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Building IP: BMY Patent Grant re "Small molecule inhibitors of Galectin-3"
Small molecule inhibitors of Galectin-3 The present disclosure relates to compounds of formula I, which inhibit Gal-3, and include pharmaceutically acceptable salts, compositions comprising such compounds, and methods using and making such compounds and compositions. ##STR00001##
Primary Examiner: Berry; Layla D Attorney, Agent or Firm: We claim: 1. A compound of formula I ##STR00080## where: Ar.sup.1 is phenyl and is substituted with 0-5 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; Ar.sup.2 is phenyl or pyridinyl and is substituted with 0-5 substituents selected from cyano, halo, alkyl, (R.sup.3)alkyl, haloalkyl, cycloalkyl, (R.sup.3)cycloalkyl, alkoxy, cycloalkoxy, haloalkoxy, and alkoxycarbonyl; R.sup.1 is hydrogen, halo, alkoxy, cyanoalkoxy, hydroxyalkoxy, alkoxyalkoxy, (R.sup.4)alkoxy, or (R.sup.4)alkenyloxy; R.sup.2 is alkyl, cycloalkyl, alkoxycarbonyl, carboxy, CON(R.sup.12)(R.sup.13), or Ar.sup.2; R.sup.3 is cyano, halo, alkoxy, or (R.sup.5)(R.sup.6)N; R.sup.4 is (R.sup.7)(R.sup.8)N, CO.sub.2(R.sup.9), or CON(R.sup.10)(R.sup.11); R.sup.5 is hydrogen or alkyl; R.sup.6 is hydrogen or alkyl; or (R.sup.5)(R.sup.6)N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, (oxo)thiomorpholinyl, (dioxo)thiomorpholinyl, homopiperidinyl, or homopiperazinyl; R.sup.7 is hydrogen or alkyl; R.sup.8 is hydrogen or alkyl; or (R.sup.7)(R.sup.8)N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or morpholinyl-N-oxide; R.sup.9 is hydrogen or alkyl; R.sup.10 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or spiro[3.3]heptanol; R.sup.11 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; or (R.sup.10)(R.sup.11)N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, (oxo)thiomorpholinyl, (dioxo)thiomorpholinyl, homopiperidinyl, or homopiperazinyl, and is substituted with 0-4 substituents selected from halo, alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, oxo, and acetamido; R.sup.12 is hydrogen, alkyl, or cycloalkyl; R.sup.13 is hydrogen or alkyl; or (R.sup.12)(R.sup.13)N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-3 substituents selected from halo and alkyl; X is S, SO, or SO.sub.2; and Y is imidazolyl or triazolyl; or a pharmaceutically acceptable salt thereof. 2. A compound of claim 1 where Ar.sup.1 is phenyl or pyridinyl, and is substituted with 0-5 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; Ar.sup.2 is phenyl or pyridinyl and is substituted with 0-5 substituents selected from cyano, halo, alkyl, (R.sup.3)alkyl, haloalkyl, cycloalkyl, (R.sup.3)cycloalkyl, alkoxy, cycloalkoxy, haloalkoxy, and alkoxycarbonyl; R.sup.1 is alkoxy, or (R.sup.4)alkoxy; and R.sup.2 is Ar.sup.2. 3. A compound of claim 1 where Ar.sup.1 is phenyl substituted with 0-5 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; Ar.sup.2 is phenyl substituted with 0-5 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; and R.sup.1 is alkoxy, cyanoalkoxy, alkoxyalkoxy, or (R.sup.3)alkoxy; or a pharmaceutically acceptable salt thereof. 4. A compound of claim 1 where Ar.sup.2 is phenyl substituted with 3 halo substituents. 5. A compound of claim 1 where R.sup.1 is alkoxy or (R.sup.4)alkoxy. 6. A compound of claim 1 where Y is triazolyl. 7. A compound of claim 1 selected from the group consisting of ##STR00081## or a pharmaceutically acceptable salt thereof. 8. A composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 9. A method for treating liver fibrosis, kidney fibrosis, lung fibrosis, heart fibrosis, skin fibrosis, acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis, liver hypofunction, hepatic blood flow disorder, solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia, invasive metastasis of cancer cell, psoriasis, nephropathy, pneumonia, irritable bowel syndrome, inflammatory bowel disease, abnormal pancreatic secretion, neuropathic pain, peripheral neuropathy, age-related macular degeneration, or diabetic retinopathy, comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a patient. 10. A method for treating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, or systemic sclerosis, comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a patient. 