PRODRUG GALACTOSIDE INHIBITOR OF GALECTINS

Abstract

A prodrug compound of the general formula I or II. The prodrug compound of formula I or II is suitable for use in a method for treating a disorder relating to the binding of a galectin, such as galectin-3 to a ligand in a mammal, such as a human. Also, a method for treatment of a disorder relating to the binding of a galectin, such as galectin-3 to a ligand in a mammal, such as a human.

Claims

1-25. (canceled)

26. A prodrug compound of formula (I) ##STR00077## wherein the pyranose ring is α- or β-D-galactopyranose (as indicated by wavy line); wherein: A.sup.1 is selected from the group consisting of i) an aryl; ii) an aryl substituted with at least one from the group consisting of a halogen; CN; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; carboxyl; C.sub.1-6 alkoxy; C.sub.1-6 thioalkyl; C.sub.1-6 alkyl; nitro; thio; C.sub.1-6 alkylthio; amino; hydroxy; C.sub.1-6 carbonyl; an amino; and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; iii) a C.sub.1-6 alkoxy; iv) a C.sub.1-6 alkoxy substituted with at least one from the group consisting of a halogen; a C.sub.1-6 alkyl; a heteroaryl; a heteroaryl substituted with at least one from the group consisting of halogen, CN, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, carboxyl, C.sub.1-6 alkoxy, C.sub.1-6 thioalkyl, amino, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy substituted with at least one halogen, a five or six membered heteroaromatic ring, a five or six membered heteroaromatic ring substituted with at least one from the group consisting of halogen, CN, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, carboxyl, C.sub.1-6 alkoxy, C.sub.1-6 thioalkyl, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one halogen, C.sub.1-6 alkoxy, and C.sub.1-6 alkoxy substituted with at least one halogen, an aryl, and an aryl substituted with at least one from the group consisting of halogen, CN, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, carboxyl, C.sub.1-6 alkoxy, C.sub.1-6 thioalkyl, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one halogen, C.sub.1-6 alkoxy, and C.sub.1-6 alkoxy substituted with at least one halogen; an amino; and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; v) a C.sub.1-6 alkylamino; vi) a C.sub.1-6 alkylamino substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; vii) a heteroaryl; viii) a heteroaryl substituted with at least one from the group consisting of a halogen; CN; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; carboxyl; C.sub.1-6 alkoxy; C.sub.1-6 thioalkyl; an amino; an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; an aryl; an aryl substituted with at least one from the group consisting of a halogen, CN, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, carboxyl, C.sub.1-6 alkoxy, C.sub.1-6 thioalkyl, C.sub.1-6 alkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy, C.sub.1-6 carbonyl, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; a heteroaryl; a heteroaryl substituted with at least one from the group consisting of halogen, CN, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, carboxyl, C.sub.1-6 alkoxy, C.sub.1-6 thioalkyl, C.sub.1-6 alkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy, C.sub.1-6 carbonyl, an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.3-7 cycloalkoxy, and C.sub.3-7 cycloalkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; a C.sub.1-6 carbonyl; a C.sub.1-6 carbonyl substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; ix) a heterocycle; x) a heterocycle substituted with at least one from the group consisting of halogen, CN, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, carboxyl, C.sub.1-6 alkoxy, C.sub.1-6 thioalkyl, C.sub.1-6 alkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy, C.sub.1-6 carbonyl, an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.3-7 cycloalkoxy, and C.sub.3-7 cycloalkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; a C.sub.1-6 carbonyl; a C.sub.1-6 carbonyl substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; xi) a C.sub.1-6 alkyl; xii) a C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen; C.sub.1-6 alkoxy; C.sub.1-6 alkyl; C.sub.3-7 cycloalkyl; nitro; thio; C.sub.1-6 alkylthio; amino; hydroxy; and C.sub.1-6 carbonyl; xiii) a C.sub.1-6 carbonyl; xiv) a C.sub.1-6 carbonyl substituted with at least one from the group consisting of a C.sub.1-6 alkyl; a C.sub.2-6 alkenyl; an aryl; a heteroaryl; and a heterocycle; xv) a C.sub.1-6 alkyl-CONH—; xvi) a C.sub.1-6 alkyl-CONH— substituted on one or more alkyl carbon with at least one from the group consisting of a heteroaryl; a heteroaryl substituted with at least one from the group consisting of a halogen, CN, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, carboxyl, C.sub.1-6 alkoxy, C.sub.1-6 thioalkyl, C.sub.1-6 alkoxy substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy, C.sub.1-6 carbonyl, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; an aryl; and an aryl substituted with at least one from the group consisting of a halogen, CN, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, carboxyl, C.sub.1-6 alkoxy, C.sub.1-6 thioalkyl, C.sub.1-6 alkoxy substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy, C.sub.1-6 carbonyl, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; or an in vivo metabolizable group of A.sup.1; X.sup.1 is selected from the group consisting of O, S, SO, SO.sub.2, C═O, amino, amino substituted with a C.sub.1-6 alkyl, and CR′R″ wherein R′ and R″ are independently selected from hydrogen, OH, or halogen; or an in vivo metabolizable group of X.sup.1; B.sup.1 is selected from the group consisting of a) a C.sub.1-6 alkyl, b) a C.sub.1-6 alkyl substituted with at least one from the group consisting of a five or six membered heteroaromatic ring; a five or six membered heteroaromatic ring substituted with at least one from the group consisting of cyano, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen, hydroxy and C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy substituted with at least one from the group consisting of halogen, hydroxy and C.sub.1-6 alkyl, hydroxy, and R.sup.#—CONH— wherein R.sup.# is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; an aryl; and an aryl substituted with at lest one from the group consisting of cyano, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen, hydroxy and C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy substituted with at least one from the group consisting of halogen, hydroxy and C.sub.1-6 alkyl, hydroxy, and R.sup.#—CONH— wherein R.sup.# is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; c) an aryl; d) an aryl substituted with at least one from the group consisting of halogen; cyano; hydroxy; carboxyl; carboxamid; carboxamid substituted with at least one from the group consisting of C.sub.1-6 alkyl and C.sub.3-6 cycloalkyl; C.sub.1-6 alkyl; C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.&—CONH— wherein R.sup.& is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.1-6 cycloalkyl; C.sub.1-6 cycloalkyl substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.%—CONH— wherein R.sup.% is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.1-6 alkoxy; C.sub.1-6 alkoxy substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.§ —CONH— wherein R.sup.§§ is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.3-6 cycloalkoxy; C.sub.3-6 cycloalkoxy substituted with at least one from the group consisting of halogen, hydroxy, and R*—CONH— wherein R* is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; amino; amino substituted with at least one from the group consisting of C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; and R**—CONH— wherein R** is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; e) a C.sub.4-10 cycloalkyl, f) a C.sub.4-10 cycloalkyl substituted with at least one from the group consisting of cyano, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen, hydroxy and C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy substituted with at least one from the group consisting of halogen, hydroxy and C.sub.1-6 alkyl, hydroxy, and R.sup.##—CONH— wherein R.sup.## is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; and g) a heterocycle substituted with at least one from the group consisting of halogen; cyano; hydroxy; carboxyl; carboxamid; carboxamid substituted with at least one from the group consisting of C.sub.1-6 alkyl and C.sub.3-6 cycloalkyl; C.sub.1-6 alkyl; C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.&&—CONH— wherein R.sup.&& is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.1-6 cycloalkyl; C.sub.1-6 cycloalkyl substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.%%—CONH— wherein R.sup.%% is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.1-6 alkoxy; C.sub.1-6 alkoxy substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.§§ —CONH— wherein R.sup.§§ is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.3-6 cycloalkoxy; C.sub.3-6 cycloalkoxy substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.a—CONH— wherein R.sup.a is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; amino; amino substituted with at least one from the group consisting of C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; R.sup.aa—CONH— wherein R.sup.aa is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; a heteroaryl substituted with at least one from the group consisting of a halogen; an amino; an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; an aryl; an aryl substituted with at least one from the group consisting of a halogen, cyano, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy, C.sub.1-6 carbonyl, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; a heteroaryl; a heteroaryl substituted with at least one from the group consisting of halogen, cyano, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy, C.sub.1-6 carbonyl, an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.3-7 cycloalkoxy, and C.sub.3-7 cycloalkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; a C.sub.1-6 carbonyl; and a C.sub.1-6 carbonyl substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; or an in vivo metabolizable group of B.sup.1; R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group; R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group; and R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group; or a pharmaceutically acceptable salt or solvate thereof; with the proviso that at least one in vivo metabolizable group is present in at least one from the group consisting of A.sup.1, X.sup.1, B.sup.1, R.sup.1, R.sup.2 and R.sup.3.

27. The prodrug compound of claim 26, wherein the prodrug is bioactivated outside a mammalian cell.

28. The prodrug compound of claim 26, wherein the prodrug is bioactivated inside a mammalian cell.

29. The prodrug compound of claim 26, wherein the in vivo metabolizable group is selected from the group consisting of carbamate, ether, phosphate, sulphate, oxy alkyl phosphate, oxy alkyl sulphate, N-Mannich base, carbonate, amide, ester, N-acylsulphonamides, sulfonamides, imines, acyloxyalkylamines, phosphates, phosphoroimidates, azoconjugates, carbonyloxymethyl, acetylthioethanol, dithioethanol, cyclosal, Hep-direct, phosphorodiimidates, ProTide phosphoroimidates, Pro Tide phosphonoimidates, alkoxyalkylmonoeters and acetyl.

30. The prodrug compound of claim 26 having formula II ##STR00078## wherein the pyranose ring is α-D-galactopyranose, wherein: A.sup.2 is selected from ##STR00079## wherein Het.sup.1a is selected from a five or six membered heteroaromatic ring, optionally substituted with a group selected from Br; F; Cl; CN; NR.sup.19aR.sup.20a, wherein R.sup.19a and R.sup.29a are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, iso-propyl, —C(═O)—R.sup.21a, wherein R.sup.21a is selected from H and C.sub.1-3 alkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; iso-propyl, optionally substituted with a F; O-cyclopropyl optionally substituted with a F; O-isopropyl optionally substituted with a F; and OC.sub.1-3 alkyl optionally substituted with a F; wherein R.sup.1a-R.sup.5a are independently selected from H, CN, NH.sub.2, F, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F; wherein R.sup.6a is selected from C.sub.1-6 alkyl optionally substituted with a halogen, branched C.sub.3-6 alkyl and C.sub.3-7 cycloalkyl; wherein R.sup.7a is selected from a five or six membered heteroaromatic ring, optionally substituted with a group selected from Br, F, Cl, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F, and a phenyl optionally substituted with a group selected from Br, F, Cl, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F; wherein R.sup.8a-R.sup.12a are independently selected from H, F, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F; wherein R.sup.13a is a five or six membered heteroaromatic ring optionally substituted with a group selected from H, OH, F, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F, or an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from H, OH, F, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F; X.sup.1 is selected from S, SO, SO.sub.2, O, C═O, and CR.sup.32aR.sup.33a wherein R.sup.32a and R.sup.33a are independently selected from hydrogen, OH, or halogen; wherein R.sup.27a is selected from a C.sub.1-6 alkyl, branched C.sub.3-6 alkyl, C.sub.1-6 alkoxy and branched C.sub.3-6 alkoxy; B.sup.2 is selected from a) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl substituted with a five or six membered heteroaromatic ring, optionally substituted with a substituent selected from CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.14a—CONH— wherein R.sup.14a is selected from C.sub.1-3 alkyl and cyclopropyl; or a C.sub.1-6 alkyl substituted with a phenyl, optionally substituted with a substituent selected from CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.15a—CONH— wherein R.sup.15a is selected from C.sub.1-3 alkyl and cyclopropyl; b) an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.22aR.sup.23a, wherein R.sup.22a and R.sup.23a are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.28aR.sup.29a, wherein R.sup.28a and R.sup.29a are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.16a—CONH— wherein R.sup.16a is selected from C.sub.1-3 alkyl and cyclopropyl; c) a C.sub.5-7 cycloalkyl, optionally substituted with a substituent selected from a halogen, CN, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.17a—CONH— wherein R.sup.17a is selected from C.sub.1-3 alkyl and cyclopropyl; and d) a heterocycle, such as heteroaryl or heterocycloalkyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.24aR.sup.25a, wherein R.sup.24a and R.sup.25a are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.30aR.sup.31a, wherein R.sup.30a and R.sup.31a are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.18a—CONH— wherein R.sup.18a is selected from C.sub.1-3 alkyl and cyclopropyl; e) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl; R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group; R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group; and R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group; or a pharmaceutically acceptable salt or solvate thereof; with the proviso that at least one in vivo metabolizable group is present in at least one from the group consisting of R.sup.1, R.sup.2 and R.sup.3.

