Novel bibenzoic acid FXR agonist, preparation method thereof and application of novel bibenzoic acid FXR agonist as medicine

Abstract

The invention relates to a novel bibenzoic acid FXR agonist as shown in a general formula (I), a preparation method of the novel bibenzoic acid FXR agonist and application of a pharmaceutical composition containing the novel bibenzoic acid FXR agonist as a medicine for preventing or / and treating FXR-mediated diseases or symptoms, wherein the diseases comprise primary biliary cirrhosis, lipid metabolism disorder, non-alcoholic fatty liver disease, obesity and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a novel biphenyl carboxylic acid derivative, a preparation method and application thereof, and belongs to the field of pharmaceutical chemistry. The structure of the related biphenyl carboxylic acid derivative in the present invention is unique and novel in the field. Background Art

[0002] Farnesoid X receptor (FXR) belongs to the nuclear receptor superfamily and is the main receptor and bioreceptor for bile acid in the body. It is mainly expressed in the liver, kidney, intestine and adrenal gland. It has been confirmed that FXR is involved in regulating metabolic pathways highly related to metabolic diseases such as bile acid, cholesterol, lipids and glucose. Therefore, FXR is a potential drug target in the treatment of primary biliary cirrhosis, lipid metabolism disorders and non-alcoholic steatohepatitis (NASH). In the liver, after activation, FXR forms a small heterodimer partner (SHP) with the retinoic acid X receptor (RXR) to bind to the response element on the downstream target gene DNA, further regulating the transcription of the downstream target gene and exerting its effect. In the intestine, activation of FXR can stimulate the secretion of growth factor 15 / 19 (Fibroblastgrowth factor 15 / 19, FGF15 / 19). FGF15 / 19 can enter the liver through the portal vein and activate FGF receptor 4 (Fibroblast growth factor receptor 4, FGFR4), thereby inhibiting the expression of CYP7A1 and CYP8B1, and further inhibiting the synthesis of bile acids in the liver.

[0003] At present, FXR agonists are mainly divided into two categories: steroidal and non-steroidal. Steroidal drugs include obeticholic acid (OCA) and chenodeoxycholic acid (CDCA). Obeticholic acid has been approved for the indication of primary biliary cirrhosis, and its indication for non-alcoholic fatty hepatitis has been terminated in Phase III clinical trials because of its serious adverse reactions, such as itching and elevated low-density lipoprotein (LDL) and potential cardiovascular risks. Several non-steroidal FXR agonists have entered clinical trials, including Cilofexor (GS-9674), Tropifexor (LJN452), Px-104, MET409 and TERN-101. However, the above-mentioned drugs under development still have defects such as insufficient efficacy and large side effects, and there is an urgent need to develop new, effective and safe FXR agonists. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a novel biphenyl carboxylic acid FXR agonist, which provides the possibility for the application of the FXR agonist in the treatment of non-alcoholic fatty liver, non-alcoholic steatohepatitis, liver fibrosis, primary bile duct sclerosis, primary sclerosing cholangitis, lipid metabolism disorders, diabetic complications, intestinal inflammatory diseases and obesity. The present invention also provides a preparation method of the drug.

[0005] The novel biphenyl carboxylic acid FXR agonist of the present invention contains an effective amount of a compound represented by the general formula (I):

[0006]

[0007] in:

[0008] R1 and R2 are each independently selected from hydrogen, halogen, trifluoromethyl or trifluoromethoxy;

[0009] R3 is selected from cyclopropyl or isopropyl;

[0010] R4 is selected from hydrogen, halogen, C1-C6 alkyl or trifluoromethyl;

[0011] R5 and R6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, trifluoromethyl or the following groups:

[0012]

[0013] R7 is selected from hydrogen, halogen, C1-C6 alkyl or trifluoromethyl.

[0014] Preferred compounds of the present invention are selected from:

[0015] R1 and R2 are each independently selected from hydrogen, chlorine, fluorine, trifluoromethyl or trifluoromethoxy;

[0016] R3 is selected from cyclopropyl or isopropyl;

[0017] R4 is selected from hydrogen, chlorine, fluorine, C1-C6 alkyl or trifluoromethyl;

[0018] R5 and R6 are each independently selected from hydrogen, chlorine, fluorine, C1-C6 alkyl, trifluoromethyl or the following groups:

[0019]

[0020] R7 is selected from hydrogen, chlorine, fluorine, C1-C6 alkyl or trifluoromethyl.

[0021] More preferred compounds of the present invention include, but are not limited to:

[0022] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-3-carboxylic acid;

[0023] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-[1,1′-biphenyl 1-4-carboxylic acid;

[0024] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2′,6′-dimethyl-[1,1′-biphenyl]-4-carboxylic acid;

[0025] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2′-methyl-[1,1′-biphenyl]-4-carboxylic acid;

[0026] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-3′-methyl-[1,1′-biphenyl]-4-carboxylic acid;

[0027] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2′-fluoro-[1,1′-biphenyl]-4-carboxylic acid;

[0028] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-3′-fluoro-[1,1′-biphenyl]-4-carboxylic acid;

[0029] 2′-Chloro-4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-4-carboxylic acid;

[0030] 3′-Chloro-4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-4-carboxylic acid;

[0031] 3-Chloro-4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-4-carboxylic acid;

[0032] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2-fluoro-[1,1′-biphenyl]-4-carboxylic acid;

[0033] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-3-fluoro-[1,1′-biphenyl]-4-carboxylic acid;

[0034] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2-methyl-[1,1′-biphenyl]-4-carboxylic acid;

[0035] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-3-methyl-[1,1′-biphenyl]-4-carboxylic acid;

[0036] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-3,5-difluoro-substituted derivatives [1,1′-biphenyl]-4-carboxylic acid;

[0037] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylic acid;

[0038] 4-(5-Cyclopropyl-3-(2-trifluoromethylphenyl)isoxazole-4-methoxy)-[1,1′-biphenyl]-4-carboxylic acid;

[0039] 4-(5-isopropyl-3-(2-trifluoromethylphenyl)isoxazole-4-methoxy)-[1,1′-biphenyl]-4-carboxylic acid;

[0040] 4-(5-Cyclopropyl-3-(2-trifluoromethoxy)phenyl)isoxazole-4-methoxy)-[1,1′-biphenyl]-4-carboxylic acid;

[0041] 4-(5-isopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-methoxy)-[1,1′-biphenyl]-4-carboxylic acid;

[0042] 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-[1,1′-biphenyl]-4-carboxamide;

[0043] 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-methyl-[1,1′-biphenyl]-4-carboxamide;

[0044] 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide;

[0045] N-cyclopropyl-4′-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-[1,1′-biphenyl]-3-carboxamide;

[0046] 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-cyclopropylmethyl-[1,1′-biphenyl]-3-carboxamide;

[0047] 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-methyl-[1,1′-biphenyl]-3-carboxamide;

[0048] 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N,N-dimethyl-[1,1′-biphenyl]-3-carboxamide;

[0049] 4′-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-isopropyl-[1,1′-biphenyl]-3-carboxamide;

[0050] 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-isopropyl-[1,1′-biphenyl]-4-carboxamide;

[0051] 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-isobutyl-[1,1′-biphenyl]-3-carboxamide;

[0052] 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-propyl-[1,1′-biphenyl]-3-carboxamide;

[0053] N-tert-butyl-4′-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-3-carboxamide;

[0054] 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-ylmethoxy)-[1,1′-biphenyl]-3-yl)(morpholinyl)methanone;

[0055] 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-ylmethoxy)-[1,1′-biphenyl]-3-yl)pyrrolidine-1-methanone;

[0056] 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-phenylsulfonyl-[1,1′-biphenyl]-4-carboxamide;

[0057] 4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-methylsulfonyl-[1,1′-biphenyl]-4-carboxamide.

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

[0059] The invention relates to use of the compound or its pharmaceutical composition in preparing medicines for treating FXR-related diseases.

[0060] The present invention also relates to the use of the compound or its pharmaceutical composition in the preparation of a drug for preventing and / or treating at least one of primary biliary cirrhosis, biliary diarrhea, non-alcoholic steatohepatitis, alcoholic steatohepatitis, cholestatic liver disease, drug-induced liver damage, primary sclerosing cholangitis, portal hypertension, atherosclerosis, dyslipidemia, hyperlipidemia, organ fibrosis, cirrhosis, liver failure, gallstones, diabetes, diabetic complications, inflammatory bowel disease and obesity.

[0061] Detailed description of the invention

[0062] Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0063] Any general formula or structure shown herein, including compounds of general formula (I), is also intended to represent unlabeled and isotopically labeled forms of the compounds. Isotope-labeled compounds have the structure shown in the molecular formula given herein, except that one or more atoms are replaced by atoms with a selected atomic mass or mass number. Examples of isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, and in the compounds of the present invention, any atom that is not explicitly indicated as a specific isotope is intended to represent any stable isotope of the atom. Unless otherwise stated, when a position is explicitly indicated with "H" or "hydrogen", it should be understood that the position is hydrogen of its isotopic composition. Therefore, in the compounds of the present invention, any atom explicitly indicated as deuterium (D) is intended to represent deuterium.

[0064] "Pharmaceutical composition" means a mixture containing one or more compounds of the present invention and other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to promote the absorption of the active ingredient by the organism and facilitate the active ingredient to exert its biological activity in the organism. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 :Observation of the efficacy of the preferred compounds in the NASH model: (A) Experimental process; (B) HE staining of liver pathological sections, scale: 100 μm (C) NAS score. One-way ANOVA analysis was used to analyze the results (n=6). * p<0.05, ** p<0.01, ***p < 0.001, compared with the model group; # p<0.05, ## p<0.01, ### p<0.001, compared with the OCA group.

[0066] Figure 2 :Observation of the efficacy of the selected compounds in the cholestatic liver disease model: (A) Experimental process; (B) HE staining of liver pathological sections, scale: 100 μm; (C) Serological data. One-way ANOVA analysis results (n=6), *p<0.05, **p<0.01, ***p<0.001, compared with the model group. DETAILED DESCRIPTION

[0067] The present invention will be further described below in conjunction with the examples. It should be noted that the following examples are only for illustration, and are not intended to limit the present invention. Various changes made by those skilled in the art based on the teachings of the present invention should be within the scope of protection of the claims of this application.

