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WO2024183807A1 - Aryl fused imidazole compound and medical use thereof - Google Patents

Aryl fused imidazole compound and medical use thereof Download PDF

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Publication number
WO2024183807A1
WO2024183807A1 PCT/CN2024/080685 CN2024080685W WO2024183807A1 WO 2024183807 A1 WO2024183807 A1 WO 2024183807A1 CN 2024080685 W CN2024080685 W CN 2024080685W WO 2024183807 A1 WO2024183807 A1 WO 2024183807A1
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compound
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substituted
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phenyl
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Inventor
戴量
孙宏斌
谢君凯
侯东亮
王锋琴
顾宇浩
冯志奇
袁浩亮
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HARBIN MEDISAN PHARMACEUTICAL Co Ltd
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of biomedicine, and specifically relates to an aryl imidazole compound with PPAR ⁇ selective agonist activity and its medical use.
  • Peroxisome proliferator-activated receptors are ligand-activated receptors in the nuclear hormone receptor family. Three mammalian peroxisome proliferator-activated receptors have been isolated, namely PPAR ⁇ , PPAR ⁇ (also known as PPAR ⁇ ) and PPAR ⁇ . After PPAR binds to its ligand and is activated, it forms a heterodimer with the retinoid X receptor (RXR). The formed PPAR/RXR heterodimer binds to the PPAR response element (PPRE) upstream of the target gene promoter, ultimately regulating the transcription of the target gene.
  • PPAR ⁇ PPAR ⁇
  • PPAR ⁇ also known as PPAR ⁇
  • PPAR ⁇ PPAR ⁇
  • RXR retinoid X receptor
  • the formed PPAR/RXR heterodimer binds to the PPAR response element (PPRE) upstream of the target gene promoter, ultimately regulating the transcription of the target gene.
  • PPAR ⁇ is widely expressed in the body, with the highest expression levels found in the digestive tract, heart, kidney, liver, fat and brain. Activation of PPAR ⁇ can significantly improve lipid metabolism, insulin sensitivity, energy balance, inflammatory response and fibrosis. In addition, activation of PPAR ⁇ can also promote mitochondrial biosynthesis and enhance mitochondrial function. Activation of PPAR ⁇ has a potential positive effect on the improvement of metabolic diseases, cardiovascular and cerebrovascular diseases, inflammatory diseases, autoimmune diseases, organ fibrosis diseases, neurological damage diseases, secondary diseases caused by pathogen infection, mitochondrial dysfunction and disordered diseases or tumors (Nature, 2000, 405, 421; J. Neurochem., 2008, 107, 497; Mol. Cells., 2012, 33, 217; J. Biomed. Sci., 2017, 24, 5; Eur. J. Med. Chem., 2019, 166, 502).
  • the main PPAR ⁇ selective agonists under clinical research include MBX-8025 (in the Phase III clinical study stage for primary biliary cholangitis), REN-001 (in the Phase II clinical study stage for mitochondrial myopathy), and ASP-0367 (in the Phase II clinical study stage for mitochondrial myopathy).
  • the present invention provides a novel aryl imidazole compound, which has a strong agonist effect on PPAR ⁇ , has good selectivity for PPAR ⁇ and PPAR ⁇ , and has good pharmacokinetic properties. Therefore, the compound of the present invention and pharmaceutically acceptable salts, deuterated compounds, tautomers, meso-forms, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates can be used to prepare PPAR ⁇ selective agonists, effectively solving the problem of the lack of effective PPAR ⁇ selective agonists in the clinic.
  • Another object of the present invention is to provide the medical use of the aryl imidazole compounds as PPAR ⁇ selective agonists.
  • the compounds and their pharmaceutically acceptable salts, deuterated compounds, tautomers, meso-racemates, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates can be used to prepare PPAR ⁇ selective agonists and to prepare drugs for preventing or treating PPAR ⁇ -related diseases.
  • the present invention provides an aryl imidazole compound or a pharmaceutically acceptable salt thereof as shown in formula (I):
  • R1 and R2 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, OR8 , a linear or branched alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, alkylsulfonyl, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkenyl group, a heterocycloalkyl group, a heterocycloalkenyl group, an alkynyl group, a phenyl group, a substituted phenyl group, a heteroaryl group, a substituted heteroaryl group, a condensed aryl group, or a substituted condensed aryl group, wherein the substituted phenyl group, the substituted heteroaryl group, and the substituted condensed aryl group may each be independently substituted by 1 to 2 of the following substituents: hal
  • R3 , R4 , R5 , R6 and R7 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, alkylsulfonyl, alkoxy, cycloalkyl of 3 to 6 carbon atoms, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl, substituted heteroaryl, fused ring aryl or substituted fused ring aryl, wherein the substituted phenyl, substituted heteroaryl and substituted fused ring aryl may each be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, straight or branched
  • n is selected from any integer between 0 and 5;
  • n is selected from any integer between 0 and 5;
  • X is selected from: O, S, CH 2 , CH 2 O, CH 2 S, CH 2 CH 2 , OCH 2 , SCH 2 , CH 2 CH 2 O, CH 2 CH 2 S, CH 2 CH 2 CH 2 , OCH 2 CH 2 , SCH 2 CH 2 , CH 2 CH 2 CH 2 O, CH 2 CH 2 CH 2 S, CH 2 CH 2 CH 2 CH 2 , OCH 2 CH 2 CH 2 or SCH 2 CH 2 CH 2 ;
  • Y is selected from:
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 are each independently selected from: CH or N;
  • R10 and R11 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, alkylsulfonyl, alkoxy, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkenyl group, a heterocycloalkyl group, a heterocycloalkenyl group, an alkynyl group, a phenyl group, a substituted phenyl group, a phenoxy group, a substituted phenyloxy group, a heteroaryl group, a substituted heteroaryl group, a fused ring aryl group, or a substituted fused ring aryl group, wherein the substituted phenyl group, the substituted heteroaryl group, and the substituted fused ring ary
  • 11 and the atoms to which they are attached may together form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring.
  • the aryl imidazole compound represented by formula (I) or a pharmaceutically acceptable salt thereof is:
  • R1 and R2 are each independently selected from the group consisting of: H, hydroxyl, halogen, cyano, OR8 , a linear or branched alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, methylsulfonyl, ethylsulfonyl, a cycloalkyl group having 3 to 6 carbon atoms, phenyl, or substituted phenyl, wherein the substituted phenyl group may be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, a linear or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, or methylsulfonyl;
  • R 8 is selected from: a straight chain or branched chain alkyl group of 1 to 4 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, or a phenyl group;
  • n is selected from any integer between 0 and 3;
  • n is selected from any integer between 0 and 3;
  • R3 , R4 , R5 , R6 and R7 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, methylsulfonyl, ethylsulfonyl, straight or branched chain alkyloxy of 1 to 4 carbon atoms, cycloalkyloxy of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl or substituted heteroaryl, wherein the substituted phenyl or substituted heteroaryl may each be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, cycl
  • X is selected from: O, S, CH 2 , CH 2 O, CH 2 S, CH 2 CH 2, OCH 2 , SCH 2 , CH 2 CH 2 O, CH 2 CH 2 S, CH 2 CH 2 CH 2 , OCH 2 CH 2 or SCH 2 CH 2 ;
  • Y is selected from:
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 are each independently selected from: CH or N;
  • R 9 is selected from: H, a linear or branched alkyl group of 1 to 4 carbon atoms, acetylaminoethyl or (CH 2 ) p OR 12 , wherein p is any integer of 2 to 6, and R 12 is selected from a linear or branched alkyl group of 1 to 4 carbon atoms;
  • R 10 and R 11 are each independently selected from: H, hydroxyl, halogen, cyano, straight chain or branched alkyl of 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, methylsulfonyl, ethylsulfonyl, straight chain or branched alkyloxy of 1 to 4 carbon atoms, cycloalkyloxy of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, substituted phenyl, phenoxy or substituted phenyloxy, wherein the substituted phenyl may be independently substituted with 1 to 2 substituents of: halogen, hydroxyl, cyano, straight chain or branched alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoro
  • aryl imidazole compounds also include pharmaceutically acceptable salts, deuterated compounds, Variomers, meso- and racemates, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates.
  • the aryl imidazole compound or its salt of the present invention is any one of the compounds shown in Table 1 below:
  • aryl imidazole compounds or pharmaceutically acceptable salts, deuterated compounds, tautomers, meso-racemates, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates of the present invention are potent PPAR ⁇ selective agonists and can thus be used to prepare PPAR ⁇ selective agonists.
  • aryl imidazole compounds or pharmaceutically acceptable salts, deuterated compounds, tautomers, mesomers, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates thereof described in the present invention can be used to prepare drugs for preventing or treating PPAR ⁇ -mediated diseases.
  • the compounds of the present invention can be used to prepare drugs for preventing and treating the following PPAR ⁇ -mediated diseases.
  • the compounds of the present invention can be used to prevent and treat metabolic diseases and cardiovascular and cerebrovascular diseases, including: insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, lipoma, painful lipomatosis, atherosclerosis, myocardial ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, myocardial hypertrophy, myocarditis, diabetic complications (including diabetic cardiomyopathy, diabetic nephropathy, polycystic kidney disease (ARPKD and ADPKD), diabetic ulcer, retinopathy and neuropathy, etc.), non-alcoholic fatty liver disease, non-alcoholic fatty hepatitis, alcoholic fatty liver disease, cirrhosis, hyperuricemia, gout, osteoporosis, polycystic ovary syndrome (PCOS), stroke or cerebral infarction, etc.
  • metabolic diseases and cardiovascular and cerebrovascular diseases including: insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia
  • the compounds of the present invention can be used to prevent and treat inflammatory diseases, autoimmune diseases, organ fibrosis diseases, neurodegenerative diseases or secondary diseases caused by pathogen infection, including: primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), liver fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis lung disease, interstitial pneumonia, tuberculosis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), Behcet's disease, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, obliterative bronchiolitis, allergic rhinitis, chronic rhinitis, sinusitis, systemic Lupus erythematosus, rheumatoid arthritis, spondylarthritis, osteoarthritis, synovitis, tendinitis, thromboangiitis obliterans,
  • the compounds of the present invention can be used to treat and regulate mitochondrial dysfunction and disorder diseases, including: muscle weakness, myoclonus, exercise intolerance, Kearns-Sayer syndrome, chronic fatigue syndrome, Leigh syndrome, mitochondrial myopathy-encephalopathy-hyperlactatemia, stroke syndrome or stroke-like attack, Duchenne muscular dystrophy, shell muscular dystrophy or Friedreich's ataxia, etc.
  • mitochondrial dysfunction and disorder diseases including: muscle weakness, myoclonus, exercise intolerance, Kearns-Sayer syndrome, chronic fatigue syndrome, Leigh syndrome, mitochondrial myopathy-encephalopathy-hyperlactatemia, stroke syndrome or stroke-like attack, Duchenne muscular dystrophy, shell muscular dystrophy or Friedreich's ataxia, etc.
  • the compounds of the present invention can be used to treat tumors, including: bone cancer, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hemangioma, granuloma, xanthomas, meningeal sarcomas, gliomas, astrocytomas, medulloblastomas, ependymomas, germ cell tumors (pineal tumors), multiforme glioblastomas, oligodendrogliomas, schwannomas, retinoblastomas, neurofibromas, sarcomas, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, colon cancer, rectal cancer, kidney cancer, prostate cancer,
  • the aryl imidazole compounds of the present invention can be used as pharmaceutically acceptable salts.
  • the salts can be salts formed by the compounds of the present invention and metal (including sodium, potassium, calcium, magnesium, etc.) ions or pharmaceutically acceptable amines (including ethylenediamine, ethanolamine, tromethamine, diisopropylamine, metformin or berberine, etc.) or ammonium ions.
  • the compounds of the present invention can be used in combination with one or more other types of drugs for preventing or treating PPAR ⁇ -mediated diseases, including but not limited to the following combinations.
  • preventive or therapeutic drugs that may be optionally used in combination with the compounds of the present invention may be one or more anti-diabetic drugs.
  • prophylactic or therapeutic agent that may be optionally used in combination with the compounds of the present invention may be one or more anti-obesity agents.
  • preventive or therapeutic drugs may be one or more anti-nonalcoholic fatty liver disease drugs.
  • preventive or therapeutic drugs that may be optionally used in combination with the compounds of the present invention may be one or more anti-PBC or PSC drugs.
  • preventive or therapeutic drugs may be one or more lipid-lowering drugs.
  • the dosage of the compound of formula (I) of the present invention or a pharmaceutically acceptable salt, deuterated compound, tautomer, meso-body, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate can be appropriately changed according to the patient's age, body weight, symptoms and route of administration.
  • the lower limit of the dosage is 0.01 mg (preferably 0.1 or 1 mg) and the upper limit is 1000 mg (preferably 500 mg); when administered intravenously, the lower limit of the dosage is 0.001 mg (preferably 0.01 or 0.1 mg) and the upper limit is 500 mg (preferably 250 mg).
  • This dosage range can also be deviated from according to the different degrees of the disease and the different dosage forms.
  • the present invention has the following advantages:
  • the present invention provides a novel aryl imidazole compound which has a potent agonist effect on PPAR ⁇ .
  • the EC50 of compounds 2, 16, 76, 108 and 110 for PPAR ⁇ reaches the picomolar level, which is significantly stronger than the phase III clinical trial drug MBX-8025.
  • the compounds of the present invention have a strong agonist effect on PPAR ⁇ , have good selectivity for PPAR ⁇ and PPAR ⁇ , and have good pharmacokinetic properties. Therefore, the compounds of the present invention or their pharmaceutically acceptable salts can be used to prepare PPAR ⁇ agonists, and further can be used to prepare drugs for preventing or treating PPAR ⁇ -mediated diseases.
  • the aryl imidazole compounds of the present invention are ingeniously designed, the raw materials are cheap and easily available, the synthesis process is safe and environmentally friendly, and they are easy to mass produce.
  • FIG1 is a Sirius red staining image of the kidneys of the mouse model of renal fibrosis of compound 129;
  • 1,2-phenylenediamine (100 mg, 0.92 mmol) was dissolved in a mixed solvent of N,N-dimethylformamide (9 mL) and water (1 mL), 4-trifluoromethoxybenzaldehyde (176 mg, 0.93 mmol) was added, and the mixture was heated and stirred at 80°C for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (20 mL x 3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • methoxymethyltriphenylphosphine chloride (387 mg, 1.13 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL).
  • anhydrous tetrahydrofuran 5 mL.
  • 2.5 M n-butyllithium n-hexane solution (0.38 mL, 0.95 mmol) was slowly added dropwise.
  • the temperature was raised to 0 ° C, stirred for 10 min, cooled to -78 ° C, and 4-oxocyclohexane ethyl acetate (104 mg, 0.56 mmol) was slowly added dropwise.
  • the temperature was slowly raised to room temperature and stirred for 6 hours. The reaction was monitored by TLC.
  • compound I-15 (100 mg, 0.54 mmol) was dissolved in anhydrous ethanol (3 mL), potassium carbonate (150 mg, 1.09 mmol) was added, (1-diazo-2-oxo-propanol)-phosphonic acid dimethyl ester (125 mg, 0.65 mmol) was slowly added dropwise under an ice-water bath, and the mixture was slowly heated to room temperature and stirred for 6 hours.
  • o-Hydroxyphenylethanol (348 mg, 2.52 mmol) was dissolved in N,N-dimethylformamide (8 mL), potassium carbonate (520 mg, 3.76 mmol) and benzyl bromide (475 mg, 2.9 mmol) were added, and the mixture was stirred at 80°C for 4 hours. The reaction was monitored by TLC. After the reaction was complete, potassium carbonate was removed by suction filtration, ethyl acetate (50 mL) was added for dilution, water (20 mL x 3) was added for washing, and the mixture was dried over anhydrous sodium sulfate.
  • compound I-4 (300 mg, 1.08 mmol) was dissolved in anhydrous N, N-dimethylformamide (3 mL), potassium tert-butoxide (150 mg, 1.34 mmol) was added under ice-water bath and stirred for 15 minutes, compound III-2 (381 mg, 1.24 mmol) was added and stirred for 15 min, and the mixture was heated and stirred at 95 ° C for 4 hours.
  • 3-Amino-2-nitropyridine 200 mg, 1.44 mmol was dissolved in anhydrous tetrahydrofuran (7 mL), 4-trifluoromethoxybenzoic acid (326 mg, 1.58 mmol) and triethylamine (437 mg, 4.32 mmol) were added in sequence, 50% 1-propylphosphoric anhydride in N,N-dimethylformamide solution (915 mg, 2.88 mmol) was added dropwise, and the reaction was stirred at 70°C for 8 hours. The reaction was monitored by TLC.
  • dimethylamine hydrochloride (3.1 g, 38 mmol) was dissolved in dichloromethane (20 mL), and N, N-diisopropylethylamine (DIPEA) (7.82 g, 60.5 mmol) and 4-trifluoromethoxybenzoyl chloride (4.28 g, 19 mmol) were added in sequence, and the temperature was slowly raised to room temperature and stirred for 4 hours.
  • DIPEA N, N-diisopropylethylamine
  • 4-trifluoromethoxybenzoyl chloride (4.28 g, 19 mmol) were added in sequence, and the temperature was slowly raised to room temperature and stirred for 4 hours.
  • Lithium aluminum tetrahydride (54 mg, 1.42 mmol) was suspended in anhydrous tetrahydrofuran (2 mL) under an ice-water bath, and a solution of compound VII-2 (200 mg, 0.96 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred and heated at 60°C for 3 hours. The reaction was monitored by TLC, and after the reaction was complete, ether (5 mL) was added for dilution, and water (200 ⁇ L) was added dropwise under an ice-water bath.
  • Embodiment 84 is a diagrammatic representation of Embodiment 84.
  • X-1 (597 mg, 3 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and lithium diisopropylamide (1.5 mL, 3 mmol) was slowly added dropwise at -78 ° C. After 30 minutes, diethyl carbonate (236 mg, 2 mmol) was added at -78 ° C, and the temperature was naturally raised to room temperature and stirred for 2 hours. The reaction was monitored by TLC. After the reaction was complete, water (10 mL) was added to quench the reaction, and ethyl acetate (30 mL x 3) was used for extraction.
  • anhydrous tetrahydrofuran (5 ml) containing ethyl 3-methoxyphenylacetate (1.0 g, 5.15 mmol) was added to a two-necked flask. Under argon protection and -78 ° C, lithium diisopropylamide (2M, 454 mL) was slowly added dropwise. After one hour, an anhydrous tetrahydrofuran solution (1 mL) of iodomethane (1.03 g, 5.41 mmol) was added dropwise. The temperature was slowly raised to room temperature and stirred for 2 hours. The reaction was detected by TLC.
  • Embodiment 107 is a diagrammatic representation of Embodiment 107.
  • Embodiment 109 is a diagrammatic representation of Embodiment 109.
  • Embodiment 121 is a diagrammatic representation of Embodiment 121.
  • Embodiment 123 is a diagrammatic representation of Embodiment 123.
  • compound XIII-2 (141 mg, 0.34 mmol), Pd 2 (dba) 3 (32 mg, 0.034 mmol), Xantphos (40 mg, 0.068 mmol) were dissolved or suspended in 1,4-dioxane solvent (5 mL), and ethyl 2-(3-bromophenyl)acetate (108 mg, 0.44 mmol) and DIPEA (88 mg, 0.68 mmol) were added, and the temperature was raised to 110°C and stirred for 12 hours. The reaction was monitored by TLC. After the reaction was complete, diatomaceous earth was filtered, and the solvent was evaporated under reduced pressure.
  • compound I-3 was replaced by compound XIV-2 to obtain compound 127 (colorless oily liquid, 110 mg, 47%):
  • Embodiment 145 is a diagrammatic representation of Embodiment 145.
  • Embodiment 147 is a diagrammatic representation of Embodiment 147.
  • Embodiment 148 is a diagrammatic representation of Embodiment 148.
  • Cos-7 cells African green monkey kidney fibroblasts, commonly used tool cells
  • the culture medium was DMEM complete medium containing 10% fetal bovine serum.
  • the cells grow to a density of about 70%, prepare for transfection.
  • the plasmid transfection working solution as follows: 15 ⁇ g pGL4.35-9 ⁇ Gal4 UAS plasmid (purchased from Beijing Promeg Biotechnology Co., Ltd.) and 15 ⁇ g pBIND-Gal4-PPAR ⁇ (LBD) plasmid or pBIND-Gal4-PPAR ⁇ (LBD) plasmid or pBIND-Gal4-PPAR ⁇ (LBD) plasmid (J.
  • the PPAR ⁇ agonist activity of GW7647 (purchased from MCE) with a final concentration of 10nM was 100%
  • the PPAR ⁇ agonist activity of GW501516 (purchased from MCE) with a final concentration of 10nM was 100%
  • the PPAR ⁇ agonist activity of Rosiglitazone (purchased from Adamas) with a final concentration of 1 ⁇ M was 100%.
  • the experiment used MBX-8025, a PPAR ⁇ selective agonist in phase III clinical trials, as a positive control compound.
  • the experimental results are shown in Table 2.
  • This experiment used MBX-8025, a PPAR selective agonist in phase III clinical trials (synthesized with reference to patent US2007060649) as a positive control compound.
  • the experimental results are shown in Table 2.
  • the experimental results show that the compounds of the present invention have significant PPAR ⁇ agonist activity and have significant selectivity for both PPAR ⁇ and PPAR ⁇ .
  • compounds 2, 4, 8, 10, 16, 22, 24, 28, 30, 32, 34, 44, 58, 60, 62, 66, 68, 76, 78, 82, 84, 86, 98, 100, 108, 110, 112, 11 and 118 can effectively activate PPAR ⁇ , and their EC 50 values are all below 10 nM, which is significantly stronger than the phase III clinical trial drug MBX-8025.
  • the above results indicate that the compounds of the present invention are potent and highly selective PPAR ⁇ agonists.
  • Rats were divided into 2 groups, 3 rats in each group, one group was oral administration group, and the other group was intravenous administration group.
  • the dosage for oral administration was 10 mpk, and the dosage for intravenous injection was 2 mpk.
  • Embodiment 150 is a diagrammatic representation of Embodiment 150
  • Embodiment 151 is a diagrammatic representation of Embodiment 151.
  • Compound 2 (50 g) prepared in Example 2, hydroxypropylmethylcellulose E (150 g), starch (200 g), appropriate amount of povidone K30 and magnesium stearate (1 g) were mixed, granulated and tableted.
  • the compounds prepared in Examples 1 to 147 can be given different pharmaceutical excipients to prepare capsules, powders, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories or patches, etc.
  • Embodiment 152 is a diagrammatic representation of Embodiment 152
  • mice 25 male C57BL/6J mice, SPF grade, 7-8 weeks old, purchased from Beijing Weitonglihua. All animals were kept on a 12-hour alternating circadian rhythm and had free access to food.
  • the positive drug enalapril maleate was purchased from Adamas.
  • mice were randomly divided into 5 groups according to their body weight: sham operation group (Sham), operation group (UUO), positive drug enalapril maleate group (Enalapril 50mpk), low-dose compound 129 group (129 3mpk) and high-dose compound 129 group (129 10mpk).
  • the procedure of unilateral ureteral ligation (UUO) surgery is as follows: 1 Fast for 12 hours before surgery and drink water freely; 2 Anesthetize the mice with Shutai combined with xylazine. After confirming that the anesthesia is successful, fix the mice in the right lateral position on the sterile operating table, remove the hair in the kidney area and disinfect the surgical area with iodine; 3 Make a left back incision, cut it layer by layer, expose and separate the left ureter at the lower pole of the left kidney; 4 Ligate twice with 4-0 sutures, with the upper ligature as close to the renal pedicle as possible and the lower ligature as downward as possible, and cut the middle part of the ureter; 5 Suture the abdominal wall incision layer by layer, close the abdominal cavity, and disinfect with iodine after surgery. After the mice wake up, give them regular diet and drinking water.
  • mice in the sham operation group were gavaged daily with a volume fraction of 0.5% CMC-Na solution, and the positive drug enalapril maleate group was gavaged daily with 50mpk of enalapril maleate (compound 129 low-dose group was gavaged daily with 3mpk of compound 129, and the compound 129 high-dose group was gavaged daily with 10mpk of compound 129.
  • the drug administration period was 13 days, and the mice were weighed every week, and their body weight, hair, feces and activity were carefully observed and recorded.
  • mice Two hours after the last administration, the mice were killed and the left kidney was removed.
  • the kidney was divided into two parts, one of which was fixed with 4% paraformaldehyde for staining and sectioning, and the other was quickly frozen in liquid nitrogen for subsequent detection of other indicators.
  • the caudate lobe of the liver was fixed in 4% paraformaldehyde overnight, processed for standard histology, and embedded in paraffin. The samples were cut to 4 ⁇ m thickness and stained with picrosirius red. All sections were scanned using Nano-Zoomer 2.0RS.
  • Sirius red section staining can evaluate the level of renal fibrosis. As shown in Figure 1, compared with the sham group, the collagen content in the surgical group increased significantly, and the collagen accumulation was significantly reduced after treatment with compound 129. Further qPCR detection found ( Figure 2) that compound 129 can reduce the expression of mouse renal fibrosis-related genes Acta2 and Col3a1, indicating that compound 129 has an anti-renal fibrosis effect. In addition, the expression of inflammation-related genes Tnf and Il1b can also be reduced after compound 129 is administered, indicating that compound 129 has an anti-inflammatory effect.
  • compound 129 improved collagen deposition and inhibited inflammatory cell infiltration in the UUO-induced renal fibrosis mouse model.

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Abstract

Disclosed in the present invention are an aryl fused imidazole compound as represented by formula (I) and the medical use thereof. The compound has a potent agonistic effect on PPARδ, and therefore the compound, or a pharmaceutically acceptable salt, deuterated compound, tautomer, mesomer, racemate, stereoisomer, metabolite, metabolic precursor, prodrug, or solvate thereof can be used in the preparation of a PPARδ agonist for preventing or treating PPARδ-related diseases.

Description

芳基并咪唑类化合物及其医药用途Aryl imidazole compounds and their medical uses 技术领域Technical Field

本发明属于生物医药领域，具体涉及一种具有PPARδ选择性激动活性的芳基并咪唑类化合物及其医药用途。The invention belongs to the field of biomedicine, and specifically relates to an aryl imidazole compound with PPARδ selective agonist activity and its medical use.

背景技术Background Art

过氧化物酶体增殖体激活受体(PPAR)是核激素受体家族中的配体激活受体，已经分离出三种哺乳动物的过氧化物酶体增殖体激活受体，分别是PPARα，PPARδ(也称作PPARβ)和PPARγ。PPAR与配体结合激活后，与视黄醇类X受体(RXR)形成异二聚体，形成的PPAR/RXR异二聚体与靶基因启动子上游的PPAR反应元件(PPRE)结合，最终调节靶基因的转录。Peroxisome proliferator-activated receptors (PPARs) are ligand-activated receptors in the nuclear hormone receptor family. Three mammalian peroxisome proliferator-activated receptors have been isolated, namely PPARα, PPARδ (also known as PPARβ) and PPARγ. After PPAR binds to its ligand and is activated, it forms a heterodimer with the retinoid X receptor (RXR). The formed PPAR/RXR heterodimer binds to the PPAR response element (PPRE) upstream of the target gene promoter, ultimately regulating the transcription of the target gene.

其中，PPARδ在体内广泛表达，最高表达水平见于消化道、心、肾、肝、脂肪以及脑中。PPARδ的激活可显著改善脂质代谢、胰岛素敏感性、能量平衡、炎症反应及纤维化。此外，激活PPARδ还可以促进线粒体生物合成及增强线粒体功能。PPARδ的激活对代谢性疾病、心脑血管疾病、炎症疾病、自身免疫性疾病、器官纤维化疾病、神经损伤性疾病、病原体感染所致的继发性疾病、线粒体功能障碍和紊乱疾病或肿瘤的改善都有着潜在的积极作用(Nature,2000,405,421；J.Neurochem.，2008,107,497；Mol.Cells.,2012,33,217；J.Biomed.Sci.,2017,24,5；Eur.J.Med.Chem.,2019,166,502)。Among them, PPARδ is widely expressed in the body, with the highest expression levels found in the digestive tract, heart, kidney, liver, fat and brain. Activation of PPARδ can significantly improve lipid metabolism, insulin sensitivity, energy balance, inflammatory response and fibrosis. In addition, activation of PPARδ can also promote mitochondrial biosynthesis and enhance mitochondrial function. Activation of PPARδ has a potential positive effect on the improvement of metabolic diseases, cardiovascular and cerebrovascular diseases, inflammatory diseases, autoimmune diseases, organ fibrosis diseases, neurological damage diseases, secondary diseases caused by pathogen infection, mitochondrial dysfunction and disordered diseases or tumors (Nature, 2000, 405, 421; J. Neurochem., 2008, 107, 497; Mol. Cells., 2012, 33, 217; J. Biomed. Sci., 2017, 24, 5; Eur. J. Med. Chem., 2019, 166, 502).

目前，临床在研的PPARδ选择性激动剂主要有MBX-8025(处于抗原发性胆汁性胆管炎III期临床研究阶段)、REN-001(处于抗线粒体肌病II期临床研究阶段)和ASP-0367(处于抗线粒体肌病II期临床研究阶段)。At present, the main PPARδ selective agonists under clinical research include MBX-8025 (in the Phase III clinical study stage for primary biliary cholangitis), REN-001 (in the Phase II clinical study stage for mitochondrial myopathy), and ASP-0367 (in the Phase II clinical study stage for mitochondrial myopathy).

目前尚无PPARδ选择性激动剂获批上市。因此，仍需要开发新型安全、有效的PPARδ选择性激动剂，用于治疗代谢性疾病、心脑血管疾病、炎症疾病、自身免疫性疾病、器官纤维化疾病、神经损伤性疾病、病原体感染所致的继发性疾病、线粒体功能障碍和紊乱疾病或肿瘤等疾病；尤其是非酒精性脂肪肝病，酒精性脂肪肝病，糖尿病及其并发症，血脂异常，肥胖，动脉粥样硬化，胆汁淤积性肝病，神经退行性疾病，帕金森氏病，线粒体肌病，杜氏肌肉营养不良症等致病原因复杂的疾病。Currently, no PPARδ selective agonist has been approved for marketing. Therefore, there is still a need to develop new, safe and effective PPARδ selective agonists for the treatment of metabolic diseases, cardiovascular and cerebrovascular diseases, inflammatory diseases, autoimmune diseases, organ fibrosis diseases, neurological damage diseases, secondary diseases caused by pathogen infection, mitochondrial dysfunction and disorder diseases or tumors, especially non-alcoholic fatty liver disease, alcoholic fatty liver disease, diabetes and its complications, dyslipidemia, obesity, atherosclerosis, cholestatic liver disease, neurodegenerative diseases, Parkinson's disease, mitochondrial myopathy, Duchenne muscular dystrophy and other diseases with complex causes.

发明内容Summary of the invention

发明目的：针对现有技术存在的问题，本发明提供一种新型芳基并咪唑类化合物，本发明的化合物对PPARδ具有强效激动作用，对PPARα和PPARγ具有较好的选择性，且具有良好的药物代谢动力学性质。因此，本发明的化合物以及药学上可接受的盐、氘代化合物、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物可应用于制备PPARδ选择性激动剂，有效解决了目前临床上缺乏有效的PPARδ选择性激动剂的问题。Purpose of the invention: In view of the problems existing in the prior art, the present invention provides a novel aryl imidazole compound, which has a strong agonist effect on PPARδ, has good selectivity for PPARα and PPARγ, and has good pharmacokinetic properties. Therefore, the compound of the present invention and pharmaceutically acceptable salts, deuterated compounds, tautomers, meso-forms, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates can be used to prepare PPARδ selective agonists, effectively solving the problem of the lack of effective PPARδ selective agonists in the clinic.

本发明的另一个目的是提供所述芳基并咪唑类化合物作为PPARδ选择性激动剂的医药用途。该类化合物以及其药学上可接受的盐、氘代化合物、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物可应用于制备PPARδ选择性激动剂，用于制备预防或治疗PPARδ相关疾病的药物。Another object of the present invention is to provide the medical use of the aryl imidazole compounds as PPARδ selective agonists. The compounds and their pharmaceutically acceptable salts, deuterated compounds, tautomers, meso-racemates, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates can be used to prepare PPARδ selective agonists and to prepare drugs for preventing or treating PPARδ-related diseases.

技术方案：为了实现上述目的，本发明本发明提供如式(I)所示的芳基并咪唑类化合物或其药学上可接受的盐：
Technical solution: In order to achieve the above-mentioned purpose, the present invention provides an aryl imidazole compound or a pharmaceutically acceptable salt thereof as shown in formula (I):

其中，R1和R2各自独立地选自：H、羟基、卤素、氰基、OR8、1～4个碳的直链或支链烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基、烷基磺酰基、3～6个碳的环烷基、环烯基、杂环烷基、杂环烯基、炔基、苯基、取代的苯基、杂芳基、取代的杂芳基、稠环芳基或取代的稠环芳基，所述取代的苯基、取代的杂芳基和取代的稠环芳基可各自独自地被1至2个如下取代基所取代：卤素、羟基、氰基、1～4个碳的直链或支链烷基、3～6个碳的环烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基或烷基磺酰基；或者，R1和R2与它们所连接到的原子可一起形成取代或非取代的苯环、取代或非取代的杂芳环、取代或非取代的环烷烃环、取代或非取代的杂环烷烃环，或取代或非取代的杂环烯烃环；wherein R1 and R2 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, OR8 , a linear or branched alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, alkylsulfonyl, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkenyl group, a heterocycloalkyl group, a heterocycloalkenyl group, an alkynyl group, a phenyl group, a substituted phenyl group, a heteroaryl group, a substituted heteroaryl group, a condensed aryl group, or a substituted condensed aryl group, wherein the substituted phenyl group, the substituted heteroaryl group, and the substituted condensed aryl group may each be independently substituted by 1 to 2 of the following substituents: halogen, hydroxyl, cyano, a linear or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, or alkylsulfonyl group; or, R1 and R2 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, a linear or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, or alkylsulfonyl group; 2 together with the atoms to which they are attached may form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring;

R8选自：1～4个碳的直链或支链烷基、3～6个碳的环烷基、苯基、取代的苯基、羟基烷基、烷氧基烷基、烷氧基烷氧基烷基、环烷基或炔基烷氧基烷基； R8 is selected from: a straight or branched chain alkyl group of 1 to 4 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, a phenyl group, a substituted phenyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxyalkyl group, a cycloalkyl group or an alkynylalkoxyalkyl group;

R3、R4、R5、R6和R7各自独立地选自：H、羟基、卤素、氰基、1～4个碳的直链或支链烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基、烷基磺酰基、烷氧基、3～6个碳的环烷基、环烯基、杂环烷基、杂环烯基、炔基、苯基、取代的苯基、苯氧基、取代的苯基氧基、杂芳基、取代的杂芳基、稠环芳基或取代的稠环芳基，所述取代的苯基、取代的杂芳基和取代的稠环芳基可各自独自地被1至2个如下取代基所取代：卤素、羟基、氰基、1～4个碳的直链或支链烷基、3～6个碳的环烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基或烷基磺酰基；或者，R3、R4、R5、R6和R7其中至少两个取代基与它们所连接到的原子可一起形成取代或非取代的苯环、取代或非取代的杂芳环、取代或非取代的环烷烃环、取代或非取代的杂环烷烃环，或取代或非取代的杂环烯烃环； R3 , R4 , R5 , R6 and R7 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, alkylsulfonyl, alkoxy, cycloalkyl of 3 to 6 carbon atoms, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl, substituted heteroaryl, fused ring aryl or substituted fused ring aryl, wherein the substituted phenyl, substituted heteroaryl and substituted fused ring aryl may each be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl; or, R3, R4, R5, R6 and R7 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl; or, R3, R4, R5, R6 and R7 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, trifluoromethyl, methylthio , trifluoromethoxy , trifluoromethylthio or alkylsulfonyl; 7 wherein at least two substituents together with the atoms to which they are attached can form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring;

m选自0～5之间的任意整数；m is selected from any integer between 0 and 5;

n选自0～5之间的任意整数；n is selected from any integer between 0 and 5;

X选自：O、S、CH2、CH2O、CH2S、CH2CH2、OCH2、SCH2、CH2CH2O、CH2CH2S、CH2CH2CH2、OCH2CH2、SCH2CH2、CH2CH2CH2O、CH2CH2CH2S、CH2CH2CH2CH2、OCH2CH2CH2或SCH2CH2CH2；X is selected from: O, S, CH 2 , CH 2 O, CH 2 S, CH 2 CH 2 , OCH 2 , SCH 2 , CH 2 CH 2 O, CH 2 CH 2 S, CH 2 CH 2 CH 2 , OCH 2 CH 2 , SCH 2 CH 2 , CH 2 CH 2 CH 2 O, CH 2 CH 2 CH 2 S, CH 2 CH 2 CH 2 CH 2 , OCH 2 CH 2 CH 2 or SCH 2 CH 2 CH 2 ;

Y选自： Y is selected from:

Z1、Z2、Z3、Z4、Z5、Z6、Z7和Z8各自独立地选自：CH或N；Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 are each independently selected from: CH or N;

R9选自：H、1～6个碳的直链或支链烷基、3～6个碳的环烷基、(CH2)pOR12或 (CH2)qNR13；其中，所述p＝2～6的任意整数；所述q＝2～6的任意整数；所述R12和R13各自独立地选自H、R14、C(O)R15；其中，所述R14和R15各自独立地选自1～6个碳的直链或支链烷基或3～6个碳的环烷基；R 9 is selected from: H, a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, (CH 2 ) p OR 12 or (CH 2 ) q NR 13 ; wherein p=any integer of 2 to 6; wherein q=any integer of 2 to 6; wherein R 12 and R 13 are each independently selected from H, R 14 , C(O)R 15 ; wherein R 14 and R 15 are each independently selected from a linear or branched alkyl group of 1 to 6 carbon atoms or a cycloalkyl group of 3 to 6 carbon atoms;

R10和R11各自独立地选自：H、羟基、卤素、氰基、1～4个碳的直链或支链烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基、烷基磺酰基、烷氧基、3～6个碳的环烷基、环烯基、杂环烷基、杂环烯基、炔基、苯基、取代的苯基、苯氧基、取代的苯基氧基、杂芳基、取代的杂芳基、稠环芳基或取代的稠环芳基，所述取代的苯基、取代的杂芳基和取代的稠环芳基可独自地被1至2个如下取代基所取代：卤素、羟基、氰基、1～4个碳的直链或支链烷基、3～6个碳的环烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基或烷基磺酰基；或者，R10和R11与它们所连接到的原子可一起形成取代或非取代的苯环、取代或非取代的杂芳环、取代或非取代的环烷烃环、取代或非取代的杂环烷烃环，或取代或非取代的杂环烯烃环。 R10 and R11 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, alkylsulfonyl, alkoxy, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkenyl group, a heterocycloalkyl group, a heterocycloalkenyl group, an alkynyl group, a phenyl group, a substituted phenyl group, a phenoxy group, a substituted phenyloxy group, a heteroaryl group, a substituted heteroaryl group, a fused ring aryl group, or a substituted fused ring aryl group, wherein the substituted phenyl group, the substituted heteroaryl group, and the substituted fused ring aryl group may be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, or alkylsulfonyl group; or, R10 and R11 are each independently selected from the group consisting of H, hydroxyl, halogen ... 11 and the atoms to which they are attached may together form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring.

作为优选，所述式(I)所示的芳基并咪唑类化合物或其药学上可接受的盐：Preferably, the aryl imidazole compound represented by formula (I) or a pharmaceutically acceptable salt thereof is:

其中，R1和R2各自独立地选自：H、羟基、卤素、氰基、OR8、1～4个碳的直链或支链烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基、甲基磺酰基、乙基磺酰基、3～6个碳的环烷基、苯基或取代的苯基，所述取代的苯基可独自地被1至2个如下取代基所取代：卤素、羟基、氰基、1～4个碳的直链或支链烷基、3～6个碳的环烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基或甲基磺酰基；wherein R1 and R2 are each independently selected from the group consisting of: H, hydroxyl, halogen, cyano, OR8 , a linear or branched alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, methylsulfonyl, ethylsulfonyl, a cycloalkyl group having 3 to 6 carbon atoms, phenyl, or substituted phenyl, wherein the substituted phenyl group may be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, a linear or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, or methylsulfonyl;

R8选自：1～4个碳的直链或支链烷基、3～6个碳的环烷基或苯基；R 8 is selected from: a straight chain or branched chain alkyl group of 1 to 4 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, or a phenyl group;

m选自0～3之间的任意整数；m is selected from any integer between 0 and 3;

n选自0～3之间的任意整数；n is selected from any integer between 0 and 3;

R3、R4、R5、R6和R7各自独立地选自：H、羟基、卤素、氰基、1～4个碳的直链或支链烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基、甲基磺酰基、乙基磺酰基、1～4个碳的直链或支链烷基氧基、3～6个碳的环烷基氧基、3～6个碳的环烷基、苯基、取代的苯基、苯氧基、取代的苯基氧基、杂芳基或取代的杂芳基，所述取代的苯基或取代的杂芳基可各自独自地被1至2个如下取代基所取代：卤素、羟基、氰基、1～4个碳的直链或支链烷基、3～6个碳的环烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基或甲基磺酰基；或者，R3、R4、R5、R6和R7其中至少两个取代基与它们所连接到的原子可一起形成取代或非取代的苯环； R3 , R4 , R5 , R6 and R7 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, methylsulfonyl, ethylsulfonyl, straight or branched chain alkyloxy of 1 to 4 carbon atoms, cycloalkyloxy of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl or substituted heteroaryl, wherein the substituted phenyl or substituted heteroaryl may each be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or methylsulfonyl; or, R3 , R4, R5, R6 and R7 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or methylsulfonyl; or 7 wherein at least two substituents together with the atoms to which they are attached can form a substituted or unsubstituted benzene ring;

X选自：O、S、CH2、CH2O、CH2S、CH2CH2、OCH2、SCH2、CH2CH2O、CH2CH2S、CH2CH2CH2、OCH2CH2或SCH2CH2；X is selected from: O, S, CH 2 , CH 2 O, CH 2 S, CH 2 CH 2, OCH 2 , SCH 2 , CH 2 CH 2 O, CH 2 CH 2 S, CH 2 CH 2 CH 2 , OCH 2 CH 2 or SCH 2 CH 2 ;

Y选自： Y is selected from:

Z1、Z2、Z3、Z4、Z5、Z6、Z7和Z8各自独立地选自：CH或N；Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 are each independently selected from: CH or N;

R9选自：H、1～4个碳的直链或支链烷基、乙酰氨基乙基或(CH2)pOR12，其中，所述p＝2～6的任意整数，所述R12选自1～4个碳的直链或支链烷基；R 9 is selected from: H, a linear or branched alkyl group of 1 to 4 carbon atoms, acetylaminoethyl or (CH 2 ) p OR 12 , wherein p is any integer of 2 to 6, and R 12 is selected from a linear or branched alkyl group of 1 to 4 carbon atoms;

R10和R11各自独立地选自：H、羟基、卤素、氰基、1～4个碳的直链或支链烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基、甲基磺酰基、乙基磺酰基、1～4个碳的直链或支链烷基氧基、3～6个碳的环烷基氧基、3～6个碳的环烷基、苯基、取代的苯基、苯氧基或取代的苯基氧基，所述取代的苯基可各自独自地被1至2个如下取代基所取代：卤素、羟基、氰基、1～4个碳的直链或支链烷基、3～6个碳的环烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基或甲基磺酰基；或者，R10和R11其中至少两个取代基与它们所连接到的原子可一起形成取代或非取代的苯环。R 10 and R 11 are each independently selected from: H, hydroxyl, halogen, cyano, straight chain or branched alkyl of 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, methylsulfonyl, ethylsulfonyl, straight chain or branched alkyloxy of 1 to 4 carbon atoms, cycloalkyloxy of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, substituted phenyl, phenoxy or substituted phenyloxy, wherein the substituted phenyl may be independently substituted with 1 to 2 substituents of: halogen, hydroxyl, cyano, straight chain or branched alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or methylsulfonyl; or, at least two of the substituents of R 10 and R 11 together with the atoms to which they are attached may form a substituted or unsubstituted benzene ring.

进一步地，所述芳基并咪唑类化合物还包括其药学上可接受的盐、氘代化合物、互 变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物。Furthermore, the aryl imidazole compounds also include pharmaceutically acceptable salts, deuterated compounds, Variomers, meso- and racemates, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates.

在某些更优选的实施方案中，本发明的芳基并咪唑类化合物或其盐为如下表1所示的任一化合物：In certain more preferred embodiments, the aryl imidazole compound or its salt of the present invention is any one of the compounds shown in Table 1 below:

表1、化合物的结构与命名


































Table 1. Structure and nomenclature of compounds


































本发明所述的芳基并咪唑类化合物或药学上可接受的盐、氘代化合物、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物是强效的PPARδ选择性激动剂，因而可用于制备PPARδ选择性激动剂。The aryl imidazole compounds or pharmaceutically acceptable salts, deuterated compounds, tautomers, meso-racemates, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates of the present invention are potent PPARδ selective agonists and can thus be used to prepare PPARδ selective agonists.

本发明所述的的芳基并咪唑类化合物或其药学上可接受的盐、氘代化合物、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物可用于制备预防或治疗PPARδ介导疾病的药物。 The aryl imidazole compounds or pharmaceutically acceptable salts, deuterated compounds, tautomers, mesomers, racemates, stereoisomers, metabolites, metabolic precursors, prodrugs or solvates thereof described in the present invention can be used to prepare drugs for preventing or treating PPARδ-mediated diseases.

具体地说，本发明的化合物可用于制备预防和治疗以下PPARδ介导疾病的药物。Specifically, the compounds of the present invention can be used to prepare drugs for preventing and treating the following PPARδ-mediated diseases.

本发明的化合物可用于预防和治疗代谢性疾病和心脑血管疾病，包括：胰岛素抵抗、代谢综合征、1型或2型糖尿病、高血脂症、肥胖症、脂肪瘤、痛性脂肪增多症、动脉粥样硬化、心肌缺血、心肌梗死、心律失常、冠心病、高血压、心衰、心肌肥大、心肌炎、糖尿病并发症(包括糖尿病心肌病、糖尿病肾病、多囊肾病(ARPKD和ADPKD)、糖尿病溃疡、视网膜病变和神经病变等)、非酒精性脂肪肝、非酒精性脂肪性肝炎、酒精性脂肪肝、肝硬化、高尿酸血症、痛风、骨质疏松、多囊卵巢综合征(PCOS)、中风或脑梗死等。The compounds of the present invention can be used to prevent and treat metabolic diseases and cardiovascular and cerebrovascular diseases, including: insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, lipoma, painful lipomatosis, atherosclerosis, myocardial ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, myocardial hypertrophy, myocarditis, diabetic complications (including diabetic cardiomyopathy, diabetic nephropathy, polycystic kidney disease (ARPKD and ADPKD), diabetic ulcer, retinopathy and neuropathy, etc.), non-alcoholic fatty liver disease, non-alcoholic fatty hepatitis, alcoholic fatty liver disease, cirrhosis, hyperuricemia, gout, osteoporosis, polycystic ovary syndrome (PCOS), stroke or cerebral infarction, etc.

本发明的化合物可用于预防和治疗炎症疾病、自身免疫性疾病、器官纤维化疾病、神经退行性疾病或病原体感染所致的继发性疾病，包括：原发性胆汁性胆管炎(PBC)、原发性硬化性胆管炎(PSC)、肝纤维化、特发性肺纤维化、囊性纤维化肺病、间质性肺炎、肺结核、炎性肠病(如克罗恩病和溃疡性结肠炎)、白塞氏病、哮喘、慢性阻塞性肺病、慢性支气管炎、肺气肿、闭塞性细支气管炎、过敏性鼻炎、慢性鼻炎、鼻窦炎、系统性红斑狼疮、类风湿关节炎、脊椎关节炎、骨关节炎、滑膜炎、肌腱炎、血栓闭塞性脉管炎、静脉炎、间歇性跛行、瘢痕瘤、银屑病、鱼鳞癣、大疱性类天疱疮、皮炎、接触性皮炎、胰腺炎、慢性肾炎、膀胱炎、脑膜炎、胃炎、败血症、坏疽性脓皮症、葡萄膜炎、帕金森病、阿尔茨海默病、α-共核蛋白病、抑郁症、多发性硬化症、肌萎缩侧索硬化病、纤维肌痛综合症、神经痛、唐氏综合征、哈勒沃登-施帕病、亨廷顿舞蹈病或威尔逊病等。The compounds of the present invention can be used to prevent and treat inflammatory diseases, autoimmune diseases, organ fibrosis diseases, neurodegenerative diseases or secondary diseases caused by pathogen infection, including: primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), liver fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis lung disease, interstitial pneumonia, tuberculosis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), Behcet's disease, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, obliterative bronchiolitis, allergic rhinitis, chronic rhinitis, sinusitis, systemic Lupus erythematosus, rheumatoid arthritis, spondylarthritis, osteoarthritis, synovitis, tendinitis, thromboangiitis obliterans, phlebitis, intermittent claudication, keloid, psoriasis, ichthyosis, bullous pemphigoid, dermatitis, contact dermatitis, pancreatitis, chronic nephritis, cystitis, meningitis, gastritis, sepsis, pyoderma gangrenosum, uveitis, Parkinson's disease, Alzheimer's disease, alpha-synucleinopathy, depression, multiple sclerosis, amyotrophic lateral sclerosis, fibromyalgia syndrome, neuralgia, Down syndrome, Hallervorden-Spahr disease, Huntington's disease or Wilson's disease, etc.

本发明的化合物可用于治疗和调节线粒体功能障碍和紊乱疾病，包括：肌无力、肌阵挛、运动不耐受、卡恩斯-赛尔综合征、慢性疲乏综合征、利氏综合征、线粒体肌病-脑病-高乳酸血症、中风综合征或中风样发作、杜氏肌营养不良、贝壳肌营养不良或弗立德希氏共济失调等。The compounds of the present invention can be used to treat and regulate mitochondrial dysfunction and disorder diseases, including: muscle weakness, myoclonus, exercise intolerance, Kearns-Sayer syndrome, chronic fatigue syndrome, Leigh syndrome, mitochondrial myopathy-encephalopathy-hyperlactatemia, stroke syndrome or stroke-like attack, Duchenne muscular dystrophy, shell muscular dystrophy or Friedreich's ataxia, etc.

本发明的化合物可用于治疗肿瘤，包括：骨癌、急性骨髓性白血病、慢性骨髓性白血病、急性淋巴细胞系白血病、慢性淋巴细胞系白血病、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、血管瘤、肉芽瘤、黄瘤、脑膜肉瘤、神经胶质瘤、星形细胞瘤、成神经管细胞瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、多形性成胶质细胞瘤、少突神经胶质细胞瘤、神经鞘瘤、成视网膜细胞瘤、纤维神经瘤、肉瘤、食道癌、胃癌、胰腺癌、大肠癌、结肠癌、直肠癌、肾癌、前列腺癌、淋巴癌、睾丸癌、间质细胞癌、肺癌、肝癌、皮肤癌、恶性黑素瘤或基底细胞癌等。The compounds of the present invention can be used to treat tumors, including: bone cancer, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hemangioma, granuloma, xanthomas, meningeal sarcomas, gliomas, astrocytomas, medulloblastomas, ependymomas, germ cell tumors (pineal tumors), multiforme glioblastomas, oligodendrogliomas, schwannomas, retinoblastomas, neurofibromas, sarcomas, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, colon cancer, rectal cancer, kidney cancer, prostate cancer, lymphoma, testicular cancer, interstitial cell cancer, lung cancer, liver cancer, skin cancer, malignant melanoma or basal cell carcinoma, etc.

在某些实施方案中，本发明的芳基并咪唑类化合物可作为药用盐使用。该盐可以是本发明的化合物与金属(包括钠、钾、钙、镁等)离子或药学上可接受的胺(包括乙二胺、乙醇胺、氨丁三醇、二异丙胺、二甲双胍或小檗碱等)或铵离子形成的盐。In certain embodiments, the aryl imidazole compounds of the present invention can be used as pharmaceutically acceptable salts. The salts can be salts formed by the compounds of the present invention and metal (including sodium, potassium, calcium, magnesium, etc.) ions or pharmaceutically acceptable amines (including ethylenediamine, ethanolamine, tromethamine, diisopropylamine, metformin or berberine, etc.) or ammonium ions.

本发明还提供了一种用于预防或治疗PPARδ介导的疾病的药物组合物，其中含有如本发明所述的治疗有效量的式(I)和表1所示的芳基并咪唑类化合物或药学上可接受的盐、氘代化合物、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物作为活性成分和药学上可接受的载体。可任意混合的载体根据剂型、给药形式等可以改变。载体的例子包括赋形剂、粘合剂、崩解剂、润滑剂、矫味剂、香味剂、着色剂和甜味剂等。所述药物组合物可以是胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂等制剂学上常规的制剂形式。The present invention also provides a pharmaceutical composition for preventing or treating a disease mediated by PPARδ, which contains a therapeutically effective amount of an aryl imidazole compound of formula (I) and shown in Table 1 as described in the present invention, or a pharmaceutically acceptable salt, deuterated compound, tautomer, meso-racemate, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate as an active ingredient and a pharmaceutically acceptable carrier. The carrier that can be mixed arbitrarily can be changed according to the dosage form, administration form, etc. Examples of carriers include excipients, binders, disintegrants, lubricants, flavoring agents, flavoring agents, colorants and sweeteners, etc. The pharmaceutical composition can be a conventional formulation form in pharmaceutical science such as capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories or patches.

进一步地，本发明的化合物可与一种或多种其他类型的预防或治疗PPARδ介导的疾病的药物联合使用，包括但不限于以下几种联合用药的情形。 Furthermore, the compounds of the present invention can be used in combination with one or more other types of drugs for preventing or treating PPARδ-mediated diseases, including but not limited to the following combinations.

