WO2019024635A1 - 1，3-二取代烯酮类化合物及其应用 - Google Patents

1，3-二取代烯酮类化合物及其应用 Download PDF

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WO2019024635A1
WO2019024635A1 PCT/CN2018/093760 CN2018093760W WO2019024635A1 WO 2019024635 A1 WO2019024635 A1 WO 2019024635A1 CN 2018093760 W CN2018093760 W CN 2018093760W WO 2019024635 A1 WO2019024635 A1 WO 2019024635A1
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alkyl
group
benzofuran
methylthio
mmol
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PCT/CN2018/093760
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English (en)
French (fr)
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蔡雄
钱长庚
叶春强
何其捷
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广州必贝特医药技术有限公司
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Priority to JP2020506217A priority Critical patent/JP7058045B2/ja
Priority to US16/634,827 priority patent/US11306102B2/en
Priority to EP18841821.4A priority patent/EP3653613B1/en
Priority to ES18841821T priority patent/ES2935635T3/es
Priority to PL18841821.4T priority patent/PL3653613T3/pl
Priority to AU2018311725A priority patent/AU2018311725B2/en
Priority to DK18841821.4T priority patent/DK3653613T5/da
Priority to CA3071015A priority patent/CA3071015C/en
Priority to HRP20230095TT priority patent/HRP20230095T1/hr
Priority to SI201830819T priority patent/SI3653613T1/sl
Publication of WO2019024635A1 publication Critical patent/WO2019024635A1/zh

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Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a 1,3-disubstituted ketene compound and use thereof.
  • Nonalcoholic fatty liver disease refers to liver disease caused by factors other than alcohol and other causes of definite damage, manifested as excessive fat accumulation in the form of triglycerides (> 5% of hepatocyte tissue). In the liver.
  • Nonalcoholic steatohepatitis is a steatosis nonalcoholic fatty liver disease associated with inflammation and hepatocyte damage.
  • Typical pathological features of early nonalcoholic steatohepatitis are fat accumulation, inflammation, and mild fibrosis, which can lead to advanced liver fibrosis, cirrhosis, liver failure, and liver tumors.
  • NAFLD liver disease
  • NASH-associated cirrhosis is the third most common cause of liver transplantation in the United States and is expected to become the main cause in 2020 (World Gastroenterology Organisation Global Guidelines: NFLD and NASH. June 2012).
  • NAFLD in Asian countries has grown rapidly and has a younger age.
  • the prevalence of NAFLD in adults in Shanghai, Guangzhou and Hong Kong is about 15% (Fan JG et al: J Dig Dis 12:38-44, 2011). ).
  • Peroxisome proliferators-activated receptors are ligand-activating receptors in the nuclear hormone receptor family, regulate transcription of target genes, and are involved in lipid regulation, lipogenesis, and glycemic control. Therefore, it plays an important regulatory role in energy balance and metabolic function.
  • the PPARs family contains three subtypes: alpha, gamma, and delta (or beta). All three subtypes are involved in the regulation of lipid metabolism.
  • PPAR ⁇ is highly expressed in the liver, skeletal muscle, kidney, heart and blood vessel walls, stimulating fatty acid oxidation and uptake and regulating lipoprotein synthesis.
  • Liver PPAR ⁇ activation increases high-density lipoprotein (HDL) high apolipoprotein Apo AI and Apo AII, increases triglyceride hydrolysis and increases free fatty acid uptake and oxidation.
  • HDL high-density lipoprotein
  • Apo AI and Apo AII increases triglyceride hydrolysis and increases free fatty acid uptake and oxidation.
  • PPAR ⁇ has an anti-inflammatory effect by inhibiting cyclooxygenase-2, interleukin-6 and C-reactive protein (Francis G et al, Ann Rev Physiol. 65:261-311, 2003; Pawlak M et al. J Hepatol 62). :720-733, 2015).
  • PPAR ⁇ agonists such as clofibrate, fenofibrate and ciprofibrate can reduce low-density lipoprotein (LDL) and reduce hypertriglyceridemia while reducing triglycerides.
  • LDL low-density lipoprotein
  • PPAR alpha agonists can be used in the treatment of cholestatic liver disease, nonalcoholic fatty liver disease and/or type 2 diabetes.
  • PPAR ⁇ regulates many physiological processes such as energy metabolism, redox balance, autophagy and cell cycle, and inflammatory responses.
  • PPAR ⁇ agonists may be involved in cardiovascular disease (Han L at al. Future Cardiol. 2017 Jun 5. doi: 10.2217/fca-2016-0059), Kidney Disease (Adedapo AA et al. Hum Exp Toxicol. 32: 323-331, 2013) And brain degenerative diseases (D Orio B at al. Curr Alzheimer Res. 2017 doi: 10.2174/1567205014666170505094549) have broad therapeutic prospects.
  • PPAR ⁇ is expressed in adipose tissue in mammals, sensitive to insulin, transcription of genes involved in lipid acid uptake and fat storage, and activation of PPAR ⁇ leads to insulin sensitization and promotes glucose metabolism (Olefsky J M et al. Trend Endocrin Met 11) : 362-368, 2000) and have anti-fibrotic effects (Koo JB et al. BMC Gastroenterol. 17: 73.2017).
  • Abnormal PPAR ⁇ may be associated with many diseases such as obesity, diabetes, atherosclerosis and cancer.
  • PPAR gamma agonists have been used in the treatment of hyperlipidemia and hyperglycemia.
  • PPAR ⁇ can reduce the inflammatory response of many cardiovascular cells, especially endothelial cells.
  • PPAR ⁇ activates the PON1 gene, increases the synthesis and release of paraoxonase 1 in the liver, and reduces atherosclerosis.
  • Many insulin sensitizing drugs such as thiazolidinediones used to treat diabetes activate PPAR ⁇ as a means to lower blood sugar without increasing insulin secretion by the pancreas.
  • PPAR ⁇ is widely expressed in vivo and is expressed at relatively high levels in the brain, stomach, and colon. PPAR ⁇ activation increases fatty acid metabolism and increases ApoA1/HDL levels, inhibiting inflammation.
  • the PPAR ⁇ agonist MBX-8025 significantly reduces human low-density lipoprotein, triglyceride and high-sensitivity C-reactive protein, increases high-density lipoprotein and reduces liver damage.
  • PPAR nuclear receptor polysubtype agonists may be more effective than single subtype agonists in the treatment of diseases associated with lipid and glucose metabolism, inflammation and fibrosis.
  • Elafibranor GFT-505 is a PPAR ⁇ and PPAR ⁇ receptor agonist that improves insulin sensitivity, regulates blood glucose balance, lipid metabolism, and reduces inflammation (Sahebkar A et al. Expert Opin Pharmacother 15:493-503m 2014; Ratziu et al.Gastroenterology 150: 1147-1159, 2016).
  • the present invention provides a novel 1,3-disubstituted ketene compound having an activity of activating PPAR.
  • R 1 and R 2 are each independently selected from the group consisting of: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C1- C6 alkoxy group, hydroxyl group;
  • R 3 and R 4 are each independently selected from the group consisting of: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, C1- C6 alkoxy, hydroxy, and R 3 , R 4 are not H at the same time; or R 3 , R 4 are bonded to form a 3-8 membered carbocyclic ring or a 3-8 membered heterocyclic ring;
  • R 5 is selected from OR 6 , NR 7 R 8 ;
  • Q is a single button or CR 7 R 8 ;
  • R 6 , R 7 and R 8 are each independently selected from the group consisting of: H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylmethyl;
  • W, W 1 and Y are each independently selected from: O or S;
  • Ring A is a 8-12 membered substituted or unsubstituted bicyclic ring, which is a saturated bicyclic ring, a partially unsaturated bicyclic ring or an aromatic bicyclic ring, and the bicyclic ring
  • the ring carbon atom is substituted by 0 to 5 hetero atoms, which means O, N or S.
  • W, W 1 are each selected from the group consisting of: O.
  • the compound has the structure of formula (II):
  • ring A is selected from:
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 are each independently selected from: CR 9 , CR 12 or N, and at least one of X 1 , X 2 , X 3 , X 4 is CR 12 ;
  • R 9 is selected from the group consisting of: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkane a hydroxy-substituted C1-C6 alkyl group, an alkoxy-substituted C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, a C1-C4 alkylamino group-substituted C1-C6 alkyl group, an aryl group, a hetero group Aryl, nitro, cyano, -OR, -N(R) 2 , -SR, -C(O)OR, -C(O)N(R) 2 , -C(O)R, -S( O) R, -S(O)
  • R 10 is selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen substituted C1-C6 alkyl, hydroxy Substituted C1-C6 alkyl, alkoxy substituted C1-C6 alkyl, amino substituted C1-C6 alkyl, C1-C4 alkylamino substituted C1-C6 alkyl;
  • R 11 is selected from the group consisting of: H, -SR, -OR, -N(R) 2 , C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl;
  • R 12 is selected from the group consisting of: H, -SR, -OR, -N(R) 2 , C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl;
  • n is selected from: 0, 1, 2;
  • Each R is independently selected from the group consisting of: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkane A hydroxy-substituted C1-C6 alkyl group, an alkoxy-substituted C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, and a C1-C4 alkylamino group substituted C1-C6 alkyl group.
  • ring A is selected from:
  • ring A is selected from:
  • ring A is selected from:
  • ring A is selected from:
  • R 9 is selected from the group consisting of: H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C4 alkylamino substituted C1-C6 alkyl, nitro, cyano, -OR, -N(R) 2 , -SR, -C(O)OR, -C(O)N(R) 2 , -C(O)R, -S(O)R, -S(O) 2 R, -S(O) 2 N(R) 2 , -N(R)C(O)R;
  • Each R is independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl.
  • R 9 is selected from the group consisting of: H, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl , -OR, -N(R) 2 , -SR, -C(O)OR, -C(O)N(R) 2 , -C(O)R, -S(O)R, -S(O 2 R,-S(O) 2 N(R) 2 , -N(R)C(O)R; each R is independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C3- C8 cycloalkylmethyl, halogen substituted C1-C6 alkyl.
  • R 9 is selected from the group consisting of: H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C4 alkylamino substituted C1-C6 alkyl, -OR, -N(R) 2 , -SR, -C(O)R, -S(O)R;
  • R is selected from the group consisting of: H, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl.
  • R 9 is selected from the group consisting of: H, C1-C6 alkyl, halo-substituted C1-C6 alkyl.
  • R 9 is selected from the group consisting of: H, methyl, ethyl, isopropyl, trifluoromethyl.
  • R 10 is selected from the group consisting of: H, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1- C6 alkyl, alkoxy substituted C1-C6 alkyl, amino substituted C1-C6 alkyl, C1-C4 alkylamino substituted C1-C6 alkyl; each R is independently selected from H, C1-C6 Alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen substituted C1-C6 alkyl.
  • R 10 is selected from the group consisting of: H, C1-C6 alkyl, halogen substituted C1-C6 alkyl; each R is independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C3 -C8 cycloalkylmethyl.
  • R 10 is selected from the group consisting of: H.
  • R 11 is selected from the group consisting of: H, -SR, -OR, -N(R) 2 , C1-C6 alkyl; wherein R is selected from the group consisting of: H, C1-C6 alkyl.
  • R 11 is selected from the group consisting of: H.
  • R 12 is selected from the group consisting of: H, -SR, -OR, -N(R) 2 , C1-C6 alkyl; wherein R is selected from the group consisting of: H, C1-C6 alkyl.
  • R 12 is selected from the group consisting of: -SR, -OR; wherein R is selected from the group consisting of: C1-C6 alkyl.
  • R 1 , R 2 are each independently selected from the group consisting of: H, C1-C6 alkyl, C1-C6 alkoxy, halogen.
  • R 1 , R 2 are each independently selected from the group consisting of: C 1 -C 3 alkyl, halo, C 1 -C 3 alkoxy.
  • R 1 , R 2 are both methyl, or R 1 , R 2 are both chlorine.
  • R 3 and R 4 are each independently selected from the group consisting of: H, C1-C6 alkyl, C1-C6 alkoxy, halogen, or R 3 , and R 4 are bonded to form a 3-8 membered carbocyclic ring.
  • R 3 , R 4 are each independently selected from the group consisting of: C1-C6 alkyl.
  • R 5 is selected from the group consisting of: OR 6 ;
  • R 6 is selected from the group consisting of: H, C1-C6 alkyl.
  • R 5 is selected from the group consisting of: OR 6 ; and R 6 is selected from the group consisting of: H.
  • Y is selected from the group consisting of: O.
  • R 1 , R 2 are each independently selected from the group consisting of: H, C1-C6 alkyl, C1-C6 alkoxy, halogen;
  • R 3 , R 4 are each independently selected from: H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, or R 3 , R 4 are bonded to form a 3-8 membered carbocyclic ring;
  • R 5 is selected from OR 6 ;
  • R 6 is selected from H, C1-C6 alkyl;
  • Y is selected from O or S
  • Ring A is selected from:
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 are each independently selected from CR 9 , CR 12 or N, and at least one of X 1 , X 2 , X 3 , X 4 is CR 12 ;
  • R 9 is selected from the group consisting of: H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen substituted C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, alkoxy Substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C4 alkylamino substituted C1-C6 alkyl, nitro, cyano, -OR, -N(R) 2 , -SR, -C(O)OR, -C(O)N(R) 2 , -C(O)R, -S(O)R, -S(O) 2 R, -S(O) 2 N(R) 2 , -N(R)C(O)R;
  • R 10 is selected from the group consisting of: H, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy a substituted C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, a C1-C4 alkylamino group-substituted C1-C6 alkyl group;
  • R 11 is selected from the group consisting of: H, -SR, -OR, -N(R) 2 , C1-C6 alkyl;
  • R 12 is selected from the group consisting of: H, -SR, -OR, -N(R) 2 , C1-C6 alkyl;
  • n is selected from: 0, 1, 2;
  • Each R is independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl.
  • R 1 , R 2 are each independently selected from: C 1 -C 3 alkyl, halo, C 1 -C 3 alkoxy;
  • R 3 , R 4 are each independently selected from: C1-C6 alkyl
  • R 5 is selected from the group consisting of: OR 6 ;
  • R 6 is selected from: H;
  • Y is selected from: O;
  • Ring A is selected from:
  • R 9 is selected from the group consisting of: H, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, -OR, -N ( R) 2 , -SR, -C(O)OR, -C(O)N(R) 2 , -C(O)R, -S(O)R, -S(O) 2 R, -S( O) 2 N(R) 2 , -N(R)C(O)R;
  • R 12 is selected from the group consisting of: H, -SR, -OR, C1-C6 alkyl;
  • n is selected from: 0, 1;
  • Each R is independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl.
  • the 1,3-disubstituted ketene compound is selected from the group consisting of
  • the present invention also provides the use of the above 1,3-disubstituted ketene compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof.
  • PPAR regulation include diseases associated with abnormal lipid and glucose metabolism, diseases associated with inflammation and fibrosis, cardiovascular diseases, kidney diseases, and degenerative brain diseases.
  • the PPAR regulates abnormally related diseases including: nonalcoholic fatty liver disease, nonalcoholic hepatitis, cholestatic liver disease, diabetes, obesity, heart failure, atherosclerosis, chronic kidney disease, kidney Failure, Alzheimer's disease.
  • the present invention also provides a pharmaceutical composition for preventing a disease associated with abnormal regulation of PPAR.
  • a pharmaceutical composition for controlling a disease associated with abnormal regulation of PPAR the active ingredient comprising the above-mentioned 1,3-disubstituted ketene compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof .
  • the above 1,3-disubstituted ketene compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof can be prepared into a pharmaceutical combination having various corresponding dosage forms together with a pharmaceutically acceptable adjuvant or carrier. Things. It can also be used in combination with other drugs with PPAR agonistic activity to enhance the agonistic activity of PPAR.
  • the 1,3-disubstituted ketene compounds provided by the present invention have an activity of modulating a PPAR agonist, and such compounds mainly activate PPAR ⁇ and also have agonistic activity against PPPA ⁇ and PPPA ⁇ . It can be used to treat various diseases related to PPAR regulation abnormalities, such as non-alcoholic fatty liver disease (NAFLD), especially non-alcoholic steatohepatitis (NASH), and also for treatment.
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • Diabetes obesity, fibrotic diseases, cardiovascular diseases (including heart failure and atherosclerosis, etc.), kidney diseases (including chronic kidney disease and renal failure, etc.), brain degenerative diseases (including Alzheimer's disease, etc.)
  • NASH non-alcoholic fatty liver disease
  • the potential of such a has greater application value.
  • Fig. 1 is a graph showing the results of blood concentration measurement of compounds 5, 62, 100, 103 and Elafibranor after intragastric administration (20 mg/kg) in rats.
  • any variable e.g. R 1, R, etc.
  • R 1, R, etc. when any variable (e.g. R 1, R, etc.) appear in any component more than once defined, it is at each occurrence independently each occurrence of other definitions. Also, combinations of substituents and variables are allowed as long as such combinations stabilize the compound.
  • a line drawn from a substituent into the ring system means that the bond referred to can be attached to any ring atom that can be substituted. It will be appreciated that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the present invention to provide compounds which are chemically stable and which are readily synthesized from readily available starting materials by techniques in the art and from the methods set forth below. If the substituent itself is substituted by more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized.
  • alkyl as used herein is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C 1 -C 6 in “C 1 -C 6 alkyl” includes a group having 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight chain or a branched chain.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl and the like.
  • alkoxy refers to a group to which an alkyl group is directly attached to oxygen, such as methoxy, ethoxy, and the like.
  • alkylthio refers to a group in which an alkyl group is directly attached to sulfur.
  • C1-C4 alkylamino substituted C1-C6 alkyl means that an alkyl group having 1, 2, 3 or 4 carbon atoms is bonded to a nitrogen atom and has a nitrogen atom of 1, 2, 3 a group in which an alkyl group of 4, 5 or 6 carbon atoms is bonded, for example, a methylaminomethyl group, a methylaminoethyl group, a dimethylaminomethyl group or the like.
  • heterocycle includes saturated heteroatom-containing cycloalkyl and heteroaryl, wherein the hetero atom may be selected from nitrogen, sulfur and oxygen and any oxidized form of nitrogen, sulfur, phosphorus, preferably a saturated heterocyclic ring containing N.
  • An alkyl group such as piperidine.
  • substituted refers to the replacement of a hydrogen radical in a particular structure with a group of the specified substituent.
  • heterocycle refers to an aromatic or non-aromatic heterocyclic ring containing from 1 to 4 heteroatoms selected from O, N and S, and includes bicyclic groups.
  • Heterocyclyl thus includes heteroaryl, as well as dihydrogenated and tetrahydrogenated analogs thereof. The attachment of a heterocyclic substituent can be achieved by a carbon atom or by a hetero atom.
  • halogen as used herein is meant to include chloro, fluoro, bromo and iodo.
  • the invention includes the free forms of the compounds of Formulas I-II, as well as the pharmaceutically acceptable salts and stereoisomers thereof.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods. Generally, salts of basic compounds are prepared by ion exchange chromatography or by reaction of a free base with a stoichiometric or excess amount of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents. Similarly, a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid.
  • conventional non-toxic salts include those prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, and hard.
  • Fatty acid lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl A salt prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.
  • a suitable "pharmaceutically acceptable salt” refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, including substituted naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, Betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine , hydrazine, polyamine resin, procaine, hydrazine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • the compounds of the invention can be prepared by the methods of the following synthetic schemes (Schemes 1-6). A better understanding of the compounds and synthetic methods described in the present invention can be obtained in conjunction with the synthetic schemes described below.
  • the described synthetic schemes describe the methods that can be used to prepare the compounds described in the present invention, which are merely illustrative of the illustrative examples and are not intended to limit the scope of the invention.
  • Step 1a 1-bromo-2-(2,2-diethoxyethoxy)-4-methoxybenzene (0102) -1)
  • 2-bromo-5-methoxyphenol (0101-1) (1.83 g, 9.02 mmol, 1.0 eq.)
  • 2-bromo-1,1-diethoxyethane (1.42 mL)
  • 9.47 mmol, 1.05 eq. was dissolved in N,N-dimethylformamide (10 mL) and then potassium carbonate (2.49 g, 18.04 mmol, 2.0 eq.).
  • the air in the reaction system was replaced with nitrogen three times, and then reacted at 95 ° C overnight.
  • Step 1b Preparation of 7-bromo-4-methoxybenzofuran (2-(1-trityl-1H-imidazol-4-yl)benzaldehyde) (Compound 0103-1) : 1-Bromo-2-(2,2-diethoxyethoxy)-4-methoxybenzene (102-1) (2.60 g, 8.15 mmol, 1.0 eq.) was added to the reaction flask. Phosphoric acid (8.26 g, 24.45 mmol, 3.0 equivalents) and 1,2-dichloroethane (40 mL) were heated to 83 ° C for 3 hours. The reaction solution was cooled to room temperature and then washed with water (30 mL ⁇ 2). Benzofuran (1.16 g, yield: 63%). LCMS (ESI): m / z 227 [M + 1] +.
  • Step 1c Preparation of 1-(4-methoxybenzofuran-7-yl)ethan-1-one (Compound 0104-1) : 7-Bromo-4-methoxybenzofuran (0103-1) (0.416 g, 1.833 mmol, 1.0 eq.), vinyl n-butyl ether (1.07 mL, 8.247 mmol, 4.5 eq.).
  • Step 1e (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(4-methoxybenzofuran-7-yl)prop-2-en-1-one
  • ((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(4-methoxybenzofuran-7-yl)prop-2-en-1-one) (Compound 0106-1): 1-(4-Methoxybenzofuran-7-yl)ethan-1-one (0104-1) (130 mg, 0.684 mmol, 1.0 eq.) and 4-hydroxy-3,5-dimethylbenzaldehyde ( Concentrated sulfuric acid (2 mL) was slowly added dropwise to a solution of 103 mg, 0.684 mmol, 1.0 eq.
  • Step 1f (E)-2-(4-(3-(4-methoxybenzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6-di Tert-butyl(E)-2-(4-(3-(4-methoxybenzofuran-7-yl)-3-oxoprop-1-en--methylphenoxy)-2-methylpropanoate
  • 1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate) (0107-1): (E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-( 4-methoxybenzofuran-7-yl)prop-2-en-1-one (0106-1) (0.22 g, 0.684 mmol, 1.0 eq.) and tert-butyl 2-bromo-2-methylpropanoate
  • EtOAc EtOAc
  • Step 1g (E)-2-(4-(3-(4-methoxybenzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6-di Methylphenoxy)-2-methylpropionic acid ((E)-2-(4-(3-(4-methoxybenzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2 ,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 1): (E)-2-(4-(3-(4-methoxybenzofuran-7-yl)-3-) Oxypropan-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid tert-butyl ester (0107-1) (113 mg, 0.244 mmol, 1.0 eq.) Concentrated sulfuric acid (1 mL) was slowly added dropwise to the hexacyclic solution (8 ml), and the mixture was re
  • Step 2a 1-bromo-2-(2,2-diethoxyethoxy)-4-fluorobenzene (compound 0102- Preparation of 2): 2-bromo-5-fluorophenol (0101-2) (1.73 g, 9.06 mmol, 1.0 eq.) and 2-bromo-1,1-diethoxyethane (5.45 mL, 36.42 mmol) , 4.0 eq.) was dissolved in N,N-dimethylformamide (20 mL), then potassium carbonate (2.50 g, 18.12 mmol, 2.0 eq.). The air in the reaction system was replaced with nitrogen three times, and then reacted at 95 ° C for 8 hours.
  • Step 2b Preparation of 7-bromo-4-fluorobenzofuran (Compound 0103-2): Add 1-bromo-2-(2,2-diethoxy) to the reaction flask Ethyloxy)-4-fluorobenzene (0102-2) (2.75 g, 8.95 mmol, 1.0 eq.), polyphosphoric acid (9.08 g, 26.86 mmol, 3.0 eq.) and 1,2-dichloroethane (40 mL) ), heated to 83 ° C for 3 hours. The reaction solution was cooled to room temperature and then washed with water (30 mL ⁇ 2). And furan (0.992 g, yield: 52%).
  • Step 2c Preparation of 1-(4-fluorobenzofuran-7-yl)ethan-1-one (Compound 0104-2): 7-Bromo-4-fluorobenzofuran (0103-2) (0.95 g, 4.42 mmol, 1.0 eq.) was dissolved in anhydrous toluene (15 mL), cooled to -78 ° C with dry ice acetone bath, then slowly added dropwise n-Butyllithium (2.5 M, 2.47 mL, 6.19 mmol, 1.4 eq.) was stirred at -78 ° C for 1.5 hr.
  • n-Butyllithium 2.5 M, 2.47 mL, 6.19 mmol, 1.4 eq.
  • Step 2d 1-(4-(methylamino)benzofuran-7-yl)ethan-1-one) (Compound 0105 -2)
  • 1-(4-fluorobenzofuran-7-yl)ethan-1-one (0104-2) (0.254 g, 1.427 mmol, 1.0 eq.).
  • 25% aqueous solution, 0.71 g, 5.708 mmol, 4.0 eq.) and dimethyl sulfoxide (5 mL) were then reacted at 60 ° C overnight.
  • the reaction mixture was cooled to room temperature and diluted with water (50 mL).
  • Step 2e (E)-2-(2,6-Dimethyl-4-(3-(4-(methylamino)benzofuran-7-yl)-3-oxoprop-1-ene- Ethyl 1-(phenyl)-2-methylpropanoate (ethyl(E)-2-(2,6-dimethyl-4-(3-(4-(methylamino)benzofuran-7-yl)-) Preparation of 3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate) (Compound 0108-2): Add 1-(4-(methylamino)benzofuran-7-yl to the reaction flask Ethyl-1-one (0105-2) (146 mg, 0.771 mmol, 1.0 eq.), tert-butyl 2-(4-formyl-2,2-dimethylphenoxy)-2-methylpropanoate (225 mg, 0.771 mmol, 1.0 eq.) and ethanol (8 mL),
  • Step 2f (E)-2-(2,6-Dimethyl-4-(3-(4-(methylamino)benzofuran-7-yl)-3-oxoprop-1-ene- 1-(1)6-dimethyl-4-(3-(4-(methylamino)benzofuran-7-yl)-3-oxoprop Preparation of -1-en-1-yl)phenoxy)-2-methylpropanoic acid)
  • Compound 2 (E)-2-(2,6-Dimethyl-4-(3-() Ethyl 4-(methylamino)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate (0108-2) (93 mg , 0.214 mmol, 1.0 eq.), sodium hydroxide (2 6 mg, 0.641 mmol, 3.0 eq.), ethanol (5 mL) and water (3 mL).
  • Step 3a Preparation of 1-bromo-2-(2,2-diethoxyethoxy)benzene (Compound 0102-3): 2 -Bromo-phenol (0101-3) (2.0 g, 11.56 mmol, 1.0 eq.) was dissolved in 30 ml of DMF, and 2-bromo-1,1-diethoxyethane (2.96 g, 15.03 mmol, 1.3 eq. Potassium carbonate (3.19 g, 23.12 mmol, 2.0 eq.) was replaced with nitrogen three times in a round bottom flask and then reacted at 100 ° C for 8 hours.
  • Step 3b Preparation of 7-bromobenzofuran (Compound 0103-3): 1-Bromo-2-(2,2-diethoxyethoxy)benzene (0102-3) ( 3.33 g, 11.56 mol, 1.0 eq.) was dissolved in DCE (60 ml), PPA (11.72 g, 34.68 mmol, 3.0 eq.) was added, and the air in the round bottom flask was replaced with nitrogen three times and then refluxed at 83 ° C for 3 hours. . After completion of the reaction, dichloromethane (100 ml) was added, and water (100 ml ⁇ 3) was washed. The organic phase was dried over anhydrous sodium sulfate and evaporated. 7-Bromobenzofuran (1.336 g, yield: 58%).
  • Step 3c Preparation of 1-(benzofuran-7-yl)ethanone (Compound 0104-3): 7-Bromobenzofuran (0103-3) 1.06 g, 5.36 mmol, 1.0 eq.) was dissolved in ethylene glycol (10 ml), butyl vinyl ether (0.698 g, 6.97 mmol, 1.3 eq.), palladium acetate (0.12 g, 0.536 mmol, 0.1 eq.), DPPP ( 0.221 g, 0.536 mmol, 0.1 eq.), TEA (1.08 g, 10.71 mmol, 2.0 eq.), and the reaction mixture was reacted in a nitrogen-filled sealed tube at 150 ° C for 1 hour.
  • Step 3d (E)-1-(benzofuran-7-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one ((E)- Preparation of 1-(benzofuran-7-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one) (Compound 0106-3): 1-(benzofuran) -7-yl)ethanone (0104-3) (0.79 g, 4.93 mol, 1.0 eq.) was dissolved in 10 ml of dioxane, and 4-hydroxy-3,5-dimethylbenzaldehyde (0.81 g, 5.42) was added.
  • Step 3e (E)-2-(4-(3-(benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy Tert-butyl 2-methylpropionate ((E)-tert-butyl 2-(4-(3-(benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2, Preparation of 6-dimethylphenoxy)-2-methylpropanoate) (Compound 0107-3): (E)-1-(benzofuran-7-yl)-3-(4-hydroxy-3,5-dimethylbenzene Propyl-2-en-1-one (0106-3) (0.8 g, 2.74 mmol, 1.0 eq.) was dissolved in 20 ml of acetonitrile, and potassium carbonate (1.88 g, 13.7 mmol, 5.0 eq.), 2-bromo Tert-butyric acid butyrate (3.05 g, 13.7 m
  • Step 3f (E)-2-(4-(3-(benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy -2-methylpropionic acid ((E)-2-(4-(3-(benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2 Preparation of -methylpropanoic acid (Compound 3): (E)-2-(4-(3-(benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2 tert-Butyl 6-dimethylphenoxy)-2-methylpropanoate (0107-3) (0.5 g, 1.15 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL) 4 ml), reacted at room temperature for 15 h.
  • Step 4a 1-(4-(methylthio)benzofuran-7-yl)ethan-1-one) (Compound 0105 Preparation of -5): To the reaction flask was added 1-(4-fluorobenzofuran-7-yl)ethan-1-one (0104-2) (0.25 g, 1.404 mmol, 1.0 eq.), sodium thiomethoxide (40%, 0.49 g, 2.81 mmol, 2.0 eq.) and dimethyl sulfoxide (5 ml) were reacted for 1 hour at room temperature.
  • Step 4b (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(4-(methylthio)benzofuran-7-yl)prop-2-ene-1 -(E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(4-(methylthio)benzofuran-7-yl)prop-2-en-1-one) (Compound 0106-5 Preparation of 1-(4-(methylthio)benzofuran-7-yl)ethan-1-one (0105-5) (214 mg, 1.04 mmol, 1.0 eq.) and 4-hydroxy-3,5 Concentrated sulfuric acid (2 mL) was slowly added dropwise to a solution of dimethylbenzaldehyde (156 mg, 1.04 mmol, 1.0 eq.) in ethanol (8 ml), and allowed to react at room temperature for 3 hours.
  • Step 4c (E)-2-(2,6-Dimethyl-4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-ene- Tert-butyl(E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)benzofuran-7-) Preparation of yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate) (Compound 0107-5): (E)-3-(4-hydroxy-3,5-dimethyl Phenyl)-1-(4-(methylthio)benzofuran-7-yl)prop-2-en-1-one (0106-5) (0.35 g, 1.04 mmol, 1.0 eq.) and 2-bromo tert-Butyl -2-methylpropanoate (1.16 mL, 6.21 mmol, 6.0 eq.) was dissolved in EtOAc (EtOAc) (EtOA
  • Step 4d (E)-2-(2,6-Dimethyl-4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-ene- 1-(E)(phenoxy)-2-methylpropanoic acid ((E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxoprop Preparation of -1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 5): (E)-2-(2,6-Dimethyl-4-(3-(4-) at room temperature (Methylthio)benzofuran-7-yl)-3-oxopropan-1-en-1-yl)phenoxy)-2-methylpropanoic acid tert-butyl ester (0107-5) (227 mg, Concentrated sulfuric acid (1 mL) was slowly added dropwise to a solution of 0.472 mmol (1.0 eq.) in
  • Step 5a (E)-3-(4-Hydroxyphenyl)-1-(4-(methylthio)benzofuran-7-yl)prop-2-en-1-one ((E)-3 Preparation of (4-hydroxyphenyl)-1-(4-(methylthio)benzofuran-7-yl)prop-2-en-1-one) (Compound 0106-12): 1-(4-(methylthio) Benzofuran-7-yl)ethanone (0105-5) (0.3 g, 1.45 mmol, 1.0 eq.) was dissolved in 10 mL of dioxane, and 4-hydroxybenzaldehyde (0.213 g, 1.75 mmol, 1.2 eq.
  • Step 5b (E)-2-Methyl-2-(4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxo-1-en-1-yl) Tert-butyl phenoxy)propionate ((E)-tert-butyl 2-methyl-2-(4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-en- Preparation of 1-yl)phenoxy)propanoate) (Compound 0107-12): E)-3-(4-Hydroxyphenyl)-1-(4-(methylthio)benzofuran-7-yl)propene 2-En-1-one (0106-12) (0.28 g, 0.9 mmol, 1.0 eq.) was dissolved in 20 mL of acetonitrile, and potassium carbonate (0.623 g, 4.5 mmol, 5.0 eq.), 2-bromoisobutyric acid Butyl ester
  • Step 5c (E)-2-Methyl-2-(4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl) Phenoxy)propionic acid ((E)-2-methyl-2-(4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)
  • propanoic acid (E)-2-methyl-2-(4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxo)
  • Step 6a (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(4-(methylthio)benzofuran-7-yl)prop-2-ene-1 -(E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(4-(methylthio)benzofuran-7-yl)prop-2-en-1-one) (Compound 0106-13 Preparation: 1-(4-(methylthio)benzofuran-7-yl)ethanone (0105-5) (0.38 g, 1.84 mmol, 1.0 eq.) was dissolved in 10 mL of dioxane.
