Quinoline compounds as selective and / or dual modulators of bile acid receptors and leukotriene cysteinyl receptors

Abstract

The present invention relates to compounds of formula (I), pharmaceutical compositions thereof, and their use for the treatment and / or prevention of diseases mediated in particular by the bile acid receptors FXR and GPBAR1, and the cysteinyl leukotriene receptor (CysLTR). [C1] JPEG2023539034000051.jpg42170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims priority to Italian Patent Application No. 102020000019210, filed August 4, 2020, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to quinoline derivatives capable of simultaneously modulating the bile acid receptors FXR and GPBAR1, and the cysteinyl leukotriene receptor (CysLTR), and their use in the treatment and / or prevention of diseases mediated by the latter. [Background technology]

[0003] Strategies to identify small molecules that can act simultaneously on multiple targets are widely recognized to be useful for identifying novel pharmacological approaches to multifactorial diseases such as chronic inflammatory disorders including nonalcoholic steatohepatitis, prevalent inflammatory liver diseases, metabolic syndrome, and cancer.

[0004] This work starts from our recent findings that REV5901, a cysteinyl-leukotriene receptor antagonist, can modulate GPBAR1 with interesting anti-inflammatory activity in animal models of intestinal inflammation, and that zafirlukast, a well-known receptor antagonist of CysLT, has weak anti-activity against FXR (S. Schierle et al., Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology, J Med Chem 61(13) (2018) pp. 5758-5764).

[0005] Leukotrienes are a large family of lipid mediators generated from arachidonic acid by an enzyme cascade and function as mediators of inflammation. Among the leukotrienes, the cysteinyl leukotrienes (CysLTs) act on cells by binding to a family of G protein-associated transmembrane proteins (CysLTRs), including LTC4, LTD4 and LTE4, expressed on many proinflammatory cells, such as neutrophils and eosinophils, mast cells and monocytes / macrophages. Activation of these receptors by endogenous lipid mediators plays an important role in inflammatory responses, leading to microvascular permeability, leukocyte trafficking, secretion of chemokines and cytokines, and tissue repair (fibrosis). Cysteinyl leukotriene receptors are well known to mediate bronchoconstriction, pulmonary mucus secretion and pulmonary edema, and therefore their antagonists are effective drugs for the treatment of asthma and, more broadly, pharmacological approaches to lung disorders. Cysteinyl leukotrienes have been implicated in many other diseases, such as cardiovascular disorders, cancer, atopic dermatitis, rheumatoid arthritis, Crohn's disease, the pathogenesis of fulminant hepatitis, as well as hepatic cholestasis, hepatic fibrosis and cirrhosis (Capra V. et al., Cysteinyl-leukotrienes and their receptors in asthma and other inflammatory diseases: critical update and emerging trends. (Med Res Rev. 2007 July; 27(4):469-527)).

[0006] FXR is highly expressed in enterohepatic tissues (liver and intestine) and regulates several metabolic pathways, including bile acid homeostasis, and lipid and glucose metabolism. FXR agonists have been proven to be useful in pharmacological approaches to metabolic disorders such as cholestasis, type 2 diabetes, hepatic fibrosis, and nonalcoholic fatty liver disease (NAFLD). In addition, FXR plays an important role in the kidney, cardiovascular system, and tumor development (Renga et al., PHASEB J. 2012, 26, 3021-3031).

[0007] GPBAR1 is highly expressed in liver and intestine, and also in muscle, adipose tissue, macrophages and endothelial cells.In muscle and brown adipose tissue, GPBAR1 increases energy consumption and oxygen consumption (Watanabe et al., Nature of 2006, 439, 484).In enteroendocrine L cells, activation of GPBAR1 stimulates the secretion of glucagon-like peptide (GLP-1), thereby controlling blood glucose levels, gastrointestinal motility and appetite (Thomas et al., Cell. Metab. 2009, 10, 167).

[0008] GPBAR1 appears to be involved in the regulation of inflammatory processes and immune function. Many innate immune cells, such as monocytes, macrophages, NKT cells, and dendritic cells, express this receptor, and mutations in this receptor are associated with an increased risk of developing primary sclerosing cholangitis and ulcerative colitis. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] S. Schierle et al., Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology, J Med Chem 61(13) (2018) pp. 5758-5764 [Non-Patent Document 2] Capra V. et al., Cysteinyl-leukotrienes and their receptors in asthma and other inflammatory diseases: critical update and emerging trends. (Med Res Rev. July 2007; 27(4):469-527) [Non-Patent Document 3] Renga et al., PHASEB J. 2012, 26, 3021-3031 [Non-Patent Document 4] Watanabe et al., Nature 2006, 439, 484 [Non-Patent Document 5] Thomas et al., Cell. Metab. 2009, 10, 167 [Non-Patent Document 6] Remington's Pharmaceutical Sciences, 17th ed., Gennaro et al., Mack Publishing Co., 1985 [Non-Patent Document 7] Remington's Pharmaceutical Sciences, edited by Gennaro AR, 20th edition, 2000, Williams & Wilkins PA, USA. [Non-Patent Document 8] Remington: The Science and Practice of Pharmacy, 21st ed., edited by Lippincott Williams & Wilkins, 2005 [Non-Patent Document 9] Loyd V. Allen and Howard C. Ansel, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 10th ed., Lippincott Williams & Wilkins, 2014 Summary of the Invention [Problem to be solved by the invention]

[0010] The object of the present invention is to identify novel compounds capable of selectively or simultaneously modulating the bile acid receptors FXR and GPBAR1, and the cysteinyl leukotriene receptor (CysLTR). [Means for solving the problem]

[0011] Such an object is achieved according to the present invention with respect to compounds of formula (I) according to claim 1, their uses according to claims 8 and 9, and compositions thereof according to claim 10. Preferred embodiments are given in the dependent claims.

[0012] The present invention will now be described in detail with reference to the figures in the accompanying drawings, in which: [Brief description of the drawings]

[0013] [Figure 1] AST levels in mice in which acute hepatitis was induced with acetaminophen and subsequently treated with CHIN117. [Diagram 2] 1 shows ALT levels in mice in which acute hepatitis was induced with acetaminophen and subsequently treated with CHIN117. [Diagram 3] 1 shows white blood cell (WBC) counts in mice in which acute hepatitis was induced with acetaminophen and subsequently treated with CHIN117. [Figure 4A] Results of CHIN117 administration in a mouse model mimicking NAFLD. Percentage change in body weight was assessed weekly. Results are mean ± SEM of 8-12 mice per group. *p ≤ 0.05. [Figure 4B] Results of administration of CHIN117 in a mouse model mimicking NAFLD. Area under the curve (AUC) for body weight is shown. Results are mean ± SEM of 8-12 mice per group. *p ≤ 0.05. [Figure 4C] Results of administration of CHIN117 in a mouse model mimicking NAFLD. Brown adipose tissue temperature (BAT temperature) (°C) is shown. Results are mean ± SEM of 8-12 mice per group. *p≦0.05. [Figure 4D] 1 shows activity results of administration of CHIN117 in a mouse model mimicking NAFLD. [Figure 4E] Results of administration of CHIN117 in a mouse model mimicking NAFLD. Glucose levels in response to an oral glucose tolerance test (OGTT) are shown. Results are the mean ± SEM of 8-12 mice per group. *p≦0.05. [Figure 4F]Shown are the results of administration of CHIN117 in a mouse model mimicking NAFLD. The AUC of OGTT is shown. Results are the mean ± SEM of 8-12 mice per group. *p ≤ 0.05. [Figure 4G] Figure 1 shows the results of administration of CHIN117 in a mouse model mimicking NAFLD. Plasma levels of AST (U / L) and ALT (U / L) are shown. Results are mean ± SEM of 8-12 mice per group. *p ≤ 0.05. [Figure 4H] Results of administration of CHIN117 in a mouse model mimicking NAFLD. Plasma levels (mg / 100 mL) of cholesterol, triglyceride, high density lipoprotein (HDL), and low density lipoprotein (LDL) are shown. Results are mean ± SEM of 8-12 mice per group. *p≦0.05. [Figure 5A] The results of CHIN117 administration in a C57BL / 6 mouse model fed an HFD-F diet for 8 weeks are shown. Hematoxylin and eosin (H&E) staining of mouse liver tissue (4×~10×). [Figure 5B] Results of CHIN117 administration in a C57BL / 6 mouse model fed an HFD-F diet for 8 weeks are shown. Disease severity was assessed by calculating the steatosis score (NAS). Results are the mean ± SEM of 8-12 mice per group. *p ≤ 0.05. [Figure 5C] Results of administration of CHIN117 in a C57BL / 6 mouse model fed an HFD-F diet for 8 weeks are shown. Disease severity was assessed by calculating the body mass index (BMI). Results are the mean ± SEM of 8-12 mice per group. *p ≤ 0.05. [Figure 5D] Results of CHIN117 administration in a C57BL / 6 mouse model fed an HFD-F diet for 8 weeks. Disease severity was assessed by calculating eWAT mass. Results are mean ± SEM of 8-12 mice per group. *p ≤ 0.05. [Figure 5E]Results of administration of CHIN117 in a C57BL / 6 mouse model fed an HFD-F diet for 8 weeks. Disease severity was assessed by calculating the ratio of eWAT mass / body weight. Results are the mean ± SEM of 8-12 mice per group. *p ≤ 0.05. [Figure 5F] Results of CHIN117 administration in a C57BL / 6 mouse model fed an HFD-F diet for 8 weeks. Disease severity was assessed by calculating BAT mass (g). Results are the mean ± SEM of 8-12 mice per group. *p ≤ 0.05. [Figure 5G] Results of CHIN117 administration in a C57BL / 6 mouse model fed an HFD-F diet for 8 weeks. Disease severity was assessed by calculating the ratio of BAT mass / body weight. Results are the mean ± SEM of 8-12 mice per group. *p ≤ 0.05. [Figure 5H] Results of CHIN117 administration in a C57BL / 6 mouse model fed an HFD-F diet for 8 weeks. Disease severity was assessed by calculating liver mass. Results are the mean ± SEM of 8-12 mice per group. *p ≤ 0.05. [Figure 5I] Results of administration of CHIN117 in a C57BL / 6 mouse model fed an HFD-F diet for 8 weeks are shown. Disease severity was assessed by calculating the liver mass / body weight ratio. Results are the mean ± SEM of 8-12 mice per group. *p ≤ 0.05. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The following paragraphs describe the chemical properties of the compounds according to the invention, which are intended to apply uniformly throughout the entire description and all claims, unless a broader definition is expressly stated otherwise.

[0015] The term "alkyl" as used herein refers to a saturated aliphatic hydrocarbon. This term includes straight (unbranched) or branched chains.

[0016] Non-limiting examples of alkyl groups according to the present invention include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, iso-pentyl, and n-hexyl.

[0017] The term "hydroxyalkyl," as used herein, refers to a saturated aliphatic hydrocarbon in which one or more hydrogen atoms have been replaced with a hydroxyl group.

[0018] Unless otherwise specified, the term "substituted," as used herein, means that one or more hydrogen atoms of the group listed above have been replaced with another non-hydrogen atom, or functional group, provided that the normal valences are maintained and that the substitution results in a stable compound.

[0019] Those skilled in the art of organic chemistry will understand that many organic compounds can form complexes with solvents in which they react or precipitate or crystallize. Such complexes are known as "solvates." For example, complexes with water are known as "hydrates." Solvates of the compounds of the present invention are within the scope of the present invention. Compounds of formula (I) or (Ia) can be easily isolated in association with solvent molecules by crystallization or evaporation of the appropriate solvent to obtain the corresponding solvates.

[0020] The compound of formula (I) or (Ia) may be in a crystalline form. In some embodiments, the crystalline form of the compound of formula (I) or (Ia) is a polymorph.

[0021] The present invention also includes isotopically labeled compounds, which are identical to those provided in formula (I) or (Ia), but differ in that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, and oxygen, e.g., 2 H, 3 H,11 C. 13 C. 14 C. 15 N, 17 Contains O.