可选择与本发明的化合物联合使用的其他类型的预防或治疗药物可以是一种或多种抗糖尿病药物。Other types of preventive or therapeutic drugs that may be optionally used in combination with the compounds of the present invention may be one or more anti-diabetic drugs.

可选择与本发明的化合物联合使用的其他类型的预防或治疗药物可以是一种或多种减肥药物。Another type of prophylactic or therapeutic agent that may be optionally used in combination with the compounds of the present invention may be one or more anti-obesity agents.

可选择与本发明的化合物联合使用的其他类型的预防或治疗药物可以是一种或多种抗非酒精性脂肪性肝病药物。Other types of preventive or therapeutic drugs that may be used in combination with the compounds of the present invention may be one or more anti-nonalcoholic fatty liver disease drugs.

可选择与本发明的化合物联合使用的其他类型的预防或治疗药物可以是一种或多种抗PBC或PSC药物。Other types of preventive or therapeutic drugs that may be optionally used in combination with the compounds of the present invention may be one or more anti-PBC or PSC drugs.

可选择与本发明的化合物联合使用的其他类型的预防或治疗药物可以是一种或多种降血脂药物。Other types of preventive or therapeutic drugs that may be used in combination with the compounds of the present invention may be one or more lipid-lowering drugs.

本发明的式(I)化合物或药学上可接受的盐、氘代化合物、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物的用量可根据患者年龄、体重、症状和给药途径等而适当改变。对成人而言，在口服给药时，一次给药量的下限是0.01mg(优选0.1或1mg)，上限是1000mg(优选500mg)；在静脉给药时，一次给药量的下限是0.001mg(优选0.01或0.1mg)，上限是500mg(优选250mg)。也可根据疾病程度的不同和剂型的不同而偏离此剂量范围。The dosage of the compound of formula (I) of the present invention or a pharmaceutically acceptable salt, deuterated compound, tautomer, meso-body, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate can be appropriately changed according to the patient's age, body weight, symptoms and route of administration. For adults, when administered orally, the lower limit of the dosage is 0.01 mg (preferably 0.1 or 1 mg) and the upper limit is 1000 mg (preferably 500 mg); when administered intravenously, the lower limit of the dosage is 0.001 mg (preferably 0.01 or 0.1 mg) and the upper limit is 500 mg (preferably 250 mg). This dosage range can also be deviated from according to the different degrees of the disease and the different dosage forms.

有益效果：与现有技术相比，本发明具有如下优点：Beneficial effects: Compared with the prior art, the present invention has the following advantages:

(1)本发明提供一种新型芳基并咪唑类化合物，其对于PPARδ具有强效的激动作用，例如，化合物2、16、76、108和110对PPARδ的EC50达到皮摩尔级别，显著强于三期临床试验药物MBX-8025。(1) The present invention provides a novel aryl imidazole compound which has a potent agonist effect on PPARδ. For example, the EC50 of compounds 2, 16, 76, 108 and 110 for PPARδ reaches the picomolar level, which is significantly stronger than the phase III clinical trial drug MBX-8025.

(2)本发明的化合物对PPARδ具有强效激动作用，对PPARα和PPARγ具有较好的选择性，且具有良好的药物代谢动力学性质。因此，本发明化合物或其药学上可接受的盐可用于制备PPARδ激动剂，进而可用于制备预防或治疗PPARδ介导的疾病的药物。(2) The compounds of the present invention have a strong agonist effect on PPARδ, have good selectivity for PPARα and PPARγ, and have good pharmacokinetic properties. Therefore, the compounds of the present invention or their pharmaceutically acceptable salts can be used to prepare PPARδ agonists, and further can be used to prepare drugs for preventing or treating PPARδ-mediated diseases.

(3)本发明的芳基咪唑类化合物设计巧妙，原料便宜易得，合成工艺安全、环保，易于规模化生产。(3) The aryl imidazole compounds of the present invention are ingeniously designed, the raw materials are cheap and easily available, the synthesis process is safe and environmentally friendly, and they are easy to mass produce.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1为化合物129对肾纤维化小鼠模型作用的肾脏天狼星红染色图；FIG1 is a Sirius red staining image of the kidneys of the mouse model of renal fibrosis of compound 129;

图2为化合物129对肾纤维化小鼠模型作用的肾脏的基因表达影响图(n＝5，与Sham组相比###p<0.001；与UUO相比*p<0.05，**p<0.01，***p<0.001；与Enalapril 50mpk组相比$$p<0.01)。Figure 2 shows the effect of compound 129 on gene expression in the kidney of a mouse model of renal fibrosis (n=5, ### p<0.001 compared with the Sham group; *p<0.05, **p<0.01, ***p<0.001 compared with the UUO group; $$ p<0.01 compared with the Enalapril 50mpk group).

具体实施方式DETAILED DESCRIPTION

下面通过实施例具体说明本发明的内容。The present invention is specifically described below by way of examples.

实施例1Example 1

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物1)
Ethyl 6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoate (Compound 1)

化合物I-1的合成Synthesis of Compound I-1

将2-羟基苯甲醛(206mg，1.69mmol)溶于N,N-二甲基甲酰胺(10mL)，加入碳酸钾(500mg，3.62mmol)，6-溴己酸乙酯(478mg，2.14mmol)，40℃搅拌反应8小时。TLC监测反应，待反应完全后，抽滤除去碳酸钾，加入乙酸乙酯(50mL)稀释，水(20mLx3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝30:1)纯化，得化合物I-1(无色油状液体，237mg，收率53％)。2-Hydroxybenzaldehyde (206 mg, 1.69 mmol) was dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (500 mg, 3.62 mmol) and ethyl 6-bromohexanoate (478 mg, 2.14 mmol) were added, and the mixture was stirred at 40°C for 8 hours. The reaction was monitored by TLC. After the reaction was complete, potassium carbonate was removed by suction filtration, ethyl acetate (50 mL) was added for dilution, water (20 mL x 3) was added for washing, and the mixture was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound I-1 (colorless oily liquid, 237 mg, yield 53%).

化合物I-2的合成Synthesis of Compound I-2

将化合物I-1(237mg，0.90mmol)溶于无水乙醇(10mL)，加入硼氢化钠(30mg，0.89mmol)，室温搅拌反应4小时。TLC监测反应，待反应完全后，加入水(1mL)淬灭反应，减压蒸除溶剂，加入乙酸乙酯(50mL)复溶，水(20mLx3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝10:1)纯化，得化合物I-2(无色油状液体，175mg，收率74％)。Compound I-1 (237 mg, 0.90 mmol) was dissolved in anhydrous ethanol (10 mL), sodium borohydride (30 mg, 0.89 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. After the reaction was complete, water (1 mL) was added to quench the reaction, the solvent was evaporated under reduced pressure, ethyl acetate (50 mL) was added to redissolve, water (20 mL x 3) was added, the mixture was washed with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound I-2 (colorless oily liquid, 175 mg, yield 74%).

化合物I-3的合成Synthesis of Compound I-3

将化合物I-2(175mg，0.66mmol)溶于二氯甲烷(4mL)，冰水浴下缓慢滴加三溴化磷(461mg，1.70mmol)，缓慢升至室温搅拌反应3小时。TLC监测反应，待反应完全后，加入水(20mL)淬灭反应，用二氯甲烷(30mL x3)萃取，合并有机相，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝50:1)纯化，得化合物I-3(无色油状液体，171mg，收率79％)。Compound I-2 (175 mg, 0.66 mmol) was dissolved in dichloromethane (4 mL), phosphorus tribromide (461 mg, 1.70 mmol) was slowly added dropwise under an ice-water bath, and the mixture was slowly heated to room temperature and stirred for 3 hours. The reaction was monitored by TLC. After the reaction was complete, water (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain compound I-3 (colorless oily liquid, 171 mg, yield 79%).

化合物I-4的合成Synthesis of Compound I-4

将1,2-苯二胺(100mg，0.92mmol)溶于N,N-二甲基甲酰胺(9mL)和水(1mL)混合溶剂，加入4-三氟甲氧基苯甲醛(176mg，0.93mmol)，80℃加热搅拌反应12小时。TLC监测反应，待反应完全后，冷至室温，加入乙酸乙酯(50mL)稀释，用水(20mL x3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝10:1)纯化，得化合物I-4(白色固体，257mg，收率99％):1H NMR(300MHz,DMSO-d6)δ13.01(s,1H),8.35-8.25(m,2H),7.69(d,J＝7.6Hz,1H),7.61-7.51(m,3H),7.31-7.14(m,2H).MS(ESI):m/z[M+H]+279.1.1,2-phenylenediamine (100 mg, 0.92 mmol) was dissolved in a mixed solvent of N,N-dimethylformamide (9 mL) and water (1 mL), 4-trifluoromethoxybenzaldehyde (176 mg, 0.93 mmol) was added, and the mixture was heated and stirred at 80°C for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (20 mL x 3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound I-4 (white solid, 257 mg, yield 99%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 13.01 (s, 1H), 8.35-8.25 (m, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.61-7.51 (m, 3H), 7.31-7.14 (m, 2H). MS (ESI): m/z [M+H] + 279.1.

化合物1的合成Synthesis of compound 1

将化合物I-4(130mg，0.47mmol)溶于乙腈(5mL)，加入碳酸铯(231mg，0.71mmol)和化合物I-3(171mg，0.52mmol)，室温搅拌反应4小时。TLC监测反应，待反应完全后，抽滤除去碳酸铯，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝15:1)纯化，得化合物1(白色固体，210mg，收率85％):1H NMR(300MHz,DMSO-d6)δ7.81(d,J＝8.3Hz,2H),7.73(d,J＝7.9Hz,1H),7.50(d,J＝8.3Hz,2H),7.41(d,J＝7.9Hz,1H),7.30-7.17(m,3H),7.00(d,J＝8.3Hz,1H),6.78(t,J＝7.5Hz,1H),6.62(d,1H),5.49(s,2H),4.00(q,J＝7.1Hz,2H),3.95(t,2H),2.24(t,2H),1.64-1.55(m,2H),1.55-1.44 (m,2H),1.36-1.22(m,2H),1.13(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+527.20531.Compound I-4 (130 mg, 0.47 mmol) was dissolved in acetonitrile (5 mL), cesium carbonate (231 mg, 0.71 mmol) and compound I-3 (171 mg, 0.52 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. After the reaction was complete, cesium carbonate was removed by suction filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1) to obtain compound 1 (white solid, 210 mg, yield 85%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.81(d,J＝8.3Hz,2H),7.73(d,J＝7.9Hz,1H),7.50(d,J＝8.3Hz,2H),7.41(d,J＝7.9Hz,1H),7.30-7.17(m,3H),7.00(d,J＝8.3Hz,1H),6.78(t,J＝7.5Hz,1 H),6.62(d,1H),5.49(s,2H),4.00(q,J＝7.1Hz,2H),3.95(t,2H),2.24(t,2H),1.64-1.55(m,2H),1.55-1.44 (m,2H),1.36-1.22(m,2H),1.13(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H] + 527.20531.

实施例2Example 2

6-(2-((2-(4-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物2)
6-(2-((2-(4-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 2)

将化合物1(210mg，0.40mmol)溶于四氢呋喃(4mL)，加入1M氢氧化锂水溶液(0.80mL，0.8mmol)，室温搅拌反应3小时。TLC监测反应，待反应完全后，减压蒸除溶剂，依次加入水(20mL)和1M盐酸调pH至4，有大量白色固体析出，抽滤，滤饼用水(10mL x3)洗涤，真空干燥得化合物2(白色固体，119mg，收率60％):1H NMR(300MHz,DMSO-d6)δ12.06(s,1H),7.81(d,J＝8.7Hz,2H),7.77-7.69(m,1H),7.50(d,J＝8.2Hz,2H),7.45-7.37(m,1H),7.30-7.16(m,3H),7.00(d,J＝8.2Hz,1H),6.77(t,J＝7.4Hz,1H),6.59(d,J＝6.8Hz,1H),5.50(s,2H),3.95(t,J＝6.3Hz,2H),2.17(t,J＝7.3Hz,2H),1.65-1.54(m,2H),1.54-1.43(m,2H),1.38-1.24(m,2H).13C NMR(126MHz,DMSO-d6)δ175.12,156.13,152.50,149.63,143.01,136.64,131.48,130.04,129.41,127.38,124.74,123.25,122.65,121.52,120.77,119.79,112.34,111.54,68.09,43.94,34.55,28.69,25.57,24.86.HRMS(ESI)calcd.for C27H25F3N2O4[M+H]+499.1839,found 499.1830.Compound 1 (210 mg, 0.40 mmol) was dissolved in tetrahydrofuran (4 mL), 1 M lithium hydroxide aqueous solution (0.80 mL, 0.8 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and water (20 mL) and 1 M hydrochloric acid were added in sequence to adjust the pH to 4. A large amount of white solid was precipitated, and the filter cake was washed with water (10 mL x 3) and dried in vacuo to obtain compound 2 (white solid, 119 mg, yield 60%): 1 H NMR (300 MHz, DMSO-d 6 )δ12.06(s,1H),7.81(d,J＝8.7Hz,2H),7.77-7.69(m,1H),7.50(d,J＝8.2Hz,2H),7.45-7.37(m,1H),7.30-7.16(m,3H),7.00(d,J＝8.2Hz,1H),6.77(t ,J＝7.4Hz,1H),6.59(d,J＝6.8Hz,1H),5.50(s,2H),3.95(t,J＝6.3Hz,2H),2.17(t,J＝7.3Hz,2H),1.65-1.54(m,2H),1.54-1.43(m,2H),1.38-1.24(m, 2H). 13C NMR (126MHz, DMSO-d 6 ) δ175.12,156.13,152.50,149.63,143.01,136.64,131.48,130.04,129.41,127.38,124.74,123.25,122.65,121.52,120.77, 119.79,112.34,111.54,68.09,43.94,34.55,28.69,25.57,24.86.HRMS(ESI)calcd.for C 27 H 25 F 3 N 2 O 4 [M+H] + 499.1839,found 499.1830.

实施例3Example 3

6-(2-((2-(4-(三氟甲基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物3)
Ethyl 6-(2-((2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoate (Compound 3)

参照实施例1的方法，将4-三氟甲氧基苯甲醛替换为4-三氟甲基苯甲醛制得化合物3(无色油状液体，127mg，收率65％):1H NMR(300MHz,DMSO-d6)δ8.03-7.83(m,4H),7.82-7.71(m,1H),7.54-7.38(m,1H),7.35-7.15(m,3H),7.00(d,J＝8.3Hz,1H),6.79(t,J＝7.4Hz,1H),6.65(d,J＝7.4Hz,1H),5.52(s,2H),4.01(q,J＝14.2,7.1Hz,2H),3.94(t,J＝6.2Hz,2H),2.23(t,J＝7.3Hz,2H),1.65-1.43(m,4H),1.36-1.21(m,2H),1.13(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na]+533.3.Referring to the method of Example 1, 4-trifluoromethoxybenzaldehyde was replaced with 4-trifluoromethylbenzaldehyde to obtain compound 3 (colorless oily liquid, 127 mg, yield 65%): 1 H NMR (300 MHz, DMSO-d 6 )δ8.03-7.83(m,4H),7.82-7.71(m,1H),7.54-7.38(m,1H),7.35-7.15(m,3H),7.00(d,J＝8.3Hz,1H),6.79(t,J＝7.4Hz,1H),6.65(d,J＝7.4Hz,1H),5. 52(s,2H),4.01(q,J＝14.2,7.1Hz,2H),3.94(t,J＝6.2Hz,2H),2.23(t,J＝7.3Hz,2H),1.65-1.43(m,4H),1.36-1.21(m,2H),1.13(t,J＝7.1Hz,3H).MS(ESI) ):m/z[M+Na] + 533.3.

实施例4Example 4

6-(2-((2-(4-(三氟甲基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物4)
6-(2-((2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 4)

参照实施例2的方法，将化合物1替换为化合物3制得化合物4(白色固体，65mg，收率54％):1H NMR(300MHz,DMSO-d6)δ11.97(s,1H),8.03-7.82(m,4H),7.79-7.67(m,1H),7.55-7.36(m,1H),7.36-7.14(m,3H),7.00(d,J＝8.1Hz,1H),6.78(t,J＝7.3Hz,1H),6.63(d,J＝7.0Hz,1H),5.53(s,2H),3.94(t,J＝6.2Hz,2H),2.16(t,J＝7.3Hz,2H),1.68-1.39(m,4H),1.37-1.17(m,2H).HRMS(ESI)calcd.for C27H25F3N2O3[M+H]+483.1890,found 483.1887.Referring to the method of Example 2, Compound 1 was replaced by Compound 3 to obtain Compound 4 (white solid, 65 mg, yield 54%): 1 H NMR (300 MHz, DMSO-d 6 )δ11.97(s,1H),8.03-7.82(m,4H),7.79-7.67(m,1H),7.55-7.36(m,1H),7.36-7.14(m,3H),7.00(d,J＝8.1Hz,1H),6.78(t,J＝7.3Hz,1H),6.63(d,J ＝7.0Hz,1H),5.53(s,2H),3.94(t,J＝6.2Hz,2H),2.16(t,J＝7.3Hz,2H),1.68-1.39(m,4H),1.37-1.17(m,2H).HRMS(ESI)calcd.for C 27 H 25 F 3 N 2 O 3 [M+H] + 4 83.1890,found 483.1887.

实施例5Example 5

6-(2-((2-(4-氟苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物5)
Ethyl 6-(2-((2-(4-fluorophenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoate (Compound 5)

参照实施例1的方法，将4-三氟甲氧基苯甲醛替换为4-氟苯甲醛制得化合物5(淡黄色固体，253mg，收率97％):1H NMR(300MHz,DMSO-d6)δ7.77-7.68(m,3H),7.40-7.29(m,3H),7.29-7.18(m,3H),7.01(d,J＝8.2Hz,1H),6.78(t,J＝7.5Hz,1H),6.57(d,J＝7.4Hz,1H),5.46(s,2H),4.05-3.93(m,4H),2.25(t,J＝7.3Hz,2H),1.68-1.46(m,4H),1.38-1.27(m,2H),1.14(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na]+483.3.Referring to the method of Example 1, 4-trifluoromethoxybenzaldehyde was replaced by 4-fluorobenzaldehyde to obtain compound 5 (light yellow solid, 253 mg, yield 97%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.77-7.68(m,3H),7.40-7.29(m,3H),7.29-7.18(m,3H),7.01(d,J＝8.2Hz,1H),6.78(t,J＝7.5Hz,1H),6.57(d,J＝7.4Hz,1H),5.46(s,2H),4.05-3. 93(m,4H),2.25(t,J＝7.3Hz,2H),1.68-1.46(m,4H),1.38-1.27(m,2H),1.14(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na] + 483.3.

实施例6Example 6

6-(2-((2-(4-氟苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物6)
6-(2-((2-(4-Fluorophenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 6)

参照实施例2的方法，将化合物1替换为化合物5制得化合物6(白色固体，102mg，收率43％):1H NMR(300MHz,DMSO-d6)δ7.78-7.65(m,3H),7.41-7.28(m,3H),7.27-7.15(m,3H),6.99(d,J＝8.2Hz,1H),6.76(t,J＝7.4Hz,1H),6.53(d,J＝7.3Hz,1H),5.47(s,2H),3.96(t,J＝6.3Hz,2H),2.05(t,J＝7.1Hz,2H),1.68-1.55(m,2H),1.55-1.42(m,2H),1.39-1.27(m,2H).HRMS(ESI)calcd.for C26H25FN2O3[M+H]+433.1922,found499.1922.Referring to the method of Example 2, Compound 1 was replaced by Compound 5 to obtain Compound 6 (white solid, 102 mg, yield 43%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.78-7.65(m,3H),7.41-7.28(m,3H),7.27-7.15(m,3H),6.99(d,J＝8.2Hz,1H),6.76(t,J＝7.4Hz,1H),6.53(d,J＝7.3Hz,1H),5.47(s,2H),3.96(t,J ＝6.3Hz,2H),2.05(t,J＝7.1Hz,2H),1.68-1.55(m,2H),1.55-1.42(m,2H),1.39-1.27(m,2H).HRMS(ESI)calcd.for C 26 H 25 FN 2 O 3 [M+H] + 433.1922,found499.19 22.

实施例7Example 7

6-(2-((2-(4-氯苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物7)
Ethyl 6-(2-((2-(4-chlorophenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoate (Compound 7)

参照实施例1的方法，将4-三氟甲氧基苯甲醛替换为4-氯苯甲醛制得化合物7(淡黄色固体，246mg，收率98％):1H NMR(300MHz,DMSO-d6)δ7.75-7.67(m,3H),7.57(d,J＝8.6Hz,2H),7.43-7.36(m,1H),7.29-7.18(m,3H),7.01(d,J＝8.1Hz,1H),6.79(t,J＝7.4Hz,1H),6.59(d,J＝6.4Hz,1H),5.48(s,2H),4.06-3.92(m,4H),2.25(t,J＝7.4Hz,2H),1.66-1.47(m,4H),1.37-1.27(m,2H),1.14(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na]+499.3.Referring to the method of Example 1, 4-trifluoromethoxybenzaldehyde was replaced with 4-chlorobenzaldehyde to obtain compound 7 (light yellow solid, 246 mg, yield 98%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.75-7.67(m,3H),7.57(d,J＝8.6Hz,2H),7.43-7.36(m,1H),7.29-7.18(m,3H),7.01(d,J＝8.1Hz,1H),6.79(t,J＝7.4Hz,1H),6.59(d,J＝6.4Hz,1H), 5.48(s,2H),4.06-3.92(m,4H),2.25(t,J＝7.4Hz,2H),1.66-1.47(m,4H),1.37-1.27(m,2H),1.14(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na] + 499.3.

实施例8Example 8

6-(2-((2-(4-氯苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物8)
6-(2-((2-(4-chlorophenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 8)

参照实施例2的方法，将化合物1替换为化合物7制得化合物8(白色固体，85mg，收率37％):1H NMR(300MHz,DMSO-d6)δ7.71(d,J＝7.9Hz,3H),7.56(d,J＝8.1Hz,2H),7.39(d,J＝6.8Hz,1H),7.30-7.15(m,3H),6.99(d,J＝8.4Hz,1H),6.75(t,J＝7.2Hz,1H),6.53(d,J＝7.0Hz,1H),5.48(s,2H),3.95(t,J＝6.1Hz,2H),1.86(t,J＝6.8Hz,2H),1.69-1.54(m,2H),1.52-1.39(m,2H),1.37-1.23(m,2H).HRMS(ESI)calcd.for C26H25FN2O3[M+H]+449.1626,found 449.1630.Referring to the method of Example 2, Compound 1 was replaced by Compound 7 to obtain Compound 8 (white solid, 85 mg, yield 37%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.71(d,J＝7.9Hz,3H),7.56(d,J＝8.1Hz,2H),7.39(d,J＝6.8Hz,1H),7.30-7.15(m,3H),6.99(d,J＝8.4Hz,1H),6.75(t,J＝7.2Hz,1H),6.53(d,J＝7.0Hz, 1H),5.48(s,2H),3.95(t,J＝6.1Hz,2H),1.86(t,J＝6.8Hz,2H),1.69-1.54(m,2H),1.52-1.39(m,2H),1.37-1.23(m,2H).HRMS(ESI)calcd.for C 26 H 25 FN 2 O 3 [M+H] + 449.1626, found 449.1630.

实施例9Embodiment 9

6-(2-((2-(4-溴苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物9)
Ethyl 6-(2-((2-(4-bromophenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoate (Compound 9)

参照实施例1的方法，将4-三氟甲氧基苯甲醛替换为4-溴苯甲醛制得化合物9(无色油状液体，216mg，收率99％):1H NMR(300MHz,DMSO-d6)δ7.76-7.67(m,3H),7.63(d,J＝8.5Hz,2H),7.43-7.34(m,1H),7.30-7.16(m,3H),7.01(d,J＝8.2Hz,1H),6.78(t,J＝7.5Hz,1H),6.59(d,J＝7.6Hz,1H),5.48(s,2H),4.07-3.92(m,4H),2.25(t,J＝7.3Hz,2H),1.66-1.46(m,4H),1.38-1.28(m,2H),1.14(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na]+543.1.Referring to the method of Example 1, 4-trifluoromethoxybenzaldehyde was replaced with 4-bromobenzaldehyde to obtain compound 9 (colorless oily liquid, 216 mg, yield 99%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.76-7.67(m,3H),7.63(d,J＝8.5Hz,2H),7.43-7.34(m,1H),7.30-7.16(m,3H),7.01(d,J＝8.2Hz,1H),6.78(t,J＝7.5Hz,1H),6.59(d,J＝7.6Hz,1H), 5.48(s,2H),4.07-3.92(m,4H),2.25(t,J＝7.3Hz,2H),1.66-1.46(m,4H),1.38-1.28(m,2H),1.14(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na] + 543.1.

实施例10Example 10

6-(2-((2-(4-溴苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物10)
6-(2-((2-(4-bromophenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 10)

参照实施例2的方法，将化合物1替换为化合物9制得化合物10(白色固体，72mg，收率35％):1H NMR(300MHz,CD3OD)δ7.73(d,J＝6.9Hz,1H),7.66(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7.37(t,J＝7.9Hz,1H),7.33-7.27(m,2H),7.23(t,1H),6.98(d,J＝8.1Hz,1H),6.76(t,J＝7.4Hz,1H),6.60(d,J＝7.2Hz,1H),5.49(s,2H),3.99(t,J＝6.4Hz,2H),2.16(t,J＝7.4Hz,2H),1.77-1.67(m,2H),1.67-1.57(m,2H),1.50-1.35(m,2H).HRMS(ESI)calcd.for C26H25FN2O3[M+H]+493.1121,found 493.1119.Referring to the method of Example 2, compound 1 was replaced by compound 9 to obtain compound 10 (white solid, 72 mg, yield 35%): 1 H NMR (300 MHz, CD 3 OD) δ7.73 (d, J=6.9 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.37 (t, J=7.9 Hz, 1H), 7.33-7.27 (m, 2H), 7.23 (t, 1H), 6.98 (d, J=8.1 Hz, 1H), 6.76 (t, J=7.4 Hz, 1H). z,1H),6.60(d,J＝7.2Hz,1H),5.49(s,2H),3.99(t,J＝6.4Hz,2H),2.16(t,J＝7.4Hz,2H),1.77-1.67(m,2H),1.67-1.57(m,2H),1.50-1.35(m,2H).HRMS( ESI)calcd.for C 26 H 25 FN 2 O 3 [M+H] + 493.1121, found 493.1119.

实施例11Embodiment 11

6-(2-((2-(4-(N，N-二甲基氨磺酰基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物11)
Ethyl 6-(2-((2-(4-(N,N-dimethylsulfamoyl)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoate (Compound 11)

化合物I-5的合成Synthesis of Compound I-5

将二甲胺的四氢呋喃溶液(浓度为2M，1.13mL)加入至四氢呋喃(4mL)中，再加入吡啶(215mg，2.72mmol)，冰水浴下加入4-(氯磺酰基)苯甲酸(200mg，0.91mmol)，缓慢升至室温搅拌反应4小时。TLC监测反应，待反应完全后，减压蒸除溶剂，加入水(10mL)和1M盐酸调pH至1，有大量固体析出，抽滤，真空干燥得化合物I-5(棕色固体，157mg，收率75％)。A tetrahydrofuran solution of dimethylamine (concentration of 2M, 1.13mL) was added to tetrahydrofuran (4mL), and then pyridine (215mg, 2.72mmol) was added, and 4-(chlorosulfonyl)benzoic acid (200mg, 0.91mmol) was added under an ice-water bath, and the mixture was slowly heated to room temperature and stirred for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and water (10mL) and 1M hydrochloric acid were added to adjust the pH to 1. A large amount of solid precipitated, which was filtered and dried in vacuo to obtain compound I-5 (brown solid, 157mg, yield 75%).

化合物I-6的合成Synthesis of Compound I-6

将化合物I-5(400mg，1.74mmol)溶于无水四氢呋喃(9mL)，在氮气保护下，缓慢滴加含1M硼烷的四氢呋喃溶液(3.5mL，3.5mmol)，70℃加热搅拌反应6小时。TLC监测反应，待反应完全后，加水(1mL)淬灭反应，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝3:1)纯化，得化合物I-6(白色固体，101mg，收率27％)。Compound I-5 (400 mg, 1.74 mmol) was dissolved in anhydrous tetrahydrofuran (9 mL), and a tetrahydrofuran solution containing 1 M borane (3.5 mL, 3.5 mmol) was slowly added dropwise under nitrogen protection, and the mixture was stirred and heated at 70°C for 6 hours. The reaction was monitored by TLC, and after the reaction was complete, water (1 mL) was added to quench the reaction, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound I-6 (white solid, 101 mg, yield 27%).

化合物I-7的合成Synthesis of Compound I-7

将化合物I-6(100mg，0.46mmol)溶于二氯甲烷(5mL)，冰水浴下加入Dess-Martin试剂(236mg，0.56mmol)，缓慢升至室温搅拌反应3小时。TLC监测反应，待反应完全后，加乙酸乙酯(50mL)稀释，依次用饱和碳酸氢钠溶液(20mL x3)和饱和硫代硫酸钠溶液(20mL x3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝5:1)纯化，得化合物I-7(白色固体，70mg，收率71％)。Compound I-6 (100 mg, 0.46 mmol) was dissolved in dichloromethane (5 mL), and Dess-Martin reagent (236 mg, 0.56 mmol) was added under an ice-water bath, and the mixture was slowly heated to room temperature and stirred for 3 hours. The reaction was monitored by TLC, and after the reaction was complete, ethyl acetate (50 mL) was added for dilution, and the mixture was washed with saturated sodium bicarbonate solution (20 mL x 3) and saturated sodium thiosulfate solution (20 mL x 3) in sequence, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain compound I-7 (white solid, 70 mg, yield 71%).

参照实施例1的方法，将4-三氟甲氧基苯甲醛替换为化合物I-7制得化合物11(淡黄色固体，115mg，收率75％):1H NMR(300MHz,DMSO-d6)δ7.96(d,J＝8.5Hz,2H),7.84(d,J＝8.5Hz,2H),7.79-7.73(m,1H),7.49-7.43(m,1H),7.31-7.24(m,2H),7.24-7.17(m,1H),6.98(d,J＝8.2Hz,1H),6.77(t,J＝7.3Hz,1H),6.65(d,J＝7.5Hz,1H),5.55(s, 2H),4.01(q,J＝7.1Hz,2H),3.92(t,J＝6.3Hz,2H),2.64(s,6H),2.24(t,J＝7.3Hz,2H),1.60-1.44(m,4H),1.33-1.26(m,2H),1.13(t,J＝7.4Hz,3H).MS(ESI):m/z[M+Na]+572.3.Referring to the method of Example 1, 4-trifluoromethoxybenzaldehyde was replaced by compound I-7 to obtain compound 11 (light yellow solid, 115 mg, yield 75%): 1 H NMR (300 MHz, DMSO-d 6 ) δ7.96 (d, J=8.5 Hz, 2H), 7.84 (d, J=8.5 Hz, 2H), 7.79-7.73 (m, 1H), 7.49-7.43 (m, 1H), 7.31-7.24 (m, 2H), 7.24-7.17 (m, 1H), 6.98 (d, J=8.2 Hz, 1H), 6.77 (t, J=7.3 Hz, 1H), 6.65 (d, J=7.5 Hz, 1H), 5.55 (s, 2H),4.01(q,J＝7.1Hz,2H),3.92(t,J＝6.3Hz,2H),2.64(s,6H),2.24(t,J＝7.3Hz,2H),1.60-1.44(m,4H),1.33-1.26(m,2H),1.13(t,J＝7.4Hz,3H).MS(ES I):m/z[M+Na] + 572.3.

实施例12Example 12

6-(2-((2-(4-(N，N-二甲基氨磺酰基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物12)
6-(2-((2-(4-(N,N-dimethylsulfamoyl)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 12)

参照实施例2的方法，将化合物1替换为化合物11制得化合物12(白色固体，47mg，收率43％):1H NMR(300MHz,DMSO-d6)δ7.97(d,J＝8.4Hz,2H),7.84(d,J＝8.4Hz,2H),7.79-7.71(m,1H),7.51-7.43(m,1H),7.31-7.24(m,2H),7.20(t,J＝7.8Hz,1H),6.98(d,J＝8.2Hz,1H),6.74(t,J＝7.4Hz,1H),6.57(d,J＝7.4Hz,1H),5.56(s,2H),3.91(t,J＝6.5Hz,2H),2.65(s,6H),1.84(t,J＝7.3Hz,2H),1.63-1.49(m,2H),1.49-1.36(m,2H),1.36-1.20(m,2H).HRMS(ESI)calcd.for C28H31N3O5S[M+H]+522.2057,found522.2067.Referring to the method of Example 2, compound 1 was replaced by compound 11 to obtain compound 12 (white solid, 47 mg, yield 43%): 1 H NMR (300 MHz, DMSO-d 6 ) δ7.97 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.4 Hz, 2H), 7.79-7.71 (m, 1H), 7.51-7.43 (m, 1H), 7.31-7.24 (m, 2H), 7.20 (t, J=7.8 Hz, 1H), 6.98 (d, J=8.2 Hz, 1H), 6.74 (t, J=7.4 Hz, 1H), 6.57(d,J＝7.4Hz,1H),5.56(s,2H),3.91(t,J＝6.5Hz,2H),2.65(s,6H),1.84(t,J＝7.3Hz,2H),1.63-1.49(m,2H),1.49-1.36(m,2H),1.36-1.20(m,2 H).HRMS(ESI)calcd.for C 28 H 31 N 3 O 5 S[M+H] + 522.2057,found522.2067.

实施例13Example 13

6-(2-((2-苯基-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物13)
Ethyl 6-(2-((2-phenyl-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoate (Compound 13)

参照实施例1的方法，将4-三氟甲氧基苯甲醛替换为苯甲醛制得化合物13(无色油状液体，193mg，收率85％):1H NMR(300MHz,DMSO-d6)δ7.77-7.63(m,3H),7.55-7.45(m,3H),7.40-7.32(m,1H),7.29-7.16(m,3H),7.02(d,J＝8.2Hz,1H),6.79(t,J＝7.3Hz,1H),6.55(d,J＝7.5Hz,1H),5.48(s,2H),4.07-3.92(m,4H),2.25(t,J＝7.3Hz,2H),1.72-1.58(m,2H),1.57-1.47(m,2H),1.39-1.28(m,2H),1.14(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na]+465.3.Referring to the method of Example 1, 4-trifluoromethoxybenzaldehyde was replaced by benzaldehyde to obtain compound 13 (colorless oily liquid, 193 mg, yield 85%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.77-7.63(m,3H),7.55-7.45(m,3H),7.40-7.32(m,1H),7.29-7.16(m,3H),7.02(d,J＝8.2Hz,1H),6.79(t,J＝7.3Hz,1H),6.55(d,J＝7.5Hz,1H),5.4 8(s,2H),4.07-3.92(m,4H),2.25(t,J＝7.3Hz,2H),1.72-1.58(m,2H),1.57-1.47(m,2H),1.39-1.28(m,2H),1.14(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na] + 465.3.

实施例14Embodiment 14

6-(2-((2-苯基-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物14)
6-(2-((2-phenyl-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 14)

参照实施例2的方法，将化合物1替换为化合物13制得化合物14(淡棕色固体，100mg，收率56％):1H NMR(300MHz,DMSO-d6)δ12.00(s,1H),7.79-7.63(m,3H),7.56-7.45(m,3H),7.42-7.32(m,1H),7.30-7.18(m,3H),7.02(d,J＝8.2Hz,1H),6.78(t,J＝7.4Hz,1H),6.54(d,J＝7.1Hz,1H),5.48(s,2H),3.98(t,J＝6.3Hz,2H),2.18(t,J＝7.3Hz,2H),1.70-1.58(m,2H),1.58-1.44(m,2H),1.41-1.26(m,2H).HRMS(ESI)calcd.for C26H26N2O3[M+H]+415.2016,found 415.2012.Referring to the method of Example 2, Compound 1 was replaced by Compound 13 to obtain Compound 14 (light brown solid, 100 mg, yield 56%): 1 H NMR (300 MHz, DMSO-d 6 )δ12.00(s,1H),7.79-7.63(m,3H),7.56-7.45(m,3H),7.42-7.32(m,1H),7.30-7.18(m,3H),7.02(d,J＝8.2Hz,1H),6.78(t,J＝7.4Hz,1H),6.54(d,J ＝7.1Hz,1H),5.48(s,2H),3.98(t,J＝6.3Hz,2H),2.18(t,J＝7.3Hz,2H),1.70-1.58(m,2H),1.58-1.44(m,2H),1.41-1.26(m,2H).HRMS(ESI)calcd.for C 26 H 2 6 N 2 O 3 [M+H] + 415.2016, found 415.2012.

实施例15Embodiment 15

6-(2-((2-(4-(呋喃-2-基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物15)
Ethyl 6-(2-((2-(4-(Furan-2-yl)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoate (Compound 15)

参照实施例1的方法，将4-三氟甲氧基苯甲醛替换为4-呋喃苯甲醛制得化合物15(无色油状液体，135mg，收率71％):1H NMR(300MHz,DMSO-d6)δ7.86-7.79(m,3H),7.79-7.70(m,3H),7.44-7.35(m,1H),7.31-7.18(m,3H),7.11-7.00(m,2H),6.80(t,J＝7.4Hz,1H),6.67-6.56(m,2H),5.52(s,2H),4.06-3.90(m,4H),2.22(t,J＝7.3Hz,2H),1.67-1.57(m,2H),1.56-1.44(m,2H),1.36-1.27(m,2H),1.11(t,J＝7.1Hz,2H).MS(ESI):m/z[M+H]+509.25263.Referring to the method of Example 1, 4-trifluoromethoxybenzaldehyde was replaced with 4-furanbenzaldehyde to obtain compound 15 (colorless oily liquid, 135 mg, yield 71%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.86-7.79(m,3H),7.79-7.70(m,3H),7.44-7.35(m,1H),7.31-7.18(m,3H),7.11-7.00(m,2H),6.80(t,J＝7.4Hz,1H),6.67-6.56(m,2H),5.52(s ,2H),4.06-3.90(m,4H),2.22(t,J＝7.3Hz,2H),1.67-1.57(m,2H),1.56-1.44(m,2H),1.36-1.27(m,2H),1.11(t,J＝7.1Hz,2H).MS(ESI):m/z[M+H] + 5 09.25263.

实施例16Example 16

6-(2-((2-(4-(呋喃-2-基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物16)
6-(2-((2-(4-(Furan-2-yl)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 16)

参照实施例2的方法，将化合物1替换为化合物15制得化合物16(白色固体，35mg，收率27％):1H NMR(300MHz,DMSO-d6)δ7.87-7.68(m,6H),7.39(d,J＝8.4Hz,1H),7.30-7.17(m,3H),7.08(d,J＝3.3Hz,1H),7.02(d,J＝8.3Hz,1H),6.77(t,J＝7.2Hz,1H),6.65-6.59(m,1H),6.52(d,J＝7.5Hz,1H),5.52(s,2H),3.98(t,J＝6.3Hz,2H),1.93(t,J＝7.1Hz,2H),1.68-1.56(m,2H),1.54-1.40(m,3H),1.39-1.27(m,3H).MS(ESI):m/z[M+Na]+481.22155.Referring to the method of Example 2, Compound 1 was replaced by Compound 15 to obtain Compound 16 (white solid, 35 mg, yield 27%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.87-7.68(m,6H),7.39(d,J＝8.4Hz,1H),7.30-7.17(m,3H),7.08(d,J＝3.3Hz,1H),7.02(d,J＝8.3Hz,1H),6.77(t,J＝7.2Hz,1H),6.65-6.59(m,1H), 6.52(d,J＝7.5Hz,1H),5.52(s,2H),3.98(t,J＝6.3Hz,2H),1.93(t,J＝7.1Hz,2H),1.68-1.56(m,2H),1.54-1.40(m,3H),1.39-1.27(m,3H).MS(ESI):m/ z[M+Na] + 481.22155.

实施例17Embodiment 17

6-(2-((2-(3-(3-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物17)
Ethyl 6-(2-((2-(3-(3-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoate (Compound 17)

参照实施例1的方法，将4-三氟甲氧基苯甲醛替换为3-三氟甲氧基苯甲醛制得化合物17(无色油状液体，224mg，收率99％):1H NMR(300MHz,DMSO-d6)δ7.83-7.70(m,2H),7.70-7.56(m,2H),7.55-7.41(m,2H),7.34-7.17(m,3H),7.01(d,J＝8.2Hz,1H),6.78(t,J＝7.4Hz,1H),6.59(d,J＝7.3Hz,1H),5.51(s,2H),4.07-3.90(m,4H),2.24(t,J＝7.3Hz,2H),1.67-1.42(m,4H),1.37-1.26(m,2H),1.13(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+527.2.Referring to the method of Example 1, 4-trifluoromethoxybenzaldehyde was replaced by 3-trifluoromethoxybenzaldehyde to obtain compound 17 (colorless oily liquid, 224 mg, yield 99%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.83-7.70(m,2H),7.70-7.56(m,2H),7.55-7.41(m,2H),7.34-7.17(m,3H),7.01(d,J＝8.2Hz,1H),6.78(t,J＝7.4Hz,1H),6.59(d,J＝7.3Hz,1H),5. 51(s,2H),4.07-3.90(m,4H),2.24(t,J＝7.3Hz,2H),1.67-1.42(m,4H),1.37-1.26(m,2H),1.13(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H] + 527.2.

实施例18Embodiment 18

6-(2-((2-(3-(3-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物18)
6-(2-((2-(3-(3-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 18)

参照实施例2的方法，将化合物1替换为化合物17制得化合物18(白色固体，106mg，收率50％):1H NMR(300MHz,DMSO-d6)δ7.80-7.70(m,2H),7.69-7.57(m,2H),7.55-7.41(m,2H),7.32-7.17(m,3H),7.00(d,1H),6.76(t,J＝7.4Hz,1H),6.54(d,1H),5.51(s,2H),3.94(t,J＝6.4Hz,2H),1.92(t,J＝7.2Hz,2H),1.68-1.52(m,2H),1.52-1.36(m,2H),1.37-1.20(m,2H).HRMS(ESI)calcd.for C27H25F3N2O4[M+H]+499.1839,found499.1839.Referring to the method of Example 2, Compound 1 was replaced by Compound 17 to obtain Compound 18 (white solid, 106 mg, yield 50%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.80-7.70(m,2H),7.69-7.57(m,2H),7.55-7.41(m,2H),7.32-7.17(m,3H),7.00(d,1H),6.76(t,J＝7.4Hz,1H),6.54(d,1H),5.51(s,2H),3.94(t ,J＝6.4Hz,2H),1.92(t,J＝7.2Hz,2H),1.68-1.52(m,2H),1.52-1.36(m,2H),1.37-1.20(m,2H).HRMS(ESI)calcd.for C 27 H 25 F 3 N 2 O 4 [M+H] + 499.1839,found49 9.1839.

实施例19Embodiment 19

6-(2-((2-(2-(2-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物19)
Ethyl 6-(2-((2-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoate (Compound 19)

参照实施例1的方法，将4-三氟甲氧基苯甲醛替换为2-三氟甲氧基苯甲醛制得化合物19(黄色油状液体，219mg，收率96％):1H NMR(300MHz,DMSO-d6)δ7.77-7.62(m,2H),7.59-7.44(m,4H),7.30-7.22(m,2H),7.16(t,J＝7.6Hz,1H),6.91(d,J＝8.2Hz,1H),6.70(t,J＝7.4Hz,1H),6.50(d,J＝7.4Hz,1H),5.29(s,2H),4.03(q,J＝7.1Hz,2H),3.85(t,J＝6.2Hz,2H),2.23(t,J＝7.3Hz,2H),1.56-1.41(m,4H),1.27-1.20(m,2H),1.15(t,J＝13.4,6.3Hz,3H).MS(ESI):m/z[M+H]+527.2. Referring to the method of Example 1, 4-trifluoromethoxybenzaldehyde was replaced by 2-trifluoromethoxybenzaldehyde to obtain compound 19 (yellow oily liquid, 219 mg, yield 96%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.77-7.62(m,2H),7.59-7.44(m,4H),7.30-7.22(m,2H),7.16(t,J＝7.6Hz,1H),6.91(d,J＝8.2Hz,1H),6.70(t,J＝7.4Hz,1H),6.50(d,J＝7.4Hz,1H),5 .29(s,2H),4.03(q,J＝7.1Hz,2H),3.85(t,J＝6.2Hz,2H),2.23(t,J＝7.3Hz,2H),1.56-1.41(m,4H),1.27-1.20(m,2H),1.15(t,J＝13.4,6.3Hz,3H).MS( ESI):m/z[M+H] + 527.2.

实施例20Embodiment 20

6-(2-((2-(2-(2-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物20)
6-(2-((2-(2-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 20)

参照实施例2的方法，将化合物1替换为化合物19制得化合物20(白色固体，70mg，收率34％):1H NMR(300MHz,DMSO-d6)δ11.98(s,1H),7.80-7.61(m,2H),7.60-7.40(m,4H),7.33-7.21(m,2H),7.16(t,J＝7.4Hz,1H),6.97-6.85(m,1H),6.70(t,J＝7.3Hz,1H),6.49(d,1H),5.29(s,2H),3.85(t,J＝5.8Hz,2H),2.17(t,J＝7.1Hz,2H),1.64-1.36(m,4H),1.32-1.12(m,2H).HRMS(ESI)calcd.for C27H25F3N2O4[M+H]+499.1839,found 499.1842.Referring to the method of Example 2, Compound 1 was replaced by Compound 19 to obtain Compound 20 (white solid, 70 mg, yield 34%): 1 H NMR (300 MHz, DMSO-d 6 )δ11.98(s,1H),7.80-7.61(m,2H),7.60-7.40(m,4H),7.33-7.21(m,2H),7.16(t,J＝7.4Hz,1H),6.97-6.85(m,1H),6.70(t,J＝7.3Hz,1H),6.49(d,1H ),5.29(s,2H),3.85(t,J＝5.8Hz,2H),2.17(t,J＝7.1Hz,2H),1.64-1.36(m,4H),1.32-1.12(m,2H).HRMS(ESI)calcd.for C 27 H 25 F 3 N 2 O 4 [M+H] + 499.1839, found 499.1842.

实施例21Embodiment 21

2-(4-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)苯基)乙酸乙酯(化合物21)
Ethyl 2-(4-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)phenyl)acetate (Compound 21)

化合物I-8的合成Synthesis of Compound I-8

将4-溴甲基苯甲酸(300mg，1.31mmol)溶于乙醇(4mL)，加入98％浓硫酸(0.3mL)，80℃加热搅拌反应4小时。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝30:1)纯化，得化合物I-8(无色油状液体，323mg，收率96％)。4-Bromomethylbenzoic acid (300 mg, 1.31 mmol) was dissolved in ethanol (4 mL), 98% concentrated sulfuric acid (0.3 mL) was added, and the mixture was stirred at 80°C for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain compound I-8 (colorless oily liquid, 323 mg, yield 96%).

参照实施例1的方法，将6-溴己酸乙酯替换为化合物I-8制得化合物21(白色固体，72mg，收率42％):1H NMR(300MHz,DMSO-d6)δ7.80(d,J＝8.7Hz,2H),7.74(d,J＝7.2Hz,1H),7.49(d,J＝8.2Hz,2H),7.38(d,J＝7.1Hz,1H),7.29-7.16(m,7H),7.08(d,J＝8.1Hz,1H),6.80(t,J＝7.4Hz,1H),6.62(d,J＝6.6Hz,1H),5.53(s,2H),5.10(s,2H),4.07(q,J＝7.1Hz,2H),3.65(s,2H),1.18(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na]+583.3.Referring to the method of Example 1, 6-bromohexanoic acid ethyl ester was replaced with compound I-8 to obtain compound 21 (white solid, 72 mg, yield 42%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.80(d,J＝8.7Hz,2H),7.74(d,J＝7.2Hz,1H),7.49(d,J＝8.2Hz,2H),7.38(d,J＝7.1Hz,1H),7.29-7.16(m,7H),7.08(d,J＝8.1Hz,1H),6.80(t,J＝7.4Hz, 1H),6.62(d,J＝6.6Hz,1H),5.53(s,2H),5.10(s,2H),4.07(q,J＝7.1Hz,2H),3.65(s,2H),1.18(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na] + 583.3.

实施例22Example 22

2-(4-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)苯基)乙酸(化合物22)
2-(4-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)phenyl)acetic acid (Compound 22)

参照实施例2的方法，将化合物1替换为化合物21制得化合物22(白色固体，40mg，收率68％):1H NMR(300MHz,DMSO-d6)δ12.26(s,1H),7.85-7.72(m,3H),7.60-7.45(m,3H),7.38(d,J＝8.1Hz,1H),7.33-7.11(m,6H),6.90(d,J＝8.5Hz,2H),6.47(d,J＝7.5Hz,1H),5.72(s,2H),5.19(s,2H),3.48(s,2H).HRMS(ESI)calcd.for C30H23F3N2O4[M+H]+533.1683,found 533.1679.Referring to the method of Example 2, Compound 22 (white solid, 40 mg, yield 68%) was prepared by replacing Compound 1 with Compound 21: 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.26 (s, 1H), 7.85-7.72 (m, 3H), 7.60-7.45 (m, 3H), 7.38 (d, J=8.1 Hz, 1H), 7.33-7.11 (m, 6H), 6.90 (d, J=8.5 Hz, 2H), 6.47 (d, J=7.5 Hz, 1H), 5.72 (s, 2H), 5.19 (s, 2H), 3.48 (s, 2H). HRMS (ESI) calcd. for C 30 H 23 F 3 N 2 O 4 [M+H] + 533.1683, found 533.1679.

实施例23Embodiment 23

2-(3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)苯基)乙酸甲酯(化合物23)
2-(3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)phenyl)acetate (Compound 23)

参照实施例21的方法，将4-(溴甲基)苯乙酸替换3-(溴甲基)苯乙酸，将乙醇替换成甲醇，制得化合物23(白色固体，20mg，收率14％):1H NMR(300MHz,Chloroform-d)δ7.90(d,J＝7.9Hz,1H),7.74(d,J＝8.7Hz,2H),7.39–7.23(m,10H),7.04(d,J＝7.9Hz,1H),6.93–6.83(m,1H),6.77(d,J＝6.0Hz,1H),5.50(s,2H),5.15(s,2H),3.69(s,3H),3.65(s,2H).MS(ESI):m/z[M+Na]+547.2.Referring to the method of Example 21, 4-(bromomethyl)phenylacetic acid was substituted for 3-(bromomethyl)phenylacetic acid, and ethanol was substituted for methanol to obtain compound 23 (white solid, 20 mg, yield 14%): 1 H NMR (300 MHz, Chloroform-d) δ 7.90 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.39-7.23 (m, 10H), 7.04 (d, J = 7.9 Hz, 1H), 6.93-6.83 (m, 1H), 6.77 (d, J = 6.0 Hz, 1H), 5.50 (s, 2H), 5.15 (s, 2H), 3.69 (s, 3H), 3.65 (s, 2H). MS (ESI): m/z [M+Na] + 547.2.

实施例24Embodiment 24

2-(3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)苯基)乙酸(化合物24)。
2-(3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)phenyl)acetic acid (Compound 24).

参照实施例2的方法，将化合物1替换为化合物23制得化合物24(白色固体，30mg，收率51％):1H NMR(300MHz,DMSO-d6)δ12.25(s,1H),7.80(d,J＝8.3Hz,2H),7.73(s,1H),7.49(d,J＝8.4Hz,2H),7.37(s,1H),7.24(d,J＝14.4Hz,7H),7.10(s,1H),6.79(d,J＝7.9Hz,1H),6.63(s,1H),5.54(s,2H),5.10(s,2H),3.55(s,2H).HRMS(ESI)calcd.for C30H23F3N2O4[M+H]+533.1688,found 533.1670.Referring to the method of Example 2, compound 1 was replaced by compound 23 to obtain compound 24 (white solid, 30 mg, yield 51%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.25 (s, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.73 (s, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.37 (s, 1H), 7.24 (d, J = 14.4 Hz, 7H), 7.10 (s, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.63 (s, 1H), 5.54 (s, 2H), 5.10 (s, 2H), 3.55 (s, 2H). HRMS (ESI) calcd. for C 30 H 23 F 3 N 2 O 4 [M+H]+533.1688,found 533.1670.

实施例25Embodiment 25

2-(4-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)环己基)乙酸乙酯(化合物25)
Ethyl 2-(4-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)cyclohexyl)acetate (Compound 25)

化合物I-9的合成Synthesis of Compound I-9

在氩气保护下，将甲氧基甲基三苯基氯化膦(387mg，1.13mmol)溶于无水四氢呋喃(5mL)，-78℃下，缓慢滴加2.5M正丁基锂的正己烷溶液(0.38mL，0.95mmol)，滴加完毕升至0℃，搅拌10min，冷至-78℃，缓慢滴加4-氧代环己烷乙酸乙酯(104mg，0.56mmol)，滴加完毕缓慢升至室温搅拌反应6小时。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝60:1)纯化，得化合物I-9(无色油状液体，92mg，收率:77％):1H NMR(300MHz,CDCl3)δ5.75(s,1H),4.12(q,J＝7.1Hz,2H),3.52(s,3H),2.80-2.68(m,1H),2.19(d,J＝7.0Hz,2H),2.09-1.99(m,1H),1.99-1.85(m,2H),1.85-1.74(m,3H),1.73-1.63(m,1H),1.24(t,J＝7.2Hz,3H),1.08-0.91(m,2H).Under argon protection, methoxymethyltriphenylphosphine chloride (387 mg, 1.13 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL). At -78 ° C, 2.5 M n-butyllithium n-hexane solution (0.38 mL, 0.95 mmol) was slowly added dropwise. After the addition was completed, the temperature was raised to 0 ° C, stirred for 10 min, cooled to -78 ° C, and 4-oxocyclohexane ethyl acetate (104 mg, 0.56 mmol) was slowly added dropwise. After the addition was completed, the temperature was slowly raised to room temperature and stirred for 6 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 60: 1) to obtain compound I-9 (colorless oily liquid, 92 mg, yield: 77%): 1 H NMR (300 MHz, CDCl 3 ) δ 5.75 (s, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.52 (s, 3H), 2.80-2.68 (m, 1H), 2.19 (d, J = 7.0 Hz, 2H), 2.09-1.99 (m, 1H), 1.99-1.85 (m, 2H), 1.85-1.74 (m, 3H), 1.73-1.63 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H), 1.08-0.91 (m, 2H).

