Galectin-3 inhibitors

Abstract

The present disclosure relates to compounds of formula (I) that inhibit Gal-3, including pharmaceutically acceptable salts, compositions containing such compounds, and methods of using and preparing such compounds and compositions. TIFF2023527396000060.tif39153

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 030,968, filed May 28, 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Galectin-3 (Gal-3) is a β-galactoside-binding lectin of approximately 30 kDa (Cell 76: 597-598) that is involved in regulating inflammatory and fibrotic processes (Immunological Reviews 230: 160-171). Under conditions of uncontrolled inflammation and fibrosis, Gal-3 promotes fibroblast proliferation and transformation and mediates collagen production (Circulation 110:3121-3128).

[0003] Gal-3 is localized in many cellular locations (e.g., cytoplasm, nucleus, and cell surface) and is secreted into the bloodstream by various cells, primarily macrophages and monocytes (J Pharmacol Exp Ther 351:336-343). Multiple lines of evidence support the involvement of Gal-3 in the progression of fibrosis in multiple organs, including 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 its modulation may be useful for the treatment of heart failure (Curr. Heart Fail. Rep. 7:1-8). Gal-3 is involved in cell proliferation and differentiation, playing a crucial role in angiogenesis, apoptosis, and metastasis (Galectin-3C: Human Lectin for Treatment of Cancer. ACS Symposium Series, Vol. 1115. Chapter 12, 195-23). ​​Therefore, regulating Gal-3 may be used for cancer treatment. Recently, it has been demonstrated that Gal-3 inhibitors can be used in combination with immunotherapy to produce favorable results (Galectin Therapeutics. Press Release, February 7, 2017).

[0004] Several publications and patent applications describe Gal-3 synthesis inhibitors being investigated as antifibrotic agents, with recent examples of such studies including WO2005113568, WO2005113569, WO2014067986, WO2017080973, WO2016120403, US20140099319, WO2018209255, WO2019067702, WO2019 / 075045, and WO2019 / 241461.

[0005] The present disclosure relates to bifunctional compounds that contain both Gal-3 binding sites and E3 ubiquitin ligase binding sites, and methods for using the same, which are useful degraders or inhibitors of Gal-3.

[0006] (Details of the invention) The present disclosure relates to compounds of the present invention that inhibit Gal-3, including pharmaceutically acceptable salts, compositions comprising such compounds, and methods of using and preparing such compounds and compositions.

[0007] In a first aspect, the present invention provides, inter alia, a compound of formula (I): [ka] [In the formula, Ar 1 independently [ka] and; Ar 2 are independently phenyl or naphthyl; where each ring moiety is selected from cyano, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, and C 1-4 substituted with 1 to 5 substituents selected from haloalkoxy; Ar 3 is independently phenyl, pyridinyl, quinolone, isoquinoline, or benzothiazolyl, where each ring moiety is selected from cyano, halogen, C 1-4 Alkyl, C 1-4 substituted with 0 to 3 substituents selected from haloalkyl; R 1 and R 1a are independently H or C 1-4 is alkyl; R 2 are independently -C(=O)NR 3 R 4 -OR 4 and; R 3are independently H, C 1-4 Alkyl, or C 1-4 is haloalkyl; R 4 is independently -(L 1 ) 1-4 -L 2 -C(=O)NHR 5 , -(L 1 ) 1-4 -L 2 -NHC(=O)R 5 , -(L 1 ) 1-4 -NHC(=O)-L 2 -OR 5 , [ka] or -NR 3 R 4 independently [ka] and; L 1 independently C 1-3 Alkylene or -C 1-3 alkylene-O-; L 2 are independently a bond or C 1-3 is alkylene; L 3 are independently -O-, -CH2-, -CH2O-, -OCH2-, or -CH2OCH2-; Ar 4 is independently phenylene or pyridinylene; where each ring moiety is selected from the group consisting of cyano, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 substituted by 0 to 2 substituents selected from haloalkoxy; R 5 independently [ka] and; R6 are independently H or C 1-4 is alkyl; R 7 are independently cyano, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 is indolyl substituted with 0 to 2 substituents selected from haloalkoxy; and Ar 5 is independently phenylene or pyridinylene; wherein each ring moiety is substituted with thiazolyl, wherein the thiazolyl is substituted with cyano, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 substituted with 0 to 2 substituents selected from haloalkoxy; or a pharmaceutically acceptable salt thereof.

[0008] In a second embodiment within the first embodiment, Ar 1 but, [ka] and; Ar 2 independently cyano, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, and C 1-4 phenyl substituted with 1 to 5 substituents selected from haloalkoxy; and Ar 3 independently cyano, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy and C 3-6 and phenyl substituted with 0 to 3 substituents selected from cycloalkyl.

[0009] In a third embodiment within the second embodiment, Ar 2 is phenyl substituted with 1 to 4 substituents independently selected from F, Cl, and Br; Ar 3 is phenyl substituted with 0-3 substituents independently selected from Cl, CH3, CF3, and -OCF3; R 3 However, independently H, C 1-3 Alkyl, or C 1-3 is haloalkyl; R 4 But independently -L 1 -L 2 -C(=O)NHR 5 , -(L 1 ) 1-3 -L 2 -NHC(=O)R 5 , -(L 1 ) 1-3 -NHC(=O)-L 2 -OR 5 , [ka] or -NR 3 R 4 But independently [ka] is.

[0010] In a fourth embodiment within the second or third embodiment, 2 But independently [ka] is.

[0011] In a fifth embodiment within the scope of the first to fourth embodiments, Ar 3 But independently [ka] is.

[0012] In a sixth embodiment within the first embodiment, the compound has formula (Ia): [ka] [In the formula, R 3 are independently H or -CH2Cl; R 4 are independently -CH2CH2OCH2C(=O)NHR 5 , -(CH2CH2O) 1-3 (CH2) 1-2 NHC(=O)R 5 , -(CH2CH2O) 1-3 (CH2)2NHC(=O)CH2OR 5 , [ka] or -NR 3 R 4 independently [ka] and; R 5 independently [ka] and R 6 are independently H or CH3] or a pharmaceutically acceptable salt thereof.

[0013] In another embodiment, R 4 is H.

[0014] In another embodiment, R 5 independently [ka] is.

[0015] In another embodiment, R5 independently [ka] is.

[0016] In another embodiment, R 6 is H.

[0017] In another aspect, the present invention provides a compound selected from the exemplified examples or a pharmaceutically acceptable salt thereof.

[0018] Unless otherwise specified, the above terms have the following meanings: "Alkyl" refers to a straight- or branched-chain alkyl group having 1 to 6 carbons. "Cycloalkyl" refers to 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" refers to a monocyclic or bicyclic aromatic ring system having 5 to 12 carbon atoms in which one or both rings are aromatic. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. "Heteroaryl" refers to 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 may occur at any suitable position as understood by a person skilled in the art. Combinations of substituents and bonding patterns are only those that result in stable compounds as understood by a person 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 a substituent R.

[0019] The present invention includes all pharmaceutically acceptable salt forms of the compound. Pharmaceutically acceptable salts are those in which the counter ion does not significantly contribute to the physiological activity or toxicity of the compound, and therefore function as pharmacological equivalents. These salts can be prepared according to common organic chemistry techniques using commercially available reagents. Some anionic salt forms include acetate, acetonitrile, besylate, bromide, chloride, citrate, fumarate, glucuronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinafoate. Some cationic salt forms include 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.

[0020] Some of the compounds of the present invention exist in stereoisomeric forms. The present invention encompasses all stereoisomeric forms of the compounds, including enantiomers and diastereomers. Methods for producing and separating stereoisomers are known in the art. The present invention encompasses all tautomeric forms of the compounds. The present invention encompasses atropisomers and rotamers.

[0021] The present invention is intended to include all isotopes of atoms contained in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14Isotopically labeled compounds of the present invention can be prepared by conventional techniques generally known to those skilled in the art, or by methods similar to those described herein, using appropriate isotopically labeled reagents in place of unlabeled reagents used elsewhere. Such compounds may have a variety of potential uses, for example, as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the ability to advantageously modify biological, pharmacological, or pharmacokinetic properties.

[0022] biological methods Assay Buffer Composition: 25 mM HEPES, 100 mM NaCl, 0.005% Tween 20, 0.05% BSA prepared in sterile water (all reagents purchased from Sigma). control: Positive control: 1 μL of 100% DMSO + 20 μL of His-tagged hGal-3 + 20 μL of B-ASF + 5 μL of anti-His terbium antibody + 5 μL of Strep d2 antibody Negative control: 100% DMSO (1 μL) + His-tagged hGal-3 (20 μL) + anti-His terbium antibody (5 μL) + Strep d2 antibody (5 μL) [Table 1] Protocol: Gal-3 assays were performed in triplicate in a 384-well white OptiPlate with gentle rocking at 250–300 rpm at room temperature. His-tagged recombinant human Gal-3 (hGal-3) and B-ASF solutions were prepared in a 2.525-fold dilution from the stock solution. hGal-3 (20 μL, 15 nM) and B-ASF (20 μL, 15 nM) prepared in the working solution were added to the plate. For negative controls, hGal-3 alone was added. Compounds dissolved in 100% DMSO were prepared at concentrations ranging from 50-fold dilutions of the working solution. Aliquots of compound (1 μL) were added to wells pre-incubated with 20 μL of hGal-3 per well for 30 minutes. 20 μL of B-ASF was then added and incubated for an additional hour. To detect the signal, 5 μL (final concentration 1.0 nM) of terbium-labeled anti-His antibody was added and incubated for 30 minutes, followed by 5 μL (final concentration 20 nM) of streptavidin d2 and an additional 1 hour of incubation. The assay signal was detected on an Envision 2104 Multilabel Reader using the HTRF screen protocol (excitation wavelength = 340 nm, emission wavelength = 615 nm / 665 nm). Data were analyzed using Toolset and Curve Master. Results (IC 50 (μM)) are listed in the experimental section.