  • Step 6b (E) 2-(2,6-Dimethyl-4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxo-1-ene-1- Tert-butyl phenoxy)acetate ((E)-tert-butyl 2-(2,6-dimethyl-4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxoprop-1 Preparation of -en-1-yl)phenoxy)acetate) (Compound 0107-13): (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(4-(A) Thio)benzofuran-7-yl)prop-2-en-1-one (0106-13) (0.52 g, 1.54 mmol, 1.0 eq.) was dissolved in 20 ml of acetonitrile and potassium carbonate (1.06 g, 7.68 mmol) , 5.0 eq.), 2-bromoisobuty
  • Step 6c ((E)-2-(2,6-Dimethyl-4-(3-(4-(methylthio))benzofuran-7-yl)-3-oxoprop-1-ene -1-yl)phenoxy)acetic acid ((E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-en- Preparation of 1-yl)phenoxy)acetic acid): (E) 2-(2,6-Dimethyl-4-(3-(4-(methylthio))benzofuran-7- tert-Butyl 3-(oxo-1-en-1-yl)phenoxy)acetate (0107-13) (0.39 g, 0.918 mmol, 1.0 eq.) was dissolved in 5 mL of THF.
  • Step 7a 1-bromo-4-fluoro-2-(prop-2-yn-1-yloxy)benzene (1-bromo-4-fluoro-2-(prop-2-yn-1-yloxy)benzene
  • 2-bromo-5-fluorophenol (0101-2) (1.91 g, 10 mmol, 1.0 eq.) and potassium carbonate (2.76 g, 20 mmol, 2.0 eq.
  • 2-bromo-5-fluorophenol (0101-2) (1.91 g, 10 mmol, 1.0 eq.
  • potassium carbonate (2.76 g, 20 mmol, 2.0 eq.
  • Step 7b Preparation of 7-bromo-4-fluoro-2-methylbenzofuran (N-081-4) (Compound 0202-14): sealing tube 1-Bromo-4-fluoro-2-(prop-2-yn-1-yloxy)benzene (0201-14) (2.29 g, 10 mmol, 1.0 eq.), cesium fluoride (2.28 g, 15 mmol, 1.5 eq.) and diethyl aniline (15 ml) were heated and refluxed for 4 hours.
  • Step 7c 1-(4-fluoro-2-methylbenzofuran-7-yl)ethan-1-one (1-(4-fluoro-2-methylbenzofuran-7-yl)ethan-1-one) ( Preparation of compound 0203-14): To the sealing tube was added 7-bromo-4-fluoro-2-methylbenzofuran (0202-14) (1.57 g, 7 mmol, 1.0 eq.), 1-(ethyleneoxy) Butane (0.91 g, 9.1 mmol, 1.3 eq.), palladium acetate (0.157 g, 0.7 mmol, 0.1 eq.), 1,3-bis(diphenylphosphino)propane (0.288 g, 0.7 mmol, 0.1 eq.).
  • Step 7d 1-(2-methyl-4-(methylthio)benzofuran-7-yl)-1-one (1-(2-methyl-4-(methylthio)benzofuran-7-yl) Preparation of ethan-1-one)
  • Compound 0204-14 1-(4-Fluoro-2-methylbenzofuran-7-yl)ethan-1-one (0203-14) (0.99 g, 5.2
  • a solution of 20% sodium thiomethoxide (4 ml, 10.4 mmol, 2.0 eq.) was added to a dimethyl sulfoxide solution (30 ml
  • the reaction mixture was diluted with EtOAc (EtOAc) (EtOAcjjjjjj 7-yl)ethan-1-one (1.04 g, yield: 91%).
  • Step 7e (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(2-methyl-4-(methylthio)benzofuran-7-yl)propene- 2-(E)-3-(4-hydroxy-4-(5-dimethylphenyl)-1-(2-methyl-4-(methylthio)benzofuran-7-yl)prop-2-en- Preparation of 1-one)
  • Compound 0205-14 1-(2-methyl-4-(methylthio)benzofuran-7-yl)ethan-1-one (0204-14) (0.44 g
  • Concentrated sulfuric acid (2 ml) was slowly added to a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (0.33 g, 2.2 mmol, 1.1 eq.) in dioxane (10 ml).
  • Step 7f (E)-2-(2,6-Dimethyl-4-(3-(2-methyl-4-(methylthio)benzofuran-7-yl)-3-oxopropane Tert-butyl(E)-2-(2,6-dimethyl-4-(3-(2-methyl-)--1-en-1-yl)phenoxy)-2-methylpropanoate
  • 4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate) (Compound 0206-14): To (E)-3-(4- Hydroxy-3,5-dimethylphenyl)-1-(2-methyl-4-(methylthio)benzofuran-7-yl)prop-2-en-1-one (0205-14) Potassium carbonate (1.38 g, 10.0 mmol, 5.0 eq.) and tert-butyl 2-bromoisobutyrate (2.23 g, 10.0 mmol, 5.0
  • Step 7g (E)-2-(2,6-Dimethyl-4-(3-(2-methyl-4-(methylthio)benzofuran-7-yl)-3-oxopropane -1-en-1-yl)phenoxy)-2-methylpropanoic acid ((E)-2-(2,6-dimethyl-4-(3-(2-methyl-4-(methylthio)benzofuran) Preparation of -7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid (Compound 14): To (E)-2-(2,6-Dimethyl-4- (3-(2-Methyl-4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid Trifluoroacetic acid (2 ml) was slowly added to a solution of tert-butyl ester (0206-14) (0.28 g, 0.57 mmol, 1.0 e
  • Example 8 (E)-2-(2,6-Dimethyl-4-(3-(2-methyl-4-(methylthio))benzo[d]oxazole-7-yl)- 3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropionic acid ((E)-2-(2,6-dimethyl-4-(3-(2-methyl-4) Preparation of (methylthio)benzo[d]oxazol-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 20)
  • Step 8a 1-(4-fluoro-2-hydroxy-3-nitrophenyl)ethan-1-one (1-(4-fluoro-2-hydroxy-3-nitrophenyl)ethan-1-one)
  • Step 8b sulfuric acid to 1-(4-fluoro-2-hydroxyphenyl)ethan-1-one (0301-20) (1.0 g, 6.49 mmol, 1.0 eq.) at 0 °C
  • 70% nitric acid 0.5 ml, 7.14 mmol, 1.1 equivalent
  • Step 8b 1-(2-Hydroxy-4-(methylthio)-3-nitrophenyl)ethan-1-one (1-(2-hydroxy-4-(methylthio)-3-nitrophenyl)ethan- Preparation of 1-one)
  • Compound 0303-20 1-(4-Fluoro-2-hydroxy-3-nitrophenyl)ethan-1-one (0302-20) (0.34 g, 1.71 mmol, 1.0 Equivalent) dimethyl sulfoxide solution (8 ml) was added with 20% sodium thiomethoxide solution (1.19 g, 3.42 mmol, 2.0 eq.), and allowed to react at room temperature for half an hour. The reaction solution was diluted with water (100 ml) with 1 M hydrochloric acid.
  • Step 8c 1-(3-amino-2-hydroxy-4-(methylthio)phenyl)ethan-1-one (1-(3-amino-2-hydroxy-4-(methylthio)phenyl)ethan Preparation of -1-one)
  • Compound 0304-20 Add 1-(2-hydroxy-4-(methylthio)-3-nitrophenyl)ethan-1-one (0303-20) to the reaction flask (0.18g, 0.8mmol, 1.0 eq.), zinc powder (0.52g, 8.0mmol, 10.0 eq.), ammonium chloride (0.432g, 8.0mmol, 10.0 eq.) and methanol (15ml), react at room temperature for half an hour . The reaction was diluted with EtOAc (EtOAc) (EtOAc) (EtOAcjjjjj g, yield: 100%).
  • Step 8d 1-(2-methyl-4-(methylthio)benzo[d]oxazol-7-yl)ethan-1-one (1-(2-methyl-4-(methylthio)benzo[ Preparation of d]oxazol-7-yl)ethan-1-one)
  • Compound 0305-20 1-(3-Amino-2-hydroxy-4-(methylthio)phenyl)ethane-1-
  • ketone (0304-20) (0.158 g, 0.8 mmol, 1.0 eq.) in toluene (20 ml) was added triethyl orthoacetate (0.5 ml, 2.6 mmol, 3.3 eq.).
  • Step 8e (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(2-methyl-4-(methylthio)benzo[d]oxazole-7- ((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(2-methyl-4-(methylthio)benzo[d]oxazol-7- Preparation of yl)prop-2-en-1-one)
  • Compound 0306-20 To 1-(2-methyl-4-(methylthio)benzo[d]oxazole-7-yl)B 1-ketone (0305-20) (0.26 g, 1.2 mmol, 1.0 eq.) and 4-hydroxy-3,5-dimethylbenzaldehyde (0.195 g, 1.3 mmol, 1.1 eq.) in dioxane ( Concentrated sulfuric acid (2 ml) was slowly added to 10 ml), and the reaction was stirred at room temperature for 2 days.
  • Step 8f (E)-2-(2,6-Dimethyl-4-(3-(2-methyl-4-(methylthio))benzo[d]oxazole-7-yl)-3 -Oxo-1-ene-piperidin-1-yl)phenoxy)-2-methylpropanoic acid tert-butyl ester (tert-butyl(E)-2-(2,6-dimethyl-4-(3) Preparation of 2-(2-methyl-4-(methylthio)benzo[d]oxazol-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate) (Compound 0307-20): To (E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(2-methyl-4-(methylthio)benzo[d]oxazole-7-yl) To a solution of prop-2-en-1-one (0306-20) (0.27 g, 0.77 mmol, 1.0 eq.) in ace
  • Step 8g (E)-2-(2,6-Dimethyl-4-(3-(2-methyl-4-(methylthio))benzo[d]oxazole-7-yl)-3 -oxopropen-1-en-1-yl)phenoxy)-2-methylpropionic acid ((E)-2-(2,6-dimethyl-4-(3-(2-methyl-4-) Preparation of (methylthio)benzo[d]oxazol-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 20): To (E)-2-(2 ,6-Dimethyl-4-(3-(2-methyl-4-(methylthio)benzo[d]oxazole-7-yl)-3-oxo-1-ene-piperidine- Trifluoroacetic acid (2 ml) was slowly added to a solution of tert-butyl 1-phenoxy)-2-methylpropanoate (0307-20) (0.076
  • reaction solution was allowed to react at room temperature overnight.
  • the reaction mixture was diluted with EtOAc (EtOAc)EtOAc. )-2-(2,6-Dimethyl-4-(3-(2-methyl-4-(methylthio))benzo[d]oxazole-7-yl)-3-oxopropene- 1-en-1-yl)phenoxy)-2-methylpropanoic acid (42 mg, yield: 64%).
  • Step 9a 4-bromo-2-(2,2-diethoxyethoxy)-1-fluorobenzene (4-bromo-2-(2,2-diethoxyethoxy)-1-fluorobenzene) (Compound 0402- Preparation of 27): 5-bromo-2-fluorophenol (0401-27) (2.1 g, 10.9 mmol, 1.0 eq.) and 2-bromo-1,1-diethoxyethane (2.15 mL, 14.29 mmol) , 1.3 equivalents) was dissolved in N,N-dimethylformamide (15 mL), then potassium carbonate (3.03 g, 21.99 mmol, 2.0 eq.).
  • Step 9b Preparation of 4-bromo-7-fluorobenzofuran (Compound 0403-27): Add 4-bromo-2-(2,2-diethoxy) to the reaction flask Ethyloxy)-1-fluorobenzene (0402-27) (3.37 g, 10.97 mmol, 1.0 eq.), polyphosphoric acid (11.12 g, 32.91 mmol, 3.0 eq.) and 1,2-dichloroethane (40 mL) ), heated to 83 ° C for 3 hours. The reaction mixture was cooled to room temperature, then washed with water (30 mL ⁇ 2). Benzofuran (0.9 g, yield: 38%). LCMS (ESI): m / z 215 [M + 1] +.
  • Step 9c Preparation of 1-(7-fluorobenzofuran-4-yl)ethan-1-one (Compound 0404-27): 4-bromo-7-fluorobenzofuran (0403-27) (0.805 g, 3.74 mmol, 1.0 eq.), vinyl n-butyl ether (2.18 mL, 16.85 mmol, 4.5 eq.), palladium acetate (42 mg).
  • Step 9d 1-(7-(methylthio)benzofuran-4-yl)ethan-1-one (compound 0405)
  • -27 To the reaction flask was added 1-(7-fluorobenzofuran-4-yl)ethan-1-one (0404-27) (0.27 g, 1.52 mmol, 1.0 eq.), sodium thiomethoxide (40%, 0.53 g, 3.04 mmol, 2.0 eq.) and dimethyl sulfoxide (5 ml) were reacted for 1 hour at room temperature.
  • the reaction mixture was diluted with water (50 mL), EtOAc (EtOAc m. Light yellow solid 1-(7-(methylthio)benzofuran-4-yl)ethan-1-one (0.29 g, yield: 93%).
  • Step 9e (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(7-(methylthio)benzofuran-4-yl)prop-2-ene-1 -(E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(7-(methylthio)benzofuran-4-yl)prop-2-en-1-one) (Compound 0406-27 Preparation of 1-(7-(methylthio)benzofuran-4-yl)ethan-1-one (0405-27) (290 mg, 1.41 mmol, 1.0 eq.) and 4-hydroxy-3,5 Concentrated sulfuric acid (2 mL) was slowly added dropwise to a solution of dimethylbenzaldehyde (210 mg, 1.41 mmol, 1.0 eq.) in ethanol (8 ml), and the mixture was reacted at room temperature for 3.5 hours.
  • Step 9f (E)-2-(2,6-Dimethyl-4-(3-(7-(methylthio)benzofuran-4-yl)-3-oxoprop-1-ene- Tert-butyl(E)-2-(2,6-dimethyl-4-(3-(7-(methylthio)benzofuran-4-) Preparation of yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate) (Compound 0407-27): (E)-3-(4-hydroxy-3,5-dimethyl Phenyl)-1-(7-(methylthio)benzofuran-4-yl)prop-2-en-1-one (0406-27) (0.47 g, 1.39 mmol, 1.0 eq.) and 2-bromo tert-Butyl -2-methylpropanoate (1.56 mL, 8.34 mmol, 6.0 eq.) was dissolved in EtOAc (10 mL).
  • Step 9g (E)-2-(2,6-Dimethyl-4-(3-(7-(methylthio)benzofuran-4-yl)-3-oxoprop-1-ene- 1-(1)6-dimethyl-4-(3-(7-(methylthio)benzofuran-4-yl)-3-oxoprop Preparation of -1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 27): (E)-2-(2,6-Dimethyl-4-(3-(7-) (Methylthio)benzofuran-4-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid tert-butyl ester (0407-27) (234 mg, Concentrated sulfuric acid (1 mL) was slowly added dropwise to a solution of 0.487 mmol (1.0 eq.) in dioxane (8 ml) and allowed to react at room temperature for 1.5 hours.
  • Example 10 (E)-2-(4-(3-(2,3-Dihydrobenzo[b]thiophen-5-yl)-3-oxoprop-1-en-1-yl)- 2,6-Dimethylphenoxy)methylpropionic acid ((E)-2-(4-(3-(2,3-dihydrobenzo[b]thiophen-5-yl)-3-oxoprop-1- Preparation of en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 36) (prepared according to Scheme 5)
  • Step 10a Preparation of benzo[b]thiophene 1,1-dioxide (Compound 0503-36): To benzothiophene (0501-36) (2.0 g, A 15% solution of hydrogen peroxide (6 ml) and a formic acid (4 ml) were added to a solution of 15 mmol, 1.0 eq. A solution of sodium benzoate (100 ml) was added, and the mixture was combined with methylene chloride (100 ml ⁇ 3). - dioxide (4.0 g, yield: 99%). LCMS (ESI): m / z 167 [M + 1] +.
  • Step 10b Preparation of 2,3-dihydrobenzo[b]thiophene 1,1-dioxide (compound 0503-36): to benzo [b]A solution of thiophene 1,1-dioxide (0502-36) (4.0 g, 22.5 mmol) in methanol (80 ml) and ethyl acetate (80 ml) was added palladium charcoal (1.0 g) and hydrogen was passed at room temperature.
  • Step 10c Preparation of 2,3-dihydrobenzo[b]thiophene (compound 0504-36): at 0 ° C, to lithium tetrahydrogenate (3.8 g, 100 mmol) , a solution of benzo[b]thiophene 1,1-dioxide (0503-36) (3.8 g, 23 mmol, 1.0 eq.) in tetrahydrofuran (50 ml) was added dropwise to a solution of 4.5 eq. Allow to room temperature overnight.
  • Step 10d 1-(2,3-Dihydrobenzo[b]thiophen-5-yl)ethan-1-one (1-(2,3-dihydrobenzo[b]thiophen-5-yl)ethan-1- Preparation of one)
  • Compound 0505-36 2,3-Dihydrobenzo[b]thiophene (0504-36) (0.78 g, 6 mmol, 1.0 eq.) and acetyl chloride (0.94 g, 10 mmol) at 0 °C
  • aluminum trichloride (0.96 g, 7.2 mmol, 1.2 eq.
  • Step 10e (E)-1-(2,3-dihydrobenzo[b]thiophen-5-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-ene -1-keto((E)-1-(2,3-dihydrobenzo[b]thiophen-5-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one)
  • (Compound 0506-36) 1-(2,3-Dihydrobenzo[b]thiophen-5-yl)ethan-1-one (0505-36) (0.81 g, 4.6 mmol, 1.0 eq.)
  • Concentrated sulfuric acid (4 ml) was slowly added to a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (0.69 g, 4.6 mmol, 1.0 eq.) in ethanol (20 ml).
  • Step 10f (E)-2-(4-(3-(2,3-Dihydrobenzo[b]thiophen-5-yl)-3-oxoprop-1-en-1-yl)-2 , 6-dimethylphenoxy)-2-methylpropionic acid tert-butyl ester (tert-butyl(E)-2-(4-(3-(2,3-dihydrobenzo[b]thiophen-5-yl Preparation of -3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate) (Compound 0507-36): To (E)-1-(2,3-dihydrobenzene And [b]thiophen-5-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one (0506-36) (0.45 g, 1.5 mmol, 1.0 To a solution of acetonitrile (30 ml) was added potassium carbonate (1.04
  • Step 10g (E)-2-(4-(3-(2,3-Dihydrobenzo[b]thiophen-5-yl)-3-oxoprop-1-en-1-yl)-2 ,6-Dimethylphenoxy)methylpropionic acid ((E)-2-(4-(3-(2,3-dihydrobenzo[b]thiophen-5-yl)-3-oxoprop-1-en Preparation of -1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 36): To (E)-2-(4-(3-(2,3-dihydrobenzo[b]] Thiophen-5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid tert-butyl ester (0507-36) (0.18 Trifluoroacetic acid (2 ml) was slowly added to a solution of EtOAc (EtOAc
  • Step 11a Preparation of benzo[b]thiophene-5-carbonitrile (compound 0603-38): Add 5-bromobenzo[b]thiophene (0601-) to the reaction flask. 38) (2.13 g, 10 mmol, 1.0 eq.), zinc cyanide (2.34 g, 20 mmol, 2.0 eq.), tetratriphenylphosphine palladium (1.16 g, 1 mmol, 0.1 eq.) and dimethylformamide (16 ml). The reaction was stirred at reflux overnight. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. :1) The white solid product benzo[b]thiophen-5-carbonitrile (1.57 g, yield: 99%) was obtained.
  • Step 11b Preparation of 1-(benzo[b]thiophen-5-yl)ethan-1-one (Compound 0603-38) To a solution of benzo[b]thiophene-5-carbonitrile (0602-38) (1.41 g, 8.9 mmol, 1.0 eq.) in tetrahydrofuran (30 ml) was added 3M methylmagnesium bromide (10.7 mmol, 1.2). Equivalent), return to room temperature and stir overnight, add saturated ammonium chloride solution (100 ml), extract with dichloromethane (1 00 ml ⁇ 2), the organic phase is combined and dried, and the residue is dissolved in dioxane (30 ml).
  • Step 11c (E)-1-(Benzo[b]thiophen-5-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one (( Preparation of E)-1-(benzo[b]thiophen-5-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one) (Compound 0604-38): 1-(Benzo[b]thiophen-5-yl)ethan-1-one (0603-38) (0.81 g, 4.6 mmol, 1.0 eq.) and 4-hydroxy-3,5-dimethylbenzaldehyde (0.69) Concentrated sulfuric acid (4 ml) was slowly added to a solution of g (4.6 mmol, 1.0 eq.) in dioxane (20 ml), and the mixture was heated to 50 ° C and stirred overnight.
  • Step 11d (E)-2-(4-(3-(Benzo[b]thiophen-5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethyl Tert-butyl(E)-2-(4-(3-(benzo[b]thiophen-5-yl)-3-oxoprop-1-en- phenoxy)-2-methylpropanoate Preparation of 1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate) (Compound 0605-38): To (E)-1-(Benzo[b]thiophen-5-yl)-3-(4- Potassium carbonate (0.497 g, added to a solution of hydroxy-3,5-dimethylphenyl)prop-2-en-1-one (0604-38) (0.22 g, 0.72 mmol, 1.0 eq.
  • Step 11e (E)-2-(4-(3-(Benzo[b]thiophen-5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethyl Phenoxy)-2-methylpropionic acid ((E)-2-(4-(3-(benzo[b]thiophen-5-yl)-3-oxoprop-1-en-1-yl)-2 ,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 38): To (E)-2-(4-(3-(benzo[b]thiophen-5-yl)-3-oxopropene- tert-Butyl 1-buten-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate (0605-38) (0.11 g, 0.24 mmol, 1.0 eq.
  • Example 12 (E)-2-(4-(3-(Benzo[d]thiazol-5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethyl (Phenyloxy)-2-methylpropionic acid ((E)-2-(4-(3-(benzo[d]thiazol-5-yl)-3-oxoprop-1-en-1-yl)- Preparation of 2,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 39) (prepared according to Scheme 6)
  • Step 12a (E)-1-(Benzo[d]thiazol-5-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one (( Preparation of E)-1-(benzo[d]thiazol-5-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one) (Compound 0604-39): 1-(Benzo[d]thiazol-5-yl)ethan-1-one (0603-39) (0.23 g, 1.30 mmol, 1.0 eq.) in ethanol (10 ml) and 1,4-dioxane (2 ml) To the mixed solution, 4-hydroxy-3,5-dimethylbenzaldehyde (0.21 g, 1.43 mmol, 1.1 equivalent) was added, and then 98% sulfuric acid (3 ml) was added dropwise, and the reaction mixture was allowed to react at room temperature overnight.
  • Step 12b (E)-2-(4-(3-(Benzo[d]thiazol-5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethyl Tert-butyl(E)-2-(4-(3-(benzo[d]thiazol-5-yl)-3-oxoprop-1-en- phenoxy)-2-methylpropanoate Preparation of 1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate) (Compound 0605-39): To ((E)-1-(Benzo[d]thiazol-5-yl)-3-(4 -Hydroxy-3,5-dimethylphenyl)prop-2-en-1-one (0604-39) (0.30 g, 0.97 mmol, 1.0 eq.) of N,N-dimethylformamide (15 ml) Potassium carbonate (0.54 g, 3.38 mmol, 4.0 eq.) and tert
  • Step 12c (E)-2-(4-(3-(Benzo[d]thiazol-5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethyl Phenoxy)-2-methylpropionic acid ((E)-2-(4-(3-(benzo[d]thiazol-5-yl)-3-oxoprop-1-en-1-yl)-2 ,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 39): To (E)-2-(4-(3-(benzo[d]thiazol-5-yl)-3-oxopropene- tert-Butyl 1-buten-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate (0605-39) (0.24 g, 0.53 mmol, 1.0 eq.
  • Trifluoroacetic acid (3 ml) was slowly added to the solution, and the reaction mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water (100 ml), EtOAc (EtOAc) (E)-2-(4-(3-(benzo[d]thiazol-5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy -2-methylpropionic acid (210 mg, yield: 100%).
  • Step 13a Preparation of 1-(6-methoxybenzofuran-2-yl)ethan-1-one (Compound 0706-43) : 2-Hydroxy-4-methoxybenzaldehyde (0701-43) (0.3 g, 1.97 mmol, 1.0 eq.) and bromoacetone (0.17 mL, 1.97 mmol, 1.0 eq.) were dissolved in N,N-dimethyl In formamide (6 mL), cesium carbonate (0.96 g, 2.96 mmol, 1.5 eq.) was then added. It was replaced with nitrogen three times and then reacted at 60 ° C overnight.
  • Step 13b (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(6-methoxybenzofuran-2-yl)prop-2-en-1-one
  • ((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(6-methoxybenzofuran-2-yl)prop-2-en-1-one) (Compound 0707-43): 1-(6-Methoxybenzofuran-2-yl)ethan-1-one (0706-43) (200 mg, 1.053 mmol, 1.0 eq.) and 4-hydroxy-3,5-dimethylbenzaldehyde ( Concentrated sulfuric acid (2 mL) was slowly added dropwise to a solution of 158 mg (1.053 mmol, 1.0 eq.) in ethanol (8 ml), and allowed to react at room temperature for 5 hours.
  • Step 13c (E)-2-(4-(3-(6-Methoxybenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-di Tert-butyl(E)-2-(4-(3-(6-methoxybenzofuran-2-yl)-3-oxoprop-1-en--methylphenoxy)-2-methylpropanoate
  • Preparation of 1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate) (Compound 0708-43): (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1- (6-Methoxybenzofuran-2-yl)prop-2-en-1-one (0707-43) (339 mg, 1.053 mmol, 1.0 eq.) and tert-butyl 2-bromo-2-methylpropanoate The ester (1.15 mL, 6.32 mmol, 6.0 eq.) was dissolved
  • Step 13d (E)-2-(4-(3-(6-Methoxybenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-di Methylphenoxy)-2-methylpropionic acid ((E)-2-(4-(3-(6-methoxybenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2 ,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 43): (E)-2-(4-(3-(6-Methoxybenzofuran-2-yl)-3- Oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid tert-butyl ester (0708-43) (158 mg, 0.341 mmol, 1.0 eq.) Concentrated sulfuric acid (1 mL) was slowly added dropwise to the hexacyclohexane solution (8 ml), and the
  • Example 14 (E)-2-(4-(3-(benzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy ((E)-2-(4-(3-(benzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)- Preparation of 2-methylpropanoic acid) (Compound 49) (prepared according to Scheme 7)
  • Step 14a Preparation of 1-(benzofuran-2-yl)ethan-1-one (Compound 0706-49): 2-Hydroxybenzaldehyde (0701-49) (0.36 g) , 2.95 mmol, 1.0 eq.) and bromoacetone (0.24 mL, 2.95 mmol, 1.0 eq.) were dissolved in N,N-dimethylformamide (6 mL), then cesium carbonate (1.25 g, 3.84 mmol, 1.5 eq.) . The air in the reaction system was reacted three times with nitrogen, three times and then reacted at 60 ° C overnight.
  • Step 14b E)-1-(benzofuran-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one ((E)-1 -(benzofuran-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one) (Compound 0707-49): Preparation to benzofuran-2-ethyl ketone (0706-49) (200 mg, 1.25 mmol, 1.0 eq.) and 4-hydroxy-3,5-dimethylbenzaldehyde (188 mg, 1.25 mmol, 1.0 eq.) in ethanol (8 ml) (2 mL), react at room temperature for 5 hours.
  • Step 14c (E)-2-(4-(3-(benzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy Tert-butyl(E)-2-(4-(3-(benzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2, Preparation of 6-dimethylphenoxy)-2-methylpropanoate) (Compound 0708-49): (E)-1-(benzofuran-2-yl)-3-(4-hydroxy-3,5-dimethylbenzene Propyl-2-en-1-one (0707-49) (365 mg, 1.25 mmol, 1.0 eq.) and tert-butyl 2-bromo-2-methylpropanoate (1.37 mL, 7.5 mmol, 6.0 eq.) Potassium carbonate (0.69 g, 5.0 mmol, 4.0 eq.) was then added in acetonitrile
  • Step 14d (E)-2-(4-(3-(benzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy -2-methylpropionic acid ((E)-2-(4-(3-(benzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2 Preparation of -methyl propanoic acid (Compound 49): (E)-2-(4-(3-(benzofuran-2-yl)-3-oxoprop-1-en-1-yl) at room temperature a long-term addition of tert-butyl-2,6-dimethylphenoxy)-2-methylpropanoate (0708-49) (163 mg, 0.375 mmol, 1.0 eq.) in dioxane (8 ml) Concentrated sulfuric acid (1 mL) was reacted at room temperature for 1.5 hours.
  • Step 15a Preparation of 1-(6-methylbenzofuran-2-yl)ethan-1-one (Compound 0706-50): 2-Hydroxy-4-methylbenzaldehyde (0701-50) (0.3 g, 2.20 mmol, 1.0 eq.) and bromoacetone (0.18 mL, 2.20 mmol, 1.0 eq.) were dissolved in N,N-dimethylformamide (6 mL), then cesium carbonate (1.08 g, 3.31 mmol, 1.5 eq.) was added. The air in the reaction system was replaced with nitrogen three times, and then reacted at 60 ° C overnight.
  • Step 15b (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(6-methylbenzofuran-2-yl)prop-2-en-1-one ( Preparation of (E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(6-methylbenzofuran-2-yl)prop-2-en-1-one) (Compound 0707-50): Towards 1 -(6-methylbenzofuran-2-yl)ethan-1-one (0706-50) (200 mg, 1.15 mmol, 1.0 eq.) and 4-hydroxy-3,5-dimethylbenzaldehyde (172 mg, Concentrated sulfuric acid (2 mL) was slowly added dropwise to a solution of 1.15 mmol, 1.0 eq.
  • Step 15c (E)-2-(2,6-Dimethyl-4-(3-(6-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl) Tert-butyl(E)-2-(2,6-dimethyl-4-(3-(6-methylbenzofuran-2-yl)-3-oxoprop Preparation of -1-en-1-yl)phenoxy)-2-methylpropanoate) (Compound 008-50): (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1- (6-Methylbenzofuran-2-yl)prop-2-en-1-one (0707-50) (352 mg, 1.15 mmol, 1.0 eq.) and tert-butyl 2-bromo-2-methylpropionate (1.26 mL, 6.9 mmol, 6.0 eq.) was dissolved in EtOAc (10 mL).
  • Step 15d (E)-2-(2,6-Dimethyl-4-(3-(6-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl) Phenoxy)-2-methylpropionic acid ((E)-2-(2,6-dimethyl-4-(3-(6-methylbenzofuran-2-yl)-3-oxoprop-1-en-1) -yl)phenoxy)-2-methylpropanoic acid) (Compound 50): (E)-2-(2,6-Dimethyl-4-(3-(6-methylbenzofuran) - at room temperature 2-Di)-3-oxoprop-1-en-1-yl-1-phenoxy)-2-methylpropanoic acid tert-butyl ester (0708-50) (175 mg, 0.391 mmol, 1.0 eq.) of diox Concentrated sulfuric acid (1 mL) was slowly added dropwise to the hexacyclic solution (8 ml), and the mixture was
  • Example 16 (E)-2-(2,6-Dimethyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-ene -1-yl)phenoxy)-2-methylpropionic acid ((E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3- Preparation of oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 51) (prepared according to Scheme 7)
  • Step 16a Preparation of ethyl 6-bromobenzofuran-2-carboxylate (compound 0702-51): 4-bromo-2-hydroxybenzaldehyde (0701-) was added to the flask. 51) (2.5 g, 12.44 mmol, 1.0 eq.), potassium carbonate (6.86 g, 49.75 mmol, 4.0 eq.) and ethyl bromoacetate (4.13mL, 37.32mmol, 3.0 eq.), then reacted at 130 ° C for 4.5 hours. The reaction solution was cooled to room temperature and diluted with water (50 mL), then ethyl acetate (40 mL ⁇ 3).
  • Step 16b Preparation of 6-bromobenzofuran-2-carboxylic acid (Compound 0703-51): Add 6-bromobenzofuran-2-carboxylic acid ethyl ester to the reaction flask ( 0702-51) (1.09 g, 4.05 mmol, 1.0 eq.), EtOAc (EtOAc (EtOAc) The reaction mixture was diluted with water (20 mL), EtOAc (EtOAc) (EtOAc) And furan-2-carboxylic acid (0.89 g, yield: 91%).
  • Step 16c Preparation of 6-bromo-N-methoxy-N-methylbenzofuran-2-carboxamide (Compound 0704-51) :(6-Bromobenzofuran-2-carboxylic acid (0703-51) (0.89 g, 3.69 mmol, 1.0 eq.), N,O-dimethylhydroxylamine hydrochloride (0.47 g, 4.80 mmol, 1.3 eq.) HATU (1.68 g, 4.43 mmol, 1.2 eq.) and triethylamine (1.28 mL, 9.23 mmol, 2.5 eq.) were dissolved in dichloromethane (20 mL) and then reacted at room temperature for 1 hour.
  • Step 16d Preparation of 1-(6-bromobenzofuran-2-yl)ethan-1-one (Compound 0705-51): 6-Bromo-N-methoxy-N-methylbenzofuran-2-carboxamide (0704-51) (1.05 g, 3.70 mmol, 1.0 eq.) dissolved in dry THF (15 mL) Cool to 0 ° C. Methylmagnesium bromide (3M in diethyl ether, 2.46 mL, 7.39 mmol, 2.0 eq.) was slowly added dropwise dropwise. The reaction solution was allowed to warm to room temperature and the reaction was continued for 1 hour.
  • Methylmagnesium bromide 3M in diethyl ether, 2.46 mL, 7.39 mmol, 2.0 eq.
  • Step 16e1-(6-(methylthio)benzofuran-2-yl)ethan-1-one) (Compound 0706-51 Preparation: 1-(6-Bromobenzofuran-2-yl)ethan-1-one (0705-51) (0.75 g, 3.14 mmol, 1.0 eq.), dimethyldisulfide (1.11) was added to the flask. mL, 12.56 mmol, 4.0 eq.), copper powder (1.69 g, 26.67 mmol, 8.5 eq.) and N,N-dimethylformamide (15 mL), and then heated to 140 ° C for 24 hours under nitrogen atmosphere.
  • Step 16f (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(6-(methylthio)benzofuran-2-yl)prop-2-ene-1 -(E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(6-(methylthio)benzofuran-2-yl)prop-2-en-1-one) (0707-51)
  • Preparation of 1-(6-(methylthio)benzofuran-2-yl)ethan-1-one (0706-51) 50 mg, 0.243 mmol, 1.0 eq.
  • 4-hydroxy-3,5- Concentrated sulfuric acid (1 mL) was slowly added dropwise to a solution of dimethylbenzaldehyde (37 mg, 0.243 mmol, 1.0 eq.) in ethanol (4 ml), and the mixture was reacted at room temperature for 3.5 hours.