31. The prodrug compound of claim 26 having formula II ##STR00080## wherein the pyranose ring is α-D-galactopyranose, A.sup.2 is selected from ##STR00081## wherein Het.sup.1b is selected from a pyridinyl, optionally substituted with a group selected from H, CN, Br, Cl, I, F, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, and SCH.sub.3 optionally substituted with a F; or a pyrimidyl, optionally substituted with a group selected from H, CN, Br, Cl, I, F, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, and SCH.sub.3 optionally substituted with a F; wherein R.sup.1b-R.sup.5b are independently selected from a group consisting of H, CN, Br, Cl, I, F, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, and SCH.sub.3 optionally substituted with a F; X.sup.1 is selected from S, SO, and SO.sub.2; B.sup.2 is selected from a) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl substituted with a five or six membered heteroaromatic ring, optionally substituted with a substituent selected from CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.14b—CONH— wherein R.sup.14b is selected from C.sub.1-3 alkyl and cyclopropyl; or a C.sub.1-6 alkyl substituted with a phenyl, optionally substituted with a substituent selected from CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.15b—CONH— wherein R.sup.15b is selected from C.sub.1-3 alkyl and cyclopropyl; b) an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.22bR.sup.23b, wherein R.sup.22b and R.sup.23b are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.28bR.sup.29b, wherein R.sup.28b and R.sup.29b are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.16b—CONH— wherein R.sup.16b is selected from C.sub.1-3 alkyl and cyclopropyl; c) a C.sub.5-7 cycloalkyl, optionally substituted with a substituent selected from a halogen, CN, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.17b—CONH— wherein R.sup.17b is selected from C.sub.1-3 alkyl and cyclopropyl; and d) a heterocycle, such as heteroaryl or heterocycloalkyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.24bR.sup.25b, wherein R.sup.24b and R.sup.25b are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.30bR.sup.31b, wherein R.sup.30b and R.sup.31b are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.18b—CONH— wherein R.sup.18b is selected from C.sub.1-3 alkyl and cyclopropyl; e) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl; R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group; R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group; and R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group; or a pharmaceutically acceptable salt or solvate thereof; with the proviso that at least one in vivo metabolizable group is present in at least one from the group consisting of R.sup.1, R.sup.2 and R.sup.3.

32. The prodrug compound of claim 31, wherein: A.sup.2 is ##STR00082## wherein R.sup.1b-R.sup.5b are independently selected from a group consisting of H, CN, Br, Cl, I, F, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, and SCH.sub.3 optionally substituted with a F; X.sup.1 is S; B.sup.2 is selected from b) a phenyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.22bR.sup.23b, wherein R.sup.22b and R.sup.23b are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.28bR.sup.29b, wherein R.sup.28b and R.sup.29b are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.16b—CONH— wherein R.sup.16b is selected from C.sub.1-3 alkyl and cyclopropyl; d) a heteroaryl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.24bR.sup.25b, wherein R.sup.24b and R.sup.25b are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.30bR.sup.31b, wherein R.sup.30b and R.sup.31b are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.18b—CONH— wherein R.sup.18b is selected from C.sub.1-3 alkyl and cyclopropyl; R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group; R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group; and R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group; or a pharmaceutically acceptable salt or solvate thereof; with the proviso that at least one in vivo metabolizable group is present in at least one from the group consisting of R.sup.1, R.sup.2 and R.sup.3.

33. The prodrug compound of claim 32, wherein: A.sup.2 is ##STR00083## wherein R.sup.1b-R.sup.5b are independently selected from a group consisting of H, Cl and F; X.sup.1 is S; B.sup.2 is selected from b) a phenyl substituted with a halogen; and d) a heteroaryl substituted with a cyano, a halogen, or a cyano and a halogen; R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group; R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group; and R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group; or a pharmaceutically acceptable salt or solvate thereof; with the proviso that at least one in vivo metabolizable group is present in at least one from the group consisting of R.sup.1, R.sup.2 and R.sup.3.

34. The prodrug compound of claim 32, wherein A.sup.2 is ##STR00084## wherein R.sup.1b-R.sup.5b are independently selected from a group consisting of H and F; X.sup.1 is S; B.sup.2 is selected from b) a phenyl substituted with a halogen; and d) a heteroaryl substituted with a halogen; R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group; R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group; R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group; or a pharmaceutically acceptable salt or solvate thereof; with the proviso that at least one in vivo metabolizable group is present in at least one from the group consisting of R.sup.1, R.sup.2 and R.sup.3.

35. The prodrug compound of claim 34, wherein A.sup.2 is ##STR00085## wherein R.sup.1b and R.sup.5b are hydrogen, and at least one of R.sup.2b-R.sup.4b is F; X.sup.1 is S; B.sup.2 is selected from b) a phenyl substituted with a Cl; and d) a pyridinyl substituted with a Br; R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group; R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group; R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group; or a pharmaceutically acceptable salt or solvate thereof; with the proviso that at least one in vivo metabolizable group is present in at least one from the group consisting of R.sup.1, R.sup.2 and R.sup.3.

36. The prodrug compound of claim 33, wherein A.sup.2 is ##STR00086## wherein R.sup.1b and R.sup.5b are hydrogen, and R.sup.2b-R.sup.4b is selected from the group consisting of Cl and F; X.sup.1 is S; B.sup.2 is selected from d) a pyridinyl substituted with a group selected from Cl, Br and CN; R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group; R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group; R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group; or a pharmaceutically acceptable salt or solvate thereof; with the proviso that at least one in vivo metabolizable group is present in at least one from the group consisting of R.sup.1, R.sup.2 and R.sup.3.

37. The prodrug compound of claim 26 having formula II ##STR00087## wherein the pyranose ring is α-D-galactopyranose, A2 is ##STR00088## wherein Het.sup.1c is a five or six membered heteroaromatic ring selected from the group consisting of formulas 2 to 9: ##STR00089## wherein R.sup.2c to R.sup.23c and R.sup.27c are independently selected from H; halogen; OH; CN; SH; S—C.sub.1-3 alkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; iso-propyl, optionally substituted with a F; O-cyclopropyl optionally substituted with a F; O-isopropyl optionally substituted with a F; OC.sub.1-3 alkyl optionally substituted with a F; NR.sup.24cR.sup.25c, wherein R.sup.24c is selected from H, and C.sub.1-3 alkyl, and R.sup.25c is selected from H, C.sub.1-3 alkyl, and COR.sup.26c, wherein R.sup.26c is selected from H, and C.sub.1-3 alkyl; X.sup.1 is selected from S, SO, SO.sub.2; B.sup.2 is selected from a) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl substituted with a five or six membered heteroaromatic ring, optionally substituted with a substituent selected from CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.27#—CONH— wherein R.sup.27# is selected from C.sub.1-3 alkyl and cyclopropyl; or a C.sub.1-6 alkyl substituted with a phenyl, optionally substituted with a substituent selected from CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.28c—CONH— wherein R.sup.28c is selected from C.sub.1-3 alkyl and cyclopropyl; b) an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.29cR.sup.30c, wherein R.sup.29c and R.sup.39c are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.31cR.sup.32c, wherein R.sup.31c and R.sup.32c are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.33c—CONH—, wherein R.sup.33c is selected from C.sub.1-3 alkyl and cyclopropyl; c) a C.sub.5-7 cycloalkyl, optionally substituted with a substituent selected from a halogen, CN, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.34c—CONH— wherein R.sup.34c is selected from C.sub.1-3 alkyl and cyclopropyl; and d) a heterocycle, such as heteroaryl or heterocycloalkyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.35cR.sup.36c, wherein R.sup.35c and R.sup.36c are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.37cR.sup.38c, wherein R.sup.37c and R.sup.38c are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.39c—CONH— wherein R.sup.39c is selected from C.sub.1-3 alkyl and cyclopropyl; e) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl; R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group; R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group; and R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group; or a pharmaceutically acceptable salt or solvate thereof; with the proviso that at least one in vivo metabolizable group is present in at least one from the group consisting of R.sup.1, R.sup.2 and R.sup.3.

38. The prodrug compound of claim 26 having formula II ##STR00090## wherein the pyranose ring is α-D-galactopyranose, A.sup.2 is ##STR00091## wherein the pyranose ring is α-D-galactopyranose, Het.sup.1d is selected from the group consisting of ##STR00092## wherein R.sup.2d is selected from the group consisting of OH and halogen; R.sup.3d is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen; R.sup.4d is selected from the group consisting of OH and halogen; R.sup.5d is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen; X.sup.1 is S; B.sup.2 is selected from a) an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.29dR.sup.30d, wherein R.sup.29d and R.sup.31d 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.31dR.sup.32d, wherein R.sup.31d and R.sup.32d are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.33d—CONH—, wherein R.sup.33d is selected from C.sub.1-3 alkyl and cyclopropyl; b) a heterocycle, such as heteroaryl or heterocycloalkyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.35dR.sup.36d, wherein R.sup.35d and R.sup.36d 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.37dR.sup.38d, wherein R.sup.37d and R.sup.38d are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.39d—CONH— wherein R.sup.39d is selected from C.sub.1-3 alkyl and cyclopropyl; R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group; R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group; and R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group; or a pharmaceutically acceptable salt or solvate thereof; with the proviso that at least one in vivo metabolizable group is present in at least one from the group consisting of R.sup.1, R.sup.2 and R.sup.3.

39. The prodrug compound of claim 26, wherein: R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group; R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group; R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group; with the proviso that one in vivo metabolizable group is present in one from the group consisting of R.sup.1, R.sup.2 and R.sup.3.

40. The prodrug of claim 39, wherein R.sup.1 is an in vivo metabolizable group; R.sup.2 is hydrogen; and R.sup.3 is hydrogen.

41. The prodrug of claim 39, wherein R.sup.2 is an in vivo metabolizable group; R.sup.1 is hydrogen; and R.sup.3 is hydrogen.

42. The prodrug of claim 39, wherein R.sup.3 is an in vivo metabolizable group; R.sup.1 is hydrogen; and R.sup.2 is hydrogen.

43. The prodrug compound of claim 39, wherein the in vivo metabolizable group is independently selected from the group consisting of carbamate, ether, phosphate, sulphate, oxy alkyl phosphate, oxy alkyl sulphate, N-Mannich base, carbonate, amide, ester, N-acylsulphoneamides, sulfonamides, imines, acyloxyalkylamines, phosphates, phosphoroimidates, azoconjugates, carbonyloxymethyl, acethylthioethanol, dithioethanol, cyclosal, Hep-direct, phosphorodiimidatesm ProTide phosphoroimidates, Pro Tide phosphonoimidates, alkoxyalkylmonoeters and acetyl.

44. The compound of claim 26 selected from the group consisting of 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-6-O-phospho-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-phospho-1-thio-α-D-galactopyranoside, 3,4-Dichlorphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-phospho-1-thio-α-D-galactopyranoside, 3,4-Dichlorphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-sulfo-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-Deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-sulfo-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-Deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-6-O-sulfo-1-thio-α-D-galactopyranoside, 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-6-O-[(phosphonooxy)methyl]-1-thio-α-D-galactopyranoside, and 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-[(phosphonooxy)methyl]-1-thio-α-D-galactopyranoside, and 5-Bromopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-[(phosphonooxy)methyl]-1-thio-α-D-galactopyranoside; or a pharmaceutically acceptable salt or solvate thereof.

45. A pharmaceutical composition comprising the compound of claim 26 and optionally a pharmaceutically acceptable additive.

46. A method for treatment of a disorder relating to the binding of a galectin-3 to a ligand in a mammal, wherein a therapeutically effective amount of at least one compound according to claim 1 is administered to a mammal in need of said treatment; wherein said disorder is selected from the group consisting of inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart; scarring; keloid formation; aberrant scar formation; surgical adhesions; septic shock; cancer, such as carcinomas, sarcomas, leukemias and lymphomas, such as T-cell lymphomas; metastasising cancers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; heart disease; heart failure; pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer; and eye diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistens; obesity; Diastolic HF; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, mesothelioma; liver disorders, such as non-alcoholic steatohepatitis.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0164] The compounds of the present invention are novel prodrugs of galactopyranose compounds that unexpectedly have good solubility and can be used to increase the maximum dose resulting in dose correlated bioavailability. The prodrug compounds of the present invention of formula (I) differ from prior art compounds in that it comprises at least one in vivo hydrolysable group which will be cleaved off upon administration to a mammal, such as a human subject, to create an active metabolite being an inhibitor of galectin 3.

[0165] The prodrugs of the present invention convert into an active metabolite which has high affinity to galectin 3 and inhibits galectin 3. Here prodrugs have been developed in which one to three functional group(s) are introduced at selected positions to prepare a prodrug which is charged in the intestine due to it's pKa.

[0166] Preferably, the pyranose ring is α-D-galactopyranose which compounds have very good solubility and suitability as prodrugs. In particular, prodrugs having an in vivo hydrolysable group on the C2, C4 and/or C6 of the galactopyranose ring have aqueous solubility above 8 mg/ml, and in some instances above 10 mg/ml.

[0167] In broad aspect the present invention concerns a prodrug compound of formula (I)

##STR00021##

wherein the pyranose ring is α- or β-D-galactopyranose (as indicated by wavy line);
and wherein R.sup.1, R.sup.2, R.sup.3, A.sup.1, X.sup.1 and B.sup.1 are as defined above.

[0168] In one embodiment A.sup.1 is selected from a heteroaryl substituted with at least one from the group consisting of a halogen; CN; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; carboxyl; C.sub.1-6 alkoxy; C.sub.1-6 thioalkyl; an amino; an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; an aryl; an aryl substituted with at least one from the group consisting of a halogen, CN, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, carboxyl, C.sub.1-6 alkoxy, C.sub.1-6 thioalkyl, C.sub.1-6 alkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy, C.sub.1-6 carbonyl, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; a heteroaryl; a heteroaryl substituted with at least one from the group consisting of halogen, CN, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, carboxyl, C.sub.1-6 alkoxy, C.sub.1-6 thioalkyl, C.sub.1-6 alkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy, C.sub.1-6 carbonyl, an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.3-7 cycloalkoxy, and C.sub.3-7 cycloalkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; a C.sub.1-6 carbonyl; a C.sub.1-6 carbonyl substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl. In a more specific embodiment A.sup.1 is a heteroaryl substituted with an aryl substituted with at least one from the group consisting of a halogen, CN, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, carboxyl, C.sub.1-6 alkoxy, C.sub.1-6 thioalkyl, C.sub.1-6 alkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl. In a still more specific embodiment A.sup.1 is a triazolyl, such as a 1,2,3-triazolyl, substituted with a phenyl substituted with at least one halogen, such a 1, 2 or 3 F.

