2,5- or 2,6-disubstituted hydroquinone derivatives having at least one carboxyl, sulfo, or amido group useful as a pharmaceutical agent

Abstract

The present invention provides a novel hydroquinone derivative of formula (I), a process for manufacturing the same, and a pharmaceutical composition and method for treating and / or preventing, for example, autoimmune, immunological, rheumatic, vascular, ophthalmic, fibrotic, metabolic and gastrointestinal disorders, neuroinflammatory and neurodegenerative diseases, neoplasms and cancer-related disorders, hormone-related diseases and viral and bacterial infectious diseases and complications thereof. In the above formula, R1 is COOR4, (CH2)nCOOR4, SO3H, (CH2)nSO3H, or CONH-R10; one of R2 and R3 is H and the other is R5.

Description

Technology Field

[0001] The present invention generally relates to novel hydroquinone derivatives, preparations thereof, and methods for treating disorders by administering these compounds to warm-blooded animals in need thereof. The present invention also relates to compounds useful for the prevention and / or treatment of autoimmune, immunological, rheumatic, vascular, ophthalmic, fibrotic, metabolic and gastrointestinal disorders, neuroinflammatory and neurodegenerative diseases, neoplasms and cancer-related disorders, hormone-related diseases and immunological disorders caused by viral and bacterial infections, and complications thereof. Background Technology

[0002] Some hydroquinone-based derivatives, such as 2,5-dihydroxybenzenesulfonic acid derivatives and in particular calcium dobesilate, ethamsylate, and persilate, are known in the art, either alone or in combination with other agents, as active agents for the treatment of male sexual dysfunction and other vascular disorders of endothelial origin. For example, U.S. Patent No. 6,147,112 describes a method of using 2,5-dihydroxybenzenesulfonic acid derivatives, preferably calcium dobesilate, ethamsylate, and persilate. Calcium dobesilate or hydroquinone calcium sulfonate, having the chemical name calcium salt of 2,5-dihydroxybenzenesulfonic acid, is sold as Dexium (Delalande) and Doxium (Carrion), and its manufacturing process is described in U.S. Patent No. 3,509,207.

[0003] There are many drugs containing phenol or catechol groups that undergo premature metabolism at the hydroxyl group during absorption after oral administration. Previous efforts to protect the hydroxyl group have generally been unsuccessful because the protecting group used was either too unstable (O=COR or O=CR) or too stable (CH3). Accordingly, the object of the present invention is to provide novel hydroquinone derivatives, pharmaceutically acceptable salts thereof, and formulations thereof. These novel hydroquinone derivatives possess particularly potent anti-fibrotic, anti-inflammatory, and anti-angiogenic properties.

[0004] International Publication WO2018160618A1 discloses specific substituted hydroquinone, 1,4-quinone, catechol, 1,2-quinone, anthraquinone, and anthrahydroquinone for use as redox mediators in emerging technologies, such as in mediated fuel cells or organic-mediated flow batteries.

[0005] The literature [Richter et al, in Synthesis, 1976, 1976(3), 192-194] discloses the preparation of bis-N-arylcarbamate and 2,5-dihydroxy-3,6-bis[N-arylcarboxamido]-1,4-benzoquinone and 2,5-dihydroxy-1,4-benzoquinone and aryl isocyanate.

[0006] Japanese Patent Publication JP 51026839A discloses Benzanilide I having antitubercular, analgesic, anti-inflammatory, and uric acid-excreting activities:

[0007]

[0008] Benzanilide I.

[0009] U.S. Patent No. 3,973,038 also discloses a benzoylanine compound having the following general formula:

[0010] .

[0011] In the above formula (R1= OH, acyloxy; R2= H, OH, lower alkyl, halo, acyloxy; R3= Cl, Br, lower alkyl; R4= OH, NH2, lower alkoxy, acyloxy; R5= H, halo, CO2H, lower alkyl, acyloxy) In vivo It has enzyme inhibitory properties, particularly histamine diacetylase and xanthine oxidase.

[0012] However, prior art documents do not disclose a novel class of hydroquinone derivative compounds of the present invention that is particularly useful for the prevention and / or treatment of various diseases, including autoimmune, immunological, rheumatic, vascular, ophthalmic, fibrotic, metabolic and gastrointestinal disorders, neuroinflammatory and neurodegenerative diseases, neoplasms and cancer-related disorders, hormone-related diseases and immunological disorders caused by viral and bacterial infections, and complications thereof.

[0013] The present invention also relates to the treatment, prevention, and reduction of metabolic disorders, such as diabetes and obesity. As blood glucose levels rise after a meal, insulin is secreted, stimulating cells in peripheral tissues (skeletal muscle and fat) to actively absorb glucose from the blood as an energy source. Loss of glucose homeostasis resulting from improper insulin secretion or action typically leads to metabolic disorders, such as diabetes, which can be co-induced or further exacerbated by obesity. Since these conditions are often fatal, strategies are required to restore proper glucose removal from the bloodstream. Metabolic disorders, particularly glucose and lipid dysregulation, are becoming increasingly widespread as the population in industrialized countries ages and sedentary lifestyles become commonplace. These disorders are often interrelated and frequently act as predictors or consequences of each other.

[0014] For example, diabetes mellitus results from a combination of insulin resistance and impaired insulin secretion by pancreatic β-cells. Individuals with insulin resistance often exhibit abdominal obesity, dyslipidemia, hypertension, glucose intolerance, and a prothrombotic state (metabolic syndrome). Consequently, obese individuals have a higher overall risk of developing insulin resistance. Therefore, the disruption of metabolic pathways can lead to numerous disorders, such as hyperlipidemia, obesity, diabetes, insulin resistance, glucose intolerance, hyperglycemia, metabolic syndrome, and hypertension; these, in turn, cause further metabolic dysfunction, leading to systemic problems and placing individuals at risk of additional complications and early morbidity. Glucose and lipid levels are partially regulated by the liver, which plays a role in synthesizing, storing, secreting, modifying, and breaking down glucose, proteins, and lipids. Disease or traumatic injury can significantly reduce the liver's ability to perform these normal activities. Therefore, most clinical symptoms of liver dysfunction stem from cellular damage and impairment of normal liver function. Liver dysfunction can result from genetic conditions, inflammatory disorders, toxins such as drugs and alcohol, immunological disorders, vascular disorders, or metabolic conditions. Regardless of the cause, liver damage has systemic effects on the function of metabolic processes and the regulation of blood glucose and serum lipid levels, which can exacerbate chronic disease states and increase the risk of additional diseases and pathologies. Both increases and decreases in blood glucose levels trigger hormonal responses designed to restore glucose homeostasis. Hypoglycemia triggers the release of glucagon from pancreatic α-cells. Hyperglycemia triggers the release of insulin from pancreatic β-cells. ACTH and growth hormone secreted by the pituitary gland act to raise blood glucose by inhibiting absorption by extrahepatic tissues. Glucocorticoids also act to raise blood glucose levels by inhibiting glucose absorption.Cortisol, the major glucocorticoid secreted by the adrenal cortex, is released in response to an increase in circulating ACTH. Epinephrine, an adrenal medullary hormone, stimulates glucose production by activating glycogenolysis in response to stress stimuli. Metabolic diseases affecting glucose and lipid metabolism—such as hyperlipidemia, obesity, diabetes, insulin resistance, hyperglycemia, glucose intolerance, metabolic syndrome, and hypertension—lead to long-term health consequences, including chronic conditions such as cardiovascular disease and premature pathogenesis. These metabolic and cardiovascular disorders can create feedback mechanisms that are interrelated, exacerbate, or trigger one another, making them difficult to interrupt. Current pharmacological treatments for metabolic and cardiovascular disorders involve combinations of lipid-lowering agents, hypoglycemic agents, antihypertensives, diet, and exercise. However, complex therapeutic regimens can lead to polypharmacy issues, such as increased side effects, drug interactions, adherence failures, and medication errors. Therefore, there is a strong, unmet need in the industry to identify novel compounds, formulations, and methods for safely and effectively treating metabolic disorders and conditions associated with cardiovascular disorders.

[0015] Examples of metabolic states include, without limitation, pain, wound healing, fever, neuroinflammatory and neurodegenerative states, inflammation, thermogenesis, homeothermia, triglyceride breakdown, glycolysis, the Krebs cycle, fermentation, photosynthesis, metabolic rate, biological and abiotic stress, secretions, oxidative stress, stress, neoplastic growth, skin conditions, cardiovascular conditions, neuroinflammatory and neurodegenerative states, and mental and behavioral disorders. These processes or states may occur in cells, cell populations, or the entire organism.

[0016] Recent advancements in molecular medicine have improved the diagnosis and treatment of neoplastic diseases to some extent. Despite this partial success, these pathologies still remain a significant challenge. In the case of certain types of cancer, current treatments sometimes fail for several reasons. On the one hand, this is due to the inherent resistance, persistent mutations, and treatment evasion capabilities of tumor cells, and on the other hand, the heterogeneity of the tumor environment. It has been shown that tumors of the same type differ significantly from individual to individual in terms of genomic profiles, indicating the need for so-called "personalized" therapies. A greater problem is the heterogeneity of mutations within the same tumor, as recently revealed regarding kidney tumors, and this situation can be expected in other types of tumors as well. For this reason, it is necessary to identify invariant points of intervention and novel approaches that are common to all or most malignant cells of a tumor and, preferably, affect the essential functions of cancer cells. Such points of intervention appear to be located at the metabolic level, for example, in mitochondria, organelles essential for energy production required for all physiological and pathophysiological processes of the cell. While tumor cells utilize a major portion known as aerobic glycolysis for energy production, mitochondrial respiration (i.e., oxygen consumption associated with ATP formation) is inherent in most (though not all) types of tumors. Therefore, there is a strong, unmet need in the industry to identify new compounds, formulations, and methods to safely and effectively treat these neoplastic disorders.

[0017] The present invention provides a novel hydroquinone derivative, a novel manufacturing process, and a novel key intermediate. The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of such hydroquinone derivative and a pharmaceutically acceptable excipient.

[0018] The present invention further provides a method for treating and / or preventing angiogenesis (vascular), inflammatory and / or fibrotic pathologies as they possess anti-fibrotic, anti-inflammatory, and anti-angiogenic effects. Accordingly, the present invention provides a method for treating and / or preventing diseases or disorders, including immunological / rheumatic / vascular disorders, ophthalmic disorders, fibrotic disorders, metabolic and gastrointestinal disorders, neoplasms, and cancer-related disorders, comprising the step of finally administering a therapeutically effective dose of the compound and / or pharmaceutical composition of the present invention as described above to a subject in need thereof. In particular, the present invention provides a method for treating and / or preventing diseases or disorders, including autoimmune, immunological, rheumatic, vascular disorders, ophthalmic disorders, fibrotic disorders, metabolic and gastrointestinal disorders, neuroinflammatory and neurodegenerative diseases, neoplasms and cancer-related disorders, hormone-related diseases, and immunological disorders caused by viral and bacterial infections and their complications. Brief explanation of the drawing

[0019] Fig. 1: (a) Confocal immunofluorescence image of vascular permeability evaluated by Evans blue dye leakage in a retinal whole mount in representative mice of each experimental group. Arrows indicate the location of extravasation. Scale bar, 30 μm. (b) Field (0.44 mm 2 Quantification of vascular leakage by evaluation of glucose extravasation. The effect of Ic-007a eye drops significantly reduced vascular leakage to the same level as that occurring in the non-diabetic control group. Compared to other groups, *p < 0.01. Fig. 2:(a) The Schmidt score is an evaluation of the efficacy of a compound according to four histopathological assessment criteria describing pancreatic injury based on the following scores (numbers in parentheses) for four parameters. (a) (0) None, (1) Interlobular, (2) Lobule-associated, (3) Edema with isolated islet scores such as acinar cells, interstitial edema. (b) Inflammatory infiltration = (0) None, (1) < 20%, (2) 20% to 50%, (3) > 50% leukocyte infiltration. (c) Parenchymal necrosis = (0) None, (1) < 5%, (2) 5% to 20%, (3) > 20% acinar cell necrosis. (d) (0) none, (1) 1 to 2 points, (2) 3 to 5 points, (3) Hemorrhage with > 5 points. The highest Schmidt score = 10 is for caerulein-induced + vehicle treatment, and the lowest score = 0 is for non-induced animals. The Schmidt score is the sum of the a+b+c+d scores, and **** indicates a statistically significant difference from the caerulein-induced group as shown in Figure 2. All products show an improved Schmidt score compared to the caerulein control animals. FIGS. 3a to dFigures 3a and 3b show a list of diseases containing major cytokines associated with selected diseases (reference [Akdis M. et al, J Allergy Clin Immunol 2016;138:984-1010]), and Figure 3c shows a portion of the search results classified by score for cytokines and genes potentially associated with the selected disease, provided as an example of "diabetic retinopathy" after searching https: / / www.targetvalidation.org / . In Figure 3d, a search was performed using VEGFA as a cytokine to find a list of diseases in which VEGFA is mentioned. Only some of the diseases associated with VEGFA are shown in Figure 3d. Reference: [Open Targets Platform: new developments and updates two years on. Denise Carvalho et al (Nucleic Acids Research, Volume 47, Issue D1, 08 January 2019, D1056-D1065, https: / / doi.org / 10.1093 / nar / gky1133)]. FIGS. 4(a to d) : Tables listing the conditions and yields of compounds of types Ia to Id as described in Examples 1.1 to 1.4. Total yield calculated from the starting material 2,5-dihydroxyterephthalic acid. FIG. 5 (a to c): A table listing the conditions and yields of compounds of types IIa to IIc as described in Examples 1.5 to 1.7 is presented. Fig. 6: A table listing the conditions and yields of Type IIIa and IIIb compounds as described in Examples 1.8 and 1.9 is presented. Fig. 7: A table listing the conditions and yields of a type IIIc compound as described in Example 1.10 is shown. Fig. 8: A table listing the deprotection process described in Example 1.12 related to compound type V. Fig. 9: Represents the non-fasting blood glucose levels (mean ± standard deviation of all animals) of an STZ-induced diabetes model in each group of all animals sampled after daily administration via intravenous or oral (per os) route on day 0 before administration, and on days 7 and 14 thereafter. Fig. 10 : It indicates that it accelerates wound healing in an STZ-induced diabetes model of 3 animals per group sampled on day 7 after daily administration by intravenous or oral route. Fig. 11 Figure 11a shows representative images of pulmonary fibrosis on day 21 of treatment; (a1) uninduced (healthy); a2, bleomycin induced by vehicle treatment; a3, bleomycin induced by pirfenidone 100 mg / kg treatment; a4, bleomycin induced by IVc-059a treatment. Figure 11b shows the Ashcroft scores of uninduced vs. pirfenidone vs. healthy, bleomycin induced by IVc-059a. Specific details for implementing the invention

[0020] Novel compounds useful for treating subjects suffering from diseases, disorders, or dysfunctions are disclosed herein. Examples of such diseases, disorders, or dysfunctions include, without limitation, autoimmune, metabolic, inflammatory, degenerative, and neoplastic disorders, particularly inflammatory pathologies, neovascularization diseases and / or fibrotic disorders such as diabetic retinopathy, diabetic nephropathy, ankylosing spondylitis, chronic pancreatitis, hepatic fibrosis, renal fibrosis, and metabolic diseases caused by pancreatic dysfunction.

[0021] Hereinafter, unless otherwise specified, the set of diseases, disorders, or dysfunctions that can be treated using the novel compounds disclosed herein is collectively referred to as "medical conditions."

[0022] As used herein, the term “subject” includes any organism and the term “patient.” A subject to be treated according to the methods described herein may be a subject diagnosed by a medical professional as suffering from a medical condition. Diagnosis may be performed by any appropriate means. Those skilled in the art will understand that a subject to be treated according to this disclosure may have undergone standard tests to diagnose a medical condition. As is known to those skilled in the art, the clinical characteristics of the type of medical condition disclosed herein vary according to the pathological mechanism.

[0023] As defined herein, "treating" refers to the use of the disclosed compounds for therapeutic purposes. Therapeutic treatment may be administered to a subject suffering from a medical condition, for example, to improve or stabilize the subject's condition. Accordingly, in the claims and embodiments described herein, "treating" refers to the subject undergoing the methodology disclosed herein for therapeutic purposes.

[0024] As used herein, the term "prodrug" refers to any broad prodrug strategy. For example, although the prodrug strategy was formally recognized by Adrian Albert in 1958 (see literature [Albert, A. Chemical aspects of selective toxicity. Nature, 1958, 182, 421-422]), it originated in the early 20th century, as exemplified by methenamine, phenacetin, and prontosil. Prodrugs are generally molecules with little to no pharmacological activity, but whether accidentally or intentionally In vivoIt possesses inherent structural instability that enables bioconversion into an active drug. This conversion can occur through chemical or enzymatic processes, or a combination of both. Active molecules are often associated with undesirable physicochemical properties that cause significant problems in delivery to appropriate biological targets. Prodrugs can mitigate metabolic instability generally attributed to hepatic metabolism. Similarly, undesirable intestinal metabolism of drugs can be overcome by selective prodrug strategies. Such instability can significantly reduce the total amount of drug reaching systemic circulation and its targets. Prodrugs can be used to protect active drugs from these first-pass effects by masking metabolically unstable but pharmacologically essential functional groups, such as phenols, to avoid rapid metabolism.

[0025] Prodrugs obtained through structural modifications are designed to enable delivery by influencing the molecule's intrinsic physicochemical properties. However, such development is not always incorporated into the design of new molecules at the discovery stage. Often, analogue optimization is the preferred pathway. Implementing an early prodrug strategy enables faster clinical development and, ultimately, the commercialization of the drug.

[0026] Many prodrug strategies can be applied to influence the lipophilicity of the parent drug. The lipophilicity of the drug was improved by masking polar and ionized functions by short-chain hydrocarbon promoties. Hydrophilic hydroxyl, carboxyl, phosphate, or amine groups, and other negatively or positively charged groups were successfully converted into more lipophilic alkyl or aryl esters or N-acyl derivatives that are rapidly hydrolyzed back into the parent drug in the body by ubiquitous esterases or peptidases.

[0027] Therefore, the present invention provides a compound of formula (I):

[0028]

[0029] Chemical formula (I)

[0030] In the above formula:

[0031] R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) n CO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6acyloxymethyl, C1-C6acyloxy-1-ethyl, C1-C6alkoxycarbonyloxymethyl, or C1-C6alkoxycarbonyloxy-1-ethyl;

[0032] R1= COOR4, (CH2) n COOR4, SO3H, (CH2) n SO3H, or CONH-R 10 And;

[0033] R2 and R3 are H or R5, provided that if one of R2 and R3 is R5, the other is H, and if one of R2 and R3 is H, the other is R5;

[0034] R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0035] R5 = R6, R7, or R8 and;

[0036] R6=CONH-R9, CONHCOR9, CONH(CH2) n -R9, or CONHCH(COOR4)(CH2) kR9, heteroaryl-R9, where k = 0 to 4;

[0037] R7= COOR4, (CH2) n COOR4, SO3H, (CH2) n It is a benzoheteroaryl substituted with at least one group selected from SO3H, OR4, azole [5-membered N-containing heterocyclic], or fluorine;

[0038] R8= (CH2) m X(CH2) p It is R9;

[0039] X = O, S, SO2, NH, NAc, or N(CH2) q It is R9;

[0040] R9= COOR4, (CH2) n COOR4, (CH2) n SO3H, OR4, SO3H, Azole [5-membered N-containing heterocyclic], Fluorine, C=O, NHCO-R 10 It is an aryl or heteroaryl substituted with at least one group selected from;

[0041] R 10 = COOR4, (CH2) n COOR4, (CH2) n It is an aryl or heteroaryl substituted with at least one group selected from SO3H, OR4, SO3H, azole [5-membered N-containing heterocyclic], and fluorine;

[0042] Here, R9 and R 10 The aryl group is an aromatic group containing 6 to 14 carbon atoms selected from phenyl, naphthyl, and biphenyl groups; heteroaryl R9 and R 10 is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen; n, m, p and q are independently 1 to 4.

[0043] The present invention further provides a compound of formula (I):

[0044]

[0045] (I)

[0046] In the above formula:

[0047] R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) n CO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6acyloxymethyl, C1-C6acyloxy-1-ethyl, C1-C6alkoxycarbonyloxymethyl, or C1-C6alkoxycarbonyloxy-1-ethyl;

[0048] R1= COOR4, (CH2) n COOR4, SO3H, (CH2) n SO3H, or CONH-R 10 And;

[0049] R2 and R3 are H or R5, provided that if one of R2 and R3 is R5, the other is H, and if one of R2 and R3 is H, the other is R5;

[0050] R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0051] R5 = R6 or R7, and,

[0052] R6=CONH-R9, CONHCOR9, CONH(CH2) n -R9, or CONHCH(COOR4)(CH2) k R9 and; where k = 0 to 4;

[0053] R7= COOR4, (CH2) n COOR4, SO3H, (CH2) n It is a benzoheteroaryl substituted with at least one group selected from SO3H, OR4, azole [5-membered N-containing heterocyclic], or fluorine;

[0054] R9= COOR4, (CH2) n COOR4, (CH2) n SO3H, OR4, SO3H, azole [5-membered N-containing heterocyclic], fluorine, C=O, or NHCO-R 10 It is an aryl or heteroaryl substituted with at least one group selected from;

[0055] R 10 = COOR4, (CH2) n COOR4, (CH2) n It is an aryl or heteroaryl substituted with at least one group selected from SO3H, OR4, SO3H, azole [5-membered N-containing heterocyclic], or fluorine; where R9 and R 10 The aryl group is an aromatic group containing 6 to 14 carbon atoms selected from phenyl, naphthyl, and biphenyl; and R9 and R 10 The heteroaryl group is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen; n is independently 1 to 4.

[0056] The present invention also provides a compound of formula (I):

[0057]

[0058] (I)

[0059] In the above formula:

[0060] R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) nCO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6acyloxymethyl, C1-C6acyloxy-1-ethyl, C1-C6alkoxycarbonyloxymethyl, or C1-C6alkoxycarbonyloxy-1-ethyl;

[0061] R1= COOR4, (CH2) n COOR4, SO3H, (CH2) n SO3H, or CONH-R 10 And;

[0062] R2 and R3 are H or R5, provided that if one of R2 and R3 is R5, the other is H, and if one of R2 and R3 is H, the other is R5;

[0063] R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0064] R5 = R8 and

[0065] R8= (CH2) m X(CH2) p It is R9;

[0066] X = O, S, SO2, NH, NAc, or N(CH2) q It is R9;

[0067] R9= COOR4, (CH2) n COOR4, (CH2) n SO3H, OR4, SO3H, azole [5-membered N-containing heterocyclic], fluorine, C=O, or NHCO-R 10 It is an aryl or heteroaryl substituted with at least one group selected from;

[0068] R 10 = COOR4, (CH2) n COOR4, (CH2) n It is an aryl or heteroaryl substituted with at least one group selected from SO3H, OR4, SO3H, azole [5-membered N-containing heterocyclic], and fluorine;

[0069] Here, R9 and R 10 The aryl group is an aromatic group containing 6 to 14 carbon atoms selected from phenyl, naphthyl, and biphenyl groups; and heteroaryl R9 and R 10 is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen; n, m, p and q are independently 1 to 4.

[0070] The term "alkyl" refers to 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, in particular 1 to 6 ( for example , 1, 2, 3, or 4) saturated, straight-chain or branched hydrocarbon groups containing carbon atoms, e.g., methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. Additionally, the term alkyl refers to a group in which one or more hydrogen atoms are substituted with halogen atoms (preferably F or Cl), such as, e.g., 2,2,2-trichloroethyl or trifluoromethyl groups.

[0071] The term “acyl” refers to (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C(O)-, and (heterocycloalkyl)-C(O)- groups, wherein said groups are attached to the parent structure through carbonyl functionalization. In some embodiments, this is a C1-C4 acyl radical referring to the total number of carbonyl carbons of the acyl, aryl, heteroaryl, or heterocycloalkyl portion of the acyloxy group and the chain or ring of the acyl, i.e., the total number of carbonyls of three different ring or chain atoms.

[0072] The term "aryl" refers to an aromatic group containing one or more rings having 6 to 14 cyclic carbon atoms, preferably 6 to 10 (particularly 6) cyclic carbon atoms.

[0073] The term "aralkyl" or "aryl C 1-4 "Alkyl" refers to a group containing both an aryl and an alkyl, alkenyl, alkynyl and / or cycloalkyl group according to the above definition, and is not limited to benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naph-2-ylethyl. The aralkyl group preferably contains one or two aromatic ring systems (one or two rings) containing 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups containing 1 or 2 to 6 carbon atoms and / or a cycloalkyl group containing 5 or 6 ring carbon atoms.

[0074] The term "heteroaryl" refers to an aromatic group containing one or more rings having 5 to 14 ring atoms, preferably 5 to 10 (particularly 5 or 6 or 9 or 10) ring atoms, and containing one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus, or sulfur ring atoms (preferably O, S, or N). Examples include pyridyl ( for example , 4-pyridyl), imidazollil( for example , 2-imidazolyl), phenylpyrrolyl( for example , 3-phenylpyrrolyl), thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, pyridazolyl, quinolinyl, isoquinolinyl, pyrrolyl, furinyl, carbazolyl, acridinyl, pyrimidyl, 2,3-bifuryl, pyrazolyl (e.g., 3-pyrazolyl) and isoquinolinyl groups.

[0075] The terms "benzoheteroaryl" or "benzoheteroaromatic" refer to a cyclic ring comprising a phenyl ring fused to a monocyclic heteroaromatic ring. Examples of benzoheteroaryls include benzisoxazolyl, benzoxazolyl, benzisothiazolyl, benzothiazolyl, benzimidazolyl, benzofuryl, benzothienyl (including S-oxide and diooxide), quinolyl, isoquinolyl, indazolyl, indolyl, etc.

[0076] The term "azole" refers to a pentatonic heteroaryl group having a nitrogen ring atom and 0 to 3 additional ring heteroatoms selected from N, O, or S. Imidazole, oxazole, thiazole, and tetrazole are representative azole groups.

[0077] The term "cycloalkyl" refers to a saturated or partially unsaturated (e.g., cycloalkenyl group) cyclic group containing one or more rings (preferably one or two) and 3 to 14 cyclic carbon atoms, preferably 3 to 10 (particularly 3, 4, 5, 6, or 7) cyclic carbon atoms. Special The genus is cyclopropyl, cyclobutyl, cyclopentyl.

[0078] The term "optionally substituted" refers to a group in which at least one, or optionally two, three, or more hydrogen atoms may be substituted with a fluorine, chlorine, bromine, iodine atom, or an OH, =O, SH, =S, NH2, =NOH, N3, or NO2 group. This term additionally refers to at least one, two, three, or more unsubstituted C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, heteroalkyl, C3-C 18 Cycloalkyl, C2-C 17 Heterocycloalkyl, C4-C 20 Alkylcycloalkyl, C2-C 19 Heteroalkylcycloalkyl, C6-C 18Aryl, C1-C 17 Heteroaryl, C7-C 20 Aralkyl or C2-C 19 It refers to a group that can be substituted with a heteroaralkyl group. This term also specifically refers to 1, 2, 3, or more unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl, C7-C 12 Alkylcycloalkyl, C2-C 11 Heteroalkylcycloalkyl, C6-C 10 Aryl, C1-C9 heteroaryl, C7-C 12 Aralkyl, or C2-C 11 It refers to a group that can be substituted with a heteroaralkyl group.

[0079] According to a preferred embodiment, all alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl, and heteroaralkyl groups described herein may be optionally substituted.

[0080] Preferably, the present invention provides a hydroquinone derivative compound of formula (I); wherein:

[0081] (A)

[0082] R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) n CO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6acyloxymethyl, C1-C6acyloxy-1-ethyl, C1-C6alkoxycarbonyloxymethyl, or C1-C6alkoxycarbonyloxy-1-ethyl, and

[0083] R1 = COOR4 and R4 = H, C 1-4 Alkyl, Aryl C 1-4Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0084] R2= H; R3= R5 and;

[0085] R5= R6= CONH-R9;

[0086] or

[0087] (B)

[0088] R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) n CO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6acyloxymethyl, C1-C6acyloxy-1-ethyl, C1-C6alkoxycarbonyloxymethyl, or C1-C6alkoxycarbonyloxy-1-ethyl, and

[0089] R1 = COOR4 and R4 = H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0090] R3= H and; R2= R5 and;

[0091] R5= R6= CONH-R9.

[0092] In the first embodiment, thus the present invention comprises a compound according to Table 1:

[0093] A. R3 = R5 = CONHR9 Compound No. Chemical names of compounds Ra Rb R4 R9 Ia-001a 4-(2-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 2-Carboxyphenyl Ia-001a-Tz 4-(2-(1H-tetrazole-5-yl)phenyl-aminocarbonyl)-2,5-dihydroxybenzoic acid H H H 2-(1H-tetrazole-5-yl)phenyl Ia-001c 2,5-Dihydroxy-4-(2-sulfophenylaminocarbonyl)benzoic acid H H H 2-sulfophenyl Ia-002a 4-(3-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 3-Carboxyphenyl Ia-002a-Tz 4-(3-(1H-tetrazole-5-yl)phenyl-aminocarbonyl)-2,5-dihydroxybenzoic acid H H H 3-(1H-tetrazole-5-yl)phenyl Ia-002c 2,5-Dihydroxy-4-(3-sulfophenylaminocarbonyl)benzoic acid H H H 3-sulfophenyl Ia-003a 4-(4-carboxyphenyl-aminocarbonyl)-2,5-dihydroxybenzoic acid H H H 4-Carboxyphenyl Ia-003a-Tz 4-(4-(1H-tetrazole-5-yl)phenyl-aminocarbonyl)-2,5-dihydroxybenzoic acid H H H 4-(1H-tetrazole-5-yl)phenyl Ia-003c 2,5-dihydroxy-4-(4-sulfophenylaminocarbonyl)benzoic acid H H H 4-sulfophenyl Ia-004a 4-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 3-Carboxy-4-hydroxyphenyl Ia-005a 4-(4-carboxy-3-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 4-Carboxy-3-hydroxyphenyl Ia-056a 4-(4-carboxy-2,5-dihydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 4-Carboxy-2,5-Dihydroxyphenyl Ia-006a 4-(2-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 2-Carboxy-4-hydroxyphenyl Ib-010a 3,5-bis(2,5-dihydroxy-4-carboxybenzoylamino)benzoic acid H H H Ia-011a 3-(4-carboxy-2,5-dihydroxybenzamido)phthalic acid; H H H 2,3-Dicarboxyphenyl Ia-012a 2-(4-carboxy-2,5-dihydroxybenzamido)terephthalic acid H H H 2,5-Dicarboxyphenyl Ia-013a Compound 36: 2-(4-carboxy-2,5-dihydroxybenzamido)isophthalic acid H H H 2,6-Dicarboxyphenyl Ia-014a Compound 38: 4-(4-carboxy-2,5-dihydroxybenzamido)phthalic acid H H H 3,4-Dicarboxyphenyl Ia-015a 5-(4-carboxy-2,5-dihydroxybenzamido)isophthalic acid H H H 3,5-Dicarboxyphenyl Ia-016a 2-(4-carboxy-2,5-dihydroxybenzamido)nicotinic acid H H H 3-Carboxypyridine-2-yl Ia-017a 2-(4-carboxy-2,5-dihydroxybenzamido)isonicotinic acid H H H 4-Carboxypyridine-2-yl Ia-018a 6-(4-carboxy-2,5-dihydroxybenzamido)nicotinic acid H H H 5-Carboxypyridine-2-yl Ia-019a 6-(4-carboxy-2,5-dihydroxybenzamido)picolinate H H H 6-Carboxypyridine-2-yl Ia-020a 2-(4-carboxy-2,5-dihydroxybenzamido)-5-fluoronicotinic acid H H H 3-carboxy-5-fluoropyridine-2-yl Ia-021a 6-(4-carboxy-2,5-dihydroxybenzamido)pyridine-2,5-dicarboxylic acid H H H 3,6-dicarboxypyridine-2-yl Ia-022a 2-(4-carboxy-2,5-dihydroxybenzamido)pyridine-3,5-dicarboxylic acid H H H 3,5-dicarboxypyridine-2-yl Ia-023a 3-(4-carboxy-2,5-dihydroxybenzamido)isonicotinic acid H H H 4-Carboxypyridine-3-yl Ia-024a 5-(4-carboxy-2,5-dihydroxybenzamido)nicotinic acid H H H 5-Carboxypyridine-3-yl Ia-025a 5-(4-carboxy-2,5-dihydroxybenzamido)picolinate H H H 6-Carboxypyridine-3-yl Ia-026a 3-(4-carboxy-2,5-dihydroxybenzamido)picolinate H H H 2-Carboxypyridine-3-yl Ia-027a 5-(4-carboxy-2,5-dihydroxybenzamido)-2-fluoroisonicotinic acid H H H 4-carboxy-6-fluoropyridine-3-yl Ia-028a 4-(4-carboxy-2,5-dihydroxybenzamido)nicotinic acid H H H 3-Carboxypyridine-4-yl Ia-029a 4-(4-carboxy-2,5-dihydroxybenzamido)picolinate H H H 2-Carboxypyridine-3-yl Ia-032a 4-(4-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 4-(carboxymethyl)phenyl Ia-033a 4-(3-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 3-(carboxymethyl)phenyl Ia-033a-HyP 2,5-Dihydroxy-4-(3-(1-hydroxy-1H-pyrazole-4-yl)phenylaminocarbonyl)benzoic acid H H H 3-(1-hydroxy-1H-pyrazole-4-yl)phenyl Ia-034a 4-(2-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 2-(carboxymethyl)phenyl Ia-001a-E2-A2 Ethyl 4-(2-(ethoxycarbonyl)phenylaminocarbonyl)-2,5-diacetoxybenzoate Ac Ac Et 2-(ethoxycarbonyl)phenyl Ia-001a-E2 Ethyl 4-(2-(ethoxycarbonyl)phenylaminocarbonyl)-2,5-dihydroxybenzoate H H Et 2-(ethoxycarbonyl)phenyl Ia-001a-Tz-E1-A2 Ethyl 4-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-diacetoxybenzoate Ac Ac Et 2-(1H-tetrazole-5-yl)phenyl Ia-001a-Tz-E1 Ethyl 4-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoate H H Et 2-(1H-tetrazole-5-yl)phenyl Ia-004a-E2 Ethyl 2,5-dihydroxy-4-(4-hydroxy-3-(methoxycarbonyl)phenylaminocarbonyl)benzoate H H Et 4-hydroxy-3-(methoxycarbonyl)phenyl Ib-010a-E3-A4 Ethyl 3,5-bis(2,5-diacetoxy-4-ethoxycarbonylbenzoylamino)benzoate Ac Ac Et Ib-010a- E3 Ethyl 3,5-bis(2,5-dihydroxy-4-ethoxycarbonylbenzoylamino)benzoate H H Et Ia-023a-E2 Ethyl 3-(4-(ethoxycarbonyl)-2,5-dihydroxybenzamido)isonicotinate H H Et 4-ethoxycarbonylpyridine-3-yl Ia-056a-E2 Compound 390: Ethyl 4-(4-ethoxycarbonyl-2,5-dihydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoate H H Et 4-ethoxycarbonyl-2,5-dihydroxyphenyl B. R2 = R5 = CONHR9 IIa-001a 3-(2-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 2-Carboxyphenyl IIa-001a-Tz 3-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 2-(1H-tetrazole-5-yl)phenyl IIa-001c 2,5-Dihydroxy-3-(2-sulfophenylaminocarbonyl)benzoic acid H H H 2-sulfophenyl IIa-002a 3-(3-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 3-Carboxyphenyl IIa-002a-Tz 3-(3-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 3-(1H-tetrazole-5-yl)phenyl IIa-002c 2,5-Dihydroxy-3-(3-sulfophenylaminocarbonyl)benzoic acid H H H 3-sulfophenyl IIa-003a 3-(4-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 4-Carboxyphenyl IIa-003a-Tz 3-(4-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 4-(1H-tetrazole-5-yl)phenyl IIa-003c 2,5-dihydroxy-3-(4-sulfophenylaminocarbonyl)benzoic acid H H H 4-sulfophenyl IIa-004a 3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 3-Carboxy-4-hydroxyphenyl IIa-005a 3-(4-carboxy-3-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 4-Carboxy-3-hydroxyphenyl IIa-006a 3-(2-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 2-Carboxy-4-hydroxyphenyl IIb-010a 3,5-bis(2,5-dihydroxy-3-carboxybenzoylamino)benzoic acid H H H IIa-011a 3-(3-carboxy-2,5-dihydroxybenzamido)phthalic acid H H H 2,3-Dicarboxyphenyl IIa-012a 2-(3-carboxy-2,5-dihydroxybenzamido)terephthalic acid H H H 2,5-Dicarboxyphenyl IIa-013a 2-(3-carboxy-2,5-dihydroxybenzamido)isophthalic acid H H H 2,6-Dicarboxyphenyl IIa-014a 4-(3-carboxy-2,5-dihydroxybenzamido)phthalic acid H H H 3,4-Dicarboxyphenyl IIa-015a 5-(3-carboxy-2,5-dihydroxybenzamido)isophthalic acid H H H 3,5-dicarboxylic acid IIa-016a 2-(3-carboxy-2,5-dihydroxybenzamido)nicotinic acid H H H 3-Carboxypyridine-2-yl IIa-017a 2-(3-carboxy-2,5-dihydroxybenzamido)isonicotinic acid H H H 4-Carboxypyridine-2-yl IIa-018a 6-(3-carboxy-2,5-dihydroxybenzamido)nicotinic acid H H H 5-Carboxypyridine-2-yl IIa-019a 6-(3-carboxy-2,5-dihydroxybenzamido)picolinate H H H 6-Carboxypyridine-2-yl IIa-020a 2-(3-carboxy-2,5-dihydroxybenzamido)-5-fluoronicotinic acid H H H 3-carboxy-5-fluoropyridine-2-yl IIa-021a 6-(3-carboxy-2,5-dihydroxybenzamido)pyridine-2,5-dicarboxylic acid H H H 3,6-dicarboxypyridine-2-yl IIa-022a 2-(3-carboxy-2,5-dihydroxybenzamido)pyridine-3,5-dicarboxylic acid H H H 3,5-dicarboxypyridine-2-yl IIa-023a 3-(3-carboxy-2,5-dihydroxybenzamido)isonicotinic acid H H H 4-Carboxypyridine-3-yl IIa-024a 5-(3-carboxy-2,5-dihydroxybenzamido)nicotinic acid H H H 5-Carboxypyridine-3-yl IIa-025a 5-(3-carboxy-2,5-dihydroxybenzamido)picolinate H H H 6-Carboxypyridine-3-yl IIa-026a 3-(3-carboxy-2,5-dihydroxybenzamido)picolinate H H H 2-Carboxypyridine-3-yl IIa-027a 5-(3-carboxy-2,5-dihydroxybenzamido)-2-fluoroisonicotinic acid H H H 4-carboxy-6-fluoropyridine-3-yl IIa-028a 4-(3-carboxy-2,5-dihydroxybenzamido)nicotinic acid H H H 3-Carboxypyridine-4-yl IIa-029a Compound 172: 4-(3-carboxy-2,5-dihydroxybenzamido)picolinic acid; H H H 2-Carboxypyridine-3-yl IIa-032a 3-(4-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 4-(carboxymethyl)phenyl IIa-033a 3-(3-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 3-(carboxymethyl)phenyl IIa-033a-Hyp 2,5-dihydroxy-3-(3-(1-hydroxy-1H-pyrazole-4-yl)phenylaminocarbonyl)benzoic acid H H H 3-(1-hydroxy-1H-pyrazole-4-yl)phenyl IIa-034a 3-(2-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid H H H 2-(carboxymethyl)phenyl IIa-001aTz-E1 Ethyl 3-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoate H H Et 2-(1H-tetrazole-5-yl)phenyl IIa-034a-E2 Ethyl 3-(2-(ethoxycarbonylmethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoate H H Et 2-(2-ethoxycarbonylmethyl)phenyl

[0094] Preferably, the present invention provides a compound of formula (I), wherein:

[0095] (A)

[0096] R a , R b = H and;

[0097] R1 = SO3H and;

[0098] R2= H; R3= R5 and;

[0099] R5= R6= CONH-R9;

[0100] or

[0101] (B)

[0102] R a , R b = H and;

[0103] R1 = SO3H and;

[0104] R3= H; R2= R5 and;

[0105] R5= R6= CONH-R9.

