Novel biphenylcarboxylic acid-based fabp1 inhibitors, methods for their preparation and use as medicaments

Abstract

The present application relates to a kind of containing effective amount of novel biphenyl carboxylic acid derivative of general formula (I), its preparation method and the use of the derivative as the preparation of drug for treating FABP1 related diseases, compared with prior art, with more broad application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to a novel class of biphenyl carboxylic acid derivatives, their preparation methods and applications, belonging to the field of pharmaceutical chemistry. The structure of the related biphenyl carboxylic acid derivatives in the present application is unique and novel in the field. BACKGROUND

[0002] Fatty acid binding proteins (FABPs) are a class of small (14-15 kDa) lipid chaperones that can reversibly bind long-chain fatty acids and other hydrophobic ligands, involved in regulating lipid transport and inflammatory response in cells, and are key mediators of metabolic and inflammatory pathways. Since FABPs were first reported in 1972, at least nine different types of FABPs have been found in mammals, with tissue distribution specificity. According to their high expression in specific tissues, they can be classified and named as follows: liver type (Liver-FABP), intestinal type (Intestinal-FABP), heart type (Heart-FABP), adipose type (Adipose-FABP), epidermal type (Epidermal-FABP), ileum type (Ileum-FABP), brain type (Brain-FABP), myelin type (Myelin-FABP) and testis type (Testis-FABP). At present, numerous literatures show that FABPs disorder is related to many diseases, including obesity, type II diabetes, non-alcoholic fatty liver disease, cardiovascular disease, chronic kidney disease and cancer. With the in-depth study of the potential mechanisms of these diseases, FABPs are considered to be a new drug target.

[0003] Among them, the liver type (Liver-FABP), also known as FABP1, its main function is to uptake, transport and utilize fatty acids, and plays an important role in lipid metabolism. FABP1 as the main fatty acid transport protein is highly expressed in the serum and liver tissue of NAFLD patients and HFD-fed mice. Current hot literature research shows that silencing FABP1 can reduce oxidative stress, inflammation and liver steatosis in NAFLD mice; gene knockout mice can be protected from obesity, steatosis and fibrosis caused by western diet. Therefore, drugs that inhibit the expression or function of FABP1 may be an effective means for treating NAFLD.

[0004] FABP1 is expressed in other tissues besides the liver, such as the kidney, intestine, lung, and pancreas. Recent studies have found that abnormal lipid metabolism and lipid droplet accumulation in the kidney will lead to chronic kidney disease (CKD), and the level of FABP1 is a sensitive indicator of CKD. Many studies emphasize that the accumulation of fatty acids promotes inflammation, including sterile inflammation of cells, through the activation of the innate immune system and fibrosis, thereby triggering mitochondrial and kidney cell damage. Therefore, the compounds in this study, as FABP1 inhibitors, are expected to play an important role in the treatment of acute kidney injury.

[0005] Based on existing research, we have reason to believe that FABP1 is a potential target for various diseases such as fatty liver, inflammation, and obesity, and its research and drug development have broad prospects. Although inhibitors of the FABPs family have become a hot research topic, such as FABP3, FABP4, and FABP5 inhibitors, no FABP1 inhibitors have been reported. Therefore, given the above reasons, it is necessary to develop new FABPI inhibitors. SUMMARY

[0006] The technical problem to be solved by the present application is to provide a novel preparation method of biphenyl carboxylic acid FABP1 inhibitors, which provides a possibility for FABPl inhibitors to be applied in the diagnosis, treatment, and prevention of primary biliary cirrhosis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, hyperlipidemia, obesity, atherosclerosis, organ fibrosis, liver cirrhosis, diabetes and its complications, acute kidney injury, and inflammatory diseases.

[0007] The novel biphenyl carboxylic acid FABP1 inhibitor provided by the present application contains an effective amount of a compound represented by the general formula (I):

[0008]

[0009] wherein ring A is selected from the following structures:

[0010]

[0011] ring B is selected from the following structures:

[0012]

[0013] When ring B is selected from a benzene ring, R is selected from one or more of hydrogen, alkyl, alkoxy, hydroxyl, halogen, and trifluoromethyl.

[0014] Preferred compounds of the present application include:

[0015] ring A is selected from any of the following structures:

[0016]

[0017] Ring B is selected from any one of the following structures:

[0018]

[0019] When Ring B is selected from a phenyl ring, R is selected from one or more of hydrogen, C1-C6 alkyl, alkoxy, hydroxy, halogen, trifluoromethyl.

[0020] More preferred compounds of the application include, but are not limited to:

[0021] 5-(4-methylbenzamido)-[l,l'-biphenyl]-3-carboxylic acid (1)

[0022] 3-(4-methylbenzamide)-5-(tetrahydrofuran-3-yl)benzoic acid (2)

[0023] 3-(furan-3-yl)-5-(4-methylbenzamide)benzoic acid (3)

[0024] 3-(4-methylbenzamide)-5-(thiazol-4-yl)benzoic acid (4)

[0025] 3-(4-methylbenzamide)-5-(thiazol-5-yl)benzoic acid (5)

[0026] 3-(lH-imidazol-l-yl)-5-(4-methylbenzamide)benzoic acid (6)

[0027] 3-(l-methyl-lH-pyrazol-5-yl)-5-(4-methylbenzamide)benzoic acid (7)

[0028] 3-(5-(hydroxymethyl)thiophen-3-yl)-5-(4-methylbenzamido)benzoic acid (8)

[0029] 3-(benzothiophen-3-yl)-5-(4-methylbenzamido)benzoic acid (9)

[0030] 5-benzamido-4'-methoxy-[l,l'-biphenyl]-3-carboxylic acid (10)

[0031] 5-benzamido-3'-methoxy-[l,l'-biphenyl]-3-carboxylic acid (11)

[0032] 5-benzamido-3'-ethoxy-[l,l'-biphenyl]-3-carboxylic acid (12)

[0033] 5-benzamido-4'-methoxy-3'-methyl-[l,l'-biphenyl]-3-carboxylic acid (13)

[0034] 5-benzamide-3'-isopropyl-[l,l'-biphenyl]-3-carboxylic acid (14)

[0035] 5-benzoylamino-4'-(tert-butyl)-[1,1'-biphenyl]-3-carboxylic acid (15)

[0036] 5-benzoylamino-4'-fluoro-[1,1'-biphenyl]-3-carboxylic acid (16)

[0037] 5-benzoylamino-3'-fluoro-[1,1'-biphenyl]-3-carboxylic acid (17).

[0038] 5-benzoylamino-3'-chloro-[1,1'-biphenyl]-3-carboxylic acid (18)

[0039] 5-benzoylamino-3'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (19)

[0040] 5-(cyclohexanecarboxamido)-[1,1'-biphenyl]-3-carboxylic acid (20)

[0041] 5-(2-methylbenzoylamino)-[1,1'-biphenyl]-3-carboxylic acid (21)

[0042] 5-(3-methylbenzoylamino)-[1,1'-biphenyl]-3-carboxylic acid (22)

[0043] 5-(4-(tert-butyl)benzoylamino)-[1,1'-biphenyl]-3-carboxylic acid (23)

[0044] 5-([1,1'-biphenyl]-3-carboxamido)-[1,1'-biphenyl]-3-carboxylic acid (24)

[0045] 5-(3-phenoxybenzoylamino)-[1,1'-biphenyl]-3-carboxylic acid (25)

[0046] 3'-methoxy-5-(3-phenoxybenzoylamino)-[1,1'-biphenyl]-3-carboxylic acid (30)

[0047] 3'-ethoxy-5-(3-phenoxybenzoylamino)-[1,1'-biphenyl]-3-carboxylic acid (31)

[0048] 4'-ethoxy-5-(3-phenoxybenzoylamino)-[1,1'-biphenyl]-3-carboxylic acid (32)

[0049] 5-(3-phenoxybenzoylamino)-3'-propoxy-[1,1'-biphenyl]-3-carboxylic acid (33)

[0050] 5-(3-phenoxybenzoylamino)-4'-propoxy-[1,1'-biphenyl]-3-carboxylic acid (34)

[0051] 3'-isobutoxy-5-(3-phenoxybenzamido)-[1,1'-biphenyl]-3-carboxylic acid (35)

[0052] 4'-isobutoxy-5-(3-phenoxybenzamido)-[1,1'-biphenyl]-3-carboxylic acid (36)

[0053] 3'-isobutoxy-5-(3-phenoxybenzamido)-[1,1'-biphenyl]-3-carboxylic acid (35)

[0054] 4'-isobutoxy-5-(3-phenoxybenzamido)-[1,1'-biphenyl]-3-carboxylic acid (36)

[0055] 5-(3-phenoxybenzamido)-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxylic acid (39)

[0056] 4'-fluoro-5-(3-phenoxybenzamido)-[1,1'-biphenyl]-3-carboxylic acid (40)

[0057] 4'-chloro-5-(3-phenoxybenzamido)-[1,1'-biphenyl]-3-carboxylic acid (41)

[0058] Another aspect of the present application relates to a pharmaceutical composition containing a therapeutically effective dose of the compound and a suitable carrier, diluent or excipient.

[0059] The present application relates to the use of a compound or a pharmaceutical composition thereof for the preparation of a medicament for the treatment of a FABP1 -related disease.