[0169] In another embodiment X.sup.1 is selected from the group consisting of 0 and S. Preferably X.sup.1 is S.

[0170] In a further embodiment B.sup.1 is selected from the group consisting of d) an aryl substituted with at least one from the group consisting of halogen; cyano; hydroxy; carboxyl; carboxamid; carboxamid substituted with at least one from the group consisting of C.sub.1-6 alkyl and C.sub.3-6 cycloalkyl; C.sub.1-6 alkyl; C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.&-CONH— wherein R.sup.& is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.1-6 cycloalkyl; C.sub.1-6 cycloalkyl substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.%-CONH— wherein R.sup.% is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.1-6 alkoxy; C.sub.1-6 alkoxy substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.§ —CONH— wherein R.sup.§ is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.3-6 cycloalkoxy; C.sub.3-6 cycloalkoxy substituted with at least one from the group consisting of halogen, hydroxy, and R*—CONH— wherein R* is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; amino; amino substituted with at least one from the group consisting of C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; and R**—CONH— wherein R** is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; and g) a heteroaryl substituted with at least one from the group consisting of halogen; cyano; hydroxy; carboxyl; carboxamid; carboxamid substituted with at least one from the group consisting of C.sub.1-6 alkyl and C.sub.3-6 cycloalkyl; C.sub.1-6 alkyl; C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.&&—CONH— wherein R.sup.&& is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.1-6 cycloalkyl; C.sub.1-6 cycloalkyl substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.%%—CONH— wherein R.sup.%% is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.1-6 alkoxy; C.sub.1-6 alkoxy substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.§§ —CONH— wherein R.sup.§§ is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.3-6 cycloalkoxy; C.sub.3-6 cycloalkoxy substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.a—CONH— wherein R.sup.a is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; amino; amino substituted with at least one from the group consisting of C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; R.sup.aa—CONH— wherein R.sup.aa is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; a heteroaryl substituted with at least one from the group consisting of a halogen; an amino; an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; an aryl; an aryl substituted with at least one from the group consisting of a halogen, cyano, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy, C.sub.1-6 carbonyl, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; a heteroaryl; a heteroaryl substituted with at least one from the group consisting of halogen, cyano, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy, C.sub.1-6 carbonyl, an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.3-7 cycloalkoxy, and C.sub.3-7 cycloalkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; a C.sub.1-6 carbonyl; and a C.sub.1-6 carbonyl substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl. Preferably B.sup.1 is selected from the group consisting of d) a phenyl substituted with at least one from the group consisting of halogen; cyano; hydroxy; carboxyl; carboxamid; carboxamid substituted with at least one from the group consisting of C.sub.1-6 alkyl and C.sub.3-6 cycloalkyl; C.sub.1-6 alkyl; C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.&-CONH— wherein R.sup.& is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.1-6 cycloalkyl; C.sub.1-6 cycloalkyl substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.%—CONH— wherein R.sup.% is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.1-6 alkoxy; C.sub.1-6 alkoxy substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.§ —CONH— wherein R.sup.§§ is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.3-6 cycloalkoxy; C.sub.3-6 cycloalkoxy substituted with at least one from the group consisting of halogen, hydroxy, and R*—CONH— wherein R* is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; amino; amino substituted with at least one from the group consisting of C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; and R**—CONH— wherein R** is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; and g) a pyridinyl substituted with at least one from the group consisting of halogen; cyano; hydroxy; carboxyl; carboxamid; carboxamid substituted with at least one from the group consisting of C.sub.1-6 alkyl and C.sub.3-6 cycloalkyl; C.sub.1-6 alkyl; C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.&&—CONH— wherein R.sup.&& is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.1-6 cycloalkyl; C.sub.1-6 cycloalkyl substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.%%—CONH— wherein R.sup.%% is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.1-6 alkoxy; C.sub.1-6 alkoxy substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.§§ —CONH— wherein R.sup.§§ is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; C.sub.3-6 cycloalkoxy; C.sub.3-6 cycloalkoxy substituted with at least one from the group consisting of halogen, hydroxy, and R.sup.a—CONH— wherein R.sup.a is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; amino; amino substituted with at least one from the group consisting of C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; R.sup.aa—CONH— wherein R.sup.aa is selected from the group consisting C.sub.1-6 alkyl and C.sub.1-6 cycloalkyl; a heteroaryl substituted with at least one from the group consisting of a halogen; an amino; an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; an aryl; an aryl substituted with at least one from the group consisting of a halogen, cyano, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy, C.sub.1-6 carbonyl, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; a heteroaryl; a heteroaryl substituted with at least one from the group consisting of halogen, cyano, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy, C.sub.1-6 carbonyl, an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, C.sub.3-7 cycloalkoxy, and C.sub.3-7 cycloalkoxy substituted with at least one from the group consisting of a halogen, an amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl; a C.sub.1-6 carbonyl; and a C.sub.1-6 carbonyl substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl, nitro, thio, C.sub.1-6 alkylthio, amino, and an amino substituted with at least one from the group consisting of halogen, C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, nitro, thio, C.sub.1-6 alkylthio, amino, hydroxy and C.sub.1-6 carbonyl. Most preferably B.sup.1 is selected from the group consisting of d) a phenyl substituted with at least one halogen, such as 1 or 2 Cl; and g) a pyridinyl substituted with at least one halogen, such as 1 Br.

[0171] In a further embodiment R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group;

[0172] R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group;

[0173] R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group;

[0174] with the proviso that one in vivo metabolizable group is present in one from the group consisting of R.sup.1, R.sup.2 and R.sup.3. Typically, R.sup.1 is an in vivo metabolizable group; R.sup.2 is hydrogen; and R.sup.3 is hydrogen. Typically, R.sup.1 is hydrogen; R.sup.2 is hydrogen; and R.sup.3 is an in vivo metabolizable group.

[0175] In a still further embodiment of the present invention the prodrug compound of formula I is bioactivated outside a mammalian cell, such as a human cell.

[0176] In another embodiment of the present invention the prodrug compound of formula I is bioactivated inside a mammalian cell, such as a human cell.

[0177] In a further embodiment of the present invention the in vivo metabolizable group is selected from the group consisting of a carbamate, an ether, a phosphate, a sulphate, an oxy alkyl phosphate, an oxy alkyl sulphate, an N-Mannich base, a carbonate, an amide, an ester, an N-acylsulphoneamide, a sulfonamide, an imine, an acyloxyalkylamine, a phosphoroimidate, an azoconjugate, a carbonyloxymethyl, an acethylthioethanol, a dithioethanol, a cyclosal, a Hep-direct, a phosphorodiimidatesm ProTide phosphoroimidate, a Pro Tide phosphonoimidate, an alkoxyalkylmonoeter and an acetyl. Typically, the in vivo metabolizable group is selected from the group consisting of a phosphate, a sulphate, an oxy C.sub.1-6 alkyl phosphate, and an oxy C.sub.1-6 alkyl sulphate.

[0178] In a still further embodiment of the present invention the prodrug compound is selected from a compound of formula II

##STR00022##

wherein the pyranose ring is α-D-galactopyranose,
wherein

[0179] A.sup.2 is selected from A.sup.1 as defined above;

[0180] X.sup.1 is selected from S, SO, SO.sub.2, O, C═O, and CR.sup.32aR.sup.33a wherein R.sup.32a and R.sup.33a are independently selected from hydrogen, OH, or halogen;

[0181] B.sup.2 is selected from B.sup.1 as defined above; [0182] R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group; [0183] R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group; [0184] R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group; or [0185] a pharmaceutically acceptable salt or solvate thereof;
with the proviso that at least one in vivo metabolizable group is present in at least one from the group consisting of R.sup.1, R.sup.2 and R.sup.3.

[0186] In a further embodiment A.sup.2 is selected from

##STR00023##

[0187] wherein Het.sup.1a is selected from a five or six membered heteroaromatic ring, optionally substituted with a group selected from Br; F; Cl; CN; NR.sup.19aR.sup.20a, wherein R.sup.19a and R.sup.20a are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, iso-propyl, —C(═O)—R.sup.21a, wherein R.sup.21a is selected from H and C.sub.1-3 alkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; iso-propyl, optionally substituted with a F; O-cyclopropyl optionally substituted with a F; O-isopropyl optionally substituted with a F; and OC.sub.1-3 alkyl optionally substituted with a F;

[0188] wherein R.sup.1a-R.sup.5a are independently selected from H, CN, NH.sub.2, F, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F;

[0189] wherein R.sup.6a is selected from C.sub.1-6 alkyl optionally substituted with a halogen, branched C.sub.3-6 alkyl and C.sub.3-7 cycloalkyl;

[0190] wherein R.sup.7a is selected from a five or six membered heteroaromatic ring, optionally substituted with a group selected from Br, F, Cl, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F, and a phenyl optionally substituted with a group selected from Br, F, Cl, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F;

[0191] wherein R.sup.8a-R.sup.12a are independently selected from H, F, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F;

[0192] wherein R.sup.13a is a five or six membered heteroaromatic ring optionally substituted with a group selected from H, OH, F, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F, or an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from H, OH, F, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F. Preferably, A.sup.2 is formula 2a, wherein R.sup.1a-R.sup.5a are independently selected from H, CN, NH.sub.2, F, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F. More preferred A.sup.2 is formula 2a, wherein R.sup.1a and R.sup.5a are hydrogen, and R.sup.2a-R.sup.4a are independently selected from H, CN, NH.sub.2, F, methyl optionally substituted with a F, and OCH.sub.3 optionally substituted with a F. Most preferred A.sup.2 is formula 2a, wherein R.sup.1a and R.sup.5a are hydrogen, and R.sup.2a-R.sup.4a are independently selected from hydrogen and F. Typically, A.sup.2 is formula 2a, wherein R.sup.1a and R.sup.5a are hydrogen, and R.sup.2a-R.sup.4a are all F.

[0193] In a still further embodiment X.sup.1 is selected from S and O. Preferably, X.sup.1 is S.

[0194] In a further embodiment B.sup.2 is selected from a) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl substituted with a five or six membered heteroaromatic ring, optionally substituted with a substituent selected from CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.14a—CONH— wherein R.sup.14a is selected from C.sub.1-3 alkyl and cyclopropyl; or a C.sub.1-6 alkyl substituted with a phenyl, optionally substituted with a substituent selected from CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.15a—CONH— wherein R.sup.15a is selected from C.sub.1-3 alkyl and cyclopropyl; b) an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.22aR.sup.23a, wherein R.sup.22a and R.sup.23a are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.28aR.sup.29a, wherein R.sup.28a and R.sup.29a are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.16a—CONH— wherein R.sup.16a is selected from C.sub.1-3 alkyl and cyclopropyl; c) a C.sub.5-7 cycloalkyl, optionally substituted with a substituent selected from a halogen, CN, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.17a—CONH— wherein R.sup.17a is selected from C.sub.1-3 alkyl and cyclopropyl; and d) a heterocycle, such as heteroaryl or heterocycloalkyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.24aR.sup.25a, wherein R.sup.24a and R.sup.25a are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.30aR.sup.31a, wherein R.sup.30a and R.sup.31a are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.18a—CONH— wherein R.sup.18a is selected from C.sub.1-3 alkyl and cyclopropyl; e) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl.

[0195] In a still further embodiment B.sup.2 is selected from b) an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.22aR.sup.23a, wherein R.sup.22a and R.sup.23a are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.28aR.sup.29a, wherein R.sup.28a and R.sup.29a are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.16a—CONH— wherein R.sup.16a is selected from C.sub.1-3 alkyl and cyclopropyl; and d) a heterocycle, such as heteroaryl or heterocycloalkyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.24aR.sup.25a, wherein R.sup.24a and R.sup.25a are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.30aR.sup.31a, wherein R.sup.30a and R.sup.31a are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.18a—CONH— wherein R.sup.18a is selected from C.sub.1-3 alkyl and cyclopropyl. In a further embodiment B.sup.2 is selected from b) a phenyl optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.22aR.sup.23a, wherein R.sup.22a and R.sup.23a are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.28aR.sup.29a, wherein R.sup.28a and R.sup.29a are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.16a—CONH— wherein R.sup.16a is selected from C.sub.1-3 alkyl and cyclopropyl; and d) a heteroaryl optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.24aR.sup.25a, wherein R.sup.24a and R.sup.25a are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.30aR.sup.31a, wherein R.sup.30a and R.sup.31a are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.18a—CONH— wherein R.sup.18a is selected from C.sub.1-3 alkyl and cyclopropyl. In a still further embodiment B.sup.2 is selected from b) a phenyl substituted with a halogen; and d) a heteroaryl, such as a pyridinyl, substituted with a halogen.

[0196] In a further embodiment R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group;

[0197] R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group;

[0198] R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group;

[0199] with the proviso that one in vivo metabolizable group is present in one from the group consisting of R.sup.1, R.sup.2 and R.sup.3. Typically, R.sup.1 is an in vivo metabolizable group; R.sup.2 is hydrogen; and R.sup.3 is hydrogen. Typically, R.sup.1 is hydrogen; R.sup.2 is hydrogen; and R.sup.3 is an in vivo metabolizable group.