化合物I-10的合成Synthesis of Compound I-10

将化合物I-9(120mg，0.57mmol)溶于乙腈(3mL)，加入1M盐酸(0.62mL，0.62mmol)，室温搅拌反应3小时。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝20:1)纯化，得化合物I-10(无色油状液体，40mg，收率:36％):1H NMR(300MHz,DMSO-d6)δ9.55(s,1H),4.05(q,2H),2.25-2.11(m,3H),1.96-1.84(m,2H),1.81-1.70(m,2H),1.69-1.49(m,1H),1.17(t,J＝8.5,5.6Hz,3H),1.09-0.92(m,2H).Compound I-9 (120 mg, 0.57 mmol) was dissolved in acetonitrile (3 mL), 1 M hydrochloric acid (0.62 mL, 0.62 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain compound I-10 (colorless oily liquid, 40 mg, yield: 36%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.55 (s, 1H), 4.05 (q, 2H), 2.25-2.11 (m, 3H), 1.96-1.84 (m, 2H), 1.81-1.70 (m, 2H), 1.69-1.49 (m, 1H), 1.17 (t, J = 8.5, 5.6 Hz, 3H), 1.09-0.92 (m, 2H).

化合物I-11的合成Synthesis of Compound I-11

将化合物I-10(643mg，3.24mmol)溶于无水乙醇(16mL)，加入硼氢化钠(92mg，2.43mmol)，室温搅拌反应1小时。TLC监测反应，待反应完全后，加入水(2mL)淬灭反应，减压蒸除溶剂，加入乙酸乙酯(50mL)复溶，水(20mLx3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝2:1)纯化，得化合物I-11(无色油状液体，578mg，收率89％)。Compound I-10 (643 mg, 3.24 mmol) was dissolved in anhydrous ethanol (16 mL), sodium borohydride (92 mg, 2.43 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the reaction was complete, water (2 mL) was added to quench the reaction, the solvent was evaporated under reduced pressure, ethyl acetate (50 mL) was added to redissolve, water (20 mL x 3) was added, the mixture was washed with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain compound I-11 (colorless oily liquid, 578 mg, yield 89%).

化合物I-12的合成Synthesis of Compound I-12

将化合物I-11(578mg，2.89mmol)溶于二氯甲烷(17mL)中，加入四溴化碳(2.393g，7.22mmol)，冰水浴下缓慢加入三苯基膦(1.968g，7.50mmol)，缓慢升至室温搅拌反应3小时。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝50:1)纯化，得化合物I-12(无色油状液体，706mg，收率93％)。Compound I-11 (578 mg, 2.89 mmol) was dissolved in dichloromethane (17 mL), carbon tetrabromide (2.393 g, 7.22 mmol) was added, triphenylphosphine (1.968 g, 7.50 mmol) was slowly added under an ice-water bath, and the mixture was slowly heated to room temperature and stirred for 3 hours. The reaction was monitored by TLC, and after the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain compound I-12 (colorless oily liquid, 706 mg, yield 93%).

参照实施例1的方法，将6-溴己酸乙酯替换为化合物I-12制得化合物25(无色油状液体，706mg，收率93％):1H NMR(300MHz,DMSO-d6)δ7.86-7.77(m,2H),7.76-7.69(m,1H),7.49(d,J＝8.0Hz,2H),7.45-7.35(m,1H),7.32-7.16(m,3H),7.08-6.96(m,1H),6.78(t,J＝7.4Hz,1H),6.59(t,J＝7.1Hz,1H),5.50(s,2H),4.11-3.99(m,2H),3.90(d,J＝6.9Hz,1H),3.79(d,J＝6.1Hz,1H),2.26(d,J＝7.4Hz,1H),2.16(d,J＝6.7Hz,1H), 2.02-1.75(m,1H),1.75-1.51(m,3H),1.51-1.27(m,4H),1.17(t,J＝7.1,3.7Hz,3H),1.04-0.88(m,2H).MS(ESI):m/z[M+H]+567.4.Referring to the method of Example 1, 6-bromohexanoic acid ethyl ester was replaced with compound I-12 to obtain compound 25 (colorless oily liquid, 706 mg, yield 93%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.86-7.77(m,2H),7.76-7.69(m,1H),7.49(d,J＝8.0Hz,2H),7.45-7.35(m,1H),7.32-7.16(m,3H),7.08-6.96(m,1H),6.78(t,J＝7.4Hz,1H),6.59 (t,J＝7.1Hz,1H),5.50(s,2H),4.11-3.99(m,2H),3.90(d,J＝6.9Hz,1H),3.79(d,J＝6.1Hz,1H),2.26(d,J＝7.4Hz,1H),2.16(d,J＝6.7Hz,1H), 2.02-1.75(m,1H),1.75-1.51(m,3H),1.51-1.27(m,4H),1.17(t,J＝7.1,3.7Hz,3H),1.04-0.88(m,2H).MS(ESI):m/z[M+H] + 567.4.

实施例26Embodiment 26

2-(4-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)环己基)乙酸(化合物26)
2-(4-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)cyclohexyl)acetic acid (Compound 26)

参照实施例2的方法，将化合物1替换为化合物25制得化合物26(白色固体，72mg，收率38％):1H NMR(300MHz,CD3OD)δ7.78-7.68(m,3H),7.45-7.34(m,3H),7.34-7.27(m,2H),7.27-7.18(m,1H),6.97(t,1H),6.76(t,J＝7.4Hz,1H),6.64(d,J＝7.5Hz,1H),5.50(s,2H),3.89(d,J＝6.8Hz,1H),3.78(d,J＝6.2Hz,1H),2.18(d,J＝7.5Hz,1H),2.11-1.96(m,2H),1.87-1.69(m,3H),1.61-1.35(m,4H),1.13-0.92(m,2H).HRMS(ESI)calcd.for C30H29F3N2O4[M+H]+539.2152,found 539.2157.Referring to the method of Example 2, Compound 1 was replaced by Compound 25 to obtain Compound 26 (white solid, 72 mg, yield 38%): 1 H NMR (300 MHz, CD 3 OD)δ7.78-7.68(m,3H),7.45-7.34(m,3H),7.34-7.27(m,2H),7.27-7.18(m,1H),6.97(t,1H),6.76(t,J＝7.4Hz,1H),6.64(d,J＝7.5Hz,1H),5.50(s,2 H),3.89(d,J＝6.8Hz,1H),3.78(d,J＝6.2Hz,1H),2.18(d,J＝7.5Hz,1H),2.11-1.96(m,2H),1.87-1.69(m,3H),1.61-1.35(m,4H),1.13-0.92(m,2H). HRMS(ESI)calcd.for C 30 H 29 F 3 N 2 O 4 [M+H] + 539.2152,found 539.2157.

实施例27Embodiment 27

2-(3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)环己基)乙酸乙酯(化合物27)
Ethyl 2-(3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)cyclohexyl)acetate (Compound 27)

化合物I-13的合成Synthesis of Compound I-13

将2-环己烯-1-酮(497mg，5.16mmol)溶于甲苯(21mL)，依次加入丙二酸二乙酯(4.11g，25.7mmol)和1,5,7-三叠氮双环(4.4.0)癸-5-烯(TBD)(72mg，0.52mmol)，室温搅拌反应30min。TLC监测反应，待反应完全后，抽滤，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝4:1)纯化，得化合物I-13(无色油状液体，1.319g，收率 99％)。2-Cyclohexene-1-one (497 mg, 5.16 mmol) was dissolved in toluene (21 mL), and diethyl malonate (4.11 g, 25.7 mmol) and 1,5,7-triazidobicyclo (4.4.0) dec-5-ene (TBD) (72 mg, 0.52 mmol) were added in sequence, and the mixture was stirred at room temperature for 30 min. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound I-13 (colorless oily liquid, 1.319 g, yield: 99%).

化合物I-14的合成Synthesis of Compound I-14

将化合物I-13(1.385g，5.40mmol)溶于四氢呋喃(11mL)和水(121mL)的混合溶剂，冰水浴下缓慢滴加0.25M氢氧化钠水溶液(151mL，37.8mmol)，搅拌反应2h。TLC监测反应，待反应完全后，冰水浴下加入1M盐酸调pH至2，加入适量氯化钠至饱和，加入乙酸乙酯(150mL x3)萃取，合并有机相，无水硫酸镁干燥，减压蒸除溶剂，得化合物I-14(无色油状液体，1.011g，收率82％)。Compound I-13 (1.385 g, 5.40 mmol) was dissolved in a mixed solvent of tetrahydrofuran (11 mL) and water (121 mL), and 0.25 M sodium hydroxide aqueous solution (151 mL, 37.8 mmol) was slowly added dropwise under an ice-water bath, and the reaction was stirred for 2 h. The reaction was monitored by TLC. After the reaction was complete, 1 M hydrochloric acid was added under an ice-water bath to adjust the pH to 2, and an appropriate amount of sodium chloride was added to saturation. Ethyl acetate (150 mL x 3) was added for extraction, and the organic phases were combined, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain compound I-14 (colorless oily liquid, 1.011 g, yield 82%).

化合物I-15的合成Synthesis of Compound I-15

将化合物I-14(1.011g，4.43mmol)溶于二甲基亚砜(22mL)和水(0.11mL)的混合溶剂，160℃搅拌反应12小时。TLC监测反应，待反应完全后，加入乙酸乙酯(200mL)稀释，用水(100mL x3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，得化合物I-15(淡黄色液体，687mg,收率84％)。Compound I-14 (1.011 g, 4.43 mmol) was dissolved in a mixed solvent of dimethyl sulfoxide (22 mL) and water (0.11 mL), and stirred at 160°C for 12 hours. The reaction was monitored by TLC. After the reaction was complete, ethyl acetate (200 mL) was added for dilution, washed with water (100 mL x 3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain compound I-15 (light yellow liquid, 687 mg, yield 84%).

化合物I-16的合成Synthesis of Compound I-16

在氩气保护下，将化合物I-15(100mg，0.54mmol)溶于无水乙醇(3mL)，加入碳酸钾(150mg，1.09mmol)，冰水浴下缓慢滴加(1-重氮-2-氧代-丙醇)-膦酸二甲酯(125mg，0.65mmol)，缓慢升至室温搅拌反应6小时。TLC监测反应，待反应完全后，抽滤，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝60:1)纯化，得化合物I-16(无色油状液体，80mg，收率65％)。Under argon protection, compound I-15 (100 mg, 0.54 mmol) was dissolved in anhydrous ethanol (3 mL), potassium carbonate (150 mg, 1.09 mmol) was added, (1-diazo-2-oxo-propanol)-phosphonic acid dimethyl ester (125 mg, 0.65 mmol) was slowly added dropwise under an ice-water bath, and the mixture was slowly heated to room temperature and stirred for 6 hours. The reaction was monitored by TLC, and after the reaction was complete, the mixture was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 60: 1) to obtain compound I-16 (colorless oily liquid, 80 mg, yield 65%).

化合物I-17的合成Synthesis of Compound I-17

将化合物I-16(511mg，2.26mmol)溶于乙腈(12mL)，加入1M盐酸(2.5mL，2.5mmol)，室温搅拌反应3小时。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝20:1)纯化，得化合物I-17(无色油状液体，417mg，收率93％)。Compound I-16 (511 mg, 2.26 mmol) was dissolved in acetonitrile (12 mL), 1 M hydrochloric acid (2.5 mL, 2.5 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC, and after the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain compound I-17 (colorless oily liquid, 417 mg, yield 93%).

化合物I-18的合成Synthesis of Compound I-18

将化合物I-17(417mg，2.10mmol)溶于无水乙醇(11mL)，加入硼氢化钠(60mg，1.59mmol)，室温搅拌反应1小时。TLC监测反应，待反应完全后，加入水(2mL)淬灭反应，减压蒸除溶剂，加入乙酸乙酯(50mL)复溶，水(20mLx3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝2:1)纯化，得化合物I-18(无色油状液体，367mg，收率87％)。Compound I-17 (417 mg, 2.10 mmol) was dissolved in anhydrous ethanol (11 mL), sodium borohydride (60 mg, 1.59 mmol) was added, and the reaction was stirred at room temperature for 1 hour. TLC monitored the reaction, and after the reaction was complete, water (2 mL) was added to quench the reaction, the solvent was evaporated under reduced pressure, ethyl acetate (50 mL) was added to redissolve, water (20 mL x 3) was washed, anhydrous sodium sulfate was dried, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain compound I-18 (colorless oily liquid, 367 mg, yield 87%).

化合物I-19的合成Synthesis of Compound I-19

将化合物I-18(367mg，183mmol)溶于二氯甲烷(10mL)中，加入四溴化碳(1.519g，4.58mmol)，冰水浴下缓慢加入三苯基膦(1.25g，4.77mmol)，缓慢升至室温搅拌反应4小时。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝50:1)纯化，得化合物I-19(无色油状液体，446mg，收率93％)。Compound I-18 (367 mg, 183 mmol) was dissolved in dichloromethane (10 mL), carbon tetrabromide (1.519 g, 4.58 mmol) was added, triphenylphosphine (1.25 g, 4.77 mmol) was slowly added under an ice-water bath, and the mixture was slowly heated to room temperature and stirred for 4 hours. The reaction was monitored by TLC, and after the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain compound I-19 (colorless oily liquid, 446 mg, yield 93%).

参照实施例1的方法，将6-溴己酸乙酯替换为化合物I-19制得化合物27(无色油状液体，183mg，收率90％):1H NMR(300MHz,DMSO-d6)δ7.88-7.76(m,2H),7.77-7.68(m,1H),7.49(d,J＝8.8Hz,2H),7.46-7.34(m,1H),7.31-7.15(m,3H),7.09-6.96(m,1H),6.77(t,J＝7.6Hz,1H),6.58(t,J＝7.7Hz,1H),5.50(s,2H),4.10-3.92(m,2H),3.88(d,J＝6.9Hz,1H),3.78(d,J＝5.9Hz,1H),2.22(d,J＝7.0Hz,1H),2.14(d,J＝6.6Hz,1H),2.11-1.86(m,1H),1.77-1.59(m,3H),1.57-1.32(m,4H),1.18-1.08(m,3H),0.94-0.78(m,2H).MS(ESI):m/z[M+Na]+589.4.Referring to the method of Example 1, 6-bromohexanoic acid ethyl ester was replaced with compound I-19 to obtain compound 27 (colorless oily liquid, 183 mg, yield 90%): 1 H NMR (300 MHz, DMSO-d 6 ) δ7.88-7.76 (m, 2H), 7.77-7.68 (m, 1H), 7.49 (d, J=8.8 Hz, 2H), 7.46-7.34 (m, 1H), 7.31-7.15 (m, 3H), 7.09-6.96 (m, 1H), 6.77 (t, J=7.6 Hz, 1H), 6.58 (t, J=7.7 Hz, 1H), 5.50 (s, 2H), 4.10-3.92 (m, 2H), 3.8 8(d,J＝6.9Hz,1H),3.78(d,J＝5.9Hz,1H),2.22(d,J＝7.0Hz,1H),2.14(d,J＝6.6Hz,1H),2.11-1.86(m,1H),1.77-1.59(m,3H),1.57-1.32(m,4H),1.18 -1.08(m,3H),0.94-0.78(m,2H).MS(ESI):m/z[M+Na] + 589.4.

实施例28Embodiment 28

2-(3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)环己基)乙酸(化合物28)
2-(3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)cyclohexyl)acetic acid (Compound 28)

参照实施例2的方法，将化合物1替换为化合物27制得化合物28(白色固体，41mg，收率24％):1H NMR(300MHz,DMSO-d6)δ11.97(s,1H),7.87-7.76(m,2H),7.76-7.69(m,1H),7.49(d,J＝8.1Hz,2H),7.45-7.37(m,1H),7.32-7.16(m,3H),7.09-6.94(m,1H),6.77(t,J＝7.5Hz,1H),6.62-6.49(m,1H),5.50(s,2H),3.87(d,J＝6.1Hz,1H),3.77(d,J＝5.8Hz,1H),2.20-2.12(m,1H),2.11-2.03(m,1H),2.04-1.87(m,1H),1.79-1.58(m,3H),1.58-1.46(m,1H),1.46-1.34(m,2H),1.29-1.18(m,1H),0.97-0.57(m,2H).HRMS(ESI)calcd.for C30H29F3N2O4[M+H]+539.2152,found 539.2156.Referring to the method of Example 2, compound 1 was replaced by compound 27 to obtain compound 28 (white solid, 41 mg, yield 24%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.97 (s, 1H), 7.87-7.76 (m, 2H), 7.76-7.69 (m, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.45-7.37 (m, 1H), 7.32-7.16 (m, 3H), 7.09-6.94 (m, 1H), 6.77 (t, J=7.5 Hz, 1H), 6.62-6.49 (m, 1H), 5.50 (s, 2H), 3.87 (d, J=6.1 Hz,1H),3.77(d,J=5.8Hz,1H),2.20-2.12(m,1H),2.11-2.03(m,1H),2.04-1.87(m,1H),1.79-1.58(m,3H),1.58-1.46(m,1H),1.46-1.34(m,2H),1 .29-1.18(m,1H),0.97-0.57(m,2H).HRMS(ESI)calcd.for C 30 H 29 F 3 N 2 O 4 [M+H] + 539.2152,found 539.2156.

实施例29Embodiment 29

2-(3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)环戊基)乙酸乙酯(化合物29)
Ethyl 2-(3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)cyclopentyl)acetate (Compound 29)

参照实施例27的方法，将2-环己烯-1-酮替换为2-环戊烯酮，制得化合物29(无色油状液体，50mg，收率25％):1H NMR(300MHz,DMSO-d6)δ7.80(d,J＝8.7Hz,2H),7.76-7.70(m,1H),7.50(d,J＝8.2Hz,2H),7.45-7.38(m,1H),7.31-7.18(m,3H),7.02(d,J＝8.3Hz,1H),6.78(t,J＝7.4Hz,1H),6.58(d,J＝7.4Hz,1H),5.49(s,2H),4.07-3.97(m,2H),3.91-3.81(m,2H),2.37-2.10(m,4H),1.95-1.84(m,1H),1.83-1.66(m,2H),1.66-1.49(m,1H),1.41-1.27(m,2H),1.18-1.10(m,3H).MS(ESI):m/z[M+H]+553.3.Referring to the method of Example 27, 2-cyclohexen-1-one was replaced by 2-cyclopentenone to obtain compound 29 (colorless oily liquid, 50 mg, yield 25%): 1 H NMR (300 MHz, DMSO-d 6 ) δ7.80 (d, J=8.7 Hz, 2H), 7.76-7.70 (m, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.45-7.38 (m, 1H), 7.31-7.18 (m, 3H), 7.02 (d, J=8.3 Hz, 1H), 6.78 (t, J=7.4 Hz, 1H), 6.58 (d, J=7.4 Hz, 1H), 5.49 ( s,2H),4.07-3.97(m,2H),3.91-3.81(m,2H),2.37-2.10(m,4H),1.95-1.84(m,1H),1.83-1.66(m,2H),1.66-1.49(m,1H),1.41-1.27(m,2H),1.1 8-1.10(m,3H).MS(ESI):m/z[M+H] + 553.3.

实施例30Embodiment 30

2-(3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)环戊基)乙酸(化合物30)
2-(3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)cyclopentyl)acetic acid (Compound 30)

参照实施例2的方法，将化合物1替换为化合物29制得化合物30(白色固体，23mg，收率49％):1H NMR(300MHz,CD3OD)δ7.77-7.69(m,3H),7.43-7.34(m,3H),7.34-7.28(m,2H),7.27-7.18(m,1H),6.96(d,J＝8.1Hz,1H),6.78(t,J＝7.5Hz,1H),6.69-6.62(m,1H),5.50(s,2H),3.86(t,J＝6.5Hz,2H),2.40-2.15(m,4H),2.02-1.56(m,3H),1.45-1.15(m,3H).HRMS(ESI)calcd.for C29H27F3N2O4[M+H]+525.1996,found 525.1998.Referring to the method of Example 2, compound 1 was replaced by compound 29 to obtain compound 30 (white solid, 23 mg, yield 49%): 1 H NMR (300 MHz, CD 3 OD) δ 7.77-7.69 (m, 3H), 7.43-7.34 (m, 3H), 7.34-7.28 (m, 2H), 7.27-7.18 (m, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.78 (t, J = 7.5 Hz, 1H), 6.69-6.62 (m, 1H), 5.50 (s, 2H), 3.86 (t, J = 6.5 Hz, 2H), 2.40-2.15 (m, 4H), 2.02-1.56 (m, 3H), 1.45-1.15 (m, 3H). HRMS (ESI) calcd. for C 29 H 27 F 3 N 2 O 4 [M+H] + 525.1996,found 525.1998.

实施例31 Embodiment 31

2-(2-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)环丙基)乙酸叔丁酯(化合物31)
tert-Butyl 2-(2-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)cyclopropyl)acetate (Compound 31)

化合物II-1的合成Synthesis of compound II-1

将2-甲氧基苯甲醇(1g，7.24mmol)溶于二氯甲烷(15mL)，冰水浴下缓慢滴加三溴化磷(2.88g，10.6mmol)，缓慢升至室温搅拌反应30分钟。TLC监测反应，待反应完全后，加入水(20mL)淬灭反应，用二氯甲烷(40mL x3)萃取，合并有机相，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝200:1)纯化，得化合物II-1(黄色油状液体，1g，收率69％)。2-Methoxybenzyl alcohol (1 g, 7.24 mmol) was dissolved in dichloromethane (15 mL), phosphorus tribromide (2.88 g, 10.6 mmol) was slowly added dropwise under an ice-water bath, and the mixture was slowly heated to room temperature and stirred for 30 minutes. The reaction was monitored by TLC. After the reaction was complete, water (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (40 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 200: 1) to obtain compound II-1 (yellow oily liquid, 1 g, yield 69%).

化合物II-2的合成Synthesis of compound II-2

将化合物I-4(400mg，1.44mmol)溶于乙腈(14mL)，加入碳酸铯(703mg，2.16mmol)，化合物II-1(320mg，1.59mmol)，室温搅拌反应4小时。TLC监测反应，待反应完全后，抽滤除去碳酸铯，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝10:1)纯化，得化合物II-2(白色固体，557mg，收率97％)。Compound I-4 (400 mg, 1.44 mmol) was dissolved in acetonitrile (14 mL), cesium carbonate (703 mg, 2.16 mmol) and compound II-1 (320 mg, 1.59 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. After the reaction was complete, cesium carbonate was removed by suction filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound II-2 (white solid, 557 mg, yield 97%).

化合物II-3的合成Synthesis of compound II-3

将化合物II-2(557mg，1.40mmol)溶于二氯甲烷(10mL)，冰水浴下缓慢滴加三溴化硼(1.75g，6.99mmol)，缓慢升至室温搅拌反应3小时。TLC监测反应，待反应完全后，加入饱和碳酸氢钠水溶液调pH至9，用乙酸乙酯(40mL x3)萃取，合并有机相，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝10:1)纯化，得化合物II-3(白色固体，430mg，收率80％)。Compound II-2 (557 mg, 1.40 mmol) was dissolved in dichloromethane (10 mL), and boron tribromide (1.75 g, 6.99 mmol) was slowly added dropwise under an ice-water bath, and the mixture was slowly heated to room temperature and stirred for 3 hours. The reaction was monitored by TLC. After the reaction was complete, a saturated aqueous sodium bicarbonate solution was added to adjust the pH to 9, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound II-3 (white solid, 430 mg, yield 80%).

化合物II-4的合成Synthesis of compound II-4

在氩气保护下，将二异丙胺(296mg，2.93mmol)溶于无水四氢呋喃(4mL)，冷至-78℃，缓慢滴加2.5M正丁基锂的正己烷溶液(1.153mL，2.88mmol)，0℃搅拌30min，冷至-78℃，加入乙酸叔丁酯(260mg，2.24mmol)，搅拌30min，缓慢滴加4-溴巴豆酸甲酯(487mg，2.72mmol)，缓慢升至室温搅拌反应3小时。TLC监测反应，待反应完全后，加入饱和氯化铵水溶液(1mL)淬灭反应，加入水(20mL)稀释，用乙酸乙酯(40mL x3)萃取，合并有机相，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝60:1)纯化，得化合物II-4(淡黄色液体，297mg，收率51％)。Under argon protection, diisopropylamine (296 mg, 2.93 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL), cooled to -78 ° C, 2.5 M n-butyl lithium in n-hexane solution (1.153 mL, 2.88 mmol) was slowly added dropwise, stirred at 0 ° C for 30 min, cooled to -78 ° C, tert-butyl acetate (260 mg, 2.24 mmol) was added, stirred for 30 min, 4-bromocrotonic acid methyl ester (487 mg, 2.72 mmol) was slowly added dropwise, and the temperature was slowly raised to room temperature and stirred for 3 hours. TLC monitored the reaction, and after the reaction was complete, saturated ammonium chloride aqueous solution (1 mL) was added to quench the reaction, water (20 mL) was added to dilute, and ethyl acetate (40 mL x 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 60: 1) to obtain compound II-4 (light yellow liquid, 297 mg, yield 51%).

化合物II-5的合成Synthesis of compound II-5

将化合物II-4(297mg，1.39mmol)溶于四氢呋喃(2mL)和乙醇(4mL)的混合溶剂，加入1M氢氧化锂水溶液(2.1mL，2.1mmol)，室温搅拌反应2小时。TLC监测反应， 待反应完全后，减压蒸除溶剂，依次加入水(20mL)和1M盐酸调pH至2，用乙酸乙酯(40mL x3)萃取，合并有机相，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(二氯甲烷:甲醇＝200:1)纯化，得化合物II-5(无色油状液体，150mg，收率54％)。Compound II-4 (297 mg, 1.39 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and ethanol (4 mL), and 1 M aqueous lithium hydroxide solution (2.1 mL, 2.1 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and water (20 mL) and 1 M hydrochloric acid were added in sequence to adjust the pH to 2, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 200: 1) to give compound II-5 (colorless oily liquid, 150 mg, yield 54%).

化合物II-6的合成Synthesis of Compound II-6

将化合物II-5(150mg，0.75mmol)溶于无水四氢呋喃(4mL)，冰水浴下缓慢滴加1M硼烷的四氢呋喃溶液(0.82mL，0.82mmol)，室温搅拌反应4小时。TLC监测反应，待反应完全后，加水(1mL)淬灭反应，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝4:1)纯化，得化合物II-6(无色油状液体，70mg，收率50％):1H NMR(300MHz,CDCl3)δ3.83-3.69(m,1H),3.21-3.11(m,1H),2.51(dd,J＝16.9,5.2Hz,1H),1.88(dd,J＝16.8,9.2Hz,1H),1.46(s,9H),0.98-0.78(m,2H),0.58-0.40(m,2H).Compound II-5 (150 mg, 0.75 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL), and a 1 M borane tetrahydrofuran solution (0.82 mL, 0.82 mmol) was slowly added dropwise under an ice-water bath, and the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. After the reaction was complete, water (1 mL) was added to quench the reaction. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound II-6 (colorless oily liquid, 70 mg, yield 50%): 1 H NMR (300 MHz, CDCl 3 ) δ 3.83-3.69 (m, 1H), 3.21-3.11 (m, 1H), 2.51 (dd, J = 16.9, 5.2 Hz, 1H), 1.88 (dd, J = 16.8, 9.2 Hz, 1H), 1.46 (s, 9H), 0.98-0.78 (m, 2H), 0.58-0.40 (m, 2H).

化合物II-7的合成Synthesis of compound II-7

将化合物II-6(70mg，0.38mmol)溶于二氯甲烷(4mL)中，加入四溴化碳(312mg，0.94mmol)，冰水浴下缓慢加入三苯基膦(256mg，0.98mmol)，缓慢升至室温搅拌反应4小时。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝60:1)纯化，得化合物II-7(无色油状液体，71mg，收率76％)。Compound II-6 (70 mg, 0.38 mmol) was dissolved in dichloromethane (4 mL), carbon tetrabromide (312 mg, 0.94 mmol) was added, triphenylphosphine (256 mg, 0.98 mmol) was slowly added under an ice-water bath, and the mixture was slowly heated to room temperature and stirred for 4 hours. The reaction was monitored by TLC, and after the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 60: 1) to obtain compound II-7 (colorless oily liquid, 71 mg, yield 76%).

化合物31的合成Synthesis of compound 31

将化合物II-3(100mg，0.26mmol)溶于N,N-二甲基甲酰胺(3mL)，加入碳酸钾(231mg，0.71mmol)，化合物II-7(71mg，0.28mmol)，90℃搅拌反应6小时。TLC监测反应，待反应完全后，抽滤除去碳酸钾，加入乙酸乙酯(50mL)稀释，用水(30mL x3)洗涤，合并有机相，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝15:1)纯化，得化合物31(无色油状液体，94mg，收率65％):1H NMR(300MHz,DMSO-d6)δ7.86-7.78(m,2H),7.77-7.70(m,1H),7.51(d,J＝8.1Hz,2H),7.45-7.38(m,1H),7.30-7.18(m,3H),6.99(d,J＝8.0Hz,1H),6.78(t,J＝7.4Hz,1H),6.59(d,J＝6.6Hz,1H),5.59-5.44(m,2H),3.87(d,J＝6.6Hz,2H),2.23-2.03(m,2H),1.35(s,9H),1.03-0.87(m,2H),0.53-0.43(m,1H),0.43-0.34(m,1H).MS(ESI):m/z[M+H]+553.2.Compound II-3 (100 mg, 0.26 mmol) was dissolved in N, N-dimethylformamide (3 mL), potassium carbonate (231 mg, 0.71 mmol) and compound II-7 (71 mg, 0.28 mmol) were added, and the mixture was stirred at 90°C for 6 hours. The reaction was monitored by TLC. After the reaction was complete, potassium carbonate was removed by suction filtration, ethyl acetate (50 mL) was added for dilution, and the mixture was washed with water (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1) to obtain compound 31 (colorless oily liquid, 94 mg, yield 65%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.86-7.78(m,2H),7.77-7.70(m,1H),7.51(d,J＝8.1Hz,2H),7.45-7.38(m,1H),7.30-7.18(m,3H),6.99(d,J＝8.0Hz,1H),6.78(t,J＝7.4Hz,1H),6.5 9(d,J＝6.6Hz,1H),5.59-5.44(m,2H),3.87(d,J＝6.6Hz,2H),2.23-2.03(m,2H),1.35(s,9H),1.03-0.87(m,2H),0.53-0.43(m,1H),0.43-0.34(m,1H) ).MS(ESI):m/z[M+H] + 553.2.

实施例32Embodiment 32

2-(2-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)环丙基)乙酸(化合物32)
2-(2-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)cyclopropyl)acetic acid (Compound 32)

将化合物31(94mg，0.17mmol)溶于二氯甲烷(2mL)，加入三氟乙酸(30mg，0.26mmol)，室温搅拌反应4小时。TLC监测反应，待反应完全后，减压蒸除溶剂，加入水和饱和碳酸氢钠调pH至4，有大量白色固体析出，抽滤，滤饼用水洗涤，真空干燥得化合物32(白色固体，94mg，收率30％):1H NMR(300MHz,DMSO-d6)δ12.01(s,1H),7.83(d,J＝8.7Hz,2H),7.77-7.67(m,1H),7.51(d,J＝8.2Hz,2H),7.47-7.37(m,1H),7.33-7.12(m,3H),6.98(d,J＝8.2Hz,1H),6.77(t,J＝7.5Hz,1H),6.55(d,J＝7.5Hz,1H),5.64-5.40(m,2H),4.00-3.75(m,2H),2.27-2.00(m,2H),1.07-0.86(m,2H),0.55-0.44(m,1H),0.45-0.34(m,1H).HRMS(ESI)calcd.for C27H23F3N2O4[M+H]+497.1683,found 497.1682.Compound 31 (94 mg, 0.17 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (30 mg, 0.26 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and water and saturated sodium bicarbonate were added to adjust the pH to 4. A large amount of white solid was precipitated, which was filtered, and the filter cake was washed with water and dried in vacuo to obtain compound 32 (white solid, 94 mg, yield 30%): 1 H NMR (300 MHz, DMSO-d 6 )δ12.01(s,1H),7.83(d,J＝8.7Hz,2H),7.77-7.67(m,1H),7.51(d,J＝8.2Hz,2H),7.47-7.37(m,1H),7.33-7.12(m,3H),6.98(d,J＝8.2Hz,1H),6.77(t . H).HRMS(ESI)calcd.for C 27 H 23 F 3 N 2 O 4 [M+H] + 497.1683, found 497.1682.

实施例33 Embodiment 33

4-甲基-6-(2-(((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物33)
4-Methyl-6-(2-(((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid ethyl ester (Compound 33)

化合物I-20的合成Synthesis of Compound I-20

将4-甲基环己酮(640mg，5.70mmol)溶于二氯甲烷(6mL)，加入间氯过氧苯甲酸(mCPBA)(1.280g，7.42mmol)，室温搅拌反应6小时。TLC监测反应，待反应完全后，抽滤，滤液加入乙酸乙酯(60mL)稀释，依次用饱和硫代硫酸钠(30mL x3)和饱和碳酸氢钠(30mL x3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝10:1)纯化，得化合物I-20(无色油状液体，510mg，收率70％)。4-Methylcyclohexanone (640 mg, 5.70 mmol) was dissolved in dichloromethane (6 mL), and m-chloroperbenzoic acid (mCPBA) (1.280 g, 7.42 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered, and the filtrate was diluted with ethyl acetate (60 mL), washed with saturated sodium thiosulfate (30 mL x 3) and saturated sodium bicarbonate (30 mL x 3) in sequence, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound I-20 (colorless oily liquid, 510 mg, yield 70%).

化合物I-21的合成Synthesis of Compound I-21

将化合物I-20(510mg)溶于无水乙醇(12mL)，加入98％浓硫酸(0.15mL)，80℃加热搅拌反应8小时。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝2:1)纯化，得化合物I-21(无色油状液体，612mg，收率88％)。Compound I-20 (510 mg) was dissolved in anhydrous ethanol (12 mL), 98% concentrated sulfuric acid (0.15 mL) was added, and the mixture was stirred at 80°C for 8 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain compound I-21 (colorless oily liquid, 612 mg, yield 88%).

化合物I-22的合成Synthesis of Compound I-22

将化合物I-21(612mg，3.51mmol)溶于二氯甲烷(10mL)中，加入四溴化碳(2.9g，8.74mmol)，冰水浴下缓慢加入三苯基膦(2.4g，9.15mmol)，缓慢升至室温搅拌反应3小时。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝50:1)纯化，得化合物I-22(无色油状液体，702mg，收率84％)。Compound I-21 (612 mg, 3.51 mmol) was dissolved in dichloromethane (10 mL), carbon tetrabromide (2.9 g, 8.74 mmol) was added, triphenylphosphine (2.4 g, 9.15 mmol) was slowly added under an ice-water bath, and the mixture was slowly heated to room temperature and stirred for 3 hours. The reaction was monitored by TLC, and after the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain compound I-22 (colorless oily liquid, 702 mg, yield 84%).

参照实施例1的方法，将6-溴己酸乙酯替换为化合物I-22制得化合物33(无色油状液体，179mg，收率92％):1H NMR(300MHz,DMSO-d6)δ7.81(d,J＝8.7Hz,2H),7.77-7.70(m,1H),7.49(d,J＝8.6Hz,2H),7.44-7.34(m,1H),7.30-7.16(m,3H),7.03(d,J＝8.3Hz,1H),6.78(t,J＝7.5Hz,1H),6.58(d,J＝7.5Hz,1H),5.48(s,2H),4.08-3.92(m,4H),2.35-2.12(m,2H),1.63-1.52(m,2H),1.47-1.36(m,2H),1.36-1.32(m,1H),1.11(t,J＝7.1Hz,3H),0.84(d,J＝5.9Hz,3H).MS(ESI):m/z[M+H]+541.3.Referring to the method of Example 1, 6-bromohexanoic acid ethyl ester was replaced with compound I-22 to obtain compound 33 (colorless oily liquid, 179 mg, yield 92%): 1 H NMR (300 MHz, DMSO-d 6 ) δ7.81 (d, J=8.7 Hz, 2H), 7.77-7.70 (m, 1H), 7.49 (d, J=8.6 Hz, 2H), 7.44-7.34 (m, 1H), 7.30-7.16 (m, 3H), 7.03 (d, J=8.3 Hz, 1H), 6.78 (t, J=7.5 Hz, 1H), 6.58 (d, J=7.5 Hz, 1H), 5.48(s,2H),4.08-3.92(m,4H),2.35-2.12(m,2H),1.63-1.52(m,2H),1.47-1.36(m,2H),1.36-1.32(m,1H),1.11(t,J＝7.1Hz,3H),0.84(d,J＝5.9Hz ,3H).MS(ESI):m/z[M+H] + 541.3.

实施例34Embodiment 34

4-甲基-6-(2-(((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物34)
4-Methyl-6-(2-(((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 34)

参照实施例2的方法，将化合物1替换为化合物33制得化合物34(白色固体，31mg，收率18％):1H NMR(300MHz,DMSO-d6)δ7.81(d,J＝8.7Hz,2H),7.77-7.69(m,1H),7.49(d,J＝8.4Hz,2H),7.45-7.35(m,1H),7.30-7.17(m,3H),7.02(d,J＝8.3Hz,1H),6.77(t,J＝7.4Hz,1H),6.55(d,J＝7.5Hz,1H),5.49(s,2H),4.08-3.91(m,2H),2.29-2.06(m,2H),1.71-1.50(m,3H),1.48-1.27(m,2H),0.84(d,J＝5.9Hz,3H).HRMS(ESI)calcd.for C28H27F3N2O4[M+H]+513.1996,found 513.2003.Referring to the method of Example 2, Compound 1 was replaced by Compound 33 to obtain Compound 34 (white solid, 31 mg, yield 18%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.81(d,J＝8.7Hz,2H),7.77-7.69(m,1H),7.49(d,J＝8.4Hz,2H),7.45-7.35(m,1H),7.30-7.17(m,3H),7.02(d,J＝8.3Hz,1H),6.77(t,J＝7.4Hz,1H), 6.55(d,J＝7.5Hz,1H),5.49(s,2H),4.08-3.91(m,2H),2.29-2.06(m,2H),1.71-1.50(m,3H),1.48-1.27(m,2H),0.84(d,J＝5.9Hz,3H).HRMS(ESI)calcd.for C 28 H 27 F 3 N 2 O 4 [M+H] + 513.1996, found 513.2003.

实施例35Embodiment 35

3,5-二甲基-6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物35)
3,5-Dimethyl-6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid ethyl ester (Compound 35)

参照实施例33的方法，将4-甲基环己酮替换为3,5-二甲基环己酮制得化合物35(无色油状液体，152mg，收率82％):1H NMR(300MHz,DMSO-d6)δ7.80(d,J＝8.8Hz,2H),7.77-7.71(m,1H),7.49(d,J＝8.1Hz,2H),7.44-7.36(m,1H),7.35-7.14(m,3H),7.01(d,J＝8.1Hz,1H),6.79(t,J＝7.4Hz,1H),6.57(d,J＝6.8Hz,1H),5.51(s,2H),3.99(q,J＝7.1Hz,2H),3.88-3.74(m,2H),3.43-3.34(m,1H),2.28-2.16(m,1H),2.06-1.81(m,3H),1.44-1.34(m,1H),1.10(t,3H),0.94-0.79(m,6H).MS(ESI):m/z[M+H]+555.3.Referring to the method of Example 33, 4-methylcyclohexanone was replaced with 3,5-dimethylcyclohexanone to obtain compound 35 (colorless oily liquid, 152 mg, yield 82%): 1 H NMR (300 MHz, DMSO-d 6 ) δ7.80 (d, J=8.8 Hz, 2H), 7.77-7.71 (m, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.44-7.36 (m, 1H), 7.35-7.14 (m, 3H), 7.01 (d, J=8.1 Hz, 1H), 6.79 (t, J=7.4 Hz, 1H), 6.57 (d, J=6.8 Hz, 1H), 5.51 (s,2H),3.99(q,J＝7.1Hz,2H),3.88-3.74(m,2H),3.43-3.34(m,1H),2.28-2.16(m,1H),2.06-1.81(m,3H),1.44-1.34(m,1H),1.10(t,3H),0.94-0 .79(m,6H).MS(ESI):m/z[M+H] + 555.3.

实施例36Embodiment 36

3,5-二甲基-6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物36)
3,5-Dimethyl-6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 36)

参照实施例2的方法，将化合物1替换为化合物35制得化合物36(白色固体，69mg，收率58％):1H NMR(300MHz,DMSO-d6)δ11.98(s,1H),7.80(d,J＝8.6Hz,2H),7.77-7.70(m,1H),7.49(d,J＝8.4Hz,2H),7.44-7.36(m,1H),7.32-7.18(m,3H),7.01(d,J＝8.2Hz,1H),6.78(t,J＝7.4Hz,1H),6.55(d,J＝7.3Hz,1H),5.51(s,2H),3.89-3.72(m, 2H),2.25-2.12(m,1H),2.00-1.82(m,3H),1.45-1.32(m,1H),1.12-0.97(m,1H),0.89(d,J＝5.2Hz,6H).HRMS(ESI)calcd.for C29H29F3N2O4[M+H]+527.2152,found 527.2157.Referring to the method of Example 2, compound 1 was replaced by compound 35 to obtain compound 36 (white solid, 69 mg, yield 58%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.98 (s, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.77-7.70 (m, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.44-7.36 (m, 1H), 7.32-7.18 (m, 3H), 7.01 (d, J = 8.2 Hz, 1H), 6.78 (t, J = 7.4 Hz, 1H), 6.55 (d, J = 7.3 Hz, 1H), 5.51 (s, 2H), 3.89-3.72 (m, 2H),2.25-2.12(m,1H),2.00-1.82(m,3H),1.45-1.32(m,1H),1.12-0.97(m,1H),0.89(d,J＝5.2Hz,6H).HRMS(ESI)calcd.for C 29 H 29 F 3 N 2 O 4 [M+H] + 52 7.2152, found 527.2157.

实施例37Embodiment 37

4,4-二甲基-6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物37)
4,4-Dimethyl-6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid ethyl ester (Compound 37)

参照实施例33的方法，将4-甲基环己酮替换为4,4-二甲基环己酮制得化合物37(无色油状液体，223mg，收率93％):1H NMR(300MHz,DMSO-d6)δ7.80(d,J＝8.8Hz,2H),7.76-7.71(m,1H),7.49(d,J＝8.1Hz,2H),7.44-7.38(m,1H),7.30-7.19(m,3H),7.05(d,J＝8.1Hz,1H),6.78(t,J＝7.3Hz,1H),6.60(d,J＝6.4Hz,1H),5.48(s,2H),4.04-3.93(m,4H),2.27-2.16(m,2H),1.57-1.45(m,4H),1.12(t,J＝7.2Hz,3H),0.87(s,6H).MS(ESI):m/z[M+H]+555.3.Referring to the method of Example 33, 4-methylcyclohexanone was replaced with 4,4-dimethylcyclohexanone to obtain compound 37 (colorless oily liquid, 223 mg, yield 93%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.80(d,J＝8.8Hz,2H),7.76-7.71(m,1H),7.49(d,J＝8.1Hz,2H),7.44-7.38(m,1H),7.30-7.19(m,3H),7.05(d,J＝8.1Hz,1H),6.78(t,J＝7.3Hz,1H), 6.60(d,J＝6.4Hz,1H),5.48(s,2H),4.04-3.93(m,4H),2.27-2.16(m,2H),1.57-1.45(m,4H),1.12(t,J＝7.2Hz,3H),0.87(s,6H).MS(ESI):m/z[M+H] + 555.3.

实施例38Embodiment 38

4,4-二甲基-6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物38)
4,4-Dimethyl-6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 38)

参照实施例2的方法，将化合物1替换为化合物37制得化合物38(白色固体，110mg，收率52％):1H NMR(300MHz,DMSO-d6)δ7.81(d,J＝8.7Hz,2H),7.76-7.69(m,1H),7.49(d,J＝8.3Hz,2H),7.44-7.37(m,1H),7.29-7.17(m,3H),7.02(d,J＝8.2Hz,1H),6.75(t,J＝7.5Hz,1H),6.53(d,J＝7.0Hz,1H),5.49(s,2H),3.99(t,J＝7.1Hz,2H),2.04-1.94(m,2H),1.54-1.41(m,4H),0.84(s,6H).HRMS(ESI)calcd.for C29H29F3N2O4[M+H]+527.2152,found 527.2156.Referring to the method of Example 2, Compound 1 was replaced by Compound 37 to obtain Compound 38 (white solid, 110 mg, yield 52%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.81(d,J＝8.7Hz,2H),7.76-7.69(m,1H),7.49(d,J＝8.3Hz,2H),7.44-7.37(m,1H),7.29-7.17(m,3H),7.02(d,J＝8.2Hz,1H),6.75(t,J＝7.5Hz,1H), 6.53(d,J＝7.0Hz,1H),5.49(s,2H),3.99(t,J＝7.1Hz,2H),2.04-1.94(m,2H),1.54-1.41(m,4H),0.84(s,6H).HRMS(ESI)calcd.for C 29 H 29 F 3 N 2 O 4 [M+H] + 527.2152,found 527.2156.

实施例39Embodiment 39

4-乙基-6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物39)
4-ethyl-6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid ethyl ester (Compound 39)

参照实施例33的方法，将4-甲基环己酮替换为4-乙基环己酮制得化合物39(无色油状液体，235mg，收率98％):1H NMR(300MHz,DMSO-d6)δ7.80(d,J＝8.7Hz,2H),7.76-7.71(m,1H),7.49(d,J＝8.3Hz,2H),7.42-7.37(m,1H),7.30-7.20(m,3H),7.03(d,J＝8.1Hz,1H),6.79(t,J＝7.5Hz,1H),6.58(d,J＝7.0Hz,1H),5.48(s,2H),4.04-3.92(m,4H),2.23(t,J＝7.7Hz,2H),1.61-1.47(m,4H),1.44-1.33(m,1H),1.29-1.22(m,2H),1.10(t,J＝7.1Hz,3H),0.78(t,J＝7.3Hz,3H).MS(ESI):m/z[M+H]+555.3.Referring to the method of Example 33, 4-methylcyclohexanone was replaced with 4-ethylcyclohexanone to obtain compound 39 (colorless oily liquid, 235 mg, yield 98%): 1 H NMR (300 MHz, DMSO-d 6 ) δ7.80 (d, J=8.7 Hz, 2H), 7.76-7.71 (m, 1H), 7.49 (d, J=8.3 Hz, 2H), 7.42-7.37 (m, 1H), 7.30-7.20 (m, 3H), 7.03 (d, J=8.1 Hz, 1H), 6.79 (t, J=7.5 Hz, 1H), 6.58 (d, J=7.0 Hz, 1H), 5. .48(s,2H),4.04-3.92(m,4H),2.23(t,J＝7.7Hz,2H),1.61-1.47(m,4H),1.44-1.33(m,1H),1.29-1.22(m,2H),1.10(t,J＝7.1Hz,3H),0.78(t,J＝7. 3Hz,3H).MS(ESI):m/z[M+H] + 555.3.

实施例40Embodiment 40

4-乙基-6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物40)
4-Ethyl-6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 40)

参照实施例2的方法，将化合物1替换为化合物39制得化合物40(白色固体，120mg，收率54％):1H NMR(300MHz,DMSO-d6)δ7.81(d,J＝8.7Hz,2H),7.76-7.69(m,1H),7.49(d,J＝8.4Hz,2H),7.44-7.35(m,1H),7.32-7.16(m,3H),7.02(d,J＝8.2Hz,1H),6.76(t,J＝7.4Hz,1H),6.53(d,J＝7.4Hz,1H),5.49(s,2H),3.99(t,J＝6.4Hz,2H),2.09(t,J＝7.6Hz,2H),1.64-1.33(m,5H),1.33-1.16(m,2H),0.77(t,J＝7.3Hz,3H).HRMS(ESI)calcd.for C29H29F3N2O4[M+H]+527.2152,found 521.2160.Referring to the method of Example 2, Compound 1 was replaced by Compound 39 to obtain Compound 40 (white solid, 120 mg, yield 54%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.81(d,J＝8.7Hz,2H),7.76-7.69(m,1H),7.49(d,J＝8.4Hz,2H),7.44-7.35(m,1H),7.32-7.16(m,3H),7.02(d,J＝8.2Hz,1H),6.76(t,J＝7.4Hz,1H),6 .53(d,J＝7.4Hz,1H),5.49(s,2H),3.99(t,J＝6.4Hz,2H),2.09(t,J＝7.6Hz,2H) ,1.64-1.33(m,5H),1.33-1.16(m,2H),0.77(t,J＝7.3Hz,3H).HRMS(ESI)calcd. for C 29 H 29 F 3 N 2 O 4 [M+H] + 527.2152, found 521.2160.

实施例41Embodiment 41

4-(2-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)乙基)庚酸乙酯(化合物41)
Ethyl 4-(2-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)ethyl)heptanoate (Compound 41)

参照实施例33的方法，将4-甲基环己酮替换为4-丙基环己酮制得化合物41(无色油状液体，220mg，收率99％):1H NMR(300MHz,DMSO-d6)δ7.80(d,J＝8.7Hz,2H),7.76-7.71(m,1H),7.49(d,J＝8.2Hz,2H),7.42-7.36(m,1H),7.31-7.20(m,3H),7.04(d,J＝8.2Hz,1H),6.79(t,J＝7.4Hz,1H),6.58(d,J＝6.7Hz,1H),5.47(s,2H),4.03-3.92(m,4H),2.23(t,J＝7.4Hz,2H),1.60-1.45(m,5H),1.24-1.18(m,4H),1.10(t,J＝7.1Hz,3H),0.84-0.76(m,3H).MS(ESI):m/z[M+H]+569.4.Referring to the method of Example 33, 4-methylcyclohexanone was replaced with 4-propylcyclohexanone to obtain compound 41 (colorless oily liquid, 220 mg, yield 99%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.80 (d, J = 8.7 Hz, 2H), 7.76-7.71 (m, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.42-7.36 (m, 1H), 7.31-7.20 (m, 3H), 7.04 (d, J = 8.2 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 6.58 (d, J = 6. 7Hz,1H),5.47(s,2H),4.03-3.92(m,4H),2.23(t,J＝7.4Hz,2H),1.60-1.45(m,5H),1.24-1.18(m,4H),1.10(t,J＝7.1Hz,3H),0.84-0.76(m,3H).MS(ESI ):m/z[M+H] + 569.4.

实施例42Embodiment 42

4-(2-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)乙基)庚酸(化合物42)
4-(2-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)ethyl)heptanoic acid (Compound 42)

参照实施例2的方法，将化合物1替换为化合物41制得化合物42(白色固体，97mg，收率46％):1H NMR(300MHz,DMSO-d6)δ7.86-7.76(m,2H),7.75-7.69(m,1H),7.48(d,J＝8.2Hz,2H),7.43-7.34(m,1H),7.29-7.16(m,3H),7.01(d,1H),6.75(t,J＝7.5Hz,1H),6.52(d,J＝7.5Hz,1H),5.48(s,2H),3.98(t,J＝6.3Hz,2H),2.02(t,2H),1.64-1.38(m,5H),1.29-1.12(m,4H),0.88-0.71(m,3H).HRMS(ESI)calcd.for C30H31F3N2O4[M+H]+541.2309,found 541.2305.Referring to the method of Example 2, Compound 1 was replaced by Compound 41 to obtain Compound 42 (white solid, 97 mg, yield 46%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.86-7.76(m,2H),7.75-7.69(m,1H),7.48(d,J＝8.2Hz,2H),7.43-7.34(m,1H),7.29-7.16(m,3H),7.01(d,1H),6.75(t,J＝7.5Hz,1H),6.52(d,J＝ 7.5Hz,1H),5.48(s,2H),3.98(t,J＝6.3Hz,2H),2.02(t,2H),1.64-1.38(m,5H),1.29-1.12(m,4H),0.88-0.71(m,3H).HRMS(ESI)calcd.for C 30 H 31 F 3 N 2 O 4 [M+H] + 541.2309, found 541.2305.

实施例43Embodiment 43

3-(2-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)乙氧基)丙酸乙酯(化合物43)
Ethyl 3-(2-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)ethoxy)propanoate (Compound 43)

化合物II-8的合成Synthesis of compound II-8

将2-苄氧基乙醇(771mg，5.07mmol)溶于无水四氢呋喃(8mL)，加入60％的钠氢(10mg，0.69mmol)，室温搅拌30min，逐滴加入丙烯酸乙酯(461mg，4.60mmol)，室温搅拌反应24小时。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝20:1)纯化，得化合物II-8(淡黄色液体，418mg，收率33％):1H NMR(300MHz,CDCl3)δ7.42-7.31(m,4H),7.31-7.26(m,1H),4.56(s,2H),4.14(q,J＝7.1Hz,2H),3.76(q,J＝6.4Hz,2H),3.70-3.59(m,4H),2.60(t,J＝6.5Hz,2H),1.25(t,J＝7.1Hz,3H).Dissolve 2-benzyloxyethanol (771 mg, 5.07 mmol) in anhydrous tetrahydrofuran (8 mL), add 60% sodium hydrogen sulfide (10 mg, 0.69 mmol), stir at room temperature for 30 min, add ethyl acrylate (461 mg, 4.60 mmol) dropwise, and react by stirring at room temperature for 24 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain compound II-8 (light yellow liquid, 418 mg, yield 33%): 1 H NMR (300MHz, CDCl 3 ) δ7.42-7.31 (m, 4H), 7.31-7.26 (m, 1H), 4.56 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 3.76 (q, J = 6.4 Hz, 2H), 3.70-3.59 (m, 4H), 2.60 (t, J = 6.5 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H).