[0060] The present application also relates to the use of a compound or a pharmaceutical composition thereof for the preparation of a medicament for the prevention or / and treatment of at least one of primary biliary cirrhosis, nonalcoholic steatohepatitis, alcoholic steatohepatitis, hyperlipidemia, obesity, atherosclerosis, organ fibrosis, liver cirrhosis, diabetes and its complications, acute kidney injury, inflammatory diseases.

[0061] Detailed description of the application

[0062] The following terms, as used in the specification and claims, have the following meanings unless otherwise indicated.

[0063] Any formula or structure shown herein, including the compounds of Formula (I), is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. The isotopically labeled compounds have the same formula as represented by the molecules given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that are within the scope of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, among others. Unless otherwise stated, positions designated as H or hydrogen are understood to mean hydrogen in its isotopic form, unless otherwise apparent from context. Thus, any atom not expressly designated as a particular isotope is meant to include all isotopes of that atom. Accordingly, any atom explicitly indicated as deuterium (D) is meant to include deuterium.

[0064] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the application of the active ingredients to the body in a form that can be absorbed by the body's biological systems. BRIEF DESCRIPTION OF DRAWINGS

[0065] Figure 1 Figure 5: Compound D5 (37) improves histological features of NASH mice: (A) Experimental procedure of NASH model; (B) Appearance of liver; (C) NAS score; (D) HE staining of liver sections, steatosis (red arrow), lobular inflammation (blue arrow) and hepatocellular ballooning (green arrow), scale bar: 100 pm; (E) NAFLD activity score. Data were analyzed by one-way ANOVA and Tukey's multiple-comparison post hoc test (n = 6), *P < 0.05, **P < 0.01, ***P < 0.001 vs. model group.

[0066] Figure 2 Figure 5: Compound D5 (37) improves histological features of NASH mice: (A) Experimental procedure of NASH model; (B) Appearance of liver; (C) NAS score; (D) HE staining of liver sections, steatosis (red arrow), lobular inflammation (blue arrow) and hepatocellular ballooning (green arrow), scale bar: 100 pm; (E) NAFLD activity score. Data were analyzed by one-way ANOVA and Tukey's multiple-comparison post hoc test (n = 6), *P < 0.05, **P < 0.01, ***P < 0.001 vs. model group. DETAILED DESCRIPTION

[0067] The application will be further described in conjunction with the following examples. It should be noted that the following examples are intended to be illustrative only and are not intended to limit the present application. Various modifications of the examples within the scope of the present application are intended to be within the scope of the claims.

[0068] Synthetic routes for the preparation of the compounds of the present application:

[0069] Synthetic Route 1:

[0070]

[0071] Reagents and conditions: (a) (3-carboxylic acid methyl ester-5-nitrobenzene boronic acid, sodium carbonate, tetrakis(triphenylphosphine)palladium, 1,4-dioxane / water, 80 °C, 18 h; (b) 5% palladium on carbon, dichloromethane / methanol, room temperature, 12 h; (c) benzoic acid / p- toluic acid, dichlorosulfide, N,N-dimethylformamide, dichloromethane, room temperature, 2 h; (d) 4-diaminopyridine, triethylamine, dichloromethane, 0 °C, 12 h; (e) lithium hydroxide monohydrate, tetrahydrofuran / methanol / water, room temperature, overnight.

[0072] Dissolve 3-carboxymethyl ester-5-nitrophenylboronic acid (1.0 equiv) and bromobenzene (1.5 equiv) in advance in a 1,4-dioxane / water (9:1, v / v) mixed solvent (15 mL), and sequentially add sodium carbonate (3.0 equiv), tetrakis(triphenylphosphine)palladium (0.05 equiv), and stir under N2protection at 80°C for 18 h in an oil bath. After the reaction is completed, cool to room temperature, and filter under reduced pressure. Dry the filtrate by rotary evaporation, extract, combine the organic phases, and make into a silica gel slurry, and then purify by column chromatography to obtain white solid 1a, which is then dissolved in a dichloromethane / methanol (1:1, v / v) mixed solvent (15 mL), and 5% Pd / C (10%) is added and replaced with hydrogen gas three times, and stirred at room temperature for 12 h. After the reaction is completed, filter with the aid of celite, and concentrate under vacuum to obtain intermediate 1b. Dissolve 4-methylbenzoic acid (1 equiv) in anhydrous dichloromethane (10 mL), and slowly add thionyl chloride (3 equiv) dropwise, and then add about 5 drops of N,N-dimethylformamide (0.1 equiv) as a catalyst, and react at room temperature for 2 h. After confirming that the reaction is complete, remove the solvent by distillation under reduced pressure, add dichloromethane, and distill under reduced pressure, and repeat the operation three times or more to completely remove the residual thionyl chloride as much as possible to obtain a chlorinated crude product for use. Dissolve 1b (1 equiv) in a dichloromethane solution (15 mL) containing triethylamine (3.0 equiv) and 4-diaminopyridine (0.1 equiv) in advance, and then add a dichloromethane solution of the above crude product dropwise under ice bath conditions. After the dropwise addition is completed, remove the ice bath, add calcium chloride to a drying tube, and maintain a dry environment, and react at room temperature for 12 h. After the reaction is completed, quench by adding saturated sodium bicarbonate solution, and remove the solvent by distillation under reduced pressure, dilute with water (10 mL), adjust the pH to weak alkaline, extract with ethyl acetate (20 mL X 3), combine the organic phases, wash with saturated brine (20 mL X 3), dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify by column chromatography to obtain 1d. Finally, dissolve 1d (1 equiv) in a tetrahydrofuran / methanol / water (3:3:1) mixed solvent (20 mL), and add lithium hydroxide monohydrate (1.5 equiv), and react at room temperature for 4 h. Dry the solvent by rotary evaporation, add dilute hydrochloric acid dropwise, adjust the pH to 3-4, and precipitate a white solid, filter, and dry to obtain the target compound 1. The synthesis methods of compounds 2-9 and compounds 13-19 are similar.

[0073] Synthesis Route 2:

[0074]

[0075] Reagents and conditions: (a) halogenated hydrocarbon, potassium carbonate, potassium iodide, acetonitrile, 65 °C, 6 h; (b) 3-carboxylic acid methyl ester-5-nitrobenzeneboronic acid, sodium carbonate, tetrakis(triphenylphosphine)palladium, 1,4-dioxane / water, 80 °C, 18 h; (c) 5% palladium on carbon, dichloromethane / methanol, room temperature, 12 h; (d) benzoic acid / 3-phenoxybenzoic acid, oxalyl chloride, N,N-dimethylformamide, dichloromethane, room temperature, 4 h; (e) 4-diaminopyridine, triethylamine, dichloromethane, 0 °C, 12 h; (f) lithium hydroxide monohydrate, tetrahydrofuran / methanol / water, room temperature, overnight.

[0076] To a solution of commercially available p- / m-bromophenol (1 equiv) in acetonitrile (15 mL) was added successively the corresponding halide (1.5 equiv), K2CO3(3 equiv) and catalyst KI (0.1 equiv). The mixture was stirred at 65 °C for 6 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude 17a, which was purified by column chromatography and dissolved in a mixture of 1,4-dioxane / H2O (9:1, v / v) (20 mL). 3-carboxymethyl ester-5-nitrobenzeneboronic acid (1.5 equiv), Na2CO3(3.0 equiv), and Pd(PPh3)4(0.05 equiv) were added successively. The mixture was stirred at 80 °C under N2atmosphere for 18 h. After the reaction was completed, the mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography to give 17b. 17b was dissolved in a mixture of dichloromethane / methanol (1:1, v / v) (20 mL) and 5% Pd / C (10%) was added. The mixture was stirred under hydrogen atmosphere for 12 h. After the reaction was completed, the mixture was filtered and concentrated under vacuum to give 17c. Benzoic acid or m-phenoxybenzoic acid (1 equiv) was dissolved in dichloromethane (15 mL) and oxalyl chloride (3 equiv) was added dropwise under ice bath condition with the help of a constant pressure funnel. After the addition was completed, a few drops of N,N-dimethylformamide (0.1 equiv) was added slowly to catalyze the reaction. A large amount of bubbles was observed. After the bubbles disappeared, the ice bath was removed and a drying tube was added. The mixture was stirred at room temperature for 2 h. After the benzoic acid was completely chlorinated, the mixture was distilled under reduced pressure to remove the solvent. The residue was dissolved in dichloromethane (15 mL) and distilled under reduced pressure. The above procedure was repeated for 3 times to remove the residual oxalyl chloride completely. Chlorinated crude was obtained and used directly. Half of 17c (1 equiv) was dissolved in dichloromethane (15 mL) and triethylamine (3.0 equiv) and 4-diaminopyridine (0.1 equiv) were added successively. The chlorinated crude in dichloromethane was added dropwise under ice bath condition with the help of a constant pressure funnel. After the addition was completed, the ice bath was removed and calcium chloride was added. The mixture was stirred at room temperature for 12 h. After the reaction was completed, the mixture was quenched with saturated NaHCO3solution. The mixture was distilled under reduced pressure to remove the solvent. The residue was diluted with water (10 mL) and the pH was adjusted to weak alkaline. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated NaCl solution (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give 17d. Finally, 17d was dissolved in a mixture of THF / CH3OH / H2O (3:3:1) (20 mL) and LiOH-H2O (1.5 equiv) was added. The mixture was stirred at room temperature for 4 h. The solvent was concentrated under reduced pressure. The pH was adjusted to 3-4 with dilute hydrochloric acid. White solid was precipitated and collected by filtration to give compound 10, compounds 11-12 and 30-37. The preparation methods of compounds 13-15 and 18-29 were similar to the above.

