NOVEL GALACTOSIDE INHIBITOR OF GALECTINS
20220380401 · 2022-12-01
Assignee
Inventors
Cpc classification
C07H19/23
CHEMISTRY; METALLURGY
A61P29/00
HUMAN NECESSITIES
C07H15/26
CHEMISTRY; METALLURGY
International classification
C07H19/23
CHEMISTRY; METALLURGY
Abstract
A compound of the general formula (1). The compound of formula (1) is suitable for use in a method for treating a disorder relating to the binding of a galectin, such as galectin-3 to a ligand in a mammal, such as a human. Also, a method for treatment of a disorder relating to the binding of a galectin, such as galectin-3 to a ligand in a mammal, such as a human.
Claims
1. A method for treatment of a disorder relating to the binding of a galectin-3 to a ligand in a mammal, such as a human, wherein a therapeutically effective amount of at least one compound of formula (1) is administered to a mammal in need of said treatment, wherein said compound of formula (1) is a D-galactopyranose compound of formula (1) ##STR00346## wherein the pyranose ring is α-D-galactopyranose, A.sup.1 is selected from ##STR00347## wherein Het.sup.1 is selected from a five or six membered heteroaromatic ring, optionally substituted with a group selected from Br; F; Cl; I; CN; NR.sup.19R.sup.20, wherein R.sup.19 and R.sup.20 are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, iso-propyl, —C(═O)—R.sup.21, wherein R.sup.21 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; wherein R.sup.1-R.sup.5 are independently selected from H, CN, NH.sub.2, Br, Cl, I, F, methyl optionally substituted with a F, SCH.sub.3 optionally substituted with a F, and OCH.sub.3 optionally substituted with a F; wherein R.sup.6 is selected from C.sub.1-6 alkyl optionally substituted with a halogen, branched C.sub.3-6 alkyl and C.sub.3-7 cycloalkyl; wherein R.sup.7 is selected from a five or six membered heteroaromatic ring, optionally substituted with a group selected from Br, F, Cl, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F, and a phenyl optionally substituted with a group selected from Br, F, Cl, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F; wherein R.sup.8-R.sup.12 are independently selected from H, F, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F; wherein R.sup.13 is a five or six membered heteroaromatic ring optionally substituted with a group selected from H, OH, F, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F, or an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from H, OH, F, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F; X is selected from S, SO, SO.sub.2, O, C═O, and CR.sup.7R.sup.8 wherein R.sup.7 and R.sup.8 are independently selected from hydrogen, OH, or halogen; wherein R.sup.27 is selected from a C.sub.1-6 alkyl, branched C.sub.3-6 alkyl, C.sub.1-6 alkoxy and branched C.sub.3-6 alkoxy; 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.14—CONH— wherein R.sup.14 is selected from C.sub.1-3 alkyl and cyclopropyl; or a C.sub.1-6 alkyl substituted with a phenyl, optionally substituted with a substituent selected from CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.15—CONH— wherein R.sup.15 is selected from C.sub.1-3 alkyl and cyclopropyl; b) an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.22R.sup.23, wherein R.sup.22 and R.sup.23 are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl, or R.sup.22 and R.sup.23 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.28R.sup.29, wherein R.sup.28 and R.sup.29 are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.16—CONH— wherein R.sup.16 is selected from C.sub.1-3 alkyl and cyclopropyl; c) a C.sub.5-7 cycloalkyl, optionally substituted with a substituent selected from a halogen, CN, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.17—CONH— wherein R.sup.17 is selected from C.sub.1-3 alkyl and cyclopropyl; 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; CN; —COOH; —CONR.sup.24R.sup.25, wherein R.sup.24 and R.sup.25 are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl or R.sup.24 and R.sup.25 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.30R.sup.31, wherein R.sup.30 and R.sup.31 are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; R.sup.18—CONH— wherein R.sup.18 is selected from C.sub.1-3 alkyl and cyclopropyl; a pyrimidinyl 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.71—CONH— wherein R.sup.71 is selected from C.sub.1-3 alkyl and cyclopropyl; a pyridinyl 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.72—CONH— wherein R.sup.72 is selected from C.sub.1-3 alkyl and cyclopropyl; a tetrahydropyridinyl 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.73—CONH— wherein R.sup.73 is selected from C.sub.1-3 alkyl and cyclopropyl; a pyrrolinyl 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.74—CONH— wherein R.sup.74 is selected from C.sub.1-3 alkyl and cyclopropyl; an oxazolyl 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.75—CONH— wherein R.sup.75 is selected from C.sub.1-3 alkyl and cyclopropyl; a thiazolyl 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.76—CONH— wherein R.sup.76 is selected from C.sub.1-3 alkyl and cyclopropyl; and a C.sub.2-4 alkynyl, or e) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl; R.sup.50 is selected from the group consisting of a) C.sub.1-6 alkyl optionally substituted with one or more halogen, CN, OR.sup.51, NR.sup.52R.sup.53, and CONH.sub.2, wherein R.sup.51 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.54—CONH— wherein R.sup.54 is selected from C.sub.1-3 alkyl and cyclopropyl, R.sup.52 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.55—CONH— wherein R.sup.55 is selected from C.sub.1-3 alkyl and cyclopropyl, and R.sup.53 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.56—CONH— wherein R.sup.56 is selected from C.sub.1-3 alkyl and cyclopropyl, b) branched C.sub.3-6 alkyl optionally substituted with one or more halogen, CN, OR.sup.57, NR.sup.58R.sup.59, and CONH.sub.2, wherein R.sup.57 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.60—CONH— wherein R.sup.60 is selected from C.sub.1-3 alkyl and cyclopropyl, R.sup.58 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.61—CONH— wherein R.sup.61 is selected from C.sub.1-3 alkyl and cyclopropyl, and R.sup.59 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.62—CONH— wherein R.sup.62 is selected from C.sub.1-3 alkyl and cyclopropyl, and c) cyclic C.sub.3-6 alkyl optionally substituted with one or more halogen, CN, OR.sup.63, NR.sup.64R.sup.65, and CONH.sub.2, wherein R.sup.63 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.66—CONH— wherein R.sup.66 is selected from C.sub.1-3 alkyl and cyclopropyl, R.sup.64 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.67—CONH— wherein R.sup.67 is selected from C.sub.1-3 alkyl and cyclopropyl, and R.sup.65 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.68—CONH— wherein R.sup.68 is selected from C.sub.1-3 alkyl and cyclopropyl; or a pharmaceutically acceptable salt or solvate thereof.
2. The method for treatment of claim 1, wherein A1 is selected from formula 3 wherein Het.sup.1 is selected from a five membered heteroaromatic ring, optionally substituted with a group independently selected from H, CN, Br, C.sub.1, 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.
3. The method for treatment of claim 1, wherein X is S.
4. The method for treatment of claim 1, wherein B1 is selected from a pyridinyl optionally substituted with a group independently selected from a Cl, Br, methyl, CF.sub.3, OCH.sub.3, N-(2-oxa)-6-azaspiro[3.3]heptanyl, OH, NH.sub.2, CONH.sub.2, —CONR.sup.24R.sup.25, wherein R.sup.24 and R.sup.25 together with the nitrogen may form a heterocycloalkyl, CN, ethynyl, pyrimidinyl, pyridinyl, tetrahydropyridinyl, pyrrolidinyl, oxazolyl, thiazolyl.
5. The method for treatment of claim 1, wherein R.sup.50 is selected from a C.sub.14 alkyl, such as methyl.
6. The compound of claim 1 selected from the group consisting of: 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromo-2-cyano-pyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 4-Bromo-N,N-dimethyl-benzamide-2-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 4-Bromo-N,N-dimethyl-benzamide-2-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-(1,1,1-trifluoro-2-hydroxyprop-3-yl)-1-thio-α-D-galactopyranoside, 2-(N-piperidinyl-carbonyl)-5-chloro-phenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 4-Chloro-N,N-dimethyl-benzamide-2-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-trifluoromethyl-1-thio-α-D-galactopyranoside, 4-Chloro-N,N-dimethyl-benzamide-2-yl 3-deoxy-2-O-trifluoromethyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-2-(N,N-dimethylcarbamoyl)-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-{N-(2-oxa)-6-azaspiro [3.3]heptanyl}-pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-{N-(2-oxa)-6-azaspiro [3.3]heptanyl}-pyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-pyridin-3-yl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-pyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methyl-phenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-phenyl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-pyridin-3-yl 3-deoxy-2-O-2,2,2-trifluoroethyl-3-[4-(3,4,5-trifluoro-phenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-pyridin-3-yl 3-deoxy-2-O-ethyl-3-[4-(3,4,5-trifluoro-phenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-ethyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-isopropyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-(2-fluoroethyl)-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-[2-(methylamino)ethyl]-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-(2-hydroxyethyl)-1-thio-α-D-galactopyranoside, 5-Chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(pyrimidin-5-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(pyridin-2-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(pyridin-3-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(pyridin-4-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(3-pyrrolin-3-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(oxazol-2-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(thiazol-2-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 2,5-Bis(thiazol-2-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 6-Trifluoromethyl-5-methylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(6-fluoro-5-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-[4-(5-chloro-6-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 3-Chloro-2-cyanopyridin-5-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-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-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyanopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyanopyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 2-Cyano-5-methylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromo-2-cyanopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromo-2-cyanopyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Ethynylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyanopyridin-3-yl 3-[4-(5-chloro-6-fluoropyridin-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 2-Cyano-5-ethynylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 2-Cyano-5-ethynylpyridin-3-yl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Cyano-6-trifluoromethylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Cyanopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside, 2-(N-azetidinyl-carbonyl)-5-bromophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 2-(N-azetidinyl-carbonyl)-5-bromophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-ethyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside, 2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, and 3,4-Dichlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside; or a pharmaceutically acceptable salt or solvate thereof.
7. The method for treatment of claim 1, wherein the disorder is selected from the group consisting of inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart; scarring; keloid formation; aberrant scar formation; surgical adhesions; septic shock; cancer, such as carcinomas, sarcomas, leukemias and lymphomas, such as T-cell lymphomas; metastasising cancers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; heart disease; heart failure; pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer; and eye diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistens; obesity; Diastolic HF; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, mesothelioma; liver disorders, such as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease.
8. The method for treatment of claim 7, wherein the disorder is cancer selected from colon carcinoma, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangeoendothelia sarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystandeocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioblastomas, neuronomas, craniopharingiomas, schwannomas, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroama, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemias and lymphomas, acute lymphocytic leukemia and acute myelocytic polycythemia vera, multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's Disease, non-Hodgkin's lymphomas, rectum cancer, urinary cancers, uterine cancers, oral cancers, skin cancers, stomach cancer, brain tumors, liver cancer, laryngeal cancer, esophageal cancer, mammary tumors, childhood-null acute lymphoid leukemia (ALL), thymic ALL, B-cell ALL, acute myeloid leukemia, myelomonocytoid leukemia, acute megakaryocytoid leukemia, Burkitt's lymphoma, acute myeloid leukemia, chronic myeloid leukemia, and T cell leukemia, small and large non-small cell lung carcinoma, acute granulocytic leukemia, germ cell tumors, endometrial cancer, gastric cancer, cancer of the head and neck, chronic lymphoid leukemia, hairy cell leukemia and thyroid cancer.
9. The method for treatment of claim 8 wherein the treatment is combination therapy.
10. The method for treatment of claim 9, wherein the combination treatment comprises treatment with an anti-fibrotic compound selected from pirfenidone, nintedanib, simtuzumab (GS-6624, AB0024), BG00011 (STX100), PRM-151, PRM-167, PEG-FGF21, BMS-986020, FG-3019, MN-001, IW001, SAR156597, GSK2126458, PAT-1251 and PBI-4050.
11. The method for treatment of claim 9, wherein the combination treatment comprises treatment with an antineoplastic chemotherapy agent selected from all-trans retinoic acid, Actimide, Azacitidine, Azathioprine, Bleomycin, Carboplatin, Capecitabine, Cisplatin, Chlorambucil, Cyclophosphamide, Cytarabine, Daunorubicin, Docetaxel, Doxifluridine, Doxorubicin, Epirubicin, Etoposide, Fludarabine, Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Irinotecan, Lenalidomide, Leucovorin, Mechlorethamine, Melphalan, Mercaptopurine, Methotrexate, Mitoxantrone, Oxaliplatin, Paclitaxel, Pemetrexed, Revlimid, Temozolomide, Teniposide, Thioguanine, Valrubicin, Vinblastine, Vincristine, Vindesine, Vinorelbine, irinotecan, 5-fluorouracil, leucovorin, and oxaliplatin.
12. The method for treatment of claim 9, wherein the combination treatment comprises treatment with an immunostimulating substances selected from cytokines, such as GM-CSF, type I IFN, interleukin 21, interleukin 2, interleukin 12 and interleukin 15; antibodies selected from an immunostimulating antibody such as anti-CD40 or anti-CTLA-4 antibodies; a substance capable of depletion of immune inhibitory cells (e.g. regulatory T-cells) or factors, such as E3 ubiquitin ligases.
13. The method for treatment of claim 9, wherein the combination treatment comprises treatment with a checkpoint inhibitor acting on one or more of the following targets: CEACAM1, galectin-9, TIM3, CD80, CTLA4, PD-1, PD-L1, HVEM, BTLA, CD160, VISTA, B7-H4, B7-2, CD155, CD226, TIGIT, CD96, LAG3, GITF, OX40, CD137, CD40, IDO, and TDO.
14. The method for treatment of claim 13, wherein the checkpoint inhibitor is selected from Anti-PD-1, such as Nivolumab, Pembrolizumab, Cemiplimab; Anti-PD-L1 such as Atezolizumab, Avelumab, Durvalumab; and Anti-CTLA-4, such as Ipilimumab.
15. The method for treatment of claim 9, wherein the combination treatment comprises treatment with an inhibitor of indoleamine-2,3-dioxygenase (IDO).
16. The method for treatment of claim 9, wherein the combination treatment comprises treatment with an inhibitor of the CTLA4 pathway, such as antibodies against CTLA4.
17. The method for treatment of claim 9, wherein the combination treatment comprises treatment with an inhibitor of the PD-1/PD-L pathway, such as one or more antibodies against PD-1, PD-L1, and/or PD-L2.
18. The method for treatment of claim 7, wherein the treatment is combination therapy.
Description
DETAILED DESCRIPTION
[0121] The present compounds of formula (1) differ from prior art compounds in particular in that the pyranose ring is α-D-galactopyranose and that the C2 carbon has an optionally substituted alkoxy attached that has the potential of reducing polarity of that position. Reduced polarity correlates in general with good uptake. 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. In general, the compounds of formula (1) are believed to be >10 fold better with respect to galectin-3 affinity compared to the corresponding beta-anomers.
[0122] In a broad aspect the present invention relates to a D-galactopyranose compound of formula (1)
##STR00010##
wherein
the pyranose ring is α-D-galactopyranose,
A.sup.1 is selected from
##STR00011##
[0123] wherein Het.sup.1 is selected from a five or six membered heteroaromatic ring, optionally substituted with a group selected from Br; F; Cl; I; CN; NR.sup.19R.sup.20, wherein R.sup.19 and R.sup.20 are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, iso-propyl, —C(═O)—R.sup.21, wherein R.sup.21 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;
[0124] wherein R.sup.1-R.sup.5 are independently selected from H, CN, NH.sub.2, Br, Cl, I, F, methyl optionally substituted with a F, SCH.sub.3 optionally substituted with a F, and OCH.sub.3 optionally substituted with a F;
[0125] wherein R.sup.6 is selected from C.sub.1-6 alkyl optionally substituted with a halogen, branched C.sub.3-6 alkyl and C.sub.3-7 cycloalkyl;
[0126] wherein R.sup.7 is selected from a five or six membered heteroaromatic ring, optionally substituted with a group selected from Br, F, Cl, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F, and a phenyl optionally substituted with a group selected from Br, F, Cl, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F;
[0127] wherein R.sup.8-R.sup.12 are independently selected from H, F, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F;
[0128] wherein R.sup.13 is a five or six membered heteroaromatic ring optionally substituted with a group selected from H, OH, F, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F, or an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from H, OH, F, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F; X.sup.1 is selected from S, SO, SO.sub.2, O, C═O, and CR.sup.7R.sup.8 wherein R.sup.7 and R.sup.8 are independently selected from hydrogen, OH, or halogen;
[0129] wherein R.sup.27 is selected from a C.sub.1-6 alkyl, branched C.sub.3-6 alkyl, C.sub.1-6 alkoxy and branched C.sub.3-6 alkoxy;
[0130] 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.14—CONH— wherein R.sup.14 is selected from C.sub.1-3 alkyl and cyclopropyl; or a C.sub.1-6 alkyl substituted with a phenyl, optionally substituted with a substituent selected from CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.15—CONH— wherein R.sup.15 is selected from C.sub.1-3 alkyl and cyclopropyl; b) an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.22R.sup.23, wherein R.sup.22 and R.sup.23 are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl, or R.sup.22 and R.sup.23 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.28R.sup.29, wherein R.sup.28 and R.sup.29 are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.16—CONH— wherein R.sup.16 is selected from C.sub.1-3 alkyl and cyclopropyl; c) a C.sub.5-7 cycloalkyl, optionally substituted with a substituent selected from a halogen, CN, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.17—CONH— wherein R.sup.17 is selected from C.sub.1-3 alkyl and cyclopropyl; and d) a heterocycle, such as heteroaryl or heterocycloalkyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.24R.sup.25, wherein R.sup.24 and R.sup.25 are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.30R.sup.31, wherein R.sup.30 and R.sup.31 are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.18—CONH— wherein R.sup.18 is selected from C.sub.1-3 alkyl and cyclopropyl; e) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl;
[0131] R.sup.50 is selected from the group consisting of a) C.sub.1-6 alkyl optionally substituted with one or more halogen, CN, OR.sup.51, NR.sup.52R.sup.53, and CONH.sub.2, wherein R.sup.51 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.54—CONH— wherein R.sup.54 is selected from C.sub.1-3 alkyl and cyclopropyl, R.sup.52 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.55—CONH— wherein R.sup.55 is selected from C.sub.1-3 alkyl and cyclopropyl, and R.sup.53 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.56—CONH— wherein R.sup.56 is selected from C.sub.1-3 alkyl and cyclopropyl, b) branched C.sub.3-6 alkyl optionally substituted with one or more halogen, CN, OR.sup.57, NR.sup.58R.sup.59, and CONH.sub.2, wherein R.sup.57 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.60—CONH— wherein R.sup.60 is selected from C.sub.1-3 alkyl and cyclopropyl, R.sup.58 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.61—CONH— wherein R.sup.61 is selected from C.sub.1-3 alkyl and cyclopropyl, and R.sup.59 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.62—CONH— wherein R.sup.62 is selected from C.sub.1-3 alkyl and cyclopropyl, and c) cyclic C.sub.3-6 alkyl optionally substituted with one or more halogen, CN, OR.sup.63, NR.sup.64R.sup.65, and CONH.sub.2, wherein R.sup.63 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.66—CONH— wherein R.sup.66 is selected from C.sub.1-3 alkyl and cyclopropyl, R.sup.64 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.67—CONH— wherein R.sup.67 is selected from C.sub.1-3 alkyl and cyclopropyl, and R.sup.65 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.68—CONH— wherein R.sup.68 is selected from C.sub.1-3 alkyl and cyclopropyl; or a pharmaceutically acceptable salt or solvate thereof.
[0132] In an embodiment A1 is selected from formula 2 wherein R.sup.1-R.sup.5 are independently selected from H, F, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F. In further embodiments A1 is selected from formula 2 wherein R.sup.1 and R.sup.5 are selected from H and R.sup.2-R.sup.4 are selected from F or wherein R.sup.1-R.sup.5 are all F or wherein R.sup.2 and R.sup.3 are F and R.sup.1, R.sup.4 and R.sup.5 are H, or wherein R.sup.2 and R.sup.4 are F and R.sup.1, R.sup.3 and R.sup.5 are H, or wherein R.sup.2 is F and R.sup.1, R.sup.3-R.sup.5 are H, or wherein R.sup.2 and R.sup.4 are F, R.sup.3 is OCH.sub.3, and R.sup.1 and R.sup.5 are H. In a further embodiment A1 is selected from formula 2 wherein R.sup.1 and R.sup.5 are H and R.sup.2-R.sup.4 are independently selected from methyl, Cl and F, such as R.sup.2 and R.sup.4 are F and R.sup.3 is methyl or R.sup.2 and R.sup.4 are F and R.sup.3 is Cl. In a further embodiment A1 is selected from formula 2 wherein R.sup.1, R.sup.4 and R.sup.5 are H and R.sup.2 and R.sup.3 are independently selected from methyl, F, and Cl, such as R.sup.2 is F and R.sup.3 is Cl, or R.sup.2 is F and R.sup.3 is methyl, or R.sup.2 is methyl and R.sup.3 is Cl.
[0133] In another embodiment A1 is selected from formula 3 wherein Het.sup.1 is selected from a six membered heteroaromatic ring, optionally substituted with a group selected from 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. In a further embodiment A1 is selected from formula 3 wherein Het.sup.1 is selected from a pyridinyl, optionally substituted with a group selected from 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. In a further embodiment A1 is selected from formula 3 wherein Het.sup.1 is selected from a pyridinyl substituted with a group independently selected from F, Cl, and methyl, such as pyridinyl substituted with two group selected from F, Cl, and methyl. In a still further embodiment A1 is selected from formula 3 wherein Het.sup.1 is selected from a pyrimidyl, optionally substituted with a group selected from 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.
[0134] In a still further embodiment X1 is selected from S, SO, SO.sub.2, and O, such as S, SO, and SO.sub.2, preferably S.
[0135] In a further embodiment B1 is selected from a heterocycle, such as heteroaryl or heterocycloalkyl, optionally substituted with a group selected from a halogen; CN; methyl optionally substituted with a F; OCH.sub.3 optionally substituted with a F; OCH.sub.2CH.sub.3 optionally substituted with a F; OH; CONH.sub.2; NR.sup.30R.sup.31, wherein R.sup.30 and R.sup.31 are independently selected from H, C.sub.1-3 alkyl and isopropyl; and R.sup.18—CONH— wherein R.sup.18 is selected from C.sub.1-3 alkyl and cyclopropyl. In a preferred embodiment B1 is selected from a pyridinyl optionally substituted with a group selected from Cl, Br, CF.sub.3, OCH.sub.3, OH, NH.sub.2, CONH.sub.2, and CN. In one example B1 is selected from a pyridinyl substituted with a group independently selected from CF.sub.3 and CH.sub.3, such as one CF.sub.3 and one CH.sub.3. In another example B1 is selected from a pyridinyl substituted with a group independently selected from CF.sub.3 and CN, such as one CF.sub.3 and one CN. In a more preferred embodiment B1 is pyridinyl substituted with a halogen, such as Br or Cl, in particular one Br or one Cl. In a preferred embodiment B1 is pyridinyl substituted with an alkynyl, such as C.sub.2-4 alkynyl, preferably one ethynyl. In a further embodiment of the present invention B1 is selected from a pyridinyl substituted with a group independently selected from a Cl, CN, and N-(2-oxa)-6-azaspiro[3.3]heptanyl, such as one Cl, one CN and one N-(2-oxa)-6-azaspiro[3.3]heptanyl. In another embodiment B1 is selected from a pyridinyl substituted with two groups selected from one Cl and one CN. In a further embodiment of the present invention B1 is selected from a pyridinyl substituted with a group independently selected from a methyl and CN, such as one methyl and one CN.
[0136] In another embodiment B1 is selected from a pyridinyl substituted with two groups selected from one Br and one CN. In a still further embodiment B1 is selected from a pyridinyl substituted with a group independently selected from Cl, pyrimidinyl, pyridinyl, tetrahydropyridinyl, pyrrolidinyl, oxazolyl, and thiazolyl, such as two substituents independently selected from Cl, pyrimidinyl, pyridinyl, tetrahydropyridinyl, pyrrolidinyl, oxazolyl, and thiazolyl; Typically, one substituent is Cl and the other is selected from pyrimidinyl, pyridinyl, tetrahydropyridinyl, pyrrolidinyl, oxazolyl, and thiazolyl. In a further embodiment B1 is selected from a pyridinyl substituted with one or two thiazolyl, such as two thiazolyl. In a further embodiment B1 is selected from a pyridinyl substituted with a group independently selected from Cl, Br and —CONR.sup.24R.sup.25, wherein R.sup.24 and R.sup.25 together with the nitrogen form a heterocycloalkyl. In a still further embodiment B1 is selected from a pyridinyl substituted with two groups independently selected from Cl, Br and —CONR.sup.24R.sup.25, wherein R.sup.24 and R.sup.25 together with the nitrogen form a heterocyclobutyl. Typically, B1 is selected from a pyridinyl substituted with two groups selected from one Cl, and one —CONR.sup.24R.sup.25, wherein R.sup.24 and R.sup.25 together with the nitrogen form a heterocyclobutyl, or B1 is selected from a pyridinyl substituted with two groups selected from one Br, and one —CONR.sup.24R.sup.25, wherein R.sup.24 and R.sup.25 together with the nitrogen form a heterocyclobutyl. In a preferred embodiment B1 is pyridinyl substituted with a group independently selected from CN and C.sub.2-4 alkynyl, such as one CN and one ethynyl. In a further embodiment of the present invention B1 is selected from a pyridinyl substituted with a CN, such as one CN.
[0137] In a further embodiment B1 is selected from a phenyl substituted with a group independently selected from a halogen, such as Cl, typically two Cl. In a still further embodiment B1 is selected from a phenyl substituted with a group independently selected from halogen and —CONR.sup.22R.sup.23, wherein R.sup.22 and R.sup.23 are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl, or R.sup.22 and R.sup.23 together with the nitrogen may form a heterocycloalkyl, such as a phenyl substituted with a group independently selected from Cl, Br and —CONR.sup.22R.sup.23, wherein R.sup.22 and R.sup.23 together with the nitrogen may form a heterocycloalkyl, such as a heterocyclobutyl or heterocyclohexyl. Typically, B1 is selected from a phenyl substituted with one Cl and one heterocycloalkyl, such as a heterocyclobutyl or heterocyclohexyl, or B1 is selected from a phenyl substituted with one Br and one heterocycloalkyl, such as a heterocyclobutyl or heterocyclohexyl.
[0138] In a further embodiment R.sup.50 is selected from C.sub.1-4 alkyl or branched C.sub.3-6 alkyl optionally substituted with at least one from the group consisting of halogen and OR.sup.51 wherein R.sup.51 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.54—CONH— wherein R.sup.54 is selected from C.sub.1-3 alkyl and cyclopropyl. In one embodiment R.sup.50 is selected from branched C.sub.3-6 alkyl, such as isopropyl.
[0139] In a still further embodiment R.sup.50 is selected from C.sub.1-4 alkyl, C.sub.1-4 alkyl substituted with at least one from the group consisting of halogen and OR.sup.51 wherein R.sup.51 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.54—CONH— wherein R.sup.54 is selected from C.sub.1-3 alkyl and cyclopropyl. In one embodiment R.sup.50 is selected from C.sub.1-4 alkyl, such as methyl or ethyl. In another embodiment R.sup.50 is selected from C.sub.1-4 alkyl substituted with at least one from the group consisting of halogen, NRS.sup.2R.sup.53, wherein R.sup.52 and R.sup.53 are independently selected from the group consisting H and methyl, and OH, such as 3F and one OH. In a still further embodiment R.sup.50 is selected from C.sub.1-4 alkyl, such as ethyl, substituted with a halogen, such as one F. In a further embodiment R.sup.50 is selected from C.sub.1-4 alkyl, such as ethyl, substituted with a OH, such as one OH. In a still further embodiment R.sup.50 is selected from C.sub.1-4 alkyl, such as ethyl, substituted with a NH.sub.2, NHCH.sub.3 or N(CH.sub.3).sub.2, such as NHCH.sub.3. In a further embodiment R.sup.50 is selected from C.sub.1-4 alkyl, such as methyl, substituted with a halogen, such as F.
[0140] In a further embodiment the compound of formula (1) is selected from the group consisting of: 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromo-2-cyano-pyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 4-Bromo-N,N-dimethyl-benzamide-2-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 4-Bromo-N,N-dimethyl-benzamide-2-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-(1,1,1-trifluoro-2-hydroxyprop-3-yl)-1-thio-α-D-galactopyranoside, 2-(N-piperidinyl-carbonyl)-5-chloro-phenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 4-Chloro-N,N-dimethyl-benzamide-2-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-trifluoromethyl-1-thio-α-D-galactopyranoside, 4-Chloro-N,N-dimethyl-benzamide-2-yl 3-deoxy-2-O-trifluoromethyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-2-(N,N-dimethylcarbamoyl)-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-{N-(2-oxa)-6-azaspiro [3.3]heptanyl}-pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-{N-(2-oxa)-6-azaspiro [3.3]heptanyl}-pyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-pyridin-3-yl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-pyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methyl-phenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-phenyl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-pyridin-3-yl 3-deoxy-2-O-2,2,2,-trifluoroethyl-3-[4-(3,4,5-trifluoro-phenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-pyridin-3-yl 3-deoxy-2-O-ethyl-3-[4-(3,4,5-trifluoro-phenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-ethyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-isopropyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-(2-fluoroethyl)-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-[2-(methylamino)ethyl]-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-(2-hydroxyethyl)-1-thio-α-D-galactopyranoside, 5-Chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(pyrimidin-5-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(pyridin-2-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(pyridin-3-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(pyridin-4-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(3-pyrrolin-3-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(oxazol-2-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(thiazol-2-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 2,5-Bis(thiazol-2-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 6-Trifluoromethyl-5-methylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(6-fluoro-5-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-[4-(5-chloro-6-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 3-Chloro-2-cyanopyridin-5-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-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-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyanopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyanopyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 2-Cyano-5-methylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromo-2-cyanopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromo-2-cyanopyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-thio-α-D-galactopyranoside, 5-Ethynylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, and 5-Chloro-2-cyanopyridin-3-yl 3-[4-(5-chloro-6-fluoropyridin-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside; or a pharmaceutically acceptable salt or solvent thereof. Typically, the compound of formula (1) is selected from the group consisting of: 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromo-2-cyano-pyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 4-Bromo-N,N-dimethyl-benzamide-2-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 4-Bromo-N,N-dimethyl-benzamide-2-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-(1,1,1-trifluoro-2-hydroxyprop-3-yl)-1-thio-α-D-galactopyranoside, 2-(N-piperidinyl-carbonyl)-5-chloro-phenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 4-Chloro-N,N-dimethyl-benzamide-2-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-trifluoromethyl-1-thio-α-D-galactopyranoside, 4-Chloro-N,N-dimethyl-benzamide-2-yl 3-deoxy-2-O-trifluoromethyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-2-(N,N-dimethylcarbamoyl)-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-{N-(2-oxa)-6-azaspiro [3.3]heptanyl}-pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-{N-(2-oxa)-6-azaspiro [3.3]heptanyl}-pyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-pyridin-3-yl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-pyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methyl-phenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-phenyl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-pyridin-3-yl 3-deoxy-2-O-2,2,2,-trifluoroethyl-3-[4-(3,4,5-trifluoro-phenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-pyridin-3-yl 3-deoxy-2-O-ethyl-3-[4-(3,4,5-trifluoro-phenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-ethyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-isopropyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-(2-fluoroethyl)-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-[2-(methylamino)ethyl]-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-(2-hydroxyethyl)-1-thio-α-D-galactopyranoside, 5-Chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(pyrimidin-5-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(pyridin-2-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(pyridin-3-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(pyridin-4-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(3-pyrrolin-3-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(oxazol-2-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(thiazol-2-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 2,5-Bis(thiazol-2-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 6-Trifluoromethyl-5-methylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-deoxy-3-[4-(6-fluoro-5-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloropyridin-3-yl 3-[4-(5-chloro-6-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 3-Chloro-2-cyanopyridin-5-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-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-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyanopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyanopyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 2-Cyano-5-methylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromo-2-cyanopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromo-2-cyanopyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Ethynylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyanopyridin-3-yl 3-[4-(5-chloro-6-fluoropyridin-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 2-Cyano-5-ethynylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 2-Cyano-5-ethynylpyridin-3-yl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Cyano-6-trifluoromethylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Cyanopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside, 2-(N-azetidinyl-carbonyl)-5-bromophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, 2-(N-azetidinyl-carbonyl)-5-bromophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-ethyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside, 5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside, 2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside, and 3,4-Dichlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside.
[0141] In a further embodiment A1 is selected from formula (2) wherein R.sup.1-R.sup.5 are independently selected from H, CN, NH.sub.2, F, methyl optionally substituted with a fluorine (F), and OCH.sub.3 optionally substituted with a F. In a further embodiment R.sup.1 is selected from H, CN, NH.sub.2, F, methyl optionally substituted with a fluorine (F), and OCH.sub.3 optionally substituted with a F, such as H, CN, NH.sub.2, F, methyl, CF.sub.3, OCH.sub.3 and OCF.sub.3. In a further embodiment R.sup.1 is selected from H and F. In a further embodiment R.sup.2 is selected from H, CN, NH.sub.2, F, methyl optionally substituted with a fluorine (F), and OCH.sub.3 optionally substituted with a F, such as H, CN, NH.sub.2, F, methyl, CF.sub.3, OCH.sub.3 and OCF.sub.3. In a further embodiment R.sup.2 is selected from F. In a further embodiment R.sup.3 is selected from H, CN, NH.sub.2, F, methyl optionally substituted with a fluorine (F), and OCH.sub.3 optionally substituted with a F, such as H, CN, NH.sub.2, F, methyl, CF.sub.3, OCH.sub.3 and OCF.sub.3. In a further embodiment R.sup.3 is selected from H, OCH.sub.3 and F. In a further embodiment R.sup.4 is selected from H, CN, NH.sub.2, F, methyl optionally substituted with a fluorine (F), and OCH.sub.3 optionally substituted with a F, such as H, CN, NH.sub.2, F, methyl, CF.sub.3, OCH.sub.3 and OCF.sub.3. In a further embodiment R.sup.4 is selected from H and F. In a further embodiment R.sup.5 is selected from H, CN, NH.sub.2, F, methyl optionally substituted with a fluorine (F), and OCH.sub.3 optionally substituted with a F, such as H, CN, NH.sub.2, F, methyl, CF.sub.3, OCH.sub.3 and OCF.sub.3. In a further embodiment R.sup.5 is selected from H and F.
[0142] In another embodiment A1 is selected from formula (3) wherein Het.sup.1 is selected from a five or six membered heteroaromatic ring, optionally substituted with a group selected from Br; F; Cl; CN; NR.sup.19R.sup.20, wherein R.sup.19 and R.sup.20 are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, iso-propyl, —C(═O)—R.sup.21, wherein R.sup.21 is selected from H and C.sub.1-3 alkyl; methyl optionally substituted with a F; and OCH.sub.3 optionally substituted with a F. In a further embodiment A is selected from formula (3) wherein Het.sub.1 is selected from a five or six membered heteroaromatic ring, optionally substituted with a group selected from Br, F, Cl, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F. In a further embodiment Het.sup.1 is selected from a five membered heteroaromatic ring. In a further embodiment Het.sup.1 is selected from a five membered heteroaromatic ring substituted with a group selected from Br, F, Cl, methyl, CF.sub.3, OCH.sub.3 and OCF.sub.3.
[0143] In a further embodiment Het.sup.1 is selected from a six membered heteroaromatic ring.
[0144] In a further embodiment Het.sup.1 is selected from a six membered heteroaromatic ring substituted with a group selected from Br, F, Cl, methyl, CF.sub.3, OCH.sub.3 and OCF.sub.3. In a further embodiment Het.sup.1 is selected from a six membered heteroaromatic ring substituted with a group selected from Br, F, and Cl.
[0145] In a further embodiment Het.sup.1 is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazyl, oxazoyl, thiazoyl, thiadiazoly, oxadiazoyl, thiophenyl, and imidazolyl optionally substituted with a group selected from Br, F, Cl, methyl, CF.sub.3, OCH.sub.3 and OCF.sub.3. In a further embodiment Het.sup.1 is selected from pyridinyl substituted with a group selected from Br, F, and Cl. In a further embodiment Het.sup.1 is selected from pyridinyl substituted with a group selected from F, such as one, two or three F, typically 3 F.
[0146] In a further embodiment A1 is selected from formula (4) wherein R.sup.6 is selected from C.sub.1-6 alkyl, branched C.sub.3-6 alkyl and C.sub.3-7 cycloalkyl. In an embodiment R.sup.6 is a C.sub.1-6 alkyl, such as methyl or ethyl. In another embodiment R.sup.6 is a cyclopropyl, cyclopentyl or cyclohexyl.
[0147] In a further embodiment A1 is selected from formula (4) wherein R.sup.6 is selected from C.sub.1-6 alkyl substituted with a halogen. In a further embodiment R.sup.6 is a C.sub.1-3 alkyl substituted with one, two or three halogens, such as one, two or three F, e.g. CH.sub.2CF.sub.3.
[0148] In a further embodiment A1 is selected from formula (5) wherein R.sup.7 is selected from a five or six membered heteroaromatic ring, optionally substituted with a group selected from Br, F, Cl, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F, and a phenyl optionally substituted with a group selected from Br, F, Cl, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F. In a further embodiment R.sup.7 is selected from a five membered heteroaromatic ring. In a further embodiment R.sup.7 is selected from a five membered heteroaromatic ring substituted with a group selected from Br, F, Cl, methyl, CF.sub.3, OCF.sub.3 and OCH.sub.3. In a further embodiment R.sup.7 is selected from a six membered heteroaromatic ring. In a further embodiment R.sup.7 is selected from a six membered heteroaromatic ring substituted with a group selected from Br, F, Cl, methyl, CF.sub.3, OCF.sub.3 and OCH.sub.3, such as 1, 2 or 3 selected from Br, F, Cl, methyl, CF.sub.3, OCF.sub.3 and OCH.sub.3. In a further embodiment R.sup.7 is selected from a phenyl. In a further embodiment R.sup.7 is selected from a phenyl substituted with a group selected from Br, F, Cl, methyl, CF.sub.3, OCF.sub.3 and OCH.sub.3, such as 1, 2 or 3 selected from Br, F, Cl, methyl, CF.sub.3, OCF.sub.3 and OCH.sub.3. In a further embodiment R.sup.7 is selected from a phenyl substituted with a group selected from C.sub.1.
[0149] In a further embodiment A1 is selected from formula (6) wherein R.sup.8-R.sup.12 are independently selected from H, F, methyl optionally substituted with a fluorine (F), and OCH.sub.3 optionally substituted with a F. In a further embodiment R.sup.8-R.sup.12 are independently selected from H and F. In a further embodiment R.sup.8-R.sup.12 are H. In a further embodiment R.sup.8-R.sup.12 are independently selected from H and F, provided that at least two of R.sup.8-R.sup.12 are F. In a further embodiment R.sup.10-R.sup.11 are F and R.sup.8, R.sup.9 and R.sup.12 are H. In a further embodiment R.sup.8 is selected from H, F, methyl optionally substituted with a fluorine (F), and OCH.sub.3 optionally substituted with a F, such as H, F, methyl, CF.sub.3, OCF.sub.3 and OCH.sub.3. In a further embodiment R.sup.9 is selected from H, F, methyl optionally substituted with a fluorine (F), and OCH.sub.3 optionally substituted with a F, such as H, F, methyl, CF.sub.3, OCF.sub.3 and OCH.sub.3. In a further embodiment R.sup.10 is selected from H, F, methyl optionally substituted with a fluorine (F), and OCH.sub.3 optionally substituted with a F, such as H, F, methyl, CF.sub.3, OCF.sub.3 and OCH.sub.3. In a further embodiment R.sup.11 is selected from H, F, methyl optionally substituted with a fluorine (F), and OCH.sub.3 optionally substituted with a F, such as H, F, methyl, CF.sub.3, OCF.sub.3 and OCH.sub.3. In a further embodiment R.sup.12 is selected from H, F, methyl optionally substituted with a fluorine (F), and OCH.sub.3 optionally substituted with a F, such as H, F, methyl, CF.sub.3, OCF.sub.3 and OCH.sub.3, typically H or methyl.
[0150] In a further embodiment A1 is selected from formula (7) wherein R.sup.13 is a five or six membered heteroaromatic ring optionally substituted with a group selected from H, OH, F, methyl optionally substituted with a fluorine (F), and OCH.sub.3 optionally substituted with a F, or an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from H, OH, F, methyl optionally substituted with a fluorine (F), and OCH.sub.3 optionally substituted with a F. In an embodiment R.sup.13 is a five membered heteroaromatic ring. In another embodiment R.sup.13 is a five membered heteroaromatic ring substituted with a group selected from H, OH, F, methyl, CF.sub.3, OCF.sub.3 and OCH.sub.3, such as 1, 2 or 3 selected from OH, F, methyl, CF.sub.3, OCF.sub.3 and OCH.sub.3. In an embodiment R.sup.13 is a six membered heteroaromatic ring. In an embodiment R.sup.13 is a six membered heteroaromatic ring substituted with a group selected from H, OH, F, methyl, CF.sub.3, OCF.sub.3 and OCH.sub.3, such as 1, 2 or 3 selected from OH, F, methyl, CF.sub.3, OCF.sub.3 and OCH.sub.3. In a further embodiment R.sup.13 is a phenyl or naphthyl. In a further embodiment R.sup.13 is a phenyl substituted with a group selected from H, OH, F, CF.sub.3, OCF.sub.3 and OCH.sub.3, such as 1, 2 or 3 selected from OH, F, methyl, CF.sub.3, OCF.sub.3 and OCH.sub.3. In a further embodiment R.sup.13 is a phenyl substituted with a group selected from F, such as one, two or three F. In a further embodiment R.sup.13 is a naphthyl substituted with a group selected from H, OH, F, CF.sub.3, OCF.sub.3 and OCH.sub.3, such as 1, 2 or 3 selected from OH, F, methyl, CF.sub.3, OCF.sub.3 and OCH.sub.3.
[0151] In a further embodiment A1 is selected from formula (8) wherein R.sup.27 is selected from a C.sub.1-6 alkyl, branched C.sub.3-6 alkyl, C.sub.1-6 alkoxy and branched C.sub.3-6 alkoxy.
[0152] In a further embodiment R.sup.27 is selected from a C.sub.1-6 alkyl, such as C.sub.1-4 alkyl, e.g. methyl, ethyl, propyl. In a further embodiment R.sup.27 is selected from a C.sub.1-6 alkoxy, such as C.sub.1-4 alkoxy, e.g. methoxy, ethoxy, propoxy.
[0153] In a still further embodiment X1 is selected from S, SO, SO.sub.2, O, C═O, and CR.sup.7R.sup.8 wherein R.sup.7 and R.sup.8 are independently selected from hydrogen, OH, or halogen (e.g. F, Cl, Br). In a further embodiment X1 is selected from S. In a further embodiment X1 is selected from SO. In a further embodiment X1 is selected from SO.sub.2. In a further embodiment X1 is selected from O. In a further embodiment X1 is selected from C═O. In a further embodiment X1 is selected from CR.sup.7R.sup.8 wherein R.sup.7 and R.sup.8 are independently selected from hydrogen, OH, F, Cl, and Br, such as CH.sub.2, CHF, CHCl, CHBr, CHOH, CF.sub.2, CCl.sub.2 and CBr.sub.2.
