2,5- or 2,6-disubstituted hydroquinone derivatives having at least one carboxyl, sulfonyl or amide group useful as drugs

Abstract

The present invention provides novel hydroquinone derivatives of formula (I), preparation methods, and pharmaceutical compositions and methods for treating and / or preventing, for example, autoimmunity, immunity, rheumatism, vascular disorders, ophthalmic disorders, fibrotic disorders, metabolic and gastrointestinal disorders, neuroinflammatory and neurodegenerative diseases, tumor and cancer-related disorders, hormone-related diseases, and immune disorders caused by viral and bacterial infectious diseases and their complications, wherein R1 is COOR4, (CH2) n COOR4, SO3H, (CH2) n SO3H or CONH‑R 10 ; One of R2 and R3 is H, and the other is R5.

Description

Technical Field

[0001] The present invention generally relates to novel hydroquinone derivatives, their preparation, and methods of treating disorders by administering such compounds to warm-blooded animals in need thereof. The present invention also relates to compounds useful for preventing and / or treating autoimmune, immune, rheumatic, vascular, ophthalmic, fibrotic, metabolic and gastrointestinal disorders, neuroinflammatory and neurodegenerative diseases, tumor and cancer-related disorders, hormone-related diseases, and immune disorders caused by viral and bacterial infectious diseases and their complications. Background Art

[0002] Some hydroquinone-based derivatives, such as 2,5-dihydroxybenzenesulfonic acid derivatives, particularly calcium dobesilate, calcium phenethylamine, and calcium 2,5-dihydroxyterephthalate (calcium persilate), are known in the art as active agents for treating male sexual dysfunction and other endothelial vascular disorders, either alone or in combination with other agents. For example, U.S. Pat. No. 6,147,112 describes methods for using 2,5-dihydroxybenzenesulfonic acid derivatives, preferably calcium dobesilate, calcium phenethylamine, and calcium persilate. Calcium dobesilate or calcium hydroquinone sulfonate, chemically known as 2,5-dihydroxybenzenesulfonic acid calcium salt, is sold under the names Dexium (Delalande) and Doxium (Carrion), and its preparation method is described in U.S. Pat. No. 3,509,207.

[0003] Many drugs containing phenolic or catechol groups are subject to premature metabolism at the hydroxyl group during absorption after oral administration. Previous attempts to protect the hydroxyl group have generally been unsuccessful because the protecting groups used were either too unstable (O═COR or O═CR) or too stable (CH3). Therefore, the present invention is directed to novel hydroquinone derivatives, their pharmaceutically acceptable salts, and formulations. These novel hydroquinone derivatives possess particularly potent antifibrotic, anti-inflammatory, and anti-angiogenic properties.

[0004] International publication 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 in mediated fuel cells or organic mediator flow batteries.

[0005] Richter et al. disclosed bis-N-arylcarbamates and 2,5-dihydroxy-3,6-bis[N-arylcarboxamido]-1,4-benzoquinone and a method for preparing the same from 2,5-dihydroxy-1,4-benzoquinone and aryl isocyanate in Synthesis, 1976, 1976(3), 192-194.

[0006] Japanese publication JP 51026839A discloses that benzanilide I (R=H, OH) has anti-tuberculosis, analgesic, anti-inflammatory and uricosuric activities:

[0007]

[0008] US Patent No. 3,973,038 also discloses a benzanilide compound having the following general formula:

[0009]

[0010] Among them (R1=OH, acyloxy; R2=H, OH, lower alkyl, halogen, acyloxy; R3=Cl, Br, lower alkyl; R4=OH, NH2, lower alkoxy, acyloxy; R5=H, halogen, CO2H, lower alkyl, acyloxy) have enzyme inhibitory properties in vivo, especially histamine deacetylase and xanthine oxidase.

[0011] However, none of the prior art documents discloses the novel hydroquinone derivative compounds of the present invention, which are particularly useful for preventing and / or treating a variety of diseases, including autoimmune, immune, rheumatic, vascular, ophthalmic, fibrotic, metabolic and gastrointestinal disorders, neuroinflammatory and neurodegenerative diseases, tumor and cancer-related disorders, hormone-related diseases, and immune diseases caused by viral and bacterial infectious diseases and their complications.

[0012] The present invention further relates to the treatment, prevention and alleviation of metabolic disorders such as diabetes and obesity. Along with the rising of postprandial blood glucose level, insulin is secreted and stimulates the cells of peripheral tissues (skeletal muscle and fat) to take the initiative to take glucose from the blood as an energy source. Due to the loss of glucose homeostasis caused by wrong insulin secretion or effect, metabolic disorders can be caused usually, such as diabetes, which may be caused or further worsened by obesity. Because these diseases are usually fatal, it is necessary to adopt strategies to recover enough glucose clearance in the bloodstream. Along with the aging of industrialized countries' population and the sedentary lifestyle, metabolic disorders, particularly glucose and lipid regulatory disorders become more and more common. Such disorders are usually interrelated and are usually predictive factors or results of each other.

[0013] For example, diabetes is caused by a combination of insulin resistance and defective insulin secretion by pancreatic beta cells. Individuals with insulin resistance often have abdominal obesity, dyslipidemia, hypertension, glucose intolerance, and a prothrombotic state (metabolic syndrome). Accordingly, obese individuals are at a higher risk of acquiring insulin resistance overall. Consequently, disruptions in metabolic pathways can lead to a wide range of conditions, such as hyperlipidemia, obesity, diabetes, insulin resistance, glucose intolerance, hyperglycemia, metabolic syndrome, and hypertension, which in turn can trigger further metabolic dysfunction, leading to systemic problems and exposing individuals to additional complications and premature morbidity. Glucose and lipid levels are partially regulated by the liver, which plays a role in the synthesis, storage, secretion, conversion, and breakdown of glucose, proteins, and lipids. Disease or trauma can significantly reduce the liver's ability to carry out these normal activities. Therefore, most clinical manifestations of liver dysfunction result from cellular damage and impairment of normal liver function. Liver dysfunction can be caused by genetic disorders, inflammatory conditions, toxins (such as drugs and alcohol), immune disorders, vascular disorders, or metabolic diseases. Regardless of the cause, liver damage can have systemic effects on the function of metabolic processes and the regulation of blood glucose and lipid levels, exacerbating chronic disease states and leading to an increased risk of further illness and morbidity. Both increases and decreases in blood glucose levels trigger hormonal responses aimed at restoring glucose homeostasis. Hypoglycemia triggers the release of glucagon from pancreatic α cells. Hyperglycemia triggers the release of insulin from pancreatic β cells. ACTH and growth hormone, released by the pituitary gland, increase blood glucose by inhibiting extrahepatic tissue uptake. Glucocorticoids also 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. The adrenal medullary hormone epinephrine stimulates glucose production by activating glycogenolysis in response to stress. Metabolic disorders affecting glucose and lipid metabolism, such as hyperlipidemia, obesity, diabetes, insulin resistance, hyperglycemia, glucose intolerance, metabolic syndrome, and hypertension, can lead to long-term health consequences, including cardiovascular disease and premature onset of chronic illness. These metabolic and cardiovascular disorders can be interconnected, exacerbating, or triggering each other, creating feedback mechanisms that are difficult to interrupt. Current pharmacological treatments for metabolic and cardiovascular disorders include a combination of lipid-lowering drugs, glucose-lowering drugs, antihypertensive drugs, diet, and exercise. However, complex treatment regimens can lead to multiple medication issues, including increased side effects, drug-drug interactions, adherence failure, and medication errors. Therefore, there is an urgent, unmet need in the art to identify new compounds, formulations, and methods for the safe and effective treatment of metabolic and cardiovascular disorders, as well as diseases associated with metabolic disorders.

[0014] Examples of metabolic diseases include, but are not limited to, pain, wound healing, fever, neuroinflammatory and neurodegenerative diseases, inflammation, thermogenesis, homeothermy, triglyceride breakdown, glycolysis, Krebs cycle, fermentation, photosynthesis, metabolic rate, biotic and abiotic stress, secretions, oxidative stress, stress, tumor growth, skin diseases, cardiovascular diseases, neuroinflammatory and neurodegenerative diseases, psychiatric and behavioral disorders. Such processes or conditions can occur in a cell, a population of cells, or a whole organism.

[0015] Recent advances in molecular medicine have led to improvements in the diagnosis and treatment of tumors. Despite some success, these conditions remain a significant challenge. For certain types of cancer, current treatments fail in some cases for a variety of reasons. One reason is the inherent resistance of tumor cells, their ability to continuously mutate and evade treatment, and another is the heterogeneity of the tumor environment. Studies have shown that tumors of the same type can vary significantly from subject to subject, based on their genomic profiles, highlighting the need for so-called "personalized" treatments. A greater challenge is the heterogeneity of mutations within the same tumor, as recently demonstrated in kidney tumors and expected to occur in other tumor types as well. Therefore, it is necessary to identify new approaches and intervention points that are common to all or most malignant cells in a tumor, preferably affecting essential functions in cancer cells. Such intervention points appear to be at the metabolic level, for example, in mitochondria, the organelles that are fundamental for the production of energy necessary for all physiological and pathophysiological processes in the cell. Although tumor cells largely utilize so-called aerobic glycolysis for energy production, mitochondrial respiration (i.e., the consumption of oxygen associated with ATP formation) is inherent to most, if not all, tumor types. Therefore, there is an unmet and urgent need in the art to identify new compounds, formulations and methods to safely and effectively treat such neoplastic disorders. Summary of the Invention

[0016] The present invention provides novel hydroquinone derivatives, novel preparation methods and novel key intermediates. The present invention also relates to pharmaceutical compositions comprising therapeutically effective amounts of the hydroquinone derivatives and pharmaceutically acceptable excipients.

[0017] The present invention also provides methods for treating and / or preventing angiogenesis (vascular), inflammatory and / or fibrotic pathobiology because they have anti-fibrotic, anti-inflammatory and anti-angiogenic effects. Therefore, the present invention ultimately provides methods for treating and / or preventing diseases or conditions, including immune / rheumatic / vascular conditions, ophthalmic conditions, fibrotic conditions, metabolic and gastrointestinal conditions, tumors and cancer-related conditions, comprising administering to a subject in need thereof a therapeutically effective dose of a compound and / or pharmaceutical composition of the present invention as described above. In particular, the present invention provides methods for treating and / or preventing diseases or conditions, including autoimmune, immune, rheumatic, vascular conditions, ophthalmic conditions, fibrotic conditions, metabolic and gastrointestinal conditions, neuroinflammatory and neurodegenerative diseases, tumors and cancer-related conditions, hormone-related diseases and immune conditions caused by viral and bacterial infectious diseases and complications thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 (A) Confocal immunofluorescence images of vascular permeability assessed by Evans blue dye leakage in whole-mount retina in representative mice from each experimental group. Arrows indicate the location of extravasation. Scale bar, 30 μm. (B) Vascular leakage was quantified by assessing the number of extravasations per field of view (0.44 mm²). The effect of Ia-007a eye drops was significant, reducing vascular leakage to levels comparable to those observed in non-diabetic controls. *p < 0.01 compared to other groups.

[0019] Figure 2 : (A) Schmidt score is an assessment of compound efficacy based on four histopathological evaluation criteria, which describes pancreatic damage based on the scores of the following four parameters (numbers in parentheses). (a) Edema Interstitial edema, scored as (0) none (1) interlobular (2) involving lobules (3) isolated islands of acinar cells. (b) Inflammatory infiltrate = leukocyte infiltration, scored as (0) none, (1) <20%, (2) 20%-50%, (3) >50%. (c) Parenchymal necrosis = acinar cell necrosis, scored as (0) none, (1) <5%, (2) 5%-20%, (3) >20%. (d) Hemorrhage, scored as (0) none, (1) 1-2 points, (2) 3-5 points, (3) >5 points. The highest Schmidt score = 10 is for caerulein-induced + vehicle-treated animals, and the lowest score = 0 is for non-induced animals. The Schmidt score is the sum of a+b+c+d scores, and ** means there is a statistically significant difference compared with the cerulein-induced group. Figure 2 All products showed improved Schmidts scores compared to cerulein control animals.

[0020] Figure 3A-D: Figure 3A -B shows a disease list of major cytokines involved in selected diseases (Akdis M. et al, J Allergy Clin Immunol 2016; 138: 984-1010), Figure 3C A partial list of search results is shown, where cytokines and genes are sorted by score and potentially involved in the selected disease given as an example "diabetic retinopathy" after searching https: / / www.targetvalidation.org / . Figure 3D In

[15] , a search was performed using VEGFA as the cytokine to find a list of diseases in which VEGFA was mentioned. Figure 3D Only some of the diseases involved in VEGFA are shown. Reference: OpenTargets 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).

[0021] Figure 4 (AD): shows a table listing the conditions and yields of compounds of type Ia-Id as described in Examples 1.1 to 1.4. Total yields calculated from the starting material 2,5-dihydroxyterephthalic acid.

[0022] Figure 5 (AC): shows a table listing the conditions and yields for compounds of type IIa-IIc as described in Examples 1.5 to 1.7.

[0023] Figure 6 : Shown is a table listing the conditions and yields for compounds of type IIIa and IIIb as described in Examples 1.8 and 1.9.

[0024] Figure 7 : Shows a table listing the conditions and yields for compounds of type IIIc as described in Example 1.10.

[0025] Figure 8 : is a table listing the deprotection steps for compound type V as described in Example 1.12.

[0026] Figure 9 : Shows the non-fasting blood glucose levels (mean ± stdev) of all animals in each group in the STZ-induced diabetes model after sampling on day 0 before drug administration and after daily administration for 7 and 14 days by intravenous injection or by os route.

[0027] Figure 10 : shows accelerated wound healing in a STZ-induced diabetic model of 3 animals per group sampled after 7 days of daily administration by iv or os route.

[0028] Figure 11 : Figure 11 A shows representative images of lung fibrosis on day 21 of treatment; (A1) non-induced (healthy); A2, bleomycin-induced, treated with vehicle; A3, bleomycin-induced, treated with pirfenidone 100 mg / kg; A4, bleomycin-induced, treated with IVc-059a. Figure 11 B shows Ashcroft scores of healthy, bleomycin-induced untreated versus pirfenidone versus IVc-059a. DETAILED DESCRIPTION

[0029] Disclosed herein are novel compounds for treating subjects suffering from diseases, conditions, or functional disorders. Examples of such diseases, conditions, or functional disorders include, but are not limited to, autoimmune, metabolic, inflammatory, degenerative, and neoplastic conditions, particularly inflammatory conditions, angiogenic diseases, and / or fibrotic conditions, such as diabetic retinopathy, diabetic nephropathy, ankylosing spondylitis, chronic pancreatitis, liver fibrosis, renal fibrosis, and metabolic diseases caused by pancreatic dysfunction.

[0030] Hereinafter, unless otherwise indicated, the collection of diseases, conditions, or disorders that can be treated using the novel compounds disclosed herein are collectively referred to as "medical conditions."

[0031] As used herein, the term "subject" includes any and all organisms and includes the term "patient." A subject to be treated according to the methods described herein may be a subject that has been diagnosed by a licensed physician as having a medical condition. Diagnosis may be performed by any suitable method. One skilled in the art will appreciate that a subject to be treated according to the present disclosure may have already undergone standard testing to diagnose a medical condition. As is known to those skilled in the art, the clinical features of medical conditions of the type disclosed herein vary depending on the pathological mechanism.

[0032] As used herein, "treating" refers to administering the disclosed compounds for therapeutic purposes. For example, therapeutic treatment can be administered to a subject suffering from a medical condition to improve or stabilize the subject's condition. Thus, in the claims and embodiments described herein, "treating" refers to subjecting a subject to the methods disclosed herein for therapeutic purposes.

[0033] As used herein, prodrugs refer to any broad range of prodrug strategies. For example, the prodrug strategy was formally recognized by Adrian Albert in 1958 (Albert, A. Chemical aspects of selective toxicity. Nature, 1958, 182, 421–422), but began at the beginning of the last century, with the development of methenamine, phenacetin, and prontosil. Prodrugs are typically molecules with little or no pharmacological activity but inherent structural instability, whether accidental or designed, that allow for bioconversion into active drugs in vivo. Conversion can be achieved by chemical or enzymatic processes or a combination of both. Active molecules are often associated with undesirable physicochemical properties, which poses considerable challenges to their delivery to appropriate biological targets. Prodrugs can improve metabolic instability typically attributed to hepatic metabolism. Similarly, unwanted intestinal metabolism of drugs can be overcome by selective prodrug strategies. This instability can greatly 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 unstable but pharmacologically necessary functional groups, such as phenol, to avoid rapid metabolism.

[0034] Prodrugs, derived through structural modifications of drugs, are designed to influence the inherent physicochemical properties of a molecule to facilitate its delivery. These developments are not always integrated into the design of new molecules during the discovery phase. Often, simulation optimization is the preferred path forward. Implementing an early prodrug strategy can lead to faster clinical development and, ultimately, commercialization of the drug.

[0035] Numerous prodrug strategies can be used to influence the lipophilicity of the parent drug. The lipophilicity of drugs has been modified by masking their polar and ionizing functionality with short-chain hydrocarbon promoieties. Hydrophilic hydroxyl, carboxyl, phosphate, or amino 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 vivo by ubiquitous esterases or peptidases.

[0036] Therefore, the present invention provides compounds of formula (I):

[0037]

[0038] in:

[0039] R a 、R b =H、C 1-4 Acyl, aryl C 1-4 Alkyl, C6-C 10 Aryl CO, HOOC(CH2) nCO, C1-C7 alkylNHCO, phosphono, phosphonooxymethyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl or C1-C6 alkoxycarbonyloxy-1-ethyl;

[0040] R1=COOR4、(CH2) n COOR4, SO3H, (CH2) n SO3H or CONH-R 10 ;

[0041] 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;

[0042] R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0043] R5=R6, R7 or R8;

[0044] R6=CONH-R9, CONHCOR9, CONH(CH2) n -R9 or CONHCH(COOR4)(CH2) k R9, heteroaryl-R9, wherein k=0-4;

[0045] R7 = benzoheteroaryl substituted by at least one or more groups selected from the group consisting of COOR4, (CH2) n COOR4, SO3H, (CH2) n SO3H, OR4, azole [5-membered N-containing heterocyclic ring] or fluorine;

[0046] R8=(CH2) m X(CH2) p R9;

[0047] X=O、S、SO2、NH、NAc or N(CH2) q R9;

[0048] R9 = aryl or heteroaryl substituted by at least one or more groups selected from the group consisting of COOR4, (CH2) nCOOR4, (CH2) n SO3H, OR4, SO3H, azole [5-membered N-containing heterocycle], fluorine, C=O, NHCO-R 10 ;

[0049] R 10 = aryl or heteroaryl substituted by at least one or more groups selected from the group consisting of COOR4, (CH2) n COOR4, (CH2) n SO3H, OR4, SO3H, azole [5-membered N-containing heterocycle], fluorine;

[0050] Among them R9 and R 10 The aryl group is an aromatic group containing 6 to 14 carbon atoms selected from phenyl, naphthyl, biphenyl; R9 and R 10 The heteroaryl group is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen atoms; n, m, p and q are independently 1-4.

[0051] The present invention also provides compounds of formula (I):

[0052]

[0053] in:

[0054] 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;

[0055] R1=COOR4、(CH2) n COOR4, SO3H, (CH2) n SO3H or CONH-R 10 ;

[0056] 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;

[0057] R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0058] R5=R6 or R7;

[0059] R6=CONH-R9, CONHCOR9, CONH(CH2) n -R9 or CONHCH(COOR4)(CH2) k R9, where k = 0-4;

[0060] R7 = benzoheteroaryl substituted by at least one or more groups selected from the group consisting of COOR4, (CH2) n COOR4, SO3H, (CH2) n SO3H, OR4, azole [5-membered N-containing heterocyclic ring] or fluorine;

[0061] R9 = aryl, heteroaryl substituted by at least one or more groups selected from the group consisting of COOR4, (CH2) n COOR4, (CH2) n SO3H, OR4, SO3H, azole [5-membered N-containing heterocyclic ring], fluorine, C=O or NHCO-R 10 ;

[0062] R 10 = aryl, heteroaryl substituted by at least one or more groups selected from the group consisting of COOR4, (CH2) n COOR4, (CH2) n SO3H, OR4, SO3H, azole [5-membered N-containing heterocyclic ring] or fluorine; wherein R9 and R 10 The aryl group is an aromatic group containing 6 to 14 carbon atoms selected from phenyl, naphthyl, biphenyl; R9 and R 10 The heteroaryl group is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen atoms; n is independently 1-4.

[0063] The present invention also provides compounds of formula (I):

[0064]

[0065] in:

[0066] R a 、R b =H、C 1-4 Acyl, aryl C 1-4 Alkyl, C6-C 10Aryl 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;

[0067] R1=COOR4、(CH2) n COOR4, SO3H, (CH2) n SO3H or CONH-R 10 ;

[0068] 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;

[0069] R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0070] R5=R8;

[0071] R8=(CH2) m X(CH2) p R9;

[0072] X=O、S、SO2、NH、NAc or N(CH2) q R9;

[0073] R9 = aryl, heteroaryl substituted by at least one or more groups selected from the group consisting of COOR4, (CH2) n COOR4, (CH2) n SO3H, OR4, SO3H, azole [5-membered N-containing heterocycle], fluorine, C=O, NHCO-R 10 ;

[0074] R 10 = aryl, heteroaryl substituted by at least one or more groups selected from the group consisting of COOR4, (CH2) n COOR4, (CH2) n SO3H, OR4, SO3H, azole [5-membered N-containing heterocycle], fluorine;

[0075] Among them R9 and R 10 The aryl group is an aromatic group containing 6 to 14 carbon atoms selected from phenyl, naphthyl, biphenyl; R9 and R 10 The heteroaryl group is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen atoms; n, m, p and q are independently 1-4.

[0076] The expression "alkyl" refers to a saturated straight-chain or branched hydrocarbon radical 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. In addition, the term alkyl refers to a radical in which one or more hydrogen atoms are replaced by a halogen atom (preferably F or Cl), such as 2,2,2-trichloroethyl or trifluoromethyl.

[0077] The expression "acyl" refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C(O-), and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure via a carbonyl functional group. In some embodiments, it is a C1-C4 acyl group, which refers to the total number of chain or ring atoms of the alkyl, aryl, heteroaryl, or heterocycloalkyl portion of the acyloxy group plus the carbonyl carbon of the acyl group, i.e., three other ring or chain atoms plus the carbonyl group.

[0078] The expression "aryl" refers to an aromatic group containing one or more rings containing 6 to 14 ring carbon atoms, preferably 6 to 10 (especially 6) ring carbon atoms.

[0079] The expression "aralkyl" or "aryl C 1-4 The term "alkyl" refers to a group containing an aryl group according to the above definition as well as an alkyl, alkenyl, alkynyl and / or cycloalkyl group, 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 (1 or 2 rings) containing 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups containing 1 or 2 to 6 carbon atoms, and / or a cycloalkyl group containing 5 or 6 ring carbon atoms.

[0080] The expression "heteroaryl" refers to aromatic groups which contain one or more rings containing 5 to 14 ring atoms, preferably 5 to 10 (in particular 5 or 6 or 9 or 10) ring atoms, and one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N). Examples are 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, benzothiazolyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidinyl, 2,3-bifuranyl, pyrazolyl (e.g. 3-pyrazolyl) and isoquinolyl.

[0081] The expression "benzoheteroaryl" or "benzoheteroaromatic" refers to a bicyclic ring comprising a benzene ring fused to a monocyclic heteroaromatic ring. Examples of benzoheteroaryl groups include benzisoxazolyl, benzoxazolyl, benzisothiazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl (including S-sulfur oxide and sulfur dioxide), quinolyl, isoquinolyl, indazolyl, indolyl, and the like.

[0082] The term "azole" refers to a five-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 oxazolyl groups.

[0083] The expression "cycloalkyl" refers to a saturated or partially unsaturated (e.g. cycloalkenyl) cyclic group comprising one or more rings (preferably 1 or 2) 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 are cyclopropyl, cyclobutyl, cyclopentyl.

[0084] The expression "optionally substituted" refers to a group in which at least one or 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 2 , ═NOH, N 3 or NO 2 group. In addition, the expression also refers to a C 1 -C 2 group which may be replaced by at least one, two, three or more unsubstituted C 1 -C 2 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-C18 Aryl, C1-C 17 Heteroaryl, C7-C 20 Arylalkyl or C2-C 19 Furthermore, this expression refers in particular to a group which may be substituted by one, two, three or more unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl, C7-C 12 Alkylcycloalkyl, C2-C 11 Heteroalkylcycloalkyl, C6-C 10 Aryl, C1-C9 heteroaryl, C7-C 12 Arylalkyl or C2-C 11 Heteroaralkyl substituted groups.

[0085] According to a preferred embodiment, all alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl and heteroaralkyl groups described herein may be optionally substituted.

[0086] Preferably, the present invention provides a hydroquinone derivative compound of formula (I), wherein:

[0087] (A)

[0088] 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;

[0089] R1=COOR4;R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

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

[0091] R5=R6=CONH-R9;

[0092] or

[0093] (B)

[0094] 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;

[0095] R1=COOR4;R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0096] R3=H; R2=R5; and

[0097] R5=R6=CONH-R9.

[0098] Thus, in a first embodiment, the present invention comprises the compounds of Table 1:

[0099] Table 1

[0100]

[0101]

[0102]

[0103]

[0104]

[0105] Preferably, the present invention provides a compound of formula (I), wherein:

[0106] (A)

[0107] R a 、R b =H;

[0108] R1=SO3H;

[0109] R2=H; R3=R5; and

[0110] R5=R6=CONH-R9;

[0111] or

[0112] (B)

[0113] R a 、R b =H;

[0114] R1=SO3H;

[0115] R3=H; R2=R5; and

[0116] R5=R6=CONH-R9.

[0117] In a second embodiment, the present invention comprises compounds of Table 2:

[0118] Table 2

[0119]

[0120]

[0121]

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

[0123] (A)

[0124] R a 、R b =H;

[0125] R1=(CH2) n COOR4; R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

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

[0127] R5=R6=CONH-R9;

[0128] or

[0129] (B)

[0130] R a 、R b =H;

[0131] R1=(CH2) n COOR4; R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

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

[0133] R5=R6=CONH-R9.

[0134] In a third embodiment, the present invention comprises the compounds of Table 3:

[0135] Table 3

[0136]

[0137]

[0138]

[0139]

[0140]

[0141] Preferably, the present invention provides a hydroquinone derivative compound of formula (I), wherein:

[0142] (A)

[0143] 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;

[0144] R1=CONH-R 10 ; R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0145] R2=H; R3=R5; and

[0146] R5=R6=CONH-R9;

[0147] or

[0148] (B)

[0149] 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;

[0150] R1=CONH-R 10 ; R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0151] R3=H; R2=R5; and

[0152] R5=R6=CONH-R9.

[0153] In a fourth embodiment, the present invention comprises the compounds of Table 4:

[0154] Table 4

[0155]

[0156]

[0157]

[0158] Preferably, the present invention provides a hydroquinone derivative compound of formula (I), wherein:

[0159] (A)

[0160] R a 、R b =H;

[0161] R1=COOR4、(CH2) n COOR4; R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0162] R2=H; R3=R5; and

[0163] R5=R6=CONHCOR9;

[0164] or

[0165] (B)

[0166] R a 、R b =H;

[0167] R1=COOR4、(CH2) n COOR4; R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0168] R3=H; R2=R5; and

[0169] R5=R6=CONHCOR9.

[0170] In a fifth embodiment, the present invention comprises compounds of Table 5:

[0171] Table 5

[0172]

[0173]

[0174] Preferably, the present invention provides a hydroquinone derivative compound of formula (I), wherein

[0175] (A)

[0176] R a 、R b =H;

[0177] R1=COOR4、(CH2) n COOR4; R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0178] R2=H; R3=R5; and

[0179] R5=R6=CONH(CH2) n -R9;

[0180] or

[0181] (B)

[0182] R a 、R b =H;

[0183] R1=COOR4、(CH2)n COOR4; R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0184] R3=H; R2=R5; and

[0185] R5=R6=CONH(CH2) n -R9.

[0186] In a sixth embodiment, the present invention comprises compounds of Table 6:

[0187] Table 6

[0188]

[0189]

[0190]

[0191] Preferably, the present invention provides a hydroquinone derivative compound of formula (I), wherein:

[0192] R a 、R b =H;

[0193] R1=SO3H;

[0194] R2=H; R3=R5; and

[0195] R5=R6=CONH(CH2) n -R9.

[0196] According to a seventh embodiment, the present invention includes the compounds of Table 7 below:

[0197] Table 7

[0198]

[0199] Preferably, the present invention relates to hydroquinone derivative compounds of formula (I), wherein:

[0200] (A)

[0201] Ra 、R b =H;

[0202] R1=COOR4、(CH2) n COOR4; R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0203] R2=H; R3=R5; and

[0204] R5=R6=CONHCH(COOR4)(CH2) k -R9;

[0205] or

[0206] (B)

[0207] R a 、R b =H;

[0208] R1=COOR4、(CH2) n COOR4; R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0209] R3=H; R2=R5; and

[0210] R5=R6=CONHCH(COOR4)(CH2) k -R9.

[0211] According to an eighth embodiment, the present invention includes the compounds of Table 8 below:

[0212] Table 8

[0213]

[0214] In a specific embodiment, the present invention provides a hydroquinone derivative compound of formula (I), wherein

[0215] (A)

[0216] R a 、R b =H;

[0217] R1=COOR4、(CH2) n COOR4, SO3H, (CH2) n SO3H or CONH-R 10 ;

[0218] R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0219] R2=H; R3=R5; and

[0220] R5=R6=heteroaryl-R9;

[0221] or

[0222] (B)

[0223] R a 、R b =H;

[0224] R1=COOR4、(CH2) n COOR4, SO3H, (CH2) n SO3H or CONH-R 10 ;

[0225] R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0226] R3=H; R2=R5; and

[0227] R5=R6=heteroaryl-R9.

[0228] According to a ninth embodiment, the present invention comprises compounds of Table 9:

[0229] Table 9

[0230]

[0231]

[0232]

[0233]

[0234]

[0235] Preferably, the present invention provides a hydroquinone derivative compound of formula (I), wherein:

[0236] (A)

[0237] R a 、R b =H;

[0238] R1=COOR4、(CH2) n COOR4, SO3H, (CH2) n SO3H or CONH-R 10 ;

[0239] R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0240] R2=H; R3=R5; and

[0241] R5=R7=benzoheteroaryl substituted by at least one or more groups selected from the group consisting of COOR4, (CH2) n COOR4, SO3H, (CH2) n SO3H, OR4, azole [5-membered N-containing heterocyclic ring] or fluorine;

[0242] or

[0243] (B)

[0244] R a 、R b =H;

[0245] R1=COOR4、(CH2) n COOR4, SO3H, (CH2) n SO3H or CONH-R 10 ;

[0246] R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0247] R3=H; R2=R5; and

[0248] R5=R7=benzoheteroaryl substituted by at least one or more groups selected from the group consisting of COOR4, (CH2) n COOR4, SO3H, (CH2) n SO3H, OR4, azole [5-membered N-containing heterocyclic ring] or fluorine.

[0249] According to a tenth embodiment, the present invention comprises the compounds of Table 10:

[0250] Table 10

[0251]

[0252]

[0253] Preferably, the present invention provides a hydroquinone derivative compound of formula (I), wherein:

[0254] (A)

[0255] Ra 、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;

[0256] R1=COOR4、(CH2) n COOR4, SO3H, (CH2) n SO3H or CONH-R 10 ;

[0257] R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0258] R2=H; R3=R5; and

[0259] R5=R8=(CH2) m X(CH2) p R9;

[0260] Where X=O, S, SO2, NH, NAc or N(CH2) q R9;

[0261] or

[0262] (B)

[0263] 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;

[0264] R1=COOR4、(CH2) n COOR4, SO3H, (CH2) n SO3H or CONH-R 10 ;

[0265] R4=H、C 1-4 Alkyl, aryl C 1-4 Alkyl, functionalized C1-C6 alkyl including morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C6-C 10 Aryl includes o-methoxyphenyl (guaiacol), C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl;

[0266] R3=H; R2=R5; and

[0267] R5=R8=(CH2) m X(CH2) p R9;

[0268] Where X=O, S, SO2, NH, NAc or N(CH2) q R9.

[0269] According to an eleventh embodiment, the present invention comprises compounds of Table 11:

[0270] Table 11

[0271]

[0272]

[0273]

[0274]

[0275] According to yet another embodiment, the present invention includes compounds of Table 12:

[0276] Table 12

[0277]

[0278]

[0279] The present invention also relates to a process for preparing a hydroquinone derivative compound of formula (I), comprising:

[0280] Step (a): coupling a hydroquinone-derived carboxylic acid protected at the phenol function with an aniline carrying a different functional group in the presence of NMI by means of the corresponding acyl chloride or using an amide coupling agent such as TCFH;

[0281] Step (b): deprotecting the ester functional group, typically by saponification; and

[0282] Step (c): The phenol function is typically deprotected by catalytic hydrogenation.

[0283] Or, alternatively,

[0284] Step (d): Reduction of the hydroquinone-derived carboxylic acid protected at the phenol function to produce benzyl alcohol

[0285] (e) activating the benzyl alcohol functional group and displacing it with a benzyl nucleophile carrying a different functional group (alcohol, thiol, primary amine, or secondary amine);

[0286] (f) deprotecting the ester functionality, typically by saponification; and

[0287] (g) Deprotection of the phenolic function is usually carried out by catalytic hydrogenation.

[0288] The process is schematically represented as follows:

[0289]

[0290] The hydroquinone derivative compounds of the present invention may exist as optically active forms (stereoisomers), E / Z isomers, enantiomers, racemates, diastereomers, and hydrates and solvates thereof. Solvates of the compounds are due to the mutual attraction between the compound molecules and the inert solvent used. Solvates include, for example, monohydrates, dihydrates, or alcoholates.

[0291] The hydroquinone derivatives of the present invention may also exist as pharmaceutically acceptable salts, wherein the parent hydroquinone derivative is modified by preparing an acidic or basic salt thereof.

[0292] Examples of pharmaceutically acceptable salts include, in particular, inorganic or organic acid salts of basic residues such as amines; and alkaline or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts may include conventional non-toxic salts or quaternary ammonium salts, which are suitable for all routes of administration of the compound, such as from non-toxic organic or inorganic acids. For example, 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 prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxyleleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanyl, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.

[0293] Pharmaceutically acceptable salts of cations and anions are described in "Pharmaceutical salts: A summary 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 penicillin, calcium, chloroprocaine, choline, diethanolamine, diethylamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, lithium, meglumine, potassium, procaine, sodium, triethylamine, and zinc. As examples of anions we may cite acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camphorsulfonate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, methylsulfate, mucate, naphthenate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate, sulfate, tartrate, teoclate, tosylate. Alternatively, zwitterions can be used as salts, such as the free amino acids arginine or lysine as cationic counterions, and glutamic acid or aspartic acid as anionic counterions. Short peptides (2 to 20 amino acids) consisting of repeating units of arginine or lysine and combinations thereof with other neutral amino acids can be used as promoters for drug penetration into cells.

[0294] 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, the salts can be prepared by reacting the free acid or basic form of these compounds with a stoichiometric amount of the 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, lists suitable salts.