[0106] In a second embodiment, the present invention comprises a compound according to Table 2:

[0107] A. R3 = R5 = CONHR9 compound No. Chemical names of compounds Ra Rb R9 Ia-001b 2-(2,5-dihydroxy-4-sulfobenzamido)benzoic acid H H 2-Carboxyphenyl Ia-001d 2,5-Dihydroxy-4-(2-sulfophenylaminocarbonyl)benzenesulfonic acid H H 2-sulfophenyl Ia-002b 3-(2,5-dihydroxy-4-sulfobenzamido)benzoic acid H H 3-Carboxyphenyl Ia-002d 2,5-Dihydroxy-4-(3-sulfophenylaminocarbonyl)benzenesulfonic acid H H 3-sulfophenyl Ia-003b 4-(2,5-dihydroxy-4-sulfobenzamido)benzoic acid H H 4-Carboxyphenyl Ia-003d 2,5-Dihydroxy-4-(4-sulfophenylaminocarbonyl)benzenesulfonic acid H H 4-sulfophenyl Ia-004b 5-(2,5-dihydroxy-4-sulfobenzamido)-2-hydroxybenzoic acid H H 3-Carboxy-4-hydroxyphenyl Ia-005b 4-(2,5-dihydroxy-4-sulfobenzamido)-2-hydroxybenzoic acid H H 4-Carboxy-3-hydroxyphenyl Ia-006b 2-(2,5-dihydroxy-4-sulfobenzamido)-5-hydroxybenzoic acid H H 2-Carboxy-4-hydroxyphenyl Ib-010b 3,5-bis(2,5-dihydroxy-4-sulfobenzamido)benzoic acid H H Ia-011b 3-(2,5-dihydroxy-4-sulfobenzamido)phthalic acid H H 2,3-Dicarboxyphenyl Ia-012b 2-(2,5-dihydroxy-4-sulfobenzamido)terephthalic acid H H 2,5-Dicarboxyphenyl Ia-013b 2-(2,5-dihydroxy-4-sulfobenzamido)isophthalic acid H H 2,6-Dicarboxyphenyl Ia-014b 4-(2,5-dihydroxy-4-sulfobenzamido)phthalic acid H H 3,4-Dicarboxyphenyl Ia-015b 5-(2,5-dihydroxy-4-sulfobenzamido)isophthalic acid H H 3,5-Dicarboxyphenyl Ia-016b 2-(2,5-dihydroxy-4-sulfobenzamido)nicotinic acid H H 3-Carboxypyridine-2-yl Ia-017b 2-(2,5-dihydroxy-4-sulfobenzamido)isonicotinic acid H H 4-Carboxypyridine-2-yl Ia-018b 6-(2,5-dihydroxy-4-sulfobenzamido)nicotinic acid H H 5-Carboxypyridine-2-yl Ia-019b 6-(2,5-dihydroxy-4-sulfobenzamido)picolinate H H 6-Carboxypyridine-2-yl Ia-020b 2-(2,5-dihydroxy-4-sulfobenzamido)-5-fluoronicotinic acid H H 3-carboxy-5-fluoropyridine-2-yl Ia-021b 6-(2,5-dihydroxy-4-sulfobenzamido)pyridine-2,5-dicarboxylic acid H H 3,6-dicarboxypyridine-2-yl Ia-022b 2-(2,5-dihydroxy-4-sulfobenzamido)pyridine-3,5-dicarboxylic acid H H 3,5-dicarboxypyridine-2-yl Ia-023b 3-(2,5-dihydroxy-4-sulfobenzamido)isonicotinic acid H H 4-Carboxypyridine-3-yl Ia-024b 5-(2,5-dihydroxy-4-sulfobenzamido)nicotinic acid H H 5-Carboxypyridine-3-yl Ia-025b 5-(2,5-dihydroxy-4-sulfobenzamido)picolinate H H 6-Carboxypyridine-3-yl Ia-026a 3-(2,5-dihydroxy-4-sulfobenzamido)picolinate H H 2-Carboxypyridine-3-yl Ia-027b 5-(2,5-dihydroxy-4-sulfobenzamido)-2-fluoroisonicotinic acid H H 4-carboxy-6-fluoropyridine-3-yl Ia-028b 4-(2,5-dihydroxy-4-sulfobenzamido)nicotinic acid H H 3-Carboxypyridine-4-yl Ia-029b 4-(2,5-dihydroxy-4-sulfobenzamido)picolinate H H 2-Carboxypyridine-3-yl Ia-032b (4-(2,5-dihydroxy-4-sulfobenzamido)phenyl)acetic acid H H 4-(carboxymethyl)phenyl Ia-033b (3-(2,5-dihydroxy-4-sulfobenzamido)phenyl)acetic acid H H 3-(carboxymethyl)phenyl Ia-034b (2-(2,5-dihydroxy-4-sulfobenzamido)phenyl)acetic acid H H 2-(carboxymethyl)phenyl B. R2 = R5 = CONHR9 IIa-001b 2-(2,5-dihydroxy-3-sulfobenzamido)benzoic acid H H 2-Carboxyphenyl IIa-001d 2,5-Dihydroxy-3-(2-sulfophenylaminocarbonyl)benzenesulfonic acid H H 2-sulfophenyl IIa-002b 3-(2,5-dihydroxy-3-sulfobenzamido)benzoic acid H H 3-Carboxyphenyl IIa-002d 2,5-Dihydroxy-3-(3-sulfophenylaminocarbonyl)benzenesulfonic acid H H 3-sulfophenyl IIa-003b 4-(2,5-dihydroxy-3-sulfobenzamido)benzoic acid H H 4-Carboxyphenyl IIa-003d 2,5-Dihydroxy-3-(4-sulfophenylaminocarbonyl)benzenesulfonic acid H H 4-sulfophenyl IIa-004b 5-(2,5-dihydroxy-3-sulfobenzamido)-2-hydroxybenzoic acid H H 3-Carboxy-4-hydroxyphenyl IIa-005b 4-(2,5-dihydroxy-3-sulfobenzamido)-2-hydroxybenzoic acid; H H 4-Carboxy-3-hydroxyphenyl IIa-006b 2-(2,5-dihydroxy-3-sulfobenzamido)-5-hydroxybenzoic acid H H 2-Carboxy-4-hydroxyphenyl IIb-010b 3-(2,5-dihydroxy-3-sulfobenzamido)-5-(2,5-dihydroxy-4-sulfobenzamido)benzoic acid H H IIa-011b 3-(2,5-dihydroxy-3-sulfobenzamido)phthalic acid; H H 2,3-Dicarboxyphenyl IIa-012b 2-(2,5-dihydroxy-3-sulfobenzamido)terephthalic acid H H 2,5-Dicarboxyphenyl IIa-013b 2-(2,5-dihydroxy-3-sulfobenzamido)isophthalic acid H H 2,6-Dicarboxyphenyl IIa-014b 4-(2,5-dihydroxy-3-sulfobenzamido)phthalic acid H H 3,4-Dicarboxyphenyl IIa-015b 5-(2,5-dihydroxy-3-sulfobenzamido)isophthalic acid H H 3,5-Dicarboxyphenyl IIa-016b 2-(2,5-dihydroxy-3-sulfobenzamido)nicotinic acid H H 3-Carboxypyridine-2-yl IIa-017b 2-(2,5-dihydroxy-3-sulfobenzamido)isonicotinic acid H H 4-Carboxypyridine-2-yl IIa-018b 6-(2,5-dihydroxy-3-sulfobenzamido)nicotinic acid H H 5-Carboxypyridine-2-yl IIa-019b 6-(2,5-dihydroxy-3-sulfobenzamido)picolinate H H 6-Carboxypyridine-2-yl IIa-020b 2-(2,5-dihydroxy-3-sulfobenzamido)-5-fluoronicotinic acid H H 3-carboxy-5-fluoropyridine-2-yl IIa-021b 6-(2,5-dihydroxy-3-sulfobenzamido)pyridine-2,5-dicarboxylic acid; H H 3,6-dicarboxypyridine-2-yl IIa-022b 2-(2,5-dihydroxy-3-sulfobenzamido)pyridine-3,5-dicarboxylic acid H H 3,5-dicarboxypyridine-2-yl IIa-023b 3-(2,5-dihydroxy-3-sulfobenzamido)isonicotinic acid H H 4-Carboxypyridine-3-yl IIa-024b 5-(2,5-dihydroxy-3-sulfobenzamido)nicotinic acid H H 5-Carboxypyridine-3-yl IIa-025b 5-(2,5-dihydroxy-3-sulfobenzamido)picolinate H H 6-Carboxypyridine-3-yl IIa-026b 3-(2,5-dihydroxy-3-sulfobenzamido)picolinate H H 2-Carboxypyridine-3-yl IIa-027b 5-(2,5-dihydroxy-3-sulfobenzamido)-2-fluoroisonicotinic acid H H 4-carboxy-6-fluoropyridine-3-yl IIa-028b 4-(2,5-dihydroxy-3-sulfobenzamido)nicotinic acid H H 3-Carboxypyridine-4-yl IIa-029b Compound 173: 4-(2,5-dihydroxy-3-sulfobenzamido)picolinate H H 2-Carboxypyridine-3-yl IIa-032b (4-(2,5-dihydroxy-3-sulfobenzamido)phenyl)acetic acid H H 4-(carboxymethyl)phenyl IIa-033b (3-(2,5-dihydroxy-3-sulfobenzamido)phenyl)acetic acid H H 3-(carboxymethyl)phenyl IIa-034b (2-(2,5-dihydroxy-3-sulfobenzamido)phenyl)acetic acid H H 2-(carboxymethyl)phenyl

[0108] Preferably, the present invention provides a hydroquinone derivative compound of formula (I), wherein:

[0109] (A)

[0110] R a , R b = H and;

[0111] R1= (CH2) n COOR4 and; R4= H, C 1-4 Alkyl, Aryl C 1-4Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0112] R2= H; R3= R5 and;

[0113] R5= R6= CONH-R9 or;

[0114] or

[0115] (B)

[0116] R a , R b = H and;

[0117] R1= (CH2) n COOR4 and; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0118] R3= H; R2= R5 and;

[0119] R5= R6= CONH-R9.

[0120] In a third embodiment, the present invention comprises a compound according to Table 3:

[0121] A. R3 = R5 = R6 = CONH-R9 Compound No. Chemical names of compounds R1 Ra Rb R9 IIIa-001a 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)benzoic acid CH2COOH H H 2-Carboxyphenyl IIIa-001a-Tz (2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid CH2COOH H H 2-(1H-tetrazole-5-yl)phenyl IIIa-001c (2,5-dihydroxy-4-(2-sulfophenylaminocarbonyl)phenyl)acetic acid CH2COOH H H 2-sulfophenyl IIIa-002a 3-(4-(carboxymethyl)-2,5-dihydroxybenzamido)benzoic acid; CH2COOH H H 3-Carboxyphenyl IIIa-002c (2,5-dihydroxy-4-(3-sulfophenylaminocarbonyl)phenyl)acetic acid; CH2COOH H H 3-sulfophenyl IIIa-003a 4-(4-(carboxymethyl)-2,5-dihydroxybenzamido)benzoic acid; CH2COOH H H 4-Carboxyphenyl IIIa-003c 2-(2,5-dihydroxy-4-(4-sulfophenylaminocarbonyl)phenyl)acetic acid; CH2COOH H H 4-sulfophenyl IIIa-004a Compound 216: 5-(4-(carboxymethyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid CH2COOH H H 3-Carboxy-4-hydroxyphenyl IIIa-005a 4-(4-(carboxymethyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid CH2COOH H H 4-Carboxy-3-hydroxyphenyl IIIa-006a 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)-5-hydroxybenzoic acid CH2COOH H H 2-Carboxy-4-hydroxyphenyl IIIb-010a 3,5-bis(2,5-dihydroxy-4-carboxymethylbenzoylamino)benzoic acid CH2COOH H H IIIa-011a 3-(4-(carboxymethyl)-2,5-dihydroxybenzamido)phthalic acid CH2COOH H H 2,3-Dicarboxyphenyl IIIa-012a 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)terephthalic acid CH2COOH H H 2,5-Dicarboxyphenyl IIIa-013a 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)isophthalic acid CH2COOH H H 2,6-Dicarboxyphenyl IIIa-014a 4-(4-(carboxymethyl)-2,5-dihydroxybenzamido)phthalic acid CH2COOH H H 3,4-Dicarboxyphenyl IIIa-015a 5-(4-(carboxymethyl)-2,5-dihydroxybenzamido)isophthalic acid CH2COOH H H 3,5-Dicarboxyphenyl IIIa-016a 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)nicotinic acid CH2COOH H H 3-Carboxypyridine-2-yl IIIa-017a 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)isonicotinic acid CH2COOH H H 4-Carboxypyridine-2-yl IIIa-018a 6-(4-(carboxymethyl)-2,5-dihydroxybenzamido)nicotinic acid CH2COOH H H 5-Carboxypyridine-2-yl IIIa-019a 6-(4-(carboxymethyl)-2,5-dihydroxybenzamido)picolinate CH2COOH H H 6-Carboxypyridine-2-yl IIIa-020a 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)-5-fluoronicotinic acid CH2COOH H H 3-carboxy-5-fluoropyridine-2-yl IIIa-021a 6-(4-(carboxymethyl)-2,5-dihydroxybenzamido)pyridine-2,5-dicarboxylic acid CH2COOH H H 3,6-dicarboxypyridine-2-yl IIIa-022a 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)pyridine-3,5-dicarboxylic acid CH2COOH H H 3,5-dicarboxypyridine-2-yl IIIa-023a 3-(4-(carboxymethyl)-2,5-dihydroxybenzamido)isonicotinic acid; CH2COOH H H 4-Carboxypyridine-3-yl IIIa-024a 5-(4-(carboxymethyl)-2,5-dihydroxybenzamido)nicotinic acid CH2COOH H H 5-Carboxypyridine-3-yl IIIa-025a 5-(4-(carboxymethyl)-2,5-dihydroxybenzamido)picolinate CH2COOH H H 6-Carboxypyridine-3-yl IIIa-026a 3-(4-(carboxymethyl)-2,5-dihydroxybenzamido)picolinate CH2COOH H H 2-Carboxypyridine-3-yl IIIa-027a 5-(4-(carboxymethyl)-2,5-dihydroxybenzamido)-2-fluoroisonicotinic acid CH2COOH H H 4-carboxy-6-fluoropyridine-3-yl IIIa-028a 4-(4-(carboxymethyl)-2,5-dihydroxybenzamido)nicotinic acid; CH2COOH H H 3-Carboxypyridine-4-yl IIIa-029a 4-(4-(carboxymethyl)-2,5-dihydroxybenzamido)picolinic acid; CH2COOH H H 2-Carboxypyridine-3-yl IIIa-032a (4-(4-(carboxymethyl)-2,5-dihydroxybenzamido)phenyl)acetic acid CH2COOH H H 4-(carboxymethyl)phenyl IIIa-033a (3-(4-(carboxymethyl)-2,5-dihydroxybenzamido)phenyl)acetic acid CH2COOH H H 3-(carboxymethyl)phenyl IIIa-034a (2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)phenyl)acetic acid CH2COOH H H 2-(carboxymethyl)phenyl IIIa-001a-E2 Methyl 2-(4-(ethoxycarbonylmethyl)-2,5-dihydroxybenzamido)benzoate CH2COOEt H H 2-(methoxycarbonyl)phenyl IIIa-001aTz-E1 Compound 383: Ethyl (4-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxyphenyl)acetate; CH2COOEt H H 2-(1H-tetrazole-5-yl)phenyl IIIa-015a-E3 Diethyl 5-(4-(ethoxycarbonylmethyl)-2,5-dihydroxybenzamido)isophthalate CH2COOEt H H 3,5-Diethoxycarbonylphenyl IIIb-010a-E3 Methyl 3,5-bis(4-(ethoxycarbonylmethyl)-2,5-dihydroxybenzamido)benzoate CH2COOEt H H B. R2 = R5 = R6 = CONHR9 IVa-001a 2-(3-(carboxymethyl)-2,5-dihydroxybenzamido)benzoic acid CH2COOH H H 2-Carboxyphenyl IVa-001c (2,5-dihydroxy-3-(2-sulfophenylaminocarbonyl)phenyl)acetic acid CH2COOH H H 2-sulfophenyl IVa-002a 3-(3-(carboxymethyl)-2,5-dihydroxybenzamido)benzoic acid CH2COOH H H 3-Carboxyphenyl IVa-002c (2,5-dihydroxy-3-(3-sulfophenylaminocarbonyl)phenyl)acetic acid CH2COOH H H 3-sulfophenyl IVa-003a 4-(3-(carboxymethyl)-2,5-dihydroxybenzamido)benzoic acid CH2COOH H H 4-Carboxyphenyl IVa-003c (2,5-dihydroxy-3-(4-sulfophenylaminocarbonyl)phenyl)acetic acid CH2COOH H H 4-sulfophenyl IVa-004a 5-(3-(carboxymethyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid CH2COOH H H 3-Carboxy-4-hydroxyphenyl IVa-005a 4-(3-(carboxymethyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid CH2COOH H H 4-Carboxy-3-hydroxyphenyl IVa-006a Compound 295: 2-(3-(carboxymethyl)-2,5-dihydroxybenzamido)-5-hydroxybenzoic acid; CH2COOH H H 2-Carboxy-4-hydroxyphenyl IVb-010a 3,5-bis(2,5-dihydroxy-3-carboxymethylbenzoylamino)benzoic acid CH2COOH H H IVa-011a 3-(3-(carboxymethyl)-2,5-dihydroxybenzamido)phthalic acid CH2COOH H H 2,3-Dicarboxyphenyl IVa-012a 2-(3-(carboxymethyl)-2,5-dihydroxybenzamido)terephthalic acid CH2COOH H H 2,5-Dicarboxyphenyl IVa-013a 2-(3-(carboxymethyl)-2,5-dihydroxybenzamido)isophthalic acid CH2COOH H H 2,6-Dicarboxyphenyl IVa-014a 4-(3-(carboxymethyl)-2,5-dihydroxybenzamido)phthalic acid CH2COOH H H 3,4-Dicarboxyphenyl IVa-015a 5-(3-(carboxymethyl)-2,5-dihydroxybenzamido)isophthalic acid CH2COOH H H 3,5-Dicarboxyphenyl IVa-016a 2-(3-(carboxymethyl)-2,5-dihydroxybenzamido)nicotinic acid CH2COOH H H 3-Carboxypyridine-2-yl IVa-017a 2-(3-(carboxymethyl)-2,5-dihydroxybenzamido)isonicotinic acid CH2COOH H H 4-Carboxypyridine-2-yl IVa-018a 6-(3-(carboxymethyl)-2,5-dihydroxybenzamido)nicotinic acid CH2COOH H H 5-Carboxypyridine-2-yl IVa-019a 6-(3-(carboxymethyl)-2,5-dihydroxybenzamido)picolinate CH2COOH H H 6-Carboxypyridine-2-yl IVa-020a 2-(3-(carboxymethyl)-2,5-dihydroxybenzamido)-5-fluoronicotinic acid CH2COOH H H 3-carboxy-5-fluoropyridine-2-yl IVa-021a 6-(3-(carboxymethyl)-2,5-dihydroxybenzamido)pyridine-2,5-dicarboxylic acid CH2COOH H H 3,6-dicarboxypyridine-2-yl IVa-022a 2-(3-(carboxymethyl)-2,5-dihydroxybenzamido)pyridine-3,5-dicarboxylic acid CH2COOH H H 3,5-dicarboxypyridine-2-yl IVa-023a 3-(3-(carboxymethyl)-2,5-dihydroxybenzamido)isonicotinic acid CH2COOH H H 4-Carboxypyridine-3-yl IVa-024a 5-(3-(carboxymethyl)-2,5-dihydroxybenzamido)nicotinic acid CH2COOH H H 5-Carboxypyridine-3-yl IVa-025a 5-(3-(carboxymethyl)-2,5-dihydroxybenzamido)picolinate CH2COOH H H 6-Carboxypyridine-3-yl IVa-026a 3-(3-(carboxymethyl)-2,5-dihydroxybenzamido)picolinate CH2COOH H H 2-Carboxypyridine-3-yl IVa-027a 5-(3-(carboxymethyl)-2,5-dihydroxybenzamido)-2-fluoroisonicotinic acid CH2COOH H H 4-carboxy-6-fluoropyridine-3-yl IVa-028a 4-(3-(carboxymethyl)-2,5-dihydroxybenzamido)nicotinic acid CH2COOH H H 3-Carboxypyridine-4-yl IVa-029a 4-(3-(carboxymethyl)-2,5-dihydroxybenzamido)picolinate CH2COOH H H 2-Carboxypyridine-3-yl IVa-032a (4-(3-(carboxymethyl)-2,5-dihydroxybenzamido)phenyl)acetic acid CH2COOH H H 4-(carboxymethyl)phenyl IVa-033a (3-(3-(carboxymethyl)-2,5-dihydroxybenzamido)phenyl)acetic acid CH2COOH H H 3-(carboxymethyl)phenyl IVa-034a (2 -(3-(carboxymethyl)-2,5-dihydroxybenzamido)phenyl)acetic acid CH2COOH H H 2-(carboxymethyl)phenyl

[0122] Preferably, the present invention provides a hydroquinone derivative compound of formula (I); wherein:

[0123] (A)

[0124] R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) n CO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6acyloxymethyl, C1-C6acyloxy-1-ethyl, C1-C6alkoxycarbonyloxymethyl, or C1-C6alkoxycarbonyloxy-1-ethyl;

[0125] R1= CONH-R 10 And; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0126] R2= H and; R3= R5 and;

[0127] R5= R6= CONH-R9 or;

[0128] or

[0129] (B)

[0130] R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) n CO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6acyloxymethyl, C1-C6acyloxy-1-ethyl, C1-C6alkoxycarbonyloxymethyl, or C1-C6alkoxycarbonyloxy-1-ethyl;

[0131] R1= CONH-R10 And; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0132] R3= H and; R2= R5 and;

[0133] R5= R6= CONH-R9.

[0134] In a fourth embodiment, the present invention comprises a compound according to Table 4:

[0135] A. R3 = R5 = R6 = CONH-R 9 Compound No. Chemical names of compounds Ra Rb R10 R9 Ic-001a-Tz / 1-004a 5-(4-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid H H 3-Carboxy-4-hydroxyphenyl 2-(1H-tetrazole-5-yl)phenyl Ic-001a-Tz(2) N1,N4-bis(2-(1H-tetrazole-5-yl)phenyl)-2,5-dihydroxyterephthalamide H H 2-(1H-tetrazole-5-yl)phenyl 2-(1H-tetrazole-5-yl)phenyl Ic-007a 5-(4-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid; H H 3-Carboxy-4-hydroxyphenyl 3-Carboxy-4-hydroxyphenyl Ic-007b 5-(2,5-dihydroxy-4-(4-hydroxy-3-sulfophenylaminocarbonyl)benzamido)-2-hydroxybenzenesulfonic acid H H 4-hydroxy-3-sulfonylphenyl 4-hydroxy-3-sulfonylphenyl Ic-008a 4-(4-(4-carboxy-3-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid H H 4-Carboxy-3-hydroxyphenyl 4-Carboxy-3-hydroxyphenyl Ic-008b 4-(2,5-dihydroxy-4-(3-hydroxy-4-sulfophenylaminocarbonyl)benzamido)-2-hydroxybenzenesulfonic acid H H 3-hydroxy-4-sulfonylphenyl 3-hydroxy-4-sulfonylphenyl Ic-009a 2-(2,5-dihydroxy-4-(4-hydroxy-2-carboxyphenylaminocarbonyl)benzamido)-5-hydroxybenzoic acid H H 2-Carboxy-4-hydroxyphenyl 2-Carboxy-4-hydroxyphenyl Ic-009b 2-(2,5-dihydroxy-4-(4-hydroxy-2-sulfophenylaminocarbonyl)benzamido)-5-hydroxybenzenesulfonic acid H H 4-hydroxy-2-sulfophenyl 4-hydroxy-2-sulfophenyl Ib-001a-Tz / 1-004a-E1 Methyl 5-(4-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoate; H H 4-hydroxy-3-(methoxycarbonyl)phenyl- 2-(1H-tetrazole-5-yl)phenyl Ic-007a-E2-A4 Methyl 5-(2,5-diacetoxy-4-(4-acetoxy-3-(methoxycarbonyl)phenylaminocarbonyl)benzamido)-2-acetoxybenzoate; Ac Ac 4-acetoxy-3-(methoxycarbonyl)phenyl 4-acetoxy-3-(methoxycarbonyl)phenyl Ic-007a-E2 Methyl 5-(2,5-dihydroxy-4-(4-hydroxy-3-(methoxycarbonyl)phenylaminocarbonyl)benzamido)-2-hydroxybenzoate; H H 4-hydroxy-3-(methoxycarbonyl)phenyl 4-hydroxy-3-(methoxycarbonyl)phenyl Ic-007a-pive2 1-(2,2-dimethylpropanoyloxy)ethyl 5-[[4-[[3-[1-(2,2-dimethylpropanoyloxy)ethoxycarbonyl]-4-hydroxy-phenyl]carbamoyl]-2,5-dihydroxy-benzoyl]amino]-2-hydroxybenzoate H H 3-[1-(2,2-dimethylpropanoyloxy)ethoxycarbonyl]-4-hydroxyphenyl 3-[1-(2,2-dimethylpropanoyloxy)ethoxycarbonyl]-4-hydroxyphenyl Ic-009a-E2 : Methyl 2-(2,5-dihydroxy-4-(4-hydroxy-2-(methoxycarbonyl)phenylaminocarbonyl)benzamido)-5-hydroxybenzoate H H 4-hydroxy-2-(methoxycarbonyl)phenyl 4-hydroxy-2-(methoxycarbonyl)phenyl B. R2 = R5 = R6 = CONH-R9 IIc-007a 5-(3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid H H 3-Carboxy-4-hydroxyphenyl 3-Carboxy-4-hydroxyphenyl IIc-007b 5-(2,5-dihydroxy-3-(4-hydroxy-3-sulfophenylaminocarbonyl)benzamido)-2-hydroxybenzenesulfonic acid H H 4-hydroxy-3-sulfophenyl 4-hydroxy-3-sulfophenyl IIc-008a 4-(3-(3-hydroxy-4-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid H H 3-hydroxy-4-carboxyphenyl 3-hydroxy-4-carboxyphenyl IIc-008b 4-(2,5-dihydroxy-3-(3-hydroxy-4-sulfophenylaminocarbonyl)benzamido)-2-hydroxybenzenesulfonic acid H H 3-hydroxy-4-sulfophenyl 3-hydroxy-4-sulfophenyl IIc-009a 2-(3-(2-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-5-hydroxybenzoic acid H H 2-Carboxy-4-hydroxyphenyl 2-Carboxy-4-hydroxyphenyl IIc-009b 2-(2,5-dihydroxy-3-(4-hydroxy-2-sulfophenylaminocarbonyl)benzamido)-5-hydroxybenzenesulfonic acid H H 4-hydroxy-2-sulfophenyl 4-hydroxy-2-sulfophenyl

[0136] Preferably, the present invention provides a hydroquinone derivative compound of formula (I), wherein:

[0137] (A)

[0138] R a , R b = H and;

[0139] R1= COOR4; (CH2) n COOR4 and; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0140] R2= H and; R3= R5 and;

[0141] R5= R6= CONHCOR9 or;

[0142] or

[0143] (B)

[0144] R a , R b = H and;

[0145] R1= COOR4; (CH2) n COOR4 and; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0146] R3= H and; R2= R5 and;

[0147] R5= R6= CONHCOR9.

[0148] In the fifth embodiment, the present invention comprises a compound according to Table 5:

[0149] A. R3 = R5 = R6 = CONHCOR 9 Compound No. Chemical names of compounds R1 R9 Ia-040a N-(1,3,4,5-tetrahydroxycyclohexylcarbonyl) 4-carboxy-2,5-dihydroxybenzamide COOH Ia-041a N-(4-carboxy-2,5-dihydroxybenzoyl) 4-carboxy-2,5-dihydroxy-benzamide COOH 2,5-Dihydroxy-4-Carboxyphenyl Ia-042a N-(3-carboxy-2,5-dihydroxybenzoyl) 4-carboxy-2,5-dihydroxy-benzamide COOH 2,5-Dihydroxy-3-Carboxyphenyl Ia-043a N-(3,4-dihydroxybenzoyl) 4-carboxy-2,5-dihydroxybenzamide COOH 3,4-Dihydroxyphenyl Ia-044a N-(3,5-dihydroxybenzoyl) 4-carboxy-2,5-dihydroxybenzamide COOH 3,5-Dihydroxyphenyl IIIa-040a N-(1,3,4,5-tetrahydroxycyclohexylcarbonyl) 3-carboxy-2,5-dihydroxybenzamide CH2COOH IIIa-041a N-(4-carboxy-2,5-dihydroxybenzoyl) 3-carboxy-2,5-dihydroxy-benzamide CH2COOH 2,5-Dihydroxy-4-Carboxyphenyl IIIa-042a N-(3-carboxy-2,5-dihydroxybenzoyl) 3-carboxy-2,5-dihydroxy-benzamide CH2COOH 2,5-Dihydroxy-3-Carboxyphenyl IIIa-043a N-(3,4-dihydroxybenzoyl) 3-carboxy-2,5-dihydroxybenzamide CH2COOH 3,4-Dihydroxyphenyl IIIa-044a N-(3,5-dihydroxybenzoyl) 3-carboxy-2,5-dihydroxybenzamide CH2COOH 3,5-Dihydroxyphenyl B. R2 = R5 = R6 = CONHCOR9 IIa-040a N-(1,3,4,5-tetrahydroxycyclohexylcarbonyl) 4-carboxymethyl-2,5-dihydroxybenzamide COOH IIa-041a N-(4-carboxy-2,5-dihydroxybenzoyl) 4-carboxymethyl-2,5-dihydroxy-benzamide COOH 2,5-Dihydroxy-4-Carboxyphenyl IIa-042a N-(3-carboxy-2,5-dihydroxybenzoyl) 4-carboxymethyl-2,5-dihydroxy-benzamide COOH 2,5-Dihydroxy-3-Carboxyphenyl IIa-043a N-(3,4-dihydroxybenzoyl) 4-carboxymethyl-2,5-dihydroxybenzamide COOH 3,4-Dihydroxyphenyl IIa-044a N-(3,5-dihydroxybenzoyl) 4-carboxymethyl-2,5-dihydroxybenzamide COOH 3,5-Dihydroxyphenyl IVa-040a N-(1,3,4,5-tetrahydroxycyclohexylcarbonyl) 3-carboxymethyl-2,5-dihydroxybenzamide CH2COOH IVa-041a N-(4-carboxy-2,5-dihydroxybenzoyl) 3-carboxymethyl-2,5-dihydroxy-benzamide CH2COOH 2,5-Dihydroxy-4-Carboxyphenyl IVa-042a N-(3-carboxy-2,5-dihydroxybenzoyl) 3-carboxymethyl-2,5-dihydroxy-benzamide CH2COOH 2,5-Dihydroxy-3-Carboxyphenyl IVa-043a N-(3,4-dihydroxybenzoyl) 3-carboxymethyl-2,5-dihydroxybenzamide CH2COOH 3,4-Dihydroxyphenyl IVa-044a N-(3,5-dihydroxybenzoyl) 3-carboxymethyl-2,5-dihydroxybenzamide CH2COOH 3,5-Dihydroxyphenyl

[0150] Preferably, the present invention provides a hydroquinone derivative compound of formula (I); wherein

[0151] (A)

[0152] R a , R b = H and;

[0153] R1= COOR4; (CH2) n COOR4 and; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl,o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0154] R2= H and; R3= R5 and;

[0155] R5= R6= CONH(CH2) n -R9 or;

[0156] or

[0157] (B)

[0158] R a , R b = H and;

[0159] R1= COOR4; (CH2) n COOR4 and; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0160] R3= H and; R2= R5 and;

[0161] R5= R6= CONH(CH2) n It is -R9.

[0162] In the sixth embodiment, the present invention comprises a compound according to Table 6:

[0163] A. R3 = R5 = R6 = CONH(CH 2 ) n -R 9 Compound No. Chemical names of compounds R1 n R9 Ia-035a 4-(3,4-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid; COOH 1 3,4-Dihydroxyphenyl Ia-035a-2 4-(2-(3,4-dihydroxyphenyl)ethylaminocarbonyl)-2,5-dihydroxybenzoic acid; COOH 2 3,4-Dihydroxyphenyl Ia-037a 4-(3,5-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid; COOH 1 3,5-Dihydroxyphenyl Ia-038a 4-((4,5-dihydroxy-3-oxocyclohex-1-enyl)methylaminocarbonyl)-2,5-dihydroxybenzoic acid; COOH 1 4,5-Dihydroxy-3-oxocyclohex-1-enyl) Ia-039a 2,5-Dihydroxy-4-((3,4,5-Trihydroxycyclohexyl)methylaminocarbonyl)benzoic acid COOH 1 3,4,5-trihydroxycyclohexyl) Ia-053a 4-(2-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid COOH 1 2-Carboxyphenyl Ia-054a 4-(3-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid COOH 1 3-Carboxyphenyl Ia-055a 4-(4-carboxyphenylmethylaminocarbonyl)2,5-dihydroxybenzoic acid COOH 1 4-Carboxyphenyl IIIa-035a 3-(3,4-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid CH2COOH 1 3,4-Dihydroxyphenyl IIIa-037a 3-(2-(3,4-dihydroxyphenyl)ethylaminocarbonyl)-2,5-dihydroxybenzoic acid CH2COOH 1 3,5-Dihydroxyphenyl IIIa-038a 3-(3,5-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid CH2COOH 1 4-((4,5-dihydroxy-3-oxocyclohex-1-enyl) IIIa-039a 3-((4,5-dihydroxy-3-oxocyclohex-1-enyl)methylaminocarbonyl)-2,5-dihydroxybenzoic acid CH2COOH 1 3,4,5-trihydroxycyclohexyl) IIIa-053a 2,5-Dihydroxy-3-((3,4,5-Trihydroxycyclohexyl)methylaminocarbonyl)benzoic acid CH2COOH 1 2-Carboxyphenyl IIIa-054a 3-(2-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid CH2COOH 1 3-Carboxyphenyl IIIa-055a 3-(3-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid CH2COOH 1 4-Carboxyphenyl B. R2 = R5 = R6 = CONH(CH2)n-R9 IIa-035a 3-(4-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid COOH 1 3,4-Dihydroxyphenyl IIa-035a-2 (4-(3,4-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid COOH 2 3,4-Dihydroxyphenyl IIa-037a (4-(3,5-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid COOH 1 3,5-Dihydroxyphenyl IIa-038a (4-((4,5-dihydroxy-3-oxocyclohex-1-enyl)methylaminocarbonyl)-2,5-dihydroxyphenyl) acetic acid COOH 1 4,5-Dihydroxy-3-oxocyclohex-1-enyl) IIa-039a Compound 191: (2,5-dihydroxy-4-((3,4,5-trihydroxycyclohexyl)methylaminocarbonyl)phenyl)acetic acid COOH 1 3,4,5-trihydroxycyclohexyl IIa-053a (4-(2-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid COOH 1 2-Carboxyphenyl IIa-054a (4-(3-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid COOH 1 3-Carboxyphenyl IIa-055a (4-(4-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid COOH 1 4-Carboxyphenyl IVa-035a (3-(3,4-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid CH2COOH 1 3,4-Dihydroxyphenyl IVa-037a (3-(3,5-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid CH2COOH 1 3,5-Dihydroxyphenyl IVa-038a (3-((4,5-dihydroxy-3-oxocyclohex-1-enyl)methylaminocarbonyl)-2,5-dihydroxyphenyl) acetic acid CH2COOH 1 4,5-Dihydroxy-3-oxocyclohex-1-enyl) IVa-039a (2,5-dihydroxy-3-((3,4,5-trihydroxycyclohexyl)methylcarbonylamino)phenyl)acetic acid CH2COOH 1 3,4,5-trihydroxycyclohexyl IVa-053a (3-(2-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid CH2COOH 1 2-Carboxyphenyl IVa-054a (3-(3-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid CH2COOH 1 3-Carboxyphenyl IVa-055a (3-(4-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid CH2COOH 1 4-Carboxyphenyl

[0164] Preferably, the present invention provides a hydroquinone derivative compound of formula (I), wherein:

[0165] R a, R b = H and;

[0166] R1 = SO3H and;

[0167] R2= H and; R3= R5 and;

[0168] R5= R6= CONH(CH2) n It is -R9.

[0169] According to the seventh embodiment, the present invention comprises a compound according to Table 7 below:

[0170] R3 = R5 = CONH(CH 2 ) n -R 9 Compound No. Chemical names of compounds n R9 Ia-053b 2-((2,5-dihydroxy-4-sulfobenzamido)methyl)benzoic acid 1 2-Carboxyphenyl Ia-054b 3-((2,5-dihydroxy-4-sulfobenzamido)methyl)benzoic acid 1 3-Carboxyphenyl Ia-055b 4-((2,5-dihydroxy-4-sulfobenzamido)methyl)benzoic acid 1 4-Carboxyphenyl

[0171] Preferably, the present invention relates to a hydroquinone derivative compound of formula (I), wherein:

[0172] (A)

[0173] R a , R b = H and;

[0174] R1= COOR4; (CH2) n COOR4 and; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0175] R2= H and; R3= R5 and;

[0176] R5= R6= CONHCH(COOR4)(CH2) k -R9 or;

[0177] or

[0178] (B)

[0179] R a , R b = H and;

[0180] R1= COOR4; (CH2) n COOR4 and; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0181] R3= H and; R2= R5 and;

[0182] R5= R6= CONHCH(COOR4)(CH2) k It is -R9.

[0183] In the eighth embodiment, the present invention comprises a compound according to Table 8 below:

[0184] A. R 3 = R 5 = R 6 = CONHCH(COOR 4 )(CH 2 ) k R 9 Compound No. Chemical names of compounds R1 R4 k R9 Ia-035a-3 4-(1-carboxy-2-(3,4-dihydroxyphenyl)ethylaminocarbonyl)-2,5-dihydroxybenzoic acid COOH H 1 3,4-Dihydroxyphenyl Ia-036a 4-(carboxy(3,4-dihydroxyphenyl)methylaminocarbonyl)-2,5-dihydroxybenzoic acid COOH H 0 3,4-Dihydroxyphenyl IIIa-036a 3-(1-carboxy-2-(3,4-dihydroxyphenyl)ethylaminocarbonyl)-2,5-dihydroxybenzoic acid CH2COOH H 0 3,4-Dihydroxyphenyl B. R 2 = R 5 = R 6 = CONHCH(COOR 4 )(CH 2 ) k R 9 IIa-035a-3 3-(carboxy(3,4-dihydroxyphenyl)methylaminocarbonyl)-2,5-dihydroxybenzoic acid COOH H 1 3,4-Dihydroxyphenyl IIa-036a (4-(carboxy(3,4-dihydroxyphenyl)methylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid COOH H 0 3,4-Dihydroxyphenyl IVa-036a (3-(carboxy(3,4-dihydroxyphenyl)methylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid CH2COOH H 0 3,4-Dihydroxyphenyl

[0185] In certain embodiments, the present invention provides a hydroquinone derivative compound of formula (I), wherein

[0186] (A)

[0187] R a , R b = H and;

[0188] R1= COOR4; (CH2) n COOR4; SO3H, (CH2) n SO3H, or CONH-R 10 And;

[0189] R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0190] R2= H and; R3= R5 and;

[0191] R5= R6= Heteroaryl-R9 or;

[0192] or

[0193] (B)

[0194] R a , R b = H and;

[0195] R1= COOR4; (CH2) n COOR4; SO3H, (CH2) n SO3H, or CONH-R 10 And;

[0196] R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0197] R3= H and; R2= R5 and;

[0198] R5= R6= is heteroaryl-R9.

[0199] According to the ninth embodiment, the present invention comprises a compound according to Table 9:

[0200] A. R3 = R5 = R6 = Heteroaryl-R9 Compound No. Chemical names of compounds R1 Heteroaryl-R9 Ia-045a 4,6-bis(4-carboxy-2,5-dihydroxyphenyl)-1,3,5-triazine-2-one COOH Ia-046a 4-(4-carboxy-2,5-dihydroxyphenyl)-6-(3-carboxy-2,5-dihydroxyphenyl)-1,3,5-triazine-2-one COOH Ia-047a 4-(4-carboxy-2,5-dihydroxyphenyl)-6-(3,4-dihydroxyphenyl)-1,3,5-triazine-2-one COOH Ia-048a 4-(4-carboxy-2,5-dihydroxyphenyl)-6-(3,5-dihydroxyphenyl)-1,3,5-triazine-2-one COOH Ia-049a 4,6-bis(4-carboxy-2,5-dihydroxyphenyl)-1,3,5-triazine COOH Ia-050a 2-(4-carboxy-2,5-dihydroxyphenyl)-4-(3-carboxy-2,5-dihydroxyphenyl)-1,3,5-triazine COOH Ia-051a 2-(4-carboxy-2,5-dihydroxyphenyl)-4-(3,4-dihydroxyphenyl)-1,3,5-triazine COOH Ia-052a 2-(4-carboxy-2,5-dihydroxyphenyl)-4-(3,5-dihydroxyphenyl)-1,3,5-triazine COOH IIa-046a 4,6-bis(3-carboxy-2,5-dihydroxyphenyl)-1,3,5-triazine-2-one COOH IIa-050a 4-(3-carboxy-2,5-dihydroxyphenyl)-6-(4-carboxy-2,5-dihydroxyphenyl)-1,3,5-triazine-2-one COOH IIIa-045a 4-(3-carboxy-2,5-dihydroxyphenyl)-6-(3,4-dihydroxyphenyl)-1,3,5-triazine-2-one CH2COOH IIIa-046a 4-(3-carboxy-2,5-dihydroxyphenyl)-6-(3,5-dihydroxyphenyl)-1,3,5-triazine-2-one CH2COOH IIIa-047a 4,6-Bis(3-carboxy-2,5-dihydroxyphenyl)-1,3,5-triazine CH2COOH IIIa-048a 2-(3-carboxy-2,5-dihydroxyphenyl)-4-(4-carboxy-2,5-dihydroxyphenyl)-1,3,5-triazine CH2COOH IIIa-049a 2-(3-carboxy-2,5-dihydroxyphenyl)-4-(3,4-dihydroxyphenyl)-1,3,5-triazine CH2COOH IIIa-050a 2-(3-carboxy-2,5-dihydroxyphenyl)-4-(3,5-dihydroxyphenyl)-1,3,5-triazine CH2COOH IIIa-051a 2-(3-carboxymethyl-2,5-dihydroxyphenyl)-4-(3,4-dihydroxyphenyl)-1,3,5-triazine CH2COOH IIIa-052a 2-(3-carboxymethyl-2,5-dihydroxyphenyl)-4-(3,5-dihydroxyphenyl)-1,3,5-triazine CH2COOH B. R2 = R5 = R6 = Heteroaryl-R9 IIa-045a 4-(4-carboxymethyl-2,5-dihydroxyphenyl)-6-(3,4-dihydroxyphenyl)-1,3,5-triazine-2-one COOH IIa-047a 4-(4-carboxymethyl-2,5-dihydroxyphenyl)-6-(3,5-dihydroxyphenyl)-1,3,5-triazine-2-one COOH IIa-048a 2-(4-carboxy-2,5-dihydroxyphenyl)-4-(4-carboxymethyl-2,5-dihydroxyphenyl)-1,3,5-triazine COOH IIa-049a 2-(3-carboxy-2,5-dihydroxyphenyl)-4-(4-carboxymethyl-2,5-dihydroxyphenyl)-1,3,5-triazine COOH IIa-051a 2-(4-carboxymethyl-2,5-dihydroxyphenyl)-4-(3,4-dihydroxyphenyl)-1,3,5-triazine COOH IIa-052a 2-(4-carboxymethyl-2,5-dihydroxyphenyl)-4-(3,5-dihydroxyphenyl)-1,3,5-triazine COOH IVa-045a 4-(4-carboxy-2,5-dihydroxyphenyl)-6-(3-carboxymethyl-2,5-dihydroxyphenyl)-1,3,5-triazine-2-one CH2COOH IVa-046a 4-(3-carboxy-2,5-dihydroxyphenyl)-6-(3-carboxymethyl-2,5-dihydroxyphenyl)-1,3,5-triazine-2-one CH2COOH IVa-047a 4-(3-carboxymethyl-2,5-dihydroxyphenyl)-6-(3,4-dihydroxyphenyl)-1,3,5-triazine-2-one CH2COOH IVa-048a 4-(3-carboxymethyl-2,5-dihydroxyphenyl)-6-(3,5-dihydroxyphenyl)-1,3,5-triazine-2-one CH2COOH IVa-049a 2-(4-carboxy-2,5-dihydroxyphenyl)-4-(3-carboxymethyl-2,5-dihydroxyphenyl)-1,3,5-triazine CH2COOH IVa-050a 2-(3-carboxy-2,5-dihydroxyphenyl)-4-(3-carboxymethyl-2,5-dihydroxyphenyl)-1,3,5-triazine CH2COOH IVa-051a 2-(3-carboxymethyl-2,5-dihydroxyphenyl)-4-(3,4-dihydroxyphenyl)-1,3,5-triazine CH2COOH IVa-052a 2-(3-carboxymethyl-2,5-dihydroxyphenyl)-4-(3,5-dihydroxyphenyl)-1,3,5-triazine CH2COOH

[0201] Preferably, the present invention provides a hydroquinone derivative compound of formula (I), wherein:

[0202] (A)

[0203] R a , R b = H and;

[0204] R1= COOR4; (CH2) n COOR4; SO3H, (CH2) n SO3H, CONH-R 10 And;

[0205] R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0206] R2= H and; R3= R5 and;

[0207] R5= R7= COOR4, (CH2) n COOR4, SO3H, (CH2) n It is a benzoheteroaryl substituted with at least one group selected from SO3H, OR4, azole [5-membered N-containing heterocyclic], or fluorine;

[0208] or

[0209] (B)

[0210] R a , R b = H and;

[0211] R1= COOR4; (CH2) n COOR4; SO3H, (CH2) n SO3H, or CONH-R 10 And;

[0212] R4= H, C 1-4 Alkyl, Aryl C 1-4Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0213] R3= H and; R2= R5 and;

[0214] R5= R7= COOR4, (CH2) n COOR4, SO3H, (CH2) n It is a benzoheteroaryl substituted with at least one group selected from SO3H, OR4, azole [5-membered N-containing heterocyclic], or fluorine.

[0215] According to the 10th embodiment, the present invention comprises a compound according to Table 10:

[0216] A. R3 = R5 = R7 Compound No. Chemical names of compounds R1 R3 Id-030a 2-(4-carboxy-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid COOH Id-030a-E2 Methyl 2-(4-ethoxycarbonyl-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-4-carboxylate COOEt Id-030b 2-(2,5-dihydroxy-4-sulfophenyl)-1H-benzo[d]imidazole-4-carboxylic acid SO3H Id-031a 2-(4-carboxy-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid COOH Id-031b 2-(2,5-dihydroxy-4-sulfophenyl)-1H-benzo[d]imidazole-5-carboxylic acid SO3H IIId-030a 2-(3-carboxy-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid CH2COOH IIId-031a 2-(2,5-dihydroxy-3-sulfophenyl)-1H-benzo[d]imidazole-4-carboxylic acid CH2COOH B. R2 = R5 = R7 IId-030a 2-(3-carboxy-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid COOH IId-030b 2-(2,5-dihydroxy-3-sulfophenyl)-1H-benzo[d]imidazole-5-carboxylic acid SO3H IId-031a 2-(4-(carboxymethyl)-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid COOH IId-030a 2-(4-(carboxymethyl)-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid SO3H IVd-030a 2-(3-(carboxymethyl)-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid CH2COOH IVd-031a 2-(3-(carboxymethyl)-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid CH2COOH

[0217] Preferably, the present invention provides a hydroquinone derivative compound of formula (I), wherein:

[0218] (A)

[0219] R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) n CO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6acyloxymethyl, C1-C6acyloxy-1-ethyl, C1-C6alkoxycarbonyloxymethyl, or C1-C6alkoxycarbonyloxy-1-ethyl;

[0220] R1= COOR4; (CH2) n COOR4; SO3H, (CH2) n SO3H, or CONH-R 10 And;

[0221] R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0222] R2= H and; R3= R5 and;

[0223] R5= R8= (CH2) m X(CH2) p It is R9;

[0224] Here X = O, S, SO2, NH, NAc, or N(CH2) q R9 or;

[0225] or

[0226] (B)

[0227] R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) n CO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6acyloxymethyl, C1-C6acyloxy-1-ethyl, C1-C6alkoxycarbonyloxymethyl, or C1-C6alkoxycarbonyloxy-1-ethyl;

[0228] R1= COOR4; (CH2) n COOR4; SO3H, (CH2) n SO3H, or CONH-R 10 And;

[0229] R4= H, C 1-4 Alkyl, Aryl C 1-4Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl;

[0230] R3= H and; R2= R5 and;

[0231] R5= R8= (CH2) m X(CH2) p It is R9;

[0232] Here X = O, S, SO2, NH, NAc, or N(CH2) q It is R9.