[0023] Target engagement by CRBN BRET (hCRBN IC 50 (μM) NanoLuc-CRBN fusions were transfected into HEK-293 cells using FuGENE HD (Promega) according to the manufacturer's instructions. Briefly, Nluc-CRBN was diluted in transfection carrier DNA (Promega) at a mass ratio of 1:10. The FuGENE HD ratio was 1:3 (µg DNA:µL FuGENE HD). A portion of the DNA:FuGENE HD complex (volume) was combined with 20 times the volume of suspended HEK-293 cells (density: 2 × 10 5). Cells were incubated at 37°C / 5% CO2 for ~20 hours. After transfection, cells were washed and resuspended in phenol red-free OptiMEM (Gibco) at 200,000 cells / mL. For BRET measurements, cells were seeded into 384-well plates (Corning) with a non-binding surface for final counting at 10,000 cells / well. Compounds were dissolved in dimethyl sulfoxide (DMSO) at 10 mM and evaluated at 11 concentrations, ranging from 20 to 50 μM. The final concentration was approximately EC 50-80 Equilibration measurements were performed using the CRBN probe. For live cell measurements, 20 nM CRBN probe was added. To achieve live cell assay conditions, the plate was incubated for 2 hours at 37°C / 5% CO2. NanoBRET NanoGlo substrate and extracellular Nanoluc inhibitor (Promega) were added according to the manufacturer's instructions. For lysed cell measurements, digitonin was added to the cells to a final concentration of 50 μg / mL, and 20 nM CRBN probe was added. For NanoBRET measurements on permeabilized cells, the extracellular Nluc inhibitor was removed during the detection step. All BRET experiments were performed using an Envision 2015 (Perkin Elmer) equipped with a BRET2 Enhancer mirror, BRET 647 nM / 75 nM bandwidth filters, and BC703 460 nM / 80 nM bandwidth filters. Each read time was standardized at 0.5 seconds. Compound potency (IC 50 To determine the BRET ratio, the BRET ratio of each dilution series was first normalized to a % inhibition value using Equation 1: where "S" is the sample BRET, "B" is the background BRET, and "T" is the total BRET. In this equation, the background control (B) is from NanoLuc-CRBN expressing cells and does not contain the CRBN probe. The total BRET ratio (T) is from NanoLuc-CRBN expressing cells, the CRBN probe, and an excess of DMSO at each concentration equal to that added when testing the compound. [ka] After normalization, the percent inhibition values ​​were plotted as a function of compound concentration and fit to Eq. [ka]

[0024] ELISA Gal3 degradation assay in THP-1 cells THP-1 cells (ATCC, Cat. No.: TIB-202), a leukemia-derived human monocytic cell line, were cultured in RPMI 1640 (200 μL / well, ThermoFisher, Cat. No.: 11835) at 2×E 6 Cells were seeded at 1000 cells / mL. Cells were treated with various concentrations of compounds, with DMSO as a control, for 48 hours. After treatment, the medium was collected. Cell pellets were washed with PBS and lysed in lysis buffer (Cell Signaling, Catalog No. 9803) supplemented with 1x protease inhibitor cocktail (Cell Signaling, Catalog No. 5872). Gal3 levels in the medium and cell lysates were quantified using an ELISA assay (Human Galectin-3 DuoSet ELISA Kit, R&D Systems, Catalog No. DY1154) according to the manufacturer's protocol. Cell culture medium was also used to assess cytotoxicity (LDH Assay Kit, R&D Systems, DY994). IC 50 (50% degradation concentration) values ​​were calculated based on cellular Gal3 protein levels using DMSO as a control.

[0025] 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.

[0026] Another aspect of the present invention is directed to the treatment of fibrosis of organs (e.g., liver, kidney, lung, heart, and skin), liver diseases and conditions (e.g., acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, liver regeneration failure, nonalcoholic steatohepatitis (NASH), liver dysfunction, and liver blood flow disorders), cell proliferative disorders, and cancer diseases (e.g., solid tumors, solid tumor metastasis, angiofibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL), and infiltrative metastasis of cancer cells), inflammatory diseases and conditions (e.g., psoriasis, nephropathy, and pneumonia), gastrointestinal diseases and conditions (e.g., irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and abnormal pancreatic secretion), kidney diseases and conditions, urinary tract-related diseases and conditions (e.g., and glaucoma filtration surgery scars).

[0027] Another aspect of the invention is a method for treating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis and systemic sclerosis, comprising administering to a patient a compound of the invention.

[0028] Another aspect of the invention is a method for treating fibrosis in an organ (eg, liver, kidney, lung, heart, and skin) comprising administering to a patient a compound of the invention.

[0029] Another aspect of the invention is a method for treating liver diseases and conditions (e.g., acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis, portal hypertension, liver regeneration failure, nonalcoholic steatohepatitis (NASH), liver dysfunction, and impaired hepatic blood flow) comprising administering to a patient a compound of the invention.

[0030] Another aspect of the present invention is a method for treating cell proliferative disorders and cancer diseases (e.g., solid tumors, metastases of solid tumors, angiofibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL), and invasive metastasis of cancer cells), which comprises administering to a patient a compound of the present invention.

[0031] Another aspect of the invention is a method for treating inflammatory diseases and conditions (eg, psoriasis, nephropathy, and pneumonia) comprising administering to a patient a compound of the invention.

[0032] Another aspect of the invention is a method for treating diseases and conditions of the gastrointestinal tract (e.g., irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and pancreatic secretory disorders), comprising administering to a patient a compound of the invention.

[0033] Another aspect of the invention is a method for treating kidney diseases and conditions, comprising administering to a patient a compound of the invention.

[0034] Another aspect of the invention is a method for treating diseases and conditions related to the urinary tract (e.g., benign prostatic hyperplasia, or conditions related to neurogenic bladder, spinal tumors, herniated discs, spinal stenosis, and conditions resulting from diabetes), which comprises administering to a patient a compound of the invention.

[0035] Another aspect of the invention is a method for treating diseases and conditions of the lower urinary tract (e.g., lower urinary tract obstruction), inflammatory diseases and conditions of the lower urinary tract (e.g., dysuria and frequent urination), which comprises administering to a patient a compound of the invention.

[0036] Another aspect of the invention is a method for treating diseases and conditions of the pancreas, comprising administering to a patient a compound of the invention.

[0037] Another aspect of the invention is a method for treating angiodysplasia-related diseases and conditions (eg, arterial occlusive disease) comprising administering to a patient a compound of the invention.

[0038] Another aspect of the invention is a method for treating brain-related diseases and conditions (eg, cerebral infarction and cerebral hemorrhage) comprising administering to a patient a compound of the invention.

[0039] Another aspect of the invention is a method for treating neuropathic pain and peripheral neuropathy, comprising administering to a patient a compound of the invention.

[0040] Another aspect of the invention is a method for treating ocular diseases and conditions (e.g., age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scars) comprising administering to a patient a compound of the invention.

[0041] The compounds of the present invention may be used in the treatment and / or prevention of conditions in which Gal-3 is involved.

[0042] The compounds of the present invention may be used in the manufacture of a medicament for the treatment and / or prophylaxis of conditions in which inhibition of Gal-3 biological activity is beneficial (e.g., diseases involving the Gal-3 receptor), in which inhibition of Gal-3 biological activity is involved in the etiology or pathology of the disease, or is associated with at least one symptom of the disease.

[0043] 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 to two, other drugs.

[0044] "Therapeutically effective amount" means the amount of drug required to provide a patient with significant improvement as understood by one skilled in the art of pain.

[0045] "Patient" means a person suffering from pain who is deemed suitable for treatment by a professional in the field.

[0046] The terms "treatment," "therapy," "regimen," and related terms understood by those skilled in the art are used.

[0047] The compounds of the present invention are generally provided as pharmaceutical compositions containing a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which may contain conventional excipients. A therapeutically effective amount is the amount necessary to bring about significant improvement in the patient. A pharmaceutically acceptable carrier is a conventionally known carrier with an acceptable safety profile. The compositions encompass all common solid and liquid forms (e.g., capsules, tablets, lozenges, and powders, as well as liquid suspensions, syrups, elixirs, and solutions). The compositions are prepared using conventional pharmaceutical techniques, and conventional excipients (e.g., binders and wetting agents) and vehicles (e.g., water and alcohol) are commonly used in the compositions. See, for example, Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA (1985).

[0048] Solid compositions are typically formulated in dosage units and compositions containing about 1 to 1,000 mg of active ingredient per dosage. Some example dosages include 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1,000 mg. Other antiretroviral drugs generally exist in unit ranges similar to those used clinically, typically 0.25 to 1,000 mg per unit.

[0049] Liquid compositions are typically present in unit dosage ranges. Generally, liquid compositions can be in dosage unit ranges of 1 to 100 mg / mL. Some example dosages include 1 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, and 100 mg / mL.

[0050] The present invention encompasses all conventional administration methods, although oral and parenteral methods are preferred. Generally, the dosage regimen is similar to that of other drugs used clinically. Generally, the daily dose is 1-100 mg / kg (body weight). Generally, compounds are desired to be administered orally and less parenterally. However, the specific dosage regimen will be determined by a physician using ordinary medical judgment.

[0051] (Chemical Methods) It will be apparent to those skilled in the art that the present disclosure is not limited to the foregoing examples, and that it may be embodied in other specific forms without departing from the essential characteristics of the present disclosure. The examples, therefore, are to be considered in all respects as illustrative and not restrictive, with reference to the claims rather than the foregoing examples, and therefore all changes which come within the meaning and range of equivalency of the claims are intended to be embraced.

[0052] LCMS analysis was performed on a Waters Acquity UPLC system equipped with a Waters TUV and SQ mass spectrometer (column: BEH C18 2.1x50mm; mobile phase A: 0.05% TFA in water; mobile phase B: acetonitrile (containing 0.05% TFA); gradient: 2-98% B over 1.6 min; flow rate: 0.8mL / min). HPLC analysis was performed on 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: 0-100% B over 40 min, followed by 100% B for 1 min; 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, the detailed conditions of which are described in the experimental procedures.