[0077] Synthesis route 3:

[0078]

[0079] Reagents and conditions: (a) corresponding substituted phenylboronic acid, sodium carbonate, tetrakis(triphenylphosphine)palladium, 1,4-dioxane / water, 80 °C, 18 h; (b) substituted benzoic acid / benzenesulfonic acid, oxalyl chloride, N,N-dimethylformamide, dichloromethane, room temperature, 4 h; (c) 4-diaminopyridine, triethylamine, dichloromethane, 0 °C, 12 h; (d) lithium hydroxide monohydrate, tetrahydrofuran / methanol / water, room temperature, overnight.

[0080] Methyl 3-amino-5-bromobenzoate (1 equiv) was dissolved in a 1,4-Dioxane / H2O (9:1, v / v) mixed solvent (20 mL) with corresponding substituted phenylboronic acid (1.5 equiv), Na2CO3(3.0 equiv), Pd(PPh3)4(0.05 equiv) was added successively, heated to 80 °C in an oil bath under nitrogen protection for 18 h, after the reaction was completed, cooled to room temperature, diatomite assisted filtration, the bright yellow filtrate was collected, rotary evaporation under reduced pressure, to obtain intermediates 38-41a. The synthesis method after the key intermediates 1c and 38-41a is the same as the subsequent synthesis steps after 17-25c, to finally obtain the target compounds compound 20-29 and compound 38-41.

[0081] Example 1

[0082] 5-(4-methylbenzamido)-[1,1'-biphenyl]-3-carboxylic acid (1)

[0083]

[0084] 3-carboxymethyl ester-5-nitrobenzoic acid (1.0 equiv) and bromobenzene (1.5 equiv) were dissolved in a 1,4-dioxane / water (9:1, v / v) mixed solvent (15 mL), and sodium carbonate (3.0 equiv), tetrakis(triphenylphosphine)palladium (0.05 equiv) were sequentially added. The reaction was stirred for 18 h at 80 °C under an N2 atmosphere. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was extracted and purified by column chromatography to obtain 1a as a white solid. The obtained 1a was dissolved in a dichloromethane / methanol (1:1, v / v) mixed solvent (15 mL), and 5% Pd / C (10%) was added. The mixture was replaced with hydrogen gas three times and reduced at room temperature for 12 h. After the reaction was completed, the mixture was filtered with the aid of celite, and the filtrate was evaporated under vacuum to obtain an intermediate 1b. 4-Methylbenzoic acid (1 equiv) was dissolved in anhydrous dichloromethane (10 mL), and thionyl chloride (3 equiv) was slowly added dropwise. After the addition, 5 drops or less of N,N-dimethylformamide (0.1 equiv) were added as a catalyst, and the reaction was allowed to proceed at room temperature for 2 h. After confirming that the reaction was completed, the solvent was distilled off under reduced pressure. Dichloromethane was added and distilled off under reduced pressure, and the above operation was repeated three times or more to remove residual thionyl chloride as much as possible, thereby obtaining a chlorinated crude product. The obtained 1b (1 equiv) was dissolved in a dichloromethane solution (15 mL) containing triethylamine (3.0 equiv) and 4-diaminopyridine (0.1 equiv), and then a dichloromethane solution of the above crude product was added dropwise under ice bath conditions. After the addition was completed, the ice bath was removed, calcium chloride was added to a drying tube, and the reaction was allowed to proceed at room temperature for 12 h. After the reaction was completed, the reaction was quenched by adding a saturated sodium bicarbonate solution, the solvent was evaporated, water (10 mL) was added, the pH was adjusted to a weak alkaline state, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with saturated brine (20 mL x 3), dried with anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography to obtain 1d. Finally, 1d (1 equiv) was dissolved in a tetrahydrofuran / methanol / water (3:3:1) mixed solvent (20 mL), and lithium hydroxide monohydrate (1.5 equiv) was added. The reaction was allowed to proceed at room temperature for 4 h, the solvent was evaporated, dilute hydrochloric acid was added dropwise, the pH was adjusted to 3-4, and a white solid was precipitated. The solid was filtered and dried to obtain the target compound. Yield: 60.3%, white powder. 1 HNMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.37 (s, 1H), 8.25 (s, 1H), 7.97 (d, J = 7.9 Hz, 3H), 7.66 (d, J = 7.6 Hz, 2H), 7.48 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.33 (d, J = 7.9 Hz, 2H), 2.38 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 169.14, 165.35, 141.53, 140.39, 139.62, 139.26, 131.98, 128.94, 128.87, 127.77, 127.41, 126.59, 122.86, 120.79, 20.99. TOF-MS m / z: calcd for: C 21 H 16 NO3 - [M-H] - : 330.1135, found: 330.1131.

[0085] Example 2

[0086]

[0087] 3-(4-methylbenzamide)-5-(tetrahydrofuran-3-yl)benzoic acid (2)

[0088] Synthesis method is the same as compound 1. Yield: 68.6%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.30 (s, 1H), 7.96 (s, 1H), 7.92 (d, J = 7.8 Hz, 2H), 7.59 (s, 1H), 7.34 (d, J = 7.9 Hz, 2H), 4.06 (t, J = 7.9 Hz, 1H), 4.02 - 3.91 (m, 1H), 3.81 (q, J = 7.8 Hz, 1H), 3.59 (t, J = 7.7 Hz, 1H), 3.52 - 3.40 (m, 1H), 2.39 (s, 3H), 2.35 - 2.21 (m, 1H), 2.01 - 1.82 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 168.11, 165.83, 144.03, 142.17, 139.95, 132.24, 129.37, 128.17, 123.73, 123.08, 119.86, 74.24, 68.10, 44.53, 34.48, 21.47. TOF-MS m / z: calcd for: C 19 H 18 NO4 - [M-H] - : 324.1241, found: 324.1247.

[0089] Example 3

[0090] 3-(Furan-3-yl)-5-(4-methylbenzamido)benzoic acid (3)

[0091]

[0092] Synthesis method is the same with compound 1. Yield: 69.4%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 10.44 (s, 1H), 8.40 (s, 1H), 8.31 (s, 2H), 7.99 (d, J = 7.9 Hz, 2H), 7.94 (s, 1H), 7.86 (s, 1H), 7.42 (d, J = 7.8 Hz, 2H), 6.99 (s, 1H), 2.45 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 167.61, 165.95, 145.10, 142.32, 140.44, 140.25, 133.11, 132.36, 132.11, 129.44, 128.19, 125.70, 121.96, 121.91, 120.28, 109.09, 21.49. TOF-MS m / z: calcd for: C 19 H 14 NO4 - [M-H] - : 320.0928, found: 320.0929.

[0093] Example 4

[0094] 3-(4-Methylbenzamido)-5-(thiazol-4-yl)benzoic acid (4)

[0095]

[0096] Synthesis method is the same with compound 1. Yield: 69.4%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 10.44 (s, 1H), 8.40 (s, 1H), 8.31 (s, 2H), 7.99 (d, J = 7.9 Hz, 2H), 7.94 (s, 1H), 7.86 (s, 1H), 7.42 (d, J = 7.8 Hz, 2H), 6.99 (s, 1H), 2.45 (s, 3H). 13CNMR (101 MHz, DMSO-d6) δ 167.55, 166.01, 155.32, 154.58, 142.32, 140.53, 135.11, 132.29, 132.03, 129.41, 128.29, 122.58, 122.44, 121.20, 115.76, 21.49. TOF-MS m / z: calcd for: C 18 H 13 N2O3S - [M-H] - : 337.0652, found: 337.0649.

[0097] Example 5

[0098] 3-(4-methylbenzamide)-5-(thiazol-5-yl)benzoic acid (5)

[0099]

[0100] Synthesis method same as compound 1. Yield: 68.1%, white powder. 1 H NMR (400 MHz, DMS0-d6) δ 10.54 (s, 1H), 9.15 (s, 1H), 8.46 (s, 1H), 8.38 (s, 1H), 8.33 (s, 1H), 7.96 (d, J = 7.9 Hz, 3H), 7.36 (d, J = 7.9 Hz, 2H), 2.40 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 166.05, 154.51, 142.38, 140.67, 140.06, 138.60, 132.00, 131.46, 129.42, 128.28, 122.52, 122.00, 121.43, 21.50. TOF-MS m / z: calcd for: C 18 H 13 N2O3S - [M-H] - : 337.0652, found: 337.0664.

[0101] Example 6

[0102] 3-(1H-imidazol-1-yl)-5-(4-methylbenzamide)benzoic acid (6)

[0103]

[0104] Synthesis method same as compound 1. Yield: 63.3%, white powder.1 H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 10.55 (s, 1H), 8.54 (t, J = 1.7 Hz, 1H), 8.19 - 8.08 (m, 2H), 7.93 - 7.83 (m, 2H), 7.63 (t, J = 1.7 Hz, 1H), 7.41 (s, 1H), 7.36 (t, J = 7.7 Hz, 3H), 2.40 (d, J = 9.9 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 181.80, 166.40, 143.86, 142.10, 140.21, 138.71, 133.69, 131.39, 129.75, 129.02, 127.78, 127.31, 121.03, 120.87, 120.48, 21.27. TOF-MS m / z: calcd for: C 18 H 14 N3O3 - [M-H] - : 320.1040, found: 320.1038.

