Compositions comprising galectin-3 inhibitor

Abstract

The present invention provides a composition comprising a compound of formula X or a pharmaceutically acceptable salt thereof, and / or a compound of formula Y or a pharmaceutically acceptable salt thereof, and / or a compound of formula Z or a pharmaceutically acceptable salt thereof, for inhibiting galectin-3. The compositions are useful for the treatment and / or prevention of a disease, disorder, state or condition, wherein inhibition of galectin-3 will be beneficial for the treatment and / or prevention of said disease, disorder, state or condition. The disease, disorder, state, or condition may be cancer, cancer metastasis, fibrosis, inflammation, diabetes, and / or one or more other disease, disorder, state, or condition affected and / or mediated by galectin-3.

Description

Technical Field

[0001] This invention relates to the prevention and / or treatment of cancer and / or cancer metastasis and / or fibrosis and / or inflammation and / or diabetes, and / or other conditions affected and / or mediated by galectin-3. More specifically, this invention relates to the prevention and / or treatment of cancer and / or cancer metastasis and / or fibrosis and / or inflammation and / or diabetes by inhibiting the activity of galectin-3. This invention relates to compounds and compositions for inhibiting the activity of galectin-3. This invention also relates to methods and kits for inhibiting the activity of galectin-3, particularly to methods for treating cancer and / or cancer metastasis and / or fibrosis and / or inflammation and / or diabetes, and / or one or more other diseases, conditions, states, or ailments affected and / or mediated by galectin-3. Background Technology

[0002] In the UK, cancer is a leading cause of death, accounting for one in four deaths and claiming more than 150,000 lives annually. Nearly half the population will develop cancer in their lifetime, with over 500,000 new cases diagnosed each year. Despite significant efforts, effective treatment of the disease remains a major challenge. A growing consensus suggests that treatment strategies targeting specific molecules or mechanisms of action, particularly multimodal therapy, may offer a solution for more effective cancer treatment.

[0003] Cancer is a group of diseases characterized by abnormal and / or uncontrolled cell growth. These cells can form tumors, which occur when cells proliferate too rapidly. The National Cancer Institute defines a tumor as "an abnormal mass of tissue formed when cells divide beyond their normal capacity or fail to die when they should." Tumors can be of any size and are generally classified as benign, precancerous, or malignant. Malignant tumors can grow and spread to other parts of the body, for example, through the bloodstream or lymphatic system. Benign tumors do not invade or destroy adjacent tissues and do not spread to other parts of the body. Precancerous tumors have not yet spread but may spread rapidly.

[0004] Galectin-3 (GAL-3) belongs to the galactosidase-binding protein family and is expressed by various types of human cells, especially epithelial cells and immune cells. It is typically overexpressed in most solid tumors, such as breast cancer, lung cancer, colon cancer, pancreatic cancer, prostate cancer, gastrointestinal cancer, urinary system cancer, thyroid cancer, and melanoma [Newlaczyl, AU and LG Yu, Galectin-3: A-jack-of-all-trades incancer. Cancer Lett, 2011. 313: p. 123-128, Liu, F.-TT and GA Rabinovich, Galectins as modulators of tumor progression. Nature Reviews Cancer, 2005. 5(1): p. 29-41]. Extensive research over the past few decades has shown that galectin-3 is a significant promoter of cancer progression and metastasis. It exerts its effects through various intracellular and extracellular mechanisms. Extracellular galactolectin-3 interacts with various cell surface molecules (such as mucins, growth factors, and cell adhesion molecules (such as MUC1, MUC16, epidermal growth factor (EGF), transforming growth factor β (TGFβ) receptor, and integrins)) and galactoterminal glycans expressed by basement membrane matrix proteins, thereby promoting tumor cell adhesion, invasion, and angiogenesis during cancer progression and metastasis. Extracellular galectin-3 (Galectin-3 can also induce T cell apoptosis, inhibit T cell infiltration in the tumor microenvironment, and weaken the body's anti-tumor immune response [Gordon-Alonso, M., et al., Galectin-3 captures interferon-gamma in the tumor matrix reducing chemokine gradient production and T-cell tumor infiltration. Nat Commun, 2017. 8(1): p. 793]). In its intracellular presence, galectin-3 is also known to promote tumor cell proliferation, the establishment of a metastatic microenvironment, oncogenic signal transduction, enhanced anti-apoptotic capacity, and cell cycle progression.The level of circulating galectin-3 is significantly elevated in cancer patients, especially in patients with metastasis [Barrow, H., et al., Serum Galectin-2,-4, and -8 Are Greatly Increased in Colon and Breast Cancer Patients and Promote Cancer Cell Adhesion to Blood Vascular Endothelium. Clinical Cancer Research, 2011. 17(22): p. 7035-7046]. Circulating galectin-3 has been found to play an important role in promoting the metastasis of circulating tumor cells to distant organs by interacting with spreading tumor cells [Zhao, Q., et al., Interaction between circulating Galectin-3 and cancer-associated MUC1 enhances tumor cell homotypic aggregation and prevents anoikis. Mol Cancer, 2010. 9:p. 154, Zhao, Q., et al., Circulating Galectin-3 promotes metastasis by modifying MUC1 localization on cancer cell surface. Cancer Res, 2009. 69(17):p. 6799-806] and by interacting with vascular endothelium [Chen, C., et al., Increased circulation of Galectin-3 in cancer induces secretion of metastasis-promoting cytokines from blood vascular endothelium. Clinical Cancer Research 2013, 19:1693-704].

[0005] Pathological fibrosis originates from abnormal tissue repair, cellular stress, chronic inflammation, and / or severe tissue damage. It can lead to organ failure and is associated with chronic fibrotic diseases (e.g., IPF24) and chronic inflammatory diseases (e.g., NASH19). In addition to its role in cancer, galectin-3 has been shown in recent years to actively participate in tissue fibrosis (e.g., fibrosis in the lungs, liver, heart, and kidneys) and plays a key role in certain heart failure states by promoting the secretion of pro-inflammatory cytokines, fibroblast proliferation / transdifferentiation, and collagen production [Li, LC, J. Li, and J. Gao, Functions of Galectin-3 and its role in fibrotic diseases. J PharmacolExp Ther, 2014. 351(2): p. 336-43]. In human fibrotic lesions, galectin-3 expression is higher than normal. Currently, there are very limited drugs for fibrotic diseases, so the search for new treatments for fibrosis is still ongoing. Given its association with tissue fibrosis, galactolectin-3 has also become a potential therapeutic target in fibrotic disease research.

[0006] Given its broad and profound impact on promoting cancer progression, metastasis, and tissue fibrosis, galectin-3 is currently considered an attractive and druggable therapeutic target in these disease areas. Therapeutic agents targeting galectin-3 are under development, including small molecule carbohydrate binding inhibitors, polysaccharides, peptides, and biologics (such as siRNA and neutralizing monoclonal antibodies), and some carbohydrate-based compounds have shown promise in early clinical trials [Marino, KV, et al., Targeting Galectin-driven regulatory circuits in cancer and fibrosis. Nat Rev Drug Discov, 2023. 22(4): p. 295-316]. However, due to the metabolic characteristics and poor physicochemical properties of carbohydrates, they are generally not ideal drug molecules [Wang, J., et al., Exploring Carbohydrates for Therapeutics: A Review on Future Directions. Front Pharmacol, 2021. 12: p. 756724].

[0007] Therefore, there is still a need for compounds with good synthetic routes and biosafety that can inhibit galactoglucosides, especially galactoglucosides-3, preferably small molecule compounds.

[0008] In particular, galectin inhibitors that target only or preferentially target specific members of the galectin family will have advantages. Several known galectin inhibitors can bind to a variety of galactoside-binding proteins, such as galectin-1, galectin-3, and galectin-8. Selective targeting of specific galectin proteins will contribute to a deeper understanding of the role of that specific galectin in disease mechanisms and will help to better control the efficacy of such inhibitors in disease treatment and management.

[0009] In view of the above, there is an urgent need to provide new therapeutic strategies for the treatment and prevention of cancer and cancer metastasis, fibrosis and fibrotic diseases, diabetes and inflammatory diseases, and other diseases, symptoms, states, or conditions affected and / or mediated by galectin-3. The object of this invention is to provide compounds and compositions for treating diseases, symptoms, states, and / or conditions (e.g., cancer, diabetes, inflammation, or fibrosis) affected and / or mediated by galectin-3. Furthermore, providing inhibitors targeting specific members of the galectin family is also a desired technical objective. Summary of the Invention

[0010] This invention is based on the understanding that certain compounds (compounds X, Y, and Z as defined below) can act as inhibitors of galectin-3 activity. These compounds are previously known but have never been identified as inhibitors of galectin-3 activity, and therefore have never been shown to be effective in targeting the treatment of diseases, symptoms, states, or conditions mediated by galectin-3 as described herein (e.g., cancer, inflammation, fibrosis, diabetes, etc.). Therefore, the compounds and compositions of this invention can serve as potentially effective formulations for the treatment and / or prevention of diseases, symptoms, states, or conditions affected and / or mediated by galectin-3, such as cancer and / or cancer metastasis and / or fibrosis and / or inflammation and / or diabetes. Furthermore, diseases, conditions, states, or illnesses affected and / or mediated by galactolectin-3 also include asthma, atherosclerosis, atopic dermatitis, cerebral infarction, chronic obstructive pulmonary disease (COPD), degenerative aortic stenosis, endometriosis, encephalitis, gastritis, HIV infection, interstitial lung disease, juvenile idiopathic arthritis, fatal cardiovascular disease (CVD) death, non-alcoholic steatohepatitis (NASH), obesity, pneumonia, pulmonary hypertension, plaque psoriasis, Q fever, rheumatoid arthritis, systemic sclerosis, urinary tract infection, COVID-19, sepsis, thrombosis, venous thrombosis, wound healing, cardiac syndrome X (CSX), yeast infection-candidiasis, or herpes zoster-related pain (hyperalodynia). In this invention, the above-mentioned diseases, conditions, states, or illnesses are collectively referred to as diseases, conditions, states, or illnesses affected and / or mediated by galactolectin-3. The compounds identified in this invention can also be used to treat and / or prevent any of the aforementioned diseases, symptoms, conditions, or illnesses. The compounds described in this invention can be used to treat and / or prevent any of the aforementioned diseases, symptoms, conditions, or illnesses affected and / or mediated by galactolectin-3.

[0011] In this invention, the compound and its metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or compositions comprising the above substances, are all capable of inhibiting galactolectin-3; when inhibition of galactolectin-3 is beneficial to the subject, it can be used to treat and / or prevent diseases, symptoms, states, or conditions, such as cancer and / or cancer metastasis and / or fibrosis and / or inflammation and / or diabetes, and / or one or more other diseases, symptoms, states, or conditions affected and / or mediated by galactolectin-3, wherein the other diseases, symptoms, states, or conditions affected and / or mediated by galactolectin-3... Diseases, symptoms, states, or conditions may include, for example, asthma, atherosclerosis, atopic dermatitis, cerebral infarction, chronic obstructive pulmonary disease, degenerative aortic stenosis, endometriosis, encephalitis, gastritis, HIV infection, interstitial lung disease, juvenile idiopathic arthritis, fatal cardiovascular disease, nonalcoholic steatohepatitis (NASH), obesity, pneumonia, pulmonary hypertension, plaque psoriasis, Q fever, rheumatoid arthritis, systemic sclerosis, urinary tract infection, COVID-19, sepsis, thrombosis, venous thrombosis, wound healing, cardiac syndrome X (CSX), yeast infection-candidiasis, or herpes zoster-related pain (hyperalodynia). In this invention, fibrosis refers to fibrosis occurring in any part of the body, such as fibrosis occurring in the liver, lungs, heart, or kidneys. In this invention, inflammation refers to inflammation caused by stimulation from inflammatory factors, either internal or external, or a combination of both, and the resulting effects, conditions, states, diseases, or symptoms. The present invention also provides methods and compositions for preventing and inhibiting cancer metastasis, cancer cell proliferation, cancer recurrence after initial treatment or intervention, tumor growth, tumor angiogenesis or fibrosis.

[0012] Compounds and compositions containing formula X (tosufloxacin tosylate), formula Y (nelfinavir mesylate), and formula Z (toremifene citrate) have for the first time been shown to potently inhibit the binding of galectin-3 to its ligands. These compounds are known, but for the first time, they have been shown to inhibit galectin-3, thereby affecting galectin-3-mediated tumor cell adhesion, invasion, and angiogenesis in vitro. They have also been shown to inhibit galectin-3-mediated secretion of inflammatory cytokines by macrophages, which plays a fundamental role in the inflammatory process and the occurrence and formation of fibrosis. Compound X showed very low or no cytotoxicity in yeast and no genotoxicity was detected.

[0013] Due to its structural similarity to compound X, compound W (Gemifloxacin) has also been identified as a potential galactolectin-3 inhibitor. Gemifloxacin is also a fluoroquinolone compound and is structurally similar to the compounds identified in this invention (especially compound X, tosufloxacin tosylate). Previous studies have shown that compound W can affect metastasis markers and has been shown to inhibit the migration, invasion and metastasis of human breast cancer cells by inhibiting TNFα-induced NFκB activation [TC Chen, YL Hsu, YC Tsai, YW Chang, PL Kuo, YH Chen, Gemifloxacin inhibits migration and invasion and induces mesenchymal-epithelial transition in human breast adenocarcinoma cells, J.Mol. Med., 92 (1) (2014), pp. 53-64; and Vikas Yadav a, Puneet Talwar, Repositioning of fluoroquinolones from antibiotic to anti-cancer agents: An underestimated truth, Biomedicine & Pharmacotherapy Volume 111, March 2019, Pages 934-946]. Gemifloxacin has also been shown to inhibit the migration and invasion of human colon cancer cells [Kan JY, HsuYL, Chen YH, Chen TC, Wang JY, Kuo PL. Gemifloxacin, a fluoroquinolone antimicrobial drug, inhibits migration and invasion of human colon cancer cells. Biomed Res Int. 2013;2013:159786. Doi: 10.1155 / 2013 / 159786. Epub 2013Dec 10. PMID: 24386633; PMCID: PMC3872387.].The effects of gemifloxacin on biomarkers shown in breast cancer cells [NFκB (downregulated), Snail (downregulated), pIκB (downregulated), IκB (upregulated), RKIP (upregulated), N-Cad (downregulated), Vimentin (downregulated), E-Cad (upregulated), SM-actin (downregulated)] and biomarkers shown in colon cancer cells [NFκB (downregulated), Snail (downregulated), E-Cad (upregulated), N-Cad (downregulated), Claudin3 (upregulated), Vimentin (downregulated), pIκB (downregulated), IκB (upregulated), TAK1 (downregulated)] indicate that compound W (gemifloxacin) functions as an inhibitor of galactolectin-3, as many of its biomarkers (e.g., N-cad, vimentin, snail, E-cad, etc.) are associated with epithelial-mesenchymal transition (EMT, a crucial step in the development and progression of epithelial carcinoma). Galactolectin-3 is known to participate in the EMT and NFκB signaling pathways, so the gemifloxacin effect reported in the above literature is likely related to its effect on galactolectin-3.

[0014] The compounds identified in this invention have never been previously identified as: (i) inhibitors of galactolectin-3; or (ii) compounds that have potentially significant therapeutic effects in treating and / or preventing diseases, conditions, states, or illnesses, such as cancer and / or cancer metastasis and / or tissue fibrosis and / or inflammation and / or diabetes, or any other related diseases, conditions, states, or illnesses affected and / or mediated by galactolectin-3.

[0015] These low molecular weight synthetic compounds have been identified as highly potent galectin-3 binding inhibitors. Compound X has been shown to bind to galectin-3 with low micromolar affinity (binding affinity (KD) of 5–7 μM for both full-length and C-terminal galectin-3). Compounds X, Y, and Z all potently inhibit the binding of galectin-3 to its ligands (IC50 of approximately 10 μM or less), and compounds X and Y have been shown to eliminate various galectin-3-mediated cancer cell activities, such as angiogenesis, cell adhesion, and migration. Their efficacy has been demonstrated in various cancer cell types, indicating their potential for treating multiple cancer types. Compounds X, Y, and Z have also been shown to inhibit galectin-3-induced secretion of pro-inflammatory cytokines (TNFα and IL-1β) by macrophages, clearly demonstrating their ability to influence inflammation and fibrosis-related diseases, symptoms, states, or conditions. The secretion of pro-inflammatory cytokines is one of the fundamental mechanisms in the pathogenesis of galactolectin-3-mediated fibrosis, and its inhibition will suppress or treat fibrosis. Furthermore, compound X did not show detectable cytotoxicity against normal or cancerous human cells, while compounds Y and Z showed only extremely low cytotoxicity against normal and cancer cells.

[0016] Furthermore, it has been demonstrated that compound X does not affect the binding of galactagglomerates-2, -4, and -8 to desialylated fetoglobulin; therefore, compound X is identified as a selective inhibitor of galactagglomerate-3. Inhibitors capable of selectively binding to single galactagglomerate proteins (such as galactagglomerate-3) are particularly advantageous because different members of the galactagglomerate family sometimes have different effects on cancer-related activities.

[0017] These compounds have been specifically demonstrated to be effective in various cancer types, including breast cancer (including triple-negative breast cancer), pancreatic cancer, lung cancer, colorectal cancer, and melanoma cells. Results from galactolectin-3 knockdown and knockout models indicate that inhibition of galactolectin-3 is a key mechanism by which these compounds exert their effects. The application of these compounds in various cancers has been demonstrated in this invention.

[0018] "Inhibition of galectin-3" refers to the inhibition of the binding of galectin-3 to its ligands and the inhibition of galectin-3-mediated cellular or tissue / organ activity that may be associated with disease, symptoms, conditions, or illnesses. The compounds described in this invention are known to bind to the galectin-3 protein, thereby inhibiting the role and mechanism of galectin-3 in related diseases, symptoms, conditions, or illnesses.

[0019] Specifically, the disease, condition, state, or symptom that is beneficial to the treatment and / or prevention of galectin-3 can be a galectin-3 mediated disease, condition, state, or symptom. The galectin-3 mediated disease, condition, state, or symptom can be any disease, condition, state, or symptom listed in this application. Such galectin-3 mediated diseases, conditions, states, or symptoms can be associated with any expression or overexpression of galectin-3, or with any known role of galectin-3 at any stage of the progression of the disease, condition, state, or symptom (including before the disease, condition, state, or symptom has occurred).

[0020] According to one aspect of the invention, a compound of formula X, or a pharmaceutically acceptable salt thereof, or a combination thereof, is provided for use as a medicament. According to one aspect of the invention, a compound of formula Y, or a pharmaceutically acceptable salt thereof, or a combination thereof, is provided for use as a medicament. According to one aspect of the invention, a compound of formula Z, or a pharmaceutically acceptable salt thereof, or a combination thereof, is provided for use as a medicament.

[0021] According to one aspect of the invention, a compound of formula X or a pharmaceutically acceptable salt thereof, or a combination thereof, is provided for the treatment and / or prevention of diseases, symptoms, states, or conditions. According to one aspect of the invention, a compound of formula Y or a pharmaceutically acceptable salt thereof, or a combination thereof, is provided for the treatment and / or prevention of diseases, symptoms, states, or conditions. According to one aspect of the invention, a compound of formula Z or a pharmaceutically acceptable salt thereof, or a combination thereof, is provided for the treatment and / or prevention of diseases, symptoms, states, or conditions.

[0022] According to one aspect of the invention, a compound of formula X or a pharmaceutically acceptable salt thereof, or a combination thereof, is provided for the treatment and / or prevention of cancer, cancer metastasis, fibrosis, inflammation, or diabetes. According to one aspect of the invention, a compound of formula Y or a pharmaceutically acceptable salt thereof, or a combination thereof, is provided for the treatment and / or prevention of cancer, cancer metastasis, fibrosis, inflammation, or diabetes. According to one aspect of the invention, a compound of formula Z or a pharmaceutically acceptable salt thereof, or a combination thereof, is provided for the treatment and / or prevention of cancer, cancer metastasis, fibrosis, inflammation, or diabetes.

[0023] According to one aspect of the invention, a compound of formula X or a pharmaceutically acceptable salt thereof, or a compound of formula Y or a pharmaceutically acceptable salt thereof, or a compound of formula Z or a pharmaceutically acceptable salt thereof, is provided for inhibiting galactogluconin-3, preferably for treating and / or preventing diseases, symptoms, states, or conditions in which inhibition of galactogluconin-3 is beneficial for its treatment and / or prevention. The invention also provides a compound of formula W for inhibiting galactogluconin-3, preferably for treating and / or preventing diseases, symptoms, states, or conditions in which inhibition of galactogluconin-3 is beneficial for its treatment and / or prevention.

[0024] According to a further aspect of the invention, a composition is provided comprising a compound of formula X and / or a pharmaceutically acceptable salt thereof, and / or a compound of formula Y and a pharmaceutically acceptable salt thereof, and / or a compound of formula Z and a pharmaceutically acceptable salt thereof, or a combination thereof, for inhibiting galactoglucoagulation-3, preferably for treating and / or preventing diseases, symptoms, states or conditions in which inhibition of galactoglucoagulation-3 is beneficial for its treatment and / or prevention.