11. A composition comprising a therapeutically effective amount of a compound of claim 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 12. A composition comprising a therapeutically effective amount of a compound of claim 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 13. A composition comprising a therapeutically effective amount of a compound of claim 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 14. A composition comprising a therapeutically effective amount of a compound of claim 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 15. A composition comprising a therapeutically effective amount of a compound of claim 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 16. A composition comprising a therapeutically effective amount of a compound of claim 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 17. A method for treating liver fibrosis, kidney fibrosis, lung fibrosis, heart fibrosis, skin fibrosis, acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis, liver hypofunction, hepatic blood flow disorder, solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia, invasive metastasis of cancer cell, psoriasis, nephropathy, pneumonia, irritable bowel syndrome, inflammatory bowel disease abnormal pancreatic secretion, neuropathic pain, peripheral neuropathy, age-related macular degeneration, or diabetic retinopathy, comprising administering a therapeutically effective amount of a compound of claim 6, or a pharmaceutically acceptable salt thereof, to a patient. 18. A method for treating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, or systemic sclerosis, comprising administering a therapeutically effective amount of a compound of claim 6, or a pharmaceutically acceptable salt thereof, to a patient. 19. A method for treating liver fibrosis, kidney fibrosis, lung fibrosis, heart fibrosis, skin fibrosis, acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis, liver hypofunction, hepatic blood flow disorder, solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia, invasive metastasis of cancer cell, psoriasis, nephropathy, pneumonia, irritable bowel syndrome, inflammatory bowel disease abnormal pancreatic secretion, neuropathic pain, peripheral neuropathy, age-related macular degeneration, or diabetic retinopathy, comprising administering a therapeutically effective amount of a compound of claim 7, or a pharmaceutically acceptable salt thereof, to a patient. 20. A method for treating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, or systemic sclerosis, comprising administering a therapeutically effective amount of a compound of claim 7, or a pharmaceutically acceptable salt thereof, to a patient. CROSS REFERENCE TO RELATED APPLICATION This application is a 371 of International Application No. PCT/US2018/055192 filed on Oct. 10, 2018, which claims the benefit of U.S. Provisional Application 62/570,821 filed Oct. 11, 2017, the entire content of which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION Galectin-3 (Gal-3) is a .beta.-galactoside binding lectin of about 30 KDa (Cell 76: 597-598), that is involved in the regulation of inflammatory and fibrotic processes. (Immunological Reviews 230: 160-171). Under uncontrolled inflammation and profibrotic condition, Gal-3 promotes fibroblast proliferation and transformation and mediates collagen production (Circulation 110:3121-3128). Gal-3 is localyzed in many cellular location such as cytoplasm, nucleus, and cell surface. Gal-3 is also secreted by various cell types, mainly macrophages and monocytes into the blood stream (J Pharmacol Exp Ther 351:336-343). There are multiple lines of evidence in the literature supporting the involment of Gal-3 in the development of fibrotic process in multiple organs such as lung (Am J. Respir. Crit. Care Med. 185: 537-546), liver (PNAS 103:5060-5065) and kidney (Am. J. Pathol. 172:288-298). Gal-3 has also been identified as a biomarker for heart failure indicating that modulation of Gal-3 has potential uses in the treatment of heart failure (Curr. Heart Fail. Rep. 7:1-8). Modulation of Gal-3 can be used in the treatment of cancer since Gal-3 is involved in cell growth and differentiation playing a critical role in angiogenic, apoptotic, and metastatic pathways (Galectin-3C: Human Lectin for Treatment of Cancer. ACS Symposium Series, Vol. 1115. Chapter 12, 195-23). Recently, Gal-3 inhibitors have proven to have positive effects when used in combination immunotherapy (Galectin Therapeutics. Press Release, Feb. 7, 2017). Several publications and patent applications describe synthetic inhibitors of Gal-3 that are being explored as antifibrotic agents. Recent examples of these approach are WO2005113568, WO2005113569, US2014067986, WO2014067986, WO2017080971, WO2016120403, US20140099319 and WO2014067986. DESCRIPTION OF THE INVENTION The present disclosure relates to compounds of formula I, which inhibit Gal-3, and include pharmaceutically acceptable salts, compositions comprising such compounds, and methods using and making such compounds and compositions. One aspect of the invention is a compound of formula I ##STR00002## where: Ar.sup.1 is phenyl, pyridinyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, or benzodioxolyl, and is substituted with 0-5 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; or Ar.sup.1 is pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl, and is substituted with 0-1 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; Ar.sup.2 is phenyl or pyridinyl and is substituted with 0-5 substituents selected from cyano, halo, alkyl, (R.sup.3)alkyl, haloalkyl, cycloalkyl, (R.sup.3)cycloalkyl, alkoxy, cycloalkoxy, haloalkoxy, and