[0154] In a still further embodiment B1 is selected from 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 a halogen (e.g. Cl, F, Br, I), 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.14—CONH— wherein R.sup.14 is selected from C.sub.1-3 alkyl and cyclopropyl. In a further embodiment B1 is selected from a C.sub.1-6 alkyl substituted with a five membered heteroaromatic ring. In a further embodiment B is selected from a branched C.sub.3-6 alkyl substituted with a five membered heteroaromatic ring. In a further embodiment B1 is selected from a C.sub.1-6 alkyl substituted with a five membered heteroaromatic ring substituted with a substituent selected from CN, Cl, F, Br, I, 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.14—CONH— wherein R.sup.14 is selected from C.sub.1-3 alkyl and cyclopropyl. In a further embodiment B1 is selected from a C.sub.1-6 alkyl substituted with a five membered heteroaromatic ring substituted with a substituent selected from CN, Cl, F, Br, I, methyl, CF.sub.3, OCH.sub.3, OCF.sub.3, OCH.sub.2CH.sub.3, OCF.sub.2CF.sub.3, OH, and R.sup.14—CONH— wherein R.sup.14 is selected from methyl. In a further embodiment B1 is selected from a branched C.sub.3-6 alkyl substituted with a five membered heteroaromatic ring substituted with a substituent selected from CN, Cl, F, Br, I, 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.14—CONH— wherein R.sup.14 is selected from C.sub.1-3 alkyl and cyclopropyl. In a further embodiment B1 is selected from a branched C.sub.3-6 alkyl substituted with a five membered heteroaromatic ring substituted with a substituent, such as 1, 2 or 3, selected from CN, Cl, F, Br, I, methyl, CF.sub.3, OCH.sub.3, OCF.sub.3, OCH.sub.2CH.sub.3, OCF.sub.2CF.sub.3, OH, and R.sup.14—CONH— wherein R.sup.14 is selected from methyl. In a further embodiment B1 is selected from a C.sub.1-6 alkyl substituted with a phenyl, such as benzyl or CH.sub.2CH.sub.2-phenyl. In a further embodiment B1 is selected from a C.sub.1-6 alkyl substituted with a phenyl substituted with a substituent, such as 1, 2 or 3, selected from CN, Cl, F, Br, I, methyl, CF.sub.3, OCH.sub.3, OCF.sub.3, OCH.sub.2CH.sub.3, OCF.sub.2CF.sub.3, OH, and R.sup.15—CONH— wherein R.sup.15 is selected from methyl. In a further embodiment B1 is selected from a C.sub.1-6 alkyl substituted with a phenyl substituted with a group selected from Cl, F, Br, methyl, CF.sub.3, OCH.sub.3, OCF.sub.3, such as benzyl substituted with one or two Cl, or CH.sub.2CH.sub.2-phenyl substituted with one Cl. In a still further embodiment B1 is selected from a phenyl. In a further embodiment B1 is selected from a naphthyl. In a further embodiment B1 is selected from a naphthyl substituted with a group selected from NR.sup.28R.sup.29, wherein R.sup.28 and R.sup.29 are independently selected from H and C.sub.1-3 alkyl. In a further embodiment B1 is selected from a naphthyl substituted with a group selected from NR.sup.28R.sup.29, wherein R.sup.28 and R.sup.29 are independently selected from H and CH.sub.3. In a further embodiment B1 is selected from a naphthyl substituted with a group selected from NR.sup.28R.sup.29, wherein R.sup.28 and R.sup.29 selected from CH.sub.3. In a further embodiment B1 is selected from a phenyl substituted with a group, such as 1, 2 or 3, selected from Cl, F, Br, I, methyl, CF.sub.3, OCH.sub.3, OCF.sub.3, OCH.sub.2CH.sub.3, OCF.sub.2CF.sub.3, OH, and R.sup.16—CONH— wherein R.sup.16 is selected from methyl. In a still further embodiment B1 is selected from a phenyl substituted with a group, such as 1, 2 or 3, selected from Cl, F, Br, I, CN, methyl, CF.sub.3, OCH.sub.3, OCF.sub.3, OCH.sub.2CH.sub.3, OCF.sub.2CF.sub.3, OH, and R.sup.16—CONH— wherein R.sup.16 is selected from methyl. In a further embodiment B1 is selected from a phenyl substituted with a group, such as 1, 2 or 3, selected from COOH and CONH.sub.2. In a still further embodiment B1 is selected from a naphthyl substituted with a group, such as 1, 2 or 3, selected from Cl, F, Br, I, methyl, CF.sub.3, OCH.sub.3, OCF.sub.3, OCH.sub.2CH.sub.3, OCF.sub.2CF.sub.3, OH, and R.sup.16—CONH— wherein R.sup.16 is selected from methyl. In a further embodiment B1 is selected from a naphthyl. In a still further embodiment B1 is selected from a naphthyl substituted with a NR.sup.28R.sup.29, wherein R.sup.28 and R.sup.29 are independently selected from H, C.sub.1-3 alkyl and isopropyl, such as naphthyl substituted with a N(CH.sub.3).sub.2.
[0155] In a further embodiment B1 is selected from a C.sub.5-7 cycloalkyl, such as cyclopentyl or cyclohexyl. In a further embodiment B is selected from cyclohexyl. In a still further embodiment B is selected from a C.sub.5-7 cycloalkyl, such as cyclohexyl, substituted with a group, such as 1, 2 or 3, selected from CN, Cl, F, Br, I, methyl, CF.sub.3, OCH.sub.3, OCF.sub.3, OCH.sub.2CH.sub.3, OCF.sub.2CF.sub.3, OH, and R.sup.17—CONH— wherein R.sup.17 is selected from methyl. In a still further embodiment B1 is selected from a cyclohexyl, substituted with a halogen, such as one or two halogens, typically F.
[0156] In a further embodiment of the present invention B1 is selected from a C.sub.1-4 alkyl. Typically, B is selected from ethyl, propyl and butyl.
[0157] In a still further embodiment B1 is selected from a heterocycle, such as heteroaryl or heterocycloalkyl. In a still further embodiment B1 is selected from a heteroaryl substituted with a group, such as 1, 2 or 3, selected from Cl, F, Br, I, methyl CF.sub.3, OCH.sub.3, OCF.sub.3, OCH.sub.2CH.sub.3, OCF.sub.2CF.sub.3, OH, and R.sup.18—CONH— wherein R.sup.18 is selected from methyl. In a further embodiment B1 is selected from a heteroaryl substituted with a group, such as 1, 2 or 3, selected from Cl, F, Br, I, CN, methyl, CF.sub.3, OCH.sub.3, OCF.sub.3, OCH.sub.2CH.sub.3, OCF.sub.2CF.sub.3, OH, and R.sup.18—CONH— wherein R.sup.18 is selected from methyl. In a still further embodiment B1 is selected from a heterocycloalkyl substituted with a group, such as 1, 2 or 3, selected from Cl, F, Br, I, methyl CF.sub.3, OCH.sub.3, OCF.sub.3, OCH.sub.2CH.sub.3, OCF.sub.2CF.sub.3, OH, and R.sup.18—CONH— wherein R.sup.18 is selected from methyl. In a further embodiment B1 is selected from a heteroaryl substituted with a group, such as 1, 2 or 3, selected from NR.sup.30R.sup.31, wherein R.sup.30 and R.sup.31 are independently selected from H, C.sub.1-3 alkyl and isopropyl. Typically, B1 is selected from a pyridinyl substituted with a group, such as 1, 2 or 3, selected from NH.sub.2, such as one NH.sub.2. In another embodiment B1 is selected from a thiophenyl substituted with a halogen, such as one Cl. In a further embodiment B1 is selected from a pyridazinyl. In a further embodiment B1 is selected from a pyridazinyl substituted with one, two or three, substituents selected from OCH.sub.3, CN, OH and Cl.
[0158] In a further aspect the present invention relates to a compound of formula (1) of the present invention for use as a medicine.
[0159] In a still further aspect the present invention relates to a pharmaceutical composition comprising a compound of formula (1) of the present invention and optionally a pharmaceutically acceptable additive, such as a carrier and/or excipient.
[0160] In a further aspect the present invention relates to a compound of formula (1) of the present invention for use in a method for treating a disorder relating to the binding of a galectin-3 to a ligand in a mammal, such as a human. In an embodiment the disorder is selected from the group consisting of inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart; scarring; keloid formation; aberrant scar formation; surgical adhesions; septic shock; cancer, such as carcinomas, sarcomas, leukemias and lymphomas, such as T-cell lymphomas; metastasising cancers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; heart disease; heart failure; pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer; and eye diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistens; obesity; Diastolic HF; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, mesothelioma; liver disorders, such as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease.
[0161] A non-limiting group of cancers given as examples of cancers that may be treated, managed and/or prevented by administration of a compound of formula (1) include: colon carcinoma, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangeosarcoma, lymphangeoendothelia sarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystandeocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioblastomas, neuronomas, craniopharingiomas, schwannomas, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroama, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemias and lymphomas, acute lymphocytic leukemia and acute myelocytic polycythemia vera, multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's Disease, non-Hodgkin's lymphomas, rectum cancer, urinary cancers, uterine cancers, oral cancers, skin cancers, stomach cancer, brain tumors, liver cancer, laryngeal cancer, esophageal cancer, mammary tumors, childhood-null acute lymphoid leukemia (ALL), thymic ALL, B-cell ALL, acute myeloid leukemia, myelomonocytoid leukemia, acute megakaryocytoid leukemia, Burkitt's lymphoma, acute myeloid leukemia, chronic myeloid leukemia, and T cell leukemia, small and large non-small cell lung carcinoma, acute granulocytic leukemia, germ cell tumors, endometrial cancer, gastric cancer, cancer of the head and neck, chronic lymphoid leukemia, hairy cell leukemia and thyroid cancer. Each of these disorders is considered a single embodiment and may be made the subject of a claim specifically to such disease or disorder.
[0162] In a still further aspect the present invention relates to a method for treatment of a disorder relating to the binding of a galectin-3 to a ligand in a mammal, such as a human, wherein a therapeutically effective amount of at least one compound of formula (1) of the present invention is administered to a mammal in need of said treatment. In an embodiment the disorder is selected from the group consisting of inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart; scarring; keloid formation; aberrant scar formation; surgical adhesions; septic shock; cancer, such as carcinomas, sarcomas, leukemias and lymphomas, such as T-cell lymphomas; metastasising cancers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; heart disease; heart failure; pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer; and eye diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistens; obesity; Diastolic HF; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, mesothelioma; liver disorders, such as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease.
[0163] Each of these disorders are considered a single embodiment and may be made the subject of a claim specifically to such disease or disorder.
[0164] The skilled person will understand that it may be necessary to adjust or change the order of steps in the processes a1 to a3, 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.
[0165] 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.
[0166] 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 proteting groups for carboxylic acid include (C.sub.1-6)-alkyl or benzyl esters. Suitable protecting groups for amino include t-butyloxycarbonyl, benzyloxycarbonyl, 2-(trimethylsilyl)-ethoxy-methyl or 2-trimethylsilylethoxycarbonyl (Teoc). Suitable protecting groups for S include S—C(═N)NH.sub.2, TIPS.
[0167] The protection and deprotection of functional groups may take place before or after any reaction in the above mentioned processes.
[0168] 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.
[0169] 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.
[0170] In a further embodiment the compound (1) is a crystalline form. The skilled person may carry out tests in order to find polymorphs, and such polymorphs are intended to be encompassed by the term “crystalline form” as used herein.
[0171] 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.
[0172] 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.
[0173] 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.
[0174] 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.
[0175] 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.
[0176] The term “C.sub.2-4 alkynyl” as used herein means an alkynyl group containing 2-4 carbon atoms and having one triple bond, such as ethynyl, propynyl, butynyl.
[0177] The term “Oxo” as used herein means an oxygen atom with double bonds, also indicated as ═O.
[0178] The term “CN” as used herein means a nitril.
[0179] 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.
[0180] 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.
[0181] The term “a spiro heterocycle” as used herein means a two-ring system connected by a common carbon atom, and containing from 5 to 12 ring members wherein from 2 to 11 are carbon atoms and at least one is a heteroatom, such as a hetero atom selected from one or more N, S, O; one example is N-(2-oxa)-6-azaspiro[3.3]heptanyl.
[0182] 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.
[0183] 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.
[0184] 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.
[0185] 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.
[0186] 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.
[0187] As mentioned above, the compositions and particularly pharmaceutical compositions as herein disclosed may, in addition to the compounds herein disclosed, further comprise at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier. In some embodiments, the pharmaceutical compositions comprise from 1 to 99 weight % of said at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier and from 1 to 99 weight % of a compound as herein disclosed. 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.
[0188] In some embodiments, only one compound as herein disclosed is used for the purposes discussed above.
[0189] In some embodiments, two or more of the compounds as herein disclosed are used in combination for the purposes discussed above.
[0190] 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.
[0191] 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.
[0192] 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.
[0193] 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.
[0194] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.
[0195] 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.
[0196] 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.
[0197] 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).
[0198] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.
[0199] 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.
[0200] 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.
[0201] 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.
[0202] 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
[0203]
TABLE-US-00001 Galectin-3 Example Name structure Kd (μM) 1 5-Bromopyridin-3-yl 3- deoxy-3-[4-(3,4,5- trifluorophenyl)-1H- 1,2,3-triazol-1-yl]-2-O- methyl-1-thio-α-D- galactopyranoside
Evaluation of Kd Values
[0204] The affinity of Example 1-71 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 Sarme, 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, (Sarme et al., 2004) and Monovalent interactions of Galectin-1 By Salomonsson, Emma; Larumbe, Amaia; Tejler, Johan; Tullberg, Erik; Rydberg, Hanna; Sundin, Anders; Khabut, Areej; Frejd, Torbjorn; Lobsanov, Yuri D.; Rini, James M.; et al, From Biochemistry (2010), 49(44), 9518-9532, (Salomonsson et al., 2010). The assay was also adapted to be able to measure the high affinity of compounds for galectin-3 by using the below probe constructed to have high affinity for galectin-3 which made it possible to use a low concentration of galectin-3 (50 nM). 100 nM albumin was included as a carrier to prevent protein loss at such low concentration of galectin.
##STR00083##
[0205] Uptake of compounds of formula 1 over CACO2 monolayers.
[0206] Uptake of a drug over the intestine can be predicted measuring the uptake over a monolayer of CACO-2 cells measured as Papp (10{circumflex over ( )}−6 cm/s). (Shah, P.; Jogani, V.; Bagchi, T.; Misra, A. Role of Caco-2 Cell Monolayers in Prediction of Intestinal Drug Absorption. Biotechnol. Prog. 2006, 22 (1), 186-198.) In general compounds like Ref 1 and 2 where the 2-OH group is unsubstituted have low (Papp<5 10{circumflex over ( )}−6 cm/s) to medium (Papp=5-10 10{circumflex over ( )}−6 cm/s) uptake due to efflux from the basolateral to the apical side of the CACO2 membranes. By introduction of small alkyl substituents to the galactoside 2-OH such as compounds of formula (1) results in low or no efflux combined with a high uptake (Papp>10 10{circumflex over ( )}−6 cm/s) over CACO-2 cells from the apical to the basolateral side of the cells.
TABLE-US-00002 CACO-2 A>B CACO-2 B>A Efflux ratio Papp Papp Papp Example (10.sup.∧-6 cm/s) (10.sup.∧-6 cm/s) (B>A/A>B) 35 31 45 1.4 01 30 38 1.2 36 28 32 1.1 43 26 34 1.3 13 18 23 1.3 Ref 1 3 30 10
Synthesis of Examples and Intermediates
General Experimental:
[0207] Nuclear Magnetic Resonance (NMR) spectra were recorded on a 400 MHz Bruker AVANCE III 500 instrument or a Varian instrument at 400 MHz or a 500 MHz Bruker Avance Neo 500 instrument, at 25° C.
[0208] 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; p, pentet; m, multiplet; br s, broad singlet. In the case of anomeric mixtures, the shifts of the individual anomers are reported separately and the α/β ratio was calculated based on the integration of the anomeric peaks.
[0209] LC-MS were acquired on an Agilent 1200 HPLC coupled with an Agilent MSD mass spectrometer operating in ES (+) ionization mode. Column: XBridge C18 (4.6×50 mm, 3.5 μm) or SunFire C18 (4.6×50 mm, 3.5 μm). Solvent A water+0.1% TFA and solvent B Acetonitrile+0.1% TFA or solvent A water (10 mM Ammonium hydrogen carbonate) and solvent B Acetonitrile. Wavelength: 254 nM. Alternatively, 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.
[0210] GC-MS were acquired on a Shimadzu GCMS-QP2010 Ultra. Column: DB-5 ms: 0.25 mm*30m*0.25 μm. Injection Temperature: 150° C.; Spilt Ratio: 99:1; He (1.5 ml/min); Inst Method: 50° C. (1 min)/15° C./min/260° C. (1 min); Ion Source Temp: 200° C.; Interface Temp: 250° C.
[0211] Preparative HPLC was performed on a Gilson 281. Flow: 20 mL/min Column: X-Select 10 μm 19×250 mm column. Wavelength: 254 nm or 214 nm. Solvent A water (10 mM Ammonium hydrogen carbonate) and solvent B Acetonitrile (Method A). Alternatively, preparative HPLC were acquired on a Gilson system. Flow: 12 ml/min Column: kromasil 100-5-C18 column. Wavelength: 220 nm. Solvent A water+0.1% TFA and solvent B Acetonitrile (Method B).
[0212] The following abbreviations are used
[0213] aq: aqueous
[0214] Calcd: Calculated
[0215] DCM: dichloromethane
[0216] DIEA: N,N-Diisopropylethylamine
[0217] DMAP: 4-dimethylaminopyridine
[0218] DMF: N,N-dimethylformamide
[0219] ESI-MS: Electrospray ionization mass spectrometry
[0220] Et.sub.3N: triethylamine
[0221] EtOAc: ethyl acetate
[0222] h: hours
[0223] HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
[0224] 3-oxid hexafluorophosphate
[0225] HPLC: High Performance liquid chormatography
[0226] MeCN: acetonitrile
[0227] min: minutes
[0228] prep. preparative
[0229] PE: petroleum ether
[0230] rt: room temperature
[0231] SFC: Supercritical Fluid Chromatography
[0232] TBS: tert-Butyldimethylsilyl
[0233] TBAF: tetrabutylarnmonium fluoride
[0234] TFA: trifluoroacetic acid
[0235] THF: tetrahydrofuran
[0236] TMS: trimethyl silyl
[0237] UV: Ultraviolet
Synthesis of Examples 1-71 from their Respective Intermediates 1-71
Example 1
5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0238] ##STR00087##
[0239] 5-Bromopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (150 mg, 0.24 mmol) and NaH (60% in oil, 19 mg, 0.48 mmol) were stirred in DMF (3 mL) for 10 min before the addition of iodomethane (22.5 μL, 0.36 mmol). The mixture was stirred 2 h at 40° C., then diluted with EtOAc and washed twice with water. The organic phase was dried, evaporated and the residue was stirred 1 h in 80% aq TFA (2 mL). The mixture was concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc). Further purification by preparative HPLC (Method B) afforded the title compound (50 mg, 38%) as a white powder. ESI-MS m/z calcd for [C.sub.20H.sub.18BrF.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 547.0; found: 547.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.71 (d, J=1.7 Hz, 1H), 8.59 (s, 2H), 8.40-8.36 (m, 1H), 7.70-7.62 (m, 2H), 6.28 (d, J=5.3 Hz, 1H), 5.04 (dd, J=11.3, 2.7 Hz, 1H), 4.65 (dd, J=11.3, 5.3 Hz, 1H), 4.46 (t, J=6.0 Hz, 1H), 4.19 (d, J=2.7 Hz, 1H), 3.75-3.66 (m, 2H), 3.41 (s, 3H).
Example 2
5-Bromo-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
Example 3
4-Chloro-N,N-dimethyl-benzamide-2-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0240] ##STR00088##
[0241] A solution of 4-chloro-N,N-dimethyl-benzamide-2-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (190 mg, 0.34 mmol), benzaldehyde dimethylacetal (207 μL, 1.36 mmol) and p-toluenesulfonic acid monohydrate (5 mg, 0.026 mmol) in MeCN (3.0 mL) were stirred 2 h at rt. The mixture was concentrated and partitioned between EtOAc and water, the organic phase was collected and evaporated. The residue was subjected to chromatography (SiO.sub.2, PE/EtOAc) and the obtained material was dissolved in DMF (2.0 mL). Iodomethane (45 μL, 0.72 mmol) followed by NaH (60% in oil, 15 mg, 0.36 mmol) were added and the mixture was stirred 1 h at rt. The mixture was poured onto ice and HCl (0.2 M), the precipitate was isolated by filtration. The precipitate was dissolved in 80% aq TFA (2.0 mL) stirred 1 h at rt before being poured on water and NaOH (20 mL, 2 M). The precipitate was isolated by filtration and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the title compound (24 mg, 12%). ESI-MS m/z calcd for [C.sub.24H.sub.24ClF.sub.3NO.sub.5O.sub.5S][M+H].sup.+: 573.1; found: 573.2. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.57 (s, 1H), 7.86 (s, 1H), 7.66 (m, 2H), 7.46 (d, J=8.1 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 6.19 (bs, 1H), 4.98 (dd, J=11.4, 2.8 Hz, 1H), 4.58 (dd, J=11.3, 5.3 Hz, 1H), 4.52 (bt, 1H), 4.18 (d, J=2.5 Hz, 1H), 3.78-3.64 (m, 2H), 3.38 (s, 3H), 3.13 (s, 3H), 2.89 (s, 3H).
Example 4
4-Chloro-N,N-dimethyl-benzamide-2-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0242] ##STR00089##
[0243] 4-Chloro-N,N-dimethyl-benzamide-2-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (34 mg, 0.059 mmol) was dissolved in MeCN (2.0 mL) and benzaldehyde dimethylacetal (36 μL, 0.24 mmol) followed by p-toluenesulfonic acid monohydrate (5 mg, 0.023 mmol) were added. The mixture was stirred 2 h at rt followed by evaporation of the solvent. The residue was dissolved in DMF (1.5 mL), iodomethane (15 μL, 0.24 mmol) followed by NaH (60% in oil, 5.0 mg, 0.12 mmol) were added. The mixture was stirred 2.5 h at rt, then poured onto ice and HCl (0.2 M). The precipitate was isolated by filtration and dried. This material was dissolved in 80% aq TFA (1.5 mL) and stirred 2 h at rt before being concentrated. The residue was purified by chromatography (SiO.sub.2, PE/EtOAc) and further purified by preparative HPLC (Method B) afforded the title compound (6.0 mg, 17%). ESI-MS m/z calcd for [C.sub.24H.sub.24Cl.sub.2F.sub.2N.sub.4O.sub.5S] [M+H].sup.+: 589.1; found: 589.2. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.63 (s, 1H), 7.87 (s, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.1 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 6.20 (bs, 1H), 4.99 (dd, J=11.3, 2.6 Hz, 1H), 4.59 (dd, J=11.5, 5.1 Hz, 1H), 4.53 (bs, 1H), 4.18 (s, 1H), 3.79-3.64 (m, 2H), 3.39 (s, 3H), 3.14 (s, 3H), 2.90 (s, 3H).
Example 5
5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-(1,1,1-trifluoro-2-hydroxyprop-3-yl)-1-thio-α-D-galactopyranoside
[0244] ##STR00090##
[0245] 5-Bromopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (1.00 g, 1.6 mmol) and NaH (60% in oil, 77 mg, 1.92 mmol) were stirred 20 min in DMF (10 mL) before 1,2-epoxy-3,3,3-trifluoropropane (0.211 mL, 1.91 M solution in THF, 1.76 mmol) was added. The mixture was stirred 1 h at rt, then water (20 mL) was added. The solids were isolated by filtration and this material was heated in MeOH (10 mL) then cooled to rt. The solids were filtered off, the filtrate was concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc). The product was treated in 80% aqueous TFA (3.0 mL) for 2 h, then concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc). Further purification by preparative HPLC (Method B) yielded the title compound (30 mg, 3%). ESI-MS m/z calcd for [C.sub.22H.sub.19BrF.sub.6N.sub.4O.sub.5S] [M+H].sup.+: 645.0; found: 645.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.69 (s, 1H), 8.58 (s, 2H), 8.35 (d, J=1.8 Hz, 1H), 7.69-7.59 (m, 2H), 6.28 (d, J=5.1 Hz, 1H), 5.09 (d, J=11.3 Hz, 1H), 4.85 (m, 1H), 4.49 (t, J=5.8 Hz, 1H), 4.25 (s, 1H), 4.03 (d, J=10.5 Hz, 1H), 3.96 (m, 1H), 3.76-3.65 (m, 2H), 3.60 (m, 1H).
Example 6
2-(N-piperidinyl-carbonyl)-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0246] ##STR00091##
[0247] 2-(N-piperidinyl-carbonyl)-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (25 mg, 0.04 mmol) was dissolved in MeCN (2.0 mL) and benzaldehyde dimethylacetal (24 μL, 0.16 mmol) followed by p-toluenesulfonic acid monohydrate (5 mg, 0.023 mmol) were added. The mixture was stirred 2.5 h at rt followed by evaporation of the solvent. The residue was dissolved in DMF (1.5 mL), iodomethane (10 μL, 0.16 mmol) followed by NaH (60% in oil, 5.0 mg, 0.12 mmol) were added. The mixture was stirred 1 h at rt, then poured onto ice and HCl (0.2 M). The precipitate was isolated by filtration and dried. This material was dissolved in 80% aq TFA (1.2 mL) and stirred 2 h at rt before being concentrated. The residue was purified by chromatography (SiO.sub.2, PE/EtOAc) and further purified by preparative HPLC (Method B) to afford the title compound (16 mg, 78%). ESI-MS m/z calcd for [C.sub.27H.sub.28Cl.sub.2F.sub.2N.sub.4O.sub.5S] [M+H].sup.+: 629.1; found: 629.2. .sup.1H NMR (400 MHz, Methanol-d.sub.4) (two conformational isomers) δ 8.63 (s, 1H), 7.95-7.79 (m, 1H), 7.66 (m, 2H), 7.55-7.35 (m, 1H), 7.34-7.19 (m, 1H), 6.37-6.08 (m, 1H), 4.99 (d, J=11.0 Hz, 1H), 4.70-4.37 (m, 2H), 4.19 (s, 1H), 3.93-3.58 (m, 4H), 3.39 (s, 3H), 3.22 (bs, 2H), 1.82-1.57 (m, 5H), 1.52 (bs, 1H).
Example 7
4-Chloro-N,N-dimethyl-benzamide-2-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-trifluoromethyl-1-thio-α-D-galactopyranoside
Example 8
4-Chloro-N,N-dimethyl-benzamide-2-yl 3-deoxy-2-O-trifluoromethyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
Example 9
5-Chloro-2-(N,N-dimethylcarbamoyl)-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
Example 10
5-Chloro-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0248] ##STR00092##
[0249] 2-Bromo-5-chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (75 mg, 0.13 mmol), 2-oxa-6-azaspiro[3.3]heptane oxalic acid (149 mg, 0.52 mmol) and DIEA (0.33 mL, 1.93 mmol) dissolved in MeCN (2.5 mL) was sealed in a microwave vial and stirred 6 h at 130° C. in a microwave reactor. The mixture was concentrated and purified by preparative HPLC (Method B) to afford the title compound (24 mg, 31%). ESI-MS m/z calcd for [C.sub.25H.sub.25ClF.sub.3N.sub.5O.sub.5S] [M+H].sup.+: 600.1; found: 600.2. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.60 (s, 1H), 8.03 (d, J=2.3 Hz, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.67 (dd, J=8.6, 6.7 Hz, 2H), 5.98 (d, J=5.2 Hz, 1H), 5.04 (dd, J=11.4, 2.8 Hz, 1H), 4.85-4.81 (m, 4H), 4.62 (dd, J=11.4, 5.3 Hz, 1H), 4.53 (d, J=9.4 Hz, 2H), 4.46-4.39 (m, 3H), 4.20 (d, J=2.5 Hz, 1H), 3.74-3.63 (m, 2H), 3.41 (s, 3H).
Example 11
5-Chloro-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0250] ##STR00093##
[0251] 5-Chloro-2-{N-(2-oxa)-6-azaspiro [3.3]heptanyl}-pyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (115 mg, 0.16 mmol) was dissolved in DCM/TFA (10 mL, 19:1) and stirred 1 h at rt. The mixture was neutralized with Et.sub.3N and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method A) to give the title compound (55.4 mg, 55%) as a white solid. ESI-MS m/z calcd for [C.sub.25H.sub.25Cl.sub.2F.sub.2N.sub.5O.sub.5S] [M+H].sup.+: 616.1; found: 616.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.92 (s, 1H), 8.06 (d, J=2.4 Hz, 1H), 7.86-7.78 (m, 3H), 6.10 (d, J=5.2 Hz, 1H), 5.56 (d, J=6.0 Hz, 1H), 4.88 (dd, J=11.6, 2.8 Hz, 1H), 4.76 (t, J=5.2 Hz, 1H), 4.72-4.65 (m, 4H), 4.47 (dd, J=11.6, 5.2 Hz, 1H), 4.35 (d, J=9.2 Hz, 2H), 4.27 (d, J=9.2 Hz, 2H), 4.24 (d, J=6.4 Hz, 1H), 4.03 (dd, J=6.0, 2.8 Hz, 1H), 3.51 (dt, J=11.2, 5.6 Hz, 1H), 3.40 (dd, J=11.2, 6.0 Hz, 1H), 3.32 (s, 3H).
Example 12
5-Chloro-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0252] ##STR00094##
[0253] 5-Chloro-2-cyanopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (80.0 mg, 0.13 mmol) was dissolved in DCM/TFA (10 mL, 19:1) and stirred 1 h at rt. The mixture was neutralized with Et.sub.3N and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method A) to give the title compound (36.2 mg, 53%) as a white solid. ESI-MS m/z calcd for [C.sub.22H.sub.20ClF.sub.2N.sub.5O.sub.4S] [M+H].sup.+: 524.1; found: 524.2. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.60 (d, J=2.0 Hz, 1H), 8.57 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 2H), 6.51 (d, J=5.2 Hz, 1H), 5.07 (dd, J=11.6, 2.8 Hz, 1H), 4.72 (dd, J=11.6, 5.2 Hz, 1H), 4.39 (t, J=6.0 Hz, 1H), 4.18 (d, J=2.4 Hz, 1H), 3.67 (d, J=6.0 Hz, 2H), 3.46 (s, 3H), 2.21 (s, 3H).
Example 13
5-Chloro-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0254] ##STR00095##
[0255] 5-Chloro-2-cyanopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (35.0 mg, 0.059 mmol) was dissolved in DCM/TFA (10 mL, 19:1). The mixture was stirred 1 h at rt and neutralized with Et.sub.3N. Solvent was removed under reduced pressure and the residue was purified by preparative HPLC (Method A) to give the title compound (16.7 mg, 56%) as a white solid. ESI-MS m/z calcd for [C.sub.22H.sub.21ClFN.sub.5O.sub.4S] [M+H].sup.+: 506.1; found: 506.1. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.50 (d, J=2.0 Hz, 1H), 8.41 (s, 1H), 8.38 (d, J=2.0 Hz, 1H), 7.52-7.38 (m, 2H), 7.21 (t, J=8.0 Hz, 1H), 6.42 (d, J=5.2 Hz, 1H), 4.97 (dd, J=11.6, 3.2 Hz, 1H), 4.63 (dd, J=11.6, 5.2 Hz, 1H), 4.30 (t, J=6.0 Hz, 1H), 4.10 (d, J=2.0 Hz, 1H), 3.59 (d, J=6.0 Hz, 2H), 3.37 (s, 3H), 2.20 (d, J=1.2 Hz, 3H).
Example 14
5-Chloro-2-cyanophenyl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0256] ##STR00096##
[0257] To a solution of 5-chloro-2-cyanophenyl 4,6-di-O-acetyl-3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (56.0 mg, 0.092 mmol) in the MeOH (3 mL), Et.sub.3N (2 mL) and water (1 mL) were added. The mixture was stirred 4 h at rt under nitrogen atmosphere. The solvent was removed under the reduced pressure the residue was purified by preparative HPLC (Method A) to give the title compound (31.0 mg, 64%) as a white solid. ESI-MS m/z calcd for [C.sub.23H.sub.21ClF.sub.2N.sub.4O.sub.4S] [M+H].sup.+: 523.1; found: 523.0. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.59 (s, 1H), 8.02 (d, J=2.0 Hz, 1H), 8.78 (d, J=8.4 Hz, 1H), 7.54 (dd, J=8.4, 2.0 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 6.43 (d, J=5.2 Hz, 1H), 5.08 (dd, J=11.2, 2.8 Hz, 1H), 4.74-4.70 (m, 1H), 4.45 (t, J=6.4 Hz, 1H), 4.21 (d, J=2.4 Hz, 1H), 3.74-3.67 (m, 2H), 3.48 (s, 3H), 2.24 (s, 3H).
Example 15
5-Chloro-2-cyanopyridin-3-yl 3-deoxy-2-O-(2,2,2-trifluoroethyl)-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
Example 16
5-Chloro-2-cyanopyridin-3-yl 3-deoxy-2-O-ethyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
[0258] ##STR00097##
[0259] A nitrogen purged solution of 2-bromo-5-chloro-pyridin-3-yl 3-deoxy-2-O-ethyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (10 mg, 0.017 mmol) in N,N-dimethylacetamide (0.5 mL) was added to a nitrogen purged solution of Zn (0.5 mg, 0.0084 mmol), Zn(CN).sub.2 (2.0 mg, 0.017 mmol), Pd(dibenzylideneacetone).sub.2 (0.8 mg, 0.0013 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (0.8 mg, 0.0013 mmol) in N,N-dimethylacetamide (0.5 mL) and the resulting mixture was stirred 23 h at 100° C. The mixture was purified by preparative HPLC (Method B) to afford the title compound (1.8 mg, 20%). ESI-MS m/z calcd for [C.sub.22H.sub.19ClF.sub.3N.sub.5O.sub.4S] [M+H].sup.+: 542.1; found: 541.8. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.60 (s, 2H), 8.47 (d, J=2.1 Hz, 1H), 7.67 (dd, J=8.6, 6.7 Hz, 2H), 6.48 (d, J=5.3 Hz, 1H), 5.08 (dd, J=11.3, 2.8 Hz, 1H), 4.80 (dd, J=11.3, 5.3 Hz, 1H), 4.39 (t, J=6.0 Hz, 1H), 4.20 (d, J=2.4 Hz, 1H), 3.92-3.83 (m, 1H), 3.68 (d, J=6.0 Hz, 2H), 3.53-3.44 (m, 1H), 1.05 (t, J=7.0 Hz, 3H).
Example 17
5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-ethyl-1-thio-α-D-galactopyranoside
[0260] ##STR00098##
[0261] 5-Bromopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (200 mg, 0.31 mmol) was stirred in DMF (3.0 mL) and NaH (60% in oil, 25 mg, 0.61 mmol) followed by ethyl iodide (52 μL, 0.61 mmol) were added. The mixture was stirred 2 h at rt, then partitioned between EtOAc and water and the organic phase was collected and evaporated. The residue was stirred 1 h in 80% aq TFA (3.0 mL). The mixture was concentrated to about 1 mL volume, then partitioned between water and EtOAc. NaOH (1 M) was added to pH approximately 10, the organic phase was collected and evaporated. The residue was purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the title compound (159 mg, 92%). ESI-MS m/z calcd for [C.sub.21H.sub.20BrF.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 561.0; found: 561.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.67 (d, J=1.8 Hz, 1H), 8.59 (s, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.33 (t, J=2.0 Hz, 1H), 7.71-7.61 (m, 2H), 6.24 (d, J=5.3 Hz, 1H), 5.05 (dd, J=11.3, 2.8 Hz, 1H), 4.74 (dd, J=11.3, 5.3 Hz, 1H), 4.45 (t, J=6.1 Hz, 1H), 4.20 (d, J=2.5 Hz, 1H), 3.85-3.76 (m, 1H), 3.75-3.64 (m, 2H), 3.49-3.40 (m, 1H), 1.03 (t, J=7.0 Hz, 3H).
Example 18
5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-isopropyl-1-thio-α-D-galactopyranoside
[0262] ##STR00099##
[0263] 5-Bromopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (200 mg, 0.31 mmol), Cs.sub.2CO.sub.3 (200 mg, 0.6 mmol), and isopropyl iodide (91 μL, 0.9 mmol) were stirred in DMF (2.0 mL) 17 h at 90° C. The mixture was poured onto cold water and the precipitate was collected, then stirred 2 h at rt in 80% aq TFA (3.0 mL). The mixture was partitioned between EtOAc and NaOH (0.5 M), the organic phase was collected and evaporated. The residue was purified by preparative HPLC (Method B) to afford the title compound (15 mg, 8%). ESI-MS m/z calcd for [C.sub.22H.sub.22BrF.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 575.1; found: 575.2. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.67 (d, J=1.7 Hz, 1H), 8.61 (s, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.33 (t, J=1.9 Hz, 1H), 7.66 (dd, J=8.8, 6.7 Hz, 2H), 6.20 (d, J=5.3 Hz, 1H), 5.03 (dd, J=11.3, 2.8 Hz, 1H), 4.79 (dd, J=11.3, 5.3 Hz, 1H), 4.43 (t, J=6.0 Hz, 1H), 4.19 (d, J=2.1 Hz, 1H), 3.79 (p, J=6.1 Hz, 1H), 3.74-3.62 (m, 2H), 1.13 (d, J=6.1 Hz, 3H), 0.87 (d, J=6.0 Hz, 3H).
Example 19
5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-(2-fluoroethyl)-1-thio-α-D-galactopyranoside
[0264] ##STR00100##
[0265] 5-Bromopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (200 mg, 0.31 mmol) was stirred in DMF (3.0 mL) and 1-fluoro-2-iodo-ethane (82 μL, 0.92 mmol) followed by NaH (60% in oil, 50 mg, 1.23 mmol) were added. The mixture was stirred 3 h at rt, then poured onto ice cooled water (30 mL) and HCl (1 M, 5 mL). The solids were isolated by filtration and purified by chromatography (SiO.sub.2, PE/EtOAc). The crude was stirred 1 h in 80% aq TFA (4.0 mL). The mixture was poured on ice and NaOH (1 M), the precipitate was collected by filtration and purified by preparative HPLC (Method B) to afford the title product (63 mg. 35%). ESI-MS m/z calcd for [C.sub.21H.sub.19BrF.sub.4N.sub.4O.sub.4S][M+H].sup.+: 579.0; found: 579.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.69 (d, J=1.4 Hz, 1H), 8.58 (d, J=1.8 Hz, 1H), 8.57 (s, 1H), 8.35 (t, J=1.6 Hz, 1H), 7.68-7.58 (m, 2H), 6.24 (d, J=5.3 Hz, 1H), 5.08 (dd, J=11.3, 2.8 Hz, 1H), 4.81 (dd, J=11.4, 5.4 Hz, 1H), 4.48 (t, 1H), 4.45 (m, 1H), 4.33 (m, 1H), 4.24 (d, J=2.6 Hz, 1H), 3.96 (m, 1H), 3.73 (m, 1H), 3.73-3.67 (m, 2H).
Example 20
5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-[2-(methylamino)ethyl]-1-thio-α-D-galactopyranoside
[0266] ##STR00101##
[0267] 2-[(tert-Butoxycarbonyl)(methyl)amino]ethyl 4-methylbenzenesulfonate (238 mg, 0.72 mmol) and 5-bromopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (155 mg, 0.25 mmol) were stirred in DMF (3.0 mL) and NaH (60% in oil, 40 mg, 1.0 mmol) was added. The mixture was stirred 5 h at rt, then poured onto ice. The solids were isolated by filtration and purified by chromatography (SiO.sub.2, PE/EtOAc). The crude was stirred 1 h in 80% aq TFA (3.0 mL). The mixture was concentrated, poured on ice and NaOH (1 M, pH>10). The precipitate was collected by filtration and purified by preparative HPLC (Method B) to afford the title product as the TFA salt (57 mg, 32%). ESI-MS m/z calcd for [C.sub.22H.sub.23BrF.sub.3N.sub.5O.sub.4S] [M+H].sup.+: 590.1; found: 589.8. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.71 (s, 1H), 8.63 (s, 1H), 8.61 (s, 1H), 8.39 (d, J=1.0 Hz, 1H), 7.72-7.60 (m, 2H), 6.30 (d, J=5.3 Hz, 1H), 5.14 (dd, J=11.3, 2.4 Hz, 1H), 4.90 (dd, J=11.2, 5.3 Hz, 1H), 4.50 (t, J=6.0 Hz, 1H), 4.23 (d, J=2.5 Hz, 1H), 4.10 (ddd, J=10.6, 7.5, 2.9 Hz, 1H), 3.79-3.65 (m, 3H), 3.22-3.13 (m, 1H), 3.13-3.04 (m, 1H), 2.61 (s, 3H).
Example 21
3,4-Dichlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-(2-hydroxyethyl)-1-thio-α-D-galactopyranoside
[0268] ##STR00102##
[0269] To a solution of 3,4-dichlorophenyl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-carboxymethyl-1-thio-α-D-galactopyranoside (50 mg, 0.081 mmol) in THF (0.5 mL) borane THF complex solution (0.5 mL, 1 M in THF, 0.5 mmol) was added. The mixture was stirred 40 min at rt and then quenched with cold HCl (1 M). The mixture was extracted with EtOAc, the solvents were removed, and the residue was purified preparative HPLC (Method B) to afford the title compound (33 mg, 67%). ESI-MS m/z calcd for [C.sub.22H.sub.20Cl.sub.3F.sub.2N.sub.3O.sub.5S][M+H].sup.+: 582.0; found: 582.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.68 (s, 1H), 7.82 (d, J=1.4 Hz, 1H), 7.65 (m, 2H), 7.55 (dd, J=8.4, 1.3 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 6.18 (d, J=5.3 Hz, 1H), 5.04 (dd, J=11.3, 2.8 Hz, 1H), 4.80 (dd, J=11.3, 5.3 Hz, 1H), 4.48 (t, J=6.1 Hz, 1H), 4.26 (d, J=2.5 Hz, 1H), 3.81 (m, 1H), 3.76-3.67 (m, 2H), 3.60-3.50 (m, 3H).
Example 22
5-Chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0270] ##STR00103##
[0271] A solution of 5-chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 4,6-di-O-acetyl-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (58.0 mg, 0.080 mmol) in MeOH (3 mL), Et.sub.3N (2 mL) and water (1 mL) was stirred 4 h at rt under a nitrogen atmosphere. The solvent was removed under reduced preesure and the residue was purified by preparative HPLC (Method A) to give the title compound (17.6 mg, 34%). ESI-MS m/z calcd for [C.sub.26H.sub.24Cl.sub.2F.sub.2N.sub.6O.sub.5S] [M+H].sup.+: 641.1; found: 641.0. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.57 (s, 1H), 7.96 (s, 1H), 7.57 (d, J=7.6 Hz, 2H), 6.14 (d, J=5.2 Hz, 1H), 4.96 (dd, J=11.6, 2.8 Hz, 1H), 4.74 (s, 4H), 4.58-4.54 (m, 1H), 4.40-4.29 (m, 4H), 4.26-4.22 (m, 1H), 4.08 (d, J=2.4 Hz, 1H), 3.59-3.58 (m, 2H), 3.30 (s, 3H).
Example 23
5-Chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0272] ##STR00104##
[0273] To a solution of 5-chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 4,6-di-O-acetyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (54.0 mg, 0.076 mmol) in MeOH (3 mL) Et.sub.3N (2 mL) and water (1 mL) were added. The mixture was stirred 4 h at rt under a nitrogen atmosphere. The solvent was removed under reduced preesure and the residue was purified by preparative HPLC (Method A) to give the title compound (26.5 mg, 56%). ESI-MS m/z calcd for [C.sub.26H.sub.24ClF.sub.3N.sub.6O.sub.5S] [M+H].sup.+: 625.1; found: 625.1. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.64 (s, 1H), 8.09 (s, 1H), 7.71-7.67 (m, 2H), 6.26 (d, J=5.2 Hz, 1H), 5.07 (dd, J=11.6, 2.8 Hz, 1H), 4.86 (s, 4H), 4.69-4.65 (m, 1H), 4.52-4.41 (m, 4H), 4.36-4.33 (m, 1H), 4.18 (d, J=2.4 Hz, 1H), 3.71-3.68 (m, 2H), 3.41 (s, 3H).