[0105] Example 7

[0106] 3-(1 -Methyl- 1 H-pyrazol-5-yl)-5-(4-methylbenzamido)benzoic acid (7)

[0107]

[0108] Synthesis method same as compound 1. Yield: 65.8%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.55 (t, J = 1.7 Hz, 1H), 8.28 (t, J = 1.8 Hz, 1H), 7.96 (d, J = 7.9 Hz, 2H), 7.76 (d, J = 1.5 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.34 (d, J = 7.9 Hz, 2H), 6.50 (d, J = 1.9 Hz, 1H), 3.91 (s, 3H), 2.38 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 167.25, 166.16, 142.41, 142.34, 140.46, 138.49, 132.33, 131.96, 131.06, 129.42, 128.32, 124.34, 121.23, 106.55, 38.08, 21.49. TOF-MS m / z: calcd for: C19 H 16 N3O3 - [M-H] - : 334.1197, found: 334.1204.

[0109] Example 8

[0110] 3-(5-(Hydroxymethyl)thiophen-3-yl)-5-(4-methylbenzamido)benzoic acid (8)

[0111]

[0112] Synthesis method same as compound 1. Yield: 66.7%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 10.52 (s, 1H), 8.57 (t, J = 1.6 Hz, 1H), 8.48 (d, J = 1.9 Hz, 1H), 8.02 - 7.93 (m, 3H), 7.84 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 7.9 Hz, 2H), 7.30 (d, J = 7.9 Hz, 1H), 2.40 (s, 3H), 2.37 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 167.75, 167.51, 166.08, 143.47, 142.40, 140.87, 140.17, 132.55, 132.08, 129.78, 129.57, 129.45, 128.49, 128.24, 122.67, 122.61, 120.85, 56.49, 21.59. TOF-MS m / z: calcd for: C 20 H 16 NO4S - [M-H] - : 366.0805, found: 366.0812.

[0113] Example 9

[0114] 3-(Benzothiophen-3-yl)-5-(4-methylbenzamido)benzoic acid (9)

[0115]

[0116] Synthesis method same as compound 1. Yield: 68.1%, white powder. 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.54 (s, 1H), 8.39 (s, 1H), 8.11 (d, J = 7.6 Hz, 1H), 8.02 - 7.93 (m, 4H), 7.89 (s, 1H), 7.56 - 7.42 (m, 2H), 7.36 (d, J = 7.9 Hz, 2H), 2.39 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 167.51, 166.13, 142.36, 140.68, 140.50, 137.38, 136.47, 136.21, 132.36, 132.10, 129.43, 128.28, 125.96, 125.33, 125.19, 124.52, 124.43, 123.84, 122.71, 120.67, 21.50. TOF-MS m / z: calcd for: C 23 H 16 NO3S - [M-H] - : 386.0856, found: 386.0871.

[0117] Example 10

[0118] 5-benzoylamino-4'-methoxy-[l,l'-biphenyl]-3-carboxylic acid (10)

[0119]

[0120] To a solution of commercially available p-bromophenol (1 equiv) in acetonitrile (15 mL) was added successively iodomethane (1.5 equiv) and K2CO3(3 equiv) and the mixture was stirred at 65 °C for 6 h. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude 17a, which was purified by column chromatography and dissolved in a mixture of 1,4-dioxane / H2O (9:1, v / v) (20 mL). Then 3-carboxylic acid methyl ester-5-nitrobenzoic acid (1.5 equiv), Na2CO3(3.0 equiv), and Pd(PPh3)4(0.05 equiv) were added successively and the mixture was heated at 80 °C under N2for 18 h. After the reaction was completed, the mixture was cooled to room temperature, filtered with the aid of celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 17b, which was dissolved in a mixture of dichloromethane / methanol (1:1, v / v) (20 mL) and 5% Pd / C (10%) was added. The mixture was stirred under hydrogen atmosphere for 12 h at room temperature. After the reaction was completed, the mixture was filtered and concentrated under vacuum to give 17c. Benzoic acid (1 equiv) was dissolved in dichloromethane (15 mL) and oxalyl chloride (3 equiv) was added dropwise with the aid of a constant pressure dropping funnel under ice bath. After the addition was completed, a few drops of N,N-dimethylformamide (0.1 equiv) were added slowly to catalyze the reaction. A large amount of gas bubbles was observed. After the gas bubbles disappeared, the ice bath was removed and a drying tube was added. The mixture was stirred at room temperature for 2 h. After the benzoic acid was completely chlorinated, the mixture was distilled under reduced pressure and the solvent was removed by evaporation. Dichloromethane (15 mL) was added and the mixture was distilled under reduced pressure. This operation was repeated three times to remove the residual oxalyl chloride completely. The chlorinated crude product was used as is. 17c (1 equiv) was dissolved in dichloromethane (15 mL) and triethylamine (3.0 equiv) and 4-diaminopyridine (0.1 equiv) were added successively. The chlorinated crude product (1.5 equiv) was added dropwise under ice bath to induce amide condensation. After the mixture was stirred at room temperature for 12 h, saturated NaHCO3solution was added to quench the reaction. The solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography to give 17d. Finally, 17d was dissolved in a mixture of THF / CH3OH / H2O (3:3:1) (20 mL) and LiOH-H2O (1.5 equiv) was added. The mixture was stirred at room temperature for 4 h. The solvent was removed by evaporation and diluted HCl was added dropwise to adjust the pH to 3-4. White solid was precipitated and collected by filtration to give compound 10. Yield: 73.5%, white powder. 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 10.51 (s, 1H), 8.49 (t, J = 1.7 Hz, 1H), 8.34 (t, J = 1.9 Hz, 1H), 8.05 - 7.99 (m, 2H), 7.92 (t, J = 1.6 Hz, 1H), 7.65 - 7.52 (m, 3H), 7.43 (t, J = 7.9 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.18 (t, J = 2.1 Hz, 1H), 7.03 - 6.97 (m, 1H), 3.84 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 166.91, 165.54, 159.64, 140.68, 140.60, 139.79, 134.34, 131.71, 131.61, 130.04, 128.25, 127.50, 122.51, 122.41, 119.94, 118.86, 113.40, 111.98, 55.02. TOF-MS m / z: calcd for: C 21 H 16 NO4 - [M-H] - : 346.1084, found: 346.1086.

[0121] Example 11

[0122] 5-benzoylamino-3'-methoxy-[l,l'-biphenyl]-3-carboxylic acid (11)

[0123]

[0124] Synthesis method same as compound 17. Yield: 77.8%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 10.51 (s, 1H), 8.49 (t, J = 1.7 Hz, 1H), 8.34 (t, J = 1.9 Hz, 1H), 8.05 - 7.99 (m, 2H), 7.92 (t, J = 1.6 Hz, 1H), 7.65 - 7.52 (m, 3H), 7.43 (t, J = 7.9 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.18 (t, J = 2.1 Hz, 1H), 7.03 - 6.97 (m, 1H), 3.84 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 166.71, 165.34, 159.43, 140.48, 140.40, 139.58, 134.14, 131.53, 131.40, 129.83, 128.04, 127.29, 122.29, 122.21, 119.74, 118.66, 113.19, 111.78, 54.81. TOF-MS m / z: calcd for: C 21 H 16 NO4 - [M-H] - : 346.1084, found: 346.1088.

[0125] Example 12

[0126] 5-benzoylamino-3'-ethoxy-[l,l'-biphenyl]-3-carboxylic acid (12)

[0127]

[0128] Synthesis method same as compound 17. Yield: 68.3%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 10.49 (s, 1H), 8.42 (t, J = 1.7 Hz, 1H), 8.33 (t, J = 1.9 Hz, 1H), 8.06 - 7.99 (m, 2H), 7.88 (t, J = 1.6 Hz, 1H), 7.63 - 7.48 (m, 5H), 7.10 - 7.02 (m, 2H), 4.08 (q, J = 6.9 Hz, 2H), 1.35 (t, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 167.20, 165.72, 158.57, 140.57, 139.99, 134.59, 132.85, 131.85, 131.79, 131.47, 129.25, 128.55, 128.45, 127.81, 127.71, 122.04, 119.34, 115.01, 63.15, 14.66. TOF-MS m / z: calcd for: C 22 H 18 NO4 - [M-H] - : 360.1241, found: 360.1237.

[0129] Example 13

[0130] 5-benzoylamino-4'-methoxy-3'-methyl-[l,l'-biphenyl]-3-carboxylic acid (13)

[0131]

[0132] Synthesis method is the same as compound 1. Yield: 71.6%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 10.47 (s, 1H), 8.42 (t, J = 1.7 Hz, 1H), 8.31 (t, J = 1.9 Hz, 1H), 8.05 - 7.99 (m, 2H), 7.97 - 7.93 (m, 1H), 7.89 (t, J = 1.6 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.58 - 7.55 (m, 1H), 7.50 - 7.47 (m, 2H), 7.09 - 7.04 (m, 1H), 3.84 (s, 3H), 2.24 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 167.31, 167.25, 165.71, 157.44, 140.71, 139.95, 134.60, 132.85, 131.79, 131.16, 130.76, 129.26, 128.66, 128.56, 128.45, 127.70, 126.29, 125.25, 122.05, 119.27, 110.82, 55.39, 16.15. TOF-MS m / z: calcd for: C 22 H 18 NO4 - [M-H] - : 360.1241, found: 360.1244.