alkoxycarbonyl; R.sup.1 is hydrogen, halo, alkoxy, cyanoalkoxy, hydroxyalkoxy, alkoxyalkoxy, (R.sup.4)alkoxy, or (R.sup.4)alkenyloxy; R.sup.2 is alkyl, cycloalkyl, alkoxycarbonyl, carboxy, CON(R.sup.12)(R.sup.13), or Ar.sup.2; R.sup.3 is cyano, halo, alkoxy, or (R.sup.5)(R.sup.6)N; R.sup.4 is (R.sup.7)(R.sup.8)N, CO.sub.2(R.sup.9), or CON(R.sup.10)(R.sup.11); R.sup.5 is hydrogen or alkyl; R.sup.6 is hydrogen or alkyl; or (R.sup.5)(R.sup.6)N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, (oxo)thiomorpholinyl, (dioxo)thiomorpholinyl, homopiperidinyl, or homopiperazinyl; R.sup.7 is hydrogen or alkyl; R.sup.8 is hydrogen or alkyl; or (R.sup.7)(R.sup.8)N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or morpholinyl-N-oxide; R.sup.9 is hydrogen or alkyl; R.sup.10 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or spiro[3.3]heptanol; R.sup.11 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; or (R.sup.10)(R.sup.11)N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, (oxo)thiomorpholinyl, (dioxo)thiomorpholinyl, homopiperidinyl, or homopiperazinyl, and is substituted with 0-4 substituents selected from halo, alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, oxo, and acetamido; R.sup.12 is hydrogen, alkyl, or cycloalkyl; R.sup.13 is hydrogen or alkyl; or (R.sup.12)(R.sup.13)N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-3 substituents selected from halo and alkyl; X is S, SO, or SO.sub.2; and Y is imidazolyl or triazolyl; or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a compound of formula I where Ar.sup.1 is phenyl or pyridinyl, and is substituted with 0-5 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; Ar.sup.2 is phenyl or pyridinyl and is substituted with 0-5 substituents selected from cyano, halo, alkyl, (R.sup.3)alkyl, haloalkyl, cycloalkyl, (R.sup.3)cycloalkyl, alkoxy, cycloalkoxy, haloalkoxy, and alkoxycarbonyl; R.sup.1 is alkoxy, or (R.sup.4)alkoxy; and R.sup.2 is Ar.sup.2. Another aspect of the invention is a compound of formula I where Ar.sup.1 is phenyl substituted with 0-5 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; Ar.sup.2 is phenyl substituted with 0-5 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; and R.sup.1 is alkoxy, cyanoalkoxy, alkoxyalkoxy, or (R.sup.4)alkoxy; or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a compound of formula I where Ar.sup.1 is phenyl substituted with 0-5 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy. Another aspect of the invention is a compound of formula I where Ar.sup.2 is phenyl substituted with 3 halo substituents. Another aspect of the invention is a compound of formula I where R.sup.1 is alkoxy or (R.sup.4)alkoxy. Another aspect of the invention is a compound of formula I where Y is triazolyl. Another aspect of the invention is a compound of formula I where Y is imidazolyl. For a compound of Formula I, the scope of any instance of a variable substituent, including R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, Ar.sup.1, Ar.sup.2, X, and Y can be used independently with the scope of any other instance of a variable substituent. As such, the invention includes combinations of the different aspects. Unless specified otherwise, these terms have the following meanings. "Alkyl" means a straight or branched alkyl group composed of 1 to 6 carbons. "Alkenyl" means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond. "Alkynyl" means a straight or branched alkyl group composed of 2 to 6 carbons with at least one triple bond. "Cycloalkyl" means a monocyclic ring system composed of 3 to 7 carbons. Terms with a hydrocarbon moiety (e.g. alkoxy) include straight and branched isomers for the hydrocarbon portion which are composed of 1 to 6 carbons. "Halo" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" and "haloalkoxy" include all halogenated isomers from monohalo to perhalo "Aryl" means a monocyclic or bicyclic aromatic ring system having 5 to 12 carbon atoms wherein one or both of the rings are aromatic. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. "Heteroaryl" means a 5 to 7 membered monocyclic or 8 to 11 membered bicyclic aromatic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Where a bonding attachment location is not specified, the bonding may be attached at any appropriate location as understood by practitioners in the art. Combinations of substituents and bonding patterns are only those that result in stable compounds as understood by practitioners in the art. