NOVEL GALACTOSIDE INHIBITOR OF GALECTINS
20240059728 ยท 2024-02-22
Assignee
Inventors
- Kristoffer PETERSON (Copenhagen N, DK)
- Fredrik ZETTERBERG (Copenhagen N, DK)
- Ulf NILSSON (Copenhagen N, DK)
Cpc classification
International classification
Abstract
A D-galactopyranose compound of formula (1)
##STR00001##
wherein the pyranose ring is beta-D-galactopyranose, and these compounds are high affinity galectin-1 and/or 3 inhibitors for use in treatment of inflammation; fibrosis; scarring; keloid formation; aberrant scar formation; surgical adhesions; scleroderma; systemic sclerosis; septic shock; cancer; metastasising cancers; autoimmune diseases; metabolic disorders; heart disease; heart failure; aortic stenosis; atherosclerosis; pathological angiogenesis; eye diseases; metabolic diseases; insulin resistance; obesity; Diastolic HF; asthma; otosclerosis; mesothelioma; liver disorders Liver cancer; cholangiocarcinoma; biliary tract cancer; and neurodegenerative disorders.
Claims
1-15. (canceled)
16. A D-galactopyranose compound of formula (1) ##STR00056## wherein the pyranose ring whereto A.sup.1 and R.sup.1 is attached is -D-galactopyranose, A.sup.1 is (R.sup.4).sub.nZ.sup.1, wherein Z.sup.1 is a five membered heterocycle having at least one heteroatom selected from 0, S, and N and is attached to the C3 position of the -D-galactopyranose; n is 1 or 2, each R.sup.4 is independently selected from a) an aryl, optionally substituted with a group selected from a halogen; CN; a spiro heterocycle; COOH; CONR.sup.5R.sup.6, wherein R.sup.5 and R.sup.6 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.5 and R.sup.6 together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.7R.sup.8, wherein R.sup.7 and R.sup.8 are independently selected from H, C.sub.1-3 alkyl and cyclopropyl; C(O)R.sup.9, wherein R.sup.9 is selected from H and C.sub.1-3 alkyl OH; and R.sup.10CONH wherein R.sup.10 is selected from C.sub.1-3 alkyl and cyclopropyl; b) a heterocycle, optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11R.sup.12, wherein R.sup.11 and R.sup.12 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11 and R.sup.12 together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13R.sup.14, wherein R.sup.13 and R.sup.14 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.15, wherein R.sup.15 is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16CONH wherein R.sup.16 is selected from C.sub.1-3 alkyl and cyclopropyl; c) a group selected from H; C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.50R.sup.51, wherein R.sup.50 and R.sup.51 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.52R.sup.53, wherein R.sup.52 and R.sup.53 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.54R.sup.55 wherein R.sup.54 and R.sup.55 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; d) a group selected from phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.56R.sup.57, wherein R.sup.56 and R.sup.57 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.58R.sup.59, wherein R.sup.58 and R.sup.59 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.60R.sup.61 wherein R.sup.60 and R.sup.61 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; e) YW wherein Y is linked to the 5 membered heterocycle Z.sup.1 of A.sup.1 and is selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, and CR.sup.62R.sup.63 wherein R.sup.62 and R.sup.63 are independently selected from hydrogen, OH, or halogen; and W is selected from the group consisting of phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.64R.sup.65, wherein R.sup.4 and R.sup.65 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.66R.sup.67, wherein R.sup.66 and R.sup.67 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.68R.sup.69 wherein R.sup.68 and R.sup.69 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; B.sup.1 is (R.sup.4a).sub.mZ.sup.2, Wherein Z.sup.2 is a five membered heterocycle having at least one heteroatom selected from O, S, and N and is attached to the C3 position of the D-galactopyranose or the C3 position of the cyclohexyl ring; m is 1 or 2, each R.sup.4a is independently selected from a) an aryl, optionally substituted with a group selected from a halogen; CN; a spiro heterocycle; COOH; CONR.sup.5aR.sup.6a, wherein R.sup.5a and R.sup.6a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.5a and R.sup.6a together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.7aR.sup.8a, wherein R.sup.7a and R.sup.8a are independently selected from H, C.sub.1-3 alkyl and cyclopropyl; C(O)R.sup.9a, wherein R.sup.9a is selected from H and C.sub.1-3 alkyl OH; and R.sup.10aCONH wherein R.sup.10a is selected from C.sub.1-3 alkyl and cyclopropyl; b) a heterocycle, optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11aR.sup.12a, wherein R.sup.11a and R.sup.12a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11a and R.sup.12a together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13aR.sup.14a, wherein R.sup.13a and R.sup.14a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.5a, wherein R.sup.15a is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16aCONH wherein R.sup.16a is selected from C.sub.1-3 alkyl and cyclopropyl; c) a group selected from H; C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.50aR.sup.51a, wherein R.sup.50a and R.sup.51a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.52R.sup.53, wherein R.sup.52a and R.sup.53a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.54aR.sup.55a wherein R.sup.54a and R.sup.55a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; d) a group selected from phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.56aR.sup.57a, wherein R.sup.56a and R.sup.57a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.58aR.sup.59a, wherein R.sup.58a and R.sup.59a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.60aR.sup.61a wherein R.sup.60a and R.sup.61a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; e) Y.sup.aW.sup.a wherein Y.sup.a is linked to the 5 membered heterocycle Z.sup.2 of B.sup.1 and is selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, and CR.sup.62aR.sup.63a wherein R.sup.62a and R.sup.63a are independently selected from hydrogen, OH, or halogen; and W.sup.a is selected from the group consisting of phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.64aR.sup.65a, wherein R.sup.64a and R.sup.65a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.66aR.sup.67a, wherein R.sup.66a and R.sup.67a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.68aR.sup.69a wherein R.sup.68a and R.sup.69a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; X.sup.1 is selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, and CR.sup.17R.sup.18 wherein R.sup.17 and R.sup.15 are independently selected from hydrogen, OH, or halogen, or X.sup.1 is X.sup.1aX.sup.1b wherein X.sup.1a and X.sup.1b are independently selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, and CR.sup.19R.sup.20 wherein R.sup.19 and R.sup.20 are independently selected from hydrogen, OH, or halogen; X.sup.2 is O or CH.sub.2; R.sup.1 is selected from the group consisting of a) H, b) OH, c) OC.sub.1-6 alkyl optionally substituted with one or more halogen, phenyl, phenyl substituted with one or more groups selected form OH and halogen, CN, OR.sup.21, NR.sup.22R.sup.23, and CONH.sub.2, wherein R.sup.21 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.24CONH wherein R.sup.24 is selected from C.sub.1-3 alkyl and cyclopropyl, R.sup.22 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.25CONH wherein R.sup.25 is selected from C.sub.1-3 alkyl and cyclopropyl, and R.sup.23 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.26CONH wherein R.sup.26 is selected from C.sub.1-3 alkyl and cyclopropyl, d) branched OC.sub.3-6 alkyl optionally substituted with one or more halogen, CN, OR.sup.27, NR.sup.28R.sup.29, and CONH.sub.2, wherein R.sup.27 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.30CONH wherein R.sup.30 is selected from C.sub.1-3 alkyl and cyclopropyl, R.sup.28 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.31CONH wherein R.sup.31 is selected from C.sub.1-3 alkyl and cyclopropyl, and R.sup.29 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.32CONH wherein R.sup.32 is selected from C.sub.1-3 alkyl and cyclopropyl, e) cyclic OC.sub.3-6 alkyl optionally substituted with one or more halogen, CN, OR.sup.33, NR.sup.34R.sup.35, and CONH.sub.2, wherein R.sup.33 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.36CONH wherein R.sup.36 is selected from C.sub.1-3 alkyl and cyclopropyl, R.sup.34 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.37CONH wherein R.sup.37 is selected from C.sub.1-3 alkyl and cyclopropyl, and R.sup.35 is selected from the group consisting of H, CN, a halogen, methyl optionally substituted with a F, OCH.sub.3 optionally substituted with a F, OCH.sub.2CH.sub.3 optionally substituted with a F, OH, and R.sup.38CONH wherein R.sup.38 is selected from C.sub.1-3 alkyl and cyclopropyl, and f) a fluorine (F); R.sup.2 is selected from H or OH R.sup.3 is selected from H or CH.sub.2OH; or a pharmaceutically acceptable salt or solvate thereof.
17. The compound of claim 16 wherein A.sup.1 is ##STR00057## wherein the asterix * indicates the X.sup.5 atom of the five membered heterocycle that is covalently attached to the galactopyranose, X.sup.3, X.sup.4, and X.sup.6 are independently selected from CH, N, O and S, provided that the five membered heterocycle is aromatic, X.sup.5 is carbon or nitrogen, C.sup.1 is a) a phenyl, optionally substituted with a group selected from a halogen; CN; COOH; CONR.sup.39R.sup.40, wherein R.sup.39 and R.sup.40 are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, or R.sup.39 and R.sup.40 together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.41R.sup.42, wherein R.sup.41 and R.sup.42 are independently selected from H and C.sub.1-3 alkyl; OH; and R.sup.43CONH wherein R.sup.43 is selected from C.sub.1-3 alkyl and cyclopropyl; or b) a heterocycle, optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.44R.sup.45, wherein R.sup.44 and R.sup.45 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.46R.sup.47, wherein R.sup.46 and R.sup.47 are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, C(O)R.sup.48, wherein R.sup.48 is selected from H and C.sub.1-3 alkyl; OH; and R.sup.49CONH wherein R.sup.49 is selected from C.sub.1-3 alkyl and cyclopropyl.
18. The compound of claim 17 wherein A.sup.1 is ##STR00058## wherein the asterix * indicates the nitrogen atom of the triazole ring that is covalently attached to the galactopyranose; and C.sup.1 is as defined in claim 17.
