Small molecule inhibitor of galectin-3

Abstract

The present disclosure relates to compounds of Formula (I) or Formula (II) that inhibit Gal-3, including pharmaceutically acceptable salts, compositions containing such compounds, and methods of using and making such compounds and compositions. TIFF2023524996000042.tif39153

Description

Technical Field

[0001] (Cross - reference to Related Applications) This application claims priority to U.S. Provisional Application No. 63 / 020,041, filed May 5, 2020, the entire contents of which are incorporated herein by reference.

Background Art

[0002] Galectin - 3 (Gal - 3) is a β - galactoside - binding lectin of approximately 30 kDa (Cell 76: 597 - 598) and is involved in the regulation of the inflammatory and fibrotic processes (Immunological Reviews 230: 160 - 171). In states where inflammation and fibrosis are not controlled, Gal - 3 promotes fibroblast proliferation and transformation and mediates collagen production (Circulation 110: 3121 - 3128).

[0003] Gal-3 localizes to many cellular compartments, such as the cytoplasm, nucleus, and cell surface. Gal-3 is also secreted into the bloodstream from various cells, primarily macrophages and monocytes (J Pharmacol Exp Ther 351:336-343). There is multiple evidence in the literature supporting the involvement of Gal-3 in the progression of fibrosis in numerous organs, such as the lung (Am J. Respir. Crit. Care Med. 185: 537-546), liver (PNAS 103:5060-5065), and kidney (Am. J. Pathol. 172:288-298). Gal-3 is also known as a biomarker for heart failure, and it has been shown that the regulation of Gal-3 may be exploitable for the treatment of heart failure (Curr. Heart Fail. Rep. 7:1-8). Since Gal-3 is involved in cell growth and differentiation, which play important roles in angiogenesis, apoptosis pathways, and metastasis pathways (Galectin-3C: Human Lectin for Treatment of Cancer. ACS Symposium Series, Vol. 1115. Chapter 12, 195-23), the regulation of Gal-3 can be used in the treatment of cancer. In recent years, it has been demonstrated that the use of Gal-3 inhibitors in combination with immunotherapy yields favorable effects (Galectin Therapeutics. Press Release, February 7, 2017).

[0004] Multiple documents and patent applications describe synthetic inhibitors of Gal-3 that have been studied as anti-fibrotic agents. Recent examples of such studies include WO2005113568, WO2005113569, WO2014067986, WO2017080973, WO2016120403, US20140099319, and WO2018209255.

[0005] (Details of the Invention) The present disclosure relates to compounds of the invention that inhibit Gal-3, and includes pharmaceutically acceptable salts, compositions comprising the compounds, and methods of use and manufacture of the compounds and compositions.

[0006] In a first aspect, the invention relates, inter alia, to formula (I) or formula (II):

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chemical formula

[0007] In a second aspect within the scope of the first aspect, in the formula, X is -C(O)-; and Ar 1 is phenyl substituted with 1 to 3 halogens.

[0008] In another aspect within the scope of the first or second aspect, in the formula, Ar 1 is phenyl substituted with 1 to 3 Fs.

[0009] In another aspect within the scope of the first or second aspect, the compound is of formula (I).

[0010] In another aspect within the scope of the first or second aspect, the compound is of formula (II).

[0011] In a third aspect within the scope of the first or second aspect, in the formula, R 3 is independently C 5-6 cycloalkyl or hetero-cycloalkyl containing 4 to 6 ring atoms, wherein 1 to 2 of the ring atoms are each independently N(R 5B ), N(R 5E ), and O; where the ring moiety is each 0 to 1 R5 and one R 5A is replaced by

[0012] In a fourth embodiment within the scope of the first to third embodiments, in the formula R 3 is independently H,

Chemical formula

[0013] In a fifth embodiment within the scope of the first to fourth embodiments, in the formula R 3 is independently

Chemical formula

[0014] In a sixth embodiment within the scope of the first to fourth embodiments, in the formula R 3 is independently

Chemical formula

[0015] In another embodiment within the scope of the first to fourth embodiments, in the formula R 3 is independently

Chemical formula

[0016] In a seventh embodiment within the scope of the first to fourth embodiments, in the formula R 1 is independently H or C 1-4 alkyl; and R 2 is independently H, C 1-4 alkyl substituted with 0 to 1 OH, C 1-4 haloalkyl, -(CH2) 0-1-Cyclopropyl, and -CH2-(phenyl substituted with 0 to 2 halogens), are selected from.

[0017] In an eighth aspect within the scope of the first to fifth aspects, in the formula, R 1 is independently H or CH3; and R 2 is independently selected from H, CH3, -CH2CH3, -CH2CH2OH, -CH2CHF2, cyclopropyl and cyclopropylmethyl.

[0018] In another aspect within the scope of the first to sixth aspects, in the formula, R 1 is H.

[0019] In another aspect within the scope of the first to sixth aspects, in the formula, R 1 is CH3.

[0020] In another aspect, the present invention provides a compound selected from the exemplified examples or pharmaceutically acceptable salts thereof.

[0021] In another aspect, the present invention provides a compound selected from the exemplified examples or pharmaceutically acceptable salts thereof.

[0022] Unless otherwise specified, the above terms have the following meanings. "Alkyl" means a straight or branched chain alkyl group having 1 to 6 carbons. "Cycloalkyl" means a monocyclic ring having 3 to 7 carbons. Terms for hydrocarbon moieties (e.g., alkoxy) include straight and branched chain isomers of hydrocarbon moieties having 1 to 6 carbons. "Halo" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" and "haloalkoxy" include all halogenated isomers from monohalogen to perhalogen. "Aryl" means a monocyclic or bicyclic aromatic ring system having 5 to 12 carbon atoms, where one or both rings are aromatic. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. "Heteroaryl" means a 5- to 7-membered monocyclic or 8- to 11-membered bicyclic aromatic ring system having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. When the bonding position is not specified, bonding can occur at any appropriate position understood by one skilled in the art. Combinations of substituents and bonding patterns are only those that result in stable compounds understood by one skilled in the art. Terms enclosed in parentheses and multiple parentheses are intended to clarify the bonding relationship for those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.

[0023] The present invention includes all pharmaceutically acceptable salt forms of the compound. A pharmaceutically acceptable salt is one in which the counterion does not significantly contribute to the biological activity or toxicity of the compound and thus functions as a pharmacological equivalent. These salts can be prepared according to general organic chemical techniques using commercially available reagents. As part of the anionic salt forms, there are acetate, ascorbate, besylate, bromide salt, chloride salt, citrate, fumarate, glucuronate, hydrobromide salt, hydrochloride salt, hydroiodide salt, iodide salt, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinafoate. As part of the cationic salt forms, there are ammonium salt, aluminum salt, benzathine salt, bismuth salt, calcium salt, choline salt, diethylamine salt, diethanolamine salt, lithium salt, magnesium salt, meglumine salt, 4-phenylcyclohexylamine salt, piperazine salt, potassium salt, sodium salt, tromethamine salt, and zinc salt.

[0024] Some of the compounds of the present invention exist in the form of stereoisomers. The present invention encompasses all stereoisomeric forms of the compound, including enantiomers and diastereomers. Methods for manufacturing and separating stereoisomers are known in the art. The present invention includes all tautomeric forms of the compound. The present invention includes atropisomers and rotational isomers.

[0025] The present invention is intended to include all isotopes of the atoms contained in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. General examples, but not limited to, include deuterium and tritium as isotopes of hydrogen. Isotopes of carbon include 13 C and 14C is included. The compounds of the present invention labeled with isotopes can be produced by using appropriate isotope-labeled reagents in place of the unlabeled reagents used otherwise, by conventional techniques generally known to those skilled in the art or by methods similar to those described herein. Such compounds can have various potential uses, for example, as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds can have the ability to advantageously modify biological, pharmacological, or pharmacokinetic properties.

[0026] Biological methods Gal-3 HTRF assay Assay buffer composition: Prepared by adding 25 mM HEPES, 100 mM NaCl, 0.005% Tween 20, and 0.05% BSA (all reagents purchased from Sigma) to sterile water Control: Positive control: 100% DMSO (1 μL) + His-tag hGal-3 (20 μL) + B-ASF (20 μL) + anti-His terbium antibody (5 μL) + Strep d2 antibody (5 μL) Negative control: 100% DMSO (1 μL) + His-tag hGal-3 (20 μL) + anti-His terbium antibody (5 μL) + Strep d2 antibody (5 μL)

Table 1

[0027] Gal-3 ELISA assay Items to be used: 1. Coating buffer: Phosphate Buffered Saline (1x) - PBS This solution was prepared by dissolving one pack of PBS (catalog number: P3813 - 5x10Pak) purchased from Sigma Aldrich in 1 L of Milli-Q water. 2. Asialofetuin: Derived from fetal bovine serum, type II, Sigma Aldrich (catalog number: A1908 - 50MG) 3. Fetal bovine serum: Invitrogen (Catalog number: 26400-044-500mL) 4. Tween-20: Sigma Aldrich (Catalog number: P1379-250mL) 5. OptEIA enzyme reagent streptavidin-HRP: BD (Catalog number: 554066) 6. Sulfuric acid: Sigma Aldrich (Catalog number: 25,810-5) 7. Paraformaldehyde: Sigma Aldrich (Catalog number: P6148-500G) 8. TMB substrate: BD Biosciences (Catalog number: 555214) 9. Biotinylated hGal-3-A 0.82mg / mL stock solution (28.6 kDa, 28.6713 μM): Synthesized in-house by the Proteomics Group This solution was used for titration. 10. TD-139 (EXT-001109-01-001): Low-molecular-weight synthesized in-house This was used as an internal standard for low-molecular-weight screening in the hGal-3 normalization binding assay.

[0028] A. Protocol a. Plate coating: ASF at a concentration of 15 nM was prepared in 1xPBS and injected into a 96-well flat-bottomed Nunc plate (Nunc Immunoplate, Maxisorp, Catalog number: 439454) according to the plate map. After sealing with a top seal, it was incubated overnight at 4°C. b. Plate fixation and blocking: On the day of the assay, the coating solution was removed, 100 μL of 2% paraformaldehyde solution was added to the plate for fixation, and it was incubated at 37 °C for 30 minutes. It was washed three times with 300 μL of washing buffer (PBS containing 0.05% Tween-20), dehydrated and dried, and then moved to blocking. The plate was blocked with 10% FBS and incubated at room temperature for 1 hour. Then, the plate was washed three times with 300 μL of washing buffer (PBS containing 0.05% Tween-20).

[0029] B. Incubation: After the washed plate was dehydrated and dried, 100 μL of the test compound was added to the plate at various concentrations specified in the plate map (human galectin-3 (hGal-3) or mouse galectin-3 (mGal-3) at a concentration of 15 nM that had been pre-incubated at room temperature for 1 hour). This was performed on multiple plates to ensure the accuracy and reproducibility of the data. These plates were incubated at room temperature for 1 hour, washed five times with the washing buffer, dehydrated and dried, 100 μL of streptavidin HRP (1:1000 dilution) was added, incubated at room temperature for 1 hour, and washed seven times with the washing buffer.

[0030] C. Detection: After the washed plate was dehydrated and dried, 100 μL of TMB substrate was added to each well and incubated at room temperature for 15 minutes. Then, the reaction was stopped with 2N sulfuric acid, and the plate was read with SpectraMax (450 nm).

[0031] Results: After normalization with the control average value, the output value (OD) obtained for the control wells was plotted, and the common logarithm value (Log IC 50 ) of the 50% inhibitory concentration of the program compound was analyzed.

[0032] Summary: The IC of the program compound 50Values were shown in the report (attached in Excel format by compilation of Curve master). On control plate TD-139, the IC 50 values of hGal-3 and mGal-3 were 10.3 nM and 108.12 nM, respectively. The same was plotted on a semi-logarithmic graph.

[0033] (Pharmaceutical Compositions and Methods of Use) The compounds of the present invention inhibit Gal-3. Accordingly, another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0034] Another aspect of the present invention is fibrosis of organs (such as the liver, kidney, lung, heart and skin), liver diseases and conditions (such as acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis, portal hypertension, hepatic regeneration failure, non-alcoholic steatohepatitis (NASH), decreased liver function, and hepatic blood flow disorder), cell proliferative diseases, and cancer diseases (such as solid tumors, solid tumor metastases, angiofibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL) and metastasis of cancer cells Infiltration (), inflammatory diseases and conditions (such as psoriasis, nephrosis, and pneumonia), gastrointestinal diseases and conditions (such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and abnormal pancreatic juice secretion), kidney diseases and conditions, urinary tract-related diseases and conditions (such as benign prostatic hyperplasia, or neurogenic bladder-related diseases, spinal cord tumors, intervertebral disc herniation, spinal canal stenosis, and diabetes-related symptoms), lower urinary tract diseases and conditions (such as lower urinary tract obstruction), lower urinary tract inflammatory diseases and conditions (such as micturition disorders and frequency of urination), pancreatic diseases and conditions, angiogenesis abnormality-related diseases and conditions (such as arteriosclerosis obliterans), scleroderma, brain-related diseases and conditions (such as cerebral infarction and cerebral hemorrhage), neuropathic pain and peripheral neuropathy, eye diseases and conditions (such as age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scar). A method for treating a patient suffering from a disease or condition selected therefrom with a compound of the present invention.

[0035] Another aspect of the present invention is a method for treating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, and systemic sclerosis, which comprises administering a compound of the present invention to a patient.

[0036] Another aspect of the present invention is a method for treating fibrosis of organs (such as the liver, kidney, lung, heart, and skin), which comprises administering a compound of the present invention to a patient.

[0037] Another aspect of the present invention is a method for treating liver diseases and conditions (such as acute hepatitis, chronic hepatitis, hepatic fibrosis, liver cirrhosis, portal hypertension, hepatic regeneration failure, non-alcoholic steatohepatitis (NASH), liver dysfunction, and hepatic blood flow disorder), which comprises administering a compound of the present invention to a patient.

[0038] Another aspect of the present invention is a method for treating cell proliferative diseases and cancer diseases (such as solid tumors, metastasis of solid tumors, angiofibroma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL), and metastasis of cancer cells Infiltration ), which comprises administering a compound of the present invention to a patient.

[0039] Another aspect of the present invention is a method for treating inflammatory diseases and conditions (such as psoriasis, nephritis, and pneumonia), which comprises administering a compound of the present invention to a patient.

[0040] Another aspect of the present invention is a method for treating diseases and conditions of the digestive tract (such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and pancreatic secretion abnormalities), which comprises administering a compound of the present invention to a patient.

[0041] Another aspect of the present invention is a method for treating kidney diseases and conditions, which comprises administering a compound of the present invention to a patient.

[0042] Another aspect of the present invention is a method for treating urologic-related diseases and conditions (such as benign prostatic hyperplasia, or neurogenic bladder, spinal cord tumors, herniated discs, symptoms related to spinal stenosis, and symptoms resulting from diabetes), which comprises administering a compound of the present invention to a patient.

[0043] Another aspect of the present invention is a method for treating lower urinary tract diseases and conditions (such as lower urinary tract obstruction), and inflammatory diseases and conditions of the lower urinary tract (such as micturition disorders and frequency of urination), which comprises administering a compound of the present invention to a patient.

[0044] Another aspect of the present invention is a method for treating pancreatic diseases and conditions, which comprises administering a compound of the present invention to a patient.

[0045] Another aspect of the present invention is a method for treating diseases and conditions associated with abnormal angiogenesis (such as arteriosclerosis obliterans), which comprises administering a compound of the present invention to a patient.

[0046] Another aspect of the present invention is a method for treating brain-related diseases and conditions (such as cerebral infarction and cerebral hemorrhage), which comprises administering a compound of the present invention to a patient.

[0047] Another aspect of the present invention is a method for treating neuropathic pain and peripheral neuropathy, which comprises administering a compound of the present invention to a patient.

[0048] Another aspect of the present invention is a method for treating eye diseases and conditions (such as age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scars), which comprises administering a compound of the present invention to a patient.

[0049] The compounds of the present invention can be used for the treatment and / or prevention of conditions related to Gal-3.

[0050] The compounds of the present invention can be used in the manufacture of a medicament for the treatment and / or prevention of a medical condition in which the suppression of the biological activity of Gal-3 is useful (for example, a disease involving the Gal-3 receptor), a medical condition in which the suppression of the biological activity of Gal-3 is involved in the etiology or pathology of the disease, or is associated with at least one symptom of the disease.

[0051] The compounds of the present invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one or two other agents.

[0052] "Therapeutically effective amount" means the amount of the agent necessary to provide a significant improvement understood by an expert in the field of pain to a patient.

[0053] "Patient" means a person suffering from pain and a person understood by an expert in the field to be suitable for treatment.

[0054] "Treatment", "therapy", "regimen", and related terms understood by an expert in this field are used.

[0055] The compounds of the present invention are generally provided as a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and may contain conventional excipients. A therapeutically effective amount is the amount necessary to obtain a significant improvement in a patient. A pharmaceutically acceptable carrier is a conventionally known carrier having an acceptable safety profile. The compositions include all common solid and liquid forms (such as capsules, tablets, lozenges, and powders as well as liquid suspensions, syrups, elixirs, and solutions, etc.). The compositions are manufactured using common formulation techniques, and conventional excipients (such as binders and wetting agents) and vehicles (such as water and alcohol) are generally used in the compositions. See, for example, Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA (1985).

[0056] Solid compositions are preferably formulated in dosage units and compositions having from about 1 to 1000 mg of active ingredient per dosage. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other antiretroviral drugs are present in a similar unit range to those of the types of drugs clinically used. It is generally 0.25 to 1000 mg / unit.