  • Step 16g (E)-2-(2,6-Dimethyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-ene- Tert-butyl(E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)benzofuran-2-)-tert-butyl(E)-2-(6-(methylthio)benzofuran-2- Preparation of yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate) (Compound 0708-51): (E)-3-(4-hydroxy-3,5-dimethyl Phenyl)-1-(6-(methylthio)benzofuran-2-yl)prop-2-en-1-one (0707-51) (82 mg, 0.243 mmol, 1.0 eq.) and 2-bromo- tert-Butyl 2-methylpropanoate (0.27 mL, 1.458 mmol
  • Step 16h (E)-2-(2,6-Dimethyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-ene- 1-(1)6-dimethyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop Preparation of -1-en-1-yl)phenoxy)-2-methylpro panoic acid)
  • Compound 51 (E)-2-(2,6-Dimethyl-4-(3-(6) at room temperature -(Methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid tert-butyl ester (0708-51) (35 mg Concentrated sulfuric acid (0.5 mL) was slowly added dropwise to a solution of 0.073 mmol, 1.0 eq.
  • Step 17a (E)-3-(4-Hydroxyphenyl)-1-(6-(methylthio)benzofuran-2-yl)prop-2-en-1-one ((E)-3 Preparation of (4-hydroxyphenyl)-1-(6-(methylthio)benzofuran-2-yl)prop-2-en-1-one) (Compound 0707-56): To 1-(6-(methylthio) a solution of benzofuran-2-yl)ethan-1-one (0706-51) (95 mg, 0.461 mmol, 1.0 eq.) and 4-hydroxybenzaldehyde (56 mg, 0.461 mmol, 1.0 eq.) in ethanol (8 ml) Concentrated sulfuric acid (2 mL) was slowly added dropwise and allowed to react at room temperature overnight.
  • Step 17b (E)-2-Methyl-2-(4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxo-1-en-1-yl) Tert-butyl(E)-2-methyl-2-(4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en- Preparation of 1-yl)phenoxy)propanoate) (Compound 0708-56): (E)-3-(4-Hydroxyphenyl)-1-(6-(methylthio)benzofuran-2-yl) Prop-2-en-1-one (0707-56) (143 mg, 0.461 mmol, 1.0 eq.) and tert-butyl 2-bromo-2-methylpropanoate (0.42 mL, 2.306 mmol, 5.0 eq.) (8 mL) was then added potassium carbonate (0.25 g, 1.844 mmol, 4.0
  • Step 17c (E)-2-Methyl-2-(4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxo-1-en-1-yl) Phenoxy)propionic acid ((E)-2-methyl-2-(4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)
  • propanoic acid (E)-2-methyl-2-(4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxo at room temperature
  • Concentrated sulfuric acid (1 mL) was slowly added dropwise to a solution of t-butyl-1-buten-1-yl)phenoxy)propanoate (0708-56) (98 mg, 0.217 mmol, 1.0 eq.) in dioxane (8 mL) ), react at room temperature for 2 hours.
  • Example 18 (E)-2-(2,6-Dimethyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-ene -1-yl)phenoxy)acetic acid ((E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en- Preparation of 1-yl)phenoxy)acetic acid) (Compound 57) (prepared according to Scheme 7)
  • Step 18a (E)-2-(2,6-Dimethyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxo-1-ene-1 Tert-butyl(E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop- Preparation of 1-en-1-yl)phenoxy)acetate) (Compound 0708-57): (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(6-( Methylthio)benzofuran-2-yl)prop-2-en-1-one (0707-51) (112 mg, 0.331 mmol, 1.0 eq.) and tert-butyl bromoacetate (0.21 mL, 1.325 mmol, 6.0 eq.
  • Step 18b (E)-2-(2,6-Dimethyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-ene- 1-(1)6-dimethyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1 -yl)phenoxy)acetic acid) (Compound 57): (E)-2-(2,6-Dimethyl-4-(3-(6-(methylthio))benzofuran) tert-Butyl 2-yl)-3-oxo-1-en-1-yl)phenoxy)acetate (0708-57) (60 mg, 0.133 mmol, 1.0 eq.) in dioxane (5 mL) Concentrated sulfuric acid (0.5 mL) was slowly added dropwise, and the mixture was reacted at room temperature for 1.5 hours.
  • Step 19a Preparation of 1-(7-bromobenzofuran-2-yl)ethan-1-one (Compound 0802-58): 3-bromo-2-hydroxybenzaldehyde (0801-58) (2.39 g, 11.9 mmol, 1.0 eq.) and bromoacetone (1.63 g, 11.9 mmol, 1.0 eq.) were dissolved in N,N-dimethylformamide (20 mL) Then, cesium carbonate (5.82 g, 17.85 mmol, 1.2 eq.) was added. The air in the reaction system was replaced with nitrogen three times, and then reacted at 60 ° C overnight.
  • Step 19b 1-(7-(methylthio)benzofuran-2-yl)ethan-1-one (compound 0803) -58)
  • 1-(7-bromobenzofuran-2-yl)ethan-1-one (0802-58) (1.27 g, 5.31 mmol, 1.0 eq.)
  • triethylenediamine 1.19 g, 10.62 mmol, 2.0 eq.
  • cuprous iodide (1.01 g, 5.31 mmol, 1.0 eq.
  • dimethyl sulfoxide (20 mL)
  • Step 19c (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(7-(methylthio)benzofuran-2-yl)prop-2-ene-1 -(E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(7-(methylthio)benzofuran-2-yl)prop-2-en-1-one) (Compound 0804-58 Preparation of 1-(7-(methylthio)benzofuran-2-yl)ethan-1-one (0803-58) (350 mg, 1.70 mmol, 1.0 eq.), 4-hydroxy-3,5 Concentrated sulfuric acid (2 mL) was slowly added dropwise to a solution of dimethylbenzaldehyde (255 mg, 1.70 mmol, 1.0 eq.) in ethanol (8 ml), and allowed to react at room temperature for 5 hours.
  • Step 19d (E)-2-(2,6-Dimethyl-4-(3-(7-(methylthio)benzofuran-2-yl)-3-oxoprop-1-ene- Tert-butyl(E)-2-(2,6-dimethyl-4-(3-(7-(methylthio)benzofuran-2-) Preparation of yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate) (Compound 0805-58): (E)-3-(4-hydroxy-3,5-dimethyl Phenyl)-1-(7-(methylthio)benzofuran-2-yl)prop-2-en-1-one (0804-58) (380 mg, 1.124 mmol, 1.0 eq.) and 2-bromo- tert-Butyl 2-methylpropanoate (1.25 mL, 6.75 mmol, 6.0 eq.) was dissolved in EtOAc (10 mL), then EtOAc (Et
  • Step 19e (E)-2-(2,6-Dimethyl-4-(3-(7-(methylthio)benzofuran-2-yl)-3-oxoprop-1-ene- 1-(E)(phenoxy)-2-methylpropanoic acid ((E)-2-(2,6-dimethyl-4-(3-(7-(methylthio)benzofuran-2-yl)-3-oxoprop Preparation of -1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 58): (E)-2-(2,6-Dimethyl-4-(3-(7-) (Methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl-1-phenoxy)-2-methylpropanoic acid tert-butyl ester (0805-58) (83 mg, Concentrated sulfuric acid (0.5 mL) was slowly added dropwise to a solution of 0.173 mmol (1.0 eq.)
  • Example 20 (E)-2-(2,6-Dimethyl-4-(3-(4-(methylthio)benzofuran-2-yl)-3-oxoprop-1-ene -1-yl)phenoxy)-2-methylpropionic acid ((E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)benzofuran-2-yl)-3- Preparation of oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 60) (prepared according to Scheme 9)
  • Step 20a Preparation of 1-(4-bromobenzofuran-2-yl)ethan-1-one (1-(4-bromobenzofuran-2-yl)ethan-1-one) (Compound 0902-60): 2-Bromo-6-hydroxybenzaldehyde (0901-60) (2.39 g, 11.9 mmol, 1.0 eq.) and bromoacetone (1.63 g, 11.9 mmol, 1.0 eq.) were dissolved in N,N-dimethylformamide (20 mL) Then, cesium carbonate (5.82 g, 17.85 mmol, 1.2 eq.) was added.
  • Step 20b 1-(4-(methylthio)benzofuran-2-yl)e-1-one (1-(4-(methylthio)benzofuran-2-yl)ethan-1-one) Preparation of 60): To the flask was added 1-(4-bromobenzofuran-2-yl)ethan-1-one (0902-60) (1.22 g, 5.10 mmol, 1.0 eq.). 2.26 mL, 25.5 mmol, 5.0 eq.), copper powder (2.76 g, 43.38 mmol, 8.5 eq.) and N,N-dimethylformamide (20 mL), then heated to 140 ° C under N2 overnight.
  • Step 20c (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(4-(methylthio)benzofuran-2-yl)prop-2-ene-1 -(E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(4-(methylthio)benzofuran-2-yl)prop-2-en-1-one)
  • Compound 0904-60 Preparation of 1-(4-(methylthio)benzofuran-2-yl)ethan-1-one (0903-60) (148 mg, 0.718 mmol, 1.0 eq.) and 4-hydroxy-3,5 Concentrated sulfuric acid (2 mL) was slowly added dropwise to a solution of dimethylbenzaldehyde (108 mg, 0.718 mmol, 1.0 eq.) in ethanol (8 ml), and allowed to react at room temperature for 5 hours.
  • Step 20d (E)-2-(2,6-Dimethyl-4-(3-(4-(methylthio)benzofuran-2-yl)-3-oxoprop-1-ene- Tert-butyl(E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)benzofuran-2-)-tert-butyl(E)-2-(2-(4-(methylthio)benzofuran-2-)
  • yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate) (Compound 0905-60): (E)-3-(4-hydroxy-3,5-dimethyl Phenyl)-1-(4-(methylthio)benzofuran-2-yl)prop-2-en-1-one (0904-60) (217 mg, 0.642 mmol, 1.0 eq.) and 2-bromo- tert-Butyl 2-methylpropanoate (0.71 mL, 3.85
  • Step 20e (E)-2-(2,6-Dimethyl-4-(3-(4-(methylthio)benzofuran-2-yl)-3-oxoprop-1-ene- 1-(E)(phenoxy)-2-methylpropanoic acid ((E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)benzofuran-2-yl)-3-oxoprop Preparation of -1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 60): (E)-2-(2,6-Dimethyl-4-(3-(4-) at room temperature (Methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid tert-butyl ester (0905-60) (98 mg, Concentrated sulfuric acid (0.5 mL) was slowly added dropwise to a solution of 0.204 mmol, 1.0 eq.
  • Example 21 (E)-2-(2,6-Dimethyl-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxo Prop-1-en-1-yl)phenoxy)-2-methylpropanoic acid ((E)-2-(2,6-dimethyl-4-(3-(3-methyl-6-(methylthio))) Preparation of benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 62) (prepared according to Scheme 10)
  • Step 21a 1-(2-hydroxy-4-(methylthio)phenyl)ethan-1-one (Compound 1002) -62)
  • a solution of sodium methanethiolate (30 ml) was refluxed at 100 ° C overnight.
  • the reaction mixture was diluted with water (150 ml), pH was adjusted to 5-6 with diluted hydrochloric acid, and extracted with ethyl acetate (80 ml ⁇ 2) Washed with brine (50 ml ⁇ 2), EtOAc (EtOAc) %).
  • Step 21b 1-(3-methyl-6-(methylthio)benzofuran-2-yl)ethan-1-one (1-(3-methyl-6-(methylthio)benzofuran-2-yl) Preparation of ethan-1-one) (Compound 1003-62): Add 1-(2-hydroxy-4-(methylthio)phenyl)ethane-1-one (1002-62) to the reaction flask (890 mg) , 4.88 mmol, 1.0 eq.) and DMF (40 ml), then EtOAc (4.77 g, 14.64 mmol, 3.0 eq.) and bromoacetone (803 mg, 5.86 mmol, 1.2 eq.). The reaction was carried out at 80 ° C overnight.
  • Step 21c (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(3-methyl-6-(methylthio)benzofuran-2-yl)-propene- 2-Ethene-1-one ((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(3-methyl-6-(methylthio)benzofuran-2-yl)prop-2-en- Preparation of 1-one) (Compound 1004-62): To 1-(3-methyl-6-(methylthio)benzofuran-2-yl)ethan-1-one (1003-62) (0.22 g) , 1.0 mmol, 1.0 eq.) and 4-hydroxy-3,5-dimethylbenzaldehyde (0.165 g, 1.1 mmol, 1.1 eq.) in dry ethanol (20 mL) Stir at room temperature for 1 day.
  • Step 21d (E)-2-(2,6-Dimethyl-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxopropane Tert-butyl(E)-2-(2,6-dimethyl-4-(3-(3-methyl-)-1-teren-1-yl)phenoxy)-2-methylpropanoate
  • 6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate) (Compound 1005-62): To ((E)-3-(4 -hydroxy-3,5-dimethylphenyl)-1-(3-methyl-6-(methylthio)benzofuran-2-yl)prop-2-en-1-one (1004-62 (0.334 g, 0.95 m
  • Step 21e (E)-2-(2,6-Dimethyl-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxopropane -1-en-1-yl)phenoxy)-2-methylpropanoic acid ((E)-2-(2,6-dimethyl-4-(3-(3-methyl-6-(methylthio)benzofuran) Preparation of -2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 62): To (E)-2-(2,6-Dimethyl-4 -(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropane Trifluoroacetic acid (2.5 ml) was slowly added to a solution of tert-butyl ester (1005-62) (0.246 g, 0.497 mmol,
  • Example 22 (E)-2-(2,6-Dimethyl-4-(3-(6-(methylthio)benzo[b]thiophen-2-yl)-3-oxo-1 -en-1-yl)phenoxy)-2-methylpropanoic acid ((E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)benzo[b]thiophen-2) -yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 81) Preparation (according to Scheme 7)
  • Step 22a 1-(6-(methylthio)benzo[b]thiophen-2-yl)ethan-1-one (1-(6-(methylthio)benzo[b]thiophen-2-yl)ethan- Preparation of 1-one)
  • Compound 0706-81 To the flask was added 2,4-dimethylthiobenzaldehyde (0701-81) (0.5 g, 2.53 mmol, 1.0 eq.), bromoacetone (0.53 mL, 6.33) M, 2.5 equivalents, cesium hydroxide (0.78 g, 4.55 mmol, 1.8 eq.) and dioxane (10 mL) were then reacted at 92 ° C for 20 hours.
  • Step 22b (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(6-(methylthio)benzo[b]thiophen-2-yl)propan-2- (E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(6-(methylthio)benzo[b]thiophen-2-yl)prop-2-en-1-
  • (Compound 0707-81) To 1-(6-(methylthio)benzo[b]thiophen-2-yl)ethan-1-one (0706-81) (250 mg, 1.126 mmol, 1.0) Ethyl acetate (2 mL) was slowly added dropwise to a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (169 mg, 1.126 mmol, 1.0 eq.) in ethanol (8 mL).
  • Step 22c (E)-2-(2,6-Dimethyl-4-(3-(6-(methylthio)benzo[b]thiophen-2-yl)-3-oxopropan-1 Tert-butyl(E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)benzo) Preparation of [b]thiophen-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate) (Compound 0708-81): (E)-3-(4-hydroxy- 3,5-Dimethylphenyl)-1-(6-(methylthio)benzo[b]thiophen-2-yl)prop-2-en-1-one (0707-81) (291 mg, 0.822 Methyl acetate (10 mL) was dissolved in acetonitrile (10 mL) then potassium carbonate (0.45 g, 3.29 mmol, 4.0 eq.
  • Step 22d (E)-2-(2,6-Dimethyl-4-(3-(6-(methylthio)benzo[b]thiophen-2-yl)-3-oxo-1- Alken-1-yl)phenoxy)-2-methylpropanoic acid ((E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)benzo[b]thiophen-2-) Preparation of yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 81): (E)-2-(2,6-Dimethyl-4-(()) at room temperature 3-(6-(Methylthio)benzo[b]thiophen-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid tert-butyl ester (0708-81) (183 mg, 0.369 mmol, 1.0 eq.) in dioxane (5
  • Step 23a 1-(6-(Methylthio)-1H-indol-2-yl)ethan-1-one (1-(6-(methylthio)-1H-indol-2-yl)ethan-1- Preparation of one)
  • Compound 0706-88 2-Trifluoroacetamido-4-methylthiobenzaldehyde (0701-88) (1.4 g, 5.32 mmol, 1.0 eq.) and bromoacetone (0.89 mL, 10.64 mmol) 2.0 equivalents were dissolved in dimethyl sulfoxide (15 mL) then potassium carbonate (1.47 g, 10.64 mmol, 2.0 eq.).
  • Step 23b (E)-2-(2,6-Dimethyl-4-(3-(6-(methylthio)-1H-indol-2-yl)-3-oxopropan-1- Tert-butyl(E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)-1H) tert-butyl(E)-2-(2-(6-(methylthio)-1H) -indol-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate) (0708-88) Preparation: Add 1-(6-(methylthio) to the reaction flask -1H-indol-2-yl)ethan-1-one (0706-88) (81 mg, 0.394 mmol, 1.0 eq.), 2-(4-formyl-2,2-dimethylphenoxy)- tert-Butyl 2-methylpropanoate (115 mg, 0.394 mmol,
  • Step 23c (E)-2-(2,6-Dimethyl-4-(3-(6-(methylthio)-1H-indol-2-yl)-3-oxopropan-1- Alken-1-yl)phenoxy)-2methylpropionic acid ((E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)-1H-indol-2-yl)) Preparation of -3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 88): (E)-2-(2,6-Dimethyl-4-(3) at room temperature -(6-(Methylthio)-1H-indol-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid tert-butyl ester (0708 -88) (0.139 g, 0.290 mmol, 1.0 eq.) of dioxane solution (5
  • Example 24 (E)-2-(4-(3-(4-(ethylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2, 6-Dimethylphenoxy)-2-methylpropionic acid ((E)-2-(4-(3-(4-(ethylthio)benzofuran-7-yl)-3-oxoprop-1-en- Preparation of 1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 6) (prepared according to Scheme 1)
  • Step 24a 1-(4-(ethylthio)benzofuran-7-yl)ethan-1-one (compound 0105) Preparation of -6): Dissolve sodium hydroxide (101 mg, 2.525 mmol, 2.5 equivalents) in water (1.5 ml), add ethanethiol (126 mg, 2.02 mmol, 2.0 eq.), stir for 10 min, add 1-(4- A solution of fluorobenzofuran-7-yl)ethan-1-one (0104-2) (180 mg, 1.01 mmol, 1.0 eq.) in DMSO (10 mL).
  • Step 24b (E)-1-(4-(ethylthio)benzofuran-7-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-ene-1 -ketone((E)-1-(4-(ethylthio)benzofuran-7-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one) (Compound 0106-6) Preparation: 1-(4-(ethylthio)benzofuran-7-yl)ethan-1-one (0105-6) (119 mg, 0.58 mmol, 1.0 eq.) was dissolved in dioxane (6 ml) 4-Hydroxy-3,5-dimethylbenzaldehyde (105 mg, 0.696 mmol, 1.28 eq.) was added, and concentrated sulfuric acid (1 ml) was added with stirring, and the mixture was allowed to react at room temperature overnight.
  • Step 24c (E)-2-(4-(3-(4-(ethylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6 -tert-butyl(E)-2-(4-(4-(4-(ethylthio)benzofuran-7-yl)-3-oxoprop Preparation of -1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate) (Compound 0107-6): ((E)-1-(4-(ethylthio)benzofuran- 7-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one (0106-6) (0.26 g, 0.397 mmol, 1.0 eq.) was dissolved in acetonitrile ( In 30 ml), potassium carbonate (5 48 mg, 3.97 mmol, 10.0 equivalent), tert-butyl 2-brom
  • Step 24d (E)-2-(4-(3-(4-(ethylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6 -(Emethylphenoxy)-2-methylpropionic acid ((E)-2-(4-(3-(4-(ethylthio)benzofuran-7-yl)-3-oxoprop-1-en-1 -yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 6): (E)-2-(4-(3-(4-(ethylthio))benzofuran-7- Tert-butyl 3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate (0107-6) (78 mg, 0.158 mmol, 1.0 equivalent) was dissolved in DCM (8 mL).
  • Example 25 (E)-2-(4-(3-(4-(isobutylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2 ,6-dimethylphenoxy)-2-methylpropionic acid ((E)-2-(4-(3-(4-(isobutylthio)benzofuran-7-yl)-3-oxoprop-1-en Preparation of -1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 9) (prepared according to Scheme 1)
  • Step 25a 1-(4-(isobutylthio)benzofuran-7-yl)ethan-1-one) Preparation of 0105-9): Sodium hydroxide (99 mg, 2.475 mmol, 2.5 eq.) was dissolved in water (1.5 ml), isobutyl mercaptan (179 mg, 1.98 mmol, 2.0 eq.) was added, stirred for 10 min, and added 1- A solution of 4-fluorobenzofuran-7-yl)ethan-1-one (0104-2) (176 mg, 0.99 mmol, 1.0 eq.) in DMSO (8 ml) was reacted at 60 ° C for one hour.
  • Step 25b (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(4-(isobutylthio)benzofuran-7-yl)prop-2-ene- 1-keto((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(4-(isobutylthio)benzofuran-7-yl)prop-2-en-1-one) (Compound 0106- 9) Preparation: 1-(4-(isobutylthio)benzofuran-7-yl)ethan-1-one (0105-9) (246 mg, 0.99 mmol, 1.0 eq.), dissolved in dioxane To the ring (10 ml), 4-hydroxy-3,5-dimethylbenzaldehyde (193 mg, 1.287 mmol, 1.3 eq.) was added, and concentrated sulfuric acid (1 ml) was added with stirring.
  • Step 25c (E)-2-(4-(3-(4-(isobutylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2, Tert-butyl(E)-2-(4-(3-(4-(isobutylthio)benzofuran-7-yl)-3-) Preparation of oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate) (Compound 0107-9): ((E)-3-(4-hydroxy-3,5-dimethyl Phenyl)-1-(4-(isobutylthio)benzofuran-7-yl)prop-2-en-1-one (0106-9) (255 mg, 0.67 mmol, 1.0 eq.) in acetonitrile (20 ml), potassium carbonate (925 mg, 6.70 mmol, 10.0 equivalent), tert-butyl 2-bromo-2-methylpropionate
  • Step 25d (E)-2-(4-(3-(4-(isobutylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2, 6-Dimethylphenoxy)-2-methylpropionic acid ((E)-2-(4-(3-(4-(isobutylthio)benzofuran-7-yl)-3-oxoprop-1-en- Preparation of 1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 9): (E)-2-(4-(3-(4-(isobutylthio))benzofuran- 7-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid tert-butyl ester (0107-9) (234 mg, 0.448) Methyl acetate (1 ml) was added to EtOAc (1 mL).
  • Example 26 (E)-2-(4-(3-(6-ethylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-di Methylphenoxy)-2-methylpropionic acid ((E)-2-(4-(3-(6-ethoxybenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2 ,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 44) Preparation (according to Scheme 7)
  • Step 26a Preparation of 1-(6-ethoxybenzofuran-2-yl)ethan-1-one (Compound 0706-44): 4-Ethoxy-2-hydroxybenzaldehyde (0701-44) (428 mg, 2.58 mol, 1.0 eq.) was dissolved in DMF (20 mL), bromoacetone (389 mg, 2.38 mmol, 3.0 eq.) at 85 ° C The reaction was carried out for 5 hours. After completion, it was diluted with ethyl acetate (50 ml), washed with EtOAc (EtOAc m. 1) A yellow solid product 1-(6-ethylbenzofuran-2-yl)ethan-1-one (317 mg, yield: 60%) was obtained.
  • Step 26b (E)-1-(6-ethoxybenzofuran-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one
  • ((E)-1-(6-ethoxybenzofuran-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one) (Compound 0707-44): 1-(6-Ethylbenzofuran-2-yl)ethan-1-one (0706-44) (317 mg, 1.55 mol, 1.0 eq.) was dissolved in dioxane (10 ml).
  • Step 26c (E)-2-(4-(3-(6-ethoxybenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-di Tert-butyl(E)-2-(4-(3-(6-ethoxybenzofuran-2-yl)-3-oxoprop-1-en--methylphenoxy)-2-methylpropanoate
  • E)-1-(6-ethoxybenzofuran-2-yl)-3-( 4-Hydroxy-3,5-dimethylphenyl)prop-2-en-1-one (0707-44) (0.473 g, 1.41 mmol, 1.0 eq.) was dissolved in acetonitrile (30 mL).
  • Step 26d (E)-2-(4-(3-(6-ethylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethyl (E)-2-(4-(3-(6-ethoxybenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2, Preparation of 6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 44): (E)-2-(4-(3-(6-ethoxybenzofuran-2-yl)-3-oxopropan tert-Butyl 1-buten-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate (0708-44) (200 mg, 0.418 mmol, 1.0 eq.) (10 ml), trifluoroacetic acid (1 ml) was added under stirring, and the mixture was reacted at room temperature for 15 hours.
  • Example 27 (E)-2-(4-(3-(3-ethyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1- (2)6-dimethylphenoxy)-2-methylpropanoic acid ((E)-2-(4-(3-(3-ethyl-6-(methylthio)benzofuran-2-yl)) Preparation of -3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 63) (prepared according to Scheme 10)
  • Step 27a 1-(3-ethyl-6-(methylthio)benzofuran-2-yl)ethan-1-one (1-(3-ethyl-6-(methylthio)benzofuran-2-yl) Preparation of ethan-1-one) (Compound 1003-63): 1-(2-Hydroxy-4-(methylthio)phenyl)propan-1-one (1002-63) (0.77 g, 3.92 mol, 1.0 eq.) was dissolved in DMF (10 ml), bromoacetone (0.81 g, 5.88 mmol, 1.5 eq.) and cesium carbonate (2.77 g, 7.84 mmol, 2.0 eq.) were reacted at 80 ° C for 3 hours.
  • Step 27b (E)-1-(3-ethyl-6-(methylthio)benzofuran-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)propene- 2-Ethene-1-one ((E)-1-(3-ethyl-6-(methylthio)benzofuran-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en- Preparation of 1-one) (Compound 1004-63): 1-(3-Ethyl-6-(methylthio)benzofuran-2-yl)ethan-1-one (1003-63) (0.7 g , 2.98 mol, 1.0 eq.) was dissolved in absolute ethanol (10 ml), then 4-hydroxy-3,5-dimethylbenzaldehyde (0.447 g, 2.98 mmol, 1.0 eq.) was added, and concentrated sulfuric acid was added with stirring at room temperature ( 2 ml) reaction for 15 hours.
  • Step 27c (E)-2-(4-(3-(3-ethyl-6-(methylthio)benzofuran-2-yl)-3-oxo-1-en-1-yl) -2,6-Dimethylphenoxy)-2-methylpropanoic acid tert-butyl ester (tert-butyl(E)-2-(4-(3-(3-ethyl-6-(methylthio)benzofuran-) Preparation of 2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate) (Compound 1005-63): (E)-1-(3-ethyl -6-(Methylthio)benzofuran-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one (1004-63) (0.27 g, 0.74 mmol, 1.0 eq.) was dissolved in 20 ml of ace
  • Step 27d (E)-2-(4-(3-(3-ethyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl) -2,6-Dimethylphenoxy)-2-methylpropanoic acid ((E)-2-(4-(3-(3-ethyl-6-(methylthio)benzofuran-2-yl)- Preparation of 3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 63): (E)-2-(4-(3-(3-ethyl) -6-(Methylthio)benzofuran-2-yl)-3-oxo-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid Butyl ester (1005-63) (0.184 g, 0.36 mmol, 1.0 eq.) was dissolved in dichlorome
  • Example 28 (E)-2-(4-(3-(3-isopropyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-ene-1 -yl)-2,6-dimethylphenoxy)-2-methylpropionic acid ((E)-2-(4-(3-(3-isopropyl-6-(methylthio)benzofuran-2-yl Preparation of -3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 64) (prepared according to Scheme 10)
  • Step 28a 1-(3-isopropyl-6-(methylthio)benzofuran-2-yl)ethan-1-one (1-(3-isopropyl-6-(methylthio)benzofuran-2-yl) Preparation of ethan-1-one) (Compound 1003-64): 1-(2-Hydroxy-4-(methylthio)phenyl)-2-methylpropan-1-one (1002-64) ( 0.71 g, 3.38 mol, 1.0 eq.) was dissolved in DMF (10 ml), then bromoacetone (0.69 g, 5.07 mmol, 1.5 eq.), cesium carbonate (2.39 g, 6.76 mmol, 2.0 eq.). hour.
  • Step 28b (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(3-isopropyl-6-(methylthio)benzofuran-2-yl)propane -(E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(3-isopropyl-6-(methylthio)benzofuran-2-yl)prop-2-en
  • -1-one Compound 1004-64
  • 1-(3-Isopropyl-6-(methylthio)benzofuran-2-yl)ethan-1-one (1003-64) 0.71 g, 2.86 mol, 1.0 eq.
  • 4-hydroxy-3,5-dimethylbenzaldehyde 0.72 g, 3.146 mmol, 1.1 eq.
  • Step 28c (E)-2-(4-(3-(3-isopropyl-6-(methylthio)benzofuran-2-yl)-3-oxo-1-en-1-yl) Tert-butyl(E)-2-(4-(3-(3-isopropyl-6-(methylthio)benzofuran) tert-butyl(E)-2-(4-(3-(3-isopropyl-6-(methylthio)benzofuran) Preparation of -2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate) (Compound 1005-64): (E)-3-(4-hydroxyl -3,5-dimethylphenyl)-1-(3-isopropyl-6-(methylthio)benzofuran-2-yl)prop-2-en-1-one (1004-64) (0.3 g, 0.79 mmol, 1.0 eq.) was
  • Step 28d (E)-2-(4-(3-(3-isopropyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1- (2) 6-dimethylphenoxy)-2-methylpropionic acid ((E)-2-(4-(3-(3-isopropyl-6-(methylthio)benzofuran-2-yl)) Preparation of -3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 64): (E)-2-(4-(3-(3-) Propyl-6-(methylthio)benzofuran-2-yl)-3-oxo-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropane
  • the acid tert-butyl ester (1005-64) (44 mg, 0.08 mmol, 1.0 eq.) was dissolved in 10 ml of dichlorome
  • Example 29 (E)-2-(2,6-Dimethyl-4-(3-(6-(methylthio)-3-(trifluoromethyl)benzofuran-2-yl)- 3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid ((E)-2-(2,6-dimethyl-4-(3-(6-(methylthio))) Preparation of -3-(trifluoromethyl)benzofuran-2-yl)-3 -oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 73) (prepared according to Scheme 10)
  • Step 29a 1-(6-(methylthio)-3-(trifluoromethyl)benzofuran-2-yl)ethan-1-one (1-(6-(methylthio)-3-(trifluoromethyl)) Preparation of benzofuran-2-yl)ethan-1-one) (1003-73). Add 2,2,2-trifluoro-1-(2-hydroxy-4-(methylthio)phenyl)ethan-1-one (1002-73) (0.94 g, 4.0 mmol, 1.0) to a round bottom flask.
  • Step 29b (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(6-(methylthio)-3-(trifluoromethyl)benzofuran-2- (E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(6-(methylthio)-3-(trifluoromethyl)benzofuran-2-yl)
  • E -3-(4-hydroxy-3,5-dimethylphenyl)-1-(6-(methylthio)-3-(trifluoromethyl)benzofuran-2-yl)
  • Step 29c (E)-2-(2,6-Dimethyl-4-(3-(6-(methylthio)-3-(trifluoromethyl)benzofuran-2-yl)-3 -Oxoprop-1-en-1-yl) phenoxy)-2-methylpropionic acid tert-butyl ester (tert-butyl(E)-2-(2,6-dimethyl-4-(3) Preparation of (6-(methylthio)-3-(trifluoromethyl)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate) (1005-73).
  • Step 29d (E)-2-(2,6-Dimethyl-4-(3-(6-(methylthio)-3-(trifluoromethyl)benzofuran-2-yl)-3 -Oxopropen-1-en-1-yl)phenoxy)-2-methylpropanoic acid ((E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)-) Preparation of 3-(trifluoromethyl)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 73).
  • Step 30a 1-(4-(ethylthio)-2-hydroxyphenyl)ethan-1-one (1-(4-(ethylthio)-2-hydroxyphenyl)ethan-1-one) (1102-74) Preparation: To a solution of sodium hydroxide (135 mg, 3.38 mmol, 1.3 eq.) in water (1 ml), EtOAc (0.24 mL, 3.38 mmol, 1.3 eq.). The mixture was stirred at room temperature for 30 minutes. A solution of 4-fluoro-2-hydroxyacetophenone (0.4 g, 2.60 mmol, 1.0 eq.) in dimethyl sulfoxide (5 ml) was added, and then heated to 120 ° C for 7 hr.
  • Step 30b 1-(6-(ethylthio)-3-methylbenzofuran-2-yl)ethan-1-one (1-(6-(ethylthio)-3-methylbenzofuran-2-yl)ethan Preparation of -1-one)(1103-74)): 1-(4-(ethylthio)-2-hydroxyphenyl)ethan-1-one (1102-74) (0.228 g, 1.163 mmol, 1.0) Ethyl acetate and bromoacetone (0.098 mL, 1.163 mmol, 1.0 eq.) were dissolved in N,N-dimethylformamide (5 mL), then EtOAc (EtOAc (EtOAc) The reaction system was replaced with nitrogen three times with air, and then reacted at 80 ° C for 3 hours.
  • EtOAc EtOAc
  • Step 30c (E)-1-(6-(ethylthio)-3-methylbenzofuran-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)propane 2-(E)-1-(6-(ethylthio)-3-methylbenzofuran-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en- 1-one) (1104-74)
  • 1-(6-(ethylthio)-3-methylbenzofuran-2-yl)ethan-1-one (1103-74) (171 mg, 0.731 Methyl acetate (2 mL) was slowly added dropwise to a solution of methyl 4-hydroxy-3,5-dimethylbenzaldehyde (110 mg, 0.731 mmol, 1.0 eq.) in ethanol (2 mL).