Example 24
5-Chloro-2-(pyrimidin-5-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0274] ##STR00105##
[0275] 5-Chloro-2-(pyrimidin-5-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (90.0 mg, 0.14 mmol) was dissolved in DCM/TFA (10 mL, 19:1) and stirred 1 h at rt. The mixture was neutralized with Et.sub.3N and then concentrated. The residue was purified by preparative HPLC (Method A) to give the title compound (52.5 mg, 67%) as a white solid. ESI-MS n/z calcd for [C.sub.24H.sub.20ClF.sub.3N.sub.6O.sub.4S] [M+H].sup.+: 581.1; found: 581.1. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 9.13 (s, 1H), 9.06 (s, 2H), 8.54 (d, J=2.0 Hz, 1H), 8.44 (s, 1H), 8.36 (d, J=2.0 Hz, 1H), 7.53 (m, 2H), 6.00 (d, J=5.2 Hz, 1H), 4.79 (m, 1H), 4.46 (dd, J=11.2, 5.2 Hz, 1H), 4.13 (t, J=6.0 Hz, 1H), 4.01 (d, J=2.4 Hz, 1H), 3.56 (d, J=6.0 Hz, 2H), 3.07 (s, 3H).
Example 25
5-Chloro-2-(pyridin-2-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0276] ##STR00106##
[0277] 5-Chloro-2-(pyridin-2-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (30.0 mg, 0.045 mmol) was dissolved in DCM/TFA (10 mL, 19:1) and stirred 1 h at rt. The mixture was neutralized with Et.sub.3N and then concentrated. The residue was purified by preparative HPLC (Method A) to give the title compound (16.3 mg, 63%) as a white solid. ESI-MS m/z calcd for [C.sub.25H.sub.21ClF.sub.3N.sub.5O.sub.4S] [M+H].sup.+: 580.1; found: 580.1. .sup.1HNMR (400 MHz, CD.sub.3OD) δ 8.59 (s, 1H), 8.44 (s, 1H), 8.42 (s, 1H), 8.36 (d, J=2.0 Hz, 1H), 7.89 (m, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.60-7.50 (m, 2H), 7.46-7.37 (m, 1H), 6.10 (d, J=5.2 Hz, 1H), 4.83 (m, 1H), 4.47 (dd, J=11.2, 5.2 Hz, 1H), 4.19 (t, J=6.0 Hz, 1H), 4.01 (d, J=2.4 Hz, 1H), 3.64-3.52 (m, 2H), 3.09 (s, 3H).
Example 26
5-Chloro-2-(pyridin-3-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0278] ##STR00107##
[0279] To a solution of 5-chloro-2-(pyridin-3-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (50 mg, 0.075 mmol) in DCM (3 mL) TFA (0.29 mL) and water (0.5 mL) were added and the mixture was stirred 12 h at rt. The mixture was neutralized with Et.sub.3N and then concentrated. The residue was purified by preparative HPLC (Method A) to give the title compound (31 mg, 70%) as a white solid. ESI-MS m/z calcd for [C.sub.25H.sub.21ClF.sub.3N.sub.5O.sub.4S] [M+H].sup.+: 580.1, found: 580.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.84 (s, 2H), 8.66 (d, J=2.0 Hz, 2H), 8.42 (d, J=2.0 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.83 (dd, J=8.8, 7.2 Hz, 2H), 7.56 (dd, J=7.6, 4.8 Hz, 1H), 6.38 (d, J=5.2 Hz, 1H), 5.59 (s, 1H), 4.77 (dd, J=11.2, 2.4 Hz, 2H), 4.46 (dd, J=11.6, 5.2 Hz, 1H), 4.09 (t, J=6.0 Hz, 1H), 3.97 (s, 1H), 3.49-3.41 (m, 2H), 3.14 (s, 3H).
Example 27
5-Chloro-2-(pyridin-4-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0280] ##STR00108##
[0281] To a solution of 5-chloro-2-(pyridin-4-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (50 mg, 0.075 mmol) in DCM (5.0 mL) TFA (0.5 mL) was added and the mixture was stirred 2 h at rt. The mixture was neutralized with Et.sub.3N (1 mL) and then concentrated. The residue was purified by preparative HPLC (Method A) to give the title compound (17 mg, 39%). ESI-MS m/z calcd for [C.sub.25H.sub.21ClF.sub.3N.sub.5O.sub.4S] [M+H].sup.+: 580.1; found: 579.8. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.70 (dd, J=4.8, 1.6 Hz, 2H), 8.60 (d, J=2.4 Hz, 1H), 8.55 (s, 1H), 8.45 (d, J=2.4 Hz, 1H), 7.76 (dd, J=4.8, 1.6 Hz, 2H), 7.65 (dd, J=8.8, 6.8 Hz, 2H), 6.11 (d, J=5.2 Hz, 1H), 4.89-4.83 (m, 1H), 4.57 (dd, J=11.2, 5.2 Hz, 1H), 4.26 (t, J=6.4 Hz, 1H), 4.16-4.09 (m, 1H), 3.73-3.61 (m, 2H), 3.17 (s, 3H).
Example 28
5-Chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0282] ##STR00109##
[0283] To a solution of 5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (60.0 mg, 0.12 mmol) in DMF (2 mL), trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (23.5 mg, 0.10 mmol), (+)-sodium L-ascorbate (18.5 mg, 0.094 mmol), copper(II) sulfate pentahydrate (23.3 mg, 0.094 mmol) and CsF (21.3 mg, 0.14 mmol) were added. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was filtered, and the filtrate was purified by preparative HPLC (Method A) to give the product (7.8 mg, 14%). ESI-MS m/z calcd for [C.sub.25H.sub.25ClF.sub.3N.sub.5O.sub.4S] [M+H].sup.+: 584.1; found: 583.9. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.62 (s, 1H), 8.39 (d, J=2.0 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 7.72-7.65 (m, 2H), 6.31 (d, J=5.2 Hz, 1H), 6.08-5.99 (m, 1H), 5.06 (dd, J=11.2, 2.8 Hz, 1H), 4.66 (dd, J=11.2, 5.2 Hz, 1H), 4.38-4.29 (m, 1H), 4.21-4.14 (m, 1H), 3.75-3.56 (m, 4H), 3.39 (s, 3H), 3.18-3.13 (m, 2H), 2.64-2.50 (m, 2H).
Example 29
5-Chloro-2-(3-pyrrolin-3-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0284] ##STR00110##
[0285] To a solution of 5-chloro-2-[1-(N-tert-butoxycarbonyl)-3-pyrrolin-3-yl]pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (50 mg, 0.066 mmol) in DCM (6 mL), TFA (0.49 mL, 6.59 mmol) was added. The mixture was stirred 2 h at rt and TEA (1 mL) was added. The mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to give the product (13 mg, 37%). ESI-MS m/z calcd for [C.sub.24H.sub.23ClF.sub.3N.sub.5O.sub.4S] [M+H].sup.+: 570.1; found: 569.8. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.63 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 7.69 (dd, J=8.8, 6.4 Hz, 2H), 6.95-6.85 (m, 1H), 6.33 (d, J=5.2 Hz, 1H), 5.08 (dd, J=11.6, 2.8 Hz, 1H), 4.67 (dd, J=11.2, 5.2 Hz, 1H), 4.38-4.31 (m, 1H), 4.30-4.25 (m, 2H), 4.22-4.17 (m, 1H), 4.12-4.04 (m, 2H), 3.76-3.61 (m, 2H), 3.39 (s, 3H).
Example 30
5-Chloro-2-(oxazol-2-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0286] ##STR00111##
[0287] To a solution of 5-chloro-2-(oxazol-2-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (80 mg, 0.11 mmol) in DCM (5 mL) TFA (618 mg, 5.42 mmol) and H.sub.2O (0.5 mL) were added. The mixture was stirred 12 h at rt before Et.sub.3N (1.5 mL) was added dropwise at 0° C. The solvent was removed by evaporation and the residue was purified by preparative HPLC (Method A) to give the title compound (31 mg, 50%) as a white solid. ESI-MS m/z calcd for [C.sub.23H.sub.19ClF.sub.3N.sub.5O.sub.5S] [M+H].sup.+:570.1; found: 570.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.91 (s, 1H), 8.60 (d, J=2.4 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 8.36 (d, J=0.8 Hz, 1H), 7.86-7.82 (m, 2H), 7.58 (d, J=0.8 Hz, 1H), 6.70 (d, J=5.2 Hz, 1H), 5.63 (d, J=6.0 Hz, 1H), 4.94 (dd, J=11.6, 2.8 Hz, 1H), 4.66 (d, J=11.2 Hz, 1H), 4.56 (dd, J=11.2, 5.2 Hz, 1H), 4.14-4.11 (m, 1H), 4.03-4.01 (m, 1H), 3.54-3.49 (m, 1H), 3.43-3.38 (m, 1H), 3.29 (s, 3H).
Example 31
5-Chloro-2-(thiazol-2-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0288] ##STR00112##
[0289] To a solution of 5-chloro-2-(thiazol-2-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (85 mg, 0.12 mmol) in DCM (6 mL) TFA (0.43 mL) and H.sub.2O (0.5 mL) were added. The mixture was stirred 12 h at rt, Et.sub.3N (1.5 mL) was added dropwise at 0° C. The solvent was removed by evaporation and the residue was purified by preparative HPLC (Method A) to give the title compound (11 mg, 16%). ESI-MS m/z calcd for [C.sub.23H.sub.19ClF.sub.3N.sub.5O.sub.4S.sub.2].sup.+[M+H].sup.+: 586.0; found: 586.0. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.60 (s, 1H), 8.43-8.40 (m, 2H), 8.00 (d, J=3.2 Hz, 1H), 7.70-7.65 (m, 3H), 6.51 (d, J=5.6 Hz, 1H), 5.14 (dd, J=11.2, 2.8 Hz, 1H), 4.70 (dd, J=11.2, 5.2 Hz, 1H), 4.36-4.33 (m, 1H), 4.16 (d, J=2.0 Hz, 1H), 3.72-3.62 (m, 2H), 3.38 (s, 3H).
Example 32
2,5-Bis(thiazol-2-yl)pyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0290] ##STR00113##
[0291] To a solution of 2,5-bis(thiazol-2-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (125 mg, 53%, 0.091 mmol) in DCM (5 mL) TFA (0.34 mL) and H.sub.2O (0.5 mL) were added. The mixture was stirred 12 h at rt, Et.sub.3N (1.5 mL) was added dropwise at 0° C. The solvent was removed by evaporation and the residue was purified by preparative HPLC (Method A) to give the title compound (23 mg, 40%) as a white solid. ESI-MS m/z calcd for [C.sub.26H.sub.21F.sub.3N.sub.6O.sub.4S.sub.3] [M+H].sup.+: 635.1; found: 635.0. .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.80 (d, J=2.0 Hz, 1H), 8.52 (s, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.79 (d, J=3.2 Hz, 1H), 7.66 (d, J=3.2 Hz, 1H), 7.61-7.55 (m, 4H), 6.32 (d, J=5.6 Hz, 1H), 4.98 (dd, J=11.2, 2.8 Hz, 1H), 4.57 (dd, J=11.2, 5.2 Hz, 1H), 4.40-4.37 (m, 1H), 4.10 (d, J=2.8 Hz, 1H), 3.61-3.59 (m, 2H), 3.33 (s, 3H).
Examples 33 and 34
5-Chloropyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0292] ##STR00114##
5-Bromopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0293] ##STR00115##
[0294] A mixture of 5-chloropyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside and 5-bromopyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (115 mg), trimethyl-[2-(4-chloro-3,5-difluorophenyl)ethynyl]silane (101 mg, 0.42 mmol) and CuI (6.3 mg, 0.033 mmol) were dissolved in MeCN (3 mL). DIEA (0.11 mL, 0.66 mmol) was added and the mixture was stirred 16 h at 50° C. The mixture was diluted with EtOAc and washed with water. The organic phase was dried, evaporated and purified by preparative HPLC (Method B) to afford the two title compounds (65 mg of the chloro analog and 31 mg of the bromo analog).
5-Chloropyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0295] ESI-MS m/z calcd for [C.sub.20H.sub.18ClF.sub.2N.sub.4O.sub.4S] [M+H].sup.+: 519.1; found: 519.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.67 (d, J=1.8 Hz, 1H), 8.64 (s, 1H), 8.49 (d, J=2.2 Hz, 1H), 8.24 (t, J=2.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 2H), 6.29 (d, J=5.3 Hz, 1H), 5.05 (dd, J=11.4, 2.9 Hz, 1H), 4.65 (dd, J=11.3, 5.3 Hz, 1H), 4.46 (t, J=6.1 Hz, 1H), 4.19 (d, J=2.4 Hz, 1H), 3.75-3.65 (m, 2H), 3.41 (s, 3H).
5-Bromopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0296] ESI-MS m/z calcd for [C.sub.20H.sub.18BrF.sub.2N.sub.4O.sub.4S] [M+H].sup.+: 563.0; found: 563.0. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.71 (d, J=1.8 Hz, 1H), 8.64 (s, 1H), 8.59 (d, J=2.1 Hz, 1H), 8.39 (t, J=2.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 2H), 6.29 (d, J=5.3 Hz, 1H), 5.05 (dd, J=11.4, 2.9 Hz, 1H), 4.65 (dd, J=11.3, 5.3 Hz, 1H), 4.46 (t, J=6.1 Hz, 1H), 4.19 (d, J=2.4 Hz, 1H), 3.76-3.66 (m, 2H), 3.41 (s, 3H).
Examples 35 and 36
5-Chloropyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0297] ##STR00116##
5-Bromopyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0298] ##STR00117##
[0299] A mixture of 5-chloropyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside and 5-bromopyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (115 mg), trimethyl-[2-(3-fluoro-4-methylphenyl)ethynyl]silane (86 mg, 0.42 mmol) and CuI (6.3 mg, 0.033 mmol) were dissolved in MeCN (3 mL). DIEA (0.11 mL, 0.66 mmol) was added and the mixture was stirred 26 h at 50° C. The mixture was diluted with EtOAc and washed with water. The organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc). Further purification by preparative HPLC (Method B) to afford the two title compounds (25 mg of the chloro analog and 12 mg of the bromo analog).
5-Chloropyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0300] ESI-MS m/z calcd for [C.sub.21H.sub.22ClFN.sub.4O.sub.4S] [M+H].sup.+: 481.1; found: 481.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.67 (d, J=1.6 Hz, 1H), 8.49 (s, 2H), 8.25 (t, J=2.0 Hz, 1H), 7.58-7.51 (m, 2H), 7.31 (t, J=8.0 Hz, 1H), 6.29 (d, J=5.3 Hz, 1H), 5.03 (dd, J=11.3, 2.8 Hz, 1H), 4.66 (dd, J=11.3, 5.3 Hz, 1H), 4.46 (t, J=6.0 Hz, 1H), 4.19 (d, J=2.5 Hz, 1H), 3.74-3.65 (m, 2H), 3.41 (s, 3H), 2.30 (s, 3H).
5-Bromopyridin-3-yl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0301] ESI-MS m/z calcd for [C.sub.21H.sub.22BrFN.sub.4O.sub.4S] [M+H].sup.+: 525.1; found: 525.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.71 (d, J=1.8 Hz, 1H), 8.59 (d, J=2.1 Hz, 1H), 8.49 (s, 1H), 8.38 (t, J=2.0 Hz, 1H), 7.58-7.51 (m, 2H), 7.31 (t, J=8.0 Hz, 1H), 6.28 (d, J=5.3 Hz, 1H), 5.03 (dd, J=11.4, 2.8 Hz, 1H), 4.66 (dd, J=11.3, 5.3 Hz, 1H), 4.46 (t, J=6.1 Hz, 1H), 4.19 (d, J=2.4 Hz, 1H), 3.75-3.65 (m, 2H), 3.41 (s, 3H), 2.30 (s, 3H).
Examples 37 and 38
5-Chloropyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0302] ##STR00118##
5-Bromopyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0303] ##STR00119##
[0304] A mixture of 5-chloropyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside and 5-bromopyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (115 mg), trimethyl-[2-(4-chloro-3-fluorophenyl)ethynyl]silane (94 mg, 0.42 mmol) and CuI (6.3 mg, 0.033 mmol) were dissolved in MeCN (3 mL). DIEA (0.11 mL, 0.66 mmol) was added and the mixture was stirred 26 h at 50° C. The mixture was diluted with EtOAc and washed with water. The organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc). Further purification by preparative HPLC (Method B) to afford the two title compounds (36 mg of the chloro analog and 14 mg of the bromo analog).
5-Chloropyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0305] ESI-MS m/z calcd for [C.sub.20H.sub.19Cl.sub.2FN.sub.4O.sub.4S] [M+H].sup.+: 501.1; found: 501.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.67 (d, J=1.8 Hz, 1H), 8.58 (s, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.25 (t, J=2.1 Hz, 1H), 7.77 (dd, J=10.4, 1.9 Hz, 1H), 7.69 (dd, J=8.4, 1.8 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 6.29 (d, J=5.3 Hz, 1H), 5.05 (dd, J=11.3, 2.9 Hz, 1H), 4.66 (dd, J=11.4, 5.3 Hz, 1H), 4.46 (t, J=6.1 Hz, 1H), 4.19 (d, J=2.5 Hz, 1H), 3.74-3.65 (m, 2H), 3.41 (s, 3H).
5-Bromopyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0306] ESI-MS m/z calcd for [C.sub.20H.sub.19BrClFN.sub.4O.sub.4S] [M+H].sup.+: 545.0; found: 545.0. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.71 (d, J=1.8 Hz, 1H), 8.60-8.57 (m, 2H), 8.38 (t, J=2.0 Hz, 1H), 7.77 (dd, J=10.4, 1.9 Hz, 1H), 7.69 (dd, J=8.4, 1.3 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 6.28 (d, J=5.3 Hz, 1H), 5.04 (dd, J=11.4, 2.9 Hz, 1H), 4.66 (dd, J=11.3, 5.3 Hz, 1H), 4.46 (t, J=6.0 Hz, 1H), 4.19 (d, J=2.2 Hz, 1H), 3.75-3.66 (m, 2H), 3.41 (s, 3H).
Example 39
6-Trifluoromethyl-5-methylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0307] ##STR00120##
[0308] 6-Trifluoromethyl-5-methylpyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (190 mg, 0.27 mmol was dissolved in solution of DCM/TFA (20 mL, 19:1) and the mixture was stirred 6 h at rt. Et.sub.3N was added to neutralize the TFA. The solvent was removed by evaporation and the residue was purified by preparative HPLC (Method A) to give the title compound (111 mg, 73%) as a white solid. ESI-MS m/z calcd for [C.sub.22H.sub.20ClF.sub.5N.sub.4O.sub.4S] [M+H].sup.+: 567.1; found: 567.1. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.65 (s, 1H), 8.62 (d, J=1.6 Hz, 1H), 8.13 (s, 1H), 7.69-7.64 (m, 2H), 6.35 (d, J=5.2 Hz, 1H), 5.06 (dd, J=11.2, 2.8 Hz, 1H), 4.65 (dd, J=11.2, 5.2 Hz, 1H), 4.46-4.43 (m, 1H), 4.17 (d, J=2.4 Hz, 1H), 3.70-3.68 (m, 2H), 3.41 (s, 3H), 2.51-2.48 (m, 3H).
Example 40
2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0309] ##STR00121##
[0310] 2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (100 mg, 0.17 mmol), benzaldehyde dimethylacetal (53 μL, 0.35 mmol) and p-toluenesulfonic acid monohydrate (catalytic amount) were stirred 20 h at rt in MeCN (1.5 mL). The mixture was neutralized with Et.sub.3N, water was added, and the precipitate was collected by filtration. The precipitate was dissolved in DMF (2 mL), iodomethane (30 μL, 0.46 mmol) followed by NaH (60% in oil, 20 mg, 0.46 mmol) were added. The mixture was stirred 4 h at rt, then poured onto ice/water. The precipitate was isolated by filtration and dried. This material was dissolved in 80% aq TFA (2.0 mL) and stirred 1 h at rt and poured onto ice/water. The precipitate was collected and purified by preparative HPLC (Method B) to afford the title compound (40 mg, 39%). ESI-MS m/z calcd for [C.sub.25H.sub.24Cl.sub.2F.sub.2N.sub.4O.sub.5S] [M+H].sup.+: 601.1; found: 600.8. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.64 (s, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 2H), 7.44 (dd, J=8.2, 2.0 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 6.23 (d, J=5.3 Hz, 1H), 5.03 (dd, J=11.4, 2.9 Hz, 1H), 4.61 (dd, J=11.4, 5.3 Hz, 1H), 4.51 (t, J=6.2 Hz, 1H), 4.26-4.15 (m, 3H), 4.01 (h, J=8.7 Hz, 2H), 3.77-3.62 (m, 2H), 3.42 (s, 3H), 2.36 (p, J=7.7 Hz, 2H).
Example 41
2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0311] ##STR00122##
[0312] To a solution of 2-(N-azetidinyl-carbonyl)-5-chlorophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (125 mg, 0.19 mmol) in DCM (4 mL) TFA (0.70 mL, 9.60 mmol) was added. The mixture was stirred 24 h at rt before Et.sub.3N (2 mL) was added at 0° C. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (Method A) to give the title compound (40.4 mg, 37%). ESI-MS m/z calcd for [C.sub.26H.sub.28ClFN.sub.4O.sub.5S] [M+H].sup.+: 563.1, found: 563.2. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.48 (s, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.56-7.51 (m, 2H), 7.44 (dd, J=8.0, 2.0 Hz, 1H), 7.34-7.27 (m, 2H), 6.22 (d, J=5.2 Hz, 1H), 5.02 (dd, J=11.6, 2.8 Hz, 1H), 4.64 (dd, J=11.6, 5.6 Hz, 1H), 4.51 (t, J=8.0 Hz, 1H), 4.21-4.17 (m, 3H), 4.03-3.97 (m, 2H), 4.73-3.64 (m, 2H), 3.41 (s, 3H), 2.38-2.31 (m, 2H), 2.29 (d, J=1.2 Hz, 3H).
Example 42
5-Chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0313] ##STR00123##
[0314] To a solution of 5-chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (100 mg, 0.17 mmol) in DCM (10 mL) TFA (0.63 mL, 8.46 mmol) was added at 0° C. The mixture was stirred 2 h at rt, then Et.sub.3N (2 mL) was added at 0° C. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (Method A) to give the title compound (47 mg, 55%). ESI-MS m/z calcd for [C.sub.20H.sub.18ClF.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 503.1; found: 503.2. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.66 (d, J=2.0 Hz, 1H), 8.60 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.22 (t, J=2.0 Hz, 1H), 7.72-7.62 (m, 2H), 6.28 (d, J=5.2 Hz, 1H), 5.04 (dd, J=11.2, 2.8 Hz, 1H), 4.64 (dd, J=11.2, 5.2 Hz, 1H), 4.46 (t, J=6.4 Hz, 1H), 4.18 (d, J=2.4 Hz, 1H), 3.75-3.66 (m, 2H), 3.41 (s, 3H).
Example 43
5-Chloropyridin-3-yl 3-deoxy-3-[4-(6-fluoro-5-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0315] ##STR00124##
[0316] To a solution of 5-chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(6-fluoro-5-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (100 mg, 0.18 mmol) in DCM (5 mL) TFA (0.70 mL, 9.60 mmol) was added. The mixture was stirred 24 h at rt before Et.sub.3N was added at 0° C. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (Method A) to give the title compound (34.3 mg, 41%). ESI-MS m/z calcd for [C.sub.20H.sub.21ClFN.sub.5O.sub.4S][M+H].sup.+: 482.1, found: 482.0. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.64 (d, J=1.6 Hz, 1H), 8.54 (s, 1H), 8.46 (d, J=2.4 Hz, 1H), 8.21 (t, J=2.0 Hz, 1H), 7.85 (s, 1H), 7.84 (d, J=4.4 Hz, 1H), 6.27 (d, J=5.2 Hz, 1H), 5.07 (dd, J=11.2, 2.8 Hz, 1H), 4.65 (dd, J=11.6, 5.6 Hz, 1H), 4.47 (t, J=6.0 Hz, 1H), 4.19 (d, J=2.4 Hz, 1H), 3.70-3.67 (m, 2H), 3.40 (s, 3H), 2.31 (s, 3H).
Example 44
5-Chloropyridin-3-yl 3-[4-(5-chloro-6-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0317] ##STR00125##
[0318] TBAF (15 μL, 1 M in THF, 15 μmol) and DIEA (51.4 μL, 300 μmol) were added to 5-chloropyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (52.0 mg, 150 μmol), 3-chloro-2-methyl-6-[2-(trimethylsilyl)ethynyl]pyridine (40.0 mg, 0.187 μmol) and CuI (2.9 mg, 15 μmol) in MeCN (2 mL). The mixture was stirred 1 h at rt and then heated to 50° C. After additionally 1 h the mixture was cooled to rt and more TBAF (150 μL, 1 M, in THF, 150 μmol) was added. The mixture was stirred for 1 h before it was concentrated. Water (10 mL) was added and the mixture was extracted twice with EtOAc (10 mL). The organic phases were dried and concentrated. Purification by preparative HPLC (Method B) yielded the title compound (36.0 mg, 48%) as a white solid. ESI-MS m/z calcd for [C.sub.20H.sub.22Cl.sub.2N.sub.5O.sub.4S] [M+H].sup.+: 498.1; found: 498.1, .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.70-8.64 (m, 1H), 8.63 (s, 1H), 8.49 (d, J=1.8 Hz, 1H), 8.27-8.20 (m, 1H), 7.95-7.84 (m, 2H), 6.29 (d, J=5.3 Hz, 1H), 5.08 (dd, J=11.4, 2.6 Hz, 1H), 4.65 (dd, J=11.3, 5.4 Hz, 1H), 4.47 (t, J=5.8 Hz, 1H), 4.26-4.16 (m, 1H), 3.78-3.64 (m, 2H), 3.41 (s, 3H), 2.66 (s, 3H).
Example 45
3-Chloro-2-cyanopyridin-5-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0319] ##STR00126##
[0320] To a solution of 5-chloro-6-cyanopyridin-3-yl 4,6-di-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (25.0 mg, 0.041 mmol) in MeOH (3 mL) Et.sub.3N (2 mL) and water (1 mL) were added. The mixture was stirred 3 h at rt. The solvent was removed under the reduced pressure and the residue was purified by preparative HPLC (method A) to give the title compound (10.5 mg, 49%) as a white solid. ESI-MS m/z calcd for [C.sub.21H.sub.17ClF.sub.3N.sub.5O.sub.4S][M+H].sup.+: 528.1; found: 528.0. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.76 (d, J=2.0 Hz, 1H), 8.63 (s, 1H), 8.40 (d, J=2.0 Hz, 1H), 7.71-7.66 (m, 2H), 6.60 (d, J=5.2 Hz, 1H), 5.09 (dd, J=11.6, 2.8 Hz, 1H), 4.74 (dd, J=11.2, 5.2 Hz, 1H), 4.35 (t, J=6.0 Hz, 1H), 4.18 (d, J=2.8 Hz, 1H), 3.72-3.70 (m, 2H), 3.42 (s, 3H).
Example 46
5-Chloro-2-cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0321] ##STR00127##
[0322] A nitrogen purged solution of 2-bromo-5-chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (75 mg, 0.13 mmol) in N,N-dimethylacetamide (1 mL) was added to a nitrogen purged solution of Zn (4.2 mg, 0.065 mmol), Zn(CN).sub.2 (15 mg, 0.13 mmol), Pd(dibenzylideneacetone).sub.2 (5.9 mg, 0.010 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (5.8 mg, 0.010 mmol) in N,N-dimethylacetamide (0.5 mL) and the resulting mixture was stirred 3 h at 100° C. The mixture was purified by preparative HPLC (Method B) to afford the title compound (14 mg, 21%). ESI-MS m/z calcd for [C.sub.21H.sub.17ClF.sub.3N.sub.5O.sub.4S] [M+H].sup.+: 528.1; found: 528.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.61-8.58 (m, 2H), 8.48 (d, J=2.1 Hz, 1H), 7.66 (dd, J=8.7, 6.7 Hz, 2H), 6.52 (d, J=5.3 Hz, 1H), 5.08 (dd, J=11.3, 2.8 Hz, 1H), 4.72 (dd, J=11.3, 5.3 Hz, 1H), 4.40 (t, J=6.0 Hz, 1H), 4.20 (d, J=2.5 Hz, 1H), 3.69 (d, J=5.9 Hz, 2H), 3.46 (s, 3H).
Example 47
5-Chloro-2-cyanopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0323] ##STR00128##
[0324] 5-Chloro-2-cyanopyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (100 mg, 0.16 mmol) was dissolved in DCM/TFA (10 mL, 19:1). The mixture was stirred 6 h at rt before Et.sub.3N was added. The solvent was removed by evaporation, and the residue was purified by preparative HPLC (Method A) to give the title compound (71.0 mg, 83%). ESI-MS m/z calcd for [C.sub.21H.sub.17Cl.sub.2F.sub.2N.sub.5O.sub.4S] [M+H].sup.+: 544.0; found: 544.2. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.65 (s, 1H), 8.60 (d, J=2.4 Hz, 1H), 8.47 (d, J=2.0 Hz, 1H), 7.66 (dd, J=10.4, 2.4 Hz, 2H), 6.51 (d, J=5.2 Hz, 1H), 5.08 (dd, J=11.2, 2.8 Hz, 1H), 4.71 (dd, J=11.2, 5.2 Hz, 1H), 4.41-4.38 (m, 1H), 4.18 (d, J=2.4 Hz, 1H), 3.67 (d, J=6.0 Hz, 2H), 3.46 (s, 3H).
Example 48
5-Chloro-2-cyanopyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0325] ##STR00129##
[0326] 5-Chloro-2-cyanopyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (97.0 mg, 0.16 mmol) was dissolved in a mixed solution of DCM/TFA (10 mL, 19:1) and stirred 1 h at rt. The mixture was neutralized with Et.sub.3N and the solvent was removed by evaporation. The residue was purified by preparative HPLC (Method A) to give the title compound (47.2 mg, 57%) as a white solid. ESI-MS m/z calcd for [C.sub.21H.sub.18Cl.sub.2FN.sub.5O.sub.4S][M+H].sup.+: 526.0; found: 526.2. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.60 (d, J=2.4 Hz, 1H), 8.59 (s, 1H), 8.48 (d, J=2.4 Hz, 1H), 7.76 (dd, J=10.4, 2.0 Hz, 1H), 7.71-7.64 (m, 1H), 7.61-7.49 (m, 1H), 6.52 (d, J=5.2 Hz, 1H), 5.08 (dd, J=11.2, 2.4 Hz, 1H), 4.72 (dd, J=11.2, 5.2 Hz, 1H), 4.39 (t, J=6.0 Hz, 1H), 4.19 (d, J=2.0 Hz, 1H), 3.68 (d, J=6.0 Hz, 2H), 3.46 (s, 3H).
Example 49
2-Cyano-5-methylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0327] ##STR00130##
[0328] 2-Cyano-5-methylpyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (80 mg, 0.13 mmol) was dissolved in a mixed solution of DCM/TFA (10 mL, 19:1) and stirred 1 h at rt. The mixture was neutralized with Et.sub.3N and then evaporated. The residue was purified by preparative HPLC (Method A) to give the title compound (31.6 mg, 46%) as a white solid. ESI-MS m/z calcd for [C.sub.22H.sub.20ClF.sub.2N.sub.5O.sub.4S] [M+H].sup.+: 524.1; found: 524.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.96 (s, 1H), 8.52 (s, 1H), 8.24 (s, 1H), 7.84 (d, J=8.4 Hz, 2H), 6.51 (d, J=4.4 Hz, 1H), 5.63 (d, J=5.6 Hz, 1H), 4.95 (d, J=10.8 Hz, 1H), 4.79 (s, 1H), 4.58 (dd, J=10.8, 4.8 Hz, 1H), 4.29 (s, 1H), 4.08 (s, 1H), 3.52 (m, 2H), 3.47 (s, 3H), 2.40 (s, 3H).
Example 50
5-Bromo-2-cyanopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0329] ##STR00131##
[0330] To a solution of 5-bromo-2-cyanopyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (45.0 mg, 0.067 mmol) in DCM (5 mL) TFA (0.247 mL, 3.32 mmol) was added at 0° C. The mixture was stirred 2 h at rt before Et.sub.3N (2 mL) was added at 0° C. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (Method A) to afford the title compound (15.0 mg, 38%) as a white solid. ESI-MS m/z calcd for [C.sub.21H.sub.17BrClF.sub.2N.sub.5O.sub.4S] [M+H].sup.+: 588.0; found: 588.0. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.70 (d, J=2.0 Hz, 1H), 8.65 (s, 1H), 8.62 (d, J=2.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 2H), 6.50 (d, J=5.2 Hz, 1H), 5.08 (dd, J=11.2, 2.8 Hz, 1H), 4.71 (dd, J=11.2, 5.2 Hz, 1H), 4.40 (t, J=6.0 Hz, 1H), 4.19 (d, J=2.4 Hz, 1H), 3.68 (d, J=6.0 Hz, 2H), 3.46 (s, 3H).
Example 51
5-Bromo-2-cyanopyridin-3-yl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0331] ##STR00132##
[0332] To a solution of 5-bromo-2-cyanopyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (45.0 mg, 0.068 mmol) in DCM (5 mL) TFA (0.203 mL, 2.73 mmol) was added. The mixture was stirred under a nitrogen atmosphere 2 h at rt. Et.sub.3N (1 mL) was added at 0° C. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (Method A) to afford the title compound (21.0 mg, 54%) as a white solid. ESI-MS m/z calcd for [C.sub.21H.sub.18BrClFN.sub.5O.sub.4S] [M+H].sup.+: 570.0; found: 570.0. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.70 (d, J=2.0 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.59 (s, 1H), 7.76 (dd, J=10.4, 2.0 Hz, 1H), 7.70-7.67 (m, 1H), 7.58-7.52 (m, 1H), 6.50 (d, J=5.2 Hz, 1H), 5.07 (dd, J=11.2, 2.8 Hz, 1H), 4.72 (dd, J=11.2, 5.2 Hz, 1H), 4.40 (t, J=6.0 Hz, 1H), 4.19 (d, J=2.4 Hz, 1H), 3.68 (d, J=6.0 Hz, 2H), 3.46 (s, 3H).
Example 52
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0333] ##STR00133##
[0334] To a solution of 5-chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (22.5 mg, 0.052 mmol), trimethyl-[2-(4-chloro-3,5-difluorophenyl)ethynyl]silane (19.2 mg, 0.079 mmol) and CuI (12.5 mg, 0.065 mmol) in MeCN (1.5 mL) DIEA (0.027 mL, 0.16 mmol) was added. The mixture was stirred 5 h at 50° C. The mixture was purified by preparative HPLC (Method B) to afford the title compound (8.0 mg, 25%). ESI-MS m/z calcd for [C.sub.24H.sub.23Cl.sub.2F.sub.2N.sub.5O.sub.5S] [M+H].sup.+: 602.1; found: 601.9. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.64 (s, 1H), 8.49 (d, J=2.1 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H), 7.67 (d, J=8.0 Hz, 2H), 6.36 (d, J=5.3 Hz, 1H), 5.07 (dd, J=11.4, 2.8 Hz, 1H), 4.65 (dd, J=11.3, 5.4 Hz, 1H), 4.44 (t, J=6.0 Hz, 1H), 4.27-4.16 (m, 5H), 3.73-3.65 (m, 2H), 3.41 (s, 3H), 2.39 (p, J=8.0 Hz, 2H).
Example 53
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0335] ##STR00134##
[0336] To a solution of 5-chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (22.5 mg, 0.052 mmol), trimethyl-[2-(4-chloro-3-fluorophenyl)ethynyl]silane (19.2 mg, 0.079 mmol) and CuI (12.5 mg, 0.065 mmol) in MeCN (1.5 mL) DIEA (0.027 mL, 0.16 mmol) was added. The mixture was stirred 5 h at 50° C. The mixture was purified by preparative HPLC (Method B) to afford the title compound (6.6 mg, 22%). ESI-MS m/z calcd for [C.sub.24H.sub.24Cl.sub.2FN.sub.5O.sub.5S] [M+H].sup.+: 584.1; found: 583.8. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.58 (s, 1H), 8.49 (d, J=1.9 Hz, 1H), 8.38 (d, J=2.2 Hz, 1H), 7.77 (d, J=10.3 Hz, 1H), 7.69 (d, J=6.8 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 6.36 (d, J=5.2 Hz, 1H), 5.06 (dd, J=11.1, 2.7 Hz, 1H), 4.66 (dd, J=11.4, 5.3 Hz, 1H), 4.44 (t, J=6.0 Hz, 1H), 4.27-4.16 (m, 5H), 3.73-3.64 (m, 2H), 3.41 (s, 3H), 2.39 (p, J=8.0 Hz, 3H).
Example 54
5-Ethynylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0337] ##STR00135##
[0338] 5-(2-Trimethylsilyl-1-ethynyl)-pyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (140 mg, 0.24 mmol) was stirred in THF (2.0 mL) and TBAF (1.0 mL, 1M in THF, 1.0 mmol) for 90 min. The mixture was partitioned between EtOAc, water, and NaOH (6 mL, 1 M). The organic phase was separated, dried, evaporated and the residue was purified by chromatography (SiO.sub.2, PE/EtOAc) to give the title compound (108 mg, 88%). ESI-MS m/z calcd for [C.sub.22H.sub.19ClF.sub.2N.sub.4O.sub.4S] [M+H].sup.+: 509.1; found: 508.8. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.71 (d, J=2.1 Hz, 1H), 8.64 (s, 1H), 8.54 (d, J=1.7 Hz, 1H), 8.20 (t, J=2.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 2H), 6.25 (d, J=5.3 Hz, 1H), 5.05 (dd, J=11.3, 2.9 Hz, 1H), 4.64 (dd, J=11.3, 5.3 Hz, 1H), 4.48 (t, J=6.1 Hz, 1H), 4.20 (d, J=2.4 Hz, 1H), 3.84 (s, 1H), 3.75-3.64 (m, 2H), 3.41 (s, 3H).
Example 55
5-Chloro-2-cyanopyridin-3-yl 3-[4-(5-chloro-6-fluoropyridin-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0339] ##STR00136##
[0340] 5-Chloro-2-cyanopyridin-3-yl 4,6-O-benzylidene-3-[4-(5-chloro-6-fluoropyridin-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (125 mg, 0.20 mmol) was dissolved in a mixed solution of DCM/TFA (10 mL, 19:1) and stirred 1 h at rt. The mixture was neutralized with Et.sub.3N and the solvent was removed by evaporation. The residue was purified by preparative HPLC (Method A) to give the title compound (48.3 mg, 45%) as a white solid. ESI-MS m/z calcd for [C.sub.20H.sub.17Cl.sub.2FN.sub.6O.sub.4S] [M+H].sup.+: 527.0; found: 527.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.86 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.57 (d, J=2.0 Hz, 1H), 8.23 (dd, J=8.8, 7.2 Hz, 1H), 7.26 (dd, J=8.8, 3.2 Hz, 1H), 6.70 (d, J=5.2 Hz, 1H), 5.01 (dd, J=11.6, 2.8 Hz, 1H), 4.79 (dd, J=11.6, 5.2 Hz, 1H), 4.25-4.15 (m, 1H), 4.08 (d, J=2.4 Hz, 1H), 3.51 (dd, J=11.2, 4.8 Hz, 1H), 3.46-3.42 (m, 3H), 3.36 (s, 3H).
Example 56
2-Cyano-5-ethynylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0341] ##STR00137##
[0342] 2-Cyano-5-(2-trimethylsilyl-1-ethynyl)-pyridin-3-yl 4,6-di-O-acetyl-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (85.0 mg, 123 μmol) was dissolved in MeOH (1.23 mL) and NaOMe (1M, 61.6 μL, 61.6 μmol) was added. After 10 min, the reaction was quenched with AcOH (30 μL) and concentrated. Purification by preparative HPLC (Method B) yielded the title compound as a white solid (29.0 mg, 44%). ESI-MS m/z calcd for [C.sub.23H.sub.19ClF.sub.2N.sub.5O.sub.4S] [M+H].sup.+: 534.1; found: 534.1, .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.96 (s, 1H), 8.72 (d, J=1.8 Hz, 1H), 8.49 (d, J=1.8 Hz, 1H), 7.83 (d, J=8.2 Hz, 2H), 6.71 (d, J=5.2 Hz, 1H), 5.62 (d, J=5.6 Hz, 1H), 4.95 (dd, J=11.4, 2.9 Hz, 1H), 4.87 (s, 1H), 4.69 (s, 1H), 4.58 (dd, J=11.4, 5.3 Hz, 1H), 4.20 (t, J=6.1 Hz, 1H), 4.10-4.04 (m, 1H), 3.49 (dd, J=11.2, 5.2 Hz, 1H), 3.40 (dd, J=11.3, 7.2 Hz, 1H), 3.37 (s, 3H).
Example 57
2-Cyano-5-ethynylpyridin-3-yl 3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0343] ##STR00138##
[0344] 2-Cyano-5-(2-trimethylsilyl-1-ethynyl)-pyridin-3-yl 4,6-di-O-acetyl-3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (92.0 mg, 137 μmol) was dissolved in MeOH (1.37 mL) and NaOMe (1M, 13.7 μL, 13.7 μmol) was added. After 10 min, the reaction was quenched with AcOH (20 μL) and concentrated. Purification by preparative HPLC (Method B) yielded the title compound as a white solid (41.0 mg, 58%). ESI-MS m/z calcd for [C.sub.24H.sub.22F.sub.2N.sub.5O.sub.4S] [M+H].sup.+: 514.1; found: 514.0, .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.67 (d, J=1.8 Hz, 1H), 8.59 (s, 1H), 8.46 (d, J=1.8 Hz, 1H), 7.51-7.44 (m, 2H), 6.51 (d, J=5.3 Hz, 1H), 5.09 (dd, J=11.3, 2.9 Hz, 1H), 4.74 (dd, J=11.3, 5.3 Hz, 1H), 4.43 (t, J=6.1 Hz, 1H), 4.22 (d, J=2.4 Hz, 1H), 4.16 (s, 1H), 3.71 (dd, J=10.5, 4.2 Hz, 1H), 3.69-3.65 (m, 1H), 3.49 (s, 3H), 2.24 (s, 3H).
Example 58
5-Cyano-6-trifluoromethylpyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0345] ##STR00139##
[0346] DIEA (44.8 μL, 262 μmol) was added to 5-cyano-6-trifluoromethylpyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (53.0 mg, 131 μmol), trimethyl-[2-(4-chloro-3,5-difluorophenyl)ethynyl]silane (48.0 mg, 196 μmol) and CuI (2.5 mg, 13.1 mmol) in MeCN (4.64 mL). After 1 h at rt the mixture was heated to 50° C. and stirred 18 h before it cooled to rt and filtered through a plug of celite and concentrated. Purification by chromatography (SiO.sub.2, PE/EtOAc) yielded the title compound as a white solid (25.9 mg, 34%). ESI-MS m/z calcd for [C.sub.22H.sub.18ClF.sub.5N.sub.5O.sub.4S][M+H].sup.+: 578.1; found: 577.9, .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 9.03 (d, J=1.6 Hz, 1H), 8.69 (d, J=1.5 Hz, 1H), 8.66 (s, 1H), 7.67 (d, J=8.1 Hz, 2H), 6.59 (d, J=5.3 Hz, 1H), 5.09 (dd, J=11.3, 2.7 Hz, 1H), 4.70 (dd, J=11.3, 5.3 Hz, 1H), 4.41-4.32 (m, 1H), 4.17 (d, J=2.2 Hz, 1H), 3.78-3.63 (m, 2H), 3.42 (s, 3H).
