 1H), 7.40 (d, J=8.3 Hz, 2H), 6.38 (d, J=5.1 Hz, 1H), 4.66 (dd, J=11.3, 2.7 Hz, 1H), 4.60 (dd, J=11.3, 5.2 Hz, 1H), 4.38 (t, J=6.2 Hz, 1H), 4.20 (d, J=1.8 Hz, 1H), 3.70 (dd, J=11.5, 5.4 Hz, 1H), 3.64 (dd, J=11.5, 6.8 Hz, 1H), 3.43 (s, 3H).

Example 45

5-Chloro-2-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside

[0452] ##STR00133##

[0453] Pd(dppf)Cl.sub.2 (6 mg, 0.0082 mmol), (4-chloro-3,5-difluorophenyl)boronic acid (15 mg, 0.076 mmol), 5-chloro-2-cyanophenyl 4,6-O-benzylidene-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-2-O-methyl-1-thio-α-D-galactopyranoside (31 mg, 0.050 mmol) and K.sub.2CO.sub.3 (35 mg, 0.25 mmol) were weighed into a vial and flushed with nitrogen. Dioxane (2.0 mL) followed by water (1.0 mL) were added to the vial and degassed with nitrogen. The mixture was stirred 2 h at 60° C. and was then partitioned between EtOAc and brine. The organic phase was evaporated, and the residue purified by chromatography (SiO.sub.2, PE/EtOAc). The obtained material was stirred 20 min at rt in TFA/water (0.5 mL, 4:1). The mixture was neutralized with NaOH (1 M) and extracted twice with EtOAc. The combined organic phases were dried, evaporated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1 TFA). The product was further purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the title compound (6.5 mg, 25%). ESI-MS m/z calcd for [C.sub.23H.sub.19ClF.sub.3N.sub.3O.sub.4S] [M+H]+: 526.1; found: 526.1. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.22 (s, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.91 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.49 (dd, J=8.4, 2.0 Hz, 1H), 7.42-7.34 (m, 2H), 6.38 (d, J=5.1 Hz, 1H), 4.65 (dd, J=11.3, 2.7 Hz, 1H), 4.59 (dd, J=11.3, 5.2 Hz, 1H), 4.38 (t, J=6.1 Hz, 1H), 4.20 (d, J=1.8 Hz, 1H), 3.70 (dd, J=11.5, 5.4 Hz, 1H), 3.64 (dd, J=11.5, 6.8 Hz, 1H), 3.42 (s, 3H).

Intermediate 1

3-(4-Bromo-1H-pyrazol-1-yl)-3-deoxy-1,2:5,6-di-O-isopropylidene-α-D-galactofuranose

[0454] ##STR00134##

[0455] A solution of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (5.00 g, 19.2 mmol) in DCM (100 mL) and pyridine (3.1 mL, 38.4 mmol) was cooled to 0° C. and trifluoromethanesulphonic anhydride (3.9 mL, 23.1 mmol) in DCM (20 mL) was added dropwise. After stirring 1 h at 10° C. the mixture was quenched by adding crushed ice. The mixture was partitioned between DCM and HCl (1 M), the organic phase was washed with saturated aq NaHCO.sub.3, dried and concentrated. To the crude and Cs.sub.2CO.sub.3 (6.25 g, 19.2 mmol) in DMF (60 mL) 4-bromopyrazole (5.65 g, 38.4 mmol) was added. After stirring 18 h at rt ice was added to the mixture, the solids were filtered off and washed with 33% aq MeOH, then dried to afford the product (7.29 g, 97%). ESI-MS m/z calcd for [C.sub.15H.sub.21BrN.sub.2O.sub.5] [M+H].sup.+: 389.1; found: 388.8. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.53 (s, 1H), 7.52 (s, 1H), 5.98 (d, J=3.9 Hz, 1H), 4.90 (dd, J=3.9, 2.3 Hz, 1H), 4.68 (dd, J=6.7, 2.1 Hz, 1H), 4.34-4.22 (m, 2H), 4.06 (dd, J=8.3, 6.8 Hz, 1H), 3.89 (dd, J=8.3, 6.8 Hz, 1H), 1.64 (s, 3H), 1.45 (s, 3H), 1.39 (s, 3H), 1.38 (s, 3H).

1,2,4,6-Tetra-O-acetyl-3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-β-D-galactopyranoside

[0456] ##STR00135##

[0457] 3-(4-Bromo-1H-pyrazol-1-yl)-3-deoxy-1,2:5,6-di-O-isopropylidene-α-D-galactofuranose (6.00 g, 15.4 mmol) was dissolved in TFA (24 mL) and water (96 mL) and stirred 3 h at rt. The mixture was evaporated using MeCN for azeotropic removal of water and TFA and finally treated in vacuum for 1 h. The crude was dissolved in EtOAc (30 mL). Et.sub.3N (23.5 mL, 167 mmol) was added, temperature was maintained at 40° C. and acetic anhydride (13.3 mL, 139 mmol) was added at a rate to maintain the same temperature. The mixture was stirred at 40° C. for 6 h and at rt for 72 h, then cooled to 0° C. HCl (42 mL, 2 M, 84 mmol) was added slowly, the mixture was partitioned between EtOAc and water. The organic phase was washed with saturated aq NaHCO.sub.3, then brine. The organic phase was evaporated, and the residue was stirred in EtOAc (10 mL) and PE (20 mL). The precipitate was isolated by filtration, washed with EtOAc/PE (1:4), dried, to afford the product (1.79 g, 27%). ESI-MS m/z calcd for [C.sub.17H.sub.21BrN.sub.2O.sub.9] [M-AcOH].sup.+: 417.0; found: 416.6. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.48 (s, 2H), 5.83-5.73 (m, 2H), 5.48 (d, J=2.9 Hz, 1H), 4.75 (dd, J=10.1, 3.0 Hz, 1H), 4.21-4.05 (m, 3H), 2.15 (s, 3H), 2.04 (s, 6H), 1.93 (s, 3H).

3-Chlorophenyl 3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside

[0458] ##STR00136##

[0459] To a solution of 1,2,4,6-tetra-O-acetyl-3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-β-D-galactopyranoside (615 mg, 1.29 mmol) and PCl.sub.5 (349 mg, 1.68 mmol) in DCM (8 mL), BF.sub.3OEt.sub.2 (0.26 mL, 2.15 mmol) was added and the resulting mixture was stirred 24 h at rt. The solution was washed with ice/water, the organic phase was washed with saturated aq NaHCO.sub.3, dried and evaporated. The crude and 3-chlorobenzenethiol (0.12 mL, 1.00 mmol) were dissolved in DMF (5 mL), NaH (60% in oil, 77 mg, 2.00 mmol) was added and the mixture was stirred 3 h at rt. The mixture was diluted with EtOAc and washed twice with water and once with brine, the organic phase was dried, concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford a mixture of products. The mixture of products was stirred 1 h at rt in MeOH (4 mL) and NaOMe (1 M, 0.5 mL). The mixture was quenched with AcOH, concentrated and purified by HPLC (C.sub.18, H.sub.2O/MeCN/0.1 TFA) to afford the product (68 mg, 12%). ESI-MS m/z calcd for [C.sub.15H.sub.16BrClN.sub.2O.sub.4S] [M+H].sup.+: 435.0; found: 434.6. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.86 (s, 1H), 7.62 (s, 1H), 7.54-7.49 (m, 2H), 7.33-7.27 (m, 2H), 5.77 (d, J=5.4 Hz, 1H), 4.77 (dd, J=11.4, 5.41H), 4.53 (dd, J=11.4, 2.8 Hz, 1H), 4.43 (t, J=6.0 Hz, 1H), 4.14 (d, J=2.2 Hz, 1H), 3.72 (dd, J=11.4, 5.8 Hz, 1H), 3.65 (dd, J=11.4, 6.5 Hz, 1H).

Intermediate 2

5-Chloropyridin-3-yl 3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside

[0460] ##STR00137##

[0461] To a solution of 1,2,4,6-tetra-O-acetyl-3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-β-D-galactopyranoside (930 mg, 1.95 mmol) and PCl.sub.5 (528 mg, 2.53 mmol) in DCM (15 mL) BF.sub.3OEt.sub.2 (0.31 mL, 2.53 mmol) was added and the resulting mixture was stirred 5 h at rt. The solution was washed with ice/water, the organic phase was washed with saturated aq NaHCO.sub.3, dried and evaporated. The residue was dissolved with 5-chloropyridine-3-thiol (213 mg, 1.46 mmol) in DMF (7 mL), NaH (60% in oil, 112 mg, 2.92 mmol) was added and the mixture was stirred 16 h at rt. The mixture was diluted with EtOAc and washed twice with water and once with brine. The organic phase was dried, concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc). The obtained material was stirred 1 h at rt with NaOMe (0.5 mL, 1M) and MeOH (6 mL). The reaction was quenched with AcOH, evaporated and purified by HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the product (49 mg, 6%). ESI-MS m/z calcd for [C.sub.14H.sub.15BrClN.sub.3O.sub.4S] [M+H].sup.+: 436.0; found: 435.6. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.63 (d, J=1.8 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H), 8.20 (t, J=2.0 Hz, 1H), 7.87 (s, 1H), 7.53 (s, 1H), 5.88 (d, J=5.4 Hz, 1H), 4.80 (dd, J=11.3, 5.41H), 4.56 (dd, J=11.4, 2.7 Hz, 1H), 4.39 (t, J=6.0 Hz, 1H), 4.14 (d, J=2.0 Hz, 1H), 3.73-3.63 (m, 2H).

Intermediate 3

2,4,6-Tri-O-acetyl-3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-β-D-galactopyranosyl Chloride

[0462] ##STR00138##

[0463] 1,2,4,6-Tetra-O-acetyl-3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-β-D-galactopyranoside (2.0 g, 4.06 mmol) and PCl.sub.5 (1.73 g, 8.12 mmol) were stirred in DCM (30 mL) and BF.sub.3OEt.sub.2 (0.65 mL, 5.30 mmol) was added. The mixture was stirred 4 h at rt, more BF.sub.3OEt.sub.2 (0.33 mL, 2.64 mmol) was added and continued stirring 2 h at rt. The mixture was partitioned between ice, water, NaOH (10 mL, 5M), and DCM, the organic phase was separated, dried and evaporated to afford the product (1.92 g, quant. yield). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.50 (s, 1H), 7.48 (s, 1H), 5.79 (dd, J=11.3, 8.5 Hz, 1H), 5.50 (d, J=3.1 Hz, 1H), 5.37 (d, J=8.5 Hz, 1H), 4.72 (dd, J=11.3, 3.2 Hz, 1H), 4.23-4.08 (m, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 1.99 (s, 3H).

5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside

[0464] ##STR00139##

[0465] NaH (60% in oil, 50 mg, 1.31 mmol) was added to 2,4,6-tri-O-acetyl-3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-β-D-galactopyranosyl chloride (495 mg, 1.09 mmol) and 5-chloropyridine-3-thiol (159 mg, 1.09 mmol) in DMF (5 mL). The mixture was stirred 21 h at rt. More 5-chloropyridine-3-thiol (80 mg, 0.55 mmol) and NaH (60% in oil, 25 mg, 0.55 mmol) were added and the mixture was stirred for additionally 4 h before it was diluted with EtOAc (50 mL) and washed with water (5×50 mL) and brine (50 mL). The organic phase was dried, concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (148 mg, 24%). ESI-MS m/z calcd for [C.sub.20H.sub.22BrClN.sub.3O.sub.7S] [M+H].sup.+: 562.0; found: 562.1. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.57 (s, 1H), 8.52 (s, 1H), 7.88 (s, 1H), 7.48 (s, 1H), 7.43 (s, 1H), 6.09 (d, J=5.1 Hz, 1H), 6.00-5.91 (m, 1H), 5.54 (s, 1H), 4.85 (d, J=11.9 Hz, 1H), 4.83-4.74 (m, 1H), 4.17-4.05 (m, 2H), 2.09-1.99 (m, 9H).