[0133] Example 14

[0134] 5-benzoylamino-4'-methoxy-3'-methyl-[l,l'-biphenyl]-3-carboxylic acid (13)

[0135]

[0136] Synthesis method is the same as compound 1. Yield: 71.6%, white powder. 1H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 10.51 (s, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.06 - 7.99 (m, 2H), 7.93 (s, 1H), 7.66 - 7.58 (m, 3H), 7.58 - 7.48 (m, 4H), 3.47 - 3.30 (m, 1H), 1.32 - 1.31 (m, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 167.19, 165.78, 150.54, 140.75, 140.06, 136.44, 134.62, 131.93, 131.81, 128.46, 127.73, 126.37, 125.94, 122.34, 119.83, 34.32, 31.10. TOF-MS m / z: calcd for: C 23 H 20 NO3 - [M-H] - : 358.1448, found: 358.1450.

[0137] Example 15

[0138] 5-benzoylamino-4'-(tert-butyl)-[1,1'-biphenyl]-3-carboxylic acid (15)

[0139]

[0140] Synthesis method same as compound 1. Yield: 77.6%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 10.54 (s, 1H), 8.45 (t, J = 1.7 Hz, 1H), 8.38 (t, J = 1.9 Hz, 1H), 8.06 - 8.00 (m, 2H), 7.92 (t, J = 1.6 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.58 - 7.51 (m, 4H), 1.32 (s, 9H). 13 C NMR (101 MHz, DMSO-d6) δ 167.17, 165.76, 150.53, 140.71, 140.04, 136.42, 134.59, 131.93, 131.79, 128.45, 127.73, 126.36, 125.93, 122.35, 122.30, 119.83, 34.32, 31.09. TOF-MS m / z: calcd for: C 24 H 22 NO3- [M-H] - : 372.1605, found: 372.1596.

[0141] Example 16

[0142] 5-benzoylamino-4'-fluoro-[l,l'-biphenyl]-3-carboxylic acid (16)

[0143]

[0144] Synthesis method is the same with compound 1. Yield: 69.8%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 10.51 (s, 1H), 8.45 (t, J = 1.7 Hz, 1H), 8.34 (t, J = 1.9 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.89 (t, J = 1.6 Hz, 1H), 7.75 - 7.68 (m, 2H), 7.64 - 7.58 (m, 1H), 7.58 - 7.52 (m, 2H), 7.39 - 7.29 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 166.87, 165.55, 163.15, 160.72, 139.86, 139.70, 135.66, 135.63, 134.32, 131.81, 131.62, 128.63, 128.54, 128.26, 127.50, 122.29, 119.78, 115.88, 115.66. TOF-MS m / z: Calcd for: C 20 H 13 FNO3 - [M-H] - : 334.0884, found: 334.0872.

[0145] Example 17

[0146] 5-benzoylamino-4'-fluoro-[l,l'-biphenyl]-3-carboxylic acid (16)

[0147]

[0148] Synthesis procedure as for compound 1. Yield: 73.1%, white powder.1H NMR (400 MHz, DMSO d6) δ 13.03 (s, 1H), 10.52 (s, 1H), 8.50 (t, J = 1.7 Hz, 1H), 8.38 (t, J = 1.9 Hz, 1H), 8.06 - 7.98 (m, 2H), 7.94 (t, J = 1.6 Hz, 1H), 7.65 - 7.46 (m, 6H), 7.31 - 7.22 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 167.00, 165.76, 163.91, 161.49, 141.88, 141.80, 140.12, 139.57, 134.49, 132.08, 131.86, 131.19, 131.10, 128.48, 127.71, 122.89, 122.87, 122.69, 122.65, 120.53, 114.87, 114.66, 113.59, 113.37. TOF-MS m / z: calcd for: C 20 H 13 FNO3 - [M-H] - : 334.0884, found: 334.0874.

[0149] Example 18

[0150] 5-benzoylamino-3'-chloro-[1,1'-biphenyl]-3-carboxylic acid (18)

[0151]

[0152] Synthesis procedure as for compound 1. Yield: 75.6%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 10.52 (s, 1H), 8.57 - 8.44 (m, 1H), 8.38 (s, 1H), 8.06 - 7.98 (m, 2H), 7.94 (s, 1H), 7.73 - 7.63 (m, 2H), 7.61 (d, J = 7.1 Hz, 1H), 7.59 - 7.51 (m, 3H), 7.51 - 7.40 (m, 1H). 13CNMR (101 MHz, DMSO-d6) δ 167.03, 165.78, 141.51, 140.17, 139.37, 134.49, 133.91, 132.13, 131.89, 131.03, 129.17, 128.49, 127.73, 126.75, 126.48, 125.51, 122.64, 120.55. TOF-MS m / z: calcd for: C 20 H 13 CINO3 - [M-H] - : 350.0589, found: 350.0593.

[0153] Example 19

[0154] 5-benzoylamino-3'-hydroxy-[l,l'-biphenyl]-3-carboxylic acid (19)

[0155]

[0156] Synthesis method same as compound 1. Yield: 69.4%, off-white powder. 1 H NMR (400 MHz, DMSO-d6) δ 13.08 (s, 1H), 10.50 (s, 1H), 9.63 (s, 1H), 8.45 (t, J = 1.7 Hz, 1H), 8.36 (t, J = 1.9 Hz, 1H), 8.08 - 7.99 (m, 2H), 7.88 (d, J = 1.6 Hz, 1H), 7.65 - 7.53 (m, 3H), 7.32 (t, J = 7.8 Hz, 1H), 7.17 - 7.05 (m, 2H), 6.86 - 6.80 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 167.13, 165.77, 157.98, 140.98, 140.67, 140.03, 134.58, 131.84, 130.22, 128.47, 127.72, 122.41, 119.96, 117.38, 115.06, 113.44. TOF-MS m / z: calcd for: C 20 H 14 NO4 - [M-H] - : 332.0928, found: 332.0940.

[0157] Example 20

[0158] 5-(cyclohexanecarboxamide)-[l,l'-biphenyl]-3-carboxylic acid (20)

[0159]

[0160] Intermediate 1c was condensed with cyclohexanecarboxylic acid to give 28d, which was hydrolyzed to give the target compound 20. Yield: 67.7%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 10.12 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 7.83 (s, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.49 (t, J = 7.6 Hz, 2H), 7.40 (t, J = 7.1 Hz, 1H), 2.36 (t, J = 11.4 Hz, 1H), 1.83 (d, J = 12.4 Hz, 2H), 1.76 (d, J = 12.4 Hz, 2H), 1.65 (d, J = 11.0 Hz, 1H), 1.42 (q, J = 12.2 Hz, 2H), 1.32 - 1.16 (m, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 174.69, 167.09, 140.95, 140.31, 139.42, 131.93, 129.09, 127.93, 126.66, 121.82, 121.32, 118.85, 44.92, 29.07, 25.38, 25.18. TOF-MS m / z: calcd for: C 20 H 20 NO3 - [M-H] - : 322.1448, found: 322.1445.

[0161] Example 21

[0162] 5-(2-Methylbenzamido)-[l,l'-biphenyl]-3-carboxylic acid (21)

[0163]

[0164] Intermediate 1c was condensed with o-toluc acid to give 29d, which was hydrolyzed to give the target compound 21. Yield: 70.1%, white powder. 1H MR (400 MHz, DMSO-d6) δ 13.08 (s, 1 H), 10.57 (s, 1 H), 8.43 (s, 1 H), 8.28 (s, 1 H), 7.92 (s, 1 H), 7.66 (d, J = 7.5 Hz, 2 H), 7.52 (t, J = 7.6 Hz, 3 H), 7.42 (dd, J = 10.6, 7.1 Hz, 2 H), 7.36 - 7.28 (m, 2 H), 2.42 (s, 3 H). 13 CNMR (101 MHz, DMSO-d6) δ 168.14, 167.09, 141.01, 140.11, 139.35, 135.41, 132.05, 130.59, 129.83, 129.13, 127.99, 127.29, 126.69, 125.65, 122.46, 121.96, 119.40, 19.34. TOF-MS m / z: calcd for: C 21 H 16 NO3 - [M-H] - : 330.1135, found: 330.1147.

[0165] Example 22

[0166] 5-(3-Methylbenzamido)-[1,1 '-biphenyl]-3-carboxylic acid (22)

[0167]

[0168] Intermediate 1c was condensed with m-toluic acid to give 30d, which was hydrolyzed to give the target compound 22. Yield: 58.5%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1 H), 8.47 (s, 1 H), 8.38 (s, 1 H), 7.94 (s, 1 H), 7.88 - 7.80 (m, 2 H), 7.71 - 7.66 (m, 2 H), 7.54 - 7.48 (m, 2 H), 7.45 - 7.39 (m, 3 H), 2.41 (s, 3 H). 13 C NMR (101 MHz, DMSO-d6) δ 167.45, 165.89, 140.83, 140.10, 139.54, 137.82, 134.61, 132.85, 132.43, 129.20, 128.42, 128.26, 128.02, 126.78, 125.00, 122.58, 122.34, 120.11, 21.05. TOF-MS m / z: calcd for: C21 H 16 NO3 - [M-H] - : 330.1135, found: 330.1139.