Example 59
5-Cyanopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0347] ##STR00140##
[0348] 5-Cyanopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (80.0 mg, 0.14 mmol) was dissolved in DCM (9.5 mL) and TFA (0.5 mL) and stirred 3 h at rt. The mixture was neutralized with Et.sub.3N and then the solvent was removed by evaporation. The residue was purified by preparative HPLC (Method A) to give the title compound (33.7 mg, 50%) as a white solid. ESI-MS m/z calcd for [C.sub.21H.sub.18F.sub.3N.sub.5O.sub.4S] [M+H].sup.+: 494.1; found: 494.1. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.95 (d, J=2.4 Hz, 1H), 8.79 (d, J=1.6 Hz, 1H), 8.59 (s, 1H), 8.49 (t, J=2.0 Hz, 1H), 7.65 (dd, J=8.8, 6.8 Hz, 2H), 6.34 (d, J=5.2 Hz, 1H), 5.05 (dd, J=11.6, 3.2 Hz, 1H), 4.65 (dd, J=11.6, 5.2 Hz, 1H), 4.43 (t, J=6.0 Hz, 1H), 4.17 (d, J=2.0 Hz, 1H), 3.69 (d, J=6.0 Hz, 2H), 3.41 (s, 3H).
Example 60
5-Cyanopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0349] ##STR00141##
[0350] To a solution of 5-cyanopyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (80.0 mg, 0.13 mmol) in DCM (6 mL) TFA (0.199 mL, 2.68 mmol) was added. The mixture was stirred under a nitrogen atmosphere at rt overnight. Then Et.sub.3N (0.5 mL) was added at 0° C. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (Method A) to obtain the title compound (21.0 mg, 31%) as a white solid. ESI-MS m/z calcd for [C.sub.21H.sub.18ClF.sub.2N.sub.5O.sub.4S][M+H].sup.+: 510.1; found: 510.2. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.96 (d, J=2.0 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H), 8.64 (s, 1H), 8.50 (t, J=2.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 2H), 6.35 (d, J=5.2 Hz, 1H), 5.06 (dd, J=11.2, 2.8 Hz, 1H), 4.65 (dd, J=11.2, 5.2 Hz, 1H), 4.43 (t, J=6.0 Hz, 1H), 4.16 (d, J=2.0 Hz, 1H), 3.68 (d, J=6.0 Hz, 2H), 3.41 (s, 3H).
Example 61
5-Bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0351] ##STR00142##
[0352] To a solution of 5-bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (60.0 mg, 0.084 mmol) in DCM (4 mL) TFA (0.205 mL, 2.76 mmol) was added. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was neutralized with Et.sub.3N at 0° C. and then the solvent was removed by evaporation. The residue was purified by preparative HPLC (Method A) to afford the title compound (32.6 mg, 62%) as a white solid. ESI-MS m/z calcd for [C.sub.24H.sub.24BrClFN.sub.5O.sub.5S] [M+H].sup.+: 628.0; found: 628.0. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.60-8.56 (m, 2H), 8.51 (d, J=2.0 Hz, 1H), 7.76 (dd, J=10.4, 2.0 Hz, 1H), 7.68 (dd, J=8.4, 1.6 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 6.34 (d, J=5.2 Hz, 1H), 5.05 (dd, J=11.2, 2.8 Hz, 1H), 4.65 (dd, J=11.2, 5.2 Hz, 1H), 4.44 (t, J=6.0 Hz, 1H), 4.28-4.10 (m, 5H), 3.73-3.61 (m, 2H), 3.40 (s, 3H), 2.46-2.32 (m, 2H).
Example 62
5-Bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0353] ##STR00143##
[0354] To a solution of 5-bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (95.0 mg, 0.13 mmol) in DCM (5 mL) TFA (0.304 mL, 4.10 mmol) was added. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was neutralized with Et.sub.3N at 0° C. and then the solvent was removed by evaporation. The residue was purified by preparative HPLC (Method A) to afford the title compound (37 mg, 44%) as a white solid. ESI-MS m/z calcd for [C.sub.24H.sub.23BrF.sub.3N.sub.5O.sub.5S] [M+H].sup.+: 630.1; found: 630.1. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.60-8.56 (m, 2H), 8.50 (d, J=2.0 Hz, 1H), 7.66 (dd, J=8.8, 2.4 Hz, 2H), 6.34 (d, J=5.2 Hz, 1H), 5.04 (dd, J=11.2, 2.8 Hz, 1H), 4.63 (dd, J=11.2, 5.2 Hz, 1H), 4.43 (t, J=6.0 Hz, 1H), 4.28-4.10 (m, 5H), 3.73-3.61 (m, 2H), 3.40 (s, 3H), 2.45-2.31 (m, 2H).
Example 63
5-Bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside
[0355] ##STR00144##
[0356] To a solution of 5-bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside (90.0 mg, 0.123 mmol) in DCM (5 mL) TFA (0.302 mL, 4.06 mmol) was added. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was neutralized with Et.sub.3N at 0° C. and then the solvent was removed by evaporation. The residue was purified by preparative HPLC (Method A) to afford the title compound (32.9 mg, 42%) as a white solid. ESI-MS m/z calcd [C.sub.25H.sub.26BrClFN.sub.5O.sub.5S] [M+H].sup.+: 642.1; found: 642.0. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.61-8.55 (m, 2H), 8.50 (d, J=2.0 Hz, 1H), 7.76 (dd, J=10.4, 1.8 Hz, 1H), 7.68 (dd, J=8.4, 1.7 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 6.31 (d, J=5.2 Hz, 1H), 5.05 (dd, J=11.2, 2.8 Hz, 1H), 4.74 (dd, J=11.2, 5.2 Hz, 1H), 4.43 (t, J=6.0 Hz, 1H), 4.30-4.07 (m, 5H), 3.89-3.75 (m, 1H), 3.75-3.62 (m, 2H), 3.49-3.37 (m, 1H), 2.51-2.29 (m, 2H), 1.03 (t, J=6.8 Hz, 3H).
Example 64
2-(N-azetidinyl-carbonyl)-5-bromophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0357] ##STR00145##
[0358] 2-(N-azetidinyl-carbonyl)-5-bromophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (120 mg, 0.17 mmol) was dissolved in a mixture of DCM/TFA (9.5 mL/0.5 mL) and stirred overnight at rt. The mixture was neutralized with Et.sub.3N and then the solvent was removed by evaporation. The residue was purified by preparative HPLC (Method A) to give the title compound (60.3 mg, 57%) as a white solid. ESI-MS m/z calcd for [C.sub.25H.sub.24BrF.sub.3N.sub.4O.sub.5S] [M+H].sup.+: 629.1; found: 629.2. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.58 (s, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.70-7.62 (m, 2H), 7.59 (dd, J=8.4, 2.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 6.21 (d, J=5.6 Hz, 1H), 5.01 (dd, J=11.2, 2.8 Hz, 1H), 4.59 (dd, J=11.2, 5.2 Hz, 1H), 4.50 (t, J=6.4 Hz, 1H), 4.27-4.14 (m, 3H), 4.03-3.95 (m, 2H), 3.74-3.65 (m, 2H), 3.40 (s, 3H), 2.43-2.29 (m, 2H).
Example 65
2-(N-azetidinyl-carbonyl)-5-bromophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-ethyl-1-thio-α-D-galactopyranoside
[0359] ##STR00146##
[0360] 2-(N-azetidinyl-carbonyl)-5-bromophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-ethyl-1-thio-α-D-galactopyranoside (120 mg, 0.16 mmol) was dissolved in a mixture of DCM/TFA (9.5 mL/0.5 mL) and stirred overnight at rt. The mixture was neutralized with Et.sub.3N and then the solvent was removed by evaporation. The residue was purified by preparative HPLC (Method A) to give the title compound (64.9 mg, 62%) as a white solid. ESI-MS m/z calcd for [C.sub.26H.sub.26BrF.sub.3N.sub.4O.sub.5S] [M+H].sup.+: 643.1; found: 643.2. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.60 (s, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.72-7.63 (m, 2H), 7.60 (dd, J=8.4, 2.0 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 6.19 (d, J=5.2 Hz, 1H), 5.03 (dd, J=11.6, 2.8 Hz, 1H), 4.70 (dd, J=11.6, 5.2 Hz, 1H), 4.51 (t, J=6.0 Hz, 1H), 4.27-4.13 (m, 3H), 4.07-3.96 (m, 2H), 3.88-3.80 (m, 1H), 3.76-3.66 (m, 2H), 3.48-3.40 (m, 1H), 2.41-2.33 (m, 2H), 1.05 (t, J=6.8 Hz, 3H).
Example 66
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0361] ##STR00147##
[0362] To a solution of 5-chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (100 mg, 0.14 mmol) in DCM (10 mL) TFA (0.5 mL, 6.73 mmol) was added and the mixture was stirred overnight at rt. The mixture was neutralized with Et.sub.3N at 0° C. and then the solvent was removed by evaporation. The residue was purified by preparative HPLC (Method A) to give the title compound (30.0 mg, 38%) as a white solid. ESI-MS m/z calcd for[C.sub.24H.sub.23ClF.sub.3N.sub.5O.sub.5S] [M+H].sup.+: 586.1; found: 586.1. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.58 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.69-7.63 (m, 2H), 6.36 (d, J=5.2 Hz, 1H), 5.05 (dd, J=11.6, 3.2 Hz, 1H), 4.64 (dd, J=11.2, 5.2 Hz, 1H), 4.43 (t, J=6.0 Hz, 1H), 4.25-4.14 (m, 5H), 3.76-3.64 (m, 2H), 3.40 (s, 3H), 2.42-2.34 (m, 2H).
Example 67
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-ethyl-1-thio-α-D-galactopyranoside
[0363] ##STR00148##
[0364] To a solution of 5-chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-ethyl-1-thio-α-D-galactopyranoside (160 mg, 0.22 mmol) in DCM (16 mL) TFA (0.82 mL, 11.0 mmol) was added and the mixture was stirred overnight at rt. The mixture was neutralized with Et.sub.3N at 0° C. and then the solvent was removed by evaporation. The residue was purified by preparative HPLC (Method A) to give the title compound (83.0 mg, 63%) as a white solid. ESI-MS m/z calcd for[C.sub.25H.sub.25ClF.sub.3N.sub.5O.sub.5S] [M+H].sup.+: 600.1; found: 600.2. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.59 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 7.70-7.62 (m, 2H), 6.32 (d, J=5.2 Hz, 1H), 5.05 (dd, J=11.2, 2.8 Hz, 1H), 4.73 (dd, J=11.6, 5.6 Hz, 1H), 4.43 (t, J=6.0 Hz, 1H), 4.24-4.13 (m, 5H), 3.84-3.77 (m, 1H), 3.72-3.64 (m, 2H), 3.47-3.34 (m, 1H), 2.42-2.34 (m, 2H), 1.04-1.01 (m, 3H).
Example 68
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside
[0365] ##STR00149##
[0366] To a solution of 5-chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside (145 mg, 0.21 mmol) in DCM (15 mL) TFA (0.76 mL, 10.2 mmol) was added and the mixture was stirred overnight at rt. The mixture was neutralized with Et.sub.3N at 0° C. and then the solvent was removed by evaporation. The residue was purified by preparative HPLC (Method A) to give the title compound (79.0 mg, 64%) as a white solid. ESI-MS m/z calcd for[C.sub.25H.sub.26Cl.sub.2FN.sub.5O.sub.5S] [M+H].sup.+: 598.1; found: 598.2. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.57 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.36 (d, J=2.0 Hz, 1H), 7.76 (dd, J=10.4, 1.6 Hz, 1H), 7.68 (dd, J=8.4, 1.6 Hz, 1H), 7.56-7.52 (m, 1H), 6.32 (d, J=5.2 Hz, 1H), 5.05 (dd, J=7.6, 3.2 Hz, 1H), 4.74 (dd, J=7.2, 1.6 Hz, 1H), 4.43 (t, J=6.0 Hz, 1H), 4.24-4.15 (m, 5H), 3.84-3.77 (m, 1H), 3.72-3.64 (m, 2H), 3.47-3.40 (m, 1H), 2.42-2.34 (m, 2H), 1.04-1.01 (m, 3H).
Example 69
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside
[0367] ##STR00150##
[0368] To a solution of 5-chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside (100 mg, 0.14 mmol) in DCM (10 mL) TFA (0.51 mL, 6.88 mmol) was added and the mixture was stirred overnight at rt. The mixture was neutralized with Et.sub.3N at 0° C. and then the solvent was removed by evaporation. The residue was purified by preparative HPLC (Method A) to give the title compound (54.0 mg, 64%) as a white solid. ESI-MS m/z calcd for[C.sub.25H.sub.25Cl.sub.2F.sub.2N.sub.5O.sub.5S] [M+H].sup.+: 616.1; found: 616.2. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.67 (s, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.38 (d, J=2.4 Hz, 1H), 7.71-7.67 (m, 2H), 6.35 (d, J=5.2 Hz, 1H), 5.08 (dd, J=11.6, 2.8 Hz, 1H), 4.76 (dd, J=11.2, 5.2 Hz, 1H), 4.45 (t, J=6.0 Hz, 1H), 4.27-4.18 (m, 5H), 3.85-3.79 (m, 1H), 3.73-3.67 (m, 2H), 3.49-3.42 (m, 1H), 2.45-2.37 (m, 2H), 1.07-1.03 (m, 3H).
Example 70
2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0369] ##STR00151##
[0370] To a solution of 2-(N-azetidinyl-carbonyl)-5-chlorophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (101 mg, 0.15 mmol) in DCM (8 mL) TFA (0.4 mL) was added and the mixture was stirred 16 h at rt. The mixture was neutralized with Et.sub.3N and then the solvent was removed by evaporation. The residue was purified by preparative HPLC (Method A) to give the title compound (20 mg, 23%) as a white solid. ESI-MS m/z calcd for[C.sub.25H.sub.24ClF.sub.3N.sub.4O.sub.5S] [M+H].sup.+: 585.1; found: 585.0. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.59 (s, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.68-7.65 (m, 2H), 7.43 (dd, J=8.0, 2.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 6.24 (d, J=5.6 Hz, 1H), 5.03 (dd, J=11.2, 2.8 Hz, 1H), 4.62 (dd, J=11.2, 5.2 Hz, 1H), 4.51 (t, J=8.0 Hz, 1H), 4.23-4.17 (m, 3H), 4.03-3.97 (m, 2H), 3.72-3.68 (m, 2H), 3.41 (s, 3H), 2.38-2.31 (m, 2H).
Example 71
3,4-Dichlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0371] ##STR00152##
[0372] 3,4-Dichlorophenyl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (80.0 mg, 0.14 mmol) was dissolved in aq 80% AcOH (5 mL) and stirred 4 h at 85° C. The solvent was removed by evaporation and the residue was purified by preparative HPLC (Method A) to give the title compound (47.4 mg, 48%) as a white solid. ESI-MS m/z calcd for [C.sub.21H.sub.18C.sub.13F.sub.2N.sub.3O.sub.4S] [M+H].sup.+: 552.1; found: 552.0. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.64 (s, 1H), 7.82 (d, J=1.2 Hz, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.54-7.48 (m, 2H), 6.18 (d, J=5.2 Hz, 1H), 5.05 (dd, J=11.2, 2.4 Hz, 1H), 4.63 (dd, J=11.2, 5.2 Hz, 1H), 4.46 (t, J=6.0 Hz, 1H), 4.18-4.17 (m, 1H), 3.74-3.65 (m, 2H), 3.39 (s, 3H).
Intermediate 1
5-Bromopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
[0373] ##STR00153##
[0374] 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (WO2016120403) (5.0 g, 9.37 mmol), MeCN (100 mL) and benzaldehyde dimethylacetal (2.88 mL, 19 mmol) were stirred at 40° C. and p-toluenesulfonic acid monohydrate (100 mg, 0.53 mmol) was added. The mixture was stirred 4 h at rt, then cooled to 0° C., the precipitate was collected by filtration, washed with cold MeCN and dried to afford the product (5.3 g, 91%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.85 (s, 1H), 8.67 (d, J=1.4 Hz, 1H), 8.62 (d, J=1.8 Hz, 1H), 8.27 (s, 1H), 7.83-7.74 (m, 2H), 7.40-7.29 (m, 5H), 6.24 (d, J=5.2 Hz, 1H), 6.16 (d, J=4.8 Hz, 1H), 5.57 (s, 1H), 5.12 (dd, J=11.3, 3.1 Hz, 1H), 4.91 (m, 1H), 4.57 (d, J=3.1 Hz, 1H), 4.29 (s, 1H), 4.12 (d, J=12.1 Hz, 1H), 3.92 (d, J=12.6 Hz, 1H).
Intermediate 3
4-Chloro-N,N-dimethyl-benzamide-2-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
[0375] ##STR00154##
5-Chloro-2-cyanophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0376] ##STR00155##
[0377] 2,4,6-Tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (9.6 g, 27.3 mmol), 4-chloro-2-sulfanylbenzonitrile (5.1 g, 30.1 mmol), Cs.sub.2CO.sub.3 (17.8 g, 54.7 mmol) and DMF (40 mL) were stirred 20 h at rt. The mixture was partitioned between ditheyl ether/EtOAc/aq HCl/water, the organic phase was separated, concentrated, and the residue was subjected to chromatography (SiO.sub.2, PE/EtOAc) to afford the product (5.63 g, 42%). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.69 (d, J=1.7 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.39 (dd, J=8.3, 1.9 Hz, 1H), 6.07 (d, J=5.5 Hz, 1H), 5.51 (d, J=2.2 Hz, 1H), 5.31 (dd, J=11.0, 5.5 Hz, 1H), 4.68-4.60 (m, 1H), 4.14 (dd, J=11.7, 5.1 Hz, 1H), 4.05 (dd, J=11.6, 7.6 Hz, 1H), 3.99 (dd, J=11.0, 3.2 Hz, 1H), 2.23 (s, 3H), 2.17 (s, 3H), 2.02 (s, 3H).
5-Chloro-2-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
[0378] ##STR00156##
[0379] 5-Chloro-2-cyanophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (454 mg, 0.94 mmol), trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (429 mg, 1.88 mmol) and K.sub.2CO.sub.3 (1.30 g, 9.41 mmol) were weighed into a glass flask and purged with nitrogen. MeOH (5.0 mL) and THF (5.0 mL) were added followed by a solution of copper(II) sulfate pentahydrate (40 mg, 0.16 mmol) and (+)-sodium L-ascorbate (70 mg, 0.35 mmol) in water (2.5 mL). The mixture was stirred 8 h at 60° C. and then copper(II) sulfate pentahydrate (40 mg, 0.16 mmol) and (+)-sodium L-ascorbate (70 mg, 0.35 mmol) were added. Stirring was continued for 4 h at 60° C. The mixture was filtered through a pad of silica eluted with EtOAc and concentrated. The residue was purified by chromatography (SiO.sub.2, PE/EtOAc) to afford a residue that was recrystallized first from EtOAc/hexanes and then from EtOH and water to give the product (248 mg, 51%). ESI-MS m/z calcd for [C.sub.21H.sub.16ClF.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 513.06; found: 513.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.55 (s, 1H), 7.98 (d, J=1.8 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.71-7.61 (m, 2H), 7.47 (dd, J=8.4, 1.9 Hz, 1H), 6.13 (d, J=5.1 Hz, 1H), 5.06 (dd, J=11.4, 2.6 Hz, 1H), 4.99 (dd, J=11.4, 5.2 Hz, 1H), 4.42 (t, J=6.1 Hz, 1H), 4.23 (d, J=2.4 Hz, 1H), 3.71 (dd, J=11.4, 5.6 Hz, 1H), 3.64 (dd, J=11.3, 6.6 Hz, 1H).
2-Carboxy-5-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
[0380] ##STR00157##
[0381] 5-Chloro-2-cyanophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (717 mg, 1.39 mmol) was stirred 5 h under nitrogen at 80° C. in a mixture of EtOH (36 mL) and NaOH (18 mL, 3 M). The mixture was concentrated to approximately 25 mL and acidified to approximately pH 1 with HCl (5 M). The precipitate was isolated by filtration and gave the product (702 mg, 95%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.55 (s, 1H), 7.96-7.88 (m, 2H), 7.70-7.59 (m, 2H), 7.29 (d, J=8.4 Hz, 1H), 6.00 (d, J=5.4 Hz, 1H), 5.09 (dd, J=11.5, 2.7 Hz, 1H), 4.99 (dd, J=11.4, 5.4 Hz, 1H), 4.42 (t, J=6.2 Hz, 1H), 4.22 (s, 1H), 3.76 (dd, J=11.3, 6.0 Hz, 1H), 3.67 (dd, J=11.2, 6.3 Hz, 1H).
4-Chloro-N,N-dimethyl-benzamide-2-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
[0382] ##STR00158##
[0383] 2-Carboxy-5-chlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (473 mg, 0.82 mmol), 1-hydroxybenzotriazole hydrate (195 mg, 1.23 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (243 mg, 1.23 mmol) were stirred in DMF (3 mL) and dimethylamine (0.82 mL, 2M solution in THF, 1.64 mmol) was added followed by DIEA (0.14 mL, 0.82 mmol). The mixture was stirred 6 h at rt, then water (20 mL) was added and decanted. The residue was stirred in EtOH (5 mL) and NaOH (1.0 mL, 2 M) 1 h at rt, then poured onto ice/water and HCl. The precipitate was collected by filtration and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (268 mg, 58%). ESI-MS m/z calcd for [C.sub.23H.sub.22ClF.sub.3N.sub.4O.sub.5S] [M+H].sup.+: 559.1; found: 558.7. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.53 (s, 1H), 7.86 (s, 1H), 7.65 (m, 2H), 7.42 (d, J=8.2 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 5.92 (d, J=5.0 Hz, 1H), 4.96 (dd, J=11.4, 2.5 Hz, 1H), 4.90 (dd, J=11.4, 5.0 Hz, 1H), 4.48 (t, J=6.1 Hz, 1H), 4.19 (s, 1H), 3.71 (m, 2H), 3.13 (s, 3H), 2.90 (s, 3H).
Intermediate 4
4-Chloro-N,N-dimethyl-benzamide-2-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
[0384] ##STR00159##
Trimethyl-[2-(4-Chloro-3,5-difluorophenyl)ethynyl]silane
[0385] ##STR00160##
[0386] Bis(triphenylphosphine)palladium(II) dichloride (1.54 g, 2.15 mmol) and CuI (836 mg, 4.39 mmol) were weighed into a glass flask and purged with nitrogen. THF (50 mL), 5-bromo-2-chloro-1,3-difluoro-benzene (10.0 g, 43.1 mmol), trimethylsilylacetylene (7.42 mL, 52.1 mmol), and DIEA (8.28 mL, 47.4 mmol) were added and the mixture was stirred 16 h at 50° C. The mixture was partitioned between HCl (0.5 M) and EtOAc. The organic phase was separated, evaporated, and the residue was purified by chromatography (SiO.sub.2, PE/EtOAc) and gave the product (10.91 g, 100% yield) as a solid. .sup.1H NMR (400 MHz, Chloroform-d) δ 7.11-7.04 (m, 2H), 0.26 (s, 9H).
5-Chloro-2-cyanophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
[0387] ##STR00161##
[0388] 5-Chloro-2-cyanophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (1.02 g, 2.1 mmol), trimethyl-[2-(4-chloro-3,5-difluorophenyl)ethynyl]silane (870 mg, 3.2 mmol) and K.sub.2CO.sub.3 (2.95 g, 21.4 mmol) were weighed into a glass flask and purged with nitrogen. MeOH (10.0 mL) and THF (5.0 mL) were added followed by a solution of copper(II) sulfate pentahydrate (53 mg, 0.21 mmol) and (+)-sodium L-ascorbate (83 mg, 0.42 mmol) in water (5.0 mL). The mixture was stirred 2 h at 60° C. and then copper(II) sulfate pentahydrate (53 mg, 0.21 mmol) and (+)-sodium L-ascorbate (83 mg, 0.42 mmol) were added. Stirring was continued for 4 h at 60° C. The mixture was partioned between water and EtOAc pH was adjusted to approximately 7 with HCl. The mixture was filtered through celite and the organic phase was evaporated. The residue was purified chromatography (SiO.sub.2, EtOAc/MeOH) to afford a residue that was recrystallized from hot EtOH and water to give the product (992 mg, 89%). ESI-MS m/z calcd for [C.sub.21H.sub.16Cl.sub.2F.sub.2N.sub.4O.sub.4S] [M+H].sup.+: 529.0; found: 529.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.61 (s, 1H), 7.98 (d, J=1.8 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.47 (dd, J=8.3, 1.9 Hz, 1H), 6.13 (d, J=5.2 Hz, 1H), 5.07 (dd, J=11.4, 2.6 Hz, 1H), 5.00 (dd, J=11.4, 5.2 Hz, 1H), 4.42 (t, J=6.1 Hz, 1H), 4.27-4.20 (m, 1H), 3.71 (dd, J=11.4, 5.6 Hz, 1H), 3.65 (dd, J=11.4, 6.6 Hz, 1H).
2-Carboxy-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
[0389] ##STR00162##
[0390] A solution of 5-chloro-2-cyanophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (3.53 g, 6.67 mmol) in EtOH (180 mL) and NaOH (90 mL, 3 M) was stirred 5 h at 80° C. under nitrogen. The mixture was cooled, concentrated to approximately 90 mL and acidified to approximately pH 1 with HCl (5 M). The precipitate was isolated by filtration, washed with 33% aq MeOH and dried to give the product (3.19 g, 87%). ESI-MS m/z calcd for [C.sub.21H.sub.17Cl.sub.2F.sub.2N.sub.3O.sub.6S][M+H].sup.+: 548.0; found: 548.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.60 (s, 1H), 7.96-7.86 (m, 2H), 7.66 (d, J=8.0 Hz, 2H), 7.29 (dd, J=8.4, 1.9 Hz, 1H), 6.00 (d, J=5.4 Hz, 1H), 5.10 (dd, J=11.5, 2.7 Hz, 1H), 4.99 (dd, J=11.5, 5.4 Hz, 1H), 4.42 (t, J=6.2 Hz, 1H), 4.26-4.18 (m, 1H), 3.76 (dd, J=11.3, 6.1 Hz, 1H), 3.67 (dd, J=11.3, 6.3 Hz, 1H).
4-Chloro-N,N-dimethyl-benzamide-2-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
[0391] ##STR00163##
[0392] 2-Carboxy-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (450 mg, 0.82 mmol), 1-hydroxybenzotriazole hydrate (195 mg, 1.23 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (243 mg, 1.23 mmol) were stirred in DMF (3 mL) and dimethylamine (0.82 mL, 2M solution in THF, 1.64 mmol) was added followed by DIEA (0.14 mL, 0.82 mmol). The mixture was stirred 18 h at rt, then water (8 mL) was added and decanted. The residue was stirred in EtOH (3 mL) and NaOH (0.5 mL, 2 M) 1 h at rt, then neutralized with HCl (0.5 mL, 2 M) and poured onto water. The precipitate was collected by filtration and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (328 mg, 70%). ESI-MS m/z calcd for [C.sub.23H.sub.22Cl.sub.2F.sub.2N.sub.4O.sub.5S] [M+H].sup.+: 575.1; found: 575.1. 1H NMR (400 MHz, Methanol-d.sub.4) δ 8.59 (s, 1H), 7.86 (s, 1H), 7.69-7.60 (m, 2H), 7.42 (d, J=8.2 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 5.92 (d, J=5.0 Hz, 1H), 4.97 (dd, J=11.5, 2.6 Hz, 1H), 4.91 (dd, J=11.4, 5.1 Hz, 1H), 4.48 (t, J=6.1 Hz, 1H), 4.20 (s, 1H), 3.77-3.66 (m, 2H), 3.13 (s, 3H), 2.90 (s, 3H).
Intermediate 6
2-(N-piperidinyl-carbonyl)-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
[0393] ##STR00164##
[0394] 2-Carboxy-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (150 mg, 0.27 mmol), 1-hydroxybenzotriazole hydrate (62 mg, 0.39 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (77 mg, 0.39 mmol) were stirred in DMF (1 mL) and piperidine (39 μL, 0.39 mmol) was added followed by Et.sub.3N (73 μL, 0.52 mmol). The mixture was stirred 3 h at rt, then water and HCl (1 M) were added. The precipitate was filtered off and recrystallized from EtOH/water. Further purification by chromatography (SiO.sub.2, PE/EtOAc) afforded the product (106 mg, 66%). ESI-MS m/z calcd for [C.sub.26H.sub.26Cl.sub.2F.sub.2N.sub.4O.sub.5S] [M+H].sup.+: 615.1; found: 615.2. .sup.1H NMR (400 MHz, Methanol-d.sub.4) (two conformational isomers) δ 8.59 (s, 1H), 7.92-7.81 (m, 1H), 7.66 (m, 2H), 7.48-7.35 (m, 1H), 7.30-7.20 (m, 1H), 5.96-5.88 (m, 1H), 5.01-4.86 (m, 2H), 4.54-4.44 (m, 1H), 4.19 (bs, 1H), 3.88-3.61 (m, 4H), 3.29-3.16 (m, 2H), 1.82-1.58 (m, 5H), 1.58-1.41 (m, 1H).
Intermediate 10
2-Bromo-5-chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0395] ##STR00165##
Intermediate 10
2,4,6-Tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride
[0396] ##STR00166##
[0397] 1,2,4,6-Tetra-O-acetyl-3-azido-3-deoxy-s-D-galactopyranoside (12.0 g, 32.1 mmol), PCl.sub.5 (7.5 g, 36.0 mmol) and boron trifluoride diethyl etherate (50 μL, 0.41 mmol) were stirred in DCM (150 mL) for 1 h, then partitioned between saturated aq NaHCO.sub.3 and DCM. The organic phase was dried, concentrated, and the residue was triturated in diethyl ether/PE to afford the product as a crystalline solid (10.2 g, 91%). 1H NMR (400 MHz, Chloroform-d) δ 5.48 (d, J=3.2 Hz, 1H), 5.34 (t, J=9.2 Hz, 1H), 5.24 (d, J=8.7 Hz, 1H), 4.18 (dd, J=11.5, 6.1 Hz, 1H), 4.10 (dd, J=11.6, 6.7 Hz, 1H), 3.98 (t, J=6.4 Hz, 1H), 3.60 (dd, J=10.3, 3.3 Hz, 1H), 2.20 (s, 3H), 2.17 (s, 3H), 2.07 (s, 3H).
Acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0398] ##STR00167##
[0399] 2,4,6-Tri-O-acetyl-3-azido-3-deoxy-s-D-galactopyranosyl chloride (4.0 g, 11.4 mmol) and potassium thioacetate (2.02 g, 17.1 mmol) were stirred in DMF (25 mL) 1 h at 40° C. The dark mixture was partitioned between EtOAc and saturated aq NaHCO.sub.3, the organic phase was separated, dried and evaporated. The residue was purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (2.90 g, 52%). ESI-MS m/z calcd for [C.sub.14H.sub.19N.sub.3O.sub.8S] [M+Na].sup.+: 412.1; found: 411.9. .sup.1H NMR (400 MHz, Chloroform-d) δ 6.25 (d, J=5.3 Hz, 1H), 5.43 (d, J=2.9 Hz, 1H), 5.40 (dd, J=11.0, 5.3 Hz, 1H), 4.16-3.97 (m, 3H), 3.71 (dd, J=10.9, 3.3 Hz, 1H), 2.43 (s, 3H), 2.16 (s, 3H), 2.08 (s, 3H), 2.04 (s, 3H).
2-Bromo-5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0400] ##STR00168##
[0401] To a solution of acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (WO2016120403) (2.46 g, 5.05 mmol) and 2-bromo-5-chloro-3-fluoropyridine (1.74 g, 8.0 mmol) in DMF (10 mL) diethylamine (1.60 mL, 15.5 mmol) was added. The mixture was stirred 1 h at rt, water and HCl (5.0 mL, 5 M, 25 mmol) was added, the solvents were decanted, the sticky residue was partitioned between DCM and water. The organic phase was evaporated, and the residue was purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (1.36 g, 50%). ESI-MS m/z calcd for [C.sub.17H.sub.18BrClN.sub.4O.sub.7S] [M+H].sup.+: 537.0; found: 537.0. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J=2.4 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 6.13 (d, J=5.6 Hz, 1H), 5.50 (d, J=2.9 Hz, 1H), 5.35 (dd, J=11.0, 5.5 Hz, 1H), 4.54 (dd, J=7.7, 4.8 Hz, 1H), 4.17-3.99 (m, 3H), 2.21 (s, 3H), 2.18 (s, 3H), 1.97 (s, 3H).
2-Bromo-5-chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
[0402] ##STR00169##
[0403] A solution of copper(II) sulfate pentahydrate (63 mg, 0.25 mmol) and (+)-sodium L-ascorbate (100 mg, 0.50 mmol) in water (5 mL) was added to a solution of 2-bromo-5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (1.35 g, 2.51 mmol), trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (860 mg, 3.77 mmol) and K.sub.2CO.sub.3 (3.47 g, 25.1 mmol) in MeOH/THF (80 mL). The mixture was stirred 24 h at 50° C., concentrated and partitioned between EtOAc and water. The organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (1.03 g, 72% yield). ESI-MS m/z calcd for [C.sub.19H.sub.15BrClF.sub.3N.sub.4O.sub.4S][M+H].sup.+: 567.0; found: 567.0. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.56 (s, 1H), 8.18 (d, J=2.5 Hz, 2H), 7.68-7.58 (m, 2H), 6.15 (d, J=5.1 Hz, 1H), 5.08 (dd, J=11.4, 2.5 Hz, 1H), 5.02 (dd, J=11.4, 5.1 Hz, 1H), 4.36 (t, J=6.1 Hz, 1H), 4.23 (d, J=2.1 Hz, 1H), 3.75-3.64 (m, 2H).
2-Bromo-5-chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
[0404] ##STR00170##
[0405] 2-Bromo-5-chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (2.04 g, 3.59 mmol) was stirred in MeCN (25 mL) and benzaldehyde dimethylacetal (0.76 mL, 5.04 mmol) followed by p-toluenesulfonic acid monohydrate (5 mg, 0.023 mmol) were added. The mixture was stirred 18 h at rt and Et.sub.3N (15 μL, 0.26 mmol) followed by water (15 mL) were added. The solids were filtered off and washed first with 33% aq MeOH then PE. The solids were dried to afford the product (1.99 g, 85%). ESI-MS m/z calcd for [C.sub.26H.sub.19BrClF.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 655.0; found: 654.7. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.86 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 8.20 (d, J=2.4 Hz, 1H), 7.79 (m, 2H), 7.42-7.30 (m, 5H), 6.48 (d, J=5.3 Hz, 1H), 6.29 (d, J=4.9 Hz, 1H), 5.58 (s, 1H), 5.18 (dd, J=11.3, 3.2 Hz, 1H), 4.98 (m, 1H), 4.59 (d, J=3.0 Hz, 1H), 4.18 (s, 1H), 4.11 (d, J=11.7 Hz, 1H), 3.96 (d, J=12.6 Hz, 1H).
2-Bromo-5-chloropyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0406] ##STR00171##
[0407] Iodomethane (133 μL, 2.13 mmol) was added to a solution of 2-bromo-5-chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (700 mg, 1.07 mmol) and Ag.sub.2O (495 mg, 2.13 mmol) in DMF (8 mL). After stirring 48 h at rt the mixture was diluted with EtOAc, washed twice with water and the organic phase was dried and evaporated. The residue was dissolved in TFA/water (8 mL, 4:1), stirred 3 h at rt before partitioned between EtOAc and aq NaOH (1 M). The organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (314 mg, 50%). ESI-MS m/z calcd for [C.sub.20H.sub.17BrClF.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 581.0; found: 581.0. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.60 (s, 1H), 8.24-8.21 (m, 2H), 7.66 (dd, J=8.7, 6.7 Hz, 2H), 6.48 (d, J=5.3 Hz, 1H), 5.08 (dd, J=11.4, 2.9 Hz, 1H), 4.72 (dd, J=11.3, 2.9 Hz, 1H), 4.35 (t, J=6.1 Hz, 1H), 4.20 (d, J=2.6 Hz, 1H), 3.74-3.64 (m, 2H), 3.43 (s, 3H).
Intermediate 11
5-Chloro-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0408] ##STR00172##
2-Bromo-5-chloropyridin-3-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0409] ##STR00173##
[0410] To a solution of 2-bromo-5-chloro-3-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (770 mg, 1.43 mmol) in MeOH (5.0 mL) catalytical amount of sodium methanolate (pH=9-10) was added. The reaction was stirred 20 min and neutralized with acidic ion resin and filtered. The filtrate was concentrated to give the crude product (350 mg, 78%). ESI-MS m/z calcd for [C.sub.11H.sub.12BrClN.sub.4O.sub.4S] [M+H].sup.+: 411.0; found: 411.0.
2-Bromo-5-chloropyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside
[0411] ##STR00174##
[0412] To a stirred solution of 2-bromo-5-chloropyridin-3-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside (350 mg, 0.66 mmol) in DMF (5 mL) benzaldehyde dimethylacetal (404 mg, 2.65 mmol) was added followed by D(+)-10-camphorsulfonic acid (30.8 mg, 0.13 mmol). The mixture was stirred 4 h at 50° C. under vacuum using a water-pump.
[0413] After cooling to rt, the reaction was poured into water (15 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were concentrated in vacuum and the residue was purified by column chromatography (PE/EtOAc=10/1˜5/1, Silica-CS 12 g, 20 m/min, silica gel, UV 254) to give the product (300 mg, 91%) as a white solid. ESI-MS m/z calcd for [C.sub.18H.sub.16BrClN.sub.4O.sub.4S] [M+H].sup.+: 499.0, found: 499.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.09 (d, J=2.3 Hz, 1H), 7.82 (d, J=2.3 Hz, 1H), 7.45 (dd, J=7.5, 1.9 Hz, 2H), 7.38-7.27 (m, 3H), 5.91 (d, J=5.3 Hz, 1H), 5.58 (s, 1H), 4.64 (dt, J=10.8, 5.4 Hz, 1H), 4.36 (d, J=3.0 Hz, 1H), 4.18 (dd, J=12.8, 1.4 Hz, 1H), 4.07-3.97 (m, 2H), 3.65 (dd, J=10.8, 3.3 Hz, 1H), 2.59 (d, J=5.7 Hz, 1H).
2-Bromo-5-chloropyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0414] ##STR00175##
[0415] 2-Bromo-5-chloro-3-pyridine-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (300 mg, 0.60 mmol) was dissolved in DMF (8.0 mL) and Ag.sub.2O (696 mg, 3.00 mmol) was added followed by iodomethane (426 mg, 3.00 mmol). The reaction was stirred 48 h at rt and filtered. The filtrares was evaporated in vacuum and the residue was purified by column chromatography (PE/EtOAc=10/1˜5/1, Silica-CS 12 g, 20 m/min, silica gel, UV 254) to give the product (240 mg, 78%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (d, J=2.4 Hz, 1H), 7.81 (t, J=3.6 Hz, 1H), 7.46 (dd, J=7.5, 1.9 Hz, 2H), 7.31 (ddd, J=6.7, 5.1, 1.5 Hz, 3H), 6.09 (d, J=5.2 Hz, 1H), 5.56 (s, 1H), 4.28-4.21 (m, 2H), 4.13 (dd, J=12.7, 1.5 Hz, 1H), 4.07-4.04 (m, 1H), 3.96 (s, 1H), 3.76 (dd, J=10.6, 3.3 Hz, 1H), 3.50 (s, 3H).
5-Chloro-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0416] ##STR00176##
[0417] To a solution of 2-bromo-5-chloropyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (400 mg, 0.78 mmol) and 2-oxa-6-azaspiro[3.3]heptane; oxalic acid (736 mg, 3.89 mmol) in DMF (5 mL) DIEA (1.33 mL, 7.79 mmol) was added. The mixture was stirred 4 h at 130° C. in a microwave reactor. The solvent was removed, and the residue was purified by column chromatography (PE/EtOAc=5/1˜2/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to give the product (190 mg, 46%) as a white solid. ESI-MS m/z calcd for [C.sub.24H.sub.26ClN.sub.5O.sub.5S][M+H].sup.+: 532.1; found: 532.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.01 (d, J=2.4 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.54-7.45 (m, 2H), 7.40-7.32 (m, 3H), 5.84 (d, J=5.2 Hz, 1H), 5.60 (s, 1H), 4.90-4.76 (m, 4H), 4.40 (d, J=9.2 Hz, 2H), 4.32 (d, J=3.2 Hz, 1H), 4.27 (d, J=9.2 Hz, 2H), 4.23-4.06 (m, 4H), 3.72 (dd, J=10.4, 3.2 Hz, 1H), 3.54 (s, 3H).
5-Chloro-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0418] ##STR00177##
[0419] To a solution of 5-chloro-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (130 mg, 0.244 mmol) and trimethyl-[2-(4-chloro-3,5-difluorophenyl)ethynyl]silane (60.0%, 120 mg, 0.29 mmol) in DMF (4 mL) (+)-sodium L-ascorbate (72.6 mg, 0.37 mmol) and copper(II) sulfate pentahydrate (30.5 mg, 0.12 mmol) were added. The mixture was stirred 4 h at rt under a nitrogen atmosphere. After diluting with water (20 mL), the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by preparative HPLC (Method A) to give the product (115 mg, 67%) as a white solid. ESI-MS m/z calcd for [C.sub.32H.sub.29Cl.sub.2F.sub.2N.sub.5O.sub.5S] [M+H].sup.+: 704.1; found: 704.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.05 (d, J=2.4 Hz, 1H), 7.98 (s, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.47-7.42 (m, 2H), 7.39 (s, 5H), 5.95 (d, J=5.2 Hz, 1H), 5.52 (s, 1H), 5.33 (dd, J=11.2, 2.8 Hz, 1H), 4.87-4.79 (m, 4H), 4.50 (d, J=2.8 Hz, 1H), 4.46 (dd, J=11.2, 5.2 Hz, 1H), 4.40 (d, J=9.2 Hz, 2H), 4.30 (d, J=9.2 Hz, 2H), 4.25 (s, 2H), 4.13 (dd, J=12.8, 2.0 Hz, 1H), 3.29 (s, 3H).
Intermediate 12
5-Chloro-2-cyanopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0420] ##STR00178##
5-Chloro-2-cyanopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0421] ##STR00179##
[0422] To a solution of 2-bromo-5-chloro-3-pyridine-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (230 mg, 0.45 mmol) in DMF (4.0 mL), Zn (14.6 mg, 0.22 mmol), Zn(CN).sub.2 (52.6 mg, 0.45 mmol), 1,1′-bis(diphenylphosphino)ferrocene (20.2 mg, 0.036 mmol) and Pd.sub.2(dibenzylideneacetone).sub.3 (32.8 mg, 0.036 mmol) were added. The mixture was stirred 3 h at 100° C. under a nitrogen atmosphere. The solvent was removed under reduced pressure and the residue was purified by column chromatography (PE/EtOAc=10/1˜5/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (105 mg, 51%). ESI-MS m/z calcd for [C.sub.20H.sub.18ClN.sub.5O.sub.4S] [M+H].sup.+: 460.0, found: 460.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.52 (d, J=2.0 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.53-7.51 (m, 2H), 7.41-7.37 (m, 3H), 6.15 (d, J=5.2 Hz, 1H), 5.64 (s, 1H), 4.37 (d, J=2.8 Hz, 1H), 4.30 (dd, J=10.8, 5.2 Hz, 1H), 4.18 (d, J=1.6 Hz, 1H), 4.15-4.12 (m, 2H), 3.79 (dd, J=10.8, 3.2 Hz, 1H), 3.61 (s, 3H).
