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

Abstract

This invention relates to compounds of formula (I), pharmaceutical compositions thereof, and uses, particularly to the treatment and / or prevention of diseases mediated by bile acid receptors (FXR and GPBAR1) and cysteine ​​leukotriene receptors (CysLTR).

Description

[0001] Cross-reference to related applications

[0002] This patent application claims priority to Italian patent application No. 102020000019210, filed on August 4, 2020, the entire disclosure of which is incorporated herein by reference. Technical Field

[0003] This invention relates to the use of quinoline derivatives and their ability to simultaneously modulate bile acid receptors (FXR and GPBAR1) and cysteyl leukotriene receptors (CysLTR), and their use for the treatment and / or prevention of diseases mediated by the latter. Background Technology

[0004] The strategy of identifying small molecules that can act on multiple targets simultaneously is widely considered to be a novel pharmacological approach for identifying multifactorial diseases such as chronic inflammatory conditions, including non-alcoholic steatohepatitis, highly prevalent inflammatory liver diseases, metabolic syndrome, and cancer.

[0005] This study begins with our recent observation that REV5901 (a cysteyl-leukotriene receptor antagonist) can modulate GPBAR1 in an animal model of intestinal inflammation to exhibit interesting anti-inflammatory activity, and that Zafirlukast (a well-known CysLT receptor antagonist) has weak activity against FXR (S. Schierle et al. Anti-Inflammatory Potency of Zafirlukast by Designed Polypharmacology, J Med Chem 61(13)(2018) 5758-5764).

[0006] Leukotrienes are a large family of lipid regulators that are produced from arachidonic acid via an enzymatic cascade and function as regulators of inflammation. Among leukotrienes, cysteyl leukotrienes (CysLTs) include LTC4, LTD4, and LTE4, which act on cells by binding to the G protein-associated transmembrane protein family (CysLTRs) expressed on many pro-inflammatory cells, such as neutrophils and eosinophils, mast cells, and monocytes / macrophages. These receptors play important roles in inflammatory responses leading to microvascular permeability, leukocyte transport, chemokine and cytokine secretion, and tissue repair (fibrosis) through activation of endogenous lipid regulators. Cysteine ​​leukotriene receptors are well known to mediate bronchoconstriction, pulmonary mucus secretion, and edema, and thus their antagonists are proven effective drugs in the treatment of asthma and more generally in pharmacological approaches targeting lung diseases. Cysteinyl leukotrienes are involved in many other diseases, such as cardiovascular disease, cancer, atopic dermatitis, rheumatoid arthritis, Crohn's disease, as well as the pathogenesis of fulminant hepatitis and hepatic cholestasis, 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 Jul; 27(4):469-527).

[0007] FXR, highly expressed in the enterohepatic tissues (liver and intestine), regulates bile acid homeostasis and several metabolic pathways, including lipid and glucose metabolism. FXR agonists have been shown to be useful in pharmacological approaches targeting metabolic disorders such as cholestasis, type 2 diabetes, liver fibrosis, and non-alcoholic fatty liver disease (NAFLD). Furthermore, FXR plays important roles in the kidneys, cardiovascular system, and tumorigenesis (Renga et al. PHASEB J. 2012, 26, 3021-3031).

[0008] GPBAR1 is highly expressed in the liver and intestine, as well as in muscle, adipose tissue, macrophages, and endothelial cells. In muscle and brown adipose tissue, GPBAR1 increases energy expenditure and oxygen consumption (Watanabe et al., Nature of 2006, 439, 484). In enteroendocrine L cells, GPBAR1 activation stimulates the secretion of glucagon-like peptide-1 (GLP-1), thereby regulating blood glucose levels, gastrointestinal motility, and appetite (Thomas et al., Cell. Metab. 2009, 10, 167).

[0009] GPBAR1 appears to be associated with 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.

[0010] Purpose of the invention

[0011] The purpose of this invention is to identify novel compounds that can selectively or simultaneously modulate bile acid receptors (FXR and GPBAR1) and cysteine ​​leukotriene receptors (CysLTR).

[0012] Such an objective is achieved by the compounds of formula (I) according to claim 1, their uses according to claims 8 and 9, and their compositions according to claim 10. Preferred embodiments are indicated in the dependent claims.

[0013] Brief description of the attached figures

[0014] The invention will now be described in detail with reference to the figures in the accompanying drawings, wherein:

[0015] - Figure 1 The AST values ​​of mice that were induced with acetaminophen to develop acute hepatitis and subsequently treated with CHIN117 are shown.

[0016] - Figure 2 The ALT values ​​of mice that were induced with acetaminophen to develop acute hepatitis and subsequently treated with CHIN117 are shown.

[0017] - Figure 3 The white blood cell (WBC) values ​​of mice that were induced with acute hepatitis by acetaminophen and subsequently treated with CHIN117 are shown.

[0018] - Figure 4 Results of CHIN117 administration in a mouse model simulating NAFLD are shown: (A) weekly changes in body weight (%); (B) area under the curve (AUC) of body weight; (C) brown adipose tissue temperature (BAT) (°C); (D) glucose levels in response to an oral glucose tolerance test (OGTT); (E) AUC of the OGTT; (G) plasma levels of AST (U / L) and ALT (U / L); (H) plasma levels of cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) (mg / 100 mL). Results are mean ± SEM for 8–12 mice per group. *p≤0.05.

[0019] - Figure 5Results of CHIN117 administration in a C57BL / 6 mouse model fed an HFD-F diet for 8 weeks are shown: (A) Hematoxylin and eosin (H&E) staining of mouse liver tissue (4x–10x). Disease severity was assessed by calculating: (B) steatosis score (NAS); (C) body mass index (BMI); (D) eWAT weight; (E) eWAT weight / body weight ratio; (F) BAT weight (g); (G) BAT weight / body weight ratio; (H) liver weight; (I) liver weight / body weight ratio. Results are mean ± SEM of 8–12 mice per group. *p≤0.05. Detailed Implementation

[0020] Preferred embodiments of the present invention

[0021] The following paragraphs provide the chemical characteristics of the compounds according to the invention and are intended to apply uniformly throughout the specification and all claims, unless otherwise expressly stated to provide a more broad definition.

[0022] As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon. This term includes both straight (unbranched) and branched chains.

[0023] 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, isopentyl, n-hexyl, etc.

[0024] As used herein, the term "hydroxyalkyl" refers to a saturated aliphatic carbohydrate in which one or more hydrogen atoms are replaced by hydroxyl groups.

[0025] Unless otherwise stated, as used herein, the term “substituted” means that one or more hydrogen atoms of the aforementioned group are replaced by other non-hydrogen atoms or functional groups, provided that the normal valence electrons remain unchanged and the substitution produces a stable compound.

[0026] Those skilled in the art of organic chemistry will understand that many organic compounds can form complexes with solvents in which they react, precipitate, or crystallize. These complexes are called "solvates." For example, complexes with water are called "hydrates." The solvates of the compounds of this invention are within the scope of this invention. The compounds of formula (I) or (Ia) associated with solvent molecules can be readily isolated to provide the corresponding solvates by crystallization or evaporation of a suitable solvent.

[0027] The compounds of formula (I) or (Ia) may be in crystalline form. In some embodiments, the compounds of formula (I) or (Ia) are polymorphic.

[0028] The present invention also includes isotopically labeled compounds that are identical to those given in formula (I) or (Ia), but differ in that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those 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, for example... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O.

[0029] Compounds of the present invention containing the aforementioned isotopes and / or other atoms, and other isotopes thereof, are within the scope of protection of the present invention. Isotope-labeled compounds of the present invention, for example, those doped with radioactive isotopes, are also included. 3 H and 14 Those with C can be used to determine the tissue distribution of drugs and / or substrates. Tritium isotopes, i.e. 3 H, and carbon-14, i.e. 14 C, is particularly preferred due to their ease of preparation and detectability. Isotopes 11 C is particularly useful for PET (positron emission tomography). Additionally, heavier isotopes (such as deuterium, i.e., 2 Substitution of H) can provide certain therapeutic advantages resulting from increased metabolic stability (e.g., increased in vivo half-life or reduced dosing requirements), and may therefore be mentioned in some cases. The isotopically labeled compounds of formula (I) or (Ia) of the present invention can generally be prepared by performing the process described in the following schematic diagrams and / or examples (replacing the non-isotopically labeled reactant with an readily available isotopically labeled reactant).

[0030] Some of the groups / substituents included in this invention can exist as isomers. Therefore, in some embodiments, compounds of formula (I) or (Ia) can have axial asymmetry and, correspondingly, can exist as optical isomers, such as form (R), form configuration (S), etc. All such isomers, including racemic mixtures, enantiomers, and mixtures thereof, are included within the scope of this invention.

[0031] In particular, the scope of protection of this invention includes all stereoisomers, including enantiomers, diastereomers and mixtures thereof, including racemates, and unless otherwise stated, compounds of formula (I) or (Ia) generally referred to include all stereoisomers.

[0032] Generally, the compounds of this invention should be considered to exclude those compounds that are chemically very unstable, either on their own or in water (if any), and which are clearly unsuitable for pharmaceutical use by all routes of administration, whether oral, parenteral, or otherwise. Such compounds are known to a skilled chemist.

[0033] Finally, compounds of formula (I) or (Ia) can form salts. In particular, the quinoline ring can form hydrochloride salts, while phenolic residues or COOH groups can form metal salts.

[0034] According to a first aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is provided:

[0035]

[0036] in:

[0037] R1 is selected from the following groups: H, a straight or branched chain with one substituent R7 (optionally substituted). 1-6 Alkyl, optionally substituted, straight or branched OC with one substituent R8 3-6 alkyl;

[0038] R2 is selected from the following groups: H, C 1-6 Hydroxyalkyl, optionally substituted, straight-chain or branched C with one substituent R7 1-6 Alkyl groups, optionally substituted phenyl groups having at least one substituent independently selected from the group consisting of: H, COOH, COO-C 1-6 Alkyl, C 1-6 Hydroxyalkyl and optionally substituted straight or branched C-chains with one substituent R9 1-6 alkyl;

[0039] R3 is selected from the following groups: H, COOH, COO-C 1-6 Alkyl group, CH2OH;

[0040] The conditions are:

[0041] -When R2 is H, R1 or R3 is not H; or

[0042] - When R1 is an optional substituent and there is a substituent R8 in the linear OC 3-6 Alkyl group, at least one of R2 and R3 is not H;

[0043] R4 is selected from the following groups: H, COOH, COO-C 1-6 Alkyl, C 1-6 Hydroxyalkyl;

[0044] R5 is selected from the following groups: H, COOH, COO-C 1-6Alkyl, C 1-6 Hydroxyalkyl;

[0045] R6 is selected from the following groups: H, COOH, COO-C 1-6 Alkyl, C 1-6 Hydroxyalkyl, OH, and optionally substituted straight or branched C-chains with one substituent R8 1-6 Alkoxy;

[0046] The condition is 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.

