New hydroquinone derivatives

Abstract

The present invention provides novel hydroquinone derivatives of formula (I), processes for their preparation, and pharmaceutical compositions and methods for treating and / or preventing diseases, including, for example, autoimmune diseases, immune disorders, rheumatic diseases, vascular diseases, ophthalmic diseases, fibrotic diseases, metabolic and gastrointestinal diseases, neuroinflammatory and neurodegenerative diseases, neoplasia and cancer-related diseases, hormone-related diseases, and immune disorders caused by viral and bacterial infections, and their complications. n COOR4, SO3H, (CH2) n SO3H or CONH-R 10 one of R2 and R3 is H and the other is R5. JPEG2023517693000173.jpg50158

Description

[Technical Field]

[0001] The present invention relates generally to novel hydroquinone derivatives, their preparation, and methods of treating diseases by administering such compounds to a warm-blooded animal in need thereof. The present invention also relates to compounds that are useful in the prevention and / or treatment of autoimmune diseases, immune diseases, rheumatic diseases, vascular diseases, ophthalmic diseases, fibrotic diseases, metabolic and gastrointestinal diseases, neuroinflammatory and neurodegenerative diseases, neoplasia and cancer-related diseases, hormone-related diseases, and immune diseases caused by viral and bacterial infections, and their complications. [Background technology]

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

[0003] Many drugs contain phenolic or catechol groups, which undergo early metabolism at the hydroxyl group during absorption after oral administration. Previous efforts to protect the hydroxyl group have generally been unsuccessful because the protecting groups employed are too unstable (O=COR or O=CR) or too stable (CH3). Therefore, the object of the present invention is to provide novel hydroquinone derivatives, their pharmaceutically acceptable salts, and formulations. These novel hydroquinone derivatives have particularly potent antifibrotic, anti-inflammatory, and anti-angiogenic properties.

[0004] International Publication No. WO2018160618A1 discloses certain substituted hydroquinones, 1,4-quinones, catechols, 1,2-quinones, anthraquinones, and anthrahydroquinones for use as redox mediators in emerging technologies, such as mediated fuel cells or organic mediator flow batteries.

[0005] Richter et al., in Synthesis, 1976, 1976(3), 192-194, disclose bis-N-arylcarbamates and 2,5-dihydroxy-3,6-bis[N-arylcarboxamido]-1,4-benzoquinones, and their preparation from 2,5-dihydroxy-1,4-benzoquinone and aryl isocyanates.

[0006] Japanese Publication JP51026839A discloses benzanilide I (R=H, OH) as having antitubercular, analgesic, anti-inflammatory, and uricosuric activity. [ka] Benzanilide I

[0007] U.S. Pat. No. 3,973,038 also describes compounds of the general formula: [ka] (wherein 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) and has in vivo enzyme inhibitory properties, particularly histamine deacetylase and xanthine oxidase.

[0008] However, none of the prior art documents discloses the novel class of hydroquinone derivative compounds of the present invention, which are particularly useful for the prevention and / or treatment of various diseases including autoimmune diseases, immune diseases, rheumatic diseases, vascular diseases, ophthalmological diseases, fibrotic diseases, metabolic and gastrointestinal diseases, neuroinflammatory and neurodegenerative diseases, neoplasia and cancer-related diseases, hormone-related diseases, and immune diseases caused by viral and bacterial infections, and their complications.

[0009] The present invention also relates to the treatment, prevention, and alleviation of metabolic diseases, such as diabetes and obesity. When blood glucose levels rise after a meal, insulin is secreted, stimulating cells in peripheral tissues (skeletal muscle and adipose tissue) to actively take up glucose from the blood as an energy source. Loss of glucose homeostasis due to abnormalities in insulin secretion or insulin action typically leads to metabolic diseases, such as diabetes, which may be simultaneously caused or further exacerbated by obesity. Because these pathological conditions are often fatal, strategies to restore adequate glucose clearance from the bloodstream are needed. Metabolic diseases, particularly disorders of glucose and lipid regulation, are becoming increasingly prevalent with the aging of the population in industrialized countries and the prevalence of sedentary lifestyles. Such diseases are frequently interrelated and are often predictors or consequences of each other.

[0010] For example, diabetes is caused by a combination of insulin resistance and insufficient insulin secretion by pancreatic beta cells. Individuals with insulin resistance often have abdominal obesity, dyslipidemia, hypertension, impaired glucose tolerance, and a prothrombotic state (metabolic syndrome). Accordingly, obese individuals are at a higher risk of developing insulin resistance overall. Therefore, disruptions in metabolic pathways can lead to numerous diseases, such as hyperlipidemia, obesity, diabetes, insulin resistance, impaired glucose tolerance, hyperglycemia, metabolic syndrome, and hypertension, which in turn can cause further metabolic dysfunction, leading to systemic problems and putting individuals at risk for further complications and early morbidity. Glucose and lipid levels are partially regulated by the liver, which is responsible for the synthesis, storage, secretion, conversion, and degradation of glucose, proteins, and lipids. Disease or trauma can significantly reduce the liver's ability to perform these normal activities. Therefore, most clinical symptoms of liver dysfunction are due to cellular damage and a decline in normal liver capacity. Liver dysfunction can result from genetic conditions, inflammatory diseases, toxins such as drugs and alcohol, immune disorders, vascular diseases, or metabolic conditions. Regardless of the cause, liver damage can have systemic effects on the function of metabolic processes and the regulation of blood glucose and serum lipid levels, exacerbating chronic disease states and leading to increased risk of further illness and morbidity. Both elevated and depressed blood glucose levels trigger hormonal responses designed to restore glucose homeostasis. Hypoglycemia triggers the release of glucagon from pancreatic alpha cells. Hyperglycemia triggers the release of insulin from pancreatic beta cells. ACTH and growth hormone, released from the pituitary gland, act to increase blood glucose by inhibiting uptake by extrahepatic tissues. Glucocorticoids also act to increase blood glucose levels by inhibiting glucose uptake. Cortisol, the primary glucocorticoid released by the adrenal cortex, is secreted in response to increased circulating ACTH. Epinephrine, an adrenal hormone, activates glycogenolysis and stimulates glucose production in response to stress stimuli.Metabolic diseases affecting glucose and lipid metabolism, such as hyperlipidemia, obesity, diabetes, insulin resistance, hyperglycemia, impaired glucose tolerance, metabolic syndrome, and hypertension, have long-term health consequences that lead to chronic diseases, including cardiovascular disease and premature morbidity. These metabolic and cardiovascular diseases are interrelated and may exacerbate or trigger each other, creating feedback mechanisms that are difficult to interrupt. Current pharmaceutical treatments for metabolic and cardiovascular diseases include combinations of lipid-lowering drugs, hypoglycemic drugs, antihypertensive drugs, diet, and exercise. However, complex treatment regimens can lead to polypharmacy problems, such as increased side effects, drug-drug interactions, poor adherence, and increased medication errors. Therefore, there is a compelling unmet need in the art to identify new compounds, formulations, and methods for safely and effectively treating metabolic and cardiovascular diseases and the pathologies associated with metabolic diseases.

[0011] Examples of metabolic conditions include, but are not limited to, pain, wound healing, fever, neuroinflammatory and neurodegenerative conditions, inflammation, thermogenesis, homeothermy, triglyceride breakdown, glycolysis, the Krebs cycle, fermentation, photosynthesis, metabolic rate, biotic and abiotic stress, secretion, oxidative stress, stress, neoplastic growth, skin conditions, cardiovascular conditions, neuroinflammatory and neurodegenerative conditions, psychiatric and behavioral disorders. Such processes or pathological conditions can occur in a cell, a group of cells, or a whole organism. Summary of the Invention [Problem to be solved by the invention]

[0012] Recent advances in molecular medicine have brought about some improvements in the diagnosis and treatment of neoplastic diseases. Despite these partial successes, these pathologies remain a considerable challenge. In certain types of cancer, current treatments can fail for several reasons. On the one hand, this is the inherent resistance of tumor cells, their constant mutations, and their ability to evade treatment. On the other hand, it is the heterogeneity of the tumor environment. It has been shown that tumors of the same type can vary greatly from one subject to another in terms of genomic profile, indicating the need for so-called "individualized" treatment. An even greater problem is the heterogeneity of mutations within the same tumor, as recently demonstrated for renal tumors, and this situation can be expected for other types of tumors as well. Therefore, new approaches are needed, and the search for invariant intervention points that are common to all or most malignant cells in tumors, preferably those that affect essential functions in cancer cells, is necessary. At the metabolic level, such intervention points may be, for example, mitochondria, organelles that are fundamental for the generation of energy required for all physiological and pathophysiological processes in cells. Tumor cells largely utilize so-called aerobic glycolysis for energy generation, but mitochondrial respiration (i.e., oxygen consumption associated with ATP formation) is inherent in most (if not all) types of tumors. Thus, there is a compelling unmet need in the art to identify new compounds, formulations, and methods for safely and effectively treating such neoplastic diseases. [Means for solving the problem]

[0013] The present invention provides novel hydroquinone derivatives, novel manufacturing processes, and novel key intermediates. The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of the hydroquinone derivatives and a pharmaceutically acceptable excipient.

[0014] The present invention further provides a method for treating and / or preventing angiogenic (vascular), inflammatory, and / or fibrotic pathologies due to the antifibrotic, anti-inflammatory, and anti-angiogenic effects of the compounds. Accordingly, the present invention ultimately provides a method for treating and / or preventing diseases or disorders, including immune / rheumatic / vascular diseases, ophthalmic diseases, fibrotic diseases, metabolic and gastrointestinal diseases, and neoplasia- and cancer-related diseases, comprising administering to a subject in need thereof a therapeutically effective dose of the compounds and / or pharmaceutical compositions of the present invention. In particular, the present invention provides a method for treating and / or preventing diseases or disorders, including autoimmune diseases, immune diseases, rheumatic diseases, vascular diseases, ophthalmic diseases, fibrotic diseases, metabolic and gastrointestinal diseases, neuroinflammatory and neurodegenerative diseases, neoplasia- and cancer-related diseases, hormone-related diseases, and immune disorders caused by viral and bacterial infections, as well as complications thereof. [Brief explanation of the drawings]

[0015] [Figure 1] (A) Confocal immunofluorescence images of vascular permeability assessed by Evans blue dye leakage in retinal whole-mount preparations in representative mice from each experimental group. Arrows indicate the location of extravasation. Scale bar, 30 μm. (B) Quantification of vascular leakage by assessing the number of extravasations per field (0.44 mm2). The effect of Ic-007a eye drops was significant by reducing vascular leakage to the same level as that observed in non-diabetic controls. *p<0.01 compared with other groups. [Figure 2](A) The Schmidt score is an assessment of compound efficacy based on four histopathological criteria describing pancreatic injury based on the following scores (numbers in parentheses) for four parameters: (a) interstitial edema, with scores of (0) none, (1) interlobular, (2) lobular involvement, and (3) isolated islet-like acinar cells. (b) inflammatory infiltration = leukocyte infiltration, with scores of (0) none, (1) <20%, (2) 20%-50%, and (3) >50%. (c) parenchymal necrosis = acinar cell necrosis, with scores of (0) none, (1) <5%, (2) 5%-20%, and (3) >20%. (d) hemorrhage, with scores of (0) none, (1) 1-2 points, (2) 3-5 points, and (3) >5 points. The highest Schmidt score = 10 is for caerulein-induced + vehicle-treated animals, and the lowest score = 0 is for uninduced animals. The Schmidt score is the sum of the a+b+c+d scores, and **** indicates a statistically significant difference from the cerulein-induced group, as shown in Figure 2. All products showed an improvement in the Schmidt score compared to the cerulein control animals. [Figure 3] Figures 3A-B show a list of diseases, including key cytokines involved in the selected diseases (Akdis M. et al., J Allergy Clin Immunol 2016;138:984-1010). Figure 3C shows a portion of the search results, ranked by score, for the selected diseases, including cytokines and genes likely involved in the selected diseases, as shown in the example results of a search on https: / / www.targetvalidation.org / for "diabetic retinopathy." Figure 3D shows a search using VEGFA as the cytokine to find a list of diseases in which VEGFA is mentioned. Only a portion of the diseases in which VEGFA is involved is 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). [Figure 4]A table listing the conditions and yields for compounds of types Ia-Id described in Examples 1.1-1.4 is provided below. Overall yields are calculated from the starting material, 2,5-dihydroxyterephthalic acid. [Figure 5] A table listing the conditions and yields of compounds of types IIa to IIc described in Examples 1.5 to 1.7 is shown. [Figure 6] A table listing the conditions and yields of compounds of type IIIa and IIIb described in Examples 1.8 and 1.9 is provided. [Figure 7] A table listing the conditions and yields of compounds of type IIIc described in Example 1.10 is provided. [Figure 8] 1 is a table listing the deprotection procedures described in Example 1.12 for Type V compounds. [Figure 9] Non-fasting blood glucose levels (mean ± standard deviation of all animals) in the STZ-induced diabetes model are shown for all animals in each group sampled after day 0 before dosing and after 7 and 14 days of continuous dosing by intravenous or oral route. [Figure 10] Figure 1 shows the promotion of wound healing in an STZ-induced diabetes model where 3 animals / group were sampled after 7 days of continuous dosing by intravenous or oral route. [Figure 11] Figure 11A shows representative images of pulmonary fibrosis on day 21 of treatment: (A1) uninduced (healthy); A2, bleomycin induced with vehicle treatment; A3, bleomycin induced with pirfenidone 100 mg / kg treatment; A4, bleomycin induced with IVc-059a treatment. Figure 11B shows the Ashcroft scores of healthy bleomycin-induced untreated vs. pirfenidone vs. IVc-059a. DETAILED DESCRIPTION OF THE INVENTION

[0016] Disclosed herein are novel compounds useful for treating a subject suffering from a disease, disorder, or dysfunction, including, but not limited to, autoimmune, metabolic, inflammatory, degenerative, and neoplastic diseases, particularly inflammatory conditions, angiogenic and / or fibrotic diseases, such as diabetic retinopathy, diabetic nephropathy, ankylosing spondylitis, chronic pancreatitis, liver fibrosis, renal fibrosis, and metabolic disorders caused by pancreatic insufficiency.

[0017] Hereinafter, unless otherwise specified, the collection of diseases, disorders or dysfunctions that may be treated utilizing the novel compounds disclosed herein will be referred to collectively as "medical conditions."

[0018] As used herein, the term "subject" includes any and all living organisms, including the term "patient." A subject treated according to the methods described herein may be one diagnosed by a physician as suffering from a medical condition. Diagnosis may be performed by any suitable means. Those skilled in the art will understand that a subject treated according to the present disclosure may have undergone standard tests to diagnose a medical condition. As known to those skilled in the art, the clinical picture of medical conditions of the type disclosed herein varies depending on the pathological mechanism.

[0019] As used herein, "treating" refers to utilizing 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. Thus, in the claims and embodiments described herein, treating refers to a subject undergoing the methodologies disclosed herein for therapeutic purposes.

[0020] As used herein, prodrug refers to any of a wide range of prodrug strategies. For example, prodrug strategies were formally recognized by Adrian Albert in 1958 (Albert, A. Chemical aspects of selective toxicity. Nature, 1958, 182, 421-422), but originated early in the last century, as exemplified by methenamine, phenacetin, and prontosil. Prodrugs are generally molecules with little or no pharmacological activity, but whether by chance or design, possess built-in structural instability that allows for bioconversion to active drugs in vivo. This conversion can occur through chemical or enzymatic processes, or a combination of the two. Active molecules are often associated with undesirable physicochemical properties, making delivery to the appropriate biological target a significant challenge. Prodrugs can ameliorate metabolic instability, typically resulting from hepatic metabolism. Similarly, undesired intestinal metabolism of drugs can be overcome through selective prodrug strategies. This instability can significantly reduce the total amount of drug reaching the systemic circulation and its target. Prodrugs can be used to protect active drugs from this first-pass effect by masking metabolically labile but pharmacologically essential functional groups, e.g., phenol, to avoid rapid metabolism.

[0021] Prodrugs, obtained through structural modifications of drugs, are designed to affect the intrinsic physicochemical properties of the molecule to enable its delivery. These considerations are not always integrated into the design of new, novel molecules at the drug discovery stage. In many cases, analogous optimization is the preferred path forward. Implementing an early prodrug strategy can lead to faster clinical development and ultimately to the commercialization of drug products.

[0022] Many prodrug strategies can be applied to affect the lipophilicity of parent drugs. Drug lipophilicity has been improved by masking their polar and ionizable functionalities with short-chain hydrocarbon promoieties. Hydrophilic hydroxyl, carboxyl, phosphate, or amine groups, as well as other negatively or positively charged groups, have been successfully converted into more lipophilic alkyl or aryl esters or N-acyl derivatives, which are rapidly hydrolyzed back to the parent drug in the body by ubiquitous esterases or peptidases.

[0023] Thus, the present invention provides a compound of formula (I): [ka] Formula (I) (In the formula, R a , R b =H, C 1-4 Acyl, aryl C 1-4 Alkyl, C6-C 10 Aryl CO, HOOC(CH2) n CO, C1-C7 alkylNHCO, 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 ; R2 and R3 are H or R5, provided that when one of R2 and R3 is R5, the other is H, and when one of R2 and R3 is H, the other is R5; R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 10aryl, 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, heteroaryl-R9 (where k=0-4); R7 = COOR4, (CH2) n COOR4, SO3H, (CH2) n benzoheteroaryl substituted with at least one or more groups selected from SO3H, OR4, azole [five-membered N-containing heterocycle] or fluorine; R8=(CH2) m X(CH2) p R9; X = O, S, SO2, NH, NAc or N(CH2) q R9; R9 = COOR4, (CH2) n COOR4, (CH2) n SO3H, OR4, SO3H, azole [five-membered N-containing heterocycle], fluorine, C=O, NHCO-R 10 aryl or heteroaryl substituted with at least one or more groups selected from the group consisting of: R 10 =COOR4, (CH2) n COOR4, (CH2) n aryl or heteroaryl substituted with at least one or more groups selected from SO3H, OR4, SO3H, azole [five-membered N-containing heterocycle], or fluorine; where R9 and R 10 The aryl in R is an aromatic group containing 6 to 14 carbon atoms selected from phenyl, naphthyl, and biphenyl groups; the heteroaryl R and R 10 is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen atoms; n, m, p, and q are independently 1 to 4. The present invention provides a compound of the formula:

[0024] The present invention further provides a compound of formula (I): [ka] (I) (In the formula, R a , R b =H, C 1-4 Acyl, aryl C 1-4 Alkyl, C6-C 10 Aryl CO, HOOC(CH2) n CO, C1-C7 alkylNHCO, 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 ; R2 and R3 are H or R5, provided that when one of R2 and R3 is R5, the other is H, and when one of R2 and R3 is H, the other is R5; R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 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; R6=CONH-R9, CONHCOR9, CONH(CH2) n -R9 or CONHCH(COOR4)(CH2) k R9 (in the formula, k=0~4); R7 = COOR4, (CH2) nCOOR4, SO3H, (CH2) n benzoheteroaryl substituted with at least one or more groups selected from SO3H, OR4, azole [five-membered N-containing heterocycle] or fluorine; R9 = COOR4, (CH2) n COOR4, (CH2) n SO3H, OR4, SO3H, azole [five-membered N-containing heterocycle], fluorine, C=O, NHCO-R 10 aryl and heteroaryl substituted with at least one or more groups selected from the group consisting of: R 10 =COOR4, (CH2) n COOR4, (CH2) n Aryl, heteroaryl substituted with at least one or more groups selected from SO3H, OR4, SO3H, azole [five-membered N-containing heterocycle], or fluorine, where R9 and R 10 aryl is an aromatic group containing 6 to 14 carbon atoms selected from phenyl, naphthyl, and biphenyl; R and R 10 heteroaryl is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen atoms; n is independently 1 to 4. A compound is provided.

[0025] The present invention also provides a compound of formula (I): [ka] (I) (In the formula, R a , R b =H, C 1-4 Acyl, aryl C 1-4 Alkyl, C6-C 10 Aryl CO, HOOC(CH2) n CO, C1-C7 alkylNHCO, 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 ; R2 and R3 are H or R5, provided that when one of R2 and R3 is R5, the other is H, and when one of R2 and R3 is H, the other is R5; R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 10 aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; R5=R8; R8=(CH2) m X(CH2) p R9; X = O, S, SO2, NH, NAc or N(CH2) q R9; R9 = COOR4, (CH2) n COOR4, (CH2) n SO3H, OR4, SO3H, azole [five-membered N-containing heterocycle], fluorine, C=O, NHCO-R 10 aryl and heteroaryl substituted with at least one or more groups selected from the group consisting of: R 10 =COOR4, (CH2) n COOR4, (CH2) n Aryl, heteroaryl substituted with at least one or more groups selected from SO3H, OR4, SO3H, azole [five-membered N-containing heterocycle], or fluorine; where R9 and R 10 The aryl in R is an aromatic group containing 6 to 14 carbon atoms selected from phenyl, naphthyl, and biphenyl groups; the heteroaryl R and R 10is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen atoms; n, m, p, and q are independently 1 to 4. The present invention provides a compound of the formula:

[0026] The expression "alkyl" refers to saturated, linear or branched hydrocarbon groups containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, in particular 1 to 6 (e.g. 1, 2, 3 or 4) carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. Furthermore, the term alkyl refers to groups in which one or more hydrogen atoms have been replaced by halogen atoms (preferably F or Cl), such as the 2,2,2-trichloroethyl group or the trifluoromethyl group.

[0027] The term "acyl" refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C(O)-, and (heterocycloalkyl)-C(O)-, which are attached to the parent structure via a carbonyl functionality. In some embodiments, acyl is a C1-C4 acyl group, where C1-C4 refers to the sum of the carbon atoms in the chain or ring of the alkyl, aryl, heteroaryl, or heterocycloalkyl portion of the acyl group and the carbonyl carbon, e.g., three ring or chain atoms plus the carbonyl.

[0028] The expression "aryl" refers to an aromatic group containing one or more rings containing from 6 to 14 ring carbon atoms, preferably from 6 to 10 (especially 6) ring carbon atoms.

[0029] "Aralkyl" or "Aryl C 1-4The expression "alkyl" refers to groups containing both aryl and alkyl, alkenyl, alkynyl and / or cycloalkyl groups in accordance with the above definitions, but is not limited to benzyl, 2-phenylethyl, 3-phenylpropyl and 2-naphth-2-ylethyl. Aralkyl groups preferably contain 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 cycloalkyl groups containing 5 or 6 ring carbon atoms.

[0030] The expression "heteroaryl" refers to an aromatic group containing one or more rings containing 5 to 14 ring atoms, preferably 5 to 10 (especially 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 (e.g., 4-pyridyl), imidazolyl (e.g., 2-imidazolyl), phenylpyrrolyl (e.g., 3-phenylpyrrolyl), thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3-bifuryl, pyrazolyl (e.g., 3-pyrazolyl), and isoquinolinyl groups.

[0031] The terms "benzoheteroaryl" or "benzoheteroaromatic" refer to a bicyclic ring comprising a phenyl ring fused to a monocyclic heteroaromatic ring. Examples of benzoheteroaryl include benzisoxazolyl, benzoxazolyl, benzisothiazolyl, benzothiazolyl, benzimidazolyl, benzofuryl, benzothienyl (including the S-oxide and dioxide), quinolyl, isoquinolyl, indazolyl, indolyl, and the like.

[0032] The term "azole" refers to a 5-membered 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.

[0033] The term "cycloalkyl" refers to a saturated or partially unsaturated (e.g., cycloalkenyl) cyclic group containing one or more rings (preferably one or two) and containing 3 to 14 ring carbon atoms, preferably 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms. Specific examples of cycloalkyl groups include cyclopropyl, cyclobutyl, and cyclopentyl groups.

[0034] The term "optionally substituted" refers to a group in which at least one, and optionally two, three or more hydrogen atoms may be replaced by a fluorine, chlorine, bromine, iodine atom, or by an OH, =O, SH, =S, NH, =NOH, N or NO group. This term also refers to at least one, two, three or four or more unsubstituted C-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 18 Aryl, C1-C 17 Heteroaryl, C7-C 20 Aralkyl or C2-C19 This term also refers to groups that are optionally substituted by one, two, three, or four or more unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 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 particularly refers to groups which are optionally substituted by heteroaralkyl groups.

[0035] According to preferred embodiments, all alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl, and heteroaralkyl groups described herein may be substituted or unsubstituted.

[0036] Preferably, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis. (A) R a , R b =H, C 1-4 Acyl, aryl C 1-4 Alkyl, C6-C 10 Aryl CO, HOOC(CH2) n CO, C1-C7 alkylNHCO, phosphono, phosphonooxymethyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl or C1-C6 alkoxycarbonyloxy-1-ethyl, R1=COOR4; R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 10aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; R2=H; R3=R5; and R5=R6=CONH-R9 or (B) R a , R b =H, C 1-4 Acyl, aryl C 1-4 Alkyl, C6-C 10 Aryl CO, HOOC(CH2) n CO, C1-C7 alkylNHCO, phosphono, phosphonooxymethyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl or C1-C6 alkoxycarbonyloxy-1-ethyl, R1=COOR4; R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 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 The present invention provides a hydroquinone derivative compound of formula (I):

[0037] In a first embodiment, the invention thus comprises compounds according to Table 1.

[0038] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0039] Preferably, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis. (A) R a , R b =H; R1 = SO3H; R2=H; R3=R5; and R5=R6=CONH-R9 or (B) R a , R b =H; R1 = SO3H; R3=H; R2=R5; and R5=R6=CONH-R9 The present invention provides a compound of formula (I),

[0040] In a second embodiment, the invention includes compounds according to Table 2.

[0041] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0042] Preferably, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis. (A) R a , R b =H; R1=(CH2) n COOR4;R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 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; and R5=R6=CONH-R9 or (B) R a , R b =H; R1=(CH2) n COOR4;R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 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 The present invention provides a hydroquinone derivative compound of formula (I):

[0043] In a third embodiment, the invention includes compounds according to Table 3.

[0044] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0045] Preferably, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis. (A) R a , R b =H, C 1-4 Acyl, aryl C 1-4 Alkyl, C6-C 10 Aryl CO, HOOC(CH2) n CO, C1-C7 alkylNHCO, phosphono, phosphonooxymethyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl or C1-C6 alkoxycarbonyloxy-1-ethyl; R1=CONH-R 10 ;R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 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; and R5=R6=CONH-R9 or (B) R a , R b =H, C 1-4 Acyl, aryl C 1-4 Alkyl, C6-C 10 Aryl CO, HOOC(CH2) n CO, C1-C7 alkylNHCO, phosphono, phosphonooxymethyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl or C1-C6 alkoxycarbonyloxy-1-ethyl; R1=CONH-R 10 ;R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 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 The present invention provides a hydroquinone derivative compound of formula (I):

[0046] In a fourth embodiment, the invention comprises compounds according to Table 4.

[0047] [Table 4-1] [Table 4-2] [Table 4-3]

[0048] Preferably, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis. (A) Ra , R b =H; R1 = COOR4;(CH2) n COOR4;R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 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; and R5=R6=CONHCOR9 or (B) R a , R b =H; R1 = COOR4;(CH2) n COOR4;R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 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 The present invention provides a hydroquinone derivative compound of formula (I):

[0049] In a fifth embodiment, the invention comprises compounds according to Table 5.

[0050] [Table 5-1] [Table 5-2]

[0051] Preferably, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis. (A) R a , R b =H; R1 = COOR4;(CH2) n COOR4; R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 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; and R5 = R6 = CONH(CH2) n -R9 or (B) R a , R b =H; R1 = COOR4;(CH2) n COOR4; R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 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(CH2) n -R9 The present invention provides a hydroquinone derivative compound of formula (I):

[0052] In a sixth embodiment, the invention comprises compounds according to Table 6.

[0053] [Table 6-1] [Table 6-2]

[0054] Preferably, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis. R a , R b =H; R1 = SO3H; R2=H; R3=R5; and R5 = R6 = CONH(CH2) n -R9 The present invention provides a hydroquinone derivative compound of formula (I):

[0055] According to a seventh embodiment, the present invention comprises compounds according to Table 7 below.

[0056] [Table 7]

[0057] Preferably, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis. (A) R a , R b =H; R1 = COOR4;(CH2) n COOR4; R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 10aryl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; R2=H; R3=R5; and R5 = R6 = CONHCH(COOR4)(CH2) k -R9; or (B) R a , R b =H; R1 = COOR4;(CH2) n COOR4; R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 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 = CONHCH(COOR4)(CH2) k -R9 The present invention relates to a hydroquinone derivative compound of formula (I):

[0058] According to an eighth embodiment, the present invention comprises compounds according to Table 8 below.

[0059] [Table 8]

[0060] In certain embodiments, the present invention provides a method for treating a cancer cell comprising: (A) R a , R b =H; R1 = COOR4;(CH2)n COOR4;SO3H, (CH2) n SO3H or CONH-R 10 ; R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 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; and R5=R6=heteroaryl-R9 or (B) R a , R b =H; R1 = COOR4;(CH2) n COOR4;SO3H, (CH2) n SO3H or CONH-R 10 ; R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 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=heteroaryl-R9 The present invention provides a hydroquinone derivative compound of formula (I):

[0061] According to a ninth embodiment, the present invention comprises compounds according to Table 9.

[0062] [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4]

[0063] Preferably, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis. (A) R a , R b =H; R1 = COOR4;(CH2) n COOR4;SO3H, (CH2) n SO3H, CONH-R 10 ; R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 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; and R5 = R7 = COOR4, (CH2) n COOR4, SO3H, (CH2) n benzoheteroaryl substituted with at least one or more groups selected from SO3H, OR4, azole [five-membered N-containing heterocycle], or fluorine; or (B) R a , Rb =H; R1 = COOR4;(CH2) n COOR4;SO3H, (CH2) n SO3H or CONH-R 10 ; R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 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 = R7 = COOR4, (CH2) n COOR4, SO3H, (CH2) n benzoheteroaryl substituted with at least one or more groups selected from SO3H, OR4, azole [five-membered N-containing heterocycle], or fluorine; The present invention provides a hydroquinone derivative compound of formula (I):

[0064] According to a tenth embodiment, the present invention comprises compounds according to Table 10.

[0065] [Table 10-1] [Table 10-2]

[0066] Preferably, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis. (A) R a , R b =H, C 1-4 Acyl, aryl C 1-4 Alkyl, C6-C 10 Aryl CO, HOOC(CH2)n CO, C1-C7 alkylNHCO, 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 ; R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 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; and R5=R8=(CH2) m X(CH2) p R9 (In the formula, X=O, S, SO2, NH, NAc or N(CH2) q R9); or (B) R a , R b =H, C 1-4 Acyl, aryl C 1-4 Alkyl, C6-C 10 Aryl CO, HOOC(CH2) n CO, C1-C7 alkylNHCO, 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-R10 ; R4=H, C 1-4 Alkyl, aryl C 1-4 Functionalized C1-C6 alkyl including alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C6-C including o-methoxyphenyl (guaiacol esters) 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=R8=(CH2) m X(CH2) p R9 (In the formula, X=O, S, SO2, NH, NAc or N(CH2) q R9) The present invention provides a hydroquinone derivative compound of formula (I):

[0067] According to an eleventh embodiment, the present invention comprises compounds according to Table 11. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4]

[0068] According to yet another embodiment, the present invention comprises compounds according to Table 12. [Table 12]

[0069] The present invention also provides Step (a): coupling a hydroquinone-derived carboxylic acid having a protected phenolic functional group with an aniline having various functional groups via the corresponding acyl chloride or using an amide coupling agent such as TCFH in the presence of NMI; Step (b): deprotecting the ester functionality, typically by saponification; and Step (c): Deprotecting the phenol functionality, typically by catalytic hydrogenation; Or, Step (d): reducing a carboxylic acid derived from hydroquinone having a protected phenolic functional group to produce a benzyl alcohol; (e) Activation of the benzyl alcohol functional group and substitution with benzyl nucleophiles with diverse functional groups (alcohols, thiols, primary or secondary amines); (f) deprotecting the ester functionality, typically by a saponification reaction; and (g) deprotecting the phenolic functionality, typically by catalytic hydrogenation; The present invention relates to a process for producing a hydroquinone derivative compound of formula (I), comprising:

[0070] The process is outlined below: [ka]

[0071] The hydroquinone derivative compound of the present invention may exist in optically active forms (stereoisomers), its E / Z isomers, optical isomers, racemates, diastereoisomers, as well as its hydrates and solvates.Solvates of compounds are due to the mutual attraction between the molecule of the compound and the inert solvent used.Solvates are, for example, monohydrates, dihydrates or alcoholates.

[0072] The hydroquinone derivatives of the present invention may also exist as pharmaceutically acceptable salts, where the parent hydroquinone derivative has been modified by making acid or base salts thereof.

[0073] Examples of pharmaceutically acceptable salts include, inter alia, mineral or organic acid salts of basic residues (e.g., amines); alkali or organic salts of acidic residues (e.g., carboxylic acids), etc. Pharmaceutically acceptable salts may include conventional non-toxic salts or quaternary ammonium salts, for example, derived from non-toxic organic or inorganic acids, which are suitable for all routes of administration of the compounds. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts made 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, pamoic acid, maleic acid, hydroxy acids, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanyl, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.

[0074] Pharmaceutically acceptable salts are described in terms of cations and anions in "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, bitartrate, bromide, camsylate, carbonate, chloride ion, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactic acid, lactobionic acid, malate, maleate, mandelic acid, mesylate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturate, propionate, salicylate, stearate, acetate, succinate, sulfate, tartarate, teoclate, and tosylate. Alternatively, zwitterions may be used as salts, such as salts of the free amino acids arginine or lysine as cationic counterions and glutamic acid or aspartic acid as anionic counterions. Short peptides (2-20 amino acids) may also be used as repeating units of arginine or lysine and their combinations with other neutral amino acids. These cationic cell-penetrating peptides (CPPs) may be used as enhancers for drug penetration into cells.

[0075] Pharmaceutically acceptable salts of the compounds useful in the present invention can be synthesized, for example, from parent compounds containing a basic or acidic moiety by conventional chemical procedures. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418 (the disclosure of which is incorporated herein by reference) provides a list of suitable salts.

[0076] Suitable dosages according to the present invention, as described in various embodiments herein, may vary depending on the pathological condition, age, and species of the subject and can be readily determined by one skilled in the art. Total daily dosages for use in both veterinary and human medicine are preferably in the range of 0.01 to 2000 mg / kg body weight, preferably 0.1 to 1000 mg / kg body weight, and preferably 1 to 100 mg / kg, and may be administered as a single dose or in divided doses, and may exceed the upper limit if indicated. Such dosages may be tailored to the individual requirements of each case, including the specific compound administered, the route of administration, the pathological condition being treated, and the patient being treated. However, compounds may also be administered weekly, monthly, or at even longer intervals as a depot preparation (e.g., implant, sustained-release formulation). In such cases, dosages may be much higher than the daily dosage and may be tailored to the administration form, body weight, and specific indication. Appropriate dosages can be determined by conventional model testing, preferably animal models. Generally, for oral or parenteral administration to an adult weighing approximately 70 kg, a daily dosage of about 10 mg to about 10,000 mg, preferably about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded if necessary. It should be understood that the therapeutically effective dosages described above do not necessarily result from a single administration but typically result from the administration of multiple unit doses. These unit doses may in turn comprise a portion of a daily or weekly dosage; thus, the therapeutically effective dose is determined over the duration of treatment (contact). For example, for oral administration, the daily dose may be about 0.04 to about 1.0 mg / kg 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 body weight. Generally, the amount of active substance administered can vary over a relatively wide range to achieve and preferably maintain the desired plasma concentration. A unit dosage form of the active ingredient can contain from about 0.1 milligram to about 15 milligrams thereof. A preferred unit dosage form contains from about 0.1 to about 1 milligram of drug and can be administered 2 to 5 times a day.It should be noted, however, that other alternative routes, such as continuous infusion at a rate designed to maintain the above plasma concentrations, are also contemplated. The duration of a particular treatment may also vary depending on the severity of the disease, whether the treatment is directed at an acute symptomatic episode or is prophylactic, and similar considerations. Typical administration periods are from about 5 days to about 14 days, usually with a 7-day course.

[0077] The course (cycle) of administration can be repeated at monthly intervals, or parenteral unit dosages can be delivered at weekly intervals. Oral unit dosages can be administered at intervals of one day to several days to provide a determined therapeutically effective dose. The appropriate dosage of the compounds of the present invention depends on the type of disease being treated, the severity and course of the disease, whether the drug is administered for prophylactic or therapeutic purposes, the patient's medical history and response to the compound, and the criteria of the attending physician. Determining the appropriate dose or route of administration is clearly within the capabilities of a practicing physician. Animal experiments provide reliable guidance for determining effective doses for human therapy. Interspecies scaling of effective doses can be performed according to the principles established by Mordenti, J. and Chappell, W. "The use of interspecies scaling in toxicokinetics," in Toxicokinetics and New Drug Development, editors Yacobi et al., Pergamon Press, New York, 1989, pp. 42-96.

[0078] 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, prodrug, or stereoisomer thereof, and (ii) a pharmaceutically acceptable excipient.

[0079] Pharmaceutical excipients 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, permeation enhancers, release modifiers, preservatives, coating agents, carriers, flavoring agents, and combinations thereof.

[0080] Pharmaceutical compositions of the compounds of the present invention containing one or more pharmaceutical ingredients may be formulated with such excipients as a liquid pharmaceutical, a solid or semi-solid pharmaceutical, and / or a gaseous pharmaceutical.

[0081] When present in a solid formulation, the solid formulation may include, but is not limited to, granules, pellets, tablets, capsules, powders, films, lozenges, crushable tablets, dissolving tablets, disintegrating tablets, dispersible tablets, film-coated tablets, and controlled-, sustained-, extended-, or modified-release forms of any of the above solid forms. Such formulations may be immediate-, delayed-, or modified-release forms. Furthermore, immediate-release compositions may be conventional dispersible, chewable, or flash-melt formulations, and modified-release compositions may contain hydrophilic or hydrophobic release rate-controlling materials, or a combination of hydrophilic and hydrophobic release rate-controlling materials, to form a matrix or reservoir, or a combination of a matrix and reservoir system.

[0082] The compositions may be prepared using any one or more of the following techniques: direct blending, dry granulation, wet granulation, homogenization, milling, micronization, extrusion, and spheronization. The compositions may be uncoated, film-coated, sugar-coated, powder-coated, enteric-coated, or modified-release coated. When present in a liquid formulation, the liquid formulation may be in any liquid form, such as, but not limited to, a solution, suspension, nanosuspension, dispersion, colloid, emulsion, lotion, cream, ointment, tincture, and lyophilized composition. When present in a gaseous formulation, the gaseous formulation may be, but is not limited to, a milled powder or blend, a micronized powder or blend, a nanosuspension, an aerosol, a spray, droplets, a mist, a nebulized solution, or a suspension, and / or an atomized vapor.