[0057] Liquid compositions are usually present in unit dosage ranges. Generally, liquid compositions can be in a dosage unit range of 1 to 100 mg / mL. Some examples of dosages are 1 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, and 100 mg / mL.

[0058] The present invention encompasses all conventional methods of administration, although oral and parenteral methods are preferred. Generally, the dosing regimen is similar to that of other drugs clinically used. Generally, the daily dose is 1 - 100 mg / kg (body weight). Generally, compounds are sought that are more oral and less parenteral. However, the specific dosing regimen is determined by the physician in accordance with ordinary medical judgment.

[0059] (Chemical method) It will be apparent to those skilled in the art that the present disclosure is not limited to the foregoing examples and can be embodied in other specific forms without departing from the essential characteristics of the present disclosure. Therefore, the examples are to be considered in all respects as illustrative rather than restrictive, and rather than the foregoing examples, should be considered as a reference for the present claims, and accordingly, all changes within the meaning and equivalent scope of the claims are intended to be included.

[0060] (Section A) LCMS analysis was performed using a Waters Acquity UPLC system equipped with Waters TUV and SQ mass spectrometers (column: BEH C18 2.1x50mm; mobile phase A: 0.05% aqueous TFA solution; mobile phase B: acetonitrile (containing 0.05% TFA); gradient: elution with 2 - 98% B over 1.6 minutes; flow rate: 0.8 mL / min). HPLC analysis was carried out using a Shimadzu LC10 - AT HPLC system equipped with an SPD - 10AV UV detector (column: YMC S5 Combiscreen ODS 4.6x50mm; mobile phase A: 5:95 acetonitrile: water (containing 0.1% TFA); mobile phase B: 95:5 acetonitrile: water (containing 0.1% TFA); gradient: elution with 0 - 100% B over 40 minutes, followed by elution with 100% B for 1 minute; flow rate: 1 mL / min). Preparative HPLC purification was performed using a Shimadzu LC - 8 preparative HPLC system equipped with an SPD 20 UV detector. Detailed conditions are described in the experimental method.

[0061] Manufacturing method For the analytical LC - MS / HPLC retention times reported for each example and intermediate, one of the following general analytical LCMS / HPLC conditions is used. LCMS conditions: Method A: Column: Ascentis Express C18 (50x2.1mm), 2.7μm; Mobile phase A: 5:95 Acetonitrile: water (containing 10 mM NH4OAc); Mobile phase B: 95:5 acetonitrile: water (containing 10 mM NH4OAc); Temperature: 50°C; Gradient: elution with 0 - 100% B over 3 minutes Method B: Column: Ascentis Express C18 (50x2.1mm), 2.7μm; Mobile phase A: 5:95 acetonitrile: water (containing 0.1% TFA); Mobile phase B: 95:5 acetonitrile: water (containing 0.1% TFA); Temperature: 50°C; Gradient: elution with 0 - 100% B over 3 minutes; Flow rate: 1.1 mL / min Method C: Column: KINETEX-XB-C18 (75 X 3mm, 2.6μm); Mobile phase A: 10mM NH4COOH aqueous solution:ACN (98:02); Mobile phase B: 10mM NH4COOH aqueous solution:ACN (02:98); Gradient = 20~100%B eluted over 4 minutes; Flow rate: 1.1mL / min; Detection: UV(254nm) Method D: Column: Waters Acquity UPLC BEH C18 (2.1 x 50 mm), 1.7μ; Mobile phase A: 0.1%TFA aqueous solution; Mobile phase B: 0.1%TFA / ACN; Gradient = 20~90%B eluted over 1.1 minutes, then eluted at 90%B for 0.6 minutes; Temperature: 50℃; Flow rate: 0.7mL / min; Detection: UV(220nm) Method E: Column: Waters Acquity UPLC BEH C18 (2.1 x 50 mm), 1.7μ, Mobile phase A: 5mM NH4OAc: acetonitrile (95:5); Mobile phase B: 5mM NH4OAc:ACN (5:95), Gradient = 20~90%B eluted over 1.1 minutes, then eluted at 90%B for 0.6 minutes; Temperature: 50℃; Flow rate: 0.7mL / min; Detection: UV(220nm) Method F: Column: ZORBAX SB-C18 (50 X 4.6mm, 5.0μm); Mobile phase A: 10mM NH4COOH aqueous solution:ACN (98:02); Mobile phase B : 10mM NH4COOH aqueous solution:ACN (02:98); Gradient = 30~100%B eluted over 4 minutes; Flow rate: 1.5mL / min; Detection: UV(254nm)

[0062] Preparative HPLC conditions Method A: Column: Waters XBridge C18, 19 x 150mm, particle size: 5μm; Mobile phase A: 10mM NH4OAc; Mobile phase B: acetonitrile; Gradient: 15~50% eluted with B over 20 minutes, then eluted at 100%B for 5 minutes; Flow rate: 15mL / min Method B: Column: Inertsil ODS (250*19) mm, particle size: 5 μm; Mobile phase A: 10 mM NH4OAc (pH 4.5); Mobile phase B: ACN; Gradient: Elute at 30 - 50% B over 27 minutes, then elute at 100% B for 5 minutes; Flow rate: 17 mL / min Method C: Column: Symmetry C8 (300 mm x 19 mm), particle size: 7 μm; Mobile phase A: 10 mM NH4OAc (pH 4.5); Mobile phase B: ACN; Gradient: Elute at 50 - 70% B over 24 minutes, then elute at 100% B for 5 minutes; Flow rate: 17 mL / min Method D: Column: Inertsil ODS (250*19) mm, particle size: 5 μm; Mobile phase A: 10 mM NH4OAc (pH 4.5); Mobile phase B: ACN; Gradient: Elute at 25 - 60% B over 20 minutes, then elute at 100% B for 5 minutes; Flow rate: 30 mL / min Method E: Column: Lux-cellulose C4 (250 X 21.2) mm, particle size: 5 μm; Mobile phase A: 0.1% DEA / MeOH; Gradient: Elute at 100% A over 20 minutes, then elute at 100% B for 5 minutes; Flow rate: 19 mL / min Method F: Column: Lux-cellulose C2 (250 X 21.2) mm, particle size: 5 μm; Mobile phase A: 10 mM ammonium formate; Mobile phase B: ACN:MeOH (1:1); Gradient: Elute at 80% B over 20 minutes, then elute at 100% B for 5 minutes; Flow rate: 19 mL / min

[0063] Synthesis of carboxylic acid intermediate:

Chemical formula

[0064] Step 1: Synthesis of (2R,3R,4S,5R,6R)-methyl 3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-carboxylate Synthesized from β-D-galactose pentaacetate according to the method in the literature (Literature: Synthesis, 2007, 6, 845 - 852 and the references cited herein).

[0065] Step 2: Synthesis of (2S,4aR,6R,7R,8R,8aR)-methyl 7,8-dihydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate p-Toluenesulfonic acid monohydrate (1.199 g, 6.30 mmol) was added to a stirred suspension of (2R,3R,4S,5R,6R)-methyl 3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-carboxylate (29 g, 90 mmol) and benzaldehyde dimethyl acetal (33.8 mL, 225 mmol) / acetonitrile (563 mL) at room temperature under an Ar atmosphere. The mixture was degassed three times with Ar and sonicated for 2 minutes. The reaction mixture was then stirred at room temperature for 4 hours, quenched with TEA (5.77 mL, 41.4 mmol), and stirred for 10 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. This was purified by silica gel chromatography (50 - 100% EtOAc / n-hexane) to give the title compound (16.3 g, 52.5 mmol, 58%) as a white solid. 1 H NMR (400 MHz, chloroform-d): δ 7.53 - 7.49 (m, 2H), 7.40 - 7.36 (m, 3H), 5.57 (s, 1H), 4.39 (dd, J = 12.5, 1.5 Hz, 1H), 4.28 (dd, J = 4.0, 1.0 Hz, 1H), 4.15 - 4.05 (m, 2H), 3.87 - 3.84 (m, 4H), 3.73 (td, J = 9.0, 4.0 Hz, 1H), 3.56 (q, J = 1.5 Hz, 1H), 3.24 (d, J = 2.5 Hz, 1H), 2.63 (d, J = 8.5 Hz, 1H)

[0066] Step 3: Synthesis of (2S,4aR,6R,7S,8S,8aS)-methyl 7-acetoxy-2-phenyl-8-(((trifluoromethyl)sulfonyl)oxy)hexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (2S,4aR,6R,7R,8R,8aR)-methyl 7,8-dihydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (17.3 g, 55.8 mmol) / DCM (180 mL) solution was added with pyridine (18.04 mL, 223 mmol) at -15 °C, and the mixture was stirred for 10 minutes. Triflic anhydride (8.48 mL, 50.2 mmol) was added dropwise over 15 minutes under an argon atmosphere, and the mixture was stirred at -15 °C for 1 hour. This reaction mixture was allowed to return to room temperature over 2 hours, acetyl chloride (4.76 mL, 66.9 mmol) was added at 0 °C, the temperature was raised to room temperature, and the mixture was stirred for 10 hours. DCM (300 mL) was added, and the solution was washed with 0.7N HCl (150 mL), saturated sodium bicarbonate (2 x 100 mL) and brine. The organic layer was separated and dried over sodium sulfate. The solvent was removed under reduced pressure and purified by silica gel chromatography (30 - 80% EtOAc / n-hexane) to obtain the title compound as a white solid (14 g, 28.9 mmol, 52%); 1 H NMR (400 MHz, chloroform-d): δ 7.53 (dd, J = 7.4, 2.1 Hz, 2H), 7.44 - 7.36 (m, 3H), 5.64 (d, J = 9.9 Hz, 1H), 5.60 (s, 1H), 5.00 (dd, J = 9.9, 3.6 Hz, 1H), 4.53 (d, J = 3.6 Hz, 1H), 4.42 (dd, J = 12.8, 1.5 Hz, 1H), 4.08 (dd, J = 12.8, 1.5 Hz, 1H), 4.03 (d, J = 9.9 Hz, 1H), 3.77 (s, 3H), 3.59 (d, J = 1.0 Hz, 1H), 2.10 (s, 3H)

[0067] Step 4: Synthesis of (2S,4aR,6R,7R,8R,8aR)-methyl-7-acetoxy-8-hydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (2S,4aR,6R,7S,8S,8aS)-methyl-7-acetoxy-2-phenyl-8-(((trifluoromethyl)sulfonyl)oxy)hexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (32 g, 66.1 mmol) / DMF (320 mL) solution was added tetrabutylammonium nitrate (50.3 g, 165 mmol), replaced twice with argon, and the mixture was heated at 50 °C for 6 hours. Then the reaction mixture was diluted with EtOAc (500 mL), washed with water (4 x 200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (60 - 100% EtOAc / n-hexane) to give the title compound as a yellow solid (15 g, 42.6 mmol, 64%); 1 H NMR (400 MHz, chloroform-d): δ 7.55 - 7.51 (m, 2H), 7.42 - 7.36 (m, 3H), 5.55 (s, 1H), 5.39 (dd, J = 10.3, 2.8 Hz, 1H), 4.45 (d, J = 10.3 Hz, 1H), 4.37 (dd, J = 12.8, 1.5 Hz, 1H), 4.23 (t, J = 3.1 Hz, 1H), 4.16 - 4.13 (m, 1H), 4.05 (dd, J = 12.8, 2.0 Hz, 1H), 3.79 (d, J = 1.5 Hz, 1H), 3.75 (s, 3H), 2.10 (s, 3H)

[0068] Step 5: Synthesis of (2S,4aR,6R,7S,8R,8aS)-methyl-7-acetoxy-2-phenyl-8-(((trifluoromethyl)sulfonyl)oxy)hexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate A solution of (2S,4aR,6R,7R,8R,8aR)-methyl 7-acetoxy-8-hydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (2.3 g, 6.53 mmol) in DCM (20 mL) was added pyridine (2.112 mL, 26.1 mmol), and the mixture was cooled to -15 °C. Subsequently, triflic anhydride (1.654 mL, 9.79 mmol) was added dropwise under an argon atmosphere, and the mixture was stirred at -15 °C for 1 h. The reaction mixture was warmed to room temperature and stirred for 2 h. Then the reaction mixture was diluted with DCM (200 mL) and washed with 0.7 N hydrochloric acid (50 mL), aqueous NaHCO3 (2 x 50 mL), and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel chromatography (30 - 80% EtOAc / n-hexane) to give the title compound as a solid (1.2 g, 2.477 mmol, 38%); 1 H NMR (400 MHz, chloroform-d): δ 7.54 - 7.49 (m, 2H), 7.43 - 7.38 (m, 3H), 5.60 (s, 1H), 5.54 (dd, J = 10.5, 3.0 Hz, 1H), 5.28 (t, J = 3.3 Hz, 1H), 4.43 - 4.37 (m, 2H), 4.30 (dd, J = 3.5, 1.0 Hz, 1H), 4.11 (dd, J = 12.8, 1.5 Hz, 1H), 3.80 (s, 3H), 3.78 (d, J = 1.5 Hz, 1H), 2.10 (s, 3H)

[0069] Step 6: Synthesis of (2S,4aR,6R,7R,8S,8aR)-methyl 7-acetoxy-8-azido-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate A solution of (2S,4aR,6R,7S,8R,8aS)-methyl 7-acetoxy-2-phenyl-8-(((trifluoromethyl)sulfonyl)oxy)hexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (1.8 g, 41.3 mmol) in DMF (18 mL) was added tetrabutylammonium azide (3.17 g, 11.15 mmol) all at once. The mixture was purged with Ar and heated at 50 °C for 5 h, diluted with EtOAc (200 mL), washed with water (3 x 100 mL), dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel chromatography (50 - 90% EtOAc / n-hexane) to give the title compound as an off-white solid (1.2 g, 3.18 mmol, 86%). LC-MS [M+18] + = 395.2, {Method C: t R = 2.37 min}; 1 H NMR (300 MHz, chloroform-d): δ 7.53 (dd, J = 7.2, 2.3 Hz, 2H), 7.42 - 7.33 (m, 3H), 5.60 (s, 1H), 5.58 - 5.51 (m, 1H), 4.40 - 4.33 (m, 2H), 4.06 (dd, J = 12.7, 1.7 Hz, 1H), 3.99 (d, J = 9.8 Hz, 1H), 3.76 (s, 3H), 3.50 (s, 1H), 3.41 (dd, J = 10.4, 3.2 Hz, 1H), 2.11 (s, 3H)

[0070] Step 7: Synthesis of (4aR,6R,7R,8S,8aR)-methyl 7-acetoxy-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (4aR,6R,7R,8S,8aR)-Methyl 7-acetoxy-8-azido-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (1.2 g, 3.18 mmol) / DMF (50 mL) and water (10.00 mL) solution, 1-ethynyl-3-fluorobenzene (1.146 g, 9.54 mmol), sodium ascorbate (0.693 g, 3.50 mmol) and copper(II) sulfate pentahydrate (0.715 g, 2.86 mmol) were added in sequence. The reaction mixture was degassed with nitrogen for 10 minutes and heated at 80 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (60 mL) and DCM (50 mL), and stirred for 1 hour. The reaction mixture was filtered through celite, washed with DCM (100 mL), and the filtrate was collected. The organic layer was separated, the aqueous layer was re-extracted with DCM (2 x 100 mL), the combined organic layers were washed with water (400 mL) and brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the obtained crude residue, the solid was filtered through a Buchner funnel, and the title compound (1.1 g, 2.211 mmol, 69.5% yield) was dried for 1 hour until it became a white solid. LCMS [M+H] + =498.2 {Method C: t R =2.71 min}; 1 H NMR (400 MHz, CDCl3): δ ppm 8.07 (s, 1H), 7.54 - 7.50 (m, 2H), 7.48 - 7.35 (m, 6H), 7.05 - 6.99 (m, 1H), 5.90 (dd, J = 11.1, 9.6 Hz, 1H), 5.52 (s, 1H), 5.21 (dd, J = 11.1, 3.4 Hz, 1H), 4.51 - 4.47 (m, 2H), 4.23 (d, J = 9.5 Hz, 1H), 4.12 (dd, J = 12.8, 1.8 Hz, 1H), 3.81 (s, 3H), 3.80 - 3.78 (m, 1H), 1.87 (s, 3H)

[0071] Step 8: Synthesis of (4aR,6R,7R,8R,8aR)-8-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-hydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (4aR,6R,7R,8S,8aR)-Methyl 7-acetoxy-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (2 g, 4.02 mmol) / tetrahydrofuran (20 mL) and water (10 mL) were stirred, and lithium hydroxide (0.48 g, 20.10 mmol) was added. The mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by LCMS, tetrahydrofuran was removed under reduced pressure, and the resulting residue was diluted with water (100 mL) and adjusted to pH about 2 - 3 using 1.5 N hydrochloric acid. The precipitated solid was filtered, washed with water, and dried under reduced pressure to obtain the title compound (1.8 g, quantitative). LCMS [M+H] + = 442.2, {Method C: t R = 3.31 min}; 1 H NMR (400 MHz, MeOH-d4) δ ppm 8.46 (s, 1H), 7.56 (dt, J = 10.2, 2.2 Hz, 2H), 7.49 - 7.40 (m, 3H), 7.37 - 7.30 (m, 3H), 7.09 (td, J = 8.4, 2.3 Hz, 1H), 5.56 (s, 1H), 5.12 (dd, J = 10.5, 3.5 Hz, 1H), 4.62 (t, J = 10.0 Hz, 1H), 4.54 (d, J = 3.5 Hz, 1H), 4.37 (d, J = 12.5 Hz, 1H), 4.18 (dd, J = 12.5, 1.5 Hz, 1H), 4.06 (d, J = 9.5 Hz, 1H), 3.89 (s, 1H)