[0047] R7 can be selected from the following groups:

[0048]

[0049] R8 is selected from the following groups: OH, COOH, COO-C 1-6 alkyl;

[0050] R9 can be selected from the following groups:

[0051]

[0052] Where R 10 Choose from the following groups: H, COOH, COO-C 1-6 Alkyl, C 1-6 Hydroxyalkyl;

[0053] R 11 Choose from the following groups: H, OH, COOH, COO-C 1-6 Alkyl, C 1-6 Hydroxyalkyl;

[0054] And R 12 Choose from the following groups: H, COOH, COO-C 1-6 Alkyl, C 1-6 Hydroxyalkyl;

[0055] Excluding the following compounds

[0056]

[0057] In the first embodiment, R1 is selected from the group consisting of: H, O-isopropyl, O-n-propyl, O-n-butyl, O-sec-butyl, O-n-pentyl, O-2-methylbutyl, -CH2-R7, -O-(CH2). 3-4 -R8.

[0058] In one embodiment, R2 is a phenyl group optionally substituted with at least one substituent independently selected from the group consisting of: H, COOH, COO-C. 1-6 Alkyl, C 1-6 Hydroxyalkyl and optionally substituted straight or branched C-chains with one substituent R9 1-6 alkyl.

[0059] In another embodiment, R2 is selected from the group consisting of: H, CH2OH, or a phenyl group having two substituents independently selected from the group consisting of: H, COOH, or COO-C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, -CH2-R9.

[0060] In the third embodiment,

[0061] R3 is selected from the following groups: H, COOH, COOCH3, CH2OH;

[0062] R4 is selected from the group consisting of: H, COOH, COOCH3, CH2OH; and

[0063] R5 is selected from the following groups: H, COOH, COOCH3, CH2OH.

[0064] In another embodiment, the compound of formula (I) is selected from the group consisting of:

[0065]

[0066]

[0067]

[0068]

[0069] Preferably, the compounds of formula (I) are selected from the group consisting of:

[0070]

[0071]

[0072]

[0073]

[0074]

[0075] A second aspect of the invention relates to a pharmaceutical composition comprising a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient. The compound of formula (Ia) has the following formula:

[0076]

[0077] in:

[0078] R1 is selected from the following groups: H, a straight or branched chain with one substituent R7 (optionally substituted). 1-6 Alkyl, optionally substituted, straight or branched OC with one substituent R8 3-6 alkyl;

[0079] R2 is selected from the following groups: H, C 1-6 Hydroxyalkyl, optionally substituted, straight-chain or branched C with one substituent R7 1-6 Alkyl groups, optionally substituted phenyl groups having at least one substituent independently selected from the group consisting of: H, COOH, COO-C 1-6 Alkyl, C 1-6 Hydroxyalkyl and optionally substituted straight or branched C-chains with one substituent R9 1-6 alkyl;

[0080] R3 is selected from the following groups: H, COOH, COO-C 1-6 Alkyl group, CH2OH;

[0081] The conditions are:

[0082] -When R2 is H, R1 or R3 is not H; or

[0083] - When R1 is an optional substituent and there is a substituent R8 in the linear OC 3-6 Alkyl group, at least one of R2 and R3 is not H;

[0084] R4 is selected from the following groups: H, COOH, COO-C 1-6 Alkyl, C 1-6 Hydroxyalkyl;

[0085] R5 is selected from the following groups: H, COOH, COO-C 1-6 Alkyl, C 1-6 Hydroxyalkyl;

[0086] R6 is selected from the following groups: H, COOH, COO-C 1-6 Alkyl, C 1-6 Hydroxyalkyl, OH, and optionally substituted straight or branched C-chains with one substituent R8 1-6 Alkoxy;

[0087] The condition is 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.

[0088] R7 can be selected from the following groups:

[0089]

[0090] R8 is selected from the following groups: OH, COOH, COO-C 1-6 alkyl;

[0091] R9 can be selected from the following groups:

[0092]

[0093] Where R 10 Choose from the following groups: H, COOH, COO-C 1-6 Alkyl, C 1-6 Hydroxyalkyl;

[0094] R 11 Choose from the following groups: H, OH, COOH, COO-C 1-6 Alkyl, C 1-6 Hydroxyalkyl;

[0095] And R 12 Choose from the following groups: H, COOH, COO-C 1-6 Alkyl, C 1-6 Hydroxyalkyl.

[0096] In one embodiment, R1 is selected from the group consisting of: H, O-isopropyl, O-n-propyl, O-sec-butyl, O-n-pentyl, O-2-methylbutyl, -CH2-R7, -O-(CH2). 3-4 -R8.

[0097] In one embodiment, R2 is a phenyl group optionally substituted with at least one substituent independently selected from the group consisting of: H, COOH, COO-C. 1-6 Alkyl, C 1-6 Hydroxyalkyl and optionally substituted straight or branched C-chains with one substituent R9 1-6 alkyl.

[0098] In one embodiment, R2 is selected from the group consisting of: H, CH2OH, or a phenyl group with two independently selected substituents from the group consisting of: H, COOH, COO-C. 1-6 Alkyl, C 1-6 Hydroxyalkyl, -CH2-R9.

[0099] In one implementation method

[0100] R3 is selected from the following groups: H, COOH, COOCH3, CH2OH;

[0101] R4 is selected from the group consisting of: H, COOH, COOCH3, CH2OH; and

[0102] R5 is selected from the following groups: H, COOH, COOCH3, CH2OH.

[0103] In one embodiment, the compound of formula (Ia) is selected from the group consisting of:

[0104]

[0105]

[0106]

[0107]

[0108] Preferably, the compound of formula (Ia) is selected from the group consisting of:

[0109]

[0110]

[0111]

[0112]

[0113] Those skilled in the art are aware of all such excipient compounds suitable for formulating pharmaceutical compositions.

[0114] Compounds of formula (Ia) may be included in pharmaceutical compositions and their dosage units together with conventionally used excipients and in such form as to be used as solids (e.g., tablets or filled capsules) or liquids (e.g., solutions, suspensions, emulsions, elixirs, or capsules filled with compounds of formula (Ia) together with conventionally used excipients), all for oral use or as sterile injectable solutions for parenteral administration (including subcutaneous and intravenous use).

[0115] Such pharmaceutical compositions and their unit dosage forms may contain ingredients in conventional percentages, with or without additional compounds or active ingredients, and such unit dosage forms may contain any appropriate effective amount of active ingredient commensurate with the intended range of daily doses to be used.

[0116] Pharmaceutical compositions containing compounds of the present invention can be prepared in a manner well known in the pharmaceutical industry and comprise at least one active compound. Generally, the compounds of the present invention are administered in pharmaceutically effective amounts. The actual amount of compound administered will typically be determined by a physician, taking into account relevant factors including the condition to be treated, the chosen route of administration, the actual compound administered, the individual patient's age, weight, and response, and the severity of the patient's symptoms.

[0117] The pharmaceutical compositions of the present invention can be administered via a variety of routes, including oral, rectal, subcutaneous, intravenous, intramuscular, nasal, and pulmonary routes. Compositions intended for oral administration may be in the form of liquid solutions or suspensions in bulk or in bulk powder form. However, more commonly, the compositions are presented in unit dose form to facilitate precise dosing. The expression "unit dose form" refers to a physically discrete unit suitable as a unit dose for human and other mammalian subjects, each unit containing a predetermined amount of active substance, calculated to produce the desired therapeutic effect, in combination with pharmaceutically acceptable excipients. Typical unit dose forms include pre-filled, pre-prepared ampoules or syringes of liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, or similar dosage forms.

[0118] Liquid forms suitable for oral administration may include suitable aqueous or anhydrous solvents containing buffers, suspending agents and dispersants, dyes, fragrances, etc. Solid forms may include, for example, any of the following components or compounds with similar properties: binders, such as microcrystalline cellulose, astragalus gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginate, Primogel, or corn starch; lubricants, such as magnesium stearate; flow agents, such as colloidal silica; sweeteners, such as sucrose, lactose, or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or citrus flavorings.

[0119] Injectable compositions are typically based on sterile injectable solutions or phosphate buffer solutions or other injectable solvents known in the art.

[0120] The pharmaceutical composition may be in the form of tablets, pills, capsules, solutions, suspensions, emulsions, powders, suppositories, or as a sustained-release formulation.

[0121] If desired, tablets can be coated using standard aqueous or anhydrous techniques. In some embodiments, such compositions and formulations may contain at least 0.1 percent of the active compound. Of course, the percentage of the active compound in these compositions can vary and can suitably range from about 1 percent to about 60 percent per unit weight. The amount of active compound in such therapeutically useful compositions is the dose that will achieve therapeutic activity. The active compound can also be administered via the nasal cavity, for example, as a liquid drop or spray.

[0122] Tablets, pills, capsules, etc., may also contain binders such as astragalus gum, gum arabic, corn starch, or jelly; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose, or saccharin. When the dosage unit is in capsule form, it may also contain a liquid carrier such as fatty oil, in addition to the materials of the types mentioned above. Various other materials may be present as coatings or to improve the physical form of the administration 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, dyes, and flavorings such as cherry or orange flavorings. To prevent the composition from breaking during transport through the upper gastrointestinal tract, the composition is an enteric-coated formulation.

[0123] Compositions for pulmonary administration include, but are not limited to, dry powder compositions consisting of powders of compounds of formula (Ia) and powders of suitable solvents and / or lubricants. Compositions for pulmonary administration can be inhaled using any suitable dry powder inhaler device known to those skilled in the art.

[0124] The composition is administered according to a protocol and at a dose sufficient to reduce inflammation and pain in the subjects. In some embodiments, one or more active ingredients in the pharmaceutical compositions of the present invention are typically formulated as dosage units. Dosage units may contain 0.1 to 1000 mg of a compound of formula (Ia) per dosage unit for daily administration.

[0125] In some embodiments, the effective amount of a particular formulation will depend on the severity of the pre-treatment disease, disorder, or condition, the individual's health status, and response to the drug. In some embodiments, the dose ranges from 0.001% by weight to about 60% by weight of the formulation.

[0126] When used in combination with one or more other active ingredients, the compounds and other active ingredients of the present invention can be used at lower doses than when used individually.