[0083] The pharmaceutical composition according to the present invention may further contain optional additives, such as a vehicle, a binder, a flavoring agent, a sweetener, a coloring agent, a preservative, an antioxidant, a stabilizer, and a surfactant, as necessary.

[0084] The pharmaceutical compositions and compounds according to the invention may be formulated for administration by enteral routes, e.g., oral routes; parenteral routes, e.g., by injection, e.g., intravenous, subcutaneous, intraocular, intramuscular, or intraperitoneal injection; topical routes, e.g., ocular routes, including sublingual / buccal routes, mucosal and transmucosal routes; and pulmonary, nasal, intranasal, intrabronchial, intrapulmonary routes. Ocular administration routes include topical ocular administration, intraocular, intravitreal, or retrobulbar administration.

[0085] Preferred formulations of the compounds according to the present invention include liquid oral formulations, ophthalmic formulations, and intravenous and intraperitoneal formulations.

[0086] Liquid oral formulations are solutions, and suspension formats for oral drug administration are considered common, convenient, and safe. They can be used to deliver relatively large amounts of drug and are frequently used in pediatric populations and those who have difficulty swallowing tablets or capsules. Delivery via the gastrointestinal tract results in rapid dissolution and drug absorption, but tolerability and interactions with other substances in the gastrointestinal tract must be considered. While the properties of an active ingredient (API) may favor formulation in a simple aqueous-based oral solution, if the API is poorly soluble, the formulation must be designed around that molecule to enhance solubility and bioavailability. The introduction of surfactants, solvents, buffers, and oils increases solubility and reduces precipitation and / or degradation due to interaction with gastric fluids. When suspensions are required, particle size is often reduced and controlled to enhance drug solubility, permeation, and ultimately drug absorption. As formulation development progresses, preservatives and flavors are introduced to validate patient acceptability and shelf-life suitability.

[0087] Ophthalmic formulations are eye drops delivered directly to the eye, often as liquids in solution or suspension form. Ocular administration avoids metabolism by the gastrointestinal tract and can be used for drugs that are poorly absorbed orally. Ophthalmic solutions are sterile and isotonic with a nominal pH of 4-8 to avoid eye irritation. Excipients, including solubilizers, chelating agents, polymers, surfactants, permeation enhancers, and cyclodextrins, are added to the formulation to improve stability, modify viscosity, or increase the solubility, permeability, and bioavailability of poorly soluble drugs.

[0088] Intravenous formulations allow the full dose of drug to be delivered parenterally, followed by rapid absorption and delivery to the patient's entire body for immediate response. This mode of delivery avoids metabolism by the gastrointestinal tract and can be used for drugs that are poorly absorbed via oral administration. Injectables are typically sterile, isotonic aqueous solutions designed not to induce pain upon administration. For poorly soluble drugs, the formulations are modified with organic cosolvents, surfactants, and buffers to increase solubility, and nanosuspension formulations are also acceptable. For molecules that are unstable in solution, the formulations can be lyophilized for dilution at the time of use.

[0089] The present invention also provides kits comprising a composition comprising a therapeutically effective dose of one or more compounds of the present invention or a formulation thereof, and a delivery device for administration of said composition or formulation, and further comprising a package insert incorporating manual instructions for use.

[0090] 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 compounding techniques. Pharmaceutically acceptable carriers that can be used in the composition include any standard pharmaceutical carrier, such as phosphate-buffered saline, water, and emulsions, such as oil-in-water or water-in-oil emulsions, as well as various types of wetting agents. The composition may further contain solid pharmaceutical excipients, such as starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, 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 (including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc.). Liquid carriers, particularly for injectable solutions, include water, saline, dextrose in water, and glycols. For examples of carriers, stabilizers, and adjuvants, see Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

[0091] The composition can also contain stabilizers and preservatives. Examples of pharmaceutically acceptable solvents that can be used in the composition can be found in reference books such as Handbook of Pharmaceutical Excipients (Ninth Edition, Pharmaceutical Press, London and American Pharmacists Association, Washington, 2020), Aulton's Pharmaceutics, The Design and Manufacture of Medicines. (5th Edition, editors: Kevin Taylor and Michael Aulton, Elsevier, 2017), "Ullmann's Encyclopedia of Industrial Chemistry, 6th Edition" (various editors, 1989-1998, Marcel Dekker) and "Pharmaceutical Dosage Forms and Drug Delivery Systems" (ANSEL et al., 1994 and 2011, WILLIAMS & WILKINS). Non-limiting examples of pharmaceutically acceptable solvents that may be used in the compositions include, but are not limited to, propylene glycol (also known as 1,2-dihydroxypropane, 2-hydroxypropanol, methylethylene 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, dimethyl isosorbide, propylene carbonate, N-methylpyrrolidone, glycofurol, tetraethylene glycol, propylene glycol fatty acid esters, and mixtures thereof.

[0092] The compounds according to the invention have shown antifibrotic, anti-inflammatory and anti-angiogenic effects. Some diseases listed below involve not just one, but two or even three targets: Disease categories that exhibit a predominant angiogenic (vascular), inflammatory and / or fibrotic pathology. In some embodiments, the present invention relates to prodrugs of compounds according to the present invention, the advantages of such prodrugs being obtained by appending suitable cleavable functional groups, e.g., resulting in better aqueous solubility, for parenteral or oral delivery, by methods known to those skilled in the art.

[0093] Prodrugs of the molecules of the present invention that are highly polar and exhibit charged properties are particularly preferred because these functional groups can positively affect the passive permeability across biological membranes.The main obstacle of polar and charged drugs is their poor membrane permeability, which often leads to low and variable oral absorption rates and low oral bioavailability.In addition, the oral absorption of polar and charged drugs is often associated with substantial interspecies variability.Drugs with poor permeability also have low exposure levels in specific target organs, even after local administration.Improving membrane permeability has been one of the most fruitful areas of prodrug research to date. In order for the drugs according to the invention to overcome the topical route barrier to the eye, the oral mucosal barrier, transporter effects or other topical uses, different prodrug strategies have been developed.

[0094] The prodrug strategy was formally recognized by Adrian Albert in 1958 (Albert, A. Chemical aspects of selective toxicity. Nature, 1958, 182, 421-422), but originated early in the last century, as exemplified by methenamine, phenacetin, and prontosil. Prodrugs are molecules with little or no pharmacological activity, but which, whether by chance or design, possess built-in structural instability that allows for bioconversion to active drugs in vivo. Such conversion can occur by chemical or enzymatic processes, or a combination of the two. Active molecules are often associated with undesirable physicochemical properties, making delivery to the appropriate biological target a significant challenge.

[0095] Prodrugs, obtained through structural modifications of drugs, are designed to affect the intrinsic physicochemical properties of the molecule to enable its delivery. These considerations are not always integrated into the design of new molecules at the drug discovery stage. In many cases, analogue optimization is the preferred path forward. Implementing an early prodrug strategy can lead to faster clinical development and ultimately to the commercialization of drug products. Prodrug strategies for the most common functional groups of parent drugs are described in Rautio J, 2018 (Jarkko Rautio et al., Nature Reviews Drug Discovery, 2018, 17, 559-587). This review describes the expanding role of prodrugs in modern drug design and development and describes prodrug strategies for the most common functional groups of parent drugs.

[0096] The advantages of prodrugs can be obtained by adding appropriate cleavable functional groups, for example, for parenteral or oral delivery, which result in better aqueous solubility. On the other hand, for highly polar and charged molecules, these functional groups can significantly affect passive permeability across biological membranes. The main obstacle for polar and charged drugs is their poor membrane permeability, which often leads to low and variable oral absorption and poor oral bioavailability.

[0097] Furthermore, oral absorption of polar and charged drugs is often associated with substantial interspecies variability. Poorly permeable drugs also result in low exposure levels in specific target organs, even after topical administration. Improving membrane permeability has been one of the most fruitful areas of prodrug research to date. Many prodrug strategies can be applied to affect the lipophilicity of parent drugs. Drug lipophilicity has been improved by masking their polar and ionizable functionalities with short-chain hydrocarbon promoieties. Hydrophilic hydroxyl, carboxyl, phosphate, or amine groups, as well as other negatively or positively charged groups, have been successfully converted to more lipophilic alkyl or aryl esters or N-acyl derivatives, which are rapidly hydrolyzed back to the parent drug in the body by ubiquitous esterases or peptidases.

[0098] The majority of 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 eye. During topical administration to the eye, prodrugs readily penetrate the cornea after instillation, where they are hydrolyzed primarily by ocular carboxylesterases. Prodrugs can also utilize carrier-mediated transport. These transporters are membrane proteins that play an important role in controlling the uptake and efflux of vital polar endogenous nutrients. Their specificity is not limited to endogenous substances; drugs with close structural similarity to endogenous substances can also be transported across cell membranes by transporters. Carrier-mediated transport is particularly important for polar and charged drugs, because their passive diffusion across biological membranes is negligible. Prodrugs that can utilize carrier-mediated transport mechanisms provide interesting targets for drug design. Similarly, prodrugs can provide improved metabolic stability.

[0099] Prodrugs can improve metabolic instability, typically caused by hepatic metabolism.Similarly, the undesired intestinal metabolism of drugs can be overcome by selective prodrug strategies.This instability can significantly reduce the total amount of drug that reaches the systemic circulation and its target.Prodrugs can be used to protect active drugs from this first-pass effect by masking metabolically unstable but pharmacologically essential functional groups, such as phenol, to avoid rapid metabolism.

[0100] To solve the problem of insufficient plasma levels and extend the duration of action, drugs are usually controlled by formulations such as suspensions and polymeric matrices that control drug release, avoid peak effects, and extend their action. Prodrugs can be used to achieve controlled release of active drugs by modifying their aqueous solubility and dissolution properties to affect the release rate, absorption rate, or tissue distribution of the active drug.

[0101] Prodrugs are particularly useful in the development of some subcutaneous or intramuscular sustained-release depot injections that maintain therapeutic plasma levels of the parent drug for weeks to months. These prodrugs are typically fatty acid esters, such as decanoate, palmitate, enanthate, cypionate, or valerate esters, which are formulated in oil-based vehicles, resulting in sustained release of the prodrug and thus modulating the kinetics of the parent drug. Due to their high lipophilicity, these prodrugs bind to blood and tissue proteins, leading to slow enzymatic conversion and resulting in the slow appearance of the active drug in the systemic circulation.

[0102] Better targeting and less side effects are often achieved by using acid-labile prodrugs to target the prodrug, which is cleaved in the acidic environment of tumor tissue, endosome or lysosome.Similar approaches can also be achieved by using site-specific enzymes, and the prodrug is cleaved predominantly in the desired organ or tissue where the enzyme is at its highest concentration.For charged drugs, cleavage within cells leads to high intracellular concentrations of negatively or positively charged drugs, which remain in target cells.

[0103] In order for the drugs according to the invention to overcome the topical route barrier to the eye, the oral mucosal barrier, transporter effects or other topical uses, different prodrug strategies have been developed. The drugs of the present invention have a charged polar group. The problem to be solved depends on the route of administration and the need for long-term or short-term drug action. There have been successful examples of the synthesis of prodrugs that are cleaved by mouse and human tissue and blood esterases.

[0104] The compounds of the present invention possess carboxylic acid and phenolic functional groups. A wide variety of prodrugs derived from these functional groups can be considered; for example, carboxylic acids are most frequently converted into esters: simple alkyl esters (methyl, ethyl, isopropyl, and longer chains), functionalized alkyl esters such as morpholinoalkyl esters, pyrrolidinoalkyl esters, and N-methylpiperazino-alkyl esters; and 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 effective prodrug functional groups for carboxylic acids. A variety of esters and functionalized ethers have been used as phenol-based prodrugs, including simple aliphatic esters, aromatic esters, hemiesters of dicarboxylic acids, amino acid esters, carbamate esters, phosphoric acid monoesters, phosphonooxymethyl ethers, acyloxymethyl (or 1-ethyl) ethers, alkoxycarbonyloxymethyl (or 1-ethyl) ethers, and aminoacyloxymethyl ethers.

[0105] Accordingly, the present invention provides methods for treating and / or preventing diseases or disorders such as autoimmune diseases, immune diseases, rheumatic diseases, vascular diseases, ophthalmic diseases, fibrotic diseases, metabolic and gastrointestinal diseases, neuroinflammatory and neurodegenerative diseases, neoplasia and cancer-related diseases, hormone-related diseases, and immune diseases caused by viral and bacterial infections, and complications thereof, comprising administering to a subject in need thereof a therapeutically effective dose of the compounds and / or pharmaceutical compositions of the present invention as described above. The pharmaceutical compositions and methods according to the present invention are particularly suitable for subjects that are human or non-human animal subjects.

[0106] The compounds of the present invention may target diseases based on their individual cytokine profiles, as described in the biodata provided for some compounds (see Figures 3A-D). The Open Targets Platform website (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 comprehensive overview based on current bibliographic information and allows searching by disease and cytokine.

[0107] Two representative examples are shown: (A) In a disease-specific search for diabetic retinopathy, the following cytokines are listed as being highly correlated with the disease (Figure 3C). The top three cytokines are VEGFA score = 1 (vascular endothelial growth factor A), HFE score = 1 (homeostatic iron regulator), and TNF score = 0.86 (tumor necrosis factor A) as an example of a diabetic retinopathy search; (b) in a search for VEGFA, which is linked to nervous system diseases, vascular diseases, eye diseases, retinopathy, and several other diseases, as shown in Figure 3D. To illustrate the potency of the compounds against a small group of inflammatory cytokines, the effects of the compounds were evaluated for their IC50 values ​​(Table 13, in μM) on inhibition of human whole blood (Example 3.6) and LPS-induced inflammation.

[0108] [Table 13]

[0109] Immune / rheumatic / vascular diseases may include, for example, peritonitis, Kawasaki disease (KD), Takayasu's arteritis (TA), microscopic polyangiitis (MP), temporal arteritis (GCA), antiphospholipid syndrome (APS), Behçet's disease (BD), granulomatosis with polyangiitis (GPA) or Wegener's granulomatosis (WG), eosinophilic granulomatosis with polyangiitis, Churg-Strauss syndrome (EGPA), and rosacea (RO). Rheumatic diseases specifically affect the joints, tendons, ligaments, and bones, with pain, loss of movement, and inflammation. These include many types of arthritis, such as osteoarthritis (OA), rheumatoid arthritis (RA), lupus, the spondyloarthropathies ankylosing spondylitis (AS) and psoriatic arthritis (PsA), Sjogren's syndrome, gout, scleroderma, infectious arthritis, juvenile idiopathic arthritis, and polymyalgia rheumatica.

[0110] Peritonitis is an inflammation of the peritoneum, usually due to bacterial or fungal infection. There are two types of peritonitis. The first type is spontaneous peritonitis, which can develop as a complication of liver or kidney disease, such as cirrhosis. Secondary peritonitis can arise from abdominal perforation or as a complication of other medical conditions. If left untreated, peritonitis can lead to serious, potentially life-threatening infections. 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. Kawasaki disease is sometimes called mucocutaneous lymph node syndrome because it also affects lymph nodes, skin, and the mucous membranes lining the mouth, nose, and throat, which swell during the infection.

[0111] Takayasu's arteritis is a rare type of vasculitis, a group of diseases that cause inflammation of the blood vessels. Takayasu's arteritis damages the aorta and its major branches. The disease can lead to narrowing or blockage of the arteries, or aneurysms. Takayasu's arteritis can also lead to pain in the arms or chest, high blood pressure, and eventually heart failure or stroke. Drug therapy is needed to control the inflammation in the arteries and prevent complications. Granulomatosis with polyangiitis is a rare disease that causes inflammation of blood vessels in the nose, sinuses, throat, lungs, and kidneys. Formerly known as Wegener's granulomatosis, this condition is part of a group of vascular diseases called vasculitis. It impairs blood flow to certain organs. Affected tissues can develop into inflamed areas called granulomas, which can affect how these organs function. Without treatment, this condition can be fatal.

[0112] Drug therapy Temporal arteritis is an inflammation of the lining of an artery. It most often affects the arteries in the head, especially the temples. For this reason, temporal arteritis is sometimes called giant cell arteritis. Temporal arteritis often causes headaches, scalp tenderness, jaw pain, and vision problems. If left untreated, it can lead to blindness. Antiphospholipid syndrome occurs when the immune system mistakenly produces antibodies that make blood more likely to clot. This can lead to dangerous blood clots in the legs, kidneys, lungs, and brain. In pregnant women, antiphospholipid syndrome can also lead to miscarriage and stillbirth. There is no cure for antiphospholipid syndrome. Only available drug treatments can reduce the risk of blood clotting.

[0113] Behçet's disease, also known as Behçet's syndrome, is a rare disease that causes vascular inflammation. The disease can lead to a number of signs and symptoms that may initially seem unrelated. These can include oral sores, eye inflammation, skin rashes and lesions, and genital sores. Current treatments can help alleviate the symptoms of Behçet's disease and prevent serious complications, such as blindness. Churg-Strauss syndrome (CSS) is a disease characterized by vascular inflammation. This inflammation can restrict blood flow to organs and tissues, sometimes permanently damaging them. This condition is also known as eosinophilic granulomatosis with polyangiitis (EGPA). Bronchial asthma is the most common symptom of CSS. The disease can also cause other problems, such as hay fever, rashes, gastrointestinal bleeding, and pain and decreased sensation in the hands and feet. There is no cure for CSS. Current medications include steroids and other potent immunosuppressants to help control symptoms.

[0114] Rosacea is a common skin condition that causes redness and visible blood vessels on the face. It can also produce small, red, pus-filled bumps. These signs and symptoms may flare up over weeks to months and then disappear for a period of time. Rosacea can be mistaken for acne, other skin problems, or natural redness. There is no cure for rosacea, but treatment can control and alleviate the signs and symptoms. Osteoarthritis is the most common form of arthritis and affects millions of people worldwide. It occurs when protective cartilage wears away over time. While osteoarthritis can damage any joint, the disease most commonly affects the joints of the hands, knees, hips, and spine. While osteoarthritis cannot reverse joint damage, the symptoms can usually be managed. Lupus is an autoimmune disease. It causes the immune system to produce proteins called autoantibodies, which attack the body's 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 can cause kidney inflammation, leading to blood in the urine, protein in the urine, high blood pressure, kidney dysfunction, or even kidney failure.

[0115] Scleroderma is a group of rare diseases involving hardening and tightening of the skin and connective tissue. There are many different types of scleroderma. In some people, scleroderma affects only the skin. However, in many people, scleroderma also affects structures beyond the skin, such as blood vessels, internal organs, and the digestive tract (systemic sclerosis), and there is no cure for scleroderma. Sjogren's syndrome is a disease of the immune system identified by the most common symptoms of dry eyes and dry mouth. This condition is often accompanied by other immune system disorders, such as rheumatoid arthritis and lupus. In Sjogren's syndrome, the mucous membranes and moisture-secreting glands of the eyes and mouth are usually affected first, resulting in decreased tear and saliva production.

[0116] Infectious or septic arthritis is a painful infection in a joint that may result from pathogens traveling through the bloodstream from another part of the body. Septic arthritis can also occur when a penetrating injury, such as an animal bite or trauma, delivers pathogens directly to the joint. People with artificial joints are also at risk for septic arthritis. While the knee is most commonly affected, septic arthritis can also affect the hip, shoulder, and other joints. Because the infection can rapidly and severely damage the cartilage and bone within the joint, prompt treatment is crucial. 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. Some children experience symptoms for only a few months, while others may experience symptoms for years. Some types of juvenile idiopathic arthritis can cause serious complications, such as growth problems, joint damage, and eye inflammation.

[0117] Polymyalgia rheumatica is an inflammatory disease that causes muscle pain and stiffness, especially in the shoulders and buttocks. The signs and symptoms of polymyalgia rheumatica usually begin rapidly and are worse in the morning. Most people with polymyalgia rheumatica are over 65 years old. This condition is associated with another inflammatory condition called temporal arteritis. Examples of ophthalmological diseases include, but are not limited to, age-related macular degeneration (AMD or ARMD, dry and wet types), pterygium (PTE), diabetic retinopathy (DR), diabetic macular edema (DME), Stargardt's disease (SD), proliferative vitreoretinopathy (PVR), dry eye syndrome (DYS), endophthalmitis, central serous retinopathy (CSC), retinitis pigmentosa (RP), glaucoma and glaucoma-related complications, and uveitis (UVE).

[0118] Wet macular degeneration (WMD) is a chronic eye disease that causes blurred vision or blind spots in the visual field. It is generally caused by abnormal blood vessels leaking fluid or blood into the macula, the part of the retina responsible for central vision. WMD 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 blurred or decreased central vision due to thinning of the macula. Dry macular degeneration can first affect one or both eyes, then affect both eyes. Vision loss is typically central, but peripheral vision is preserved. Diabetic retinopathy is a diabetic complication that manifests in the eyes. It is caused by damage to the blood vessels of the retina. Diabetic retinopathy may initially have no symptoms or cause only mild vision loss. Eventually, it can cause blindness. This condition can manifest in anyone with type 1 or type 2 diabetes. DME is a serious eye complication that occurs when microaneurysms protrude from blood vessel walls, causing fluid and blood to leak or exude into the retina, thereby causing edema in the macula.

[0119] Stargardt disease is an eye disease that causes vision loss in children and young adults. It is a genetic disease and is therefore passed down from parent to child. Stargardt disease is a form of macular degeneration, often referred to as juvenile macular degeneration. PVR is a complication of rhegmatogenous retinal detachment. PVR occurs in approximately 8-10% of patients undergoing primary retinal detachment surgery and precludes successful surgical repair of rhegmatogenous retinal detachment. PVR can be treated with surgery to reattach the detached retina, but visual outcomes from surgery are very poor.

[0120] Dry eye disease is a common pathological condition that occurs when tears cannot provide sufficient lubrication for the eye. Tears can be insufficient and unstable for many reasons. For example, dry eye can occur when tears are not produced sufficiently or when tears of poor quality are produced. This instability of tears can lead to inflammation and damage to the surface of the eye. Endophthalmitis is inflammation inside the eye that can occur after eye injections or surgery. Symptoms are typically blurred or other changes in vision, eye pain, eye redness, eye sensitivity to light, or tearing.

[0121] Retinitis pigmentosa (RP) is a group of rare genetic disorders involving the breakdown 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 side (peripheral) vision. Glaucoma is a group of eye conditions that damage the optic nerve, the health of which 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 60 years of age. It can occur at any age, but is more common in older people. Many forms of glaucoma have no warning signs. The effects are gradual, with no changes in vision until the condition has reached an advanced stage. Uveitis is a form of ophthalmitis. It affects the middle layer of tissue in the eye wall, or uvea. Warning signs of uveitis often appear suddenly and rapidly worsen. They include redness of the eye, pain, and blurred vision. Possible causes of uveitis are infection, injury, or autoimmune or inflammatory diseases. Uveitis can be severe and lead to permanent vision loss.

[0122] The compounds and pharmaceutical compositions according to the present invention may also be used in methods for treating and / or preventing retinal neurodegeneration selected from the group consisting of diabetic retinopathy, age-related macular degeneration, glaucoma, and retinitis pigmentosa. Retinal neurodegeneration refers to a pathological condition of the retina characterized by progressive neuronal cell death. Diabetic retinopathy, age-related macular degeneration, glaucoma, and retinitis pigmentosa are considered retinal diseases in which neurodegeneration plays an essential role.

[0123] According to this preferred embodiment, the compounds according to the invention, for use in the topical treatment of the eye and / or the prevention of retinal neurodegeneration, may be combined with other active agents to enhance the therapeutic efficacy of the pathological condition being treated, in particular with a dipeptidyl peptidase-4 inhibitor (DPPIV) or a pharmaceutically acceptable salt thereof. 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.

[0124] The compounds of the present invention may be advantageously used in combination with anti-VEGF treatment to reduce the number of intraocular injections of anti-VEGF antibodies a patient requires. Administration to patients with retinal neurodegeneration, 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.

[0125] Examples of fibrotic diseases include, but are not limited to, cystic fibrosis, retroperitoneal fibrosis, idiopathic pulmonary fibrosis, pulmonary fibrosis with emphysema (CPFE), eosinophilic angiocentric fibrosis, intestinal fibrosis, ovarian fibrosis, nephrogenic systemic fibrosis, oral submucous fibrosis (OSMF), and hepatic fibrosis. Cystic fibrosis (CF) is a genetic disease that causes severe damage to the lungs, digestive system, and other organs in the body. It affects the cells that produce mucus, sweat, and digestive juices. Instead of acting as a lubricant, the secretions clog ducts, ducts, and passageways, especially in the lungs and pancreas.

[0126] Pulmonary fibrosis is a lung disease that occurs when lung tissue is damaged and scarred. This thick, stiff tissue makes it more difficult for the lungs to function properly. The scarring associated with pulmonary fibrosis can be caused by a number of factors. While lung damage caused by pulmonary fibrosis cannot be repaired, medications and treatments can help relieve symptoms and improve quality of life. Emphysema is a lung condition that causes shortness of breath. The alveoli become damaged, and over time, the lining of the alveoli weakens and ruptures, creating larger air spaces instead of many smaller ones. This reduces the surface area of ​​the lungs, which in turn reduces the amount of oxygen that reaches the bloodstream. Damaged alveoli do not function properly, and stale air becomes trapped, leaving no room for fresh, oxygen-rich air to enter.

[0127] Metabolic and gastrointestinal diseases may include, but are not limited to, diabetes-induced complications: diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic cardiomyopathy (DCDM), or diabetic foot ulcer (DFU). Liver diseases may include nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), primary biliary cholangitis (PBC), liver fibrosis or cirrhosis (HF), inflammatory bowel disease (IBD): ulcerative colitis, Crohn's disease, and 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). Diabetic nephropathy is a serious kidney-related complication of type 1 and type 2 diabetes. It is also called diabetic kidney disease. Approximately 25% of people with diabetes eventually develop kidney disease. Diabetic nephropathy affects the kidneys' ability to perform their normal function of removing waste products and excess fluid from the body. Over the years, this condition gradually damages the kidneys' delicate filtering system and can progress to kidney failure, also known as end-stage renal disease. Kidney failure is a life-threatening condition.

[0128] Nonalcoholic fatty liver disease (NAFLD) is an umbrella term for a range of liver conditions that affect people who drink little or no alcohol. As the name suggests, NAFLD is primarily characterized by too much fat stored in liver cells. It is the most common form of chronic liver disease. Some people with NAFLD may develop nonalcoholic steatohepatitis (NASH), an aggressive form of fatty liver disease characterized by liver inflammation and which can progress to advanced scarring (cirrhosis) and liver failure. This damage is similar to that caused by heavy alcohol consumption. Primary biliary cholangitis (PBC) is a chronic autoimmune disease that gradually destroys the bile ducts in the liver. Damage to the bile ducts can cause bile to back up into the liver, sometimes leading to irreversible cirrhosis. A combination of genetic and environmental factors contributes to the disease.

[0129] IBD refers to diseases involving chronic inflammation of the digestive tract. Types of IBD include ulcerative colitis, which involves ulcers along the surface of the colon and rectum, and Crohn's disease, which is characterized by inflammation of the digestive tract lining, often extending deep into the digestive tract. Both ulcerative colitis and Crohn's disease are typically characterized by diarrhea, rectal bleeding, abdominal pain, fatigue, and weight loss, and sometimes lead to life-threatening complications. Neoplasia and cancer-related diseases include, but are not limited to, for example, pancreatic cancer: predominantly fibrotic, renal cell carcinoma, radiation-induced fibrosis, primary myelofibrosis, fibroplasia, fibrosarcoma, hepatocellular carcinoma, retinal glioma, intraocular lymphoma, and melanoma (desmoplastic, conjunctival, uveal).

[0130] The present invention also relates to the treatment, prevention, and alleviation of viral infections via binding to heparan sulfate binding sites on viral proteins. The compounds of the present invention interact 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 moieties bound to cell membranes. Viruses with heparan sulfate (HS)-binding domains on their surface proteins use this HS affinity as one of the primary entry points to access and infect cells and bind to heparan sulfate attached to cells. Once bound to HS, viruses can infect cells using various entry mechanisms specific to each virus. The strong interaction of the compounds of the present invention with proteins, particularly heparan-binding domains of viral proteins, prevents viral infection of blood cells, endothelial cells lining blood vessels and organs, and surface epithelial cells present in the oral, nasal mucosa, lungs, and digestive tract. Several viral species are known to have a high affinity for heparan sulfate, including, but not limited to, 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 their variants). HS is a necessary cofactor for SARS-CoV-2 infection. HS interacts with the receptor-binding domain of the SARS-CoV-2 spike glycoprotein adjacent to ACE2, shifting the spike conformation to an open conformation and promoting ACE2 binding. Viral and bacterial infectious diseases can also include septic shock and ocular inflammation, such as endophthalmitis resulting from surgery or infection. [Example]

[0131] Example 1: Synthesis of compounds and intermediates Example 1.1: Type Ia molecules: monoamides, 25 examples [ka]

[0132] Precursor synthesis Scheme 1. Synthetic intermediates KI-1 and KI-6 [ka]

[0133] procedure: Synthesis of KI-1 and KI-6 (Steps [1], [2]) Diethyl 2,5-bis(benzyloxy)terephthalate (KI-0) (Step [1]) Potassium carbonate-325 mesh (326.1 g, 2.4 mol) was added portionwise over 15 minutes to a stirred solution of diethyl 2,5-dihydroxyterephthalate (200.0 g, 0.79 mol) in DMF (800.0 mL) at ambient temperature. Benzyl bromide (280.0 mL, 2.4 mol) was then added dropwise to the reaction flask over 30 minutes, and the resulting mixture was heated at 100°C for 2 hours, resulting in the formation of a thick cream-colored precipitate. The reaction mixture was cooled to ambient temperature and treated with saturated aqueous ammonium chloride (2 L). The resulting suspension was stirred for 30 minutes and then filtered. The solid material was washed with saturated aqueous ammonium chloride (2 x 200 mL). The solid was then suspended in ethanol (400 mL), filtered, and dried in a vacuum oven to give the desired product as a white solid (341.0 g, 0.785 mol, 99.8%).

[0134] UPLC-MS (acidic method, 2 min): rt = 1.36 min, no ionization observed, peak area >95% 1 H NMR (400 MHz, DMSO-d6) 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).

[0135] 2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid (KI-1) and 2,5-bis(benzyloxy)terephthalic acid (KI-6) (Step [2]) A solution of sodium 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. The solvent was removed under reduced pressure to form a white slurry. The crude material was suspended in EtOH (500 mL), filtered, and the collected solid was dried in a vacuum oven to give pure diethyl 2,5-bis(benzyloxy)terephthalate (23.0 g, 0.053 mol, 23%).

[0136] UPLC-MS (acidic method, 2 min): rt = 1.36 min, no ionization observed, peak area 98%

[0137] The ethanolic filtrate was concentrated to give an oil, and ethyl acetate (500 mL) was added to form a precipitate, which was filtered and washed with ethyl acetate (200 mL) to give 2,5-bis(benzyloxy)terephthalic acid (KI-6) as a white solid (18.9 g, 0.042 mol, 18%).

[0138] UPLC-MS (acidic method, 2 min): rt = 1.22 min, m / z 377.1 [MH] - , Peak area 95% 1 H NMR (400 MHz, DMSO-d6) δ 7.52-7.45 (m, 4H), 7.41-7.33 (m, 4H), 7.33-7.26 (m, 4H), 5.13 (s, 4H).

[0139] The filtrate was washed with saturated aqueous sodium carbonate (200 mL), 1 M hydrochloric acid (500 mL), and brine (500 mL), then dried (NaSO), filtered, and concentrated to dryness to give 2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid (KI-1) as a white solid (53 g, 0.130 mol, 57.0%).

[0140] UPLC-MS (acidic method, 2 min): rt = 1.22 min, m / z 405.3 [MH] - , Peak area 96% 1 H NMR (400 MHz, DMSO-d6) 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).

[0141] Large-scale protocol for KI-1 synthesis A 10 L jacketed vessel was charged with 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). The reaction mixture was stirred at room temperature overnight. LCMS analysis indicated the reaction was half complete and also showed the by-product (diacid) and starting material (diester) in a ratio of (diester:monoacid:diacid = 28:58:14). (diacid: 4.44 rt, monoacid: 5.08 rt, diester: 5.68 rt). At this stage, the solvent was removed under reduced pressure. The crude product was taken up in a 2:1 mixture of ethanol and water (3 L) in a 10 L jacketed vessel, stirred overnight, and filtered to give: Solid: (diester:monoacid:diacid = 86:12:2, 110.00 g, colorless solid) Filtrate: (diester:monoacid:diacid 3:63:34)

[0142] The filtrate was concentrated under reduced pressure to give an oil, which was taken up in ethyl acetate (2.5 L), stirred in a 10 L jacketed vessel overnight, and filtered to give a white solid (150.00 g). Solid: (Diester:Monoacid:Diacid=Trace:40:60). The filtrate was collected, washed with saturated aqueous sodium bicarbonate (100 mL), 1 N hydrochloric acid (200 mL), and brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure to give the desired product, 2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid (KI-1), as a white solid, which was dried in a vacuum oven at 50 °C for 48 h (225.00 g, 49% yield; yields varied from 49 to 65%).

[0143] Scheme 2: Synthetic intermediate KI-1Bn [ka]

[0144] procedure: Synthesis of KI-1Bn: 2,5-Bis(benzyloxy)-4-(benzyloxycarbonyl)benzoic acid (KI-1Bn) To a solution of 2,5-dihydroxyterephthalic acid (1.97 g, 10 mmol) in DMF (20 mL) at 0 °C, sodium hydride (2.0 g, 50 mmol) was added under stirring, followed by the dropwise addition of benzyl bromide (5.95 mL, 50 mmol, 5 equiv.) over 5 min, and the resulting mixture was maintained at room temperature for 2 h. The mixture was then heated at 60 °C for 18 h. 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 coevaporated with heptane (3 ×). The residue was taken up in DCM (30 mL), the organic phase was washed with 1 M HCl (25 mL), the separated aqueous layer was extracted with DCM (3 × 30 mL), and the combined organic phases were dried (MgSO4) and concentrated. The crude solid was recrystallized from EtOH (approximately 30 mL) to give pure KI-OBn (2.286 g, 41%). A sample of KI-OBn (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 to 80 °C for 3 days. The mixture was cooled to room temperature, taken up 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 give the monoester KI-IBn contaminated with approximately 16% of the diester KI-OBn.

[0145] 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). KI-1Bn: 1 H 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).

[0146] Synthesis of monoamides Scheme 3. Synthesis of monoamide Ia [ka]

[0147] General Procedure A for Amide Coupling [3A] Coupling via acyl chloride from KI-1 or KI-6 Model reaction (Ia-013a) 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 reduced pressure, and the residue was co-distilled with toluene (3 × 20 mL) to give the acyl chloride. A solution of the acyl chloride in DCM (10 mL) was added rapidly to a solution of the amine (dimethyl 2-aminoisophthalate, 210 mg, 3.1 mmol) and N,N-diisopropylethylamine (0.53 mL, 3.045 mmol) in DCM (10 mL) at ambient temperature, and the reaction was stirred for 18 hours. The reaction was diluted with DCM (70 mL), washed with 1 M hydrochloric acid (100 mL), water (100 mL), dried (Na2SO4), filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with a gradient of ethyl acetate (0 to 25%) in isohexane to give the desired product as a white solid (1.24 g, 2.075 mmol, 75%).

[0148] UPLC-MS (acidic method, 2 min): rt = 1.37 min; m / z = 598.2 [M+H] + , Peak area >95% 1H NMR (400 MHz, DMSO- d6) 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).

[0149] General Procedure B for Amide Coupling [3B] Coupling from KI-1 or KI-6 using a condensing agent Model reaction (Ia-001a) Methyl 2-(2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoylamino)benzoate 1-methylimidazole (13.0 mL, 163 mmol) was added to a mixture of 2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid (KI-1, 12.95 g, 32 mmol) and methyl anthranilate (5.729 g, 38 mmol, 1.190 equiv.) in MeCN (150 mL) at ambient temperature. Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (10.728 g, 0.038 mol) was added portionwise 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). The solid was then suspended in ethanol (200 mL), filtered, washed with ether (100 mL), and dried in a vacuum oven to give the desired product as a white solid (14.7 g, 27 mmol, 86%).

[0150] UPLC-MS (acidic method, 2 min): rt = 1.43 min; m / z = 540.2 [M+H] + , Peak area >99% 1H NMR (400 MHz, DMSO-d6) 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

[0151] General deprotection procedure[4],[5] Saponification Model reaction (Ia-013a) A solution of lithium hydroxide (42 mg, 1 mmol) in aqueous 2-(2,5-bis(benzyloxy)-4-carboxybenzoylamino)isophthalic acid (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 equiv) in water (4 mL) was added to the reaction mixture, which was stirred for an additional 23 hours. Upon completion, water (50 mL) was added to the reaction, and the mixture was washed with ethyl acetate (50 mL). The aqueous layer was acidified to pH = 2 with 1 M aqueous hydrochloric acid and extracted with ethyl acetate (2 x 50 mL). The organic layer was collected, dried (Na2SO4), filtered and concentrated to give the title compound as a white solid (82 mg, 0.151 mmol, 91%).

[0152] UPLC-MS (acidic method, 2 min): rt = 1.02 min; m / z = 542.1 [M+H] + , Peak area >95% 1H NMR (400 MHz, DMSO-d6) 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).

[0153] Debenzylation Model reaction (Ia-013a) 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 placed under hydrogen at ambient temperature and atmospheric pressure and stirred for 18 h. Upon completion, the mixture was filtered through Celite, which was washed with DCM and MeOH. The filtrate and washings were combined and concentrated under reduced pressure to give the desired product Ia-013a as a yellow solid (644 mg, 1.69 mmol, 98%).

[0154] UPLC-MS (acidic method, 4 min): rt = 0.91 min; m / z =362.0 [M+H] + , Peak area >98% 1 H NMR (DMSO-d6) 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)

[0155] Scheme 4a. Synthesis of monoamide Ia from KI-1Bn [ka]

[0156] Basic Procedures from KI-1Bn Acyl chloride-mediated coupling Model reaction: synthesis of Ia-032a To a solution of KI-1Bn (233 mg, 84% purity) in DCM (10 mL) was added SOCl (1.8 mL, 60 equiv.), and the mixture was heated at 50 °C for 3 h. The solvent was evaporated, and the residue was coevaporated with toluene (3 × 10 mL) to give the crude acyl chloride (237 mg, 99%). This material was dissolved in DCM (3 mL), and diisopropylethylamine (0.08 mL, 1.15 equiv.) was added, followed by a solution of benzyl 4-aminophenylacetate (92 mg, 0.95 equiv.) in DCM (3 mL). The final reaction volume was 10 mL. The reaction mixture was stirred at room temperature for 18 h. 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), and the combined organic phases were dried (MgSO4), and concentrated. The crude product was subjected to column chromatography (Pet.Et. / DCM 1:1, then gradient to 100% DCM) to give a first fraction of pure KI-OBn and a second fraction containing the pure desired product (237 mg, 86%, corrected for the purity of KI-IBn).

