Galactoside inhibitor of galectins
11827666 · 2023-11-28
Assignee
Inventors
Cpc classification
International classification
Abstract
An α-D-galactopyranose compound of the general formula (1). The α-D-galactopyranose 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-1 to a ligand in a mammal, such as a human. Furthermore, a method for treatment of a disorder relating to the binding of a galectin, such as galectin-1 to a ligand in a mammal, such as a human.
Claims
1. A D-galactopyranose compound of formula (1) ##STR00160## wherein the pyranose ring is α-D-galactopyranose, R.sup.1 is selected from the group consisting of ##STR00161## and ##STR00162## wherein the asterix * indicates the carbon atom of the heteroaromatic ring that is covalently attached to the triazole group of formula (1); wherein R.sup.2 is selected from the group consisting of OH and halogen; R.sup.3 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen; R.sup.4 is selected from the group consisting of OH and halogen; R.sup.5 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen; B.sup.1 is selected from a) an aryl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.29R.sup.30, wherein R.sup.29 and R.sup.30 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; SC.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.31R.sup.32, wherein R.sup.31 and R.sup.32 are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.33—CONH—, wherein R.sup.33 is selected from C.sub.1-3 alkyl and cyclopropyl; and b) a heterocycle, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.35R.sup.36, wherein R.sup.35 and R.sup.36 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; SC.sub.1-3 alkyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.37R.sup.38, wherein R.sup.37 and R.sup.38 are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.39—CONH— wherein R.sup.39 is selected from C.sub.1-3 alkyl and cyclopropyl; or a pharmaceutically acceptable salt or solvate thereof.
2. The compound of claim 1 wherein R.sup.1 is selected from formula 2 wherein R.sup.2 is selected from the group consisting of OH; and R.sup.3 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen.
3. The compound of claim 2, wherein R.sup.2 is OH, and R.sup.3 is H.
4. The compound of claim 1 wherein R.sup.1 is selected from formula 3 wherein R.sup.4 is selected from the group consisting of OH and halogen; and R.sup.5 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen.
5. The compound of claim 4 wherein R.sup.4 is OH and R.sup.5 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen.
6. The compound of claim 4 wherein R.sup.4 is halogen and R.sup.5 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen.
7. The compound of claim 1 wherein B.sup.1 is selected from phenyl optionally substituted with a group selected from halogen, SC.sub.1-3 alkyl optionally substituted with a F; C.sub.1-6 alkyl; CN; and —CONR.sup.35R.sup.36, wherein R.sup.35 and R.sup.36 are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl.
8. The compound of claim 1 wherein B.sup.1 is selected from a phenyl substituted with one, two or three substituents selected from Cl, F, Br, CF.sub.3, SCF.sub.3, CH.sub.3, CON(CH.sub.3).sub.2 and CN.
9. The compound of claim 1 wherein B.sup.1 is selected from a pyridinyl, optionally substituted with a group selected from a halogen; —COOH; —CONR.sup.35R.sup.36, wherein R.sup.35 and R.sup.36 are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; isopropyl, optionally substituted with a F; CN; and a methyl optionally substituted with a F.
10. The compound of claim 1 wherein B1 is selected from a pyridinyl substituted with one, or two substituents selected from the group consisting of Cl, Br, isopropyl, COOH, CONH.sub.2, CN, CON(CH.sub.3).sub.2 and CF.sub.3.
11. The compound of claim 1 selected from: 5-Bromo-6-trifluoromethyl-pyridine-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Bromo-6-trifluoromethyl-pyridine-3-yl 3-[4-(4-bromothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Chloro-6-cyano-pyridine-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Bromo-2-cyano-pyridine-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-pyridine-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Bromo-6-cyano-3-pyridyl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-[4-(2-chlorothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-deoxy-3-[4-(2-fluorothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-deoxy-3-[4-(4-fluorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-deoxy-3-[4-(4,5-difluorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-deoxy-3-[4-(4-hydroxythiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-6-cyano-pyridine-3-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Bromo-2-cyano-pyridine-3-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Bromo-6-cyano-3-pyridyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-3-pyridyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-6-trifluoromethyl-pyridin-3-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3,5-dichloro-4-fluoro-phenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3-Chloro-4-fluoro-phenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3,4,5-trichlorophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3,5-dibromo-4-fluorophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3-Bromo-4-cyanophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Bromo-6-trifluoromethyl-3-pyridyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3-Chloro-4-trifluoromethylphenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3-Chloro-4-trifluoromethylthiophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3-Chloro-4-methylphenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-picolinamide-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 2-Carboxy-5-chloropyridyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Bromo-6-trifluoromethyl-pyridine-3-yl 3-deoxy-3-[4-(4,5-dichlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Bromo-2-isopropyl-pyridine-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 3,4-Dichloro-6-fluoro-phenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 4-Chloro-N,N′-dimethylbenzamide-2-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, and 5-Chloro-N,N′-dimethyl-picolinamide-3-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside; or a pharmaceutically acceptable salt or solvate thereof.
12. A pharmaceutical composition comprising the compound of claim 1 and optionally a pharmaceutically acceptable additive.
13. A method for treatment of a disorder relating to the binding of a galectin-1 to a ligand in a mammal, wherein a therapeutically effective amount of at least one compound according to claim 1 is administered to a mammal in need of said treatment wherein said disorder is selected from the group consisting of inflammation; fibrosis; scarring; keloid formation; aberrant scar formation; scleroderma; sclerosis; surgical adhesions; septic shock; cancer; metastasising cancers; neovascularization related to cancer; autoimmune diseases; transplant rejection; metabolic disorders; heart disease; heart failure; pathological angiogenesis, or a disease or condition associated with ocular angiogenesis; eye diseases; atherosclerosis; metabolic diseases; obesity; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, mesothelioma; and liver disorders.
Description
DETAILED DESCRIPTION OF THE INVENTION
(1) The present compounds of formula (1) differ from prior art compounds particularly in that the pyranose ring is α-D-galactopyranose. It is important to emphasize that alpha and beta anomers are very different isomers and it is by no means considered to be obvious to the skilled person to expect same or similar activity of both anomers. Consequently, alpha and beta anomers do not in general posses the same activity, and this is common knowledge to the skilled person. The compounds of the present invention are novel α-D-galactopyranose compounds that unexpectedly have shown very high affinity and specificity for galectin-1, and are considered novel potent drug candidates. Some of the novel α-D-galactopyranose compounds have both galectin-1 and galectin-3 affinity and, as such have a broader disease treatment profile compared to selective galectin-1 inhibitors.
(2) In a broad aspect, the present invention concerns a compound of the above formula (1) wherein R.sup.1 and B.sup.1 are as defined. Below are described further embodiments.
(3) In an embodiment R.sup.1 is
(4) ##STR00025## wherein the asterix * indicates the carbon atom of the heteroaromatic ring that is covalently attached to the triazole group of formula (1); wherein R.sup.2 is selected from the group consisting of OH and halogen; and R.sup.3 is selected from the group consisting of hydrogen (H), C.sub.1-6 alkyl and halogen.
(5) In an embodiment R.sup.2 is selected from the group consisting of OH, chloro, bromo and fluoro. In a preferred embodiment R.sup.2 is OH. In another preferred embodiment R.sup.2 is Cl. In a further preferred embodiment R.sup.2 is Br. In a still further preferred embodiment R.sup.2 is F.
(6) In a further embodiment R.sup.3 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen.
(7) In another embodiment R.sup.2 is OH, and R.sup.3 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen. When R.sup.2 is OH and R.sup.3 is H then depending on conditions such as acidic or basic the OH group may be on the oxo tautomer form.
(8) In a further embodiment R.sup.2 is halogen, and R.sup.3 is selected from the group consisting of hydrogen and halogen. Typically, R.sup.2 is halogen, and R.sup.3 is H. In a further embodiment both R.sup.2 and R.sup.3 are halogen, such as Cl or F.
(9) The above compounds wherein R.sup.1 is formula 2 have high affinity to both galectin-1 and galectin-3.
(10) In a further embodiment R.sup.1 is
(11) ##STR00026## wherein the asterix * indicates the carbon atom of the heteroaromatic ring that is covalently attached to the triazole group of formula (1); wherein R.sup.4 is selected from the group consisting of OH and halogen, preferably F, Cl, and Br; and R.sup.5 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen. In a preferred embodiment R.sup.4 is OH.
(12) In an embodiment R.sup.4 is OH and R.sup.5 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen. When R.sup.4 is OH in the present compounds of formula (1) wherein R.sup.1 is 3, data have shown that such compounds have galectin 1 selectivity, and in particular when R.sup.4 is OH and R.sup.5 is H, then such compounds are highly selective galectin-1 inhibitors.
(13) In a further embodiment R.sup.4 is halogen and R.sup.5 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen. Typically, R.sup.4 is selected from C.sub.1 and F. In a further embodiment R.sup.4 is selected from Cl and F and R.sup.5 is H.
(14) In a further embodiment B.sup.1 is selected from phenyl optionally substituted with a group selected from halogen, SC.sub.1-3 alkyl, optionally substituted with a F; C.sub.1-6 alkyl and CN.
(15) In a still further embodiment B.sup.1 is selected from a phenyl substituted with one, two or three substituents selected from Cl, F, Br, CF.sub.3, SCF.sub.3, CH.sub.3, and CN. Typically, the phenyl is substituted with at least 2 Cl, such as 3 Cl or 2 Cl and one F. In another embodiment the phenyl is substituted with one C.sub.1 and one F. In a further embodiment the phenyl is substituted with at least one Br, such as two Br and one F, or one Br and one CN. In a still further embodiment phenyl is substituted with one halogen, such as Cl, and one substituent selected from CF.sub.3, SCF.sub.3, and CH.sub.3.
(16) In a further embodiment B.sup.1 is selected from phenyl optionally substituted with a group selected from halogen and —CONR.sup.35R.sup.36, wherein R.sup.35 and R.sup.36 are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl. In one embodiment B.sup.1 is selected from phenyl substituted with a group selected from halogen, such as 1, 2 or 3 halogens, for instance Cl and F, such as 2Cl and one F or 1Cl and 2 F. In another embodiment B.sup.1 is selected from phenyl substituted with a group selected from halogen, such as Cl, and —CONR.sup.35R.sup.36, wherein R.sup.35 and R.sup.36 are independently selected from H and C.sub.1-3 alkyl, such as methyl. Thus, in one example is selected from phenyl substituted with one halogen, such as Cl, and one —CONR.sup.35R.sup.36, wherein R.sup.35 and R.sup.36 are both methyl.
(17) In a further embodiment B.sup.1 is selected from a pyridinyl, optionally substituted with a group selected from a halogen; —COOH; —CONR.sup.35R.sup.36, wherein R.sup.35 and R.sup.36 are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; isopropyl, optionally substituted with a F; CN; and a methyl optionally substituted with a F.
(18) In a still further embodiment B.sup.1 is selected from a pyridinyl substituted with two substituents selected from Cl, Br, COOH, CONH.sub.2, isopropyl, CN and CF.sub.3. Typically, in individual embodiments the substituents are Br and CF.sub.3, or Br and CN, or Cl and CN, or Cl and CF.sub.3. In other individual embodiments the substituents are Cl and CONH.sub.2, Cl and COOH, Br and isopropyl.
(19) In a further embodiment B.sup.1 is selected from a pyridinyl substituted with a group selected from halogen, such as Cl, and —CONR.sup.35R.sup.36, wherein R.sup.35 and R.sup.36 are independently selected from H and C.sub.1-3 alkyl, such as methyl. Thus, in one example B is selected from pyridinyl substituted with one halogen, such as Cl, and one —CONR.sup.35R.sup.36, wherein R.sup.35 and R.sup.36 are both methyl.
(20) In a further embodiment the compound of formula (1) is selected from any one of: 5-Bromo-6-trifluoromethyl-pyridine-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Bromo-6-trifluoromethyl-pyridine-3-yl 3-[4-(4-bromothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Chloro-6-cyano-pyridine-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Bromo-2-cyano-pyridine-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-pyridine-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 5-Bromo-6-cyano-3-pyridyl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-[4-(2-chlorothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-deoxy-3-[4-(2-fluorothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-deoxy-3-[4-(4-fluorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-deoxy-3-[4-(4,5-difluorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-deoxy-3-[4-(4-hydroxythiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3,4-Dichlorophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-6-cyano-pyridine-3-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Bromo-2-cyano-pyridine-3-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Bromo-6-cyano-3-pyridyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-2-cyano-3-pyridyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-6-trifluoromethyl-pyridin-3-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3,5-dichloro-4-fluoro-phenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3-Chloro-4-fluoro-phenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3,4,5-trichlorophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3,5-dibromo-4-fluorophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3-Bromo-4-cyanophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Bromo-6-trifluoromethyl-3-pyridyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3-Chloro-4-trifluoromethylphenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3-Chloro-4-trifluoromethylthiophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 3-Chloro-4-methylphenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-picolinamide-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 2-Carboxy-5-chloropyridyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Bromo-6-trifluoromethyl-pyridine-3-yl 3-deoxy-3-[4-(4,5-dichlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Bromo-2-isopropyl-pyridine-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside. In a still further embodiment the compound of formula (1) is selected from any one of: 3,4-Dichloro-6-fluoro-phenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 4-Chloro-N,N′-dimethylbenzamide-2-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 5-Chloro-N,N′-dimethyl-picolinamide-3-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside.
(21) The skilled person will understand that it may be necessary to adjust or change the order of steps in the processes a1 to a23, 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.
(22) 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.
(23) Functional groups that it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include optionally substituted and/or unsaturated alkyl groups (e.g. methyl, allyl, benzyl or tert-butyl), trialkyl silyl or diarylalkylsilyl groups (e.g. t-butyldimethylsilyl, t-butyldipheylsilyl or trimethylsilyl), AcO (acetoxy), TBS (t-butyldimethylsilyl), TMS (trimethylsilyl), PMB (p-methoxybensyl), and tetrahydropyranyl. Suitable protecting groups for carboxylic acid include (C.sub.1-6)-alkyl or benzyl esters. Suitable protecting groups for amino include t-butyloxycarbonyl, benzyloxycarbonyl, 2-(trimethylsilyl)-ethoxy-methyl or 2-trimethylsilylethoxycarbony 1 (Teoc). Suitable protecting groups for S include 5-C(═N)NH.sub.2, TIPS.
(24) The protection and deprotection of functional groups may take place before or after any reaction in the above-mentioned processes.
(25) 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.
(26) 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.
(27) In a further embodiment the compound of formula (1) is a crystalline form. The skilled person may carry out tests in order to find polymorphs, and such polymorphs are intended to be encompassed by the term “crystalline form” as used herein.
(28) 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.
(29) 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.
(30) 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.
(31) 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.
(32) 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.
(33) The term “Oxo” as used herein means an oxygen atom with double bonds, also indicated as ═O.
(34) The term “CN” as used herein means a nitril.
(35) 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.
(36) 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.
(37) 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.
(38) 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.
(39) 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.
(40) 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.
(41) 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.
(42) As mentioned above, the compositions and particularly pharmaceutical compositions as herein disclosed may, in addition to the compounds herein disclosed, further comprise at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier. In some embodiments, the pharmaceutical compositions comprise from 1 to 99% by weight of said at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier and from 1 to 99% by weight of a compound as herein disclosed. The combined amount of the active ingredient and of the pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier may not constitute more than 100% by weight of the composition, particularly the pharmaceutical composition.
(43) In some embodiments, only one compound as herein disclosed is used for the purposes discussed above.
(44) In some embodiments, two or more of the compounds as herein disclosed are used in combination for the purposes discussed above.
(45) 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.
(46) 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.
(47) 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.
(48) 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.
(49) All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.
(50) 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.
(51) 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.
(52) Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless other-wise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Unless otherwise stated, all exact values provided herein are representative of corresponding approximate values (e.g., all exact exemplary values provided with respect to a particular factor or measurement can be considered to also pro-vide a corresponding approximate measurement, modified by “about,” where appropriate).
(53) All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.
(54) 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.
(55) 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.
(56) 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.
(57) 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 in diverse forms thereof.
(58) Experimental Procedures (Evaluation of Kd Values)
(59) The affinity of Example 1-33 for galectins were determined by a fluorescence anisotropy assay where the compound was used as an inhibitor of the interaction between galectin and a fluorescein tagged saccharide probe as described Sörme, P., Kahl-Knutsson, B., Huflejt, M., Nilsson, U. J., and Leffler H. (2004) Fluorescence polarization as an analytical tool to evaluate galectin-ligand interactions. Anal. Biochem. 334: 36-47, (Sörme 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).