[0127] For formulations relating to any of the various routes of administration, methods and formulations for drug administration are described in Remington’s Pharmaceutical Sciences, 17th edition, Gennaro et al., Mack Publishing, 1985; Remington’s Pharmaceutical Sciences, Gennaro AR, 20th edition, 2000, Williams & Wilkins PA, USA; and Remington: Pharmaceutical Sciences and Practice, 21st edition, Lippincott Williams & Wilkins, 2005; and described in Loyd V. Allen e Howard C. Ansel, Ansel’s Dosage Forms and Drug Delivery Systems, 10th edition, Lippincott Williams & Wilkins, 2014.

[0128] The ingredients of the oral or injectable compositions described above are merely representative.

[0129] The compounds of the present invention can also be administered in a sustained-release form or via a sustained-release drug delivery system.

[0130] A third aspect of the present invention relates to the use of compounds of formula (Ia) as described above as pharmaceuticals.

[0131] As shown above, compounds of formula (Ia) can be used to prevent and / or treat conditions selected from the group consisting of: gastrointestinal conditions, liver conditions, cardiovascular conditions, metabolic conditions, infectious diseases, cancer, kidney conditions, inflammatory conditions, and nervous system conditions.

[0132] In one implementation, liver conditions include primary biliary cirrhosis (PBC), cerebral tendon xanthomas (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), host diseases associated with liver transplantation, living donor transplantation, liver regeneration, congenital liver fibrosis, granulomatous liver disease, intrahepatic or extrahepatic malignancies, Wilson's disease, hemochromatosis, and α-1-antitrypsin deficiency.

[0133] In one implementation, 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.

[0134] In one implementation, kidney diseases include diabetic nephropathy, hypertensive nephropathy, chronic glomerulonephritis (including chronic transplanted glomerulonephritis), chronic tubulointerstitial disease, and vascular diseases of the kidneys.

[0135] In one implementation, cardiovascular disease is selected from the group consisting of: atherosclerosis, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hypertension (also known as hypertension), inflammatory heart disease (including myocarditis and endocarditis), ischemic heart disease, stable angina, unstable angina, myocardial infarction, cerebrovascular disease (including ischemic stroke), pulmonary heart disease (including pulmonary hypertension), peripheral artery disease (PAD), also known as peripheral vascular disease (PVD), peripheral artery occlusive disease, and peripheral occlusive artery disease.

[0136] In one implementation, metabolic diseases are selected from the group consisting of: insulin resistance, metabolic syndrome, type I and type II diabetes, hypoglycemia, and adrenocortical disorders including adrenocortical insufficiency.

[0137] In one implementation, metabolic disorders are selected from the group consisting of obesity and conditions related to bariatric surgery.

[0138] In one implementation, cancer is selected from the group consisting of: liver cancer, bile duct cancer, pancreatic cancer, stomach cancer, colorectal cancer, breast cancer, ovarian cancer, and pathology associated with chemotherapy resistance.

[0139] In one implementation, the infectious disease is selected from the group consisting of acquired immunodeficiency syndrome (AIDS) and related diseases, B virus and C virus infection.

[0140] In one implementation, the inflammatory condition is selected from the group consisting of rheumatoid arthritis, fibromyalgia, Sjögren's syndrome, scleroderma, Behcet's syndrome, vasculitis, and systemic lupus erythematosus.

[0141] According to another aspect of the invention, the use of compounds of formula (Ia) as selective agonists of GPBAR1 is provided. CHIN114 is particularly relevant.

[0142] According to another aspect of the invention, compounds of formula (Ia) are provided for use as dual CysLT1R / FXR modulators. The most popular example of such compounds of formula I is CHIN104.

[0143] According to another aspect of the invention, the use of compounds of formula (Ia) as dual CysLT1R / GPBAR1 modulators is provided. Preferred examples of such compounds of formula (Ia) are CHIN105, CHIN106, and CHIN117.

[0144] Other features of the invention will become apparent from the following description of some of the embodiments, which are merely illustrative and non-limiting.

[0145] 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 (H2O), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), time (h), room temperature (rt), retention time (t). R ).

[0146] Example

[0147] Example 1: Synthesis of CHIN104-106

[0148] Alcohol 1 was synthesized from methyl quinoline-2-carboxylic acid by reduction with diisobutylaluminum hydride (DIBAL-H). The resulting alcohol 1 is a substrate for the photoelectrophoresis reaction with methyl 3-hydroxybenzoate (illustrated). Figure 1 CHIN104 was synthesized in high yield.

[0149] The provided methyl esters were subjected to alkaline hydrolysis or reduction with DIBAL-H, starting from CHIN104, CHIN105 (carboxylic acid), and CHIN106 (alcohol).

[0150] Indication Figure 1

[0151]

[0152] Reagents and conditions: a) DIBAL-H, dry THF, 0℃; b) PPh3, DIAD, dry THF, 0℃; c) NaOH, MeOH:H2O 1:1 v / v.

[0153] General process.

[0154] Reaction a). Reduction with DIBAL-H. At 0°C, a solution of DIBAL-H (2.0 equivalents, 1.0 M in THF) was added dropwise to a solution of quinoline methyl ester or a solution of CHIN104 in anhydrous THF (25 mL). The resulting mixture was stirred at 0°C for 4–8 hours. A saturated aqueous solution of Rochelle salt (potassium sodium tartrate) was added to the reaction mixture, followed by dilution with DCM. Quenching was performed with stirring for two hours. The aqueous phase was extracted with DCM (3 x 50 mL), and the collected organic phase was washed with water, dehydrated with Na2SO4, and concentrated under vacuum on a rotary evaporator to obtain a crude residue, which was purified by column chromatography or HPLC.

[0155] Step b) Photoelectrophoresis. At 0°C, diisopropyl azodicarboxylate (DIAD, 3.5 equivalents) was added dropwise to a solution of triphenylphosphine (PPh3, 3.5 equivalents) in dried THF. After 10 minutes, a solution of alcohol 1 dissolved in dried THF was added. After another 10 minutes, a solution of methyl 3-hydroxybenzoate dissolved in dried THF was added. After approximately 12 hours, water was added and the reaction mixture was dried to remove THF. The dried residue was extracted with EtOAc (3 x 50 mL), and the collected organic phase was washed with 2.5 M KOH aqueous solution and water, dehydrated, and dried under vacuum on a rotary evaporator. Purification on a column and silica gel yielded CHIN104.

[0156] Step c) Alkaline hydrolysis. A small fraction of CHIN104 ester was dissolved in a MeOH:H₂O 1:1 v / v (30 mL) solution and treated with NaOH (5.0 equivalents) under alkaline conditions. The reaction mixture was stirred under reflux at approximately 150 °C for 8 hours. The resulting solution was quenched with 6 M HCl and then extracted with EtOAc (3 x 50 mL). The collected organic phase was washed with water, treated with anhydrous Na₂SO₄, and then dried on a rotary evaporator to obtain CHIN105 as a crude residue, which was further purified.

[0157] Example 1A. Synthesis of methyl 3-(quinoline-2-ylmethoxy)benzoate (CHIN104).

[0158] Purification was achieved using a hexane:EtOAc 9:1 v / v and 0.1% TEA as the eluent mixture via silica gel, yielding CHIN104 (78%). Sample analysis was performed on a Nucleodur 100-5C18 column (5 μm; 10 mm id x 250 mm) with MeOH / H2O 82:18 v / v as the eluent (flow rate 3 mL / min, t). RIt was obtained by HPLC separation (14.8 min).

[0159] CHIN104 C 18 H 15 NO3

[0160] 1 H NMR (CDCl3, 400MHz): δ8.22 (1H, d, J = 8.4Hz), 8.10 (1H, d, J = 8.0Hz), 7.85 (1H, d, J = 8.0Hz), 7.74 (2H, ovl), 7 .68(2H,ovl),7.57(1H,t,J=8.0Hz),7.37(1H,t,J=7.7Hz),7.24(1H,d,J=7.7Hz),5.44(2H,s),3.91(3H,s).

[0161] 13 C NMR(CDCl3,100MHz)δ169.6,158.4,157.3,147.5,137.1,131.6,129.8,12 9.5,128.9,127.7,127.6,126.6,122.4,119.7,119.0,115.6,71.4,52.1.

[0162] Example 2A. Synthesis of 3-(quinoline-2-ylmethoxy)benzoic acid (CHIN105).

[0163] Purification of CHIN105 (68%) was performed on a silica column using DCM:MeOH 99:1 v / v as the eluent. The analytical sample was processed using a Nucleodur 100-5 column (5 μm; 10 mm id x 250 mm) and an eluent mixture of hexane / EtOAc 40:60 v / v (flow rate 3 mL / min, t). R (6.9 min) was purified by HPLC.

[0164] CHIN105 C 17 H 13 NO2

[0165] 1H NMR (CD3OD, 400MHz): δ8.40(1H,d,J=8.5Hz), 8.06(1H,d,J=8.3Hz), 7.95(1H,d,J=8.3Hz), 7.80(1H,t,J=8.3Hz), 7.74(1H ,d,J=8.5Hz),7.70(1H,s),7.64(1H,t,J=8.3Hz),7.62(1H,d,ovl),7.41(1H,t),7.30(1H,dd,J=1.5,8.0Hz),5.42(2H,s).

[0166] 13 C NMR (CD3OD, 100MHz) δ169.4,159.9,158.8,148.4,139.1,133.5,131.3,130.7,129.2,129.1,129.0,128.0,123.7,120.8,120.7,116.6,71.9.

[0167] Example 3A. Synthesis of (3-(quinoline-2-ylmethoxy)phenyl)methanol (CHIN106).

[0168] CHIN106 (60%) was purified by silica column chromatography using DCM:MeOH 99:1 v / v as the eluent. The sample was analyzed using MeOH / H2O 75:15 as the eluent (flow rate 3 mL / min, t). R =9.3 min) was obtained by HPLC separation on a Nucleodur 100-5C18 column (5 μm; 10 mm id x 250 mm).

[0169] CHIN106 C 17 H 15 NO2

[0170] 1 H NMR (CDCl3, 400MHz): δ8.20 (1H, d, J = 8.4Hz), 8.10 (1H, d, J = 7.4Hz), 7.84 (1H, d, J = 7.4Hz), 7.75 (1H, t, J = 7.4Hz), 7.68 (1H, d, J = 8.4Hz) ,7.56(1H,t,J=7.4Hz),7.28(1H,dd,J=7.3,8.0Hz),7.08(1H,s),7.0(1H,d,J=8.4Hz),6.95(1H,d,J=7.3Hz),5.40(2H,s),4.68(2H,s).