[0025] According to a further aspect of the invention, a composition is provided comprising a compound of formula X or a pharmaceutically acceptable salt thereof, and / or a compound of formula Y or a pharmaceutically acceptable salt thereof, and / or a compound of formula Z or a pharmaceutically acceptable salt thereof, or a combination thereof, for treating and / or preventing diseases, symptoms, states, or conditions. Preferably, the disease, symptom, state, or condition is mediated by galactolectin-3. Preferably, the disease, symptom, state, or condition is cancer, cancer metastasis, fibrosis, inflammation, or diabetes. Preferably, the disease, symptom, state, or condition is cancer, cancer metastasis, fibrosis, inflammation, or diabetes and / or one or more other diseases, symptoms, states, or conditions affected and / or mediated by galactolectin-3.

[0026] According to one aspect of the invention, a compound of formula X or its metabolized and / or hydrolyzed and / or oxidized forms, or a pharmaceutically acceptable salt thereof, is provided for in vitro or in vivo inhibition of galactolectin-3. According to one aspect of the invention, a compound of formula Y or its metabolized and / or hydrolyzed and / or oxidized forms, or a pharmaceutically acceptable salt thereof, is provided for in vitro or in vivo inhibition of galactolectin-3. According to one aspect of the invention, a compound of formula Z or its metabolized and / or hydrolyzed and / or oxidized forms, or a pharmaceutically acceptable salt thereof, is provided for in vitro or in vivo inhibition of galactolectin-3. According to a further aspect of the invention, a composition comprising a compound of formula X and / or a pharmaceutically acceptable salt thereof, and / or a compound of formula Y or a pharmaceutically acceptable salt thereof, and / or a compound of formula Z or a pharmaceutically acceptable salt thereof, or a combination thereof, is provided for in vitro or in vivo inhibition of galactolectin-3.

[0027] According to any aspect of the invention, the use may include administering an effective amount of compound X and / or compound Y and / or compound Z and / or compound W, or a composition containing the same, or a metabolic form and / or hydrolyzed form and / or oxidized form thereof, or a pharmaceutically acceptable salt thereof, or a composition containing one or more of the above compounds.

[0028] According to a further aspect of the invention, compounds of formula X or pharmaceutically acceptable salts thereof, and / or compounds of formula Y and / or compounds of formula Z are provided for the treatment and / or prevention of cancer, cancer metastasis, diabetes, fibrosis, inflammation and / or one or more other diseases, conditions, states or illnesses affected and / or mediated by galactolectin-3.

[0029] According to a further aspect of the invention, a composition is provided comprising a compound of formula X or a pharmaceutically acceptable salt thereof, and / or a compound of formula Y or a pharmaceutically acceptable salt thereof, and / or a compound of formula Z or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention of cancer, cancer metastasis, fibrosis, inflammation, and / or diabetes and / or one or more other diseases, conditions, states, or illnesses affected and / or mediated by galactolectin-3. Preferably, the compound of formula X or a pharmaceutically acceptable salt thereof, and / or the compound of formula Y or a pharmaceutically acceptable salt thereof, and / or the compound of formula Z or a pharmaceutically acceptable salt thereof, may be mixed in the composition with a pharmaceutically acceptable diluent or carrier.

[0030] According to a further aspect of the invention, a method for treating and / or preventing a disease, symptom, state, or condition is provided, the method comprising administering to a subject a composition comprising a compound of formula X or a pharmaceutically acceptable salt thereof, and / or a compound of formula Y or a pharmaceutically acceptable salt thereof, and / or a compound of formula Z or a pharmaceutically acceptable salt thereof. Preferably, the disease, symptom, state, or condition is cancer, cancer metastasis, fibrosis, inflammation, and / or diabetes. Preferably, the disease, symptom, state, or condition is mediated by galactolectin-3.

[0031] According to a further aspect of the invention, a method for preventing, managing, improving, and / or treating a disease, symptom, condition, or illness is provided, preferably wherein the disease, symptom, condition, or illness is cancer, cancer metastasis, fibrosis, inflammation, and / or diabetes, the method comprising administering to a subject in need a therapeutically effective amount of a composition comprising a compound of formula X or a pharmaceutically acceptable salt thereof, and / or a compound of formula Y or a pharmaceutically acceptable salt thereof, and / or a compound of formula Z or a pharmaceutically acceptable salt thereof, and / or the method comprising administering one or more compositions comprising compounds of formula X and / or formula Y and / or formula Z or pharmaceutically acceptable salts thereof.

[0032] According to a further aspect of the invention, a method for treating and / or preventing a disease, symptom, state, or condition is provided, wherein inhibition of galectin-3 is beneficial to the treatment of said disease, symptom, state, or condition, or wherein said disease, symptom, state, or condition is influenced or mediated by galectin-3, the method comprising administering to a subject a composition comprising a compound of formula X or a pharmaceutically acceptable salt thereof, and / or a compound of formula Y or a pharmaceutically acceptable salt thereof, and / or a compound of formula Z or a pharmaceutically acceptable salt thereof. Preferably, the disease, symptom, state, or condition is mediated by galectin-3.

[0033] According to a further aspect of the invention, a method is provided for the prevention, management, improvement, and / or treatment of cancer, cancer metastasis, fibrosis, inflammation, and / or diabetes and / or one or more other diseases, symptoms, states, or conditions affected and / or mediated by galactolectin-3, the method comprising administering to a subject in need a therapeutically effective amount of a composition comprising a compound of formula X or a pharmaceutically acceptable salt thereof, and / or a compound of formula Y or a pharmaceutically acceptable salt thereof, and / or a compound of formula Z or a pharmaceutically acceptable salt thereof, and / or the method comprising administering more than one composition comprising a compound of formula X and / or formula Y and / or formula Z or a pharmaceutically acceptable salt thereof. Preferably, inhibition of galactolectin-3 is beneficial for the treatment and / or prevention of said diseases, symptoms, states, or conditions. The administration of said one or more compounds or compositions may be carried out in any order or scheme described in the invention.

[0034] In related aspects, the present invention may include a compound of formula X or a pharmaceutically acceptable salt thereof, and / or a compound of formula Y or a pharmaceutically acceptable salt thereof, and / or a compound of formula Z or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament. Preferably, the medicament is used to treat cancer, cancer metastasis, fibrosis, inflammation, diabetes and / or one or more other diseases, conditions, states or ailments affected and / or mediated by galactolectin-3, and / or for the manufacture of a medicament for inhibiting galactolectin-3.

[0035] The present invention also provides a compound of formula W for inhibiting galactolectin-3, preferably for treating and / or preventing diseases, symptoms, states, or conditions, wherein inhibition of galactolectin-3 is beneficial for the treatment and / or prevention of said diseases, symptoms, states, or conditions. According to a further aspect of the invention, a composition is provided comprising a compound of formula X and / or a pharmaceutically acceptable salt thereof for inhibiting galactolectin-3, preferably for treating and / or preventing diseases, symptoms, states, or conditions, wherein inhibition of galactolectin-3 is beneficial for the treatment and / or prevention of said diseases, symptoms, states, or conditions. According to a further aspect of the invention, a composition is provided comprising a compound of formula W or a pharmaceutically acceptable salt thereof, or a combination thereof, for treating and / or preventing diseases, symptoms, states, or conditions mediated by galactolectin-3. Preferably, said diseases, symptoms, states, or conditions are cancer, cancer metastasis, fibrosis, inflammation, or diabetes and / or one or more other diseases, symptoms, states, or conditions affected and / or mediated by galactolectin-3. According to one aspect of the invention, a compound of formula W or its metabolic and / or hydrolyzed and / or oxidized forms, or a pharmaceutically acceptable salt thereof, is provided for in vitro or in vivo inhibition of galactolectin-3. According to a further aspect of the invention, a compound of formula W or a pharmaceutically acceptable salt thereof is provided for the treatment and / or prevention of cancer, cancer metastasis, diabetes, fibrosis, inflammation, and / or one or more other diseases, conditions, states, or illnesses affected and / or mediated by galactolectin-3. According to a further aspect of the invention, a composition is provided comprising a compound of formula W or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of cancer, cancer metastasis, fibrosis, inflammation, and / or diabetes, and / or one or more other diseases, conditions, states, or illnesses affected and / or mediated by galactolectin-3. Preferably, the compound of formula W or a pharmaceutically acceptable salt thereof may be present in the composition mixed with a pharmaceutically acceptable diluent or carrier. According to a further aspect of the invention, a method for treating and / or preventing a disease, symptom, state, or condition is provided, wherein inhibition of galactolectin-3 is beneficial to the treatment of said disease, symptom, state, or condition, or wherein said disease, symptom, state, or condition is affected or mediated by galactolectin-3, the method comprising administering to a subject a composition comprising a compound of formula W or a pharmaceutically acceptable salt thereof. According to a further aspect of the invention, a method for preventing, managing, improving, and / or treating cancer, cancer metastasis, fibrosis, inflammation, and / or diabetes and / or one or more other diseases, symptoms, states, or conditions affected and / or mediated by galactolectin-3 is provided, the method comprising administering to a subject in need a therapeutically effective amount of a composition comprising a compound of formula W or a pharmaceutically acceptable salt thereof.In related aspects, the present invention may include a compound of formula W or a pharmaceutically acceptable salt thereof for manufacturing a medicament for treating cancer, cancer metastasis, fibrosis, inflammation, diabetes and / or one or more other diseases, symptoms, states or conditions affected and / or mediated by galactolectin-3, and / or for manufacturing a medicament for inhibiting galactolectin-3.

[0036] Based on the foregoing aspects, the compounds and compositions of the present invention can be used to manufacture medicaments for the prevention and / or treatment of the diseases, symptoms, states or conditions described in the present invention, preferably for the manufacture of medicaments for the treatment of cancer, cancer metastasis, fibrosis, inflammation, diabetes and / or one or more other diseases, symptoms, states or conditions affected and / or mediated by galactolectin-3, and / or for the manufacture of medicaments for the inhibition of galactolectin-3.

[0037] Preferably, in all aspects of the invention, the composition is a pharmaceutical composition comprising a compound of formula X and / or Y and / or Z and / or W, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The compound of formula X and / or Y and / or Z and / or W may be in a metabolic form and / or a hydrolyzed form and / or an oxidized form, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0038] Preferably, the disease, symptom, condition, or illness is mediated by galactolectin-3. Preferably, the disease, symptom, condition, or illness is cancer, cancer metastasis, fibrosis, inflammation, diabetes, and / or related or associated diseases, symptoms, conditions, or illnesses, and / or one or more other diseases, symptoms, conditions, or illnesses affected and / or mediated by galactolectin-3.

[0039] Preferably, cancer treatment and / or prevention includes inhibiting metastasis, inhibiting cancer recurrence after initial treatment or intervention, inhibiting cancer cell proliferation, inhibiting tumor growth, inhibiting angiogenesis, or inhibiting immunosuppression.

[0040] Preferably, the cancer is one or more of the following: breast cancer (including triple-negative breast cancer), pancreatic cancer, colorectal cancer, head and neck cancer, ovarian cancer, lung cancer, melanoma, thyroid cancer, bladder cancer, urinary system cancer, esophageal cancer, prostate cancer, digestive or gastrointestinal cancer, leukemia, lymphoma, liver cancer, or musculoskeletal cancer. Preferably, the cancer is breast cancer, pancreatic cancer, colorectal cancer, lung cancer, or melanoma. Preferably, the breast cancer is triple-negative breast cancer. Preferably, the cancer is colorectal cancer. Preferably, the cancer is pancreatic cancer. Preferably, the cancer is melanoma. Preferably, the cancer is lung cancer. Preferably, the cancer is triple-negative breast cancer.

[0041] Preferably, the treatment and / or prevention of cancer metastasis includes inhibiting the motility of cancer or tumor cells, inhibiting angiogenesis, inhibiting immunosuppression, inhibiting the spread and invasiveness of cancer cells to inhibit the growth of metastatic tumors, or inhibiting the spread and invasiveness of cancer cells to improve the clinical outcomes of subjects.

[0042] Preferably, the treatment and / or prevention of fibrosis includes the treatment / prevention of fibrotic conditions, fibrotic disease, fibrotic disorders, or uncontrolled wound healing reactive conditions or states.

[0043] Preferably, fibrosis includes fibrotic diseases or conditions caused by fibrosis. Preferably, it can be abnormal scar formation or wound healing, chronic or acute inflammation, chronic graft rejection, or fibrotic conditions or fibrosis affecting the heart, brain, lungs, liver, kidneys, vascular system, mediastinum, bones, retroperitoneal space, skin, digestive or gastrointestinal tract, connective tissue, eyes, or muscles.

[0044] Preferably, the treatment and / or prevention of inflammation includes treating / preventing inflammation-related diseases or conditions caused by inflammation.

[0045] Preferably, the inflammation includes suppression of inflammation-related diseases, conditions, states, or illnesses associated with inflammation. Preferably, the inflammation can be or originates from the following inflammation-related diseases or conditions, such as acute or chronic organ transplant rejection, graft-versus-host disease, inflammatory bowel disease, inflammatory skin diseases, multiple sclerosis, arteriosclerosis, pancreatitis, acute bronchitis, chronic bronchitis, Alzheimer's disease, inflammatory lung disease, acute bronchiolitis, folliculitis, chronic bronchiolitis, musculoskeletal pain or connective tissue inflammation, osteoarthritis, gout, spondyloarthritis, Reiter's syndrome, psoriatic arthritis, inflammation caused by one or more diseases associated with bacterial, fungal, and viral infections, atherosclerosis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome, nephritis, Parkinson's disease, chronic inflammation, and inflammation caused by or resulting from chronic inflammation. One or more neurodegenerative diseases or conditions caused by aging-related tumors, inflammatory symptoms caused by autoimmune diseases, including ulcerative colitis (UC) and Crohn's disease (CD), lupus erythematosus, hyperthyroidism, IgA nephropathy, type I or type II diabetes and its complications, dry eye syndrome, rheumatoid arthritis, simple obesity, ankylosing spondylitis, bronchial asthma, neurodermatitis, oral ulcers, psoriasis, vitiligo, Behcet's disease, autoimmune iridocyclitis, autoimmune eczema, autoimmune uveitis, autoimmune conjunctivitis, autoimmune dry eye, autoimmune glaucoma, autoimmune cataracts, allergic rhinitis, irritable bowel syndrome, and pruritus.

[0046] Preferably, diabetes includes type 1 or type 2 diabetes and / or any related diabetes-related diseases, conditions, states, or illnesses, such as obesity.

[0047] Preferably, one or more other diseases, conditions, states, or illnesses affected and / or mediated by galactolectin-3 include asthma, atherosclerosis, atopic dermatitis, cerebral infarction, chronic obstructive pulmonary disease (COPD), degenerative aortic stenosis, endometriosis, encephalitis, gastritis, HIV infection, interstitial lung disease, juvenile idiopathic arthritis, fatal cardiovascular disease, nonalcoholic steatohepatitis (NASH), obesity, pneumonia, pulmonary hypertension, plaque psoriasis, Q fever, rheumatoid arthritis, systemic sclerosis, urinary tract infection, COVID-19, sepsis, thrombosis, venous thrombosis, wound healing, cardiac syndrome X (CSX), yeast infection-candidiasis, or herpes zoster-related pain (hyperalgesia).

[0048] In all aspects of the invention, compounds of formula X and / or formula Y and / or formula Z and / or formula W may be analogs of them or derivatives thereof.

[0049] In all aspects of the invention, compounds of formula X and / or formula Y and / or formula Z and / or formula W may be their metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0050] Preferably, the disease, symptom, state, or condition described in any aspect of the present invention, such as cancer, may be associated with, or is suspected to be associated with, the expression of galactoglobulin-3.

[0051] Preferably, the method of the present invention may further include first determining the level of galectin-3 or the expression level of LGALS3 in a biological sample obtained from a subject. This determination may be performed before, during, and / or after treatment with the galectin-3 inhibitor described in this invention. This may include determining the level or expression in a biological sample, such as a fluid sample (e.g., blood, tears, or urine) or a tissue sample (e.g., a tissue biopsy sample, a tumor sample, or a suspected tumor sample). The galectin-3 inhibitor may be one or more of compounds of formula X and / or Y and / or Z and / or W, or a composition comprising one or more of these, or a pharmaceutically acceptable salt thereof.

[0052] Preferably, the subject is suspected of having a disease, condition, state, or symptom associated with galectin-3 expression. Preferably, the subject is known to have a disease, condition, state, or symptom associated with galectin-3 expression.

[0053] Preferably, the biological sample or sample may be tumor tissue, suspected tumor tissue, tissue biopsy sample, mucus, feces, tears, urine, blood, serum, cell extract, biopsy specimen and / or liquid that has been introduced into an individual and subsequently removed.

[0054] Preferably, any method of the present invention may include determining the level of galectin-3 or the expression of LGALS3 in a subject, for example, in a biological sample obtained from the subject. Preferably, this determination is performed before administering a galectin-3 inhibitor to the subject, said galectin-3 inhibitor being, for example, a compound of formula X, and / or a compound of formula Y and / or a compound of formula Z and / or a compound of formula W, or a combination thereof. This determination may be performed before any administration, and the method may subsequently include administering to the subject a composition comprising compound X or a pharmaceutically acceptable salt thereof, and / or a composition comprising compound Y or a pharmaceutically acceptable salt thereof, and / or a composition comprising compound Z or a pharmaceutically acceptable salt thereof, and / or a composition comprising compound W or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable excipient, or any other similar compound, composition, or administration described in the present invention. The administration may be performed when any galectin-3 or any LGALS3 expression is found or detected in a biological sample obtained from the subject. The administration may also be performed when the level of galactolectin-3 or LGALS3 expression, or the LGALS3 expression level, in a biological sample obtained from the subject is found to be higher than baseline or higher than a reference value, or overexpression occurs. The terms "above baseline" or "overexpression" in this invention can be compared to a reference value, such as a literature reference value or a reference sample. The reference value or baseline can be zero. The method may further include the following steps: administering to the subject a composition comprising compound X or a pharmaceutically acceptable salt thereof, and / or a composition comprising compound Y or a pharmaceutically acceptable salt thereof, and / or a composition comprising compound Z or a pharmaceutically acceptable salt thereof, and / or a composition comprising compound W or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable excipient, wherein the administration is performed when the level of galactolectin-3 or LGALS3 expression, or the LGALS3 expression level, in a biological sample obtained from the subject is found to be higher than baseline or overexpression occurs, for example, higher than a reference value, such as a literature reference value or a reference sample. The reference value or baseline can be zero.

[0055] Therefore, any treatment method of the present invention may first include diagnosing the subject with a disease, condition, state, or ailment that is associated with or suspected to be associated with galactoglucan-3 or LGALS3 expression or LGALS3 expression levels higher than expected. This is performed prior to administration.

[0056] According to a further aspect of the invention, a method for inhibiting galactoglucan-3 in a patient or in a biological sample is provided, the method comprising the steps of: administering to the patient or exposing the biological sample to a compound of formula X or a pharmaceutically acceptable salt thereof, and / or a compound of formula Y or a pharmaceutically acceptable salt thereof, and / or a compound of formula Z or a pharmaceutically acceptable salt thereof, and / or a compound of formula W or a pharmaceutically acceptable salt thereof, or a composition comprising one or more of the above compounds. Preferably, the method is an in vitro method.

[0057] Preferably, for all aspects, the compounds and / or compositions can be administered alone or in combination with other treatments, either simultaneously or sequentially. These other treatments may include chemotherapy, radiotherapy, immunotherapy, and / or surgery.

[0058] Preferably, for all aspects, the compositions according to the invention may further comprise other active agents, such as one or more additional antitumor agents and / or antimetastatic agents and / or chemotherapeutic agents and / or radiotherapy agents and / or immunotherapy agents and / or antifibrotic agents and / or anti-inflammatory agents and / or one or more other galactoglobulin inhibitors.

[0059] Preferably, the compound and / or composition may be administered in combination with at least one additional antitumor agent, antimetastatic agent, chemotherapeutic agent, immunotherapeutic agent, surgical and / or radiotherapy agent, antifibrotic agent, anti-inflammatory agent and / or one or more other galactolectin inhibitors. The compound and / or composition may also be administered in combination with surgical methods for the treatment of cancer, fibrosis, or other diseases, such as tumor debulking surgery or cryosurgery.

[0060] According to a further aspect of the invention, a kit is provided comprising an effective amount of one or more of the following substances, individually packaged, dispensed, or individually measured: a compound of formula X, a compound of formula Y, a compound of formula Z, a composition comprising a compound of formula X, a composition comprising a compound of formula Y, a composition comprising a compound of formula Z, a compound of formula W, and / or a composition comprising one or more of compounds of formula X and / or formula Y and / or formula Z and / or formula W, and / or a pharmaceutically acceptable salt or pharmaceutical formulation thereof, and optionally comprising one or more pharmaceutically or cosmetically acceptable ingredients or excipients, or individually packaged, dispensed, or individually measured amounts of said pharmaceutically or cosmetically acceptable ingredients or excipients, and / or optionally comprising an effective amount of another active ingredient, such as those described in this invention. The kit may also optionally comprise a suitable container, such as a box, individual bottles, bags, or ampoules. The kit may, for example, comprise individual ampoules, each containing an effective amount of said compound or composition and / or a pharmaceutically acceptable salt thereof, and optionally containing an effective amount of another active ingredient, which may be in a dissolved or lyophilized form or one or more. The kit may also include instructions or means for administering one or more compounds or compositions in the kit. The kit may also include instructions for using the components for the treatment and / or prevention of the disease, condition, state, or illness, wherein inhibition of galactoglucan-3 is beneficial for the treatment and / or prevention of the disease, condition, state, or illness.