(60) TABLE-US-00001 Galectin-1 Galectin-3 Example Name Structure Kd (μM) Kd (μM) 1 5-Bromo-6- trifluoromethyl- pyridine-3-yl 3-[4-(4- chlorothiazol-2-yl)-1H- 1,2,3-triazol-1-yl]-3- deoxy-1-thio-α-D- galactopyranoside
Synthesis of Examples and Intermediates
General Procedures
(61) Nuclear Magnetic Resonance (NMR) spectra were recorded on a 400 MHz Bruker AVANCE LII 500 instrument or a Varian instrument at 400 MHz, at 25° C. Chemical shifts are reported in ppm (d) using the residual solvent as internal standard. Peak multiplicities are expressed as follow: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplet; q, quartet; m, multiplet; br s, broad singlet. LC-MS were acquired on an Agilent 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. Preparative HPLC was performed on a Gilson 215. Flow: 25 mL/min Column: XBrige prep C18 10 μm OBD (19×250 mm) column. Wavelength: 254 nM. Solvent A water (10 mM Ammonium hydrogen carbonate) and solvent B Acetonitrile. Alternatively preparative HPLC were acquired on a Gilson system. Flow: 15 10124EP00
(62) 52 ml/min Column: kromasil 100-5-C18 column. Wavelength: 220 nm. Solvent A water+0.1% TFA and solvent B Acetonitrile+0.1% TFA.
(63) The following abbreviations are used aq: aqueous Calcd: Calculated CH.sub.3CN: Acetonitrile CuI: Copper Iodide DCM: Dichloromethane DIPEA: Diisopropylethylamine DMF: N,N-dimethylformamide ESI-MS: Electrospray ionization mass spectrometry EtOAc or EA: Ethylacetate GC: Gas chromatography h: hour(s) HPLC: High performance liquid chromatography LC: Liquid Chromatography MeCN: Acetonitrile mL: milliliter MeOH: Methanol MeOD: Deuterated methanol mm: millimeter mM: millimolar MS: Mass spectroscopy nm: nanometer NaI: Sodium Iodide NaOMe: Sodium methoxide NMP: N-Methyl-2-pyrrolidone N.sub.2: Nitrogen gas NMR: Nuclear magnetic resonance PE: petroleum ether pH: acidity PMB: p-methoxybenzyl Prep: Preparative rt: Room temperature TEA: Triethylamine TFA: trifluoroacetic acid THF: Tetrahydrofuran TMS: Trimethylsilyl UV: Ultraviolet Å: Ångström
Example 1
5-Bromo-6-trifluoromethyl-pyridine-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(64) ##STR00060##
(65) A solution of 5-bromo-6-trifluoromethyl-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D -galactopyranoside (50.0 mg, 0.0699 mmol) in MeOH/TEA/H.sub.2O (1/0.6/0.2) (1.8 mL) was stirred at room temperature for 4 h. The reaction mixture was evaporated to dryness and the crude product was purified by Prep-HPLC to afford the title compound (24.0 mg, 58%) as a white solid. .sup.1H-NMR (400 MHz, MeOD) δ 8.74 (d, J=2 Hz 1H), 8.60 (s, 1H), 8.50 (d, J=1.2 Hz, 1H), 7.46 (m, 1H), 6.11 (d, J=5.2 Hz, 1H), 5.10-5.07 (m, 1H), 4.98-4.93 (m, 1H), 4.40-4.39 (t, J=5.6 Hz, 1H), 4.20 (d, J=2.8 Hz, 1H), 3.70-3.68 (m, 2H). m/z calcd for [C.sub.17H.sub.14BrClF.sub.3N.sub.5O.sub.4S.sub.2].sup.+ [M+H].sup.+: 588.0; found: 588.0.
Example 2
5-Bromo-6-trifluoromethyl-pyridine-3-yl 3-[4-(4-bromothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(66) ##STR00061##
(67) 5-Bromo-6-trifluoromethyl-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-bromothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (22.0 mg, 0.0290 mmol) was dissolved in MeOH (15 mL) followed by addition of TEA (14.6 mg, 0.145 mmol). The mixture was stirred at rt for 6 hours. The mixture was acidified to pH=6 by addition of 2 M HCl. The mixture was purified by reverse-phase chromatography to obtain the title compound (3.80 mg 20.7%) as white solid. .sup.1H NMR (400 MHz, MeOD) δ 8.74 (d, J=2 Hz 1H), 8.61 (s, 1H), 8.50 (d, J=1.6 Hz, 1H), 7.58 (m, 1H), 6.12-6.11 (d, J=5.6 Hz, 1H), 5.07 (m, 1H), 4.98-4.96 (d, J=5.6 Hz, 1H), 4.40 (t, J=3.4 Hz, 1H), 4.20 (d, J=2.4 Hz, 1H), 3.70-3.69 (m, 2H). m/z calcd for [C.sub.17H.sub.14Br.sub.2F.sub.3N.sub.5O.sub.4S.sub.2].sup.+ [M+H].sup.+: 632.0; found: 632.0.
Example 3
5-Chloro-6-cyano-pyridine-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(68) ##STR00062##
(69) A solution of 5-chloro-6-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (110 mg, 0.175 mmol) in MeOH/TEA/H.sub.2O (0.5/0.3/0.1)(5 mL) was stirred at room temperature for 4 h. The mixture was evaporated to dryness and the crude product was purified by Prep-HPLC to afford the title compound 50.0 mg (56.9% yield). .sup.1H NMR (400 MHz, MeOD) δ 8.72 (d, J=1.9 Hz, 1H), 8.60 (s, 1H), 8.33 (d, J=1.9 Hz, 1H), 7.46 (s, 1H), 6.20 (d, J=5.3 Hz, 1H), 5.09 (dd, J=11.4, 2.8 Hz, 1H), 4.97 (dd, J=11.3, 5.4 Hz, 1H), 4.34 (t, J=6.1 Hz, 1H), 4.19 (d, J=2.8 Hz, 1H), 3.69 (d, J=6.0 Hz, 2H). m/z calcd for [C.sub.17H.sub.14Cl.sub.2N.sub.6O.sub.4S.sub.2].sup.+ [M+H].sup.+:501.4 found: 502.
Example 4
5-Bromo-2-cyano-pyridine-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(70) ##STR00063##
(71) A solution of 5-bromo-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (40.0 mg, 0.0597 mmol) in MeOH/TEA/H.sub.2O (0.5/0.3/0.1)(5 mL) was stirred at room temperature for 4 h. The mixture was evaporated to dryness and the crude product was purified by Prep-HPLC to afford 20.0 mg (62%) of the title compound. .sup.1H NMR (400 MHz, MeOD) δ 8.67 (d, J=2.0 Hz, 1H), 8.63-8.56 (m, 2H), 7.46 (s, 1H), 6.21 (d, J=5.4 Hz, 1H), 5.13 (dd, J=11.4, 2.8 Hz, 1H), 4.99 (dd, J=11.3, 5.4 Hz, 1H), 4.37 (t, J=6.2 Hz, 1H), 4.22 (d, J=2.0 Hz, 1H), 3.72-3.63 (m, 2H). m/z calcd for [C.sub.17H.sub.14BrClN.sub.6O.sub.4S.sub.2].sup.+[M+H].sup.+:544; found: 545.
Example 5
5-Chloro-2-cyano-pyridine-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(72) ##STR00064##
(73) A solution of 5-chloro-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (46.0 mg, 0.0733 mmol) in 5 mL of MeOH/TEA/H.sub.2O (5/3/1) was stirred at room temperature for 4 h. The mixture was evaporated to dryness and the crude product was purified by Prep-HPLC to afford the title compound 21.4 mg (58.1%) as a white solid. .sup.1H NMR (400 MHz, MeOD) δ 8.61 (s, 1H), 8.56 (d, J=2.2 Hz, 1H), 8.44 (d, J=2.2 Hz, 1H), 7.46 (s, 1H), 6.22 (d, J=5.4 Hz, 1H), 5.13 (dd, J=11.3, 2.8 Hz, 1H), 4.99 (dd, J=11.3, 5.4 Hz, 1H), 4.36 (t, J=6.0 Hz, 1H), 4.24-4.18 (m, 1H), 3.71-3.64 (m, 2H). m/z calcd for [C.sub.17H.sub.15Cl.sub.2N.sub.6O.sub.4S.sub.2].sup.+ [M+H].sup.+: 501.0; found: 501.1.
Example 6
5-Bromo-6-cyano-3-pyridyl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(74) ##STR00065##
(75) To a solution of 5-bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (57.0 mg, 0.0908 mmol) in 5 mL of MeOH/TEA/H.sub.2O (5/3/1) was stirred at room temperature for 4 h. The mixture was evaporated to dryness and the crude product was purified by Prep-HPLC to afford the title compound 25.9 mg (56.9%) as a white solid. .sup.1H NMR (400 MHz, MeOD) δ 8.76 (d, J=1.9 Hz, 1H), 8.60 (s, 1H), 8.47 (d, J=1.9 Hz, 1H), 7.46 (s, 1H), 6.18 (d, J=5.3 Hz, 1H), 5.09 (dd, J=11.4, 2.8 Hz, 1H), 4.97 (dd, J=11.4, 5.3 Hz, 1H), 4.35 (t, J=6.0 Hz, 1H), 4.23-4.19 (m, 1H), 3.75-3.66 (m, 2H). m/z calcd for [C.sub.17H.sub.15BrClN.sub.6O.sub.4S.sub.2].sup.+ [M+H].sup.+: 544.95; found: 545.0.
Example 7
3,4-Dichlorophenyl 3-[4-(2-chlorothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(76) ##STR00066##
(77) To a solution of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl 3-[4-(2-chlorothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (10.0 mg, 0.0157 mmol) in MeOH/TEA/H.sub.2O (0.5/0.3/0.1)(1 mL) was stirred at room temperature with for 4 h. The mixture was evaporated to dryness and the crude product was purified by prep-HPLC to afford the title compound as a white solid (1.91 mg, 0.00322 mmol, yield: 20.5%). .sup.1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 7.86 (s, 1H), 7.80 (d, J=1.7 Hz, 1H), 7.58-7.51 (m, 1H), 7.48 (d, J=8.4 Hz, 1H), 5.84 (d, J=5.3 Hz, 1H), 4.99 (dd, J=11.5, 2.7 Hz, 1H), 4.91 (dd, J=11.5, 5.3 Hz, 1H), 4.48 (t, J=6.5 Hz, 1H), 4.20 (d, J=2.2 Hz, 1H), 3.76-3.65 (m, 2H). m/z calcd for [C.sub.17H.sub.15Cl.sub.3N.sub.4O.sub.4S.sub.2].sup.+[M+H].sup.+:509.0; found: 509.0.
Example 8
3,4-Dichlorophenyl 3-deoxy-3-[4-(2-fluorothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(78) ##STR00067##
(79) This compound is made via process a24 or a1 as described above.
Example 9
3,4-Dichlorophenyl 3-deoxy-3-[4-(4-fluorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(80) ##STR00068##
(81) This compound is made via process a25 or a1 as described above.
Example 10
3,4-Dichlorophenyl 3-deoxy-3-[4-(4,5-difluorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(82) ##STR00069##
(83) This compound is made via process a25 or a1 as described above.
Example 11
3,4-Dichlorophenyl 3-deoxy-3-[4-(4-hydroxythiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(84) ##STR00070##
(85) A solution of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-hydroxythiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (60.0 mg, 0.0972 mmol) in MeOH (2 mL) and the pH was adjusted to 8-9 by addition of sodium methoxide. The reaction was stirred at room temperature for 2 h. The mixture was evaporated to dryness under low temperature and the crude product was purified by Prep-HPLC to afford the title compound 10.0 mg (21%). 1H NMR (400 MHz, MeOD) δ 8.66 (dd, J=94.9, 48.9 Hz, 1H), 7.79 (d, J=2.1 Hz, 1H), 7.56-7.43 (m, 2H), 5.83 (dd, J=7.7, 4.7 Hz, 1H), 5.02 (s, 1H), 4.95-4.86 (m, 3H), 4.47 (d, J=5.2 Hz, 1H), 4.23-4.12 (m, 1H), 3.70 (t, J=6.0 Hz, 2H). m/z calcd for [C.sub.17H.sub.16C.sub.12N.sub.4O.sub.5S.sub.2].sup.+ [M+H].sup.+:617.0; found: 617.0.
Example 12
3,4-Dichlorophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(86) ##STR00071##
(87) A solution of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (23.0 mg, 0.0372 mmol) in MeOH/TEA/H.sub.2O (0.5/0.3/0.1)(0.9 mL) was stirred at room temperature for 4 h. The mixture was evaporated to dryness and the crude product was purified by Prep-HPLC to afford the title compound as a white solid 10.0 mg (27%). .sup.1H NMR (400 MHz, MeOD) δ 8.35 (s, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.53 (dd, J=8.4, 2.0 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 6.69 (s, 1H), 5.83 (d, J=5.3 Hz, 1H), 4.98 (dd, J=11.4, 2.8 Hz, 1H), 4.83 (dd, J=11.4, 5.3 Hz, 1H), 4.47 (t, J=6.0 Hz, 1H), 4.18 (d, J=2.0 Hz, 1H), 3.76-3.64 (m, 2H). m/z calcd for [C.sub.17H.sub.16Cl.sub.2N.sub.4O.sub.5S.sub.2].sup.+ [M+H].sup.+:491.0; found: 491.2.
Example 13
5-Chloro-6-cyano-pyridine-3-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(88) ##STR00072##
(89) To a solution of 5-chloro-6-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (60.0 mg, 0.099 mmol) in MeOH (5.00 mL) was added TEA (0.841 mL, 6.03 mmol) and water (280 mg, 16 mmol). The mixture was stirred at rt for overnight followed by removal of the solvents. The residue was purified by C-18 column to obtain the title compound (16.0 mg, 0.053 mmol, yield: 54%). .sup.1H NMR (400 MHz, MeOD) δ 8.74 (d, J=1.9 Hz, 1H), 8.41-8.33 (m, 2H), 6.72 (s, 1H), 6.21 (d, J=5.3 Hz, 1H), 5.07 (dd, J=11.3, 2.9 Hz, 1H), 4.95 dd, J=11.3, 5.3 Hz, 1H), 4.35 (t, J=6.0 Hz, 1H), 4.18 (s, 1H), 3.70 (d, J=6.0 Hz, 2H). m/z calcd for [C.sub.17H.sub.15ClN.sub.6O.sub.5S.sub.2].sup.+ [M+H].sup.+:482.9; found: 483.
Example 14
5-Bromo-2-cyano-pyridine-3-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(90) ##STR00073##
(91) To a solution of 5-bromo-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (25.0 mg, 0.0383 mmol) in the MeOH (5.00 mL) was added TEA (0.841 mL, 6.03 mmol) and water (280 mg, 15.6 mmol). The mixture was stirred at rt for overnight. Removal of solvent gave a residue which was purified by Prep HPLC to obtain the title compound (8.00 mg, 0.015 mmol, yield: 40%). .sup.1H NMR (400 MHz, MeOD) δ 8.69 (d, J=2.0 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.34 (s, 1H), 6.71 (s, 1H), 6.22 (d, J=5.4 Hz, 1H), 5.08 (dd, J=11.3, 2.8 Hz, 1H), 4.96 (dd, J=11.4, 5.4 Hz, 1H), 4.37 (t, J=6.0 Hz, 1H), 4.22 (s, 1H), 3.72-3.63 (m, 2H). m/z calcd for [C.sub.17H.sub.15BrN.sub.6O.sub.5S.sub.2].sup.+ [M+H].sup.+:527; found: 527.
Example 15
5-Bromo-6-cyano-3-pyridyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(92) ##STR00074##
(93) To a solution of 5-bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (45.0 mg, 0.069 mmol) in the MeOH (5.00 mL) was added TEA (0.841 mL, 6.03 mmol) and water (280 mg, 15.6 mmol). The mixture was stirred at rt for overnight. Removal of solvent gave a residue which was purified by Prep HPLC to obtain the title compound (16.0 mg, 0.0303 mmol, yield: 44.1%). .sup.1H NMR (400 MHz, MeOD) δ 8.78 (d, J=1.8 Hz, 1H), 8.49 (d, J=1.9 Hz, 1H), 8.38 (s, 1H), 6.72 (s, 1H), 6.20 (d, J=5.3 Hz, 1H), 5.06 (dd, J=11.4, 2.8 Hz, 1H), 4.93 (dd, J=11.4, 5.4 Hz, 1H), 4.36 (t, J=6.0 Hz, 1H), 4.19 (s, 1H), 3.71 (d, J=6.0 Hz, 2H). m/z calcd for [C.sub.17H.sub.15BrN.sub.6O.sub.5S.sub.2].sup.+[M+H].sup.+:527; found: 527.