[0295] According to the present invention and as described herein in various embodiments, suitable dosage can be changed according to the condition, age and species of the subject, and can be easily determined by those skilled in the art. The total daily dose used in veterinary and human medicine will be suitably 0.01-2000mg / kg body weight, preferably 0.1-1000mg / kg body weight, preferably 1-100mg / kg body weight, and these can be administered in single doses or divided doses. In addition, when it is found that there is an indication, the upper limit can also be exceeded. This dosage can be adjusted according to the individual requirements in each case, including the specific compound given, the route of administration, the disease treated, and the patient treated. However, these compounds can also be administered weekly, monthly, or even longer time intervals as long-acting preparations (implants, sustained-release preparations, etc.). In this case, dosage can be much higher than the daily dose and can be adjusted according to form of administration, body weight, and specific indications. Suitable dosage can be determined by carrying out conventional model testing, preferably animal model. In general, in the case of oral or parenteral administration to an adult weighing about 70 kg, a daily dose of about 10 mg to about 10.000 mg, preferably about 200 mg to about 1000 mg should be suitable, although the upper limit may be exceeded when indicated. It should be understood that the above-mentioned therapeutically effective dose does not have to be the result of a single administration, but is typically the result of multiple unit doses. Those unit doses can include portions of daily or weekly doses, and therefore, the therapeutically effective dose is determined during treatment (contact). For example, for oral administration, the daily dose can 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. In general, the dosage of the active substance can vary within a relatively wide range to achieve and preferably maintain the desired plasma concentration. The unit dosage form of the active ingredient can contain about 0.1 milligram to about 15 milligrams of active ingredient. Preferred unit dosage forms contain about 0.1 to about 1 milligram of the agent and can be administered 2 to 5 times a day. However, it should be noted that other alternative routes are also contemplated, such as continuous infusion at a rate designed to maintain the above-mentioned plasma concentrations. The duration of a particular treatment may also vary, depending on the severity of the disease, whether the treatment is for acute manifestations or for preventive purposes, and similar considerations. Typical administration continues for about 5 to about 14 days, usually over a 7-day period.

[0296] The course of administration (cycle) may also be repeated at monthly intervals, or the parenteral unit dose may be delivered at weekly intervals. The oral unit dose may be administered every one to several days to provide a defined therapeutically effective dose. The appropriate dose of the compound of the invention will depend on the type of disease to be treated, the severity and course of the disease, whether the agent is administered for preventive 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 current physicians. Animal experiments provide reliable guidance for determining effective doses for human treatment. 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.

[0297] The present invention also provides a pharmaceutical composition comprising (i) a therapeutically effective amount of a hydroquinone derivative compound of formula (I) or a pharmaceutically acceptable salt thereof, or a prodrug or stereoisomer thereof, and (ii) one or more pharmaceutically acceptable excipients.

[0298] The pharmaceutical excipients of the present invention can be selected from conventional excipients such as, but not limited to, solubilizers, binders, fillers, disintegrants, lubricants, pH adjusters, penetration enhancers, release modifiers, preservatives, coating agents, carriers, taste masking agents, and combinations thereof.

[0299] The pharmaceutical composition of the compound of the present invention having one or more pharmaceutical ingredients can be formulated together with the excipients as a liquid drug, a solid or semisolid drug and / or a gaseous drug.

[0300] When they are present in solid preparations, these can include but not limited to granules, pills, tablets, capsules, powders, thin films, lozenges, compressible tablets, soluble tablets, disintegrating tablets, dispersible tablets, film-coated tablets, and the controlled, lasting, extended or delayed release form of any above-mentioned solid form. Such preparations can also be the form of immediate release, delayed release or delayed release. In addition, immediate release compositions can be conventional, dispersible, chewable, oral dissolving or fast-dissolving preparations, and delayed release compositions can comprise hydrophilicity or hydrophobicity or hydrophilic and hydrophobic combination, rate of release controlled material to form the combination of matrix or reservoir or matrix and reservoir system.

[0301] The compositions can be prepared using any one or more techniques, such as direct mixing, dry granulation, wet granulation, homogenization, grinding, micronization, extrusion and spheronization. The compositions can exist in the form of uncoated, film-coated, sugar-coated, powder-coated, enteric-coated and slow-release coated. When they are present in liquid preparations, these can include but are not limited to any liquid form, such as solution, suspension, nanosuspension, dispersion, colloid, emulsion, lotion, cream, ointment, tincture and freeze-dried composition. When they are present in gaseous preparations, these can include but are not limited to powder or mixture, micronized powder or mixture, nanosuspension, aerosol, spray, drop, mist, atomized solution or suspension and / or atomized steam.

[0302] If necessary, the pharmaceutical composition of the present invention may further comprise any additives such as carriers, binders, perfumes, flavorings, sweeteners, colorants, preservatives, antioxidants, stabilizers and surfactants.

[0303] The pharmaceutical compositions and compounds of the present invention can be formulated for administration by the following routes: enteral routes, such as oral routes; parenteral routes by injection, such as intravenous, subcutaneous, intraocular, intramuscular or intraperitoneal injection; topical routes, such as ocular routes, mucosal and transmucosal routes, including sublingual / buccal routes; and pulmonary, nasal, intranasal, intrabronchial, intrapulmonary routes. Ocular routes of administration include topical ocular administration, intraocular administration, intravitreal administration or retrobulbar administration.

[0304] Preferred formulations of the compounds of the present invention include liquid oral formulations, ophthalmic formulations, and intravenous and intraperitoneal injection formulations.

[0305] Liquid oral formulations are solutions and suspensions used for oral drug administration. They are common, convenient, and considered safe. They can be used to deliver relatively large amounts of drug and are commonly used in pediatric populations and those who have difficulty swallowing tablets or capsules. Introduction through the gastrointestinal tract can achieve rapid dissolution and drug absorption, but tolerability and interactions with other substances in the gastrointestinal tract must be considered. The properties of the active pharmaceutical ingredient (API) allow for formulation into a simple water-based oral solution. However, when the API is poorly soluble, the formulation needs to be designed around the molecule to improve solubility and bioavailability. The introduction of surfactants, solvents, buffers, and oils increases solubility and reduces precipitation and / or degradation upon interaction with gastric fluid. Where a suspension is required, particle size is often reduced and controlled to improve drug solubility, permeability, and ultimately drug absorption. As formulation development progresses, preservatives and flavorings are introduced to ensure patient compliance and an appropriate shelf life.

[0306] Ophthalmic formulations are eye preparations delivered directly to the eye, typically in the form of liquid solutions or suspensions. Ophthalmic administration avoids metabolism in the gastrointestinal tract and can be used for drugs that are poorly absorbed when administered orally. Eye drops are sterile and isotonic, with a nominal pH of 4-8 to avoid eye irritation. Excipients, including solubilizers, chelating agents, polymers, surfactants, penetration enhancers, and cyclodextrins, are added to formulations to improve stability, change viscosity, or increase the solubility, permeability, and bioavailability of poorly soluble drugs.

[0307] Intravenous formulations allow for rapid absorption of the entire dose of parenteral drug delivery once it reaches the patient's system, resulting in an immediate response. This mode of introduction avoids metabolism in the gastrointestinal tract and can be used for drugs that are poorly absorbed orally when administered orally. Injections are typically sterile, isotonic, water-based solutions designed to be painless upon administration. For poorly soluble drugs, the formulation is modified with organic cosolvents, surfactants, and buffers to increase solubility, and nanosuspension formulations are also acceptable. For molecules that are unstable in solution, the formulation can be lyophilized for dilution at the time of use.

[0308] The present invention also provides a kit 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 administering the composition or formulation, and further comprising a package insert containing instructions for use.

[0309] In order to prepare pharmaceutical composition of the present invention, according to conventional drug formulation technology, active component of the present invention can be mixed with pharmaceutically acceptable carrier, adjuvant and / or vehicle. Pharmaceutically acceptable carrier that can be used for composition of the present invention comprises any standard pharmaceutical carrier, for example phosphate buffered saline solution, water and emulsion, for example oil / water or water / oil emulsion, and various types of wetting agents. Composition can also contain solid pharmaceutical excipient, as starch, cellulose, talcum, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, skim milk powder etc. Liquid and semisolid excipient can be selected from glycerol, propylene glycol, polyethylene glycol, water, ethanol and various oils, and it comprises the oil of petroleum, animal, plant or synthetic origin, for example peanut oil, soybean oil, mineral oil, sesame oil etc. Liquid carrier, particularly the liquid carrier for injection solution, comprises water, saline, glucose aqueous solution and ethylene glycol. For examples of carriers, stabilizers, and adjuvants, see Remington's Pharmaceutical Sciences, edited by EW Martin (Mack Publishing Company, 18th ed., 1990).

[0310] The composition may also include a stabilizer and a preservative. Examples of pharmaceutically acceptable solvents that can be used for the compositions of the present invention 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. (fifth edition, editors: Kevin Taylor and Michael Aulton, Elsevier, 2017), " Ullmann's Encyclopedia of Industrial Chemistry, 6th Ed." (multiple editors, 1989-1998, Marcel Dekker) and " Pharmaceutical Dosage Forms and Drug Delivery Systems " (ANSEL et al., 1994 et 2011, WILLIAMS & WILKINS). Non-limiting examples of pharmaceutically acceptable solvents that can be used in the compositions of the present invention include, but are not limited to, propylene glycol (also known as 1,2-dihydroxypropane, 2-hydroxypropanol, methyl ethylene glycol, methyl glycol, or propane-1,2-diol), ethanol, methanol, propanol, isopropanol, butanol, glycerol, polyethylene glycol (PEG), ethylene 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.

[0311] The compounds of the present invention have shown anti-fibrotic, anti-inflammatory and anti-angiogenic effects. Several diseases listed below involve not only one target, but also two or even three targets. The disease categories show a primary angiogenic (vascular), inflammatory and / or fibrotic pathobiology.

[0312] In some embodiments, the present invention relates to prodrugs of the compounds of the present invention. The benefits of such prodrugs are obtained by methods known to those skilled in the art, such as by adding suitable cleavable functional groups that will produce, for example, better water solubility for parenteral delivery or for oral delivery.

[0313] Prodrugs of the present molecules that exhibit strong polarity and charge properties are particularly preferred because these functional groups can positively influence passive permeability across biological membranes. A major obstacle to polar and charged drugs is their poor membrane permeability, which often leads to low and variable oral absorption and low oral bioavailability. Furthermore, oral absorption of polar and charged drugs is often associated with substantial interspecies variation. Even after topical administration, poorly permeable drugs often exhibit low levels of exposure to specific target organs. Improving membrane permeability is one of the most fruitful areas of prodrug research to date.

[0314] Different prodrug strategies have been developed for the drugs of the present invention to overcome topical route barriers on the eye, oral mucosal barriers, transporter effects or other topical uses.

[0315] The prodrug strategy was formally recognized by Adrian Albert in 1958 (Albert, A. Chemical aspects of selective toxicity. Nature, 1958, 182, 421–422), but it began at the beginning of the last century, for example, with methenamine, phenacetin and prontosil. Prodrugs are molecules with little or no pharmacological activity but with inherent structural instability, whether accidental or by design, which allows them to be bioconverted into active drugs in the body. This conversion can be achieved by chemical or enzymatic processes or a combination of both. Active molecules are often associated with undesirable physicochemical properties, which poses considerable challenges to their delivery to appropriate biological targets.

[0316] Prodrugs, derived through structural modifications of drugs, are designed to influence the inherent physicochemical properties of a molecule to facilitate its delivery. These developments are not always integrated into the design of new molecules during the discovery phase. Often, simulation-based optimization is the preferred path forward. Implementing an early prodrug strategy can lead to faster clinical development and, ultimately, commercialization of the drug product.

[0317] Rautio J, 2018 (Jarkko Rautio et al, Nature Reviews Drug Discovery, 2018, 17, 559-587) describes prodrug strategies for the most common functional groups on parent drugs. This review documents the expanding role of prodrugs in contemporary drug design and development, as well as prodrug strategies targeting the most common functional groups on parent drugs.

[0318] The benefits of prodrugs can be achieved by adding suitable cleavable functional groups that result in improved aqueous solubility, for example, for parenteral or oral delivery. On the other hand, for very polar and charged molecules, these functional groups may positively influence passive permeability across biological membranes. A major obstacle for polar and charged drugs is their poor membrane permeability, which often results in low and variable oral absorption and low oral bioavailability.

[0319] Furthermore, oral absorption of polar and charged drugs is often associated with substantial interspecies variability. Even after topical administration, poorly permeable drugs often exhibit low exposure levels in specific target organs. Improving membrane permeability has been one of the most fruitful areas of prodrug research to date. Numerous prodrug strategies can be used to influence the lipophilicity of the parent drug. The lipophilicity of drugs has been modified by masking their polar and ionizing functionality 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 vivo by ubiquitous esterases or peptidases.

[0320] Most lipophilic prodrugs have been developed to improve membrane permeability and oral absorption. The same prodrug strategy can be used to improve topical administration of parent drugs absorbed through the skin or eyes. During topical ocular administration, prodrugs readily penetrate the cornea after instillation, where they are primarily hydrolyzed by ocular carboxylesterases.

[0321] Prodrugs can also exploit carrier-mediated transport. These transporters are membrane proteins that play a crucial role in controlling the uptake and excretion of key polar endogenous nutrients. Their specificity is not limited to endogenous substrates; drugs with close structural similarities to endogenous substrates can also be carried across cell membranes by transporters. Carrier-mediated transport is particularly important for polar and charged drugs, for which passive diffusion across biological membranes is negligible. Prodrugs that can exploit carrier-mediated transport mechanisms offer interesting targets for drug design. Prodrugs can also improve metabolic stability.

[0322] Prodrugs can ameliorate the metabolic instability typically attributed to hepatic metabolism. Similarly, undesirable 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 unstable but pharmacologically necessary functional groups, such as phenol, to avoid rapid metabolism.

[0323] To address the problem of insufficient plasma levels and prolonged duration of action, drugs are often controlled by formulations such as suspensions and polymer matrices, which control drug release, avoid peak effects, and prolong their effects. Prodrugs can be used to achieve controlled release of active drugs by changing their water solubility and dissolution characteristics in a way that affects the release rate, absorption rate, or tissue distribution of the active drug.

[0324] Prodrugs are particularly useful in developing several subcutaneous or intramuscular sustained-release long-acting injections that can maintain therapeutic plasma levels of the parent drug for weeks to months. These prodrugs are typically fatty acid esters, such as decanoate, palmitate, enanthate, cyclopentanepropionate, or valerate, formulated in an oil-based vehicle to result in sustained-release prodrugs and thus regulate the disposal of the parent drug. The high lipophilicity of these prodrugs can also lead to binding to blood and tissue proteins, slowing down enzymatic conversion and thus causing the active drug to slowly appear in the systemic circulation.

[0325] Better targeting and reduced side effects are often achieved by targeting prodrugs with acid-labile prodrugs that cleave in endosomes or lysosomes within the acidic environment of tumor tissue. Similar approaches have been achieved using site-specific enzymes, with the prodrug cleaved primarily in the desired organ or tissue where enzyme concentration is highest. For charged drugs, intracellular cleavage results in high cellular concentrations of the negatively or positively charged drug, which is confined to the target cell.

[0326] Different prodrug strategies have been developed for the drugs of the present invention to overcome topical route barriers on the eye, oral mucosal barriers, transporter effects or other topical uses.

[0327] The drugs of the present invention contain charged polar groups. The problem to be solved depends on the route of administration and the desired duration of action. Examples of prodrugs that are cleaved by mouse and human tissue and blood esterases have been successfully synthesized.

[0328] The compounds of the present invention bear carboxyl functional groups and phenolic groups. A variety of prodrugs derived from these functional groups are contemplated: for example, carboxylic acids are most commonly converted into esters: simple alkyl esters (methyl, ethyl, isopropyl, and longer chains), functionalized alkyl esters such as morpholinoalkyl esters, pyrrolidinylalkyl esters, N-methylpiperazinyl-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: simple aliphatic esters, aromatic esters, half-esters of dicarboxylic acids, amino acid esters, carbamates, phosphate monoesters, phosphonooxymethyl ethers, acyloxymethyl (or 1-ethyl) ethers, alkoxycarbonyloxymethyl (or 1-ethyl) ethers, aminoacyloxymethyl ethers, and the like.

[0329] Therefore, the present invention provides a method for treating and / or preventing diseases or conditions, such as autoimmune, immune, rheumatic, vascular, ophthalmic, fibrotic, metabolic and gastrointestinal diseases, neuroinflammatory and neurodegenerative diseases, tumor and cancer-related diseases, hormone-related diseases, and immune disorders caused by viral and bacterial infectious diseases and their complications, which comprises administering to a subject in need thereof a therapeutically effective dose of the compound and / or pharmaceutical composition of the present invention as described above.

[0330] The pharmaceutical compositions and methods of the present invention are particularly suitable for human or non-human animal subjects.

[0331] The compounds of the present invention can target diseases based on their respective cytokine profiles, as described in the biological data provided for several compounds (see Figure 3A The Open Targets Platform (URL: https: / / www.targetvalidation.org / , Denise Carvalho et al, Nucleic Acids Research, Volume 47, Issue D1, 8 January 2019, D1056–D1065, https: / / doi.org / 10.1093 / nar / gky1133) provides a complete picture based on current literature bibliographic information and can be searched by disease or cytokine.

[0332] Two typical examples: (a) A disease-specific search for diabetic retinopathy resulted in the following cytokines being described as highly associated with the disease ( Figure 3C ). The first three cytokines are used as examples for searching for diabetic retinopathy, indicating VEGFA score = 1 (vascular endothelial growth factor A), HFE score = 1 (homeostatic iron regulator), and TNF score = 0.86 (tumor necrosis factor); and (b) searching for VEGFA: leading to neurological diseases, vascular diseases, eye diseases, retinopathy and several other diseases, such as Figure 3D shown.

[0333] To demonstrate the potency of the compounds against a small panel of inflammatory cytokines, the compounds were evaluated on human whole blood (Example 3.6) and their IC50 values ​​for inhibition of LPS-induced inflammation were assessed (Table 13, in μM).

[0334] Table 13:

[0335]

[0336]

[0337] Immune / rheumatological / vascular disorders may include, for example, peritonitis, Kawasaki disease (KD), Takayasu arteritis (TA), microscopic polyangiitis (MP), giant cell 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).

[0338] Rheumatic diseases particularly affect the joints, tendons, ligaments, and bones, with pain, loss of motion, and inflammation. These include various types of arthritis, such as osteoarthritis (OA), rheumatoid arthritis (RA), lupus, the spondyloarthritis types ankylosing spondylitis (AS) and psoriatic arthritis (PsA), Sjögren's syndrome, gout, scleroderma, infectious arthritis, juvenile idiopathic arthritis, and polymyalgia rheumatica.

[0339] Peritonitis is inflammation of the peritoneum, usually caused by a bacterial or fungal infection. There are two types of peritonitis. The first type, spontaneous peritonitis, can develop as a complication of liver disease, such as cirrhosis, or kidney disease. Secondary peritonitis can develop as a result of a perforated abdominal cavity or as a complication of other medical conditions. If left untreated, peritonitis can lead to a serious, potentially life-threatening infection.

[0340] Kawasaki disease causes inflammation of the walls of medium-sized arteries throughout the body. It primarily affects children. The inflammation often affects the coronary arteries that supply blood to the heart muscle. Kawasaki disease is sometimes called mucocutaneous lymph node syndrome because it also affects the lymph nodes, which swell during infection, as well as the skin and the mucous membranes lining the mouth, nose, and throat.

[0341] Takayasu arteritis is a rare type of vasculitis, a group of conditions that cause inflammation of blood vessels. In Takayasu arteritis, inflammation damages the aorta and its major branches. This disease can cause arteries to narrow or become blocked, or lead to aneurysms. Takayasu arteritis can also cause arm or chest pain, high blood pressure, and ultimately heart failure or stroke. Medications are needed to control arterial inflammation and prevent complications.

[0342] Granulomatosis with polyangiitis is a rare disease that causes inflammation of the blood vessels of the nose, sinuses, throat, lungs, and kidneys. Formerly known as Wegener's granulomatosis, this disease is one of a group of vascular conditions called vasculitis. It slows blood flow to certain organs. Affected tissue forms inflamed areas called granulomas, which can affect how these organs work. Without treatment, this disease can be fatal.

[0343] Giant cell arteritis is an inflammation of the lining of the arteries. Most commonly, it affects the arteries in the head, particularly the temples. For this reason, giant cell arteritis is sometimes called temporal arteritis. Giant cell arteritis often causes headaches, scalp tenderness, jaw pain, and vision problems. Untreated, it can lead to blindness.

[0344] Antiphospholipid syndrome occurs when the immune system mistakenly produces antibodies that make the 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 cause miscarriage and stillbirth. There is no cure for antiphospholipid syndrome. Only available medications can reduce the risk of blood clots.

[0345] Behçet's disease, also known as Behçet's syndrome, is a rare disorder that causes inflammation of blood vessels. It can lead to a variety of signs and symptoms that may initially appear unrelated. These may include mouth sores, eye inflammation, rashes and lesions, and genital ulcers. Current treatments can help alleviate Behçet's symptoms and prevent serious complications, such as blindness.

[0346] Churg-Strauss syndrome is a condition marked by inflammation of the blood vessels. This inflammation can restrict blood flow to organs and tissues, sometimes causing permanent damage to them. This condition is also known as eosinophilic granulomatosis with polyangiitis (EGPA). Asthma is the most common sign of Churg-Strauss syndrome. The condition can also cause other problems such as hay fever, rash, gastrointestinal bleeding, and pain and numbness in the hands and feet. There is no cure for Churg-Strauss syndrome. Current medications include steroids and other powerful immunosuppressant drugs to help control symptoms.

[0347] Rosacea is a common skin condition that causes facial redness and visible blood vessels. It may also cause small, red, pus-filled bumps. These signs and symptoms may last for 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 reduce signs and symptoms. Osteoarthritis is the most common form of arthritis, affecting millions of people worldwide. It occurs when protective cartilage wears away over time. While osteoarthritis can damage any joint, the condition most commonly affects the joints of the hands, knees, hips, and spine. Osteoarthritis symptoms can usually be managed, although joint damage cannot be reversed.

[0348] 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 common complication in people with systemic lupus erythematosus (commonly known as lupus). Lupus nephritis occurs when lupus autoantibodies affect the structure of the kidneys. This results in kidney inflammation, which can lead to blood in the urine, protein in the urine, high blood pressure, kidney damage, and even kidney failure.

[0349] Scleroderma is a group of rare diseases that involve hardening and tightening of the skin and connective tissue. There are many different types of scleroderma. In some people, scleroderma affects only the skin. But in many people, scleroderma also damages structures beyond the skin, such as blood vessels, internal organs, and the digestive tract (systemic scleroderma). There is no cure for scleroderma.

[0350] Sjögren's syndrome is an immune system disorder identified by its two most common symptoms: dry eyes and dry mouth. The condition often occurs alongside other immune system disorders, such as rheumatoid arthritis and lupus. In Sjögren's syndrome, the mucous membranes and moisture-secreting glands of the eyes and mouth are often affected first, leading to a decrease in tears and saliva.

[0351] Infectious or septic arthritis is a painful infection of the joints that can be caused by bacteria spread 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 bacteria directly to the joint. People who have artificial joints are also at risk for septic arthritis. The knee is most commonly affected, but septic arthritis can also affect the hip, shoulder, and other joints. The infection can quickly and severely damage the cartilage and bone in the joint, so prompt treatment is crucial.

[0352] Juvenile idiopathic arthritis, formerly known as juvenile rheumatoid arthritis, is the most common type of arthritis in children under 16 years old. JIA can cause persistent joint pain, swelling, and stiffness. Some children may experience symptoms for only a few months, while others may have symptoms for years. Certain types of JIA can lead to serious complications, such as growth problems, joint damage, and eye inflammation.

[0353] Polymyalgia rheumatica is an inflammatory condition that causes muscle pain and stiffness, especially in the shoulders and hips. Signs and symptoms of polymyalgia rheumatica typically begin quickly 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 giant cell arteritis.

[0354] Ophthalmic conditions may include, for example, but are not limited to, age-related macular degeneration (AMD or ARMD, dry and wet forms), pterygium (PTE), diabetic retinopathy (DR), diabetic macular edema (DME), Stargardt's disease (SD), proliferative vitreoretinopathy (PVR), dry eye syndrome (DYS), endophthalmitis, central serous chorioretinopathy (CSC), retinitis pigmentosa (RP), glaucoma and glaucoma-related complications, and uveitis (UVE).

[0355] Wet macular degeneration is a chronic eye condition that causes blurred vision or blind spots in the visual field. It is usually caused by abnormal blood vessels leaking fluid or blood into the macula, the part of the retina responsible for central vision. Wet macular degeneration is one of two types of age-related macular degeneration. The wet form always precedes the dry form. Dry macular degeneration is more common and less severe. Due to thinning of the macula, it can also cause blurred or reduced central vision. Dry macular degeneration may first develop in one or both eyes and then affect both eyes. Vision loss is usually central, but some peripheral vision may remain.

[0356] Diabetic retinopathy is a complication of diabetes that affects the eyes. It is caused by damage to the blood vessels in the retina. Initially, diabetic retinopathy may not cause any symptoms or only mild vision problems. Eventually, it can lead to blindness. The disease can occur in anyone with type 1 or type 2 diabetes. DME is a serious eye complication that occurs when microaneurysms protrude from blood vessel walls, allowing fluid and blood to leak, or seep, into the retina, causing macular edema.

[0357] Stargadt disease is an eye disease that causes vision loss in children and young adults. It is a hereditary condition, so it is passed down from parents to their children. Stargardt disease is a form of macular degeneration and is often called juvenile macular degeneration.

[0358] PVR is a condition that develops as a complication of rhegmatogenous retinal detachment. Approximately 8-10% of patients undergoing surgery for primary retinal detachment develop PVR, which can prevent successful surgical repair of the rhegmatogenous retinal detachment. PVR can be treated with surgery to reattach the detached retina, but the visual outcome is very poor.

[0359] Dry eye is a common condition that occurs when tears don't provide adequate lubrication for the eyes. Tear production can be insufficient and unstable for many reasons. For example, dry eye can develop if you don't produce enough tears or if you produce low-quality tears. This unstable tear production can lead to inflammation and damage to the eye's surface.

[0360] Endophthalmitis is an inflammation of the eye that may occur after an injection or surgery in the eye. Signs are usually blurred vision or other vision changes, eye pain, eye redness, sensitivity to light, or tearing.

[0361] Retinitis pigmentosa (RP) is a group of rare inherited disorders that involve 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.

[0362] Glaucoma is a group of eye diseases that damage the optic nerve, a nerve crucial for good vision. This damage is usually caused by abnormally high intraocular pressure. Glaucoma is one of the leading causes of blindness in people over 60. It can occur at any age but is more common in older adults. Many types of glaucoma have no warning signs. The effects are gradual, and vision changes may not occur until the disease is advanced.

[0363] Uveitis is an inflammation of the eye. It affects the middle tissue layer of the eye wall, or uvea. Warning signs of uveitis usually appear suddenly and worsen rapidly. They include eye redness, pain, and blurred vision. Uveitis can be caused by infection, injury, or an autoimmune or inflammatory disease. Uveitis can be serious and cause permanent vision loss.

[0364] The compounds and pharmaceutical compositions of the present invention may also be used in methods of treating and / or preventing retinal neurodegenerative diseases selected from diabetic retinopathy, age-related macular degeneration, glaucoma, and retinitis pigmentosa.

[0365] Retinal neurodegenerative diseases are retinal diseases characterized by progressive neuronal loss. Diabetic retinopathy, age-related macular degeneration, glaucoma, and retinitis pigmentosa are considered retinal diseases in which neurodegeneration plays a major role.

[0366] According to this preferred embodiment, the compounds of the present invention can be combined with other active agents to enhance the therapeutic efficacy of the condition to be treated, in particular in combination with a dipeptidyl peptidase-4 inhibitor (DPPIV) or a pharmaceutically acceptable salt thereof for topical ocular treatment and / or prevention of retinal neurodegenerative diseases. The DPPIV inhibitor can be selected from sitagliptin, saxagliptin, vildagliptin, linagliptin, alagliliptin, teneligliptin, alogliptin, trelagliptin, gemagliptin, alogliptin, pharmaceutically acceptable salts thereof, and mixtures thereof.

[0367] The compounds of the present invention can also be advantageously combined with anti-VEGF therapy to reduce the number of intraocular anti-VEGF antibody injections required by the patient. Administration to patients with retinal neurodegenerative diseases (e.g., diabetic retinopathy, age-related macular degeneration) can slow the progression of these diseases and reduce the need for anti-VEGF drug therapy in patients.

[0368] Fibrotic disorders may include, for example, but are not limited to, cystic fibrosis, retroperitoneal fibrosis, idiopathic pulmonary fibrosis, combined pulmonary fibrosis and emphysema (CPFE), eosinophilic angiocentric fibrosis, intestinal fibrosis, ovarian fibrosis, nephrotic systemic fibrosis, oral submucous fibrosis (OSMF), and hepatic fibrosis.

[0369] Cystic fibrosis (CF) is a genetic disorder 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, tubes, and passages, particularly in the lungs and pancreas.

[0370] Pulmonary fibrosis is a lung disease that occurs when lung tissue becomes damaged and scarred. This thickened, stiff tissue makes it harder for the lungs to function properly. The scarring associated with pulmonary fibrosis can be caused by a variety of factors. Lung damage caused by pulmonary fibrosis cannot be repaired, but medications and treatments can sometimes help relieve symptoms and improve quality of life.

[0371] Emphysema is a lung disease that causes shortness of breath. The alveoli (alveoli) of the lungs become damaged, and over time, their linings weaken and break down, creating larger air spaces instead of many smaller ones. This reduces the lungs' surface area, which in turn reduces the amount of oxygen reaching the bloodstream. The damaged alveoli cannot function properly, trapping old air and leaving no room for fresh, oxygen-rich air to enter.

[0372] Metabolic and gastrointestinal disorders may include, for example, but not limited to, diabetes-induced complications: diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic cardiomyopathy (DCDM), or diabetic foot ulcers (DFU). Liver diseases may include non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), primary biliary cholangitis (PBC), liver fibrosis or cirrhosis (HF), inflammatory bowel disease (IBD): ulcerative colitis, Crohn's disease, 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).

[0373] Diabetic nephropathy is a serious kidney-related complication of both type 1 and type 2 diabetes. Also known as diabetic nephropathy, it affects approximately 25% of people with diabetes. Diabetic nephropathy affects the kidneys' ability to perform their daily tasks of removing waste and excess fluid from the body. Over years, the disease slowly damages the kidneys' delicate filtration system and can progress to kidney failure, also known as end-stage renal disease. Kidney failure is a life-threatening condition.

[0374] Non-alcoholic fatty liver disease (NAFLD) is an umbrella term for a range of liver diseases that affect people who drink little or no alcohol. As the name suggests, NAFLD is characterized by excess fat storage in liver cells. It is the most common form of chronic liver disease. Some people with NAFLD may develop non-alcoholic steatohepatitis (NASH), an aggressive fatty liver disease characterized by liver inflammation that can progress to advanced scarring (cirrhosis) and liver failure. This damage is similar to that caused by heavy alcohol consumption.

[0375] Primary biliary cholangitis (PBCH) is a chronic autoimmune disease in which the bile ducts in the liver are slowly destroyed. When the bile ducts are damaged, bile backs up into the liver, sometimes leading to irreversible cirrhosis. A combination of genetic and environmental factors triggers this disease.

[0376] IBD describes a condition 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 lining of the digestive tract, often involving deeper layers. Both ulcerative colitis and Crohn's disease are typically characterized by diarrhea, rectal bleeding, abdominal pain, fatigue, weight loss, and can sometimes lead to life-threatening complications.

[0377] Tumors and cancer-related conditions may include, for example, but are not limited to, pancreatic cancer: predominantly fibrosis, renal cell carcinoma, radiation-induced fibrosis, primary myelofibrosis, desmoplasia, fibrosarcoma, hepatocellular carcinoma, retinoblastoma, intraocular lymphoma, and melanoma (desmoplasia, conjunctival, uveal).

[0378] The present invention further relates to treating, preventing and reducing viral infections by binding to viral protein heparan sulfate binding sites. The compound of the present invention interacts with the heparan sulfate binding region of growth factors (FGF, VEGF and other growth factors) and growth factor receptors (FGFR, VEGFR and other). Many known viruses utilize their affinity for the heparan sulfate portion bound to the cell membrane to interact with mammalian cells. Viruses that carry heparan sulfate (HS) binding domains on their surface proteins use this HS affinity as one of the main entrances to approach and infect cells and bind to the heparan sulfate attached to the cells. When attached to HS, viruses can utilize the unique invasion mechanism of various viruses to infect cells. The strong interaction of the compound of the present invention with proteins, particularly the heparan binding domains of viral proteins, prevents viral infections of blood cells, blood vessels and organ endothelial cells and surface epithelial cells present in the mouth, nasal mucosa and lungs and the gastrointestinal tract. Several viruses are known to have a high affinity for heparan sulfate, such as, but not limited to, respiratory syncytial virus, human metapneumovirus, influenza (H1N1, etc.), human rhinovirus (HRV), nasal syncytial virus (RV), chikungunya virus, coronaviruses such as CoV, SARS-CoV, MERS-Cov, COVID-19 (SARS-CoV-2 and its variants). HS is an essential cofactor for SARS-CoV-2 infection. HS interacts with the receptor binding domain of the SARSCoV-2 spike glycoprotein adjacent to ACE2, converting the spike structure into an open conformation to facilitate ACE2 binding. Viral and bacterial infectious diseases can also include septic shock and ocular inflammation, such as endophthalmitis caused by surgery or infection.

[0379] Example

[0380] Example 1: Synthesis of compounds and intermediates

[0381] Example 1.1: Type Ia molecules: monoamides, 25 examples

[0382]

[0383] Synthesis of precursors

[0384] Scheme 1. Synthesis of intermediates KI-1 and KI-6

[0385]

[0386] step:

[0387] Synthesis of KI-1 and KI-6 (Steps [1], [2])

[0388] Diethyl 2,5-bis(benzyloxy)terephthalate (KI-0) (step [1]). Potassium carbonate-325 mesh (326.1 g, 2.4 mol) was added portionwise to a stirred solution of diethyl 2,5-dihydroxyterephthalate (200.0 g, 0.79 mol) in DMF (800.0 mL) at ambient temperature over 15 min. Benzyl bromide (280.0 mL, 2.4 mol) was then added dropwise to the reaction flask over 30 min, and the resulting mixture was heated at 100°C for 2 h, forming a thick, cream-colored precipitate. The reaction mixture was cooled to ambient temperature and treated with a saturated aqueous solution of ammonium chloride (2 L). The resulting suspension was stirred for 30 min and then filtered. The solid material was washed with a saturated aqueous solution of 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%)

[0389] UPLC-MS (acidic method, 2 min): rt = 1.36 min, no ionization observed, peak area > 95%

[0390] 1 H NMR (400MHz, DMSO-d6) δ7.51–7.44(m,6H),7.44–7.36(m,4H),7.36–7.28(m,2H),5.17(s,4H),4.29(q,J=7.1Hz,4H),1.26(t,J=7.1Hz,6H).

[0391] 2,5-Bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid (KI-1) and 2,5-bis(benzyloxy)terephthalic acid (KI-6) (step [2])

[0392] A solution of potassium hydroxide (14.2 g, 0.25 mol) in water (200.0 mL) was quickly 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 in vacuo to form a white slurry. The crude product was suspended in EtOH (500 mL) and 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%).

[0393] UPLC-MS (acidic method, 2 min): rt = 1.36 min, no ionization observed, peak area 98%

[0394] The ethanol filtrate was concentrated to give an oil. 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%).

[0395] UPLC-MS (acidic method, 2 min): rt = 1.22 min, m / z 377.1 [M–H] – , peak area 95%

[0396] 1 H NMR (400MHz, DMSO-d6) δ7.52–7.45(m,4H),7.41–7.33(m,4H),7.33–7.26(m,4H),5.13(s,4H).

[0397] The filtrate was washed with saturated aqueous sodium carbonate (200 mL), 1 M aqueous hydrochloric acid (500 mL) and brine (500 mL), then dried (Na2SO4), 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%).

[0398] UPLC-MS (acidic method, 2 min): rt = 1.22 min, m / z 405.3 [MH] - , peak area 96%

[0399] 1 H NMR (400MHz, DMSO-d6) δ7.52–7.27(m,13H),5.17(s,4H),4.28(q,J=7.1Hz,2H),1.26(t,J=7.1Hz,3H).