[0061] Compositions according to all aspects of the invention may further comprise one or more pharmaceutically or cosmetically acceptable ingredients or excipients. Pharmaceutically acceptable ingredients are known to those skilled in the art and include, but are not limited to, pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), flavor maskers, colorants, fragrances, and penetrants.

[0062] Preferably, for all aspects, the composition can be provided in the form of a suspension containing pharmaceutically or cosmetically acceptable excipients, diluents, or carriers.

[0063] The compounds and / or their pharmaceutically acceptable salts, or combinations thereof, of the present invention can be administered orally, parenterally, by inhalation spray, externally, rectally, nasally, buccally, vaginally, or via an implantable reservoir. Preferably, administration is by oral, intraperitoneal, or intravenous administration. Preferably, the pharmaceutically acceptable compositions of the present invention are prepared for oral administration. Exemplary oral dosage forms include capsules, tablets, aqueous suspensions, or solutions. Such compositions are prepared according to methods known in the art of pharmaceutical formulation.

[0064] The compositions of the present invention can be prepared as pharmaceuticals, i.e., as medicines or medical devices. The pharmaceuticals may include other pharmaceutically acceptable ingredients known to those skilled in the art, including but not limited to pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), flavor masking agents, coloring agents, flavoring agents, and sweeteners. The formulations may further contain other active agents, such as other therapeutic or preventative agents.

[0065] The compounds and compositions according to the method of the present invention can be administered at any effective dose and via any route of administration for treating or alleviating the severity of the aforementioned diseases. The exact dose required varies from subject to subject, depending on factors such as the subject's species, age, and overall condition, the severity of the disease, symptom, condition, or state, the specific agent used, and its administration method. This may include administering an effective or therapeutically effective amount of any compound or composition described in the present invention.

[0066] Preferably, for all aspects, the compounds and / or compositions can be administered alone or in combination with other treatments, either simultaneously or sequentially. These other treatments may be chemotherapy, radiotherapy, immunotherapy, and / or surgery. The compositions according to the invention may further comprise other active agents, such as one or more additional antitumor agents, antimetastatic agents, chemotherapeutic agents, and / or radiotherapy agents and / or immunotherapy agents, and / or antifibrotic agents, anti-inflammatory agents, and / or one or more other galactoglobulin inhibitors. The compounds and / or compositions may be administered in combination with at least one additional antitumor agent, antimetastatic agent, chemotherapeutic agent, immunotherapy agent, surgery, antifibrotic agent, anti-inflammatory agent, one or more other galactoglobulin inhibitors, and / or radiotherapy agent. The compounds and / or compositions may also be administered in combination with surgical methods for treating cancer, fibrosis, or other diseases, such as tumor debulking surgery or cryosurgery.

[0067] According to a further aspect of the invention, a combination therapy is provided for treating cancer, fibrosis, inflammation, diabetes, cancer metastasis, and / or one or more other diseases, conditions, states, or illnesses affected and / or mediated by galactolectin-3, said combination therapy comprising a compound or composition of the invention, or a pharmaceutically acceptable salt thereof, and another antitumor agent and / or antimetastatic agent and / or chemotherapeutic agent and / or radiotherapy agent and / or immunotherapy agent and / or antifibrotic agent and / or antiinflammatory agent and / or one or more other galactolectin inhibitors.

[0068] According to a further aspect of the invention, compounds or compositions of the invention, or pharmaceutically acceptable salts thereof, are provided for the treatment of cancer, fibrosis, inflammation, diabetes, cancer metastasis, and / or one or more other diseases, conditions, states, or illnesses affected and / or mediated by galactolectin-3, wherein said compounds or compositions are administered in combination with antitumor agents and / or antimetastatic agents and / or chemotherapeutic agents and / or radiotherapy agents and / or immunotherapy agents and / or antifibrotic agents and / or antiinflammatory agents and / or one or more other galactolectin inhibitors.

[0069] According to a further aspect of the invention, a pharmaceutical composition is provided comprising compound X and / or compound Y and / or compound Z, or a pharmaceutically acceptable salt thereof, and / or compound W, or a pharmaceutically acceptable salt thereof, in combination with an antitumor agent and / or an antimetastatic agent and / or a chemotherapeutic agent and / or a radiotherapy agent and / or an immunotherapy agent and / or an antifibrotic agent and / or an anti-inflammatory agent and / or one or more other galactolectin inhibitors. Preferably, the pharmaceutical composition is used to inhibit galactolectin-3. Preferably, the composition is used to treat and / or prevent a disease, condition, state, or ailment, wherein inhibition of galactolectin-3 is beneficial to the treatment and / or prevention of the disease, condition, state, or ailment, or the disease, condition, state, or ailment is mediated by galactolectin-3. Preferably, the disease, condition, state, or ailment is cancer, cancer metastasis, fibrosis, inflammation, diabetes, and / or one or more other diseases, conditions, states, or ailments affected and / or mediated by galactolectin-3.

[0070] According to a further aspect of the invention, a method is provided for treating a human or animal subject suffering from cancer, fibrosis, inflammation, diabetes, cancer metastasis, and / or one or more other diseases, conditions, states, or ailments affected and / or mediated by galactolectin-3, the method comprising administering to the subject a therapeutically effective amount of a compound or composition of the invention, or a pharmaceutically acceptable salt thereof, concurrently, sequentially, or separately with surgery and / or at least one additional antitumor and / or antimetastatic and / or chemotherapeutic and / or radiotherapy and / or immunotherapy and / or antifibrotic and / or antiinflammatory and / or one or more other galactolectin inhibitors.

[0071] According to a further aspect of the invention, compounds or compositions as defined herein, or pharmaceutically acceptable salts thereof, are provided for use simultaneously, sequentially, or in combination with surgery and / or at least one additional antitumor and / or antimetastatic and / or chemotherapeutic and / or radiotherapy and / or immunotherapy and / or antifibrotic and / or anti-inflammatory and / or one or more other galactoglobulin inhibitors for the treatment of cancer, fibrosis, inflammation, diabetes, and / or cancer metastasis.

[0072] It should be understood that preferred features of one aspect of the present invention, after necessary modifications, are equally applicable to all aspects of the present invention.

[0073] While the present invention may involve any compound or particular group of compounds used in the methods defined herein, such use may be defined by optional features, preferred features or suitable features or by particular embodiments, the present invention may also involve any compound or particular group of compounds that explicitly excludes the optional features, preferred features or suitable features or particular embodiments. Attached Figure Description

[0074] Embodiments of the present invention will now be described by way of example with reference to the accompanying drawings, wherein:

[0075] Figure 1A , Figure 1B and Figure 1C Compounds X, Y, and Z are shown to inhibit the binding of galactolectin-3 to its ligand desialylated fetoglobulin (ASF). ELISA was used to assess the effects of different concentrations of compound X in the absence or presence of these compounds. Figure 1A ), compound formula Y ( Figure 1B ) or compound formula Z ( Figure 1C Under certain conditions, galactolectin-3 (5 μg / ml) binds to desialized fetoglobulin (ASF, 20 μg / ml). Compounds X, Y, and Z all inhibit the binding of galactolectin-3 to ASF in a dose-dependent manner.

[0076] Figure 2A , Figure 2B , Figure 2C and Figure 2D The binding affinity analysis of compounds X, Y, and Z with galactolectin-3 is shown. The binding affinity analysis of compound X with the full-length (…) is also shown. Figure 2A ) and C-terminal (aa 115-250) galactolectin-3 ( Figure 2B The combination of ) and the compound formula Y ( Figure 2C ) and compound formula Z ( Figure 2D The binding of compound X to galactolectin-3 was evaluated using tryptophan fluorescence spectroscopy (TFS). The binding affinity (KD) of compound X to full-length and C-terminal galactolectin-3 was 5–7 μM. The binding affinity (KD) of compound Y to full-length galactolectin-3 was approximately 90 μM. The binding affinity (KD) of compound Z to full-length galactolectin-3 was approximately 35 μM.

[0077] Figure 3A and Figure 3B Compound X was shown to inhibit the adhesion of cancer cells to vascular endothelial cells. Human melanoma ACA19 cells were evaluated in the absence or presence of galactolectin-3 (2 μg / ml) and different concentrations of compound X. Figure 3A ) and colon cancer SW620 cells ( Figure 3B Compound X inhibited the adhesion of SW620 and ACA19 cells to human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner. *** P<0.001, **P<0.01, *P<0.05 (ANOVA).

[0078] Figure 4A and Figure 4B Compounds Y and Z were shown to inhibit the adhesion of cancer cells to vascular endothelial cells. In the absence or presence of galactolectin-3 (2 μg / ml) and at different concentrations of compound Y (…),… Figure 4A ) or compound formula Z ( Figure 4B In this study, the adhesion of human colon cancer SW620 cells to HUVECs was evaluated. Both compounds inhibited galactolectin-3-induced adhesion of SW620 cells to HUVECs in a dose-dependent manner.

[0079] Figure 5A and Figure 5B This demonstrates that compound X inhibits the invasion of cancer cells through vascular endothelial cells. Human melanoma ACA19 cells were evaluated in a Transwell chamber with or without compound X (20 μM) or the galactolectin-3 disaccharide inhibitor lactose (Lac, 100 μM). Figure 5A ) and colon cancer SW620 cells ( Figure 5B Compound X significantly inhibited galactolectin-3-mediated invasion of ACA19 and SW620 cells through HUVECs. ***P<0.001, *P<0.05 (ANOVA).

[0080] Figure 6A and Figure 6B Compounds Y and Z were shown to inhibit cancer cell invasion through vascular endothelial cells. In a Transwell chamber, the invasion of human colon cancer SW620 cells through HUVECs was evaluated in the absence or presence of galactolectin-3 (1 μg / ml), the galactolectin-3 disaccharide inhibitor lactose (100 μM), and compounds Y and Z. Compound Y ( Figure 6A ) and compound formula Z ( Figure 6B Both are similar to lactose and inhibit the invasion of SW620 cells through HUVECs in a dose-dependent manner.

[0081] Figure 7A and Figure 7B This study demonstrates that compound X inhibits the formation of tubular structures (angiogenesis) in human vascular cells. Tubular structure formation in HUVECs was assessed in the absence or presence of galactolectin-3 (2 μg / ml) and compound X (10 μM). Tubular length was measured. Figure 7A ) and number of pipes ( Figure 7B When compound X was present, it significantly inhibited galactolectin-3-mediated angiogenesis. *** P < 0.001 (ANOVA).

[0082] Figure 8A , Figure 8B , Figure 8C and Figure 8D Compounds Y and Z were shown to inhibit the formation of tubular structures in vascular cells (angiogenesis). In the absence or presence of galactolectin-3 (2 μg / ml) and at different concentrations of compound Y (…),… Figure 8A and Figure 8C ) or compound formula Z ( Figure 8B and Figure 8D Under these conditions, assess the formation of vascular tubular structures in HUVECs. Measure the length of the vascular tubules ( Figure 8A and Figure 8B ) and number of pipes ( Figure 8C and Figure 8D When either compound Y or compound Z was present, the presence of either compound Y or Z inhibited angiogenesis in a dose-dependent manner. *P<0.05, ***P<0.001 (ANOVA).

[0083] Figure 9A , Figure 9B , Figure 9C and Figure 9D Compounds X, Y, and Z were shown to have low or no significant toxicity. The effects of compound X on human colon cancer SW620 cells were evaluated using a lactate dehydrogenase (LDH) release assay, in the absence or presence of different concentrations of compound X. Figure 9A ) and HUVECs ( Figure 9B The cytotoxicity of compound X to HUVECs and SW620 cells was assessed. Compound X showed no cytotoxicity against HUVECs and SW620 cells at 100 μM. The effects of LDH release assays on SW620 cells were evaluated in the absence or presence of different concentrations of compounds Y and Z. Figure 9C ) and HUVECs ( Figure 9D The cytotoxicity of compounds Y and Z was low in both HUVECs and SW620 cells.

[0084] Figure 10A , Figure 10B and Figure 10C The results show that compound X does not affect the binding of galactolectins-2, -4, and -8 to desialylated fetoglobulin. Galactolectin-2 (Gal-2) was evaluated using an ELISA method in the absence or presence of different concentrations of compound X or the positive control galactolectin inhibitor lactose. Figure 10A -4 (Gal-4, Figure 10B ) and -8 (Gal-8, Figure 10C (5 μg / ml) binds to desialized fetoglobulin (ASF, 20 μg / ml). Compound X does not affect the binding of the above-mentioned galactagglutinin family members to ASF. Disaccharide lactose inhibits the binding of galactagglutinin-8 to ASF in a dose-dependent manner (positive control).

[0085] Figure 11A , Figure 11B and Figure 11C Compounds X, Y, and Z were shown to inhibit galactolectin-3-induced secretion of the pro-inflammatory cytokine TNFα by macrophages. ELISA was used to investigate the effects of galactolectin-3 in the absence or presence of 10 μg / ml and different concentrations of compound X. Figure 11A ), formula Y ( Figure 11B ) or formula Z ( Figure 11C In the case of ), the secretion of TNFα by THP-1 differentiated macrophages was analyzed. Galactolectin-3 significantly increased TNFα secretion, while the presence of compounds X, Y, and Z inhibited galactolectin-3-induced TNFα secretion in a dose-dependent manner.

[0086] Figure 12A , Figure 12B and Figure 12C Compounds X, Y, and Z were shown to inhibit galactolectin-3-induced secretion of the pro-inflammatory cytokine IL-1β by macrophages. ELISA was used to investigate the effects of galactolectin-3 in the absence or presence of 10 μg / ml and different concentrations of compound X. Figure 12A ), formula Y ( Figure 12B ) or formula Z ( Figure 12C In the case of ), the secretion of IL-1β by THP-1 differentiated macrophages was analyzed. Galactolectin-3 significantly increased IL-1β secretion, while the presence of compounds X, Y and Z inhibited galactolectin-3-induced IL-1β secretion in a dose-dependent manner.

[0087] Figure 13 shows the compound formula X ( Figure 13A ), compound formula Y ( Figure 13B ) and compound formula Z ( Figure 13CAll three compounds inhibited the adhesion of human lung cancer cells to the basement membrane matrix in a dose-dependent manner. **P<0.01, ***P<0.001.

[0088] Figure 14 shows the effects of CRISPR / Cas9 on human triple-negative breast cancer MDA-MB-231 cells ( Figure 14A ) and pancreatic cancer PANC1 cells ( Figure 14B Galactolectin-3 gene knockout was performed. Galactolectin-3 expression in control and knockout cells was detected by Western blotting. The same blot membrane was analyzed using an anti-actin antibody to verify protein loading.

[0089] Figure 15 illustrates how compounds Y and Z inhibit galactolectin-3-mediated adhesion of human triple-negative breast cancer cells to the basement membrane matrix. Compound Y ( Figure 15A ) and compound formula Z ( Figure 15B Both compounds inhibited matrix adhesion in a dose-dependent manner in triple-negative breast cancer MDA-MB-231 cells. Compared with control MDA-MB-231 cells (Con), which showed significant inhibition of adhesion, the compound Y (…) showed significantly reduced adhesion when galactolectin-3 expression (Gal3KO) was knocked out in cells using CRISPR / Cas9. Figure 15C ) and compound formula Z ( Figure 15D All of them lost their inhibitory effect on cell adhesion. ***P<0.05, P<0.01, ***P<0.001.

[0090] Figure 16 illustrates how compounds X, Y, and Z inhibit galactolectin-3-mediated adhesion of human pancreatic cancer cells to the basement membrane matrix. Compound X ( Figure 16A ), compound formula Y ( Figure 16B ) and compound formula Z ( Figure 16C Both compounds inhibited the adhesion of human pancreatic cancer PANC1 cells to the matrix in a dose-dependent manner. Compared with the significant inhibition of PANC1 cell adhesion, when galactolectin-3 expression (Gal3KO) was knocked out in cells by CRISPR / Cas9, compound X (… Figure 16D ), compound formula Y ( Figure 16E ) and compound formula Z ( Figure 16F All of them lost their inhibitory effect on cell adhesion. *P<0.05, **P<0.01, ***P<0.001. Detailed Implementation

[0091] The embodiments will now be described in detail with reference to the accompanying drawings. In the following detailed description, numerous specific details are illustrated by way of example to provide a full understanding of the relevant technical content. However, those skilled in the art will understand that the invention can be practiced without these specific details.

[0092] Throughout this invention, the terms "comprising" and "including," as well as their variations, mean "including but not limited to," and are not intended (and should not be construed as) excluding other parts, additives, components, elements, or steps. In this invention and throughout the claims, unless the context clearly specifies otherwise, the singular form also includes the plural form. In particular, when using the indefinite article, unless the context clearly specifies otherwise, this invention should be understood to cover both singular and plural cases simultaneously.

[0093] Features, elements, properties, compounds, chemical groups, or structures described together with a particular aspect, embodiment, or example of the invention should be understood to be equally applicable to any other aspect, embodiment, or example described herein, unless incompatible with that aspect. All features disclosed in this invention (including any appended claims, abstracts, and drawings) and / or all steps of any disclosed method or process can be combined in any way, unless at least some features and / or steps are mutually exclusive. This invention is not limited to the specific details of the above embodiments. This invention covers any novel feature disclosed herein, or any novel combination thereof (including any appended claims, abstracts, and drawings), and any novel feature or any novel combination thereof of any disclosed method or process step.

[0094] Readers should note that all documents and literature related to this application and submitted simultaneously with or prior to this invention are publicly available for review along with this invention, and their entire contents are incorporated herein by reference.

[0095] The compounds described in this invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service) nomenclature systems. It should be understood that, unless otherwise expressly stated, "compound formula X, Y, and / or Z" and the more general term "compound" refers to and includes any and all compounds described and / or referenced by formula X, Y, or Z. The foregoing understanding also applies to any other compounds mentioned in this invention. It should also be understood that these terms include all stereoisomers of such compounds, i.e., cis and trans isomers, and optical isomers, i.e., R-type and S-type enantiomers, and all their salts, present in substantially pure form and / or in mixtures in any proportion. This understanding also applies to pharmaceutical compositions and treatment methods comprising or employing one or more compound formulas X and / or Y and / or Z, whether used alone or in combination with other pharmaceutical agents.

[0096] In this invention, "treatment" refers to achieving a desired pharmacological and / or physiological effect, which can be preventative, i.e., complete or partial prevention of the occurrence of a disease, state, symptom, or condition or its symptoms, or therapeutic, i.e., partial or complete cure of a disease, state, symptom, or condition and / or its adverse effects. In this invention, "treatment" encompasses any prevention or treatment of a disease, state, symptom, or condition in mammals (especially humans), and includes: (a) preventing or delaying the onset of a disease or clinical symptom in subjects susceptible but not yet diagnosed with said disease, state, symptom, or condition; (b) preventing or delaying the onset of a disease or its clinical symptom in subjects already suffering from said disease, state, symptom, or condition, i.e., inhibiting, reducing, or delaying the development or recurrence of the disease (e.g., under maintenance treatment); and (c) alleviating or reducing a disease, state, symptom, or condition, even if it reverses. In this invention, "disease" can also refer to a state, symptom, or condition.

[0097] In this invention, "therapeutic treatment" refers to treatment administered when the subject is known to have the stated disease, condition, symptom, or illness before administration, i.e., the presence of pre-existing symptoms. "Prophylactic treatment" refers to treatment administered when the subject has not yet been diagnosed with the stated disease, condition, symptom, or illness before administration. In some embodiments, the subject has a high risk of developing the disease or is suspected of being affected before treatment. In some embodiments, the subject is suspected of having a high probability of developing the disease. The subject may be suspected of having a disease, condition, symptom, or illness associated with galactoglucan-3 expression.

[0098] In this invention, "subject" includes any human or non-human animal. "Patient," "subject," and "subject requiring treatment" are used interchangeably throughout the text. "Non-human animal" includes all mammals, such as non-human primates, sheep, rabbits, dogs, cats, cattle, horses, camels, apes, monkeys, and pigs.

[0099] "Therapeutic effective amount" refers to an amount of active ingredient (e.g., compound X and / or compound Y and / or compound Z, or other compounds described in this invention (i.e., compound W)), compound, or composition, which, when administered to a subject for the treatment of a disease, condition, symptom, or illness, is sufficient to produce, achieve, or initiate a therapeutic effect on that disease, condition, symptom, or illness. The "therapeutic effective amount" will vary depending on the active ingredient used, the type and severity of the disease, the subject's age, weight, and other factors. It should be understood that, for example in humans or other mammals, the therapeutic effective amount can be determined experimentally in a laboratory or clinical setting, or the dosage appropriate for a specific disease and subject can be determined according to the guidelines of the U.S. Food and Drug Administration (FDA) or other equivalent regulatory agencies. Those skilled in the art can determine the appropriate dosage form, dosage, and route of administration. The "effective amount" as used in this invention can be an amount sufficient to inhibit galactoglucan-3 in vitro or in vivo. An "effective amount" can be an amount sufficient to inhibit galactoglucan-3 to treat and / or prevent a subject's disease, condition, symptom, or illness. "Effective amount" can refer to "therapeutic effective amount."