化合物II-9的合成Synthesis of compound II-9

将化合物II-8(418mg，1.66mmol)溶于无水乙醇(5mL)，加入10％的钯碳(42 mg)，置于氢气氛中，室温搅拌反应12小时。TLC监测反应，待反应完全后，硅藻土抽滤，减压蒸除溶剂，得化合物II-9(无色油状液体，269mg，收率99％)。Compound II-8 (418 mg, 1.66 mmol) was dissolved in anhydrous ethanol (5 mL), and 10% palladium carbon (42 mg), placed in a hydrogen atmosphere, stirred at room temperature for 12 hours. The reaction was monitored by TLC. After the reaction was complete, diatomaceous earth was filtered and the solvent was evaporated under reduced pressure to obtain compound II-9 (colorless oily liquid, 269 mg, yield 99%).

化合物II-10的合成Synthesis of compound II-10

将化合物II-9(269mg，1.66mmol)溶于二氯甲烷(10mL)中，加入四溴化碳(1.375g，4.15mmol)，冰水浴下缓慢加入三苯基膦(1.131g，4.31mmol)，缓慢升至室温搅拌反应6小时。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝60:1)纯化，得化合物II-10(无色油状液体，252mg，收率85％)。Compound II-9 (269 mg, 1.66 mmol) was dissolved in dichloromethane (10 mL), carbon tetrabromide (1.375 g, 4.15 mmol) was added, triphenylphosphine (1.131 g, 4.31 mmol) was slowly added under an ice-water bath, and the mixture was slowly heated to room temperature and stirred for 6 hours. The reaction was monitored by TLC, and after the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 60: 1) to obtain compound II-10 (colorless oily liquid, 252 mg, yield 85%).

化合物43的合成Synthesis of compound 43

将化合物II-3(97mg，0.43mmol)溶于N,N-二甲基甲酰胺(4mL)，加入碳酸钾(81mg，0.59mmol)，化合物II-10(150mg，0.39mmol)，60℃搅拌反应4小时。TLC监测反应，待反应完全后，抽滤除去碳酸钾，加入乙酸乙酯(50mL)稀释，用水(30mL x3)洗涤，合并有机相，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝10:1)纯化，得化合物43(无色油状液体，205mg，收率99％):1H NMR(300MHz,DMSO-d6)δ7.87-7.79(m,2H),7.77-7.70(m,1H),7.50(d,J＝8.0Hz,2H),7.45-7.37(m,1H),7.31-7.18(m,3H),7.03(d,J＝8.0Hz,1H),6.79(t,J＝7.4Hz,1H),6.54(d,J＝6.4Hz,1H),5.50(s,2H),4.14-4.05(m,2H),3.96(q,J＝7.1Hz,2H),3.68-3.60(m,4H),2.49-2.46(m,2H),1.08(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+529.3.Compound II-3 (97 mg, 0.43 mmol) was dissolved in N, N-dimethylformamide (4 mL), potassium carbonate (81 mg, 0.59 mmol) and compound II-10 (150 mg, 0.39 mmol) were added, and the mixture was stirred at 60°C for 4 hours. The reaction was monitored by TLC. After the reaction was complete, potassium carbonate was removed by suction filtration, ethyl acetate (50 mL) was added for dilution, and the mixture was washed with water (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound 43 (colorless oily liquid, 205 mg, yield 99%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.87-7.79(m,2H),7.77-7.70(m,1H),7.50(d,J＝8.0Hz,2H),7.45-7.37(m,1H),7.31-7.18(m,3H),7.03(d,J＝8.0Hz,1H),6.79(t,J＝7.4Hz,1H),6.5 4(d,J＝6.4Hz,1H),5.50(s,2H),4.14-4.05(m,2H),3.96(q,J＝7.1Hz,2H),3.68-3.60(m,4H),2.49-2.46(m,2H),1.08(t,J＝7.1Hz,3H).MS(ESI):m/z[M+ H] + 529.3.

实施例44Embodiment 44

3-(2-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)乙氧基)丙酸(化合物44)
3-(2-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)ethoxy)propanoic acid (Compound 44)

参照实施例2的方法，将化合物1替换为化合物43制得化合物44(白色固体，101mg，收率52％):1H NMR(300MHz,CD3OD)δ7.84-7.69(m,3H),7.49-7.37(m,3H),7.36-7.28(m,2H),7.23(t,J＝8.0Hz,1H),6.99(d,J＝8.1Hz,1H),6.79(t,J＝7.5Hz,1H),6.60(d,J＝7.3Hz,1H),5.55(s,2H),4.11(t,2H),3.76-3.65(m,4H),2.49(t,J＝6.0Hz,2H).HRMS(ESI)calcd.for C26H23F3N2O5[M+H]+501.1632,found 501.1635.Referring to the method of Example 2, compound 1 was replaced by compound 43 to obtain compound 44 (white solid, 101 mg, yield 52%): 1 H NMR (300 MHz, CD 3 OD) δ 7.84-7.69 (m, 3H), 7.49-7.37 (m, 3H), 7.36-7.28 (m, 2H), 7.23 (t, J = 8.0 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.79 (t, J = 7.5 Hz, 1H), 6.60 (d, J = 7.3 Hz, 1H), 5.55 (s, 2H), 4.11 (t, 2H), 3.76-3.65 (m, 4H), 2.49 (t, J = 6.0 Hz, 2H). HRMS (ESI) calcd. for C 26 H 23 F 3 N 2 O 5 [M+H] + 501.1632, found 501.1635.

实施例45Embodiment 45

6-(2-((2-(4-(4-(三氟甲氧基)苄基))-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物45)

Ethyl 6-(2-((2-(4-(4-(trifluoromethoxy)benzyl))-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoate (Compound 45)

化合物I-23的合成Synthesis of Compound I-23

将1,2-苯二胺(100mg，0.92mmol)溶于乙二醇(4mL)，加入4-三氟甲氧基苯乙酸(407mg，1.85mmol)，190℃加热搅拌反应12小时。TLC监测反应，待反应完全后，冷至室温，将反应液滴入冷的10％氢氧化钠水溶液(20mL)，室温搅拌12h，抽滤，滤饼经硅胶柱层析(石油醚:乙酸乙酯＝1:1)纯化，得化合物I-23(淡黄色固体，110mg，收率41％)。1H NMR(300MHz,DMSO-d6)δ12.30(s,1H),7.46(d,J＝8.3Hz,4H),7.32(d,J＝8.2Hz,2H),7.16-7.08(m,2H),4.22(s,2H).1,2-phenylenediamine (100 mg, 0.92 mmol) was dissolved in ethylene glycol (4 mL), 4-trifluoromethoxyphenylacetic acid (407 mg, 1.85 mmol) was added, and the mixture was heated and stirred at 190°C for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was dropped into a cold 10% aqueous sodium hydroxide solution (20 mL). The mixture was stirred at room temperature for 12 hours, and then filtered. The filter cake was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound I-23 (light yellow solid, 110 mg, yield 41%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.30 (s, 1H), 7.46 (d, J = 8.3 Hz, 4H), 7.32 (d, J = 8.2 Hz, 2H), 7.16-7.08 (m, 2H), 4.22 (s, 2H).

参照实施例1的方法，将化合物I-4替换为化合物I-23制得化合物45(无色油状液体，200mg，收率99％):1H NMR(300MHz,DMSO-d6)δ7.65-7.55(m,1H),7.39-7.27(m,3H),7.25-7.09(m,5H),6.98(d,J＝8.2Hz,1H),6.72(t,J＝7.4Hz,1H),6.52(d,J＝7.4Hz,1H),5.39(s,2H),4.30(s,2H),4.07-3.94(m,4H),2.28(t,J＝7.3Hz,2H),1.76-1.63(m,2H),1.62-1.49(m,2H),1.44-1.32(m,2H),1.14(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+541.3.Referring to the method of Example 1, Compound I-4 was replaced by Compound I-23 to obtain Compound 45 (colorless oily liquid, 200 mg, yield 99%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.65-7.55(m,1H),7.39-7.27(m,3H),7.25-7.09(m,5H),6.98(d,J＝8.2Hz,1H),6.72(t,J＝7.4Hz,1H),6.52(d,J＝7.4Hz,1H),5.39(s,2H),4.30(s, 2H),4.07-3.94(m,4H),2.28(t,J＝7.3Hz,2H),1.76-1.63(m,2H),1.62-1.49(m,2H),1.44-1.32(m,2H),1.14(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H] + 541. 3.

实施例46Embodiment 46

6-(2-((2-(4-(4-(三氟甲氧基)苄基))-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物46)
6-(2-((2-(4-(4-(trifluoromethoxy)benzyl))-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 46)

参照实施例2的方法，将化合物1替换为化合物45制得化合物46(白色固体，83mg，收率44％):1H NMR(300MHz,CD3OD)δ7.69-7.62(m,1H),7.38-7.30(m,1H),7.29-7.11(m,5H),7.10-7.02(m,2H),6.90(d,1H),6.63(t,J＝7.5Hz,1H),6.38(d,1H),5.40(s,2H),4.33(s,2H),4.00(t,J＝6.4Hz,2H),2.20(t,J＝7.4Hz,2H),1.84-1.73(m,2H),1.72-1.60(m,2H),1.55-1.42(m,2H).HRMS(ESI)calcd.for C28H27F3N2O4[M+H]+513.1996,found 513.1997.Referring to the method of Example 2, Compound 1 was replaced by Compound 45 to obtain Compound 46 (white solid, 83 mg, yield 44%): 1 H NMR (300 MHz, CD 3 OD)δ7.69-7.62(m,1H),7.38-7.30(m,1H),7.29-7.11(m,5H),7.10-7.02(m,2H),6.90(d,1H),6.63(t,J＝7.5Hz,1H),6.38(d,1H),5.40(s,2H),4.33 (s,2H),4.00(t,J＝6.4Hz,2H),2.20(t,J＝7.4Hz,2H),1.84-1.73(m,2H),1.72-1.60(m,2H),1.55-1.42(m,2H).HRMS(ESI)calcd.for C 28 H 27 F 3 N 2 O 4 [M+H] + 513.1996,found 513.1997.

实施例47Embodiment 47

6-(2-((2-(4-(4-(三氟甲氧基)苯乙基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物47)
Ethyl 6-(2-((2-(4-(4-(trifluoromethoxy)phenethyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoate (Compound 47)

参照实施例45的方法，将4-三氟甲氧基苯乙酸替换为4-三氟甲氧基苯丙酸制得化合物47(无色油状液体，70mg，收率90％):1H NMR(300MHz,DMSO-d6)δ7.62-7.56(m,1H),7.41-7.30(m,3H),7.27-7.20(m,3H),7.17-7.09(m,2H),7.01(d,J＝8.2Hz,1H),6.79 (t,J＝7.4Hz,1H),6.65(d,J＝6.5Hz,1H),5.34(s,2H),4.09-3.92(m,4H),3.17-3.06(m,4H),2.25(t,J＝7.3Hz,2H),1.69-1.61(m,2H),1.56-1.47(m,2H),1.38-1.29(m,2H),1.15(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+555.3.Referring to the method of Example 45, 4-trifluoromethoxyphenylacetic acid was replaced by 4-trifluoromethoxyphenylpropionic acid to obtain compound 47 (colorless oily liquid, 70 mg, yield 90%): 1 H NMR (300 MHz, DMSO-d 6 ) δ7.62-7.56 (m, 1H), 7.41-7.30 (m, 3H), 7.27-7.20 (m, 3H), 7.17-7.09 (m, 2H), 7.01 (d, J=8.2 Hz, 1H), 6.79 (t,J＝7.4Hz,1H),6.65(d,J＝6.5Hz,1H),5.34(s,2H),4.09-3.92(m,4H),3.17-3.06(m,4H),2.25(t,J＝7.3Hz,2H),1.69-1.61(m,2H),1.56-1.47(m,2 H),1.38-1.29(m,2H),1.15(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H] + 555.3.

实施例48Embodiment 48

6-(2-((2-(4-(4-(三氟甲氧基)苯乙基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物48)
6-(2-((2-(4-(4-(trifluoromethoxy)phenethyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 48)

参照实施例2的方法，将化合物1替换为化合物47制得化合物48(白色固体，24mg，收率36％):1H NMR(300MHz,CD3OD)δ7.67-7.59(m,1H),7.41-7.32(m,1H),7.30-7.09(m,7H),7.01-6.94(m,1H),6.80(t,J＝7.5Hz,1H),6.75-6.69(m,1H),5.31(s,2H),3.97(t,J＝6.3Hz,2H),3.18(t,2H),3.02(t,2H),2.25(t,J＝7.3Hz,2H),1.72-1.62(m,2H),1.62-1.52(m,2H),1.40-1.28(m,2H).HRMS(ESI)calcd.for C29H29F3N2O4[M+H]+527.2152,found 527.2155.Referring to the method of Example 2, Compound 1 was replaced by Compound 47 to obtain Compound 48 (white solid, 24 mg, yield 36%): 1 H NMR (300 MHz, CD 3 OD)δ7.67-7.59(m,1H),7.41-7.32(m,1H),7.30-7.09(m,7H),7.01-6.94(m,1H),6.80(t,J＝7.5Hz,1H),6.75-6.69(m,1H),5.31(s,2H),3.97(t,J＝ 6.3Hz,2H),3.18(t,2H),3.02(t,2H),2.25(t,J＝7.3Hz,2H),1.72-1.62(m,2H),1.62-1.52(m,2H),1.40-1.28(m,2H).HRMS(ESI)calcd.for C 29 H 29 F 3 N 2 O 4 [M+H] + 527.2152, found 527.2155.

实施例49Embodiment 49

6-(2-(2-(2-(2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)乙基)苯氧基)己酸乙酯(化合物49)
Ethyl 6-(2-(2-(2-(2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)ethyl)phenoxy)hexanoate (Compound 49)

化合物III-1的合成Synthesis of compound III-1

将邻羟基苯乙醇(348mg，2.52mmol)溶于N,N-二甲基甲酰胺(8mL)，加入碳酸钾(520mg，3.76mmol)，溴化苄(475mg，2.9mmol)，80℃搅拌反应4小时。TLC监测反应，待反应完全后，抽滤除去碳酸钾，加入乙酸乙酯(50mL)稀释，水(20mLx3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝5:1)纯化，得化合物III-1(无色油状液体，335mg，收率57％)。o-Hydroxyphenylethanol (348 mg, 2.52 mmol) was dissolved in N,N-dimethylformamide (8 mL), potassium carbonate (520 mg, 3.76 mmol) and benzyl bromide (475 mg, 2.9 mmol) were added, and the mixture was stirred at 80°C for 4 hours. The reaction was monitored by TLC. After the reaction was complete, potassium carbonate was removed by suction filtration, ethyl acetate (50 mL) was added for dilution, water (20 mL x 3) was added for washing, and the mixture was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound III-1 (colorless oily liquid, 335 mg, yield 57%).

化合物III-2的合成Synthesis of compound III-2

将化合物III-1(335mg，1.47mmol)溶于二氯甲烷(3mL)，加入三乙胺(298mg，2.61mmol)，冰水浴下逐滴加入甲基磺酰氯(207mg，1.81mmol)，缓慢升至室温搅拌反应3小时。TLC监测反应，待反应完全后，减压蒸除溶剂，加入乙酸乙酯(50mL)复溶，水(20mLx3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝10:1)纯化，得化合物III-2(无色油状液体，381mg，收率85％)。Compound III-1 (335 mg, 1.47 mmol) was dissolved in dichloromethane (3 mL), triethylamine (298 mg, 2.61 mmol) was added, and methylsulfonyl chloride (207 mg, 1.81 mmol) was added dropwise under an ice-water bath, and the mixture was slowly heated to room temperature and stirred for 3 hours. The reaction was monitored by TLC, and after the reaction was complete, the solvent was evaporated under reduced pressure, ethyl acetate (50 mL) was added for redissolution, washed with water (20 mL x 3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound III-2 (colorless oily liquid, 381 mg, yield 85%).

化合物III-3的合成 Synthesis of compound III-3

在氩气保护下，将化合物I-4(300mg，1.08mmol)溶于无水N,N-二甲基甲酰胺(3mL)，冰水浴下加入叔丁醇钾(150mg，1.34mmol)搅拌15分钟，加入化合物III-2(381mg，1.24mmol)搅拌15min，95℃加热搅拌反应4小时。TLC监测反应，待反应完全后，抽滤除去碳酸钾，加入乙酸乙酯(50mL)稀释，水(20mLx3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝20:1)纯化，得化合物III-3(无色油状液体，335mg，收率57％):1H NMR(300MHz,DMSO-d6)δ7.69-7.60(m,3H),7.51(d,J＝7.7Hz,1H),7.50-7.43(m,1H),7.43-7.35(m,8H),7.28-7.11(m,4H),6.94-6.85(m,1H),6.76-6.69(m,2H),4.91(s,2H),4.48(t,J＝7.1Hz,2H),3.01(t,J＝7.1Hz,2H).Under argon protection, compound I-4 (300 mg, 1.08 mmol) was dissolved in anhydrous N, N-dimethylformamide (3 mL), potassium tert-butoxide (150 mg, 1.34 mmol) was added under ice-water bath and stirred for 15 minutes, compound III-2 (381 mg, 1.24 mmol) was added and stirred for 15 min, and the mixture was heated and stirred at 95 ° C for 4 hours. TLC monitored the reaction, and after the reaction was complete, potassium carbonate was removed by suction filtration, ethyl acetate (50 mL) was added for dilution, water (20 mL x 3) was added for washing, and anhydrous sodium sulfate was dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain compound III-3 (colorless oily liquid, 335 mg, yield 57%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.69-7.60(m,3H),7.51(d,J=7.7Hz,1H),7.50-7.43(m,1H),7.43-7.35(m,8H),7.28-7.11(m,4H),6.94-6.85(m,1H),6.76-6.69(m,2H),4.91(s, 2H), 4.48(t,J＝7.1Hz,2H), 3.01(t,J＝7.1Hz,2H).

化合物III-4的合成Synthesis of compound III-4

将化合物III-3(183mg，0.37mmol)溶于甲醇(4mL)，加入5％的钯碳(20mg)，置于氢气氛中，室温搅拌反应12小时。TLC监测反应，待反应完全后，硅藻土抽滤，减压蒸除溶剂，得化合物III-4(无色油状液体，104mg，收率70％)。Compound III-3 (183 mg, 0.37 mmol) was dissolved in methanol (4 mL), 5% palladium carbon (20 mg) was added, and the mixture was placed in a hydrogen atmosphere and stirred at room temperature for 12 hours. The reaction was monitored by TLC. After the reaction was complete, diatomaceous earth was used for filtration, and the solvent was evaporated under reduced pressure to obtain compound III-4 (colorless oily liquid, 104 mg, yield 70%).

化合物49的合成Synthesis of compound 49

将化合物III-4(104mg，0.26mmol)溶于N,N-二甲基甲酰胺(4mL)，加入碳酸铯(128mg，0.39mmol)，6-溴己酸乙酯(65mg，0.29mmol)，室温搅拌反应4小时。TLC监测反应，待反应完全后，抽滤除去碳酸铯，加入乙酸乙酯(50mL)稀释，用水(30mL x3)洗涤，合并有机相，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝10:1)纯化，得化合物49(无色油状液体，125mg，收率89％):1H NMR(300MHz,DMSO-d6)δ7.69(t,J＝7.4Hz,2H),7.52(d,J＝8.6Hz,2H),7.41(d,J＝8.2Hz,2H),7.36-7.22(m,2H),7.15-7.03(m,1H),6.72-6.58(m,2H),6.53(d,J＝7.1Hz,1H),4.52(t,J＝6.6Hz,2H),4.04(q,2H),3.64(t,J＝6.2Hz,2H),2.96(d,J＝6.1Hz,2H),2.29(t,J＝7.2Hz,2H),1.62-1.45(m,4H),1.36-1.30(m,2H),1.16(t,J＝8.9,5.3Hz,3H).MS(ESI):m/z[M+Na]+563.2.Compound III-4 (104 mg, 0.26 mmol) was dissolved in N, N-dimethylformamide (4 mL), cesium carbonate (128 mg, 0.39 mmol) and ethyl 6-bromohexanoate (65 mg, 0.29 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. After the reaction was complete, cesium carbonate was removed by suction filtration, ethyl acetate (50 mL) was added for dilution, and the mixture was washed with water (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound 49 (colorless oily liquid, 125 mg, yield 89%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.69(t,J＝7.4Hz,2H),7.52(d,J＝8.6Hz,2H),7.41(d,J＝8.2Hz,2H),7.36-7.22(m,2H),7.15-7.03(m,1H),6.72-6.58(m,2H),6.53(d,J＝7.1Hz,1H), 4.52(t,J＝6.6Hz,2 H),4.04(q,2H),3.64(t,J＝6.2Hz,2H),2.96(d,J＝6.1Hz,2H),2.29(t,J＝7.2Hz,2H),1.62-1.45(m,4H),1.36-1.30(m,2H),1.16(t,J＝8.9,5.3Hz,3H). MS(ESI):m/z[M+Na] + 563.2.

实施例50Embodiment 50

6-(2-(2-(2-(2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)乙基)苯氧基)己酸(化合物50)
6-(2-(2-(2-(2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)ethyl)phenoxy)hexanoic acid (Compound 50)

参照实施例2的方法，将化合物1替换为化合物49制得化合物50(白色固体，65mg，收率55％):1H NMR(300MHz,CD3OD)δ7.68(t,J＝8.0Hz,2H),7.44-7.32(m,2H),7.31-7.23(m,4H),7.12-7.04(m,1H),6.61-6.49(m,2H),6.27-6.22(m,1H),4.64(t,2H),3.57(t,J＝6.2Hz,2H),3.02(t,2H),2.25(t,J＝7.4Hz,2H),1.71-1.49(m,4H),1.46-1.34(m,2H).HRMS(ESI)calcd.for C28H27F3N2O4[M+H]+513.1996,found 513.2001.Referring to the method of Example 2, compound 1 was replaced by compound 49 to obtain compound 50 (white solid, 65 mg, yield 55%): 1 H NMR (300 MHz, CD 3 OD) δ 7.68 (t, J = 8.0 Hz, 2H), 7.44-7.32 (m, 2H), 7.31-7.23 (m, 4H), 7.12-7.04 (m, 1H), 6.61-6.49 (m, 2H), 6.27-6.22 (m, 1H), 4.64 (t, 2H), 3.57 (t, J = 6.2 Hz, 2H), 3.02 (t, 2H), 2.25 (t, J = 7.4 Hz, 2H), 1.71-1.49 (m, 4H), 1.46-1.34 (m, 2H). HRMS (ESI) calcd. for C 28 H 27 F 3 N 2 O 4 [M+H] + 513.1996, found 513.2001.

实施例51Embodiment 51

6-(2-(3-(2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)丙基)苯氧基)己酸乙酯(化合物51)
Ethyl 6-(2-(3-(2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)propyl)phenoxy)hexanoate (Compound 51)

化合物IV-1的合成Synthesis of compound IV-1

将2-(3-羟丙基)苯酚(264mg，1.73mmol)溶于N,N-二甲基甲酰胺(6mL)，加入碳酸钾(360mg，2.60mmol)，6-溴己酸乙酯(426mg，1.91mmol)，80℃搅拌反应3小时。TLC监测反应，待反应完全后，抽滤除去碳酸钾，加入乙酸乙酯(50mL)稀释，水(20mLx3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝5:1)纯化，得化合物IV-1(无色油状液体，381mg，收率75％)。2-(3-Hydroxypropyl)phenol (264 mg, 1.73 mmol) was dissolved in N,N-dimethylformamide (6 mL), potassium carbonate (360 mg, 2.60 mmol) and ethyl 6-bromohexanoate (426 mg, 1.91 mmol) were added, and the mixture was stirred at 80°C for 3 hours. The reaction was monitored by TLC, and after the reaction was complete, potassium carbonate was removed by suction filtration, ethyl acetate (50 mL) was added for dilution, water (20 mL x 3) was added for washing, and the mixture was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain compound IV-1 (colorless oily liquid, 381 mg, yield 75%).

化合物IV-2的合成Synthesis of compound IV-2

将化合物IV-1(381mg，1.29mmol)溶于二氯甲烷(10mL)中，加入四溴化碳(1.1g，3.32mmol)，冰水浴下缓慢加入三苯基膦(883mg，3.37mmol)，缓慢升至室温搅拌反应4小时。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝60:1)纯化，得化合物IV-2(无色油状液体，141mg，收率31％)。Compound IV-1 (381 mg, 1.29 mmol) was dissolved in dichloromethane (10 mL), carbon tetrabromide (1.1 g, 3.32 mmol) was added, triphenylphosphine (883 mg, 3.37 mmol) was slowly added under an ice-water bath, and the mixture was slowly heated to room temperature and stirred for 4 hours. The reaction was monitored by TLC, and after the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 60: 1) to obtain compound IV-2 (colorless oily liquid, 141 mg, yield 31%).

化合物51的合成Synthesis of compound 51

将化合物I-4(100mg，0.36mmol)溶于乙腈(4mL)，加入碳酸铯(176mg，0.54mmol)和化合物IV-2(141mg，0.39mmol)，室温搅拌反应6小时。TLC监测反应，待反应完全后，抽滤除去碳酸铯，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝15:1)纯化，得化合物51(无色油状液体，178mg，收率89％):1H NMR(300MHz,DMSO-d6)δ7.81(d,J＝8.6Hz,2H),7.69(d,J＝7.1Hz,1H),7.59(d,J＝7.2Hz,1H),7.46(d,J＝8.5Hz,2H),7.33-7.21(m,2H),7.13(t,J＝7.8Hz,1H),7.01(d,J＝6.3Hz,1H),6.87(d,J＝8.1Hz,1H),6.78(t,J＝7.4Hz,1H),4.29(t,J＝7.5Hz,2H),4.00(q,J＝7.1Hz,2H),3.84(t,J＝6.3Hz,2H),2.47(s,2H),2.23(t,J＝7.3Hz,2H),2.07-1.91(m,2H),1.63-1.43(m,4H),1.37-1.25(m,2H),1.13(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+555.1.
Compound I-4 (100 mg, 0.36 mmol) was dissolved in acetonitrile (4 mL), cesium carbonate (176 mg, 0.54 mmol) and compound IV-2 (141 mg, 0.39 mmol) were added, and the mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC. After the reaction was complete, cesium carbonate was removed by suction filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1) to obtain compound 51 (colorless oily liquid, 178 mg, yield 89%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.81(d,J＝8.6Hz,2H),7.69(d,J＝7.1Hz,1H),7.59(d,J＝7.2Hz,1H),7.46(d,J＝8.5Hz,2H),7.33-7.21(m,2H),7.13(t,J＝7.8Hz,1H),7.01(d,J＝6.3Hz, 1H),6.87(d,J＝8.1Hz,1H),6.78(t,J＝7.4Hz,1H), 4.29(t,J＝7.5Hz,2H),4.00(q,J＝7.1Hz,2H),3.84(t,J＝6.3Hz,2H),2.47(s,2H),2.23(t,J＝7.3Hz,2H),2.07-1.91(m,2H),1.63-1.43(m,4H),1.37-1. 25(m,2H),1.13(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H] + 555.1.

实施例52Embodiment 52

6-(2-(3-(2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)丙基)苯氧基)己酸(化合物52)6-(2-(3-(2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)propyl)phenoxy)hexanoic acid (Compound 52)

参照实施例2的方法，将化合物1替换为化合物51制得化合物52(无色油状液体，66mg，收率39％):1H NMR(300MHz,CD3OD)δ7.74-7.67(m,3H),7.53-7.47(m,1H),7.39(d,J＝8.4Hz,2H),7.36-7.30(m,2H),7.18-7.10(m,1H),7.02-6.96(m,1H),6.89-6.75(m,2H),4.30(t,2H),3.87(t,J＝6.3Hz,2H),2.58(t,J＝7.1Hz,2H),2.24(t,J＝7.3Hz,2H),2.16-2.02(m,2H),1.71-1.53(m,4H),1.46-1.31(m,2H).HRMS(ESI)calcd.for C29H29F3N2O4[M+H]+527.2152,found 527.2157.Referring to the method of Example 2, Compound 1 was replaced by Compound 51 to obtain Compound 52 (colorless oily liquid, 66 mg, yield 39%): 1 H NMR (300 MHz, CD 3 OD)δ7.74-7.67(m,3H),7.53-7.47(m,1H),7.39(d,J＝8.4Hz,2H),7.36-7.30(m,2H),7.18-7.10(m,1H),7.02-6.96(m,1H),6.89-6.75(m,2H),4.30 (t,2H),3.87(t,J＝6.3Hz,2H),2.58(t,J＝7.1Hz,2H),2.24(t,J＝7.3Hz,2H),2.16-2.02(m,2H),1.71-1.53(m,4H),1.46-1.31(m,2H).HRMS(ESI)calcd.for C 2 9 H 29 F 3 N 2 O 4 [M+H] + 527.2152, found 527.2157.

实施例53Embodiment 53

6-(3-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物53)
Ethyl 6-(3-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoate (Compound 53)

参照实施例1的方法，将2-羟基苯甲醛替换为3-羟基苯甲醛制得化合物53(无色油状液体，126mg，收率96％):1H NMR(300MHz,DMSO-d6)δ7.87(d,J＝8.6Hz,2H),7.78-7.69(m,1H),7.58-7.48(m,3H),7.32-7.24(m,2H),7.17(t,J＝7.9Hz,1H),6.79(d,J＝7.9Hz,1H),6.52(d,J＝11.2Hz,2H),5.56(s,2H),4.03(q,J＝7.1Hz,2H),3.82(t,J＝6.3Hz,2H),2.27(t,J＝7.3Hz,2H),1.67-1.57(m,2H),1.57-1.48(m,2H),1.40-1.30(m,2H),1.16(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+527.2.Referring to the method of Example 1, 2-hydroxybenzaldehyde was replaced by 3-hydroxybenzaldehyde to obtain compound 53 (colorless oily liquid, 126 mg, yield 96%): 1 H NMR (300 MHz, DMSO-d 6 ) δ7.87 (d, J=8.6 Hz, 2H), 7.78-7.69 (m, 1H), 7.58-7.48 (m, 3H), 7.32-7.24 (m, 2H), 7.17 (t, J=7.9 Hz, 1H), 6.79 (d, J=7.9 Hz, 1H), 6.52 (d, J=11.2 Hz, 2H), 5.56 (s, 2H), 4. .03(q,J＝7.1Hz,2H),3.82(t,J＝6.3Hz,2H),2.27(t,J＝7.3Hz,2H),1.67-1.57(m,2H),1.57-1.48(m,2H),1.40-1.30(m,2H),1.16(t,J＝7.1Hz,3H).MS(ES I):m/z[M+H] + 527.2.

实施例54Embodiment 54

6-(3-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物54)
6-(3-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 54)

参照实施例2的方法，将化合物1替换为化合物53制得化合物54(白色固体，98mg，收率82％):1H NMR(300MHz,DMSO-d6)δ7.87(d,2H),7.78-7.69(m,1H),7.59-7.47(m,3H),7.32-7.21(m,2H),7.16(t,J＝7.9Hz,1H),6.78(d,1H),6.56(s,1H),6.48(d,1H),5.56(s,2H),3.82(t,J＝6.2Hz,2H),2.14(t,J＝7.2Hz,2H),1.68-1.56(m,2H),1.56-1.43(m,2H),1.40-1.27(m,2H).HRMS(ESI)calcd.for C27H25F3N2O4[M+H]+499.1839,found 499.1841.Referring to the method of Example 2, Compound 1 was replaced by Compound 53 to obtain Compound 54 (white solid, 98 mg, yield 82%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.87(d,2H),7.78-7.69(m,1H),7.59-7.47(m,3H),7.32-7.21(m,2H),7.16(t,J＝7.9Hz,1H),6.78(d,1H),6.56(s,1H),6.48(d,1H),5.56(s,2H) ,3.82(t,J＝6.2Hz,2H),2.14(t,J＝7.2Hz,2H),1.68-1.56(m,2H),1.56-1.43(m,2H),1.40-1.27(m,2H).HRMS(ESI)calcd.for C 27 H 25 F 3 N 2 O 4 [M+H] + 499.1 839,found 499.1841.

实施例55Embodiment 55

6-(4-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物55)
Ethyl 6-(4-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoate (Compound 55)

参照实施例1的方法，将2-羟基苯甲醛替换为4-羟基苯甲醛制得化合物55(无色油状液体，115mg，收率78％):1H NMR(300MHz,DMSO-d6)δ7.87(d,J＝8.6Hz,2H), 7.77-7.68(m,1H),7.56-7.47(m,3H),7.30-7.21(m,2H),6.91(d,J＝8.6Hz,2H),6.81(d,J＝8.6Hz,2H),5.51(s,2H),4.03(q,J＝7.1Hz,2H),3.87(t,J＝6.4Hz,2H),2.27(t,J＝7.3Hz,2H),1.70-1.60(m,2H),1.59-1.49(m,2H),1.40-1.33(m,2H),1.15(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na]+549.2.Referring to the method of Example 1, 2-hydroxybenzaldehyde was replaced by 4-hydroxybenzaldehyde to obtain compound 55 (colorless oily liquid, 115 mg, yield 78%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.87 (d, J = 8.6 Hz, 2H), 7.77-7.68(m,1H),7.56-7.47(m,3H),7.30-7.21(m,2H),6.91(d,J＝8.6Hz,2H),6.81(d,J＝8.6Hz,2H),5.51(s,2H),4.03(q,J＝7.1Hz,2H),3.87(t,J ＝6.4Hz,2H),2.27(t,J＝7.3Hz,2H),1.70-1.60(m,2H),1.59-1.49(m,2H),1.40-1.33(m,2H),1.15(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na] + 549.2.

实施例56Embodiment 56

6-(4-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物56)
6-(4-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 56)

参照实施例2的方法，将化合物1替换为化合物55制得化合物56(白色固体，71mg，收率65％):1H NMR(300MHz,DMSO-d6)δ11.95(s,1H),7.87(d,2H),7.77-7.67(m,1H),7.59-7.46(m,3H),7.31-7.22(m,2H),6.91(d,2H),6.81(d,J＝8.6Hz,2H),5.51(s,2H),3.87(t,J＝6.3Hz,2H),2.20(t,J＝7.2Hz,2H),1.72-1.60(m,2H),1.58-1.45(m,2H),1.44-1.30(m,2H).HRMS(ESI)calcd.for C27H25F3N2O4[M+H]+499.1839,found 499.1837.Referring to the method of Example 2, compound 1 was replaced by compound 55 to obtain compound 56 (white solid, 71 mg, yield 65%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.95 (s, 1H), 7.87 (d, 2H), 7.77-7.67 (m, 1H), 7.59-7.46 (m, 3H), 7.31-7.22 (m, 2H), 6.91 (d, 2H), 6.81 (d, J = 8.6 Hz, 2H), 5.51 (s, 2H), 3.87 (t, J = 6.3 Hz, 2H), 2.20 (t, J = 7.2 Hz, 2H), 1.72-1.60 (m, 2H), 1.58-1.45 (m, 2H), 1.44-1.30 (m, 2H). HRMS (ESI) calcd. for C 27 H 25 F 3 N 2 O 4 [M+H] + 499.1839, found 499.1837.

实施例57Embodiment 57

6-(2-((2-(4-(4-(三氟甲氧基)苯基))-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯氧基)己酸乙酯(化合物57)
Ethyl 6-(2-((2-(4-(4-(trifluoromethoxy)phenyl))-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenoxy)hexanoate (Compound 57)

化合物V-1的合成Synthesis of Compound V-1

将3-氨基-2-硝基吡啶(200mg，1.44mmol)溶于无水四氢呋喃(7mL)，依次加入4-三氟甲氧基苯甲酸(326mg，1.58mmol)和三乙胺(437mg，4.32mmol)，逐滴加入50％1-丙基磷酸酐的N,N-二甲基甲酰胺溶液(915mg，2.88mmol)，70℃搅拌反应8小时。TLC监测反应，待反应完全后，减压蒸除溶剂，加入乙酸乙酯(50mL)复溶，水(20mLx3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝5:1)纯化，得化合物V-1(白色固体，117mg，收率43％):1H NMR(300MHz,DMSO-d6)δ11.64(s,1H),8.82-8.72(m,1H),8.50-8.42(m,1H),8.14(d,J＝8.8Hz,2H),7.59-7.51(m,3H).3-Amino-2-nitropyridine (200 mg, 1.44 mmol) was dissolved in anhydrous tetrahydrofuran (7 mL), 4-trifluoromethoxybenzoic acid (326 mg, 1.58 mmol) and triethylamine (437 mg, 4.32 mmol) were added in sequence, 50% 1-propylphosphoric anhydride in N,N-dimethylformamide solution (915 mg, 2.88 mmol) was added dropwise, and the reaction was stirred at 70°C for 8 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, ethyl acetate (50 mL) was added for redissolution, washed with water (20 mL x 3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain compound V-1 (white solid, 117 mg, yield 43%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.64 (s, 1H), 8.82-8.72 (m, 1H), 8.50-8.42 (m, 1H), 8.14 (d, J = 8.8 Hz, 2H), 7.59-7.51 (m, 3H).

化合物V-2的合成 Synthesis of Compound V-2

将化合物V-1(117mg，1.44mmol)溶于无水甲醇(5mL)，加入10％的钯碳(20mg)，置于氢气氛中，室温搅拌反应6小时。TLC监测反应，待反应完全后，硅藻土抽滤，减压蒸除溶剂，得化合物V-2(灰白色固体，269mg，收率83％)。Compound V-1 (117 mg, 1.44 mmol) was dissolved in anhydrous methanol (5 mL), 10% palladium carbon (20 mg) was added, and the mixture was placed in a hydrogen atmosphere and stirred at room temperature for 6 hours. The reaction was monitored by TLC. After the reaction was complete, diatomaceous earth was used for filtration, and the solvent was evaporated under reduced pressure to obtain compound V-2 (off-white solid, 269 mg, yield 83%).

化合物V-3的合成Synthesis of Compound V-3

将化合物V-2(88mg，0.30mmol)溶于乙酸乙酯(2mL)，依次加入化合物I-1(93mg，0.35mmol)、三氟乙酸(69mg，0.61mmol)和三乙酰氧基硼氢化钠(76mg，0.36mmol)，室温搅拌反应4小时。TLC监测反应，待反应完全后，加入饱和碳酸氢钠调pH至8，乙酸乙酯(20mLx3)萃取，合并有机相，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝10:1)纯化，得化合物V-3(绿色液体，67mg，收率41％):1H NMR(300MHz,DMSO-d6)δ10.45(s,1H),8.17(d,J＝8.7Hz,2H),7.67(d,J＝3.4Hz,1H),7.52(d,J＝8.2Hz,2H),7.33-7.24(m,1H),7.18(t,J＝8.0Hz,1H),7.12-7.02(m,1H),6.97(d,J＝8.1Hz,1H),6.84(t,J＝7.3Hz,2H),5.83-5.70(m,1H),4.31(d,J＝6.0Hz,2H),4.08-3.95(m,4H),2.28(t,J＝7.2Hz,3H),1.82-1.64(m,3H),1.62-1.50(m,3H),1.49-1.37(m,3H),1.15(t,J＝7.1Hz,3H).Compound V-2 (88 mg, 0.30 mmol) was dissolved in ethyl acetate (2 mL), and compound I-1 (93 mg, 0.35 mmol), trifluoroacetic acid (69 mg, 0.61 mmol) and sodium triacetoxyborohydride (76 mg, 0.36 mmol) were added in sequence, and the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. After the reaction was complete, saturated sodium bicarbonate was added to adjust the pH to 8, and ethyl acetate (20 mL x 3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound V-3 (green liquid, 67 mg, yield 41%): 1 H NMR (300 MHz, DMSO-d 6 )δ10.45(s,1H),8.17(d,J＝8.7Hz,2H),7.67(d,J＝3.4Hz,1H),7.52(d,J＝8.2Hz,2H),7.33-7.24(m,1H),7.18(t,J＝8.0Hz,1H),7.12-7.02(m,1H),6.97 (d,J＝8.1Hz,1H),6.84(t, J＝7.3Hz,2H),5.83-5.70(m,1H),4.31(d,J＝6.0Hz,2H),4.08-3.95(m,4H),2.28(t,J＝7.2Hz,3H),1.82-1.64(m,3H),1.62-1.50(m,3H),1.49-1.37(m ,3H),1.15(t,J＝7.1Hz,3H).

化合物57的合成Synthesis of compound 57

将化合物V-3(67mg，0.12mmol)溶于乙酸(2mL)，加入乙酸钠(11mg，0.13mmol)，120℃加热搅拌反应12小时。TLC监测反应，待反应完全后，加入饱和碳酸氢钠调pH至8，乙酸乙酯(20mLx3)萃取，合并有机相，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝1:1)纯化，得化合物57(白色固体，46mg，收率71％):1H NMR(300MHz,DMSO-d6)δ8.50-8.40(m,1H),7.86(d,J＝8.9Hz,3H),7.52(d,J＝8.1Hz,2H),7.29-7.17(m,2H),6.96(d,J＝8.1Hz,1H),6.83-6.70(m,2H),5.54(s,2H),4.02(q,J＝7.1Hz,2H),3.88(t,J＝6.3Hz,2H),2.22(t,J＝7.4Hz,2H),1.53-1.39(m,4H),1.24-1.20(m,2H),1.13(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na]+550.3.Compound V-3 (67 mg, 0.12 mmol) was dissolved in acetic acid (2 mL), sodium acetate (11 mg, 0.13 mmol) was added, and the mixture was stirred at 120°C for 12 hours. The reaction was monitored by TLC. After the reaction was complete, saturated sodium bicarbonate was added to adjust the pH to 8, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 57 (white solid, 46 mg, yield 71%): 1 H NMR (300 MHz, DMSO-d 6 )δ8.50-8.40(m,1H),7.86(d,J＝8.9Hz,3H),7.52(d,J＝8.1Hz,2H),7.29-7.17(m,2H),6.96(d,J＝8.1Hz,1H),6.83-6.70(m,2H),5.54(s,2H),4.02(q, J＝7.1Hz,2H),3.88(t,J＝6.3Hz,2H),2.22(t,J＝7.4Hz,2H),1.53-1.39(m,4H),1.24-1.20(m,2H),1.13(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na] + 550.3.

实施例58Embodiment 58

6-(2-((2-(4-(4-(三氟甲氧基)苯基))-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯氧基)己酸(化合物58)
6-(2-((2-(4-(4-(trifluoromethoxy)phenyl))-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenoxy)hexanoic acid (Compound 58)

参照实施例2的方法，将化合物1替换为化合物57制得化合物58(白色固体，28mg，收率65％):1H NMR(300MHz,DMSO-d6)δ8.50-8.42(m,1H),7.93-7.82(m,3H),7.52(d,J＝8.1Hz,2H),7.31-7.17(m,2H),6.96(d,J＝8.1Hz,1H),6.78(t,J＝7.4Hz,1H),6.74-6.67(m,1H),5.54(s,2H),3.88(t,J＝6.3Hz,2H),2.14(t,J＝7.4Hz,2H),1.56-1.37(m,4H),1.30-1.15(m,2H).HRMS(ESI)calcd.for C26H24F3N3O4[M+Na]+522.1611,found522.1615.Referring to the method of Example 2, Compound 1 was replaced by Compound 57 to obtain Compound 58 (white solid, 28 mg, yield 65%): 1 H NMR (300 MHz, DMSO-d 6 )δ8.50-8.42(m,1H),7.93-7.82(m,3H),7.52(d,J＝8.1Hz,2H),7.31-7.17(m,2H),6.96(d,J＝8.1Hz,1H),6.78(t,J＝7.4Hz,1H),6.74-6.67(m,1H),5.5 4(s,2H),3.88(t,J＝6.3Hz,2H),2.14(t,J＝7.4Hz,2H),1.56-1.37(m,4H),1.30-1.15(m,2H).HRMS(ESI)calcd.for C 26 H 24 F 3 N 3 O 4 [M+Na] + 522.1611,found522. 1615.

实施例59Embodiment 59

6-(2-((2-(4-(三氟甲氧基)苯基)-3H-咪唑并[4,5-b]吡啶-3-基)甲基)苯氧基)己酸乙酯(化合物59)
Ethyl 6-(2-((2-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenoxy)hexanoate (Compound 59)

化合物VI-1的合成Synthesis of compound VI-1

将化合物I-1(100mg，0.38mmol)悬浮于水(2mL)中，加入50％羟胺的水溶液(125mg，1.89mmol)，100℃搅拌反应4小时。TLC监测反应，待反应完全后，冷至0℃，有大量白色固体析出，抽滤，滤饼用水洗涤，真空干燥得化合物VI-1(白色固体，86mg，收率81％)。Compound I-1 (100 mg, 0.38 mmol) was suspended in water (2 mL), and a 50% aqueous solution of hydroxylamine (125 mg, 1.89 mmol) was added, and the mixture was stirred at 100° C. for 4 hours. The reaction was monitored by TLC, and after the reaction was complete, the mixture was cooled to 0° C. A large amount of white solid precipitated, which was filtered, and the filter cake was washed with water and dried in vacuo to obtain compound VI-1 (white solid, 86 mg, yield 81%).

化合物VI-2的合成Synthesis of Compound VI-2

将化合物VI-1(86mg，0.31mmol)溶于无水乙醇(5mL)，加入10％的钯碳(20mg)，置于氢气氛中，室温搅拌反应4小时。TLC监测反应，待反应完全后，硅藻土抽滤，减压蒸除溶剂，得化合物VI-2(淡黄色油状液体，66mg，收率80％)。Compound VI-1 (86 mg, 0.31 mmol) was dissolved in anhydrous ethanol (5 mL), 10% palladium carbon (20 mg) was added, and the mixture was placed in a hydrogen atmosphere and stirred at room temperature for 4 hours. The reaction was monitored by TLC. After the reaction was complete, diatomaceous earth was used for filtration, and the solvent was evaporated under reduced pressure to obtain compound VI-2 (light yellow oily liquid, 66 mg, yield 80%).

化合物VI-3的合成Synthesis of Compound VI-3

将化合物VI-2(86mg，0.31mmol)溶于1,4-二氧六环(5mL)，依次加入碳酸铯(86mg，0.31mmol)和2-氯-3-硝基吡啶(86mg，0.31mmol)，100℃搅拌反应。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝30:1)纯化，得化合物VI-3(黄绿色油状液体，180mg，收率68％)。Compound VI-2 (86 mg, 0.31 mmol) was dissolved in 1,4-dioxane (5 mL), and cesium carbonate (86 mg, 0.31 mmol) and 2-chloro-3-nitropyridine (86 mg, 0.31 mmol) were added in sequence, and the mixture was stirred at 100° C. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain compound VI-3 (yellow-green oily liquid, 180 mg, yield 68%).

化合物VI-4的合成Synthesis of compound VI-4

将铁粉(260mg，4.66mmol)悬浮于水(1mL)中，加入浓盐酸(0.2mL，2.33mmol)，80℃搅拌15min，加入化合物VI-3(180mg)的乙醇(4mL)溶液，80℃搅拌反应4小时。TLC监测反应，待反应完全后，硅藻土抽滤，减压蒸除溶剂，加入饱和碳酸氢钠调pH至9，乙酸乙酯(20mLx3)萃取，合并有机相，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝1:1)纯化，得化合物VI-4(红色油状液体，111mg，收率67％)。Iron powder (260 mg, 4.66 mmol) was suspended in water (1 mL), concentrated hydrochloric acid (0.2 mL, 2.33 mmol) was added, and the mixture was stirred at 80 ° C for 15 min. A solution of compound VI-3 (180 mg) in ethanol (4 mL) was added, and the mixture was stirred at 80 ° C for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered off with diatomaceous earth, the solvent was evaporated under reduced pressure, saturated sodium bicarbonate was added to adjust the pH to 9, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain compound VI-4 (red oily liquid, 111 mg, yield 67%).

化合物59的合成Synthesis of compound 59

将化合物VI-4(111mg，0.31mmol)溶于N,N-二甲基甲酰胺(2.7mL)和水(0.3mL)的混合溶剂，加入4-三氟甲氧基苯甲醛(64mg，0.37mmol)，100℃搅拌反应6小时。TLC监测反应，待反应完全后，加入乙酸乙酯(50mL)稀释，水(20mLx3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝20:1)纯化，得化合物59(淡黄色油状液体，121mg，收率74％):1H NMR(300MHz,DMSO-d6)δ8.42-8.33(m,1H),8.23-8.14(m,1H),7.83(d,J＝8.8Hz,2H),7.48(d,J＝8.1Hz,2H),7.40-7.32(m,1H),7.19(t,J＝7.1Hz,1H),6.96(d,J＝8.1Hz,1H),6.72(t,J＝7.4Hz,1H),6.56(d,J＝6.8Hz,1H),5.58(s,2H),4.02(q,J＝7.1Hz,2H),3.92(t,J＝6.3Hz,2H),2.25(t,J＝7.3Hz, 2H),1.58-1.49(m,4H),1.48-1.39(m,2H),1.14(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na]+550.3.Compound VI-4 (111 mg, 0.31 mmol) was dissolved in a mixed solvent of N,N-dimethylformamide (2.7 mL) and water (0.3 mL), 4-trifluoromethoxybenzaldehyde (64 mg, 0.37 mmol) was added, and the mixture was stirred at 100°C for 6 hours. The reaction was monitored by TLC. After the reaction was complete, ethyl acetate (50 mL) was added for dilution, washed with water (20 mL x 3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain compound 59 (light yellow oily liquid, 121 mg, yield 74%): 1 H NMR (300 MHz, DMSO-d 6 )δ8.42-8.33(m,1H),8.23-8.14(m,1H),7.83(d,J＝8.8Hz,2H),7.48(d,J＝8.1Hz,2H),7.40-7.32(m,1H),7.19(t,J＝7.1Hz,1H),6.96(d,J＝8.1Hz,1H),6 .72(t,J＝7.4Hz,1H),6.56(d,J＝6.8Hz,1H),5.58(s,2H),4.02(q,J＝7.1Hz,2H),3.92(t,J＝6.3Hz,2H),2.25(t,J＝7.3Hz, 2H),1.58-1.49(m,4H),1.48-1.39(m,2H),1.14(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na] + 550.3.

实施例60Embodiment 60

6-(2-((2-(4-(三氟甲氧基)苯基)-3H-咪唑并[4,5-b]吡啶-3-基)甲基)苯氧基)己酸(化合物60)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenoxy)hexanoic acid (Compound 60)

参照实施例2的方法，将化合物1替换为化合物59制得化合物60(白色固体，55mg，收率48％):1H NMR(300MHz,DMSO-d6)δ11.97(s,1H),8.42-8.34(m,1H),8.23-8.14(m,1H),7.83(d,J＝8.8Hz,2H),7.48(d,J＝8.1Hz,2H),7.41-7.32(m,1H),7.18(t,J＝7.1Hz,1H),6.96(d,J＝8.1Hz,1H),6.71(t,J＝7.3Hz,1H),6.55(d,J＝6.5Hz,1H),5.59(s,2H),3.92(t,J＝6.3Hz,2H),2.18(t,J＝7.3Hz,2H),1.59-1.42(m,4H),1.38-1.24(m,2H).HRMS(ESI)calcd.for C26H24F3N3O4[M+H]+500.1792,found 500.1797.Referring to the method of Example 2, Compound 1 was replaced by Compound 59 to obtain Compound 60 (white solid, 55 mg, yield 48%): 1 H NMR (300 MHz, DMSO-d 6 )δ11.97(s,1H),8.42-8.34(m,1H),8.23-8.14(m,1H),7.83(d,J＝8.8Hz,2H),7.48(d,J＝8.1Hz,2H),7.41-7.32(m,1H),7.18(t,J＝7.1Hz,1H),6.96(d ,J＝8.1Hz,1H),6.71(t,J＝7.3Hz,1H),6.55(d,J＝6.5Hz,1H),5.59(s,2H),3.92(t,J＝6.3Hz,2H),2.18(t,J＝7.3Hz,2H),1.59-1.42(m,4H),1.38-1.24( m,2H).HRMS(ESI)calcd.for C 26 H 24 F 3 N 3 O 4 [M+H] + 500.1792,found 500.1797.

实施例61Embodiment 61

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-咪唑并[4,5-c]吡啶-1-基)甲基)苯氧基)己酸乙酯(化合物61)
Ethyl 6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-c]pyridin-1-yl)methyl)phenoxy)hexanoate (Compound 61)

化合物VI-5的合成Synthesis of compound VI-5

在氩气保护下，将4-氯-3-硝基吡啶(33mg，0.21mmol)溶于无水二氯甲烷(2mL)，依次加入三乙胺(32mg，0.31mmol)和化合物Ⅵ-2(66mg，0.25mmol)，40℃搅拌反应5小时。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝3:1)纯化，得化合物VI-5(黄绿色油状液体，77mg，收率96％)。Under argon protection, 4-chloro-3-nitropyridine (33 mg, 0.21 mmol) was dissolved in anhydrous dichloromethane (2 mL), triethylamine (32 mg, 0.31 mmol) and compound VI-2 (66 mg, 0.25 mmol) were added in sequence, and the mixture was stirred at 40°C for 5 hours. The reaction was monitored by TLC, and after the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound VI-5 (yellow-green oily liquid, 77 mg, yield 96%).