  • Step 30d (E)-2-(4-(3-(6-(ethylthio)-3-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl) Tert-butyl(E)-2-(4-(3-(6-(ethylthio)-3-methylbenzofuran-)-2,6-dimethylphenoxy)-2-methylpropanoate
  • 2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate) (1105-74): (E)-1-(6-(ethyl) Thio)-3-methylbenzofuran-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one (1104-74) (268 mg , 0.731 mmol, 1.0 eq.) and 2-bromo-2-methylpropanoic acid tert-butyl ester (0.8 mL,
  • Step 30e (E)-2-(4-(3-(6-(ethylthio)-3-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl) -2,6-Dimethylphenoxy)-2-methylpropionic acid ((E)-2-(4-(3-(6-(ethylthio)-3-methylbenzofuran-2-yl)-3) Preparation of -oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 74): (E)-2-(4-(3-(6-( Ethylthio)-3-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropane Concentrated sulfuric acid (1 mL) was slowly added dropwise to a solution of tert-butyl ester (1105-74) (107 mg, 0.211
  • Step 31a 1-(2-hydroxy-4-(propylthio)phenyl)ethan-1-one (1102-75) Preparation of a solution of sodium hydroxide (156 mg, 3.9 mmol, 1.5 eq.) in water (1 ml). The mixture was stirred at room temperature for 30 minutes. A solution of 4-fluoro-2-hydroxyacetophenone (0.4 g, 2.60 mmol, 1.0 eq.) in dimethyl sulfoxide (5 ml) was added, and then heated to 120 ° C for 5 hours. The reaction solution was cooled to room temperature, diluted with water (30 mL), The extract was washed with brine (30 mL ⁇ 1) and dried over anhydrous sodium sulfate.
  • Step 31b 1-(3-methyl-6-(propylthio)benzofuran-2-yl)ethan-1-one (1-(3-methyl-6-(propylthio)benzofuran-2-yl) Preparation of ethan-1-one) (1103-75): 1-(2-Hydroxy-4-(propylthio)phenyl)ethan-1-one (1102-75) (0.283 g, 1.35 mmol, 1.0) Ethyl acetate and bromoacetone (0.113 mL, 1.35 mmol, 1.0 eq.) were dissolved in N,N-dimethylformamide (5 mL), then EtOAc (0.528 g, 1.6.
  • the reaction system was replaced with nitrogen three times with air, and then reacted at 80 ° C for 3 hours.
  • the reaction solution was diluted with water (30 mL), and then evaporated.
  • the extract was washed with brine (20 mL ⁇ 1) and dried over anhydrous sodium sulfate.
  • the crude product was purified by silica gel column chromatography (EtOAc:EtOAc:EtOAc Ethyl ketone (194 mg, yield: 58%).
  • Step 31c (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(3-methyl-6-(propylthio)benzofuran-2-yl)-propene- 2-Ethene-1-one ((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(3-methyl-6-(propylthio)benzofuran-2-yl)prop-2-en- Preparation of 1-one) (1104-75): 1-(3-methyl-6-(propylthio)benzofuran-2-yl)ethan-1-one (194 mg, 0.782 mmol, 1.0 eq) Concentrated sulfuric acid (2 mL) was slowly added dropwise to a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (117 mg, 0.782 mmol, 1.0 eq.) in ethanol (8 mL).
  • Step 31d (E)-2-(2,6-Dimethyl-4-(3-(3-methyl-6-(propylthio))benzofuran-2-yl)-3-oxopropan Tert-butyl(E)-2-(2,6-dimethyl-4-(3-(3-methyl-)-1-teren-1-yl)phenoxy)-2-methylpropanoate
  • 6-(propylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate) (1105-75): (E)-3-(4-hydroxyl) -3,5-dimethylphenyl)-1-(3-methyl-6-(propylthio)benzofuran-2-yl)prop-2-en-1-one (1104-75) ( 297 mg, 0.782 mmol, 1.0 eq.) and 2-bromo-2-methylpropanoic acid tert-butyl ester (0.86 m
  • Step 31e (E)-2-(2,6-Dimethyl-4-(3-(3-methyl-6-(propylthio))benzofuran-2-yl)-3-oxopropan -1-en-1-yl)phenoxy)-2-methylpropionic acid ((E)-2-(2,6-dimethyl-4-(3-(3-methyl-6-(propylthio)benzofuran) Preparation of -2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 75): (E)-2-(2,6-dimethyl at room temperature 4-(3-(3-methyl-6-(propylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methyl Concentrated sulfuric acid (1 mL) was slowly added dropwise to a solution of tert-butyl propionate (1105-75) (158 mg, 0.303 mmol, 1.0
  • Example 32 (E)-2-(4-(3-(6-(isobutylthio)-3-methylbenzofuran-2-yl)-3-oxoprop-1-ene-1 -yl)-2,6-dimethylphenoxy)-2-methylpropionic acid ((E)-2-(4-(3-(6-(isobutylthio)-3-methylbenzofuran-2-yl)) Preparation of -3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 76) (prepared according to Scheme 11)
  • Step 32a 1-(2-hydroxy-4-(isobutylthio)phenyl)ethan-1-one) (1102- Preparation of 76) To a solution of sodium hydroxide (195 mg, 4.87 mmol, 1.5 eq.) in water (1.5 ml) was added isobutylthiol (0.525 mL, 4.87 mmol, 1.5 eq.). The mixture was stirred at room temperature for 30 minutes. A solution of 4-fluoro-2-hydroxyacetophenone (0.5 g, 3.25 mmol, 1.0 eq.) in dimethyl sulfoxide (5 ml) was added, followed by heating to 120 ° C for 6 hours.
  • Step 32b 1-(6-(isobutylthio)-3-methylbenzofuran-2-yl)ethan-1-one (1-(6-(isobutylthio)-3-methylbenzofuran-2-yl)
  • ethan-1-one (1103-76): 1-(2-Hydroxy-4-(isobutylthio)phenyl)ethan-1-one (1102-76) (0.263 g, 1.174 mmol, 1.0 eq.) and bromoacetone (0.099 mL, 1.174 mmol, 1.0 eq.) were dissolved in N,N-dimethylformamide (5 mL) and then EtOAc (0.45 g, The reaction system was replaced with nitrogen three times with air, and then reacted at 80 ° C for 5 hours.
  • Step 32c (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(6-(isobutylthio)-3-methylbenzofuran-2-yl)propane 2-(E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(6-(isobutylthio)-3-methylbenzofuran-2-yl)prop-2-en-
  • 1-one) (1104-76): 1-(6-(isobutylthio)-3-methylbenzofuran-2-yl)ethan-1-one (1103-76) (140 mg, 0.534 mmol, 1.0 eq.) and 4-hydroxy-3,5-dimethylbenzaldehyde (80 mg, 0.534 mmol, 1.0 eq.) in ethanol (8 ml) were slowly added dropwise concentrated sulfuric acid (2 mL), and reacted for 5 hours at room temperature.
  • Step 32d (E)-2-(4-(3-(6-(isobutylthio)-3-methylbenzofuran-2-yl)-3-oxopropan-1-ene-1- Tert-butyl(E)-2-(4-(3-(6-(isobutylthio)-3-methylbenzofuran) tert-butyl(E)-2-methylbenzofuran Preparation of -2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate) (1105-76): (E)-3-(4-hydroxy- 3,5-Dimethylphenyl)-1-(6-(isobutylthio)-3-methylbenzofuran-2-yl)prop-2-en-1-one (1104-76) ( 210 mg, 0.534 mmol, 1.0 eq.) and 2-bromo-2-methylpropanoic acid tert-butyl ester (0.59
  • Step 32e (E)-2-(4-(3-(6-(isobutylthio)-3-methylbenzofuran-2-yl)-3-oxopropan-1-ene-1- -2,6-Dimethylphenoxy)-2-methylpropanoic acid ((E)-2-(4-(3-(6-(isobutylthio)-3-methylbenzofuran-2-yl)- Preparation of 3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 76): (E)-2-(4-(3-(6-) (isobutylthio)-3-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methyl Trifluoroacetic acid (0.7 mL) was slowly added dropwise to a solution of tert-butyl-propionate (1105-76) (110 mg
  • Example 33 (E)-2-(4-(3-(6-(Isopropylthio)-3-methylbenzofuran-2-yl)-3-oxoprop-1-ene- 1-yl)-2,6-dimethylphenoxy)-2-methylpropionic acid ((E)-2-(4-(3-(6-(isopropylthio)-3-methylbenzofuran-2-yl) Preparation of -3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 77) (prepared according to Scheme 11)
  • Step 33a 1-(2-hydroxy-4-(isopropylthio)phenyl)ethan-1-one (1102) Preparation of -77) To a solution of sodium hydroxide (156 mg, 3.9 mmol, 1.5 eq.) in water (1 ml), isopropylthiol (0.36 mL, 3.9 mmol, 1.5 eq.). The mixture was stirred at room temperature for 30 minutes. A solution of 4-fluoro-2-hydroxyacetophenone (0.4 g, 2.60 mmol, 1.0 eq.) in dimethyl sulfoxide (5 ml) was added, and then heated to 120 ° C for 5 hours.
  • Step 33b 1-(3-methyl-6-(isopropylthio)benzofuran-2-yl)ethan-1-one (1-(6-(isopropylthio)-3-methylbenzofuran-2-yl)
  • ethan-1-one (1103-77): 1-(2-Hydroxy-4-(isopropylthio)phenyl)ethan-1-one (95 mg, 0.452 mmol, 1.0 eq.) and bromo Acetone (62 mg, 0.452 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (5 mL), then EtOAc (0.177 g, 0.542 The reaction system was replaced with nitrogen three times with air, and then reacted at 80 ° C for 5 hours.
  • Step 33c (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(3-methyl-6-(isopropylthio)benzofuran-2-yl)propan 2-(E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(6-(isopropylthio)-3-methylbenzofuran-2-yl)prop-2-en-
  • 1-one) (1104-77) 1-(3-methyl-6-(isopropylthio)benzofuran-2-yl)ethan-1-one (1103-77) (80 mg, 0.323 mmol, 1.0 eq.) and 4-hydroxy-3,5-dimethylbenzaldehyde (48.4 mg, 0.323 mmol, 1.0 eq.) in ethanol (8 ml) were slowly added dropwise concentrated sulfuric acid (2 mL) and reacted at room temperature 4 hour.
  • Step 33d (E)-2-(2,6-Dimethyl-4-(3-(3-methyl-6-(isopropylthio)benzofuran-2-yl)-3-oxo Tert-butyl(E)-2-(4-(3-(6-(isopropylthio)-3-methylbenzofuran) tert-butyl(E)-2-(4-(3-(6-(isopropylthio)-3-methylbenzofuran) Preparation of -2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate) (1105-77): (E)-3-(4-hydroxy- 3,5-Dimethylphenyl)-1-(3-methyl-6-(isopropylthio)benzofuran-2-yl)prop-2-en-1-one (1104-77) ( 122.7 mg, 0.323 mmol, 1.0 eq.) and 2-bromo-2-
  • Step 33e (E)-2-(4-(3-(6-(Isopropylthio)-3-methylbenzofuran-2-yl)-3-oxoprop-1-ene-1 -yl)-2,6-dimethylphenoxy)-2-methylpropionic acid ((E)-2-(4-(3-(6-(isopropylthio)-3-methylbenzofuran-2-yl)) Preparation of -3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 77): (E)-2-(2,6-dimethyl at room temperature 4-(3-(3-methyl-6-(isopropylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2- Concentrated sulfuric acid (1 mL) was slowly added dropwise to a solution of tert-butyl methacrylate (1105-77) (75 mg
  • Example 34 (E)-2-(2,6-Dimethyl-4-(3-(3-methyl-6-(methylthio))benzo[b]thiophen-2-yl)-3 -oxopropen-1-en-1-yl)phenoxy)-2-methylpropionic acid ((E)-2-(2,6-dimethyl-4-(3-(3-methyl-6-) Preparation of (methylthio)benzo[b]thiophen-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 82) (prepared according to Scheme 12)
  • Step 34a Preparation of 2,4-dimethylthio(acetophenone) (1202-82): to 2,4-difluorobenzene
  • ethyl ketone 0.6 g, 3.84 mmol, 1.0 eq.
  • sodium methanethiolate 20% aqueous solution, 3.37 g, 9.61 mmol, 2.5 eq.
  • the mixture was stirred at room temperature for 2 hours.
  • the reaction solution was diluted with water (30 mL), and then evaporated.
  • the extract was washed with brine (20 mL ⁇ 1) and dried over anhydrous sodium sulfate.
  • Step 34b 1-(3-methyl-6-(methylthio)benzo[b]thiophen-2-yl)ethan-1-one (1-(3-methyl-6-(methylthio)benzo[b] Preparation of thiophen-2-yl)ethan-1-one) (1203-82): 2,4-Dimethylthioacetophenone (1202-82) (0.73 g, 3.44 mmol, 1.0 eq.) and bromine Acetone (0.72 mL, 8.61 mmol, 2.5 eq.) was dissolved in dioxane (10 mL) then EtOAc (1. The air in the reaction system was replaced with nitrogen three times, and then reacted at 105 ° C for 24 hours.
  • Step 34c (E)-3-(4-Hydroxy-3,5-dimethylphenyl)-1-(3-methyl-6-(methylthio)benzo[b]thiophen-2-yl )(E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(3-methyl-6-(methylthio)benzo[b]thiophen-2-yl
  • prop-2-en-1-one) (1204-82) to 1-(3-methyl-6-(methylthio)benzo[b]thiophen-2-yl)ethyl-1-
  • ketone (1203-82) (128 mg, 0.542 mmol, 1.0 eq.
  • 4-hydroxy-3,5-dimethylbenzaldehyde (81 mg, 0.542 mmol, 1.0 eq.) in ethanol (8 ml) (2 mL), react at room temperature for 4 hours.
  • Step 34d (E)-2-(2,6-Dimethyl-4-(3-(3-methyl-6-(methylthio))benzo[b]thiophen-2-yl)-3- O-propan-1-ene-1-carboxylic acid tert-butyl ester piperidin-1-yl)phenoxy)-2-methylpropionic acid tert-butyl ester (tert-butyl(E)-2-(2,6 -dimethyl-4-(3-(3-methyl-6-(methylthio)benzo[b]thiophen-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(1205 -82)
  • Step 34e (E)-2-(2,6-Dimethyl-4-(3-(3-methyl-6-(methylthio))benzo[b]thiophen-2-yl)-3- Oxoprop-1-en-1-yl)phenoxy)-2-methylpropionic acid ((E)-2-(2,6-dimethyl-4-(3-(3-methyl-6-( Preparation of methylthio)benzo[b]thiophen-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 82): (E)-2-( at room temperature) 2,6-Dimethyl-4-(3-(3-methyl-6-(methylthio)benzo[b]thiophen-2-yl)-3-oxoprop-1-ene-1- tert-Butyl carboxylic acid tert-butyl ester piperidin-1-yl)phenoxy)-2-methylpropanoate (1205-82) (52 mg, 0.102
  • Step 35a Preparation of 2,4-diethylthioacetophenone (1202-94): To sodium hydroxide (448 mg, 11.21) Ethyl mercaptan (0.81 mL, 11.21 mmol, 2.5 eq.) was added to a solution of EtOAc (4 mL). The mixture was stirred at room temperature for 30 minutes. A solution of 2,4-difluoroacetophenone (0.7 g, 4.48 mmol, 1.0 eq.) in dimethyl sulfoxide (10 ml) was added and then allowed to react at room temperature overnight. The reaction solution was diluted with water (40 mL), and then evaporated. The extract was washed with brine (30 mL ⁇ 1) and dried over anhydrous sodium sulfate. LCMS (ESI): m / z 241 [M + 1] +.
  • Step 35b 1-(6-(ethylthio)-3-methylbenzo[b]thiophen-2-yl)ethan-1-one (1-(6-(ethylthio)-3-methylbenzo[b]]
  • Step 35c (E)-1-(6-(ethylthio)-3-methylbenzo[b]thiophen-2-yl)-3-(4-hydroxy-3,5-dimethylbenzene
  • ketone (1203-94) 233 mg, 0.932 mmol, 1.0 eq.
  • 4-hydroxy-3,5-dimethylbenzaldehyde 140 mg, 0.932 mmol, 1.0 eq.
  • Step 35d (E)-2-(4-(3-(6-(ethylthio)-3-methylbenzo[b]thiophen-2-yl)-3-oxoprop-1-ene- Tert-butyl(E)-2-(4-(3-(6-(ethylthio)-3-methylbenzo[]]-tert-butyl(E)-2-methylbenzo[2-(3-(6-(ethylthio)-3-methylbenzo[ Preparation of b]thiophen-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate) (1205-94): (E)-1-(6) -(ethylthio)-3-methylbenzo[b]thiophen-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one (1204-94) (356 mg, 0.932 mmol, 1.0 e
  • Step 35e (E)-2-(4-(3-(6-(ethylthio)-3-methylbenzo[b]thiophen-2-yl)-3-oxoprop-1-ene- 1-(yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid ((E)-2-(4-(3-(6-(ethylthio)-3-methylbenzo[b]thiophen) Preparation of -2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid) (Compound 94): (E)-2-(4-(4- at room temperature (3-(6-(ethylthio)-3-methylbenzo[b]thiophen-2-yl)-3-oxoprop-1-en-1-yl)6-dimethylphenoxy Trifluoroacetic acid (1 mL) was slowly added dropwise to a solution of tert-butyl 2-
  • Example 36 (E)-2-(2,6-Dimethoxy-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxopropan-1- Alken-1-yl)phenoxy)-2-methylpropanoic acid ((E)-2-(2,6-dimethoxy-4-(3-(6-(methylthio)benzofuran-2-yl)-3) Preparation of -oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 99) (prepared according to Scheme 7)
  • Step 36a (E)-3-(4-Hydroxy-3,5-dimethoxyphenyl)-1-(6-(methylthio)benzofuran-2-yl)prop-2-ene- 1-keto((E)-3-(4-hydroxy-3,5-dimethoxyphenyl)-1-(6-(methylthio)benzofuran-2-yl)prop-2-en-1-one)(0707-99 Preparation of). To a round bottom flask was added 1-(6-(methylthio)benzofuran-2-yl)ethan-1-one (0706-51) (0.206 g, 1.0 mmol, 1.0 eq.).
  • Step 36b (E)-2-(2,6-Dimethoxy-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-ene Tert-butyl(E)-2-(2,6-dimethoxy-4-(3-(6-(methylthio)benzofuran-2-) -1-yl)phenoxy)-2-methylpropanoate Preparation of yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate) (0708-99).
  • Step 36c (E)-2-(2,6-Dimethoxy-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-ene -1-yl)phenoxy)-2-methylpropionic acid ((E)-2-(2,6-dimethoxy-4-(3-(6-(methylthio)benzofuran-2-yl)-3- Preparation of oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 99).
  • Step 37a (E)-3-(3,5-Dichloro-4-hydroxyphenyl)-1-(6-(methylthio)benzofuran-2-yl)prop-2-en-1- Ketone ((E)-3-(3,5-dichloro-4-hydroxyphenyl)-1-(6-(methylthio)benzofuran-2-yl)prop-2-en-1-one) (0707-100) preparation.
  • Step 37b (E)-2-(2,6-Dichloro-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-ene-1 Tert-butyl(E)-2-(2,6-dichloro-4-(3-(6-(methylthio)benzofuran-2-yl)) Preparation of -3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate) (0708-100).
  • Step 37c (E)-2-(2,6-Dichloro-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-ene-1 -(Phenyloxy)-2-methylpropanoic acid ((E)-2-(2,6-dichloro-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop- Preparation of 1-en-1-yl)phenoxy)-2-methylpropanoic acid) (100).
  • Example 38 (E)-2-(2,6-Diisopropyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxopropan-1- Alken-1-yl)phenoxy)-2-methylpropanoic acid ((E)-2-(2,6-diisopropyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3) Preparation of -oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 101) (prepared according to Scheme 7)
  • Step 38a (E)-3-(4-Hydroxy-3,5-diisopropylphenyl)-1-(6-(methylthio)benzofuran-2-yl)prop-2-ene- 1-keto((E)-3-(4-hydroxy-3,5-diisopropylphenyl)-1-(6-(methylthio)benzofuran-2-yl)prop-2-en-1-one)(0707-101 Preparation of). To a round bottom flask was added 1-(6-(methylthio)benzofuran-2-yl)ethan-1-one (0706-51) (0.206 g, 1.0 mmol, 1.0 eq.).
  • Step 38b (E)-2-(2,6-Diisopropyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-ene Tert-butyl(E)-2-(2,6-diisopropyl-4-(3-(6-(methylthio)benzofuran-2-) Preparation of yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate) (0708-101).
  • Step 38c (E)-2-(2,6-Diisopropyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-ene -1-yl)phenoxy)-2-methylpropionic acid ((E)-2-(2,6-diisopropyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3- Preparation of oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 101).
  • Example 39 (E)-2-(2,6-Dimethoxy-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxo Propyl-1-en-1-yl)phenoxy)-2-methylpropionic acid ((E)-2-(2,6-dimethoxy-4-(3-(3-methyl-6-(methylthio)) Preparation of benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 102) (prepared according to Scheme 10)
  • Step 39a (E)-3-(4-Hydroxy-3,5-dimethoxyphenyl)-1-(3-methyl-6-(methylthio)benzofuran-2-yl)propane -(E)-3-(4-hydroxy-3,5-dimethoxyphenyl)-1-(3-methyl-6-(methylthio)benzofuran-2-yl)prop-2-en
  • -1-one 1004-102
  • Step 39b (E)-2-(2,6-Dimethoxy-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxo Tert-butyl(E)-2-(2,6-dimethoxy-4-(3-(3-methyl)]-propen-1-en-1-yl)phenoxy)-2-methylpropanoate
  • -6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate) (1005-102):
  • Step 39c (E)-2-(2,6-Dimethoxy-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxo Prop-1-en-1-yl)phenoxy)-2-methylpropionic acid ((E)-2-(2,6-dimethoxy-4-(3-(3-methyl-6-(methylthio))) Preparation of benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 102): (E)-2-(2,6-dimethyl at room temperature) Oxy-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2 Trifluoroacetic acid (1.5 mL) was slowly added dropwise to a solution of tert-butylmethylpropionate (1005-102) (180 mg, 0.342 mmol, 1.0
  • Example 40 (E)-2-(2,6-Dichloro-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxopropane -1-en-1-yl)phenoxy)-2-methylpropionic acid ((E)-2-(2,6-dichloro-4-(3-(3-methyl-6-(methylthio)benzofuran) Preparation of -2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 103) (prepared according to Scheme 10)
  • Step 40a (E)-3-(3,5-Dichloro-4-hydroxyphenyl)-1-(3-methyl-6-(methylthio)benzofuran-2-yl)propane-2 -(E)-3-(3,5-dichloro-4-hydroxyphenyl)-1-(3-methyl-6-(methylthio)benzofuran-2-yl)prop-2-en-1 -one) (1004-103)
  • Concentrated sulfuric acid (2 mL) was slowly added dropwise to a solution of 3,5-dichloro-4-hydroxy-benzaldehyde (130 mg, 0.682 mmol, 1.0 eq.) in ethanol (8 mL).
  • Step 40b (E)-2-(2,6-Dichloro-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxopropene- Tert-butyl(E)-2-(2,6-dichloro-4-(3-(3-methyl-6) 1-teren-1-yl)phenoxy)-2-methylpropanoate -(methylthio)benzofuran-2-yl)-3-oxopro p-1-en-1-yl)phenoxy)-2-methylpropanoate) (1005-103)
  • Step 40c (E)-2-(2,6-Dichloro-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxopropene- 1-en-1-yl)phenoxy)-2-methylpropanoic acid ((E)-2-(2,6-dichloro-4-(3-(3-methyl-6-(methylthio)benzofuran-) Preparation of 2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 103): (E)-2-(2,6-Dichloro-4) at room temperature -(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropane Trifluoroacetic acid (1.0 mL) was slowly added dropwise to a solution of tert-butyl ester (1005-103) (96 mg, 0.179 m
  • Example 41 (E)-2-(2,6-Diisopropyl-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxo Propyl-1-en-1-yl)phenoxy)-2-methylpropionic acid ((E)-2-(2,6-diisopropyl-4-(3-(3-methyl-6-(methylthio)) Preparation of benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 104) (prepared according to Scheme 10)
  • Step 41a (E)-3-(4-Hydroxy-3,5-diisopropylphenyl)-1-(3-methyl-6-(methylthio)benzofuran-2-yl)propane -(E)-3-(4-hydroxy-3,5-diisopropylphenyl)-1-(3-methyl-6-(methylthio)benzofuran-2-yl)prop-2-en
  • -1-one) 1004-104: 1-(3-methyl-6-(methylthio)benzofuran-2-yl)ethan-1-one (1003-62) (120 mg, 0.545 mmol, 1.0 eq.) and 4-hydroxy-3,5-diisopropylbenzaldehyde (112.4 mg, 0.545 mmol, 1.0 eq.) in ethanol (8 ml) were slowly added dropwise concentrated sulfuric acid (2 mL).
  • Step 41b (E)-2-(2,6-Diisopropyl-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxo Tert-butyl(E)-2-(2,6-diisopropyl-4-(3-(3-methyl))-propen-1-en-1-yl)phenoxy)-2-methylpropanoate
  • Step 41c (E)-2-(2,6-Diisopropyl-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxo Prop-1-en-1-yl)phenoxy)-2-methylpropionic acid ((E)-2-(2,6-diisopropyl-4-(3-(3-methyl-6-(methylthio))) Preparation of benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid) (Compound 104): (E)-2-(2,6-diiso) at room temperature Propyl-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2 Trifluoroacetic acid (0.5 mL) was slowly added dropwise to a solution of tert-butyl methacrylate (1005-104) (50 mg,
  • This example measures the biological activity of a PPAR agonist using the Hela cell/luciferase reporter gene method.
  • the target plasmids PCMV PPAR ⁇ (Ampicillin+), PCMV PPAR ⁇ (Ampicillin+), PCMV PPAR ⁇ (Ampicillin+), and pPPRE3-TK-Luciferase (Ampicillin+) were introduced into DH5 ⁇ competent cells by heat shock treatment, respectively. After incubating at 37 ° C for 1 hour at 180 ° C, the cells were inoculated onto an LB agar solid medium containing the antibiotic Ampicillin, and cultured at 37 ° C for 12 to 16 hours. Then, the monoclonal colonies cultured on the medium were inoculated into LB liquid medium to expand the culture.
  • the resulting bacterial solution was cultured to extract the desired plasmid with a Plasmid Midi Kit (Qiagen; #12143).
  • the plasmid obtained by centrifugation was suspended in TE buffer, and the plasmid concentration was measured and stored at -20 °C.
  • the Hela cells in the growing phase were seeded in 6-well plates (8 ⁇ 10 5 cells/well) and cultured for 6-8 hours. Transfection was performed by 3000 Transfection Reagent (Invitrogen; #L3000015).
  • a plasmid containing a PPAR binding site (PPRE) and a firefly luciferase gene (pPPRE3-TK-Luciferase) was co-transfected into a HeLa cell with a total amount of plasmid DNA of 2.5.
  • the PPAR binds to the ligand and then binds to the peroxisome proliferator response element (PPRE), thereby initiating downstream firefly luciferase expression, the intensity of which is proportional to the degree of PPAR activation.
  • PPRE peroxisome proliferator response element
  • test compound mother liquor 10 mM 1000 ⁇ was diluted with DMSO 4 times serially into 8 concentration gradients, diluted to 50 uM (5 ⁇ ) with 1% FBS medium, and 25 ⁇ l of compound dilution 25 ⁇ l was added to each well according to different concentration gradients. Incubate for 24 h at 37 ° C in a 5% CO 2 incubator. Remove the 96 well plate, each well was added 30 ⁇ l Bright-Glo TM Luciferase Assay Reagent Bright-Glo TM Luciferase Assay System ( Promega; # E2620), the emission intensity was measured by Luciferase SynergyH1 fully functional Microplate Reader. The obtained data were used to calculate the EC50 using GraphPad Prism 5.0 software to determine the biological activity of the compound.
  • EC 50 refers to the concentration of a drug when the compound is assayed for 50% increase in agonistic activity of PPAR.
  • the compound numbers in Table 1 correspond to the compound numbers in Examples 1-41.
  • Table 1 The agonistic activity of compounds on three subtypes of PPAR (EC 50 , nM)
  • Elafibranor has agonistic activity on PPAR ⁇ in addition to agonists of PPAR ⁇ and PPAR ⁇ .
  • the compound of the present invention is similar to Elafibranor and is an agonist of three subtypes of PPAR ⁇ , PPAR ⁇ and PPAR ⁇ nuclear hormone receptors. Different compounds have different EC 50 values for the three subtypes. Compared with Elafibranor, the activation of PPAR ⁇ and PPAR ⁇ by compound 51 increased by 7-fold and 2-fold, respectively, while the difference in PPAR ⁇ was small. Compound 62 activated PPAR ⁇ activity. Increased by a factor of 1, but the activation of PPAR ⁇ is weak.
  • Glitazars-like PPAR ⁇ and PPAR ⁇ dual agonists eg, Aleglitazar, mulaglitazar, and tesaglitazar
  • Several treatments for Glitazars-like PPAR ⁇ and PPAR ⁇ dual agonists have terminated development due to cardiotoxicity or renal toxicity in clinical trials (Robert S et al. Am Heart J 164:672–680, 2012) Conlon D. Br J Diabetes Vasc Dis 6: 135–137, 2006).
  • the cause of the toxicity of PPAR ⁇ and PPAR ⁇ dual agonists is not well understood.
  • Aleglitazar activates PPAR ⁇ activity with a higher EC 50 for activation of PPAR ⁇ and PPAR ⁇ of 38 nM and 19 nM, respectively, and an EC 50 ratio of PPAR ⁇ /PPAR ⁇ of 0.5 (Bénardeau A et al. Bioorg Med Chem Lett. 19: 2468-2473, 2009).
  • Elafibranor has a relatively higher PPAR ⁇ -selective activity than the Glitazars class.
  • the ratio of Elafibranor-activated PPAR ⁇ /PPAR ⁇ is 2.97, and the ratio of the compounds of the present invention 51, 62, 100 and 103 to activate PPAR ⁇ /PPAR ⁇ is significantly higher on the Elafibranor basis. Improvements were 8.83, 7.98, 237.55 and 90.59 respectively. It is suggested that the safety of the compounds of the invention may be higher.
  • test compound Male Sprague-Dawley rats weighing 250-300 g were fasted overnight before the test. The test compound was dissolved in 30% sulfobutyl- ⁇ -cyclodextrin (SBE- ⁇ -CD) and administered orally at a dose of 20 mg/kg. Blood was taken at 15 minutes, 30 minutes, and 1, 2, 3, 4, 6, 8 and 24 hours after administration. About 0.3 ml of blood was taken at each time point and placed in K2-EDTA (dipotassium ethylenediaminetetraacetate). In a centrifuge tube, plasma was taken by centrifugation (2,000 g, 10 minutes, 4 ° C) and stored in an ultra-low temperature freezer at -80 °C.
  • SBE- ⁇ -CD sulfobutyl- ⁇ -cyclodextrin
  • the compounds provided by the present invention were 5, 36, 43, 51, 62, 63, 81, 100 and 103 (numbers are identical to those in Examples 1-41) compared to the control Elafibranor (GFT-505) (see Table 2 for results).
  • Figure 1 after oral administration in rats, the absorption is good, the blood exposure is high, and the half-life is significantly prolonged.
  • the Cmax of compounds 5, 36, 62 and 43 was 1.6-2.5 times that of the reference compound Elafibranor; AUC 0-24h was 1.2-2.5 times that of Elafibranor.
  • the Cmax of compounds 100 and 103 was 4.4-6.8 times that of the reference compound Elafibranor; AUC 0-24h was 10.2-37.3 times that of Elafibranor.
  • Cmax refers to the maximum blood concentration
  • T1/2 is the half-life
  • AUC 0-24 refers to the area under the time-concentration curve of 0-24 hours
  • AUC 0-inf refers to the area under the time-concentration curve of 0-Inf.