[0100] compound

[0101] This invention relates to the use of four specific compounds that have been identified as having the beneficial properties and uses described in this invention. These compounds are:

[0102]

[0103] The compound formula is X-tosufloxacin toluenesulfonate (TT);

[0104]

[0105] The compound formula is Y-nefinavir methanesulfonate;

[0106]

[0107] The compound formula is Z-toremifene citrate;

[0108]

[0109] The compound formula is W-Gimidalis.

[0110] In this invention, compound X can be referred to as "TT". Compound Y can be referred to as "NM". Compound Z can be referred to as "TC".

[0111] In this invention, "compound of the present invention", "composition of the present invention", "composition", "compound described in the present invention" and "compound" refer to the compounds and / or compositions disclosed in this invention, whether in a general or specific description, and in particular include compounds of formula W, X, Y and / or Z.

[0112] Any use of a compound or composition described in this invention may refer to one or more of the following:

[0113] (i) Use in any of the purposes described in this invention;

[0114] (ii) Use in the preparation of medicaments for the treatment and / or prevention of diseases, symptoms, states or conditions;

[0115] (iii) A method of treating a subject’s disease, symptom, condition or illness, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or a combination thereof;

[0116] (iv) A method for inhibiting a target of the present invention (e.g., galactolectin-3), the method comprising administering to a subject a therapeutically effective amount of one or more of the compounds, or a pharmaceutically acceptable salt thereof, or a metabolic and / or hydrolyzed and / or oxidized form thereof, or a composition comprising one or more of the compounds thereof, or administering such compound to a biological sample or target in vitro on the subject.

[0117] (v) Use in the methods for treating a subject’s disease, ailment, condition or illness as described in this invention.

[0118] Uses, medical applications and treatments

[0119] Cancer and cancer metastasis

[0120] Compound X (tosufloxacin tosylate), or its metabolized and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, and / or compound Y (nelfinavir mesylate), or its metabolized and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, and / or compound Z (toremifene citrate), or its metabolized and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, or other compounds described in this invention (i.e., compound W, gemifloxacin), or compositions comprising one or more compounds of formula X, compound Y, compound Z, or other compounds described in this invention (i.e., compound W), or their metabolized and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, may be used for the treatment and / or prevention of cancer. The methods, compositions, and compounds may be used to prevent or inhibit cancer, cancer metastasis, cancer cell proliferation, cancer recurrence after initial treatment or intervention, tumor growth, tumor / cancer angiogenesis, or immunosuppression.

[0121] Cancer is a group of diseases that can cause a variety of different symptoms and may present with a variety of different signs, depending on the location, size, and type of the cancer. In this invention, "cancer" may refer to precancerous tumors or precancerous cells or precancerous states, tumors, cancerous tumors, solid tumors, pre-metastatic cancer, tumors that have begun to cause metastatic growth, or other related meanings known in the art. Therefore, “treatment of cancer” includes treatment of any type of tumor, including reducing tumor cell / cancer cell angiogenesis, reducing tumor size (also known as “tumor regression”), reducing tumor volume, suppressing immunosuppression, improving clinical outcomes in subjects treated as described in this invention, reducing the number of tumors, reducing the number of metastatic lesions in distant tissues or organs of the primary tumor, improving the mean survival time of the treated group compared to the untreated group, improving the mean survival time compared to the untreated group, reducing mortality compared to the untreated group, reducing tumor growth, reducing tumor regrowth, reducing cell proliferation rate, reducing the proportion of proliferating cells, reducing the size of cell proliferation regions or the proportion of cells with abnormal morphology, inhibiting the motility of cancer cells or tumor cells, controlling and / or treating solid tumors, preventing or inhibiting tumor metastasis, reversing tumor metastasis, increasing tumor / cancer cell death, and all definitions below regarding cancer metastasis treatment or any other cancer treatment or evaluation method known in the art.

[0122] As described in this invention, galactolectin-3 activity is associated with tumor metastasis. Therefore, the compounds and compositions described in this invention can also be used for the prevention and / or treatment of tumor metastasis.

[0123] In this invention, "cancer metastasis" refers to the spread of cancer from one site in a subject's body to another secondary or different site within the same subject's body. Therefore, "treatment of cancer metastasis" includes inhibiting the motility of cancer cells or tumor cells, inhibiting the dissemination and invasiveness of cancer cells to suppress metastatic tumor growth, inhibiting the dissemination and invasiveness of cancer cells to improve the clinical outcomes of the subjects treated as described in this invention, all the above definitions of cancer treatment, and any other known methods of cancer metastasis treatment or evaluation in the art.

[0124] For example, the incidence of metastasis can be assessed by detecting the relative extent of dissemination (e.g., the number of organ systems involved) and the relative tumor burden at those sites. Metastatic growth can be determined by microscopic or macroscopic analysis. Tumor metastasis can be reduced by approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or higher.

[0125] In this invention, "treatment of cancer metastasis" can be achieved by inhibiting the activity of circulating galactolectin-3 in the bloodstream, or by inhibiting the activity of galactolectin-3 in one or more tumor sites. This can also be achieved prophylactically by using galactolectin-3 inhibitors, such as compounds X, Y, Z, or other compounds described in this invention (i.e., compound W), or combinations thereof, before potential metastasis occurs. Prevention of cancer metastasis may include prophylactic treatment when the risk of cancer metastasis is elevated, such as in situations that may interfere with the tumor, such as surgery, the use of cytotoxic drugs, or radiation therapy. Treatments as described in this invention can reduce the risk of cancer metastasis by inhibiting galactolectin-3 in the primary tumor or circulating cells.

[0126] In this invention, "outcome," "clinical outcome," or "improved outcome" refers to the course of the disease and / or the result of disease progression, which can be characterized by recurrence, recurrence time, metastasis, metastasis time, number of metastases, number of metastatic sites, and / or disease-related death. For example, positive clinical outcomes include cure, prevention or delay of cancer recurrence, prevention or delay of metastasis, and / or survival within a fixed time (no recurrence); negative clinical outcomes include accelerated disease progression, cancer metastasis, and / or death within a fixed time.

[0127] Cancers suitable for treatment with the compounds and compositions described in this invention include epithelial tumors and hematologic malignancies. Cancers include breast cancer [Iurisci et al, Clin Cancer Res, 2000, 6, 1389-93], especially triple-negative breast cancer [Zhang et al, PLOS one, 2014, 9, e103482], colorectal / rectal cancer [Watanabe et al., Oncology Reports, 2011, 25, 1217-1226; Barrow et al, ClinCancer Res, 2011 Sep 20], head and neck cancer [Saussez et ah, Oral Oncology, 2008, 44, 86-93], pancreatic cancer [Senapati et al., Clin Cancer Res, 2011, 17, 267-274], and lung cancer [Iurisci et al, Clin Cancer Res, 20 ... 6,1389-93], melanoma [Vereecken et al., Melanoma Research, 2009, 19, 316-320; Vereecken et ah, Clinical and Experimental Dermatology, 2005, 31, 105-109], thyroid cancer [Saussez et al., Thyroid, 2008, 18(7), 705-712 and Isic et ah, J Cancer Res Clin Oncol, 2010,136, 1805-1812], bladder cancer [Sakaki et al, J Med Invest, 2008, 55, 127-132], gastric cancer (Kang, et al, Mol Cancer Res. 2020, 18:403-413), ovarian cancer (Mohammed, et al, World J Surg Oncol, 2022, 20, 276), leukemia [Mansorunov et al, Int J Mol Sci.2022,23,13846], lymphoma (Shi et al, Front Oncol, 2022 May 23;12:889034), musculoskeletal tumors (Nakajima, et al, Cancer Metastasis Rev.).2021, 40:297-302), liver cancer (Setayesh et al, Liver Res. 2020;4:173-179). All of the above references are incorporated herein by reference.

[0128] Triple-negative breast cancer (also known as basal-like breast cancer) is a type of breast cancer in which cells lack or express low levels of estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER2).

[0129] Galactolectin-3 activity is associated with tumor angiogenesis [Califice et al., Oncogene 2004;23, 7527-7536, herein incorporated by reference]. Therefore, the compounds and compositions described in this invention may also serve as potentially useful agents for the prevention and / or treatment of tumor angiogenesis.

[0130] In this invention, "tumor angiogenesis" or simply "angiogenesis" refers to the proliferation of a vascular network that provides a supportive microenvironment rich in oxygen and nutrients for the tumor, thereby maintaining its optimal growth.

[0131] Therefore, the present invention also provides compounds and compositions for inhibiting, preventing, and / or treating tumor angiogenesis, or methods for using the above purposes. This content is consistent with the description of the treatment / prevention of cancer and cancer metastasis in this invention.

[0132] Galactolectin-3 participates in tumor immunosuppression through multiple mechanisms, such as preventing T cell infiltration, inducing apoptosis, and directly interacting with tumor cells, as well as acting as a ligand for immune checkpoint molecules and cytokines [Stillman et al., 2006, J Immunol. 176, 778-789, herein incorporated by reference]. Therefore, the compounds and compositions described in this invention can also serve as potentially useful agents for reducing or inhibiting tumor immunosuppression, also known as reducing or inhibiting immunosuppression or reducing or inhibiting cancer immunosuppression.

[0133] Therefore, we provide compound X or a pharmaceutically acceptable salt thereof, and / or compound Y or a pharmaceutically acceptable salt thereof, and / or compound Z or a pharmaceutically acceptable salt thereof, or a combination of any of the foregoing compounds, or one or more other compounds or combinations thereof described in this invention, for inhibiting galactoglucoside-3, preferably for treating and / or preventing a disease, symptom, state, or condition, wherein inhibition of galactoglucoside-3 is beneficial for the treatment and / or prevention of said disease, symptom, state, or condition, wherein said disease, symptom, state, or condition is cancer, cancer metastasis, cancer recurrence after initial treatment or intervention, cancer cell proliferation, tumor growth, (tumor / cancer) angiogenesis, or immunosuppression. The compounds may be used to treat cancer, cancer metastasis, cancer recurrence after initial treatment or intervention, cancer cell proliferation, tumor growth, (tumor / cancer) angiogenesis, or immunosuppression in subjects of need, for example, methods of treating such subjects or uses for treating such subjects.

[0134] Fibrotic diseases

[0135] Compound X or its metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, and / or compound Y or its metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, and / or compound Z or its metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, or a composition comprising one or more of compound X, compound Y, and compound Z, or their metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, may be used for the treatment and / or prevention of fibrosis. This disease can also be called a fibrotic disease, a fibroproliferative disease, or a disease or condition of uncontrolled wound healing response [Thomas A. Wynnin J Clin Invest. 2007 Mar 1; 117(3): 524–529. doi: 10.1172 / JCI31487,'Galectin-3: One Molecule for an Alphabet of Diseases, from A to Z', Int JMol Sci. 2018 Feb; 19(2): 379, doi: 10.3390 / ijms19020379 (The contents of the above references are incorporated herein by reference).

[0136] As described in the background section, galectin-3 has been shown to actively participate in fibrotic processes (e.g., fibrosis in the lungs, liver, kidneys, and heart) and plays a key role in certain states of heart failure. Therefore, the compounds and compositions described in this invention can be used to treat fibrosis or fibrotic diseases. Fibrosis can be defined as an uncontrolled wound healing response. It is normal for tissues to repair themselves in place of dead or damaged cells after trauma or other injury. Such injury or trauma can be caused by a variety of acute or chronic stimuli, including infection, autoimmune responses, and mechanical damage. Mesenchymal stem cells (MSCs) have also been shown to play a role in the treatment of renal fibrosis via the galectin-3 pathway (Mesenchymal stem cells ameliorate renal fibrosis by Galectin-3 / Akt / GSK3β / Snail signalling pathway in adenine-induced nephropathy rat Stem Cell Research & Therapy volume 12, Article number: 409 (2021), the contents of which are incorporated herein by reference). Further evidence suggests that Belapectin (GR-MD-02) may be used to treat nonalcoholic steatohepatitis (NASH) (Review of Galectin-3 inhibitors in the treatment of nonalcoholic steatohepatitis, Expert Review of Clinical Pharmacology Volume 14, 2021 – Issue 4, the contents of which are incorporated herein by reference).

[0137] The term "fibrosis" as used in this invention can refer to fibrotic diseases, fibrotic states, fibrotic proliferative diseases, or diseases or states of uncontrolled wound healing responses. Fibrosis can refer to the excessive growth, hardening, and / or scarring of various tissues caused by the deposition of extracellular matrix components (such as collagen) beyond normal levels.

[0138] Fibrosis can be caused by excessive fibrosis, and fibroproliferative disorders include or may manifest as excessive fibrosis (i.e., an excess of fibrous connective tissue in a tissue or organ, for example, due to reparative or reactive processes, such as a response to injury (e.g., scar formation, healing), or an excess of fibrous tissue originating from a single cell line (e.g., fibroma)). The fibrosis, fibrotic disease, fibrotic state, or fibroproliferative disorder can be abnormal scar or wound healing, chronic or acute inflammation, chronic graft rejection, or fibrotic diseases affecting the heart, brain, lungs, liver, kidneys, cardiac or vascular system, mediastinum, bone, retroperitoneum, skin, digestive or gastrointestinal tract, connective tissue, eye, or muscle. Fibrotic diseases affecting the heart or vascular system can include cardiovascular disease, pulmonary fibrosis, endocardial myocardial fibrosis, reactive fibrosis, arterial stiffness, old myocardial infarction, atrial fibrosis, congestive heart failure, cardiomyopathy, hypertensive heart disease (HHD), hypertension (e.g., pulmonary hypertension) and hypertension-related fibrosis, atherosclerosis, restenosis (e.g., coronary artery, carotid artery, and brain lesions), ANCA vasculitis, Behçet's disease, antiphospholipid syndrome, and heart disease associated with myocardial ischemia. Fibrotic diseases affecting the brain can include cerebral fibrosis (e.g., glial scarring). Fibrotic diseases affecting the lungs can include cystic fibrosis, idiopathic pulmonary fibrosis, coal miner's progressive massive fibrosis, popcorn lung or obliterative bronchiolitis, interstitial lung disease, cryptogenic fibrotic alveolitis, chronic fibrotic interstitial pneumonia, interstitial lung disease (ILD), diffuse parenchymal lung disease (DPLD), relapsing polychondritis, emphysema, chronic obstructive pulmonary disease (COPD), or chronic asthma. Fibrotic diseases affecting the liver can include cirrhosis and related conditions such as chronic hepatitis B or C, Wilson's disease, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis, biliary cirrhosis, or autoimmune hepatitis. Fibrotic diseases affecting the kidneys can include progressive nephropathy, diabetic nephropathy, vesicoureteral reflux, tubulointerstitial renal fibrosis; glomerulonephritis or glomerulonephritis, including focal segmental glomerulosclerosis and membranous glomerulonephritis or mesangial capillary glomerulonephritis. Fibrotic diseases affecting the mediastinum can include mediastinal fibrosis. Fibrotic diseases affecting the bones, joints, or musculoskeletal system can include myelofibrosis, including primary myelofibrosis, arteritis, adhesive capsulitis, giant cell arteritis, familial Mediterranean fever, and myelofibrosis following polycythemia vera or essential thrombocythemia. Fibrotic diseases affecting the retroperitoneum can include retroperitoneal fibrosis.Fibrous diseases affecting the skin can include renal systemic fibrosis, bullous pemphigoid, hidradenitis suppurativa, discoid lupus erythematosus, Dupuytren's contracture, bullous pemphigoid, keloid formation and scarring, systemic sclerosis or scleroderma, scleroderma without scleroderma phenotypes, or scleroderma-like diseases. Fibrous diseases affecting the digestive or gastrointestinal tract can include intestinal fibrosis, inflammatory bowel disease, ulcerative colitis, or Crohn's disease. Fibrous diseases affecting connective tissue can include joint fibrosis or capsulitis. Fibrous diseases affecting the eye can include macular degeneration, Graves' eye disease, postoperative ocular fibrosis, or pseudoexfoliative glaucoma. Fibrous diseases affecting muscles can include polymyositis. Other multi-organ or other organ-related fibrotic diseases include abnormal scar or wound healing, chronic graft rejection, sarcoidosis, Peyronie's disease, or oral fibrosis.

[0139] The effect of the compounds described in this invention on inhibiting the secretion of pro-inflammatory cytokines by macrophages mediated by galectin-3 (Figure 12) further demonstrates how these compounds can be used to treat fibrosis and related diseases. The secretion of pro-inflammatory cytokines is one of the fundamental mechanisms in the pathogenesis of galectin-3-mediated fibrosis; inhibiting this process will suppress or treat fibrosis.

[0140] Therefore, compounds of formula X or pharmaceutically acceptable salts thereof, and / or compounds of formula Y or pharmaceutically acceptable salts thereof, and / or compounds of formula Z or pharmaceutically acceptable salts thereof, or combinations thereof, or one or more other compounds or combinations thereof described in this invention, are provided for inhibiting galactogluconin-3, preferably for treating and / or preventing a disease, condition, state, or symptom, wherein inhibition of galactogluconin-3 is beneficial for the treatment and / or prevention of said disease, condition, state, or symptom, wherein said disease, condition, state, or symptom is fibrosis, fibrotic disease, fibrotic state, fibrotic proliferative disease, or a disease, condition, state, or symptom of uncontrolled wound healing response. One or more of said compounds may be used to reduce fibrosis or fibrosis-related diseases in subjects in need, for example, in methods of treating such subjects or for use in treating such subjects.

[0141] inflammation

[0142] Compound X or its metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, and / or compound Y or its metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, and / or compound Z or its metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, or any other compound described in this invention, or a composition comprising one or more of compound X, compound Y, compound Z or any other compound described in this invention (i.e., compound W), or its metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, may be used for the treatment and / or prevention of inflammation or one or more inflammation-related conditions.

[0143] Inflammation originates from stimulation of the body by endogenous or exogenous inflammatory factors, or a combination of both, and produces corresponding physiological and pathological effects. Inflammation can form the basis of many chronic diseases, including infectious diseases, autoimmune diseases, or degenerative / aging-related diseases (such as Alzheimer's disease). Inflammation can also be associated with the induction, promotion, malignant transformation, invasion, and metastasis of cancer. In addition, inflammation is particularly closely related to fibrosis (pathological fibrosis originates from abnormal tissue repair, cellular stress, chronic inflammation, and / or severe tissue damage). Chronic inflammation, accompanied by fibrosis, tissue structure destruction, scar formation, and organ failure, is an important component of the pathogenesis of many chronic diseases and a significant cause of morbidity and mortality.

[0144] Galactoglobulin-3 is known to be expressed in a variety of cells involved in the initiation or mediation of inflammatory responses, such as macrophages, monocytes, dendritic cells, eosinophils, mast cells (activated), natural killer cells, neutrophil activation and adhesion, opsonization of apoptotic neutrophils, as well as T lymphocytes and activated B lymphocytes and phagocytic macrophages (including as a marker of macrophage activation).

[0145] Therefore, compounds of formula X and / or formula Y and / or formula Z, and / or pharmaceutically acceptable salts thereof are provided for inhibiting galactoglucan-3, preferably for treating and / or preventing a disease, condition, state, or symptom, wherein inhibition of galactoglucan-3 is beneficial for the treatment and / or prevention of said disease, condition, state, or symptom, wherein said disease, condition, state, or symptom is inflammation, an inflammatory disease, or an inflammation-related disease, condition, state, or symptom. The compounds may be used to reduce inflammation in subjects in need, including but not limited to subjects suffering from autoimmune diseases, for example, for use in methods of treating such subjects or for the purpose of treating such subjects.

[0146] Inflammation and inflammation-related diseases, symptoms, states, and conditions include, but are not limited to, acute or chronic organ transplant rejection, graft-versus-host disease, inflammatory bowel disease, inflammatory skin diseases, multiple sclerosis, arteriosclerosis, pancreatitis, acute bronchitis, chronic bronchitis, Alzheimer's disease, inflammatory lung disease, inflammatory skin diseases, acute bronchiolitis, folliculitis, chronic bronchiolitis, musculoskeletal pain or connective tissue inflammation, osteoarthritis, gout, spondyloarthropathy, Reiter's syndrome, psoriatic arthropathy, and one or more inflammatory diseases caused by bacterial, fungal, and viral infections, as well as inflammation caused by autoimmune diseases. Symptoms of autoimmune diseases include, but are not limited to, ulcerative colitis (UC) and Crohn's disease (CD), lupus, hyperthyroidism, IgA nephropathy, type I or type II diabetes and its complications, dry eye syndrome, rheumatoid arthritis, simple obesity, ankylosing spondylitis, bronchial asthma, neurodermatitis, ulcerative colitis, oral ulcers, psoriasis, vitiligo, Behcet's disease, autoimmune iridocyclitis, autoimmune eczema, autoimmune uveitis, autoimmune conjunctivitis, autoimmune dry eye, autoimmune glaucoma, autoimmune cataracts, allergic rhinitis, irritable bowel syndrome, and pruritus. Other inflammations and inflammation-related conditions include, but are not limited to, atherosclerosis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome, nephritis, Parkinson's disease, chronic inflammation, one or more neurodegenerative diseases or conditions caused by chronic inflammation and aging, and tumors caused by chronic inflammation. Tumors caused by chronic inflammation include, but are not limited to, melanoma, or tumors related to the breast, liver, lungs, skin, oral cavity, esophagus, stomach, intestines, kidneys, prostate, brain, nervous system, bladder, lymphatic system, pancreas, etc., especially digestive tract tumors, such as intestinal tumors.