5-Chloro-2-cyanopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0423] ##STR00180##
[0424] To a solution of 2-bromo-5-chloro-3-pyridine-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (100 mg, 0.22 mmol) and trimethyl-[2-(3,5-difluoro-4-methylphenyl)ethynyl]silane (70.0%, 58.5 mg, 0.18 mmol) in DMF (4 mL) (+)-sodium L-ascorbate (64.6 mg, 0.33 mmol) and copper(II) sulfate pentahydrate (27.1 mg, 0.11 mmol) were added. The mixture was stirred 4 h at rt under a nitrogen atmosphere. After diluting with water (20 mL), the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by preparative HPLC (Method A) to give the product (80.0 mg, 60%) as a white solid. ESI-MS m/z calcd for [C.sub.29H.sub.24ClF.sub.2N.sub.5O.sub.4S] [M+H].sup.+: 612.1; found: 612.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.56 (d, J=2.0 Hz, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.97 (s, 1H), 7.44-7.36 (m, 5H), 7.31 (m, 2H), 6.24 (d, J=4.8 Hz, 1H), 5.54 (s, 1H), 5.31 (dd, J=11.2, 2.8 Hz, 1H), 4.58 (dd, J=11.2, 5.2 Hz, 1H), 4.54 (d, J=2.8 Hz, 1H), 4.39 (s, 1H), 4.28 (dd, J=12.8, 1.2 Hz, 1H), 4.16 (dd, J=12.8, 1.2 Hz, 1H), 3.37 (s, 3H), 2.22 (s, 3H).
Intermediate 13
5-Chloro-2-cyanopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0425] ##STR00181##
[0426] To a solution of 5-chloro-2-cyanopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (110 mg, 0.24 mmol) and trimethyl-[2-(3-fluoro-4-methylphenyl)ethynyl]silane (98.7 mg, 0.48 mmol) in DMF (5 mL) (+)-sodium L-ascorbate (94.8 mg, 0.48 mmol) and copper(II) sulfate pentahydrate (29.9 mg, 0.12 mmol) were added. The mixture was stirred overnight at rt under nitrogen atmosphere. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (Method A) to give the product (35 mg, 25%). ESI-MS m/z calcd for [C.sub.29H.sub.25ClFN.sub.5O.sub.4S] [M+H].sup.+: 594.1; found: 594.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.50 (d, J=1.2 Hz, 1H), 8.02 (s, 1H), 7.92 (s, 1H), 7.38-7.34 (m, 7H), 7.17-7.14 (m, 1H), 6.18 (d, J=4.8 Hz, 1H), 5.49 (s, 1H), 5.25 (d, J=10.8 Hz, 1H), 4.53 (m, 2H), 4.33 (s, 1H), 4.21 (d, J=12.4 Hz, 1H), 4.11 (d, J=12.4 Hz, 1H), 3.31 (s, 3H), 2.24 (d, J=1.2 Hz, 3H).
Intermediate 14
5-Chloro-2-cyanophenyl 4,6-di-O-acetyl-3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0427] ##STR00182##
3-Azido-4,6-O-benzylidene-3-deoxy-D-galactopyranose
[0428] ##STR00183##
[0429] To a solution of 3-azido-3-deoxy-D-galactopyranose (Lowary, T. L.; Hindsgaul, O. Recognition of Synthetic O-Methyl, Epimeric, and Amino Analogues of the Acceptor A-L-Fucp-(1.fwdarw.2)-B-D-Galp- or Glycosyltransferases. Carbohydrate Research 1994, 251, 33-67.) (16.4 g, 79.9 mmol) in DMF (120 mL) benzaldehyde dimethylacetal (18.2 g, 120 mmol) was added followed by D(+)-10-Camphorsulfonic acid (3.71 g, 16.0 mmol). The mixture was stirred 4 h at 50° C. The mixture was added dropwise to saturated aq NaHCO.sub.3 (200 mL). The mixture was filtered and the white solid was washed with water and dried in vacuum to afford the product (15.0 g, 64%, α/β=1:1).
3-Azido-4,6-O-benzylidene-3-deoxy-α-D-galactopyranose
[0430] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.51-7.53 (m, 2H), 7.35-7.39 (m, 3H), 5.65 (s, 1H), 5.25 (d, J=3.2 Hz, 1H, H-1α), 3.35-3.45 (m, 6H).
3-Azido-4,6-O-benzylidene-3-deoxy-beta-D-galactopyranose
[0431] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.51-7.53 (m, 2H), 7.35-7.39 (m, 3H), 5.65 (s, 1H), 4.58 (d, J=7.6 Hz, 1H, H-1β), 3.35-3.45 (m, 6H).
Methyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-D-galactopyranoside
[0432] ##STR00184##
[0433] To a solution of 3-azido-4,6-O-benzylidene-3-deoxy-D-galactopyranose (5.00 g, 17.0 mmol) in DMF (40 mL) NaH (60% in oil, 1.96 g, 51.1 mmol) was added at 0° C. under a nitrogen atmosphere and the mixture was stirred 20 min. Iodomethane (3.18 mL, 51.1 mmol) was added and the mixture was stirred 1 h at rt. After diluting with water (50 mL), the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to give the product (5.10 g, 93%, α/β=0.5:1).
Methyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-α-D-galactopyranoside
[0434] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.42-7.44 (m, 2H), 7.27-7.29 (m, 3H), 5.56 (s, 1H), 4.99 (d, J=3.2 Hz, 1H, H-1α), 3.62-4.27 (m, 4H), 3.44 (s, 3H), 3.39 (s, 3H), 3.32-3.40 (m, 1H), 3.23-3.25 (m, 1H).
Methyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-D-D-galactopyranoside
[0435] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.42-7.44 (m, 2H), 7.27-7.29 (m, 3H), 5.55 (s, 1H), 4.31 (d, J=7.6 Hz, 1H, H-1β), 3.62-4.27 (m, 4H), 3.51 (s, 3H), 3.49 (s, 3H), 3.32-3.40 (m, 1H), 3.23-3.25 (m, 1H).
Acetyl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-D-galactopyranoside
[0436] ##STR00185##
[0437] To a solution of methyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-D-galactopyranoside (5.10 g, 15.9 mmol) in acetic anhydride (40.0 mL) and acetic acid (20 mL), drops of concentrated H.sub.2SO.sub.4 was added at 0° C. The mixture was stirred 4 h at 0° C., followed by dropwise addition to a saturated aq NaHCO.sub.3 solution. The mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 4 g, 12 mL/min, silica gel, UV 254). The obtained material was suspended in EtOAc (4.00 mL). The mixture was heated to 60° C., then cooled to 25° C. and n-heptane (20.0 mL) was added while stirring. The mixture was cooled to 0° C. and stirred for 1 h, filtered, washed with n-heptane/EtOAc (4:1, 10 mL), to give the product (1.2 g) as a white solid used as is in the next step. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.38 (d, J=3.6 Hz, 1H), 5.33 (dd, J=3.2, 1.2 Hz, 1H), 4.14-4.17 (m, 1H), 3.91-4.03 (m, 2H), 3.80 (dd, J=6.4, 3.2 Hz, 1H), 3.62 (dd, J=10.4, 3.6 Hz, 1H), 3.43 (s, 3H), 2.11 (s, 3H), 2.10 (s, 3H), 1.98 (s, 3H).
Acetyl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-D-galactopyranoside
[0438] ##STR00186##
[0439] To a solution of acetyl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-D-galactopyranoside (1.17 g, 3.39 mmol) in DCM (15 mL) PCl.sub.5 (1.06 g, 5.08 mmol) was added followed by boron trifluoride diethyl etherate (0.209 mL, 1.69 mmol) at 30° C. under a nitrogen atmosphere. The mixture was stirred 30 min at 30° C. followed by dropwise addition to a saturated aq NaHCO.sub.3 solution. The mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuum. The residue was dissolved in DMF (4.0 mL) and potassium thioacetate (731 mg, 6.4 mmol) was added. The mixture was stirred overnight at rt under a nitrogen atmosphere. After diluting with water (50 mL), the mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuum. The residue was purified by column chromatography (PE/EtOAc=10/1˜3/1, Silica-CS 20 g, 18 mL/min, silica gel, UV 254) to give the product (1.15 g, 75%, α/β=0.23:1).
Acetyl 4,6-di-O-acetyl-3-azido-2-O-methyl-3-deoxy-1-thio-α-D-galactopyranoside
[0440] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.25 (d, J=5.2 Hz, 1H, H-1α), 5.27-5.29 (m, 1H), 3.85-4.08 (m, 4H), 3.42-3.45 (m, 1H), 3.39 (s, 3H), 2.39 (s, 3H), 2.09 (s, 3H), 1.97 (s, 3H).
Acetyl 4,6-di-O-acetyl-3-azido-2-O-methyl-3-deoxy-1-thio-β-D-galactopyranoside
[0441] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.32-5.33 (m, 1H), 5.04 (d, J=10.0 Hz, 1H, H-1β), 3.85-4.08 (m, 3H), 3.57 (dd, J=9.2, 3.2 Hz, 1H), 3.52 (s, 3H), 3.33 (t, J=9.6 Hz, 1H), 2.36 (s, 3H), 2.08 (s, 3H), 1.97 (s, 3H).
5-Chloro-2-cyanophenyl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-D-galactopyranoside
[0442] ##STR00187##
[0443] To a solution of acetyl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-D-galactopyranoside (300 mg, 0.83 mmol) and 4-chloro-2-fluoro-benzonitrile (250 mg, 1.61 mmol) in DMF (5.0 mL) diethylamine (121 mg, 1.66 mmol) was added. The mixture was stirred overnight at rt under nitrogen atmosphere. After diluting with water (20 mL), the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc=10/1˜3/1, Silica-CS 4 g, 12 mL/min, silica gel, UV 254) to give the product (180 mg, 62%, α/β=0.44/1). ESI-MS m/z calcd for [C.sub.18H.sub.19ClN.sub.4O.sub.6S] [M+H].sup.+: 455.1; found: 455.0.
5-Chloro-2-cyanophenyl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0444] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.64 (d, J=2.0 Hz, 1H), 7.57-7.53 (m, 1H), 7.33-7.27 (m, 1H), 6.04 (d, J=5.2 Hz, 1H, H-1α), 5.34 (d, J=3.2 Hz, 1H), 4.47-4.46 (m, 1H), 4.08-3.78 (m, 3H), 3.54 (s, 3H), 3.44-3.34 (m, 1H), 2.09 (s, 3H), 1.98 (s, 3H).
5-Chloro-2-cyanophenyl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0445] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.69 (d, J=2.0 Hz, 1H), 7.57-7.53 (m, 1H), 7.33-7.27 (m, 1H), 5.33 (d, J=3.2 Hz, 1H), 4.66 (d, J=9.2 Hz, 1H, H-1β), 4.08-3.78 (m, 3H), 3.61 (s, 3H), 3.57-3.55 (m, 1H), 3.43-3.33 (m, 1H), 2.12 (s, 3H), 2.01 (s, 3H).
5-Chloro-2-cyanophenyl 4,6-di-O-acetyl-3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0446] ##STR00188##
[0447] To a solution of 5-chloro-2-cyanophenyl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-D-galactopyranoside (260 mg, 0.57 mmol) and trimethyl-[2-(3,5-difluoro-4-methylphenyl)ethynyl]silane (247 mg, 1.10 mmol) in DMF (6 mL) copper(II) sulfate pentahydrate (71.4 mg, 0.29 mmol) and (+)-sodium L-ascorbate (113 mg, 0.57 mmol) were added. The mixture was stirred 3 h at rt under nitrogen atmosphere. After diluting with water (20 mL), the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 4 g, 12 mL/min, silica gel, UV 254) to give an anomeric mixture of the product. The mixture was purified by preparative —SFC to give the product (56.0 mg, 16%) as a white solid. ESI-MS m/z calcd for [C.sub.27H.sub.25ClF.sub.2N.sub.4O.sub.6S][M+H].sup.+: 607.1; found: 607.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.74 (s, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.36 (dd, J=8.4, 2.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 6.25 (d, J=5.2 Hz, 1H), 5.53 (d, J=2.0 Hz, 1H), 4.90-4.78 (m, 2H), 4.68 (d, J=6.4 Hz, 1H), 4.02-3.99 (m, 2H), 3.39 (s, 3H), 2.15 (s, 3H), 2.00 (s, 3H), 1.90 (s, 3H).
Intermediate 16
2-Bromo-5-chloropyridin-3-yl 3-deoxy-2-O-ethyl-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
[0448] ##STR00189##
[0449] 2-Bromo-5-chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (202 mg, 0.31 mmol) and NaH (60% in oil, 24 mg, 0.62 mmol) were dissolved in DMF (3 mL) and stirred 10 min before the addition of iodoethane (37 μL, 0.46 mmol). After stirring 3 h at rt the mixture was diluted with EtOAc, washed twice with water and the organic phase was dried and evaporated. Another batch was made in parallel. 2-Bromo-5-chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (202 mg, 0.31 mmol) and Ag.sub.2O (143 mg, 0.62 mmol) were dissolved in DMF (3 mL) and stirred 5 min before the addition of iodoethane (49 μL, 0.62 mmol). After stirring 20 h at 50° C. the mixture was diluted with EtOAc, washed twice with water and the organic phase was dried and evaporated. The crude from the two batches were pooled and dissolved in TFA/water (4 mL, 4:1). The mixture was stirred 3 h at rt before being partitioned between EtOAc and aq NaOH (1 M). The organic phase was dried, evaporated and purified by preparative HPLC (Method B) to afford the product (10 mg, 3%) as a white powder. ESI-MS m/z calcd for [C.sub.21H.sub.19BrClF.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 595.0; found: 594.7. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.60 (s, 1H), 8.22 (s, 2H), 7.69-7.63 (m, 2H), 6.44 (d, J=5.4 Hz, 1H), 5.09 (dd, J=11.3, 2.8 Hz, 1H), 4.80 (dd, J=11.3, 5.4 Hz, 1H), 4.34 (t, J=6.0 Hz, 1H), 4.20 (d, J=2.6 Hz, 1H), 3.85-3.78 (m, 1H), 3.73-3.63 (m, 2H), 3.51-3.42 (m, 1H), 1.03 (t, J=7.0 Hz, 3H).
Intermediate 21
3,4-Dichlorophenyl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-carboxymethyl-1-thio-α-D-galactopyranoside
[0450] ##STR00190##
3,4-Dichlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
[0451] ##STR00191##
[0452] Copper(II) sulfate pentahydrate (127 mg, 0.5 mmol) was dissolved in hot water (5.0 mL) and added to (+)-sodium L-ascorbate (198 mg, 1.0 mmol). The resulting brownish dispersion was added to a mixture of 3,4-dichlorophenyl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside (2.33 g, 4.7 mmol), K.sub.2CO.sub.3 (6.5 g, 47 mmol), and trimethyl-[2-(4-chloro-3,5-difluorophenyl)ethynyl]silane (1.40 g, 5.68 mmol) in MeOH (20 mL) and THF (20 mL). The resulting mixture was stirred 20 h at 50° C., celite was added, the mixture was filtered, and the filter cake was washed with EtOAc/MeOH. The filtrate was partitioned between EtOAc and aqueous HCl (0.5 M), the organic phase was concentrated. The residue was purified by chromatography (SiO.sub.2, PE/EtOAc) and the crude was triturated in MeCN (30 mL) to give the product (1.73 g, 68%). ESI-MS m/z calcd for [C.sub.20H.sub.16C.sub.13F.sub.2N.sub.3O.sub.4S] [M+H].sup.+: 538.0; found: 538.0. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.60 (s, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 2H), 7.54 (dd, J=8.4, 2.0 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 5.85 (d, J=5.2 Hz, 1H), 4.99 (dd, J=11.4, 2.7 Hz, 1H), 4.96-4.90 (m, 1H), 4.49 (t, J=6.0 Hz, 1H), 4.20 (d, J=1.9 Hz, 1H), 3.77-3.66 (m, 2H).
3,4-Dichlorophenyl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
[0453] ##STR00192##
[0454] To a solution of 3,4-dichlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (1.73 g, 3.2 mmol) in MeCN (40 mL) benzaldehyde dimethylacetal (0.974 mL, 6.46 mmol) followed by p-toluenesulfonic acid monohydrate (50 mg, 0.26 mmol) were added. The suspension was stirred 72 h at rt, then cooled to 0° C. and filtered to give the product (1.876 g, 93%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.92 (s, 1H), 7.86-7.75 (m, 3H), 7.63 (d, J=8.5 Hz, 1H), 7.52 (dd, J=8.5, 2.0 Hz, 1H), 7.35 (dt, J=11.3, 3.9 Hz, 5H), 6.18 (d, J=5.2 Hz, 1H), 6.13 (d, J=4.7 Hz, 1H), 5.57 (s, 1H), 5.10 (dd, J=11.3, 3.2 Hz, 1H), 4.91 (dt, J=10.9, 5.0 Hz, 1H), 4.56 (d, J=3.0 Hz, 1H), 4.29 (s, 1H), 4.13 (d, J=12.1 Hz, 1H), 3.96 (d, J=12.4 Hz, 1H).
3,4-Dichlorophenyl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-(methoxycarbonyl)methyl-1-thio-α-D-galactopyranoside
[0455] ##STR00193##
[0456] 3,4-Dichlorophenyl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (800 mg, 1.28 mmol) and NaH (60% in oil, 77 mg, 1.91 mmol) were stirred 5 min in DMF (3.0 mL) before methyl 2-bromoacetate (0.16 mL, 1.66 mmol) was added. The mixture was stirred 2 h at rt and was then poured onto ice cooled water (30 mL) and HCl (4 mL, 1 M). The solids were isolated by filtration and recrystallized from EtOAc/PE to give the product (746 mg, 84%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.97 (s, 1H), 7.86 (d, J=1.9 Hz, 1H), 7.73 (d, J=8.5 Hz, 2H), 7.66 (d, J=8.4 Hz, 1H), 7.54 (dd, J=8.3, 1.8 Hz, 1H), 7.34 (s, 5H), 6.61 (d, J=5.2 Hz, 1H), 5.59 (s, 1H), 5.23 (dd, J=11.5, 3.2 Hz, 1H), 4.87 (dd, J=11.4, 5.1 Hz, 1H), 4.61 (d, J=3.1 Hz, 1H), 4.34 (s, 1H), 4.31 (s, 2H), 4.14 (d, J=12.6 Hz, 1H), 3.99 (d, J=12.5 Hz, 1H), 3.54 (s, 3H).
3,4-Dichlorophenyl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-carboxymethyl-1-thio-α-D-galactopyranoside
[0457] ##STR00194##
[0458] 3,4-Dichlorophenyl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-(methoxycarbonyl)methyl-1-thio-α-D-galactopyranoside (721 mg, 1.103 mmol) was stirred 30 min in 80% aq TFA (10 mL), the mixture was concentrated and water was added, which resulted in precipitation. The precipitate was collected by filtration and then stirred 2 h in EtOH (5.0 mL) and NaOH (3.0 mL, 2 M). The mixture was neutralized with HCl (1 M), concentrated, water was added, and pH was adjusted to approximately 1 with HCl (1 M). The precipitate was collected and then triturated in MeOH/water, the solids were collected and to the crude MeOH (3.0 mL) and 28% ammonia (0.20 mL) were added. The mixture was concentrated to dryness, then triturated in Et.sub.2O, the precipitate was collected, and the product was obtained as the ammonium salt (381 mg, 60%). ESI-MS m/z calcd for [C.sub.22H.sub.18C.sub.13F.sub.2N.sub.3O.sub.6S] [M+H].sup.+: 596.0; found: 596.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 9.18 (s, 1H), 7.83 (d, J=1.9 Hz, 1H), 7.67 (d, J=8.1 Hz, 2H), 7.57 (dd, J=8.4, 1.8 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 6.24 (d, J=3.9 Hz, 1H), 5.05 (m, 2H), 4.48 (t, J=6.1 Hz, 1H), 4.29 (s, 1H), 4.04 (d, J=15.7 Hz, 1H), 3.96 (d, J=15.7 Hz, 1H), 3.76-3.63 (m, 2H).
Intermediate 22
5-Chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 4,6-di-O-acetyl-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0459] ##STR00195##
5-Bromo-3-chloro-2-cyano-pyridine-N-oxide
[0460] ##STR00196##
[0461] To a solution of 5-bromo-3-chloro-2-cyano-pyridine (1.50 g, 6.90 mmol) in TFA (10 mL) H.sub.2O.sub.2 (35.0%, 1.01 g, 10.3 mmol) was slowly added. The mixture was heated to 70° C. and was kept stirring 3 h. The solvent was carefully removed under reduced pressure. The residue was dissolved in EtOAc and washed with water, brine, dried over Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated to give the product (1.30 g, 81%) as a light yellow solid. ESI-MS m/z calcd for [C.sub.6H.sub.2BrClN.sub.2O] [M+H].sup.+: 232.9; found: 232.9.
5-Bromo-3,6-dichloro-2-cyano-pyridine
[0462] ##STR00197##
[0463] To a stirred solution of 5-bromo-3-chloro-2-cyano-pyridine-N-oxide (700 mg, 3.00 mmol) in toluene (7 mL) POCl.sub.3 (0.823 mL, 9.00 mmol) was added. The mixture was stirred 3 h at 100° C. The mixture was cooled to rt and was poured into ice-water under vigorous stirring. The solution was extracted with EtOAc and the organic layer was washed with water, saturated aq NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue by was purified by column chromatography (PE/EtOAc=10/1˜3/1, Silica-CS 4 g, 12 mL/min, silica gel, UV 254) to give the product (400 mg, 53%) as a light yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.34 (s, 1H).
5-Bromo-3-chloro-2-cyano-6-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridine
[0464] ##STR00198##
[0465] To a solution of 5-bromo-3,6-dichloro-2-cyano-pyridine (50.0 mg, 0.20 mmol) and 2-oxa-6-azaspiro[3.3]heptane (21.6 mg, 0.22 mmol) in MeCN (2 mL) K.sub.2CO.sub.3 (41.1 mg, 0.30 mmol) was added. The mixture was stirred overnight at 60° C. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜3/1, Silica-CS 4 g, 12 mL/min, silica gel, UV 254) to give the product (33.0 mg, 53%) as a light yellow solid. ESI-MS m/z calcd for [C.sub.11H.sub.9BrClN.sub.3O] [M+H].sup.+: 314.0; found: 314.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.31 (s, 1H), 4.70 (s, 4H), 4.40 (s, 4H).
5-Chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-D-galactopyranoside
[0466] ##STR00199##
[0467] To a solution of 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-D-galactopyranoside (950 mg, 2.63 mmol) and 5-bromo-3-chloro-2-cyano-6-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridine (992 mg, 3.15 mmol) in DMF (10 mL) diethylamine (385 mg, 5.26 mmol) was added. The mixture was stirred overnight at rt under nitrogen atmosphere. After diluting with water (20 mL), the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc=10/1˜3/1, Silica-CS 4 g, 12 mL/min, silica gel, UV 254) to give the product (280 mg, 74%, a/0=0.44:1). ESI-MS m/z calcd for [C.sub.22H.sub.25ClN.sub.6O.sub.7S] [M+H].sup.+: 553.1; found: 553.0.
5-Chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0468] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.68 (s, 1H), 5.82 (d, J=5.2 Hz, 1H, 1-Hu), 5.33 (d, J=3.6 Hz, 1H), 4.78 (s, 4H), 4.38-4.26 (m, 5H), 4.08-3.72 (m, 3H), 3.49 (s, 3H), 3.33-3.32 (m, 1H), 2.09 (s, 3H), 1.92 (s, 3H).
5-Chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-β-D-galactopyranoside
[0469] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.70 (s, 1H), 5.31 (d, J=2.8 Hz, 1H), 4.77 (s, 4H), 4.49 (d, J=9.2 Hz, 1H, 1-HO), 4.38-4.26 (m, 4H), 4.08-3.72 (m, 3H), 3.57-3.55 (m, 1H), 3.33-3.32 (m, 1H), 2.12 (s, 3H), 1.97 (s, 3H).
5-Chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 4,6-di-O-acetyl-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0470] ##STR00200##
[0471] To a solution of 5-chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-D-galactopyranoside (400 mg, 0.72 mmol) and trimethyl-[2-(4-chloro-3,5-difluorophenyl)ethynyl]silane (215 mg, 0.94 mmol) in DMF (6 mL) copper(II) sulfate pentahydrate (90.3 mg, 0.362 mmol) and (+)-sodium L-ascorbate (143 mg, 0.72 mmol) were added. The mixture was stirred 3 h at rt under nitrogen atmosphere. After diluting with water (20 mL), the mixture was extracted three times with EtOAc (10 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 4 g, 12 mL/min, silica gel, UV 254) to give an anomeric mixture of the product. The mixture was separated by preparative —SFC to give the product (58.0 mg, 11%). ESI-MS m/z calcd for [C.sub.30H.sub.28Cl.sub.2F.sub.2N.sub.6O.sub.7S] [M+H].sup.+: 725.1; found: 725.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.81 (s, 1H), 7.74 (s, 1H), 7.38 (d, J=7.6 Hz, 2H), 6.02 (d, J=4.8 Hz, 1H), 5.50 (d, J=1.6 Hz, 1H), 4.86-4.75 (m, 6H), 4.59-4.56 (m, 1H), 4.40-4.29 (m, 4H), 4.07-3.96 (m, 2H), 3.34 (s, 3H), 2.00 (s, 3H), 1.93 (s, 3H).
Intermediate 23
5-Chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 4,6-di-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0472] ##STR00201##
[0473] To a solution of 5-chloro-6-cyano-2-{N-(2-oxa)-6-azaspiro[3.3]heptanyl}-pyridin-3-yl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-D-galactopyranoside (400 mg, 0.72 mmol) and trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (215 mg, 0.94 mmol) in DMF (6 mL) copper(II) sulfate pentahydrate (90.3 mg, 0.362 mmol) and (+)-sodium L-ascorbate (143 mg, 0.72 mmol) were added. The mixture was stirred 3 h at rt under nitrogen atmosphere. After diluting with water (20 mL), the mixture was extracted three times with EtOAc (10 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 4 g, 12 mL/min, silica gel, UV 254) to give an anomeric mixture of the product. The mixture was separated by preparative —SFC to give the product (54.0 mg, 11%). ESI-MS m/z calcd for [C.sub.30H.sub.28ClF.sub.3N.sub.6O.sub.7S][M+H].sup.+: 709.1; found: 709.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.80 (s, 1H), 7.75 (s, 1H), 7.41-7.36 (m, 2H), 6.03 (d, J=5.2 Hz, 1H), 5.50 (s, 1H), 4.85-4.76 (m, 6H), 4.59-4.56 (m, 1H), 4.40-4.28 (m, 4H), 4.07-3.96 (m, 2H), 3.33 (s, 3H), 2.00 (s, 3H), 1.93 (s, 3H).
Intermediate 24
5-Chloro-2-(pyrimidin-5-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0474] ##STR00202##
5-Chloro-2-(pyrimidin-5-yl)pyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0475] ##STR00203##
[0476] To a solution of 2-bromo-5-chloropyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (350 mg, 0.68 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (281 mg, 1.36 mmol) in 1,4-dioxane/water (3.3 mL, 10:1) in a microwave tube, bis(triphenylphosphine)palladium(II) chloride (47.8 mg, 0.068 mmol) and K.sub.2CO.sub.3 (282 mg, 2.04 mmol) were added. The mixture was degassed by bubbling argon through the solution and it was then stirred 1 h at 100° C. in a microwave reactor. The solvent was removed, and the residue was purified by column chromatography (PE/EtOAc=5/1˜1/1, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to give the product (260 mg, 74%). ESI-MS m/z calcd for [C.sub.23H.sub.21ClN.sub.6O.sub.4S] [M+H].sup.+: 513.1; found: 513.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.22 (s, 1H), 9.01 (s, 2H), 8.49 (d, J=2.4 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.42 (m, 2H), 7.35-7.26 (m, 3H), 5.86 (d, J=5.2 Hz, 1H), 5.52 (s, 1H), 4.19 (d, J=2.4 Hz, 1H), 4.12 (dd, J=10.4, 5.2 Hz, 1H), 4.07-3.93 (m, 2H), 3.72 (s, 1H), 3.54 (dd, J=10.4, 2.8 Hz, 1H), 3.37 (s, 3H).
5-Chloro-2-(pyrimidin-5-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0477] ##STR00204##
[0478] To a solution of 5-chloro-2-(pyrimidin-5-yl)pyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (130 mg, 0.25 mmol) and trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (69.4 mg, 0.30 mmol) in DMF (3 mL), (+)-sodium L-ascorbate (100 mg, 0.51 mmol) and copper(II) sulfate pentahydrate (31.6 mg, 0.13 mmol) were added. The mixture was stirred overnight at rt under nitrogen atmosphere and was then concentrated under reduced pressure. The residue was purified by preparative HPLC (Method A) to give the product (90.0 mg, 53%). ESI-MS m/z calcd for [C.sub.31H.sub.24ClF.sub.3N.sub.6O.sub.4S] [M+H].sup.+: 669.1; found: 669.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.56 (s, 1H), 8.07 (s, 1H), 7.84 (s, 1H), 7.34-7.30 (m, 10H), 5.92 (d, J=5.2 Hz, 1H), 5.45 (s, 1H), 5.12 (s, 1H), 4.44-4.40 (m, 2H), 4.04-4.02 (m, 3H), 3.13 (s, 3H).
Intermediate 25
5-Chloro-2-(pyridin-2-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0479] ##STR00205##
5-Chloro-2-(pyridin-2-yl)pyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0480] ##STR00206##
[0481] To a solution of 2-bromo-5-chloropyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (200 mg, 0.39 mmol) and tributyl(2-pyridyl)stannane (143 mg, 0.39 mmol) in DMF (3 mL) bis(triphenylphosphine)palladium(II) chloride (27.3 mg, 0.039 mmol) was added. The mixture was stirred 6 h at 110° C. under a nitrogen atmosphere. After cooling to rt, the mixture was purified by preparative HPLC (Method A) to give the product (25.0 mg, 13%). ESI-MS m/z calcd for [C.sub.24H.sub.22ClN.sub.5O.sub.4S] [M+H].sup.+: 512.1; found: 512.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.65 (s, 1H), 8.39 (s, 1H), 8.15 (m, 1H), 7.93 (m, 1H), 7.83-7.69 (m, 1H), 7.54-7.40 (m, 2H), 7.37-7.26 (m, 4H), 5.91 (d, J=5.6 Hz, 1H), 5.55 (s, 1H), 4.29-4.12 (m, 3H), 4.09-3.99 (m, 2H), 3.72 (dd, J=10.8, 3.2 Hz, 1H), 3.39 (s, 3H).
5-Chloro-2-(pyridin-2-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0482] ##STR00207##
[0483] To a solution of 5-chloro-2-(pyridin-2-yl)pyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (50.0 mg, 0.098 mmol) and trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (24.5 mg, 0.11 mmol) in DMF (3 mL), (+)-sodium L-ascorbate (38.7 mg, 0.20 mmol) and copper(II) sulfate pentahydrate (12.2 mg, 0.049 mmol) were added. The mixture was stirred overnight at rt under nitrogen atmosphere and was then purified by preparative HPLC (Method A) to give the product (30.0 mg, 46%). ESI-MS m/z calcd for [C.sub.32H.sub.25ClF.sub.3N.sub.5O.sub.4S] [M+H].sup.+: 668.1; found: 668.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.15 (s, 1H), 7.92 (s, 2H), 7.47-7.26 (m, 11H), 6.11 (s, 1H), 5.45 (s, 1H), 5.32 (d, J=10.0 Hz, 1H), 4.57 (s, 1H), 4.43 (s, 1H), 4.27 (m, 2H), 4.08 (d, J=11.8 Hz, 1H), 3.17 (s, 3H).
Intermediate 26
5-Chloro-2-(pyridin-3-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0484] ##STR00208##
5-Chloro-2-(pyridin-3-yl)pyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0485] ##STR00209##
[0486] To a solution of 2-bromo-5-chloropyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (320 mg, 0.62 mmol) in DMF (5 mL) 3-pyridylboronic acid (153 mg, 1.25 mmol), bis(triphenylphosphine)palladium(II) chloride (91 mg, 0.013 mmol) and K.sub.2CO.sub.3 (172 mg, 1.25 mmol) were added. The mixture was stirred 6 h at rt. The mixture was concentrated and purified by column chromatography (DCM/MeOH=10/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (150 mg, 47%). ESI-MS m/z calcd for [C.sub.24H.sub.22ClN.sub.5O.sub.4S] [M+H].sup.+: 512.1, found: 512.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.90 (s, 1H), 8.65 (d, J=3.6 Hz, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.12 (d, J=8.0 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.52-7.49 (m, 1H), 7.43-7.39 (m, 2H), 7.33-7.28 (m, 3H), 5.87 (d, J=4.8 Hz, 1H), 5.52 (s, 1H), 4.19 (d, J=2.8 Hz, 1H), 4.13-4.04 (m, 2H), 3.99 (d, J=12.8 Hz, 1H), 3.72 (d, J=4.4 Hz, 1H), 3.57 (dd, J=10.8, 3.2 Hz, 1H), 3.36 (s, 3H).
5-Chloro-2-(pyridin-3-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0487] ##STR00210##
[0488] To a solution of 5-chloro-2-(pyridin-3-yl)pyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (72 mg, 0.14 mmol) in DMF (3 mL), trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (48 mg, 0.21 mmol), (+)-sodium L-ascorbate (28 mg, 0.14 mmol) and copper(II) sulfate pentahydrate (35 mg, 0.14 mmol) were added. The mixture was stirred 6 h at rt. The mixture was concentrated and was then purified by column chromatography (DCM/MeOH=10/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (59.0 mg, 63%). ESI-MS m/z calcd for [C.sub.32H.sub.25ClF.sub.3N.sub.5O.sub.4S] [M+H].sup.+: 668.1, found: 668.2.
Intermediate 27
5-Chloro-2-(pyridin-4-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0489] ##STR00211##
5-Chloro-2-(pyridin-4-yl)pyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0490] ##STR00212##
[0491] To a solution of 2-bromo-5-chloro-3-pyridine-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (180 mg, 0.35 mmol) in 1,4-dioxane (4.0 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (144 mg, 0.70 mmol), K.sub.2CO.sub.3 (145 mg, 1.05 mmol), bis(triphenylphosphine)palladium(II) chloride (12.3 mg, 0.018 mmol) and H.sub.2O (0.5 mL) were added. The mixture was stirred 1 h at 100° C. in a microwave reactor. The solvent was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with water (80 mL), brine (80 mL), dried over Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (PE/EtOAc=10/1˜2/1, Silica-CS 12 g, 20 m/min, silica gel, UV 254) to afford the the product (130 mg, 73%). ESI-MS m/z calcd for [C.sub.24H.sub.22ClN.sub.5O.sub.4S] [M+H].sup.+: 512.1; found: 511.9.
5-Chloro-2-(pyridin-4-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0492] ##STR00213##
[0493] To a solution of 5-chloro-2-(pyridin-4-yl)pyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (60.0 mg, 0.12 mmol) in DMF (5 mL), trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (53.5 mg, 0.23 mmol), (+)-sodium L-ascorbate (23.2 mg, 0.12 mmol), copper(II) sulfate pentahydrate (29.3 mg, 0.12 mmol) and CsF (17.8 mg, 0.12 mmol) were added. The mixture was stirred at rt overnight. The mixture was poured into water (20 mL) and extracted with EtOAc (2×10 mL). the organic layers were washed with water (25 mL), dried with Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 4 g, 10 mL/min, silica gel, UV 254) to give the product (50.0 mg, 64%). ESI-MS m/z calcd for [C.sub.32H.sub.25ClF.sub.3N.sub.5O.sub.4S] [M+H].sup.+: 668.1; found: 668.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.60 (d, J=2.0 Hz, 1H), 8.19-8.14 (m, 2H), 7.98-7.94 (m, 1H), 7.74-7.62 (m, 2H), 7.54-7.41 (m, 8H), 6.12 (d, J=5.2 Hz, 1H), 5.54 (s, 1H), 5.34 (d, J=10.0 Hz, 1H), 4.59-4.54 (m, 1H), 4.50 (dd, J=11.2, 5.2 Hz, 1H), 4.27-4.18 (m, 1H), 4.16-4.11 (m, 2H), 3.19 (s, 3H).
Intermediate 28
5-Chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0494] ##STR00214##
5-Chloro-2-[1-(N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]pyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0495] ##STR00215##
[0496] To a solution of 2-bromo-5-chloro-3-pyridine-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (400 mg, 0.78 mmol) in 1,4-dioxane (10 mL), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (361 mg, 1.17 mmol), K.sub.2CO.sub.3 (215 mg, 1.56 mmol), bis(triphenylphosphine)palladium(II) chloride (546 mg, 0.78 mmol) and H.sub.2O (1 mL) were added. The mixture was stirred 1 h at 100° C. in a microwave reactor. The solvent was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with water (80 mL), brine (80 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜3/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (220 mg, 46%). ESI-MS m/z calcd for [C.sub.29H.sub.34ClN.sub.5O.sub.6S] [M+Na].sup.+: 638.2; found: 637.9. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.29 (d, J=2.0 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 7.48-7.45 (m, 1H), 7.35-7.27 (m, 4H), 5.99-5.82 (m, 2H), 5.56 (s, 1H), 4.26 (d, J=3.2 Hz, 1H), 4.20 (dd, J=10.4, 5.2 Hz, 1H), 4.16-4.11 (m, 1H), 4.09-4.03 (m, 2H), 3.92 (d, J=11.6 Hz, 1H), 3.71-3.57 (m, 4H), 3.45 (s, 3H), 2.57-2.41 (m, 2H), 1.44 (s, 9H).
5-Chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0497] ##STR00216##
[0498] To a solution of 5-chloro-2-[1-(N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]pyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (400 mg, 0.65 mmol) in DCM (15 mL) TFA (2.41 mL, 32.5 mmol) was added. The mixture was stirred 2 h at rt and Et.sub.3N (4 mL) was added at 0° C. followed by concentration of the mixture. The residue was purified by preparative HPLC (Method A) to give the product (97 mg, 35%) as a white solid. ESI-MS m/z calcd for [C.sub.17H.sub.22ClN.sub.5O.sub.4S] [M+H].sup.+: 428.1; found: 428.0. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.35 (d, J=2.0 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 6.09 (d, J=5.2 Hz, 1H), 6.05-5.95 (m, 1H), 4.16-4.04 (m, 2H), 4.00 (d, J=2.4 Hz, 1H), 3.73-3.55 (m, 5H), 3.51 (s, 3H), 3.18-3.13 (m, 2H), 2.61-2.48 (m, 2H).
Intermediate 29
5-Chloro-2-[1-(N-tert-butoxycarbonyl)-3-pyrrolin-3-yl]pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0499] ##STR00217##
[0500] 5-Chloro-2-[1-(N-tert-butoxycarbonyl)-3-pyrrolin-3-yl]pyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
##STR00218##
[0501] To a solution of 2-bromo-5-chloropyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (100 mg, 0.20 mmol) in 1,4-dioxane (10 mL) a solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (91.9 mg, 0.31 mmol), K.sub.2CO.sub.3 (53.8 mg, 0.39 mmol), bis(triphenylphosphine)palladium(II) chloride (10.9 mg, 0.016 mmol) in water (1 mL) was added. The mixture was stirred 1 h at 100° C. in a microwave reactor. The mixture was concentrated, and the residue was dissolved in EtOAc (100 mL) and washed with water and brine. The organic layer was dried with Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜3/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (90 mg, 77%). ESI-MS m/z calcd for [C.sub.28H.sub.32ClN.sub.5O.sub.6S] [M+Na].sup.+: 624.2; found: 623.8. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.35 (d, J=2.0 Hz, 1H), 8.00-7.94 (m, 1H), 7.54-7.51 (m, 2H), 7.40-7.36 (m, 3H), 6.08 (d, J=5.2 Hz, 1H), 5.63 (s, 1H), 4.67-4.53 (m, 2H), 4.44-4.00 (m, 6H), 3.95-3.92 (m, 1H), 3.79-3.66 (m, 2H), 3.54 (s, 3H), 1.48 (s, 9H).
5-Chloro-2-[1-(N-tert-butoxycarbonyl)-3-pyrrolin-3-yl]pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0502] ##STR00219##
[0503] To a solution of 5-chloro-2-[1-(N-tert-butoxycarbonyl)-3-pyrrolin-3-yl]pyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (90 mg, 0.15 mmol) in DMF (2 mL), trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (37.5 mg, 0.16 mmol), (+)-sodium L-ascorbate (29.6 mg, 0.15 mmol), copper(II) sulfate pentahydrate (37.3 mg, 0.15 mmol) and CsF (34.1 mg, 0.22 mmol) were added. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was filtered and the filtrate was purified by reverse-phase column [CH.sub.3CN/water (0.01% TFA)=0-65%, C18 40 g, 50 mL/min, UV 254] to give the product (50 mg, 44%). ESI-MS m/z calcd for [C.sub.36H.sub.35ClF.sub.3N.sub.5O.sub.6S] [M+H].sup.+: 758.2; found: 758.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.40 (s, 1H), 8.04-7.99 (m, 1H), 7.98-7.94 (m, 1H), 7.46-7.41 (m, 7H), 6.80-6.44 (m, 1H), 6.22-6.15 (m, 1H), 5.55 (s, 1H), 5.45-5.27 (m, 1H), 4.71-4.38 (m, 5H), 4.31 (d, J=12.8 Hz, 1H), 4.30-4.10 (m, 2H), 3.30 (s, 3H), 1.51 (s, 9H).
Intermediate 30
5-Chloro-2-(oxazol-2-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0504] ##STR00220##
2-Bromo-5-chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0505] ##STR00221##
[0506] To a solution of 2-bromo-5-chloro-3-pyridine-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (185 mg, 0.36 mmol) in DMF (3 mL) trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (123 mg, 0.54 mmol), copper(II) sulfate pentahydrate (45.0 mg, 0.18 mmol) and (+)-sodium L-ascorbate (36 mg, 0.18 mmol) were added. The mixture was stirred 3 h at rt, water (50 mL) and DCM (50 mL) were added, and the aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL) and dried over anhydrous Na.sub.2SO.sub.4. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 20 g, 20 m/min, silica gel, UV 254) to afford the product (210 mg, 85%). ESI-MS m/z calcd for [C.sub.27H.sub.21BrClF.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 669.0; found: 669.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.97 (s, 1H), 8.36 (d, J=2.4 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 7.80-7.75 (m, 2H), 7.39-7.35 (m, 5H), 6.93 (d, J=5.2 Hz, 1H), 5.60 (s, 1H), 5.23 (dd, J=11.2, 3.2 Hz, 1H), 4.73 (dd, J=11.6, 5.2 Hz, 1H), 4.60 (d, J=3.2 Hz, 1H), 4.23 (s, 1H), 4.12-3.98 (m, 2H), 3.37 (s, 3H).
5-Chloro-2-(oxazol-2-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0507] ##STR00222##
[0508] To a solution of 2-bromo-5-chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (180 mg, 0.26 mmol) in DMF (5 mL) tributyl(oxazol-2-yl)stannane (283 mg, 0.79 mmol), tetrakis(triphenylphosphine)palladium(0) (37 mg, 0.053 mmol) and CsF (80 mg, 0.53 mmol) were added. The mixture was stirred 16 h at 60° C. under a nitrogen atmosphere. The solvent was removed by evaporation and the residue was purified by column chromatography (PE/EtOAc=10/1˜5/7, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (72 mg, 37%). ESI-MS m/z calcd for [C.sub.30H.sub.23ClF.sub.3N.sub.5O.sub.5S] [M+H].sup.+: 658.1; found: 658.1. .sup.1H NMR (400 MHz, DMSO-ds) δ 8.97 (s, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.39-8.38 (m, 2H), 7.80-7.76 (m, 2H), 7.60 (s, 1H), 7.40-7.35 (m, 5H), 6.91 (d, J=5.2 Hz, 1H), 5.58 (s, 1H), 5.22 (dd, J=11.6, 3.2 Hz, 1H), 4.72 (dd, J=7.6, 4.2 Hz, 1H), 4.56 (d, J=2.8, 1H), 4.18 (s, 1H), 4.09-3.96 (m, 2H), 3.37 (s, 3H).