[0022] Compounds of the invention that contain the above isotopes and / or other isotopes of other atoms fall within the scope of protection of the invention. Isotopically labeled compounds of the invention, e.g. 3 H and 14 Those incorporating radioactive isotopes such as C are useful in assays of drug and / or substrate tissue distribution. Tritium isotopes, i.e. 3 H, and carbon 14, i.e. 14 C is particularly preferred due to its ease of preparation and detectability. 11 C is particularly useful in PET (positron emission tomography). In addition, deuterium, i.e. 2 Substitution with heavier isotopes such as H may confer certain therapeutic advantages resulting from increased metabolic stability, e.g., increased in vivo half-life or reduced need for administration, and therefore may be of interest in certain circumstances. Isotopically labeled compounds of formula (I) or (Ia) of the invention can generally be prepared by carrying out the methods illustrated in the following schematics and / or examples, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0023] Some groups / substituents included in the present invention may exist as isomers. Thus, in some embodiments, the compounds of formula (I) or (Ia) may have axial chirality and may exist accordingly in the form of optical isomers, such as (R) and (S) forms. The present invention includes within its scope of protection all such isomers, including racemates, enantiomers and mixtures thereof.

[0024] In particular, the scope of protection of the present invention includes all stereoisomers, including enantiomers, diastereoisomers and mixtures thereof, including racemates, and a general reference to a compound of formula (I) or (Ia) includes all stereoisomers, unless otherwise specified.

[0025] Generally, compounds which, if any, are highly chemically unstable alone or in water and clearly unsuitable for pharmaceutical use by any route of administration, whether oral, parenteral or otherwise, are to be considered excluded from the compounds of the present invention. Such compounds are known to the skilled chemist.

[0026] Finally, the compounds of formula (I) or (Ia) can form salts, in particular the quinoline ring can form hydrochlorides and the phenolic residues or the COOH groups can form metal salts.

[0027] According to a first aspect of the present invention, there is provided a compound of formula (I):

[0028] [ka]

[0029] [In formula: R1 is H, a linear or branched C optionally substituted with one substituent R7 1~6 Alkyl, linear or branched OC optionally substituted with one substituent R8 3~6 is selected from the group consisting of alkyl, R2 is H, C 1~6 Hydroxyalkyl, linear or branched C optionally substituted with one substituent R 1~6 Alkyl; H, COOH, COO-C 1~6 Alkyl, C 1~6 phenyl optionally substituted with at least one substituent independently selected from the group consisting of hydroxyalkyl, and linear or branched C optionally substituted with one substituent R 1~6 is selected from the group consisting of alkyl, R3 is H, COOH, COO-C 1~6 alkyl, CHOH; however, - if R2 is H, then R1 or R3 is not H; or - linear OC, in which R1 is optionally substituted with one substituent R8; 3~6 When alkyl, at least one of R2 and R3 is not H; R4 is H, COOH, COO-C 1~6 Alkyl, C 1~6 hydroxyalkyl; R5 is H, COOH, COO-C 1~6 Alkyl, C 1~6 hydroxyalkyl; R6 is H, COOH, COO-C 1~6 Alkyl, C 1~6 hydroxyalkyl, OH; and linear or branched C optionally substituted with one substituent R8 1~6 alkoxyl; With the proviso that when one of R4, R5, and R6 is COOH or CH2OH, at least one of the remaining R4, R5, and R6 is not H; R7 is,

[0030] [ka]

[0031] is selected from the group consisting of R8 is OH, COOH, COO-C 1~6 is selected from the group consisting of alkyl, R9 is,

[0032] [ka]

[0033] (In the formula, R 10 H, COOH, COO-C 1~6 Alkyl, C 1~6 hydroxyalkyl; R 11 are H, OH, COOH, and COO-C 1~6 Alkyl, C 1~6hydroxyalkyl; and R 12 H, COOH, COO-C 1~6 Alkyl, C 1~6 hydroxyalkyl) selected from the group consisting of The compound of the formula:

[0034] [ka]

[0035] There is provided a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, which excludes:

[0036] In a first embodiment, R1 is H, Oi-propyl, On-propyl, On-butyl, O-sec-butyl, On-pentyl, O-2-methylbutyl, -CH2-R7, -O-(CH2) 3~4 -R8.

[0037] In one embodiment, R2 is H, COOH, COO-C 1~6 Alkyl, C 1~6 phenyl optionally substituted with at least one substituent independently selected from the group consisting of hydroxyalkyl; or linear or branched C optionally substituted with one substituent R 1~6 It is an alkyl.

[0038] In further embodiments, R2 is H, CH2OH; H, COOH, COO-C 1~6 Alkyl, C 1~6 phenyl substituted with two substituents independently selected from the group consisting of -hydroxyalkyl, -CH2-R9.

[0039] In the third embodiment, R3 is selected from the group consisting of H, COOH, COOCH3, CH2OH; R4 is selected from the group consisting of H, COOH, COOCH3, CH2OH, and R5 is selected from the group consisting of H, COOH, COOCH3, and CH2OH.

[0040] In a further embodiment, the compound of formula (I) is

[0041] [ka]

[0042] [ka]

[0043] [ka]

[0044] [ka]

[0045] is selected from the group consisting of:

[0046] Preferably, the compound of formula (I) is

[0047] [ka]

[0048] [ka]

[0049] [ka]

[0050] [ka]

[0051] is selected from the group consisting of:

[0052] A second aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (Ia) and at least one pharma- ceutically acceptable excipient. The compound of formula (Ia) has the formula:

[0053] [ka]

[0054] [In formula: R1 is H, a linear or branched C optionally substituted with one substituent R7 1~6 Alkyl, linear or branched OC optionally substituted with one substituent R8 3~6 is selected from the group consisting of alkyl, R2 is H, C 1~6 Hydroxyalkyl, linear or branched C optionally substituted with one substituent R 1~6 Alkyl; H, COOH, COO-C 1~6 Alkyl, C 1~6 phenyl optionally substituted with at least one substituent independently selected from the group consisting of hydroxyalkyl, and linear or branched C optionally substituted with one substituent R 1~6 is selected from the group consisting of alkyl, R3 is H, COOH, COO-C 1~6 alkyl, CHOH; however, - if R2 is H, then R1 or R3 is not H; or - linear OC, in which R1 is optionally substituted with one substituent R8; 3~6 When alkyl, at least one of R2 and R3 is not H; R4 is H, COOH, COO-C 1~6 Alkyl, C 1~6 hydroxyalkyl; R5 is H, COOH, COO-C 1~6 Alkyl, C 1~6 hydroxyalkyl; R6 is H, COOH, COO-C 1~6 Alkyl, C 1~6 hydroxyalkyl, OH; and linear or branched C optionally substituted with one substituent R8 1~6 alkoxyl; With the proviso that when one of R4, R5, and R6 is COOH or CH2OH, at least one of the remaining R4, R5, and R6 is not H; R7 is,

[0055] [ka]

[0056] is selected from the group consisting of R8 is OH, COOH, COO-C 1~6 is selected from the group consisting of alkyl, R9 is,

[0057] [ka]

[0058] (In the formula, R 10 H, COOH, COO-C 1~6 Alkyl, C 1~6 hydroxyalkyl; R 11 are H, OH, COOH, and COO-C 1~6 Alkyl, C 1~6 hydroxyalkyl; and R 12 H, COOH, COO-C 1~6 Alkyl, C 1~6 hydroxyalkyl) selected from the group consisting of or a pharma- ceutically acceptable salt or solvate thereof.

[0059] In one embodiment, R1 is H, Oi-propyl, On-propyl, O-sec-butyl, On-pentyl, O-2-methylbutyl, -CH2-R7, -O-(CH2) 3~4 -R8.

[0060] In one embodiment, R2 is H, COOH, COO-C 1~6 Alkyl, C 1~6 phenyl optionally substituted with at least one substituent independently selected from the group consisting of hydroxyalkyl; or linear or branched C optionally substituted with one substituent R 1~6 It is an alkyl.

[0061] In one embodiment, R2 is H, CH2OH; H, COOH, COO-C 1~6 Alkyl, C 1~6 phenyl substituted with two substituents independently selected from the group consisting of -hydroxyalkyl, -CH2-R9.

[0062] In one embodiment, R3 is selected from the group consisting of H, COOH, COOCH3, CH2OH; R4 is selected from the group consisting of H, COOH, COOCH3, CH2OH, and R5 is selected from the group consisting of H, COOH, COOCH3, and CH2OH.

[0063] In one embodiment, the compound of formula (Ia) is

[0064] [ka]

[0065] [ka]

[0066] [ka]

[0067] [ka]

[0068] is selected from the group consisting of:

[0069] Preferably, the compound of formula (Ia) is

[0070] [ka]

[0071] [ka]

[0072] [ka]

[0073] [ka]

[0074] [ka]

[0075] is selected from the group consisting of:

[0076] Those skilled in the art are aware of a wide variety of excipient compounds suitable for formulating such pharmaceutical compositions.

[0077] The compounds of formula (Ia), together with commonly used excipients, can be included in pharmaceutical compositions and dosage units thereof and can be used in such forms as solids (e.g., tablets or filled capsules), or liquids (e.g., solutions, suspensions, emulsions, elixirs or filled capsules), all for oral use or as sterile injectable solutions for parenteral administration (including subcutaneous and intravenous use).

[0078] Such pharmaceutical compositions and unit dosage forms thereof may contain the ingredients in common percentages with or without additional compounds or active ingredients, and such unit dosage forms may contain any suitable effective amount of the active ingredient corresponding to the intended daily dosage range to be used.

[0079] The pharmaceutical composition containing the compound of the present invention can be prepared by a method well known in the pharmaceutical technical field, and can contain at least one active compound.Generally, the compound of the present invention is administered in a pharmacologic effective amount.The amount of the compound actually administered is usually determined by a physician in consideration of the relevant circumstances, including the condition to be treated, the selected administration route, the actual compound to be administered, the age, weight and response of individual patient, and the severity of the patient's symptoms, etc.

[0080] The pharmaceutical compositions of the present invention can be administered by many routes, including oral, rectal, subcutaneous, intravenous, intramuscular, intranasal and pulmonary. Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are provided in unit dosage forms to facilitate accurate dosing. The expression "unit dosage form" refers to physically discrete units suitable as unitary dosages for human and other mammalian subjects, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in association with acceptable pharmaceutical excipients. Typical unit dosage forms include pre-filled or pre-dosed ampoules or syringes with liquid compositions, or pills, tablets, capsules or the like in the case of solid compositions.

[0081] Liquid forms suitable for oral administration can include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispersing agents, colorants, and flavorings, etc. Solid forms can include, for example, any of the following ingredients, or compounds of a similar nature: binders such as microcrystalline cellulose, gum tragacanth, or gelatin; additives such as starch or lactose; disintegrating agents such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; flow agents such as colloidal silicon dioxide; sweetening agents such as sucrose, lactose, or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0082] Injectable compositions are typically made from sterile injectable fluids or phosphate buffer or other injectable vehicles known in the art.

[0083] The pharmaceutical compositions may be in the form of tablets, pills, capsules, solutions, suspensions, emulsions, powders, suppositories, and as sustained release formulations.

[0084] If desired, tablets may be coated using standard aqueous or nonaqueous techniques. In certain embodiments, such compositions and preparations may contain at least 0.1 percent of the active compound. Of course, the percentage of the active compound in these compositions may vary and may suitably be between about 1 percent and about 60 percent of the mass of the unit. The amount of active compound in such therapeutically useful compositions is such that a therapeutically active dosage is obtained. The active compound may also be administered intranasally, for example, as liquid drops or spray.

[0085] Tablets, pills, capsules, etc. may also contain binders such as gum tragacanth, gum arabic, corn starch, or jelly; additives such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it may contain a liquid carrier such as fatty oil in addition to the above-mentioned types of materials. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. Syrups or elixirs may contain, in addition to the active ingredient, sucrose as a sweetener, methylparaben and propylparaben as preservatives, coloring agents, and flavoring agents such as cherry or orange flavor. In order to avoid breakage during passage through the upper digestive tract, the composition is an enteric coating formulation.

[0086] Pulmonary compositions include, but are not limited to, dry powder compositions consisting of a powder of a compound of formula (Ia) and a suitable vehicle and / or lubricant. Pulmonary compositions may be inhaled by any suitable dry powder inhaler device known to those skilled in the art.

[0087] The administration of the composition is carried out according to the protocol at a dosage sufficient to reduce inflammation and pain in the subject. In some embodiments, one or more active ingredients in the pharmaceutical composition of the present invention are generally formulated into dosage units. The dosage unit can contain 0.1-1000 mg of the compound of formula (Ia) per dosage unit for daily administration.