[0200] In a further embodiment of the present invention the prodrug compound is selected from a compound of formula II

##STR00024##

wherein the pyranose ring is α-D-galactopyranose,

[0201] A2 is

##STR00025##

wherein Het.sup.1c is a five or six membered heteroaromatic ring selected from the group consisting of formulas 2c to 9c:

##STR00026##

wherein R.sup.2c to R.sup.23c and R.sup.27c are independently selected from H; halogen; OH; CN; SH; S—C.sub.1-3 alkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; iso-propyl, optionally substituted with a F; O-cyclopropyl optionally substituted with a F; O-isopropyl optionally substituted with a F; OC.sub.1-3 alkyl optionally substituted with a F; NR.sup.24cR.sup.25c, wherein R.sup.24c is selected from H, and C.sub.1-3 alkyl, and R.sup.25c is selected from H, C.sub.1-3 alkyl, and COR.sup.26c, wherein R.sup.26c is selected from H, and C.sub.1-3 alkyl;

[0202] X.sup.1 is selected from S;

[0203] B.sup.2 is selected from a) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl substituted with a five or six membered heteroaromatic ring, optionally substituted with a substituent selected from CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.27#—CONH— wherein R.sup.27# is selected from C.sub.1-3 alkyl and cyclopropyl; or a C.sub.1-6 alkyl substituted with a phenyl, optionally substituted with a substituent selected from CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.28c—CONH— wherein R.sup.28c is selected from C.sub.1-3 alkyl and cyclopropyl; b) a phenyl optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.29cR.sup.30c, wherein R.sup.29c and R.sup.39c are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.31cR.sup.32c, wherein R.sup.31c and R.sup.32c are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.33c—CONH—, wherein R.sup.33c is selected from C.sub.1-3 alkyl and cyclopropyl; c) a C.sub.5-7 cycloalkyl, optionally substituted with a substituent selected from a halogen, CN, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.34c—CONH— wherein R.sup.34c is selected from C.sub.1-3 alkyl and cyclopropyl; and d) a heterocycle, such as heteroaryl or heterocycloalkyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.35cR.sup.36c, wherein R.sup.35c and R.sup.36c are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.37cR.sup.38c, wherein R.sup.37c and R.sup.38c are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.39c—CONH— wherein R.sup.39c is selected from C.sub.1-3 alkyl and cyclopropyl; e) a C.sub.1-6 alkyl or branched C.sub.3-6 alkyl; [0204] R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group; [0205] R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group; [0206] R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group; or [0207] a pharmaceutically acceptable salt or solvate thereof;
with the proviso that at least one in vivo metabolizable group is present in at least one from the group consisting of R.sup.1, R.sup.2 and R.sup.3.

[0208] In a still further embodiment of the present invention the prodrug compound is selected from a compound of formula II

##STR00027##

wherein the pyranose ring is α-D-galactopyranose,

[0209] A2 is

##STR00028##

[0210] wherein Het.sup.1d is selected from the group consisting of

##STR00029##

[0211] wherein R.sup.2d is selected from the group consisting of OH and halogen;

[0212] R.sup.3d is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen;

[0213] R.sup.4d is selected from the group consisting of OH and halogen;

[0214] R.sup.5d is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and halogen;

[0215] X.sup.1 is S;

[0216] B.sup.2 is selected from a) an aryl, such as phenyl or naphthyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.29dR.sup.30d, wherein R.sup.29d and R.sup.30d 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.31dR.sup.32d, wherein R.sup.31d and R.sup.32d are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.33d—CONH—, wherein R.sup.33d is selected from C.sub.1-3 alkyl and cyclopropyl; b) a heterocycle, such as heteroaryl or heterocycloalkyl, optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.35dR.sup.36d, wherein R.sup.35d and R.sup.36d 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.37dR.sup.38d, wherein R.sup.37d and R.sup.38d are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.39d—CONH— wherein R.sup.39d is selected from C.sub.1-3 alkyl and cyclopropyl; [0217] R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group; [0218] R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group; [0219] R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group; or [0220] a pharmaceutically acceptable salt or solvate thereof;
with the proviso that at least one in vivo metabolizable group is present in at least one from the group consisting of R.sup.1, R.sup.2 and R.sup.3.

[0221] In a further embodiment of the present invention the prodrug compound is selected from a compound of formula II

##STR00030##

wherein the pyranose ring is α-D-galactopyranose,
wherein [0222] A.sup.2 is selected from A.sup.1 as defined above; [0223] X.sup.1 is selected from S, SO, SO.sub.2, and O; [0224] B.sup.2 is selected from B.sup.1 as defined above; [0225] R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group; [0226] R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group; [0227] R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group; or [0228] a pharmaceutically acceptable salt or solvate thereof;
with the proviso that at least one in vivo metabolizable group is present in at least one from the group consisting of R.sup.1, R.sup.2 and R.sup.3.

[0229] In an embodiment A.sup.2 is selected from

##STR00031##

[0230] wherein Het.sup.1b is selected from a pyridinyl, optionally substituted with a group selected from H, CN, Br, Cl, I, F, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, and SCH.sub.3 optionally substituted with a F; or a pyrimidyl, optionally substituted with a group selected from H, CN, Br, Cl, I, F, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, and SCH.sub.3 optionally substituted with a F.

[0231] In another embodiment A.sup.2 is selected from

##STR00032##

[0232] wherein R.sup.1b-R.sup.5b are independently selected from a group consisting of H, CN, Br, Cl, I, F, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, and SCH.sub.3 optionally substituted with a F. Preferably, A.sup.2 is formula 2b, and R.sup.1b and R.sup.5b are both hydrogen, and R.sup.2b-R.sup.4b are independently selected from a group consisting of H, CN, Br, Cl, I, F, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, and SCH.sub.3 optionally substituted with a F. Typically, A.sup.2 is formula 2b, and R.sup.1b and R.sup.5b are both hydrogen, and R.sup.2b-R.sup.4b are independently selected from a group consisting of H, Br, Cl, I, and F, for instance R.sup.2b-R.sup.4b are all F, or R.sup.2b is F, R.sup.3b is Cl and R.sup.4b is F.

[0233] In a further embodiment X.sup.1 is S.

[0234] In a still further embodiment B.sup.2 is selected from b) a phenyl optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.22bR.sup.23b, wherein R.sup.22b and R.sup.23b are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.28bR.sup.29b, wherein R.sup.28b and R.sup.29b are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.16b—CONH— wherein R.sup.16b is selected from C.sub.1-3 alkyl and cyclopropyl; and d) a heteroaryl optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.24bR.sup.25b, wherein R.sup.24b and R.sup.25b are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.30bR.sup.31b, wherein R.sup.30b and R.sup.31b are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.18b—CONH— wherein R.sup.18b is selected from C.sub.1-3 alkyl and cyclopropyl.

[0235] In one embodiment B.sup.2 is selected from a phenyl optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.22bR.sup.23b, wherein R.sup.22b and R.sup.23b are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.28bR.sup.29b, wherein R.sup.28b and R.sup.29b are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.16b—CONH— wherein R.sup.16b is selected from C.sub.1-3 alkyl and cyclopropyl. Typically, B.sup.2 is selected from a phenyl substituted with a halogen, such as 1-3 selected from Cl, F, Br, and I. In a particular embodiment B.sup.2 is selected from a phenyl substituted with 1-3 Cl, such as two Cl. In another particular embodiment B.sup.2 is selected from a phenyl substituted with one halogen and optionally one or two group(s) selected from CN; —COOH; —CONR.sup.22bR.sup.23b, wherein R.sup.22b and R.sup.23b are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.28bR.sup.29b, wherein R.sup.28b and R.sup.29b are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.16b—CONH— wherein R.sup.1b is selected from C.sub.1-3 alkyl and cyclopropyl.

[0236] In another embodiment B.sup.2 is selected from a heteroaryl optionally substituted with a group selected from a halogen; CN; —COOH; —CONR.sup.24bR.sup.25b, wherein R.sup.24b and R.sup.25b are independently selected from H, C.sub.1-3 alkyl, cyclopropyl, and iso-propyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; isopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; O-isopropyl, optionally substituted with a F; NR.sup.30bR.sup.31b, wherein R.sup.30b and R.sup.31b are independently selected from H, C.sub.1-3 alkyl and isopropyl; OH; and R.sup.18b—CONH— wherein R.sup.18b is selected from C.sub.1-3 alkyl and cyclopropyl. Typically, B.sup.2 is selected from a pyridinyl substituted with a group selected from a cyano and a halogen, such as 1-3 selected from Cl, F, Br, and I. In a particular embodiment B.sup.2 is selected from a pyridinyl substituted with 1-3 Br, such as one Br. In another particular embodiment B.sup.2 is selected from a pyridinyl substituted with one Cl and one CN.

[0237] In a still further embodiment of the present invention wherein the prodrug has formula II, wherein A.sup.2 is formula 2b, X.sup.1 is selected from S, SO, SO.sub.2, and O; and B.sup.2 is selected from B.sup.1 as defined above, R.sup.1 is selected from the group consisting of hydrogen and an in vivo metabolizable group; R.sup.2 is selected from the group consisting of hydrogen and an in vivo metabolizable group; R.sup.3 is selected from the group consisting of hydrogen and an in vivo metabolizable group; with the proviso that at least one in vivo metabolizable group is present in at least one from the group consisting of R.sup.1, R.sup.2 and R.sup.3. In a still further embodiment of the present invention R.sup.1 is an in vivo metabolizable group; R.sup.2 is hydrogen; and R.sup.3 is hydrogen. In a further embodiment of the present invention R.sup.1 is hydrogen; R.sup.2 is an in vivo metabolizable group; and R.sup.3 is hydrogen. In a still further embodiment of the present invention R.sup.1 is hydrogen; R.sup.2 is hydrogen; and R.sup.3 is an in vivo metabolizable group. In a further embodiment of the present invention R.sup.1 is an in vivo metabolizable group; R.sup.2 is an in vivo metabolizable group; and R.sup.3 is hydrogen. In a still further embodiment of the present invention R.sup.1 is hydrogen; R.sup.2 is an in vivo metabolizable group; and R.sup.3 is an in vivo metabolizable group. In a further embodiment of the present invention R.sup.1 is an in vivo metabolizable group; R.sup.2 is hydrogen; and R.sup.3 is an in vivo metabolizable group. In a still further embodiment of the present invention R.sup.1 is an in vivo metabolizable group; R.sup.2 is an in vivo metabolizable group; and R.sup.3 is an in vivo metabolizable group.

[0238] In a further embodiment of the present invention the in vivo metabolizable group is independently selected from the group consisting of carbamate, ether, phosphate, sulphate, oxy alkyl phosphate, oxy alkyl sulphate, N-Mannich base, carbonate, amide, ester, N-acylsulphoneamides, sulfonamides, imines, acyloxyalkylamines, phosphates, phosphoroimidates, azoconjugates, carbonyloxymethyl, acethylthioethanol, dithioethanol, cyclosal, Hep-direct, phosphorodiimidatesm ProTide phosphoroimidates, Pro Tide phosphonoimidates, alkoxyalkylmonoeters and acetyl. Typically, the in vivo metabolizable group is independently selected from the group consisting of phosphate, sulphate, oxy C.sub.1-6 alkyl phosphate, and oxy C.sub.1-6 alkyl sulphate. Each of these in vivo metabolizable groups is considered a single embodiment and may be made the subject of a claim specifically to such in vivo metabolizable group.

[0239] In a still further embodiment of the present invention the compound is selected from the group consisting of [0240] 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-6-O-phospho-1-thio-α-D-galactopyranoside, [0241] 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-phospho-1-thio-α-D-galactopyranoside, [0242] 3,4-Dichlorphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-phospho-1-thio-α-D-galactopyranoside, [0243] 3,4-Dichlorphenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-sulfo-1-thio-α-D-galactopyranoside, [0244] 5-Bromopyridin-3-yl 3-Deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-sulfo-1-thio-α-D-galactopyranoside, [0245] 5-Bromopyridin-3-yl 3-Deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-6-O-sulfo-1-thio-α-D-galactopyranoside, [0246] 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-6-O-[(phosphonooxy)methyl]-1-thio-α-D-galactopyranoside, [0247] 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-[(phosphonooxy)methyl]-1-thio-α-D-galactopyranoside, [0248] 5-Bromopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-2-O-[(phosphonooxy)methyl]-1-thio-α-D-galactopyranoside.

[0249] In a further aspect the present invention relates to a prodrug compound of the present invention for use as a medicine. In one embodiment the prodrug compound has formula I. In a more preferred embodiment the prodrug compound has formula II.

[0250] In a still further aspect the present invention relates to a pharmaceutical composition comprising a compound of formula I or II of the present invention and optionally a pharmaceutically acceptable additive, such as a carrier and/or excipient.