[0400] Large-scale protocol for the synthesis of KI-1

[0401] In a 10L jacketed container, 2,5-bis(benzyloxy)diethyl terephthalate (500.00g, 1.15mol), 1,4-dioxane (2.5L), potassium hydroxide (71.00g, 1.26mol) and water (500mL) were loaded. The reaction mixture was stirred at room temperature overnight. LCMS analysis showed that the reaction was half complete, and also showed the ratio of by-product (diacid) and raw material (diester) (diester: monoacid: diacid=28:58:14). (diacid: 4.44rt, monoacid: 5.08rt, diester: 5.68rt). At this stage, the solvent was removed in vacuo. In a 10L jacketed container, the crude product was added to a 2:1 mixture (3L) of ethanol: water, stirred overnight and filtered to obtain:

[0402] Solid: (diester:monoacid:diacid=86:12:2, 110.00 g, colorless solid)

[0403] Filtrate: (diester:monoacid:diacid 3:63:34)

[0404] The filtrate was concentrated in vacuo to give an oil. This oil was taken up in ethyl acetate (2.5 L), stirred overnight in a 10 L jacketed vessel, and filtered to give a white solid (150.00 g).

[0405] Solid: (diester: monoacid: diacid = trace: 40:60).

[0406] The filtrate was collected and washed with a saturated aqueous solution of sodium bicarbonate (100 mL), a 1N hydrochloric acid solution (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) (yield varied between 49-65%).

[0407] Scheme 2: Synthesis of intermediate KI-1Bn

[0408]

[0409] step:

[0410] Synthesis of KI-1Bn:

[0411] 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) was added sodium hydride (2.0 g, 50 mmol) at 0 ° C with stirring, followed by dropwise addition of benzyl bromide (5.95 mL, 50 mmol, 5 eq) over 5 min, and the resulting mixture was kept 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 residual material was co-evaporated with heptane (3x). The residue was placed in DCM (30 mL), the organic phase was washed with 1M HCl (25 mL), the separated aqueous layer was extracted with DCM (3x30 mL), and the combined organic phases were dried (MgSO4) and concentrated. The crude solid was recrystallized from EtOH (~30 mL) to yield pure KI-0Bn (2.286 g, 41%). A sample of KI-0Bn (282 mg, 0.5 mmol) was added to a mixture of 1,4-dioxane (10 mL) and lithium hydroxide hydrate (22 mg, 0.52 mmol), and the mixture was heated to 80°C for 3 days. The mixture was cooled to room temperature, placed in AcOEt (30 mL), and the solution was washed with 1M HCl (2 mL). The organic phase was dried and concentrated, and the residue was subjected to column chromatography to yield the monoester KI-1Bn contaminated with approximately 16% of the diester KI-0Bn.

[0412] KI-0Bn: 1 H NMR (400MHz, CDCl3): δ7.51(s,2H),7.36–7.30(m,20H),5.34(s,4H),5.11(s,4H).

[0413] KI-1Bn: 1 H NMR (250MHz, CDCl3): δ7.86(s,1H),7.61(s,1H),7.41–7.30(m,20H),5.36(s,2H),5.26(s,2H),5.16(s,2H).

[0414] Synthesis of monoamides

[0415] Scheme 3. Synthesis of Monoamide Ia

[0416]

[0417] General Procedure A for Amide Coupling [3A]

[0418] Coupling from KI-1 or KI-6 via acyl chloride

[0419] Model reaction (Ia-013a)

[0420] 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 min. A few drops of DMF were added, and the resulting mixture was stirred at ambient temperature for 18 h. The excess thionyl chloride was removed in vacuo, and the residue was co-distilled with toluene (3 x 20 mL) to provide the acid chloride. A solution of the acid chloride in DCM (10 mL) was quickly added 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 h. The reaction was diluted with DCM (70 mL) and washed with 1M aqueous 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%).

[0421] UPLC-MS (acidic method, 2 min): rt = 1.37 min; m / z = 598.2 [M+H] + , peak area>95%

[0422] 1 H NMR(400MHz,DMSO-d6)δ11.60(s,1H),8.02(d,J=7.8Hz,2H),7.69(s,1H),7.59–7.23(m,1 2H), 5.49 (s, 2H), 5.19 (s, 2H), 4.28 (q, J = 7.1Hz, 2H), 3.71 (s, 6H), 1.26 (t, J = 7.1Hz, 3H).

[0423] General Procedure B for Amide Coupling [3B]

[0424] Coupling from KI-1 or KI-6 using a condensing agent

[0425] Model reaction (Ia-001a)

[0426] 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 eq) in MeCN (150 mL) at ambient temperature. Chloro-N,N,N',N'-tetramethylfluorouronium hexafluorophosphate (TCFH) (10.728 g, 0.038 mol) was added portionwise over 30 min, and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was treated with 1 M aqueous hydrochloric acid (700 mL). The resulting suspension was stirred for 10 min and then filtered. The solid material was washed with water (2×200 mL). The solid was then suspended in ethanol (200 mL), filtered, washed with diethyl ether (100 mL), and dried in a vacuum oven to give the desired product as a white solid (14.7 g, 27 mmol, 86%)

[0427] UPLC-MS (acidic method, 2 min): rt = 1.43 min; m / z = 540.2 [M+H] + , peak area>99%

[0428] 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),8.65(d,J=8.4Hz,1H),7.98(dd,J=8.0,1.7Hz,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=7.1Hz,2H),3.74(s,3H),1.27(t,J=7.1Hz,3H).

[0429] General deprotection steps [4], [5]

[0430] Saponification

[0431] Model reaction (Ia-013a)

[0432] 2-(2,5-bis(benzyloxy)-4-carboxybenzoylamino)isophthalic acid. A solution of lithium hydroxide (42 mg, 1 mmol) in water (4 mL) was added to a solution of dimethyl 2-(2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoylamino)isophthalate (100 mg, 0.167 mmol) in THF (6 mL), and the resulting mixture was stirred at ambient temperature for 18 h. Additional LiOH (6 eq) was added to the reaction mixture in water (4 mL) and stirred for an additional 23 h. 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 × 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%).

[0433] UPLC-MS (acidic method, 2 min): rt = 1.02 min; m / z = 542.1 [M+H] + , peak area>95%

[0434] 1 H NMR(400MHz,DMSO-d6)δ13.18(s,2H),11.74(s,1H),8.00(d,J=7.8Hz,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).

[0435] Debenzylation

[0436] Model reaction (Ia-013a)

[0437] 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 atmospheric pressure and ambient temperature and stirred for 18 h. After completion, the mixture was filtered through celite and 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%).

[0438] UPLC-MS (acidic method, 4 min): rt = 0.91 min; m / z = 362.0 [M+H] +, peak area>98%

[0439] 1 H NMR(DMSO-d6)δ:13.11(s,2H),11.70(s,1H),11.13(s,1H),7.97(d,J=7.8Hz,2H),7.47(s,1H),7.41(s,1H),7.38(t,J=7.7Hz,1H)

[0440] Scheme 4a. Synthesis of Monoamide Ia from KI-1Bn

[0441]

[0442] Common steps from KI-1Bn

[0443] Coupling via acyl chloride

[0444] Model reaction: Synthesis of Ia-032a

[0445] Benzyl 4-(2,5-bis(benzyloxy)-4-(benzyloxycarbonyl)benzoylamino)phenylacetate. To a solution of KI-1Bn (233 mg, 84% purity) in DCM (10 mL) was added SOCl2 (1.8 mL, 60 eq), and the mixture was heated at 50 ° C for 3 h. The solvent was evaporated, and the residue was co-evaporated with toluene (3x10 mL) to give a crude acid chloride (237 mg, 99%). The substance was dissolved in DCM (3 mL), and diisopropylethylamine (0.08 mL, 1.15 eq) was added, followed by a solution of benzyl 4-aminophenylacetate (92 mg, 0.95 eq) in DCM (3 mL). The final reaction volume was 10 mL. The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with DCM (15 mL) and washed with a saturated aqueous solution of ammonium chloride (12 mL). The separated aqueous phase was extracted with DCM (2 x 2 mL), and the organic phases were combined, dried (MgSO 4 ), 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-0Bn and a second fraction containing pure desired product (237 mg, 86%, corrected for the purity of KI-1Bn).

[0446] 1 H NMR (400MHz, CDCl3): δ10.10(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).

[0447] 4-(4-(Carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid (Ia-032a). To a solution of the above-prepared precursor (225 mg, 0.33 mmol) in DCM (20 mL) was added 5% Pd / charcoal (72 mg), followed by EtOH (20 mL). The flask was flushed with Ar (3x) and then filled with hydrogen (atmospheric pressure), and the mixture was stirred at room temperature for 2 h. The catalyst was removed by filtration through a microporous filter, the filtrate was evaporated, and the residue was dried to give the product Ia-032a as a light yellow solid (107 mg, 99%).

[0448] 1 H NMR (250MHz, DMSO-d6): δ12.28(br,1H),10.92(s,1H),10.44(s,1H),7.65(brd,2H),7.41(s,1H),7.38(s,1H),7.25(br d,2H),3.55(s,2H).

[0449] For example:

[0450]

[0451]

[0452] Conditions and yields: see Figure 4A -D

[0453] 1) 4-(2-Carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-001a

[0454] UPLC-MS (acidic method, 2 min): rt = 0.95 min, m / z = 316 [MH] - , peak area>97%

[0455] 1 H NMR (400MHz, DMSO-d6) δ12.22(s,1H),10.85(s,1H),8.65(d,J=8.4Hz,1H),8.01(dd ,J=8.0,1.7Hz,1H),7.71–7.56(m,1H),7.41(d,J=6.9Hz,2H),7.22(t,J=7.6Hz,1H).

[0456] HRMS:[M+H] + ,C 15 H 12 NO7 calculated value: 318.06083, actual value: 318.06080.

[0457] Biological data: Ia-001a: FGF-1 IC50 [μM] = 41; FGF-2 IC50 [μM] = 39; VEGF-A1 IC50 [μM] = 7.3; VEGFR-phosphorylation inhibition IC50 [μM] = 2.25; PMN ROS inhibition [%] at 0.3 μM = 48; PMN ROS inhibition IC50 [μM] = 0.355; neutrophil adhesion 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; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.02; TNFβIC50[μM]=13.2

[0458] Diethyl ester:

[0459] UPLC-MS (acidic method, 2 min): rt = 1.39 min, m / z = 372.2 [MH] - , peak area>98%

[0460] 1 H NMR (400MHz, DMSO-d6) δ11.96(s,1H),11.05(s,1H),9.87(s,1H),8.57(dd,J=8.5,1.2Hz,1H),7.99(dd,J=7.9,1.7Hz,1 H),7.65(ddd,J=8.7,7.3,1.7Hz,1H),7.49(s,1H),7.40(s,1H),7.25(td,J=7.6,1.2Hz,1H),4.35(m,4H),1.33(m,6H).

[0461] HRMS:[M+H] + ,C 19 H 20Calculated value of NO7: 374.12342, actual value: 374.12354

[0462] Biodata: Ia-001a-E2: FGF-1 IC50 [μM] = 9.2; FGF-2 IC50 [μM] = 200; VEGF-A1 IC50 [μM] = 123; VEGFR-phosphorylation inhibition IC50 [μM] = 1.25; PMN ROS inhibition [%] = 51.47; PMN ROS inhibition IC50 [μM] = 2.58; Neutrophil adhesion inhibition [%] = 50.5

[0463] 2) 4-(2-(1H-tetrazol-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-001aTz:

[0464] UPLC-MS (acidic method, 4 min): rt = 1.17 min; m / z = 342.0 [M+H] + , peak area>96%

[0465] 1 H NMR (400MHz, DMSO-d6) δ11.60(s,1H),10.90(s,2H),8.47(d,J=8.4Hz,1H),7.93(d,J=7.9Hz,1H),7.61(t,J=7.9Hz,1H),7.50–7.32(m,3H).

[0466] HRMS:[M+H] + ,C 15 H 12 Calculated value of N5O5: 342.08329, Actual value: 342.08318

[0467] Biological data: Ia-001a-Tz: FGF-1 IC50 [μM] = 6.2; FGF-2 IC50 [μM] = 20; VEGF-A1 IC50 [μM] = 17; VEGFR-phosphorylation inhibition IC50 [μM] = 0.23; PMN ROS inhibition [%] at 0.3 μM = 54.33; PMN ROS inhibition IC50 [μM] = 1.54; neutrophil adhesion 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-33IC50[μM]=23.6; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.63; TNFβIC50[μM]=53

[0468] Ethyl ester:

[0469] UPLC-MS (acidic method, 2 min): rt = 1.08 min, m / z = 370.1 [M+H] + , peak area>97%

[0470] 1 H NMR (400MHz, DMSO-d6) δ11.48(s,1H),9.88(s,1H),8.46(d,J=8.4Hz,1H),7.89(dd,J=7.8,1.6Hz,1H),7.62 (ddd,J=8.6,7.4,1.6Hz,1H),7.47(s,1H),7.42–7.34(m,2H),4.37(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H).

[0471] HRMS:[M+H] + ,C 17 H 16 Calculated value of N5O5: 370.11460, actual value: 370.11458

[0472] Biodata: Ia-001a-Tz-E1: FGF-1 IC50 [μM] = 200; FGF-2 IC50 [μM] = 200; VEGF-A1 IC50 [μM] = 200; VEGFR-phosphorylation inhibition IC50 [μM] = 3.8; PMN ROS inhibition [%] at 0.3 μM = 75.97; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 98.88

[0473] Ethyl acetate:

[0474] UPLC-MS (acidic method, 4 min): rt = 1.57 min, m / z = 454.1 [M+H] + , peak area>97%

[0475] 1 H NMR (400MHz, DMSO-d6) δ11.23(s,1H),8.23(d,J=8.6Hz,1H),7.96(dd,J=7.9,1.7Hz,1H),7.84(s,1H),7.73(s,1H),7.6 4(t,J=7.5Hz,1H),7.43(td,J=7.6,1.2Hz,1H),4.32(q,J=7.1Hz,2H),2.34(s,3H),2.18(s,3H),1.32(t,J=7.1Hz,3H).

[0476] HRMS:[M+H] + ,C 21 H 20 Calculated value of N5O7: 454.13572, actual value: 454.13542

[0477] Biodata: Ia-001a-Tz-E1-A2: FGF-1 IC50 [μM] = 60; FGF-2 IC50 [μM] = 200; VEGF-A1 IC50 [μM] = 200; VEGFR-phosphorylation inhibition IC50 [μM] = ND; PMN ROS inhibition [%] = 49.85 at 0.3 μM; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 98.2

[0478] 3) 2,5-Dihydroxy-4-(2-sulfophenylaminocarbonyl)benzoic acid, compound Ia-001c:

[0479] UPLC-MS (acidic method, 2 min): rt = 0.73 min; m / z = 352.0 [MH] -, peak area>99%

[0480] 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H),10.99(s,1H),8.34(d,J=8.2Hz,1H),7.74(dd,J=7.7,1.7Hz,1H),7.42–7.28(m,3H),7.12(td,J=7.5,1.2Hz,1H).

[0481] HRMS:[M+H] + ,C 14 H 12 The calculated value of NO8S is 354.02781, and the actual value is 354.02754.

[0482] Biological data: Ia-001c: FGF-1 IC50 [μM] = 21; FGF-2 IC50 [μM] = 13; VEGF-A1 IC50 [μM] = 100; VEGFR-phosphorylation inhibition IC50 [μM] = 3.31; PMN ROS inhibition [%] at 0.3 μM = 40.36; PMNROS inhibition IC50 [μM] = 2.4; neutrophil adhesion 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; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.05; TNFβIC50[μM]=29.7

[0483] 4) 4-(3-Carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-002a:

[0484] 1H-NMR(250MHZ,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)

[0485] Biodata: 1a-002a: FGF-1 IC50 [μM] = 20; FGF-2 IC50 [μM] = 59; VEGF-A1 IC50 [μM] = 71; VEGFR-phosphorylation inhibition IC50 [μM] = 5.7; PMN ROS inhibition [%] at 0.3 μM = 42.1; PMN ROS inhibition IC50 [μM] = 0.312; Neutrophil adhesion inhibition [%] = 27.92

[0486] 5) 4-(3-(1H-tetrazol-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-002aTz:

[0487] UPLC-MS (acidic method, 4 min): rt = 1.13 min; m / z = 342.0 [M+H] + , peak area>99%

[0488] 1 H NMR(400MHz,DMSO-d6)δ10.81(s,1H),10.67(s,1H),8.54(s,1H),7.91–7.84(m ,1H),7.79(dt,J=7.8,1.4Hz,1H),7.60(t,J=7.9Hz,1H),7.41(d,J=2.2Hz,2H).

[0489] HRMS:[M+H] + ,C 15 H 12 Calculated value of N5O5: 342.08329, Actual value: 342.08317

[0490] 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

[0491] 6) 2,5-Dihydroxy-4-(3-sulfophenylaminocarbonyl)benzoic acid, compound Ia-002c:

[0492] 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)

[0493] 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 [%] = 38.9 at 0.3 μM; PMNROS inhibition IC50 [μM] = 0.405; Neutrophil adhesion inhibition [%] = 1.87

[0494] 7) 4-(4-Carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-003a:

[0495] 1 H-NMR(250MHz,DMSO-d6)δ12.8(br,1H),10.73(s,1H),10.68(s,1H),7.94(d ofAB,2H),7.84(d of AB,2H),7.39(s,1H),7.34(s,1H)

[0496] HRMS(AX033)

[0497] Biodata: Ia-003a: FGF-1 IC50 [μM] = 12; FGF-2 IC50 [μM] = 34; VEGF-A1 IC50 [μM] = 150; VEGFR-phosphorylation inhibition IC50 [μM] = ND; PMN ROS inhibition [%] at 0.3 μM = 44.4; PMN ROS inhibition IC50 [μM] = 0.414; Neutrophil adhesion inhibition [%] = 39.1

[0498] 8) 4-(4-(1H-tetrazol-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-003aTz:

[0499] UPLC-MS (acidic method, 2 min): rt = 0.79 min; m / z = 342.0 [M+H]+, peak area > 97%

[0500] 1H NMR (400MHz, DMSO-d6) δ10.77(s,1H),10.70(s,1H),8.04(d,J=8.7Hz,2H),7.96(d,J=8.5Hz,2H),7.41(s,1H),7.37(s,1H).

[0501] HRMS:[M+H] + ,C 15 H 12 Calculated value of N5O5: 342.08329, Actual value: 342.08326

[0502] Biological data: Ia-003a-Tz: FGF-1 IC50 [μM] = 6.7; FGF-2 IC50 [μM] = 45; VEGF-A1 IC50 [μM] = 13; VEGFR-phosphorylation inhibition IC50 [μM] = 6.4; PMN ROS inhibition [%] at 0.3 μM = 62.21; PMN ROS inhibition IC50 [μM] = 2.49; neutrophil adhesion 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-33IC50[μM]=72.2; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.18; TNFβIC50[μM]=55.

[0503] 9) 2,5-dihydroxy-4-(4-sulfophenylaminocarbonyl)benzoic acid, compound Ia-003c:

[0504] 1 H-NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.51 (s, 1H), 7.66 (AB d, 2H), 7.58 (AB d, 2H), 7.40 (s, 1H), 7.39 (s, 1H)

[0505] Biodata: Ia-003c: FGF-1 IC50 [μM] = 35; FGF-2 IC50 [μM] = 150; VEGF-A1 IC50 [μM] = 150; VEGFR-phosphorylation inhibition IC50 [μM] = 0.4; PMN ROS inhibition [%] at 0.3 μM = ND; PMNROS inhibition IC50 [μM] -; Neutrophil adhesion inhibition [%] = ND

[0506] 10) 4-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-004a:

[0507] UPLC-MS (acidic method, 6.5 min): rt = 1.40 min; m / z = 332.0 [MH] - , peak area>96%

[0508] 1 H NMR(400MHz,DMSO-d6)δ10.94(s,1H),10.37(s,1H),8.20(d,J=2.7Hz,1H),7 .74(dd,J=8.9,2.8Hz,1H),7.39(s,1H),7.34(s,1H),6.93(d,J=8.9Hz,1H).

[0509] HRMS:[M+H] + ,C 15 H 12 Calculated value of NO8: 334.05574, actual value: 334.05572

[0510] Biodata: Ia-004a: FGF-1 IC50 [μM] = 32; FGF-2 IC50 [μM] = 15; VEGF-A1 IC50 [μM] = 28; VEGFR-phosphorylation inhibition IC50 [μM] = 7.7; PMN ROS inhibition [%] at 0.3 μM = 64.61; PMN ROS inhibition IC50 [μM] = 0; Neutrophil adhesion inhibition [%] = 28.38

[0511] Ethyl methyl ester:

[0512] UPLC-MS (acidic method, 2 min): rt = 1.16 min, m / z = 376.1 [M+H] + , peak area>95%

[0513] 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H),10.50(s,1H),10.36(s,1H),9.91(s,1H),8.26(d,J=2.7Hz,1H),7.76(dd,J=8.9, 2.8Hz, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 7.01 (d, J = 8.9Hz, 1H), 4.37 (q, J = 7.1Hz, 2H), 3.91 (s, 3H), 1.34 (t, J = 7.1Hz, 3H).

[0514] HRMS:[M+H] + ,C 18 H 18 Calculated value of NO8: 376.10269, actual value: 376.10259

[0515] Biodata: Ia-004a-E2: FGF-1 IC50 [μM] = 35; FGF-2 IC50 [μM] = 36; VEGF-A1 IC50 [μM] = 200; VEGFR-phosphorylation inhibition IC50 [μM] = 6.1; PMN ROS inhibition [%] at 0.3 μM = 85.34; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 97.65

[0516] 11) 4-(2-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-006a:

[0517] UPLC-MS (acidic method, 2 min): rt = 0.81 min; m / z = 334.0 [M+H] + , peak area>96%

[0518] 1 H NMR(400MHz,DMSO-d6)δ13.33(s,1H),11.86(s,1H),10.90(s,1H),9.66(s,1 H), 8.39 (d, J = 9.0Hz, 1H), 7.40 (d, J = 6.8Hz, 2H), 7.03 (dd, J = 9.0, 3.0Hz, 1H).

[0519] HRMS:[M+H] + ,C 15 H 12 The calculated value of NO8 is 334.05574, and the actual value is 334.05562.

[0520] Biodata: Ia-006a: FGF-1 IC50 [μM] = 89; FGF-2 IC50 [μM] = 224; VEGF-A1 IC50 [μM] = 100; VEGFR-phosphorylation inhibition IC50 [μM] = 11.8; PMN ROS inhibition [%] at 0.3 μM = 60.56; PMNROS inhibition IC50 [μM] = 1.2; Neutrophil adhesion inhibition [%] = 25.33

[0521] 12) 3-(4-carboxy-2,5-dihydroxybenzamido)phthalic acid, compound Ia-011a:

[0522] UPLC-MS (acidic method, 2 min): rt = 0.69 min; m / z = 360.1 [MH] - , peak area>89%

[0523] 1 H NMR (400MHz, DMSO-d6) δ13.46(s,2H),11.37(s,1H),10.97(s,1H),8.33(dd,J=8.2,1. 3Hz, 1H), 7.63 (dd, J = 7.7, 1.3Hz, 1H), 7.57 (t, J = 7.9Hz, 1H), 7.52 (s, 1H), 7.44 (s, 1H).

[0524] HRMS:[M+H] + ,C 16 H 12 Calculated value of NO9: 362.05065, actual value: 362.05036

[0525] Biodata: Ia-011a: FGF-1 IC50 [μM] = 35; FGF-2 IC50 [μM] = 110; VEGF-A1 IC50 [μM] = 200; VEGFR-phosphorylation inhibition IC50 [μM] = 100; PMN ROS inhibition [%] = 57.71 at 0.3 μM; PMNROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 42.32

[0526] 13) 2-(4-carboxy-2,5-dihydroxybenzamido)terephthalic acid, compound Ia-012a:

[0527] UPLC-MS (acidic method, 4 min): rt = 1.12 min; m / z = 362.1 [M+H] + , peak area>96%

[0528] 1H NMR(400MHz,DMSO-d6)δ13.41(brs,2H),12.29(s,1H),10.94(s,1H),9.26(d, J=1.7Hz, 1H), 8.09 (d, J=8.2Hz, 1H), 7.73 (dd, J=8.2, 1.7Hz, 1H), 7.42 (s, 2H).

[0529] HRMS:[M+H] + ,C 16 H 12 The calculated value of NO9: 362.05065, the actual value: 362.05046.

[0530] Biodata: Ia-012a: FGF-1 IC50 [μM] = 38; FGF-2 IC50 [μM] = 36; VEGF-A1 IC50 [μM] = 30; VEGFR-phosphorylation inhibition IC50 [μM] = 100; PMN ROS inhibition [%] = 59.52 at 0.3 μM; PMN ROS inhibition IC50 [μM] = 1.85; Neutrophil adhesion inhibition [%] = 28.5

[0531] 14) 2-(4-carboxy-2,5-dihydroxybenzamido)isophthalic acid, compound Ia-013a:

[0532] UPLC-MS (acidic method, 4 min): rt = 0.91 min; m / z = 362.0 [M+H] + , peak area>98%

[0533] 1 H NMR (400MHz, DMSO-d6) δ13.11(s,2H),11.70(s,1H),11.13(s,1H),7.97(d,J=7.8Hz,2H),7.47(s,1H),7.41(s,1H),7.38(t,J=7.7Hz,1H)

[0534] HRMS:[M+H] + ,C 16 H 12 Calculated value of NO9: 362.05065, actual value: 362.05041

[0535] Biodata: Ia-013a: FGF-1 IC50 [μM] = 29; FGF-2 IC50 [μM] = 18; VEGF-A1 IC50 [μM] = 17; VEGFR-phosphorylation inhibition IC50 [μM] = 100; PMN ROS inhibition [%] = 38.52 at 0.3 μM; PMN ROS inhibition IC50 [μM] = 2.38; Neutrophil adhesion inhibition [%] = 27.67

[0536] 15) 4-(4-carboxy-2,5-dihydroxybenzamido)phthalic acid, compound Ia-014a:

[0537] UPLC-MS (acidic method, 4 min): rt = 0.98 min; m / z = 362.1 [M+H] + , peak area>94%

[0538] 1 H NMR (400MHz, DMSO-d6) δ10.76(s,1H),10.70(s,1H),8.14(s,1H),7.94–7.84(m,2H),7.38(s,1H),7.30(s,1H).

[0539] HRMS:[M+H] + ,C 16 H 12 Calculated value of NO9: 362.05065, actual value: 362.05047

[0540] 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 [%] = 61.3 at 0.3 μM; PMN ROS inhibition IC50 [μM] = 1; Neutrophil adhesion inhibition [%] = 9.667

[0541] 16) 5-(4-carboxy-2,5-dihydroxybenzamido)isophthalic acid, compound Ia-015a:

[0542] 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)

[0543] Biological data: Ia-015a: FGF-1 IC50 [μM] = 20; FGF-2 IC50 [μM] = 9.3; VEGF-A1 IC50 [μM] = 19; VEGFR-phosphorylation inhibition IC50 [μM] = 0.15; PMN ROS inhibition [%] at 0.3 μM = 43.8; PMNROS inhibition IC50 [μM] = 0.387; neutrophil adhesion 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-33IC50[μM]=0.24; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.17; TNFβIC50[μM]=0.3.

[0544] 17) 3-(4-carboxy-2,5-dihydroxybenzamido)isonicotinic acid, compound Ia-023a:

[0545] UPLC-MS (acidic method, 4 min): rt = 0.63 min; m / z = 319.1 [M+H] + , peak area>93%

[0546] 1 H NMR (400MHz, DMSO-d6) δ12.17(s,1H),11.03(s,1H),9.78(s,1H),8.46(d,J=5.0Hz,1H),7.82(d,J=5.0Hz,1H),7.45(s,1H),7.43(s,1H).

[0547] HRMS:[M+H] + ,C 14 H 11 Calculated value of N2O7: 319.05608, Actual value: 319.05610

[0548] Biodata: Ia-023a: FGF-1 IC50 [μM] = ND; FGF-2 IC50 [μM] = 63; VEGF-A1 IC50 [μM] = 143; VEGFR-phosphorylation inhibition IC50 [μM] = 100; PMN ROS inhibition [%] at 0.3 μM = 61.95; PMNROS inhibition IC50 [μM] = 0; Neutrophil adhesion inhibition [%] = 13.37

[0549] Diethyl ester:

[0550] UPLC-MS (acidic method, 4 min): rt = 1.87 min, m / z = 375.1 [M+H] + , peak area>98%

[0551] 1 H NMR (400MHz, DMSO-d6) δ11.79(s,1H),11.23(s,1H),9.87(s,1H),9.68(s,1H),8.50(d,J=5.0Hz, 1H),7.81(dd,J=5.1,0.7Hz,1H),7.53(s,1H),7.41(s,1H),4.46–4.27(m,4H),1.41–1.25(m,6H).

[0552] HRMS:[M+H] + ,C 18 H 19 Calculated value of N2O7: 375.11867, Actual value: 375.11867

[0553] 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

[0554] 18) 4-(4-(Carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-032a:

[0555] 1H NMR (250MHz, DMSO-d6): δ12.28(br,1H),10.92(s,1H),10.44(s,1H),7.65(brd,2H),7.41(s,1H),7.38(s,1H),7.25(br d,2H),3.55(s,2H).

[0556] 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; PMNROS inhibition IC50 [μM] -; Neutrophil adhesion inhibition [%] = ND

[0557] 19) 4-(3-(Carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-033a:

[0558] UPLC-MS (acidic method, 6.5 min): rt = 1.71 min; m / z = 332.1 [M+H] + , peak area>99%

[0559] 1 H NMR(400MHz,DMSO-d6)δ10.89(s,1H),10.46(s,1H),7.65(s,1H),7.59(d,J =8.1Hz,1H),7.40(s,1H),7.38(s,1H),7.03(d,J=7.6Hz,1H),3.57(s,2H).

[0560] HRMS:[M+H] + ,C 16 H 14 Calculated value of NO7: 332.07647, actual value: 332.07644

[0561] Biodata: Ia-033a: FGF-1 IC50 [μM] = 60; FGF-2 IC50 [μM] = 165; VEGF-A1 IC50 [μM] = 281; VEGFR-phosphorylation inhibition IC50 [μM] = 100; PMN ROS inhibition [%] = 57.73 at 0.3 μM; PMNROS inhibition IC50 [μM] = 1.32; Neutrophil adhesion inhibition [%] = 38

[0562] 20) 4-(2-(Carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-034a:

[0563] UPLC-MS (acidic method, 2 min): rt = 0.82 min; m / z = 332.1 [M+H] + , peak area>98%

[0564] 1 H NMR (400MHz, DMSO-d6) δ7.78 (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).

[0565] HRMS:[M+H] + ,C 16 H 14 Calculated value of NO7: 332.07648, actual value: 332.07641

[0566] Biodata: Ia-034a: FGF-1 IC50 [μM] = 79; FGF-2 IC50 [μM] = 14; VEGF-A1 IC50 [μM] = 102; VEGFR-phosphorylation inhibition IC50 [μM] = 100; PMN ROS inhibition [%] at 0.3 μM = 49.07; PMNROS inhibition IC50 [μM] = 2.28; Neutrophil adhesion inhibition [%] = 15

[0567] 21) 4-(3,4-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-035a:

[0568] UPLC-MS (acidic method, 2 min): rt = 1.02 min; m / z = 320.1 [M+H] + , peak area>91%

[0569] 1 H NMR (400MHz, DMSO-d6) δ11.56(s,1H),9.21(t,J=5.9Hz,1H),8.91(s,1H),8.79(s,1H),7.46(s,1H),7.28 (s, 1H), 6.72 (d, J = 2.1Hz, 1H), 6.67 (d, J = 8.0Hz, 1H), 6.57 (dd, J = 8.0, 2.1Hz, 1H), 4.32 (d, J = 5.8Hz, 2H).

[0570] HRMS:[M+H] + ,C 15 H 14Calculated value of NO7: 320.07648, actual value: 320.07650

[0571] Biodata: Ia-035a: FGF-1 IC50 [μM] = 20; FGF-2 IC50 [μM] = 71; VEGF-A1 IC50 [μM] = 200; VEGFR-phosphorylation inhibition IC50 [μM] = 36; PMN ROS inhibition [%] = 75.13; PMN ROS inhibition IC50 [μM] = 0.41; Neutrophil adhesion inhibition [%] = 27

[0572] 22) 4-(2-(3,4-dihydroxyphenyl)ethylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-035a-2:

[0573] UPLC-MS (acidic method, 2 min): rt = 0.77 min; m / z = 332.0 [MH] - , peak area>99%

[0574] 1 H NMR (400MHz, DMSO-d6) δ11.50(s,1H),8.85(t,J=5.6Hz,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=8.0,2.1Hz,1H),3.44(q,J=6.8Hz,2H),2.67(dd,J=8.6 ,6.0Hz,2H).δ11.56(s,1H),9.21(t,J=5.9Hz,1H),8.91(s,1H),8.79(s,1H),7.46(s,1H),7.28(s,1 H), 6.72 (d, J = 2.1Hz, 1H), 6.67 (d, J = 8.0Hz, 1H), 6.57 (dd, J = 8.0, 2.1Hz, 1H), 4.32 (d, J = 5.8Hz, 2H).

[0575] HRMS:[M+H] + ,C 16 H 16 Calculated value of NO7: 334.09213, actual value: 334.09242

[0576] Biodata: Ia-035a-2: FGF-1 IC50 [μM] = 10; FGF-2 IC50 [μM] = 65; VEGF-A1 IC50 [μM] = 109; VEGFR-phosphorylation inhibition IC50 [μM] = 10; PMN ROS inhibition [%] = 58.81 at 0.3 μM; PMNROS inhibition IC50 [μM] = 1.1; Neutrophil adhesion inhibition [%] = 21.5

[0577] 23) 4-(1-carboxy-2-(3,4-dihydroxyphenyl)ethylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-035a-3:

[0578] UPLC-MS (acidic method, 2 min): rt = 0.70 min; m / z = 376.0 [MH] - , peak area>99%

[0579] 1 H NMR (400MHz, DMSO-d6) δ12.90(s,1H),11.11(s,1H),8.98(d,J=7.4Hz,1H),8.73(d,J=13.1Hz,2H),7.45(s,1H),7.3 1(s,1H),6.61(dd,J=5.1,2.9Hz,2H),6.47(dd,J=8.1,2.1Hz,1H),3.01(dd,J=13.9,4.9Hz,1H),2.96–2.84(m,1H).

[0580] HRMS:[M+H] + ,C 17 H 16 Calculated value of NO9: 378.08196, actual value: 378.08195

[0581] 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 [%] = 79.62 at 0.3 μM; PMN ROS inhibition IC50 [μM] = 0.66; Neutrophil adhesion inhibition [%] = 22

[0582] 24) 4-(Carboxy(3,4-dihydroxyphenyl)methylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-036a:

[0583] UPLC-MS (acidic method, 2 min): rt = 0.62 min; m / z = 362.1 [MH] - , peak area>92%

[0584] 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.32(d,J=6.7Hz,1H),9.05(s,1H),8.97(s,1H),7 .40(s,1H),7.34(s,1H),6.81(d,J=2.1Hz,1H),6.75–6.64(m,2H),5.29(d,J=6.6Hz,1H).

[0585] HRMS:[M+H] + ,C 16 H 14 Calculated value of NO9: 364.06630, actual value: 364.06615

[0586] Biodata: Ia-036a: FGF-1 IC50 [μM] = ND; FGF-2 IC50 [μM] = 37; VEGF-A1 IC50 [μM] = 123; VEGFR-phosphorylation inhibition IC50 [μM] = 1.6; PMN ROS inhibition [%] at 0.3 μM = 87.17; PMNROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 30.77

[0587] 25) 4-(2-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-053a:

[0588] UPLC-MS (acidic method, 4 min): rt = 1.08 min; m / z = 332.0 [M+H] + , peak area>97%

[0589] 1 H NMR (400MHz, DMSO-d6) δ13.09(s,1H),11.19(s,1H),9.34–9.27(m,1H),7.91(dd,J=7.8,1.4Hz,1H),7.55(d d,J=7.5,1.5Hz,1H),7.46(d,J=7.9Hz,2H),7.39(td,J=7.5,1.4Hz,1H),7.32(s,1H),4.82(d,J=5.9Hz,2H).