[0233] According to the 11th embodiment, the present invention comprises a compound according to Table 11:

[0234] A. R3 = (CH 2 ) m X(CH 2 ) p R 9 No. Chemical names of compounds R1 Ra Rb m X p R9 IIIc-056a bis(4-carboxy-2,5-dihydroxyphenylmethyl)amine COOH H H 1 NH 1 4-Carboxy-2,5-Dihydroxyphenyl IIIc-056b 4-((2,5-dihydroxy-4-sulfophenylmethylamino)methyl)-2,5-dihydroxybenzoic acid SO3H H H 1 NH 1 4-Carboxy-2,5-Dihydroxyphenyl IIIc-056c Compound 267: 4-((2,5-dihydroxy-3-sulfophenylmethylamino)methyl)-2,5-dihydroxybenzoic acid COOH H H 1 NH 1 2,5-Dihydroxy-3-sulfophenyl IIIc-056d bis(2,5-dihydroxy-4-sulfophenylmethyl)amine SO3H H H 1 NH 1 2,5-Dihydroxy-4-sulfophenyl IIIc-057a N,N-bis(4-carboxy-2,5-dihydroxyphenylmethyl)acetamide COOH H H 1 NH(COCH3) 1 4-Carboxy-2,5-Dihydroxyphenyl IIIc-057b N-(2,5-dihydroxy-4-sulfophenylmethyl) N-(4-carboxy-2,5-dihydroxyphenylmethyl) acetamide SO3H H H 1 NH(COCH3) 1 4-Carboxy-2,5-Dihydroxyphenyl IIIc-057c N-(2,5-dihydroxy-3-sulfophenylmethyl) N-(4-carboxy-2,5-dihydroxyphenylmethyl) acetamide COOH H H 1 NH(COCH3) 1 2,5-Dihydroxy-3-sulfophenyl IIIc-057d N,N-bis(2,5-dihydroxy-4-sulfophenylmethyl)acetamide SO3H H H 1 NH(COCH3) 1 2,5-Dihydroxy-4-sulfophenyl IIIc-058a 4-((2,5-dihydroxy-4-carboxyphenyl)methylthiomethyl)-2,5-dihydroxybenzoic acid COOH H H 1 S 1 4-Carboxy-2,5-Dihydroxyphenyl IIIc-058b 4-((2,5-dihydroxy-4-sulfophenyl)methylthiomethyl)-2,5-dihydroxybenzoic acid SO3H H H 1 S 1 4-Carboxy-2,5-Dihydroxyphenyl IIIc-058c 4-((2,5-dihydroxy-3-sulfophenyl)methylthiomethyl)-2,5-dihydroxybenzoic acid COOH H H 1 S 1 2,5-Dihydroxy-3-sulfophenyl IIIc-058d 4-((2,5-dihydroxy-4-sulfophenyl)methylthiomethyl)-2,5-dihydroxybenzenesulfonic acid; SO3H H H 1 S 1 2,5-Dihydroxy-4-sulfophenyl IIIc-059a 4-((2,5-dihydroxy-4-carboxyphenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid; COOH H H 1 SO2 1 4-Carboxy-2,5-Dihydroxyphenyl IIIc-059b 4-((2,5-dihydroxy-4-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid; SO3H H H 1 SO2 1 4-Carboxy-2,5-Dihydroxyphenyl IIIc-059c 4-((2,5-dihydroxy-3-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid COOH H H 1 SO2 1 2,5-Dihydroxy-3-sulfophenyl IIIc-059d 4-((2,5-dihydroxy-4-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzenesulfonic acid SO3H H H 1 SO2 1 2,5-Dihydroxy-4-sulfophenyl IIIc-060a 4-((2,5-dihydroxy-4-carboxyphenyl)methoxymethyl)-2,5-dihydroxybenzoic acid COOH H H 1 O 1 4-Carboxy-2,5-Dihydroxyphenyl IIIc-060b 4-((2,5-dihydroxy-4-sulfophenyl)methoxymethyl)-2,5-dihydroxybenzoic acid; SO3H H H 1 O 1 4-Carboxy-2,5-Dihydroxyphenyl IIIc-060c 4-((2,5-dihydroxy-3-sulfophenyl)methoxymethyl)-2,5-dihydroxybenzoic acid COOH H H 1 O 1 2,5-Dihydroxy-3-sulfophenyl IIIc-060d 4-((2,5-dihydroxy-4-sulfophenyl)methoxymethyl)-2,5-dihydroxybenzenesulfonic acid SO3H H H 1 O 1 2,5-Dihydroxy-4-sulfophenyl IIIc-061a tris(4-carboxy-2,5-dihydroxyphenylmethyl)amine COOH H H 1 N(CH2)qR9q = 1:R9 = 4-carboxy-2,5-dihydroxyphenyl 1 4-Carboxy-2,5-Dihydroxyphenyl IIIc-061a-E3 tris(4-ethoxycarbonyl-2,5-dihydroxyphenylmethyl)amine COOEt H H (CH2)qR9q = 1:R9 = 4-ethoxycarboxy-2,5-dihydroxyphenyl 1 4-ethoxycarbonyl-2,5-dihydroxyphenyl B. R2 = (CH 2 ) m X(CH 2 ) p R 9 IVc-056a bis(3-carboxy-2,5-dihydroxyphenylmethyl)amine COOH H H 1 NH 1 3-Carboxy-2,5-Dihydroxyphenyl IVc-056b 3-((2,5-dihydroxy-3-sulfophenylmethylamino)methyl)-2,5-dihydroxybenzoic acid SO3H H H 1 NH 1 3-Carboxy-2,5-Dihydroxyphenyl IVc-056c 3-((2,5-dihydroxy-4-sulfophenylmethylamino)methyl)-2,5-dihydroxybenzoic acid COOH H H 1 NH 1 2,5-Dihydroxy-3-sulfophenyl IVc-056d bis(2,5-dihydroxy-3-sulfophenylmethyl)amine SO3H H H 1 NH 1 2,5-Dihydroxy-4-sulfophenyl IVc-057a N,N-bis(3-carboxy-2,5-dihydroxyphenylmethyl)acetamide COOH H H 1 NH(COCH3) 1 3-Carboxy-2,5-Dihydroxyphenyl IVc-057b N-(2,5-dihydroxy-3-sulfophenylmethyl) N-(3-carboxy-2,5-dihydroxyphenylmethyl) acetamide SO3H H H 1 NH(COCH3) 1 3-Carboxy-2,5-Dihydroxyphenyl IVc-057c N-(2,5-dihydroxy-4-sulfophenylmethyl) N-(3-carboxy-2,5-dihydroxyphenylmethyl) acetamide COOH H H 1 NH(COCH3) 1 2,5-Dihydroxy-3-sulfophenyl IVc-057d N,N-bis(2,5-dihydroxy-3-sulfophenylmethyl)acetamide SO3H H H 1 NH(COCH3) 1 2,5-Dihydroxy-4-sulfophenyl IVc-058a 3-((2,5-dihydroxy-3-carboxyphenyl)methylthiomethyl)-2,5-dihydroxybenzoic acid COOH H H 1 S 1 3-Carboxy-2,5-Dihydroxyphenyl IVc-058b 3-((2,5-dihydroxy-3-sulfophenyl)methylthiomethyl)-2,5-dihydroxybenzoic acid SO3H H H 1 S 1 3-Carboxy-2,5-Dihydroxyphenyl IVc-058c 3-((2,5-dihydroxy-4-sulfophenyl)methylthiomethyl)-2,5-dihydroxybenzoic acid COOH H H 1 S 1 2,5-Dihydroxy-3-sulfophenyl IVc-058d 3-((2,5-dihydroxy-3-sulfophenyl)methylthiomethyl)-2,5-dihydroxybenzenesulfonic acid SO3H H H 1 S 1 2,5-Dihydroxy-4-sulfophenyl IVc-059a 3-((2,5-dihydroxy-3-carboxyphenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid COOH H H 1 SO2 1 3-Carboxy-2,5-Dihydroxyphenyl IVc-059b 3-((2,5-dihydroxy-3-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid SO3H H H 1 SO2 1 3-Carboxy-2,5-Dihydroxyphenyl IVc-059c 3-((2,5-dihydroxy-4-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid COOH H H 1 SO2 1 2,5-Dihydroxy-3-sulfophenyl IVc-059d 3-((2,5-dihydroxy-3-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzenesulfonic acid SO3H H H 1 SO2 1 2,5-Dihydroxy-4-sulfophenyl IVc-060a 3-((2,5-dihydroxy-3-carboxyphenyl)methoxymethyl)-2,5-dihydroxybenzoic acid COOH H H 1 O 1 3-Carboxy-2,5-Dihydroxyphenyl IVc-060b 3-((2,5-dihydroxy-3-sulfophenyl)methoxymethyl)-2,5-dihydroxybenzoic acid SO3H H H 1 O 1 3-Carboxy-2,5-Dihydroxyphenyl IVc-060c 3-((2,5-dihydroxy-4-sulfophenyl)methoxymethyl)-2,5-dihydroxybenzoic acid COOH H H 1 O 1 2,5-Dihydroxy-3-sulfophenyl IVc-060d 3-((2,5-dihydroxy-3-sulfophenyl)methoxymethyl)-2,5-dihydroxybenzenesulfonic acid SO3H H H 1 O 1 2,5-Dihydroxy-4-sulfophenyl IVc-061a tris(3-carboxy-2,5-dihydroxyphenylmethyl)amine COOH H H 1 N(CH2)qR9q = 1:R9=3-carboxy-2,5-dihydroxyphenyl 1 3-Carboxy-2,5-Dihydroxyphenyl IVc-059a-E2-A4 Methyl 3-((2,5-diacetoxy-3-methoxycarbonylphenyl)methylsulfonylmethyl)-2,5-diacetoxybenzoate COOMe Ac Ac 1 SO2 1 2,5-diacetoxy-3-(methoxycarbonyl)phenyl IVc-059a-E2 Methyl 3-((2,5-dihydroxy-3-methoxycarbonylphenyl)methylsulfonylmethyl)-2,5-hydroxybenzoate COOMe H H 1 SO2 1 2,5-Dihydroxy-3-(methoxycarbonyl)phenyl IVc-059a-mpe2 2-Mopolinoethyl 3-((2,5-Dihydroxy-3-(2-Mopolinoethoxycarbonyl)phenyl)methylsulfonylmethyl)-2,5-hydroxybenzoate COORR=2-Mopolinoethyl H H 1 SO2 1 2,5-Dihydroxy-3-(2-Mopolinoethoxycarbonyl)phenyl IVc-061a-E3 tris(3-carboxy-2,5-dihydroxyphenylmethyl)amine COOEt H H 1 N(CH2)qR9q = 1:R9=3-ethoxycarbonyl-2,5-dihydroxyphenyl 1 3-ethoxycarbonyl-2,5-dihydroxyphenyl

[0235] According to another embodiment, the present invention comprises a compound according to Table 12:

[0236] Compound No. Chemical names of compounds structure V-001a 4-(3-(2,5-dihydroxy-4-carboxyphenylcarbamoyl)-5-hydroxybenzamido)-2,5-dihydroxybenzoic acid V-001a diethyl ester 4-(3-(4-(ethoxycarbonyl)-2,5-dihydroxyphenylcarbamoyl)-5-hydroxybenzamido)-2,5-dihydroxybenzoate ethyl ester V-002a 2-hydroxy-5-(3-hydroxy-5-(4-hydroxy-3-carboxyphenylcarbamoyl)benzamido)benzoic acid V-002a diethyl ester 5-(3-(3-(ethoxycarbonyl)-4-hydroxyphenylcarbamoyl)-5-hydroxybenzamido)-2-ethyl hydroxybenzoate V-003a 4,4'-Carbonylbis(azandyl)bis(2,5-Dihydroxybenzoic acid) V-003a diethyl ester Diethyl 4,4'-carbonylbis(azandyl)bis(2,5-dihydroxybenzoate)

[0237] The present invention also relates to a process for preparing a hydroquinone derivative compound of formula (I), comprising the following:

[0238] Step (a): Coupling a hydroquinone-derived carboxylic acid protected by a phenolic functional group with an aniline having various functional groups by means of a corresponding acyl chloride or an amide coupling agent such as TCFH in the presence of NMI;

[0239] Step (b): typically deprotection of the ester functional group by saponification; and

[0240] Step (c): Typically, deprotection of phenolic functional groups by catalytic hydrogenation.

[0241] Or, alternatively,

[0242] Step (d): Production of benzyl alcohol by reducing a hydroquinone-derived carboxylic acid protected by a phenolic functional group.

[0243] (e) activation of the benzyl alcohol functional group and substitution with a benzyl nucleophile having various functional groups (alcohol, thiol, primary or secondary amine);

[0244] (f) typically deprotection of the ester functional group by saponification reaction; and

[0245] (g) Typically, deprotection of phenolic functional groups by catalytic hydrogenation.

[0246] The above process is schematically represented as follows:

[0247]

[0248] The hydroquinone derivative compounds of the present invention may exist in an optically active form (stereoisomer), E / Z isomer, enantiomer, racemic mixture, diastereomer thereof, and as hydrates and solvates thereof. Solvents of the compound are formed due to the mutual attraction between the molecules of the compound and the inert solvent used. Solvents, e.g., monohydrate, dihydrate, or alcoholate.

[0249] The hydroquinone derivative of the present invention may also exist as a pharmaceutically acceptable salt, wherein the parent hydroquinone derivative is modified by preparing its acidic or basic salt.

[0250] Examples of pharmaceutically acceptable salts include, in particular, inorganic or organic acid salts of basic residues, e.g., amines; and alkaline or organic acid salts of acidic residues, e.g., carboxylic acids. Pharmaceutically acceptable salts may include, for example, conventional non-toxic salts or quaternary ammonium salts suitable for all routes of administration of compounds derived from non-toxic organic or inorganic acids. For example, the conventional non-toxic salts are those derived from inorganic salts, e.g., hydrochloric acid, hydrobromide, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc. It includes salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, parmolic acid, maleic acid, hydroxylic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc.

[0251] Pharmaceutically acceptable salts are described in the literature regarding cations and anions ["Pharmaceutical salts: A summary on doses of salt formers from the Orange Book. Saal C, European Journal of Pharmaceutical Sciences, 2013, 49, 614-623"]. Examples of cations include aluminum, arginine, benzathine, calcium, chloroprocaine, choline, diethanolamine, diethylamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, lithium, meglumine, potassium, procaine, sodium, triethylamine, and zinc. Examples of anions include acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, vitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, and gluteptate. Examples include gluconates, glutamates, glycolates, hexanoates, hydroxynaphtoates, iodides, isethionates, lactates, lactobionates, maleates, maleates, mandelates, mesylates, methyl sulfates, mucates, napsylates, nitrates, octanoates, oleates, pamoates, pantothenates, phosphates, polygalacturonates, propionates, salicylates, stearates, acetates, succinates, sulfates, tartrates, teoclates, and tosylates. Alternatively, the zwitterion may be used as a salt such as glutamate or aspartate, with the free amino acid arginine or lysine as the cationic counterion. Short peptides (2 to 20 amino acids) and other neutrals may be used as repeating units of arginine or lysine. Their combination with amino acids. These cell-penetrating peptides (CPPs) can be used as enhancers for drugs to penetrate into cells.

[0252] Pharmaceutically acceptable salts of compounds useful in the present invention may be synthesized, for example, from a parent compound containing a basic or acidic moiety by conventional chemical procedures. Generally, said salts may be prepared by reacting a free acid or a basic form of such compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent, or a mixture of both; generally, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred. A list of suitable salts is provided in the literature [Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418], the disclosure of which is incorporated herein by reference.

[0253] According to the present invention and in various embodiments, the suitable dosage described herein may vary depending on the condition, age, and species of the subject and can be easily determined by those skilled in the art. The total daily dosage used in both veterinary and human pharmaceuticals will suitably be in the range of 0.01 to 2000 mg / kg body weight, preferably 0.1 to 1000 mg / kg body weight, preferably 1 to 100 mg / kg, which may be administered as a single or divided dose and may also be exceeded even if an upper limit is indicated. Such dosages may be adjusted to individual requirements in each case, including the specific compound administered, the route of administration, the condition being treated, and the patient being treated. However, the compound may also be administered as a depot preparation (implant, sustained-release formulation, etc.) at weekly, monthly, or longer intervals. In such cases, the dosage may be much higher than the daily dosage and may be adjusted according to the form of administration, body weight, and specific indication. The appropriate dosage may be determined by performing conventional model tests, preferably animal model tests. Generally, when administered orally or parenterally to an adult weighing about 70 kg, a daily dose of about 10 mg to about 10.000 mg, preferably about 200 mg to about 1000 mg, should be appropriate, but the upper limit may be exceeded if indicated. It should be understood that the above therapeutically effective dose does not need to be the result of a single administration, but is generally the result of administering multiple unit doses. These unit doses may now comprise a portion of the daily or weekly doses, and thus, the therapeutically effective dose is determined over the course of treatment (contact). For example, in the case of oral administration, the daily dose may be about 0.04 to about 1.0 mg / kg of body weight, more preferably about 0.04 to about 0.20 mg / kg / day, even more preferably about 0.05 to about 0.15 mg / kg / day, and most preferably about 0.1 mg / kg of body weight.Generally, the amount of active substance administered may vary over a relatively wide range to achieve and, preferably, maintain the desired plasma concentration. Unit dosage forms of the active ingredient may contain about 0.1 milligrams to about 15 milligrams thereof. Preferred unit dosage forms may contain about 0.1 to about 1 milligram of the formulation and be administered 2 to 5 times per day. However, it should be noted that other alternative routes, such as continuous infusion at a rate designed to maintain the aforementioned plasma concentrations, are also considered. The duration of a specific treatment may also vary depending on considerations such as the severity of the disease and whether the treatment is for acute indications or for prophylactic purposes. Typical administration lasts for a period of about 5 to about 14 days, with a 7-day time course being common.

[0254] The course of administration (cycle) may also be repeated at monthly intervals, or parenteral unit doses may be delivered at weekly intervals. Oral unit doses may be administered at intervals of one day to several days to provide a determined therapeutically effective dose. The appropriate dose of the compounds of the present invention will depend on the type of disease to be treated, the severity and course of the disease, whether the formulation is administered for prophylactic or therapeutic purposes, the patient's medical history and response to the compounds, and the attending physician's criteria. The determination of the appropriate dose or route of administration is clearly within the current physician's capacity. Animal studies provide reliable guidelines for determining the effective dose of human therapy. Inter-species scaling of the effective dose may be performed according to principles established by the literature [Mordenti, J. and Chappell, W. "The use of interspecies scaling in toxicokinetics", in Toxicokinetics] and the literature [New Drug Development, editors Yacobi et al., Pergamon Press, New York, 1989, pp. 42-96].

[0255] The present invention further provides a pharmaceutical composition comprising (i) a therapeutically effective amount of a hydroquinone derivative compound of formula (I) or a pharmaceutically acceptable salt, or prodrug, or stereoisomer thereof, and (ii) a pharmaceutically acceptable excipient or excipients.

[0256] The pharmaceutical excipient according to the present invention may be selected from the group consisting of conventional excipients, such as, but not limited to, solubilizers, binders, fillers, disintegrants, lubricants, pH adjusters, permeability enhancers, release regulators, preservatives, coating agents, carriers, taste masking agents, and combinations thereof.

[0257] A pharmaceutical composition of a compound of the present invention together with one or more pharmaceutical components may be formulated with the said excipient as a liquid medicine, a solid or semi-solid medicine, and / or a gaseous medicine.

[0258] When present in solid formulations, they may include, without limitation, granules, pellets, tablets, capsules, powders, films, lozenges, crushable tablets, soluble tablets, disintegrating tablets, dispersible tablets, film-coated tablets, and controlled, sustained, extended, or modified release of any of the above-mentioned solid forms. These formulations may also be in the form of immediate release, delayed release, or modified release. Additionally, immediate release compositions may be conventional, dispersible, chewable, orally soluble, or flash-melt formulations, and modified release compositions that may include a release rate-controlling material that is hydrophilic or hydrophobic, or a combination of hydrophilic and hydrophobic, to form a matrix or reservoir or a combination of a matrix and reservoir system.

[0259] The composition may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, homogenization, milling, micronization, extrusion, and spherification. The composition may be provided as uncoated, film-coated, sugar-coated, powder-coated, enteric-coated, and modified release-coated. When present in a liquid formulation, they may include, without limitation, any liquid form such as a solution, suspension, nanosuspension, dispersion, colloid, emulsion, lotion, cream, ointment, tincture, and freeze-dried composition. When present in a gaseous formulation, they may include, without limitation, milled powder or blend, micronized powder or blend, nanosuspension, aerosol, spray, droplet, mist, spray solution or suspension, and / or atomized vapor.

[0260] The pharmaceutical composition according to the present invention may additionally include any additives such as a vehicle, a binder, a perfume, a flavoring agent, a sweetener, a coloring agent, a preservative, an antioxidant, a stabilizer, and a surfactant, if desired.

[0261] The pharmaceutical compositions and compounds according to the present invention may be formulated for administration via enteral routes such as oral routes; parenteral routes via injection such as intravenous, subcutaneous, intraocular, intramuscular, or intraperitoneal injections; local routes such as mucosal and transmucosal routes including ocular routes and sublingual / buccal routes; and routes to the lungs, nasal cavity, intranasal cavity, bronchial cavity, and lungs. Ocular administration routes include local ocular administration, intraocular, intravitreal, or retrobulbar administration.

[0262] Preferred formulations of the compound according to the present invention include liquid oral formulations, ocular formulations, and intravenous and intraperitoneal formulations.

[0263] Liquid oral formulations, specifically solutions and suspensions, are considered common, convenient, and safe for oral drug administration. They can be used to deliver relatively large amounts of medication and are frequently used by pediatric populations and individuals who have difficulty swallowing tablets or capsules. While administration via the gastrointestinal tract offers rapid dissolution and drug absorption, tolerability and interactions with other substances in the gastrointestinal tract must be considered. The characteristics of an active pharmaceutical ingredient (API) allow for formulation into a simple aqueous-based oral solution; however, if the API is poorly soluble, the formulation must be designed around the molecule to improve solubility and bioavailability. The introduction of surfactants, solvents, buffers, and oils increases solubility and reduces precipitation and / or degradation resulting from interactions with gastric juices. When suspensions are required, particle size is often reduced and controlled to enhance drug solubility, permeability, and ultimately, drug absorption. As formulation development progresses, preservatives and flavoring agents are introduced to ensure patient suitability and adequate shelf life.

[0264] Ophthalmic formulations are ophthalmic formulations delivered directly to the eye and are often liquids in the form of solutions or suspensions. When administered to the eye, they prevent metabolism by the gastrointestinal tract and can be used for drugs that are not well absorbed when administered orally. To avoid eye irritation, eye drops are sterile and isotonic solutions with a nominal pH of 4 to 8. Excipients, including solubilizers, chelating agents, polymers, surfactants, permeability enhancers, and cyclodextrins, are added to the formulation to improve stability, modify viscosity, or increase solubility, permeability, and bioavailability of poorly soluble drugs.

[0265] Intravenous formulations enable rapid absorption following parenteral drug delivery of the full dose to the patient system for an immediate response. This method of delivery bypasses metabolism by the gastrointestinal tract and can be used for drugs that are poorly absorbed when administered orally. Injectables are typically sterile isotonic aqueous solutions designed to avoid causing pain during administration. For poorly soluble drugs, formulations are modified with organic cosolvents, surfactants, and buffers to increase solubility and enable nano-suspension formulations. For molecules unstable in solution, formulations can be lyophilized for dilution at the point of use.

[0266] The present invention also provides a kit comprising a composition having a therapeutically effective amount of one or more compounds of the present invention or a formulation thereof, and a package insert having a delivery device for administering said composition or formulation and an instruction manual.

[0267] To prepare the pharmaceutical composition, the active ingredient according to the present invention may be mixed with pharmaceutically acceptable carriers, adjuvants, and / or excipients according to conventional pharmaceutical formulation techniques. Pharmaceutically acceptable carriers that may be used in the composition include any standard pharmaceutical carriers, such as phosphate buffered brine solutions, water, and emulsions, such as oil / water or water / oil emulsions, and various types of wetting agents. The composition may further contain solid pharmaceutical excipients, such as starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, etc. Liquid and semi-solid excipients may be selected from glycerol, propylene glycol, polyethylene glycol, water, ethanol, and various oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. In particular, liquid carriers for injectable solutions include water, saline solution, aqueous dextrose, and glycol. For examples of carriers, stabilizers, and adjuvants, refer to the literature [Remington's Pharmaceutical Sciences, edited by EW Martin (Mack Publishing Company, 18th ed., 1990)].

[0268] The composition may also include stabilizers and preservatives. Examples of pharmaceutically acceptable solvents that may be used in the composition are [Handbook of Pharmaceutical Excipients (Ninth Edition, Pharmaceutical Press, London and American Pharmacists Association, Washington, 2020)], [Aulton's Pharmaceutics, The Design and Manufacture of Medicines. (Fifth edition, Editors: Kevin Taylor and Michael Aulton, Elsevier, 2017)], [ " Ullmann's Encyclopedia of Industrial Chemistry, 6th Ed." (various editors, 1989-1998, Marcel Dekker)] and [ " References such as "Pharmaceutical Dosage Forms and Drug Delivery Systems" (ANSEL et al., 1994 et 2011, WILLIAMS & WILKINS) can be found. Non-limiting examples of pharmaceutically acceptable solvents that may be used in the composition include, but are not limited to, propylene glycol (also known as 1,2-dihydroxypropane, 2-hydroxypropanol, methyl ethylene glycol, methyl glycol, or propane-1,2-diol), ethanol, methanol, propanol, isopropanol, butanol, glycerol, polyethylene glycol (PEG), glycol, cremophor EL, or any form of polyethoxylated castor oil, dipropylene glycol, diisosorbide, propylene carbonate, N-methylpyrrolidone, glycofurol, tetraethylene glycol, propylene glycol fatty acid esters, and mixtures thereof.

[0269] The compound according to the present invention has demonstrated anti-fibrotic, anti-inflammatory, and anti-angiogenic effects. Several diseases listed herein include not only one but two or even three targets. The disease categories represent pre-dominant angiogenesis (vascular), inflammatory, and / or fibrotic pathology.

[0270] In some embodiments, the present invention relates to a prodrug of a compound according to the present invention. The advantages of such a prodrug are obtained by methods known to those skilled in the art, for example, by adding a suitable cleavable functional group that produces better water solubility for parenteral or oral delivery.

[0271] The molecular prodrugs of the present invention, which exhibit highly polar and charged characteristics, are particularly desirable because these functional groups can positively influence passive permeability through biological membranes. A major obstacle for polar and charged drugs is their low membrane permeability, which often leads to low and variable oral absorption and low oral bioavailability. Furthermore, the oral absorption of polar and charged drugs is often associated with significant interspecies variability. Drugs with low permeability also exhibit low exposure levels in specific target organs even after topical administration. Improving membrane permeability has been one of the most beneficial areas in prodrug research to date.

[0272] Different prodrug strategies have been developed for the drug according to the present invention to overcome local route barriers to the eye, oral mucosal barriers, carrier effects, or other local uses.

[0273] The prodrug strategy was formally recognized by Adrian Albert in 1958 (Albert, A. Chemical aspects of selective toxicity. Nature, 1958, 182, 421-422), but as exemplified by methenamine, phenacetin, and prontosil, it originated in the early part of the previous century. Prodrugs are molecules with little to no pharmacological activity, but whether accidentally or intentionally In vivo It possesses inherent structural instability that allows for bioconversion into an active drug. Conversion can occur through chemical or enzymatic processes, or a combination of both. Active molecules are often associated with undesirable physicochemical properties that cause significant problems in delivery to appropriate biological targets.

[0274] Prodrugs obtained through structural modifications are designed to enable delivery by influencing the molecule's intrinsic physicochemical properties. However, such development is not always incorporated into the design of new molecules at the discovery stage; analog optimization is often the preferred path. Implementing an early prodrug strategy can enable faster clinical development and, ultimately, the commercialization of the drug.

[0275] Prodrug strategies for the most common sites of action of parent drugs are described in the literature [Rautio J, 2018 (Jarkko Rautio et al, Nature Reviews Drug Discovery, 2018, 17, 559-587)]. This review explains the expanding role of prodrugs in modern drug design and development, as well as prodrug strategies for the most common sites of action of parent drugs.

[0276] The benefits of prodrugs are obtained by adding appropriate cleavable functional groups that generate better water solubility for, for example, parenteral or oral delivery. On the other hand, for highly polar and charged molecules, these functional groups can have a positive effect on passive permeability through biological membranes. A major obstacle for polar and charged drugs is low membrane permeability, which often leads to low and variable oral absorption and low oral bioavailability.

[0277] Furthermore, the oral absorption of polar and charged drugs is often associated with significant interspecies variability. Drugs with low permeability exhibit low exposure levels in specific target organs even after topical administration. Improving membrane permeability has been one of the most fruitful areas in prodrug research to date. Many prodrug strategies can be applied to influence the lipophilicity of the parent drug. The lipophilicity of the drug has been improved by masking polar and ionized functions through short-chain hydrocarbon promoiety. Hydrophilic hydroxyl, carboxyl, phosphate, or amine groups, along with other negatively or positively charged groups, have been successfully converted into more lipophilic alkyl or aryl esters or N-acyl derivatives that are rapidly hydrolyzed back into the parent drug in the body by ubiquitous esterases or peptidases.

[0278] Most lipophilic prodrugs have been developed to improve membrane permeability and oral absorption. The same prodrug strategy can be applied to improve the topical administration of parent drugs absorbed through the skin or eyes. During topical administration to the eyes, the prodrug readily penetrates the cornea after instillation and is primarily hydrolyzed by ocular carboxyl esterases.

[0279] Prodrugs can also utilize carrier-mediated transport. These transporters are membrane proteins that play a crucial role in regulating the uptake and extravasation of important polar endogenous nutrients. Their specificity is not limited to endogenous substrates; drugs structurally very similar to endogenous substrates can also be transported across the cell membrane by these transporters. Carrier-mediated transport is particularly important because polar and charged drugs undergo negligible passive diffusion across biological membranes. Prodrugs capable of utilizing carrier-mediated transport mechanisms provide interesting targets in drug design. Similarly, prodrugs can lead to improved metabolic stability.

[0280] Prodrugs can improve metabolic instability typically attributed to hepatic metabolism. Similarly, unwanted intestinal metabolism of a drug can be overcome by selective prodrug strategies. Such instability can significantly reduce the total amount of drug reaching systemic circulation and its targets. Prodrugs can be used to protect active drugs from these first-pass effects by masking metabolically unstable but pharmacologically essential functional groups, such as phenol, to avoid rapid metabolism.

[0281] To address the problem of insufficient plasma levels and extend the duration of action, drugs are generally controlled by formulations such as suspensions and polymer matrices that control drug release, avoid maximum effect, and prolong action. Prodrugs can be used to achieve controlled release of the active drug by modifying the water solubility and solubility characteristics of the active drug in a manner that affects the release rate, absorption rate, or tissue distribution of the active drug.

[0282] Prodrugs have been particularly useful in the development of various subcutaneous or intramuscular sustained-release depot injections that maintain therapeutic plasma levels of the parent drug for several weeks to months. These prodrugs are typically fatty acid esters, e.g., decanoates, palmitates, enanthates, cypioneates, or valerates, which are formulated in oil-based vehicles, resulting in the slow release of the prodrug and thus regulating the treatment of the parent drug. The high lipophilicity of these prodrugs also binds to blood and tissue proteins, slowing enzymatic conversion and consequently delaying the appearance of the active drug in systemic circulation.

[0283] Better targeting and lower side effects are often achieved by targeting prodrugs cleaved in the acidic environment of tumor tissue, in endosomes or lysosomes containing acid-unstable prodrugs. A similar approach can also be achieved using site-specific enzymes, where the prodrug is primarily cleaved in the desired organ or tissue where the enzyme is at its highest concentration. In the case of charged drugs, intracellular cleavage leads to high cellular concentrations of the negatively or positively charged drug trapped within the target cells.

[0284] Different prodrug strategies have been developed for the drug according to the present invention to overcome local route barriers to the eye, oral mucosal barriers, transporter effects, or other local uses.

[0285] The drug according to the present invention possesses a charged polar group. The problem to be solved depends on the route of administration and the need for a long or short duration of drug action. Examples of prodrugs cleaved by mouse, as well as human tissue and blood esterases, have been successfully synthesized.

[0286] The compounds of the present invention possess carboxylic acid functional groups and phenolic groups. Various prodrugs derived from these functions can be considered: for example, carboxylic acids are most frequently converted to esters: simple alkyl esters (methyl, ethyl, isopropyl, and longer chains), functionalized alkyl esters such as morphopropyl alkyl esters, pyrrolidinoalkyl esters, N-methylpiperazino-alkyl esters, and also aryl esters such as guaiacol-derived esters; mixed acetal esters such as acyloxymethyl (or 1-ethyl) or alkoxycarbonyloxymethyl (or 1-ethyl) esters and (oxodioxolyl)methyl esters are also efficient prodrug functional groups for carboxylic acids. Various esters and functionalized ethers have been used as phenol-based prodrugs: simple aliphatic esters, aromatic esters, dicarboxylic acid halfesters, amino acid esters, carbamate esters, phosphate monoesters, phosphonooxymethyl ethers, acyloxymethyl (or 1-ethyl) ethers, alkoxycarbonyloxymethyl (or 1-ethyl) ethers, aminoacyloxymethyl ethers, etc.

[0287] Accordingly, the present invention provides a method for treating and / or preventing diseases or disorders, including autoimmune, immunological, rheumatic, vascular, ophthalmic, fibrotic, metabolic and gastrointestinal disorders, neuroinflammatory and neurodegenerative diseases, neoplasms and cancer-related disorders, hormone-related disorders, and immunological disorders and complications caused by viral and bacterial infections, comprising the step of administering a therapeutically effective amount of the compound and / or pharmaceutical composition of the present invention as described above to a subject in need thereof.

[0288] The pharmaceutical composition and method according to the present invention are particularly suitable for human or non-human subjects.

[0289] Compounds according to the present invention can target diseases based on individual cytokine profiles as described in the biodata provided for various compounds (see Figs. 3a to d). The following website, Open Targets Platform (URL: https: / / www.targetvalidation.org / , Denise Carvalho et al, Nucleic Acids Research, Volume 47, Issue D1, 08 January 2019, D1056-D1065, https: / / doi.org / 10.1093 / nar / gky1133), provides a complete picture based on current bibliographic information and can be searched for by disease or cytokine.

[0290] Two typical examples: (a) A disease-specific search for diabetic retinopathy triggers the following cytokines that show a high correlation with the disease (Fig. 3c). The three top cytokines are VEGFA score = 1 (vascular endothelial growth factor A), HFE score = 1 (homeostatic iron regulator), and TNF score = 0.86 (tumor necrosis factor) as examples of a search for diabetic retinopathy, and (b) a search for VEGFA triggers: neurological disease, vascular disease, ophthalmic disease, retinopathy, and several other diseases shown in Fig. 3d.

[0291] To explain the efficacy of the compound against inflammatory cytokines of the subgroup, the effect of the compound was evaluated for IC50 values ​​for inhibition of human whole blood (Example 3.6) and LPS-induced inflammation (Table 13, in μM units).

[0292] compound GM-CSF IFNγ IL-1b IL-2 IL-4 IL-5 IL-6 IL-9 IL-10 IL-12p70 IL-13 IL-17A IL-17F IL-18 IL-21 IL-33 TGF beta TNFα TNFβ Ia-001a 100 30.5 34.4 94.3 100 100 1.24 5.63 100 1.5 26.4 0.1 14.7 100 100 19.3 100 0.02 13.20 Ia-001a-Tz 100 100 100 7.99 100 100 0.75 8.63 26.1 32.4 32.1 0.11 46.5 100 100 23.6 100 0.63 53.00 Ia-001a-Tz / 004a 3.4 0.61 100 4.91 100 100 3.04 8.48 19.5 12.2 1.5 0.02 2.4 46.6 0.3 1.67 100 0.002 3.02 Ic-001a-Tz2 100 1.38 100 9.45 100 100 0.52 9.13 100 29.1 0.12 0.31 0.15 33.9 32 0.23 100 0.1 0.41 Ia-001c 100 0.44 100 12.8 100 100 0.95 46.9 1.9 0.44 86.1 0.09 89.7 100 100 100 100 0.05 29.70 Ia-003a-Tz 100 2.95 100 43 100 100 1.41 3.62 6.94 1.26 89.6 0.07 83.9 100 1.49 72.2 100 0.18 55.00 Ic-007a 100 1.44 100 100 100 100 0.09 27.1 12.5 0.49 30.1 0.04 22.9 100 1.9 18.4 100 0.27 6.52 Ib-010a 100 2.22 33.3 2.74 100 100 1.02 11.58 100 0.27 100 0.42 100 100 67.8 31.3 100 0.31 49.30 Ib-010a-E3 100 2.79 100 36.2 100 100 0.24 26.8 100 0.84 33 0.52 34.2 100 100 20 100 0.98 38.20 Ia-015a 2.76 100 100 7.08 100 100 0.77 1.47 5.27 0.12 0.15 0.05 0.15 100 57.2 0.24 100 0.17 0.30 IIc-007a 26 0.11 100 12.8 100 100 0.05 2.14 17.9 3.37 0.25 0.01 0.26 100 9.41 0.18 100 0.03 0.29 IIc-009a 100 0.54 100 19.6 100 100 0.27 18.9 11.31 100 0.13 0.001 0.13 2.95 8.01 0.29 100 0.11 6.94 IIa-053a 100 1.04 100 1.67 100 100 2.2 1.41 100 0.27 29.9 100 28.8 100 100 12.1 100 0.02 91.50 IIIa-001aTz 100 18.9 100 100 100 100 1.98 3.01 7.78 0.48 0.15 0.17 0.16 27.7 3 0.14 100 0.31 0.23 IIIa-013a 27.8 0.15 100 57.1 100 100 3.55 11.9 37.3 0.5 0.37 0.15 0.41 100 1.63 1.11 100 0.51 0.89 IIIc-057a 100 0.9 16.2 24.2 100 100 0.19 11.1 100 0.73 4.73 1.32 5.06 100 1.56 2.93 100 0.15 1.58 IIIc-061a 31.2 2.48 100 100 100 100 0.18 8.85 17.9 37.2 0.31 0.04 0.32 32.4 6.38 0.31 100 0.03 0.81 IVc-058a 100 10.6 27.5 3.82 100 100 0.21 31.1 16.4 4.23 55.9 0.1 86.8 100 3.2 33.9 100 0.18 59.30 IVc-059a 100 4.34 38.6 21.2 100 100 0.11 0.4 1.31 42 100 0.16 100 100 1.87 27.5 100 0.16 0.33 IVc-059a-E2-A4 1.83 3.5 14.1 10.4 100 100 0.99 2.9 16.8 51.4 18.7 0.02 25.8 100 100 23.2 100 0.3 19.40

[0293] Immunological / rheumatic / vascular disorders may include, for example, peritonitis, Kawasaki disease (KD), Takayasu arteritis (TA), microscopic polyangiitis (MP), giant cell arteritis (GCA), antiphospholipid syndrome (APS), Behcet's disease (BD), granulomatosis with polyangiitis (GPA) or Wegener's granulomatosis (WG), eosinophilic granulomatosis with polyangiitis, Churg-Strauss syndrome (EGPA), and rosacea (RO).

[0294] Rheumatic diseases particularly affect the tendons, ligaments, and bones of the joints, accompanied by pain, loss of movement, and inflammation. This includes various types of arthritis, such as osteoarthritis (OA), rheumatoid arthritis (RA), lupus, spondyloarthropathies: ankylosing spondylitis (AS) and psoriatic arthritis (PsA), Sjogren's syndrome, gout, scleroderma, infectious arthritis, juvenile idiopathic arthritis, and polymyalgia rheumatica.

[0295] Peritonitis is generally inflammation of the peritoneum caused by bacterial or fungal infection. There are two types of peritonitis. The first type is spontaneous peritonitis, which can develop as a complication of liver diseases such as cirrhosis or kidney disease. Secondary peritonitis can occur due to abdominal perforation or complications of other medical conditions. If left untreated, peritonitis can lead to a serious and potentially life-threatening infection.

[0296] Kawasaki disease causes inflammation in the walls of medium-sized arteries throughout the body. It primarily affects children. The inflammation tends to affect the coronary arteries that supply blood to the heart muscle. Because Kawasaki disease also affects lymph nodes, the skin, and the mucous membranes inside the mouth, nose, and throat, which swell upon infection, it is often referred to as cutaneous mucosal lymph node syndrome.

[0297] Takayasu's arteritis is a rare type of vasculitis belonging to a group of diseases that cause inflammation of blood vessels. In Takayasu's arteritis, inflammation damages the aorta and its major branches. This condition can cause arteries to narrow, become blocked, or develop aneurysms. Takayasu's arteritis can also cause pain in the arms or chest, high blood pressure, and eventually heart failure or stroke. Medication is necessary to control inflammation in the arteries and prevent complications.

[0298] Granulomatosis with polyangiitis is a rare disease that causes inflammation of the blood vessels in the nose, sinuses, throat, lungs, and kidneys. Formerly known as Wegener's granulomatosis, this condition is one of a group of vascular disorders called vasculitis. It slows blood flow to certain organs. Affected tissues can develop sites of inflammation called granulomas, which can affect how these organs function. If left untreated, the condition can be fatal.

[0299] Giant cell arteritis is inflammation of the inner lining of arteries. Most often, it affects the arteries in the head, particularly the temples. For this reason, giant cell arteritis is sometimes referred to as temporal arteritis. Giant cell arteritis frequently causes headaches, scalp tenderness, jaw pain, and vision problems. If left untreated, it can lead to blindness.

[0300] Antiphospholipid syndrome occurs when the immune system mistakenly produces antibodies, significantly increasing the likelihood of blood clotting. This can lead to dangerous blood clots in the legs, kidneys, lungs, and brain. In pregnant women, antiphospholipid syndrome can also cause miscarriage and stillbirth. There is no cure for antiphospholipid syndrome. Only available medications can reduce the risk of blood clots.

[0301] Behcet's disease, also known as Behcet's syndrome, is a rare disorder that causes inflammation of blood vessels. This disease can cause numerous signs and symptoms that may initially appear unrelated. These can include oral ulcers, eye inflammation, skin rashes and lesions, and genital inflammation. Current treatments can help reduce the symptoms of Behcet's disease and prevent serious complications such as blindness.

[0302] Churg-Strauss syndrome is a disorder characterized by vascular inflammation. This inflammation can restrict blood flow to organs and tissues, and sometimes cause permanent damage to blood flow. This condition is also known as eosinophilic granulomatosis with polyangiitis (EGPA). Asthma is the most common sign of Churg-Strauss syndrome. This disorder can cause other problems such as hay fever, rashes, gastrointestinal bleeding, and pain and numbness in the hands and feet. There is no cure for Churg-Strauss syndrome. Currently, medications, including steroids and other potent immunosuppressants, help control symptoms.

[0303] Rosacea is a common skin condition that causes facial redness and visible blood vessels. It can also produce small, red, pus-filled bumps. These signs and symptoms can worsen rapidly for weeks to months before disappearing for a while. Rosacea can be mistaken for acne, other skin problems, or natural erythema. While there is no cure for rosacea, treatment can help control and reduce its signs and symptoms. Osteoarthritis is the most common form of arthritis, affecting millions of people worldwide. It occurs as protective cartilage wears away over time. While osteoarthritis can damage any joint, this disorder most commonly affects the joints of the hands, knees, hips, and spine. Although joint damage is irreversible, the symptoms of osteoarthritis can generally be managed.