[0053] (Manufacturing method) Intermediate 1: 2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetic acid [ka] To a solution of (4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-ol (WO 2019067702, 0.80 g, 1.128 mmol) in THF (22 mL) was added sodium hydride (60% oil dispersion, 0.090 g, 2.255 mmol) in one portion at 0 °C. After stirring for 15 min at 0 °C, ethyl 2-bromoacetate (0.150 mL, 1.353 mmol) in THF (4 mL) was added over 1 min. The mixture was stirred at 0°C for 50 minutes and then quenched with EtOH (2 mL). The mixture was diluted with ethyl acetate (200 mL), washed with water (2 x 40 mL) and brine (40 mL), and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give 2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)ethyl acetate and 2-( A mixture of ((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetic acids (2:1 ratio, 0.881 g) was obtained. To a solution of this mixture (0.881 g) in THF (35 mL) was added lithium oxide (0.106 g, 4.43 mmol) in water (7 mL) over 1 minute at room temperature, stirred at room temperature for 1.5 hours, and then concentrated under reduced pressure to approximately 7 mL. The resulting residue was diluted with water (15 mL) and acidified to pH 5-6 with 1 N hydrochloric acid.The insoluble product: 2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetic acid (0.807 g, 1.051 mmol, 93% yield) was collected by suction filtration as a white solid and dried under vacuum at 50° C. LCMS (M+H). + =766.9; 1 H NMR (500MHz, DMSO-d6) δ 12.76-12.41(m, 1H), 9.28(s, 1H), 8.19-8.08(m, 1H), 8.07(d, J=8.5Hz, 1H), 7.98(br d, J=8.3Hz, 1H), 7.83(d, J=8.3Hz, 2H), 7.44-7.32(m, 5H), 5.55(s, 1H), 5.48(dd, J=10.6, 3.4Hz, 1H), 4.89(br t, J=9.6Hz, 1H), 4.65(d, J=9.1Hz, 1H), 4.44(d, J=3.3Hz, 1H), 4.08(br d, J=11.6Hz, 1H), 3.95(br d, J=12.1Hz, 2H), 3.83(s, 1H), 3.64(br d, J=11.6Hz, 1H), 2.34(s, 3H)

[0054] Intermediate 2: 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0055] Step 1. 3-(5-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A mixture of methyl 2-(bromomethyl)-4-nitrobenzoate (1.00 g, 3.65 mmol), 3-aminopiperidine-2,6-dione HCl (0.721 g, 4.38 mmol), and triethylamine (0.712 mL, 5.11 mmol) in methanol (15 mL) was stirred at room temperature for 24 hours and then heated at 70 °C for 8 hours. The mixture was concentrated under reduced pressure and dried. Water (50 mL) was added to the resulting residue, and the heterogeneous mixture was stirred at room temperature for 10 minutes. The insoluble material was collected by suction filtration, and the filter cake was suspended in diethyl ether (80 mL) and stirred at room temperature for 1 hour. The insoluble material was collected by suction filtration and dried under vacuum at 50° C. to give the desired product: 3-(5-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.634 g, 2.192 mmol, 60.1% yield) as a tan solid. LCMS (M+H) + =290.1

[0056] Step 2. 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione A mixture of 3-(5-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.346 mmol) and 10% Pd / C (36.8 mg, 0.035 mmol) in methanol (10 mL) and tetrahydrofuran (3 mL) was attached to a H balloon and stirred at room temperature under an H atmosphere for 1.5 hours. The solid phase was removed by filtration under reduced pressure, and the filtrate was concentrated under reduced pressure and dried. The resulting residue was dried under vacuum at 50 °C to give the desired product: 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (90 mg, 0.347 mmol, 100% yield) as a beige solid. LCMS (M+H) + =260.1

[0057] Intermediate 3: 3-(5-amino-1-oxoisoindolin-2-yl)-1-methylpiperidine-2,6-dione [ka]

[0058] Step 1. 1-Methyl-3-(5-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione To a solution of 3-(5-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (315 mg, 1.089 mmol) in DMF (5 mL) was added sodium hydride (60% dispersion, 87 mg, 2.178 mmol) in one portion at 0 °C. After stirring at 0 °C for 30 min, iodomethane (0.136 mL, 2.178 mmol) was added. The mixture was stirred at room temperature for 2 h, and the reaction was quenched with ice-water (0.5 mL). The resulting mixture was diluted with ethyl acetate (60 mL), washed with water (2 × 15 mL) and brine (15 mL), and dried over anhydrous MgSO4. The desired product: 1-methyl-3-(5-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (129 mg, 0.425 mmol, 39.1% yield) was isolated as a white solid by ISCO chromatography (24 g silica gel, dusted column, 10-60% ethyl acetate / hexanes). LCMS (M+H) + =304.3

[0059] Step 2. 3-(5-amino-1-oxoisoindolin-2-yl)-1-methylpiperidine-2,6-dione A mixture of 1-methyl-3-(5-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (129 mg, 0.425 mmol) and 10% Pd / C (45.3 mg, 0.043 mmol) in methanol (10 mL) and tetrahydrofuran (3 mL) was attached to a H balloon and stirred at room temperature under an H atmosphere for 1.5 hours. The solid phase was removed by vacuum filtration, and the filtrate was concentrated under reduced pressure and dried. The resulting residue was dried in vacuo at 50 °C to give the desired product: 3-(5-amino-1-oxoisoindolin-2-yl)-1-methylpiperidine-2,6-dione (105 mg, 0.384 mmol, 90% yield) as a beige solid. LCMS (M+H) + =274.3

[0060] Intermediate 4: 3-(6-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0061] Step 1. 3-(6-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione A mixture of methyl 2-(bromomethyl)-5-nitrobenzoate (1.00 g, 3.65 mmol), 3-aminopiperidine-2,6-dione HCl (0.721 g, 4.38 mmol), and triethylamine (0.712 mL, 5.11 mmol) in methanol (15 mL) was stirred at 75 °C for 7.5 hours and concentrated to dryness under reduced pressure. Water (80 mL) was added to the resulting residue, and the heterogeneous mixture was stirred at room temperature for 10 minutes. The insoluble material was collected by suction filtration, and the filter cake was suspended in diethyl ether (100 mL) and stirred at room temperature for 1 hour. The insoluble material was collected by suction filtration and dried under vacuum at 50° C. to give the desired product: 3-(6-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.548 g, 1.895 mmol, 51.9% yield) as a tan solid. LCMS (M+H) + =289.9

[0062] Step 2. 3-(6-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione A mixture of 3-(6-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (548 mg, 1.895 mmol) and 10% Pd / C (202 mg, 0.189 mmol) in methanol (45 mL) and tetrahydrofuran (12.5 mL) was attached to a H balloon and stirred at room temperature under an H atmosphere for 1.5 hours. The catalyst was removed by filtration under reduced pressure, and the filtrate was concentrated under reduced pressure and dried. The resulting residue was dried under vacuum at 50 °C to give the desired product: 3-(6-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (491 mg, 1.894 mmol, 100% yield) as a beige solid. LCMS (M+H) +=259.9

[0063] Example 1: 2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)-2-oxoethoxy)ethyl)acetamide [ka]

[0064] Step 1. tert-Butyl (2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)-2-oxoethoxy)ethyl)carbamate A mixture of 2-(2-((tert-butoxycarbonyl)amino)ethoxy)acetic acid (1.319 g, 6.02 mmol), 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.20 g, 4.63 mmol), N,N-diisopropylethylamine (2.021 mL, 11.57 mmol), and 1-propanephosphonic anhydride (2.209 g, 6.94 mmol) in DMF (20 mL) was stirred at 100° C. for 8 h, and the volatiles were removed in vacuo. The resulting residue was dissolved in water and extracted with dichloromethane (2 x 50 mL). The combined extracts were dried over anhydrous Na2SO4 and the desired product: tert-butyl (2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)-2-oxoethoxy)ethyl)carbamate (1.289 g, 59%) was isolated as an off-white solid by ISCO chromatography (silica gel column, eluent: 0-5% methanol / chloroform). LCMS (M+H) + =461.3

[0065] Step 2. 2-(2-aminoethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide To a solution of tert-butyl (2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)-2-oxoethoxy)ethyl)carbamate (55 mg, 0.119 mmol) in dichloromethane (1.5 mL) at room temperature, 4N hydrogen chloride in 1,4-dioxane (1.5 mL, 6.00 mmol) was added in one portion and stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure to give the desired product: 2-(2-aminoethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide·HCl (48 mg, 0.121 mmol, 101% yield) as a white solid. LCMS (M+H) + =361.3

[0066] Step 3: 2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)-2-oxoethoxy)ethyl)acetamide 2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetic acid (68 mg, 0.089 mmol), 2-(2-aminoethoxy)-N- A mixture of (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide HCl (47.5 mg, 0.120 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (52.9 mg, 0.120 mmol), and N,N-diisopropylethylamine (0.062 mL, 0.354 mmol) in DMF (2 mL) was stirred at room temperature for 3 h. The mixture was diluted with ethyl acetate (60 mL) and washed with water (15 mL), 5% hydrochloric acid (15 mL), and brine (15 mL). The organic solution was dried over anhydrous MgSO4 and concentrated to dryness in vacuo to give the crude product: 2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)-2-oxoethoxy)ethyl)acetamide (105 mg, 0.095 mmol, 107% yield) as a beige solid. LCMS (M+H) + =1109.6

[0067] Step 4. 2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)-2-oxoethoxy)ethyl)acetamide A mixture of 2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)-2-oxoethoxy)ethyl)acetamide (105 mg, 0.089 mmol) and 70% acetic acid (4 mL) was heated at 70° C. for 10 hours. After cooling to room temperature, the mixture was diluted with methanol and purified by preparative HPLC (column: Sunfire C18 OBD Purification was performed using a 5u 30 x 100mm column (solvent A: 90% HO / 10% methanol / 0.1% TFA; solvent B: 10% methanol / 90% HO / 0.1% TFA; starting %B: 25; final %B: 100; gradient time: 15 min). The desired fractions were combined, concentrated in vacuo, basified to pH 8 with saturated NaHCO3 solution, extracted with dichloromethane (4 x 30 mL), and the combined extracts were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give the desired product: 2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)amino)-2-oxoethoxy)ethyl)acetamide (51 mg, 0.049 mmol, 55.0% yield) as a white solid. LCMS (M+H) + =1021.8; 1H NMR (500MHz, methanol-d4)δ 8.81(d, J=1.4Hz, 1H), 7.99(dd, J=16.9, 1.0Hz, 1H), 7.93(dd, J=11.1, 8.4Hz, 1H), 7.88-7.80(m, 2H), 7.72(dd, J=8.3, 1.7Hz, 1H), 7.65-7.56(m, 3H), 5.17(dd, J=13.3, 5.1Hz, 1H), 5.14-5.09(m, 1H), 5.02-4.94(m, 1H), 4.55-4.44(m, 3H), 4.11(dd, J=6.6, 2.8Hz, 1H), 4.08(dd, J=2.5, 1.4Hz, 2H), 3.99(d, J=15.1Hz, 1H), 3.71-3.62(m, 4H), 3.59-3.50(m, 2H), 3.41-3.35(m, 1H), 3.30-3.23(m, 1H), 2.98-2.89(m, 1H), 2.85-2.78(m, 1H), 2.53(qd, J=13.2, 4.7Hz, 1H), 2.45(d, J=1.1Hz, 3H), 2.21(dtt, J=12.7, 5.2, 2.4Hz, 1H); hGal-3 IC 50 =0.082 μM; hCRBN IC 50 =0.78μM

[0068] Example 2: 4-((2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)methyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide [ka]