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Abstract

提供一种具有式(I)所示结构的1，3-二取代烯酮类化合物及其应用。该类化合物主要激活PPARα，对PPPAδ和PPPAγ亦有激动活性。能够用于治疗PPAR调控异常相关的各种疾病，如非酒精性脂肪肝病特别是治疗非酒精性肝炎，还具有用于治疗糖尿病、肥胖症、纤维化疾病、心血管疾病(包括心力衰竭和动脉粥样硬化等)、肾脏疾病(包括慢性肾病和肾功能衰竭等)、脑退行性疾病(包括阿尔茨海默病等)等的潜力，具有较大的应用价值。

Description

1，3-二取代烯酮类化合物及其应用 技术领域
本发明涉及药物化学领域，特别是涉及一种1，3-二取代烯酮类化合物及其应用。
背景技术
非酒精性脂肪肝病(NAFLD)是指除了酒精及其他明确损伤原因之外的因素所导致的肝脏疾病，表现为过多的脂肪以甘油三酯(>5％的肝细胞组织)的形式堆积在肝脏中。非酒精性脂肪性肝炎(NASH，nonalcoholic steatohepatitis)是一种伴随有炎症及肝细胞损伤的脂肪变性非酒精性脂肪肝病。早期非酒精性脂肪肝炎的典型病理特征是脂肪堆积、炎症及轻微纤维化，发展至晚期可导致晚期肝脏纤维化、肝硬化，肝衰竭及肝脏肿瘤的产生。
在过去的20年里，NAFLD急剧增加，现已成为西方国家中最为常见的肝脏疾病。在美国，NAFLD的发病率约占总人口的27-34％，尤其在肥胖症人群中，NAFLD更高达75-92％。大约10-20％左右的NAFLD患者会发展成为NASH，而37％高危严重肥胖症的NAFLD患者会发展成为NASH。美国约600万人已经进展到NASH，其中60万有NASH相关肝硬化。导致NASH的主要危险因素包括肥胖、2型糖尿病(T2DM)及血脂异常与代谢综合征。目前，NASH相关的肝硬化是美国肝移植的第三大常见原因，预计在2020年将成为主要原因(World Gastroenterology Organisation Global Guidelines:NFLD and NASH.June 2012)。近20年，亚洲国家NAFLD增长迅速且呈低龄化发病趋势，中国上海、广州和香港等发达地区成人NAFLD患病率约为15％(Fan JG et al:J Dig Dis 12:38-44,2011)。
过氧化物酶体增殖剂激活受体(peroxisome proliferators-activated receptors，PPARs)是核激素受体家族中的配体激活受体，调节靶基因的转录，参与脂质调节、脂肪生成和血糖控制。因此，在能量平衡和代谢功能方面起着重要调控作用。
PPARs家族包含三种亚型：α、γ、和δ(或β)。三种亚型都参与脂质代谢的调节。
PPARα主要在肝脏、骨骼肌、肾脏、心脏和血管壁中高度表达,刺激脂肪酸氧化和摄取和调节脂蛋白合成。肝脏PPARα激活，升高高密度脂蛋白(HDL)高载脂蛋白Apo AI和Apo AII，增加甘油三酯水解和增加游离脂肪酸的摄取和氧化。此外，PPARα通过抑制环氧化酶-2、白介素-6和C-反应蛋白具有抗炎作用(Francis G et al,Ann Rev Physiol.65:261–311,2003；Pawlak M et al.J Hepatol 62:720-733,2015)。氯贝特，非诺贝特和环丙贝特等纤维酸衍生物类PPARα激动剂在减低甘油三酯的同时，能够减少低密度脂蛋白(LDL),用于治疗高甘油三酯症。PPARα激动剂可以用于胆汁淤积性肝病、非酒精性脂肪肝和/或2型糖尿病的治疗。
近年来研究还表明，PPARα通过调节许多生理过程，如能量代谢、氧化还原平衡、自噬和细胞周期，炎症反应等。PPARα激动剂可能在心血管疾病(Han L at al.Future Cardiol.2017 Jun 5.doi:10.2217/fca-2016-0059)，肾脏疾病(Adedapo AA et al.Hum Exp Toxicol.32:323-331,2013)和大脑退行性疾病(D Orio B at al.Curr Alzheimer Res.2017doi:10.2174/1567205014666170505094549)有广泛的治疗前景。
PPARγ在哺乳动物的脂肪组织表达，对胰岛素敏感性，参与脂防酸摄取和脂肪储存的基因的转录，PPARγ的活化会导致胰岛素增敏并促进糖代谢(Olefsky J M et al.Trend Endocrin Met 11：362-368,2000)和具有抗纤维化作用(Koo JB et al.BMC Gastroenterol.17:73.2017)。PPARγ功能异常可能与肥胖症、糖尿病、动脉粥样硬化和癌症等许多疾病有关。PPARγ激动剂已用于高脂血症和高血糖的治疗。PPARγ能够减少许多心血管细胞的炎症反应，特别是内皮细胞。PPARγ激活PON1基因，增加肝脏对氧磷酶1合成和释放，减少动脉粥样硬化。许多用于治疗糖尿病的胰岛素增敏药物(如噻唑烷二酮类药物)激活PPARγ作为一种手段来降低血糖，不增加胰腺分泌胰岛素。
PPARδ在体内广泛表达，在脑、胃、结肠内相对高水平表达。PPARδ激活增加脂肪酸代谢和提升ApoA1/HDL水平，抑制炎症。PPARδ激动剂MBX-8025可显著降低人体低密度脂蛋白、甘油三酯和高敏C反应蛋白，增加高密度脂蛋白和减少肝脏损害。(Bays HE el al.J Clin Endocrinol Metab 2889-97,2012)。
PPAR核受体多亚型激动剂可能比单一亚型激动剂对脂质和糖代谢、炎症和纤维化异常相关疾病的治疗更加有效。Elafibranor(GFT-505)是PPARα和PPARδ受体激动剂，可以改善胰岛素敏感性、调节血糖平衡、脂质代谢以及减少炎症反应(Sahebkar A et al.Expert Opin Pharmacother 15:493-503m 2014；Ratziu et al.Gastroenterology 150:1147-1159,2016)。
发明内容
基于此，本发明提供了一种新的1，3-二取代烯酮类化合物，该类化合物具有激活PPAR的活性。
具体技术方案如下：
具有式(I)所示结构的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子：
Figure PCTCN2018093760-appb-000001
其中：
R 1,R 2分别独立选自：H，卤素，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基,C1-C6烷氧基，羟基；
R 3,R 4分别独立选自：H，卤素，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基,C1-C6烷氧基，羟基，并且R 3,R 4不同时为H；或者R 3,R 4相连组成3-8元碳环或3-8元杂环；
R 5选自OR 6，NR 7R 8；
Q是一个单键或者为CR 7R 8；
R 6，R 7和R 8分别独立选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基；
W，W 1和Y分别独立选自：O或S；
环A为8-12元取代或未取代的双环并环，所述双环并环为饱和的双环并环、部分不饱和的双环并环或者芳香的双环并环，并且所述双环并环上的环碳原子被0至5个杂原子取代，所述杂原子是指O、N或S。
在其中一些实施例中，W，W 1均选自：O。
在其中一些实施例中，所述化合物具有式(II)所示结构：
Figure PCTCN2018093760-appb-000002
在其中一些实施例中，环A选自：
Figure PCTCN2018093760-appb-000003
其中：
X 1、X 2、X 3、X 4、X 5、X 6、X 7分别独立选自：CR 9，CR 12或N，并且X 1、X 2、X 3、X 4中至少有一个是CR 12；
R 9选自：H，卤素，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,C1-C4烷基胺基取代的C1-C6烷基，芳基，杂芳基，硝基，氰基，-OR，-N(R) 2，-SR，-C(O)OR，-C(O)N(R) 2，-C(O)R，-S(O)R，-S(O) 2R，-S(O) 2N(R) 2，-N(R)C(O)R；
R 10选自：H，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代C1-C6烷基，羟基取代C1-C6烷基，烷氧基取代C1-C6烷基，氨基取代的C1-C6烷基,C1-C4烷基胺基取代C1-C6烷基；
R 11选自：H，-SR，-OR，-N(R) 2，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基；
R 12选自：H，-SR，-OR，-N(R) 2，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基；
m选自：0,1,2；
每个R独立选自：H，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,C1-C4烷基胺基取代C1-C6烷基。
在其中一些实施例中，环A选自：
Figure PCTCN2018093760-appb-000004
在其中一些实施例中，环A选自：
Figure PCTCN2018093760-appb-000005
在其中一些实施例中，环A选自：
Figure PCTCN2018093760-appb-000006
在其中一些实施例中，环A选自：
Figure PCTCN2018093760-appb-000007
在其中一些实施例中，R 9选自：H，卤素，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,C1-C4烷基胺基取代的C1-C6烷基，硝基，氰基，-OR，-N(R) 2，-SR，-C(O)OR，-C(O)N(R) 2，-C(O)R，-S(O)R，-S(O) 2R，-S(O) 2N(R) 2，-N(R)C(O)R；
每个R独立选自H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基。
在其中一些实施例中，R 9选自：H，卤素，C1-C6烷基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，-OR，-N(R) 2，-SR，-C(O)OR，-C(O)N(R) 2，-C(O)R，-S(O)R，-S(O) 2R，-S(O) 2N(R) 2，-N(R)C(O)R；每个R独立选自H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基。
在其中一些实施例中，R 9选自：H，卤素，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,C1-C4烷基胺基取代的C1-C6烷基，-OR，-N(R) 2，-SR，-C(O)R，-S(O)R；
其中R选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基。
在其中一些实施例中，R 9选自：H，C1-C6烷基，卤素取代的C1-C6烷基。
在其中一些实施例中，R 9选自：H，甲基，乙基，异丙基，三氟甲基。
在其中一些实施例中，R 10选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,C1-C4烷基胺基取代的C1-C6烷基；每个R独立选自H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基。
在其中一些实施例中，R 10选自：H，C1-C6烷基，卤素取代C1-C6烷基；每个R独立选自H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基。
在其中一些实施例中，R 10选自：H。
在其中一些实施例中，R 11选自：H，-SR，-OR，-N(R) 2，C1-C6烷基；其中，R选自：H，C1-C6烷基。
在其中一些实施例中，R 11选自：H。
在其中一些实施例中，R 12选自：H，-SR，-OR，-N(R) 2，C1-C6烷基；其中，R选自：H，C1-C6烷基。
在其中一些实施例中，R 12选自：-SR，-OR；其中，R选自：C1-C6烷基。
在其中一些实施例中，R 1,R 2分别独立选自：H，C1-C6烷基，C1-C6烷氧基，卤素。
在其中一些实施例中，R 1,R 2分别独立选自：C1-C3烷基，卤素，C1-C3烷氧基。
在其中一些实施例中，R 1,R 2均为甲基，或者R 1,R 2均为氯。
在其中一些实施例中，R 3,R 4分别独立选自：H，C1-C6烷基，C1-C6烷氧基，卤素，或者R 3,R 4相连组成3-8元碳环。
在其中一些实施例中，R 3,R 4分别独立选自：C1-C6烷基。
在其中一些实施例中，R 5选自：OR 6；R 6选自：H，C1-C6烷基。
在其中一些实施例中，R 5选自：OR 6；R 6选自：H。
在其中一些实施例中，Y选自：O。
在其中一些实施例中，R 1,R 2分别独立选自：H，C1-C6烷基，C1-C6烷氧基，卤素；
R 3,R 4分别独立选自：H，C1-C6烷基，C1-C6烷氧基，卤素，或者R 3,R 4相连组成3-8元碳环；
R 5选自OR 6；R 6选自H，C1-C6烷基；
Y选自O或S；
环A选自：
Figure PCTCN2018093760-appb-000008
X 1、X 2、X 3、X 4、X 5、X 6、X 7分别独立选自CR 9，CR 12或N，并且X 1、X 2、X 3、X 4中至少有一个是CR 12；
R 9选自：H，卤素，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代C1-C6烷基，羟基取代C1-C6烷基，烷氧基取代C1-C6烷基，氨基取代的C1-C6烷基,C1-C4烷基胺基取代的C1-C6烷基，硝基，氰基，-OR，-N(R) 2，-SR，-C(O)OR，-C(O)N(R) 2，-C(O)R，-S(O)R，-S(O) 2R，-S(O) 2N(R) 2，-N(R)C(O)R；
R 10选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,C1-C4烷基胺基取代的C1-C6烷基；
R 11选自：H，-SR，-OR，-N(R) 2，C1-C6烷基；
R 12选自：H，-SR，-OR，-N(R) 2，C1-C6烷基；
n选自：0,1,2；
每个R独立选自H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基。
在其中一些实施例中，R 1,R 2分别独立选自：C1-C3烷基，卤素，C1-C3烷氧基；
R 3,R 4分别独立选自：C1-C6烷基；
R 5选自：OR 6；R 6选自：H；
Y选自：O；
环A选自：
Figure PCTCN2018093760-appb-000009
R 9选自：H，卤素，C1-C6烷基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，-OR，-N(R) 2，-SR，-C(O)OR，-C(O)N(R) 2，-C(O)R，-S(O)R，-S(O) 2R，-S(O) 2N(R) 2，-N(R)C(O)R；
R 12选自：H，-SR，-OR，C1-C6烷基；
n选自：0,1；
每个R独立选自H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基。
在其中一些实施例中，所述1，3-二取代烯酮类化合物选自：
Figure PCTCN2018093760-appb-000010
Figure PCTCN2018093760-appb-000011
Figure PCTCN2018093760-appb-000012
Figure PCTCN2018093760-appb-000013
Figure PCTCN2018093760-appb-000014
Figure PCTCN2018093760-appb-000015
Figure PCTCN2018093760-appb-000016
本发明还提供了上述1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子的应用。
具体技术方案如下：
上述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备PPAR激动剂中的应用。
上述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备预防或治疗PPAR调控异常相关的疾病中的应用，所述PPAR调控异常相关的疾病包括：脂质和糖代谢异常相关的疾病、炎症和纤维化异常相关的疾病、心血管疾病、肾脏疾病、大脑退行性疾病。
在其中一些实施例中，所述PPAR调控异常相关的疾病包括：非酒精性脂肪肝病、非酒精性肝炎、胆汁淤积性肝病、糖尿病、肥胖症、心力衰竭、动脉粥样硬化、慢性肾病、肾功能衰竭、阿尔茨海默病。
本发明还提供了一种防治PPAR调控异常相关的疾病的药物组合物。
具体技术方案如下：
一种防治PPAR调控异常相关的疾病的药物组合物，其活性成分包括有上述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。
上述1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子可以与药学上可接受的辅料或载体制备成具有各种相应剂型的药物组合物。也可以与其它具有PPAR激动活性的药物联合使用，以增强PPAR的激动活性。
本发明提供的1，3-二取代烯酮类化合物具有调节PPAR激动剂的活性，这类化合物主要激活PPARα，对PPPAδ和PPPAγ亦有激动活性。能够用于治疗PPAR调控异常相关的各种疾病，如非酒精性脂肪肝病(non-alcoholic fatty liver disease,NAFLD)特别是治疗非酒精性肝炎(non-alcoholic steatohepatitis,NASH)，还具有用于治疗糖尿病、肥胖症、纤维化疾病、心血管疾病(包括心力衰竭和动脉粥样硬化等)、肾脏疾病(包括慢性肾病和肾功能衰竭等)、脑退行性疾病(包括阿尔茨海默病等)等的潜力，具有较大的应用价值。
附图说明
图1为化合物5、62、100、103和Elafibranor在大鼠灌胃给药(20mg/kg)后的血药浓度测定结果图。
具体实施方式
以下结合具体实施例和附图对本发明做进一步的解释说明，但并不对本发明造成任何限制。
本发明所述化合物中，当任何变量(例如R 1、R等)在任何组分中出现超过一次，则其每次出现的定义独立于其它每次出现的定义。同样，允许取代基及变量的组合，只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易合成的化合物。如果取代基自身被超过一个基团取代，应理解这些基团可在相同碳原子上或不同碳原子上，只要使结构稳定。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如，“C 1-C 6烷基”中“C 1-C 6”的定义包括以直链或支链排列的具有1、2、3、4、5或6个碳原子的基团。术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、甲基-环丙基、2,2-二甲基-环丁基、2-乙基-环戊基、环己基等。
术语“烷氧基”指烷基与氧直接连接的基团，如甲氧基，乙氧基等。
术语“烷硫基”指烷基与硫直接连接的基团。
术语“C1-C4烷基胺基取代的C1-C6烷基”指的是具有1、2、3、4个碳原子的烷基与氮原子相连后其氮原子再与具有1、2、3、4、5、6个碳原子的烷基相连的基团，例如甲胺基甲基，甲胺基乙基，二甲胺基甲基等。
术语“杂环”包括饱和的含有杂原子的环烷基和杂芳基，其中杂原子可以选自氮、硫和氧及氮、硫、磷的任何氧化态形式，优选含N的饱和杂环烷基，如哌啶等。
术语“取代的”是指用指定取代基的基团置换特定结构中的氢基。
术语“杂环”或“杂环基”是指含有1-4个选自O、N和S的杂原子的芳香性或非芳香性杂环，且包括双环基团。“杂环基”因此包括杂芳基，也包括其二氢化及四氢化类似物。杂环取代基的连接可通过碳原子或通过杂原子实现。
正如本领域技术人员所理解的，本文中所用“卤素”意指包括氯、氟、溴和碘。
本发明包括式Ⅰ-II化合物的游离形式，也包括其药学上可接受的盐及立体异构体。可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常，通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的，通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此，本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如，常规的无毒盐包括自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等制备的盐，也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2一乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的，则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐，包括伯胺、仲胺和叔胺的盐，取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'－二苄基乙二胺、二乙胺、2一二乙基氨基乙醇、2一二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N一乙基吗啉、N一乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
除在文献中已知的或在实验程序中例证的标准方法外，可采用如下合成方案(方案1-6)中的方法制备本发明化合物。结合下述的合成方案，能够对本发明中所述的化合物以及合成方法进行更好的理解。所述的合成方案描述了可以用于制备本发明中所述的化合物的方法，所述的方法仅仅是为说明目的的说明性方案描述，并不构成对本发明所具有的范围的限制。
方案1
Figure PCTCN2018093760-appb-000017
方案2
Figure PCTCN2018093760-appb-000018
方案3
Figure PCTCN2018093760-appb-000019
方案4
Figure PCTCN2018093760-appb-000020
方案5
Figure PCTCN2018093760-appb-000021
方案6
Figure PCTCN2018093760-appb-000022
方案7
Figure PCTCN2018093760-appb-000023
方案8
Figure PCTCN2018093760-appb-000024
方案9
Figure PCTCN2018093760-appb-000025
方案10
Figure PCTCN2018093760-appb-000026
方案11
Figure PCTCN2018093760-appb-000027
方案12
Figure PCTCN2018093760-appb-000028
以下为具体实施例：
实施例1：(E)-2-(4-(3-(4-甲氧基苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(4-methoxybenzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物1)的制备(按照方案一线路制备)
步骤1a:1-溴-2-(2,2-二乙氧基乙氧基)-4-甲氧基苯(1-bromo-2-(2,2-diethoxyethoxy)-4-methoxybenzene)(0102-1)的制备：将2-溴-5-甲氧基苯酚(0101-1)(1.83g,9.02mmol,1.0当量)和2-溴-1,1-二乙氧基乙烷(1.42mL,9.47mmol,1.05当量)溶于N,N-二甲基甲酰胺(10mL)中，然后加入碳酸钾(2.49g,18.04mmol,2.0当量)。用氮气置换反应体系中的空气三遍，然后在95 °C下反应过夜。反应液加水(100mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝20：1)得到淡黄色油状液体产物1-溴-2-(2,2-二乙氧基乙氧基)-4-甲氧基苯(2.65g，收率：92％)。LCMS(ESI)：m/z 319[M+1] +。
步骤1b:7-溴-4-甲氧基苯并呋喃(7-bromo-4-methoxybenzofuran)(2-(1-trityl-1H-imidazol-4-yl)benzaldehyde)(化合物0103-1)的制备:往反应瓶中加入1-溴-2-(2,2-二乙氧基乙氧基)-4-甲氧基苯(102-1)(2.60g，8.15mmol，1.0当量)，多聚磷酸(8.26g，24.45mmol，3.0当量)和1,2-二氯乙烷(40mL)，加热到83℃反应3小时。反应液冷却到室温然后用水(30mL×2)洗涤，有机层用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚)得到白色固体产物7-溴-4-甲氧基苯并呋喃(1.16g，收率：63％)。LCMS(ESI)：m/z 227[M+1] +。
步骤1c:1-(4-甲氧基苯并呋喃-7-基)乙-1-酮(1-(4-methoxybenzofuran-7-yl)ethan-1-one)(化合物0104-1)的制备：往反应瓶中加入7-溴-4-甲氧基苯并呋喃(0103-1)(0.416g，1.833mmol，1.0当量)，乙烯基正丁醚(1.07mL，8.247mmol，4.5当量)，醋酸钯(20.6mg，0.092mmol，0.05当量)，1,3-二(三苯基膦基)丙烷(75.5mg，0.183mmol，0.10当量)，三乙胺(0.76mL，5.499mmol，3.0当量)和乙二醇(6mL)，然后在氮气保护下加热到125℃反应6小时。反应液冷却到室温然后加水(30mL)稀释，用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩得到的油状物溶于1N稀盐酸溶液(15mL)中，并在室温下搅拌2小时。反应液用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝30：1)得到白色固体产物1-(4-甲氧基苯并呋喃-7-基)乙-1-酮(0.13g，收率：37％)。LCMS(ESI)：m/z 191[M+1] +。
步骤1e:(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-甲氧基苯并呋喃-7-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(4-methoxybenzofuran-7-yl)prop-2-en-1-one)(化合物0106-1)的制备:往1-(4-甲氧基苯并呋喃-7-基)乙-1-酮(0104-1)(130mg，0.684mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(103mg，0.684mmol，1.0当量)的乙醇溶液(8ml)中缓慢滴加浓硫酸(2mL)，室温下反应3.5小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩得到黄色固体产物(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-甲氧基苯并呋喃-7-基)丙-2-烯-1-酮(0.22g)。LCMS(ESI)：m/z 323[M+1] +。
步骤1f:(E)-2-(4-(3-(4-甲氧基苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(4-(3-(4-methoxybenzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate)(0107-1)的制备：将(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-甲氧基苯并呋喃-7-基)丙-2-烯-1-酮(0106-1)(0.22g,0.684mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(0.75mL,4.104mmol,6.0当量)溶于乙腈(10mL)中，然后加入碳酸钾(0.38g,2.74mmol,4.0当量)。用氮气置换反应体系中的空气三遍，然后在83℃下反应过夜。反应完成后浓缩得到粗产品，通过硅胶柱层析法(石油醚：乙酸乙酯＝8： 1)纯化得淡黄色固体产物(E)-2-(4-(3-(4-甲氧基苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(113mg，收率：36％)。LCMS(ESI)：m/z 465[M+1] +。
步骤1g:(E)-2-(4-(3-(4-甲氧基苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(4-methoxybenzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物1)的制备：室温下往(E)-2-(4-(3-(4-甲氧基苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(0107-1)(113mg，0.244mmol，1.0当量)的二氧六环溶液(8ml)中缓慢滴加浓硫酸(1mL)，室温下反应2小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(二氯甲烷：甲醇＝20：1)得到黄色固体产物(E)-2-(4-(3-(4-甲氧基苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(70mg，收率：70％)。LCMS(ESI)：m/z 409[M+1] +；熔点：190～193℃； 1HNMR(DMSO-d 6，400MHz)：δ12.95(s,1H),8.11(d,J＝2.0Hz,1H),8.04(d,J＝7.6Hz,1H),7.87(d,J＝15.6Hz,1H),7.65(d,J＝15.6Hz,1H),7.51(s,2H),7.07(d,J＝2.4Hz,1H),6.99(d,J＝8.4Hz,1H),4.02(s,3H),2.23(s,6H),1.40(s,6H)。
实施例2：(E)-2-(2,6-二甲基-4-(3-(4-(甲基氨基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(4-(methylamino)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物2)的制备(按照方案一线路制备)
步骤2a:1-溴-2-(2,2-二乙氧基乙氧基)-4-氟苯(1-bromo-2-(2,2-diethoxyethoxy)-4-fluorobenzene)(化合物0102-2)的制备:将2-溴-5-氟苯酚(0101-2)(1.73g,9.06mmol,1.0当量)和2-溴-1,1-二乙氧基乙烷(5.45mL,36.42mmol,4.0当量)溶于N,N-二甲基甲酰胺(20mL)中，然后加入碳酸钾(2.50g,18.12mmol,2.0当量)。用氮气置换反应体系中的空气三遍，然后在95℃下反应8小时。反应液加水(100mL)稀释，然后用乙酸乙酯(40mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝50：1)得到无色油状液体产物1-溴-2-(2,2-二乙氧基乙氧基)-4-氟苯(2.78g，收率：100％)。LCMS(ESI)：m/z 307[M+1] +。
步骤2b:7-溴-4-氟苯并呋喃(7-bromo-4-fluorobenzofuran)(化合物0103-2)的制备:往反应瓶中加入1-溴-2-(2,2-二乙氧基乙氧基)-4-氟苯(0102-2)(2.75g，8.95mmol，1.0当量)，多聚磷酸(9.08g，26.86mmol，3.0当量)和1,2-二氯乙烷(40mL)，加热到83℃反应3小时。反应液冷却到室温然后用水(30mL×2)洗涤，有机层用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚)得到淡黄色固体产物7-溴-4-氟苯并呋喃(0.992g，收率：52％)。LCMS(ESI)：m/z 215[M+1] +。
步骤2c:1-(4-氟苯并呋喃-7-基)乙-1-酮(1-(4-fluorobenzofuran-7-yl)ethan-1-one)(化合物0104-2)的制备:将7-溴-4-氟苯并呋喃(0103-2)(0.95g,4.42mmol,1.0当量)溶于无水甲苯(15mL)中，用干冰丙酮浴冷却到-78℃，然后缓慢地滴加正丁基锂(2.5M,2.47mL,6.19mmol,1.4当量),滴加完毕后在-78℃下搅拌1.5小时。把N-甲氧基-N-甲基乙酰胺(1.17mL,11.05mmol,2.5当量)滴加进去然后缓慢升到室温并搅拌4小时。加入饱和氯化铵溶液(50mL)淬灭反应，水层用乙酸乙酯(30mL×3)萃取，合并有机层后用无水硫酸钠干燥，浓缩，得到的粗产品用硅胶柱层析法(石油醚：乙酸乙酯＝30:1)纯化得淡黄色固体产物1-(4-氟苯并呋喃-7-基)乙-1-酮(0.28g，收率：36％)。LCMS(ESI)：m/z 179[M+1] +。
步骤2d:1-(4-(甲基氨基)苯并呋喃-7-基)乙-1-酮(1-(4-(methylamino)benzofuran-7-yl)ethan-1-one)(化合物0105-2)的制备:往烧瓶中加入1-(4-氟苯并呋喃-7-基)乙-1-酮(0104-2)(0.254g,1.427mmol,1.0当量)，二甲胺水溶液(25％水溶液，0.71g,5.708mmol,4.0当量)和二甲亚砜(5mL)，然后在60℃下反应过夜。反应液冷却到室温并加水(50mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝2：1)得到淡黄色固体产物1-(4-(甲基氨基)苯并呋喃-7-基)乙-1-酮(0.251g，收率：93％)。LCMS(ESI)：m/z 190[M+1] +。
步骤2e:(E)-2-(2,6-二甲基-4-(3-(4-(甲基氨基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸乙酯(ethyl(E)-2-(2,6-dimethyl-4-(3-(4-(methylamino)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(化合物0108-2)的制备:往反应瓶中加入1-(4-(甲基氨基)苯并呋喃-7-基)乙-1-酮(0105-2)(146mg，0.771mmol，1.0当量)，2-(4-甲酰基-2,2-二甲基苯氧基)-2-甲基丙酸叔丁酯(225mg，0.771mmol，1.0当量)和乙醇(8mL)，然后逐滴滴加浓硫酸(2mL)，30℃下搅拌过夜。反应液加水(30mL)稀释，用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，得到的粗产品用硅胶柱层析法(二氯甲烷：甲醇＝60:1)纯化得黄色固体产物(E)-2-(2,6-二甲基-4-(3-(4-(甲基氨基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸乙酯(93mg，收率：28％)。LCMS(ESI)：m/z 436[M+1] +。
步骤2f:(E)-2-(2,6-二甲基-4-(3-(4-(甲基氨基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(4-(methylamino)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物2)的制备:往反应瓶中加入(E)-2-(2,6-二甲基-4-(3-(4-(甲基氨基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸乙酯(0108-2)(93mg，0.214mmol，1.0当量)，氢氧化钠(2 6mg，0.641mmol，3.0当量)，乙醇(5mL)和水(3mL)，30℃下搅拌过夜。反应液加水(20mL)稀释，加入稀盐酸调节pH＝5，然后用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，得到的粗产品用硅胶柱层析法(二氯甲烷：甲醇＝30:1)纯化得黄色固体产物(E)-2-(2,6-二甲基-4-(3-(4-(甲基氨基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(50mg，收率：57％)。LCMS(ESI)：m/z 408[M+1] +；熔点：196～199℃； 1HNMR(DMSO-d 6，400MHz)：δ12.92(s,1H),7.95-7.88(m,3H),7.59-7.46(m,3H),7.18-7.14(m,2H),6.40(d,J＝8.4Hz,1H),2.92(d,J＝4.8Hz,3H),2.23(s,6H),1.39(s,6H)。
实施例3：(E)-2-(4-(3-(苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物3)的制备(按照方案一线路制备)
步骤3a:1-溴-2-(2,2-二乙氧基乙氧基)苯(1-bromo-2-(2,2-diethoxyethoxy)benzene)(化合物0102-3)的制备:将2-溴-苯酚(0101-3)(2.0g，11.56mmol,1.0当量)溶于30mlDMF中，加入2-溴-1,1-二乙氧基乙烷(2.96g，15.03mmol，1.3当量)、碳酸钾(3.19g,23.12mmol,2.0当量)，用氮气置换圆底烧瓶瓶内空气三遍，然后在100℃下反应8小时。反应完成后反应液加入乙酸乙酯(100ml)稀释，半饱和食盐水(150ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝20：1)得到淡黄色油状液体产物1-溴-2-(2,2-二乙氧基乙氧基)苯(3.33g，收率：100％)。
步骤3b:7-溴苯并呋喃(7-bromobenzofuran)(化合物0103-3)的制备:将1-溴-2-(2,2-二乙氧基乙氧基)苯(0102-3)(3.33g，11.56mol，1.0当量)溶于DCE(60ml)中，加入PPA(11.72g，34.68mmol,3.0当量)，用氮气置换圆底烧瓶瓶内空气三遍然后在83℃下回流反应3小时。反应完成后加入二氯甲烷(100ml)，水(100ml×3)洗，有机相用无水硫酸钠干燥后浓缩，然后用硅胶柱层析法纯化(石油醚＝100％)得淡黄色固体产物7-溴苯并呋喃(1.336g，收率：58％)。
步骤3c:1-(苯并呋喃-7-基)乙酮(1-(benzofuran-7-yl)ethanone)(化合物0104-3)的制备:将7-溴苯并呋喃(0103-3)(1.06g，5.36mmol，1.0当量)溶于乙二醇(10ml)中，加入丁基乙烯醚(0.698g，6.97mmol，1.3当量)、醋酸钯(0.12g,0.536mmol,0.1当量)、DPPP(0.221g,0.536mmol,0.1当量)、TEA(1.08g,10.71mmol,2.0当量)，反应液在充满氮气的封管中150℃下反应1小时。反应结束后加入乙酸乙酯(50ml)稀释，水(100ml×3)洗，有机相用无水硫酸钠干燥，浓缩后溶解在四氢呋喃(15ml)中，加入1M HCl(12ml)室温反应3小时，反应结束后用乙酸乙酯(100ml)萃取，有机相用无水硫酸钠干燥，浓缩后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝10:1)得淡黄色固体产物1-(苯并呋喃-7-基)乙酮(0.79g，收率：92％)。LCMS(ESI)：m/z 161[M+1] +。
步骤3d:(E)-1-(苯并呋喃-7-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮((E)-1-(benzofuran-7-yl)-3-(4-hydroxy-3,5-dimethyl phenyl)prop-2-en-1-one)(化合物0106-3)的制备:将1-(苯并呋喃-7-基)乙酮(0104-3)(0.79g，4.93mol,1.0当量)溶于10ml二氧六环中，加入4-羟基-3,5-二甲基苯甲醛(0.81g，5.42mmol，1.1当量)，搅拌下加入浓硫酸(3ml)，室温反应15h。反应完成后反应液加入乙酸乙酯(100ml)稀释，半饱和食盐水(150ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝5：1)得到淡黄色固体产物(E)-1-(苯并呋喃-7-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(0.8g，收率：56％)。LCMS(ESI)：m/z 293[M+1] +。
步骤3e:(E)-2-(4-(3-(苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯((E)-tert-butyl 2-(4-(3-(benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate)(化合物0107-3)的制备:将(E)-1-(苯并呋喃-7-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(0106-3)(0.8g，2.74mmol,1.0当量)溶于20ml乙腈中，加入碳酸钾(1.88g，13.7mmol，5.0当量)、2-溴异丁酸叔丁醇(3.05g,13.7mmol,5.0当量)，用氮气置换圆底烧瓶瓶内空气三遍，然后在82℃下反应20h。反应完成后浓缩，然后反应液加入乙酸乙酯(100ml)稀释，水(150ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝15：1)得到淡黄色固体产物(E)-2-(4-(3-(苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(0.5g，收率：42％)。LCMS(ESI)：m/z 435[M+1] +。
步骤3f:(E)-2-(4-(3-(苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物3)的制备:将(E)-2-(4-(3-(苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(0107-3)(0.5g，1.15mmol,1.0当量)溶于10ml二氯甲烷中，搅拌下加入三氟乙酸(4ml)，室温反应15h。反应完成后将反应液加入二氯甲烷(50ml)稀释，半饱和食盐水(150ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用混合液(石油醚：乙酸乙酯＝1:1)洗涤得到淡黄色固体产物(E)-2-(4-(3-(苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(0.17g，收率：40％)。LCMS(ESI)：m/z 339[M+1] +；熔点：125～128℃； 1HNMR(DMSO-d 6，300MHz):δ12.95(s，1H)，8.19(d，J＝2.1Hz,1H)，7.96(d，J＝7.8Hz，1H)，7.92(d，J＝7.8Hz，1H)，7.84(d，J＝15.6Hz,1H)，7.66(d，J＝15.6Hz，1H)，7.42(d，J＝7.8Hz，1H)，7.52(s，2H)，7.11(d，J＝2.1Hz，1H)，2.22(s，6H)，1.39(s,6H)。
实施例4：(E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物5)的制备(按照方案一线路制备)
步骤4a：1-(4-(甲硫基)苯并呋喃-7-基)乙-1-酮(1-(4-(methylthio)benzofuran-7-yl)ethan-1-one)(化合物0105-5)的制备：往反应瓶中加入1-(4-氟苯并呋喃-7-基)乙-1-酮(0104-2)(0.25g，1.404mmol，1.0当量)，甲硫醇钠(40％，0.49g，2.81mmol，2.0当量)和二甲亚砜(5ml)，室温下反应1小时。反应液加水(50mL)稀释，用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝15：1)得到淡黄色固体产物1-(4-(甲硫基)苯并呋喃-7-基)乙-1-酮(0.224g，收率：78％)。LCMS(ESI)：m/z 207[M+1] +。
步骤4b：(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-(甲硫基)苯并呋喃-7-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(4-(methylthio)benzofuran-7-yl)prop-2-en-1-one)(化合物0106-5)的制备:往1-(4-(甲硫基)苯并呋喃-7-基)乙-1-酮(0105-5)(214mg，1.04mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(156mg，1.04mmol，1.0当量)的乙醇溶液(8ml)中缓慢滴加浓硫酸(2mL)，室温下反应3小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩得到黄色固体产物(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-(甲硫基)苯并呋喃-7-基)丙-2-烯-1-酮(0.35g)。LCMS(ESI)：m/z 339[M+1] +。
步骤4c：(E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(化合物0107-5)的制备:将(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-(甲硫基)苯并呋喃-7-基)丙-2-烯-1-酮(0106-5)(0.35g,1.04mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(1.16mL,6.21mmol,6.0当量)溶于乙腈(10mL)中，然后加入碳酸钾(0.57g,4.16mmol,4.0当量)。用氮气置换反应体系中的空气三遍，然后在83℃下反应24小时。反应完成后浓缩得到粗产品，通过硅胶柱层析法(石油醚：乙酸乙酯＝10：1)纯化得黄色固体产物(E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(227mg，收率：45％)。LCMS(ESI)：m/z 481[M+1] +。
步骤4d：(E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物5)的制备:室温下往(E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(0107-5)(227mg，0.472mmol，1.0当量)的二氧六环溶液(8ml)中缓慢滴加浓硫酸(1mL)，室温下反应1.5小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(二氯甲烷：甲醇＝20：1)得到黄色固体产物(E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(110mg，收率：55％)。LCMS(ESI)：m/z 425[M+1] +；熔点：102～105℃； 1HNMR(DMSO-d 6，400MHz)：δ12.94(s,1H),8.22(d,J＝2.4Hz,1H),7.97(d,J＝8.0Hz,1H),7.85(d,J＝16.0Hz,1H),7.66(d,J＝15.6Hz,1H),7.64(s,2H),7.27(d,J＝7.6Hz,1H),7.06(d,J＝2.0Hz,1H),2.67(s,3H),2.23(s,6H),1.40(s,6H)。
实施例5：(E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物12)的制备(按照方案一线路制备)