[0251] In a further aspect the present invention relates to a compound of formula I or II of the present invention for use in a method for treating a disorder relating to the binding of a galectin-3 to a ligand in a mammal, such as a human. In an embodiment the disorder is selected from the group consisting of inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart; scarring; keloid formation; aberrant scar formation; surgical adhesions; septic shock; cancer, such as carcinomas, sarcomas, leukemias and lymphomas, such as T-cell lymphomas; metastasising cancers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; heart disease; heart failure; pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer; and eye diseases, such as age-related macular degeneration and conical neovascularization; atherosclerosis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistens; obesity; Diastolic HF; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, mesothelioma; liver disorders, such as non-alcoholic steatohepatitis. A non-limiting group of cancers given as examples of cancers that may be treated, managed and/or prevented by administration of a compound of formula I or II include: colon carcinoma, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangeosarcoma, lymphangeoendothelia sarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystandeocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioblastomas, neuronomas, craniopharingiomas, schwannomas, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroama, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemias and lymphomas, acute lymphocytic leukemia and acute myelocytic polycythemia vera, multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's Disease, non-Hodgkin's lymphomas, rectum cancer, urinary cancers, uterine cancers, oral cancers, skin cancers, stomach cancer, brain tumors, liver cancer, laryngeal cancer, esophageal cancer, mammary tumors, childhood-null acute lymphoid leukemia (ALL), thymic ALL, B-cell ALL, acute myeloid leukemia, myelomonocytoid leukemia, acute megakaryocytoid leukemia, Burkitt's lymphoma, acute myeloid leukemia, chronic myeloid leukemia, and T cell leukemia, small and large non-small cell lung carcinoma, acute granulocytic leukemia, germ cell tumors, endometrial cancer, gastric cancer, cancer of the head and neck, chronic lymphoid leukemia, hairy cell leukemia and thyroid cancer. Each of these disorders is considered a single embodiment and may be made the subject of a claim specifically to such disease or disorder.

[0252] In a still further aspect the present invention relates to a method for treatment of a disorder relating to the binding of a galectin-3 to a ligand in a mammal, such as a human, wherein a therapeutically effective amount of at least one compound of formula I or II of the present invention is administered to a mammal in need of said treatment. In an embodiment the disorder is selected from the group consisting of inflammation; fibrosis, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis, ophthalmological fibrosis and fibrosis of the skin and heart; scarring; keloid formation; aberrant scar formation; surgical adhesions; septic shock; cancer, such as carcinomas, sarcomas, leukemias and lymphomas, such as T-cell lymphomas; metastasising cancers; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; heart disease; heart failure; pathological angiogenesis, such as ocular angiogenesis or a disease or condition associated with ocular angiogenesis, e.g. neovascularization related to cancer; and eye diseases, such as age-related macular degeneration and conical neovascularization; atherosclerosis; metabolic diseases such as diabetes; type 2 diabetes; insulin resistens; obesity; Diastolic HF; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, mesothelioma; liver disorders, such as non-alcoholic steatohepatitis. Each of these disorders are considered a single embodiment and may be made the subject of a claim specifically to such disease or disorder.

[0253] The skilled person will understand that it may be necessary to adjust or change the order of steps in the processes a1-a3 and such change of order is encompassed by the aspects of the process as described above in the reaction schemes and accompanying description of the process steps.

[0254] 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.

[0255] 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), TB S (t-butyldimethylsilyl), TMS (trimethylsilyl), PMB (p-methoxybensyl), and tetrahydropyranyl. Suitable protecting groups for carboxylic acid include (C.sub.1-6)-alkyl or benzyl esters. Suitable protecting groups for amino include t-butyloxycarbonyl, benzyloxycarbonyl, 2-(trimethylsilyl)-ethoxy-methyl or 2-trimethylsilylethoxycarbonyl (Teoc). Suitable protecting groups for S include S—C(═N)—NH.sub.2, TIPS.

[0256] The protection and deprotection of functional groups may take place before or after any reaction in the above-mentioned processes.

[0257] 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.

[0258] In a still further embodiment the compound of formula I or II is on free form. “On free form” as used herein means a compound of formula I or II, 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.

[0259] In a further embodiment the compound of formula I or II 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] The term “Oxo” as used herein means an oxygen atom with double bonds, also indicated as ═O.

[0266] The term “CN” as used herein means a nitril.

[0267] 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.

[0268] 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.

[0269] 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.

[0270] The term “in vivo metabolizable” as used herein means any group that is cleaved of to form an active metabolite when administered to a mammalian subject, which active metabolite has affinity to galectin, such as galectin 3 and is a galectin inhibitor, such as a galectin 3 inhibitor. A typical, in vivo metabolizable group is any one of carbamate, ether, phosphate, sulphate, oxy alkyl phosphate, oxy alkyl sulphate, N-Mannich base, carbonate, amide, ester, N-acylsulphoneamides, sulfonamides, imines, acyloxyalkylamines, phosphates, phosphoroimidates, azoconjugates, carbonyloxymethyl, acethylthioethanol, dithioethanol, cyclosal, Hep-direct, phosphorodiimidatesm ProTide phosphoroimidates, Pro Tide phosphonoimidates, alkoxyalkylmonoeters and acetyl.

[0271] The term “a prodrug” as used herein means a compound of formula I or II of the present invention which upon administration to a mammalian body convert into an active metabolite which has high affinity to galectin, such as galectin 3 and is a galectin inhibitor, such as a galectin 3 inhibitor. In particular prodrugs have been developed in which one to three functional group(s) are introduced at selected positions to prepare a prodrug which is charged in the intestine of a mammal, such as a human, due to it's pKa, and in such manner improves solubility for a drug which results in the possibility to give a higher dose. Typical, prodrugs and prodrug strategies are described in Boyapelly, K.; Bonin, M.-A.; Traboulsi, H.; Cloutier, A.; Phaneuf, S. C.; Fortin, D.; Cantin, A. M.; Richter, M. V.; Marsault, E. Synthesis and Characterization of a Phosphate Prodrug of Isoliquiritigenin. J. Nat. Prod. 2017, 80 (4), 879-886. DeGoey, D. A.; Grampovnik, D. J.; Flosi, W. J.; Marsh, K. C.; Wang, X. C.; Klein, L. L.; McDaniel, K. F.; Liu, Y.; Long, M. A.; Kati, W. M.; Molla, A.; Kempf, D. J. Water-Soluble Prodrugs of the Human Immunodeficiency Virus Protease Inhibitors Lopinavir and Ritonavir. J. Med. Chem. 2009, 52 (9), 2964-2970. Rautio, J.; Meanwell, N. A.; Di, L.; Hageman, M. J. The Expanding Role of Prodrugs in Contemporary Drug Design and Development. Nat. Rev. Drug Disc. 2018, 99, 4755. The prodrug may be bioactivated inside or outside a mammalian cell. The preferred prodrugs herein are bioactivated outside a mammalian cell.

[0272] The term “a therapeutically effective amount” of a compound of formula I or II 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.

[0273] In a still further aspect the present invention relates to a pharmaceutical composition comprising the compound of formula I or II and optionally a pharmaceutically acceptable additive, such as a carrier or an excipient.

[0274] 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.

[0275] 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 I or II 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.

[0276] As mentioned above, the compositions and particularly pharmaceutical compositions as herein disclosed may, in addition to the compounds herein disclosed, further comprise at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier. In some embodiments, the pharmaceutical compositions comprise from 1 to 99 weight % of said at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier and from 1 to 99 weight % of a compound as herein disclosed. The combined amount of the active ingredient and of the pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier may not constitute more than 100% by weight of the composition, particularly the pharmaceutical composition.

[0277] In some embodiments, only one compound as herein disclosed is used for the purposes discussed above.

[0278] In some embodiments, two or more of the compounds as herein disclosed are used in combination for the purposes discussed above.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0284] 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.

[0285] 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.

[0286] 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).

[0287] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] The present invention is further illustrated by the following examples that, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realizing the invention indiverse forms thereof.

Experimental Procedures (Evaluation of Kd Values)

[0292] The affinity of Example 1-10 and ref. 1 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.

TABLE-US-00001 Aqueous Solubility Galectin-3 Example Name Structure (mg/mL) Kd (μM) 1 5-Bromopyridin-3-yl 3- deoxy-3-[4-(3,4,5- trifluorophenyl)-1H- 1,2,3-triazol-1-yl]-6-O- phospho-1-thio-α-D- galactopyranoside [00033] 8.5 35 2 5-Bromopyridin-3-yl deoxy-3-[4-(3,4,5- trifluorophenyl)-1H- 1,2,3-triazol-1-yl]-2-O- phospho-1-thio-α-D- galactopyranoside [00034] 9.8 0.006 3 3,4-Dichlorphenyl 3- deoxy-3-[4-(3,4,5- trifluorophenyl)-1H- 1,2,3-triazol-1-yl]-2-O- phospho-1-thio-α-D- galactopyranoside [00035] 0.007 4 3,4-Dichlorphenyl 3- deoxy-3-[4-(3,4,5- trifluorophenyl)-1H- 1,2,3-triazol-1-yl]-2-O- sulfo-1-thio-α-D- galactopyranoside [00036] 0.014 5 5-Bromopyridin-3-yl 3- Deoxy-3-[4-(3,4,5- trifluorophenyl)-1H- 1,2,3-triazol-1-yl]-2-O- sulfo-1-thio-α-D- galactopyranoside [00037] 0.004 6 5-Bromopyridin-3-yl 3- Deoxy-3-[4-(3,4,5- trifluorophenyl)-1H- 1,2,3-triazol-1-yl]-6-O- sulfo-1-thio-α-D- galactopyranoside [00038] 9.6 27 7 5-Bromopyridin-3-yl 3- deoxy-3-[4-(3,4,5- trifluorophenyl)-1H- 1,2,3-triazol-1-yl]-6-O- [(phosphonooxy)methyl]- 1-thio-α-D- galactopyranoside [00039] >10 15 8 5-Bromopyridin-3-yl 3- deoxy-3-[4-(3,4,5- trifluorophenyl)-1H- 1,2,3-triazol-1-yl]-2-O- [(phosphonooxy)methyl]- 1-thio-α-D- galactopyranoside [00040] >10 0.01 9 5-Bromopyridin-3-yl 3- [4-(4-chloro-3,5- difluorophenyl)-1H- 1,2,3-triazol-1-yl]-3- deoxy-2-O- [(phosphonooxy)methyl]- 1-thio-α-D- galactopyranoside [00041] 0.8 0.007 Ref 1 5-Bromopyridin-3-yl 3- deoxy-3-[4-(3,4,5- trifluorophenyl)-1H- 1,2,3-triazol-1-yl]-1-thio- α-D-galactopyranoside [00042] 0.007 0.0248 Ref 2 3,4-Dichlorophenyl 3- deoxy-3-[4-(3,4,5- trifluorophenyl)-1H- 1,2,3-triazol-1-yl]-1-thio- α-D-galactopyranoside [00043] 0.037 0.037 Ref 3 5-Bromopyridin-3-yl 3- deoxy-3-[4-(4-chloro-3,5- difluorophenyl)-1H- 1,2,3-triazol-1-yl]-1-thio- α-D-galactopyranoside [00044] 0.007 0.011

[0293] Solubility of a drug can limit the maximum possible systemic exposure after per oral (p.o.) administration. This means that there is a correlation between increased dose and the blood concentration up to the solubility limit. Beyond that a drug can crystallise out in the intestine resulting in low and variable exposure. One strategy to enable a drug to be dosed beyond the solubility limit resulting in correlating increased systemic exposure would be to introduce a functional group which both improves the intestinal solubility and is metabolized in the intestine to release the free drug. Examples of such compounds are phosphate ester pro-drugs. In general phosphates are polar, having two negative charges at physiological pH and therefore improve the solubility of a drug. This polarity is also in general limiting the uptake over the intestine resulting in low exposure in plasma of such a pro-drug after p.o. administration. These pro-drugs can be metabolized by phosphates in the intestine to release the drug which is taken up. [Boyapelly, K.; Bonin, M.-A.; Traboulsi, H.; Cloutier, A.; Phaneuf, S. C.; Fortin, D.; Cantin, A. M.; Richter, M. V.; Marsault, E. Synthesis and Characterization of a Phosphate Prodrug of Isoliquiritigenin. J. Nat. Prod. 2017, 80 (4), 879-886.

[0294] (2) (1) DeGoey, D. A.; Grampovnik, D. J.; Flosi, W. J.; Marsh, K. C.; Wang, X. C.; Klein, L. L.; McDaniel, K. F.; Liu, Y.; Long, M. A.; Kati, W. M.; Molla, A.; Kempf, D. J. Water-Soluble Prodrugs of the Human Immunodeficiency Virus Protease Inhibitors Lopinavir and Ritonavir. J. Med. Chem. 2009, 52 (9), 2964-2970.

[0295] (3) (1) Rautio, J.; Meanwell, N. A.; Di, L.; Hageman, M. J. The Expanding Role of Prodrugs in Contemporary Drug Design and Development. Nat. Rev. Drug Disc. 2018, 99, 47551 There are several examples of how this strategy can be used to increase the maximum dose resulting in dose correlated bioavailability at concentrations high above the drugs aqueous solubility.

[0296] Compounds of formula 1 can be pro-drugs with either low (example 1,6 and 7) or high affinity (examples 2-5 and 8) towards the corresponding galectin.

[0297] Phosphate esters 7 and 8 are pro-drugs of Ref 1 and have a dose correlated exposure in mice PK far beyond the aqueous solubility of Ref 1.

[0298] Ref 1 has a low solubility in water (0.007 mg/mL) and therefore has limited oral availability in some formulations when dosed above 10 mg/kg in mouse pharmacokinetic (PK) experiments. By the introduction of a phosphate group as exemplified by example 7 and 8 the aqueous solubility was improved >1000 fold over Ref 1 and dose correlated exposure was observed after per oral (p.o) administration in mice up to 160 mg/kg.

##STR00045##

[0299] FIG. 1 shows Plasma exposure of Ref 1 after p.o. administration of 7 at 20, 40, 80 and 160 mg/kg in mouse PK experiments.