[0157] 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).

[0158] 4-(4-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid (Ia-032a). To a solution of the precursor prepared above (225 mg, 0.33 mmol) in DCM (20 mL) was added 5% Pd on charcoal (72 mg), followed by EtOH (20 mL). The flask was flushed with Ar (3×) and then filled with hydrogen (atmospheric pressure), and the mixture was stirred at room temperature for 2 h. The catalyst was removed by filtration over a Millipore filter, the filtrate was evaporated, and the residue was dried to give the product Ia-032a as a pale yellow solid (107 mg, 99%).

[0159] 1 H NMR (250 MHz, DMSO-d6): 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).

[0160] example: [ka] [ka]

[0161] The conditions and yields are as follows: see Figures 4A-D.

[0162] 1) 4-(2-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-001a UPLC-MS (acidic method, 2 min): rt = 0.95 min, m / z = 316 [MH] - , Peak area > 97% 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 10.85 (s, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.01 (dd, J = 8.0, 1.7 Hz, 1H), 7.71 - 7.56 (m, 1H), 7.41 (d, J = 6.9 Hz, 2H), 7.22 (t, J = 7.6 Hz, 1H). HRMS: [M+H] + , calc. for C 15 H 12 NO7: 318.06083, found: 318.06080. Biodata: Ia-001a: FGF-1 IC50 [μM] = 41; FGF-2 IC50 [μM] = 39; VEGF-A1 IC50 [μM] = 7.3; VEGFR-1 kinase inhibition IC50 [μM] = 2.25; PMN ROS inhibition at 0.3 μM [%] = 48; PMN ROS inhibition IC50 [μM] = 0.355; GM-CSF inhibition [%] = 44.3; Whole blood: GM-CSF IC50 [μM] = >100; IFNγ IC50 [μM] = 30.5; IL-1β IC50 [μM] = 34.4; IL-2 IC50 [μM] = 94.3; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 1.24; IL-9 IC50 [μM] = 5.63; IL-10 IC50 [μM] = >100; IL-12p70 IC50 [μM] = 1.5; IL-13 IC50 [μM] = 26.4; IL-17A IC50 [μM] = 0.1; IL-17F IC50 [μM] = 14.7; IL-18 IC50 [μM] = >100; IL-21 IC50 [μM] = >100; IL-33 IC50 [μM] = 19.3; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.02; TNFβ IC50 [μM] = 13.2

[0163] ジエチルエステル: UPLC-MS (acidic method, 2 min): rt = 1.39 min, m / z = 372.2 [MH] - , ピークarea > 98% 1 H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 11.05 (s, 1H), 9.87 (s, 1H), 8.57 (dd, J = 8.5, 1.2 Hz, 1H), 7.99 (dd, J = 7.9, 1.7 Hz, 1H), 7.65 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.49 (s, 1H), 7.40 (s, 1H), 7.25 (td, J = 7.6, 1.2 Hz, 1H), 4.35 (m, 4H), 1.33 (m, 6H). HRMS: [M+H] + , calc. for C 19 H 20 NO7: 374.12342, found: 374.12354 バイオデータ:Ia-001a-E2: FGF-1 IC50 [μM] = 9.2; FGF-2 IC50 [μM] = 200; VEGF-A1 IC50 [μM] = 123; VEGFR-リン acidification inhibition IC50 [μM] =1.25; PMN ROS [Block at 0.3 μM [%] = 51.47; PMN ROS Blockage IC50 [μM] = 2.58; Good hit followed by blockage [%] = 50.5

[0164] 2) 4-(2-(1H-Tactrol-5-イル)フェニルアミノカルボニル)-2,5-ジヒドロキシbenzoic acid, compound Ia-001aTz: UPLC-MS (acidic method, 4 minutes): rt = 1.17 minutes; m / z = 342.0 [M+H] + , ピークarea>96% 1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 10.90 (s, 2H), 8.47 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.50 - 7.32 (m, 3H). HRMS: [M+H] + , calc. for C 15 H 12 N5O5: 342.08329, found: 342.08318 Biodata: Ia-001a-Tz: FGF-1 IC50 [μM] = 6.2; FGF-2 IC50 [μM] = 20; VEGF-A1 IC50 [μM] = 17; VEGFR-1 kinase inhibition IC50 [μM] = 0.23; PMN ROS inhibition at 0.3 μM [%] = 54.33; PMN ROS inhibition IC50 [μM] = 1.54; IL-4 inhibition [%] = 69.75; Whole blood: GM-CSF IC50 [μM] = >100; IFNγ IC50 [μM] = >100; IL-1β IC50 [μM] = >100; IL-2 IC50 [μM] = 7.99; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 0.75; IL-9 IC50 [μM] = 8.63; IL-10 IC50 [μM] = 26.1; IL-12p70 IC50 [μM] = 32.4; IL-13 IC50 [μM] = 32.1; IL-17A IC50 [μM] = 0.11; IL-17F IC50 [μM] = 46.5; IL-18 IC50 [μM] = >100; IL-21 IC50 [μM] = >100; IL-33 IC50 [μM] = 23.6; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.63; TNFβ IC50 [μM] = 53

[0165] エチルエステル: UPLC-MS (acidic method, 2 min): rt = 1.08 min, m / z = 370.1 [M+H] + , ピーク area> 97% 1 H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 9.88 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 7.89 (dd, J = 7.8, 1.6 Hz, 1H), 7.62 (ddd, J = 8.6, 7.4, 1.6 Hz, 1H), 7.47 (s, 1H), 7.42 - 7.34 (m, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H). HRMS: [M+H] + , calc. for C 17 H 16 N5O5: 370.11460, found: 370.11458 バイオデータ:Ia-001a-Tz-E1: FGF-1 IC50 [μM] = 200; FGF-2 IC50 [μM] = 200; VEGF-A1 IC50 [μM] = 200; VEGFR-リン acidification inhibition IC50 [μM] =3.8; PMN ROS [Block at 0.3 μM [%] = 75.97; PMN ROS Blockage IC50 [μM] = ND; Good hit followed by blockage [%] = 98.88

[0166] エチルエステルジアセテート: UPLC-MS (acidic method, 4 min): rt = 1.57 min, m / z = 454.1 [M+H] + , ピーク area> 97% 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.23 ​​(d, J = 8.6 Hz, 1H), 7.96 (dd, J = 7.9, 1.7 Hz, 1H), 7.84 (s, 1H), 7.73 (s, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.43 (td, J = 7.6, 1.2 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.34 (s, 3H), 2.18 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). HRMS: [M+H] + , calc. for C 21 H 20 N5O7: 454.13572, found: 454.13542 バイオデータ:Ia-001a-Tz-E1-A2: FGF-1 IC50 [μM] = 60; FGF-2 IC50 [μM] = 200; VEGF-A1 IC50 [μM] = 200; VEGFR-リン acidification blocking IC50 [μM] =ND; PMN ROS [Block at 0.3 μM [%] = 49.85; PMN ROS Blockage IC50 [μM] = ND; Good hit followed by blockage [%] = 98.2

[0167] 3) 2,5-ジヒドロキシー4-(2-スルホフェニルアミノカルボニル)benzoic acid, compound Ia-001c: UPLC-MS (acidic method, 2 min): rt = 0.73 min; m / z = 352.0 [MH] - , ピークarea>99% 1 H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 10.99 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.74 (dd, J = 7.7, 1.7 Hz, 1H), 7.42 - 7.28 (m, 3H), 7.12 (td, J = 7.5, 1.2 Hz, 1H). HRMS: [M+H] +, calc. for C 14 H 12 NO8S: 354.02781, found: 354.02754. Biodata: Ia-001c: FGF-1 IC50 [μM] = 21; FGF-2 IC50 [μM] = 13; VEGF-A1 IC50 [μM] = 100; VEGFR-1 kinase inhibition IC50 [μM] = 3.31; PMN ROS inhibition at 0.3 μM [%] = 40.36; PMN ROS inhibition IC50 [μM] = 2.4; IL-4 inhibition [%] = 31.33; Whole blood: GM-CSF IC50 [μM] = >100; IFNγ IC50 [μM] = 0.44; IL-1β IC50 [μM] = >100; IL-2 IC50 [μM] = 12.8; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 0.95; IL-9 IC50 [μM] = 46.9; IL-10 IC50 [μM] = 1.9; IL-12p70 IC50 [μM] = 0.44; IL-13 IC50 [μM] = 86.1; IL-17A IC50 [μM] = 0.09; IL-17F IC50 [μM] = 89.7; IL-18 IC50 [μM] = >100; IL-21 IC50 [μM] = >100; IL-33 IC50 [μM] = >100; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.05; TNFβ IC50 [μM] = 29.7

[0168] 4) 4-(3-カルボキシフェニルアミノカルボニル)-2,5-ジヒドロキシbenzoic acid, compound Ia-002a: 1H-NMR (250 MHZ, DMSO-d6) δ ~13 (v br, 1H), 10.82 (br s, 1H), 10.60 (br s, 1H), 8.38 (s, 1H). 7.92 (d, 1H), 7.71 (d, 1H), 7.49 (t, 1H), 7.39 (s, 2H) バイオデータ:1a-002a: FGF-1 IC50 [μM] = 20; FGF-2 IC50 [μM] = 59; VEGF-A1 IC50 [μM] = 71; VEGFR-リン acidification inhibition IC50 [μM] =5.7; PMN ROS [inhibition at 0.3 μM [%] = 42.1; PMN ROS blocking IC50 [μM] = 0.312; Good hit and then blocking [%] = 27.92

[0169] 5) 4-(3-(1H-Tactulic acid-5-イル)フェニルアミノカルボニル)-2,5-ジヒドロキシbenzoic acid, compound Ia-002aTz: UPLC-MS (acidic method, 4 min): rt = 1.13 min; m / z = 342.0 [M+H] + , ピークarea>99% 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 10.67 (s, 1H), 8.54 (s, 1H), 7.91 - 7.84 (m, 1H), 7.79 (dt, J = 7.8, 1.4 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.41 (d, J = 2.2 Hz, 2H). HRMS: [M+H] + , calc. for C 15 H 12 N5O5: 342.08329, found: 342.08317 Biodata: Ia-002a-Tz: FGF-1 IC50 [μM] = 10; FGF-2 IC50 [μM] = 53; VEGF-A1 IC50 [μM] = 57; VEGFR phosphorylation inhibition IC50 [μM] = 100; PMN ROS inhibition at 0.3 μM [%] = 66.61; PMN ROS inhibition IC50 [μM] = 1.86; Neutrophil adhesion inhibition [%] = 38.5

[0170] 6) 2,5-dihydroxy-4-(3-sulfophenylaminocarbonyl)benzoic acid, compound Ia-002c: 1 H-NMR (250 MHZ, DMSO-d6) δ 11.04 (s, 1H), 10.53 (s, 1H), 7.96 (s, 1H), 7.69 (d, 1H), 7.43 (s, 2H) and 7.40-7.28 (m, 2H) Biodata: Ia-002c: FGF-1 IC50 [μM] = 14; FGF-2 IC50 [μM] = 150; VEGF-A1 IC50 [μM] = 150; VEGFR phosphorylation inhibition IC50 [μM] = 100; PMN ROS inhibition at 0.3 μM [%] = 38.9; PMN ROS inhibition IC50 [μM] = 0.405; Neutrophil adhesion inhibition [%] = 1.87

[0171] 7) 4-(4-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-003a: 1 H-NMR (250 MHz, DMSO-d6) δ 12.8 (br, 1H), 10.73 (s, 1H), 10.68 (s, 1H), 7.94 (d of AB, 2H), 7.84 (d of AB, 2H), 7.39 (s, 1H), 7.34 (s, 1H) HRMS (AX033) バイオデータ:Ia-003a: FGF-1 IC50 [μM] = 12; FGF-2 IC50 [μM] = 34; VEGF-A1 IC50 [μM] = 150; VEGFR-RIAcid blocking IC50 [μM] =ND; PMN ROS [blocking at 0.3 μM [%] = 44.4; PMN ROS blocking IC50 [μM] = 0.414; Good hit followed by blocking [%] = 39.1

[0172] 8) 4-(4-(1H-Tactrol-5-イル)フェニルアミノカルボニル)-2,5-ジヒドロキシbenzoic acid, compound Ia-003aTz: UPLC-MS (acidic method, 2 minutes): rt = 0.79 minutes; m / z = 342.0 [M+H] + , ピークarea>97% 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.70 (s, 1H), 8.04 (d, J = 8.7 Hz, 2H), 7.96 (d, J = 8.5 Hz, 2H), 7.41 (s, 1H), 7.37 (s, 1H). HRMS: [M+H] + , calc. for C 15 H 12 N5O5: 342.08329, found: 342.08326 Biodata: Ia-003a-Tz: FGF-1 IC50 [μM] = 6.7; FGF-2 IC50 [μM] = 45; VEGF-A1 IC50 [μM] = 13; VEGFR-1 kinase inhibition IC50 [μM] = 6.4; PMN ROS inhibition at 0.3 μM [%] = 62.21; PMN ROS inhibition IC50 [μM] = 2.49; IL-4 inhibition [%] = 30.33; Whole blood: GM-CSF IC50 [μM] = >100; IFNγ IC50 [μM] = 2.95; IL-1β IC50 [μM] = >100; IL-2 IC50 [μM] = 43; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 1.41; IL-9 IC50 [μM] = 3.62; IL-10 IC50 [μM] = 6.94; IL-12p70 IC50 [μM] = 1.26; IL-13 IC50 [μM] = 89.6; IL-17A IC50 [μM] = 0.07; IL-17F IC50 [μM] = 83.9; IL-18 IC50 [μM] = >100; IL-21 IC50 [μM] = 1.49; IL-33 IC50 [μM] = 72.2; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.18; TNFβ IC50 [μM] = 55.

[0173] 9) 2,5-ジヒドロキシー4-(4-スルホフェニルアミノカルボニル)benzoic acid, compound Ia-003c: 1 H-NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.51 (s, 1H), 7.66 (d of AB, 2H), 7.58 (d of AB, 2H), 7.40 (s, 1H), 7.39 (S, 1H) バイオデータ:Ia-003c: FGF-1 IC50 [μM] = 35; FGF-2 IC50 [μM] = 150; VEGF-A1 IC50 [μM] = 150; 0.3 μM [%] = ND; PMN ROS blocking IC50 [μM]-; Good hit ball then blocking [%] = ND

[0174] 10) 4-(3-カルボキシ-4-ヒドロキシフェニルアミノカルボニル)-2,5-ジヒドロキシbenzoic acid, compound Ia-004a: UPLC-MS (acidic method, 6.5 min): rt = 1.40 min; m / z = 332.0 [MH] - , ピークarea>96% 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 10.37 (s, 1H), 8.20 (d, J = 2.7 Hz, 1H), 7.74 (dd, J = 8.9, 2.8 Hz, 1H), 7.39 (s, 1H), 7.34 (s, 1H), 6.93 (d, J = 8.9 Hz, 1H). HRMS: [M+H] + , calc. for C 15 H 12 NO8: 334.05574, found: 334.05572 バイオデータ:Ia-004a: FGF-1 IC50 [μM] = 32; FGF-2 IC50 [μM] = 15; VEGF-A1 IC50 [μM] = 28; VEGFR-リン acidification inhibition IC50 [μM] =7.7; PMN ROS [inhibition at 0.3 μM [%] = 64.61; PMN ROS blocking IC50 [μM] = 0; good hit and then blocking [%] = 28.38

[0175] エチルメチルエステル: UPLC-MS (acidic method, 2 min): rt = 1.16 min, m / z = 376.1 [M+H]+ , ピークarea > 95% 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.50 (s, 1H), 10.36 (s, 1H), 9.91 (s, 1H), 8.26 (d, J = 2.7 Hz, 1H), 7.76 (dd, J = 8.9, 2.8 Hz, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 7.01 (d, J = 8.9 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.91 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). HRMS: [M+H] + , calc. for C 18 H 18 NO8: 376.10269, found: 376.10259 バイオデータ:Ia-004a-E2: FGF-1 IC50 [μM] = 35; FGF-2 IC50 [μM] = 36; VEGF-A1 IC50 [μM] = 200; VEGFR-リン acidification blocking IC50 [μM] =6.1; PMN ROS [blocking at 0.3 μM [%] = 85.34; PMN ROS blocking IC50 [μM] = ND; Good hit and then blocking [%] = 97.65

[0176] 11) 4-(2-カルボキシ-4-ヒドロキシフェニルアミノカルボニル)-2,5-ジヒドロキシbenzoic acid, compound Ia-006a: UPLC-MS (acidic method, 2 minutes): rt = 0.81 minutes; m / z = 334.0 [M+H] + , ピークarea>96% 1H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 11.86 (s, 1H), 10.90 (s, 1H), 9.66 (s, 1H), 8.39 (d, J = 9.0 Hz, 1H), 7.40 (d, J = 6.8 Hz, 2H), 7.03 (dd, J = 9.0, 3.0 Hz, 1H). HRMS: [M+H] + , calc. for C 15 H 12 NO8: 334.05574, found: 334.05562. バイオデータ: Ia-006a: FGF-1 IC50 [μM] = 89; FGF-2 IC50 [μM] = 224; VEGF-A1 IC50 [μM] = 100; 0.3 μM [%] = 60.56; PMN ROS blocking IC50 [μM] = 1.2; Good hit and subsequent blocking [%] = 25.33

[0177] 12) 3-(4-Kuronic acid-2,5-ジヒドロキシベンズアミド)fluoric acid, compound Ia-011a: UPLC-MS (acidic method, 2 min): rt = 0.69 min; m / z = 360.1 [MH] - , ピークarea>89% 1 H NMR (400 MHz, DMSO-d6) δ 13.46 (s, 2H), 11.37 (s, 1H), 10.97 (s, 1H), 8.33 (dd, J = 8.2, 1.3 Hz, 1H), 7.63 (dd, J = 7.7, 1.3 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.52 (s, 1H), 7.44 (s, 1H). HRMS: [M+H] + , calc. for C 16 H 12 NO9: 362.05065, found: 362.05036 バイオデータ:Ia-011a: FGF-1 IC50 [μM] = 35; FGF-2 IC50 [μM] = 110; VEGF-A1 IC50 [μM] = 200; 0.3 μM [%] = 57.71; PMN ROS blocking IC50 [μM] = ND; Good hit and then blocking [%] = 42.32

[0178] 13) 2-(4-カルボキシ-2,5-ジヒドロキシベンズアミド)テレフタル acid, compound Ia-012a: UPLC-MS (acidic method, 4 min): rt = 1.12 min; m / z = 362.1 [M+H] + , ピークarea>96% 1 H NMR (400 MHz, DMSO-d6) δ 13.41 (brs, 2H), 12.29 (s, 1H), 10.94 (s, 1H), 9.26 (d, J = 1.7 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.73 (dd, J = 8.2, 1.7 Hz, 1H), 7.42 (s, 2H). HRMS: [M+H] + , calc. for C 16 H 12 NO9: 362.05065, found: 362.05046. バイオデータ:Ia-012a: FGF-1 IC50 [μM] = 38; FGF-2 IC50 [μM] = 36; VEGF-A1 IC50 [μM] = 30; μM [%] = 59.52; PMN ROS blocking IC50 [μM] = 1.85; Good hit and subsequent blocking [%] = 28.5

[0179] 14) 2-(4-Kuronic acid-2,5-ジヒドロキシベンズアミド)イソFructus acid, compound Ia-013a: UPLC-MS (acidic method, 4 min): rt = 0.91 min; m / z = 362.0 [M+H] + , ピークarea>98% 1 H NMR (400 MHz, DMSO-d6) 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) HRMS: [M+H] + , calc. for C 16 H 12 NO9: 362.05065, found: 362.05041 バイオデータ:Ia-013a: FGF-1 IC50 [μM] = 29; FGF-2 IC50 [μM] = 18; VEGF-A1 IC50 [μM] = 17; VEGFR-リン acidification inhibition IC50 [μM] =100; PMN ROS [inhibition at 0.3 μM [%] = 38.52; PMN ROS blocking IC50 [μM] = 2.38; Good hit and subsequent blocking [%] = 27.67

[0180] 15) 4-(4-Kuronic acid-2,5-ジヒドロキシベンズアミド)fluoric acid, compound Ia-014a: UPLC-MS (acidic method, 4 min): rt = 0.98 min; m / z = 362.1 [M+H] + , ピークarea>94% 1 H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.70 (s, 1H), 8.14 (s, 1H), 7.94 - 7.84 (m, 2H), 7.38 (s, 1H), 7.30 (s, 1H). HRMS: [M+H] + , calc. for C 16 H 12 NO9: 362.05065, found: 362.05047 Biodata: Ia-014a: FGF-1 IC50 [μM] = 20; FGF-2 IC50 [μM] = 20; VEGF-A1 IC50 [μM] = 88; VEGFR phosphorylation inhibition IC50 [μM] = 100; PMN ROS inhibition at 0.3 μM [%] = 61.3; PMN ROS inhibition IC50 [μM] = 1; Neutrophil adhesion inhibition [%] = 9.667

[0181] 16) 5-(4-carboxy-2,5-dihydroxybenzamido)isophthalic acid, compound Ia-015a: 1 H NMR (250 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.56 (narrow d, 2H), 8.22 (narrow t, 1H), 7.41 (s, 1H), and 7.37 (s, 1H). Biodata: Ia-015a: FGF-1 IC50 [μM] = 20; FGF-2 IC50 [μM] = 9.3; VEGF-A1 IC50 [μM] = 19; VEGFR-1 kinase inhibition IC50 [μM] = 0.15; PMN ROS inhibition at 0.3 μM [%] = 43.8; PMN ROS inhibition IC50 [μM] = 0.387; GM-CSF inhibition [%] = 17.38; Whole blood: GM-CSF IC50 [μM] = 2.76; IFNγ IC50 [μM] = >100; IL-1β IC50 [μM] = >100; IL-2 IC50 [μM] = 7.08; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 0.77; IL-9 IC50 [μM] = 1.47; IL-10 IC50 [μM] = 5.27; IL-12p70 IC50 [μM] = 0.12; IL-13 IC50 [μM] = 0.15; IL-17A IC50 [μM] = 0.05; IL-17F IC50 [μM] = 0.15; IL-18 IC50 [μM] = >100; IL-21 IC50 [μM] = 57.2; IL-33 IC50 [μM] = 0.24; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.17; TNFβ IC50 [μM] = 0.3.

[0182] 17) 3-(4-Kuronic acid-2,5-Kuronic acid, Compound Ia-023a: UPLC-MS (acidic method, 4 min): rt = 0.63 min; m / z = 319.1 [M+H] + , ピークarea>93% 1H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 11.03 (s, 1H), 9.78 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 7.82 (d, J = 5.0 Hz, 1H), 7.45 (s, 1H), 7.43 (s, 1H). HRMS: [M+H] + , calc. for C 14 H 11 N2O7: 319.05608, found: 319.05610 バイオデータ:Ia-023a: FGF-1 IC50 [μM] = ND; FGF-2 IC50 [μM] = 63; VEGF-A1 IC50 [μM] = 143; VEGFR-リン acidification inhibition IC50 [μM] =100; PMN ROS [inhibition at 0.3 μM [%] = 61.95; PMN ROS blocking IC50 [μM] = 0; good hit and then blocking [%] = 13.37

[0183] ジエチルエステル: UPLC-MS (acidic method, 4 min): rt = 1.87 min, m / z = 375.1 [M+H] + , ピークarea > 98% 1 H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 11.23 (s, 1H), 9.87 (s, 1H), 9.68 (s, 1H), 8.50 (d, J = 5.0 Hz, 1H), 7.81 (dd, J = 5.1, 0.7 Hz, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 4.46 - 4.27 (m, 4H), 1.41 - 1.25 (m, 6H). HRMS: [M+H] + , calc. for C 18 H 19 N2O7: 375.11867, found: 375.11867 Biodata: Ia-023a-E2: FGF-1 IC50 [μM] = ND; FGF-2 IC50 [μM] = 76; VEGF-A1 IC50 [μM] = 141; VEGFR phosphorylation inhibition IC50 [μM] = 6.6; PMN ROS inhibition at 0.3 μM [%] = 69.47; PMN ROS inhibition IC50 [μM] = 0; Neutrophil adhesion inhibition [%] = 34

[0184] 18) 4-(4-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-032a: 1 H NMR (250 MHz, DMSO-d6): 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). Biodata: Ia-032a: FGF-1 IC50 [μM] = ND; FGF-2 IC50 [μM] = 91; VEGF-A1 IC50 [μM] = ND; VEGFR phosphorylation inhibition IC50 [μM] = 100; PMN ROS inhibition at 0.3 μM [%] = ND; PMN ROS inhibition IC50 [μM] -; Neutrophil adhesion inhibition [%] = ND

[0185] 19) 4-(3-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-033a: UPLC-MS (acidic method, 6.5 min): rt = 1.71 min; m / z = 332.1 [M+H] + , Peak area >99% 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 10.46 (s, 1H), 7.65 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 3.57 (s, 2H). HRMS: [M+H] + , calc. for C 16 H 14 NO7: 332.07647, found: 332.07644 バイオデータ:Ia-033a: FGF-1 IC50 [μM] = 60; FGF-2 IC50 [μM] = 165; VEGF-A1 IC50 [μM] = 281; 0.3 μM [%] = 57.73; PMN ROS blocking IC50 [μM] = 1.32; Good hit followed by blocking [%] = 38

[0186] 20) 4-(2-(カルボキシメチル)フェニルアミノカルボニル)-2,5-ジヒドロキシbenzoic acid, compound Ia-034a: UPLC-MS (acidic method, 2 min): rt = 0.82 min; m / z = 332.1 [M+H] + , ピークarea>98% 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 3.0 Hz, 2H), 7.28 (d, J = 7.6 Hz, 2H), 7.15 (t, J = 7.4 Hz, 1H), 3.63 (s, 2H). HRMS: [M+H] + , calc. for C 16 H 14 NO7: 332.07648, found: 332.07641 バイオデータ:Ia-034a: FGF-1 IC50 [μM] = 79; FGF-2 IC50 [μM] = 14; VEGF-A1 IC50 [μM] = 102; VEGFR-リン acidification inhibition IC50 [μM] =100; PMN ROS [inhibition at 0.3 μM [%] = 49.07; PMN ROS blocking IC50 [μM] = 2.28; Good hit and then blocking [%] = 15

[0187] 21) 4-(3,4-ジヒドロキシフェニルメチルアミノカボニル)-2,5-ジヒドロキシbenzoic acid, compound Ia-035a: UPLC-MS (acidic method, 2 min): rt = 1.02 min; m / z = 320.1 [M+H] + , ピークarea>91% 1 H NMR (400 MHz, DMSO- d6) δ 11.56 (s, 1H), 9.21 (t, J = 5.9 Hz, 1H), 8.91 (s, 1H), 8.79 (s, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 6.72 (d, J = 2.1 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.57 (dd, J = 8.0, 2.1 Hz, 1H), 4.32 (d, J = 5.8 Hz, 2H). HRMS: [M+H] + , calc. for C 15 H 14 NO7: 320.07648, found: 320.07650 バイオデータ:Ia-035a: FGF-1 IC50 [μM] = 20; FGF-2 IC50 [μM] = 71; VEGF-A1 IC50 [μM] = 200; VEGFR-リン acidification inhibition IC50 [μM] =36; PMN ROS [inhibition at 0.3 μM [%] = 75.13; PMN ROS blocking IC50 [μM] = 0.41; Good hit and then blocking [%] = 27

[0188] 22) 4-(2-(3,4-ジヒドロキシフェニル)エチルアミノカルボニル)-2,5-ジヒドロキシbenzoic acid, compound Ia-035a-2: UPLC-MS (acidic method, 2 min): rt = 0.77 min; m / z = 332.0 [MH] - , ピークarea>99% 1 H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.85 (t, J = 5.6 Hz, 1H), 8.76 (s, 1H), 8.66 (s, 1H), 7.41 (s, 1H), 7.28 (s, 1H), 6.67 -6.60 (m, 2H), 6.48 (dd, J = 8.0, 2.1 Hz, 1H), 3.44 (q, J = 6.8 Hz, 2H), 2.67 (dd, J = 8.6, 6.0 Hz, 2H).δ 11.56 (s, 1H), 9.21 (t, J = 5.9 Hz, 1H), 8.91 (s, 1H), 8.79 (s, 1H), 7.46 (s, 1H), 7.28 (s, 1H), 6.72 (d, J = 2.1 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.57 (dd, J = 8.0, 2.1 Hz, 1H), 4.32 (d, J = 5.8 Hz, 2H). HRMS: [M+H] + , calc. for C 16 H 16 NO7: 334.09213, found: 334.09242 バイオデータ:Ia-035a-2: FGF-1 IC50 [μM] = 10; FGF-2 IC50 [μM] = 65; VEGF-A1 IC50 [μM] = 109; 0.3 μM [%] = 58.81; PMN ROS blocking IC50 [μM] = 1.1; Good hit and subsequent blocking [%] = 21.5

[0189] 23) 4-(1-carboxy-2-(3,4-dihydroxyphenyl)ethylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-035a-3: UPLC-MS (acidic method, 2 min): rt = 0.70 min; m / z = 376.0 [MH] - , Peak area >99% 1 H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 11.11 (s, 1H), 8.98 (d, J = 7.4 Hz, 1H), 8.73 (d, J = 13.1 Hz, 2H), 7.45 (s, 1H), 7.31 (s, 1H), 6.61 (dd, J = 5.1, 2.9 Hz, 2H), 6.47 (dd, J = 8.1, 2.1 Hz, 1H), 3.01 (dd, J = 13.9, 4.9 Hz, 1H), 2.96 - 2.84 (m, 1H). HRMS: [M+H] + , calc. for C 17 H 16 NO9: 378.08196, found: 378.08195 Biodata: Ia-035a-3: FGF-1 IC50 [μM] = 34; FGF-2 IC50 [μM] = 207; VEGF-A1 IC50 [μM] = 198; VEGFR phosphorylation inhibition IC50 [μM] = 10; PMN ROS inhibition at 0.3 μM [%] = 79.62; PMN ROS inhibition IC50 [μM] = 0.66; Neutrophil adhesion inhibition [%] = 22

[0190] 24) 4-(carboxy(3,4-dihydroxyphenyl)methylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-036a: UPLC-MS (acidic method, 2 min): rt = 0.62 min; m / z = 362.1 [MH] - , Peak area >92% 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.32 (d, J = 6.7 Hz, 1H), 9.05 (s, 1H), 8.97 (s, 1H), 7.40 (s, 1H), 7.34 (s, 1H), 6.81 (d, J = 2.1 Hz, 1H), 6.75 - 6.64 (m, 2H), 5.29 (d, J = 6.6 Hz, 1H). HRMS: [M+H] + , calc. for C 16 H 14 NO9: 364.06630, found: 364.06615 バイオデータ:Ia-036a: FGF-1 IC50 [μM] = ND; FGF-2 IC50 [μM] = 37; VEGF-A1 IC50 [μM] = 123; VEGFR-RIA acid blocking IC50 [μM] =1.6; PMN ROS [blocking at 0.3 μM [%] = 87.17; PMN ROS blocking IC50 [μM] = ND; Good hit and then blocking [%] = 30.77

[0191] 25) 4-(2-カルボキシフェニルメチルアミノカルボニル)-2,5-ジヒドロキシbenzoic acid, compound Ia-053a: UPLC-MS (acidic method, 4 min): rt = 1.08 min; m / z = 332.0 [M+H] + , ピークarea>97% 1 H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 11.19 (s, 1H), 9.34 - 9.27 (m, 1H), 7.91 (dd, J = 7.8, 1.4 Hz, 1H), 7.55 (dd, J = 7.5, 1.5 Hz, 1H), 7.46 (d, J = 7.9 Hz, 2H), 7.39 (td, J = 7.5, 1.4 Hz, 1H), 7.32 (s, 1H), 4.82 (d, J = 5.9 Hz, 2H). HRMS: [M+H] +, calc. for C 16 H 14 NO7: 332.07648, found: 332.07622 Biodata: Ia-053a: FGF-1 IC50 [μM] = 150; FGF-2 IC50 [μM] = 124; VEGF-A1 IC50 [μM] = 210; VEGFR phosphorylation inhibition IC50 [μM] = 100; PMN ROS inhibition at 0.3 μM [%] = 52.92; PMN ROS inhibition IC50 [μM] = 2.5; Neutrophil adhesion inhibition [%] = 18.67

[0192] Scheme 4b. Synthesis of ethyl 4-amino-2,5-dibenzyloxybenzoate (aniline A) [ka]

[0193] Protocol: Synthesis of aniline A Ethyl 4-amino-2,5-dibenzyloxybenzoate (aniline A). To a cooled (ice bath) solution of 2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid (KI-1) (2.0 g, 4.9 mmol) and EtN (1.6 mL, 11.3 mmol) in THF (25 mL) was added DPPA (1.1 mL, 5.2 mmol) slowly under an inert atmosphere (N). The mixture was slowly warmed to room temperature and stirred at this temperature for 3 h. Water (8 mL) was then added, and the reaction mixture was heated to 70 °C for 2 h. The reaction mixture was poured into a saturated solution of sodium bicarbonate (250 mL) and stirred for 5 min, followed by extraction with EtOAc (3 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a colorless oil. The residue was purified by flash column chromatography (isohexane / EtOAc, 1:0, then grading to 30% EtOAc) to give the title compound aniline A (1.0 g, 53%) as an off-white solid.

[0194] UPLC-MS (acidic method, 2 min): rt = 1.26 min; m / z = 378.2 [M+H] + , Peak area 94% 1 H NMR (400 MHz, DMSO-d6) 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).

[0195] 26) 4-(4-carboxy-2,5-dihydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-056a: UPLC-MS (acidic method, 4 min): rt = 0.90 min; m / z = 348.0 [MH]-, peak area 97% 1H NMR (400 MHz, DMSO-d6) δ 11.28 (brs, 1H), 11.26 (s, 1H), 9.97 (s, 1H), 8.09 (s, 1H), 7.48 (s, 1H), 7.42 (s, 1H), 7.26 (s, 1H).

[0196] Diethyl ester: UPLC-MS (acidic method, 4 min): rt = 1.86 min; m / z = 404.2 [MH] - , Peak area 92% 1 H NMR (400 MHz, DMSO-d6) δ 11.48 (brs, 1H), 11.32 (brs, 1H), 10.28 (s, 1H), 10.07 (brs, 1H), 9.88 (s, 1H), 8.12 (s, 1H), 7.58 (s, 1H), 7.39 (s, 1H), 7.28 (s, 1H), 4.46 - 4.27 (m, 4H), 1.46 - 1.12 (m, 6H).

[0197] Example 1.2 - Molecules of Type Ib: Diamides from Diamines, One Example [ka]

[0198] Scheme 5. Synthesis of diamides of type Ib [ka]

[0199] Synthetic procedure: See general procedure, steps [3], [4], [5]. example: [ka]

[0200] The conditions and yields are as follows: see Figures 4A-D.

[0201] 27) 3,5-bis(2,5-dihydroxy-4-carboxybenzoylamino)benzoic acid, compound Ib-010a: UPLC-MS (acidic method, 4 min): rt = 0.98 min; m / z = 511.0 [MH] - , Peak area >93% 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 2H), 10.65 (s, 2H), 8.38 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 2.0 Hz, 2H), 7.39 (d, J = 2.3 Hz, 4H). HRMS: [M+H] + , calc. for C 23 H 17 N2O 12 : 513.07760, found: 513.07736, Biodata: Ib-010a: FGF-1 IC50 [μM] = 14; FGF-2 IC50 [μM] = 3.8; VEGF-A1 IC50 [μM] = 15; VEGFR-1 phosphatase inhibition IC50 [μM] = 1.6; PMN ROS inhibition at 0.3 μM [%] = 71.84; PMN ROS inhibition IC50 [μM] = 1.06; IL-4 inhibition [%] = 1.5; Whole blood: GM-CSF IC50 [μM] = >100; IFNγ IC50 [μM] = 2.22; IL-1β IC50 [μM] = 33.3; IL-2 IC50 [μM] = 2.74; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 1.02; IL-9 IC50 [μM] = 11.58; IL-10 IC50 [μM] = >100; IL-12p70 IC50 [μM] = 0.27; IC50 [μM] = 0.42; IL-17F IC50 [μM] = >100; IL-18 IC50 [μM] = >100; IL-21 IC50 [μM] = 67.8; IL-33 IC50 [μM] = 31.3; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.31; TNFβ IC50 [μM] = 49.3

[0202] トリエチルエステル: UPLC-MS (acidic method, 2 min): rt = 1.29 min, m / z = 597.1 [M+H] + , ピーク area> 96% 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 2H), 10.68 (s, 2H), 9.95 (s, 2H), 8.40 (t, J = 2.0 Hz, 1H), 8.15 (d, J = 2.0 Hz, 2H), 7.42 (s, 2H), 7.39 (s, 2H), 4.42 - 4.33 (m, 6H), 1.38 - 1.33 (m, 9H). HRMS: [M+H] + , calc. for C 29 H 29 N2O 12 : 597.17150, found: 597.17131 Biodata: Ib-010a-E3: FGF-1 IC50 [μM] = 26; FGF-2 IC50 [μM] = 226; VEGF-A1 IC50 [μM] = 200; VEGFR-1 kinase inhibition IC50 [μM] = 0.09; PMN ROS inhibition at 0.3 μM [%] = 36.41; PMN ROS inhibition IC50 [μM] = 6.52; IL-4 inhibition [%] = 79.5; Whole blood: GM-CSF IC50 [μM] = >100; IFNγ IC50 [μM] = 2.79; IL-1β IC50 [μM] = >100; IL-2 IC50 [μM] = 36.2; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 0.24; IL-9 IC50 [μM] = 26.8; IL-10 IC50 [μM] = >100; IL-12p70 IC50 [μM] = 0.84; IL-13 IC50 [μM] = 33; IL-17A IC50 [μM] = 0.52; IL-17F IC50 [μM] = 34.2; IL-18 IC50 [μM] = >100; IL-21 IC50 [μM] = >100; IL-33 IC50 [μM] = 20; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.98; TNFβ IC50 [μM] = 38.2.