Example 16
5-Chloro-2-cyano-3-pyridyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(94) ##STR00075##
(95) To a solution of 5-chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (45.0 mg, 0.0739 mmol) in MeOH (5.00 mL) was added TEA (0.841 mL, 6.03 mmol) and water (280 mg, 15.6 mmol). The mixture was stirred at rt for overnight. Removal of solvent gave a residue which was purified by Prep-HPLC to obtain the title compound (20.0 mg, 0.0414 mmol, yield: 56.1%). .sup.1H NMR (400 MHz, MeOD) δ 8.47 (d, J=2.1 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 8.27 (s, 1H), 6.60 (s, 1H), 6.12 (d, J=5.3 Hz, 1H), 4.98 (dd, J=11.5, 2.5 Hz, 1H), 4.85 (dd, J=11.3, 5.4 Hz, 2H), 4.25 (t, J=6.1 Hz, 1H), 4.10 (s, 1H), 3.57 (d, J=6.0 Hz, 2H). m/z calcd for [C.sub.17H.sub.15ClN.sub.6O.sub.5S.sub.2].sup.+ [M+H].sup.+:482.9; found: 483.0.
Example 17
5-Chloro-6-trifluoromethyl-pyridin-3-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(96) ##STR00076##
(97) To a solution of 5-Bromo-6-trifluoromethyl-pyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (12.0 mg, 0.0184 mmol) in the MeOH (5.00 mL) was added TEA (0.841 mL, 6.03 mmol) and water (280 mg, 15.6 mmol). The mixture was stirred at rt overnight. Removal of solvent gave a residue which was purified by C-18 column to obtain the title compound (2.45 mg, 0.00466 mmol, yield: 25.3%). .sup.1H NMR (400 MHz, MeOD) δ 8.72 (d, J=1.6 Hz, 1H), 8.40-8.32 (m, 2H), 6.71 (s, 1H), 6.14 (d, J=5.5 Hz, 1H), 5.05 (dd, J=11.8, 2.9 Hz, 1H), 4.95 (dd, J=11.8, 5.4 Hz, 1H), 4.41 (t, J=5.5 Hz, 1H), 4.19 (d, J=2.3 Hz, 1H), 3.71 (d, J=6.4 Hz, 2H). m/z calcd for [C.sub.17H.sub.12ClF.sub.3N.sub.5O.sub.5S.sub.2].sup.+ [M+H].sup.+:526.0; found: 526.0.
Example 18
3,5-Dichloro-4-fluoro-phenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(98) ##STR00077##
(99) To a solution of 3,5-Dichloro-4-fluoro-phenyl 3-2,4,6-tri-O-acetyl-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (70.0 mg, 0.110 mmol) in MeOH/TEA/H.sub.2O (5/3/1)(2 mL) was stirred at room temperature for 4 h. The mixture was evaporated to dryness and the crude product was purified by prep-HPLC to afford the title compound as a white solid (9.00 mg, 0.0177 mmol, yield: 16.0%). .sup.1H NMR (400 MHz, MeOD) δ 8.26 (s, 1H), 7.63 (d, J=6.3 Hz, 2H), 6.60 (s, 1H), 5.72 (d, J=5.3 Hz, 1H), 4.88 (dd, J=11.4, 2.8 Hz, 1H), 4.74 (dd, J=11.4, 5.3 Hz, 1H), 4.38 (t, J=6.0 Hz, 1H), 4.08 (d, J=2.0 Hz, 1H), 3.66-3.56 (m, 2H). m/z calcd for [C.sub.17H.sub.12Cl.sub.2FN.sub.4O.sub.5S.sub.2].sup.+ [M+H].sup.+:509.0; found: 509.0.
Example 19
3-Chloro-4-fluoro-phenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(100) ##STR00078##
Example 20
3,4,5-trichlorophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(101) ##STR00079##
(102) To a solution of 3,4,5-trichlorophenyl 2,4,6-tri-O-acetyl-3-[4-(2-hydroxythiazol-4-yl)triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (35.0 mg, 0.0537 mmol) in the MeOH (2 mL) was added TEA (1.00 mL, 7.17 mmol) and water (19.3 mg, 1.07 mmol). The mixture was stirred at rt for overnight. After concentration, the residue was purified by column chromatography (MeCN/H.sub.2O=10/1˜95/5, C-18 column, 10 mL/min, UV 254) to obtain the title compound (15.0 mg, 0.030 mmol, yield: 52%). .sup.1H NMR (400 MHz, MeOD) δ 8.24 (s, 1H), 7.67 (s, 2H), 6.59 (s, 1H), 5.81 (d, J=5.3 Hz, 1H), 4.88 (dd, J=11.3, 2.6 Hz, 1H), 4.79 (m, 1H), 4.34 (t, J=5.9 Hz, 1H), 4.08 (s, 1H), 3.67-3.55 (m, 2H). m/z calcd for [C.sub.17H.sub.15Cl.sub.3N.sub.4O.sub.5S.sub.2]: [M+1].sub.+: 525.0; found: 525.
Example 21
3,5-dibromo-4-fluorophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(103) ##STR00080##
(104) A solution of 3,5-dibromo-4-fluorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (50.0 mg, 0.0690 mmol) in MeOH/Et.sub.3N/H.sub.2O (0.5/0.3/0.1)(0.9 mL) was stirred at room temperature for 4 hours followed by removal of solvent by evaporation. The residue was purified by preparative HPLC (X-Select10 um 19*250 mm, 20 mL/min, MeOH/H.sub.2O (10 mM NH.sub.4HCO.sub.3)=20%˜90%) to afford the title compound as a white solid (16.0 mg, 0.0267 mmol, yield: 38.7%). .sup.1H NMR (400 MHz, MeOD) δ 8.32 (s, 1H), 7.88 (d, J=5.9 Hz, 2H), 6.68 (s, 1H), 5.79 (d, J=5.3 Hz, 1H), 4.96 (dd, J=11.4, 2.7 Hz, 1H), 4.84 (d, J=6.1 Hz, 1H), 4.47 (t, J=6.0 Hz, 1H), 4.16 (d, J=1.8 Hz, 1H), 3.71 (dd, J=6.0, 2.0 Hz, 2H). m/z calcd for [C.sub.17H.sub.12Br.sub.2FN.sub.4O.sub.4S.sub.2].sup.+ [M+H].sup.+: 597; found: 597.
Example 22
3-Bromo-4-cyanophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(105) ##STR00081##
(106) A solution of 3-bromo-4-cyanophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (30.0 mg, 0.0460 mmol) in MeOH (5.00 mL) was added TEA (0.841 mL, 6.03 mmol) and water (280 mg, 15.6 mmol). The mixture was stirred at room temperature overnight. Removal of solvent gave a residue. The residue was purified by column chromatography (MeCN/H.sub.2O=1/20˜3/1, C-18 column, 20 mL/min, UV 254) to obtain the title compound (95.0%, 20.0 mg, 0.0361 mmol, yield: 78.5%). 1H NMR (400 MHz, MeOD) δ 8.26 (s, 1H), 7.91 (s, 1H), 7.64-7.51 (m, 2H), 6.60 (s, 1H), 5.99 (d, J=5.3 Hz, 1H), 4.90 (d, J=2.8 Hz, 1H), 4.83-4.78 (m, 1H), 4.27 (s, 1H), 4.08 (s, 1H), 3.65-3.51 (m, 2H). m/z calcd for [C.sub.18H.sub.16BrN.sub.5O.sub.5S.sub.2]: [M+1].sup.+: 526; found: 526.
Example 23
5-Bromo-6-trifluoromethyl-3-pyridyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(107) ##STR00082##
(108) A solution of 5-bromo-6-trifluoromethyl-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (65.0 mg, 0.0933 mmol) in MeOH/Et.sub.3N/H.sub.2O (5/3/1, 8 mL) was stirred at room temperature overnight. The solvents were removed by evaporation to afford crude product which was purified by Prep HPLC (X-Select10 um 19*250 mm, 20 mL/min, MeCN/H.sub.2O (10 mM NH.sub.4HCO.sub.3)=20%˜80%) to give the title compound as white solid (21.0 mg, 0.0368 mmol, yield: 39.5%). .sup.1H NMR (400 MHz, MeOD) δ 8.76 (d, J=1.7 Hz, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 6.72 (s, 1H), 6.13 (d, J=5.3 Hz, 1H), 5.06 (dd, J=11.3, 2.9 Hz, 1H), 4.93 (dd, J=11.3, 5.4 Hz, 1H), 4.42 (t, J=6.4 Hz, 1H), 4.21 (s, 1H), 3.77-3.66 (m, 2H). m/z calcd for [C.sub.17H.sub.15BrF.sub.3N.sub.5O.sub.5S.sub.2] [M+H].sup.+: 572; found: 572.
Example 24
3-Chloro-4-trifluoromethylphenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(109) ##STR00083##
(110) To a solution of 3-chloro-4-trifluoromethylphenyl 2,4,6-tri 0-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (30.0 mg, 0.0461 mmol) in MeOH (5.00 mL) was added TEA (704 mg, 6.96 mmol) and water (323 mg, 17.9 mmol). The reaction mixture was stirred at room temperature overnight. Removal of solvent gave a residue. The residue was purified by column chromatography (MeCN/H.sub.2O=1/20˜1/5, C-18 column, 20 mL/min, UV 254) to obtain 1-(3-chloro-4-(trifluoromethyl)phenyl)-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1,3-dideoxy-1-thio-α-D-galactopyranoside (9.00 mg, yield: 36.5%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.26 (s, 1H), 7.73 (s, 1H), 7.58 (s, 2H), 6.60 (s, 1H), 5.95 (s, 1H), 4.89 (d, J=11.6 Hz, 1H), 4.81 (m, 1H), 4.31 (m, 1H), 4.08 (m, 1H), 3.60 (m, 2H). m/z calcd for [C.sub.18H.sub.16ClF.sub.3N.sub.4O.sub.5S.sub.2] [M+1].sup.+: 525; found: 525.
Example 25
3-Chloro-4-trifluoromethylthiophenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(111) ##STR00084##
(112) This compound is made via process a1 or a2 described above.
Example 26
3-Chloro-4-methylphenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(113) ##STR00085##
(114) A solution of 3-chloro-4-methylphenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (50.0 mg, 0.0837 mmol) in MeOH/Et.sub.3N/H.sub.2O (5/3/1)(8 mL) was stirred at room temperature overnight. After removal of the solvents, the residue was purified by Prep HPLC (X-Select10 um 19*250 mm, 20 mL/min, MeCN/H.sub.2O (10 mM NH.sub.4HCO.sub.3)=30%˜90%) to give the title compound (20.6 mg, 0.0437 mmol, yield: 52.2%) as white solid. .sup.1H NMR (400 MHz, MeOD) δ 8.35 (s, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.43 (dd, J=7.9, 1.6 Hz, 1H), 7.25 (d, J=7.9 Hz, 1H), 6.69 (s, 1H), 5.73 (d, J=5.3 Hz, 1H), 4.97 (dd, J=11.5, 2.7 Hz, 1H), 4.83-4.77 (m, 1H), 4.52 (t, J=6.2 Hz, 1H), 4.18 (d, J=1.9 Hz, 1H), 3.70 (qd, J=11.4, 6.2 Hz, 2H), 2.35 (s, 3H). m/z calcd for [C.sub.18H.sub.19ClN.sub.4O.sub.5S.sub.2] [M+H].sup.+: 471; found: 471.
Example 27
5-Chloro-picolinamide-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(115) ##STR00086##
(116) This compound is made via process a1 or a2 described above.
Example 28
2-carboxy-5-chloropyridyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(117) ##STR00087##
(118) A stirred solution of 5-chloro-2-(methoxycarbonyl)pyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (200.0 mg, 0.311 mmol) in MeOH (5 mL) was added TEA (2 mL) and H.sub.2O (1 mL). The reaction was stirred at room temperature for 24 hours. LiOH.Math.H.sub.2O (65.4 mg, 1.56 mmol) was added and the reaction was stirred at room temperature for 4 hours. Acidic resin was added into the solution and the pH value was adjusted to 3-4. After filtration, the solvent was removed and the obtained residue was purified twice by Preparative HPLC (X-Select10 um 19*250 mm, 20 mL/min, MeCN/H.sub.2O=0%˜10%) to afford the title compound (10 mg, 0.02 mmol, yield: 6.4%). .sup.1H NMR (400 MHz, D.sub.2O) δ 8.44 (s, 1H), 8.42 (s, 1H), 8.27 (s, 1H), 6.80 (s, 1H), 6.06 (d, J=5.5 Hz, 1H), 5.20 (dd, J=11.4, 2.8 Hz, 1H), 5.00 (dd, J=11.6, 5.5 Hz, 1H), 4.58 (dd, J=7.7, 4.4 Hz, 1H), 4.29 (d, J=2.4 Hz, 1H), 3.78-3.68 (m, 2H). m/z calcd for [C.sub.17H.sub.16ClN.sub.5O.sub.7S.sub.2] [M+1].sup.+: 502, found: 502.
Example 29
5-Bromo-6-trifluoromethyl-pyridine-3-yl 3-deoxy-3-[4-(4,5-dichlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(119) ##STR00088##
(120) A solution of 5-bromo-6-(trifluoromethyl)pyridin-3-yl 3-deoxy-3-[4-(4,5-dichlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (45.0 mg, 0.0601 mmol) in MeOH/TEA/H.sub.2O (5/3/1) (2 mL) was stirred at room temperature for 4 hours. The solvents were evaporated and the crude product was purified by prep HPLC (X-Select10 μm 19*250 mm, 20 mL/min, MeCN/H.sub.2O (10 mM NH.sub.4HCO.sub.3)=20%˜80%) to afford the title compound. (26.0 mg, 0.0417 mmol, yield: 69.5%). .sup.1H NMR (400 MHz, MeOD) δ 8.76 (d, J=1.6 Hz, 1H), 8.63 (s, 1H), 8.52 (s, 1H), 6.13 (d, J=5.3 Hz, 1H), 5.11 (dd, J=11.3, 2.8 Hz, 1H), 4.98 (dd, J=11.3, 5.3 Hz, 1H), 4.42 (t, J=6.1 Hz, 1H), 4.22 (s, 1H), 3.78-3.66 (m, 2H). m/z calcd for [C.sub.17H.sub.10BrCl.sub.2F.sub.3N.sub.5O.sub.4S.sub.2].sup.+ [M+H].sup.+: 622; found: 622.
Example 30
5-Bromo-2-isopropyl-pyridine-3-yl 3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(121) ##STR00089##
(122) This compound is made via process a1 or a25 described above.
Example 31
3,4-Dichloro-6-fluoro-phenyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(123) ##STR00090##
(124) A solution of 3,4-dichloro-6-fluoro-phenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (53.0 mg, 0.0834 mmol) in MeOH (3 mL) was added TEA (1.50 mL, 10.8 mmol), and water (500 mg, 27.8 mmol). The mixture was stirred at room temperature overnight. After concentration, the residue was purified by column chromatography (MeCN/H.sub.2O=1/20˜1/5, C-18 column, 15 mL/min, UV 254) to obtain the title compound (97.0%, 15.6 mg, 0.0297 mmol, yield: 35.6%). .sup.1H NMR (400 MHz, MeOD) δ 8.35 (s, 1H), 7.89 (d, J=7.0 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 6.69 (s, 1H), 5.93 (d, J=5.4 Hz, 1H), 5.05 (dd, J=11.4, 2.8 Hz, 1H), 4.88 (m, 1H), 4.39 (t, J=6.2 Hz, 1H), 4.18 (d, J=2.5 Hz, 1H), 3.71-3.50 (m, 2H). m/z calcd for [C.sub.17H.sub.15Cl.sub.2FN.sub.4O.sub.5S.sub.2] [M+1].sup.+: 509, found: 509.