[0171] 13C NMR (CDCl3, 100MHz) δ158.6,157.8,147.4,142.8,137.1,129.8,129.6,128.7,127.7,127.6,126.5,119.6,119.1,113.9,113.4,71.1,64.9.

[0172] Example 2. Synthesis of CHIN107, CHIN108 and CHIN109.

[0173] For the synthesis of compounds CHIN107-CHIN109, the first step involved monoprotecting methyl 3,5-dihydroxybenzoate, which must bind to quinoline, with TBS. After obtaining the monoprotected derivative, it binds to quinoline via the Williamson reaction between (phenol) and methanesulfonyl alcohol derivative 1. The final step was deprotection of TBS with tetrabutylammonium fluoride (TBAF) to obtain CHIN107. The esters from two aliquots were subjected to alkaline hydrolysis and reduction with DIBAL-H to obtain CHIN108 and CHIN109.

[0174] Indication Figure 2

[0175]

[0176] Reagents and conditions: a) TBS-Cl, imidazole, dry DMF, 45% yield; b) methanesulfonyl chloride, TEA, ether, -20°C, quantitative yield; c) (phenol) (compound 3), K2CO3, anhydrous DMF, 100°C; d) 1.0M tetrabutylammonium fluoride (TBAF) in dry THF, overnight; e) excess NaOH flakes, MeOH:H2O 1:1 v / v, overnight, reflux; f) DIBAL-H, dry THF, 0°C.

[0177] General process.

[0178] Reaction a). Protected with TBSCl. Imidazole (1.5 equivalents) and tert-butyldimethylchlorosilane (1.2 equivalents) were added to a solution of compound 2 in dried DMF. After one hour, the DMF was removed, and the mixture was extracted three times with EtOAc / NH4Cl. The collected organic phase was then washed with H2O. The organic phase was dehydrated (Na2SO4), filtered, and concentrated in a rotary evaporator to obtain compound 3 in a crude state. Purification on silica gel using a hexane / EtOAc 9:1 mixture as the eluent yielded compound 3 in 45% yield.

[0179] Reaction b). Methanesulfonation of alcohol 1. Compound 1 was dissolved in dry diethyl ether, and triethylamine (6 equivalents) and methanesulfonyl chloride (5 equivalents) were added to the solution at -20°C. After about 1 hour, the solution was washed with a saturated aqueous solution of NaHCO3, and the collected organic phase was extracted once with water. The organic phase was dehydrated (Na2SO4), filtered, and concentrated in a rotary evaporator to obtain a crude form of compound 4 in quantitative yield.

[0180] Reaction c). Williamson reaction. Potassium carbonate (2.5 equivalents) was added to a solution of (phenol) in DMF (compound 3) and allowed to stand for 15 minutes. A methanesulfonic acid derivative (1.2 equivalents, compound 4) dissolved in dry DMF was added, and the solution was kept at 100°C for approximately 12 hours. The DMF was cooled and removed by rotary evaporation. The solid residue was extracted with water and ethyl acetate (3 x 50 mL). The collected organic phase was dehydrated with Na₂SO₄, filtered, and then concentrated by rotary evaporation to obtain a crude reaction product, which was directly used for subsequent reactions.

[0181] Reaction d) Deprotection from TBS. At room temperature, the crude product from the previous reaction was dissolved in dry THF, and a 1.0 M TBAF tetra-N-butylammonium fluoride solution (0.63 mL, 5 equivalents) in THF was added to the solution. The reaction was completed after 8 hours and treated by adding AcOEt and extraction with H2O. The combined organic phases were dehydrated with Na2SO4, filtered, and concentrated on a rotary evaporator to obtain the crude compound CHIN107.

[0182] Reaction e) Alkaline hydrolysis. Perform the same synthesis and testing process as in step c) of Example 1.

[0183] Reaction f) involves ester reduction using DIBAL-H. The same synthesis and testing procedures as in step a) of Example 1 are performed.

[0184] Example 2A. Synthesis of methyl 3-hydroxy-5-(quinoline-2-ylmethoxy)benzoate (CHIN107).

[0185] Purification was carried out on a silica gel packed column using a DCM / MeOH 998:2 mixture as the eluent, resulting in an 85% yield of compound CHIN107.

[0186] The sample was analyzed on a direct-phase semi-preparative Nucleodur 100-5 column (5 μm; 10 mm id x 250 mm) using a hexane / AcOEt 7:3 v / v eluent mixture (flow rate 3 mL / min, t). R =23.70 min) was separated by HPLC.

[0187] CHIN107 C 18 H 15 NO4

[0188] 1 H NMR (400MHz, CDCl3): δ8.17(1H,d,J=8.5Hz), 8.00(1H,d,J=8.0Hz), 7.79(1H,d,J=8.0Hz), 7.68(1H,t,J=8.0Hz) ,7.62(1H,t,J=8.5Hz),7.54(1H,t,J=8.0Hz),7.28(1H,s),7.21(1H,s),6.76(1H,s),5.38(2H,s),3.89(3H,s).

[0189] 13 C NMR (100MHz, CDCl3): δ167.2,159.1,157.9,157.3,146.7,137.8,131.8,1 30.2,127.8,127.7,127.6,126.8,119.2,109.8,107.8,106.8,70.4,52.1.

[0190] Example 2B. Synthesis of 3-hydroxy-5-(quinoline-2-ylmethoxy)benzoic acid (CHIN108).

[0191] Purification was performed on a silica gel packed column using a DCM / MeOH 95:5 mixture as eluent, thus yielding the compound CHIN108 in quantitative yield. The purified sample was then eluented on a Phenomenex pentafluorophenyl C18 reversed-phase column using a MeOH / H₂O 55:45 v / v mixture and 0.1% TFA (flow rate 1 mL / min, t). R The mixture was obtained by separation by HPLC (9.25 min).

[0192] CHIN108 C 17 H 13 NO4

[0193] 1H NMR (400MHz, CD3OD): δ8.39(1H,d,J=8.4Hz), 8.05(1H,d,J=8.0Hz), 7.96(1H,d,J=8.0Hz), 7.79(1H,t,J= 8.0Hz),7.72(1H,d,J=8.4Hz),7.62(1H,t,J=8.0Hz),7.18(1H,s),7.08(1H,s),6.66(1H,s),5.37(2H,s).

[0194] 13 C NMR (100MHz, CD3OD): δ160.7,159.7,158.2,148.2,139.1,131.4,131.3,129.2,129.1,129.0,128.9,128.0,120.6,110.8,107.8,107.0,71.8.

[0195] Example 2 Synthesis of C.3-(hydroxymethyl)-5-(quinoline-2-ylmethoxy)phenol (CHIN109).

[0196] Pure analytical sample (92% yield) was obtained by eluent reaction on a Phenomenex pentafluorophenyl C18 reversed-phase column with MeOH / H2O 60:40 v / v and 0.1% TFA (flow rate 1 mL / min, t R The mixture was obtained by separation by HPLC (12.24 min).

[0197] CHIN109 C 17 H 15 NO3

[0198] 1 H NMR (400MHz, CDCl3): δ8.20(1H,d,J=8.5Hz), 8.10(1H,d,J=8.0Hz), 7.84(1H,d,J=8.0Hz), 7.75(1H,t,J=8.0Hz) ,7.67(1H,d,J=8.5Hz),7.57(1H,t,J=8.0Hz),6.65(1H,s),6.49(1H,s),6.46(1H,s),5.40(2H,s),4.62(2H,s).

[0199] 13C NMR (100MHz, CDCl3): δ161.1,159.8,159.6,148.3,145.5,139.0,131.3,129.1,129.0,128.9,127.9,120.6,107.8,105.5,102.1,71.6,65.1.

[0200] Example 3. Synthesis of CHIN111, CHIN112 and CHIN114

[0201] In order to synthesize compounds CHIN111, CHIN112 and CHIN114, substituted phenols must first be prepared.

[0202] Compound 5, prepared by photoelongation reaction and deprotection with TBAF as described in step a) of Example 2, can be converted into (phenol) 6-8, and then combined with quinoline by Williamson reaction to obtain derivatives CHIN110-115.

[0203] Indication Figure 3

[0204]

[0205] Reagents and conditions: a) PPh3, DIAD, alcohols of different properties, dry THF, 0℃; b) 1.0 M tetrabutylammonium fluoride (TBAF) in dry THF, overnight; c) (phenol) (compounds 6-8), K2CO3, anhydrous DMF, 100℃.

[0206] Example 3A. Synthesis of 2-((3-isopropoxyphenoxy)methyl)quinoline (CHIN111).

[0207] Purification of CHIN111 (61%) was performed on a direct-phase semi-preparative Nucleodur 100-5 column (5 μm; 10 mm id x 250 mm) using a hexane / EtOAc 95:5 v / v eluent mixture (flow rate 3 mL / min, t). R =38 min) was performed by HPLC.

[0208] CHIN111 C 19 H 19 NO2

[0209] 1H NMR (400MHz, CDCl3): δ8.19(1H,d,J=8.6Hz), 8.09(1H,d,J=7.5Hz), 7.84(1H,d,J=7.5Hz), 7.74(1H,t,J=7.5Hz), 7.68(1H,d,J=8.6Hz), 7.56(1H,t,J =7.5Hz),7.17(1H,t,J=8.0Hz),6.61(1H,s),6.60(1H,ovl),6.52(1H,dd,J =8.0, 2.0Hz), 5.38 (2H, s), 4.52 (1H, septet, J = 6.0Hz), 1.32 (6H, d, J = 6.0Hz).

[0210] 13 C NMR (100MHz, CDCl3): δ159.6,159.2,157.9,147.5,136.9,129.9,129.7,128 .9,127.7,127.6,126.4,119.1,108.8,106.8,103.0,71.3,69.9,22.0(2C).

[0211] Example 3B. Synthesis of 2-((3-(sec-butoxy)phenoxy)methyl)quinoline (CHIN112).

[0212] Purification was performed on a direct-phase semi-preparative Nucleodur 100-5 column (5 μm; 10 mm id x 250 mm) using a hexane / EtOAc 9:1 v / v eluent mixture (flow rate 3 mL / min, t). R The reaction was performed by HPLC (15 min). Compounds with quantitative yields were obtained.

[0213] CHIN112 C 20 H 21 NO2

[0214] 1H NMR (400MHz, CDCl3): δ8.19(1H,d,J=8.6Hz), 8.09(1H,d,J=7.5Hz), 7.84(1H,d,J=7.5H z),7.74(1H,t,J=7.5Hz),7.68(1H,d,J=8.6Hz),7.56(1H,t,J=7.5Hz),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, sextuplet, 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).