[0072] Synthesis of C2-methoxycarboxylic acid intermediate:

Chemical Structure

[0073] Step 1: Synthesis of (4aR,6R,7R,8R,8aR)-methyl 8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-hydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (4aR,6R,7R,8R,8aR)-8-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-hydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (1.55 g, 3.51 mmol) / DMF (10 mL) in a stirred solution, K2CO3 (4.85 g, 35.1 mmol) was added, followed by MeI (1.976 mL, 31.6 mmol), and the mixture was stirred at room temperature for 16 h. After confirming the completion of the reaction by LCMS, the reaction was quenched with ice water (100 mL) and stirred for 10 min. The resulting solid was filtered, washed with water, and dried under reduced pressure to obtain the title compound as an off-white solid (1.45 g, 91%). LCMS [M+H] + = 456.2, {Method F: t R = 1.95 min}; 1 H NMR (400 MHz, MeOH-d4) δ ppm 8.41 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.47 - 7.40 (m, 3H), 7.37 - 7.32 (m, 3H), 7.07 (td, J = 8.3, 2.5 Hz, 1H), 5.56 (s, 1H), 5.11 (dd, J = 11.0, 3.5 Hz, 1H), 4.68 - 4.61 (m, 1H), 4.53 (d, J = 2.5 Hz, 1H), 4.32 - 4.26 (m, 1H), 4.20 - 4.13 (m, 2H), 3.89 (s, 1H), 3.82 (s, 3H)

[0074] Step 2: Synthesis of (4aR,6R,7R,8R,8aR)-methyl 8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (4aR,6R,7R,8R,8aR)-Methyl 8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-hydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (1.45 g, 3.18 mmol) in a stirred solution of DMF (20 mL) was added 4A MS (1 g) and stirred at room temperature for 10 minutes. Then, silver oxide (3.69 g, 15.92 mmol) and MeI (0.1 mL, 15.92 mmol) were added sequentially and stirred at room temperature for 16 hours. The reaction mixture was filtered through celite, washed with excess DCM (20 mL), and the filtrate was concentrated under reduced pressure to give (4aR,6R,7R,8R,8aR)-methyl 8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate as an off-white solid (1.3 g, 87%). This was used in the next step without further purification. LCMS [M+H] + = 470.2, {Method F: t R = 2.15 min}; 1 H NMR (400 MHz, MeOH-d4) δ ppm 8.59 (s, 1H), 7.62 - 7.58 (m, 1H), 7.55 (dt, J = 10.0, 2.0 Hz, 1H), 7.50 - 7.42 (m, 3H), 7.40 - 7.35 (m, 3H), 7.08 (td, J = 8.4, 2.3 Hz, 1H), 5.58 (s, 1H), 5.19 (dd, J = 10.5, 3.5 Hz, 1H), 4.50 (d, J = 2.5 Hz, 1H), 4.47 - 4.43 (m, 1H), 4.29 (dd, J = 12.8, 1.8 Hz, 1H), 4.19 - 4.13 (m, 2H), 3.87 (s, 1H), 3.84 (s, 3H), 3.12 (s, 3H)

[0075] Step 3: Synthesis of (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (4aR,6R,7R,8R,8aR)-Methyl 8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (1.3 g, 2.8 mmol) / A stirred solution of tetrahydrofuran (50 mL) and water (50 mL) was added lithium hydroxide (0.33 g, 13.85 mmol), and stirred at room temperature for 1 hour. After confirming the completion of the reaction by LCMS, the solvent was removed under reduced pressure. The resulting residue was then diluted with water (100 mL), and the pH was adjusted to about 2 - 3 using 1.5 N hydrochloric acid. The precipitated solid was filtered, washed with water, and dried under reduced pressure to obtain the title compound as an off-white solid (1.1 g, 85%). LCMS [M+H] + = 456.2; {Method F: t R = 0.64 min}; 1 H NMR (400 MHz, MeOH-d4) δ ppm 8.58 (s, 1H), 7.61 (d, J = 6.5 Hz, 1H), 7.55 (dd, J = 10.0, 2.5 Hz, 1H), 7.50 - 7.41 (m, 3H), 7.36 (d, J = 3.5 Hz, 3H), 7.11 - 7.04 (m, 1H), 5.58 (s, 1H), 5.16 (dd, J = 11.0, 3.5 Hz, 1H), 4.50 (d, J = 3.0 Hz, 1H), 4.42 - 4.35 (m, 1H), 4.34 - 4.29 (m, 1H), 4.16 (dd, J = 12.8, 1.8 Hz, 1H), 4.06 (d, J = 9.0 Hz, 1H), 3.84 (s, 1H), 3.18 (s, 3H)

[0076] Synthesis of C2-deoxycarboxylic acid intermediate (e.g., (4aR,6R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid)

Chemical Structure

[0077] Step 1: Synthesis of Methyl (4aR,6R,7R,8S,8aR)-8-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-((methylsulfonyl)oxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (4aR,6R,7R,8R,8aR)-Methyl 8-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-hydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (300 mg, 0.66 mmol) / pyridine (4 mL) was stirred, and methanesulfonyl chloride (0.13 mL, 1.71 mmol) was added at 0 °C. The mixture was stirred for 6 hours. The reaction mixture was quenched with ice water and stirred for 5 minutes. The resulting solid was filtered, washed with excess water, and dried to obtain the title compound as an off-white solid (0.26 g, 72%). LCMS [M+H] + = 534.2, {Method C: t R = 1.990 min}

[0078] Step 2: Synthesis of Methyl (4aR,8R,8aR)-8-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenyl-4,4a,8,8a-tetrahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (4aR,6R,7R,8S,8aR)-Methyl 8-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-((methylsulfonyl)oxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (260 mg, 0.487 mmol) / 2,6-lutidine (25 mL) solution was added with aluminum oxide (basic) (2.5 g, 24.37 mmol) at room temperature and heated at 50 °C for 16 hours. The solvent was removed under reduced pressure, and the crude residue was purified by silica gel chromatography (2 - 3% MeOH / DCM) to obtain the title compound as a pale yellow solid (0.19 g, 83%). LCMS [M+1] + = 438.2, {Method C: t R = 1.966 min}; 11H NMR (400 MHz, chloroform-d) δ ppm 7.93 (s, 1H), 7.50 - 7.56 (m, 2H), 7.28 - 7.41 (m, 6H), 7.00 - 7.05 (m, 1H), 6.00 - 6.04 (m, 1H), 5.96 - 5.99 (m, 1H), 5.57 (s, 1H), 4.64 (dd, J = 12.8, 1.8 Hz, 1H), 4.50 - 4.54 (m, 1H), 4.29 - 4.34 (m, 1H), 4.12 - 4.20 (m, 1H), 3.85 (s, 3H)

[0079] Step 3: Synthesis of Methyl (4aR,6R,8R,8aR)-8-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (4aR,8R,8aR)-Methyl 8-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenyl-4,4a,8,8a-tetrahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (0.22 g, 0.503 mmol) in a degassed solution of EtOAc (8 mL) was added palladium / carbon (10% w / w, 50% wet, 54 mg, 0.05 mmol), and the mixture was stirred at room temperature under a hydrogen atmosphere (~1 atm) for 12 h. The reaction mixture was filtered through Celite and washed with excess EtOAc / MeOH (1:1, 30 mL). The filtrate was concentrated under reduced pressure to give the title compound (0.2 g, 90%) as an off-white solid. LC / MS [M+H] + = 440.2, {Method B: t R = 1.25 min}; 11H NMR (400 MHz, chloroform-d) δ ppm 7.94 (s, 1H), 7.48 - 7.56 (m, 2H), 7.34 - 7.44 (m, 6H), 6.96 - 7.11 (m, 1H), 5.54 (s, 1H), 5.13 - 5.26 (m, 1H), 4.50 (dd, J = 12.5, 1.5 Hz, 1H), 4.27 - 4.42 (m, 2H), 4.03 - 4.20 (m, 1H), 3.82 (s, 3H), 3.70 (d, J = 1.5 Hz, 1H), 2.58 - 2.69 (m, 1H), 2.34 - 2.42 (m, 1H)

[0080] Step 4: Synthesis of (4aR,6R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (4aR,6R,8R,8aR)-Methyl 8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (0.2 g, 0.455 mmol) / THF (8 mL) in a stirred solution, water (2.0 mL), LiOH (0.044 g, 1.821 mmol) was added at room temperature, and stirring was continued for 2 hours. After confirming the completion of the reaction by LCMS, tetrahydrofuran was removed under reduced pressure. The resulting residue was diluted with water (100 mL), and the pH was adjusted to about 2 - 3 using 1.5 N hydrochloric acid. The precipitated solid was filtered, washed with water, and dried under reduced pressure to obtain the title compound (0.17 g, 88%) as an off-white solid. LC / MS [M+H] + = 426.2, {Method A: t R= 0.79 min}

[0081] Examples 1a and 1b: Synthesis of (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1S,2R,3R)-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxycyclohexyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide (Isomer 1 and Isomer 2)

Chemical formula

[0082] Step 1: Synthesis of 3-azidocyclohex-1-ene Sodium azide (14.1 g, 217 mmol) was added to a stirred solution of 3-bromocyclohex-1-ene (7.1 mL, 62.1 mmol) in a mixed solvent of CCl4 (100 mL) and water (100 mL) at room temperature, and the mixture was stirred for 48 h. The aqueous layer was separated and extracted with DCM (2×50 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, concentrated, and 3-azidocyclohex-1-ene (6.6 g, 86%) was obtained as a pale yellow liquid. 1 1H NMR (400 MHz, chloroform-d) δ ppm 5.94 - 6.07 (m, 1H), 5.66 - 5.75 (m, 1H), 3.83 - 3.92 (m, 1H), 1.96 - 2.17 (m, 2H), 1.84 - 1.94 (m, 1H), 1.69 - 1.80 (m, 2H), 1.57 - 1.68 (m, 1H)

[0083] Step 2: Synthesis of (1R,2R,6S)-2-azido-7-oxabicyclo[4.1.0]heptane (racemate) To a solution of 3-azidocyclohex-1-ene (5.5 g, 44.7 mmol) in dichloromethane (200 mL) was added mCPBA (15.4 g, 67.0 mmol) dissolved in DCM (20 mL) at 0 °C. The mixture was returned to room temperature and stirred for 16 h. The reaction mixture was cooled to 0 °C, and the precipitated solid was filtered and washed with DCM (50 mL). The filtrate was washed with saturated Na2SO3 solution, 10% aqueous NaHCO3 solution, brine, dried over sodium sulfate, concentrated to obtain a crude product. The obtained crude residue was purified by flash chromatography (0 - 2% EtOAc / n-hexane) to give (1R,2R,6S)-2-azido-7-oxabicyclo[4.1.0]heptane (1.9 g, 30%, cis isomer) and (1S,2R,6R)-2-azido-7-oxabicyclo[4.1.0]heptane (2.9 g, 46%, trans isomer). Cis isomer: 1 H NMR (400 MHz, chloroform-d) δ ppm 3.50 - 3.66 (m, 1H), 3.32 (dd, J = 4.0, 2.0 Hz, 1H), 3.25 - 3.28 (m, 1H), 1.77 - 1.97 (m, 2H), 1.58 - 1.74 (m, 3H), 1.19 - 1.38 (m, 1H) Trans isomer: 1 H NMR (400 MHz, chloroform-d) δ ppm 3.83 (t, J = 6.8 Hz, 1H), 3.19 - 3.28 (m, 1H), 3.09 (d, J = 3.5 Hz, 1H), 1.97 - 2.08 (m, 1H), 1.76 - 1.93 (m, 2H), 1.45 - 1.53 (m, 1H), 1.28 - 1.40 (m, 2H)

[0084] Step 3: Synthesis of 1-((1S,2R,6R)-7-oxabicyclo[4.1.0]heptan-2-yl)-4-(3-fluorophenyl)-1H-1,2,3-triazole (racemic) To a solution of (1S,2R,6R)-2-azido-7-oxabicyclo[4.1.0]heptane (0.5 g, 3.59 mmol) in DMF (5 mL) and water (1.5 mL) were added sodium ascorbate (0.71 g, 3.59 mmol), copper(II) sulfate pentahydrate (0.81 g, 3.23 mmol) and 3-fluorophenylacetylene (1.7 mL, 14.37 mmol) at room temperature, and the mixture was heated at 85 °C for 30 minutes. The reaction mixture was cooled to room temperature, diluted with 1:1 DCM (50 mL) and water (50 mL), and stirred at room temperature for 15 minutes. The reaction mixture was filtered through celite, washed with DCM (20 mL), the organic layer was separated from the filtrate, and the aqueous layer was re-extracted with DCM (2 x 20 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, concentrated to give a crude residue. The obtained crude residue was purified by flash chromatography (40 - 50% EtOAc / n-hexane) to give 1-((1S,2R,6R)-7-oxabicyclo[4.1.0]heptan-2-yl)-4-(3-fluorophenyl)-1H-1,2,3-triazole (0.53 g, 57%) as a pale yellow solid. LC / MS [M+H] + = 260.2, t R = 2.266 min (Method C)

[0085] Step 4: Synthesis of (1R,2R,6S)-2-azido-6-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)cyclohexanol (racemic) A solution of 1-((1R,2S,6S)-7-oxabicyclo[4.1.0]heptan-2-yl)-4-(3-fluorophenyl)-1H-1,2,3-triazole (200 mg, 0.771 mmol) in MeOH (16 mL) and water (4.00 mL) was added with ammonium chloride (103 mg, 1.928 mmol) and sodium azide (251 mg, 3.86 mmol) at room temperature and heated at 75 °C for 16 h. The reaction mixture was cooled to room temperature, MeOH was removed under reduced pressure, and the mixture was extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, concentrated under reduced pressure to obtain a crude residue. The obtained crude residue was purified by flash chromatography (20 - 25% EtOAc / n-hexane) to give (1R,2R,6S)-2-azido-6-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)cyclohexanol (0.22 g, 98%) as an off-white solid. LC / MS [M+H] + = 303.2, t R = 1.699 min (Method F)

[0086] Step 5: Synthesis of (1S,2R,6S)-2-amino-6-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)cyclohexanol (racemic) To a degassed solution of (1R,2R,6S)-2-azido-6-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)cyclohexanol (210 mg, 0.695 mmol) in MeOH (20 mL) was added palladium / carbon (10% w / w, 50% wet, 74 mg, 0.069 mmol), and the mixture was stirred at room temperature for 2 h under a hydrogen atmosphere (~1 atm). The reaction mixture was filtered through celite, washed with excess MeOH (10 mL), and the filtrate was concentrated under reduced pressure to give (1S,2R,6S)-2-amino-6-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)cyclohexanol (170 mg, 71%). LC / MS [M+H] + = 277.0, t R = 1.255 min (Method F)

[0087] Step 6: Synthesis of ((2R,3R,4S,5R,6R)-4-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1R,2S,3S)-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxycyclohexyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide (2S,4aR,6R,7R,8R,8aR)-8-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (50 mg, 0.110 mmol) (50 mg, 0.110 mmol) / DMF (2 mL) solution was added with DIPEA (0.06 mL, 0.329 mmol) and HATU (62.6 mg, 0.165 mmol) at room temperature and stirred for 15 minutes. Then (1S,2R,6S)-2-amino-6-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)cyclohexanol (36.4 mg, 0.132 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was quenched with ice-cold water (10 mL) and stirred for 15 minutes. The resulting solid was filtered, washed with excess water, and the residue was dried to obtain the crude residue as a diastereomer mixture. The obtained crude residue was further purified by preparative HPLC [Method F] to obtain two isomers. Isomer 1: 20 mg, 21% yield; LC / MS [M+H] + = 714.2, t R = 2.897 minutes (Method C) Isomer 2: 15 mg, 19% yield; LC / MS [M+H] + = 714.2, t R = 2.878 minutes (Method C)

[0088] Step 7: A solution of ((4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1S,2R,3R)-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxycyclohexyl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (20 mg, 0.028 mmol, isomer 1) / 70% acetic acid (5 mL) was stirred at 70 °C overnight, cooled to room temperature, and the solvent was removed under reduced pressure to obtain a crude residue. The obtained crude product was purified by preparative LCMS (Method A) to obtain Example 1a as a white solid (4.5 mg, 25% yield). LCMS [M+H] + = 626.2, [t R = 1.688 min, Method A] and [t R = 1.710 min, Method B]; 1 H NMR (400 MHz, MeOH-d4) δ ppm 8.59 (s, 1H), 8.39 (s, 1H), 7.66 (dd, J = 7.8, 4.2 Hz, 2H), 7.62 - 7.56 (m, 2H), 7.49 - 7.41 (m, 2H), 7.08 (m, 2H), 4.91 (dd, J = 10.8, 2.7 Hz, 1H), 4.57 - 4.44 (m, 1H), 4.28 - 4.21 (m, 1H), 4.11 (d, J = 2.7 Hz, 1H), 4.03 - 3.89 (m, 3H), 3.82 - 3.77 (m, 2H), 3.75 - 3.69 (m, 1H), 3.19 - 3.12 (m, 3H), 2.24 - 2.12 (m, 2H), 2.05 (d, J = 11.7 Hz, 1H), 1.95 (d, J = 13.2 Hz, 1H), 1.68 - 1.54 (m, 2H); hGal3 IC 50 (ELISA) = 0.7 μM; hGal3 IC 50 (HTRF) = 0.29 μM

[0089] Example 1b: A solution of ((4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1S,2R,3R)-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxycyclohexyl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (15 mg, 0.021 mmol, isomer 2) / 70% acetic acid (5 mL) was stirred at 70 °C overnight, cooled to room temperature, and the solvent was removed under reduced pressure to obtain a crude residue. The obtained crude product was purified by preparative LCMS (Method A) to obtain Example 1b as a white solid (1.1 mg, 8% yield). LCMS [M+H] + = 626.2, [t R = 1.690 min, Method A] and [t R = 1.688 min, Method B]; 1 H NMR (400 MHz, MeOH-d4) δ ppm 8.63 (s, 1H), 8.40 (s, 1H), 7.72 - 7.57 (m, 4H), 7.51 - 7.42 (m, 2H), 7.13 - 7.05 (m, 2H), 4.93 (dd, J = 10.8, 2.7 Hz, 1H), 4.58 - 4.45 (m, 1H), 4.27 (t, J = 9.9 Hz, 1H), 4.12 (d, J = 2.4 Hz, 1H), 4.02 - 3.89 (m, 3H), 3.85 - 3.79 (m, 2H), 3.77 - 3.71 (m, 1H), 3.20 (s, 3H), 2.26 - 2.14 (m, 2H), 2.12 (br. s., 1H), 1.98 (d, J = 11.5 Hz, 1H), 1.71 - 1.59 (m, 2H); hGal3 IC 50 (ELISA) = 16 μM

[0090] The examples in Table 1 were prepared in the same manner as Examples 1a and 1b by replacing 1-fluoro-3-ethynylbenzene with the appropriate acetylene in the synthesis procedure.