Example 32
4-Chloro-N,N′-dimethylbenzamide-2-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(125) ##STR00091##
(126) 5-Chloro-N,N′-dimethyl-benzamide-2-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside (53 mg, 0.13 mmol), 4-(2-trimethylsilylethynyl)thiazol-2-ol (39 mg, 0.20 mmol) and CuI (2.5 mg, 0.013 mmol) were dissolved in MeCN (3 mL) followed by addition of DIPEA (68 μL, 0.40 mmol) and stirring 16 h at 50° C. The mixture was concentrated and purification by HPLC (Cis, H.sub.2O/MeCN/0.1% TFA) and freeze drying afforded the title compound as a white powder (53 mg, 76%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.35 (s, 1H), 7.86 (s, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.27 (d, J=8.2, 1H), 6.69 (s, 1H), 5.91 (d, J=5.3 Hz, 1H), 4.96 (dd, J=11.5, 2.7 Hz, 1H), 4.87-4.85 (m, 1H), 4.47 (t, J=6.1 Hz, 1H), 4.18 (d, J=2.5 Hz, 1H), 3.76-3.65 (m, 2H), 3.13 (s, 3H), 2.89 (s, 3H). ESI-MS m/z calcd for [C.sub.20H.sub.22ClN.sub.5O.sub.6S.sub.2].sup.+ (M+H).sup.+: 528.1; found: 528.1.
Example 33
5-Chloro-N,N′-dimethyl-picolinamide-3-yl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(127) ##STR00092##
(128) A solution of CuSO.sub.4.Math.5H.sub.2O (5.5 mg, 0.022 mmol) and L-ascorbic acid sodium salt (8.7 mg, 0.044 mmol) in H.sub.2O (0.5 mL) was added to a solution of 5-chloro-2-(dimethylcarbamoyl)-3-pyridyl 2,4,6-tri-0-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (116 mg, 0.22 mmol), 4-(2-trimethylsilylethynyl)thiazol-2-ol (65 mg, 0.33 mmol) and K.sub.2CO.sub.3 (303 mg, 2.19 mmol) in MeOH (3 mL) and THF (3 mL). After stirring 20 h at 50° C. CuI (10 mg, 0.053 mmol) was added and after stirring an additional 20 h at 50° C. the mixture was concentrated. Purification by HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) and freeze drying afforded the title compound as a white powder (6 mg, 5%), .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.50 (d, J=1.5 Hz, 1H), 8.35 (s, 2H), 6.69 (s, 1H), 6.02 (d, J=5.3 Hz, 1H), 4.99 (dd, J=11.4, 2.7 Hz, 1H), 4.89-4.85 (m, 1H), 4.43 (t, J=6.1 Hz, 1H), 4.17 (d, J=2.5 Hz, 1H), 3.70 (d, J=6.0 Hz, 2H), 3.15 (s, 3H), 2.89 (s, 3H). ESI-MS m/z calcd for [C.sub.19H.sub.21ClN.sub.6O.sub.6S.sub.2].sup.+ (M+H).sup.+: 529.1; found: 529.1.
(129) Intermediates Used to Make Examples 1-33
(130) Intermediate 1
5-Bromo-6-trifluoromethyl-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
3-Bromo-5-fluoro-2-iodo-pyridine
(131) ##STR00093##
(132) To a solution of 2,3-dibromo-5-fluoro-pyridine (5.00 g, 19.6 mmol) in MeCN (20 mL) were added NaI (8.82 g, 58.9 mmol) and trimethylsilyl chloride (2.12 g, 19.6 mmol). The reaction was stirred at room temperature for 2 h under N.sub.2. Removal of solvent gave a residue which was purified by column chromatography (PE) to give the title compound (3.5 g, 44.8%). m/z calcd for [C.sub.5H.sub.2BrFIN].sup.+ [M+H].sup.+: 301.0; found: 301.0.
3-bromo-5-fluoro-2-(trifluoromethyl)pyridine
(133) ##STR00094##
(134) KF (423 mg, 7.29 mmol) and Iodocopper (1.26 g, 6.63 mmol) were thoroughly mixed before being heated under vacuum (1 mm Hg) with the flame of a Bunsen burner with gentle shaking until an homogeneous greenish color was obtained. NMP (20 mL), (Trifluoromethyl)trimethylsilane (942 mg, 6.63 mmol) was added. The mixture was stirred at 50° C. for 45 min followed by addition of 3-bromo-5-fluoro-2-iodo-pyridine (2 g, 6.63 mmol). The mixture was stirred at 50° C. for overnight. The reaction was monitored by GC-MS. Water (20 mL) was added to the mixture and extracted with EA (30 mL×3). The combined organic layers were washed with brine and evaporated to afford crude product, which was purified by flash chromatography on a Biotage® (EA/PE=1%˜50%, ISCO® 40 g, 25 mL/min, normal phase silica gel, UV 254) to afford the title compound 1.15 g (71.1%) as a white solid. m/z calcd for [C.sub.6H.sub.2BrF.sub.4N].sup.+ [M+H].sup.+: 244.0; found: 244.0.
3-thiol 5-bromo-6-(trifluoromethyl)pyridine
(135) ##STR00095##
(136) To a solution of 3-bromo-5-fluoro-2-(trifluoromethyl)pyridine (1.15 g, 4.71 mmol) in DMF (20 mL) was added sodium sulfide (1.245 g, 5.18 mmol). The reaction mixture was stirred at room temperature for 3 h. The pH was adjusted to pH-9 by adding 10% NaOH(aq). The mixture was extracted with Et.sub.2O (30 mL×3) and the aqueous layer was acidified with 2M NaHSO.sub.4 to pH˜3. The mixture was extracted with EA (20 mL×3). The combined organic layers were washed with brine and evaporated to afford crude product, which was purified by flash chromatography using a Biotage® (EA/PE=1%˜50%, ISCO® 20 g, 15 mL/min, normal phase silica gel, UV 254) to afford the title compound 729 mg (60%) as a brown oil. m/z calcd for [C.sub.6H.sub.3BrF.sub.3NS].sup.+ [M+H].sup.+: 257.0; found: 257.0.
5-Bromo-6-trifluoromethyl-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(137) ##STR00096##
(138) Cs.sub.2CO.sub.3 (1.40 g, 4.29 mmol) was added to a solution of 5-bromo-6-(trifluoromethyl)pyridine-3-thiol (738 mg, 2.86 mmol) in DMF (20 mL) at 0° C. The solution was stirred at rt for 30 min. Then 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (1.00 g, 2.86 mmol) was added to mixture. The reaction was stirred at 50° C. for 2 h. The mixture was cooled to room temperature followed by addition of water (30 mL). The aqueous phase was extracted with EtOAc (30 mL×3) and the combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford crude product, which was purified by flash chromatography on a Biotage® (EA/PE=5% 40%, ISCO® 40 g, 30 mL/min, normal phase silica gel, uv 254) to afford the target compound (226 mg, 13.8%) as a white solid. m/z calcd for [C.sub.18H.sub.18BrF.sub.3N.sub.4O.sub.7S]+ [M+H]+: 571.0; found: 571.0.
5-Bromo-6-trifluoromethyl-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(139) ##STR00097##
(140) To a solution of 5-Bromo-6-trifluoromethyl-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (80.0 mg, 0.140 mmol) in CH.sub.3CN (2 mL) were added TEA (0.0976 mL) 0.700 mmol), Copper(I)Iodide (8.00 mg, 0.0420 mmol), CsF (31.9 mg, 0.210 mmol), 2-(4-chlorothiazol-2-yl)ethynyl-trimethyl-silane (45.3 mg, 0.210 mmol). The reaction was stirred at room temperature 20 h under a nitrogen atmosphere. Water (5 mL) and DCM (5 mL) were added and the phases were separated. The aqueous phase was extracted with DCM (10 mL×2) and the combined organic phases were washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulphate. The solvents were removed and the crude material was purified by column chromatography (PE/EA=2/1) to give the title compound (50.0 mg, 50%) as a white solid. m/z calcd for [C.sub.23H.sub.20BrClF.sub.3N.sub.5O.sub.7S.sub.2]+ [M+H]+: 714.0; found: 714.0.
(141) Intermediate 2
5-Bromo-6-trifluoromethyl-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-bromothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
4-bromo-2-((trimethylsilyl)ethynyl)thiazole
(142) ##STR00098##
(143) To a solution of 2,4-dibromothiazole (500 mg, 2.07 mmol) in CH.sub.3CN (10 mL) was added CuI (20 mg, 0.10 mmol), TEA (1.4 mL), Pd(PPh.sub.3).sub.2Cl.sub.2 (73 mg, 0.10 mmol), ethynyl(trimethyl)silane (304 mg, 3.10 mmol). The mixture was heated under Na at 50° C. for 20 h. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=10/1) to obtain the title compound (350 mg, 65.3%). m/z calcd for [C8H10BrNSSi] [M]: 258.9; found: 260.0 [M+H].
5-Bromo-6-trifluoromethyl-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-bromothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(144) ##STR00099##
(145) To a solution of 5-Bromo-6-trifluoromethyl-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (38.0 mg, 0.0665 mmol) in CH.sub.3CN (5 mL) was added 2-(4-bromothiazol-2-yl)ethynyl-trimethyl-silane (26.0 mg, 0.0998 mmol), DIPEA (0.0569 mL) 0.333 mmol), Copper(I)Iodide (12.7 mg, 0.0665 mmol) and CsF (10.1 mg, 0.0665 mmol). The mixture was heated under a Na atmosphere at reflux overnight. Removal of solvent gave a residue which was purified by column chromatography to obtain the title compound 22.0 mg (43.6%) as a white solid. m/z calcd for [C.sub.23H.sub.20Br.sub.2F.sub.3N.sub.5O.sub.7S.sub.2].sup.+ [M+H].sup.+: 758.0; found: 758.0.
(146) Intermediate 3
5-Chloro-6-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(147) and
(148) Intermediate 4
5-Bromo-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
Acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(149) ##STR00100##
(150) To a solution of 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (3.49 g, 10.0 mmol) in DMF (40 mL), potassium thioacetate (2.28 g, 20.0 mmol) and 4 Å molecular sieves (3.5 g) were added. The reaction was stirred at rt overnight followed by followed by removal of solvents in vacuum. The residue was purified by column chromatography to obtain the title compound (2.2 g 57%).sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.18 (d, J=5.3 Hz, 1H), 5.36 (d, J=3.1 Hz, 1H), 5.33 (dd, J=11.0, 5.3 Hz, 1H), 4.08-4.00 (m, 2H), 3.98-3.92 (m, 1H), 3.64 (dd, J=10.9, 3.3 Hz, 1H), 2.36 (s, 3H), 2.10 (s, 3H), 2.02 (s, 3H), 1.97 (s, 3H). m/z calcd for [C.sub.14H.sub.19N.sub.3O.sub.8S].sup.+ [M+H].sup.+: 390.1; found: 390.1.
5-Chloro-6-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside and 5-Bromo-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(151) ##STR00101##
(152) To a solution of acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (900 mg, 2.31 mmol) in DMF (10 mL) was added 2-cyano-3-bromo-5-chloro-pyridine (1379 mg, 4.62 mmol) and diethylamine (502 mg, 2.31 mmol). The mixture was stirred under a N.sub.2 atmosphere at rt overnight. The solvents were removed and the residue was purified by column chromatography to obtain the title mixture of products (450 mg).
5-Chloro-6-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(153) m/z calcd for [C.sub.18H.sub.18ClN.sub.5O.sub.7S].sup.+ [M+H].sup.+: 484.1; found: 484.1.
5-Bromo-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(154) m/z calcd for [C.sub.18H.sub.18BrN.sub.5O.sub.7S].sup.+ [M+H].sup.+:529.0; found: 529.0.
(155) Intermediate 3
5-Chloro-6-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(156) ##STR00102##
and
Intermediate 4
5-Bromo-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(157) ##STR00103##
(158) To a mixture of 5-chloro-6-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside and 5-bromo-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (107 mg, 0.203 mmol) in acetonitrile (5 mL) was added 2-(4-chlorothiazol-2-yl)ethynyl-trimethyl-silane (65 mg, 0.304 mmol). Triethylamine (102 mg, 1.01 mmol), copper(I) iodide (11.6 mg, 0.061 mmol) and CsF (46.3 mg, 0.305 mmol) were added. The reaction was stirred at room temperature overnight. The mixture was concentrated in vacuum and the residue was purified by column chromatography (PE/EA=5/1) to obtain
(159) Intermediate 3
5-Chloro-6-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 110 mg
(160) m/z calcd for [C.sub.23H.sub.20Cl.sub.2N.sub.6O.sub.7S.sub.2].sup.+[M+H].sup.+: 627.5; found: 628.
(161) and
(162) Intermediate 4
5-Bromo-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside, 40 mg
(163) m/z calcd for [C.sub.23H.sub.20BrClN.sub.6O.sub.7S.sub.2].sup.+ [M+H].sup.+:671.9; found: 672.
(164) Intermediate 5
5-Chloro-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(165) and
(166) Intermediate 6
5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
4-chloro-2-((trimethylsilyl)ethynyl)thiazole
(167) ##STR00104##
(168) To a solution of 2-bromo-4-chlorothiazole (500 mg, 2.52 mmol) in THF (10 mL) were added copper(I) iodide (24 mg, 0.13 mmol), TEA (1.76 mL) 12.6 mmol), [(C.sub.6H.sub.5).sub.3P].sub.2PdCl.sub.2 (88.4 mg, 0.126 mol), ethynyl(trimethyl)silane (0.495 g, 5.04 mmol). The mixture was stirred under Na atmosphere for 3 h. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=10/1) to obtain 110 mg (20%) of the title compound. m/z calcd for [C.sub.8H.sub.11ClNSSi].sup.+ [M+H].sup.+: 216.01; found: 216.0.
5-Chloro-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(169) and
5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(170) ##STR00105##
(171) Acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (784 mg, 2.01 mmol) and 3-bromo-5-chloro-pyridine-2-carbonitrile (876 mg, 4.03 mmol) were dissolved in DMF (30 mL). Diethylamine (295 mg, 4.03 mmol) was added. The reaction was stirred at room temperature for 20 h. Water (50 mL) and DCM (50 mL) were added. The phases were separated and the aqueous phase was extracted with DCM (50 mL×2), the combined organic phases were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=3/1) to obtain the title compound mixture 265 mg (25%).
5-Chloro-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(172) m/z calcd for [C.sub.18H.sub.19ClN.sub.5O.sub.7S].sup.+ [M+H].sup.+: 484.07; found: 484.1.
5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(173) m/z calcd for [C.sub.18H.sub.19BrN.sub.5O.sub.7S].sup.+ [M+H].sup.+: 528.02; found: 528.0.
(174) Intermediate 5
5-Chloro-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(175) and
(176) Intermediate 6
5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(177) ##STR00106##
(178) To a mixture of 5-bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside and 5-chloro-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (100 mg, 0.189 mmol) in DCM (5 mL) were added TEA (0.132 mL, 0.946 mmol), copper(I) iodide (10.8 mg, 0.0568 mmol), CsF (43.1 mg, 0.284 mmol), 2-(4-chlorothiazol-2-yl)ethynyl-trimethyl-silane (61.3 mg, 0.284 mmol). The reaction was stirred at room temperature for 4 h under a Na atmosphere. Water (10 mL) and DCM (10 mL) were added. The phases were separated and the aqueous phase was extracted with DCM (10 mL×2), the combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=4/1) to obtain
(179) Intermediate 5
5-Chloro-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside 46.0 mg (38.7%)
(180) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.53 (d, J=2.2 Hz, 1H), 8.09 (s, 1H), 8.00 (d, J=2.2 Hz, 1H), 7.07 (s, 1H), 6.22 (d, J=5.6 Hz, 1H), 5.98 (dd, J=11.7, 5.6 Hz, 1H), 5.58 (d, J=2.3 Hz, 1H), 5.18 (dd, J=11.8, 3.0 Hz, 1H), 4.83-4.67 (m, 1H), 4.11 (dd, J=11.8, 4.9 Hz, 1H), 4.02 (td, J=11.6, 7.3 Hz, 1H), 2.02 (s, 3H), 1.96 (s, 3H), 1.95 (s, 3H). m/z calcd for [C.sub.23H.sub.21Cl.sub.2N.sub.6O.sub.7S.sub.2].sup.+ [M+H].sup.+: 627.03; found: 627.0.
(181) Intermediate 6
5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-[4-(4-chlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside 57.0 mg (45%)
(182) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.60 (d, J=1.9 Hz, 1H), 8.12-8.01 (m, 2H), 7.08 (s, 1H), 6.28 (d, J=5.6 Hz, 1H), 5.97 (dd, J=11.7, 5.6 Hz, 1H), 5.56 (d, J=2.5 Hz, 1H), 5.18 (dd, J=11.7, 3.0 Hz, 1H), 4.72-4.57 (m, 1H), 4.10 (dd, J=11.8, 4.7 Hz, 1H), 4.02 (td, J=11.6, 7.4 Hz, 1H), 2.04 (s, 3H), 1.93 (s, 3H), 1.91 (s, 3H). m/z calcd for [C.sub.23H.sub.21BrClN.sub.6O.sub.7S.sub.2].sup.+ [M+H].sup.+: 670.98; found: 671.0.