[0215] 13 C NMR (100MHz, CDCl3): δ159.7,159.6,158.0,147.5,136.9,129.9,129.7,128.9 ,127.7,127.6,126.4,119.2,108.9,106.7,103.1,75.2,71.1,29.2,19.2,9.9.

[0216] Example 3 Synthesis of C.2-((3-(2-methylbutoxy)phenoxy)methyl)quinoline (CHIN114).

[0217] Purification was performed on a direct-phase semi-preparative Nucleodur 100-5 column (5 μm; 10 mm id x 250 mm) using a hexane / EtOAc 9:1 v / v eluent mixture (flow rate 3 mL / min, t). R The reaction was performed by HPLC (14 min). CHIN114 was obtained in 90% yield.

[0218] CHIN114 C 21 H 23 NO2

[0219] 1H NMR (400MHz, CDCl3): δ8.19(1H,d,J=8.6Hz), 8.09(1H,d,J=7.5Hz), 7.84(1H,d,J=7.5Hz), 7.74(1H,t ,J=7.5Hz),7.68(1H,d,J=8.6Hz),7.56(1H,t,J=7.5Hz),7.17(1H,t,J=8.0Hz),6.61(1H,s),6.60(1H ,ovl),6.52(1H,dd,J=8.0,2.0Hz),5.38(2H,s),3.80(1H,dd,J=9.0,6.0Hz),3.71(1H,dd,J=9.0,6.6Hz),1.85(1H,septet,J=6.6Hz),1.56(1H,m),1.25(1H,m),1.00(3H,d,J=6.6Hz),0.94(3H,t,J=7.3Hz).

[0220] 13 C NMR (100MHz, CDCl3): δ160.6,159.6,158.0,147.5,136.9,129.9,129.8,128.9,12 7.8,127.6,126.5,119.1,107.7,106.8,101.8,73.0,71.2,34.6,26.1,16.5,11.3.

[0221] Example 4. Synthesis of CHIN116-CHIN121

[0222] Esters CHIN116 and CHIN119 were synthesized via the Williamson synthesis, starting from 2-(chloromethyl)quinoline (9) and alternatively from methyl 4'-hydroxy-[1,1'-biphenyl]-3-carboxylate (10) or methyl 4'-hydroxy-[1,1'-biphenyl]-4-carboxylate (11), using the same experimental procedure as in reaction c of Example 2.

[0223] The ester was then reduced and hydrolyzed according to the experimental procedures described in steps a) and c) of the previous Example 1.

[0224] Indication Figure 4 .

[0225]

[0226] Reagents and conditions. a) Compound 10 or 11, K2CO3, dry DMF, 100°C, yielded quantitative and 87% respectively; b) excess NaOH, MeOH:H2O 1:1 v / v, reflux, yielded quantitative results for both reactions; c) DIBAL-H, dry THF, 0°C, yielded quantitative and 92% respectively.

[0227] Example 4A. Synthesis of methyl 4'-(quinoline-2-ylmethoxy)-[1,1'-biphenyl]-3-carboxylic acid (CHIN116).

[0228] The derivative CHIN116 (quantitative yield) was purified on a silica column using hexane:EtOAc 9:1 v / v. The analytical sample was eluent using a hexane:EtOAc mixture 7:3 v / v (flow rate 3 mL / min, t). R =12.1 min) was obtained by HPLC on a Nucleodur 100-5 column (5 μm; 10 mm id x 250 mm).

[0229] CHIN116 C 24 H 19 NO3

[0230] 1 H NMR (400MHz, CDCl3): δ8.23 (1H, t, J = 2.0Hz), 8.21 (1H, d, J = 8.4Hz), 8.11 (1H, d ,J=8.6Hz),7.98(1H,d,J=8.0Hz),7.84(1H,d,J=7.9Hz),7.77(1H,t,J=8.6Hz) ,7.73(1H,d,J=8.4Hz),7.71(1H,d,J=8.0Hz),7.57(1H,t,ovl),7.57(2H,d,J= 8.7Hz), 7.48(1H,t,J=8.0Hz), 7.13(2H,d,J=8.7Hz), 5.45(2H,s), 3.94(3H,s).

[0231] 13 C NMR (100MHz, CDCl3): δ167.0,158.2,157.7,147.5,140.8,137.1,133.1,131.0,130.6,129. 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.

[0232] Example 4B. Synthesis of 4'-(quinoline-2-ylmethoxy)-[1,1'-biphenyl]-3-carboxylic acid (CHIN117).

[0233] The compound CHIN117 was purified on a silica column (DCM:MeOH 95:5v / v) and obtained in quantitative yield.

[0234] CHIN117 C 23 H 17 NO3

[0235] 1 H NMR (400MHz, CDCl3): δ8.29 (1H, t, J = 1.6Hz), 8.23 ​​(1H, d, J = 8.5Hz), 8.14 (1 H,d,J=8.4Hz),8.03(1H,d,J=7.8Hz),7.85(1H,d,J=8.0Hz),7.79(1H,d,J=7 .8Hz),7.77(1H,t,J=8.4Hz),7.72(1H,d,J=8.5Hz),7.58(2H,d,J=8.4Hz), 7.57(1H,t,ovl), 7.52(1H,t,J=7.8Hz), 7.14(2H,d,J=8.4Hz), 5.47(2H,s).

[0236] 13 C NMR(100MHz,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.

[0237] Example 4 Synthesis of C.4'-(quinoline-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)methanol (CHIN118).

[0238] Hexane / EtOAc 1:1 v / v (flow rate 3 mL / min, t) was used as the eluent. R Purification by HPLC on a Nucleodur 100-5 column (5 μm; 10 mm id x 250 mm) for 20 min provided us with a quantitative yield of CHIN118.

[0239] CHIN118 C 23 H 19 NO2

[0240] 1H NMR (400MHz, CDCl3): δ8.22 (1H, d, J = 8.6Hz), 8.12 (1H, d, J = 7.8Hz), 7.85 (1H, d,J=7.8Hz),7.76(1H,t,J=7.8Hz),7.71(1H,d,J=8.6Hz),7.57(1H,t,J=7.7H z),7.55(1H,s),7.52(2H,d,J=8.6Hz),7.47(1H,d,J=7.6Hz),7.40(1H,t,J=7 .6Hz), 7.31(1H,d,J=7.6Hz), 7.09(2H,d,J=8.6Hz), 5.42(2H,s), 4.76(2H,s).

[0241] 13 C NMR (100MHz, CDCl3): δ158.1,157.8,147.5,141.4,140.9,137.1,133.9,129.8,128.9,1 28.8,128.3(2C),127.7,127.6,126.6,126.0,125.3(2C),119.1,115.1(2C),71.2,65.4.

[0242] Example 4: Synthesis of D.4'-(quinoline-2-ylmethoxy)-[1,1'-biphenyl]-4-carboxylic acid methyl ester (CHIN119)

[0243] Compound CHIN119 (87% yield) was purified by passing it through a silica column using a hexane:EtOAc 9:1 v / v mixture as the eluent. The pure analytical sample was purified by passing it through a gradient (t0 = 60% MeOH-t...). 20min =95% MeOH; flow rate 1 mL / min, t R The sample was separated by HPLC on a Nucleodur 100-5C18 column (5 μm; 4.6 mm id x 250 mm) (5.5 min).

[0244] CHIN119 C 24 H 19 NO3

[0245] 1H NMR (400MHz, CDCl3): δ8.22(1H,d,J=8.6Hz), 8.11(1H,d,J=8.2Hz), 8.08(2H,d,J=8. 6Hz),7.85(1H,d,J=8.2Hz),7.76(1H,t,J=8.2Hz),7.70(1H,d,J=8.6Hz),7.61(2H,d J=8.6Hz), 7.58(2H,d,J=8.9Hz), 7.57(1H,t,ovl), 7.13(2H,d,J=8.9Hz), 5.46(2H,s), 3.94(3H,s).

[0246] 13 C NMR (100MHz, CDCl3): δ167.1,158.6,157.6,147.5,145.0,137.1,132.9,130.1(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.

[0247] Example 4 Synthesis of E.4'-(quinoline-2-ylmethoxy)-[1,1'-biphenyl]-4-carboxylic acid (CHIN120).

[0248] Purification was performed using DCM:MeOH 95:5 v / v as the eluent on a rapid chromatography column and silica gel to obtain quantitative yields of CHIN120.

[0249] CHIN120 C 23 H 17 NO3

[0250] 1 H NMR(400MHz,CD3OD+0.1% TFA): δ9.23(1H,d,J=8.5Hz), 8.42(1H,d,J=8.0Hz), 8.39(1H,d,J=7.5Hz), 8.24(1H,t,J=7.5Hz), 8.23(1H,d,J=8.5Hz), 8. 10(2H,d,J=8.5Hz), 8.03(1H,t,J=8.0Hz), 7.76(2H,d,J=8.5Hz), 7.73(2H,d,J=8.5Hz), 7.32(2H,d,J=8.5Hz), 5.80(2H,s).

[0251] 13C NMR (100MHz, CDCl3): δ168.7,158.3,157.3,145.7,145.0,138.8,133.2,130.9,130 .4(2C),128.5(2C),128.4,128.3,127.8(2C),126.5(3C),119.2,115.3(2C),69.8.

[0252] Example 4F. Synthesis of (4'-(quinoline-2-ylmethoxy)-[1,1'-biphenyl]-3-yl)methanol (CHIN121).

[0253] Compound CHIN121 was purified (92% yield) using hexane:EtOAc 8:2 v / v as eluent on a silica gel column. The analytical sample was then purified using hexane / EtOAc 1:1 v / v (flow rate 3 mL / min, t). R The sample was further purified by HPLC on a Nucleodur 100-5 column (5 μm; 10 mm id x 250 mm) for 18 min.

[0254] CHIN121 C 23 H 19 NO2

[0255] 1 H NMR (400MHz, CDCl3): δ8.22 (1H, d, J = 8.4Hz), 8.11 (1H, d, J = 8.5Hz), 7.85 (1H, d, J = 8.0Hz), 7.76 (1H, t, J = 8.5Hz), 7.71 (1H, d, J = 8.4Hz), 7 .57(1H,t,J=8.0Hz), 7.55(2H,d,J=8.6Hz), 7.53(2H,d,J=8.6Hz), 7.42(2H,d,J=8.6Hz), 7.10(2H,d,J=8.6Hz), 5.44(2H,s), 4.74(2H,s).