Intermediate 6

3-Deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-1,2:5,6-di-O-isopropylidene-α-D-galactofuranose

[0466] ##STR00140##

[0467] A solution of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (12.54 g, 48.2 mmol) in DCM (150 mL) and pyridine (7.8 mL, 96.4 mmol) was cooled to 0° C. and trifluoromethanesulphonic anhydride (9.8 mL, 57.9 mmol) in DCM (30 mL) was added dropwise. After stirring 1 h at 10° C. the mixture was quenched by adding crushed ice. The mixture was partitioned between DCM and HCl (1 M), the organic phase was washed with saturated aq NaHCO.sub.3, dried and concentrated. To a solution of the crude and Cs.sub.2CO.sub.3 (15.7 g, 48.2 mmol) in DMF (150 mL) 4-iodopyrazole (13.36 g, 67.5 mmol) was added. After stirring 2 h at rt ice was added to the mixture, the solids were filtered off and washed with 33% aq MeOH, then dried to afford the product (23.9 g, quantitative yield). ESI-MS m/z calcd for [C.sub.15H.sub.21IN.sub.2O.sub.5] [M+H].sup.+: 437.1; found: 436.9. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.58 (s, 1H), 7.54 (s, 1H), 5.98 (d, J=4.0 Hz, 1H), 4.89 (dd, J=3.9, 2.3 Hz, 1H), 4.71 (dd, J=6.7, 2.1 Hz, 1H), 4.31 (dd, J=6.7, 4.4 Hz, 1H), 4.29-4.22 (m, 1H), 4.05 (dd, J=8.3, 6.8 Hz, 1H), 3.88 (dd, J=8.3, 6.8 Hz, 1H), 1.64 (s, 3H), 1.45 (s, 3H), 1.38 (s, 6H).

1,2,4,6-Tetra-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D-galactopyranoside

[0468] ##STR00141##

[0469] 3-Deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-1,2:5,6-di-O-isopropylidene-α-D-galactofuranose (6.00 g, 15.4 mmol) was dissolved in TFA (40 mL) and water (100 mL) and stirred 1 h at rt. The mixture was evaporated using MeCN for azeotropic removal of water and TFA and finally treated in vacuum. The crude was dissolved in EtOAc (105 mL), Et.sub.3N (105 mL) and acetic anhydride (53 mL, 560 mmol) were added and the mixture was stirred 20 h at rt. The mixture was cooled to 0° C. and EtOAc (200 mL) followed by HCl (280 mL, 2 M) were added slowly. The mixture was stirred 20 min, then filtered through celite. The organic phase was separated, washed with saturated aq NaHCO.sub.3 and brine, dried and evaporated. The residue was filtered through silica using EtOAc/PE (1:1) and concentrated. The obtained syrup was dissolved in EtOAc (50 mL), and PE (80 mL) was added slowly, which resulted in crystallization. The crystals were isolated by filtration to afford the product (9.68 g, 58% purity, 38%). The filtrate was evaporated to afford more of the product (15.8 g, 65% purity, 62%). ESI-MS m/z calcd for [C.sub.17H.sub.21IN.sub.2O.sub.9] [M+H].sup.+: 525.0; found: 524.8. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.52 (s, 1H), 7.50 (s, 1H), 5.82-5.75 (m, 2H), 5.47 (d, J=3.1 Hz, 1H), 4.79 (m, 1H), 4.16-4.07 (m, 3H), 2.15 (s, 3H), 2.04 (s, 6H), 1.93 (s, 3H).

1,2,4,6-Tetra-O-acetyl-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D-galactopyranoside

[0470] ##STR00142##

[0471] Pd(dppf)Cl.sub.2 (582 mg, 0.76 mmol), 1,2,4,6-tetra-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D-galactopyranoside (2.2 g, 3.78 mmol), K.sub.2CO.sub.3 (2.61 g, 18.9 mmol) and (4-chloro-3,5-difluorophenyl)boronic acid (994 mg, 4.9 mmol) were weighed into a flask and flushed with nitrogen. Dioxane (10 mL) followed by water (5.0 mL) were added to the flask and degassed with nitrogen. The mixture was stirred 1 h at 60° C. and then partitioned between EtOAc and brine. The organic phase was evaporated, and the residue purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (1.03 g, 77%). ESI-MS m/z calcd for [C.sub.23H.sub.23ClF.sub.2N.sub.2O.sub.9] [M+H].sup.+: 545.1; found: 544.9. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.75 (s, 1H), 7.72 (s, 1H), 7.04 (d, J=7.9 Hz, 2H), 5.85 (bs, 2H), 5.55 (bs, 1H), 4.81 (bs, 1H), 4.21-4.07 (m, 3H), 2.17 (s, 3H), 2.02 (s, 3H), 1.93 (s, 3H).

2,4,6-Tri-O-acetyl-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D-galactopyranosyl chloride

[0472] ##STR00143##

[0473] To a solution of 1,2,4,6-tetra-O-acetyl-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D-galactopyranoside (1.022 g, 1.87 mmol) and PCl.sub.5 (996 mg, 4.7 mmol) in DCM (10 mL), BF.sub.3OEt.sub.2 (0.48 mL, 3.74 mmol) was added and the mixture was stirred 2.5 h at rt. The solution was partitioned between DCM and ice/water/NaOH (2 M). The organic phase was dried and evaporated to afford the product (1.34 g, quantitative yield). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.81 (bs, 2H), 7.04 (d, J=7.3 Hz, 2H), 5.86 (bs, 1H), 5.58 (s, 1H), 5.43 (bs, 1H), 4.91 (bs, 1H), 4.26-4.11 (m, 3H), 2.07 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H).

Intermediate 9

5-Chloro-2-cyanophenyl 3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside

[0474] ##STR00144##

[0475] 2,4,6-Tri-O-acetyl-3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-β-D-galactopyranosyl chloride (1.00 g, 1.32 mmol), 4-chloro-2-sulfanylbenzonitrile (314 mg, 1.85 mmol) and K.sub.2CO.sub.3 (360 mg, 2.6 mmol) were stirred 2 h at 60° C. in DMF (8.0 mL). The mixture was partitioned between EtOAc/water/HCl, the organic phase was collected, dried, and evaporated. The residue was purified by chromatography (SiO.sub.2, PE/EtOAc) and the obtained material was stirred 18 h at rt in MeOH (4 mL) and NaOMe (1 M, 0.5 mL). The mixture was neutralized with acetic acid (60 μL), evaporated, and the residue was purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1 TFA) to afford the product (80 mg, 13%). ESI-MS m/z calcd for [C.sub.16H.sub.15BrClN.sub.3O.sub.4S] [M+H].sup.+: 460.0; found: 459.7. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.97 (d, J=1.9 Hz, 1H), 7.88 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.53 (s, 1H), 7.45 (dd, J=8.4, 2.0 Hz, 1H), 6.07 (d, J=5.4 Hz, 1H), 4.84 (m, 1H), 4.61 (dd, J=11.4, 2.7 Hz, 1H), 4.33 (t, J=6.1 Hz, 1H), 4.17 (d, J=2.0 Hz, 1H), 3.68 (dd, J=11.4, 5.6 Hz, 1H), 3.61 (dd, J=11.4, 6.7 Hz, 1H).

2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside

[0476] ##STR00145##

[0477] A mixture of 5-chloro-2-cyanophenyl 3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside (302 mg, 0.65 mmol) in EtOH (8.0 mL) and NaOH (3 M, 4.0 mL) was stirred 17 h at 50° C. The mixture was stirred 2 h at 70° C. before being concentrated and partitioned between EtOAc/water/HCl at pH 1-2. The organic phase was dried, evaporated, and the residue was purified by chromatography (SiO.sub.2, PE/EtOAc). The obtained material, 1-hydroxybenzotriazole hydrate (147 mg, 0.93 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (183 mg, 0.93 mmol) were stirred in DMF (4 mL) and azetidine (91 μL, 1.24 mmol) was added followed by Et.sub.3N (91 μL, 0.62 mmol). The mixture was stirred 18 h at rt, it was then partitioned between brine and EtOAc. The aqueous phase was extracted three times with EtOAc, and the combined organic phases were dried, evaporated, and purified by chromatography (SiO.sub.2, EtOAc/MeOH) to give the product (157 mg, 49%). ESI-MS m/z calcd for [C.sub.19H.sub.21BrClN.sub.3O.sub.4S] [M+H].sup.+: 518.0; found: 517.8. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.86 (s, 1H), 7.85 (d, J=1.8 Hz, 1H), 7.53 (s, 1H), 7.38 (dd, J=8.2, 1.8 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 5.87 (d, J=5.4 Hz, 1H), 4.78 (dd, J=11.4, 5.4 Hz, 1H), 4.54 (dd, J=11.4, 2.7 Hz, 1H), 4.39 (t, J=6.1 Hz, 1H), 4.19 (d, J=7.8 Hz, 2H), 4.14 (d, J=2.5 Hz, 1H), 4.02 (d, J=7.7 Hz, 2H), 3.71 (dd, J=11.5, 5.5 Hz, 1H), 3.66 (dd, J=11.3, 6.8 Hz, 1H), 2.34 (p, J=7.7 Hz, 2H).

Intermediate 12

2-Bromo-5-chloro-pyridine-3-thiol

[0478] ##STR00146##

[0479] To an ice-cold solution of 2-bromo-5-chloro-3-fluoro-pyridine (2.00 g, 9.5 mmol) in DMF (10 mL) sodium hydrosulfide hydrate (682 mg, 8.5 mmol) was added. After 2 h at rt the mixture was partitioned between diethyl ether and HCl (0.5 M). The organic phase was extracted with NaOH (0.5 M). The aqueous phase was acidified with HCl (5 M) until a precipitate was formed. Filtration yielded the product (735 mg, 34%). ESI-MS m/z calcd for [C.sub.5H.sub.4BrClNS] [M+H].sup.+: 223.9; found: 223.6. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.12 (d, J=2.3 Hz, 1H), 7.64 (d, J=2.3 Hz, 1H), 4.04 (s, 1H).

2,4,6-Tri-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D-galactopyranosyl Chloride

[0480] ##STR00147##

[0481] To a solution of 1,2,4,6-tetra-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D-galactopyranoside (7.74 g, 14.7 mmol), PCl.sub.5 (6.28 g, 29.5 mmol) in DCM (100 mL) and BF.sub.3OEt.sub.2 (3.95 mL, 29.5 mmol) was added. The mixture was stirred 4 h at rt and was then partitioned between ice/water and DCM, NaOH (85 mL, 2 M) was added and pH became approximately 5 during the washing. The organic phase was dried and evaporated to give the product (6.2 g, 60% purity), which was used without purification in subsequent steps.

2-Bromo-5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-1-thio-α-D-galactopyranoside

[0482] ##STR00148##

[0483] A solution of 2,4,6-tri-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D-galactopyranosyl chloride (2.20 g, 60% purity, 2.63 mmol), 2-bromo-5-chloro-pyridine-3-thiol (710 mg, 3.16 mmol) and K.sub.2CO.sub.3 (729 mg, 5.27 mmol) in DMF (10 mL) was stirred 3 h at rt followed by 2 h at 50° C. The mixture was diluted with EtOAc and washed with water, NaOH (1 M) and brine. The organic phase was concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to yield the product (700 mg, 60% purity). ESI-MS m/z calcd for [C.sub.20H.sub.21BrClIN.sub.3O.sub.7S] [M+H].sup.+: 687.9; found: 687.7. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.23 (d, J=2.4 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.53 (s, 1H), 7.48 (s, 1H), 6.24 (d, J=5.7 Hz, 1H), 6.02 (dd, J=11.8, 5.6 Hz, 1H), 5.56-5.51 (m, 1H), 4.93 (dd, J=11.8, 3.1 Hz, 1H), 4.73-4.67 (m, 1H), 4.18-4.04 (m, 2H), 2.05 (d, J=2.6 Hz, 3H), 2.01 (d, J=2.4 Hz, 3H), 1.97 (s, 3H).

2-Bromo-5-chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0484] ##STR00149##

[0485] A solution of 2-bromo-5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-1-thio-α-D-galactopyranoside (700 mg, 60% purity, 1.0 mmol), Pd(dppf)Cl.sub.2 (112 mg, 0.152 mmol), (3,4,5-trifluorophenyl)boronic acid (215 mg, 1.22 mmol) and K.sub.2CO.sub.3 (702 mg, 5.08 mmol) in dioxane (6 mL) and water (3 mL) was stirred 80 min at 60° C. followed by 16 h at rt. The mixture was concentrated and partitioned between EtOAc and water. The organic phase was washed with water and brine, dried and concentrated. The residue was purified by chromatography (SiO.sub.2, PE/EtOAc) and the obtained material was dissolved in MeOH (20 mL) and NaOMe (2 mL, 1 M). After 1 h at rt the reaction was quenched with acetic acid (200 μL) and the mixture was concentrated. The residue was partitioned between EtOAc and water. The organic phase was washed with brine, dried and concentrated. Purification by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) yielded the product (60 mg, 9%). ESI-MS m/z calcd for [C.sub.20H.sub.17BrClF.sub.3N.sub.3O.sub.4S] [M+H].sup.+: 566.0; found: 565.8. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.21-8.16 (m, 3H), 7.92 (s, 1H), 7.40-7.33 (m, 2H), 6.12 (d, J=5.5 Hz, 1H), 4.94 (dd, J=11.3, 5.5 Hz, 1H), 4.66 (dd, J=11.3, 2.7 Hz, 1H), 4.30 (t, J=6.1 Hz, 1H), 4.20 (d, J=2.1 Hz, 1H), 3.75-3.63 (m, 2H).