19. The compound of claim 16 wherein A.sup.1 is ##STR00059## wherein the asterix * indicates the X.sup.8 atom of the five membered heterocycle that is covalently attached to the galactopyranose, X.sup.7 and X.sup.9 are independently selected from CH, N, O and S, provided that the five membered heterocycle is aromatic, X.sup.8 is CH or N, C.sup.2 is a) a phenyl, optionally substituted with a group selected from a halogen; CN; COOH; CONR.sup.39aR.sup.40a, wherein R.sup.39a and R.sup.40a are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, or R.sup.39a and R.sup.40a together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.41aR.sup.42a, wherein R.sup.41a and R.sup.42a are independently selected from H and C.sub.1-3 alkyl; OH; and R.sup.43aCONH wherein R.sup.43a is selected from C.sub.1-3 alkyl and cyclopropyl; or b) a heterocycle, optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.44aR.sup.45a, wherein R.sup.44a and R.sup.45a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.46aR.sup.47a, wherein R.sup.46a and R.sup.47a are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, C(O)R.sup.48a, wherein R.sup.48a is selected from H and C.sub.1-3 alkyl; OH; and R.sup.49aCONH wherein R.sup.49a is selected from C.sub.1-3 alkyl and cyclopropyl; and C.sup.3 is selected from the group consisting of a) H; C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.50R.sup.51, wherein R.sup.50 and R.sup.51 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.52R.sup.53, wherein R.sup.52 and R.sup.53 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.54R.sup.55 wherein R.sup.54 and R.sup.55 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; b) phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.56R.sup.57, wherein R.sup.56 and R.sup.57 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.58R.sup.59, wherein R.sup.58 and R.sup.59 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.60R.sup.61 wherein R.sup.60 and R.sup.61 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; c) YW wherein Y is linked to the 5 membered heterocycle of A.sup.1 and is selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, and CR.sup.62R.sup.63 wherein R.sup.62 and R.sup.63 are independently selected from hydrogen, OH, or halogen; and W is selected from the group consisting of phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.64R.sup.65, wherein R.sup.4 and R.sup.65 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.66R.sup.67, wherein R.sup.66 and R.sup.67 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.68R.sup.69 wherein R.sup.68 and R.sup.69 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
20. The compound of claim 18 wherein A.sup.1 is ##STR00060## wherein the asterix * indicates the nitrogen atom of the pyrazole ring that is covalently attached to the galactopyranose; and C.sup.2 and C.sup.3 are as defined in claim 19.
21. The compound of claim 16 wherein B.sup.1 is ##STR00061## wherein the asterix * indicates the X.sup.12 atom of the five membered heterocycle that is covalently attached to the galactopyranose or cyclohexyl ring; X.sup.10, X.sup.11 and X.sup.13 are independently selected from CH, N, O and S, provided that the five membered heterocycle is aromatic, X.sup.12 is CH or N, C.sup.4 is a) a phenyl, optionally substituted with a group selected from a halogen; CN; COOH; CONR.sup.39bR.sup.40b, wherein R.sup.39b and R.sup.40b are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, or R.sup.39b and R.sup.40b together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.41bR.sup.42b, wherein R.sup.41b and R.sup.42b are independently selected from H and C.sub.1-3 alkyl; OH; and R.sup.43bCONH wherein R.sup.43b is selected from C.sub.1-3 alkyl and cyclopropyl; or b) a heterocycle, optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.44bR.sup.45b, wherein R.sup.44b and R.sup.45b are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.46bR.sup.47b, wherein R.sup.46b and R.sup.47b are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, C(O)R.sup.48b, wherein R.sup.48b is selected from H and C.sub.1-3 alkyl; OH; and R.sup.49bCONH wherein R.sup.49b is selected from C.sub.1-3 alkyl and cyclopropyl.
22. The compound of claim 16 wherein B.sup.1 is ##STR00062## wherein the asterix * indicates the nitrogen atom of the triazole ring that is covalently attached to the galactopyranose or cyclohexyl ring; and C.sup.7 is as defined for R.sup.4a in claim 16.
23. The compound of claim 16 wherein B.sup.1 is ##STR00063## wherein the asterix * indicates the X.sup.15 atom of the five membered heterocycle that is covalently attached to the galactopyranose or cyclohexyl ring; X.sup.14 and X.sup.16 are independently selected from CH, N, O and S, provided that the five membered heterocycle is aromatic, X.sup.15 is CH or N, C.sup.5 is selected from a) a phenyl, optionally substituted with a group selected from a halogen; CN; COOH; CONR.sup.39cR.sup.40c, wherein R.sup.39c and R.sup.40c are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, or R.sup.39c and R.sup.40c together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.41cR.sup.42c, wherein R.sup.41c and R.sup.42c are independently selected from H and C.sub.1-3 alkyl; OH; and R.sup.43cCONH wherein R.sup.43c is selected from C.sub.1-3 alkyl and cyclopropyl; or b) a heterocycle, optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.44cR.sup.45c, wherein R.sup.44c and R.sup.45c are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.46cR.sup.47c, wherein R.sup.46c and R.sup.47c are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, C(O)R.sup.48c, wherein R.sup.48c is selected from H and C.sub.1-3 alkyl; OH; and R.sup.49cCONH wherein R.sup.49c is selected from C.sub.1-3 alkyl and cyclopropyl; and C.sup.6 is selected from c) a H; C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.50aR.sup.51a, wherein R.sup.50 and R.sup.51 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.52R.sup.53, wherein R.sup.52a and R.sup.53a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.54aR.sup.55a wherein R.sup.54a and R.sup.55a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; d) a phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.56aR.sup.57a, wherein R.sup.56a and R.sup.57a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.58aR.sup.59a, wherein R.sup.58a and R.sup.59a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.60aR.sup.61a wherein R.sup.60a and R.sup.61a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; e) Y.sup.aW.sup.a wherein Y.sup.a is linked to the 5 membered heterocycle of B.sup.1 and is selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, and CR.sup.62aR.sup.63a wherein R.sup.62a and R.sup.63a are independently selected from hydrogen, OH, or halogen; and W.sup.a is selected from the group consisting of phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.64aR.sup.65a, wherein R.sup.64a and R.sup.65a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.66aR.sup.67a, wherein R.sup.66a and R.sup.67a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.68aR.sup.69a wherein R.sup.68a and R.sup.69a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
24. The compound of claim 16 wherein B.sup.1 is ##STR00064## wherein the asterix * indicates the nitrogen atom of the pyrazole ring that is covalently attached to the galactopyranose or cyclohexyl ring; and C.sup.8 is as defined for R.sup.4a in claim 16, and C.sup.9 is as defined for R.sup.4a in claim 16.
25. The compound of claim 16 wherein X.sup.1 is selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, or X.sup.1 is X.sup.1aX.sup.1b wherein X.sup.1a and X.sup.1b are independently selected from the group consisting of S, Se, SO, SO.sub.2, O, CO.
26. The compound of claim 16 wherein R.sup.1 is selected from the group consisting of a) H, b) OH, c) OC.sub.1-4 alkyl, d) branched OC.sub.3-4 alkyl, e) cyclic OC.sub.3-4 alkyl.
27. The compound of claim 16 wherein R.sup.2 is H or OH.
28. The compound of claim 16 wherein R.sup.3 is H or CH.sub.2OH.
29. The compound of claim 16 selected from any one of the group consisting of: 3,3-Dideoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1,1-sulfanediyl-di--D-galactopyranoside, 3-[4-(4-Chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3,3-dideoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1,1-sulfanediyl-di--D-galactopyranoside, 3-[4-(2-Aminothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3,3-dideoxy-1,1-sulfanediyl-di--D-galactopyranoside, 1,1-Sulfanediyl-bis-{3-deoxy-3-[4-(3-fluorophenyl)-1H-1,2-pyrazol-1-yl]--D-galactopyranoside}, 1,1-Sulfanediyl-bis-{3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]--D-galactopyranoside}, 3,3-Dideoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1,1-sulfanediyl-di--D-galactopyranoside, 3,3-Dideoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-3-[4-(morpholin-4-yl)-1H-1,2-pyrazol-1-yl]-1,1-sulfanediyl-di--D-galactopyranoside, 3,3-Dideoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-3-(4-isopropyl-1H-1,2-pyrazol-1-yl)-1,1-sulfanediyl-di--D-galactopyranoside, (2S,3R,4S)-3-Hydroxy-4-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]tetrahydropyran-2-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio--D-galactopyranoside, (1R,2R,6S)-1-Hydroxy-6-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]cyclohexan-2-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]-2-O-methyl-1-thio--D-galactopyranoside, 3-Deoxy-3-[4-(3-fluorophenyl)-1H-1,2-pyrazol-1-yl]--D-galactopyranosyl 3-deoxy-3-[4-(3-fluorophenyl)-1H-1,2-pyrazol-1-yl]--D-galactopyranoside, 1,1-Selenediyl-bis-{3-deoxy-3-[4-(3-fluorophenyl)-1H-1,2-pyrazol-1-yl]--D-galactopyranoside}, and Bis-{3-deoxy-3-[4-(3-fluorophenyl)-1H-1,2-pyrazol-1-yl]--D-galactopyranos-1-yl}disulfide; or a pharmaceutically acceptable salt or solvate thereof.
30. A pharmaceutical composition comprising the compound of claim 16 and optionally a pharmaceutically acceptable additive.
Description
DETAILED DESCRIPTION OF THE INVENTION
[0142] The present compounds of formula (1) differ from prior art compounds particularly in that the pyranose ring is -D-galactopyranose. It is important to emphasize that alpha and beta anomers are very different isomers and it is by no means considered to be obvious to the skilled person to expect same or similar activity of both anomers. Consequently, alpha and beta anomers do not in general posses the same activity, and this is common knowledge to the skilled person. The compounds of the present invention are novel -D-galactopyranose compounds that unexpectedly have shown very high affinity and specificity for galectin-1 and/or -3, and typically have a higher specificity for galectin-3 over galectin-1, and are considered novel potent drug candidates.
[0143] In broad aspect the present invention concerns a -D-galactopyranose compound of formula (1)
##STR00020##
Wherein A.sup.1, R.sup.1, R.sup.2, R.sup.3, X.sup.1, X.sup.2 and B.sup.1 are as defined in the above aspects and embodiments.
[0144] In a first embodiment A.sup.1 is (R.sup.4).sub.nZ.sup.1, wherein n is 1.
[0145] In a further embodiment, when n is 1, Z.sup.1 is a five membered heterocycle containing 2 or 3 nitrogens, such as a pyrazole or triazole.
[0146] In a still further embodiment, when n is 1, R.sup.4 is a phenyl optionally substituted with a group selected from a halogen; CN; a spiro heterocycle; COOH; CONR.sup.5R.sup.6, wherein R.sup.5 and R.sup.6 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.5 and R.sup.6 together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.7R.sup.8, wherein R.sup.7 and R.sup.8 are independently selected from H, C.sub.1-3 alkyl and cyclopropyl; C(O)R.sup.9, wherein R.sup.9 is selected from H and C.sub.1-3 alkyl OH; and R.sup.10CONH wherein R.sup.10 is selected from C.sub.1-3 alkyl and cyclopropyl. Typically, the phenyl is substituted with one, two or three substituents.
[0147] In a further embodiment, when n is 1, R.sup.4 is a heteroaryl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11R.sup.12, wherein R.sup.11 and R.sup.12 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11 and R.sup.12 together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13R.sup.14, wherein R.sup.13 and R.sup.14 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.15, wherein R.sup.15 is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16CONH wherein R.sup.16 is selected from C.sub.1-3 alkyl and cyclopropyl. Typically, the heteroaryl is substituted with one, two or three substituents.