[0300] FIG. 2 shows Plasma exposure of Ref 1 after p.o. administration of 8 at 20, 40, 80 and 160 mg/kg in mouse PK experiments.

[0301] Upon metabolic or chemical removal of the prodrug group examples 1-9 the corresponding active metabolite Ref 1-Ref 3 will be formed.

General Experimental

[0302] 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.

[0303] 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 ml/min Column-kromasil 100-5-C18 column Wavelength: 220 nm. Solvent A water+0.1% TFA and solvent B Acetonitrile+0.1% TFA.

[0304] The following abbreviations are used

aq: aqueous

Calcd: Calculated

[0305] DCM: dichloromethane

DIEA: N,N-Diisopropylethylamine

[0306] DMAP: 4-dimethylaminopyridine

DMF: N,N-dimethylformamide

[0307] ESI-MS: Electrospray ionization mass spectrometry
EtOAc: ethyl acetate
h: hours
MeCN: acetonitrile
min: minutes
prep. preparative
PE: petroleum ether
rt: Room temperature
TBS: tort-Butyldimethylsilyi
TBA: tetrabutylarnmonium Fluoride
TFA: trifluoroacetic acid
TMS: trimethyl silyl

UV: Ultraviolet

Example 1

5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-6-O-phospho-1-thio-α-D-galactopyranoside

[0308] ##STR00046##

5-Bromopyridin-3-yl 6-O-tert-butyldimethylsilyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0309] ##STR00047##

[0310] To a solution of 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (200 mg, 0.375 mmol) in DMF (5 mL) was added Imidazolidine (43.9 mg, 0.563 mmol) and TBS-Cl (84.4 mg, 0.563 mmol). The reaction was stirred at rt over 6 h under Na atmosphere. Water (20 mL) and DCM (20 mL) were added. The aqueous phase was extracted with DCM (15 mL×2), the combined organic phases were washed with water (20 mL) and brine (20 mL) and dried over anhydrous sodium sulphate. Removal of the solvent in vacuo gave the title compound which was used next step without further purification.

[0311] m/z calcd for [C25H30BrF3N4O4SSi].sup.+ [M+H].sup.+:647, 649; found: 647, 649.

Bromopyridin-3-yl 2,4-O-dibenzoyl-6-O-tert-butyldimethylsilyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0312] ##STR00048##

[0313] To a solution of 5-Bromopyridin-3-yl 6-O-tert-butyldimethylsilyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (243 mg, 0.375 mmol) in pyridine (5.00 mL) was added benzoyl chloride (211 mg, 1.50 mmol). The reaction was stirred at room temperature 6 h under a Na atmosphere. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=4/1) to obtain the title compound (250 mg, 0.292 mmol, yield: 77.9%).

[0314] .sup.1H NMR (400 MHz, CDCl3) δ 8.60 (dd, J=6.7, 1.9 Hz, 2H), 8.04-7.99 (m, 2H), 7.97 (t, J=2.0 Hz, 1H), 7.89-7.82 (m, 2H), 7.71-7.63 (m, 2H), 7.58-7.47 (m, 3H), 7.39 (t, J=7.8 Hz, 2H), 7.05 (dd, J=8.0, 6.6 Hz, 2H), 6.35-6.22 (m, 2H), 6.02 (d, J=2.0 Hz, 1H), 5.70-5.57 (m, 1H), 4.82 (t, J=6.5 Hz, 1H), 3.81-3.70 (m, 2H), 0.81 (s, 9H), −0.02 (s, 3H), −0.08 (s, 3H).

Bromopyridin-3-yl 2,4-O-dibenzoyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-6-O-phospho-1-thio-α-D-galactopyranoside

[0315] ##STR00049##

[0316] To a solution of Bromopyridin-3-yl 2,4-O-dibenzoyl-6-O-tert-butyldimethylsilyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (250 mg, 0.292 mmol) in TBAF-THF (5.00 mL) was stirred at rt for 2 h under a Na atmosphere. Removal of solvent gave a residue which was purified by column chromatography (PE/EA=2/1) to obtain the title compound. (160 mg, 0.216 mmol, yield: 73.9%).

[0317] m/z calcd for [C33H24BrF3N4O6S].sup.+ [M+H].sup.+:741, 743; found: 741.0, 743.0.

[0318] .sup.1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.48 (s, 1H), 8.08 (s, 1H), 8.02-7.93 (m, 3H), 7.88 (d, J=7.7 Hz, 2H), 7.64-7.53 (m, 2H), 7.50-7.36 (m, 4H), 7.28 (m, 1H), 6.26 (d, J=5.2 Hz, 1H), 6.17 (dd, J=11.5, 5.3 Hz, 1H), 5.40 (d, J=11.8 Hz, 1H), 4.84 (m, 2H), 4.45 (m, 3H).

Bromopyridin-3-yl 2,4-O-dibenzoyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-6-O-phospho-1-thio-α-D-galactopyranoside

[0319] ##STR00050##

[0320] To a solution of bromopyridin-3-yl 2,4-O-dibenzoyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-6-O-phospho-1-thio-α-D-galactopyranoside (90.0 mg, 0.121 mmol) and DMAP (29.7 mg, 0.243 mmol) in DCM (15.00 mL) under Na atmosphere at 0° C. was added DIEA (0.0416 mL, 0.243 mmol) followed by POCl.sub.3 (0.0667 mL, 0.728 mmol). The reaction was stirred for 5 minutes. Water (15 mL) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was extracted with DCM twice. The combined DCM layer was dried, concentrated and purified by prep.-HPLC to give the title compound (40.0 mg, 0.0487 mmol, yield: 40.1%).

[0321] m/z calcd for [C33H25BrF3N4O9PS].sup.+ [M+H].sup.+:823; found: 823.7.

[0322] .sup.1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=10.8 Hz, 2H), 8.28 (s, 1H), 7.90 (s, 1H), 7.85 (d, J=7.2 Hz, 2H), 7.59 (d, J=6.3 Hz, 2H), 7.42 (m, 8H), 7.19 (m, 2H), 6.44 (d, J=4.5 Hz, 1H), 6.39-6.25 (m, 1H), 5.78-5.64 (m, 1H), 5.01 (d, J=9.4 Hz, 1H), 4.81 (d, J=12.0 Hz, 1H), 4.59-4.46 (m, 1H), 4.45-4.31 (m, 1H).

5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-6-O-phospho-1-thio-α-D-galactopyranoside

[0323] ##STR00051##

[0324] Bromopyridin-3-yl 2,4-O-dibenzoyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-6-O-phospho-1-thio-α-D-galactopyranoside (40.0 mg, 0.0487 mmol) was dissolved in 7M NH.sub.3 in MeOH (15 mL) solution and the reaction was stirred at rt for 24 h. Solvent was removed and the residue was purified by prep.-HPLC to give the title compound (15.0 mg, 0.0245 mmol, yield: 50.2%) as a white solid.

[0325] m/z calcd for [C19H17BrF3N4O7PS].sup.− [M−H].sup.−:611, 613; found: 610.9, 612.9.

[0326] .sup.1H NMR (400 MHz, MeOD) δ 8.66-8.59 (m, 2H), 8.55 (d, J=1.8 Hz, 1H), 8.23 (s, 1H), 7.72-7.59 (m, 2H), 5.95 (d, J=5.1 Hz, 1H), 5.14 (d, J=9.3 Hz, 1H), 4.97 (dd, J=11.4, 5.3 Hz, 1H), 4.79 (m, 1H), 4.49-4.39 (m, 1H), 3.94-3.80 (m, 1H), 3.47 (dd, J=11.7, 5.7 Hz, 1H).

Example 2

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

[0327] ##STR00052##

5-Bromopyridin-3-yl 4,6-O-benzyliden-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-phosopho-1-thio-α-D-galactopyranoside

[0328] ##STR00053##

[0329] To a solution of 5-Bromopyridin-3-yl 4,6-O-benzyliden-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (200 mg, 0.322 mmol) and DMAP (78.6 mg, 0.644 mmol) in DCM (15.00 mL) under Na atmosphere at 0° C. was added DIEA (1.38 mL, 8.05 mmol) followed by POCl.sub.3 (0.147 mL, 1.61 mmol) dropwise. After TLC showed no remaining starting material the solvent was removed under vacuo at r.t and ammonium hydroxide (15 mL) was added, white solid precipitated out which was collected by filtration and was used directly to the next step without further purification.

[0330] m/z calcd for [C26H21BrF3N4O7PS].sup.− [M−H].sup.−:699, 701; found: 699, 701.

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

[0331] ##STR00054##

[0332] 5-Bromopyridin-3-yl 4,6-O-benzyliden-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-phospho-1-thio-α-D-galactopyranoside (220 mg, 0.314 mmol) was dissolved in 10% TFA in DCM and the reaction was stirred for 3 h. The solvent was removed and the residue was purified by Prep.-HPLC to give the title compound. (63.4 mg, 0.103 mmol, yield: 33.0%).

[0333] m/z calcd for [C19H17BrF3N4O7PS].sup.− [M−H].sup.−:611, 613; found: 610.8, 613.8. .sup.1H NMR (400 MHz, MeOD) δ 8.71 (d, J=1.7 Hz, 1H), 8.63 (s, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.38 (t, J=1.9 Hz, 1H), 7.66 (dd, J=8.8, 6.7 Hz, 2H), 6.24 (d, J=5.3 Hz, 1H), 5.43-5.31 (m, 1H), 5.13 (dd, J=11.5, 2.7 Hz, 1H), 4.55 (t, J=5.9 Hz, 1H), 4.22 (s, 1H), 3.77-3.65 (m, 2H).

Example 3

3,4-Dichlorophenyl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-phospho-1-thio-α-D-galactopyranoside

[0334] ##STR00055##

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

[0335] ##STR00056##

[0336] To a solution of 3,4-Dichlorophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (605 mg, 1,158 mmol) in dry MeCN (24 ml), Bn(OMe).sub.2 (0.87 mL, 5.791 mmol) and camphorsulfonic acid (30 mg, 0.116 mmol) dissolved in dry MeCN (1 mL) was added. The transparent yellow mixture was left stirring at r.t. After 20 min the reaction mixture became turbid of white precipitate. After 2 h the reaction was stopped by evaporation of solvent. The reaction crude was dissolved in EtOH (180 mL) under heating and left at r.t. for 36 h to crystalize. The crystals formed were filtered off and dried under vacuum to obtain the title compound (247 mg, 35%) as amorphous white solid.

[0337] .sup.1H NMR ((CD3).sub.2SO, 400 MHz): δ 8.85 (s, 1H, Ph), 7.84-7.76 (m, 3H, Ph), 7.63 (d, J=8.6 Hz, 1H, Ph), 7.52 (dd, J=8.6, 2.1 Hz, 1H, Ph), 7.39-7.30 (m, 5H, Ph), 6.17 (d, J=5.3 Hz, 1H, H-1), 6.10 (d, J=4.8 Hz, 1H, OH-2), 5.57 (s, 1H, CH), 5.09 (dd, J=11.0, 3.1 Hz, 1H, H-3), 4.90 (m, 1H, H-2), 4.56 (d, J=2.9 Hz, 1H, H-4), 4.26 (s, 1H, H-5), 4.13 (d, J=12.5 Hz, 1H, H-6), 3.96 (d, J=12.5 Hz, 1H, H-6). .sup.13C NMR ((CD3).sub.2SO, 100 MHz): δ 137.8, 135.1, 131.7, 131.5, 130.9, 130.7, 129.4, 128.7, 128.0, 125.9, 122.8, 109.5, 109.3, 99.4, 88.2, 74.1, 68.3, 64.2, 63.1, 61.5. HRMS calculated for [C.sub.27H.sub.21F.sub.3Cl.sub.2N.sub.3O.sub.4S].sup.+, 610.0582; found: 610.0575.

3,4-Dichlorophenyl-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-phospho-1-thio-α-D-galactopyranoside

[0338] ##STR00057##

[0339] Imidazole and 3,4-dichlorophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyrano side was rendered anhydrous by co-evaporation with toluene. PCl.sub.3 (0.10 mL, 1.18 mmol) in dry MeCN:DCM 1:1 (4 mL) was cannulated into a stirring solution of imidazole (380 mg, 5.50 mmol) in dry MeCN:DCM 1:1 (6 mL) under N.sub.2-atmosphere. The reaction mixture turned white/light green and turbid. Directly following, Et.sub.3N (0.44 mL, 3.15 mmol) in dry MeCN:DCM 1:1 (4 mL) was cannulated into the stirring solution. 3,4-Dichlorophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyrano side (240 mg, 0.39 mmol) dissolved in dry MeCN:DCM 1:1 (50+10 mL) and was slowly cannulated into the stirring solution over 25 min. The reaction mixture was stirred at 0° C. for 45 min before pyridine:H.sub.2O 4:1 (50 mL) was added. TLC showed complete consumption of starting material. The reaction crude was concentrated and purified by column chromatography (SiO.sub.2, DCM:MeOH 10:1 with 1% Et.sub.3N). The phosphonate was dissolved in dry pyridine (9 mL). TMS-Cl (0.5 mL, 3.93 mmol) was added and the reaction left stirring at r.t. for 5 min before iodine (205 mg, 0.79 mmol) in dry pyridine (1 mL) was added. After stirring for 10 min, water (0.35 mL) was added and the solvent was evaporated. The reaction crude was purified by repeated column chromatography (SiO.sub.2, DCM:MeOH:H.sub.2O 10:1:0->65:35:1). The resulting solid material was dissolved in HOAc (70% aq., 20 mL) and left stirring at 40° C. After 30 h the solvent was evaporated and the crude purified by column chromatography (SiO.sub.2, DCM:MeOH:H.sub.2O 5:1:0->65:35:1) to give the title compound (48 mg, 20%) as amorphous white solid.