[0304] Lupus is an autoimmune disease. It causes the immune system to produce proteins called autoantibodies that attack its own tissues and organs, including the kidneys. Lupus nephritis is a frequent complication in people with Systemic lupus erythematosus (commonly known as lupus). Lupus nephritis occurs when lupus autoantibodies affect the structure of the kidneys. This causes inflammation of the kidneys and can lead to blood in the urine, protein in the urine, high blood pressure, impaired kidney function, or kidney failure.

[0305] Scleroderma is a group of rare diseases involving the hardening and tightening of the skin and connective tissue. Various types of scleroderma exist. For some people, scleroderma affects only the skin. However, for many, scleroderma also damages structures other than the skin, such as blood vessels, internal organs, and the digestive tract (systemic scleroderma). There is no cure for scleroderma.

[0306] Sjögren's syndrome is an immune system disorder identified by the two most common symptoms: dry eyes and dry mouth. This condition is often accompanied by other immune system disorders, such as rheumatoid arthritis and lupus. In Sjögren's syndrome, the mucous membranes and fluid-secreting glands of the eyes and mouth are typically affected first, leading to a decrease in tears and saliva.

[0307] Infectious or septic arthritis is a painful infection of the joints that can be caused by bacteria traveling through the bloodstream from other parts of the body. Septic arthritis can also occur when penetrating injuries, such as animal bites or trauma, deliver bacteria directly to the joint. People with artificial joints are also at risk of septic arthritis. While the knees are most commonly affected, septic arthritis can also impact the hips, shoulders, and other joints. Prompt treatment is crucial because the infection can rapidly and severely damage the cartilage and bone within the joint.

[0308] Juvenile idiopathic arthritis, formerly known as juvenile rheumatoid arthritis, is the most common type of arthritis in children under the age of 16. Juvenile idiopathic arthritis can cause persistent joint pain, swelling, and stiffness. While some children may experience symptoms for only a few months, others may experience them for years. Some types of juvenile idiopathic arthritis can lead to serious complications, such as growth problems, joint damage, and eye inflammation.

[0309] Polymyalgia rheumatica is an inflammatory disorder that causes muscle pain and stiffness, particularly in the shoulders and hips. The signs and symptoms of polymyalgia rheumatica typically begin quickly and are more severe in the morning. Most people who develop polymyalgia rheumatica are over the age of 65. This condition is associated with another inflammatory condition called giant cell arteritis.

[0310] Ophthalmic disorders may include, for example, without limitation, age macular degeneration (AMD or ARMD, dry and wet forms), pterygium (PTE), diabetic retinopathy (DR), diabetic macular edema (DME), Stargardt disease (SD), proliferative vitreoretinopathy (PVR), dry eye syndrome (DYS), endophthalmitis, central serous chorioretinopathy (CSC), retinitis pigmentosa (RP), glaucoma and glaucoma-related complications, and uveitis (UVE).

[0311] Wet macular degeneration is a chronic eye disorder that causes blurred vision or blind spots. It is typically caused by abnormal blood vessels that leak fluid or blood into the macula. The macula is the part of the retina responsible for central vision. Wet macular degeneration is one of two types of age-related macular degeneration. The wet type always begins as the dry type. Dry macular degeneration is more common and less severe. It also causes central vision to become blurred or reduced due to the thinning of the macula. Dry macular degeneration can first occur in one or both eyes and then affect both. Vision loss typically affects central vision but persists in peripheral vision.

[0312] Diabetic retinopathy is a complication of diabetes that affects the eyes. It occurs when the blood vessels in the retina are damaged. Initially, diabetic retinopathy may be asymptomatic or cause mild vision problems. Eventually, it can lead to blindness. This condition can occur in anyone with type 1 or type 2 diabetes. DME is a serious eye complication in which microaneurysms protrude from the blood vessel walls, causing fluid and blood to leak or seep into the retina and cause edema in the macula.

[0313] Stargardt disease is an ophthalmic condition that causes vision loss in children and young adults. As it is a genetic disease, it is passed down from parents to children. Stargardt disease is a form of macular degeneration and is often referred to as juvenile macular degeneration.

[0314] PVR is a condition that develops as a complication of rhegmatogenous retinal detachment. PVR occurs in approximately 8 to 10% of patients undergoing primary retinal detachment surgery and hinders the successful surgical repair of the rhegmatogenous retinal detachment. PVR can be treated with surgery to reattach the detached retina, but the visual outcomes of the surgery are very poor.

[0315] Dry eye disease is a common condition that occurs when tears fail to provide adequate lubrication to the eye. Tears can be inadequate and unstable for various reasons. For example, dry eye syndrome can develop if tears are not produced in sufficient quantities or if tears of poor quality are produced. This instability of tears causes inflammation and damage to the surface of the eye.

[0316] Endophthalmos is inflammation inside the eye that can occur after an ocular injection or surgery. Signs typically include blurred vision or other changes in vision, eye pain, redness, sensitivity to light, or tearing.

[0317] Retinitis pigmentosa (RP) is a group of rare genetic disorders involving the destruction and loss of cells in the retina, the light-sensitive tissue that lines the back of the eye. Common symptoms include difficulty seeing at night and loss of lateral (peripheral) vision.

[0318] Glaucoma is a group of eye diseases that damage the optic nerve, and the health of the optic nerve is crucial for good vision. This damage is often caused by abnormally high intraocular pressure. Glaucoma is one of the leading causes of blindness in people over the age of 60. While it can occur at any age, it is more common in the elderly. Many forms of glaucoma have no warning signs. The effects are very gradual, without any change in vision, until the condition reaches an advanced stage.

[0319] Uveitis is a form of inflammation of the eye. It affects the wall of the eyeball or the middle layer of the uvea tissue. Warning signs of uveitis often appear suddenly and worsen rapidly. These include redness of the eye, pain, and blurred vision. Possible causes of uveitis include infection, injury, autoimmune, or inflammatory diseases. Uveitis is severe and can lead to permanent vision loss.

[0320] The compound and pharmaceutical composition according to the present invention may also be used in a method for treating and / or preventing retinal neurodegenerative diseases selected from the group consisting of diabetic retinopathy, age-related macular degeneration, glaucoma, and retinitis pigmentosa.

[0321] Retinal neurodegenerative diseases refer to retinal conditions characterized by progressive nerve loss. Diabetic retinopathy, age-related macular degeneration, glaucoma, and retinitis pigmentosa are considered retinal diseases in which neurodegeneration plays a significant role.

[0322] According to these preferred embodiments, the compound according to the present invention may be combined with other active agents, particularly with a dipeptidyl peptidase-4 inhibitor (DPPIV) or a pharmaceutically acceptable salt thereof, to enhance the therapeutic efficacy of the condition to be treated, for use in the local ocular treatment and / or prevention of retinal neurodegenerative diseases. The DPPIV inhibitor may be selected from the group consisting of sitagliptin, saxagliptin, vildagliptin, linagliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, gemigliptin, omarigliptin, pharmaceutically acceptable salts thereof, and mixtures thereof.

[0323] The compound according to the present invention can also be advantageously combined with anti-VEGF therapy to reduce the number of intraocular anti-VEGF antibody injections required by the patient. For example, administration to patients with retinal neurodegenerative diseases such as diabetic retinopathy and age-related macular degeneration slows the progression of these diseases and reduces the anti-VEGF drug therapy required by the patient.

[0324] Fibrotic disorders may include, for example without any limitation, cystic fibrosis, retroperitoneal fibrosis, idiopathic pulmonary fibrosis, combined pulmonary fibrosis & emphysema (CPFE), eosinophilic angiocentric fibrosis, intestinal fibrosis, ovarian fibrosis, nephrotenic systemic fibrosis, oral submucous fibrosis (OSMF), and liver fibrosis.

[0325] Cystic fibrosis (CF) is a genetic disorder that causes severe damage to the lungs, digestive system, and other body organs. It affects the cells that produce mucus, sweat, and digestive fluids. Instead of acting as a lubricant, these secretions block tubes, ducts, and passages, particularly in the lungs and pancreas.

[0326] Pulmonary fibrosis is a lung disease that occurs when lung tissue is damaged and scars form. This thickened and stiff tissue makes it more difficult for the lungs to function properly. Scarring associated with pulmonary fibrosis can be caused by various factors. While lung damage caused by pulmonary fibrosis cannot be repaired, medications and treatments can sometimes help alleviate symptoms and improve quality of life.

[0327] Emphysema is a lung condition that causes shortness of breath. As the alveoli become damaged, the inner walls of the alveoli weaken and rupture over time, creating larger air spaces instead of many small ones. This reduces the surface area of ​​the lungs, which in turn reduces the amount of oxygen reaching the bloodstream. Because the damaged alveoli do not function properly, old air becomes trapped, leaving no room for fresh, oxygen-rich air to enter.

[0328] Metabolic and gastrointestinal disorders may include, for example, diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic cardiomyopathy (DCDM), or diabetic foot ulcer (DFU), without any limitation. Liver diseases may include nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatic hepatosis (NASH), primary biliary cholangitis (PBC), hepatic fibrosis or cirrhosis (HF), inflammatory bowel disease (IBD): ulcerative colitis, Crohn's disease, or intestinal fibrosis. In addition to diabetic nephropathy, other kidney diseases may include polycystic kidney disease (PKD), chronic kidney disease (CKD), nephrogenic systemic fibrosis (NSF), and pancreatitis (acute and chronic).

[0329] Diabetic nephropathy is a serious kidney-related complication of Type 1 and Type 2 diabetes. It is also known as diabetic kidney disease. Approximately 25% of people with diabetes eventually develop kidney disease. Diabetic nephropathy affects the kidneys' ability to perform the daily task of removing waste products and excess fluid from the body. Over the years, this condition slowly damages the kidneys' delicate filtration system and can progress to renal failure, also known as end-stage renal disease. Renal failure is a life-threatening condition.

[0330] Non-alcoholic fatty liver disease (NAFLD) is a comprehensive term for various liver conditions affecting people who drink little to no alcohol. As the name suggests, the primary characteristic of NAFLD is the storage of excessive fat in liver cells. It is the most common form of chronic liver disease. Some individuals with NAFLD may develop non-alcoholic steatohepatitis (NASH), an aggressive form of fatty liver disease characterized by liver inflammation that can progress to progressive scarring (cirrhosis) and liver failure. This damage is similar to that caused by excessive alcohol use.

[0331] Primary biliary cholangitis is a chronic autoimmune disease in which the bile ducts in the liver are slowly destroyed. When the bile ducts are damaged, bile flows back into the liver, which can sometimes lead to irreversible liver cirrhosis. This disease is caused by a complex interplay of genetic and environmental factors.

[0332] IBD describes a disorder associated with chronic inflammation of the digestive tract. Types of IBD include ulcerative colitis, which involves ulcers along the surface lining of the colon and rectum, and Crohn's disease, which is characterized by inflammation of the lining of the digestive tract that can often affect the deeper layers of the tract. Both ulcerative colitis and Crohn's disease are generally characterized by diarrhea, rectal bleeding, abdominal pain, fatigue, and weight loss, and sometimes cause life-threatening complications.

[0333] Neoplasms and cancer-related disorders may include, for example, pancreatic cancer without any limitation: mostly fibrotic, renal cell carcinoma, radiation-induced fibrosis, primary myelofibrosis, fibrosis, fibrosarcoma, hepatocellular carcinoma, retinoblastoma, intraocular lymphoma, and melanoma (fibrogenic, conjunctival, uveal).

[0334] The present invention also relates to the treatment, prevention, and reduction of viral infections through binding to the heparan sulfate binding site of viral proteins. The compound according to the present invention interacts with the heparan sulfate binding domains of growth factors (FGF, VEGF, and other growth factors) and growth factor receptors (FGFR, VEGFR, and others). Many viruses are known to interact with mammalian cells by utilizing their affinity for heparan sulfate moiety bound to the cell membrane. Viruses possessing a heparan sulfate (HS) binding domain on their surface proteins use this HS affinity as one of the primary entry points to approach and infect cells and bind to heparan sulfate attached to the cells. Once attached to the HS virus, they can infect cells using various invasion mechanisms specific to each virus. The potent interaction between the compound according to the present invention and the heparan binding domain of proteins, particularly viral proteins, prevents viral infection of surface epithelial cells present in the mouth, nasal mucosa, lungs, and gastrointestinal tract, as well as blood cells and endothelial cells surrounding blood vessels and organs. Some virus species are known to have a high affinity for heparan sulfate, to a non-limiting degree, such as respiratory syncytial virus, human metapneumovirus, influenza (H1N1, etc.), human rhinovirus (HRV), rhinosyncitial virus (RV), chikungunya virus, and coronaviruses such as CoV, SARS-CoV, MERS-CoV, and COVID-19 (SARS-CoV-2 and its variants). HS is a cofactor required for SARS-CoV-2 infection.HS interacts with the receptor-binding domain of the SARSCoV-2 spike glycoprotein adjacent to ACE2, shifting the spike structure to an open structure to facilitate ACE2 binding. Viral and bacterial infectious diseases can also include septic shock and inflammation of the eyes, such as endophthalmitis caused by surgery or infection.

[0335] Examples

[0336] Example 1: Synthesis of Compounds and Intermediates

[0337] Example 1.1: Type Ia molecule: monoamide, 25 examples

[0338]

[0339] Synthesis procedure

[0340] Reaction Equation 1.

[0341] intermediate KI-1 and KI-6 Synthesis of

[0342]

[0343] procedure :

[0344] KI-1 and KI-6 Synthesis of (Step [1],[2])

[0345] Diethyl 2,5-bis(benzyloxy)terephthalate (KI-0)(Stage [1]) . Potassium carbonate-325 mesh (326.1 g, 2.4 mol) was added dropwise to a stirred solution of diethyl 2,5-dihydroxyterephthalate (200.0 g, 0.79 mol) in DMF (800.0 mL) over 15 minutes at ambient temperature. Subsequently, benzyl bromide (280.0 mL, 2.4 mol) was added to the reaction flask dropwise over 30 minutes, and the resulting mixture was heated at 100°C for 2 hours, resulting in the formation of a dark cream-colored precipitate. The reaction mixture was cooled to ambient temperature and treated with a saturated aqueous ammonium chloride (2 L) solution. The resulting suspension was stirred for 30 minutes and then filtered. The solid material was washed with a saturated aqueous ammonium chloride (2 x 200 mL) solution. The solid was then suspended in ethanol (400 mL) and filtered and dried in a vacuum oven to obtain the desired product as a white solid (341.0 g, 0.785 mol, 99.8%).

[0346] UPLC-MS (acidic method, 2 min): rt = 1.36 min, no ionization observed, peak area >95%

[0347] 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.51-7.44 (m, 6H), 7.44-7.36 (m, 4H), 7.36-7.28 (m, 2H), 5.17 (s, 4H), 4.29 (q, J = 7.1 Hz, 4H), 1.26 (t, J = 7.1 Hz, 6H).

[0348] 2,5-Bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid ( KI-1 ) and 2,5-bis(benzyloxy)terephthalic acid ( KI-6 ) (Step [2])

[0349] A solution of potassium hydroxide (14.2 g, 0.25 mol) in water (200.0 mL) was rapidly added to a solution of diethyl 2,5-bis(benzyloxy)terephthalate (100 g, 0.23 mol) in 1,4-dioxane (1 L), and the resulting mixture was stirred overnight at ambient temperature. As a result of removing the solvent under vacuum, a white slurry was formed. The crude was suspended in EtOH (500 mL), filtered, and the collected solid was dried in a vacuum oven to obtain pure diethyl 2,5-bis(benzyloxy)terephthalate (23.0 g, 0.053 mol, 23%).

[0350] UPLC-MS (acidic method, 2 min): rt = 1.36 min, no ionization observed, peak area 98%

[0351] The ethanol filtrate was concentrated to obtain the citrate. Ethyl acetate (500 mL) was added to form a precipitate, which was filtered and washed with ethyl acetate (200 mL) to obtain 2,5-bis(benzyloxy)terephthalic acid as a white solid. (KI-6) was obtained (18.9 g, 0.042 mol, 18%).

[0352] UPLC-MS (acid method, 2 min): rt = 1.22 min, m / z 377.1 [MH] - , peak area 95%

[0353] 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.52-7.45 (m, 4H), 7.41-7.33 (m, 4H), 7.33-7.26 (m, 4H), 5.13 (s, 4H).

[0354] The filtrate is washed with a saturated aqueous solution of sodium carbonate (200 mL), aqueous 1 M hydrochloric acid (500 mL), and brine (500 mL), then dried (Na2SO4), filtered, concentrated, and dried to obtain 2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid as a white solid ( KI-1) was obtained (53 g, 0.130 mol, 57.0%).

[0355] UPLC-MS (acid method, 2 min): rt = 1.22 min, m / z 405.3 [MH] - , peak area 96%

[0356] 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.52-7.27 (m, 13H), 5.17 (s, 4H), 4.28 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H).

[0357] Large-scale protocol for KI-1 synthesis

[0358] Diethyl 2,5-bis(benzyloxy)terephthalate (500.00 g, 1.15 mol), 1,4-dioxane (2.5 L), potassium hydroxide (71.00 g, 1.26 mol), and water (500 mL) were filled into a 10 L jacketed vessel. The reaction mixture was stirred overnight at room temperature. LCMS analysis indicated that the reaction was about half complete, showing a ratio of byproduct (di-acid) to starting material (di-ester) (diester:mono-acid:diacid = 28:58:14) (di-acid: 4.44 rt, mono-acid: 5.08 rt, diester: 5.68 rt). At this stage, the solvent was removed under vacuum. The crude product was placed in a 10 L jacketed container with a 2:1 mixture of ethanol:water (3 L), stirred overnight, and filtered to obtain the following:

[0359] Solid: (Diester:mon-acid:di-acid = 86:12:2, 110.00 g, colorless solid)

[0360] Filtrate: (Diester:mon-acid:di-acid 3:63:34)

[0361] The filtrate was concentrated under vacuum to obtain oil. This oil was dissolved in ethyl acetate (2.5 L), stirred overnight in a 10 L jacketed container, and filtered to obtain a white solid (150.00 g).

[0362] Solid: (Diester:mon-acid:di-acid = trace:40:60).

[0363] The filtrate was collected, washed with a saturated aqueous solution of sodium bicarbonate (100 mL), a 1 N hydrochloric acid solution (200 mL), and brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure to obtain the desired product, 2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid ( KI-1 ) was obtained as a white solid and dried in a vacuum oven at 50°C for 48 hours (225.00 g, 49% yield) (yield varied between 49 and 65%).

[0364] Reaction Equation 2 : Intermediate KI-1Bn synthesis

[0365]

[0366] procedure:

[0367] KI-1Bn Synthesis of :

[0368] 2,5-bis(benzyloxy)-4-(benzyloxycarbonyl)benzoic acid (KI-1Bn) . Sodium hydride (2.0 g, 50 mmol) was added to a solution of 2,5-dihydroxyterephthalic acid (1.97 g, 10 mmol) in DMF (20 mL) at 0°C under stirring, followed by the addition of benzyl bromide (5.95 mL, 50 mmol, 5 eq) dropwise over 5 minutes, and the resulting mixture was maintained at room temperature for 2 hours. Subsequently, the mixture was heated at 60°C for 18 hours. The reaction mixture was cooled to ambient temperature and carefully treated with MeOH (5 mL). The mixture was concentrated under reduced pressure, and the residue was co-evaporated with heptane (3x). The residue was dissolved in DCM (30 mL), the organic phase was washed with 1 M HCl (25 mL), the separated aqueous layer was extracted with DCM (3x30 mL), and the combined organic phase was dried (MgSO4) and concentrated. The crude solid was recrystallized in EtOH (approx. 30 mL) to obtain pure KI-0Bn (2.286 g, 41%) was obtained. A sample of KI-0Bn (282 mg, 0.5 mmol) was added to a mixture of 1,4-dioxane (10 mL) and lithium hydroxide hydrate (22 mg, 0.52 mmol), and the mixture was heated at 80°C for 3 days. The mixture was cooled to room temperature, dissolved in AcOEt (30 mL), and the solution was washed with 1 M HCl (2 mL). The organic phase was dried and concentrated, and the residue was subjected to column chromatography to obtain approximately 16% diester KI-0Bn Monoester contaminated with KI-1Bn obtained.

[0369] KI-0Bn : 1 H NMR (400 MHz, CDCl3): δ 7.51 (s, 2H), 7.36-7.30 (m, 20H), 5.34 (s, 4H), 5.11 (s, 4H).

[0370] KI-1Bn : 1H NMR (250 MHz, CDCl3): δ 7.86 (s, 1H), 7.61 (s, 1H), 7.41-7.30 (m, 20H), 5.36 (s, 2H), 5.26 (s, 2H), 5.16 (s, 2H).

[0371] Synthesis of monoamines

[0372] Reaction Equation 3. monoamide Ia Synthesis of

[0373]

[0374] General procedure for amide coupling [3A]

[0375] ▷ KI-1 or KI-6 From, coupling via acyl chloride

[0376] Model response (Ia-013a)

[0377] Dimethyl 2-(2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoylamino)isophthalate. 2,5-Bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid ( KI-1 , 1.1 g, 2.8 mmol) was dissolved in thionyl chloride (6 mL), and the resulting mixture was stirred for 5 minutes. A few drops of DMF were added, and the resulting mixture was stirred at ambient temperature for 18 hours. Excess thionyl chloride was removed under vacuum, and the residue was co-distilled with toluene (3 × 20 mL) to obtain acyl chloride. The acyl chloride solution in DCM (10 mL) was mixed at ambient temperature with the amine (dimethyl 2-aminoisophthalate, 210 mg, 3.1 mmol) and in DCM (10 mL). N,N- The mixture was rapidly added to a solution of diisopropylethylamine (0.53 mL, 3.045 mmol) and stirred for 18 hours. The residue was diluted with DCM (70 mL), washed with 1 M aqueous hydrochloric acid (100 mL) and water (100 mL), dried (Na2SO4), filtered, and concentrated to obtain a crude product, which was purified by silica gel chromatography eluted with a gradient of ethyl acetate (0 to 25%) in iso-hexane to obtain the desired product as a white solid (1.24 g, 2.075 mmol, 75%).

[0378] UPLC-MS (acid method, 2 min): rt = 1.37 min; m / z = 598.2 [M+H] + , peak area >95%

[0379] 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.60 (s, 1H), 8.02 (d, J = 7.8 Hz, 2H), 7.69 (s, 1H), 7.59 - 7.23 (m, 12H), 5.49 (s, 2H), 5.19 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.71 (s, 6H), 1.26 (t, J = 7.1 Hz, 3H).

[0380] General procedure for amide coupling [3B] B

[0381] ▷ KI-1 or KI-6 From, coupling using a condensation agent

[0382] Model response (Ia-001a)

[0383] Methyl 2-(2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoylamino)benzoate. 1-methylimidazole (13.0 mL, 163 mmol) in 2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid (1-methylimidazole) in MeCN (150 mL) at ambient temperature ( KI-1It was added to a mixture of , 12.95 g, 32 mmol) and methyl anthranilate (5.729 g, 38 mmol, 1.190 eq). Chloro- N , N,N',N''- Tetramethylformamidinium hexafluorophosphate (TCFH) (10.728 g, 0.038 mol) was added gradually over 30 minutes, and the resulting mixture was stirred overnight at ambient temperature. The reaction mixture was treated with 1 M aqueous hydrochloric acid (700 mL). The resulting suspension was stirred for 10 minutes and then filtered. The solid material was washed with water (2 x 200 mL). Subsequently, the solid was suspended in ethanol (200 mL), filtered, washed with ether (100 mL), and dried in a vacuum oven to obtain the desired product as a white solid (14.7 g, 27 mmol, 86%).

[0384] UPLC-MS (acid method, 2 min): rt = 1.43 min; m / z = 540.2 [M+H] + , peak area >99%

[0385] 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 11.87 (s, 1H), 8.65 (d, J = 8.4 Hz, 1H), 7.98 (dd, J = 8.0, 1.7 Hz, 1H), 7.81 - 7.61 (m, 2H), 7.59 - 7.12 (m, 12H), 5.41 (s, 2H), 5.20 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).0

[0386] General deprotection procedure [4], [5]

[0387] Saponification

[0388] Model response (Ia-013a)

[0389] 2-(2,5-bis(benzyloxy)-4-carboxybenzoylamino)isophthalic acid. A solution of lithium hydroxide (42 mg, 1 mmol) in water (4 mL) was added to a solution of dimethyl 2-(2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoylamino)isophthalate (100 mg, 0.167 mmol) in THF (6 mL), and the resulting mixture was stirred at ambient temperature for 18 hours. Additional LiOH (6 eq) in water (4 mL) was added to the reaction mixture and stirred for an additional 23 hours. After completion, water (50 mL) was added to the reaction, and the mixture was washed with ethyl acetate (50 mL). The aqueous layer was acidified with 1 M aqueous hydrochloric acid to pH=2 and extracted with ethyl acetate (2 x 50 mL). The organic layer was collected, dried (Na2SO4), filtered, and concentrated to obtain the title compound as a white solid (82 mg, 0.151 mmol, 91%).

[0390] UPLC-MS (acid method, 2 min): rt = 1.02 min; m / z = 542.1 [M+H] + , peak area >95%

[0391] 1 ¹H NMR (400 MHz, DMSO) -d 6 ) δ 13.18 (s, 2H), 11.74 (s, 1H), 8.00 (d, J = 7.8 Hz, 2H), 7.71 (s, 1H), 7.58 - 7.43 (m, 5H), 7.40 - 7.24 (m, 7H), 5.47 (s, 2H), 5.14 (s, 2H).

[0392] Debenzylization

[0393] Model response (Ia-013a)

[0394] 2-(2,5-dihydroxy-4-carboxybenzoylamino)isophthalic acid( Ia-013a) . Pd / C (94 mg, 10%) was added to a solution of 2-(2,5-bis(benzyloxy)-4-carboxybenzoylamino)isophthalic acid (0.94 g, 1.74 mmol) in a 10:30 mixture of EtOH and DCM. The mixture was stirred under hydrogen at ambient temperature and atmospheric pressure for 18 hours. After completion, the mixture was filtered through Celite and washed with DCM and MeOH. The filtrate and washes were combined and concentrated under reduced pressure to obtain the desired product as a yellow solid. Ia-013a was obtained (644 mg, 1.69 mmol, 98%).

[0395] UPLC-MS (acid method, 4 min): rt = 0.91 min; m / z =362.0 [M+H] + , peak area >98%

[0396] 1 1 H NMR (DMSO- d 6 ) δ: 13.11 (s, 2H), 11.70 (s, 1H), 11.13 (s, 1H), 7.97 (d, J = 7.8 Hz, 2H), 7.47 (s, 1H), 7.41 (s, 1H), 7.38 (t, J = 7.7 Hz, 1H)

[0397] Reaction Scheme 4a. KI-1Bn monoamide from Ia Synthesis of

[0398]

[0399] General procedures from KI-1Bn

[0400] ▷ Coupling via acyl chloride

[0401] Model Reaction: Synthesis of Ia-032a

[0402] Benzyl 4-(2,5-bis(benzyloxy)-4-(benzyloxycarbonyl)benzoylamino)phenylacetate. in DCM (10 mL) KI-1BnSOCl2 (1.8 mL, 60 eq) was added to a solution (233 mg, 84% purity) and the mixture was heated at 50°C for 3 hours. The solvent was evaporated and co-evaporated with toluene (3 × 10 mL) to obtain crude acyl chloride (237 mg, 99%). This substance was dissolved in DCM (3 mL), diisopropylethylamine (0.08 mL, 1.15 eq) was added, followed by the addition of a solution of benzyl 4-aminophenylacetate (92 mg, 0.95 eq) in DCM (3 mL). The final reaction volume was 10 mL. The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with DCM (15 mL) and washed with saturated aqueous ammonium chloride (12 mL). The separated aqueous phase was extracted with DCM (2 × 2 mL), the organic phase was combined, dried (MgSO4), and concentrated. The crude product was subjected to column chromatography (Pet. Et. / DCM 1:1 followed by a gradient to 100% DCM) to obtain a first fraction of pure KI-0Bn and a second fraction containing pure desired product (237 mg, 86%, corrected for purity of KI-1Bn).

[0403] 1 H NMR (400 MHz, CDCl3): δ 10.10 (s, 1H), 8.08 (s, 1H), 7.65 (s, 1H), 7.53-7.30 (m, 20H), 7.22-7.13 (br AB, 4H), 5.39, 5.22, 5.21, 5.12 (4s, 4x 2H), 3.61 (s, 2H).

[0404] 4-(4-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid (Ia-032a).5% Pd in ​​charcoal (72 mg) was added to the solution of the prepared precursor (225 mg, 0.33 mmol) in DCM (20 mL), followed by the addition of EtOH (20 mL). The flask was flushed with Ar (3x), filled with hydrogen (atmospheric pressure), and the mixture was stirred at room temperature for 2 hours. The catalyst was removed by filtration over a Millipore filter, the filtrate was evaporated, and the residue was dried to obtain the product as a pale yellow solid. Ia-032a was obtained (107 mg, 99%).

[0405] 1 ¹H NMR (250 MHz, DMSO- d 6 ): δ 12.28 (br, 1H), 10.92 (s, 1H), 10.44 (s, 1H), 7.65 (br d, 2H), 7.41 (s, 1H), 7.38 (s, 1H), 7.25 (br d, 2H), 3.55 (s, 2H).

[0406] for example:

[0407]

[0408] For conditions and yield: Refer to FIGS. 4a through d.

[0409] 1) 4-(2-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-001a

[0410] UPLC-MS (acid method, 2 min): rt = 0.95 min, m / z = 316 [MH] - , peak area > 97%

[0411]

[0412]

[0413] diethyl ester :

[0414] UPLC-MS (acid method, 2 min): rt = 1.39 min, m / z = 372.2 [MH] - , peak area > 98%

[0415]

[0416]

[0417] 2) 4-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound Ia-001aTz :

[0418] UPLC-MS (acid method, 4 min): rt = 1.17 min; m / z =342.0 [M+H] + , peak area >96%

[0419]

[0420]

[0421] Ethyl ester:

[0422] UPLC-MS (acid method, 2 min): rt = 1.08 min, m / z = 370.1 [M+H] + , peak area > 97%

[0423]

[0424]

[0425] Ethyl ester diacetate:

[0426] UPLC-MS (acid method, 4 min): rt = 1.57 min, m / z = 454.1 [M+H] + , peak area > 97%

[0427]

[0428] 3) 2,5-Dihydroxy-4-(2-sulfophenylaminocarbonyl)benzoic acid , compound Ia-001c :

[0429] UPLC-MS (acid method, 2 min): rt = 0.73 min; m / z =352.0 [MH] - , peak area >99%

[0430]

[0431] 4) 4-(3-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound Ia-002a :

[0432]

[0433] 5) 4-(3-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound Ia-002aTz :

[0434] UPLC-MS (acid method, 4 min): rt = 1.13 min; m / z =342.0 [M+H] + , peak area >99%

[0435]

[0436] 6) 2,5-Dihydroxy-4-(3-sulfophenylaminocarbonyl)benzoic acid , compound Ia-002c :

[0437]

[0438] 7) 4-(4-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound Ia-003a :

[0439]

[0440] 8) 4-(4-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound Ia-003aTz :

[0441] UPLC-MS (acid method, 2 min): rt = 0.79 min; m / z =342.0 [M+H] + , peak area >97%

[0442]

[0443] 9) 2,5-Dihydroxy-4-(4-sulfophenylaminocarbonyl)benzoic acid , compound Ia-003c :

[0444]

[0445] 10) 4-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound Ia-004a :

[0446] UPLC-MS (acid method, 6.5 min): rt = 1.40 min; m / z =332.0 [MH] - , peak area >96%

[0447]

[0448] Ethyl methyl ester:

[0449] UPLC-MS (acid method, 2 min): rt = 1.16 min, m / z = 376.1 [M+H] + , peak area > 95%

[0450]

[0451] 11) 4-(2-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound Ia-006a :

[0452] UPLC-MS (acid method, 2 min): rt = 0.81 min; m / z =334.0 [M+H] + , peak area >96%

[0453]

[0454] 12) 3-(4-carboxy-2,5-dihydroxybenzamido)phthalic acid , compound Ia-011a :

[0455] UPLC-MS (acid method, 2 min): rt = 0.69 min; m / z = 360.1 [MH] - , peak area >89%

[0456]

[0457] 13) 2-(4-carboxy-2,5-dihydroxybenzamido)terephthalic acid , compound Ia-012a :

[0458] UPLC-MS (acid method, 4 min): rt = 1.12 min; m / z = 362.1 [M+H] + , peak area >96%

[0459]

[0460] 14) 2-(4-carboxy-2,5-dihydroxybenzamido)isophthalic acid , compound Ia-013a :

[0461] UPLC-MS (acid method, 4 min): rt = 0.91 min; m / z = 362.0 [M+H] + , peak area >98%

[0462]

[0463]

[0464] 15) 4-(4-carboxy-2,5-dihydroxybenzamido)phthalic acid , compound Ia-014a :

[0465] UPLC-MS (acid method, 4 min): rt = 0.98 min; m / z = 362.1 [M+H] + , peak area >94%

[0466]

[0467] 16) 5-(4-carboxy-2,5-dihydroxybenzamido)isophthalic acid , compound Ia-015a :

[0468]

[0469] 17) 3-(4-carboxy-2,5-dihydroxybenzamido)isonicotinic acid , compound Ia-023a :

[0470] UPLC-MS (acid method, 4 min): rt = 0.63 min; m / z = 319.1 [M+H] + , peak area >93%

[0471]

[0472]

[0473] Diethyl ester:

[0474] UPLC-MS (acid method, 4 min): rt = 1.87 min, m / z = 375.1 [M+H] + , peak area > 98%

[0475]

[0476] 18) 4-(4-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound Ia-032a :

[0477]

[0478] 19) 4-(3-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound Ia-033a :

[0479] UPLC-MS (acid method, 6.5 min): rt = 1.71 min; m / z = 332.1 [M+H] + , peak area >99%

[0480]

[0481] 20) 4-(2-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound Ia-034a :

[0482] UPLC-MS (acid method, 2 min): rt = 0.82 min; m / z = 332.1 [M+H] + , peak area >98%

[0483]

[0484] 21) 4-(3,4-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound Ia-035a :

[0485] UPLC-MS (acid method, 2 min): rt = 1.02 min; m / z = 320.1 [M+H] + , peak area >91%

[0486]

[0487] 22) 4-(2-(3,4-dihydroxyphenyl)ethylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-035a-2 :

[0488] UPLC-MS (acid method, 2 min): rt = 0.77 min; m / z = 332.0 [MH] - , peak area >99%

[0489]

[0490] 23) 4-(1-carboxy-2-(3,4-dihydroxyphenyl)ethylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound Ia-035a-3 :

[0491] UPLC-MS (acid method, 2 min): rt = 0.70 min; m / z = 376.0 [MH] - , peak area >99%

[0492]

[0493] 24) 4-(carboxy(3,4-dihydroxyphenyl)methylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound Ia-036a :

[0494] UPLC-MS (acid method, 2 min): rt = 0.62 min; m / z = 362.1 [MH]- , peak area >92%

[0495]

[0496] 25) 4-(2-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound Ia-053a :

[0497] UPLC-MS (acid method, 4 min): rt = 1.08 min; m / z = 332.0 [M+H] + , peak area >97%

[0498]

[0499]

[0500] Reaction Equation 4b. Ethyl 4-amino-2,5-dibenzyloxybenzoate (aniline A Synthesis of )

[0501]

[0502] Protocol: Aniline A synthesis

[0503] Ethyl 4-amino-2,5-dibenzyloxybenzoate (aniline A ). in THF (25 mL) under an inert atmosphere (N2) 2,5-Bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid (KI-1) DPPA (1.1 mL, 5.2 mmol) was slowly added to a cooled solution (ice bath) of (2.0 g, 4.9 mmol) and Et3N (1.6 mL, 11.3 mmol). The mixture was slowly heated to room temperature and stirred at this temperature for 3 hours. Subsequently, water (8 mL) was added, and the reaction mixture was heated to 70°C for 2 hours. The reaction mixture was poured into a saturated solution of sodium hydrocarbonate (250 mL), stirred for 5 minutes, and extracted with EtOAc (3 x 100 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a colorless oil. The residue was purified by flash column chromatography (iso-hexane / EtOAc 1:0 followed by a gradient to 30% EtOAc) to obtain the title compound as a grayish-white solid. Aniline A(1.0 g, 53%) was obtained.

[0504] UPLC-MS (acid method, 2 min): rt = 1.26 min; m / z = 378.2 [M+H] + , peak area 94%

[0505] 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.54 - 7.46 (m, 4H), 7.44 - 7.36 (m, 4H), 7.35 - 7.25 (m, 3H), 6.46 (s, 1H), 5.65 (s, NH2), 5.06 (s, 2H), 5.02 (s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H).

[0506] 26) 4-(4-carboxy-2,5-dihydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound Ia-056a :

[0507] UPLC-MS (acid method, 4 min): rt = 0.90 min; m / z = 348.0 [MH]-, peak area 97%

[0508]

[0509] Diethyl ester:

[0510] UPLC-MS (acid method, 4 min): rt = 1.86 min; m / z = 404.2 [MH] - , peak area 92%

[0511]

[0512] Example 1.2 - Molecule of Type Ib: Diamide from diamine, 1 example

[0513]

[0514] Reaction Equation 5. category Ib synthesis of diamide

[0515]

[0516] Synthesis procedure: See general procedure steps [3], [4], [5]

[0517] Example:

[0518]

[0519] For conditions and yield: Refer to FIGS. 4a through d.

[0520] 27) 3,5-bis(2,5-dihydroxy-4-carboxybenzoylamino)benzoic acid, compound Ib-010a:

[0521] UPLC-MS (acid method, 4 min): rt = 0.98 min; m / z = 511.0 [MH] - , peak area >93%

[0522]

[0523] triethyl ester :

[0524] UPLC-MS (acid method, 2 min): rt = 1.29 min, m / z = 597.1 [M+H] + , peak area > 96%

[0525]

[0526] Triethyl ester tetraacetate:

[0527] UPLC-MS (acid method, 2 min): rt = 1.19 min, m / z = 782.1 [M+NH4] + , peak area 91%

[0528]

[0529] Example 1.3. - Molecule of Type Ic: Diamide from diamide, 4 examples

[0530]

[0531] Reaction Equation 6. Types where R = R' Ic amide synthesis

[0532]

[0533] procedure: KI-6Refer to the general procedure from [3], [4], and [5].

[0534] Example:

[0535]

[0536] For conditions and yield: Refer to FIGS. 4a through d.

[0537] 28) N 1 ,N 4- Bis(2-(1H-tetrazole-5-yl)phenyl)-2,5-dihydroxyterephthalamide, compound Ic-001aTz2 :

[0538] UPLC-MS (acid method, 2 min): rt = 0.97 min; m / z = 485.1 [M+H] + , peak area >97%

[0539]

[0540] 29) 5-(4-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid , compound Ic-007a :

[0541] UPLC-MS (acid method, 2 min): rt = 0.80 min; m / z = 469.1 [M+H] + , peak area >91%

[0542]

[0543]

[0544] Dimethyl ester :

[0545] UPLC-MS (acid method, 2 min): rt = 1.13 min, m / z = 497.0 [M+H] + , peak area > 95%

[0546]

[0547] Alternative large-scale synthesis of Ic-007a

[0548] a) 5-(4-(3-methoxycarbonyl-4-hydroxyphenylaminocarbonyl)-2,5-dibenzyloxybenzamido)-2-methyl hydroxybenzoate

[0549] 2,5-bis(benzyloxy)terephthalic acid (KI-6, 141.00 g, 0.373 mol), benzyltriethylammonium chloride (850 mg, 3.73 mmol, 0.01 eq), and chloroform (2.5 L) were filled into a 5 L flanged flask. Subsequently, a nitrogen inlet, a thermometer, a pressure-equalizing dropping funnel, an outlet to an empty Dreschel bottle, and a sodium hydroxide bubbler were installed. The stirred solution was heated to 55°C, and thionyl chloride (59 mL, 0.802 mol, 2.15 eq) was added dropwise over 40 minutes. The solution was maintained at 55°C for 6 hours and allowed to cool to room temperature overnight. A fraction was sonicated in ethanol for 5 minutes and analyzed by LCMS, revealing only diethyl ester. The mixture was transferred to two round-bottom flasks, and volatile substances were removed under vacuum; acid chloride was azeotropically mixed with toluene (800 mL in each flask). Methyl 5-amino-2-hydroxybenzoate (137.00 g, 0.819 mol, 2.2 eq) and dichloromethane (2.5 L, 18 vol) were filled into a 10 L jacketed vessel; the solution was cooled to 15°C. The acid chloride was dissolved in dichloromethane (2.5 L, 18 vol) and added to the stirred reaction. The reaction immediately formed a large amount of solid, and stirring became difficult; furthermore, the reaction was exothermic up to 30°C. However, with prolonged stirring, the mixture became a pink / purple fine suspension. The mixture was stirred at 25°C for 72 hours. The suspension was filtered, washed with dichloromethane (2 L, 14 vol), and the resulting solid was dried in a vacuum oven to obtain 240.00 g of product (94% yield).

[0550] b) 5-(4-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid, Ic-007a

[0551] Saponification: Freshly ground in a 5L 3-neck round-bottom flask 5-(4-(3-methoxycarbonyl-4-hydroxyphenylaminocarbonyl)-2,5-dibenzyloxybenzamido)-2-hydroxy-benzoate methyl ester(150.00 g, 0.22 mol) and isopropanol (1.5 L, 10 vol) were added. The mixture was heated to 50°C, and tetrabutylammonium hydroxide (444 mL, 0.67 mol, 3 eq) and water (1.1 L, 7 vol) were added. After 1 hour, some solid remained, so an additional 60 mL of tetrabutylammonium hydroxide solution was added along with water (120 mL), the mixture was stirred at 50°C for 6 hours, and allowed to cool to room temperature overnight. An additional 80 mL of tetrabutylammonium hydroxide was added, and the mixture was stirred at 60°C for 1 hour until no solid remained.

[0552] Hydrocracking:The reaction was degassed (cycled 3 times with N2), and then the catalyst (30.00 g, 10% of phase C) was added as a slurry in water (100 mL). The reaction was further degassed (cycled 3 times with N2, 2 times with H2) and incubated overnight under H2 at 50°C (balloon pressure). The reaction was recharged with hydrogen and maintained at 50°C for an additional 4 hours, after which LCMS analysis indicated a complete reaction. The reaction mixture was degassed (cycled 3 times with N2), filtered through a Celite pad, and washed with warm water / isopropanol (1 L, 1:1, 60°C). The volume was reduced to approximately 1.2 L under vacuum. The mixture was transferred to a 5 L flanged flask containing water (approx. 3 L). An overhead stirrer (large anchor-type) was fitted to the flask, and it was acidified with hydrochloric acid (35%). A heavy precipitate formed during the addition. The mixture was heated at 55°C for 6 hours and allowed to cool at room temperature over 72 hours. The mixture was filtered, and the solid slurry in 1 M aq HCl (3 L) was heated at 50°C for 3 hours and allowed to cool overnight at room temperature. The mixture was filtered and washed with 1 M aq HCl (2 L), water (1.5 L), and acetone (1 L). The solid was dried in a vacuum oven to obtain 100.00 g of product, which was still contaminated with approximately 5 mol% of tetrabutylammonium salt (NMR). This solid was stirred in 1 M aq hydrochloric acid (3 L) at 70°C for 8 hours and then allowed to cool overnight at room temperature. The solid was filtered, washed with water, and dried in a vacuum oven. The amount of tetrabutylammonium was reduced to approximately 0.62 mol% (85.90 g, 82% yield) (brown powder).

[0553] 30) 2-(2,5-dihydroxy-4-(4-hydroxy-2-carboxyphenylaminocarbonyl)benzamido)-5-hydroxybenzoic acid , compound Ic-009a :

[0554] UPLC-MS (acid method, 2 min): rt = 0.85 min; m / z = 469.0 [M+H] + , peak area >98%

[0555]

[0556] Dimethyl ester:

[0557] UPLC-MS (acid method, 2 min): rt = 1.03 min, m / z = 497.1 [M+H] + , peak area > 92%

[0558]

[0559] Reaction Equation 7. Types where R ≠ R Ic amide synthesis

[0560]

[0561] Synthesis Procedure: KI-1 Refer to the general procedure from.

[0562] Example:

[0563]

[0564] For conditions and yield: Refer to FIGS. 4a through d.