[0148] In a still further embodiment, when n is 1, R.sup.4 is a heterocycloalkyl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11R.sup.12, wherein R.sup.11 and R.sup.12 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11 and R.sup.12 together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13R.sup.14, wherein R.sup.13 and R.sup.14 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.15, wherein R.sup.15 is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16CONH wherein R.sup.16 is selected from C.sub.1-3 alkyl and cyclopropyl. Typically, the heterocycloalkyl is substituted with one, two or three substituents.
[0149] In a further embodiment, when n is 1, R.sup.4 is a group selected from YW wherein Y is linked to the 5 membered heterocycle Z.sup.1 of A.sup.1 and is selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, and CR.sup.62R.sup.63 wherein R.sup.62 and R.sup.63 are independently selected from hydrogen, OH, or halogen; and W is selected from the group consisting of phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.64R.sup.65, wherein R.sup.64 and R.sup.65 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.66R.sup.67, wherein R.sup.66 and R.sup.67 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.68R.sup.69 wherein R.sup.68 and R.sup.69 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0150] In a further embodiment A.sup.1 is
##STR00021##
wherein the asterix * indicates the X.sup.5 atom of the five membered heterocycle that is covalently attached to the galactopyranose, and C.sup.1, X.sup.3, X.sup.4, X.sup.5 and X.sup.6 are as defined in the above aspects and embodiments.
[0151] In an embodiment X.sup.5 is selected from CH or N, typically N.
[0152] In a further embodiment X.sup.3 is selected from CH, N, O and S, typically CH and N.
[0153] In a further embodiment X.sup.4 is selected from CH, N, O and S, typically CH and N.
[0154] In a further embodiment X.sup.6 is selected from CH, N, O and S, typically CH and N.
[0155] In a further embodiment C.sup.1 is a phenyl, optionally substituted with a group selected from a halogen; CN; COOH; CONR.sup.39R.sup.40, wherein R.sup.39 and R.sup.40 are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, or R.sup.39 and R.sup.40 together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.41R.sup.42, wherein R.sup.41 and R.sup.42 are independently selected from H and C.sub.1-3 alkyl; OH; and R.sup.43CONH wherein R.sup.43 is selected from C.sub.1-3 alkyl and cyclopropyl.
[0156] In another embodiment C.sup.1 is a heteroaryl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.41R.sup.45, wherein R.sup.4 and R.sup.45 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.46R.sup.47, wherein R.sup.46 and R.sup.47 are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, C(O)R.sup.48, wherein R.sup.48 is selected from H and C.sub.1-3 alkyl; OH; and R.sup.49CONH wherein R.sup.49 is selected from C.sub.1-3 alkyl and cyclopropyl.
[0157] In a further embodiment C.sup.1 is a heterocycloalkyl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.44R.sup.45, wherein R.sup.44 and R.sup.45 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.46R.sup.47, wherein R.sup.46 and R.sup.47 are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, C(O)R.sup.48, wherein R.sup.48 is selected from H and C.sub.1-3 alkyl; OH; and R.sup.49CONH wherein R.sup.49 is selected from C.sub.1-3 alkyl and cyclopropyl.
[0158] Typically, A.sup.1 is
##STR00022## [0159] wherein the asterix * indicates the nitrogen atom of the triazole ring that is covalently attached to the galactopyranose; and [0160] C.sup.1 is a phenyl substituted with one, two or three substituents selected from halogen, such as a phenyl substituted with three substituents selected from F and Cl.
[0161] In a second embodiment A.sup.1 is (R.sup.4).sub.nZ.sup.1, wherein n is 2.
[0162] In a further embodiment, when n is 2, Z.sup.1 is a five membered heterocycle containing 2 or 3 nitrogens, such as a pyrazole or triazole.
[0163] In a still further embodiment, when n is 2, one R.sup.4 is a phenyl optionally substituted with a group, such as one, two or three substituents, selected from a halogen; CN; a spiro heterocycle; COOH; CONR.sup.5R.sup.6, wherein R.sup.5 and R.sup.6 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.5 and R.sup.6 together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.7R.sup.8, wherein R.sup.7 and R.sup.8 are independently selected from H, C.sub.1-3 alkyl and cyclopropyl; C(O)R.sup.9, wherein R.sup.9 is selected from H and C.sub.1-3 alkyl OH; and R.sup.10CONH wherein R.sup.10 is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4 is a group selected from H; C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.50R.sup.51, wherein R.sup.50 and R.sup.51 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.52R.sup.53, wherein R.sup.52 and R.sup.53 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.54R.sup.55 wherein R.sup.54 and R.sup.55 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0164] In a further embodiment, when n is 2, one R.sup.4 is a phenyl optionally substituted with a group, such as one, two or three substituents, selected from a halogen; CN; a spiro heterocycle; COOH; CONR.sup.5R.sup.6, wherein R.sup.5 and R.sup.6 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.5 and R.sup.6 together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.7R.sup.8, wherein R.sup.7 and R.sup.8 are independently selected from H, C.sub.1-3 alkyl and cyclopropyl; C(O)R.sup.9, wherein R.sup.9 is selected from H and C.sub.1-3 alkyl OH; and R.sup.10CONH wherein R.sup.10 is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4 is a group selected from phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.56R.sup.57, wherein R.sup.56 and R.sup.57 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.58R.sup.59, wherein R.sup.58 and R.sup.59 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.60R.sup.61 wherein R.sup.60 and R.sup.61 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0165] In a further embodiment, when n is 2, one R.sup.4 is a phenyl optionally substituted with a group, such as one, two or three substituents, selected from a halogen; CN; a spiro heterocycle; COOH; CONR.sup.5R.sup.6, wherein R.sup.5 and R.sup.6 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.5 and R.sup.6 together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.7R.sup.8, wherein R.sup.7 and R.sup.8 are independently selected from H, C.sub.1-3 alkyl and cyclopropyl; C(O)R.sup.9, wherein R.sup.9 is selected from H and C.sub.1-3 alkyl OH; and R.sup.10CONH wherein R.sup.10 is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4 is a group selected from YW wherein
[0166] Y is linked to the 5 membered heterocycle Z.sup.1 of A.sup.1 and is selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, and CR.sup.62R.sup.63 wherein R.sup.62 and R.sup.63 are independently selected from hydrogen, OH, or halogen; and
[0167] W is selected from the group consisting of phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.64R.sup.65, wherein R.sup.64 and R.sup.65 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.66R.sup.67, wherein R.sup.66 and R.sup.67 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.68R.sup.69 wherein R.sup.68 and R.sup.69 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0168] In a further embodiment, when n is 2, one R.sup.4 is a heteroaryl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11R.sup.12, wherein R.sup.11 and R.sup.12 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11 and R.sup.12 together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13R.sup.14, wherein R.sup.13 and R.sup.14 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.15, wherein R.sup.15 is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16CONH wherein R.sup.16 is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4 is a group selected from H; C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.50R.sup.51, wherein R.sup.50 and R.sup.51 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.52R.sup.53, wherein R.sup.52 and R.sup.53 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.54R.sup.55 wherein R.sup.54 and R.sup.55 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0169] In a further embodiment, when n is 2, one R.sup.4 is a heteroaryl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11R.sup.12, wherein R.sup.11 and R.sup.12 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11 and R.sup.12 together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13R.sup.14, wherein R.sup.13 and R.sup.14 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.15, wherein R.sup.15 is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16CONH wherein R.sup.16 is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4 is a group selected from phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.56R.sup.57, wherein R.sup.56 and R.sup.57 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.58R.sup.59, wherein R.sup.58 and R.sup.59 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.60R.sup.61 wherein R.sup.60 and R.sup.61 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0170] In a further embodiment, when n is 2, one R.sup.4 is a heteroaryl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11R.sup.12, wherein R.sup.11 and R.sup.12 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11 and R.sup.12 together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13R.sup.14, wherein R.sup.13 and R.sup.14 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.15, wherein R.sup.15 is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16CONH wherein R.sup.16 is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4 is a group selected from YW wherein
[0171] Y is linked to the 5 membered heterocycle Z.sup.1 of A.sup.1 and is selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, and CR.sup.62R.sup.63 wherein R.sup.62 and R.sup.63 are independently selected from hydrogen, OH, or halogen; and
[0172] W is selected from the group consisting of phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.64R.sup.65, wherein R.sup.64 and R.sup.65 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.66R.sup.67, wherein R.sup.66 and R.sup.67 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.68R.sup.69 wherein R.sup.68 and R.sup.69 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0173] In a further embodiment, when n is 2, one R.sup.4 is a heterocycloalkyl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11R.sup.12, wherein R.sup.11 and R.sup.12 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11 and R.sup.12 together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13R.sup.14, wherein R.sup.13 and R.sup.14 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.15, wherein R.sup.15 is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16CONH wherein R.sup.16 is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4 is a group selected from H; C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.50R.sup.51, wherein R.sup.50 and R.sup.51 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.52R.sup.53, wherein R.sup.52 and R.sup.53 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.54R.sup.55 wherein R.sup.54 and R.sup.55 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0174] In a further embodiment, when n is 2, one R.sup.4 is a heterocycloalkyl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11R.sup.12, wherein R.sup.11 and R.sup.12 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11 and R.sup.12 together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13R.sup.14, wherein R.sup.13 and R.sup.14 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.15, wherein R.sup.15 is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16CONH wherein R.sup.16 is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4 is a group selected from phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.56R.sup.57, wherein R.sup.56 and R.sup.57 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.58R.sup.59, wherein R.sup.58 and R.sup.59 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.60R.sup.61 wherein R.sup.60 and R.sup.61 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0175] In a further embodiment, when n is 2, one R.sup.4 is a heterocycloalkyl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11R.sup.12, wherein R.sup.11 and R.sup.12 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11 and R.sup.12 together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13R.sup.14, wherein R.sup.13 and R.sup.14 are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.15, wherein R.sup.15 is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16CONH wherein R.sup.16 is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4 is a group selected from YW wherein
[0176] Y is linked to the 5 membered heterocycle Z.sup.1 of A.sup.1 and is selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, and CR.sup.62R.sup.63 wherein R.sup.62 and R.sup.63 are independently selected from hydrogen, OH, or halogen; and
[0177] W is selected from the group consisting of phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.64R.sup.65, wherein R.sup.64 and R.sup.65 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.66R.sup.67, wherein R.sup.66 and R.sup.67 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.68R.sup.69 wherein R.sup.68 and R.sup.69 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0178] In a further embodiment A.sup.1 is
##STR00023##
wherein the asterix * indicates the X.sup.8 atom of the five membered heterocycle that is covalently attached to the galactopyranose, and C.sup.2, C.sup.3, X.sup.7, X.sup.8, and X.sup.9 are as defined in the above aspects and embodiments.
[0179] In an embodiment X.sup.8 is CH or N, typically N.
[0180] In a further embodiment X.sup.7 is selected from CH, N, O and S, typically CH and N.