[0088] In some embodiments, the effective amount of a particular formulation will depend on the severity of the disease, disorder or condition prior to treatment, the individual's health status and response to the drug, hi some embodiments, the dosage ranges from 0.001% to about 60% by weight of the formulation.

[0089] When used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used separately.

[0090] Methods and formulations for drug administration, with respect to formulations for any of the various routes of administration, are described in Remington's Pharmaceutical Sciences, 17th Edition, edited by Gennaro et al., Mack Publishing Co., 1985, and Remington's Pharmaceutical Sciences, edited by Gennaro AR, 20th Edition, 2000, Williams & Wilkins PA, USA, and Remington: The Science and Practice of Pharmacy, 21st Edition, edited by Lippincott Williams & Wilkins, 2005; and Loyd V. Allen and Howard C. Ansel, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 10th Edition, edited by Lippincott Williams & Wilkins, 2014.

[0091] The above components for orally administered or injectable compositions are merely representative.

[0092] The compounds of the invention can also be administered in sustained release forms or by sustained release drug delivery systems.

[0093] A third aspect of the present invention relates to a compound of formula (Ia) above for use as a medicament.

[0094] The compounds of formula (Ia) can be used for the prevention and / or treatment of disorders selected from the group consisting of gastrointestinal disorders, hepatic disorders, cardiovascular disorders, metabolic disorders, infectious diseases, cancer, renal disorders, inflammatory disorders and neurological disorders, as indicated above.

[0095] In one embodiment, liver disorders include primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, cholestasis associated with parenteral nutrition, cholestasis associated with bacterial overgrowth and sepsis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver transplant associated host disease, living donor transplantation, liver regeneration, congenital hepatic fibrosis, granulomatous liver disease, intrahepatic or extrahepatic malignancies, Wilson's disease, hemochromatosis, and alpha-1-antitrypsin deficiency.

[0096] In one embodiment, gastrointestinal disorders include inflammatory bowel disease (IBD) (including Crohn's disease, ulcerative colitis, and indeterminate colitis), irritable bowel syndrome (IBS), bacterial overgrowth, acute and chronic pancreatitis, malabsorption, post-radiation colitis, and microscopic colitis.

[0097] In one embodiment, renal disorders include diabetic nephropathy, hypertensive nephropathy, chronic glomerulonephritis, including chronic transplant glomerulonephritis, chronic tubulointerstitial disease, and vascular disorders of the kidney.

[0098] In one embodiment, the cardiovascular disease is selected from the group consisting of atherosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hypertension, also known as high blood pressure, inflammatory heart disease including myocarditis and endocarditis, ischemic heart disease, cerebrovascular disease including stable angina, unstable angina, myocardial infarction, ischemic stroke, pulmonary heart disease including pulmonary hypertension, peripheral arterial disease (PAD), also known as peripheral vascular disease (PVD), peripheral arterial occlusive disease, and peripheral occlusive arteriopathy.

[0099] In one embodiment, the metabolic disease is selected from the group consisting of insulin resistance, metabolic syndrome, type I and type II diabetes, hypoglycemia, and adrenal cortical disorders including adrenal insufficiency.

[0100] In one embodiment, the metabolic disorder is selected from the group consisting of obesity and conditions associated with bariatric surgery.

[0101] In one embodiment, the cancer is selected from the group including liver cancer, bile duct cancer, pancreatic cancer, gastric cancer, colorectal cancer, breast cancer, ovarian cancer, and conditions associated with chemotherapy resistance.

[0102] In one embodiment, the infectious disease is selected from the group of acquired immune deficiency syndrome (AIDS) and related disorders, B virus and C virus infections.

[0103] In one embodiment, the inflammatory disorder is selected from the group of rheumatoid arthritis, fibromyalgia, Sjogren's syndrome, scleroderma, Behcet's syndrome, vasculitis, and systemic lupus erythematosus.

[0104] According to a further aspect of the invention, there is provided a compound of formula (Ia) for use as a selective agonist of GPBAR1. In particular, there is provided CHIN114.

[0105] According to a further aspect of the present invention, there is provided a compound of formula (Ia) for use as a dual modulator of CysLT1R / FXR. A preferred example of such a compound of formula (Ia) is CHIN104.

[0106] According to a further aspect of the present invention, there is provided a compound of formula (Ia) for use as a dual modulator of CysLT1R / GPBAR1. Exemplary of such compounds of formula (Ia) are CHIN105, CHIN106, and CHIN117.

[0107] Further characteristics of the invention will become apparent from the following description of some purely illustrative and non-limiting examples.

[0108] The following abbreviations are used in the accompanying examples: methanol (MeOH), sodium bicarbonate (NaHCO3), ethyl acetate (EtOAc), dichloromethane (DCM), sodium sulfate (Na2SO4), dimethylformamide (DMF), diisobutylaluminum hydride (DIBAL-H), triphenylphosphine (PPh3). 、Diisopropyl azodicarboxylate (DIAD), hydrochloric acid (HCl), triethylamine (TEA), trifluoroacetic acid (TFA), sodium hydroxide (NaOH), tetrahydrofuran (THF), water (HO), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), time (h), room temperature (rt), retention time (t R ). EXAMPLES

[0109] Example 1 Synthesis of CHIN104-106 Alcohol 1 was synthesized from methylquinoline-2-carboxylate by reduction with diisobutylaluminum hydride (DIBAL-H). The alcohol 1 thus obtained is a substrate for the synthesis of CHIN104 in high yield via Mitsunobu reaction with methyl 3-hydroxybenzoate (Scheme 1).

[0110] Starting from CHIN104, basic hydrolysis of the methyl ester or reduction with DIBAL-H gave the carboxylic acid CHIN105 and alcohol CHIN106, respectively.

[0111] [ka]

[0112] Reagents and conditions a) DIBAL-H, dry THF, 0°C, b) PPh3, DIAD, dry THF, 0°C, c) NaOH, MeOH:H2O 1:1v / v.

[0113] General method. Reaction a). Reduction with DIBAL-H. A solution of DIBAL-H (2.0 equiv., 1.0 M in THF) is added dropwise to a solution of quinoline methyl ester or CHIN104 in anhydrous THF (25 mL) at 0° C. The resulting mixture is stirred at 0° C. for 4-8 h. A saturated aqueous solution of Rochelle's salt (potassium sodium tartrate) is added to the reaction mixture, which is then diluted with DCM. Quench with stirring for 2 h. The aqueous phase is extracted with DCM (3×50 mL) and the pooled organic phases are washed with water, dried over Na2SO4, and concentrated under reduced pressure on a Rotavapor to give a crude residue, which is purified by chromatography column or HPLC.

[0114] Step b) Mitsunobu reaction. Diisopropyl azodicarboxylate (DIAD, 3.5 equiv.) is added dropwise to a solution of triphenylphosphine (PPh3, 3.5 equiv.) in dry THF at 0° C. After 10 min, a solution of alcohol 1 in dry THF is added. After another 10 min, a solution of methyl 3-hydroxybenzoate in dry THF is added. After about 12 h, water is added and the reaction mixture is dried to remove the THF. The dry residue is extracted with EtOAc (3×50 mL) and the pooled organic phases are washed with 2.5 M KOH and water, dried and dried under reduced pressure on a Rotavapor. Purification by chromatography column and silica gel afforded CHIN104.

[0115] Step c) Basic hydrolysis. A small aliquot of CHIN104 ester is dissolved in a solution of MeOH:H2O 1:1 v / v (30 mL) and treated with NaOH (5.0 equiv.) in a basic environment. The reaction mixture is stirred at reflux for 8 h at a temperature of about 150° C. The resulting solution is quenched by treatment with 6 M HCl and then extracted with EtOAc (3×50 mL). The pooled organic phase is washed with water, treated with anhydrous Na2SO4, and then dried on a Rotavapor to give CHIN105 as a crude residue, which is subjected to further purification.

[0116] Example 1A Synthesis of methyl 3-(quinolin-2-ylmethoxy)benzoate (CHIN104). Purification was performed on silica gel using hexane:EtOAc 9:1 v / v and 0.1% TEA as the mixed eluent to give CHIN104 (78%). The analytical sample was purified by HPLC separation on a Nucleodur 100-5 C18 column (5 μm, 10 mm id×250 mm) using MeOH / HO 82:18 v / v as the eluent (flow rate 3 mL / min, t R = 14.8 min) was obtained.

[0117] CHIN104C 18 H 15 No.3 1 H NMR (CDCl3, 400 MHz): δ 8.22 (1H, d, J = 8.4 Hz), 8.10 (1H, d, J = 8.0 Hz), 7.85 (1H, d, J = 8.0 Hz), 7.74 (2H, ovl), 7.68 (2H, ovl), 7.57 (1H, t, J = 8.0 Hz), 7.37 (1H, t, J = 7.7 Hz), 7.24 (1H, d, J = 7.7 Hz), 5.44 (2H, s), 3.91 (3H, s). 13 C NMR (CDCl3, 100 MHz) δ 169.6, 158.4, 157.3, 147.5, 137.1, 131.6, 129.8, 129.5, 128.9, 127.7, 127.6, 126.6, 122.4, 119.7, 119.0, 115.6, 71.4, 52.1.

[0118] Example 1B Synthesis of 3-(quinolin-2-ylmethoxy)benzoic acid (CHIN105). Purification of CHIN105 (68%) was carried out on a silica chromatography column using DCM:MeOH 99:1 v / v as the eluent. Analytical samples were purified by HPLC on Nucleodur 100-5 The column (5 μm, 10 mm id × 250 mm) and the mixed eluent hexane / EtOAc 40:60 v / v were used (flow rate 3 mL / min, t R = 6.9 min) was purified.

[0119] CHIN105C 17 H 13 NO2 1 H NMR (CD3OD, 400 MHz): δ 8.40 (1H, d, J = 8.5 Hz), 8.06 (1H, d, J = 8.3 Hz), 7.95 (1H, d, J = 8.3 Hz), 7.80 (1H, t, J = 8.3 Hz), 7.74 (1H, d, J = 8.5 Hz), 7.70 (1H, s), 7.64 (1H, t, J = 8.3 Hz), 7.62 (1H, d, ovl), 7.41 (1H, t), 7.30 (1H, dd, J = 1.5, 8.0 Hz), 5.42 (2H, s). 13 C NMR (CD3OD, 100 MHz) δ 169.4, 159.9, 158.8, 148.4, 139.1, 133.5, 131.3, 130.7, 129.2, 129.1, 129.0, 128.0, 123.7, 120.8, 120.7, 116.6, 71.9.

[0120] Example 1C Synthesis of (3-(quinolin-2-ylmethoxy)phenyl)methanol (CHIN106). Purification on a silica column using DCM:MeOH 99:1 v / v as eluent gave CHIN106 (60%). An analytical sample was purified by HPLC separation on a Nucleodur 100-5 C18 column (5 μm, 10 mm id×250 mm) using MeOH / HO 75:15 as eluent (flow rate 3 mL / min, t R = 9.3 minutes).

[0121] CHIN106C 17 H 15NO2 1 H NMR (CDCl3, 400 MHz): δ 8.20 (1H, d, J = 8.4 Hz), 8.10 (1H, d, J = 7.4 Hz), 7.84 (1H, d, J = 7.4 Hz), 7.75 (1H, t, J = 7.4 Hz), 7.68 (1H, d, J = 8.4 Hz), 7.56 (1H, t, J = 7.4 Hz), 7.28 (1H, dd, J = 7.3, 8.0 Hz), 7.08 (1H, s), 7.0 (1H, d, J = 8.4 Hz), 6.95 (1H, d, J = 7.3 Hz), 5.40 (2H, s), 4.68 (2H, s). 13 C NMR (CDCl3, 100 MHz) δ 158.6, 157.8, 147.4, 142.8, 137.1, 129.8, 129.6, 128.7, 127.7, 127.6, 126.5, 119.6, 119.1, 113.9, 113.4, 71.1, 64.9.

[0122] Example 2 Synthesis of CHIN107, CHIN108 and CHIN109. For the synthesis of compounds CHIN107-CHIN109, the first step is the monoprotection with TBS of the methyl 3,5-dihydroxybenzoate that must be coupled to the quinoline. Once the monoprotected derivative is obtained, it will be coupled to the quinoline by Williamson reaction between the phenol and the mesylated alcohol derivative 1. The final step is the deprotection of the TBS with tetrabutylammonium fluoride (TBAF) to give CHIN107. Two aliquots of this ester undergo basic hydrolysis and reduction with DIBAL-H to give CHIN108 and CHIN109.