Intermediate 13

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

[0486] ##STR00150##

[0487] To a solution of 2,4,6-tri-O-acetyl-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2-pyrazol-1-yl]-3-deoxy-β-D-galactopyranosyl chloride (270 mg, 0.52 mmol), 2-bromo-5-chloro-pyridine-3-thiol (291 mg, 1.30 mmol) in DMF (5 mL) Cs.sub.2CO.sub.3 (844 mg, 2.59 mmol) was added. After stirring 18 h at 40° C. more 2-bromo-5-chloro-pyridine-3-thiol (100 mg, 0.45 mmol) was added. After 6 h at 50° C. the mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried, concentrated onto silica and purified by chromatography (SiO.sub.2, PE/EtOAc). Further purification by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) yielded the product (51 mg, 17%) as a white solid. ESI-MS m/z calcd for [C.sub.20H.sub.17BrCl.sub.2F.sub.2N.sub.3O.sub.4S] [M+H].sup.+: 581.9; found: 581.8. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.28 (s, 1H), 8.23-8.19 (m, 2H), 7.99 (s, 1H), 7.41 (d, J=8.3 Hz, 2H), 6.14 (d, J=5.4 Hz, 1H), 4.96 (dd, J=11.3, 5.4 Hz, 1H), 4.69 (dd, J=11.3, 2.8 Hz, 1H), 4.32 (t, J=6.2 Hz, 1H), 4.22 (d, J=2.1 Hz, 1H), 3.77-3.64 (m, 2H).

Intermediate 14

3-Fluoro-5-methyl-pyridine-2-carbonitrile

[0488] ##STR00151##

[0489] A nitrogen purged solution of 2-bromo-3-fluoro-5-methyl-pyridine (300 mg, 1.58 mmol), zinc cyanide (371 mg, 3.16 mmol), 1,1′-bis(diphenylphosphino)ferrocene (71 mg, 0.13 mmol), tris(dibenzylideneacetone)dipalladium(0) (72.6 mg, 0.13 mmol) and Zn (51 mg, 0.79 mmol) in DMF (5 mL) was stirred 16 h at 100° C. The mixture was removed from stirring and the solids were allowed to sink. The supernatant was partitioned between EtOAc and brine. The organic phase was washed with brine, dried, concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to yield the product (202 mg, 94%). .sup.1H NMR (500 MHz, Chloroform-d) δ 8.37 (s, 1H), 7.44-7.36 (m, 1H), 2.48 (s, 3H).

5-Chloro-2-methylpyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-1-thio-α-D-galactopyranoside

[0490] ##STR00152##

[0491] To a solution of 2,4,6-tri-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D-galactopyranosyl chloride (420 mg, 60% purity, 0.84 mmol) in DMF (4 mL) potassium thioacetate (144 mg, 1.26 mmol) was added. After stirring 19 h at rt the mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried, concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc). The obtained material was dissolved together with 3-fluoro-5-methyl-pyridine-2-carbonitrile (90.7 mg, 0.67 mmol) in DMF (2 mL) and diethylamine (114 μL, 1.11 mmol) was added. After 20 h at rt the mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried, concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to yield the product (200 mg, 50% purity, 59%). ESI-MS m/z calcd for [C.sub.22H.sub.20F.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 615.0; found: 614.8.

Intermediate 15

5-Bromo-2-cyanopyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0492] ##STR00153##

[0493] A nitrogen purged solution of 1,2,4,6-tetra-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D-galactopyranoside (2.70 g, 5.15 mmol), K.sub.2CO.sub.3 (3.56 g, 25.8 mmol), (3,4,5-trifluorophenyl)boronic acid (1.36 g, 7.73 mmol) and Pd(dppf)Cl.sub.2 (565 mg, 0.77 mmol) in water/dioxane (1:2, 22.5 mL) was heated 1 h at 60° C. The mixture was partitioned between EtOAc and water and the organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc). The obtained material and PCl.sub.5 (1.17 g, 5.63 mmol) were dissolved in DCM (45 mL) and BF.sub.3OEt.sub.2 (0.80 mL, 6.50 mmol) was added. The mixture was stirred 5 h at rt before it was diluted with DCM and washed with water and saturated aq NaHCO.sub.3, dried and evaporated. The residue was dissolved with potassium thioacetate (742 mg, 6.50 mmol) in DMF (20 mL) and the mixture was stirred 18 h at 30° C. The mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc). The obtained material and 5-bromo-3-fluoropyridine-2-carbonitrile (750 mg, 3.73 mmol) were dissolved in DMF (8 mL) and diethylamine (0.72 mL, 7.00 mmol) was added and the mixture was stirred 2 h at rt. The mixture was partitioned between water and EtOAc, the organic phase was washed with water, dried and evaporated. The residue was purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (453 mg, 13%). ESI-MS m/z calcd for [C.sub.27H.sub.22BrF.sub.3N.sub.4O.sub.7S] [M+H].sup.+: 683.0; found: 683.0. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.70 (d, J=2.0 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 7.72 (s, 1H), 7.66 (s, 1H), 7.06 (dd, J=8.2, 6.4 Hz, 2H), 6.27 (d, J=5.6 Hz, 1H), 6.12 (dd, J=11.6, 5.6 Hz, 1H), 5.62 (d, J=2.4 Hz, 1H), 4.89 (dd, J=11.6, 3.0 Hz, 1H), 4.83-4.77 (m, 1H), 4.20-4.08 (m, 2H), 2.07 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H).

Intermediate 17

5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0494] ##STR00154##

[0495] 5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside (428 mg, 0.76 mmol), Pd(dppf)Cl.sub.2 (56 mg, 0.076 mmol), bis(pinacolato)diboron (579 mg, 2.28 mmol) and potassium acetate (373 mg, 3.80 mmol) were weighed into a vial and flushed with argon. Degassed DMSO (7.0 mL) was added to the vial and the mixture was stirred 17 h at 85° C. The mixture was diluted with EtOAc (100 mL) and washed with water (3×100 mL) and brine (100 mL). The organic phase was dried, evaporated, and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (228 mg, 34%). ESI-MS m/z calcd for [C.sub.26H.sub.33BClN.sub.3O.sub.9S] [M+H].sup.+: 610.2; found: 610.0. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.52 (s, 1H), 7.93 (s, 1H), 7.77 (s, 1H), 7.70 (s, 1H), 6.16 (d, J=5.6 Hz, 1H), 5.97 (dd, J=11.7, 5.4 Hz, 1H), 5.54 (d, J=2.2 Hz, 1H), 4.91 (dd, J=11.7, 3.0 Hz, 1H), 4.82-4.77 (m, 1H), 4.19-4.11 (m, 1H), 4.08 (dd, J=11.5, 7.5 Hz, 1H), 2.04 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H), 1.32 (d, J=3.8 Hz, 12H).

Intermediate 18

5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D-galactopyranoside

[0496] ##STR00155##

[0497] A solution of 2,4,6-tri-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D-galactopyranosyl chloride (3.0 g, 60% purity, 3.59 mmol), 5-chloropyridine-3-thiol (1.05 g, 7.2 mmol) and Cs.sub.2CO.sub.3 (2.4 g, 7.2 mmol) in DMF (10.0 mL) was stirred 3 h at rt. The mixture was partitioned between EtOAc and brine, the organic phase was dried and evaporated. The residue was purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (1.48 g, 75% purity, 26%). ESI-MS m/z calcd for [C.sub.20H.sub.21ClIN.sub.3O.sub.7S] [M+H].sup.+: 610.0; found: 609.8. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.52 (s, 1H), 7.92 (s, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 6.11 (d, J=5.6 Hz, 1H), 5.96 (dd, J=11.7, 5.5 Hz, 1H), 5.53 (d, J=2.9 Hz, 1H), 4.88 (dd, J=11.7, 3.1 Hz, 1H), 4.80-4.74 (m, 1H), 4.19-4.06 (m, 2H), 2.04 (s, 6H), 2.01 (s, 3H).

Intermediate 28

1,2,4,6-Tetra-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-β-D-galactopyranoside

[0498] ##STR00156##

[0499] 1,2,4,6-Tetra-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D-galactopyranoside (5.243 g, 10.0 mmol), Pd(dppf)Cl.sub.2 (732 mg, 1.00 mmol), bis(pinacolato)diboron (7.618 g, 30.0 mmol) and potassium acetate (4.907 g, 50.0 mmol) were dissolved in degassed DMF (100 mL) and the mixture was stirred 2 h at 60° C. The mixture was filtered through celite and concentrated to approximately 50 mL and diluted with PE/EtOAc (1:1, 500 mL). The solution was washed with water (3×500 mL) and brine (300 mL). The organic phase was dried, evaporated, and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (4.22 g, 50% purity, 81%). ESI-MS m/z calcd for [C.sub.23H.sub.33BN.sub.2O.sub.11] [M+H].sup.+: 525.2; found: 525.0. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.76 (s, 1H), 7.73 (s, 1H), 5.88-5.78 (m, 2H), 5.47 (s, 1H), 4.88-4.77 (m, 1H), 4.24-4.07 (m, 3H), 2.15 (s, 3H), 2.03 (s, 6H), 1.90 (s, 3H), 1.35-1.22 (m, 12H).

2,4,6-Tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranosyl chloride

[0500] ##STR00157##

[0501] To a solution of 1,2,4,6-tetra-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (1.00 g, 50% purity, 1.19 mmol) and PCl.sub.5 (794 mg, 3.81 mmol) in DCM (15.7 mL) BF.sub.3OEt.sub.2 (0.47 mL, 3.81 mmol) was added. The mixture was stirred 24 h at rt and was then poured on ice/DCM (1:1, 70 mL) and neutralized with NaOH (1 M). The organic phase was separated, and the aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were washed with brine, dried and evaporated to give the product (1.01 g, 50% purity), which was used without purification in subsequent steps.

5-Bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0502] ##STR00158##

[0503] To a solution of 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranosyl chloride (500 mg, 50% purity, 1.00 mmol) and 5-bromopyridine-3-thiol (285 mg, 1.50 mmol) in DMF (8.1 mL) NaH (60% in oil, 76.5 mg, 2.00 mmol) was added and the mixture was stirred 21 h at rt. The mixture was diluted with EtOAc (100 mL) and washed with water (5×100 mL) and brine (100 mL). The organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (189 mg, 20% purity, 29%). ESI-MS m/z calcd for [C.sub.26H.sub.33BBrN.sub.3O.sub.9S] [M+H].sup.11: 654.1; found: 654.0. .sup.1H NMR (500 MHz, Chloroform-d) δ 8.61 (d, J=2.0 Hz, 2H), 8.03 (t, J=1.8 Hz, 1H), 7.77 (s, 1H), 7.70 (s, 1H), 6.14 (d, J=5.5 Hz, 1H), 5.96 (dd, J=11.8, 5.6 Hz, 1H), 5.54 (d, J=2.6 Hz, 1H), 4.90 (dd, J=11.7, 3.2 Hz, 1H), 4.79 (t, J=6.4 Hz, 1H), 4.19-4.05 (m, 2H), 2.03 (s, 6H), 1.98 (s, 3H), 1.25 (s, 12H).