[0147] Therefore, compounds of formula X and / or formula Y and / or formula Z, and / or their pharmaceutically acceptable salts, or combinations of any of the foregoing compounds, or one or more other compounds or combinations thereof described in this invention, are provided for inhibiting galactogluconin-3, preferably for treating and / or preventing a disease, condition, state, or symptom, wherein inhibition of galactogluconin-3 is beneficial for the treatment and / or prevention of said disease, condition, state, or symptom, wherein said disease, condition, state, or symptom is inflammation or one or more inflammation-related conditions. One or more of these compounds may be used to treat inflammation or one or more inflammation-related conditions in a subject in need, including but not limited to subjects suffering from one or more inflammation-related conditions, for example, in methods of treating such subjects or for use in treating such subjects.

[0148] diabetes

[0149] Compound X or its metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, and / or compound Y or its metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, and / or compound Z or its metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, or any other compound described in this invention (i.e., compound W), or a composition comprising one or more of compound X, compound Y, compound Z or any other compound described in this invention (i.e., compound W), or its metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, may be used for the treatment and / or prevention of diabetes.

[0150] The scientific name for diabetes is diabetes mellitus, but it is commonly referred to simply as diabetes. Diabetes is classified as a chronic inflammatory disease, and galectin-3 (Gal-3) is considered to play an active role in diabetes, particularly in type 2 diabetes (T2DM). Gal-3 is thought to be involved in the regulation of glucose homeostasis, and it functions in adipose tissue and pancreatic islets, thus potentially contributing to the pathogenesis of obesity and type 2 diabetes. [Galectin-3: One Molecule for an Alphabet of Diseases, from A to Z', Int J Mol Sci. 2018Feb; 19(2): 379, doi: 10.3390 / ijms19020379 (the entire contents of which are incorporated herein by reference).]

[0151] Insulin resistance is a hallmark of type 2 diabetes and plays a central role in this metabolic disease. Previous studies have shown that galectin-3 can lead to both cellular and systemic insulin resistance. This effect is thought to stem in part from galectin-3 binding to the insulin receptor (IR) and inhibiting downstream IR signaling (Li et al, Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance. Cell. 2016;167:973–984).

[0152] Therefore, compounds of formula X and / or formula Y and / or formula Z, and / or pharmaceutically acceptable salts thereof, or combinations of any of the foregoing compounds, or one or more other compounds or combinations thereof described in this invention, are provided for inhibiting galactoglucoagulation-3, preferably for treating and / or preventing a disease, condition, state, or symptom, wherein inhibition of galactoglucoagulation-3 is beneficial for the treatment and / or prevention of said disease, condition, state, or symptom, wherein said disease, condition, state, or symptom is diabetes. The compounds may be used to treat diabetes in subjects in need, including but not limited to subjects with diabetes, for example, in methods of treating such subjects or for use in treating such subjects. The diabetes may be type I or type II diabetes and / or related diabetes-related diseases or conditions, such as obesity.

[0153] Other diseases, states, symptoms, or conditions affected and / or mediated by galactoglobulin-3.

[0154] Galectin-3 is known to play a role in several other diseases, states, symptoms, conditions, or related pathogenesis. A comprehensive review of this topic can be found in [Galectin-3: One Molecule for an Alphabet of Diseases, from A to Z”, Int J Mol Sci. 2018 Feb; 19(2): 379, doi: 10.3390 / ijms19020379 (the contents of which are incorporated herein by reference).]

[0155] Further conditions mediated by galactolectin-3 include: asthma (Gal-3 plays a role in the pathophysiology of immune responses, particularly in asthma, where it is associated with neutrophil recruitment, activation, and clearance); and atherosclerosis (Gal-3 can be detected near the lipid core or in areas of fibrosis, angiogenesis, calcification, hemorrhage, or thrombosis, and is also detectable in advanced atherosclerotic lesions of the carotid and lower extremity arteries). mRNA); atopic dermatitis (AD, Gal-3 is a pro-inflammatory mediator of skin inflammation in atopic skin diseases and participates in the development of Th2 inflammatory responses through its effects on dendritic cells (DCs) and T cells, and is considered to play a key role in the development of allergic inflammatory responses in AD); cerebral infarction (Gal-3 levels are elevated in ischemic brain injury, and serum Gal-3 levels are elevated in patients who present to the emergency department and are clinically suspected of having ischemic stroke but have normal CCT); chronic obstructive pulmonary disease (COPD, compared with healthy controls, COPD patients with elevated pulmonary artery systolic blood pressure have elevated Gal-3 levels); regression Gal-3 expression is elevated in aortic stenosis (in patients with aortic stenosis accompanied by myocardial hypertrophy and a relatively reduced ejection fraction); endometriosis (caused by inflammation and vascular signaling dysregulation, in which Gal-3 plays an important role and is overexpressed in endometriotic tissues; high levels of Gal-3 can be detected in the peritoneal fluid of women with endometriosis); encephalitis (Gal-3 participates in inflammatory responses and interactions with the extracellular matrix, and has a potential role in various central nervous system inflammations, especially viral encephalitis); and gastritis (caused by various infectious agents, such as trypanosoma). Gal-3 has been reported to be induced by various factors including: * **Gal-3 upregulation:** * **Gal-3 infection:** Gal-3 has been found to be associated with early stages of HIV infection, particularly during HIV mRNA transport and / or splicing. * **Gal-3 promotion in idiopathic pulmonary fibrosis (IPF):** Gal-3 levels are elevated in the serum of IPF patients, and elevated Gal-3 concentrations are associated with decreased lung volume and abnormal gas exchange. Due to the lack of effective treatments, Gal-3 is considered a potential new therapeutic target. * **Juvenile idiopathic arthritis:** Studies have shown that Gal-3 plays a key role in its pathogenesis. * **Fatal cardiovascular disease (CVD):** Gal-3 concentrations are associated with new-onset heart failure and mortality in the general population. * **Non-alcoholic steatohepatitis (NASH):** Gal-3 is considered an important regulator of liver fibrosis. The link between Gal-3 and liver fibrosis was established when Gal-3 gene-deficient mice were resistant to toxin-induced liver fibrosis.Obesity (experiments in Gal-3 knockout mice showed that in vivo administration of Gal-3 led to impaired glucose tolerance and insulin resistance, while in vitro treatment with selective small-molecule Gal-3 inhibitors directly reduced insulin sensitivity in muscle cells, hepatocytes, and adipocytes, suggesting a possible link between inflammation and decreased insulin sensitivity); pneumonia (Gal-3 is involved in neutrophil recruitment during Streptococcus pneumoniae infection); pulmonary hypertension (Gal-3 can regulate fibroblast and endothelial behavior by acting on fibroblasts and vascular endothelial growth factor, playing a key role in acute and chronic inflammatory responses, vascular remodeling, and fibrosis after endothelial injury); plaque psoriasis (Gal-3 is associated with keratinocyte differentiation and maturation, and is highly expressed in Langerhans cells in skin biopsy samples of plaque psoriasis); Q fever (its pathogen is Coxiella). Gal-3 may act as a dangerous receptor for membrane damage, playing a crucial role in infected lysosomes and potentially participating in autophagy mechanisms during membrane repair; rheumatoid arthritis (RA), where Gal-3 promotes inflammation, and animal models and human studies have shown its key role in arthritis development; systemic sclerosis (elevated serum Gal-3 levels in patients, correlated with signs of advanced organ sclerosis and inflammatory laboratory markers); urinary tract infections and kidney infections (Gal-3 plays a key role in bacterial infections, especially *Proteus mirabilis* infection, a common bacterium in the urinary system; Gal-3 affects the adhesion of this bacterium to the renal epithelial cell membrane, and experiments using specific monoclonal antibodies against Gal-3 have confirmed its crucial role in *Proteus mirabilis* infection, indicating its central role in infection-induced renal pathology); COVID-19 (multiple studies have shown that galectin-3 is involved in COVID-19 infection and progression, such as [Immunopathology of Galectin-3: an increasingly promising target]). [in COVID-19 (F1000Research 2020, 9:1078, Last Updated: February 6, 2023)];Currently, there are clinical trials of Gal-3 inhibitors for the treatment of COVID-19 (e.g., see Sigamani et al, An Oral Galectin Inhibitor in COVID-19-A Phase IIRandomized Controlled Trial. Vaccines (Basel) and Computational Study of Potential Galectin-3 Inhibitors in the Treatment of COVID-19 (Biomedicines2021, 9, 1208)); sepsis is also mediated and / or exacerbated by Gal-3 (e.g., see 'Serum galectin-3 levels predict poor prognosis in sepsis and septic shock patients', Rev AssocMed Bras (1992). 2023; 69(8): e20220940; and 'Galectin-3 aggravates experimental polymicrobial sepsis by impairing neutrophil recruitment to the infectious focus', Journal of Infection, Volume 77, Issue 5, November 2018, pp. 391-397; Thrombosis and Venous Thrombosis (Gal-3 is associated with thrombosis. In experimental venous thrombosis models, this protein is particularly characterized by its dual pro-thrombotic and pro-inflammatory properties; during venous thrombosis in mice and humans, serum galactolectin-3 and its binding proteins are elevated. Related studies have also confirmed that galactolectin-3 inhibitors can be used as novel antithrombotic drugs for development and application (see European Heart Journal, October 1, 2022, Volume 43, Issue 37, pp. 3575-3577, https: / / doi.org / 10.1093 / eurheartj / ehac128); other studies have shown that galactolectin-3 can promote platelet aggregation and accelerate thrombosis by activating lectin-like receptor-1 (Dectin-1) (see European Heart Journal). Journal, October 1, 2022, Vol. 43, No. 37, pp. 3556-3574, https: / / doi.org / 10.1093 / eurheartj / ehac034Wound healing (Gal-3 regulates cell migration by influencing cell adhesion and cell-matrix interactions, and is an important regulator of re-epithelialization in various tissue wounds); Cardiac syndrome X (CSX; studies have examined serum Gal-3 levels in CSX patients, showing a significant increase compared to healthy controls); Yeast infection-candidiasis (inhibiting galactolectin-3 (Gal-3) in neutrophils may be a promising therapeutic strategy for systemic candidiasis, as inhibiting Gal-3 can suppress neutrophil reactive oxygen species production and enhance neutrophil bactericidal ability when encountering "hard-to-kill" Candida); and herpes zoster-related pain (hyperalgesia; Gal-3 is involved in Wallerian degeneration distal to injury and subsequent axonal regeneration and functional reinnervation, making Gal-3 a novel target for the treatment and clinical management of neuropathic pain caused by peripheral nerve injury). More detailed explanations of these topics can be found in the aforementioned literature. The aforementioned diseases, conditions, symptoms, or illnesses can be collectively referred to as diseases, conditions, symptoms, or illnesses affected and / or mediated by galactolectin-3.

[0156] Therefore, we provide compound X or its metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, and / or compound Y or its metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, and / or compound Z or its metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, or any other compound described in this invention (i.e., compound W), or a composition comprising one or more of compound X, compound Y, compound Z or any other compound described in this invention (i.e., compound W), or its metabolic and / or hydrolyzed and / or oxidized forms, or pharmaceutically acceptable salts thereof, which may be used or used to inhibit galactoglucoside-3, preferably for the treatment and / or prevention of a disease, condition, state or symptom, wherein inhibition of galactoglucoside-3 is beneficial for the treatment and / or prevention of said disease, condition, state or symptom, wherein said disease, condition, state or symptom is any of the above.

[0157] Combination therapy

[0158] The compositions and compounds defined in this invention can be used alone to produce therapeutic effects. For example, in cancer treatment, the compositions and compounds defined in this invention can also be administered in combination with one or more of the following: surgery and / or additional antitumor agents, antimetastatic agents, chemotherapeutic agents / chemotherapy, and / or radiotherapy agents / radiotherapy, antifibrotic agents / fibrotic agents, anti-inflammatory agents / inflammatory agents, one or more other galactoglobulin inhibitors and / or immunotherapy agents / immunotherapy.

[0159] The chemotherapy may include one or more of the following classes of antitumor agents:

[0160] (i) Other antiproliferative / antitumor drugs and their combinations, such as those used in medical oncology, include alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates, such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxyurea); antitumor antibiotics (e.g., anthracyclines like doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, actinomycin D, and mitoxin); antimitotic agents (e.g., vinblastines like vincristine, vinblastine, vinorelbine, and vinorelbine, as well as taxanes like paclitaxel and docetaxel, and polar kinase inhibitors); and topoisomerase inhibitors (e.g., etoposide, teniposide, dapsone, topotecan, and camptothecin).

[0161] (ii) Cell inhibitors, such as anti-estrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxifen), anti-androgens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and 5α-reductase inhibitors such as finasteride.

[0162] (iii) Anti-invasive agents, such as c-Src kinase family inhibitors (e.g., 4-(6-chloro-2,3-methylenedioxyaniline)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazolyl-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606); as well as metalloproteinase inhibitors, such as marimastat, urokinase plasminogen activator receptor function inhibitors, or heparanase antibodies.

[0163] (iv) Growth factor function inhibitors, such as growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab (Herceptin™), anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab (Erbitux, C225), etc.), and any growth factor or growth factor receptor antibody; (Stern et al. Critical reviews inoncology / haematology, 2005, Vol. 54, pp. 11–29); such inhibitors also include tyrosine kinase inhibitors, such as epidermal growth factor family inhibitors (e.g., EGFR family tyrosine kinase inhibitors, including: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-di(2-methoxyethoxy) Quinazoline-4-amine (erlotinib, OSI-774), 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoline-4-amine (CI 1033), hepatocyte growth factor family inhibitors; insulin-like growth factor family inhibitors; platelet-derived growth factor family inhibitors, such as imatinib and / or nilotinib (AMN107); also includes serine / threonine kinase inhibitors (such as Ras / Raf signaling pathway inhibitors, i.e., farnesyltransferase inhibitors, such as sorafenib (BAY 43-9006), tilpifanib (R115777), and lonafanib (SCH66336)); cell signaling inhibitors via MEK and / or AKT kinases; c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Flt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF inhibitors. Receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (such as AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528, and AX39459); and cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 inhibitors.

[0164] (v) Anti-angiogenic agents, such as drugs that inhibit the action of vascular endothelial growth factor (VEGF) (e.g., the anti-VEGF antibody bevacizumab (Avastin™); and VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), vastarani (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034), and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidone-1-ylpropoxy) quinazoline (AZD2171; Example 240 in International Patent Application WO 00 / 47212); also including International Patent Applications WO97 / 22596, WO 97 / 30035, WO 97 / 32856, and WO 98 / 13354). The disclosed compounds, as well as compounds that function through other mechanisms (e.g., linolamine, integrin ανβ3 function inhibitors, and angiostatin).

[0165] (vi) Vascular disruptors, such as tamponade A4 and compounds disclosed in international patent applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213;

[0166] (vii) Endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan.

[0167] (viii) Antisense therapy, such as antisense drugs targeting the above-mentioned targets, such as ras antisense nucleic acid ISIS 2503; and / or

[0168] (ix) Gene therapy methods, including, for example, methods for replacing abnormal genes (such as abnormal p53, abnormal BRCA1 or BRCA2), gene-guided enzyme prodrug therapy (GDEPT, such as using cytosine deaminase, thymidine kinase or bacterial nitroreductase), and methods for improving patients' tolerance to chemotherapy or radiotherapy (such as multidrug-resistant gene therapy).

[0169] Such immunotherapies may include one or more of the following immunotherapeutic agents: immunotherapeutic methods, including, for example, methods to enhance the immunogenicity of a patient's tumor cells in vitro and in vivo (e.g., transfection with cytokines such as interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factor), methods to reduce T cell incompetence, methods to block the activation of immune checkpoint molecules (e.g., PD-1, lymphocyte activation gene-3 (LAG3)), methods to use transfected immune cells (e.g., dendritic cells transfected with cytokines), methods to use cytokines to transfect tumor cell lines, and methods to use anti-idiotype antibodies.

[0170] For example, in the treatment of fibrosis, the compositions and compounds described herein may also be used in combination with surgery and / or other antifibrotic drugs. The antifibrotic drug may be any one of those described in Z. Manyu, “Targeting fibrosis: mechanisms and clinical trials,” Signal Transduction and Targeted Therapy, Vol. 7, Article No. 206 (2022) (the contents of which are incorporated herein by reference), such as: TGF-β / TGFβR targets, FGF targets, RTKs targets, CTGF targets, PI3K targets, JAK targets, WNT / β-catenin targets, ASK targets, MAPK targets, LOXL targets, PPAR targets, FXR targets, TLR targets, GLP / GIP targets, CFTR targets, HDAC targets, THRβ targets, CCR targets, MPC targets, SCD targets, ATX targets, FATP5 targets, ACC targets, PDE targets, AMPK targets, MMP targets, A3AR targets, etc. Targeted therapies, FASN targeted therapies, bio-homogeneous testosterone targeted therapies, stem cell targeted therapies, HSP targeted therapies, CD targeted therapies, ileal bile acid transport targeted therapies, aldosterone receptor targeted therapies, GPR targeted therapies, ROCK2 targeted therapies, BAFFR targeted therapies, LPA1 targeted therapies, telomerase targeted therapies, KHK targeted therapies, calpain targeted therapies, P-selectin targeted therapies, SMO targeted therapies, Bcl-2 targeted therapies, BET family targeted therapies, ENaC targeted therapies, DNase I targeted therapies, AA / DHA imbalance targeted therapies, neutrophil elastase targeted therapies, leukotriene B4 targeted therapies, CDK targeted therapies, LSD targeted therapies, MDM2 targeted therapies, PLK1 targeted therapies, IL-1α targeted therapies, HSD17B13 targeted therapies, MOTS-c targeted therapies, IFN-γ targeted therapies, autosecretion targeted therapies, glutathione-dependent PGD. Synthase-targeting agents, arginase-targeting agents, GSNOR-targeting agents, Pim kinase inhibitor-targeting agents, and PRMT-targeting agents.

[0171] For example, TGF-β / TGFβR targets can be pirfenidone, hydroxynidone, HEC-585, PLN-74809, BG00011, IDL-2965, TRK-250, rusoxasipro, sotascept, AVID200; FGF targets can be BIO89-100, epoximine, pebefenimine, adafenimine; RTKs targets can be nintedanib, ZSP1603, MK-3655; CTGF targets can be pembrolizumab; PI3K targets can be persalicoxib, omepalicoxib, HEC-68498, bupalicoxib, ubalicoxib; JAK Targeted therapies may include ruxolitinib, fintatinib, momotinib, paclinib, jakitinib, itatinib, and ilgitinib; WNT / β-catenin targeted therapies may include SM04646 and PRI-724; ASK / MAPK targeted therapies may include serotoninib, CC-90001, and MG-S-2525; LOXL targeted therapies may include eporutinone, tipyruvic, PAT-1251, and PXS-5382A; PPAR targeted therapies may include ellafenox, sarograza, lanifenox, pemafibate, and ZSP0678; FXR targeted therapies may include obeticholic acid, silofexo, nidufexo, TERN-101, vonarfexo, EDP-305, and tropifexo; TLR targeted therapies may include JKB-121 and JKB-122; GLP / GIP Targeted therapies may include semaglutide, telpoxetine, cotapetine, and HM-15211; CFTR targeted therapies may include ivacafodo, ivacafodo, GLPG1837, FDL169, olacafodo, VX-152, MRT5005, GLPG2737, nesocafodo, VX-121, ABBV-3067, ELX-02, elufsen, dirocafodo, FDL176, poscecafodo, and GLPG2451; HDAC targeted therapies may include pabistal and plasinostat; THRβ targeted therapies may include resmetirol and VK2809; CCR targeted therapies may include sinivirol; MPC targeted therapies may include azamiglitazone potassium and deuterium-stabilized (R)-pioglitazone; SCD targeted therapies may include alactal; ATX targeted therapies may include ziritastastat; FATP5 Targeted therapies could include ursodeoxycholic acid; ACC targeted therapies could include PF-05221304 and filsostat; PDE targeted therapies could include ZSP1601, eporutoline, tepirushtastat, and ensifenteline; AMPK targeted therapies could include PXL-770 and ALS-L1023; MMP targeted therapies could include ALS-L1023; A3AR targeted therapies could include namodinosine; FASN targeted therapies could include TVB-2640; a biocompatible testosterone targeted therapies could include LPCN 1144; and stem cell targeted therapies could include HepaStem.HSP targets could be BMS-986263 or PU-H71; CD targets could be fulanumab or tagutuximab; ileal bile acid transport targets could be eloxibart; aldosterone receptor targets could be aparinone; GPR targets could be RVT1601, GLPG-1205, or PBI-4050; ROCK2 targets could be berumosudi; BAFFR targets could be inarubicin; LPA1 targets could be BMS-986278; telomerase targets could be imatinib; KHK targets could be PF-06835919; calpain targets could be BLD-2660; P-selectin targets could be kalizumab; SMO targets could be sonidiclofenac; Bcl-2 targets could be navitocin; BET family targets could be perapux; ENaC... Targeted therapies may include BI-1265162, P-1037, QBW276, IONIS-ENaCRx, AZD5634, BI 443651, and Adelalipi; DNase I targeted therapies may include AIR DNase; AA / DHA imbalance targeted therapies may include fenivel-Amin; neutrophil elastase targeted therapies may include lonostat and CHF 6333; leukotriene B4 targeted therapies may include acerolstat; CDK targeted therapies may include cexicoxib and ribociclib; LSD targeted therapies may include bamicin dimethylbenzenesulfonate; MDM2 targeted therapies may include KRT-232; PLK1 targeted therapies may include regorastat; IL-1α targeted therapies may include bemigrimizumab (MABp1); HSD17B13 targeted therapies may include ARO-HSD; MOTS-c Targeting agents could include CB4211; interferon-γ for IFN-γ; BBT-877 for autosecodylin; ZL-2102 for glutathione-dependent PGD synthase; CB-280 for arginase; N-6022 for GSNOR; TP-3654 for Pim kinase inhibitors; and PRT-543 for PRMT.