[0068] Preparation of key intermediates for the synthesis of the compounds of the present invention:

[0069] 4-(Bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (6a)

[0070]

[0071] Synthesis route 1: Reagents and conditions: (a) Hydroxylamine hydrochloride, NaOH, methanol, room temperature, 6h; (b) N-chlorosuccinimide, DMF, room temperature, 2h; (c) Methyl isobutyryl acetate / methyl 3-cyclopropyl-3-oxopropanoate, triethylamine, room temperature, 8h; (d) Lithium aluminum hydride, anhydrous tetrahydrofuran, -20℃, 2.5h; (e) Phosphorus tribromide, anhydrous dichloromethane, -20℃, 2.5h.

[0072] First, prepare NaOH particles into a 3mol / L solution for standby use; then add 20mL of water and 1.53g (22mmol) of hydroxylamine salt into a 100mL round-bottom flask, and slowly drop the prepared NaOH solution into the suspension of hydroxylamine hydrochloride with a rubber-tipped dropper; take out another round-bottom flask, add 3.5g (20mmol) of 2,6-dichlorobenzaldehyde and 20mL of ethanol solution, then place the prepared reaction solution on an ice bath, and drop the prepared hydroxylamine hydrochloride sodium hydroxide solution thereto. After reacting at room temperature for 6h, extract with ethyl acetate and spin dry to obtain 3g of (E)-2,6-dichlorobenzaldehyde oxime.

[0073] 3 g (17.1 mmol) of (E)-2,6-dichlorobenzaldehyde oxime, 2.29 g (17.14 mmol) of N-chlorosuccinimide and 30 mL of DMF were added to the reaction bottle in sequence. After reacting at room temperature for 2 h, the mixture was extracted and dried to obtain 3.2 g of (Z)-2,6-dichloro-N-hydroxybenzoyl chloride.

[0074] 3.2 g (14.26 mmol) of (Z)-2,6-dichloro-N-hydroxybenzoyl chloride and 2.03 g (14.26 mmol) of methyl 3-cyclopropyl-3-oxopropanoate were added to triethylamine, and the mixture was reacted at room temperature for 8 h. The product 4 g was extracted and dried by spin drying to obtain methyl 5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carboxylate.

[0075] After strict dehydration, the above product is quickly placed in a reaction bottle with a drying tube, and an appropriate amount of anhydrous tetrahydrofuran is added to the bottle; anhydrous tetrahydrofuran and 1.46g (38.44mmol) of lithium aluminum hydride are used to prepare a suspension and quickly poured into a constant pressure bottom liquid funnel (the whole process is guaranteed to be anhydrous); then the lithium aluminum hydride suspension in the dropping funnel is dripped into the reaction liquid in a low-temperature constant temperature stirring reactor (-20°C), and the reaction is quenched with ice water after reacting for 2.5h. After extraction and spin drying, 2g of (5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methanol is obtained.

[0076] The anhydrous dichloromethane solution of phosphorus tribromide was added dropwise to (5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazole-4-yl)methanol through a constant pressure dropping funnel. After 2.5 hours of reaction, water was added dropwise to quench the reaction, and the reaction was dried and extracted. All operations were performed in a low-temperature constant temperature stirring reactor (-20°C). Silica gel was added to make sand, and then purified by column chromatography (petroleum ether: ethyl acetate = 10: 1). Finally, a white solid intermediate 4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (6a) was obtained with a yield of 63%. 1 H NMR (400MHz, DMSO-d6) δ7.73-7.57(m, 3H), 4.45(s, 2H), 2.47-2.41(m, 1H), 1.23-1.12(m, 4H)

[0077] 4-(Bromomethyl)-5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazole (6b)

[0078]

[0079] The first step raw material was changed to o-trifluoromethylbenzaldehyde and hydroxylamine hydrochloride. The rest was the same as the synthesis method of 6a. The product 6b was a light yellow solid with a yield of 45%. 1H NMR (400MHZ, CDCl3) δ7.84 (d, J=7.4Hz, 1H), 7.73-7.61 (m, 2H), 7.57 (d, J=7.4Hz, 1H), 4.23 (s, 2H), 2.17-2.09 (m, 1H), 1.32-1.17 (m, 4H).

[0080] 4-(Bromomethyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (6c)

[0081]

[0082] 2-(Trifluoromethoxy)benzaldehyde was used as the first step raw material to react with hydroxylamine hydrochloride, and the rest was the same as the synthesis method of 6a to obtain a pure white solid with a yield of 42%. 1 H NMR (400MHz, CDCl3) δ7.55-7.50 (m, 1H), 7.49-7.45 (m, 1H), 7.40-7.32 (m, 2H), 4.27 (s, 2H), 2.11-1.99 (m, 1H), 1.24-1.09 (m, 4H).

[0083] The preparation methods of the remaining 6d-6f are the same as those of 6a-6c above.

[0084] Example 1

[0085] 2-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)phenyl)imidazolyl-[1,2-a]pyridine-6-carboxylic acid (1)

[0086]

[0087] 1 g (6.57 mmol) of 6-aminonicotinic acid methyl ester and 1.41 g (6.57 mmol) of 2-bromo-4′-hydroxyacetophenone were added to a reaction bottle, and an appropriate amount of analytical pure ethanol was added. The mixture was placed in a heat-collecting constant temperature heating magnetic stirrer (70° C.) and heated to reflux. After reacting for 6 hours, the plate was tapped to determine that the reaction was complete, and the mixture was extracted with ethyl acetate and distilled under reduced pressure to obtain 1.45 g of the product. The above-mentioned product 2-(4-hydroxyphenyl)imidazole-[1,2-a]pyridine-6-dicarboxylic acid dibutyl ester methyl ester was reacted with 6a by Williamson etherification, wherein potassium carbonate (2.24 g, 16.21 mmol) was used to provide alkalinity, potassium iodide (89.72 mg, 0.54 mmol) was used as a catalyst for the reaction, the reaction temperature was 70° C., and the corresponding crude product was obtained after 8 hours of post-treatment. The pure product was purified by column chromatography, and 1 mL of water, 3 mL of methanol, and 3 mL of THF and lithium hydroxide monohydrate (3 equivalents) were reacted for 2 hours, and the mixture was spin-dried. The pH was adjusted to 3-4 to precipitate a white solid, which was filtered and dried to obtain compound 1.1 H NMR (300MHz, DMSO-d6) δ9.34 (s, 1H), 8.59 (s, 1H), 8.02-7.80 (m, 4H), 7.70-7.48 (m, 3H), 7.11-6.86 (m, 2H), 4.96 (s, 2H), 1.23-1.12 (m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.14, 161.40, 159.23, 157.61, 149.15, 147.44, 134.67, 132.52, 1 28.46, 127.20, 127.07, 126.36, 119.02, 114.92, 110.56, 109.16, 58.85, 8.49, 7.35.ESI-MS m / z:[MH] - calcd.forC 27 H 19 Cl2N3O4, 518.0680; found, 518.0665.

[0088] Example 2

[0089] 2-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)phenyl)imidazolyl-[1,2-a]pyridine-5-carboxylic acid (2)

[0090]

[0091] The first step raw material was changed to 6-aminopyridine-2-carboxylic acid methyl ester (1 g, 6.57 mmol), which was reacted with 1.41 g (6.57 mmol) of 2-bromo-4′-hydroxyacetophenone to form a ring. The rest was the same as the synthesis method of compound 1, and the target compound 2 (white solid) was finally obtained with a yield of 46%. 1 H NMR(300 MHz, DMSO-d6) δ8.77 (d, J=6.9Hz, 1H), 8.69 (s, 1H), 8.23 ​​(s, 1H), 7.98-7.86 (m, 2H), 7.68- 7.51(m, 4H), 7.05-6.90(m, 2H), 4.96(s, 2H), 2.48-2.43(m, 1H), 1.23-1.12(m, 4H).ESI-MS m / z:[MH] - calcd.for C 27 H 19 Cl2N3O4, 518.0680; found, 518.0683.

[0092] Example 3

[0093] 2-(3-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)phenyl)imidazolyl-[1,2-a]pyridine-5-carboxylic acid (3)

[0094]

[0095] The first step is to use 6-aminopyridine-2-carboxylic acid methyl ester (1 g, 6.57 mmol) and 2-bromo-3-hydroxyacetophenone (1.41 g, 6.57 mmol) as raw materials, and react at 70° C. for 6 h. The remaining synthetic steps are the same as compound 1. 1 H NMR (300MHz, DMSO-d6) δ8.79 (d, J=7.0Hz, 1H), 8.72 (s, 1H), 8.26 (s, 1H), 8.00-7.89 (m, 2H) , 7.64-7.54(m, 4H), 7.04-6.92(m, 2H), 4.96(s, 2H), 2.49-2.43(m, 1H), 1.21-1.12(m, 4H). 13 C NMR (75MHz, DMSO-d6) δ172.43, 165.11, 159.27, 158.49, 134.70, 132.59, 130.54, 1 28.52, 127.02, 119.11, 116.77, 112.23, 112.14, 110.44, 59.14, 8.61, 7.46.ESI-MS m / z:[MH] - calcd.for C 27 H 19 Cl2N3O4, 518.0680; found, 518.0687.

[0096] Example 4

[0097] 2-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)phenyl)-1H-benzo[d]imidazole-6-carboxylic acid (4)

[0098]

[0099] 4-Hydroxybenzaldehyde (0.5 g, 4.09 mmol), methyl 3,4-diaminobenzoate (0.82 g, 4.91 mmol) and sodium metabisulfite were added to DMF, heated to 80°C for reflux, and reacted for 3 hours. The remaining steps were the same as compound 1. 1H NMR (300MHz, DMSO-d6) δ7.80-7.69 (m, 1H), 7.69-7.54 (m5H), 7.27-7.10 (m, 2H) , 7.09-7.00(m, 3H), 5.00(s, 2H), 2.58-2.51(m, 1H), 1.23-1.14(m, 4H).ESI-MS m / z:[MH] - calcd.for C 27 H 19 Cl2N3O4, 518.0680; found, 518.0675.

[0100] Example 5

[0101] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-3-carboxylic acid (5)

[0102]

[0103] First, prepare a nitrogen protection device, take 0.96g (mmol) 4-hydroxyphenylboronic acid and 1g (4.65mmol) methyl o-bromobenzoate in a 100mL reaction bottle, then add solvent 1,4-dioxane and water (3:1), 1.48g (13.95mmol) sodium carbonate, and finally quickly add 0.27g (0.23mmol) tetrakis(triphenylphosphine)palladium, install nitrogen protection, vacuumize to replace the air in the bottle, reflux at 90°C for 12h to obtain the product; the product is extracted, and after reduced pressure distillation, 6a Williamson ether is added to form ether, and finally hydrolysis reaction is carried out to obtain compound 5 (white solid) with a yield of 83%. 1 H NMR (400MHz, DMSO-d6) δ13.08 (s, 1H), 8.12-8.06 (m, 1H), 7.92-7.79 (m, 2H), 7.70- 7.44(m, 6H), 6.98-6.86(m, 2H), 4.92(s, 2H), 2.48-2.42(m, 1H), 1.24-1.08(m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.18, 167.32, 159.25, 157.85, 140.07, 134.67, 132.54, 132.12, 131.45, 1 30.68, 129.31, 128.47, 127.90, 127.68, 127.07, 126.83, 115.26, 110.54, 58.91, 8.51, 7.36.ESI-MS m / z:[MH] - calcd.forC 26H 19 Cl2NO4, 478.0618; found, 478.0609.