[0590] HRMS:[M+H] + ,C 16 H14 Calculated value of NO7: 332.07648, actual value: 332.07622

[0591] 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; PMNROS inhibition IC50 [μM] = 2.5; Neutrophil adhesion inhibition [%] = 18.67

[0592] Scheme 4b. Synthesis of ethyl 4-amino-2,5-dibenzyloxybenzoate (aniline A)

[0593]

[0594] Scheme: Synthesis of Aniline A

[0595] 4-amino-2,5-dibenzyloxybenzoic acid ethyl ester (aniline A). Under an inert atmosphere (N2), DPPA (1.1 mL, 5.2 mmol) was slowly added to a cooling solution (ice bath) of 2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid (KI-1) (2.0 g, 4.9 mmol) and Et3N (1.6 mL, 11.3 mmol) in THF (25 mL). The mixture was slowly heated to rt 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, then extracted with EtOAc (3x100 mL). The combined organic layer was 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 afford the title compound aniline A as an off-white solid (1.0 g, 53%).

[0596] UPLC-MS (acidic method, 2 min): rt = 1.26 min; m / z = 378.2 [M+H] + , peak area 94%

[0597] 1H NMR(400MHz,DMSO-d6)δ7.54–7.46(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 = 7.1Hz, 2H), 1.22 (t, J = 7.1Hz, 3H).

[0598] 26) 4-(4-carboxy-2,5-dihydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound Ia-056a:

[0599] UPLC-MS (acidic method, 4 min): rt = 0.90 min; m / z = 348.0 [MH]-, peak area 97%

[0600] 1H NMR (400MHz, DMSO-d6) δ11.28(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).

[0601] Diethyl ester:

[0602] UPLC-MS (acidic method, 4 min): rt = 1.86 min; m / z = 404.2 [MH] - , peak area 92%

[0603] 1 H NMR(400MHz,DMSO-d6)δ11.48(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).

[0604] Example 1.2-Ib type molecules: diamides from diamines, 1 example

[0605]

[0606] Scheme 5. Synthesis of Type Ib Diamide

[0607]

[0608] Synthesis steps: See general steps, steps [3], [4], [5]

[0609] Example:

[0610]

[0611] Conditions and yields: see Figure 4A -D

[0612] 27) 3,5-bis(2,5-dihydroxy-4-carboxybenzoylamino)benzoic acid, compound Ib-010a:

[0613] UPLC-MS (acidic method, 4 min): rt = 0.98 min; m / z = 511.0 [MH] - , peak area>93%

[0614] 1 H NMR (400MHz, DMSO-d6) δ10.81 (s, 2H), 10.65 (s, 2H), 8.38 (d, J = 2.0Hz, 1H), 8.12 (d, J = 2.0Hz, 2H), 7.39 (d, J = 2.3Hz, 4H).

[0615] HRMS:[M+H] + ,C 23 H 17 N2O 12 Calculated value: 513.07760, actual value: 513.07736,

[0616] Biological data: Ib-010a: FGF-1 IC50 [μM] = 14; FGF-2 IC50 [μM] = 3.8; VEGF-A1 IC50 [μM] = 15; VEGFR-phosphorylation inhibition IC50 [μM] = 1.6; PMN ROS inhibition [%] = 71.84 at 0.3 μM; PMNROS inhibition IC50 [μM] = 1.06; neutrophil adhesion 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; IL-13 IC50[μM]=>100; IL-17A 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; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.31; TNFβIC50[μM]=49.3

[0617] Triethyl ester:

[0618] UPLC-MS (acidic method, 2 min): rt = 1.29 min, m / z = 597.1 [M+H] + , peak area>96%

[0619] 1 H NMR (400MHz, DMSO-d6) δ10.80(s,2H),10.68(s,2H),9.95(s,2H),8.40(t,J=2.0Hz,1H) ,8.15(d,J=2.0Hz,2H),7.42(s,2H),7.39(s,2H),4.42–4.33(m,6H),1.38–1.33(m,9H).

[0620] HRMS:[M+H] + ,C 29 H 29 N2O 12 Calculated value: 597.17150, found: 597.17131

[0621] Biological data: Ib-010a-E3: FGF-1 IC50 [μM] = 26; FGF-2 IC50 [μM] = 226; VEGF-A1 IC50 [μM] = 200; VEGFR-phosphorylation inhibition IC50 [μM] = 0.09; PMN ROS inhibition [%] at 0.3 μM = 36.41; PMN ROS inhibition IC50 [μM] = 6.52; neutrophil adhesion 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; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.98; TNFβIC50[μM]=38.2.

[0622] Triethyl tetraacetate:

[0623] UPLC-MS (acidic method, 2 min): rt = 1.19 min, m / z = 782.1 [M+NH4] + , peak area 91%

[0624] 1 H NMR (400MHz, DMSO-d6) δ10.84 (s, 2H), 8.40 (m, 1H), 8.08 (d, J = 2.0Hz, 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).

[0625] 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 [%] = 54.86 at 0.3 μM; PMN ROS inhibition IC50 [μM] = 1.49; Neutrophil adhesion inhibition [%] = 96

[0626] Example 1.3. Type Ic molecules: diamides from diacids, 4 examples

[0627]

[0628] Scheme 6. Synthesis of amides of type Ic with R=R'

[0629]

[0630] Steps: Refer to the general steps of KI-6 [3], [4], [5]

[0631] Example:

[0632]

[0633] Conditions and yields: see Figure 4A -D

[0634] 28) N1,N4-bis(2-(1H-tetrazol-5-yl)phenyl)-2,5-dihydroxyterephthalamide, compound Ic-001aTz2:

[0635] UPLC-MS (acidic method, 2 min): rt = 0.97 min; m / z = 485.1 [M+H] + , peak area>97%

[0636] 1 H NMR (400MHz, DMSO-d6) δ11.53(s,1H),10.98(s,1H),8.49(dd,J=8.4,1.2Hz,1H),7.90(dd,J= 7.8, 1.6Hz, 1H), 7.62 (ddd, J=8.7, 7.4, 1.6Hz, 1H), 7.58 (s, 1H), 7.37 (td, J=7.6, 1.2Hz, 1H).

[0637] HRMS:[M+H] + ,C 22 H 17 N 10Calculated value of O4: 485.14287, Actual value: 485.17274

[0638] Biological data: Ic-001aTz2: FGF-1 IC50 [μM] = 200; FGF-2 IC50 [μM] = 70; VEGF-A1 IC50 [μM] = 45; VEGFR-phosphorylation inhibition IC50 [μM] = 2.2; PMN ROS inhibition [%] at 0.3 μM = 60.64; PMN ROS inhibition IC50 [μM] = ND; neutrophil adhesion 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-10IC50[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; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.1; TNFβIC50[μM]=0.41.

[0639] 29) 5-(4-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid, compound Ic-007a:

[0640] UPLC-MS (acidic method, 2 min): rt = 0.80 min; m / z = 469.1 [M+H] + , peak area>91%

[0641] 1 H NMR (400MHz, DMSO-d6) δ8.08 (s, 2H), 7.65 (s, 2H), 7.59 (s, 2H), 7.30–6.89 (m, 5H), 6.79 (d, J = 8.8Hz, 2H).

[0642] 13C NMR (100MHz, DMSO-d6) δ172.1,165.2,158.3,150.1,130.2,129.2(CH),122.8,122.6(CH),117.7(CH),117.3(CH),113.3.

[0643] HRMS:[M+H] + ,C 22 H 17 N2O 10 Calculated value: 469.08777, actual value: 469.08739

[0644] Biological data: Ic-007a: FGF-1 IC50 [μM] = 13; FGF-2 IC50 [μM] = 5.4; VEGF-A1 IC50 [μM] = 3.2; VEGFR-phosphorylation inhibition IC50 [μM] = 0.09; PMN ROS inhibition [%] = 57.99 at 0.3 μM; PMNROS inhibition IC50 [μM] = 2.7; neutrophil adhesion 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; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.27; TNFβIC50[μM]=6.52

[0645] Dimethyl ester:

[0646] UPLC-MS (acidic method, 2 min): rt = 1.13 min, m / z = 497.0 [M+H] + , peak area>95%

[0647] 1H NMR (400MHz, DMSO-d6) δ11.08(s,2H),10.48(s,2H),10.38(s,2H),8.27(d,J=2 .8Hz,2H),7.89–7.74(m,2H),7.56(s,2H),7.03(d,J=8.9Hz,2H),3.93(s,6H).

[0648] HRMS:[M+H] + ,C 24 H 21 N2O 10 Calculated value: 497.11907, actual value: 497.11874.

[0649] 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

[0650] Alternative, large-scale synthesis of Ic-007a

[0651] a) 5-(4-(3-methoxycarbonyl-4-hydroxyphenylaminocarbonyl)-2,5-dibenzyloxybenzamido)-2-hydroxybenzoic acid methyl ester

[0652] 2,5-Bis(benzyloxy)terephthalic acid (KI-6, 141.00 g, 0.373 mol), benzyltriethylammonium chloride (850 mg, 3.73 mmol, 0.01 eq), and chloroform (2.5 L) were placed in a 5 L flanged flask. This flask was then equipped with a nitrogen inlet, a thermometer, a pressure-equalizing dropping funnel, an outlet for a blank Dreschel bottle, and a sodium hydroxide bubbler. The stirred solution was heated to 55°C, and thionyl chloride (59 mL, 0.802 mol, 2.15 eq) was added dropwise over 40 min. The solution was maintained at 55°C for 6 h and then cooled to room temperature overnight. An aliquot was sonicated in ethanol for 5 min and then analyzed by LCMS, which revealed only the diethyl ester. The mixture was transferred to two round-bottom flasks, and the volatiles were removed in vacuo; the acid chloride was azeotroped with toluene (800 mL in each flask). Methyl 5-amino-2-hydroxybenzoate (137.00 g, 0.819 mol, 2.2 eq) and dichloromethane (2.5 L, 18 vol) were added to a 10-L jacketed vessel; the solution was cooled to 15°C. The acid chloride was taken up 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; in addition, the reaction 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 h. The suspension was filtered, washed with dichloromethane (2 L, 14 vol), and the resulting solid was dried in a vacuum oven to yield 240.00 g of product (94% yield).

[0653] b) 5-(4-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid, Ic-007a

[0654] Saponification: A 5 L 3-necked round-bottom flask was charged with freshly ground methyl 5-(4-(3-methoxycarbonyl-4-hydroxyphenylaminocarbonyl)-2,5-dibenzyloxybenzamido)-2-hydroxybenzoate (150.00 g, 0.22 mol) and isopropyl alcohol (1.5 L, 10 volumes). The mixture was heated to 50°C, and tetrabutylammonium hydroxide (444 mL, 0.67 mol, 3 eq) and water (1.1 L, 7 volumes) were added. After 1 h, some solids remained, so an additional 60 mL of tetrabutylammonium hydroxide solution and water (120 mL) were added, 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 stirred at 60°C for an additional 1 h until no solids remained.

[0655] Hydrogenolysis: The reaction was degassed (3 cycles with N2) and the catalyst (30.00 g, 10% Pd / C) was added as a slurry in water (100 mL). The reaction was further degassed (3 cycles with N2 and 2 cycles with H2) and placed under H2 (balloon pressure) at 50°C overnight. Additional hydrogen was added to the reaction and maintained at 50°C for an additional 4 hours, after which LCMS analysis showed that the reaction was complete. The reaction mixture was degassed (3 cycles with N2), filtered through a pad of celite, and washed with warm water / isopropanol (1 L, 1:1, 60°C). The volume was reduced to ~1.2 L under vacuum. The mixture was transferred to a 5 L flanged flask containing water (~3 L). The flask was equipped with an overhead stirrer (large anchor type) and acidified with hydrochloric acid (35%). During the addition, a large amount of precipitate was formed. 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) and heated to 50° C. for 3 h, 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 which was still contaminated with ~5 mol % tetrabutylammonium salt (NMR). The solid was stirred in 1M aqueous hydrochloric acid (3 L) at 70° C. for 8 h, then allowed to cool to room temperature overnight. The solid was filtered, washed with water, and dried in a vacuum oven. The amount of tetrabutylammonium was reduced to ~0.62 mol % (85.90 g, 82% yield) (brown powder).

[0656] 30) 2-(2,5-dihydroxy-4-(4-hydroxy-2-carboxyphenylaminocarbonyl)benzamido)-5-hydroxybenzoic acid, compound Ic-009a:

[0657] UPLC-MS (acidic method, 2 min): rt = 0.85 min; m / z = 469.0 [M+H] + , peak area>98%

[0658] 1 H NMR(400MHz,DMSO-d6)δ13.31(s,2H),11.93(s,2H),10.85(s,2H),9.64(s,2H),8.4 1(d,J=9.0Hz,2H),7.55(s,2H),7.39(d,J=3.0Hz,2H),7.03(dd,J=9.0,3.0Hz,2H).

[0659] HRMS:C 22 H 17 N2O 10 Calculated value: 469.08777, actual value: 469.08755

[0660] Biodata: Ic-009a: FGF-1 IC50 [μM] = 32; FGF-2 IC50 [μM] = 202; VEGF-A1 IC50 [μM] = 208; VEGFR-phosphorylation inhibition IC50 [μM] = ND; PMN ROS inhibition [%] at 0.3 μM = 72.85; PMNROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 72.21

[0661] Dimethyl ester:

[0662] UPLC-MS (acidic method, 2 min): rt = 1.03 min, m / z = 497.1 [M+H] + , peak area>92%

[0663] 1 H NMR (400MHz, DMSO-d6) δ11.69(s,2H),11.01(s,2H),9.75(s,2H),8.36(d,J=9.0Hz ,2H),7.62(s,2H),7.37(d,J=3.0Hz,2H),7.07(dd,J=9.0,3.0Hz,2H),3.87(s,6H).

[0664] HRMS:C 24 H 21 N2O 10 Calculated value: 497.11907, actual value: 497.11913

[0665] 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

[0666] Scheme 7. Synthesis of amides of type Ic with R≠R'

[0667]

[0668] Synthesis steps: refer to the general steps of KI-1.

[0669] Example:

[0670]

[0671]

[0672] Conditions and yields: see Figure 4A -D

[0673] 31) 5-(4-(2-(1H-tetrazol-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid, compound Ic-001aTz / 004a:

[0674] UPLC-MS (acidic method, 4 min): rt = 1.40 min; m / z = 477.2 [MH] - , peak area>99%

[0675] 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),10.42(s,1H),8.47(dd,J=8.4,1.2Hz,1H),8.25(d,J=2.7Hz,1H),7.98–7.88(m ,1H),7.76(dd,J=8.9,2.8Hz,1H),7.63–7.56(m,2H),7.51(s,1H),7.37(td,J=7.6,1.2Hz,1H),6.97(d,J=8.9Hz,1H).

[0676] HRMS:[M+H] + ,C 22 H 17 Calculated value of N6O7: 477.11532, Actual value: 477.11475

[0677] Biodata: Ic-001a-Tz / 004a: FGF-1 IC50 [μM] = 19; FGF-2 IC50 [μM] = 87; VEGF-A1 IC50 [μM] = 25; VEGFR-phosphorylation inhibition IC50 [μM] = 2.6; PMN ROS inhibition [%] at 0.3 μM = 82.83; PMN ROS inhibition IC50 [μM] = ND; neutrophil adhesion 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; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.002; TNFβIC50[μM]=3.02

[0678] Methyl ester:

[0679] UPLC-MS (acidic method, 2 min): rt = 1.06 min, m / z = 491.1 [M+H] + , peak area>89%

[0680] 1 H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.90(s,1H),10.45(s,1H),10.37(s,1H ),8.47(dd,J=8.4,1.2Hz,1H),8.30(d,J=2.7Hz,1H),7.91(dd,J=7.8,1.6Hz,1 H),7.76(dd,J=8.9,2.7Hz,1H),7.63(ddd,J=8.7,7.4,1.6Hz,1H),7.58(s,1H) ,7.51(s,1H),7.38(td,J=7.6,1.2Hz,1H),7.02(d,J=8.8Hz,1H),3.93(s,4H).

[0681] HRMS:[M+H]+ ,C 23 H 19 Calculated value of N6O7: 491.13097, Actual value: 491.13071

[0682] Biodata: Ic-001a-Tz / 004a-E1: FGF-1 IC50 [μM] = 104; FGF-2 IC50 [μM] = 200; VEGF-A1 IC50 [μM] = 35; VEGFR-phosphorylation inhibition IC50 [μM] = 0.1; PMN ROS inhibition [%] at 0.3 μM = 73.97; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 97.56

[0683] Example 1.4. Id-type molecules: benzimidazole-linked, 1 example

[0684]

[0685] Scheme 8. Synthesis of Type Id Compounds

[0686]

[0687] Synthesis steps: See the general steps of KI-1 [3], [4], [5]

[0688] Cyclization step: see Figure 4A -D

[0689] Example:

[0690]

[0691] 32) 2-(4-Carboxy-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid, compound Id-030a:

[0692] UPLC-MS (acidic method, 4 min): rt = 0.99 min; m / z = 313.1 [MH] - , peak area>97%

[0693] 1 H NMR (400MHz, DMSO-d6) δ8.10(d,J=8.2Hz,1H),8.05(d,J=7.7Hz,1H),7.80(s,1H),7.68(t,J=8.0Hz,1H),7.62(s,1H)

[0694] Biodata - unstable in DMSO

[0695] Ethyl methyl ester:

[0696] UPLC-MS (acidic method, 4 min): rt = 2.09 min, m / z = 357.1 [M+H] + , peak area>89%

[0697] 1 H NMR(400MHz,DMSO-d6+D2O 10%) δ7.97(d,J=8.0Hz,1H),7.90–7.83(m,2H),7.44–7.36(m,2H),4.35(q,J=7.1Hz,2H),3.94(s,3H),1.33(t,J=7.1Hz,3H).

[0698] HRMS:[M+H] + ,C 18 H 17 Calculated value of N2O6: 357.10811, actual value: 357.10827

[0699] 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; PMNROS inhibition IC50 [μM] = 0; Neutrophil adhesion inhibition [%] = 43

[0700] Example 1.5: Type IIa molecules: monoamides, 16 examples

[0701]

[0702] Synthesis of precursors

[0703] Scheme 9a. Synthesis of intermediates KI-2 and KI-7

[0704]

[0705] step:

[0706] Synthesis of KI-2 and KI-7

[0707] 2,6-bis(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 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 temperature over 30 min. After 2 h, the reaction was complete, and the mixture was cooled to room temperature and then added by Filter; wash the solid residue with THF (200 mL) and then remove the solvent under reduced pressure. The crude product is purified by flash column chromatography (hexane / EtOAc 0 to 20%) to give the title compound (9.3 g, 37% yield).

[0708] UPLC-MS (acidic method, 2 min): rt = 1.01 min; m / z = 257.1 [M+H] - , peak area>74%

[0709] 1 H NMR (400 MHz, DMSO-d6) enol and complex mixture of 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).

[0710] Diethyl 2,5-dihydroxyisophthalate [Step 2]: [Scheme taken from Zhong et al.: Chem Eur. J. 25 (2019) 8177-8169]: To a stirred solution of 2,6-bis(ethoxycarbonyl)-cyclohexane-1,4-dione (5.0 g, 20 mmol) in AcOH (17 mL) was added NBS (3.5 g, 20 mmol) in portions over 30 min at room temperature. After another 20 min, water (100 ml) was added to quench the reaction. The isolated desired product was a solid. After filtration and drying, the title compound (4.6 g, 93% yield) was isolated as a white solid.

[0711] UPLC-MS (acidic method, 2 min): rt = 1.00 min; m / z = 253.1 [MH] - , peak area>90%

[0712] 1H NMR (400MHz, DMSO-d6) δ 10.85 (s, 1H), 9.57 (s, 1H), 7.39 (s, 2H), 4.32 (q, J = 7.1Hz, 4H), 1.31 (t, J = 7.1Hz, 6H).

[0713] 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 hours. 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 (3x250 mL), and the collected organic layer was washed with brine (300 mL), dried over Na2SO4, filtered, and then concentrated under reduced pressure. The crude material was purified by flash column chromatography (hexane / EtOAc 0 to 15%) to give the title compound (29.4 g, 90% yield).

[0714] UPLC-MS (acidic method, 2 min): rt = 1.38 min; m / z = 435.2 [M+H] + , peak area>90%

[0715] 1 H NMR(400MHz,DMSO-d6)δ7.50(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=7.1Hz,4H),1.22(t,J=7.1Hz,6H).

[0716] 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 quickly 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. 1,4-dioxane was removed under reduced pressure, and then a saturated aqueous solution of Na2CO3 (1 L) was added. The aqueous layer was extracted with EtOAc (3 x 500 mL), dried over Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified by filtration through a pad of silica gel using hexane / EtOAc (1 / 1) and then EtOAc (1% v / v AcOH) as eluents to give two different fractions:

[0717] Starting material: diethyl 2,5-bis(benzyloxy)isophthalate (20.4 g, 65% yield).

[0718] UPLC-MS (acidic method, 2 min): rt = 1.38 min; m / z = 435.2 [M+H] + , peak area>78%

[0719] 1 H NMR(400MHz,DMSO-d6)δ7.50(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=7.1Hz,4H),1.22(t,J=7.1Hz,6H).

[0720] 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).

[0721] UPLC-MS (acidic method, 2 min): rt = 1.22 min; m / z = 405.1 [MH] - , peak area>90%

[0722] 1 H NMR(400MHz,DMSO-d6)δ13.30(s,1H),7.48(t,J=3.0Hz,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=7.1Hz,2H),1.22(t,J=7.1Hz,3H)

[0723] The original Na2CO3 saturated aqueous solution was then acidified to pH 7 using concentrated hydrochloric acid. It was then extracted with EtOAc (2 x 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).

[0724] 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%

[0725] 1H NMR (400MHz, DMSO-d6) δ13.23(s,2H),7.52–7.29(m,12H),5.17(s,2H),4.97(s,2H).

[0726] Scheme 9b: Alternative synthesis of KI-7

[0727]

[0728] 2,6-Dimethyl-1,4-phenylene diacetate [Step 1]: To a stirred solution of 2,6-dimethylhydroquinone (5.0 g, 36 mmol) in pyridine (10 mL) was quickly added acetic anhydride (10 mL). The solution was stirred at room temperature for 18 h. The solvent was then removed under reduced pressure, and the residue was dissolved in EtOAc (250 mL), followed by washing with aqueous hydrochloric acid (1 M, 250 mL), saturated aqueous NaHCO₃ (250 mL), and water (250 mL). The mixture was dried over Na₂SO₄, filtered, and the solvent removed in vacuo to afford the title compound (7.4 g, 92%) as a white solid.

[0729] UPLC-MS (acidic method, 2 min): rt = 1.07 min; m / z = 240.2 [M+NH4] + , peak area>90%

[0730] 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).

[0731] 2,6-bis(dibromomethyl)-1,4-phenylene diacetate [Step 2]: To a stirred solution of 2,6-dimethyl-1,4-phenylene diacetate (6.34 g, 29 mmol) in 1,2-dichloroethane (130 mL) were added 2,2'-azobis(2-methylpropionitrile) (AIBN) (0.93 g, 6 mmol) and N-bromosuccinimide (NBS) (25.39 g, 143 mmol) sequentially. The solution was stirred at reflux for 24 h. 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 another 24 h. The reaction was cooled to room temperature, and the residual solid was 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.

[0732] UPLC-MS (acidic method, 2 min): rt = 1.23 min; m / z = 553.1 [M+NH4] + , peak area>88%

[0733] 1 H NMR (400MHz, DMSO-d6) δ7.69(s,2H),7.31(s,2H),2.49(s,3H),2.32(s,3H).

[0734] 2,5-Dihydroxyisophthalaldehyde [Step 3]: To a stirred suspension of 2,6-bis(dibromomethyl)-1,4-phenylene diacetate (3.89 g, 7.23 mmol) in formic acid (50 mL) was added water (5 mL). The mixture was stirred at reflux for 18 h. The reaction mixture was then slowly poured into a saturated aqueous solution of sodium bicarbonate (300 mL). The resulting precipitate was then isolated by filtration to afford the title compound (0.94 g, 78%) as a brown solid.

[0735] UPLC-MS (acidic method, 2 min): rt = 0.74 min; m / z = 165.0 [MH] - , peak area>98%

[0736] 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 h. The reaction mixture was cooled to ambient temperature and treated with a saturated aqueous solution of ammonium chloride (100 mL). The resulting suspension was stirred for 30 min and then filtered. The solid material was washed with a saturated aqueous solution of ammonium chloride (2×50 mL). The solid was then triturated with ethanol (5 mL) and suction dried to give the desired product as a brown solid (1.58 g, 68%)

[0737] UPLC-MS (acidic method, 2 min): rt = 1.28 min, no ionization observed, peak area 78%

[0738] 1 H NMR (400MHz, DMSO-d6) δ10.14(s,2H),7.63(s,2H),7.53–7.28(m,10H),5.23(s,2H),5.21(s,2H).

[0739] 2,5-Bis(benzyloxy)isophthalic acid (KI-7) [Step 5]: 2,5-Bis(benzyloxy)isophthalaldehyde (1.58 g, 4.5 mmol) was dissolved in a solution of 2-methyl-2-butene in THF (2.0 M, 25 mL). 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 h. The reaction mixture was then poured into a saturated aqueous solution of NaHCO₃ (400 mL). The aqueous layer was washed with EtOAc (3 x 100 mL) and then acidified with concentrated hydrochloric acid (pH ~1). The aqueous layer was then extracted with DCM (2 x 150 mL) and Et₂O (2 x 200 mL), and the collected organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then triturated with n-pentane (3 x 50 mL) to afford the title compound KI-7 as a white solid (0.98 g, 58%).

[0740] UPLC-MS (acidic method, 2 min): rt = 1.03 min, m / z = 379.1 [M+H] + , peak area>96%

[0741] 11H NMR (400 MHz, DMSO-d6) δ 13.23 (s, 2H), 7.57–7.28 (m, 12H), 5.17 (s, 2H), 4.97 (s, 2H).

[0742] Scheme 9c: Synthesis of KI-2Ac2

[0743]

[0744] Methyl 2,5-diacetoxy-3-methylbenzoate. As reported by Nudenberg et al (J. Org. Chem. 1943, 8, 500 - 508), 3-methylsalicylic acid was oxidized with persulfate. 3-Methylsalicylic acid (15.0 g, 98.6 mmol) was dissolved in a solution of sodium hydroxide (15.0 g, 375 mmol, 3.8 eq.) in water (37.5 mL). The light brown solution was cooled to 20 °C and treated with 7.75 mL portions of 40% sodium hydroxide and 33.8 mL portions of 10% potassium persulfate solution with stirring, starting with the hydroxide and maintaining the temperature at 30 - 35 °C until 10 portions were added in each case. After the addition was complete, stirring was continued for 1 h, and the mixture was allowed to stand at room temperature for 16 - 20 h, then concentrated HCl was added until the color changed from blue to Congo red. At this point, the unreacted 3-methylsalicylic acid separated as a solid and was removed by filtration. The filtrate was extracted several times with ether (5 x 50 mL) to recover the remaining 3-methylsalicylic acid. Then the aqueous solution was treated with concentrated HCl (100 mL) and refluxed for 2 h to decompose the intermediate monosulfate. The warm solution was allowed to cool 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 obtain another batch of brown solid 2,5-dihydroxy-3-methylbenzoic acid (total: 7.71 g, 47%). Mp 212 - 214 °C; 1 1H 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).

[0745] Esterification. Under 0 °C and nitrogen, 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). Then the reaction mixture was stirred at 100 °C for 6 h. After cooling to room temperature, the solvent was removed under reduced pressure. The obtained crude product was dissolved in ethyl acetate (50 mL), and the solution was washed with water (20 mL), 10% aqueous NaHCO3 (20 mL), 5% aqueous HCl (20 mL) and brine (20 mL), and then dried (MgSO4). After filtration, the organic layer was concentrated in vacuo to give a residue, which 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 1H 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 + ): C9H 11 O4 [M + H] + Calculated m / z for: 183.0652; found 183.0651.

[0746] Acetylation. Under argon, acetic anhydride (10 mL) in excess was added to a solution of methyl 2,5-dihydroxy-3-methylbenzoate (4.43 g, 24.3 mmol) in pyridine (10 mL). After stirring at room temperature for 12 h, pyridine and acetic anhydride were removed by co-evaporation with toluene (25 mL) under reduced pressure. Then the crude product was dissolved in ethyl acetate (15 mL), and the solution was washed successively with 2% aqueous HCl (5 mL), saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic phase was dried (MgSO4), and the solvent was evaporated under reduced pressure. The obtained colorless oil was purified by flash chromatography on silica gel (petroleum ether / ethyl acetate = 8 / 2) to give the acetylated title product (2,5-acetoxy-3-methylbenzoate) as a white solid (6.25 g, 97%). Mp 69 - 71 °C; 1 1H NMR (250 MHz, CDCl3): 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+ ):C 13 H 18 NO6[M+NH4] + Calculated m / z: 284.1129; found: 284.1128.

[0747] Methyl 2,5-diacetoxy-3-dibromomethylbenzoate. Methyl 2,5-acetoxy-3-methylbenzoate (2.15 g, 8.08 mmol), N-bromosuccinimide (2.87 mg, 16.2 mmol, 2.0 eq.) and azobisisobutyronitrile (AIBN, 27.0 mg, 0.162 mmol, 0.02 eq.) were refluxed in carbon tetrachloride (45 mL) for about 12 h until a white solid floated on the surface. After cooling, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting colorless oil was purified by silica gel flash chromatography (petroleum ether / ethyl acetate = 9 / 1) to give the dibrominated product (3.29 g, 84%) as a white solid. Mp 117-119 ° C; 1 H NMR (250MHz, CDCl3): δ7.86 (d, J=2.75Hz, 1H ar ),7.78(d,J=2.75Hz,1H ar ),6.81(s,1H),3.86(s,3H),2.42(s,3H),2.33(s,3H); HRMS(ESI + ):C 13 H 12 Br2NaO6[M+Na] + Calculated m / z: 444.8893; found: 444.8896.

[0748] 2,5-diacetoxy-3-formylbenzoic acid methyl ester. A solution of 2,5-diacetoxy-3-dibromo-methylbenzoic acid methyl ester (2.30g, 5.42mmol) and silver nitrate (2.29g, 13.5mmol, 2.5eq.) in a mixture of acetone-H2O (4.7:1, 40mL) was stirred for 12h at room temperature and in the dark. The mixture was then filtered and the filtrate was extracted with ethyl acetate (2x20mL). The combined organic phase was washed with brine (5mL), dried (MgSO4), 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 aldehyde (1.14g, 75%) as a yellow solid. MP 102-104℃; IHNMR (250MHz, CDC13): 10.17 (s, 1H), 8.00 (d, J = 3.00Hz, 1Har), 7.82 (d, J = 3.00Hz, 1Har), 3.90 (s, 3H), 2.44 (s, 3H), 2.34 (s, 3H).

[0749] 2,5-diacetoxyisophthalic acid monomethyl ester (KI-2Ac2). A solution of sodium hydrogen phosphate (1.35 g, 9.81 mmol, 2.5 eq.) in water (3.5 mL) was added dropwise to a solution of 2,5-diacetoxy-3-formylbenzoic acid methyl ester (1.10 g, 3.93 mmol) in DMSO (14 mL). The mixture was then cooled to 0 ° C., and a solution of sodium chlorite (1.06 g, 9.34 mmol, 2.4 eq.) in water (3.5 mL) was slowly added. After stirring at room temperature for 72 h, the mixture was quenched with a saturated aqueous solution of NaHCO3 (10 mL) and extracted with ethyl acetate (2x30 mL). The aqueous phase was then acidified to pH = 1 with 1 M HCl and extracted with ethyl acetate (2x30 mL). The combined organic phases were washed with brine (5 mL), dried (MgSO4), and concentrated under reduced pressure. The obtained orange oil was used for the next step without any purification.

[0750] Synthesis of monoamides

[0751] Scheme 10. Synthesis of Monoamide IIa

[0752]

[0753] Scheme: Synthesis of monoamides

[0754] Amide coupling and deprotection steps

[0755] See the common steps [3], [4], [5] for KI-1 and KI-6, and the same steps for KI-2, KI-2Ac2, and KI-7

[0756] Example

[0757]

[0758]

[0759] Conditions and yields: see Table 2 ( Figure 5A -C)

[0760] 33) 3-(2-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound IIa-001a:

[0761] UPLC-MS (acidic method, 2 min): rt = 0.86 min; m / z = 318.0 [M+H] + , peak area>92%

[0762] 1 H NMR (400MHz, DMSO-d6) δ13.49(s,1H),12.16(s,1H),9.54(s,1H),8.70(dd,J=8.5,1.2Hz,1H),7. 99(dd,J=7.9,1.7Hz,1H),7.70–7.51(m,2H),7.42(d,J=3.3Hz,1H),7.20(td,J=7.6,1.2Hz,1H).

[0763] HRMS:[M+H] + ,C 15 H 12 Calculated value of NO7: 318.06083, actual value: 318.06082

[0764] Biological data: IIa-001a: FGF-1 IC50 [μM] = 8.6; FGF-2 IC50 [μM] = 11; VEGF-A1 IC50 [μM] = 150; VEGFR-phosphorylation inhibition IC50 [μM] = 100; PMN ROS inhibition [%] at 0.3 μM = 30.5; PMNROS inhibition IC50 [μM] = 0.408; Neutrophil adhesion inhibition [%] = 36.24

[0765] 34) 3-(2-(1H-tetrazol-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound IIa-001aTz:

[0766] UPLC-MS (acidic method, 2 min): rt = 0.71 min; m / z = 342.1 [M+H] + , peak area>99%

[0767] 1H NMR (400MHz, DMSO-d6) δ11.40(s,1H),9.49(s,1H),8.51(d,J=8.3Hz,1H),7.87(d,J=7.7Hz,1H),7.72–7.51(m,2H),7.51–7.26(m,2H)

[0768] HRMS:[M+H] + ,C 15 H 12 Calculated value of N5O5: 342.08329, Actual value: 342.08317

[0769] Biological data: IIa-001a-Tz: FGF-1 IC50 [μM] = ND; FGF-2 IC50 [μM] = 9.8; VEGF-A1 IC50 [μM] = 187; VEGFR-phosphorylation inhibition IC50 [μM] = ND; PMN ROS inhibition [%] at 0.3 μM = 74.15; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 24.18

[0770] Ethyl ester

[0771] UPLC-MS (acidic method, 4 min): rt = 1.46 min; m / z = 370.1 [M+H] + , peak area>92%

[0772] 1 H NMR (400MHz, DMSO-d6) δ11.51(s,1H),11.37(s,1H),9.63(s,1H),8.47(d,J=8.3Hz,1H),7.92(dd,J=7.8,1.6Hz,1H) ,7.66–7.57(m,2H),7.43(d,J=3.2Hz,1H),7.38(td,J=7.6,1.2Hz,1H),4.40(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H),

[0773] HRMS:[M+H] + ,C 17 H 16 Calculated value of N5O5: 370.11460, actual value: 370.11444

[0774] Biological data: IIa-001aTz-E1: FGF-1 IC50 [μM] = 200; FGF-2 IC50 [μM] = 42; VEGF-A1 IC50 [μM] = 200; VEGFR-phosphorylation inhibition IC50 [μM] = 100; PMN ROS inhibition [%] = 68.86 at 0.3 μM; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 81.94

[0775] 35) 2,5-dihydroxy-3-(2-sulfophenylaminocarbonyl)benzoic acid, compound IIa-001c:

[0776] UPLC-MS (acidic method, 2 min): rt = 0.63 min; m / z = 354.0 [M+H] + , peak area>80%

[0777] 1 H NMR (400MHz, DMSO-d6) δ11.18(s,1H),9.48(s,1H),8.34–8.27(m,1H),7.72(dd,J=7. 7,1.7Hz,1H),7.52(d,J=3.2Hz,1H),7.41–7.31(m,2H),7.08(td,J=7.5,1.2Hz,1H).