[0172] For example, in the treatment of inflammation, the compositions and compounds described herein may also be used in combination with one or more of surgical and / or other anti-inflammatory drugs, such as anti-inflammatory agents (also known as anti-inflammatory drugs), such as nonsteroidal anti-inflammatory drugs (NSAIDs), anti-leukotriene drugs, and immunoselective anti-inflammatory derivatives (ImSAIDs).

[0173] Nonsteroidal anti-inflammatory drugs (NSAIDs) include aspirin, ibuprofen, naproxen, diclofenac, celecoxib, mefenamic acid, etoricoxib, and indomethacin. Anti-leukotriene drugs, also known as leukotriene modulators and leukotriene receptor antagonists, include leukotriene-associated enzyme inhibitors (arachidonic acid 5-lipoxygenase) or leukotriene receptor antagonists (cysteyl leukotriene receptors), such as montelukast, zafirlukast, and prolamsterase, as well as 5-lipoxygenase inhibitors such as zileutone and St. John's wort. Immunoselective anti-inflammatory derivatives (ImSAIDs) are a class of peptides with anti-inflammatory activity, including salivary gland-derived peptides.

[0174] The compositions and compounds described herein may also be used in combination with one or more other galactagogue inhibitors. Compounds of formula X, Y, Z, or any other compound described herein (i.e., compound W) may be used in combination with each other. Alternatively, one or more of compounds of formula X, Y, Z, or any other compound described herein may be used in combination with another galactagogue inhibitor (such as another galactagogue-3 inhibitor), for example, berapetin, servagarine, GB1211, GB0139, GB1107, G3-C12 TFA, β-lactose, G3-C12, Galectin-3-IN-1, or galactagogue-3 antagonist 1; or galactagogue-1 inhibitors, such as OTX008 or apoptosis inducer 8; or a variety of broad-spectrum galactagogue inhibitors, such as thiodilactose.

[0175] The compositions and compounds described herein may be used as monotherapy or in combination with surgery, radiotherapy, chemotherapy, immunotherapy or other treatments (such as anti-metastatic drugs) in addition to the compounds / compositions described herein.

[0176] Such treatments can be achieved by administering the components of the treatment simultaneously, sequentially, or separately. These combination products use the compounds / compositions described herein within the dosage ranges described herein, and other pharmaceutically active agents within their approved dosage ranges.

[0177] In this document, the term "combination" should be understood as simultaneous, separate, or sequential administration. In one aspect of the invention, "combination" refers to simultaneous administration; in another aspect, it refers to separate administration; and in yet another aspect, it refers to sequential administration. In the case of sequential or separate administration, a delay in the administration of the second component should not result in the loss of the beneficial effects of the combination.

[0178] The compounds or compositions described herein may be used in conjunction with surgical treatments, such as surgical treatment of cancer and / or cancer metastasis, and / or fibrosis, and / or inflammation, and / or diabetes. Surgical removal of cancerous or fibrotic tissue may be performed, for example, by cryosurgery.

[0179] Alternatively or concurrently, the compounds or compositions described herein may be used as adjunctive therapies in the treatment of galactagogue-3-mediated diseases, symptoms, states, or conditions. Adjunctive therapies are medications given to patients concurrently with or following “primary” treatment or therapy. For example, in cancer treatment, the compounds or compositions described herein may be given after primary anticancer therapy (such as surgical resection of a tumor) to prevent cancer recurrence following primary treatment. They may be given after surgical resection or tumor debulking, or as part of such treatment; or, for example, for the surgical resection of fibrotic tissue. Compositions

[0180] Compositions according to various aspects of the invention may further comprise one or more pharmaceutically or cosmetically acceptable ingredients or excipients. Pharmaceutically acceptable ingredients are well known to those skilled in the art and include, but are not limited to, pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), flavor masking agents, colorants, fragrances, and penetration enhancers. Conventional methods suitable for selecting and preparing appropriate pharmaceutical formulations can be found, for example, in ME Aulton's *Pharmaceuticals - The Science of Dosage Form Designs*, Churchill Livingstone, 1988.

[0181] In some embodiments, the composition may be provided as a suspension suspended in a pharmaceutically or cosmetically acceptable excipient, diluent, or carrier.

[0182] The compositions of the present invention can be formulated into forms suitable for oral administration (e.g., tablets, lozenges, hard capsules or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), forms suitable for external use (e.g., creams, ointments, gels, aqueous or oily solutions or suspensions), forms suitable for inhalation (e.g., fine powders or liquid aerosols), forms suitable for nasal administration (e.g., fine powders), or forms suitable for parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular or intraperitoneal administration, or suppositories for rectal administration).

[0183] The compositions described in this invention can be prepared using conventional pharmaceutical excipients known in the art and employing conventional methods. Therefore, compositions for oral administration may, for example, contain one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[0184] The effects of the compounds or compositions described in this invention in vivo may be partly achieved by one or more metabolites formed after administration to humans or animals.

[0185] Further information regarding the preparation of the compounds described in this invention is contained in the Examples section. The general reaction schemes and specific methods described in the examples constitute another aspect of this invention.

[0186] The compounds described in this invention can be separated and purified using techniques known in the art.

[0187] Typically, salts can be prepared in situ during the separation and / or purification of compounds (including intermediates), or by reacting the compound (or intermediate) separately with a suitable organic or inorganic acid or base (as applicable) and separating the resulting salt. The degree of ionization in the salt can range from complete ionization to almost non-ionization. In practice, various salts can be collected by precipitation (optionally with the addition of one or more co-solvents and / or antisolvents) and by filtration, or by solvent recovery through evaporation. The salts of this application can also be prepared by "salt replacement" or ion exchange / double decomposition reactions, i.e., one ion is wholly or partially replaced by another ion with the same charge. Those skilled in the art will understand that the salts can be prepared and / or separated by a single method or a combination of methods.

[0188] Representative salts include, but are not limited to, acetates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, camphorsulfonates, citrates, ethanesulfonates, methanesulfonates, formates, fumarates, gluconates, glucurons, hexafluorophosphates, hydrochlorides / chlorides, hydrobromates / bromines, hydroiodates / iodides, lactates, malates, maleates, malonates, methyl sulfates, naphthalates, nitrates, oxalates, palmitates, phosphates / hydrophosphates / dihydrophosphates, stearates, succinates, tartrates, p-toluenesulfonates, trifluoroacetates, etc. Other representative examples of salts include alkali metal or alkaline earth metal cations, such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzyl benzoate, choline, tromethamine, ethanolamine, glycine, meglumine, and oleylamine.

[0189] The compounds described in this invention can exist in single crystal form, as a mixture of multiple crystal forms, or in an amorphous form. Therefore, the compounds described in this invention for pharmaceutical use can be administered in crystalline or amorphous form. For example, solid masses, powders, or films can be obtained by methods such as precipitation, crystallization, freeze-drying, spray drying, or evaporative drying. Microwave or radio frequency drying can also be used.

[0190] The process defined in this invention may further include a salt-changing step for the compounds described in this invention, particularly when one or more of the compounds described in this invention are present in a mixture of different salt forms. The salt-changing step may include immobilizing one or more of the compounds described in this invention onto a suitable solid support or resin and eluting with a suitable acid to obtain a single salt form of the one or more compounds.

[0191] In another aspect of the invention, a compound of the invention is provided that can be obtained by any process defined in the invention.

[0192] The compounds and their salts described in this invention can be isotopically labeled (or radioactively labeled). Therefore, one or more atoms can be replaced by atoms with atomic weights or mass numbers different from those normally found in nature. Doped radionuclides include, for example... 2 H (deuterium) 3 H (tritium) 11 C 13 C 14 C 15 O、 17 O、 18 O、 18 F, etc. The radionuclide used will depend on the specific application of the radiolabeled derivative. For example, in in vitro competitive analysis, 3 H or 14 C is generally more suitable; in radiographic imaging applications... 11 C or 18 F is generally more suitable. In some embodiments, the radionuclide is... 3 H; in some implementations, is 14 C; in some implementations, is 11 C; in some implementations, is 18 F.

[0193] It should also be understood that some compounds described in this invention may exhibit polymorphism, and this invention covers all polymorphs having the advantageous properties described in this invention.

[0194] The compounds described in this invention can exist in various tautomeric forms, and all references to the compounds described in this invention include all such tautomeric forms. To avoid ambiguity, when a compound can exist in multiple tautomeric forms, and only one is specifically described or shown, the other tautomeric forms are also included within the scope of the compounds described in this invention. Examples of tautomeric forms include keto / enol, imine / enamine, amide / imineol, imine / guanidine, nitroso / oxime, thionone / enthiol, and nitro / acid nitro forms, etc.

[0195] The compounds described in this invention can be used in their authentic form in the methods disclosed herein, or in pharmaceutically acceptable salt forms. It should also be understood that some of the compounds described in this invention can exist in solvated or non-solvated forms, such as hydrates. This invention covers all such solvated forms having the advantageous properties described herein.

[0196] Route of administration and dosage

[0197] The compounds and compositions described in this invention can be administered in various ways depending on the desired site of action. According to the method described in this invention, the compounds and compositions can be administered at any dose and route of administration sufficient to treat or alleviate the severity of the aforementioned diseases, symptoms, states, or conditions. The exact dose required will vary from subject to subject, depending on factors such as the subject's species, age, overall condition, severity of the disease, symptom, state, or condition, the specific active ingredient used, and its route of administration.

[0198] The compounds and / or their pharmaceutically acceptable salts, solvates, hydrates, or compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, via oral mucosa, vaginally, or through an implanted reservoir. Oral, intraperitoneal, or intravenous administration is preferred. More preferably, the pharmaceutically acceptable compositions of the present invention are prepared as oral formulations. Exemplary oral dosage forms include capsules, tablets, aqueous suspensions, or solutions. The compositions can be prepared according to pharmaceutical formulation techniques known in the art.

[0199] Suitably, the compounds and compositions of the present invention can be administered by injection. The injection may be intravenous, intra-arterial, intradermal, subcutaneous, intraperitoneal, intracerebral, intraventricular, or intrathecal injection. The injection may be performed continuously over a period of time (infusion) or as a single bolus injection. The compounds / compositions of the present invention may also be administered in certain circumstances by inhalation (e.g., intranasal administration), oral administration, transdermal administration, or rectal or vaginal administration. The compounds / compositions of the present invention can also be formulated as sustained-release or delayed-release formulations or devices. For example, the formulations or devices may be implanted on the skin surface or subcutaneously to allow the continuous release of the compounds / compositions over weeks or even months.

[0200] It should be understood that the required dosage of the compounds / compositions described in this invention depends on their biological activity and bioavailability, which in turn depends on the route of administration, the physicochemical properties of the compound used, and whether the compound is used as monotherapy or in combination therapy. The frequency of administration will also be affected by the above factors, especially the half-life of the compound / composition in the subject.

[0201] The optimal dosage of the compounds / compositions described in this invention can be determined by those skilled in the art and will vary depending on the specific compound used, the concentration of the formulation, the route of administration, and the stage of the disease state.

[0202] Other factors relevant to the specific subject may also require dosage adjustments, including the subject's age, weight, sex, diet, and timing of administration.

[0203] When using one or more compounds of the present invention for therapeutic or preventative purposes, subjects are typically given a daily dose, for example, selected from 0.1 mg / kg to 100 mg / kg, 1 mg / kg to 75 mg / kg, 1 mg / kg to 50 mg / kg, 1 mg / kg to 20 mg / kg, or 5 mg / kg to 10 mg / kg body weight, which may be divided into multiple doses if necessary. Generally, when administered via parenteral route, the dose may be relatively low. For example, for intravenous or intraperitoneal administration, a dose range of 0.1 mg / kg to 30 mg / kg body weight is typically used. Similarly, for inhalation administration, a dose range of 0.05 mg / kg to 25 mg / kg body weight is typically used. Suitably, one or more compounds of the present invention may be administered orally, for example, in tablet or capsule form. The total daily dose for oral administration may be selected, for example, from 1 mg to 2000 mg, 5 mg to 2000 mg, 5 mg to 1500 mg, 10 mg to 750 mg, or 25 mg to 500 mg. Typically, a unit dose may contain about 0.5 mg to 0.5 g of one or more compounds described in this invention.

[0204] Well-known methods, such as those commonly used in the pharmaceutical industry (e.g., in vivo experiments, clinical trials, etc.), can be used to determine the specific formulation and precise dosing regimen of the compounds / compositions described in this invention.

[0205] Detection

[0206] The method of the present invention may include: determining the level of galectin-3, the expression of LGALS3, or the LGALS3 expression level in a biological sample taken from a subject. The subject may be suspected of having a disease, symptom, condition, or illness associated with the expression or overexpression of galectin-3. This determination may be performed prior to any administration, and the method may subsequently include administering to the subject a composition comprising compound X and / or a composition comprising compound Y and / or a composition comprising compound Z, or a pharmaceutically acceptable salt thereof, or a composition of any of the foregoing compounds, or one or more other compounds or compositions of the present invention, optionally administered with a pharmaceutically acceptable excipient.

[0207] The assay for determining galectin-3 levels, LGALS3 expression, or LGALS3 expression levels or overexpression thereof can be performed on biological samples, preferably before the subject receives a galectin-3 inhibitor (e.g., compound X, compound Y, or compound Z). This assay can provide information to clinicians to determine whether a subject is likely to respond to galectin-3 inhibitor treatment, thereby facilitating more targeted treatment. The galectin-3 inhibitor is preferably a compound described in this invention, such as one or more of compound X, compound Y, or compound Z, or one of the other compounds described in this invention.

[0208] The level, content, or expression can be determined based on one type of target molecule (e.g., DNA, RNA, or protein). The level can also be determined based on a combination of two or more target molecules (e.g., two or more of DNA, RNA, and protein). The level of a target molecule can be expressed as a direct measurement of its content (e.g., concentration (mg / sample volume)).

[0209] Galactosyllectrin-3 levels, LGALS3 expression, or LGALS3 expression levels can be determined using any appropriate method known in the art, such as biomarker expression assays like ELISA, immunohistochemistry, Western blotting, mass spectrometry, flow cytometry, or transcriptome analysis. Appropriate techniques for determining RNA / mRNA levels in a sample (e.g., transcriptome analysis) can include hybridization techniques (e.g., by detecting binding to a nucleic acid library), quantitative PCR, and high-throughput sequencing, including tag-based sequencing methods such as SAGE (gene expression serialization analysis) and RNA-seq.

[0210] Predicting treatment response by detecting galactolectin-3 levels, LGALS3 expression, or LGALS3 expression levels can increase the likelihood of effective treatment. This testing can be performed during other alternative therapies, or before or after planned alternative therapies.

[0211] The elevated level can refer to an increase relative to the level of the same target molecule in another subject (e.g., a subject with normal galectin-3 levels or normal LGALS3 expression levels, or a subject known not to have a galectin-3-related disease, condition, state, or symptom); or an increase relative to the level of the same subject prior to the elevation; or an increase relative to the level prior to diagnosis of a galectin-3-related disease, condition, state, or symptom. The level can be compared to a subject not having a galectin-3-related disease, condition, state, or symptom, or to a normal reference value reported in the literature. The comparison can also be with a known reference value or baseline value, or with a control sample, such as literature data or a sample from a subject not having a galectin-3-related disease, condition, state, or symptom. The reference value can be the average of multiple control samples or literature data. The level can be the level in a specific tissue or a specific sample type. The control sample can be age-matched to the subject being tested. Reference or baseline values ​​may be derived from appropriate individuals and serve as general reference values ​​for multiple analyses. The subjects may be suspected of having a disease, condition, state, or pathology associated with galactoglucan-3 expression or overexpression.

[0212] The term "biological sample," "biological sample taken from a subject," or "sample" as used in this invention refers to any biological material sample derived from a subject, such as, but not limited to, tumor tissue, suspected tumor tissue, tissue biopsy samples, mucus, feces, tears, urine, blood, serum, cell extracts, biopsy specimens, and / or liquids introduced into an individual and then removed, such as solutions extracted after being added to tissue (e.g., lung or colon) (e.g., enema fluid). The biological sample may be used directly or altered, processed, or otherwise treated before use. The sample may be taken from a subject suspected of having a disease, condition, state, or symptom associated with galactoglobulin-3 expression or overexpression, or from a subject known to have a disease, condition, state, or symptom associated with galactoglobulin-3 expression or overexpression. The sample may be a blood sample, tumor sample, tissue biopsy sample, or suspected tumor sample. Sampling may be performed before or in sequence with treatment using a galactoglobulin-3 inhibitor. The detection may include measuring the level or expression of galactoglucan-3 in biological samples (e.g., bodily fluid samples such as blood, tears, or urine) or tissue samples (e.g., tissue biopsy samples, biopsy specimens, tumor samples, or suspected tumor samples) taken from the subject. The subject may be suspected of having a disease, condition, state, or ailment associated with galactoglucan-3 expression.

[0213] Dosing may be administered when galectin-3 or LGALS3 expression is detected in the subject's biological sample. Specifically, dosing may be administered when galectin-3 levels, LGALS3 expression, or LGALS3 expression levels in the biological sample are detected to be above baseline or to be overexpressed. The terms "above baseline" or "overexpressed" may be compared to reference values, such as literature reference values ​​or reference samples. Optionally, when galectin-3 levels, LGALS3 expression, or LGALS3 expression levels in the biological sample are detected to be above baseline or to be overexpressed (e.g., above reference values, literature reference values, or reference samples), the method may further include administering to the subject a composition comprising compound X and / or a composition comprising compound Y and / or a composition comprising compound Z, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable excipient.

[0214] Therefore, any treatment method of the present invention may first include diagnosing the subject as having a disease, condition, state, or ailment associated with galactoglobulin-3 or LGALS3 expression or elevated LGALS3 expression levels.

[0215] Mechanism of action

[0216] As previously stated, and without being limited by any particular theory, it is believed that the therapeutic effect of the compounds described in this invention is achieved at least in part by inhibiting the activity of galactolectin-3.

[0217] According to one aspect of the invention, a compound of formula X and / or formula Y and / or formula Z, and / or a pharmaceutically acceptable salt thereof, or a composition of any of the foregoing compounds, or one or more other compounds or compositions described in this invention, is provided for inhibiting the activity of galactoglucan-3. The composition may comprise the foregoing compounds.

[0218] The stated use can be for the treatment of a disease, symptom, condition or illness, wherein inhibition of galactoglucan-3 activity is beneficial for the treatment of the disease, symptom, condition or illness.

[0219] In a further aspect of the invention, compounds of formula X and / or formula Y and / or formula Z, and / or their pharmaceutically acceptable salts, or combinations of any of the foregoing compounds, or one or more other compounds or combinations described in the invention, are provided as inhibitors of galactolectin-3 activity (in vitro).

[0220] In a further aspect of the invention, a method (in vitro or in vivo) for inhibiting galactolectin-3 activity is provided, the method comprising administering a compound of formula X and / or formula Y and / or formula Z, and / or a pharmaceutically acceptable salt thereof, or a combination of any of the foregoing compounds, or an effective amount of one or more other compounds or combinations of the present invention.

[0221] Compounds that bind to galectin-3 are known to inhibit the interaction between galectin-3 and transmembrane mucins (e.g., MUC1 and MUC16), and also to inhibit galectin-3-induced adhesion of cancer cells to endothelial cells. This may be one reason why the compounds described in this invention are useful in treating cancer metastases.