Intermediate 29

5-Chloro-2-cyanophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0504] ##STR00159##

[0505] To a solution of 1,2,4,6-tetra-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-β-D-galactopyranoside (4.22 g, 50% purity, 8.05 mmol) and PCl.sub.5 (3.35 g, 16.1 mmol) in DCM (66.2 mL) BF.sub.3OEt.sub.2 (1.99 mL, 16.1 mmol) was added. The mixture was stirred 1.5 h at rt and was then poured on ice and neutralized with NaOH (1 M). The organic phase was separated, and the aqueous phase was extracted with DCM (70 mL). The combined organic phases were dried and evaporated. The residue was dissolved in DMF (25 mL) and 4-chloro-2-sulfanyl-benzonitrile (500 mg, 2.95 mmol) followed by NaH (60% in oil, 130 mg, 3.40 mmol) were added and the mixture was heated 1 h at 60° C. EtOAc (250 mL) was added and the mixture was washed with NaOH (0.1 M, 250 mL), water (3×250 mL) and brine (250 mL). The organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (92 mg, 50% purity, 2%). ESI-MS m/z calcd for [C.sub.28H.sub.33BClN.sub.3O.sub.9S] [M+H].sup.11: 634.2; found: 634.0. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 6.22 (d, J=5.4 Hz, 1H), 6.00 (dd, J=11.4, 5.6 Hz, 1H), 5.58-5.54 (m, 1H), 4.90 (dd, J=11.0, 3.1 Hz, 1H), 4.81 (t, J=4.3 Hz, 1H), 4.14-4.09 (m, 2H), 2.02 (s, 6H), 2.00 (s, 3H), 1.35-1.30 (m, 12H).

Intermediate 30

2-Bromo-5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0506] ##STR00160##

[0507] To a solution of 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranosyl chloride (500 mg, 50% purity, 1.00 mmol) and 2-bromo-5-chloropyridine-3-thiol (336 mg, 1.50 mmol) in DMF (8.1 mL) NaH (60% in oil, 76.5 mg, 2.00 mmol) was added and the mixture was heated 3 h at 50° C. The mixture was diluted with EtOAc (100 mL) and washed with water (5×100 mL) and brine (100 mL). The organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (53 mg, 50% purity, 8%). ESI-MS m/z calcd for [C.sub.26H.sub.32BBrClN.sub.3O.sub.9S] [M+H].sup.+: 688.1; found: 688.0. .sup.1H NMR (500 MHz, Chloroform-d) δ 8.23 (d, J=2.4 Hz, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.79 (s, 1H), 7.73 (s, 1H), 6.29 (d, J=5.6 Hz, 1H), 6.04 (dd, J=11.8, 5.6 Hz, 1H), 5.56 (d, J=2.2 Hz, 1H), 4.98 (dd, J=11.7, 3.1 Hz, 1H), 4.76-4.69 (m, 1H), 4.17-4.09 (m, 2H), 2.05 (s, 3H), 2.01 (s, 3H), 1.98 (s, 3H), 1.34 (d, J=3.8 Hz, 12H).

5-Chloro-2-cyanopyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0508] ##STR00161##

[0509] A solution of 2-bromo-5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (53 mg, 0.077 mmol), zinc cyanide (9.0 mg, 0.077 mmol), Zn (2.5 mg, 0.038 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.8 mg, 0.0031 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (3.5 mg, 0.0062 mmol) in argon purged DMF (1.0 mL) was stirred 3 h at 100° C. More zinc cyanide (4.5 mg, 0.038 mmol) was added and the mixture was stirred 2 h at 100° C. The mixture was diluted with EtOAc (10 mL), filtered through a plug of celite, washed with water (5×10 mL) and brine (10 mL). The organic phase was dried, concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (23 mg, 40% purity, 47%). ESI-MS m/z calcd for [C.sub.27H.sub.32BClN.sub.4O.sub.9S] [M+H].sup.+; 635.2; found: 634.9. .sup.1H NMR (500 MHz, Chloroform-d) δ 8.57 (s, 1H), 8.08 (s, 1H), 7.77 (s, 1H), 7.72 (s, 1H), 6.26 (d, J=4.9 Hz, 1H), 6.13-5.98 (m, 1H), 5.65-5.48 (m, 1H), 5.02-4.85 (m, 1H), 4.84-4.66 (m, 1H), 4.20-4.05 (m, 2H), 2.03 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H), 1.25 (s, 12H).

Intermediate 31

2-Benzyloxy-4-bromothiazole

[0510] ##STR00162##

[0511] Benzyl alcohol (2.00 g, 18.3 mmol) and NaH (60% in oil, 1.1 g, 27.5 mmol) were weighed into a bottle and THF (10 mL) was added. When the gas evolution ceased 2,4-dibromothiazole (3.25 g, 13.0 mmol) was added and the mixture was stirred 1 h at rt. The mixture was partitioned between diethyl ether and water. The organic phase was washed with brine, dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc) to give the product (3.23 g, 92%). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.49-7.34 (m, 5H), 6.62 (s, 1H), 5.46 (s, 2H).

5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-benzyloxythiazol-4-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0512] ##STR00163##

[0513] 5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (100 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol) and 2-benzyloxy-4-bromothiazole (133 mg, 0.49 mmol) were dissolved in a degassed mixture of toluene (1.0 mL), EtOH (0.2 mL) and aq Na.sub.2CO.sub.3 (246 μL, 2 M) and the resulting mixture was refluxed 2 h. The mixture was cooled to rt and the organic phase was separated. The aqueous phase was extracted with EtOAc (2×1 mL) and the combined organic phases were dried and concentrated. The residue was purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (77 mg, 70%). ESI-MS m/z calcd for [C.sub.30H.sub.29ClN.sub.4O.sub.8S.sub.2] [M+H].sup.11: 673.1; found: 673.2. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.52 (s, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.76 (s, 1H), 7.51-7.45 (m, 2H), 7.45-7.35 (m, 3H), 6.59 (s, 1H), 6.13 (d, J=5.5 Hz, 1H), 6.00 (dd, J=11.6, 5.6 Hz, 1H), 5.59 (d, J=9.4 Hz, 1H), 5.48 (s, 1H), 4.91 (d, J=9.2 Hz, 1H), 4.85-4.77 (m, 1H), 4.18-4.06 (m, 2H), 2.04 (s, 6H), 2.01 (s, 3H).

Intermediate 35

2-Bromo-5-chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside

[0514] ##STR00164##

[0515] A solution of 2-bromo-5-chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (511 mg, 0.90 mmol), benzaldehyde dimethylacetal (176 μL, 1.17 mmol) and methanesulfonic acid (67 μL, 1.03 mmol) was stirred 30 min at rt before Et.sub.3N (200 μL) was added. The mixture was diluted with EtOAc (50 mL), washed with water (50 mL) and brine (50 mL), dried and concentrated. The residue was purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (158 mg, 27%). ESI-MS m/z calcd for [C.sub.27H.sub.20BrClF.sub.3N.sub.3O.sub.4S] [M+H].sup.+: 654.0; found: 653.8. .sup.1H NMR (500 MHz, Chloroform-d) δ 8.19 (d, J=2.3 Hz, 1H), 7.92 (s, 1H), 7.78 (d, J=2.3 Hz, 1H), 7.77 (s, 1H), 7.47-7.38 (m, 5H), 7.09-7.02 (m, 2H), 6.51 (d, J=3.6 Hz, 1H), 5.59 (s, 1H), 4.99 (dd, J=11.0, 3.1 Hz, 1H), 4.77 (dd, J=11.0, 3.6 Hz, 1H), 4.57 (d, J=2.5 Hz, 1H), 4.42 (dd, J=12.8, 1.4 Hz, 1H), 4.24 (s, 1H), 4.19 (dd, J=12.9, 1.7 Hz, 1H).

2-Bromo-5-chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside

[0516] ##STR00165##

[0517] To a solution of 2-bromo-5-chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-1-thio-α-D-galactopyranoside (158 mg, 0.24 mmol) in DMF (2.0 mL) NaH (60% in oil, 19 mg, 0.48 mmol) and iodomethane (22.5 μL, 0.36 mmol) were added and the mixture was stirred 30 min at rt. The mixture was diluted with EtOAc (10 mL), washed with water (5×10 mL) and brine (10 mL), dried and concentrated. The residue was stirred 20 min at rt in 80% aq TFA (0.83 mL). NaOH (10 mL, 1 M) was added and the mixture was extracted with EtOAc (2×10 mL). The combined organic phases were dried, concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (124 mg, 84%). ESI-MS m/z calcd for [C.sub.21H.sub.18BrClF.sub.3N.sub.3O.sub.4S] [M+H].sup.+: 580.0; found: 579.7. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.22 (s, 1H), 8.13 (d, J=2.4 Hz, 1H), 7.92 (s, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.44-7.31 (m, 2H), 6.43 (d, J=5.2 Hz, 1H), 4.68 (dd, J=11.6, 2.6 Hz, 1H), 4.61 (dd, J=11.1, 5.1 Hz, 1H), 4.29 (t, J=6.1 Hz, 1H), 4.17 (s, 1H), 3.75 (d, J=6.1 Hz, 2H), 3.44 (s, 3H).

Intermediate 36

N-[p-Tolylsulfonyl-(3,4,5-trifluorophenyl)methyl]formamide

[0518] ##STR00166##

[0519] To a solution of p-toluenesulfinic acid sodium salt (250 mg, 1.41 mmol) in water (1.67 mL) and tert-butyl methyl ether (0.83 mL) concentrated HCl (125 μL) was added dropwise and the mixture was stirred 10 min at rt. The mixture was diluted, and the phases were separated. The organic phase was washed with brine, dried and evaporated. The obtained material was dissolved together with 3,4,5-trifluorobenzaldehyde (150 mg, 0.94 mmol), D(+)-10-camphorsulfonic acid (22 mg, 0.094 mmol) and formamide (93 μL, 2.34 mmol) toluene/MeCN (2.0 mL, 1:1). After stirring 18 h at 60° C. the mixture was concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (54 mg, 17%). ESI-MS m/z calcd for [C.sub.15H.sub.12F.sub.3NO.sub.3S] [M+Na].sup.+: 366.0; found: 366.0. .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.76 (d, J=10.7 Hz, 1H), 7.99 (s, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.62 (dd, J=10.4, 4.8 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 6.62 (d, J=10.6 Hz, 1H), 2.43 (s, 3H).

5-Chloropyridin-3-yl 3-amino-3-deoxy-1-thio-α-D-galactopyranoside

[0520] ##STR00167##

[0521] A solution of 5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (330 mg, 0.72 mmol) in MeOH (2 mL) and NaOMe (0.5 mL, 1 M) was stirred 3 h at rt. The mixture was quenched with acetic acid (0.1 mL), concentrated and partitioned between EtOAc and water. The organic phase was dried, evaporated and dissolved in MeOH (7 mL). 1,3-Propanedithiol (216 μL, 2.16 mmol) followed by Et.sub.3N (301 μL, 2.16 mmol) were added and the mixture was stirred 18 h at rt. The mixture was concentrated and partitioned between EtOAc and water. The aqueous phase was evaporated to afford the product (169 mg, 77%). ESI-MS m/z calcd for [C.sub.11H.sub.15ClN.sub.2O.sub.4S] [M+H].sup.+: 307.0; found: 307.0. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.59 (d, J=1.9 Hz, 1H), 8.44 (d, J=2.2 Hz, 1H), 8.14 (t, J=2.1 Hz, 1H), 5.72 (d, J=5.3 Hz, 1H), 4.28 (t, J=6.0 Hz, 1H), 4.08 (dd, J=10.6, 5.3 Hz, 1H), 3.96 (d, J=2.4 Hz, 1H), 3.75-3.66 (m, 2H), 2.92 (dd, J=10.6, 3.1 Hz, 1H).

Intermediate 37

2-Bromo-5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside

[0522] ##STR00168##

[0523] A solution of 2,4,6-tri-O-acetyl-3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-β-D-galactopyranosyl chloride (798 mg, 1.58 mmol), 2-bromo-5-chloropyridine-3-thiol (474 mg, 1.90 mmol) and K.sub.2CO.sub.3 (445 mg, 3.2 mmol) in DMF (4.0 mL) was stirred 19 h at rt. The mixture was partitioned between EtOAc and water. The organic phase was dried, concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (234 mg, 23%). .sup.1H NMR (400 MHz, Chloroform-d) δ 8.22 (d, J=2.3 Hz, 1H), 7.88 (d, J=2.3 Hz, 1H), 7.48 (s, 1H), 7.46 (d, J=3.3 Hz, 1H), 6.24 (d, J=5.6 Hz, 1H), 6.02 (dd, J=11.7, 5.6 Hz, 1H), 5.54 (s, 1H), 4.90 (dd, J=11.7, 3.0 Hz, 1H), 4.74-4.65 (m, 1H), 4.10 (m, 2H), 2.05 (s, 3H), 2.02 (s, 3H), 1.97 (s, 3H).