[0256] 13 C NMR (100MHz, CDCl3): δ157.9,157.8,157.3,147.5,140.1,137.1,133.9,129.8,128.9,1 28.5,128.4,127.7,127.6,127.5(2C),126.8(2C),126.5,119.1,115.2(2C),71.3,65.1.

[0257] Example 5: Synthesis of CHIN125-CHIN127 and CHIN131-CHIN133.

[0258] For the synthesis of esters CHIN125 and CHIN131, the first step was to use the Williamson synthesis method, starting with methyl 3,5-dihydroxybenzoate (2) and reacting it alternately with methyl 5-bromopentanoate (14) and methyl 4-bromobutyrate (15) to obtain (phenol) 12 and 13. The resulting monoalkylated (phenol) was further subjected to a Williamson reaction with 2-(chloromethyl)quinoline (9) using the same experimental procedure as used in reaction c of Example 2. The esters were then subjected to LiBH4 reduction and hydrolysis according to the experimental procedure described in reaction c) of Example 1.

[0259] Indication Figure 5

[0260]

[0261] a Reagents and conditions. a) Compound 14 or 15, K2CO3, dry DMF, 100°C, yielded 48% and 47% of compounds 12 and 13, respectively; b) Compound 12 or 13, K2CO3, dry DMF, 100°C, yielded 80% and 74% of compounds 12 and 13, respectively; c) Excess NaOH, MeOH:H2O 1:1 v / v, reflux, yielded 98% of the quantitative yields; d) LiBH4, dry THF, 0°C, yielded 80% and 76% of compounds 12 and 13, respectively.

[0262] General process.

[0263] Reaction a). Williamson reaction. Methyl 5-bromopentanoate (0.5 equivalents) or methyl 4-bromobutyrate and K₂CO₃ (1 equivalent) were added to a solution of compound 2 in dried DMF, and the solution was placed at 100°C for approximately 12 hours. The solution was cooled, acidified with 6N HCl, and the DMF was removed by rotary evaporation. The dried residue was extracted with water and ethyl acetate (3 x 50 mL). The collected organic phases were dehydrated with Na₂SO₄, filtered, and then concentrated on a rotary evaporator to obtain a crude reaction product, which was purified by open column chromatography.

[0264] Reaction d). Reduction reaction using LiBH4.

[0265] At 0 °C, a solution of dried methanol (1 equivalent) and a 2M solution of LiBH4 in dried THF (2 equivalents) were added to a solution of ester CHIN125 or CHIN131 in dried THF. After approximately 5 hours, TLC monitoring showed that the substrate was exhausted, and the reaction was quenched by adding 1N NaOH solution (2 equivalents) at 0 °C. The quenching was continued for 1 hour, and then the mixture was extracted with water and ethyl acetate (3 x 50 mL). The collected organic phase was dehydrated with Na2SO4, filtered, and then concentrated by rotary evaporation to obtain a crude reaction product, which was purified by HPLC.

[0266] Example 5A. Synthesis of methyl 3-((5-methoxy-5-oxopentyl)oxy)-5-(quinoline-2-ylmethoxy)benzoate (CHIN125).

[0267] Compound CHIN125 (80% yield) was purified on a silica column using a hexane:EtOAc 9:1 v / v mixture as the eluent. Pure analytical samples were eluented using a hexane:EtOAc 7:3 v / v mixture (flow rate 3 mL / min, t). R =20.4 min) was obtained by separation by HPLC on a Nucleodur 100-5 column (5 μm; 10 mm id x 250 mm).

[0268] CHIN125 C 24 H 25 NO6

[0269] 1 H NMR (400MHz, CDCl3): δ8.21(1H,d,J=8.5Hz), 8.10(1H,d,J=8.5Hz), 7.83(1H,d,J=8.2 Hz),7.74(1H,t,J=8.5Hz),7.66(1H,d,J=8.5Hz),7.56(1H,t,J=8.1Hz),7.33(1H,dd, J=1.3Hz,2.3Hz),7.19(1H,dd,J=1.3Hz,2.3Hz),6.78(1H,t,J=2.3Hz),5.40(2H,s),3 .98(2H,t,J=6.5Hz), 3.89(3H,s), 3.67(3H,s), 2.38(2H,t,J=7.5Hz), 1.81(2H,ovl).

[0270] 13C NMR (700MHz, CDCl3): δ173.8,166.7,160.1,159.5,157.3,147.6,137.1,132.1,129.8,129.0 ,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.

[0271] Example 5B. Synthesis of 3-(4-carboxybutoxy)-5-(quinoline-2-ylmethoxy)benzoic acid (CHIN126).

[0272] Purification was performed using a gradient (t0 = 10% MeCN + 0.1% TFA-t). 20min =70% MeCN 0.1% TFA-t 25min =95% MeCN 0.1% TFA; flow rate 3 mL / min, t R =16.3 min) was obtained by HPLC on a Phenomenex Luna C18(2) column (5 μm; 10 mm id x 250 mm) to provide the quantitative yield of compound CHIN126.

[0273] CHIN126 C 22 H 21 NO6

[0274] 1 H NMR (400MHz, CD3OD): δ9.17(1H,d,J=8.5Hz),8.38(1H,d,J=8.5Hz),8.34(1H,d ,J=8.2Hz),8.20(1H,t,J=8.5Hz),8.18(1H,d,J=8.5Hz),7.98(1H,t,J=8.1Hz), 7.38(1H,dd,J=1.3Hz,2.3Hz),7.31(1H,dd,J=1.3Hz,2.3Hz),6.98(1H,t,J=2. 3Hz), 5.74 (2H, s), 4.06 (2H, t, J = 5.5Hz), 2.38 (2H, t, J = 8.0Hz), 1.82 (2H, ovl).

[0275] 13C NMR (700MHz, CD3OD): δ177.3,169.2,161.8,160.4,157.9,143.6,133.5,132.1,129.7, 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.

[0276] Example 5. Synthesis of 5-(3-(hydroxymethyl)-5-(quinolin-2-ylmethoxy)phenoxy)pentane-1-ol (CHIN127).

[0277] Purification was performed using MeCN / H2O 55:45 (flow rate 3 mL / min, t R =5.16 min) was obtained by HPLC on a Phenomenex Luna C18(2) column (5 μm; 10 mm id x 250 mm) to provide compound CHIN127 (80%).

[0278] CHIN127 C 22 H 25 NO4

[0279] 1 H NMR (400MHz, CDCl3): δ8.21(1H,d,J=8.5Hz), 8.11(1H,d,J=8.5Hz), 7.84(1H,d,J=8.2Hz), 7.75(1H,t,J=8.5Hz),7.68(1H,d,J=8.5Hz),7.56(1H,t,J=8.1Hz),6.64(1H,dd,J=1.3Hz,2 0.3Hz), 6.55(1H,t,J=2.3Hz), 6.52(1H,dd,J=1.3Hz,2.3Hz), 5.38(2H,s), 4.62(2H,s), 3.94(2H,t,J=6.5Hz), 3.67(2H,t,J=6.5), 1.79(2H,quintet,J=6.2Hz,7.5Hz), 1.63-1.53(4H,ovl).

[0280] 13 C NMR (700MHz, CDCl3): δ160.3,159.6,157.8,147.2,143.9,137.3,130.0,129.2,127.7 ,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.

[0281] Example 5D. Synthesis of methyl 3-(4-methoxy-4-oxobutoxy)-5-(quinoline-2-ylmethoxy)benzoate (CHIN131).

[0282] The derivative CHIN131 (74%) was purified on a silica column using hexane:EtOAc 9:1 v / v. The analytical sample was eluent using a hexane:EtOAc mixture of 7:3 v / v (flow rate 3 mL / min, t). R =22.1 min) was obtained by HPLC on a Nucleodur 100-5 column (5 μm; 10 mm id x 250 mm).

[0283] CHIN131 C 23 H 23 NO6

[0284] 1 H NMR (400MHz, CDCl3): δ8.24(1H,d,J=8.5Hz), 8.13(1H,d,J=8.5Hz), 7.85(1H,d,J=8.2Hz) ,7.76(1H,t,J=8.5Hz),7.68(1H,d,J=8.5Hz),7.58(1H,t,J=8.1Hz),7.34(1H,dd,J=8.1H z, 2.3Hz), 7.19 (1H,dd,J=2.3Hz), 6.78 (1H,dd,J=8.1Hz,2.3Hz), 5.38 (2H,s), 4.02 (2H,t,J=6.3Hz), 3.71 (2H,t,J=7.0Hz), 2.51 (2H,t,J=7.3Hz), 2.10 (2H, quintet,J=6.3Hz,7.3Hz).

[0285] 13 C NMR (700MHz, CDCl3): δ173.6,166.7,160.3,159.6,157.3,147.6,137.2,132.2,129.9,12 9.1,127.8,127.7,126.7,119.2,108.5,108.3,106.8,71.5,67.1,52.3,51.8,30.5,24.5.

[0286] Example 5: Synthesis of E. 3-(3-carboxypropoxy)-5-(quinoline-2-ylmethoxy)benzoic acid (CHIN132).

[0287] The derivative CHIN132 (98%) was processed in a gradient (t0 = 10% MeCN 0.1% TFA-t). 20min=70% MeCN0.1% TFA-t 25min =95% MeCN 0.1% TFA; flow rate 3 mL / min, t R Purification was performed by HPLC on a Phenomenex Luna C18(2) column (5 μm; 10 mm id x 250 mm) for 15 min.

[0288] CHIN132 C 21 H 19 NO6

[0289] 1 H NMR (400MHz, CD3OD): δ9.04(1H,d,J=8.5Hz), 8.33(1H,d,J=8.5Hz), 8.29(1H,d,J=8 .2Hz),8.14(1H,t,J=8.5Hz),8.11(1H,d,J=8.5Hz),7.93(1H,t,J=8.1Hz),7.38(1H ,dd,J=8.1Hz,2.3Hz),7.28(1H,dd,J=2.3Hz),6.99(1H,dd,J=8.1Hz,2.3Hz),5.69( 2H, s), 4.09 (2H, t, J = 6.3Hz), 2.50 (2H, t, J = 7.3Hz), 2.08 (2H, quintet, J = 6.3Hz, 7.3Hz).

[0290] 13 C NMR (700MHz, CD3OD): δ176.9,169.0,161.3,160.2,159.7,148.1,133.7,132.0,130 .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.

[0291] Example 5 Synthesis of F. 4-(3-(hydroxymethyl)-5-(quinoline-2-ylmethoxy)phenoxy)but-1-ol (CHIN133).