[0104] Example 6

[0105] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-4-carboxylic acid (6)

[0106]

[0107] The raw material of the first step was changed to methyl p-bromobenzoate, and the remaining reaction steps were the same as compound 5. Finally, a slightly sticky white solid-like compound 6 was obtained with a yield of 78%. 1 H NMR (400MHz, DMSO-d6) δ8.07-7.84(m, 2H), 7.74-7.28(m, 7H), 7.04-6.75(m, 2H), 4.92(s, 2H), 2.49-2.42(m, 1H), 1.26-1.09(m, 4H). 13 C NMR (101MH-z, DMSO-d6) δ172.10, 159.19, 157.80, 134.64, 132.46, 129.81, 128.42, 127.87, 127.06, 125.57, 115.13, 110.53, 58.90, 8.41, 7.31.ESI-MS m / z:[M.-.H] - calcd.for C 26 H 19 Cl2NO4, 478.0618; found, 478.0614.

[0108] Example 7

[0109] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2′,6′-dimethyl-[1,1′-biphenyl]-4-carboxylic acid (7)

[0110]

[0111] The first step raw materials were changed to 4-methoxycarbonylphenylboronic acid (1 g, 5.56 mmol) and 4-bromo-3,5-dimethylphenol (1.68 g, 8.33 mmol) for reaction. The remaining steps were the same as compound 5 (light yellow solid), with a yield of 79%. 1H NMR (400MHz, DMSO-d6) δ12.96 (s, 1H), 7.98 (d, J=8.0Hz, 2H), 7.74-7.58 (m, 2H), 7.59-7.52 (m, 1H), 7.20 (d, J=8.1Hz, 2H), 6.57 (s, 2H), 4.85 (s, 2H), 2.48-2.40 (m, 1H), 1.86 (s, 6H), 1.22-1.10 (m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.19, 167.23, 159.12, 156.79, 145.01, 136.29, 134.70, 133.56, 132.44, 129.74, 129.48, 129.18, 128.43, 127.08, 113.71, 113.58, 110.69, 58.62, 20.61, 8.33, 7.31.ESI-MS m / z:[MH] - calcd.for C 28 H 23 Cl2NO4, 506.0931; found, 506.0921.

[0112] Example 8

[0113] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2′-methyl-[1,1′-biphenyl]-4-carboxylic acid (8)

[0114]

[0115] The first step raw materials were changed to 4-methoxycarbonylphenylboronic acid (1 g, 5.56 mmol) and 4-bromo-3-methylphenol (1.56 g, 8.33 mmol) for reaction. The remaining steps were the same as compound 5, and a white solid was finally obtained with a yield of 70%. 1 H NMR (400MHz, DMSO-d6) δ12.96 (s, 1H), 7.96 (d, J=8.2Hz, 2H), 7.63 (d, J=7.8Hz, 2H), 7.57-7.51 (m, 1H), 7.39 (d, J=8. 2Hz, 2H), 7.07 (d, J=8.4Hz, 1H), 6.81-6.67 (m, 2H), 4.89 (s, 2H), 2.49-2.42 (m, 1H), 2.16 (s, 3H), 1.22-1.10 (m, 4H). 13CNMR (101MHz, DMSO-d6) δ172.12, 167.18, 159.13, 157.40, 145.40, 136.12, 134.66, 133.28, 132.42, 131.62, 130 .47, 129.29, 129.17, 128.93, 128.40, 127.37, 127.05, 116.42, 112.46, 110.57, 58.77, 20.33, 8.35, 7.29.ESI-MS m / z:[MH] - calcd.for C 27 H 21 Cl2NO4, 492.0775; found, 492.0763.

[0116] Example 9

[0117] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-3′-methyl-[1,1′-biphenyl]-4-carboxylic acid (9)

[0118]

[0119] The first step raw materials were changed to 4-methoxycarbonylphenylboronic acid (1 g, 5.56 mmol) and 4-bromo-2-methylphenol (1.56 g, 8.33 mmol) for reaction. The rest of the synthesis operation was the same as compound 5, and a white solid was finally obtained with a yield of 73%. 1 H NMR (400MHz, DMSO-d6) δ12.90 (s, 1H), 7.96 (d, J = 8.2Hz, 2H), 7.71 (d, J = 8.2Hz, 2H), 7.66-7.59 (m, 2H), 7 .58-7.45(m, 3H), 7.07(d, J=8.3Hz, 1H), 4.97(s, 2H), 2.49-2.42(m, 1H), 1.94(s, 3H), 1.23-1.13(m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.04, 167.17, 158.97, 156.24, 144.00, 134.60, 132.43, 131.26, 129.86, 128. 99, 128.78, 128.47, 127.19, 126.58, 126.11, 125.39, 111.83, 110.58, 58.98, 15.63, 8.35, 7.23.ESI-MS m / z:[MH] - calcd.forC 27 H 21Cl2NO4, 492.0775; found, 492.0774.

[0120] Example 10

[0121] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2′-fluoro-[1,1′-biphenyl]-4-carboxylic acid (10)

[0122]

[0123] The first step raw materials were changed to 4-methoxycarbonylphenylboronic acid (1 g, 5.56 mmol) and 4-bromo-3-fluorophenol (1.59 g, 8.33 mmol) for reaction. The rest of the synthesis operation was the same as compound 5, and finally a light yellow solid was obtained with a yield of 84%. 1 H NMR (400MHz, DMSO-d6) δ7.98 (d, J=8.0Hz, 1H), 7.80 (d, J=8.4Hz, 1H), 7.68-7.47 (m, 5H), 7.46-7.28(m, 1H), 6.90-6.69(m, 2H), 4.95(s, 2H), 2.48-2.40(m, 1H), 1.20-1.11(m, 4H). 13 CNMR (101MHz, DMSO-d6) δ172.34, 172.21, 167.75, 167.30, 160.73, 159.51 (d, J=2 47.5Hz), 159.12, 158.90 (d, J=11.1Hz), 138.06, 134.65, 134.60, 132.50, 132.47 , 131.09, 129.45, 128.43, 128.40, 128.24 (d, J=3.0Hz), 126.94, 120.25, 120.11, 114.13, 111.74, 110.25, 110.19, 102.77 (d, J=26.3Hz), 59.32, 8.46, 7.28.ESI-MS m / z:[MH] - calcd.forC 26 H 18 Cl2FNO4, 496.0524; found, 496.0526.

[0124] Embodiment 11

[0125] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-3′-fluoro-1,1′-biphenyl]-4-carboxylic acid (11)

[0126]

[0127] The first step raw materials were changed to 4-methoxycarbonylphenylboronic acid (1 g, 5.56 mmol) and 4-bromo-fluorophenol (1.59 g, 8.33 mmol) for reaction. The rest of the synthesis operation was the same as compound 5, and finally a light yellow solid was obtained with a yield of 86%. 1 H NMR (400MHz, DMSO-d6) δ12.99 (s, 1H), 7.97 (d, J = 8.2Hz, 2H), 7.75 (d, J = 8.2Hz, 2H), 7.66-7.50 ( m, 4H), 7.49-7.41 (m, 1H), 7.28-7.18 (m, 1H), 5.02 (s, 2H), 2.50-2.43 (m, 1H), 1.33-1.00 (m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.59, 167.05, 159.06, 152.15 (d, J = 245.4Hz), 145.67 (d, J = 11.1Hz), 142.60, 134.64, 132.63 (d, J = 6.1HZ), 132.46, 1 31.56, 129.90, 129.46, 128.41, 126.78, 126.39, 122.96 (d, J=3.0Hz), 1 16.03, 116.01, 114.51 (d, J=19.2Hz), 110.12, 59.89, 8.45, 7.29.ESI-MS m / z:[MH] - calcd.for C 26 H 18 Cl2FNO4, 496.0524; found, 496.0521.

[0128] Example 12

[0129] 2′-Chloro-4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-4-carboxylic acid (12)

[0130]

[0131] The first step raw materials were changed to 4-methoxycarbonylphenylboronic acid (1 g, 5.56 mmol) and 4-bromo-3-chlorophenol (1.73 g, 8.33 mmol) for reaction. The rest of the synthesis operation was the same as compound 5, and finally a light yellow solid was obtained with a yield of 82%. 1H NMR (400MHz, DMSO-d6) δ7.98 (d, J=8.1Hz, 2H), 7.67-7.59 (m, 2H), 7.58-7.51 (m, 1H), 7.48 (d, J=8.2Hz, 2H), 7.2 8 (d, J=8.5Hz, 1H), 7.05 (d, J=2.5Hz, 1H), 6.91-6.83 (m, 1H), 4.97 (s, 2H), 2.49-2.39 (m, 1H), 1.26-0.98 (m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.35, 167.14, 159.10, 158.06, 142.56, 134.65, 132.49, 131.99, 131.68, 1 31.64, 130.02, 129.52, 129.12, 128.42, 126.95, 115.79, 114.54, 110.21, 59.32, 8.47, 7.28.ESI-MS m / z:[MH] - calcd.forC 26 H 18 Cl3NO4, 512.0229; found, 512.0223.

[0132] Embodiment 13

[0133] 3′-Chloro-4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-4-carboxylic acid (13)

[0134]

[0135] The first step raw materials were changed to 4-methoxycarbonylphenylboronic acid (1 g, 5.56 mmol) and 4-bromo-2-chlorophenol (1.73 g, 8.33 mmol) for reaction. The rest of the synthesis operation was the same as compound 5, and finally a light yellow solid was obtained with a yield of 80%. 1 H NMR (400MHz, DMSO-d6)_δ12.99 (s, 1H), 7.97 (d, J=8.3Hz, 2H), 7.79-7.70 (m, 3H), 7.65-7.58 (m, 3 H), 7.58-7.49 (m, 1H), 7.26 (d, J=8.7Hz, 1H), 5.06 (s, 2H), 2.58-2.51 (m, 1H), 1.23-1.14 (m, 4H). 13C NMR (101MHz, DMSO-d6) δ172.48, 167.05, 158.94, 153.18, 142.42, 134.68, 132.82, 132.40, 129.91, 1 29.45, 128.46, 128.17, 126.84, 126.55, 126.40, 122.44, 114.62, 110.04, 59.92, 8.44, 7.31.ESI-MS m / z:[MH] - calcd.for C 26 H 18 Cl3NO4, 512.0229; found, 512.0224.