[0778] HRMS:[M+H] + ,C 14 H 12 Calculated value of NO8S: 354.02781, Actual value: 354.02781

[0779] Biological data: IIa-001c: FGF-1 IC50 [μM] = ND; FGF-2 IC50 [μM] = 71; VEGF-A1 IC50 [μM] = 283; VEGFR-phosphorylation inhibition IC50 [μM] = ND; PMN ROS inhibition [%] at 0.3 μM = 72.62; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 43.53

[0780] 36) 3-(3-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound IIa-002a:

[0781] 1H NMR (250MHz, CD3OD): δ8.37(t,1H),7.93(br d,1H),7.81(br d,1),7.76(d,1H),7.52(d,1H),7.48(t,1H).

[0782] HRMS(ESI-):[MH] - ,C 15 H 10 Calculated value of NO7: 316.0461, actual value: 318.0463

[0783] Biological data: 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; PMNROS inhibition IC50 [μM] = 0.299; Neutrophil adhesion inhibition [%] = 17.39

[0784] 37) 3-(4-carboxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid)amide, compound IIa-003a:

[0785] 1 H NMR (250MHz, CD3OD): 8.06 (BB' of AA'BB', 2H), 7.85 (AA' of AA'BB', 2H), 7.75 (d, 1H), 7.58 (d, 1H)

[0786] HRMS(ESI-):C 15 H 10 NO7[MH] - Calculated value: 316.0461; actual value: 316.0462

[0787] Biological data: 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; PMNROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 35.27

[0788] 38) 3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound IIa-004a:

[0789] UPLC-MS (acidic method, 2 min): rt = 0.76 min; m / z = 334.0 [M+H] + , peak area>99%

[0790] 1 H NMR (400MHz, DMSO-d6) δ14.02(brs,1H),11.07(brs,1H),10.32(s,1H),9.47(brs,1H),8.27(d,J=2.7H z, 1H), 7.76 (dd, J = 8.9, 2.7Hz, 1H), 7.42 (d, J = 3.2Hz, 1H), 7.36 (d, J = 3.2Hz, 1H), 6.96 (d, J = 8.9Hz, 1H).

[0791] HRMS:[M+H] + ,C 15 H 12 Calculated value of NO8: 334.05574, actual value: 334.05571

[0792] Biological data: IIa-004a: FGF-1 IC50 [μM] = 47; FGF-2 IC50 [μM] = 33; VEGF-A1 IC50 [μM] = 200; VEGFR-phosphorylation inhibition IC50 [μM] = 100; PMN ROS inhibition [%] at 0.3 μM = 63.5; PMNROS inhibition IC50 [μM] = 1.002; Neutrophil adhesion inhibition [%] = 36

[0793] 39) 3-(2-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound IIa-006a:

[0794] UPLC-MS (acidic method, 2 min): rt = 0.65 min; m / z = 334.0 [M+H] + , peak area>99%

[0795] 1 H NMR (400MHz, DMSO-d6) δ13.36(s,1H),11.83(s,1H),9.62(s,1H),9.47(s,1H),8.47(d,J=9.1Hz,1H ), 7.64 (d, J = 3.3Hz, 1H), 7.41 (d, J = 3.2Hz, 1H), 7.37 (d, J = 3.0Hz, 1H), 7.03 (dd, J = 9.1, 3.0Hz, 1H).

[0796] HRMS:[M+H] + ,C15 H 12 Calculated value of NO8: 334.05574, actual value: 334.05548

[0797] Biological data: IIa-006a: FGF-1 IC50 [μM] = ND; FGF-2 IC50 [μM] = 43; VEGF-A1 IC50 [μM] = 121; VEGFR-phosphorylation inhibition IC50 [μM] = 2.9; PMN ROS inhibition [%] at 0.3 μM = 84.29; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 20.29

[0798] 40) 3-(3-carboxy-2,5-dihydroxybenzamido)phthalic acid, compound IIa-011a:

[0799] UPLC-MS (acidic method, 2 min): rt = 0.72 min; m / z = 360.1 [MH] - , peak area>77%

[0800] 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.55(s,1H),8.43(dd,J=7.9,1.5Hz,1H),7.73(d,J=3.3Hz,1H),7.63–7.53(m,2H),7.46(d,J=3.3Hz,1H),

[0801] HRMS:[M+H] + ,C 16 H 12 Calculated value of NO9: 362.05066, actual value: 362.05045,

[0802] Biological data: IIa-011a: FGF-1 IC50 [μM] = 141; FGF-2 IC50 [μM] = 123; VEGF-A1 IC50 [μM] = 200; VEGFR-phosphorylation inhibition IC50 [μM] = 100; PMN ROS inhibition [%] = 58.1 at 0.3 μM; PMN ROS inhibition IC50 [μM] = 1.18; Neutrophil adhesion inhibition [%] = 26

[0803] 41) 2-(3-carboxy-2,5-dihydroxybenzamido)terephthalic acid, compound IIa-012a:

[0804] UPLC-MS (acidic method, 2 min): rt = 0.73 min; m / z = 362.0 [M+H], peak area > 97%

[0805] 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=1.6Hz,1H), 8.06(d,J=8.2Hz,1H),7.71(dd,J=8.2,1.7Hz,1H),7.64(d,J=3.3Hz,1H),7.43(d,J=3.3Hz,1H),

[0806] HRMS:[M+H] + ,C 16 H 12 Calculated value of NO9: 362.05066, actual value: 362.05046,

[0807] Biological data: 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

[0808] 42) 2-(3-carboxy-2,5-dihydroxybenzamido)isophthalic acid, compound IIa-013a:

[0809] UPLC-MS (acidic method, 2 min): rt = 1.68 min; m / z = 362.0 [M+H] + , peak area>96%

[0810] 1 H NMR(400MHz,DMSO-d6)δ13.12(brs,3H),11.71(s,1H),9.47(s,1H),7.96(s,1H), 7.94 (s, 1H), 7.66 (d, J = 3.3Hz, 1H), 7.44 (d, J = 3.3Hz, 1H), 7.35 (t, J = 7.8Hz, 1H).

[0811] HRMS:[M+H] + ,C 16 H 12 Calculated value of NO9: 362.05066, actual value: 362.05047

[0812] Biological data: IIa-013a: FGF-1 IC50 [μM] = 137; FGF-2 IC50 [μM] = 12; VEGF-A1 IC50 [μM] = 34; VEGFR-phosphorylation inhibition IC50 [μM] = 100; PMN ROS inhibition [%] at 0.3 μM = 57.68; PMNROS inhibition IC50 [μM] = 2.54; Neutrophil adhesion inhibition [%] = 15.75

[0813] 43) 4-(3-carboxy-2,5-dihydroxybenzamido)phthalic acid, compound IIa-014a:

[0814] UPLC-MS (acidic method, 2 min): rt = 0.63 min; m / z = 362.1 [M+H] + , peak area>88%

[0815] 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),9.45(s,1H),8.01(d,J=2.2Hz,1H),7.86(dd,J=8.5,2.2Hz,1H),7.74(d,J=8.5Hz,1H),7.45–7.33(m,2H),

[0816] HRMS:[M+H] + ,C 16 H 12 Calculated value of NO9: 362.05066, actual value: 362.05048

[0817] Biological data: IIa-014a: FGF-1 IC50 [μM] = 40; FGF-2 IC50 [μM] = 61; VEGF-A1 IC50 [μM] = 91; VEGFR-phosphorylation inhibition IC50 [μM] = 17.6; PMN ROS inhibition [%] at 0.3 μM = 73.94; PMNROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 21.5

[0818] 44) 5-(3-carboxy-2,5-dihydroxybenzamido)isophthalic acid, compound IIa-015a:

[0819] 1H NMR (250MHz, CD3OD): δ8.60(d,J=1.5Hz,2H),8.44(t,J=1.5Hz,1H),7.75(d,J=3.2Hz,1H),7.56(d,J=3.2Hz,1)

[0820] HRMS (ESI+): m / z Calcd. for C16H12NO9 [M+H]+: 362.0507; Found: 362.0505 [LM-163]

[0821] Biological data: IIa-015a: FGF-1 IC50 [μM] = ND; FGF-2 IC50 [μM] = 125; VEGF-A1 IC50 [μM] = ND; VEGFR-phosphorylation inhibition IC50 [μM] = ND; PMN ROS [inhibition at 0.3 μM [%]] = ND; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = ND

[0822] 45)(3-(3-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound IIa-033a:

[0823] UPLC-MS (acidic method, 2 min): rt = 0.78 min; m / z = 330.1 [MH] - , peak area>98%

[0824] 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),9.45(s,1H),7.66(t,J=1.9Hz,1H),7.63–7.57(m,1H),7.4 5(d,J=3.3Hz,1H),7.38(d,J=3.2Hz,1H),7.29(t,J=7.8Hz,1H),7.05–6.95(m,1H),3.56(s,2H).

[0825] HRMS:[M+H] + ,C 16 H 14 Calculated value of NO7: 332.07648, actual value: 332.07644,

[0826] Biological data: IIa-033a: FGF-1 IC50 [μM] = 35; FGF-2 IC50 [μM] = 32; VEGF-A1 IC50 [μM] = 200; VEGFR-phosphorylation inhibition IC50 [μM] = 4.9; PMN ROS inhibition [%] at 0.3 μM = 50.64; PMNROS inhibition IC50 [μM] = 0.914; Neutrophil adhesion inhibition [%] = 11.75

[0827] 46) 3-(2-(carboxymethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound IIa-034a:

[0828] UPLC-MS (acidic method, 2 min): rt = 0.74 min; m / z = 332.0 [M+H] + , peak area>95%

[0829] 1 H NMR (400MHz, DMSO-d6) δ12.48(s,1H),10.65(s,1H),9.30(s,1H),7.97(d,J=8.3Hz,1H),7.64(d, J=3.2Hz,1H),7.40(d,J=3.3Hz,1H),7.33–7.26(m,2H),7.13(td,J=7.5,1.3Hz,1H),3.70(s,2H).

[0830] HRMS:[M+H] + ,C 16 H 14 Calculated value of NO7: 332.07648, actual value: 332.07653

[0831] Biological data: IIa-034a: FGF-1 IC50 [μM] = 22; FGF-2 IC50 [μM] = 5.7; VEGF-A1 IC50 [μM] = 86; VEGFR-phosphorylation inhibition IC50 [μM] = 100; PMN ROS inhibition [%] at 0.3 μM = 69.2; PMNROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 26.58

[0832] Diethyl ester

[0833] UPLC-MS (acidic method, 2 min): rt = 1.12 min; m / z = 388.1 [M+H] + , peak area>99%

[0834] 1H NMR (400MHz, DMSO-d6) δ11.81(s,1H),9.58(s,1H),7.77(t,J=8.5Hz,1H),7.65(d,J=3.4Hz,1H),7.42(d,J=3.4Hz,1H),7.36–7.31(m ,2H),7.20(t,J=7.4Hz,1H),4.39(q,J=7.1Hz,2H),4.05(q,J=7.1Hz,2H),3.77(s,2H),1.36(t,J=7.1Hz,3H),1.13(t,J=7.1Hz,3H).

[0835] HRMS:[M+H] + ,C 20 H 22 Calculated value of NO7: 388.13907, actual value: 388.13887

[0836] Biological data: IIa-034a-E2: FGF-1 IC50 [μM] = ND; FGF-2 IC50 [μM] = 164; VEGF-A1 IC50 [μM] = 200; VEGFR-phosphorylation inhibition IC50 [μM] = ND; PMN ROS inhibition [%] at 0.3 μM = 68.73; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 11.86

[0837] 47) 3-(3,4-dihydroxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound IIa-035a:

[0838] UPLC-MS (acidic method, 2 min): rt = 0.69 min; m / z = 318.0 [MH] - , peak area>99%

[0839] 1 H NMR (400MHz, DMSO-d6) δ9.38(s,1H),8.84(s,1H),8.75(s,1H),7.55(d,J=3.2Hz,1H),7.34(d,J=3.2Hz ,1H),6.74(d,J=2.1Hz,1H),6.67(d,J=8.0Hz,1H),6.58(dd,J=8.1,2.1Hz,1H),4.34(d,J=5.7Hz,2H).

[0840] HRMS:[M+H] + ,C 15 H 14Calculated value of NO7: 320.07647, actual value: 320.07625.

[0841] Biological data: IIa-035a: FGF-1 IC50 [μM] = 16; FGF-2 IC50 [μM] = 61; VEGF-A1 IC50 [μM] = 45; VEGFR-phosphorylation inhibition IC50 [μM] = 0.52; PMN ROS inhibition [%] at 0.3 μM = 76.99; PMNROS inhibition IC50 [μM] = 1; Neutrophil adhesion inhibition [%] = 36.67

[0842] 48) 3-(2-carboxyphenylmethylaminocarbonyl)-2,5-dihydroxybenzoic acid, compound IIa-053a:

[0843] UPLC-MS (acidic method, 4 min): rt = 1.08 min; m / z = 332.0 [M+H] + , peak area>97%

[0844] 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, 1.4Hz, 1H), 7.65–7.29 (m, 5H), 4.80 (d, J = 6.1Hz, 2H).

[0845] HRMS:[M+H] + ,C 16 H 14 Calculated value of NO7: 332.07648, actual value: 332.07626

[0846] Biological data: IIa-053a: FGF-1 IC50 [μM] = 84; FGF-2 IC50 [μM] = 18; VEGF-A1 IC50 [μM] = 37; VEGFR-phosphorylation inhibition IC50 [μM] = 0.27; PMN ROS inhibition [%] at 0.3 μM = 63.13; PMNROS inhibition IC50 [μM] = 0.62; neutrophil adhesion 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; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.02; TNFβIC50[μM]=91.5.

[0847] Example 1.6. Type IIb molecules: diamides from diamines, 1 example

[0848]

[0849] Scheme 11. Synthesis of Type IIb Diamide

[0850]

[0851] Steps: Refer to the general steps of KI-1 [3], [4], [5]

[0852] For example:

[0853]

[0854] Conditions and yields: see Table 2 ( Figure 5A -C)

[0855] 49) 3,5-bis(2,5-dihydroxy-3-carboxybenzoylamino)benzoic acid, compound IIb-010a:

[0856] UPLC-MS (acidic method, 4 min): rt = 0.98 min; m / z = 511.1 [MH] - , peak area>93%

[0857] 1 H NMR (400MHz, DMSO-d6) δ 10.81 (s, 2H), 10.65 (s, 2H), 8.38 (m, 1H), 8.12 (d, J = 2.0Hz, 2H), 7.39 (d, J = 2.3Hz, 4H).

[0858] HRMS:[M+H] + ,C 23 H 17 N2O 12 Calculated value: 513.07760, actual value: 513.07774

[0859] 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

[0860] Example 1.7. Type IIc molecules: diamides from diacids, 2 examples

[0861]

[0862] Scheme 12. Synthesis of Type IIc Amides with R=R'

[0863]

[0864] Steps: Refer to the general steps of KI-6 [3], [4], [5]

[0865] For example

[0866]

[0867] Conditions and yields: see Table 2 ( Figure 5A -C)

[0868] 50) 5-(3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid, compound IIc-007a:

[0869] UPLC-MS (acidic method, 4 min): rt = 1.20 min; m / z = 469.1 [M+H] + , peak area>91%

[0870] 1 H NMR (400MHz, DMSO-d6) δ10.41(s,2H),9.51(s,1H),8.22(d,J=2.7Hz,2H),7.79(dd,J=9.0,2.7Hz,2H),7.58(s,2H),6.98(d,J=8.9Hz,2H),

[0871] 13 C NMR (100MHz, DMSO-d6) δ172.1,166.1,158.3,152.0,149.4,130.2,129.5(CH),122.8(CH),120.3,119.8(CH),117.7(CH).113.0.

[0872] HRMS:[M+H] + ,C 22 H 17 N2O 10 Calculated value: 469.08777, actual value: 469.08803

[0873] Biological data: IIc-007a: FGF-1 IC50 [μM] = 11; FGF-2 IC50 [μM] = 91; VEGF-A1 IC50 [μM] = 8.2; VEGFR-phosphorylation inhibition IC50 [μM] = 0.44; PMN ROS inhibition [%] at 0.3 μM = 93.04; PMNROS inhibition IC50 [μM] = ND; neutrophil adhesion 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; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.03; TNFβIC50[μM]=0.29

[0874] Alternative large-scale synthesis of IIc-007a

[0875] 2,5-Dibenzyloxyisophthalic acid (KI-7)

[0876] A 5 L jacketed vessel was charged with 2,5-dibenzyloxyisophthalaldehyde (Scheme 9b) (300 g, 866 mmol), resorcinol (286 g, 2.60 ml), KH2PO4 (354 g, 2.60 ml), acetone (1.5 L), and water (516 ml). The slurry was stirred at 15-25 ° C. Over 90 min at 15-30 ° C (exotherm), a solution of 80% NaClO2 (294 g, 2.60 mol) in water (1 L) was added. After the addition was complete, the reaction was stirred at 15-25 ° C for 1 hr. Over 10 min at T < 30 ° C (exotherm), a solution of 85% H3PO4 (85 ml, 1.24 mol) in water (1175 ml) [~1 M] was added to give a precipitate. The batch was cooled to 0-5 ° C and filtered. The solid was washed with water (3 x 1.2 L) and dried in an oven (50° C.) to give 325.6 g of diacid KI-7. HPLC: 98.9%; NMR>95%. Corrected yield (90.6%).

[0877] Methyl 5-(3-(3-methoxycarbonyl-4-hydroxyphenylaminocarbonyl)-2,5-dibenzyloxybenzamido)-2-hydroxybenzoate. A 2 L jacketed vessel was charged with 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 added. After 30 min, methyl 5-amino-2-hydroxybenzoate (77.8 g, 466 mmol) was added, and the reaction was stirred at 25 °C overnight. Water (1.2 L) was added, and the batch was stirred at 20 °C for 30 min. The batch was filtered, washed with water (2x480ml), then washed with MeCN (320ml). The resulting solid (236g) was returned to the container along with MeCN (800ml). The slurry was heated to 50°C for 40min and then cooled to 20°C. The batch was filtered and washed with MeCN (320ml). NMR analysis of the solid (156g) showed no TMU, HOBt, NMI, or HBTU. The material was dried at 50°C overnight to give 125g of the diamide. HPLC: 98.2%. NMR: >97%. Yield: 88%.

[0878] 5-(3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dibenzyloxybenzamido)-2-hydroxybenzoic acid. A 2 L jacketed vessel was charged with the previous 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 added (small exotherm). The solution was heated to 50 ° C for 4 h, then cooled to 20 ° C and stirred overnight. 6 M aqueous AcOH (550 ml, 3.3 mol) was then charged at 15-25 ° C over 30 min. After the addition was complete, the batch was stirred for 30 min and then filtered. The solid was washed with water (3x550 ml) and then dried in a 50 ° C oven. 102 g of the free diacid was produced. HPLC: 98.9% (0.3% monoamide, 0.19% monoacid). NMR:>97%. Yield: 97%.

[0879] 5-(3-(3-Carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid IIc-007a. Under N2, a 2 L jacketed vessel was charged with 10% Pd / C (10 g, 50% wet, 87 L type) followed by the previous diacid (100 g, 154 mmol), AcOH (5 ml, 88 mmol), and THF (1200 ml). The batch was stirred, then sparged with H2 and heated to 40°C for 2 hr. The batch was dried with N2 spray and then filtered (GF / F). The vessel was rinsed with THF (300 ml) and the catalyst was washed from the filter with the rinse. The filtrate was charged to a vessel and the volume was adjusted to 2 L with THF (400 ml). The solution was heated to 30°C, SPM32 (10 g) was charged, and the batch was stirred at 30°C overnight. SPM32 was filtered out and washed with THF (200 ml). The solvent was removed in vacuo 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 out. The solid was washed with EtOH (400 ml) and oven-dried at 60° C. overnight. NMR showed 8.7% EtOH and no THF. The material was further dried at 80° C. for 4 nights to give 66.5 g of IIc-007a as an off-white solid in a 92% yield. HPLC: 99.5% (0.31% monoamide). NMR: 4.6% EtOH and no THF. Pd by ICP-OES: <2 pm.

[0880] IIc-007a - THF solvate: Concentration of the THF filtrate afforded a yellow solid which, by NMR analysis, typically contained 25-30% THF which could not be removed by drying, indicating a non-stoichiometric solvate.

[0881] A small portion of the THF solvate (1.45 g) was heated to 50° C. for 1 hr in THF (10 ml), cooled to RT, isolated, and washed with 3 ml of THF. 1.13 g of IIc-007a-THF was obtained. NMR: 27% THF. HPLC: 99.6% (0.1% monoamide). Isolation of the THF solvate by filtration improved the purity and effectively eliminated the major impurity (monoamide, IIa-004a) from 0.7% to 0.1%. Recovery: 78%. The solubility of the THF solvate in THF, calculated at 20° C., was approximately 25 mg / ml.

[0882] The material was desolvated in acetone, EtOH, and EtOAc. Each batch was heated at 50°C in 20 volumes of solvent for 1 hr, then separated and oven dried at RT (60°C). Ethanol was chosen as the desolvation solvent due to the low level of EtOH incorporated into the product after drying and the excellent THF scavenging effect in the system. The desolvation step was performed on 12.1 g of product (25% THF). EtOH (20 volumes) was charged to the material and the batch was stirred at RT overnight. A sample was filtered off, indicating successful desolvation at RT. Total yield: 8.67 g. HPLC: 99.4%. NMR: >97% (0.8% EtOH). XRPD indicated high crystallinity of the isolated product.

[0883] The product IIc-007a also formed a DMSO solvate (DMSO:product ratio was 3:2).

[0884] 51) 2-(3-(2-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-5-hydroxybenzoic acid, compound IIc-009a:

[0885] UPLC-MS (acidic method, 2 min): rt = 0.79 min; m / z = 469.1 [M+H] + , peak area>95%

[0886] 1 H NMR (400MHz, DMF-d7) δ 10.11 (s, 1H), 10.01 (s, 2H), 8.71 (d, J = 9.0Hz, 2H), 8.01 (s, 2H), 7.82 (d, J = 3.0Hz, 2H), 7.46 (d, J = 8.9Hz, 2H).

[0887] HRMS:[M+H] + ,C 22 H 17 N2O 10 Calculated value: 469.08777, actual value: 469.08714

[0888] Biological data: IIc-009a: FGF-1 IC50 [μM] = 30; FGF-2 IC50 [μM] = ND; VEGF-A1 IC50 [μM] = 182; VEGFR-phosphorylation inhibition IC50 [μM] = 1.7; PMN ROS inhibition [%] at 0.3 μM = 75.31; PMN ROS inhibition IC50 [μM] = ND; neutrophil adhesion 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-10IC50[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-33IC50[μM]=0.29; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.11; TNFβIC50[μM]=6.94.

[0889] Example 1.8: Type IIIa molecules: monoamides, 4 examples

[0890]

[0891] Synthesis of precursors

[0892] Scheme 13. Synthesis of intermediates: KI-8 and KI-9 from KI-1

[0893]

[0894] Synthesis scheme

[0895] Intermediates KI-8 and KI-9 (via KI-10 and KI-11)

[0896] Ethyl 2,5-bis(benzyloxy)-4-(hydroxymethyl)benzoate (KI-10) [Step 1]: To a -20°C cooled solution of KI-1 (62.3 g, 153 mmol) in THF (700 mL) was slowly added a pre-cooled solution of BH3.THF (615.0 mL, 615 mmol) at -10°C under a positive flow of inert gas (N2). The internal temperature of the reaction should not exceed -15°C when added in this manner. The reaction was heated slightly, not allowing the internal temperature to 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 cloudy white mixture was stirred at room temperature for 2 h, and the remaining white suspension was filtered through a sintered 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.

[0897] UPLC-MS (acidic method, 2 min): rt = 1.25 min; m / z = 391.2 [MH] - , peak area>68%

[0898] 1 H NMR (400MHz, DMSO-d6) δ7.54–7.48(m,2H),7.48–7.43(m,2H),7.43–7.35(m,4H),7.35–7.27(m,4H),5.28(t, J=5.4Hz,1H),5.13(s,2H),5.11(s,2H),4.58(d,J=5.4Hz,2H),4.25(q,J=7.1Hz,2H),1.26(t,J=7.1Hz,3H).

[0899] The alternative intermediate KI-10 can be obtained from KI-1 via a 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).

[0900] 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 solution (ice bath) 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, which was judged to be complete. DCM (100 mL) was added, and the organic layer was separated and washed with saturated aqueous sodium bicarbonate solution (4 x 50 mL), water (2 x 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%).

[0901] UPLC-MS (acidic method, 2 min): rt = 1.39 min; m / z = no ion, peak area > 84%.

[0902] 1 H NMR(400MHz,DMSO-d6)δ7.54–7.44(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=7.1Hz,2H),1.25(t,J=7.1Hz,3H).

[0903] The alternative 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).

[0904] 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 H2O (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 (2x200 mL), and the combined organic phases were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was isolated as a mixture of ethyl 2,5-bis(benzyloxy)-4-(cyanomethyl)benzoate and 2,5-bis(benzyloxy)-4-(cyanomethyl)benzoic acid (7.1 g) and used in the next step without further purification.

[0905] UPLC-MS (acidic method, 2 min): rt = 1.30 min; m / z = 402.2 [M+H] + , peak area>65%, and rt=1.15min; m / z=374.1[M+H] + , peak area>8%.

[0906] 1 H NMR (400MHz, DMSO-d6) δ7.56–7.27(m,12H),5.19(s,2H),5.14(s,2H),4.26(q,J=7.1Hz,2H),3.95(s,2H),1.25(t,J=7.1Hz,3H).

[0907] 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) was added a solution of sodium hydroxide (8.5 g, 212.5 mmol) in water (50 mL), and the reaction mixture was stirred at reflux for 18 h. The reaction mixture was diluted with water (100 mL), and the resulting solution was washed with EtOAc (2 x 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 saturated aqueous 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 light yellow solid.

[0908] UPLC-MS (acidic method, 2 min): rt = 1.07 min; m / z = 393.2 [M+H] + , peak area >74%.

[0909] 1 H NMR (400MHz, DMSO-d6) δ12.46(s,2H),7.55–7.27(m,11H),7.19(s,1H),5.11(s,2H),5.09(s,2H),3.61(s,2H).

[0910] 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), the suspension was treated with thionyl chloride (0.52 mL, 7.1 mmol), and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was then poured into saturated sodium bicarbonate solution (1 L) to give a white suspension. The solid was isolated by filtration and further triturated with Et2O (2 x 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.

[0911] UPLC-MS (acidic method, 2 min): rt = 1.23 min; m / z = 419.3 [MH] - , peak area >79%.

[0912] 1 H NMR(400MHz,DMSO-d6)δ12.68(brs,1H),7.58–7.27(m,11H),7.19(s,1H),5.11 (s,2H),5.08(s,2H),4.01(q,J=7.1Hz,2H),3.66(s,2H),1.11(t,J=7.1Hz,3H).

[0913] Synthesis of monoamides

[0914] Scheme 14. Synthesis of Monoamide IIIa

[0915]

[0916] Synthesis scheme

[0917] Amide coupling and deprotection steps:

[0918] See the common steps for KI-1 and KI-6, steps [3], [4], [5]

[0919] Example

[0920]

[0921]

[0922] Conditions and yields: see Table 3 ( Figure 6 )

[0923] 52) 2-(4-(Carboxymethyl)-2,5-dihydroxybenzamido)benzoic acid, compound IIIa-001a:

[0924] UPLC-MS (acidic method, 2 min): rt = 0.89 min; m / z = 332.1 [M+H] + , peak area>98%

[0925] 1 H NMR (400MHz, DMSO-d6) δ13.38(s,1H),12.17(s,1H),10.67(s,1H),9.23(s,1H),8.64(dd,J=8.5,1.2Hz,1H),8.00(dd,J =7.9,1.7Hz,1H),7.62(ddd,J=8.7,7.3,1.7Hz,1H),7.33(s,1H),7.19(td,J=7.6,1.2Hz,1H),6.80(s,1H),3.49(s,2H).

[0926] HRMS:[M+H] + ,C 16 H 14 Calculated value of NO7: 332.07648, actual value: 332.07666

[0927] 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; PMNROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 30.4

[0928] Ethyl methyl ester

[0929] UPLC-MS (acidic method, 2 min): rt = 1.14 min; m / z = 374.2 [M+H] + , peak area>96%.

[0930] 1 H NMR (400MHz, DMSO-d6) δ11.91(s,1H),10.78(s,1H),9.25(s,1H),8.60(dd,J=8.5,1.2Hz,1H),7.97(dd,J=8.0,1.7Hz,1H),7.64(ddd,J=8 .7,7.3,1.7Hz,1H),7.38(s,1H),7.26–7.18(m,1H),6.81(s,1H),4.08(q,J=7.1Hz,2H),3.88(s,3H),3.56(s,2H),1.19(t,J=7.1Hz,3H).

[0931] HRMS:[M+H] + ,C 19 H 20 Calculated value of NO7: 374.12342, actual value: 374.12333

[0932] Biodata: IIIa-001a-E2: FGF-1 IC50 [μM] = 200; FGF-2 IC50 [μM] = 33; VEGF-A1 IC50 [μM] = 43; VEGFR-phosphorylation inhibition IC50 [μM] = ND; PMN ROS inhibition [%] = 69.66; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 44.46

[0933] 53)(2-(1H-tetrazol-5-yl)phenylaminocarbonyl)-2,5-dihydroxyphenyl)acetic acid, compound IIIa-001aTz:

[0934] UPLC-MS (acidic method, 2 min): rt = 0.87 min; m / z = 356.1 [M+H], peak area > 95%.

[0935] 1 H NMR (400MHz, DMSO-d6) δ12.22(s,1H),11.43(s,1H),10.74(s,1H),9.21(s,1H),8.46(dd,J=8.5,1.2Hz,1 H),7.87(d,J=8.1Hz,1H),7.60(td,J=8.6,7.9,1.6Hz,1H),7.39–7.30(m,2H),6.80(s,1H),3.48(s,2H).

[0936] HRMS:[M+H] + ,C 16 H 14 Calculated value of N5O5: 356.09894, Actual value: 356.09889

[0937] Biodata: IIIa-001aTz: FGF-1 IC50 [μM] = 51; FGF-2 IC50 [μM] = 14; VEGF-A1 IC50 [μM] = 12; VEGFR-phosphorylation inhibition IC50 [μM] = 0.71; PMN ROS inhibition [%] at 0.3 μM = 69.35; PMN ROS inhibition IC50 [μM] = ND; neutrophil adhesion 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; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.31; TNFβIC50[μM]=0.23.

[0938] Ethyl ester:

[0939] UPLC-MS (acidic method, 4 min): rt = 1.56 min; m / z = 384.2 [M+H] + , peak area>95%.

[0940] 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),10.73(s,1H),9.25(s,1H),8.45(dd,J=8.5,1.2Hz,1H),7.85(dd,J=7.8,1.6Hz,1H),7 .61(ddd,J=8.7,7.4,1.6Hz,1H),7.39–7.30(m,2H),6.80(s,1H),4.08(q,J=7.1Hz,2H),3.56(s,2H),1.19(t,J=7.1Hz,3H).

[0941] HRMS:[M+H] + ,C 18 H 18Calculated value of N5O5: 384.13024, actual value: 384.12999

[0942] Biodata: IIIa-001aTz-E1: FGF-1 IC50 [μM] = 200; FGF-2 IC50 [μM] = 200; VEGF-A1 IC50 [μM] = 200; VEGFR-phosphorylation inhibition IC50 [μM] = 0.32; PMN ROS inhibition [%] at 0.3 μM = 70.03; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 91.76

[0943] 54) 2-(4-(Carboxymethyl)-2,5-dihydroxybenzamido)isophthalic acid, compound IIIa-013a:

[0944] UPLC-MS (acidic method, 4 min): rt = 0.82 min; m / z = 376.0 [M+H] + , peak area >89%.

[0945] 1 H NMR(400MHz,DMSO-d6)δ13.67–11.48(m,3H),10.82(s,1H),9.19(s,1H),7.95( d,J=7.8Hz,2H),7.36(s,1H),7.33(t,J=7.8Hz,1H),6.79(s,1H),3.48(s,2H).

[0946] HRMS:[M+H] + ,C 17 H 14 Calculated value of NO9: 376.06630, actual value: 376.06638

[0947] Biological data: IIIa-013a: FGF-1 IC50 [μM] = 17; FGF-2 IC50 [μM] = 31; VEGF-A1 IC50 [μM] = 43; VEGFR-phosphorylation inhibition IC50 [μM] = 1.3; PMN ROS inhibition [%] at 0.3 μM = 76.55; PMNROS inhibition IC50 [μM] = ND; neutrophil adhesion 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-33IC50[μM]=1.11; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.51; TNFβIC50[μM]=0.89.

[0948] 55) 5-(4-(Carboxymethyl)-2,5-dihydroxybenzamido)isophthalic acid, compound IIIa-015a:

[0949] UPLC-MS (acidic method, 4 min): rt = 0.93 min; m / z = 376.0 [M+H] + , peak area>96%.

[0950] 1 H NMR (400MHz, DMSO-d6+10%D2O) δ8.34(s,2H),8.18(s,1H),7.38(s,1H),6.71(s,1H),3.39(s,2H).

[0951] HRMS:[M+H] + ,C 17 H 14 Calculated value of NO9: 376.06630, actual value: 376.06665

[0952] Biodata: IIIa-015a: FGF-1 IC50 [μM] = 16; FGF-2 IC50 [μM] = 114; VEGF-A1 IC50 [μM] = 202; VEGFR-phosphorylation inhibition IC50 [μM] = 0.89; PMN ROS inhibition [%] at 0.3 μM = 78.76; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 12.13

[0953] Ethyl dimethyl ester

[0954] UPLC-MS (acidic method, 4 min): rt = 1.69 min; m / z = 432.1 [M+H] + , peak area >97%.

[0955] 1 H NMR(400MHz,DMSO-d6)δ9.23(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=7.0Hz,2H),3.91(s,6H),3.58(s,2H),1.19(t,J=7.1Hz,3H),

[0956] HRMS:[M+H] + ,C 21 H 22 Calculated value of NO9: 432.12891, actual value: 432.02903

[0957] 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

[0958] Example 1.9. Type IIIb molecules: diamides from diamines, 1 example

[0959]

[0960] Scheme 15. Synthesis of Type IIIb Diamide

[0961]

[0962] Steps: Refer to the general steps of KI-1, steps [3], [4], [5]

[0963] For example:

[0964]

[0965] Conditions and yields: see Table 3 ( Figure 6 )

[0966] 56) 3,5-bis(2,5-dihydroxy-4-carboxymethylbenzoylamino)benzoic acid, compound IIIb-010a:

[0967] UPLC-MS (acidic method, 4 min): rt = 1.08 min; m / z = 539.2.1 [MH] - , peak area 80%.

[0968] 1 H NMR (400MHz, DMSO-d6) δ 10.85 (brs, 2H), 10.57 (brs, 2H), 9.20 (s, 2H), 8.26 (m, 1H), 8.09 (d, J = 2.0Hz, 2H), 7.36 (s, 2H), 6.82 (s, 2H), 3.50 (s, 4H).

[0969] HRMS: [M+H]+, calculated for C23H17N2O12: 513.07760, found: 513.07774

[0970] triethyl ester

[0971] UPLC-MS (acidic method, 4 min): rt = 1.81 min; m / z = 623.3 [MH] - , peak area 94%.

[0972] 1 H NMR (400MHz, DMSO-d6) δ10.87(s,2H),10.65(s,2H),9.23(s,2H),8.31–8.28(m,1H),8.10(d,J=2.0Hz,2H),7.35(s,2H ), 6.81 (s, 2H), 4.35 (q, J = 7.1Hz, 2H), 4.08 (q, J = 7.1Hz, 4H), 3.58 (s, 4H), 1.35 (t, J = 7.1Hz, 3H), 1.19 (t, J = 7.1Hz, 6H).