[0203] Triethyl ester tetraacetate: UPLC-MS (acidic method, 2 min): rt = 1.19 min, m / z = 782.1 [M+NH4] + , Peak area 91% 1 H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 2H), 8.40 (m, 1H), 8.08 (d, J = 2.0 Hz, 2H), 7.80 (s, 2H), 7.63 (s, 2H), 4.45 - 4.22 (m, 6H), 2.32 (s, 6H), 2.23 (s, 6H), 1.38 - 1.27 (m, 9H). Biodata: Ib-010a-E3-A4: FGF-1 IC50 [μM] = 200; FGF-2 IC50 [μM] = 200; VEGF-A1 IC50 [μM] = 200; VEGFR phosphorylation inhibition IC50 [μM] = 0.54; PMN ROS inhibition at 0.3 μM [%] = 54.86; PMN ROS inhibition IC50 [μM] = 1.49; Neutrophil adhesion inhibition [%] = 96

[0204] Example 1.3. Type Ic molecules: diacids from diamines, 4 examples [ka]

[0205] Scheme 6. Synthesis of Amides of Type Ic Where R=R' [ka]

[0206] Procedure: See basic procedure from KI-6 [3], [4], [5]. example: [ka] [ka]

[0207] The conditions and yields are as follows: see Figures 4A-D.

[0208] 28) N1,N4-bis(2-(1H-tetrazol-5-yl)phenyl)-2,5-dihydroxyterephthalamide, compound Ic-001aTz2: UPLC-MS (acidic method, 2 min): rt = 0.97 min; m / z = 485.1 [M+H] + , Peak area >97% 1 H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 10.98 (s, 1H), 8.49 (dd, J = 8.4, 1.2 Hz, 1H), 7.90 (dd, J = 7.8, 1.6 Hz, 1H), 7.62 (ddd, J = 8.7, 7.4, 1.6 Hz, 1H), 7.58 (s, 1H), 7.37 (td, J = 7.6, 1.2 Hz, 1H). HRMS: [M+H] + , calc. for C 22 H 17 N 10 O4: 485.14287, found: 485.17274 Biodata: Ic-001aTz2: FGF-1 IC50 [μM] = 200; FGF-2 IC50 [μM] = 70; VEGF-A1 IC50 [μM] = 45; VEGFR-1 kinase inhibition IC50 [μM] = 2.2; PMN ROS inhibition at 0.3 μM [%] = 60.64; PMN ROS inhibition IC50 [μM] = ND; GM-CSF inhibition [%] = 97.15; Whole blood: GM-CSF IC50 [μM] = >100; IFNγ IC50 [μM] = 1.38; IL-1β IC50 [μM] = >100; IL-2 IC50 [μM] = 9.45; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 0.52; IL-9 IC50 [μM] = 9.13; IL-10 IC50 [μM] = >100; IL-12p70 IC50 [μM] = 29.1; IL-13 IC50 [μM] = 0.12; IL-17A IC50 [μM] = 0.31; IL-17F IC50 [μM] = 0.15; IL-18 IC50 [μM] = 33.9; IL-21 IC50 [μM] = 32; IL-33 IC50 [μM] = 0.23; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.1; TNFβ IC50 [μM] = 0.41.

[0209] 29)5-(4-(3-カルボキシ-4-ヒドロキシフェニルアミノカルボニル)-2 ,5-ジヒドロキシベンズアミド)-2-ヒドロキシbenzoic acid, compound Ic-007a: UPLC-MS (acidic method, 2 min): rt = 0.80 min; m / z = 469.1 [M+H] + , ピークarea>91% 1 H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 2H), 7.65 (s, 2H), 7.59 (s, 2H), 7.30 - 6.89 (m, 5H), 6.79 (d, J = 8.8 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.1, 165.2, 158.3, 150.1, 130.2, 129.2 (CH), 122.8, 122.6 (CH), 117.7 (CH), 117.3 (CH), 113.3. HRMS: [M+H] + , calc. for C 22 H 17 N2O 10 : 469.08777, found: 469.08739 Biodata: Ic-007a: FGF-1 IC50 [μM] = 13; FGF-2 IC50 [μM] = 5.4; VEGF-A1 IC50 [μM] = 3.2; VEGFR-1 phosphatase inhibition IC50 [μM] = 0.09; PMN ROS inhibition at 0.3 μM [%] = 57.99; PMN ROS inhibition IC50 [μM] = 2.7; IL-4 inhibition [%] = 57.5; Whole blood: GM-CSF IC50 [μM] = >100; IFNγ IC50 [μM] = 1.44; IL-1β IC50 [μM] = >100; IL-2 IC50 [μM] = >100; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 0.09; IL-9 IC50 [μM] = 27.1; IL-10 IC50 [μM] = 12.5; IL-12p70 IC50 [μM] = 0.49; IL-13 IC50 [μM] = 30.1; IL-17A IC50 [μM] = 0.04; IL-17F IC50 [μM] = 22.9; IL-18 IC50 [μM] = >100; IL-21 IC50 [μM] = 1.9; IL-33 IC50 [μM] = 18.4; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.27; TNFβ IC50 [μM] = 6.52

[0210] ジメチルエステル: UPLC-MS (acidic method, 2 min): rt = 1.13 min, m / z = 497.0 [M+H] + , Peak area > 95% 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 2H), 10.48 (s, 2H), 10.38 (s, 2H), 8.27 (d, J = 2.8 Hz, 2H), 7.89 - 7.74 (m, 2H), 7.56 (s, 2H), 7.03 (d, J = 8.9 Hz, 2H), 3.93 (s, 6H). HRMS: [M+H] + , calc. for C 24 H 21 N2O 10 : 497.11907, found: 497.11874. Biodata: Ic-007a-E2: FGF-1 IC50 [μM] = 23; FGF-2 IC50 [μM] = 49; VEGF-A1 IC50 [μM] = 200; VEGFR phosphorylation inhibition IC50 [μM] = 0.25; PMN ROS inhibition at 0.3 μM [%] = 21.33; PMN ROS inhibition IC50 [μM] = 7.9; Neutrophil adhesion inhibition [%] = 2

[0211] Alternative large-scale synthesis of Ic-007a a) 5-(4-(3-methoxycarbonyl-4-hydroxyphenylaminocarbonyl)-2,5-dibenzyloxybenzamido)-2-hydroxybenzoic acid methyl ester A 5 L flange flask was charged with 2,5-bis(benzyloxy)terephthalic acid (KI-6, 141.00 g, 0.373 mol), benzyltriethylammonium chloride (850 mg, 3.73 mmol, 0.01 equiv.), and chloroform (2.5 L). It was then equipped with a nitrogen inlet, a thermometer, a pressure-equalizing dropping funnel, an outlet to an empty Dreschel bottle, and a sodium hydroxide bubbler. The stirred solution was warmed to 55 °C, and thionyl chloride (59 mL, 0.802 mol, 2.15 equiv.) was added dropwise over 40 min. The solution was held at 55 °C for 6 h before being cooled to room temperature overnight. An aliquot was sonicated in ethanol for 5 min and then analyzed by LCMS analysis, which showed only the diethyl ester. The mixture was transferred to two round-bottom flasks, and the volatiles were removed under reduced pressure; the acid chloride was azeotroped with toluene (800 mL in each flask). A 10 L jacketed vessel was charged with methyl 5-amino-2-hydroxybenzoate (137.00 g, 0.819 mol, 2.2 equiv) and dichloromethane (2.5 L, 18 vol), and 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, making stirring difficult; the reaction also exothermed to 30°C. However, with prolonged stirring, the mixture became a fine pink / purple suspension. The mixture was stirred at 25°C for 72 hours. The suspension was filtered and washed with dichloromethane (2 L, 14 vol), and the resulting solid was dried in a vacuum oven to give 240.00 g of product (94% yield).

[0212] b) 5-(4-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid, Ic-007a Saponification: A 5 L three-necked round-bottom flask was charged with freshly ground 5-(4-(3-methoxycarbonyl-4-hydroxyphenylaminocarbonyl)-2,5-dibenzyloxybenzamido)-2-hydroxy-benzoic acid methyl ester (150.00 g, 0.22 mol) and isopropanol (1.5 L, 10 vol). The mixture was warmed to 50° C. and tetrabutylammonium hydroxide (444 mL, 0.67 mol, 3 eq) and water (1.1 L, 7 vol) were added. After 1 h, some solid remained, so an additional 60 mL of tetrabutylammonium hydroxide solution was added along with water (120 mL) and the mixture was stirred at 50° C. for 6 h, then cooled to room temperature overnight. Additional tetrabutylammonium hydroxide (80 mL) was added and the mixture was further stirred at 60° C. for 1 h until no solid remained.

[0213] Hydrogenolysis: The reaction was degassed (three cycles with N), then the catalyst (30.00 g, 10% Pd / C) was added as a slurry in water (100 mL). The reaction was further degassed (three cycles with N, two cycles with H) and placed under H (balloon pressure) at 50 °C overnight. The reaction was recharged with hydrogen and held at 50 °C for an additional 4 h, after which LCMS analysis indicated the reaction was complete. The reaction mixture was degassed (three cycles with N), filtered through a Celite pad, and washed with hot water / isopropanol (1 L, 1:1, 60 °C). The volume was reduced to approximately 1.2 L under reduced pressure. The mixture was transferred to a 5 L flange flask containing water (approximately 3 L). The flask was equipped with an overhead stirrer (large anchor type) and acidified with hydrochloric acid (35%). A heavy precipitate formed during the addition. The mixture was heated at 55°C for 6 hours and then cooled to room temperature over 72 hours. The mixture was filtered, and the solid was slurried in 1M aqueous HCl (3 L), heated to 50°C for 3 hours, and then cooled to room temperature overnight. The mixture was filtered and washed with 1M aqueous HCl (2 L), water (1.5 L), and acetone (1 L). The solid was dried in a vacuum oven to give 100.00 g of product still contaminated with approximately 5 mol% tetrabutylammonium salt (NMR). This solid was stirred in 1M aqueous hydrochloric acid (3 L) at 70°C for 8 hours and then cooled to room temperature overnight. 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).

[0214] 30) 2-(2,5-dihydroxy-4-(4-hydroxy-2-carboxyphenylaminocarbonyl)benzamido)-5-hydroxybenzoic acid, compound Ic-009a: UPLC-MS (acidic method, 2 min): rt = 0.85 min; m / z = 469.0 [M+H] + , Peak area >98% 1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 2H), 11.93 (s, 2H), 10.85 (s, 2H), 9.64 (s, 2H), 8.41 (d, J = 9.0 Hz, 2H), 7.55 (s, 2H), 7.39 (d, J = 3.0 Hz, 2H), 7.03 (dd, J = 9.0, 3.0 Hz, 2H). HRMS: calc. for C 22 H 17 N2O 10 : 469.08777, found: 469.08755 バイオデータ:Ic-009a: FGF-1 IC50 [μM] = 32; FGF-2 IC50 [μM] = 202; VEGF-A1 IC50 [μM] = 208; VEGFR-Rin acid blocking IC50 [μM] =ND; PMN ROS [blocking at 0.3 μM [%] = 72.85; PMN ROS blocking IC50 [μM] = ND; Good hit and then blocking [%] = 72.21

[0215] ジメチルエステル: UPLC-MS (acidic method, 2 min): rt = 1.03 min, m / z = 497.1 [M+H] + , ピーク area> 92% 1 H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 2H), 11.01 (s, 2H), 9.75 (s, 2H), 8.36 (d, J = 9.0 Hz, 2H), 7.62 (s, 2H), 7.37 (d, J = 3.0 Hz, 2H), 7.07 (dd, J = 9.0, 3.0 Hz, 2H), 3.87 (s, 6H). HRMS: calc. for C 24 H 21 N2O 10 : 497.11907, found: 497.11913 Biodata: Ic-009a-E2: FGF-1 IC50 [μM] = 23; FGF-2 IC50 [μM] = 30; VEGF-A1 IC50 [μM] = 200; VEGFR phosphorylation inhibition IC50 [μM] = 0.02; PMN ROS inhibition at 0.3 μM [%] = 24.12; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 41.05

[0216] Scheme 7. Synthesis of Amides of Type Ic Where R≠R' [ka]

[0217] Synthesis procedure: See the general procedure from KI-1. example: [ka] [ka]

[0218] The conditions and yields are as follows: see Figures 4A-D.

[0219] 31) 5-(4-(2-(1H-tetrazol-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid, compound Ic-001aTz / 004a: UPLC-MS (acidic method, 4 min): rt = 1.40 min; m / z = 477.2 [MH] - , Peak area >99% 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.42 (s, 1H), 8.47 (dd, J = 8.4, 1.2 Hz, 1H), 8.25 (d, J = 2.7 Hz, 1H), 7.98 - 7.88 (m, 1H), 7.76 (dd, J = 8.9, 2.8 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.51 (s, 1H), 7.37 (td, J = 7.6, 1.2 Hz, 1H), 6.97 (d, J = 8.9 Hz, 1H). HRMS: [M+H] + , calc. for C 22 H 17 N6O7: 477.11532, found: 477.11475 Biodata: Ic-001a-Tz / 004a: FGF-1 IC50 [μM] = 19; FGF-2 IC50 [μM] = 87; VEGF-A1 IC50 [μM] = 25; VEGFR-1 kinase inhibition IC50 [μM] = 2.6; PMN ROS inhibition at 0.3 μM [%] = 82.83; PMN ROS inhibition IC50 [μM] = ND; GM-CSF inhibition [%] = 96.99; Whole blood: GM-CSF IC50 [μM] = 3.4; IFNγ IC50 [μM] = 0.61; IL-1β IC50 [μM] = >100; IL-2 IC50 [μM] = 4.91; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 3.04; IL-9 IC50 [μM] = 8.48; IL-10 IC50 [μM] = 19.5; IL-12p70 IC50 [μM] = 12.2; IL-13 IC50 [μM] = 1.5; IL-17A IC50 [μM] = 0.02; IL-17F IC50 [μM] = 2.4; IL-18 IC50 [μM] = 46.6; IL-21 IC50 [μM] = 0.3; IL-33 IC50 [μM] = 1.67; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.002; TNFβ IC50 [μM] = 3.02

[0220] メチルエステル: UPLC-MS (acidic method, 2 min): rt = 1.06 min, m / z = 491.1 [M+H] + , ピーク area> 89% 1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 10.90 (s, 1H), 10.45 (s, 1H), 10.37 (s, 1H), 8.47 (dd, J = 8.4, 1.2 Hz, 1H), 8.30 (d, J = 2.7 Hz, 1H), 7.91 (dd, J = 7.8, 1.6 Hz, 1H), 7.76 (dd, J = 8.9, 2.7 Hz, 1H), 7.63 (ddd, J = 8.7, 7.4, 1.6 Hz, 1H), 7.58 (s, 1H), 7.51 (s, 1H), 7.38 (td, J = 7.6, 1.2 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 3.93 (s, 4H). HRMS: [M+H] + , calc. for C 23 H 19 N6O7: 491.13097, found: 491.13071 バイオデータ:Ic-001a-Tz / 004a-E1: FGF-1 IC50 [μM] = 104; FGF-2 IC50 [μM] = 200; VEGF-A1 IC50 [μM] = 35; VEGFR-リン acidification inhibition IC50 [μM] = 0.1; PMN ROS [blocking at 0.3 μM [%] = 73.97; PMN ROS blocking IC50 [μM] = ND; good hit and then blocking [%] = 97.56

[0221] Example 1.4. Polymer Id molecule: Polymer-conjugated type, 1 example

change

[0222] スキーム8. Synthesis of タイプId compounds

change

[0223] Synthetic procedure: See basic procedure from KI-1 [3], [4], [5]. Cyclization step: See Figure 4A-D. example: [ka]

[0224] 32) 2-(4-carboxy-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid, compound Id-030a: UPLC-MS (acidic method, 4 min): rt = 0.99 min; m / z = 313.1 [MH] - , Peak area >97% 1 H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.80 (s, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.62 (s, 1H) Biodata: Unstable in DMSO

[0225] Ethyl methyl ester: UPLC-MS (acidic method, 4 min): rt = 2.09 min, m / z = 357.1 [M+H] + , Peak area > 89% 1 H NMR (400 MHz, DMSO-d6+D2O 10%) δ 7.97 (d, J = 8.0 Hz, 1H), 7.90 - 7.83 (m, 2H), 7.44 - 7.36 (m, 2H), 4.35 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). HRMS: [M+H] + , calc. for C 18 H 17 N2O6: 357.10811, found: 357.10827 Biodata: Id-030a-E2: FGF-1 IC50 [μM] = 115; FGF-2 IC50 [μM] = 200; VEGF-A1 IC50 [μM] = 200; VEGFR phosphorylation inhibition IC50 [μM] = 0.33; PMN ROS inhibition at 0.3 μM [%] = 0; PMN ROS inhibition IC50 [μM] = 0; Neutrophil adhesion inhibition [%] = 43

[0226] Example 1.5. Type IIa molecules: monoamides, 16 examples [ka]

[0227] Precursor synthesis Scheme 9a. Synthesis of Intermediates KI-2 and KI-7 [ka]

[0228] procedure: Synthesis of KI-2 and KI-7 2,6-Di(ethoxycarbonyl)cyclohexane-1,4-dione [Step 1] [Reference: 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 min to a suspension of diethyl 1,3-acetonedicarboxylate (18 mL, 0.1 mol) and potassium carbonate-325 mesh (21.5 g, 0.15 mol) in THF (1 L) at reflux. After 2 h, the reaction was complete, and the mixture was cooled to room temperature and then filtered through Celite®; the solid residue was washed with THF (200 mL), and the solvent was then removed under reduced pressure. The crude product was purified by flash column chromatography (hexane / EtOAc 0-20%) to give the title compound (9.3 g, 37% yield).

[0229] UPLC-MS (acidic method, 2 min): rt = 1.01 min; m / z = 257.1 [M+H] - , Peak area >74% 1 H NMR (400 MHz, DMSO-d6): Complex mixture of enol and cis / trans isomers δ 12.10 (s), 4.23 (q, J = 7.1 Hz), 4.11 (m), 3.85 - 3.77 (m), 3.70 (s), 3.10 - 2.89 (m), 2.89 - 2.80 (m), 2.62 - 2.58 (m), 1.25 (t, J = 7.1 Hz), 1.22 - 1.15 (m, 9H).

[0230] Diethyl 2,5-dihydroxyisophthalate [Step 2]: 1668040188778_32 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, NBS (3.5 g, 20 mmol) was added portionwise over 30 min. After a further 20 min, the reaction was quenched by the addition of water (100 ml). 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).

[0231] UPLC-MS (acidic method, 2 min): rt = 1.00 min; m / z = 253.1 [MH] - , Peak area >90% 1 H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.57 (s, 1H), 7.39 (s, 2H), 4.32 (q, J = 7.1 Hz, 4H), 1.31 (t, J = 7.1 Hz, 6H).

[0232] Diethyl 2,5-bis(benzyloxy)isophthalate [Step 3]: 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) was added benzyl bromide (43.0 mL, 362 mmol) dropwise over 10 min. The reaction mixture was heated at 100 °C for 2 h. After cooling to room temperature, the solvent was removed under reduced pressure. Water (500 mL) was then added to the residue. The mixture was extracted with EtOAc (3 × 250 mL), and the combined organic layers were washed with brine (300 mL), dried over NaSO, filtered, and then concentrated under reduced pressure. The crude material was purified by flash column chromatography (hexane / EtOAc 0–15%) to give the title compound (29.4 g, 90% yield).

[0233] UPLC-MS (acidic method, 2 min): rt = 1.38 min; m / z = 435.2 [M+H] + , Peak area >90% 1 H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 2H), 7.49 - 7.45 (m, 2H), 7.44 - 7.37 (m, 5H), 7.37 - 7.29 (m, 3H), 5.17 (s, 2H), 4.95 (s, 2H), 4.26 (q, J = 7.1 Hz, 4H), 1.22 (t, J = 7.1 Hz, 6H).

[0234] 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 h. 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 was removed under reduced pressure. The residue was purified by filtration through a silica pad using hexane / EtOAc (1 / 1) followed by EtOAc (1% v / v AcOH) as eluents to give two distinct fractions.

[0235] Starting material: diethyl 2,5-bis(benzyloxy)isophthalate (20.4 g, 65% yield) UPLC-MS (acidic method, 2 min): rt = 1.38 min; m / z = 435.2 [M+H] + , Peak area >78% 1 H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 2H), 7.49 - 7.45 (m, 2H), 7.44 - 7.37 (m, 5H), 7.37 - 7.29 (m, 3H), 5.17 (s, 2H), 4.95 (s, 2H), 4.26 (q, J = 7.1 Hz, 4H), 1.22 (t, J = 7.1 Hz, 6H).

[0236] The desired product, 2,5-bis(benzyloxy)-3-(ethoxycarbonyl)benzoic acid, was obtained as a white fluffy solid (KI-2) (3.5 g, 12% yield). UPLC-MS (acidic method, 2 min): rt = 1.22 min; m / z = 405.1 [MH] - , Peak area >90% 1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 7.48 (t, J = 3.0 Hz, 2H), 7.46 - 7.42 (m, 5H), 7.39 (m, 3H), 7.37 - 7.31 (m, 2H), 5.17 (s, 2H), 4.96 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H). The original saturated aqueous NaCO solution was then acidified with concentrated hydrochloric acid to pH 7. It was then extracted with EtOAc (2×500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a mixture of KI-2 and KI-7 (3.0 g, 11% yield).

[0237] UPLC-MS (acidic 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% 1 H NMR (400 MHz, DMSO-d6) δ 13.23 (s, 2H), 7.52 - 7.29 (m, 12H), 5.17 (s, 2H), 4.97 (s, 2H).

[0238] Scheme 9b: Alternative synthesis of KI-7 [ka]

[0239] 2,6-Dimethyl-1,4-phenylenediacetate [Step 1]: To a stirred solution of 2,6-dimethylhydroquinone (5.0 g, 36 mmol) in pyridine (10 mL) was added acetic anhydride (10 mL) rapidly. The solution was stirred at room temperature for 18 hours. The solvent was then removed under reduced pressure, and the residue was dissolved in EtOAc (250 mL), washed subsequently with aqueous hydrochloric acid (1 M, 250 mL), saturated aqueous NaHCO (250 mL), and water (250 mL), dried over NaSO, filtered, and the solvent was removed under reduced pressure to give the title compound (7.4 g, 92%) as a white solid.

[0240] UPLC-MS (acidic method, 2 min): rt = 1.07 min; m / z = 240.2 [M+NH4] + , Peak area >90% 1 H NMR (400 MHz, DMSO-d6) δ 6.88 (H Ar , 2H), 2.37 - 2.30 (m, 3H), 2.27 - 2.21 (m, 3H), 2.12 - 2.02 (m, 6H).

[0241] 2,6-Bis(dibromomethyl)-1,4-phenylenediacetate [Step 2]: To a stirred solution of 2,6-dimethyl-1,4-phenylenediacetate (6.34 g, 29 mmol) in 1,2-dichloroethane (130 mL), 2,2'-azobis(2-methylpropionitrile) (AIBN) (0.93 g, 6 mmol) and N-bromosuccinimide (NBS) (25.39 g, 143 mmol) were added sequentially. Additional 2,2'-azobis(2-methylpropionitrile) (AIBN) (0.93 g, 6 mmol) and N-bromosuccinimide (NBS) (5.08 g, 28.6 mmol) were added, and the reaction mixture was stirred at reflux for an additional 24 h. The reaction was cooled to room temperature, and the remaining solids were removed by filtration and washed with DCM (250 mL). The filtrate was washed with saturated aqueous sodium bicarbonate (250 mL), aqueous hydrochloric acid (1 M, 250 mL), and brine (250 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (9.38 g, 61%) as an orange oil.

[0242] UPLC-MS (acidic method, 2 min): rt = 1.23 min; m / z = 553.1 [M+NH4] + , Peak area >88% 1 H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 2H), 7.31 (s, 2H), 2.49 (s, 3H), 2.32 (s, 3H).

[0243] 2,5-Dihydroxyisophthalaldehyde [Step 3]: To a stirred suspension of 2,6-bis(dibromomethyl)-1,4-phenylenediacetate (3.89 g, 7.23 mmol) in formic acid (50 mL) was added water (5 mL). The mixture was stirred under reflux for 18 hours. The reaction mixture was then slowly poured into saturated aqueous sodium bicarbonate (300 mL). The precipitate that formed was then isolated by filtration to give the title compound (0.94 g, 78%) as a brown solid.

[0244] UPLC-MS (acidic method, 2 min): rt = 0.74 min; m / z = 165.0 [MH] - , Peak area >98%

[0245] 2,5-Bis(benzyloxy)isophthalaldehyde [Step 4]: Potassium carbonate-325 mesh (2.34 g, 17.0 mmol) was added to a stirred solution of 2,5-dihydroxyisophthalaldehyde (0.94 g, 5.7 mmol) in DMF (6 mL) at ambient temperature. Benzyl bromide (2.0 mL, 17.0 mmol) was then 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 saturated aqueous ammonium chloride (100 mL). The resulting suspension was stirred for 30 minutes and then filtered. The solid material was washed with saturated aqueous ammonium chloride (2×50 mL). The solid was then triturated with ethanol (5 mL) and dried by suction to give the desired product as a brown solid (1.58 g, 68%).

[0246] UPLC-MS (acidic method, 2 min): rt = 1.28 min, no ionization observed, peak area 78% 1 H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 2H), 7.63 (s, 2H), 7.53 - 7.28 (m, 10H), 5.23 (s, 2H), 5.21 (s, 2H).

[0247] 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 2-methyl-2-butene solution in THF (2.0 M, 25 mL). 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 then added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then poured into saturated aqueous NaHCO (400 mL). The aqueous layer was washed with EtOAc (3 × 100 mL) and subsequently acidified with concentrated hydrochloric acid (pH ∼1). The aqueous layer was then extracted with DCM (2 × 150 mL) and EtO (2 × 200 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then triturated with n-pentane (3×50 mL) to give the title compound KI-7 as a white solid (0.98 g, 58%).

[0248] UPLC-MS (acidic method, 2 min): rt = 1.03 min, m / z = 379.1 [M+H] + , Peak area >96% 1 H NMR (400 MHz, DMSO-d6) δ 13.23 (s, 2H), 7.57 - 7.28 (m, 12H), 5.17 (s, 2H), 4.97 (s, 2H).

[0249] Scheme 9c: Synthesis of KI-2Ac2 [ka]

[0250] Methyl 2,5-diacetoxy-3-methylbenzoate 3-Methylsalicylic acid was oxidized with persulfate as reported by Nudenberg et al. (J. Org. Chem. 1943, 8, 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).

[0251] 3-Methylsalicylic acid (15.0 g, 98.6 mmol) was dissolved in a solution of sodium hydroxide (15.0 g, 375 mmol, 3.8 equiv.) in water (37.5 mL). The light brown solution was cooled to 20 °C and treated with stirring with 7.75 mL portions of 40% sodium hydroxide and 33.8 mL portions of 10% potassium persulfate solution, starting with the hydroxide, at a rate sufficient to maintain a temperature of 30–35 °C until 10 parts of each had been added. After addition was complete, stirring was continued for 1 hour, and the mixture was allowed to stand at room temperature for 16–20 hours. Concentrated HCl was then added until the blue color turned Congo. Unreacted 3-methylsalicylic acid separated as a solid at this point and was removed by filtration. The filtrate was extracted several times with ether (5 × 50 mL) to recover the remaining 3-methylsalicylic acid. The aqueous solution was then treated with concentrated HCl (100 mL) and then refluxed for 2 hours to decompose the intermediate monosulfate salt. The warm solution was cooled to room temperature, and the precipitated almost black crystalline solid was filtered, washed with water, and dried. The aqueous filtrate was extracted with ether to give an additional batch of 2,5-dihydroxy-3-methylbenzoic acid as a brown solid (total: 7.71 g, 47%). Mp 212-214 °C; 1 H NMR (250 MHz, DMSO): δ 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).

[0252] Esterification: Concentrated sulfuric acid (0.7 mL) was carefully added to a solution of 2,5-dihydroxy-3-methylbenzoic acid (2.05 g, 12.2 mmol) in MeOH (7 mL) at 0 °C under nitrogen. The reaction mixture was then stirred at 100 °C for 6 h. After cooling to room temperature, the solvent was removed under reduced pressure. The resulting crude product was dissolved in ethyl acetate (50 mL), and the solution was washed with water (20 mL), 10% aqueous NaHCO (20 mL), 5% aqueous HCl (20 mL), and brine (20 mL), and then dried (MgSO). After filtration, the organic layer was concentrated under reduced pressure to give a residue that was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 9 / 1) to give methyl 2,5-dihydroxy-3-methylbenzoate as a white solid (370 mg, 75%). Mp 101-103 °C; 1 H NMR (250 MHz, CDCl3): δ 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 calculation for C9H 11 O4 [M+H] + : 183.0652; found 183.0651.

[0253] Acetylated excess acetic anhydride (10 mL) was added to a solution of methyl 2,5-dihydroxy-3-methylbenzoate (4.43 g, 24.3 mmol) in pyridine (10 mL) under argon. After stirring at room temperature for 12 hours, pyridine and acetic anhydride were removed by coevaporation with toluene (25 mL) under reduced pressure. The crude product was then dissolved in ethyl acetate (15 mL), and the solution was washed successively with 2% aqueous HCl (5 mL), saturated aqueous NaHCO (5 mL), and brine (5 mL). The organic phase was dried (MgSO), and the solvent was evaporated under reduced pressure. The resulting colorless oil was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 8 / 2) to give the acetylated title product (2,5-acetoxy-3-methylbenzoate) as a white solid (6.25 g, 97%). Mp 69-71 °C; 1 H NMR (250 MHz, CDCl): δ 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 calcd for C 13 H 18 NO6[M+NH4] + : 284.1129; found 284.1128.

[0254] A solution of methyl 2,5-diacetoxy-3-dibromomethylbenzoate (2.15 g, 8.08 mmol), N-bromosuccinimide (2.87 mg, 16.2 mmol, 2.0 equiv.), and azobisisobutyronitrile (AIBN, 27.0 mg, 0.162 mmol, 0.02 equiv.) in carbon tetrachloride (45 mL) was refluxed for approximately 12 hours until a white solid floated to the surface. After cooling, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting colorless oil was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 9 / 1) to give the dibrominated product as a white solid (3.29 g, 84%). Mp 117-119 °C; 1 H NMR (250 MHz, CDCl3): δ 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 calcd for C 13 H 12 Br2NaO6[M+Na] + : 444.8893; found 444.8896.

[0255] A solution of methyl 2,5-diacetoxy-3-dibromomethylbenzoate (2.30 g, 5.42 mmol) and silver nitrate (2.29 g, 13.5 mmol, 2.5 equiv.) in a 4.7:1 acetone-HO mixture (40 mL) was stirred at room temperature in the dark for 12 h. The mixture was then filtered, and the filtrate was extracted with ethyl acetate (2 × 20 mL). The combined organic phases were washed with brine (5 mL), dried (MgSO), and concentrated under reduced pressure. The colorless oil thus obtained was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 9 / 1) to give the aldehyde as a yellow solid (1.14 g, 75%). Mp 102-104℃; 1H NMR (250 MHz, CDCl3): δ 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).

[0256] A solution of sodium hydrogen phosphate (1.35 g, 9.81 mmol, 2.5 equiv.) in 2,5-diacetoxyisophthalic acid monomethyl ester (KI-2Ac2) 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 equiv.) in water (3.5 mL) was slowly added. After stirring at room temperature for 72 h, the mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (2 × 30 mL). The aqueous phase was then acidified to pH = 1 with 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 resulting orange oil was used in the next step without purification.

[0257] Synthesis of monoamides Scheme 10. Synthesis of monoamide IIa [ka]

[0258] Protocol: Synthesis of monoamides Amide Coupling and Deprotection Procedure. See the basic procedure from KI-1 and KI-6, steps [3], [4], [5], and the same procedure from KI-2, KI-2Ac2, and KI-7.

[0259] example [ka] [ka]

[0260] The conditions and yields are as follows: see Table 2 (Figures 5A-C).

[0261] 33) 3-(2-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound IIa-001a: UPLC-MS (acidic method, 2 min): rt = 0.86 min; m / z = 318.0 [M+H] + , Peak area >92% 1 H NMR (400 MHz, DMSO-d6) δ 13.49 (s, 1H), 12.16 (s, 1H), 9.54 (s, 1H), 8.70 (dd, J = 8.5, 1.2 Hz, 1H), 7.99 (dd, J = 7.9, 1.7 Hz, 1H), 7.70 - 7.51 (m, 2H), 7.42 (d, J = 3.3 Hz, 1H), 7.20 (td, J = 7.6, 1.2 Hz, 1H). HRMS: [M+H] + , calc. for C 15 H 12 NO7: 318.06083, found: 318.06082 バイオデータ:IIa-001a: FGF-1 IC50 [μM] = 8.6; FGF-2 IC50 [μM] = 11; VEGF-A1 IC50 [μM] = 150; VEGFR-リン acidification inhibition IC50 [μM] =100; PMN ROS [inhibition at 0.3 μM [%] = 30.5; PMN ROS blocking IC50 [μM] = 0.408; Good hit and then blocking [%] = 36.24

[0262] 34) 3-(2-(1H-テトラゾール-5-イル)フェニルアミノカルボニル)-2,5-ジヒドロキシbenzoic acid, compound IIa-001aTz: UPLC-MS (acidic method, 2 min): rt = 0.71 min; m / z = 342.1 [M+H] + , ピークarea>99% 1 H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 9.49 (s, 1H), 8.51 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.72 - 7.51 (m, 2H), 7.51 - 7.26 (m, 2H) HRMS: [M+H] + , calc. for C 15 H 12 N5O5: 342.08329, found: 342.08317 バイオデータ:IIa-001a-Tz: FGF-1 IC50 [μM] = ND; FGF-2 IC50 [μM] = 9.8; VEGF-A1 IC50 [μM] = 187; 0.3 μM [%] = 74.15; PMN ROS blocking IC50 [μM] = ND; Good hit and then blocking [%] = 24.18

[0263] エチルエステル UPLC-MS (acidic method, 4 min): rt = 1.46 min; m / z = 370.1 [M+H]+ , ピークarea>92% 1 H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 11.37 (s, 1H), 9.63 (s, 1H), 8.47 (d, J = 8.3 Hz, 1H), 7.92 (dd, J = 7.8, 1.6 Hz, 1H), 7.66 -7.57 (m, 2H), 7.43 (d, J = 3.2 Hz, 1H), 7.38 (td, J = 7.6, 1.2 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H), HRMS: [M+H] + , calc. for C 17 H 16 N5O5: 370.11460, found: 370.11444 バイオデータ:IIa-001aTz-E1: FGF-1 IC50 [μM] = 200; FGF-2 IC50 [μM] = 42; VEGF-A1 IC50 [μM] = 200; VEGFR-リン acidification inhibition IC50 [μM] =100; PMN ROS [Block at 0.3 μM [%] = 68.86; PMN ROS Blockage IC50 [μM] = ND; Good hit followed by blockage [%] = 81.94

[0264] 35) 2,5-ジヒドロキシー3-(2-スルホフェニルアミノカルボニル)benzoic acid, compound IIa-001c: UPLC-MS (acidic method, 2 min): rt = 0.63 min; m / z = 354.0 [M+H] + , ピークarea>80% 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.48 (s, 1H), 8.34 - 8.27 (m, 1H), 7.72 (dd, J = 7.7, 1.7 Hz, 1H), 7.52 (d, J = 3.2 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.08 (td, J = 7.5, 1.2 Hz, 1H). HRMS: [M+H] + , calc. for C 14 H 12 NO8S: 354.02781, found: 354.02781 バイオデータ:IIa-001c: FGF-1 IC50 [μM] = ND; FGF-2 IC50 [μM] = 71; VEGF-A1 IC50 [μM] = 283; [%] = 72.62; PMN ROS blocking IC50 [μM] = ND; Good hit and then blocking [%] = 43.53

[0265] 36) 3-(3-カルボキシフェニルアミノカボニル)-2,5-ジヒドロキシbenzoic acid, compound IIa-002a: 1 H NMR (250 MHz, CD3OD): δ 8.37 (t, 1H), 7.93 (br d, 1H), 7.81 (br d, 1), 7.76 (d, 1H), 7.52 (d, 1H), 7.48 (t, 1H). HRMS (ESI-): [MH] - , calc. for C 15 H 10 NO7: 316.0461, found: 318.0463 Biodata: IIa-002a: FGF-1 IC50 [μM] = 19; FGF-2 IC50 [μM] = 131; VEGF-A1 IC50 [μM] = 150; VEGFR phosphorylation inhibition IC50 [μM] = ND; PMN ROS inhibition at 0.3 μM [%] = 43.3; PMN ROS inhibition IC50 [μM] = 0.299; Neutrophil adhesion inhibition [%] = 17.39

[0266] 37) 3-(4-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid)amide, compound IIa-003a: 1 H NMR (250 MHz, CD3OD): δ 8.06 (BB' of AA'BB', 2H), 7.85 (AA' of AA'BB', 2H), 7.75 (d, 1H), 7.58 (d, 1H) HRMS (ESI-): calculated for C 15 H 10 NO7[MH] - : 316.0461; found 316.0462 Biodata: IIa-003a: FGF-1 IC50 [μM] = 22; FGF-2 IC50 [μM] = 13; VEGF-A1 IC50 [μM] = 150; VEGFR phosphorylation inhibition IC50 [μM] = 2.5; PMN ROS inhibition at 0.3 μM [%] = 59.3; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 35.27

[0267] 38) 3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound IIa-004a: UPLC-MS (acidic method, 2 min): rt = 0.76 min; m / z = 334.0 [M+H] + , Peak area >99% 1H NMR (400 MHz, DMSO-d6) δ 14.02 (brs, 1H), 11.07 (brs, 1H), 10.32 (s, 1H), 9.47 (brs, 1H), 8.27 (d, J = 2.7 Hz, 1H), 7.76 (dd, J = 8.9, 2.7 Hz, 1H), 7.42 (d, J = 3.2 Hz, 1H), 7.36 (d, J = 3.2 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H). HRMS: [M+H] + , calc. for C 15 H 12 NO8: 334.05574, found: 334.05571 バイオデータ:IIa-004a: FGF-1 IC50 [μM] = 47; FGF-2 IC50 [μM] = 33; VEGF-A1 IC50 [μM] = 200; VEGFR-リン acidification inhibition IC50 [μM] =100; PMN ROS [inhibition at 0.3 μM [%] = 63.5; PMN ROS blocking IC50 [μM] = 1.002; Good hit and then blocking [%] = 36

[0268] 39) 3-(2-カルボキシ-4-ヒドロキシフェニルアミノカルボニル)-2,5-ジヒドロキシbenzoic acid, compound IIa-006a: UPLC-MS (acidic method, 2 min): rt = 0.65 min; m / z = 334.0 [M+H] + , ピークarea>99% 1 H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 11.83 (s, 1H), 9.62 (s, 1H), 9.47 (s, 1H), 8.47 (d, J = 9.1 Hz, 1H), 7.64 (d, J = 3.3 Hz, 1H), 7.41 (d, J = 3.2 Hz, 1H), 7.37 (d, J = 3.0 Hz, 1H), 7.03 (dd, J = 9.1, 3.0 Hz, 1H). HRMS: [M+H]+ , calc. for C 15 H 12 NO8: 334.05574, found: 334.05548 バイオデータ:IIa-006a: FGF-1 IC50 [μM] = ND; FGF-2 IC50 [μM] = 43; VEGF-A1 IC50 [μM] = 121; VEGFR-リン acidification inhibition IC50 [μM] =2.9; PMN ROS [inhibition at 0.3 μM [%] = 84.29; PMN ROS blocking IC50 [μM] = ND; Good hit and then blocking [%] = 20.29