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R. The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc. Some of the compounds of the invention exist in stereoisomeric forms. The invention includes all stereoisomeric forms of the compounds including enantiomers and diastereomers. Methods of making and separating stereoisomers are known in the art. The invention includes all tautomeric forms of the compounds. The invention includes atropisomers and rotational isomers. The invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include .sup.13C and .sup.14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties. Biological Methods ASSAY BUFFER Composition: 25 mM HEPES, 100 mM NaCl, 0.005% Tween 20, 0.05% BSA prepared in sterile water (all reagents from Sigma) Controls: Positive Control: 100% DMSO (1 .mu.l)+His-tagged hGal-3 (20 .mu.L)+B-ASF (20 .mu.l)+Anti-His Terbium Antibody (5 .mu.l)+Strep d2 Antibody (5 .mu.l). Negative Control: 100% DMSO (1 .mu.l)+His-tagged hGal-3 (20.mu.L)+Anti His Terbium Antibody (5 .mu.l)+Strep d2 Aantibody (5 .mu.l). Stocks Preparation: TABLE-US-00001 Intermediate Final Assay Stock Conc. Conc. Conc. Volume His-tagged 49.82 .mu.M or 2.525X 15 nM 20 .mu.l hGal-3 can vary batch to batch B-ASF 25 .mu.M 2.525X 15 nM 20 .mu.l Compounds 20 mM in Various Various 1 .mu.l 100% DMSO concentration concentration 100% DMSO 2% DMSO Anti-His Tb 5.75 .mu.M (10X) 10 nM 1 nM 5 .mu.l Ab Strep d2 16.67 .mu.M (10X) 200 nM 20 nM 5 .mu.l Total Assay 51 .mu.l volume PROTOCOL: The Gal-3 assays were performed in 384 white Opti plates in three replicates at room temperature with gentle shaking at 250-300 rpm From the original stocks, 2.525.times. working stock concentrations of His-tagged recombinant human Gal-3 (hGal-3) and that of B-ASF were prepared. From the working stock, 20 .mu.l of hGal-3 (15 nM) and 20 .mu.l B-ASF (15 nM) were added to the plates. In Negative Control, only hGal-3 was added. A concentration range of 50.times. working stocks were prepared for the compounds in 100% DMSO. Aliquots of 1 uL of the compounds were added to the wells and pre-incubated with 20 .mu.l hGal-3 per well for 30 minutes Then 20 .mu.l B-ASF were added and incubated for another 1 hour. To detect the signal, 5 .mu.(final conc. of 1.0 nM) terbium labelled Anti-His antibody was added and incubated for 30 min followed by adding 5 .mu.(final conc. of 20 nM) Streptavidin d2 and incubation for another 1 hour. The assay signal was detected using HTRF screen protocol (Excitation wavelength=340 nm, emission wavelength=615 nm/665 nm) on Envision 2104 Multilabel Reader. Data analysed using Toolset and Curve Master. Results are reported in the experimental section (IC.sub.50 in .mu.M). Pharmaceutical Composition and Methods of Use The compounds of this invention inhibit Gal-3. Accordingly, another aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Another aspect of the invention is a method for treating a patient afflicted with a disease or condition selected from fibrosis of organs (including liver, kidney, lung, heart and skin), liver diseases and conditions (including acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), liver hypofunction, and hepatic blood flow disorder), cell proliferative diseases, cancers, and conditions (including solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL)) and invasive metastasis of cancer cell), inflammatory diseases and conditions (including psoriasis, nephropathy, and pneumonia), gastrointestinal tract diseases and conditions (including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and abnormal pancreatic secretion), renal diseases and conditions, urinary tract-associated diseases and conditions (including benign prostatic hyperplasia or symptoms associated with neuropathic bladder disease, spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis, and symptoms derived from diabetes), lower urinary tract diseases and conditions (including obstruction of lower urinary tract), inflammatory diseases and conditions of lower urinary tract (including dysuria and frequent urination), pancreatic diseases and conditions, abnormal angiogenesis-associated diseases and conditions (including arterial obstruction), scleroderma, brain-associated diseases and conditions (including cerebral infarction and cerebral hemorrhage), neuropathic pain and peripheral neuropathy, ocular diseases and conditions (including age-related to macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scarring) with a compound of formula I. Another aspect of the invention is a method of treating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis and systemic sclerosis comprising administering to a compound of formula I to a patient. Another aspect of the invention is a method for treating fibrosis of organs (including liver, kidney, lung, heart and skin) comprising administering to a compound of formula I to a patient. Another aspect of the invention is a method for treating liver diseases and conditions (including acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), liver hypofunction, and hepatic blood flow disorder) comprising administering to a compound of formula I to a patient. Another aspect of the invention is a method for treating cell proliferative diseases, cancers, and conditions (including solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL)) and invasive metastasis of cancer cell) comprising administering to a