步骤5a：(E)-3-(4-羟基苯基)-1-(4-(甲硫基)苯并呋喃-7-基)丙-2-烯-1-酮((E)-3-(4-hydroxyphenyl)-1-(4-(methylthio)benzofuran-7-yl)prop-2-en-1-one)(化合物0106-12)的制备：将1-(4-(甲硫基)苯并呋喃-7-基)乙酮(0105-5)(0.3g，1.45mmol,1.0当量)溶于10ml二氧六环中，加入4-羟基苯甲醛(0.213g，1.75mmol，1.2当量)，搅拌下加入浓硫酸(3ml)，室温反应15h。反应完成后反应液加入乙酸乙酯(100ml)稀释，半饱和食盐水(150ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝5：1)得到淡黄色固体产物E)-3-(4-羟基苯基)-1-(4-(甲硫基)苯并呋喃-7-基)丙-2-烯-1-酮(0.28g，收率：62％)。LCMS(ESI)：m/z 311[M+1] +。
步骤5b：(E)-2-甲基-2-(4-(3-(4-(甲硫基)苯并呋喃-7-基)-3-氧代-1-烯-1-基)苯氧基)丙酸叔丁酯((E)-tert-butyl 2-methyl-2-(4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)propanoate)(化合物0107-12)的制备：将E)-3-(4-羟基苯基)-1-(4-(甲硫基)苯并呋喃-7-基)丙-2-烯-1-酮(0106-12)(0.28g，0.9mmol,1.0当量)溶于20ml乙腈中，加入碳酸钾(0.623g，4.5mmol，5.0当量)、2-溴异丁酸叔丁酯(1.007g,4.5mmol,5.0当量)，用氮气置换圆底烧瓶瓶内空气三遍，然后在82℃下反应20h。反应完成后浓缩，然后反应液加入乙酸乙酯(100ml)稀释，水(150ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝15：1)得到黄色固体产物(E)-2-甲基-2-(4-(3-(4-(甲硫基)苯并呋喃-7-基)-3-氧代-1-烯-1-基)苯氧基)丙酸叔丁酯(0.2g，收率：50％)。LCMS(ESI)：m/z 453[M+1] +。
步骤5c：(E)-2-甲基-2-(4-(3-(4-(甲硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)丙酸((E)-2-methyl-2-(4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)propanoic acid)(化合物12)的制备:将(E)-2-甲基-2-(4-(3-(4-(甲硫基)苯并呋喃-7-基)-3-氧代-1-烯-1-基)苯氧基)丙酸叔丁酯(0107-12)(0.2g，0.44mmol,1.0当量)溶于10ml二氯甲烷中，搅拌下加入三氟乙酸(4ml)，室温反应15h。反应完成后将反应液加入二氯甲烷(50ml)稀释，半饱和食盐水(150ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用混合液(石油醚：乙酸乙酯＝1:1)洗涤得到黄色固体产物E)-2-甲基-2-(4-(3-(4-(甲硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)丙酸(0.041g，收率：23％)。LCMS(ESI)：m/z 397[M+1] +；熔点：167～170℃； 1HNMR(DMSO-d 6，400MHz):δ13.20(s，1H)，8.20(d,J＝1.6Hz，1H)，7.95(d,J＝8Hz，1H)，7.86(d,J＝15.6Hz，1H)，7.77(d,J＝8.4Hz，2H)，7.73(d,J＝16.4Hz，1H)，7.26(d，J＝8Hz，1H)，7.06(d，J＝1.6Hz，1H)，6.88(d，J＝8.4Hz，2H)，2.66(s，3H)，1.57(s,6H)。
实施例6：2-(5H-咪唑[5,1-a]异吲哚啉-5-基)-1-(7-甲氧基苯并呋喃-5-基)乙烷-1-醇(2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(7-methoxybenzofuran-5-yl)ethan-1-ol)(化合物13)的制备(按照方案一线路制备)
步骤6a:(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-(甲硫基)苯并呋喃-7-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(4-(methylthio)benzofuran-7-yl)prop-2-en-1-one)(化合物0106-13)的制备:将1-(4-(甲硫基)苯并呋喃-7-基)乙酮(0105-5)(0.38g，1.84mmol,1.0当量)溶于10ml二氧六环中，加入4-羟基-3,5-二甲基苯甲醛(0.332g，2.21mmol，1.2当量)，搅拌下加入浓硫酸(3ml)，室温反应15h。反应完成后反应液加入乙酸乙酯(100ml)稀释，半饱和食盐水(150ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝5：1)得到淡黄色固体产物(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-(甲硫基)苯并呋喃-7-基)丙-2-烯-1-酮(0.52g，收率：84％)。LCMS(ESI)：m/z 339[M+1] +。
步骤6b:(E)2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-7-基)-3-氧代-1-烯-1-基)苯氧基)乙酸叔丁酯((E)-tert-butyl 2-(2,6-dimethyl-4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)acetate)(化合物0107-13)的制备:将(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-(甲硫基)苯并呋喃-7-基)丙-2-烯-1-酮(0106-13)(0.52g，1.54mmol,1.0当量)溶于20ml乙腈中，加入碳酸钾(1.06g，7.68mmol，5.0当量)、2-溴异丁酸叔丁醇(1.28g,7.68mmol,5.0当量)，用氮气置换圆底烧瓶瓶内空气三遍，然后在82℃下反应20h。反应完成后浓缩，然后反应液加入乙酸乙酯(100ml)稀释，水(150ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝15：1)得到黄色固体产物(E)2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-7-基)-3-氧代-1-烯-1-基)苯氧基)乙酸叔丁酯(0.39g，收率：60％)。LCMS(ESI)：m/z 425[M+1] +。
步骤6c:((E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)乙酸((E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)acetic acid)(化合物13)的制备:将(E)2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-7-基)-3-氧代-1-烯-1-基)苯氧基)乙酸叔丁酯(0107-13)(0.39g，0.918mmol,1.0当量)溶于5ml四氢呋喃中，加入4ml乙醇、5ml水、氢氧化钠(0.07g，1.837mmol，2.0当量)，室温反应15h。反应完成后加入1M盐酸(20ml)至pH＝1，用乙酸乙酯(100ml)萃取，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(二氯甲烷：甲醇：乙酸＝100:1：0.25)得到黄色固体产物(E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)乙酸(0.139g，收率：38％)。LCMS(ESI)：m/z 397[M+1] +；熔点：218～221℃； 1HNMR(DMSO-d 6，400MHz):δ12.9(s，1H)，8.22(d,J＝2.4Hz,1H),7.97(d,J＝8Hz,1H),7.86(d,J＝15.6Hz,1H),7.67(d,J＝15.6Hz,1H),7.53(s,2H),7.26(d,J＝8Hz,1H),7.06(d,J＝2Hz,1H),4.44(s,2H),2.67(s，3H)，2.29(s,6H)。
实施例7：(E)-2-(2,6-二甲基-4-(3-(2-甲基-4-(甲硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(2-methyl-4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物14)的制备(按照方案二线路制备)
步骤7a：1-溴-4-氟-2-(丙-2-炔-1-基氧基)苯(1-bromo-4-fluoro-2-(prop-2-yn-1-yloxy)benzene(化合物0201-14)的制备:在室温下，往2-溴-5-氟苯酚(0101-2)(1.91g，10mmol，1.0当量)和碳酸钾(2.76g，20mmol，2.0当量)的二甲基甲酰胺溶液(20ml)中加入3-溴丙-1-炔(1.31g，11mmol，1.1当量)，室温反应1小时。反应液用乙酸乙酯(100ml)稀释，分别用水(50ml×1)和半饱和食盐水洗涤(100ml×2)，有机相旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝10:1)得到淡黄色液体产物1-溴-4-氟-2-(丙-2-炔-1-基氧基)苯(2.29g，收率：100％)。LCMS(ESI)：m/z 230[M+1] +。
步骤7b：7-溴-4-氟-2-甲基苯并呋喃(7-bromo-4-fluoro-2-methylbenzofuran)(N-081-4)(化合物0202-14)的制备:往封管中加入1-溴-4-氟-2-(丙-2-炔-1-基氧基)苯(0201-14)(2.29g,10mmol，1.0当量)，氟化铯(2.28g,15mmol，1.5当量)和二乙基苯胺(15ml)，加热回流反应4小时，将反应液冷却至室温，用乙醚(100ml)稀释，过滤，滤液用1M盐酸洗涤(60ml×3),有机相旋干，剩余物用硅胶柱层析法纯化(洗脱剂：100％石油醚)得到白色固体产物7-溴-4-氟-2-甲基苯并呋喃(1.57g，收率：69％)。LCMS(ESI)：m/z 230[M+1] +。
步骤7c：1-(4-氟-2-甲基苯并呋喃-7-基)乙-1-酮(1-(4-fluoro-2-methylbenzofuran-7-yl)ethan-1-one)(化合物0203-14)的制备:往封管中加入7-溴-4-氟-2-甲基苯并呋喃(0202-14)(1.57g，7mmol，1.0当量)，1-(乙烯氧基)丁烷(0.91g，9.1mmol，1.3当量)，醋酸钯(0.157g，0.7mmol，0.1当量)，1,3-二(二苯基膦基)丙烷(0.288g，0.7mmol，0.1当量)，三乙胺(1.42g，14mmol，2.0当量)和乙二醇(20ml),在145℃下反应1小时。将反应液用乙酸乙酯(100ml)稀释，用半饱和食盐水洗涤(100ml×3),有机相旋干，溶于四氢呋喃(30ml),加入1M盐酸(15ml)，室温搅拌3小时，用乙酸乙酯(100ml×1)萃取，有机相拌样旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝10:1)得到浅黄色固体产物1-(4-氟-2-甲基苯并呋喃-7-基)乙-1-酮(0.99g，收率：74％)。LCMS(ESI)：m/z 193[M+1] +。
步骤7d：1-(2-甲基-4-(甲硫基)苯并呋喃-7-基)乙-1-酮(1-(2-methyl-4-(methylthio)benzofuran-7-yl)ethan-1-one)(化合物0204-14)的制备:在1-(4-氟-2-甲基苯并呋喃-7-基)乙-1-酮(0203-14)(0.99g，5.2mmol，1.0当量)的二甲基亚砜溶液(30ml)中加入20％甲硫醇钠溶液(4ml，10.4mmol，2.0当量)，室温下反应两小时。反应液用乙酸乙酯(150ml)稀释，用半饱和食盐水洗涤(100ml×3)，有机相旋干得到黄色固体产物1-(2-甲基-4-(甲硫基)苯并呋喃-7-基)乙-1-酮(1.04g，收率：91％)。LCMS(ESI)：m/z 221[M+1] +。
步骤7e：(E)-3-(4-羟基-3,5-二甲基苯基)-1-(2-甲基-4-(甲硫基)苯并呋喃-7-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(2-methyl-4-(methylthio)benzofuran-7-yl)prop-2-en-1-one)(化合物0205-14)的制备:往1-(2-甲基-4-(甲硫基)苯并呋喃-7-基)乙-1-酮(0204-14)(0.44g，2.0mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(0.33g，2.2mmol，1.1当量)的二氧六环溶液(10ml)中慢慢加入浓硫酸(2ml)，反应室温搅拌3天。反应液用乙酸乙酯(150ml)稀释，用半饱和食盐水洗涤(100ml×3)，有机相旋干，剩余物用硅胶柱层析法纯化(洗脱剂：100％二氯甲烷)得到黄色固体产物(E)-3-(4-羟基-3,5-二甲基苯基)-1-(2-甲基-4-(甲硫基)苯并呋喃-7-基)丙-2-烯-1-酮(0.74g，收率：100％)。LCMS(ESI)：m/z 353[M+1] +。
步骤7f：(E)-2-(2,6-二甲基-4-(3-(2-甲基-4-(甲硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dimethyl-4-(3-(2-methyl-4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(化合物0206-14)的制备:往(E)-3-(4-羟基-3,5-二甲基苯基)-1-(2-甲基-4-(甲硫基)苯并呋喃-7-基)丙-2-烯-1-酮(0205-14)(0.704g，2.0mmol，1.0当量)的乙腈(50ml)溶液中加入碳酸钾(1.38g，10.0mmol，5.0当量)和2-溴代异丁酸叔丁酯(2.23g，10.0mmol，5.0当量)，将反应液在氮气的保护下加热至82℃回流过夜。反应液旋干，剩余物用乙酸乙酯(150ml)稀释，用水(100ml×2)洗，有机相旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝10:1)得到黄色油状物产物(E)-2-(2,6-二甲基-4-(3-(2-甲基-4-(甲硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(0.28g，收率：28％)。LCMS(ESI)：m/z 495[M+1] +。
步骤7g：(E)-2-(2,6-二甲基-4-(3-(2-甲基-4-(甲硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(2-methyl-4-(methylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid(化合物14)的制备:往(E)-2-(2,6-二甲基-4-(3-(2-甲基-4-(甲硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(0206-14)(0.28g，0.57mmol，1.0当量)的二氯甲烷(10ml)溶液中缓慢加入三氟乙酸(2ml)，反应液室温下反应两小时。将反应液用二氯甲烷(100ml)稀释，再用水(100ml×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液旋干，剩余物用甲醇(2ml)重结晶得到黄色固体产物(E)-2-(2,6-二甲基-4-(3-(2-甲基-4-(甲硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(140mg，收率：56.0％)。LCMS(ESI)：m/z 439[M+1] +；熔点：187～190℃； 1HNMR(DMSO，300MHz)：δ12.95(s，1H)，6.68-7.89(m，7H)，2.64(s，3H)，2.54(s，3H)，2.23(s，6H)，1.39(s，6H)。
实施例8：(E)-2-(2,6-二甲基-4-(3-(2-甲基-4-(甲硫基)苯并[d]恶唑-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(2-methyl-4-(methylthio)benzo[d]oxazol-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物20)的制备(按照方案三线路制备)
步骤8a：1-(4-氟-2-羟基-3-硝基苯基)乙-1-酮(1-(4-fluoro-2-hydroxy-3-nitrophenyl)ethan-1-one)(化合物0302-20)的制备:在0℃下，往1-(4-氟-2-羟基苯基)乙-1-酮(0301-20)(1.0g，6.49mmol，1.0当量)的82％硫酸溶液(9ml)中加入70％硝酸(0.5ml，7.14mmol，1.1当量)，0℃反应半小时。将反应液倒入冰水(100ml)中，用二氯甲烷萃取(50ml×2)，有机相旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝10:1)得到淡黄色固体产物1-(4-氟-2-羟基-3-硝基苯基)乙-1-酮(0.36g，收率：28％)。LCMS(ESI)：m/z 200[M+1] +。
步骤8b：1-(2-羟基-4-(甲硫基)-3-硝基苯基)乙-1-酮(1-(2-hydroxy-4-(methylthio)-3-nitrophenyl)ethan-1-one)(化合物0303-20)的制备:往1-(4-氟-2-羟基-3-硝基苯基)乙-1-酮(0302-20)(0.34g,1.71mmol，1.0当量)的二甲基亚砜溶液(8ml)中加入20％的甲硫醇钠溶液(1.19g,3.42mmol，2.0当量)，室温反应半小 时，将反应液用水(100ml)稀释，用1M盐酸调整pH值到2,用乙酸乙酯(100ml×1)萃取，再用半饱和食盐水洗涤(100ml×2),有机相旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝2:1)得到黄色固体产物1-(2-羟基-4-(甲硫基)-3-硝基苯基)乙-1-酮(0.30g，收率：73％)。LCMS(ESI)：m/z 228[M+1] +。
步骤8c:1-(3-氨基-2-羟基-4-(甲硫基)苯基)乙烷-1-酮(1-(3-amino-2-hydroxy-4-(methylthio)phenyl)ethan-1-one)(化合物0304-20)的制备:往反应瓶中加入1-(2-羟基-4-(甲硫基)-3-硝基苯基)乙-1-酮(0303-20)(0.18g，0.8mmol，1.0当量)，锌粉(0.52g，8.0mmol，10.0当量)，氯化铵(0.432g，8.0mmol，10.0当量)和甲醇(15ml),在室温下反应半小时。将反应液用乙酸乙酯(100ml)稀释，过滤，旋干得到棕色固体产物1-(3-氨基-2-羟基-4-(甲硫基)苯基)乙烷-1-酮粗品(0.158g，收率：100％)。LCMS(ESI)：m/z198[M+1] +。
步骤8d:1-(2-甲基-4-(甲硫基)苯并[d]恶唑-7-基)乙-1-酮(1-(2-methyl-4-(methylthio)benzo[d]oxazol-7-yl)ethan-1-one)(化合物0305-20)的制备：在1-(3-氨基-2-羟基-4-(甲硫基)苯基)乙烷-1-酮(0304-20)(0.158g，0.8mmol，1.0当量)的甲苯溶液(20ml)中加入原乙酸三乙酯(0.5ml，2.6mmol，3.3当量)，加热回流1小时。向反应液中加入1M盐酸(20ml)，旋干，剩余物用乙酸乙酯(100ml)稀释，用半饱和食盐水(100ml×1)洗涤,有机相干燥，过滤，旋干得到棕色固体产物1-(2-甲基-4-(甲硫基)苯并[d]恶唑-7-基)乙-1-酮(0.26g，收率：77％)。LCMS(ESI)：m/z 222[M+1] +。
步骤8e:(E)-3-(4-羟基-3,5-二甲基苯基)-1-(2-甲基-4-(甲硫基)苯并[d]恶唑-7-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(2-methyl-4-(methylthio)benzo[d]oxazol-7-yl)prop-2-en-1-one)(化合物0306-20)的制备:往1-(2-甲基-4-(甲硫基)苯并[d]恶唑-7-基)乙-1-酮(0305-20)(0.26g，1.2mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(0.195g，1.3mmol，1.1当量)的二氧六环溶液(10ml)中慢慢加入浓硫酸(2ml)，反应室温搅拌2天。反应液用乙酸乙酯(100ml)稀释，用半饱和食盐水洗涤(100ml×3)，有机相旋干，剩余物用混合溶剂(石油醚：乙酸乙酯＝3:1，28ml)超声5分钟，过滤，用石油醚(30ml)洗涤，得到黄色固体产物(E)-3-(4-羟基-3,5-二甲基苯基)-1-(2-甲基-4-(甲硫基)苯并[d]恶唑-7-基)丙-2-烯-1-酮(0.27g，收率：64％)。LCMS(ESI)：m/z 354[M+1] +。
步骤8f:(E)-2-(2,6-二甲基-4-(3-(2-甲基-4-(甲硫基)苯并[d]恶唑-7-基)-3-氧代-1-烯-哌啶-1-基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dimethyl-4-(3-(2-methyl-4-(methylthio)benzo[d]oxazol-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(化合物0307-20)的制备:往(E)-3-(4-羟基-3,5-二甲基苯基)-1-(2-甲基-4-(甲硫基)苯并[d]恶唑-7-基)丙-2-烯-1-酮(0306-20)(0.27g，0.77mmol，1.0当量)的乙腈(20ml)溶液中加入碳酸钾(0.159g，1.15mmol，1.5当量)和2-溴代异丁酸叔丁酯(0.256g，1.15mmol，1.5当量)，将反应液在氮气的保护下加热至82℃回流过夜。反应液旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝3:1)得到黄色油状物产物(E)-2-(2,6-二甲基-4-(3-(2-甲基-4-(甲硫基)苯并[d]恶唑-7-基)-3-氧代-1-烯-哌啶-1-基)苯氧基)-2-甲基丙酸叔丁酯(0.076g，收率：20％)。LCMS(ESI)：m/z 496[M+1] +。
步骤8g:(E)-2-(2,6-二甲基-4-(3-(2-甲基-4-(甲硫基)苯并[d]恶唑-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(2-methyl-4-(methylthio)benzo[d]oxazol-7-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物20)的制备:往(E)-2-(2,6-二甲基-4-(3-(2-甲基-4-(甲硫基)苯并[d]恶唑-7-基)-3-氧代-1-烯-哌啶-1-基)苯氧基)-2-甲基丙酸叔丁酯(0307-20)(0.076g，0.15mmol，1.0当量)的二氯甲烷(10ml)溶液中缓慢加入三氟乙酸(2ml)，反应液室温下反应过夜。将反应液用二氯甲烷(50ml)稀释，再用水(50ml×2)洗涤，有机相旋干，剩余物用石油醚：乙酸乙酯＝2:1(2ml)重结晶得到黄色固体产物(E)-2-(2,6-二甲基-4-(3-(2-甲基-4-(甲硫基)苯并[d]恶唑-7-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(42mg，收率：64％)。LCMS(ESI)：m/z 440[M+1] +；熔点：186～189℃； 1HNMR(DMSO，300MHz)：δ12.97(s，1H)，7.27-8.03(m，6H)，2.71(s，3H)，2.66(s，3H)，2.23(s，6H)，1.39(s，6H)。
实施例9：(E)-2-(2,6-二甲基-4-(3-(7-(甲硫基)苯并呋喃-4-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(7-(methylthio)benzofuran-4-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物27)的制备(按照方案四线路制备)
步骤9a:4-溴-2-(2,2-二乙氧基乙氧基)-1-氟苯(4-bromo-2-(2,2-diethoxyethoxy)-1-fluorobenzene)(化合物0402-27)的制备:将5-溴-2-氟苯酚(0401-27)(2.1g,10.9mmol,1.0当量)和2-溴-1,1-二乙氧基乙烷(2.15mL,14.29mmol,1.3当量)溶于N,N-二甲基甲酰胺(15mL)中，然后加入碳酸钾(3.03g,21.99mmol,2.0当量)。用氮气置换反应体系中的空气三遍，然后在95℃下反应过夜。反应液加水(100mL)稀释，然后用乙酸乙酯(40mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝50：1)得到无色油状液体产物4-溴-2-(2,2-二乙氧基乙氧基)-1-氟苯(3.37g，收率：100％)。LCMS(ESI)：m/z 307[M+1] +。
步骤9b:4-溴-7-氟苯并呋喃(4-bromo-7-fluorobenzofuran)(化合物0403-27)的制备:往反应瓶中加入4-溴-2-(2,2-二乙氧基乙氧基)-1-氟苯(0402-27)(3.37g，10.97mmol，1.0当量)，多聚磷酸(11.12g，32.91mmol，3.0当量)和1,2-二氯乙烷(40mL)，加热到83℃反应3小时。反应液冷却到室温，然后用水(30mL×2)洗涤，有机层用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚)得到淡黄色固体产物4-溴-7-氟苯并呋喃(0.9g，收率：38％)。LCMS(ESI)：m/z 215[M+1] +。
步骤9c:1-(7-氟苯并呋喃-4-基)乙-1-酮(1-(7-fluorobenzofuran-4-yl)ethan-1-one)(化合物0404-27)的制备:往反应瓶中加入4-溴-7-氟苯并呋喃(0403-27)(0.805g，3.74mmol，1.0当量)，乙烯基正丁醚(2.18mL，16.85mmol，4.5当量)，醋酸钯(42mg，0.187mmol，0.05当量)，1,3-二(三苯基膦基)丙烷(0.154g，0.37mmol，0.10当量)，三乙胺(1.56mL，11.22mmol，3.0当量)和乙二醇(8mL)，然后在氮气保护下加热到125℃反应6小时。反应液冷却到室温，然后加水(30mL)稀释，用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩得到的油状物溶于1N稀盐酸溶液(15mL)中，并在室温下搅拌2小时。反应液用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝30：1)得到白色固体1-(7-氟苯并呋喃-4-基)乙-1-酮(0.57g，收率：86％)。LCMS(ESI)：m/z 179[M+1] +。
步骤9d:1-(7-(甲硫基)苯并呋喃-4-基)乙-1-酮(1-(7-(methylthio)benzofuran-4-yl)ethan-1-one)(化合物0405-27)的制备:往反应瓶中加入1-(7-氟苯并呋喃-4-基)乙-1-酮(0404-27)(0.27g，1.52mmol，1.0当量)，甲硫醇钠(40％，0.53g，3.04mmol，2.0当量)和二甲亚砜(5ml)，室温下反应1小时。反应液加水(50mL)稀释，用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝15：1)得到淡黄色固体1-(7-(甲硫基)苯并呋喃-4-基)乙-1-酮(0.29g，收率：93％)。LCMS(ESI)：m/z 207[M+1] +。
步骤9e:(E)-3-(4-羟基-3,5-二甲基苯基)-1-(7-(甲硫基)苯并呋喃-4-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(7-(methylthio)benzofuran-4-yl)prop-2-en-1-one)(化合物0406-27)的制备:往1-(7-(甲硫基)苯并呋喃-4-基)乙-1-酮(0405-27)(290mg，1.41mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(210mg，1.41mmol，1.0当量)的乙醇溶液(8ml)中缓慢滴加浓硫酸(2mL)，室温下反应3.5小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩得到黄色固体产物(E)-3-(4-羟基-3,5-二甲基苯基)-1-(7-(甲硫基)苯并呋喃-4-基)丙-2-烯-1-酮(0.47g)。LCMS(ESI)：m/z 339[M+1] +。
步骤9f:(E)-2-(2,6-二甲基-4-(3-(7-(甲硫基)苯并呋喃-4-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dimethyl-4-(3-(7-(methylthio)benzofuran-4-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(化合物0407-27)的制备:将(E)-3-(4-羟基-3,5-二甲基苯基)-1-(7-(甲硫基)苯并呋喃-4-基)丙-2-烯-1-酮(0406-27)(0.47g,1.39mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(1.56mL,8.34mmol,6.0当量)溶于乙腈(10mL)中，然后加入碳酸钾(0.77g,5.56mmol,4.0当量)。用氮气置换反应体系中的空气三遍，然后在83℃下反应过夜。反应完成后浓缩得到粗产品，通过硅胶柱层析法(石油醚：乙酸乙酯＝10：1)纯化得淡黄色固体产物(E)-2-(2,6-二甲基-4-(3-(7-(甲硫基)苯并呋喃-4-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(234mg，收率：35％)。LCMS(ESI)：m/z 481[M+1] +。
步骤9g:(E)-2-(2,6-二甲基-4-(3-(7-(甲硫基)苯并呋喃-4-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(7-(methylthio)benzofuran-4-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物27)的制备:室温下往(E)-2-(2,6-二甲基-4-(3-(7-(甲硫基)苯并呋喃-4-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(0407-27)(234mg，0.487mmol，1.0当量)的二氧六环溶液(8ml)中缓慢滴加浓硫酸(1mL)，室温下反应1.5小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(二氯甲烷：甲醇＝20：1)得到淡黄色固体产物(E)-2-(2,6-二甲基-4-(3-(7-(甲硫基)苯并呋喃-4-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(160mg，收率：77％)。LCMS(ESI)：m/z 425[M+1] +；熔点：162～165℃； 1HNMR(DMSO-d 6，500MHz)：δ12.95(s,1H),8.26-8.21(m,2H),7.89(d,J＝8.4Hz,1H),7.63(d,J＝5.6Hz,1H),7.58-7.54(m,3H),7.32(d,J＝8.0Hz,1H),2.70(s,3H),2.23(s,6H),1.40(s,6H)。
实施例10：(E)-2-(4-(3-(2,3-二氢苯并[b]噻吩-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)甲基丙酸((E)-2-(4-(3-(2,3-dihydrobenzo[b]thiophen-5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物36)的制备(按照方案五线路制备)
步骤10a:苯并[b]噻吩1,1-二氧化物(benzo[b]thiophene 1,1-dioxide)(化合物0502-36)的制备:往苯并噻吩(0501-36)(2.0g，15mmol，1.0当量)的二氯甲烷溶液(20ml)分别加入30％的过氧化氢溶液(6ml)和甲酸(4ml)，反应室温搅拌过夜。加入碳酸氢钠溶液(100ml),用二氯甲烷(100ml×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液旋干，得到白色固体产物苯并[b]噻吩1,1-二氧化物(4.0g，收率：99％)。LCMS(ESI)：m/z 167[M+1] +。
步骤10b:2,3-二氢苯并[b]噻吩1,1-二氧化物(2,3-dihydrobenzo[b]thiophene 1,1-dioxide)(化合物0503-36)的制备:往苯并[b]噻吩1,1-二氧化物(0502-36)(4.0g,22.5mmol)的甲醇(80ml)和乙酸乙酯(80ml)溶液中加入钯炭(1.0g)并通入氢气，室温下搅拌过夜，将反应液过滤，旋干得到白色固体产物2,3-二氢苯并[b]噻吩1,1-二氧化物粗产物(3.80g，收率：99％)。LCMS(ESI)：m/z 169[M+1] +。
步骤10c:2,3-二氢苯并[b]噻吩(2,3-dihydrobenzo[b]thiophene)(化合物0504-36)的制备:在0℃下，往四氢铝锂(3.8g，100mmol，4.5当量)的四氢呋喃(150ml)溶液中滴加苯并[b]噻吩1,1-二氧化物(0503-36)(3.8g，23mmol，1.0当量)的四氢呋喃溶液(50ml)，反应液恢复至室温过夜。反应液冷却至0℃，分别慢慢加入水(3.8ml),15％氢氧化钠溶液(12ml)和水(3.8ml)，搅拌半小时，将溶液过滤，滤液旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝20:1)得到无色油状物产物2,3-二氢苯并[b]噻吩(0.91g，收率：29％)。LCMS(ESI)：m/z 137[M+1] +。
步骤10d:1-(2,3-二氢苯并[b]噻吩-5-基)乙-1-酮(1-(2,3-dihydrobenzo[b]thiophen-5-yl)ethan-1-one)(化合物0505-36)的制备:在0℃下往2,3-二氢苯并[b]噻吩(0504-36)(0.78g，6mmol，1.0当量)和乙酰氯(0.94g，10mmol，2.0当量)的二氯甲烷(40ml)溶液中加入三氯化铝(0.96g，7.2mmol，1.2当量)，将反应液在0℃下搅拌反应半小时。回入1N盐酸(20ml)，搅拌半小时，两相分层，水相用二氯甲烷萃取(50ml×2),有机相合并旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝10:1)得到黄色油状物产物1-(2,3-二氢苯并[b]噻吩-5-基)乙-1-酮(0.99g，收率：79％)。LCMS(ESI)：m/z 179[M+1] +。
步骤10e:(E)-1-(2,3-二氢苯并[b]噻吩-5-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮((E)-1-(2,3-dihydrobenzo[b]thiophen-5-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one)(化合物0506-36)的制备:往1-(2,3-二氢苯并[b]噻吩-5-基)乙-1-酮(0505-36)(0.81g，4.6mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(0.69g，4.6mmol，1.0当量)的乙醇溶液(20ml)中慢慢加入浓硫酸(4ml)，反应室温搅拌过夜。反应液用乙酸乙酯(150ml)稀释，用半饱和食盐水洗涤(100ml×3)，有机相旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝6:1)得到黄色固体产物(E)-1-(2,3-二氢苯并[b]噻吩-5-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(0.45g，收率：26％)。LCMS(ESI)：m/z 311[M+1] +。
步骤10f:(E)-2-(4-(3-(2,3-二氢苯并[b]噻吩-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(4-(3-(2,3-dihydrobenzo[b]thiophen-5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate)(化合物0507-36)的制备:往(E)-1-(2,3-二氢苯并[b]噻吩-5-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(0506-36)(0.45g，1.5mmol，1.0当量)的乙腈(30ml)溶液中加入碳酸钾(1.04g，7.5mmol，5.0当量)和2-溴代异丁酸叔丁酯(1.67g，7.5mmol，5.0当量)，将反应液在氮气的保护下加热至82℃回流过夜。反应液旋干，剩余物用乙酸乙酯(100ml)稀释，用水(100ml×2)洗，有机相旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝20:1)得到黄色油状物产物(E)-2-(4-(3-(2,3-二氢苯并[b]噻吩-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(0.18g，收率：27％)。LCMS(ESI)：m/z 453[M+1] +。
步骤10g:(E)-2-(4-(3-(2,3-二氢苯并[b]噻吩-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)甲基丙酸((E)-2-(4-(3-(2,3-dihydrobenzo[b]thiophen-5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物36)的制备:往(E)-2-(4-(3-(2,3-二氢苯并[b]噻吩-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(0507-36)(0.18g，0.40mmol，1.0当量)的二氯甲烷(12ml)溶液中缓慢加入三氟乙酸(2ml)，反应液室温下搅拌过夜。将反应液倒入水(100ml)中，用二氯甲烷(100ml×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液旋干，剩余物用硅胶柱层析法纯化(洗脱剂：二氯甲烷：甲醇：甲酸＝300:3:0.5)得到黄色固体产物(E)-2-(4-(3-(2,3-二氢苯并[b]噻吩-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)甲基丙酸(150mg，收率：95.0％)。LCMS(ESI)：m/z 397[M+1] +；熔点：157～160℃； 1HNMR(DMSO，500MHz)：δ12.57(s，1H)，7.40-8.01(m，7H)，3.44-3.46(t，2H，J＝7.5Hz)，3.33-3.37(t，2H，J＝7.5Hz)，2.22(s，6H)，1.39(s，6H)。
实施例11：(E)-2-(4-(3-(苯并[b]噻吩-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(benzo[b]thiophen-5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物38)的制备(按照方案六线路制备)
步骤11a:苯并[b]噻吩-5-腈(benzo[b]thiophene-5-carbonitrile)(化合物0602-38)的制备:往反应瓶中加入5-溴苯并[b]噻吩(0601-38)(2.13g，10mmol，1.0当量)，氰化锌(2.34g，20mmol，2.0当量)，四三苯基膦钯(1.16g，1mmol，0.1当量)和二甲基甲酰胺(16ml)，反应回流搅拌过夜。反应液用乙酸乙酯(200ml)稀释，用半饱和食盐水(100ml×3)洗涤，有机相旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝10:1)得到白色固体产物苯并[b]噻吩-5-腈(1.57g，收率：99％)。LCMS(ESI)：m/z 160[M+1] +。
步骤11b:1-(苯并[b]噻吩-5-基)乙-1-酮(1-(benzo[b]thiophen-5-yl)ethan-1-one)(化合物0603-38)的制备:在0℃下往苯并[b]噻吩-5-腈(0602-38)(1.41g,8.9mmol,1.0当量)的四氢呋喃(30ml)溶液中加入3M甲基溴化镁(10.7mmol,1.2当量)，恢复至室温搅拌过夜，加入饱和氯化铵溶液(100ml),用二氯甲烷萃取(1 00ml×2),有机相合并旋干，剩余物溶于二氧六环(30ml)中，加入10％硫酸(30ml),加热回流过夜。反应液冷却至室温，用二氯甲烷萃取(100ml×2)，有机相合并旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝10:1)得到白色固体产物1-(苯并[b]噻吩-5-基)乙-1-酮(0.99g，收率：63％)。LCMS(ESI)：m/z 177[M+1] +。
步骤11c:(E)-1-(苯并[b]噻吩-5-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮((E)-1-(benzo[b]thiophen-5-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one)(化合物0604-38)的制备:往1-(苯并[b]噻吩-5-基)乙-1-酮(0603-38)(0.81g，4.6mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(0.69g，4.6mmol，1.0当量)的二氧六环溶液(20ml)中慢慢加入浓硫酸(4ml)，反应加热到50℃搅拌过夜。反应液用乙酸乙酯(100ml)稀释，用半饱和食盐水洗涤(100ml×3)，有机相旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝5:1)得到黄色固体产物(E)-1-(苯并[b]噻吩-5-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(0.22g，收率：16％)。LCMS(ESI)：m/z 309[M+1] +。
步骤11d:(E)-2-(4-(3-(苯并[b]噻吩-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(4-(3-(benzo[b]thiophen-5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate)(化合物0605-38)的制备:往(E)-1-(苯并[b]噻吩-5-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(0604-38)(0.22g，0.72mmol，1.0当量)的乙腈(20ml)溶液中加入碳酸钾(0.497g，3.6mmol，5.0当量)和2-溴代异丁酸叔丁酯(0.796g，3.6mmol，5.0当量)，将反应液在氮气的保护下加热至82℃回流过夜。反应液旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝10:1)得到黄色油状物产物(E)-2-(4-(3-(苯并[b]噻吩-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(0.11g，收率：34％)。LCMS(ESI)：m/z 451[M+1] +。
步骤11e:(E)-2-(4-(3-(苯并[b]噻吩-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(benzo[b]thiophen-5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物38)的制备:往(E)-2-(4-(3-(苯并[b]噻吩-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(0605-38)(0.11g，0.24mmol，1.0当量)的二氯甲烷(20ml)溶液中缓慢加入三氟乙酸(1ml)，反应液室温下搅拌过夜。将反应液倒入水(100ml)中，用二氯甲烷(100ml×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液旋干，剩余物用硅胶柱层析法纯化(洗脱剂：二氯甲烷：甲醇：甲酸＝300:3:0.5)得到黄色固体产物(E)-2-(4-(3-(苯并[b]噻吩-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(100mg，收率：99.0％)。LCMS(ESI)：m/z 395[M+1] +；熔点：150～152℃； 1HNMR(DMSO，500MHz)：δ12.92(s，1H)，8.78(d,1H,J＝3Hz),8.20(d,1H,J＝8.7Hz),8.10(dd，1H,J 1＝8.7Hz,J 2＝1.5Hz)，7.97(m,2H),7.70(m,4H),2.23(s，6H)，1.40(s，6H)。
实施例12：(E)-2-(4-(3-(苯并[d]噻唑-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(benzo[d]thiazol-5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物39)的制备(按照方案六线路制备)
步骤12a:(E)-1-(苯并[d]噻唑-5-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮((E)-1-(benzo[d]thiazol-5-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one)(化合物0604-39)的制备:往1-(苯并[d]噻唑-5-基)乙-1-酮(0603-39)(0.23g，1.30mmol，1.0当量)的乙醇(10ml)和1,4-二氧六环(2ml)混合溶液中加入4-羟基-3,5-二甲基苯甲醛(0.21g，1.43mmol，1.1当量)，再滴加98％硫酸(3ml)，反应液室温下反应过夜。补加乙醇(8ml)，继续在室温下反应5小时。补加4-羟基-3,5-二甲基苯甲醛(0.10g，0.65mmol，0.5当量)和98％硫酸(2ml)，反应液在室温下搅拌过夜。将反应液剩余用乙酸乙酯(100ml)稀释，用水(100ml×2)洗，有机相旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝4：1→二氯甲烷：甲醇＝40：1)得到黄色固体产物((E)-1-(苯并[d]噻唑-5-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(0.35g，收率：80.7％)。LCMS(ESI)：m/z 310[M+1] +。