5-Chloro-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside

[0524] ##STR00169##

[0525] A solution of 2-bromo-5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-(4-bromo-1H-1,2-pyrazol-1-yl)-3-deoxy-1-thio-α-D-galactopyranoside (100 mg, 0.15 mmol), DIPEA (0.29 mL, 2.25 mmol) and 2-oxa-6-azaspiro[3.3]heptane oxalate (73 mg, 0.5 mmol) in MeCN (2.0 mL) was stirred 3 h at 130° C. in a microwave reactor. The mixture was partitioned between EtOAc and water, and the organic phase was dried and evaporated. The obtained material was stirred 4 h at rt in MeOH (2.0 mL) and NaOMe (1.0 mL, 1 M). The mixture was neutralized with acetic acid (0.2 mL), concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the product (42 mg, 43%). ESI-MS m/z calcd for [C.sub.19H.sub.22BrClN.sub.4O.sub.5S] [M+H].sup.+: 533.0; found: 533.0. .sup.1H NMR (400 MHz, Methanol-d4) δ 7.99 (d, J=2.3 Hz, 1H), 7.96 (d, J=2.3 Hz, 1H), 7.86 (s, 1H), 7.54 (s, 1H), 5.62 (d, J=5.4 Hz, 1H), 4.83 (s, 4H), 4.78 (dd, J=11.4, 5.4 Hz, 1H), 4.61 (d, J=9.8 Hz, 2H), 4.54 (dd, J=11.4, 2.7 Hz, 1H), 4.49 (d, J=9.7 Hz, 2H), 4.36 (t, J=5.9 Hz, 1H), 4.13 (d, J=1.9 Hz, 1H), 3.72-3.60 (m, 2H).

Intermediate 38

3-Deoxy-3-(3-iodo-1H-1,2-pyrazol-1-yl)-1,2:5,6-di-O-isopropylidene-α-D-galactofuranose

[0526] ##STR00170##

[0527] A solution of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (5.00 g, 19.2 mmol) in DCM (100 mL) and pyridine (3.11 mL, 38.4 mmol) was cooled to 0° C. and trifluoromethanesulphonic anhydride (3.88 mL, 23.1 mmol) in DCM (15 mL) was added dropwise. After stirring 30 min at 10° C. the mixture was quenched by dropwise addition of HCl (1 M). The mixture was partitioned between DCM and HCl (1 M), the organic phase was washed with saturated aq NaHCO.sub.3, dried and concentrated. Part of the obtained material (2.3 g, 5.86 mmol) and Cs.sub.2CO.sub.3 (1.91 g, 5.86 mmol) were dissolved in DMF (30 mL). To the solution 3-iodopyrazole (1.31 g, 6.74 mmol) was added and the mixture was stirred 20 h at rt. Ice was added and the solids were filtered off. The solids were purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (1.22 g, 48%). ESI-MS m/z calcd for [C.sub.15H.sub.21IN.sub.2O.sub.5] [M+H].sup.+: 437.1; found: 437.0. .sup.1H NMR (500 MHz, Chloroform-d) δ 7.32 (d, J=2.3 Hz, 1H), 6.43 (d, J=2.3 Hz, 1H), 5.99 (d, J=4.0 Hz, 1H), 4.94 (dd, J=4.0, 2.4 Hz, 1H), 4.69 (dd, J=7.1, 2.4 Hz, 1H), 4.32 (dd, J=7.1, 4.1 Hz, 1H), 4.22 (td, J=6.8, 4.1 Hz, 1H), 4.04 (dd, J=8.3, 6.9 Hz, 1H), 3.89 (dd, J=8.3, 6.9 Hz, 1H), 1.63 (s, 3H), 1.44 (s, 3H), 1.38 (s, 3H), 1.37 (s, 3H).

1,2,4,6-Tetra-O-acetyl-3-deoxy-3-(3-iodo-1H-1,2-pyrazol-1-yl)-β-D-galactopyranoside

[0528] ##STR00171##

[0529] A solution of 3-deoxy-3-(3-iodo-1H-1,2-pyrazol-1-yl)-1,2:5,6-di-O-isopropylidene-α-D-galactofuranose (1.22 g, 2.79 mmol) in TFA/water (5 mL, 4:1) was stirred 1 h at rt. Water (2 mL) was added and the mixture was evaporated using MeCN for azeotropic removal of water and TFA. Finally, the residue was treated in vacuum. The crude was dissolved in EtOAc (8 mL) and Et.sub.3N (4.57 mL, 33.5 mmol) followed by acetic anhydride (2.64 mL, 27.9 mmol) were added. The mixture was stirred 16 h at 30° C. The mixture was cooled to 0° C. and EtOAc (15 mL) followed by HCl (30 mL, 1 M) were added slowly. The mixture was stirred 20 min, then filtered through celite. The organic phase was separated, washed with saturated aq NaHCO.sub.3 and brine, dried and evaporated. The residue was purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (1.135 g) as a furanoside/pyranoside mixture. The mixture was used without further purification in the next step. ESI-MS m/z calcd for [C.sub.17H.sub.21IN.sub.2O.sub.9] [M+H].sup.+: 525.0; found: 525.0.

5-Chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-(3-iodo-1H-1,2-pyrazol-1-yl)-1-thio-α-D-galactopyranoside

[0530] ##STR00172##

[0531] To a solution of 1,2,4,6-tetra-O-acetyl-3-deoxy-3-(3-iodo-1H-1,2-pyrazol-1-yl)-β-D-galactopyranoside (1.10 g, 2.10 mmol) and PCl.sub.5 (568 mg, 2.73 mmol) in DCM (20 mL) boron trifluoride diethyl etherate (0.78 mL, 6.29 mmol) was added and the mixture was stirred 7 h at rt. The solution was diluted with DCM and washed with ice/water and saturated aq NaHCO.sub.3. The organic phase was dried, evaporated and the residue was dissolved together with 5-chloropyridine-3-thiol (458 mg, 3.15 mmol) in DMF (10 mL). K.sub.2CO.sub.3 (580 mg, 4.20 mmol) was added and the mixture was stirred 16 h at rt. The mixture was diluted with EtOAc and washed twice with water and once with brine. The organic phase was dried, concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc). The obtained material was stirred 1 h at rt in MeOH (15 mL) and NaOMe (1 mL, 1 M). The reaction was quenched with dowex, filtered and the filtrate was evaporated. The obtained residue and p-toluenesulfonic acid monohydrate (58 mg, 0.30 mmol) were dissolved in MeCN (40 mL) and benzaldehyde dimethyl acetal (0.23 mL, 1.51 mmol) was added. The mixture was stirred 3 days at rt before more p-toluenesulfonic acid monohydrate (58 mg, 0.30 mmol) and benzaldehyde dimethyl acetal (0.23 mL, 1.51 mmol) were added and the mixture was stirred an additional 20 h at rt. Et.sub.3N (0.14 mL mL, 1.01 mmol) was added and the mixture was concentrated. The residue was partitioned between EtOAc and saturated aq NaHCO.sub.3. The organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (226 mg, 19% yield). ESI-MS m/z calcd for [C.sub.21H.sub.19ClIN.sub.3O.sub.4S] [M+H].sup.+: 572.0; found: 572.0. .sup.1H NMR (500 MHz, Chloroform-d) δ 8.57 (d, J=1.9 Hz, 1H), 8.46 (d, J=2.2 Hz, 1H), 7.90 (t, J=2.1 Hz, 1H), 7.52 (d, J=2.4 Hz, 1H), 7.43-7.35 (m, 6H), 6.49 (d, J=2.4 Hz, 1H), 5.96 (d, J=5.1 Hz, 1H), 5.54 (s, 1H), 4.92 (dd, J=11.3, 5.1 Hz, 1H), 4.78 (dd, J=11.3, 3.0 Hz, 1H), 4.52-4.48 (m, 1H), 4.30 (dd, J=12.7, 1.5 Hz, 1H), 4.15 (dd, J=12.4, 1.8 Hz, 1H).

5-Chloropyridin-3-yl 3-deoxy-3-(3-iodo-1H-1,2-pyrazol-1-yl)-2-O-methyl-1-thio-α-D-galactopyranoside

[0532] ##STR00173##

[0533] To a solution of 5-chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-(3-iodo-1H-1,2-pyrazol-1-yl)-1-thio-α-D-galactopyranoside (226 mg, 0.40 mmol) in DMF (5 mL) NaH (60% in oil, 30 mg, 0.79 mmol) followed by iodomethane (37 μL, 0.59 mmol) were added and the mixture was stirred 1 h at rt. The mixture was diluted with EtOAc, washed trice with water and the organic phase was dried and evaporated. The residue was stirred 3 h at 80° C. in acetic acid/water (5 mL, 9:1). The mixture was partitioned between EtOAc and water and the organic phase was washed with saturated aq NaHCO.sub.3, dried and evaporated. The residue was stirred 1 h at rt in NaOMe (0.1 mL, 1 M) and MeOH (1.5 mL). The mixture was concentrated and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the product (145 mg, 74%). ESI-MS m/z calcd for [C.sub.15H.sub.17ClIN.sub.3O.sub.4S] [M+H].sup.+: 498.0; found: 498.0. .sup.1H NMR (500 MHz, Chloroform-d) δ 8.64 (d, J=1.9 Hz, 1H), 8.48 (d, J=2.2 Hz, 1H), 8.22 (t, J=2.1 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H), 6.50 (d, J=2.4 Hz, 1H), 6.21 (d, J=5.3 Hz, 1H), 4.61 (dd, J=11.3, 2.8 Hz, 1H), 4.47 (dd, J=11.3, 5.3 Hz, 1H), 4.37 (t, J=6.1 Hz, 1H), 4.12 (d, J=1.9 Hz, 1H), 3.71-3.63 (m, 2H), 3.36 (s, 3H).

Intermediate 39

2-Bromo-1-(3,4,5-trifluorophenyl)ethanone

[0534] ##STR00174##

[0535] To a solution of 1-(3,4,5-trifluorophenyl)ethanone (960 mg, 5.51 mmol) in DCM (50 mL) tert-butyldimethylsilyl trifluoromethanesulfonate (2.186 g, 8.27 mmol) and Et.sub.3N (1.12 g, 11.0 mmol) were added and the mixture was stirred 1 h at rt. The mixture was partitioned between DCM (50 mL) and aq NaHCO.sub.3 (60 mL). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated. The residue was dissolved in THF (50 mL) and N-bromosuccinimide (981 mg, 5.51 mmol) and water (993 mg) were added. The mixture was stirred 15 min at rt before diethyl ether (100 mL) was added. The mixture was washed with water (80 mL), aq NaHCO.sub.3 (60 mL) and brine (80 mL). The organic phase was dried over MgSO.sub.4, concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (800 mg, 57%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.72-7.57 (m, 2H), 4.35 (s, 2H).

Methyl 3-O-allyl-α-D-galactopyranoside

[0536] ##STR00175##

[0537] To a solution of methyl α-D-galactopyranoside (19.4 g, 100 mmol) in anhydrous methanol (200 mL) dibutyltin oxide (27.4 g, 110 mmol) was added and the mixture was refluxed 4 h. The mixture was concentrated. The dried residue was suspended in toluene (200 mL) and treated with allyl bromide (14.5 g, 120 mmol) and tetrabutylammonium bromide (32.2 g, 100 mmol). The suspension was stirred 18 h at 60° C. The mixture was evaporated and purified by chromatography (SiO.sub.2, EtOAc) to afford the product (20 g, 85%). ESI-MS m/z calcd for [C.sub.10H.sub.18O.sub.6] [M+NH.sub.4].sup.+: 252.1; found:252.1.

Methyl 3-O-allyl-2,4,6-tri-O-benzyl-α-D-galactopyranoside

[0538] ##STR00176##

[0539] To a cooled (0° C.) solution of methyl 3-O-allyl-α-D-galactopyranoside (15 g, 64 mmol) in DMF (150 mL) NaH (60% in oil, 12.81 g, 320 mmol) was added. After 15 min, benzyl bromide (36.14 g, 0.21 mol) was added and the mixture was stirred 16 h at rt. EtOAc (600 mL) was added and the mixture was washed with HCl (400 mL, 1 M), water (400 mL) and brine. The organic phase was concentrated and was purified by chromatography (SiO.sub.2, PE/EtOAc) to give the product (27 g, 84%). ESI-MS m/z calcd for [C.sub.31H.sub.36O.sub.6] [M+NH.sub.4].sup.+: 522.3; found: 522.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.42-7.20 (m, 15H), 6.08-5.85 (m, 1H), 5.40-5.30 (m, 1H), 5.21-5.14 (m, 1H), 4.94 (d, J=11.5 Hz, 1H), 4.83 (d, J=12.1 Hz, 1H), 4.72-4.61 (m, 2H), 4.57 (d, J=11.5 Hz, 1H), 4.48 (d, J=11.8 Hz, 1H), 4.40 (d, J=11.8 Hz, 1H), 4.31-4.24 (m, 1H), 4.24-4.16 (m, 1H), 3.97 (dd, J=10.1, 3.7 Hz, 1H), 3.93-3.85 (m, 2H), 3.81 (dd, J=10.1, 2.8 Hz, 1H), 3.53 (d, J=6.4 Hz, 2H), 3.36 (s, 3H).