Table 2

Table 3

[0091] Examples 6a and 6b: Synthesis of (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1R,2S,3S)-3-(5-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxycyclohexyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide (Isomer 1 and Isomer 2)

Chemical Structure

[0092] Step 1: Synthesis of 1-((1R,2S,6S)-7-oxabicyclo[4.1.0]heptan-2-yl)-5-(3-fluorophenyl)-1H-1,2,3-triazole (racemate) (1R,2S,6S)-2-Azido-7-oxabicyclo[4.1.0]heptane (100 mg, 0.719 mmol) and 3-fluorophenylacetylene (0.34 mL, 2.87 mmol) / toluene (3 mL) were stirred, and chloro(1,5-cyclooctadiene)(pentamethylcyclopentadienyl)ruthenium (8.19 mg, 0.022 mmol) was added. The mixture was heated at 85 °C for 4 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure to obtain a crude residue. The obtained crude residue was purified by flash chromatography (40 - 50% EtOAc / n-hexane) to obtain the title compound (175 mg, 92%) as an off-white solid. LC / MS [M+H] + = 260.2, t R = 2.12 min (Method C)

[0093] Step 2: Synthesis of (1R,2R,6S)-2-azido-6-(5-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)cyclohexanol (racemate) To a solution of 1 - ((1R,2S,6S)-7-oxabicyclo[4.1.0]heptan-2-yl)-5-(3-fluorophenyl)-1H-1,2,3-triazole (170 mg, 0.656 mmol) in MeOH (8 mL) and water (2 mL) were added ammonium chloride (88 mg, 1.639 mmol) and sodium azide (213 mg, 3.28 mmol) at room temperature, and the mixture was heated at 75 °C for 16 h. The reaction mixture was cooled to room temperature, MeOH was removed under reduced pressure, and the residue was extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, concentrated under reduced pressure to give a crude residue. The obtained crude residue was purified by flash chromatography (20 - 25% EtOAc / n-hexane) to afford the title compound (0.15 g, 72%) as a brown solid. LC / MS [M+H] + = 303.5, t R = 1.10 min (Method E)

[0094] Step 3: Synthesis of (1S,2R,6S)-2-amino-6-(5-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)cyclohexanol (racemic) To a degassed solution of (1R,2R,6S)-2-azido-6-(5-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)cyclohexanol (150 mg, 0.496 mmol) in MeOH (10 mL) was added palladium / carbon (10% w / w, 50% wet, 53 mg, 0.050 mmol), and the mixture was stirred at room temperature under a hydrogen atmosphere (~1 atm) for 2 h. The reaction mixture was filtered through celite and washed with excess MeOH (10 mL), and the filtrate was concentrated under reduced pressure to give the title compound (68 mg, 40%). LC / MS [M+H] + = 277.2, t R = 1.18 min (Method F)

[0095] Step 4: Synthesis of (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1R,2S,3S)-3-(5-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxycyclohexyl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide To a solution of ((4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (50 mg, 0.110 mmol) in DMF (2 mL), DIPEA (0.06 mL, 0.329 mmol) and HATU (62.6 mg, 0.165 mmol) were added at room temperature and stirred for 15 minutes. Then (1S,2R,6S)-2-amino-6-(5-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)cyclohexanol (36.4 mg, 0.132 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was quenched with ice-cold water (10 mL) and stirred for 15 minutes. The resulting solid was filtered, washed with excess water, and the obtained residue was dried to give the crude residue as a mixture of diastereomers. The obtained crude residue was further purified by preparative HPLC [Method E] to give Isomer 1 and Isomer 2. Isomer 1: 10 mg, 13% yield; LC / MS [M+H] + = 714.2, t R = 2.461 min (Method F) Isomer 2: 15 mg, 17% yield; LC / MS [M+H] + = 714.2, t R = 2.457 min (Method F)

[0096] Step 5: ((4aR,6R,7R,8R,8aR)-8-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1R,2S,3S)-3-(5-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxycyclohexyl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (isomer 1, 10 mg, 0.014 mmol) was suspended in 70% acetic acid (3 mL, 52.4 mmol) and heated at 70 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a crude residue. The crude residue was purified by preparative HPLC [Method A] to give Example 6a, (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1R,2S,3S)-3-(5-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxycyclohexyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide (isomer 1, 2.9 mg, 33%). LC / MS [M+H] + = 626.1, t R = 1.667 min (Method A); 1 H NMR (400 MHz, MeOH-d4) δ ppm 8.63 (s, 1H), 7.80 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.66 - 7.54 (m, 2H), 7.51 - 7.38 (m, 3H), 7.29 (td, J = 8.6, 2.4 Hz, 1H), 7.10 (td, J = 8.6, 2.4 Hz, 1H), 4.93 (dd, J = 10.6, 2.8 Hz, 1H), 4.38 - 4.30 (m, 1H), 4.29 - 4.16 (m, 2H), 4.12 (d, J = 2.7 Hz, 1H), 3.94 (d, J = 9.3 Hz, 1H), 3.92 - 3.79 (m, 3H), 3.77 - 3.69 (m, 1H), 3.19 (s, 3H), 2.28 - 2.16 (m, 1H), 2.06 (d, J = 10.8 Hz, 2H), 1.89 (d, J = 13.4 Hz, 1H), 1.67 - 1.44 (m, 2H); hGal3 IC50 = 27 μM Example 6b: (2S,4aR,6R,7R,8R,8aR)-8-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1R,2S,3S)-3-(5-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxycyclohexyl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (isomer 2, 15 mg, 0.021 mmol) was suspended in 70% acetic acid (5 mL, 87 mmol) and heated at 70 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a crude residue. The obtained crude residue was purified by preparative HPLC [Method A] to give (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1R,2S,3S)-3-(5-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxycyclohexyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide (isomer 2, 5.5 mg, 42%). LC / MS [M+H] + = 626.1, t R = 1.683 min (Method A); 1 H NMR (400 MHz, MeOH-d4) δ ppm 8.61 (s, 1H), 7.81 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.51 - 7.40 (m, 3H), 7.32 - 7.26 (m, 1H), 7.14 - 7.07 (m, 1H), 4.92 (dd, J = 10.9, 3.1 Hz, 1H), 4.39 - 4.31 (m, 1H), 4.29 - 4.16 (m, 2H), 4.12 (d, J = 2.7 Hz, 1H), 3.94 (d, J = 9.3 Hz, 1H), 3.90 (br. s., 1H), 3.85 - 3.79 (m, 2H), 3.77 - 3.72 (m, 1H), 3.17 (s, 3H), 2.28 - 2.16 (m, 1H), 2.11 - 1.98 (m, 2H), 1.88 (d, J = 13.7 Hz, 1H), 1.63 - 1.47 (m, 2H); hGal3 IC 50=0.90 μM

[0097] Synthesis Scheme of Indazole Derivatives: [Chemical Formula]

[0098] Step 1: Synthesis of (1R,2R,6S)-2-azido-6-(4-fluoro-1H-indazol-1-yl)cyclohexanol and (1R,2R,6S)-2-azido-6-(4-fluoro-2H-indazol-2-yl)cyclohexanol (racemic) (1S,2R,6R)-2-azido-7-oxabicyclo[4.1.0]heptane (300 mg, 2.156 mmol) and 4-fluoro-1H-indazole (308 mg, 2.264 mmol) in DMSO (3 mL) were added with DBU (0.975 mL, 6.47 mmol) at room temperature and heated at 100 °C for 16 h. The reaction mixture was cooled to room temperature, extracted with EtOAc (3 x 30 mL), washed with water and brine, dried over sodium sulfate, concentrated under reduced pressure to obtain the crude product. The obtained crude residue was purified by preparative HPLC (Method B) to give N1-position isomer (1R,2R,6S)-2-azido-6-(4-fluoro-1H-indazol-1-yl)cyclohexanol (120 mg, 20%) and N2-position isomer (1R,2R,6S)-2-azido-6-(4-fluoro-2H-indazol-2-yl)cyclohexanol (150 mg, 20%). N1-position isomer: 1 H NMR (400 MHz, chloroform-d) δ ppm 8.12 (d, J = 0.8 Hz, 1H), 7.16 - 7.39 (m, 2H), 6.76 - 6.83 (m, 1H), 4.29 - 4.38 (m, 1H), 4.15 - 4.23 (m, 1H), 3.48 - 3.57 (m, 1H), 2.39 (d, J = 3.5 Hz, 1H), 2.13 - 2.20 (m, 1H), 2.04 - 2.11 (m, 1H), 1.94 - 2.00 (m, 1H), 1.43 - 1.68 (m, 3H); LC / MS [M + H] + =276.2, tR = 1.98 minutes (Method F) N2 - positional isomer: 1 H NMR (400 MHz, chloroform - d) δ ppm 8.06 (d, J = 0.8 Hz, 1H), 7.43 (s, 1H), 7.11 - 7.25 (m, 1H), 6.66 - 6.73 (m, 1H), 4.19 - 4.36 (m, 1H), 4.06 (t, J = 9.6 Hz, 1H), 3.46 - 3.57 (m, 1H), 2.20 - 2.26 (m, 1H), 2.09 - 2.17 (m, 2H), 1.96 - 2.02 (m, 1H), 1.50 - 1.59 (m, 2H); LC / MS [M + H] + = 276.2, t R = 2.12 minutes (Method C)

[0099] Step 2: Synthesis of (1S,2R,6S)-2 - amino - 6-(4 - fluoro - 1H - indazol - 1 - yl)cyclohexanol (racemic) (1R,2R,6S)-2 - azido - 6-(4 - fluoro - 1H - indazol - 1 - yl)cyclohexanol (100 mg, 0.363 mmol) / MeOH (5 mL) deaerated solution was added palladium / carbon (10% w / w, 39 mg, 0.036 mmol), and stirred at room temperature under a hydrogen atmosphere (~1 atm) for 2 hours. The reaction mixture was filtered through celite, washed with excess MeOH (10 mL), and the filtrate was concentrated under reduced pressure to obtain (1S,2R,6S)-2 - amino - 6-(4 - fluoro - 1H - indazol - 1 - yl)cyclohexanol (65 mg, 62%). LC / MS [M + H] + = 250.0, t R = 1.26 minutes (Method F)

[0100] Step 3: Synthesis of (4aR,6R,7R,8R,8aR)-N - ((1R,2S,3S)-3-(4 - fluoro - 1H - indazol - 1 - yl)-2 - hydroxycyclohexyl)-8-(4-(3 - fluorophenyl)-1H - 1,2,3 - triazol - 1 - yl)-7 - methoxy - 2 - phenylhexahydropyrano[3,2 - d][1,3]dioxine - 6 - carboxamide To a solution of (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (50 mg, 0.110 mmol) in DMF (5 mL) were added DIPEA (0.19 mL, 1.098 mmol) and HATU (83 mg, 0.220 mmol) at room temperature, and the mixture was stirred for 15 minutes. Then (1S,2R,6S)-2-amino-6-(4-fluoro-1H-indazol-1-yl)cyclohexanol (racemic, 28 mg, 0.110 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice-cold water (10 mL) and stirred for 15 minutes. The resulting solid was filtered, washed with excess water, and the residue was dried to obtain the crude residue as a mixture of diastereomers. This crude residue was purified by preparative HPLC [Method E] to obtain isomer 1 and isomer 2. Isomer 1: 21 mg, 27% yield; LC / MS [M+H] + = 687.2, t R = 2.54 min (Method F) Isomer 2: 20 mg, 26% yield; LC / MS [M+H] + = 6872, t R = 2.55 min (Method F)

[0101] Step 4: Synthesis of (2R,3R,4S,5R,6R)-N-((1R,2S,3S)-3-(4-fluoro-1H-indazol-1-yl)-2-hydroxycyclohexyl)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide (isomers 1 and 2) (4aR,6R,7R,8R,8aR)-N-((1R,2S,3S)-3-(4-Fluoro-1H-indazol-1-yl)-2-hydroxycyclohexyl)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (isomer 1, 20 mg, 0.029 mmol) was suspended in 70% acetic acid (5 mL) and heated at 70 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a crude residue. The obtained crude residue was purified by preparative HPLC [Method A] to give Example 7a, (2R,3R,4S,5R,6R)-N-((1R,2S,3S)-3-(4-fluoro-1H-indazol-1-yl)-2-hydroxycyclohexyl)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide (isomer 1, 7.8 mg, 45%). LC / MS [M+H] + = 599.1, t R = 1.77 min (Method A); 1 H NMR (400 MHz, MeOH-d4) δ = 8.60 (s, 1H), 8.14 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 10.3 Hz, 1H), 7.49 - 7.43 (m, 2H), 7.39 - 7.34 (m, 1H), 7.12 - 7.07 (m, 1H), 6.83 - 6.81 (m, 1H), 4.93 (dd, J = 10.9, 2.8 Hz, 1H), 4.57 (br.s, 1H), 4.27 - 4.12 (m, 1H), 4.13 - 4.05 (m, 3H), 4.03 (d, J = 9.3 Hz, 1H), 3.93 - 3.73 (m, 3H), 3.16 (s, 3H), 2.16 - 1.92 (m, 4H), 1.71 - 1.52 (m, 2H); hGal3 IC50 = 0.64 μM Example 7b: Prepared in the same manner as the method described in Example 7a (isomer 1) using (4aR,6R,7R,8R,8aR)-N-((1R,2S,3S)-3-(4-fluoro-1H-indazol-1-yl)-2-hydroxycyclohexyl)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (isomer 2, 20 mg, 0.029 mmol). The resulting crude residue was purified by preparative HPLC [Method A] to obtain (2R,3R,4S,5R,6R)-N-((1R,2S,3S)-3-(4-fluoro-1H-indazol-1-yl)-2-hydroxycyclohexyl)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide (isomer 2, 8.1 mg, 46%). LC / MS [M+H] + = 599.1, t R = 1.747 min (Method A); 1 1H NMR (400 MHz, MeOH-d4) δ ppm 8.63 (s, 1H), 8.13 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 10.3 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.38 - 7.33 (m, 1H), 7.12 - 7.07 (m, 1H), 6.82 - 6.80 (m, 1H), 4.93 (dd, J = 10.6, 2.8 Hz, 1H), 4.60 - 4.47 (m, 1H), 4.28 (t, J = 10.0 Hz, 1H), 4.15 - 3.98 (m, 3H), 3.94 (d, J = 9.3 Hz, 1H), 3.87 - 3.76 (m, 2H), 3.76 - 3.67 (m, 1H), 3.18 (s, 3H), 2.22 - 1.89 (m, 4H), 1.77 - 1.56 (m, 2H); hGal3IC 50 = 23 μM

[0102] Example 8: Synthesis of (2R,3R,4S,5R,6R)-N-((1R,2S,3S)-3-(4-Fluoro-2H-indazol-2-yl)-2-hydroxycyclohexyl)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide [Chemical formula]

[0103] Step 1: Synthesis of (1S,2R,6S)-2-amino-6-(4-fluoro-2H-indazol-2-yl)cyclohexanol (racemate) (1R,2R,6S)-2-Azido-6-(4-fluoro-2H-indazol-2-yl)cyclohexanol (150 mg, 0.545 mmol) / MeOH (10 mL) degassed solution was added with palladium / carbon (10% w / w, 58 mg, 0.054 mmol), and stirred at room temperature under a hydrogen atmosphere (~1 atm) for 2 hours. The reaction mixture was filtered through celite, washed with excess MeOH (10 mL), and the filtrate was concentrated under reduced pressure to obtain the title compound (80 mg, 45%) as an off-white solid. LC / MS [M+H] + = 250.2, t R = 0.74 min (Method C)

[0104] Step 2: Synthesis of (4aR,6R,7R,8R,8aR)-N-((1R,2S,3S)-3-(4-fluoro-2H-indazol-2-yl)-2-hydroxycyclohexyl)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide A solution of (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (50 mg, 0.110 mmol) in DMF (5 mL) was added with DIPEA (0.19 mL, 1.098 mmol) and HATU (83 mg, 0.220 mmol) at room temperature and stirred for 15 minutes. Then, (1S,2R,6S)-2-amino-6-(4-fluoro-2H-indazol-2-yl)cyclohexanol (racemic, 27.4 mg, 0.110 mmol) was added at room temperature and stirred for 1 hour. The reaction mixture was quenched with ice-cold water (10 mL) and stirred for 15 minutes. The resulting solid was filtered, washed with excess water, dried, and the crude residue was obtained as a diastereomer mixture. This crude residue was further purified by preparative HPLC [Method E] to obtain isomer 1 and isomer 2. Isomer 1: 10 mg, 13% yield; LC / MS [M+H] + = 687.0, t R = 2.318 min (Method F) Isomer 2: 12 mg, 15% yield; LC / MS [M+H] + = 687.2, t R = 2.328 min (Method F)