参照实施例59的方法，将化合物VI-3替换为化合物VI-5制得化合物61(淡黄油状液体，200mg，收率51％):1H NMR(300MHz,DMSO-d6)δ9.02(s,1H),8.32(d,J＝5.6Hz,1H),7.85(d,J＝8.6Hz,2H),7.50(t,J＝7.1Hz,3H),7.22(t,J＝6.9Hz,1H),6.96(d,J ＝8.2Hz,1H),6.84--6.69(m,2H),5.53(s,2H),4.02(q,J＝10.4,5.5Hz,2H),3.87(t,J＝6.3Hz,2H),2.22(t,J＝7.4Hz,2H),1.51-1.39(m,4H),1.28-1.20(m,2H),1.15(t,J＝7.2Hz,3H).MS(ESI):m/z[M+Na]+528.3.Referring to the method of Example 59, compound VI-3 was replaced by compound VI-5 to obtain compound 61 (light yellow oily liquid, 200 mg, yield 51%): 1 H NMR (300 MHz, DMSO-d 6 ) δ9.02 (s, 1H), 8.32 (d, J＝5.6 Hz, 1H), 7.85 (d, J＝8.6 Hz, 2H), 7.50 (t, J＝7.1 Hz, 3H), 7.22 (t, J＝6.9 Hz, 1H), 6.96 (d, J =8.2Hz,1H),6.84--6.69(m,2H),5.53(s,2H),4.02(q,J＝10.4,5.5Hz,2H),3.87(t,J＝6.3Hz,2H),2.22(t,J＝7.4Hz,2H),1.51-1.39(m,4H),1.28-1.2 0(m,2H),1.15(t,J＝7.2Hz,3H).MS(ESI):m/z[M+Na] + 528.3.

实施例62Embodiment 62

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-咪唑并[4,5-c]吡啶-1-基)甲基)苯氧基)己酸(化合物62)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-c]pyridin-1-yl)methyl)phenoxy)hexanoic acid (Compound 62)

参照实施例2的方法，将化合物1替换为化合物61制得化合物62(白色固体，67mg，收率35％):1H NMR(300MHz,DMSO-d6)δ11.96(s,1H),9.02(s,1H),8.33(d,J＝5.6Hz,1H),7.84(d,J＝8.7Hz,2H),7.56-7.45(m,3H),7.22(t,J＝7.0Hz,1H),6.96(d,J＝8.2Hz,1H),6.77(t,J＝7.3Hz,1H),6.71(d,J＝6.2Hz,1H),5.53(s,2H),3.86(t,J＝6.3Hz,2H),2.15(t,J＝7.3Hz,2H),1.52-1.37(m,4H),1.28-1.11(m,2H).HRMS(ESI)calcd.for C26H24F3N3O4[M+H]+500.1792,found 500.1793.Referring to the method of Example 2, Compound 1 was replaced by Compound 61 to obtain Compound 62 (white solid, 67 mg, yield 35%): 1 H NMR (300 MHz, DMSO-d 6 )δ11.96(s,1H),9.02(s,1H),8.33(d,J＝5.6Hz,1H),7.84(d,J＝8.7Hz,2H),7.56-7.45(m,3H),7.22(t,J＝7.0Hz,1H),6.96(d,J＝8.2Hz,1H),6.77(t,J＝ 7.3Hz,1H),6.71(d,J＝6.2Hz,1H),5.53(s,2H),3.86(t,J＝6.3Hz,2H),2.15(t,J＝7.3Hz,2H),1.52-1.37(m,4H),1.28-1.11(m,2H).HRMS(ESI)calcd.for C 26 H 24 F 3 N 3 O 4 [M+H] + 500.1792,found 500.1793.

实施例63Embodiment 63

6-(2-((2-(4-(三氟甲氧基)苯基)-3H-咪唑并[4,5-c]吡啶-3-基)甲基)苯氧基)己酸乙酯(化合物63)
Ethyl 6-(2-((2-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-c]pyridin-3-yl)methyl)phenoxy)hexanoate (Compound 63)

化合物VI-7的合成Synthesis of compound VI-7

在氩气保护下，将3-溴-4-硝基吡啶-N-氧化物(50mg，0.25mmol)溶于四氢呋喃(3mL)，加入化合物VI-2(121mg，0.46mmol)，60℃搅拌反应6小时。TLC监测反应，待反应完全后，减压蒸除溶剂，加入饱和碳酸氢钠调pH至9，乙酸乙酯(20mLx3)萃取，合并有机相，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝1:1)纯化，得化合物VI-7(黄色固体，71mg，收率77％)。Under argon protection, 3-bromo-4-nitropyridine-N-oxide (50 mg, 0.25 mmol) was dissolved in tetrahydrofuran (3 mL), compound VI-2 (121 mg, 0.46 mmol) was added, and the mixture was stirred at 60°C for 6 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, saturated sodium bicarbonate was added to adjust the pH to 9, and ethyl acetate (20 mL x 3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain compound VI-7 (yellow solid, 71 mg, yield 77%).

化合物VI-8的合成 Synthesis of compound VI-8

将化合物VI-7(71mg，0.18mmol)溶于无水乙醇(3mL)，加入10％的钯碳(10mg)，置于氢气氛中，室温搅拌反应4小时。TLC监测反应，待反应完全后，硅藻土抽滤，减压蒸除溶剂，得化合物VI-8(无色油状液体，66mg，收率99％)。Compound VI-7 (71 mg, 0.18 mmol) was dissolved in anhydrous ethanol (3 mL), 10% palladium carbon (10 mg) was added, and the mixture was placed in a hydrogen atmosphere and stirred at room temperature for 4 hours. The reaction was monitored by TLC. After the reaction was complete, diatomaceous earth was used for filtration, and the solvent was evaporated under reduced pressure to obtain compound VI-8 (colorless oily liquid, 66 mg, yield 99%).

化合物VI-9的合成Synthesis of compound VI-9

将化合物VI-8(67mg，0.18mmol)溶于乙酸(2mL)，加入铁粉(10mg)，90℃搅拌反应4小时。TLC监测反应，待反应完全后，硅藻土抽滤，加入饱和碳酸氢钠调pH至9，乙酸乙酯(20mLx3)萃取，合并有机相，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(二氯甲烷:甲醇＝40:1)纯化，得化合物VI-9(淡红色油状液体，40mg，收率63％)。Compound VI-8 (67 mg, 0.18 mmol) was dissolved in acetic acid (2 mL), iron powder (10 mg) was added, and the mixture was stirred at 90°C for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered with diatomaceous earth, saturated sodium bicarbonate was added to adjust the pH to 9, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 40: 1) to obtain compound VI-9 (light red oily liquid, 40 mg, yield 63%).

参照实施例59的方法，将化合物VI-4替换为化合物VI-9制得化合物63(淡绿色油状液体，133mg，收率41％):1H NMR(300MHz,DMSO-d6)δ8.78(s,1H),8.36(d,J＝5.6Hz,1H),7.89(d,J＝8.8Hz,2H),7.70(d,J＝5.6Hz,1H),7.54(d,J＝8.1Hz,2H),7.28-7.20(m,1H),6.96(d,J＝8.2Hz,1H),6.89-6.76(m,2H),5.60(s,2H),4.02(q,J＝7.1Hz,2H),3.85(t,J＝6.3Hz,2H),2.21(t,J＝7.4Hz,2H),1.49-1.39(m,4H),1.29-1.19(m,2H),1.14(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+528.3.Referring to the method of Example 59, compound VI-4 was replaced by compound VI-9 to obtain compound 63 (light green oily liquid, 133 mg, yield 41%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.78 (s, 1H), 8.36 (d, J = 5.6 Hz, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 5.6 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.28-7.20 (m, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.89-6.76 (m, 2 H),5.60(s,2H),4.02(q,J＝7.1Hz,2H),3.85(t,J＝6.3Hz,2H),2.21(t,J＝7.4Hz,2H),1.49-1.39(m,4H),1.29-1.19(m,2H),1.14(t,J＝7.1Hz,3H).MS(ESI) :m/z[M+H] + 528.3.

实施例64Embodiment 64

6-(2-((2-(4-(三氟甲氧基)苯基)-3H-咪唑并[4,5-c]吡啶-3-基)甲基)苯氧基)己酸(化合物62)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-c]pyridin-3-yl)methyl)phenoxy)hexanoic acid (Compound 62)

参照实施例2的方法，将化合物1替换为化合物63制得化合物64(白色固体，25mg，收率20％):1H NMR(300MHz,DMSO-d6)δ11.95(s,1H),8.78(s,1H),8.36(d,J＝5.5Hz,1H),7.88(d,J＝8.7Hz,2H),7.71(d,J＝5.6Hz,1H),7.53(d,J＝8.3Hz,2H),7.28-7.19(m,1H),6.96(d,J＝8.3Hz,1H),6.86-6.76(m,2H),5.60(s,2H),3.85(t,J＝6.3Hz,2H),2.14(t,J＝7.4Hz,2H),1.51-1.35(m,4H),1.25-1.09(m,2H).HRMS(ESI)calcd.for C26H24F3N3O4[M+H]+500.1792,found 500.1786.Referring to the method of Example 2, Compound 1 was replaced by Compound 63 to obtain Compound 64 (white solid, 25 mg, yield 20%): 1 H NMR (300 MHz, DMSO-d 6 )δ11.95(s,1H),8.78(s,1H),8.36(d,J＝5.5Hz,1H),7.88(d,J＝8.7Hz,2H),7.71(d,J＝5.6Hz,1H),7.53(d,J＝8.3Hz,2H),7.28-7.19(m,1H),6.96(d,J＝ 8.3Hz,1H),6.86-6.76(m,2H),5.60(s,2H),3.85(t,J＝6.3Hz,2H),2.14(t,J＝7.4Hz,2H),1.51-1.35(m,4H),1.25-1.09(m,2H).HRMS(ESI)calcd.for C 26 H 24 F 3 N 3 O 4 [M+H] + 500.1792, found 500.1786.

实施例65Embodiment 65

6-(2-((8-(4-(三氟甲氧基)苯基)-9H-嘌呤-9-基)甲基)苯氧基)己酸乙酯(化合物65)

Ethyl 6-(2-((8-(4-(trifluoromethoxy)phenyl)-9H-purin-9-yl)methyl)phenoxy)hexanoate (Compound 65)

化合物VI-10的合成Synthesis of Compound VI-10

将4,6-二氯-5-硝基嘧啶(100mg，0.52mmol)溶于乙醇(6mL)，冰水浴下依次加入N,N-二异丙基乙胺(203mg，1.57mmol)和化合物VI-2(144mg，0.54mmol)，60℃加热搅拌反应6小时。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝15:1)纯化，得化合物VI-10(淡黄色油状液体，148mg，收率68％):1H NMR(300MHz,DMSO-d6)δ8.76(t,J＝5.6Hz,1H),8.43(s,1H),7.23(t,J＝7.8Hz,1H),7.13(d,J＝6.4Hz,1H),6.98(d,J＝8.1Hz,1H),6.88(t,J＝7.4Hz,1H),4.66(d,J＝5.7Hz,2H),4.09-4.02(m,2H),3.99(t,J＝4.3Hz,2H),2.29(t,J＝7.3Hz,2H),1.79-1.65(m,2H),1.64-1.52(m,2H),1.49-1.37(m,2H),1.16(t,J＝7.1Hz,3H).4,6-dichloro-5-nitropyrimidine (100 mg, 0.52 mmol) was dissolved in ethanol (6 mL), and N,N-diisopropylethylamine (203 mg, 1.57 mmol) and compound VI-2 (144 mg, 0.54 mmol) were added in turn under ice-water bath, and stirred at 60°C for 6 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1) to obtain compound VI-10 (light yellow oily liquid, 148 mg, yield 68%): 1 H NMR (300 MHz, DMSO-d 6 )δ8.76(t,J＝5.6Hz,1H),8.43(s,1H),7.23(t,J＝7.8Hz,1H),7.13(d,J＝6.4Hz,1H),6.98(d,J＝8.1Hz,1H),6.88(t,J＝7.4Hz,1H),4.66(d,J＝5.7Hz,2H),4. 09-4.02(m,2H),3.99(t,J＝4.3Hz,2H),2.29(t,J＝7.3Hz,2H),1.79-1.65(m,2H),1.64-1.52(m,2H),1.49-1.37(m,2H),1.16(t,J＝7.1Hz,3H).

化合物VI-11的合成Synthesis of compound VI-11

将化合物VI-10(50mg，0.12mmol)溶于无水乙醇(4mL)，加入10％的钯碳(50mg)，置于氢气氛围中，室温搅拌反应6小时。TLC监测反应，待反应完全后，硅藻土抽滤，减压蒸除溶剂，加入饱和碳酸氢钠调pH至9，乙酸乙酯(20mLx3)萃取，合并有机相，无水硫酸钠干燥，得化合物VI-11(黄绿色油状液体，30mg，收率71％):1H NMR(300MHz,DMSO-d6)δ7.86(s,1H),7.55(s,1H),7.25-7.11(m,2H),6.96(d,J＝8.0Hz,1H),6.86(t,J＝7.3Hz,1H),6.63(t,J＝5.3Hz,1H),4.81(s,2H),4.57(d,J＝5.4Hz,2H),4.08-3.96(m,4H),2.29(t,J＝7.2Hz,2H),1.79-1.67(m,2H),1.64-1.52(m,2H),1.50-1.38(m,2H),1.16(t,J＝7.1Hz,3H).Compound VI-10 (50 mg, 0.12 mmol) was dissolved in anhydrous ethanol (4 mL), 10% palladium carbon (50 mg) was added, and the mixture was placed in a hydrogen atmosphere and stirred at room temperature for 6 hours. The reaction was monitored by TLC. After the reaction was complete, diatomaceous earth was filtered, the solvent was evaporated under reduced pressure, saturated sodium bicarbonate was added to adjust the pH to 9, and ethyl acetate (20 mL x 3) was used for extraction. The organic phases were combined and dried over anhydrous sodium sulfate to obtain compound VI-11 (yellow-green oily liquid, 30 mg, yield 71%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.86(s,1H),7.55(s,1H),7.25-7.11(m,2H),6.96(d,J＝8.0Hz,1H),6.86(t,J＝7.3Hz,1H),6.63(t,J＝5.3Hz,1H),4.81(s,2H),4.57(d,J＝5.4Hz,2H) ,4.08-3.96(m,4H),2.29(t,J＝7.2Hz,2H),1.79-1.67(m,2H),1.64-1.52(m,2H),1.50-1.38(m,2H),1.16(t,J＝7.1Hz,3H).

参照实施例59的方法，将化合物VI-4替换为化合物VI-11制得化合物65(淡黄色油状液体，144mg，收率44％):1H NMR(300MHz,DMSO-d6)δ9.24(s,1H),8.97(s,1H),7.84(d,J＝8.6Hz,2H),7.49(d,J＝8.3Hz,2H),7.26-7.11(m,1H),6.92(d,J＝8.2Hz,1H),6.76-6.63(m,2H),5.58(s,2H),4.03(q,J＝7.1Hz,2H),3.84(t,J＝6.2Hz,2H),2.24(t,J＝7.3Hz,2H),1.56-1.31(m,4H),1.29-1.20(m,2H),1.15(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na]+551.2.Referring to the method of Example 59, Compound VI-4 was replaced by Compound VI-11 to obtain Compound 65 (light yellow oily liquid, 144 mg, yield 44%): 1 H NMR (300 MHz, DMSO-d 6 )δ9.24(s,1H),8.97(s,1H),7.84(d,J＝8.6Hz,2H),7.49(d,J＝8.3Hz,2H),7.26-7.11(m,1H),6.92(d,J＝8.2Hz,1H),6.76-6.63(m,2H),5.58(s,2H),4 .03(q,J＝7.1Hz,2H),3.84(t,J＝6.2Hz,2H),2.24(t,J＝7.3Hz,2H),1.56-1.31(m,4H),1.29-1.20(m,2H),1.15(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na] + 551.2 .

实施例66Embodiment 66

6-(2-((8-(4-(三氟甲氧基)苯基)-9H-嘌呤-9-基)甲基)苯氧基)己酸(化合物66)
6-(2-((8-(4-(trifluoromethoxy)phenyl)-9H-purin-9-yl)methyl)phenoxy)hexanoic acid (Compound 66)

参照实施例2的方法，将化合物1替换为化合物65制得化合物66(白色固体，80mg，收率59％):1H NMR(300MHz,DMSO-d6)δ11.97(s,1H),9.24(s,1H),8.97(s,1H),7.84(d,J＝8.7Hz,2H),7.49(d,J＝8.2Hz,2H),7.23-7.12(m,1H),6.92(d,J＝8.2Hz,1H), 6.75-6.63(m,2H),5.58(s,2H),3.83(t,J＝6.2Hz,2H),2.17(t,J＝7.3Hz,2H),1.51-1.33(m,4H),1.28-1.14(m,2H).HRMS(ESI)calcd.for C25H23F3N4O4[M+H]+501.1744,found501.1749.Referring to the method of Example 2, Compound 1 was replaced by Compound 65 to obtain Compound 66 (white solid, 80 mg, yield 59%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.97 (s, 1H), 9.24 (s, 1H), 8.97 (s, 1H), 7.84 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.23-7.12 (m, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.75-6.63(m,2H),5.58(s,2H),3.83(t,J＝6.2Hz,2H),2.17(t,J＝7.3Hz,2H),1.51-1.33(m,4H),1.28-1.14(m,2H).HRMS(ESI)calcd.for C 25 H 23 F 3 N 4 O 4 [M+H] + 501.1744,found501.1749.

实施例67Embodiment 67

6-(2-((2-(4-(4-(三氟甲氧基)苯基))-1H-咪唑并[4,5-b]吡嗪-1-基)甲基)苯氧基)己酸乙酯(化合物67)
Ethyl 6-(2-((2-(4-(4-(trifluoromethoxy)phenyl))-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)phenoxy)hexanoate (Compound 67)

化合物VII-1的合成Synthesis of Compound VII-1

冰水浴下将二甲胺盐酸盐(3.1g，38mmol)溶于二氯甲烷(20mL)，依次加入N,N-二异丙基乙胺(DIPEA)(7.82g，60.5mmol)和4-三氟甲氧基苯甲酰氯(4.28g，19mmol)，缓慢升至室温搅拌反应4小时。TLC监测反应，待反应完全后，加入乙酸乙酯(150mL)稀释，水(50mLx3)洗涤，1M盐酸(50mLx3)洗涤，饱和碳酸氢钠(50mLx3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，得化合物VII-1(淡黄色固体，3.73g，收率84％)。Under an ice-water bath, dimethylamine hydrochloride (3.1 g, 38 mmol) was dissolved in dichloromethane (20 mL), and N, N-diisopropylethylamine (DIPEA) (7.82 g, 60.5 mmol) and 4-trifluoromethoxybenzoyl chloride (4.28 g, 19 mmol) were added in sequence, and the temperature was slowly raised to room temperature and stirred for 4 hours. The reaction was monitored by TLC, and after the reaction was complete, ethyl acetate (150 mL) was added to dilute, and the mixture was washed with water (50 mL x 3), 1M hydrochloric acid (50 mL x 3), saturated sodium bicarbonate (50 mL x 3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain compound VII-1 (light yellow solid, 3.73 g, yield 84%).

化合物VII-2的合成Synthesis of Compound VII-2

将邻羟基苯甲腈(2g，16.8mmol)溶于N,N-二甲基甲酰胺(20mL)，依次加入碳酸钾(4.6g，33.3mmol)和溴化苄(3.2g，18.5mmol)，室温搅拌反应3小时。TLC监测反应，待反应完全后，抽滤除去碳酸钾，加入乙酸乙酯(100mL)稀释，水(50mLx3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝30:1)纯化，得化合物VII-2(白色固体，3g，收率86％)。o-Hydroxybenzonitrile (2g, 16.8mmol) was dissolved in N,N-dimethylformamide (20mL), potassium carbonate (4.6g, 33.3mmol) and benzyl bromide (3.2g, 18.5mmol) were added in sequence, and the mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC, and after the reaction was complete, potassium carbonate was removed by suction filtration, ethyl acetate (100mL) was added for dilution, water (50mLx3) was added for washing, and the mixture was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain compound VII-2 (white solid, 3g, yield 86%).

化合物VII-3的合成Synthesis of Compound VII-3

冰水浴下将四氢铝锂(54mg，1.42mmol)悬浮于无水四氢呋喃(2mL)，逐滴加入化合物VII-2(200mg，0.96mmol)的无水四氢呋喃(1mL)溶液，60℃加热搅拌反应3小时。TLC监测反应，待反应完全后，加入乙醚(5mL)稀释，冰水浴下滴加水(200μL)， 加入15％氢氧化钠水溶液(200μL)、水(600μL)，升至室温搅拌15min，加入无水硫酸镁(200mg)搅拌15min，硅藻土抽滤，减压蒸除溶剂，得化合物VII-3(淡黄色油状液体，194mg，收率95％)。Lithium aluminum tetrahydride (54 mg, 1.42 mmol) was suspended in anhydrous tetrahydrofuran (2 mL) under an ice-water bath, and a solution of compound VII-2 (200 mg, 0.96 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred and heated at 60°C for 3 hours. The reaction was monitored by TLC, and after the reaction was complete, ether (5 mL) was added for dilution, and water (200 μL) was added dropwise under an ice-water bath. Add 15% aqueous sodium hydroxide solution (200 μL) and water (600 μL), warm to room temperature and stir for 15 min, add anhydrous magnesium sulfate (200 mg) and stir for 15 min, filter through celite, and evaporate the solvent under reduced pressure to obtain compound VII-3 (light yellow oily liquid, 194 mg, yield 95%).

化合物VII-4的合成Synthesis of Compound VII-4

将化合物VII-3(2.9g，13.6mmol)溶于N-甲基吡咯烷酮(10mL)，依次加入N,N-二异丙基乙胺(DIPEA)(860mg，6.65mmol)和2-氨基-3-氯吡嗪(587mg，4.53mmol)，130℃搅拌反应8小时。TLC监测反应，待反应完全后，加入乙酸乙酯(50mL)稀释，水(20mLx3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝3:1)纯化，得化合物VII-4(淡黄色油状液体，606mg，收率44％)。Compound VII-3 (2.9 g, 13.6 mmol) was dissolved in N-methylpyrrolidone (10 mL), and N,N-diisopropylethylamine (DIPEA) (860 mg, 6.65 mmol) and 2-amino-3-chloropyrazine (587 mg, 4.53 mmol) were added in sequence, and stirred at 130°C for 8 hours. The reaction was monitored by TLC, and after the reaction was complete, ethyl acetate (50 mL) was added for dilution, washed with water (20 mL x 3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain compound VII-4 (light yellow oily liquid, 606 mg, yield 44%).

化合物VII-5的合成Synthesis of Compound VII-5

将化合物VII-4(922mg，3.95mmol)溶于无水1,2-二氯乙烷(6mL)，逐滴加入草酰氯(510mg，40.2mmol)，35℃搅拌反应2h，逐滴加入化合物VII-1(606mg，1.99mmol)的无水1,2-二氯乙烷(2mL)溶液，35℃搅拌反应2h，升至85℃搅拌反应8h。TLC监测反应，待反应完全后，加入乙酸乙酯(60mL)稀释，饱和碳酸氢钠(30mLx3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝8:1)纯化，经石油醚和乙酸乙酯(10:1)的混合溶液打浆，得化合物VII-5(白色固体，300mg，收率32％)。Compound VII-4 (922 mg, 3.95 mmol) was dissolved in anhydrous 1,2-dichloroethane (6 mL), oxalyl chloride (510 mg, 40.2 mmol) was added dropwise, and the mixture was stirred at 35 ° C for 2 h. A solution of compound VII-1 (606 mg, 1.99 mmol) in anhydrous 1,2-dichloroethane (2 mL) was added dropwise, and the mixture was stirred at 35 ° C for 2 h, and the mixture was stirred at 85 ° C for 8 h. The reaction was monitored by TLC. After the reaction was complete, ethyl acetate (60 mL) was added for dilution, and the mixture was washed with saturated sodium bicarbonate (30 mL x 3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1), and slurried with a mixed solution of petroleum ether and ethyl acetate (10: 1) to obtain compound VII-5 (white solid, 300 mg, yield 32%).

化合物VII-6的合成Synthesis of Compound VII-6

将化合物VII-5(50mg，0.1mmol)溶于四氢呋喃(4mL)，加入10％的钯碳(20mg)，置于氢气氛围中，室温搅拌反应12小时。TLC监测反应，待反应完全后，硅藻土抽滤，减压蒸除溶剂，经石油醚(10mL)和乙酸乙酯(2mL)的混合溶液打浆，得化合物VII-6(白色固体，35mg，收率85％):1H NMR(300MHz,DMSO-d6)δ9.77(s,1H),8.58(d,J＝2.7Hz,1H),8.43(d,J＝2.6Hz,1H),7.94(d,J＝8.7Hz,2H),7.55(d,J＝8.2Hz,2H),7.11-7.00(m,1H),6.79(d,J＝8.0Hz,1H),6.65-6.54(m,2H),5.56(s,2H).Compound VII-5 (50 mg, 0.1 mmol) was dissolved in tetrahydrofuran (4 mL), 10% palladium carbon (20 mg) was added, and the mixture was placed in a hydrogen atmosphere and stirred at room temperature for 12 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered through diatomaceous earth, the solvent was evaporated under reduced pressure, and the mixture was slurried with a mixed solution of petroleum ether (10 mL) and ethyl acetate (2 mL) to obtain compound VII-6 (white solid, 35 mg, yield 85%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.77 (s, 1H), 8.58 (d, J = 2.7 Hz, 1H), 8.43 (d, J = 2.6 Hz, 1H), 7.94 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.11-7.00 (m, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.65-6.54 (m, 2H), 5.56 (s, 2H).

化合物67的合成Synthesis of compound 67

将化合物VII-6(114mg，0.30mmol)溶于N,N-二甲基甲酰胺(3mL)，加入碳酸铯(144mg，0.44mmol)，6-溴己酸乙酯(73mg，0.33mmol)，室温搅拌反应4小时。TLC监测反应，待反应完全后，抽滤除去碳酸铯，加入乙酸乙酯(50mL)稀释，用水(30mL x3)洗涤，合并有机相，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝10:1)纯化，得化合物67(无色油状液体，111mg，收率71％):1H NMR(300MHz,DMSO-d6)δ8.58(d,J＝2.6Hz,1H),8.44(d,J＝2.6Hz,1H),7.89(d,J＝8.8Hz,2H),7.51(d,J＝8.3Hz,2H),7.18(t,J＝7.4Hz,1H),6.93(d,J＝8.3Hz,1H),6.78-6.67(m,2H),5.60(s,2H),4.02(q,J＝7.1Hz,2H),3.85(t,J＝6.2Hz,2H),2.23(t,J＝7.4Hz,2H),1.54-1.35(m,4H),1.26-1.22(m,2H),1.14(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na]+551.17677.Compound VII-6 (114 mg, 0.30 mmol) was dissolved in N, N-dimethylformamide (3 mL), cesium carbonate (144 mg, 0.44 mmol) and ethyl 6-bromohexanoate (73 mg, 0.33 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. After the reaction was complete, cesium carbonate was removed by suction filtration, ethyl acetate (50 mL) was added for dilution, and the mixture was washed with water (30 mL x3). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound 67 (colorless oily liquid, 111 mg, yield 71%): 1 H NMR (300 MHz, DMSO-d 6 )δ8.58(d,J＝2.6Hz,1H),8.44(d,J＝2.6Hz,1H),7.89(d,J＝8.8Hz,2H),7.51(d,J＝8.3Hz,2H),7.18(t,J＝7.4Hz,1H),6.93(d,J＝8.3Hz,1H),6.78-6.67(m, 2H),5.60(s,2H),4.02(q,J＝7.1Hz,2H),3.85(t,J＝6.2Hz,2H),2.23(t,J＝7.4Hz,2H),1.54-1.35(m,4H),1.26-1.22(m,2H),1.14(t,J＝7.1Hz,3H).MS( ESI):m/z[M+Na] + 551.17677.

实施例68Embodiment 68

6-(2-((2-(4-(4-(三氟甲氧基)苯基))-1H-咪唑并[4,5-b]吡嗪-1-基)甲基)苯氧基)己酸(化合物68)
6-(2-((2-(4-(4-(trifluoromethoxy)phenyl))-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)phenoxy)hexanoic acid (Compound 68)

参照实施例2的方法，将化合物1替换为化合物67制得化合物68(白色固体，65mg，收率31％):1H NMR(300MHz,DMSO-d6)δ11.98(s,1H),8.58(d,J＝2.6Hz,1H),8.45(d,J＝2.6Hz,1H),7.89(d,J＝8.7Hz,2H),7.51(d,J＝8.2Hz,2H),7.24-7.12(m,1H),6.93(d,J＝8.3Hz,1H),6.77-6.65(m,2H),5.61(s,2H),3.84(t,J＝6.2Hz,2H),2.16(t,J＝7.3Hz,2H),1.52-1.30(m,4H),1.27-1.11(m,2H).MS(ESI):m/z[M+Na]+523.16489.Referring to the method of Example 2, Compound 1 was replaced by Compound 67 to obtain Compound 68 (white solid, 65 mg, yield 31%): 1 H NMR (300 MHz, DMSO-d 6 )δ11.98(s,1H),8.58(d,J＝2.6Hz,1H),8.45(d,J＝2.6Hz,1H),7.89(d,J＝8.7Hz,2H),7.51(d,J＝8.2Hz,2H),7.24-7.12(m,1H),6.93(d,J＝8.3Hz,1H),6. 77-6.65(m,2H),5.61(s,2H),3.84(t,J＝6.2Hz,2H),2.16(t,J＝7.3Hz,2H),1.52-1.30(m,4H),1.27-1.11(m,2H).MS(ESI):m/z[M+Na] + 523.16489.

实施例69Embodiment 69

2-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯甲酸乙酯(化合物69)
Ethyl 2-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)benzoate (Compound 69)

化合物VIII-1的合成Synthesis of compound VIII-1

将邻甲基苯甲酸(3.0g，22mmol)溶于乙醇(50mL)，缓慢加入浓硫酸(4.4mL)，80℃加热搅拌反应4小时。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝10:1)纯化，得化合物VIII-1(浅黄色油状液体，3.54g，收率96％)。o-Toluic acid (3.0 g, 22 mmol) was dissolved in ethanol (50 mL), concentrated sulfuric acid (4.4 mL) was slowly added, and the mixture was stirred at 80°C for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound VIII-1 (light yellow oily liquid, 3.54 g, yield 96%).

化合物VIII-2的合成Synthesis of compound VIII-2

将VIII-1(3.54g，21.6mmol)溶于四氯化碳(137mL)，加入N-溴代丁二酰亚胺(4.11g，23.1mmol)，加入偶氮二异丁腈(361mg，2.2mmol)，升温至80℃回流5小时。TLC监测反应，待反应完全后，减压蒸除溶剂，加入水(100mL)，乙酸乙酯(100mL x3)萃取，无水硫酸钠干燥，残余物经硅胶柱层析(石油醚:乙酸乙酯＝40:1)纯化，得化合物VIII-2(黄色油状液体，2.67g，收率50％)。VIII-1 (3.54 g, 21.6 mmol) was dissolved in carbon tetrachloride (137 mL), N-bromosuccinimide (4.11 g, 23.1 mmol) was added, azobisisobutyronitrile (361 mg, 2.2 mmol) was added, and the temperature was raised to 80 ° C and refluxed for 5 hours. TLC was used to monitor the reaction. After the reaction was complete, the solvent was evaporated under reduced pressure, water (100 mL) was added, and ethyl acetate (100 mL x 3) was extracted, and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40: 1) to obtain compound VIII-2 (yellow oily liquid, 2.67 g, yield 50%).

化合物VIII-3的合成Synthesis of compound VIII-3

将化合物I-4(1.53g，5.49mmol)溶于N,N-二甲基甲酰胺溶液(45mL)，依次加入碳酸铯(5.37g，16.47mmol)，VIII-2(2.67g，10.98mmol)，室温搅拌反应6小时。TLC监测反应，待反应完全后，抽滤除去碳酸铯，加入乙酸乙酯(150mL)稀释，水(100mLx3)洗涤，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝20:1→15:1)纯化，得化合物VIII-3(浅黄色固体，895mg，收率37％)。Compound I-4 (1.53 g, 5.49 mmol) was dissolved in N, N-dimethylformamide solution (45 mL), and cesium carbonate (5.37 g, 16.47 mmol) and VIII-2 (2.67 g, 10.98 mmol) were added in sequence, and the mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC, and after the reaction was complete, cesium carbonate was removed by suction filtration, ethyl acetate (150 mL) was added for dilution, water (100 mL x 3) was added for washing, and the mixture was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1 → 15: 1) to obtain compound VIII-3 (light yellow solid, 895 mg, yield 37%).

化合物VIII-4的合成Synthesis of compound VIII-4

将化合物VIII-3(895mg，2.03mmol)溶于无水四氢呋喃(15mL)，在冰水浴条件 下，缓慢滴入三乙基硼氢化锂(1M，4mL，4mmol)，缓慢升至室温搅拌反应8小时。TLC监测反应，待反应完全后，加入水(15mL)淬灭反应，乙酸乙酯(30mL x3)萃取，无水硫酸钠干燥，减压蒸除溶剂，残余物悬浮于无水乙醚溶液(10mL)，室温搅拌，抽滤得化合物VIII-4(白色固体，534mg，收率66％)：1H NMR(300MHz,DMSO-d6)δ7.91–7.69(m,3H),7.58–6.98(m,9H),6.39(d,J＝7.5Hz,1H),5.66(s,2H),4.60(s,2H).Compound VIII-3 (895 mg, 2.03 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) and stirred in an ice-water bath. Under 40 ℃, slowly drip lithium triethylborohydride (1M, 4mL, 4mmol), slowly warm to room temperature and stir to react for 8 hours. TLC monitors the reaction. After the reaction is complete, water (15mL) is added to quench the reaction, extracted with ethyl acetate (30mL x3), dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is suspended in anhydrous ether solution (10mL), stirred at room temperature, and filtered to obtain compound VIII-4 (white solid, 534mg, yield 66%): 1H NMR (300MHz, DMSO- d6 ) δ7.91-7.69 (m, 3H), 7.58-6.98 (m, 9H), 6.39 (d, J = 7.5Hz, 1H), 5.66 (s, 2H), 4.60 (s, 2H).

化合物69的合成Synthesis of compound 69

将VIII-4(199mg，0.5mmol)，三苯基膦(197mg，0.75mg)加入史莱克试管，在氩气的保护下，加入2-羟基苯甲酸乙酯的无水四氢呋喃溶液(114mg，0.75mmol，3mL dryTHF)，在冰水浴条件下，缓慢滴入偶氮二甲酸二异丙酯的无水四氢呋喃溶液(148μL，0.75mmol，2mL dryTHF)，缓慢升温至室温搅拌4小时。TLC监测反应，待反应完全后，残余物经硅胶柱层析(石油醚:乙酸乙酯＝7:1)纯化,得化合物69(白色固体，172mg，收率63％)：1H NMR(300MHz,DMSO-d6)δ7.83–7.76(m,3H),7.73–7.66(m,2H),7.62–7.54(m,1H),7.44(d,J＝8.3Hz,2H),7.39(d,J＝7.7Hz,1H),7.30(d,J＝7.8Hz,2H),7.27–7.17(m,3H),7.10–7.02(m,1H),6.48(d,J＝7.6Hz,1H),5.82(s,2H),5.34(s,2H),3.70(s,3H).MS(ESI):m/z[M+H]+533.2.VIII-4 (199 mg, 0.5 mmol) and triphenylphosphine (197 mg, 0.75 mg) were added to a Shrek test tube. Under the protection of argon, an anhydrous tetrahydrofuran solution of ethyl 2-hydroxybenzoate (114 mg, 0.75 mmol, 3 mL dryTHF) was added. In an ice-water bath, an anhydrous tetrahydrofuran solution of diisopropyl azodicarboxylate (148 μL, 0.75 mmol, 2 mL dryTHF) was slowly added dropwise. The temperature was slowly raised to room temperature and stirred for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7:1) to obtain compound 69 (white solid, 172 mg, yield 63%): 1 H NMR (300MHz, DMSO-d6) δ7.83–7.76(m,3H),7.73–7.66(m,2H),7.62–7.54(m,1H),7.44(d,J＝8.3Hz,2H),7.39(d,J＝7.7Hz,1H),7.30(d,J＝7.8Hz,2H),7.27– 7.17(m,3H),7.10–7.02(m,1H),6.48(d,J＝7.6Hz,1H),5.82(s,2H),5.34(s,2H),3.70(s,3H).MS(ESI):m/z[M+H] + 533.2.

实施例70Embodiment 70

2-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯甲酸(化合物70)
2-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)benzoic acid (Compound 70)

参照实施例2的方法，将化合物1替换为化合物69制得化合物70(白色固体，44mg，收率87％):1H NMR(300MHz,DMSO-d6)δ12.83(s,1H),7.87(dd,J＝8.4,6.5Hz,3H),7.73–7.65(m,2H),7.50(dq,J＝25.1,9.3Hz,6H),7.36–7.29(m,1H),7.26–7.16(m,2H),7.07–6.99(m,1H),6.61(d,J＝7.7Hz,1H),5.88(s,2H),5.31(s,2H).HRMS(ESI)calcd.for C29H21F3N2O4[M+H]+519.1532,found 519.1519.Referring to the method of Example 2, compound 1 was replaced by compound 69 to obtain compound 70 (white solid, 44 mg, yield 87%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.83 (s, 1H), 7.87 (dd, J = 8.4, 6.5 Hz, 3H), 7.73-7.65 (m, 2H), 7.50 (dq, J = 25.1, 9.3 Hz, 6H), 7.36-7.29 (m, 1H), 7.26-7.16 (m, 2H), 7.07-6.99 (m, 1H), 6.61 (d, J = 7.7 Hz, 1H), 5.88 (s, 2H), 5.31 (s, 2H). HRMS (ESI) calcd. for C 29 H 21 F 3 N 2 O 4 [M+H] + 519.1532, found 519.1519.

实施例71Embodiment 71

3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯甲酸乙酯(化合物71)
Ethyl 3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)benzoate (Compound 71)

参照化合物69的合成方法，将化合物2-羟基苯甲酸乙酯替换为3-羟基苯甲酸乙酯制得化合物71(白色固体，145mg，收率95％)：1H NMR(300MHz,DMSO-d6)δ7.82–7.74(m,3H),7.55(ddd,J＝10.4,4.4,2.2Hz,3H),7.49–7.47(m,1H),7.46–7.37(m,3H),7.30(s,1H),7.28–7.25(m,2H),7.23(d,J＝1.6Hz,1H),7.22–7.17(m,1H),6.45(d,J＝7.2Hz,1H),5.74(s,2H),5.30(s,2H),4.30(q,J＝7.1Hz,2H),1.32(d,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+547.2. Referring to the synthesis method of compound 69, the compound 2-hydroxybenzoic acid ethyl ester was replaced with 3-hydroxybenzoic acid ethyl ester to prepare compound 71 (white solid, 145 mg, yield 95%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.82–7.74(m,3H),7.55(ddd,J＝10.4,4.4,2.2Hz,3H),7.49–7.47(m,1H),7.46–7.37(m,3H),7.30(s,1H),7.28–7.25(m,2H),7.23(d,J＝1.6Hz,1H) ,7.22–7.17(m,1H),6.45(d,J＝7.2Hz,1H),5.74(s,2H),5.30(s,2H),4.30(q,J＝7.1Hz,2H),1.32(d,J＝7.1Hz,3H).MS(ESI):m/z[M+H] + 547.2.

实施例72Embodiment 72

3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯甲酸(化合物72)
3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)benzoic acid (Compound 72)

参照实施例2的方法，将化合物1替换为化合物71制得化合物72(白色固体，78mg，收率60％)：1H NMR(300MHz,DMSO-d6)δ12.91(s,1H),7.79(dd,J＝15.0,7.8Hz,3H),7.60–7.54(m,3H),7.49(d,J＝8.3Hz,2H),7.43–7.37(m,2H),7.34–7.29(m,1H),7.29–7.19(m,4H),6.44(d,J＝7.6Hz,1H),5.75(s,2H),5.30(s,2H).HRMS(ESI)calcd.for C29H21F3N2O4[M+H]+519.1532,found 519.1516Referring to the method of Example 2, compound 1 was replaced by compound 71 to obtain compound 72 (white solid, 78 mg, yield 60%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.91 (s, 1H), 7.79 (dd, J = 15.0, 7.8 Hz, 3H), 7.60-7.54 (m, 3H), 7.49 (d, J = 8.3 Hz, 2H), 7.43-7.37 (m, 2H), 7.34-7.29 (m, 1H), 7.29-7.19 (m, 4H), 6.44 (d, J = 7.6 Hz, 1H), 5.75 (s, 2H), 5.30 (s, 2H). HRMS (ESI) calcd. for C 29 H 21 F 3 N 2 O 4 [M+H] + 519.1532, found 519.1516

实施例73Embodiment 73

2-(2-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸乙酯(化合物73)
Ethyl 2-(2-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetate (Compound 73)

参照化合物69的合成方法，将化合物2-羟基苯甲酸乙酯替换为2-羟基-苯乙酸乙酯制得化合物73(无色油状液体，115mg，收率84％)：1H NMR(300MHz,DMSO-d6)δ7.54–7.46(m,4H),7.39(d,J＝8.1Hz,2H),7.32–7.26(m,4H),7.23–7.15(m,3H),7.08(d,J＝8.4Hz,1H),6.93(d,J＝7.6Hz,1H),6.46(d,J＝7.6Hz,1H),5.72(s,2H),5.21(s,2H),3.57(s,2H),3.37(s,3H).MS(ESI):m/z[M+H]+547.2.Referring to the synthesis method of compound 69, compound 73 (colorless oily liquid, 115 mg, yield 84%) was prepared by replacing ethyl 2-hydroxybenzoate with ethyl 2-hydroxy-phenylacetate: 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.54–7.46 (m, 4H), 7.39 (d, J = 8.1 Hz, 2H), 7.32–7.26 (m, 4H), 7.23–7.15 (m, 3H), 7.08 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.46 (d, J = 7.6 Hz, 1H), 5.72 (s, 2H), 5.21 (s, 2H), 3.57 (s, 2H), 3.37 (s, 3H). MS (ESI): m/z [M+H] + 547.2.

实施例74Embodiment 74

2-(2-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸(化合物74)
2-(2-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetic acid (Compound 74)

参照实施例2的方法，将化合物1替换为化合物73制得化合物74(白色固体，53mg，收率48％)：1H NMR(300MHz,DMSO-d6)δ12.05(s,1H),7.87–7.80(m,3H),7.63–7.57(m,1H),7.55–7.47(m,3H),7.38–7.28(m,3H),7.25–7.16(m,3H),7.07(d,J＝8.1Hz,1H),6.93(td,J＝7.4,1.0Hz,1H),6.51(d,J＝7.7Hz,1H),5.77(s,2H),5.24(s,2H),3.52(s,2H).HRMS(ESI)calcd.for C30H23F3N2O4[M+H]+533.1688,found 533.1669.Referring to the method of Example 2, compound 1 was replaced by compound 73 to obtain compound 74 (white solid, 53 mg, yield 48%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.05 (s, 1H), 7.87–7.80 (m, 3H), 7.63–7.57 (m, 1H), 7.55–7.47 (m, 3H), 7.38–7.28 (m, 3H), 7.25–7.16 (m, 3H), 7.07 (d, J=8.1 Hz, 1H), 6.93 (td, J=7.4, 1.0 Hz, 1H), 6.51 (d, J=7.7 Hz, 1H), 5.77 (s, 2H), 5.24 (s, 2H), 3.52 (s, 2H). HRMS (ESI) calcd. for C 30 H 23 F 3 N 2 O 4 [M+H] + 533.1688, found 533.1669.

实施例75 Embodiment 75

2-(3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸乙酯(化合物75)
Ethyl 2-(3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetate (Compound 75)

参照化合物69的合成方法，将化合物2-羟基苯甲酸乙酯替换为3-羟基-苯乙酸乙酯制得化合物75(白色固体，43mg，收率51％)：1H NMR(300MHz,Chloroform-d)δ7.89(d,J＝7.9Hz,1H),7.69(d,J＝8.7Hz,2H),7.51(d,J＝7.2Hz,1H),7.37–7.26(m,5H),7.23–7.11(m,2H),6.92–6.73(m,5H),5.59(s,2H),5.08(s,2H),4.12(t,J＝7.1Hz,2H),3.56(s,2H),1.24(d,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+561.2.Referring to the synthesis method of compound 69, compound 75 (white solid, 43 mg, yield 51%) was prepared by replacing ethyl 2-hydroxybenzoate with ethyl 3-hydroxy-phenylacetate: 1 H NMR (300 MHz, Chloroform-d) δ7.89 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 7.2 Hz, 1H), 7.37–7.26 (m, 5H), 7.23–7.11 (m, 2H), 6.92–6.73 (m, 5H), 5.59 (s, 2H), 5.08 (s, 2H), 4.12 (t, J = 7.1 Hz, 2H), 3.56 (s, 2H), 1.24 (d, J = 7.1 Hz, 3H). MS (ESI): m/z [M+H] + 561.2.

实施例76Embodiment 76

2-(3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸(化合物76)
2-(3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetic acid (Compound 76)

参照实施例2的方法，将化合物1替换为化合物75制得化合物76(白色固体，79mg，收率92％)：1H NMR(300MHz,DMSO-d6)δ12.32(s,1H),7.83–7.76(m,3H),7.57(s,1H),7.57–7.48(m,3H),7.40(d,J＝7.4Hz,1H),7.28(d,J＝6.9Hz,3H),7.21(d,J＝7.1Hz,2H),6.91–6.84(m,3H),6.46(d,J＝7.6Hz,1H),5.73(s,2H),5.20(s,2H),3.52(s,2H).HRMS(ESI)calcd.for C30H23F3N2O4[M+H]+533.1688,found 533.1672.Referring to the method of Example 2, compound 1 was replaced by compound 75 to obtain compound 76 (white solid, 79 mg, yield 92%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.32 (s, 1H), 7.83-7.76 (m, 3H), 7.57 (s, 1H), 7.57-7.48 (m, 3H), 7.40 (d, J = 7.4 Hz, 1H), 7.28 (d, J = 6.9 Hz, 3H), 7.21 (d, J = 7.1 Hz, 2H), 6.91-6.84 (m, 3H), 6.46 (d, J = 7.6 Hz, 1H), 5.73 (s, 2H), 5.20 (s, 2H), 3.52 (s, 2H). HRMS (ESI) calcd. for C 30 H 23 F 3 N 2 O 4 [M+H] + 533.1688, found 533.1672.

实施例77Embodiment 77

2-(4-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸乙酯(化合物77)
Ethyl 2-(4-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetate (Compound 77)

参照化合物69的合成方法，将化合物2-羟基苯甲酸乙酯替换为4-羟基-苯乙酸乙酯制得化合物77(白色固体，200mg，74％)：1H NMR(300MHz,DMSO-d6)δ7.81(dd,J＝9.0,7.2Hz,3H),7.57(dd,J＝7.5,1.5Hz,1H),7.51(d,J＝8.3Hz,2H),7.41(dd,J＝7.2,1.9Hz,1H),7.26(dddd,J＝27.0,13.8,7.0,2.0Hz,6H),6.98–6.89(m,2H),6.50(d,J＝7.5Hz,1H),5.75(s,2H),5.22(s,2H),4.08(q,J＝7.1Hz,2H),3.60(s,2H),1.19(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na]+583.3.Referring to the synthesis method of compound 69, the compound 2-hydroxybenzoic acid ethyl ester was replaced with 4-hydroxy-phenylacetic acid ethyl ester to obtain compound 77 (white solid, 200 mg, 74%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.81(dd,J＝9.0,7.2Hz,3H),7.57(dd,J＝7.5,1.5Hz,1H),7.51(d,J＝8.3Hz,2H),7.41(dd,J＝7.2,1.9Hz,1H),7.26(dddd,J＝27.0,13.8,7.0,2.0Hz,6H),6.98 –6.89(m,2H),6.50(d,J＝7.5Hz,1H),5.75(s,2H),5.22(s,2H),4.08(q,J＝7.1Hz,2H),3.60(s,2H),1.19(t,J＝7.1Hz,3H).MS(ESI):m/z[M+Na] + 583.3.

实施例78Embodiment 78

2-(4-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸(化合物78)
2-(4-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetic acid (Compound 78)

参照实施例2的方法，将化合物1替换为化合物77制得化合物78(白色固体，100mg，52％)：1H NMR(300MHz,DMSO-d6)δ12.26(s,1H),7.85–7.73(m,3H),7.52(dd,J＝16.6,7.8Hz,3H),7.38(d,J＝8.1Hz,1H),7.23(ddd,J＝31.0,15.5,7.9Hz,6H),6.90(d,J＝8.5Hz,2H),6.47(d,J＝7.5Hz,1H),5.72(s,2H),5.19(s,2H),3.48(s,2H).HRMS(ESI)calcd.for C30H23F3N2O4[M+H]+533.1683,found 533.1679.Referring to the method of Example 2, Compound 1 was replaced by Compound 77 to obtain Compound 78 (white solid, 100 mg, 52%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.26 (s, 1H), 7.85–7.73 (m, 3H), 7.52 (dd, J=16.6, 7.8 Hz, 3H), 7.38 (d, J=8.1 Hz, 1H), 7.23 (ddd, J=31.0, 15.5, 7.9 Hz, 6H), 6.90 (d, J=8.5 Hz, 2H), 6.47 (d, J=7.5 Hz, 1H), 5.72 (s, 2H), 5.19 (s, 2H), 3.48 (s, 2H). HRMS (ESI) calcd. for C 30 H 23 F 3 N 2 O 4 [M+H] + 533.1683, found 533.1679.

实施例79Embodiment 79

3-(3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)丙酸乙酯(化合物79)
Ethyl 3-(3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)propanoate (Compound 79)

参照化合物69的合成方法，将化合物2-羟基苯甲酸乙酯替换为3-羟基-苯丙酸乙酯制得化合物79(白色固体，61mg，收率42％):1H NMR(300MHz,DMSO-d6)δ7.82–7.75(m,3H),7.51(dd,J＝19.3,7.8Hz,3H),7.41–7.36(m,1H),7.31–7.14(m,5H),6.80(d,J＝9.3Hz,3H),6.46(d,J＝7.6Hz,1H),5.71(s,2H),5.18(s,2H),4.02(q,J＝7.1Hz,2H),2.79(t,J＝7.7Hz,2H),2.57(t,J＝7.7Hz,2H),1.12(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+575.2.Referring to the synthesis method of compound 69, the compound 2-hydroxybenzoic acid ethyl ester was replaced with 3-hydroxy-phenylpropionic acid ethyl ester to obtain compound 79 (white solid, 61 mg, yield 42%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.82–7.75(m,3H),7.51(dd,J＝19.3,7.8Hz,3H),7.41–7.36(m,1H),7.31–7.14(m,5H),6.80(d,J＝9.3Hz,3H),6.46(d,J＝7.6Hz,1H),5.71(s,2H),5. 18(s,2H),4.02(q,J＝7.1Hz,2H),2.79(t,J＝7.7Hz,2H),2.57(t,J＝7.7Hz,2H),1.12(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H] + 575.2.

实施例80Embodiment 80

3-(3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)丙酸
3-(3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)propanoic acid

参照实施例2的方法，将化合物1替换为化合物79制得化合物80(白色固体，38mg，收率66％)：1H NMR(300MHz,DMSO-d6)δ11.89(s,1H),7.88–7.82(m,3H),7.61–7.53(m,4H),7.41(ddd,J＝7.1,5.0,1.6Hz,2H),7.33(d,J＝7.5Hz,1H),7.25–7.15(m,2H),6.83–6.75(m,3H),6.66(d,J＝7.6Hz,1H),5.78(s,2H),5.18(s,2H),2.77(t,J＝7.7Hz,2H),2.53(t,2H).HRMS(ESI)calcd.for C31H25F3N2O4[M+H]+547.1845,found547.1827.Referring to the method of Example 2, compound 1 was replaced by compound 79 to obtain compound 80 (white solid, 38 mg, yield 66%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.89 (s, 1H), 7.88–7.82 (m, 3H), 7.61–7.53 (m, 4H), 7.41 (ddd, J=7.1, 5.0, 1.6 Hz, 2H), 7.33 (d, J=7.5 Hz, 1H), 7.25–7.15 (m, 2H), 6.83–6.75 (m, 3H), 6.66 (d, J=7.6 Hz, 1H), 5.78 (s, 2H), 5.18 (s, 2H), 2.77 (t, J=7.7 Hz, 2H), 2.53 (t, 2H). HRMS (ESI) calcd. for C 31 H 25 F 3 N 2 O 4 [M+H] + 547.1845,found547.1827.

实施例81Embodiment 81

2-(4-甲基-3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸乙酯(化合物81)
Ethyl 2-(4-methyl-3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetate (Compound 81)

化合物IX-1的合成Synthesis of Compound IX-1

在氩气保护下，将3-甲氧基-4-甲基苯甲醛(1.0g，6.66mmol)溶于无水四氢呋喃(10mL)，加入甲基甲基硫代甲砜(1.3g，10.65mmol)，缓慢加入苄基三甲基氢氧化铵(1.45g，8.66mmol)，升温至80℃搅拌反应6小时。TLC监测反应，待反应完全后，残余物经硅胶柱层析(石油醚:乙酸乙酯＝5:1→2:1)纯化，得化合物Ⅸ-1(黄色油状液体，563mg，收率33％)。Under argon protection, 3-methoxy-4-methylbenzaldehyde (1.0 g, 6.66 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), methyl methyl thiosulfone (1.3 g, 10.65 mmol) was added, and benzyltrimethylammonium hydroxide (1.45 g, 8.66 mmol) was slowly added, and the temperature was raised to 80°C and stirred for 6 hours. The reaction was monitored by TLC. After the reaction was complete, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1→2:1) to obtain compound IX-1 (yellow oily liquid, 563 mg, yield 33%).

化合物IX-2的合成Synthesis of compound IX-2

将IX-1(563mg，2.2mmol)溶于无水盐酸乙醇(10mL)，无水乙醇(15mL)，升温至80℃搅拌反应4小时。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝15:1)纯化，得化合物Ⅸ-2(黄色油状液体，375mg，收率82％)。IX-1 (563 mg, 2.2 mmol) was dissolved in anhydrous hydrochloric acid ethanol (10 mL) and anhydrous ethanol (15 mL), and the mixture was heated to 80°C and stirred for 4 hours. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain compound IX-2 (yellow oily liquid, 375 mg, yield 82%).