Methyl 2,4,6-tri-O-benzyl-α-D-galactopyranoside

[0540] ##STR00177##

[0541] To a solution of methyl 3-O-allyl-2,4,6-tri-O-benzyl-α-D-galactopyranoside (23 g, 46 mmol) in MeOH (200 mL) palladium(II) chloride (840 mg, 4.73 mmol) was added and the mixture was stirred 16 h at rt. The mixture was concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to give the product (21 g, 91%). ESI-MS m/z calcd for [C.sub.28H.sub.32O.sub.6] [M+NH.sub.4].sup.+: 482.2; found: 482.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.48-7.07 (m, 15H), 4.81 (d, J=11.6 Hz, 1H), 4.72-4.58 (m, 4H), 4.51 (d, J=11.8 Hz, 1H), 4.42 (d, J=11.8 Hz, 1H), 4.08-4.01 (m, 1H), 3.98-3.88 (m, 2H), 3.79 (dd, J=10.0, 3.5 Hz, 1H), 3.56 (d, J=6.5 Hz, 2H), 3.33 (s, 3H), 2.25 (d, J=3.9 Hz, 1H).

Methyl 2,4,6-tri-O-benzyl-α-D-xylo-hex-3-ulopyranoside

[0542] ##STR00178##

[0543] To a solution of methyl 2,4,6-tri-O-benzyl-α-D-galactopyranoside (11 g, 24 mmol) in DCM (120 mL) Dess-Martin Periodinane (15.06 g, 40 mmol) was added and the mixture was stirred 24 h at rt. The mixture was concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to give the product (10 g, 91%). ESI-MS m/z calcd for [C.sub.28H.sub.30O.sub.6] [M+NH.sub.4].sup.+: 480.2; found: 480.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.38-7.17 (m, 15H), 5.01 (d, J=4.1 Hz, 1H), 4.80 (d, J=12.4 Hz, 1H), 4.64 (d, J=4.1 Hz, 1H), 4.58-4.44 (m, 3H), 4.41 (d, J=11.7 Hz, 1H), 4.30 (d, J=11.7 Hz, 1H), 4.15 (td, J=6.3, 1.6 Hz, 1H), 3.88 (d, J=1.7 Hz, 1H), 3.69 (dd, J=6.3, 1.2 Hz, 2H), 3.38 (s, 3H).

Methyl 2,4,6-tri-O-benzyl-3-C-cyano-α-D-gulopyranoside

[0544] ##STR00179##

[0545] To a cooled (0° C.) solution of methyl 2,4,6-tri-O-benzyl-α-D-xylo-hex-3-ulopyranoside (1.29 g, 2.8 mmol) and trimethylsilyl cyanide (1.29 g, 13.0 mmol) in DCM (20 mL) AlCl.sub.3 (1.15 g, 8.65 mmol) was added and the mixture was stirred 3 h at rt. NH.sub.4Cl (aq, 100 mL) was added and the mixture was extracted with DCM. The organic phase was dried over Na.sub.2SO.sub.4, concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to give the product (1.5 g, 71%). ESI-MS m/z calcd for [C.sub.29H.sub.31NO.sub.6] [M+NH.sub.4].sup.+: 507.2; found: 507.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.44-7.26 (m, 15H), 4.97 (d, J=10.5 Hz, 1H), 4.88 (d, J=11.8 Hz, 1H), 4.73 (d, J=11.9 Hz, 1H), 4.63 (d, J=3.8 Hz, 1H), 4.56 (d, J=10.5 Hz, 1H), 4.52 (d, J=11.9 Hz, 1H), 4.43 (d, J=11.9 Hz, 1H), 4.34 (s, 1H), 4.24 (t, J=6.7 Hz, 1H), 3.98 (d, J=3.8 Hz, 1H), 3.91 (s, 1H), 3.59-3.41 (m, 2H), 3.34 (s, 3H).

Methyl 2,4,6-tri-O-benzyl-3-C-cyano-3-O-phenoxythiocarbonyl-α-D-gulopyranoside

[0546] ##STR00180##

[0547] To a cooled (0° C.) solution of methyl 2,4,6-tri-O-benzyl-3-C-cyano-α-D-gulopyranoside (2.05 g, 4.19 mmol), Et.sub.3N (424 mg, 4.19 mmol) and 4-(dimethylamino)pyridine (153 mg, 1.26 mmol) in MeCN (25 mL) 0-phenyl chloromethanethioate (1084 mg, 6.28 mmol) was added and the mixture was stirred overnight at rt. The mixture was concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to give the product (1.7 g, 65%). ESI-MS m/z calcd for [C.sub.36H.sub.35NO.sub.7S] [M+H].sup.+: 626.2; found: 626.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.54-7.22 (m, 18H), 7.20-7.06 (m, 2H), 5.08 (d, J=11.0 Hz, 1H), 5.01 (s, 1H), 4.97 (d, J=12.1 Hz, 1H), 4.84 (d, J=12.1 Hz, 1H), 4.66 (d, J=11.0 Hz, 1H), 4.53 (d, J=4.2 Hz, 1H), 4.44 (d, J=11.9 Hz, 1H), 4.34 (d, J=11.9 Hz, 1H), 4.23 (d, J=4.2 Hz, 1H), 4.16-4.05 (m, 1H), 3.43 (dd, J=9.5, 6.2 Hz, 1H), 3.38 (s, 3H), 3.29 (dd, J=9.5, 6.8 Hz, 1H).

Methyl 2,4,6-tri-O-benzyl-3-C-cyano-3-deoxy-α-D-galactopyranoside

[0548] ##STR00181##

[0549] A solution of methyl 2,4,6-tri-O-benzyl-3-C-cyano-3-O-phenoxythiocarbonyl-α-D-gulopyranoside (1.7 g, 2.72 mmol), tris(trimethylsilyl)silane (1351 mg, 5.43 mmol) and 2,2′-azobis(2-methylpropionitrile (446 mg, 2.72 mmol) in toluene (10 mL) was stirred 2 h at 100° C. under a nitrogen atmosphere. The mixture was concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to give the product (610 mg, 47%). ESI-MS m/z calcd for [C.sub.29H.sub.31NO.sub.5] [M+NH.sub.4].sup.+: 491.2; found: 491.3. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.44-7.26 (m, 15H), 4.96 (d, J=10.8 Hz, 1H), 4.81 (d, J=12.0 Hz, 1H), 4.66 (d, J=11.6 Hz, 1H), 4.61-4.57 (m, 2H), 4.49 (d, J=11.6 Hz, 1H), 4.42 (d, J=12.0 Hz, 1H), 4.07-4.02 (m, 2H), 3.85 (t, J=6.4 Hz, 1H), 3.55-3.44 (m, 2H), 3.35 (s, 3H), 3.26 (dd, J=11.2, 2.4 Hz, 1H).

Methyl 2,4,6-tri-O-benzyl-3-C-carbamoyl-3-deoxy-α-D-galactopyranoside

[0550] ##STR00182##

[0551] To a solution of methyl 2,4,6-tri-O-benzyl-3-C-cyano-3-deoxy-α-D-galactopyranoside (630 mg, 1.33 mmol) in DMSO (25 mL) K.sub.2CO.sub.3 (96 mg, 0.7 mmol) was added and the mixture was cooled to 0° C. Hydrogen peroxide (4 mL, 30 wt. % in H.sub.2O) was added and the mixture was stirred 1 h at 30° C. The mixture was poured into water (150 mL) and the precipitate was collected and dissolved in EtOAc (100 mL). The mixture was washed with brine (80 mL), dried over Na.sub.2SO.sub.4 and concentrated to afford the product (500 mg, 77%). ESI-MS m/z calcd for [C.sub.29H.sub.33NO.sub.6] [M+H].sup.+: 492.2; found: 492.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.42-7.17 (m, 15H), 6.60 (s, 1H), 5.31 (s, 1H), 4.84 (d, J=3.2 Hz, 1H), 4.75 (d, J=11.1 Hz, 1H), 4.69 (d, J=11.5 Hz, 1H), 4.61 (d, J=11.5 Hz, 1H), 4.54 (d, J=11.8 Hz, 1H), 4.51-4.42 (m, 2H), 4.36 (s, 1H), 4.21 (dd, J=11.5, 3.3 Hz, 1H), 3.98 (t, J=6.5 Hz, 1H), 3.67-3.51 (m, 2H), 3.40 (s, 3H), 2.96 (dd, J=11.5, 2.5 Hz, 1H).

Methyl 2,4,6-tri-O-benzyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-oxazol-2-yl]-α-D-galactopyranoside

[0552] ##STR00183##

[0553] To a solution of methyl 2,4,6-tri-O-benzyl-3-C-carbamoyl-3-deoxy-α-D-galactopyranoside (110 mg, 0.22 mmol) in EtOAc (25 mL) silver trifluoromethanesulfonate (115 mg, 0.45 mmol) and 2-bromo-1-(3,4,5-trifluorophenyl)ethanone (113 mg, 0.45 mmol) were added and the mixture was stirred 16 h at 60° C. in the dark. The mixture was concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to give the product (60 mg, 42%). ESI-MS m/z calcd for [C.sub.37H.sub.34F.sub.3NO.sub.6] [M+H].sup.+: 646.2; found: 646.2.

Methyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-oxazol-2-yl]-α-D-galactopyranoside

[0554] ##STR00184##

[0555] To a solution of methyl 2,4,6-tri-O-benzyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-oxazol-2-yl]-α-D-galactopyranoside (1.00 g, 1.55 mmol) in MeOH (50 mL) Pd/C (5% Pd, 200 mg) was added and the mixture was stirred 48 h under a H.sub.2 pressure at rt. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in pyridine (5 mL) and acetic anhydride (2 mL) was added. The mixture was stirred overnight at rt. The mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were washed with water (50 mL), HCl (50 mL, 1M) and brine (50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (PE/EA=10/1˜1/1, Silica-CS 4 g, 10 mL/min, silica gel, UV 254) to give the product (590 mg, 76%). ESI-MS m/z calcd for [C.sub.22H.sub.22F.sub.3NO.sub.9] [M+H].sup.+: 502.1; found: 502.2. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.81 (s, 1H), 7.32-7.27 (m, 2H), 5.62 (dd, J=12.0, 3.2 Hz, 1H), 5.50-5.46 (m, 1H), 5.08 (d, J=3.2 Hz, 1H), 4.31-4.23 (m, 1H), 4.21-4.04 (m, 2H), 3.87 (dd, J=12.0, 2.8 Hz, 1H), 3.48 (s, 3H), 2.06 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H).

Acetyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-oxazol-2-yl]-α-D-galactopyranoside

[0556] ##STR00185##

[0557] To a solution of methyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-oxazol-2-yl]-α-D-galactopyranoside (560 mg, 1.12 mmol) in acetic anhydride (4 mL) and acetic acid (2 mL) H.sub.2SO.sub.4 (98.0%, 112 mg, 1.12 mmol) was added and the mixture was stirred overnight at rt. The mixture was poured into saturated aq NaHCO.sub.3 (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were washed with water (50 mL), brine (50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (PE/EA=10/1˜1/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (400 mg, 68%). ESI-MS m/z calcd for [C.sub.23H.sub.22F.sub.3NO.sub.10] [M+H].sup.+: 530.1; found: 530.2. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.83 (s, 1H), 7.33-7.27 (m, 2H), 6.47 (d, J=3.2 Hz, 1H), 5.79 (dd, J=12.0, 3.2 Hz, 1H), 5.57-5.52 (m, 1H), 4.45-4.37 (m, 1H), 4.19-4.05 (m, 2H), 3.91-3.79 (m, 1H), 2.20 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 1.91 (s, 3H).