[0292] The derivative CHIN133 (76%) was eluent using a mixture of n-hexane:EtOAc 4:6 v / v (flow rate 3 mL / min, t). R The sample was purified by HPLC on a Nucleodur 100-5 column (5 μm; 10 mm id x 250 mm) at a wavelength of 26.32 min.

[0293] CHIN133 C 21 H23 NO4

[0294] 1 H NMR (400MHz, CD3OD): δ8.23(1H,d,J=8.5Hz), 8.12(1H,d,J=8.5Hz), 7.85(1H,d,J=8. 2Hz),7.76(1H,t,J=8.5Hz),7.69(1H,d,J=8.5Hz),7.57(1H,t,J=8.1Hz),6.65(1H,dd ,J=8.1Hz,2.3Hz),6.55(1H,dd,J=8.1Hz,2.3Hz),6.52(1H,dd,J=2.3Hz),5.39(2H,s) ,4.64(2H,s),4.07(2H,t,J=6.3Hz),3.86(2H,t,J=6.3Hz),2.49(2H,m),2.02(2H,m).

[0295] 13 C NMR (700MHz, CD3OD): δ176.9,169.0,161.3,160.2,159.7,148.1,133.7,132.0,130 .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.

[0296] Example 6: Synthesis of CHIN134-CHIN142.

[0297] The first reaction step began with methyl 3,5-dihydroxybenzoate (2) and proceeded with a photoelectrophoresis reaction described in step b) of Example 1 using propan-2 alcohol (16), propan-1 alcohol (17), and butan-2 alcohol (18). The resulting monoalkylated derivative was then subjected to a Williamson reaction with 2-(chloromethyl)quinoline (9) using the same experimental procedure as described in reaction c) of Example 2. These esters were then reduced and hydrolyzed, respectively, according to the experimental procedures described in reaction d) of Example 5 and reaction c) of Example 1.

[0298] Schematic diagram 6.

[0299]

[0300] aReagents and conditions. a) Alcohol 16, 17, or 18, DIAD, PPh3, dry THF, 0°C, compounds 19, 20, and 21 yielded 50%, 45%, and 42% quantitative yields, respectively; b) Compounds 19-21, K2CO3, dry DMF, 100°C, yielded 57% and 70% quantitative yields, respectively; c) Excess NaOH, MeOH:H2O 1:1 v / v, reflux, yielded 84%, 86%, and 91% yields, respectively; d) LiBH4, dry THF, 0°C, yielded 88%, 94%, and 89% yields, respectively.

[0301] Example 6A. Synthesis of methyl 3-isopropoxy-5-(quinoline-2-ylmethoxy)benzoate (CHIN134).

[0302] The derivative CHIN134 (50%) was purified on a silica column using hexane:EtOAc 9:1 v / v. The analytical sample was eluent using a mixture of n-hexane:EtOAc 7:3 v / v (flow rate 3 mL / min, t). R =9.9 min) was obtained by HPLC on a Nucleodur 100-5 column (5 μm; 10 mm id x 250 mm).

[0303] CHIN134 C 21 H 21 NO4

[0304] 1 H NMR (400MHz, CDCl3): δ8.21 (1H, d, J = 8.5Hz), 8.10 (1H, d, J = 8.5Hz), 7.84 (1H, d,J=8.2Hz),7.75(1H,t,J=8.5Hz),7.67(1H,d,J=8.5Hz),7.56(1H,t,J=8.1H z),7.31(1H,dd,J=2.4Hz),7.20(1H,dd,J=2.3Hz),6.78(1H,dd,J=2.4Hz,2.3 Hz), 5.40 (2H, s), 4.57 (1H, quintet, J = 6.1Hz), 3.89 (3H, s), 1.32 (6H, d, J = 6.1Hz).

[0305] 13 C NMR (700MHz, CDCl3): δ166.8,159.5,159.1,157.3,147.6,137.1,132.2,129.9,12 9.0,127.8,127.7,126.7,119.2,109.7,108.2,108.0,71.4,70.4,52.1,21.9(2C).

[0306] Example 6B. Synthesis of 3-isopropoxy-5-(quinoline-2-ylmethoxy)benzoic acid (CHIN135).

[0307] The derivative CHIN135 (84%) was purified on a silica column of DCM:MeOH 9:1 v / v.

[0308] CHIN135 C 20 H 19 NO4

[0309] 1 H NMR (400MHz, CD3OD): δ9.21(1H,d,J=8.5Hz), 8.39(1H,d,J=8.5Hz), 8.37(1H,d,J=8.2Hz), 8.22(1H,t,J=8.5Hz), 8.20(1H,d,J=8.5Hz), 8.01(1H,t,J =8.1Hz), 7.38(1H,dd,J=2.4Hz), 7.29(1H,dd,J=2.3Hz), 6.97(1H,dd,J=2.4Hz,2.3Hz), 5.75(2H,s), 4.68(1H, quintet, J=6.1Hz), 1.35(6H,d,J=6.1Hz).

[0310] 13 C NMR (700MHz, CD3OD): δ169.0,160.7,159.8,156.8,148.6,136.6,134.4,131.2, 130.5,129.9,129.2,126.2,121.7,111.8,109.1,108.8,71.6,67.7,22.1(2C).

[0311] Example 6C. Synthesis of (3-isopropoxy-5-(quinoline-2-ylmethoxy)phenyl)methanol (CHIN136).

[0312] The derivative CHIN136 (88%) was eluent using a mixture of n-hexane:EtOAc 7:3 v / v (flow rate 3 mL / min, t). R The sample was purified by HPLC on a Nucleodur 100-5 column (5 μm; 10 mm id x 250 mm) at a depth of 38.79 min.

[0313] CHIN136 C 20 H 21 NO3

[0314] 1H NMR (400MHz, CDCl3): δ8.21 (1H, d, J = 8.5Hz), 8.12 (1H, d, J = 8.5Hz), 7.84 (1H, d,J=8.2Hz),7.75(1H,t,J=8.5Hz),7.68(1H,d,J=8.5Hz),7.56(1H,t,J=8.1H z), 6.63 (1H, dd, J = 2.4Hz), 6.54 (1H, dd, J = 2.3Hz), 6.51 (1H, dd, J = 2.4Hz, 2.3 Hz), 5.38 (2H, s), 4.61 (2H, s), 4.52 (1H, quintet, J = 6.1Hz), 1.30 (6H, d, J = 6.1Hz).

[0315] 13 C NMR (700MHz, CDCl3): δ159.8,159.4,157.9,147.5,143.9,137.2,129.9,129.3,12 7.8,127.7,127.8,127.7,119.3,107.3,105.3,102.2,70.1,65.2,50.6,22.1(2C).

[0316] Example 6D. Synthesis of methyl 3-propoxy-5-(quinoline-2-ylmethoxy)benzoate (CHIN137).

[0317] The derivative CHIN137 (50%) was purified on a silica column using hexane:EtOAc 9:1 v / v. Analytical samples were eluent using a mixture of n-hexane:EtOAc 7:3 v / v (flow rate 3 mL / min, t). R =11.44 min) was obtained by HPLC on a Nucleodur 100-5 column (5 μm; 10 mm id x 250 mm).

[0318] CHIN137 C 21 H 21 NO4

[0319] 1H NMR (400MHz, CDCl3): δ8.21(1H,d,J=8.5Hz), 8.10(1H,d,J=8.5Hz), 7.84(1H,d,J=8 .2Hz),7.75(1H,t,J=8.5Hz),7.67(1H,d,J=8.5Hz),7.56(1H,t,J=8.1Hz),7.33(1H ,dd,J=2.4Hz),7.20(1H,dd,J=2.3Hz),6.80(1H,dd,J=2.4Hz,2.3Hz),5.40(2H,s), 3.93 (2H, t, J = 6.4Hz), 3.89 (3H, s), 1.79 (2H, sext, J = 7.4Hz), 1.02 (3H, t, J = 7.4Hz).

[0320] 13 C NMR (700MHz, CDCl3): δ166.9,160.3,159.5,157.5,147.5,137.2,132.2,129.9,129 .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.

[0321] Example 6 Synthesis of E. 3-propoxy-5-(quinoline-2-ylmethoxy)benzoic acid (CHIN138).

[0322] The derivative CHIN135 (86%) was purified on a silica column of DCM:MeOH 9:1 v / v.

[0323] CHIN138 C 20 H 19 NO4

[0324] 1 H NMR (400MHz, CD3OD): δ8.40(1H,d,J=8.5Hz), 8.06(1H,d,J=8.5Hz), 7.96(1H,d, J=8.2Hz),7.80(1H,t,J=8.5Hz),7.73(1H,d,J=8.5Hz),7.62(1H,t,J=8.1Hz),7 .28(1H,dd,J=2.4Hz),7.18(1H,dd,J=2.3Hz),6.85(1H,dd,J=2.4Hz,2.3Hz),5. 39 (2H, s), 3.95 (2H, t, J = 6.4Hz), 1.78 (2H, sext, J = 7.4Hz), 1.03 (3H, t, J = 7.4Hz).

[0325] 13 C NMR (700MHz, CD3OD): δ169.5,161.7,160.8,158.9,148.3,139.0,134.2,131.2, 129.2,129.1,129.0,128.0,120.7,109.7,109.2,107.5,72.0,70.8,23.5,10.7.

[0326] Example 6F. Synthesis of (3-propoxy-5-(quinoline-2-ylmethoxy)phenyl)methanol (CHIN139).

[0327] The derivative CHIN139 (94%) was eluent using a mixture of n-hexane:EtOAc 4:6 v / v (flow rate 3 mL / min, t). R Purification was performed by HPLC on a Nucleodur 100-5 column (5 μm; 10 mm id x 250 mm) for 24.5 min.

[0328] CHIN139 C 20 H 21 NO3

[0329] 1 H NMR (400MHz, CD3OD): δ8.38(1H,d,J=8.5Hz), 8.05(1H,d,J=8.5Hz), 7.95(1H,d,J=8 .2Hz),7.80(1H,t,J=8.5Hz),7.73(1H,d,J=8.5Hz),7.62(1H,t,J=8.1Hz),6.65(1H ,dd,J=2.4Hz),6.55(1H,dd,J=2.3Hz),6.51(1H,dd,J=2.4Hz,2.3Hz),5.34(2H,s), 4.52 (2H, s), 3.90 (2H, t, J = 6.4Hz), 1.75 (2H, sext, J = 7.4Hz), 1.01 (3H, t, J = 7.4Hz).