[0565] 31) 5-(4-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid , compound Ic-001aTz / 004a :

[0566] UPLC-MS (acid method, 4 min): rt = 1.40 min; m / z = 477.2 [MH] - , peak area >99%

[0567]

[0568] Methyl ester:

[0569] UPLC-MS (acid method, 2 min): rt = 1.06 min, m / z = 491.1 [M+H] + , peak area > 89%

[0570]

[0571]

[0572] Example 1.4. Molecule of Type Id: Benzimidazole-linkage, 1 example

[0573]

[0574] Reaction Equation 8. category Id Synthesis of compounds

[0575]

[0576] Synthesis Procedure: KI-1 Refer to the general procedures from [3], [4], and [5].

[0577] Circulation step: Refer to Figures 4a to 4d.

[0578] Example:

[0579]

[0580] 32) 2-(4-carboxy-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid , compound Id-030a :

[0581] UPLC-MS (acid method, 4 min): rt = 0.99 min; m / z = 313.1 [MH] - , peak area >97%

[0582]

[0583] ethyl methyl ester :

[0584] UPLC-MS (acid method, 4 min): rt = 2.09 min, m / z = 357.1 [M+H] + , peak area > 89%

[0585]

[0586] Example 1.5: Type IIa molecule: monoamide, 16 examples

[0587]

[0588] Synthesis procedure

[0589] Reaction Equation 9a. intermediate KI-2 and KI-7 Synthesis of

[0590]

[0591] procedure:

[0592] KI-2 and KI-7 Synthesis of

[0593] 2,6-di(ethoxycarbonyl)cyclohexane-1,4-dione [Step 1][Reference: Literature[Rodriguez et al. Synth. Comm . 28 (1998) 2259-69]]: 1,3-dichloroacetone (12.5 g, 0.1 mol) in THF (500 mL) was added dropwise over 30 minutes to obtain a suspension of diethyl 1,3-acetone dicarboxylate (18 mL, 0.1 mol) and potassium carbonate-325 mesh (21.5 g, 0.15 mol) in THF (1 L) at reflux temperature. After 2 hours, the reaction was complete, and the mixture was cooled to room temperature and then Celite ⓒ The solid residue was filtered through; the solid residue was washed with THF (200 mL), and then the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (hexane / EtOAc 0 to 20%) to obtain the title compound (9.3 g, 37% yield).

[0594] UPLC-MS (acid method, 2 min): rt = 1.01 min; m / z = 257.1 [M+H] - , peak area >74%

[0595]

[0596] Diethyl 2,5-dihydroxyisophthalate [Step 2]: [Literature[Zhong et al.: Chem Eur. J.Protocol taken from 25 (2019) 8177-8169]: NBS (3.5 g, 20 mmol) was added gradually over 30 minutes to a stirred solution of 2,6-di(ethoxycarbonyl)-cyclohexane-1,4-dione (5.0 g, 20 mmol) in AcOH (17 mL) at room temperature. After an additional 20 minutes, water (100 ml) was added to quench the reaction. The desired product was isolated as a solid. After filtration and drying, the title compound was isolated as a white solid (4.6 g, 93% yield).

[0597] UPLC-MS (acid method, 2 min): rt = 1.00 min; m / z = 253.1 [MH] - , peak area >90%

[0598]

[0599] Diethyl 2,5-bis(benzyloxy)isophthalate [Step 3]: Benzyl bromide (43.0 mL, 362 mmol) was added dropwise over 10 minutes to a suspension of diethyl 2,5-dihydroxyisophthalate (19.0 g, 75 mmol) and potassium carbonate-325 mesh (82.6 g, 598 mmol) in DMF (83 mL). The reaction mixture was heated at 100°C for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure. Then, water (500 mL) was added to the residue. The mixture was extracted with EtOAc (3 x 250 mL), the collected organic layer was washed with brine (300 mL), dried over Na2SO4, filtered, and then concentrated under reduced pressure. The crude material was purified by flash column chromatography (hexane / EtOAc 0 to 15%) to obtain the title compound (29.4 g, 90% yield).

[0600] UPLC-MS (acid method, 2 min): rt = 1.38 min; m / z = 435.2 [M+H] + , peak area >90%

[0601]

[0602] 2,5-Bis(benzyloxy)-3-(ethoxycarbonyl)benzoic acid (KI-2) [Step 4]: A solution of potassium hydroxide (4.4 g, 79 mmol) in water (66 mL) was rapidly added to a solution of diethyl 2,5-bis(benzyloxy)isophthalate (31.3 g, 72 mmol) in 1,4-dioxane (430 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The 1,4-dioxane was removed under reduced pressure, followed by the addition of a saturated aqueous solution of Na2CO3 (1 L), the aqueous layer was extracted with EtOAc (3 x 500 mL), dried over Na2SO4, filtered, and the solvent removed under vacuum. The residue was purified by filtering over a silica pad using hexane / EtOAc (1 / 1) followed by EtOAc (1% v / v AcOH) as the eluent to obtain two different fractions:

[0603] Starting material: Diethyl 2,5-bis(benzyloxy)isophthalate (20.4 g, 65% yield).

[0604] UPLC-MS (acid method, 2 min): rt = 1.38 min; m / z = 435.2 [M+H] + , peak area >78%

[0605]

[0606] 2,5-bis(benzyloxy)-3-(ethoxycarbonyl)benzoic acid, the desired product, as a white, fluffy solid KI-2 ) was obtained (3.5 g, 12% yield).

[0607] UPLC-MS (acid method, 2 min): rt = 1.22 min; m / z = 405.1 [MH] - , peak area >90%

[0608]

[0609] Next, the original saturated aqueous solution of Na2CO3 was acidified to a pH of approximately 7 using concentrated hydrochloric acid. Subsequently, it was extracted with EtOAc (2 x 500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. KI-2 and KI-7 A mixture of was obtained (3.0 g, 11% yield).

[0610] UPLC-MS (acid method, 2 min): rt = 1.00 min; m / z = 377.1 [MH] - , peak area 25%, rt = 1.22 min; m / z = 405.1 [MH] - , peak area 56%

[0611]

[0612] Reaction Scheme 9b: KI-7 an alternative synthesis of

[0613]

[0614] 2,6-Dimethyl-1,4-phenylene diacetate [Step 1] Acetic anhydride (10 mL) was rapidly added to a stirred solution of 2,6-dimethylhydroquinone (5.0 g, 36 mmol) in pyridine (10 mL). The solution was stirred at room temperature for 18 hours. Then, the solvent was removed under reduced pressure, and the residue was dissolved in EtOAc (250 mL), then washed with an aqueous solution of hydrochloric acid (1 M, 250 mL), a saturated aqueous solution of NaHCO3 (250 mL), and water (250 mL), dried over Na2SO4, filtered, and the solvent was removed under vacuum to obtain the title compound (7.4 g, 92%) as a white solid.

[0615] UPLC-MS (acid method, 2 min): rt = 1.07 min; m / z = 240.2 [M+NH4] + , peak area >90%

[0616]

[0617] 2,6-Bis(dibromomethyl)-1,4-phenylene diacetate [Step 2]:in 1,2-dichloroethane (130 mL) 2,6-dimethyl-1,4-phenylene diacetate 2,2'-azobis(2-methylpropionitrile)(AIBN) (0.93 g, 6 mmol) and in a stirred solution (6.34 g, 29 mmol) N -Bromosuccinimide (NBS) (25.39 g, 143 mmol) was added sequentially. The solution was stirred under reflux for 24 hours. Additional 2,2'-azobis(2-methylpropionitrile) (AIBN) (0.93 g, 6 mmol) and N Bromosuccinimide (NBS) (5.08 g, 28.6 mmol) was added, and the reaction mixture was stirred under reflux for 24 hours. The reaction was cooled to room temperature, the residual solid was removed by filtration, and the mixture was washed with DCM (250 mL). The filtrate was washed with a saturated aqueous solution of sodium hydrogen carbonate (250 mL), an aqueous solution of hydrochloric acid (1 M, 250 mL), and brine (250 mL). The organic layer was then dried with sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (9.38 g, 61%) as an orange oil.

[0618] UPLC-MS (acid method, 2 min): rt = 1.23 min; m / z = 553.1 [M+NH4] + , peak area >88%

[0619]

[0620] 2,5-Dihydroxyisophthalaldehyde [Step 3] : in formic acid (50 mL) 2,6-Bis(dibromomethyl)-1,4-phenylene diacetate Water (5 mL) was added to a stirred suspension of (3.89 g, 7.23 mmol). The mixture was stirred under reflux for 18 hours. The reaction mixture was then slowly poured into aqueous saturated sodium hydrogen carbonate (300 mL). The resulting precipitate was then filtered and isolated to obtain the title compound (0.94 g, 78%) as a brown solid.

[0621] UPLC-MS (acid method, 2 min): rt = 0.74 min; m / z = 165.0 [MH] - , peak area >98%

[0622] 2,5-Bis(benzyloxy)isophthalaldehyde [Step 4]: Potassium carbonate-325 mesh (2.34 g, 17.0 mmol) in DMF (6 mL) at ambient temperature 2,5-Dihydroxyisophthalaldehyde It was added to a stirred solution of (0.94 g, 5.7 mmol). Subsequently, benzyl bromide (2.0 mL, 17.0 mmol) was added to the reaction flask, and the resulting mixture was heated at 100°C for 18 hours. The reaction mixture was cooled to ambient temperature and treated with a saturated aqueous ammonium chloride solution (100 mL). The resulting suspension was stirred for 30 minutes and filtered. The solid material was washed with a saturated aqueous ammonium chloride solution (2 × 50 mL). The solid was then polished with ethanol (5 mL) and suction-dried to obtain the desired product as a brown solid (1.58 g, 68%).

[0623] UPLC-MS (acidic method, 2 min): rt = 1.28 min, no ionization observed, peak area 78%

[0624]

[0625] 2,5-Bis(benzyloxy)isophthalic acid (KI-7) [Step 5]: 2,5-Bis(benzyloxy)isophthalaldehyde(1.58 g, 4.5 mmol) was dissolved in a solution of 2-methyl-2-butene in THF (2.0 M, 25 mL). Subsequently, a solution of sodium chlorite (5.1 g, 45.0 mmol) and potassium dihydrogen phosphate (4.6 g, 33.8 mmol) in water (25 mL) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then poured into a saturated aqueous solution of NaHCO3 (400 mL). The aqueous layer was washed with EtOAc (3 × 100 mL) and acidified with concentrated hydrochloric acid (pH approx. 1). The aqueous layer was then extracted with DCM (2 × 150 mL) and Et2O (2 × 200 mL), the collected organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then n- The title compound as a white solid after grinding with pentane (3 x 50 mL). KI-7 0.98 g, 58% was obtained.

[0626] UPLC-MS (acid method, 2 min): rt = 1.03 min, m / z = 379.1 [M+H] + , peak area >96%

[0627]

[0628] Reaction Scheme 9c: KI-2Ac 2 Synthesis of

[0629]

[0630] Methyl 2,5-diacetoxy-3-methylbenzoate. 3-methylsalicylic acid [Nudenberg et al ( J. Org. Chem. 1943 , 8Oxidized to persulfate as reported in [ , 500-508). 3-methylsalicylic acid (15.0 g, 98.6 mmol) was dissolved in a solution of sodium hydroxide (15.0 g, 375 mmol, 3.8 eq.) in water (37.5 mL). The pale brown solution was cooled to 20°C and, while stirring, treated with 7.75 mL of 40% sodium hydroxide and 33.8 mL of 10% potassium persulfate solution, starting with hydroxide and maintaining the temperature at 30 to 35°C, until 10 parts of each were added. After the addition was completed, stirring was continued for 1 hour, the mixture was left at room temperature for 16 to 20 hours, and then concentrated HCl was added until the color changed from blue to congo. At this point, unreacted 3-methylsalicylic acid was separated and removed by filtration. The filtrate was extracted with ether several times (5 × 50 mL) to recover the remaining 3-methylsalicylic acid. Subsequently, the aqueous solution was treated with concentrated HCl (100 mL) and refluxed for 2 hours to decompose the intermediate monosulfate. The warm solution was allowed to cool to room temperature, and the precipitated, nearly black crystalline solid was filtered, washed with water, and dried. The aqueous filtrate was extracted with ether to obtain a brown solid, which is the result of an additional batch of 2,5-dihydroxy-3-methylbenzoic acid ...was obtained (Total: 7.71 g, 47%). Mp 212-214 o C; 1 H NMR (250 MHz, DMSO): d 10.94 (br. s., 1H), 7.00 (dd, J = 3.0 and 0.75, 1H ar ), 6.86 (dd, J = 3.0 and 0.75, 1H ar ), 2.12 (s, 3H).

[0631] Esterification. Sulfuric acid (0.7 mL) concentrated under nitrogen at 0°C was carefully added to a solution of 2,5-dihydroxy-3-methylbenzoic acid (2.05 g, 12.2 mmol) in MeOH (7 mL). The reaction mixture was then stirred at 100°C for 6 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The obtained crude product was dissolved in ethyl acetate (50 mL), and the solution was washed with water (20 mL), 10% aq. NaHCO3 (20 mL), 5% aq. HCl (20 mL), and brine (20 mL), followed by drying (MgSO4). After filtration, the organic layer was concentrated under vacuum to obtain the residue, which was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 9 / 1) as a white solid (370 mg, 75%). Methyl 2,5-dihydroxy-3-methylbenzoate was obtained. Mp 101-103℃; 1 H NMR (250 MHz, CDCl3): d 10.56 (d, J = 0.50 Hz, 1H), 7.12 (dd, J = 3.25 and 0.50 Hz, 1H ar ), 6.90 (dt, J = 3.00 and 0.50 Hz, 1H ar ), 4.45 (s, 3H), , 2.24 (s, 3H); HRMS (ESI + ): m / z calculated value C9H 11 O4[M+H] + : 183.0652; Actual value 183.0651.

[0632] Acetylation. Excess acetic anhydride was added to a solution of methyl 2,5-dihydroxy-3-methyl-benzoate (4.43 g, 24.3 mmol) in pyridine (10 mL) under argon. After stirring for 12 hours at room temperature, the pyridine and acetic anhydride were removed by co-evaporation with toluene (25 mL) under reduced pressure. The crude product was then dissolved in ethyl acetate (15 mL), and the solution was washed sequentially with 2% aq HCl (5 mL), saturated aq NaHCO3 (5 mL), and brine (5 mL). The organic phase was dried (MgSO4), and the solvent was evaporated under reduced pressure. The obtained colorless oil was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 8 / 2) to obtain the acetylated title compound (2,5-acetoxy-3-methyl-benzoate) as a white solid (6.25 g, 97%). Mp 69-71℃; 1 H NMR (250 MHz, CDCl3): d 7.58 (dd, J = 3.00 and 0.50 Hz, 1H ar ), 7.18 (dd, J = 3.00 and 0.75 Hz, 1H ar ), 3.85 (s, 3H), 2.37 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H); HRMS (ESI + ): m / z calculated value C 13 H 18 NO6[M+NH4] + : 284.1129; measured value 284.1128.

[0633] Methyl 2,5-diacetoxy-3-dibromomethylbenzoate. Methyl 2,5-acetoxy-3-methyl-benzoate (2.15 g, 8.08 mmol) in carbon tetrachloride (45 mL), NSolutions of bromosuccinimide (2.87 mg, 16.2 mmol, 2.0 eq.) and azobisisobutyronitrile (AIBN, 27.0 mg, 0.162 mmol, 0.02 eq.) were refluxed for approximately 12 hours until a white solid floated on the surface. After cooling, the mixture was filtered, and the filtrate was subsequently concentrated under reduced pressure. The resulting colorless oil was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 9 / 1) to obtain a dibrominated product as a white solid (3.29 g, 84%). Mp 117-119 o C; 1 H NMR (250 MHz, CDCl3): d 7.86 (d, J = 2.75 Hz, 1H ar ), 7.78 (d, J = 2.75 Hz, 1H ar ), 6.81 (s, 1H), 3.86 (s, 3H), 2.42 (s, 3H), 2.33 (s, 3H); HRMS (ESI + ): m / z calculated value C 13 H 12 Br2NaO6[M+Na] + : 444.8893; measured value 444.8896.

[0634] methyl 2,5-diacetoxy-3-formylbenzoate.A solution of methyl 2,5-diacetoxy-3-dibromo-methylbenzoate (2.30 g, 5.42 mmol) and silver nitrate (2.29 g, 13.5 mmol, 2.5 eq.) in a mixture of acetone and H2O (4.7:1, 40 mL) was stirred at room temperature in the dark for 12 hours. The mixture was then filtered, and the filtrate was extracted with ethyl acetate (2 x 20 mL). The combined organic phase was washed with brine (5 mL), dried (MgSO4), and concentrated under reduced pressure. The resulting colorless oil was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 9 / 1) to obtain an aldehyde as a yellow solid. Mp 102-104 °C; 1H NMR (250 MHz, CDCl3): 10.17 (s, 1H), 8.00 (d, J = 3.00 Hz, 1Har), 7.82 (d, J = 3.00 Hz, 1Har), 3.90 (s, 3H), 2.44 (s, 3H), 2.34 (s, 3H).

[0635] 2,5-Diacetoxyisophthalic acid monomethyl ester (KI-2Ac 2 ). A solution of sodium hydrogen phosphate (1.35 g, 9.81 mmol, 2.5 eq.) in water (3.5 mL) was added dropwise to a solution of methyl 2,5-diacetoxy-3-formylbenzoate (1.10 g, 3.93 mmol) in DMSO (14 mL). The mixture was then cooled to 0°C, and a solution of sodium chlorite (1.06 g, 9.34 mmol, 2.4 eq.) in water (3.5 mL) was slowly added. After stirring at room temperature for 72 hours, the mixture was quenched with aqueous saturated NaHCO3 (10 mL) and extracted with ethyl acetate (2 × 30 mL). Subsequently, the aqueous phase was acidified to pH=1 using 1 M HCl and extracted with ethyl acetate (2 × 30 mL). The combined organic phase was washed with brine (5 mL), dried (MgSO4), and concentrated under reduced pressure. The obtained orange oil was used in the next step without any purification.

[0636] Synthesis of monoamides

[0637] Reaction Equation 10. monoamide IIa Synthesis of

[0638]

[0639] Protocol: Synthesis of Monoamides

[0640] Amidation coupling and deprotection procedures

[0641] KI-2, KI-2Ac 2 and KI-7 The same procedure from, KI-1 and KI-6 Steps [3], [4], [5] General procedures from Refer to .

[0642] Examples

[0643]

[0644]

[0645] For conditions and yield: Refer to Table 2 (Figs. 5a to c).

[0646] 33) 3-(2-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound IIa-001a :

[0647] UPLC-MS (acid method, 2 min): rt = 0.86 min; m / z = 318.0 [M+H] + , peak area >92%

[0648]

[0649] 34) 3-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound IIa-001aTz :

[0650] UPLC-MS (acid method, 2 min): rt = 0.71 min; m / z = 342.1 [M+H] + , peak area >99%

[0651]

[0652] ethyl ester

[0653] UPLC-MS (acid method, 4 min): rt = 1.46 min; m / z = 370.1 [M+H] + , peak area >92%

[0654]

[0655] 35) 2,5-Dihydroxy-3-(2-sulfophenylaminocarbonyl)benzoic acid , compound IIa-001c :

[0656] UPLC-MS (acid method, 2 min): rt = 0.63 min; m / z = 354.0 [M+H] + , peak area >80%

[0657]

[0658] 36) 3-(3-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound IIa-002a :

[0659]

[0660]

[0661] 37) 3-(4-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid)amide , compound IIa-003a :

[0662]

[0663]

[0664] 38) 3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound IIa-004a :

[0665] UPLC-MS (acid method, 2 min): rt = 0.76 min; m / z = 334.0 [M+H] + , peak area >99%

[0666]

[0667] 39) 3-(2-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound IIa-006a :

[0668] UPLC-MS (acid method, 2 min): rt = 0.65 min; m / z = 334.0 [M+H] + , peak area >99%

[0669]

[0670]

[0671] 40) 3-(3-carboxy-2,5-dihydroxybenzamido)phthalic acid, compound IIa-011a :

[0672] UPLC-MS (acid method, 2 min): rt = 0.72 min; m / z = 360.1 [MH] - , peak area >77%

[0673]

[0674] 41) 2-(3-carboxy-2,5-dihydroxybenzamido)terephthalic acid , compound IIa-012a :

[0675] UPLC-MS (acid method, 2 min): rt = 0.73 min; m / z = 362.0 [M+H], peak area >97%

[0676]

[0677] 42) 2-(3-carboxy-2,5-dihydroxybenzamido)isophthalic acid , compound IIa-013a :

[0678] UPLC-MS (acid method, 2 min): rt = 1.68 min; m / z = 362.0 [M+H] + , peak area >96%

[0679]

[0680]

[0681] 43) 4-(3-carboxy-2,5-dihydroxybenzamido)phthalic acid , compound IIa-014a :

[0682] UPLC-MS (acid method, 2 min): rt = 0.63 min; m / z = 362.1 [M+H] + , peak area >88%

[0683]

[0684] 44) 5-(3-carboxy-2,5-dihydroxybenzamido)isophthalic acid , compound IIa-015a :

[0685]

[0686] 45) (3-(3-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound IIa-033a :

[0687] UPLC-MS (acid method, 2 min): rt = 0.78 min; m / z = 330.1 [MH] - , peak area >98%

[0688]

[0689]

[0690] 46) 3-(2-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound IIa-034a :

[0691] UPLC-MS (acid method, 2 min): rt = 0.74 min; m / z = 332.0 [M+H] + , peak area >95%

[0692]

[0693] diethyl ester

[0694] UPLC-MS (acid method, 2 min): rt = 1.12 min; m / z = 388.1 [M+H] + , peak area >99%

[0695]

[0696] 47) 3-(3,4-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound IIa-035a :

[0697] UPLC-MS (acid method, 2 min): rt = 0.69 min; m / z = 318.0 [MH] - , peak area >99%

[0698]

[0699]

[0700] 48) 3-(2-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid , compound IIa-053a :

[0701] UPLC-MS (acid method, 4 min): rt = 1.08 min; m / z = 332.0 [M+H] + , peak area >97%

[0702]

[0703] Example 1.6. Type The molecule of IIb : Diamide from diamine, 1 example

[0704]

[0705] Reaction Equation 11. category IIb Synthesis of diamide

[0706]

[0707] procedure: KI-1 Refer to the general procedure from [3], [4], and [5].

[0708] for example:

[0709]

[0710] Regarding conditions and yield: Refer to Table 2 (Figs. 5a to c).

[0711] 49) 3,5-bis(2,5-dihydroxy-3-carboxybenzoylamino)benzoic acid , compound IIb-010a:

[0712] UPLC-MS (acid method, 4 min): rt = 0.98 min; m / z = 511.1 [MH] - , peak area >93%

[0713]

[0714] Example 1.7. Molecule of type IIc: Diamide from diacid, 2 examples

[0715]

[0716] Reaction Equation 12. Types where R = R' IIc Synthesis of amides

[0717]

[0718] procedure: KI-6 Refer to the general procedure from [3], [4], and [5].

[0719] for example

[0720]

[0721] Regarding conditions and yield: Refer to Table 2 (Figs. 5a to c).

[0722] 50) 5-(3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid, compound IIc-007a :

[0723] UPLC-MS (acid method, 4 min): rt = 1.20 min; m / z = 469.1 [M+H] + , peak area >91%

[0724]

[0725] Alternative large-scale synthesis of IIc-007a

[0726] 2,5-Dibenzyloxyisophthalic acid (KI-7)

[0727] 2,5-dibenzyloxyisophthalaldehyde (Equation 9b) (300 g, 866 mmol), resorcinol (286 g, 2.60 mol), KH2PO4 (354 g, 2.60 mol), acetone (1.5 L), and water (516 ml) were added to a 5 L jacketed container. The slurry was stirred at 15 to 25°C. An 80% NaClO2 (294 g, 2.60 mol) solution in water (1 L) was added at 15 to 30°C for 90 minutes (exothermic). After the addition was completed, the reaction was stirred at 15 to 25°C for 1 hour. A solution of H3PO4 (85 ml, 1.24 mol) [approx. 1 M] in water (1175 ml) was charged over 10 minutes at T < 30°C (exothermic) to obtain a precipitate. The batch was cooled to 0 to 5°C and filtered. The solid was washed with water (3 × 1.2 L) and dried in an oven (50°C) to obtain 325.6 g of discrete KI-7 was obtained. HPLC: 98.9%; NMR >95%. Corrected yield (90.6%).

[0728] 5-(3-(3-methoxycarbonyl-4-hydroxyphenylaminocarbonyl)-2,5-dibenzyloxybenzamido)-2-hydroxybenzoic acid Methyl ester. Dispersed in a 2 L jacketed container KI-7 (80 g, 211 mmol), HBTU(2-(1 H -benzotriazole-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate) (176.8 g, 466 mmol) and THF (560 ml) were added. The batch was stirred at 15 to 25°C and N-methylimidazole (50.6 ml, 635 mmol) was added. After 30 minutes, methyl 5-amino-2-hydroxybenzoate (77.8 g, 466 mmol) was added and the reaction was stirred overnight at 25°C. Water (1.2 L) was added and the batch was stirred at 20°C for 30 minutes. The batch was filtered and washed with water (2 × 480 ml) and then with MeCN (320 ml). The resulting solid (236 g) was returned to the container with MeCN (800 ml). The slurry was heated at 50°C for 40 minutes and then cooled to 20°C. The batch was filtered and washed with MeCN (320 ml). NMR analysis of the solid (156 g) indicated the absence of TMU, HOBt, NMI, or HBTU. The material was dried overnight at 50°C to obtain 125 g of diamide. HPLC: 98.2%. NMR: >97%. Yield: 88%.

[0729] 5-(3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dibenzyloxybenzamido)-2-hydroxybenzoic acid.The previous diamide (110 g, 163 mmol), THF (550 ml), and water (1100 ml) were filled into a 2 L jacketed vessel. The batch was stirred at 15 to 25 °C, and 85% KOH (32.2 g, 488 mmol) was added (slightly exothermic). The solution was heated to 50 °C for 4 hours, then cooled to 20 °C and stirred overnight. Subsequently, 6 M aq. AcOH (550 ml, 3.3 mol) was added over 30 minutes at 15 to 25 °C. After the addition was complete, the batch was stirred for 30 minutes and then filtered. The solid was washed with water (3 × 550 ml) and dried at 50 °C. This yielded 102 g of free diacid. HPLC: 98.9% (0.3% monoamide, 0.19% monoacid). NMR: >97%. Yield: 97%.

[0730] 5-(3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid IIc-007a.10% Pd / C (10 g, 50% wet, type 87 L) was filled into a 2 L jacketed container under N2, followed by the previous discrete acid (100 g, 154 mmol), AcOH (5 ml, 88 mmol), and THF (1200 ml). The batch was stirred, then sprayed with H2 and heated at 40°C for 2 hours. The batch was sprayed with N2 and then filtered (GF / F). The container was rinsed with THF (300 ml), and the catalyst on the filter was washed using a rinse. The filtrate was filled into the container, and the volume was adjusted to 2 L using THF (400 ml). The solution was heated to 30°C, SPM32 (10) was added, and the batch was stirred overnight at 30°C. SPM32 was filtered and washed with THF (200 ml). The solvent was removed under vacuum to obtain a pale yellow solid (110 g). NMR analysis indicated 28% THF. The material was slurried in 1 L of EtOH at 20°C for 2 hours and then filtered. The solid was washed with 400 ml of EtOH and dried in an oven overnight at 60°C. NMR indicated 8.7% EtOH and the absence of THF. The material was further dried at 80°C for 4 days to yield 66.5 g of a grayish-white solid with a 92% yield. IIc-007a [The following was obtained]. HPLC: 99.5% (0.31% monoamide). NMR: 4.6% EtOH, no THF. Pd by ICP-OES: <2 ppm.

[0731] IIc-007a - THF solvate: A yellow solid containing typically 25 to 30% THF was obtained by concentrating the THF filtrate, as determined by NMR, which cannot be removed by drying and represents a non-stoichiometric solvate.

[0732] A small sample of THF solvate (1.45 g) was heated in THF (10 ml) at 50°C for 1 hour, cooled to room temperature, isolated, and washed with 3 ml THF. This resulted in 1.13 g of IIc-007a-THF was obtained. NMR: 27% THF. HPLC: 99.6% (0.1% monoamide). The THF solvate was isolated by filtration to increase purity and remove major impurities (monamide, IIa-004a ) was effectively purged from 0.7% to 0.1%. Recovery rate: 78%. The solubility of THF solvate in THF is calculated to be approximately 25 mg / ml at 20°C.

[0733] Desolvation experiments were performed on the material in acetone, EtOH, and EtOAc. Each batch was heated in 20 volumes of solvent at 50°C for 1 hour, then isolated at room temperature and dried in an oven (60°C). Ethanol was selected as the desolvation solvent due to the low levels of EtOH incorporated into the product after drying and the excellent purging of THF from the system. The desolvation step was performed on 12.1 g of the product (25% THF). The material was filled with EtOH (20 volumes), and the batch was stirred overnight at room temperature. The sample was filtered, which indicated successful desolvation at room temperature. Overall yield: 8.67 g. HPLC: 99.4%. NMR: >97% (0.8% EtOH). XRPD indicates a high degree of crystallinity of the isolated product.

[0734] product IIc-007a It also forms a DMSO solvate (DMSO:product in a 3:2 ratio).

[0735] 51) 2-(3-(2-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-5-hydroxybenzoic acid, compound IIc-009a :

[0736] UPLC-MS (acid method, 2 min): rt = 0.79 min; m / z = 469.1 [M+H] + , peak area >95%

[0737]

[0738]

[0739] Example 1.8: Type IIIa molecule: monoamide, 4 examples

[0740]

[0741] Synthesis of precursors

[0742] Reaction Equation 13. Synthetic intermediate: KI-1 from KI-8 and KI-9

[0743]

[0744] Synthesis protocol

[0745] intermediate KI-8 and KI-9(KI-10 and KI-11 diesel )

[0746] Ethyl 2,5-bis(benzyloxy)-4-(hydroxymethyl)benzoate (KI-10) [Step 1]: in THF (700 mL) under a positive flow of inert gas (N2) KI-1 A pre-cooled solution of BH3.THF (615.0 mL, 615 mmol) (at -10°C) was slowly added to a solution of (62.3 g, 153 mmol) cooled at -20°C. The addition was performed in such a manner that the internal temperature of the reaction did not exceed -15°C. The reaction was slightly warmed, ensuring that the internal temperature did not exceed -7°C. The mixture was maintained at this temperature for 2.5 hours. Subsequently, the reaction mixture was poured into ice / water (8 L). The resulting cloudy white mixture was left to be stirred at room temperature for 2 hours, and the remaining white suspension was filtered through a fritted funnel (Porosity 3). The resulting white solid was further dried overnight in a vacuum oven at 40°C to obtain ethyl 2,5-bis(benzyloxy)-4-(hydroxymethyl)benzoate as a white solid. (KI-10) (60.5 g, 97% yield) was obtained.

[0747] UPLC-MS (acid method, 2 min): rt = 1.25 min; m / z = 391.2 [MH] - , peak area >68%

[0748]

[0749] Alternatively, mixed anhydride (as isobutylchloroformate in THF in the presence of triethylamine) KI-1 Following the treatment, the mixed anhydride is reduced with sodium borohydride in THF to produce an intermediate KI-10 It can be obtained (yield 85 to 90%, 150g-scale).

[0750] Ethyl 2,5-bis(benzyloxy)-4-(chloromethyl)benzoate (KI-11) [Step 2] : Tosyl chloride (17.0 g, 70 mmol) in DCM (260 mL) KI-10 It was slowly added to a cooled solution (ice bath) of (25.0 g, 64 mmol), DIPEA (12.2 mL, 70 mmol), and DMAP (0.778 g, 6 mmol). The reaction mixture was stirred at 60°C for 30 hours, after which the reaction was deemed complete. DCM (100 mL) was added, the organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate (4 × 50 mL), water (2 × 50 mL), and brine (50 mL), dried, and concentrated over sodium sulfate. The crude product was subjected to column chromatography (hexane / EtOAc 0 to 20%) to ethyl 2,5-bis(benzyloxy)-4-(chloromethyl)benzoate (KI-11) (23.5 g, 75%) was obtained.

[0751] UPLC-MS (acid method, 2 min): rt = 1.39 min; m / z = No ions, peak area >84%.

[0752]

[0753] Alternatively, at -10℃ KI-10The intermediate is treated with thionyl chloride (1.14 equivalents) in dichloromethane, then the solvent is evaporated and precipitated from heptane. KI-11 Can be obtained (yield 90%, 300 g-scale)

[0754] Ethyl 2,5-bis(benzyloxy)-4-(cyanomethyl)benzoate [Step 3]: in a mixture of EtOH (90 mL) and H2O (45 mL) KI-11 A suspension of (7.5 g, 18.2 mmol) was treated with potassium cyanide (1.8 g, 27.4 mmol). The reaction mixture was heated to 75°C and stirred at the temperature for 16 hours. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (2 × 200 mL), and the combined organic phase was then washed with brine (200 mL), dried in sodium sulfate, filtered, and concentrated under vacuum. The crude product was isolated as a mixture of ethyl 2,5-bis(benzyloxy)-4-(cyanomethyl)benzoate and 2,5-bis(benzyloxy)-4-(cyanomethyl)benzoic acid (7.1 g), and the product was used in the next step without further purification.

[0755] UPLC-MS (acid method, 2 min): rt = 1.30 min; m / z = 402.2 [M+H] + , peak area >65% and rt = 1.15 min; m / z = 374.1 [M+H] + , peak area >8%.

[0756]

[0757] 2,5-Bis(benzyloxy)-4-(carboxymethyl)benzoic acid (KI-9)[Step 4]: A solution of sodium hydroxide (8.5 g, 212.5 mmol) in water (50 mL) was added to a suspension of ethyl 2,5-bis(benzyloxy)-4-(cyanomethyl)benzoate (7.1 g, 13.2 mmol) in EtOH (20 mL), and the reaction mixture was stirred under reflux for 18 hours. The reaction mixture was diluted with water (100 mL), the resulting solution was washed with EtOAc (2 x 100 mL), the organic layer obtained was extracted with water (100 mL), and all aqueous layers were collected. The aqueous layer was then acidified to a pH of approximately 3 with a saturated aqueous solution of citric acid, and the formed precipitate was filtered and dried under reduced pressure. The solid was further dried overnight in a vacuum oven at 40°C to obtain 2,5-bis(benzyloxy)-4-(carboxymethyl)benzoic acid ( KI-9 )(6.4 g, 92% yield) was obtained.

[0758] UPLC-MS (acid method, 2 min): rt = 1.07 min; m / z = 393.2 [M+H] + , peak area >74%.

[0759]

[0760] 2,5-Bis(benzyloxy)-4-(2-ethoxycarbonylmethyl)benzoic acid (KI-8) [Step 5]: KI-9 5.5 g (14.0 mmol) was suspended in 30 mL of EtOH, the suspension was treated with thionyl chloride (0.52 mL, 7.1 mmol), and the reaction mixture was stirred at room temperature for 24 hours. Subsequently, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (1 L), resulting in a white suspension. The solid was isolated by filtration and further polished with Et2O (2 × 20 mL). The solid was further dried overnight in a vacuum oven to obtain 2,5-bis(benzyloxy)-4-(2-ethoxycarbonylmethyl)benzoic acid as a white solid. (KI-8) (4.2 g, 64%) was obtained.

[0761] UPLC-MS (acid method, 2 min): rt = 1.23 min; m / z = 419.3 [MH] - , peak area >79%.

[0762]

[0763] Synthesis of monoamides

[0764] Reaction Equation 14. monoamide IIIa Synthesis of

[0765]

[0766] Synthesis protocol

[0767] Amidation Coupling and Deprotection Procedures:

[0768] KI-1 and KI-6 Refer to the general procedure from steps [3], [4], and [5].

[0769] Examples

[0770]

[0771] Regarding conditions and yield: Refer to Table 3 (Fig. 6).

[0772] 52) 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)benzoic acid , compound IIIa-001a :

[0773] UPLC-MS (acid method, 2 min): rt = 0.89 min; m / z = 332.1 [M+H] + , peak area >98%

[0774]

[0775] ethyl methyl ester

[0776] UPLC-MS (acid method, 2 min): rt = 1.14 min; m / z = 374.2 [M+H] + , peak area >96%.

[0777]

[0778] 53) (2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid , compound IIIa- 001aTz :

[0779] UPLC-MS (acid method, 2 min): rt = 0.87 min; m / z = 356.1 [M+H], peak area >95%.

[0780]

[0781] Ethyl ester:

[0782] UPLC-MS (acid method, 4 min): rt = 1.56 min; m / z = 384.2 [M+H] + , peak area >95%.

[0783]

[0784]

[0785] 54) 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)isophthalic acid , compound IIIa-013a :

[0786] UPLC-MS (acid method, 4 min): rt = 0.82 min; m / z = 376.0 [M+H] + , peak area >89%.

[0787]

[0788] 55) 5-(4-(carboxymethyl)-2,5-dihydroxybenzamido)isophthalic acid, compound IIIa-015a :

[0789] UPLC-MS (acid method, 4 min): rt = 0.93 min; m / z = 376.0 [M+H] + , peak area >96%.

[0790]

[0791] ethyl dimethyl ester

[0792] UPLC-MS (acid method, 4 min): rt = 1.69 min; m / z = 432.1 [M+H] + , peak area >97%.

[0793]

[0794]

[0795] Example 1.9. Molecule of Type IIIb: Diamide from diamine, 1 example

[0796]

[0797] Example 15. category IIIb Synthesis of diamide

[0798]

[0799] procedure: KI-1 Refer to the general procedure from steps [3], [4], and [5].

[0800] for example:

[0801]

[0802] Regarding conditions and yield: Refer to Table 3 (Fig. 6).

[0803] 56) 3,5-Bis(2,5-dihydroxy-4-carboxymethylbenzoylamino)benzoic acid , compound IIIb-010a:

[0804] UPLC-MS (acid method, 4 min): rt = 1.08 min; m / z = 539.2.1 [MH] - , peak area 80%.

[0805]

[0806] triethyl ester

[0807] UPLC-MS (acid method, 4 min): rt = 1.81 min; m / z = 623.3 [MH] - , peak area 94%.

[0808]

[0809]

[0810] Example 1.10: Type IIIc molecule. Dimer, 6 Examples

[0811]

[0812] Synthesis reaction equation and procedure

[0813] Reaction Equation 16: X=O

[0814]

[0815] Synthesis procedure

[0816] KI-10 and KI-11 Formation of ether link from

[0817] Ethyl 2,5-dibenzyloxy-4-[(2,5-dibenzyloxy-4-ethoxycarboniferyl)methoxymethyl]benzoate [Step 1]: DMF (6 mL) cooled in an ice bath KI-11 (340 mg, 0.83 mmol) and KI-10 Sodium hydride (76 mg, 1.9 mmol) was added in small amounts to a solution of (250 mg, 0.64 mmol). After 1 hour, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride (50 mL), the substance was extracted with EtOAc (3 × 30 mL), the organic phase was further washed with water (2 x 50 mL) and brine (50 mL), dried with sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane / EtOAc 0 to 20%) to obtain the title compound (161 mg, 33% yield) as a brown solid.

[0818] Deprotection Procedure:

[0819] Refer to general procedures [4], [5].

[0820] for example

[0821]

[0822] Regarding conditions and yield: Refer to Table 4 (deprotection) (Fig. 7).

[0823] 57) 4-((2,5-dihydroxy-4-carboxyphenyl)methoxymethyl)-2,5-dihydroxybenzoic acid, compound IIIc-060a :

[0824] UPLC-MS (acid method, 4 min): rt = 0.94 min; m / z = 349.1 [MH] - , peak area >90%.

[0825]

[0826] Reaction Equation 17: X = NH

[0827]

[0828] Synthesis procedure

[0829] KI-10 and KI-11 through KI-12 and KI-13 amine link formation from

[0830] Ethyl 2,5-bis(benzyloxy)-4-formylbenzoate (KI-12) : in dichloromethane (50 mL) KI-10 Manganese dioxide (4.5 g, 51.9 mmol) was added to a solution (3.4 g, 8.6 mmol). The resulting suspension was stirred under reflux for 4 hours. The reaction was filtered through a Celite® pad, the solid was washed with dichloromethane (300 mL), and the solvent was then removed under reduced pressure to obtain the title compound (3.2 g, 94% yield) as a yellow solid.

[0831] UPLC-MS (acid method, 2 min): rt = 1.33 min; m / z = No ions, peak area >93%

[0832]

[0833] Ethyl 4-(azidomethyl)-2,5-bis(benzyloxy)benzoate: in toluene (30 mL) KI-10 Diphenylphosphoryl azide (DPPA) (2 mL, 9.1 mmol) was added to a suspension of (3.0 g, 7.6 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.5 mL, 9.9 mmol). The resulting mixture was stirred at room temperature for 18 hours. An aqueous solution of 1 M hydrogen chloride (200 mL) was added, and the product was extracted with EtOAc (3 × 100 mL). The combined organic layer was washed with water (2 × 50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / EtOAc 0 to 20%) to obtain the title compound (3.1 g, 98%) as a colorless oil, which became a white solid over time.

[0834] UPLC-MS (acid method, 2 min): rt = 1.37 min; m / z = 390.2, [M+H-N2] + , peak area >93%

[0835]

[0836] Ethyl 4-(aminomethyl)-2,5-bis(benzyloxy)benzoate (KI-13): Polymer-bonded triphenylphosphine (4.7 g, approx. 3 mmol / g loading) was added to a solution of ethyl 4-(azidomethyl)-2,5-bis(benzyloxy)benzoate (2.8 g, 6.7 mmol) in THF (60 mL) and water (6 mL), and the resulting mixture was stirred at room temperature for 18 hours. The resin was removed by filtration and washed with water (100 mL) and EtOAc (2 × 100 mL). The phases were separated, the aqueous layer was further extracted with EtOAc (100 mL), the collected organic layer was washed with brine (200 mL), dried and concentrated over sodium sulfate to obtain the title compound as a white solid. (KI-13) (1.8 g, 70% yield) was obtained.

[0837] UPLC-MS (basic method, 2 min): rt = 1.20 min; m / z = 392.2, [M+H] + , peak area >93%

[0838]

[0839] Ethyl 2,5-dibenzyloxy-4-[(2,5-dibenzyloxy-4-ethoxycarbonylphenyl)methylaminomethyl]benzo-ate: KI-12 (500 mg, 1.3 mmol) and KI-13Sodium triacetoxyborohydride (641 mg, 1.6 mmol) was dissolved in DCM (35 mL), and then an activated molecular sieve (10 beads) was added. The resulting mixture was stirred at room temperature for 5 hours. Subsequently, sodium triacetoxyborohydride (654 mg, 3.1 mmol) was added, and the resulting mixture was stirred at room temperature for 18 hours. DCM (25 mL) was added, the reaction mixture was decanted into a separating funnel, washed with water (50 mL), dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / EtOAc 0 to 50%) to obtain the title compound (631 mg, 64% yield) as a colorless oil, which solidified over time.

[0840] UPLC-MS (acid method, 2 min): rt = 1.37 min; m / z = 766.3, [M+H] + , peak area >92%

[0841]

[0842] Deprotection procedure: Refer to general procedure [4], [5].

[0843] Regarding conditions and yield: Refer to Fig. 7.

[0844] for example

[0845]

[0846] 58) Bis(4-carboxy-2,5-dihydroxyphenylmethyl)amine , compound IIIc-056a :

[0847] UPLC-MS (acid method, 4 min): rt = 0.57 min; m / z = 350.0 [M+H] + , peak area >96%.

[0848]

[0849] Equation 18: X = NAc

[0850]

[0851] Synthesis procedure

[0852] N,N-bis-[2,5-dibenzyloxy-4-ethoxycarbonylphenylmethyl]acetamide: Acetic anhydride (0.2 mL, 2.1 mmol) was added to a solution of N,N-bis-[2,5-dibenzyloxy-4-ethoxycarbonylphenylmethyl]amine (300 mg, 0.39 mmol) and pyridine (0.2 mL, 2.4 mmol) in DCM (6 mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / EtOAc, 0 to 50%) to obtain the title compound (316 mg, 92% yield) as a colorless oil.

[0853] UPLC-MS (acid method, 2 min): rt = 1.44 min; m / z = 808.2 [M+H] + , peak area >95%.

[0854]

[0855] Deprotection Procedure:

[0856] Refer to general procedures [4], [5].