[0123] [ka]

[0124] Reagents and conditions: a) TBS-Cl, imidazole, dry DMF, 45% yield, b) mesyl chloride, TEA, ether, -20°C, quantitative yield, c) phenol (compound 3), K2CO3, anhydrous DMF, 100°C, d) tetrabutylammonium fluoride (TBAF) 1.0 M in dry THF, overnight, e) NaOH tablet excess, MeOH:H2O 1:1 v / v, overnight, reflux, f) DIBAL-H, dry THF, 0°C.

[0125] General method. Reaction a). Protection with TBSCl. Imidazole (1.5 eq.) and tert-butyldimethylsilyl chloride (1.2 eq.) are added to a solution of compound 2 in dry DMF. After 1 h, DMF is removed, extracted 3 times with EtOAc / NH4Cl, and the pooled organic phases are washed with H2O. The organic phase is dried (Na2SO4), filtered, and concentrated in a Rotavapor to give compound 3 in crude form. Purification on silica gel using a 9:1 mixture of hexane / EtOAc as eluent gave compound 3 in 45% yield.

[0126] Reaction b). Mesylation of alcohol 1. Compound 1 is dissolved in dry ether, and triethylamine (6 eq.) and methanesulfonyl chloride (5 eq.) are added to the solution at -20°C. After about 1 h, the solution is washed with a saturated aqueous solution of NaHCO3 and the pooled organic phases are extracted once with water. The organic phase is dried (Na2SO4), filtered and concentrated in a Rotavapor to give compound 4 in a quantitative yield as crude.

[0127] Reaction c). Williamson reaction. Potassium carbonate (2.5 eq.) is added to a solution of the phenol (compound 3) in DMF and left for 15 min. The mesylate derivative (1.2 eq., compound 4) dissolved in dry DMF is added and the solution is placed at 100° C. for about 12 h. The DMF is cooled and removed on a Rotavapor and the solid residue is extracted with water and ethyl acetate (3×50 mL). The pooled organic phases are dried over Na2SO4, filtered and then concentrated on a Rotavapor to give the crude reaction product, which will be sent directly to the next reaction.

[0128] Reaction d) Deprotection from TBS. The crude product from the previous reaction is dissolved in dry THF at room temperature and to this solution is added 1.0 M TBAF, i.e., a solution of tetra-N-butylammonium fluoride in THF (0.63 mL, 5 eq.). After 8 h the reaction is complete and treated by adding AcOEt and extracted with H2O. The combined organic phases are dried over Na2SO4, filtered and concentrated on a Rotavapor to give compound CHIN107 in its crude form.

[0129] Reaction e) Alkaline hydrolysis. The synthesis and work-up process are the same as in Example 1, step c).

[0130] Reaction f) Reduction of the ester with DIBAL-H. The synthesis and work-up process are the same as in Example 1, reaction a).

[0131] Example 2A Synthesis of methyl 3-hydroxy-5-(quinolin-2-ylmethoxy)benzoate (CHIN107). Purification is carried out on a column packed with silica gel using a 998:2 mixture of DCM / MeOH as the eluent to give compound CHIN107 in 85% yield.

[0132] Analytical samples were prepared by HPLC using a normal phase semi-preparative Nucleodur 100-5 column (5 μm, 10 mm id × 250 mm) with hexane / AcOEt 7:3 v / v as the eluent mixture (flow rate 3 mL / min, t R = 23.70 min) and separate.

[0133] CHIN107C 18 H 15 No.4 1H NMR (400 MHz, CDCl3): δ 8.17 (1H, d, J = 8.5 Hz), 8.00 (1H, d, J = 8.0 Hz), 7.79 (1H, d, J = 8.0 Hz), 7.68 (1H, t, J = 8.0 Hz), 7.62 (1H, t, J = 8.5 Hz), 7.54 (1H, t, J = 8.0 Hz), 7.28 (1H, s), 7.21 (1H, s), 6.76 (1H, s), 5.38 (2H, s), 3.89 (3H, s). 13 C NMR (100 MHz, CDCl3): δ 167.2, 159.1, 157.9, 157.3, 146.7, 137.8, 131.8, 130.2, 127.8, 127.7, 127.6, 126.8, 119.2, 109.8, 107.8, 106.8, 70.4, 52.1.

[0134] Example 2B Synthesis of 3-hydroxy-5-(quinolin-2-ylmethoxy)benzoic acid (CHIN108). Purification is carried out on a column packed with silica gel using a 95:5 mixture of DCM / MeOH as the eluent to give compound CHIN108 in quantitative yield. A pure analytical sample was obtained by subjecting the mixture to HPLC on a Phenomenex pentafluorophenyl C18 reversed phase column using a mixture of MeOH / HO 55:45 v / v and 0.1% TFA as the eluent (flow rate 1 mL / min, t R = 9.25 min) was obtained by separation.

[0135] CHIN108C 17 H 13 No.4 1H NMR (400 MHz, CD3OD): δ 8.39 (1H, d, J = 8.4 Hz), 8.05 (1H, d, J = 8.0 Hz), 7.96 (1H, d, J = 8.0 Hz), 7.79 (1H, t, J = 8.0 Hz), 7.72 (1H, d, J = 8.4 Hz), 7.62 (1H, t, J = 8.0 Hz), 7.18 (1H, s), 7.08 (1H, s), 6.66 (1H, s), 5.37 (2H, s). 13 C NMR (100 MHz, CD3OD): δ 160.7, 159.7, 158.2, 148.2, 139.1, 131.4, 131.3, 129.2, 129.1, 129.0, 128.9, 128.0, 120.6, 110.8, 107.8, 107.0, 71.8.

[0136] Example 2C Synthesis of 3-(hydroxymethyl)-5-(quinolin-2-ylmethoxy)phenol (CHIN109). A pure analytical sample (92% yield) was isolated by HPLC of the mixture on a Phenomenex pentafluorophenyl C18 reversed-phase column using a mixture of MeOH / HO 60:40 v / v with 0.1% TFA (flow rate 1 mL / min, t R = 12.24 min) was obtained by separation.

[0137] CHIN109C 17 H 15 No.3 1H NMR (400 MHz, CDCl3): δ 8.20 (1H, d, J = 8.5 Hz), 8.10 (1H, d, J = 8.0 Hz), 7.84 (1H, d, J = 8.0 Hz), 7.75 (1H, t, J = 8.0 Hz), 7.67 (1H, d, J = 8.5 Hz), 7.57 (1H, t, J = 8.0 Hz), 6.65 (1H, s), 6.49 (1H, s), 6.46 (1H, s), 5.40 (2H, s), 4.62 (2H, s). 13 C NMR (100 MHz, CDCl3): δ 161.1, 159.8, 159.6, 148.3, 145.5, 139.0, 131.3, 129.1, 129.0, 128.9, 127.9, 120.6, 107.8, 105.5, 102.1, 71.6, 65.1.

[0138] Example 3 Synthesis of CHIN111, CHIN112 and CHIN114. To synthesize compounds CHIN111, CHIN112, and CHIN114, a substituted phenol must first be prepared.

[0139] Compound 5, prepared as described in Example 2, reaction a), can be converted to phenols 6-8 by Mitsunobu reaction and deprotection with TBAF, which can then be coupled to quinolines via Williamson reaction to give derivatives CHINs 111, 112 and 114.

[0140] [ka]

[0141] Reagents and conditions: a) PPh3, DIAD, alcohols of different nature, dry THF, 0°C, b) tetrabutylammonium fluoride (TBAF) 1.0 M in dry THF, overnight, c) phenols (compounds 6-8), K2CO3, anhydrous DMF, 100°C.

[0142] Example 3A Synthesis of 2-((3-isopropoxyphenoxy)methyl)quinoline (CHIN111). Purification of CHIN111 (61%) was carried out by HPLC on a normal phase semi-preparative Nucleodur 100-5 column (5 μm, 10 mm id×250 mm) using hexane / EtOAc 95:5 v / v as the eluent (flow rate 3 mL / min, t R =38 minutes) to run.

[0143] CHIN111C 19 H 19 NO2 1 H NMR (400 MHz, CDCl3): δ 8.19 (1H, d, J = 8.6 Hz), 8.09 (1H, d, J = 7.5 Hz), 7.84 (1H, d, J = 7.5 Hz), 7.74 (1H, t, J = 7.5 Hz), 7.68 (1H, d, J = 8.6 Hz), 7.56 (1H, t, J = 7.5 Hz), 7.17 (1H, t, J = 8.0 Hz), 6.61 (1H, s), 6.60 (1H, ovl), 6.52 (1H, dd, J = 8.0, 2.0 Hz),5.38 (2H, s), 4.52 (1H, septet, J = 6.0 Hz), 1.32 (6H, d, J = 6.0 Hz). 13 C NMR (100 MHz, CDCl3): δ 159.6, 159.2, 157.9, 147.5, 136.9, 129.9, 129.7, 128.9, 127.7, 127.6, 126.4, 119.1, 108.8, 106.8, 103.0, 71.3, 69.9, 22.0 (2C).

[0144] Example 3B Synthesis of 2-((3-(sec-butoxy)phenoxy)methyl)quinoline (CHIN112). Purification was performed by HPLC on a normal phase semi-preparative Nucleodur 100-5 column (5 μm, 10 mm id×250 mm) using hexane / EtOAc 9:1 v / v as the eluent mixture (flow rate 3 mL / min, t R = 15 min) to obtain the compound in quantitative yield.

[0145] CHIN112C 20 H 21 NO2 1 H NMR (400 MHz, CDCl3): δ 8.19 (1H, d, J = 8.6 Hz), 8.09 (1H, d, J = 7.5 Hz), 7.84 (1H, d, J = 7.5 Hz), 7.74 (1H, t, J = 7.5 Hz), 7.68 (1H, d, J = 8.6 Hz), 7.56 (1H, t, J = 7.5 Hz), 7.17 (1H, t, J = 8.0 Hz), 6.61 (1H, s), 6.60 (1H, ovl), 6.52 (1H, dd, J = 8.0, 2.0 Hz), 5.37 (2H, s), 4.27 (2H, sextet, J = 6.1 Hz), 1.73 (1H, m), 1.60 (1H, m), 1.27 (2H, d, J = 6.1 Hz), 0.96 (3H, t, J = 7.4 Hz). 13 C NMR (100 MHz, CDCl3): δ 159.7, 159.6, 158.0, 147.5, 136.9, 129.9, 129.7, 128.9, 127.7, 127.6, 126.4, 119.2, 108.9, 106.7, 103.1, 75.2, 71.1, 29.2, 19.2, 9.9.

[0146] Example 3C Synthesis of 2-((3-(2-methylbutoxy)phenoxy)methyl)quinoline (CHIN114). Purification was performed by HPLC on a normal phase semi-preparative Nucleodur 100-5 column (5 μm, 10 mm id×250 mm) using a mixture of hexane / AcOEt 9:1 v / v as eluent (flow rate 3 mL / min, t R = 14 min) to obtain CHIN114 in 90% yield.

[0147] CHIN114C 21 H 23 NO2 1 H NMR (400 MHz, CDCl3): δ 8.19 (1H, d, J = 8.6 Hz), 8.09 (1H, d, J = 7.5 Hz), 7.84 (1H, d, J = 7.5 Hz), 7.74 (1H, t, J = 7.5 Hz), 7.68 (1H, d, J = 8.6 Hz), 7.56 (1H, t, J = 7.5 Hz), 7.17 (1H, t, J = 8.0 Hz), 6.61 (1H, s), 6.60 (1H, ovl), 6.52 (1H, dd, J = 8.0, 2.0 Hz), 5.38 (2H, s), 3.80 (1H, dd, J = 9.0, 6.0 Hz), 3.71 (1H, dd, J = 9.0, 6.6 Hz), 1.85 (1H, septet, J = 6.6 Hz), 1.56 (1H, m), 1.25 (1H, m), 1.00 (3H, d, J = 6.6 Hz), 0.94 (3H, t, J = 7.3 Hz). 13 C NMR (100 MHz, CDCl3): δ 160.6, 159.6, 158.0, 147.5, 136.9, 129.9, 129.8, 128.9, 127.8, 127.6, 126.5, 119.1, 107.7, 106.8, 101.8, 73.0, 71.2, 34.6, 26.1, 16.5, 11.3.