[0973] Biodata: IIIb-010a-E3: FGF-1 IC50 [μM] = 200; FGF-2 IC50 [μM] = 200; VEGF-A1 IC50 [μM] = 200; VEGFR-phosphorylation inhibition IC50 [μM] = 0.65; PMN ROS [inhibition at 0.3 μM [%]] = ND; PMN ROS inhibition IC50 [μM] = ND; Neutrophil adhesion inhibition [%] = 0

[0974] Example 1.10: Type IIIc dimer, 6 examples

[0975]

[0976] Synthesis scheme and steps

[0977] Solution 16: X=O

[0978]

[0979] Synthesis steps

[0980] Ether bond formation from KI-10 and KI-11

[0981] 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) (after cooling in an ice bath), sodium hydride (76 mg, 1.9 mmol) was added portionwise. After 1 h, the reaction mixture was poured into saturated aqueous ammonium chloride solution (50 mL), extracted with EtOAc (3 x 30 mL), and the organic phase was further washed with water (2 x 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 to 20%) to give the title compound (161 mg, 33% yield) as a brown solid.

[0982] Deprotection steps:

[0983] See general steps [4], [5]

[0984] For example

[0985]

[0986] Conditions and yields: see Table 4 (deprotection) ( Figure 7 )

[0987] 57) 4-((2,5-dihydroxy-4-carboxyphenyl)methoxymethyl)-2,5-dihydroxybenzoic acid, compound IIIc-060a:

[0988] UPLC-MS (acidic method, 4 min): rt = 0.94 min; m / z = 349.1 [MH] - , peak area>90%.

[0989] 1 H NMR(400MHz,DMSO-d6)δ7.20(s,2H),6.92(s,2H),4.56(s,4H),

[0990] 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

[0991] Scheme 17: X=NH

[0992]

[0993] Synthesis steps

[0994] Amine bonds are formed from KI-12 and KI-13 via KI-10 and KI-11

[0995] 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 h. The reaction solution was filtered through a Celite pad, and the solid was washed with dichloromethane (300 mL), and then the solvent was removed under reduced pressure to give the title compound (3.2 g, 94% yield) as a light yellow solid.

[0996] UPLC-MS (acidic method, 2 min): rt = 1.33 min; m / z = no ion, peak area > 93%

[0997] 1H NMR (400MHz, DMSO-d6) δ10.39(s,1H),7.56(s,1H),7.54–7.26(m,11H),5.28(s,2H),5.20(s,2H),4.30(q,J=7.1Hz,2H),1.27(t,J=7.1Hz,3H).

[0998] 4-(Azidomethyl)-2,5-bis(benzyloxy)benzoic acid ethyl ester: 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 solution (200 mL) was added, the product was extracted with EtOAc (3x100 mL), and the combined organic layers were washed with water (2x50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / EtOAc 0 to 20%) to give the title compound (3.1 g, 98%) as a colorless oil that became a white solid over time.

[0999] UPLC-MS (acidic method, 2 min): rt = 1.37 min; m / z = 390.2, [M+H-N2] + , peak area>93%

[1000] 1 H NMR (400MHz, DMSO-d6) δ7.53–7.46(m,4H),7.44–7.26(m,8H),5.16(s,2H),5.14(s,2H),4.48(s,2H),4.26(q,J=7.1Hz,2H),1.25(t,J=7.1Hz,3H).

[1001] 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, ~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 (2x100 mL). The phases were separated, the aqueous layer was further extracted with EtOAc (100 mL), and the collected organic layer was 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.

[1002] UPLC-MS (basic method, 2 min): rt = 1.20 min; m / z = 392.2, [M+H] + , peak area>93%

[1003] 1 H NMR (400MHz, DMSO-d6) δ7.60–7.22(m,12H),5.14(s,2H),5.10(s,2H),4.24(q,J=7.1Hz,2H),3.75(s,2H),1.25(t,J=7.1Hz,3H).

[1004] 2,5-dibenzyloxy-4-[(2,5-dibenzyloxy-4-ethoxycarbonylphenyl)methylaminomethyl]benzoic acid ethyl ester: KI-12 (500 mg, 1.3 mmol) and KI-13 (641 mg, 1.6 mmol) were dissolved in DCM (35 mL) and activated molecular sieves (10 beads) were added. 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 poured 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 to 50%) to give the title compound (631 mg, 64% yield) as a colorless oil that became a solid over time.

[1005] UPLC-MS (acidic method, 2 min): rt = 1.37 min; m / z = 766.3, [M+H] + , peak area>92%

[1006] 1 H NMR (400MHz, DMSO-d6) δ7.47–7.42(m,4H),7.38–7.25(m,20H),5.08(s,4H),5.04(s,4H),4.25(q,J=7.1Hz,4H),3.76(s,4H),1.25(t,J=7.1Hz,6H).

[1007] Deprotection step: See general steps [4], [5]

[1008] Conditions and yields: see Figure 7 .

[1009] For example

[1010]

[1011] 58) Bis(4-carboxy-2,5-dihydroxyphenylmethyl)amine, compound IIIc-056a:

[1012] UPLC-MS (acidic method, 4 min): rt = 0.57 min; m / z = 350.0 [M+H] + , peak area>96%.

[1013] 1 H NMR (400MHz, DMSO-d6) δ9.97(s,2H),9.08(s,2H),7.31(s,2H),7.02(s,2H),4.11(s,4H).

[1014] HRMS:[M+H] + ,C 16 H 16 Calculated value of NO8: 350.08704, actual value: 350.08706

[1015] 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

[1016] Scheme 18: X = NAc

[1017]

[1018] Synthesis step N, N-bis-[2,5-dibenzyloxy-4-ethoxycarbonylphenylmethyl] acetamide: Under a nitrogen atmosphere, acetic anhydride (0.2mL, 2.1mmol) was added to a solution of N, N-bis-[2,5-dibenzyloxy-4-ethoxycarbonylphenylmethyl] amine (300mg, 0.39mmol) and pyridine (0.2mL, 2.4mmol) in DCM (6mL). The reaction mixture was stirred at room temperature for 1h and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane / EtOAc, 0 to 50%) to give the title compound (316mg, 92% yield) as a colorless oil.

[1019] UPLC-MS (acidic method, 2 min): rt = 1.44 min; m / z = 808.2 [M+H] + , peak area>95%.

[1020] 1H NMR(400MHz,DMSO-d6)δ7.49–7.17(m,22H),6.92(s,1H),6.72(s,1H),5.03(s,2H),5.00(s,2 H),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).

[1021] Deprotection steps:

[1022] See general steps [4], [5]

[1023] For example

[1024]

[1025] Conditions and yields: see Figure 7 (Deprotection)

[1026] 59) N,N-bis(4-carboxy-2,5-dihydroxyphenylmethyl)acetamide, compound IIIc-057a:

[1027] UPLC-MS (acidic method, 4 min): rt = 0.84 min; m / z = 392.1 [M+H] + , peak area>99%.

[1028] 1 H NMR (400MHz, DMSO-d6) δ9.50(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).

[1029] HRMS:[M+H] + ,C 18 H 18 Calculated value of NO9: 392.09761, actual value: 392.09766

[1030] Biodata: IIIc-057a: FGF-1 IC50 [μM] = 87; FGF-2 IC50 [μM] = 77; VEGF-A1 IC50 [μM] = 38; VEGFR-phosphorylation inhibition IC50 [μM] = 0.2; PMN ROS inhibition [%] at 0.3 μM = 90.34; PMNROS inhibition IC50 [μM] = ND; neutrophil adhesion 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-33IC50[μM]=2.93; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.15; TNFβIC50[μM]=1.58.

[1031] Scheme 19: X=NCH2C6H3(OH)2COOH

[1032]

[1033] Synthesis steps

[1034] Formation of tertiary amine from KI-11 and NH3

[1035] 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 test 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, as well as monomer and dimer structures. Water (100 mL) was added, and the resulting mixture was extracted with EtOAc (3x100 mL), and the collected organic layer was dried over Na2SO4, 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), DIPEA (10 mL, 58 mmol) were added, and the resulting solution was heated at 60 ° C. After 18h, water (100mL) was added and the resulting mixture was extracted with EtOAc (3x100mL). The collected organic layer was dried over NaSO, filtered and concentrated under reduced pressure. The residue was purified by recrystallization using EtOH / EtOAc 95 / 5 (20mL) as solvent to give the title compound (15.0g, 50%) as white crystals.

[1036] UPLC-MS (basic method, 2 min): rt = 1.71 min; m / z = 1140.3 [M+H] + , peak area>99%.

[1037] 1 H NMR (400MHz, DMSO-d6) δ6.56–6.49(m,12H),6.48–6.38(m,24H),4.22(s,6H),4.04(s,6H),3.42(q,J=7.1Hz,6H),3.00(s,6H),0.42(t,J=7.1Hz,9H).

[1038] Alternatively, the product can be purified by silica gel flash column chromatography: Scale, up to 270 g; Instrument: Combiflash Torrent; Column: RediSep column, silica gel 3 kg; Loading type: Crude oil dissolved in 1 L heptane: toluene (1:1). Elution with ethyl acetate / heptane. Detection: UV-240 nm

[1039] Deprotection step: See general steps [4], [5]

[1040] Conditions and yields: see Figure 7 (Deprotection)

[1041] Alternative large-scale deprotection procedure:

[1042] Saponification. To a 5L round-bottom flask were added tris(4-ethoxycarbonyl-2,5-dibenzyloxyphenylmethyl)amine (95.00g, 0.083mol), sodium hydroxide (40.00g, 0.99mol), water (570mL) and tetrahydrofuran (1.9L). The reaction mixture was heated at 80°C (reflux temperature of 65°C) for 48h using a temperature block and then stirred at room temperature for 24h. The solvent was then removed in vacuo. The crude material was collected and further diluted with water (2.85L). In another 10L flask, a mixture of acetic acid (180mL) and water (950mL) was stirred at room temperature. The mixture of the crude product in water was added to the acetic acid mixture over 30min while stirring with an overhead stirrer, and a frosty solid precipitated. The reaction mixture was stirred for an additional 1h and the solid was separated upon filtration; the mother liquor pH was 4.2. The separated solid was stirred with water (1425mL) for 1h and then filtered. The mother liquor pH was 4.5. The recovered solid was stirred with more water (1425 mL) for 1 h and then filtered; the mother liquor had a pH of 4.5. The solid was stirred with acetone (950 mL) for 1 h and filtered. The off-white solid (82.00 g, 93% yield) was dried in a vacuum oven at 50°C for 48 h (yields varied between 90-95%) prior to analysis.

[1043] Note: pH is a critical parameter during the washing process in order to maintain the product in the free acid form and remove excess acetic acid in the product.

[1044] Ideal pH: 4.2 to 4.5 (final sodium content varies between 2ppm-20ppm).

[1045] Hydrogenolysis and separation. A 2L round-bottom flask was charged with tris (4-carboxyl-2,5-dibenzyloxyphenylmethyl) amine (58.00 g, 54.00 mmol, 1 eq) and tetrahydrofuran (1160 mL). The mixture was degassed with nitrogen and then flushed with hydrogen / vacuum cycled 4-5 times. Palladium / carbon (JM10% 424Pd / C, 70 g, 15% loading) was added to the reaction mixture and stirred at 25 ° C for 5-6 h. The reaction solution was then degassed and the catalyst was removed by filtration through a diatomaceous earth 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 in a vacuum oven at 50 ° C (32.50 g, >100% yield based on crude product). 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. over 15-20 min (maintaining a temperature of at least 50° C. during the addition). At this stage, a turbid liquid was observed. The turbid reaction mixture was stirred at reflux temperature for 30 min.

[1046] After this time, the reaction mixture was cooled to room temperature for another 30 min. The precipitated solid was isolated by filtration and washed with a 1:1 mixture of ethanol and water (66 mL). Prior to analysis, the solid was dried in a vacuum oven at 50 ° C for at least 72 h to give the desired product IIIc-061a (22.00 g, 76% yield) (yield varied between 65-75%). LCMS: >95%, NMR: >95% purity.

[1047]

[1048] Tris(4-carboxy-2,5-dihydroxyphenylmethyl)amine, compound IIIc-061a:

[1049] UPLC-MS (acidic method, 4 min): rt = 0.74 min; m / z = 516.0 [M+H] + , peak area>86%.

[1050] 1 H NMR (400MHz, DMSO-d6) δ7.27(s,3H),6.83(s,3H),4.33(s,6H).

[1051] 13 C NMR (100MHz, DMSO-d6) δ172.0,154.3,148.3,134,117.8(CH),114.9(CH),112.4,53.6(CH2).

[1052] HRMS:[M+H] + ,C 24 H 22 NO 12 Calculated value: 516.11365, actual value: 516.11389

[1053] Biodata: IIIc-061a: FGF-1 IC50 [μM] = 9; FGF-2 IC50 [μM] = 7.6; VEGF-A1 IC50 [μM] = 21; VEGFR-phosphorylation inhibition IC50 [μM] = 4.3; PMN ROS inhibition [%] at 0.3 μM = 92.5; PMNROS inhibition IC50 [μM] = ND; neutrophil adhesion 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-33IC50[μM]=0.31; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.03; TNFβIC50[μM]=0.81

[1054] triethyl ester

[1055] UPLC-MS (acidic method, 2 min): rt = 1.05 min; m / z = 600.2 [M+H] + , peak area >82%.

[1056] 1 H NMR (400MHz, DMSO-d6) δ 10.02 (s, 3H), 9.54 (s, 3H), 7.17 (s, 3H), 7.00 (s, 3H), 4.33 (q, J = 7.1Hz, 6H), 3.59 (s, 6H), 1.31 (t, J = 7.1Hz, 9H).

[1057] HRMS:[M+H] + ,C 30 H 34 NO 12 Calculated value: 600.20755, actual value: 600.20790

[1058] 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

[1059] Solution 20: X = S

[1060]

[1061] Synthesis steps

[1062] Thioether bond formation from KI-11

[1063] See Scheme 21. The conditions for generating the thioether bond are the same.

[1064] Deprotection step: See general steps [4], [5]

[1065] For example

[1066]

[1067] Conditions and yields: see Figure 7 (Deprotection)

[1068] 60) 4-((2,5-dihydroxy-4-carboxyphenyl)methylthiomethyl)-2,5-dihydroxybenzoic acid, compound IIIc-058a:

[1069] UPLC-MS (acidic method, 2 min): rt = 0.84 min; m / z = 365.1 [MH] - , peak area>79%

[1070] 1 H NMR (400 MHz, methanol-d4) δ 7.25 (s, 2H), 6.83 (s, 2H), 3.69 (s, 4H).

[1071] HRMS:[M+H] + ,C 16 H 15 The calculated value of O8S is 367.04822, the actual value is 367.04768.

[1072] 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; PMNROS inhibition IC50 [μM] = 1.17; Neutrophil adhesion inhibition [%] = 23

[1073] Scheme 21: X = SO2

[1074]

[1075] Synthesis steps

[1076] Oxidation of thioether bonds

[1077] See preparation of IVc-059a: same oxidation conditions.

[1078] Deprotection step: See general steps [4], [5]

[1079] For example

[1080]

[1081] Conditions and yields: see Figure 7 (Deprotection)

[1082] 61) 4-((2,5-dihydroxy-4-carboxyphenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid, compound Ic-059a:

[1083] UPLC-MS (acidic method, 2 min): rt = 0.72 min; m / z = 397.1 [MH] - , peak area>97%

[1084] 1 H NMR (400MHz, DMSO-d6) δ13.94(brs,2H),10.63(brs,2H),9.71(s,2H),7.27(s,2H),6.91(s,2H),4.44(s,4H).

[1085] HRMS:[M+H] + ,C 16 H 15 O 10 Calculated value of S: 399.03804, actual value: 399.03768

[1086] 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; PMNROS inhibition IC50 [μM] = 1; Neutrophil adhesion inhibition [%] = 14.67

[1087] Example 1.11: Compound Type IVc

[1088]

[1089] Solution 22: X = S

[1090] Synthesized from dimethyl ether

[1091]

[1092] Synthesis steps

[1093] Synthesis of 5-O-methylgentisic acid

[1094] 3-Formyl-2-hydroxy-5-methoxybenzoic acid. To a mixture of 2-hydroxy-5-methoxybenzoic acid (24.0 g, 0.143 mol) in trifluoroacetic acid (190.0 mL) was added cyclohexamethylenetetramine (40.019 g, 0.285 mol). The reaction was refluxed for 18 h. After completion, the reaction was cooled to ambient temperature, and 2 M hydrochloric acid solution (700 mL) was added to the mixture and stirred at ambient temperature for 24 h. 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 light yellow solid (21.30 g, 0.11 mol, 77.0%).

[1095] UPLC-MS (acidic method, 2 min): rt = 0.69 min; m / z = 195.1 [MH] - , peak area>98%

[1096] 1 H NMR (400MHz, DMSO-d6) δ 10.36 (s, 1H), 7.62 (d, J = 3.4Hz, 1H), 7.44 (d, J = 3.4Hz, 1H), 3.78 (s, 3H).

[1097] Methyl 3-formyl-2,5-dimethoxybenzoate. 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) was added iodomethane (6.7 mL, 0.107 mol). The resulting mixture was stirred at ambient temperature for 18 h. The reaction was cooled to ambient temperature and treated with cold water (400 mL) to form a precipitate. The resulting suspension was stirred for 10 min, 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%).

[1098] UPLC-MS (acidic method, 2 min): rt = 0.95 min; m / z = 225.1 [M+H] + , peak area>98%

[1099] 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),7.55(d,J=3.4Hz,1H),7.41(d,J=3.4Hz,1H),3.88(s,3H),3.87(s,3H),3.83(s,3H).

[1100] 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 min. The solvent was removed in vacuo, and the residue was dissolved in DCM (200 mL) and then washed with water (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness to give methyl 3-(hydroxymethyl)-2,5-dimethoxybenzoate as a white solid (45.6 g, 0.20 mol, 95.0%).

[1101] UPLC-MS (acidic method, 2 min): rt = 0.84 min; no ionization, peak area > 98%

[1102] 1 H NMR (400MHz, DMSO-d6) δ7.20(d,J=3.2Hz,1H),7.08(d,J=3.3Hz,1H),5.24(t ,J=5.7Hz,1H),4.54(d,J=5.6Hz,2H),3.83(s,3H),3.76(s,3H),3.68(s,3H).

[1103] Methyl 3-(chloromethyl)-2,5-dimethoxybenzoate. To a solution of methyl 3-(hydroxymethyl)-2,5-dimethoxybenzoate (45.60 g, 0.20 mol) was added dropwise thionyl chloride (17.2 mL, 0.235 mol) at ambient temperature over 30 min. The resulting mixture was stirred at ambient temperature for 18 h. Upon completion, the reaction mixture was washed with saturated aqueous sodium carbonate solution (3 x 500 mL) and brine (500 mL). The organic layer was dried over Na2SO4, filtered and concentrated to dryness to give methyl 3-(chloromethyl)-2,5-dimethoxybenzoate as a brown solid (49.1 g, 0.18 mol, 90%).

[1104] UPLC-MS (acidic method, 2 min): rt = 1.10 min; no ionization, peak area > 92%

[1105] 1 H NMR (400MHz, DMSO-d6) δ7.29 (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).

[1106] 3-(Acetylthiomethyl)-2,5-dimethoxybenzoic acid methyl ester. At ambient temperature, potassium thioacetate (15.54g, 0.136mol) is added to a solution of 3-(chloromethyl)-2,5-dimethoxybenzoic acid methyl ester (22.20g, 0.091mol) in THF (500.0mL). The reaction mixture is stirred at 75 ° C for 18h. After completion, the solvent is removed under reduced pressure to obtain a red oily residue, which is treated with a saturated saline solution (500mL) and then extracted with diethyl ether (2x250mL). The organic phases are combined, dried over Na2SO4, filtered and concentrated to dryness to obtain 3-(acetylthiomethyl)-2,5-dimethoxybenzoic acid methyl ester as a brown solid (25.50g, 0.09mol, 99%).

[1107] UPLC-MS (acidic method, 2 min): rt = 1.10 min; no ionization, peak area > 92%

[1108] 1 H NMR (400MHz, DMSO-d6) δ7.12(d,J=3.3Hz,1H),7.10(d,J=3.2Hz,1H),4.10(s,2H),3.84(s,3H),3.74(s,3H),3.70(s,3H),2.35(s,3H).

[1109] Methyl 3-(mercaptomethyl)-2,5-dimethoxybenzoate. To a solution of methyl 3-(acetylthiomethyl)-2,5-dimethoxybenzoate (25.5 g, 89.68 mmol) in dry methanol (800 mL) was added a solution of sodium methoxide (5.81 g, 107.62 mmol) dropwise at 0°C under a nitrogen atmosphere. The mixture was stirred at room temperature for 45 min and then treated with Dowex X8 (H + ) ion exchange resin quenched and stirred for 15min. After filtration, the solvent was evaporated under reduced pressure to obtain a brown oily crude product (which contains the desired product and the corresponding disulfide compound in a ratio of 2: 1). The residue was dissolved in DMF (400.0mL) and treated with dithiothreitol (DTT) (33.95g, 0.26mol) under a nitrogen atmosphere. The reaction mixture was stirred at 75 ° C for 18h. After completing the conversion of disulfide to thiol, the solvent was evaporated. The resulting residue was dissolved in DCM (1L), washed with brine (7x500mL), dried over Na2SO4, filtered and concentrated to dryness to obtain homogeneous 3-(mercaptomethyl)-2,5-dimethoxybenzoic acid methyl ester as a brown oil (21.40g, 88.32mmol, 99%).

[1110] UPLC-MS (acidic method, 2 min): rt = 1.05 min; m / z = 243.1 [M+H] + , peak area>95%

[1111] 1 H NMR(400MHz,DMSO-d6)δ7.19(d,J=3.2Hz,1H),7.09(d,J=3.3Hz,1H),3.83(s ,3H),3.76(s,3H),3.73(s,3H),3.71(d,J=8.0Hz,2H),2.93(t,J=8.0Hz,1H).

[1112] Dimethyl 3,3'-(thiobis(methylene))bis(2,5-dimethoxybenzoate). Under a nitrogen atmosphere, triethylamine (19.0mL, 136.61mmol) was added to a solution of methyl 3-(mercaptomethyl)-2,5-dimethoxybenzoate (21.40g, 88.32mmol) and methyl 3-(chloromethyl)-2,5-dimethoxybenzoate (22.69g, 92.74mmol). The reaction was stirred for 18h at ambient temperature. After completion, the solvent was removed under vacuum to obtain a brown oily residue, which was treated with water (1L) and then extracted with diethyl ether (3x500mL). The organic phases were combined, washed with brine (5 x 250 mL), dried over Na2SO4, filtered and concentrated to dryness to give the crude product as a brown oil, which was purified by silica gel chromatography: gradient elution with ethyl acetate (0 to 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%).

[1113] UPLC-MS (acidic method, 2 min): rt = 1.22 min; m / z = 451.2 [M+H] + , peak area>92%

[1114] 1 H NMR (400MHz, DMSO-d6) δ7.12–7.08(m,4H),3.83(s,6H),3.76(s,4H),3.73(s,6H),3.67(s,6H).

[1115] 3,3'-(thiobis(methylene))bis(2,5-dimethoxybenzoic acid). A solution of lithium hydroxide monohydrate (1.0 g, 23.83 mmol) in water (30.0 mL) was added to a solution of dimethyl 3,3'-(thiobis(methylene))bis(2,5-dimethoxybenzoate) (2.0 g, 4.44 mmol) in THF (100.0 mL). The reaction was stirred at ambient temperature for 48 h. 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 1M aqueous hydrochloric acid and extracted with ethyl acetate (3X100 mL). The organic layer was collected, dried (Na2SO4), filtered and concentrated to afford 3,3'-(thiobis(methylene))bis(2,5-dimethoxybenzoic acid) as a brown solid (1.91 g, 4.11 mmol, 93%).

[1116] UPLC-MS (acidic method, 2 min): rt = 0.93 min; m / z = 421.1 [MH] - , peak area>95%

[1117] 1 H NMR (400MHz, DMSO-d6) δ 12.96 (s, 2H), 7.10 (d, J = 3.3Hz, 2H), 7.08 (d, J = 3.2Hz, 2H), 3.76 (s, 4H), 3.73 (s, 6H), 3.69 (s, 6H).

[1118] 3-[(2,5-dihydroxy-3-carboxylphenyl)methylthiomethyl]-2,5-dihydroxybenzoic acid. To a solution of the previous 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. Afterwards, the solid was filtered, washed with DCM (500 mL), and then suspended in a 1 M hydrochloric acid solution (50 mL). The resulting mixture was refluxed for 2 h. The resulting brown suspension was filtered and dried to give a crude product, which was purified by reverse phase column chromatography (25 g, MeCN: H2O 5% to 95%, 12CV) to give 2,5-dihydroxy-3-[(2,5-dihydroxy-3-carboxylphenyl)methylthiomethyl]benzoic acid as a white solid (1.1 g, 0.003 mol, 26%).

[1119] UPLC-MS (acidic method, 2 min): rt = 0.70 min; m / z = 365.1 [MH] - , peak area>95%

[1120] 1 H NMR (400MHz, DMSO-d6) δ 13.86 (s, 2H), 11.09 (s, 2H), 9.14 (s, 2H), 7.08 (d, J = 3.1Hz, 2H), 7.02 (d, J = 3.1Hz, 2H), 3.65 (s, 4H).

[1121] Example:

[1122] 62) 3-((2,5-dihydroxy-3-carboxyphenyl)methylthiomethyl)-2,5-dihydroxybenzoic acid, compound IVc-058a:

[1123] UPLC-MS (acidic method, 2 min): rt = 0.70 min; m / z = 365.1 [MH] - , peak area>95%

[1124] 1H NMR (400MHz, DMSO-d6) δ 13.86 (s, 2H), 11.09 (s, 2H), 9.14 (s, 2H), 7.08 (d, J = 3.1Hz, 2H), 7.02 (d, J = 3.1Hz, 2H), 3.65 (s, 4H).

[1125] HRMS:[M+H] + ,C 16 H 15 Calculated value of O8S: 367.04822, actual value: 367.04734

[1126] Biodata: IVc-058a: FGF-1 IC50 [μM] = 36; FGF-2 IC50 [μM] = 4.9; VEGF-A1 IC50 [μM] = 83; VEGFR-phosphorylation inhibition IC50 [μM] = 0.53; PMN ROS inhibition [%] = 77.04 at 0.3 μM; PMNROS inhibition IC50 [μM] = 0.29; neutrophil adhesion 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; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.18; TNFβIC50[μM]=59.3.

[1127] Scheme 23: X = SO2

[1128]

[1129] Synthesis of compound IVc-058a

[1130] 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-carboperoxyacid (mCPBA purity grade ≤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%).

[1131] UPLC-MS (acidic method, 4 min): rt = 0.68 min; m / z = 397.1 [MH] - , peak area>95%

[1132] 63) 3-((2,5-dihydroxy-3-carboxyphenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid, compound IVc-059a:

[1133] UPLC-MS (acidic method, 4 min): rt = 0.68 min; m / z = 397.1 [MH] - , peak area>95%

[1134] 1 H NMR (400MHz, DMSO-d6) δ11.24(s,1H),9.32(s,1H),7.21(d,J=3.1Hz,1H),7.09(d,J=3.1Hz,1H),4.44(s,2H).

[1135] 13 C NMR (100MHz, DMSO-d6) δ172.4, 153.4, 149.2, 117.4, 116.1 (CH), 113.3 (CH), 53.6 (CH2).

[1136] HRMS:[M+H] + ,C 16 H 15 O 10 Calculated value of S: 399.03804, actual value: 399.03775

[1137] Biological data: IVc-059a: FGF-1 IC50 [μM] = 6.7; FGF-2 IC50 [μM] = 2.7; VEGF-A1 IC50 [μM] = 12; VEGFR-phosphorylation inhibition IC50 [μM] = 4.8; PMN ROS inhibition [%] = 74 at 0.3 μM; PMNROS inhibition IC50 [μM] = 0.147; neutrophil adhesion 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; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.16; TNFβIC50[μM]=0.33

[1138] Dimethyl ester

[1139] UPLC-MS (acidic method, 2 min): rt = 0.94 min; m / z = 427.1 [M+H] + , peak area>95%

[1140] 1 H NMR (400MHz, DMSO-d6) δ10.28(s,2H),9.43(s,2H),7.21(d,J=3.1Hz,2H),7.13(d,J=3.1Hz,2H),4.47(s,4H),3.91(s,6H).

[1141] HRMS:[M+H] + ,C 18 H 19 O 10 Calculated value of S: 427.06934, actual value: 427.06942

[1142] Biodata: IVc-059a-E2: FGF-1 IC50 [μM] = 78; FGF-2 IC50 [μM] = 94; VEGF-A1 IC50 [μM] = 200; VEGFR-phosphorylation inhibition IC50 [μM] = 2.7; PMN ROS inhibition [%] = 45.67; PMN ROS inhibition IC50 [μM] = 2.64; Neutrophil adhesion inhibition [%] = 50.5

[1143] Dimethyl tetraacetate

[1144] UPLC-MS (acidic method, 2 min): rt = 1.05 min; m / z = 593.1 [MH] - , peak area>95%

[1145] 1 H NMR (400MHz, DMSO-d6) δ7.75 (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).

[1146] HRMS:[M+H] + ,C 26 H 27 O 14 Calculated value of S: 595.11160, actual value: 595.11149

[1147] Biodata: IVc-059a-E2-A4: FGF-1 IC50 [μM] = 54; FGF-2 IC50 [μM] = 200; VEGF-A1 IC50 [μM] = 25; VEGFR-phosphorylation inhibition IC50 [μM] = ND; PMN ROS inhibition [%] at 0.3 μM = 29.17; PMN ROS inhibition IC50 [μM] = 4.13; neutrophil adhesion 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; TGFβIC50[μM]=>100; TNFαIC50[μM]=0.3; TNFβIC50[μM]=19.4

[1148] Alternative, Scalable Synthesis of IVc-059a

[1149] Scheme 24: Synthesis of IVc-059a from 2,5-dibenzyloxyphthalaldehyde

[1150]

[1151] 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 nitrogen flow and stirred at room temperature for 10 minutes, then solid NaBH4 (695 mg, 18.37 mmol) was added portionwise over 20 minutes, not allowing the internal temperature of the reaction to exceed 25°C (using a water bath). The reaction mixture was stirred at room temperature for 30 minutes, then additional NaBH4 was added every 15 minutes until complete conversion of the starting material (total: 107 mg, in two portions). 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 in a vacuum oven at 40°C until the mass remained constant to afford the title compound (22.9 g, 76% corrected yield) as a brown oil. NMR spectrum showed 83% desired product, 15% over-reduced diol, 2% starting material and this material was carried forward to the next step without further purification.

[1152] UPLC-MS (acidic method, 2 min): rt = 1.19 min, 86%, m / z = 347.2 [MH]-

[1153] 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),7.52–7.28(m,11H),7.19(d,J=3.3Hz, 1H), 5.34 (t, J = 5.6Hz, 1H), 5.15 (s, 2H), 4.99 (s, 2H), 4.60 (d, J = 5.6Hz, 2H).

[1154] 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 min. A solution of sodium chlorite (21.5 g, 191 mmol) in water (60 mL) was slowly added over 30 min, ensuring that the internal temperature did not exceed 25°C. The reaction mixture was stirred at room temperature for 3 h, and 2M aqueous H3PO4 (95 mL) was added. The mixture was stirred for 20 min, 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 ~6. The obtained solid was suspended in water (ca 300mL) and a solution of pre-cooled (5-10°C) NaOH (17g, 412mmol) in water (200mL) was added. The suspension was stirred at room temperature for 30min and then filtered on a sinter funnel. The isolated solid was further washed with 1M aqueous NaOH (2x50mL) and water (50mL). The alkali solution was then acidified to pH~1 using a pre-cooled (5-10°C) 6N HCl aqueous solution. The obtained suspension was magnetically stirred for 20min and then filtered, and the obtained solid was further dried in a 40°C vacuum oven until constant mass to obtain the title compound as a light beige solid (34.8g, 88%).

[1155] UPLC-MS (acidic method, 2 min): rt = 1.06 min, 99%, m / z = 363.2 [MH] - .

[1156] 1H NMR(400MHz,DMSO-d6)δ13.02(s,1H),7.51–7.31(m,10H),7.28(d,J=3.2Hz,1 H),7.22(d,J=3.3Hz,1H),5.21(s,1H),5.12(s,2H),4.88(s,2H),4.53(s,2H).

[1157] Ethyl 2,5-bis(benzyloxy)-3-(hydroxymethyl)benzoate [Step 3]: 2,5-bis(benzyloxy)-3-(hydroxymethyl)benzoic acid (32.5 g, 89.3 mmol) and Cs2CO3 (32.3 g, 99.2 mmol) were suspended in DMF (200 mL) and iodoethane (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 NH4Cl (1 L) and solid NaCl (~30 g) was added. After stirring for 10 min, the material was extracted with EtOAc (2 x 500 mL). The collected organic layer was washed with brine (2 x 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 used in the next step without further purification.

[1158] UPLC-MS (acidic method, 2 min): rt = 1.24 min, 93%, m / z = weak ionization.

[1159] 1H NMR (400MHz, DMSO-d6) δ7.51–7.32(m,10H),7.31(d,J=3.3Hz,1H),7.22(d,J=3.3Hz,1H),5.24(t,J=5. 6Hz,1H),5.13(s,2H),4.87(s,2H),4.54(d,J=5.6Hz,2H),4.26(q,J=7.1Hz,2H),1.24(t,J=7.1Hz,3H)

[1160] Ethyl 2,5-bis(benzyloxy)-3-(chloromethyl)benzoate (KI-14) [Step 4]: Under an inert atmosphere (N2), ethyl 2,5-bis(benzyloxy)-3-(hydroxymethyl)benzoate (42 g of crude material from the previous step, 89.3 mmol) was dissolved in DCM (200 mL). SOCl2 (9.8 mL, 133.9 mmol) was then 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 and then azeotropically distilled with toluene (3 x 100 mL) to give a semisolid brown oil (38.0 g, crude, 89.3 mmol).

[1161] UPLC-MS (acidic method, 2 min): rt = 1.40 min, 91%, m / z = weak ionization.

[1162] 1H NMR (400MHz, DMSO-d6) δ7.54–7.26(m,12H),5.14(s,2H),4.95(s,2H),4.71(s,2H),4.28(q,J=7.1Hz,2H),1.28–1.22(t,J=7.1Hz,3H).

[1163] 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 KCO-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 before the addition of thioacetamide (2.5 g, 33.3 mmol) and KCO-325 mesh (5.0 g, 36.1 mmol) and stirred at 45°C for a further 18 h to complete the reaction. The reaction mixture was poured into water (4 L). The reaction mixture was stirred for 20 min before the addition of EtOAc (2 L) followed by solid NaCl (~60 g). The phases were separated and then re-extracted with EtOAc (1.5 L). The collected organic layers were washed with brine (1.5 L), dried over Na 2 SO 4 , 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.

[1164] UPLCMS (acidic method, 2 min): rt = 1.57 min, m / z = 800.5 [M+NH4]+, peak area 77%.

[1165] 1H NMR (400MHz, DMSO-d6) δ7.46–7.17(m,24H),5.05(s,4H),4.83(s,4H),4.23(q,J=7.1Hz,4H),3.73(s,4H),1.20(t,J=7.1Hz,6H).

[1166] 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 30 wt% hydrogen peroxide solution (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, then EtOAc (2 L) and solid NaCl (~40 g) were added. After phase separation, the aqueous layer was extracted once more with EtOAc (1 L). The collected organic layer was washed with brine (1.5 L), dried over Na2SO4, filtered and concentrated under reduced pressure to 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 4 steps).