(183) Intermediate 7
3,4-Dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
4-bromo-2-[(4-methoxyphenyl)methoxy]thiazole
(184) ##STR00107##
(185) To a solution of (4-methoxyphenyl)methanol (313 mg, 2.26 mmol) in THF (5 mL) was added NaH (59.3 mg, 2.47 mmol). The mixture was stirred at room temperature for 0.5 h. Then 2,4-dibromothiazole (500 mg, 2.06 mmol) was added. The reaction was stirred at room temperature over night. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=10/1) to obtain 500 mg (80.9%) of the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.31 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 6.51 (s, 1H), 5.30 (s, 2H), 3.75 (s, 3H). m/z calculated for [C.sub.3H.sub.2BrNOS] [M−PMB+H=]+: 180.0; found: 180.1.
2-[2-[(4-methoxyphenyl)methoxy]thiazol-4-yl]ethynyl-trimethyl-silane
(186) ##STR00108##
(187) To a solution of 4-bromo-2-[(4-methoxyphenyl)methoxy]thiazole (500 mg, 1.67 mmol) in DMF (5 mL) was added Copper(I)Iodide (15.9 mg, 0.0833 mmol), TEA (1.16 mL) 8.33 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (58.5 mg, 0.0833 mmol), ethynyl(trimethyl)silane (469 mg, 4.77 mmol). The mixture was heated under Na at 50° C. for 20 h. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=10/1) to obtain the title compound 60.0 mg (11.3%).
(188) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.31 (dd, J=8.9, 2.5 Hz, 2H), 6.88-6.81 (m, 3H), 5.33 (s, 2H), 3.75 (s, 3H), 0.18 (s, 9H). m/z calcd for [C.sub.16H.sub.19NO.sub.2SSi]+ [M-PMB+H]+:198.0; found: 198.1.
3,4-Dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-((4-methoxybenzyl)oxy)thiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(189) ##STR00109##
(190) To a solution of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (60.0 mg, 0.122 mmol) (Prepared in according to WO2016/120403) in CH.sub.3CN (5 mL) were added TEA (0.0849 mL) 0.609 mmol), copper(I) iodide (6.96 mg, 0.0366 mmol), CsF (27.8 mg, 0.183 mmol), 2-[2-[(4-methoxyphenyl)methoxy]thiazol-4-yl]ethynyl-trimethyl-silane (58.0 mg, 0.183 mmol). The reaction was stirred at room temperature for 20 h under a Na atmosphere. Water (10 mL) and DCM (10 mL) were added. The phases were separated and the aqueous phase was extracted with DCM (5 mL×2), the combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=2/1) to obtain the product 55.0 mg (61.2%).
(191) m/z calcd for [C.sub.31H.sub.30Cl.sub.2N.sub.4O.sub.9S.sub.2].sup.+ [M+H].sup.+:737.1; found: 737.1.
3,4-Dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(192) ##STR00110##
(193) To a solution of 3,4-Dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-((4-methoxybenzyl)oxy)thiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (55.0 mg, 0.0746 mmol) in DCM (5 mL) was added TFA (0.0277 mL) 0.373 mmol). The reaction was stirred at room temperature for 4 h. The mixture was evaporated to dryness and the crude product was purified by column chromatography (PE/EA=2/1) to obtain the title compound (30.0 mg, 0.0356 mmol, yield: 47.8%). m/z calcd for [C.sub.23H.sub.22Cl.sub.2N.sub.4O.sub.8S.sub.2].sup.+ [M+H].sup.+:617.0; found: 617.0.
3,4-Dichlorophenyl 2,4,6-tri-O-acetyl 3-[4-(2-chlorothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(194) ##STR00111##
(195) 3,4-Dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (60.0 mg, 0.0972 mmol) was dissolved in POCl.sub.3 (2 mL) and the reaction was heated to 100° C. overnight. The reaction was cooled to room temperature and poured into saturated NaHCO.sub.3 (aq). The aqueous phase was extracted with DCM (5 mL×2) and the combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=2/1) to obtain 10.0 mg (16.2%) of the title compound. m/z calcd for [C.sub.23H.sub.21Cl.sub.3N.sub.4O.sub.7S.sub.2].sup.+ [M+H].sup.+:635.0; found: 635.0.
(196) Intermediate 11
3,4-Dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-carbamoyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(197) ##STR00112##
(198) To a solution of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (4.00 g, 8.12 mmol)(Prepared in according to WO2016/120403) in CH.sub.3CN (20 mL) were added TEA (5.66 mL) 40.6 mmol), copper(I) iodide (77.4 mg, 0.406 mmol), prop-2-ynamide (842 mg, 12.2 mmol). The reaction was stirred at room temperature for 20 h under a Na atmosphere. Water (10 mL) and DCM (10 mL) were added. The phases were separated and the aqueous phase was extracted with DCM (5 mL*2), the combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=2/1) to give 1.20 g (26.3%) of the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.12 (s, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.32 (dd, J=8.4, 2.0 Hz, 1H), 7.00 (s, 1H), 6.14 (d, J=5.5 Hz, 1H), 5.93 (dd, J=11.7, 5.5 Hz, 1H), 5.65 (s, 1H), 5.59 (d, J=2.4 Hz, 1H), 5.26 (dd, J=11.7, 2.9 Hz, 1H), 4.82 (t, J=6.2 Hz, 1H), 4.19-4.00 (m, 1H), 2.07 (s, 3H), 2.00 (s, 3H), 1.98 (s, 3H). m/z calcd for [C.sub.21H.sub.22Cl.sub.2N.sub.4O.sub.8S].sup.+ [M+H].sup.+:561.1; found: 561.2.
3,4-Dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-carbamothioyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(199) ##STR00113##
(200) To a solution of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-carbamoyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (1.20 g, 2.1 mmol) in DCM (20 mL) was added Lawessons reagent (1.73 g, 4.3 mmol). The mixture was stirred at room temperature for 20 h. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=2/1) to obtain the title compound (650 mg, 1.13 mmol, yield: 52.7%). m/z calcd for [C.sub.21H.sub.22C.sub.12N.sub.4O.sub.7S.sub.2].sup.+ [M+H].sup.+:577.0; found: 577.0.
3,4-Dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-hydroxythiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(201) ##STR00114##
(202) To a solution of 3,4-dichlorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(4-carbamothioyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (100 mg, 0.173 mmol) in DCM (5 mL) were added NaHCO.sub.3 (145 mg, 1.73 mmol), 2-chloroacetyl chloride (156 mg, 1.39 mmol). The reaction was stirred at room temperature with for 20 h under a Na atmosphere. Water (10 mL) and DCM (10 mL) were added. The phases were separated and the aqueous phase was extracted with DCM (5 mL*2), the combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=2/1) to the title compound (60.0 mg, 0.0972 mmol, yield: 56.1%) m/z calcd for [C.sub.23H.sub.22C.sub.12N.sub.4O.sub.8S.sub.2].sup.+ [M+H].sup.+:617.0; found: 617.0.
(203) Intermediate 12
(204) See Intermediate 7
(205) Intermediate 13
5-Chloro-6-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(206) and
(207) Intermediate 14
5-Bromo-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
4-bromo-2-[(4-methoxyphenyl)methoxy]thiazole
(208) ##STR00115##
(209) To a solution of (4-methoxyphenyl)methanol (6.256 g, 45.3 mmol) in THF (100 mL) was added NaH (1.087 g, 45.3 mmol). The mixture was stirred at room temperature for 0.5 h. Then 2,4-dibromothiazole (10.0 g, 41.2 mmol) was added in. The reaction was stirred at room temperature overnight. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=10/1) to obtain the title compound. (7.00 g, 23.3 mmol, yield: 56.6%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.31 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 6.51 (s, 1H), 5.30 (s, 2H), 3.75 (s, 3H). m/z calcd for C.sub.11H.sub.10BrNO.sub.2S: 300.1; found: 300.1.
2-[2-[(4-methoxyphenyl)methoxy]thiazol-4-yl]ethynyl-trimethyl-silane
(210) ##STR00116##
(211) To a solution of 4-bromo-2[(4-methoxyphenyl)methoxy]thiazole (7.00 g, 23.3 mmol) in DMF (70 mL) was added Copper(I)Iodide (222 mg, 1.17 mmol), TEA (16.3 mL, 117 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (819 mg, 1.17 mmol), ethynyl(trimethyl)silane (3.4 g, 35.0 mmol). The mixture was heated under Na atmosphere at 50° C. for 20 h. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=10/1) to afford the title compound (2.5 g, 7.9 mmol, yield: 34%).sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.30 (d, J=8.7 Hz, 2H), 6.89-6.80 (m, 3H), 5.33 (s, 2H), 3.75 (s, 3H), 0.18 (s, 9H). m/z calcd for [C.sub.16H.sub.19NO.sub.2SSi]: 317; found: 317.
4-(2-trimethylsilylethynyl)thiazol-2-ol
(212) ##STR00117##
(213) To a solution of 2-[2-[(4-methoxyphenyl)methoxy]thiazol-4-yl]ethynyl-trimethyl-silane (2.50 g, 7.87 mmol) in TFA/DCM (20 mL, v/v=1/20) was stirred at room temperature for 4 h. Then the pH was adjusted to adjust pH 7-8 by addition of NaHCO.sub.3 aq. to. The phases were separated and the organic layer was dried and concentrated to dryness. The crude product was purified by column chromatography to obtain the title compound (1.2 g, 6.08 mmol, yield: 77.2%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.09 (s, 1H), 6.30 (s, 1H), 0.17 (s, 9H). m/z calcd for [C.sub.8H.sub.11NOSSi].sup.+ [M+H].sup.+:197.3; found: 197.
5-Chloro-6-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside and 5-Bromo-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(214) ##STR00118##
(215) To a solution of acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (900 mg, 2.31 mmol) in DMF (10 mL) was added 2-cyano-5-bromo-3-chloro-pyridine (1379 mg, 4.62 mmol) and diethylamine (502 mg, 2.31 mmol). The mixture was stirred under N.sub.2 at rt overnight. Removal of solvent gave a residue which was purified by column chromatography to obtain the title mixture of products (450 mg).
5-Chloro-6-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(216) m/z calcd for [C18H18ClN5O7S]+ [M+H]+: 484.1; found: 484.1.
5-Bromo-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(217) m/z calcd for [C18H18BrN5O7S]+ [M+H]+: 529.0; found: 529.0.
5-Chloro-6-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(218) and
5-Bromo-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(219) ##STR00119##
(220) To a solution of 5-chloro-6-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside and 5-bromo-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside in acetonitrile (5 mL) and 4-(2-trimethylsilylethynyl)thiazol-2-ol (112 mg, 0.568 mmol) was dissolved in acetonitrile (5 ml). Triethylamine (102 mg, 1.01 mmol), Copper(I)Iodide (21.6 mg, 0.114 mmol) and CsF (46.3 mg, 0.305 mmol) was added. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuum and the residue was purified by column chromatography to obtain the two title compounds:
5-Chloro-6-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 60.0 mg (26.0%)
(221) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 11.26 (s, 1H), 8.57 (d, J=1.9 Hz, 1H), 7.97-7.90 (m, 2H), 6.66 (s, 1H), 6.29 (d, J=5.5 Hz, 1H), 6.03 (dd, J=11.7, 5.6 Hz, 1H), 5.57 (d, J=2.4 Hz, 1H), 5.20 (dd, J=11.7, 2.9 Hz, 1H), 4.69 (dd, J=7.5, 4.9 Hz, 1H), 4.21-3.96 (m, 2H), 2.05 (s, 3H), 1.93 (d, J=6.3 Hz, 6H). m/z calcd for [C.sub.23H.sub.21ClN.sub.6O.sub.8S.sub.2].sup.+ [M+H.sub.2O].sup.+:609; found: 627.
5-Bromo-2-cyano-pyridine-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 25 mg (10%)
(222) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.48 (s, 1H), 8.63 (d, J=1.8 Hz, 1H), 8.15 (d, J=1.9 Hz, 1H), 7.89 (s, 1H), 6.54 (s, 1H), 6.23 (d, J=5.5 Hz, 1H), 6.05 (dd, J=11.6, 5.5 Hz, 1H), 5.58 (s, 1H), 5.16 (dd, J=11.7, 2.7 Hz, 1H), 4.84-4.70 (m, 1H), 4.14-4.03 (m, 2H), 2.02 (s, 3H), 1.96 (d, J=3.3 Hz, 6H). m/z calcd for [C.sub.23H.sub.21BrN.sub.6O.sub.8S.sub.2].sup.+ [M+H.sub.2O].sup.+:653; found: 671.
(223) Intermediate 15
5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(224) and
(225) Intermediate 16
5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(226) and
5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(227) ##STR00120##
(228) To a solution of acetyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (900 mg, 2.31 mmol) in DMF (10 mL) was added 2-cyano-3-bromo-5-chloro-pyridine (1379 mg, 4.62 mmol) and diethylamine (502 mg, 2.31 mmol). The mixture was stirred under N.sub.2 atmosphere at rt overnight. Removal of solvent to give a residue which was purified by column chromatography to obtain the title product mixture (450 mg)
5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(229) m/z calcd for [C.sub.18H.sub.18BrN.sub.5O.sub.7S].sup.+ [M+H].sup.+:529.0; found: 529.0.
5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(230) m/z calcd for [C.sub.18H.sub.18ClN.sub.5O.sub.7S].sup.+ [M+H].sup.+: 484.1; found: 484.1.
5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside and 5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(231) ##STR00121##
(232) To a solution of the mixture of 5-bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside and 5-chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (200 mg) in acetonitrile (5 mL) was added 4-(2-trimethylsilylethynyl)thiazol-2-ol (112 mg, 0.568 mmol) was dissolved in acetonitrile (5 ml) followed by triethylamine (102 mg, 1.01 mmol), Copper(I)Iodide (21.6 mg, 0.114 mmol) and CsF (46.3 mg, 0.305 mmol). The reaction was stirred at room temperature overnight. The mixture was concentrated in vacuum and the residue was purified by column chromatography (PE/EA=5/1) to obtain the two title compounds.
5-Bromo-6-cyano-3-pyridyl 2,4,6-tri-O-acetyl 3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside. 45 mg (17%)
(233) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.74 (s, 1H), 8.60 (d, J=1.9 Hz, 1H), 8.08 (d, J=1.9 Hz, 1H), 7.88 (s, 1H), 6.57 (s, 1H), 6.28 (d, J=5.5 Hz, 1H), 6.03 (dd, J=11.7, 5.5 Hz, 1H), 5.56 (d, J=2.5 Hz, 1H), 5.17 (dd, J=11.7, 3.0 Hz, 1H), 4.76-4.62 (m, 1H), 4.24-3.97 (m, 2H), 2.05 (s, 3H), 1.93 (d, J=8.2 Hz, 6H). m/z calcd for [C.sub.23H.sub.21BrN.sub.6O.sub.882].sup.+ [M+H.sub.2O].sup.+:653; found: 671.
5-Chloro-2-cyano-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside, 45 mg (18%)
(234) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.71 (s, 1H), 8.53 (d, J=2.1 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.90 (s, 1H), 6.57 (s, 1H), 6.24 (d, J=5.5 Hz, 1H), 6.05 (dd, J=11.6, 5.5 Hz, 1H), 5.59 (d, J=2.3 Hz, 1H), 5.17 (dd, J=11.7, 2.9 Hz, 1H), 4.86-4.71 (m, 1H), 4.25-3.92 (m, 2H), 2.03 (s, 3H), 1.97 (d, J=4.0 Hz, 6H).
(235) m/z calcd for [C.sub.23H.sub.21ClN.sub.6O.sub.8S.sub.2].sup.+ [M+H.sub.2O].sup.+:609; found: 627.