[0181] In a still further embodiment X.sup.9 is selected from CH, N, O and S, typically CH and N.
[0182] In a further embodiment C.sup.2 is a phenyl, optionally substituted with a group selected from a halogen; CN; COOH; CONR.sup.39aR.sup.40a, wherein R.sup.39a and R.sup.40a are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, or R.sup.39a and R.sup.40a together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.41aR.sup.42a, wherein R.sup.41a and R.sup.42a are independently selected from H and C.sub.1-3 alkyl; OH; and R.sup.43aCONH wherein R.sup.43a is selected from C.sub.1-3 alkyl and cyclopropyl.
[0183] In a still further embodiment C.sup.2 is a heteroaryl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.44aR.sup.45a, wherein R.sup.44a and R.sup.45a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.46aR.sup.47a, wherein R.sup.46a and R.sup.47a are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, C(O)R.sup.48a, wherein R.sup.48a is selected from H and C.sub.1-3 alkyl; OH; and R.sup.49aCONH wherein R.sup.49a is selected from C.sub.1-3 alkyl and cyclopropyl.
[0184] In a further embodiment C.sup.2 is a heterocycloalkyl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.4aR.sup.45a, wherein R.sup.44a and R.sup.45a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.46aR.sup.47a, wherein R.sup.46a and R.sup.47a are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, C(O)R.sup.48a, wherein R.sup.48a is selected from H and C.sub.1-3 alkyl; OH; and R.sup.49aCONH wherein R.sup.49a is selected from C.sub.1-3 alkyl and cyclopropyl.
[0185] In a still further embodiment C.sup.3 is selected from H; C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.50R.sup.51, wherein R.sup.50 and R.sup.51 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.52R.sup.53, wherein R.sup.52 and R.sup.53 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.54R.sup.55 wherein R.sup.54 and R.sup.55 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0186] In a still further embodiment C.sup.3 is selected from phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.56R.sup.57, wherein R.sup.56 and R.sup.57 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.58R.sup.59, wherein R.sup.58 and R.sup.59 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.60R.sup.61 wherein R.sup.60 and R.sup.61 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0187] In a still further embodiment C.sup.3 is selected from YW wherein Y is linked to the 5 membered heterocycle of A.sup.1 and is selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, and CR.sup.62R.sup.63 wherein R.sup.62 and R.sup.63 are independently selected from hydrogen, OH, or halogen; and W is selected from the group consisting of phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.64R.sup.65, wherein R.sup.64 and R.sup.65 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.66R.sup.67, wherein R.sup.66 and R.sup.67 are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.68R.sup.69 wherein R.sup.68 and R.sup.69 are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0188] Typically, A.sup.1 is
##STR00024## [0189] wherein the asterix * indicates the nitrogen atom of the pyrazole ring that is covalently attached to the galactopyranose; [0190] C.sup.2 is phenyl substituted with one, two or three substitutents selected from halogen; and [0191] C.sup.3 is H.
[0192] In a first embodiment B.sup.1 is (R.sup.4a).sub.mZ.sup.2, wherein m is 1.
[0193] In a further embodiment, when m is 1, Z.sup.2 is a five membered heterocycle containing 2 or 3 nitrogens, such as a pyrazole or triazole.
[0194] In a still further embodiment, when m is 1, R.sup.4a is a phenyl optionally substituted with a group selected from a halogen; CN; a spiro heterocycle; COOH; CONR.sup.5aR.sup.6a, wherein R.sup.5a and R.sup.6a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.5a and R.sup.6a together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.7aR.sup.8a, wherein R.sup.7a and R.sup.8a are independently selected from H, C.sub.1-3 alkyl and cyclopropyl; C(O)R.sup.9a, wherein R.sup.9a is selected from H and C.sub.1-3 alkyl OH; and R.sup.10aCONH wherein R.sup.10a is selected from C.sub.1-3 alkyl and cyclopropyl. Typically, the phenyl is substituted with one, two or three substituents.
[0195] In a still further embodiment, when m is 1, R.sup.4a is a heteroaryl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11aR.sup.12a, wherein R.sup.11a and R.sup.12a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11a and R.sup.12a together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13aR.sup.14a, wherein R.sup.13a and R.sup.14a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.15a, wherein R.sup.15a is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16aCONH wherein R.sup.16a is selected from C.sub.1-3 alkyl and cyclopropyl. Typically, the heteroaryl is substituted with one, two or three substituents.
[0196] In a still further embodiment, when m is 1, R.sup.4a is a heterocycloalkyl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11aR.sup.12a, wherein R.sup.11a and R.sup.12a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11a and R.sup.2a together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13aR.sup.14a, wherein R.sup.13a and R.sup.14a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.15a, wherein R.sup.15a is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16aCONH wherein R.sup.16a is selected from C.sub.1-3 alkyl and cyclopropyl. Typically, the heterocycloalkyl is substituted with one, two or three substituents.
[0197] In a further embodiment, when m is 1, R.sup.4a is a group selected from H; C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.50aR.sup.51a, wherein R.sup.50a and R.sup.51a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.52R.sup.53, wherein R.sup.52a and R.sup.53a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.54aR.sup.55a wherein R.sup.54a and R.sup.55a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0198] In a further embodiment, when m is 1, R.sup.4a is a group selected from phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.56aR.sup.57a, wherein R.sup.56a and R.sup.57a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.58aR.sup.59a, wherein R.sup.58a and R.sup.59a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.60aR.sup.61a wherein R.sup.60a and R.sup.61a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0199] In a further embodiment, when m is 1, R.sup.4a is a group selected from Y.sup.aW.sup.a wherein [0200] Y.sup.a is linked to the 5 membered heterocycle Z.sup.2 of B.sup.1 and is selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, and CR.sup.62aR.sup.63a wherein R.sup.62a and R.sup.63a are independently selected from hydrogen, OH, or halogen; and [0201] W.sup.a is selected from the group consisting of phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.64aR.sup.65a, wherein R.sup.64a and R.sup.65a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.66aR.sup.67a, wherein R.sup.66a and R.sup.67a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.68aR.sup.69a wherein R.sup.68a and R.sup.69a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0202] In a still further embodiment B.sup.1 is
##STR00025## [0203] wherein the asterix * indicates the X.sup.12 atom of the five membered heterocycle that is covalently attached to the galactopyranose or cyclohexyl ring.
[0204] In a further embodiment X.sup.10 is selected from CH, N, O and S, typically CH and N.
[0205] In a still further embodiment X.sup.11 is selected from CH, N, O and S, typically CH and N.
[0206] In a further embodiment X.sup.13 is selected from CH, N, O and S, typically CH and N.
[0207] In a still further embodiment X.sup.12 is CH or N, preferably N.
[0208] In a further embodiment C.sup.4 is a phenyl, optionally substituted with a group selected from a halogen; CN; COOH; CONR.sup.39bR.sup.40b, wherein R.sup.39b and R.sup.40b are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, or R.sup.39b and R.sup.40b together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.41bR.sup.42b, wherein R.sup.41b and R.sup.42b are independently selected from H and C.sub.1-3 alkyl; OH; and R.sup.43bCONH wherein R.sup.43b is selected from C.sub.1-3 alkyl and cyclopropyl. Typically, C.sup.4 is a phenyl substituted with one, two or three groups selected from a halogen.
[0209] In a further embodiment C.sup.4 is a heteroaryl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.44bR.sup.45b, wherein R.sup.44b and R.sup.45b are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.46bR.sup.47b, wherein R.sup.46b and R.sup.47b are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, C(O)R.sup.48b, wherein R.sup.48b is selected from H and C.sub.1-3 alkyl; OH; and R.sup.49bCONH wherein R.sup.49b is selected from C.sub.1-3 alkyl and cyclopropyl. Typically, C.sup.4 is a heteroaryl, such as a thiazolyl, substituted with one, two or three groups selected from OH and NH.sub.2.
[0210] In a further embodiment C.sup.4 is a heterocycloalkyl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.44bR.sup.45b, wherein R.sup.44b and R.sup.45b are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.46bR.sup.47b, wherein R.sup.46b and R.sup.47b are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, C(O)R.sup.48b wherein R.sup.48b is selected from H and C.sub.1-3 alkyl; OH; and R.sup.49bCONH wherein R.sup.49b is selected from C.sub.1-3 alkyl and cyclopropyl. Typically, C.sup.4 is a heterocycloalkyl, such as a morpholinyl.
[0211] In a further embodiment C.sup.4 is a group selected from H; C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.50aR.sup.51a, wherein R.sup.50a and R.sup.51a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.52R.sup.53, wherein R.sup.52a and R.sup.53a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.54aR.sup.55a wherein R.sup.54a and R.sup.55a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen. Typically, C.sup.4 is a C.sub.1-6 alkyl optionally substituted with a halogen, such as a C.sub.1-4 alkyl, e.g. isopropyl.
[0212] In a second embodiment B.sup.1 is (R.sup.4a).sub.mZ.sup.2, wherein m is 2.
[0213] In a further embodiment, when m is 2, Z.sup.2 is a five membered heterocycle containing 2 or 3 nitrogens, such as a pyrazole or triazole.