[0269] 40) 3-(3-Kuronic acid-2,5-ジヒドロキシベンズアミド)フタル acid, compound IIa-011a: UPLC-MS (acidic method, 2 min): rt = 0.72 min; m / z = 360.1 [MH] - , ピークarea>77% 1 H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.55 (s, 1H), 8.43 (dd, J = 7.9, 1.5 Hz, 1H), 7.73 (d, J = 3.3 Hz, 1H), 7.63 - 7.53 (m, 2H), 7.46 (d, J = 3.3 Hz, 1H), HRMS: [M+H] + , calc. for C 16 H 12 NO9: 362.05066, found: 362.05045, バイオデータ:IIa-011a: FGF-1 IC50 [μM] = 141; FGF-2 IC50 [μM] = 123; VEGF-A1 IC50 [μM] = 200; VEGFR-リン acidification inhibition IC50 [μM] =100; PMN ROS [inhibition at 0.3 μM [%] = 58.1; PMN ROS blocking IC50 [μM] = 1.18; Good hit then blocking [%] = 26

[0270] 41) 2-(3-carboxy-2,5-dihydroxybenzamido)terephthalic acid, compound IIa-012a: UPLC-MS (acidic method, 2 min): rt = 0.73 min; m / z = 362.0 [M+H], peak area >97% 1 H NMR (DMSO-d6) δ: 13.81 (s, 1H), 13.34 (s, 1H), 12.23 (s, 1H), 9.50 (s, 1H), 9.30 (d, J = 1.6 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.71 (dd, J = 8.2, 1.7 Hz, 1H), 7.64 (d, J = 3.3 Hz, 1H), 7.43 (d, J = 3.3 Hz, 1H), HRMS: [M+H] + , calc. for C 16 H 12 NO9: 362.05066, found: 362.05046, Biodata: IIa-012a: FGF-1 IC50 [μM] = 150; FGF-2 IC50 [μM] = 150; VEGF-A1 IC50 [μM] = 32; VEGFR phosphorylation inhibition IC50 [μM] = 3.31; PMN ROS inhibition at 0.3 μM [%] = 44.8; PMN ROS inhibition IC50 [μM] = 0.313; Neutrophil adhesion inhibition [%] = 7.5

[0271] 42) 2-(3-carboxy-2,5-dihydroxybenzamido)isophthalic acid, compound IIa-013a: UPLC-MS (acidic method, 2 min): rt = 1.68 min; m / z = 362.0 [M+H] + , Peak area >96% 1H NMR (400 MHz, DMSO-d6) δ 13.12 (brs, 3H), 11.71 (s, 1H), 9.47 (s, 1H), 7.96 (s, 1H), 7.94 (s, 1H), 7.66 (d, J = 3.3 Hz, 1H), 7.44 (d, J = 3.3 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H). HRMS: [M+H] + , calc. for C 16 H 12 NO9: 362.05066, found: 362.05047 Biodata: IIa-013a: FGF-1 IC50 [μM] = 137; FGF-2 IC50 [μM] = 12; VEGF-A1 IC50 [μM] = 34; VEGFR-lysine kinase inhibition IC50 [μM] = 100; PMN ROS inhibition at 0.3 μM [%] = 57.68; PMN ROS inhibition IC50 [μM] = 2.54; Anti-inflammatory cytotoxicity [%] = 15.75

[0272] 43) 4-(3-Kuronic acid-2,5-ジヒドロキシベンズアミド)フタル acid, compound IIa-014a: UPLC-MS (acidic method, 2 min): rt = 0.63 min; m / z = 362.1 [M+H] + , ピークarea>88% 1 H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.45 (s, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.86 (dd, J = 8.5, 2.2 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.45 - 7.33 (m, 2H), HRMS: [M+H] + , calc. for C 16 H 12 NO9: 362.05066, found: 362.05048 バイオデータ:IIa-014a: FGF-1 IC50 [μM] = 40; FGF-2 IC50 [μM] = 61; VEGF-A1 IC50 [μM] = 91; VEGFR-リン acidification inhibition IC50 [μM] =17.6; PMN ROS [inhibition at 0.3 μM [%] = 73.94; PMN ROS blocking IC50 [μM] = ND; Good hit and then blocking [%] = 21.5

[0273] 44) 5-(3-カルボキシ-2,5-ジヒドロキシベンズアミド)イソフタル acid, compound IIa-015a: 1 H NMR (250 MHz, CD3OD): δ 8.60 (d, J = 1.5 Hz, 2H), 8.44 (t, J = 1.5 Hz, 1H), 7.75 (d, J = 3.2 Hz, 1H), 7.56 (d, J = 3.2 Hz, 1) HRMS (ESI+): m / z calcd for C16H12NO9 [M+H]+: 362.0507; found 362.0505 [LM-163] バイオデータ:IIa-015a: FGF-1 IC50 [μM] = ND; FGF-2 IC50 [μM] = 125; VEGF-A1 IC50 [μM] = ND; VEGFR-リン acidification blocking IC50 [μM] = ND; PMN ROS [blocking at 0.3 μM [%] = ND; PMN ROS blocking IC50 [μM] = ND; Good hit and then blocking [%] = ND

[0274] 45) (3-(3-(カルボキシメチル)フェニルアミノカルボニル)-2,5-ジヒドロキシbenzoic acid, compound IIa-033a: UPLC-MS (acidic method, 2 min): rt = 0.78 min; m / z = 330.1 [MH] - , ピークarea>98% 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.45 (s, 1H), 7.66 (t, J = 1.9 Hz, 1H), 7.63 - 7.57 (m, 1H), 7.45 (d, J = 3.3 Hz, 1H), 7.38 (d, J = 3.2 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.05 - 6.95 (m, 1H), 3.56 (s, 2H). HRMS: [M+H] + , calc. for C 16 H 14 NO7: 332.07648, found: 332.07644, Biodata: IIa-033a: FGF-1 IC50 [μM] = 35; FGF-2 IC50 [μM] = 32; VEGF-A1 IC50 [μM] = 200; VEGFR-lysine kinase inhibition IC50 [μM] = 4.9; PMN ROS inhibition at 0.3 μM [%] = 50.64; PMN ROS inhibition IC50 [μM] = 0.914; β-catenin inhibition [%] = 11.75

[0275] 46) 3-(2-(カルボキシメチル)フェニルアミノカルボニル)-2,5-ジヒドロキシbenzoic acid, compound IIa-034a: UPLC-MS (acidic method, 2 min): rt = 0.74 min; m / z = 332.0 [M+H] + , ピークarea>95% 1 H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 10.65 (s, 1H), 9.30 (s, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 3.2 Hz, 1H), 7.40 (d, J = 3.3 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.13 (td, J = 7.5, 1.3 Hz, 1H), 3.70 (s, 2H). HRMS: [M+H] +, calc. for C 16 H 14 NO7: 332.07648, found: 332.07653 バイオデータ:IIa-034a: FGF-1 IC50 [μM] = 22; FGF-2 IC50 [μM] = 5.7; VEGF-A1 IC50 [μM] = 86; VEGFR-リン acidification inhibition IC50 [μM] =100; PMN ROS [inhibition at 0.3 μM [%] = 69.2; PMN ROS blocking IC50 [μM] = ND; Good hit and then blocking [%] = 26.58

[0276] ジエチルエステル UPLC-MS (acidic method, 2 min): rt = 1.12 min; m / z = 388.1 [M+H] + , ピークarea>99% 1 H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 9.58 (s, 1H), 7.77 (t, J = 8.5 Hz, 1H), 7.65 (d, J = 3.4 Hz, 1H), 7.42 (d, J = 3.4 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.20 (t, J = 7.4 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.05 (q, J = 7.1 Hz, 2H), 3.77 (s, 2H), 1.36 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H). HRMS: [M+H] + , calc. for C 20 H 22 NO7: 388.13907, found: 388.13887 バイオデータ:IIa-034a-E2: FGF-1 IC50 [μM] = ND; FGF-2 IC50 [μM] = 164; VEGF-A1 IC50 [μM] = 200; VEGFR-リン acidification blocking IC50 [μM] = ND; PMN ROS [blocking at 0.3 μM [%] = 68.73; PMN ROS blocking IC50 [μM] = ND; Good hit and then blocking [%] = 11.86

[0277] 47) 3-(3,4-ジヒドロシフェニルメチルアミノカボニル)-2,5-ジヒドロキシbenzoic acid, compound IIa-035a: UPLC-MS (acidic method, 2 min): rt = 0.69 min; m / z = 318.0 [MH] - , ピークarea>99% 1 H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.84 (s, 1H), 8.75 (s, 1H), 7.55 (d, J = 3.2 Hz, 1H), 7.34 (d, J = 3.2 Hz, 1H), 6.74 (d, J = 2.1 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.58 (dd, J = 8.1, 2.1 Hz, 1H), 4.34 (d, J = 5.7 Hz, 2H). HRMS: [M+H] + , calc. for C 15 H 14 NO7: 320.07647, found: 320.07625. バイオデータ:IIa-035a: FGF-1 IC50 [μM] = 16; FGF-2 IC50 [μM] = 61; VEGF-A1 IC50 [μM] = 45; VEGFR-リン acidification inhibition IC50 [μM] =0.52; PMN ROS [inhibition at 0.3 μM [%] = 76.99; PMN ROS blocking IC50 [μM] = 1; Good hit and then blocking [%] = 36.67

[0278] 48) 3-(2-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound IIa-053a: UPLC-MS (acidic method, 4 min): rt = 1.08 min; m / z = 332.0 [M+H] + , Peak area >97% 1 H NMR (DMSO-d6) δ: 13.13 (brs, 1H), 12.73 (brs, 1H), 9.40 (s, 1H), 9.05 (s, 1H), 7.91 (dd, J = 7.8, 1.4 Hz, 1H), 7.65 - 7.29 (m, 5H), 4.80 (d, J = 6.1 Hz, 2H). HRMS: [M+H] + , calc. for C 16 H 14 NO7: 332.07648, found: 332.07626 Biodata: IIa-053a: FGF-1 IC50 [μM] = 84; FGF-2 IC50 [μM] = 18; VEGF-A1 IC50 [μM] = 37; VEGFR-1 phosphatase inhibition IC50 [μM] = 0.27; PMN ROS inhibition at 0.3 μM [%] = 63.13; PMN ROS inhibition IC50 [μM] = 0.62; TNF-α inhibition [%] = 20; Whole blood: GM-CSF IC50 [μM] = >100; IFNγ IC50 [μM] = 1.04; IL-1β IC50 [μM] = >100; IL-2 IC50 [μM] = 1.67; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 2.2; IL-9 IC50 [μM] = 1.41; IL-10 IC50 [μM] = >100; IL-12p70 IC50 [μM] = 0.27; IL-13 IC50 [μM] = 29.9; IL-17A IC50 [μM] = >100; IL-17F IC50 [μM] = 28.8; IL-18 IC50 [μM] = >100; IL-21 IC50 [μM] = >100; IL-33 IC50 [μM] = 12.1; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.02; TNFβ IC50 [μM] = 91.5.

[0279] Example 1.6. Molecule of タイプIIb: ジアミンからのジアミド, 1 example

change

[0280] スキーム11.タイプIIbのジアミドの synthesis

change

[0281] Sequence: KI-1 [3], [4], [5] is the basic sequence for reference.

[0282] for example: [ka]

[0283] The conditions and yields are as follows: see Table 2 (Figures 5A-C).

[0284] 49) 3,5-bis(2,5-dihydroxy-3-carboxybenzoylamino)benzoic acid, compound IIb-010a: UPLC-MS (acidic method, 4 min): rt = 0.98 min; m / z = 511.1 [MH] - , Peak area >93% 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 2H), 10.65 (s, 2H), 8.38 (m, 1H), 8.12 (d, J = 2.0 Hz, 2H), 7.39 (d, J = 2.3 Hz, 4H). HRMS: [M+H] + , calc. for C 23 H 17 N2O 12 : 513.07760, found: 513.07774 Biodata: IIb-010a: FGF-1 IC50 [μM] = 200; FGF-2 IC50 [μM] = 102; VEGF-A1 IC50 [μM] = 28; VEGFR phosphorylation inhibition IC50 [μM] = ND; PMN ROS inhibition at 0.3 μM [%] = 81.87; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 59.84

[0285] Example 1.7. Type IIc Molecules: Diacids from Diamines, Two Examples [ka]

[0286] Scheme 12. Synthesis of Type IIc Amides Where R=R' [ka]

[0287] Procedure: See basic procedure from KI-6 [3], [4], [5]. for example [ka] [ka]

[0288] The conditions and yields are as follows: see Table 2 (Figures 5A-C).

[0289] 50) 5-(3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid, compound IIc-007a: UPLC-MS (acidic method, 4 min): rt = 1.20 min; m / z = 469.1 [M+H] + , Peak area >91% 1 H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 2H), 9.51 (s, 1H), 8.22 (d, J = 2.7 Hz, 2H), 7.79 (dd, J = 9.0, 2.7 Hz, 2H), 7.58 (s, 2H), 6.98 (d, J = 8.9Hz, 2H), 13 C NMR (100 MHz, DMSO-d6) δ 172.1, 166.1, 158.3, 152.0, 149.4, 130.2, 129.5 (CH), 122.8 (CH), 120.3, 119.8 (CH), 117.7 (CH). 113.0. HRMS: [M+H] + , calc. for C 22 H 17 N2O10 : 469.08777, found: 469.08803 Biodata: IIc-007a: FGF-1 IC50 [μM] = 11; FGF-2 IC50 [μM] = 91; VEGF-A1 IC50 [μM] = 8.2; VEGFR-1 kinase inhibition IC50 [μM] = 0.44; PMN ROS inhibition at 0.3 μM [%] = 93.04; PMN ROS inhibition IC50 [μM] = ND; GM-CSF inhibition [%] = 64.61; Whole blood: GM-CSF IC50 [μM] = 26; IFNγ IC50 [μM] = 0.11; IL-1β IC50 [μM] = >100; IL-2 IC50 [μM] = 12.8; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 0.05; IL-9 IC50 [μM] = 2.14; IL-10 IC50 [μM] = 17.9; IL-12p70 IC50 [μM] = 3.37; IL-13 IC50 [μM] = 0.25; IL-17A IC50 [μM] = 0.01; IL-17F IC50 [μM] = 0.26; IL-18 IC50 [μM] = >100; IL-21 IC50 [μM] = 9.41; IL-33 IC50 [μM] = 0.18; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.03; TNFβ IC50 [μM] = 0.29

[0290] Large-scale synthesis of IIc-007a replacement 2,5-ジベンジルオキシイソフタル acid (KI-7) A 5 L jacketed vessel was charged with 2,5-dibenzyloxyisophthalaldehyde (Scheme 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). The slurry was stirred at 15-25 °C. A solution of 80% NaClO2 (294 g, 2.60 mol) in water (1 L) was charged over 90 min at 15-30 °C (exothermic). After the addition was complete, the reaction was stirred at 15-25 °C for 1 h. A solution of 85% H3PO4 (85 mL, 1.24 mol) [approximately 1 M] in water (1175 mL) was charged over 10 min at T < 30 °C (exothermic), resulting in a precipitate. The batch was cooled to 0-5 °C and filtered. The solid was washed with water (3 x 1.2 L) and oven dried (50 °C) to give 325.6 g of diacid KI-7. HPLC: 98.9%; NMR >95%. Corrected yield (90.6%).

[0291] 5-(3-(3-Methoxycarbonyl-4-hydroxyphenylaminocarbonyl)-2,5-dibenzyloxybenzamido)-2-hydroxybenzoic acid methyl ester. A 2 L jacketed vessel was charged with the diacid KI-7 (80 g, 211 mmol), HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (176.8 g, 466 mmol), and THF (560 mL). The batch was stirred at 15-25 °C and N-methylimidazole (50.6 mL, 635 mmol) was charged. After 30 minutes, methyl 5-amino-2-hydroxybenzoate (77.8 g, 466 mmol) was charged and the reaction was stirred overnight at 25 °C. Water (1.2 L) was charged and the batch was stirred at 20 °C for 30 minutes. The batch was filtered and washed with water (2 x 480 ml) followed by MeCN (320 ml). The resulting solid (236 g) was transferred back to the vessel with MeCN (800 ml). The slurry was heated to 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) showed no TMU, HOBt, NMI or HBTU. The material was dried overnight at 50°C to give 125 g of diamide. HPLC: 98.2%, NMR: >97%, Yield: 88%.

[0292] 5-(3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dibenzyloxybenzamido)-2-hydroxybenzoic acid. A 2 L jacketed vessel was charged with the diamide (110 g, 163 mmol), THF (550 mL), and water (1100 mL). The batch was stirred at 15-25°C and 85% KOH (32.2 g, 488 mmol) was charged (slight exotherm). The solution was heated to 50°C for 4 hours, then cooled to 20°C and stirred overnight. Next, aqueous 6MAcOH (550 mL, 3.3 mol) was charged over 30 minutes at 15-25°C. After the addition was complete, the batch was stirred for 30 minutes and then filtered. The solid was washed with water (3 x 550 mL) and then oven-dried at 50°C. This gave 102 g of the free diacid. HPLC: 98.9% (0.3% monoamide, 0.19% monoacid). NMR: >97%. Yield: 97%.

[0293] 5-(3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid, IIc-007a. To a 2 L jacketed vessel under N was charged 10% Pd / C (10 g, 50% wet, 87 L type), followed by the diacid (100 g, 154 mmol), AcOH (5 mL, 88 mmol), and THF (1200 mL). The batch was stirred, then sparged with H and heated to 40° C. for 2 hours. The batch was sparged with N and then filtered (GF / F). The vessel was rinsed with THF (300 mL), and the rinse was used to wash the catalyst on the filter. The filtrate was charged to the vessel, and the volume was adjusted to 2 L with THF (400 mL). The solution was warmed to 30°C, SPM32 (10 g) was charged, and the batch was stirred at 30°C overnight. SPM32 was filtered off and washed with THF (200 ml). The solvent was removed under reduced pressure to give a pale yellow solid (110 g). NMR analysis showed 28% THF. The material was slurried in EtOH (1 L) at 20°C for 2 hours and then filtered off. The solid was washed with EtOH (400 ml) and oven-dried at 60°C overnight. NMR showed 8.7% EtOH and no THF. This material was further dried at 80°C for four nights to give 66.5 g of IIc-007a as an off-white solid in 92% yield. HPLC: 99.5% (0.31% monoamide). NMR: 4.6% EtOH, no THF. Pd by ICP-OES: <2 ppm.

[0294] IIc-007a-THF solvate: Concentration of the THF filtrate typically affords a yellow solid containing 25-30% THF by NMR, which cannot be removed by drying, indicating a non-stoichiometric solvate.

[0295] A small sample of the THF solvate (1.45 g) was heated to 50° C. in THF (10 ml) for 1 h, cooled to room temperature, isolated, and washed with 3 ml of THF. This gave 1.13 g of IIc-007a-THF. NMR: 27% THF. HPLC: 99.6% (0.1% monoamide). Isolation of the THF solvate by filtration increased the purity and effectively purged the major impurity (monoamide, IIa-004a) from 0.7% to 0.1%. Recovery: 78%. The solubility of the THF solvate in THF was calculated to be approximately 25 mg / ml at 20° C.

[0296] Desolvation studies were performed on 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 oven-dried (60°C). Ethanol was chosen as the desolvation solvent due to the low level of EtOH incorporated into the product after drying and its excellent purging of THF from the system. The desolvation step was performed on 12.1 g of product (25% THF). The material was charged with EtOH (20 volumes) and the batch was stirred overnight at room temperature. A sample was filtered, indicating successful desolvation at room temperature. Overall yield: 8.67 g. HPLC: 99.4%. NMR: >97% (0.8% EtOH). XRPD indicated high crystallinity of the isolated product.

[0297] Product IIc-007a also forms a DMSO solvate (DMSO:product ratio 3:2).

[0298] 51) 2-(3-(2-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-5-hydroxylbenzoic acid, compound IIc-009a: UPLC-MS (acidic method, 2 min): rt = 0.79 min; m / z = 469.1 [M+H] + , Peak area >95% 1H NMR (400 MHz, DMF-d7) δ 10.11 (s,1H), 10.01 (s,2H), 8.71 (d, J = 9.0 Hz, 2H), 8.01 (s, 2H), 7.82 (d, J = 3.0 Hz, 2H), 7.46 (d, J = 8.9 Hz, 2H). HRMS: [M+H] + , calc. for C 22 H 17 N2O 10 : 469.08777, found: 469.08714 Biodata: IIc-009a: FGF-1 IC50 [μM] = 30; FGF-2 IC50 [μM] = ND; VEGF-A1 IC50 [μM] = 182; VEGFR-1 kinase inhibition IC50 [μM] = 1.7; PMN ROS inhibition at 0.3 μM [%] = 75.31; PMN ROS inhibition IC50 [μM] = ND; TNF-α inhibition [%] = 53.15; Whole blood: GM-CSF IC50 [μM] = >100; IFNγ IC50 [μM] = 0.54; IL-1β IC50 [μM] = >100; IL-2 IC50 [μM] = 19.6; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 0.27; IL-9 IC50 [μM] = 18.9; IL-10 IC50 [μM] = 11.31; IL-12p70 IC50 [μM] = >100; IL-13 IC50 [μM] = 0.13; IL-17A IC50 [μM] = 0.001; IL-17F IC50 [μM] = 0.13; IL-18 IC50 [μM] = 2.95; IL-21 IC50 [μM] = 8.01; IL-33 IC50 [μM] = 0.29; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.11; TNFβ IC50 [μM] = 6.94.

[0299] Example 1.8. Type IIIa molecules: monoamides, 4 examples [ka]

[0300] Precursor synthesis Scheme 13. Synthetic Intermediates: KI-8 and KI-9 from KI-1 [ka]

[0301] Synthesis protocol Intermediates KI-8 and KI-9 (via KI-10 and KI-11) Ethyl 2,5-bis(benzyloxy)-4-(hydroxymethyl)benzoate (KI-10) [Step 1]: To a cooled solution of KI-1 (62.3 g, 153 mmol) in THF (700 mL) at −20 °C, a pre-cooled solution of BH THF (615.0 mL, 615 mmol) was added slowly (at −10 °C) under a positive flow of inert gas (N). The addition was carried out so that the internal temperature of the reaction never exceeded −15 °C. The reaction was allowed to warm slightly, ensuring that the internal temperature did not exceed −7 °C. The mixture was maintained at this temperature for 2.5 h. The reaction mixture was then poured into ice / water (8 L). The resulting hazy white mixture was stirred at room temperature for 2 h, and the remaining white suspension was filtered through a fritted funnel (porosity 3). The white solid thus obtained was further dried in a vacuum oven at 40 °C overnight to give ethyl 2,5-bis(benzyloxy)-4-(hydroxymethyl)benzoate (KI-10) (60.5 g, 97% yield) as a white solid.

[0302] UPLC-MS (acidic method, 2 min): rt = 1.25 min; m / z = 391.2 [MH] - , Peak area >68% 1H NMR (400 MHz, DMSO-d6) δ 7.54 - 7.48 (m, 2H), 7.48 - 7.43 (m, 2H), 7.43 - 7.35 (m, 4H), 7.35 - 7.27 (m, 4H), 5.28 (t, J = 5.4 Hz, 1H), 5.13 (s, 2H), 5.11 (s, 2H), 4.58 (d, J = 5.4 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H).

[0303] Alternatively, intermediate KI-10 can be obtained from KI-1 via the mixed anhydride (treatment of KI-1 with isobutyl chloroformate in THF in the presence of triethylamine) followed by reduction of the mixed anhydride with sodium borohydride in THF (85–90% yield, 150 g scale).

[0304] Ethyl 2,5-bis(benzyloxy)-4-(chloromethyl)benzoate (KI-11) [Step 2]: Tosyl chloride (17.0 g, 70 mmol) was slowly added to a cooled (ice bath) solution of KI-10 (25.0 g, 64 mmol), DIPEA (12.2 mL, 70 mmol), and DMAP (0.778 g, 6 mmol) in DCM (260 mL). The reaction mixture was stirred at 60 °C for 30 h, at which point the reaction was judged complete. DCM (100 mL) was added, and the organic layer was separated and washed with saturated aqueous sodium bicarbonate (4 × 50 mL), water (2 × 50 mL), and brine (50 mL), dried over sodium sulfate, and concentrated. The crude product was subjected to column chromatography (hexane / EtOAc 0-20%) to give ethyl 2,5-bis(benzyloxy)-4-(chloromethyl)benzoate (KI-11) (23.5 g, 75%).

[0305] UPLC-MS (acidic method, 2 min): rt = 1.39 min; m / z = no ion, peak area >84%. 1H NMR (400 MHz, DMSO-d6) δ 7.54 - 7.44 (m, 4H), 7.43 - 7.36 (m, 6H), 7.36 - 7.28 (m, 2H), 5.18 (s, 2H), 5.13 (s, 2H), 4.76 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H).

[0306] Alternatively, intermediate KI-11 can be obtained by treating KI-10 with thionyl chloride (1.14 equiv.) in dichloromethane at −10° C., followed by evaporation of the solvent and precipitation from heptane (90% yield, 300 g scale).

[0307] Ethyl 2,5-bis(benzyloxy)-4-(cyanomethyl)benzoate [Step 3]: A suspension of KI-11 (7.5 g, 18.2 mmol) in a mixture of EtOH (90 mL) and HO (45 mL) was treated with potassium cyanide (1.8 g, 27.4 mmol). The reaction mixture was heated to 75 °C and stirred at this temperature for 16 h. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (2 × 200 mL). The combined organic phase was then washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. 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), which was used in the next step without further purification.

[0308] UPLC-MS (acidic 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%. 1H NMR (400 MHz, DMSO-d6) δ 7.56 - 7.27 (m, 12H), 5.19 (s, 2H), 5.14 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.95 (s, 2H), 1.25 (t, J = 7.1 Hz, 3H).

[0309] 2,5-Bis(benzyloxy)-4-(carboxymethyl)benzoic acid (KI-9) [Step 4]: To a suspension of ethyl 2,5-bis(benzyloxy)-4-(cyanomethyl)benzoate (7.1 g, 13.2 mmol) in EtOH (20 mL), a solution of sodium hydroxide (8.5 g, 212.5 mmol) in water (50 mL) was added, and the reaction mixture was stirred under reflux for 18 hours. The reaction mixture was diluted with water (100 mL), and the resulting solution was washed with EtOAc (2 × 100 mL). The organic layer thus obtained was extracted with water (100 mL), and all the aqueous layers were collected. The aqueous layer was then acidified to pH 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 in a vacuum oven at 40 °C overnight to give 2,5-bis(benzyloxy)-4-(carboxymethyl)benzoic acid (KI-9) (6.4 g, 92% yield) as a yellowish solid.

[0310] UPLC-MS (acidic method, 2 min): rt = 1.07 min; m / z = 393.2 [M+H] + , peak area >74%. 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 2H), 7.55 - 7.27 (m, 11H), 7.19 (s, 1H), 5.11 (s, 2H), 5.09 (s, 2H), 3.61 (s, 2H).

[0311] 2,5-Bis(benzyloxy)-4-(2-ethoxycarbonylmethyl)benzoic acid (KI-8) [Step 5]: KI-9 (5.5 g, 14.0 mmol) was suspended in EtOH (30 mL), and the suspension was treated with thionyl chloride (0.52 mL, 7.1 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was then poured into saturated sodium bicarbonate solution (1 L), forming a white suspension. The solid was isolated by filtration and further triturated with EtO (2 × 20 mL). The solid was further dried in a vacuum oven overnight to give 2,5-bis(benzyloxy)-4-(2-ethoxycarbonylmethyl)benzoic acid (KI-8) (4.2 g, 64%) as a white solid.

[0312] UPLC-MS (acidic method, 2 min): rt = 1.23 min; m / z = 419.3 [MH] - , peak area >79%. 1 H NMR (400 MHz, DMSO-d6) δ 12.68 (brs, 1H), 7.58 - 7.27 (m, 11H), 7.19 (s, 1H), 5.11 (s, 2H), 5.08 (s, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.66 (s, 2H), 1.11 (t, J = 7.1 Hz, 3H).

[0313] Synthesis of monoamides Scheme 14. Synthesis of monoamide IIIa [ka]

[0314] Synthesis protocol Amide Coupling and Deprotection Procedure: See the basic procedure from KI-1 and KI-6, steps [3], [4], and [5].

[0315] example [ka] [ka]

[0316] The conditions and yields are as follows: see Table 3 (Figure 6).

[0317] 52) 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)benzoic acid, compound IIIa-001a: UPLC-MS (acidic method, 2 min): rt = 0.89 min; m / z = 332.1 [M+H] + , Peak area >98% 1 H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 12.17 (s, 1H), 10.67 (s, 1H), 9.23 (s, 1H), 8.64 (dd, J = 8.5, 1.2 Hz, 1H), 8.00 (dd, J = 7.9, 1.7 Hz, 1H), 7.62 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.33 (s, 1H), 7.19 (td, J = 7.6, 1.2 Hz, 1H), 6.80 (s, 1H), 3.49 (s, 2H). HRMS: [M+H] + , calc. for C 16 H 14 NO7: 332.07648, found: 332.07666 Biodata: IIIa-001a: FGF-1 IC50 [μM] = 62; FGF-2 IC50 [μM] = 10; VEGF-A1 IC50 [μM] = 32; VEGFR phosphorylation inhibition IC50 [μM] = ND; PMN ROS inhibition at 0.3 μM [%] = 74.79; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 30.4

[0318] Ethyl methyl ester UPLC-MS (acidic method, 2 min): rt = 1.14 min; m / z = 374.2 [M+H] + , ピークarea>96%. 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 10.78 (s, 1H), 9.25 (s, 1H), 8.60 (dd, J = 8.5, 1.2 Hz, 1H), 7.97 (dd, J = 8.0, 1.7 Hz, 1H), 7.64 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.38 (s, 1H), 7.26 - 7.18 (m, 1H), 6.81 (s, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 3.56 (s, 2H), 1.19 (t, J = 7.1 Hz, 3H). HRMS: [M+H] + , calc. for C 19 H 20 NO7: 374.12342, found: 374.12333 バイオデータ:IIIa-001a-E2: FGF-1 IC50 [μM] = 200; FGF-2 IC50 [μM] = 33; VEGF-A1 IC50 [μM] = 43; 0.3 μM [%] = 69.66; PMN ROS blocking IC50 [μM] = ND; Good hit and then blocking [%] = 44.46

[0319] 53)(2-(1H-テトラゾール-5-イル)フェニルアミノカルボニル)-2,5-Hydrocarboxylic acid, compound IIIa-001aTz: UPLC-MS (acidic method, 2 min): rt = 0.87 min; m / z = 356.1 [M+H], pixel area >95%. 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 11.43 (s, 1H), 10.74 (s, 1H), 9.21 (s, 1H), 8.46 (dd, J = 8.5, 1.2 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.60 (td, J = 8.6, 7.9, 1.6 Hz, 1H), 7.39 - 7.30 (m, 2H), 6.80 (s, 1H), 3.48 (s, 2H). HRMS: [M+H] + , calc. for C 16 H 14 N5O5: 356.09894, found: 356.09889 Biodata: IIIa-001aTz: FGF-1 IC50 [μM] = 51; FGF-2 IC50 [μM] = 14; VEGF-A1 IC50 [μM] = 12; VEGFR-1 kinase inhibition IC50 [μM] = 0.71; PMN ROS inhibition at 0.3 μM [%] = 69.35; PMN ROS inhibition IC50 [μM] = ND; GM-CSF inhibition [%] = 39.74; Whole blood: GM-CSF IC50 [μM] = >100; IFNγ IC50 [μM] = 18.9; IL-1β IC50 [μM] = >100; IL-2 IC50 [μM] = >100; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 1.98; IL-9 IC50 [μM] = 3.01; IL-10 IC50 [μM] = 7.78; IL-12p70 IC50 [μM] = 0.48; IL-13 IC50 [μM] = 0.15; IL-17A IC50 [μM] = 0.17; IL-17F IC50 [μM] = 0.16; IL-18 IC50 [μM] = 27.7; IL-21 IC50 [μM] = 3; IL-33 IC50 [μM] = 0.14; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.31; TNFβ IC50 [μM] = 0.23.

[0320] エチルエステル: UPLC-MS (acidic method, 4 min): rt = 1.56 min; m / z = 384.2 [M+H] + , ピークarea>95%. 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 10.73 (s, 1H), 9.25 (s, 1H), 8.45 (dd, J = 8.5, 1.2 Hz, 1H), 7.85 (dd, J = 7.8, 1.6 Hz, 1H), 7.61 (ddd, J = 8.7, 7.4, 1.6 Hz, 1H), 7.39 - 7.30 (m, 2H), 6.80 (s, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.56 (s, 2H), 1.19 (t, J = 7.1 Hz, 3H). HRMS: [M+H] + , calc. for C 18 H 18 N5O5: 384.13024, found: 384.12999 バイオデータ:IIIa-001aTz-E1: FGF-1 IC50 [μM] = 200; FGF-2 IC50 [μM] = 200; VEGF-A1 IC50 [μM] = 200; VEGFR-リン acidification inhibition IC50 [μM] =0.32; PMN ROS [Block at 0.3 μM [%] = 70.03; PMN ROS Blockage IC50 [μM] = ND; Good hit followed by blockage [%] = 91.76

[0321] 54) 2-(4-(カルボキシメチル)-2,5-ジヒドロキシベンズアミド)イソフタル acid, compound IIIa-013a: UPLC-MS (acidic method, 4 min): rt = 0.82 min; m / z = 376.0 [M+H] + , ピークarea>89%. 1 H NMR (400 MHz, DMSO-d6) δ 13.67 - 11.48 (m, 3H), 10.82 (s, 1H), 9.19 (s, 1H), 7.95 (d, J = 7.8 Hz, 2H), 7.36 (s, 1H), 7.33 (t, J = 7.8 Hz, 1H), 6.79 (s, 1H), 3.48 (s, 2H). HRMS: [M+H] + , calc. for C 17 H 14 NO9: 376.06630, found: 376.06638 Biodata: IIIa-013a: FGF-1 IC50 [μM] = 17; FGF-2 IC50 [μM] = 31; VEGF-A1 IC50 [μM] = 43; VEGFR-1 kinase inhibition IC50 [μM] = 1.3; PMN ROS inhibition at 0.3 μM [%] = 76.55; PMN ROS inhibition IC50 [μM] = ND; GM-CSF inhibition [%] = 30.667; Whole blood: GM-CSF IC50 [μM] = 27.8; IFNγ IC50 [μM] = 0.15; IL-1β IC50 [μM] = >100; IL-2 IC50 [μM] = 57.1; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 3.55; IL-9 IC50 [μM] = 11.9; IL-10 IC50 [μM] = 37.3; IL-12p70 IC50 [μM] = 0.5; IL-13 IC50 [μM] = 0.37; IL-17A IC50 [μM] = 0.15; IL-17F IC50 [μM] = 0.41; IL-18 IC50 [μM] = >100; IL-21 IC50 [μM] = 1.63; IL-33 IC50 [μM] = 1.11; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.51; TNFβ IC50 [μM] = 0.89.

[0322] 55) 5-(4-(カルボキシメチル)-2,5-ジヒドロキシベンズアミド)イソフタル acid, compound IIIa-015a: UPLC-MS (acidic method, 4 min): rt = 0.93 min; m / z = 376.0 [M+H] + , ピークarea>96%. 1H NMR (400 MHz, DMSO-d6+10% D2O) δ 8.34 (s, 2H), 8.18 (s, 1H), 7.38 (s, 1H), 6.71 (s, 1H), 3.39 (s, 2H). HRMS: [M+H] + , calc. for C 17 H 14 NO9: 376.06630, found: 376.06665 バイオデータ:IIIa-015a: FGF-1 IC50 [μM] = 16; FGF-2 IC50 [μM] = 114; VEGF-A1 IC50 [μM] = 202; 0.3 μM [%] = 78.76; PMN ROS blocking IC50 [μM] = ND; Good hit and then blocking [%] = 12.13

[0323] エチルジメチルエステル UPLC-MS (acidic method, 4 min): rt = 1.69 min; m / z = 432.1 [M+H] + , ピークarea>97%. 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.58 (s, 1H), 8.58 (s, 1H), 8.23 ​​- 8.21 (m, 1H), 7.31 (s, 1H), 6.81 (s, 1H), 4.08 (q, J = 7.0 Hz, 2H), 3.91 (s, 6H), 3.58 (s, 2H), 1.19 (t, J = 7.1 Hz, 3H), HRMS: [M+H] + , calc. for C 21 H 22 NO9: 432.12891, found: 432.02903 Biodata: IIIa-015a-E3: FGF-1 IC50 [μM] = ND; FGF-2 IC50 [μM] = 191; VEGF-A1 IC50 [μM] = 87; VEGFR phosphorylation inhibition IC50 [μM] = 7.2; PMN ROS inhibition at 0.3 μM [%] = 91.37; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 61.22

[0324] Example 1.9. Type IIIa Molecules: Diamides from Diamines, One Example [ka]

[0325] Scheme 15. Synthesis of Type IIIb Diamides [ka]

[0326] Procedure: See basic procedure from KI-1, steps [3], [4], [5]. for example: [ka] IIIb-010a

[0327] The conditions and yields are as follows: see Table 3 (Figure 6).