[0148] Example 4 Synthesis of CHIN116–CHIN121. Esters CHIN116 and CHIN119 were synthesized by Williamson synthesis using the same experimental process as in Example 2, reaction c, starting from 2-(chloromethyl)quinoline (9) and selectively from methyl 4'-hydroxy-[1,1'-biphenyl]-3-carboxylate (10) or methyl 4'-hydroxy-[1,1'-biphenyl]-4-carboxylate (11).

[0149] The ester is then subjected to reduction and hydrolysis according to the experimental process already described in Example 1, reaction a) and step c).

[0150] [ka]

[0151] Reagents and conditions: a) Compound 10 or 11, K2CO3, dry DMF, 100°C, quantitative yield and 87%, respectively, b) excess NaOH, MeOH:H2O 1:1 v / v, reflux, quantitative yield for both reaction products, c) DIBAL-H, dry THF, 0°C, quantitative yield and 92%, respectively.

[0152] Example 4A Synthesis of methyl 4'-(quinolin-2-ylmethoxy)-[1,1'-biphenyl]-3-carboxylate (CHIN116). The derivative CHIN116 (quantitative yield) is purified on a chromatography column of silica in hexane:EtOAc 9:1 v / v. An analytical sample is purified on a HPLC column Nucleodur 100-5 (5 μm, 10 mm id×250 mm) using the mixture hexane:EtOAc 7:3 v / v as eluent (flow rate 3 mL / min, t R = 12.1 minutes).

[0153] CHIN116C 24 H 19 No.3 1H NMR (400 MHz, CDCl3): δ 8.23 ​​(1H, t, J = 2.0 Hz), 8.21 (1H, d, J = 8.4 Hz), 8.11 (1H, d, J = 8.6 Hz), 7.98 (1H, d, J = 8.0 Hz), 7.84 (1H, d, J = 7.9 Hz), 7.77 (1H, t, J = 8.6 Hz), 7.73 (1H, d, J = 8.4 Hz), 7.71 (1H, d, J = 8.0 Hz), 7.57 (1H, t, ovl), 7.57 (2H, d, J = 8.7 Hz), 7.48 (1H, t, J = 8.0 Hz), 7.13 (2H, d, J = 8.7 Hz), 5.45 (2H, s), 3.94 (3H, s). 13 C NMR (100 MHz, CDCl3): δ 167.0, 158.2, 157.7, 147.5, 140.8, 137.1, 133.1, 131.0, 130.6, 129.8, 128.9, 128.8, 128.3 (2C), 127.8 (2C), 127.7, 127.6, 126.5, 119.1, 115.3 (2C), 71.4, 52.1.

[0154] Example 4B Synthesis of 4'-(quinolin-2-ylmethoxy)-[1,1'-biphenyl]-3-carboxylic acid (CHIN117). Compound CHIN117 is obtained in quantitative yield after purification on a silica chromatography column (DCM:MeOH 95:5 v / v).

[0155] CHIN117C 23 H 17 No.3 1H NMR (400 MHz, CDCl3): δ 8.29 (1H, t, J = 1.6 Hz), 8.23 ​​(1H, d, J = 8.5 Hz), 8.14 (1H, d, J = 8.4 Hz), 8.03 (1H, d, J = 7.8 Hz), 7.85 (1H, d, J = 8.0 Hz), 7.79 (1H, d, J = 7.8 Hz), 7.77 (1H, t, J = 8.4 Hz), 7.72 (1H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.4 Hz), 7.57 (1H, t, ovl), 7.52 (1H, t, J = 7.8 Hz), 7.14 (2H, d, J = 8.4 Hz), 5.47 (2H, s). 13 C NMR (100 MHz, DMSO-d6): 168.3, 159.0, 158.5, 147.9, 141.0, 138.2, 133.1, 132.4, 131.0, 130.3, 129.5, 129.0, 128.9, 128.6, 128.3, 127.8, 127.7, 127.6, 120.6, 116.5 (2C), 71.9.

[0156] Example 4C Synthesis of 4'-(quinolin-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)methanol (CHIN118). The HPLC analysis was performed on a Nucleodur 100-5 column (5 μm, 10 mm id×250 mm) using hexane / EtOAc 1:1 v / v as the eluent (flow rate 3 mL / min, t R = 20 min) to give CHIN118 in quantitative yield.

[0157] CHIN118C 23 H 19 NO2 1H NMR (400 MHz, CDCl3): δ 8.22 (1H, d, J = 8.6 Hz), 8.12 (1H, d, J = 7.8 Hz), 7.85 (1H, d, J = 7.8 Hz), 7.76 (1H, t, J = 7.8 Hz), 7.71 (1H, d, J = 8.6 Hz), 7.57 (1H, t, J = 7.7 Hz), 7.55 (1H, s), 7.52 (2H, d, J = 8.6 Hz), 7.47 (1H, d, J = 7.6 Hz), 7.40 (1H, t, J = 7.6 Hz), 7.31 (1H, d, J = 7.6 Hz), 7.09 (2H, d, J = 8.6 Hz), 5.42 (2H, s), 4.76 (2H, s). 13 C NMR (100 MHz, CDCl3): δ 158.1, 157.8, 147.5, 141.4, 140.9, 137.1, 133.9, 129.8, 128.9, 128.8, 128.3 (2C), 127.7, 127.6, 126.6, 126.0, 125.3 (2C), 119.1, 115.1 (2C), 71.2, 65.4.

[0158] Example 4D Synthesis of methyl 4'-(quinolin-2-ylmethoxy)-[1,1'-biphenyl]-4-carboxylate (CHIN119). Compound CHIN119 (87% yield) is purified by chromatography on a silica column using a mixture of hexane:EtOAc 9:1 v / v as eluent. A pure analytical sample was purified by HPLC on a Nucleodur 100-5 C18 column (5 μm, 4.6 mm id×250 mm) with a gradient (t0=60% MeOH to t 20分 =95% MeOH, flow rate 1 mL / min, t R = 5.5 min).

[0159] CHIN119C 24 H 19 No.3 1H NMR (400 MHz, CDCl3): δ 8.22 (1H, d, J = 8.6 Hz), 8.11 (1H, d, J = 8.2 Hz), 8.08 (2H, d, J = 8.6 Hz), 7.85 (1H, d, J = 8.2 Hz), 7.76 (1H, t, J = 8.2 Hz), 7.70 (1H, d, J = 8.6 Hz), 7.61 (2H, d J = 8.6 Hz), 7.58 (2H, d, J = 8.9 Hz), 7.57 (1H, t, ovl), 7.13 (2H, d, J = 8.9 Hz), 5.46 (2H, s), 3.94 (3H, s). 13 C NMR (100 MHz, CDCl3): δ 167.1, 158.6, 157.6, 147.5, 145.0, 137.1, 132.9, 130.1 (2C), 129.8, 128.9, 128.5 (2C), 128.3, 127.7, 127.6, 126.6 (2C), 126.5, 119.0, 115.3 (2C), 71.5, 52.1.

[0160] Example 4E Synthesis of 4'-(quinolin-2-ylmethoxy)-[1,1'-biphenyl]-4-carboxylic acid (CHIN120). Purification is carried out by flash chromatography column and silica gel using DCM:MeOH 95:5 v / v as eluent to give CHIN120 in quantitative yield.

[0161] CHIN120C 23 H 17 No.3 1H NMR (400 MHz, CD3OD+0.1% TFA): δ 9.23 (1H, d, J = 8.5 Hz), 8.42 (1H, d, J = 8.0 Hz), 8.39 (1H, d, J = 7.5 Hz), 8.24 (1H, t, J = 7.5 Hz), 8.23 (1H, d, J = 8.5 Hz), 8.10 (2H, d, J = 8.5 Hz), 8.03 (1H, t, J = 8.0 Hz), 7.76 (2H, d, J = 8.5 Hz), 7.73 (2H, d, J = 8.5 Hz), 7.32 (2H, d, J = 8.5 Hz), 5.80 (2H, s). 13 C NMR (100 MHz, CDCl3): δ 168.7, 158.3, 157.3, 145.7, 145.0, 138.8, 133.2, 130.9, 130.4 (2C), 128.5 (2C), 128.4, 128.3, 127.8 (2C), 126.5 (3C), 119.2, 115.3 (2C), 69.8.

[0162] Example 4F Synthesis of (4'-(quinolin-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)methanol (CHIN121). Compound CHIN121 is obtained after purification on a silica gel chromatography column using hexane:EtOAc 8:2 v / v as the eluent (yield 92%). The analytical sample was purified on a Nucleodur 100-5 column (5 μm, 10 mm id×250 mm) in HPLC with hexane / EtOAc 1:1 v / v (flow rate 3 mL / min, t R = 18 min) and further refined.

[0163] CHIN121C 23 H 19 NO2 1H NMR (400 MHz, CDCl3): δ 8.22 (1H, d, J = 8.4 Hz), 8.11 (1H, d, J = 8.5 Hz), 7.85 (1H, d, J = 8.0 Hz), 7.76 (1H, t, J = 8.5 Hz), 7.71 (1H, d, J = 8.4 Hz), 7.57 (1H, t, J = 8.0 Hz), 7.55 (2H, d, J = 8.6 Hz), 7.53 (2H, d, J = 8.6 Hz), 7.42 (2H, d, J = 8.6 Hz), 7.10 (2H, d, J = 8.6 Hz), 5.44 (2H, s), 4.74 (2H, s). 13 C NMR (100 MHz, CDCl3): δ 157.9, 157.8, 157.3, 147.5, 140.1, 137.1, 133.9, 129.8, 128.9, 128.5, 128.4, 127.7, 127.6, 127.5 (2C), 126.8 (2C), 126.5, 119.1, 115.2 (2C), 71.3, 65.1.

[0164] Example 5 Synthesis of CHIN125-CHIN127 and CHIN131-CHIN133. For the synthesis of esters CHIN125 and CHIN131, the first step uses the Williamson synthesis, starting from methyl 3,5-dihydroxybenzoate (2), which is reacted alternately with methyl 5-bromopentanoate (14) and methyl 4-bromobutanoate (15) to give phenols 12 and 13. The resulting monoalkylated phenols are subjected to a further Williamson reaction with 2-(chloromethyl)quinoline (9) by the same experimental process as used in Example 2, reaction c. The esters are then subjected to reduction with LiBH4 and hydrolysis according to the experimental process already described in Example 1, step c).

[0165] [ka]

[0166] a Reagents and conditions: a) Compound 14 or Compound 15, K2CO3, dry DMF, 100°C, 48% and 47% yields for Compounds 12 and 13, respectively, b) Compound 12 or 13, K2CO3, dry DMF, 100°C, 80% and 74% yields, respectively, c) NaOH excess, MeOH:H2O 1:1 v / v, reflux, 98% quantitative yield, respectively, d) LiBH4, dry THF, 0°C, 80% and 76% yields, respectively.

[0167] General method. Reaction a). Williamson reaction. Methyl 5-bromopentanoate (0.5 eq.) or methyl 4-bromobutanoate and K2CO3 (1 eq.) are added to a solution of compound 2 in dry DMF and the solution is placed at 100°C for about 12 hours. It is cooled, acidified with HCl 6N and the DMF is removed by Rotavapor. The dry residue is extracted with water and ethyl acetate (3 x 50 mL). The pooled organic phases are dried over Na2SO4, filtered and then concentrated on Rotavapor to give the crude reaction product, which will be purified by open column chromatography.

[0168] Reaction d). Reduction reaction with LiBH4. Dry methanol (1 eq.) and a solution of LiBH42M in dry THF (2 eq.) are added to a solution of the ester CHIN125 or CHIN131 in dry THF at 0° C. After about 5 h, TLC monitoring of the reaction indicates completion of the substrate, and the reaction is worked up by adding 1N NaOH solution (2 eq.) at 0° C. After quenching for 1 h, the mixture is then extracted with water and ethyl acetate (3×50 mL). The pooled organic phases are dried over Na2SO4, filtered, and then concentrated by Rotavapor to give the crude reaction product, which will be purified by HPLC.