[0222] Therefore, the present invention also provides a compound of formula X and / or formula Y and / or formula Z, and / or a pharmaceutically acceptable salt thereof, or a combination of any of the foregoing compounds, or one or more other compounds or combinations described in the present invention, for inhibiting galectin-3-mediated binding between cancer cells and endothelial cells. Furthermore, a compound of formula X or formula Y or formula Z, or a salt thereof, or other compounds described in the present invention, is provided as an inhibitor of galectin-3-mediated binding between cancer cells and endothelial cells. A method (in vitro or in vivo) for inhibiting galectin-3-mediated binding between cancer cells and endothelial cells is also provided, the method comprising administering an effective amount of a compound of formula X or formula Y or formula Z, or a salt thereof, or other compounds described in the present invention. Furthermore, a compound of formula X or formula Y or formula Z, or a salt thereof, or other compounds described in the present invention, is provided for inhibiting the interaction between galectin-3 and its binding ligands (e.g., mucins, growth factors, growth factor receptors, adhesion molecules, immune checkpoint molecules, other cell surface or intracellular molecules, matrix molecules). In addition, one or more of compound X, Y, or Z, or salts thereof, or other compounds of the present invention (e.g., compound W), are provided as inhibitors of the interaction between intracellular and extracellular galactolectin-3 and its binding ligands. A method (in vitro or in vivo) for inhibiting the binding activity of galactolectin-3 to cancer-associated cell membrane proteins is also provided, the method comprising administering an effective amount of compound X, Y, or Z, or salts thereof, or other compounds of the present invention.

[0223] Example

[0224] The present invention will be described through the following embodiments.

[0225] Example 1 - Compounds X, Y, and Z inhibit the binding of galactolectin-3 to its ligand desialylated fetoglobulin (ASF).

[0226] Figure 1A , Figure 1B and Figure 1C This demonstrates that compounds X, Y, and Z inhibit the binding of galactolectin-3 to its ligand desialylated fetoglobulin (ASF). Using ELISA, different concentrations of compound X (Figure 1, Figure <A) and compound Y (Figure 2) were observed in the absence or presence of these compounds. Figure 1B ) or compound of formula Z ( Figure 1C Under certain conditions, the binding of galactolectin-3 (5 μg / ml) to desialized fetoglobulin (ASF, 20 μg / ml) was detected. Compounds X, Y, and Z inhibited the binding of galactolectin-3 to ASF in a dose-dependent manner.

[0227] Example 2 - Determination of the binding affinity of compound X to galactolectin-3

[0228] Figure 2A , Figure 2B , Figure 2C and Figure 2D The binding affinity analysis of compounds X, Y, and Z with galactolectin-3 is shown. The binding affinity analysis of compound X with the full-length ( Figure 2A ) and C-terminal (aa 115–250) galactolectin-3 ( Figure 2B The binding of compound Y is shown. Figure 2C ) and compound Z ( Figure 2D The binding affinity of compound X to galactolectin-3 was assessed using tryptophan fluorescence spectroscopy (TFS). The binding affinity (KD) of compound X to full-length and C-terminal galactolectin-3 was 5–7 μM. The binding affinity (KD) of compound Y to full-length galactolectin-3 was approximately 90 μM. The binding affinity (KD) of compound Z to full-length galactolectin-3 was approximately 35 μM.

[0229] Example 3 - Inhibiting the adhesion of cancer cells to vascular endothelial cells

[0230] Figure 3A and Figure 3B Compound X was shown to inhibit the adhesion of cancer cells to vascular endothelial cells. Human melanoma ACA19 cells were tested in the absence or presence of galactolectin-3 (2 μvg / ml) and different concentrations of compound X. Figure 3A ) and colon cancer SW620 cells ( Figure 3BCompound X inhibited the adhesion of SW620 and ACA19 cells to human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner. ***P<0.001, **P<0.01, *P<0.05 (ANOVA).

[0231] Figure 4A and Figure 4B Compounds Y and Z were shown to inhibit the adhesion of cancer cells to vascular endothelial cells. In the absence or presence of galactolectin-3 (2 μg / ml) and different concentrations of compound Y (…),… Figure 4A ) or compound of formula Z ( Figure 4B Under these conditions, the adhesion of human colon cancer SW620 cells to human umbilical vein endothelial cells (HUVECs) was examined. Both compounds inhibited galactolectin-3-induced adhesion of SW620 cells to HUVECs in a dose-dependent manner.

[0232] Example 4 - Determination of the invasive ability of cancer cells to penetrate HUVECs

[0233] Figure 5A and Figure 5B Compound X was shown to inhibit the invasion of cancer cells through vascular endothelial cells. Human melanoma ACA19 cells were detected using Transwell chambers in the absence or presence of compound X (20 μM) or the galactolectin-3 disaccharide inhibitor lactose (Lac, 100 μM). Figure 5A ) and colon cancer SW620 cells ( Figure 5B Invasive invasion of human umbilical vein endothelial cells (HUVECs). Compound X significantly inhibited galactolectin-3-mediated invasion of ACA19 and SW620 cells through HUVECs. ***P<0.001, *P<0.05 (ANOVA).

[0234] Figure 6A and Figure 6B This study demonstrates how compounds Y and Z inhibit cancer cell invasion through vascular endothelial cells. The invasion of human colon cancer SW620 cells through human umbilical vein endothelial cells (HUVECs) was detected using Transwell chambers in the absence or presence of galectin-3 (1 μg / ml), the galectin-3 disaccharide inhibitor lactose (100 μM), compound Y, or compound Z. Figure 6A ) and compound Z ( Figure 6B Both inhibited galactolectin-3-mediated invasion of SW620 cells through HUVECs in a dose-dependent manner, with effects similar to those of the galactolectin-3 inhibitor lactose.

[0235] Example 6 - Inhibition of tubular structure formation in vascular cells (angiogenesis)

[0236] Figure 7A and Figure 7B Compound X was shown to inhibit the formation of tubular structures in vascular cells (angiogenesis). The formation of tubular structures in human umbilical vein endothelial cells (HUVECs) was detected in the absence or presence of galactolectin-3 (2 μg / ml) and compound X (10 μM). The length of the tubular structures was measured... Figure 7A ) and the number of tubular structures ( Figure 7B When galactoglobulin-3 was present, the presence of compound X significantly inhibited the formation of tubular structures in vascular cells induced by galactoglobulin-3. ***P<0.001 (ANOVA).

[0237] Figure 8A , Figure 8B , Figure 8C and Figure 8D Compounds Y and Z were shown to inhibit the formation of tubular structures in vascular cells (angiogenesis). The effects of galactolectin-3 (2 μg / ml) and different concentrations of compound Y were observed in the absence or presence of galactolectin-3 (2 μg / ml). Figure 8A and Figure 8C ) or compound of formula Z ( Figure 8B and Figure 8D Under these conditions, the formation of vascular tubular structures in human umbilical vein endothelial cells (HUVECs) was examined. When measuring the length of the vascular tubular structures (…),… Figure 8A and Figure 8B ) and the number of tubular structures ( Figure 8C and Figure 8D When either compound Y or compound Z was present, the formation of tubular structures in vascular cells was inhibited in a dose-dependent manner. *P<0.05, ***P<0.001 (ANOVA).

[0238] Example 7 - Determination of the cytotoxicity of the compound

[0239] Figure 9A , Figure 9B , Figure 9C and Figure 9D Compounds X, Y, and Z were shown to have low or almost no toxicity. The effects of compound X on human colon cancer SW620 cells were evaluated using a lactate dehydrogenase (LDH) release assay, in the absence or presence of different concentrations of compound X. Figure 9A ) and vascular endothelial HUVECs cells ( Figure 9BThe cytotoxicity of compound X to human HUVEC cells and SW620 cells was assessed. At a concentration of 100 μM, compound X showed no significant cytotoxicity against either human HUVEC or SW620 cells. The effects of compound Y and compound Z on human colon cancer SW620 cells (in the absence of compounds Y and Z, or in the presence of different concentrations) were evaluated using an LDH release assay. Figure 9C ) and vascular endothelial HUVECs cells ( Figure 9D The cytotoxicity of compounds X and Z was low in both human HUVEC and SW620 cells.

[0240] Example 8 - Determination of the selectivity of compound X

[0241] Figure 10A , Figure 10B and Figure 10C The results show that compound X does not affect the binding of galactolectins-2, -4, and -8 to their ligand desialytemoglobin. Galactolectin-2 (Gal-2) was detected using an ELISA method in the absence or in the presence of different concentrations of compound X or the positive control galactolectin inhibitor lactose. Figure 10A ), galactolectin-4 (Gal-4, Figure 10B ) and galactolectin-8 (Gal-8, Figure 10C The binding of compound X (5 μg / ml) to desialized fetoglobulin (ASF, 20 μg / ml) was observed. Compound X did not affect the binding of the above-mentioned galactagglutinin to ASF. Disaccharide lactose inhibited the binding of galactagglutinin-8 to ASF in a dose-dependent manner (positive control). Figure 10C ).

[0242] Example 9 - Determination of macrophage pro-inflammatory cytokine secretion

[0243] Figure 11A , Figure 11B and Figure 11C Compounds X, Y, and Z were shown to inhibit galactolectin-3-induced secretion of the pro-inflammatory cytokine TNFα by macrophages. ELISA was used to measure the inhibitory effects of compounds X, Y, and Z in the absence or presence of galactolectin-3 (10 μg / ml) and at different concentrations of compound X. Figure 11A Compound Y () Figure 11B ) or compound of formula Z ( Figure 11C Under these conditions, the secretion of TNFα by THP-1 differentiated macrophages was analyzed. Galactolectin-3 significantly increased TNFα secretion, while the presence of compounds X, Y, and Z inhibited galactolectin-3-induced TNFα secretion in a dose-dependent manner.

[0244] Figure 12A , Figure 12B and Figure 12C Compounds X, Y, and Z were shown to inhibit galactolectin-3-induced secretion of the pro-inflammatory cytokine IL-1β by macrophages. ELISA was used to measure the inhibitory effects of compounds X, Y, and Z in the absence or presence of galactolectin-3 (10 μg / ml) and at different concentrations of compound X. Figure 12A Compound Y () Figure 12B ) or compound of formula Z ( Figure 12C Under these conditions, the secretion of IL-1β by THP-1 differentiated macrophages was analyzed. Galactolectin-3 significantly increased IL-1β secretion, while the presence of compounds X, Y, and Z inhibited galactolectin-3-induced IL-1β secretion in a dose-dependent manner.

[0245] Example 10 - Inhibiting the adhesion of human lung cancer cells to the basement membrane matrix

[0246] Figure 13 shows compound X ( Figure 13A Compound Y () Figure 13B ) and compound Z ( Figure 13C The compounds inhibited the adhesion of human lung cancer H1975 cells to the basement membrane matrix in a dose-dependent manner. The IC50 of compounds X and Y was approximately 5 μM, and the IC50 of compound Z was approximately 5–10 μM. **P<0.01, ***P<0.001.

[0247] Example 11 - CRISPR / Cas9-based galactoglucosinolate-3 gene knockout in human triple-negative breast cancer MDA-MB-231 cells and pancreatic cancer PANC1 cells

[0248] Figure 14 shows the effects of CRISPR / Cas9 on human triple-negative breast cancer MDA-MB-231 cells ( Figure 14A ) and pancreatic cancer PANC1 cells ( Figure 14B Galactolectin-3 gene knockout was performed. Galactolectin-3 expression levels in control and knockout cells were detected by Western blotting. The same blot membrane was analyzed using an anti-actin antibody to verify protein loading.

[0249] Example 12 - Inhibition of galactolectin-3-mediated adhesion of human triple-negative breast cancer cells to the basement membrane matrix

[0250] Figure 15 illustrates how compounds Y and Z inhibit galactolectin-3-mediated adhesion of human triple-negative breast cancer MDA-MB-231 cells to the basement membrane matrix. Compound Y ( Figure 15A ) and compound Z ( Figure 15BAll three compounds inhibited MDA-MB-231 cell adhesion to the matrix in a dose-dependent manner, with compounds X and Y having an IC50 of approximately 10 μM. Compared to control cells, galactolectin-3 knockout significantly reduced MDA-MB-231 cell adhesion to the matrix. Compound Y ( Figure 15C ) and compound Z ( Figure 15D It significantly reduced the adhesion of untransfected control (con) MDA-MB-231 cells, but had no significant effect on the adhesion of galactolectin-3 knockout (Gal3KO) cells. ***P<0.05, P<0.01, ***P<0.001.

[0251] Example 13 - Inhibition of galactolectin-3-mediated adhesion of human pancreatic cancer cells to the basement membrane matrix

[0252] Figure 16 illustrates how compounds X, Y, and Z inhibit galactolectin-3-mediated adhesion of human pancreatic cancer PANC1 cells to the basement membrane matrix. Compound X ( Figure 16A Compound Y () Figure 16B ) and compound Z ( Figure 16C All three compounds inhibited PANC1 cell adhesion to the matrix in a dose-dependent manner. Compared with control cells, galactolectin-3 knockout significantly reduced PANC1 cell adhesion to the matrix. Compound X ( Figure 16D Compound Y () Figure 16E ) and compound Z ( Figure 16F All three significantly reduced the adhesion of untransfected control (con) PANC1 cells, but had no significant effect on the adhesion of galactolectin-3 knockout (Gal3KO) PANC1 cells. *P<0.05, **P<0.01, ***P<0.001.

[0253] Material

[0254] Monoclonal antibodies against galactolectin-2, -3, -4, or -8, as well as recombinant human galactolectin-8, were purchased from R&D Systems (Abingdon, UK). Horseradish peroxidase (HRP)-labeled anti-mouse antibodies were purchased from Dako (Glostrup, Denmark). FAST OPD substrate tablets and desialyl fetoglobulin (ASF) were purchased from Sigma-Aldrich (Dorset, UK). Falcon 8 μm pore size Transwell chambers and LDH cytotoxicity assay kits were purchased from Thermo Fisher Scientific (Waltham, USA). Matrigel matrix was purchased from BD Biosciences (Wokingham, UK). Fluorescent cell labeling dye DiI was purchased from Molecular Probes (Eugene, OR, USA). HUVEC cells, EBM medium, and EBM-2 Bullet kit were purchased from Lonza (Verviers, Belgium). Recombinant human galectin-2, -3, and -4 were expressed in Escherichia coli according to the method described in the literature [Sindrewicz, P., et al., Intrinsictryptophan fluorescence spectroscopy reliably determines galectin-ligand interactions. Sci Rep, 2019. 9(1): p. 11851]. CRISPR / Cas9 galectin-3 knockout plasmid (sc-417680), galectin-3 HDR plasmid (sc-417680-HD), and plasmid transfection medium (sc-108062) were purchased from Santa Cruz.

[0255] Determination of galactolectin binding to its ligands

[0256] The effect of inhibitors on the binding of galactolectin to its ligand desialized fetoglobulin (ASF) was detected using an ELISA method. 20 μg / ml ASF was used to coat 96-well plates overnight in coating buffer (15 mM Na₂CO₃, 17 mM NaHCO₃, pH 9.6). After washing the wells twice with PBS, blocking buffer (PBS containing 1% BSA) was added and incubated for 1 hour. The supernatant was discarded, and 5 μg / ml recombinant human galactolectin (containing different concentrations of inhibitor or lactose, dissolved in blocking buffer) was added and incubated at room temperature for 1 hour. After washing the plate, 1 μg / ml anti-galactolectin antibody was added and incubated for 2 hours, followed by incubation with HRP-labeled secondary antibody for 1 hour. FAST OPD chromogenic solution was then added and reacted for 15–20 minutes, with the reaction terminated by adding 4 M sulfuric acid. The absorbance was read at 492 nm (reference wavelength 595 nm) using a microplate reader.

[0257] Determination of the binding affinity of the compound to galactolectin-3

[0258] The binding affinity of the inhibitor to galectin-3 was determined using endogenous tryptophan fluorescence spectroscopy (TFS) [Sindrewicz, P., et al., Intrinsictryptophan fluorescence spectroscopy reliably determines galectin-ligand interactions. Sci Rep, 2019. 9(1): p. 11851]. The concentration of galectin-3 was 10 μM, and the titration concentration of the inhibitor ranged from 0 to 224 μM. Titration was performed with DMSO / control buffer (PBS containing 2 mM EDTA) and used for background subtraction.

[0259] Assay of cancer cell adhesion to HUVECs

[0260] Will be 1×10 5 HUVECs cells at a density of 10 cells / ml in EGM medium were seeded into 24-well plates pre-placed with 13 mm slides and cultured at 37°C and 5% CO2 for 24 hours to form a monolayer. ACA19+ or SW620 cell suspensions (5 × 10⁻⁶ cells / ml) were then added. 5 The cells were mixed with 5 μl / ml of fluorescent cell labeling solution DiI (DMEM) and incubated at 37°C for 30 minutes. The fluorescently labeled cells were washed twice with PBS and resuspended in DEM to a final volume of 1×10⁻⁶ cells / ml. 5Cells / ml. Galactolectin-3 (2 μg / ml) and different concentrations of inhibitors were added to the cancer cell suspension and incubated at 37°C for 1 hour. After washing twice with PBS to remove unattached cells, the cells were fixed with 2% paraformaldehyde for 10 minutes. The coverslips were carefully removed from the wells and placed on a slide. A fluorescent mounting medium containing DAPI was added, and the fluorescently labeled cells were quantitatively analyzed under a fluorescence microscope.

[0261] Determination of the invasive ability of cancer cells to penetrate HUVECs

[0262] HUVECs cells were loaded at 1.5 × 10⁻⁶ 4 HUVEC cells were seeded at a density of 1,000 cells / well in 8 μm Transwell chambers of 24-well plates and cultured for 3 days to form a dense monolayer. The integrity of the HUVEC monolayer was determined by TEER, using only cells with a TEER value >800 Ω / cm. 2 Monolayers of cells were used for invasion assays. ACA19+ or SW620 cell suspensions (5 × 10⁻⁶) were prepared. 5 Cells / ml (DMEM) were mixed with 5 μl / ml of fluorescent cell labeling solution DiI and incubated at 37°C for 30 minutes. The fluorescently labeled cells were washed twice with PBS and resuspended in DEM to a final volume of 1×10⁻⁶ cells / ml. 5 Cells / ml. Cancer cell suspensions were incubated at 37°C for 20 minutes with or without galactolectin-3 (2 μg / ml) and different concentrations of compound inhibitors or lactose, and then added to a HUVEC monolayer and cultured at 37°C for 24 hours. Cells in the upper layer of the Transwell chamber were gently wiped with a cotton swab and fixed with 2% paraformaldehyde for 10 minutes. The filter membrane of the Transwell chamber was removed and placed on a glass slide. After adding a fluorescent mounting medium containing DAPI, the fluorescently labeled cells on the membrane were quantitatively analyzed under a fluorescence microscope.

[0263] Effect of inhibitors on angiogenesis assay

[0264] Add 50 μl of Matrigel matrix to a 96-well plate and incubate at 37°C for 60 minutes to gel. Add HUVEC cells (1×10⁶ cells / well) to the plate. 5 Cells / ml, 1:1 EGM / EBM2 medium, cultured at 37°C for 24 hours in the absence or presence of galactolectin-3 (2 μg / ml) and different concentrations of compound inhibitors. The formation of endothelial cell tubular structures was observed using a laser microscope. The total number of branching points and the total length of the tubular structures were measured.

[0265] Compound cytotoxicity assay

[0266] SW620 cells (5 × 10⁻⁶)4 HUVECs (1×10⁻⁶ cells / ml) were seeded in 96-well plates and cultured in DMEM medium at 37°C and 5% CO₂ for 24 hours. 5 Cells were seeded at 1000 cells / ml in EBM medium and cultured for 24–36 hours until a monolayer of cells was formed. Different concentrations of compound inhibitors were then added to the cells (10× lysis buffer was used as the maximum LDH activity control), and incubated for 24 hours. The culture supernatant was transferred to a new plate and mixed with an equal volume of the reaction solution provided in the kit. The mixture was incubated at room temperature for 30 minutes, and then the absorbance was measured at 490 nm using a spectrophotometer (reference wavelength 680 nm).

[0267] Measurement of pro-inflammatory cytokines secreted by macrophages

[0268] Macrophages differentiated from THP-1 monocytes were used to evaluate the effects of inhibitors of tested compounds on the secretion of pro-inflammatory cytokines by macrophages. THP-1 monocytes were induced to differentiate into macrophages by incubation at 37°C for 48 hours with 10 ng / ml PMA. The culture medium was then replaced with fresh medium, and the macrophages were cultured at 37°C for 24 hours in the absence of galactolectin-3 (10 μg / ml) and with different concentrations of inhibitors. The culture medium was collected, and the concentrations of TNFα and IL-1β in the culture medium were detected by TNFα and IL-1β ELISA.

[0269] Measurement of cancer cell adhesion to matrix proteins

[0270] 96-well plates were coated with 50 μl Matrigel (1:30 diluted in PBS) and incubated at 37°C for 1 hour. Cancer cells were pre-labeled with the fluorescent dye DiI at 37°C for 20 minutes, followed by washing twice with PBS and resuspending in serum-free medium to a final volume of 3 × 10⁻⁶. 4 Cells / ml. The 96-well plates coated with the matrix were washed twice with PBS, then 100 μl of cell suspension containing different concentrations of inhibitors or PBS / DMSO (control) was added, and incubated at 37°C for 1 hour. After washing the plates twice with PBS, three fields of view (FOV) were randomly selected under a fluorescence microscope for imaging, and the number of adherent cells was quantitatively analyzed using ImageJ software.