[0328] 56) 3,5-bis(2,5-dihydroxy-4-carboxymethylbenzoylamino)benzoic acid, compound IIIb-010a: UPLC-MS (acidic method, 4 min): rt = 1.08 min; m / z = 539.2.1 [MH] - , peak area 80%. 1H NMR (400 MHz, DMSO-d6) δ 10.85 (brs, 2H), 10.57 (brs, 2H), 9.20 (s, 2H), 8.26 (m, 1H), 8.09 (d, J = 2.0 Hz, 2H), 7.36 (s, 2H), 6.82 (s, 2H), 3.50 (s, 4H). HRMS: [M+H]+, calc. for C23H17N2O12: 513.07760, found: 513.07774

[0329] トリエチルエステル UPLC-MS (acidic method, 4 min): rt = 1.81 min; m / z = 623.3 [MH] - , ピーク area 94%. 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 2H), 10.65 (s, 2H), 9.23 (s, 2H), 8.31 - 8.28 (m, 1H), 8.10 (d, J = 2.0 Hz, 2H), 7.35 (s, 2H), 6.81 (s, 2H), 4.35 (q, J = 7.1 Hz, 2H), 4.08 (q, J = 7.1 Hz, 4H), 3.58 (s, 4H), 1.35 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 6H). バイオデータ:IIIb-010a-E3: FGF-1 IC50 [μM] = 200; FGF-2 IC50 [μM] = 200; VEGF-A1 IC50 [μM] = 200; VEGFR-リン acidification inhibition IC50 [μM] =0.65; PMN ROS [Block at 0.3 μM [%] = ND; PMN ROS Blockage IC50 [μM] = ND; Good hit then blockage [%] = 0

[0330] Example 1.10. Diphthyl IIIc molecular duplex, 6 examples

change

[0331] Synthetic Schemes and Procedures Scheme 16: X=O [ka]

[0332] Synthesis procedure Ether bond formation from KI-10 and KI-11 Ethyl 2,5-dibenzyloxy-4-[(2,5-dibenzyloxy-4-ethoxycarbonylphenyl)methoxymethyl]benzoate [Step 1]: To a solution of KI-11 (340 mg, 0.83 mmol) and KI-10 (250 mg, 0.64 mmol) in DMF (6 mL) was cooled in an ice bath and sodium hydride (76 mg, 1.9 mmol) was added portionwise. After 1 h, the reaction mixture was poured into saturated aqueous ammonium chloride (50 mL), and the material was extracted with EtOAc (3 × 30 mL). The organic phase was further washed with water (2 × 50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (hexane / EtOAc 0–20%) to afford the title compound (161 mg, 33% yield) as a brown solid.

[0333] Deprotection Procedure: See basic steps [4], [5]. for example [ka]

[0334] Conditions and yields are as follows: see Table 4 (deprotection) (Figure 7).

[0335] 57) 4-((2,5-dihydroxy-4-carboxyphenyl)methoxymethyl)-2,5-dihydroxybenzoic acid, compound IIIc-060a: UPLC-MS (acidic method, 4 min): rt = 0.94 min; m / z = 349.1 [MH] -, peak area >90%. 1 H NMR (400 MHz, DMSO-d6) δ 7.20 (s, 2H), 6.92 (s, 2H), 4.56 (s, 4H), Biodata: IIIc-060a: FGF-1 IC50 [μM] = 200; FGF-2 IC50 [μM] = 51; VEGF-A1 IC50 [μM] = 114; VEGFR phosphorylation inhibition IC50 [μM] = 1.3; PMN ROS inhibition at 0.3 μM [%] = 86.84; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 41.38

[0336] Scheme 17: X = NH [ka]

[0337] Synthesis procedure Amine bond formation from KI-12 and KI-13 via KI-10 and KI-11 Ethyl 2,5-bis(benzyloxy)-4-formylbenzoate (KI-12): To a solution of KI-10 (3.4 g, 8.6 mmol) in dichloromethane (50 mL) was added manganese dioxide (4.5 g, 51.9 mmol). The resulting suspension was stirred under reflux for 4 hours. The reaction was filtered through a pad of Celite®, the solid was washed with dichloromethane (300 mL), and the solvent was then removed under reduced pressure to give the title compound (3.2 g, 94% yield) as a yellowish solid.

[0338] UPLC-MS (acidic method, 2 min): rt = 1.33 min; m / z = no ion, peak area >93% 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.56 (s, 1H), 7.54 - 7.26 (m, 11H), 5.28 (s, 2H), 5.20 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H).

[0339] Ethyl 4-(azidomethyl)-2,5-bis(benzyloxy)benzoate: To a suspension of KI-10 (3.0 g, 7.6 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.5 mL, 9.9 mmol) in toluene (30 mL) was added diphenylphosphoryl azide (DPPA) (2 mL, 9.1 mmol). The resulting mixture was stirred at room temperature for 18 h. 1 M aqueous hydrochloric acid (200 mL) was added, and the product was extracted with EtOAc (3 × 100 mL). The combined organic layers were 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, 0–20%) to afford the title compound (3.1 g, 98%) as a colorless oil that became a white solid over time.

[0340] UPLC-MS (acidic method, 2 min): rt = 1.37 min; m / z = 390.2, [M+H-N2] + , Peak area >93% 1 H NMR (400 MHz, DMSO-d6) δ 7.53 - 7.46 (m, 4H), 7.44 - 7.26 (m, 8H), 5.16 (s, 2H), 5.14 (s, 2H), 4.48 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H).

[0341] Ethyl 4-(aminomethyl)-2,5-bis(benzyloxy)benzoate (KI-13): 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) was added polymer-bound triphenylphosphine (4.7 g, approximately 3 mmol / g loading), and the resulting mixture was stirred at room temperature for 18 h. 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), and the combined organic layers were washed with brine (200 mL), dried over sodium sulfate, and concentrated to give the title compound (KI-13) (1.8 g, 70% yield) as a white solid.

[0342] UPLC-MS (basic method, 2 min): rt = 1.20 min; m / z = 392.2, [M+H] + , Peak area >93% 1 H NMR (400 MHz, DMSO-d6) δ 7.60 - 7.22 (m, 12H), 5.14 (s, 2H), 5.10 (s, 2H), 4.24 (q, J = 7.1 Hz, 2H), 3.75 (s, 2H), 1.25 (t, J = 7.1 Hz, 3H).

[0343] Ethyl 2,5-dibenzyloxy-4-[(2,5-dibenzyloxy-4-ethoxycarbonylphenyl)methylaminomethyl]benzoate KI-12 (500 mg, 1.3 mmol) and KI-13 (641 mg, 1.6 mmol) were dissolved in DCM (35 mL), followed by the addition of activated molecular sieves (10 beads). The resulting mixture was stirred at room temperature for 5 h. Sodium triacetoxyborohydride (654 mg, 3.1 mmol) was then added, and the resulting mixture was stirred at room temperature for 18 h. DCM (25 mL) was added, and the reaction mixture was decanted into a separatory funnel, washed with water (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / EtOAc, 0–50%) to afford the title compound (631 mg, 64% yield) as a colorless oil that solidified over time.

[0344] UPLC-MS (acidic method, 2 min): rt = 1.37 min; m / z = 766.3, [M+H] + , Peak area >92% 1 H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.42 (m, 4H), 7.38 - 7.25 (m, 20H), 5.08 (s, 4H), 5.04 (s, 4H), 4.25 (q, J = 7.1 Hz, 4H), 3.76 (s, 4H), 1.25 (t, J = 7.1 Hz, 6H).

[0345] Deprotection procedure: See general procedure [4], [5]. The conditions and yields are as follows: see FIG. for example [ka]

[0346] 58) Bis(4-carboxy-2,5-dihydroxyphenylmethyl)amine, compound IIIc-056a: UPLC-MS (acidic method, 4 min): rt = 0.57 min; m / z = 350.0 [M+H] + , peak area >96%. 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 2H), 9.08 (s, 2H), 7.31 (s, 2H), 7.02 (s, 2H), 4.11 (s, 4H). HRMS: [M+H] + , calc. for C 16 H 16 NO8: 350.08704, found: 350.08706 Biodata: IIIc-056a: FGF-1 IC50 [μM] = 200; FGF-2 IC50 [μM] = 35; VEGF-A1 IC50 [μM] = 200; VEGFR phosphorylation inhibition IC50 [μM] = ND; PMN ROS inhibition at 0.3 μM [%] = 90.07; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 35

[0347] Scheme 18: X = NAc [ka]

[0348] Synthesis procedure N,N-Bis-[2,5-dibenzyloxy-4-ethoxycarbonylphenylmethyl]acetamide: 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) was added acetic anhydride (0.2 mL, 2.1 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / EtOAc, 0-50%) to afford the title compound (316 mg, 92% yield) as a colorless oil.

[0349] UPLC-MS (acidic method, 2 min): rt = 1.44 min; m / z = 808.2 [M+H] + , peak area >95%. 1 H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.17 (m, 22H), 6.92 (s, 1H), 6.72 (s, 1H), 5.03 (s, 2H), 5.00 (s, 2H), 4.96 (s, 2H), 4.94 (s, 2H), 4.46 (s, 4H), 4.31 -4.16 (m, 4H), 1.96 (s, 3H), 1.28 - 1.20 (m, 6H).

[0350] Deprotection Procedure: See basic steps [4], [5]. for example [ka]

[0351] Conditions and yields are as follows: see Figure 7 (deprotection).

[0352] 59) N,N-bis(4-carboxy-2,5-dihydroxyphenylmethyl)acetamide, compound IIIc-057a: UPLC-MS (acidic method, 4 min): rt = 0.84 min; m / z = 392.1 [M+H] + , peak area >99%. 1 H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 9.34 (s, 1H), 7.22 (s, 1H), 7.17 (s, 1H), 6.63 (s, 1H), 6.53 (s, 1H), 4.48 (s, 2H), 4.39 (s, 2H), 2.11 (s, 3H). HRMS: [M+H] + , calc. for C 18 H 18NO9: 392.09761, found: 392.09766 Biodata: IIIc-057a: FGF-1 IC50 [μM] = 87; FGF-2 IC50 [μM] = 77; VEGF-A1 IC50 [μM] = 38; VEGFR-1 kinase inhibition IC50 [μM] = 0.2; PMN ROS inhibition at 0.3 μM [%] = 90.34; PMN ROS inhibition IC50 [μM] = ND; GM-CSF inhibition [%] = 40.04; Whole blood: GM-CSF IC50 [μM] = >100; IFNγ IC50 [μM] = 0.9; IL-1β IC50 [μM] = 16.2; IL-2 IC50 [μM] = 24.2; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 0.19; IL-9 IC50 [μM] = 11.1; IL-10 IC50 [μM] = >100; IL-12p70 IC50 [μM] = 0.73; IL-13 IC50 [μM] = 4.73; IL-17A IC50 [μM] = 1.32; IL-17F IC50 [μM] = 5.06; IL-18 IC50 [μM] = >100; IL-21 IC50 [μM] = 1.56; IL-33 IC50 [μM] = 2.93; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.15; TNFβ IC50 [μM] = 1.58.

[0353] スキーム19:X = NCH2C6H3(OH)2COOH

change

[0354] Synthetic Hands The formation of KI-11 and the third level of NH3からの Tris(4-ethoxycarbonyl-2,5-dibenzyloxyphenylmethyl)amine: A sealed tube was charged with KI-11 (32.5 g, 79 mmol), sodium iodide (0.79 g, 5 mmol), a solution of ammonia in MeOH (7N) (38 mL, 264 mmol), and EtOAc (80 mL). The tube was then sealed, and the reaction mixture was heated at 60 °C for 24 h. After 24 h, the starting material (KI-11) was consumed, and the reaction mixture contained the desired product, but also monomeric and dimeric structures. Water (100 mL) was added, and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (165 mL), 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 h, water (100 mL) was added, and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by recrystallization using EtOH / EtOAc 95 / 5 (20 mL) as the solvent to give the title compound (15.0 g, 50%) as white crystals.

[0355] UPLC-MS (basic method, 2 min): rt = 1.71 min; m / z = 1140.3 [M+H] + , peak area >99%. 1 H NMR (400 MHz, DMSO-d6) δ 6.56 -6.49 (m, 12H), 6.48 - 6.38 (m, 24H), 4.22 (s, 6H), 4.04 (s, 6H), 3.42 (q, J = 7.1 Hz, 6H), 3.00 (s, 6H), 0.42 (t, J = 7.1 Hz, 9H).

[0356] Alternatively, the product can be purified by silica gel flash column chromatography: Scale up to 270 g; Equipment: Combiflash Torrent; Cartridge: RediSep column, 3 kg silica; Loading type: Crude dissolved in 1 L heptane:toluene (1:1). Elution with ethyl acetate / heptane. Detection: UV-240 nm.

[0357] Deprotection procedure: See general procedure [4], [5]. See Figure 7 (deprotection) for conditions and yields.

[0358] Alternative large scale deprotection procedure: Saponification. Tris(4-ethoxycarbonyl-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) using a temperature block for 48 hours, then stirred at room temperature for 24 hours. The solvent was then removed under reduced pressure. The crude product was collected and further diluted with water (2.85 L). In a separate 10 L flask, a mixture of acetic acid (180 mL) and water (950 mL) was stirred at room temperature. The mixture of crude product in water was added to the acetic acid mixture over 30 minutes while stirring with an overhead stirrer, causing a cream-colored solid to precipitate. The reaction mixture was stirred for an additional hour, and the solid was isolated by filtration; the pH of the mother liquor was 4.2. The isolated solid was stirred with water (1425 mL) for 1 hour and then filtered. The pH of the mother liquor was 4.5. The collected solid was stirred with additional water (1425 mL) for 1 hour and then filtered; the pH of the mother liquor 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 then analyzed (82.00 g, 93% yield) (yields vary between 90-95%).

[0359] NOTE: pH is an important parameter during washing to keep the product in the free acid form and to remove excess acetic acid from the product. Ideal pH: 4.2-4.5 (final sodium content varies between 2 ppm and 20 ppm).

[0360] Hydrogenolysis and Isolation. Tris(4-carboxy-2,5-dibenzyloxyphenylmethyl)amine (58.00 g, 54.00 mmol, 1 equiv.) and tetrahydrofuran (1160 mL) were charged to a 2 L round-bottom flask. The mixture was degassed with nitrogen and then flushed with hydrogen / vacuum cycles 4–5 times. Palladium on carbon (JM 10% 424 Pd / C, 70 g, 15% loading) was added to the reaction mixture and stirred at 25 °C for 5–6 h. The reaction was then degassed and the catalyst removed by filtering through a Celite pad, which 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 give a gray solid, which was dried overnight at 50 °C in a vacuum oven (32.50 g, >100% yield (crude basis)). The collected crude material was dissolved in ethanol (325 mL) and heated to 60°C (clear solution). Water (325 mL) was then added slowly at 60°C (maintaining the temperature at least 50°C during the addition) over 15-20 minutes. A cloudy liquid was observed at this stage. The cloudy reaction mixture was stirred at reflux temperature for 30 minutes.

[0361] After this time, the reaction mixture was cooled to room temperature for an additional 30 minutes. The precipitated solid was isolated immediately by filtration and washed with a 1:1 mixture of ethanol:water (66 mL). The solid was dried in a vacuum oven at 50 °C for at least 72 hours before analysis to give the desired product IIIc-061a (22.00 g, 76% yield) (yield varied between 65-75%). LCMS: >95%, NMR: >95% purity.

[0362] [ka]

[0363] Tris(4-carboxy-2,5-dihydroxyphenylmethyl)amine, compound IIIc-061a: UPLC-MS (acidic method, 4 min): rt = 0.74 min; m / z = 516.0 [M+H] + , ピーク area>86%. 1 H NMR (400 MHz, DMSO-d6) δ 7.27 (s, 3H), 6.83 (s, 3H), 4.33 (s, 6H). 13 C NMR (100 MHz, DMSO-d6) δ 172.0, 154.3, 148.3, 134, 117.8 (CH), 114.9 (CH), 112.4, 53.6 (CH2). HRMS: [M+H] + , calc. for C 24 H 22 NO 12 : 516.11365, found: 516.11389 Biodata: IIIc-061a: FGF-1 IC50 [μM] = 9; FGF-2 IC50 [μM] = 7.6; VEGF-A1 IC50 [μM] = 21; VEGFR-1 phosphatase inhibition IC50 [μM] = 4.3; PMN ROS inhibition at 0.3 μM [%] = 92.5; PMN ROS inhibition IC50 [μM] = ND; GM-CSF inhibition [%] = 58.69; Whole blood: GM-CSF IC50 [μM] = 31.2; IFNγ IC50 [μM] = 2.48; IL-1β IC50 [μM] = >100; IL-2 IC50 [μM] = >100; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 0.18; IL-9 IC50 [μM] = 8.85; IL-10 IC50 [μM] = 17.9; IL-12p70 IC50 [μM] = 37.2; IL-13 IC50 [μM] = 0.31; IL-17A IC50 [μM] = 0.04; IL-17F IC50 [μM] = 0.32; IL-18 IC50 [μM] = 32.4; IL-21 IC50 [μM] = 6.38; IL-33 IC50 [μM] = 0.31; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.03; TNFβ IC50 [μM] = 0.81

[0364] トリエチルエステル UPLC-MS (acidic method, 2 min): rt = 1.05 min; m / z = 600.2 [M+H] + , ピーク area>82%. 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 3H), 9.54 (s, 3H), 7.17 (s, 3H), 7.00 (s, 3H), 4.33 (q, J = 7.1 Hz, 6H), 3.59 (s, 6H), 1.31 (t, J = 7.1 Hz, 9H). HRMS: [M+H] +, calc. for C 30 H 34 NO 12 : 600.20755, found: 600.20790 Biodata: IIIc-061a-E3: FGF-1 IC50 [μM] = 200; FGF-2 IC50 [μM] = 200; VEGF-A1 IC50 [μM] = 200; VEGFR phosphorylation inhibition IC50 [μM] = 0.34; PMN ROS inhibition at 0.3 μM [%] = ND; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 10.4

[0365] Scheme 20: X = S [ka]

[0366] Synthesis procedure Thioether bond formation from KI-11 See Scheme 21. Same conditions for forming the thioether bond.

[0367] Deprotection procedure: See general procedure [4], [5]. for example [ka] Conditions and yields are as follows: see Figure 7 (deprotection).

[0368] 60) 4-((2,5-dihydroxy-4-carboxyphenyl)methylthiomethyl)-2,5-dihydroxybenzoic acid, compound IIIc-058a: UPLC-MS (acidic method, 2 min): rt = 0.84 min; m / z = 365.1 [MH] - , Peak area >79% 1H NMR (400 MHz, Methanol-d4) δ 7.25 (s, 2H), 6.83 (s, 2H), 3.69 (s, 4H). HRMS: [M+H] + , calc. for C 16 H 15 O8S: 367.04822, found: 367.04768, Biodata: IIIc-058a: FGF-1 IC50 [μM] = 12; FGF-2 IC50 [μM] = 12; VEGF-A1 IC50 [μM] = 124; VEGFR phosphorylation inhibition IC50 [μM] = 0.29; PMN ROS inhibition at 0.3 μM [%] = 61.22; PMN ROS inhibition IC50 [μM] = 1.17; Neutrophil adhesion inhibition [%] = 23

[0369] Scheme 21: X = SO2 [ka]

[0370] Synthesis procedure Oxidation of thioether bonds See preparation of IVc-059a: oxidation conditions are similar.

[0371] Deprotection procedure: See general procedure [4], [5]. for example [ka]

[0372] See Figure 7 (deprotection) for conditions and yields.

[0373] 61) 4-((2,5-dihydroxy-4-carboxyphenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid, compound IIIc-059a: UPLC-MS (acidic method, 2 min): rt = 0.72 min; m / z = 397.1 [MH] -, Peak area >97% 1 H NMR (400 MHz, DMSO-d6) δ 13.94 (brs, 2H), 10.63 (brs, 2H), 9.71 (s, 2H), 7.27 (s, 2H), 6.91 (s, 2H), 4.44 (s, 4H). HRMS: [M+H] + , calc. for C 16 H 15 O 10 S: 399.03804, found: 399.03768 Biodata: IIIc-059a: FGF-1 IC50 [μM] = 47; FGF-2 IC50 [μM] = 50; VEGF-A1 IC50 [μM] = 200; VEGFR phosphorylation inhibition IC50 [μM] = 3.61; PMN ROS inhibition at 0.3 μM [%] = 66.39; PMN ROS inhibition IC50 [μM] = 1; Neutrophil adhesion inhibition [%] = 14.67

[0374] Example 1.11. Compounds of Type IVc [ka]

[0375] Scheme 22: X=S Synthesis with dimethyl ether [ka]

[0376] Synthesis procedure Synthesis from 5-O-methylgentisic acid 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. Upon completion, the reaction was cooled to ambient temperature, and 2 M hydrochloric acid (700 mL) was added to the mixture, which was stirred at ambient temperature for 24 hours. The precipitate was filtered, washed with water (500 mL), and dried in a vacuum oven to give 3-formyl-2-hydroxy-5-methoxybenzoic acid as a pale yellow solid (21.30 g, 0.11 mol, 77.0%).

[0377] UPLC-MS (acidic method, 2 min): rt = 0.69 min; m / z = 195.1 [MH] - , Peak area >98% 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.62 (d, J = 3.4 Hz, 1H), 7.44 (d, J = 3.4 Hz, 1H), 3.78 (s, 3H).

[0378] 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 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, then filtered and dried in a vacuum oven to give methyl 3-formyl-2,5-dimethoxybenzoate as a yellow solid (8.90 g, 0.04 mol, 78.0%).

[0379] UPLC-MS (acidic method, 2 min): rt = 0.95 min; m / z = 225.1 [M+H] + , Peak area >98% 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.55 (d, J = 3.4 Hz, 1H), 7.41 (d, J = 3.4 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H).

[0380] Methyl 3-(hydroxymethyl)-2,5-dimethoxybenzoate. Sodium borohydride (16.198 g, 0.428 mol) was slowly added to a solution of methyl 3-formyl-2,5-dimethoxybenzoate (48.0 g, 0.214 mol) in MeOH (900 mL) at 0 °C, and the resulting mixture was stirred at ambient temperature for 15 minutes. The solvent was removed under reduced pressure, and the residue was dissolved in DCM (200 mL) and then washed with water (200 mL). The organic layer was dried over Na SO , filtered, and concentrated to dryness to give methyl 3-(hydroxymethyl)-2,5-dimethoxybenzoate as a white solid (45.6 g, 0.20 mol, 95.0%).

[0381] UPLC-MS (acidic method, 2 min): rt = 0.84 min; no ionization, peak area >98% 1 H NMR (400 MHz, DMSO-d6) δ 7.20 (d, J = 3.2 Hz, 1H), 7.08 (d, J = 3.3 Hz, 1H), 5.24 (t, J = 5.7 Hz, 1H), 4.54 (d, J = 5.6 Hz, 2H), 3.83 (s, 3H), 3.76 (s, 3H), 3.68 (s, 3H).

[0382] Methyl 3-(chloromethyl)-2,5-dimethoxybenzoate thionyl chloride (17.2 mL, 0.235 mol) was added dropwise over 30 minutes to a solution of methyl 3-(hydroxymethyl)-2,5-dimethoxybenzoate (45.60 g, 0.20 mol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 18 hours. Upon 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 NaSO, filtered, and concentrated to dryness to provide methyl 3-(chloromethyl)-2,5-dimethoxybenzoate as a brown solid (49.1 g, 0.18 mol, 90%).

[0383] UPLC-MS (acidic method, 2 min): rt = 1.10 min; no ionization, peak area >92% 1 H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J = 3.2 Hz, 1H), 7.22 (d, J = 3.3 Hz, 1H), 4.74 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H).

[0384] 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. Upon completion, the solvent was removed under reduced pressure to give a red oily residue, which was treated with saturated aqueous salt solution (500 mL) and then extracted with diethyl ether (2 × 250 mL). The organic phases were combined, dried over NaSO, filtered, and concentrated to dryness to give methyl 3-(acetylthiomethyl)-2,5-dimethoxybenzoate as a brown solid (25.50 g, 0.09 mol, 99%).

[0385] UPLC-MS (acidic method, 2 min): rt = 1.10 min; no ionization, peak area >92% 1H NMR (400 MHz, DMSO-d6) δ 7.12 (d, J = 3.3 Hz, 1H), 7.10 (d, J = 3.2 Hz, 1H), 4.10 (s, 2H), 3.84 (s, 3H), 3.74 (s, 3H), 3.70 (s, 3H), 2.35 (s, 3H).

[0386] To a solution of methyl 3-(mercaptomethyl)-2,5-dimethoxybenzoate (25.5 g, 89.68 mmol) in dry methanol (800 mL) was added a solution of sodium methanolate (5.81 g, 107.62 mmol) dropwise at 0° C. under a nitrogen atmosphere. The mixture was stirred at room temperature for 45 minutes and then washed with Dowex X8 (H + The reaction mixture was quenched with ion exchange resin and stirred for 15 minutes. After filtration, the solvent was evaporated under reduced pressure to give the crude product as a brown oil, which contained the desired product and the corresponding disulfide compound 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 the thiol was complete, the solvent was evaporated. The resulting residue was dissolved in DCM (1 L), washed with brine (7 x 500 mL), dried over NaSO, filtered, and concentrated to dryness to give homogeneous methyl 3-(mercaptomethyl)-2,5-dimethoxybenzoate as a brown oil (21.40 g, 88.32 mmol, 99%).

[0387] UPLC-MS (acidic method, 2 min): rt = 1.05 min; m / z = 243.1 [M+H] + , Peak area >95% 1H NMR (400 MHz, DMSO-d6) δ 7.19 (d, J = 3.2 Hz, 1H), 7.09 (d, J = 3.3 Hz, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.73 (s, 3H), 3.71 (d, J = 8.0 Hz, 2H), 2.93 (t, J = 8.0 Hz, 1H).

[0388] 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. Upon completion, the solvent was removed under reduced pressure to give a brown oily residue, which was treated with water (1 L) and then extracted with diethyl ether (3 x 500 mL). The organic phases were combined, washed with brine (5 × 250 mL), dried over NaSO, filtered, and concentrated to dryness to give the crude product as a brown oil, which was purified by silica gel chromatography; elution was performed with a gradient of ethyl acetate (0–20%) in isohexane to give dimethyl 3,3′-(thiobis(methylene))bis(2,5-dimethoxybenzoate) as a brown solid (29.9 g, 66.37 mmol, 76%).

[0389] UPLC-MS (acidic method, 2 min): rt = 1.22 min; m / z = 451.2 [M+H] + , Peak area >92% 1 H NMR (400 MHz, DMSO-d6) δ 7.12 - 7.08 (m, 4H), 3.83 (s, 6H), 3.76 (s, 4H), 3.73 (s, 6H), 3.67 (s, 6H).

[0390] A solution of lithium hydroxide monohydrate (1.0 g, 23.83 mmol) in 3,3'-(thiobis(methylene))bis(2,5-dimethoxybenzoic acid) 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. Upon 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 with 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 give 3,3'-(thiobis(methylene))bis(2,5-dimethoxybenzoic acid) as a brown solid (1.91 g, 4.11 mmol, 93%).

[0391] UPLC-MS (acidic method, 2 min): rt = 0.93 min; m / z = 421.1 [MH] - , Peak area >95% 1 H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 2H), 7.10 (d, J = 3.3 Hz, 2H), 7.08 (d, J = 3.2 Hz, 2H), 3.76 (s, 4H), 3.73 (s, 6H), 3.69 (s, 6H).

[0392] 3-[(2,5-Dihydroxy-3-carboxyphenyl)methylthiomethyl]-2,5-dihydroxybenzoic acid. To a solution of the above thioether (5.0 g, 0.01 mol) in DCM (200.0 mL) was slowly added a 1 M solution of tribromoborane in DCM (100.7 mL, 0.101 mol) at 0 °C, and the reaction mixture was refluxed for 48 h. After this time, the solid was filtered, washed with DCM (500 mL), and then suspended in 1 M hydrochloric acid (50 mL). The resulting mixture was refluxed for 2 h. The resulting brown suspension was filtered and dried to give the crude product, which was purified by reverse-phase column chromatography (25 g, MeCN:HO 5% to 95% over 12 CV) to give 2,5-dihydroxy-3-[(2,5-dihydroxy-3-carboxyphenyl)methylthiomethyl]benzoic acid as a white solid (1.1 g, 0.003 mol, 26%).

[0393] UPLC-MS (acidic method, 2 min): rt = 0.70 min; m / z = 365.1 [MH] - , Peak area >95% 1 H NMR (400 MHz, DMSO-d6) δ 13.86 (s, 2H), 11.09 (s, 2H), 9.14 (s, 2H), 7.08 (d, J = 3.1 Hz, 2H), 7.02 (d, J = 3.1 Hz, 2H), 3.65 (s, 4H).

[0394] example: 62) 3-((2,5-dihydroxy-3-carboxyphenyl)methylthiomethyl)-2,5-dihydroxybenzoic acid, compound IVc-058a: UPLC-MS (acidic method, 2 min): rt = 0.70 min; m / z = 365.1 [MH] - , Peak area >95% 1H NMR (400 MHz, DMSO-d6) δ 13.86 (s, 2H), 11.09 (s, 2H), 9.14 (s, 2H), 7.08 (d, J = 3.1 Hz, 2H), 7.02 (d, J = 3.1 Hz, 2H), 3.65 (s, 4H). HRMS: [M+H] + , calc. for C 16 H 15 O8S: 367.04822, found: 367.04734 Biodata: IVc-058a: FGF-1 IC50 [μM] = 36; FGF-2 IC50 [μM] = 4.9; VEGF-A1 IC50 [μM] = 83; VEGFR-1 kinase inhibition IC50 [μM] = 0.53; PMN ROS inhibition at 0.3 μM [%] = 77.04; PMN ROS inhibition IC50 [μM] = 0.29; GM-CSF inhibition [%] = 43.5; Whole blood: GM-CSF IC50 [μM] = >100; IFNγ IC50 [μM] = 10.6; IL-1β IC50 [μM] = 27.5; IL-2 IC50 [μM] = 3.82; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 0.21; IL-9 IC50 [μM] = 31.1; IL-10 IC50 [μM] = 16.4; IL-12p70 IC50 [μM] = 4.23; IL-13 IC50 [μM] = 55.9; IL-17A IC50 [μM] = 0.1; IL-17F IC50 [μM] = 86.8; IL-18 IC50 [μM] = >100; IL-21 IC50 [μM] = 3.2; IL-33 IC50 [μM] = 33.9; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.18; TNFβ IC50 [μM] = 59.3.

[0395] スキーム23:X=SO2

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[0396] Synthesis from compound IVc-058a 3-((2,5-Dihydroxy-3-carboxyphenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid. To a solution of thioether IVc-058a (4.25 g, 9.28 mmol) in DMF (20.0 mL) was slowly added a solution of 3-chlorobenzene-1-carboperoxy acid (mCPBA purity ≦77%, 5.80 g, 25.88 mmol) in DMF (20.0 mL). The reaction mixture was stirred at ambient temperature for 18 h. The crude product was subjected to HPLC purification (see general conditions) to give a white solid (3.20 g), which was triturated with 1 M HCl (50 mL) to give the desired product as a white solid (2.55 g, 6.40 mmol, 56%).

[0397] UPLC-MS (acidic method, 4 min): rt = 0.68 min; m / z = 397.1 [MH] - , Peak area >95%

[0398] 63) 3-((2,5-dihydroxy-3-carboxyphenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid, compound IVc-059a: UPLC-MS (acidic method, 4 min): rt = 0.68 min; m / z = 397.1 [MH] - , Peak area >95% 1 H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 9.32 (s, 1H), 7.21 (d, J = 3.1 Hz, 1H), 7.09 (d, J = 3.1 Hz, 1H), 4.44 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.4, 153.4, 149.2, 117.4, 116.1 (CH), 113.3 (CH), 53.6 (CH2). HRMS: [M+H] + , calc. for C 16 H 15 O 10 S: 399.03804, found: 399.03775 Biodata: IVc-059a: FGF-1 IC50 [μM] = 6.7; FGF-2 IC50 [μM] = 2.7; VEGF-A1 IC50 [μM] = 12; VEGFR-1 kinase inhibition IC50 [μM] = 4.8; PMN ROS inhibition at 0.3 μM [%] = 74; PMN ROS inhibition IC50 [μM] = 0.147; GM-CSF inhibition [%] = 10; Whole blood: GM-CSF IC50 [μM] = >100; IFNγ IC50 [μM] = 4.34; IL-1β IC50 [μM] = 38.6; IL-2 IC50 [μM] = 21.2; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 0.11; IL-9 IC50 [μM] = 0.4; IL-10 IC50 [μM] = 1.31; IL-12p70 IC50 [μM] = 42; IL-13 IC50 [μM] = >100; IL-17A IC50 [μM] = 0.16; IL-17F IC50 [μM] = >100; IL-18 IC50 [μM] = >100; IL-21 IC50 [μM] = 1.87; IL-33 IC50 [μM] = 27.5; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.16; TNFβ IC50 [μM] = 0.33

[0399] ジメチルエステル UPLC-MS (acidic method, 2 min): rt = 0.94 min; m / z = 427.1 [M+H] + , ピークarea>95% 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 2H), 9.43 (s, 2H), 7.21 (d, J = 3.1 Hz, 2H), 7.13 (d, J = 3.1 Hz, 2H), 4.47 (s, 4H), 3.91 (s, 6H). HRMS: [M+H] + , calc. for C 18 H 19 O 10 S: 427.06934, found: 427.06942 バイオデータ:IVc-059a-E2: FGF-1 IC50 [μM] = 78; FGF-2 IC50 [μM] = 94; VEGF-A1 IC50 [μM] = 200; VEGFR-リン acidification inhibition IC50 [μM] =2.7; 0.3 μM [%] = 45.67; PMN ROS blocking IC50 [μM] = 2.64; Good hit then blocking [%] = 50.5

[0400] ジメチルエステルテトラアセテート UPLC-MS (acidic method, 2 min): rt = 1.05 min; m / z = 593.1 [MH] - , ピークarea>95% 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 2.8 Hz, 2H), 7.53 (d, J = 2.9 Hz, 2H), 4.65 (s, 4H), 3.81 (s, 6H), 2.31 (s, 6H), 2.23 (s, 6H). HRMS: [M+H] + , calc. for C 26 H 27 O 14 S: 595.11160, found: 595.11149 Biodata: IVc-059a-E2-A4: FGF-1 IC50 [μM] = 54; FGF-2 IC50 [μM] = 200; VEGF-A1 IC50 [μM] = 25; VEGFR-1 kinase inhibition IC50 [μM] = ND; PMN ROS inhibition at 0.3 μM [%] = 29.17; PMN ROS inhibition IC50 [μM] = 4.13; GM-CSF inhibition [%] = 87.5; Whole blood: GM-CSF IC50 [μM] = 1.83; IFNγ IC50 [μM] = 3.5; IL-1β IC50 [μM] = 14.1; IL-2 IC50 [μM] = 10.4; IL-4 IC50 [μM] = >100; IL-5 IC50 [μM] = >100; IL-6 IC50 [μM] = 0.99; IL-9 IC50 [μM] = 2.9; IL-10 IC50 [μM] = 16.8; IL-12p70 IC50 [μM] = 51.4; IL-13 IC50 [μM] = 18.7; IL-17A IC50 [μM] = 0.02; IL-17F IC50 [μM] = 25.8; IL-18 IC50 [μM] = >100; IL-21 IC50 [μM] = >100; IL-33 IC50 [μM] = 23.2; TGFβ IC50 [μM] = >100; TNFα IC50 [μM] = 0.3; TNFβ IC50 [μM] = 19.4

[0401] IVc-059a のスケーラブル synthesis Synthesis of スキーム24:2,5-ジベンジルオキシフタルアルデヒドからのIVc-059a

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[0402] 2,5-Bis(benzyloxy)-3-(hydroxymethyl)benzaldehyde [Step 1]: 2,5-Bis(benzyloxy)-isophthalaldehyde (25.0 g, 72.1 mmol) (see Scheme 9b) was dissolved in THF (150 mL) and EtOH (15 mL) was added. The brown solution was kept under a positive stream of nitrogen and stirred at room temperature for 10 minutes. Solid NaBH (695 mg, 18.37 mmol) was then added portionwise over 20 minutes, ensuring that the internal temperature of the reaction did not exceed 25°C (using a water bath). The reaction mixture was stirred at room temperature for 30 minutes, and then additional NaBH was added every 15 minutes (total: 107 mg, in two portions) until complete conversion of the starting material was achieved. The reaction mixture was then poured into water (1.2 L) and stirred for 20 minutes. The brown precipitate thus formed was isolated by filtration, and the resulting solid was further dried to constant weight in a vacuum oven at 40° C. to afford the title compound (22.9 g, 76% corrected yield) as a brown oil. The NMR profile showed 83% desired product, 15% over-reduced diol, and 2% starting material, and this material was carried on to the next step without further purification.

[0403] UPLC-MS (acidic method, 2 min): rt = 1.19 min, 86%, m / z = 347.2 [MH]- 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 7.52 - 7.28 (m, 11H), 7.19 (d, J = 3.3 Hz, 1H), 5.34 (t, J = 5.6 Hz, 1H), 5.15 (s, 2H), 4.99 (s, 2H), 4.60 (d, J = 5.6 Hz, 2H).

[0404] 2,5-Bis(benzyloxy)-3-(hydroxymethyl)benzoic acid [Step 2]: 2,5-Bis(benzyloxy)-3-(hydroxymethyl)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 added slowly 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 then a 2 M aqueous solution of H3PO4 (95 mL) was added. The mixture was stirred for 20 minutes, cooled to 6°C in an ice bath, and then filtered. The solid was further washed with water until the pH of the filtrate reached approximately 6. The resulting solid was suspended in water (approximately 300 mL) and a pre-cooled (5-10°C) solution of NaOH (17 g, 412 mmol) in water (200 mL) was added. The suspension was stirred at room temperature for 30 minutes and then filtered through a sintered funnel. The isolated solid was further washed with 1 M aqueous NaOH (2 × 50 mL) and water (50 mL). The alkaline solution was then acidified to a pH of approximately 1 using pre-cooled (5-10°C) 6N aqueous HCl. The resulting suspension was magnetically stirred for 20 minutes before filtering, and the resulting solid was further dried in a vacuum oven at 40°C to a constant weight to afford the title compound as a light beige solid (34.8 g, 88%).

[0405] UPLC-MS (acidic method, 2 min): rt = 1.06 min, 99%, m / z = 363.2 [MH] - . 1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 7.51 - 7.31 (m, 10H), 7.28 (d, J = 3.2 Hz, 1H), 7.22 (d, J = 3.3 Hz, 1H), 5.21 (s, 1H), 5.12 (s, 2H), 4.88 (s, 2H), 4.53 (s, 2H).

[0406] Ethyl 2,5-bis(benzyloxy)-3-(hydroxylmethyl)benzoate [Step 3]: 2,5-Bis(benzyloxy)-3-(hydroxymethyl)benzoic acid (32.5 g, 89.3 mmol) and CsCO (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 h, the reaction mixture was poured into a saturated aqueous solution of NHCl (1 L), and solid NaCl (approximately 30 g) was added. After stirring for 10 min, the material was extracted with EtOAc (2 × 500 mL). The combined organic layers were washed with brine (2 × 500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oily residue (42.0 g, crude, 89.3 mmol). The crude material was carried on to the next step without further purification.