3,4-Dichlorophenyl 2,4-di-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-oxazol-2-yl]-1-thio-α-D-galactopyranoside

[0558] ##STR00186##

[0559] To a solution of acetyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-oxazol-2-yl]-α-D-galactopyranoside (110 mg, 0.21 mmol) in 1,2-dichloroethane (10.0 mL) 3,4-dichlorobenzenethiol (446 mg, 2.49 mmol) and boron trifluoride diethyl etherate (0.256 mL, 2.08 mmol) were added and the mixture was stirred 16 h at 55° C. The mixture was poured into water (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were washed with water (50 mL), brine (50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (PE/EA=10/1˜1/1, Silica-CS 4 g, 10 mL/min, silica gel, UV 254) to give the product (40.0 mg, 32%). ESI-MS m/z calcd for [C.sub.25H.sub.20Cl.sub.2F.sub.3NO.sub.7S] [M+H].sup.+: 606.0; found: 606.0. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.89 (s, 1H), 7.70-7.69 (m, 1H), 7.41-7.29 (m, 4H), 5.86 (d, J=5.2 Hz, 1H), 5.67-5.62 (m, 1H), 4.97-4.88 (m, 1H), 4.77-4.70 (m, 1H), 4.18-4.11 (m, 1H), 4.11-4.02 (m, 1H), 3.54 (dd, J=11.2, 2.8 Hz, 1H), 2.02 (s, 3H), 1.97 (s, 3H).

Intermediate 40

Methyl 2,4,6-tri-O-benzyl-3-C-carbamothioyl-3-deoxy-α-D-galactopyranoside

[0560] ##STR00187##

[0561] To a solution of methyl 2,4,6-tri-O-benzyl-3-C-carbamoyl-3-deoxy-α-D-galactopyranoside (1.00 g, 2.03 mmol) in THF (20.0 mL) Lawesson's reagent (823 mg, 2.03 mmol) was added and the mixture was stirred 2 h under reflux. The mixture was concentrated and purified by reversed-phase chromatography (MeCN/H.sub.2O=1/20˜3/1, C-18 column, 20 mL/min, UV 254) to give the product (600 mg, 58%). ESI-MS m/z calcd for [C.sub.29H.sub.33NO.sub.5S] [M+H].sup.+: 508.2; found: 508.2. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.41-7.07 (m, 15H), 4.79 (d, J=3.2 Hz, 1H), 4.58 (dd, J=11.6, 2.8 Hz, 2H), 4.52-4.32 (m, 5H), 4.06-3.95 (m, 2H), 3.56-3.42 (m, 3H), 3.32 (s, 3H).

Methyl 2,4,6-tri-O-benzyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-thiazol-2-yl]-α-D-galactopyranoside

[0562] ##STR00188##

[0563] To a solution of methyl 2,4,6-tri-O-benzyl-3-C-carbamothioyl-3-deoxy-α-D-galactopyranoside (600 mg, 1.18 mmol) in EtOH (20.0 mL) 2-bromo-1-(3,4,5-trifluorophenyl)ethanone (598 mg, 2.36 mmol) was added and the mixture was refluxed 2 h. The mixture was concentrated and purified by column chromatography (PE/EA=10/1˜5/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to give the product (670 mg, 86%). ESI-MS m/z calcd for [C.sub.37H.sub.34F.sub.3NO.sub.5S] [M+H].sup.+: 662.2; found: 662.2. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.50-7.38 (m, 2H), 7.34-7.08 (m, 14H), 7.01-6.94 (m, 2H), 4.70 (d, J=3.2 Hz, 1H), 4.58 (d, J=11.6 Hz, 1H), 4.53-4.45 (m, 2H), 4.40 (d, J=11.6 Hz, 1H), 4.30-4.01 (m, 5H), 3.86 (dd, J=11.6, 2.8 Hz, 1H), 3.59-3.46 (m, 2H), 3.34 (s, 3H).

Methyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-thiazol-2-yl]-α-D-galactopyranoside

[0564] ##STR00189##

[0565] To a solution of methyl 2,4,6-tri-O-benzyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-thiazol-2-yl]-α-D-galactopyranoside (450 mg, 0.68 mmol) in DCM (25 mL) trichloroborane (1 M in DCM, 10.2 mL) was added at −70° C. The mixture was slowly warmed to rt. After 2 hours, MeOH (5 mL) was added and the mixture was concentrated. The residue was dissolved in pyridine (3 mL) and acetic anhydride (1.5 mL) was added and the mixture was stirred overnight at rt. The mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were washed with water (50 mL), HCl (1 M, 50 mL), brine (50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (PE/EA=10/1˜1/1, Silica-CS 4 g, 10 mL/min, silica gel, UV 254) to afford the product (160 mg, 46%). ESI-MS m/z calcd for [C.sub.22H.sub.22F.sub.3NO.sub.8S] [M+H].sup.+: 518.1; found: 518.2. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.50-7.36 (m, 2H), 7.33 (s, 1H), 5.60-5.46 (m, 2H), 5.00 (d, J=3.2 Hz, 1H), 4.27-4.20 (m, 1H), 4.13-3.97 (m, 3H), 3.42 (s, 3H), 2.00 (s, 3H), 1.92 (s, 3H), 1.89 (s, 3H).

Acetyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-thiazol-2-yl]-α-D-galactopyranoside

[0566] ##STR00190##

[0567] To a solution of methyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-thiazol-2-yl]-α-D-galactopyranoside (160 mg, 0.31 mmol) in acetic anhydride (3 mL) and acetic acid (1 mL) H.sub.2SO.sub.4 (98.0%, 61.8 mg, 0.62 mmol) was added and the mixture was stirred overnight at rt. The mixture was poured into saturated aq NaHCO.sub.3 (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were washed with water (50 mL), brine (50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (PE/EA=10/1˜1/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (100 mg, 59%). ESI-MS m/z calcd for [C.sub.23H.sub.22F.sub.3NO.sub.9S] [M+H].sup.+: 546.1; found: 546.1. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.57-7.42 (m, 2H), 7.40 (s, 1H), 6.46 (d, J=3.2 Hz, 1H), 5.77 (dd, J=12.0, 3.4 Hz, 1H), 5.66-5.62 (m, 1H), 4.47-4.43 (m, 1H), 4.22-4.12 (m, 1H), 4.11-4.01 (m, 2H), 2.21 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 1.91 (s, 3H).

3,4-Dichlorophenyl 2,4-di-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-thiazol-2-yl]-1-thio-α-D-galactopyranoside

[0568] ##STR00191##

[0569] To a solution of acetyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-thiazol-2-yl]-α-D-galactopyranoside (100 mg, 0.18 mmol) in 1,2-dichloroethane (10.0 mL) 3,4-dichlorobenzenethiol (263 mg, 1.47 mmol) and boron trifluoride diethyl etherate (0.226 mL, 1.83 mmol) were added and the mixture was stirred 16 h at 55° C. The mixture was poured into water (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were washed with water (50 mL), brine (50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (PE/EA=10/1˜1/1, Silica-CS 4 g, 10 mL/min, silica gel, UV 254) to give the product (20 mg, 12%). ESI-MS m/z calcd for [C.sub.25H.sub.20Cl.sub.2F.sub.3NO.sub.6S.sub.2] [M+H].sup.+: 622.0; found: 622.0. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.72-7.69 (m, 1H), 7.49-7.45 (m, 2H), 7.42-7.37 (m, 3H), 5.87 (d, J=5.2 Hz, 1H), 5.69-5.64 (m, 1H), 4.97-4.88 (m, 1H), 4.81-4.76 (m, 1H), 4.23-4.11 (m, 2H), 3.70 (dd, J=11.2, 2.8 Hz, 1H), 2.03 (s, 3H), 1.98 (s, 3H).

Intermediate 41

Methyl 2,4,6-tri-O-benzyl-3-C-carboxy-3-deoxy-α-D-galactopyranoside

[0570] ##STR00192##

[0571] To a cooled (0° C.) solution of methyl 2,4,6-tri-O-benzyl-3-C-carbamoyl-3-deoxy-α-D-galactopyranoside (1.20 g, 2.44 mmol) in dioxane (18 mL) concentrated hydrochloric acid (2.03 mL, 2.44 mmol) was added dropwise, followed by portionwise addition of solid sodium nitrite (1.68 g, 2.44 mmol). The mixture was stirred 3 h at rt before being poured into ice/water (30 mL) and extracted with DCM (2×20 mL). The combined organic layers were dried over MgSO.sub.4 and evaporated to give the product (1.10 g, 92%). ESI-MS m/z calcd for [C.sub.29H.sub.32O.sub.7] [M+NH.sub.4].sup.+: 510.2; found: 510.4. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.28-7.13 (m, 15H), 4.67 (d, J=11.6 Hz, 1H), 4.56-4.33 (m, 6H), 4.14-4.11 (m, 2H), 3.89 (t, J=6.8 Hz, 1H), 3.50-3.40 (m, 2H), 3.26 (s, 3H), 3.03 (dd, J=11.2, 2.8 Hz, 1H).

Methyl 2,4,6-tri-O-benzyl-3-C-[2-(3,4,5-trifluorophenyl)carbohydrazide]-3-deoxy-α-D-galactopyranoside

[0572] ##STR00193##

[0573] To a solution of methyl 2,4,6-tri-O-benzyl-3-C-carboxy-3-deoxy-α-D-galactopyranoside (1.10 g, 2.23 mmol) in DCM (15 mL) HATU (1.02 g, 2.68 mmol), Et.sub.3N (1.25 mL, 8.93 mmol) and 3,4,5-trifluorobenzohydrazide (510 mg, 2.68 mmol) were added and the mixture was stirred 3 h under a nitrogen atmosphere at rt. The mixture was poured into water (20 mL) and extracted with DCM (2×20 mL). The organic layers were washed with water (50 mL), brine (50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (PE/EA=1/1˜0/1, Silica-CS 20 g, 20 mL/min, silica gel, UV254) to give the product (1.04 g, 63%). ESI-MS m/z calcd for [C.sub.36H.sub.35F.sub.3N.sub.2O.sub.7] [M+H].sup.+: 665.2; found: 665.3. .sup.1H NMR (400 MHz, Chloroform-d) δ 9.41 (d, J=5.6 Hz, 1H), 8.57 (d, J=5.6 Hz, 1H), 7.40-7.14 (m, 17H), 4.73-4.59 (m, 4H), 4.48-4.35 (m, 3H), 4.28-4.20 (m, 2H), 3.89 (t, J=6.8 Hz, 1H), 3.54-3.44 (m, 2H), 3.29 (s, 3H), 3.04 (dd, J=11.2, 2.4 Hz, 1H).

Methyl 2,4,6-tri-O-benzyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1,3,4-oxadiazol-2-yl]-α-D-galactopyranoside

[0574] ##STR00194##

[0575] To a solution of methyl 2,4,6-tri-O-benzyl-3-C-[2-(3,4,5-trifluorophenyecarbohydrazide]-3-deoxy-α-D-galactopyranoside (1.04 g, 1.56 mmol) in DMF (10 mL) and THF (1 mL) Burgess Reagent (1.49 g, 6.26 mmol) was added and the mixture was stirred 90 min at 125° C. in a microwave reactor. The mixture was concentrated and purified by column chromatography (PE/EA=2:1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (610 mg, 60%). ESI-MS m/z calcd for [C.sub.36H.sub.33F.sub.3N.sub.2O.sub.6] [M+H].sup.+: 647.2; found: 647.3. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.37-6.90 (m, 17H), 4.70 (d, J=3.6 Hz, 1H), 4.55-4.27 (m, 6H), 4.06-4.04 (m, 2H), 3.94 (d, J=11.6 Hz, 1H), 3.78 (dd, J=11.6, 2.8 Hz, 1H), 3.58-3.49 (m, 2H), 3.36 (s, 3H).

Methyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1,3,4-oxadiazol-2-yl]-α-D-galactopyranoside

[0576] ##STR00195##

[0577] To a solution of methyl 2,4,6-tri-O-benzyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1,3,4-oxadiazol-2-yl]-α-D-galactopyranoside (610 mg, 0.94 mmol) in MeOH (10 mL) Pd/C (5% Pd, 150 mg) was added and the mixture was stirred 48 h under a H.sub.2 pressure at rt. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in pyridine (5 mL) and acetic anhydride (2 mL) was added and the mixture was stirred overnight at rt. The mixture was poured into water (10 mL) and extracted with EtOAc (2×100 mL). The organic layers were washed with water (20 mL), HCl (20 mL, 1M) and brine (20 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (PE/EA=10/1˜1/1, Silica-CS 4 g, 10 mL/min, silica gel, UV 254) to give the product (320 mg, 68%). ESI-MS m/z calcd for [C.sub.21H.sub.21F.sub.3N.sub.2O.sub.9] [M+NH.sub.4].sup.+: 520.1; found: 520.1. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.66 (t, J=7.2 Hz, 2H), 5.64 (dd, J=12.0, 3.6 Hz, 1H), 5.48 (s, 1H), 5.11 (d, J=3.2 Hz, 1H), 4.31-4.28 (m, 1H), 4.18-4.09 (m, 2H), 4.01 (dd, J=11.6, 2.8 Hz, 1H), 3.49 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H).

Acetyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1,3,4-oxadiazol-2-yl]-α-D-galactopyranoside

[0578] ##STR00196##

[0579] To a solution of methyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1,3,4-oxadiazol-2-yl]-α-D-galactopyranoside (320 mg, 0.64 mmol) in acetic anhydride (2.5 mL) and acetic acid (1 mL) H.sub.2SO.sub.4 (98.0%, 63.7 mg, 0.64 mmol) was added and the mixture was stirred overnight at rt. The mixture was poured into saturated aq NaHCO.sub.3 (30 mL) and extracted with EtOAc (2×30 mL). The organic layers were washed with water (50 mL), brine (50 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (PE/EA=10/1˜3/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (230 mg, 68%). ESI-MS m/z calcd for [C.sub.22H.sub.21F.sub.3N.sub.2O.sub.10] [M+H].sup.+: 531.1; found: 531.1. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.68-7.65 (m, 2H), 6.49 (d, J=3.2 Hz, 1H), 5.81 (dd, J=12.4, 3.6 Hz, 1H), 5.55 (s, 1H), 4.46-4.42 (m, 1H), 4.18-4.08 (m, 2H), 4.01 (dd, J=12.0, 2.4 Hz, 1H), 2.20 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H), 1.94 (s, 3H).

3,4-Dichlorophenyl 2,4-di-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1,3,4-oxadiazol-2-yl]-1-thio-D-galactopyranoside

[0580] ##STR00197##

[0581] To a cooled (0° C.) solution of acetyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1,3,4-oxadiazol-2-yl]-α-D-galactopyranoside (110 mg, 0.21 mmol) and 3,4-dichlorobenzenethiol (186 mg, 1.04 mmol) in 1,2-dichloroethane (5.0 mL) boron trifluoride diethyl etherate (0.256 mL, 2.07 mmol) was added and the mixture was stirred 16 h at 50° C. The mixture was poured into water (20 mL) and extracted with EtOAc (2×20 mL). The organic layers were washed with water (20 mL), brine (20 mL), dried over Na.sub.2SO.sub.4, concentrated and purified by column chromatography (PE/EA=10/1˜1/1, Silica-CS 4 g, 10 mL/min, silica gel, UV 254) to give the product (19 mg, 15%). ESI-MS m/z calcd for [C.sub.24H.sub.19Cl.sub.2F.sub.3N.sub.2O.sub.7S] [M+H].sup.+: 607.0; found: 607.0.

Intermediate 42

2-(2-Benzyloxythiazol-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0582] ##STR00198##

[0583] 2-Benzyloxy-4-bromothiazole (1.00 g, 3.7 mmol), potassium acetate (1.1 g, 11.1 mmol) and bis(pinacolato)diboron (1.92 g, 7.4 mmol) were suspended in dioxane (10 mL), degassed with nitrogen, and (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (156 mg, 0.19 mmol) and potassium tert-butoxide (21 mg, 0.19 mmol) were added. The mixture was stirred 10 h at 80° C. and was then partitioned between EtOAc and brine. The organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc) to give the product (1.00 g, 85%). .sup.1H NMR (500 MHz, Chloroform-d) δ 7.46-7.33 (m, 6H), 5.54 (s, 2H), 1.36 (s, 12H).

3,4-Dichlorophenyl 3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-1-thio-α-D-galactopyranoside

[0584] ##STR00199##

[0585] A solution of 2,4,6-tri-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D-galactopyranosyl chloride (3.17 g, 4.00 mmol), 3,4-dichlorobenzenethiol (0.64 mL, 4.8 mmol) and Cs.sub.2CO.sub.3 (1.63 g, 5.00 mmol) in DMF (25 mL) was stirred 20 h at rt. The mixture was partitioned between EtOAc and brine, and the organic phase was dried, concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc). The obtained material was stirred 3 h at rt in MeOH (30 mL) and NaOMe (2.0 mL, 1 M). The mixture was neutralized with dowex, filtered, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc) to yield the product (1.31 g, 63%). ESI-MS m/z calcd for [C.sub.15H.sub.15Cl.sub.2IN.sub.2O.sub.4S] [M+H]+: 516.9; found: 516.9. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.86 (s, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.56 (s, 1H), 7.51 (dd, J=8.4, 2.0 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 5.79 (d, J=5.4 Hz, 1H), 4.78 (dd, J=11.4, 5.4 Hz, 1H), 4.55 (dd, J=11.4, 2.8 Hz, 1H), 4.40 (t, J=6.1 Hz, 1H), 4.13 (d, J=1.9 Hz, 1H), 3.73-3.63 (m, 2H).

3,4-Dichlorophenyl 3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-2-O-methyl-1-thio-α-D-galactopyranoside

[0586] ##STR00200##

[0587] To a solution of 3,4-dichlorophenyl 3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-1-thio-α-D-galactopyranoside (1.313 g, 2.5 mmol) in MeCN (30 mL) benzaldehyde dimethylacetal (0.57 mL, 3.75 mmol) and p-toluenesulfonic acid monohydrate (50 mg, 0.26 mmol) were added and the mixture was stirred 1 h at rt. Et.sub.3N (0.5 mL) was added followed by water (5 mL) and the mixture was stirred 15 min at rt. The formed precipitate was isolated by filtration, washed with PE, then washed with 33% aq MeOH and dried. The obtained material was dissolved in DMF (10 mL) and NaH (60% in oil, 155 mg, 3.86 mmol) followed by iodomethane (0.24 mL, 3.86 mmol) were added. After stirring 1 h at rt MeOH (20 mL) and water (5 mL) were added. The precipitate was isolated by filtration, washed with 50% aq MeOH, and dried. The obtained material was stirred 30 min at rt in 80% aq TFA (15 mL) and was then partitioned between EtOAc and water. The organic phase was washed NaOH (5 M, 40 mL), dried, and evaporated to obtain a white solid that was triturated in PE to give the product (828 mg, 61%). ESI-MS m/z calcd for [C.sub.16H.sub.17Cl.sub.2IN.sub.2O.sub.4S] [M+H].sup.+: 530.9; found: 530.9. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.87 (s, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.54 (s, 1H), 7.52 (dd, J=8.4, 2.1 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 6.10 (d, J=5.3 Hz, 1H), 4.58 (dd, J=11.2, 2.7 Hz, 1H), 4.45 (dd, J=11.3, 5.3 Hz, 1H), 4.38 (t, J=6.1 Hz, 1H), 4.11 (d, J=2.2 Hz, 1H), 3.70 (dd, J=11.5, 5.6 Hz, 1H), 3.65 (dd, J=11.5, 6.7 Hz, 1H), 3.34 (s, 3H).

Intermediate 43

tert-Butyl N-(4-bromothiazol-2-yl)carbamate

[0588] ##STR00201##

[0589] An argon degassed solution of 2,4-dibromothiazole (972 mg, 4.00 mmol), tert-butyl carbamate (515 mg, 4.40 mmol), tris(dibenzylideneacetone)dipalladium(0) (69 mg, 0.12 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (93 mg, 0.16 mmol) and Cs.sub.2CO.sub.3 (2.61 g, 8.00 mmol) in dioxane (13 mL) was stirred 24 h at 85° C. The mixture was cooled to rt, filtered through a plug of celite and concentrated. The residue was purified by chromatography (SiO.sub.2, PE/EtOAc) to give the product (113 mg, 8%). .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 6.95 (s, 1H), 1.54 (s, 9H).

[2-(tert-Butoxycarbonylamino)thiazol-4-yl]boronic Acid

[0590] ##STR00202##

[0591] To an argon degassed solution of (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (3.8 mg, 0.0045 mmol) and potassium tert-butoxide (0.5 mg, 0.0045 mmol) in dioxane (0.5 mL) tert-butyl N-(4-bromothiazol-2-yl)carbamate (50 mg, 0.15 mmol), potassium acetate (44 mg, 0.45 mmol) and bis(pinacolato)diboron (76 mg, 0.30 mmol) were added and the mixture was stirred 19.5 h at 80° C. More (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (1.8 mg, 0.0021 mmol) and and potassium tert-butoxide (0.24 mg, 0.0021 mmol) were added and the mixture was stirred 24 h at 80° C. The mixture was cooled to rt, filtered through a plug of celite and evaporated. The residue was added to a plug of silica, washed with EtOAc and eluted with MeOH/AcOH (20:1) to give the product (20 mg, 55%). .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 6.75 (s, 1H), 1.55 (s, 9H).

Intermediate 44

5-Chloro-2-cyanophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-1-thio-α-D-galactopyranoside

[0592] ##STR00203##

[0593] A solution of 2,4,6-tri-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-β-D-galactopyranosyl chloride (2.83 g, 3.56 mmol), 4-chloro-2-sulfanylbenzonitrile (950 mg, 3.92 mmol) and Cs.sub.2CO.sub.3 (1.74 g, 5.34 mmol) in DMF (9.0 mL) was stirred 16 h at rt. The mixture was partitioned between EtOAc and brine, and the organic phase was dried, concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to yield the product (686 mg, 30%). ESI-MS m/z calcd for [C.sub.22H.sub.21ClIN.sub.3O.sub.7S] [M+H].sup.+: 634.0; found: 634.0. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 7.72 (d, J=2.0 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 7.41 (dd, J=8.3, 2.0 Hz, 1H), 6.18 (d, J=5.6 Hz, 1H), 5.99 (dd, J=11.8, 5.6 Hz, 1H), 5.55-5.53 (m, 1H), 4.88 (dd, J=11.8, 3.1 Hz, 1H), 4.79 (t, J=6.6 Hz, 1H), 4.16-4.05 (m, 2H), 2.04 (s, 3H), 2.03 (s, 3H), 2.01 (s, 3H).

5-Chloro-2-cyanophenyl 4,6-O-benzylidene-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-2-O-methyl-1-thio-α-D-galactopyranoside

[0594] ##STR00204##

[0595] A solution of 5-chloro-2-cyanophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-(4-iodo-1H-1,2-pyrazol-1-yl)-1-thio-α-D-galactopyranoside (686 mg, 1.08 mmol) in MeOH (25 mL) and NaOMe (2.0 mL, 1 M) was stirred 2 h at rt. The mixture was neutralized with dowex, filtered and evaporated. Water was added and the precipitate was isolated by filtration, washed with 33% aq MeOH and dried. The obtained material was dissolved in MeCN (8 mL) and benzaldehyde dimethylacetal (0.17 mL, 1.1 mmol) and p-toluenesulfonic acid monohydrate (50 mg, 0.26 mmol) were added. The mixture was stirred 16 h at rt before Et.sub.3N (70 μL) was added followed by water (3 mL). The formed precipitate was isolated by filtration, washed with 33% aq MeOH and dried. The obtained material was stirred in DMF (2.0 mL) and NaH (60% in oil, 50 mg, 1.25 mmol) followed by iodomethane (60 μL, 0.93 mmol) were added. After stirring 3 h at rt the mixture was poured onto ice and HCl (1 M). The precipitate was isolated by filtration, washed with 33% aq MeOH, dried and purified by chromatography (SiO.sub.2, PE/EtOAc) to give the product (63 mg, 17%). ESI-MS m/z calcd for [C.sub.24H.sub.21ClIN.sub.3O.sub.4S] [M+H].sup.+: 610.0; found: 610.0. .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 7.74 (d, J=1.9 Hz, 1H), 7.69 (s, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.58 (s, 1H), 7.46-7.34 (m, 6H), 6.19 (d, J=5.2 Hz, 1H), 5.53 (s, 1H), 4.92 (dd, J=11.3, 3.1 Hz, 1H), 4.50 (dd, J=11.3, 5.2 Hz, 1H), 4.46 (d, J=2.5 Hz, 1H), 4.35 (s, 1H), 4.24 (dd, J=12.8, 1.5 Hz, 1H), 4.13 (dd, J=12.8, 1.7 Hz, 1H), 3.39 (s, 3H).

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