[0069] Step 1. tert-Butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)benzyl)carbamate A mixture of 4-(((tert-butoxycarbonyl)amino)methyl)benzoic acid (116 mg, 0.463 mmol), 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.386 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 183 mg, 0.482 mmol), and N,N-diisopropylethylamine (0.269 mL, 1.543 mmol) in DMF (4 mL) was stirred at room temperature for 7 days, diluted with ethyl acetate (60 mL), washed with water (2 × 20 mL) and brine (20 mL), and dried over anhydrous MgSO. The desired product: tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)benzyl)carbamate (107 mg, 0.217 mmol, 56.3% yield) was isolated as a beige solid using ISCO chromatography (24 g silica gel, dusted column, 1-6% MeOH / CH2Cl2). LCMS (M+H) + =493.1; 1 H NMR(500MHz, DMSO-d6)δ 10.99(s, 1H), 10.51(s, 1H), 8.15(s, 1H), 7.94(br d, J=8.3Hz, 2H), 7.84(dd, J=8.4, 1.2Hz, 1H), 7.72(d, J=8.3Hz, 1H), 7.50(br t, J=6.1Hz, 1H), 7.40(d, J=8.3Hz, 2H), 5.11(dd, J=13.2, 5.0Hz, 1H), 4.48(d, J=17.1Hz, 1H), 4.38-4.29(m, 1H), 4.22(br d, J=6.1Hz, 2H), 2.99-2.86(m, 1H), 2.66-2.57(m, 1H), 2.44-2.38(m, 1H), 2.07-1.97(m, 1H), 1.41(s, 9H)

[0070] Step 2. 4-(aminomethyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide To a solution of tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)benzyl)carbamate (104 mg, 0.211 mmol) in dichloromethane (5 mL) was added 4N hydrogen chloride in 1,4-dioxane (5 mL, 20.00 mmol) over 1 minute at room temperature, stirred at room temperature for 1 hour, and then concentrated to dryness under reduced pressure to give 4-(aminomethyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide HCl (101 mg, 0.235 mmol, 112% yield) as a white solid. LCMS (M+H) + =393.1

[0071] Step 3: 4-((2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetamido)methyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide 2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetic acid (75 mg) A mixture of 4-(aminomethyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide HCl (35 mg, 0.082 mmol), BOP (57.8 mg, 0.131 mmol), and N,N-diisopropylethylamine (0.071 mL, 0.408 mmol) in DMF (3 mL) was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate (50 mL), washed with water (2 × 20 mL), 0.5 N hydrochloric acid (20 mL), and brine (20 mL), and dried over anhydrous MgSO. The desired product: 4-((2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetamido)methyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide (66 mg, 0.058 mmol, 70.8% yield) was isolated as a white solid by ISCO chromatography (24 g silica gel, dusted column, 0-6% methanol / dichloromethane). LCMS (M+H) + =1141.1

[0072] Step 4. 4-((2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)methyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide A mixture of 4-((2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetamido)methyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide (66 mg, 0.058 mmol) in 70% acetic acid (4 mL) was heated at 70° C. for 18 hours. The solution was diluted with methanol and purified by preparative HPLC (Column: Phenomenex Luna AXIA 5u C18 30.0x100; Solvent A: 90% HO / 10% methanol / 0.1% TFA; Solvent B: 10% methanol / 90% HO / 0.1% TFA; Starting %B: 25; Final %B: 100; Gradient time: 15 min). The collected fractions were combined, concentrated in vacuo, extracted with dichloromethane (4 x 40 mL), and the combined extracts were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give the desired product: 4-((2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)methyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide (34 mg, 0.032 mmol, 54.7% yield) as a white solid. LCMS (M+H) + =1053.1; 1H NMR (500MHz, methanol-d4) δ 8.81(s, 1H), 8.17(s, 1H), 7.98(d, J=8.8Hz, 1H), 7.92-7.86(m, 2H), 7.80(d, J=8.0Hz, 3H), 7.78-7.74(m, 1H), 7.64(d, J=8.0Hz, 2H), 7.21(d, J=8.3Hz, 2H), 5.21-5.11(m, 2H), 5.03(br t, J=9.5Hz, 1H), 4.59-4.48(m, 3H), 4.40-4.33(m, 1H), 4.29-4.22(m, 1H), 4.14(d, J=2.5Hz, 1H), 4.04(br d, J=14.9Hz, 1H), 3.78(d, J=15.1Hz, 1H), 3.74-3.69(m, 1H), 3.69-3.61(m, 2H), 2.99-2.88(m, hGal-3 IC 50 =0.109 μM; hCRBN IC 50 =0.269μM

[0073] Example 3: 4-(cis-3-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)cyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide [ka]

[0074] Step 1. Ethyl 4-(cis-3-((tert-butoxycarbonyl)amino)cyclobutoxy)benzoate To a mixture of ethyl 4-hydroxybenzoate (0.300 g, 1.805 mmol), tert-butyl trans-3-hydroxycyclobutylcarbamate (0.423 g, 2.257 mmol), and triphenylphosphine (0.710 g, 2.71 mmol) in toluene (10 mL) was added diisopropyl azodicarboxylate (DIAD, 0.533 mL, 2.71 mmol) over 1 minute at room temperature, followed by heating at 105° C. for 16 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (50 mL), silica gel (5 g) was added, and the volatiles were removed in vacuo. The resulting residue was purified by ISCO chromatography (80 g silica gel, 10-35% ethyl acetate / hexanes) to give ethyl 4-(cis-3-((tert-butoxycarbonyl)amino)cyclobutoxy)benzoate (0.595 g, 1.774 mmol, 98% yield) as a white solid. LCMS (M+H) + =336.3; 1 H NMR(500MHz, DMSO-d6)δ 7.95-7.82(m, 2H), 7.21(br d, J=8.0Hz, 1H), 7.03-6.89(m, 2H), 4.48(t, J=7.0Hz, 1H), 4.28(q, J=7.2Hz, 2H), 3.80-3.63(m, 1H), 2.79(td, J=9.1, 7.3Hz, 2H), 2.02-1.98(m, 2H), 1.39(s, 9H), 1.31(t, J=7.0Hz, 3H)

[0075] Step 2. 4-(cis-3-((tert-butoxycarbonyl)amino)cyclobutoxy)benzoic acid To a solution of ethyl 4-(cis-3-((tert-butoxycarbonyl)amino)cyclobutoxy)benzoate (300 mg, 0.894 mmol) in tetrahydrofuran (20 mL) and methanol (5 mL) was added lithium hydroxide (129 mg, 5.37 mmol) in water (5 mL) over 1 minute at room temperature. The mixture was stirred at room temperature for 70 hours and then concentrated under reduced pressure to approximately 5 mL. The residue was diluted with water (15 mL) and acidified to pH = 5-6 with 1N hydrochloric acid. The precipitated product: 4-(cis-3-((tert-butoxycarbonyl)amino)cyclobutoxy)benzoic acid (258 mg, 0.839 mmol, 94% yield) was collected by suction filtration as a white solid and dried under vacuum at 50 °C. LCMS (M+H) + =308.3; 1 H NMR(500MHz, DMSO-d6)δ 12.80-12.47(m, 1H), 7.94-7.81(m, 2H), 7.21(br d, J=8.0Hz, 1H), 6.93(d, J=8.8Hz, 2H), 4.47(quin, J=7.1Hz, 1H), 3.77-3.65(m, 1H), 2.86-2.72(m, 2H), 2.08-1.92(m, 2H), 1.39(s, 9H)

[0076] Step 3: tert-Butyl (cis-3-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)phenoxy)cyclobutyl)carbamate A mixture of 4-(cis-3-((tert-butoxycarbonyl)amino)cyclobutoxy)benzoic acid (122 mg, 0.398 mmol), 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (86 mg, 0.332 mmol), HATU (151 mg, 0.398 mmol), and N,N-diisopropylethylamine (0.232 mL, 1.327 mmol) was stirred at room temperature for 4 days, diluted with ethyl acetate (60 mL), washed with water (2 × 20 mL) and saturated NaHCO solution (20 mL), and dried over anhydrous MgSO. The desired product: tert-butyl (cis-3-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)phenoxy)cyclobutyl)carbamate (68 mg, 0.124 mmol, 37.4% yield) was isolated as a white solid by ISCO chromatography (40 g silica gel, dusted column, 1-8% MeOH / CH2Cl2). LCMS (M+H) + =308.3; 1 H NMR(500MHz, DMSO-d6)δ 10.98(s, 1H), 10.39(s, 1H), 8.14(s, 1H), 7.96(d, J=8.8Hz, 2H), 7.83(dd, J=8.4, 1.5Hz, 1H), 7.70(d, J=8.5Hz, 1H), 7.22(br d, J=8.0Hz, 1H), 7.00(d, J=8.8Hz, 2H), 5.11(dd, J=13.3, 5.1Hz, 1H), 4.56-4.43(m, 2H), 4.38-4.28(m, 1H), 3.79-3.67(m, 1H), 3.00-2.87(m, 1H), 2.86-2.75(m, 2H), 2.67-2.58(m, 1H), 2.45-2.36(m, 1H), 2.06-1.97(m, 3H), 1.39(s, 9H)

[0077] Step 4. 4-(cis-3-aminocyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide To a solution of tert-butyl (cis-3-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)phenoxy)cyclobutyl)carbamate (68 mg, 0.124 mmol) in dichloromethane (4 mL) at room temperature was added 4N hydrogen chloride in 1,4-dioxane (4 mL, 16.00 mmol) over 1 minute. The mixture was stirred at room temperature for 1 hour and then concentrated to dryness under reduced pressure to give 4-(cis-3-aminocyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide hydrochloride (66 mg, 0.136 mmol, 110% yield) as a white solid. LCMS (M+H) + =449.1

[0078] Step 5. 4-(cis-3-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetamido)cyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide 2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetic acid (60.8 mg, 0. A mixture of 4-(cis-3-aminocyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide·HCl (32 mg, 0.066 mmol), BOP (43.8 mg, 0.099 mmol), and N,N-diisopropylethylamine (0.058 mL, 0.330 mmol) in DMF (2 mL) was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate (50 mL), washed with water (2 × 20 mL), 0.5 N hydrochloric acid (20 mL), and brine (20 mL), and dried over anhydrous MgSO. Desired product: 4-((1S,3s)-3-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d] [1,3]dioxin-7-yl)oxy)acetamido)cyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide (47 mg, 0.039 mmol, 59.5% yield) was isolated by ISCO chromatography (12 g silica gel, dusted column, 0-6% methanol / dichloromethane) as a white solid. LCMS (M+H) + =1197.6