Intermediate 31
5-Chloro-2-(thiazol-2-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0509] ##STR00223##
[0510] To a solution of 2-bromo-5-chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (200 mg, 0.30 mmol) in DMF (5 mL) tributyl(thiazol-2-yl)stannane (223 mg, 0.6 mmol), tetrakis(triphenylphosphine)palladium(0) (63 mg, 0.09 mmol) and CsF (91 mg, 0.9 mmol) were added. The mixture was stirred 3 h at 100° C. under a nitrogen atmosphere before the solvent was removed by evaporation. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (85 mg, 39%). ESI-MS m/z calcd for [C.sub.30H.sub.23ClF.sub.3N.sub.5O.sub.4S.sub.2] [M+H].sup.+: 674.1; found: 674.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.98 (s, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.14 (d, J=3.2 Hz, 1H), 7.94 (d, J=3.6 Hz, 1H), 7.81-7.77 (m, 2H), 7.41-7.35 (m, 5H), 6.92 (d, J=5.60 Hz, 1H), 5.58 (s, 1H), 5.27 (dd, J=11.6, 3.6 Hz, 1H), 4.74 (dd, J=7.6, 5.2 Hz, 1H), 4.57 (d, J=3.6 Hz, 1H), 4.22 (s, 1H), 4.10-3.98 (m, 2H), 3.35 (s, 3H).
Intermediate 32
2,5-Bis(thiazol-2-yl)pyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0511] ##STR00224##
[0512] To a solution of 2-bromo-5-chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (180 mg, 0.27 mmol) in DMF (5 mL) tributyl(thiazol-2-yl)stannane (302 mg, 0.81 mmol), tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.08 mmol) and CsF (122 mg, 0.81 mmol) were added. The mixture was stirred 3 h at 100° C. under a nitrogen atmosphere before the solvent was removed by evaporation. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (125 mg, 34%). ESI-MS m/z calcd for [C.sub.33H.sub.25F.sub.3N.sub.6O.sub.4S.sub.3] [M+H].sup.+: 722.8; found: 723.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.97 (s, 1H), 8.88 (d, J=2.4 Hz, 1H), 8.33 (d, J=2.4 Hz, 1H), 7.95-7.94 (m, 2H), 7.92-7.89 (m. 2H), 7.79 (d, J=3.2 Hz, 2H), 7.38-7.35 (m, 5H), 6.82 (d, J=5.2 Hz, 1H), 5.76 (s, 1H), 5.22 (dd, J=11.2, 4.8 Hz, 1H), 4.69 (dd, J=11.2, 4.8 Hz, 1H), 4.60 (d, J=3.2, 1H), 4.38 (s, 1H), 4.16-3.97 (m, 2H), 3.34 (s, 3H).
Intermediates 33 and 34
5-Chloropyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside and 5-Bromopyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (mixture)
[0513] ##STR00225##
5-Chloropyridine-3-thiol and 5-Bromopyridine-3-thiol (mixture)
[0514] ##STR00226##
[0515] To a solution of 3-bromo-5-chloropyridine (4.52 g, 23.5 mmol) and NaH (60% in oil, 0.90 g, 23.5 mmol) in DMF (40 mL) benzyl mercaptan (2.51 mL, 21.3 mmol) was added dropwise and the mixture was stirred 2 h at rt. The mixture was concentrated, diluted with EtOAc, washed twice with water and the organic phase was dried and evaporated. The residue was dissolved in toluene (15 mL) and cooled to 0° C. To the formed suspension, a solution of AlCl.sub.3 (4.83 g, 36.2 mmol) in toluene (55 mL) was added and the mixture reached rt in 30 min, it was then stirred 2 h at rt. The mixture was cooled to 0° C. and quenched by addition of water. The phases were separated, and the organic phase was washed with water, dried and concentrated. The residue was purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the mixture of products (3.05 g).
5-Chloropyridine-3-thiol
[0516] ESI-MS m/z calcd for [C.sub.5H.sub.4ClNS] [M+H].sup.+: 146.0; found: 145.9.
5-Bromopyridine-3-thiol
[0517] ESI-MS m/z calcd for [C.sub.5H.sub.4BrNS] [M+H].sup.+: 189.9; found: 189.9.
5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside and 5-Bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (mixture)
[0518] ##STR00227##
[0519] To a mixture of 5-chloropyridine-3-thiol and 5-bromopyridine-3-thiol (650 mg) was dissolved together with 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (1.72 g, 4.91 mmol) in DMF (20 mL) NaH (60% in oil, 428 mg, 11.2 mmol) was added. The mixture was stirred 3 h at rt before being 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 the mixture of products (1.17 g).
5-Chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0520] ESI-MS m/z calcd for [C.sub.17H.sub.19ClN.sub.4O.sub.7S] [M+H].sup.+: 459.0; found: 459.1. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.53 (d, J=1.8 Hz, 1H), 8.50 (d, J=2.2 Hz, 1H), 7.84 (t, J=2.1 Hz, 1H), 5.99 (d, J=5.5 Hz, 1H), 5.50 (d, J=3.3 Hz, 1H), 5.30 (dd, J=10.9, 5.5 Hz, 1H), 4.68-4.60 (m, 1H), 4.14 (dd, J=11.7, 4.6 Hz, 1H), 4.03 (dd, J=11.6, 7.9 Hz, 1H), 3.96 (dd, J=10.9, 3.4 Hz, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 2.04 (s, 3H).
5-Bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0521] ESI-MS m/z calcd for [C.sub.17H.sub.19BrN.sub.4O.sub.7S] [M+H].sup.+: 503.0; found: 503.1. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.60 (d, J=2.0 Hz, 1H), 8.57 (d, J=1.8 Hz, 1H), 7.98 (t, J=2.1 Hz, 1H), 5.99 (d, J=5.5 Hz, 1H), 5.50 (d, J=3.3 Hz, 1H), 5.30 (dd, J=10.9, 5.5 Hz, 1H), 4.68-4.60 (m, 1H), 4.14 (dd, J=11.7, 4.6 Hz, 1H), 4.03 (dd, J=11.6, 7.9 Hz, 1H), 3.96 (dd, J=10.9, 3.4 Hz, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 2.04 (s, 3H).
5-Chloropyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside and 5-Bromopyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (mixture)
[0522] ##STR00228##
[0523] A mixture of 5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside and 5-bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (1.17 g) was dissolved in MeOH (20 mL) and NaOMe (1 mL, 1 M) and stirred 2 h at rt. AcOH (0.2 mL) was added and the mixture was concentrated and the residue was partitioned between EtOAc and NaOH (aq, 1M). The organic phase was dried, evaporated and the residue was dissolved together with p-toluenesulfonic acid monohydrate (146 mg, 0.77 mmol) in MeCN (100 mL). Benzaldehyde dimethyl acetal (0.77 mL, 5.10 mmol) was added and the mixture was stirred 2 h at rt, precipitation was observed. The solids were filtered off and the filtrate was evaporated, diluted with EtOAc and washed with saturated aq NaHCO.sub.3. The organic phase was dried and evaporated. The residue and the solid material were dissolved together with NaH (60% in oil, 164 mg, 4.28 mmol) in DMF (10 mL). The mixture was stirred 5 min before the addition of iodomethane (0.2 mL, 3.21 mmol). After stirring 2 h at rt the mixture was diluted with EtOAc, washed twice with water and the organic phase was dried and evaporated. The residue was stirred 30 min at rt in TFA/water (7.5 mL, 4:1). The mixture was concentrated to a third of its volume and partitioned between EtOAc and NaOH (aq, 1M). The organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the mixture of products (380 mg).
5-Chloropyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0524] ESI-MS m/z calcd for [C.sub.12H.sub.15ClN.sub.4O.sub.4S] [M+H].sup.+: 347.1; found: 347.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.59 (d, J=1.9 Hz, 1H), 8.44 (d, J=2.2 Hz, 1H), 8.15 (t, J=2.1 Hz, 1H), 6.07 (d, J=5.2 Hz, 1H), 4.23 (t, J=6.0 Hz, 1H), 4.06 (dd, J=10.6, 5.3 Hz, 1H), 4.00 (d, J=2.5 Hz, 1H), 3.70-3.60 (m, 3H), 3.53 (s, 3H).
5-Bromopyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0525] ESI-MS m/z calcd for [C.sub.12H.sub.15BrN.sub.4O.sub.4S] [M+H].sup.+: 391.0; found: 391.0. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.63 (d, J=1.8 Hz, 1H), 8.54 (d, J=2.2 Hz, 1H), 8.29 (t, J=1.9 Hz, 1H), 6.07 (d, J=5.2 Hz, 1H), 4.23 (t, J=6.0 Hz, 1H), 4.06 (dd, J=10.6, 5.3 Hz, 1H), 4.00 (d, J=2.5 Hz, 1H), 3.70-3.60 (m, 3H), 3.53 (s, 3H).
Intermediate 39
6-Trifluoromethyl-5-methylpyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0526] ##STR00229##
5-Fluoro-3-methyl-2-(trifluoromethyl)pyridine
[0527] ##STR00230##
[0528] To a solution of 2-bromo-5-fluoro-3-methylpyridine (3.8 g, 20 mmol) in DMF (20 mL) CuI (6.0 g, 31.5 mmol) and methyl 2,2-difluoro-2-fluorosulfonyl-acetate (11.5 g, 60 mmol) were added. The mixture was stirred 5 h at 100° C. in a microwave reactor. Water (100 mL) was added, then extracted with diethyl ether (3×100 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated to afford the product. (2.5 g, 63%). GC-MS calcd for [C.sub.7H.sub.5F.sub.4N] [M]: 179.0; found: 179.0.
5-Methyl-6-(trifluoromethyl)pyridine-3-thiol
[0529] ##STR00231##
[0530] To a solution of 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine (2.5 g, 12.6 mmol) in DMF (20 mL) Na.sub.2S (1.96 g, 25.1 mmol) was added. The mixture was stirred overnight at rt. The solvent was removed to afford the product (2.0 g, 82%). ESI-MS m/z calcd for [C.sub.7H.sub.6F.sub.3NS] [M−H].sup.−: 192.0; found: 192.0.
6-Trifluoromethyl-5-methylpyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0531] ##STR00232##
[0532] To a solution of 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (3.50 g, 10.0 mmol) and 5-methyl-6-(trifluoromethyl)pyridine-3-thiol (2.0 g, 10.4 mmol) in DMF (50 mL) Cs.sub.2CO.sub.3 (6.52 g, 20.0 mmol) was added. The mixture was stirred 6 h at rt before water (200 mL) was added. The mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 40 g, 40 m/min, silica gel, UV 254) to give the product (2.6 g, 51%). ESI-MS m/z calcd for [C.sub.19H.sub.21F.sub.3N.sub.4O.sub.7S][M+H].sup.+: 507.1; found: 507.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.50 (d, J=1.6 Hz, 1H), 7.71 (s, 1H), 6.07 (d, J=5.6 Hz, 1H), 5.48 (d, J=2.8 Hz, 1H), 5.29 (dd, J=11.2, 5.6 Hz, 1H), 4.60-4.57 (m, 1H), 4.12-3.96 (m, 3H), 2.51-2.48 (m, 3H), 2.18 (s, 3H), 2.16 (s, 3H), 1.94 (s, 3H).
6-Trifluoromethyl-5-methylpyridin-3-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0533] ##STR00233##
[0534] To a solution of 6-trifluoromethyl-5-methylpyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (2.6 g, 5.13 mmol) in MeOH (50 mL) NaOMe (0.03 g, 0.51 mmol) was added. The mixture was stirred 6 h at rt before the solvent was removed by evaporation. The residue was purified by preparative HPLC (Method A) to give the product (1.90 g, 93%). ESI-MS m/z calcd for [C.sub.13H.sub.15F.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 381.1; found: 381.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.53 (d, J=1.6 Hz, 1H), 8.04 (d, J=0.4 Hz, 1H), 5.82 (d, J=5.2 Hz, 1H), 4.40 (dd, J=10.8, 5.6 Hz, 1H), 4.24-4.20 (m, 1H), 4.03 (d, J=2.0 Hz, 1H), 3.70-3.62 (m, 2H), 3.54 (dd, J=10.8, 2.8 Hz, 1H), 2.51-2.48 (m, 3H).
6-Trifluoromethyl-5-methylpyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside
[0535] ##STR00234##
[0536] To a stirred solution of 6-trifluoromethyl-5-methylpyridin-3-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside (1.90 g, 4.8 mmol) in DMF (15 mL) benzaldehyde dimethyl acetal (2.19 g, 14.4 mmol) was added followed by D(+)-10-camphorsulfonic acid (334 mg, 1.44 mmol). The mixture was stirred 2 h at 50° C. The mixture was added dropwise to aq NaHCO.sub.3 (200 mL) then filtered. The white solid was collected and dried in vacuum to afford the product (1.10 g, 47%). ESI-MS m/z calcd for [C.sub.20H.sub.19F.sub.3N.sub.4O.sub.4S][M+H].sup.+: 469.1; found: 469.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.52 (d, J=1.6 Hz, 1H), 7.78 (s, 1H), 7.52-7.35 (m, 5H), 5.94 (d, J=5.6 Hz, 1H), 5.64 (s, 1H), 4.68-4.63 (m, 1H), 4.42 (d, J=3.2 Hz, 1H), 4.27-4.14 (m, 3H), 3.61 (dd, J=10.8, 3.2 Hz, 1H), 2.51-2.48 (m, 3H).
6-Trifluoromethyl-5-methylpyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0537] ##STR00235##
[0538] To a solution of 6-trifluoromethyl-5-methylpyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (400 mg, 0.82 mmol) in DMF (8 mL) Cs.sub.2CO.sub.3 (0.534 g, 1.64 mmol) and iodomethane (0.349 g, 2.46 mmol) were added. The mixture was stirred 6 h at rt. Water (100 mL) was added, and the mixture was extracted with EtOAc (3×50 mL). The organic layers were washed with brine (3×50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 20 g, 20 m/min, silica gel, UV 254) to afford the product (350 mg, 82%) as a white solid. ESI-MS m/z calcd for [C.sub.21H.sub.21F.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 483.1; found: 483.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.53 (d, J=2.0 Hz, 1H), 7.78 (d, J=0.8 Hz, 1H), 7.55-7.38 (m, 5H), 6.14 (d, J=5.2 Hz, 1H), 5.64 (s, 1H), 4.35 (d, J=2.8 Hz, 1H), 4.28 (dd, J=10.8, 5.2 Hz, 1H), 4.24-4.01 (m, 3H), 3.77-3.73 (m, 1H), 3.57 (s, 3H), 2.51-2.48 (m, 3H).
6-Trifluoromethyl-5-methylpyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0539] ##STR00236##
[0540] To a solution of 6-trifluoromethyl-5-methylpyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (200 mg, 0.39 mmol) in DMF (6 mL) trimethyl-[2-(4-chloro-3,5-difluorophenyl)ethynyl]silane (236 mg, 60%, 0.58 mol), copper(II) sulfate pentahydrate (48.2 mg, 0.19 mmol) and (+)-sodium L-ascorbate (38.2 mg, 0.19 mmol) were added. The mixture was stirred 3 h at rt under nitrogen atmosphere. Water (50 mL) and DCM (50 mL) were added. The aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were washed with water (50 mL) and brine (3×50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to afford the product (200 mg, 73%). ESI-MS m/z calcd for [C.sub.29H.sub.24ClF.sub.5N.sub.4O.sub.4S] [M+H].sup.+: 655.1; found: 655.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.57 (d, J=1.6 Hz, 1H), 8.00 (s, 1H), 7.79 (s, 1H), 7.45 (d, J=7.6 Hz, 2H), 7.39 (s, 5H), 6.24 (d, J=4.8 Hz, 1H), 5.52 (s, 1H), 5.32 (dd, J=11.2, 3.2 Hz, 1H), 4.56-4.51 (m, 2H), 4.32-4.13 (m, 3H), 3.33 (s, 3H), 2.51-2.48 (m, 3H).
Intermediate 40
2-(N-azetidinyl-carbonyl)-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
[0541] ##STR00237##
[0542] 2-Carboxy-5-chlorophenyl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (150 mg, 0.27 mmol), 1-hydroxybenzotriazole hydrate (65 mg, 0.41 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (81 mg, 0.41 mmol) were stirred in DMF (2.0 mL) and azetidine (39 μL, 0.55 mmol) was added followed by Et.sub.3N (39 μL, 0.27 mmol). The mixture was stirred 5 h at rt, then water (8.0 mL) was added and decanted. The residue was stirred in EtOH (3 mL) and NaOH (0.5 mL, 2 M) 1 h at rt, then neutralized with HCl (0.5 mL, 2 M) and poured onto water. The precipitate was collected by filtration and further purification by chromatography (SiO.sub.2, PE/EtOAc) afforded the product (93 mg, 58%). ESI-MS m/z calcd for [C.sub.24H.sub.22Cl.sub.2F.sub.2N.sub.4O.sub.5S] [M+H].sup.+: 587.1; found: 587.1. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.60 (s, 1H), 7.87 (d, J=1.8 Hz, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.40 (dd, J=8.2, 1.9 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 5.93 (d, J=5.2 Hz, 1H), 5.01 (dd, J=11.5, 2.7 Hz, 1H), 4.93 (dd, J=11.5, 5.2 Hz, 1H), 4.48 (t, J=6.1 Hz, 1H), 4.26-4.15 (m, 3H), 4.03 (m, 2H), 3.72 (m, 2H), 2.34 (m, 2H).
Intermediate 41
2-(N-azetidinyl-carbonyl)-5-chlorophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0543] ##STR00238##
5-Chloro-2-cyanophenyl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside
[0544] ##STR00239##
[0545] To a solution of 5-chloro-2-cyanophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (1.33 g, 2.75 mmol) in MeOH (5.0 mL) was added catalytical amount of NaOMe (pH=9-10). The mixture was stirred for 20 min before being neutralized with acid ion resin and filtrated. The filtrate was concentrated, and the residue was dissolved in DMF (10 mL). To the solution D(+)-10-camphorsulfonic acid (195 mg, 0.84 mmol) and benzaldehyde dimethyl acetal (1.28 g, 8.41 mmol) were added and the mixture was stirred 2 h at 60° C. The mixture was concentrated and the residue was purified by column chromatography (PE/EtOAc=2/1˜1/1, Silica-CS 12 g, 12 mL/min, silica gel, UV 254) to give the product (768 mg, 62%). ESI-MS m/z calcd for [C.sub.20H.sub.17ClN.sub.4O.sub.4S] [M+H].sup.+: 445.1; found: 445.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.76 (d, J=2.0 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.51-7.49 (m, 2H), 7.38-7.34 (m, 4H), 5.89 (d, J=5.2 Hz, 1H), 5.63 (s, 1H), 4.67-4.62 (m, 1H), 4.42 (d, J=2.8 Hz, 1H), 4.29-4.25 (m, 2H), 4.17-4.14 (m, 1H), 3.64 (dd, J=10.8, 3.2 Hz, 1H), 2.48 (d, J=6.4 Hz, 1H).
2-Cyano-5-chlorophenyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0546] ##STR00240##
[0547] To a solution of 5-chloro-2-cyanophenyl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (768 mg, 1.73 mmol) in DMF (2 mL) iodomethane (490 mg, 3.45 mmol) and Cs.sub.2CO.sub.3 (1.69 g, 5.18 mmol) were added. The mixture was stirred 16 h at rt under nitrogen atmosphere. The mixture was concentrated, and the residue was purified by column chromatography (PE/EtOAc=25/1˜6/1, Silica-CS 12 g, 12 mL/min, silica gel, UV 254) to give the product (407 mg, 51%). ESI-MS m/z calcd for [C.sub.21H.sub.19ClN.sub.4O.sub.4S] [M+H].sup.+: 459.1; found: 459.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.72 (d, J=2.0 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.51-7.49 (m, 2H), 7.36-7.34 (m, 4H), 6.11 (d, J=5.2 Hz, 1H), 5.61 (s, 1H), 4.34 (d, J=3.2 Hz, 1H), 4.27 (dd, J=10.8, 5.2 Hz, 1H), 4.20-4.17 (m, 2H), 4.13-4.09 (m, 1H), 3.78 (dd, J=10.8, 3.2 Hz, 1H), 3.60 (s, 3H).
2-Cyano-5-chlorophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0548] ##STR00241##
[0549] To a solution of 2-cyano-5-chlorophenyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (338 mg, 0.74 mmol) and trimethyl-[2-(3-fluoro-4-methylphenyl)ethynyl]silane (0.304 g, 1.47 mmol) in DMF (5 mL) (+)-sodium L-ascorbate (72.9 mg, 0.37 mmol) and copper(II) sulfate pentahydrate (92.1 mg, 0.37 mmol) were added. The mixture was stirred 3 h at rt under nitrogen atmosphere. The solvent was removed under reduced pressure and the residue was purified by column chromatography (PE/EtOAc=10/1˜4/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (260 mg, 60%). ESI-MS m/z calcd for [C.sub.30H.sub.26ClFN.sub.4O.sub.4S][M+H].sup.+: 593.1, found: 593.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.95 (s, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H) 7.49-7.36 (m, 8H), 7.25 (s, 1H), 6.21 (d, J=4.8 Hz, 1H), 5.52 (s, 1H), 5.32 (dd, J=12.0, 3.2 Hz, 1H), 4.57-4.41 (m, 2H), 4.35 (s, 1H), 4.29 (dd, J=12.8, 1.6 Hz, 1H), 4.16 (dd, J=12.8, 1.6 Hz, 1H), 3.38 (s, 3H), 2.30 (d, J=1.2 Hz, 3H).
2-Carboxy-5-chlorophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0550] ##STR00242##
[0551] A mixture of 2-cyano-5-chlorophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (250 mg, 0.42 mmol) in ethanol (20 mL) and NaOH (11.4 mL, 3 M) was stirred 5 h at 80° C. After cooling to rt, the mixture was concentrated to a volume of approx. 12 mL, and then acidified with HCl (5 M) to pH approximately 1. The precipitation was collected by filtration, washed with 33% aq MeOH, and dried to afford the product (200 mg, 78%). ESI-MS m/z calcd for [C.sub.30H.sub.27ClFN.sub.3O.sub.6S] [M+H].sup.+: 612.1, found: 612.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.36 (s, 1H), 8.81 (s, 1H), 7.89-7.87 (m, 2H), 7.58-7.56 (m, 2H) 7.39-7.32 (m, 7H), 6.68 (d, J=5.2 Hz, 1H), 5.56 (s, 1H), 5.18 (dd, J=11.6, 3.6 Hz, 1H), 4.75 (dd, J=12.0, 5.6 Hz, 1H), 4.53 (d, J=3.2 Hz, 1H) 4.21 (s, 1H), 4.11-4.08 (m, 1H), 3.97-3.94 (m, 1H), 3.30 (s, 3H), 2.23 (s, 3H).
2-(N-azetidinyl-carbonyl)-5-chlorophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyrandoside
[0552] ##STR00243##
[0553] To a stirred mixture of 2-carboxy-5-chlorophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3-fluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (200 mg, 0.33 mmol), azetidine hydrochloride (0.122 g, 1.31 mmol) and Et.sub.3N (0.198 g, 1.96 mmol) in DMF (3 mL) 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.373 g, 0.98 mol) was added in portions. The mixture was stirred overnight at rt, and was then concentrated under reduced pressure. The residue was purified by column chromatography (PE/EtOAc=1/2, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (127 mg, 60%). ESI-MS m/z calcd for [C.sub.33H.sub.32ClFN.sub.4O.sub.5S] [M+H].sup.+: 651.2, found: 651.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.95 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.48-7.45 (m, 2H), 7.41-7.35 (m, 5H) 7.33-7.30 (m, 2H), 7.27 (s, 1H), 6.24 (d, J=4.8 Hz, 1H), 5.50 (s, 1H), 5.34 (dd, J=11.2, 3.2 Hz, 1H), 4.50-4.46 (m, 2H), 4.41 (s, 1H), 4.26-4.10 (m, 4H), 3.95 (t, J=8.0 Hz, 2H), 3.34 (s, 3H), 2.95 (s, 1H), 2.87 (s, 1H), 2.29 (s, 3H).
Intermediate 42
5-Chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0554] ##STR00244##
5-Chloropyridin-3-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0555] ##STR00245##
[0556] To a solution of 5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (WO2016120403) (2.80 g, 6.10 mmol) in MeOH (30 mL) NaOMe (330 mg, 6.10 mmol) was added. The mixture was stirred 2 h at rt, then AcOH was added to adjust pH to 7. The solvent was removed under reduced pressure and the residue was purified by column chromatography (PE/EtOAc=1/1˜0/1, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (1.50 g, 74%) as a white solid. ESI-MS m/z calcd for [C.sub.11H.sub.13ClN.sub.4O.sub.4S] [M+H].sup.+: 333.0; found: 333.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.55 (d, J=2.0 Hz, 1H), 8.48 (d, J=2.0 Hz, 1H), 8.09 (t, J=2.0 Hz, 1H), 6.01 (d, J=5.2 Hz, 1H), 5.77 (d, J=5.2 Hz, 1H), 5.31 (d, J=6.4 Hz, 1H), 4.68 (t, J=5.6 Hz, 1H), 4.24 (dt, J=10.4, 5.2 Hz, 1H), 3.98 (t, J=6.0 Hz, 1H), 3.94-3.88 (m, 1H), 3.54-3.45 (m, 1H), 3.43-3.34 (m, 1H), 3.34-3.18 (m, 1H).
5-Chloropyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside
[0557] ##STR00246##
[0558] To a solution of 5-chloropyridin-3-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside (1.50 g, 4.51 mmol) in DMF (10 mL) benzaldehyde dimethyl acetal (2.06 g, 13.5 mmol) and D(+)-10-camphorsulfonic acid (314 mg, 1.35 mmol) were added. The mixture was stirred 2 h at 60° C., then it was cooled to rt and Et.sub.3N (1 mL) was added. The solvent was removed under reduced pressure and the residue was purified by column chromatography (PE/EtOAc=1/1˜1/3, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (1.00 g, 53%). ESI-MS m/z calcd for [C.sub.18H.sub.17ClN.sub.4O.sub.4S] [M+H].sup.+: 421.1; found: 421.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.57 (d, J=2.0 Hz, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.08 (t, J=2.0 Hz, 1H), 7.48-7.33 (m, 5H), 6.23 (d, J=5.2 Hz, 1H), 6.05 (d, J=5.2 Hz, 1H), 5.68 (s, 1H), 4.43 (d, J=3.2 Hz, 1H), 4.40-4.24 (m, 1H), 4.12-4.06 (m, 1H), 4.02 (s, 1H), 3.92-3.85 (m, 1H), 3.69 (dd, J=10.8, 3.2 Hz, 1H).
5-Chloropyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0559] ##STR00247##
[0560] To a solution of 5-chloropyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (1.00 g, 2.38 mmol) in DMF (10 mL) NaH (60% in oil, 190 mg, 4.75 mmol) was added at 0° C. After 2 min, iodomethane (0.296 mL, 4.75 mmol) was added and the mixture was stirred under nitrogen atmosphere 30 min at rt. The mixture was poured into water (20 mL) and extracted with EtOAc (2×50 mL). The organic layers were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (PE/EtOAc=2/1˜1/2, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (420 mg, 41%). ESI-MS m/z calcd for [C.sub.19H.sub.19ClN.sub.4O.sub.4S] [M+H].sup.+: 435.1; found: 435.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.53 (s, 1H), 8.44 (s, 1H), 7.84 (t, J=2.0 Hz, 1H), 7.57-7.49 (m, 2H), 7.42-7.35 (m, 3H), 6.04 (d, J=5.2 Hz, 1H), 5.62 (s, 1H), 4.34 (d, J=3.2 Hz, 1H), 4.30-4.20 (m, 2H), 4.17-4.09 (m, 2H), 3.72 (dd, J=10.8, 3.2 Hz, 1H), 3.56 (s, 3H).
5-Chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0561] ##STR00248##
[0562] To a solution of 5-chloropyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (100 mg, 0.230 mmol) in DMF (5 mL) trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (78.7 mg, 0.35 mmol), (+)-sodium L-ascorbate (45.6 mg, 0.23 mmol), copper(II) sulfate pentahydrate (57.4 mg, 0.23 mmol) and CsF (34.9 mg, 0.23 mmol) were added. The mixture was stirred under nitrogen atmosphere at rt overnight. The mixture was poured into water (20 mL) and extracted twice with EtOAc (50 mL). The organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 4 g, 10 mL/min, silica gel, UV 254) to afford the product (100 mg, 74%). ESI-MS m/z calcd for [C.sub.27H.sub.22ClF.sub.3N.sub.4O.sub.4S][M+H].sup.+: 591.1; found: 591.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.71-8.33 (m, 2H), 7.96-7.93 (m, 1H), 7.90-7.86 (m, 1H), 7.47-7.37 (m, 7H), 6.15 (d, J=5.2 Hz, 1H), 5.54 (s, 1H), 5.31 (dd, J=10.8, 3.6 Hz, 1H), 4.55-4.48 (m, 2H), 4.36-4.28 (m, 2H), 4.20-4.14 (m, 1H), 3.34 (s, 3H).
Intermediate 43
5-Chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(6-fluoro-5-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0563] ##STR00249##
6-Bromo-2-fluoro-3-methylpyridine
[0564] ##STR00250##
[0565] A solution of lithium diisopropylamide (6.25 mL, 2 M in THF, 12.5 mmol) was added dropwise to 2-bromo-6-fluoro-pyridine (2.0 g, 11.4 mmol) in THF (6 mL) at −78° C., and then stirred 30 min. Iodomethane (1.77 g, 12.5 mmol) was added slowly, and then continued to stir 3 h at −78° C. The mixture slowly reached rt and was then stirred 1 h. The reaction was quenched with EtOAc/water (50 mL/100 mL) and kept for 1 h. The layers were separated, and the organic layer was concentrated. The residue was purified by column chromatography (PE/EtOAc=20/1˜10/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to give the product (1.00 g, 46%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.47 (t, J=8.8 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H) 2.23 (s, 3H).
2-Fluoro-3-methyl-6-[2-(trimethylsilyl)ethynyl]pyridine
[0566] ##STR00251##
[0567] To a solution of 6-bromo-2-fluoro-3-methylpyridine (1.00 g, 5.26 mmol) and trimethylsilylacetylene (1.03 g, 10.5 mmol) in DMF (5 mL) CuI (50.1 mg, 0.26 mmol), bis(triphenylphosphine)palladium(II) dichloride (185 mg, 0.26 mol) and Et.sub.3N (1.47 mL, 10.5 mmol) were added. The mixture was stirred 2 h at 50° C. under nitrogen atmosphere. The solvent was removed to afford the product (300 mg, 28%). ESI-MS m/z calcd for [C.sub.11H.sub.14FNSi] [M+H].sup.+: 208.1, found: 208.2.
5-Chloropyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(6-fluoro-5-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0568] ##STR00252##
[0569] To a solution of 5-chloropyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (114 mg, 0.26 mmol) and 2-fluoro-3-methyl-6-[2-(trimethylsilyl)ethynyl]pyridine (81.6 mg, 0.39 mmol) in DMF (2 mL) (+)-sodium L-ascorbate (25.0 mg, 0.13 mmol) and copper(II) sulfate pentahydrate (33.0 mg, 0.13 mmol) were added. The mixture was stirred 3 h at rt under a nitrogen atmosphere. The solvent was removed, and the residue was purified by column chromatography (PE/EtOAc=10/1˜4/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (100 mg, 67%). ESI-MS m/z calcd for [C.sub.27H.sub.25ClFN.sub.5O.sub.4S] [M+H].sup.+: 570.1, found: 570.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.74 (d, J=2.0 Hz, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.33 (s, 1H), 7.97 (dd, J=7.6, 1.2 Hz, 1H), 7.87 (t, J=2.0 Hz, 1H), 7.69 (dd, J=9.6, 8.0 Hz, 1H), 7.43-7.35 (m, 5H), 6.17 (d, J=4.8 Hz, 1H), 5.51 (s, 1H), 5.32 (dd, J=11.2, 3.2 Hz, 1H), 4.60 (dd, J=11.6, 5.2 Hz, 1H), 4.52 (d, J=2.8 Hz, 1H), 4.32-4.27 (m, 2H), 4.16 (dd, J=12.8, 1.2 Hz, 1H), 3.34 (s, 3H), 2.21 (s, 3H).
Intermediate 44
3-Chloro-2-methyl-6-[2-(trimethylsilyl)ethynyl]pyridine
[0570] ##STR00253##
[0571] 6-Bromo-3-chloro-2-methyl-pyridine (413 mg, 2 mmol) and trimethylsilylacetylene (416 μl, 3 mmol) were added to a solution of bis(triphenylphosphine)palladium(II) dichloride (73.0 mg, 0.10 mmol), CuI (38.1 mg, 0.20 mmol) and Et.sub.3N (1.36 mL, 10 mmol) in THF (4 mL, degassed). The mixture was stirred 1 h at rt before it was diluted with PE (7 mL) and cooled to −20° C. The suspension was filtered through a plug of celite and concentrated. Purification by chromatography (SiO.sub.2, PE/EtOAc) yielded the product (400 mg, 89%). ESI-MS m/z calcd for [C.sub.11H.sub.15ClNSi] [M+H].sup.+: 224.1; found: 224.1, .sup.1H NMR (400 MHz, Chloroform-d) δ 7.58 (d, J=8.2 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 2.63 (s, 3H), 0.27 (s, 9H).
5-Chloropyridin-3-yl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0572] ##STR00254##
[0573] NaOMe (2.18 mL, 1M, 2.18 mmol) was added to 5-chloropyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (2.00 g, 4.36 mmol) in MeOH (40 mL). After 20 minutes the reaction was quenched with AcOH (200 μL) and concentrated. NaOH (100 mL, 1 M) was added and the mixture was extracted with EtOAc (2×100 mL). The organic phases were dried and concentrated. The crude was suspended in MeCN (200 mL). Benzaldehyde dimethyl acetal (1.31 mL, 8.72 mmol) and p-toluenesulfonic acid monohydrate (249 mg, 1.31 mmol) were added. After 2 h additional benzaldehyde dimethyl acetal (1.31 mL, 8.72 mmol) was added and the mixture was stirred 45 min before it was concentrated. The crude was suspended in MeCN (200 mL) and benzaldehyde dimethyl acetal (1.31 ml, 8.72 mmol) was added. The mixture was stirred overnight and then concentrated. EtOAc (200 mL) was added and the mixture was washed with saturated aq NaHCO.sub.3 (100 mL) and water (100 ml). The organic phase was concentrated. Toluene was added and the mixture was concentrated once more. The crude was dissolved in DMF (20 mL) and NaH (60% in oil, 334 mg, 8.72 mmol) was added. After 5 minutes iodomethane (0.407 mL, 6.54 mmol) was added and the mixture was stirred for additionally 45 min. The mixture was diluted with EtOAc (200 mL), washed with water (5×200 mL) and concentrated. Water/TFA (15 mL, 1:4) was added. After 30 min the mixture was diluted with water (25 mL) and TFA was removed under reduced pressure. NaOH (50 mL, 1 M) was added and the mixture was made basic using NaOH (50%). The mixture was extracted with EtOAc (2×50 mL). The organic phases were dried and concentrated. Recrystallization from EtOAc:PE yielded the product (1.10 g). The mother liquor was concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to yield the product (501 mg). ESI-MS m/z calcd for [C.sub.12H.sub.16ClN.sub.4O.sub.4S] [M+H].sup.+: 347.1; found: 347.1, .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.59 (d, J=1.8 Hz, 1H), 8.44 (d, J=2.2 Hz, 1H), 8.15 (t, J=2.0 Hz, 1H), 6.07 (d, J=5.3 Hz, 1H), 4.23 (t, J=6.0 Hz, 1H), 4.06 (dd, J=10.5, 5.3 Hz, 1H), 4.00 (d, J=2.4 Hz, 1H), 3.71-3.59 (m, 3H), 3.53 (s, 3H).
Intermediate 45
3-Chloro-2-cyanopyridin-5-yl 4,6-di-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0574] ##STR00255##
3-Chloro-2-cyanopyridin-5-yl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-D-galactopyranoside
[0575] ##STR00256##
[0576] To a solution of acetyl 4,6-di-O-acetyl-3-azido-2-methyl-3-deoxy-1-thio-D-galactopyranoside (280 mg, 0.78 mmol) and 3-chloro-5-fluoro-pyridine-2-carbonitrile (146 mg, 0.93 mmol) in DMF (5.00 mL) diethylamine (113 mg, 1.55 mmol) was added at 0° C. The mixture was stirred at 0° C. under a nitrogen atmosphere for 8 h. After diluting with water (20 mL), the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc=10/1˜3/1, Silica-CS 4 g, 12 mL/min, silica gel, UV 254) to give the product (260 mg, 74%, ax/0=0.25:1). ESI-MS m/z calcd for [C.sub.17H.sub.18ClN.sub.5O.sub.6S] [M+H].sup.+: 456.1; found: 456.1
3-Chloro-2-cyano-pyridine-5-yl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0577] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.55 (d, J=2.0 Hz, 1H), 8.08 (d, J=1.6 Hz, 1H), 6.02 (d, J=5.6 Hz, 1H), 5.34 (d, J=2.8 Hz, 1H), 4.37-4.39 (m, 1H), 3.91-4.01 (m, 2H), 3.74 (dd, J=10.4, 3.2 Hz, 1H), 3.49 (s, 3H), 3.32-3.38 (m, 1H), 2.11 (s, 3H), 1.91 (s, 3H).
3-Chloro-2-cyano-pyridine-5-yl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-β-D-galactopyranoside
[0578] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.57 (d, J=2.0 Hz, 1H), 7.30 (d, J=1.6 Hz, 1H), 5.34 (d, J=2.8 Hz, 1H), 4.68 (d, J=9.6 Hz, 1H), 3.91-4.01 (m, 2H), 3.86-3.88 (m, 1H), 3.57 (s, 3H), 3.55-3.36 (m, 1H), 3.32-3.38 (m, 1H), 2.12 (s, 3H), 2.03 (s, 3H).
3-Chloro-2-cyanopyridin-5-yl 4,6-di-O-acetyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0579] ##STR00257##
[0580] To a solution of 3-chloro-2-cyanopyridin-5-yl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-D-galactopyranoside (180 mg, 0.40 mmol) and trimethyl-[2-(3,4,5-tri-fluorophenyl)ethynyl]silane (135 mg, 0.59 mmol) in DMF (3.00 mL) copper(II) sulfate pentahydrate (49.3 mg, 0.20 mmol) and (+)-sodium L-ascorbate (78.2 mg, 0.40 mmol) were added. The mixture was stirred 3 h at rt under nitrogen atmosphere. After diluting with water (20 mL), the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 4 g, 12 m/min, silica gel, UV 254) to give an anomeric mixture of the product. The mixture was separated by preparative-TLC (PE/EtOAc=1/1) to afford the product (25.0 mg, 10%) as a white solid. ESI-MS m/z calcd for [C.sub.25H.sub.21ClF.sub.3N.sub.5O.sub.6S][M+H].sup.+: 612.1; found: 612.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.60 (d, J=2.0 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.72 (s, 1H), 7.40-7.36 (m, 2H), 6.24 (d, J=4.8 Hz, 1H), 5.51 (s, 1H), 4.84-4.81 (m, 2H), 4.61-4.57 (m, 1H), 3.99-4.10 (m, 2H), 3.34 (s, 3H), 2.02 (s, 3H), 1.92 (s, 3H).
Intermediate 47
5-Chloro-2-cyanopyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0581] ##STR00258##
[0582] To a solution of 5-chloro-2-cyanopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (100 mg, 0.20 mmol) in DMF (5 mL) trimethyl-[2-(4-chloro-3,5-difluorophenyl)ethynyl]silane (122 mg, 60%, 0.3 mmol), (+)-sodium L-ascorbate (40 mg, 0.20 mmol) and copper(II) sulfate pentahydrate (50 mg, 0.20 mmol) were added. The mixture was stirred 3 h at rt under nitrogen atmosphere. Water (50 mL) and DCM (50 mL) were added. The aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were washed with water (50 mL) and brine (3×50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 20 g, 20 m/min, silica gel, UV 254) to give the product (100 mg, 79%). ESI-MS m/z calcd for [C.sub.28H.sub.21Cl.sub.2F.sub.2N.sub.5O.sub.4S] [M+H].sup.+: 632.1; found: 632.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.57 (d, J=2.4 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H), 7.99 (s, 1H), 7.47-7.42 (m, 2H), 7.39 (s, 5H), 6.25 (d, J=5.2 Hz, 1H), 5.54 (s, 1H), 5.31 (dd, J=11.2, 3.2 Hz, 1H), 4.59-4.54 (m, 2H), 4.39 (s, 1H), 4.30-4.14 (m, 2H), 3.38 (s, 3H).
Intermediate 48
5-Chloro-2-cyanopyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0583] ##STR00259##
[0584] To a solution of 5-chloro-2-cyanopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (120 mg, 0.26 mmol) and trimethyl-[2-(4-chloro-3-fluorophenyl)ethynyl]silane (101 mg, 70%, 0.31 mmol) in DMF (4 mL) (+)-sodium L-ascorbate (77.5 mg, 0.39 mmol) and copper(II) sulfatepentahydrate (32.6 mg, 0.13 mmol) were added. The mixture was stirred 4 h at rt under a nitrogen atmosphere. After diluting with water (20 mL), the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, and concentrated. The residue was purified by preparative HPLC (Method A) to give the product (97.0 mg, 61%) as a white solid. ESI-MS m/z calcd for [C.sub.28H.sub.22Cl.sub.2FN.sub.5O.sub.4S][M+H].sup.+: 614.1; found: 614.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.95 (s, 1H), 8.76 (d, J=2.4 Hz, 1H), 8.52 (d, J=2.4 Hz, 1H), 7.88-7.81 (m, 1H), 7.75-7.67 (m, 2H), 7.44-7.30 (m, 5H), 6.92 (d, J=5.2 Hz, 1H), 5.60 (s, 1H), 5.22 (dd, J=11.6, 3.2 Hz, 1H), 4.77 (dd, J=11.6, 5.2 Hz, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.30 (s, 1H), 4.12 (d, J=11.6 Hz, 1H), 3.99 (d, J=11.6 Hz, 1H), 3.40 (s, 3H).
Intermediate 49
2-Cyano-5-methylpyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0585] ##STR00260##
2-Bromo-5-methylpyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0586] ##STR00261##
[0587] To a solution of 2-bromo-3-fluoro-5-methylpyridine (300 mg, 1.58 mmol) in DMF (10 mL) Na.sub.2S (246 mg, 3.16 mmol) was added. The mixture was stirred 1 h at 100° C. in a microwave reactor. The mixture cooled to rt and 2,4,6-tri-O-acetyl-3-azido-3-deoxy-α-D-galactopyranosyl chloride (300 mg, 0.858 mmol) and Cs.sub.2CO.sub.3 (559 mg, 1.72 mmol) were added. The mixture was stirred overnight at rt. The mixture was extracted with EtOAc (30 mL) and washed with brine. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (PE/EA=10/1˜5/1, Silica-CS 20 g, 20 m/min, silica gel, UV 254) to afford the crude product. ESI-MS m/z calcd for [C.sub.18H.sub.21BrN.sub.4O.sub.7S] [M+H].sup.+: 517.0; found: 517.0.