[0340] .sup.1H NMR (MeOD, 400 MHz): δ 8.55 (s, 1H, Ph), 7.64 (dd, J=9.0, 6.8 Hz, 2H, Ph) 7.57 (dd, J=8.4, 2.2 Hz, 1H, Ph), 7.49 (d, J=8.4 Hz, 1H, Ph), 6.08 (d, J=5.4 Hz, 1H, H-1), 5.41 (m, 1H, H-2), 5.17 (dd, J=11.5, 2.9 Hz, 1H, H-3) 4.57 (t, J=6.3 Hz, 1H, H-5), 4.23 (m, 1H, H-4), 3.73 (m, 2H, H-6). .sup.13C NMR (MeOD, 100 MHz): δ 135.3, 135.3, 133.6, 133.0, 131.9, 123.2, 111.0, 110.8, 89.2, 73.6, 71.0, 69.9, 64.3, 64.2, 64.1. HRMS calculated for [C.sub.20H.sub.18F.sub.3Cl.sub.2N.sub.3O.sub.7PS].sup.+, 601.9932; found: 601.9934.

Example 4

3,4-Dichlorphenyl 3-Deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-sulfo-1-thio-α-D-galactopyranoside

[0341] ##STR00058##

[0342] 3,4-Dichlorophenyl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (225 mg, 0.37 mmol) and sulfur trioxide-triethylamine complex (560 mg, 3.82 mmol) were dissolved in dry DMF (20 mL) and stirred at 50° C. After 30 h the solvents were evaporated of solvent and the reaction crude purified by column chromatography (SiO.sub.2, EtOAc:Heptane 9:1->1:0). Partial desulfation during evaporation of solvent after column chromatography was observed. The crude was dissolved in HOAc (90% aq., 30 mL) and left stirring at 40° C. for 22 h followed by evaporation of the solvent. The crude was purified by column chromatography (SiO.sub.2, EtOAc:Hep 1:1->EtOAc:Hep 1:0) to give the title compound (48 mg, 22%) as amorphous white solid.

[0343] .sup.1H NMR (MeOD, 400 MHz): δ 8.56 (s, 1H, Ph), 7.83 (d, J=2.1 Hz, 1H, Ph), 7.62 (dd, J=9.0, 6.3 Hz, 2H, Ph), 7.57 (dd, J=8.3, 2.1 Hz, 1H, Ph), 7.48 (d, J=8.3 Hz, 1H, Ph), 6.24 (d, J=5.3 Hz, 1H, H-1), 5.48 (dd, J=11.7, 5.3 Hz, 1H, H-2), 5.13 (dd, J=11.7, 2.9 Hz, 1H, H-3), 4.56 (t, J=6.1 Hz, 1H, H-5), 4.26 (d, J=2.8 Hz, 1H, H-4), 4.12 (d, J=7.2 Hz, 1H, H-6), 4.08 (d, J=7.2 Hz, 1H, H-6).

Example 5

5-Bromopyridin-3-yl 3-Deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-sulfo-1-thio-α-D-galactopyranoside

[0344] ##STR00059##

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

[0345] ##STR00060##

[0346] To a stirred solution of 5-bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (200 mg, 0.375 mmol) in DMF (10 mL) was added benzaldehyde dimethyl acetal (285 mg, 1.88 mmol) followed by D(+)-10-Camphorsulfonic acid (17.4 mg, 0.0750 mmol). The resulting mixture was stirred at 50° C. for 3 hours under vacuum. LCMS showed full consumption of starting material and a resulting product spot. The solution was added to aq NaHCO.sub.3 (100 mL) dropwise with vigorous stirring. Then it was filtrated and washed with water to get 220 mg (94.4%) of the title compound as a white solid.

[0347] m/z calcd for [C.sub.26H.sub.20BrF.sub.3N.sub.4O.sub.4S].sup.+ [M+H].sup.+: 621.0, 623.0; found: 621.0, 623.0.

[0348] .sup.1H NMR (400 MHz, DMSO) δ 8.86 (s, 1H), 8.67 (d, J=1.5 Hz, 1H), 8.62 (d, J=1.9 Hz, 1H), 8.28 (s, 1H), 7.87-7.72 (m, 2H), 7.35 (dt, J=9.8, 4.9 Hz, 5H), 6.25 (d, J=5.2 Hz, 1H), 6.17 (d, J=4.8 Hz, 1H), 5.57 (s, 1H), 5.12 (dd, J=11.3, 3.2 Hz, 1H), 4.91 (dd, J=10.9, 5.4 Hz, 1H), 4.57 (d, J=2.9 Hz, 1H), 4.29 (s, 1H), 4.12 (d, J=12.2 Hz, 1H), 3.92 (d, J=12.7 Hz, 1H).

5-Bromopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-sulfo-1-thio-α-D-galactopyranoside

[0349] ##STR00061##

[0350] 5-Bromopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (150.0 mg, 0.24 mmol) and sulfur trioxide trimethylamine complex(672 mg, 4.83 mmol) were dissolved in anhydrous DMF (10.0 mL), the reaction was stirred at rt o/n under Na. LCMS indicated almost full consumption of starting material. The reaction mixture was purified by Prep.-HPLC to give the title compound (65.0 mg, 0.093 mmol, yield: 38%) obtained as white solid.

[0351] m/z calcd for [C.sub.26H.sub.20BrF.sub.3N.sub.4O.sub.7S.sub.2].sup.− [M−H]−: 699.0, 701.0; found: 699.0, 701.0.

5-Bromopyridin-3-yl 3-Deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-sulfo-1-thio-α-D-galactopyranoside

[0352] ##STR00062##

[0353] 5-Bromopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-sulfo-1-thio-α-D-galactopyranoside (20.0 mg, 0.0285 mmol) was dissolved in CH.sub.3CO.sub.2H (1.60 mL) and H.sub.2O (0.400 mL). The reaction was stirred at 50° C. for 4 h. TLC indicated full consumption of starting material. Solvent was removed and the residue was purified by Prep.-HPLC to give the title compound (3.20 mg, 0.005 mmol, yield: 18.3%).

[0354] m/z calcd for [C.sub.19H.sub.16BrF.sub.3N.sub.4O.sub.7S.sub.2].sup.− [M−H].sup.−: 611.0, 613.0; found: 611.0, 613.0.

[0355] .sup.1H NMR (400 MHz, MeOD) δ 8.71 (s, 1H), 8.56 (s, 2H), 8.35 (s, 1H), 7.75-7.49 (m, 2H), 6.26 (d, J=5.3 Hz, 1H), 5.49 (dd, J=11.7, 5.3 Hz, 1H), 5.16 (dd, J=11.8, 2.6 Hz, 1H), 4.56 (dd, J=13.5, 7.6 Hz, 1H), 4.27 (s, 1H), 3.71 (d, J=6.0 Hz, 2H).

Example 6

5-Bromopyridin-3-yl 3-Deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-6-O-sulfo-1-thio-α-D-galactopyranoside

[0356] ##STR00063##

[0357] To a solution of 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (100 mg, 0.188 mmol) and sulfur trioxide trimethylamine (52.0 mg, 0.374 mmol) in DMF (5.00 mL) was stirred at room temperature overnight under a nitrogen atmosphere. Removal of solvent gave a residue which was purified by column chromatography to obtain the title compound (56 mg, yield: 48.7%).

[0358] m/z calcd for [C.sub.19H.sub.16Br.sub.13F.sub.3N.sub.4O.sub.7S.sub.2].sup.+ [M+H].sup.+:614; found: 614.

[0359] .sup.1H NMR (400 MHz, MeOD) δ 8.67 (d, J=1.8 Hz, 1H), 8.59-8.52 (m, 2H), 8.28 (t, J=2.0 Hz, 1H), 7.66 (dd, J=8.9, 6.7 Hz, 2H), 5.89 (d, J=5.3 Hz, 1H), 5.03 (dd, J=11.4, 2.8 Hz, 1H), 4.94 (dd, J=11.4, 5.3 Hz, 1H), 4.75 (t, J=6.7 Hz, 1H), 4.26 (d, J=1.9 Hz, 1H), 4.12 (ddd, J=59.7, 10.6, 6.4 Hz, 2H).

Example 7

5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-6-O-[(phosphonooxy)methyl]-1-thio-α-D-galactopyranoside

[0360] ##STR00064##

5-Bromopyridin-3-yl 6-O-tert-butyldimethylsilyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0361] ##STR00065##

[0362] 5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (GB1211, 10.0 g, 18.7 mmol), imidazole (29 mmol, 2.0 g) and TBDMS-Cl (1.1 eq., 20.6 mmol, 3.2 g) were stirred at room temperature in DMF (40 ml). TLC (EtOAc) after 15 min was OK. Water (80 ml) was added under vigorous stirring, the precipitate was isolated by filtration, washed with water and then dried on a rotary evaporator until constant weight. The title compound weighed 12.2 g (100% yield); .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.80 (s, 1H), 8.65 (d, J=1.7 Hz, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.20 (t, J=1.9 Hz, 1H), 7.85 (m, 2H), 6.13 (d, J=5.2 Hz, 1H), 5.97 (d, J=4.8 Hz, 1H), 5.54 (d, J=6.5 Hz, 1H), 4.87 (dd, J=11.3, 2.5 Hz, 1H), 4.77 (dt, J=11.0, 5.0 Hz, 1H), 4.24 (t, J=5.7 Hz, 1H), 4.03 (d, J=4.5 Hz, 1H), 3.70 (dd, J=10.8, 4.6 Hz, 1H), 3.57 (dd, J=10.7, 7.0 Hz, 1H), 0.78 (s, 9H), −0.03 (s, 3H), −0.04 (s, 3H).

5-Bromopyridin-3-yl 2,4-di-O-benzoyl-6-O-tert-butyldimethylsilyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0363] ##STR00066##

[0364] To 5-bromopyridin-3-yl 6-O-tert-butyldimethylsilyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (12.2 g, 18.7 mmol) in pyridine (70 ml) benzoyl chloride (3 eq., 56.4 mmol, 6.61 ml) was added. The reaction is slow, and the mixture was stirred for 20 h at 35° C. TLC (PE/EtOAc: 3/1) indicated complete reaction. Water (160 ml) was added, which resulted in precipitation of sticky material, the mixture was decanted, and the sticky residue was stirred in EtOH (120 ml), acetic acid (4 ml) and water (20 ml), which resulted in crystallization. The precipitate was isolated by filtration, washed with 33% aqueous MeOH, and dried to afford the title compound (14.0 g, 87% yield); .sup.1H NMR (400 MHz, Chloroform-d) δ 8.65-8.57 (m, 2H), 8.03 (d, J=7.3 Hz, 2H), 7.99 (d, J=1.9 Hz, 1H), 7.87 (d, J=7.5 Hz, 2H), 7.72-7.64 (m, 2H), 7.62-7.48 (m, 3H), 7.40 (t, J=7.8 Hz, 2H), 7.12-6.98 (m, 2H), 6.34-6.26 (m, 2H), 6.07-6.01 (m, 1H), 5.70-5.60 (m, 1H), 4.82 (t, J=6.5 Hz, 1H), 3.83-3.70 (m, 2H), 0.82 (s, 9H), −0.01 (s, 3H), −0.07 (s, 3H).

5-bromopyridin-3-yl 2,4-di-O-benzoyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside

[0365] ##STR00067##

[0366] 5-Bromopyridin-3-yl 2,4-di-O-benzoyl-6-O-tert-butyldimethylsilyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (6.5 g, 7.59 mmol) was dissolved in THF (45 ml) and acetic acid (4.0 eq., 1.8 ml) followed by addition of TBAF (3.0 eq., 1 M solution, 22.75 mmol, 22.75 ml). The mixture was stirred at 40° C. for 30 min, it was then cooled and concentrated to one third of the volume at <30° C. and applied directly onto a silica column conditioned in PE/EtOAc 4/1. The column was eluted with PE/EtOAc 2/1-1/1-0/1 and gave the title compound (4.65 g, 83% yield); .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.88 (s, 1H), 8.66 (d, J=1.6 Hz, 1H), 8.63 (d, J=1.9 Hz, 1H), 8.32 (t, J=1.7 Hz, 1H), 7.94 (d, J=7.8 Hz, 2H), 7.77 (d, J=7.9 Hz, 2H), 7.70 (t, J=7.3 Hz, 1H), 7.67-7.53 (m, 5H), 7.47 (t, J=7.8 Hz, 2H), 6.56 (d, J=5.5 Hz, 1H), 6.38 (dd, J=11.6, 5.5 Hz, 1H), 5.93 (s, 1H), 5.89 (dd, J=11.6, 2.8 Hz, 1H), 5.08 (t, J=5.3 Hz, 1H), 4.78 (t, J=6.4 Hz, 1H), 3.56-3.40 (m, 2H). The faster moving (TLC) impurity, formed by migration of a benzoate group (from 4- to 6-position) during the desilylation reaction was also present in the chromatographed product (2%).