步骤12b:(E)-2-(4-(3-(苯并[d]噻唑-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(4-(3-(benzo[d]thiazol-5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate)(化合物0605-39)的制备:往((E)-1-(苯并[d]噻唑-5-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(0604-39)(0.30g，0.97mmol，1.0当量)的N,N-二甲基甲酰胺(15ml)溶液中加入碳酸钾(0.54g，3.38mmol，4.0当量)和2-溴代异丁酸叔丁酯(1.30g，5.82mmol，6.0当量)，将反应液在氮气的保护下加热至82℃回流0.75天。将反应液用乙酸乙酯(300ml)稀释，用半饱和食盐水(300ml×3)洗，有机相旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝4:1)得到浅黄色固体产物(E)-2-(4-(3-(苯并[d]噻唑-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(0.24g，收率：47.1％)。LCMS(ESI)：m/z 452[M+1] +。
步骤12c:(E)-2-(4-(3-(苯并[d]噻唑-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(benzo[d]thiazol-5-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物39)的制备:往(E)-2-(4-(3-(苯并[d]噻唑-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙 酸叔丁酯(0605-39)(0.24g，0.53mmol，1.0当量)的二氯甲烷(12ml)溶液中缓慢加入三氟乙酸(3ml)，反应液室温下搅拌3小时。将反应液倒入水(100ml)中，用二氯甲烷(100ml×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液旋干，剩余物用甲醇带旋一次得到黄色固体产物(E)-2-(4-(3-(苯并[d]噻唑-5-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(210mg，收率：100％)。LCMS(ESI)：m/z 396[M+1] +；熔点：170～172℃； 1HNMR(DMSO，500MHz)：δ12.94(s，1H)，9.56(s，1H)，8.98(s，1H)，8.35-8.38(d，1H，J＝11Hz)，8.20-8.23(dd，1H，J 1＝10.5Hz，J 2＝1.5Hz)，8.02-8.06(d，1H，J＝19Hz)，7.69-7.73(d，1H，J＝19Hz)，7.65(s，2H)，2.24(s，6H)，1.40(s，6H)。
实施例13：(E)-2-(4-(3-(6-甲氧基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(6-methoxybenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物43)的制备(按照方案七线路制备)
步骤13a:1-(6-甲氧基苯并呋喃-2-基)乙-1-酮(1-(6-methoxybenzofuran-2-yl)ethan-1-one)(化合物0706-43)的制备:将2-羟基-4-甲氧基苯甲醛(0701-43)(0.3g,1.97mmol,1.0当量)和溴丙酮(0.17mL,1.97mmol,1.0当量)溶于N,N-二甲基甲酰胺(6mL)中，然后加入碳酸铯(0.96g,2.96mmol,1.5当量)。用氮气置换三遍然后在60℃下反应过夜。反应液加水(50mL)稀释，然后用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝6：1)得到白色固体产物1-(6-甲氧基苯并呋喃-2-基)乙-1-酮(0.308g，收率：82％)。LCMS(ESI)：m/z 191[M+1] +。
步骤13b:(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-甲氧基苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(6-methoxybenzofuran-2-yl)prop-2-en-1-one)(化合物0707-43)的制备：往1-(6-甲氧基苯并呋喃-2-基)乙-1-酮(0706-43)(200mg，1.053mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(158mg，1.053mmol，1.0当量)的乙醇溶液(8ml)中缓慢滴加浓硫酸(2mL)，室温下反应5小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩得到黄色固体产品(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-甲氧基苯并呋喃-2-基)丙-2-烯-1-酮(339mg)。LCMS(ESI)：m/z323[M+1] +。
步骤13c:(E)-2-(4-(3-(6-甲氧基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(4-(3-(6-methoxybenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate)(化合物0708-43)的制备:将(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-甲氧基苯并呋喃-2-基)丙-2-烯-1-酮(0707-43)(339mg,1.053mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(1.15mL,6.32mmol,6.0当量)溶于乙腈(10mL)中，然后加入碳酸钾(0.58g,4.21mmol,4.0当量)。用氮气置换反应体系中的空气三遍，然后在83℃下反应过夜。反应完成后浓缩得到粗产品，通过硅胶柱层析法(石油醚：乙酸乙酯＝8：1)纯化得黄色固体产物(E)-2-(4-(3-(6-甲氧基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(158mg，收率：28％)。LCMS(ESI)：m/z 465[M+1] +
步骤13d:(E)-2-(4-(3-(6-甲氧基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(6-methoxybenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物43)的制备:室温下往(E)-2-(4-(3-(6-甲氧基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(0708-43)(158mg，0.341mmol，1.0当量)的二氧六环溶液(8ml)中缓慢滴加浓硫酸(1mL)，室温下反应1.5小时。反应液加水(20mL)稀释，然后用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(二氯甲烷：甲醇＝20：1)得到黄色固体产物(E)-2-(4-(3-(6-甲氧基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(87mg，收率：63％)。LCMS(ESI)：m/z 409[M+1] +；熔点：177～179℃； 1HNMR(DMSO-d 6，400MHz)：δ12.94(s,1H),8.23(s,1H),7.76-7.64(m,3H),7.57(s,2H),7.35(d,J＝1.6Hz,1H),7.04-7.01(m,1H),3.87(s,3H),2.23(s,6H),1.40(s,6H)。
实施例14：(E)-2-(4-(3-(苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(benzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物49)的制备(按照方案七线路制备)
步骤14a:苯并呋喃-2-乙酮(1-(benzofuran-2-yl)ethan-1-one)(化合物0706-49)的制备：将2-羟基苯甲醛(0701-49)(0.36g,2.95mmol,1.0当量)和溴丙酮(0.24mL,2.95mmol,1.0当量)溶于N,N-二甲基甲酰胺(6mL)中，然后加入碳酸铯(1.25g,3.84mmol,1.5当量)。用氮气反应体系中的空气三遍，三遍然后在60℃下反应过夜。反应液加水(50mL)稀释，然后用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝10：1)得到白色固体产物苯并呋喃-2-乙酮(0.356g，收率：75％)。LCMS(ESI)：m/z 161[M+1] +。
步骤14b:E)-1-(苯并呋喃-2-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮((E)-1-(benzofuran-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one)(化合物0707-49)的制备：往苯并呋喃-2-乙酮(0706-49)(200mg，1.25mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(188mg，1.25mmol，1.0当量)的乙醇溶液(8 ml)中缓慢滴加浓硫酸(2mL)，室温下反应5小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩得到黄色固体产物(E)-1-(苯并呋喃-2-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(365mg)。LCMS(ESI)：m/z 293[M+1] +。
步骤14c:(E)-2-(4-(3-(苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(4-(3-(benzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate)(化合物0708-49)的制备：将(E)-1-(苯并呋喃-2-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(0707-49)(365mg,1.25mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(1.37mL,7.5mmol,6.0当量)溶于乙腈(10mL)中，然后加入碳酸钾(0.69g,5.0mmol,4.0当量)。用氮气置换反应体系中的空气三遍，然后在83℃下反应过夜。反应完成后浓缩得到粗产品，通过硅胶柱层析法(石油醚：乙酸乙酯＝10：1)纯化得黄色固体产物(E)-2-(4-(3-(苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(163mg，收率：30％)。LCMS(ESI)：m/z 435[M+1] +。
步骤14d:(E)-2-(4-(3-(苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(benzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methyl propanoic acid)(化合物49)的制备：室温下往(E)-2-(4-(3-(苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(0708-49)(163mg，0.375mmol，1.0当量)的二氧六环溶液(8ml)中缓慢滴加浓硫酸(1mL)，室温下反应1.5小时。反应液加水(20mL)稀释，然后用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(二氯甲烷：甲醇＝20：1)得到黄色固体产物(E)-2-(4-(3-(苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(91mg，收率：64％)。。LCMS(ESI)：m/z 379[M+1] +，熔点：157～160℃； 1HNMR(DMSO-d 6，400MHz)：δ12.95(s,1H),8.29(s,1H),7.88(d,J＝8.0Hz,1H),7.80-7.69(m,3H),7.59-7.56(m,3H),7.42-7.39(m,1H),2.24(s,6H),1.40(s,6H)。
实施例15：(E)-2-(2,6-二甲基-4-(3-(6-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(6-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物50)的制备(按照方案七线路制备)
步骤15a:1-(6-甲基苯并呋喃-2-基)乙-1-酮(1-(6-methylbenzofuran-2-yl)ethan-1-one)(化合物0706-50)的制备:将2-羟基-4-甲基苯甲醛(0701-50)(0.3g,2.20mmol,1.0当量)和溴丙酮(0.18mL,2.20mmol,1.0当量)溶于N,N-二甲基甲酰胺(6mL)中，然后加入碳酸铯(1.08g,3.31mmol,1.5当量)。用氮气置换反应体系中的空气三遍，然后在60℃下反应过夜。反应液加水(50mL)稀释，然后用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝10：1)得到白色固体产物1-(6-甲基苯并呋喃-2-基)乙-1-酮(0.305g，收率：80％)。LCMS(ESI)：m/z 175[M+1] +。
步骤15b:(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-甲基苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(6-methylbenzofuran-2-yl)prop-2-en-1-one)(化合物0707-50)的制备：往1-(6-甲基苯并呋喃-2-基)乙-1-酮(0706-50)(200mg，1.15mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(172mg，1.15mmol，1.0当量)的乙醇溶液(8ml)中缓慢滴加浓硫酸(2mL)，室温下反应5小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩得到黄色固体产物(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-甲基苯并呋喃-2-基)丙-2-烯-1-酮(352mg)。LCMS(ESI)：m/z 307[M+1] +。
步骤15c:(E)-2-(2,6-二甲基-4-(3-(6-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dimethyl-4-(3-(6-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(化合物008-50)的制备：将(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-甲基苯并呋喃-2-基)丙-2-烯-1-酮(0707-50)(352mg,1.15mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(1.26mL,6.9mmol,6.0当量)溶于乙腈(10mL)中，然后加入碳酸钾(0.63g,4.6mmol,4.0当量)。用氮气置换反应体系中的空气三遍，然后在83℃下反应过夜。反应完成后浓缩得到粗产品，通过硅胶柱层析法(石油醚：乙酸乙酯＝15：1)纯化得黄色固体产物(E)-2-(2,6-二甲基-4-(3-(6-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(175mg，收率：34％)。LCMS(ESI)：m/z 449[M+1] +。
步骤15d:(E)-2-(2,6-二甲基-4-(3-(6-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(6-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物50)的制备:室温下往(E)-2-(2,6-二甲基-4-(3-(6-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(0708-50)(175mg，0.391mmol，1.0当量)的二氧六环溶液(8ml)中缓慢滴加浓硫酸(1mL)，室温下反应1.5小时。反应液加水(20mL)稀释，然后用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(二氯甲烷：甲醇＝20：1)得到黄色固体产物(E)-2-(2,6-二甲基-4-(3-(6-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(89mg，收率：58％)。LCMS(ESI)：m/z 393[M+1] +；熔点：180～182℃； 1HNMR(DMSO-d 6，400MHz)：δ12.96(s,1H),8.25(s,1H),7.77-7.57(m,3H),7.57(d,J＝6.8Hz,3H),7.24(d,J＝8.0Hz,1H),2.49(s,3H),2.24(s,6 H),1.40(s,6H)。
实施例16：(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物51)的制备(按照方案七线路制备)
步骤16a:6-溴苯并呋喃-2-甲酸乙酯(ethyl 6-bromobenzofuran-2-carboxylate)(化合物0702-51)的制备:往烧瓶中加入4-溴-2-羟基苯甲醛(0701-51)(2.5g,12.44mmol,1.0当量)，碳酸钾(6.86g,49.75mmol,4.0当量)和溴乙酸乙酯(4.13mL,37.32mmol,3.0当量)，然后在130℃下反应4.5小时。反应液冷却到室温并加水(50mL)稀释，然后用乙酸乙酯(40mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝30：1)得到白色固体产物6-溴苯并呋喃-2-甲酸乙酯(1.09g，收率：33％)。LCMS(ESI)：m/z 269[M+1] +。
步骤16b:6-溴苯并呋喃-2-甲酸(6-bromobenzofuran-2-carboxylic acid)(化合物0703-51)的制备:往反应瓶中加入6-溴苯并呋喃-2-甲酸乙酯(0702-51)(1.09g，4.05mmol，1.0当量)，氢氧化钠(0.65g，16.21mmol，4.0当量)，四氢呋喃(12mL)和水(10mL)，45℃下搅拌2小时。反应液加水(20mL)稀释，滴加1N稀盐酸溶液调节pH值为5，然后用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩得到黄色固体产物6-溴苯并呋喃-2-甲酸(0.89g，收率：91％)。LCMS(ESI)：m/z 241[M+1] +。
步骤16c:6-溴-N-甲氧基-N-甲基苯并呋喃-2-甲酰胺(6-bromo-N-methoxy-N-methylbenzofuran-2-carboxamide)(化合物0704-51)的制备:将(6-溴苯并呋喃-2-甲酸(0703-51)(0.89g，3.69mmol，1.0当量)、N,O-二甲基羟胺盐酸盐(0.47g，4.80mmol，1.3当量)、HATU(1.68g，4.43mmol，1.2当量)和三乙胺(1.28mL，9.23mmol，2.5当量)溶于二氯甲烷(20mL)，然后在室温下反应1小时。反应液加水(20mL)稀释，用二氯甲烷(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝5：1)得到白色固体产物6-溴-N-甲氧基-N-甲基苯并呋喃-2-甲酰胺(1.07g，收率：100％)。LCMS(ESI)：m/z 284[M+1] +。
步骤16d:1-(6-溴苯并呋喃-2-基)乙-1-酮(1-(6-bromobenzofuran-2-yl)ethan-1-one)(化合物0705-51)的制备:将6-溴-N-甲氧基-N-甲基苯并呋喃-2-甲酰胺(0704-51)(1.05g，3.70mmol，1.0当量)溶于干燥的四氢呋喃(15mL)中并在冰水浴中冷却到0℃。甲基溴化镁(3M乙醚溶液，2.46mL，7.39mmol，2.0当量)逐滴缓慢地滴加进去。反应液升到室温并继续反应1小时。加入饱和氯化铵溶液(30mL)淬灭反应，用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩得到白色固体产物1-(6-溴苯并呋喃-2-基)乙-1-酮(0.81g，收率：92％)。LCMS(ESI)：m/z 239[M+1] +。
步骤16e1-(6-(甲硫基)苯并呋喃-2-基)乙-1-酮(1-(6-(methylthio)benzofuran-2-yl)ethan-1-one)(化合物0706-51)的制备:往烧瓶中加入1-(6-溴苯并呋喃-2-基)乙-1-酮(0705-51)(0.75g,3.14mmol,1.0当量)，二甲基二硫(1.11mL,12.56mmol,4.0当量)，铜粉(1.69g,26.67mmol,8.5当量)和N,N-二甲基甲酰胺(15mL))，然后在氮气保护下加热到140℃反应24小时。反应液冷却到室温并加水(50mL)稀释，然后用乙酸乙酯(40mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝30：1)得到淡黄色固体产物1-(6-(甲硫基)苯并呋喃-2-基)乙-1-酮(0.142g，收率：22％)。LCMS(ESI)：m/z 207[M+1] +。
步骤16f:(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(6-(methylthio)benzofuran-2-yl)prop-2-en-1-one)(0707-51)的制备:往1-(6-(甲硫基)苯并呋喃-2-基)乙-1-酮(0706-51)(50mg，0.243mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(37mg，0.243mmol，1.0当量)的乙醇溶液(4ml)中缓慢滴加浓硫酸(1mL)，室温下反应3.5小时。反应液加水(20mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩得到黄色固体产物(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(82mg)。LCMS(ESI)：m/z 339[M+1] +。
步骤16g:(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(化合物0708-51)的制备:将(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(0707-51)(82mg,0.243mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(0.27mL,1.458mmol,6.0当量)溶于乙腈(6mL)中，然后加入碳酸钾(0.134g,0.972mmol,4.0当量)。用氮气置换反应体系中的空气三遍，然后在83℃下反应24小时。反应完成后浓缩得到粗产品，通过硅胶柱层析法(石油醚：乙酸乙酯＝10：1)纯化得黄色固体产物(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(35mg，收率：30％)。LCMS(ESI)：m/z 481[M+1] +。
步骤16h:(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpro panoic acid)(化合物51)的制备:室温下往(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(0708-51)(35mg，0.073mmol，1.0当量)的二氧六环(5ml)溶液中缓慢滴加浓硫酸(0.5mL)，室温下反应1.5小时。反应液加水(20mL)稀释，然后用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(二氯甲烷：甲醇＝20：1)得到黄色固体产物(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(25mg，收率：81％)。LCMS(ESI)：m/z 425[M+1] +；熔点：180～182℃； 1HNMR(DMSO-d 6，400MHz)：δ12.96(s,1H),8.24(s,1H),7.78-7.64(m,4H),7.58(s,2H),7.30-7.27(m,1H),2.59(s,3H),2.23(s,6H),1.40(s,6H)。
实施例17：(E)-2-甲基-2-(4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代-1-烯-1-基)苯氧基)丙酸((E)-2-methyl-2-(4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)propanoic acid)(化合物56)的制备(按照方案七线路制备)
步骤17a:(E)-3-(4-羟基苯基)-1-(6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxyphenyl)-1-(6-(methylthio)benzofuran-2-yl)prop-2-en-1-one)(化合物0707-56)的制备：往1-(6-(甲硫基)苯并呋喃-2-基)乙-1-酮(0706-51)(95mg，0.461mmol，1.0当量)和4-羟基苯甲醛(56mg，0.461mmol，1.0当量)的乙醇溶液(8ml)中缓慢滴加浓硫酸(2mL)，室温下反应过夜。反应液加水(20mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩得到黄色固体产物(E)-3-(4-羟基苯基)-1-(6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(143mg)。LCMS(ESI)：m/z 311[M+1] +。
步骤17b:(E)-2-甲基-2-(4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代-1-烯-1-基)苯氧基)丙酸叔丁酯(tert-butyl(E)-2-methyl-2-(4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)propanoate)(化合物0708-56)的制备:将(E)-3-(4-羟基苯基)-1-(6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(0707-56)(143mg,0.461mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(0.42mL,2.306mmol,5.0当量)溶于乙腈(8mL)中，然后加入碳酸钾(0.25g,1.844mmol,4.0当量)。用氮气置换反应体系中的空气三遍，然后在83℃下反应过夜。反应完成后浓缩得到粗产品，通过硅胶柱层析法(石油醚：乙酸乙酯＝10：1)纯化得黄色固体产物(E)-2-甲基-2-(4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代-1-烯-1-基)苯氧基)丙酸叔丁酯(98mg，收率：47％)。LCMS(ESI)：m/z 453[M+1] +。
步骤17c:(E)-2-甲基-2-(4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代-1-烯-1-基)苯氧基)丙酸((E)-2-methyl-2-(4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)propanoic acid)(化合物56)的制备:室温下往(E)-2-甲基-2-(4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代-1-烯-1-基)苯氧基)丙酸叔丁酯(0708-56)(98mg，0.217mmol，1.0当量)的二氧六环(8ml)溶液中缓慢滴加浓硫酸(1mL)，室温下反应2小时。反应液加水(20mL)稀释，然后用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(二氯甲烷：甲醇＝20：1)得到黄色固体产物(E)-2-甲基-2-(4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代-1-烯-1-基)苯氧基)丙酸(70mg，收率：81％)。LCMS(ESI)：m/z 397[M+1] +；熔点：218～220℃； 1HNMR(DMSO-d 6，400MHz)：δ13.24(s,1H),8.21(s,1H),7.84-7.74(m,5H),7.63(s,1H),7.30-7.27(m,1H),6.88(d,J＝8.4Hz,2H),2.59(s,3H),1.58(s,6H)。
实施例18：(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)乙酸((E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)acetic acid)(化合物57)的制备(按照方案七线路制备)
步骤18a:(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代-1-烯-1-基)苯氧基)乙酸叔丁酯(tert-butyl(E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)acetate)(化合物0708-57)的制备:将(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(0707-51)(112mg,0.331mmol,1.0当量)和溴乙酸叔丁酯(0.21mL,1.325mmol,6.0当量)溶于乙腈(8mL)中，然后加入碳酸钾(0.183g,1.325mmol,4.0当量)。用氮气置换反应体系中的空气三遍，然后在83℃下反应过夜。反应完成后浓缩得到粗产品，通过硅胶柱层析法(石油醚：乙酸乙酯＝10：1)纯化得黄色固体产物(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代-1-烯-1-基)苯氧基)乙酸叔丁酯(60mg，收率：40％)。LCMS(ESI)：m/z 453[M+1] +。
步骤18b:(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)乙酸((E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)acetic acid)(化合物57)的制备:室温下往(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代-1-烯-1-基)苯氧基)乙酸叔丁酯(0708-57)(60mg，0.133mmol，1.0当量)的二氧六环(5ml)溶液中缓慢滴加浓硫酸(0.5mL)，室温下反应1.5小时。反应液加水(20mL)稀释，然后用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(二氯甲烷：甲醇＝20：1)得到黄色固体(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)乙酸(30mg，收率：57％)。LCMS(ESI)：m/z 397[M+1] +；熔点：220～223℃； 1HNMR(DMSO-d 6，400MHz)：δ12.96(s,1H),8.25(s,1H),7.7 9-7.70(m,3H),7.66-7.59(m,3H),7.30-7.28(m,1H),4.45(s,2H),2.59(s,3H),2.30(s,6H)。
实施例19：(E)-2-(2,6-二甲基-4-(3-(7-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(7-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物58)的制备(按照方案八线路制备)
步骤19a:1-(7-溴苯并呋喃-2-基)乙-1-酮(1-(7-bromobenzofuran-2-yl)ethan-1-one)(化合物0802-58)的制备:将3-溴-2-羟基苯甲醛(0801-58)(2.39g,11.9mmol,1.0当量)和溴丙酮(1.63g,11.9mmol,1.0当量)溶于N,N-二甲基甲酰胺(20mL)中，然后加入碳酸铯(5.82g,17.85mmol,1.2当量)。用氮气置换反应体系中的空气三遍，然后在60℃下反应过夜。反应液加水(50mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝10：1)得到白色固体产物1-(7-溴苯并呋喃-2-基)乙-1-酮(1.37g，收率：40％)。LCMS(ESI)：m/z 239[M+1] +。
步骤19b:1-(7-(甲硫基)苯并呋喃-2-基)乙-1-酮(1-(7-(methylthio)benzofuran-2-yl)ethan-1-one)(化合物0803-58)的制备:往烧瓶中加入1-(7-溴苯并呋喃-2-基)乙-1-酮(0802-58)(1.27g,5.31mmol,1.0当量)，三乙烯二胺(1.19g,10.62mmol,2.0当量)，碘化亚铜(1.01g,5.31mmol,1.0当量)和二甲亚砜(20mL))，然后在氮气保护下加热到170℃反应过夜。反应液冷却到室温并加水(50mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝30：1)得到淡黄色固体产物1-(7-(甲硫基)苯并呋喃-2-基)乙-1-酮(0.35g，收率：30％)。LCMS(ESI)：m/z 207[M+1] +。
步骤19c:(E)-3-(4-羟基-3,5-二甲基苯基)-1-(7-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(7-(methylthio)benzofuran-2-yl)prop-2-en-1-one)(化合物0804-58)的制备:往1-(7-(甲硫基)苯并呋喃-2-基)乙-1-酮(0803-58)(350mg，1.70mmol，1.0当量)，4-羟基-3,5-二甲基苯甲醛(255mg，1.70mmol，1.0当量)的乙醇溶液(8ml)中缓慢滴加浓硫酸(2mL)，室温下反应5小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝5：1)得到黄色固体产物(E)-3-(4-羟基-3,5-二甲基苯基)-1-(7-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(380mg，收率：66％)。LCMS(ESI)：m/z 339[M+1] +。
步骤19d:(E)-2-(2,6-二甲基-4-(3-(7-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dimethyl-4-(3-(7-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(化合物0805-58)的制备:将(E)-3-(4-羟基-3,5-二甲基苯基)-1-(7-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(0804-58)(380mg,1.124mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(1.25mL,6.75mmol,6.0当量)溶于乙腈(10mL)中，然后加入碳酸钾(0.62g,4.50mmol,4.0当量)。用氮气置换反应体系中的空气三遍，然后在83℃下反应过夜。反应完成后浓缩得到粗产品，通过硅胶柱层析法(石油醚：乙酸乙酯＝10：1)纯化得黄色固体产物(E)-2-(2,6-二甲基-4-(3-(7-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(83mg，收率：15％)。LCMS(ESI)：m/z 481[M+1] +。
步骤19e:(E)-2-(2,6-二甲基-4-(3-(7-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(7-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物58)的制备:室温下往(E)-2-(2,6-二甲基-4-(3-(7-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(0805-58)(83mg，0.173mmol，1.0当量)的二氧六环(5ml)溶液中缓慢滴加浓硫酸(0.5mL)，室温下反应2小时。反应液加水(20mL)稀释，然后用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(二氯甲烷：甲醇＝20：1)得到黄色固体产物(E)-2-(2,6-二甲基-4-(3-(7-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(70mg，收率：95％)。LCMS(ESI)：m/z 425[M+1] +；熔点：151～154℃； 1HNMR(DMSO-d 6，400MHz)：δ12.97(s,1H),8.34(s,1H),7.78-7.68(m,3H),7.60(s,2H),7.46-7.38(m,2H),2.63(s,3H),2.24(s,6H),1.40(s,6H)。
实施例20：(E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物60)的制备(按照方案九线路制备)
步骤20a:1-(4-溴苯并呋喃-2-基)乙-1-酮(1-(4-bromobenzofuran-2-yl)ethan-1-one)(化合物0902-60)的制备:将2-溴-6-羟基苯甲醛(0901-60)(2.39g,11.9mmol,1.0当量)和溴丙酮(1.63g,11.9mmol,1.0当量)溶于N,N-二甲基甲酰胺(20mL)中，然后加入碳酸铯(5.82g,17.85mmol,1.2当量)。用氮气置换反应体系中的空气三遍，然后在60℃下反应过夜。反应液加水(50mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝10：1)得到白色固体产物1-(4-溴苯并呋喃-2-基)乙-1-酮(1.44g，收率：42％)。LCMS(ESI)：m/z 239[M+1] +。
步骤20b:1-(4-(甲硫基)苯并呋喃-2-基)乙-1-酮(1-(4-(methylthio)benzofuran-2-yl)ethan-1-one(化 合物0903-60)的制备:往烧瓶中加入1-(4-溴苯并呋喃-2-基)乙-1-酮(0902-60)(1.22g,5.10mmol,1.0当量)，二甲基二硫(2.26mL,25.5mmol,5.0当量)，铜粉(2.76g,43.38mmol,8.5当量)和N,N-二甲基甲酰胺(20mL))，然后在氮气保护下加热到140℃反应过夜。反应液冷却到室温并加水(50mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝30：1)得到淡黄色固体产物1-(4-(甲硫基)苯并呋喃-2-基)乙-1-酮(0.148g，收率：14％)。LCMS(ESI)：m/z 207[M+1] +。
步骤20c:(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(4-(methylthio)benzofuran-2-yl)prop-2-en-1-one)(化合物0904-60)的制备:往1-(4-(甲硫基)苯并呋喃-2-基)乙-1-酮(0903-60)(148mg，0.718mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(108mg，0.718mmol，1.0当量)的乙醇溶液(8ml)中缓慢滴加浓硫酸(2mL)，室温下反应5小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩得到黄色固体(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(217mg，收率：89％)。LCMS(ESI)：m/z 339[M+1] +。
步骤20d:(E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(化合物0905-60)的制备:将(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(0904-60)(217mg,0.642mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(0.71mL,3.85mmol,6.0当量)溶于乙腈(10mL)中，然后加入碳酸钾(0.35g,2.568mmol,4.0当量)。用氮气置换反应体系中的空气三遍，然后在83℃下反应过夜。反应完成后浓缩得到粗产品，通过硅胶柱层析法(石油醚：乙酸乙酯＝10：1)纯化得黄色固体产物(E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(98mg，收率：32％)。LCMS(ESI)：m/z 481[M+1] +。
步骤20e:(E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物60)的制备:室温下往(E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(0905-60)(98mg，0.204mmol，1.0当量)的二氧六环(5ml)溶液中缓慢滴加浓硫酸(0.5mL)，室温下反应1.5小时。反应液加水(20mL)稀释，然后用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(二氯甲烷：甲醇＝20：1)得到黄色固体产物(E)-2-(2,6-二甲基-4-(3-(4-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(63mg，收率：73％)。LCMS(ESI)：m/z 425[M+1] +；熔点：196～198℃； 1HNMR(DMSO-d 6，400MHz)：δ12.96(s,1H),8.36(s,1H),7.87(d,J＝15.6Hz,1H),7.70(d,J＝15.6Hz,1H),7.62(s,2H),7.56-7.52(m,2H),7.26-7.22(m,1H),2.65(s,3H),2.24(s,6H),1.40(s,6H)。
实施例21：(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物62)的制备(按照方案十线路制备)
步骤21a:1-(2-羟基-4-(甲硫基)苯基)乙烷-1-酮(1-(2-hydroxy-4-(methylthio)phenyl)ethan-1-one)(化合物1002-62)的制备:往1-(4-氟-2-羟基苯基)乙-1-酮(1001-62)(2.3g,14.92mmol，1.0当量)的水溶液(3ml)中加入20％的甲硫醇钠水溶液(30ml)，100℃下回流过夜，将反应液用水(150ml)稀释，用稀盐酸调整pH值到5-6,用乙酸乙酯(80ml×2)萃取，再用半饱和食盐水洗涤(50ml×2),有机相旋干得到淡黄色油状产物1-(2-羟基-4-(甲硫基)苯基)乙烷-1-酮粗品(2.69g，收率：98.9％)。LCMS(ESI)：m/z 183[M+1] +。
步骤21b:1-(3-甲基-6-(甲硫基)苯并呋喃-2-基)乙-1-酮(1-(3-methyl-6-(methylthio)benzofuran-2-yl)ethan-1-one)(化合物1003-62)的制备:往反应瓶中加入1-(2-羟基-4-(甲硫基)苯基)乙烷-1-酮(1002-62)(890mg，4.88mmol，1.0当量)和DMF(40ml)，然后加入碳酸铯(4.77g，14.64mmol，3.0当量)和溴丙酮(803mg，5.86mmol，1.2当量)。在80℃下反应过夜。冷却至室温，将反应液倒入水(200ml)中，用乙酸乙酯(100ml×2)萃取，用饱和食盐水洗3次以上，无水硫酸钠干燥，过滤，旋干得到的剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝10:1)得到白色固体产物1-(3-甲基-6-(甲硫基)苯并呋喃-2-基)乙-1-酮(251mg，收率：25.1％)。LCMS(ESI)：m/z 221[M+1] +。
步骤21c:(E)-3-(4-羟基-3,5-二甲基苯基)-1-(3-甲基-6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(3-methyl-6-(methylthio)benzofuran-2-yl)prop-2-en-1-one)(化合物1004-62)的制备:往1-(3-甲基-6-(甲硫基)苯并呋喃-2-基)乙-1-酮(1003-62)(0.22g，1.0mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(0.165g，1.1mmol，1.1当量)的无水乙醇(20ml)溶液中慢慢加入浓硫酸(4ml)，反应室温搅拌1天。反应液倒入冰水中，用二氯甲烷(100ml×2)萃取，用半饱和食盐水洗涤(100ml×3)，无水硫酸钠干燥，有机相旋干得到黄色液体产物((E)-3-(4-羟基-3,5-二甲基苯基)-1-(3-甲基-6-(甲硫基) 苯并呋喃-2-基)丙-2-烯-1-酮粗品(0.334g，收率：94.7％)。LCMS(ESI)：m/z 353[M+1] +。
步骤21d:(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dimethyl-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(化合物1005-62)的制备:往((E)-3-(4-羟基-3,5-二甲基苯基)-1-(3-甲基-6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(1004-62)(0.334g，0.95mmol，1.0当量)的DMF(30ml)溶液中加入碳酸钾(0.393g，2.85mmol，3.0当量)和分3个批次加2-溴代异丁酸叔丁酯(2.11g，9.5mmol，10.0当量)，反应液在氮气的保护下加热至100℃过夜反应。反应液冷却至室温，倒入水中，用乙酸乙酯(100ml×2)萃取，合并有机相，用食盐水洗3次，无水硫酸钠干燥，减压浓缩得到的剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝3:1)得到黄色固体产物(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(0.246g，收率：52.3％)。LCMS(ESI)：m/z 495[M+1] +。
步骤21e:(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物62)的制备:往(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(1005-62)(0.246g，0.497mmol，1.0当量)的二氯甲烷(25ml)溶液中缓慢加入三氟乙酸(2.5ml)，反应液室温下反应过夜。将反应液用二氯甲烷(75ml)稀释，再用水(50ml×2)洗涤，有机相无水硫酸钠干燥，减压旋干，剩余物用硅胶柱层析法纯化(洗脱剂：二氯甲烷：甲醇＝20:1)得到橙色固体产物(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(127mg，收率：58.3％)。LCMS(ESI)：m/z439[M+1] +；熔点：193～196℃； 1HNMR(DMSO，300MHz)：δ12.96(s，1H)，7.26-7.75(m，7H)，2.60(s，3H)，2.58(s，3H)，2.23(s，6H)，1.39(s，6H)。