[0079] Step 6. 4-(cis-3-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)cyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide A mixture of 4-(cis-3-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetamido)cyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide (47 mg, 0.039 mmol) in 70% acetic acid (1.5 mL) was heated at 75 °C for 15 h, and the solution was diluted with methanol and purified by preparative HPLC (column: Phenomenex Luna AXIA 5u C18). Purification was performed using a 21.2x100 (solvent A: 90% HO / 10% methanol / 0.1% TFA; solvent B: 10% methanol / 90% HO / 0.1% TFA; starting %B: 25; final %B: 100; gradient time: 15 min) mixture. The combined collected fractions were concentrated in vacuo and extracted with dichloromethane (4 x 30 mL). The combined extracts were dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to give the desired product: 4-(cis-3-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)cyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide (28 mg, 0.025 mmol, 63.0% yield) as a white solid. LCMS (M+H) + =1109.4; 1H NMR (500MHz, methanol-d4)δ 8.82(s, 1H), 8.16(s, 1H), 7.99(d, J=8.8Hz, 1H), 7.97-7.93(m, 2H), 7.91-7.88(m, 2H), 7.82-7.79(m, 1H), 7.77-7.74(m, 1H), 7.70-7.66(m, 2H), 6.96-6.92(m, 2H), 5.20-5.13(m, 2H), 4.99(br t, J=9.6Hz, 1H), 4.58-4.46(m, 4H), 4.14(d, J=2.8Hz, 1H), 3.95-3.85(m, 2H), 3.74-3.63(m, 4H), 2.99-2.88(m, 1H), 2.87-2.73(m, 3H), 2.53(qd, J=13.3, 4.5Hz, 1H), 2.47(s, 3H), 2.24-2.17(m, 1H), 2.01(dt, J=10.9, 8.6Hz, 1H), 1.94-1.86(m, 1H); hGal-3 IC 50 =0.070 μM; hCRBN IC 50 =0.126μM

[0080] Example 4: 5-(cis-3-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)cyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide [ka]

[0081] Step 1. 5-(cis-3-((tert-butoxycarbonyl)amino)cyclobutoxy)methyl picolinate To a mixture of methyl 5-hydroxypicolinate (0.488 g, 3.19 mmol), tert-butyl trans-3-hydroxycyclobutylcarbamate (0.716 g, 3.82 mmol), and triphenylphosphine (1.254 g, 4.78 mmol) in toluene (18 mL) was added diisopropyl azodicarboxylate (DIAD, 0.941 mL, 4.78 mmol) over 1 min at room temperature, and the resulting solution was heated at 105 °C for 15 h. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (60 mL) and silica gel (5 g) was added. The volatiles were removed in vacuo, and the resulting residue was purified by ISCO chromatography (80 g silica gel, 20-65% ethyl acetate / hexane) to afford methyl 5-(cis-3-((tert-butoxycarbonyl)amino)cyclobutoxy)picolinate (0.820 g, 2.54 mmol, 80% yield) as a white solid. LCMS(M+H) + =323.0; 1 H NMR(500MHz, DMSO-d6)δ 8.32(d, J=2.8Hz, 1H), 8.01(d, J=8.8Hz, 1H), 7.41(dd, J=8.8, 2.8Hz, 1H), 7.23(br d, J=8.0Hz, 1H), 4.57(br t, J=7.0Hz, 1H), 3.84(s, 3H), 3.78-3.64(m, 1H), 2.90-2.74(m, 2H), 2.10-1.94(m, 2H), 1.38(s, 9H)

[0082] Step 2. 5-(cis-3-((tert-butoxycarbonyl)amino)cyclobutoxy)picolinic acid To a solution of methyl 5-(cis-3-((tert-butoxycarbonyl)amino)cyclobutoxy)picolinate (812 mg, 2.52 mmol) in tetrahydrofuran (50 mL) and methanol (12 mL) was added lithium hydroxide (362 mg, 15.11 mmol) in water (12 mL) over 1 minute at room temperature. The mixture was heated at 50°C for 2.5 hours, then concentrated under reduced pressure to approximately 5 mL. The residue was acidified with 1N HCl to pH = 5-6, and the precipitated product: 5-(cis-3-((tert-butoxycarbonyl)amino)cyclobutoxy)picolinic acid (650 mg, 2.108 mmol, 84% yield) was collected by suction filtration as a white solid and dried under vacuum at 50°C. LCMS (M+H) + =309.0

[0083] Step 3: tert-Butyl (cis-3-((6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)pyridin-3-yl)oxy)cyclobutyl)carbamate A mixture of 5-(cis-3-((tert-butoxycarbonyl)amino)cyclobutoxy)picolinic acid (114 mg, 0.370 mmol), 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (80 mg, 0.309 mmol), HATU (147 mg, 0.386 mmol), and N,N-diisopropylethylamine (0.216 mL, 1.234 mmol) was stirred at room temperature for 48 hours. The mixture was diluted with ethyl acetate (60 mL), washed with water (2 x 15 mL) and brine (15 mL), dried over anhydrous MgSO4, and the desired product: tert-butyl (cis-3-((6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)pyridin-3-yl)oxy)cyclobutyl)carbamate (56 mg, 0.102 mmol, 33.0% yield) was isolated by ISCO chromatography (40 g silica gel, dusted column, 0-8% methanol / dichloromethane) as a white solid. LCMS (M+H) + =550.2; 1H NMR (500MHz, DMSO-d6) δ 10.98(s, 1H), 10.79(s, 1H), 8.35(d, J=2.8Hz, 1H), 8.26(s, 1H), 8.13(d, J=8.8Hz, 1H), 7.98(dd, J=8.4, 1.2Hz, 1H), 7.71(d, J=8.3Hz, 1H), 7.53(dd, J=8.8, 2.8Hz, 1H), 7.25(br d, J=8.0Hz, 1H), 5.11(dd, J=13.2, 5.2Hz, 1H), 4.62(br t, J=6.9Hz, 1H), 4.48(d, J=17.3Hz, 1H), 4.39-4.27(m, 1H), 3.81-3.69(m, 1H), 3.01-2.89(m, 1H), 2.85(br d, J=6.9Hz, 2H), 2.67-2.58(m, 1H), 2.47-2.37(m, 1H), 2.11-1.98(m, 3H), 1.39(s, 9H)

[0084] Step 4. 5-(cis-3-aminocyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide To a solution of tert-butyl ((1s,3s)-3-((6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)pyridin-3-yl)oxy)cyclobutyl)carbamate (55 mg, 0.100 mmol) in dichloromethane (3 mL) was added 4N hydrogen chloride in 1,4-dioxane (3 mL, 12.00 mmol) over 1 minute at room temperature, followed by stirring at room temperature for 4 hours. The mixture was then concentrated to dryness under reduced pressure to give 5-(cis-3-aminocyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide 2HCl (57 mg, 0.109 mmol, 109% yield) as a white solid. LCMS (M+H) + =450.1

[0085] Step 5. 5-((cis-3-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetamido)cyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide 2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetic acid (88 mg, 0.114 mmol), 5-(cis A mixture of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide·2HCl (57 mg, 0.099 mmol), BOP (70.3 mg, 0.159 mmol), and N,N-diisopropylethylamine (0.104 mL, 0.596 mmol) in DMF (3 mL) was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate (50 mL), washed with water (2 × 20 mL), 0.5 N hydrochloric acid (20 mL), and brine (20 mL), and dried over anhydrous MgSO. The solvent was removed to give the desired product: 5-((cis)-3-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetamido)cyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide (109 mg, 0.091 mmol, 92% yield) as a beige solid.

[0086] Step 6. 5-(cis-3-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)cyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide A mixture of 5-(cis-3-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetamido)cyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide (109 mg, 0.091 mmol) in 70% acetic acid (6 mL) was heated at 70° C. for 18 hours. The solution was diluted with methanol and purified by preparative HPLC (Column: Phenomenex Luna AXIA 5u C18 21.2 x 100; Solvent A: 90% HO / 10% methanol / 0.1% TFA; Solvent B: 10% methanol / 90% HO / 0.1% TFA; Starting %B: 28; Final %B: 100; Gradient time: 15 min). The collected fractions were combined, concentrated in vacuo, and extracted with dichloromethane (4 x 40 mL). The combined extracts were dried over anhydrous Na2SO4 and the solvent removed under reduced pressure to give the desired product: 5-(cis-3-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)cyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide (49 mg, 0.042 mmol, 46.1% yield) as a white solid. LCMS (M+H) + =1110.0; 1H NMR(500MHz、メタノール-d4)δ 8.82(s, 1H), 8.28(d, J=2.8Hz, 1H), 8.24(s, 1H), 8.18(d, J=8.8Hz, 1H), 7.99(d, J=8.8Hz, 1H), 7.92-7.80(m, 4H), 7.69-7.64(m, 2H), 7.40(dd, J=8.5, 2.8Hz, 1H), 5.21-5.13(m, 2H), 5.00(br t, J=9.8Hz, 1H), 4.61-4.48(m, 4H), 4.14(d, J=2.8Hz, 1H), 3.95-3.87(m, 2H), 3.74-3.63(m, 4H), 2.99-2.89(m, 1H), 2.89-2.77(m, 3H), 2.60-2.50(m, 1H), 2.47(s, 3H), 2.25-2.18(m, 1H), 2.10-2.01(m, 1H), 1.96-1.87(m, 1H); hGal-3 IC 50 =0.081μM; HCRBNIC 50 =0.174μM

[0087] Examples 5 and 6: 5-(cis-3-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)cyclobutoxy)-N-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide and and 5-(cis-3-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetamido)cyclobutoxy)-N-(2-((R)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide [ka] 5-(cis-3-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyrazol (N-(2-(2,6-dioxopiperidin-3-yl)oxy)acetamido)cyclobutoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide (Example 3, 44 mg) was separated using the following chiral SFC conditions to give Example 4 (20 mg, 0.018 mmol, 45.0% yield) and Example 5 (18.5 mg, 0.016 mmol, 41.6% yield). Both products are white solids.