[0214] In a still further embodiment, when m is 2, one R.sup.4a is a phenyl optionally substituted with a group selected from a halogen; CN; a spiro heterocycle; COOH; CONR.sup.5aR.sup.6a, wherein R.sup.5a and R.sup.6a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.5a and R.sup.6a together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.7aR.sup.8a, wherein R.sup.7a and R.sup.8a are independently selected from H, C.sub.1-3 alkyl and cyclopropyl; C(O)R.sup.9a, wherein R.sup.9a is selected from H and C.sub.1-3 alkyl OH; and R.sup.10aCONH wherein R.sup.10a is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4a is a group selected from H; C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.50aR.sup.51a, wherein R.sup.50a and R.sup.51a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.52R.sup.53, wherein R.sup.52a and R.sup.53a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.54aR.sup.55a wherein R.sup.54a and R.sup.55a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0215] In a still further embodiment, when m is 2, one R.sup.4a is a phenyl optionally substituted with a group selected from a halogen; CN; a spiro heterocycle; COOH; CONR.sup.5aR.sup.6a, wherein R.sup.5a and R.sup.6a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.5a and R.sup.6a together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.7aR.sup.8a, wherein R.sup.7a and R.sup.8a are independently selected from H, C.sub.1-3 alkyl and cyclopropyl; C(O)R.sup.9a, wherein R.sup.9a is selected from H and C.sub.1-3 alkyl OH; and R.sup.10aCONH wherein R.sup.10a is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4a is a group selected from phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.56aR.sup.57a, wherein R.sup.56a and R.sup.57a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.58aR.sup.59a, wherein R.sup.58a and R.sup.59a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.60aR.sup.61a wherein R.sup.60a and R.sup.61a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0216] In a still further embodiment, when m is 2, one R.sup.4a is a phenyl optionally substituted with a group selected from a halogen; CN; a spiro heterocycle; COOH; CONR.sup.5aR.sup.6a, wherein R.sup.5a and R.sup.6a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.5a and R.sup.6a together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.7aR.sup.8a, wherein R.sup.7a and R.sup.8a are independently selected from H, C.sub.1-3 alkyl and cyclopropyl; C(O)R.sup.9a, wherein R.sup.9a is selected from H and C.sub.1-3 alkyl OH; and R.sup.10aCONH wherein R.sup.10a is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4a is a group selected from Y.sup.aW.sup.a wherein [0217] Y.sup.a is linked to the 5 membered heterocycle Z.sup.2 of B.sup.1 and is selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, and CR.sup.62aR.sup.63a wherein R.sup.62a and R.sup.63a are independently selected from hydrogen, OH, or halogen; and [0218] W.sup.a is selected from the group consisting of phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.64aR.sup.65a, wherein R.sup.64a and R.sup.65a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.66aR.sup.67a, wherein R.sup.66a and R.sup.67a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.68aR.sup.69a wherein R.sup.68a and R.sup.69a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0219] In a still further embodiment, when m is 2, one R.sup.4a is a heteroaryl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11aR.sup.12a, wherein R.sup.11a and R.sup.12a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11a and R.sup.2a together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13aR.sup.14a, wherein R.sup.13a and R.sup.14a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.15a, wherein R.sup.15a is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16aCONH wherein R.sup.16a is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4a is a group selected from H; C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.50aR.sup.51a, wherein R.sup.50a and R.sup.51a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.52R.sup.53, wherein R.sup.52a and R.sup.53a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.54aR.sup.55a wherein R.sup.54a and R.sup.55a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0220] In a still further embodiment, when m is 2, one R.sup.4a is a heteroaryl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11aR.sup.12a, wherein R.sup.11a and R.sup.12a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11a and R.sup.2a together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13aR.sup.14a, wherein R.sup.13a and R.sup.14a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.15a, wherein R.sup.15a is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16aCONH wherein R.sup.16a is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4a is a group selected from phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.56aR.sup.57a, wherein R.sup.56a and R.sup.57a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.58aR.sup.59a, wherein R.sup.58a and R.sup.59a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.60aR.sup.61a wherein R.sup.60a and R.sup.61a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0221] In a still further embodiment, when m is 2, one R.sup.4a is a heteroaryl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11aR.sup.12a, wherein R.sup.11a and R.sup.12a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11a and R.sup.2a together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13aR.sup.14a, wherein R.sup.13a and R.sup.14a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.15a, wherein R.sup.15a is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16aCONH wherein R.sup.16a is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4a is a group selected from Y.sup.aW.sup.a wherein Y.sup.a is linked to the 5 membered heterocycle Z.sup.2 of B.sup.1 and is selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, and CR.sup.62aR.sup.63a wherein R.sup.62a and R.sup.63a are independently selected from hydrogen, OH, or halogen; and W.sup.a is selected from the group consisting of phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.64aR.sup.65a, wherein R.sup.64a and R.sup.65a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.66aR.sup.67a, wherein R.sup.66a and R.sup.67a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.68aR.sup.69a wherein R.sup.68a and R.sup.69a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0222] In a still further embodiment, when m is 2, one R.sup.4a is a heterocycloalkyl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11aR.sup.12a, wherein R.sup.11a and R.sup.12a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11a and R.sup.2a together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13aR.sup.14a, wherein R.sup.13a and R.sup.14a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.15a, wherein R.sup.15a is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16aCONH wherein R.sup.16a is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4a is a group selected from H; C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.50aR.sup.51a, wherein R.sup.50a and R.sup.51a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.52R.sup.53, wherein R.sup.52a and R.sup.53a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.54aR.sup.55a wherein R.sup.54a and R.sup.55a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0223] In a still further embodiment, when m is 2, one R.sup.4a is a heterocycloalkyl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11aR.sup.12a, wherein R.sup.11a and R.sup.2a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11a and R.sup.2a together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13aR.sup.14a, wherein R.sup.13a and R.sup.14a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.15a, wherein R.sup.15a is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16aCONH wherein R.sup.16a is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4a is a group selected from phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.56aR.sup.57a, wherein R.sup.56a and R.sup.57a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.58aR.sup.59a, wherein R.sup.58a and R.sup.59a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.60aR.sup.61a wherein R.sup.60a and R.sup.61a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0224] In a still further embodiment, when m is 2, one R.sup.4a is a heterocycloalkyl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.11aR.sup.12a, wherein R.sup.11a and R.sup.12a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl, or R.sup.11a and R.sup.2a together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.13aR.sup.14a, wherein R.sup.13a and R.sup.14a are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C(O)R.sup.5a, wherein R.sup.15a is selected from H and C.sub.1-3 alkyl; OH; and R.sup.16aCONH wherein R.sup.16a is selected from C.sub.1-3 alkyl and cyclopropyl; and the second R.sup.4a is a group selected from Y.sup.aW.sup.a wherein [0225] Y.sup.a is linked to the 5 membered heterocycle Z.sup.2 of B.sup.1 and is selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, and CR.sup.62aR.sup.63a wherein R.sup.62a and R.sup.63a are independently selected from hydrogen, OH, or halogen; and [0226] W.sup.a is selected from the group consisting of phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.64aR.sup.65a, wherein R.sup.64a and R.sup.65a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.66aR.sup.67a, wherein R.sup.66a and R.sup.67a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.68aR.sup.69a wherein R.sup.68a and R.sup.69a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0227] In a further embodiment B.sup.1 is
##STR00026## [0228] wherein the asterix * indicates the nitrogen atom of the triazole ring that is covalently attached to the galactopyranose or cyclohexyl ring; and [0229] C.sup.7 is a heteroaryl, such as thiazolyl, optionally substituted with one or two groups selected from OH and NH.sub.2. Typically, C.sup.7 is a thiazolyl substituted with one group selected from OH and NH.sub.2.
[0230] In a further embodiment B.sup.1 is
##STR00027## [0231] wherein the asterix * indicates the X.sup.15 atom of the five membered heterocycle that is covalently attached to the galactopyranose or cyclohexyl ring.
[0232] In an embodiment X.sup.14 is selected from CH, N, O and S, typically CH and N.
[0233] In a further embodiment X.sup.16 is selected from CH, N, O and S, typically CH and N.
[0234] In a still further embodiment X.sup.15 is CH or N, typically N.
[0235] In a further embodiment C.sup.5 is selected from a phenyl, optionally substituted with a group selected from a halogen; CN; COOH; CONR.sup.39cR.sup.40c, wherein R.sup.39c and R.sup.40c are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, or R.sup.39c and R.sup.40c together with the nitrogen may form a heterocycloalkyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.41cR.sup.42c, wherein R.sup.41c and R.sup.42c are independently selected from H and C.sub.1-3 alkyl; OH; and R.sup.43cCONH wherein R.sup.43c is selected from C.sub.1-3 alkyl and cyclopropyl.
[0236] Typically, C.sup.5 is selected from a phenyl substituted with one, two or three groups selected from a halogen.
[0237] In a still further embodiment C.sup.5 is selected from a heteroaryl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.44cR.sup.45c, wherein R.sup.44c and R.sup.45c are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.46cR.sup.47c, wherein R.sup.46c and R.sup.47c are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, C(O)R.sup.48c, wherein R.sup.48c is selected from H and C.sub.1-3 alkyl; OH; and R.sup.49cCONH wherein R.sup.49c is selected from C.sub.1-3 alkyl and cyclopropyl.
[0238] In a further embodiment C.sup.5 is selected from a heterocycloalkyl optionally substituted with a group selected from a halogen; a spiro heterocycle; CN; COOH; CONR.sup.44cR.sup.45c, wherein R.sup.44c and R.sup.45c are independently selected from H, C.sub.1-3 alkyl, and cyclopropyl; C.sub.1-3 alkyl, optionally substituted with a F; cyclopropyl, optionally substituted with a F; OC.sub.1-3 alkyl, optionally substituted with a F; O-cyclopropyl, optionally substituted with a F; NR.sup.46cR.sup.47c, wherein R.sup.46c and R.sup.47c are independently selected from H, C.sub.1-3 alkyl and cyclopropyl, C(O)R.sup.48c, wherein R.sup.48c is selected from H and C.sub.1-3 alkyl; OH; and R.sup.49cCONH wherein R.sup.49c is selected from C.sub.1-3 alkyl and cyclopropyl.
[0239] In a still further embodiment C.sup.6 is selected from a H; C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.50aR.sup.51a, wherein R.sup.50a and R.sup.51a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.52R.sup.53, wherein R.sup.52a and R.sup.53a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.54aR.sup.55a wherein R.sup.54a and R.sup.55a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0240] In a further embodiment C.sup.6 is selected from a phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.56aR.sup.57a, wherein R.sup.56a and R.sup.57a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.58aR.sup.59a, wherein R.sup.58a and R.sup.59a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.60aR.sup.61a wherein R.sup.60a and R.sup.61a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0241] In a still further embodiment C.sup.6 is selected from Y.sup.aW.sup.a wherein [0242] Y.sup.a is linked to the 5 membered heterocycle of B.sup.1 and is selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, and CR.sup.62aR.sup.63a wherein R.sup.62a and R.sup.63a are independently selected from hydrogen, OH, or halogen; and [0243] W.sup.a is selected from the group consisting of phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, dihydrobenzothiophene-2,2-dioxide, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl; optionally substituted with one or more substituents selected from the group consisting of C.sub.1-6 alkyl optionally substituted with a halogen; halogen; CN; C.sub.2-alkynyl; OH; OC.sub.1-6 alkyl optionally substituted with a halogen; C.sub.3-6 cycloalkyl optionally substituted with a halogen; SH; SC.sub.1-6 alkyl optionally substituted with a halogen; NR.sup.64aR.sup.65a, wherein R.sup.64a and R.sup.65a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, C.sub.3-6 cycloalkyl optionally substituted with a halogen, C(O)C.sub.1-6 alkyl optionally substituted with a halogen, and S(O.sub.2)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; S(O.sub.2)C.sub.3-6 cycloalkyl optionally substituted with a halogen; C.sub.1-6 alkenyl optionally substituted with a halogen; C(O)C.sub.1-6 alkyl optionally substituted with a halogen; C(O)C.sub.3-6 cycloalkyl optionally substituted with a halogen; COOH; C(O)OC.sub.1-6 alkyl optionally substituted with a halogen; C(O)OC.sub.3-6 cycloalkyl optionally substituted with a halogen; C(O)NR.sup.66aR.sup.67a, wherein R.sup.66a and R.sup.67a are independently selected from H, C.sub.1-3 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen; and S(O.sub.2)NR.sup.68aR.sup.69a wherein R.sup.68a and R.sup.69a are independently selected from H, C.sub.1-6 alkyl optionally substituted with a halogen, and cyclopropyl optionally substituted with a halogen.