[0136] Embodiment 14

[0137] 3-Chloro-4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-4-carboxylic acid (14)

[0138]

[0139] The first step raw materials were changed to 4-hydroxyphenylboronic acid (0.83 g, 6.01 mmol) and methyl 4-bromo-2-chlorobenzoate (1.0 g, 4.01 mmol) for reaction. The rest of the synthetic operation was the same as compound 5, and a white solid was finally obtained with a yield of 74%. 1 H NMR (400MHz, DMSO-d6) δ7.84 (d, J=8.1Hz, 1H), 7.74 (s, 1H), 7.69-7.56 (m, 5H), 7.56-7 .48(m, 1H), 6.91(d, J=8.6Hz, 2H), 4.92(s, 2H), 2.48-2.41(m, 1H), 1.21-1.06(m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.17, 166.42, 159.21, 158.48, 143.90, 134.67, 132.71, 132.49, 131.73, 1 30.31, 128.89, 128.44, 128.24, 127.94, 127.07, 124.72, 115.26, 110.47, 58.98, 8.45, 7.33.ESI-MS m / z:[MH] - calcd.for C 26 H 18 Cl3NO4, 512.0229; found, 512.0230.

[0140] Embodiment 15

[0141] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2-fluoro-[1,1′-biphenyl]-4-carboxylic acid (15)

[0142]

[0143] The first step raw materials were changed to 4-hydroxyphenylboronic acid (0.89 g, 6.44 mmol) and methyl 4-bromo-3-fluorobenzoate (1.0 g, 4.29 mmol) for reaction. The rest of the synthesis operation was the same as compound 5, and a white solid was finally obtained with a yield of 66%. 1 H NMR (400MHz, DMSO-d6) δ13.26 (s, 1H), 7.81 (d, J = 8.0Hz, 1H), 7.72 (d, J = 11.3Hz, 1H), 7.65-7.50 (m, 4 H), 7.47 (d, J=7.8Hz, 2H), 6.94 (d, J=8.5Hz, 2H), 4.93 (s, 2H), 2.49-2.38 (m, 1H), 1.21-1.09 (m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.17, 166.08, 166.05, 159.86, 159.16, 158.63 (d , J=247.5Hz), 134.65, 132.44, 132.11 (d, J=13.1Hz), 13138 (d, J=8.1Hz), 13 0.68 (d, J=4.0Hz, 2H), 130.08, 130.05, 128.40, 126.90 (d, J=24.2Hz), 125.6 7, 125.64, 116.65 (d, J=24.2Hz), 114.89, 110.41, 58.88, 8.39, 7.29.ESI-MS m / z: [MH] - calcd.for C 26 H 18 Cl2FNO4, 496.0524; found, 496.0533.

[0144] Example 16

[0145] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-3-fluoro-[1,1′-biphenyl]-4-carboxylic acid (16)

[0146]

[0147] The first step raw materials were changed to 4-hydroxyphenylboronic acid (0.89 g, 6.44 mmol) and methyl 2-fluoro-4-bromobenzoate (1.0 g, 4.29 mmol) for reaction. The rest of the synthesis operation was the same as compound 5, and a white solid was finally obtained with a yield of 76%. 1 H NMR (400MHz, DMSO-d6) δ7.92-7.85 (m, 1H), 7.73-7.42 (m, 7H), 6.91 (d, J=8.8Hz, 2H), 4.93 (s, 2H), 2.48-2.39 (m, 1H), 1.24-1.08 (m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.16, 164.88, 164.85, 161.73 (d, J=257.6Hz), 159.20, 158.58, 146.00 (d, J=9.1Hz), 134.66, 132.51, 130.36, 130 .34, 128.44, 128.24, 127.06, 121.82 (d, J=3.0Hz), 117.06 (d, J=10.1Hz), 115.22, 114.01 (d, J=23.2Hz), 110.46, 58.98, 8.45, 7.33.ESI-MS m / z:[MH] - calcd.forC 26 H 18 Cl2FNO4, 496.0524; found, 496.0532.

[0148] Embodiment 17

[0149] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2-methyl-[1,1′-biphenyl]-4-carboxylic acid (17)

[0150]

[0151] The first step raw materials were changed to 4-hydroxyphenylboronic acid (0.90 g, 6.55 mmol) and methyl 4-bromo-3-methylbenzoate (1.0 g, 4.37 mmol) for reaction. The rest of the synthesis operation was the same as compound 5, and a white solid was finally obtained with a yield of 63%. 1HNMR (400MHz, DMSO-d6) δ7.81 (s, 1H), 7.74 (d, J = 7.8Hz, 1H), 7.64-7.59 (m, 2H), 7.57-7.51 (m, 1H), 7.18 (d, J = 8.4Hz , 2H), 7.07 (d, J=7.8Hz, 1H), 6.86 (d, J=8.5Hz, 2H), 4.90 (s, 2H), 2.49-2.40 (m, 1H), 2.20 (s, 3H), 1.23-1.04 (m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.15, 169.72, 159.20, 156.85, 141.77, 137.51, 134.70, 134.11, 133.47, 132. 49, 131.32, 129.98, 128.73, 128.44, 127.11, 126.84, 114.41, 110.63, 58.83, 20.38, 8.41, 7.33.ESI-MS m / z:[MH] - calcd.for C 27 H 21 Cl2NO4, 492.0775; found, 492.0772.

[0152] Embodiment 18

[0153] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-3-methyl-[1,1′-biphenyl]-4-carboxylic acid (18)

[0154]

[0155] The first step raw materials were changed to 4-hydroxyphenylboronic acid (0.90 g, 6.55 mmol) and methyl 2-methyl-4-bromobenzoate (1.0 g, 4.37 mmol) for reaction. The rest of the synthetic operation was the same as compound 5, and a white solid was finally obtained with a yield of 60%. 1 HNMR (400MHz, DMSO-d6) δ7.86 (d, J=8.1Hz, 1H), 7.72-7.38 (m, 7H), 6.89 (d, J =8.7Hz, 2H), 4.91(s, 2H), 2.56(s, 3H), 2.49-2.39(m, 1H), 1.26-1.05(m, 4H). 13C NMR (101MHz, DMSO-d6) δ172.15, 168.45, 159.23, 158.08, 142.76, 139.98, 134.68, 132.51, 131.83, 131.15, 129.21, 128.46, 128.02, 127.10, 123.50, 115.18, 110.55, 58.98, 21.59, 8.45, 7.35.ESI-MS m / z:[MH] - calcd.for C 27 H 21 Cl2NO4, 492.0775; found, 492.0777.

[0156] Embodiment 19

[0157] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-3,5-difluoro-substituted derivatives [1,1′-biphenyl]-4-carboxylic acid (19)

[0158]

[0159] The first step raw materials were changed to 4-hydroxyphenylboronic acid (0.82 g, 5.98 mmol) and methyl 4-bromo-2,6-difluorobenzoate (1.0 g, 3.98 mmol) for reaction. The rest of the synthesis operation was the same as compound 5, and a white solid was finally obtained with a yield of 66%. 1 HNMR (400MHz, DMSO-d6) δ7.68 (d, J=8.7Hz, 2H), 7.64-7.58 (m, 2H), 7.56-7.51 (m, 1H), 7.47 (d, J=9.8Hz, 2H), 6.91 (d, J=8.6Hz, 2H), 4.93 (s, 2H), 2.48-2.42 (m, 1H), 1.23-1.10 (m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.12, 162.13, 159.90 (dd, J=252.5Hz), 159.16, 158.77, 144.27, 134.62, 132. 46, 129.47, 128.40, 128.23, 127.02, 115.14, 110.40, 109.98, 109.58, 109.33, 58.97, 8.41, 7.29.ESI-MS m / z:[MH] - calcd.for C 26 H 17 Cl2F2NO4, 514.0430; found, 514.0442.

[0160] Embodiment 20

[0161] 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylic acid (20)

[0162]

[0163] The first step raw materials were changed to 4-hydroxyphenylboronic acid (0.73 g, 5.30 mmol) and methyl-4-bromo-3-(trifluoromethyl)benzoate (1.0 g, 3.53 mmol) for reaction. The rest of the synthesis operation was the same as compound 5, and a white solid was finally obtained with a yield of 66%. 1 H NMR (400MHz, DMSO-d6) δ8.24 (s, 1H), 8.18 (d, J=8.0Hz, 1H), 7.68-7.58 (m, 2H), 7.58-7.44 (m, 2H) , 7.20 (d, J = 8.4Hz, 2H), 6.90 (d, J = 8.6Hz, 2H), 4.92 (s, 2H), 2.49-2.40 (m, 1H), 1.22-1.10 (m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.23, 165.94, 159.17, 157.85, 144.67, 134.68, 133.19, 132.72, 132.49, 131.04, 130.20, 129. 71, 128.43, 127.42, 127.12, 127.05, 126.72, 126.67, 123.74 (q, J=274.7Hz), 114.22, 110.46, 58.81, 8.43, 7.31.ESI-MS m / z:[MH] - calcd.for C 27 H 18 Cl2F3NO4, 546.0492; found, 546.0486.

[0164] Embodiment 21

[0165] 2-(4′-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-4-yl)ethan-1-ol (21)

[0166]

[0167] The first step raw materials were changed to 4-hydroxyphenylboronic acid (0.90 g, 6.55 mmol) and methyl 4-bromophenylacetate (1.0 g, 4.37 mmol) for reaction. The rest of the synthetic operation was the same as compound 5. The product after hydrolysis was selectively reduced with lithium aluminum hydride to reduce the hydroxy acid to alcohol, and the final product (light yellow solid) was obtained with a yield of 54%. 1 H NMR (400MHz, DMS0-d6) δ7.63-7.60 (m, 2H), 7.51-7.45 (m, 5H), 7.25 (d, J=8.0Hz, 2H), 6.87 (d, J=8.6Hz, 2H), 4 .89 (s, 2H), 4.62 (s, 1H), 3.65-3.59 (m, 2H), 2.73 (t, J=6.9Hz, 2H), 2.41 (d, J=5.3Hz, 1H), 1.17-1.11 (m, 4H). 13 C NMR (101MHz, DMSO-dd6) δ172.03, 159.14, 157.27, 138.14, 137.35, 134.62, 133.09, 132.40, 130.68, 130.57, 129 .35, 128.37, 128.34, 128.02, 127.42, 127.05, 125.95, 115.05, 110.54, 62.11, 58.87, 38.59, 8.32, 7.26.ESI-MS m / z:[MH] - calCd.for C 27 H 23 Cl2NO3, 478.0982; found, 478.0972.