(236) Intermediate 17
5-Chloro-6-trifluoromethyl-pyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(237) ##STR00122##
(238) To a solution of 5-chloro-6-trifluoromethyl-pyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (15.0 mg, 0.0285 mmol)(WO2016/120403) in CH.sub.3CN (2 mL) were added TEA (0.0198 mL, 0.142 mmol), copper(I) iodide (1.63 mg, 0.00854 mmol), CsF (6.49 mg, 0.0427 mmol), 4-(2-trimethylsilylethynyl)thiazol-2-ol (8.43 mg, 0.0427 mmol). The reaction was stirred at room temperature with stirring for 20 h under N.sub.2 atmosphere. Water (10 mL) and DCM (10 mL) were added and the phases were separated. The aqueous phase was extracted with DCM (5 mL×2) and the combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=2/1) to obtain the title compound (12 mg, 0.0184 mmol, yield: 64.6%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 11.14 (s, 1H), 8.55 (d, J=1.8 Hz, 1H), 7.95 (d, J=1.3 Hz, 1H), 7.91 (s, 1H), 6.62 (s, 1H), 6.26 (d, J=5.5 Hz, 1H), 6.02 (dd, J=11.7, 5.5 Hz, 1H), 5.57 (d, J=2.4 Hz, 1H), 5.21 (dd, J=11.7, 2.9 Hz, 1H), 4.72 (dd, J=7.5, 4.9 Hz, 1H), 4.14-3.94 (m, 2H), 2.05 (s, 3H), 1.92 (d, J=2.6 Hz, 6H).
(239) Intermediate 18
3,5-Dichloro-4-fluoro-phenyl 3-2,4,6-tri-O-acetyl-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
3,5-dichloro-4-fluoro-benzenethiol
(240) ##STR00123##
(241) A solution of 3,5-dichloro-4-fluoroaniline (1 g, 5.58 mmol) in con. HCl (20 mL) was cooled to 0-5° C. A solution of sodium nitrite (424 mg, 6.14 mmol) in water (1 mL) was added dropwise over 20 min with stirring. The resulting solution was stirred for 1 h at 0-5° C. Potassium ethyl xantogenate (1.33 g, 8.37 mmol) was added and the reaction mixture was stirred at 70° C. overnight. The resulting solution was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuum to give crude product, which was purified by FC to afford crude product. The crude product dissolved in EtOH (20 mL) followed by addition of 2M NaOH (5.6 mL). The mixture was stirred at 70° C. for 2 h. The mixture was extracted with DCM (30 mL) and the water layer pH was adjusted to pH5-6 by NaHSO.sub.4 aq. followed by addition of DCM (30 mL). The organic layer was isolated and was washed, dried over sodium sulphate and concentrated to dryness to give the title compound 90.2 mg which was used in the next step without further purification. m/z calcd for [C.sub.6H.sub.3Cl.sub.2FS].sup.+ [M−H].sup.−:195.0; found: 195.0.
3,5-dichloro-4-fluoro-phenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(242) ##STR00124##
(243) Cs.sub.2CO.sub.3 (149 mg, 0.458 mmol) was added to a solution of 3,5-dichloro-4-fluoro-benzenethiol (90.2 mg, 0.458 mmol) in DMF (5 mL) at 0° C. The solution was stirred at rt for 30 min. Then 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (80.0 mg, 0.229 mmol) was added to mixture. The reaction was stirred at 50° C. for 2 h. The mixture was cooled to room temperature and water (50 mL) was added. The reaction mixture was extracted with EtOAc (15 mL×3) and the combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford crude product, which was purified by flash chromatography on a Biotage® (EA/PE=5% 40%, 30 mL/min, normal phase silica gel, uv 254) to afford the title compound (80 mg, 0.157 mmol, yield: 68.5%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.37 (d, J=6.1 Hz, 2H), 5.86 (d, J=5.5 Hz, 1H), 5.41 (d, J=3.1 Hz, 1H), 5.19 (dd, J=11.0, 5.6 Hz, 1H), 4.53 (dd, J=7.4, 4.6 Hz, 1H), 4.01 (ddd, J=19.6, 11.7, 6.4 Hz, 2H), 3.84 (dd, J=11.0, 3.2 Hz, 1H). m/z calcd for [C.sub.18H.sub.18Cl.sub.2FN.sub.3O.sub.7S].sup.+ [M+H].sup.+:510.0; found: 510.0.
3,5-Dichloro-4-fluoro-phenyl 3-2,4,6-tri-O-acetyl-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(244) ##STR00125##
(245) To a solution of 3,5-dichloro-4-fluoro-phenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (80.0 mg, 0.157 mmol) in CH.sub.3CN (5 mL) were added TEA (0.109 mL, 0.784 mmol), Copper(I)Iodide (1.63 mg, 0.00854 mmol), CsF (35.7 mg, 0.235 mmol), 4-(2-trimethylsilylethynyl)thiazol-2-ol (46.4 mg, 0.235 mmol). The reaction was stirred at room temperature for 20 h under N.sub.2 atmosphere. Water (10 mL) and DCM (10 mL) were added and the phases were separated, the aqueous phase was extracted with DCM (5 mL×2) and the combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=2/1) to obtain the title compound (70.0 mg, 0.110 mmol, yield: 70.3%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 11.00 (s, 1H), 7.95 (s, 1H), 7.49 (d, J=6.0 Hz, 2H), 6.66 (s, 1H), 6.12 (d, J=5.6 Hz, 1H), 6.02 (dd, J=11.7, 5.5 Hz, 1H), 5.62 (d, J=2.8 Hz, 1H), 5.21 (dd, J=11.6, 3.0 Hz, 1H), 4.90-4.78 (m, 1H), 4.22-4.02 (m, 2H). m/z calcd for [C.sub.23H.sub.21Cl.sub.2FN.sub.4O.sub.8S.sub.2].sup.+ [M+H].sup.+:635.0; found: 635.0.
(246) Intermediate 20
3,4,5-trichlorophenyl 2,4,6-tri-O-acetyl-3-[4-(2-hydroxythiazol-4-yl)triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
3,4,5-trichlorobenzenethiol
(247) ##STR00126##
(248) To a solution of 3,4,5-trichloroaniline (1000 mg, 5.09 mmol) in aqueous HCl (10 mL) was added NaNO.sub.2 (702 mg, 10.2 mmol). The mixture was stirred at 0° C. for 2 hours. Then an aqueous solution of potassium ethyl xanthogenate (1632 mg, 10.2 mmol) (10 mL) was added into the above mixture and the reaction was stirred at 55° C. for 1 hour. The reaction mixture was cooled to room temperature and extracted with EtOAc (15 mL×2) and the combined organic layers were concentrated to afford a residue. The residue was dissolved in EtOH (5 mL) and 2M NaOH aqueous solution (2 mL) was added. The mixture was stirred at 70° C. under a nitrogen atmosphere for 2 hours. Water (10 mL) and DCM (10 mL) were added. After separation, the aqueous phase was extracted with DCM (5 mL×2) and then the pH was adjusted to pH=6-7 with saturated NaHSO.sub.4 aqueous solution. The resulting solution was extracted with DCM (5 mL×2) and the combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4. Removal of solvent gave the title compound (50.0% purity, 710 mg, 1.66 mmol, yield: 32.7%) which was used to the next step without any further purification
3,4,5-trichlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(249) ##STR00127##
(250) A solution of 3,4,5-trichlorobenzenethiol (300 mg, 1.41 mmol) in DMF (10 mL) was added 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (442 mg, 1.26 mmol) and Cs.sub.2CO.sub.3 (687 mg, 2.11 mmol). The mixture was stirred under a nitrogen atmosphere at room temperature overnight. The reaction mixture was poured into 20 mL of water and extracted with EA (10 mL×2). The organic layers were washed with water (5 mL×5). The organic layer was concentrated to give a brown residue which was purified by column chromatography (PE/EA=8/1˜2/1, Silica-CS 12 g, 30 mL/min, silica gel, UV 254) to obtain the title compound (200 mg, 0.380 mmol, yield: 27.0%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.42 (s, 2H), 5.94 (d, J=5.5 Hz, 1H), 5.40 (d, J=2.9 Hz, 1H), 5.21 (dd, J=10.9, 5.6 Hz, 1H), 4.51 (dd, J=7.5, 4.9 Hz, 1H), 4.04 (s, 1H), 3.98-3.88 (m, 1H), 3.85 (dd, J=11.0, 3.3 Hz, 1H), 2.11 (d, J=7.5 Hz, 6H), 1.94 (s, 3H). m/z calcd for [C.sub.18H.sub.18Cl.sub.3N.sub.3O.sub.7S]: [M+18].sup.+: 543; found: 543.
3,4,5-trichlorophenyl 2,4,6-tri-O-acetyl-3-[4-(2-hydroxythiazol-4-yl)triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside
(251) ##STR00128##
(252) To a solution of 3,4,5-trichlorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (200 mg, 0.380 mmol) in DMF (10 mL) was added 4-(2-trimethylsilylethynyl)thiazol-2-ol (150 mg, 0.759 mmol), Copper(I)Iodide (21.7 mg, 0.114 mmol), CsF (115 mg, 0.759 mmol) and DIPEA (0.195 mL, 1.14 mmol). The mixture was stirred under a nitrogen atmosphere at room temperature overnight. The reaction mixture was poured into 20 mL of water and extracted with EtOAc (10 mL×2). The organic layer was washed with water (5 mL×5). The organic layer was concentrated to give a brown-black residue which was purified by column chromatography (PE/EA=10/1˜1/1, Silica-CS 4 g, 10 mL/min, silica gel, UV 254) to obtain the title compound (35.0 mg, 0.0537 mmol, yield: 14.1%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.84 (s, 1H), 7.47 (s, 2H), 6.49 (s, 1H), 6.11 (d, J=5.5 Hz, 1H), 5.97 (dd, J=11.8, 5.3 Hz, 1H), 5.53 (s, 1H), 5.13 (d, J=9.5 Hz, 1H), 4.81-4.64 (m, 1H), 4.15-4.05 (m, 2H), 2.02 (s, 3H), 1.95 (s, 3H), 1.91 (s, 3H). m/z calcd for [C.sub.23H.sub.21Cl.sub.3N.sub.4O.sub.8S.sub.2]: [M+1].sup.+: 651.0; found: 651.0.
(253) Intermediate 21
3,5-dibromo-4-fluorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
O-ethyl (3,5-dibromo-4-fluoro-phenyl)sulfanylmethanethioate
(254) ##STR00129##
(255) A solution of NaNO.sub.2 (192 mg, 2.79 mmol) in water (1 mL) was added dropwise over 20 min to a stirred solution of 3,5-dibromo-4-fluoro-aniline (500 mg, 1.86 mmol) in aqueous concentrated HCl/H.sub.2O (1/3, 12 mL) at 0-5° C. The resulting reaction mixture was stirred for 1 hour at 0-5° C. and then added dropwise to a solution of Potassium ethyl xanthate (894 mg, 5.58 mmol) in 2 mL of water. The reaction mixture was stirred at 50° C. for 2 hours. The resulting reaction mixture was cooled and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuum to give crude product, which was purification by column chromatography (PE/EA=20/1˜10/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the title compound (400 mg, 1.07 mmol, yield: 57.5%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.59 (d, J=5.7 Hz, 2H), 4.56 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H).
3,5-dibromo-4-fluoro-benzenethiol
(256) ##STR00130##
(257) A solution of O-ethyl (3,5-dibromo-4-fluoro-phenyl)sulfanylmethanethioate (400 mg, 1.07 mmol) in EtOH (5 mL) was added NaOH (2M aqueous solution, 2 mL). The mixture was stirred under a nitrogen atmosphere at 70° C. for 2 hours. Water (10 mL) and DCM (10 mL) were added. The phases were separated and the aqueous phase was extracted with DCM (5 mL×2). The pH of the aqueous solution was adjusted to pH=6-7 with saturated aqueous NaHSO.sub.4 solution. The resulting solution was extracted with DCM (15 mL×2). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate. Removal of solvent gave the crude product (250 mg, 0.874 mmol, yield: 81.8%) which was used to the next step without further purification.
(258) m/z calcd for [C.sub.6H.sub.3Br.sub.2FS].sup.− [M−H].sup.−: 285; found: 285.5.
3,5-dibromo-4-fluorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(259) ##STR00131##
(260) Cs.sub.2CO.sub.3 (279 mg, 0.858 mmol) was added to a solution of 3,5-dibromo-4-fluoro-benzenethiol (245 mg, 0.858 mmol) in DMF (5 mL) at 0° C. The solution was stirred at room temperature for 30 min. Then 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (200 mg, 0.572 mmol) was added to the mixture. The reaction was stirred at room temperature over night. Then it was extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuum to afford crude product, which was purified by column chromatography (PE/EA=10/1˜4/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to obtain the title compound (180 mg, 0.300 mmol, yield: 52.5%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.54 (d, J=5.7 Hz, 2H), 5.87 (d, J=5.5 Hz, 1H), 5.41 (d, J=2.7 Hz, 1H), 5.19 (dd, J=11.0, 5.5 Hz, 1H), 4.56-4.49 (m, 1H), 4.01 (ddd, J=19.4, 11.6, 6.2 Hz, 2H), 3.84 (dd, J=11.0, 3.2 Hz, 1H), 2.11 (d, J=11.1 Hz, 6H), 1.98 (s, 3H). m/z calcd for [C.sub.18H.sub.18Br.sub.2FN.sub.3O.sub.7S].sup.+ [M+H].sup.+: 598; found: 598.
3,5-dibromo-4-fluorophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(261) ##STR00132##
(262) To a solution of 3,5-dibromo-4-fluorophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (90.0 mg, 0.150 mmol) in DMF (3 mL) was added TEA (0.105 mL, 0.751 mmol), Copper(I)Iodide (8.58 mg, 0.0451 mmol), CsF (34.2 mg, 0.225 mmol), 4-(2-trimethylsilylethynyl)thiazol-2-ol (44.5 mg, 0.225 mmol). The reaction was stirred at room temperature under a nitrogen atmosphere for 20 hours. Water (10 mL) and DCM (10 mL) were added. The phases were separated and the aqueous phase was extracted with DCM (5 mL×2). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried and over anhydrous sodium sulfate. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=10/1˜2/1, Silica-CS 4 g, 12 mL/min, silica gel, UV 254) to obtain the title compound (50.0 mg, 0.0690 mmol, yield: 46.0%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.13 (s, 1H), 7.81 (s, 1H), 7.59 (s, 2H), 6.47 (s, 1H), 6.01 (d, J=27.9 Hz, 2H), 5.53 (s, 1H), 5.13 (s, 1H), 4.75 (s, 1H), 4.07 (d, J=19.0 Hz, 2H), 2.00 (d, J=14.8 Hz, 6H), 1.92 (s, 3H). m/z calcd for [C.sub.23H.sub.21Br.sub.2FN.sub.4O.sub.8S.sub.2].sup.+ [M+H].sup.+: 723; found: 723.
(263) Intermediate 22
3-Bromo-4-cyanophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
3-Bromo-4-cyanophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(264) ##STR00133##
(265) A solution of 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (544 mg, 1.56 mmol) and 2-bromo-4-sulfanyl-benzonitrile (500 mg, 2.33 mmol) in DMF (10 mL) was added Cs.sub.2CO.sub.3 (3000 mg, 9.2 mmol). The solution was stirred at room temperature overnight. The reaction mixture was poured into 20 mL of water and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give a brown residue. The residue was purified by column chromatography (PE/EA=10/1˜3/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the title compound (0.3 g, yield: 37%). 1H NMR (400 MHz, CDCl.sub.3) δ 7.69 (d, J=1.7 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.38 (dd, J=8.2, 1.7 Hz, 1H), 6.09 (d, J=5.6 Hz, 1H), 5.41 (d, J=2.5 Hz, 1H), 5.24 (dd, J=11.0, 5.6 Hz, 1H), 4.50-4.37 (m, 1H), 4.07 (dd, J=11.6, 5.0 Hz, 1H), 3.90 (ddd, J=14.3, 11.3, 5.5 Hz, 2H), 2.10 (t, J=4.3 Hz, 6H), 1.89 (d, J=7.0 Hz, 3H). m/z calcd for [C.sub.19H.sub.19BrN.sub.4O.sub.7S] [M+18-3Ac].sup.+: 418; found: 418.
3-Bromo-4-cyanophenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(266) ##STR00134##
(267) A solution of 3-bromo-4-cyanophenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (15.0 mg, 0.0284 mmol) in MeCN (2.0 mL) was added 4-(2-trimethylsilylethynyl)thiazol-2-ol (13.9 mg, 0.0706 mmol), Copper(I)Iodide (1.63 mg, 0.00853 mmol), CsF (8.64 mg, 0.0569 mmol) and DIPEA (18.4 mg, 0.143 mmol). The mixture was stirred at room temperature for 3 hours and concentrated under vacuum. The residue was purified by column chromatography (PE/EA=8/1˜3/1, Silica-CS 4 g, 10 mL/min, silica gel, UV 254) to obtain the title compound (15 mg, 80.8% yield).