化合物IX-3的合成Synthesis of compound IX-3

在氩气的保护条件下，将IX-2(375mg，1.8mmol)溶于无水二氯甲烷(15mL)，在冰盐浴条件下，缓慢滴加入三溴化硼(676mg，2.7mmol)，自然升温至室温搅拌反应2小时。TLC监测反应，待反应完全后，加入水(20mL)淬灭反应，二氯甲烷(30mL x3)萃取，合并有机相，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝10:1→2:1)纯化，得化合物IX-3(黄色油状液体，140mg，40％)。Under the protection of argon, IX-2 (375 mg, 1.8 mmol) was dissolved in anhydrous dichloromethane (15 mL), and boron tribromide (676 mg, 2.7 mmol) was slowly added dropwise under ice-salt bath conditions, and the temperature was naturally raised to room temperature and stirred for 2 hours. The reaction was monitored by TLC. After the reaction was complete, water (20 mL) was added to quench the reaction, and dichloromethane (30 mL x 3) was used for extraction. The organic phases were combined, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 → 2: 1) to obtain compound IX-3 (yellow oily liquid, 140 mg, 40%).

化合物81的合成Synthesis of compound 81

参照化合物69的合成方法，将化合物2-羟基苯甲酸乙酯替换为化合物Ⅸ-3制得化合物81(无色油状液体，85mg，收率59％):1H NMR(300MHz,DMSO-d6)δ7.78(dd,J＝8.3,3.7Hz,3H),7.62–7.55(m,1H),7.46(d,J＝8.4Hz,2H),7.37–7.20(m,5H),7.05(d,J＝7.6Hz,1H),6.95(s,1H),6.76(d,J＝7.6Hz,1H),6.51(d,J＝7.6Hz,1H),5.74(s,2H),5.18(s,2H),4.07(q,J＝7.1Hz,2H),3.60(s,2H),2.00(s,3H),1.15(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+575.2.Referring to the synthesis method of compound 69, the compound 2-hydroxybenzoic acid ethyl ester was replaced by compound IX-3 to obtain compound 81 (colorless oily liquid, 85 mg, yield 59%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.78(dd,J＝8.3,3.7Hz,3H),7.62–7.55(m,1H),7.46(d,J＝8.4Hz,2H),7.37–7.20(m,5H),7.05(d,J＝7.6Hz,1H),6.95(s,1H),6.76(d,J＝7.6Hz,1H),6 .51(d,J＝7.6Hz,1H),5.74(s,2H),5.18(s,2H),4.07(q,J＝7.1Hz,2H),3.60(s,2H),2.00(s,3H),1.15(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H] + 575.2.

实施例82Embodiment 82

2-(4-甲基-3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸(化合物82)
2-(4-methyl-3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetic acid (Compound 82)

参照实施例2的方法，将化合物1替换为化合物81制得化合物82(白色固体，42mg，收率52％)：1H NMR(300MHz,DMSO-d6)δ12.46(s,1H),7.86–7.81(m,3H),7.62(dd,J＝7.7,1.4Hz,1H),7.55(d,J＝8.3Hz,2H),7.48–7.44(m,1H),7.41(d,J＝7.1Hz,1H),7.37–7.31(m,2H),7.24(td,J＝7.6,1.4Hz,1H),7.04(d,J＝7.6Hz,1H),6.95(d,J＝1.6Hz,1H),6.75(dd,J＝7.5,1.4Hz,1H),6.64(d,J＝7.6Hz,1H),5.78(s,2H),5.19(s,2H),3.51(s,2H),1.97(s,3H).HRMS(ESI)calcd.for C31H25F3N2O4[M+H]+547.1845,found 547.1828.Referring to the method of Example 2, Compound 82 (white solid, 42 mg, yield 52%) was prepared by replacing Compound 1 with Compound 81: 1 H NMR (300 MHz, DMSO-d 6 ) δ12.46 (s, 1H), 7.86–7.81 (m, 3H), 7.62 (dd, J=7.7, 1.4 Hz, 1H), 7.55 (d, J=8.3 Hz, 2H), 7.48–7.44 (m, 1H), 7.41 (d, J=7.1 Hz, 1H), 7.37–7.31 (m, 2H), 7.24 (td, J=7.6, 1.4 Hz, 1 H),7.04(d,J＝7.6Hz,1H),6.95(d,J＝1.6Hz,1H),6.75(dd,J＝7.5,1.4Hz,1H),6.64(d,J＝7.6Hz,1H),5.78(s,2H),5.19(s,2H),3.51(s,2H),1.97(s,3H) .HRMS(ESI)calcd.for C 31 H 25 F 3 N 2 O 4 [M+H] + 547.1845,found 547.1828.

实施例83Embodiment 83

2-(3-甲基-5-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸乙酯(化合物83)
Ethyl 2-(3-methyl-5-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetate (Compound 83)

参照实施例81的方法，将化合物3-甲氧基-4-甲基苯甲醛替换为3-甲氧基-5-甲基苯甲醛制得化合物83(黄色油状液体，104mg，收率72％):1H NMR(300MHz,DMSO-d6)δ7.82–7.74(m,3H),7.57–7.48(m,3H),7.44–7.36(m,2H),7.34–7.17(m,5H),6.68(d,1H),6.46(d,1H),5.72(s,2H),5.17(s,2H),4.05(q,2H),3.55(s,2H),2.24(s,3H),1.17(t,3H).MS(ESI):m/z[M+H]+575.2.Referring to the method of Example 81, the compound 3-methoxy-4-methylbenzaldehyde was replaced by 3-methoxy-5-methylbenzaldehyde to obtain compound 83 (yellow oily liquid, 104 mg, yield 72%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.82–7.74 (m, 3H), 7.57–7.48 (m, 3H), 7.44–7.36 (m, 2H), 7.34–7.17 (m, 5H), 6.68 (d, 1H), 6.46 (d, 1H), 5.72 (s, 2H), 5.17 (s, 2H), 4.05 (q, 2H), 3.55 (s, 2H), 2.24 (s, 3H), 1.17 (t, 3H). MS (ESI): m/z [M+H] + 575.2.

实施例84Embodiment 84

2-(3-甲基-5-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸(化合物84)
2-(3-methyl-5-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetic acid (Compound 84)

参照实施例2的方法，将化合物1替换为化合物83制得化合物84(白色固体，49mg，收率49％)：1H NMR(300MHz,DMSO-d6)δ12.29(s,1H),7.81(d,J＝8.7Hz,3H),7.53(dd,J＝15.9,7.8Hz,4H),7.41(d,J＝7.4Hz,1H),7.29(s,2H),7.19(d,J＝6.7Hz,1H),6.68(d,J＝6.1Hz,3H),6.48(d,J＝7.7Hz,1H),5.73(s,2H),5.16(s,2H),3.47(s,2H),2.24(s,3H).HRMS(ESI)calcd.for C31H25F3N2O4[M+H]+547.1845,found 547.1828.Referring to the method of Example 2, compound 1 was replaced by compound 83 to obtain compound 84 (white solid, 49 mg, yield 49%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.29 (s, 1H), 7.81 (d, J = 8.7 Hz, 3H), 7.53 (dd, J = 15.9, 7.8 Hz, 4H), 7.41 (d, J = 7.4 Hz, 1H), 7.29 (s, 2H), 7.19 (d, J = 6.7 Hz, 1H), 6.68 (d, J = 6.1 Hz, 3H), 6.48 (d, J = 7.7 Hz, 1H), 5.73 (s, 2H), 5.16 (s, 2H), 3.47 (s, 2H), 2.24 (s, 3H). HRMS (ESI) calcd. for C 31 H 25 F 3 N 2 O 4 [M+H] + 547.1845,found 547.1828.

实施例85Embodiment 85

2-(2-甲基-5-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸乙酯(化合物85)
Ethyl 2-(2-methyl-5-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetate (Compound 85)

参照实施例81的方法，将化合物3-甲氧基-4-甲基苯甲醛替换为5-甲氧基-2-甲基苯甲醛制得化合物85(黄色固体，70mg，收率53％):1H NMR(300MHz,DMSO-d6)δ7.86–7.74(m,3H),7.55(d,J＝7.4Hz,1H),7.49(d,J＝8.3Hz,2H),7.39(d,J＝7.6Hz,1H),7.29(q,J＝7.0Hz,3H),7.24–7.17(m,1H),7.07(d,J＝8.1Hz,1H),6.86–6.74(m,2H),6.46(d,J＝7.6Hz,1H),5.73(s,2H),5.17(s,2H),4.07(q,J＝7.2Hz,2H),3.61(s,2H),2.14(s,3H),1.17(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+575.2.Referring to the method of Example 81, the compound 3-methoxy-4-methylbenzaldehyde was replaced by 5-methoxy-2-methylbenzaldehyde to obtain compound 85 (yellow solid, 70 mg, yield 53%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.86–7.74(m,3H),7.55(d,J＝7.4Hz,1H),7.49(d,J＝8.3Hz,2H),7.39(d,J＝7.6Hz,1H),7.29(q,J＝7.0Hz,3H),7.24–7.17(m,1H),7.07(d,J＝8.1Hz,1H ),6.86–6.74(m,2H),6.46(d,J＝7.6Hz,1H),5.73(s,2H),5.17(s,2H),4.07(q,J＝7.2Hz,2H),3.61(s,2H),2.14(s,3H),1.17(t,J＝7.1Hz,3H).MS(ESI) :m/z[M+H] + 575.2.

实施例86Embodiment 86

2-(2-甲基-5-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸(化合物86)
2-(2-methyl-5-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetic acid (Compound 86)

参照实施例2的方法，将化合物1替换为化合物85制得化合物86(白色固体，46mg，收率74％):1H NMR(300MHz,DMSO-d6)δ12.32(s,1H),7.79(td,J＝7.0,1.9Hz,3H),7.57–7.48(m,3H),7.42–7.37(m,1H),7.32–7.24(m,3H),7.23–7.17(m,1H),7.06(d,J＝8.4Hz,1H),6.83(d,J＝2.7Hz,1H),6.77(dd,J＝8.3,2.7Hz,1H),6.45(d,J＝7.6Hz,1H),5.73(s,2H),5.17(s,2H),3.52(s,2H),2.14(s,3H).HRMS(ESI)calcd.for C31H25F3N2O4[M+H]+547.1845,found 547.1830.Referring to the method of Example 2, Compound 1 was replaced by Compound 85 to obtain Compound 86 (white solid, 46 mg, yield 74%): 1 H NMR (300 MHz, DMSO-d 6 )δ12.32(s,1H),7.79(td,J＝7.0,1.9Hz,3H),7.57–7.48(m,3H),7.42–7.37(m,1H),7.32–7.24(m,3H),7.23–7.17(m,1H),7.06(d,J＝8.4Hz,1H),6.8 3(d,J＝2.7Hz,1H),6.77(dd,J＝8.3,2.7Hz,1H),6.45(d,J＝7.6Hz,1H),5.73(s,2H),5.17(s,2H),3.52(s,2H),2.14(s,3H).HRMS(ESI)calcd.for C 31 H 25 F 3 N 2 O 4 [M+H] + 547.1845, found 547.1830.

实施例87Embodiment 87

2-(4-氯-3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸乙酯(化合物87)
Ethyl 2-(4-chloro-3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetate (Compound 87)

参照实施例81的方法，将化合物3-甲氧基-4-甲基苯甲醛替换为3-氯-4-甲氧基苯甲醛制得化合物87(白色固体，205mg，收率73％):1H NMR(300MHz,DMSO-d6)δ7.84–7.70(m,3H),7.62(d,J＝7.5Hz,1H),7.47(d,J＝8.4Hz,2H),7.38–7.14(m,7H),6.88(d,J＝8.0Hz,1H),6.50(d,J＝7.4Hz,1H),5.78(s,2H),5.32(s,2H),4.08(q,J＝7.1Hz,2H),3.68(s,2H),1.18(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+595.2.Referring to the method of Example 81, the compound 3-methoxy-4-methylbenzaldehyde was replaced with 3-chloro-4-methoxybenzaldehyde to obtain compound 87 (white solid, 205 mg, yield 73%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.84–7.70(m,3H),7.62(d,J＝7.5Hz,1H),7.47(d,J＝8.4Hz,2H),7.38–7.14(m,7H),6.88(d,J＝8.0Hz,1H),6.50(d,J＝7.4Hz,1H),5.78(s,2H),5.32(s ,2H),4.08(q,J＝7.1Hz,2H),3.68(s,2H),1.18(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H] + 595.2.

实施例88Embodiment 88

2-(4-氯-3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸(化合物88)
2-(4-chloro-3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetic acid (Compound 88)

参照实施例2的方法，将化合物1替换为化合物87制得化合物88(白色固体，75mg，收率79％):1H NMR(300MHz,DMSO-d6)δ12.40(s,1H),7.86–7.67(m,3H),7.62(d,J＝7.6Hz,1H),7.48(d,J＝8.3Hz,2H),7.39–7.12(m,7H),6.88(d,J＝8.5Hz,1H),6.51(d,J＝7.9Hz,1H),5.78(s,2H),5.31(s,2H),3.59(s,2H).HRMS(ESI)calcd.for C30H22ClF3N2O4[M+H]+567.1298,found 567.1279Referring to the method of Example 2, compound 1 was replaced by compound 87 to obtain compound 88 (white solid, 75 mg, yield 79%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.40 (s, 1H), 7.86–7.67 (m, 3H), 7.62 (d, J=7.6 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.39–7.12 (m, 7H), 6.88 (d, J=8.5 Hz, 1H), 6.51 (d, J=7.9 Hz, 1H), 5.78 (s, 2H), 5.31 (s, 2H), 3.59 (s, 2H). HRMS (ESI) calcd. for C 30 H 22 ClF 3 N 2 O 4 [M+H] + 567.1298, found 567.1279

实施例89Embodiment 89

2-(2-氯-5-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸乙酯(化合物89)
Ethyl 2-(2-chloro-5-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetate (Compound 89)

参照实施例81的方法，将化合物3-甲氧基-4-甲基苯甲醛替换为2-氯-5-甲氧基苯甲醛制得化合物89(黄色油状液体，130mg，收率75％):1H NMR(300MHz,DMSO-d6)δ7.83–7.76(m,3H),7.52(dd,J＝20.0,7.8Hz,3H),7.37(dd,J＝11.3,8.0Hz,2H),7.28–7.17(m,4H),7.05(d,J＝3.1Hz,1H),6.94(dd,J＝8.9,3.0Hz,1H),6.79(d,J＝3.0Hz,1H),6.71–6.66(m,1H),6.47(d,J＝7.8Hz,1H),5.72(s,2H),5.21(s,2H),4.77(q,2H),3.68(s,2H),1.17(t,3H).MS(ESI):m/z[M+H]+595.2.Referring to the method of Example 81, the compound 3-methoxy-4-methylbenzaldehyde was replaced with 2-chloro-5-methoxybenzaldehyde to obtain compound 89 (yellow oily liquid, 130 mg, yield 75%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.83–7.76(m,3H),7.52(dd,J＝20.0,7.8Hz,3H),7.37(dd,J＝11.3,8.0Hz,2H),7.28–7.17(m,4H),7.05(d,J＝3.1Hz,1H),6.94(dd,J＝8.9,3.0Hz,1H),6. 79(d,J＝3.0Hz,1H),6.71–6.66(m,1H),6.47(d,J＝7.8Hz,1H),5.72(s,2H),5.21(s,2H),4.77(q,2H),3.68(s,2H),1.17(t,3H).MS(ESI):m/z[M+H] + 59 5.2.

实施例90Embodiment 90

2-(2-氯-5-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸(化合物90)
2-(2-Chloro-5-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetic acid (Compound 90)

参照实施例2的方法，将化合物1替换为化合物89制得化合物90(白色固体，49mg，收率40％):1H NMR(300MHz,DMSO-d6)δ12.49(s,1H),7.80(dt,J＝10.2,4.7Hz,3H),7.52(dd,J＝17.4,7.9Hz,3H),7.39(d,J＝6.8Hz,1H),7.26(dt,J＝20.3,7.7Hz,5H),7.05(d,J＝3.1Hz,1H),6.88(dd,J＝9.1,2.7Hz,1H),6.46(d,J＝7.7Hz,1H),5.72(s,2H),5.20(s,2H),3.58(s,2H).HRMS(ESI)calcd.for C30H22ClF3N2O4[M+H]+567.1298,found 567.1282.Referring to the method of Example 2, compound 1 was replaced by compound 89 to obtain compound 90 (white solid, 49 mg, yield 40%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.49 (s, 1H), 7.80 (dt, J = 10.2, 4.7 Hz, 3H), 7.52 (dd, J = 17.4, 7.9 Hz, 3H), 7.39 (d, J = 6.8 Hz, 1H), 7.26 (dt, J = 20.3, 7.7 Hz, 5H), 7.05 (d, J = 3.1 Hz, 1H), 6.88 (dd, J = 9.1, 2.7 Hz, 1H), 6.46 (d, J = 7.7 Hz, 1H), 5.72 (s, 2H), 5.20 (s, 2H), 3.58 (s, 2H). HRMS (ESI) calcd. for C 30 H 22 ClF 3 N 2 O 4 [M+H] + 567.1298,found 567.1282.

实施例91Embodiment 91

2-(2-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)吡啶-4-基)乙酸乙酯(化合物91)
Ethyl 2-(2-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)pyridin-4-yl)acetate (Compound 91)

化合物X-1的合成Synthesis of compound X-1

将60％的氢化钠(936mg，23.4mmol)悬浮于无水二甲基亚砜(50mL)，滴加入苄醇(2g，18.7mmol)，30分钟后，缓慢滴加入2-氯-4-甲基吡啶(2g，15.6mmol)，升温至80℃搅拌反应3小时。TLC监测反应，待反应完全后，加水(30mL)淬灭反应，加入乙酸乙酯(150mL)稀释，水(200mL x3)洗涤，饱和氯化钠(50mL)洗涤，减压蒸除溶剂，经硅胶柱层析(石油醚:乙酸乙酯＝50:1)纯化，得化合物X-1(无色油状液体，2.3g，收率74％)。60% sodium hydride (936 mg, 23.4 mmol) was suspended in anhydrous dimethyl sulfoxide (50 mL), and benzyl alcohol (2 g, 18.7 mmol) was added dropwise. After 30 minutes, 2-chloro-4-methylpyridine (2 g, 15.6 mmol) was slowly added dropwise, and the temperature was raised to 80 ° C and stirred for 3 hours. TLC monitored the reaction. After the reaction was complete, water (30 mL) was added to quench the reaction, ethyl acetate (150 mL) was added to dilute, and water (200 mL x 3) was washed with saturated sodium chloride (50 mL). The solvent was evaporated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain compound X-1 (colorless oily liquid, 2.3 g, yield 74%).

化合物X-2的合成Synthesis of Compound X-2

在氩气保护条件下，将X-1(597mg，3mmol)溶于无水四氢呋喃(5mL)，在-78℃条件下，缓慢滴入二异丙基氨基锂(1.5mL，3mmol)。30分钟后，在-78℃条件下，加入碳酸二乙酯(236mg，2mmol)，自然升温至室温搅拌反应2小时。TLC监测反应，待反应完全后，加水(10mL)淬灭反应，乙酸乙酯(30mL x3)萃取，合并有机相，无水硫酸钠干燥，减压蒸除溶剂，经硅胶柱层析(石油醚:乙酸乙酯＝40:1→30:1)纯化，得化合物X-2(浅黄色油状液体，178mg，收率33％)。Under argon protection, X-1 (597 mg, 3 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and lithium diisopropylamide (1.5 mL, 3 mmol) was slowly added dropwise at -78 ° C. After 30 minutes, diethyl carbonate (236 mg, 2 mmol) was added at -78 ° C, and the temperature was naturally raised to room temperature and stirred for 2 hours. The reaction was monitored by TLC. After the reaction was complete, water (10 mL) was added to quench the reaction, and ethyl acetate (30 mL x 3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The compound X-2 (light yellow oily liquid, 178 mg, yield 33%) was obtained by purification by silica gel column chromatography (petroleum ether: ethyl acetate = 40: 1 → 30: 1).

化合物X-3的合成Synthesis of Compound X-3

将化合物X-2(178mg，0.66mmol)溶于无水乙醇(5mL)，加入10％的钯碳(20mg)，置于氢气氛围中，室温搅拌反应6小时。TLC监测反应，待反应完全后，硅藻土抽滤，减压蒸除溶剂，得化合物X-3(浅黄色油状液体，114mg，收率95％)。Compound X-2 (178 mg, 0.66 mmol) was dissolved in anhydrous ethanol (5 mL), 10% palladium carbon (20 mg) was added, and the mixture was placed in a hydrogen atmosphere and stirred at room temperature for 6 hours. The reaction was monitored by TLC. After the reaction was complete, diatomaceous earth was used for filtration, and the solvent was evaporated under reduced pressure to obtain compound X-3 (light yellow oily liquid, 114 mg, yield 95%).

化合物91的合成：Synthesis of compound 91:

参照化合物69的合成方法，将化合物2-羟基苯甲酸乙酯替换为化合物X-3制得化合物91(无色油状液体，70mg，收率16％):1H NMR(300MHz,DMSO-d6)δ7.84–7.80(m,3H),7.77–7.71(m,3H),7.53–7.47(m,3H),7.41(d,J＝7.6Hz,1H),7.29–7.22(m,3H),7.14(d,J＝7.6Hz,1H),7.05(d,J＝7.7Hz,1H),6.38(d,1H),6.26(d,J＝7.0Hz,1H),5.83(s,2H),5.19(s,2H),4.11(q,J＝7.1Hz,2H),3.58(s,2H),1.19(t,J＝6.8Hz,3H).MS(ESI):m/z[M+H]+562.2.Referring to the synthesis method of compound 69, the compound 2-hydroxybenzoic acid ethyl ester was replaced by compound X-3 to obtain compound 91 (colorless oily liquid, 70 mg, yield 16%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.84–7.80(m,3H),7.77–7.71(m,3H),7.53–7.47(m,3H),7.41(d,J＝7.6Hz,1H),7.29–7.22(m,3H),7.14(d,J＝7.6Hz,1H),7.05(d,J＝7.7Hz,1H),6.3 8(d,1H),6.26(d,J＝7.0Hz,1H),5.83(s,2H),5.19(s,2H),4.11(q,J＝7.1Hz,2H),3.58(s,2H),1.19(t,J＝6.8Hz,3H).MS(ESI):m/z[M+H] + 562.2.

实施例92Embodiment 92

2-(2-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)吡啶-4-基)乙酸(化合物92)
2-(2-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)pyridin-4-yl)acetic acid (Compound 92)

参照实施例2的方法，将化合物1替换为化合物91制得化合物92(白色固体，40mg，收率68％):1H NMR(300MHz,DMSO-d6)δ12.79(s,1H),7.86–7.81(m,2H),7.78(d,J＝7.5Hz,1H),7.73(d,J＝7.0Hz,1H),7.52–7.47(m,2H),7.41(d,J＝7.5Hz,1H),7.30–7.24(m,2H),7.22(s,1H),7.11(d,J＝7.5Hz,1H),7.05(d,J＝7.6Hz,1H),6.35(d,J＝7.2Hz,2H),6.26(d,J＝6.9Hz,1H),5.84(s,2H),5.18(s,2H),3.47(s,2H).HRMS(ESI)calcd.for C29H22F3N3O4[M+H]+534.1641,found 534.1631.Referring to the method of Example 2, Compound 1 was replaced by Compound 91 to obtain Compound 92 (white solid, 40 mg, yield 68%): 1 H NMR (300 MHz, DMSO-d 6 )δ12.79(s,1H),7.86–7.81(m,2H),7.78(d,J＝7.5Hz,1H),7.73(d,J＝7.0Hz,1H),7.52–7.47(m,2H),7.41(d,J＝7.5Hz,1H),7.30–7.24(m,2H),7.22(s ,1H),7.11(d,J＝7.5Hz,1H),7.05(d,J＝7.6Hz,1H),6.35(d,J＝7.2Hz,2H),6.26(d,J＝6.9Hz,1H),5.84(s,2H),5.18(s,2H),3.47(s,2H).HRMS(ESI)calcd.for C 2 9 H 22 F 3 N 3 O 4 [M+H] + 534.1641,found 534.1631.

实施例93Embodiment 93

2-(4-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)吡啶-2-基)乙酸乙酯(化合物93)
Ethyl 2-(4-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)pyridin-2-yl)acetate (Compound 93)

参照实施例91的方法，将化合物2-氯-4-甲基吡啶替换为4-氯-2-甲基吡啶制得化合物93(白色固体，80mg，收率31％):1H NMR(300MHz,DMSO-d6)δ8.30(d,J＝5.7Hz,1H),7.85–7.72(m,3H),7.52(dd,J＝20.7,7.8Hz,3H),7.38(d,J＝8.1Hz,1H),7.26(dt,J＝13.2,7.3Hz,4H),7.00–6.85(m,2H),6.48(d,J＝7.5Hz,1H),5.72(s,2H),5.29(s,2H),4.07(q,J＝7.1Hz,2H),3.74(s,2H),1.16(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+562.2.Referring to the method of Example 91, the compound 2-chloro-4-methylpyridine was replaced by 4-chloro-2-methylpyridine to obtain compound 93 (white solid, 80 mg, yield 31%): 1 H NMR (300 MHz, DMSO-d 6 )δ8.30(d,J＝5.7Hz,1H),7.85–7.72(m,3H),7.52(dd,J＝20.7,7.8Hz,3H),7.38(d,J＝8.1Hz,1H),7.26(dt,J＝13.2,7.3Hz,4H),7.00–6.85(m,2H),6.48( d,J＝7.5Hz,1H),5.72(s,2H),5.29(s,2H),4.07(q,J＝7.1Hz,2H),3.74(s,2H),1.16(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H ]+ 562.2.

实施例94Embodiment 94

2-(4-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)吡啶-2-基)乙酸(化合物94)
2-(4-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)pyridin-2-yl)acetic acid (Compound 94)

参照实施例2的方法，将化合物1替换为化合物93制得化合物94(白色固体，57mg，收率76％):1H NMR(300MHz,DMSO-d6)δ12.95(s,1H),δ8.24(d,J＝5.7Hz,1H),7.82–7.76(m,3H),7.53(dd,J＝17.8,7.9Hz,3H),7.41–7.37(m,1H),7.33–7.28(m,2H),7.27–7.19(m,2H),6.85–6.78(m,2H),6.48(d,J＝7.6Hz,1H),5.71(s,2H),5.28(s,2H),2.39(s,2H).HRMS(ESI)calcd.for C29H22F3N3O4[M+H]+534.1641,found 534.1632.Referring to the method of Example 2, compound 1 was replaced by compound 93 to obtain compound 94 (white solid, 57 mg, yield 76%): 1 H NMR (300 MHz, DMSO-d 6 ) δ12.95 (s, 1H), δ8.24 (d, J=5.7 Hz, 1H), 7.82–7.76 (m, 3H), 7.53 (dd, J=17.8, 7.9 Hz, 3H), 7.41–7.37 (m, 1H), 7.33–7.28 (m, 2H), 7.27–7.19 (m, 2H), 6.85–6.78 (m, 2H), 6.48 (d, J=7.6 Hz, 1H), 5.71 (s, 2H), 5.28 (s, 2H), 2.39 (s, 2H). HRMS (ESI) calcd. for C 29 H 22 F 3 N 3 O 4 [M+H] + 534.1641, found 534.1632.

实施例95Embodiment 95

2-(3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)丙酸乙酯(化合物95)
Ethyl 2-(3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)propanoate (Compound 95)

化合物XI-1的合成Synthesis of Compound XI-1

在氩气保护条件下，将含3-甲氧基苯基乙酸乙酯(1.0g，5.15mmol)的无水四氢呋喃(5ml)加入到二颈瓶中，在氩气保护和-78℃条件下，缓慢滴入二异丙基氨基锂(2M，454mL)，一个小时后，滴加入碘甲烷(1.03g，5.41mmol)的无水四氢呋喃溶液(1mL)，缓慢自然升温至室温搅拌反应2小时。TLC检测反应，待反应完全，饱和氯化铵(20mL)淬灭反应，乙酸乙酯(30mL x3)萃取，无水硫酸钠干燥，减压蒸除溶剂，残余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝40:1)得化合物XI-1(无色油状液体，1.01g，94％)。Under argon protection, anhydrous tetrahydrofuran (5 ml) containing ethyl 3-methoxyphenylacetate (1.0 g, 5.15 mmol) was added to a two-necked flask. Under argon protection and -78 ° C, lithium diisopropylamide (2M, 454 mL) was slowly added dropwise. After one hour, an anhydrous tetrahydrofuran solution (1 mL) of iodomethane (1.03 g, 5.41 mmol) was added dropwise. The temperature was slowly raised to room temperature and stirred for 2 hours. The reaction was detected by TLC. After the reaction was complete, saturated ammonium chloride (20 mL) was used to quench the reaction, and ethyl acetate (30 mL x 3) was used for extraction, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40: 1) to obtain compound XI-1 (colorless oily liquid, 1.01 g, 94%).

化合物XI-2的合成Synthesis of Compound XI-2

在氩气保护条件下，加入XI-1(600mg，2.88mmol)的无水二氯甲烷溶液(3mL)， 在冰盐浴条件下和氩气保护条件下，缓慢滴入三溴化硼(6mL)，缓慢升温至室温搅拌反应3小时。TLC检测反应，待反应完全后，饱和碳酸氢钠(10mL)淬灭反应，乙酸乙酯(20mL x3)萃取，无水硫酸钠干燥，减压蒸除溶剂，残余物经过硅胶柱层析纯化(石油醚:乙酸乙酯＝15:1→10：1)得化合物XI-2(黄色油状液体，115mg，21％)。Under argon protection, a solution of XI-1 (600 mg, 2.88 mmol) in anhydrous dichloromethane (3 mL) was added. Under ice-salt bath conditions and argon protection conditions, boron tribromide (6 mL) was slowly added dropwise, and the temperature was slowly raised to room temperature and stirred for 3 hours. The reaction was detected by TLC. After the reaction was complete, saturated sodium bicarbonate (10 mL) was used to quench the reaction, and ethyl acetate (20 mL x 3) was used for extraction, and the mixture was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1 → 10: 1) to obtain compound XI-2 (yellow oily liquid, 115 mg, 21%).

化合物95的合成Synthesis of compound 95

参照化合物69的合成方法，将化合物2-羟基苯甲酸乙酯替换为化合物Ⅺ-2制得化合物95(白色固体，97mg，收率80％):1H NMR(400MHz,DMSO-d6)δ7.83–7.80(m,2H),7.79–7.77(m,1H),7.56(dd,J＝7.6,1.4Hz,1H),7.51–7.49(m,2H),7.40–7.38(m,1H),7.29(dtd,J＝11.4,3.7,2.2Hz,3H),7.25–7.20(m,2H),6.90–6.86(m,3H),6.48(d,J＝7.6Hz,1H),5.74(s,2H),5.22(s,2H),4.04(dd,J＝12.2,7.1Hz,2H),3.73(t,J＝7.1Hz,1H),1.36(d,J＝7.1Hz,3H),1.10(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+575.2.Referring to the synthesis method of compound 69, the compound 2-hydroxybenzoic acid ethyl ester was replaced by compound Ⅺ-2 to prepare compound 95 (white solid, 97 mg, yield 80%): 1 H NMR (400 MHz, DMSO-d 6 )δ7.83–7.80 (m, 2H), 7.79–7.77 (m, 1H), 7.56 (dd, J＝7.6, 1.4 Hz, 1H), 7.51–7.49 (m, 2H), 7.40–7.38 (m, 1H), 7.29 (dtd, J＝11.4, 3.7, 2.2 Hz, 3H), 7.25–7.20 (m, 2H), 6.90–6.86 (m,3H),6.48(d,J＝7.6Hz,1H),5.74(s,2H),5.22(s,2H),4.04(dd,J＝12.2,7.1Hz,2H),3.73(t,J＝7.1Hz,1H),1.36(d,J＝7.1Hz,3H),1.10(t,J＝7.1Hz,3H ).MS(ESI):m/z[M+H] + 575.2.

实施例96Embodiment 96

2-(3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)丙酸(化合物96)
2-(3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)propanoic acid (Compound 96)

参照实施例2的方法，将化合物1替换为化合物95制得化合物96(白色固体，66mg，收率75％):1H NMR(300MHz,DMSO-d6)δ7.84–7.75(m,3H),7.56–7.49(m,3H),7.40(dd,J＝6.8,2.2Hz,1H),7.31–7.24(m,3H),7.21–7.16(m,1H),7.09(t,J＝7.9Hz,1H),6.97–6.93(m,1H),6.87(d,J＝7.6Hz,1H),6.70(dd,J＝8.2,2.4Hz,1H),6.41(d,J＝7.6Hz,1H),5.73(s,2H),5.17(s,2H),3.28(q,J＝7.1Hz,1H),1.22(d,J＝7.0Hz,3H).HRMS(ESI)calcd.for C31H25F3N2O4[M+H]+547.1845,found 547.1829.Referring to the method of Example 2, Compound 1 was replaced by Compound 95 to obtain Compound 96 (white solid, 66 mg, yield 75%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.84–7.75(m,3H),7.56–7.49(m,3H),7.40(dd,J＝6.8,2.2Hz,1H),7.31–7.24(m,3H),7.21–7.16(m,1H),7.09(t,J＝7.9Hz,1H),6.97–6.93(m,1H),6.87(d,J＝7.6Hz,1H),6.70(dd,J＝8.2,2.4Hz,1H),6.41(d,J＝7.6Hz,1H),5.73(s,2H),5.17(s,2H),3.28(q,J＝7.1Hz,1H),1.22(d,J＝7.0Hz,3H).HRMS(ESI)calcd.for C 31 H 25 F 3 N 2 O 4 [M+H] + 547.1845,found 547.1829.

实施例97Embodiment 97

2-甲基-2-(3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)丙酸乙酯(化合物97)
2-Methyl-2-(3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)propanoic acid ethyl ester (Compound 97)

参照实施例95的方法，将3-甲氧基苯基乙酸乙酯替换为Ⅺ-1制得化合物97(无色油状液体，122mg，收率94％):1H NMR(400MHz,DMSO-d6)δ7.83–7.77(m,3H),7.56(dd,J＝7.6,1.4Hz,1H),7.51–7.48(m,2H),7.40–7.36(m,1H),7.33–7.28(m,2H),7.27–7.20(m,3H),6.88(d,J＝6.8Hz,3H),6.46(d,J＝7.6Hz,1H),5.73(s,2H),5.23(s,2H),4.02(q,J＝7.0Hz,2H),1.45(s,6H),1.06(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+589.2.Referring to the method of Example 95, ethyl 3-methoxyphenylacetate was replaced with XI-1 to obtain compound 97 (colorless oily liquid, 122 mg, yield 94%): 1 H NMR (400 MHz, DMSO-d 6 )δ7.83–7.77(m,3H),7.56(dd,J＝7.6,1.4Hz,1H),7.51–7.48(m,2H),7.40–7.36(m,1H),7.33–7.28(m,2H),7.27–7.20(m,3H),6.88(d,J＝6.8Hz,3H), 6.46(d,J＝7.6Hz,1H),5.73(s,2H),5.23(s,2H),4.02(q,J＝7.0Hz,2H),1.45(s,6H),1.06(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H] + 589.2.

实施例98Embodiment 98

2-甲基-2-(3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)丙酸(化合物98)
2-Methyl-2-(3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)propanoic acid (Compound 98)

参照实施例2的方法，将化合物1替换为化合物97制得化合物98(白色固体，70mg，收率62％):1H NMR(300MHz,DMSO-d6)δ12.28(s,1H),7.84–7.80(m,2H),7.77(dd,J＝8.0,1.4Hz,1H),7.58–7.54(m,1H),7.52–7.48(m,2H),7.39(dd,J＝6.8,2.0Hz,1H),7.33–7.26(m,3H),7.23(d,J＝3.0Hz,1H),7.21–7.18(m,1H),6.96–6.91(m,2H),6.86(dd,J＝8.6,2.1Hz,1H),6.46(d,J＝7.6Hz,1H),5.74(s,2H),5.22(s,2H),1.43(s,6H).HRMS(ESI)calcd.for C32H27F3N2O4[M+H]+561.2001,found 561.1983.Referring to the method of Example 2, Compound 1 was replaced by Compound 97 to obtain Compound 98 (white solid, 70 mg, yield 62%): 1 H NMR (300 MHz, DMSO-d 6 )δ12.28(s,1H),7.84–7.80(m,2H),7.77(dd,J＝8.0,1.4Hz,1H),7.58–7.54(m,1H),7.52–7.48(m,2H),7.39(dd,J＝6.8,2.0Hz,1H),7.33–7.26(m,3H),7 .23(d,J＝3.0Hz,1H),7.21–7.18(m,1H),6.96–6.91(m,2H),6.86(dd,J＝8.6,2.1Hz,1H),6.46(d,J＝7.6Hz,1H),5.74(s,2H),5.22(s,2H),1.43(s,6H) .HRMS(ESI)calcd.for C 32 H 27 F 3 N 2 O 4 [M+H] + 561.2001,found 561.1983.

实施例99Embodiment 99

2-(2-氟-5-((2-(2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯)乙酸乙酯(化合物99)
Ethyl 2-(2-fluoro-5-((2-(2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetate (Compound 99)

参照实施例81的方法，将化合物3-甲氧基-4-甲基苯甲醛替换为2-氟-5-甲氧基苯甲醛制得化合物99(白色固体，225mg，收率78％):1H NMR(400MHz,DMSO-d6)δ7.83–7.77(m,3H),7.55(dd,J＝7.6,1.4Hz,1H),7.51–7.48(m,2H),7.39(dd,J＝7.1,1.6Hz,1H),7.32–7.29(m,1H),7.29–7.24(m,2H),7.23–7.19(m,1H),7.13–7.08(m,1H),6.96(dd,J＝6.1,3.1Hz,1H),6.94–6.89(m,1H),6.49–6.46(m,1H),5.73(s,2H),5.18(s,2H),4.08(q,J＝7.1Hz,2H),3.66(s,2H),1.17(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+579.2.Referring to the method of Example 81, the compound 3-methoxy-4-methylbenzaldehyde was replaced by 2-fluoro-5-methoxybenzaldehyde to obtain compound 99 (white solid, 225 mg, yield 78%): 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.83–7.77 (m, 3H), 7.55 (dd, J=7.6, 1.4 Hz, 1H), 7.51–7.48 (m, 2H), 7.39 (dd, J=7.1, 1.6 Hz, 1H), 7.32–7.29 (m, 1H), 7.29–7.24 (m, 2H), 7.23–7.19 (m, 1H), 7.13–7.08 (m, 1H ),6.96(dd,J＝6.1,3.1Hz,1H),6.94–6.89(m,1H),6.49–6.46(m,1H),5.73(s,2H),5.18(s,2H),4.08(q,J＝7.1Hz,2H),3.66(s,2H),1.17(t,J＝7.1Hz,3 H).MS(ESI):m/z[M+H] + 579.2.

实施例100Embodiment 100

2-(2-氟-5-((2-(2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯)乙酸(化合物100)
2-(2-Fluoro-5-((2-(2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetic acid (Compound 100)

参照实施例2的方法，将化合物1替换为化合物99制得化合物100(白色固体，135mg，收率79％):1H NMR(300MHz,DMSO-d6)δ12.46(s,1H),7.82(d,J＝2.1Hz,1H),7.80–7.76(m,2H),7.56(dd,J＝7.5,1.4Hz,1H),7.52–7.48(m,2H),7.39(dd,J＝7.7,1.6Hz,1H),7.32–7.29(m,1H),7.29–7.24(m,2H),7.20(dd,J＝7.9,6.4Hz,1H),7.12–7.06(m,1H),6.97(dd,J＝6.2,3.1Hz,1H),6.92–6.87(m,1H),6.46(d,J＝7.6Hz,1H),5.73(s,2H),5.18(s,2H),3.57(d,J＝1.5Hz,2H).HRMS(ESI)calcd.for C30H22F4N2O4[M+H]+551.1594,found 551.1578.Referring to the method of Example 2, compound 1 was replaced by compound 99 to obtain compound 100 (white solid, 135 mg, yield 79%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.46 (s, 1H), 7.82 (d, J = 2.1 Hz, 1H), 7.80–7.76 (m, 2H), 7.56 (dd, J = 7.5, 1.4 Hz, 1H), 7.52–7.48 (m, 2H), 7.39 (dd, J = 7.7, 1.6 Hz, 1H), 7.32–7.29 (m, 1H), 7.29–7.24 (m, 2H), 7.20 (d d,J＝7.9,6.4Hz,1H),7.12–7.06(m,1H),6.97(dd,J＝6.2,3.1Hz,1H),6.92–6.87(m,1H),6.46(d,J＝7.6Hz,1H),5.73(s,2H),5.18(s,2H),3.57(d,J＝1 .5Hz,2H).HRMS(ESI)calcd.for C 30 H 22 F 4 N 2 O 4 [M+H] + 551.1594,found 551.1578.

实施例101Embodiment 101

2-(4-氟-3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸乙酯(化合物101)
Ethyl 2-(4-fluoro-3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetate (Compound 101)

参照实施例81的方法，将化合物3-甲氧基-4-甲基苯甲醛替换为3-甲氧基-4-氟苯甲醛制得化合物101(淡黄色油状液体，214mg，收率86％):1H NMR(300MHz,DMSO-d6)δ7.84–7.75(m,3H),7.57(dd,J＝7.5,1.5Hz,1H),7.50–7.43(m,2H),7.37(dd,J＝7.2,1.7Hz,1H),7.34–7.26(m,2H),7.23(ddd,J＝9.1,5.5,1.8Hz,3H),7.14(dd,J＝11.4,8.3Hz,1H),6.89–6.82(m,1H),6.47(d,J＝7.6Hz,1H),5.76(s,2H),5.28(s,2H),4.07(q,J＝7.1Hz,2H),3.64(s,2H),1.17(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+579.2.Referring to the method of Example 81, the compound 3-methoxy-4-methylbenzaldehyde was replaced by 3-methoxy-4-fluorobenzaldehyde to obtain compound 101 (light yellow oily liquid, 214 mg, yield 86%): 1 H NMR (300 MHz, DMSO-d 6 ) δ7.84–7.75 (m, 3H), 7.57 (dd, J=7.5, 1.5 Hz, 1H), 7.50–7.43 (m, 2H), 7.37 (dd, J=7.2, 1.7 Hz, 1H), 7.34–7.26 (m, 2H), 7.23 (ddd, J=9.1, 5.5, 1.8 Hz, 3H), 7.14 (dd, J= 11.4,8.3Hz,1H),6.89–6.82(m,1H),6.47(d,J＝7.6Hz,1H),5.76(s,2H),5.28(s,2H),4.07(q,J＝7.1Hz,2H),3.64(s,2H),1.17(t,J＝7.1Hz,3H).MS(ESI ):m/z[M+H] + 579.2.

实施例102Embodiment 102

2-(4-氟-3-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸(化合物102)
2-(4-Fluoro-3-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetic acid (Compound 102)

参照实施例2的方法，将化合物1替换为化合物101制得化合物102(白色固体，135mg，收率70％):1H NMR(300MHz,DMSO-d6)δ12.40(s,1H),7.88–7.78(m,3H),7.60–7.50(m,3H),7.49–7.44(m,1H),7.39–7.28(m,3H),7.22(ddd,J＝14.8,7.9,1.7Hz,2H),7.12(dd,J＝11.4,8.3Hz,1H),6.84(ddd,J＝8.4,4.3,1.9Hz,1H),6.59(d,J＝7.6Hz,1H),5.80(s,2H),5.27(s,2H),3.55(s,2H).HRMS(ESI)calcd.for C30H22F4N2O4[M+H]+551.1588,found 551.1574.Referring to the method of Example 2, Compound 1 was replaced by Compound 101 to obtain Compound 102 (white solid, 135 mg, yield 70%): 1 H NMR (300 MHz, DMSO-d 6 )δ12.40(s,1H),7.88–7.78(m,3H),7.60–7.50(m,3H),7.49–7.44(m,1H),7.39–7.28(m,3H),7.22(ddd,J＝14.8,7.9,1.7Hz,2H),7.12(dd,J＝11.4,8.3 Hz,1H),6.84(ddd,J＝8.4,4.3,1.9Hz,1H),6.59(d,J＝7.6Hz,1H),5.80(s,2H),5.27(s,2H),3.55(s,2H).HRMS(ESI)calcd.for C 30 H 22 F 4 N 2 O 4 [M+H] + 551.15 88,found 551.1574.

实施例103Embodiment 103

2-(3-氟-5-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸乙酯(化合物103)
Ethyl 2-(3-fluoro-5-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetate (Compound 103)

参照实施例81的方法，将化合物3-甲氧基-4-甲基苯甲醛替换为3-氟-5-甲氧基苯甲醛制得化合物103(无色油状液体，95mg，收率78％):1H NMR(300MHz,DMSO-d6)δ7.83–7.74(m,3H),7.56(d,J＝7.4Hz,1H),7.53–7.46(m,2H),7.42–7.36(m,1H),7.34–7.19(m,4H),6.82–6.71(m,3H),6.47(d,J＝7.6Hz,1H),5.72(s,2H),5.22(s,2H),4.07(q,J＝7.1Hz,2H),3.64(s,2H),1.17(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+579.2.Referring to the method of Example 81, the compound 3-methoxy-4-methylbenzaldehyde was replaced with 3-fluoro-5-methoxybenzaldehyde to obtain compound 103 (colorless oily liquid, 95 mg, yield 78%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.83–7.74(m,3H),7.56(d,J＝7.4Hz,1H),7.53–7.46(m,2H),7.42–7.36(m,1H),7.34–7.19(m,4H),6.82–6.71(m,3H),6.47(d,J＝7.6Hz,1H),5.72 (s,2H),5.22(s,2H),4.07(q,J＝7.1Hz,2H),3.64(s,2H),1.17(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H] + 579.2.

实施例104 Embodiment 104

2-(3-氟-5-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)乙酸(化合物104)
2-(3-Fluoro-5-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetic acid (Compound 104)

参照实施例2的方法，将化合物1替换为化合物103制得化合物104(白色固体，66mg，收率75％):1H NMR(300MHz,DMSO-d6)δ12.46(s,1H),7.84–7.75(m,3H),7.59–7.47(m,3H),7.40(dd,J＝7.7,1.7Hz,1H),7.33–7.18(m,4H),6.79–6.69(m,3H),6.47(d,J＝7.6Hz,1H),5.73(s,2H),5.22(s,2H),3.56(s,2H).HRMS(ESI)calcd.for C30H22F4N2O4[M+H]+551.1588,found 551.1597.Referring to the method of Example 2, compound 1 was replaced by compound 103 to obtain compound 104 (white solid, 66 mg, yield 75%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.46 (s, 1H), 7.84–7.75 (m, 3H), 7.59–7.47 (m, 3H), 7.40 (dd, J=7.7, 1.7 Hz, 1H), 7.33–7.18 (m, 4H), 6.79–6.69 (m, 3H), 6.47 (d, J=7.6 Hz, 1H), 5.73 (s, 2H), 5.22 (s, 2H), 3.56 (s, 2H). HRMS (ESI) calcd. for C 30 H 22 F 4 N 2 O 4 [M+H] + 551.1588, found 551.1597.

实施例105Embodiment 105

2-(3-氯-5-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧)苯基)乙酸乙酯(化合物105)
Ethyl 2-(3-chloro-5-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetate (Compound 105)

参照实施例81的方法，将化合物3-甲氧基-4-甲基苯甲醛替换为3-氯-5-甲氧基苯甲醛制得化合物105(无色油状液体，160mg，收率96％):1H NMR(400MHz,DMSO-d6)δ7.82–7.76(m,3H),7.56(dd,J＝7.7,1.4Hz,1H),7.52–7.47(m,2H),7.39(dd,J＝7.0,1.7Hz,1H),7.33–7.27(m,2H),7.22(ddd,J＝15.0,7.4,1.5Hz,2H),7.01–6.95(m,2H),6.88–6.85(m,1H),6.46(d,J＝7.6Hz,1H),5.72(s,2H),5.24(s,2H),4.07(q,J＝7.1Hz,2H),3.65(s,2H),1.17(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+595.2.Referring to the method of Example 81, the compound 3-methoxy-4-methylbenzaldehyde was replaced with 3-chloro-5-methoxybenzaldehyde to obtain compound 105 (colorless oily liquid, 160 mg, yield 96%): 1 H NMR (400 MHz, DMSO-d 6 )δ7.82–7.76(m,3H),7.56(dd,J＝7.7,1.4Hz,1H),7.52–7.47(m,2H),7.39(dd,J＝7.0,1.7Hz,1H),7.33–7.27(m,2H),7.22(ddd,J＝15.0,7.4,1.5Hz,2H),7 .01–6.95(m,2H),6.88–6.85(m,1H),6.46(d,J＝7.6Hz,1H),5.72(s,2H),5.24(s,2H),4.07(q,J＝7.1Hz,2H),3.65(s,2H),1.17(t,J＝7.1Hz,3H).MS(ESI ):m/z[M+H] + 595.2.

实施例106Embodiment 106

2-(3-氯-5-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧)苯基)乙酸(化合物106)
2-(3-Chloro-5-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)acetic acid (Compound 106)

参照实施例2的方法，将化合物1替换为化合物105制得化合物106(白色固体，106mg，收率75％):1H NMR(300MHz,DMSO-d6)δ12.49(s,1H),7.85–7.75(m,3H),7.56(d,J＝7.4Hz,1H),7.50(d,J＝8.3Hz,2H),7.39(dd,J＝6.7,2.3Hz,1H),7.33–7.19(m,4H),6.96(dt,J＝8.6,2.0Hz,2H),6.88(t,J＝1.9Hz,1H),6.46(d,J＝7.6Hz,1H),5.73(s,2H),5.24(s,2H),3.56(s,2H).HRMS(ESI)calcd.for C30H22ClF3N2O4[M+H]+567.1293,found 567.1309. Referring to the method of Example 2, Compound 1 was replaced by Compound 105 to obtain Compound 106 (white solid, 106 mg, yield 75%): 1 H NMR (300 MHz, DMSO-d 6 )δ12.49(s,1H),7.85–7.75(m,3H),7.56(d,J＝7.4Hz,1H),7.50(d,J＝8.3Hz,2H),7.39(dd,J＝6.7,2.3Hz,1H),7.33–7.19(m,4H),6.96(dt,J＝8.6,2.0Hz ,2H),6.88(t,J＝1.9Hz,1H),6.46(d,J＝7.6Hz,1H),5.73(s,2H),5.24(s,2H),3.56(s,2H).HRMS(ESI)calcd.for C 30 H 22 ClF 3 N 2 O 4 [M+H] + 567.1293, found 567. 1309.

实施例107Embodiment 107

2-(2-甲基-5-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)苯基)乙酸乙酯(化合物107)
Ethyl 2-(2-methyl-5-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)phenyl)acetate (Compound 107)

化合物XII-1的合成Synthesis of compound XII-1

将2,5-二甲基苯乙酸乙酯(2.0g，10.40mmol，cas：58358-37-5)溶于四氯化碳(25mL)，加入N-溴代丁二酰亚胺(1.8g，9.9mmol)，加入偶氮二异丁腈(170mg，1.0mmol)，升温至80℃回流5小时。TLC监测反应，待反应完全后，减压蒸除溶剂，加入水(100mL)，乙酸乙酯(100mL x3)萃取，无水硫酸钠干燥，残余物经硅胶柱层析(石油醚:乙酸乙酯＝70:1)纯化，得化合物XII-1(无色油状液体，302mg，收率13％)。Ethyl 2,5-dimethylphenylacetate (2.0 g, 10.40 mmol, cas: 58358-37-5) was dissolved in carbon tetrachloride (25 mL), N-bromosuccinimide (1.8 g, 9.9 mmol) was added, azobisisobutyronitrile (170 mg, 1.0 mmol) was added, and the temperature was raised to 80 ° C and refluxed for 5 hours. TLC was used to monitor the reaction. After the reaction was complete, the solvent was evaporated under reduced pressure, water (100 mL) was added, and ethyl acetate (100 mL x 3) was extracted, and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 70: 1) to obtain compound XII-1 (colorless oily liquid, 302 mg, yield 13%).

化合物107的合成Synthesis of compound 107

参照实施例1的方法，将6-溴己酸乙酯替换为化合物XII-1制得化合物107(无色油状液体，104mg，收率70％):1H NMR(400MHz,DMSO-d6)δ7.82–7.77(m,2H),7.76–7.72(m,1H),7.51–7.46(m,2H),7.37(dd,J＝7.4,1.4Hz,1H),7.28–7.19(m,3H),7.14–7.06(m,4H),6.80(td,J＝7.5,1.0Hz,1H),6.63(dd,J＝7.6,1.6Hz,1H),5.52(s,2H),5.06(s,2H),4.04(q,J＝7.0Hz,2H),3.62(s,2H),2.20(s,3H),1.16(t,J＝7.3Hz,3H).MS(ESI):m/z[M+H]+575.2.Referring to the method of Example 1, 6-bromohexanoic acid ethyl ester was replaced with compound XII-1 to obtain compound 107 (colorless oily liquid, 104 mg, yield 70%): 1 H NMR (400 MHz, DMSO-d 6 )δ7.82–7.77(m,2H),7.76–7.72(m,1H),7.51–7.46(m,2H),7.37(dd,J＝7.4,1.4Hz,1H),7.28–7.19(m,3H),7.14–7.06(m,4H),6.80(td,J＝7.5,1.0Hz ,1H),6.63(dd,J＝7.6,1.6Hz,1H),5.52(s,2H),5.06(s,2H),4.04(q,J＝7.0Hz,2H),3.62(s,2H),2.20(s,3H),1.16(t,J＝7.3Hz,3H).MS(ESI):m/z[M+H] + 575.2.