[0088] Equipment: Thar 350 Colum: キラルIC (3 X 25cm, 5μm) カラムTemperature: 40℃ Flow rate: 130 m / min Mobile phase: CO2 / [MeOH / CH3CN=50:50]=35 / 65 Back pressure: 100 bar インジェクション Volume: 2.0mL (concentration=4mg / mL) Analysis wavelength: 220nm

[0089] Example of implementation 5: LCMS(M+H) + =1110.1; 1 H NMR(500MHz, メタノール-d4)δ 8.82(s, 1H), 8.28(br s, 1H), 8.24(s, 1H), 8.18(br d, J=8.0Hz, 1H), 7.99(d, J=9.1Hz, 1H), 7.93-7.79(m, 4H), 7.66(d, J=8.0Hz, 2H), 7.40(dd, J=8.8, 2.5Hz, 1H), 5.21-5.13(m, 2H), 5.00(br t, J=9.6Hz, 1H), 4.61-4.47(m, 4H), 4.14(d, J=2.8Hz, 1H), 3.97-3.85(m, 2H), 3.72-3.65(m, 4H), 2.99-2.89(m, 1H), 2.88-2.76(m, 3H), 2.60-2.50(m, 1H), 2.47(s, 3H), 2.21(dtd, J=12.7, 5.2, 2.2Hz, 1H), 2.10-2.00(m, 1H), 1.97-1.87(m, 1H); hGal-3 IC 50 =0.084μM; hCRBN IC 50 =0.039μM Example of implementation 6: LCMS(M+H) + =1110.1; 1H NMR (500MHz, methanol-d4)δ 8.82(s, 1H), 8.28(d, J=2.5Hz, 1H), 8.24(s, 1H), 8.18(d, J=8.8Hz, 1H), 7.99(d, J=9.1Hz, 1H), 7.92-7.80(m, 4H), 7.66(d, J=8.0Hz, 2H), 7.40(dd, J=8.8, 2.8Hz, 1H), 5.21-5.13(m, 2H), 5.00(br t, J=9.8Hz, 1H), 4.60-4.48(m, 4H), 4.14(d, J=2.8Hz, 1H), 3.95-3.87(m, 2H), 3.74-3.64(m, 4H), 2.99-2.89(m, 1H), 2.89-2.77(m, 3H), 2.59-2.49(m, 1H), 2.47(s, 3H), 2.25-2.18(m, 1H), 2.09-2.01(m, 1H), 1.97-1.88(m, 1H); hGal-3 IC 50 =0.074 μM; hCRBN IC 50 >50 μM

[0090] Example 7: 4-((1-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide [ka]

[0091] Step 1. tert-Butyl 3-((4-(ethoxycarbonyl)phenoxy)methyl)azetidine-1-carboxylate To a mixture of ethyl 4-hydroxybenzoate (0.35 g, 2.106 mmol), tert-butyl cis-3-hydroxycyclobutyl)carbamate (0.493 g, 2.63 mmol), and triphenylphosphine (0.829 g, 3.16 mmol) in toluene (12 mL) was added diisopropyl azodicarboxylate (DIAD, 0.622 mL, 3.16 mmol) over 1 minute at room temperature, followed by heating at 105° C. for 16 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (50 mL), and silica gel (5 g) was added. The volatiles were removed in vacuo and the resulting residue was purified by ISCO chromatography (80 g silica gel, 0-35% ethyl acetate / hexanes) to afford ethyl 4-(trans-3-((tert-butoxycarbonyl)amino)cyclobutoxy)benzoate (704 mg, 2.099 mmol, 100% yield) as a viscous oil. LCMS (M+H) + =336.0; 1 H NMR (400MHz, chloroform-d)δ 8.19-7.78(m, 2H), 7.06-6.62(m, 2H), 4.35(q, J=7.1Hz, 2H), 4.14(d, J=6.6Hz, 2H), 4.10(t, J=8.5Hz, 2H), 3.80(dd, J=8.8, 5.2Hz, 2H), 2.98(ttt, J=8.3, 6.6, 5.2Hz, 1H), 1.45(s, 9H), 1.38(t, J=7.1Hz, 3H)

[0092] Step 2. 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methoxy)benzoic acid To a solution of tert-butyl 3-((4-(ethoxycarbonyl)phenoxy)methyl)azetidine-1-carboxylate (300 mg, 0.894 mmol) in tetrahydrofuran (10 mL) and methanol (2.5 mL) was added lithium hydroxide (129 mg, 5.37 mmol) in water (2.5 mL) over 1 minute at room temperature, and the mixture was stirred at room temperature for 60 hours. The mixture was then concentrated under reduced pressure to approximately 5 mL. The resulting residue was diluted with water (15 mL) and acidified to pH 5-6 with 1N HCl. The precipitated product: 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methoxy)benzoic acid (218 mg, 0.709 mmol, 79% yield) was collected as a white solid by suction filtration and dried under vacuum at 50 °C. 1 H NMR (400MHz, methanol-d4)δ 8.10-7.88(m, 2H), 7.08-6.94(m, 2H), 4.21(d, J=6.1Hz, 2H), 4.10(t, J=8.5Hz, 2H), 3.83(dd, J=8.7, 5.3Hz, 2H), 3.06(tdd, J=8.4, 7.0, 4.2Hz, 1H), 1.47(s, 9H)

[0093] Step 3: tert-butyl 3-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate A mixture of 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methoxy)benzoic acid (122 mg, 0.397 mmol), 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Intermediate 2, 86 mg, 0.332 mmol), HATU (151 mg, 0.398 mmol), and N,N-diisopropylethylamine (0.232 mL, 1.327 mmol) was stirred at room temperature for 7 days. The mixture was diluted with ethyl acetate (60 mL), water (20 mL), saturated aqueous HCl (HCl), and HCl (HCl). The mixture was washed with aqueous NaHCO3 solution (20 mL) and dried over anhydrous MgSO4. The desired product: tert-butyl 3-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (102 mg, 0.186 mmol, 56.1% yield) was isolated by ISCO chromatography (40 g silica gel, dusted column, 0-10% MeOH / CH2Cl2) as a white solid. LCMS (M+H) + =548.8; 1 H NMR(400MHz, DMSO-d6)δ 10.98(s, 1H), 10.40(s, 1H), 8.15(d, J=1.7Hz, 1H), 8.05-7.94(m, 2H), 7.84(dd, J=8.4, 1.8Hz, 1H), 7.71(d, J=8.3Hz, 1H), 7.11(d, J=8.9Hz, 2H), 5.11(dd, J=13.2, 5.1Hz, 1H), 4.47(d, J=17.3Hz, 1H), 4.33(d, J=17.3Hz, 1H), 4.23(d, J=6.4Hz, 2H), 4.07-3.92(s, 2H), 3.78-3.63(m, 2H), 3.07-2.84(m, 2H), 2.66-2.57(m, 1H), 2.44-2.36(m, 1H), 2.13-1.92(m, 1H), 1.40(s, 9H)

[0094] Step 4. 4-(azetidin-3-ylmethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide To a solution of tert-butyl 3-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (102 mg, 0.186 mmol) in CHCl (5 mL) at room temperature, 4 M hydrogen chloride in 1,4-dioxane (5 mL, 20.00 mmol) was added over 1 minute, stirred at room temperature for 1 hour, and then concentrated to dryness under reduced pressure to give 4-(azetidin-3-ylmethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide·HCl (129 mg, 0.186 mmol, 100% yield) as a white solid (ring-opened product ) was also observed). LCMS (M+H) + =448.9

[0095] Step 5. 4-((1-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide 2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetic acid (25 mg, 0.033 mmol) A mixture of 4-(azetidin-3-ylmethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide·HCl (20 mg, 0.029 mmol), BOP (20.43 mg, 0.046 mmol), and N,N-diisopropylethylamine (0.025 mL, 0.144 mmol) in DMF (1 mL) was stirred at room temperature for 2 h, and the crude material was purified by preparative LC (conditions: Column: Phenomenex Luna Axia C18, 21.2 x 100 mm, particle size: 5 μm; Mobile phase A: 5:95 acetonitrile:water (containing 0.1% TFA); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% TFA); Gradient: 30–100% B over 10 min, followed by 100% B for 2 min; Flow rate: The resulting mixture was purified at 20 mL / min (20 mL / min) and the combined fractions containing the desired product were dried on a centrifugal evaporator to give the desired product: 4-((1-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide (15 mg, 0.013 mmol, 43.4% yield) as a white solid. LCMS(M+H) + =1197.2

[0096] Step 6. 4-((1-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide A mixture of 4-((1-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide (25 mg, 0.021 mmol) in 70% acetic acid (3 mL) was heated at 75° C. for 17 hours. This mixture was diluted with methanol (4 mL), separated into two solutions, and purified by preparative HPLC. The collected fractions were combined and concentrated in vacuo to give the product, which was diluted with saturated aqueous NaHCO3 and extracted with dichloromethane (2 x 50 mL), and the combined extracts were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give the desired product: 4-((1-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide (21.3 mg, 0.019 mmol, 90% yield) as a white solid. LCMS (M+H) + =1109.1; 1H NMR(400MHz, DMSO-d6)δ 10.98(s, 1H), 10.39(d, J=3.4Hz, 1H), 9.14(d, J=4.4Hz, 1H), 8.15(s, 1H), 8.11-7.61(m, 8H), 6.99(t, J=8.9Hz, 3H), 5.48(d, J=6.0Hz, 1H), 5.20(d, J=10.7Hz, 1H), 5.11(dd, J=13.1, 5.1Hz, 1H), 4.88-4.62(m, 2H), 4.54-4.43(m, 2H), 4.34(d, J=17.4Hz, 1H), 4.13-3.98(m, 2H), 3.99-3.57(m, 6H), 3.51-3.35(m, 2H), 3.05-2.75(m, 2H), 2.65-2.57(m, 1H), 2.46-2.28(m, 4H), 2.11-1.87(m, 1H); hGal-3 IC 50 =0.056 μM; hCRBN IC 50 =0.601μM

[0097] Example 8: 4-((1-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetyl)azetidin-3-yl)oxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide [ka]

[0098] Step 1. tert-Butyl 3-(4-(ethoxycarbonyl)phenoxy)azetidine-1-carboxylate To a mixture of ethyl 4-hydroxybenzoate (0.35 g, 2.106 mmol), tert-butyl 3-hydroxyazetidine-1-carboxylate (0.456 g, 2.63 mmol), and triphenylphosphine (0.829 g, 3.16 mmol) in toluene (12 mL) was added diisopropyl azodicarboxylate (DIAD, 0.622 mL, 3.16 mmol) over 1 minute at room temperature and heated at 105 °C for 16 h. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (50 mL), silica gel (5 g) was added, and the volatiles were removed in vacuo. The resulting residue was purified by ISCO chromatography (80 g silica gel, 0-35% ethyl acetate / hexane) to afford tert-butyl 3-(4-(ethoxycarbonyl)phenoxy)azetidine-1-carboxylate (637 mg, 1.982 mmol, 94% yield) as a viscous oil. 1 H NMR (400 MHz, chloroform-d) δ 8.15-7.74 (m, 2H), 6.95-6.58 (m, 2H), 4.93 (tt, J = 6.4, 4.1 Hz, 1H), 4.40-4.28 (m, 4H), 4.01 (ddd, J = 9.7, 4.1, 1.1 Hz, 2H), 1.45 (s, 9H), 1.38 (t, J = 7.1 Hz, 3H).