compound of formula I to a patient. Another aspect of the invention is a method for treating inflammatory diseases and conditions (including psoriasis, nephropathy, and pneumonia) comprising administering to a compound of formula I to a patient. Another aspect of the invention is a method for treating gastrointestinal tract diseases and conditions (including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and abnormal pancreatic secretion) comprising administering to a compound of formula I to a patient. Another aspect of the invention is a method for treating renal diseases and conditions comprising administering to a compound of formula I to a patient. Another aspect of the invention is a method for treating urinary tract-associated diseases and conditions (including benign prostatic hyperplasia or symptoms associated with neuropathic bladder disease, spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis, and symptoms derived from diabetes) comprising administering to a compound of formula I to a patient. Another aspect of the invention is a method for treating lower urinary tract diseases and conditions (including obstruction of lower urinary tract), inflammatory diseases and conditions of lower urinary tract (including dysuria and frequent urination) comprising administering to a compound of formula I to a patient. Another aspect of the invention is a method for treating pancreatic diseases and conditions comprising administering to a compound of formula I to a patient. Another aspect of the invention is a method for treating abnormal angiogenesis-associated diseases and conditions (including arterial obstruction) comprising administering to a compound of formula I to a patient. Another aspect of the invention is a method for treating brain-associated diseases and conditions (including cerebral infarction and cerebral hemorrhage) comprising administering to a compound of formula I to a patient. Another aspect of the invention is a method for treating neuropathic pain and peripheral neuropathy comprising administering to a compound of formula I to a patient. Another aspect of the invention is a method for treating ocular diseases and conditions (including age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scarring) comprising administering to a compound of formula I to a patient. The compounds of the invention may be used in the treatment and/or prophylaxis of conditions in which Gal-3 plays a role. The compounds of the present invention may be used for the manufacture of a medicament for the treatment and/or prophylaxis of a condition in which inhibition of the physiological activity of Gal-3 is useful, such as diseases in which a Gal-3 receptor participates, is involved in the etiology or pathology of the disease, or is otherwise associated with at least one symptom of the disease. The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two other agent(s). "Therapeutically effective" means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of pain. "Patient" means a person afflicted with pain and suitable for therapy as understood by practitioners in the field. "Treatment," "therapy," "regimen," and related terms are used as understood by practitioners in the field. The compounds of this invention are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients. A therapeutically effective amount is that which is needed to provide a meaningful patient benefit. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms including capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions. See, for example, Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa. (1985). Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit. Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL. The invention encompasses all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to other agents used clinically. Typically, the daily dose will be 1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, will be determined by a physician using sound medical judgement. Chemical Methods The compounds of this invention can be made by various methods known in the art including those of the following schemes and in the specific embodiments section. The structure numbering and variable numbering shown in the synthetic schemes are distinct from, and should not be confused with, the structure or variable numbering in the claims or the rest of the specification. The variables in the schemes are meant only to illustrate how to make some of the compounds of this invention. The disclosure is not limited to the foregoing illustrative examples and the examples should be considered in all respects as illustrative and not restrictive, reference being made to the claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced. Analytical LC-MS/HPLC retention time reported for each example and intermediate uses one of the following general analytical LC-MS/HPLC conditions: |
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