[0169] (Example 5A). Synthesis of methyl 3-((5-methoxy-5-oxopentyl)oxy)-5-(quinolin-2-ylmethoxy)benzoate (CHIN125). Compound CHIN125 (80% yield) is purified by chromatography column on silica using a mixture of hexane: EtOAc 9: 1 v / v as eluent. A pure analytical sample is purified by HPLC on a Nucleodur 100-5 column (5 μm, 10 mm id × 250 mm) using n-hexane: EtOAc 7: 3 v / v as eluent (flow rate 3 mL / min, t R = 20.4 min) to obtain

[0170] CHIN125C 24 H 25 No.6 1 H NMR (400 MHz, CDCl3): δ 8.21 (1H, d, J = 8.5 Hz), 8.10 (1H, d, J = 8.5 Hz), 7.83 (1H, d, J = 8.2 Hz), 7.74 (1H, t, J = 8.5 Hz), 7.66 (1H, d, J = 8.5 Hz), 7.56 (1H, t, J = 8.1 Hz), 7.33 (1H, dd, J = 1.3 Hz, 2.3 Hz), 7.19 (1H, dd, J = 1.3 Hz, 2.3 Hz), 6.78 (1H, t, J = 2.3 Hz), 5.40 (2H, s), 3.98 (2H, t, J = 6.5 Hz), 3.89 (3H, s), 3.67 (3H, s), 2.38 (2H, t, J = 7.5 Hz), 1.81 (2H, ovl). 13 C NMR (700 MHz, CDCl3): δ 173.8, 166.7, 160.1, 159.5, 157.3, 147.6, 137.1, 132.1, 129.8, 129.0, 127.7, 127.6, 126.6, 119.1, 108.4, 108.3, 106.7, 71.5, 67.8, 52.3, 51.5, 33.6, 28.5, 21.5.

[0171] Example 5B Synthesis of 3-(4-carboxybutoxy)-5-(quinolin-2-ylmethoxy)benzoic acid (CHIN126). Purification was performed by HPLC on a Phenomenex Luna C18(2) column (5 μm, 10 mm id × 250 mm) with a gradient (t0 = 10% MeCN 0.1% TFA to t 20分 =70% MeCN 0.1% TFA 25分 =95% MeCN 0.1% TFA, flow rate 3mL / min, t R =16.3 min) to give compound CHIN126 (quantitative yield).

[0172] CHIN126C 22 H 21 No.6 1 H NMR (400 MHz, CD3OD): δ 9.17 (1H, d, J = 8.5 Hz), 8.38 (1H, d, J = 8.5 Hz), 8.34 (1H, d, J = 8.2 Hz), 8.20 (1H, t, J = 8.5 Hz), 8.18 (1H, d, J = 8.5 Hz), 7.98 (1H, t, J = 8.1 Hz), 7.38 (1H, dd, J = 1.3 Hz, 2.3 Hz), 7.31 (1H, dd, J = 1.3 Hz, 2.3 Hz), 6.98 (1H, t, J = 2.3 Hz), 5.74 (2H, s), 4.06 (2H, t, J = 5.5 Hz), 2.38 (2H, t, J = 8.0 Hz), 1.82 (2H, ovl). 13 C NMR (700 MHz, CD3OD): δ 177.3, 169.2, 161.8, 160.4, 157.9, 143.6, 133.5, 132.1, 129.7, 129.5, 129.4, 129.1, 125.9, 121.1, 109.2, 108.9, 107.1, 70.0, 68.9, 34.5, 29.6, 22.7.

[0173] Example 5C Synthesis of 5-(3-(hydroxymethyl)-5-(quinolin-2-ylmethoxy)phenoxy)pentan-1-ol (CHIN127). Purification was performed by HPLC on a Phenomenex Luna C18(2) column (5 μm, 10 mm id × 250 mm) using MeCN / HO 55:45 (flow rate 3 mL / min, t R =5.16 min) to give compound CHIN127 (80%).

[0174] CHIN127C 22 H 25 No.4 1 H NMR (400 MHz, CDCl3): δ 8.21 (1H, d, J = 8.5 Hz), 8.11 (1H, d, J = 8.5 Hz), 7.84 (1H, d, J = 8.2 Hz), 7.75 (1H, t, J = 8.5 Hz), 7.68 (1H, d, J = 8.5 Hz), 7.56 (1H, t, J = 8.1 Hz), 6.64 (1H, dd, J = 1.3 Hz, 2.3 Hz), 6.55 (1H, t, J = 2.3 Hz), 6.52 (1H, dd, J = 1.3 Hz, 2.3 Hz), 5.38 (2H, s), 4,62 (2H, s), 3.94 (2H, t, J = 6.5 Hz), 3.67 (2H, t, J = 6.5), 1.79 (2H, quintet J = 6.2 Hz, 7.5 Hz), 1.63-1.53 ​​(4H, ovl). 13 C NMR (700 MHz, CDCl3): δ 160.3, 159.6, 157.8, 147.2, 143.9, 137.3, 130.0, 129.2, 127.7, 127.6, 126.9, 119.3, 105.9, 105.1, 100.8, 71.9, 67.9, 64.8, 62.5, 32.3, 28.9, 22.3.

[0175] Example 5D Synthesis of methyl 3-(4-methoxy-4-oxobutoxy)-5-(quinolin-2-ylmethoxy)benzoate (CHIN131). The derivative CHIN131 (74%) is purified on a silica chromatography column in hexane:EtOAc 9:1 v / v. The analytical sample is purified on a HPLC column Nucleodur 100-5 (5 μm, 10 mm id×250 mm) using a mixture of n-hexane:EtOAc 7:3 v / v as eluent (flow rate 3 mL / min, t R = 22.1 minutes).

[0176] CHIN131C 23 H 23 No.6 1 H NMR (400 MHz, CDCl3): δ 8.24 (1H, d, J = 8.5 Hz), 8.13 (1H, d, J = 8.5 Hz), 7.85 (1H, d, J = 8.2 Hz), 7.76 (1H, t, J = 8.5 Hz), 7.68 (1H, d, J = 8.5 Hz), 7.58 (1H, t, J = 8.1 Hz), 7.34 (1H, dd, J = 8.1 Hz, 2.3 Hz), 7.19 (1H, dd, J = 2.3 Hz), 6.78 (1H, dd, J = 8.1 Hz, 2.3 Hz), 5.38 (2H, s), 4.02 (2H, t, J = 6.3 Hz), 3.71 (2H, t, J = 7.0 Hz), 2.51 (2H, t, J = 7.3 Hz), 2.10 (2H, quintet, J = 6.3 Hz, 7.3 Hz). 13 C NMR (700 MHz, CDCl3): δ 173.6, 166.7, 160.3, 159.6, 157.3, 147.6, 137.2, 132.2, 129.9, 129.1, 127.8, 127.7, 126.7, 119.2, 108.5, 108.3, 106.8, 71.5, 67.1, 52.3, 51.8, 30.5, 24.5.

[0177] (Example 5E) Synthesis of 3-(3-カルボキシプロポキシ)-5-(キノリン-2-イルメトキシ) benzoic acid (CHIN132). Inducer CHIN132 (98%), HPLC により, Phenomenex Luna C18(2) カラム(5μm, 10mm id×250mm) にて, blended (t0=10% MeCN 0.1% TFA~t 20分 =70% MeCN 0.1% TFA~t 25分 =95% MeCN 0.1% TFA, flow rate 3mL / min, t R =15 points)でRefinedする.

[0178] CHIN132 C 21 H 19 NO6 1 H NMR (400 MHz, CD3OD): δ 9.04 (1H, d, J = 8.5 Hz), 8.33 (1H, d, J = 8.5 Hz), 8.29 (1H, d, J = 8.2 Hz), 8.14 (1H, t, J = 8.5 Hz), 8.11 (1H, d, J = 8.5 Hz), 7.93 (1H, t, J = 8.1 Hz), 7.38 (1H, dd, J = 8.1 Hz, 2.3 Hz), 7.28 (1H, dd, J = 2.3 Hz), 6.99 (1H, dd, J = 8.1 Hz, 2.3 Hz), 5.69 (2H, s), 4.09 (2H, t, J = 6.3 Hz), 2.50 (2H, t, J = 7.3 Hz), 2.08 (2H, quintet, J = 6.3 Hz, 7.3 Hz). 13 C NMR (700 MHz, CD3OD): δ 176.9, 169.0, 161.3, 160.2, 159.7, 148.1, 133.7, 132.0, 130.1, 129.5, 129.4, 129.1, 124.7, 121.3, 109.3, 107.6, 107.5, 69.6, 68.8, 33.0, 25.7.

[0179] (Example 5F) Synthesis of 4-(3-(hydroxymethyl)-5-(quinolin-2-ylmethoxy)phenoxy)butan-1-ol (CHIN133). The derivative CHIN133 (76%) was purified by HPLC on a Nucleodur 100-5 column (5 μm, 10 mm id × 250 mm) using a mixture of n-hexane:EtOAc 4:6 v / v as eluent (flow rate 3 mL / min, t R = 26.32 min) and purify.

[0180] CHIN133C 21 H 23 No.4 1 H NMR (400 MHz, CD3OD): δ 8.23 ​​(1H, d, J = 8.5 Hz), 8.12 (1H, d, J = 8.5 Hz), 7.85 (1H, d, J = 8.2 Hz), 7.76 (1H, t, J = 8.5 Hz), 7.69 (1H, d, J = 8.5 Hz), 7.57 (1H, t, J = 8.1 Hz), 6.65 (1H, dd, J = 8.1 Hz, 2.3 Hz), 6.55 (1H, dd, J = 8.1 Hz, 2.3 Hz), 6.52 (1H, dd, J = 2.3 Hz), 5.39 (2H, s), 4.64 (2H, s), 4.07 (2H, t, J = 6.3 Hz), 3.86 (2H, t, J = 6.3 Hz), 2.49 (2H, m), 2.02 (2H, m). 13 C NMR (700 MHz, CD3OD): δ 176.9, 169.0, 161.3, 160.2, 159.7, 148.1, 133.7, 132.0, 130.1, 129.5, 129.4, 129.1, 124.7, 121.3, 109.3, 107.6, 107.5, 69.6, 68.8, 33.0, 25.7.

[0181] Example 6 Synthesis of CHIN134–CHIN142. The first reaction step is the Mitsunobu reaction, the process of which is described in Example 1, step b), starting from methyl 3,5-dihydroxybenzoate (2) with propan-2-ol (16), propan-1-ol (17) and butan-2-ol (18). The monoalkylated derivative obtained is subjected to a Williamson reaction with 2-(chloromethyl)quinoline (9) using the same experimental process as that used in Example 2, reaction c. The ester is then subjected to reduction and hydrolysis, respectively, according to the experimental processes already described in Example 5, reaction d) and Example 1, step c).

[0182] [ka]

[0183] a Reagents and conditions: a) alcohols 16 or 17 or 18, DIAD, PPh3, dry THF, 0°C, quantitative yields 50%, 45% and 42% for compounds 19, 20 and 21, respectively; b) compounds 19-21, K2CO3, dry DMF, 100°C, quantitative yields 57% and 70%, respectively; c) excess NaOH, MeOH:H2O 1:1 v / v, reflux, yields 84%, 86% and 91%, respectively; d) LiBH4, dry THF, 0°C, yields 88%, 94% and 89%, respectively.

[0184] Example 6A Synthesis of methyl 3-isopropoxy-5-(quinolin-2-ylmethoxy)benzoate (CHIN134). The derivative CHIN134 (50%) is purified on a silica chromatographic column in hexane:EtOAc 9:1 v / v. Analytical samples are purified on a Nucleodur 100-5 column (5 μm, 10 mm id×250 mm) in HPLC using a mixture of n-hexane:EtOAc 7:3 v / v as eluent (flow rate 3 mL / min, t R = 9.9 minutes).