[0099] Step 2. 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)benzoic acid To a solution of tert-butyl 3-(4-(ethoxycarbonyl)phenoxy)azetidine-1-carboxylate (637 mg, 1.982 mmol) in tetrahydrofuran (20 mL) and methanol (5 mL) was added lithium hydroxide (285 mg, 11.9 mmol) in water (5 mL) over 1 minute at room temperature, stirred at 50 °C for 16 hours, and then concentrated under reduced pressure to approximately 5 mL. The resulting residue was diluted with water (15 mL) and acidified with 1 N HCl to pH = 5-6. The precipitated product: 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)benzoic acid (516 mg, 1.759 mmol, 89% yield) was collected as a white solid by suction filtration and dried under vacuum at 50 °C. The product was used in the next step without further purification.

[0100] Step 3: tert-Butyl 3-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)phenoxy)azetidine-1-carboxylate A mixture of 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)oxy)benzoic acid (122 mg, 0.416 mmol), 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (86 mg, 0.332 mmol), HATU (151 mg, 0.398 mmol), and N,N-diisopropylethylamine (0.232 mL, 1.327 mmol) in DMF (3 mL) was stirred at room temperature for 7 days. The mixture was diluted with ethyl acetate (60 mL), washed with water (2 × 20 mL), saturated NaHCO solution (20 mL), and dried over anhydrous MgSO. The desired product: tert-butyl 3-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)phenoxy)azetidine-1-carboxylate (110 mg, 0.206 mmol, 62.0% yield) was isolated by ISCO chromatography (40 g silica gel, dusted column, 0-10% MeOH / CHCl) as a white solid. LCMS (M+H) + =534.8

[0101] Step 4. 4-(azetidin-3-yloxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide A mixture of tert-butyl 3-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)phenoxy)azetidine-1-carboxylate (110 mg, 0.206 mmol) in CHCl (2 mL) and TFA (2 mL) was stirred at room temperature for 2 hours. The solvent was concentrated to give 4-(azetidin-3-yloxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide·TFA (113 mg, 0.206 mmol, 100% yield) as a viscous oil. The product was used in the next step without further purification.

[0102] Step 5. 4-((1-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetyl)azetidin-3-yl)oxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide 4-(azetidin-3-yloxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide·TFA (34 mg, 0.062 mmol), 2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3 A mixture of (1,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetic acid (48 mg, 0.063 mmol), BOP (43.9 mg, 0.099 mmol), and N,N-diisopropylethylamine (0.054 mL, 0.310 mmol) in DMF (1.5 mL) was stirred at room temperature for 2 hours. The crude material was purified by preparative HPLC (conditions: Column: Phenomenex Luna Axia C18, 30 x 100 mm, particle size: 5 μm; Mobile phase A: 5:95 acetonitrile:water (containing 0.1% TFA); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% TFA); Gradient: 25-100% B over 10 min, followed by 100% B for 2 min; Flow rate: The resulting mixture was purified at 20 mL / min (20 mL / min) and the combined fractions containing the desired product were dried on a centrifugal evaporator to give the desired product: 4-((1-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetyl)azetidin-3-yl)oxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide (58 mg, 0.049 mmol, 79% yield) as a white solid. LCMS(M+H) + =1183.2

[0103] Step 6. 4-((1-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetyl)azetidin-3-yl)oxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide A mixture of 4-((1-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetyl)azetidin-3-yl)oxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide (58 mg, 0.049 mmol) in 70% acetic acid (3 mL) was heated at 70° C. for 17 hours, diluted with methanol (3 mL), separated into two solutions, and purified by preparative HPLC. The collected fractions were combined and concentrated in vacuo to give the product, which was dissolved in DCM (100 mL) and washed with saturated NaHCO3 solution (5 mL). The organic layer was separated, dried over MgSO and concentrated to give the desired product: 4-((1-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetyl)azetidin-3-yl)oxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide (26 mg, 0.023 mmol, 46.0% yield) as a white solid. LCMS (M+H)+ =1095.0; 1 H NMR(400MHz, DMSO-d6)δ 10.98(s, 1H), 10.42(d, J=2.3Hz, 1H), 9.14(d, J=15.3Hz, 1H), 8.15(s, 1H), 8.06(dd, J=8.8, 6.5Hz, 1H), 8.02-7.93(m, 3H), 7.93-7.79(m, 3H), 7.71(d, J=8.3Hz, 1H), 6.92-6.77(m, 2H), 5.47(t, J=6.3Hz, 1H), 5.21(d, J=10.7Hz, 1H), 5.11(dd, J=13.2, 5.1Hz, 1H), 5.02-4.91(m, 1H), 4.86-4.73(m, 1H), 4.73-4.64(m, 1H), 4.55-4.42(m, 2H), 4.34(d, J=17.4Hz, 1H), 4.24-3.99(m, 2H), hGal-3 IC 50 =0.048 μM; hCRBN IC 50 μM=1.42μM

[0104] Example 9: 4-((1-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide [ka]

[0105] Step 1. tert-Butyl 3-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)phenoxy)azetidine-1-carboxylate A mixture of 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methoxy)benzoic acid (98 mg, 0.319 mmol), 3-(5-amino-1-oxoisoindolin-2-yl)-1-methylpiperidine-2,6-dione (105 mg, 0.384 mmol, Intermediate 3), HATU (145 mg, 0.383 mmol), and N,N-diisopropylethylamine (0.223 mL, 1.275 mmol) in DMF (3 mL) was stirred at room temperature for 5 days. The crude material was purified by preparative HPLC (conditions: column: Sunfire C18, 30x100 mm, OBD particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 0.1% TFA); mobile phase B: 95:5 acetonitrile:water (containing 0.1% TFA); gradient: 5-100% B over 10 min, then 100% B for 2 min; flow rate: 40 mL / min). Fractions containing the desired product were combined and dried on a centrifugal evaporator to give the desired product: tert-butyl 3-((4-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (44 mg, 0.078 mmol, 24.53% yield). LCMS(M+H) + =562.8; 1H NMR(400MHz, DMSO-d6)δ 10.40(s, 1H), 8.15(d, J=2.0Hz, 1H), 8.05-7.93(m, 2H), 7.85(dd, J=8.3, 1.8Hz, 1H), 7.71(d, J=8.3Hz, 1H), 7.11(d, J=8.9Hz, 2H), 5.18(dd, J=13.4, 5.1Hz, 1H), 4.47(d, J=17.4Hz, 1H), 4.32(d, J=17.2Hz, 1H), 4.23(d, J=6.5Hz, 2H), 4.05-3.92(m, 2H), 3.79-3.61(m, 2H), 3.47 (bs, 1H), 3.10-2.92(m, 4H), 2.88-2.70(m, 1H), 2.47-2.29(m, 1H), 2.06-1.96(m, 1H), 1.40(s, 9H)

[0106] Step 2. 4-(azetidin-3-ylmethoxy)-N-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide A mixture of tert-butyl 3-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)carbamoyl)phenoxy)azetidine-1-carboxylate (44 mg, 0.078 mmol) in CHCl (2 mL) and TFA (2 mL) was stirred at room temperature for 2 hours, and the solvent was concentrated to give 4-(azetidin-3-ylmethoxy)-N-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide·TFA (45 mg, 0.078 mmol) as a viscous oil (LCMS (M+H)). + =462.9). The product was used in the next step without further purification.

[0107] Step 3: 4-((1-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide 4-(azetidin-3-ylmethoxy)-N-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide·TFA (36 mg, 0.062 mmol), 2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-2-trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)- A mixture of (1,3-dichloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetic acid (48 mg, 0.063 mmol), BOP (44.3 mg, 0.100 mmol), and N,N-diisopropylethylamine (0.055 mL, 0.313 mmol) in DMF (1.5 mL) was stirred at room temperature for 2 hours. The crude material was purified by preparative HPLC (conditions: Column: Phenomenex Luna Axia C18, 30 x 100 mm, particle size: 5 μm; Mobile phase A: 5:95 acetonitrile:water (containing 0.1% TFA); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% TFA); Gradient: 35-100% B over 10 min, followed by 100% B for 2 min; Flow rate: The mixture was purified at 40 mL / min., and the fractions containing the desired product were combined and dried on a centrifugal evaporator to give the desired product: 4-((1-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H- 1,2,3-Triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide (65 mg, 0.054 mmol, 86% yield) was obtained as a white solid. LCMS (M+H) + =1211.1

[0108] Step 4. 4-((1-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide A mixture of 4-((1-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide (65 mg, 0.054 mmol) in 70% acetic acid (4 mL) was heated at 70° C. for 17 hours, and the solvent was concentrated. The resulting crude product was purified by preparative HPLC (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 27% B at 0 min, followed by 27-67% B over 22 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions containing the desired product were combined and dried on a centrifugal evaporator to give the desired product: 4-((1-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)benzamide (33.6 mg, 0.030 mmol, 55.1% yield) as a white solid. LCMS (M+H) + =1123.0; 1H NMR(500MHz, DMSO-d6)δ 10.40(d, J=5.0Hz, 1H), 9.13(d, J=5.9Hz, 1H), 8.16(s, 1H), 8.05(dd, J=15.2, 8.6Hz, 1H), 8.02-7.90(m, 4H), 7.89-7.79(m, 3H), 7.73(d, J=8.3Hz, 1H), 6.99(dd, J=12.8, 8.7Hz, 2H), 5.49(d, J=5.8Hz, 1H), 5.26-5.11(m, 2H), 4.89-4.67(m, 2H), 4.57-4.42(m, 2H), 4.34(d, J=17.2Hz, 1H), 4.14-3.96(m, 2H), 3.97-3.57(m, 7H), 3.51-3.37(m, 2H), 3.02(s, 3H), 3.05-2.93(m, 1H), 2.95-2.71(m, 2H), 2.46-2.33(m, 1H), 2.36(s, 3H), 2.14-1.96(m, 1H); 50 =0.085 μM; hCRBN IC 50 =8.95μM

[0109] Example 10: 5-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide [ka]

[0110] Step 1. 5-(benzyloxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide A mixture of 5-(benzyloxy)picolinic acid (85 mg, 0.371 mmol), 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (95 mg, 0.366 mmol), HATU (169 mg, 0.445 mmol), and N,N-diisopropylethylamine (0.259 mL, 1.483 mmol) in DMF (2 mL) was stirred at room temperature over the weekend, and water (3 mL) was added. The insoluble product: 5-(benzyloxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide (127 mg, 0.270 mmol, 72.8% yield) was collected by filtration as a beige solid and dried under vacuum. LCMS (M+H) + =470.8

[0111] Step 2. N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-hydroxypicolinamide A mixture of 5-(benzyloxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide (127 mg, 0.270 mmol) and 10% Pd / C (28.7 mg, 0.027 mmol) in methanol (18 mL) and tetrahydrofuran (5 mL) was attached to a H balloon and stirred under an H atmosphere at room temperature for 6 hours. The H balloon was removed, and the reaction mixture was purged with N and heated to reflux. The catalyst was removed by filtration while the mixture was still hot, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was dried in vacuo at 50 °C to give the desired product: N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-hydroxypicolinamide (70 mg, 0.018 mmol, 70% yield) as a pale yellow solid. LCMS(M+H) + =380.8

[0112] Step 3: 2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)ethan-1-ol To a solution of 2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetic acid (Intermediate 1, 100 mg, 0.130 mmol) in THF (0.8 mL) was added borane-tetrahydrofuran complex (1 M, THF solution, 0.860 mL, 0.860 mmol) at room temperature and stirred for 4 hours. The reaction was quenched by the dropwise addition of MeOH until bubbles disappeared. The reaction was stirred for 60 min and then concentrated under reduced pressure. The resulting residue was diluted with EtOAc, washed with brine, dried over MgSO, and concentrated. The crude material was purified by silica gel flash column (elution: 0–90% EtOAc / hexanes) to afford 2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)ethan-1-ol (97 mg, 0.129 mmol, 99% yield) as a foam.