[0244] In a still further embodiment B.sup.1 is
##STR00028## [0245] wherein the asterix * indicates the nitrogen atom of the pyrazole ring that is covalently attached to the galactopyranose or cyclohexyl ring.
[0246] In an embodiment C.sup.8 is a phenyl optionally substituted with one, two or three halogens, such as one, two or three F. In another embodiment C.sup.8 is a heterocycloalkyl, such as morpholinyl, optionally substituted with one or two groups selected from halogen or C.sub.1-4 alkyl. Typically, C.sup.8 is a morpholinyl. In a still other embodiment C.sup.8 is a C.sub.1-6 alkyl, such as C.sub.1-4 alkyl, e.g. isopropyl.
[0247] In a further embodiment C.sup.9 is selected from H or C.sub.1-6 alkyl, such as H.
[0248] In a still further embodiment X.sup.1 is selected from the group consisting of S, Se, SO, SO.sub.2, O, CO, such as S, SO, or SO.sub.2.
[0249] In a further embodiment X.sup.1 is X.sup.1aX.sup.1b wherein X.sup.1a and X.sup.1b are independently selected from the group consisting of S, Se, SO, SO.sub.2, O, CO. In one embodiment X.sup.1a is selected from S, SO, or SO.sub.2, such as S. In a further embodiment X.sup.1b is selected from S, SO, or SO.sub.2, such as S. Typically, X.sup.1 is SS.
[0250] In a further embodiment X.sup.2 is O. Alternatively, X.sup.2 is CH.sub.2.
[0251] In a still further embodiment R.sup.1 is H. In a further embodiment R.sup.1 is OH. In a still further embodiment R.sup.1 is OC.sub.1-4 alkyl, such as OCH.sub.3.
[0252] In a still further embodiment R.sup.2 is H. Alternatively, R.sup.2 is OH.
[0253] In a further aspect the present invention concerns a -D-galactopyranose compound of formula (1) selected from any one of the exemplified compounds of examples 1-14, or a pharmaceutically acceptable salt thereof.
[0254] The skilled person will understand that it may be necessary to adjust or change the order of steps in the processes herein, 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.
[0255] 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.
[0256] Functional groups that it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include optionally substituted and/or unsaturated alkyl groups (e.g. methyl, allyl, benzyl or tert-butyl), trialkyl silyl or diarylalkylsilyl groups (e.g. t-butyldimethylsilyl, t-butyldipheylsilyl or trimethylsilyl), AcO(acetoxy), TBS(t-butyldimethylsilyl), TMS(trimethylsilyl), PMB (p-methoxybensyl), and tetrahydropyranyl. Suitable protecting groups for carboxylic acid include (C.sub.1-6)-alkyl or benzyl esters. Suitable protecting groups for amino include t-butyloxycarbonyl, benzyloxycarbonyl, 2-(trimethylsilyl)-ethoxy-methyl or 2-trimethylsilylethoxycarbonyl (Teoc). Suitable protecting groups for S include SC(N)NH.sub.2, TIPS.
[0257] The protection and deprotection of functional groups may take place before or after any reaction in the above-mentioned processes.
[0258] 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.
[0259] In a still further embodiment the compound (1) is on free form. On free form as used herein means a compound of formula (1), either an acid form or base form, or as a neutral compound, depending on the substitutents. The free form does not have any acid salt or base salt in addition. In one embodiment the free form is an anhydrate. In another embodiment the free form is a solvate, such as a hydrate.
[0260] In a further embodiment the compound of formula (1) is a crystalline form. The skilled person may carry out tests in order to find polymorphs, and such polymorphs are intended to be encompassed by the term crystalline form as used herein.
[0261] Whenever a compound of formula (1) is used herein it means the compound of formula (1) in any form incl the free form or as a salt thereof, such as a pharmaceutically acceptable salt thereof, unless otherwise indicated herein or clearly contradicted by context.
[0262] 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.
[0263] 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.
[0264] 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.
[0265] The term C.sub.3-x cycloalkyl as used herein means a cyclic alkyl group containing 3-x carbon atoms, e.g. C.sub.3-6 or C.sub.3-7, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 1-methylcyclopropyl.
[0266] 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.
[0267] The term Oxo as used herein means an oxygen atom with double bonds, also indicated as O.
[0268] The term CN as used herein means a cyano group.
[0269] The term halogen as used herein means Cl, F, Br or I.
[0270] The term halo-C.sub.1-6 alkyl as used herein means one or more halogens linked to a C.sub.1-6 alkyl, such as CF.sub.3, CH(Cl)CHF.sub.2.
[0271] The term C.sub.1-6 alkoxy as used herein means an oxygen linked to a C.sub.1-6 alkyl, such as methoxy or ethoxy.
[0272] The term C.sub.1-6 alkylthio as used herein means a sulphur linked to a C.sub.1-6 alkyl, such as thiomethoxy or thioethoxy.
[0273] The term halo-C.sub.1-6 alkoxy as used herein means one or more halogens linked to a C.sub.1-6 alkoxy, such as CH(F.sub.2)CH(Br)O.
[0274] The term C.sub.1-6 alkoxycarbonyl as used herein means a C.sub.1-6 alkoxy linked to a carbonyl, such as methoxycarbonyl (CH.sub.2OC(O)).
[0275] The term a five or six membered heteroaromatic ring as used herein means one five membered heteroaromatic ring or one six membered heteroaromatic ring.
[0276] 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.
[0277] 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.
[0278] 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, morpholinyl, tetrahydrothipyranyl, or piperidonyl.
[0279] The term a spiro heterocycle as used herein means a two-ring system connected by a common carbon atom, and containing from 5 to 12 ring members wherein from 2 to 11 are carbon atoms and at least one is a heteroatom, such as a hetero atom selected from one or more N, S, O; one example is N-(2-oxa)-6-azaspiro[3.3]heptanyl.
[0280] 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.
[0281] The term a pharmaceutically acceptable salt as used herein is used to specify that the salt is suitable for use in the human or animal body. An example list of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, editors, Weinheim/Zurich:Wiley-VCH/VHCA, 2002. A pharmaceutically acceptable salt of a compound of Formula (1) includes such salts that may be formed within the human or animal body after administration of said compound to said human or animal body.
[0282] The term a therapeutically effective amount of a compound of formula (1) of the present invention as used herein means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications. An amount adequate to accomplish this is defined as therapeutically effective amount. Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary.
[0283] In a still further aspect, the present invention relates to a pharmaceutical composition comprising the compound of formula (1) and optionally a pharmaceutically acceptable additive, such as a carrier or an excipient.
[0284] 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.
[0285] The adjuvants, diluents, excipients and/or carriers that may be used in the composition of the invention must be pharmaceutically acceptable in the sense of being compatible with the compound of formula (1) and the other ingredients of the pharmaceutical composition, and not deleterious to the recipient thereof. It is preferred that the compositions shall not contain any material that may cause an adverse reaction, such as an allergic reaction. The adjuvants, diluents, excipients and carriers that may be used in the pharmaceutical composition of the invention are well known to a person skilled within the art.
[0286] As mentioned above, the compositions and particularly pharmaceutical compositions as herein disclosed may, in addition to the compounds herein disclosed, further comprise at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier. In some embodiments, the pharmaceutical compositions comprise from 1 to 99% by weight of said at least one pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier and from 1 to 99% by weight of a compound as herein disclosed. The combined amount of the active ingredient and of the pharmaceutically acceptable adjuvant, diluent, excipient and/or carrier may not constitute more than 100% by weight of the composition, particularly the pharmaceutical composition.
[0287] In some embodiments, only one compound as herein disclosed is used for the purposes discussed above.
[0288] In some embodiments, two or more of the compounds as herein disclosed are used in combination for the purposes discussed above.
[0289] 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.
[0290] 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.
[0291] 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.
[0292] 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.
[0293] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.
[0294] 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.
[0295] 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.
[0296] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Unless otherwise stated, all exact values provided herein are representative of corresponding approximate values (e.g., all exact exemplary values provided with respect to a particular factor or measurement can be considered to also pro-vide a corresponding approximate measurement, modified by about, where appropriate).
[0297] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.
[0298] 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.
[0299] 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.
[0300] The term and/or as used herein is intended to mean both alternatives as well as each of the alternatives individually. For instance, the expression xxx and/or yyy means xxx and yyy; xxx; or yyy, all three alternatives are subject to individual embodiments.
[0301] 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).
[0302] The present invention is further illustrated by the following examples that, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realizing the invention in diverse forms thereof.
Experimental Procedures (Evaluation of Kd Values)
[0303] The affinity of Example 1-14 for galectins were determined by a fluorescence anisotropy assay where the compound was used as an inhibitor of the interaction between galectin and a fluorescein tagged saccharide probe as described Srme, P., Kahl-Knutsson, B., Huflejt, M., Nilsson, U. J., and Leffler H. (2004) Fluorescence polarization as an analytical tool to evaluate galectin-ligand interactions. Anal. Biochem. 334: 36-47, (Sarme et al., 2004) and Monovalent interactions of Galectin-1 By Salomonsson, Emma; Larumbe, Amaia; Tejler, Johan; Tullberg, Erik; Rydberg, Hanna; Sundin, Anders; Khabut, Areej; Frejd, Torbjorn; Lobsanov, Yuri D.; Rini, James M.; et al, From Biochemistry (2010), 49(44), 9518-9532, (Salomonsson et al., 2010).
TABLE-US-00001 Galectin- Galectin- 1 3 Example Name Structure Kd (M) Kd (M) 1 3,3-Dideoxy-3-[4- (3,4,5- trifluorophenyl)-1H- 1,2,3-triazol-1-yl]-3- [4-(2-hydroxythiazol- 4-yl)-1H-1,2,3-triazol- 1-yl]-1,1-sulfanediyl- di--D- galactopyranoside
SYNTHESIS OF EXAMPLES AND INTERMEDIATES
General Experimental:
[0304] Nuclear Magnetic Resonance (NMR) spectra were recorded on a 400 MHz Bruker AVANCE III 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 (4.650 mm, 3.5 m) or SunFire C18 (4.650 mm, 3.5 m). 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 2.130 mm C18 or Chromolith RP-18 250 mm. Solvent A water+0.1% TFA and solvent B Acetonitrile+0.1% TFA. Wavelength 254 nm.
[0305] Preparative HPLC was performed on a Gilson 215. Flow: 25 mL/min Column: XBridge prep C18 10 m OBD (19250 mm) column. Wavelength: 254 nM. Solvent A 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.