[0105] Step 3: (4aR,6R,7R,8R,8aR)-N-((1R,2S,3S)-3-(4-Fluoro-2H-indazol-2-yl)-2-hydroxycyclohexyl)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (isomer 1, 10 mg, 0.015 mmol) was suspended in 70% acetic acid (5 mL) and heated at 70 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a crude residue. This crude residue was purified by preparative HPLC [Method A] to give (2R,3R,4S,5R,6R)-N-((1R,2S,3S)-3-(4-fluoro-2H-indazol-2-yl)-2-hydroxycyclohexyl)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide of Example 8 (1.6 mg, 18%). LC / MS [M+H] + = 599.1, t R = 1.685 min (Method A); 1 H NMR (400 MHz, MeOH-d4) δ = 8.60 (s, 1H), 8.37 (s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 10.0 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.29 - 7.21 (m, 1H), 7.09 (t, J = 8.4 Hz, 1H), 6.72 (dd, J = 10.5, 7.6 Hz, 1H), 4.92 (dd, J = 10.8, 2.4 Hz, 1H), 4.46 (br.s., 1H), 4.25 (t, J = 9.9 Hz, 1H), 4.12 (d, J = 2.2 Hz, 1H), 4.07 - 3.91 (m, 3H), 3.86 - 3.67 (m, 3H), 3.17 (s, 3H), 2.31 - 2.13 (m, 2H), 2.10 - 1.90 (m, 2H), 1.72 - 1.55 (m, 2H); hGal3 IC50 = 0.57 μM

[0106] Examples 9a and 9b: Synthesis of (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1S,2R,3R)-3-(3-(3-fluorophenyl)-1H-1,2,4-triazol-1-yl)-2-hydroxycyclohexyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide isomers 1 and 2 [Chemical Formula]

[0107] Step 1: Synthesis of (1R,2R,6S)-2-azido-6-(3-bromo-1H-1,2,4-triazol-1-yl)cyclohexanol (racemate) (1S,2R,6R)-2-Azido-7-oxabicyclo[4.1.0]heptane (200 mg, 1.437 mmol) and 3-bromo-1H-1,2,4-triazole (213 mg, 1.437 mmol) in DMSO (2 mL) were added with DBU (0.650 mL, 4.31 mmol), and heated at 100 °C for 16 h. After confirming the completion of the reaction by LCMS, the reaction mixture was diluted with EtOAc (20 mL) and water (20 mL), the organic layer was separated, and the aqueous layer was re-extracted with EtOAc (2 x 10 mL). The combined organic extraction layers were washed with brine (20 mL) and dried over Na2SO4. The solvent was removed under reduced pressure, and the obtained crude product was purified by flash chromatography (60 - 120 mesh; silica column, 50 - 60% ethyl acetate / petroleum ether), concentrated after purification, and (1R,2R,6S)-2-azido-6-(3-bromo-1H-1,2,4-triazol-1-yl)cyclohexanol (143 mg, 0.5 mmol, 35%) was obtained as an off-white solid. LCMS [M + 2] + = 289.0, {Method F, tR: 1.030 min, detection: ELSD}

[0108] Step 2: Synthesis of (1R,2R,6S)-2-azido-6-(3-(3-fluorophenyl)-1H-1,2,4-triazol-1-yl)cyclohexanol (racemate) (1R,2R,6S)-2-Azido-6-(3-bromo-1H-1,2,4-triazol-1-yl)cyclohexanol (110 mg, 0.383 mmol), (3-fluorophenyl)boronic acid (64.3 mg, 0.460 mmol) / a solution of 1,4-dioxane (3 mL) and water (0.450 mL), K2CO3 (116 mg, 0.843 mmol) was added. The reaction mixture was degassed with N2, and Pd(Ph3P)4 (22.14 mg, 0.019 mmol) was added under N2. The vial was sealed and heated at 95 °C for 16 h, cooled to room temperature, the solvent was removed under reduced pressure to give a crude residue. This was purified by flash chromatography (60 - 120 silica gel, 80 - 90% ethyl acetate / petroleum ether) to give (1R,2R,6S)-2-azido-6-(3-(3-fluorophenyl)-1H-1,2,4-triazol-1-yl)cyclohexanol (58 mg, 47%) as an off-white solid. LCMS [M+H] + = 303.2, t R : 2.256 min {Method C}

[0109] Step 3: Synthesis of (1S,2R,6S)-2-amino-6-(3-(3-fluorophenyl)-1H-1,2,4-triazol-1-yl)cyclohexanol (racemate) (1R,2R,6S)-2-Azido-6-(3-(3-fluorophenyl)-1H-1,2,4-triazol-1-yl)cyclohexanol was prepared in the same manner as described in Step 5 of Example 1a to give (1S,2R,6S)-2-amino-6-(3-(3-fluorophenyl)-1H-1,2,4-triazol-1-yl)cyclohexanol (0.048 g, 87% yield) as an off-white solid. LCMS [M+H] + = 277.2 {t R : 0.730 min, Method E}

[0110] Step 4: Synthesis of (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1R,2S,3S)-3-(3-(3-fluorophenyl)-1H-1,2,4-triazol-1-yl)-2-hydroxycyclohexyl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide Prepared in a similar manner to the method described in Step 6 of Example 1a using (1S,2R,6S)-2-amino-6-(3-(3-fluorophenyl)-1H-1,2,4-triazol-1-yl)cyclohexanol (33.4 mg, 0.121 mmol) and (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (0.05 g, 0.110 mmol). The crude product obtained was purified by flash chromatography (60-120 silica gel, 6-10% MeOH / CHCl3) to give (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1R,2S,3S)-3-(3-(3-fluorophenyl)-1H-1,2,4-triazol-1-yl)-2-hydroxycyclohexyl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (isomer 1, 0.020 g, 24% yield) and (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1R,2S,3S)-3-(3-(3-fluorophenyl)-1H-1,2,4-triazol-1-yl)-2-hydroxycyclohexyl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (isomer 2, 0.024 g, 22% yield). LCMS [M+H] + =714.2 {Method F, isomer 1: t R : 2.375 / isomer 2: 2.350}

[0111] Step 5: To a stirred solution of (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1R,2S,3S)-3-(3-(3-fluorophenyl)-1H-1,2,4-triazol-1-yl)-2-hydroxycyclohexyl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (isomer 1, 20 mg, 0.028 mmol) / dichloromethane (1 mL) was added trifluoroacetic acid (0.15 mL, 1.947 mmol), and the mixture was stirred at room temperature for 2 h. The solvent was then removed under reduced pressure, and the crude product was purified by preparative HPLC {Method A}. The desired fraction was concentrated under reduced pressure to give Example 9a: (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1S,2R,3R)-3-(3-(3-fluorophenyl)-1H-1,2,4-triazol-1-yl)-2-hydroxycyclohexyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide (isomer 1, 4.8 mg, 27.4% yield) as an off-white solid. LCMS [M+H] + = 626.1, [t R = 1.682 min, Method A] and [t R = 1.691 min, Method B]; 11H NMR (400 MHz, MeOH-d4) δ ppm 8.61 (s, 1H), 8.50 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 10.3 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 10.0 Hz, 1H), 7.53 - 7.42 (m, 2H), 7.17 (td, J = 8.4, 2.3 Hz, 1H), 7.13 - 7.06 (m, 1H), 4.92 (dd, J = 10.8, 2.9 Hz, 1H), 4.36 - 4.22 (m, 2H), 4.12 (d, J = 2.9 Hz, 1H), 4.02 - 3.88 (m, 3H), 3.85 - 3.78 (m, 2H), 3.76 - 3.70 (m, 1H), 3.18 (s, 3H), 2.22 - 2.12 (m, 2H), 2.08 - 2.02 (m, 1H), 1.98 - 1.92 (m, 1H), 1.68 - 1.52 (m, 2H); hGal3 IC 50 = 0.5 μM Example 9b: Prepared in a manner similar to the method described in Example 9a, and in step 5, (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1R,2S,3S)-3-(3-(3-fluorophenyl)-1H-1,2,4-triazol-1-yl)-2-hydroxycyclohexyl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (isomer 2, 0.024 g, 0.034 mmol) was used. The obtained crude product was purified by preparative HPLC {Method A}, and the desired fraction was concentrated under reduced pressure to give (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1S,2R,3R)-3-(3-(3-fluorophenyl)-1H-1,2,4-triazol-1-yl)-2-hydroxycyclohexyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide (isomer 2, 1.01 mg, 4.5% yield) as an off-white solid. LCMS [M+H] + = 626.1, [t R= 1.661 minutes, Method A] and [t R = 1.668 minutes, Method B]; 1 1H NMR (400 MHz, MeOH-d4) δ ppm 8.63 (s, 1H), 8.49 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 10.3 Hz, 1H), 7.70 (d, J = 7.3 Hz, 1H), 7.63 (d, J = 11.0 Hz, 1H), 7.51 - 7.44 (m, 2H), 7.20 - 7.07 (m, 2H), 4.94 - 4.90 (m, 1H), 4.35 - 4.24 (m, 2H), 4.12 (d, J = 3.4 Hz, 1H), 3.97 - 3.86 (m, 3H), 3.84 - 3.79 (m, 2H), 3.76 - 3.70 (m, 1H), 3.20 (s, 3H), 2.22 - 2.06 (m, 4H), 1.94 (br. s., 1H), 1.65 - 1.57 (m, 1H); hGal3 IC 50 => 100 μM

[0112] Cyclohexyl N-methyl analog:

Chemical Structure

[0113] Step 1: Synthesis of 1 - ((1S,2R,6R)-7-oxabicyclo[4.1.0]heptan-2-yl)-4-(3-fluorophenyl)-1H-1,2,3-triazole (racemic) To a solution of (1S,2R,6R)-2-azido-7-oxabicyclo[4.1.0]heptane (0.5 g, 3.59 mmol) in DMF (5 mL) and water (1.5 mL) were added sodium ascorbate (0.71 g, 3.59 mmol), copper(II) sulfate pentahydrate (0.81 g, 3.23 mmol) and 3-fluorophenylacetylene (1.7 mL, 14.37 mmol) at room temperature, and the mixture was heated at 85 °C for 30 minutes. The reaction mixture was cooled to room temperature, diluted with 1:1 DCM (50 mL) and water (50 mL), and stirred at room temperature for 15 minutes. The reaction mixture was filtered through celite and washed with DCM (20 mL). The organic layer was separated from the filtrate, and the aqueous layer was re-extracted with DCM (2 x 20 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, concentrated to give a crude residue. The obtained crude residue was purified by flash chromatography (40 - 50% EtOAc / n-hexane) to give 1-((1S,2R,6R)-7-oxabicyclo[4.1.0]heptan-2-yl)-4-(3-fluorophenyl)-1H-1,2,3-triazole (0.53 g, 57%) as a pale yellow solid. LC / MS [M+H] + = 260.2, t R = 2.266 min (Method C)

[0114] Step 2: Synthesis of (1R,2R,6S)-2-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(methylamino)cyclohexanol (racemic) In a sealed tube, 1-((1S,2R,6R)-7-oxabicyclo[4.1.0]heptan-2-yl)-4-(3-fluorophenyl)-1H-1,2,3-triazole (110 mg, 0.424 mmol) and methylamine (33% ethanol solution, 5 mL, 0.424 mmol) were heated at 65 °C for 16 hours, cooled to room temperature, and the solvent was removed under reduced pressure to give a crude residue. The obtained crude residue was triturated with n-pentane and dried to give (1R,2R,6S)-2-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(methylamino)cyclohexanol (109 mg, 88%). LC / MS [M+H] += 291.0, t R = 1.372 minutes (Method F)

[0115] Step 3: Synthesis of (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1S,2R,3R)-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxycyclohexyl)-7-methoxy-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide ((2S,4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (50 mg, 0.11 mmol) / DMF (2 mL) solution was added with DIPEA (0.06 mL, 0.33 mmol) and HATU (63 mg, 0.16 mmol) at room temperature and stirred for 15 minutes. Then (1R,2R,6S)-2-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-6-(methylamino)cyclohexanol (35.1 mg, 0.121 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was quenched with ice-cold water (10 mL) and stirred for 15 minutes. The resulting solid was filtered, washed with excess water, dried, and the crude residue was obtained as a diastereomer mixture. This crude residue was further purified by preparative SFC to obtain isomer 1 and isomer 2.

[0116] Preparative SFC conditions Column / size: Chiralcel OD-H (250 X 21) mm, 5u %CO2: 60% % Co-solvent: 40% MeOH (containing 0.2% DEA) Total flow rate: 80.0 g / min Back pressure: 100 bar Temperature: 25 °C UV: 242 nm Isomer 1: 35 mg, 37% yield; LC / MS [M+H] +=728.2, t R =3.178 minutes (Method C) Isomer 2: 25 mg, 31% yield; LC / MS [M+H] + =728.0, t R =2.635 minutes (Method F)

[0117] Example 10a: (2S,4aR,6R,7R,8R,8aR)-8-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1S,2R,3R)-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxycyclohexyl)-7-methoxy-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (Isomer 1, 35 mg, 0.048 mmol) was suspended in 70% acetic acid (5 mL) and heated at 70 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude residue. The crude residue was purified by preparative HPLC [Method A] to give ((2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1S,2R,3R)-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxycyclohexyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-N-methyltetrahydro-2H-pyran-2-carboxamide (Isomer 1, 9.3 mg, 30%) as an off-white solid. LC / MS [M+H] + =640.2, t R =1.788 minutes (Method A); 11H NMR (400 MHz, MeOH-d4) δ ppm 8.71, 8.70 (two singlets, 1H), 8.53, 8.42 (two singlets, 1H), 7.76 - 7.57 (m, 4H), 7.53 - 7.42 (m, 2H), 7.15 - 7.05 (m, 2H), 5.03 - 4.96 (m, 1H), 4.76 - 4.66 (m, 1H), 4.58 (m, 1H), 4.55 - 4.35 (m, 3H), 4.34 - 4.04 (m, 4H), 3.21, 3.00 (two singlets, 3H), 3.13, 3.11 (two singlets, 3H), 2.27 - 2.09 (m, 2H), 2.04 - 1.90 (m, 2H), 1.85 (m, 2H) {mixture of rotamers}; hGal3 IC 50 = 5.5 μM

[0118] Example 10b: ((2S,4aR,6R,7R,8R,8aR)-8-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1S,2R,3R)-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxycyclohexyl)-7-methoxy-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (isomer 2, 25 mg, 0.034 mmol) was suspended in 70% acetic acid (5 mL, 87 mmol) and heated at 70 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a crude residue. The crude residue was purified by preparative HPLC [Method A] to give ((2R,3R,4S,5R,6R)-4-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((1S,2R,3R)-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-hydroxycyclohexyl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-N-methyltetrahydro-2H-pyran-2-carboxamide (isomer 2, 2.2 mg, 10%). LC / MS [M + H] + = 640.2, t R = 1.78 min (Method A); 11H NMR (400 MHz, MeOH-d4) δ ppm 8.72, 8.71 (two singlets, 1H), 8.47, 8.45 (two singlets, 1H), 7.75 - 7.57 (m, 4H), 7.53 - 7.43 (m, 2H), 7.10 (t, J = 8.4 Hz, 2H), 5.03 - 4.95 (m, 1H), 4.65 - 4.49 (m, 3H), 4.47 - 4.40 (m, 1H), 4.21 - 4.00 (m, 2H), 3.94 - 3.84 (m, 1H), 3.83 - 3.64 (m, 2H), 3.21, 2.98 (two singlets, 3H), 3.14, 3.11 (two singlets, 3H), 2.28 - 2.11 (m, 2H), 2.10 - 1.95 (m, 2H), 1.94 - 1.64 (m, 2H); [Rotational isomer mixture]; hGal3IC 50 = 0.091 μM

[0119] The examples in Table 2 were prepared in the same manner as Examples 10a and 10b by replacing methylamine with an appropriate alkylamine in the synthesis procedure.