(268) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.78 (s, 1H), 8.66 (d, J=1.8 Hz, 1H), 8.20 (d, J=1.6 Hz, 1H), 8.02 (s, 1H), 7.97 (s, 1H), 6.64 (s, 1H), 6.32 (d, J=5.5 Hz, 1H), 6.09 (dd, J=11.7, 5.6 Hz, 1H), 5.63 (d, J=2.4 Hz, 1H), 5.26 (dd, J=11.7, 3.0 Hz, 1H), 4.79 (dd, J=7.4, 4.8 Hz, 1H), 4.13 (ddd, J=19.5, 11.8, 6.2 Hz, 2H), 2.11 (s, 3H), 1.99 (d, J=1.8 Hz, 6H). m/z calcd for [C.sub.24H.sub.22BrN.sub.5O.sub.8S.sub.2]: [M+1].sup.+: 652; found: 652.
(269) Intermediate 23
5-Bromo-6-trifluoromethyl-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
3-bromo-5-fluoro-2-iodo-pyridine
(270) ##STR00135##
(271) A mixture of 2,3-dibromo-5-fluoro-pyridine (5.00 g, 19.6 mmol), NaI (8.821 g, 58.9 mmol) and chloro(trimethyl)silane (2.131 g, 19.6 mmol) in MeCN (50 mL) was heated at reflux for 45 min. The reaction mixture was then poured into a 2.0 M aqueous solution of sodium hydroxide (10 mL) and extracted with diethyl ether (3×20 mL). The combined organic layers were washed with brine and evaporated to afford crude product, which was purified by column chromatography (EA/PE=1%˜10%, Silica-CS 40 g, 25 mL/min, silica gel, UV 254) to afford the target compound as a gray solid (2.2 g, 37.2% yield). .sup.1H NMR (400 MHz, CDCl.sub.3).sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.21 (d, J=2.7 Hz, 1H), 7.56 (dd, J=7.5, 2.7 Hz, 1H). m/z calcd for [C.sub.5H.sub.2BrFIN] [M]: 300.8; found: 301. (GCMS)
3-bromo-5-fluoro-2-(trifluoromethyl)pyridine
(272) ##STR00136##
(273) To a solution of 3-bromo-5-fluoro-2-iodo-pyridine (800 mg, 2.65 mmol) in DMF (15 mL) was added CuI (3.533 g, 18.6 mmol), methyl fluorosulfonyldifluoroacetate (3.564 g, 18.6 mmol). The mixture was heated under a nitrogen atmosphere at 80° C. for 3 h. The reaction mixture was cooled to room temperature and water (50 mL) was added followed by extraction with EtOAc (15 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford crude product, which was purified by column chromatography (EA/PE=5% 40%, Silica-CS 40 g, 30 mL/min, silica gel, UV 254) to afford the title compound (400 mg, 1.64 mmol, yield: 61.9%).
(274) m/z calcd for [C.sub.6H.sub.2BrF.sub.4N] [M]: 243; found: 243 (GCMS).
5-bromo-6-(trifluoromethyl)pyridine-3-thiol
(275) ##STR00137##
(276) To a solution of 3-bromo-5-fluoro-2-(trifluoromethyl)pyridine (410 mg, 1.68 mmol) in DMF (10 mL) was added Na.sub.2S (393 mg, 5.04 mmol). The mixture was stirred under a nitrogen atmosphere at room temperature for 8 hours. 10% aqeuous NaOH solution was added into the mixture to adjust the pH to 9. The mixture was extracted with Et.sub.2O (3×30 mL) and the aqueous layer was acidified with 2 M NaHSO.sub.4 to pH=3. The mixture was extracted with EA (3×20 mL). The combined organic layers were washed with brine and evaporated to afford the crude product (280 mg, 1.09 mmol, yield: 64.6%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.43 (d, J=2.3 Hz, 1H), 8.19 (d, J=2.6 Hz, 1H), 3.65 (dd, J=6.8, 4.3 Hz, 1H). m/z calcd for [C.sub.6H.sub.3BrF.sub.3NS] [M−1].sup.−: 256; found: 256.
5-Bromo-6-(trifluoromethyl)-3-pyridinyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(277) ##STR00138##
(278) Cs.sub.2CO.sub.3 (405 mg, 1.24 mmol) was added to a solution of 5-bromo-6-(trifluoromethyl)pyridine-3-thiol (300 mg, 1.16 mmol) in DMF (8 mL) at 0° C. The solution was stirred at rt for 30 min. Then 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (290 mg, 0.829 mmol) was added to mixture. The reaction was stirred at room temperature over night. Water (30 mL) was added. Then the mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to afford crude product, which was purified by column chromatography (EA/PE=5% 40%, Silica-CS 40 g, 30 mL/min, silica gel, UV 254) to afford the title compound (220 mg, 0.385 mmol, yield: 46.4%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.53 (d, J=1.8 Hz, 1H), 8.07 (d, J=1.5 Hz, 1H), 6.06 (d, J=5.5 Hz, 1H), 5.42 (d, J=2.6 Hz, 1H), 5.25 (dd, J=10.9, 5.5 Hz, 1H), 4.48 (dd, J=7.4, 4.6 Hz, 1H), 3.97-3.87 (m, 2H), 3.65 (dd, J=7.0, 5.1 Hz, 1H), 2.12 (d, J=7.3 Hz, 6H), 1.91 (s, 3H). m/z calcd for [C.sub.18H.sub.18BrF.sub.3N.sub.4O.sub.7S] [M+1].sup.+: 571; found: 571.
5-Bromo-6-trifluoromethyl-3-pyridyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(279) ##STR00139##
(280) To a solution of 5-bromo-6-(trifluoromethyl)-3-pyridinyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (70.0 mg, 0.123 mmol) in DMF (5 mL) was added TEA (0.0854 mL, 0.613 mmol), Copper(I)Iodide (7.00 mg, 0.0368 mmol), CsF (37.2 mg, 0.245 mmol), 4-(2-trimethylsilylethynyl)thiazol-2-ol (48.4 mg, 0.245 mmol). The reaction was stirred at room temperature for 20 h under a nitrogen atmosphere. Water (10 mL) and DCM (10 mL) were added. The aqueous phase was separated and extracted with DCM (5 mL×2), the combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=2/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to obtain the title compound (65.0 mg, 0.0933 mmol, yield: 76.2%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.30 (s, 1H), 8.58 (d, J=1.9 Hz, 1H), 8.12 (s, 1H), 7.84 (s, 1H), 6.50 (s, 1H), 6.25 (d, J=5.5 Hz, 1H), 6.03 (dd, J=11.6, 5.5 Hz, 1H), 5.55 (d, J=2.9 Hz, 1H), 5.17 (dd, J=11.6, 2.9 Hz, 1H), 4.71 (d, J=7.0 Hz, 1H), 4.06 (ddd, J=19.7, 11.9, 6.5 Hz, 2H), 2.04 (s, 3H), 1.92 (d, J=1.5 Hz, 6H). m/z calcd for [C.sub.23H.sub.21BrF.sub.3N.sub.5O.sub.8S.sub.2].sup.+ [M+H].sup.+: 698; found: 697.8.
(281) Intermediate 24
3-Chloro-4-trifluoromethylphenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(282) ##STR00140##
(283) A solution of 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (500 mg, 1.43 mmol) and 3-chloro-4-(trifluoromethyl)benzenethiol (454 mg, 2.145 mmol) in DMF (10 mL) was added Cs.sub.2CO.sub.3 (1.4 g, 4.3 mmol) and the solution was stirred at room temperature overnight. The reaction was poured into 30 mL of water and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo to obtain crude product. The crude target was purified by column chromatography (PE/EA=10/1˜3/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the title compound. (0.386 g, yield: 51.3%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.53 (d, J=7.7 Hz, 2H), 7.37-7.29 (m, 1H), 6.06 (d, J=5.5 Hz, 1H), 5.41 (d, J=2.6 Hz, 1H), 5.27-5.20 (m, 1H), 4.49 (dd, J=7.3, 5.3 Hz, 1H), 4.05 (d, J=4.6 Hz, 1H), 3.97-3.93 (m, 1H), 3.88 (dd, J=11.0, 3.3 Hz, 1H), 2.11 (d, J=2.5 Hz, 6H), 1.86 (d, J=3.7 Hz, 3H). m/z calcd for [C.sub.19H.sub.19ClF.sub.3N.sub.3O.sub.7S] [M+18].sup.+: 543; found: 543.
3-Chloro-4-trifluoromethylphenyl 2,4,6-tri 0-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(284) ##STR00141##
(285) A solution of 3-chloro-4-trifluoromethylphenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (15.0 mg, 0.0260 mmol) in MeCN (2.0 mL) was added 4-(2-trimethylsilylethynyl)thiazol-2-ol (14 mg, 0.0708 mmol), Copper(I)Iodide (1.63 mg, 0.00856 mmol), CsF (8.67 mg, 0.0570 mmol) and DIPEA (18.4 mg, 0.143 mmol). The mixture was stirred at room temperature for 3 hours followed by solvent evaporation. The residue was purified by column chromatography (PE/EA=10/1˜1/1, Silica-CS 4 g, 12 mL/min, silica gel, UV 254) to obtain the title compound (15 mg, 80.8% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.52 (s, 1H), 7.86 (s, 1H), 7.60-7.55 (m, 2H), 7.39 (d, J=8.1 Hz, 1H), 6.53 (s, 1H), 6.25 (d, J=5.5 Hz, 1H), 6.01 (dd, J=11.7, 5.5 Hz, 1H), 5.55 (s, 1H), 5.18 (dd, J=11.6, 2.9 Hz, 1H), 4.75-4.67 (m, 1H), 4.10-4.02 (m, 2H), 2.04 (s, 3H), 1.93-1.86 (m, 6H). m/z calcd for [C.sub.24H.sub.22ClF.sub.3N.sub.4O.sub.8S.sub.2] [M+1].sup.+: 651; found: 651.
(286) Intermediate 26
3-Chloro-4-methylphenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
3-Chloro-4-methylphenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(287) ##STR00142##
(288) Cs.sub.2CO.sub.3 (838 mg, 2.57 mmol) was added to a solution of 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (300 mg, 0.858 mmol) and 3-chloro-4-methyl-benzenethiol (272 mg, 1.72 mmol) in DMF (5 mL) at room temperature. The reaction was stirred at room temperature overnight. After diluting with water (20 mL), the reaction mixture was extracted with EtOAc (10 mL×3). 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/EA=10/1˜3/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to give the title compound (270 mg, 0.572 mmol, yield: 66.7%) as pale yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.45 (s, 1H), 7.22 (s, 1H), 7.15 (d, J=7.9 Hz, 1H), 5.89 (t, J=9.4 Hz, 1H), 5.46 (s, 1H), 5.25 (dd, J=10.8, 5.4 Hz, 1H), 4.65 (t, J=5.9 Hz, 1H), 4.11 (dd, J=11.5, 4.8 Hz, 1H), 4.05-3.87 (m, 2H), 2.34 (s, 3H), 2.16 (d, J=12.3 Hz, 6H), 2.02 (d, J=13.2 Hz, 3H). m/z calcd for [C.sub.19H.sub.22ClN.sub.3O.sub.7S] [M+18].sup.+: 489; found: 489.2.
3-Chloro-4-methylphenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(289) ##STR00143##
(290) To a solution of 3-chloro-4-methylphenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (100 mg, 0.212 mmol) in DMF (5 mL) were added DIPEA (0.181 mL, 1.06 mmol), Copper(I)Iodide (12.1 mg, 0.0636 mmol), CsF (64.4 mg, 0.424 mmol), 4-(2-trimethylsilylethynyl)thiazol-2-ol (83.6 mg, 0.424 mmol). The reaction was stirred at room temperature under a nitrogen atmosphere overnight. Water (10 mL) and DCM (10 mL) were added. The separated aqueous phase was extracted with DCM (5 mL×2), the combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulphate. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=8/1˜1/1, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to obtain the title compound. (50.0 mg, 0.0837 mmol, yield: 39.5%) as pale yellow solid.
(291) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.79 (s, 1H), 7.92 (s, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.31-7.27 (m, 1H), 7.19 (d, J=7.9 Hz, 1H), 6.62 (s, 1H), 6.09 (d, J=5.5 Hz, 1H), 6.00 (dd, J=11.6, 5.6 Hz, 1H), 5.60 (s, 1H), 5.25 (dd, J=11.6, 2.9 Hz, 1H), 4.87 (t, J=6.0 Hz, 1H), 4.14 (dd, J=11.7, 5.5 Hz, 1H), 4.06 (dd, J=11.6, 7.3 Hz, 1H), 2.36 (s, 3H), 2.08 (s, 3H), 1.99 (d, J=14.5 Hz, 6H). m/z calcd for [C.sub.24H.sub.25ClN.sub.4O.sub.8S.sub.2] [M+H].sup.+: 597; found: 597.1.
(292) Intermediate 28
5-chloro-2-(methoxycarbonyl)pyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
5-Chloro-3-fluoro-2-(methoxycarbonyl)pyridine
(293) ##STR00144##
(294) A solution of 5-chloro-3-fluoro-pyridine-2-carboxylic acid (1000 mg, 5.70 mmol) in MeOH (20 mL) was added thionyl chloride (1355 mg, 11.4 mmol). The mixture was stirred under a nitrogen atmosphere at room temperature overnight. After concentration, the residue was diluted with DCM (20 mL) and the pH adjusted to pH=8-9 with K.sub.2CO.sub.3 aqueous solution. The organic layer was concentrated in vacuum to afford the title compound (720 mg, 3.80 mmol, yield: 66.7%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.52 (d, J=1.1 Hz, 1H), 7.63 (dd, J=9.5, 1.9 Hz, 1H), 4.02 (s, 3H). m/z calcd for [C.sub.7H.sub.5ClFNO.sub.2] [M+1].sup.+: 190, found: 190.
5-chloro-2-(methoxycarbonyl)pyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(295) ##STR00145##
(296) A solution of 5-chloro-3-fluoro-2-(methoxycarbonyl)pyridine (300 mg, 1.58 mmol) in DMF (20 mL) was added 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (1232 mg, 3.17 mmol) and diethylamine (231 mg, 3.17 mmol). The reaction was stirred under a nitrogen atmosphere at room temperature overnight. The reaction mixture was poured into 20 mL of water followed by extraction with EtOAc (10 mL×3). The combined organic layer was washed with water (10 mL×3) and brine (10 mL×3). The EtOAc solution was dried over Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated and the residue was purified by column chromatography (PE/EA=10/1˜2/1, Silica-CS 12 g, 15 mL/min, silica gel, UV 254) to obtain the title compound. (240 mg, 0.464 mmol, yield: 29.3%). .sup.1H NMR (400 MHz, CDCl.sub.3) 8.46 (d, J=2.0 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 6.13 (d, J=5.6 Hz, 1H), 5.47 (d, J=2.6 Hz, 1H), 5.37 (dd, J=11.0, 5.6 Hz, 1H), 4.57-4.48 (m, 1H), 4.11 (ddd, J=13.1, 8.5, 4.3 Hz, 3H), 4.03 (d, J=5.5 Hz, 3H), 2.18 (d, J=2.7 Hz, 6H), 1.92 (s, 3H). m/z calcd for [C.sub.19H.sub.21ClN.sub.4O.sub.9S] [M+1].sup.+: 517, found: 517.
5-chloro-2-(methoxycarbonyl)pyridin-3-yl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(297) ##STR00146##
(298) A solution of 5-chloro-2-(methoxycarbonyl)pyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (240 mg, 0.464 mmol) in DMF (10 mL) was added 4-(2-trimethylsilylethynyl)thiazol-2-ol (183 mg, 0.929 mmol), copper(I) iodide (26.5 mg, 0.139 mmol), CsF (141 mg, 0.929 mmol) and DIPEA (0.318 mL, 1.86 mmol). The reaction was stirred under a nitrogen atmosphere overnight. The reaction mixture was poured into 20 mL of water followed by extraction with EtOAc (10 mL×3). The combined organic layers were washed with water (10 mL×3) and brine (10 mL×3). The EtOAc solution was dried over Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated and the residue was purified by column chromatography (PE/EA=8/1˜1/2, Silica-CS 12 g, 15 mL/min, silica gel, UV 254) to obtain the title compound (150 mg, 0.234 mmol, yield: 40.3%). .sup.1H NMR (400 MHz, CDCl.sub.3) 10.86 (s, 1H), 8.43 (s, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 6.60 (s, 1H), 6.27 (d, J=5.4 Hz, 1H), 6.10 (d, J=6.3 Hz, 1H), 5.54 (s, 1H), 5.31 (d, J=10.9 Hz, 1H), 4.71 (s, 1H), 4.05 (mz, 2H), 3.98 (s, 3H), 2.03 (s, 3H), 1.98 (s, 3H), 1.90 (s, 3H). m/z calcd for [C.sub.24H.sub.24ClN.sub.5O10S.sub.2] [M+1].sup.+: 642, found: 642.