[0168] Embodiment 22

[0169] 1-(4′-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-4-yl)cyclopropylmethanol (22)

[0170]

[0171] The first step raw materials were changed to 4-hydroxyphenylboronic acid (0.81 g, 5.88 mmol) and 1-(4-bromophenyl)cyclopropanecarboxylic acid methyl ester (1.0 g, 3.92 mmol) for reaction. The rest of the synthetic operation was the same as compound 21, and finally a yellow solid was obtained with a yield of 57%. 1HNMR (400MHz, DMSO-d6) δ7.62 (d, J=7.6Hz, 2H), 7.59-7.49 (m, 2H), 7.51-7.46 (m, 3H), 7.39-7.27 (m, 2H), 7.22 (d, J=7.4Hz, 1H), 6.89 (t, J=9.2Hz, 2H), 4.90 (s, 2H), 4.64 (t, J=5.3Hz, 1H), 3.56 (d, J=5.1Hz, 2H), 2.47-2.38 (m, 1H), 1.19-1.10 (m, 4H), 0.84 (s, 2H), 0.78 (s, 2H). 13 C NMR (101MHz, DMSO-d6) δ172.00, 159.13, 157.38, 144.53, 139.43, 134.61, 133.43, 132.38, 131.57, 131.48, 128.41, 128.36, 128.32, 127.73, 127.70, 127.05, 126.68, 126.30, 123.75, 115.23, 115.02, 110.53, 67.62, 58.89, 27.12, 11.33, 8.31, 7.24.ESI-MSm / z: [MH] - calcd.for C 29 H 25 Cl2NO3, 504.1139; found, 504.1138.

[0172] Embodiment 23

[0173] 2-(4′-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-4-yl)oxy)ethyl-1-ol (23)

[0174]

[0175] The first step raw materials were changed to 4-hydroxyphenylboronic acid (0.84 g, 6.12 mmol) and (4-bromophenoxy)acetic acid methyl ester (1.0 g, 4.08 mmol) for reaction. The rest of the synthetic operation was the same as compound 21, and finally a yellow solid was obtained with a yield of 50%. 1HNMR (400MHz, DMSO-d6) δ7.62 (d, J=7.9Hz, 1H), 7.56-7.42 (m, 6H), 7.04-6.92 (m, 2H), 6.92-6.79 (m, 2H), 4.90 (m, 2H), 4.00 (t, J=5.0Hz, 2H), 3.72 (t, J=4.9Hz, 2H), 2.45-2.35 (m, 1H), 1.22-1.10 (m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.12, 161.12, 157.83, 156.90, 134.60, 132.38, 132.08, 131.57, 131.48, 129.71, 128.36 , 127.32, 127.21, 127.11, 127.08, 115.24, 115.02, 114.81, 110.50, 69.54, 59.57, 59.05, 8.30, 8.08, 7.18.ESI-MS m / z:[MH] - calcd.for C 27 H 23 Cl2NO4, 494.0931; found, 494.0935.

[0176] Embodiment 24

[0177] 4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)pyridin-2-yl)benzoic acid (24)

[0178]

[0179] The first step of the reaction was to react 2-bromo-5-hydroxypyridine (1 g, 5.75 mmol) and p-methoxycarbonylphenylboronic acid pinacol ester (1.06 g, 3.83 mmol). The remaining synthetic operations were the same as compound 5, and a white solid was finally obtained with a yield of 33%. 1 HNMR (400MHz, DMSO-d6) δ8.26 (d, J=2.9Hz, 1H), 8.10 (d, J=8.4Hz, 2H), 8.02 (d, J=8.3Hz, 3H ), 7.64-7.59(m, 2H), 7.58-7.50(m, 2H), 5.09(s, 2H), 2.55-2.51(m, 1H), 1.23-1.12(m, 4H). 13C NMR (101MHz, DMSO-d6) δ172.59, 167.01, 159.11, 154.16, 147.06, 140.91, 136.61, 134.63, 132.56, 131. 61, 130.68, 129.77, 128.47, 126.86, 126.42, 126.40, 123.97, 122.30, 110.02, 59.62, 8.57, 7.31.ESI-MS m / z:[MH] - calcd.for C 25 H 18 Cl2N2O4, 479.0571; found, 479.0578.

[0180] Embodiment 25

[0181] 4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)pyrazin-2-yl)benzoic acid (25)

[0182]

[0183] The first step raw material was changed to 2-bromo-5-hydroxypyrazine (1 g, 5.71 mmol) and p-methoxycarbonylphenylboronic acid pinacol ester (1.05 g, 3.81 mmol) for reaction. The rest of the synthesis operation was the same as compound 5, and a white solid was finally obtained with a yield of 41%. 1 HNMR (400MHz, DMSO-d6) δ11.68 (s, 1H), 8.08-7.87 (m, 3H), 7.63 (d, J=8.2Hz, 2H), 7.47-7.33(m, 4H), 4.97(d, J=11.7Hz, 2H), 2.71-2.59(m, 1H), 1.23-1.12(m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.85, 167.10, 158.52, 154.37, 149.54, 147.56, 139.57, 134.72, 132.58, 129.73, 129.60, 128.35, 124.11, 121.32, 108.88, 54.02, 8.38, 8.34, 7.41.ESI-MS m / z:[MH] - calcd.for C 24 H 17 Cl2N3O4, 480.0523; found, 480.0515.

[0184] Embodiment 26

[0185] 6-(4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)phenyl)nicotinic acid (26)

[0186]

[0187] The first step raw materials were changed to 6-bromonicotinoic acid methyl ester (1 g, 4.63 mmol) and 4-hydroxyphenylboronic acid (0.42 g, 3.09 mmol) for reaction. The rest of the operation was the same as compound 5, and the product was white with a yield of 42%. 1 H NMR (400MHz, DMSO-d6) δ9.08 (d, J=1.6Hz, 1H), 8.32 (dd, J=8.4, 2.2Hz, 1H), 8.14-7.99 (m, 3H), 7.66-7. 59 (m, 2H), 7.58-7.51 (m, 1H), 6.97 (d, J=8.9Hz, 2H), 4.98 (s, 2H), 2.50-2.37 (m, 1H), 1.22-1.10 (m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.17, 166.02, 159.67, 159.16, 158.58, 149.75, 138.46, 134.63, 132. 48, 129.92, 128.65, 128.42, 127.02, 124.49, 119.49, 114.99, 110.38, 58.98, 8.41, 7.30.ESI-MS m / z:[MH] - calcd.for C 25 H 18 Cl2N2O4, 479.0571; found, 479.0570.

[0188] Embodiment 27

[0189] 5-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-ylmethoxy)phenyl)thiophene-2-carboxylic acid (27)

[0190]

[0191] The first step raw materials were changed to 5-bromothiophene-2-carboxylic acid methyl ester (1 g, 4.52 mmol) and 4-hydroxyphenylboronic acid (0.42 g, 3.02 mmol). The rest of the synthesis operation was the same as compound 5, and finally a yellow solid was obtained with a yield of 33%. 1H NMR (400MH, DMSO-d6) δ7.86 (d, J=17.2Hz, 2H), 7.64-7.52 (m, 5H), 6.83 (d, J=8.5Hz, 2H), 4.89 (s, 3H), 2.51-2.34 (m, 1H), 1.25-0.85 (m, 4H). 13 C NMR (101MH [z, DMSO-d6) δ172.03, 163.71, 159.17, 157.23, 141.10, 134.64, 132.42, 129.14, 128.39, 128.06, 127.07, 124.30, 115.03, 110.56, 58.89, 8.38, 7.29.ESI-MS m / z:[MH] - calcd.for C 24 H 17 Cl2NO4S, 484.0183; found, 484.0187.

[0192] Embodiment 28

[0193] 4-(5-Cyclopropyl-3-(2-trifluoromethylphenyl)isoxazole-4-methoxy)-[1,1′-biphenyl]-4-carboxylic acid (28)

[0194]

[0195] Synthesis steps of compound 6 In the third step, the raw material was changed to 6b to undergo Williamson etherification, and the remaining steps were the same. A white solid was finally obtained with a yield of 79%. 1 H NMR (400MHz, DMSO-d6) δ12.94 (s, 1H), 7.97 (d, J = 8.1Hz, 2H), 7.90 (d, J = 7.7Hz, 1H), 7.81-7.67 (m, 4H), 7.66-7.56 (m, 3H), 6.96 (d, J=8.5Hz, 2H), 4.89 (s, 2H), 2.47-2.39 (m, 1H), 1.26-1.09 (m, 4H). 13 C NMR (101MHz, DMSO-d6) δ171.95, 167.14, 161.24, 158.12, 143.81, 132.40, 131.84, 131.78, 130.34, 129.91, 128. 92, 128.33, 128.05, 126.56, 126.51, 126.16, 123.62 (q, J=274.7Hz), 115.32, 110.45, 58.63, 8.24, 7.12.ESI-MS m / z:[MH] -calcd.for C 27 H 20 F3NO4, 478.1272; found, 478.1286.

[0196] Embodiment 29

[0197] 4-(5-Isopropyl-3-(2-trifluoromethylphenyl)isoxazole-4-methoxy)-[1,1′-biphenyl]-4-carboxylic acid (29)

[0198]

[0199] The synthesis steps of compound 6: In the third step, the raw material was changed to 6e to undergo Williamson etherification, and the remaining steps were the same. Finally, a white solid was obtained with a yield of 47%. 1 H NMR (400MHz, DMSO-d6) δ7.97 (d, J=8.0Hz, 2H), 7.91 (d, J=7.5Hz, 1H), 7.80-7.68 (m, 5H), 7.63-7.60 (m, 2H), 6.94 (d, J=8.4Hz, 2H), 4.83 (s, 2H), 1.33 (d, J=7.0Hz, 6H). 13 CNMR (101MHz, DMSO-d6) δ175.75, 161.00, 158.05, 143.58, 132.42, 131.91, 131.85, 130.34, 1 29.88, 128.05, 126.73, 126.54, 126.11, 124.98, 115.34, 109.42, 58.67, 25.95, 20.65.ESI-MS m / z:[MH] - calcd.for C 27 H 22 F3NO4, 480.1428; found, 480.1417.