[0407] UPLC-MS (acidic method, 2 min): rt = 1.24 min, 93%, m / z = weak ionization. 1H NMR (400 MHz, DMSO-d6) δ 7.51 -7.32 (m, 10H), 7.31 (d, J = 3.3 Hz, 1H), 7.22 (d, J = 3.3 Hz, 1H), 5.24 (t, J = 5.6 Hz, 1H), 5.13 (s, 2H), 4.87 (s, 2H), 4.54 (d, J = 5.6 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H)

[0408] Ethyl 2,5-bis(benzyloxy)-3-(chloromethyl)benzoate (KI-14) [Step 4]: Ethyl 2,5-bis(benzyloxy)-3-(hydroxymethyl)benzoate (42 g, 89.3 mmol, crude material from the previous step) was dissolved in DCM (200 mL) under an inert atmosphere (N), then SOCl (9.8 mL, 133.9 mmol) was added at 0 °C (ice bath) and the reaction mixture was allowed to warm to room temperature. After 2 h, the volatiles were removed under reduced pressure, followed by azeotropic distillation with toluene (3 × 100 mL) to give a semi-solid brown oil (38.0 g, crude, 89.3 mmol).

[0409] UPLC-MS (acidic method, 2 min): rt = 1.40 min, 91%, m / z = weak ionization. 1H NMR (400 MHz, DMSO-d6) δ 7.54 -7.26 (m, 12H), 5.14 (s, 2H), 4.95 (s, 2H), 4.71 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.28 - 1.22 (t, J = 7.1Hz, 3H).

[0410] Bis(2,5-dibenzyloxy-3-ethoxycarbonylphenylmethyl)sulfide [Step 5]: To a solution of KI-14 (38.0 g, crude material, 89.3 mmol) in DMF (420 mL) was added thioacetamide (8.4 g, 111.8 mmol), followed by K2CO3-325 mesh (16.7 g, 120.8 mmol). The reaction was heated at 45 °C for 48 h. The reaction was cooled to room temperature, followed by the addition of thioacetamide (2.5 g, 33.3 mmol) and K2CO3-325 mesh (5.0 g, 36.1 mmol), and further stirred at 45 °C for 18 h to complete the reaction. The reaction mixture was poured into water (4 L). The reaction mixture was stirred for 20 min, followed by the addition of EtOAc (2 L), followed by solid NaCl (approximately 60 g). The phases were separated followed by further extraction with EtOAc (1.5 L). The combined organic layers were washed with brine (1.5 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound (39.8 g, 44.6 mmol) as a brown oil, which was used in the next step without purification.

[0411] UPLCMS (acidic method, 2 min): rt = 1.57 min, m / z = 800.5 [M+NH4]+, peak area 77%. 1H NMR (400 MHz, DMSO-d6) δ 7.46 -7.17 (m, 24H), 5.05 (s, 4H), 4.83 (s, 4H), 4.23 (q, J = 7.1 Hz, 4H), 3.73 (s, 4H), 1.20 (t, J = 7.1 Hz, 6H).

[0412] Bis(2,5-dibenzyloxy-3-ethoxycarbonylphenylmethyl)sulfone [Step 6]: To a solution of bis(2,5-dibenzyloxy-3-ethoxycarbonylphenylmethyl)sulfide (39.8 g crude, 44.6 mmol) in acetic acid (850 mL) was slowly added a 30 wt% solution of hydrogen peroxide (50 mL, 490 mmol). The reaction was stirred at room temperature for 18 h. The reaction mixture was poured into ice / water (5 L) and stirred at room temperature for 30 min, followed by the addition of EtOAc (2 L) and solid NaCl (ca. 40 g). After phase separation, the aqueous layer was extracted once more with EtOAc (1 L). The combined organic layers were washed with brine (1.5 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a brown solid. The solid was suspended in MTBE (250 mL) and magnetically stirred for 30 min, then filtered and further triturated with MTBE (150 mL) to give the title compound (23.56 g, 28.9 mmol, 64% yield over four steps).

[0413] UPLC-MS (acidic method, 2 min): rt = 1.48 min; m / z = 832.5 [M+NH4]+, peak area 96% 1H NMR (400 MHz, DMSO-d6) δ 7.50 -7.24 (m, 24H), 5.08 (s, 4H), 4.85 (s, 4H), 4.50 (s, 4H), 4.26 (q, J = 7.1 Hz, 4H), 1.25 - 1.17 (m, 6H).

[0414] Bis(2,5-dibenzyloxy-3-carboxyphenylmethyl)sulfone [Step 7]: A solution of lithium hydroxide (9.7 g, 233 mmol) in water (100 mL) was added to a solution of bis(2,5-dibenzyloxy-3-ethoxycarbonylphenylmethyl)sulfone (33.3 g, 38.8 mmol) in THF (350 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 give a white suspension. Water (3 L) and aqueous sodium hydroxide (1 M, 1 L) were added, but the mixture remained a suspension. The suspension was stirred at room temperature for 18 hours, the aqueous layer was acidified to pH 1 by addition of 6 M aqueous hydrochloric acid, the resulting solid was collected by filtration and washed with water until the liquid was neutral, and the white solid thus obtained was further dried in a vacuum oven at 40°C to constant weight to give the title compound as a white solid (29.4 g, 38.7 mmol, 99%).

[0415] UPLC-MS (acidic method, 2 min): rt = 1.39 min; m / z = 757.1 [MH]-, peak area 100% 1H NMR (400 MHz, DMSO-d6) δ 13.23 (s, 2H), 7.47 - 7.25 (m, 24H), 5.08 (s, 4H), 4.88 (s, 4H), 4.48 (s, 4H).

[0416] 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), palladium on charcoal (20 wt%, 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 H atmosphere and stirred for 20 hours. Upon completion, the mixture was filtered through Celite® using THF. The filtrate was concentrated under reduced pressure to give an off-white solid. The residue was then suspended in acetonitrile (100 mL) and heated to reflux under magnetic stirring. The mixture was then cooled to -5°C before being filtered and washed with additional cold acetonitrile. The product was further dried in a vacuum oven at 40° C. to a constant weight to give the desired product as a white solid (5.35 g, 12.78 mmol, 96%).

[0417] UPLC-MS (acidic method, 4 min): rt = 0.67 min; m / z = 397.1 [MH]-, peak area 100%

[0418] NMR data: see above.

[0419] Example 1.12. Type V Molecules: Reference Compounds Diamides derived from 5-hydroxyisophthalic acid 2 examples [ka]

[0420] Synthetic Schemes and Procedures Scheme 25: Synthesis of V-001a [ka]

[0421] Amide bond formation See general procedure B for amide coupling [3B] using aniline A (2 mol) or methyl 5-aminosalicylate.

[0422] Deprotection procedure: See general procedure [4], [5]. See Figure 8 for details. for example [ka]

[0423] 64) 5-Hydroxyisophthalic acid bis-N-(4-carboxy-2,5-dihydroxyphenyl)amide (V-001a) UPLC-MS (acidic method, 2 min): rt = 0.72 min; m / z = 483.0 [M+H] + , Peak area >95% 1 H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.83 (s, 2H), 9.48 (s, 2H), 7.92 (s, 1H), 7.68 (s, 2H), 7.52 (d, J = 1.5 Hz, 2H), 7.30 (s, 2H).

[0424] Diethyl ester UPLC-MS (acidic method, 2 min): rt = 1.09 min; m / z = 539.2 [MH] - , Peak area 94% 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 2H), 9.92 (s, 2H), 9.49 (s, 2H), 7.91 (s, 1H), 7.73 (s, 2H), 7.51 (d, J = 1.5 Hz, 2H), 7.32 (s, 2H), 4.35 (q, J = 7.1 Hz, 4H), 1.34 (t, J = 7.1 Hz, 6H). [ka]

[0425] 65) 5-Hydroxyisophthalic acid bis-N-(3-carboxy-4-hydroxyphenyl)amide (V-002a) UPLC-MS (acidic method, 4 min): rt = 1.00 min; m / z = 451.1 [MH] - , Peak area 97% 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 2H), 10.11 (s, 1H), 8.28 (d, J = 2.7 Hz, 2H), 7.98 (m, 1H), 7.89 (dd, J = 9.0, 2.7 Hz, 2H), 7.50 (d, J = 1.5 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H).

[0426] Urea-linked gentisic acid unit: 1 example [ka]

[0427] Synthetic Scheme and Procedure Scheme 26: Synthesis of V-003a [ka]

[0428] Urea bond formation Instructions from KI-1: N,N'-Bis(2,5-dibenzyloxy-4-ethoxycarbonylphenyl)urea: To a cooled (ice bath) solution of 2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid (KI-1) (2.0 g, 4.9 mmol) and EtN (1.6 mL, 11.3 mmol) in THF (25 mL) under an inert atmosphere (N), DPPA (1.1 mL, 5.2 mmol) was slowly added. The mixture was slowly warmed to room temperature and stirred at this temperature for 3 h. tBuOH (8 mL) was then added, and the reaction mixture was stirred at room temperature for 18 h. The reaction profile showed that the urea-coupled product dominated, rather than the desired Boc-aniline. The mixture was poured into a saturated solution of sodium bicarbonate (250 mL) and stirred for 5 min, followed by extraction with EtOAc (3 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a colorless oil. The residue was purified by flash column chromatography (isohexane / EtOAc, 1:0, then gradient to 30% EtOAc) to give the title compound (1.1 g, 56%) as an off-white solid.

[0429] UPLC-MS (basic method, 2 min): rt = 1.50 min; m / z = 781.2 [M+H] + , Peak area 85% 1 H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 2H), 8.18 (s, 2H), 7.58 - 7.45 (m, 8H), 7.43 - 7.35 (m, 8H), 7.35 - 7.28 (m, 6H), 5.27 (s, 4H), 5.11 (s, 4H), 4.22 (q, J = 7.1 Hz, 4H), 1.24 (t, J = 7.1 Hz, 6H).

[0430] Deprotection procedure: See general procedure [4], [5]. See Figure 8 for details. for example 66) N,N'-Bis(2,5-dihydroxy-4-carboxyphenyl)urea (V-003a) [ka]

[0431] UPLC-MS (acidic method, 4 min): rt = 0.90 min; m / z = 363.1 [MH] - , Peak area 93% 1 H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 2H), 10.86 (s, 2H), 9.64 (s, 2H), 9.48 (s, 2H), 7.77 (s, 2H), 7.17 (s, 2H).

[0432] Diethyl ester UPLC-MS (acidic method, 4 min): rt = 1.79 min; m / z = 419.2 [MH] - , Peak area 97% 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 2H), 9.74 (s, 2H), 9.53 (s, 2H), 7.81 (s, 2H), 7.20 (s, 2H), 4.32 (q, J = 7.1 Hz, 4H), 1.33 (t, J = 7.1Hz, 6H).

[0433] Example 1.13. Salt Formation a) solid General protocol: The appropriate number of equivalents of base was added to a solution or suspension of the desired compound in water, sonicated until complete dissolution, and the pH was adjusted to 7.0-7.4 by adding aqueous HCl or excess base as needed. The solution was then lyophilized to obtain the salt as a solid. Alternatively, certain salts could be obtained by dissolving in DMSO followed by precipitation with EtOH (IIc-007a). Solids were generated from the following bases: sodium hydroxide, diethylamine (DEA), lysine (Lys), meglumine (Meg), and triethanolamine (TEA).

[0434] example: The sodium and diethylammonium (DEA) salts of Ic-007a, IIc-007a, IIIc-061a as solids were obtained following the general protocol without adjusting the pH.

[0435] -Approximate solubility in water: Ic-007a-DEA2:<10mg / mL Ic-007a-DEA3:>20mg / mL IIc-007a-DEA1:>10mg / mL IIc-007a-DEA2:>20mg / mL IIIc-061a-DEA3:>25 mg / mL

[0436] -Stability of the free acid and salts as solids: The free acids Ic-007a, IIc-007a, IIIc-061a and the following salts Ic-007a-DEA2, IIc-007a-DEA2, IIIc-061a-DEA3 were stable as solids for up to 56 days at temperatures of 4°C, 20°C, and 40°C; salt Ic-007a-DEA3 was stable for up to 36 days at the same temperatures.

[0437] b) solution General protocol: The salt was obtained as a solution by adding the appropriate number of equivalents of base to a solution or suspension of the desired compound in water, sonicating until complete dissolution, and adjusting the pH to a value between 7.0 and 7.4 by adding aqueous HCl or excess base as needed. The following bases were investigated: ethylamine, triethylamine, ethylenediamine, diethanolamine, triethanolamine, choline, meglumine, lysine, and arginine.

[0438] for example: Ic-007a salt: After stirring the mixture at 40°C for 2 days, a soluble salt was obtained using meglumine, lysine, and diethanolamine. A solid Ic-007a-Lys2 salt was obtained from DMSO by precipitation with ethanol. The salt was stable in aqueous solution at room temperature for at least 7 days.

[0439] IIc-007a Salt: DEA1-salt: On a small scale, the monodiethylammonium salt was obtained by the basic procedure without adjusting the pH. Solubility: 17.4 mg / mL vs. 1.8 mg / mL for the parent diacid.

[0440] Large-scale processing and characterization: IIc-007a (20 g, 42.7 mmol) was charged with EtOH (200 mL). The reaction was stirred at room temperature to give a slurry. DEA (4.4 mL, 42.7 mmol) was charged and the reaction was heated at 50° C. for 2 hours. The batch was cooled to room temperature and the solid was filtered off. The filter cake was washed with EtOH (50 mL) and oven-dried at 40° C. to give 21.5 g of the mono-DEA salt as a yellow solid in 98% yield. NMR: 1.6% EtOH, 1.04 eq DEA. HPLC: 99.6%.

[0441] Solid-state data for the mono-DEA salt of IIc-007a showed a clear crystalline pattern in XRPD analysis. The TGA trace showed a small amount of EtOH loss below 120 °C, indicating that EtOH could be evaporated at 60-80 °C. A loss of DEA (13.5 wt% of the theoretical for the 1:1 salt) was then observed in DSC, accompanied by a melting endotherm (peak at 273.8 °C), followed by melting of the free acid form.

[0442] DEA2-salt, pH adjusted: Obtained by the basic procedure with pH adjustment (an additional 0.51 equivalents of EtNH was required to reach pH = 7.25). The salt in solution shows clear decomposition after 21 days at 40 °C and extensive decomposition after 24 hours at 80 °C. DEA2-salt, pH not adjusted: Obtained by the general procedure without pH adjustment. Solution pH = 5.87. The salt in solution showed no decomposition after 21 days at 4°C, 20°C, and 40°C. Lys2-salt, pH not adjusted: Obtained by the general procedure using 2 equivalents of L-lysine. Solution pH=5.74.

[0443] NOTE: By analogy with the bis(N-methyl)amide of 2-hydroxyisophthalic acid (phenolic pKa = 6.81), the 2-OH group of the isophthalic acid bis-amide core of IIc-007a is significantly acidic, and its ionization leads to decomposition of the molecule. This effect is not observed in Ic-007a (the expected pKa of the phenolic functional group is in the range of 9.8-10.0). Therefore, it is important not to adjust the pH of the solution of the dicationic salt of IIc-007a.

[0444] IIIc-061a salt: DEA3-salt, pH adjusted: Obtained by the general procedure using 3 equivalents of EtNH with pH adjustment (an additional 0.8 equivalents of HCl (0.5 M) was required to reach a final pH of 7.22). The salt in solution showed no decomposition after 21 days at 4 °C and 20 °C, and slight decomposition after 33 days at 40 °C. Meg3-salt, pH adjusted: Obtained by the general procedure using 3 equivalents of meglumine with pH adjustment to reach a final pH of 7.22 (0.5 M HCl). The salt in solution showed no decomposition after 21 days at 4°C and 20°C, and no decomposition after 14 days at 40°C.

[0445] Salt of IVc-059a DEA2-salt, pH adjusted: Obtained by the general procedure with pH adjustment (0.32 additional equivalents of EtNH were required to reach pH = 7.3). The salt in solution is stable after 26 days at 4 °C, 20 °C, and 40 °C.

[0446] Example 1.14. Prodrugs Prodrug of Ic-007a 1) 2-Morpholinoethyl 5-[[2,5-dihydroxy-4-[[4-hydroxy-3-(2-morpholinoethoxycarbonyl)phenyl]carbamoyl]benzoyl]amino]-2-hydroxy-benzoate (Ic-007a-mpe2). [ka]

[0447] Esterification: A suspension of 5-[[2,5-dibenzyloxy-4-[(3-carboxy-4-hydroxyphenyl)carbamoyl]benzoyl]amino]-2-hydroxybenzoic acid (130 mg, 0.2 mmol) in N,N-dimethylformamide (4 mL) was stirred at room temperature. N,N-dimethylpyridin-4-amine (49 mg, 0.4 mmol) and a solution of 2-morpholinoethanol (53 mg, 0.4 mmol) in N,N-dimethylformamide (0.5 mL) were 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 eluting with 0-40% methanol in dichloromethane to give the title product as a white solid (80 mg, 45%). LCMS (m / z) [M+H] 875.1.

[0448] Hydrogenolysis: A solution of the diester obtained above (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 10–97% (acetonitrile + 0.1% formic acid):(water + 0.1% formic acid). The residue was triturated with diethyl ether and dried under reduced pressure to give the title product Ic-007a-mpe2 as a yellow solid (22 mg, 35%).

[0449] 1H NMR (d6-DMSO ppm) δ 11.16-11.00 (br s, 1H), 10.46 (s, 1H), 10.45-10.15 (br s, 1H), 8.25 (d, J=2.7 Hz, 1H), 7.77 (dd, J=9.0, 2.7Hz, 1H), 7.53 (s, 1H), 7.01 (d, J=9.0 Hz, 1H), 4.46 (t, J=5.4 Hz, 2H), 3.62-3.56 (m, 4H), 2.77-2.69 (m, 2H), 2.56-2.50 (m, 4H, partially obscured by DMSO peak). LCMS (m / z) [M+H] 695.0.

[0450] 2) 5-[[2,5-dihydroxy-4-[[4-hydroxy-3-(2-morpholinoethoxycarbonyl)phenyl]carbamoyl]benzoyl]amino]-2-hydroxybenzoic acid (IC-007a-mpe1) [ka]

[0451] Esterification. A solution of 5-[[2,5-dibenzyloxy-4-[(3-carboxy-4-hydroxyphenyl)-carbamoyl]benzoyl]amino]-2-hydroxybenzoic 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-dimethylpyridin-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 and 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 triturated with diethyl ether to give a mixture of mono and diesters (230 mg). LCMS (m / z) [M+H] 762.0 (monoester)

[0452] Hydrogenolysis: The mixture of mono- and diesters obtained above (230 mg) was dissolved in acetic acid (10 ml), tetrahydrofuran (15 ml), and water (5 ml), and 10% palladium on carbon (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 give a yellow gum (140 mg). The residue was purified by reverse-phase preparative HPLC on a C18 column using a gradient of 10–70% (acetonitrile + 0.1% formic acid):(water + 0.1% formic acid). The residue was triturated with diethyl ether and dried under reduced pressure to give the title monoester Ic-007a-mpel as a yellow solid (11 mg).

[0453] 1 H NMR (d6-DMSO ppm) δ 11.33-11.29 (br s, 1H), 11.13-10.08 (br s, 1H), 10.50-10.44 (br s, 2H), 10.36-10.30 (br s, 1H), 8.25 (d, J=2.4 Hz, 1H), 8.06-8.02 (m, 1H), 7.78 (dd, J=9.0, 2.4Hz, 1H), 7.69-7.60 (m, 2H), 7.52 (s, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 4.50-4.45 (m, 2H), 3.65-3.55 (m, 4H), 2.81-2.71 (m, 2H), 2.60-2.50 (m, 4H, partially obscured by DMSO peak). LCMS (m / z) [M+H] 582.0.

[0454] 3) 1-(2,2-dimethylpropanoyloxy)ethyl 5-[[4-[[3-[1-(2,2-dimethylpropanoyloxy)ethoxycarbonyl]-4-hydroxy-phenyl]carbamoyl]-2,5-dihydroxy-benzoyl]amino]-2-hydroxy-benzoate (IC-007a-pive2) and

[0455] 4) 5-[[4-[[3-[1-(2,2-dimethylpropanoyloxy)ethoxycarbonyl]-4-hydroxy-phenyl]carbamoyl]-2,5-dihydroxy-benzoyl]amino]-2-hydroxy-benzoic acid (IC-007a-pive1) [ka]

[0456] Esterification: A solution of 5-[[2,5-dibenzyloxy-4-[(3-carboxy-4-hydroxyphenyl)carbamoyl]benzoyl]amino]-2-hydroxybenzoic 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 warmed to room temperature and stirred at room temperature for 24 h. The dimethylformamide was evaporated, and the residue was partitioned between dichloromethane and aqueous sodium disulfite. The organic phase was dried over anhydrous magnesium sulfate and evaporated to give a 1:1 mixture of mono- and diesters (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). [ka]

[0457] Hydrocracking The mixture of mono- and diesters obtained above (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 40-97% (acetonitrile + 0.1% formic acid):(water + 0.1% formic acid). The residue was triturated with diethyl ether and dried under reduced pressure to give the title product.

[0458] Diester (Ic-007a-pive2): yellow solid (60 mg). 1 H NMR (d6-DMSO ppm) δ 11.05 (s, 1H), 10.46 (s, 1H), 10.18 (s, 1H), 8.18 (br s, 1H), 7.83-7.77 (m, 1H), 7.52 (s, 1H), 7.05-6.96 (m, 2H), 1.58 (d, J=5.5 Hz, 3H), 1.17 (s, 9H). LCMS (m / z) [M+H] 724.9. Biodata:T 1 / 2 (Mouse plasma): 62.2 min (ester cleavage; 65% remaining after 1 h); T 1 / 2 (Human plasma): > 180 min.

[0459] Monoester (Ic-007a-pive1): yellow solid (35 mg). 1H NMR (d6-DMSO ppm) δ 11.13 (s, 1H), 11.06 (s, 1H), 10.46 (s, 1H), 10.42 (s, 1H), 10.18 (s, 1H), 8.21-8.18 (m, 2H), 8.78-8.72 (m, 2H), 7.55 (s, 1H), 7.52 (s, 1H), 7.03-6.92 (m, 3H), 1.58 (d, J=5.5 Hz, 3H), 1.17 (s, 9H). LCMS (m / z) [M+H] 596.9 Biodata:T 1 / 2 (Mouse plasma): 44.6 min (ester cleavage; 49% remaining after 1 h); T 1 / 2 (Human plasma): > 180 min.

[0460] Prodrug of IIc-007a 1) 2,2-Dimethylpropanoyloxymethyl 5-[[3-[[3-(2,2-dimethylpropanoyloxymethoxycarbonyl)-4-hydroxy-phenyl]carbamoyl]-2,5-dihydroxy-benzoyl]amino]-2-hydroxy-benzoate (IIc-007a-pivm2) [ka]

[0461] Esterification: A solution of 5-[[2,5-dibenzyloxy-3-[(3-carboxy-4-hydroxy-phenyl)carbamoyl]benzoyl]amino]-2-hydroxy-benzoic 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 partitioned between saturated ammonium chloride solution and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a silica column using a gradient of 100% isohexane to 50% ethyl acetate, 50% isohexane to give the diester as a colorless gum (192 mg, 51%). LCMS(m / z)[M+H]876.9.

[0462] Hydrogenolysis: A solution of the diester obtained above (192 mg, 0.219 mmol) in tetrahydrofuran (4.5 mL) was prepared and added to a stirred suspension of 10% palladium on carbon (40 mg, 0.04 mmol) in water (1.5 mL). The stirred reaction mixture was placed under a hydrogen atmosphere for 18 hours. The reaction was filtered to remove the catalyst, and the solution was evaporated to give a cream-colored solid (142 mg). The solid was purified by HPLC on a C18 column using a gradient of 60% acetonitrile, 40% water to 100% acetonitrile (0.1% formic acid) to give the title diester IIc-007a-pivm2 as a white solid (75 mg, 49%). 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.

[0463] 2) 5-[[3-[[3-[1-(2,2-dimethylpropanoyloxy)ethoxycarbonyl]-4-hydroxy-phenyl]carbamoyl]-2,5-dihydroxy-benzoyl]amino]-2-hydroxy-benzoic acid (IIc-007a-pive1) [ka]

[0464] Esterification: A solution of 5-[[2,5-dibenzyloxy-3-[(3-carboxy-4-hydroxyphenyl)carbamoyl]benzoyl]amino]-2-hydroxybenzoic 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 h. 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 h. The solvent was evaporated. The residue was partitioned between dichloromethane and sodium disulfite solution. The organic extracts were combined, washed with brine, and the solution was dried by passing through a hydrophobic frit. The filtrate was evaporated to give a mixture of mono- and diesters. The residue was purified by silica gel chromatography eluting with 5-100% ethyl acetate in isohexane followed by 10% methanol in dichloromethane to give the monoester as a yellow solid (121 mg). LCMS (m / z) [M+H] 777.

[0465] A solution of the monoester obtained above (121 mg, 0.15 mmol) in tetrahydrofuran (16 mL) and water (4 mL) containing hydrogenolysis 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 40-97% (acetonitrile + 0.1% formic acid):(water + 0.1% formic acid) to give the monoester IIc-007a-pive1 as a yellow solid (34 mg). 1 H 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.

[0466] Prodrug of IVc-059a 1) 2,5-dihydroxy-3-[[2,5-hydroxy-3-(2-morpholinoethoxycarbonyl)phenyl]methylsulfonyl-methyl]benzoic acid (IVc-059a-mpe1) [ka]

[0467] 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-dimethylpyridin-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 to dryness, 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 give the morpholinoethyl ester as a colorless gum (111 mg, 32%). LCMS (m / z) [M+H] 872.1.

[0468] Hydrogenolysis: A solution of the above monoester (111 mg, 0.127 mmol) in tetrahydrofuran (3 mL) was added to a stirred suspension of 10% palladium on carbon (20 mg, 0.019 mmol) in water (1 mL). The stirred reaction mixture was placed under an atmosphere of hydrogen for 18 hours.

[0469] The reaction was filtered to remove the catalyst, and the solution was evaporated to give a brown solid. The solid was purified by HPLC on a C18 column using a gradient of 10% acetonitrile, 90% water to 60% acetonitrile, 40% water (0.1% formic acid) to give a white solid (20.5 mg). The solid was triturated with diethyl ether and dried under reduced pressure to give the title product IVc-059a-mpel as a white solid (5 mg, 8%).

[0470] 1H NMR (DMSO-d6 ppm) δ 10.33 (br s, 1H), 9.30 (s, 1H) 8.92 (s, 1H), 7.08-7.15 (m, 3H), 6.91 (d, J=3.1Hz, 1H), 4.40 (t, J=5.0Hz, 2H), 4.36 (s, 2H), 3.65-3.72 (m, 4H), 3.05 (t, J=5.0Hz, 2H), 2.78-2.87 (m, 4H). LCMS (m / z) [M+H] 511.9. Biodata: Stable in mouse plasma for up to 60 minutes

[0471] 2) 2,5-Dihydroxy-3-[[2,5-hydroxy-3-(2-morpholinoethoxycarbonyl)phenyl]methylsulfonyl-methyl]benzoic acid 2-morpholinoethyl ester (IVc-059a-mpe2) [ka]

[0472] 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-dimethylpyridin-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 to dryness, and the residue was purified by chromatography on a silica column using 10% methanol, 90% dichloromethane to give the title product as a colorless gum (58 mg, 65%). LCMS (m / z) [M+H] 985.0.

[0473] A solution of the diester obtained above (58 mg, 0.059 mmol) in tetrahydrofuran (1.5 mL) was prepared and added to a stirred suspension of 10% palladium on carbon (5 mg, 0.005 mmol) in water (0.5 mL). The stirred reaction mixture was placed under a hydrogen atmosphere for 18 hours. The reaction was filtered to remove the catalyst, and the solution was evaporated to give a brown solid. The solid was purified by HPLC on a C18 column using a gradient of 10% acetonitrile, 90% water to 60% acetonitrile, 40% water (0.1% formic acid) to give a white solid (13.7 mg). The solid was triturated with diethyl ether and dried under reduced pressure to give the title product IVc-059a-mpe2 as a white solid (9.1 mg, 25%).

[0474] 1 H NMR (CD3OD ppm) δ 8.34 (br s, 2H), 7.32 (d, J=3.1Hz, 2H), 7.16 (d, J=3.1Hz, 2H), 4.52 (t, J=5.5Hz, 4H), 4.45 (s, 4H), 3.68-3.73 (m, 8H), 2.83 (t, J=5.5Hz, 4H), 2.58-2.65 (m, 8H). LCMS (m / z) [M+H] 625.0. Biodata: Stable in mouse plasma for up to 60 minutes; T 1 / 2 (Human plasma):>180 min.

[0475] 3) 3-[[3-[1-(2,2-dimethylpropanoyloxy)ethoxycarbonyl]-2,5-dihydroxy-phenyl]methyl-sulfonyl-methyl]-2,5-dihydroxy-benzoic acid 1-(2,2-dimethylpropanoyloxy)ethyl ester (IVc-059a-pive2) [ka]

[0476] Esterification: A 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 (approximately 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 partitioned between dichloromethane and sodium thiosulfate solution. The organic layer was filtered through a hydrophobic frit and evaporated. The residue was purified by chromatography on a silica gel column eluting with a gradient of 100% isohexane to 50:50 ethyl acetate / isohexane to give the diester as a colorless gum (110 mg, 41%). LCMS(m / z)[M+Na] 1037.0 The monoester was also isolated from the same column as a colorless gum (90 mg, 40%). LCMS (m / z) [M+Na] 909.6.

[0477] Hydrocracking: [ka]

[0478] A solution of the above-isolated diester (110 mg, 0.108 mmol) in tetrahydrofuran (3 mL) was added to a stirred suspension of 10% palladium on carbon (20 mg, 0.02 mmol) in water (1 mL). The stirred reaction mixture was placed under a hydrogen atmosphere for 48 hours. The reaction mixture was filtered to remove the catalyst, the solution evaporated, and the residue purified by chromatography on a silica column eluted with a gradient of 100% dichloromethane to 10% methanol, 90% dichloromethane to give the title product IVc-059a-pive2 as a cream-colored solid (55 mg, 78%).

[0479] 1H NMR (CDCl3ppm) δ 10.55 (s, 2H), 7.24-7.28 (m, 2H), 7.14-7.18 (m, 2H), 7.05 (q, J=5.4Hz, 2H), 6.18 (br s, 2H), 4.30-4.50 (m, 4H), 1.60 (d, J=5.4Hz, 6H), 1.21 (s, 18H). LCMS (m / z) [MH] 653.9. Biodata: Rapidly hydrolyzed in mouse and human plasma.

[0480] 4) 3-[[3-[1-(2,2-dimethylpropanoyloxy)ethoxycarbonyl]-2,5-dihydroxy-phenyl]methylsulfonyl-methyl]-2,5-dihydroxy-benzoic acid (IVc-059a-pive1) Hydrocracking: [ka]

[0481] A solution of the monoester isolated above (90 mg, 0.104 mmol) in tetrahydrofuran (3 mL) was added to a stirred suspension of 10% palladium on carbon (20 mg, 0.02 mmol) in water (1 mL). The stirred reaction mixture was placed under a hydrogen atmosphere for 48 hours. The reaction was filtered to remove the catalyst, the solution evaporated, and the residue purified by chromatography on a silica column eluted with a gradient of 100% dichloromethane to 20% methanol, 80% dichloromethane to afford the title product IVc-059a-pive1 as a cream-colored solid (22.5 mg, 43%).

[0482] 1H NMR (CD3OD ppm) δ 7.39 (d, , J=3.1Hz, 1H), 7.25 (d, J=3.1Hz, 1H), 7.18 (d, J=3.1Hz, 1H), 7.05 (q, J=5.4Hz, 1H), 6.96 (d, J=3.1Hz, 1H), 4.40-4.45 (m, 4H), 1.61 (d, J=5.4Hz, 3H), 1.21 (s, 9H). LCMS (m / z) [MH] 524.9. Biodata: Rapidly hydrolyzed in mouse plasma.

[0483] 5) 2,2-dimethylpropanoyloxymethyl 2,5-dihydroxy-3-[[2,5-dihydroxy-3-(2,2-dimethyl-propanoyloxymethoxycarbonyl)phenyl]methylsulfonylmethyl]benzoate (IVc-059a-pivm2) [ka]

[0484] Esterification: A 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 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 partitioned 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 eluting with a gradient of 100% isohexane to 50% ethyl acetate, 50% isohexane to give the diester product as a colorless gum (85 mg, 66%). LCMS(m / z)[M+Na]1010.0

[0485] Hydrogenolysis: A solution of the diester obtained above (85 mg, 0.086 mmol) in tetrahydrofuran (3 mL) was added to a stirred suspension of 10% palladium on carbon (20 mg, 0.02 mmol) in water (1 mL). The stirred reaction mixture was placed under a hydrogen atmosphere for 18 hours. The reaction was filtered to remove the catalyst, the solution evaporated, and the residue purified by chromatography on a silica gel column eluting with a gradient of 100% isohexane to 60% ethyl acetate, 40% isohexane to give diester IVc-059a-pivm2 as a white solid (31 mg, 57%).

[0486] 1 H NMR (CDCl3ppm) δ 7.29 (d, J=2.9Hz, 2H), 7.19 (d, J=2.9Hz, 2H), 5.97 (s, 4H), 4.42 (s, 4H), 1.22 (s, 18H). LCMS (m / z) [MH] 624.8. Biodata: Rapidly hydrolyzed in mouse plasma, T 1 / 2 =14.1 min;T 1 / 2 (Human plasma):>180 min.

[0487] 6) 2,5-dihydroxy-3-[[2,5-dihydroxy-3-(2,2-dimethylpropanoyloxymethoxycarbonyl)phenyl]methyl-sulfonylmethyl]benzoic acid (IVc-059a-pivm1) [ka]

[0488] 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, and chloromethyl 2,2-dimethylpropanoate (57 μL, 0.395 mmol) was added, followed by 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 then evaporated. The residue was purified by chromatography on a silica column eluting with a gradient from 20% ethyl acetate, 80% isohexane to 80% ethyl acetate, 20% isohexane to give the monoester product as a white solid (121 mg, 35%). LCMS (m / z) [MH] 871.0.

[0489] Hydrogenolysis: A solution of the monoester obtained above (121 mg, 0.138 mmol) in tetrahydrofuran (3 mL) was added to a stirred suspension of 10% palladium on carbon (20 mg, 0.02 mmol) in water (1 mL). The stirred reaction mixture was placed under a hydrogen atmosphere for 48 hours. The reaction was filtered to remove the catalyst, the solution evaporated, and the residue purified by HPLC on a C18 column eluting with a gradient of 30% acetonitrile, 70% water to 100% acetonitrile (0.1% formic acid) to give the monoester IVc-059a-pivm1 as a white solid (30 mg, 42%).

[0490] 1 H NMR (CD3OD ppm) δ 7.34 (d, J=3.0Hz, 1H), 7.27 (d, J=3.1Hz, 1H), 7.20 (d, J=3.1Hz, 1H), 7.08 (d, J=3.0Hz, 1H) , 6.01 (s, 2H), 4.45 (s, 4H), 1.22 (s, 9H). LCMS (m / z) [MH] 510.9. Biodata: Rapidly hydrolyzed in mouse plasma, T 1 / 2 = 6.7 minutes; T 1 / 2 (Human plasma): > 180 min.

[0491] Example 2. General Experimental Methods NMR spectroscopy 1 H NMR spectra were recorded at 400 MHz on a Bruker Advance III NMR spectrometer. Samples were prepared in deuterated chloroform (CDCl3) or dimethyl sulfoxide (DMSO-d6), and raw data were processed using Mnova NMR software. High-resolution mass spectra were recorded on a MaxIs ESI qTOF ultra-high resolution mass spectrometer.

[0492] UPLC-MS analysis UPLC-MS analysis was performed on a Waters Acquity UPLC system consisting of an Acquity I-Class Sample Manager-FL, an Acquity I-Class Binary Solvent Manager, and an 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; positive and negative modes simultaneously). Analyte separation was achieved using a Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 mm).

[0493] Samples were prepared by dissolving (with or without sonication) in 1 mL of a 1:1 (v / v) mixture of MeCN in HO. The resulting solution was filtered through a 0.45 μm syringe filter prior to analysis. All solvents used (including formic acid and 36% ammonia solution) were HPLC grade. Four different analytical methods were used for this study, which are detailed below. Acidic run (2 min): 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.

[0494] [Table 14]

[0495] Acidic run (4 min): 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.

[0496] [Table 15]

[0497] Acidic run (6.5 min): 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.

[0498] [Table 16]

[0499] Basic run (2 min): 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.

[0500] [Table 17]

[0501] Basic run (4 min): 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.

[0502] [Table 18]

[0503] Basic run (6.5 min): 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.

[0504] [Table 19]

[0505] Preparative HPLC purification Preparative HPLC was performed using a Waters autopurification system equipped with an XBridge Prep C18 column (19 × 150 mm). The Waters system consisted 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. The purification system was controlled by MassLynx software (version 4.2) equipped with the Open Access Login module.

[0506] The mobile phase consisted of (A) 10 mM ammonium formate (+0.1% v / v formic acid) and (B) acetonitrile (+0.1% v / v formic acid). Samples were prepared by dissolving in 10% v / v water in DMSO to obtain a concentration of approximately 150 mg / mL. A volume of 320 mL of the prepared sample was loaded onto the column and purified using gradient elution at room temperature with a flow rate of 25 mL / min, with a 1.5 minute equilibration between injections.

[0507] [Table 20]

[0508] Example 3. In vitro screening method Example 3.1. In Vitro HUVEC Cell FGF1, FGF2 and VEGF-A Inhibition Methods The purpose 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 angiogenesis assay. Cells were preincubated with the compounds before adding the growth factors. Sunitinib was tested as a control (no preincubation). The sunitinib control inhibited FGF-2, FGF-1, and VEGF-A-induced HUVEC sprouting, as expected. IC values ​​determined for test compounds are expressed in micromolar [μM], and values ​​for inhibition of FGF-1, FGF2, and VEGF-A-induced proliferation (sprouting) are listed after each compound in the Examples after chemical characterization.

[0509] The sprouting test was performed on compounds dissolved in DMSO to reach a 100x concentrated stock solution and then dissolved in culture medium. Sunitinib, the reference compound, was provided by ProQinase GmbH. Growth factors were purchased from Peprotech, New Jersey, USA, #100-18C, Lot# 0415571 (rhFGF-basic (FGF-2)), Peprotech, New Jersey, USA, #100-17A, Lot# 031207; hVEGF-A165 (ProQinase GmbH, Freiburg, Germany; 05.02.2010) to stimulate HUVEC cell proliferation. Test system: Human umbilical vein (HUVEC)-derived endothelial cells from pooled donors were cultured at approximately 1 x 10 in 70% medium, 20% FCS, 10% DMSO. 6HUVEC cells, primary human umbilical vein endothelial cells (PromoCell, Heidelberg, Germany), were used after 3-4 passages. The cells were adherent, growing as a monolayer in a cobblestone-like pattern, and cultured in endothelial cell growth medium and basal medium (ECGM / ECBM, PromoCell). Subcultures were split 1:3 and subcultured every 3-5 days at approximately 1 x 10 4 cells / cm 2 and incubated at 37°C, 5% CO2, with a doubling time of 24-48 hours.