[0306] The following abbreviations are used [0307] aq: aqueous [0308] Calcd: Calculated [0309] MeCN: Acetonitrile [0310] CuI: Copper Iodide [0311] DCM: Dichloromethane [0312] DIPEA: Diisopropylethylamine [0313] DMF: N,N-dimethylformamide [0314] ESI-MS: Electrospray ionization mass spectrometry [0315] EtOAc or EA: Ethylacetate [0316] Et.sub.3N: Triethylamine [0317] h: hour(s) [0318] HPLC: High performance liquid chromatography [0319] LC: Liquid Chromatography [0320] MeCN: Acetonitrile [0321] mL: milliliter [0322] MeOH: Methanol [0323] MeOD: Deuterated methanol [0324] mm: millimeter [0325] mM: millimolar [0326] MS: Mass spectroscopy [0327] nm: nanometer [0328] NaOMe: Sodium methoxide [0329] N.sub.2: Nitrogen gas [0330] NMR: Nuclear magnetic resonance [0331] PE: petroleum ether [0332] pH: acidity [0333] Prep: preparative [0334] rt: room temperature [0335] TFA: trifluoroacetic acid [0336] THF: Tetrahydrofuran [0337] TMS: Trimethylsilyl [0338] UV: Ultraviolet [0339] : ngstrm
Synthesis of examples 1-5 and 14 from their respective intermediates 1-5.
Synthesis of examples 6-13 are made as described in process steps a1) to a18) above.
Example 1
3,3-Dideoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1,1-sulfanediyl-di--D-galactopyranoside
[0340] ##STR00043##
[0341] To a solution of 1,1-sulfanediyl-bis-(2,4,6-tri-O-acetyl-3-azido-3-deoxy--D-galactopyranoside) (described in van Scherpenzeel, M; Moret, E. E.; Ballell, L.; Liskamp, R. M. J.; Nilsson, U. J.; Leffler, H.; Pieters, R. J. Synthesis and Evaluation of New Thiodigalactoside-Based Chemical Probes to Label Galectin-3. ChemBioChem, 2009, 10, 1724-1733 as well as in PCT/EP2020/067620 filed 24 Jun. 2020) (400 mg, 0.61 mmol), 4-(2-trimethylsilylethynyl)thiazol-2-ol (120 mg, 0.61 mmol) and CuI (24 mg, 0.12 mmol) in MeCN (4 mL) DIPEA (0.14 mL, 0.78 mmol) followed by TBAF (61 L, 1 M in THF, 0.061 mmol) were added and the mixture was stirred 6 h at 50 C. The mixture was purified by chromatography (SiO.sub.2, EtOAc). The obtained material (358 mg) was dissolved together with 3,4,5-trifluorophenylacetylene (156 mg, 0.68 mmol) and CuI (18 mg, 0.09 mmol) in MeCN (5 mL). To the solution DIPEA (0.10 mL, 0.59 mmol) followed by TBAF (50 L, 1 M in THF, 0.050 mmol) were added and the mixture was stirred 6 h at 50 C. The mixture was purified by chromatography (SiO.sub.2, EtOAc). The obtained material (81 mg) was stirred 90 min at rt in MeOH (1.5 mL) and NaOMe (0.25 mL, 1 M). The mixture was purified by chromatography (SiO.sub.2, EtOAc/MeOH) and further purification by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (40 mg, 10%). ESI-MS m/z calcd for [C.sub.25H.sub.26F.sub.3N.sub.7O.sub.9S.sub.2] [M+H].sup.+: 690.1; found: 690.2. .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.56 (s, 1H), 8.40 (s, 1H), 7.66-7.56 (m, 2H), 6.63 (s, 1H), 4.97-4.86 (m, 4H), 4.60 (t, J=10.1 Hz, 1H), 4.55 (t, J=10.1 Hz, 1H), 4.14 (s, 2H), 3.91-3.78 (m, 4H), 3.71 (dd, J=11.2, 4.4 Hz, 2H).
Example 2
3-[4-(4-Chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3,3-dideoxy-3-[4-(2-hydroxythiazol-4-yl)-1H-1,2,3-triazol-1-yl]-1,1-sulfanediyl-di--D-galactopyranoside
[0342] ##STR00044##
[0343] To a solution of 1,1-sulfanediyl-bis-(2,4,6-tri-O-acetyl-3-azido-3-deoxy--D-galactopyranoside) (400 mg, 0.61 mmol), 4-(2-trimethylsilylethynyl)thiazol-2-ol (120 mg, 0.61 mmol), 4-chloro-3,5-difluorophenylacetylene (150 mg, 0.61 mmol) and CuI (24 mg, 0.12 mmol) in MeCN (6 mL) DIPEA (0.14 mL, 0.78 mmol) followed by TBAF (61 L, 1 M in THF, 0.061 mmol) were added and the mixture was stirred 3 h at 50 C. The mixture was partitioned between EtOAc, water and HCl (2 mL, 1 M), and the organic phase was dried and evaporated. The residue was first purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA), then by chromatography (SiO.sub.2, PE/EtOAc). The obtained material (64 mg) was stirred 30 min at rt in MeOH (3.0 mL) and NaOMe (0.5 mL, 1 M). The mixture was purified by chromatography (SiO.sub.2, EtOAc/MeOH) to afford the title compound (43 mg, 10%). ESI-MS m/z calcd for [C.sub.25H.sub.26ClF.sub.2N.sub.7O.sub.9S.sub.2] [M+H].sup.+: 706.1; found: 706.2. .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.61 (s, 1H), 8.41 (s, 1H), 7.62 (d, J=7.9 Hz, 2H), 6.64 (s, 1H), 4.97-4.88 (m, 4H), 4.61 (t, J=10.1 Hz, 1H), 4.56 (t, J=10.1 Hz, 1H), 4.15 (s, 2H), 3.92-3.78 (m, 4H), 3.72 (dd, J=11.3, 4.5 Hz, 2H).
Example 3
3-[4-(2-Aminothiazol-4-yl)-1H-1,2,3-triazol-1-yl]-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3,3-dideoxy-1,1-sulfanediyl-di--D-galactopyranoside
[0344] ##STR00045##
[0345] To a solution of 3-azido-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3,3-dideoxy-1,1-sulfanediyl-di--D-galactopyranoside (32 mg, 0.055 mmol), 4-(2-trimethylsilylethynyl)thiazol-2-amine (16 mg, 0.083 mmol) and CuI (1.1 mg, 0.0055 mmol) in MeCN (0.5 mL) DIPEA (19 L, 0.78 mmol) was added and the mixture was stirred 42 h at 50 C. The mixture was purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (22 mg, 57%). ESI-MS m/z calcd for [C.sub.25H.sub.27ClF.sub.2N.sub.8O.sub.8S.sub.2] [M+H].sup.+: 705.1; found: 705.2. .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.62 (s, 1H), 8.53 (s, 1H), 7.61 (d, J=7.9 Hz, 2H), 7.06 (s, 1H), 4.97-4.89 (m, 4H), 4.67-4.57 (m, 2H), 4.17 (d, J=2.4 Hz, 2H), 3.92-3.79 (m, 4H), 3.72 (dt, J=11.4, 3.7 Hz, 2H).
Example 4
1,1-Sulfanediyl-bis-{3-deoxy-3-[4-(3-fluorophenyl)-1H-1,2-pyrazol-1-yl]--D-galactopyranoside}
[0346] ##STR00046##
[0347] To a solution of 1,1-sulfanediyl-bis-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy--D-galactopyranoside} (85 mg, 0.11 mmol) in EtOH (4 mL) 3-(dimethylamino)-2-(3-fluorophenyl)prop-2-enal (47 mg, 0.25 mmol) and concentrated HCl (0.2 mL) were added and the mixture was stirred 2 h at 80 C. The mixture was evaporated and purified by preparative HPLC (MeCN/H.sub.2O (10 mmol/L NH.sub.4HCO.sub.3), X-Select 10 m 19*250 mm, 20 mL/min, UV 254) to afford the title compound (6.88 mg, 10%). ESI-MS m/z calcd for [C.sub.30H.sub.32F.sub.2N.sub.4O.sub.8S] [M+H].sup.+: 647.2; found: 648.8. .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.25 (s, 2H), 7.90 (s, 2H), 7.42-7.27 (m, 6H), 6.93-6.87 (m, 2H), 4.85 (d, J=9.6 Hz, 2H), 4.66 (t, J=10.0 Hz, 2H), 4.41 (dd, J=10.8, 2.8 Hz, 2H), 4.12 (d, J=2.8 Hz, 2H), 3.87-3.77 (m, 4H), 3.73-3.68 (m, 2H).
Example 5
1,1-Sulfanediyl-bis-{3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2-pyrazol-1-yl]--D-galactopyranoside}
[0348] ##STR00047##
[0349] To a solution of 1,1-sulfanediyl-bis-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy--D-galactopyranoside} (55 mg, 0.072 mmol) in DCM (2 mL) TFA (0.2 mL) was added and the mixture was stirred overnight at rt. The mixture was evaporated and dissolved in EtOH (4 mL). 3-(Dimethylamino)-2-(3,4,5-trifluorophenyl)prop-2-enal (49.6 mg, 0.22 mmol) and concentrated HCl (0.2 mL) were added and the mixture was stirred 2 h at 80 C. The mixture was evaporated and purified by preparative HPLC (MeCN/H.sub.2O (10 mmol/L NH.sub.4HCO.sub.3), X-Select 10 m 19*250 mm, 20 mL/min, UV 254) to afford the title compound (8.08 mg, 16%). ESI-MS m/z calcd for [C.sub.30H.sub.28F.sub.6N.sub.4O.sub.8S] [M+H].sup.+: 719.2; found: 718.8. .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.25 (s, 2H), 7.90 (s, 2H), 7.53-7.20 (m, 4H), 4.85 (d, J=9.6 Hz, 2H), 4.64 (t, J=10.1 Hz, 2H), 4.41 (dd, J=10.4, 2.8 Hz, 2H), 4.11 (d, J=2.8 Hz, 2H), 3.87-3.77 (m, 4H), 3.71 (dd, J=16, 8.8 Hz, 2H).