[0200] Embodiment 30

[0201] 4-(5-Cyclopropyl-3-(2-trifluoromethoxy)phenyl)isoxazole-4-methoxy)-[1,1′-biphenyl 1-4-carboxylic acid (30)

[0202]

[0203] The synthesis steps of compound 6: The raw material in the third step is changed to 6c to undergo Williamson etherification, and the remaining steps are the same. A white solid is finally obtained with a yield of 45%. 1H NMR (400MHz, DMSO-d6) δ8.01-7.96 (m, 2H), 7.72-7.61 (m, 6H), 7.57-7.51 (m, 2H) 7.01-6.92 (m, 2H), 4.98 (s, 2H), 2.44-2.40 (m, 1H), 1.18-1.10 (m, 4H). 13 CNMR (101MHz, DMSO-d6) δ172.52, 158.98, 158.05, 145.95, 143.25, 132.00, 131.93, 131.66, 129.87, 128.02, 127.79, 126.00, 122.25, 121.38, 115.29, 110.15, 58.94, 8.15, 7.16.ESI-MS m / z:[MH] - calcd.for C 27 H 20 F3NO5, 494.1221; found, 494.1222.

[0204] Embodiment 31

[0205] 4-(5-Isopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-methoxy)-[1,1′-biphenyl]4-carboxylic acid (31)

[0206]

[0207] The synthesis steps of compound 6 are as follows: in the third step, the raw material is changed to 6f to undergo Williamson etherification, and the remaining steps are the same, and the product is a yellow solid with a yield of 36%. 1 H NMR (400MHz, DMSO-d6) δ7.98-7.93 (m, 2H), 7.73-7.60 (m, 6H), 7.58-7.52 (m, 2H), 6.97-6.90 (m, 2H), 4.91 (s, 2H), 1.33 (d, J=7.0Hz, 6H).ESI-MS m / z:[MH] - calcd.for C 27 H 22 F3NO5, 496.1377; found, 496.1376.

[0208] Embodiment 32

[0209] 4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-[1,1′-biphenyl]-4-carboxamide (32)

[0210]

[0211] Take 0.5g (1.04mmol) of compound 6 and dissolve it in anhydrous dichloromethane. In a low-temperature constant temperature stirring reactor (-20°C), a dichloromethane solution of thionyl chloride is dripped dropwise into it with a constant pressure bottom liquid funnel. The whole process is completely anhydrous. After reacting for 2h, it is directly distilled under reduced pressure and dried without extraction, and then 4-dimethylaminopyridine, 2mL DMF and 10mL dichloromethane are added thereto. The reaction bottle is placed in a low temperature device, and a dichloromethane solution containing 0.04g (2.41mmol) methylamine is dripped into it. After reacting for 3h, it is purified by column chromatography to obtain compound 34 (yellow viscous solid) with a yield of 40%. 1 H NMR (400MHz, DMSO.-d6) δ8.02-7.88(m, 3H), 7.69-7.50(m, 7H), 7.39-7.25(m, 1H), 6.91 (d, J=8.7Hz, 2H), 4.92 (s, 2H), 2.49-2.35 (m, 1H), 1.20-1.02 (m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.04, 167.54, 159.13, 157.91, 142.24, 134.61, 132.39, 132. 00, 128.36, 128.07, 127.88, 127.03, 125.80, 115.11, 110.47, 58.90, 8.33, 7.25.ESI-MS m / z:[M+H] + calcd.for C 26 H 20 Cl2N2O3, 479.0924; found, 479.0920.

[0212] Embodiment 33

[0213] 4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-methyl-[1,1′-biphenyl]-4-carboxamide (33)

[0214]

[0215] The last amine solution added was methylamine, and the remaining synthetic operations were the same as compound 32, yielding a light yellow viscous solid with a yield of 46%. 1H NMR (400MHz, DMSO-d6) δ8.41 (d, J=4.4Hz, 1H), 7.87 (d, J=8.3Hz, 2H), 7.70-7.51 (m, 7H), 6.9 1 (d, J=8.7Hz, 2H), 4.92 (s, 2H), 2.79 (d, J=4.4Hz, 3H), 2.48-2.41 (m, 1H), 1.22-1.12 (m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.05, 166.25, 159.13, 157.90, 142.03, 134.61, 132.63, 132.41, 131. 97, 128.37, 127.86, 127.62, 127.03, 125.86, 115.12, 110.47, 58.90, 26.22, 8.33, 7.25.ESI-MS m / z:[M+H] + calcd.for C 27 H 22 Cl2N2O3, 493.1080; found, 493.1074.

[0216] Embodiment 34

[0217] 4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide (34)

[0218]

[0219] The last amine solution added was dimethylamine, and the remaining synthetic operations were the same as compound 32. Finally, a dark brown viscous solid was obtained with a yield of 56%. 1 H NMR(400MHz,DMSO-d6)_δ7.68-7.60(m,4H),7.60-7.53(m,3H),7.44(d,2H),6.92 (t, J=9.4Hz, 2H), 4.92 (s, 2H), 2.97 (s, 6H), 2.47-2.40 (m, 1H), 1.21-1.11 (m, 4H). 13C NMR (101MHz, DMSO-d6) δ172.05, 169.88, 159.12, 157.77, 140.53, 134.68, 134.61, 132.40, 132.15, 131.57, 128. 37, 127.80, 127.77, 127.62, 127.33, 127.03, 125.88, 115.34, 115.13, 110.48, 58.87, 56.00, 8.32, 7.25.ESI-MS m / z:[M+H] + calcd.for C 28 H 24 Cl2N2O3, 507.1237; found, 507.1238.

[0220] Embodiment 35

[0221] N-Cyclopropyl-4′-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-[1,1′-biphenyl]-3-carboxamide (35)

[0222]

[0223] The initial raw material was changed to compound 5, and the last amine solution added was changed to cyclopropylamine. The remaining synthetic operations were the same as compound 34. Finally, a brown sticky solid was obtained with a yield of 61%. 1 H NMR (400MHz, DMSO-d6) δ8.50 (d, 1H), 7.98 (t, 1H), 7.78-7.68 (m, 2H), 7.63-7.47 (m, 6H), 6.94-6.88 (m, 2H), 4.92(s, 2H), 2.89-2.83(m, 1H), 2.49-2.42(m, 1H), 1.20-1.13(m, 4H), 0.73-0.68(m, 2H), 0.60-0.55(m, 2H). 13 C NMR (101MHz, DMSO-d6) δ172.03, 167.37, 159.15, 157.71, 139.63, 134.97, 134.62, 132.42, 128.80, 128 .75, 128.39, 127.86, 127.06, 125.69, 124.76, 115.09, 110.51, 58.92, 23.06, 8.38, 7.28, 5.75.ESI-MS m / z:[M+H] + calcd.for C 29 H 24 Cl2N2O3, 519.1237; found, 519.1243.

[0224] Embodiment 36

[0225] 4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-cyclopropylmethyl-[1,1′-biphenyl]-3-carboxamide (36)

[0226]

[0227] The last amine added was cyclopropylmethylamine, and the remaining steps were the same as compound 35. The product was a yellow viscous solid with a yield of 44%. 1 H NMR (400MHz, DMSO-d6) δ8.65(t,J=5.6Hz,1H),8.05(t,J=1.6Hz,1H),7.80-7.77(m,1H),7.76-7.72(m,1H),7.64-7.49(m,6H),6.95-6.90( m, 2H), 4.93 (s, 2H), 3.17 (t, J = 6.2Hz, 2H), 2.49-2.44 (m, 1H), 1.21-1.14 (m, 4H), 1.08-1.02 (m, 1H), 0.47-0.43 (m, 2H), 0.26-0.22 (m, 2H). 13 C NMR (101MHz, DMSO-d6)_δ172.04, 165.98, 159.15, 157.72, 139.66, 135.17, 134.62, 132.43, 128.84, 128.7 2, 128.39, 127.86, 127.06, 125.75, 124.80, 115.11, 110.51, 58.92, 43.55, 11.01, 8.37, 7.28, 3.33.ESI-MS m / z:[M+H] + calcd.forC 30 H 26 Cl2N2O3, 533.1393; found, 533.1385.

[0228] Embodiment 37

[0229] 4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-methyl-[1,1′-biphenyl]-3-carboxamide (37)

[0230]

[0231] The raw material was changed to compound 5, and the remaining synthetic steps were the same as compound 33, obtaining a dark brown solid with a yield of 55%. 1HNMR(400MHz,DMSO-d6)δ8.57-8.41(m,1H)8.02(s,1H),7.80-7.68(m,2H),7.64-7.46(m,6H) ,6.95-6.86(m,2H),4.92(s,2H),2.81(d,J=4.4Hz,3H),2.49-2.37(m,1H),1.20-1.12(m,4H). 13 C NMR (101MHz, DMSO-d6) δ172.03, 166.53, 159.13, 157.71, 139.67, 135.08, 134.62, 132.41, 132.39, 128. 85, 128.65, 128.37, 127.81, 127.06, 125.55, 124.67, 115.11, 110.51, 58.92, 26.22, 8.33, 7.26.ESI-MS m / z:[M+H] + calcd.for C 27 H 22 Cl2N2O3, 493.1080; found, 493.1072.

[0232] Embodiment 38

[0233] 4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N,N-dimethyl-[1,1′-biphenyl]-3-carboxamide (38)

[0234]

[0235] The raw material was changed to compound 5, and the other operations were the same as compound 34. The product was a dark brown sticky solid with a yield of 61%. 1 HNMR (400MHz, DMSO-d6) δ7.67-7.58(m,3H),7.58-7.51(m,4H),7.47(t,J=7.6Hz,1H),7.31(d,J=7.4Hz ,1H),6.90(d,J=8.3Hz,2H),4.91(s,2H),2.96(d,J=25.2Hz,6H),2.48-2.40(m,1H),1.21-1.09(m,4H). 13C NMR (101MH-z, DMSO-d6) δ172.03, 169.97, 159.12, 157.70, 139.64, 137.15, 134.60, 132.38, 132.24, 128.81, 128.36, 127.77, 127.03, 126.98, 125.18, 124.48, 115.11, 110.48, 58.88, 8.31, 7.24.ESI-MS m / z:[M+H] + calcd.for C 28 H 24 Cl2N2O3, 507.1237; found, 507.1234.