[0510] Test compound dilution: 100x concentrated solutions (with respect to final assay concentration) of each test compound were prepared using the appropriate solvent (DMSO or water). These 100x compound solutions were further diluted 1:7.5 with endothelial cell growth and basal medium (ECBM) to obtain 13.33x concentrated solutions. 75 μl of the 13.33x solution was subsequently mixed with 25 μl of 40x concentrated stimuli (dissolved in ECBM) to obtain a 10x concentrated stimuli / compound mixture. This mixture (100 μl) was incubated at 37°C for 30 minutes and then added to 900 μl of gel containing HUVEC spheroids (resulting in the final assay concentration). Test Method: Experiments were performed using a modified version of the originally published protocol (Korff and Augustin: J Cell Sci 112: 3249-58, 1999). Briefly, spheroids were prepared as described (Korff and Augustin: J Cell Biol 143: 1341-52, 1998) by pipetting 400 HUVECs in hanging drops onto a plastic dish and allowing the spheroids to aggregate overnight. Fifty HUVEC spheroids were seeded into 0.9 ml of collagen gel and pipetted into individual wells of a 24-well plate for polymerization. Test compounds were preincubated with growth factors (FGF-1, FGF-2, or VEGF-A, final concentration 25 ng / mL) in a 10x concentrated solution, and then 100 μl of this solution was added on top of the polymerized gel. All compounds were initially diluted in solvent (DMSO or water) as 100x stocks (meaning that 100x stocks of each final assay concentration were prepared in solvent). These stocks were then further diluted in media (resulting in 13.33x stocks of each final assay concentration) to give final concentrations of 100, 50, 25, 12.5, 6.25, 3.13, and 1.56x10. -6 Plates were incubated at 37°C for 24 hours and fixed by adding 4% PFA (Roth, Karlsruhe, Germany).

[0511] Quantification of growth factor inhibition: The sprouting intensity of HUVEC spheroids treated with growth factors and inhibitors was quantified using an image analysis system that determined the cumulative sprout length per spheroid (CSL). Photographs of single spheroids were taken using an inverted microscope and digital imaging software NIS-Elements BR 3.0 (Nikon). Spheroid photographs were then uploaded to the Wimasis website for image analysis. The cumulative sprout length of each spheroid was determined using the image analysis tool WimSprout. The average cumulative sprout length of 10 randomly selected spheroids was analyzed as individual data points. For IC50 determination, raw data were converted to the percentage of HUVEC sprouting relative to the solvent control (with stimuli) set at 100% and the basal control (without stimuli) set at 0%. IC50 values ​​were determined using GraphPad Prism 5 software using a nonlinear regression curve fitted with a variable Hill slope, constraining the bottom to 0 and the top to 100.

[0512] Results: Dose-response relationships for growth factor-induced sprouting of endothelial cells were evaluated for all compounds. IC50 values ​​were determined using standard parameters based on the solvent control signal as the maximum constraint (100% HUVEC sprouting) and the base control signal as the minimum constraint (0%). The respective IC50 values ​​of each compound for FGF1, FGF2, and VEGFA are summarized under each compound under their chemical characterization in the biodata section.

[0513] Example 3.2. In vitro neutrophil adhesion method under static conditions Human neutrophils obtained from the buffy coat of healthy donors were cultured at 3 × 10 in adhesion buffer (PBS, pH 7.2, containing 1 mM CaCl / MgCl and 10% FCS). 6 Neutrophils were pre-incubated with 40 μM and 80 μM of the compounds for 30 minutes at 37°C. Adhesion assays were performed on 18-well glass slides coated with human fibrinogen (20 μg / well in endotoxin-free PBS) for 18 hours at 4°C; 20 μl of cell suspension was added to each well and stimulated with 5 μl of fMLP (1 nM final concentration) for 1 minute at 37°C. After washing, adherent cells were fixed in 1.5% glutaraldehyde in PBS and counted by computer-assisted enumeration. Statistical analysis was performed by calculating the mean and standard deviation (SD); significance was calculated by unpaired t-test. All statistical analyses were performed using GraphPad Prism 6 (GraphPad Software). The respective inhibition of neutrophil adhesion, expressed in [%] for each compound, is summarized under each compound under their chemical characterization in the biodata paragraph.

[0514] Example 3.3: In vitro testing for inhibition of reactive oxygen species (ROS) production in human neutrophils NADPH oxidase, located in the plasma membrane and in the membranes of specific granules, produces superoxide anions, which then generate ROS, such as hydrogen peroxide, singlet oxygen, hypochlorite, and reactive hydroxyl radicals. ROS are released into the surrounding medium or membrane-enclosed intracellular organelles. One method for rapid and sensitive measurement of the production of these metabolites is chemiluminescence (CL). The isoluminol-amplified CL method is highly sensitive and has been widely used to study the respiratory burst induced in neutrophils (primarily due to the extracellular production of ROS).

[0515] Human neutrophils were isolated from buffy coats obtained from healthy donors. Isolated neutrophils (3 × 10 6Neutrophils (100 μg / ml) were suspended in Hank's balanced salt solution (HBSS) containing calcium and magnesium. Neutrophils were preincubated with different concentrations of compounds (0.1, 0.3, 1, 3, and 10 μM) at 37°C for 30 minutes. 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) at 37°C for 10 minutes (priming). Then, 75 μl of cell suspension and 75 μl of isoluminol + HRP solution were added to each well. After fMLP (1 μM) activation, chemiluminescence was recorded (every 25 seconds for 250 seconds) using a Multilabel Reader Victor3 (Perkin Elmer, USA). A background value, defined as the mean chemiluminescence value of isoluminol diluted in HBSS, was subtracted from all readings (CPS, counts per second). Assays were performed in duplicate or triplicate.

[0516] The results obtained from the isoluminor-amplified CL assay revealed that the compounds strongly reduced ROS levels in a concentration-dependent manner in fMLP+TNF-α-stimulated PMNs. PMN ROS inhibition at 0.3 μM expressed in [%] and IC50 [μM] are summarized under each compound under their chemical characterization in the biodata section.

[0517] Example 3.4: In vitro human neutrophil and human monocyte inflammatory cytokine production, methods Neutrophils and monocytes were isolated from buffy coats of healthy donors under endotoxin-free conditions. Briefly, buffy coats were layered on a Ficoll-Paque PLUS gradient and then centrifuged at 400 × g for 30 minutes at room temperature. Neutrophils were then collected and subjected to dextran sedimentation, followed by hypotonic lysis to remove red blood cells. Alternatively, monocytes were isolated from PBMCs after centrifugation on a Percoll gradient. Human neutrophils and monocytes were suspended at 5 × 106 / ml and 2.5 × 106 / ml, respectively, in RPMI 1640 medium supplemented with 10% low-endotoxin FBS (<0.5 EU / ml; BioWhittaker-Lonza, Basel, Switzerland) and then seeded into 24-well tissue culture plates at 37°C in a 5% CO2 atmosphere in the presence or absence of different concentrations (20–40 μM) of compounds. After 1 hour of drug treatment, monocytes were stimulated with 0.1 μg / ml LPS, and neutrophils were stimulated with 1 μg / ml ultra-pure LPS from E. coli 0111:B4 (InvivoGen). Six hours after LPS stimulation, neutrophils and monocytes were collected and spun at 300 × g for 5 minutes. The cell-free supernatant was immediately frozen at -80°C.

[0518] Cytokine concentrations in cell-free supernatants were measured by human-specific commercially available ELISA kits: CXCL8, IL-6, and TNF-α (Mabtech, Sweden). The detection limits of these ELISAs were as follows: 4 pg / ml for CXCL8, 10 pg / ml for IL-6, and 4 pg / ml for TNF-α. Statistical analysis was performed by calculating the mean and standard deviation (SD); significance was calculated by unpaired t-test. All statistical analyses were performed using GraphPad Prism 6 (GraphPad Software). Cytokine values ​​were expressed in ng / ml for each compound and are summarized for each compound under their chemical characterization in the biodata section.

[0519] Example 3.5. In vitro inhibition by compounds of VEGF-165-induced phosphorylation of VEGF receptors on primary human umbilical vein endothelial cells (HUVECs). Methods Cell culture: Primary human umbilical vein endothelial cells (HUVECs) were routinely cultured in flasks or dishes pre-coated with 0.1% gelatin up to passage 6. The effect of compounds alone at different concentrations (0, 1.25, 2.5, 5, 10, and 20 μM) on cell viability was assessed by CCK-8 kit using a Tecan Microplate Reader (Genios). To measure the effect of compounds on VEGF-induced cell viability, HUVECs (1 × 10 4 Cells (1000 cells / well) were treated with VEGF (25 ng / ml) premixed with various concentrations of compounds (0, 1.25, 2.5, 5, 10, and 20 μM) in serum- and growth factor-free culture medium (starvation medium) for 24 and 48 hours. Compounds in this concentration range did not affect cell viability.

[0520] The rabbit primary antibody against VEGFR-2, p-Tyr1175, was obtained from Cell Signaling Technology (Leiden, The Netherlands). The Phospho-VEGFR-2 (Tyr1175) Sandwich ELISA kit was from Cell Signaling Technology. HUVECs were preincubated with compounds at 0, 0.16, 0.31, 0.63, 1.25, 2.5, 5, 10, and 20 μM for 60 min, washed three times with warm medium, and then stimulated with VEGF165 (25 ng / mL) for 2 min. Western blot analysis was performed using anti-phospho-VEGFR-2 antibody, and total VEGFR-2 was used as a loading control after membrane stripping.

[0521] The results of inhibition of VEGFR-2 phosphorylation are expressed as IC50 [μM] relative to the VEGF-treated HUVEC control without inhibitor compound. The respective IC50s, expressed as [μM] values ​​for each compound, are summarized below each compound under their chemical characterization in the biodata section.

[0522] Example 3.6. In vitro inhibition of cytokine release by compounds following LPS induction in human whole blood The purpose of this in vitro method was to evaluate the effect of compounds on the release of a panel of cytokines from whole blood following a lipopolysaccharide (LPS)-induced inflammatory response. Whole blood was incubated with compounds for 1 hour prior to LPS induction. Blood cytokine levels were measured using a multiplexed FACS-based panel. The IC50 values ​​determined for the test compounds are expressed in [μM] and the values ​​for inhibition of cytokines are listed for each compound. The effect on cytokine release after LPS induction was assessed for compounds dissolved in DMSO or H2O to reach a 10-fold concentrated stock solution and then dissolved in culture medium.

[0523] Test system: Whole blood was drawn from a single donor (in lithium heparin-coated tubes; BD Vacutainer; 367886) and diluted 1:5 with RPMI 1640 (Thermo Fisher, 61870036). Within 30 minutes of sampling, blood was incubated with compound for 1 hour and then subjected to LPS stimulation (O111:B4-Sigma L4391; final concentration 10 ng / ml). Stimulation continued overnight (18 hours) under standard cell culture conditions (37°C, 5% CO), after which the plates were centrifuged, and the supernatant removed and frozen at -80°C until use in analysis. Test compound dilutions: 10x concentrated solutions (with respect to final assay concentration) of each test compound were prepared using the appropriate solvent (DMSO or water). These 10x compound solutions (10 μl) were then added to 90 μl of pre-diluted whole blood (whole blood:RPMI1640, 1:5) to give the final assay concentration. Test method: Diluted whole blood (80 μl) was pre-incubated with compound (10 μl) and the following concentrations were measured: 100, 30, 10, 3, 1, 0.3, and 0.1 × 10 -6 A final assay concentration of 1000 mg LPS was obtained. Blood was incubated at 37°C, 5% CO2 for 1 hour. LPS was diluted in cell culture medium to a concentration of 110 ng / ml; 10 μl was added to whole blood to give a final concentration of 10 ng / ml. Plates were incubated at 37°C for 18 hours. Plates were centrifuged at 3,000 RPM for 5 minutes at 4°C, and the supernatant was removed and frozen at -80°C until FACS analysis.

[0524] Cytokine release was measured using a custom multiplex system (ELISA Genie) according to the manufacturer's instructions. Prepared samples were run on an Attune NxT flow cytometer (Thermo Fisher). Quantification of cytokine release inhibition: To allow for quantification of each cytokine concentration in each sample, standards of known concentrations were run as part of the cytokine panel. This was performed using FCAP Array v3.0 software. For IC50 determination, raw data were converted to percent concentration relative to the solvent control, which was set at 100%. IC50 values ​​were determined using GraphPad Prism 8 software using a nonlinear regression curve fitted with a variable Hill slope, constrained to a bottom of 0 and a top of 100.

[0525] Results: Dose-response relationships for cytokine release after LPS induction of an inflammatory response in whole blood were assessed for all compounds. IC50 values ​​were determined for each compound for a panel of cytokines (GM-CSF, IFN-gamma, IL-1beta, 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, and TNF-beta). The respective cytokine IC50s, expressed as [μM] values ​​for each compound, are summarized below each compound under their chemical characterization in the biodata section and in Table 13.

[0526] Example 4. Compound Formulation Example 4.1. Oral Formulation of Compound Ic-007a Five formulations were developed and tested for suitability, both suspensions and solutions, the details of which are shown in the table below.

[0527] [Table 21]

[0528] Preparation: Suspension A and Solution D: Example Method for 100 mL (scale appropriate to required final volume): Solvent stock was prepared by weighing 5 mL of DMSO into a clean container. The correct amount of compound Ic-007a was weighed and slowly added to the DMSO solution while mixing on a shaker, vortex, or sonicator. Solutol was melted in a 60°C water bath in a clean, dry container. Because solutol solidified at room temperature, the molten solutol was kept in the 60°C water bath during formulation preparation. 10 g (10% w / v) of molten solutol was added to an appropriately marked warmed container (to a final volume of 100 mL). 10 mL of PEG 400 was added to the solutol in the warmed 100 mL container. The DMSO drug stock solution was added to the Solutol and PEG400 mixture, the contents were mixed immediately, and 35 mL of deionized water was added and mixed in a 40°C bath with intermittent vortexing to dissolve large particles. The formulation was cooled to room temperature and brought to a final volume of 100 mL with deionized water.

[0529] Preparation of solutions A, B and C: Example Method for 100 mL (scale appropriate to required final volume): Solvent stock was prepared by weighing 5 mL of DMSO into a clean container. 1 g of compound Ic-007a was weighed and slowly added to the DMSO solution while mixing with a shaker, vortex, or sonication as needed. Solutol was melted in a 60°C water bath in a clean, dry container. Because solutol solidifies at room temperature, the molten solutol was kept in a 60°C water bath during formulation preparation. 10 g (10% w / v) of molten solutol was weighed into an appropriately marked, warmed container (to a final volume of 100 mL). 10 mL of PEG400 was added to the solutol in the warmed 100 mL container. The DMSO drug stock solution was added to the marked container of the solutol and PEG400 mixture and immediately mixed into the contents. 35 mL of deionized water was added, mixed with the contents, and placed in a 40°C bath with intermittent vortexing to dissolve large particles. The formulations were cooled to room temperature, and the pH of the formulations was adjusted to pH 6, 7, 8, and 9 using 1 M sodium hydroxide (NaOH) solution. Initial formulations were made at a 1 mL scale with a starting pH of 4.3. A volume of 3 μL of 1 M NaOH was added to achieve pH 6 (Solution A), 22 μL to achieve pH 8 (Solution B), and 43 μL to achieve pH 9 (Solution C). These formulations were administered immediately after manufacturing. The 10 mg / mL suspension and 1 mg / mL solution formulations were found to be physically stable for 2 weeks at ambient conditions.

[0530] Example 4.2. Oral Formulation of Compound Ia-001a-Tz Compound Ia-001a-Tz was prepared as a 10 mg / mL oral solution in a formulation with the vehicle composition shown in the table below. A vehicle was a carrier or inert medium used as a vehicle (or diluent) in which a pharmaceutically active agent was formulated and / or administered.

[0531] [Table 22]

[0532] Manufacturing method To prepare a 10 mg / g solution, 10 mg of compound was accurately weighed into a vial and 1 ml of vehicle was added directly onto the API and vortexed to obtain a solution.

[0533] Vehicle preparation Formulation A: 10 g of vehicle was prepared by weighing 4 g of PEG 400 into a clean 20 mL glass container. 1 g of Transcutol was added and the ingredients were mixed by stirring. To this, 1 g of Solutol HS15 was added, followed by 4 g of Type 1 water. The mixture was stirred at room temperature for 1 hour to dissolve all ingredients.

[0534] Formulation B: 10 g of vehicle was prepared by weighing 4 g of PEG400 into a clean 20 mL glass container. 1 g of Transquitol was added, and the ingredients were mixed by stirring. To this, 1 g of Solutol HS15 was added. A 0.5% HPMC606 aqueous solution was prepared by weighing 50 mg of HPMC606 into a clean glass vial. To this, 9.95 g of Type 1 water was added. The ingredients were stirred at room temperature for 1 hour to ensure thorough mixing. 4 g of the 0.5% HPMC606 aqueous solution was then added to the PEG400, Transquitol, and Solutol HS15 solution. The mixture was stirred at room temperature for 1 hour to dissolve all ingredients.

[0535] Formulation C: 10 g of vehicle was prepared by weighing 4 g of PEG400 into a clean 20 mL glass container. 1 g of Transquitol was added, and the ingredients were mixed by stirring. To this, 1 g of Solutol HS15 was added. A 0.5% Kollidon VA64 aqueous solution was prepared by weighing 50 mg of Kollidon VA64 into a clean glass vial. To this, 9.95 g of Type 1 water was added. The ingredients were stirred for 1 hour at room temperature to ensure thorough mixing. 4 g of the aqueous solution containing Kollidon VA64 was then added to the PEG400, Transquitol, and Solutol HS15 solution. The mixture was stirred for 1 hour at room temperature to dissolve all ingredients. Formulation D: 10 g of vehicle was prepared by weighing 4 g of PEG400 into a clean 20 mL glass container. 1 g of Transquitol was added, and the ingredients were mixed by stirring. To this was added 1 g of Cremophor RH40 followed by 4 g of water Type 1. The mixture was stirred at room temperature for 1 hour to allow all ingredients to dissolve.

[0536] Formulation E: 10 g of vehicle was prepared by weighing 4 g of PEG 400 into a clean 20 mL glass container. 1 g of Transquitol was added, and the ingredients were mixed by stirring. To this...

Claims

1. Formula (I): 【Chemistry 1】 (I) (In the formula, R a , R b = H or C 1-4 Acyl; R 1 =COOR 4 , (CH 2 ) n COOR 4 , S.O. 3 H or CONH-R 10 ; R 2 and R 3 is H or R 5 where R2 and R 3 One of them is H and the other is R 5 and R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 5 = R 6 , R 7 or R 8 ; R 6 =CONH-R 9 、CONHCOR 9 、CONH(CH 2 ) n -R 9 、CONHCH(COOR 4 )(CH 2 ) k R 9 (where k = 0 to 4); R 7 =COOR 4 , (CH 2 ) n COOR 4 , S.O. 3 H, OR 4 benzo(C 5 -C 14 )heteroaryl substituted with at least one or more groups selected from azole, a five-membered N-containing heterocycle, or fluorine; R 8 =(CH 2 ) m X(CH 2 ) p R 9 ; X=O, S, SO 2 , NH, NAc or N(CH 2 ) q R 9 ; R 9 =COOR 4 , (CH 2 ) n COOR 4 , OR 4 , S.O. 3 H, azole, which is a five-membered N-containing heterocycle, fluorine, C=O or NHCO-R 10 aryl, heteroaryl substituted with at least one or more groups selected from the following: R 10 =COOR 4 , (CH 2 ) n COOR 4 , OR 4 , S.O. 3 H, aryl, heteroaryl substituted with at least one or more groups selected from azole, a five-membered N-containing heterocycle, and fluorine; Here, R 9 and R 10 Aryl in R is an aromatic radical containing 6 to 14 carbon atoms selected from phenyl, naphthyl, and biphenyl radicals; 9 and R 10 heteroaryl is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen atoms; n, m, p and q are independently 1 to 4. Substituted hydroquinones, except for ethyl 4-{[2-(3-fluorophenyl)ethyl]carbamoyl}-2,5-dihydroxybenzoate (CAS number 1260505-92-7).

2. Formula (I): 【Chemistry 2】 (I) (In the formula, R a , R b = H or C 1-4 Acyl; R 1 =COOR 4 , (CH 2 ) n COOR 4 , S.O. 3 H or CONH-R 10 ; R 2 and R 3 is H or R 5 where R 2 and R 3 One of them is H and the other is R 5 and R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 5 = R 6 or R 7 ; R 6 = CONH-R 9 ,CONHCOR 9 , CONH(CH 2 ) n -R 9 or CONHCH(COOR 4 )(CH 2 ) k R 9 (In the formula, k = 0 to 4); R 7 =COOR 4 , (CH 2 ) n COOR 4 , S.O. 3 H, OR 4 benzo(C 5 -C 14 )heteroaryl substituted with at least one or more groups selected from azole, a five-membered N-containing heterocycle, or fluorine; R 9 =COOR 4 , (CH 2 ) n COOR 4 , OR 4 , S.O. 3 H, azole, which is a five-membered N-containing heterocycle, fluorine, C=O or NHCO-R 10 aryl or heteroaryl substituted with at least one or more groups selected from the following: R 10 =COOR 4 , (CH 2 ) n COOR 4 , OR 4 , S.O. 3 H, aryl, heteroaryl substituted with at least one or more groups selected from azole, a five-membered N-containing heterocycle, or fluorine, where R 9 and R 10 Aryl in R is an aromatic radical containing 6 to 14 carbon atoms selected from phenyl, naphthyl, and biphenyl radicals; 9 and R 10 heteroaryl is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen atoms; n is independently 1 to 4. (excluding ethyl 4-{[2-(3-fluorophenyl)ethyl]carbamoyl}-2,5-dihydroxybenzoate (CAS number 1260505-92-7)).

3. (A) R a , R b = H or C 1-4 Acyl; R 1 =COOR 4 ; R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 2 = H; R 3 = R 5 and R 5 =R 6 =CONH-R 9 Or (B) R a , R b = H or C 1-4 Acyl; R 1 =COOR 4 ; R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 3 = H; R 2 = R 5 and R 5 =R 6 =CONH-R 9 or 4-(2-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 4-(2-(1H-tetrazol-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-tetrazol-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 2,5-Dihydroxy-4-(3-sulfophenylaminocarbonyl)benzoic acid; 4-(4-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 4-(4-(1H-tetrazol-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-pyrazol-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-tetrazol-5-yl)phenylaminocarbonyl)-2,5-diacetoxybenzoate; Ethyl 4-(2-(1H-tetrazol-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-tetrazol-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 2,5-Dihydroxy-3-(2-sulfophenylaminocarbonyl)benzoic acid; 3-(3-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid; 3-(3-(1H-tetrazol-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-tetrazol-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-dihydroxybenzamido)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)picolinic 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-pyrazol-4-yl)phenylaminocarbonyl)benzoic acid; 3-(2-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid; Ethyl 3-(2-(1H-tetrazol-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoate; and Ethyl 3-(2-(ethoxycarbonylmethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoate 3. The compound of claim 2 selected from the group consisting of:

4. (A) R a 、R b =H; R 1 =SO 3 H; R 2 = H; R 3 = R 5 and R 5 =R 6 =CONH-R 9 Or (B) R a 、R b =H; R 1 =SO 3 H; R 3 = H; R 2 = R 5 and R 5 =R 6 =CONH-R 9 or 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-dihydroxy-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-dihydroxy-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-sulfobenzamido)phthalic acid; 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 3. The compound of claim 2 selected from the group consisting of:

5. (A) R a 、Rb=H; R 1 =(CH 2 ) n COOR 4 ; R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 2 = H or R 5 , R 3 = R 5 and R 5 =R 6 =CONH-R 9 Or (B) R a 、R b =H; R 1 =(CH 2 ) n COOR 4 ; R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 3 = H; R 2 = R 5 and R 5 =R 6 =CONH-R 9 or 2-(4-(carboxymethyl)-2,5-dihydroxybenzamido)benzoic acid; (2-(1H-tetrazol-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-(carboxymethyl)-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-dihydroxybenzamido)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-tetrazol-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-dihydroxybenzamido)-2-hydroxybenzoic acid; 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-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 3. The compound of claim 2 selected from the group consisting of:

6. (A) R a , R b = H or C 1-4 Acyl; R 1 =CONH-R 10 ; R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 2 = H; R 3 = R 5 and R 5 =R 6 =CONH-R 9 Or (B) R a , R b = H or C 1-4 Acyl; R 1 =CONH-R 10 ; R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 3 = H; R 2 = R 5 and R 5 =R 6 =CONH-R 9 or 5-(4-(2-(1H-tetrazol-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid; N 1 ,N 4 -bis(2-(1H-tetrazol-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-dihydroxybenzamido)-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-hydroxybenzenesulfonic acid; Methyl 5-(4-(2-(1H-tetrazol-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-dimethylpropanoyloxy)ethyl 5-[[4-[3-[1-(2,2-dimethylpropanoyloxy)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)benzamido)-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-hydroxylbenzoic acid; and 2-(2,5-dihydroxy-3-(4-hydroxy-2-sulfophenylaminocarbonyl)benzamido)-5-hydroxybenzenesulfonic acid 3. The compound of claim 2 selected from the group consisting of:

7. Formula (I): 【Chemistry 4】 (I) (In the formula, R a , R b = H; R1 = CONH-R10; R10 = phenyl substituted with COOR4 and OR4; R2 = H; R3 = CONH-R9; R 9 = phenyl substituted with COOR 4 and OR 4 ; and R4 = H) A compound having the formula:

3. The compound of claim 2 which is 5-(4-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid.

8. Formula (I): 【Chemistry 5】 (I) (In the formula, R a , R b = H; R1 = CONH-R10; R10 = phenyl substituted with COOR4 and OR4; R 2 =CONH-R 9 ; R3=H; R 9 = phenyl substituted with COOR 4 and OR 4 ; and R4 = H) A compound having the formula:

3. The compound of claim 2 which is 5-(3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid.

9. (A) R a 、R b =H; R 1 =COOR 4 ;(CH 2 ) n COOR 4 ; R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 2 = H; R 3 = R 5 and R 5 =R 6 =CONHCOR 9 Or (B) R a 、R b =H; R 1 =COOR 4 ;(CH 2 ) n COOR 4 ; R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 3 = H; R 2 = R 5 and R 5 =R 6 =CONHCOR 9 or 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; and N-(3,5-dihydroxybenzoyl) 3-carboxymethyl-2,5-dihydroxybenzamide 3. The compound of claim 2 selected from the group consisting of:

10. (A) R a 、R b =H; R 1 =COOR 4 ;(CH 2 ) n COOR 4 ; R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 2 = H; R 3 = R 5 and R 5 =R 6 =CONH(CH 2 ) n -R 9 Or (B) R a 、R b =H; R 1 =COOR 4 ;(CH 2 ) n COOR 4 ; R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 3 = H; R 2 = R 5 and R 5 =R 6 =CONH(CH 2 ) n -R 9 or 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)methylaminocarbonyl)-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-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)methylaminocarbonyl)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; (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 3. The compound of claim 2 selected from the group consisting of:

11. R a 、R b =H; R 1 =SO 3 H; R 2 = H; R 3 = R 5 and R 5 =R 6 =CONH(CH 2 ) n -R 9 or 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 3. The compound of claim 2 selected from the group consisting of:

12. (A) R a 、R b =H; R 1 =COOR 4 ;(CH 2 ) n COOR 4 ; R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 2 = H; R 3 = R 5 and R 5 =R 6 =CONHCH(COOR 4 )(CH 2 ) k R 9 Or (B) R a 、R b =H; R 1 =COOR 4 ;(CH 2 ) n COOR 4 ; R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 3 = H; R 2 = R 5 and R 5 =R 6 =CONHCH(COOR 4 )(CH 2 ) k R 9 or 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; and (3-(carboxy(3,4-dihydroxyphenyl)methylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid 3. The compound of claim 2 selected from the group consisting of:

13. (A) R a 、R b =H; R 1 =COOR 4 、(CH 2 ) n COOR 4 、SO 3 H、(CH 2 ) n SO 3 H、CONH-R 10 ; R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 2 = H; R 3 = R 5 and R 5 = R 7 =COOR 4 , (CH 2 ) n COOR 4 , S.O. 3 H, OR 4 benzo(C 5 -C 14 )heteroaryl substituted with at least one or more groups selected from azole, a five-membered N-containing heterocycle, or fluorine; Or (B) R a 、R b =H; R 1 =COOR 4 、(CH 2 ) n COOR 4 、SO 3 H、(CH 2 ) n SO 3 H、CONH-R 10 ; R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 3 = H; R 2 = R 5 and R 5 = R 7 =COOR 4 , (CH 2 ) n COOR 4 , S.O. 3 H, OR 4 benzo(C 5 -C 14 )heteroaryl substituted with at least one or more groups selected from azole, a five-membered N-containing heterocycle, or fluorine; or 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; and 2-(3-(carboxymethyl)-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid 3. The compound of claim 2 selected from the group consisting of:

14. Formula (I): 【Chemistry 3】 (I) (In the formula, R a , R b = H or C 1-4 Acyl; R 1 =COOR 4 , (CH 2 ) n COOR 4 , S.O. 3 H or CONH-R 10 ; R 2 and R 3 is H or R 5 where R2 and R 3 One of them is H and the other is R 5 and R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 5 =R 8 ; R 8 =(CH 2 ) m X(CH 2 ) p R 9 ; X=O, S, SO 2 , NH, NAc or N(CH 2 ) q R 9 ; R 9 =COOR 4 , (CH 2 ) n COOR 4 , OR 4 , S.O. 3 H, azole, which is a five-membered N-containing heterocycle, fluorine, C=O or NHCO-R 10 aryl or heteroaryl substituted with at least one or more groups selected from the following: R 10 =COOR 4 , (CH 2 ) n COOR 4 , OR 4 , S.O. 3 H, aryl, heteroaryl substituted with at least one or more groups selected from azole, a five-membered N-containing heterocycle, and fluorine; Here, R 9 and R 10 aryl is an aromatic radical containing 6 to 14 carbon atoms selected from a phenyl, naphthyl or biphenyl radical; Heteroaryl R 9 and R 10 is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen atoms; n, m, p and q are independently 1 to 4.

15. (A) R a , R b = H or C 1-4 Acyl; R 1 =COOR 4 、(CH 2 ) n COOR 4 、SO 3 H、CONH-R 10 ; R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 2 = H; R 3 = R 5 and R 5 =R 8 =(CH 2 ) m X(CH 2 ) p R 9 ; Here, X = O, S, SO 2 , NH, NAc or N(CH 2 ) q R 9 Or (B) R a , R b = H or C 1-4 Achilles; R 1 =COOR 4 、(CH 2 ) n COOR 4 、SO 3 H、CONH-R 10 ; R 4 = H, C 1-4 Alkyl, aryl C 1-4 Alkyl, morpholino-C 1 -C 6 Alkyl, pyrrolidino-C 1 -C 6 Alkyl, N-methylpiperazino-C 1 -C 6 Alkyl, C 1 -C 6 Acyloxymethyl, C 1 -C 6 Acyloxy-1-ethyl, C 1 -C 6 Alkoxycarbonyloxymethyl, C 1 -C 6 Alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol esters); R 3 = H; R 2 = R 5 and R 5 = R 8 =(CH 2 ) m X(CH 2 ) p R 9 (Wherein, X=O, S, SO 2 , NH, NAc or N(CH 2 ) q R 9 ) ; or 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-dihydroxybenzoic 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-dihydroxy-4-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid; 4-((2,5-dihydroxy-3-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid; 4-((2,5-dihydroxy-4-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzenesulfonic acid; 4-((2,5-dihydroxy-4-carboxyphenyl)methoxymethyl)-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-dihydroxybenzoic 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-dihydroxy-3-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid; 3-((2,5-dihydroxy-4-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid; 3-((2,5-dihydroxy-3-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzenesulfonic acid; 3-((2,5-dihydroxy-3-carboxyphenyl)methoxymethyl)-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; and Tris(3-ethoxycarbonyl-2,5-dihydroxyphenylmethyl)amine 15. The compound of claim 14, selected from the group consisting of:

16. Formula (I): 【Chemistry 6】 (I) (In the formula, R a , R b = H; R1=COOR4; R2 = H; R3=R8; R4 = H; R 8 =(CH 2 ) m X(CH 2 ) p R 9 ; R 9 = phenyl substituted with COOR 4 and OR 4 ; X=N(CH2)qR9; and m, p and q = 1) A compound having the formula:

15. The compound of claim 14 which is tris(4-carboxy-2,5-dihydroxyphenylmethyl)amine.

17. Formula (I): 【Chemistry 7】 (I) (In the formula, R a , R b = H; R1=COOR4; R 2 =(CH 2 ) m X(CH 2 ) p R 9 ; R3=H; R 9 = phenyl substituted with COOR 4 and OR 4 ; R4 = H; X=SO2; and m and p = 1) 15. The compound of claim 14 having the formula:

15. The compound of claim 14 which is 3-((2,5-dihydroxy-3-carboxyphenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid.

18. Formula (I): 【Chemistry 8】 (I) (In the formula, R a , R b = H; R1=COOR4; R2 = H; R 3 =(CH 2 ) m X(CH 2 ) p R 9 ; R 9 = phenyl substituted with COOR 4 and OR 4 ; R4 = H; X=NH; and m and p = 1) A compound having the formula:

15. The compound of claim 14 which is bis(4-carboxy-2,5-dihydroxyphenylmethyl)amine.

19. Formula (I): 【Chemistry 9】 (I) (In the formula, R a , R b = H; R1=COOR4; R 2 =(CH 2 ) m X(CH 2 ) p R 9 ; R3=H; R 9 = phenyl substituted with COOR 4 and OR 4 ; R4 = H; X=S; and m and p = 1) A compound having the formula:

15. The compound of claim 14 which is 3-((2,5-dihydroxy-3-carboxyphenyl)methylthiomethyl)-2,5-dihydroxybenzoic acid.

20. Formula (I): 【Chemistry 10】 (I) (In the formula, R a , R b = H; R1=COOR4; R2 = H; R 3 =(CH 2 ) m X(CH 2 ) p R 9 ; R 9 = phenyl substituted with COOR 4 and OR 4 ; R4 = H; X = NH(COCH3); and m and p = 1) A compound having the formula:

15. The compound of claim 14 which is N,N-bis(4-carboxy-2,5-dihydroxyphenylmethyl)acetamide.

21. 21. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

22. 2. A compound for use in a method for the treatment and / or prevention of autoimmune diseases, immune diseases, rheumatic diseases, vascular diseases, ophthalmic diseases, fibrotic diseases, metabolic and gastrointestinal diseases, neuroinflammatory and neurodegenerative diseases, neoplastic and cancer related diseases, hormone related diseases, or immune diseases caused by viral and / or bacterial infections, and / or complications thereof, comprising a compound represented by the following formula (I): 【Chemistry 11】 (I) (In the formula, R a , R b =H or C 1-4 acyl; R1 = COOR4, (CH2)nCOOR4, SO3H or CONH-R10; R 2 and R 3 are H or R 5 , with the proviso that one of R 2 and R 3 is H and the other is R 5 ; R4 = H, C1-4 alkyl, arylC1-4 alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol ester); R5 = R6, R7 or R8; R 6 = CONH-R 9 , CONHCOR 9 , CONH(CH 2 ) n -R 9 , CONHCH(COOR 4 )(CH 2 ) k R 9 (in the formula, k=0 to 4); R7 = benzo(C5-C14)heteroaryl substituted with at least one or more groups selected from COOR4, (CH2)nCOOR4, SO3H, OR4, azole, a five-membered N-containing heterocycle, or fluorine; R 8 =(CH 2 ) m X(CH 2 ) p R 9 ; X = O, S, SO2, NH, NAc or N(CH2)qR9; R 9 = aryl or heteroaryl substituted with at least one or more groups selected from COOR 4 , (CH 2 ) n COOR 4 , OR 4 , SO 3 H, azole which is a five-membered N-containing heterocycle, fluorine, C═O, and NHCO-R 10 ; R10 = aryl, heteroaryl substituted with at least one or more groups selected from COOR4, (CH2)nCOOR4, OR4, SO3H, azole, a five-membered N-containing heterocycle, or fluorine; wherein R 9 and R 10 aryl are aromatic groups containing 6 to 14 carbon atoms selected from phenyl, naphthyl, and biphenyl groups; R 9 and R 10 heteroaryl are aromatic groups containing 1 to 14 carbon atoms and one or more nitrogen atoms; n, m, p and q are independently 1 to 4. A compound represented by the formula:

23. An intermediate in the synthesis of the compound of 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-(hydroxylmethyl)benzoate.

24. A compound for use in a method for treating and / or preventing acute pancreatic cancer, pancreatic and renal cancer, diabetic retinopathy, diabetic macular edema, diabetes, diabetic wound healing, diabetic retinopathy and diabetic nephropathy, diabetic kidney disease and pulmonary fibrosis, comprising a compound represented by the following formula (I): 【Chemistry 12】 (I) (In the formula, R a , R b =H or C 1-4 acyl; R1 = COOR4, (CH2)nCOOR4, SO3H or CONH-R10; R 2 and R 3 are H or R 5 , with the proviso that one of R 2 and R 3 is H and the other is R 5 ; R4 = H, C1-4 alkyl, arylC1-4 alkyl, morpholino-C1-C6 alkyl, pyrrolidino-C1-C6 alkyl, N-methylpiperazino-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl, (oxodioxolyl)methyl or o-methoxyphenyl (guaiacol ester); R5 = R6, R7 or R8; R 6 = CONH-R 9 , CONHCOR 9 , CONH(CH 2 ) n -R 9 , CONHCH(COOR 4 )(CH 2 ) k R 9 (in the formula, k=0 to 4); R7 = benzo(C5-C14)heteroaryl substituted with at least one or more groups selected from COOR4, (CH2)nCOOR4, SO3H, OR4, azole, a five-membered N-containing heterocycle, or fluorine; R 8 =(CH 2 ) m X(CH 2 ) p R 9 ; X = O, S, SO2, NH, NAc or N(CH2)qR9; R 9 = aryl or heteroaryl substituted with at least one or more groups selected from COOR 4 , (CH 2 ) n COOR 4 , OR 4 , SO 3 H, azole which is a five-membered N-containing heterocycle, fluorine, C═O, and NHCO-R 10 ; R10 = aryl, heteroaryl substituted with at least one or more groups selected from COOR4, (CH2)nCOOR4, OR4, SO3H, azole, a five-membered N-containing heterocycle, or fluorine; wherein R 9 and R 10 aryl are aromatic groups containing 6 to 14 carbon atoms selected from phenyl, naphthyl, and biphenyl groups; R 9 and R 10 heteroaryl are aromatic groups containing 1 to 14 carbon atoms and one or more nitrogen atoms; n, m, p and q are independently 1 to 4. A compound represented by the formula:

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