5-Bromopyridin-3-yl 2,4-di-O-benzoyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-6-O-[(phosphonooxy)methyl]-1-thio-α-D-galactopyranoside

[0367] ##STR00068##

[0368] Anhydrous HCl was slowly bubbled through a mixture of 5-bromopyridin-3-yl 2,4-di-O-benzoyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (612 mg, 0.825 mmol) and paraformaldehyde (2.0 eq., 1.65 mmol, 49.6 mg) in dichloromethane (16.0 ml) for 3 hours at 0° C. The mixture was diluted with dry THF (6 ml), dried (MgSO4), filtered and concentrated. Di-tetrabutylammonium phosphate (959 mg, 1.65 mmol) in THF (2.0 ml) was added, the mixture was stirred for 30 min and then concentrated. The crude material was purified by reversed phase chromatography, eluting with 30-80% acetonitrile in water (25 mM NH.sub.4OAc, pH 5.2) to afford the title compound as the mono tetrabutylammonium salt (378 mg, 42% yield); ESI-MS m/z calcd for [C.sub.34H.sub.27BrF.sub.3N.sub.4O.sub.10PS].sup.+ (M+H).sup.+: 851.0; found: 851.1, .sup.1H NMR (400 MHz, Methanol-d4) δ 8.68-8.62 (m, 1H), 8.59 (s, 2H), 8.39-8.33 (m, 1H), 8.01 (d, J=7.2 Hz, 2H), 7.84 (d, J=7.3 Hz, 2H), 7.64 (t, J=7.5 Hz, 1H), 7.58 (t, J=7.4 Hz, 1H), 7.51 (t, J=7.7 Hz, 2H), 7.47-7.37 (m, 4H), 6.50 (dd, J=11.6, 5.6 Hz, 1H), 6.42 (d, J=5.6 Hz, 1H), 6.11-6.01 (m, 1H), 5.85 (dd, J=11.6, 2.7 Hz, 1H), 5.24-5.16 (m, 1H), 5.08 (dd, J=9.4, 5.5 Hz, 1H), 5.03 (dd, J=9.6, 5.4 Hz, 1H), 3.94 (dd, J=11.0, 4.6 Hz, 1H), 3.79 (dd, J=10.8, 7.5 Hz, 1H), 3.28-3.19 (m, 8H), 1.72-1.60 (m, 8H), 1.49-1.35 (m, 8H), 1.03 (t, J=7.4 Hz, 12H).

5-Bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-6-O-[(phosphonooxy)methyl]-1-thio-α-D-galactopyranoside

[0369] ##STR00069##

[0370] Ammonium hydroxide (28% aqueous ammonia, 47.4 mmol, 5.0 ml) was added to (5-bromopyridin-3-yl) 2,4-di-O-benzoyl-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-6-O-[(phosphonooxy)methyl]-1-thio-α-D-galactopyranoside (565 mg, 0.517 mmol) in MeOH (5.0 ml) and THF (5.0 ml). The mixture was heated 6 hours at 60° C., then cooled to rt and concentrated. The crude material was purified by reversed phase chromatography, eluting with 10-50% acetonitrile in water (25 mM NH.sub.4OAc) to afford the title compound as the ammonium salt (225 mg, 66% yield); HPLC 99%, ESI-MS m/z calcd for [C.sub.20H.sub.19BrF.sub.3N.sub.4O.sub.8PS].sup.+ (M+H).sup.+: 643.0; found: 643.1, .sup.1H NMR (400 MHz, Methanol-d4) δ 8.68-8.63 (m, 1H), 8.58 (s, 1H), 8.58-8.54 (m, 1H), 8.32 (t, J=1.8 Hz, 1H), 7.66 (dd, J=8.8, 6.7 Hz, 2H), 5.88 (d, J=5.3 Hz, 1H), 5.15 (dd, J=8.6, 5.8 Hz, 1H), 5.05 (dd, J=11.4, 2.7 Hz, 1H), 4.99-4.89 (m, 2H), 4.63 (t, J=6.1 Hz, 1H), 4.27 (d, J=2.1 Hz, 1H), 4.01 (dd, J=9.9, 6.1 Hz, 1H), 3.64 (dd, J=9.8, 6.9 Hz, 1H).

Example 8

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

[0371] ##STR00070##

5-Bromopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-[(ditert-butyl-phosphonooxy)methyl]-1-thio-α-D-galactopyranoside

[0372] ##STR00071##

[0373] 5-Bromopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside (200 mg, 0.322 mmol), Silver oxide (149 mg, 0.644 mmol), NaI (96.5 mg, 0.644 mmol) and Molecular Sieves 4 Å (500 mg) were dissolved in DMF (6 mL) under a nitrogen atmosphere. Ditert-butyl chloromethyl phosphate (167 mg, 0.644 mmol) in DMF (0.5 mL) was added. The reaction was stirred over night at rt and LCMS showed all starting material consumed. The reaction was filtered through Celite® and solvent was removed. The residue was purified by Prep.-HPLC to give the title compound (260 mg, 0.308 mmol, yield: 95.8%) as white solid.

[0374] m/z calcd for [C.sub.35H.sub.39BrF.sub.3N.sub.4O.sub.8PS].sup.+ [M+H].sup.+: 843.0, 845.0; found: 633.0, 635.0; 731.0, 733.0.

[0375] .sup.1H NMR (400 MHz, DMSO) δ 8.73 (s, 1H), 8.70 (d, J=1.9 Hz, 1H), 8.68 (d, J=2.1 Hz, 1H), 8.30 (t, J=2.0 Hz, 1H), 7.72 (dd, J=8.9, 6.7 Hz, 2H), 7.34 (s, 5H), 6.40 (d, J=5.1 Hz, 1H), 5.62 (s, 1H), 5.30 (dd, J=11.6, 3.2 Hz, 1H), 5.19 (dd, J=9.8, 5.7 Hz, 1H), 5.13 (dd, J=9.8, 5.8 Hz, 1H), 5.04 (dd, J=11.5, 5.2 Hz, 1H), 4.65 (d, J=3.1 Hz, 1H), 4.42 (s, 1H), 4.14 (d, J=11.6 Hz, 1H), 4.01 (d, J=11.7 Hz, 1H), 1.31 (d, J=4.0 Hz, 18H).

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

[0376] ##STR00072##

[0377] 5-Bromopyridin-3-yl 4,6-O-benzylidene-3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-2-O-[(ditert-butyl-phosphonooxy)methyl]-1-thio-α-D-galactopyranoside (210 mg, 0.249 mmol) was dissolved in 10% (v/v) TFA in DCM and the reaction mixture was stirred for 4 hours. LCMS indicated consumption of all starting material and that the product was the main peak. Solvent was removed and the residue was purified by Prep.-HPLC to give (73.6 mg, 0.114 mmol, yield: 45.9%) as a white solid. m/z calcd for [C20H19BrF3N4O8PS].sup.− [M−H].sup.−: 641.0, 643.0; found: 641.0, 643.0. .sup.1H NMR (400 MHz, MeOD) δ 8.79-8.64 (m, 2H), 8.54 (d, J=2.0 Hz, 1H), 8.37 (s, 1H), 7.79-7.61 (m, 2H), 6.36 (d, J=5.1 Hz, 1H), 5.20 (dd, J=11.6, 5.2 Hz, 1H), 5.16-5.08 (m, 2H), 4.94-4.89 (m, 1H), 4.48 (t, J=5.9 Hz, 1H), 4.18 (s, 1H), 3.76-3.59 (m, 2H).

Example 9

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

[0378] ##STR00073##

[0379] A solution of 5-bromopyridin-3-yl 2,4,6-tri-O-acetyl-3-azido-3-deoxy-1-thio-α-D-galactopyranoside (WO2016120403) (1.67 g, 3.32 mmol), K.sub.2CO.sub.3 (4.6 g, 33.2 mmol) and trimethyl-[2-(4-chloro-3,5-difluorophenyl)ethynyl]silane (1.58 g, 6.47 mmol) in MeOH (40 mL) and THF (40 mL) was stirred and degassed with nitrogen. Copper(II) sulfate pentahydrate (84 mg, 0.33 mmol) in hot water (10 mL) was added to (+)-sodium L-ascorbate (134 mg, 0.66 mmol) and the resulting suspension was added to the above mixture and stirred 18 h at 50° C. Silica was then added, and the suspension was concentrated, dried, and placed at the top of a column (silica). The column was eluted with EtOAc and concentrated. The residue was triturated in EtOAc/PE, the precipitate was isolated by filtration and gave the product (1.683 g, 92%). ESI-MS calcd for [C.sub.19H.sub.16BrClF.sub.2N.sub.4O.sub.4S] [M+H].sup.+: 549.0; found: 548.8. 1H NMR (400 MHz, Methanol-d.sub.4) δ 8.69 (s, 1H), 8.60 (s, 1H), 8.57 (s, 1H), 8.32 (s, 1H), 7.66 (d, J=8.8 Hz, 2H), 5.92 (d, J=5.1 Hz, 1H), 5.03 (d, J=11.2 Hz, 1H), 4.95 (dd, J=11.3, 5.2 Hz, 1H), 4.49 (t, J=5.9 Hz, 1H), 4.21 (s, 1H), 3.78-3.65 (m, 2H).

5-Bromopyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside

[0380] ##STR00074##

[0381] 5-Bromopyridin-3-yl 3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (1.625 g, 2.95 mmol) was stirred in MeCN (25 mL) and benzaldehyde dimethyl acetal (0.91 mL, 6.0 mmol) followed by p-toluenesulfonic acid monohydrate (100 mg, 0.53 mmol) were added and the mixture was stirred 17 h at 35° C. More benzaldehyde dimethyl acetal (0.91 mL, 6.0 mmol) and p-toluenesulfonic acid monohydrate (100 mg, 0.53 mmol) were added and the mixture was stirred 3 h at 40° C. Addition of Et.sub.3N (0.30 mL) followed by water (30 mL), filtering and washing the precipitate with 33% aq MeOH and drying gave the product (1.647 g, 87%). ESI-MS nilz calcd for [C.sub.26H.sub.20BrClF.sub.2N.sub.4O.sub.4] [M+H].sup.+: 637.0; found: 637.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.92 (s, 1H), 8.68 (s, 1H), 8.63 (s, 1H), 8.27 (s, 1H), 7.80 (d, J=8.5 Hz, 2H), 7.39-7.28 (m, 5H), 6.25 (d, J=5.1 Hz, 1H), 6.18 (d, J=4.6 Hz, 1H), 5.57 (s, 1H), 5.13 (dd, J=11.3, 2.9 Hz, 1H), 4.91 (m, 1H), 4.57 (d, J=3.0 Hz, 1H), 4.29 (s, 1H), 4.12 (d, J=12.3 Hz, 1H), 3.92 (d, J=12.6 Hz, 1H).

5-Bromopyridin-3-yl 4,6-O-benzylidene-2-O-[(di-tert-butyl-phosphonooxy)methyl]-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside

[0382] ##STR00075##

[0383] To a solution of 5-bromopyridin-3-yl 4,6-O-benzylidene-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyrano side (1.00 g, 1.489 mmol), KI (374 mg, 2.23 mmol) and di-tert-butyl chloromethyl phosphate (610 mg, 2.23 mmol) in DMF (10 mL) NaH (60% in oil, 90 mg, 2.23 mmol) was added. The mixture was stirred 2 h at rt, then partitioned between water and EtOAc. The organic phase was dried, evaporated and the residue was purified by chromatography (SiO.sub.2, PE/EtOAc) to give the product (526 mg, 41%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.79 (s, 1H), 8.69 (d, J=1.8 Hz, 1H), 8.67 (d, J=1.8 Hz, 1H), 8.29 (d, J=1.7 Hz, 1H), 7.72 (d, J=8.3 Hz, 2H), 7.34 (s, 5H), 6.40 (d, J=5.0 Hz, 1H), 5.62 (s, 1H), 5.31 (dd, J=11.5, 3.1 Hz, 1H), 5.19 (dd, J=9.8, 5.8 Hz, 1H), 5.13 (dd, J=9.9, 5.7 Hz, 1H), 5.05 (dd, J=11.5, 5.1 Hz, 1H), 4.66 (d, J=3.1 Hz, 1H), 4.42 (s, 1H), 4.15 (d, J=12.1 Hz, 1H), 4.01 (d, J=12.5 Hz, 1H), 1.31 (s, 9H), 1.30 (s, 9H).

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

[0384] ##STR00076##

[0385] 5-Bromopyridin-3-yl 4,6-O-benzylidene-2-O-[(di-tert-butyl-phosphonooxy)methyl]-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy-1-thio-α-D-galactopyranoside (515 mg, 0.59 mmol) was stirred 1.5 h at rt in 80% aq TFA (5.0 mL). The mixture was poured onto ice/water, the precipitate was collected by filtration and dissolved in EtOAc. The solution was washed with water and the organic phase was collected and evaporated. The residue was triturated in diethyl ether to afford crude title compound (255 mg, 58%). Part of this material (70 mg) was purified by prep-HPLC (20-50% ACN/20 min) to give the title compound (50 mg, 81%). ESI-MS calcd for [C.sub.20H.sub.19BrClF.sub.2N.sub.4O.sub.8PS] [M+H].sup.+: 659.0; found: 658.8.

[0386] .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.72 (s, 1H), 8.63 (s, 1H), 8.60 (s, 1H), 8.39 (t, J=1.9 Hz, 1H), 7.66 (d, J=8.0 Hz, 2H), 6.21 (d, J=4.8 Hz, 1H), 5.22 (dd, J=9.8, 5.9 Hz, 1H), 5.17 (dd, J=11.5, 2.5 Hz, 1H), 5.12 (dd, J=11.5, 4.8 Hz, 1H), 5.06 (dd, J=11.1, 5.9 Hz, 1H), 4.53 (t, J=6.0 Hz, 1H), 4.22 (m, 1H), 3.76-3.66 (m, 2H).

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