实施例108Embodiment 108

2-(2-甲基-5-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)苯基)乙酸(化合物108)
2-(2-methyl-5-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)phenyl)acetic acid (Compound 108)

参照实施例2的方法，将化合物1替换为化合物107制得化合物108(白色固体，65mg，收率70％):1H NMR(300MHz,DMSO-d6)δ12.33(s,1H),7.83–7.73(m,3H),7.55–7.48(m,2H),7.44–7.38(m,1H),7.32–7.19(m,3H),7.14–7.04(m,4H),6.83–6.77(m,1H),6.66(d,J＝7.5Hz,1H),5.54(s,2H),5.04(s,2H),3.55(s,2H),2.21(s,3H).HRMS(ESI)calcd.for C31H25F3N2O4[M+H]+547.1839,found 547.1847.Referring to the method of Example 2, compound 1 was replaced by compound 107 to obtain compound 108 (white solid, 65 mg, yield 70%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.33 (s, 1H), 7.83–7.73 (m, 3H), 7.55–7.48 (m, 2H), 7.44–7.38 (m, 1H), 7.32–7.19 (m, 3H), 7.14–7.04 (m, 4H), 6.83–6.77 (m, 1H), 6.66 (d, J=7.5 Hz, 1H), 5.54 (s, 2H), 5.04 (s, 2H), 3.55 (s, 2H), 2.21 (s, 3H). HRMS (ESI) calcd. for C 31 H 25 F 3 N 2 O 4 [M+H] + 547.1839, found 547.1847.

实施例109Embodiment 109

2-(2-氟-5-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)苯基)乙酸乙酯(化合物109)
Ethyl 2-(2-fluoro-5-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)phenyl)acetate (Compound 109)

参照实施例107的方法，将2,5-二甲基苯乙酸乙酯替换为2-氟-5甲基苯乙酸乙酯(cas：1250638-04-0)制得化合物109(无色油状液体，83mg，收率60％):1H NMR(300MHz,DMSO-d6)δ7.83–7.77(m,2H),7.74(d,J＝7.5Hz,1H),7.52–7.46(m,2H),7.40–7.35(m,1H),7.30–7.19(m,5H),7.17–7.07(m,2H),6.81(d,J＝1.0Hz,1H),6.65(s,1H),5.54(s,2H),5.08(s,2H),4.07(q,J＝7.1Hz,2H),3.67(s,2H),1.15(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+579.2.Referring to the method of Example 107, ethyl 2,5-dimethylphenylacetate was replaced with ethyl 2-fluoro-5-methylphenylacetate (cas: 1250638-04-0) to obtain compound 109 (colorless oily liquid, 83 mg, yield 60%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.83–7.77(m,2H),7.74(d,J＝7.5Hz,1H),7.52–7.46(m,2H),7.40–7.35(m,1H),7.30–7.19(m,5H),7.17–7.07(m,2H),6.81(d,J＝1.0Hz,1H),6.65 (s,1H),5.54(s,2H),5.08(s,2H),4.07(q,J＝7.1Hz,2H),3.67(s,2H),1.15(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H] + 579.2.

实施例110Embodiment 110

2-(2-氟-5-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)苯基)乙酸(化合物110)
2-(2-Fluoro-5-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)phenyl)acetic acid (Compound 110)

参照实施例2的方法，将化合物1替换为化合物109制得化合物110(白色固体，63mg，收率82％):1H NMR(300MHz,DMSO-d6)δ12.29(s,1H),7.88–7.79(m,3H),7.60–7.50(m,3H),7.44–7.31(m,2H),7.28–7.19(m,2H),7.18–7.05(m,3H),6.83(d,J＝4.8Hz,2H),5.60(s,2H),5.02(s,2H).HRMS(ESI)calcd.for C30H22F4N2O4[M+H]+551.1588,found 551.1596.Referring to the method of Example 2, compound 1 was replaced by compound 109 to obtain compound 110 (white solid, 63 mg, yield 82%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.29 (s, 1H), 7.88–7.79 (m, 3H), 7.60–7.50 (m, 3H), 7.44–7.31 (m, 2H), 7.28–7.19 (m, 2H), 7.18–7.05 (m, 3H), 6.83 (d, J=4.8 Hz, 2H), 5.60 (s, 2H), 5.02 (s, 2H). HRMS (ESI) calcd. for C 30 H 22 F 4 N 2 O 4 [M+H] + 551.1588, found 551.1596.

实施例111Embodiment 111

2-(2-氯-5-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)苯基)乙酸乙酯(化合物111)
Ethyl 2-(2-chloro-5-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)phenyl)acetate (Compound 111)

参照实施例107的方法，将2,5-二甲基苯乙酸乙酯替换为2-氯-5-甲基苯乙酸乙酯(cas 91552-39-5)制得化合物111(无色油状液体，89mg，收率58％):1H NMR(300MHz,DMSO-d6)δ7.84–7.79(m,2H),7.75(dd,J＝6.9,1.4Hz,1H),7.53–7.47(m,2H),7.43–7.37(m,2H),7.32(d,J＝2.1Hz,1H),7.30–7.19(m,4H),7.08(d,J＝8.2Hz,1H),6.82(dd,J＝8.0,6.9Hz,1H),6.68–6.63(m,1H),5.56(s,2H),5.11(s,2H),4.08(q,J＝7.1Hz,2H),3.76(s,2H),1.16(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+595.2.Referring to the method of Example 107, ethyl 2,5-dimethylphenylacetate was replaced with ethyl 2-chloro-5-methylphenylacetate (cas 91552-39-5) to obtain compound 111 (colorless oily liquid, 89 mg, yield 58%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.84–7.79(m,2H),7.75(dd,J＝6.9,1.4Hz,1H),7.53–7.47(m,2H),7.43–7.37(m,2H),7.32(d,J＝2.1Hz,1H),7.30–7.19(m,4H),7.08(d,J＝8.2Hz,1H ),6.82(dd,J＝8.0,6.9Hz,1H),6.68–6.63(m,1H),5.56(s,2H),5.11(s,2H),4.08(q,J＝7.1Hz,2H),3.76(s,2H),1.16(t,J＝7.1Hz,3H).MS(ESI):m/z[M+ H] + 595.2.

实施例112Embodiment 112

2-(2-氯-5-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)甲基)苯基)乙酸(化合物112)
2-(2-Chloro-5-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)methyl)phenyl)acetic acid (Compound 112)

参照实施例2的方法，将化合物1替换为化合物111制得化合物112(白色固体，65mg，收率84％):1H NMR(400MHz,DMSO-d6)δ12.47(s,1H),7.86–7.81(m,2H),7.78(d,J＝7.9Hz,1H),7.53(d,J＝8.2Hz,2H),7.47(d,J＝8.0Hz,1H),7.39–7.32(m,2H),7.31–7.26(m,2H),7.24(td,J＝7.9,7.3,1.8Hz,1H),7.17(dd,J＝8.2,2.2Hz,1H),7.07(d,J＝8.2Hz,1H),6.85–6.79(m,1H),6.74(d,J＝7.5Hz,1H),5.59(s,2H),5.07(s,2H),3.67(s,2H).HRMS(ESI)calcd.for C30H22ClF3N2O4[M+H]+567.1293,found 567.1304.Referring to the method of Example 2, compound 1 was replaced by compound 111 to obtain compound 112 (white solid, 65 mg, yield 84%): 1 H NMR (400 MHz, DMSO-d 6 ) δ12.47 (s, 1H), 7.86–7.81 (m, 2H), 7.78 (d, J=7.9 Hz, 1H), 7.53 (d, J=8.2 Hz, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.39–7.32 (m, 2H), 7.31–7.26 (m, 2H), 7.24 (td, J=7.9, 7.3, 1 .8Hz,1H),7.17(dd,J＝8.2,2.2Hz,1H),7.07(d,J＝8.2Hz,1H),6.85–6.79(m,1H),6.74(d,J＝7.5Hz,1H),5.59(s,2H),5.07(s,2H),3.67(s,2H).HRMS(ESI) calcd.for C 30 H 22 ClF 3 N 2 O 4 [M+H] + 567.1293,found 567.1304.

实施例113Embodiment 113

6-(2-((2-(对甲苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物113)
Ethyl 6-(2-((2-(p-Tolyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoate (Compound 113)

参照实施例1的方法，将4-三氟甲氧基苯甲醛替换为4-甲基苯甲醛制得化合物113(黄色油状液体，300mg，收率91％):1H NMR(300MHz,DMSO-d6)δ7.74–7.69(m,1H),7.59–7.54(m,2H),7.36–7.28(m,3H),7.26–7.16(m,3H),7.02(dd,J＝8.3,1.1Hz,1H),6.78(td,J＝7.5,1.0Hz,1H),6.52(dd,J＝7.5,1.6Hz,1H),5.46(s,2H),4.04–3.94(m,4H),2.36(s,3H),2.25(t,J＝7.3Hz,2H),1.68–1.60(m,2H),1.56–1.49(m,2H),1.38–1.30(m,2H),1.13(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+457.3.Referring to the method of Example 1, 4-trifluoromethoxybenzaldehyde was replaced by 4-methylbenzaldehyde to prepare compound 113 (yellow oily liquid, 300 mg, yield 91%): 1 H NMR (300 MHz, DMSO-d 6 ) δ7.74–7.69 (m, 1H), 7.59–7.54 (m, 2H), 7.36–7.28 (m, 3H), 7.26–7.16 (m, 3H), 7.02 (dd, J=8.3, 1.1 Hz, 1H), 6.78 (td, J=7.5, 1.0 Hz, 1H), 6.52 (dd, J=7.5, 1.6 Hz, 1H), 5 .46(s,2H),4.04–3.94(m,4H),2.36(s,3H),2.25(t,J＝7.3Hz,2H),1.68–1.60(m,2H),1.56–1.49(m,2H),1.38–1.30(m,2H),1.13(t,J＝7.1Hz,3H).MS (ESI):m/z[M+H] + 457.3.

实施例114Embodiment 114

6-(2-((2-(对甲苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物114)
6-(2-((2-(p-Tolyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 114)

参照实施例2的方法，将化合物1替换为化合物113制得化合物114(白色固体，65mg，收率92％):1H NMR(300MHz,DMSO-d6)δ11.86(s,1H),7.87–7.81(m,1H),7.70(d,J＝8.1Hz,2H),7.66–7.60(m,1H),7.52–7.40(m,4H),7.26(ddd,J＝8.6,7.1,2.0Hz,1H),7.01(d,J＝8.3Hz,1H),6.90–6.78(m,2H),5.61(s,2H),3.92(t,J＝6.3Hz,2H),2.41(s,3H),2.15(t,J＝7.4Hz,2H),1.49(ddd,J＝17.2,14.5,7.2Hz,4H),1.22(td,J＝8.3,3.9Hz,2H).HRMS(ESI)calcd.for C27H28N2O3[M+H]+429.2173,found 429.2188.Referring to the method of Example 2, compound 1 was replaced by compound 113 to obtain compound 114 (white solid, 65 mg, yield 92%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.86 (s, 1H), 7.87–7.81 (m, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.66–7.60 (m, 1H), 7.52–7.40 (m, 4H), 7.26 (ddd, J=8.6, 7.1, 2.0 Hz, 1H), 7.01 (d, J=8.3 Hz, 1H), 6.90–6.78 ( HRMS(ESI) calcd.for C 27 H 28 N 2 O 3 [M+H] + 429.2173, found 429.2188.

实施例115Embodiment 115

6-(2-((2-(4-甲氧基苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物115)
Ethyl 6-(2-((2-(4-methoxyphenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoate (Compound 115)

参照实施例1的方法，将4-三氟甲氧基苯甲醛替换为4-甲氧基苯甲醛制得化合物115(黄色油状液体，213mg，收率67％):1H NMR(300MHz,DMSO-d6)δ7.72–7.66(m,1H),7.64–7.59(m,2H),7.34–7.29(m,1H),7.28–7.14(m,3H),7.08–7.00(m,3H),6.81–6.75(m,1H),6.53(dd,J＝7.5,1.6Hz,1H),5.45(s,2H),4.03–3.96(m,4H),3.80(s,3H),2.25(t,J＝7.3Hz,2H),1.71–1.60(m,2H),1.59–1.48(m,2H),1.40–1.30(m,2H),1.13(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+473.2.Referring to the method of Example 1, 4-trifluoromethoxybenzaldehyde was replaced by 4-methoxybenzaldehyde to obtain compound 115 (yellow oily liquid, 213 mg, yield 67%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.72–7.66(m,1H),7.64–7.59(m,2H),7.34–7.29(m,1H),7.28–7.14(m,3H),7.08–7.00(m,3H),6.81–6.75(m,1H),6.53(dd,J＝7.5,1.6Hz,1H),5. 45(s,2H),4.03–3.96(m,4H),3.80(s,3H),2.25(t,J＝7.3Hz,2H),1.71–1.60(m,2H),1.59–1.48(m,2H),1.40–1.30(m,2H),1.13(t,J＝7.1Hz,3H).MS( ESI):m/z[M+H] + 473.2.

实施例116Embodiment 116

6-(2-((2-(4-甲氧基苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物116)
6-(2-((2-(4-methoxyphenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 116)

参照实施例2的方法，将化合物1替换为化合物115制得化合物116(白色固体，55mg，收率22％):1H NMR(300MHz,DMSO-d6)δ12.00(s,1H),7.81–7.76(m,1H),7.73–7.67(m,2H),7.52(d,J＝7.7Hz,1H),7.46–7.29(m,3H),7.28–7.22(m,1H),7.17–7.11(m,2H),7.02(d,J＝8.2Hz,1H),6.85–6.73(m,2H),5.55(s,2H),3.96(t,J＝6.3Hz,2H),3.83(s,3H),2.16(t,J＝7.3Hz,2H),1.61–1.52(m,2H),1.51–1.43(m,2H),1.33–1.22(m,2H).HRMS(ESI)calcd.for C27H28N2O4[M+H]+445.2122,found 445.2154.Referring to the method of Example 2, compound 1 was replaced by compound 115 to obtain compound 116 (white solid, 55 mg, yield 22%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.00 (s, 1H), 7.81–7.76 (m, 1H), 7.73–7.67 (m, 2H), 7.52 (d, J=7.7 Hz, 1H), 7.46–7.29 (m, 3H), 7.28–7.22 (m, 1H), 7.17–7.11 (m, 2H), 7.02 (d, J=8.2 Hz, 1H), 6.85–6.33 (m, 3H). HRMS(ESI) )calcd.for C 27 H 28 N 2 O 4 [M+H] + 445.2122 , found 445.2154.

实施例117Embodiment 117

6-(2-((2-([1,1'-联苯]-4-基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸乙酯(化合物117)
Ethyl 6-(2-((2-([1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoate (Compound 117)

参照实施例1的方法，将4-三氟甲氧基苯甲醛替换为4-苯基苯甲醛制得化合物117(白色固体，185mg，收率96％):1H NMR(400MHz,DMSO-d6)δ7.83–7.77(m,4H),7.76–7.72(m,3H),7.51–7.46(m,2H),7.39(ddt,J＝13.8,7.4,1.0Hz,2H),7.28–7.20(m,3H),7.04(dd,J＝8.4,1.1Hz,1H),6.81(td,J＝7.5,1.0Hz,1H),6.60(dd,J＝7.6,1.6Hz,1H),5.53(s,2H),4.02–3.98(m,2H),3.96(t,J＝7.1Hz,2H),2.21(t,J＝7.3Hz,2H),1.64(p,J＝6.5Hz,2H),1.51(p,J＝7.4Hz,2H),1.34(dt,J＝11.7,6.8Hz,2H),1.10(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+519.3. Referring to the method of Example 1, 4-trifluoromethoxybenzaldehyde was replaced by 4-phenylbenzaldehyde to prepare compound 117 (white solid, 185 mg, yield 96%): 1 H NMR (400 MHz, DMSO-d 6 ) δ7.83–7.77 (m, 4H), 7.76–7.72 (m, 3H), 7.51–7.46 (m, 2H), 7.39 (ddt, J=13.8, 7.4, 1.0 Hz, 2H), 7.28–7.20 (m, 3H), 7.04 (dd, J=8.4, 1.1 Hz, 1H), 6.81 (td, J=7.5, 1.0 Hz, 1H), 6.60 (dd, J=7.6, 1.6 Hz, 1 H),5.53(s,2H),4.02–3.98(m,2H),3.96(t,J＝7.1Hz,2H),2.21(t,J＝7.3Hz,2H),1.64(p,J＝6.5Hz,2H),1.51(p,J＝7.4Hz,2H),1.34(dt,J＝11.7,6.8Hz, 2H),1.10(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H] + 519.3.

实施例118Embodiment 118

6-(2-((2-([1,1'-联苯]-4-基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸(化合物118)
6-(2-((2-([1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid (Compound 118)

参照实施例2的方法，将化合物1替换为化合物117制得化合物118(白色固体，120mg，收率84％):1H NMR(400MHz,DMSO-d6)δ11.99(s,1H),7.84–7.78(m,4H),7.77–7.72(m,3H),7.49(dd,J＝8.4,6.9Hz,2H),7.43–7.38(m,2H),7.31–7.21(m,3H),7.04(d,J＝8.2Hz,1H),6.80(td,J＝7.5,1.0Hz,1H),6.61(dd,J＝7.6,1.7Hz,1H),5.55(s,2H),3.99(t,J＝6.4Hz,2H),2.15(t,J＝7.3Hz,2H),1.63(p,J＝6.6Hz,2H),1.49(p,J＝7.4Hz,2H),1.33(tt,J＝9.4,5.9Hz,2H).HRMS(ESI)calcd.for C32H30N2O3[M+H]+490.2329,found 491.2328.Referring to the method of Example 2, compound 1 was replaced by compound 117 to obtain compound 118 (white solid, 120 mg, yield 84%): 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.99 (s, 1H), 7.84–7.78 (m, 4H), 7.77–7.72 (m, 3H), 7.49 (dd, J=8.4, 6.9 Hz, 2H), 7.43–7.38 (m, 2H), 7.31–7.21 (m, 3H), 7.04 (d, J=8.2 Hz, 1H), 6.80 (td, J=7.5, 1.0 Hz, 1H), 6.61 (dd,J＝7.6,1.7Hz,1H),5.55(s,2H),3.99(t,J＝6.4Hz,2H),2.15(t,J＝7.3Hz,2H),1.63(p,J＝6.6Hz,2H),1.49(p,J＝7.4Hz,2H),1.33(tt,J＝9.4,5.9Hz,2H) .HRMS(ESI)calcd.for C 32 H 30 N 2 O 3 [M+H] + 490.2329,found 491.2328.

实施例119Embodiment 119

4-((2-(2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯甲酸乙酯(化合物119)
Ethyl 4-((2-(2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)benzoate (Compound 119)

参照实施例69化合物69的合成方法，将化合物2-羟基苯甲酸乙酯替换为4-羟基-苯甲酸乙酯制得化合物119(白色固体，106mg，74％):1H NMR(300MHz,DMSO-d6)δ7.90(d,J＝8.3Hz,2H),7.78(t,J＝7.5Hz,3H),7.57(d,J＝7.5Hz,1H),7.49(d,J＝8.4Hz,2H),7.40(d,J＝7.6Hz,1H),7.33–7.19(m,4H),7.08(d,J＝8.4Hz,2H),6.46(d,J＝7.7Hz,1H),5.73(s,2H),5.33(s,2H),4.27(q,J＝7.1Hz,2H),1.30(t,J＝7.3Hz,3H).Referring to the synthesis method of compound 69 in Example 69, the compound 2-hydroxybenzoic acid ethyl ester was replaced with 4-hydroxy-benzoic acid ethyl ester to prepare compound 119 (white solid, 106 mg, 74%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.90(d,J＝8.3Hz,2H),7.78(t,J＝7.5Hz,3H),7.57(d,J＝7.5Hz,1H),7.49(d,J＝8.4Hz,2H),7.40(d,J＝7.6Hz,1H),7.33–7.19(m,4H),7.08(d,J＝8.4Hz, 2H), 6.46 (d, J = 7.7Hz, 1H), 5.73 (s, 2H), 5.33 (s, 2H), 4.27 (q, J = 7.1Hz, 2H), 1.30 (t, J = 7.3Hz, 3H).

实施例120Embodiment 120

4-((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄氧基)苯甲酸(化合物120)
4-((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyloxy)benzoic acid (Compound 120)

参照实施例2的方法，将化合物1替换为化合物119制得化合物120(白色固体，78mg，收率84％):1H NMR(300MHz,DMSO-d6)δ12.67(s,1H),7.91–7.86(m,2H),7.83–7.75(m,3H),7.60–7.55(m,1H),7.50(d,J＝8.3Hz,2H),7.43–7.37(m,1H),7.33–7.20(m,4H),7.09–7.02(m,2H),6.47(d,J＝7.6Hz,1H),5.73(s,2H),5.31(s,2H).Referring to the method of Example 2, Compound 1 was replaced by Compound 119 to obtain Compound 120 (white solid, 78 mg, yield 84%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.67 (s, 1H), 7.91–7.86 (m, 2H), 7.83–7.75 (m, 3H), 7.60–7.55 (m, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.43–7.37 (m, 1H), 7.33–7.20 (m, 4H), 7.09–7.02 (m, 2H), 6.47 (d, J=7.6 Hz, 1H), 5.73 (s, 2H), 5.31 (s, 2H).

实施例121Embodiment 121

3-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯丙酸乙酯(化合物121)
Ethyl 3-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenylpropanoate (Compound 121)

参照实施例69化合物69的合成方法，将化合物2-羟基苯甲酸乙酯替换为2-羟基-苯丙酸乙酯制得化合物121(白色固体，122mg，84％):1H NMR(400MHz,DMSO-d6)δ7.83–7.75(m,3H),7.60(dd,J＝7.6,1.4Hz,1H),7.51–7.45(m,2H),7.39–7.19(m,6H),7.15(dd,J＝7.5,1.7Hz,1H),7.07(dd,J＝8.3,1.1Hz,1H),6.89(td,J＝7.4,1.1Hz,1H),6.49(d,J＝7.6Hz,1H),5.75(s,2H),5.25(s,2H),3.97(q,J＝7.1Hz,2H),2.80(t,J＝7.5Hz,2H),2.49(t,J＝4.6Hz,2H),1.08(t,J＝7.1Hz,3H).Referring to the synthesis method of compound 69 in Example 69, the compound 2-hydroxybenzoic acid ethyl ester was replaced with 2-hydroxy-phenylpropionic acid ethyl ester to obtain compound 121 (white solid, 122 mg, 84%): 1 H NMR (400 MHz, DMSO-d 6 )δ7.83–7.75(m,3H),7.60(dd,J＝7.6,1.4Hz,1H),7.51–7.45(m,2H),7.39–7.19(m,6H),7.15(dd,J＝7.5,1.7Hz,1H),7.07(dd,J＝8.3,1.1Hz,1H),6.89(t d,J＝7.4,1.1Hz,1H),6.49(d,J＝7.6Hz,1H),5.75(s,2H),5.25(s,2H),3.97(q,J＝7.1Hz,2H),2.80(t,J＝7.5Hz,2H),2.49(t,J＝4.6Hz,2H),1.08(t,J＝7 .1Hz,3H).

实施例122Embodiment 122

3-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯丙酸(化合物122)
3-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)benzenepropanoic acid (Compound 122)

参照实施例2的方法，将化合物1替换为化合物121制得化合物122(白色固体，83mg，收率80％):1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),7.86–7.73(m,3H),7.60(dd,J＝7.5,1.4Hz,1H),7.50–7.45(m,2H),7.39–7.36(m,1H),7.34–7.15(m,6H),7.09–7.04(m,1H),6.89(td,J＝7.4,1.1Hz,1H),6.48(d,J＝7.7Hz,1H),5.75(s,2H),5.24(s,2H),2.79(t,J＝7.6Hz,2H),2.44(t,J＝7.6Hz,2H).Referring to the method of Example 2, Compound 1 was replaced by Compound 121 to obtain Compound 122 (white solid, 83 mg, yield 80%): 1 H NMR (400 MHz, DMSO-d 6 )δ12.08(s,1H),7.86–7.73(m,3H),7.60(dd,J＝7.5,1.4Hz,1H),7.50–7.45(m,2H),7.39–7.36(m,1H),7.34–7.15(m,6H),7.09–7.04(m,1H),6.89(t d,J＝7.4,1.1Hz,1H),6.48(d,J＝7.7Hz,1H),5.75(s,2H),5.24(s,2H),2.79(t,J＝7.6Hz,2H),2.44(t,J＝7.6Hz,2H).

实施例123Embodiment 123

3-(4-((2-((2-((4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)丙酸乙酯(化合物123)
Ethyl 3-(4-((2-((2-((4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)propanoate (Compound 123)

参照实施例69化合物69的合成方法，将化合物2-羟基苯甲酸乙酯替换为4-羟基-苯丙酸乙酯制得化合物123(白色固体，122mg，84％):1H NMR(400MHz,DMSO-d6)δ7.81–7.76(m,3H),7.54(dd,J＝7.6,1.4Hz,1H),7.51–7.47(m,2H),7.42–7.38(m,1H),7.32–7.24(m,4H),7.14–7.10(m,2H),6.89–6.85(m,2H),6.45(d,J＝7.6Hz,1H),5.72(s,2H),5.19(s,2H),4.02(q,J＝7.1Hz,2H),2.77(t,J＝7.5Hz,2H),2.55(t,J＝7.5Hz,2H),1.13(t,J＝7.1Hz,3H).MS(ESI):m/z[M+H]+575.2.Referring to the synthesis method of compound 69 in Example 69, the compound 2-hydroxybenzoic acid ethyl ester was replaced with 4-hydroxy-phenylpropionic acid ethyl ester to obtain compound 123 (white solid, 122 mg, 84%): 1 H NMR (400 MHz, DMSO-d 6 )δ7.81–7.76(m,3H),7.54(dd,J＝7.6,1.4Hz,1H),7.51–7.47(m,2H),7.42–7.38(m,1H),7.32–7.24(m,4H),7.14–7.10(m,2H),6.89–6.85(m,2H),6. 45(d,J＝7.6Hz,1H),5.72(s,2H),5.19(s,2H),4.02(q,J＝7.1Hz,2H),2.77(t,J＝7.5Hz,2H),2.55(t,J＝7.5Hz,2H),1.13(t,J＝7.1Hz,3H).MS(ESI):m/z[M +H] + 575.2.

实施例124Embodiment 124

3-(4-((2-((2-((4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)氧基)苯基)丙酸(化合物124)
3-(4-((2-((2-((4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)oxy)phenyl)propanoic acid (Compound 124)

参照实施例2的方法，将化合物1替换为化合物123制得化合物124(白色固体，82mg，收率79％):1H NMR(300MHz,DMSO-d6)δ12.11(s,1H),7.84–7.76(m,3H),7.57–7.47(m,3H),7.39(dd,J＝7.9,1.6Hz,1H),7.32–7.24(m,3H),7.20(td,J＝7.7,1.5Hz,1H),7.15–7.10(m,2H),6.90–6.85(m,2H),6.47–6.42(m,1H),5.72(s,2H),5.18(s,2H),2.74(t,J＝7.5Hz,2H),2.49–2.45(t,2H).HRMS(ESI)calcd.for C31H25F3N2O4[M+H]+547.1839,found 547.1852.Referring to the method of Example 2, Compound 1 was replaced by Compound 123 to obtain Compound 124 (white solid, 82 mg, yield 79%): 1 H NMR (300 MHz, DMSO-d 6 )δ12.11(s,1H),7.84–7.76(m,3H),7.57–7.47(m,3H),7.39(dd,J＝7.9,1.6Hz,1H),7.32–7.24(m,3H),7.20(td,J＝7.7,1.5Hz,1H),7.15–7.10(m,2H) ,6.90–6.85(m,2H),6.47–6.42(m,1H),5.72(s,2H),5.18(s,2H),2.74(t,J＝7.5Hz,2H),2.49–2.45(t,2H).HRMS(ESI)calcd.for C 31 H 25 F 3 N 2 O 4 [M+H] + 5 47.1839,found 547.1852.

实施例125Embodiment 125

2-(3-((2-((2-((4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)硫基)苯基)乙酸乙酯(化合物125)
Ethyl 2-(3-((2-((2-((4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)thio)phenyl)acetate (Compound 125)

化合物XIII-1的合成Synthesis of compound XIII-1

将化合物VIII-4(600mg，1.5mmol)溶于无水二氯甲烷(5mL)，加入三乙胺(303mg，3.0mmol)，在冰水浴条件下，缓慢加入甲基磺酰氯(258mg，2.25mmol)，升温至室温搅拌反应4小时。TLC监测反应，待反应完全后，在冰浴条件下，缓慢滴加入水(5mL)淬灭反应，二氯甲烷(10mL x3)萃取，合并有机相，无水硫酸钠干燥，减压蒸除溶剂得中间体，将该中间体溶于乙腈(5mL)，加入碳酸钾(414mg，3.0mmol)和硫代乙酸(150mg，1.95mmol)，室温搅拌6小时。TLC监测反应，待反应完全后，减压蒸除溶剂，加入水(10mL)稀释，乙酸乙酯(20mL x3)萃取，合并有机相，无水硫酸钠干燥过夜，减压蒸除溶剂得化合物XIII-1(黄色固体，510mg，两步产率：61％)。Compound VIII-4 (600 mg, 1.5 mmol) was dissolved in anhydrous dichloromethane (5 mL), triethylamine (303 mg, 3.0 mmol) was added, and methylsulfonyl chloride (258 mg, 2.25 mmol) was slowly added under ice-water bath conditions, and the temperature was raised to room temperature and stirred for 4 hours. The reaction was monitored by TLC. After the reaction was complete, water (5 mL) was slowly added dropwise under ice bath conditions to quench the reaction, and dichloromethane (10 mL x 3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain an intermediate, which was dissolved in acetonitrile (5 mL), potassium carbonate (414 mg, 3.0 mmol) and thioacetic acid (150 mg, 1.95 mmol) were added, and stirred at room temperature for 6 hours. The reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure, and water (10 mL) was added to dilute it. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate overnight. The solvent was evaporated under reduced pressure to obtain compound XIII-1 (yellow solid, 510 mg, two-step yield: 61%).

化合物XIII-2的合成 Synthesis of compound XIII-2

将化合物XIII-1(510mg，1.12mmol)溶于甲醇(5mL)，加入碳酸钾(235mg，1.70mmol)，室温搅拌反应8小时。TLC监测反应，待反应完全后，加入1N盐酸(1mL)淬灭反应，减压蒸除溶剂，加入水(10mL)稀释，乙酸乙酯(20mL x3)萃取，合并有机相，减压蒸除溶剂，残余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)得化合物XIII-2(浅黄色固体，180mg，39％)。1H NMR(300MHz,DMSO-d6)δ7.81–7.76(m,3H),7.43(d,J＝8.2Hz,2H),7.28(ddd,J＝7.2,3.8,1.9Hz,3H),7.25–7.17(m,2H),7.16–7.09(m,1H),6.41(d,J＝7.2Hz,1H),5.70(s,2H),3.99(s,2H).Compound XIII-1 (510 mg, 1.12 mmol) was dissolved in methanol (5 mL), potassium carbonate (235 mg, 1.70 mmol) was added, and the mixture was stirred at room temperature for 8 hours. The reaction was monitored by TLC. After the reaction was complete, 1N hydrochloric acid (1 mL) was added to quench the reaction, the solvent was evaporated under reduced pressure, water (10 mL) was added to dilute, and ethyl acetate (20 mL x3) was used for extraction. The organic phases were combined, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain compound XIII-2 (light yellow solid, 180 mg, 39%). 1 H NMR (300MHz, DMSO-d 6 ) δ7.81–7.76(m,3H),7.43(d,J＝8.2Hz,2H),7.28(ddd,J＝7.2,3.8,1.9Hz,3H),7.25–7.17(m,2H),7.16–7.09(m,1H),6.41(d,J＝ 7.2Hz,1H),5.70(s,2H),3.99(s,2H).

化合物125的合成Synthesis of compound 125

在氩气保护条件下，将化合物XIII-2(141mg，0.34mmol)，Pd2(dba)3(32mg，0.034mmol)，Xantphos(40mg，0.068mmol)溶于或悬浮于1,4-二氧六环溶剂(5mL)，再加入2-(3-溴苯基)乙酸乙酯(108mg，0.44mmol)和DIPEA(88mg，0.68mmol)，升温至110℃搅拌反应12小时。TLC监测反应，待反应完全后，硅藻土抽滤，减压蒸除溶剂，残余物经硅胶柱层析纯化(石油醚:乙酸乙酯＝10:1)得化合物125(黄色油状液体，80mg，41％):1H NMR(400MHz,DMSO-d6)δ7.83–7.76(m,3H),7.52–7.48(m,2H),7.35–7.26(m,4H),7.25(dd,J＝4.2,3.0Hz,2H),7.24–7.20(m,1H),7.16(td,J＝7.4,1.5Hz,1H),7.13–7.08(m,2H),6.40–6.36(m,1H),5.79(s,2H),4.35(s,2H),4.04(t,J＝7.1Hz,2H),3.62(s,2H),1.15(t,J＝7.1Hz,3H).Under argon protection, compound XIII-2 (141 mg, 0.34 mmol), Pd 2 (dba) 3 (32 mg, 0.034 mmol), Xantphos (40 mg, 0.068 mmol) were dissolved or suspended in 1,4-dioxane solvent (5 mL), and ethyl 2-(3-bromophenyl)acetate (108 mg, 0.44 mmol) and DIPEA (88 mg, 0.68 mmol) were added, and the temperature was raised to 110°C and stirred for 12 hours. The reaction was monitored by TLC. After the reaction was complete, diatomaceous earth was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound 125 (yellow oily liquid, 80 mg, 41%): 1 H NMR (400 MHz, DMSO-d 6 )δ7.83–7.76(m,3H),7.52–7.48(m,2H),7.35–7.26(m,4H),7.25(dd,J＝4.2,3.0Hz,2H),7.24–7.20(m,1H),7.16(td,J＝7.4,1.5Hz,1H),7.13–7.08(m ,2H),6.40–6.36(m,1H),5.79(s,2H),4.35(s,2H),4.04(t,J＝7.1Hz,2H),3.62(s,2H),1.15(t,J＝7.1Hz,3H).

实施例126Embodiment 126

2-(3-((2-((2-((4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苄基)硫基)苯基)乙酸(化合物126)
2-(3-((2-((2-((4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)benzyl)thio)phenyl)acetic acid (Compound 126)

参照实施例2的方法，将化合物1替换为化合物125制得化合物126(白色固体，42mg，收率30％):1H NMR(300MHz,DMSO-d6)δ12.41(s,1H),7.79(td,J＝7.1,1.6Hz,3H),7.53–7.47(m,2H),7.34–7.25(m,5H),7.23–7.15(m,3H),7.13–7.06(m,2H),6.37(dd,J＝7.6,1.5Hz,1H),5.80(s,2H),4.35(s,2H),3.50(s,2H).Referring to the method of Example 2, Compound 1 was replaced by Compound 125 to obtain Compound 126 (white solid, 42 mg, yield 30%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.41 (s, 1H), 7.79 (td, J = 7.1, 1.6 Hz, 3H), 7.53-7.47 (m, 2H), 7.34-7.25 (m, 5H), 7.23-7.15 (m, 3H), 7.13-7.06 (m, 2H), 6.37 (dd, J = 7.6, 1.5 Hz, 1H), 5.80 (s, 2H), 4.35 (s, 2H), 3.50 (s, 2H).

实施例127Embodiment 127

2-(3-(((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯基)硫)甲基)苯基)乙酸乙酯(化合物127)

Ethyl 2-(3-(((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl)thio)methyl)phenyl)acetate (Compound 127)

化合物XIV-1的合成Synthesis of compound XIV-1

将(2-巯基苯基)甲醇(136mg，0.97mmol)溶于乙腈(10mL)，加入碳酸钾(201mg，1.46mmol)和3-溴甲基苯乙酸乙酯(299mg，1.16mmol)，室温搅拌反应8小时。TLC监测反应，待反应完全后，抽滤除去碳酸钾，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝10:1)纯化得化合物XIV-1(无色油状液体，220mg，收率72％)：1H NMR(300MHz,Chloroform-d)δ7.44–7.35(m,2H),7.27(d,J＝1.2Hz,1H),7.25–7.19(m,2H),7.16–7.02(m,3H),4.58(s,2H),4.14(q,J＝7.1Hz,2H),4.04(s,2H),3.53(s,2H),1.26(d,J＝7.2Hz,3H).(2-Mercaptophenyl)methanol (136 mg, 0.97 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (201 mg, 1.46 mmol) and ethyl 3-bromomethylphenylacetate (299 mg, 1.16 mmol) were added, and the mixture was stirred at room temperature for 8 hours. The reaction was monitored by TLC. After the reaction was complete, potassium carbonate was removed by suction filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound XIV-1 (colorless oily liquid, 220 mg, yield 72%): 1 H NMR (300 MHz, Chloroform-d) δ7.44-7.35 (m, 2H), 7.27 (d, J = 1.2 Hz, 1H), 7.25-7.19 (m, 2H), 7.16-7.02 (m, 3H), 4.58 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 4.04 (s, 2H), 3.53 (s, 2H), 1.26 (d, J = 7.2 Hz, 3H).

化合物XIV-2的合成Synthesis of Compound XIV-2

将化合物XIV-1(215mg，0.68mmol)溶于二氯甲烷(5mL)，在冰浴条件下加入四溴化碳(338mg，1.02mmol)，缓慢加入三苯基膦(250mg，0.95mmol)，缓慢升至室温搅拌反应3小时。TLC监测反应，待反应完全后，减压蒸除溶剂，残余物经硅胶柱层析(石油醚:乙酸乙酯＝30:1)纯化，得化合物XIV-2(无色油状液体，232mg，收率90％)。Compound XIV-1 (215 mg, 0.68 mmol) was dissolved in dichloromethane (5 mL), and carbon tetrabromide (338 mg, 1.02 mmol) was added under ice bath conditions, and triphenylphosphine (250 mg, 0.95 mmol) was slowly added, and the mixture was slowly heated to room temperature and stirred for 3 hours. The reaction was monitored by TLC, and after the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound XIV-2 (colorless oily liquid, 232 mg, yield 90%).

化合物127的合成Synthesis of compound 127

参考化合物1的合成，将化合物I-3替换为化合物XIV-2制得化合物127(无色油状液体，110mg，47％):1H NMR(400MHz,DMSO-d6)δ7.77–7.73(m,3H),7.53(dd,J＝7.9,1.2Hz,1H),7.51–7.47(m,2H),7.29–7.23(m,3H),7.19(ddd,J＝9.4,6.4,1.2Hz,3H),7.16–7.12(m,1H),7.12–7.06(m,2H),6.52(dd,J＝7.8,1.4Hz,1H),5.45(s,2H),4.19(s,2H),4.00(q,J＝7.1Hz,2H),3.59(s,2H),1.12(t,J＝7.1Hz,3H).Referring to the synthesis of compound 1, compound I-3 was replaced by compound XIV-2 to obtain compound 127 (colorless oily liquid, 110 mg, 47%): 1 H NMR (400 MHz, DMSO-d 6 )δ7.77–7.73(m,3H),7.53(dd,J＝7.9,1.2Hz,1H),7.51–7.47(m,2H),7.29–7.23(m,3H),7.19(ddd,J＝9.4,6.4,1.2Hz,3H),7.16–7.12(m,1H),7.12–7. 06(m,2H),6.52(dd,J＝7.8,1.4Hz,1H),5.45(s,2H),4.19(s,2H),4.00(q,J＝7.1Hz,2H),3.59(s,2H),1.12(t,J＝7.1Hz,3H).

实施例128Embodiment 128

2-(3-(((2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯基)硫)甲基)苯基)乙酸(化合物128)
2-(3-(((2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl)thio)methyl)phenyl)acetic acid (Compound 128)

参照实施例2的方法，将化合物1替换为化合物127制得化合物128(白色固体，50mg，收率51％):1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),7.75(dd,J＝8.3,4.0Hz,3H),7.55–7.47(m,3H),7.29–7.15(m,6H),7.14–7.07(m,3H),6.51(d,J＝7.7Hz,1H),5.46(s,2H),4.19(s,2H),3.51(s,2H). Referring to the method of Example 2, Compound 1 was replaced by Compound 127 to obtain Compound 128 (white solid, 50 mg, yield 51%): 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.33 (s, 1H), 7.75 (dd, J = 8.3, 4.0 Hz, 3H), 7.55–7.47 (m, 3H), 7.29–7.15 (m, 6H), 7.14–7.07 (m, 3H), 6.51 (d, J = 7.7 Hz, 1H), 5.46 (s, 2H), 4.19 (s, 2H), 3.51 (s, 2H).

实施例129Embodiment 129

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸钠盐(化合物129)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid sodium salt (Compound 129)

将化合物2(400mg，0.8mmol)溶于乙醇/水(5mL/0.1mL)，加入氢氧化钠(32mg，0.8mmol)，升温至80℃搅拌反应6小时。冷却至室温，减压蒸除溶剂，残余物悬浮于水(3mL)，室温搅拌6小时，抽滤得白色固体，将残余物悬浮于无水乙醚(5mL)，室温搅拌6小时，抽滤，立即干燥得化合物129(334mg，80％):1H NMR(300MHz,DMSO-d6)δ7.85–7.79(m,2H),7.76–7.70(m,1H),7.51(d,J＝8.3Hz,2H),7.45–7.37(m,1H),7.28–7.18(m,3H),6.99(d,J＝8.2Hz,1H),6.79–6.71(m,1H),6.54(dd,J＝7.6,1.7Hz,1H),5.50(s,2H),3.93(t,J＝6.5Hz,2H),1.85(t,J＝7.3Hz,2H),1.61–1.54(m,2H),1.49–1.38(m,2H),1.34–1.22(m,2H).Compound 2 (400 mg, 0.8 mmol) was dissolved in ethanol/water (5 mL/0.1 mL), sodium hydroxide (32 mg, 0.8 mmol) was added, and the mixture was heated to 80°C and stirred for 6 hours. The mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was suspended in water (3 mL), stirred at room temperature for 6 hours, and filtered to obtain a white solid. The residue was suspended in anhydrous ether (5 mL), stirred at room temperature for 6 hours, filtered, and dried immediately to obtain compound 129 (334 mg, 80%): 1 H NMR (300 MHz, DMSO-d 6 )δ7.85–7.79(m,2H),7.76–7.70(m,1H),7.51(d,J＝8.3Hz,2H),7.45–7.37(m,1H),7.28–7.18(m,3H),6.99(d,J＝8.2Hz,1H),6.79–6.71(m,1H),6.54 (dd,J＝7.6,1.7Hz,1H),5.50(s,2H),3.93(t,J＝6.5Hz,2H),1.85(t,J＝7.3Hz,2H),1.61–1.54(m,2H),1.49–1.38(m,2H),1.34–1.22(m,2H).

实施例130Embodiment 130

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸镁盐(化合物130)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid magnesium salt (Compound 130)

参照实施例129的方法，将氢氧化钠替换为氢氧化镁制得化合物130(白色固体，293mg，98％):1H NMR(400MHz,DMSO-d6)δ7.82–7.78(m,2H),7.71(dd,J＝6.8,2.1Hz,1H),7.47(d,J＝8.3Hz,2H),7.40–7.35(m,1H),7.25–7.15(m,3H),6.94(d,J＝8.2Hz,1H),6.72(t,J＝7.5Hz,1H),6.52(dd,J＝7.5,1.7Hz,1H),5.46(s,2H),3.88(t,J＝6.5Hz,2H),1.91(t,J＝7.4Hz,2H),1.57–1.50(m,2H),1.42(p,J＝7.4Hz,2H),1.26(q,J＝8.3,7.8Hz,2H).Referring to the method of Example 129, the sodium hydroxide was replaced by magnesium hydroxide to obtain compound 130 (white solid, 293 mg, 98%): 1 H NMR (400 MHz, DMSO-d 6 )δ7.82–7.78(m,2H),7.71(dd,J＝6.8,2.1Hz,1H),7.47(d,J＝8.3Hz,2H),7.40–7.35(m,1H),7.25–7.15(m,3H),6.94(d,J＝8.2Hz,1H),6.72(t,J＝7.5Hz,1 H),6.52(dd,J＝7.5,1.7Hz,1H),5.46(s,2H),3.88(t,J＝6.5Hz,2H),1.91(t,J＝7.4Hz,2H),1.57–1.50(m,2H),1.42(p,J＝7.4Hz,2H),1.26(q,J＝8.3,7. 8Hz,2H).

实施例131Embodiment 131

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸钾盐(化合物131)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid potassium salt (Compound 131)

参照实施例129的方法，将氢氧化钠替换为氢氧化钾制得化合物131(白色固体，61mg，57％):1H NMR(400MHz,DMSO-d6)δ7.84–7.79(m,2H),7.75–7.70(m,1H),7.50(d,J＝8.3Hz,2H),7.41(dd,J＝6.4,2.6Hz,1H),7.26–7.16(m,3H),6.97(d,J＝8.2Hz,1H),6.74(t,J＝7.5Hz,1H),6.52(dd,J＝7.6,1.7Hz,1H),5.49(s,2H),3.91(t,J＝6.5Hz,2H),1.89(t,J＝7.4Hz,2H),1.61–1.52(m,2H),1.46–1.37(m,2H),1.30–1.22(m,2H).Referring to the method of Example 129, the sodium hydroxide was replaced by potassium hydroxide to prepare compound 131 (white solid, 61 mg, 57%): 1 H NMR (400 MHz, DMSO-d 6 )δ7.84–7.79(m,2H),7.75–7.70(m,1H),7.50(d,J＝8.3Hz,2H),7.41(dd,J＝6.4,2.6Hz,1H),7.26–7.16(m,3H),6.97(d,J＝8.2Hz,1H),6.74(t,J＝7.5Hz, 1H),6.52(dd,J＝7.6,1.7Hz,1H),5.49(s,2H),3.91(t,J＝6.5Hz,2H),1.89(t,J＝7.4Hz,2H),1.61–1.52(m,2H),1.46–1.37(m,2H),1.30–1.22(m,2H).

实施例132Embodiment 132

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸，(2R,3R,4R,5S)-6-(甲基氨基)-1,2,3,4,5-戊醇己烷盐(化合物132)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid, (2R,3R,4R,5S)-6-(methylamino)-1,2,3,4,5-pentanol hexane salt (Compound 132)

参照实施例129的方法，将氢氧化钠替换为葡甲胺制得化合物132(白色固体，256mg，92％):1H NMR(400MHz,DMSO-d6)δ7.84–7.78(m,2H),7.75–7.70(m,1H),7.50(d,J＝8.3Hz,2H),7.44–7.38(m,1H),7.27–7.18(m,3H),6.99(d,J＝8.2Hz,1H),6.78–6.72(m,1H),6.55(dd,J＝7.6,1.7Hz,1H),5.49(s,2H),3.93(t,J＝6.4Hz,2H),3.69–3.61(m,3H),3.59(d,J＝3.5Hz,1H),3.56(d,J＝3.5Hz,1H),3.51–3.32(m,6H),2.57(d,J＝4.7Hz,2H),2.27(s,3H),2.00(t,J＝7.4Hz,2H),1.57(q,J＝7.0Hz,2H),1.45(p,J＝7.4Hz,2H),1.28(qd,J＝9.4,8.8,5.8Hz,2H).Referring to the method of Example 129, the sodium hydroxide was replaced by meglumine to obtain compound 132 (white solid, 256 mg, 92%): 1 H NMR (400 MHz, DMSO-d 6 ) δ7.84–7.78 (m, 2H), 7.75–7.70 (m, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.44–7.38 (m, 1H), 7.27–7.18 (m, 3H), 6.99 (d, J=8.2 Hz, 1H), 6.78–6.72 (m, 1H), 6.55 (dd, J=7.6, 1.7 Hz, 1H), 5.49 (s, 2H), 3.93 (t, J=6.4 Hz, 2H), 3.69–3. 3.61(m,3H),3.59(d,J＝3.5Hz,1H),3.56(d,J＝3.5Hz,1H),3.51–3.32(m,6H),2.57(d,J＝4.7Hz,2H),2.27(s,3H),2.00(t,J＝7.4Hz,2H),1.57(q,J＝7. 0Hz, 2H), 1.45 (p, J＝7.4Hz, 2H), 1.28 (qd, J＝9.4, 8.8, 5.8Hz, 2H).

实施例133Embodiment 133

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸，2-氨基-2-羟甲基-1,3-丙二醇盐(化合物133)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid, 2-amino-2-hydroxymethyl-1,3-propanediol salt (Compound 133)

参照实施例129的方法，将氢氧化钠替换为氨丁三醇制得化合物133(白色固体，218mg，84％):1H NMR(400MHz,DMSO-d6)δ7.84–7.78(m,2H),7.75–7.70(m,1H),7.52–7.47(m,2H),7.43–7.38(m,1H),7.27–7.18(m,3H),6.99(dd,J＝8.4,1.0Hz,1H),6.75(td,J＝7.5,1.0Hz,1H),6.55(dd,J＝7.6,1.6Hz,1H),5.49(s,2H),3.93(t,J＝6.4Hz,2H),3.23(s,6H),2.00(t,J＝7.4Hz,2H),1.58(p,J＝6.7Hz,2H),1.45(p,J＝7.4Hz,2H), 1.28(qd,J＝9.6,9.1,6.3Hz,2H).Referring to the method of Example 129, the sodium hydroxide was replaced by tromethamine to prepare compound 133 (white solid, 218 mg, 84%): 1 H NMR (400 MHz, DMSO-d 6 )δ7.84–7.78(m,2H),7.75–7.70(m,1H),7.52–7.47(m,2H),7.43–7.38(m,1H),7.27–7.18(m,3H),6.99(dd,J＝8.4,1.0Hz,1H),6.75(td,J＝7.5,1.0Hz, 1H),6.55(dd,J＝7.6,1.6Hz,1H),5.49(s,2H),3.93(t,J＝6.4Hz,2H),3.23(s,6H),2.00(t,J＝7.4Hz,2H),1.58(p,J＝6.7Hz,2H),1.45(p,J＝7.4Hz,2H), 1.28(qd,J＝9.6,9.1,6.3Hz,2H).

实施例134Embodiment 134

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸，L-精氨酸盐(化合物134)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid, L-arginine salt (Compound 134)

参照实施例129的方法，将氢氧化钠替换为精氨酸制得化合物134(白色固体，252mg，94％):1H NMR(400MHz,DMSO-d6)δ8.36(s,2H),7.84–7.80(m,2H),7.74–7.71(m,1H),7.50(d,J＝8.3Hz,2H),7.44–7.40(m,1H),7.27–7.18(m,3H),6.99(d,J＝8.2Hz,1H),6.77–6.73(m,1H),6.54(dd,J＝7.6,1.7Hz,1H),5.49(s,2H),3.93(t,J＝6.5Hz,2H),3.15–3.08(m,1H),3.02(dq,J＝14.0,6.5Hz,2H),1.94(t,J＝7.4Hz,2H),1.69–1.36(m,8H),1.29(td,J＝8.5,4.2Hz,2H).Referring to the method of Example 129, sodium hydroxide was replaced with arginine to obtain compound 134 (white solid, 252 mg, 94%): 1 H NMR (400 MHz, DMSO-d 6 ) δ8.36 (s, 2H), 7.84–7.80 (m, 2H), 7.74–7.71 (m, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.44–7.40 (m, 1H), 7.27–7.18 (m, 3H), 6.99 (d, J=8.2 Hz, 1H), 6.77–6.73 (m, 1H), 6.54 (dd, J=7.73 Hz, 2H). .6,1.7Hz,1H),5.49(s,2H),3.93(t,J＝6.5Hz,2H),3.15–3.08(m,1H),3.02(dq,J＝14.0,6.5Hz,2H),1.94(t,J＝7.4Hz,2H),1.69–1.36(m,8H),1.29(t d,J＝8.5,4.2Hz,2H).

实施例135Embodiment 135

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸，L-赖氨酸盐(化合物135)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid, L-lysine salt (Compound 135)

参照实施例129的方法，将氢氧化钠替换为赖氨酸制得化合物135(白色固体，240mg，93％):1H NMR(400MHz,DMSO-d6)δ7.81(d,J＝8.3Hz,2H),7.75–7.70(m,1H),7.50(d,J＝8.2Hz,2H),7.44–7.39(m,1H),7.27–7.18(m,3H),6.98(d,J＝8.2Hz,1H),6.78–6.72(m,1H),6.55(d,J＝7.5Hz,1H),5.49(s,2H),3.93(t,J＝6.5Hz,2H),3.13–3.01(m,1H),2.60–2.51(m,2H),1.99(t,J＝7.4Hz,2H),1.77–1.18(m,12H).Referring to the method of Example 129, the sodium hydroxide was replaced with lysine to obtain compound 135 (white solid, 240 mg, 93%): 1 H NMR (400 MHz, DMSO-d 6 )δ7.81(d,J＝8.3Hz,2H),7.75–7.70(m,1H),7.50(d,J＝8.2Hz,2H),7.44–7.39(m,1H),7.27–7.18(m,3H),6.98(d,J＝8.2Hz,1H),6.78–6.72(m,1H),6.5 5(d,J＝7.5Hz,1H),5.49(s,2H),3.93(t,J＝6.5Hz,2H),3.13–3.01(m,1H),2.60–2.51(m,2H),1.99(t,J＝7.4Hz,2H),1.77–1.18(m,12H).