(299) Intermediate 29
5-bromo-6-(trifluoromethyl)pyridin-3-yl 3-deoxy-3-[4-(4,5-dichlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
2-(4,5-dichlorothiazol-2-yl)ethynyl-trimethyl-silane
(300) ##STR00147##
(301) A solution of 2,4,5-trichlorothiazole (500 mg, 2.39 mmol) in DMF (5 mL) was added CuI (15.2 mg, 0.0796 mmol), TEA (1.11 mL, 7.96 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (55.9 mg, 0.0796 mmol) and ethynyl(trimethyl)silane (313 mg, 3.18 mmol). The reaction was stirred under a nitrogen atmosphere at 30° C. for 20 hours. Removal of solvent in vacuum gave a residue. The residue was purified by column chromatography (PE/EA=50/1˜10/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to obtain the title compound. (200 mg, 0.799 mmol, yield: 50.2%). m/z calcd for [C.sub.8H.sub.9Cl.sub.2NSSi] [M]: 249; found: 249 (GCMS).
5-bromo-6-(trifluoromethyl)pyridin-3-yl 3-deoxy-3-[4-(4,5-dichlorothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(302) ##STR00148##
(303) A solution of 5-Bromo-6-(trifluoromethyl)-3-pyridinyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (intermediate 23) (50.0 mg, 0.0875 mmol) in DMF (3 mL) were added TEA (0.0610 mL, 0.438 mmol), Copper(I)Iodide (5.00 mg, 0.0263 mmol), CsF (26.6 mg, 0.175 mmol), and trimethyl-[2-(2-pyridyl)ethynyl]silane (140 mg, 0.57 mmol). The reaction was stirred under a nitrogen atmosphere at room temperature for 20 hours. Water (10 mL) and DCM (10 mL) were added. After separation, the aqueous phase was extracted with DCM (5 mL×2). The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate. Removal of solvent gave a residue. The residue was purified by column chromatography (PE/EA=8/1˜2/1, Silica-CS 12 g, 15 mL/min, silica gel, UV 254) to obtain the title compound (45.0 mg, 0.0601 mmol, yield: 68.6%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.58 (d, J=1.8 Hz, 1H), 8.17-8.07 (m, 1H), 8.03 (s, 1H), 6.25 (d, J=5.5 Hz, 1H), 5.97 (dd, J=11.7, 5.6 Hz, 1H), 5.55 (d, J=2.2 Hz, 1H), 5.19 (dd, J=11.7, 3.1 Hz, 1H), 4.77-4.66 (m, 1H), 4.16-3.95 (m, 2H), 2.03 (s, 3H), 1.92 (d, J=2.8 Hz, 6H). m/z calcd for [C.sub.23H.sub.19BrCl.sub.2F.sub.3N.sub.5O.sub.7S.sub.2].sup.+[M+H].sup.+: 748; found: 748.
(304) Intermediate 31
3,4-Dichloro-6-fluoro-phenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
4,5-dichloro-2-fluoro-benzenethiol
(305) ##STR00149##
(306) A solution of 4,5-dichloro-2-fluoro-aniline (500 mg, 2.78 mmol) in HCl (10 mL) was added NaNO.sub.2 (383 mg, 5.56 mmol). The reaction was stirred at 0° C. for 2 hours. A solution of ethylxanthic acid potassium salt (891 mg, 5.56 mmol) in water (10 mL) was added into the reaction mixture and stirred at 55° C. for 1 hour. The solvents were removed in vacuo and the residue was diluted with EtOH (5 mL) followed by addition of 2M NaOH (2 mL). The mixture was heated at 70° C. under a nitrogen atmosphere for 2 hours. After cooling to room temperature, the reaction was added 10 mL of water and 10 mL of DCM. After separation, the aqueous phase was extracted with DCM (5 mL×2) and the pH was adjusted to pH=6-7 with saturated NaHSO.sub.4. The resulted solution was extracted with DCM (5 mL×3) and the combined organic phases were washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate. Removal of solvent gave the crude product (60.0% purity, 547 mg, yield: 50.2%) which was used to the next step without any purification
4,5-dichloro-2-fluoro-phenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(307) ##STR00150##
(308) A solution of 4,5-dichloro-2-fluoro-benzenethiol (410 mg, 2.08 mmol) in DMF (10 mL) was added 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (655 mg, 1.87 mmol) and Cs.sub.2CO.sub.3 (1017 mg, 3.12 mmol). The mixture was stirred under a nitrogen atmosphere at room temperature overnight. The reaction mixture was poured into 20 mL of water followed by extraction with EtOAc (10 mL×3). The combined organic layer was washed with water (10 mL×3) and brine (10 mL×3). The EtOAc solution was dried over Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated and the residue was purified by column chromatography (PE/EA=10/1˜3/1, Silica-CS 20 g, 20 mL/min, silica gel, UV 254) to obtain the title compound (220 mg, 0.431 mmol, yield: 17.2%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.61 (d, J=6.9 Hz, 1H), 7.24 (s, 1H), 5.98 (d, J=5.5 Hz, 1H), 5.48 (d, J=2.5 Hz, 1H), 5.28 (dd, J=11.0, 5.5 Hz, 1H), 4.65-4.54 (m, 1H), 4.08 (d, J=4.9 Hz, 1H), 4.03-3.91 (m, 2H), 2.22-2.12 (m, 6H), 1.99 (s, 3H). m/z calcd for [C.sub.18H.sub.18Cl.sub.2FN.sub.3O.sub.7S] [M+1].sup.+: 510, found: 510.
3,4-Dichloro-6-fluoro-phenyl 2,4,6-tri-O-acetyl-3-deoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside
(309) ##STR00151##
(310) A solution of 4,5-dichloro-2-fluoro-phenyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (100 mg, 0.196 mmol) in DMF (3 mL) was added 4-(2-trimethylsilylethynyl)thiazol-2-ol (77.3 mg, 0.392 mmol), Copper(I)Iodide (11.2 mg, 0.0588 mmol), CsF (59.5 mg, 0.392 mmol) and DIPEA (0.101 mL, 0.588 mmol). The reaction was stirred under a nitrogen atmosphere at room temperature overnight. The reaction mixture was poured into 8 mL of water followed by extraction with EtOAc (5 mL×3). The combined organic layers were washed with water (5 mL×3) and brine (5 mL×3). The EtOAc solution was dried over Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated and the residue was purified by column chromatography (PE/EA=8/1˜1/1, Silica-CS 12 g, 15 mL/min, silica gel, UV 254) to obtain the title compound (17.0 mg, 0.0268 mmol, yield: 13.7%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.65 (s, 1H), 7.97 (s, 1H), 7.64 (d, J=6.9 Hz, 1H), 7.27 (s, 1H), 6.60 (s, 1H), 6.14 (d, J=5.5 Hz, 1H), 6.02 (dd, J=11.6, 5.5 Hz, 1H), 5.60 (s, 1H), 5.28 (dd, J=11.7, 2.8 Hz, 1H), 4.85-4.71 (m, 1H), 4.05 (ddd, J=18.9, 11.7, 6.3 Hz, 2H), 2.02 (dd, J=27.5, 8.7 Hz, 9H). m/z calcd for [C.sub.23H.sub.21Cl.sub.2FN.sub.4O.sub.8S.sub.2] [M+1].sup.+: 635, found: 635.
(311) Intermediate 32
5-Chloro-N,N′-dimethyl-benzamid-2-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside
2,4,6-Tri-O-acetyl-3-azido-3-deoxy-α-D-galactopyranosyl chloride
(312) ##STR00152##
(313) 1,2,4,6-Tetra-O-acetyl-3-azido-3-deoxy-β-D-galactopyranoside (12.0 g, 32.1 mmol), PCl.sub.5 (7.5 g, 36.0 mmol) and BF.sub.3OEt.sub.2 (50 μL, 8.16 mmol) were stirred in DCM (150 mL) for 1 h, then partitioned between NaHCO.sub.3 (sat) and DCM. The organic phase was dried, concentrated and triturated in ether/petroleum ether to afford the title compound as a crystalline solid (10.2 g, 91%). .sup.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).
4-Chloro-2-sulfanylbenzonitrile
(314) ##STR00153##
(315) 4-Chloro-2-fluoro-benzonitrile (8.0 g, 50.4 mmol), NaHS.Math.H.sub.2O (50.4 mmol, 4.006 g) and DMF (30 mL) were stirred on an ice bath for 1 h. The mixture was partitioned between diethyl ether and HCl (0.5 M), the organic phase was then extracted with NaOH (2 M, 50 ml) and the aqueous phase was concentrated a little, then acidified with HCl which gave a precipitate that was isolated and dried to afford the title compound (5.1 g, 59%). .sup.1H NMR (400 MHz, Chloroform-d) δ 7.53 (d, J=8.4 Hz, 1H), 7.43 (d, J=1.7 Hz, 1H), 7.22 (dd, J=8.4, 1.8 Hz, 1H), 4.15 (s, 1H).
4-Chloro-benzonitrile-2-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(316) ##STR00154##
(317) 2,4,6-Tri-0-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (9.6 g, 27.3 mmol), 4-Chloro-2-sulfanylbenzonitrile (5.1 g, 30.06 mmol), Cs.sub.2CO.sub.3 (17.8 g, 54.7 mmol) and DMF (40 mL) were stirred at room temperature for 20 h, then partitioned between diethyl ether/EtOAc/aq. HCl/water, the organic phase was separated, concentrated, and the residue was subjected to chromatography (SiO.sub.2, petroleum ether/EtOAc) and gave the title compound (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-N,N′-dimethyl-benzamid-2-yl 3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(318) ##STR00155##
(319) A solution of 4-chloro-benzonitrile-2-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (200 mg, 0.41 mmol) in EtOH (12 mL) and NaOH (aq. 2M, 6 mL) was stirred 8 h at 80° C. The solution was acidified with HCl (12 M), pH 2-3, concentrated and MeOH was added. The formed suspension was filtered and evaporated to give a dark brown residue that was partitioned between EtOAc and water. The organic phase was dried, evaporated and the obtained carboxylic acid was dissolved, along with 1-hydroxybenzotriazole hydrate (63 mg, 0.41 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (79 mg, 0.41 mmol), in DMF (2 mL). Dimethylamine (0.41 mL, 2M in THF, 0.83 mmol) was added to the mixture, which was stirred 5 h at 40° C. The mixture was concentrated and purification by HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) and freeze drying afforded the title compound as a white powder (53 mg, 32%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.81 (s, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.23 (d, J=8.2, 1H), 5.74 (d, J=5.4 Hz, 1H), 4.37 (dd, J=10.8, 5.4 Hz, 1H), 4.24 (t, J=6.1 Hz, 1H), 4.03 (d, J=2.8 Hz, 1H), 3.70 (dd, J=11.5, 5.4 Hz, 1H), 3.65 (dd, J=11.4, 6.8 Hz, 1H), 3.47 (dd, J=10.8, 2.8 Hz, 1H), 3.12 (s, 3H), 2.88 (s, 3H). ESI-MS m/z calcd for [C.sub.15H.sub.19ClN.sub.4O.sub.5S].sup.+ (M+H).sup.+: 403.1; found: 403.1.
(320) Intermediate 33
5-Chloro-2-(dimethylcarbamoyl)-3-pyridyl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
3-Bromo-5-chloro-N,N′-dimethyl-pyridine-2-carboxamide
(321) ##STR00156##
(322) Dimethylamine (1.16 mL, 2M in THF, 2.31 mmol) was added to a solution of 3-bromo-5-chloro-pyridine-2-carboxylic acid (455 mg, 1.92 mmol), 1-hydroxybenzotriazole hydrate (354 mg, 2.31 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (443 mg, 2.31 mmol), in DMF (6 mL) and Et.sub.3N (0.32 mL, 2.31 mmol). After stirring 22 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, evaporated and purified by chromatography (SiO.sub.2, EtOAc/petroleum ether) to yield the title compound (346 mg, 68%). .sup.1H NMR (400 MHz, Chloroform-d) δ 8.54-8.52 (m, 1H), 7.97-7.95 (m, 1H), 3.17 (s, 3H), 2.87 (s, 3H). ESI-MS m/z calcd for [C.sub.8H.sub.8BrClN.sub.2O].sup.+ (M+H).sup.+: 263.0; found: 262.9.
5-Chloro-3-[(2,4-dimethoxyphenyl)methylsulfanyl]-N,N′-dimethyl-pyridine-2-carboxamide
(323) ##STR00157##
(324) To a nitrogen purged solution of 3-bromo-5-chloro-N,N′-dimethyl-pyridine-2-carboxamide (346 mg, 1.31 mmol), Pd(dba).sub.2 (45 mg, 0.079 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (38 mg, 0.066 mmol) in 1,4-dioxane (2 mL), a solution of (2,4-dimethoxyphenyl)methanethiol (266 mg, 1.44 mmol) in 1,4-dioxane (3 mL) and DIPEA (0.45 mL, 2.63 mmol) was added and the resulting mixture was heated 4 h at 100° C. The mixture was concentrated and purified by chromatography (SiO.sub.2, EtOAc/petroleum ether) to yield the title compound (332 mg, 69%). ESI-MS m/z calcd for [C.sub.17H.sub.19ClN.sub.2O.sub.2].sup.+ (M+H).sup.+: 367.1; found: 367.1.
5-Chloro-N,N′-dimethyl-3-sulfanyl-pyridine-2-carboxamide
(325) ##STR00158##
(326) TFA (1.5 mL) was added to a solution of 5-chloro-3-[(2,4-dimethoxyphenyl)methylsulfanyl]-N,N′-dimethyl-pyridine-2-carboxamide (332 mg, 0.91 mmol) in DCM (3 mL) and Et.sub.3SiH (1.5 mL) and the mixture was stirred 5 days at rt. The mixture was concentrated and purified by chromatography (SiO.sub.2, EtOAc/petroleum ether) to yield the title compound (159 mg, 81%). .sup.1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J=2.0 Hz, 1H), 7.69 (d, J=1.9 Hz, 1H), 4.34 (s, 1H), 3.15 (s, 3H), 2.93 (s, 3H). ESI-MS m/z calcd for [C.sub.8H.sub.9ClN.sub.2OS].sup.+ (M+H).sup.+: 217.0; found: 217.0.
5-Chloro-2-(dimethylcarbamoyl)-3-pyridyl 2,4,6-tri-0-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside
(327) ##STR00159##
(328) NaH (84 mg, 60% in oil, 2.20 mmol) was added to a solution of 5-chloro-N,N′-dimethyl-3-sulfanyl-pyridine-2-carboxamide (159 mg, 0.73 mmol) and 2,4,6-tri-O-acetyl-3-azido-3-deoxy-β-D-galactopyranosyl chloride (385 mg, 1.10 mmol) in DMF (5 mL) and the mixture was stirred 5 h at rt. The mixture was diluted with EtOAc and washed twice with water and once with brine, the organic phase was dried, evaporated and purified by chromatography (SiO.sub.2, EtOAc/petroleum ether) to yield the title compound (202 mg, 52%). .sup.1H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J=2.1 Hz, 1H), 7.98 (d, J=2.1 Hz, 1H), 6.05 (d, J=5.5 Hz, 1H), 5.48 (d, J=3.1 Hz, 1H), 5.28 (dd, J=11.0, 5.5 Hz, 1H), 4.63 (dd, J=7.4, 4.6 Hz, 1H), 4.13-4.09 (m, 1H), 4.05 (dd, J=11.6, 7.7 Hz, 1H), 3.97 (dd, J=11.0, 3.3 Hz, 1H), 3.16 (s, 3H), 2.88 (s, 3H), 2.18 (s, 3H), 2.17 (s, 3H), 2.03 (s, 3H). ESI-MS m/z calcd for [C.sub.20H.sub.24ClN.sub.5O.sub.8S].sup.+ (M+H).sup.+: 530.1; found: 530.2.