[0185] CHIN134C 21 H21 No.4 1 H NMR (400 MHz, CDCl3): δ 8.21 (1H, d, J = 8.5 Hz), 8.10 (1H, d, J = 8.5 Hz), 7.84 (1H, d, J = 8.2 Hz), 7.75 (1H, t, J = 8.5 Hz), 7.67 (1H, d, J = 8.5 Hz), 7.56 (1H, t, J = 8.1 Hz), 7.31 (1H, dd, J = 2.4 Hz), 7.20 (1H, dd, J = 2.3 Hz), 6.78 (1H, dd, J = 2.4 Hz, 2.3 Hz), 5.40 (2H, s), 4.57 (1H, quintet, J = 6.1 Hz), 3.89 (3H, s), 1.32 (6H, d, J = 6.1 Hz). 13 C NMR (700 MHz, CDCl3): δ 166.8, 159.5, 159.1, 157.3, 147.6, 137.1, 132.2, 129.9, 129.0, 127.8, 127.7, 126.7, 119.2, 109.7, 108.2, 108.0, 71.4, 70.4, 52.1, 21.9(2C).

[0186] Example 6B Synthesis of 3-isopropoxy-5-(quinolin-2-ylmethoxy)benzoic acid (CHIN135). The derivative CHIN135 (84%) is purified on a silica chromatography column in DCM:MeOH 9:1 v / v.

[0187] CHIN135C 20 H 19 No.4 1H NMR (400 MHz, CD3OD): δ 9.21 (1H, d, J = 8.5 Hz), 8.39 (1H, d, J = 8.5 Hz), 8.37 (1H, d, J = 8.2 Hz), 8.22 (1H, t, J = 8.5 Hz), 8.20 (1H, d, J = 8.5 Hz), 8.01 (1H, t, J = 8.1 Hz), 7.38 (1H, dd, J = 2.4 Hz), 7.29 (1H, dd, J = 2.3 Hz), 6.97 (1H, dd, J = 2.4 Hz, 2.3 Hz), 5.75 (2H, s), 4.68 (1H, quintet, J = 6.1 Hz), 1.35 (6H, d, J = 6.1 Hz). 13 C NMR (700 MHz, CD3OD): δ 169.0, 160.7, 159.8, 156.8, 148.6, 136.6, 134.4, 131.2, 130.5, 129.9, 129.2, 126.2, 121.7, 111.8, 109.1, 108.8, 71.6, 67.7, 22.1(2C).

[0188] Example 6C Synthesis of (3-isopropoxy-5-(quinolin-2-ylmethoxy)phenyl)methanol (CHIN136). The derivative CHIN136 (88%) was purified by HPLC on a Nucleodur 100-5 column (5 μm, 10 mm id × 250 mm) using a mixture of n-hexane:EtOAc 7:3 v / v as the eluent (flow rate 3 mL / min, t R = 38.79 min) and purified.

[0189] CHIN136C 20 H 21 No.3 1H NMR (400 MHz, CDCl3): δ 8.21 (1H, d, J = 8.5 Hz), 8.12 (1H, d, J = 8.5 Hz), 7.84 (1H, d, J = 8.2 Hz), 7.75 (1H, t, J = 8.5 Hz), 7.68 (1H, d, J = 8.5 Hz), 7.56 (1H, t, J = 8.1 Hz), 6.63 (1H, dd, J = 2.4 Hz), 6.54 (1H, dd, J = 2.3 Hz), 6.51 (1H, dd, J = 2.4 Hz, 2.3 Hz), 5.38 (2H, s), 4.61 (2H, s), 4.52 (1H, Quintet, J = 6.1 Hz), 1.30 (6H, d, J = 6.1 Hz). 13 C NMR (700 MHz, CDCl3): δ 159.8, 159.4, 157.9, 147.5, 143.9, 137.2, 129.9, 129.3, 127.8, 127.7, 127.8, 127.7, 119.3, 107.3, 105.3, 102.2, 70.1, 65.2, 50.6, 22.1(2C).

[0190] Example 6D Synthesis of methyl 3-propoxy-5-(quinolin-2-ylmethoxy)benzoate (CHIN137). The derivative CHIN137 (50%) is purified on a silica chromatography column in hexane:EtOAc 9:1 v / v. The analytical sample is purified on a HPLC column Nucleodur 100-5 (5 μm, 10 mm id×250 mm) using a mixture of n-hexane:EtOAc 7:3 v / v as eluent (flow rate 3 mL / min, t R = 11.44 minutes).

[0191] CHIN137C 21 H 21 No.4 1H NMR (400 MHz, CDCl3): δ 8.21 (1H, d, J = 8.5 Hz), 8.10 (1H, d, J = 8.5 Hz), 7.84 (1H, d, J = 8.2 Hz), 7.75 (1H, t, J = 8.5 Hz), 7.67 (1H, d, J = 8.5 Hz), 7.56 (1H, t, J = 8.1 Hz), 7.33 (1H, dd, J = 2.4 Hz), 7.20 (1H, dd, J = 2.3 Hz), 6.80 (1H, dd, J = 2.4 Hz, 2.3 Hz), 5.40 (2H, s), 3.93 (2H, t, J = 6.4 Hz), 3.89 (3H, s), 1.79 (2H, sextet, J = 7.4 Hz), 1.02 (3H, t, J = 7.4 Hz). 13 C NMR (700 MHz, CDCl3): δ 166.9, 160.3, 159.5, 157.5, 147.5, 137.2, 132.2, 129.9, 129.0, 127.7, 127.6, 126.7, 119.2, 108.5, 108.2, 106.8, 71.5, 69.9, 52.3, 22.6, 10.5.

[0192] Example 6E Synthesis of 3-propoxy-5-(quinolin-2-ylmethoxy)benzoic acid (CHIN138). The derivative CHIN138 (86%) is purified on a silica chromatography column in DCM:MeOH 9:1 v / v.

[0193] CHIN138C 20 H 19 No.4 1H NMR (400 MHz, CD3OD): δ 8.40 (1H, d, J = 8.5 Hz), 8.06 (1H, d, J = 8.5 Hz), 7.96 (1H, d, J = 8.2 Hz), 7.80 (1H, t, J = 8.5 Hz), 7.73 (1H, d, J = 8.5 Hz), 7.62 (1H, t, J = 8.1 Hz), 7.28 (1H, dd, J = 2.4 Hz), 7.18 (1H, dd, J = 2.3 Hz), 6.85 (1H, dd, J = 2.4 Hz, 2.3 Hz), 5.39 (2H, s), 3.95 (2H, t, J = 6.4 Hz), 1.78 (2H, sextet, J = 7.4 Hz), 1.03 (3H, t, J = 7.4 Hz). 13 C NMR (700 MHz, CD3OD): δ 169.5, 161.7, 160.8, 158.9, 148.3, 139.0, 134.2, 131.2, 129.2, 129.1, 129.0, 128.0, 120.7, 109.7, 109.2, 107.5, 72.0, 70.8, 23.5, 10.7.

[0194] Example 6F Synthesis of (3-propoxy-5-(quinolin-2-ylmethoxy)phenyl)methanol (CHIN139). The derivative CHIN139 (94%) was purified by HPLC on a Nucleodur 100-5 column (5 μm, 10 mm id × 250 mm) using a mixture of n-hexane:EtOAc 4:6 v / v as eluent (flow rate 3 mL / min, t R =24.5 min) and purify.

[0195] CHIN139C 20 H 21 No.3 1H NMR (400 MHz, CD3OD): δ 8.38 (1H, d, J = 8.5 Hz), 8.05 (1H, d, J = 8.5 Hz), 7.95 (1H, d, J = 8.2 Hz), 7.80 (1H, t, J = 8.5 Hz), 7.73 (1H, d, J = 8.5 Hz), 7.62 (1H, t, J = 8.1 Hz), 6.65 (1H, dd, J = 2.4 Hz), 6.55 (1H, dd, J = 2.3 Hz), 6.51 (1H, dd, J = 2.4 Hz, 2.3 Hz), 5.34 (2H, s), 4.52 (2H, s), 3.90 (2H, t, J = 6.4 Hz), 1.75 (2H, sextet, J = 7.4 Hz), 1.01 (3H, t, J = 7.4 Hz). 13 C NMR (700 MHz, CD3OD): δ 160.5, 159.6, 158.0, 146.9, 144.1, 137.5, 129.9, 129.0, 127.7, 127.5, 126.5, 119.3, 105.5, 104.9, 100.2, 70.3, 69.2, 63.7, 22.2, 09.4.

[0196] Example 6G Synthesis of methyl 3-(sec-butoxy)-5-(quinolin-2-ylmethoxy)benzoate (CHIN140). The derivative CHIN140 (70%) is purified on a silica chromatography column in hexane:EtOAc 9:1 v / v. Analytical samples are purified on a HPLC column Nucleodur 100-5 (5 μm, 10 mm id×250 mm) using a mixture of n-hexane:EtOAc 7:3 v / v as eluent (flow rate 3 mL / min, t R = 11.5 minutes).

[0197] CHIN140C 22 H 23 No.4 1H NMR (400 MHz, CDCl3): δ 8.21 (1H, d, J = 8.5 Hz), 8.10 (1H, d, J = 8.5 Hz), 7.84 (1H, d, J = 8.2 Hz), 7.75 (1H, t, J = 8.5 Hz), 7.67 (1H, d, J = 8.5 Hz), 7.56 (1H, t, J = 8.1 Hz), 7.31 (1H, dd, J = 2.4 Hz), 7.20 (1H, dd, J = 2.3 Hz), 6.78 (1H, dd, J = 2.4 Hz, 2.3 Hz), 5.40 (2H, s), 4.32 (1H, sextet J = 6.0 Hz), 3.88 (3H, s), 1.72-1.61 (2H, ovl), 1.26 (3H, d, J = 6.1 Hz), 0.95 (3H, t, J = 7.4 Hz). 13 C NMR (700 MHz, CDCl3): δ 166.9, 159.5, 159.4, 157.3, 147.5, 137.4, 132.5, 130.0, 128.9, 127.8, 127.7, 126.7, 119.2, 109.9, 108.1, 108.0, 75.6, 71.5, 52.3, 19.2, 09.7.

[0198] Example 6H Synthesis of 3-(sec-butoxy)-5-(quinolin-2-ylmethoxy)benzoic acid (CHIN141). The derivative CHIN141 (91%) is purified on a silica chromatography column in DCM:MeOH 9:1 v / v.

[0199] CHIN141C 21 H 21 No.4 1H NMR (400 MHz, CD3OD): δ 8.39 (1H, d, J = 8.5 Hz), 8.06 (1H, d, J = 8.5 Hz), 7.96 (1H, d, J = 8.2 Hz), 7.80 (1H, t, J = 8.5 Hz), 7.72 (1H, d, J = 8.5 Hz), 7.62 (1H, t, J = 8.1 Hz), 7.27 (1H, dd, J = 2.4 Hz), 7.16 (1H, dd, J = 2.3 Hz), 6.83 (1H, dd, J = 2.4 Hz, 2.3 Hz), 5.39 (2H, s), 4.36 (1H, sextet J = 6.0 Hz), 1.69-1.60 (2H, ovl), 1.24 (3H, d, J = 6.1 Hz), 0.96 (3H, t, J = 7.4 Hz). 13 C NMR (700 MHz, CD3OD): δ 169.4, 160.8, 158.8, 148.3, 139.0, 134.0, 131.3, 131.0, 129.2, 129.1, 129.0, 128.0, 120.7, 110.9, 109.2, 108.6, 76.5, 72.0, 30.0, 19.4, 09.9.

[0200] Example 6I Synthesis of (3-(sec-butoxy)-5-(quinolin-2-ylmethoxy)phenyl)methanol (CHIN142). The derivative CHIN142 (89%) was purified by HPLC on a Nucleodur 100-5 column (5 μm, 10 mm id × 250 mm) using a mixture of n-hexane:EtOAc 4:6 v / v as the eluent (flow rate 3 mL / min, t R = 24.74 min) and purify.

[0201] CHIN142C 21 H 23 No.3 1H NMR (400 MHz, CDCl3): δ 8.21 (1H, d, J = 8.5 Hz), 8.12 (1H, d, J = 8.5 Hz), 7.83 (1H, d, J = 8.2 Hz), 7.75 (1H, t, J = 8.5 Hz), 7.68 (1H, d, J = 8.5 Hz), 7.56 (1H, t, J = 8.1 Hz), 6.63 (1H, dd, J = 2.4 Hz), 6.54 (1H, dd, J = 2.3 Hz), 6.51 (1H, dd, J = 2.4 Hz, 2.3 Hz), 5.38 (2H, s), 4.61 (2H, s), 4.27 (1H, sextet J = 6.0 Hz), 1.71-1.59 (2H, ovl), 1.25 (3H, d, J = 6.1 Hz), 0.94 (3H, t, J = 7.4 Hz). 13 C NMR (700 MHz, CDCl3): δ 159.8, 159.7, 157.9, 147.4, 143.8, 137.1, 129.9, 128.8, 127.7, 127.6, 126.6, 119.2, 107.3, 105.3, 102.1, 75.1, 71.2, 65.1, 29.1, 19.3, 09.8.