[1167] UPLC-MS (acidic method, 2 min): rt = 1.48 min; m / z = 832.5 [M+NH4]+, peak area 96%

[1168] 1H NMR (400MHz, DMSO-d6) δ7.50–7.24(m,24H),5.08(s,4H),4.85(s,4H),4.50(s,4H),4.26(q,J=7.1Hz,4H),1.25–1.17(m,6H).

[1169] 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 at reflux for 18 h. After this time, most of the THF was removed under reduced pressure to obtain a white suspension. After the addition of water (3 L) and aqueous sodium hydroxide solution (1 M, 1 L), the mixture remained a suspension. The suspension was stirred at room temperature for 18 h. The aqueous layer was acidified to pH ~1 by the addition of 6 M aqueous hydrochloric acid. The resulting solid was collected by filtration and washed with water until the liquid was neutral. The white solid thus obtained was further dried in a vacuum oven at 40°C until the mass remained constant to afford the title compound as a white solid (29.4 g, 38.7 mmol, 99%).

[1170] UPLC-MS (acidic method, 2 min): rt = 1.39 min; m / z = 757.1 [MH]-, peak area 100%

[1171] 1H NMR (400MHz, DMSO-d6) δ13.23(s,2H),7.47–7.25(m,24H),5.08(s,4H),4.88(s,4H),4.48(s,4H).

[1172] 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) was added palladium on carbon (20 wt%, 2 g) as a suspension in water (20 mL). After several vacuum / hydrogen cycles, the mixture was kept under H2 atmosphere at 25°C and stirred for 20 h. After completion, THF was used to remove the residue by filtration. The mixture was filtered. The filtrate was concentrated under reduced pressure to obtain 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, filtered, and further washed with cold acetonitrile. The product was further dried in a vacuum oven at 40°C until the mass was constant to obtain the desired product as a white solid (5.35 g, 12.78 mmol, 96%).

[1173] UPLC-MS (acidic method, 4 min): rt = 0.67 min; m / z = 397.1 [MH]-, peak area 100%

[1174] NMR data: see above.

[1175] Example 1.12-V-type molecules : Reference compound

[1176] Diamide derived from 5-hydroxyisophthalic acid

[1177] 2 Examples

[1178]

[1179] Synthesis scheme and steps

[1180] Scheme 25: Synthesis of V-001a

[1181]

[1182] Amide bond formation

[1183] See General Procedure B for amide coupling using aniline A (2 moles) or methyl 5-aminosalicylate [3B]

[1184] Deprotection step: See general steps [4], [5]

[1185] For details, see Figure 8

[1186] For example

[1187]

[1188] 64) 5-Hydroxyisophthalic acid bis-N-(4-carboxy-2,5-dihydroxyphenyl)amide (V-001a)

[1189] UPLC-MS (acidic method, 2 min): rt = 0.72 min; m / z = 483.0 [M+H] + , peak area>95%

[1190] 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),9.83(s,2H),9.48(s,2H),7.92(s,1H),7.68(s,2H),7.52(d,J=1.5Hz,2H),7.30(s,2H).

[1191] Diethyl ester

[1192] UPLC-MS (acidic method, 2 min): rt = 1.09 min; m / z = 539.2 [MH] - , peak area 94%

[1193] 1 H NMR(400MHz,DMSO-d6)δ10.23(s,2H),9.92(s,2H),9.49(s,2H),7.91(s,1H),7.73(s, 2H), 7.51 (d, J = 1.5Hz, 2H), 7.32 (s, 2H), 4.35 (q, J = 7.1Hz, 4H), 1.34 (t, J = 7.1Hz, 6H).

[1194]

[1195] 65) 5-Hydroxyisophthalic acid bis(N-(3-carboxy-4-hydroxyphenyl)amide) (V-002a)

[1196] UPLC-MS (acidic method, 4 min): rt = 1.00 min; m / z = 451.1 [MH] - , peak area 97%

[1197] 1H NMR (400MHz, DMSO-d6) δ10.31(s,2H),10.11(s,1H),8.28(d,J=2.7Hz,2H),7.98( m, 1H), 7.89 (dd, J = 9.0, 2.7Hz, 2H), 7.50 (d, J = 1.5Hz, 2H), 6.97 (d, J = 9.0Hz, 2H).

[1198] Urea-linked gentisate units 1 embodiment

[1199]

[1200] Synthesis scheme and steps

[1201] Scheme 26: Synthesis of V-003a

[1202]

[1203] Urea bond formation

[1204] Steps from KI-1:

[1205] N , N'-bis(2,5-dibenzyloxy-4-ethoxycarbonylphenyl)urea. Under an inert atmosphere (N2), DPPA (1.1 mL, 5.2 mmol) was slowly added to a cooled solution (ice bath) of 2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid (KI-1) (2.0 g, 4.9 mmol) and Et3N (1.6 mL, 11.3 mmol) in THF (25 mL). 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 curve showed most of the urea bond product, rather than the desired Boc-aniline. The mixture was poured into a saturated sodium bicarbonate solution (250 mL), stirred for 5 min, and then extracted with EtOAc (3x50 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.

[1206] UPLC-MS (basic method, 2 min): rt = 1.50 min; m / z = 781.2 [M+H] + , peak area 85%

[1207] 1H NMR(400MHz,DMSO-d6)δ9.49(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=7.1Hz,4H),1.24(t,J=7.1Hz,6H).

[1208] Deprotection step: See general steps [4], [5]

[1209] For details, see Figure 8

[1210] For example

[1211] 66) N ,N'-bis(2,5-dihydroxy-4-carboxyphenyl)urea(V-003a)

[1212]

[1213] UPLC-MS (acidic method, 4 min): rt = 0.90 min; m / z = 363.1 [MH] - , peak area 93%

[1214] 1 H NMR (400MHz, DMSO-d6) δ13.36(s,2H),10.86(s,2H),9.64(s,2H),9.48(s,2H),7.77(s,2H),7.17(s,2H).

[1215] Diethyl ester

[1216] UPLC-MS (acidic method, 4 min): rt = 1.79 min; m / z = 419.2 [MH] - , peak area 97%

[1217] 1 H NMR (400MHz, DMSO-d6) δ10.26(s,2H),9.74(s,2H),9.53(s,2H),7.81(s,2H),7.20(s,2H),4.32(q,J=7.1Hz,4H),1.33(t,J=7.1Hz,6H).

[1218] Example 1.13: Salt formation

[1219] a) Solid.

[1220] General Protocol: Solid salts are obtained by adding an appropriate equivalent of base to a solution or suspension of the desired compound in water, sonicating until completely dissolved, adjusting the pH to 7.0 to 7.4 by adding aqueous HCl or excess base as needed, and then lyophilizing the solution. Alternatively, certain salts (IIc-007a) can be obtained by dissolving in DMSO followed by precipitation with EtOH. Solids are generated with the following bases: sodium hydroxide, diethylamine (DEA), lysine (Lys), meglumine (Meg), triethanolamine (TEA).

[1221] For example:

[1222] According to the general protocol, the sodium and diethylammonium salts (DEA) of Ic-007a, IIc-007a, and IIIc-061a were obtained as solids without adjusting the pH.

[1223] -Approximate solubility in water:

[1224] Ic-007a-DEA2:<10mg / mL

[1225] Ic-007a-DEA3:>20mg / mL

[1226] IIc-007a-DEA1:>10mg / mL

[1227] IIc-007a-DEA2:>20mg / mL

[1228] IIIc-061a-DEA3:>25mg / mL

[1229] - Stability of free acid and salt as solid:

[1230] The free acids Ic-007a, IIc-007a, IIIc-061a and the following salts Ic-007a-DEA2, IIc-007a-DEA2, IIIc-061a-DEA3 were stable in solid form for up to 56 days at 4°C, 20°C, and 40°C; the salt Ic-007a-DEA3 was stable for up to 36 days at the same temperatures.

[1231] b) Solution

[1232] General Protocol: Salts are obtained in solution by adding an appropriate equivalent of base to a solution or suspension of the desired compound in water, sonicating until complete dissolution, and adjusting the pH to 7.0 to 7.4, if necessary, by addition of aqueous HCl or excess base. The following bases were studied: ethylamine, triethylamine, ethylenediamine, diethanolamine, triethanolamine, choline, meglumine, lysine, and arginine.

[1233] For example:

[1234] Salt of Ic-007a:

[1235] After stirring the mixture at 40°C for 2 days, a soluble salt was obtained using meglumine, lysine, and diethanolamine. The Ic-007a-Lys2 salt was obtained as a solid from DMSO by precipitation with ethanol. The salt was stable as an aqueous solution at room temperature for at least 7 days.

[1236] Salt of IIc-007a:

[1237] DEA1-salt: In small scale, the monodiethylammonium salt was obtained by the general procedure without pH adjustment. Solubility: 17.4 mg / mL vs. 1.8 mg / mL for the parent diacid

[1238] Large-Scale Processing and Characterization :

[1239] To IIc-007a (20 g, 42.7 mmol) was added EtOH (200 mL). The reaction was stirred at room temperature to obtain a slurry. DEA (4.4 mL, 42.7 mmol) was added and the reaction was heated at 50°C for 2 h. The batch was cooled to room temperature (RT) and the solid was filtered. The filter cake was washed with EtOH (50 mL) and oven-dried at 40°C to obtain 21.5 g of the mono-DEA salt as a yellow solid in a 98% yield. NMR: 1.6% EtOH, 1.04 eq DEA. HPLC: 99.6%.

[1240] 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 loss of EtOH <120°C, suggesting that EtOH can be dried at 60-80°C. A loss of DEA (13.5 wt% theoretical for a 1:1 salt) was then observed in association with a melt endotherm in DSC (peak at 273.8°C), followed by melting of the free acid form.

[1241] DEA2-salt, pH adjusted: obtained by the general procedure for pH adjustment (0.51 equivalents of Et2NH are required to reach pH = 7.25). The salt in solution showed obvious degradation after 21 days at 40°C and significant degradation after 24 hours at 80°C.

[1242] DEA2-salt, pH unadjusted: obtained by the general procedure without pH adjustment. The pH of the solution was 5.87. After 21 days at 4°C, 20°C, and 40°C, the salt in solution showed no degradation.

[1243] Lys2-salt, pH not adjusted: obtained by the general procedure using 2 equivalents of L-lysine. The pH of the solution was 5.74.

[1244] Note: Similar to the bis(N-methyl)amide of 2-hydroxyisophthalic acid (phenol has a pKa of 6.81), the 2-OH group of the isophthalic acid bisamide core of IIc-007a is significantly acidic, and its ionization leads to molecular degradation. This effect was not observed for Ic-007a (the expected pKa of the phenol functional group is in the range of 9.8-10.0). Therefore, it is important not to adjust the pH of the IIc-007a dicationic salt solution.

[1245] Salt of IIIc-061a:

[1246] DEA3-salt, pH adjusted: obtained by the general procedure with pH adjustment using 3 equivalents of Et2NH (0.8 equivalents of HCl (0.5 M) were also required to reach a final pH = 7.22). The salt in solution did not degrade after 21 days at 4 ° C and 20 ° C, and slightly degraded after 33 days at 40 ° C.

[1247] Meg3-salt, pH adjusted: obtained by the general procedure using 3 equivalents of meglumine with pH adjusted to final pH = 7.22 (HCl 0.5 M). The salt in solution was not degraded after 21 d at 4°C, 20°C and 14 d at 40°C.

[1248] A salt of IVc-059a,

[1249] DEA2-salt, pH adjusted: obtained by the general procedure with pH adjustment (0.32 equivalents of Et2NH were required to reach pH = 7.3). The salt in solution showed stability after 26 days at 4°C, 20°C and 40°C.

[1250] Example 1.14: Prodrugs

[1251] Prodrug of Ic-007a

[1252] 1) 2-Morpholinoethyl 5-[[2,5-dihydroxy-4-[[4-hydroxy-3-(2-morpholinoethoxycarbonyl)phenyl]carbamoyl]benzoyl]amino]-2-hydroxybenzoate (Ic-007a-mpe2)

[1253]

[1254] Esterification. A suspension of 5-[[2,5-dibenzyloxy-4-[(3-carboxy-4-hydroxyphenyl)carbamoyl]-benzoyl]amino]-2-hydroxy-benzoic acid (130 mg, 0.2 mmol) in N,N-dimethylformamide (4 ml) was stirred at room temperature. A solution of N,N-dimethylpyridin-4-amine (49 mg, 0.4 mmol) and 2-morpholinoethanol (53 mg, 0.4 mmol) in N,N-dimethylformamide (0.5 ml) was added. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.6 mmol) was added, and the reaction mixture was heated at 60 ° C in a microwave reactor 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.

[1255] Hydrogenolysis: Prepare a solution of the diester obtained above (80 mg, 0.092 mmol) in tetrahydrofuran (12 ml) and water (4 ml) and add 10% palladium on carbon (50 mg, 10% paste). The reaction mixture is stirred under a hydrogen atmosphere for 17 hours. The catalyst is removed by filtration and the solvent is evaporated. The residue is 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 is triturated with diethyl ether and dried in vacuo to give the title product Ic-007a-mpe2 as a yellow solid (22 mg, 35%).

[1256] 1 H 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, 2.7 Hz, 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.

[1257] 2) 5-[[2,5-Dihydroxy-4-[[4-hydroxy-3-(2-morpholinoethoxycarbonyl)phenyl]carbamoyl]benzoyl]amino]-2-hydroxy-benzoic acid (Ic-007a-mpe1)

[1258]

[1259] Esterification. A solution of 5-[[2,5-dibenzyloxy-4-[(3-carboxy-4-hydroxy-phenyl)-carbamoyl]benzoyl]amino]-2-hydroxy-benzoic acid (324 mg, 0.5 mmol) and triethylamine (101 mg, 0.15 ml, 1 mmol) in N,N-dimethylformamide (7 ml) was stirred at room temperature. A solution of 2-morpholinoethanol (66 mg, 0.5 mmol) in N,N-dimethylformamide (1 ml) and N,N-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 ether to give a mixture of monoester and diester (230 mg). LCMS (m / z) [M+H] 762.0 (monoester).

[1260] Hydrogenolysis. The mixture of the monoester and diester obtained above (230mg) was dissolved in acetic acid (10ml), tetrahydrofuran (15ml) and water (5ml), and 10% palladium on carbon (150mg, 10% paste) was added. The reaction mixture was stirred for 16 hours under a hydrogen atmosphere. The catalyst was removed by filtration and the solvent was evaporated to obtain a yellow colloid (140mg). The residue was purified by a gradient of 10-70% (acetonitrile+0.1% formic acid): (water+0.1% formic acid) on a C18 column using reversed-phase preparative HPLC. The residue was ground with diethyl ether and dried in vacuo to obtain the title monoester Ic-007a-mpe1 as a yellow solid (11mg).

[1261] 1 H NMR(d6-DMSO ppm)δ11.33-11.29(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, 2.4 Hz, 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.

[1262] 3) 1-(2,2-dimethylpropionyloxy)ethyl 5-[[4-[[3-[1-(2,2-dimethylpropionyloxy)ethoxycarbonyl]-4-hydroxy-phenyl]carbamoyl]-2,5-dihydroxy-benzoyl]amino]-2-hydroxy-benzoate (Ic-007a-pive2)

[1263] and

[1264] 4) 5-[[4-[[3-[1-(2,2-dimethylpropionyloxy)ethoxycarbonyl]-4-hydroxy-phenyl]carbamoyl]-2,5-dihydroxy-benzoyl]amino]-2-hydroxy-benzoic acid (Ic-007a-pive1)

[1265]

[1266] Esterification. A solution of 5-[[2,5-dibenzyloxy-4-[(3-carboxy-4-hydroxy-phenyl)carbamoyl]benzoyl]amino]-2-hydroxy-benzoic acid (324 mg, 0.5 mmol) and triethylamine (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 allowed to warm to room temperature and stirred at room temperature for 24 hours. Dimethylformamide was evaporated and the residue was distributed between dichloromethane and aqueous sodium metabisulfite. The organic phase was dried over anhydrous magnesium sulfate and evaporated to give a 1:1 mixture of monoester and diester (187 mg). The reaction was repeated and the 1:1 mixture of esters was combined. LCMS (m / z) [M+H] 777.0 (monoester) and 905.1 (diester).

[1267]

[1268] hydrogenolysis

[1269] The mixture (320mg) of the monoester and diester obtained above is dissolved in tetrahydrofuran (50ml) and water (5ml), and 10% palladium on carbon (300mg, 10% paste) is added. The reaction mixture is stirred for 20 hours under a hydrogen atmosphere. The catalyst is removed by filtration and the solvent is evaporated. LCMS shows that only partial deprotection has been achieved. The residue is dissolved in tetrahydrofuran (36ml) and water (6ml), 10% palladium on carbon (600mg, 10% paste) is added. The reaction mixture is stirred for 22 hours under a hydrogen atmosphere. The catalyst is removed by filtration and the solvent is evaporated. The residue is purified by the gradient of 40-97% (acetonitrile+0.1% formic acid): (water+0.1% formic acid) on a C18 column by reversed-phase preparative HPLC. The residue is ground with ether and dried in vacuo to obtain the title product:

[1270] Diester (Ic-007a-pive2): yellow solid (60 mg). 1 H NMR(d6-DMSO ppm)δ11.05(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=5.5Hz,3H),1.17(s,9H). LCMS(m / z)[M+H]724.9.

[1271] Biological data: T 1 / 2 (mouse plasma): 62.2 min (ester cleavage; 65% remaining after 1 h); T 1 / 2 (Human plasma):>180min.

[1272] Monoester (Ic-007a-pive1): yellow solid (35 mg). 1 H NMR(d6-DMSO ppm)δ11.13(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=5.5Hz,3H),1.17(s,9H).LCMS(m / z)[M+H]596.9

[1273] Biological data: T 1 / 2 (mouse plasma): 44.6 min (ester cleavage; 49% remaining after 1 h); T 1 / 2 (Human plasma):>180min.

[1274] Prodrug of IIc-007a

[1275] 1) 2,2-dimethylpropionyloxymethyl 5-[[3-[[3-(2,2-dimethylpropionyloxymethoxycarbonyl)-4-hydroxy-phenyl]carbamoyl]-2,5-dihydroxy-benzoyl]amino]-2-hydroxy-benzoate (IIc-007a-pivm2)

[1276]

[1277] Esterification. Prepare 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, add 2,2-dimethylpropionic acid chloromethyl ester (137 μL, 0.95 mmol), 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 a saturated ammonium chloride solution and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography 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.

[1278] 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 reactants were filtered, the catalyst was removed, and the solution was evaporated to give a milky white 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-D6 ppm)δ13.03(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.

[1279] 2) 5-[[3-[[3-[1-(2,2-dimethylpropionyloxy)ethoxycarbonyl]-4-hydroxy-phenyl]carbamoyl]-2,5-dihydroxy-benzoyl]amino]-2-hydroxy-benzoic acid (IIc-007a-pive1)

[1280]

[1281] Esterification. A solution of 5-[[2,5-dibenzyloxy-3-[(3-carboxy-4-hydroxy-phenyl)carbamoyl]benzoyl]amino]-2-hydroxy-benzoic acid (324 mg, 0.5 mmol) and triethylamine (101 mg, 0.14 ml, 1.0 mmol) in N,N-dimethylformamide (10 ml) was stirred at 0 ° C. 1-iodoethyl 2,2-dimethylpropanoate (154 mg, 0.6 mmol) was added. The reaction mixture was stirred at room temperature for 21 hours. Additional triethylamine (0.14 ml, 1.0 mmol) and 1-iodoethyl 2,2-dimethylpropanoate (154 mg, 0.6 mmol) were added and the reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated. The residue was partitioned between dichloromethane and sodium metabisulfite solution. The organic extracts were combined, washed with brine, and the solution was dried over a hydrophobic glass frit. The filtrate was evaporated to give a mixture of monoesters and diesters. The residue was purified by silica chromatography using 5-100% ethyl acetate in isohexane followed by 10% methanol in dichloromethane to afford the monoester as a yellow solid (121 mg).LCMS (m / z) [M+H] 777.

[1282] Hydrogenolysis. A solution of the monoester obtained above (121 mg, 0.15 mmol) in tetrahydrofuran (16 ml) and water (4 ml) containing 10% palladium on carbon (250 mg, 10% paste) was stirred under a hydrogen atmosphere for 18 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was purified by reverse phase preparative HPLC using a gradient of 40-97% (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)δ13.15(br s,1H),10.47(br s,2H),10.18(s,1H),9.47(br s,1H),8.21(d,J=3Hz1H),8.17(d,J=3Hz1H),7.82(dd,J=9,3Hz 1H),7.78(dd,J=9,3Hz 1H),7.59-7.55(m,2H),7.03(d,J=9Hz1H),6.99(q,J=5.4Hz 1H),7.96(d,J=9Hz 1H), 1.58 (d, J = 5.4Hz, 3H), 1.17 (s, 9H). LCMS (m / z) [MH] 595.1.

[1283] Prodrug of IVc-059a

[1284] 1) 2,5-Dihydroxy-3-[[2,5-hydroxy-3-(2-morpholinoethoxycarbonyl)phenyl]methylsulfonylmethyl]benzoic acid (IVc-059a-mpe1)

[1285]

[1286] Esterification. Prepare a solution of 2,5-dibenzyloxy-3-[(2,5-dibenzyloxy-3-carboxylphenyl)methylsulfonyl-methyl]benzoic acid (300 mg, 0.40 mmol) and 2-morpholinoethanol (53 mg, 0.40 mmol) in N, N-dimethylformamide (93 mL), add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 93 mg, 0.48 mmol) and N, N-dimethylpyridine-4-amine (10 mg, 0.08 mmol). 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 morpholinoethyl ester as a colorless gum (111 mg, 32%). LCMS (m / z) [M+H] 872.1.

[1287] 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 a hydrogen atmosphere for 18 hours.

[1288] 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 vacuum to give the title product IVc-059a-mpe1 as a white solid (5 mg, 8%).

[1289] 1 H NMR(DMSO-d6 ppm)δ10.33(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.

[1290] Biological data: Stable in mouse plasma for 60 minutes

[1291] 2) 2-Morpholinoethyl 2,5-dihydroxy-3-[[2,5-hydroxy-3-(2-morpholinoethoxycarbonyl)phenyl]methylsulfonyl-methyl]benzoate (IVc-059a-mpe2)

[1292]

[1293] Prepare 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), add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (42 mg, 0.48 mmol) and N,N-dimethylpyridin-4-amine (5 mg, 0.04 mmol). The reaction mixture was stirred at room temperature for 18 hours. The resulting solution was evaporated to dryness, and the residue was purified by silica gel column chromatography using 10% methanol and 90% dichloromethane to give the title product as a colorless gum (58 mg, 65%). LCMS (m / z) [M+H] 985.0.

[1294] Prepare a solution of the diester (58 mg, 0.059 mmol) obtained above in tetrahydrofuran (1.5 mL) and add it 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 reactants were 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).

[1295] The solid was triturated with diethyl ether and dried under vacuum to give the title product IVc-059a-mpe2 as a white solid (9.1 mg, 25%).

[1296] 1 H NMR(CD3OD ppm)δ8.34(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.

[1297] Biological data: Stable in mouse plasma for 60 minutes; T 1 / 2(Human plasma): >180min.

[1298] 3) 3-[[3-[1-(2,2-dimethylpropionyloxy)ethoxycarbonyl]-2,5-dihydroxy-phenyl]methyl-sulfonyl-methyl]-2,5-dihydroxy-benzoic acid 1-(2,2-dimethylpropionyloxy)ethyl ester (IVc-059a-pive2)

[1299]

[1300] Esterification. Prepare a solution of 2,5-dibenzyloxy-3-[(2,5-dibenzyloxy-3-carboxyl-phenyl)methyl-sulfonylmethyl]benzoic acid (200 mg, 0.263 mmol) in anhydrous N,N-dimethylformamide (5 mL), and add triethylamine (88 μL, 0.63 mmol), sodium iodide (8 mg, 0.053 mmol) and crude 1-iodoethyl 2,2-dimethylpropanoate (about 4.2 mmol). The reaction mixture was stirred at room temperature for 18 hours. The resulting solution was evaporated to a small volume, and the residue was distributed between dichloromethane and sodium thiosulfate solution. The organic layer was filtered through a hydrophobic glass frit and evaporated. The residue was purified by silica gel column chromatography, 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

[1301] The monoester (90 mg, 40%) was also isolated as a colorless gum from the same column. LCMS (m / z) [M+Na] 909.6.

[1302] Hydrogenolysis:

[1303]

[1304] A solution of the 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 was evaporated, and the residue was purified by silica gel column chromatography eluting with a gradient of 100% dichloromethane to 10% methanol, 90% dichloromethane to give the title product IVc-059a-pive2 as a cream solid (55 mg, 78%).

[1305] 1H NMR (CDCl3 ppm) δ10.55(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.

[1306] Biodata: Rapidly hydrolyzed in mouse and human plasma

[1307] 4) 3-[[3-[1-(2,2-dimethylpropionyloxy)ethoxycarbonyl]-2,5-dihydroxy-phenyl]methylsulfonyl-methyl]-2,5-dihydroxy-benzoic acid (IVc-059a-pive1)

[1308] Hydrogenolysis:

[1309]

[1310] A solution of the isolated monoester (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 mixture was filtered to remove the catalyst, the solution was evaporated, and the residue was purified by silica gel column chromatography using a gradient elution from 100% dichloromethane to 20% methanol, 80% dichloromethane to afford the title product IVc-059a-pive1 as a creamy white solid (22.5 mg, 43%).

[1311] 1H NMR(CD3OD ppm)δ7.39(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.

[1312] Biodata: Rapidly hydrolyzed in mouse plasma

[1313] 5) 2,2-dimethylpropionyloxymethyl 2,5-dihydroxy-3-[[2,5-dihydroxy-3-(2,2-dimethylpropionyloxymethoxycarbonyl)phenyl]methylsulfonylmethyl]benzoate (IVc-059a-pivm2)

[1314]

[1315] Esterification. Prepare a solution of 2,5-dibenzyloxy-3-[(2,5-dibenzyloxy-3-carboxyl-phenyl)methylsulfonyl-methyl]benzoic acid (100 mg, 0.131 mmol) in anhydrous N,N-dimethylformamide (1 mL), add 2,2-dimethylpropionic acid chloromethyl ester (91 μL, 0.631 mmol), 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 distributed between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography, 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.

[1316] 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 mixture was filtered to remove the catalyst, the solution was evaporated, and the residue was purified by silica gel column chromatography using a gradient elution from 100% isohexane to 60% ethyl acetate, then 40% isohexane to afford diester IVc-059a-pivm2 (31 mg, 57%) as a white solid.

[1317] 1 H NMR (CDCl3 ppm) δ7.29 (d, J = 2.9 Hz, 2H), 7.19 (d, J = 2.9 Hz, 2H), 5.97 (s, 4H), 4.42 (s, 4H), 1.22 (s, 18H). LCMS(m / z)[MH]624.8.

[1318] Biological Data: Rapidly hydrolyzed in mouse plasma, T 1 / 2 =14.1min; T 1 / 2 (Human plasma): >180min.

[1319] 6) 2,5-Dihydroxy-3-[[2,5-dihydroxy-3-(2,2-dimethylpropionyloxymethoxycarbonyl)phenyl]methyl-sulfonylmethyl]benzoic acid (IVc-059a-pivm1)

[1320]

[1321] Esterification: Prepare 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) and add chloromethyl 2,2-dimethylpropanoate (57 μL, 0.395 mmol) 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 silica gel column chromatography eluting with a gradient of 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.

[1322] 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 solution was filtered to remove the catalyst, the solution was evaporated, and the residue was 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%).

[1323] 1 H NMR (CD3OD ppm) δ7.34(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.

[1324] Biological Data: Rapidly hydrolyzed in mouse plasma, T 1 / 2 =6.7min; T 1 / 2 (Human plasma): >180min.

[1325] Example 2: General Experimental Method

[1326] NMR spectroscopy

[1327] The NMR spectra were recorded at 400 MHz on a Bruker Advance III NMR spectrometer. 1H NMR spectroscopy. 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 using a MaXis ESI qTOF ultra-high-resolution mass spectrometer.

[1328] UPLC-MS analysis

[1329] UPLC-MS analysis was performed on a Waters Acquity UPLC system consisting of an Acquity Class I Sample Manager-FL, an Acquity Class I Binary Solvent Manager, and an Acquity Class I UPLC Column Manager. UV detection was achieved using an Acquity Class I UPLC PDA detector (scan range 210–400 nm), while mass detection was achieved using an Acquity QDa detector (mass scan range 100–1250 Da; simultaneous positive and negative modes). Analytes were separated using a Waters Acquity UPLCBEH C18 column (2.1 × 50 mm, 1.7 mm).

[1330] The samples were prepared by dissolving the samples (with or without ultrasonic treatment) in 1 mL of a 1:1 (v / v) mixture of MeCN in H2O. 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.

[1331] This work used four different analytical approaches, which are detailed below.

[1332] 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, equilibration time between samples 1.5 min.

[1333] Table 14:

[1334] Time (min) Eluent A (%) Eluent B (%) 0.00 95 5 0.25 95 5 1.25 5 95 1.55 5 95 1.65 95 5 2.00 95 5

[1335] 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, equilibration time between samples 1.5 min.

[1336] Table 15:

[1337] Time (min) Eluent A (%) Eluent B (%) 0.00 95 5 0.25 95 5 2.75 5 95 3.25 5 95 3.35 95 5 4.00 95 5

[1338] 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.

[1339] Table 16:

[1340]

[1341]

[1342] 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, equilibration time between samples 1.5 min.

[1343] Table 17:

[1344] Time (min) Eluent A (%) Eluent B (%) 0.00 95 5 0.25 95 5 1.25 5 95 1.55 5 95 1.65 95 5 2.00 95 5

[1345] 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, equilibration time between samples 1.5 min.

[1346] Table 18:

[1347] Time (min) Eluent A (%) Eluent B (%) 0.00 95 5 0.25 95 5 2.75 5 95 3.25 5 95 3.35 95 5 4.00 95 5

[1348] 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.

[1349] Table 19:

[1350] Time (min) Eluent A (%) Eluent B (%) 0.00 95 5 0.50 95 5 4.00 5 95 4.50 5 95 4.52 95 5 6.50 95 5

[1351] Preparative HPLC purification

[1352] Preparative HPLC was performed using a Waters automated purification system equipped with an XBridge Prep C18 column (19 x 150 mm). The Waters system consisted of a Waters 2545 binary preparative pump, a Waters 2767 sample manager, a Waters SFO column manager, a Waters 2998 DAD, a Waters 515 make-up pump, and an Acquity QDa mass spectrometer.

[1353] The purification system was controlled by MassLynx software (version 4.2) with an open access login module.

[1354] 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).

[1355] The sample was prepared by dissolving in 10% v / v water in DMSO at a concentration of ~150 mg / mL. A volume of 320 mL of the prepared sample was loaded onto the column and purified using a gradient elution at room temperature at a flow rate of 25 mL / min. A 1.5 minute equilibration time was allowed between injections.

[1356] Table 20: Gradient:

[1357] Time (min) ％(A) 0.0 95 0.5 95 14.5 0 17.4 0 17.5 95 18.0 95

[1358] Example 3: In vitro screening method

[1359] Example 3.1: In vitro HUVEC cell FGF1, FGF2 and VEGF-A inhibition method

[1360] The purpose of this in vitro method is to evaluate the effects of compounds on FGF-2, FGF-1, or VEGF-A-induced sprouting of human umbilical vein endothelial cells (HUVEC) in a spheroid-based cellular angiogenesis assay. Cells are pre-incubated with the compounds before the addition of growth factors. Sunitinib is tested as a control (no pre-incubation).

[1361] As expected, sunitinib control inhibited HUVEC sprouting induced by FGF-2, FGF-1 and VEGF-A. The IC50 values ​​of the test compounds determined are expressed in microM [μM] and the inhibition values ​​of FGF-1, FGF2 and VEGF-A induced growth (sprouting) are listed after each compound in the Examples after chemical characterization.

[1362] Compounds dissolved in DMSO were used for germination assays, resulting in 100-fold concentrated stock solutions and dissolved in culture medium. Sunitinib, a reference compound, was provided by ProQinase GmbH. Growth factors were purchased from rhFGF-basic (FGF-2), Peprotech, New Jersey, USA, #100-18C, lot #0415571; rhFGF-acidic (FGF-1), Peprotech, New Jersey, USA, #100-17A, lot #031207; and hVEGF-A165 (ProQinase GmbH, Freiburg, Germany; February 2, 2010 May) and used to stimulate HUVEC cell growth.

[1363] Test system Human umbilical vein endothelial cells (HUVEC) from the pooled donors were mixed with 70% culture medium, 20% FCS, and 10% DMSO at a concentration of approximately 1×10 6 Cells / ampoules were cryopreserved. HUVEC cells, i.e., primary human umbilical vein endothelial cells (PromoCell, Heidelberg, Germany), were used after passage 3 to 4. The cells were adherent, growing in a cobblestone monolayer and cultured in endothelial cell growth medium and basal medium (ECGM / ECBM, PromoCell). The subcultures were split 1:3; approximately 1 × 10 4 cells / cm 2 Inoculate and incubate at 37°C with 5% CO2 for a doubling time of 24-48 hours

[1364] Dilution of test compounds : Prepare a 100-fold concentrated solution of each test compound (relative to the final assay concentration) using the appropriate solvent (DMSO or water). These 100-fold compound solutions were further diluted 1:7.5 in endothelial cell growth and basal medium (ECBM) to yield a 13.33-fold concentrated solution. Subsequently, 75 μl of this 13.33-fold solution was mixed with 25 μl of a 40-fold concentrated stimulus (dissolved in ECBM) to yield a 10-fold concentrated stimulus / compound mixture. This mixture (100 μl) was incubated at 37°C for 30 min and then added to 900 μl of the HUVEC spheroid-containing gel (to yield the final assay concentration).

[1365] Test Method:The experiment is carried out by adopting the modification scheme of the scheme (Korff and Augustin:J Cell Sci 112:3249-58,1999) that is initially announced.In brief, as described in (Korff and Augustin:J Cell Biol 143:1341-52,1998), spheroids are prepared, 400 HUVEC are pipetted onto a plastic dish with the hanging drop method, and spheroids are aggregated overnight.Then 50 HUVEC spheroids are seeded in 0.9ml collagen gel and pipetted into each well of a 24-well plate to allow polymerization.The test compound is pre-incubated with growth factor (FGF-1, FGF-2 or VEGF-A final concentration 25ng / mL) in 10 times concentrated solution, and subsequently 100 μl of this solution is added to the top of the polymerized gel.First, all compounds are diluted to 100 times stock solution in solvent (DMSO or water) (this means that 100 times stock solution of each final test concentration is prepared in solvent). Subsequently, these stock solutions were further diluted in culture medium (to obtain 13.33-fold stock solutions of each final test concentration), with final test concentrations of 100, 50, 25, 12.5, 6.25, 3.13, and 1.56 × 10 -6 M. The plates were incubated at 37° C. for 24 h and then fixed with 4% PFA (Roth, Karlsruhe, Germany).

[1366] Quantification of Growth Factor Inhibition: The sprouting intensity of HUVEC spheroids treated with growth factors and inhibitors was quantified by an image analysis system that determined the cumulative sprout length (CSL) of each spheroid. Individual spheroids were photographed using an inverted microscope and the digital imaging software NIS-Elements BR 3.0 (Nikon). Subsequently, the spheroid photographs were uploaded to the Wimasis website for image analysis. The cumulative sprout length of each spheroid was determined using the imaging analysis tool WimSprout. The average of the cumulative sprout lengths of 10 randomly selected spheroids was analyzed as a single data point. For IC50 determinations, raw data were converted to percentage HUVEC sprouting relative to the solvent control (with stimulant) (set to 100%) and the basal control (without stimulant) (set to 0%). IC50 values ​​were determined using GraphPad Prism 5 software, with a lower limit of 0 and an upper limit of 100, using a nonlinear regression curve fit with a variable Hill slope.