[0857] for example

[0858]

[0859] Regarding conditions and yield: Refer to Example 7 (deprotection).

[0860] 59) N,N-bis(4-carboxy-2,5-dihydroxyphenylmethyl)acetamide , compound IIIc-057a :

[0861] UPLC-MS (acid method, 4 min): rt = 0.84 min; m / z = 392.1 [M+H] + , peak area >99%.

[0862]

[0863]

[0864] Reaction Equation 19: X = NCH 2 C 6H 3 (OH) 2 COOH

[0865]

[0866] Synthesis procedure

[0867] KI-11 and NH 3 tertiary amine formation from

[0868] Tris(4-ethoxycarboni-2,5-dibenzyloxyphenylmethyl)amine : In a sealed tube KI-11 (32.5 g, 79 mmol), sodium iodide (0.79 g, 5 mmol), ammonia solution in MeOH (7 N) (38 mL, 264 mmol), and EtOAc (80 mL) were added. The tube was then sealed, and the reaction mixture was heated at 60°C for 24 hours. After 24 hours, the starting material ( KI-11) ...was consumed, and the reaction mixture contained not only the desired product but also monomer and dimer structures. Water (100 mL) was added, and the resulting mixture was extracted with EtOAc (3 x 100 mL). The collected organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was dissolved in EtOAc (165 mL) and KI-11 (2.5 g, 6 mmol), sodium iodide (0.79 g, 5 mmol), and DIPEA (10 mL, 58 mmol) were added, and the resulting solution was heated at 60°C. After 18 hours, water (100 mL) was added, and the resulting mixture was extracted with EtOAc (3 x 100 mL). The collected organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization using EtOH / EtOAc 95 / 5 (20 mL) as a solvent to obtain the title compound (15.0 g, 50%) as a white crystal.

[0869] UPLC-MS (basic method, 2 min): rt = 1.71 min; m / z = 1140.3 [M+H]+ , peak area >99%.

[0870]

[0871] Alternatively, the product can be purified via silica gel flash column chromatography: Scale, max 270 g; Instrument: Combi flash Torrent; Cartridge: RediSep Column, Silica 3kg; Loading Type: Heptane:Toluene (1:1) dissolved in 1L. Eluted with ethyl acetate / heptane. Detection: UV - 240 nm

[0872] Deprotection procedure: Refer to general procedure [4], [5].

[0873] Regarding conditions and yield: Refer to Example 7 (deprotection).

[0874] Alternative, Large-Scale Deprotection Procedures:

[0875] SaponificationTris(4-ethoxycarboni-2,5-dibenzyloxyphenylmethyl)amine (95.00 g, 0.083 mol), sodium hydroxide (40.00 g, 0.99 mol), water (570 mL), and tetrahydrofuran (1.9 L) were added to a 5 L round-bottom flask. The reaction mixture was heated at 80°C (reflux temperature was 65°C) for 48 hours using a temperature block, and then stirred at room temperature for 24 hours. Subsequently, the solvent was removed under vacuum. The crude material was collected and further diluted with water (2.85 L). In another 10 L flask, a mixture of acetic acid (180 mL) and water (950 mL) was stirred at room temperature. The mixture of the crude product in water was added to the acetic acid mixture over 30 minutes while stirring with an overhead stirrer, and a cream solid precipitated. The reaction mixture was stirred for an additional 1 hour, and the solid was isolated upon filtration; the mother liquor pH was 4.2. The isolated solid was stirred with water (1425 mL) for 1 hour and then filtered. The mother liquor pH was 4.5. The solid was recovered and stirred with additional water (1425 mL) for 1 hour and then filtered; the mother liquor pH was 4.5. The solid was stirred with acetone (950 mL) for 1 hour and filtered. The cream-colored solid was dried in a vacuum oven at 50°C for 48 hours and analyzed (82.00 g, 93% yield) (yield varied between 90 and 95%).

[0876] Note: pH is an important parameter during washing to maintain the product in a free acid form and remove excess acetic acid from the product.

[0877] Ideal pH: 4.2 to 4.5 (final sodium content varies between 2 ppm and 20 ppm).

[0878] Hydrocracking and IsolationTris(4-carboxy-2,5-dibenzyloxyphenylmethyl)amine (58.00 g, 54.00 mmol, 1 eq) and tetrahydrofuran (1160 mL) were placed in a 2 L round-bottom flask. The mixture was degassed with nitrogen and then flushed with 4 to 5 hydrogen / vacuum cycles. Palladium on carbon (JM 10% 424 Pd / C, 70 g, 15% loading) was added to the reaction mixture and stirred at 25°C for 5 to 6 hours. The reaction mixture was then degassed, the catalyst was removed by filtration through a Celite pad, and the mixture was washed with tetrahydrofuran (3 × 1160 mL). Finally, the filtrate was concentrated under reduced pressure. The crude solid was collected, stirred with heptane (1160 mL), and filtered to obtain a gray solid, which was dried overnight in a vacuum oven at 50°C (32.50 g, crude-based >100% yield). The collected crude material was dissolved in ethanol (325 mL) and heated to 60°C (clear solution). Subsequently, water (325 mL) was slowly added over 15 to 20 minutes at 60°C (maintaining the temperature at least at 50°C during addition). At this stage, a cloudy liquid was observed. The cloudy reaction mixture was stirred at reflux temperature for 30 minutes.

[0879] After this time, the reaction mixture was allowed to cool to room temperature for an additional 30 minutes. The precipitated solid was isolated by filtration and washed with a 1:1 mixture of ethanol and water (66 mL). The solid was dried in a vacuum oven at 50°C for at least 72 hours and analyzed to obtain the desired product. IIIc-061a (22.00 g, 76% yield) (yield varied between 65 and 75%) was obtained. LCMS : >95%, NMR : >95% purity.

[0880]

[0881] tris(4-carboxy-2,5-dihydroxyphenylmethyl)amine , compound IIIc-061a :

[0882] UPLC-MS (acid method, 4 min): rt = 0.74 min; m / z = 516.0 [M+H] + , peak area >86%.

[0883]

[0884] triethyl ester

[0885] UPLC-MS (acid method, 2 min): rt = 1.05 min; m / z = 600.2 [M+H] + , peak area >82%.

[0886]

[0887]

[0888] Reaction Equation 20: X = S

[0889]

[0890] Synthesis procedure

[0891] KI-11 Formation of thioter connection from

[0892] Reaction Equation 21 Refer to the same conditions for forming a thiothermic connection.

[0893] Deprotection procedure: Refer to general procedure [4], [5].

[0894] for example

[0895]

[0896] Regarding conditions and yield: Refer to Example 7 (deprotection).

[0897] 60) 4-((2,5-dihydroxy-4-carboxyphenyl)methylthiomethyl)-2,5- Dihydroxybenzoic acid, compound IIIc-058a :

[0898] UPLC-MS (acid method, 2 min): rt = 0.84 min; m / z = 365.1 [MH] - , peak area >79%

[0899]

[0900] Reaction Equation 21: X = SO 2

[0901]

[0902] Synthesis procedure

[0903] Oxidation of the thioether linkage

[0904] IVc-059a Refer to the manufacture of: the same conditions of oxidation.

[0905] Deprotection procedure: Refer to general procedure [4], [5].

[0906] for example

[0907]

[0908] Regarding conditions and yield: Refer to Example 7 (deprotection).

[0909] 61) 4-((2,5-dihydroxy-4-carboxyphenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid , compound IIIc-059a :

[0910] UPLC-MS (acid method, 2 min): rt = 0.72 min; m / z = 397.1 [MH] - , peak area >97%

[0911]

[0912] Example 1.11: Compounds of Type IVc

[0913]

[0914] Reaction Equation 22: X = S

[0915] Synthesis via dimethyl ether

[0916]

[0917] Synthesis procedure

[0918] Synthesis from 5-O-methylgentisic acid

[0919] 3-Formyl-2-hydroxy-5-methoxybenzoic acid.Hexamethylenetetramine (40.019 g, 0.285 mol) was added to a mixture of 2-hydroxy-5-methoxybenzoic acid (24.0 g, 0.143 mol) in trifluoroacetic acid (190.0 mL). The reaction was refluxed for 18 hours. After completion, the reaction was cooled to ambient temperature, 2 M hydrochloric acid (700 mL) was added to the mixture, and the mixture was stirred at ambient temperature for 24 hours. The precipitate was filtered, washed with water (500 mL), and dried in a vacuum oven to obtain 3-formyl-2-hydroxy-5-methoxybenzoic acid as a pale yellow solid (21.30 g, 0.11 mol, 77.0%).

[0920] UPLC-MS (acid method, 2 min): rt = 0.69 min; m / z = 195.1 [MH] - , peak area >98%

[0921]

[0922] Methyl 3-formyl-2,5-dimethoxybenzoate. Methyl iodide (6.7 mL, 0.107 mol) was added to a mixture of 3-formyl-2-hydroxy-5-methoxybenzoic acid (10.0 g, 0.05 mol) and potassium carbonate-325 mesh (28.18 g, 0.20 mol) in DMF (100.0 mL). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was cooled to ambient temperature and treated with cold water (400 mL), resulting in the formation of a precipitate. The resulting suspension was stirred for 10 minutes and then filter-dried in a vacuum oven to obtain methyl 3-formyl-2,5-dimethoxybenzoate as a yellow solid (8.90 g, 0.04 mol, 78.0%).

[0923] UPLC-MS (acid method, 2 min): rt = 0.95 min; m / z = 225.1 [M+H] + , peak area >98%

[0924]

[0925] Methyl 3-(hydroxymethyl)-2,5-dimethoxybenzoate.Sodium borohydride (16.198 g, 0.428 mol) was slowly added at 0°C to a solution of methyl 3-formyl-2,5-dimethoxybenzoate (48.0 g, 0.214 mol) in MeOH (900 mL), and the resulting mixture was stirred at ambient temperature for 15 minutes. The solvent was removed under vacuum, and the residue was dissolved in DCM (200 mL) and then washed with water (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated and dried to obtain methyl 3-(hydroxymethyl)-2,5-dimethoxybenzoate as a white solid (45.6 g, 0.20 mol, 95.0%).

[0926] UPLC-MS (acidic method, 2 min): rt = 0.84 min; no ionization, peak area >98%

[0927]

[0928] Methyl 3-(chloromethyl)-2,5-dimethoxybenzoate. Thionyl chloride (17.2 mL, 0.235 mol) was added dropwise to a solution of methyl 3-(hydroxymethyl)-2,5-dimethoxybenzoate (45.60 g, 0.20 mol) over 30 minutes at ambient temperature. The resulting mixture was stirred at ambient temperature for 18 hours. After completion, the reaction mixture was washed with a saturated aqueous solution of sodium carbonate (3 × 500 mL) and brine (500 mL). The organic layer was dried over Na2SO4, filtered, and concentrated and dried to obtain methyl 3-(chloromethyl)-2,5-dimethoxybenzoate as a brown solid (49.1 g, 0.18 mol, 90%).

[0929] UPLC-MS (acidic method, 2 min): rt = 1.10 min; no ionization, peak area >92%

[0930]

[0931] Methyl 3-(acetylthiomethyl)-2,5-dimethoxybenzoate.Potassium thioacetate (15.54 g, 0.136 mol) was added to a solution of methyl 3-(chloromethyl)-2,5-dimethoxybenzoate (22.20 g, 0.091 mol) in THF (500.0 mL) at ambient temperature. The reaction mixture was stirred at 75°C for 18 hours. After completion, the solvent was removed under reduced pressure to obtain a red oily residue, which was treated with a saturated brine solution (500 mL) and then extracted with diethyl ether (2 × 250 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated and dried to obtain methyl 3-(acetylthiomethyl)-2,5-dimethoxybenzoate as a brown solid (25.50 g, 0.09 mol, 99%).

[0932] UPLC-MS (acidic method, 2 min): rt = 1.10 min; no ionization, peak area >92%

[0933]

[0934] Methyl 3-(mercaptomethyl)-2,5-dimethoxybenzoate. A solution of sodium methanolate (5.81 g, 107.62 mmol) was added dropwise at 0°C under a nitrogen atmosphere to a solution of methyl 3-(acetylthiomethyl)-2,5-dimethoxybenzoate (25.5 g, 89.68 mmol) in dry methanol (800 mL). The mixture was stirred at room temperature for 45 minutes, and then Dowex X8 (H +The mixture was quenched with an ion-exchange resin and stirred for 15 minutes. After filtration, the solvent was evaporated under reduced pressure to obtain the crude product as a brown oil (containing disulfide compounds corresponding to the desired product in a 2:1 ratio). The residue was dissolved in DMF (400.0 mL) and treated with dithiothreitol (DTT) (33.95 g, 0.26 mol) under a nitrogen atmosphere. The reaction mixture was stirred at 75°C for 18 hours. After the conversion of the disulfide to thiol was complete, the solvent was evaporated. The resulting residue was dissolved in DCM (1 L), washed with brine (7 × 500 mL), dried over Na2SO4, filtered, and concentrated and dried to obtain homogeneous methyl 3-(mercaptomethyl)-2,5-dimethoxybenzoate as a brown oil (21.40 g, 88.32 mmol, 99%).

[0935] UPLC-MS (acid method, 2 min): rt = 1.05 min; m / z = 243.1 [M+H] + , peak area >95%

[0936]

[0937] Dimethyl 3,3'-(thiobis(methylene))bis(2,5-dimethoxybenzoate).Triethylamine (19.0 mL, 136.61 mmol) was added to a solution of methyl 3-(mercaptomethyl)-2,5-dimethoxybenzoate (21.40 g, 88.32 mmol) and methyl 3-(chloromethyl)-2,5-dimethoxybenzoate (22.69 g, 92.74 mmol) under a nitrogen atmosphere. The reaction was stirred at ambient temperature for 18 hours. After completion, the solvent was removed under vacuum to obtain a brown oil residue, which was treated with water (1 L) and then extracted with diethyl ether (3 × 500 mL). The organic phases were combined, washed with brine (5 × 250 mL), dried over Na2SO4, filtered, and concentrated to obtain a crude product as a brown oil, which was purified by silica gel chromatography: dimethyl 3,3'-(thiobis(methylene))bis(2,5-dimethoxybenzoate) was obtained as a brown oil by eluting with an ethyl acetate (0 to 20%) gradient in iso-hexane (29.9 g, 66.37 mmol, 76%).

[0938] UPLC-MS (acid method, 2 min): rt = 1.22 min; m / z = 451.2 [M+H] + , peak area >92%

[0939]

[0940] 3,3'-(thiobis(methylene))bis(2,5-dimethoxybenzoic acid).A solution of lithium hydroxide monohydrate (1.0 g, 23.83 mmol) in water (30.0 mL) was added to a solution of dimethyl 3,3'-(thiobis(methylene))bis(2,5-dimethoxybenzoate) (2.0 g, 4.44 mmol) in THF (100.0 mL). The reaction was stirred at ambient temperature for 48 hours. After completion, water (100 mL) was added to the reaction, and the mixture was washed with ethyl acetate (100 mL). The aqueous layer was acidified to pH=2 using 1 M aqueous hydrochloric acid and extracted with ethyl acetate (3 x 100 mL). The organic layer was collected, dried (Na2SO4), filtered, and concentrated to obtain 3,3'-(thiobis(methylene))bis(2,5-dimethoxybenzoic acid) as a brown solid (1.91 g, 4.11 mmol, 93%).

[0941] UPLC-MS (acid method, 2 min): rt = 0.93 min; m / z = 421.1 [MH] - , peak area >95%

[0942]

[0943] 3-[(2,5-dihydroxy-3-carboxyphenyl)methylthiomethyl]-2,5-dihydroxybenzoic acid. To the previous thioether (5.0 g, 0.01 mol) solution in DCM (200.0 mL), a 1 M solution of tribromoborane in DCM (100.7 mL, 0.101 mol) was slowly added at 0°C, and the reaction mixture was refluxed for 48 hours. After this time, the solid was filtered, washed with DCM (500 mL), and suspended in a 1 M hydrochloric acid (50 mL) solution. The resulting mixture was refluxed for 2 hours. The resulting brown suspension was filtered and dried to obtain a crude product, which was purified by reverse-phase column chromatography (25 g, MeCN:H2O 5% to 95% on 12 CV) to obtain 2,5-dihydroxy-3-[(2,5-dihydroxy-3-carboxyphenyl)methylthiomethyl]benzoic acid as a white solid (1.1 g, 0.003 mol, 26%).

[0944] UPLC-MS (acid method, 2 min): rt = 0.70 min; m / z = 365.1 [MH] - , peak area >95%

[0945]

[0946] Example:

[0947] 62) 3-((2,5-dihydroxy-3-carboxyphenyl)methylthiomethyl)-2,5-dihydroxybenzoic acid, compound IVc-058a :

[0948] UPLC-MS (acid method, 2 min): rt = 0.70 min; m / z = 365.1 [MH] - , peak area >95%

[0949]

[0950] Reaction Equation 23: X = SO 2

[0951]

[0952] compound IVc-058a Synthesis from

[0953] 3-((2,5-dihydroxy-3-carboxyphenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid. in DMF (20.0 mL) Thioeter IVc-058a A solution of 3-chlorobenzene-1-carboperoxysan (mCPBA purity grade ≤77%, 5.80 g, 25.88 mmol) in DMF (20.0 mL) was slowly added to the (4.25 g, 9.28 mmol) solution. The reaction mixture was stirred at ambient temperature for 18 hours. The crude product was subjected to HPLC purification (see general conditions) to obtain a white solid (3.20 g), which was polished with 1 M HCl (50 mL) to obtain the desired product as a white solid (2.55 g, 6.40 mmol, 56%).

[0954] UPLC-MS (acid method, 4 min): rt = 0.68 min; m / z = 397.1 [MH] - , peak area >95%

[0955] 63) 3-((2,5-dihydroxy-3-carboxyphenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid , compound IVc-059a:

[0956] UPLC-MS (acid method, 4 min): rt = 0.68 min; m / z = 397.1 [MH] - , peak area >95%

[0957]

[0958] Dimethyl ester

[0959] UPLC-MS (acid method, 2 min): rt = 0.94 min; m / z = 427.1 [M+H] + , peak area >95%

[0960]

[0961] Dimethyl ester tetraacetate

[0962] UPLC-MS (acid method, 2 min): rt = 1.05 min; m / z = 593.1 [MH] - , peak area >95%

[0963]

[0964] Synthesis of alternative, scalable IVc-059a

[0965] Reaction Equation 24: Synthesis of IVc-059a from 2,5-Dibenzyloxyphthalaldehyde

[0966]

[0967] 2,5-Bis(benzyloxy)-3-(hydroxymethyl)benzaldehyde[Step 1]: 2,5-bis(benzyloxy)-isophthalaldehyde (25.0 g, 72.1 mmol) (see Reaction Scheme 9b) was dissolved in THF (150 mL) and EtOH (15 mL) was added. The brown solution was maintained under a positive nitrogen flow and stirred at room temperature for 10 minutes, then solid NaBH4 (695 mg, 18.37 mmol) was added gradually over 20 minutes, ensuring that the internal temperature of the reaction did not exceed 25°C (using a water bath). The reaction mixture was left to stir at room temperature for 30 minutes, then additional NaBH4 was added every 15 minutes until the conversion of the starting material (total: 107 mg, 2 parts) was complete. Subsequently, the reaction mixture was poured into water (1.2 L) and stirred for 20 minutes. The brown precipitate formed accordingly was isolated by filtration, and the obtained solid was further dried in a vacuum oven at 40°C until a constant mass was achieved to obtain the title compound as a brown oil (22.9 g, 76% corrected yield). The NMR profile showed 83% of the desired product, 15% of the per-reduced diol, and 2% of the starting material, and the material was sent to the next step without further purification.

[0968] UPLC-MS (acid method, 2 min): rt = 1.19 min, 86%, m / z = 347.2 [MH]-

[0969]

[0970] 2,5-bis(benzyloxy)-3-(hydroxymethyl)benzoic acid[Step 2]: 2,5-bis(benzyloxy)-3-(hydroxy-methyl)benzaldehyde (44.3 g, 103 mmol, 81% purity) and KH2PO4 (25.9 g, 190 mmol) were dissolved in acetone (440 mL) and water (130 mL). Resorcinol (21.0 g, 191 mmol) was added, and the reaction mixture was stirred at room temperature for 10 minutes. A solution of sodium chlorite (21.5 g, 191 mmol) in water (60 mL) was slowly added over 30 minutes, ensuring that the internal temperature did not exceed 25°C. The reaction mixture was stirred at room temperature for 3 hours, and a 2 M aqueous solution of H3PO4 (95 mL) was added. The mixture was stirred for 20 minutes, cooled to 6°C using an ice bath, and filtered. The solid was further washed with water until the pH of the filtrate reached approximately 6. The obtained solid was suspended in water (approx. 300 mL) and added to a pre-cooled (5 to 10°C) solution of NaOH (17 g, 412 mmol) in water (200 mL). The suspension was stirred at room temperature for 30 minutes and filtered in a sintering funnel. The isolated solid was further washed with 1 M aqueous NaOH (2 × 50 mL) and water (50 mL). The alkaline liquid was then acidified using a pre-cooled (5 to 10°C) 6 N HCl aqueous solution until the pH reached approximately 1. The resulting suspension was magnetically stirred for 20 minutes and filtered, and the obtained solid was further dried in a vacuum oven at 40°C until a constant mass was obtained to obtain the title compound as a pale beige solid (34.8 g, 88%).

[0971] UPLC-MS (acid method, 2 min): rt = 1.06 min, 99%, m / z = 363.2 [MH] - .

[0972]

[0973] Ethyl 2,5-bis(benzyloxy)-3-(hydroxymethyl)benzoate[Step 3]: 2,5-bis(benzyloxy)-3-(hydroxy-methyl)benzoic acid (32.5 g, 89.3 mmol) and Cs2CO3 (32.3 g, 99.2 mmol) were suspended in DMF (200 mL), and ethyl iodide (9.0 mL, 112 mmol) was added to the reaction mixture. After stirring at room temperature for 3 hours, the reaction mixture was poured into a saturated aqueous solution of NH4Cl (1 L), and solid NaCl (about 30 g) was added. After stirring for 10 minutes, the material was extracted with EtOAc (2 × 500 mL). The collected organic layer was washed with brine (2 × 500 mL), dried with sodium sulfate, filtered, and concentrated under reduced pressure to obtain a brown oil residue (42.0 g, crude, 89.3 mmol). The crude material was transferred to the next step without further purification.

[0974] UPLC-MS (acidic method, 2 min): rt = 1.24 min, 93%, m / z = weak ionization.

[0975]

[0976] Ethyl 2,5-bis(benzyloxy)-3-(chloromethyl)benzoate ( KI-14 ) [Step 4]: Ethyl 2,5-bis(benzyloxy)-3-(hydroxymethyl)benzoate (42 g of crude material from the previous step, 89.3 mmol) was dissolved in DCM (200 mL) under an inert atmosphere (N2), then SOCl2 (9.8 mL, 133.9 mmol) was added at 0°C (ice bath) and the reaction mixture was heated to room temperature. After 2 hours, volatile substances were removed under reduced pressure, and then semi-solid brown oil was obtained by azeotrope distillation using toluene (3 × 100 mL) (38.0 g, crude, 89.3 mmol).

[0977] UPLC-MS (acidic method, 2 min): rt = 1.40 min, 91%, m / z = weak ionization.

[0978]

[0979] Bis(2,5-dibenzyloxy-3-ethoxycarbonylphenylmethyl)sulfide [Step 5]: in DMF (420 mL) KI-14 Thioacetamide (8.4 g, 111.8 mmol) was added to a solution (38.0 g, crude material, 89.3 mmol), followed by the addition of K2CO3-325 mesh (16.7 g, 120.8 mmol). The reaction was heated at 45°C for 48 hours. After cooling the reaction to room temperature, thioacetamide (2.5 g, 33.3 mmol) and K2CO3-325 mesh (5.0 g, 36.1 mmol) were added, and the reaction was completed by stirring for an additional 18 hours at 45°C. The reaction mixture was poured into water (4 L). The reaction mixture was stirred for 20 minutes, followed by the addition of EtOAc (2 L) and then solid NaCl (approx. 60 g). The phases were separated, and further extraction was performed using EtOAc (1.5 L). The collected organic layer was washed with brine (1.5 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude title compound (39.8 g, 44.6 mmol) as a brown oil, which was used in the next step without purification.

[0980] UPLCMS (acidic method, 2 min): rt = 1.57 min, m / z = 800.5 [M+NH4]+, peak area 77%.

[0981]

[0982] bis(2,5-dibenzyloxy-3-ethoxycarbonylphenylmethyl)sulfone[Step 6]: A 30 wt% solution of hydrogen peroxide (50 mL, 490 mmol) was slowly added to a solution of bis(2,5-dibenzyloxy-3-ethoxycarbonylphenylmethyl)sulfide (39.8 g crude, 44.6 mmol) in acetic acid (850 mL). The reaction was stirred at room temperature for 18 hours. The reaction mixture was poured into ice / water (5 L) and stirred at room temperature for 30 minutes, after which EtOAc (2 L) and solid NaCl (about 40 g) were added. After phase separation, the aqueous layer was extracted once more with EtOAc (1 L). The collected organic layer was washed with brine (1.5 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a brown solid. The solid was suspended in MTBE (250 mL) and magnetically stirred for 30 minutes, then filtered and further ground with MTBE (150 mL) to obtain the title compound (23.56 g, 28.9 mmol, 64% yield over 4 steps).

[0983] UPLC-MS (acid method, 2 min): rt = 1.48 min; m / z = 832.5 [M+NH4]+, peak area 96%

[0984]

[0985] bis(2,5-dibenzyloxy-3-carboxyphenylmethyl)sulfone[Step 7]: A solution of bis(2,5-dibenzyloxy-3-ethoxycarbonylphenylmethyl)sulfone (33.3 g, 38.8 mmol) in THF (350 mL) was added to a solution of lithium hydroxide (9.7 g, 233 mmol) in water (100 mL), and the resulting mixture was stirred under reflux for 18 hours. After this time, most of the THF was removed under reduced pressure to obtain a white suspension. Upon addition of water (3 L) and an aqueous sodium hydroxide solution (1 M, 1 L), the mixture remained a suspension. The suspension was stirred at room temperature for 18 hours, and a 6 M aqueous hydrochloric acid solution was added to acidify the aqueous layer to a pH of about 1. The resulting solid was filtered and collected, washed with water until the liquid became neutral, and the white solid obtained was further dried in a vacuum oven at 40°C until a constant mass was obtained to obtain the title compound (29.4 g, 38.7 mmol, 99%) as a white solid.

[0986] UPLC-MS (acid method, 2 min): rt = 1.39 min; m / z = 757.1 [MH]-, peak area 100%

[0987]

[0988] Bis(2,5-dihydroxy-3-carboxyphenylmethyl)sulfone [Step 8], IVc-059a: To a suspension of bis(2,5-dibenzyloxy-3-carboxyphenylmethyl)sulfone (10.08 g, 13.28 mmol) in EtOH (140 mL) and THF (140 mL), charcoal-phase palladium (20% by weight, 2 g) was added as a suspension in water (20 mL). After several vacuum / hydrogen cycles, the mixture was maintained at 25°C under an atmosphere of H2 and stirred for 20 hours. After completion, the mixture was filtered through Celite® using THF. The filtrate was concentrated under reduced pressure to obtain a grayish-white solid. The residue was then suspended in acetonitrile (100 mL) and heated under reflux with magnetic stirring, and the mixture was then cooled to -5°C, filtered, and further washed with cold acetonitrile. The product was further dried in a vacuum oven at 40°C until a constant mass was obtained to obtain the desired product as a white solid (5.35 g, 12.78 mmol, 96%).

[0989] UPLC-MS (acid method, 4 min): rt = 0.67 min; m / z = 397.1 [MH]-, peak area 100%

[0990] NMR data: Refer to the above.

[0991] Example 1.12 - Type V molecule : Reference Compound

[0992] Diamide derived from 5-hydroxyisophthalic acid

[0993] 2 examples

[0994]

[0995] Synthesis reaction equation and procedure

[0996] Reaction Scheme 25: Synthesis of V-001a

[0997]

[0998] amide link formation

[0999] Aniline A (2 mol) or using methyl 5-aminosalicylate General procedure for amide coupling [3B] BRefer to .

[1000] Deprotection procedure: Refer to general procedure [4], [5].

[1001] Refer to Fig. 8 for more details.

[1002] for example

[1003]

[1004] 64) 5-hydroxyisophthalic acid bis-N-(4-carboxy-2,5-dihydroxyphenyl)amide(V-001a)

[1005] UPLC-MS (acid method, 2 min): rt = 0.72 min; m / z = 483.0 [M+H] + , peak area >95%

[1006]

[1007] diethyl ester

[1008] UPLC-MS (acid method, 2 min): rt = 1.09 min; m / z = 539.2 [MH] - , peak area 94%

[1009]

[1010]

[1011] 65) 5-hydroxyisophthalic acid bis-N-(3-carboxy-4-hydroxyphenyl)amide(V-002a)

[1012] UPLC-MS (acid method, 4 min): rt = 1.00 min; m / z = 451.1 [MH] - , peak area 97%

[1013]

[1014] Urea-linked gentisic acid unit 1 example

[1015]

[1016] Synthesis reaction equation and procedure

[1017] Reaction Scheme 26: Synthesis of V-003a

[1018]

[1019] Urea linkage formation

[1020] KI-1 Procedure from:

[1021] N ,N'-bis(2,5-dibenzyloxy-4-ethoxycarbonylphenyl)urea . 2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid (in THF (25 mL) under an inert atmosphere (N2) KI-1 DPPA (1.1 mL, 5.2 mmol) was slowly added to a cooled solution (ice bath) of ) (2.0 g, 4.9 mmol) and Et3N (1.6 mL, 11.3 mmol). The mixture was slowly heated to room temperature and stirred at this temperature for 3 hours. Subsequently, tBuOH (8 mL) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction profile showed a urea-linked product instead of the desired Boc-aniline. The mixture was poured into a saturated solution of sodium hydrocarbonate (250 mL), stirred for 5 minutes, and extracted with EtOAc (3 × 50 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a colorless oil. The residue was purified by flash column chromatography (gradient to 30% EtOAc after iso-hexane / EtOAc 1:0) to obtain the title compound (1.1 g, 56%) as a grayish-white solid.

[1022] UPLC-MS (basic method, 2 min): rt = 1.50 min; m / z = 781.2 [M+H] + , peak area 85%

[1023]

[1024] Deprotection procedure: Refer to general procedure [4], [5].

[1025] Refer to Fig. 8 for more details.

[1026] for example

[1027] 66) N ,N'-bis(2,5-dihydroxy-4-carboxyphenyl)urea(V-003a)

[1028]

[1029] UPLC-MS (acid method, 4 min): rt = 0.90 min; m / z = 363.1 [MH] - , peak area 93%

[1030]

[1031] diethyl ester

[1032] UPLC-MS (acid method, 4 min): rt = 1.79 min; m / z = 419.2 [MH] - , peak area 97%

[1033]

[1034] Example 1.13: Formation of salt

[1035] a) Solid.

[1036] General protocol: An appropriate number of bases was added to a solution or suspension of the desired compound in water, sonicated until completely dissolved, and, if necessary, aqueous HCl or an excess amount of base was added to adjust the pH to a value between 7.0 and 7.4, and then the solution was freeze-dried to obtain the salt as a solid. Alternatively, a specific salt can be obtained by dissolving in DMSO and then precipitating with EtOH ( IIc-007a A solid was produced from the following bases: sodium hydroxide, diethylamine (DEA), lysine (Lys), meglumine (Meg), and triethanolamine (TEA).

[1037] for example :

[1038] As a solid according to a standard protocol without pH adjustment Ic-007a, IIc-007a, IIIc-061a Sodium and diethylammonium (DEA) salts were obtained.

[1039] - Approximate solubility in water:

[1040] Ic-007a -DEA2: < 10 mg / mL

[1041] Ic-007a -DEA3: > 20 mg / mL

[1042] IIc-007a- DEA1: > 10 mg / mL

[1043] IIc-007a -DEA2: > 20 mg / mL

[1044] IIIc-061a -DEA3: > 25 mg / mL

[1045] - Salt stability as a free acid and solid:

[1046] Glass Mountain Ic-007a , IIc-007a, IIIc-061a, and the following salts Ic-007a- DEA2, IIc-007a -DEA2, IIIc-061a -DEA3 was stable as a solid for up to 56 days at temperatures of 4°C, 20°C, and 40°C; salt Ic-007a -DEA3 was stable at the same temperature for up to 36 days.

[1047] b) solution

[1048] General protocol: Add an appropriate number of equivalents of base to a solution or suspension of the desired compound in water, sonicate until completely dissolved, and, if necessary, add aqueous HCl or an excess amount of base to adjust the pH to a value between 7.0 and 7.4. As a solution Salts were obtained. The following bases were investigated: ethylamine, triethylamine, ethylenediamine, diethanolamine, triethanolamine, choline, meglumine, lysine, and arginine.

[1049] for example:

[1050] Salt of Ic-007a:

[1051] After stirring the mixture at 40°C for 2 days, soluble salts were obtained with meglumine, lysine, and diethanolamine. Ic-007aThe solid form of the -Lys2 salt was obtained from DMSO by precipitating it with ethanol. The salt was stable as a solution in water at room temperature for at least 7 days.

[1052] Salt of IIc-007a :

[1053] DEA1-salt On a small scale, the mono-diethylammonium salt was obtained via a standard procedure without pH adjustment. Solubility: 17.4 mg / mL versus 1.8 mg / mL for the parent diacid.

[1054] Large-scale Process and Characterization:

[1055] IIc-007a (20 g, 42.7 mmol) was filled with EtOH (200 ml). The reaction was stirred at room temperature to obtain a slurry. DEA (4.4 ml, 42.7 mmol) was added, and the reaction was heated at 50°C for 2 hours. The batch was cooled to room temperature, and the solid was filtered. The filter cake was washed with EtOH (50 mL) and dried in an oven at 40°C to obtain 21.5 g of mono-DEA salt as a yellow solid with a 98% yield. NMR: 1.6% EtOH, 1.04 eq DEA. HPLC: 99.6%.

[1056] IIc-007a Solid-state data for the mono-DEA salt showed a distinct crystalline pattern in XRPD analysis. TGA traces showed a small loss of EtOH below 120°C, indicating that EtOH could dry off at 60 to 80°C. Then, in DSC, a loss of DEA (theoretical 13.5% wt for the 1:1 salt) associated with the endothermic melting (peak at 273.8°C) was observed, followed by melting in the form of free acid.

[1057] DEA2-salt, pH adjusted: It was obtained by a standard procedure with pH adjustment (0.51 additional equivalents of Et2NH required to reach pH=7.25). The salt in the solution exhibits clear decomposition after 21 days at 40°C and extensive decomposition after 24 hours at 80°C.

[1058] DEA2-salt , pH not adjusted : Obtained by a standard procedure without pH adjustment. pH of the solution = 5.87. The salt in the solution did not show decomposition after 21 days at 4°C, 20°C, and 40°C.

[1059] Lys2-salt, pH not adjusted : Obtained by a standard procedure using 2 equivalents of L-lysine. pH of solution = 5.74.

[1060] Note: Similar to bis(N-methyl)amide of 2-hydroxyisophthalic acid (pKa of phenol = 6.81), IIc-007a The 2-OH group of the isophthalic acid bis-amide core is significantly acidic, and when it is ionized, molecular decomposition occurs. This effect Ic-007a It is not observed (expected pKa of phenolic functional groups in the range of 9.8 to 10.0). Therefore IIc-007a It is important not to adjust the pH of the divalent cationic salt solution.

[1061] Salt of IIIc-061a:

[1062] DEA3-salt, pH adjusted: It was obtained by a standard procedure using 3 equivalents of Et2NH along with pH adjustment (0.8 equivalents of additional HCl (0.5 M) required to reach a final pH=7.22). The salt in the solution showed no decomposition after 21 days at 4°C and 20°C, and showed slight decomposition after 33 days at 40°C.

[1063] Meg3-salt, pH adjusted: It was obtained by a standard procedure using 3 equivalents of meglumine with pH adjustment to reach a final pH of 7.22 (HCl 0.5 M). The salt in the solution did not show decomposition after 21 days at 4°C and 20°C, and after 14 days at 40°C.

[1064] IVc-059a salt,

[1065] DEA2-salt, pH adjusted : Obtained by a standard procedure with pH adjustment (0.32 additional equivalents of Et2NH required to reach pH=7.3). The salt in the solution exhibits stability after 26 days at 4°C, 20°C, and 40°C.

[1066] Example 1.14: Prodrug

[1067] Ic-007a prodrug

[1068] 1) 2-Mopolinoethyl 5-[[2,5-Dihydroxy-4-[[4-hydroxy-3-(2-Mopolinoethoxycarbonyl)phenyl]carbamoyl]benzoyl]amino]-2-hydroxy-benzoate(Ic-007a-mpe2)

[1069]

[1070] Esterification A suspension of 5-[[2,5-dibenzyloxy-4-[(3-carboxy-4-hydroxyphenyl)carbamoyl]-benzoyl]amino]-2-hydroxy-benzoic acid (130 mg, 0.2 mmol) in N,N-dimethylformamide (4 ml) was stirred at room temperature. A solution of 2-morpholinoethanol (53 mg, 0.4 mmol) in N,N-dimethylpyridine-4-amine (49 mg, 0.4 mmol) and N,N-dimethylformamide (0.5 ml) was added. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.6 mmol) was added, and the reaction mixture was heated in a microwave reactor at 60°C for 1.5 hours. The reaction mixture was filtered, the filtrate was diluted with tetrahydrofuran, and the solvent was evaporated. The residue was purified by silica gel chromatography eluted with 0 to 40% methanol in dichloromethane to obtain the title compound as a white solid (80 mg, 45%). LCMS (m / z) [M+H] 875.1.

[1071] Hydrocracking A solution of the obtained diester (80 mg, 0.092 mmol) in tetrahydrofuran (12 ml) and water (4 ml) was prepared, and 10% palladium on carbon (50 mg, 10% paste) was added. The reaction mixture was stirred under a hydrogen atmosphere for 17 hours. The catalyst was removed by filtration, and the solvent was evaporated. The residue was purified by reverse-phase preparative HPLC on a C18 column using a gradient of 10 to 97% (acetonitrile + 0.1% formic acid):(water + 0.1% formic acid). The residue was polished with diethyl ether and dried under vacuum to obtain the title compound as a yellow solid. Ic-007a-mpe2 was obtained (22 mg, 35%).

[1072]

[1073] 2) 5-[[2,5-dihydroxy-4-[[4-hydroxy-3-(2-morpholinothoxycarbonyl)phenyl]carbamoyl]benzoyl]amino]-2-hydroxy-benzoic acid(Ic-007a-mpe1)

[1074]

[1075] Esterification A solution of 5-[[2,5-dibenzyloxy-4-[(3-carboxy-4-hydroxy-phenyl)-carbamoyl]benzoyl]amino]-2-hydroxy-benzoic acid (324 mg, 0.5 mmol) and triethylamine (101 mg, 0.15 ml, 1 mmol) in N,N-dimethylformamide (7 ml) was stirred at room temperature. A solution of 2-morpholinoethanol (66 mg, 0.5 mmol) in N,N-dimethylformamide (1 ml) and N,N-dimethylpyridine-4-amine (122 mg, 1 mmol) was added. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.6 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours, then heated in a microwave at 60°C for 4 hours. The reaction was repeated on a similar scale and the reaction mixtures were combined. The solvent was evaporated and the residue was ground with diethyl ether to obtain a mixture of mono- and diesters (230 mg). LCMS (m / z) [M+H] 762.0 (mono-ester).

[1076] Hydrogenation The mixture of the obtained mono and diester (230 mg) was dissolved in acetic acid (10 ml), tetrahydrofuran (15 ml), and water (5 ml), and 10% palladium carbonate (150 mg, 10% paste) was added. The reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The catalyst was removed by filtration, and the solvent was evaporated to obtain a yellow gum (140 mg). The residue was purified by reverse-phase preparative HPLC on a C18 column using a gradient of 10 to 70% (acetonitrile + 0.1% formic acid):(water + 0.1% formic acid). The residue was polished with diethyl and dried under vacuum to obtain the title monoester as a yellow solid. Ic-007a-mpe1 11 mg was obtained.

[1077]

[1078] 3) 1-(2,2-dimethylpropaneoiloxy)ethyl 5-[[4-[[3-[1-(2,2-dimethylpropaneoiloxy)ethoxycarbonyl]-4-hydroxy-phenyl]carbamoyl]-2,5-dihydroxy-benzoyl]amino]-2-hydroxy-benzoate(Ic-007a-pive2)

[1079] and

[1080] 4) 5-[[4-[[3-[1-(2,2-dimethylpropaneoiloxy)ethoxycarbonyl]-4-hydroxy-phenyl]carbamoyl]-2,5-dihydroxy-benzoyl]amino]-2-hydroxy-benzoic acid(Ic-007a-pive1)

[1081]

[1082] EsterificationA solution of 5-[[2,5-dibenzyloxy-4-[(3-carboxy-4-hydroxy-phenyl)carbamoyl]benzoyl]amino]-2-hydroxy-benzoic acid (324 mg, 0.5 mmol) and triethylamine (152 mg, 0.21 mmol) in N,N-dimethylformamide (10 mL) was stirred at 0°C, and 1-iodoethyl 2,2-dimethylpropanoate (572 mg, 2 mmol) was added. The reaction mixture was heated to room temperature and stirred at room temperature for 24 hours. The dimethylformamide was evaporated, and the residue was separated between dichloromethane and aqueous sodium metabisulfite. The organic phase was dried and evaporated over anhydrous magnesium sulfate to obtain a 1:1 mixture of mono and diester (187 mg). The reaction was repeated, and the 1:1 mixture of esters was combined. LCMS (m / z) [M+H] 777.0 (monoester) and 905.1 (diester).

[1083]

[1084] Hydrocracking

[1085] The mixture of the obtained mono and diester (320 mg) was dissolved in tetrahydrofuran (50 ml) and water (5 ml), and 10% palladium on carbon (300 mg, 10% paste) was added. The reaction mixture was stirred under a hydrogen atmosphere for 20 hours. The catalyst was removed by filtration, and the solvent was evaporated. LCMS indicated that only partial deprotection was achieved. The residue was dissolved in tetrahydrofuran (36 ml) and water (6 ml), and 10% palladium on carbon (600 mg, 10% paste) was added. The reaction mixture was stirred under a hydrogen atmosphere for 22 hours. The catalyst was removed by filtration, and the solvent was evaporated. The residue was purified by reverse-phase preparative HPLC on a C18 column using a gradient of 40 to 97% (acetonitrile + 0.1% formic acid):(water + 0.1% formic acid). The residue was polished with diethyl ether and dried under vacuum to obtain the title product:

[1086]

[1087] Biodata: T 1 / 2 (Mouse plasma): 62.2 min (ester cleaved; 65% residue after 1 hour); T 1 / 2 (Human Plasma): > 180 minutes.

[1088]

[1089] Biodata: T 1 / 2 (Mouse plasma): 44.6 min (ester cleaved; 49% residue after 1 hour); T 1 / 2 (Human Plasma): > 180 minutes.

[1090] IIc-007a prodrug

[1091] 1) 2,2-Dimethylpropaneoiloxymethyl 5-[[3-[[3-(2,2-Dimethylpropaneoiloxymethoxycarbonyl)-4-hydroxy-phenyl]carbamoyl]-2,5-Dihydroxy-benzoyl]amino]-2-hydroxy-benzoate (IIc-007a-pivm2)

[1092]

[1093] Esterification A solution of 5-[[2,5-dibenzyloxy-3-[(3-carboxy-4-hydroxy-phenyl)carbamoyl]benzoyl]amino]-2-hydroxybenzoic acid (280 mg, 0.432 mmol) in N,N-dimethylformamide was prepared, and chloromethyl 2,2-dimethylpropanoate (137 μL, 0.95 mmol) was added, followed by triethylamine (167 μL, 1.2 mmol) and sodium iodide (143 mg, 0.95 mmol). The stirred solution was heated at 50°C for 18 hours. The solution was then cooled and separated between a saturated ammonium chloride solution and ethyl acetate. The organic layer was dried over sodium sulfate and filtered to evaporate. The residue was 100% Iso -Hexane to 50% ethyl acetate, 50% Iso - A diester was obtained as a colorless gum by purification by chromatography on a silica column using a hexane gradient (192 mg, 51%). LCMS (m / z) [M+H] 876.9.