Table 4

Table 5

[0120] Examples 16a and 16b: Synthesis of (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4S,5S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxypiperidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-N-methyltetrahydro-2H-pyran-2-carboxamide (isomers 1 and 2)

Chemical formula

[0121] Step 1: Synthesis of tert-butyl (1S,5R,6R)-5-hydroxy-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (racemate) To a solution of N-Boc-3-hydroxy-1,2,3,6-tetrahydropyridine (500 mg, 2.51 mmol) in DCM (25 mL) was added sodium bicarbonate (211 mg, 2.51 mmol) at 0 °C under N2, followed by mCPBA (928 mg, 3.76 mmol) in DCM (3 mL). The mixture was warmed to room temperature and stirred for 24 h. The reaction mixture was diluted with DCM (100 mL), filtered through celite, and the filtrate was washed with saturated Na2SO3 (2 x 50 mL), saturated NaHCO3 (2 x 50 mL), and saturated NaCl (25 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and the resulting crude residue was purified by silica gel chromatography (40% → 50% ethyl acetate / hexane) to afford the title compound as a white solid (430 mg, 80% yield); 1 1H NMR (400 MHz, chloroform-d) δ 4.01 (br.s, 1H), 3.92 - 3.44 (m, 5H), 3.10 (dd, J = 12.8, 7.2 Hz, 1H), 1.29 (s, 9H) (mixture of rotamers)

[0122] Step 2: Synthesis of tert-butyl (1S,5S,6R)-5-azido-7-oxa-3-azabicyclo[4.1.0] heptane-3-carboxylate (racemate) To a stirred solution of (1S,5R,6R)-tert-butyl 5-hydroxy-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (325 mg, 1.510 mmol) in THF (50 mL) was added triphenylphosphine (792 mg, 3.02 mmol), and the mixture was cooled to 0 °C. DEAD (0.478 mL, 3.02 mmol) and DPPA (0.651 mL, 3.02 mmol) were added sequentially under N2, and the mixture was warmed to room temperature and stirred for 16 h. The solvent was removed under reduced pressure, and the resulting crude residue was purified by silica gel chromatography (10% → 15% ethyl acetate / hexane) to afford the title compound as a pale yellow oil (230 mg, 64% yield); 11H NMR (400 MHz, DMSO-d6) δ 4.09 - 3.82 (m, 2H), 3.62 - 3.38 (m, 4H), 3.17 (dd, J = 13.1, 3.3 Hz, 1H), 1.40 (s, 9H) (mixture of rotamers)

[0123] Step 3: Synthesis of tert-butyl (1S,5S,6R)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (racemate) (1R,5R,6S)-tert-butyl 5-azido-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (1.6 g, 6.66 mmol) / DMF (30 mL) and water (7.50 mL) solution was added sodium ascorbate (1.319 g, 6.66 mmol), copper(II) sulfate pentahydrate (1.496 g, 5.99 mmol) and 3-fluorophenylacetylene (3.08 mL, 26.6 mmol) in sequence at room temperature. The reaction mixture was degassed with N2 for 5 minutes and heated at 85 °C for 30 minutes. The mixture was cooled to room temperature, diluted with ice-cold water (100 mL), stirred for 15 minutes to obtain a solid. The obtained solid was filtered, suspended in DCM (100 mL), filtered through celite and washed with excess DCM. The filtrate was dried over sodium sulfate and concentrated. The obtained residue was purified by silica gel (40% → 80% ethyl acetate / hexane) to obtain the title compound (1.1 g, 46% yield) as a white solid. 1 1H NMR (400 MHz, chloroform-d) δ 7.83 (br.s, 1H), 7.59 - 7.55 (m, 2H), 7.42 - 7.38 (m, 1H), 7.10 - 7.07 (m, 1H), 5.18 - 5.06 (m, 1H), 4.34 - 4.29 (m, 1H), 3.93 - 3.45 (m, 5H), 1.47 - 1.11 (m, 9H) (mixture of rotamers); LC / MS [M+H] + = 361.0, t R = 2.01 min (Method E)

[0124] Step 4: Synthesis of (3S,4S,5R)-tert-butyl 3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxy-5-(methylamino)piperidine-1-carboxylate (racemate) In a sealed tube, (1S,5S,6R)-tert-butyl 5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (100 mg, 0.277 mmol) / methanamine (33% ethanol solution, 5 mL, 0.277 mmol) was heated at 65 °C for 16 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure to give a crude residue. The obtained crude residue was triturated with pentane and dried under reduced pressure to give (3S,4S,5R)-tert-butyl 3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxy-5-(methylamino)piperidine-1-carboxylate (105 mg, 94%). LCMS [M+H] + = 392.2 {Method C: t R = 1.855 min}

[0125] Step 5: To a stirred solution of (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (50 mg, 0.110 mmol) in DMF (2 mL) were added DIPEA (0.058 mL, 0.329 mmol) and HATU (62.6 mg, 0.165 mmol) sequentially at room temperature, and the mixture was stirred for 15 minutes. Then (3S,4S,5R)-tert-butyl 3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxy-5-(methylamino)piperidine-1-carboxylate (47.3 mg, 0.121 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice water and stirred for 15 minutes. The resulting solid was filtered and dried to give a crude residue. The obtained crude residue was purified by silica gel (5-10% MeOH / chloroform) to give tert-butyl (3S,4S,5R)-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-((4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamido)-4-hydroxypiperidine-1-carboxylate as a diastereomeric mixture. This was further purified by chiral SFC to give two isomers.

[0126] Preparative SFC method details: Column / size: Chiralcel OJ-H (250 X 21) mm, 5u % CO2: 70% % Co-solvent: 30% IPA + ACN Total flow rate: 70.0 g / min Back pressure: 100 bar Temperature: 25 °C UV: 244 nm

[0127] Analytical chiral SFC conditions: Analysis column: Chiralcel OJH (250 X 4.6) mm, 5u BPR pressure: 100 bars Temperature: 22.3 °C Flow rate: 2.8 g / min Mobile phase: CO2 / IPA + ACN (70 / 30) Detection wavelength: UV 200 - 400 nm Isomer 1: (30 mg, 31% yield); chiral SFC t R = 1.8 min; LCMS[M+H] + = 829.0 {Method F: t R = 2.855 min}; Isomer 2: (28 mg, 31% yield); chiral SFC t R = 5.15 min; LCMS[M+H] + = 829.0 {Method F: t R = 3.0 min};

[0128] Step 6: To a solution of (3S,4S,5R)-tert-butyl 3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-((4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide)-4-hydroxypiperidine-1-carboxylate (isomer 1, 30 mg, 0.036 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.15 mL, 1.947 mmol), and the mixture was stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure to give a crude residue. The crude material was purified by preparative HPLC (method A) to give (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4S,5S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxypiperidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-N-methyltetrahydro-2H-pyran-2-carboxamide (isomer 1, 10.6 mg, 47% yield) of Example 16a as an off-white solid. LCMS [M+H] + =641.3{Method A: t R =1.520}; 11H NMR (400 MHz, MeOH-d4) δ ppm 8.72, 8.68 (two singlets, 1H), 8.45 (m, 1H), 7.74 - 7.55 (m, 4H), 7.51 - 7.41 (m, 2H), 7.14 - 7.04 (m, 2H), 4.97 (dd, J = 10.6, 2.8 Hz, 1H), 4.67 - 4.49 (m, 2H), 4.48 - 4.24 (m, 3H), 4.10 (dd, J = 7.9, 2.6 Hz, 1H), 3.95 (dd, J = 8.4, 3.8 Hz, 1H), 3.89 - 3.76 (m, 2H), 3.74 - 3.68 (m, 1H), 3.43 - 3.35 (m, 1H), 3.23, 3.00 (two singlets, 3H), 3.22 - 3.16 (m, 1H), 3.14 - 3.10 (m, 3H), 3.09 - 3.01 (m, 1H) [rotational isomer mixture]; hGal3 IC 50 = 3.5 μM

[0129] Example 16b: To a solution of (3S,4S,5R)-tert-butyl 3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-((4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide)-4-hydroxypiperidine-1-carboxylate (isomer 2, 28 mg, 0.034 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.15 mL, 1.947 mmol) at room temperature and the mixture was stirred for 2 hours. Then the solvent was removed under reduced pressure to give a crude residue. The crude material was purified by preparative LC / MS (method A) to give (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4S,5S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxypiperidine-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-N-methyltetrahydro-2H-pyran-2-carboxamide (isomer 2, 12.4 mg, 0.019 mmol, 57%) as an off-white solid. LCMS [M+H] + =641.1 {Method A: t R =1.517}; 1 H NMR (400 MHz, MeOH-d4) δ ppm 8.71, 8.68 (two singlets,, 1H), 8.53, 8.51 (two singlets, 1H), 7.73 - 7.57 (m, 4H), 7.51 - 7.42 (m, 2H), 7.14 - 7.05 (m, 2H), 4.97 (dt, J = 10.3, 3.4 Hz, 1H), 4.57 - 4.37 (m, 2H), 4.30 - 4.21 (m, 1H), 4.08 (dd, J = 7.5, 2.3 Hz, 1H), 4.01 - 3.96 (m, 1H), 3.90 - 3.67 (m, 5H), 3.50 - 3.41 (m, 2H), 3.27, 3.00 (two singlets, 3H), 3.13 - 3.10 (m, 3H), 3.04 (m, 1H) {rotamer mixture}; hGal3 IC50 = 0.044 μM

[0130] Examples 17a and 17b: Synthesis of (2R,4R,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4S,5S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxypiperidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-N-methyltetrahydro-2H-pyran-2-carboxamide (Isomers 1 and 2)

Chemical Structure

[0131] Step 1: Synthesis of tert-butyl (3S,4S,5R)-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-((4aR,6R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide)-4-hydroxypiperidine-1-carboxylate (4aR,6R,8R,8aR)-8-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (50 mg, 0.118 mmol) / DMF (2 mL) was stirred, and DIPEA (0.062 mL, 0.353 mmol) and HATU (67.0 mg, 0.176 mmol) were added sequentially at room temperature and stirred for 15 minutes. Then, (3S,4S,5R)-tert-butyl 3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxy-5-(methylamino)piperidine-1-carboxylate (50.6 mg, 0.129 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice water and stirred for 15 minutes. The resulting solid was filtered and dried to obtain a crude residue. The obtained crude residue was purified by silica gel (5-10% MeOH / chloroform) to obtain (3S,4S,5R)-tert-butyl 3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-((4aR,6R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamido)-4-hydroxypiperidine-1-carboxylate as a diastereomeric mixture. This was further purified by chiral SFC to obtain two isomers.

[0132] Preparative SFC method details: Column / size: Chiralcel OJ-H (250 X 21) mm, 5u %CO2: 80% % Co-solvent: 20% IPA + ACN Total flow rate: 70.0 g / min Back pressure: 100 bar Temperature: 25 °C UV: 244 nm

[0133] Analytical chiral SFC conditions: Analytical column: Chiralcel OJH (250 X 4.6) mm, 5u BPR Pressure: 100 bars Temperature: 22.3 °C Flow Rate: 3 g / min Mobile Phase: CO2 / IPA + ACN (75 / 25) Detection Wavelength: UV 200 - 400 nm Isomer 1: (28 mg, 0.035 mmol, 30%); Chiral SFC t R = 3.74 min; LCMS [M+H] + = 799.1 {Method F: t R = 3.888 min} Isomer 2: (29 mg, 0.034 mmol, 29%); Chiral SFC t R = 5.91 min; LCMS [M+H] + = 799.2 {Method F: t R = 3.505 min}

[0134] Step 2: To a solution of (3S,4S,5R)-tert-butyl 3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-((4aR,6R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide)-4-hydroxypiperidine-1-carboxylate (Isomer 1, 28 mg, 0.035 mmol) / DCM (1 mL) was added trifluoroacetic acid (0.15 mL, 1.947 mmol) at room temperature and stirred for 2 h. Then the solvent was removed under reduced pressure to obtain a crude residue. The crude material was purified by preparative HPLC (Method A) to give (2R,4R,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4S,5S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxypiperidine-3-yl)-5-hydroxy-6-(hydroxymethyl)-N-methyltetrahydro-2H-pyran-2-carboxamide (Isomer 1, 10.9 mg, 50%) of Example 17a as an off-white solid. LCMS [M+H] + = 611.3 {Method A: t R = 1.257};1 1H NMR (400 MHz, MeOH-d4) δ ppm 8.53 - 8.46 (m, 2H), 7.71 - 7.59 (m, 4H), 7.52 - 7.42 (m, 2H), 7.15 - 7.06 (m, 2H), 5.13 (d, J = 12.5 Hz, 1H), 4.81 - 4.74 (m, 1H), 4.68 (dd, J = 9.2, 6.5 Hz, 1H), 4.56 - 4.35 (m, 2H), 4.14 (s, 1H), 4.01 - 3.56 (m, 5H), 3.48 - 3.36 (m, 1H), 3.25, 3.00 (two singlets, 3H), 3.06 (q, J = 7.3 Hz, 1H), 2.91 - 2.79 (m, 1H), 2.25 - 2.14 (m, 1H) {rotational isomer mixture}; hGal3 IC50 = 5.2 μM

[0135] Example 17b: To a solution of (3S,4S,5R)-tert-butyl 3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-((4aR,6R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide) (isomer 2, 29 mg, 0.036 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.15 mL, 1.947 mmol) at room temperature and stirred for 2 h. Then the solvent was removed under reduced pressure to obtain the crude residue. The crude material was purified by preparative LC / MS (method A) to give ((2R,4R,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4S,5S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxypiperidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-N-methyltetrahydro-2H-pyran-2-carboxamide) (isomer 2, 6.7 mg, 0.011 mmol, 30%) as an off-white solid. LCMS [M + H] + = 611.3 {method A: t R = 1.255}; 11H NMR (400 MHz, MeOH-d4) δ ppm 8.54 - 8.46 (m, 2H), 7.70 - 7.57 (m, 4H), 7.51 - 7.41 (m, 2H), 7.14 - 7.05 (m, 2H), 5.15 - 5.06 (m, 1H), 4.95 - 4.86 (m, 1H), 4.74 - 4.61 (m, 1H), 4.48 - 4.41 (m, 1H), 4.32 (td, J = 10.9, 4.3 Hz, 1H), 4.10 (s, 1H), 4.01 - 3.70 (m, 5H), 3.57 - 3.43 (m, 1H), 3.24, 2.99 (two singlets, 3H), 3.05 (q, J = 7.4 Hz, 1H), 2.85 - 2.69 (m, 1H), 2.32 - 2.15 (m, 1H) {mixture of rotamers}; hGal3 IC50 = 0.13 μM

[0136] Example 18a and 18b: Synthesis of (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3S,4R,5R)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxypiperidin-3-yl)-3,5-dihydroxy-6-(hydroxymethyl)-N-methyltetrahydro-2H-pyran-2-carboxamide (isomers 1 and 2) [Chemical formula]

[0137] Step 1: To a stirred solution of (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-hydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (50 mg, 0.113 mmol) in DMF (2 mL) were added DIPEA (0.059 mL, 0.340 mmol) and HATU (64.6 mg, 0.170 mmol) sequentially at room temperature and the mixture was stirred for 15 minutes. Then (3S,4S,5R)-tert-butyl 3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxy-5-(methylamino)piperidine-1-carboxylate (48.8 mg, 0.125 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice water and stirred for 15 minutes. The resulting solid was filtered and dried to give a crude residue. The obtained crude residue was purified by silica gel (5-10% MeOH / chloroform) to give (3S,4S,5R)-tert-butyl 3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-((4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-hydroxy-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide)-4-hydroxypiperidine-1-carboxylate as a diastereomeric mixture. This was further purified by preparative HPLC (Method C) to give two isomers.

[0138] Analytical HPLC conditions: Analytical column: Symmetry C9 (250 X 4.6) mm, 5u Mobile phase A: 0.1% aqueous TFA Mobile phase B: ACN Flow rate: 1 mL / min Gradient: Elution was carried out at 20-100% B over 20 minutes, then at 100% B for 10 minutes Detection wavelength: UV 200-400 nm Isomer 1: (25 mg, 0.030 mmol, 27%); HPLC t R=16.083 min; LCMS [M+H] + =815.0 {Method F: t R =2.683 min} Isomer 2: (21 mg, 0.025 mmol, 22%); HPLC t R =16.700 min; LCMS [M+H] + =815.2 {Method F: t R =3.98 min}

[0139] Step 2: To a solution of (3S,4S,5R)-tert-butyl 3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-((4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-hydroxy-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide)-4-hydroxypiperidine-1-carboxylate (Isomer 1, 25 mg, 0.031 mmol) / DCM (1 mL) was added trifluoroacetic acid (0.15 mL, 1.947 mmol) at room temperature and stirred for 2 h. Then the solvent was removed under reduced pressure to obtain a crude residue. The crude material was purified by preparative HPLC (Method D) to give (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4S,5S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxypiperidine-3-yl)-3,5-dihydroxy-6-(hydroxymethyl)-N-methyltetrahydro-2H-pyran-2-carboxamide (Isomer 1, 8 mg, 41% yield) of Example 18a as an off-white solid. LCMS [M+H] + =627.2 {Method C: t R =1.500}; 11H NMR (400 MHz, MeOH-d4) δ ppm 8.44, 8.43 (two singlets, 1H), 8.36, 8.34 (two singlets, 1H), 7.70 - 7.56 (m, 4H), 7.50 - 7.41 (m, 2H), 7.13 - 7.04 (m, 2H), 4.98 - 4.90 (m, 1H), 4.80 - 4.75 (m, 1H), 4.65 - 4.50 (m, 2H), 4.44 (d, J = 9.0 Hz, 1H), 4.37 - 4.28 (m, 1H), 4.23 (td, J = 10.7, 4.8 Hz, 1H), 4.14 (d, J = 2.5 Hz, 1H), 4.01 (dd, J = 8.3, 3.8 Hz, 1H), 3.93 - 3.77 (m, 2H), 3.75 - 3.69 (m, 2H), 3.43 - 3.34 (m, 1H), 3.24 (s, 1H), 3.22 - 3.12 (m, 2H) [rotamer mixture]; hGal3 IC50 = 1.8 μM

[0140] Example 18b: To a solution of (3S,4S,5R)-tert-butyl 3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-((4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-hydroxy-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide) (isomer 2, 16 mg, 0.020 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.15 mL, 1.947 mmol) at room temperature and the mixture was stirred for 2 h. The solvent was then removed under reduced pressure to give a crude residue. The crude material was purified by preparative LC / MS (method A) to give (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4S,5S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxypiperidin-3-yl)-3,5-dihydroxy-6-(hydroxymethyl)-N-methyltetrahydro-2H-pyran-2-carboxamide (isomer 2, 2.8 mg, 22%) as an off-white solid. LCMS [M+H] + =627.1 {Method A: t R =1.517}; 1 H NMR (400 MHz, MeOH-d4) δ ppm 8.55 (d, J = 2.9 Hz, 1H), 8.53 (d, J = 2.4 Hz, 1H), 7.72 - 7.66 (m, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.53 - 7.44 (m, 2H), 7.16 - 7.07 (m, 2H), 4.97 (dd, J = 10.6, 2.8 Hz, 1H), 4.80 - 4.73 (m, 1H), 4.48 - 4.39 (m, 2H), 4.16 (d, J = 3.4 Hz, 1H), 4.05 (d, J = 5.4 Hz, 1H), 3.94 - 3.70 (m, 6H), 3.55 - 3.46 (m, 1H), 3.29, 3.02 (two singlets, 3H), 3.06 (d, J = 7.8 Hz, 1H) {mixture of rotamers}; hGal3 IC50 = 0.05 μM

[0141] Example 19: Synthesis of (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3S,4R,5R)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxy-1-methylpiperidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-N-methyltetrahydro-2H-pyran-2-carboxamide

Chem.