[0169] Example 23

[0170] 5-(4-(tert-butyl)benzamido)-[1,1'-biphenyl]-3-carboxylic acid (23)

[0171]

[0172] Condensation of intermediate 1c with 4-tert-butylbenzoic acid gave 31d, which upon hydrolysis afforded the target compound 23. Yield: 66.5%, white powder. 1 H NMR (400 MHz, Chloroform-d) δ 8.45 (s, 1H), 8.13 (dd, J = 3.9, 1.5 Hz, 1H), 8.09 - 7.97 (m, 3H), 7.86 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.51 - 7.44 (m, 3H), 7.42 - 7.37 (m, 1H), 1.35 (s, 9H). 13 C NMR (101 MHz, Chloroform-d) δ 171.28, 165.59, 157.39, 142.59, 138.65, 129.94, 128.74, 127.13, 126.76, 126.24, 125.72, 125.32, 119.93, 115.73, 35.02, 30.93. TOF-MS m / z: calcd for: C 24 H 22 NO3 - [M-H] - : 372.1605, found: 372.1621.

[0173] Example 24

[0174] 5-([1,1'-biphenyl]-3-carboxamido)-[1,1'-biphenyl]-3-carboxylic acid (24)

[0175]

[0176] Condensation of intermediate 1c with m-phenylbenzoic acid gave 32d, which upon hydrolysis afforded the target compound 24. Yield: 37.9%, white powder. 1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.49 - 8.25 (m, 2H), 8.05 - 7.85 (m, 3H), 7.72 (d, J = 38.6 Hz, 5H), 7.51 (s, 4H), 7.41 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 167.62, 166.21, 141.48, 140.87, 140.45, 139.91, 139.76, 135.63, 132.46, 130.51, 129.73, 129.65, 129.53, 128.54, 128.37, 127.39, 127.20, 126.29, 123.15, 120.60. TOF-MS m / z: calcd for: C 26 H 18 NO3 - [M-H] - : 392.1292, found: 392.1287.

[0177] Example 25

[0178] 5-(3-Phenoxybenzamido)-[l,l'-biphenyl]-3-carboxylic acid (25)

[0179]

[0180] Intermediate lc was condensed with 3-phenoxybenzoic acid to give 33d, which was hydrolyzed to give the target compound 25. Yield: 73.5%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 10.53 (s, 1H), 8.44 (t, J = 1.8 Hz, 1H), 8.36 (t, J = 1.9 Hz, 1H), 7.93 (d, J = 1.7 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 2.8 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.43 (q, J = 7.4, 6.9 Hz, 3H), 7.25 (dd, J = 8.1, 2.5 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 7.09 (d, J = 7.8 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 167.07, 164.86, 156.83, 156.28, 140.93, 139.86, 139.30, 136.37, 131.96, 130.20, 129.13, 128.01, 126.70, 123.87, 121.86, 120.09, 118.87, 117.64. TOF-MS m / z: calcd for: C 26 H 18 NO4 - [M-H] - : 408.1241, found: 408.1236.

[0181] Example 26

[0182] 5-(phenylsulfonamide)-[l,l'-biphenyl]-3-carboxylic acid (26)

[0183]

[0184] The target compound 26 was obtained by condensation of intermediate lc with phenylsulfonyl chloride and hydrolysis. Yield: 59.2%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 7.85 - 7.81 (m, 2H), 7.80 (d, J = 1.5 Hz, 1H), 7.72 - 7.66 (m, 1H), 7.63 - 7.58 (m, 1H), 7.56 (d, J = 7.5 Hz, 2H), 7.54 - 7.51 (m, 2H), 7.51 (s, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.1 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 167.36, 140.91, 139.51, 139.26, 138.53, 132.98, 129.34, 129.14, 127.96, 126.69, 126.59, 123.07, 121.05, 119.83. TOF-MS m / z: calcd for: C 19 H 14 NO4S - [M-H] - : 352.0649, found: 352.0653.

[0185] Example 27

[0186] 5-(4-methylphenyl)sulfonamide)-[l,l'-biphenyl]-3-carboxylic acid (27)

[0187]

[0188] Intermediate 1c was condensed with p-methylbenzenesulfonyl chloride to give 36d, which was hydrolyzed to give the target compound 27. Yield: 45.9%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 10.62 (s, 1H), 7.81 (t, J = 1.4 Hz, 1H), 7.74-7.69 (m, 2H), 7.69 (s, 1H), 7.59 (t, J = 1.8 Hz, 1H), 7.54 (d, J = 1.4 Hz, 1H), 7.52 (s, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.40 (t, J = 7.2 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 2.31 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 166.664, 143.60, 141.49, 138.87, 138.79, 136.37, 132.48, 129.86, 129.22, 128.22, 126.74, 126.65, 122.89, 121.80, 119.17, 20.95. TOF-MS m / z: calcd for: C 20 H 16 NO4S - [M-H] - : 366.0805, found: 366.0799.

[0189] Example 28

[0190] 5-((4-(trifluoromethoxy)phenyl)sulfonamido)-[1,1'-biphenyl]-3-carboxylic acid (28)

[0191]

[0192] Intermediate 1c was condensed with p-trifluoromethoxybenzenesulfonyl chloride to give 35d, which was hydrolyzed to give the target compound 28. Yield: 50.2%, yellow powder. 1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 10.75 (s, 1H), 7.95 - 7.89 (m, 2H), 7.86 (d, J = 1.5 Hz, 1H), 7.68 (t, 1H), 7.59 (s, 1H), 7.58 - 7.55 (m, 2H), 7.54 (t, J = 1.7 Hz, 1H), 7.53 (s, 1H), 7.51 - 7.45 (m, 2H), 7.43 - 7.38 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 166.54, 151.22, 141.69, 138.69, 138.33, 138.06, 132.62, 129.38, 129.21, 128.29, 126.68, 123.52, 122.55, 121.62, 119.88. TOF-MS m / z: calcd for: C 20 H 13 F3NO5S - [M-H] - : 436.0472, found: 436.0478.

[0193] Example 29

[0194] 5-((2,6-dichlorophenyl)sulfonamido)-[1,1'-biphenyl]-3-carboxylic acid (29)

[0195]

[0196] Intermediate 1c was condensed with 2,6-dichlorobenzenesulfonyl chloride to give 37d, which was hydrolyzed to give the target compound 29. Yield: 55.2%, yellow powder. 1 H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 7.81 (t, J = 1.5 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.66 (d, J = 1.0 Hz, 1H), 7.64 (s, 1H), 7.61 (t, J = 1.9 Hz, 1H), 7.58 - 7.45 (m, 5H), 7.41 (t, J = 7.1 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 166.51, 141.63, 138.68, 137.94, 134.59, 134.46, 133.46, 132.69, 132.02, 129.21, 128.29, 126.62, 122.76, 120.09, 117.98. TOF-MS m / z: calcd for: C 19 H12 Cl2NO4S - [M-H] - : 419.9869, found: 419.9858.

[0197] Example 30

[0198] 3'-Methoxy-5-(3-phenoxybenzamido)-[1,1'-biphenyl]-3-carboxylic acid (30)

[0199]

[0200] Synthesis method same as compound 17. Yield: 61.7%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 7.91 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.63 (s, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.42 (t, J = 7.8 Hz, 3H), 7.28 - 7.13 (m, 4H), 7.07 (d, J = 7.9 Hz, 2H), 6.99 (d, J = 8.1 Hz, 1H), 3.82 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 167.25, 165.10, 159.98, 157.00, 156.39, 141.00, 140.94, 139.90, 136.47, 132.05, 130.43, 130.37, 124.07, 122.98, 122.93, 122.81, 122.04, 120.41, 119.22, 119.03, 117.74, 113.75, 112.34, 55.37. TOF-MS m / z: calcd for: C 27 H 20 NO5 - [M-H] - : 438.1346, found: 438.1341.

[0201] Example 31

[0202] 3'-Ethoxy-5-(3-phenoxybenzamido)-[1,1'-biphenyl]-3-carboxylic acid (31)

[0203]

[0204] Synthesis procedure was same as compound 17. Yield: 57.9%, light yellow powder. 1H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.43 (s, 1H), 8.30 (s, 1H), 7.91 (s, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.63 (s, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.46 - 7.37 (m, 3H), 7.30 - 7.11 (m, 4H), 7.07 (d, J = 7.9 Hz, 2H), 6.96 (d, J = 8.0 Hz, 1H), 4.09 (q, J = 6.9 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 167.26, 165.09, 159.25, 157.00, 156.38, 140.97, 140.88, 139.89, 136.47, 132.08, 130.43, 130.37, 124.07, 122.93, 122.88, 122.80, 122.03, 120.37, 119.07, 119.03, 117.73, 114.17, 112.87, 63.33, 14.79. TOF-MS m / z: calcd for: C 28 H 22 NO5 - [M-H] - : 452.1503, found: 452.1518.

[0205] Example 32

[0206] 4'-Ethoxy-5-(3-phenoxybenzamido)-[1,1'-biphenyl]-3-carboxylic acid (32)

[0207]

[0208] Synthesis procedure was same as compound 17. Yield: 66.4%, white powder. 1H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 7.89 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.71 - 7.64 (m, 1H), 7.63 - 7.57 (m, 2H), 7.50 - 7.39 (m, 3H), 7.26 - 7.16 (m, 2H), 7.06 (dd, J = 16.7, 8.2 Hz, 4H), 4.07 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 167.22, 164.73, 158.47, 156.75, 156.26, 140.39, 139.65, 136.39, 131.49, 130.09, 127.70, 123.75, 122.62, 122.08, 121.89, 121.72, 119.46, 119.09, 118.77, 117.62, 114.96, 63.10, 14.55. TOF-MS m / z: calcd for: C 28 H 22 NO5 - [M-H] - : 452.1503, found: 452.1501.