[0113] Step 4. 5-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-hydroxypicolinamide (38.9 mg, 0.102 mmol), 2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)- To a mixture of 1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)ethan-1-ol (77.00 mg, 0.102 mmol) and triphenylphosphine (40.2 mg, 0.153 mmol) in THF (6 mL) was added DIAD (0.030 mL, 0.153 mmol) over 1 minute at room temperature and stirred at room temperature for 2.5 hours. The reaction mixture was heated at 70° C. for 0.5 hours, and the volatiles were removed in vacuo. The resulting residue was subjected to preparative HPLC (conditions: column: Phenomenex Luna Axia C18, 30x100mm, particle size: 5µm; mobile phase A: 5:95 acetonitrile:water (containing 0.1% TFA); mobile phase B: 95:5 acetonitrile:water (containing 0.1% TFA); gradient: 45-100% B over 10 min, followed by 100% B for 2 min; flow rate: The resulting mixture was purified at 40 mL / min., and the combined fractions containing the desired product were dried on a centrifugal evaporator to give the desired product: 5-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide (16.5 mg, 0.015 mmol, 14.5% yield) as a white solid. LCMS (M+H) + =1115.0

[0114] Step 5. 5-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide 5-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl) A mixture of (4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide (18 mg, 0.016 mmol) in 70% acetic acid (3 mL) was heated at 70° C. for 17 hours, and the solution was diluted with methanol and purified by preparative HPLC (conditions: column: Phenomenex Luna Axia C18, 21.2×100 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 0.1% TFA); mobile phase B: 95:5 Purification was performed using acetonitrile:water (containing 0.1% TFA); gradient: 15–100% B over 16 min, followed by 100% B for 2 min; flow rate: 20 mL / min. Fractions containing the desired product were combined and dried in a centrifugal evaporator to give the desired product. This product was diluted with saturated aqueous NaHCO3 (5 mL) and extracted with dichloromethane (2 × 30 mL). The combined extracts were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give the desired product: 5-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)picolinamide (12.0 mg, 0.011 mmol, 71% yield) as a white solid. LCMS (M+H) + =1127.0; 1H NMR(400MHz, DMSO-d6)δ 10.98(s, 1H), 10.63(s, 1H), 9.14(s, 1H), 8.24(d, J=1.8Hz, 1H), 8.07(d, J=8.7Hz, 1H), 8.02-7.89(m, 4H), 7.83-7.64(m, 4H), 7.25(dd, J=8.9, 2.9Hz, 1H), 5.52(d, J=5.9Hz, 1H), 5.16(dd, J=10.7, 2.9Hz, 1H), 5.11(dd, J=13.3, 5.1Hz, 1H), 4.83(t, J=9.8Hz, 1H), 4.71(t, J=5.8Hz, 1H), 4.56-4.39(m, 2H), 4.33(d, J=17.3Hz, 1H), 3.95-3.88(m, 2H), 3.82-3.73(m, 1H), 3.71(t, J=6.3Hz, 1H), 3.67-3.57(m, 1H), 3.54-3.39(m, 3H), 3.03-2.84(m, 1H), 2.65-2.57(m, 1H), 2.44-2.38(m, 1H), 2.36(s, 3H), 2.11-1.84(m, 1H); hGal-3 IC 50 =0.074 μM; hCRBN IC 50 =0.214μM

[0115] Example 11 4-((1-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)benzamide [ka]

[0116] Step 1. tert-Butyl 3-((4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate A mixture of 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methoxy)benzoic acid (65.0 mg, 0.211 mmol), 3-(6-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50 mg, 0.193 mmol, Intermediate 4), HATU (88 mg, 0.231 mmol), and N,N-diisopropylethylamine (0.135 mL, 0.77 mmol) in DMF (2 mL) was stirred at room temperature for 16 h, and the crude material was purified by preparative HPLC (conditions: column: Phenomenex Luna Axia C18, 30x100 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (with 0.1% TFA); mobile phase B: 95:5 acetonitrile:water (with 0.1% TFA); Purification was performed using a gradient of 15-100% B over 10 min, followed by 100% B for 2 min; flow rate: 40 mL / min. Fractions containing the desired product were combined and dried using a centrifugal evaporator to give the desired product: tert-butyl 3-((4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (77 mg, 0.140 mmol, 72.8% yield) as a white solid. LCMS (M+H) + =548.8

[0117] Step 2. 4-(azetidin-3-ylmethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)benzamide A solution of tert-butyl 3-((4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)carbamoyl)phenoxy)methyl)azetidine-1-carboxylate (42 mg, 0.077 mmol) in CHCl (2 mL) and TFA (2 mL) was stirred at room temperature for 2 hours, and the solvent was concentrated to give 4-(azetidin-3-ylmethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)benzamide·TFA (43 mg, 0.077 mmol, 100% yield) as a viscous oil. LCMS (M+H) + =449.8

[0118] Step 3: 4-((1-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)benzamide 2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetic acid (48 mg, 0.063 mmol), 4 A mixture of N-(azetidin-3-ylmethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)benzamide·TFA (43.1 mg, 0.077 mmol), BOP (44.3 mg, 0.100 mmol), and N,N-diisopropylethylamine (0.055 mL, 0.313 mmol) in DMF (1.5 mL) was stirred at room temperature for 2 h, and the crude material was purified by preparative HPLC (conditions: Column: Phenomenex Luna Axia C18, 30x100mm, particle size: 5µm; Mobile phase A: 5:95 acetonitrile:water (containing 0.1% TFA); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% TFA); Gradient: 30-100% B over 10 min, followed by 100% B for 2 min; Flow rate: 40mL / min. Fractions containing the desired product were combined and dried on a centrifugal evaporator to give the desired product: 4-((1-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)benzamide (61 mg, 0.051 mmol, 81% yield) as a white solid. LCMS (M+H) + =1199.2

[0119] Step 4. 4-((1-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)benzamide 4-((1-(2-(((4aR,6S,7R,8R,8aR)-6-(1-(5-chloro-2-(trifluoromethyl) A mixture of (phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-8-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)benzamide (61 mg, 0.051 mmol) in 70% acetic acid (3 mL) was heated at 70° C. for 17 hours, and the solvent was concentrated. The resulting crude product was dissolved in DMF and purified by preparative HPLC (conditions: column: XBridge C18, 200 mm x 19 mm, particle size: 5 μm; mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); gradient: 19% B at 0 min, followed by 19-58% B over 28 min, then 100% B at 0 min; flow rate: 20 mL / min; column temperature: 25°C). Fractions containing the desired product were combined and dried on a centrifugal evaporator to give the desired product: 4-((1-(2-(((2S,3R,4S,5R,6R)-2-(1-(5-chloro-2-(trifluoromethyl)phenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-4-(4-(4-chloro-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)acetyl)azetidin-3-yl)methoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)benzamide (22.6 mg, 0.020 mmol, 57% yield) as a white solid. LCMS (M+H) + =1109.3; 1H NMR(500MHz, DMSO-d6)δ 11.00(s, 1H), 10.33(d, J=6.3Hz, 1H), 9.09(d, J=6.5Hz, 1H), 8.23(s, 1H), 8.05(dd, J=15.5, 8.6Hz, 1H), 8.01-7.89(m, 5H), 7.83(dd, J=21.7, 8.9Hz, 2H), 7.60(d, J=8.4Hz, 1H), 6.97(dd, J=15.9, 8.4Hz, 2H), 5.51(d, J=5.9Hz, 1H), 5.19(d, J=10.7Hz, 1H), 5.10(dd, J=13.0, 5.1Hz, 1H), 4.83-4.72(m, 2H), 4.54-4.38(m, 2H), 4.33(d, J=17.1Hz, 1H), 4.14-3.95(m, 2H), 3.94-3.50(m, 8H), 2.97-2.80(m, 2H), 2.67-2.59(m, 1H), 2.44-2.39(m, 1H), 2.38(d, J=2.7Hz, 3H), 2.13-1.96(m, 1H); hGal-3 IC50=0.040μM; hCRBN IC 50 =1.27μM

[0120] Table 1 below shows Examples 12 to 35 and the methods described in the Examples above are used to synthesize した. Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11

[0121] Table 12

Claims

1. Examples 1-35 below: 【Chemistry 1】 【change】 【change】 【change】 【change】 【change】 【change】 or a pharmaceutically acceptable salt thereof.

2. 10. A composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

3. 10. A pharmaceutical composition for treating a disease or condition, comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the disease or condition is selected from the group consisting of fibrosis of organs (including the liver, kidney, lung, heart, and skin), liver diseases and conditions (including acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis, portal hypertension, aplastic anemia, nonalcoholic steatohepatitis (NASH), liver failure, and impaired hepatic blood flow), 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 infiltrative metastasis of cancer cells, inflammatory diseases and conditions (including psoriasis, nephropathy, and pneumonia), gastrointestinal diseases and conditions (including irritable bowel syndrome (IBS), inflammatory bowel disease, and inflammatory bowel disease). and abnormal pancreatic secretion), kidney diseases and conditions, urinary tract-related diseases and conditions (including benign prostatic hyperplasia or neurogenic bladder-related diseases, spinal tumors, herniated discs, spinal stenosis, and diabetes-related conditions), lower urinary tract diseases and conditions (including lower urinary tract obstruction), inflammatory diseases and conditions of the lower urinary tract (including dysuria and frequent urination), pancreatic diseases and conditions, abnormal angiogenesis-related diseases and conditions (including arterial occlusion), 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 post-glaucoma filtration surgery scarring).

4. 4. The pharmaceutical composition of claim 3, wherein the disease or condition is renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, or systemic sclerosis.

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