[1094] Hydrocracking:A solution of the obtained diester (192 mg, 0.219 mmol) in tetrahydrofuran (4.5 mL) was prepared and added to a stirred suspension of 10% palladium (40 mg, 0.04 mmol) on carbon in water (1.5 mL). The stirred reaction mixture was incubated under a hydrogen atmosphere for 18 hours. The reaction was filtered to remove the catalyst, and the solution was evaporated to obtain a cream solid (142 mg). The solid was purified by HPLC on a C18 column using a gradient of 60% acetonitrile, 40% water versus 100% acetonitrile (0.1% formic acid) to obtain the title diester as a white solid. IIc-007a-pivm2 75 mg, 49% was obtained. 1 H NMR (DMSO-D6ppm) δ 13.03 (br s, 1H), 10.43 (br s, 2H), 10.16 (s, 2H), 9.52 (br s, 1H), 8.17 (d, J= 2.7Hz, 2H), 7.82 (dd, J =8.9Hz , 2.7Hz, 2H), 7.55 (s, 2H), 7.02 (d, J =8.9Hz, 2H), 5.98 (s, 4H), 1.17 (s, 18H). LCMS (m / z) [MH] 694.9.

[1095] 2) 5-[[3-[[3-[1-(2,2-dimethylpropaneoiloxy)ethoxycarbonyl]-4-hydroxy-phenyl]carbamoyl]-2,5-dihydroxy-benzoyl]amino]-2-hydroxy-benzoic acid(IIc-007a-pive1)

[1096]

[1097] EsterificationA solution of 5-[[2,5-dibenzyloxy-3-[(3-carboxy-4-hydroxy-phenyl)carbamoyl]benzoyl]amino]-2-hydroxy-benzoic acid (324 mg, 0.5 mmol) and triethylamine (101 mg, 0.14 ml, 1.0 mmol) in N,N-dimethylformamide (10 ml) was stirred at 0°C. 1-iodoethyl 2,2-dimethylpropanoate (154 mg, 0.6 mmol) was added. The reaction mixture was stirred at room temperature for 21 hours. Additional triethylamine (0.14 ml, 1.0 mmol) and 1-iodoethyl 2,2-dimethylpropanoate (154 mg, 0.6 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated. The residue was separated between a solution of dichloromethane and sodium metabisulfite. The organic extracts were combined, washed with brine, and the solution was dried by passing it through a hydrophobic frit. The filtrate was evaporated to obtain a mixture of mono- and diesters. The residue was purified by silica gel chromatography eluted with 5 to 100% ethyl acetate in iso-hexane and subsequently with 10% methanol in dichloromethane to obtain the mono-ester as a yellow solid (121 mg). LCMS (m / z) [M+H] 777.

[1098] Hydrogenation The obtained monoester solution (121 mg, 0.15 mmol) in tetrahydrofuran (16 ml) and water (4 ml) containing 10% palladium on carbon (250 mg, 10% paste) was stirred under a hydrogen atmosphere for 18 hours. The catalyst was removed by filtration, and the solvent was evaporated. The residue was purified by reverse-phase preparative HPLC using a gradient of 40 to 97% (acetonitrile + 0.1% formic acid):(water + 0.1% formic acid) to obtain the monoester as a yellow solid. IIc-007a-pive1 34 mg was obtained. 1H NMR (DMSO-D6" ppm) δ 13.15 (br s, 1H), 10.47 (br s, 2H), 10.18 (s, 1H), 9.47 (br s, 1H), 8.21 (d, J=3 Hz 1H), 8.17 (d, J=3 Hz 1H), 7.82 (dd, J=9, 3 Hz 1H), 7.78 (dd, J=9, 3 Hz 1H), 7.59-7.55 (m, 2H), 7.03 (d, J=9 Hz 1H), 6.99 (q, J=5.4 Hz 1H), 7.96 (d, J=9 Hz 1H), 1.58 (d, J=5.4 Hz, 3H), 1.17 (s, 9H). LCMS (m / z) [MH] 595.1.

[1099] IVc-059a prodrug

[1100] 1) 2,5-Dihydroxy-3-[[2,5-hydroxy-3-(2-Mopolinoethoxycarbonyl)phenyl]methylsulfonyl-methyl]benzoic acid (IVc-059a-mpe1)

[1101]

[1102] Esterification A solution of 2,5-dibenzyloxy-3-[(2,5-dibenzyloxy-3-carboxyphenyl)methylsulfonyl-methyl]benzoic acid (300 mg, 0.40 mmol) and 2-morpholinoethanol (53 mg, 0.40 mmol) in N,N-dimethylformamide (93 mL) was prepared, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 93 mg, 0.48 mmol) and N,N-dimethylpyridine-4-amine (10 mg, 0.08 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. The resulting solution was evaporated, and the residue was purified by HPLC on a C18 column using a gradient of 30% acetonitrile, 70% water to 100% acetonitrile (0.1% formic acid) to obtain morpholinoethyl ester as a colorless gum (111 mg, 32%). LCMS (m / z) [M+H] 872.1.

[1103] Hydrogenation The solution of the monoester (111 mg, 0.127 mmol) in tetrahydrofuran (3 mL) was added to a stirred suspension of 10% palladium (20 mg, 0.019 mmol) on carbon in water (1 mL). The stirred reaction mixture was left under a hydrogen atmosphere for 18 hours.

[1104] The reaction was filtered to remove the catalyst, and the solution was evaporated to obtain a brown solid. The solid was purified by HPLCf on a C18 column using a gradient of 10% acetonitrile, 90% water versus 60% acetonitrile, 40% water (0.1% formic acid) to obtain a white solid (20.5 mg). The solid was polished with diethyl ether and dried under vacuum to obtain the title product as a white solid. IVc-059a-mpe1 5 mg, 8% was obtained.

[1105]

[1106] Biodata: Stable in mouse plasma for up to 60 minutes

[1107] 2) 2,5-Dihydroxy-3-[[2,5-hydroxy-3-(2-morpholinothoxycarbonyl)phenyl]methylsulfonyl-methyl]benzoic acid 2-morpholinoethyl ester (IVc-059a-mpe2)

[1108]

[1109] A solution of 2,5-dibenzyloxy-3-[(2,5-dibenzyloxy-3-carboxyphenyl)methylsulfonylmethyl]benzoic acid (69 mg, 0.091 mmol) and 2-morpholinoethanol (25 mg, 0.19 mmol) in N,N-dimethylformamide (1 mL) was prepared, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (42 mg, 0.48 mmol) and N,N-dimethylpyridine-4-amine (5 mg, 0.04 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. The resulting solution was evaporated, and the residue was purified by chromatography on a silica column using 10% methanol and 90% dichloromethane to obtain the title product as a colorless gum (58 mg, 65%). LCMS (m / z) [M+H] 985.0.

[1110] A solution of the obtained diester (58 mg, 0.059 mmol) in tetrahydrofuran (1.5 mL) was prepared and added to a stirred suspension of 10% palladium (5 mg, 0.005 mmol) on carbon in water (0.5 mL). The stirred reaction mixture was left under a hydrogen atmosphere for 18 hours. The reaction was filtered to remove the catalyst, and the solution was evaporated to obtain a brown solid. The solid was purified by HPLC on a C18 column using a gradient of 10% acetonitrile, 90% water versus 60% acetonitrile, 40% water (0.1% formic acid) to obtain a white solid (13.7 mg).

[1111] The solid is polished with diethyl ether and dried under vacuum to obtain the title product as a white solid. IVc-059a-mpe2 9.1 mg, 25% was obtained.

[1112]

[1113] Biodata: Stable for up to 60 minutes in mouse plasma; T 1 / 2 (Human Plasma): > 180 minutes.

[1114] 3) 3-[[3-[1-(2,2-dimethylpropaneoiloxy)ethoxycarbonyl]-2,5-dihydroxy-phenyl]methyl-sulfonyl-methyl]-2,5-dihydroxy-benzoic acid 1-(2,2-dimethylpropaneoiloxy)ethyl ester(IVc-059a-pive2)

[1115]

[1116] EsterificationA solution of 2,5-dibenzyloxy-3-[(2,5-dibenzyloxy-3-carboxy-phenyl)methyl-sulfonylmethyl]benzoic acid (200 mg, 0.263 mmol) in anhydrous N,N-dimethylformamide (5 mL) was prepared, and triethylamine (88 μL, 0.63 mmol), sodium iodide (8 mg, 0.053 mmol), and crude 1-iodoethyl 2,2-dimethylpropanoate (approx. 4.2 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. The resulting solution was evaporated to a small volume, and the residue was separated between a solution of dichloromethane and sodium thiosulfate. The organic layer was passed through a hydrophobic frit, filtered, and evaporated. The residue was purified by chromatography on a silica gel column eluted with a gradient of 100% iso-hexane to 50:50 ethyl acetate / iso-hexane to obtain the di-ester as a colorless gum (110 mg, 41%). LCMS (m / z) [M+Na] 1037.0

[1117] In addition, the monoester was isolated from the same column as a colorless gum (90 mg, 40%). LCMS (m / z) [M+Na] 909.6.

[1118] Hydrocracking:

[1119]

[1120] The solution of the isolated diester (110 mg, 0.108 mmol) in tetrahydrofuran (3 mL) was added to a stirred suspension of 10% palladium (20 mg, 0.02 mmol) on carbon in water (1 mL). The stirred reaction mixture was left under a hydrogen atmosphere for 48 hours. The reaction mixture was filtered to remove the catalyst, the solution was evaporated, and the residue was purified by chromatography on a silica column eluted with a gradient of 100% dichloromethane versus 10% methanol and 90% dichloromethane to obtain the title product as a cream solid. IVc-059a-pive2 55 mg, 78% was obtained.

[1121]

[1122] Biodata: Rapidly hydrolyzed in mouse and human plasma

[1123] 4) 3-[[3-[1-(2,2-dimethylpropaneoiloxy)ethoxycarbonyl]-2,5-dihydroxy-phenyl]methylsulfonyl-methyl]-2,5-dihydroxy-benzoic acid IVc-059a-pive1)

[1124] Hydrocracking:

[1125]

[1126] The solution of the isolated monoester (90 mg, 0.104 mmol) in tetrahydrofuran (3 mL) was added to a stirred suspension of 10% palladium (20 mg, 0.02 mmol) on carbon in water (1 mL). The stirred reaction mixture was left under a hydrogen atmosphere for 48 hours. The reaction was filtered to remove the catalyst, the solution was evaporated, and the residue was purified by chromatography on a silica column eluted with a gradient of 100% dichloromethane versus 20% methanol and 80% dichloromethane to obtain the title product as a cream solid. IVc-059a-pive1 22.5 mg, 43% was obtained.

[1127]

[1128] Biodata: Rapidly hydrolyzed in mouse plasma

[1129] 5) 2,2-Dimethylpropaneoiloxymethyl 2,5-Dihydroxy-3-[[2,5-Dihydroxy-3-(2,2-Dimethyl-propaneoiloxymethoxycarbonyl)phenyl]methylsulfonylmethyl]benzoate(IVc-059a-pivm2)

[1130]

[1131] EsterificationA solution of 2,5-dibenzyloxy-3-[(2,5-dibenzyloxy-3-carboxy-phenyl)methylsulfonyl-methyl]benzoic acid (100 mg, 0.131 mmol) in anhydrous N,N-dimethylformamide (1 mL) was prepared, and chloromethyl 2,2-dimethylpropanoate (91 μL, 0.631 mmol) was added, followed by the addition of triethylamine (110 μL, 0.789 mmol) and sodium iodide (87 mg, 0.579 mmol). The reaction mixture was heated at 50°C for 6.5 hours. The resulting solution was evaporated, and the residue was separated between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a silica gel column eluted with a gradient of 100% iso-hexane versus 50% ethyl acetate and 50% iso-hexane to obtain a diester product as a colorless gum (85 mg, 66%). LCMS (m / z) [M+Na] 1010.0 .

[1132] Hydrocracking: A solution of the obtained diester (85 mg, 0.086 mmol) in tetrahydrofuran (3 mL) was added to a stirred suspension of 10% palladium (20 mg, 0.02 mmol) on carbon in water (1 mL). The stirred reaction mixture was left under a hydrogen atmosphere for 18 hours. The reaction was filtered to remove the catalyst, the solution was evaporated, and the residue was purified by chromatography on a silica gel column eluted by a gradient of 100% iso-hexane versus 60% ethyl acetate and 40% iso-hexane to obtain the diester as a white solid. IVc-059a-pivm2 31 mg, 57% was obtained.

[1133]

[1134] Biodata: Rapidly hydrolyzed in mouse plasma, T 1 / 2 = 14.1 min; T 1 / 2 (Human Plasma): > 180 minutes.

[1135] 6) 2,5-Dihydroxy-3-[[2,5-Dihydroxy-3-(2,2-Dimethylpropaneoiloxymethoxycarbonyl)phenyl]methyl-sulfonylmethyl]benzoic acid(IVc-059a-pivm1)

[1136]

[1137] Esterification: A solution of 2,5-dibenzyloxy-3-[(2,5-dibenzyloxy-3-carboxyphenyl)methylsulfonylmethyl]benzoic acid (300 mg, 0.395 mmol) in anhydrous N,N-dimethylformamide (3 mL) was prepared, chloromethyl 2,2-dimethylpropanoate (57 μL, 0.395 mmol) was added, followed by the addition of triethylamine (68 μL, 0.489 mmol) and sodium iodide (129 mg, 0.870 mmol). The reaction mixture was heated at 50°C for 4 hours. The resulting solution was cooled and evaporated. The residue was purified by chromatography on a silica column eluted with a gradient of 20% ethyl acetate, 80% iso-hexane versus 80% ethyl acetate, 20% iso-hexane to obtain a monoester product as a white solid (121 mg, 35%). LCMS (m / z) [MH] 871.0.

[1138] Hydrocracking: A solution of the obtained monoester (121 mg, 0.138 mmol) in tetrahydrofuran (3 mL) was added to a stirred suspension of 10% palladium (20 mg, 0.02 mmol) on carbon in water (1 mL). The stirred reaction mixture was left under a hydrogen atmosphere for 48 hours. The reaction was filtered to remove the catalyst, the solution was evaporated, and the residue was purified by HPLC on a C18 column eluted by a gradient of 30% acetonitrile, 70% water to 100% acetonitrile (0.1% formic acid) to obtain the monoester as a white solid. IVc-059a-pivm1 30 mg, 42% was obtained.

[1139]

[1140] Biodata : Rapidly hydrolyzed in mouse plasma, T 1 / 2 = 6.7 minutes; T 1 / 2 (Human Plasma): > 180 minutes.

[1141] Example 2: General experimental method

[1142] NMR Spectroscopic Analysis

[1143] 1 H NMR spectra were recorded at 400 MHz on a Bruker Advance III NMR spectrometer. Samples were chlorinated in deuterated chloroform (CDCl3) or dimethyl sulfoxide (DMSO- d 6 Manufactured in ) and raw data M It was processed using nova NMR software. High-resolution mass spectra were recorded using a MaXis ESI qTOF ultra-high-resolution mass spectrometer.

[1144] UPLC-MS analysis

[1145] UPLC-MS analysis was performed on a Waters Acquity UPLC system composed of the Acquity I-Class Sample Manager-FL, Acquity I-Class Binary Solvent Manager, and Acquity I-Class UPLC Column Manager. UV detection was achieved using an Acquity I-Class UPLC PDA detector (scanning from 210 to 400 nm), while mass detection was achieved using an Acquity QDa detector (mass scanning from 100 to 1250 Da; simultaneous positive and negative modes). Analytes were separated using a Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 mm).

[1146] Samples were prepared by dissolving the sample in 1 mL of a 1:1 (v / v) mixture of MeCN in H2O (with or without sonication). The resulting solution was filtered through a 0.45 μm syringe filter before application to analysis. All solvents used (including formic acid and 36% ammonia solution) were HPLC grade.

[1147] Four different analysis methods were used in this work, and details are presented below.

[1148] Acidic run (2 minutes) : 0.1% v / v formic acid in water [Eluent A]; 0.1% v / v formic acid in MeCN [Eluent B]; flow rate 0.8 mL / min; injection volume 2 μL and equilibration time 1.5 min between samples.

[1149] Time (minutes) Eluent A (%) Eluent B(%) 0.00 95 5 0.25 95 5 1.25 5 95 1.55 5 95 1.65 95 5 2.00 95 5

[1150] Acidic run (4 minutes): 0.1% v / v formic acid in water [Eluent A]; 0.1% v / v formic acid in MeCN [Eluent B]; flow rate 0.8 mL / min; injection volume 2 μL and equilibration time 1.5 min between samples.

[1151] Time (minutes) Eluent A (%) Eluent B(%) 0.00 95 5 0.25 95 5 2.75 5 95 3.25 5 95 3.35 95 5 4.00 95 5

[1152] Acidic run (6.5 minutes): 10 mM ammonium formate + 0.1% v / v formic acid [Eluent A]; 0.1% v / v formic acid in MeCN [Eluent B]; flow rate 0.6 mL / min; injection volume 2 μL.

[1153] Time (minutes) Eluent A (%) Eluent B(%) 0.00 95 5 0.50 95 5 4.00 5 95 4.50 5 95 4.52 95 5 6.50 95 5

[1154] Basic run (2 minutes): 0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; flow rate 0.8 mL / min; injection volume 2 μL and equilibration time 1.5 min between samples.

[1155] Time (minutes) Eluent A (%) Eluent B(%) 0.00 95 5 0.25 95 5 1.25 5 95 1.55 5 95 1.65 95 5 2.00 95 5

[1156] Basic run (4 minutes): 0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; flow rate 0.8 mL / min; injection volume 2 μL and equilibration time 1.5 min between samples.

[1157] Time (minutes) Eluent A (%) Eluent B(%) 0.00 95 5 0.25 95 5 2.75 5 95 3.25 5 95 3.35 95 5 4.00 95 5

[1158] Basic run (6.5 minutes):10 mM ammonium bicarbonate + 0.1% v / v 35% ammonia solution [Eluent A]; 0.1% v / v formic acid in MeCN [Eluent B]; flow rate 0.6 mL / min; injection volume 2 μL.

[1159] Time (minutes) Eluent A (%) Eluent B(%) 0.00 95 5 0.50 95 5 4.00 5 95 4.50 5 95 4.52 95 5 6.50 95 5

[1160] HPLC purification for partial dispensing

[1161] Preparative HPLC was performed using a Waters automated purification system equipped with an XBridge Prep C18 column (19 × 150 mm). The Waters system consists of a Waters 2545 Binary Prep Pump, a Waters 2767 Sample Manager, a Waters SFO Column Organizer, a Waters 2998 DAD, a Waters 515 Make-up Pump, and an Acquity QDa mass spectrometer.

[1162] The refinement system was controlled by MassLynx software (version 4.2) with an Open Access Login module.

[1163] Lee Dong-sang (A) 10 mM ammonium formate (+ 0.1% v / v formic acid) and (B) It consists of acetonitrile (+ 0.1% v / v formic acid).

[1164] The sample was prepared by dissolving it in 10% v / v water in DMSO to provide a concentration of approximately 150 mg / mL. A volume of 320 mL of the prepared sample was loaded onto a column and purified using gradient elution at a flow rate of 25 mL / min at room temperature. There is an equilibrium of 1.5 minutes between injections.

[1165] gradient: Time (minutes) % (A) 0.0 95 0.5 95 14.5 0 17.4 0 17.5 95 18.0 95

[1166] Example 3: In a test tube Screening method

[1167] Example 3.1: In a test tube Methods to inhibit FGF1, FGF2, and VEGF-A in HUVEC cells

[1168] The objective of this in vitro method was to evaluate the effects of compounds on FGF-2, FGF-1, or VEGF-A-induced sprouting of human umbilical vein endothelial cells (HUVECs) in a spheroid-based cell angiogenesis assay. Cells were pre-incubated with the compounds prior to the addition of growth factors. Sunitinib was tested as a control (no pre-culture).

[1169] As expected, the sunitinib control inhibited FGF-2, FGF-1, and VEGF-A-induced HUVEC germination. The IC50 values ​​measured for the tested compounds are expressed in microM [μM], and the values ​​for FGF-1, FGF2, and VEGF-A-induced growth (germination) inhibition are listed after each compound in the examples after chemical characterization.

[1170] Germination tests were performed on compounds dissolved in DMSO to obtain a 100-fold concentrated stock solution, which was then dissolved in culture medium. The reference compound, sunitinib, was provided by ProQinase GmbH. Growth factors were purchased from rhFGF-basic (FGF-2), Peprotech, NJ, USA, #100-18C, Lot# 0415571; rhFGF-acidic (FGF-1), Peprotech, NJ, USA, #100-17A, Lot# 031207; and hVEGF-A165 (ProQinase GmbH, Freiburg, Germany; 05.02.2010) and used to stimulate HUVEC cell growth.

[1171] Test system : Approximately 1 x 10⁶ endothelial cells from pooled human umbilical veins (HUVECs) of donors 6Cells were frozen in ampoules with 70% medium, 20% FCS, and 10% DMSO. Primary human umbilical vein endothelial cells, HUVEC cells (PromoCell, Heidelberg, Germany), were used after passages 3 to 4. The cells grew as adherent, monolayer, and gravel-like morphology and were cultured in endothelial cell growth and basal medium (ECGM / ECBM, PromoCell). Subcultures were divided at a 1:3 ratio; approximately 1 × 10⁶ cells were divided every 3 to 5 days. 4 Cells / cm 2 Seeds were incubated at 37°C and 5% CO2 for a doubling time of 24 to 48 hours.

[1172] Dilution of the test compound : A 100× concentrated solution of each test compound (for the final analytical concentration) was prepared using an appropriate solvent (in DMSO or water). This 100× compound solution was further diluted in Endothelial Cell Growth and Basal Medium (ECBM) 1:7.5 to obtain a 13.33× concentrated solution. 75 μl of the 13.33× solution was subsequently mixed with 25 μl of the 40× concentrated stimulus (dissolved in ECBM) to produce a 10× concentrated stimulus / compound mixture. This mixture (100 μl) was incubated at 37°C for 30 minutes and then added to a 900 μl gel containing HUVEC ellipsoids (to produce the final analytical concentration).

[1173] Test methodExperiments were performed by modifying the originally published protocol (reference [Korff and Augustin: J Cell Sci 112: 3249-58, 1999]). Briefly, 400 HUVECs were pipetted into a drop suspended in a plastic dish as described (reference [Korff and Augustin: J Cell Biol 143: 1341-52, 1998]) and allowed to aggregate overnight to form ellipsoids. Then, 50 HUVEC ellipsoids were seeded into 0.9 ml of collagen gel and pipetted into individual wells of a 24-well plate to allow polymerization. The test compound was pre-incubated with a growth factor (FGF-1, FGF-2, or VEGF-A at a final concentration of 25 ng / mL) in a 10-fold concentrated solution, and then 100 μl of this solution was added to the polymerized gel. All compounds were first diluted in a solvent (DMSO or water) as 100× stock solutions (i.e., meaning that the 100× stock solutions of each final analytical concentration were prepared in the solvent). Subsequently, these stock solutions were further diluted in a medium to the final concentrations tested (becoming the 13.33× stock solutions of each final analytical concentration: 100, 50, 25, 12.5, 6.25, 3.13, and 1.56 × 10⁻⁶). -6 M). The plates were incubated at 37°C for 24 hours and fixed by adding 4% PFA (Roth, Karlusch, Germany).

[1174] Quantification of Growth Factor Inhibition:The germination intensity of HUVEC ellipsoids treated with growth factors and inhibitors was quantified using an image analysis system that determines the cumulative sprout length (CSL) per ellipsoid. Photographs of single ellipsoids were captured using an inverted microscope and the digital imaging software NIS-Elements BR 3.0 (Nikon). Subsequently, the ellipsoid images were uploaded to the Wimasis website for image analysis. The cumulative sprout length of each ellipsoid was determined using the imaging analysis tool WimSprout. The average of the cumulative sprout lengths of 10 randomly selected ellipsoids was analyzed as individual data points. For IC50 measurement, the raw data was converted into percentage HUVEC germinations relative to a solvent control group (with stimulation) set to 100% and a baseline control group (without stimulation) set to 0%. The IC50 values ​​were determined using GraphPad Prism 5 software with a non-linear regression curve fitting with a variable hill slope, constraining the bottom to 0 and the top to 100.

[1175] result The dose-response relationship for endothelial growth factor-induced germination was evaluated for all compounds. IC50 values ​​were determined using standard parameters based on the signal of the solvent control as the upper constraint (100% HUVEC germination) and the signal of the baseline control as the lower constraint (0%). The respective IC50 values ​​for each of the compounds FGF1, FGF2, and VEGFA are summarized in the biodata section under their chemical characterization analysis below each compound.

[1176] Example 3.2: In vitro neutrophil adhesion under static conditions, method

[1177] Human neutrophils obtained from the buffy coat of a healthy donor were placed in adhesion buffer (PBS containing 1 mM CaCl2 / MgCl2 and 10% FCS, pH 7.2) at a rate of 3 × 10⁶ 6 It was suspended in / ml. Neutrophils were pre-incubated with 40 μM and 80 μM compounds at 37°C for 30 minutes.

[1178] Adhesion analysis was performed on 18-well glass slides coated with human fibrinogen (20 μg / well in endotoxin-free PBS) at 4°C for 18 hours; 20 μl of cell suspension was added to each well and stimulated at 37°C for 1 minute with 5 μl of fMLP at a final concentration of 1 nM. After washing, adherent cells were fixed in 1.5% glutaraldehyde in PBS and counted using a computer-aided count. Statistical analysis was performed by calculating the mean and standard deviation (SD); significance was calculated by unpaired t-tests. All statistical analyses were performed using GraphPad Prism 6 (GraphPad software).

[1179] The respective inhibition of neutrophil attachment, expressed in [%] for each compound, is summarized under each compound in the chemical characteristics section of the biodata paragraph.

[1180] Example 3.3: On the inhibition of reactive oxygen species (ROS) generation in human neutrophils In a test tube test

[1181] NADPH oxidases located on the plasma membrane and the membranes of specific granules generate superoxide anions from other ROS, such as hydrogen peroxide, singlet oxygen, hypochlorite, and active hydroxyl radicals. ROS are released into the surrounding medium or membrane-bound organelles. One rapid and sensitive method for measuring the production of these metabolites is chemiluminescence (CL). Isoluminol-amplified CL technology is highly sensitive and is widely used to study neutrophil-induced respiratory bursts (primarily the extracellular production of ROS).

[1182] Human neutrophils were isolated from buffy coats obtained from healthy donors. Isolated neutrophils (3 × 10⁶ 6 Neutrophils ( / ml) were suspended in Hanks' Balanced Salt Solution (HBSS) containing calcium and magnesium. Neutrophils were pre-incubated with compounds at different concentrations (0.1, 0.3, 1, 3, and 10 μM) for 30 minutes at 37°C. Black 96-well cell culture plates were coated with human fibrinogen (0.25 mg / ml in PBS) and incubated overnight at 4°C or for 2 hours at 37°C. The plates were then washed with endotoxin-free PBS. Neutrophils were incubated with TNF-α (20 ng / ml) for 10 minutes at 37°C (priming). Subsequently, 75 μl of cell suspension and 75 μl of isoruminol + HRP solution were added to each well. Chemiluminescence was recorded after 1 μM fMLP activation using a Multilabel Reader victor3 (Perkin Elmer, USA) (every 25 seconds for 250 seconds). A background value, defined as the average chemiluminescence value of isoluminol diluted in HBSS, was subtracted from all readings (CPS, counts per second). The analysis was performed in duplicate or triple.

[1183] Results obtained from the isoluminol-amplified CL analysis showed that the compound significantly reduced ROS levels in fMLP + TNF-α-stimulated PMNs in a concentration-dependent manner.

[1184] PMN ROS inhibition at 0.3 μM, expressed as [%] and IC50[μM], is summarized in the biodata section under the chemical characterization analysis for each compound.

[1185] Example 3.4: In a test tube Production of inflammatory cytokines in human neutrophils and human monocytes, method

[1186] Neutrophils and monocytes were isolated from healthy donor buffy coats under endotoxin-free conditions. Briefly, the buffy coats were stratified on a Ficoll-Paque PLUS gradient and centrifuged at 400 × g for 30 minutes at room temperature. Neutrophils were then collected, and erythrocytes were removed by hypotonic lysis following dextran precipitation. After centrifugation via a Percoll gradient, monocytes were isolated from PBMCs instead. Human neutrophils and monocytes were each isolated at a rate of 5 × 10⁶ 6 / ml and 2.5 × 10 6 The cells were suspended in RPMI 1640 medium supplemented with 10% low-endotoxin FBS (<0.5 EU / ml; from BioWhittaker-Lonza, Basel, Switzerland) at 1 / ml, and then plated in 24-well tissue culture plates at 37°C in the presence or absence of compounds at different concentrations (20 to 40 μM). One hour after drug treatment, monocytes were stimulated to 0.1 μg / ml, while neutrophils were stimulated to 0.1 μg / ml. E. coli Stimulation was performed with 1 μg / ml ultrapure LPS of strain O111:B4 (InvivoGen). Six hours after LPS stimulation, neutrophils and monocytes were collected and centrifuged at 300 xg for 5 minutes. The cell-free supernatant was immediately frozen at -80℃.

[1187] Cytokine concentrations in the cell-free supernatant were measured using a commercially available human-specific ELISA kit: CXCL8, IL-6, and TNF-α (Mabtech, Sweden). The detection limits of these ELISAs were 4 pg / ml for CXCL8, 10 pg / ml for IL-6, and 4 pg / ml for TNF-α.

[1188] Statistical analysis was performed by calculating the mean and standard deviation (SD); significance was calculated using an unpaired t-test. All statistical analyses were performed using GraphPad Prism 6 (GraphPad Software).

[1189] Cytokine values ​​were expressed in ng / ml for each compound, and each compound was summarized in the biodata section under the chemical characterization analysis.

[1190] Example 3.5: VEGF-165-induced phosphorylation of VEGF-receptors in primary human umbilical vein endothelial cells (HUVEC) by a compound In a test tube Suppression, method

[1191] cell culture Primary human umbilical vein endothelial cells (HUVECs) were routinely cultured for up to 6 passages in 0.1% gelatin-pre-coated flasks or dishes. The effect of the compound alone on cell viability at different concentrations (0, 1.25, 2.5, 5, 10, and 20 μM) was evaluated using the CCK-8 kit with a Tecan Microplate Reader (Genios). To measure the effect of the compound on VEGF-induced cell viability, HUVECs (1 × 10⁶) were cultured for 24 and 48 hours in serum and growth factor-free culture medium (starvation medium). 4 Cells / well were treated with VEGF (25 ng / ml) pre-mixed with compounds at various concentrations (0, 1.25, 2.5, 5, 10, and 20 μM). Compounds in this concentration range did not affect cell viability.

[1192] Rabbit primary antibodies against VEGFR-2, p-Tyr1175 were purchased from Cell Signaling Technology (Leiden, Netherlands). Phospho-VEGFR-2 (Tyr1175) Sandwich ELISA kits were purchased from Cell Signaling Technology.

[1193] HUVECs were pre-incubated with compounds at concentrations of 0, 0.16, 0.31, 0.63, 1.25, 2.5, 5, 10, and 20 μM for 60 minutes with three subsequent washing steps in warm medium before stimulating with VEGF165 (25 ng / mL) for 2 minutes. Western blot analysis was performed using anti-phospho-VEGFR-2 antibodies, and total VEGFR-2 was used as a loading control after membrane stripping.

[1194] The inhibition of VEGFR-2 phosphorylation results was expressed as IC50 in microM [μM] units versus VEGF-treated HUVEC control without inhibitory compounds.

[1195] For each compound, the respective IC50 expressed in [μM] values ​​is summarized in the biodata section under the chemical characterization analysis below each compound.

[1196] Example 3.6: by the compound after LPS induction in human whole blood In a test tube Inhibition of cytokine release

[1197] this In a test tube The purpose of the method is to evaluate the effect of the compound on the release of a cytokine panel from whole blood following a lipopolysaccharide (LPS)-induced inflammatory response. Whole blood was incubated with the compound for 1 hour prior to LPS induction. Cytokine levels in the blood were measured using a multiplex FACS-based panel.

[1198] The determined IC50 values ​​and cytokine inhibition values ​​for test compounds expressed in microM [μM] are listed for each compound.

[1199] The effect on cytokine release after LPS induction was performed on compounds dissolved in DMSO or H2O to reach a 10-fold concentrated stock solution and dissolved in culture medium.

[1200] Test system Whole blood was removed from a single donor (into a lithium heparin-coated tube; BD Vacutainer; 367886) and diluted 1:5 with RPMI 1640 (Thermo Fisher, 61870036). Within 30 minutes of sampling, the blood was incubated with the compound for 1 hour prior to LPS stimulation (O111:B4 - Sigma L4391; final concentration of 10 ng / ml). Stimulation was continued overnight (18 hours) under standard cell culture conditions (37°C, 5% CO2), after which the plates were centrifuged, the supernatant removed, and frozen at -80°C until use for analysis.

[1201] Dilution of the test compound : A 10× concentrated solution of each test compound (for the final analytical concentration) was prepared in a suitable solvent (DMSO or water). This 10× compound solution (10 μl) was added to 90 μl of pre-diluted whole blood (whole blood: RPMI1640, 1:5) to obtain the final analytical concentration.

[1202] Test method : Pre-incubate diluted whole blood (80 μl) with compound (10 μl) to obtain 100, 30, 10, 3, 1, 0.3, and 0.1 × 10⁻⁶ -6 The final analytical concentration of M was obtained. Blood was incubated at 37°C with 5% CO2 for 1 hour. LPS was diluted to a concentration of 110 ng / ml in cell culture medium; 10 μl was added to whole blood to achieve a final concentration of 10 ng / ml. The plates were incubated at 37°C for 18 hours. The plates were centrifuged at 3,000 RPM for 5 minutes at 4°C, the supernatant was removed, and the plates were frozen at -80°C until FACS analysis was performed.

[1203] Cytokine release was measured using a custom multiplex system (ELISA Genie) according to the manufacturer's instructions. The prepared samples were run on an Attune NxT flow cytometer (Thermo Fisher).

[1204] Quantification of cytokine release inhibition The concentration of each cytokine in each sample was quantified by running known concentration standards as part of the cytokine panel. This was performed using FCAP Array v3.0 software. For IC50 measurements, the raw data was converted into a percentage of concentration relative to a solvent control set to 100%. The IC50 values ​​were determined using GraphPad Prism 8 software, which uses non-linear regression curve fitting with a variable hill slope, constraining the bottom to 0 and the top to 100.

[1205] result The dose-response relationship regarding cytokine release following LPS induction of inflammatory response in whole blood was evaluated for all compounds. IC50 values ​​were determined for each compound in the cytokine panel (GM-CSF, IFN-gamma, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12p40, IL-13, IL-17A, IL-17F, IL-18, IL-21, IL-22, IL-33, TGF-beta, TNF-alpha, TNF-beta).

[1206] For each compound, the cytokine IC50 expressed in [μM] values ​​is summarized in the biodata section and Table 13 under the chemical characterization analysis of each compound.

[1207] Example 4: Compound formulation

[1208] Example 4.1: Oral formulation of compound Ic-007a

[1209] Five formulations were developed and their suitability was reviewed. These were suspensions and solutions, the details of which are shown in the following table.

[1210] Formulation details for suspension and solution of compound Ic-007a. Suspension A Solution D Solution A Solution B Solution C ingredient sheep (%) API 1% w / v (10 mg / mL) 0.1% w / v (1 mg / mL) 1% w / v (10 mg / mL) 1% w / v (10 mg / mL) 1% w / v (10 mg / mL) DMSO 5% v / v 5% v / v 5% v / v 5% v / v 5% v / v PEG 400 10% v / v 10% v / v 10% v / v 10% v / v 10% v / v Solutol HS15 10% w / v 10% w / v 10% w / v 10% w / v 10% w / v Sodium Hydroxide 1M n / a n / a With pH 6 pH 8 pH 9 water Up to 100% Up to 100% Up to 100% Up to 100% Up to 100%

[1211] Preparation: Suspension A and Solution D:

[1212] Example of method for 100 mL (scaled appropriately according to the required final volume). A solvent stock solution was prepared by measuring 5 mL of DMSO in a clean container. An accurate amount of compound Ic-007a was weighed and gradually added to the DMSO solution while mixing in a shaker, vortex, or ultrasonic grinder. Solutol was melted in a clean, dry container in a 60°C water bath. As the solutol solidified at room temperature, the molten solutol was stored in a 60°C water bath during formulation preparation. 10 g (10% w / v) of molten solutol was added to a heated container with a suitable label (to a final volume of 100 mL). 10 mL of PEG 400 was added to the solutol in the heated 100 mL container. A DMSO drug stock solution was added to the mixture of solutol and PEG400, and the contents were mixed immediately. Then, 35 mL of deionized water was added, and the mixture was stirred in a 40°C bath with intermittent vortexing to dissolve large particles. The formulation was cooled to room temperature and adjusted to a final volume of 100 mL with deionized water.

[1213] Preparation of Solutions A, B & C:

[1214] Example of method for 100 mL (scaled appropriately according to the required final volume). A solvent stock solution was prepared by weighing out 5 mL of DMSO in a clean container. 1 g of compound Ic-007a was weighed and gradually added to the DMSO solution while mixing in a shaker, vortex, or ultrasonic grinder if necessary. Solutol was melted in a clean, dry container in a 60°C water bath. As the solutol solidified at room temperature, the molten solutol was stored in a 60°C water bath during formulation preparation. 10 g (10% w / v) of molten solutol was weighed into a heated container with a suitable label (up to a final volume of 100 mL). 10 mL of PEG 400 was added to the solutol in the heated 100 mL container. The DMSO drug stock solution was added to the container with the solutol and PEG 400 mixture, and the contents were mixed immediately. 35 mL of deionized water was added, the contents were mixed, and the mixture was placed in a 40°C bath with intermittent vortexing to dissolve large particles. The formulation was cooled to room temperature, and the formulation was further adjusted to pH 6, 7, 8, and 9 using a 1 M sodium hydroxide (NaOH) solution. The initial formulation was prepared in a 1 mL scale with a starting pH of 4.3. To achieve pH 6 (Solution A), 3 μL of 1 M NaOH was added, while 22 μL was added for pH 8 (Solution B) and 43 μL for pH 9 (Solution C). These formulations were administered immediately after preparation.

[1215] The 10 mg / mL suspension formulation and the 1 mg / mL solution formulation were found to be physically stable over 2 weeks under ambient conditions.

[1216] Example 4.2: Oral formulation of compound Ia-001a-Tz

[1217] Compound Ia-001a-Tz was prepared as a 10 mg / mL oral solution in a formulation having the vehicle composition shown in the table below.

[1218] The vehicle was a carrier or inert medium used as a solvent (or diluent) in which the pharmaceutical active agent is formulated and / or administered.

[1219] [Table 22] Formulation details for the oral formulation of compound Ia-001aTz.

[1220] Vehicle furtherance A 40% PEG400, 10% transcutol, 10% solutol HS15, 40% Type 1 water B 40% aqueous solution containing 40% PEG400, 10% Transcutol, 10% Solutol HS15, and 0.5% HPMC 606 C 40% aqueous solution containing 40% PEG400, 10% Transcutol, 10% Solutol HS15, and 0.5% Kollidon VA 64 D 40% PEG400, 10% Transcutol, 10% Cremopore RH40, 40% Type 1 Water E 40% PEG400, 10% Transcutol, 10% Vitamin E TPGS, 40% Type 1 water F 40% PEG400, 10% Transcutol, 5% Solutol HS15, 45% Type 1 water G 45% aqueous solution containing 40% PEG400, 10% Transcutol, 5% Solutol HS15, and 1% Colidone VA 64

[1221] manufacturing method

[1222] To prepare a 10 mg / g solution, 10 mg of compound was accurately weighed into a vial, 1 ml of vehicle was added directly to API, and the solution was obtained by vortexing.

[1223] Vehicle manufacturing

[1224] Formulation A: 4 g of PEG400 was weighed to prepare 10 g of vehicle in a clean 20 mL glass container. 1 g of transcutol was added, and the ingredients were mixed by stirring. 1 g of solutol HS15 was added to this, followed by 4 g of Type 1 water. The mixture was stirred at room temperature for 1 hour to dissolve all ingredients.

[1225] Formulation B: 4 g of PEG400 was weighed to prepare 10 g of vehicle in a clean 20 mL glass container. 1 g of Transcutol was added, and the components were mixed by stirring. 1 g of Solutol HS15 was added to this. 50 mg of HPMC 606 was weighed into a clean glass vial to prepare a...