[0209] Example 33

[0210] 5-(3-Phenoxybenzamido)-3'-propoxy-[l,l'-biphenyl]-3-carboxylic acid (33)

[0211]

[0212] Synthesis method same as compound 17. Yield: 59.6%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 7.91 (s, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.63 (s, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.45 - 7.37 (m, 3H), 7.27 - 7.13 (m, 4H), 7.07 (d, J = 7.9 Hz, 2H), 6.96 (d, J = 8.0 Hz, 1H), 3.98 (t, J = 6.4 Hz, 2H), 1.79 - 1.67 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H). 13CNMR (101 MHz, DMSO-d6) δ 167.25, 165.09, 159.42, 157.00, 156.38, 140.96, 140.86, 139.90, 136.47, 132.04, 130.42, 130.36, 124.06, 122.94, 122.87, 122.80, 122.03, 120.37, 119.06, 119.02, 117.74, 114.16, 112.91, 69.22, 22.23, 10.56. TOF-MS m / z: calcd for: C 29 H 24 NO5 - [M-H] - : 466.1659, found: 466.1647.

[0213] Example 34

[0214] 5-(3-Phenoxybenzamido)-4'-propoxy-[l,l'-biphenyl]-3-carboxylic acid (34)

[0215]

[0216] Synthesis method is same with compound 17. Yield: 66.9%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.41-8.27 (m, 2H), 7.88 (s, 1H), 7.85-7.79 (m, 1H), 7.68-7.64 (m, 1H), 7.63-7.54 (m, 3H), 7.47-7.41 (m, 2H), 7.28-7.15 (m, 2H), 7.11-7.01 (m, 4H), 3.96 (t, J = 6.5 Hz, 2H), 1.81-1.68 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13 CNMR (101 MHz, DMSO-d6) δ 167.25, 165.09, 159.42, 157.00, 156.38, 140.96, 140.86, 139.90, 136.47, 132.04, 130.42, 130.36, 124.06, 122.94, 122.87, 122.80, 122.03, 120.37, 119.06, 119.02, 117.74, 114.16, 112.91, 69.22, 22.23, 10.56. TOF-MS m / z: calcd for: C 29 H 24 NO5- [M-H] - : 466.1659, found: 466.1650.

[0217] Example 35

[0218] 3'-isobutoxy-5-(3-phenoxybenzamido)-[1,1'-biphenyl]-3-carboxylic acid (35)

[0219]

[0220] Synthesis method same as compound 17. Yield: 63.6%, light yellow powder. 1 H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.64-8.18 (m, 2H), 8.09-7.75 (m, 2H), 7.70-6.83 (m, 12H), 3.94-3.70 (m, 2H), 2.04 (s, 1H), 1.00 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 167.04, 164.80, 159.36, 156.78, 156.25, 140.73, 139.74, 136.35, 131.92, 130.17, 130.13, 129.07, 126.65, 123.81, 122.68, 122.64, 121.80, 120.16, 118.87, 118.80, 117.62, 113.97, 112.79, 73.81, 27.77, 19.01. TOF-MS m / z: calcd for: C 30 H 26 NO5 - [M-H] - : 480.1816, found: 480.1810.

[0221] Example 36

[0222] 4'-isobutoxy-5-(3-phenoxybenzamido)-[1,1'-biphenyl]-3-carboxylic acid (36)

[0223]

[0224] Synthesis method same as compound 17. Yield: 63.6%, light yellow powder. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.59 - 8.17 (m, 2H), 8.01 - 7.75 (m, 2H), 7.71 - 7.36 (m, 6H), 7.34 - 6.90 (m, 6H), 3.97 - 3.65 (m, 2H), 2.03 (s, 1H), 1.00 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 167.16, 164.77, 158.81, 156.79, 156.27, 140.50, 139.74, 136.40, 131.97, 131.42, 130.17, 130.14, 129.08, 127.73, 126.66, 123.82, 122.64, 122.09, 122.01, 121.80, 119.41, 118.82, 117.63, 115.06, 73.83, 27.69, 18.99. TOF-MS m / z: calcd for: C 30 H 26 NO5 - [M-H] - : 480.1816, found: 480.1821.

[0225] Example 37

[0226] 3'- (Cyclopropylmethoxy) -5- (3- phenoxybenzamido) - [1, 1'-biphenyl] -3-carboxylic acid (37)

[0227]

[0228] Synthesis method is the same as compound 17. Yield: 68.3%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.43 (s, 1H), 8.29 (s, 1H), 7.90 (s, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.63 (s, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.45 - 7.36 (m, 3H), 7.26 - 7.13 (m, 4H), 7.07 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.2 Hz, 1H), 3.88 (d, J = 6.9 Hz, 2H), 1.26 - 1.18 (m, 1H), 0.56 (d, J = 7.8 Hz, 2H), 0.33 (d, J = 5.1 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 167.27, 165.08, 159.35, 157.00, 156.38, 140.99, 140.88, 139.87, 136.47, 132.10, 130.43, 130.39, 130.36, 129.30, 126.84, 124.07, 122.95, 122.89, 122.80, 122.03, 120.37, 119.06, 119.02, 117.73, 114.33, 112.88, 72.26, 10.31, 3.23. TOF-MS m / z: calcd for: C 30 H 24 NO5 - [M-H] - : 478.1659, found: 478.1651.

[0229] Example 38

[0230] 4'-tert-Butyl-5-(3-phenoxybenzamido)-[1,1'-biphenyl]-3-carboxylic acid (38)

[0231] Methyl 3-amino-5-bromobenzoate (1 equiv) was dissolved in a mixture of 1,4- Dioxane / H2O (9:1, v / v) (20 mL) with 4-tert-butylbenzeneboronic acid (1.5 equiv), Na2CO3(3.0 equiv), and Pd(PPh3)4(0.05 equiv) was added successively. The reaction mixture was heated to 80 °C under nitrogen protection. After 18 h, the reaction was cooled to room temperature and filtered with the aid of celite. The bright yellow filtrate was collected and concentrated under reduced pressure to give intermediate 38a. Subsequent amidation with chlorinated m-phenoxybenzoic acid and hydrolysis gave the target compound 38. Yield: 71.2%, light yellow powder.

[0232]

[0233] 80 °C for 18 h. After the reaction was completed, it was cooled to room temperature and filtered with the aid of celite. The bright yellow filtrate was collected and concentrated under reduced pressure to give intermediate 38a. Subsequent amidation with chlorinated m-phenoxybenzoic acid and hydrolysis gave the target compound 38. Yield: 71.2%, light yellow powder. 1 H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.41 - 8.29 (m, 2H), 7.94 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.61 - 7.55 (m, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.47 - 7.38 (m, 3H), 7.24 (d, J = 8.2 Hz, 1H), 7.18 (t, J = 7.3 Hz, 1H), 7.08 (d, J = 8.0 Hz, 2H), 1.31 (s, 9H).13 2H), 7.94-7.77 (m, 5H), 7.68 (s, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.43 (t, J = 7.4 Hz, 2H), 7.23 (d, J = 7.6 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.08 (d, J = 7.6 Hz, 2H).13C NMR (101 MHz, DMSO-d6) δ 167.72, 164.71, 156.74, 156.28, 150.25, 140.20, 139.47, 136.68, 136.50, 130.09, 128.97, 126.58, 126.23, 125.74, 123.75, 122.67, 122.47, 121.69, 121.55, 120.12, 119.02, 118.84, 118.78, 117.66, 34.20, 31.03. TOF-MS m / z: calcd for: C 30 H 26 NO4 - [M-H] - : 464.1867, found: 464.1865.

[0234] Example 39

[0235] 5-(3-Phenoxybenzamido)-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxylic acid (39)

[0236]

[0237] Synthesis was similar to compound 38. Yield: 63.9%, white powder. 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.39 (d, J = 26.7 Hz, 2H), 8.03 (s, 1H), 7.94-7.77 (m, 5H), 7.68 (s, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.43 (t, J = 7.4 Hz, 2H), 7.23 (d, J = 7.6 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.08 (d, J = 7.6 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.73, 156.80, 156.32, 144.02, 139.43, 136.53, 130.12, 127.36, 125.84, 125.80, 123.78, 123.09, 122.70, 121.70, 121.50, 120.95, 118.83, 117.69. TOF-MS m / z: calcd for: C 27 H 17 F3NO4 - [M-H] - : 476.1115, found: 476.1107.​

[0238] Example 40

[0239] 4'-Fluoro-5-(3-phenoxybenzamido)-[1,1'-biphenyl]-3-carboxylic acid (40)

[0240]

[0241] Synthesis method is similar to compound 38. Yield: 55.3%, White powder. 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.35 (d, J = 35.0 Hz, 2H), 7.92 (s, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.71 (s, 1H), 7.67 (s, 2H), 7.55 (t, J = 7.7 Hz, 1H), 7.43 (t, J = 7.3 Hz, 2H), 7.31 (t, J = 8.3 Hz, 2H), 7.23 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.08 (d, J = 7.6 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 167.85, 164.75, 156.80, 156.30, 139.50, 139.32, 136.47, 130.13, 128.67, 128.59, 123.79, 122.69, 121.73, 121.57, 120.38, 118.83, 117.68, 115.91, 115.70. TOF-MS m / z: ealcd for: C 26 H 17 FNO4 - [M-H] - : 426.1147, found: 426.1133.