[0271] Crispr / Cas9-mediated galactoglucosidin-3 gene knockout

[0272] MDA-MB-231 or PANC-1 cells were seeded in 6-well plates (2 × 10⁶ cells per well). 5Cells were cultured at 37°C for 24 hours. The galactolectin-3 CRISPR / Cas9 knockout plasmid (2 μg) and galactolectin-3 HDR plasmid (2 μg) were mixed with 21 μl of plasmid transfection medium for 5 minutes. Then, a mixture of Lipofectamine STEM transfection reagent (STEM00001, 1 μl) and plasmid transfection medium (25 μl) was added, and the mixture was incubated at room temperature for 10 minutes. Cells in 6-well plates were washed, and the plasmid DNA / Lipofectamine STEM transfection reagent complex was added. The cells were cultured at 37°C for 24 hours. After replacing the medium with antibiotic-free fresh medium for another 24 hours, medium containing 10 μg / ml puromycin was added every 3 days. Successful co-transfection of the CRISPR / Cas9 knockout plasmid and HDR plasmid was confirmed by red fluorescent protein expression in the cells, and the knockout of the galactolectin-3 gene was further confirmed by Western blotting.

[0273] Those skilled in the art should understand that various improvements and modifications can be made to the above embodiments without departing from the scope of protection of this invention, and all such improvements and modifications should fall within the scope of protection of this invention.

Claims

1. A composition comprising: a compound of formula X or a pharmaceutically acceptable salt thereof, and / or a compound of formula Y or a pharmaceutically acceptable salt thereof, and / or a compound of formula Z or a pharmaceutically acceptable salt thereof, said composition for inhibiting galactoglucan-3.

2. The composition of claim 1, wherein the composition is used to treat and / or prevent a disease, symptom, condition or illness, wherein inhibition of galactoglucan-3 is beneficial to the treatment and / or prevention of said disease, symptom, condition or illness.

3. The composition of claim 2, wherein the disease, condition, state, or ailment is cancer, cancer metastasis, fibrosis, inflammation, diabetes, and / or one or more other diseases, conditions, states, or ailments affected and / or mediated by galactolectin-3.

4. A composition comprising: a compound of formula X or a pharmaceutically acceptable salt thereof, and / or a compound of formula Y or a pharmaceutically acceptable salt thereof, and / or a compound of formula Z or a pharmaceutically acceptable salt thereof, said composition for treating and / or preventing a disease, condition, state, or ailment, said disease, condition, state, or ailment being cancer, cancer metastasis, fibrosis, diabetes, inflammation, and / or one or more other diseases, conditions, states, or ailments affected and / or mediated by galactolectin-3.

5. The composition according to any one of claims 2 to 4, wherein the disease, symptom, condition or illness is cancer, and wherein the treatment and / or prevention of the cancer includes inhibition or prevention of metastasis, cancer recurrence after initial treatment or intervention, cancer cell proliferation, tumor growth, angiogenesis or immunosuppression.

6. The composition according to any one of claims 2 to 4, wherein the disease, symptom, condition or illness is cancer metastasis, and wherein the treatment and / or prevention of said cancer metastasis includes inhibiting the motility of cancer or tumor cells, inhibiting angiogenesis, inhibiting immunosuppression, inhibiting the spread and invasiveness of cancer cells thereby inhibiting metastatic tumor growth, and inhibiting the spread and invasiveness of cancer cells thereby improving the clinical outcomes of the subject.

7. The composition according to any one of claims 2 to 6, wherein the cancer is one or more of the following: breast cancer, triple-negative breast cancer, pancreatic cancer, lung cancer, melanoma, colorectal cancer, head and neck cancer, ovarian cancer, esophageal cancer, thyroid cancer, bladder cancer, urinary system cancer, prostate cancer, digestive or gastrointestinal cancer, leukemia, lymphoma, liver cancer, or musculoskeletal cancer.

8. The composition according to any one of claims 2 to 4, wherein the disease, condition, state, or ailment is fibrosis, and wherein the treatment and / or prevention of the fibrosis includes treating / preventing fibrotic conditions, fibrotic ailments, fibrotic disorders, or uncontrolled wound healing reactive conditions or states.

9. The composition of claim 8, wherein the fibrotic condition, fibrotic disease, fibrotic disorder, or uncontrolled wound healing reactive condition or condition is one or more of the following: abnormal scar formation or wound healing, chronic or acute inflammation, chronic graft rejection, or fibrotic condition or fibrosis affecting the heart, brain, lungs, liver, kidneys, cardiac or vascular system, mediastinum, bones, retroperitoneal space, skin, digestive or gastrointestinal tract, connective tissue, eyes, or muscles.

10. The composition according to any one of claims 2 to 4, wherein the disease, symptom, condition or illness is inflammation, and wherein the treatment and / or prevention of the inflammation includes treating / preventing inflammation-related diseases or illnesses caused by inflammation.

11. The composition of claim 10, wherein the inflammation-related disease or condition caused by inflammation is one or more of the following: acute or chronic organ transplant rejection, graft-versus-host disease, inflammatory bowel disease, inflammatory dermatitis, multiple sclerosis, arteriosclerosis, pancreatitis, acute bronchitis, chronic bronchitis, Alzheimer's disease, inflammatory lung disease, inflammatory dermatitis, acute bronchiolitis, folliculitis, chronic bronchiolitis, musculoskeletal pain or connective tissue inflammation, osteoarthritis, gout, spondyloarthritis, Reiter's syndrome, psoriatic arthritis, inflammation caused by one or more diseases related to bacterial, fungal, and viral infections, atherosclerosis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome, nephritis, Parkinson's disease, chronic inflammation. Inflammatory symptoms caused by chronic inflammation and aging-related tumors resulting from chronic inflammation, including ulcerative colitis and Crohn's disease, lupus erythematosus, hyperthyroidism, IgA nephritis, type I or II diabetes and its complications, dry eye syndrome, rheumatoid arthritis, simple obesity, ankylosing spondylitis, bronchial asthma, neurodermatitis, ulcerative colitis, oral ulcers, psoriasis, vitiligo, Behcet's disease, autoimmune iridocyclitis, autoimmune eczema, autoimmune uveitis, autoimmune conjunctivitis, autoimmune dry eye, autoimmune glaucoma, autoimmune cataracts, allergic rhinitis, irritable bowel syndrome, and pruritus.

12. The composition according to any one of claims 2 to 4, wherein the disease, condition, state, or ailment is diabetes, and wherein the treatment and / or prevention of the fibrosis comprises treatment / prevention of type I or type II diabetes and / or any associated diabetes-related disease or ailment, such as obesity.

13. The composition according to any one of claims 2 to 4, wherein the disease, condition, state, or symptom is one or more other diseases, conditions, states, or symptoms affected and / or mediated by galactolectin-3, preferably wherein the one or more other diseases, conditions, states, or symptoms affected and / or mediated by galactolectin-3 are asthma, atherosclerosis, atopic dermatitis, cerebral infarction, COPD, degenerative aortic stenosis, endometriosis, encephalitis, gastritis, HIV infection, interstitial lung disease, juvenile idiopathic arthritis, fatal cardiovascular disease, non-alcoholic steatohepatitis, obesity, pneumonia, pulmonary hypertension, plaque psoriasis, Q fever, rheumatoid arthritis, systemic sclerosis, urinary tract infection, COVID-19, sepsis, thrombosis, venous thrombosis, wound healing, cardiac syndrome X, yeast infection-candidiasis, or herpes zoster-related pain (hyperalodynia).

14. The composition according to any one of the preceding claims, wherein the composition further comprises one or more pharmaceutically or cosmetically acceptable ingredients or excipients, preferably one or more of the following: pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants, wetting agents, flavor masking agents, colorants, fragrances, and penetrants, preferably wherein the composition is in a form suitable for oral use.

15. The composition according to any one of the preceding claims, wherein the compound of formula X and / or the compound of formula Y and / or the compound of formula Z is a metabolic form and / or a hydrolyzed form and / or an oxidized form, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

16. The composition according to any one of the preceding claims, wherein the composition further comprises one or more other active agents, preferably one or more additional antitumor agents, and / or chemotherapeutic agents, and / or antimetastatic agents and / or radiotherapy agents and / or immunotherapy agents and / or antifibrotic agents and / or anti-inflammatory agents and / or one or more other galactoglobulin inhibitors.

17. A method for inhibiting galactoglucan-3 in vitro or in vivo, the method comprising administering an effective amount of the composition according to any one of claims 1 to 16.

18. A method for treating and / or preventing a disease, symptom, state, or condition, wherein inhibition of galactoglucan-3 is beneficial for the treatment of said disease, symptom, state, or condition, said method comprising administering to a subject an effective amount of the composition according to any one of claims 1 to 16.

19. The method of claim 18, wherein the disease, symptom, condition or illness is cancer, cancer metastasis, fibrosis, inflammation, diabetes and / or one or more other diseases, symptoms, conditions or illnesses affected and / or mediated by galactolectin-3.

20. A method for treating and / or preventing a disease, condition, state, or illness, wherein the disease, condition, state, or illness is cancer, cancer metastasis, fibrosis, inflammation, diabetes, and / or one or more other diseases, conditions, states, or illnesses affected and / or mediated by galactolectin-3, the method comprising administering to a subject an effective amount of the composition according to any one of claims 1 to 16.

21. The method according to any one of claims 17 to 20, wherein the disease, symptom, condition or illness is cancer, and wherein the treatment and / or prevention of the cancer includes suppression of metastasis, cancer recurrence after initial treatment or intervention, cancer cell proliferation, tumor growth, angiogenesis or immunosuppression.

22. The method according to any one of claims 17 to 20, wherein the disease, symptom, state, or condition is cancer metastasis, and wherein the treatment and / or prevention of said cancer metastasis includes inhibiting the motility of cancer or tumor cells, inhibiting angiogenesis, inhibiting immunosuppression, inhibiting the spread and invasiveness of cancer cells to inhibit metastatic tumor growth, or inhibiting the spread and invasiveness of cancer cells to improve the clinical outcomes of the subject.

23. The method according to any one of claims 19 to 22, wherein the cancer is one or more of the following: breast cancer, pancreatic cancer, lung cancer, melanoma, colorectal cancer, head and neck cancer, ovarian cancer, esophageal cancer, thyroid cancer, bladder cancer, urinary system cancer, prostate cancer, digestive or gastrointestinal cancer, leukemia, lymphoma, liver cancer, or musculoskeletal cancer.

24. The method according to any one of claims 17 to 20, wherein the disease, condition, state, or ailment is fibrosis, and wherein the treatment and / or prevention of the fibrosis includes treating / preventing fibrotic conditions, fibrotic ailments, fibrotic disorders, or uncontrolled wound healing reactive conditions or states.

25. The method of claim 24, wherein the fibrotic condition, fibrotic disease, fibrotic disorder, or uncontrolled wound healing reactive condition or condition is one or more of the following: abnormal scar formation or wound healing, chronic or acute inflammation, chronic graft rejection, or fibrotic condition or fibrosis affecting the heart, brain, lungs, liver, kidneys, cardiac or vascular system, mediastinum, bones, retroperitoneal space, skin, digestive or gastrointestinal tract, connective tissue, eyes, or muscles.

26. The method according to any one of claims 17 to 20, wherein the disease, symptom, condition or illness is inflammation, and wherein the treatment and / or prevention of the inflammation includes treating / preventing inflammation-related diseases or illnesses caused by inflammation.

27. The method of claim 26, wherein the inflammation-related disease or condition caused by inflammation is one or more of the following: acute or chronic organ transplant rejection, graft-versus-host disease, inflammatory bowel disease, inflammatory skin disease, multiple sclerosis, arteriosclerosis, pancreatitis, acute bronchitis, chronic bronchitis, Alzheimer's disease, inflammatory lung disease, inflammatory skin disease, acute bronchiolitis, folliculitis, chronic bronchiolitis, musculoskeletal pain or connective tissue inflammation, osteoarthritis, gout, spondyloarthritis, Reiter's syndrome, psoriatic arthritis, one or more inflammation-related diseases caused by bacterial, fungal, and viral infections, atherosclerosis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome, nephritis, Parkinson's disease, chronic inflammation. One or more neurodegenerative diseases or conditions caused by chronic inflammation and aging-related tumors caused by chronic inflammation; inflammatory symptoms caused by autoimmune diseases, including ulcerative colitis and Crohn's disease, lupus erythematosus, hyperthyroidism, IgA nephritis, type I or type II diabetes and its complications, dry eye syndrome, rheumatoid arthritis, simple obesity, ankylosing spondylitis, bronchial asthma, neurodermatitis, ulcerative colitis, oral ulcers, psoriasis, vitiligo, Behcet's disease, autoimmune iridocyclitis, autoimmune eczema, autoimmune uveitis, autoimmune conjunctivitis, autoimmune dry eye, autoimmune glaucoma, autoimmune cataracts, allergic rhinitis, irritable bowel syndrome, and pruritus.

28. The method of any one of claims 17 to 20, wherein the disease, condition, state, or ailment is diabetes, and wherein the treatment and / or prevention of the fibrosis includes treatment / prevention of type I or type II diabetes and / or any associated diabetes-related disease or condition, such as obesity.

29. The method according to any one of claims 17 to 20, wherein the disease, symptom, state, or condition is one or more other diseases, symptoms, states, or conditions affected and / or mediated by galactolectin-3, preferably wherein the one or more other diseases, symptoms, states, or conditions affected and / or mediated by galactolectin-3 are asthma, atherosclerosis, atopic dermatitis, cerebral infarction, COPD, degenerative aortic stenosis, endometriosis, encephalitis, gastritis, HIV infection, interstitial lung disease, juvenile idiopathic arthritis, fatal cardiovascular disease, non-alcoholic steatohepatitis (NASH), obesity, pneumonia, pulmonary hypertension, plaque psoriasis, Q fever, rheumatoid arthritis, systemic sclerosis, urinary tract infection, COVID-19, sepsis, thrombosis, venous thrombosis, wound healing, cardiac syndrome X, yeast infection-candidiasis, or herpes zoster-related pain (hyperalodynia).

30. The method according to any one of claims 17 to 29, wherein the composition is administered simultaneously or sequentially in combination with one or more other treatments, preferably wherein the one or more other treatments are one or more of chemotherapy, radiotherapy, immunotherapy, surgery, and / or surgical methods for cancer treatment, preferably debulking surgery or cryosurgery.

31. The method according to any one of claims 17 to 30, wherein the method further comprises determining the level of galactolectin-3 or the expression of LGALS3 in the subject, and / or wherein the method further comprises determining the level of galactolectin-3 or the expression of LGALS3 in a biological sample obtained from the subject.

32. The method of claim 31, wherein the subject is suspected of having a disease, condition, state, or illness related to galactoglobulin-3 expression, or wherein the subject is known to have a disease, condition, state, or illness related to galactoglobulin-3 expression.

33. The method according to claim 31 or claim 32, wherein the biological sample is tumor tissue, suspected tumor tissue, tissue biopsy sample, mucus, feces, tears, urine, blood, serum, cell extract, biopsy specimen and / or fluid that has been introduced into an individual and subsequently removed.

34. The method according to any one of claims 31 to 33, wherein before administering an effective amount of the composition according to any one of claims 1 to 16 to the subject, the level of galactolectin-3 or the expression of LGALS3 or the level of LGALS3 expression in the subject is determined, preferably: the administration is performed when any expression of galactolectin-3 or any expression of LGALS3 is detected in a biological sample obtained from the subject; and / or the administration is performed when the level of galactolectin-3 or the expression of LGALS3 or the level of LGALS3 expression is found to be overexpressed or above baseline or above reference value in a biological sample obtained from the subject.

35. The composition according to any one of claims 1 to 16 is used to manufacture a medicament for the prevention and / or treatment of cancer, cancer metastasis, fibrosis, inflammation, diabetes, and / or one or more other diseases, symptoms, states or conditions affected and / or mediated by galactolectin-3, and / or the composition according to any one of claims 1 to 16 is used to manufacture a medicament for inhibiting galactolectin-3.

36. A method for inhibiting galactoglucan-3 in a patient or in a biological sample, the method comprising administering to the patient or exposing the biological sample to a compound of formula X or a pharmaceutically acceptable salt thereof, and / or a compound of formula Y or a pharmaceutically acceptable salt thereof, and / or a compound of formula Z or a pharmaceutically acceptable salt thereof.

37. A reagent kit comprising individually packaged, dispensed, or separately measured effective amounts of one or more of the following substances: Compound X, compound Y, compound Z, a composition comprising compound X, a composition comprising compound Y, a composition comprising compound Z, a composition comprising two or more of compounds X, Y and Z, and / or a pharmaceutically acceptable salt or pharmaceutical preparation of any one thereof, and optionally comprising an effective amount of another active ingredient and / or instructions for use.

38. A combination product for treating cancer, fibrosis, diabetes, inflammation, cancer metastasis, and / or one or more other diseases, conditions, states, or illnesses affected and / or mediated by galactolectin-3, comprising the composition according to any one of claims 1 to 16, and another antitumor agent and / or antimetastatic agent and / or chemotherapeutic agent, and / or radiotherapy agent, and / or immunotherapy agent, and / or antifibrotic agent and / or antiinflammatory agent and / or one or more other galactolectin inhibitors.

39. A pharmaceutical composition comprising: a compound of formula X or a pharmaceutically acceptable salt thereof, and / or a compound of formula Y or a pharmaceutically acceptable salt thereof, and / or a compound of formula Z or a pharmaceutically acceptable salt thereof, in combination with an antitumor agent and / or an antimetastatic agent and / or a chemotherapeutic agent, and / or a radiotherapy agent and / or an immunotherapy agent.

40. The pharmaceutical composition of claim 39, wherein it is used to inhibit galactolectin-3, preferably, wherein the composition is used to treat and / or prevent a disease, condition, state, or ailment, wherein inhibition of galactolectin-3 is beneficial to the treatment and / or prevention of said disease, condition, state, or ailment, preferably, wherein said disease, condition, state, or ailment is cancer, cancer metastasis, fibrosis, inflammation, diabetes, and / or one or more other diseases, conditions, states, or ailments affected and / or mediated by galactolectin-3.

41. A method of treating a subject suffering from cancer, fibrosis, inflammation, diabetes, cancer metastasis, and / or one or more other diseases, conditions, states, or ailments affected and / or mediated by galactolectin-3, the method comprising administering to the subject a therapeutically effective amount of the composition according to any one of claims 1 to 16, concurrently, sequentially, or separately with surgery and / or at least one additional antitumor agent and / or antimetastatic agent and / or chemotherapeutic agent, and / or radiotherapy agent, and / or immunotherapy agent and / or antifibrotic agent and / or antiinflammatory agent and / or one or more other galactolectin inhibitors.

42. The composition according to any one of claims 1 to 16, used simultaneously, sequentially, or separately, with at least one additional antitumor agent and / or antimetastatic agent and / or chemotherapeutic agent, and / or radiotherapy agent and / or immunotherapy agent and / or antifibrotic agent and / or anti-inflammatory agent and / or one or more other galactoglobulin inhibitors, for the treatment of cancer, fibrosis, diabetes, inflammation, cancer metastasis, and / or one or more other diseases, conditions, states, or illnesses affected and / or mediated by galactoglobulin-3.

43. A compound of formula X, and / or a compound of formula Y and / or a compound of formula Z, or a pharmaceutically acceptable salt thereof, or a combination thereof, used as a medicine.

44. A compound of formula X, and / or a compound of formula Y and / or a compound of formula Z, or a pharmaceutically acceptable salt thereof, or a combination thereof, for the treatment and / or prevention of a disease, symptom, condition or illness, preferably wherein said disease, symptom, condition or illness is cancer, cancer metastasis, fibrosis, inflammation or diabetes.

45. A method of treating and / or preventing a disease, symptom, state, or condition, the method comprising administering to the subject a composition comprising a compound of formula X or a pharmaceutically acceptable salt thereof, and / or a compound of formula Y or a pharmaceutically acceptable salt thereof, and / or a compound of formula Z or a pharmaceutically acceptable salt thereof, preferably wherein the disease, symptom, state, or condition is cancer, cancer metastasis, fibrosis, inflammation, and / or diabetes.

46. ​​A method for preventing, controlling, improving, and / or treating a disease, symptom, state, or condition, preferably wherein the disease, symptom, state, or condition is cancer, cancer metastasis, fibrosis, inflammation, and / or diabetes, the method comprising administering to a subject in need a therapeutically effective amount of a composition comprising a compound of formula X or a pharmaceutically acceptable salt thereof, and / or a compound of formula Y or a pharmaceutically acceptable salt thereof, and / or a compound of formula Z or a pharmaceutically acceptable salt thereof, and / or the method comprising administering more than one composition comprising a compound of formula X and / or a compound of formula Y and / or a compound of formula Z or a pharmaceutically acceptable salt thereof.

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