[0202] Example 7 - Biological data The activity data of the compounds of the present invention against each receptor of FXR, TGR5 / GPBAR1 and CysLT1R are listed in Table 1. In this table, the activity of each compound is compared with a specific reference compound, namely, CDCA for FXR, TLCA for TGR5 / GPBAR1, and MK571 for CysLT1R. Each compound is tested at a concentration of 10 microM, and the activity of the reference compound is considered to be 100%.

[0203] [Table 1]

[0204] For FXR-mediated transactivation, HepG2 cells were transfected with 200 ng of p(hsp27)-TK-LUC reporter vector, which contains the FXR response element (IR1) cloned from the heat shock protein 27 (hsp27) promoter, 100 ng of pSG5-FXR, 100 ng of pSG5-RXR, and 100 ng of pGL4.70 (Promega, Madison WI), a vector encoding the human Renilla gene.

[0205] For GPBAR1-mediated transactivation, HEK-293T cells were transfected with 200 ng of pGL4.29 (Promega, Madison WI), a reporter vector containing a cAMP response element (CRE) that drives transcription of the luc2P luciferase reporter gene, 100 ng of human pCMVSPORT6-GPBAR1, and 100 ng of pGL4.70.

[0206] 24 hours after transfection, cells were stimulated for 18 hours with the specific receptor agonists CDCA (10 μM) or TLCA (10 μM) or with the derivatives CHIN104-112 and CHIN114-121 (10 μM and 50 μM). In another experimental setup, 24 hours after transfection, cells were stimulated with 50 μM of the derivative CHIN in combination with 10 μM of CDCA or TLCA.

[0207] For dose-response curves, cells were stimulated with increasing concentrations of the compound of interest (0.1-75 μM). 18 hours after stimulation, cell lysates were used to assess luciferase and Renilla activity by Dual-Luciferase Reporter assay (E1980, Promega Madison WI). Luminescence was measured using a Glomax 20 / 20 luminometer (Promega, Madison WI) and luciferase activity was normalized to Renilla activity.

[0208] Antagonistic activity assays were performed by Eurofins Cerep-Panlabs (France). Cells were suspended in DMEM buffer (Invitrogen) and then diluted with 3 × 10 4 Cells were seeded at a density of 10000 cells / plate. A fluorescent probe (Fluo4 Direct, Invitrogen) mixed with probenicid in HBSS buffer (Invitrogen) supplemented with 20 mM Hepes (Invitrogen) (pH 7.4) was then added to each well and left with the cells for 60 minutes at 37°C and then 15 minutes at 22°C. The plate was then placed in a microplate reader (CellLux, PerkinElmer) which was used to add the compound to be tested or HBSS buffer, followed 5 minutes later by the addition of 0.1 nM LTD4 or HBSS buffer solution (used as a control). Free Ca in the cytoplasm was then measured. 2+ The change in intensity and fluorescence, which varies proportionally with the concentration of the ion, is measured. Results are expressed as the percentage of inhibition compared to the control response to 0.1 nM LTD4. The antagonist standard is MK 571.

[0209] Of particular interest is CHIN117 and its effect in reducing acetaminophen (APAP)-induced liver injury. In the experimental setting, acute hepatitis was induced in wild-type C57 / Bl6 mice by administration of acetaminophen (APAP) at a concentration of 500 mg / kg via oral gavage. 45 minutes after disease induction, CHIN117 was administered orally at a concentration of 30 mg / kg. 24 hours after disease induction, mice were sacrificed and blood was collected to analyze blood counts and AST and ALT transaminase values.

[0210] The results show (Figures 1-3) that administration of APAP induces a significant increase in AST and ALT levels (between 3000 and 4000), in addition to the liver damage caused, which attracts immune cells involved in the pathogenesis of the disease to the liver, resulting in a decrease in circulating white blood cell (WBC) levels. Administration of the compound CHIN117 was able to attenuate APAP-induced liver damage by reducing AST and ALT levels by approximately 10-fold when compared to those recorded in a group of mice treated with APAP alone. CHIN117 was also able to maintain WBC levels comparable to those found in non-treated mice (NT).

[0211] Of particular interest is CHIN117 and its efficacy in a mouse model of chronic hepatitis induced by a high-fat diet. This mouse model mimics NAFLD, a rapidly growing epidemic in industrialized countries that represents a prohibitive cost to the health care system. In this model, mice (male C57BL / 6 mice) were fed a lipid- and cholesterol-rich diet (2% cholesterol) and fructose (3%) in water (HFD-F) for 60 days. CHIN117 was administered daily starting on day 7 at a dose of 30 mg / kg. Body weight trends show that CHIN117 reduces body weight gain by approximately 3 grams (Figure 4A, Figure 4B). After 8 weeks, the mice develop insulin resistance as shown by the results of the OGTT (Figure 4E, Figure 4F). Treating the mice with CHIN117 reverses the effects of the diet and reduces the AUC of the OGTT. In addition, CHIN117 counteracted the hepatotoxic effects of the HFD-F diet, statistically reducing AST, ALT, and LDL levels (Figures 4G-H).

[0212] Mice fed the HFD-F diet for 8 weeks developed features similar to human NASH with droplet steatosis, hepatocyte swelling, lobular inflammation, and macrophage influx as revealed by H&E staining of liver sections (Figure 5A), leading to a significant increase in hepatic steatosis (NAS) score (Figure 5B). In addition, HFD-F exhibits increased body mass index (BMI) and epididymal white adipose tissue (eWAT), brown adipose tissue (BAT), and liver mass (Figure 5C-Figure 5I). CHIN117 almost completely reversed the disease by reducing hepatic steatosis, BMI, and eWAT, BAT, and liver mass (Figure 5).

[0213] CHIN117 has been proposed as a potential treatment for cancer due to its excellent pharmacokinetic properties, with an aqueous solubility of 66 μM at pH 7.4 and LogD equal to 2.0, and its potent t 1 / 2 =578 minutes (CL int = 4), and when exposed in vitro to the S9 fraction, which also contains enzymes involved in phase II metabolism, t 1 / 2 =385 minutes(CL int It is of particular interest due to its promising metabolic stability (i.e., .alpha.-methylphenylsulfonyl ester (MPS) = 6).

Claims

1. Formula (I): 【Chemistry 1】 [In formula: R 1 is selected from the group consisting of H, Oi-propyl, On-propyl, O-sec-butyl, On-pentyl, O-2-methylbutyl, -CH2-R7, -O-(CH2)3-4-R8; R 2 is selected from the group consisting of H, CH 2 OH, -CH 2 -R 7 ; phenyl optionally substituted with at least one substituent independently selected from the group consisting of COOH, COO-C 1-6 alkyl, C 1-6 hydroxyalkyl, -CH 2 -R 9 ; R 3 H, COOH, COO-C 1～6 Alkyl, CH 2 OH; however, - R 2 If H, then R 1 or R 3 is not H, or - R 1 When is -O-(CH 2 ) 3-4 -R 8, R 2 and R 3 At least one of them is not H, R 4 H, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl; R 5 H, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl; R 6 H, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl, OH; and one substituent R 8 Linear or branched C optionally substituted with 1～6 alkoxyl; However, R 4 , R 5 and R 6 One of the groups is COOH or CH 2 If OH, R 4 , R 5 and R 6 At least one of the remaining ones is not H, R 7 teeth, 【Chemistry 2】 is selected from the group consisting of R 8 OH, COOH, COO-C 1～6 is selected from the group consisting of alkyl, R 9 teeth, 【Chemistry 3】 (In the formula, R 10 H, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl; R 11 are H, OH, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl; and R 12 H, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl; However, R 10 , R 11 and R 12 are not H at the same time. selected from the group consisting of The compound of formula (I) is: 【Chemistry 4】 The compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof is excluded.

2. R 3 H, COOH, COOCH 3 , C.H. 2 OH; R 4 H, COOH, COOCH 3 , C.H. 2 OH, and R 5 H, COOH, COOCH 3 , C.H. 2 Selected from the group consisting of OH A compound of formula (I) according to claim 1, characterized in that 【Request 3】 【Chemistry 5A】 【Chemistry 5B】 【Chemistry 5C】 【5D】 3. A compound of formula (I) according to claim 1 or 2, selected from the group consisting of:

4. 【Chemical 6A】 【Chemistry 6B】 【Chemistry 6C】 【Chemistry 6D】 4. The compound of formula (I) according to claim 3, selected from the group consisting of:

5. A compound of formula (Ia) for use as a medicine 【Chemistry 7】 [In formula: R 1 is selected from the group consisting of H, Oi-propyl, On-propyl, O-sec-butyl, On-pentyl, O-2-methylbutyl, -CH2-R7, -O-(CH2)3-4-R8; R 2 is selected from the group consisting of H, CH 2 OH, -CH 2 -R 7 ; phenyl optionally substituted with at least one substituent independently selected from the group consisting of COOH, COO-C 1-6 alkyl, C 1-6 hydroxyalkyl, -CH 2 -R 9 ; R 3 H, COOH, COO-C 1～6 Alkyl, CH 2 OH; however, - R 2 If H, then R 1 or R 3 is not H, or - R 1 When is -O-(CH 2 ) 3-4 -R 8, R 2 and R 3 At least one of them is not H, R 4 H, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl; R 5 H, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl; R 6 H, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl, OH; and one substituent R 8 Linear or branched C optionally substituted with 1～6 alkoxyl; However, R 4 , R 5 and R 6 One of the groups is COOH or CH 2 If OH, R 4 , R 5 and R 6 At least one of the remaining ones is not H, R 7 teeth, 【Chemistry 8】 is selected from the group consisting of R 8 OH, COOH, COO-C 1～6 is selected from the group consisting of alkyl, R 9 teeth, 【Chemistry 9】 (In the formula, R 10 H, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl; R 11 are H, OH, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl; and R 12 H, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl; However, R 10 , R 11 and R 12 are not H at the same time. selected from the group consisting of or a pharma- ceutically acceptable salt or solvate thereof.

6. 6. The compound of formula (Ia) for use according to claim 5 in the prevention and / or treatment of a disorder selected from the group consisting of gastrointestinal disorders, liver diseases, cardiovascular diseases, atherosclerosis, metabolic diseases, metabolic disorders, infectious diseases, cancer, renal disorders, inflammatory disorders, and neurological disorders.

7. Formula (Ia): 【Chemistry 10】 [In formula: R 1 is selected from the group consisting of H, Oi-propyl, On-propyl, O-sec-butyl, On-pentyl, O-2-methylbutyl, -CH2-R7, -O-(CH2)3-4-R8; R 2 is selected from the group consisting of H, CH 2 OH, -CH 2 -R 7 ; phenyl optionally substituted with at least one substituent independently selected from the group consisting of COOH, COO-C 1-6 alkyl, C 1-6 hydroxyalkyl, -CH 2 -R 9 ; R 3 H, COOH, COO-C 1～6 Alkyl, CH 2 OH; however, - R 2 If H, then R 1 or R 3 is not H, or - R 1 When is -O-(CH 2 ) 3-4 -R 8, R 2 and R 3 At least one of them is not H, R 4 H, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl; R 5 H, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl; R 6 H, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl, OH; and one substituent R 8 Linear or branched C optionally substituted with 1～6 alkoxyl; However, R 4 , R 5 and R 6 One of the groups is COOH or CH 2 If OH, R 4 , R 5 and R 6 At least one of the remaining ones is not H, R 7 teeth, 【Chemistry 11】 is selected from the group consisting of R 8 OH, COOH, COO-C 1～6 is selected from the group consisting of alkyl, R 9 teeth, 【Chemistry 12】 (In the formula, R 10 H, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl; R 11 are H, OH, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl; and R 12 H, COOH, COO-C 1～6 Alkyl, C 1～6 hydroxyalkyl; However, R 10 , R 11 and R 12 are not H at the same time. selected from the group consisting of or a pharma- ceutically acceptable salt or solvate thereof, and at least one pharma- ceutically acceptable excipient.

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