2-Bromo-5-methylpyridin-3-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0588] ##STR00262##
[0589] 2-Bromo-5-methylpyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (300 mg, 56%, 0.325 mmol) was dissolved in a mixed solution of MeOH/Et.sub.3N/H.sub.2O (9 mL, 5:3:1). The mixture was stirred overnight at rt. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC (Method A) to afford the product (65.0 mg) as a white solid. ESI-MS m/z calcd for [C.sub.12H.sub.15BrN.sub.4O.sub.4S] [M+H].sup.+: 391.0; found: 391.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.00 (d, J=1.2 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 6.03 (d, J=4.8 Hz, 1H), 5.85 (d, J=5.2 Hz, 1H), 5.30 (d, J=6.0 Hz, 1H), 4.60 (t, J=6.0 Hz, 1H), 4.28 (dt, J=10.8, 5.2 Hz, 1H), 3.89 (m, 2H), 3.47 (m 2H), 3.34 (m, 1H), 2.22 (s, 3H).
2-Bromo-5-methylpyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside
[0590] ##STR00263##
[0591] To a stirred solution of 2-bromo-5-methylpyridin-3-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside (300 mg, 0.77 mmol) in DMF (6 mL) benzaldehyde dimethylacetal (350 mg, 2.30 mmol) was added followed by D(+)-10-camphorsulfonic acid (35.6 mg, 0.15 mmol). The mixture was stirred 3 h at 50° C. under nitrogen atmosphere. The mixture was neutralized with Et.sub.3N and concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc=5/1˜3/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (250 mg, 68%) as a white solid. ESI-MS m/z calcd for [C.sub.19H.sub.19BrN.sub.4O.sub.4S] [M+H].sup.+: 479.0; found: 479.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.04 (d, J=2.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.51-7.49 (m, 2H), 7.42-7.34 (m, 3H), 5.94 (d, J=5.2 Hz, 1H), 5.64 (s, 1H), 4.72-4.62 (m, 1H), 4.41 (d, J=3.2 Hz, 1H), 4.24 (dd, J=13.2, 2.0 Hz, 1H), 4.12-4.10 (m, 2H), 3.68 (dd, J=10.8, 3.2 Hz, 1H), 2.46 (d, J=7.2 Hz, 1H), 2.28 (s, 3H).
2-Bromo-5-methylpyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0592] ##STR00264##
[0593] To a solution of 2-bromo-5-methylpyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (250 mg, 0.52 mmol) and iodomethane (370 mg, 2.61 mmol) in DMF (5 mL) Cs.sub.2CO.sub.3 (510 mg, 1.56 mmol) was added. The mixture was stirred 4 h at rt and then extracted with EtOAc (30 mL). The solvent was removed, and the residue was purified by column chromatography (PE/EtOAc=5/1˜2/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to give the product (180 mg, 70%) as a white solid. ESI-MS m/z calcd for [C.sub.20H.sub.21BrN.sub.4O.sub.4S] [M+H].sup.+: 493.0; found: 493.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.02 (d, J=1.6 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.55-7.48 (m, 2H), 7.41-7.33 (m, 3H), 6.14 (d, J=5.2 Hz, 1H), 5.62 (s, 1H), 4.33 (d, J=3.2 Hz, 1H), 4.28 (dd, J=10.4, 5.2 Hz, 1H), 4.18-4.05 (m, 3H), 3.83 (dd, J=10.4, 3.2 Hz, 1H), 3.57 (s, 3H), 2.27 (s, 3H).
2-Cyano-5-methylpyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0594] ##STR00265##
[0595] To a solution of 2-bromo-5-methylpyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (180 mg, 0.37 mmol) in DMF (10.0 mL) Zn (23.9 mg, 0.37 mmol), Pd.sub.2(dibenzylideneacetone).sub.3, (26.7 mg, 0.029 mmol) Zn(CN).sub.2 (129 mg, 1.09 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (16.5 mg, 0.029 mmol) were added. The mixture was stirred 2.5 h at 100° C. under nitrogen atmosphere. The solvent was removed, and the residue was purified by column chromatography (PE/EtOAc=10/1˜3/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (100 mg, 62%). ESI-MS m/z calcd for [C.sub.21H.sub.21N.sub.5O.sub.4S] [M+H].sup.+: 440.1; found: 440.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.42 (d, J=1.2 Hz, 1H), 7.83 (d, J=0.8 Hz, 1H), 7.49 (m, 2H), 7.40-7.31 (m, 3H), 6.04 (d, J=5.2 Hz, 1H), 5.60 (s, 1H), 4.34 (d, J=2.8 Hz, 1H), 4.25 (dd, J=10.6, 5.2 Hz, 1H), 4.21 (s, 1H), 4.16 (dd, J=12.8, 1.6 Hz, 1H), 4.11 (dd, J=12.8, 1.6 Hz, 1H), 3.78 (dd, J=10.6, 3.2 Hz, 1H), 3.60 (s, 3H), 2.41 (s, 3H).
2-Cyano-5-methylpyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0596] ##STR00266##
[0597] To a solution 2-cyano-5-methylpyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (100 mg, 0.23 mmol) and trimethyl-[2-(4-chloro-3,5-difluorophenyl)ethynyl]silane (60.0%, 111 mg, 0.27 mmol) in DMF (4 mL) (+)-sodium L-ascorbate (67.6 mg, 0.34 mmol) and copper(II) sulfate pentahydrate (28.4 mg, 0.11 mmol) were added. The mixture was stirred 4 h at rt under nitrogen atmosphere before being purified by preparative HPLC (Method A) to give the product (80 mg, 57%) as a white solid. ESI-MS m/z calcd for [C.sub.29H.sub.24ClF.sub.2N.sub.5O.sub.4S] [M+H].sup.+: 612.1; found: 612.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.99 (s, 1H), 8.52 (d, J=1.2 Hz, 1H), 8.18 (d, J=0.8 Hz, 1H), 7.75 (d, J=8.0 Hz, 2H), 7.33 (s, 5H), 6.68 (d, J=5.2 Hz, 1H), 5.58 (s, 1H), 5.20 (dd, J=11.2, 3.2 Hz, 1H), 4.69 (dd, J=11.2, 5.2 Hz, 1H), 4.61 (d, J=3.2 Hz, 1H), 4.34 (s, 1H), 4.13 (d, J=12.0 Hz, 1H), 3.99 (d, J=12.0 Hz, 1H), 3.39 (s, 3H), 2.42 (s, 3H).
Intermediate 50
5-Bromo-2-cyanopyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0598] ##STR00267##
2,5-Dibromopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0599] ##STR00268##
[0600] To a solution of acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (3 g, 7.70 mmol) in DMF (30 mL) 2,5-dibromo-3-fluoropyridine (2.16 g, 8.47 mmol) and diethylamine (1.13 g, 15.4 mmol) were added at 0° C. The mixture was stirred under a nitrogen atmosphere overnight at rt. The mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (2.6 g, 58%). ESI-MS m/z calcd for [C.sub.17H.sub.18Br.sub.2N.sub.4O.sub.7S] [M+H].sup.+: 580.9; found: 581.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.28 (d, J=2.4 Hz, 1H), 7.94 (d, J=2.4 Hz, 1H), 6.12 (d, J=5.6 Hz, 1H), 5.49 (d, J=2.8 Hz, 1H), 5.34 (dd, J=11.2, 5.6 Hz, 1H), 4.53 (dd, J=7.6, 4.8 Hz, 1H), 4.15-4.11 (m, 1H), 4.04-3.98 (m, 2H), 2.20 (s, 3H), 2.17 (s, 3H), 1.97 (s, 3H).
2,5-Dibromopyridin-3-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0601] ##STR00269##
[0602] To a solution of 2,5-dibromopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (2.60 g, 4.47 mmol) in MeOH (30 mL) Et.sub.3N (2 mL) and H.sub.2O (1 mL) were added. The mixture was stirred under a nitrogen atmosphere overnight at rt. The solvent was removed under reduced pressure and the residue was suspended in DCM (50 mL). The solid was collected and washed by DCM and Et.sub.2O. The product (1.10 g, 54%) was obtained as a white solid. ESI-MS m/z calcd for [C.sub.11H.sub.12Br.sub.2N.sub.4O.sub.4S][M+H].sup.+: 454.9; found: 455.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.31 (d, J=2.4 Hz, 1H), 8.20 (d, J=2.4 Hz, 1H), 6.13 (d, J=5.2 Hz, 1H), 6.02 (d, J=5.2 Hz, 1H), 5.33 (d, J=6.0 Hz, 1H), 4.60 (t, J=5.6 Hz, 1H), 4.28 (dt, J=10.4, 5.2 Hz, 1H), 3.90 (dd, J=6.0, 2.4 Hz, 1H), 3.83 (t, J=6.4 Hz, 1H), 3.55-3.44 (m, 2H), 3.35-3.32 (m, 1H).
2,5-Dibromopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside
[0603] ##STR00270##
[0604] To a solution of 2,5-dibromopyridin-3-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside (1.10 g, 2.41 mmol) in DMF (10 mL) benzaldehyde dimethyl acetal (1.1 g, 7.24 mmol) and D(+)-10-camphorsulfonic acid (112 mg, 0.48 mmol) were added. The mixture was stirred under a nitrogen atmosphere 2 h at 50° C. The mixture was cooled to rt and Et.sub.3N (1 mL) was added. The solvent was removed under reduced pressure and the residue was purified by column chromatography (PE/EtOAc=1/1˜1/3, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (1.05 g, 80%) as a white solid. ESI-MS m/z calcd for [C.sub.18H.sub.6Br.sub.2N.sub.4O.sub.4S] [M+H].sup.+: 542.9; found: 543.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.19 (d, J=2.4 Hz, 1H), 7.94 (d, J=2.4 Hz, 1H), 7.48-7.42 (m, 2H), 7.36-7.28 (m, 3H), 5.92 (d, J=5.2 Hz, 1H), 5.59 (s, 1H), 4.64 (dt, J=10.4, 5.2 Hz, 1H), 4.37 (d, J=2.8 Hz, 1H), 4.19 (dd, J=12.8, 1.6 Hz, 1H), 4.08 (dd, J=12.8, 1.6 Hz, 1H), 4.05-4.02 (m, 1H), 3.65 (dd, J=10.8, 3.2 Hz, 1H), 2.42 (d, J=5.6 Hz, 1H).
2,5-Dibromopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0605] ##STR00271##
[0606] To a solution of 2,5-dibromopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (1.05 g, 1.93 mmol) in DMF (10 mL) Cs.sub.2CO.sub.3 (1.86 g, 5.79 mmol) and iodomethane (0.601 mL, 9.65 mmol) were added. The mixture was stirred under a nitrogen atmosphere overnight at rt. The mixture was poured into water (100 mL), the precipitate was collected, and dried in vacuo to afford the product (900 mg, 84%). ESI-MS m/z calcd for [C.sub.19H.sub.18Br.sub.2N.sub.4O.sub.4S] [M+H].sup.+: 556.9; found: 556.8. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.24 (d, J=2.4 Hz, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.55-7.47 (m, 2H), 7.40-7.35 (m, 3H), 6.15 (d, J=5.2 Hz, 1H), 5.63 (s, 1H), 4.36-4.27 (m, 2H), 4.19 (dd, J=12.8, 1.6 Hz, 1H), 4.11-4.05 (m, 1H), 4.05-4.00 (m, 1H), 3.82 (dd, J=10.8, 3.2 Hz, 1H), 3.57 (s, 3H).
5-Bromo-2-cyanopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0607] ##STR00272##
[0608] To a solution of 2,5-dibromopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (400 mg, 0.72 mmol) in DMSO (15 mL) copper(I) cyanide (77.0 mg, 0.86 mmol) was added. The mixture was stirred under a nitrogen atmosphere 2 h at 120° C. in a microwave reactor. The mixture was poured into water (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 4 g, 10 mL/min, silica gel, UV 254) to afford the product (140 mg, 39%) as a white solid. ESI-MS m/z calcd for [C.sub.20H.sub.18BrN.sub.5O.sub.4S] [M+H].sup.+: 504.0; found: 504.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.61 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.53-7.49 (m, 2H), 7.39-7.34 (m, 3H), 6.13 (d, J=5.2 Hz, 1H), 5.62 (s, 1H), 4.35 (d, J=3.2 Hz, 1H), 4.29-4.25 (m, 1H), 4.18-4.08 (m, 3H), 3.77 (dd, J=10.4, 3.2 Hz, 1H), 3.59 (s, 3H).
5-Bromo-2-cyanopyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0609] ##STR00273##
[0610] To a solution of 5-bromo-2-cyanopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (60.0 mg, 0.12 mmol) in DMF (5 mL) trimethyl-[2-(4-chloro-3,5-difluorophenyl)ethynyl]silane (58.2 mg, 0.24 mmol), (+)-sodium L-ascorbate (23.6 mg, 0.12 mmol), copper(II) sulfate pentahydrate (29.7 mg, 0.12 mmol) and CsF (18.1 mg, 0.12 mmol) were added. The mixture was stirred under a nitrogen atmosphere overnight at rt. The mixture was poured into water (50 mL) and extracted with EtOAc (2×80 mL). The organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 4 g, 10 mL/min, silica gel, UV 254) to afford the product (40.0 mg, 50%). ESI-MS m/z calcd for [C.sub.28H.sub.21BrClF.sub.2N.sub.5O.sub.4S][M+H].sup.+: 676.0; found: 675.9. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.68 (d, J=2.0 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.00-7.98 (m, 1H), 7.47-7.43 (m, 2H), 7.43-7.37 (m, 5H), 6.25 (d, J=5.2 Hz, 1H), 5.55 (s, 1H), 5.32 (dd, J=11.2, 3.2 Hz, 1H), 4.61-4.55 (m, 2H), 4.42-4.37 (m, 1H), 4.32-4.27 (m, 1H), 4.20-4.14 (m, 1H), 3.39 (s, 3H).
Intermediate 51
5-Bromo-2-cyanopyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0611] ##STR00274##
[0612] To a solution of 5-bromo-2-cyanopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (60.0 mg, 0.12 mmol) in DMF (5 mL) trimethyl-[2-(4-chloro-3-fluorophenyl)ethynyl]silane (40.5 mg, 0.18 mmol), (+)-sodium L-ascorbate (23.6 mg, 0.12 mmol), copper(II) sulfate pentahydrate (29.7 mg, 0.12 mmol) and CsF (18.1 mg, 0.12 mmol) were added. The mixture was stirred under a nitrogen atmosphere overnight at rt. The mixture was poured into water (50 mL) and extracted with EtOAc (2×80 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 4 g, 10 m/min, silica gel, UV 254) to afford the product (40 mg, 51%). ESI-MS m/z calcd for [C.sub.28H.sub.22BrClFN.sub.5O.sub.4S] [M+H].sup.+: 658.0; found: 658.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.67 (d, J=2.0 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.98 (s, 1H), 7.43-7.36 (m, 8H), 6.24 (d, J=5.2 Hz, 1H), 5.55 (s, 1H), 5.31 (dd, J=11.2, 3.2 Hz, 1H), 4.61-4.53 (m, 2H), 4.40 (s, 1H), 4.31-4.14 (m, 2H), 3.38 (s, 3H).
Intermediate 52
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0613] ##STR00275##
2-(Azetidin-1-ylcarbonyl)-3-bromo-5-chloropyridine
[0614] ##STR00276##
[0615] Azetidine (171 μL, 2.54 mmol) was added to a solution of 3-bromo-5-chloropyridine-2-carboxylic acid (500 mg, 2.11 mmol), 1-hydroxybenzotriazole hydrate (389 mg, 2.54 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (486 mg, 2.54 mmol) in DMF (8 ml) and Et.sub.3N (0.35 mL, 2.54 mmol). After stirring 26 h at rt the mixture was diluted with EtOAc and washed with water. The aqueous phase was extracted with EtOAc and the combined organic phases were dried and evaporated. Purification of the residue by chromatography (SiO.sub.2, PE/EtOAc) yielded the product (264 mg, 45% yield). ESI-MS m/z calcd for [C.sub.9H.sub.8BrClN.sub.20] [M+H].sup.+: 275.0; found: 274.6. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.49-8.46 (m, 1H), 7.97-7.94 (m, 1H), 4.29-4.21 (m, 2H), 4.14-4.07 (m, 2H), 2.40-2.29 (m, 2H).
2-(Azetidin-1-ylcarbonyl)-3-[(2,4-dimethoxyphenyl)methylsulfanyl]-5-chloropyridine
[0616] ##STR00277##
[0617] To a nitrogen purged solution of 2-(azetidin-1-ylcarbonyl)-3-bromo-5-chloropyridine (277 mg, 1.01 mmol), Pd(dibenzylideneacetone).sub.2 (35 mg, 0.060 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (29 mg, 0.050 mmol) in 1,4-dioxane (1 mL) a solution of 2,4-dimethoxybenzyl thiol (278 mg, 1.51 mmol) and DIEA (0.34 mL, 2.00 mmol) in 1,4-dioxane (2 mL) was added and the mixture was stirred 4 h at 100° C. The mixture was purified by chromatography (SiO.sub.2, PE/EtOAc) to yield the product (359 mg, 94%). ESI-MS m/z calcd for [C.sub.18H.sub.19ClN.sub.2O.sub.3S] [M+H].sup.+: 379.1; found: 379.1. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.49 (d, J=2.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.27 (s, 1H), 6.47-6.42 (m, 2H), 4.28 (s, 4H), 4.09 (s, 2H), 3.86 (s, 2H), 3.80 (s, 3H), 2.30 (p, J=7.8 Hz, 2H).
2-(Azetidin-1-ylcarbonyl)-5-chloropyridine-3-thiol
[0618] ##STR00278##
[0619] TFA (1.5 mL) was added to a solution of 2-(azetidin-1-ylcarbonyl)-3-[(2,4-dimethoxyphenyl)methylsulfanyl]-5-chloropyridine (359 mg, 0.95 mmol) in DCM (2 mL) and triethylsilane (1.5 mL) and the mixture was stirred 20 h at rt. The mixture was concentrated and purified by chromatography (SiO.sub.2, PE/EtOAc) to afford the product (199 mg, 92%). ESI-MS m/z calcd for [C.sub.9H.sub.9ClN.sub.2OS] [M+H].sup.+: 229.0; found: 228.7. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.23 (d, J=2.2 Hz, 1H), 7.63 (d, J=2.2 Hz, 1H), 4.41 (br s, 5H), 2.34 (p, J=7.8 Hz, 2H).
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0620] ##STR00279##
[0621] NaH (60% in oil, 70 mg, 1.81 mmol) was added to a solution of 2-(azetidin-1-ylcarbonyl)-5-chloropyridine-3-thiol (166 mg, 0.73 mmol) and 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (317 mg, 0.91 mmol) in DMF (6 mL) and the mixture was stirred 6 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 the product (315 mg, 67% yield). ESI-MS m/z calcd for [C.sub.21H.sub.24ClN.sub.5O.sub.8S] [M+H].sup.+: 542.1; found: 541.9. .sup.1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J=2.0 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 6.06 (d, J=5.6 Hz, 1H), 5.45 (d, J=2.8 Hz, 1H), 5.33 (dd, J=11.0, 5.6 Hz, 1H), 4.62-4.49 (m, 2H), 4.45-4.36 (m, 1H), 4.24 (t, J=7.7 Hz, 2H), 4.15-4.00 (m, 4H), 2.35 (p, J=7.7 Hz, 2H), 2.16 (s, 6H), 1.91 (s, 3H).
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0622] ##STR00280##
[0623] 5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (275 mg, 0.51 mmol) was dissolved in MeOH (10 mL), Et.sub.3N (1.5 mL) and water (0.5 mL) and stirred 24 h at rt. The mixture was concentrated and purified by preparative HPLC (Method B) to afford the product (206 mg, 98%). ESI-MS m/z calcd for [C.sub.15H.sub.18ClN.sub.5O.sub.5S] [M+H].sup.+: 416.1; found: 415.8. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.41 (d, J=2.1 Hz, 1H), 8.30 (d, J=2.1 Hz, 1H), 5.83 (d, J=5.5 Hz, 1H), 4.41 (dd, J=10.8, 5.4 Hz, 1H), 4.26-4.14 (m, 5H), 4.04 (d, J=2.2 Hz, 1H), 3.72-3.61 (m, 2H), 3.56 (dd, J=10.8, 3.0 Hz, 1H), 2.38 (p, J=7.8 Hz, 2H).
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0624] ##STR00281##
[0625] 5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside (200 mg, 0.48 mmol) was dissolved in MeCN (20 mL), p-toluenesulfonic acid monohydrate (92 mg, 0.48 mmol) followed by benzaldehyde dimethyl acetal (0.15 mL, 0.96 mmol) were added and the mixture was stirred 2 h at rt. Et.sub.3N (0.1 mL, 0.72 mmol) was added and the mixture was concentrated. The residue was partitioned between EtOAc and saturated aq NaHCO.sub.3. The organic phase was washed with brine, dried and evaporated. The residue and NaH (60% in oil, 37 mg, 0.96 mmol) were dissolved in DMF (3 mL) and stirred 5 min before the addition of iodomethane (45 μL, 0.72 mmol). After stirring 2 h at rt the mixture was diluted with EtOAc, washed twice with water and the organic phase was dried and evaporated. The residue was stirred 1 h at rt in TFA/water (2.5 mL, 4:1). The mixture was purified by preparative HPLC (Method B) to afford the product (45 mg, 22%). ESI-MS m/z calcd for [C.sub.16H.sub.20ClN.sub.5O.sub.5S] [M+H].sup.+: 430.1; found: 429.9. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.44 (d, J=2.1 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H), 6.15 (d, J=5.4 Hz, 1H), 4.26-4.14 (m, 5H), 4.06 (dd, J=10.6, 5.4 Hz, 1H), 3.99 (d, J=2.6 Hz, 1H), 3.69-3.59 (m, 3H), 3.52 (s, 3H), 2.39 (p, J=7.8 Hz, 2H).
Intermediate 54
5-(2-Trimethylsilyl-1-ethynyl)-pyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0626] ##STR00282##
[0627] 5-Bromopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (174 mg, 0.30 mmol), bis(triphenylphosphine)palladium(II) chloride (22 mg, 0.03 mmol) and CuI (6.0 mg, 0.03 mmol) were evacuated and purged with nitrogen. THF (3.0 mL) followed by trimethylsilylacetylene (65 μL, 0.45 mmol) and DIEA (79 μL, 0.45 mmol) were added and the mixture was stirred 18 h at 50° C. Concentration and purification by chromatography (SiO.sub.2, PE/EtOAc) gave the product (150 mg, 86%). ESI-MS m/z calcd for [C.sub.25H.sub.27ClF.sub.2N.sub.4O.sub.4SSi] [M+H].sup.+: 581.1; found: 580.9. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.68 (s, 1H), 8.64 (s, 1H), 8.51 (s, 1H), 8.14 (s, 1H), 7.66 (d, J=8.2 Hz, 2H), 6.25 (d, J=5.3 Hz, 1H), 5.05 (dd, J=11.3, 2.4 Hz, 1H), 4.64 (dd, J=11.3, 5.2 Hz, 1H), 4.47 (t, J=6.0 Hz, 1H), 4.19 (s, 1H), 3.75-3.63 (m, 2H), 3.41 (s, 3H), 0.27 (s, 9H).
Intermediate 55
5-Chloro-2-cyanopyridin-3-yl 4,6-O-benzylidene-3-[4-(5-chloro-6-fluoropyridin-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0628] ##STR00283##
3-Chloro-2-fluoro-6-[2-(trimethylsilyl)ethynyl]pyridine
[0629] ##STR00284##
[0630] To a solution of 6-bromo-3-chloro-2-fluoro-pyridine (200 mg, 0.95 mmol) and trimethylsilylacetylene (140 mg, 1.43 mmol) in DMF (4 mL) CuI (9.05 mg, 0.048 mmol), bis(triphenylphosphine)palladium(II) dichloride (33.4 mg, 0.048 mmol) and DIEA (0.325 mL, 1.90 mmol) were added. The mixture was stirred overnight at rt under a nitrogen atmosphere. The solvent was removed, and the residue was purified by column chromatography (PE/EtOAc=20/1) to afford the product (165 mg, 76%). GC-MS calcd for [C.sub.10H.sub.11ClFNSi] [M]: 227.0; found: 227.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.77 (dd, J=8.8, 6.8 Hz, 1H), 6.86 (dd, J=8.8, 3.6 Hz, 1H), 0.28 (s, 9H).
5-Chloro-2-cyanopyridin-3-yl 4,6-O-benzylidene-3-[4-(5-chloro-6-fluoropyridin-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0631] ##STR00285##
[0632] To a solution of 5-chloro-2-cyanopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (120 mg, 0.26 mmol) 3-chloro-2-fluoro-6-[2-(trimethylsilyl)ethynyl]pyridine (71.3 mg, 0.31 mmol) in DMF (4 mL) (+)-sodium L-ascorbate (77.5 mg, 0.39 mmol) and copper(II) sulfatepentahydrate (32.6 mg, 0.13 mmol) were added. The mixture was stirred 4 h at rt under a nitrogen atmosphere. After diluting with water (20 mL), the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, and concentrated. The residue was purified by preparative HPLC (Method A) to give the product (125 mg, 78%) as a white solid. ESI-MS m/z calcd for [C.sub.27H.sub.21Cl.sub.2FN.sub.6O.sub.4S][M+H].sup.+: 615.1; found: 615.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.93 (s, 1H), 8.75 (d, J=2.0 Hz, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.22 (dd, J=8.8, 7.2 Hz, 1H), 7.47-7.40 (m, 2H), 7.40-7.33 (m, 3H), 7.27 (dd, J=8.8, 3.6 Hz, 1H), 6.89 (d, J=5.2 Hz, 1H), 5.64 (s, 1H), 5.29 (dd, J=11.6, 3.2 Hz, 1H), 4.92 (dd, J=11.6, 5.2 Hz, 1H), 4.66 (d, J=3.2 Hz, 1H), 4.29 (s, 1H), 4.12 (d, J=11.6 Hz, 1H), 3.99 (d, J=11.6 Hz, 1H), 3.36 (s, 3H).
Intermediate 56
2-Cyano-5-(2-trimethylsilyl-1-ethynyl)-pyridin-3-yl 4,6-di-O-acetyl-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0633] ##STR00286##
4,6-Di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranose
[0634] ##STR00287##
[0635] Boron trifluoride diethyl etherate (0.96 mL, 7.78 mmol) was added to acetyl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-D-galactopyranoside (895 mg, 2.59 mmol) in DCM (18 mL) and the mixture was subjected to H.sub.2S (1 atm). The mixture was stirred vigorously for 21 h. Water (100 mL) was added and the mixture was extracted with DCM (3×100 mL). The combined organic phases were dried and concentrated. Purification by chromatography (SiO.sub.2, PE/EtOAc) yielded the product (324 mg, 39%). ESI-MS m/z calcd for [C.sub.11H.sub.21NO.sub.6S] [M+NH.sub.4].sup.+: 337.0; found: 337.1, .sup.1H NMR (400 MHz, Chloroform-d) δ 5.96 (t, J=3.9 Hz, 1H), 5.40-5.34 (m, 1H), 4.55 (t, J=6.3 Hz, 1H), 4.13 (dd, J=12.0, 6.7 Hz, 1H), 4.01 (dd, J=12.0, 7.4 Hz, 1H), 3.84 (dd, J=10.4, 4.8 Hz, 1H), 3.78 (dd, J=10.3, 2.8 Hz, 1H), 3.51 (s, 3H), 2.16 (s, 3H), 2.07 (s, 3H), 1.85 (d, J=3.8 Hz, 1H).
5-Bromo-2-cyanopyridin-3-yl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0636] ##STR00288##
[0637] DIEA (261 μL, 1.52 mmol) was added to 5-bromo-3-fluoropyridine-2-carbonitrile (245 mg, 1.22 mmol) and 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranose (324 mg, 1.01 mmol) in DMF (4 mL). The mixture was stirred 30 min at rt before it was diluted with EtOAc (40 mL) and washed with HCl (1 M, 40 mL), water (3×40 mL) and brine (40 mL). The organic phase was dried and concentrated. Purification by chromatography (SiO.sub.2, PE/EtOAc) yielded the product (465 mg, 92%). ESI-MS m/z calcd for [C.sub.17H.sub.18BrN.sub.4O.sub.6S] [M+H].sup.+: 500.0; found: 499.8, .sup.1H NMR (500 MHz, Chloroform-d) δ 8.67-8.62 (m, 1H), 8.22-8.18 (m, 1H), 6.11 (d, J=5.3 Hz, 1H), 5.42 (d, J=3.1 Hz, 1H), 4.49 (dd, J=7.3, 5.0 Hz, 1H), 4.05 (dd, J=11.7, 4.7 Hz, 1H), 4.00 (dd, J=9.8, 4.8 Hz, 1H), 3.97 (dd, J=10.9, 6.9 Hz, 1H), 3.86 (dd, J=10.4, 3.2 Hz, 1H), 3.61 (s, 3H), 2.16 (s, 3H), 1.97 (s, 3H).
5-Bromo-2-cyanopyridin-3-yl 4,6-di-O-acetyl-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0638] ##STR00289##
[0639] DIEA (79.4 μL, 464 μmol) was added to 5-bromo-2-cyanopyridin-3-yl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (232 mg, 464 μmol), trimethyl-[2-(4-chloro-3,5-difluorophenyl)ethynyl]silane (96.0 mg, 556 μmol) and CuI (8.8 mg, 46.4 mmol) in MeCN (4.64 mL). After 19 h at 40° C., the mixture was filtered through a plug of celite and concentrated. Purification by chromatography (SiO.sub.2, PE/EtOAc) yielded the product (277 mg, 89%). ESI-MS m/z calcd for [C.sub.26H.sub.22BrClF.sub.2N.sub.5O.sub.6S] [M+H].sup.+: 672.0; found: 672.0, .sup.1H NMR (400 MHz, Chloroform-d) δ 8.70 (d, J=2.0 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.87 (s, 1H), 7.50-7.43 (m, 2H), 6.34 (d, J=3.9 Hz, 1H), 5.60 (s, 1H), 4.97-4.91 (m, 2H), 4.71 (t, J=6.4 Hz, 1H), 4.12-4.01 (m, 2H), 3.47 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H).
2-Cyano-5-(2-trimethylsilyl-1-ethynyl)-pyridin-3-yl 4,6-di-O-acetyl-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0640] ##STR00290##
[0641] 5-Bromo-2-cyanopyridin-3-yl 4,6-di-O-acetyl-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (85 mg, 126 μmol) and trimethylsilylacetylene (52.5 μL, 379 μmol) were added to bis(triphenylphosphine)palladium(II) chloride (4.6 mg, 6.3 μmol) and CuI (2.4 mg, 12.6 μmol) in THF (0.50 mL) and Et.sub.3N (83.1 μL, 632 μmol). After 1.5 h the mixture was concentrated. Purification by chromatography (SiO.sub.2, PE/EtOAc) yielded the product (72.0 mg, 83%). ESI-MS m/z calcd for [C.sub.30H.sub.31ClF.sub.2N.sub.5O.sub.6SSi] [M+H].sup.+: 690.1; found: 690.0, .sup.1H NMR (500 MHz, Chloroform-d) δ 8.66 (d, J=1.8 Hz, 1H), 8.10 (d, J=1.8 Hz, 1H), 7.88 (s, 1H), 7.52-7.43 (m, 2H), 6.35 (d, J=5.1 Hz, 1H), 5.62 (d, J=2.0 Hz, 1H), 4.98 (dd, J=11.0, 2.8 Hz, 1H), 4.92 (dd, J=11.0, 5.2 Hz, 1H), 4.75 (dd, J=7.0, 5.3 Hz, 1H), 4.11 (dd, J=11.7, 5.0 Hz, 1H), 4.06 (dd, J=11.7, 7.5 Hz, 1H), 3.49 (s, 3H), 2.10 (s, 3H), 1.99 (s, 3H), 0.31 (s, 9H).
Intermediate 57
2-Cyano-5-(2-trimethylsilyl-1-ethynyl)-pyridin-3-yl 4,6-di-O-acetyl-3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0642] ##STR00291##
5-Bromo-2-cyanopyridin-3-yl 4,6-di-O-acetyl-3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0643] ##STR00292##
[0644] DIEA (79.4 μL, 464 μmol) was added to 5-bromo-2-cyanopyridin-3-yl 4,6-di-O-acetyl-3-azido-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (232 mg, 464 μmol), trimethyl-[2-(3,5-difluoro-4-methylphenyl)ethynyl]silane (84.7 mg, 556 μmol) and CuI (8.8 mg, 46.4 mmol) in MeCN (4.64 mL). After 25 h at rt, the mixture was filtered through a plug of celite and concentrated. Purification by chromatography (SiO.sub.2, PE/EtOAc) yielded the product (259 mg, 86%). ESI-MS m/z calcd for [C.sub.26H.sub.25BrF.sub.2N.sub.5O.sub.6S] [M+H].sup.+: 652.1; found: 652.0, .sup.1H NMR (400 MHz, Chloroform-d) δ 8.69 (d, J=2.0 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.82 (s, 1H), 7.33 (d, J=7.7 Hz, 2H), 6.34 (d, J=3.6 Hz, 1H), 5.61 (s, 1H), 4.95-4.91 (m, 2H), 4.70 (t, J=6.2 Hz, 1H), 4.12-4.08 (m, 1H), 4.04 (dd, J=11.7, 7.3 Hz, 1H), 3.46 (s, 3H), 2.23 (s, 3H), 2.09 (s, 3H), 1.98 (s, 3H).
2-Cyano-5-(2-trimethylsilyl-1-ethynyl)-pyridin-3-yl 4,6-di-O-acetyl-3-deoxy-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0645] ##STR00293##
[0646] 5-Bromo-2-cyanopyridin-3-yl 4,6-di-O-acetyl-3-[4-(3,5-difluoro-4-methylphenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (100 mg, 153 μmol) and trimethylsilylacetylene (63.7 μL, 460 μmol) were added to bis(triphenylphosphine)palladium(II) chloride (5.6 mg, 7.7 μmol) and CuI (2.9 mg, 15.3 μmol) in THF (0.50 mL) and Et.sub.3N (105 μL, 766 μmol). After 1 h the mixture was concentrated. Purification by chromatography (SiO.sub.2, PE/EtOAc) yielded the product (93.0 mg, 91%). ESI-MS m/z calcd for [C.sub.31H.sub.34F.sub.2N.sub.5O.sub.6SSi] [M+H].sup.+: 670.2; found: 670.2, .sup.1H NMR (500 MHz, Chloroform-d) δ 8.64 (s, 1H), 8.08 (d, J=1.4 Hz, 1H), 7.82 (s, 1H), 7.32 (d, J=5.4 Hz, 2H), 6.33 (d, J=5.1 Hz, 1H), 5.65-5.55 (m, 1H), 4.95 (s, 1H), 4.89 (dd, J=10.9, 5.2 Hz, 1H), 4.77-4.66 (m, 1H), 4.09-4.06 (m, 1H), 4.04 (dd, J=11.7, 7.5 Hz, 1H), 3.46 (s, 3H), 2.22 (s, 3H), 2.07 (s, 3H), 1.97 (s, 3H), 0.29 (s, 9H).
Intermediate 58
5-Cyano-6-trifluoromethylpyridin-3-yl 3-azido3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0647] ##STR00294##
5-Fluoro-2-(trifluoromethyl)pyridine-3-carbonitrile
[0648] ##STR00295##
[0649] CuCN (91.8 mg, 1.02 mmol) was added to 3-bromo-5-fluoro-2-(trifluoromethyl)pyridine (200 mg, 0.82 mmol) in DMSO (0.80 mL) and the mixture was heated to 150° C. After 2 h, the mixture was cooled to rt. EtOAc (20 mL) and water (20 mL) were added and the resulting suspension was filtered. The organic phase was dried and concentrated to afford the product (147 mg, 94%). .sup.1H NMR (400 MHz, Chloroform-d) δ 8.78 (d, J=2.6 Hz, 1H), 7.92 (dd, J=7.1, 2.5 Hz, 1H).
5-Cyano-6-trifluoromethylpyridin-3-yl 2,4,6-tri-O-acetyl-3-azido3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0650] ##STR00296##
[0651] Et.sub.2NH (198 μL, 191 mmol) was added to a solution of acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (350 mg, 0.76 mmol) and 5-fluoro-2-(trifluoromethyl)pyridine-3-carbonitrile (145 mg, 0.76 mmol) in DMF (3 mL) at 0° C. The mixture was allowed to reach rt and then stirred for 30 min before it was diluted with EtOAc (30 mL) and washed with HCl (0.2 M, 30 mL), water (3×30 mL) and brine (30 mL). The organic phase was dried and concentrated. Purification by chromatography (SiO.sub.2, PE/EtOAc) yielded the product (241 mg, 61%). ESI-MS m/z calcd for [C.sub.19H.sub.19F.sub.3N.sub.5O.sub.7S] [M+H].sup.+: 518.1; found: 517.9, .sup.1H NMR (400 MHz, Chloroform-d) δ 8.88 (d, J=2.1 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 6.18 (d, J=5.5 Hz, 1H), 5.51 (d, J=2.9 Hz, 1H), 5.34 (dd, J=10.9, 5.5 Hz, 1H), 4.54 (dd, J=8.0, 4.1 Hz, 1H), 4.16 (dd, J=11.8, 4.4 Hz, 1H), 4.03 (dd, J=11.8, 8.0 Hz, 1H), 3.98 (dd, J=10.9, 3.3 Hz, 1H), 2.21 (s, 3H), 2.20 (s, 3H), 2.00 (s, 3H).
5-Cyano-6-trifluoromethylpyridin-3-yl 3-azido3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0652] ##STR00297##
[0653] 5-Cyano-6-trifluoromethylpyridin-3-yl 2,4,6-tri-O-acetyl-3-azido3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (242 mg, 0.47 mmol) was dissolved in MeOH (20 mL) and NaOMe (1M, 234 μL) was added. After 45 min the reaction was quenched with AcOH (50 μL) and concentrated. Water (10 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried and concentrated. The crude was dissolved in MeCN (25 mL). Benzaldehyde dimethyl acetal (140 μL, 0.94 mmol) and p-toluenesulfonic acid monohydrate (26.7 mg, 0.14 mmol) were added. After 1.5 h the reaction was quenched with Et.sub.3N (50 μL) and concentrated. The material was dissolved in EtOAc (25 mL) and washed with saturated aq NaHCO.sub.3 (25 mL) and brine (25 mL). The organic phase was dried, concentrated and the residue was purified by chromatography (SiO.sub.2, PE/EtOAc). The obtained material was dissolved in DCM (3 mL). Proton sponge (301 mg, 1.40 mmol) and trimethyloxonium tetrafluoroborate (138 mg, 0.94 mmol) were added. The reaction was stirred 18 h at rt before it was quenched with MeOH and concentrated. HCl (1 M, 20 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were dried and concentrated. TFA (3.35 mL) and water (0.75 mL) were added. After 1 h the mixture was concentrated to ˜1/3 of its volume and NaOH (1 M, 10 mL) was added. The mixture was basified using NaOH (5 M) and extracted with EtOAc (2×10 mL). The combined organic phases were dried and concentrated. Purification by chromatography (SiO.sub.2, PE/EtOAc) yielded the product (107 mg, 56%). ESI-MS m/z calcd for [C.sub.14H.sub.15F.sub.3N.sub.5O.sub.4S] [M+H].sup.+: 406.1; found: 405.9, .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.97 (s, 1H), 8.61 (s, 1H), 6.37 (d, J=5.3 Hz, 1H), 4.15-4.09 (m, 2H), 3.98 (d, J=2.2 Hz, 1H), 3.72-3.60 (m, 3H), 3.54 (s, 3H).
Intermediate 59
5-Cyanopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0654] ##STR00298##
5-Bromopyridin-3-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0655] ##STR00299##
[0656] To a solution of 5-bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (1.2 g, 2.38 mmol) in MeOH (20 mL) Et.sub.3N (1.99 mL, 14.3 mmol) and water (1 mL) were added. The solvent was removed under reduced pressure, and the residue was washed by DCM (20 mL) to give the product (700 mg, 78%). ESI-MS m/z calcd for [C.sub.11H.sub.13BrN.sub.4O.sub.4S] [M+H].sup.+: 377.0; found: 377.2. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.61 (d, J=2.0 Hz, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.25 (t, J=2.0 Hz, 1H), 5.72 (d, J=5.2 Hz, 1H), 4.38 (dd, J=10.8, 5.2 Hz, 1H), 4.30-4.20 (m, 1H), 4.06-4.00 (m, 1H), 3.70-3.58 (m, 2H), 3.52 (dd, J=10.8, 3.2 Hz, 1H).
5-Bromopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside
[0657] ##STR00300##
[0658] To a solution of 5-bromopyridin-3-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside (0.700 g, 1.86 mmol) in DMF (10 mL) benzaldehyde dimethyl acetal (847 mg, 5.57 mmol) and D(+)-10-camphorsulfonic acid (129 mg, 0.557 mmol) were added. The mixture was stirred 2 h under a nitrogen atmosphere at 50° C. The mixture was cooled to rt and poured into water. The solid was collected and dried in vacuum to the product (650 mg, 75%). ESI-MS m/z calcd for [C.sub.18H.sub.17BrN.sub.4O.sub.4S] [M+H].sup.+: 465.0; found: 465.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.59-8.54 (m, 2H), 8.18 (t, J=2.0 Hz, 1H), 7.42-7.33 (m, 5H), 6.20 (d, J=5.2 Hz, 1H), 6.02 (d, J=5.2 Hz, 1H), 5.66 (s, 1H), 4.41 (d, J=3.2 Hz, 1H), 4.33-4.25 (m, 1H), 4.10-4.05 (m, 1H), 4.00 (s, 1H), 3.89-3.82 (m, 1H), 3.67 (dd, J=10.8, 3.2 Hz, 1H).
5-Bromopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0659] ##STR00301##
[0660] To a solution of 5-bromopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (400 mg, 0.86 mmol) in DMF (10 mL) sodium hydride (60% in oil, 68.8 mg, 1.72 mmol) was added at 0° C. After 20 min, iodomethane (0.214 mL, 3.44 mmol) was added. The mixture was stirred 30 min under a nitrogen atmosphere at rt. The mixture was poured into water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (PE/EtOAc=3/1˜1/1, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (350 mg, 85%). ESI-MS m/z calcd for [C.sub.19H.sub.19BrN.sub.4O.sub.4S] [M+H].sup.+: 479.0; found: 479.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.62-8.57 (m, 2H), 8.27-8.21 (m, 1H), 7.50-7.30 (m, 5H), 6.42 (d, J=5.2 Hz, 1H), 5.67 (s, 1H), 4.41 (d, J=2.8 Hz, 1H), 4.13-3.98 (m, 3H), 3.90-3.74 (m, 2H), 3.44 (s, 3H).
5-Cyanopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0661] ##STR00302##
[0662] To a solution of 5-bromopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (500 mg, 1.04 mmol) in DMF (10 mL) Zn (68.2 mg, 1.04 mmol), Zn(CN).sub.2 (368 mg, 3.13 mmol), 1,1′-bis(diphenylphosphino)ferrocene (58.9 mg, 0.10 mmol) and Pd.sub.2(dibenzylideneacetone).sub.3 (95.4 mg, 0.104 mmol) were added. The mixture was stirred 2.5 h at 100° C. under a nitrogen atmosphere. After diluting with water (20 mL), the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc=10/1˜2/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (200 mg, 45%). ESI-MS m/z calcd for [C.sub.20H.sub.19N.sub.5O.sub.4S] [M+H].sup.+: 426.1; found: 426.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.83 (d, J=2.4 Hz, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.07 (t, J=2.0 Hz, 1H), 7.55-7.48 (m, 2H), 7.41-7.33 (m, 3H), 6.08 (d, J=5.2 Hz, 1H), 5.62 (s, 1H), 4.34 (d, J=2.8 Hz, 1H), 4.26 (dd, J=10.8, 5.2 Hz, 1H), 4.21 (dd, J=12.8, 1.6 Hz, 1H), 4.12 (dd, J=12.8, 1.6 Hz, 1H), 4.05 (s, 1H), 3.71 (dd, J=10.8, 3.6 Hz, 1H), 3.56 (s, 3H).