实施例136Embodiment 136

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸，2-氨基-1-乙醇盐(化合物136)

6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid, 2-amino-1-ethanol salt (Compound 136)

将化合物2(100mg，0.2mmol)溶于二氯甲烷(5mL)，加入乙醇胺(12mg，0.2mmol)，升温至50℃回流搅拌反应6小时。冷却至室温，减压蒸除大部分溶剂，剩余0.5mL二氯甲烷溶剂，缓慢加入无水乙醚，固体析出，抽滤，立即干燥得化合物136(白色固体，88mg，79％):1H NMR(400MHz,DMSO-d6)δ7.83–7.78(m,2H),7.75–7.71(m,1H),7.50(d,J＝8.2Hz,2H),7.44–7.39(m,1H),7.28–7.23(m,2H),7.20(dd,J＝8.1,1.7Hz,1H),6.99(d,J＝8.2Hz,1H),6.76(t,J＝7.4Hz,1H),6.57(dd,J＝7.6,1.7Hz,1H),5.49(s,2H),3.94(t,J＝6.4Hz,2H),3.41(t,J＝5.6Hz,2H),2.64(t,J＝5.6Hz,2H),2.07(t,J＝7.4Hz,2H),1.58(p,J＝6.6Hz,2H),1.47(p,J＝7.5Hz,2H),1.30(td,J＝8.4,3.9Hz,2H).Compound 2 (100 mg, 0.2 mmol) was dissolved in dichloromethane (5 mL), and ethanolamine (12 mg, 0.2 mmol) was added. The mixture was heated to 50°C and stirred under reflux for 6 hours. After cooling to room temperature, most of the solvent was evaporated under reduced pressure, leaving 0.5 mL of dichloromethane solvent. Anhydrous ether was slowly added to precipitate solids, which were filtered and dried immediately to obtain compound 136 (white solid, 88 mg, 79%): 1 H NMR (400 MHz, DMSO-d 6 )δ7.83–7.78(m,2H),7.75–7.71(m,1H),7.50(d,J＝8.2Hz,2H),7.44–7.39(m,1H),7.28–7.23(m,2H),7.20(dd,J＝8.1,1.7Hz,1H),6.99(d,J＝8.2Hz,1H ),6.76(t,J＝7.4Hz,1H),6.57(dd,J＝7.6 ,1.7Hz,1H),5.49(s,2H),3.94(t,J＝6.4Hz,2H),3.41(t,J＝5.6Hz,2H),2.64(t,J＝5.6Hz,2H),2.07(t,J＝7.4Hz,2H),1.58(p,J＝6.6Hz,2H),1.47(p,J＝7 .5Hz,2H),1.30(td,J=8.4,3.9Hz,2H).

实施例137Embodiment 137

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸，2,2'-氮二基双(乙醇)盐(化合物137)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid, 2,2'-nitrodiylbis(ethanol) salt (Compound 137)

参照实施例136的方法，将乙醇胺替换为二乙醇胺制得化合物137(白色固体，92mg，76％):1H NMR(400MHz,DMSO-d6)δ7.84–7.78(m,2H),7.77–7.71(m,1H),7.50(d,J＝8.3Hz,2H),7.44–7.39(m,1H),7.28–7.19(m,3H),6.99(d,J＝8.2Hz,1H),6.80–6.73(m,1H),6.58(dd,J＝7.6,1.7Hz,1H),5.49(s,2H),3.94(t,J＝6.4Hz,2H),3.46(t,J＝5.6Hz,4H),2.62(t,J＝5.6Hz,4H),2.13(t,J＝7.4Hz,2H),1.58(p,J＝6.6Hz,2H),1.48(p,J＝7.4Hz,2H),1.30(q,J＝8.1Hz,2H).Referring to the method of Example 136, ethanolamine was replaced by diethanolamine to obtain Compound 137 (white solid, 92 mg, 76%): 1 H NMR (400 MHz, DMSO-d 6 ) δ7.84-7.78 (m, 2H), 7.77-7.71 (m, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.44-7.39 (m, 1H), 7.28-7.19 (m, 3H), 6.99 (d, J=8.2 Hz, 1H), 6.80-6.73 (m, 1H), 6.58 (dd, J=7.6, 1.7 Hz, 1H), 1.3 0(q,J＝8.1Hz,2H).

实施例138Embodiment 138

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸，2,2',2”-次氮基三(乙醇)盐(化合物138)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid, 2,2',2"-nitrilotri(ethanol) salt (Compound 138)

参照实施例136的方法，将乙醇胺替换为三乙醇胺制得化合物138(白色固体，85mg，66％):1H NMR(400MHz,DMSO-d6)δ7.84–7.79(m,2H),7.76–7.72(m,1H),7.49(d,J＝8.3Hz,2H),7.44–7.39(m,1H),7.28–7.19(m,3H),6.99(d,J＝8.2Hz,1H),6.79–6.74(m,1H),6.60(d,J＝7.6Hz,1H),5.49(s,2H),3.93(t,J＝6.2Hz,2H),3.40(t,J＝6.1Hz,6H),2.55(t,J＝6.1Hz,6H),2.15(t,J＝7.4Hz,2H),1.62–1.54(m,2H),1.52–1.44(m, 2H),1.34–1.23(m,2H).Referring to the method of Example 136, ethanolamine was replaced with triethanolamine to prepare Compound 138 (white solid, 85 mg, 66%): 1 H NMR (400 MHz, DMSO-d 6 )δ7.84–7.79(m,2H),7.76–7.72(m,1H),7.49(d,J＝8.3Hz,2H),7.44–7.39(m,1H),7.28–7.19(m,3H),6.99(d,J＝8.2Hz,1H),6.79–6.74(m,1H),6.60( d,J＝7.6Hz,1H),5.49(s,2H),3.93(t,J＝6.2Hz,2H),3.40(t,J＝6.1Hz,6H),2.55(t,J＝6.1Hz,6H),2.15(t,J＝7.4Hz,2H),1.62–1.54(m,2H),1.52–1.44( m, 2H), 1.34–1.23 (m, 2H).

实施例139Embodiment 139

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸，2-甲基-2-丙胺盐(化合物139)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid, 2-methyl-2-propylamine salt (Compound 139)

参照实施例136的方法，将乙醇胺替换为叔丁胺制得化合物139(白色固体，102mg，89％):1H NMR(400MHz,DMSO-d6)δ7.83–7.78(m,2H),7.75–7.70(m,1H),7.53–7.48(m,2H),7.44–7.39(m,1H),7.27–7.22(m,2H),7.21–7.17(m,1H),7.01–6.96(m,1H),6.79–6.74(m,1H),6.56(dd,J＝7.6,1.7Hz,1H),5.49(s,2H),3.93(t,J＝6.4Hz,2H),2.03(t,J＝7.4Hz,2H),1.62–1.54(m,2H),1.51–1.42(m,2H),1.33–1.26(m,2H),1.12(s,9H).Referring to the method of Example 136, ethanolamine was replaced with tert-butylamine to prepare compound 139 (white solid, 102 mg, 89%): 1 H NMR (400 MHz, DMSO-d 6 )δ7.83–7.78(m,2H),7.75–7.70(m,1H),7.53–7.48(m,2H),7.44–7.39(m,1H),7.27–7.22(m,2H),7.21–7.17(m,1H),7.01–6.96(m,1H),6.79–6.7 4(m,1H),6.56(dd,J＝7.6,1.7Hz,1H),5.49(s,2H),3.93(t,J＝6.4Hz,2H),2.03(t,J＝7.4Hz,2H),1.62–1.54(m,2H),1.51–1.42(m,2H),1.33–1.26(m, 2H),1.12(s,9H).

实施例140Embodiment 140

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸，2-羟基-N,N,N-三甲基乙-1-铵盐(化合物140)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid, 2-hydroxy-N,N,N-trimethyleth-1-ammonium salt (Compound 140)

将化合物2(300mg，0.6mmol)溶于二氯甲烷(5mL)，加入49％胆碱水溶液(148mg，0.6mmol)，升温至50℃回流搅拌反应6小时。冷却至室温，减压蒸除溶剂，加入无水乙醚，固体析出，室温搅拌6小时，抽滤，立即干燥得化合物140(白色固体，336mg，93％):1H NMR(400MHz,Methanol-d4)δ7.79–7.71(m,3H),7.40(d,J＝7.9Hz,3H),7.31(s,2H),7.27–7.18(m,1H),6.96(d,J＝8.3Hz,1H),6.76(t,J＝7.5Hz,1H),6.61(s,1H),5.50(s,2H),4.04–3.92(m,4H),3.51–3.44(m,2H),3.20(s,9H),2.20–2.09(m,2H),1.65(d,J＝28.7Hz,4H),1.41(s,2H).Compound 2 (300 mg, 0.6 mmol) was dissolved in dichloromethane (5 mL), and 49% choline aqueous solution (148 mg, 0.6 mmol) was added. The mixture was heated to 50°C and refluxed with stirring for 6 hours. The mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. Anhydrous ether was added to precipitate a solid. The mixture was stirred at room temperature for 6 hours, filtered, and dried immediately to obtain compound 140 (white solid, 336 mg, 93%): 1 H NMR (400 MHz, Methanol-d 4 )δ7.79–7.71(m,3H),7.40(d,J＝7.9Hz,3H),7.31(s,2H),7.27–7.18(m,1H),6.96(d,J＝8.3Hz,1H),6.76(t,J＝7.5Hz,1H),6.61(s,1H),5.50(s,2H),4 .04–3.92(m,4H),3.51–3.44(m,2H),3.20(s,9H),2.20–2.09(m,2H),1.65(d,J＝28.7Hz,4H),1.41(s,2H).

实施例141Embodiment 141

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸，甘氨酸钠盐(化合物141)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid, glycine sodium salt (Compound 141)

参照实施例136的方法，将乙醇胺替换为甘氨酸钠制得化合物141(白色固体，101mg，66％):1H NMR(400MHz,Methanol-d4)δ7.77–7.72(m,3H),7.44–7.38(m,3H), 7.35–7.28(m,2H),7.23(ddd,J＝8.4,7.5,1.7Hz,1H),6.97(dd,J＝8.3,1.1Hz,1H),6.76(td,J＝7.5,1.0Hz,1H),6.60(dd,J＝7.6,1.6Hz,1H),5.51(s,2H),3.98(t,J＝6.5Hz,2H),3.37(s,2H),2.16(t,J＝7.5Hz,2H),1.70(dt,J＝14.5,6.9Hz,2H),1.65–1.58(m,2H),1.42(tt,J＝9.8,6.2Hz,2H).Referring to the method of Example 136, ethanolamine was replaced with sodium glycine to prepare compound 141 (white solid, 101 mg, 66%): 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.77-7.72 (m, 3H), 7.44-7.38 (m, 3H), 7.35–7.28(m,2H),7.23(ddd,J＝8.4,7.5,1.7Hz,1H),6.97(dd,J＝8.3,1.1Hz,1H),6.76(td,J＝7.5,1.0Hz,1H),6.60(dd,J＝7.6,1.6Hz,1H),5.51(s,2H),3 .98(t,J＝6.5Hz,2H),3.37(s,2H),2.16(t,J＝7.5Hz,2H),1.70(dt,J＝14.5,6.9Hz,2H),1.65–1.58(m,2H),1.42(tt,J＝9.8,6.2Hz,2H).

实施例142Embodiment 142

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸盐酸盐(化合物142)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid hydrochloride (Compound 142)

将化合物2(100mg，0.2mmol)溶于二氯甲烷(5mL)，加入浓盐酸(100uL)，升温至50℃回流搅拌反应6小时。冷却至室温，减压蒸除溶剂，加入无水乙醚，固体析出，抽滤，立即干燥得化合物142(白色固体，95mg，89％):1H NMR(300MHz,DMSO-d6)δ11.73(s,1H),7.98–7.92(m,2H),7.92–7.86(m,1H),7.82–7.77(m,1H),7.68–7.62(m,2H),7.59–7.51(m,2H),7.24(ddd,J＝8.5,7.4,1.7Hz,1H),7.00–6.92(m,2H),6.81–6.75(m,1H),5.65(s,2H),3.86(t,J＝6.3Hz,2H),2.13(t,J＝7.4Hz,2H),1.46–1.35(m,4H),1.20–1.10(m,2H).Compound 2 (100 mg, 0.2 mmol) was dissolved in dichloromethane (5 mL), concentrated hydrochloric acid (100 uL) was added, and the mixture was heated to 50°C and stirred under reflux for 6 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and anhydrous ether was added to precipitate a solid, which was filtered and dried immediately to obtain compound 142 (white solid, 95 mg, 89%): 1 H NMR (300 MHz, DMSO-d 6 )δ11.73(s,1H),7.98–7.92(m,2H),7.92–7.86(m,1H),7.82–7.77(m,1H),7.68–7.62(m,2H),7.59–7.51(m,2H),7.24(ddd,J＝8.5,7.4,1.7Hz,1H),7 .00–6.92(m,2H),6.81–6.75(m,1H),5.65(s,2H),3.86(t,J＝6.3Hz,2H),2.13(t,J＝7.4Hz,2H),1.46–1.35(m,4H),1.20–1.10(m,2H).

实施例143Embodiment 143

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸硫酸盐(化合物143)

6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid sulfate (Compound 143)

将化合物2(100mg，0.2mmol)溶于二氯甲烷(5mL)，加入98％浓硫酸(100uL)，升温至50℃回流搅拌反应6小时。冷却至室温，减压蒸除溶剂，残余物悬浮于水(5mL)，室温搅拌6小时，抽滤，立即干燥得化合物143(白色固体，98mg，82％):1H NMR(400MHz,DMSO-d6)δ12.25(s,1H),7.95–7.91(m,2H),7.90–7.87(m,1H),7.79–7.75(m,1H),7.71–7.66(m,2H),7.58(pd,J＝7.3,1.4Hz,2H),7.51(dd,J＝8.5,2.2Hz,1H),7.30(d,J＝2.1Hz,1H),5.66(s,2H),3.91(t,J＝6.4Hz,2H),2.12(t,J＝7.4Hz,2H),1.50–1.38(m,4H),1.17(qd,J＝7.4,6.4,4.2Hz,2H).Compound 2 (100 mg, 0.2 mmol) was dissolved in dichloromethane (5 mL), 98% concentrated sulfuric acid (100 uL) was added, the temperature was raised to 50°C, refluxed and stirred for 6 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, the residue was suspended in water (5 mL), stirred at room temperature for 6 hours, filtered, and dried immediately to obtain compound 143 (white solid, 98 mg, 82%): 1 H NMR (400 MHz, DMSO-d 6 )δ12.25(s,1H),7.95–7.91(m,2H),7.90–7.87(m,1H),7.79–7.75(m,1H),7.71–7.66(m,2H),7.58(pd,J＝7.3,1.4Hz,2H),7.51(dd,J＝8.5,2.2Hz,1H) ,7.30(d,J＝2.1Hz,1H),5.66(s,2H),3.91(t,J＝6.4Hz,2H),2.12(t,J＝7.4Hz,2H),1.50–1.38(m,4H),1.17(qd,J＝7.4,6.4,4.2Hz,2H).

实施例144Embodiment 144

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸甲磺酸盐(化合物144)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid methanesulfonate (Compound 144)

参照实施例136的方法，将乙醇胺替换为甲磺酸制得化合物144(白色固体，105mg，88％):1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),7.97–7.93(m,2H),7.91–7.89(m,1H),7.83–7.79(m,1H),7.67–7.63(m,2H),7.61–7.53(m,2H),7.25(ddd,J＝8.4,7.5,1.7Hz,1H),6.96(td,J＝8.3,1.4Hz,2H),6.78(td,J＝7.5,1.0Hz,1H),5.66(s,2H),3.86(t,J＝6.4Hz,2H),2.33(s,3H),2.13(t,J＝7.4Hz,2H),1.41(p,J＝7.3Hz,4H),1.15(td,J＝8.2,7.4,3.1Hz,2H).Referring to the method of Example 136, ethanolamine was replaced by methanesulfonic acid to obtain compound 144 (white solid, 105 mg, 88%): 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.34 (s, 1H), 7.97–7.93 (m, 2H), 7.91–7.89 (m, 1H), 7.83–7.79 (m, 1H), 7.67–7.63 (m, 2H), 7.61–7.53 (m, 2H), 7.25 (ddd, J=8.4, 7.5, 1.7 Hz, 1H), 6.96 (td, J=8.3, 1. 4Hz,2H),6.78(td,J＝7.5,1.0Hz,1H),5.66(s,2H),3.86(t,J＝6.4Hz,2H),2.33(s,3H),2.13(t,J＝7.4Hz,2H),1.41(p,J＝7.3Hz,4H),1.15(td,J＝8.2,7 .4,3.1Hz,2H).

实施例145Embodiment 145

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸4-甲基苯磺酸盐(化合物145)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid 4-methylbenzenesulfonate (Compound 145)

参照实施例136的方法，将乙醇胺替换为对甲苯磺酸制得化合物145(白色固体，106mg，79％):1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),7.96–7.92(m,2H),7.91–7.87(m,1H),7.84–7.78(m,1H),7.68–7.62(m,2H),7.61–7.52(m,2H),7.49–7.45(m,2H),7.25(ddd,J＝9.0,7.3,1.7Hz,1H),7.11(d,J＝7.9Hz,2H),7.00–6.92(m,2H),6.78 (td,J＝7.5,1.1Hz,1H),5.65(d,J＝2.2Hz,2H),3.86(t,J＝6.4Hz,2H),2.28(s,3H),2.13(t,J＝7.4Hz,2H),1.41(p,J＝7.6Hz,4H),1.15(dd,J＝6.5,3.2Hz,2H).Referring to the method of Example 136, ethanolamine was replaced by p-toluenesulfonic acid to prepare Compound 145 (white solid, 106 mg, 79%): 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.67 (s, 1H), 7.96–7.92 (m, 2H), 7.91–7.87 (m, 1H), 7.84–7.78 (m, 1H), 7.68–7.62 (m, 2H), 7.61–7.52 (m, 2H), 7.49–7.45 (m, 2H), 7.25 (ddd, J=9.0, 7.3, 1.7 Hz, 1H), 7.11 (d, J=7.9 Hz, 2H), 7.00–6.92 (m, 2H), 6.78 (td,J＝7.5,1.1Hz,1H),5.65(d,J＝2.2Hz,2H),3.86(t,J＝6.4Hz,2H),2.28(s,3H),2.13(t,J＝7.4Hz,2H),1.41(p,J＝7.6Hz,4H),1.15(dd,J＝6.5,3.2Hz,2H ).

实施例146Embodiment 146

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸苯磺酸盐(化合物146)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid benzenesulfonate (Compound 146)

参照实施例136的方法，将乙醇胺替换为苯磺酸制得化合物146(白色固体，110mg，84％):1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),7.97–7.92(m,2H),7.90(dd,J＝6.6,1.7Hz,1H),7.82(dd,J＝7.4,1.9Hz,1H),7.68–7.64(m,2H),7.61–7.54(m,4H),7.33–7.29(m,3H),7.25(td,J＝7.8,1.7Hz,1H),6.98–6.94(m,2H),6.78(td,J＝7.5,1.0Hz,1H),5.66(s,2H),3.86(t,J＝6.4Hz,2H),2.13(t,J＝7.4Hz,2H),1.40(td,J＝8.1,4.2Hz,4H),1.19–1.11(m,2H).Referring to the method of Example 136, ethanolamine was replaced by benzenesulfonic acid to prepare Compound 146 (white solid, 110 mg, 84%): 1 H NMR (400 MHz, DMSO-d 6 ) δ12.04 (s, 1H), 7.97-7.92 (m, 2H), 7.90 (dd, J=6.6, 1.7 Hz, 1H), 7.82 (dd, J=7.4, 1.9 Hz, 1H), 7.68-7.64 (m, 2H), 7.61-7.54 (m, 4H), 7.33-7.29 (m, 3H), 7.25 (td, J=7.8 ,1.7Hz,1H),6.98–6.94(m,2H),6.78(td,J＝7.5,1.0Hz,1H),5.66(s,2H),3.86(t,J＝6.4Hz,2H),2.13(t,J＝7.4Hz,2H),1.40(td,J＝8.1,4.2Hz,4H),1. 19–1.11(m,2H).

实施例147Embodiment 147

6-(2-((2-(4-(三氟甲氧基)苯基)-1H-苯并[d]咪唑-1-基)甲基)苯氧基)己酸萘磺酸盐(化合物147)
6-(2-((2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazol-1-yl)methyl)phenoxy)hexanoic acid naphthalenesulfonate (Compound 147)

参照实施例136的方法，将乙醇胺替换为萘磺酸制得化合物147(白色固体，112mg，79％):1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),8.14(d,J＝1.6Hz,1H),7.99–7.92(m,3H),7.91–7.83(m,3H),7.82–7.77(m,1H),7.70(dd,J＝8.5,1.7Hz,1H),7.64(d,J＝8.3Hz,2H),7.59–7.49(m,4H),7.25(ddd,J＝8.6,7.5,1.7Hz,1H),6.99–6.90(m,2H),6.78(td,J＝7.5,1.0Hz,1H),5.65(s,2H),3.86(t,J＝6.4Hz,2H),2.13(t,J＝7.4Hz,2H),1.41(p,J＝7.2Hz,4H),1.15(ddd,J＝9.3,5.2,2.1Hz,2H).Referring to the method of Example 136, ethanolamine was replaced with naphthalenesulfonic acid to obtain compound 147 (white solid, 112 mg, 79%): 1H NMR (400 MHz, DMSO-d6) δ11.73 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.99-7.92 (m, 3H), 7.91-7.83 (m, 3H), 7.82-7.77 (m, 1H), 7.70 (dd, J = 8.5, 1.7 Hz, 1H), 7.64 (d, J = 8.3 Hz ,2H),7.59–7.49(m,4H),7.25(ddd,J＝8.6,7.5,1.7Hz,1H),6.99–6.90(m,2H),6.78(td,J＝7.5,1.0Hz,1H),5.65(s,2H),3.86(t,J＝6.4Hz,2H),2.13( t,J＝7.4Hz,2H),1.41(p,J＝7.2Hz,4H),1.15(ddd,J＝9.3,5.2,2.1Hz,2H).

实施例148Embodiment 148

利用GAL4杂交报告基因的方法对化合物的PPARα/PPARδ/PPARγ激动活性的测试Testing of PPARα/PPARδ/PPARγ agonist activity of compounds using GAL4 hybrid reporter gene method

在10cm的细胞培养皿中，培养Cos-7细胞(非洲绿猴肾成纤维细胞，常用的工具细胞)，培养基为含10％胎牛血清的DMEM完全培养基。当细胞生长至密度为70％左右时，准备转染。首先制备质粒转染工作液，操作如下：将15μg pGL4.35-9×Gal4 UAS质粒(购自北京普洛麦格生物技术有限公司)和15μg pBIND-Gal4-PPARα(LBD)质粒或pBIND-Gal4-PPARδ(LBD)质粒或pBIND-Gal4-PPARγ(LBD)质粒(J.Chem.Inf.Model.,2020,60,1717)及60μL转染试剂(HighGene，购自武汉爱博泰克生物科技有限公司)加入到2mL Opti-MEM中，室温放置15分钟后即得质粒转染工作液。随后将上述工作液合并8 mL DMEM完全培养基，加入到细胞培养皿中，进行细胞转染。在转染4小时后，将细胞消化重悬，种植到96孔板中，每孔2.5万个细胞。贴壁培养24小时后，将用完全培养基配制成适合的测试浓度的受试化合物及阳性药，加入到96孔板中。测试中定终浓度为10nM的GW7647(购自MCE公司)的PPARα激动活性为100％，终浓度为10nM的GW501516(购自MCE公司)的PPARδ激动活性为100％，终浓度为1μM的Rosiglitazone(购自Adamas公司)的PPARγ激动活性为100％。药物作用18小时后，将培养基去除，加入100μL报告基因裂解液(购自上海碧云天生物技术有限公司)，震荡裂解细胞15分钟后吸取10μL裂解液，加入到白色不透光384孔板中，再加入10μL报告基因检测液(购自上海碧云天生物技术有限公司)，混合反应后，利用多功能酶标仪检测生物荧光，并根据检测数值计算相应的半最大效应浓度(EC50)值。实验采用处于三期临床试验的PPARδ选择性激动剂MBX-8025作为阳性对照化合物。实验结果如表2所示。本实验采用处于三期临床试验的PPAR选择性激动剂MBX-8025(参考专利US2007060649合成)作为阳性对照化合物。实验结果如表2所示。Cos-7 cells (African green monkey kidney fibroblasts, commonly used tool cells) were cultured in a 10 cm cell culture dish, and the culture medium was DMEM complete medium containing 10% fetal bovine serum. When the cells grow to a density of about 70%, prepare for transfection. First, prepare the plasmid transfection working solution as follows: 15 μg pGL4.35-9×Gal4 UAS plasmid (purchased from Beijing Promeg Biotechnology Co., Ltd.) and 15 μg pBIND-Gal4-PPARα (LBD) plasmid or pBIND-Gal4-PPARδ (LBD) plasmid or pBIND-Gal4-PPARγ (LBD) plasmid (J. Chem. Inf. Model., 2020, 60, 1717) and 60 μL transfection reagent (HighGene, purchased from Wuhan Aibotek Biotechnology Co., Ltd.) were added to 2 mL Opti-MEM and placed at room temperature for 15 minutes to obtain the plasmid transfection working solution. The above working solution was then combined with 8 mL DMEM complete medium was added to the cell culture dish for cell transfection. After 4 hours of transfection, the cells were digested and resuspended and planted in a 96-well plate with 25,000 cells per well. After 24 hours of adherent culture, the test compound and positive drug prepared with complete medium at appropriate test concentrations were added to the 96-well plate. In the test, the PPARα agonist activity of GW7647 (purchased from MCE) with a final concentration of 10nM was 100%, the PPARδ agonist activity of GW501516 (purchased from MCE) with a final concentration of 10nM was 100%, and the PPARγ agonist activity of Rosiglitazone (purchased from Adamas) with a final concentration of 1μM was 100%. After 18 hours of drug action, the culture medium was removed, 100 μL reporter gene lysis solution (purchased from Shanghai Biyuntian Biotechnology Co., Ltd.) was added, and the cells were shaken and lysed for 15 minutes, and then 10 μL lysis solution was aspirated and added to a white opaque 384-well plate, and then 10 μL reporter gene detection solution (purchased from Shanghai Biyuntian Biotechnology Co., Ltd.) was added. After mixed reaction, the bioluminescence was detected by a multifunctional microplate reader, and the corresponding half-maximum effect concentration (EC 50 ) value was calculated based on the detection value. The experiment used MBX-8025, a PPARδ selective agonist in phase III clinical trials, as a positive control compound. The experimental results are shown in Table 2. This experiment used MBX-8025, a PPAR selective agonist in phase III clinical trials (synthesized with reference to patent US2007060649) as a positive control compound. The experimental results are shown in Table 2.

表2化合物对PPARs的激动活性

Table 2 Agonist activity of compounds on PPARs

实验结果表明，本发明的化合物具有显著的PPARδ激动活性，并且对于PPARα和PPARγ均具有显著的选择性。例如，化合物2、4、8、10、16、22、24、28、30、32、34、44、58、60、62、66、68、76、78、82、84、86、98、100、108、110、112、11和118等均可有效地激活PPARδ，且其EC50值均在10nM以下，显著强于三期临床试验药物MBX-8025。以上结果提示本发明的化合物是强效和高选择性的PPARδ激动剂。The experimental results show that the compounds of the present invention have significant PPARδ agonist activity and have significant selectivity for both PPARα and PPARγ. For example, compounds 2, 4, 8, 10, 16, 22, 24, 28, 30, 32, 34, 44, 58, 60, 62, 66, 68, 76, 78, 82, 84, 86, 98, 100, 108, 110, 112, 11 and 118 can effectively activate PPARδ, and their EC 50 values are all below 10 nM, which is significantly stronger than the phase III clinical trial drug MBX-8025. The above results indicate that the compounds of the present invention are potent and highly selective PPARδ agonists.

实施例149Embodiment 149

化合物2的大鼠体内药代动力学评价Pharmacokinetic evaluation of compound 2 in rats

动物：雄性SD大鼠6只，SPF级，来源于北京维通利华实验动物技术有限公司。Animals: Six male SD rats, SPF grade, were obtained from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.

分组：大鼠分为2组，每组3只，一组为口服给药组，另一组为静脉注射给药组。 口服给药组给药量为10mpk，静脉注射给药量为2mpk。Grouping: Rats were divided into 2 groups, 3 rats in each group, one group was oral administration group, and the other group was intravenous administration group. The dosage for oral administration was 10 mpk, and the dosage for intravenous injection was 2 mpk.

实验方法：静脉注射给药组经尾静脉注射给药后，分别在0.083、0.25、0.5、1、2、4、6、8、24小时经眼眶取血约0.25mL，取血后迅速加入肝素钠抗凝，血液采集后放置于冰上。口服给药组大鼠给药前禁食12小时，给药4小时后给食；大鼠经口服给药后，分别0.083、0.25、0.5、1、2、4、6、8、24小时经眼眶取血约0.25mL，取血后迅速加入肝素钠抗凝，血液采集后放置于冰上。所有样品在低温离心机中6000r/min，离心3分钟，分离得到血浆，经由LC-MS/MS-18检测血浆中化合物的含量，并根据不同时间点的血药浓度数据计算相关药代动力学参数。实验结果如表3所示。Experimental method: After the intravenous administration group was administered by tail vein injection, about 0.25 mL of blood was collected from the eye socket at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, and sodium heparin was quickly added for anticoagulation. The blood was placed on ice after collection. The rats in the oral administration group fasted for 12 hours before administration and were fed 4 hours after administration; after the rats were orally administered, about 0.25 mL of blood was collected from the eye socket at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, and sodium heparin was quickly added for anticoagulation. The blood was placed on ice after collection. All samples were centrifuged at 6000r/min in a low-temperature centrifuge for 3 minutes to separate plasma. The content of the compound in the plasma was detected by LC-MS/MS-18, and the relevant pharmacokinetic parameters were calculated based on the blood drug concentration data at different time points. The experimental results are shown in Table 3.

表3、大鼠静脉注射和口服给药化合物2的药代动力学参数
Table 3. Pharmacokinetic parameters of compound 2 administered intravenously and orally to rats

实验结果(表3)表明，化合物2的口服半衰期为3.57±0.53小时，峰浓度可以达到6816±696ng/mL，且化合物的生物利用度为91.5％，说明化合物2具有优异的药代动力学性质。本发明的其他化合物也具有较好的体内药代动力学性质。The experimental results (Table 3) show that the oral half-life of compound 2 is 3.57±0.53 hours, the peak concentration can reach 6816±696 ng/mL, and the bioavailability of the compound is 91.5%, indicating that compound 2 has excellent pharmacokinetic properties. Other compounds of the present invention also have good in vivo pharmacokinetic properties.

实施例150Embodiment 150

化合物76的大鼠体内药代动力学评价Pharmacokinetic evaluation of compound 76 in rats

实验方案与实施例149一致，实验结果如表4所示。The experimental scheme is consistent with Example 149, and the experimental results are shown in Table 4.

表4、大鼠静脉注射和口服给药化合物76的药代动力学参数
Table 4. Pharmacokinetic parameters of compound 76 after intravenous and oral administration in rats

实验结果(表4)表明，化合物76的口服半衰期为2.89±0.43小时，峰浓度可以达到2420±432ng/mL，且化合物的生物利用度为37.5％，说明化合物76具有良好的药代动力学性质。本发明的其他化合物也具有较好的体内药代动力学性质。The experimental results (Table 4) show that the oral half-life of compound 76 is 2.89±0.43 hours, the peak concentration can reach 2420±432 ng/mL, and the bioavailability of the compound is 37.5%, indicating that compound 76 has good pharmacokinetic properties. Other compounds of the present invention also have good in vivo pharmacokinetic properties.

实施例151Embodiment 151

片剂tablet

将实施例2中制得的化合物2(50g)、羟丙甲基纤维素E(150g)、淀粉(200g)、聚维酮K30适量和硬脂酸镁(1g)混合，制粒，压片。此外，可以根据药典2015版常规制剂法，将实施例1～147制得的化合物赋予不同的药物辅料制成胶囊剂、散剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂等。Compound 2 (50 g) prepared in Example 2, hydroxypropylmethylcellulose E (150 g), starch (200 g), appropriate amount of povidone K30 and magnesium stearate (1 g) were mixed, granulated and tableted. In addition, according to the conventional preparation method of the Pharmacopoeia 2015 edition, the compounds prepared in Examples 1 to 147 can be given different pharmaceutical excipients to prepare capsules, powders, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories or patches, etc.

实施例152Embodiment 152

化合物的体内抗肾纤维化效应评价Evaluation of the anti-renal fibrosis effects of compounds in vivo

动物：雄性C57BL/6J小鼠25只，SPF级，7-8周龄，购于北京维通利华。所有动物保持12小时交替的昼夜节律，自由饮食。 Animals: 25 male C57BL/6J mice, SPF grade, 7-8 weeks old, purchased from Beijing Weitonglihua. All animals were kept on a 12-hour alternating circadian rhythm and had free access to food.

试剂：阳性药马来酸依那普利购自阿达玛斯。Reagents: The positive drug enalapril maleate was purchased from Adamas.

实验过程：Experimental process:

1、动物分组1. Animal grouping

小鼠按照体重随机分成5组：假手术组(Sham)、手术组(UUO)、阳性药马来酸依那普利组(Enalapril 50mpk)、化合物129低剂量组(129 3mpk)和化合物129高剂量组(129 10mpk)。The mice were randomly divided into 5 groups according to their body weight: sham operation group (Sham), operation group (UUO), positive drug enalapril maleate group (Enalapril 50mpk), low-dose compound 129 group (129 3mpk) and high-dose compound 129 group (129 10mpk).

1、造模与给药1. Modeling and drug administration

单侧输尿管结扎手术(UUO)过程：①术前禁食12小时，自由饮水；②舒泰联合赛拉利嗪麻醉小鼠，确认其麻醉成功后，将小鼠右侧卧位固定于无菌手术台上，将肾区域毛脱去后用碘伏消毒手术区；③行左侧背部切口，逐层切开，在左肾下极暴露并分离左侧输尿管；④用4-0缝合线接扎两次，上端结扎线尽量靠近肾蒂，下端结扎线尽量向下，中间部分的输尿管剪断；⑤逐层缝合腹壁切口，关闭腹腔，术后用碘伏消毒，待小鼠苏醒后，给予常规饮食和饮水。The procedure of unilateral ureteral ligation (UUO) surgery is as follows: ① Fast for 12 hours before surgery and drink water freely; ② Anesthetize the mice with Shutai combined with xylazine. After confirming that the anesthesia is successful, fix the mice in the right lateral position on the sterile operating table, remove the hair in the kidney area and disinfect the surgical area with iodine; ③ Make a left back incision, cut it layer by layer, expose and separate the left ureter at the lower pole of the left kidney; ④ Ligate twice with 4-0 sutures, with the upper ligature as close to the renal pedicle as possible and the lower ligature as downward as possible, and cut the middle part of the ureter; ⑤ Suture the abdominal wall incision layer by layer, close the abdominal cavity, and disinfect with iodine after surgery. After the mice wake up, give them regular diet and drinking water.

除假手术组外，其余各组均按照上述手术过程进行造模。假手术组仅游离左侧输尿管，而不进行结扎等操作。手术后24小时后，开始分组给药。每组5只，假手术组小鼠和手术组小鼠每日灌胃给予体积分数为0.5％CMC-Na溶液，阳性药马来酸依那普利组每日灌胃给予50mpk的马来酸依那普利(化合物129低剂量组每日灌胃给予3mpk的化合物129，化合物129高剂量组每日灌胃给予10mpk的化合物129。给药时间为13天，每周对小鼠称重，仔细观察并记录其体重、毛发、粪便及活动情况。Except for the sham operation group, the models of the other groups were established according to the above surgical procedures. In the sham operation group, only the left ureter was freed, and no ligation or other operations were performed. 24 hours after the operation, group drug administration began. There were 5 mice in each group. The mice in the sham operation group and the operation group were gavaged daily with a volume fraction of 0.5% CMC-Na solution, and the positive drug enalapril maleate group was gavaged daily with 50mpk of enalapril maleate (compound 129 low-dose group was gavaged daily with 3mpk of compound 129, and the compound 129 high-dose group was gavaged daily with 10mpk of compound 129. The drug administration period was 13 days, and the mice were weighed every week, and their body weight, hair, feces and activity were carefully observed and recorded.

3、取材3. Material

最后一次给药2小时，处死小鼠取左肾。肾脏分为两部分，其中一部分部用4％多聚甲醛固定，用于染色切片；另一部分液氮速冻，以备后续其他指标检测。Two hours after the last administration, the mice were killed and the left kidney was removed. The kidney was divided into two parts, one of which was fixed with 4% paraformaldehyde for staining and sectioning, and the other was quickly frozen in liquid nitrogen for subsequent detection of other indicators.

4、肾脏组织学分析4. Renal Histological Analysis

将肝尾状叶在4％多聚甲醛中固定过夜，进行标准组织学处理，石蜡包埋。将样品切割至4μm厚，用天狼猩红染色。所有切片均采用Nano-Zoomer 2.0RS扫描。The caudate lobe of the liver was fixed in 4% paraformaldehyde overnight, processed for standard histology, and embedded in paraffin. The samples were cut to 4 μm thickness and stained with picrosirius red. All sections were scanned using Nano-Zoomer 2.0RS.

5、肾脏qPCR检测5. Kidney qPCR detection

提取冻存的肾脏组织的RNA，反转录后进行纤维化和炎症相关基因的qPCR检测。RNA was extracted from frozen kidney tissues and reverse transcribed for qPCR detection of genes related to fibrosis and inflammation.

6、实验结果6. Experimental results

天狼星红切片染色可以评估肾纤维化水平的水平。如图1所示，与假手术组相比，手术组胶原蛋白含量明显增加，经化合物129处理后胶原蛋白积累明显减轻。进一步qPCR检测发现(图2)，化合物129可以降低小鼠肾脏纤维化相关基因Acta2和Col3a1的表达，表明化合物129具有抗肾纤维化作用。此外，炎症相关基因Tnf和Il1b的表达在给化合物129后也可以降低，说明化合物129具有抗炎作用。此外，化合物129的抗纤维化作用与肾纤维化临床用药马来酸依那普利效应相当，且在抗炎方面优于阳性药。综上所述，化合物129改善了UUO诱导的肾纤维化小鼠模型中的胶原沉积并抑制了炎症细胞浸润。Sirius red section staining can evaluate the level of renal fibrosis. As shown in Figure 1, compared with the sham group, the collagen content in the surgical group increased significantly, and the collagen accumulation was significantly reduced after treatment with compound 129. Further qPCR detection found (Figure 2) that compound 129 can reduce the expression of mouse renal fibrosis-related genes Acta2 and Col3a1, indicating that compound 129 has an anti-renal fibrosis effect. In addition, the expression of inflammation-related genes Tnf and Il1b can also be reduced after compound 129 is administered, indicating that compound 129 has an anti-inflammatory effect. In addition, the anti-fibrosis effect of compound 129 is comparable to the effect of enalapril maleate, a clinical drug for renal fibrosis, and is superior to positive drugs in anti-inflammatory aspects. In summary, compound 129 improved collagen deposition and inhibited inflammatory cell infiltration in the UUO-induced renal fibrosis mouse model.

以上结果表明，化合物129对于肾纤维化模型小鼠具有显著地改善保护作用。本发明的其他化合物也具有类似的性质，提示此类化合物可以用于预防和治疗肾纤维化及其相关疾病。 The above results show that compound 129 has a significant protective effect on renal fibrosis model mice. Other compounds of the present invention also have similar properties, suggesting that such compounds can be used to prevent and treat renal fibrosis and related diseases.

Claims (10)

如式(I)所示的芳基并咪唑类化合物或其药学上可接受的盐：
The aryl imidazole compound or a pharmaceutically acceptable salt thereof is represented by formula (I):
其中，R1和R2各自独立地选自：H、羟基、卤素、氰基、OR8、1～4个碳的直链或支链烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基、烷基磺酰基、3～6个碳的环烷基、环烯基、杂环烷基、杂环烯基、炔基、苯基、取代的苯基、杂芳基、取代的杂芳基、稠环芳基或取代的稠环芳基，所述取代的苯基、取代的杂芳基和取代的稠环芳基可各自独自地被1至2个如下取代基所取代：卤素、羟基、氰基、1～4个碳的直链或支链烷基、3～6个碳的环烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基或烷基磺酰基；或者，R1和R2与它们所连接到的原子可一起形成取代或非取代的苯环、取代或非取代的杂芳环、取代或非取代的环烷烃环、取代或非取代的杂环烷烃环，或取代或非取代的杂环烯烃环；wherein R1 and R2 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, OR8 , a linear or branched alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, alkylsulfonyl, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkenyl group, a heterocycloalkyl group, a heterocycloalkenyl group, an alkynyl group, a phenyl group, a substituted phenyl group, a heteroaryl group, a substituted heteroaryl group, a condensed aryl group, or a substituted condensed aryl group, wherein the substituted phenyl group, the substituted heteroaryl group, and the substituted condensed aryl group may each be independently substituted by 1 to 2 of the following substituents: halogen, hydroxyl, cyano, a linear or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, or alkylsulfonyl group; or, R1 and R2 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, a linear or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, or alkylsulfonyl group; 2 together with the atoms to which they are attached may form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring; R8选自：1～4个碳的直链或支链烷基、3～6个碳的环烷基、苯基、取代的苯基、羟基烷基、烷氧基烷基、烷氧基烷氧基烷基、环烷基或炔基烷氧基烷基； R8 is selected from: a straight or branched chain alkyl group of 1 to 4 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, a phenyl group, a substituted phenyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxyalkoxyalkyl group, a cycloalkyl group or an alkynylalkoxyalkyl group; R3、R4、R5、R6和R7各自独立地选自：H、羟基、卤素、氰基、1～4个碳的直链或支链烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基、烷基磺酰基、烷氧基、3～6个碳的环烷基、环烯基、杂环烷基、杂环烯基、炔基、苯基、取代的苯基、苯氧基、取代的苯基氧基、杂芳基、取代的杂芳基、稠环芳基或取代的稠环芳基，所述取代的苯基、取代的杂芳基和取代的稠环芳基各自可独自地被1至2个如下取代基所取代：卤素、羟基、氰基、1～4个碳的直链或支链烷基、3～6个碳的环烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基或烷基磺酰基；或者，R3、R4、R5、R6和R7其中至少两个取代基与它们所连接到的原子可一起形成取代或非取代的苯环、取代或非取代的杂芳环、取代或非取代的环烷烃环、取代或非取代的杂环烷烃环，或取代或非取代的杂环烯烃环； R3 , R4 , R5 , R6 and R7 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, alkylsulfonyl, alkoxy, cycloalkyl of 3 to 6 carbon atoms, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl, substituted heteroaryl, fused ring aryl or substituted fused ring aryl, wherein the substituted phenyl, substituted heteroaryl and substituted fused ring aryl are each independently substituted with 1 to 2 substituents of halogen, hydroxyl, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or alkylsulfonyl; or, R3, R4, R5, R6 and R7 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy , trifluoromethylthio or alkylsulfonyl; 7 wherein at least two substituents together with the atoms to which they are attached can form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring; m选自0～5之间的任意整数；m is selected from any integer between 0 and 5; n选自0～5之间的任意整数；n is selected from any integer between 0 and 5; X选自：O、S、CH2、CH2O、CH2S、CH2CH2、OCH2、SCH2、CH2CH2O、 CH2CH2S、CH2CH2CH2、OCH2CH2、SCH2CH2、CH2CH2CH2O、CH2CH2CH2S、CH2CH2CH2CH2、OCH2CH2CH2或SCH2CH2CH2；X is selected from: O, S, CH 2 , CH 2 O, CH 2 S, CH 2 CH 2 , OCH 2 , SCH 2 , CH 2 CH 2 O, CH 2 CH 2 S, CH 2 CH 2 CH 2 , OCH 2 CH 2 , SCH 2 CH 2 , CH 2 CH 2 CH 2 O, CH 2 CH 2 CH 2 S, CH 2 CH 2 CH 2 CH 2 , OCH 2 CH 2 CH 2 or SCH 2 CH 2 CH 2 ; Y选自： Y is selected from: Z1、Z2、Z3、Z4、Z5、Z6、Z7和Z8各自独立地选自：CH或N；Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 are each independently selected from: CH or N; R9选自：H、1～6个碳的直链或支链烷基、3～6个碳的环烷基、(CH2)pOR12或(CH2)qNR13；其中，所述p＝2～6的任意整数；所述q＝2～6的任意整数；所述R12和R13各自独立地选自H、R14或C(O)R15；其中，所述R14和R15各自独立地选自1～6个碳的直链或支链烷基或3～6个碳的环烷基；R 9 is selected from: H, a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, (CH 2 ) p OR 12 or (CH 2 ) q NR 13 ; wherein p=any integer of 2 to 6; q=any integer of 2 to 6; R 12 and R 13 are each independently selected from H, R 14 or C(O)R 15 ; wherein R 14 and R 15 are each independently selected from a straight or branched alkyl group of 1 to 6 carbon atoms or a cycloalkyl group of 3 to 6 carbon atoms; R10和R11各自独立地选自：H、羟基、卤素、氰基、1～4个碳的直链或支链烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基、烷基磺酰基、烷氧基、3～6个碳的环烷基、环烯基、杂环烷基、杂环烯基、炔基、苯基、取代的苯基、苯氧基、取代的苯基氧基、杂芳基、取代的杂芳基、稠环芳基或取代的稠环芳基，所述取代的苯基、取代的杂芳基和取代的稠环芳基可独自地被1至2个如下取代基所取代：卤素、羟基、氰基、1～4个碳的直链或支链烷基、3～6个碳的环烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基或烷基磺酰基；或者，R10和R11与它们所连接到的原子可一起形成取代或非取代的苯环、取代或非取代的杂芳环、取代或非取代的环烷烃环、取代或非取代的杂环烷烃环，或取代或非取代的杂环烯烃环。 R10 and R11 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, alkylsulfonyl, alkoxy, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkenyl group, a heterocycloalkyl group, a heterocycloalkenyl group, an alkynyl group, a phenyl group, a substituted phenyl group, a phenoxy group, a substituted phenyloxy group, a heteroaryl group, a substituted heteroaryl group, a fused ring aryl group, or a substituted fused ring aryl group, wherein the substituted phenyl group, the substituted heteroaryl group, and the substituted fused ring aryl group may be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, a straight or branched chain alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, or alkylsulfonyl group; or, R10 and R11 are each independently selected from the group consisting of H, hydroxyl, halogen ... 11 and the atoms to which they are attached may together form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring. 根据权利要求1所述的芳基并咪唑类化合物或其药学上可接受的盐，其特征在于，The aryl imidazole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: 其中，R1和R2各自独立地选自：H、羟基、卤素、氰基、OR8、1～4个碳的直链或支链烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基、甲基磺酰基、乙基磺酰基、3～6个碳的环烷基、苯基或取代的苯基，所述取代的苯基可独自地被1至2个如下取代基所取代：卤素、羟基、氰基、1～4个碳的直链或支链烷基、3～6个碳的环烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基或甲基磺酰基；wherein R1 and R2 are each independently selected from the group consisting of: H, hydroxyl, halogen, cyano, OR8 , a linear or branched alkyl group having 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, methylsulfonyl, ethylsulfonyl, a cycloalkyl group having 3 to 6 carbon atoms, phenyl, or substituted phenyl, wherein the substituted phenyl group may be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, a linear or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, or methylsulfonyl; R8选自：1～4个碳的直链或支链烷基、3～6个碳的环烷基或苯基；R 8 is selected from: a straight chain or branched chain alkyl group of 1 to 4 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, or a phenyl group; m选自0～3之间的任意整数；m is selected from any integer between 0 and 3; n选自0～3之间的任意整数；n is selected from any integer between 0 and 3; R3、R4、R5、R6和R7各自独立地选自：H、羟基、卤素、氰基、1～4个碳的直链或支链烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基、甲基磺酰基、乙基磺酰基、1～4个碳的直链或支链烷基氧基、3～6个碳的环烷基氧基、3～6个碳的环烷基、苯基、取代的苯基、苯氧基、取代的苯基氧基、杂芳基或取代的杂芳基，所述取代的苯基或取代的杂芳基可各自独自地被1至2个如下取代基所取代：卤素、羟基、氰基、1～4个碳的直链或支链烷基、3～6个碳的环烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基或甲基磺酰基，或者，R3、R4、R5、R6和R7其中至少两个取代基与它们所连 接到的原子可一起形成取代或非取代的苯环； R3 , R4 , R5 , R6 and R7 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, methylsulfonyl, ethylsulfonyl, straight or branched chain alkyloxy of 1 to 4 carbon atoms, cycloalkyloxy of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl or substituted heteroaryl, wherein the substituted phenyl or substituted heteroaryl may each be independently substituted with 1 to 2 of the following substituents: halogen, hydroxyl, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or methylsulfonyl; or, R3 , R4, R5, R6 and R7 are each independently selected from the group consisting of H, hydroxyl, halogen, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio or methylsulfonyl. 7At least two of the substituents are attached to The attached atoms can together form a substituted or unsubstituted benzene ring; X选自：O、S、CH2、CH2O、CH2S、CH2CH2、OCH2、SCH2、CH2CH2O、CH2CH2S、CH2CH2CH2、OCH2CH2或SCH2CH2；X is selected from: O, S, CH 2 , CH 2 O, CH 2 S, CH 2 CH 2, OCH 2 , SCH 2 , CH 2 CH 2 O, CH 2 CH 2 S, CH 2 CH 2 CH 2 , OCH 2 CH 2 or SCH 2 CH 2 ; Y选自： Y is selected from: Z1、Z2、Z3、Z4、Z5、Z6、Z7和Z8各自独立地选自：CH或N；Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 are each independently selected from: CH or N; R9选自：H、1～4个碳的直链或支链烷基、乙酰氨基乙基或(CH2)pOR12，其中，所述p＝2～6的任意整数，所述R12选自1～4个碳的直链或支链烷基；R 9 is selected from: H, a linear or branched alkyl group of 1 to 4 carbon atoms, acetylaminoethyl or (CH 2 ) p OR 12 , wherein p is any integer of 2 to 6, and R 12 is selected from a linear or branched alkyl group of 1 to 4 carbon atoms; R10和R11各自独立地选自：H、羟基、卤素、氰基、1～4个碳的直链或支链烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基、甲基磺酰基、乙基磺酰基、1～4个碳的直链或支链烷基氧基、3～6个碳的环烷基氧基、3～6个碳的环烷基、苯基、取代的苯基、苯氧基或取代的苯基氧基，所述取代的苯基可独自地被1至2个如下取代基所取代：卤素、羟基、氰基、1～4个碳的直链或支链烷基、3～6个碳的环烷基、三氟甲基、甲硫基、三氟甲氧基、三氟甲硫基或甲基磺酰基，或者，R10和R11其中至少两个取代基与它们所连接到的原子可一起形成取代或非取代的苯环。 R10 and R11 are each independently selected from the group consisting of H, hydroxy, halogen, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, methylsulfonyl, ethylsulfonyl, straight or branched chain alkyloxy of 1 to 4 carbon atoms, cycloalkyloxy of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, substituted phenyl, phenoxy, or substituted phenyloxy, wherein the substituted phenyl may be independently substituted with 1 to 2 of the following substituents: halogen, hydroxy, cyano, straight or branched chain alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, trifluoromethyl, methylthio, trifluoromethoxy, trifluoromethylthio, or methylsulfonyl, or at least two of the substituents of R10 and R11 together with the atoms to which they are attached may form a substituted or unsubstituted benzene ring. 根据权利要求1所述的芳基并咪唑类化合物或其药学上可接受的盐，其特征在于，所述化合物优选还包括其氘代化合物、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物。The aryl imidazole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound preferably also includes a deuterated compound, tautomer, mesomer, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate thereof. 根据权利要求1所述的芳基并咪唑类化合物或其药学上可接受的盐，其特征在于，所述化合物或其盐为如下所示的任一化合物：



































The aryl imidazole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound or its salt is any one of the following compounds:



































一种权利要求1-4任一所述的芳基并咪唑类化合物或其药学上可接受的盐、氘代化合物、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物在制备PPARδ激动剂中的应用。A use of an aryl imidazole compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, deuterated compound, tautomer, mesoform, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate thereof in the preparation of a PPARδ agonist. 一种权利要求1-4任一所述的芳基并咪唑类化合物或其药学上可接受的盐、氘代化合物、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物在制备预防或治疗PPARδ介导的疾病的药物中的用途。A use of an aryl imidazole compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, deuterated compound, tautomer, mesomer, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate thereof in the preparation of a medicament for preventing or treating a PPARδ-mediated disease. 根据权利要求6所述的用途，其特征在于，所述PPARδ介导的疾病包括代谢性疾病、心脑血管疾病、炎症疾病、自身免疫性疾病、器官纤维化疾病、神经退行性疾病、病原体感染所致的继发性疾病、线粒体功能障碍和紊乱疾病或肿瘤。The use according to claim 6, characterized in that the PPARδ-mediated diseases include metabolic diseases, cardiovascular and cerebrovascular diseases, inflammatory diseases, autoimmune diseases, organ fibrosis diseases, neurodegenerative diseases, secondary diseases caused by pathogen infection, mitochondrial dysfunction and disorder diseases or tumors. 一种芳基并咪唑类化合物的盐，其特征在于，所述芳基并咪唑类化合物的盐包括权利要求1-4任一所述的芳基并咪唑类化合物与金属离子或药学上可接受的胺或铵离子形成的盐。A salt of an aryl imidazole compound, characterized in that the salt of the aryl imidazole compound comprises a salt formed by the aryl imidazole compound according to any one of claims 1 to 4 and a metal ion or a pharmaceutically acceptable amine or ammonium ion. 一种预防或治疗PPARδ介导的疾病的药物组合物，其含有如权利要求1-4任一所述的芳基并咪唑类化合物或其药学上可接受的盐、氘代化合物、互变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物作为活性成分和药学上可接受的载体。A pharmaceutical composition for preventing or treating a PPARδ-mediated disease, comprising an aryl imidazole compound or a pharmaceutically acceptable salt, deuterated compound, tautomer, mesomer, racemate, stereoisomer, metabolite, metabolic precursor, prodrug or solvate thereof as claimed in any one of claims 1 to 4 as an active ingredient and a pharmaceutically acceptable carrier. 根据权利要求9所述的药物组合物，其特征在于，所述药物组合物是胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。 The pharmaceutical composition according to claim 9, characterized in that the pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository or patch.
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