[0142] Step 1: Synthesis of (1R,5R,6S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-oxa-3-azabicyclo[4.1.0]heptane (homo chiral) To a stirred solution of tert-butyl (1R,5R,6S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (100 mg, 0.277 mmol) in dichloromethane (5 mL) were added 4A molecular sieves (100 mg) and BF3·OEt2 (0.105 mL, 0.832 mmol) sequentially at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was filtered through Celite and washed with excess DCM (20 mL), and the filtrate was concentrated under reduced pressure to give (1R,5R,6S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-oxa-3-azabicyclo[4.1.0]heptane (70 mg, 83% yield) as a pale yellow oil. LCMS [M+H] + = 261.4 {Method E: t R = 0.90 min}

[0143] Step 2: Synthesis of (1R,5R,6S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-3-methyl-7-oxa-3-azabicyclo[4.1.0]heptane (1R,5R,6S)-5-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-oxa-3-azabicyclo[4.1.0]heptane (70 mg, 0.269 mmol) / MeOH (5 mL) was added paraformaldehyde (40.4 mg, 1.345 mmol) and AcOH (0.1 mL), and the mixture was stirred at room temperature for 10 minutes. Then sodium cyanoborohydride (16.90 mg, 0.269 mmol) was added, and the mixture was stirred at room temperature for 16 hours. MeOH was removed under reduced pressure, and the resulting crude residue was extracted with 10% MeOH / DCM (2 X 30 mL), washed with water, brine, dried over sodium sulfate, and concentrated. The resulting residue was purified by silica gel chromatography (20 - 50% EtOAc / n-hexane) to give (1R,5R,6S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-3-methyl-7-oxa-3-azabicyclo[4.1.0]heptane (70 mg, 92% yield) as an off-white solid. LCMS [M+H] + =275.2{Method C: t R =1.828 min}

[0144] Step 3: Synthesis of (3R,4R,5S)-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-1-methyl-5-(methylamino)piperidin-4-ol In a sealed tube, (1R,5R,6S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-3-methyl-7-oxa-3-azabicyclo[4.1.0]heptane (70 mg, 0.255 mmol) / methanamine (33% ethanol solution, 5 mL, 0.255 mmol) was heated at 65 °C for 16 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the title compound (65 mg, 81% yield) was obtained as a brown solid. LCMS [M+H] + =306.2{Method C: t R =0.833 min}

[0145] Step 4: Synthesis of (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3S,4R,5R)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxy-1-methylpiperidin-3-yl)-7-methoxy-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (30 mg, 0.066 mmol) / DMF (2 mL) was stirred at room temperature, and DIPEA (0.035 mL, 0.198 mmol) and HATU (37.6 mg, 0.099 mmol) were added sequentially and stirred for 15 minutes. Then, (3R,4R,5S)-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-1-methyl-5-(methylamino)piperidin-4-ol (24.14 mg, 0.079 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was quenched with ice water and stirred for 15 minutes. The resulting solid was filtered and dried to give the title compound (35 mg, 55% yield) as a brown solid. LCMS [M+H] + = 743.2 {Method C: t R = 2.88 min}

[0146] Step 5: To a solution of (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3S,4R,5R)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxy-1-methylpiperidin-3-yl)-7-methoxy-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (30 mg, 0.040 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.5 mL, 6.49 mmol) at room temperature, and the mixture was stirred for 2 h. Then the solvent was removed under reduced pressure to give a crude residue. The crude material was purified by preparative HPLC (Method D) to afford (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3S,4R,5R)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxy-1-methylpiperidin-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-N-methyltetrahydro-2H-pyran-2-carboxamide (18.7 mg, 0.029 mmol, 71%) of Example 19 as an off-white solid. LCMS [M+H] + =655.1 {Method A: t R =1.685 min}; 1 H NMR (400 MHz, MeOH-d4) δ ppm 8.62, 8.59 (two singlets, 1H), 8.41, 8.38 (two singlets, 1H), 7.63 - 7.48 (m, 4H), 7.42 - 7.33 (m, 2H), 7.05 - 6.96 (m, 2H), 4.88 (dd, J = 10.1, 3.1 Hz, 1H), 4.54 - 4.47 (m, 1H), 4.41 - 4.23 (m, 3H), 4.01 (d, J = 2.9 Hz, 1H), 3.89 (d, J = 3.2 Hz, 1H), 3.81 - 3.74 (m, 2H), 3.71 - 3.59 (m, 4H), 3.17 - 3.15 (m, 3H), 3.05 - 2.86 (m, 6H), 2.75 (s, 1H) {mixture of rotamers}; hGal3 IC50 = 0.02 μM

[0147] Examples 20a and 20b: Synthesis of (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4S,5S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide (isomers 1 and 2)

Chemical formula

[0148] Step 1: Synthesis of 3-azido-3,6-dihydro-2H-pyran To a stirred solution of 3,6-dihydro-2H-pyran-3-ol (1 g, 9.99 mmol) in DCM (50 mL) under N2 at 0 °C, triethylamine (2.78 mL, 19.98 mmol) and mesyl chloride (0.934 mL, 11.99 mmol) were added sequentially and stirred for 30 minutes. The reaction mixture was then extracted with DCM (100 mL), washed with water and brine, dried over sodium sulfate, and concentrated. The resulting crude mesylate was dissolved in DMSO (10 mL), sodium azide (2.74 g, 42.1 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with EtOAc (3 x 50 mL), washed with water and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to give a crude residue. This was purified by flash chromatography (15 - 20% EtOAc / n-hexane) to give 3-azido-3,6-dihydro-2H-pyran (0.75 g, 5.95 mmol, 71%). 1 1H NMR (400 MHz, chloroform-d) δ ppm 6.07 - 6.22 (m, 1H), 5.84 - 5.97 (m, 1H), 4.18 - 4.25 (m, 1H), 4.07 - 4.15 (m, 1H), 3.96 (ddd, J = 12.0, 3.0, 1.0 Hz, 1H), 3.81 - 3.86 (m, 1H), 3.55 (br.s, 1H)

[0149] Step 2: Synthesis of 1-(3,6-dihydro-2H-pyran-3-yl)-4-(3-fluorophenyl)-1H-1,2,3-triazole To a solution of 3-azido-3,6-dihydro-2H-pyran (0.74 g, 5.91 mmol) in DMF (10 mL) and water (3 mL), sodium ascorbate (1.172 g, 5.91 mmol), copper(II) sulfate pentahydrate (1.329 g, 5.32 mmol) and 3-fluorophenylacetylene (2.73 mL, 23.66 mmol) were added. The mixture was degassed with N2 for 10 minutes and heated at 85 °C for 15 minutes. Then the reaction mixture was cooled to room temperature, diluted with DCM (50 mL) / water (50 mL) and stirred for 30 minutes. The organic layer was separated, the aqueous layer was re-extracted with DCM (2 x 30 mL), the combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated. The resulting crude residue was purified by flash chromatography (35 - 50% EtOAc / n-hexane) to give the title compound (1.36 g, 5.45 mmol, 92%) as a pale yellow solid. LCMS [M+H] + = 246.2 {Method C: t R = 2.006 min}

[0150] Step 3: Synthesis of (3S,4R,5S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,4-diol (racemic) To a stirred solution of 1-(3,6-dihydro-2H-pyran-3-yl)-4-(3-fluorophenyl)-1H-1,2,3-triazole (0.4 g, 1.631 mmol) in acetone (4 mL) and water (1 mL), 4-methylmorpholine-N-oxide (0.287 g, 2.446 mmol) and osmium tetroxide (2.048 mL, 0.163 mmol, 2.5% w / v t-butanol solution) were added at room temperature and stirred for 14 h. The reaction mixture was quenched with saturated Na2SO3 solution and acetone was removed under reduced pressure to give a crude residue. The obtained crude residue was extracted with EtOAc (2 X 100 mL), washed with water and brine, dried over sodium sulfate and concentrated. The obtained crude residue was purified by flash chromatography (80 - 100% EtOAc / n-hexane) to give the title compound (0.25 g, 0.895 mmol, 55%). LCMS [M+H] + = 280.2 {Method C: t R = 1.025 min}

[0151] Step 4: Synthesis of (3aS,7S,7aR)-7-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-3aH-[1,3,2]dioxathiol[4,5-c]pyran 2,2-dioxide (racemic) To a stirred solution of (3S,4R,5S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,4-diol (0.25 g, 0.895 mmol) in DCM (10 mL), TEA (0.250 mL, 1.790 mmol) was added at room temperature and stirred for 5 min. The reaction mixture was then cooled to 0 °C and SOCl2 (0.131 mL, 1.790 mmol) was added under N2, and the mixture was returned to room temperature and stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the crude product was extracted with EtOAc (2 X 50 mL), washed with water and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (60 - 95% EtOAc / n-hexane) to give the title compound (0.23 g, 0.707 mmol, 79%). LCMS [M+H] + = 326.4 {Method E: t R = 1.08 min}

[0152] Step 5: Synthesis of (3aS,7S,7aR)-7-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-3aH-[1,3,2]dioxathiol[4,5-c]pyran 2,2-dioxide (racemate) (3aS,7S,7aR)-7-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-3aH-[1,3,2]dioxathiol[4,5-c]pyran 2-oxide (0.2 g, 0.615 mmol) / acetonitrile (3 mL) and water (1 mL) in a stirred solution, sodium periodate (0.263 g, 1.230 mmol) and ruthenium(III) chloride hydrate (0.014 g, 0.061 mmol) were added at room temperature and stirred for 12 h. The solvent was removed under reduced pressure, and the crude product was extracted with EtOAc (2 X 50 mL), washed with water and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the crude residue was purified by flash chromatography (80 - 100% of EtOAc / n-hexane) to give the title compound (160 mg, 0.469 mmol, 76%). LCMS [M+H] + = 342.2 {Method F: t R = 2.028 min}

[0153] Step 6: Synthesis of (3R,4R,5S)-3-azido-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-4-ol (racemate) (3aS,7S,7aR)-7-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-3aH-[1,3,2]dioxathiol[4,5-c]pyran 2,2-dioxide (160 mg, 0.469 mmol) / DMF (4 mL) was stirred, and sodium azide (122 mg, 1.875 mmol) was added at room temperature. The mixture was heated at 60 °C for 3 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure to obtain a crude residue. The obtained crude residue was dissolved in THF (2 mL), and 1 mL of a stock solution [H2SO4 (1 mL) + water (0.4 mL) + THF (8.6 mL)] was added at 0 °C, and the mixture was stirred for 30 min. The reaction mixture was basified with NaHCO3, filtered through celite, washed with excess EtOAc, and the filtrate was concentrated under reduced pressure to obtain a crude residue. This was purified by flash chromatography (60 - 95% EtOAc / n-hexane) to obtain the title compound (90 mg, 0.296 mmol, 63%). LCMS [M+H] + = 305.2 {Method C: t R = 1.94 min}

[0154] Step 7: Synthesis of (3R,4S,5S)-3-amino-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-4-ol (racemic) (3R,4R,5S)-3-Azido-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-4-ol (90 mg, 0.296 mmol) / MeOH (4 mL) was stirred, and 10% Pd / C (6.30 mg, 0.030 mmol) was added. The mixture was stirred at room temperature for 16 h under a hydrogen atmosphere. The reaction mixture was filtered through celite, washed with excess MeOH, and the filtrate was concentrated to obtain the title compound (60 mg, 0.216 mmol, 73%). LCMS [M+H] + = 279.5 {Method E: t R = 0.72 min}

[0155] Step 8: To a stirred solution of (3R,4S,5S)-3-amino-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-4-ol (45.8 mg, 0.165 mmol) in DMF (2 mL) was added DIPEA (0.192 mL, 1.098 mmol) at room temperature. After 5 minutes, (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (50 mg, 0.110 mmol) and HATU (104 mg, 0.274 mmol) were added and the reaction mixture was stirred at room temperature for 12 hours, then diluted with ice-cold water and stirred for 10 minutes. The resulting solid was filtered, dried, and the crude residue containing (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4S,5S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide was obtained as a diastereomeric mixture. The resulting crude residue was purified by preparative HPLC to separate two diastereomers.

[0156] Preparative HPLC method details: Column: Lux-cellulose C4 (250 X 21.2) mm, 5 μm; Mobile phase A / Mobile phase B: 0.1% DEA / MeOH; Flow rate: 19 mL / min; Time (min) / %B: 0 / 100, 20 / 100 Isomer 1: (20 mg, 0.028 mmol, 25.5% yield); LCMS [M+H] + = 716.0 {Method F: t R = 2.287 min} Isomer 2: (18 mg, 0.025 mmol, 22.91% yield); LCMS [M+H] + = 716.0 {Method F: t R = 2.30 min}

[0157] Step 9: (4aR,6R,7R,8R,8aR)-8-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4S,5S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (isomer 1, 20 mg, 0.028 mmol) was suspended in 80% acetic acid (1 mL) and heated at 70 °C for 14 h. The reaction mixture was then cooled to room temperature and the solvent removed in vacuo to give a crude residue. The crude material was purified by preparative HPLC [Method A] to give (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4S,5S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide of Example 20a (isomer 1, 5 mg, 7.89 μmol, 28%). LCMS [M+H] + =628.1 {Method A: t R =1.618 min}; 1 H NMR (400 MHz, MeOH-d4) δ = 8.63 (s, 1H), 8.48 (s, 1H), 7.70 (dd, J = 7.7, 3.1 Hz, 2H), 7.66 - 7.61 (m, 2H), 7.53 - 7.46 (m, 2H), 7.13 (td, J = 8.1, 4.0 Hz, 2H), 4.95 (dd, J = 10.6, 2.8 Hz, 1H), 4.67 (d, J = 4.4 Hz, 1H), 4.35 - 4.25 (m, 3H), 4.21 (dd, J = 10.3, 4.9 Hz, 1H), 4.15 (d, J = 2.7 Hz, 1H), 4.11 - 4.05 (m, 1H), 4.03 - 3.94 (m, 2H), 3.87 - 3.81 (m, 2H), 3.79 - 3.73 (m, 1H), 3.47 (t, J = 10.9 Hz, 1H), 3.20 (s, 3H); hGal3 IC 50 =36 μM

[0158] Example 20b: (2R,3R,4S,5R,6R)-4-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4S,5S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide (isomer 2, 5.5 mg, 8.76 μmol, 34.8% yield) was used in the same manner as in Example 20a of Step 9 to produce (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4S,5S)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (isomer 2) using it as a starting material. LCMS [M+H] + =628.1 {Method A: t R =1.610 min}; 1 H NMR (400 MHz, MeOH-d4) δ = 8.63 (s, 1H), 8.48 (s, 1H), 7.70 (dd, J = 7.7, 3.1 Hz, 2H), 7.66 - 7.61 (m, 2H), 7.53 - 7.46 (m, 2H), 7.13 (td, J = 8.1, 4.0 Hz, 2H), 4.95 (dd, J = 10.6, 2.8 Hz, 1H), 4.67 (d, J = 4.4 Hz, 1H), 4.35 - 4.25 (m, 3H), 4.21 (dd, J = 10.3, 4.9 Hz, 1H), 4.15 (d, J = 2.7 Hz, 1H), 4.11 - 4.05 (m, 1H), 4.03 - 3.94 (m, 2H), 3.87 - 3.81 (m, 2H), 3.79 - 3.73 (m, 1H), 3.47 (t, J = 10.9 Hz, 1H), 3.20 (s, 3H); hGal3 IC 50 =0.09 μM

[0159] Example 21: Synthesis of (2R,3R,4S,5R,6R)-4-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3R,4S,5S)-5-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxytetrahydro-2H-pyran-2-carboxamide

Chemical formula

[0160] Step 2: Synthesis of N-((3S,4R,5S)-4,5-Dihydroxytetrahydro-2H-pyran-3-yl)-N-methyl-4-nitrobenzenesulfonamide (racemate) To a stirred solution of N-(3,6-dihydro-2H-pyran-3-yl)-N-methyl-4-nitrobenzenesulfonamide (4.0 g, 13.41 mmol) in acetone (50 mL) and water (13.33 mL) were added 4-methylmorpholine-N-oxide (2.356 g, 20.11 mmol) and osmium tetroxide (5.05 mL, 0.402 mmol, 2.5% w / v in t-butanol) at room temperature, and the mixture was stirred for 16 h. The reaction mixture was quenched with saturated Na2SO3 solution, and the acetone was removed under reduced pressure to give a crude residue. The obtained crude product was extracted with EtOAc (2 x 100 mL), washed with water and brine, dried over sodium sulfate, and concentrated. The resulting residue was purified by flash chromatography (80 - 100% EtOAc / n-hexane) to give the title compound (3.5 g, 10.53 mmol, 79%) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ ppm 8.36 (d, J = 8.7 Hz, 2H), 8.06 (d, J = 8.7 Hz, 2H), 4.75 (d, J = 4.2 Hz, 1H), 4.53 (d, J = 6.4 Hz, 1H), 3.98 (br td, J = 10.6, 4.9 Hz, 1H), 3.50 - 3.70 (m, 4H), 3.24 - 3.37 (m, 2H, overlapping with water peak), 2.79 (s, 3H)