5-Cyanopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0663] ##STR00303##
[0664] To a solution of 5-cyanopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (80.0 mg, 0.19 mmol) and trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (51.5 mg, 0.23 mmol) in DMF (4.0 mL) (+)-sodium L-ascorbate (55.9 mg, 0.28 mmol) and copper(II) sulfate pentahydrate (23.5 mg, 0.094 mmol). The mixture was stirred 4 h at rt under a nitrogen atmosphere. After diluting with water (20 mL), the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by preparative HPLC (Method A) to give the product (80.0 mg, 73%) as a white solid. ESI-MS m/z calcd for [C.sub.28H.sub.22F.sub.3N.sub.5O.sub.4S] [M+H].sup.+: 582.1; found: 582.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.89 (d, J=2.0 Hz, 1H), 8.77 (d, J=1.6 Hz, 1H), 8.13 (t, J=2.0 Hz, 1H), 7.97 (s, 1H), 7.50-7.36 (m, 7H), 6.22 (d, J=5.2 Hz, 1H), 5.54 (s, 1H), 5.31 (dd, J=11.2, 3.2 Hz, 1H), 4.61-4.50 (m, 2H), 4.35-4.27 (m, 2H), 4.19-4.13 (m, 1H), 3.33 (s, 3H).
Intermediate 60
5-Cyanopyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0665] ##STR00304##
[0666] To a solution of 5-cyanopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (80.0 mg, 0.19 mmol) and trimethyl-[2-(4-chloro-3,5-difluorophenyl)ethynyl]silane (69.0 mg, 0.28 mmol) in DMF (4 mL) (+)-sodium L-ascorbate (55.9 mg, 0.28 mmol) and copper(II) sulfate pentahydrate (23.5 mg, 0.094 mmol) were added. The mixture was stirred 4 h at rt under a nitrogen atmosphere. After diluting with water (20 mL), the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (80.0 mg, 71%). ESI-MS m/z calcd for [C.sub.28H.sub.22ClF.sub.2N.sub.5O.sub.4S] [M+H].sup.+: 598.1; found: 598.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.02-8.70 (m, 2H), 8.14-8.09 (m, 1H), 8.01-7.94 (m, 1H), 7.46-7.40 (m, 7H), 6.21 (d, J=5.2 Hz, 1H), 5.55 (s, 1H), 5.31 (dd, J=11.2, 3.2 Hz, 1H), 4.58-4.47 (m, 2H), 4.33-4.27 (m, 2H), 4.20-4.11 (m, 1H), 3.33 (s, J=10.6 Hz, 3H).
Intermediate 61
5-Bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0667] ##STR00305##
5-Bromo-2-cyanopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0668] ##STR00306##
[0669] To a solution of acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (4.00 g, 10.3 mmol) in DMF (30 mL) 5-bromo-3-fluoro-pyridine-2-carbonitrile (4.13 g, 20.5 mmol) and N-ethylethanamine (1.50 g, 20.5 mmol) were added at 0° C. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was poured into water (150 mL) and extracted with EtOAc (200 mL). The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (3.0 g, 55%). ESI-MS m/z calcd for [C.sub.18H.sub.18BrN.sub.5O.sub.7S] [M+H].sup.+: 528.0; found: 528.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.66 (d, J=2.0 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 6.11 (d, J=5.6 Hz, 1H), 5.52 (d, J=2.4 Hz, 1H), 5.31 (dd, J=11.2, 5.6 Hz, 1H), 4.60 (dd, J=7.2, 4.8 Hz, 1H), 4.17-4.11 (m, 1H), 4.04-3.98 (m, 2H), 2.24 (s, 3H), 2.18 (s, 3H), 2.02 (s, 3H).
5-Bromo-2-cyanopyridin-3-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0670] ##STR00307##
[0671] To a solution of 5-bromo-2-cyanopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (3.00 g, 5.68 mmol) in MeOH (50 mL) Et.sub.3N (3.96 mL, 28.4 mmol) and water (2 mL) were added. The mixture was stirred 16 h at rt. The solvent was removed under reduced pressure and the obtained residue was washed by DCM (20 mL). The solid was collected and dried in vacuum to afford the product (1.80 g, 79%) as a white solid. ESI-MS m/z calcd for [C.sub.12H.sub.12BrN.sub.5O.sub.4S] [M+H].sup.+: 402.0; found: 402.1. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.62 (d, J=2.0 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 6.01 (d, J=5.2 Hz, 1H), 4.43 (dd, J=10.8, 5.2 Hz, 1H), 4.13 (t, J=6.0 Hz, 1H), 4.04 (d, J=2.4 Hz, 1H), 3.65-3.58 (m, 3H).
5-Bromo-2-cyanopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside
[0672] ##STR00308##
[0673] To a solution of 5-bromo-2-cyanopyridin-3-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside (1.80 g, 4.48 mmol) in DMF (10 mL) benzaldehyde dimethyl acetal (2.04 g, 13.4 mmol) and D(+)-10-camphorsulfonic acid (312 mg, 1.34 mmol) were added. The mixture was stirred under a nitrogen atmosphere 2 h at 50° C. The mixture was cooled to rt and poured into water. The solid was collected and dried in vacuum to give the product (2.0 g, 91%). ESI-MS m/z calcd for [C.sub.19H.sub.16BrN.sub.5O.sub.4S] [M+H].sup.+: 490.0; found: 490.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.61 (d, J=2.0 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 7.52-7.47 (m, 2H), 7.39-7.34 (m, 3H), 5.93 (d, J=5.2 Hz, 1H), 5.64 (s, 1H), 4.67 (dd, J=10.8, 5.2 Hz, 1H), 4.43 (d, J=2.4 Hz, 1H), 4.23-3.89 (m, 3H), 3.67 (dd, J=10.8, 3.2 Hz, 1H).
5-Bromo-2-carboxypyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside
[0674] ##STR00309##
[0675] To a solution of 5-bromo-2-cyanopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (2.00 g, 4.08 mmol) in EtOH (80 mL) and water (40 mL) NaOH (2.45 mg, 61.2 mmol) was added. The mixture was kept stirring overnight at 80° C. Then EtOH was removed under reduced pressure. The mixture was acidified by 1M HCl to pH=6. The mixture was filtered, and the solid was dried in vacuum to give the product (1.20 g, 58%). ESI-MS m/z calcd for [C.sub.19H.sub.17BrN.sub.4O.sub.6S] [M+H].sup.+: 509.0; found: 509.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.46 (s, 1H), 8.16 (s, 1H), 7.50-7.26 (m, 5H), 5.87 (d, J=5.2 Hz, 1H), 5.64 (s, 1H), 4.49-3.65 (m, 7H).
5-Bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside
[0676] ##STR00310##
[0677] To a solution of 5-bromo-2-carboxypyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (1.00 g, 1.96 mmol) in DMF (10 mL) azetidine hydrochloride (367 mg, 3.93 mmol), DIEA (1.68 mL, 9.82 mmol) and HATU (1344 mg, 3.53 mmol) were added. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=1/1˜0/1, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (620 mg, 58%). ESI-MS m/z calcd for [C.sub.22H.sub.22BrN.sub.5O.sub.5S] [M+H].sup.+: 548.1; found: 548.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.52 (d, J=2.0 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 7.45-7.34 (m, 5H), 6.07 (d, J=5.2 Hz, 1H), 5.67 (s, 1H), 4.50-3.64 (m, 11H), 2.26 (dt, J=15.2, 7.6 Hz, 2H).
5-Bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0678] ##STR00311##
[0679] To a solution of 5-bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (440 mg, 0.80 mmol) in DMF (5 mL) Cs.sub.2CO.sub.3 (523 mg, 1.60 mmol) and iodomethane (0.321 mL, 4.41 mmol) were added. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (250 mg, 55%). ESI-MS m/z calcd for [C.sub.23H.sub.24BrN.sub.5O.sub.5S] [M+H].sup.+: 562.1; found: 562.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.41 (d, J=2.0 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.55-7.49 (m, 2H), 7.42-7.32 (m, 3H), 6.08 (d, J=5.2 Hz, 1H), 5.61 (s, 1H), 4.32-4.06 (m, 9H), 3.87 (dd, J=10.8, 3.2 Hz, 1H), 3.54 (s, J=4.0 Hz, 3H), 2.47-2.21 (m, 2H).
5-Bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0680] ##STR00312##
[0681] To a solution of 5-bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (110 mg, 0.20 mmol) in DMF (4 mL) were added trimethyl-[2-(4-chloro-3-fluorophenyl)ethynyl]silane (66.5 mg, 0.29 mmol), copper(II) sulfate pentahydrate (47.6 mg, 0.19 mmol) and (+)-sodium L-ascorbate (37.8 mg, 0.19 mmol). The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 4 g, 10 mL/min, silica gel, UV 254) to afford the product (60 mg, 43%). ESI-MS m/z calcd for [C.sub.31H.sub.28BrClFN.sub.5O.sub.5S] [M+H].sup.+: 716.1; found: 716.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.44 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 8.04 (s, 1H), 7.63 (dd, J=10.0, 1.6 Hz, 1H), 7.54 (dd, J=8.4, 1.6 Hz, 1H), 7.48-7.39 (m, 1H), 7.39-7.30 (m, 5H), 6.27 (d, J=5.2 Hz, 1H), 5.49 (s, 1H), 5.40 (dd, J=11.2, 3.2 Hz, 1H), 4.61 (dd, J=11.2, 5.2 Hz, 1H), 4.51 (d, J=2.8 Hz, 1H), 4.42-4.06 (m, 7H), 3.33 (s, 3H), 2.32 (p, J=7.6 Hz, 2H).
Intermediate 62
5-Bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0682] ##STR00313##
[0683] To a solution of 5-bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (110 mg, 0.20 mmol) in DMF (4 mL) were added trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (66.5 mg, 0.29 mmol), copper(II) sulfate pentahydrate (47.6 mg, 0.19 mmol) and (+)-sodium L-ascorbate (37.8 mg, 0.19 mmol). The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 4 g, 10 mL/min, silica gel, UV 254) to afford the product (95 mg, 68%). ESI-MS m/z calcd for [C.sub.31H.sub.27BrF.sub.3N.sub.5O.sub.5S][M+H].sup.+: 718.1; found: 718.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.46 (d, J=2.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 8.00-7.92 (m, 1H), 7.48-7.40 (m, 2H), 7.38-7.33 (m, 5H), 6.27 (d, J=5.2 Hz, 1H), 5.50 (s, 1H), 5.40 (dd, J=11.2, 3.2 Hz, 1H), 4.59 (dd, J=11.2, 5.2 Hz, 1H), 4.51 (d, J=3.2 Hz, 1H), 4.42-4.19 (m, 6H), 4.16-4.09 (m, 1H), 3.34 (s, 3H), 2.34 (p, J=7.6 Hz, 2H).
Intermediate 63
5-Bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside
[0684] ##STR00314##
5-Bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside
[0685] ##STR00315##
[0686] To a solution of 5-bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (200 mg, 0.37 mmol) in DMF (5 mL) Cs.sub.2CO.sub.3 (238 mg, 0.73 mmol) and iodoethane (0.146 mL, 1.82 mmol) were added. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 4 g, 10 mL/min, silica gel, UV 254) to afford the product (120 mg, 57%). ESI-MS m/z calcd for [C.sub.24H.sub.26BrN.sub.5O.sub.5S] [M+H].sup.+: 576.1; found: 576.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.39 (d, J=2.0 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.53-7.47 (m, 2H), 7.38-7.31 (m, 3H), 6.06 (d, J=5.2 Hz, 1H), 5.58 (s, 1H), 4.44-4.31 (m, 2H), 4.31-4.02 (m, 7H), 3.89 (dd, J=10.8, 3.2 Hz, 1H), 3.84-3.68 (m, 1H), 3.68-3.52 (m, 1H), 2.40-2.24 (m, 2H), 1.25 (t, J=6.8 Hz, 3H).
5-Bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0687] ##STR00316##
[0688] To a solution of 5-bromo-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside (110 mg, 0.19 mmol) in DMF (4 mL) trimethyl-[2-(4-chloro-3-fluorophenyl)ethynyl]silane (64.9 mg, 0.29 mmol), copper(II) sulfate pentahydrate (47.6 mg, 0.19 mmol) and (+)-sodium L-ascorbate (37.8 mg, 0.19 mmol) were added. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 4 g, 10 mL/min, silica gel, UV 254) to afford the product (90 mg, 65%). ESI-MS m/z calcd for [C.sub.32H.sub.30BrClFN.sub.5O.sub.5S] [M+H].sup.+: 730.1; found: 730.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.48 (d, J=2.0 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.99-7.95 (m, 1H), 7.63 (dd, J=10.0, 1.6 Hz, 1H), 7.54 (dd, J=8.4, 1.2 Hz, 1H), 7.46-7.33 (m, 6H), 6.23 (d, J=5.2 Hz, 1H), 5.52 (s, 1H), 5.41 (d, J=11.2 Hz, 1H), 4.65 (dd, J=11.2, 5.2 Hz, 1H), 4.58-4.05 (m, 8H), 3.78-3.64 (m, 1H), 3.38-3.23 (m, 1H), 2.50-2.21 (m, 2H), 1.01 (t, J=6.8 Hz, 3H).
Intermediate 64
2-(N-azetidinyl-carbonyl)-5-bromophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0689] ##STR00317##
5-Bromo-2-cyanophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0690] ##STR00318##
[0691] To a solution of acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (3.70 g, 10.6 mmol) 4-bromo-2-sulfanylbenzonitrile (4.13 g, 20.5 mmol) in DMF (25 mL) Cs.sub.2CO.sub.3 (6.89 g, 21.2 mmol) was added. The mixture was stirred at rt overnight. Water (100 mL) was added and the mixture was extracted with EtOAc (150 mL). The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜3/1, Silica-CS 40 g, 20 m/min, silica gel, UV 254) to give the product (2.50 g, 45%). ESI-MS m/z calcd for [C.sub.19H.sub.19BrN.sub.4O.sub.7S] [M+H.sub.2O].sup.+:544.0; found: 544.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.82 (d, J=1.2 Hz, 1H), 7.59-7.46 (m, 2H), 6.06 (d, J=5.6 Hz, 1H), 5.49 (d, J=2.4 Hz, 1H), 5.29 (dd, J=11.2, 5.6 Hz, 1H), 4.75-4.48 (m, 1H), 4.12 (dd, J=11.6, 5.2 Hz, 1H), 4.00-4.05 (m, 1H), 3.97 (dd, J=10.8, 3.2 Hz, 1H), 2.21 (s, 3H), 2.16 (s, 3H), 2.01 (s, 3H).
5-Bromo-2-cyanophenyl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0692] ##STR00319##
[0693] 5-Bromo-2-cyanophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (1.30 g, 2.47 mmol) was dissolved in a mixed solution of MeOH/Et.sub.3N/H.sub.2O (18 mL, v/v/v=5/3/1). The mixture was stirred overnight at rt. The solvent was removed under reduced pressure and the obtained solid was washed with DCM to afford the product (850 mg, 86%). ESI-MS m/z calcd for [C.sub.13H.sub.13BrN.sub.4O.sub.4S][M+H.sub.2O].sup.+: 418.0; found: 418.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.01 (d, J=2.0 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.60 (dd, J=8.4, 2.0 Hz, 1H), 6.10 (d, J=5.2 Hz, 1H), 6.00 (d, J=5.2 Hz, 1H), 5.32 (d, J=6.0 Hz, 1H), 4.62 (t, J=5.6 Hz, 1H), 4.27 (dt, J=10.4, 5.2 Hz, 1H), 3.97-3.85 (m, 2H), 3.54-3.44 (m, 2H), 3.36-3.25 (m, 1H).
5-Bromo-2-cyanophenyl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside
[0694] ##STR00320##
[0695] To a solution of 5-bromo-2-cyanophenyl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside (850 mg, 2.12 mmol) in DMF (10 mL) benzaldehyde dimethyl acetal (967 mg, 6.36 mmol) was added followed by D(+)-10-camphorsulfonic acid (98.4 mg, 0.42 mmol). The mixture was stirred 3 h at 50° C. under reduced pressure. The mixture was neutralized with Et.sub.3N and concentrated. The residue was purified by column chromatography (PE/EtOAc=5/1˜3/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to give the product (900 mg, 87%). ESI-MS m/z calcd for [C.sub.20H.sub.17BrN.sub.4O.sub.4S] [M+H].sup.+: 489.0; found: 489.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.92 (d, J=1.2 Hz, 1H), 7.54-7.47 (m, 4H), 7.39-7.32 (m, 3H), 5.89 (d, J=5.2 Hz, 1H), 5.63 (s, 1H), 4.64 (dd, J=10.8, 5.2 Hz, 1H), 4.42 (d, J=2.8 Hz, 1H), 4.25-4.28 (m, 2H), 4.15 (dd, J=12.4, 1.2 Hz, 1H), 3.62 (dd, J=10.8, 3.2 Hz, 1H).
5-Bromo-2-cyanophenyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0696] ##STR00321##
[0697] To a solution of 5-bromo-2-cyanophenyl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (450 mg, 0.92 mmol) in DMF (10 mL) Cs.sub.2CO.sub.3 (599 mg, 1.84 mmol) was added followed by iodomethane (653 mg, 4.60 mmol). The mixture was stirred overnight at rt and then partitioned between water and EtOAc. The organic phase was washed with brine, concentrated and purified by column chromatography (PE/EtOAc=10/1˜5/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to give the product (226 mg, 49%). ESI-MS m/z calcd for [C.sub.21H.sub.19BrN.sub.4O.sub.4S] [M+H].sup.+: 503.0; found: 503.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.88 (s, 1H), 7.57-7.46 (m, 4H), 7.43-7.33 (m, 3H), 6.10 (d, J=5.2 Hz, 1H), 5.61 (s, 1H), 4.33 (d, J=3.2 Hz, 1H), 4.26 (dd, J=10.4, 5.2 Hz, 1H), 4.22-4.16 (m, 2H), 4.10-4.13 (m, 1H), 3.76 (dd, J=10.8, 3.2 Hz, 1H), 3.60 (s, 3H).
2-(N-azetidinyl-carbonyl)-5-bromophenyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0698] ##STR00322##
[0699] To a solution of 5-bromo-2-cyanophenyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (226 mg, 0.45 mmol) in ethanol (18 mL) and H.sub.2O (6 mL) NaOH (269 mg, 6.73 mmol) was added. The mixture was stirred overnight at 80° C. Ethanol was removed under reduced pressure, the pH of the solution was adjusted to 5-6 with 1M HCl and then extracted with EtOAc (2×30 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated. The obtained material was dissolved in together with azetidine hydrochloride (108 mg, 1.15 mmol) in DMF (5 mL). To the solution HATU (335 mg, 0.88 mmol) was added followed by DIEA (0.377 mL, 2.20 mmol). The reaction was stirred 2 h at rt and then partitioned between water and EtOAc. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=5/1˜1/2, Silica-CS 20 g, 30 m/min, silica gel, UV 254) to give the product (130 mg, 52%). ESI-MS m/z calcd for [C.sub.24H.sub.25BrN.sub.4O.sub.5S] [M+H].sup.+: 561.1; found: 561.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.75 (d, J=1.6 Hz, 1H), 7.49-7.51 (m, 2H), 7.41 (dd, J=8.0, 2.0 Hz, 1H), 7.39-7.31 (m, 3H), 7.15 (d, J=8.0 Hz, 1H), 6.13 (d, J=5.2 Hz, 1H), 5.58 (s, 1H), 4.30 (d, J=3.2 Hz, 1H), 4.26-4.13 (m, 5H), 4.08 (dd, J=12.8, 2.0 Hz, 1H), 3.92 (td, J=8.0, 2.8 Hz, 2H), 3.77 (dd, J=10.4, 3.2 Hz, 1H), 3.56 (s, 3H), 2.37-2.27 (m, 2H).
2-(N-azetidinyl-carbonyl)-5-bromophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0700] ##STR00323##
[0701] To a solution of 2-(N-azetidinyl-carbonyl)-5-bromophenyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (130 mg, 0.23 mmol) and trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (63.4 mg, 0.28 mmol) in DMF (4 mL) (+)-sodium L-ascorbate (68.8 mg, 0.35 mmol) and copper(II) sulfate pentahydrate (28.9 mg, 0.12 mmol) were added. The mixture was stirred 4 h at rt under a nitrogen atmosphere. After diluting with water (20 mL), the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=2/1˜1/2, Silica-CS 20 g, 30 mL/min, silica gel, UV 254) to give the product (120 mg, 72%). ESI-MS m/z calcd for [C.sub.32H.sub.28BrF.sub.3N.sub.4O.sub.5S] [M+H].sup.+: 717.1; found: 716.7. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.94 (s, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.77 (dd, J=8.8, 6.8 Hz, 2H), 7.57 (dd, J=8.4, 2.0 Hz, 1H), 7.41-7.29 (m, 6H), 6.59 (d, J=5.2 Hz, 1H), 5.59 (s, 1H), 5.14 (dd, J=11.2, 3.2 Hz, 1H), 4.64 (dd, J=11.2, 5.2 Hz, 1H), 4.59 (d, J=3.2 Hz, 1H), 4.36 (s, 1H), 4.20-4.13 (m, 1H), 4.06 (t, J=7.7 Hz, 2H), 4.00-3.85 (m, 3H), 3.37 (s, 3H), 2.32-2.17 (m, 2H).
Intermediate 65
2-(N-azetidinyl-carbonyl)-5-bromophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-ethyl-1-thio-α-D-galactopyranoside
[0702] ##STR00324##
5-Bromo-2-carboxyphenyl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside
[0703] ##STR00325##
[0704] To a solution of 5-bromo-2-cyanophenyl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (400 mg, 0.82 mmol) in ethanol (18 mL) and H.sub.2O (6 mL) NaOH (490 mg, 12.3 mmol) was added. The mixture was stirred overnight at 80° C. Ethanol was removed under reduced pressure, the pH of the solution was adjusted to 5-6 with 1M HCl and then extracted with EtOAc (2×30 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated. The residue was 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 (300 mg, 60%). ESI-MS m/z calcd for [C.sub.20H.sub.18BrN.sub.3O.sub.6S] [M−H].sup.−: 506.0; found: 506.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.72 (d, J=1.2 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.50-7.35 (m, 5H), 7.31 (dd, J=8.0, 1.2 Hz, 1H), 5.77 (d, J=5.2 Hz, 1H), 5.64 (s, 1H), 4.38 (d, J=2.4 Hz, 1H), 4.31 (dd, J=11.2, 5.2 Hz, 1H), 4.13-3.86 (m, 4H), 3.71 (dd, J=11.2, 3.2 Hz, 1H).
2-(N-azetidinyl-carbonyl)-5-bromophenyl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside
[0705] ##STR00326##
[0706] To a solution of 5-bromo-2-carboxyphenyl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (300 mg, 0.59 mmol) and azetidine hydrochloride (144 mg, 1.54 mmol) in DMF (5 mL) HATU (449 mg, 1.18 mmol) was added followed by DIEA (0.505 mL, 2.95 mmol). The mixture was stirred overnight at rt and then partitioned between water and EtOAc. The organic layer was dried, concentrated and the residue was purified by column chromatography (PE/EtOAc=5/1˜1/2, Silica-CS 20 g, 30 m/min, silica gel, UV 254) to give the product (240 mg, 74%). ESI-MS m/z calcd for [C.sub.23H.sub.23BrN.sub.4O.sub.5S] [M+H].sup.+: 547.1; found: 546.7. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.84 (d, J=2.0 Hz, 1H), 7.55-7.48 (m, 2H), 7.46 (dd, J=8.0, 2.0 Hz, 1H), 7.40-7.32 (m, 3H), 7.15 (d, J=8.0 Hz, 1H), 5.85 (d, J=5.2 Hz, 1H), 5.61 (s, 1H), 4.61 (dd, J=10.8, 5.2 Hz, 1H), 4.35-4.10 (m, 6H), 4.03-3.90 (m, 2H), 3.58 (dd, J=10.8, 3.2 Hz, 1H), 2.39-2.27 (m, 2H).
2-(N-azetidinyl-carbonyl)-5-bromophenyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside
[0707] ##STR00327##
[0708] To a solution of 2-(N-azetidinyl-carbonyl)-5-bromophenyl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (240 mg, 0.44 mmol) in DMF (5 mL) Cs.sub.2CO.sub.3 (429 mg, 1.32 mmol) was added followed by iodoethane (342 mg, 2.19 mmol). The mixture was stirred overnight at rt, diluted with EtOAc (30 mL) and washed with water (3×30 mL). The organic layer was dried with anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=5/1-1/2, Silica-CS 20 g, 20 m/min, silica gel, UV 254) to give the product (110 mg, 44%). ESI-MS m/z calcd for [C.sub.25H.sub.27BrN.sub.4O.sub.5S] [M+H].sup.+: 575.1; found: 574.8. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.76 (d, J=1.6 Hz, 1H), 7.56-7.48 (m, 2H), 7.43 (dd, J=8.4, 2.0 Hz, 1H), 7.40-7.31 (m, 3H), 7.16 (d, J=8.4 Hz, 1H), 6.13 (d, J=5.2 Hz, 1H), 5.60 (s, 1H), 4.34 (dd, J=10.8, 5.2 Hz, 1H), 4.30 (d, J=3.2 Hz, 1H), 4.27-4.03 (m, 5H), 4.02-3.78 (m, 4H), 3.66-3.62 (m, 1H), 2.38-2.30 (m, 2H), 1.31 (t, J=6.8 Hz, 3H).
2-(N-azetidinyl-carbonyl)-5-bromophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-ethyl-1-thio-α-D-galactopyranoside
[0709] ##STR00328##
[0710] To a solution of 2-(N-azetidinyl-carbonyl)-5-bromophenyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside (110 mg, 0.19 mmol) and trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (52.4 mg, 0.23 mmol) in DMF (4 mL) (+)-sodium L-ascorbate (56.8 mg, 0.29 mmol) and copper(II) sulfate pentahydrate (23.9 mg, 0.096 mmol). The mixture was stirred 4 h at rt under a nitrogen atmosphere before diluting with water (20 mL) and extracting with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=2/1˜1/2, Silica-CS 20 g, 30 m/min, silica gel, UV 254) to give the product (120 mg, 86%) as a white solid. ESI-MS m/z calcd for [C.sub.33H.sub.30BrF.sub.3N.sub.4O.sub.5S] [M+H].sup.+: 731.1; found: 730.6. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.93 (s, 1H), 7.95 (d, J=1.6 Hz, 2H), 7.79 (dd, J=8.8, 6.4 Hz, 2H), 7.57 (dd, J=8.4, 2.0 Hz, 1H), 7.45-7.26 (m, 5H), 6.55 (d, J=5.2 Hz, 1H), 5.58 (s, 1H), 5.13 (dd, J=11.6, 3.2 Hz, 1H), 4.71 (dd, J=11.6, 5.2 Hz, 1H), 4.59 (d, J=3.2 Hz, 1H), 4.40-4.32 (m, 1H), 4.20-4.13 (m, 1H), 4.05-4.09 (m, 2H), 3.99-3.70 (m, 4H), 3.49 (dq, J=14.0, 7.2 Hz, 1H), 2.26-2.22 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).
Intermediate 66
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0711] ##STR00329##
5-Chloro-2-cyanopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0712] ##STR00330##
[0713] To a solution of acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (4.50 g, 11.5 mmol) in DMF (30 mL) 5-chloro-3-fluoro-pyridine-2-carbonitrile (1.81 g, 11.5 mmol) and N-ethylethanamine (1.69 g, 23.0 mmol) were added at 0° C. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was poured into water (150 mL) and extracted with EtOAc (2×200 mL). The organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 40 g, 50 mL/min, silica gel, UV 254) to afford the product (3.30 g, 59%). ESI-MS m/z calcd for [C.sub.18H.sub.18ClN.sub.5O.sub.7S] [M+H].sup.+: 484.1; found: 484.0. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.64 (d, J=2.4 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 6.17 (d, J=5.6 Hz, 1H), 5.54 (d, J=2.8 Hz, 1H), 5.29 (dd, J=11.2, 5.2 Hz, 1H), 4.68 (dd, J=7.6, 4.0 Hz, 1H), 4.27 (dd, J=10.8, 3.2 Hz, 1H), 4.15 (dd, J=7.6, 4.0 Hz, 1H), 3.98 (dd, J=11.6, 8.0 Hz, 1H), 2.18 (s, 3H), 2.14 (s, 3H), 2.14 (s, 3H).
5-Chloro-2-cyanopyridin-3-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside
[0714] ##STR00331##
[0715] To a solution of 5-chloro-2-cyanopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (3.30 g, 6.83 mmol) in MeOH (30 mL) Et.sub.3N (12 mL, 86.2 mmol) and water (3 mL) were added. The mixture was stirred overnight at rt. The solvent was removed under reduced pressure and the obtained residue was washed by DCM (20 mL). The solid was collected to afford the product (2.20 g, 90%) as a white solid. ESI-MS m/z calcd for [C.sub.12H.sub.12ClN.sub.5O.sub.4S] [M+H].sup.+: 358.0; found: 358.0. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.51 (d, J=2.0 Hz, 1H), 8.37 (d, J=2.4 Hz, 1H), 6.03 (d, J=5.2 Hz, 1H), 4.43 (dd, J=6.8, 1.6 Hz, 1H), 4.12 (t, J=6.0 Hz, 1H), 4.04 (d, J=2.4 Hz, 1H), 3.66-3.58 (m, 3H).
5-Chloro-2-cyanopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside
[0716] ##STR00332##
[0717] To a solution of 5-chloro-2-cyanopyridin-3-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside (2.20 g, 6.15 mmol) in DMF (15 mL) benzaldehyde dimethyl acetal (2.81 g, 18.4 mmol) and D(+)-10-camphorsulfonic acid (429 mg, 1.84 mmol) were added. The mixture was stirred under a nitrogen atmosphere 2 h at 50° C. The mixture was cooled to rt and poured into water. The solid was collected and dried in vacuum to give the product (2.0 g, 70%). ESI-MS m/z calcd for [C.sub.19H.sub.16ClN.sub.5O.sub.4S] [M+H].sup.+: 446.1; found: 446.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.51 (d, J=2.0 Hz, 1H), 8.08 (d, J=2.4 Hz, 1H), 7.51-7.35 (m, 5H), 5.92 (d, J=5.2 Hz, 1H), 5.64 (s, 1H), 4.66 (dd, J=10.8, 5.2 Hz, 1H), 4.44 (d, J=2.8 Hz, 1H), 4.25-4.13 (m, 3H), 3.67 (dd, J=10.8, 3.2 Hz, 1H).
5-Chloro-2-carboxypyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside
[0718] ##STR00333##
[0719] To a solution of 5-chloro-2-cyanopyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (2.00 g, 4.33 mmol) in EtOH (50 mL) and water (20 mL) NaOH (2.6 mg, 64.9 mmol) was added. The mixture was kept stirring overnight at 80° C. Then EtOH was removed under reduced pressure. The mixture was acidified by 1M HCl to pH=6. The mixture was filtered, and the solid was dried in vacuum to give the product (1.80 g, 90%). ESI-MS m/z calcd for [C.sub.19H.sub.17ClN.sub.4O.sub.6S] [M+H].sup.+: 465.1; found: 465.1. .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.34-8.28 (m, 2H), 7.49-7.34 (m, 5H), 5.94 (d, J=5.2 Hz, 1H), 5.63 (s, 1H), 4.57 (dd, J=12.0, 4.0 Hz, 1H), 4.41 (s, 1H), 4.14-4.00 (m, 3H), 3.73 (dd, J=8.4, 2.8 Hz, 1H).
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside
[0720] ##STR00334##
[0721] To a solution of 5-chloro-2-carboxypyridin-3-yl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (1.80 g, 3.87 mmol) in DMF (20 mL) azetidine hydrochloride (2.21 g, 5.81 mmol), Et.sub.3N (2.70 mL, 19.4 mmol) and HATU (724 mg, 7.74 mmol) were added. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=1/1˜0/1, Silica-CS 80 g, 50 mL/min, silica gel, UV 254) to afford the product (1.20 g, 55%). ESI-MS m/z calcd for [C.sub.22H.sub.22ClN.sub.5O.sub.5S] [M+H].sup.+: 504.1; found: 504.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.35 (d, J=2.4 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.53-7.34 (m, 5H), 5.86 (d, J=5.2 Hz, 1H), 5.63 (s, 1H), 4.65 (dd, J=10.8, 5.6 Hz, 1H), 4.48-4.42 (m, 1H), 4.36-4.11 (m, 7H), 3.67 (dd, J=10.8, 3.2 Hz, 1H), 2.38-2.30 (m, 2H).
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0722] ##STR00335##
[0723] To a solution of 5-chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (200 mg, 0.36 mmol) in DMF (8 mL) Cs.sub.2CO.sub.3 (348 mg, 1.07 mmol) and iodomethane (0.111 mL, 1.78 mmol) were added. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (120 mg, 60%). ESI-MS m/z calcd for [C.sub.23H.sub.24ClN.sub.5O.sub.5S] [M+H].sup.+: 518.1; found: 518.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.31 (d, J=2.4 Hz, 1H), 8.09 (d, J=2.4 Hz, 1H), 7.54-7.26 (m, 5H), 6.09 (d, J=5.6 Hz, 1H), 5.61 (s, 1H), 4.52-4.41 (m, 1H), 4.31-4.08 (m, 8H), 3.88 (dd, J=10.8, 3.2 Hz, 1H), 3.54 (s, 3H), 2.38-2.30 (m, 2H).
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0724] ##STR00336##
[0725] To a solution of 5-chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside (120 mg, 0.22 mmol) in DMF (8 mL) trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (73.5 mg, 0.32 mmol), copper(II) sulfate pentahydrate (26.8 mg, 0.11 mmol) and (+)-sodium L-ascorbate (21.2 mg, 0.11 mmol) were added. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 12 g, 20 m/min, silica gel, UV 254) to afford the product (100 mg, 63%). ESI-MS m/z calcd for [C.sub.31H.sub.27ClF.sub.3N.sub.5O.sub.5S] [M+H].sup.+: 674.1; found: 674.1. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.38 (s, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.95 (s, 1H), 7.47-7.40 (m, 7H), 6.26 (d, J=5.2 Hz, 1H), 5.53 (s, 1H), 5.42 (d, J=10.8 Hz, 1H), 4.57 (dd, J=10.8, 4.8 Hz, 1H), 4.51-4.11 (m, 8H), 3.34 (s, 3H), 2.38-2.34 (m, 2H).
Intermediate 67
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside
[0726] ##STR00337##
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside
[0727] ##STR00338##
[0728] To a solution of 5-chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-4,6-O-benzylidene-3-deoxy-1-thio-α-D-galactopyranoside (880 mg, 1.56 mmol) in DMF (16 mL) Cs.sub.2CO.sub.3 (1.02 g, 3.13 mmol) and iodoethane (732 mg, 4.69 mmol) were added. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 40 g, 35 mL/min, silica gel, UV 254) to afford the product (620 mg, 71%). ESI-MS m/z calcd for [C.sub.24H.sub.26ClN.sub.5O.sub.5S] [M+H].sup.+: 532.1; found: 531.8. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.30 (s, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.53-7.25 (m, 5H), 6.07 (d, J=5.6 Hz, 1H), 5.59 (s, 1H), 4.46-4.06 (m, 9H), 3.91 (dd, J=10.8, 3.2 Hz, 1H), 3.84-3.77 (m, 1H), 3.64-3.57 (m, 1H), 2.38-2.30 (m, 2H), 1.28-1.24 (m, 3H).
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0729] ##STR00339##
[0730] To a solution of 5-chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside (200 mg, 0.36 mmol) in DMF (8 mL) trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (122 mg, 0.54 mmol), copper(II) sulfate pentahydrate (44.6 mg, 0.18 mmol) and (+)-sodium L-ascorbate (35.4 mg, 0.18 mmol) were added. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 12 g, 20 m/min, silica gel, UV 254) to afford the product (160 mg, 62%). ESI-MS m/z calcd for [C.sub.32H.sub.29ClF.sub.3N.sub.5O.sub.5S][M+H].sup.+: 688.2; found: 687.7. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.36 (d, J=2.0 Hz, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.95 (s, 1H), 7.46-7.25 (m, 7H), 6.24 (d, J=5.2 Hz, 1H), 5.51 (s, 1H), 5.41 (dd, J=11.6, 3.6 Hz, 1H), 4.65 (dd, J=11.2, 5.2 Hz, 1H), 4.51 (d, J=3.2 Hz, 1H), 4.39-4.20 (m, 6H), 4.12 (dd, J=12.8, 2.4 Hz, 1H), 3.75-3.67 (m, 1H), 3.34-3.27 (m, 1H), 2.38-2.31 (m, 2H), 1.02-0.99 (m, 3H).
Intermediate 68
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-[4-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0731] ##STR00340##
[0732] To a solution of 5-chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside (200 mg, 0.36 mmol) in DMF (8 mL) trimethyl-[2-(4-chloro-3-fluorophenyl)ethynyl]silane (121 mg, 0.54 mmol), copper(II) sulfate pentahydrate (44.6 mg, 0.18 mmol) and (+)-sodium L-ascorbate (35.4 mg, 0.18 mmol) were added. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 12 g, 20 m/min, silica gel, UV 254) to afford the product (145 mg, 57%). ESI-MS m/z calcd for [C.sub.32H.sub.30Cl.sub.2FN.sub.5O.sub.5S] [M+H].sup.+: 686.1; found: 685.7. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.37 (s, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.97 (s, 1H), 7.62 (dd, J=10.0, 1.6 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.46-7.36 (m, 6H), 6.23 (d, J=5.2 Hz, 1H), 5.52 (s, 1H), 5.41 (d, J=10.8 Hz, 1H), 4.66 (dd, J=11.2, 5.2 Hz, 1H), 4.52-4.11 (m, 8H), 3.72-3.68 (m, 1H), 3.33-3.16 (m, 1H), 2.39-2.32 (m, 2H), 1.03-0.99 (m, 3H).
Intermediate 69
5-Chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0733] ##STR00341##
[0734] To a solution of 5-chloro-2-(N-azetidinylcarbamoyl)-3-pyridyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside (200 mg, 0.36 mmol) in DMF (8 mL) trimethyl-[2-(4-chloro-3,5-difluorophenyl)ethynyl]silane (131 mg, 0.54 mmol), copper(II) sulfate pentahydrate (44.6 mg, 0.18 mmol) and (+)-sodium L-ascorbate (35.4 mg, 0.18 mmol) were added. The mixture was stirred under a nitrogen atmosphere at rt overnight. The mixture was poured into water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 12 g, 20 m/min, silica gel, UV 254) to afford the product (100 mg, 40%). ESI-MS m/z calcd for [C.sub.32H.sub.29Cl.sub.2F.sub.2N.sub.5O.sub.5S] [M+H].sup.+: 704.1; found: 703.7. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.37 (d, J=2.0 Hz 1H), 8.05 (d, J=2.0 Hz, 1H), 7.98 (s, 1H), 7.47-7.44 (m, 2H), 7.41-7.25 (m, 5H), 6.23 (d, J=5.2 Hz, 1H), 5.52 (s, 1H), 5.42 (dd, J=11.2, 3.2 Hz, 1H), 4.65 (dd, J=11.6, 5.2 Hz, 1H), 4.51 (d, J=2.8 Hz, 1H), 4.59-4.20 (m, 6H), 4.12 (dd, J=12.8, 1.2 Hz, 1H), 3.74-3.67 (m, 1H), 3.34-3.26 (m, 1H), 2.39-2.31 (m, 2H), 1.02-0.99 (m, 3H).
Intermediate 70
2-(N-azetidinyl-carbonyl)-5-chlorophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0735] ##STR00342##
5-Chloro-2-cyanophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0736] ##STR00343##
[0737] To a solution of 5-chloro-2-cyanophenyl 3-azido-4,6-O-benzylidene-3-deoxy-2-O-ethyl-1-thio-α-D-galactopyranoside (220 mg, 0.53 mmol) and trimethyl-[2-(3,4,5-trifluorophenyl)ethynyl]silane (179 mg, 0.78 mmol) in DMF (4 mL) copper(II) sulfate pentahydrate (65.4 mg, 0.26 mmol) and (+)-sodium L-ascorbate (51.8 mg, 0.26 mmol) were added. The mixture was stirred 6 h under a nitrogen atmosphere at rt. The mixture concentrated and purified by column chromatography (PE/EtOAc=10/1˜1/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (220 mg, 68%). ESI-MS m/z calcd for [C.sub.29H.sub.22ClF.sub.3N.sub.4O.sub.4S] [M+H].sup.+: 615.1; found: 615.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.94 (s, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H) 7.46-7.36 (m, 8H), 6.22 (d, J=5.2 Hz, 1H), 5.52 (s, 1H), 5.32 (dd, J=11.6, 3.2 Hz, 1H), 4.56-4.52 (m, 2H), 4.45 (s, 1H), 4.27-4.09 (m, 2H), 3.40 (s, 3H).
2-(N-azetidinyl-carbonyl)-5-chlorophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside
[0738] ##STR00344##
[0739] A solution of 5-chloro-2-cyanophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-methyl-1-thio-α-D-galactopyranoside (220 mg, 0.36 mmol) in ethanol (10 mL) and NaOH (3 M aq, 4 mL) was stirred 16 h at 80° C. After cooling to rt the mixture was concentrated to approximately 10 mL, and then acidified with HCl (3 M) to pH—3. The solid precipitate was collected by filtration, washed with 33% aq MeOH and dried. To a solution of the obtained material, HATU (204 mg, 0.54 mmol) and Et.sub.3N (109 mg, 1.07 mmol) in DMF (3 mL) azetidine hydrochloride (122 mg, 1.31 mmol) was added. The was stirred at rt overnight, and then concentrated. The residue was purified by column chromatography (PE/EtOAc=5/1˜1/2, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (101 mg, 42%). ESI-MS m/z calcd for [C.sub.32H.sub.28ClF.sub.3N.sub.4O.sub.5S] [M+H].sup.+: 673.1; found: 673.0. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.95 (s, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.44-7.29 (m, 9H), 6.26 (d, J=4.8 Hz, 1H), 5.50 (s, 1H), 5.35 (dd, J=11.6, 3.2 Hz, 1H), 4.50-4.46 (m, 2H), 4.42 (s, 1H), 4.26-4.10 (m, 4H), 3.94-3.90 (m, 2H), 3.36 (s, 3H), 3.38-3.30 (m, 2H).
Intermediate 71
3,4-Dichlorophenyl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-methyl-1-thio-α-D-galactopyranoside
[0740] ##STR00345##
[0741] To a stirred solution of 3,4-dichlorophenyl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (140 mg, 0.22 mmol) in DMF (2 mL) NaH (60% in oil, 24.0 mg, 0.63 mmol) was added at 0° C. under a nitrogen atmosphere. The mixture was stirred 10 min at 0° C., then iodomethane (0.0278 mL, 0.45 mmol) was added. The mixture was stirred 2 h at rt. After diluting with water (20 mL), the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EtOAc=10/1˜4/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the product (114 mg, 80%) as a white solid. ESI-MS m/z calcd for [C.sub.28H.sub.22C.sub.13F.sub.2N.sub.3O.sub.4S][M+Na].sup.+: 663.1; found: 663.2. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.91 (s, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.39-7.29 (m, 9H), 6.07 (d, J=5.2 Hz, 1H), 5.46 (s, 1H), 5.22 (dd, J=11.2, 3.2 Hz, 1H), 4.45-4.41 (m, 2H), 4.27-4.24 (m, 2H), 4.11-4.08 (m, 1H), 3.26 (s, 3H).
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