[1367] resultAll compounds were evaluated for their dose-response relationship on growth factor-induced endothelial cell sprouting. IC50 values ​​were determined using standard parameters, based on the solvent control signal as the upper limit (100% HUVEC sprouting) and the basal control signal as the lower limit (0%). The individual IC50 values ​​for each compound against FGF1, FGF2, and VEGFA are summarized below the chemical characteristics of each compound in the biological data section.

[1368] Example 3.2: In vitro neutrophil adhesion under static conditions, method

[1369] Human neutrophils obtained from buffy coats of healthy donors were collected at a concentration of 3 × 10 6 Neutrophils were suspended in adhesion buffer (PBS containing 1 mM CaCl2 / MgCl2 and 10% FCS, pH 7.2) at a concentration of 1:1 / ml. Neutrophils were pre-incubated with 40 μM and 80 μM compounds at 37°C for 30 min.

[1370] Adhesion assays were performed on 18-well glass slides coated with human fibrinogen (20 μg / well in endotoxin-free PBS) for 18 h at 4°C. 20 μl of cell suspension was added to each well and stimulated with 5 μl of fMLP at a final concentration of 1 nM for 1 min at 37°C. After washing, adherent cells were fixed in 1.5% glutaraldehyde in PBS and counted using computer-assisted counting. Statistical analysis was performed by calculating the mean and standard deviation (SD); significance was calculated using an unpaired t-test. All statistical analyses were performed using GraphPad Prism 6 (GraphPad Software).

[1371] The respective inhibition of neutrophil adhesion by each compound expressed in [%] is summarized below the chemical properties of each compound in the biological data section.

[1372] Example 3.3: In vitro assay for inhibition of reactive oxygen species (ROS) production in human neutrophils

[1373] NADPH oxidase, located in the plasma membrane and the membranes of specific granules, produces superoxide anions, from which other ROS, such as hydrogen peroxide, singlet oxygen, hypochlorite, and reactive hydroxyl radicals, are generated. ROS are released into the surrounding medium or into membrane-bound subcellular organelles. A rapid and sensitive method for measuring the production of these metabolites is chemiluminescence (CL). Isoluminol-amplified CL is highly sensitive and widely used to study the respiratory burst induced by neutrophils (primarily the production of extracellular ROS).

[1374] Human neutrophils were isolated from buffy coats obtained from healthy donors. The isolated neutrophils (3×10 6The cells were incubated with 1% paraformaldehyde (5% paraformaldehyde) at 37°C for 30 min with 0.1% paraformaldehyde (5% paraformaldehyde) and 0.5% paraformaldehyde (5% paraformaldehyde) at 4°C for 10 min. The cells were incubated with 1% paraformaldehyde (5% paraformaldehyde) at 37°C for 30 min with 0.1% paraformaldehyde (5% paraformaldehyde) and 0.3% paraformaldehyde (5% paraformaldehyde) at 4°C for 10 min. The cells were then incubated with 1% paraformaldehyde (5% paraformaldehyde) at 37°C for 10 min with 0.1% paraformaldehyde (5% paraformaldehyde) and 0.3% paraformaldehyde (5% paraformaldehyde) at 4°C for 10 min. 75 μl of cell suspension and 75 μl of isoluminol + HRP solution were subsequently added to each well. Chemiluminescence was recorded (once every 25 seconds for 250 seconds) after fMLP (1 μM) activation using Multilabel Reader victor3 (Perkin Elmer, USA). Background values ​​(defined as the mean chemiluminescence value of isoluminol diluted in HBSS) were subtracted from all readings (CPS, counts per second). Experiments were performed in duplicate or triplicate.

[1375] Results obtained from isoluminol-amplified CL assays showed that the compounds strongly reduced ROS levels in fMLP+TNF-α-stimulated PMNs in a concentration-dependent manner.

[1376] PMN ROS inhibition at 0.3 μM expressed as [%] and IC50 [μM] are summarized below the chemical properties of each compound in the Biological Data section.

[1377] Example 3.4: In vitro production of inflammatory cytokines by human neutrophils and human monocytes, methods

[1378] 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 x g for 30 min at room temperature. Neutrophils were then collected and subjected to dextran precipitation followed by hypotonic lysis to remove erythrocytes. Following Percoll gradient centrifugation, monocytes were isolated from PBMCs. Human neutrophils and monocytes were each isolated at 5 × 10 6 / ml and 2.5×10 6The cells were suspended in RPMI 1640 medium supplemented with 10% low endotoxin FBS (<0.5 EU / ml; from BioWhittaker-Lonza, Basel, Switzerland) at a concentration of 100 μg / ml and then placed in a 24-well tissue culture plate at 37°C, 5% CO2 atmosphere in the presence or absence of different concentrations (20-40 μM) of the compound. After drug treatment for 1 hour, monocytes were stimulated with 0.1 μg / ml ultrapure LPS (InvivoGen) from Escherichia coli (E. coli) 0111: B4 strain, while neutrophils were stimulated with 1 μg / ml ultrapure LPS (InvivoGen) from Escherichia coli 0111: B4 strain. After 6 hours of LPS stimulation, neutrophils and monocytes were collected and spun at 300 x g for 5 minutes. The cell-free supernatant was immediately frozen at -80°C.

[1379] Cytokine concentrations in cell-free supernatants were measured using commercially available ELISA kits, human-specific for: CXCL8, IL-6, TNF-α (Mabtech, Sweden). The detection limits of these ELISAs were: 4 pg / ml for CXCL8, 10 pg / ml for IL-6, and 4 pg / ml for TNF-α.

[1380] Statistical analysis was performed by calculating the mean and standard deviation (SD); significance was calculated using unpaired t-test. All statistical analyses were performed using GraphPad Prism 6 (GraphPad Software).

[1381] The cytokine values ​​for each compound are expressed in ng / ml and are summarized below the chemical identity of each compound in the biological data section.

[1382] Example 3.5: In vitro inhibition of VEGF-receptor phosphorylation on primary human umbilical vein endothelial cells (HUVEC) induced by VEGF-165 compounds, Method

[1383] Cell culture: Primary human umbilical vein endothelial cells (HUVECs) were routinely cultured in 0.1% gelatin pre-coated flasks or culture dishes until passage 6. The effects of individual compounds at different concentrations (0, 1.25, 2.5, 5, 10, and 20 μM) on cell viability were assessed using a Tecan microplate reader (Genios) using a CCK-8 kit. To measure the effects of compounds on VEGF-induced cell viability, HUVECs (1×10 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 medium (starvation medium). 4The compounds within this concentration range did not affect cell viability.

[1384] Rabbit primary antibodies against VEGFR-2 and p-Tyr1175 were obtained from Cell Signaling Technology (Leiden, The Netherlands). Phospho-VEGFR-2 (Tyr1175) sandwich ELISA kit was from Cell Signaling Technology.

[1385] HUVEC were pre-incubated with 0, 0.16, 0.31, 0.63, 1.25, 2.5, 5, 10 and 20 μM of the compound for 60 min, followed by three wash steps with warm medium and then stimulated with VEGF165 (25 ng / mL) for 2 min. Immunoblot analysis was performed using anti-phospho-VEGFR-2 antibody, and total VEGFR-2 was used as a loading control after membrane stripping.

[1386] VEGFR-2 phosphorylation inhibition results are expressed as IC50 (microM [μM]) relative to VEGF-treated HUVEC controls without added inhibitory compounds.

[1387] The respective IC50 values ​​for each compound expressed as [μM] are summarized below the chemical properties of each compound in the Biological Data section.

[1388] Example 3.6: Inhibitory effect of compounds on in vitro cytokine release from LPS-induced human whole blood

[1389] The purpose of this in vitro method is to evaluate the effect of compounds on the release of a panel of cytokines in whole blood following lipopolysaccharide (LPS)-induced inflammatory responses. Whole blood is incubated with compounds for 1 hour prior to LPS induction. Cytokine levels in blood are measured using a multiplex FACS-based plate.

[1390] IC50 values ​​determined for the test compounds are listed in microM [μM] as well as the cytokine inhibition value for each compound.

[1391] Compounds dissolved in DMSO or H2O to a 10-fold concentrated stock solution and dissolved in culture medium were evaluated for their effects on LPS-induced cytokine release.

[1392] Test systemWhole blood was collected from a single donor (into lithium heparin-coated tubes; BD Vacutainer; 367886) and diluted 1:5 with RPMI 1640 (Thermo Fisher, 61870036). Within 30 minutes of collection, blood was incubated with compound for 1 hour before LPS stimulation (O111:B4–Sigma L4391; 10 ng / ml final concentration). Stimulation continued overnight (18 hours) under standard cell culture conditions (37°C, 5% CO2). The plate was then centrifuged and the supernatant removed and frozen at -80°C until analysis.

[1393] Dilution of test compounds : Use suitable solvent (in DMSO or water) to prepare 10x concentrated solution (related to final test concentration) of each test compound.Then this 10x compound solution (10 μl) is added in 90 μl pre-diluted whole blood (whole blood:RPMI1640, 1:5) to obtain final test concentration.

[1394] Test Method Diluted whole blood (80 μl) was pre-incubated with compound (10 μl) to obtain final test concentrations of 100, 30, 10, 3, 1, 0.3 and 0.1×10 -6 M. Blood was incubated at 37°C and 5% CO2 for 1 hour. LPS was diluted in cell culture medium to a concentration of 110 ng / ml; 10 μl was added to the whole blood for a final concentration of 10 ng / ml. The plate was incubated at 37°C for 18 hours. The plate was centrifuged at 3,000 RPM at 4°C for 5 minutes, and the supernatant was removed and frozen at -80°C until FACS analysis.

[1395] 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).

[1396] Quantification of cytokine release inhibition : Standards of known concentrations were run as part of the cytokine panel to quantify the concentration of each cytokine in each sample. This was performed using FCAP Array v3.0 software. For IC50 determinations, raw data were converted to percentage concentration relative to the solvent control (set to 100%). IC50 values ​​were determined using GraphPad Prism 8 software with a lower limit of 0 and an upper limit of 100, using nonlinear regression curve fitting with a variable Hill slope.

[1397] resultAll compounds were evaluated for their dose-response effects on cytokine release following LPS-induced whole-blood inflammatory responses. IC50 values ​​were determined for each compound against a panel of cytokines (GM-CSF, IFN-γ, IL-1β, 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-β, TNF-α, and TNF-β).

[1398] The respective cytokine IC50 values ​​for each compound expressed as [μM] are summarized below the chemical properties of each compound in the Biological Data section and in Table 13.

[1399] Example 4: Compound Preparation

[1400] Example 4.1: Oral Formulation of Compound Ic-007a

[1401] Five formulations were developed and reviewed for suitability. These were suspensions and solutions, the specific compositions of which are given in the table below.

[1402] Table 21: Formulation details of suspensions and solutions of compound Ic-007a.

[1403]

[1404] Preparation: Suspension A and Solution D:

[1405] Method example for 100 mL (scale appropriately based on the desired final volume). Prepare a solvent stock solution by weighing 5 mL of DMSO into a clean container. Weigh the correct amount of compound Ic-007a and gradually add it to the DMSO solution while mixing on an oscillator, vortexer, or sonicator. Melt Solutol in a clean, dry container in a 60°C water bath. Since solutol solidifies at room temperature, the melted Solutol was kept in a 60°C water bath during the formulation preparation process. Add 10 g (10% w / v) of melted Solutol to a warm, appropriately labeled (final volume 100 mL) container. Add 10 mL of PEG 400 to the Solutol in the warm 100 mL container. Add the DMSO drug stock solution to the Solutol and PEG 400 mixture, mix the contents immediately, and add 35 mL of deionized water and mix in a 40°C water bath while vortexing intermittently to dissolve large particles. The formulation was cooled to room temperature and made up to a final volume of 100 mL with deionized water.

[1406] Preparation of solutions A, B and C:

[1407] Method example for 100 mL (scale appropriately based on desired final volume). Prepare solvent stock by weighing 5 mL of DMSO into a clean container. Weigh 1 g of compound Ic-007a and gradually add to the DMSO solution while mixing on an oscillator, vortexer, or sonicator (if necessary). Melt Solutol in a clean, dry container in a 60°C water bath. Since Solutol solidifies at room temperature, the melted Solutol was kept in a 60°C water bath during formulation preparation. Weigh 10 g (10% w / v) of melted Solutol into a warm, appropriately labeled (final volume 100 mL) container. Add 10 mL of PEG 400 to the Solutol in the warm 100 mL container. Add the DMSO drug stock to the labeled Solutol and PEG 400 mixture container and immediately mix with the contents. 35mL deionized water was added and mixed with the contents, placed in a 40°C water bath while performing intermittent vortexing to dissolve large particles. The preparation was cooled to room temperature and the pH value of the preparation was further adjusted to pH 6, 7, 8 and 9 using 1M sodium hydroxide (NaOH) solution. The initial preparation was prepared on a 1mL scale with an initial pH value of 4.3. 3 μL NaOH 1M was added to reach pH 6 (solution A), 22 μL to reach pH 8 (solution B), and 43 μL to reach pH 9 (solution C). These preparations were administered immediately after preparation.

[1408] The 10 mg / mL suspension formulation and the 1 mg / mL solution formulation were found to be physically stable under ambient conditions for two weeks.

[1409] Example 4.2: Oral Formulation of Compound Ia-001a-Tz

[1410] Compound Ia-001a-Tz was prepared as a 10 mg / mL oral solution. The composition of the carrier in the preparation is shown in the following table.

[1411] A carrier is a vehicle or inert medium used as a solvent (or diluent) in which a pharmaceutically active agent is formulated and / or administered.

[1412] Table 22 : Formulation details of the oral formulation of Compound Ia-001aTz.

[1413] carrier composition A 40% PEG400, 10% Transcutol, 10% Solutol HS15, 40% Type 1 Water B 40% PEG400, 10% Transcutol, 10% Solutol HS15, 40% aqueous solution containing 0.5% HPMC 606 C 40% PEG400, 10% Transcutol, 10% Solutol HS15, 40% aqueous solution containing 0.5% Kollidon VA 64 D 40% PEG400, 10% Transcutol, 10% Cremophor RH40, 40% Type 1 Water E 40% PEG400, 10% Transcutol, 10% Vitamin E TPGS, 40% Type 1 Water F 40% PEG400, 10% Transcutol, 5% Solutol HS15, 45% Type 1 Water G 40% PEG400, 10% Transcutol, 5% Solutol HS15, 45% aqueous solution containing 1% Kollidon VA 64

[1414] Preparation method

[1415] To prepare a 10 mg / g solution, accurately weigh 10 mg of compound into a vial, add 1 ml of vehicle directly to the API and vortex to obtain a solution.

[1416] Vector preparation

[1417] Formulation A: Prepare 10 g of vehicle by weighing 4 g of PEG 400 into a clean 20 mL glass container. Add 1 g of Transcutol and stir to combine. Add 1 g of Solutol HS15, followed by 4 g of Type 1 water. Stir the mixture at room temperature for 1 hour to dissolve all components.

[1418] Formulation B: Prepare 10 g of vehicle by weighing 4 g of PEG 400 into a clean 20 mL glass container. Add 1 g of Transcutol and stir to combine the components. Add 1 g of Solutol HS15. Prepare a 0.5% HPMC 606 aqueous solution by weighing 50 mg of HPMC 606 into a clean glass bottle. Add 9.95 g of Type 1 water. Stir the components at room temperature for 1 hour to ensure thorough mixing. Then, add 4 g of the 0.5% HPMC 606 aqueous solution to the PEG 400, Transcutol, and Solutol HS15 solution. Stir the mixture at room temperature for 1 hour to dissolve...

Claims

1. Substituted hydroquinones of formula (I): in: R a , R b =H or C 1-4 acyl group; R1=COOR4、(CH2) n COOR4, 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 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R5=R6, R7 or R8; <h2 style=";text-align:left;direction:ltr">R6=CONH-R9、CONHCOR9、CONH(CH2)<h2 style=";text-align:left;direction:ltr"> n <h2 style=";text-align:left;direction:ltr"> -R9、 CONHCH(COOR4)(CH2) k R9, where k = 0-4; R7 = benzoheteroaryl substituted by at least one or more groups selected from the group consisting of COOR4 or (CH2) n COOR4; R8=(CH2) m X(CH2) p R9; X=O、S、SO2、NH、NAc or N(CH2) q R9; R9 = aryl, heteroaryl substituted by at least one or more groups selected from the following: COOR4, (CH2) n COOR4, OR4, SO3H, azole [5-membered N-containing heterocyclic ring], fluorine, C=O or NHCO-R 10 ; R 10 = aryl, heteroaryl substituted by at least one or more groups selected from the following: COOR4, (CH2) n COOR4, OR4, SO3H, azole [5-membered N-containing heterocyclic ring] or fluorine; Among them, R9 and R 10 The aryl group is an aromatic group containing 6 to 14 carbon atoms selected from phenyl, naphthyl, biphenyl; R9 and R 10 The heteroaryl group is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen atoms; and n, m, p and q are independently 1-4.

2. Compounds of formula (I): in: R a , R b =H or C 1-4 acyl group; R1=COOR4、(CH2) n COOR4, 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 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R5=R6 or R7; R6=CONH-R9, CONHCOR9, CONH(CH2) n -R9 or CONHCH(COOR4)(CH2) k R9, where k = 0-4; R7 = benzoheteroaryl substituted by at least one or more groups selected from the group consisting of COOR4 or (CH2) n COOR4; R9 = aryl, heteroaryl substituted by at least one or more groups selected from the following: COOR4, (CH2) n COOR4, OR4, SO3H, azole [5-membered N-containing heterocyclic ring], fluorine, C=O or NHCO-R 10 ; R 10 = aryl, heteroaryl substituted by at least one or more groups selected from the following: COOR4, (CH2) n COOR4, OR4, SO3H, azole [5-membered N-containing heterocyclic ring] or fluorine; where R9 and R 10 The aryl group is an aromatic group containing 6 to 14 carbon atoms selected from phenyl, naphthyl, biphenyl; R9 and R 10 The heteroaryl group is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen atoms; and n is independently 1-4.

3. The compound according to claim 2, wherein: (A) R a , R b =H or C 1-4 acyl group; R1=COOR4;R4=H、C 1-4 Alkyl, C 6-10 Aryl C 1-4 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R2=H;R3=R5;and R5=R6=CONH-R9; or (B) R a , R b =H or C 1-4 acyl group; R1=COOR4;R4=H、C 1-4 Alkyl, aryl C 1-4 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R3=H; R2=R5; and R5=R6=CONH-R9.

4. The compound according to claim 3, wherein the compound is selected from: 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; 3,5-bis(2,5-dihydroxy-4-ethoxycarbonylbenzoylamino)benzoic acid ethyl ester; 3-(4-(ethoxycarbonyl)-2,5-dihydroxybenzamido)isonicotinic acid ethyl ester; 4-(4-ethoxycarbonyl-2,5-dihydroxyphenylaminocarbonyl)-2,5-dihydroxybenzoic acid ethyl ester; 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; 3-(2-(1H-tetrazol-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid ethyl ester; and 3-(2-(ethoxycarbonylmethyl)phenylaminocarbonyl)-2,5-dihydroxybenzoic acid ethyl ester.

5. The compound according to claim 2, wherein: (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.

6. The compound according to claim 5, wherein the compound is selected from: 2-(2,5-dihydroxy-4-sulfonbenzoamido)benzoic acid; 2,5-Dihydroxy-4-(2-sulfophenylaminocarbonyl)benzenesulfonic acid; 3-(2,5-dihydroxy-4-sulfonbenzoamido)benzoic acid; 2,5-Dihydroxy-4-(3-sulfophenylaminocarbonyl)benzenesulfonic acid; 4-(2,5-dihydroxy-4-sulfonbenzoamido)benzoic acid; 2,5-Dihydroxy-4-(4-sulfophenylaminocarbonyl)benzenesulfonic acid; 5-(2,5-dihydroxy-4-sulfonbenzoamido)-2-hydroxybenzoic acid; 4-(2,5-dihydroxy-4-sulfonbenzoamido)-2-hydroxybenzoic acid; 2-(2,5-dihydroxy-4-sulfonylbenzamide)-5-hydroxybenzoic acid; 3,5-bis(2,5-dihydroxy-4-sulfonylbenzamide)benzoic acid; 3-(2,5-dihydroxy-4-sulfonbenzoamido)phthalic acid; 2-(2,5-dihydroxy-4-sulfonbenzoamido)terephthalic acid; 2-(2,5-dihydroxy-4-sulfonbenzoamido)isophthalic acid; 4-(2,5-dihydroxy-4-sulfonbenzoamido)phthalic acid; 5-(2,5-dihydroxy-4-sulfonbenzoamido)isophthalic acid; 2-(2,5-dihydroxy-4-sulfonylbenzamido)nicotinic acid; 2-(2,5-dihydroxy-4-sulfonbenzoylamido)isonicotinic acid; 6-(2,5-dihydroxy-4-sulfonbenzoylamido)nicotinic acid; 6-(2,5-dihydroxy-4-sulfonbenzoylamino)picolinic acid; 2-(2,5-dihydroxy-4-sulfonylbenzamido)-5-fluoronicotinic acid; 6-(2,5-dihydroxy-4-sulfonylbenzamide)pyridine-2,5-dicarboxylic acid; 2-(2,5-dihydroxy-4-sulfonylbenzamide)pyridine-3,5-dicarboxylic acid; 3-(2,5-dihydroxy-4-sulfonylbenzamide)isonicotinic acid; 5-(2,5-dihydroxy-4-sulfonylbenzamido)nicotinic acid; 5-(2,5-dihydroxy-4-sulfonbenzoylamido)picolinic acid; 3-(2,5-dihydroxy-4-sulfonbenzoylamido)picolinic acid; 5-(2,5-dihydroxy-4-sulfonylbenzamido)-2-fluoroisonicotinic acid; 4-(2,5-dihydroxy-4-sulfonbenzoylamido)nicotinic acid; 4-(2,5-dihydroxy-4-sulfonbenzoylamino)picolinic acid; (4-(2,5-dihydroxy-4-sulfonbenzamido)phenyl)acetic acid; (3-(2,5-dihydroxy-4-sulfonbenzoylamido)phenyl)acetic acid; (2-(2,5-dihydroxy-4-sulfonbenzamido)phenyl)acetic acid; 2-(2,5-dihydroxy-3-sulfonbenzoamido)benzoic acid; 2,5-Dihydroxy-3-(2-sulfophenylaminocarbonyl)benzenesulfonic acid; 3-(2,5-dihydroxy-3-sulfonbenzamido)benzoic acid; 2,5-Dihydroxy-3-(3-sulfophenylaminocarbonyl)benzenesulfonic acid; 4-(2,5-dihydroxy-3-sulfonbenzoamido)benzoic acid; 2,5-Dihydroxy-3-(4-sulfophenylaminocarbonyl)benzenesulfonic acid; 5-(2,5-dihydroxy-3-sulfonylbenzamide)-2-hydroxybenzoic acid; 4-(2,5-dihydroxy-3-sulfonylbenzamide)-2-hydroxybenzoic acid; 2-(2,5-dihydroxy-3-sulfonbenzoamido)-5-hydroxybenzoic acid; 3-(2,5-dihydroxy-3-sulfonylbenzamido)-5-(2,5-dihydroxy-4-sulfonylbenzamido)benzoic acid 3-(2,5-dihydroxy-3-sulfonbenzoamido)phthalic acid; 2-(2,5-dihydroxy-3-sulfonbenzoamido)terephthalic acid; 2-(2,5-dihydroxy-3-sulfonbenzoamido)isophthalic acid; 4-(2,5-dihydroxy-3-sulfonbenzoamido)phthalic acid; 5-(2,5-dihydroxy-3-sulfonbenzoamido)isophthalic acid; 2-(2,5-dihydroxy-3-sulfonbenzoamido)nicotinic acid; 2-(2,5-dihydroxy-3-sulfonbenzoylamido)isonicotinic acid; 6-(2,5-dihydroxy-3-sulfonbenzoamido)nicotinic acid; 6-(2,5-dihydroxy-3-sulfonbenzoylamino)picolinic acid; 2-(2,5-dihydroxy-3-sulfonylbenzamido)-5-fluoronicotinic acid; 6-(2,5-dihydroxy-3-sulfonbenzoylamido)pyridine-2,5-dicarboxylic acid; 2-(2,5-dihydroxy-3-sulfonbenzoylamido)pyridine-3,5-dicarboxylic acid; 3-(2,5-dihydroxy-3-sulfonbenzoylamido)isonicotinic acid; 5-(2,5-dihydroxy-3-sulfonbenzoylamido)nicotinic acid; 5-(2,5-dihydroxy-3-sulfonbenzoylamino)picolinic acid; 3-(2,5-dihydroxy-3-sulfonbenzoylamino)picolinic acid; 5-(2,5-dihydroxy-3-sulfonylbenzamido)-2-fluoroisonicotinic acid; 4-(2,5-dihydroxy-3-sulfonbenzoamido)nicotinic acid; 4-(2,5-dihydroxy-3-sulfonbenzoylamido)picolinic acid; (4-(2,5-dihydroxy-3-sulfonbenzamido)phenyl)acetic acid; (3-(2,5-dihydroxy-3-sulfonbenzamido)phenyl)acetic acid; and (2-(2,5-dihydroxy-3-sulfonbenzamido)phenyl)acetic acid.

7. The compound according to claim 2, wherein: (A) R a 、R b =H; R1=(CH2) n COOR4; R4=H, C 1-4 Alkyl, aryl C 1-4 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R2=H or R5, 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 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R3=H; R2=R5; and R5=R6=CONH-R9.

8. The compound according to claim 7, wherein the compound is selected from: 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-tetrazolyl-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.

9. The compound according to claim 2, wherein: (A) R a , R b =H or C 1-4 acyl group; R1=CONH-R 10 ; R4=H、C 1-4 Alkyl, aryl C 1-4 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R2=H;R3=R5;and R5=R6=CONH-R9; or (B) R a , R b =H or C 1-4 acyl group; R1=CONH-R 10 ; R4=H、C 1-4 Alkyl, aryl C 1-4 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R3=H; R2=R5; and R5=R6=CONH-R9.

10. The compound according to claim 9, wherein the compound is selected from: 5-(4-(2-(1H-tetrazol-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid; N1,N4-bis(2-(1H-tetrazolyl-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; 5-(4-(2-(1H-tetrazol-5-yl)phenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid methyl ester; 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; 2-(2,5-dihydroxy-4-(4-hydroxy-2-(methoxycarbonyl)phenylaminocarbonyl)benzamido)-5-hydroxybenzoic acid methyl ester; 1-(2,2-dimethylpropionyloxy)ethyl 5-[[4-[[3-[1-(2,2-dimethylpropionyloxy)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-hydroxybenzoic acid; and 2-(2,5-Dihydroxy-3-(4-hydroxy-2-sulfophenylaminocarbonyl)benzamido)-5-hydroxybenzenesulfonic acid.

11. The compound according to claim 2, having formula (I): in: R a 、R b =H; R1=CONH-R 10 ; R 10 =phenyl substituted by COOR4 and by OR4; R2=H; R3 = CONH-R9; R9 =phenyl substituted by COOR4 and by OR4; and R4=H.

12. The compound according to claim 11, wherein the compound is 5-(4-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid, wherein the compound has the following chemical structure:

13. The compound according to claim 2, having formula (I): in: R a 、R b =H; R1=CONH-R 10 ; R 10 =phenyl substituted by COOR4 and by OR4; R2 = CONH-R9; R3=H; R9 =phenyl substituted by COOR4 and by OR4; and R4=H.

14. The compound according to claim 13, wherein the compound is 5-(3-(3-carboxy-4-hydroxyphenylaminocarbonyl)-2,5-dihydroxybenzamido)-2-hydroxybenzoic acid; and wherein the compound has the following chemical structure:

15. The compound according to claim 2, wherein: (A) R a 、R b =H; R1=COOR4、(CH2) n COOR4; R4=H, C 1-4 Alkyl, aryl C 1-4 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); 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 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R3=H; R2=R5; and R5=R6=CONHCOR9.

16. The compound according to claim 15, wherein the compound is selected from: N-(1,3,4,5-tetrahydroxycyclohexylcarbonyl)4-carboxy-2,5-dihydroxybenzamide; N-(4-carboxy-2,5-dihydroxybenzoyl)4-carboxy-2,5-dihydroxybenzamide; N-(3-carboxy-2,5-dihydroxybenzoyl)4-carboxy-2,5-dihydroxybenzamide; 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-dihydroxybenzamide; N-(3-carboxy-2,5-dihydroxybenzoyl)3-carboxy-2,5-dihydroxybenzamide; 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-dihydroxybenzamide; N-(3-carboxy-2,5-dihydroxybenzoyl)4-carboxymethyl-2,5-dihydroxybenzamide; 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-dihydroxybenzamide; N-(3-carboxy-2,5-dihydroxybenzoyl)3-carboxymethyl-2,5-dihydroxybenzamide; N-(3,4-dihydroxybenzoyl) 3-carboxymethyl-2,5-dihydroxybenzamide; and N-(3,5-dihydroxybenzoyl) 3-carboxymethyl-2,5-dihydroxybenzamide.

17. The compound according to claim 2, wherein (A) R a 、R b =H; R1=COOR4、(CH2) n COOR4; R4=H, C 1-4 Alkyl, aryl C 1-4 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R2=H;R3=R5;and <h2 style=";text-align:left;direction:ltr">R5 = R6 = CONH(CH2)<h2 style=";text-align:left;direction:ltr"> n <h2 style=";text-align:left;direction:ltr"> -R9; or (B) R a 、R b =H; R1=COOR4、(CH2) n COOR4; R4=H, C 1-4 Alkyl, aryl C 1-4 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R3=H; R2=R5; and <h2 style=";text-align:left;direction:ltr">R5 = R6 = CONH(CH2)<h2 style=";text-align:left;direction:ltr"> n <h2 style=";text-align:left;direction:ltr"> -R9.

18. The compound according to claim 17, wherein the compound is selected from: 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.

19. The compound according to claim 2, wherein: R a 、R b =H; R1=SO3H; R2=H;R3=R5;and <h2 style=";text-align:left;direction:ltr">R5 = R6 = CONH(CH2)<h2 style=";text-align:left;direction:ltr"> n <h2 style=";text-align:left;direction:ltr"> -R9.

20. The compound according to claim 19, wherein the compound is selected from: 2-((2,5-dihydroxy-4-sulfonbenzamido)methyl)benzoic acid; 3-((2,5-dihydroxy-4-sulfonbenzamido)methyl)benzoic acid; and 4-((2,5-Dihydroxy-4-sulfonbenzamido)methyl)benzoic acid.

21. The compound according to claim 2, wherein: (A) R a 、R b =H; R1=COOR4、(CH2) n COOR4; R4=H, C 1-4 Alkyl, aryl C 1-4 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R2=H;R3=R5;and <h2 style=";text-align:left;direction:ltr">R5 = R6 = CONHCH(COOR4)(CH2)<h2 style=";text-align:left;direction:ltr"> k <h2 style=";text-align:left;direction:ltr"> R9; or (B) R a 、R b =H; R1=COOR4、(CH2) n COOR4; R4=H, C 1-4 Alkyl, aryl C 1-4 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R3=H; R2=R5; and <h2 style=";text-align:left;direction:ltr">R5 = R6 = CONHCH(COOR4)(CH2)<h2 style=";text-align:left;direction:ltr"> k <h2 style=";text-align:left;direction:ltr"> R9.

22. The compound according to claim 21, wherein the compound is selected from: 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.

23. The compound according to claim 2, wherein: (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 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R2=H;R3=R5;and R5=R7=benzoheteroaryl substituted by at least one or more groups selected from the group consisting of COOR4 or (CH2) n COOR4; 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 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R3=H; R2=R5; and R5=R7=benzoheteroaryl substituted by at least one or more groups selected from the group consisting of COOR4 or (CH2) n COOR4.

24. The compound according to claim 23, wherein the compound is selected from: 2-(4-Carboxy-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid; 2-(4-ethoxycarbonyl-2,5-dihydroxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid methyl ester; 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.

25. Compounds of formula (I): in: 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, phosphonyl, phosphonyloxymethyl, 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 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R5=R8; R8=(CH2) m X(CH2) p R9; X=O、S、SO2、NH、NAc or N(CH2) q R9; R9 = aryl, heteroaryl substituted by at least one or more groups selected from the following: COOR4, (CH2) n COOR4, OR4, SO3H, azole [5-membered N-containing heterocyclic ring], fluorine, C=O or NHCO-R 10 ; R 10 = aryl, heteroaryl substituted by at least one or more groups selected from the following: COOR4, (CH2) n COOR4, OR4, SO3H, azole [5-membered N-containing heterocyclic ring] or fluorine; Among them, R9 and R 10 The aryl group is an aromatic group containing 6 to 14 carbon atoms selected from phenyl, naphthyl or biphenyl; and R9 and R 10 The heteroaryl group is an aromatic group containing 1 to 14 carbon atoms and one or more nitrogen atoms; and n, m, p and q are independently integers equal to 1-4.

26. The compound according to claim 25, wherein: (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, phosphonyl, phosphonyloxymethyl, 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 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R2=H;R3=R5;and R5=R8=(CH2) m X(CH2) p R9; Where 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, phosphonyl, phosphonyloxymethyl, 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 alkyl, morpholino-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, N-methylpiperazinyl-C1-C6 alkyl, C1-C6 acyloxymethyl, C1-C6 acyloxy-1-ethyl, C1-C6 alkoxycarbonyloxymethyl, C1-C6 alkoxycarbonyloxy-1-ethyl or (oxodioxolyl)methyl; o-methoxyphenyl(guaiacol); R3=H; R2=R5; and R5=R8=(CH2) m X(CH2) p R9; Where X=O, S, SO2, NH, NAc or N(CH2) q R9.

27. The compound according to claim 26, wherein the compound is selected from: 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-sulfonylphenylmethyl)amine; N,N-Bis(4-carboxy-2,5-dihydroxyphenylmethyl)acetamide; N-(2,5-dihydroxy-4-sulfonylphenylmethyl)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-sulfonylphenylmethyl)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; 3-((2,5-diacetoxy-3-methoxycarbonylphenyl)methylsulfonylmethyl)-2,5-diacetoxybenzoic acid methyl ester; 3-((2,5-dihydroxy-3-methoxycarbonylphenyl)methylsulfonylmethyl)-2,5-hydroxybenzoic acid methyl ester; 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.

28. The compound according to claim 2, having formula (I): in: R a 、R b =H; R1=COOR4; R2=H; R3=R8; R4=H; R8=(CH2) m X(CH2) p R9; R9 =phenyl substituted by COOR4 and by OR4; X=N(CH2) q R9; and m, p and q=1.

29. The compound of claim 28, wherein the compound is tris(4-carboxy-2,5-dihydroxyphenylmethyl)amine; and wherein the compound has the following chemical structure:

30. The compound according to claim 2, having formula (I): in: R a 、R b =H; R1=COOR4; R2=(CH2) m X(CH2) p R9; R3=H; R9 =phenyl substituted by COOR4 and by OR4; R4=H; X = SO2; and m and p=1.

31. The compound of claim 30, wherein the compound is 3-((2,5-dihydroxy-3-sulfophenyl)methylsulfonylmethyl)-2,5-dihydroxybenzoic acid; and wherein the compound has the following chemical structure:

32. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

33. Use of a compound according to any one of claims 1 to 31 for the preparation of a medicament for the treatment and / or prevention of acute pancreatitis, pancreatic cancer and renal cancer, diabetic retinopathy, peritonitis, diabetes and diabetic wound healing, diabetic macular edema, diabetic nephropathy, diabetic kidney disease and pulmonary fibrosis.

34. An intermediate in the synthesis of a compound according to claim 2, wherein the intermediate is selected from 2,5-bis(benzyloxy)-4-(ethoxycarbonyl)benzoic acid; 2,5-bis(benzyloxy)isophthalaldehyde; 2,5-bis(benzyloxy)isophthalic acid; 2,5-bis(benzyloxy)ethyl-4-(hydroxymethyl)benzoate; or 2,5-bis(benzyloxy)ethyl-3-(hydroxymethyl)benzoate.

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