[0236] Embodiment 39

[0237] 4′-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-isopropyl-[1,1′-biphenyl]-3-carboxamide (39)

[0238]

[0239] The last amine added was isopropylamine, and the remaining steps were the same as compound 35. The product was a yellow viscous solid with a yield of 51%. 1 H NMR(400MHz, DMSO-d6)δ8.29(d,J=7.7Hz,1H),8.01(t,J=1.8Hz,1H),7.79-7.69(m,2H),7.65-7.45 (m,7H),6.94-6.89(m,2H),4.92(s,2H),4.16-4.07(m,1H),2.48-2.43(m,1H),1.20-1.13(m,11H). 13 C NMR (101MHz, DMSO-d6) δ172.03, 165.24, 159.16, 157.71, 139.61, 135.38, 134.62, 132.50, 132.43, 128.75, 128.65, 128.39, 127.88, 127.06, 125.81, 124.82, 115.09, 110.51, 58.92, 41.01, 22.37, 8.38, 7.28.ESI-MS m / z:[M+H] + calcd.for C 29 H 26 Cl2N2O3, 521.1393; found.521.1396.

[0240] Embodiment 40

[0241] 4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-isopropyl-[1,1′-biphenyl]-4-carboxamide (40)

[0242]

[0243] The last amine added was isopropylamine, and the remaining steps were the same as compound 32. The product was a light yellow viscous solid with a yield of 73%. 1 H NMR (400MHz, DMSO-d6) δ8.18 (d, J = 7.7Hz, 1H), 7.96-7.84 (m, 2H), 7.69-7.46 (m, 7H), 6. 98-6.84(m,2H),4.92(s,2H),4.20-4.03(m,1H),2.49-2.40(m,1H),1.21-1.11(m,10H). 13 C NMR (101MHz, DMSO-d6) δ171.94, 164.94, 159.04, 157.85, 141.90, 134.56, 132.96, 132.30, 132.00, 128 .29, 127.78, 127.74, 127.01, 125.64, 115.30, 115.09, 110.43, 58.92, 40.88, 22.26, 8.18, 7.17.ESI-MS m / z:[M+H] + calcd.for C 29 H 26 Cl2N2O3, 521.1393; found, 521.1391.

[0244] Embodiment 41

[0245] 4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-isobutyl-[1,1′-biphenyl]-3-carboxamide (41)

[0246]

[0247] The last amine added was isobutylamine, and the remaining steps were the same as compound 35. The product was a brown viscous solid with a yield of 46%. 1H NMR(400MHz,DMSO-d6)δ8.54(t,J=5.8Hz,1H),8.03(t,J=1.5 Hz, 1H), 7.79-7.70 (m, 2H), 7.63-7.46 (m, 6H), 7.01-6.85 (m, 2H), 4.92 (s, 2H), 3.13-3.0 4(m, 2H), 2.49-2.44(m, 1H), 1.91-1.81(m, 1H), 1.22-1.13(m, 4H), 0.90(d, J=6.7Hz, 6H). 13 C NMR (101MHz, DMSO-d6) δ172.05, 166.16, 159.16, 157.71, 139.66, 135.32, 134.62, 132.47, 132.42, 128.83, 128 .67, 128.39, 127.86, 127.06, 125.73, 124.78, 115.11, 110.51, 58.92, 46.76, 28.13, 20.24, 8.38, 7.28.ESI-MS m / z:[M+H] + calcd.for C 30 H 28 Cl2N2O3, 535.1550; found, 535.1553.

[0248] Embodiment 42

[0249] 4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-propyl-I1,1′-biphenyl]-3-carboxamide (42)

[0250]

[0251] The last amine added was propylamine, and the remaining steps were the same as compound 35 to obtain the product as a dark brown solid with a yield of 51%. 1 H NMR (400MHz, DMSO-d6) δ8.54(t,J=5.6Hz,1H),8.02(t,J=1.8Hz,1H),7.78-7.70(m,2H),7.64-7.47(m,6H),6.95-6.89( m,2H),4.92(s,2H),3.27-3.21(m,2H),2.48-2.43(m,1H),1.59-1.52(m,2H),1.20-1.13(m,4H),0.90(t,J=7.4Hz,3H), 13C NMR (101MHz, DMSO-d6) δ172.04, 166.02, 159.15, 157.71, 139.65, 135.27, 134.62, 132.46, 132.42, 128.83, 128 .66, 128.39, 127.85, 127.06, 125.69, 124.75, 115.10, 110.51, 58.92, 41.01, 22.41, 11.48, 8.37, 7.28.ESI-MS m / z:[M+H] + ca1cd.for C 29 H 26 Cl2N2O3, 521.1393; found, 521.1389.

[0252] Embodiment 43

[0253] N-tert-butyl-4′-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-3-carboxamide (43)

[0254]

[0255] The last amine added was tert-butylamine, and the remaining steps were the same as compound 35, and a brown viscous solid was finally obtained with a yield of 66%. 1 H NMR (400MHz, DMSO-d6) δ7.94 (t, J = 1.6Hz, 1H), 7.84 (s, 1H), 7.73-7.67 (m, 2H), 7.64-7.53 (m, 5H), 7. 49-7.44(m, 1H), 6.94-6.89(m, 2H), 4.92(s, 2H), 2.48-2.40(m, 1H), 1.39(s, 9H), 1.19-1.13(m, 4H). 13 C NMR (101MHz, DMSO-d6) δ172.03, 166.23, 159.16, 157.67, 139.48, 136.43, 134.62, 132.57, 132.42, 128.61, 128.46, 128.39, 127.90, 127.06, 125.86, 125.01, 115.07, 110.51, 58.91, 50.82, 28.61, 8.37, 7.28.ESI-MS m / z:[M+H] + calcd.for C 30 H 28 Cl2N2O3, 535.1550; found, 535.1554.

[0256] Embodiment 44

[0257] 4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-ylmethoxy)-[1,1′-biphenyl-1-3-yl)(morpholinyl)methanone (44)

[0258]

[0259] The last amine added was changed to morpholine, and the remaining steps were the same as compound 35. The final product was obtained as a dark yellow oil with a yield of 37%. 1 H NMR (400MHz, DMSO-d6) δ7.68-7.60 (m, 3H), 7.59-7.52 (m, 4H), 7.50-7.45 (m, 1H), 7.32 (d, J = 7.5H z, 1H), 6.94-6.87 (m, 2H), 4.92 (s, 2H), 3.66-3.35 (m, 8H), 2.48-2.42 (m, 1H), 1.22-1.13 (m, 4H). 13 C NMR (101MHz, DMSO-d6) δ171.95, 168.88, 159.04, 157.70, 139.78, 136.22, 134.56, 132.30, 132.13, 128. 91, 128.30, 127.74, 127.16, 127.01, 125.19, 124.48, 115.09, 110.44, 65.98, 58.89, 8.18, 7.17.ESI-MS m / z:[M+H] + calcd.forC 30 H 26 Cl2N2O4, 549.1342; found, 549.1338.

[0260] Embodiment 45

[0261] 4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-ylmethoxy)-[1,1′-biphenyl]-3-yl)pyrrolidine-1-methanone (45)

[0262]

[0263] The last amine added was tetrahydropyrrole, and the remaining steps were the same as compound 35. The final product was a dark yellow viscous solid with a yield of 42%. 1H NMR (400MHz, DMSO-d6) δ7.69-7.61(m,3H),7.60-7.52(m,3H),7.52-7.22(m,3H),6.97-6.82(m,2H),4.9 1(s, 2H), 3.55-3.44(m, 2H), 3.44-3.36(m, 2H), 2.48-2.42(m, 1H), 1.94-1.73(m, 4H), 1.20-1.08(m, 4H). 13 C NMR (101MHz, DMSO-d6) δ171.95, 168.03, 159.04, 157.65, 139.54, 137.88, 134.56, 132.30, 128.69, 128.30, 12 7.72, 127.25, 127.01, 125.20, 124.53, 115.08, 110.45, 58.89, 48.81, 45.77, 25.85, 23.83, 8.18, 7.17.ESI-MS m / z:[M+H] + calcd.for C 30 H 26 Cl2N2O3, 533.1393; found, 533.1396.

[0264] Embodiment 46

[0265] 4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-phenylsulfonyl-[1,1′-biphenyl]-4-carboxamide (46)

[0266]

[0267] 0.2 g (0.416 mmol) of compound 6 and 0.091 g (0.582 mmol) of benzenesulfonamide were placed in a reaction bottle, and a condensing agent EDCI (0.096 g, 0.624 mmol) was added. Then, 0.084 g (0.624 mmol) of 1-hydroxybenzotriazole and 0.076 g (0.624 mmol) of 4-dimethylaminopyridine were added to react. The solvent was dichloromethane. The reaction was carried out at room temperature for 14 h. The white solid was obtained by purification by column chromatography with a yield of 42%. 1 H NMR (400MHz, DMSO-d6) 68.25 (dd, J=48.3, 8.3Hz, 2H), 8.01-7.92 (m, 3H), 7.77-7.68 (m, 3H), 7.65-7.50 (m, 5H), 7.41 (t, 1H), 6.95 (dd, J=23.9, 8.4Hz, 2H), 4.95 (d, J=15.1Hz, 2H), 2.47-2.41 (m, 1H), 1.24-1.19 (m, 2H), 1.16-1.12 (m, 2H). 13 C NMR (101MHz, DMSO-d6) δ172.56, 167.61, 159.61, 158.62, 144.29, 135.11, 132.89, 132.25, 131.97, 130.37, 130.22, 129.4 0, 128.87, 128.51, 128.29, 127.82, 127.53, 126.77, 126.77, 126.63, 124.88, 115.67, 110.95, 110.00, 59.42, 8.81, 7.74.

[0268] Embodiment 47

[0269] 4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-methylsulfonyl-[1,1′-biphenyl]-4-carboxamide (47)

[0270]

[0271] The reaction raw material was changed to methylsulfonamide, and the remaining steps were the same as compound 46 to obtain a white solid with a yield of 47%. 1 H NMR (400MHz, DMSO-d6) δ7.98 (dd, J=8.3Hz, 2H), 7.73-7.70 (m, 2H), 7.62-7.60 (m, 2H), 7.57-7.51 (m, 2H), 7.41 (t, J=7 .8Hz, 1H), 6.92 (d, J=8.8Hz, 2H), 4.92 (s, 2H), 3.02 (s, 3H), 2.47-2.39 (m, 1H), 1.15-1.10 (m, 2H), 0.85-0.80 (m, 2H). 13 C NMR (101MHz, DMSO-d6) δ172.52, 169.51, 159.63, 158.29, 142.31, 135.93, 135.10, 132.89, 132.75, 131.97, 129.45, 128.86, 128.29, 127.53, 125.86, 115.59, 110.99, 59.39, 41.17, 14.55, 8.82, 7.75.