Examples 6-13 are Made as Described in Process Steps a1) to a18) Above
Example 14
1,1-Sulfanediyl-bis-{3-[4-(4-chloro-2,3-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3-deoxy--D-galactopyranoside}
[0350] ##STR00048##
[0351] To a solution of 1,1-sulfanediyl-bis-(2,4,6-tri-O-acetyl-3-azido-3-deoxy--D-galactopyranoside) (100 mg, 0.15 mmol) and 2-(4-chloro-2,3-difluorophenyl)ethynyltrimethylsilane (77.8 mg, 0.32 mmol) and CuI (2.9 mg, 0.12 mmol) in MeCN (5 mL) DIPEA (0.079 mL, 0.45 mmol) followed by TBAF (15 L, 1 M in THF, 0.015 mmol) were added and the mixture was stirred overnight at 50 C. Additional CuI (2.9 mg, 0.12 mmol) and TBAF (15 L, 1 M in THF, 0.015 mmol) were added and the mixture was stirred 3 h at 50 C. The mixture was diluted with MeOH and water and purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA). The obtained material was stirred overnight at 35 C. in MeOH (5 mL) and NaOMe (60.6 L, 5 M in THF, 0.30 mmol). The mixture was purified by prep HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the title compound (13 mg, 11%). ESI-MS m/z calcd for [C.sub.28H.sub.26Cl.sub.2F.sub.4N.sub.6O.sub.8S] [M+H].sup.+: 753.1; found: 753.0. .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.56 (d, J=3.3 Hz, 2H), 7.90 (s, 2H), 7.40 (s, 2H), 4.99-4.81 (m, 6H), 4.16 (d, J=2.7 Hz, 2H), 3.93-3.81 (m, 4H), 3.72 (dd, J=10.4, 3.0 Hz, 2H).
Intermediate 3
3-Azido-3-[4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl]-3,3-dideoxy-1,1-sulfanediyl-di--D-galactopyranoside
[0352] ##STR00049##
[0353] To a solution of 1,1-sulfanediyl-bis-(2,4,6-tri-O-acetyl-3-azido-3-deoxy--D-galactopyranoside) (1.00 g, 1.51 mmol), 4-chloro-3,5-difluorophenylacetylene (370 mg, 1.51 mmol) and CuI (29 mg, 0.15 mmol) in MeCN (10 mL) DIPEA (0.52 mL, 3.0 mmol) was added and the mixture was stirred 3 h at 50 C. The mixture was partitioned between EtOAc and brine. The organic phase was dried, evaporated, and purified by chromatography (SiO.sub.2, PE/EtOAc). The obtained material (700 mg) was stirred 14 h at rt in MeOH (21 mL) and NaOMe (7 mL, 1 M). The mixture was neutralized with acetic acid, evaporated, and purified by HPLC (C.sub.18, H.sub.2O/MeCN/0.1% TFA) to afford the product (204 mg, 23%). ESI-MS m/z calcd for [C.sub.20H.sub.23ClF.sub.2N.sub.6O.sub.8S] [M+H].sup.+: 581.1; found: 581.2. .sup.1H NMR (400 MHz, Methanol-d.sub.4) 8.58 (s, 1H), 7.61 (d, J=8.1 Hz, 2H), 4.95-4.88 (m, 2H), 4.77 (d, J=9.7 Hz, 1H), 4.44 (t, J=10.1 Hz, 1H), 4.14 (d, J=3.0 Hz, 1H), 4.04-3.97 (m, 2H), 3.90-3.58 (m, 6H), 3.39 (dd, J=9.9, 3.0 Hz, 1H).
Intermediate 4
3-(Dimethylamino)-2-(3-fluorophenyl)prop-2-enal
[0354] ##STR00050##
[0355] To a cooled (0 C.) solution of N,N-dimethylformamide (2134 mg, 29.2 mmol) and phosphoryl trichloride (4029 mg, 26.3 mmol) 2-(3-fluorophenyl)acetic acid (900 mg, 5.84 mmol) was added and the mixture was stirred overnight at 60-70 C. After cooling to rt, the mixture was slowly added to a mixture of ice and water with external cooling and ice intermittently to keep the temperature <10 C. K.sub.2CO.sub.3 was added slowly until pH=11 was achieved. Small quantities of ethanol (2 mL) were added to control frothing. To the alkaline mixture toluene (30 mL) was added, and the mixture was refluxed for 1.5 h and cooled to rt. The aqueous layer was extracted with an additional 40 mL of toluene. The combined organic layers were washed with water, dried using Na.sub.2SO.sub.4 and evaporated. The obtained solid was recrystallized from hexane to give the product (560 mg, 50%). ESI-MS m/z calcd for [C.sub.11H.sub.12FNO] [M+H].sup.+: 194.1; found: 194.2. .sup.1H NMR (400 MHz, Chloroform-d) 9.02 (s, 1H), 7.26-7.21 (m, 1H), 6.96-6.66 (m, 4H), 2.80 (s, 6H).
1,1-Sulfanediyl-bis-(3-azido-3-deoxy--D-galactopyranoside)
[0356] ##STR00051##
[0357] To a solution of 1,1-sulfanediyl-bis-(2,4,6-tri-O-acetyl-3-azido-3-deoxy--D-galactopyranoside) (800 mg, 1.21 mmol) in MeOH (10 mL) NaOMe (65.4 mg, 1.21 mmol) was added and the mixture was stirred 2 h at rt. The mixture was evaporated and purified by chromatography (MeOH/DCM=0/11/3, Silica-CS 20 g, 25 mL/min, silica gel, UV 254) to afford the product (280 mg, 57%). .sup.1H NMR (400 MHz, Methanol-d.sub.4) 4.71 (d, J=9.6 Hz, 2H), 3.93 (d, J=2.4 Hz, 2H), 3.83 (t, J=9.8 Hz, 2H), 3.73 (dd, J=11.6, 7.2 Hz, 2H), 3.63 (dd, J=11.6, 4.8 Hz, 2H), 3.58-3.53 (m, 2H), 3.34 (dd, J=10.0, 2.8 Hz, 2H).
1,1-Sulfanediyl-bis-(3-azido-4,6-O-benzylidene-3-deoxy--D-galactopyranoside)
[0358] ##STR00052##
[0359] To a solution of 1,1-sulfanediyl-bis-(3-azido-3-deoxy--D-galactopyranoside) (410 mg, 1.00 mmol) in DMF (3 mL) benzaldehyde dimethylacetal (489 mg, 3.21 mmol) and D(+)-10-camphorsulfonic acid (70 mg, 0.30 mmol) were added and the mixture was stirred 3 h at 60 C. The mixture was evaporated and purified by chromatography (DCM/EtOAc=10/13/2, Silica-CS 12 g, 20 mL/min, silica gel, UV 254) to afford the product (300 mg, 51%). ESI-MS m/z calcd for [C.sub.26H.sub.28N.sub.6O.sub.8S] [M+NH.sub.4].sup.+: 602.2; found: 602.2. .sup.1H NMR (400 MHz, Chloroform-d) 7.50-7.39 (m, 4H), 7.25-7.16 (m, 6H), 5.51 (s, 2H), 4.55 (td, J=9.6, 3.6 Hz, 2H), 4.44 (d, J=9.6 Hz, 2H), 4.31 (dd, J=12.6, 1.4 Hz, 2H), 4.21 (d, J=3.2 Hz, 2H), 4.03 (dd, J=12.8, 1.6 Hz, 2H), 3.58-3.49 (m, 4H), 3.42 (d, J=3.6 Hz, 2H).
1,1-Sulfanediyl-bis-(3-amino-4,6-O-benzylidene-3-deoxy--D-galactopyranoside)
[0360] ##STR00053##
[0361] To a solution of 1,1-sulfanediyl-bis-(3-azido-4,6-O-benzylidene-3-deoxy--D-galactopyranoside) (300 mg, 0.51 mmol) in THF (10 mL) and water (2 mL) triphenylphosphine (1.01 g, 4.11 mmol) was added and the mixture was stirred overnight at 50 C. The was evaporated and purified by column chromatography (MeOH/DCM=0/12/3, Silica-CS 12 g, 20 m/min, silica gel, UV 254) to the product (220 mg, 81%). ESI-MS m/z calcd for [C.sub.26H.sub.32N.sub.2O.sub.8S] [M+H].sup.+: 533.2; found: 533.0. .sup.1H NMR (400 MHz, Chloroform-d) 7.41-7.35 (m, 4H), 7.33-7.23 (m, 6H), 5.51 (s, 2H), 4.31 (d, J=9.6 Hz, 2H), 4.27 (d, J=12.4, 2H), 4.16 (t, J=10.2 Hz, 2H), 4.13-4.09 (m, 2H), 4.02 (d, J=11.6 Hz, 2H), 3.51 (s, 2H), 2.64 (dd, J=9.6, 2.8 Hz, 2H).
1,1-Sulfanediyl-bis-{4,6-O-benzylidene-3-[(2-tert-butoxycarbonyl)hydrazinyl]-3-deoxy--D-galactopyranoside}
[0362] ##STR00054##
[0363] To a solution of 1,1-sulfanediyl-bis-(3-amino-4,6-O-benzylidene-3-deoxy--D-galactopyranoside) (220 mg, 0.41 mmol) in DCM (5 mL) tert-butyl 3-(4-cyanophenyl)oxaziridine-2-carboxylate (224 mg, 0.91 mmol) was added and the mixture was stirred overnight at rt. The was evaporated and purified by column chromatography (MeOH/DCM=0/11/5, Silica-CS 12 g, 20 m/min, silica gel, UV 254) to give the product (180 mg, 57%). ESI-MS m/z calcd for [C.sub.36H.sub.50N.sub.4O.sub.12S] [M+H].sup.+: 763.3; found: 763.0. .sup.1H NMR (400 MHz, Chloroform-d) 7.41-7.09 (m, 10H), 6.60 (s, 2H), 5.48 (s, 2H), 4.48-4.45 (m, 2H), 4.38-4.31 (m, 4H), 4.27 (d, J=12.4 Hz, 2H), 4.02 (d, J=11.6 Hz, 2H), 3.55-3.45 (m, 6H), 2.86 (t, J=8.0 Hz, 2H), 1.47 (s, 18H).
Intermediate 5
3-(Dimethylamino)-2-(3,4,5-trifluorophenyl)prop-2-enal
[0364] ##STR00055##
[0365] To a cooled (0 C.) solution of N,N-dimethylformamide (913 mg, 12.5 mmol) and phosphoryl trichloride (1724 mg, 11.2 mmol) 2-(3,4,5-trifluorophenyl)acetic acid (475 mg, 2.50 mmol) was added and the mixture was stirred overnight at 60-70 C. After cooling to rt, the mixture was slowly added to a mixture of ice and water with external cooling and ice intermittently to keep the temperature <10 C. K.sub.2CO.sub.3 was added slowly until pH=11 was achieved. Small quantities of ethanol were added to control frothing. To the alkaline mixture toluene (10 mL) was added, and the mixture was refluxed for 1.5 h and cooled to rt. The aqueous layer was extracted with an additional 20 mL of toluene. The combined organic layers were washed with water, dried using Na.sub.2SO.sub.4 and evaporated. The obtained solid was recrystallized from hexane to give the product (320 mg, 56%). ESI-MS m/z calcd for [C.sub.11H.sub.10F.sub.3NO] [M+H].sup.+: 230.1; found: 230.1. .sup.1H NMR (400 MHz, Chloroform-d) 9.05 (s, 1H), 6.91 (s, 1H), 6.82 (dd, J=8.2, 6.6 Hz, 2H), 2.91 (s, 6H).
REFERENCES
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