Claims

Claim 1 Substituted hydroquinone of chemical formula (I): (I) In the above formula: R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) n CO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, or C1-C6 alkoxycarbonyloxy-1-ethyl; R1= COOR4, (CH2) n COOR4, SO3H, (CH2) n SO3H, or CONH-R 10 And; R2 and R3 are H or R5, provided that if one of R2 and R3 is R5, the other is H, and if one of R2 and R3 is H, the other is R5, and R4 = H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R5= R6, R7 or R8; R6= CONH-R9, CONHCOR9, CONH(CH2) n -R9, or CONHCH(COOR4)(CH2) k R9 and; where k = 0 to 4 and; R7= COOR4, (CH2) n COOR4, SO3H, (CH2) n It is a benzoheteroaryl substituted with at least one group selected from SO3H, OR4, 5-membered N-containing heterocyclic rings, or fluorine; R8= (CH2) m X(CH2) p R9 and; X = O, S, SO2, NH, NAc or N(CH2) q R9 and;R9= COOR4, (CH2) n COOR4, (CH2) n SO3H, OR4, SO3H, 5-membered N-containing heterocyclic, C=O, or NHCO-R 10 An aryl substituted with at least one group selected from; or COOR4, (CH2) n COOR4, (CH2) n SO3H, OR4, SO3H, 5-membered N-containing heterocyclic ring, fluorine, C=O, or NHCO-R 10 It is a heteroaryl substituted with at least one group selected from; R 10 = COOR4, (CH2) n COOR4, (CH2) n It is an aryl or heteroaryl substituted with at least one group selected from SO3H, OR4, SO3H, 5-membered N-containing heterocyclic ring, and fluorine; where R9 and R 10 The aryl group is an aromatic group containing 6 to 14 carbon atoms selected from phenyl, naphthyl, and biphenyl groups; and R9 and R 10 The heteroaryl group is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen; n, m, p and q are independently 1 to 4. Claim 2 In paragraph 1, the compound of chemical formula (I) is: In the above formula: R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) n CO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, or C1-C6 alkoxycarbonyloxy-1-ethyl; R1= COOR4, (CH2) n COOR4, SO3H, (CH2) n SO3H, or CONH-R 10 And; R2 and R3 are H or R5, provided that if one of R2 and R3 is R5, the other is H, and if one of R2 and R3 is H, the other is R5, and R4 = H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R5= R6, or R7, and R6= CONH-R9, CONHCOR9, CONH(CH2) n -R9, or CONHCH(COOR4)(CH2) k R9 and; where k = 0 to 4 and; R7= COOR4, (CH2) n COOR4, SO3H, (CH2) n It is a benzoheteroaryl substituted with at least one group selected from SO3H, OR4, 5-membered N-containing heterocyclic rings, or fluorine; R9= COOR4, (CH2) n COOR4, (CH2) n SO3H, OR4, SO3H, 5-membered N-containing heterocyclic, C=O, or NHCO-R 10 An aryl substituted with at least one group selected from; or COOR4, (CH2) n COOR4, (CH2) n SO3H, OR4, SO3H, 5-membered N-containing heterocyclic ring, fluorine, C=O, or NHCO-R 10 It is a heteroaryl substituted with at least one group selected from; R 10 = COOR4, (CH2) n COOR4, (CH2) n It is an aryl or heteroaryl substituted with at least one group selected from SO3H, OR4, SO3H, a 5-membered N-containing heterocyclic ring, or fluorine; where R9 and R 10 The aryl group is an aromatic group containing 6 to 14 carbon atoms selected from phenyl, naphthyl, and biphenyl; and R9 and R 10 A compound of formula (I), wherein the heteroaryl group is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen; and n is independently 1 to 4. Claim 3 In paragraph 2, the above compound is: (A)R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) n CO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6acyloxymethyl, C1-C6acyloxy-1-ethyl, C1-C6alkoxycarbonyloxymethyl, or C1-C6alkoxycarbonyloxy-1-ethyl; R1= COOR4; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R2= H; R3= R5; R5= R6= CONH-R9 or; (B)R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) n CO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6acyloxymethyl, C1-C6acyloxy-1-ethyl, C1-C6alkoxycarbonyloxymethyl, or C1-C6alkoxycarbonyloxy-1-ethyl; R1= COOR4; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R3= H; R2= R5 and R5= R6= CONH-R9 or the above The compounds are: 4-(2-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 4-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 2,5-dihydroxy-4-(2-sulfophenylaminocarbonyl)benzoic acid; 4-(3-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 4-(3-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 2,5-dihydroxy-4-(3-sulfophenylaminocarbonyl)benzoic acid; 4-(4-carboxyphenyl 4-(4-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 2,5-dihydroxy-4-(4-sulfophenylaminocarbonyl)benzoic acid; 4-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 4-(4-carboxy-3-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 4-(4-carboxy-2,5-dihydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 4-(2-carboxy- 4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 3,5-bis(2,5-dihydroxy-4-carboxybenzoylamino)benzoic acid; 3-(4-carboxy-2,5-dihydroxybenzamido)phthalic acid; 2-(4-carboxy-2,5-dihydroxybenzamido)terephthalic acid; 2-(4-carboxy-2,5-dihydroxybenzamido)isophthalic acid; 4-(4-carboxy-2,5-dihydroxybenzamido)phthalic acid; 5-(4-carboxy-2,5-dihydroxybenzamido)isophthalic acid; 2-(4-carboxy-2, 5-Dihydroxybenzamido)nicotinic acid; 2-(4-carboxy-2,5-dihydroxybenzamido)isonicotinic acid; 6-(4-carboxy-2,5-dihydroxybenzamido)nicotinic acid; 6-(4-carboxy-2,5-dihydroxybenzamido)picolinic acid; 2-(4-carboxy-2,5-dihydroxybenzamido)-5-fluoronicotinic acid; 6-(4-carboxy-2,5-dihydroxybenzamido)pyridine-2,5-dicarboxylic acid; 2-(4-carboxy-2,5-dihydroxybenzamido)pyridine-3,5-dicarboxylic acid;3-(4-carboxy-2,5-dihydroxybenzamido)isonicotinic acid; 5-(4-carboxy-2,5-dihydroxybenzamido)nicotinic acid; 5-(4-carboxy-2,5-dihydroxybenzamido)picolinic acid; 3-(4-carboxy-2,5-dihydroxybenzamido)picolinic acid; 5-(4-carboxy-2,5-dihydroxybenzamido)-2-fluoroisonicotinic acid; 4-(4-carboxy-2,5-dihydroxybenzamido)nicotinic acid ;4-(4-carboxy-2,5-dihydroxybenzamido)picolinic acid; 4-(4-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 4-(3-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 2,5-dihydroxy-4-(3-(1-hydroxy-1H-pyrazole-4-yl)phenylaminocarbonyl)benzoic acid; 4-(2-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid; ethyl 4-(2-(ethoxycarbonyl)phenylaminocarbonyl)-2,5-diacetoxybenzoate; ethyl 4-(2-(ethoxycarbonyl)phenylaminocarbonyl)-2,5-dihydroxybenzoate; ethyl 4-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-diacetoxybenzoate; ethyl 4-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoate; Ethyl 2,5-dihydroxy-4-(4-hydroxy-3-(methoxycarbonyl)phenylaminocarbonyl)benzoate; ethyl 3,5-bis(2,5-diacetoxy-4-ethoxycarbonylbenzoylamino)benzoate; ethyl 3,5-bis(2,5-dihydroxy-4-ethoxycarbonylbenzoylamino)benzoate; ethyl 3-(4-(ethoxycarbonyl)-2,5-dihydroxybenzamido)isonicotinate; ethyl 4-(4-ethoxycarbonyl-2,5-dihydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoate; 3-(2-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 3-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 2,5-dihydroxy-3-(2-sulfophenylamino Carbonyl)benzoic acid; 3-(3-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 3-(3-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 2,5-dihydroxy-3-(3-sulfophenylaminocarbonyl)benzoic acid; 3-(4-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid;3-(4-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 2,5-dihydroxy-3-(4-sulfophenylaminocarbonyl)benzoic acid; 3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 3-(4-carboxy-3-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 3-(2-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 3,5-bis(2,5-dihydroxy-3-carboxybenzoylamino)benzoic acid; 3-(3-carboxy-2,5-dihydroxybenzoa Mido)phthalic acid; 2-(3-carboxy-2,5-dihydroxybenzamido)terephthalic acid; 2-(3-carboxy-2,5-dihydroxybenzamido)isophthalic acid; 4-(3-carboxy-2,5-dihydroxybenzamido)phthalic acid; 5-(3-carboxy-2,5-dihydroxybenzamido)isophthalic acid; 2-(3-carboxy-2,5-dihydroxybenzamido)nicotinic acid; 2-(3-carboxy-2,5-dihydroxybenzamido)isonicotinic acid; 6-(3-carboxy-2,5-dihydroxybenzamido)nicotinic acid; 6-(3-carboxy-2,5-dihydroxybenzamido)picol Phosphoric acid; 2-(3-carboxy-2,5-dihydroxybenzamido)-5-fluoronicotinic acid; 6-(3-carboxy-2,5-dihydroxybenzamido)pyridine-2,5-dicarboxylic acid; 2-(3-carboxy-2,5-dihydroxybenzamido)pyridine-3,5-dicarboxylic acid; 3-(3-carboxy-2,5-dihydroxybenzamido)isonicotinic acid; 5-(3-carboxy-2,5-dihydroxybenzamido)nicotinic acid; 5-(3-carboxy-2,5-dihydroxybenzamido)picolinic acid; 3-(3-carboxy-2,5-dihydroxybenzamido)picolinic acid 5-(3-carboxy -2,5-dihydroxybenzamido)-2-fluoroisonicotinic acid; 4-(3-carboxy-2,5-dihydroxybenzamido)nicotinic acid; 4-(3-carboxy-2,5-dihydroxybenzamido)picolinic acid; 3-(4-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 3-(3-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 2,5-dihydroxy-3-(3-(1-hydroxy-1H-pyrazole-4-yl)phenylaminocarbonyl)benzoic acid; 3-(2-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid;A compound selected from the group consisting of ethyl 3-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoate; and ethyl 3-(2-(ethoxycarbonylmethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoate.; Claim 4 In paragraph 2, the above compound is: (A)R a , R b = H and; R1= SO3H and; R2= H and; R3= R5 and; R5= R6= CONH-R9 or; (B)R a , R b = H and; R1= SO3H and; R3= H and; R2= R5 and; R5= R6= CONH-R9 or the above The compounds are: 2-(2,5-dihydroxy-4-sulfobenzamido)benzoic acid; 2,5-dihydroxy-4-(2-sulfophenylaminocarbonyl)benzenesulfonic acid; 3-(2,5-dihydroxy-4-sulfobenzamido)benzoic acid; 2,5-dihydroxy-4-(3-sulfophenylaminocarbonyl)benzenesulfonic acid; 4-(2,5-dihydroxy-4-sulfobenzamido)benzoic acid; 2,5-dihydroxy-4-(4-sulfophenylaminocarbonyl)benzenesulfonic acid; 5-(2,5-dihydroxy-4-sulfobenzamido)-2-hydroxybenzoic acid; 4-(2,5-dihydroxy- 4-sulfobenzamido)-2-hydroxybenzoic acid; 2-(2,5-dihydroxy-4-sulfobenzamido)-5-hydroxybenzoic acid; 3,5-bis(2,5-dihydroxy-4-sulfobenzamido)benzoic acid; 3-(2,5-dihydroxy-4-sulfobenzamido)phthalic acid; 2-(2,5-dihydroxy-4-sulfobenzamido)terephthalic acid; 2-(2,5-dihydroxy-4-sulfobenzamido)isophthalic acid; 4-(2,5-dihydroxy-4-sulfobenzamido)phthalic acid; 5-(2,5-dihydroxy-4-sulfobenzamido)isophthalic acid; 2-( 2,5-Dihydroxy-4-sulfobenzamido)nicotinic acid; 2-(2,5-Dihydroxy-4-sulfobenzamido)isonicotinic acid; 6-(2,5-Dihydroxy-4-sulfobenzamido)nicotinic acid; 6-(2,5-Dihydroxy-4-sulfobenzamido)picolinic acid; 2-(2,5-Dihydroxy-4-sulfobenzamido)-5-fluoronicotinic acid; 6-(2,5-Dihydroxy-4-sulfobenzamido)pyridine-2,5-dicarboxylic acid; 2-(2,5-Dihydroxy-4-sulfobenzamido)pyridine-3,5-dicarboxylic acid; 3-(2,5-Dih Droxy-4-sulfobenzamido)isonicotinic acid; 5-(2,5-dihydroxy-4-sulfobenzamido)nicotinic acid; 5-(2,5-dihydroxy-4-sulfobenzamido)picolinic acid; 3-(2,5-dihydroxy-4-sulfobenzamido)picolinic acid; 5-(2,5-dihydroxy-4-sulfobenzamido)-2-fluoroisonicotinic acid; 4-(2,5-dihydroxy-4-sulfobenzamido)nicotinic acid; 4-(2,5-dihydroxy-4-sulfobenzamido)picolinic acid; (4-(2,5-dihydroxy-4-sulfobenzamido)phenyl)acetic acid;(3-(2,5-dihydroxy-4-sulfobenzamido)phenyl)acetic acid; (2-(2,5-dihydroxy-4-sulfobenzamido)phenyl)acetic acid; 2-(2,5-dihydroxy-3-sulfobenzamido)benzoic acid; 2,5-dihydroxy-3-(2-sulfophenylaminocarbonyl)benzenesulfonic acid; 3-(2,5-dihydroxy-3-sulfobenzamido)benzoic acid; 2,5-dihydroxy-3-(3-sulfophenylaminocarbonyl)benzenesulfonic acid; 4-(2,5-dihydroxy-3-sulfobenzamido)benzoic acid; 2,5-dihydroxy-3-(4-sulfophenylaminocarbonyl)benzenesulfonic acid; 5-(2,5-di hydroxy-3-sulfobenzamido)-2-hydroxybenzoic acid; 4-(2,5-dihydroxy-3-sulfobenzamido)-2-hydroxybenzoic acid; 2-(2,5-dihydroxy-3-sulfobenzamido)-5-hydroxybenzoic acid; 3-(2,5-dihydroxy-3-sulfobenzamido)-5-(2,5 -Dihydroxy-4-sulfobenzamido)benzoic acid 3-(2,5-dihydroxy-3-sulfobenzamido)phthalic acid; 2-(2,5-dihydroxy-3-sulfobenzamido)terephthalic acid; 2-(2,5-dihydroxy-3-sulfobenzamido)isophthalic acid; 4-(2,5-dihydroxy-3-sulfobenza 5-(2,5-dihydroxy-3-sulfobenzamido)isophthalic acid; 2-(2,5-dihydroxy-3-sulfobenzamido)nicotinic acid; 2-(2,5-dihydroxy-3-sulfobenzamido)isonicotinic acid; 6-(2,5-dihydroxy-3-sulfobenzamido)nicotinic acid; 6-(2,5-dihydroxy-3-sulfobenzamido)picolinic acid; 2-(2,5-dihydroxy-3-sulfobenzamido)-5-fluoronicotinic acid; 6-(2,5-dihydroxy-3-sulfobenzamido)pyridine-2,5-dicarboxylic acid; 2-(2,5-dihydroxy-3-sulfobenzamido)pyridine- 3,5-Dicarboxylic acid; 3-(2,5-Dihydroxy-3-sulfobenzamido)isonicotinic acid; 5-(2,5-Dihydroxy-3-sulfobenzamido)nicotinic acid; 5-(2,5-Dihydroxy-3-sulfobenzamido)picolinic acid; 3-(2,5-Dihydroxy-3-sulfobenzamido)picolinic acid; 5-(2,5-Dihydroxy-3-sulfobenzamido)-2-fluoroisonicotinic acid; 4-(2,5-Dihydroxy-3-sulfobenzamido)nicotinic acid; 4-(2,5-Dihydroxy-3-sulfobenzamido)picolinic acid; (4-(2,5-Dihydroxy-3-sulfobenzamido)phenyl)acetic acid;(3-(2,5-dihydroxy-3-sulfobenzamido)phenyl)acetic acid; and (2-(2,5-dihydroxy-3-sulfobenzamido)phenyl)acetic acid, a compound selected from the group consisting of (2-(2,5-dihydroxy-3-sulfobenzamido)phenyl)acetic acid.; Claim 5 In paragraph 2, the above compound is: (A)R a , R b = H and R1= (CH2) n COOR4 and; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R2= H or R5, R3= R5; R5= R6= CONH-R9 or; (B)R a , R b = H and;R1= (CH2) n COOR4; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R3= H; R2= R5; R5= R6= CONH-R9 or the above The compounds are: 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)benzoic acid; (2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid; (2,5-dihydroxy-4-(2-sulfophenylaminocarbonyl)phenyl)acetic acid; 3-(4-(carboxymethyl)-2,5-dihydroxybenzamido)benzoic acid; (2,5-dihydroxy-4-(3-sulfophenylaminocarbonyl)phenyl)acetic acid; 4-(4-(carboxymethyl)-2,5-dihydroxybenzamido)benzoic acid; 2 -(2,5-dihydroxy-4-(4-sulfophenylaminocarbonyl)phenyl)acetic acid; 5-(4-(carboxymethyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid; 4-(4-(carboxymethyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid; 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)-5-hydroxybenzoic acid; 3,5-bis(2,5-dihydroxy-4-carboxymethylbenzoylamino)benzoic acid 3-(4-(carboxymethyl)-2,5-dihydroxybenzamido) Phthalic acid; 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)terephthalic acid; 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)isophthalic acid; 4-(4-(carboxymethyl)-2,5-dihydroxybenzamido)phthalic acid; 5-(4-(carboxymethyl)-2,5-dihydroxybenzamido)isophthalic acid; 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)nicotinic acid; 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)isonicotinic acid; 6-(4-(carboxy methyl)-2,5-dihydroxybenzamido)nicotinic acid; 6-(4-(carboxymethyl)-2,5-dihydroxybenzamido)picolinic acid; 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)-5-fluoronicotinic acid; 6-(4-(carboxymethyl)-2,5-dihydroxybenzamido)pyridine-2,5-dicarboxylic acid; 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)pyridine-3,5-dicarboxylic acid; 3-(4-(carboxymethyl)-2,5-dihydroxybenzamido)isonicotinic acid;5-(4-(carboxymethyl)-2,5-dihydroxybenzamido)nicotinic acid; 5-(4-(carboxymethyl)-2,5-dihydroxybenzamido)picolinic acid; 3-(4-(carboxymethyl)-2,5-dihydroxybenzamido)picolinic acid; 5-(4-(carboxymethyl)-2,5-dihydroxybenzamido)-2-fluoroisonicotinic acid; 4-(4-(carboxymethyl)-2,5-dih Droxybenzamido)nicotinic acid; 4-(4-(carboxymethyl)-2,5-dihydroxybenzamido)picolinic acid; (4-(4-(carboxymethyl)-2,5-dihydroxybenzamido)phenyl)acetic acid; (3-(4-(carboxymethyl)-2,5-dihydroxybenzamido)phenyl)acetic acid; (2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)phenyl)acetic acid; methyl 2-(4-(ethoxycarbonylmethyl)-2,5-dihydroxybenzamido)benzoate; ethyl (4-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxyphenyl)acetate; Diethyl 5-(4-(ethoxycarbonylmethyl)-2,5-dihydroxybenzamido)isophthalate; methyl 3,5-Bis(4-(ethoxycarbonylmethyl)-2,5-dihydroxybenzamido)benzoate; 2-(3-(carboxymethyl)-2,5-dihydroxybenzamido)benzoic acid; (2,5-dihydroxy-3-(2-sulfophenylaminocarbonyl)phenyl)acetic acid; 3-(3-(carboxymethyl)-2,5-dihydroxybenzamido)benzoic acid; (2,5-dihydroxy-3-(3-sulfophenylaminocarbonyl)phenyl)acetic acid; 4-(3-(carboxymethyl)-2,5-dihydroxybenzamido)benzoic acid; (2,5-dihydroxy-3-(4-sulfophenylaminocarbonyl)phenyl)acetic acid; 5-(3-(carboxymethyl)-2,5-dihydroxy 4-(3-(carboxymethyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid; 2-(3-(carboxymethyl)-2,5-dihydroxybenzamido)-5-hydroxybenzoic acid; 3,5-bis(2,5-dihydroxy-3-carboxymethylbenzoylamino)benzoic acid 3-(3-(carboxymethyl)-2,5-dihydroxybenzamido)phthalic acid; 2-(3-(carboxymethyl)-2,5-dihydroxybenzamido)terephthalic acid; 2-(3-(carboxymethyl)-2,5-dihydroxybenzamido)isophthalic acid; 4-(3-(carboxymethyl)-2,5-dihydroxybenzamido)phthalic acid;5-(3-(carboxymethyl)-2,5-dihydroxybenzamido)isophthalic acid; 2-(3-(carboxymethyl)-2,5-dihydroxybenzamido)nicotinic acid; 2-(3-(carboxymethyl)-2,5-dihydroxybenzamido)isonicotinic acid; 6-(3-(carboxymethyl)-2,5-dihydroxybenzamido)nicotinic acid; 6-(3-(carboxymethyl)-2,5- dihydroxybenzamido)picolinic acid; 2-(3-(carboxymethyl)-2,5-dihydroxybenzamido)-5-fluoronicotinic acid; 6-(3-(carboxymethyl)-2,5-dihydroxybenzamido)pyridine-2,5-dicarboxylic acid; 2-(3-(carboxymethyl)-2,5-dihydroxybenzamido)pyridine-3,5-dicarboxylic acid; 3-(3-(carboxymethyl) -2,5-dihydroxybenzamido)isonicotinic acid; 5-(3-(carboxymethyl)-2,5-dihydroxybenzamido)nicotinic acid; 5-(3-(carboxymethyl)-2,5-dihydroxybenzamido)picolinic acid; 3-(3-(carboxymethyl)-2,5-dihydroxybenzamido)picolinic acid; 5-(3-(carboxymethyl)-2,5-dihydroxybenzamido)-2 A compound selected from the group consisting of -fluoroisonicotinic acid; 4-(3-(carboxymethyl)-2,5-dihydroxybenzamido)nicotinic acid; 4-(3-(carboxymethyl)-2,5-dihydroxybenzamido)picolinic acid; (4-(3-(carboxymethyl)-2,5-dihydroxybenzamido)phenyl)acetic acid; (3-(3-(carboxymethyl)-2,5-dihydroxybenzamido)phenyl)acetic acid; and (2-(3-(carboxymethyl)-2,5-dihydroxybenzamido)phenyl)acetic acid.; Claim 6 In paragraph 2, the above compound is: (A)R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) n CO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, or C1-C6 alkoxycarbonyloxy-1-ethyl; and R1 = CONH - R 10 And; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R2= H; R3= R5; R5= R6= CONH-R9 or; (B)R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) n CO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, or C1-C6 alkoxycarbonyloxy-1-ethyl, and R1 = CONH-R 10 And; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R3= H; R2= R5; R5= R6= CONH-R9 or. The above compound is: 5-(4-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid; N1,N 4- Bis(2-(1H-tetrazole-5-yl)phenyl)-2,5-dihydroxyterephthalamide; 5-(4-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid; 5-(2,5-dihydroxy-4-(4-hydroxy-3-sulfophenylaminocarbonyl)benzamido)-2-hydroxybenzenesulfonic acid; 4-(4-(4-carboxy-3-hydroxyphenylaminocarbonyl)-2,5-di hydroxybenzamido)-2-hydroxybenzoic acid; 4-(2,5-dihydroxy-4-(3-hydroxy-4-sulfophenylaminocarbonyl)benzamido)-2-hydroxybenzenesulfonic acid; 2-(2,5-dihydroxy-4-(4-hydroxy-2-carboxyphenylaminocarbonyl)benzamido)-5-hydroxybenzoic acid; 2-(2,5-dihydroxy-4-(4-hydroxy-2-sulfophenylaminocarbonyl)benzamido)-5-hydroxybenzene Sulfonic acid; methyl 5-(4-(2-(1H-tetrazole-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoate; methyl 5-(2,5-diacetoxy-4-(4-acetoxy-3-(methoxycarbonyl)phenylaminocarbonyl)benzamido)-2-acetoxybenzoate; methyl 5-(2,5-dihydroxy-4-(4-hydroxy-3-(methoxycarbonyl)phenylaminocarbonyl)benzamido)-2-hydroxybenzoate; methyl 2-(2,5-dihydroxy-4-(4-hydroxy-2-(methoxycarbonyl)phenylaminocarbonyl)benzamido)-5-hydroxybenzoate; 1-(2,2-dimethylpropaneoiloxy)ethyl 5-[[4-[[3-[1-(2,2-dimethylpropaneoiloxy)ethoxycarbonyl]-4-hydroxy-phenyl]aminocarbonyl]-2,5-dihydroxy-benzoyl]amino]-2-hydroxybenzoate 5-(3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid; 5-(2,5-dihydroxy-3-(4-hydroxy-3-sulfophenylaminocarbonyl)benza Mido)-2-hydroxybenzenesulfonic acid; 4-(3-(3-hydroxy-4-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid; 4-(2,5-dihydroxy-3-(3-hydroxy-4-sulfophenylaminocarbonyl)benzamido)-2-hydroxybenzenesulfonic acid; 2-(3-(2-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-5-hydroxybenzoic acid;A compound selected from the group consisting of and 2-(2,5-dihydroxy-3-(4-hydroxy-2-sulfophenylaminocarbonyl)benzamido)-5-hydroxybenzenesulfonic acid.; Claim 7 In paragraph 2, the compound comprises the following chemical formula (I): In the above chemical formula, R a , R b = H; R1= CONH-R 10 ;R 10 = phenyl substituted with COOR4 and OR4; R2= H; R3= CONH-R9; R9= phenyl substituted with COOR4 and OR4; R4= H; and the compound is 5-(4-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid. Claim 8 In paragraph 2, the compound comprises the following chemical formula (I): In the above chemical formula, R a , R b = H; R1= CONH-R 10 ;R 10 = phenyl substituted with COOR4 and OR4; R2= CONH-R9; R3= H; R9= phenyl substituted with COOR4 and OR4; R4= H; and the compound is 5-(3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid. Claim 9 In paragraph 2, the above compound is: (A)R a , R b = H and; R1 = COOR4; (CH2) n COOR4 and; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R2= H; R3= R5; R5= R6= CONHCOR9 or; (B)R a , R b = H and;R 1 = COOR4; (CH2) n COOR4 and; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R3= H; R2= R5 and; R5= R6= CONHCOR9 or; the above compounds are: N-(1,3,4,5-tetrahydroxycyclohexylcarbonyl) 4-carboxy-2,5-dihydroxybenzamide; N-(4-carboxy-2,5-dihydroxybenzoyl) 4-carboxy-2,5-dihydroxy-benzamide; N-(3-carboxy-2,5-dihydroxybenzoyl) 4-carboxy-2,5-dihydroxy-benzamide; N-(3,4-dihydroxybenzoyl) 4-carboxy-2,5-dihydroxybenzamide; N-(3,5-dihydroxybenzoyl) 4-Carboxy-2,5-Dihydroxybenzamide;N-(1,3,4,5-Tetrahydroxycyclohexylcarbonyl) 3-Carboxy-2,5-Dihydroxybenzamide;N-(4-Carboxy-2,5-Dihydroxybenzoyl) 3-Carboxy-2,5-Dihydroxy-benzamide;N-(3-Carboxy-2,5-Dihydroxybenzoyl) 3-Carboxy-2,5-Dihydroxy-benzamide;N-(3,4-Dihydroxybenzoyl) 3-Carboxy-2,5-Dihydroxybenzamide;N-(3,5-Dihydroxybenzoyl) 3-Carboxy-2,5-Dihydroxybenzamide;N-(1,3,4,5-Tetrahydroxycyclohexylcarbonyl) 4-Carboxymethyl-2,5-dihydroxybenzamide;N-(4-carboxy-2,5-dihydroxybenzoyl)4-Carboxymethyl-2,5-dihydroxy-benzamide;N-(3-carboxy-2,5-dihydroxybenzoyl)4-Carboxymethyl-2,5-dihydroxy-benzamide;N-(3,4-dihydroxybenzoyl)4-Carboxymethyl-2,5-dihydroxybenzamide;N-(3,5-dihydroxybenzoyl)4-Carboxymethyl-2,5-dihydroxybenzamide;N-(1,3,4,5-tetrahydroxycyclohexylcarbonyl) 3-Carboxymethyl-2,5-dihydroxybenzamide;N-(4-carboxy-2,5-dihydroxybenzoyl)3-carboxymethyl-2,5-dihydroxy-benzamide;N-(3-carboxy-2,5-dihydroxybenzoyl)3-carboxymethyl-2,5-dihydroxy-benzamide;N-(3,4-dihydroxybenzoyl)3-carboxymethyl-2,5-dihydroxybenzamide;A compound selected from the group consisting of and N-(3,5-dihydroxybenzoyl) 3-carboxymethyl-2,5-dihydroxybenzamide.; Claim 10 In paragraph 2, the compound is: (A)R a , R b = H and;R1= COOR4; (CH2) n COOR4 and; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R2= H; R3= R5; R5= R6= CONH(CH2) n -R9 or; (B)R a , R b = H and; R1= COOR4; (CH2) n COOR4 and; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R3= H; R2= R5; R5= R6= CONH(CH2) n -R9 or; the above compounds are: 4-(3,4-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid; 4-(2-(3,4-dihydroxyphenyl)ethylaminocarbonyl)-2,5-dihydroxybenzoic acid; 4-(3,5-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid; 4-((4,5-dihydroxy-3-oxocyclohex-1-enyl)methyl aminocarbonyl)-2,5-dihydroxybenzoic acid; 2,5-dihydroxy-4-((3,4,5-trihydroxycyclohexyl)methylaminocarbonyl)benzoic acid; 4-(2-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid; 4-(3-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid; 4-(4-carboxyphenylmethylaminocarbonyl) 2,5-Dihydroxybenzoic acid; 3-(3,4-Dihydroxyphenylmethylaminocarbonyl)-2,5-Dihydroxybenzoic acid; 3-(2-(3,4-Dihydroxyphenyl)ethylaminocarbonyl)-2,5-Dihydroxybenzoic acid; 3-(3,5-Dihydroxyphenylmethylaminocarbonyl)-2,5-Dihydroxybenzoic acid; 3-((4,5-Dihydroxy-3-oxocyclohex-1-enyl)methylaminocarbonyl)- 2,5-Dihydroxybenzoic acid; 2,5-Dihydroxy-3-((3,4,5-Trihydroxycyclohexyl)methylaminocarbonyl)benzoic acid; 3-(2-Carboxyphenylmethylaminocarbonyl)-2,5-Dihydroxybenzoic acid; 3-(3-Carboxyphenylmethylaminocarbonyl)-2,5-Dihydroxybenzoic acid; 3-(4-Carboxyphenylmethylaminocarbonyl)-2,5-Dihydroxybenzoic acid; (4-(3,4-Dihydroxybenzoic acid ((3,5-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid; (4-(3,5-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid; (4-((4,5-dihydroxy-3-oxocyclohex-1-enyl)methylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid; (2,5-dihydroxy-4-((3,4,5-trihydroxycyclohexyl)methylami Nocarbonyl)phenyl)acetic acid; (4-(2-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid; (4-(3-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid; (4-(4-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid; (3-(3,4-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid;A compound selected from the group consisting of (3-(3,5-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid; (3-((4,5-dihydroxy-3-oxocyclohex-1-enyl)methylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid; (2,5-dihydroxy-3-((3,4,5-trihydroxycyclohexyl)methylcarbonylamino)phenyl)acetic acid; (3-(2-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid; (3-(3-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid; and (3-(4-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid. Claim 11 In paragraph 2, the above compound is: N-(1,3,4,5-tetrahydroxycyclohexylcarbonyl) 4-carboxy-2,5-dihydroxybenzamide; N-(1,3,4,5-tetrahydroxycyclohexylcarbonyl) 3-carboxy-2,5-dihydroxybenzamide; N-(1,3,4,5-tetrahydroxycyclohexylcarbonyl) 4-carboxymethyl-2,5-dihydroxybenzamide; N-(1,3,4,5-tetrahydroxycyclohexylcarbonyl) 3-Carboxymethyl-2,5-dihydroxybenzamide; 4-((4,5-dihydroxy-3-oxocyclohex-1-enyl)methylaminocarbonyl)-2,5-dihydroxybenzoic acid; 2,5-dihydroxy-4-((3,4,5-trihydroxycyclohexyl)methylaminocarbonyl)benzoic acid; 3-(3,5-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid; 3-((4,5-dihydroxy-3-oxocyclohex-1-enyl) A compound selected from the group consisting of methylaminocarbonyl)-2,5-dihydroxybenzoic acid; (4-((4,5-dihydroxy-3-oxocyclohex-1-enyl)methylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid; (2,5-dihydroxy-4-((3,4,5-trihydroxycyclohexyl)methylaminocarbonyl)phenyl)acetic acid; (3-((4,5-dihydroxy-3-oxocyclohex-1-enyl)methylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid; and (2,5-dihydroxy-3-((3,4,5-trihydroxycyclohexyl)methylcarbonylamino)phenyl)acetic acid. Claim 12 In paragraph 2, the compound is: R a , R b = H and; R1= SO3H and; R2= H and; R3= R5 and; R5= R6= CONH(CH2) n -R9 or; the above compound is a compound selected from the group consisting of: 2-((2,5-dihydroxy-4-sulfobenzamido)methyl)benzoic acid; 3-((2,5-dihydroxy-4-sulfobenzamido)methyl)benzoic acid; and 4-((2,5-dihydroxy-4-sulfobenzamido)methyl)benzoic acid. Claim 13 In paragraph 2, the above compound is: (A) R a , R b = H and; R1= COOR4; (CH2) n COOR4 and; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R2= H; R3= R5; R5= R6= CONHCH(COOR4)(CH2) k R9 or; (B)R a , R b = H and; R1= COOR4; (CH2) n COOR4 and; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R3= H; R2= R5; R5= R6= CONHCH(COOR4)(CH2) k R9 or; the above compound is: 4-(1-carboxy-2-(3,4-dihydroxyphenyl)ethylaminocarbonyl)-2,5-dihydroxybenzoic acid; 4-(carboxy(3,4-dihydroxyphenyl)methylaminocarbonyl)-2,5-dihydroxybenzoic acid; 3-(1-carboxy-2-(3,4-dihydroxyphenyl)ethylaminocarbonyl)-2,5-dihydroxybenzoic acid; 3-(carboxy(3,4-dihydroxyphenyl)methylaminocarbonyl)-2,5-dihydroxybenzoic acid; (4-(carboxy(3,4-dihydroxyphenyl)methylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid; A compound selected from the group consisting of and (3-(carboxy(3,4-dihydroxyphenyl)methylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid. Claim 14 In paragraph 2, the above compound is: (A)R a , R b = H and; R1= COOR4, (CH2) n COOR4, SO3H, (CH2) n SO3H, CONH-R 10 And; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R2= H; R3= R5; R5= R7= COOR4, (CH2) n COOR4, SO3H, (CH2) n Benzoheteroaryl substituted with at least one group selected from SO3H, OR4, 5-membered N-containing heterocyclic rings, or fluorine; (B)R a , R b = H and;R1= COOR4, (CH2) n COOR4, SO3H, (CH2) n SO3H, CONH-R 10 And; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R3= H; R2= R5; R5= R7= COOR4, (CH2) n COOR4, SO3H, (CH2) n Benzoheteroaryl substituted with at least one group selected from SO3H, OR4, 5-membered N-containing heterocyclic rings, or fluorine; said compound is: 2-(4-carboxy-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid; methyl 2-(4-ethoxycarbonyl-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-4-carboxylate; 2-(2,5-dihydroxy-4-sulfophenyl)-1H-benzo[d]imidazole-4-carboxylic acid; 2-(4-carboxy-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid; 2-(2,5-dihydroxy-4-sulfophenyl)-1H-benzo[d]imidazole-5-carboxylic acid; 2-(3-carboxy-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid; 2-(2,5-dihydroxy-3-sulfophenyl)-1H- Benzo[d]imidazole-4-carboxylic acid; 2-(3-carboxy-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid; 2-(2,5-dihydroxy-3-sulfophenyl)-1H-benzo[d]imidazole-5-carboxylic acid; 2-(4-(carboxymethyl)-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid; 2-(4-(carboxymethyl)-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid; 2-(3-(carboxymethyl)-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid; A compound selected from the group consisting of 2-(3-(carboxymethyl)-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid. Claim 15 In paragraph 1, the compound of chemical formula (I) is: In the above formula: R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) n CO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, or C1-C6 alkoxycarbonyloxy-1-ethyl; R1= COOR4, (CH2) n COOR4, SO3H, (CH2) n SO3H, or CONH-R 10 And; R2 and R3 are H or R5, provided that if one of R2 and R3 is R5, the other is H, and if one of R2 and R3 is H, the other is R5, and R4 = H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R5= R8 and R8= (CH2) m X(CH2) p R9 and; X = O, S, SO2, NH, NAc or N(CH2) q R9 and;R9= COOR4, (CH2) n COOR4, (CH2) n SO3H, OR4, SO3H, 5-membered N-containing heterocyclic ring, fluorine, C=O, or NHCO-R 10 It is an aryl or heteroaryl substituted with at least one group selected from; R 10 = COOR4, (CH2) n COOR4, (CH2) n It is an aryl or heteroaryl substituted with at least one group selected from SO3H, OR4, SO3H, a 5-membered N-containing heterocyclic ring, or fluorine; where R9 and R 10 The aryl group is an aromatic group containing 6 to 14 carbon atoms selected from phenyl, naphthyl, or biphenyl groups; R9 and R 10 A compound of formula (I), wherein the heteroaryl group is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen; and n, m, p and q are independently integers from 1 to 4. Claim 16 In paragraph 15, the above compound is: (A)R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) n CO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, or C1-C6 alkoxycarbonyloxy-1-ethyl; R1= COOR4, (CH2) n COOR4, SO3H, (CH2) n SO3H, CONH-R 10 And; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R2= H; R3= R5; R5= R8= (CH2) m X(CH2)pR9 and; where X = O, S, SO2, NH, NAc, or N(CH2) q R9 or;(B)R a , R b = H, C 1-4 Asil, Aril C 1-4 Alkyl, C6-C 10 ArilCO, HOOC(CH2) n CO, C1-C7alkylNHCO, phosphono, phosphonooxymethyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, or C1-C6 alkoxycarbonyloxy-1-ethyl and; R1 = COOR4, (CH2) n COOR4, SO3H, (CH2) n SO3H, CONH-R 10 And; R4= H, C 1-4 Alkyl, Aryl C 1-4 Functionalized C1-C6 alkyls including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, and N-methylpiperazino-C1-C6 alkyl, o C6-C containing -methoxyphenyl (guaiacol ester) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, or (oxodioxolyl)methyl; R3= H; R2= R5; R5= R8= (CH2) m X(CH2) p R9 and; where X = O, S, SO2, NH, NAc, or N(CH2) q R9 or; the above compound is: bis(4-carboxy-2,5-dihydroxyphenylmethyl)amine; 4-((2,5-dihydroxy-4-sulfophenylmethylamino)methyl)-2,5-dihydroxybenzoic acid; 4-((2,5-dihydroxy-3-sulfophenylmethylamino)methyl)-2,5-dihydroxybenzoic acid; bis(2,5-dihydroxy-4-sulfophenylmethyl)amine; N,N-bis(4-carboxy-2,5-dihydroxyphenylmethyl)acetamide; N-(2,5-dihydroxy-4-sulfophenylmethyl) N-(4-carboxy-2,5-dihydroxyphenylmethyl)acetamide; N-(2,5-dihydroxy-3-sulfophenylmethyl) N-(4-carboxy-2,5-dihydroxyphenylmethyl)acetamide; N,N-bis(2,5-dihydroxy-4-sulfophenylmethyl)acetamide; 4-((2,5-dihydroxy-4-carboxyphenyl)methylthiomethyl)-2,5-dihydroxybenzoic acid; 4-((2,5-dihydroxy-4-sulfophenyl)methylthiomethyl)-2,5-dihydroxy Benzoic acid; 4-((2,5-dihydroxy-3-sulfophenyl)methylthiomethyl)-2,5-dihydroxybenzoic acid; 4-((2,5-dihydroxy-4-sulfophenyl)methylthiomethyl)-2,5-dihydroxybenzenesulfonic acid; 4-((2,5-dihydroxy-4-carboxyphenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid; 4-((2,5-dihydroxybenzoic acid 4-((2,5-dihydroxy-3-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid; 4-((2,5-dihydroxy-4-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid; 4-((2,5-dihydroxy-4-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzenesulfonic acid; 4-((2,5-dihydroxy-4-carboxyphenyl)methoxy methyl)-2,5-dihydroxybenzoic acid; 4-((2,5-dihydroxy-4-sulfophenyl)methoxymethyl)-2,5-dihydroxybenzoic acid; 4-((2,5-dihydroxy-3-sulfophenyl)methoxymethyl)-2,5-dihydroxybenzoic acid; 4-((2,5-dihydroxy-4-sulfophenyl)methoxymethyl)-2,5-dihydroxybenzenesulfonic acid; tris(4-carboxy-2,5-dihydroxyphenylmethyl)amine; tris(4-ethoxycarbonyl-2,5-dihydroxyphenylmethyl)amine; bis(3-carboxy-2,5-dihydroxyphenylmethyl)amine; 3-((2,5-dihydroxy-3-sulfophenylmethylamino)methyl)-2,5-dihydroxybenzoic acid;3-((2,5-dihydroxy-4-sulfophenylmethylamino)methyl)-2,5-dihydroxybenzoic acid; bis(2,5-dihydroxy-3-sulfophenylmethyl)amine; N,N-bis(3-carboxy-2,5-dihydroxyphenylmethyl)acetamide; N-(2,5-dihydroxy-3-sulfophenylmethyl) N-(3-carboxy-2,5-dihydroxyphenylmethyl)acetamide; N-(2,5-dihydroxy-4-sulfophenylmethyl) N-(3-carboxy-2,5-dihydroxyphenylmethyl)acetamide; N,N-bis(2,5-dihydroxy-3-sulfophenylmethyl)acetamide; 3-((2,5-dihydroxy-3-carboxyphenyl)methylthiomethyl)-2,5-dihydroxybenzoic acid; 3-((2,5-dihydroxy-3-sulfophenyl)methylthiomethyl)-2,5-dihydroxy Benzoic acid; 3-((2,5-dihydroxy-4-sulfophenyl)methylthiomethyl)-2,5-dihydroxybenzoic acid; 3-((2,5-dihydroxy-3-sulfophenyl)methylthiomethyl)-2,5-dihydroxybenzenesulfonic acid; 3-((2,5-dihydroxy-3-carboxyphenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid; 3-((2,5-dihydroxybenzoic acid 3-((2,5-dihydroxy-4-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid; 3-((2,5-dihydroxy-3-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid; 3-((2,5-dihydroxy-3-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzenesulfonic acid; 3-((2,5-dihydroxy-3-carboxyphenyl)methoxy Cymethyl)-2,5-dihydroxybenzoic acid; 3-((2,5-dihydroxy-3-sulfophenyl)methoxymethyl)-2,5-dihydroxybenzoic acid; 3-((2,5-dihydroxy-4-sulfophenyl)methoxymethyl)-2,5-dihydroxybenzoic acid; 3-((2,5-dihydroxy-3-sulfophenyl)methoxymethyl)-2,5-dihydroxybenzenesulfonic acid; methyl 3-((2,5-diacetoxy-3-methoxycarbonylphenyl)methylsulfonylmethyl)-2,5-diacetoxybenzoate; Methyl 3-((2,5-dihydroxy-3-methoxycarbonylphenyl)methylsulfonylmethyl)-2,5-hydroxybenzoate; 2-morpholinoethyl 3-((2,5-dihydroxy-3-(2-morpholinoethoxycarbonyl)phenyl)methylsulfonylmethyl)-2,5-hydroxybenzoate; tris(3-carboxy-2,5-dihydroxyphenylmethyl)amine;A compound selected from the group consisting of and tris(3-ethoxycarbonyl-2,5-dihydroxyphenylmethyl)amine.; Claim 17 In paragraph 2, the compound is a compound comprising the following chemical formula (I): In the above chemical formula, R a , R b =H; R1= COOR4;R2= H;R3= R8;R4= H;R8= (CH2) m X(CH2) p R9;R9= phenyl substituted with COOR4 and OR4;X = N(CH2) q R9; and, m, p and q = 1; and the compound is tris(4-carboxy-2,5-dihydroxyphenylmethyl)amine. Claim 18 In paragraph 2, the compound comprises the following chemical formula (I): In the above chemical formula, R a , R b = H;R1= COOR4;R2= (CH2) m X(CH2) p R9R3= H; R9= phenyl substituted with COOR4 and OR4; R4= H; X = SO2; and m and p = 1; and the compound is 3-((2,5-dihydroxy-3-carboxyphenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid. Claim 19 A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the pharmaceutical composition is intended to treat and / or prevent immunological disorders and / or complications thereof caused by autoimmune, immunological, rheumatic, vascular disorders, ophthalmic disorders, fibrotic disorders, metabolic and gastrointestinal disorders, neuroinflammatory and neurodegenerative diseases, neoplasms and cancer-related disorders, hormone-related disorders, or viral and / or bacterial infectious diseases, and wherein the autoimmune, immunological, rheumatic, and vascular disorders include peritonitis, Kawasaki disease (KD), Takayasu arteritis (TA), microscopic polyangiitis (MP), giant cell arteritis (GCA), antiphospholipid syndrome (APS), and Behcet's disease (BD). Disease), granulomatosis with polyangiitis (GPA), Wegener's granulomatosis (WG), eosinophilic granulomatosis with polyangiitis, Churg-Strauss syndrome (EGPA), rosacea (RO), osteoarthritis (OA), rheumatoid arthritis (RA), lupus, spondyloarthropathies, Sjogren's syndrome, gout, scleroderma, infectious arthritis,One or more selected from the group consisting of juvenile idiopathic arthritis and polymyalgia rheumatica, and the ophthalmic disorder is one or more selected from the group consisting of age macular degeneration (AMD or ARMD), pterygium (PTE), diabetic retinopathy (DR), diabetic macular edema (DME), Stargardt disease (SD), proliferative vitreoretinopathy (PVR), dry eye syndrome (DYS), endophthalmitis, central serous chorioretinopathy (CSC), retinitis pigmentosa (RP), glaucoma, and uveitis (UVE), and the fibrous disorder is cystic One or more selected from the group consisting of cystic fibrosis, retroperitoneal fibrosis, idiopathic pulmonary fibrosis, combined pulmonary fibrosis & emphysema (CPFE), eosinophilic angiocentric fibrosis, intestinal fibrosis, ovarian fibrosis, nephrotenic systemic fibrosis, oral submucous fibrosis (OSMF), and liver fibrosis, andThe aforementioned metabolic and gastrointestinal disorders include diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic cardiomyopathy (DCDM), diabetic foot ulcer (DFU), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatic hepatosis (NASH), primary biliary cholangitis (PBC), hepatic fibrosis, hepatic cirrhosis (HF), inflammatory bowel disease (IBD), Crohn's disease, intestinal fibrosis, polycystic kidney disease (PKD), chronic kidney disease (CKD), and nephrogenic systemic fibrosis (NSF). One or more selected from the group consisting of fibrosis), acute pancreatitis, and chronic pancreatitis, and the neoplasms and cancer-related disorders are one or more selected from the group consisting of pancreatic cancer, renal cell carcinoma, radiation-induced fibrosis, primary myelofibrosis, fibrosis, fibrosarcoma, hepatocellular carcinoma, retinoblastoma, intraocular lymphoma, and melanoma, and the viral infectious diseases are respiratory syncytial virus, human metapneumovirus, influenza, human rhinovirus (HRV), rhinosyncitial virus (RV), chikungunya virus,A pharmaceutical composition caused by any one or more viruses selected from the group consisting of coronaviruses. Claim 20 In claim 19, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. Claim 21 An intermediate in the synthesis of a compound according to claim 2, selected from 2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid; 2,5-bis(benzyloxy)isophthalaldehyde; 2,5-bis(benzyloxy)isophthalic acid; ethyl 2,5-bis(benzyloxy)-4-(hydroxymethyl)benzoate; or ethyl 2,5-bis(benzyloxy)-3-(hydroxymethyl)benzoate.

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