[0272] Example 48 In vitro biological activity test

[0273] 1) Determination of FXR agonist activity based on fluorescence resonance energy transfer (TR-FRET)

[0274] Different concentrations of FXR agonist (GW4064 as positive control), FXR-LBD, fluorescein-SRC2-2 and Tbanti-GST antibodies were added to a 384-well plate in sequence. The microplate was placed on an oscillator and gently mixed, and then incubated at room temperature in the dark for 3 hours. EnVision multifunctional microplate reader was used to detect TR-FRET signals at wavelengths of 520nm and 495nm. The TR-FRET ratio of the emission signal at a wavelength of 520nm to the emission signal at a wavelength of 495nm was calculated. EC50 was calculated using GraphPad software. Excitation efficiency (%) = (compound signal-blank signal) / (control signal-blank signal) × 100%, where GW4064 is the control signal and DMSO is the blank signal. The test results are shown in Table 1.

[0275] 2) Determination of FXR agonist activity based on transfected cells

[0276] Using the FuGene6 transfection kit, strictly follow the operating procedures in the instructions, and co-transfect HepG2 cells with 10ng of hRXR, 10ng of pCMV Gal, 10ng of FXR expression vector and 30ng of the corresponding reporter gene in each well. After 24 hours, the cells were incubated with DMEM (containing 10% FBS) medium and treated with the test compound or GW4064. 24 hours after treatment, the cells were collected using cell culture lysis buffer. According to the instructions, luciferase activity was tested using a luciferase assay kit. Beta-galactosidase was measured in a microplate using a Promega kit, and the data was read in a microplate reader. The relative activity value was obtained by dividing the multiple value of the test compound by the multiple value of GW4064 at 3μM. EC was calculated using GraphPad software 50 , the test results are shown in Table 1.

[0277] Table 1: FXR agonist activity

[0278]

[0279] Note: EC 50 The values ​​are the average of three independent experiments, and the agonist efficacy is the relative value of the full agonist GW4064. ND means not determined.

[0280] The above results show that the compounds of the present invention have good FXR agonist activity.

[0281] Example 49 In vivo anti-NASH activity study

[0282] 20-25g male C57BL / 6 mice were raised in an SPF barrier environment with free access to food and water. They were adaptively raised for one week before the experiment. They were randomly divided into a normal group, a model group, an obeticholic acid (OCA) administration group, and a test compound administration group. The normal group was given normal basal feed and drinking water, and the other groups were fed a high-fat diet and prepared with sugar water (23.1g / L fructose: 18.9g / L glucose) for drinking. At the same time, all groups except the normal group were intraperitoneally injected with CCl4 (2%, 2mL / kg) twice a week for three months. Daily gavage began in the 9th week, with 10% sodium carboxymethylcellulose (CMC-Na) in the normal group, OCA group (20mg / kg), and different doses of the test compound. Fasting for 8h before sampling, blood was drawn and mice were killed, and liver and ileum were dissected. A piece of tissue was taken from the same part of each liver and placed in 10% neutral buffered formalin for section analysis. The remaining livers were placed in cryopreservation tubes and stored at -80°C. Liver tissue pathological analysis was performed using H&E staining. Figure 1 .

[0283] The experimental results showed that: the liver cells in the model group underwent degeneration and necrosis, and multiple and dense vacuoles appeared in the liver cells; lipids accumulated in the cells, and there was a very obvious infiltration of inflammatory cell groups; there was local focal necrosis of the liver cells, and macrophages and lymphocytes gathered at the necrotic cells. The OCA-treated group had significantly fewer vacuoles than the model group, and there were no dense macrophages and lymphocytes gathering, but severe inflammation could still be observed. The compound 6-treated group had mild inflammation, normal liver cell morphology, no ballooning, neatly arranged cells, and significantly improved fat deformation, but some lipid accumulation could still be observed. Compared with OCA, the improvement effect of compound 6 was better. The liver condition in the compound 37-treated group improved in a dose-dependent manner (see Appendix). Figure 1 ).

[0284] Example 50 In vivo anti-cholestatic liver disease study

[0285] After the adaptive feeding of six-week-old male C57BL / 6 mice, the mice were randomly divided into a normal group, a model group, an OCA group, and a compound 6 group. The normal group and the model group were given the solvent by gavage, and the OCA group (20 mg / kg) and the compound 6 group (3 mg / kg) were given by gavage every day for 5 days. Two hours after the administration on the fifth day, 50 mg / kg ANIT (the solvent was olive oil) was gavaged for modeling. 48 hours after the completion of the modeling, the mice were killed to collect blood and liver. A part of each liver was cut from the same position and fixed in a 4% paraformaldehyde solution for sectioning. The remaining tissue was placed in a cryopreservation tube and stored at -80°C; after the blood was centrifuged (5000rpm, 15min), the supernatant was aspirated into a centrifuge tube and stored at -20°C. Each kit strictly followed the instructions of the kit to add serum and various detection solutions to a 96-well plate in sequence, and then the absorbance was detected at the corresponding wavelength on the microplate reader. The experimental results are attached. Figure 2 .

[0286] The experimental results showed that the liver lobule cells in the model group showed focal infiltration, loose cytoplasm of liver cells, cell necrosis and hemorrhage, and pathological sections proved the success of the model. After preventive treatment with compound 6, the liver had a small amount of inflammatory cell infiltration, clear cell structure, and compact arrangement, which was significantly improved compared with the model group. Histological results showed that compound 6 had a significant protective effect on ANIT-induced liver tissue damage. Serum liver function indicators ALT and TBIL were significantly improved (Appendix Figure 2 ).

Claims

1. The compound represented by the general formula (I): in: R1 and R2 are each independently selected from hydrogen, halogen, trifluoromethyl or trifluoromethoxy; R3 is selected from cyclopropyl or isopropyl; R4 is selected from hydrogen, halogen, C1-C6 alkyl or trifluoromethyl; R5 and R6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, trifluoromethyl or the following groups: R7 is selected from hydrogen, halogen, C1-C6 alkyl or trifluoromethyl.

2. A compound of the general formula (I) as defined in claim 1: R1 and R2 are each independently selected from hydrogen, chlorine, fluorine, trifluoromethyl or trifluoromethoxy; R3 is selected from cyclopropyl or isopropyl; R4 is selected from hydrogen, chlorine, fluorine, C1-C6 alkyl or trifluoromethyl; R5 and R6 are each independently selected from hydrogen, chlorine, fluorine, C1-C6 alkyl, trifluoromethyl or the following groups: R7 is selected from hydrogen, chlorine, fluorine, C1-C6 alkyl or trifluoromethyl.

3. The compound of general formula (I) as defined in claims 1-2 is selected from: 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-3-carboxylic acid; 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-4-carboxylic acid; 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2′,6′-dimethyl-[1,1′-biphenyl]-4-carboxylic acid; 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2′-methyl-[1,1′-biphenyl]-4-carboxylic acid; 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-3′-methyl-[1,1′-biphenyl]-4-carboxylic acid; 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2′-fluoro-[1,1′-biphenyl]-4-carboxylic acid; 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-3′-fluoro-[1,1′-biphenyl]-4-carboxylic acid; 2′-Chloro-4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-4-carboxylic acid; 3′-Chloro-4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-4-carboxylic acid; 3-Chloro-4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-4-carboxylic acid; 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2-fluoro-[1,1′-biphenyl]-4-carboxylic acid; 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-3-fluoro-[1,1′-biphenyl]-4-carboxylic acid; 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2-methyl-[1,1′-biphenyl]-4-carboxylic acid; 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-3-methyl-[1,1′-biphenyl]-4-carboxylic acid; 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-3,5-difluoro-substituted derivatives [1,1′-biphenyl]-4-carboxylic acid; 4′-((5-cyclopropyl-3-(2,6-dichlorophenyl))isoxazol-4-yl)methoxy)-2-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylic acid; 4-(5-Cyclopropyl-3-(2-trifluoromethylphenyl)isoxazole-4-methoxy)-[1,1′-biphenyl]-4-carboxylic acid; 4-(5-isopropyl-3-(2-trifluoromethylphenyl)isoxazole-4-methoxy)-[1,1′-biphenyl]-4-carboxylic acid; 4-(5-Cyclopropyl-3-(2-trifluoromethoxy)phenyl)isoxazole-4-methoxy)-[1,1′-biphenyl]-4-carboxylic acid; 4-(5-isopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-methoxy)-[1,1′-biphenyl]-4-carboxylic acid; 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-[1,1′-biphenyl]-4-carboxamide; 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-methyl-[1,1′-biphenyl]-4-carboxamide; 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide; N-cyclopropyl-4′-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-[1,1′-biphenyl]-3-carboxamide; 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-cyclopropylmethyl-[1,1′-biphenyl]-3-carboxamide; 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-methyl-[1,1′-biphenyl]-3-carboxamide; 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N,N-dimethyl-[1,1′-biphenyl]-3-carboxamide; 4′-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-isopropyl-[1,1′-biphenyl]-3-carboxamide; 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-isopropyl-[1,1′-biphenyl]-4-carboxamide; 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-isobutyl-[1,1′-biphenyl]-3-carboxamide; 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-propyl-[1,1′-biphenyl]-3-carboxamide; N-tert-butyl-4′-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-[1,1′-biphenyl]-3-carboxamide; 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-ylmethoxy)-[1,1′-biphenyl]-3-yl)(morpholinyl)methanone; 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-ylmethoxy)-[1,1′-biphenyl]-3-yl)pyrrolidine-1-methanone; 4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-phenylsulfonyl-[1,1′-biphenyl]-4-carboxamide; 4-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)-N-methylsulfonyl-[1,1′-biphenyl]-4-carboxamide.

4. A pharmaceutical composition comprising the compound according to claims 1-3 and a suitable carrier or excipient.

5. Use of the compound defined in claims 1 to 3 in the preparation of a medicament for treating FXR-mediated diseases.

6. Use of the compound defined in claims 1 to 3 or the pharmaceutical composition according to claim 4 in the preparation of a medicament for preventing and / or treating at least one of primary biliary cirrhosis, biliary diarrhea, nonalcoholic steatohepatitis, alcoholic steatohepatitis, cholestatic liver disease, drug-induced liver injury, primary sclerosing cholangitis, portal hypertension, atherosclerosis, dyslipidemia, hyperlipidemia, organ fibrosis, cirrhosis, liver failure, gallstones, diabetes and its complications, inflammatory bowel disease and obesity.

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