[0161] Step 3: Synthesis of N-((3aS,7S,7aR)-2,2-dioxidotetrahydro-3aH-[1,3,2]dioxathiol[4,5-c]pyran-7-yl)-N-methyl-4-nitrobenzenesulfonamide (racemic) To a stirred solution of N-((3S,4R,5S)-4,5-dihydroxytetrahydro-2H-pyran-3-yl)-N-methyl-4-nitrobenzenesulfonamide (3.5 g, 10.53 mmol) in DCM (30 mL) were added TEA (2.94 mL, 21.06 mmol) and thionyl chloride (1.537 mL, 21.06 mmol) sequentially at 0 °C, and the mixture was stirred for 1 h. The reaction mixture was then extracted with DCM (2 x 75 mL), washed with water and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to give a residue, which was used in the next step without further purification. To a stirred solution of N-methyl-4-nitro-N-((3aS,7S,7aR)-2-oxidotetrahydro-3aH-[1,3,2]dioxathiol[4,5-c]pyran-7-yl)benzenesulfonamide (3.8 g, 10.04 mmol) in acetonitrile (100 mL) and water (66.7 mL) were added sodium periodate (4.30 g, 20.09 mmol) and ruthenium(III) chloride hydrate (0.163 g, 0.036 mmol) sequentially at 0 °C. The reaction mixture was then warmed to room temperature and stirred for 12 h. The solvent was removed under reduced pressure to give a crude residue, which was extracted with EtOAc (150 mL), washed with water (100 mL), saturated NaHSO4 solution (3 x 50 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to give a crude residue. This was purified by flash chromatography (70 - 100% EtOAc / n-hexane) to give N-((3aS,7S,7aR)-2,2-dioxidotetrahydro-3aH-[1,3,2]dioxathiol[4,5-c]pyran-7-yl)-N-methyl-4-nitrobenzenesulfonamide (3.5 g, 8.87 mmol, 88%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (d, J = 9.0 Hz, 2H), 8.06 - 8.10 (m, 2H), 5.55 - 5.61 (m, 1H), 5.38 - 5.42 (m, 1H), 4.23 - 4.32 (m, 2H), 3.76 (dd, J = 14.8, 1.8 Hz, 1H), 3.62 - 3.68 (m, 1H), 3.48 - 3.55 (m, 1H), 2.89 (s, 3H)

[0162] Step 4: Synthesis of N-((3S,4S,5R)-5-azido-4-hydroxytetrahydro-2H-pyran-3-yl)-N-methyl-4-nitrobenzenesulfonamide (racemic) To a stirred solution of N-((3aS,7S,7aR)-2,2-dioxidotetrahydro-3aH-[1,3,2]dioxathiol[4,5-c]pyran-7-yl)-N-methyl-4-nitrobenzenesulfonamide (0.7 g, 1.775 mmol) in DMF (15 mL) was added sodium azide (0.462 g, 7.10 mmol) at room temperature, and the mixture was heated at 60 °C for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure to give a crude residue. The obtained crude residue was dissolved in THF (8.6 mL), and water (0.4 mL) and H2SO4 (1 mL) were added at 0 °C, and the mixture was stirred for 30 minutes. This reaction mixture was basified with solid NaHCO3, filtered through celite, and washed with excess EtOAc. The filtrate was concentrated under reduced pressure to give a crude residue. This was purified by flash chromatography (30 - 50% EtOAc / n-hexane) to give the title compound (0.5 g, 1.352 mmol, 76%). LCMS [M+18] + = 375.2 {Method C: t R = 1.917 min}

[0163] Step 5: Synthesis of N-((3S,4S,5R)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-N-methyl-4-nitrobenzenesulfonamide (racemic) To a solution of N-((3S,4S,5R)-5-azido-4-hydroxytetrahydro-2H-pyran-3-yl)-N-methyl-4-nitrobenzenesulfonamide (2.2 g, 6.16 mmol) in DMF (20 mL) and water (5.00 mL) were added sodium ascorbate (1.220 g, 6.16 mmol), copper(II) sulfate pentahydrate (1.383 g, 5.54 mmol) and 1-ethynyl-3-fluorobenzene (2.85 mL, 24.63 mmol) at room temperature. The mixture was degassed with N2 for 10 minutes and heated at 80 °C for 30 minutes. The reaction mixture was then cooled to room temperature, diluted with DCM (100 mL) / water (100 mL), stirred for 30 minutes, the organic layer was separated, and the aqueous layer was re-extracted with DCM (2 x 50 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated. The resulting crude residue was purified by flash chromatography (0 - 15% MeOH / DCM) to give N-((3S,4S,5R)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-N-methyl-4-nitrobenzenesulfonamide (2.1 g, 4.40 mmol, 71%) as an off-white solid. LCMS [M+H] + =478.2 {Method C: t R =2.453 min}

[0164] Step 6: Synthesis of (3R,4R,5S)-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-(methylamino)tetrahydro-2H-pyran-4-ol To a solution of N-((3S,4S,5R)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-N-methyl-4-nitrobenzenesulfonamide (1 g, 2.094 mmol) in acetone (10 mL), potassium carbonate (0.868 g, 6.28 mmol) and benzenethiol (0.346 g, 3.14 mmol) were added sequentially at room temperature, and the mixture was stirred for 16 h. Then the solvent was removed under reduced pressure to obtain a crude residue. This was purified by flash chromatography (0 - 20% MeOH (10% ammonia) / DCM) to give (3R,4R,5S)-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-(methylamino)tetrahydro-2H-pyran-4-ol as a racemic mixture.

[0165] The racemic mixture was further purified by SFC to separate the enantiomers. Preparative chiral HPLC conditions: Preparative column: Chiralpak IA (250 X 30) mm, 5um BPR pressure: 100 bars Temperature: 25 °C Flow rate: 60 g / min Mobile phase: CO2 / 0.2% DEA + MeOH (70 / 30) Detection wavelength: 245 nm Sample preparation: 10 mg / MeOH (1 mL)

[0166] Analytical chiral HPLC conditions: Analytical column: Chiralpak IA (250 X 30) mm, 5um BPR pressure: 100 bars Temperature: 30 °C Flow rate: 3 g / min Mobile phase: CO2 / 0.2% DEA + MeOH (70 / 30) Detection wavelength: UV 200 - 400 nm

[0167] Enantiomer 1 (by-product): 0.15 g: chiral HPLC t R= 3.63 minutes; LCMS [M+H] + = 293.2 {Method C: t R = 0.934 minutes} Enantiomer 2 (target compound): 0.18 g: Chiral HPLC t R = 5.77 minutes; LCMS [M+H] + = 293.1 {Method C: t R = 0.941 minutes}

[0168] Step 7: To a stirred solution of (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (200 mg, 0.439 mmol) / DMF (5 mL) at room temperature were added HATU (334 mg, 0.878 mmol), DIPEA (0.767 mL, 4.39 mmol) and (3R,4R,5S)-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-(methylamino)tetrahydro-2H-pyran-4-ol (enantiomer 2, 128 mg, 0.439 mmol) in sequence, and the mixture was stirred for 16 h. The reaction mixture was poured into ice-cold water (100 mL) and stirred for 10 min. The resulting solid was filtered and dried to give a crude residue. This was further purified by flash chromatography (0 - 10% MeOH / DCM) to give (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3S,4R,5R)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-7-methoxy-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (0.195 g, 0.259 mmol, 59%) as an off-white solid. LCMS [M+H] + = 730.2 {Method C: t R = 3.051 minutes}

[0169] Step 8: (4aR,6R,7R,8R,8aR)-8-(4-(3-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3S,4R,5R)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-7-methoxy-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (195 mg, 0.267 mmol) was suspended in 70% acetic acid (10 mL) and heated at 70 °C for 16 h. The reaction mixture was then cooled to room temperature and the solvent was removed under reduced pressure to give a crude residue. The obtained crude residue was purified by preparative HPLC (Method B) to give (2R,3R,4S,5R,6R)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N-((3S,4R,5R)-5-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-N-methyltetrahydro-2H-pyran-2-carboxamide (0.095 g, 0.148 mmol, 55%) of Example 21 as an off-white solid. LCMS [M+H] + =642.2 {Method C: t R =1.95}; 1 H NMR (400 MHz, MeOH-d4) δ ppm 8.70 (d, J = 8.5 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H), 7.57 - 7.71 (m, 4H), 7.43 - 7.49 (m, 2H), 7.06 - 7.12 (m, 2H), 4.98 (br d, J = 8.0 Hz, 1H), 4.62 - 4.78 (m, 1H), 4.41 - 4.60 (m, 3H), 4.06 - 4.26 (m, 3H), 3.65 - 4.01 (m, 6H), 2.99 - 3.26 (m, 6H) [rotamer mixture]; hGal3 IC 50 =0.03 μM

[0170] Example 22: Synthesis of (2R,3R,4S,5R,6R)-N-((3S,4R,5R)-5-(5-Fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-N-methyltetrahydro-2H-pyran-2-carboxamide (Isomers 1 and 2) [Chemical formula]

[0171] Step 1: To a stirred solution of 5-fluoro-1H-pyrazolo[3,4-b]pyridine (67.8 mg, 0.494 mmol) in THF (3 mL) were added 18-crown-6 (171 mg, 0.647 mmol) and NaH (25.9 mg, 0.647 mmol, 60% w / w) at room temperature, and the mixture was refluxed at 80 °C for 10 minutes. Then, N-((3aS,7S,7aR)-2,2-dioxidotetrahydro-3aH-[1,3,2]dioxathiol[4,5-c]pyran-7-yl)-N-methyl-4-nitrobenzenesulfonamide (150 mg, 0.380 mmol) / THF (3 mL) was added dropwise over 5 minutes, and the mixture was refluxed at 80 °C for 16 hours. The reaction mixture was cooled to 0 °C, acidified with concentrated hydrochloric acid (approx. pH = 1), and further refluxed at 80 °C for 2 hours. The reaction mixture was cooled to room temperature, neutralized with 10% aqueous NaHCO3, and extracted with EtOAc (2 X 25 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated. The resulting crude residue was purified by flash chromatography (60 - 80% EtOAc / n-hexane) to obtain N-((3S,4S,5R)-5-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-N-methyl-4-nitrobenzenesulfonamide as a racemate. The racemate was further purified by chiral SFC to obtain pure enantiomer 1 and enantiomer 2.

[0172] Preparative chiral HPLC conditions: Fractionation column: Chiralpak ADH (250 X 30) mm, 5um BPR pressure: 100 bars Temperature: 25 °C Flow rate: 60 g / min Mobile phase: CO2 / 0.4% DEA + EtOH (60 / 40) Detection wavelength: 245 nm Sample preparation: 10 mg / MeOH (1 mL)

[0173] Analytical chiral HPLC conditions: Analytical column: Chiralpak ADH (250 X 4.6) mm, 5um BPR pressure: 100 bars Temperature: 25 °C Flow rate: 3 g / min Mobile phase: CO2 / 0.4% DEA + EtOH (60 / 40) Detection wavelength: UV 200 - 400 nm

[0174] Enantiomer 1: (50 mg, 0.111 mmol, 29.1% yield); chiral HPLC t R = 5.59 min; LCMS [M+H] + = 452.2 {Method C: t R = 2.352 min} Enantiomer 2: (50 mg, 0.111 mmol, 29.1% yield); chiral HPLC t R = 8.23 min; LCMS [M+H] + = 452.2 {Method C: t R = 2.353 min}

[0175] Step 2: To a stirred solution of N-((3S,4S,5R)-5-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-N-methyl-4-nitrobenzenesulfonamide (enantiomer 1, 50 mg, 0.111 mmol) / acetone (2 mL) was added K2CO3 (45.9 mg, 0.332 mmol), followed by thiophenol (0.031 mL, 0.299 mmol) at room temperature. The mixture was stirred for 2 hours, then the solvent was removed under reduced pressure to give a crude residue. The obtained crude product was purified by flash chromatography (5 - 15% MeOH(5% NH3) / CHCl3) to give (3R,4R,5S)-3-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-(methylamino)tetrahydro-2H-pyran-4-ol (20 mg, 0.075 mmol, 68%). LCMS [M+H] + = 267.2 {Method D: t R = 0.57 min}

[0176] Step 3: To a stirred solution of (4aR,6R,7R,8R,8aR)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylic acid (25 mg, 0.055 mmol) and (3R,4R,5S)-3-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-(methylamino)tetrahydro-2H-pyran-4-ol (14.62 mg, 0.055 mmol) in DMF (0.6 mL) were added DIPEA (0.048 mL, 0.274 mmol) and HATU (31.3 mg, 0.082 mmol) sequentially at room temperature and the mixture was stirred for 16 h. The reaction mixture was then diluted with ice-cold water (20 mL) and stirred for 10 min. The resulting solid was filtered off, dried to give (4aR,6R,7R,8R,8aR)-N-((3S,4R,5R)-5-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (25 mg, 0.036 mmol, 65%). LCMS [M+H] + =704.4{Method D: t R =1.28 min}

[0177] Step 4: (4aR,6R,7R,8R,8aR)-N-((3S,4R,5R)-5-(5-Fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-8-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-7-methoxy-N-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxamide (30 mg, 0.043 mmol) was suspended in 70% acetic acid (10 mL) and heated at 75 °C for 16 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC (Method A) to give (2R,3R,4S,5R,6R)-N-((3S,4R,5R)-5-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-hydroxytetrahydro-2H-pyran-3-yl)-4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)-3-methoxy-N-methyltetrahydro-2H-pyran-2-carboxamide (isomer 1, 13.4 mg, 0.022 mmol, 51%) of Example 22a. LCMS [M+H] + =616.1 {Method A: t R =1.54 min}; 1 H NMR (400 MHz, MeOH-d4) δ = 8.71 (d, J = 7.0 Hz, 1H), 8.52 (dt, J = 6.5, 2.0 Hz, 1H), 8.15 (d, J = 3.0 Hz, 1H), 7.97 (dt, J = 8.4, 3.1 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.67 - 7.60 (m, 1H), 7.47 (td, J = 7.9, 5.8 Hz, 1H), 7.09 (td, J = 8.5, 2.5 Hz, 1H), 5.16 - 4.95 (m, 2H), 4.79 - 4.65 (m, 1H), 4.58 - 4.51 (m, 1H), 4.46 - 4.41 (m, 1H), 4.25 - 4.13 (m, 2H), 4.09 - 3.88 (m, 3H), 3.88 - 3.65 (m, 4H), 3.26 (s, 1H), 3.12 (s, 2H), 3.09 (s, 2H), 3.01 (s, 1H); hGal3 IC 50 =>10 μM

[0178] Example 22b: Prepared in the same manner as described in Example 22a, using enantiomer 2 as the starting material in Step 2. LCMS [M+H]+ = 616.1 {Method A: t R = 1.54 min}; 1 1H NMR (400 MHz, MeOH-d4) δ ppm 8.67 - 8.75 (m, 1H), 8.39 - 8.53 (m, 1H), 8.13 - 8.22 (m, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.38 - 7.80 (m, 3H), 7.02 - 7.17 (m, 1H), 5.18 - 5.32 (m, 1H), 4.92 - 5.12 (m, 2H), 4.71 - 4.82 (m, 2H), 4.38 - 4.49 (m, 1H), 3.66 - 4.15 (m, 8H), 3.27 (s, 1H), 3.09 - 3.12 (m, 3H), 3.04 (s, 2H) (mixture of rotamers); hGal3 IC 50 = 0.04

Claims

1. A compound selected from the following Compounds 1 to 22 or a pharmaceutically acceptable salt thereof. 【Table 1】 【Table 2】 【Table 3】 【Table 4】

2. A composition comprising the compound according to Claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

3. A medicament for treating fibrosis of organs (including liver, kidney, lung, heart, and skin), liver diseases and conditions (including acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis, portal hypertension, aplasia, non-alcoholic steatohepatitis (NASH), liver failure, and hepatic blood flow disorder), cell proliferative diseases, cell proliferative cancers, and cell proliferative conditions (including solid tumors, solid tumor metastasis, angiofibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL), and infiltration and metastasis of cancer cells), inflammatory diseases and conditions (including psoriasis, nephrosis, and pneumonia), gastrointestinal diseases and conditions (including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and abnormal pancreatic secretion), kidney diseases and conditions, urinary tract-related diseases and conditions (including benign prostatic hyperplasia or neurogenic bladder-related diseases, spinal cord tumors, intervertebral disc herniation, spinal canal stenosis, and diabetes-related symptoms), lower urinary tract diseases and conditions (including lower urinary tract obstruction), inflammatory diseases and conditions of the lower urinary tract (including micturition disorders and frequent urination), pancreatic diseases and conditions, abnormal angiogenesis-related diseases and conditions (including arteriosclerosis obliterans), scleroderma, brain-related diseases and conditions (including cerebral infarction and cerebral hemorrhage), neuropathic pain and peripheral neuropathy, eye diseases and conditions (including age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and scar after glaucoma filtration surgery), which comprises the compound according to Claim 1 or a pharmaceutically acceptable salt thereof.

4. The medicament according to Claim 3, wherein the disease or condition is renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, or systemic sclerosis.

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