[0242] Example 41

[0243] 4'-Chloro-5-(3-phenoxybenzamido)-[1,1'-biphenyl]-3-carboxylic acid (41)

[0244]

[0245] Synthesis method is similar to compound 38. Yield: 76.5%, white powder. 1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.42 (d, J = 28.7 Hz, 2H), 7.92 (s, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.71 (s, 1H), 7.68 (d, J = 7.0 Hz, 2H), 7.56 (s, 2H), 7.54 (s, 1H), 7.42 (t, J = 7.5 Hz, 2H), 7.23 (d, J = 6.7 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.08 (s, 1H), 7.06 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 164.88, 156.84, 156.30, 139.38, 138.21, 136.33, 132.82, 130.17, 129.06, 128.45, 123.85, 122.75, 122.55, 122.38, 121.84, 120.57, 118.87, 117.71. TOF-MS m / z: calcd for: C 26 H 17 ClNO4 - [M-H] - : 442.0851, found: 442.0856.

[0246] Example 42 In vitro biological activity test

[0247] 1) FABP1 inhibitory activity was determined based on 8-anilino-1-naphthalenesulfonic acid (1,8-ASN) displacement assay

[0248] 1,8-ANS was prepared into a 100 mM / L stock solution with DMSO, diluted 3000 times with PBS, 60 μL was taken and added to a 96-well plate, then 80 μL of FABP1 protein (1 μmol / L, final concentration) was mixed, and finally 60 μL of compound solution of different concentrations was added, mixed well, and incubated at room temperature for 3 min. The fluorescence intensity of the system at 370 nm (excitation) / 470 nm (emission) was determined using a Thermo multifunctional enzyme marker. The test results are shown in Table 1.

[0249] Table 1: FABP1 inhibitory activity

[0250]

[0251]

[0252] Note: The inhibition rate is the average value of three independent experiments, and the IC 50 value is the average value ± standard deviation of three independent experiments. ND indicates not tested.

[0253] The above results show that the compounds of the present application all have good FABP1 inhibitory activity.

[0254] Example 43 In vivo anti-NASH activity study

[0255] 18-22g of six-week-old male C57BL / 6 mice were purchased from Guangdong Medical Laboratory Animal Center (License No.: SCXK(Y)2022-0002) and were raised in a SPF barrier environment. During the entire experiment, the temperature and relative humidity of the animal room were controlled at 23±2℃ and 50±10%, respectively, and the light / dark cycle was constant at 12 hours. Before starting the animal experiment, all mice were adaptively fed for one week. Unless otherwise specified, the mice were fed under specific pathogen-free conditions and had free access to feed and water. The Guangdong Pharmaceutical University Ethics Committee approved all animal-related procedures and they were performed in accordance with the Chinese Regulations on the Management of Laboratory Animals and the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication No. 85-23, revised in 2011).

[0256] The mice were randomly divided into a normal group, a model group, an obeticholic acid (OCA) administration group, and a test compound administration D5 (37) group, with 6 mice in each group. The normal group was given normal basal feed and drinking water, and the other groups were fed with high-fat feed (Dyets, D18061501, containing 21.1% fat, 41% fructose, and 1.25% cholesterol) and sugar water (23.1 g / L fructose: 18.9 g / L glucose) was prepared. At the same time, except for the normal group, the other groups were intraperitoneally injected with 0.2 μL / g of CCl4 oil solution once a week for 12 weeks to induce a NASH model. From the 9th week, daily gavage administration was performed, and the normal and model groups were given 0.5% carboxymethylcellulose sodium (CMC-Na), the OCA group (20 mg / kg), and the test compound group (20 mg / kg), which lasted for 4 weeks. Half an hour after the last administration, 0.2 μL / g of CCl4 oil solution was injected, the mice were fasted for 8 h (free drinking water) before sampling, 2% sodium pentobarbital (50 mg / kg) was intraperitoneally injected for anesthesia, and then blood was collected through the orbit, the mice were sacrificed by cervical dislocation, fixed on a mouse table, and the skin, subcutaneous tissue, and peritoneum were successively cut along the midline of the abdomen, the abdominal cavity was exposed, the liver tissue was taken out, washed with normal saline, and then the left lobe of the liver tissue of appropriate size was cut and soaked in a tissue fixative for fixation. (1X 1 X 0.5 cm liver tissue was taken from the right lobe of the liver at a distance of 5 mm from the edge, soaked in 4% paraformaldehyde for fixation, and used for paraffin embedding and HE staining.) The remaining tissue was placed in a cryogenic tube and stored in a -80℃ freezer after being sealed with liquid nitrogen. The experimental results are shown in the following table. 3 Size liver tissue, fixed in 4% paraformaldehyde, used for paraffin embedding and HE staining. The remaining tissue was placed in a cryogenic tube and stored in a -80℃ freezer after being sealed with liquid nitrogen. The experimental results are shown in the following table. Figure 1 and 2 .

[0257] The experimental results show that the liver of the normal group is bright red, the texture is tough, and the edge is sharp. The liver volume of the model group is larger, the color is lighter, and there is a greasy feeling. The liver texture is mottled. HE pathological sections show that the model induces typical histological features of NASH, including steatosis, lobular inflammation and hepatocyte ballooning. Compared with the model group, the OCA treatment group has significantly reduced lipid vacuoles and no dense macrophages and lymphocyte aggregation. After treatment with compound D5(37), the inflammation is significantly reduced, the hepatocyte morphology is normal, there is no ballooning, the cell arrangement is relatively neat, but some slight lipid vacuoles can still be observed. The results of the NAFLD activity score (NAS) show that the treatment effect of D5(37) is comparable to that of OCA (see Figure 1 ).

[0258] In addition, compared with the normal group, the total triglyceride (TG), total cholesterol (TC) and serum TC levels of the NASH mouse model induced by WD and CCl4 are significantly increased, while after treatment with OCA and compound D5(37), they are significantly reduced and the effects are comparable. Due to the interference of the fibrosis promoter CCl4, the mouse liver is damaged to a certain extent, so the model group has significantly higher levels of mouse liver LDH and serum AST, ALT, TBA and TBIL than the normal group, but there is no significant difference in ALP. The indicators of the administration group all return to normal levels, indicating that OCA and compound D5(37) have good protective effects on liver function (see Figure 2 ).

Claims

1. A compound comprising an effective amount of a compound of formula (I): ###0001### wherein, ring A is selected from any one of the following structures: ###0002### ring B is selected from any one of the following structures: ###0003### and R is selected from one or more of hydrogen, C1-C6 alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, when ring B is selected from a phenyl ring.

2. A pharmaceutical composition comprising an effective amount of a compound selected from the group consisting of: 5-([1,1 '-biphenyl]-3-carboxamide)-[1,1 '-biphenyl]-3-carboxylic acid; 5-(3-phenoxybenzamide)-[1,1 '-biphenyl]-3-carboxylic acid; 3'-methoxy-5-(3-phenoxybenzamide)-[1,1 '-biphenyl]-3-carboxylic acid; 3'-ethoxy-5-(3-phenoxybenzamide)-[1,1 '-biphenyl]-3-carboxylic acid; 4'-ethoxy-5-(3-phenoxybenzamide)-[1,1 '-biphenyl]-3-carboxylic acid; 5-(3-phenoxybenzamide)-3'-propoxy-[1,1 '-biphenyl]-3-carboxylic acid; 5-(3-phenoxybenzamide)-4'-propoxy-[1,1 '-biphenyl]-3-carboxylic acid; 3'-isobutoxy-5-(3-phenoxybenzamide)-[1,1 '-biphenyl]-3-carboxylic acid; 4'-isobutoxy-5-(3-phenoxybenzamide)-[1,1 '-biphenyl]-3-carboxylic acid; 3'-(cyclopropylmethoxy)-5-(3-phenoxybenzamide)-[1,1 '-biphenyl]-3-carboxylic acid; 4'-(tert-butyl)-5-(3-phenoxybenzamide)-[1,1 '-biphenyl]-3-carboxylic acid; 5-(3-phenoxybenzamide)-4'-(trifluoromethyl)-[1,1 '-biphenyl]-3-carboxylic acid; 4'-fluoro-5-(3-phenoxybenzamide)-[1,1 '-biphenyl]-3-carboxylic acid; 4'-chloro-5-(3-phenoxybenzamide)-[1,1 '-biphenyl]-3-carboxylic acid.

3. A pharmaceutical composition comprising a compound of any one of claims 1-2 and a suitable carrier.

4. Use of a compound as defined in any one of claims 1-2 for the manufacture of a medicament for the treatment of a FABP1 mediated disease.

5. Use of a compound as defined in any one of claims 1-2, or a pharmaceutical composition of claim 4, for the manufacture of a medicament for the prevention or / and treatment of at least one of non-alcoholic steatohepatitis, alcoholic steatohepatitis, hyperlipidemia, obesity, atherosclerosis, organ fibrosis, liver cirrhosis, diabetes and its complications, acute kidney injury. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​

Images