[0330] 13 C NMR (700MHz, CD3OD): δ160.5,159.6,158.0,146.9,144.1,137.5,129.9,129.0, 127.7,127.5,126.5,119.3,105.5,104.9,100.2,70.3,69.2,63.7,22.2,09.4.

[0331] Example 6 Synthesis of G.3-(sec-butoxy)-5-(quinoline-2-ylmethoxy)benzoate (CHIN140).

[0332] The derivative CHIN140 (70%) was purified on a silica column using hexane:EtOAc 9:1 v / v. Analytical samples were eluent using a mixture of n-hexane:EtOAc 7:3 v / v (flow rate 3 mL / min, t). R =11.5 min) was obtained by HPLC on a Nucleodur 100-5 column (5 μm; 10 mm id x 250 mm).

[0333] CHIN140 C 22 H 23 NO4

[0334] 1 H NMR (400MHz, CDCl3): δ8.21(1H,d,J=8.5Hz), 8.10(1H,d,J=8.5Hz), 7.84(1H,d,J=8.2Hz ),7.75(1H,t,J=8.5Hz),7.67(1H,d,J=8.5Hz),7.56(1H,t,J=8.1Hz),7.31(1H,dd,J=2.4 Hz), 7.20 (1H,dd,J=2.3Hz), 6.78 (1H,dd,J=2.4Hz,2.3Hz), 5.40 (2H,s), 4.32 (1H,set,J=6.0Hz), 3.88 (3H,s), 1.72-1.61 (2H,ovl), 1.26 (3H,d,J=6.1Hz), 0.95 (3H,t,J=7.4Hz).

[0335] 13 C NMR (700MHz, CDCl3): δ166.9,159.5,159.4,157.3,147.5,137.4,132.5,130.0,128 .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.

[0336] Example 6 Synthesis of H.3-(sec-butoxy)-5-(quinoline-2-ylmethoxy)benzoic acid (CHIN141).

[0337] The derivative CHIN141 (91%) was purified on a silica column of DCM:MeOH 9:1 v / v.

[0338] CHIN141 C21 H 21 NO4

[0339] 1 H NMR (400MHz, CD3OD): δ8.39 (1H, d, J = 8.5Hz), 8.06 (1H, d, J = 8.5Hz), 7.96 (1H, d, J = 8. 2Hz),7.80(1H,t,J=8.5Hz),7.72(1H,d,J=8.5Hz),7.62(1H,t,J=8.1Hz),7.27(1H,dd ,J=2.4Hz), 7.16(1H,dd,J=2.3Hz), 6.83(1H,dd,J=2.4Hz,2.3Hz), 5.39(2H,s), 4.36(1H,set,J=6.0Hz), 1.69-1.60(2H,ovl), 1.24(3H,d,J=6.1Hz), 0.96(3H,t,J=7.4Hz).

[0340] 13 C NMR (700MHz, CD3OD): δ169.4,160.8,158.8,148.3,139.0,134.0,131.3,131.0,129 .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.

[0341] Example 6I. Synthesis of (3-(sec-butoxy)-5-(quinoline-2-ylmethoxy)phenyl)methanol (CHIN142).

[0342] The derivative CHIN142 (89%) was eluent using a mixture of n-hexane:EtOAc 4:6 v / v (flow rate 3 mL / min, t). R The sample was purified by HPLC on a Nucleodur 100-5 column (5 μm; 10 mm id x 250 mm) at a wavelength of 24.74 min.

[0343] CHIN142 C 21 H 23 NO3

[0344] 1H NMR (400MHz, CDCl3): δ8.21(1H,d,J=8.5Hz), 8.12(1H,d,J=8.5Hz), 7.83(1H,d,J=8.2Hz ),7.75(1H,t,J=8.5Hz),7.68(1H,d,J=8.5Hz),7.56(1H,t,J=8.1Hz),6.63(1H,dd,J=2.4 Hz), 6.54 (1H,dd,J=2.3Hz), 6.51 (1H,dd,J=2.4Hz,2.3Hz), 5.38 (2H,s), 4.61 (2H,s), 4.27 (1H,set,J=6.0Hz), 1.71-1.59 (2H,ovl), 1.25 (3H,d,J=6.1Hz), 0.94 (3H,t,J=7.4Hz).

[0345] 13 C NMR (700MHz, CDCl3): δ159.8,159.7,157.9,147.4,143.8,137.1,129.9,128.8,12 7.7,127.6,126.6,119.2,107.3,105.3,102.1,75.1,71.2,65.1,29.1,19.3,09.8.

[0346] Example 7 - Biological Data

[0347] Table 1 describes the activity data of the compounds of the present invention against the FXR, TGR5 / GPBAR1, and CysLT1R receptors. In this table, the activities of the compounds are compared with specific reference compounds (i.e., CDCA for FXR, TLCA for TGR5 / GPBAR1, and MK571 for CysLT1R). Each compound was tested at a concentration of 10 μM, and the activity of the reference compounds was considered 100%.

[0348] Table 1

[0349]

[0350]

[0351] For FXR-mediated transcriptional activation, HepG2 cells were transfected with 200 ng of the p(hsp27)-TK-LUC reporter vector containing 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 the vector pGL4.70 (Promega, Madison WI) encoding the human Renilla gene.

[0352] For GPBAR1-mediated transcriptional activation, HEK-293T cells were transfected with 200 ng of the reporter vector pGL4.29 (Promega, Madison WI) containing the cAMP response element (CRE) that drives the transcription of the luc2P luciferase reporter gene, 100 ng of human pCMVSPORT6-GPBAR1, and 100 ng of pGL4.70.

[0353] Twenty-four hours post-transfection, cells were stimulated for 18 hours with the specific receptor agonist CDCA (10 μM) or TLCA (10 μM), or with derivatives CHIN104-112 and CHIN114-121 (10 μM and 50 μM). In another experimental setup, cells were stimulated for 24 hours post-transfection with 50 μM of the derivative CHIN in combination with 10 μM CDCA or TLCA.

[0354] For dose-response curves, cells were stimulated with increasing concentrations of the target compound (0.1–75 μM). Eighteen hours post-stimulation, cell lysates were used to assess luciferase and Renilla activities using a dual-luciferase reporter assay (E1980, Promega Madison WI). Luminescence was measured using a Glomax 20 / 20 spectrophotometer (Promega, Madison WI), and luciferase activity was normalized using Renilla activity.

[0355] Antagonistic activity was detected using Eurofins Cerep-Panlabs (France). Cells were suspended in DMEM buffer (Invitrogen) and then... 4 Cells were seeded at a density of 100 cells / plate. A fluorescent probe (Fluo4Direct, Invitrogen) mixed with probenecid was then added to each well in HBSS buffer (Invitrogen) supplemented with 20 mM Hepes (Invitrogen) (pH 7.4) and incubated with cells at 37°C for 60 min, followed by 22°C for 15 min. The plate was then placed on a microplate reader (CellLux, PerkinElmer) for adding the test compound or HBSS buffer, followed by 0.1 nM LTD4 or HBSS buffer solution (as a control) after 5 min. Free Ca2+ in the cytosol was measured. 2+ The intensity and fluorescence changes proportionally to the ion concentration. Results are expressed as the percentage of inhibition compared to the control response with 0.1 nMLTD4. The standard antagonist reference is MK571.

[0356] CHIN117 and its role in reducing acetaminophen-induced liver injury (APAP) are of particular interest. In the experimental setup, acute hepatitis was induced in wild-type C57 / Bl6 mice by oral administration of acetaminophen (APAP) at a concentration of 500 mg / kg. Forty-five minutes after induction, CHIN117 was administered orally at a concentration of 30 mg / kg. Mice were sacrificed 24 hours after induction, and blood was collected for analysis of blood cell counts and AST and ALT transaminase levels.

[0357] The results show ( Figure 1-3 APAP administration induced a sharp increase in AST and ALT levels (between 3000 and 4000). Furthermore, the resulting liver damage attracted immune cells involved in the pathogenesis of the disease to the liver, leading to a decrease in circulating white blood cell (WBC) levels. Administration of the compound CHIN117 alleviated APAP-induced liver damage by reducing AST and ALT levels approximately 10-fold compared to those recorded in mice treated with APAP alone. CHIN117 also maintained WBC levels comparable to those found in untreated mice (NT).

[0358] CHIN117 and its efficacy in a mouse model of chronic hepatitis induced by a high-fat diet are of particular interest. This mouse model mimics NAFLD, representing a rapidly growing epidemic in industrialized countries and imposing very high costs on healthcare systems. In this model, mice (male C57BL / 6 mice) were fed a diet rich in lipids and cholesterol (2% cholesterol) with fructose (3%) added to the water (HFD-F) for 60 days. Starting from day 7, CHIN117 was administered daily at a dose of 30 mg / kg. Weight trend showed that CHIN117 reduced weight gain by approximately 3 grams. Figure 4 A, B). After eight weeks, the mice developed insulin resistance, as shown in the OGTT results ( Figure 4 E, F). Treatment of mice with CHIN117 reversed the effects of diet and reduced the AUC of OGTT. Furthermore, CHIN117 statistically reduced AST, ALT, and LDL levels, thereby offsetting the hepatotoxic effects of the HFD-F diet. Figure 4 GH).

[0359] Mice fed the HFD-F diet for 8 weeks developed features similar to human NASH as revealed by H&E staining in liver sections, including microcystic steatosis, hepatocyte swelling, lobular inflammation, and macrophage influx. Figure 5 A), thus leading to a significant increase in the hepatic steatosis (NAS) score. Figure 3B). Furthermore, HFD-F indicates an increase in body mass index (BMI), epididymal white adipose tissue (eWAT) weight, brown adipose tissue (BAT) weight, and liver weight. Figure 5 CI). CHIN117 almost completely reversed the disease by reducing hepatic steatosis, BMI and eWAT, BAT and liver weight (CI). Figure 5 ).

[0360] CHIN117 is valued for its excellent pharmacokinetic properties (water solubility of 66 μM at pH 7.4 and LogD = 2.0) and its promising metabolic stability (t < 0.0 when exposed to microsomal enzymes in vitro). 1 / 2 =578min(CL) int =4), and exposed in vitro to S9 stage time-sharing t which also contains enzymes responsible for the second stage of metabolism. 1 / 2 =385min(CLint=6)) and is particularly noteworthy.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:

2. Use of the compound according to claim 1 in the preparation of a medicament, wherein the medicament is used to prevent and / or treat conditions selected from the group consisting of: liver injury, chronic hepatitis, and hepatic steatosis.

3. A pharmaceutical composition comprising: The compound according to claim 1: And at least one pharmaceutically acceptable excipient.

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