实施例22：(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并[b]噻吩-2-基)-3-氧代-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)benzo[b]thiophen-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物81)的制备(按照方案七线路制备)
步骤22a:1-(6-(甲硫基)苯并[b]噻吩-2-基)乙-1-酮(1-(6-(methylthio)benzo[b]thiophen-2-yl)ethan-1-one)(化合物0706-81)的制备:往烧瓶中加入2,4-二甲硫基苯甲醛(0701-81)(0.5g,2.53mmol,1.0当量)，溴丙酮(0.53mL,6.33mmol,2.5当量)，氢氧化钡(0.78g,4.55mmol,1.8当量)和二氧六环(10mL)，然后在92℃下反应20小时。反应液冷却到室温并加水(50mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝10：1)得到淡黄色固体产物1-(6-(甲硫基)苯并[b]噻吩-2-基)乙-1-酮(0.44g，收率：78％)。LCMS(ESI)：m/z 223[M+1] +。
步骤22b:(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-(甲硫基)苯并[b]噻吩-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(6-(methylthio)benzo[b]thiophen-2-yl)prop-2-en-1-one)(化合物0707-81)的制备:往1-(6-(甲硫基)苯并[b]噻吩-2-基)乙-1-酮(0706-81)(250mg，1.126mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(169mg，1.126mmol，1.0当量)的乙醇(8ml)溶液中缓慢滴加浓硫酸(2mL)，室温下反应4小时。反应液加水(20mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝5：1)得到黄色固体产物(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-(甲硫基)苯并[b]噻吩-2-基)丙-2-烯-1-酮(0.291g，收率：73％)。LCMS(ESI)：m/z355[M+1] +。
步骤22c:(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并[b]噻吩-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)benzo[b]thiophen-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(化合物0708-81)的制备:将(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-(甲硫基)苯并[b]噻吩-2-基)丙-2-烯-1-酮(0707-81)(291mg,0.822mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(0.91mL,4.93mmol,6.0当量)溶于乙腈(10mL)中，然后加入碳酸钾(0.45g,3.29mmol,4.0当量)。用氮气置换反应体系中的空气三遍，然后在83℃下反应过夜。反应完成后浓缩得到粗产品，通过硅胶柱层析法(石油醚：乙酸乙酯＝10：1)纯化得淡黄色固体产物(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并[b]噻吩-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(183mg，收率：45％)。LCMS(ESI)：m/z 497[M+1] +。
步骤22d:(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并[b]噻吩-2-基)-3-氧代-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)benzo[b]thiophen-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物81)的制备:室温下(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并[b]噻吩-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(0708-81)(183mg，0.369mmol，1.0当量)的二氧六环(5ml)溶液中缓慢滴加浓硫酸(0.5mL)，室温下反应1.5小时。反应液加水(20mL)稀释，然后用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(二氯甲烷：甲醇＝ 20：1)得到淡黄色固体产物(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)苯并[b]噻吩-2-基)-3-氧代-1-烯-1-基)苯氧基)-2-甲基丙酸(130mg，收率：80％)。LCMS(ESI)：m/z 441[M+1] +；熔点：203～205℃； 1H NMR(DMSO-d 6，400MHz)：δ12.98(s,1H),8.67(s,1H),7.94-7.87(m,3H),7.64(d,J＝15.6Hz,1H),7.60(s,2H),7.39-7.37(m,1H),2.59(s,3H),2.24(s,6H),1.40(s,6H)。
实施例23：(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)-1H-吲哚-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)-1H-indol-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物88)的制备(按照方案七线路制备)
步骤23a:1-(6-(甲硫基)-1H-吲哚-2-基)乙-1-酮(1-(6-(methylthio)-1H-indol-2-yl)ethan-1-one)(化合物0706-88)的制备：将2-三氟乙酰氨基-4-甲硫基苯甲醛(0701-88)(1.4g,5.32mmol,1.0当量)和溴丙酮(0.89mL,10.64mmol,2.0当量)溶于二甲亚砜(15mL)中，然后加入碳酸钾(1.47g,10.64mmol,2.0当量)。用氮气置换反应体系中的空气三遍，然后在60℃下反应过夜。反应液加水(50mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(石油醚：乙酸乙酯＝5：1)得到淡黄色固体产物1-(6-(甲硫基)-1H-吲哚-2-基)乙-1-酮(0.56g，收率：51％)。LCMS(ESI)：m/z 206[M+1] +。
步骤23b:(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)-1H-吲哚-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)-1H-indol-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(0708-88)的制备:往反应瓶中加入1-(6-(甲硫基)-1H-吲哚-2-基)乙-1-酮(0706-88)(81mg，0.394mmol，1.0当量)，2-(4-甲酰基-2,2-二甲基苯氧基)-2-甲基丙酸叔丁酯(115mg，0.394mmol，1.0当量)，氢氧化钠(0.205g，5.122mmol，13.0当量)，乙醇(10mL)和水(5mL)，30℃下搅拌过夜。反应液加水(20mL)稀释，加入1N稀盐酸溶液调节pH值为5，然后用乙酸乙酯(20mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，得到的粗产品用硅胶柱层析法(二氯甲烷：甲醇＝100:1)纯化得黄色固体产物(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)-1H-吲哚-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(0.139g，收率：74％)。LCMS(ESI)：m/z 480[M+1] +。
步骤23c:(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)-1H-吲哚-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)-1H-indol-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物88)的制备:室温下往(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)-1H-吲哚-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(0708-88)(0.139g，0.290mmol，1.0当量)的二氧六环溶液(5ml)中缓慢滴加浓硫酸(0.5mL)，室温下反应1.5小时。反应液加水(30mL)稀释，滴加2N氢氧化钠溶液调节pH值为5，然后用乙酸乙酯(30mL×3)萃取，萃取液用无水硫酸钠干燥，浓缩，然后用硅胶柱层析法纯化(二氯甲烷：甲醇＝15：1)得到黄色固体产物(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)-1H-吲哚-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2甲基丙酸(60mg，收率：49％)。LCMS(ESI)：m/z 424[M+1] +，熔点：184～186℃； 1HNMR(DMSO-d 6，400MHz)：δ12.95(s,1H),11.80(s,1H),7.80-7.73(m,2H),7.66-7.58(m,4H),7.28(s,1H),7.04-7.02(m,1H),2.53(s,3H),2.23(s,6H),1.40(s,6H)。
实施例24：(E)-2-(4-(3-(4-(乙硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(4-(ethylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物6)的制备(按照方案一线路制备)
步骤24a：1-(4-(乙硫基)苯并呋喃-7-基)乙-1-酮(1-(4-(ethylthio)benzofuran-7-yl)ethan-1-one)(化合物0105-6)的制备：将氢氧化钠(101mg,2.525mmol,2.5当量)溶于水(1.5ml)，加入乙硫醇(126mg，2.02mmol，2.0当量)，搅拌10min，加入1-(4-氟苯并呋喃-7-基)乙-1-酮(0104-2)(180mg，1.01mmol,1.0当量)的DMSO(10ml)溶液，反应液在室温下反应过夜。反应完成后反应液加入乙酸乙酯(100ml)稀释，水(150ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用硅胶硅胶柱层析法纯化(石油醚：乙酸乙酯＝15：1)得到产物1-(4-(乙硫基)苯并呋喃-7-基)乙-1-酮(119mg，收率：54％)。
步骤24b：(E)-1-(4-(乙硫基)苯并呋喃-7-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮((E)-1-(4-(ethylthio)benzofuran-7-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one)(化合物0106-6)的制备：将1-(4-(乙硫基)苯并呋喃-7-基)乙-1-酮(0105-6)(119mg，0.58mmol,1.0当量)溶于二氧六环(6ml)中，加入4-羟基-3,5-二甲基苯甲醛(105mg，0.696mmol，1.28当量)，搅拌下加入浓硫酸(1ml)，室温反应过夜。反应完成后反应液加入乙酸乙酯(100ml)稀释，半饱和食盐水(150ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝5：1)得到黄色固体产物(E)-1-(4-(乙硫基)苯并呋喃-7-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(140mg，收率：69％)。
步骤24c：(E)-2-(4-(3-(4-(乙硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(4-(3-(4-(ethylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate)(化合物0107-6)的制备：将((E)-1-(4-(乙硫基)苯并呋喃-7-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(0106-6)(0.26g，0.397mmol,1.0当量)溶于乙腈(30ml)中，加入碳酸钾(5 48mg，3.97mmol，10.0当量)、叔丁基2-溴-2-甲基丙酸酯(886mg,3.97mmol,10.0当量)，用氮气置换圆底烧瓶瓶内空气三遍，然后在91℃下反应20小时。反应完成后浓缩，然后反应液加入乙酸乙酯(100ml)稀释，水(150ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝15：1)得到黄色固体产物(E)-2-(4-(3-(4-(乙硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(91mg，收率：46％)。LCMS(ESI)：m/z 495[M+1] +。
步骤24d：(E)-2-(4-(3-(4-(乙硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(4-(ethylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物6)的制备：将(E)-2-(4-(3-(4-(乙硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(0107-6)(78mg，0.158mmol,1.0当量)溶于DCM(8ml)，加入三氟乙酸(1.5ml)，搅拌过夜。反应完成后加入水(100ml×3)洗，用二氯甲烷(100ml)萃取，有机相用无水硫酸钠干燥后浓缩，得到黄色固体产物(E)-2-(4-(3-(4-(乙硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(45mg，收率：65％)。LCMS(ESI)：m/z 439[M+1] +。熔点：102～105℃； 1HNMR(DMSO-d 6，300MHz):δ12.95(s，1H)，7.05-8.22(m,8H),3.24(q,J＝6.0HZ,2H),2.23(s,6H),1.40(s,6H),1.36(t,J＝6.0HZ,3H).
实施例25：(E)-2-(4-(3-(4-(异丁硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(4-(isobutylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物9)的制备(按照方案一线路制备)
步骤25a：1-(4-(异丁硫基)苯并呋喃-7-基)乙-1-酮(1-(4-(isobutylthio)benzofuran-7-yl)ethan-1-one)(化合物0105-9)的制备：将氢氧化钠(99mg,2.475mmol,2.5当量)溶于水(1.5ml)，加入异丁硫醇(179mg，1.98mmol，2.0当量)，搅拌10min，加入1-(4-氟苯并呋喃-7-基)乙-1-酮(0104-2)(176mg，0.99mmol,1.0当量)的DMSO(8ml)溶液，反应液在60℃下反应1小时。反应完成后反应液加入乙酸乙酯(100ml)稀释，水(150ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝20:1)得到1-(4-(异丁硫基)苯并呋喃-7-基)乙-1-酮(246mg)。
步骤25b：(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-(异丁硫基)苯并呋喃-7-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(4-(isobutylthio)benzofuran-7-yl)prop-2-en-1-one)(化合物0106-9)的制备：将1-(4-(异丁硫基)苯并呋喃-7-基)乙-1-酮(0105-9)(246mg，0.99mmol，1.0当量)，溶于二氧六环(10ml)中，加入4-羟基-3,5-二甲基苯甲醛(193mg，1.287mmol，1.3当量)，搅拌下加入浓硫酸(1ml)，室温反应过夜。反应完成后反应液加入乙酸乙酯(100ml)稀释，半饱和食盐水(150m×3)洗，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝5：1)得到黄色固体产物(E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-(异丁硫基)苯并呋喃-7-基)丙-2-烯-1-酮(255mg，收率：68％)。
步骤25c：(E)-2-(4-(3-(4-(异丁硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(4-(3-(4-(isobutylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate)(化合物0107-9)的制备：将((E)-3-(4-羟基-3,5-二甲基苯基)-1-(4-(异丁硫基)苯并呋喃-7-基)丙-2-烯-1-酮(0106-9)(255mg，0.67mmol,1.0当量)溶于乙腈(20ml)中，加入碳酸钾(925mg，6.70mmol，10.0当量)、叔丁基2-溴-2-甲基丙酸酯(1.49g,6.70mmol,10.0当量)，用氮气置换圆底烧瓶瓶内空气三遍，然后在91℃下反应20小时。反应完成后浓缩，然后反应液加入乙酸乙酯(100ml)稀释，水(150ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝20：1)得到黄色固体产物(E)-2-(4-(3-(4-(异丁硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(234mg，收率：67％)。LCMS(ESI)：m/z 523[M+1] +。
步骤25d：(E)-2-(4-(3-(4-(异丁硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(4-(isobutylthio)benzofuran-7-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物9)的制备：将(E)-2-(4-(3-(4-(异丁硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(0107-9)(234mg，0.448mmol,1.0当量)溶于DCM(10ml)，加入三氟乙酸(1ml)，搅拌过夜。反应完成后加入水(100ml×3)洗，用二氯甲烷(100ml)萃取，有机相用无水硫酸钠干燥后浓缩，通过制备液相纯化得到黄色固体产物(E)-2-(4-(3-(4-(异丁硫基)苯并呋喃-7-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(136mg，收率：65％)。LCMS(ESI)：m/z 467[M+1] +。熔点：110～113℃； 1HNMR(DMSO-d 6，300MHz):δ12.88(s，1H)，7.09-8.24(m,8H),3.12(d,J＝6.9HZ,2H),2.25(s,6H),1.95(m,1H),1.41(s,6H),1.08(d,J＝6.6HZ,6H)。
实施例26：(E)-2-(4-(3-(6-乙基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(6-ethoxybenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物44)的制备(按照方案七线路制备)
步骤26a:1-(6-乙基苯并呋喃-2-基)乙-1-酮(1-(6-ethoxybenzofuran-2-yl)ethan-1-one)(化合物0706-44)的制备：将4-乙氧基-2-羟基苯甲醛(0701-44)(428mg，2.58mol,1.0当量)溶于DMF(20ml)中，加入溴丙 酮(389mg，2.838mmol，3.0当量)，在85℃下反应5小时。完成后加入乙酸乙酯(50ml)稀释，半饱和食盐水(50ml×3)洗涤，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝15：1)得到黄色固体产物1-(6-乙基苯并呋喃-2-基)乙-1-酮(317mg，收率：60％)。LCMS(ESI)：m/z 205[M+1] +。
步骤26b:(E)-1-(6-乙氧基苯并呋喃-2-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮((E)-1-(6-ethoxybenzofuran-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one)(化合物0707-44)的制备：将1-(6-乙基苯并呋喃-2-基)乙-1-酮(0706-44)(317mg，1.55mol,1.0当量)溶于二氧六环(10ml)中，再加入4-羟基-3,5-二甲基苯甲醛(0.279g，1.86mmol，1.2当量)，室温搅拌下加入浓硫酸(1ml)反应15小时。反应完成后加入乙酸乙酯(50ml)稀释，半饱和食盐水(50ml×3)洗涤，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝5：1)得到黄色固体产物(E)-1-(6-乙氧基苯并呋喃-2-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(0.473g，收率：91％)。LCMS(ESI)：m/z 337[M+1] +。
步骤26c:(E)-2-(4-(3-(6-乙氧基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(4-(3-(6-ethoxybenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate)(化合物0708-44)的制备：将(E)-1-(6-乙氧基苯并呋喃-2-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(0707-44)(0.473g，1.41mmol,1.0当量)溶于乙腈(30ml)中，加入碳酸钾(1.946g，14.1mmol，10.0当量)、2-溴异丁酸叔丁酯(3.146g,14.1mmol,10.0当量)，用氮气置换圆底烧瓶瓶内空气三遍，然后在91℃下反应20小时。反应完成后浓缩，然后反应液加入乙酸乙酯(50ml)稀释，水(50ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝15：1)得到黄色固体产物(E)-2-(4-(3-(6-乙氧基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(0.495g，收率：74％)。LCMS(ESI)：m/z 479[M+1] +。
步骤26d:(E)-2-(4-(3-(6-乙基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(6-ethoxybenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物44)的制备：将(E)-2-(4-(3-(6-乙氧基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(0708-44)(200mg，0.418mmol,1.0当量)溶于二氯甲烷(10ml)中，搅拌下加入三氟乙酸(1ml)，室温反应15小时。反应完成后将反应液加入二氯甲烷(50ml)稀释，水(50ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用3ml甲醇洗涤得到黄色固体产物(E)-2-(4-(3-(6-乙基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(137mg，收率：78％)。LCMS(ESI)：m/z 423[M+1] +。熔点：146～148℃； 1HNMR(DMSO-d 6，300MHz):δ12.95(s，1H)，6.98-8.21(m,8H),4.17(q,J＝6.9HZ,2H),2.23(s,6H),1.39(m,9H)。
实施例27：(E)-2-(4-(3-(3-乙基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(3-ethyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物63)的制备(按照方案十线路制备)
步骤27a:1-(3-乙基-6-(甲硫基)苯并呋喃-2-基)乙-1-酮(1-(3-ethyl-6-(methylthio)benzofuran-2-yl)ethan-1-one)(化合物1003-63)的制备：将1-(2-羟基-4-(甲硫基)苯基)丙-1-酮(1002-63)(0.77g，3.92mol,1.0当量)溶于DMF(10ml)中，再加入溴丙酮(0.81g，5.88mmol，1.5当量)、碳酸铯(2.77g，7.84mmol，2.0当量)，在80℃反应3小时。反应完成后加入乙酸乙酯(50ml)稀释，半饱和食盐水(50ml×3)洗涤，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝15：1)得到黄色油状产物1-(3-乙基-6-(甲硫基)苯并呋喃-2-基)乙-1-酮(0.72g，收率：78％)。LCMS(ESI)：m/z 235[M+1] +。
步骤27b:(E)-1-(3-乙基-6-(甲硫基)苯并呋喃-2-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮((E)-1-(3-ethyl-6-(methylthio)benzofuran-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one)(化合物1004-63)的制备：将1-(3-乙基-6-(甲硫基)苯并呋喃-2-基)乙-1-酮(1003-63)(0.7g，2.98mol,1.0当量)溶于无水乙醇(10ml)中，再加入4-羟基-3,5-二甲基苯甲醛(0.447g，2.98mmol，1.0当量)，室温搅拌下加入浓硫酸(2ml)反应15小时。反应完成后加入乙酸乙酯(50ml)稀释，半饱和食盐水(50ml×3)洗涤，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝5：1)得到黄色固体产物(E)-1-(3-乙基-6-(甲硫基)苯并呋喃-2-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(0.95g，收率：87％)。LCMS(ESI)：m/z 367[M+1] +。
步骤27c:(E)-2-(4-(3-(3-乙基-6-(甲硫基)苯并呋喃-2-基)-3-氧代-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(4-(3-(3-ethyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate)(化合物1005-63)的制备：将(E)-1-(3-乙基-6-(甲硫基)苯并呋喃-2-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(1004-63)(0.27g，0.74mmol,1.0当量)溶于20ml乙腈中，加入碳酸钾(1.0g，7.4mmol，10.0当量)、2-溴异丁酸叔丁酯(1.65g,7.4mmol,10.0当量)，用氮气置换圆底烧瓶瓶内空气三遍，然后在83℃下反应20小时。反应完成后浓缩，然后反应液加入乙酸乙酯(50ml)稀释，水(50ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙 酯＝15：1)得到黄色油状产物(E)-2-(4-(3-(3-乙基-6-(甲硫基)苯并呋喃-2-基)-3-氧代-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(0.184g，收率：49％)。LCMS(ESI)：m/z 509[M+1] +。
步骤27d:(E)-2-(4-(3-(3-乙基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(3-ethyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物63)的制备：将(E)-2-(4-(3-(3-乙基-6-(甲硫基)苯并呋喃-2-基)-3-氧代-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(1005-63)(0.184g，0.36mmol,1.0当量)溶于10ml二氯甲烷中，搅拌下加入三氟乙酸(1ml)，室温反应15小时。反应完成后将反应液加入二氯甲烷(50ml)稀释，水(50ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用3ml混合液(石油醚：乙酸乙酯＝1:1)洗涤得到黄色固体产物(E)-2-(4-(3-(3-乙基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(35mg，收率：21％)。LCMS(ESI)：m/z 453[M+1] +；熔点：174～176℃； 1HNMR(DMSO-d 6，300MHz):δ13.000(s，1H)，7.780(d，J＝8.4Hz，1H)，7.691(d，J＝15.6Hz,1H)，7.624(d,J＝16Hz,1H),7.593(s,1H),7.501(s,2H),7.274(d,J＝8.8Hz,1H),3.125(q,J＝7.6HZ,2H),2.589(s,3H),2.237(s,6H),1.397(s,6H),1.245(t,J＝7.6HZ,3H)
实施例28：(E)-2-(4-(3-(3-异丙基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(3-isopropyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物64)的制备(按照方案十线路制备)
步骤28a:1-(3-异丙基-6-(甲硫基)苯并呋喃-2-基)乙-1-酮(1-(3-isopropyl-6-(methylthio)benzofuran-2-yl)ethan-1-one)(化合物1003-64)的制备：将1-(2-羟基-4-(甲硫基)苯基)-2-甲基丙-1-酮(1002-64)(0.71g，3.38mol,1.0当量)溶于DMF(10ml)中，再加入溴丙酮(0.69g，5.07mmol，1.5当量)、碳酸铯(2.39g，6.76mmol，2.0当量)，在80℃反应3小时。反应完成后加入乙酸乙酯(50ml)稀释，半饱和食盐水(50ml×3)洗涤，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝15：1)得到黄色油状产物1-(3-异丙基-6-(甲硫基)苯并呋喃-2-基)乙-1-酮(0.74g，收率：88％)。LCMS(ESI)：m/z 249[M+1] +。
步骤28b:(E)-3-(4-羟基-3,5-二甲基苯基)-1-(3-异丙基-6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(3-isopropyl-6-(methylthio)benzofuran-2-yl)prop-2-en-1-one)(化合物1004-64)的制备：将1-(3-异丙基-6-(甲硫基)苯并呋喃-2-基)乙-1-酮(1003-64)(0.71g，2.86mol,1.0当量)溶于无水乙醇(20ml)中，再加入4-羟基-3,5-二甲基苯甲醛(0.472g，3.146mmol，1.1当量)，室温搅拌下加入浓硫酸(3ml)反应15小时。反应完成后加入乙酸乙酯(50ml)稀释，半饱和食盐水(50ml×3)洗涤，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝5：1)得到黄色固体产物(E)-3-(4-羟基-3,5-二甲基苯基)-1-(3-异丙基-6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(0.95g，收率：87％)。LCMS(ESI)：m/z 381[M+1] +。
步骤28c:(E)-2-(4-(3-(3-异丙基-6-(甲硫基)苯并呋喃-2-基)-3-氧代-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(4-(3-(3-isopropyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate)(化合物1005-64)的制备：将(E)-3-(4-羟基-3,5-二甲基苯基)-1-(3-异丙基-6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(1004-64)(0.3g，0.79mmol,1.0当量)溶于20ml乙腈中，加入碳酸钾(1.1g，7.9mmol，10.0当量)、2-溴异丁酸叔丁酯(1.76g,7.9mmol,10.0当量)，用氮气置换圆底烧瓶瓶内空气三遍，然后在83℃下反应20小时。反应完成后浓缩，然后反应液加入乙酸乙酯(50ml)稀释，水(50ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用硅胶柱层析法纯化(石油醚：乙酸乙酯＝15：1)得到黄色油状产物(E)-2-(4-(3-(3-异丙基-6-(甲硫基)苯并呋喃-2-基)-3-氧代-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(44mg，收率：10％)。LCMS(ESI)：m/z 523[M+1] +。
步骤28d:(E)-2-(4-(3-(3-异丙基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(3-isopropyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物64)的制备：将(E)-2-(4-(3-(3-异丙基-6-(甲硫基)苯并呋喃-2-基)-3-氧代-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(1005-64)(44mg，0.08mmol,1.0当量)溶于10ml二氯甲烷中，搅拌下加入三氟乙酸(1ml)，室温反应15小时。反应完成后将反应液加入二氯甲烷(50ml)稀释，水(50ml×3)洗，有机相用无水硫酸钠干燥后浓缩，用3ml混合液(石油醚：乙酸乙酯＝1:1)洗涤得到黄色固体产物(E)-2-(4-(3-(3-异丙基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(30mg，收率：39％)。LCMS(ESI)：m/z 467[M+1] +；熔点：183～186℃； 1HNMR(DMSO-d 6，300MHz):δ13.00(s，1H)，7.90(d，J＝8.4Hz，1H)，7.68(d，J＝15.6Hz,1H)，7.63(d,J＝16Hz,1H),7.60(s,1H),7.49(s,2H),7.24(d,J＝8.4Hz,1H),4.18(m,J＝10.8HZ,H),2.58(s,3H),2.23(s,6H),1.40(d,J＝10.8HZ,6H),1.39(s,6H)。
实施例29：(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)-3-(三氟甲基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)-3-(trifluoromethyl)benzofuran-2-yl)-3 -oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物73)的制备(按照方案十线路制备)
步骤29a:1-(6-(甲硫基)-3-(三氟甲基)苯并呋喃-2-基)乙-1-酮(1-(6-(methylthio)-3-(trifluoromethyl)benzofuran-2-yl)ethan-1-one)(1003-73)的制备。在圆底烧瓶中加入2,2,2-三氟-1-(2-羟基-4-(甲硫基)苯基)乙-1-酮(1002-73)(0.94g，4.0mmol，1.0当量)，溴丙酮(0.55g，4.0mmol，1.0当量)，碳酸钾(1.66g，12.0mmol，3.0当量)和N，N-二甲基甲酰胺(20ml)，加热至100℃反应1小时。反应液用乙酸乙酯(150ml)稀释，用半饱和食盐水洗涤(100ml×4)，有机相旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝10:1)得到黄色固体产物1-(6-(甲硫基)-3-(三氟甲基)苯并呋喃-2-基)乙-1-酮(0.61g，收率：50％)。LCMS(ESI)：275[M+1] +。
步骤29b:(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-(甲硫基)-3-(三氟甲基)苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(6-(methylthio)-3-(trifluoromethyl)benzofuran-2-yl)prop-2-en-1-one)(1004-73)的制备。往浓硫酸(2ml)的乙醇溶液(10ml)中慢慢加入1-(6-(甲硫基)-3-(三氟甲基)苯并呋喃-2-基)乙-1-酮(1003-73(0.274g，1.0mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(0.151g，1.0mmol，1.0当量)，室温搅拌过夜。反应液过滤，固体用乙酸乙酯(2ml×2)和水(20ml×2)洗涤，真空干燥得到黄色固体产物(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-(甲硫基)-3-(三氟甲基)苯并呋喃-2-基)丙-2-烯-1-酮(0.35g，收率：86％)。LCMS(ESI)：407[M+1] +。
步骤29c:(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)-3-(三氟甲基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)-3-(trifluoromethyl)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(1005-73)的制备。在圆底烧瓶中加入(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-(甲硫基)-3-(三氟甲基)苯并呋喃-2-基)丙-2-烯-1-酮(1004-73)(0.35g，0.86mmol，1.0当量),2-溴代异丁酸叔丁酯(1.92g，8.6mmol，10.0当量),碳酸钾(1.2g，8.6mmol，10.0当量)和乙腈(30ml)，将反应液在氮气的保护下加热回流过夜。反应液旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝10:1)得到黄色膏状物产物(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)-3-(三氟甲基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)基)苯氧基)-2-甲基丙酸叔丁酯(0.31g，收率：66％)。LCMS(ESI)：549[M+1] +。
步骤29d:(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)-3-(三氟甲基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(6-(methylthio)-3-(trifluoromethyl)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物73)的制备。往(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)-3-(三氟甲基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)基)苯氧基)-2-甲基丙酸叔丁酯(1005-73)(0.31g，0.57mmol，1.0当量)的二氯甲烷(15ml)溶液中缓慢加入三氟乙酸(3ml)，反应液室温下搅拌1小时。将反应液用乙酸乙酯(100ml)稀释，用水(100ml×1)洗涤，有机相旋干，剩余物用甲醇(4ml)重结晶得到黄色固体产物(E)-2-(2,6-二甲基-4-(3-(6-(甲硫基)-3-(三氟甲基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(224mg，收率：80％)。LCMS(ESI)：493[M+1] +；熔点：201～203℃； 1HNMR(DMSO，500MHz)：δ12.90(s，1H)，7.40-7.79(m，7H)，2.61(s，3H)，2.23(s，6H)，1.40(s，6H)。
实施例30：(E)-2-(4-(3-(6-(乙硫基)-3-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(6-(ethylthio)-3-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物74)的制备(按照方案十一线路制备)
步骤30a:1-(4-(乙硫基)-2-羟基苯基)乙-1-酮(1-(4-(ethylthio)-2-hydroxyphenyl)ethan-1-one)(1102-74)的制备:往氢氧化钠(135mg，3.38mmol，1.3当量)的水(1ml)溶液中加入乙硫醇(0.24mL，3.38mmol，1.3当量)。混合物在室温下搅拌30分钟。加入4-氟-2-羟基苯乙酮(0.4g，2.60mmol，1.0当量)的二甲基亚砜(5ml)溶液，然后加热到120℃反应7小时。反应液冷却到室温，加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥。浓缩得到的粗产品用硅胶柱层析法(石油醚：乙酸乙酯＝60：1)纯化得到淡黄色油状液体1-(4-(乙硫基)-2-羟基苯基)乙-1-酮(228mg，收率：45％)。LCMS(ESI)：m/z 197[M+1] +。
步骤30b:1-(6-(乙硫基)-3-甲基苯并呋喃-2-基)乙-1-酮(1-(6-(ethylthio)-3-methylbenzofuran-2-yl)ethan-1-one)(1103-74))的制备:将1-(4-(乙硫基)-2-羟基苯基)乙-1-酮(1102-74)(0.228g,1.163mmol,1.0当量)和溴丙酮(0.098mL,1.163mmol,1.0当量)溶于N,N-二甲基甲酰胺(5mL)中，然后加入碳酸铯(0.455g,1.396mmol,1.2当量)。反应体系用氮气置换三遍空气，然后在80℃下反应3小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥。浓缩得到的粗产品用硅胶柱层析法纯化(石油醚：乙酸乙酯＝10：1)得到淡黄色油状液体1-(6-(乙硫基)-3-甲基苯并呋喃-2-基)乙-1-酮(171mg，收率：63％)。LCMS(ESI)：m/z 235[M+1] +。
步骤30c:(E)-1-(6-(乙基硫基)-3-甲基苯并呋喃-2-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮((E)-1-(6-(ethylthio)-3-methylbenzofuran-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one)(1104-74) 的制备:往1-(6-(乙硫基)-3-甲基苯并呋喃-2-基)乙-1-酮(1103-74)(171mg，0.731mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(110mg，0.731mmol，1.0当量)的乙醇溶液(8ml)中缓慢滴加浓硫酸(2mL)，室温下反应3小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥，浓缩得到黄色固体(E)-1-(6-(乙基硫基)-3-甲基苯并呋喃-2-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(267mg，粗品)。LCMS(ESI)：m/z 367[M+1] +。
步骤30d:(E)-2-(4-(3-(6-(乙硫基)-3-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(4-(3-(6-(ethylthio)-3-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate)(1105-74)的制备:将(E)-1-(6-(乙基硫基)-3-甲基苯并呋喃-2-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(1104-74)(268mg,0.731mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(0.8mL,4.386mmol,6.0当量)溶于乙腈(8mL)中，然后加入碳酸钾(0.404g,2.924mmol,4.0当量)。反应体系用氮气置换三遍空气，然后在85℃下反应过夜。反应完成后浓缩得到粗产品，用硅胶柱层析法(石油醚：乙酸乙酯＝20：1)纯化得到黄色油状液体(E)-2-(4-(3-(6-(乙硫基)-3-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(107mg，收率：29％)。LCMS(ESI)：m/z 509[M+1] +。
步骤30e:(E)-2-(4-(3-(6-(乙硫基)-3-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(6-(ethylthio)-3-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物74)的制备:室温下往(E)-2-(4-(3-(6-(乙硫基)-3-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(1105-74)(107mg，0.211mmol，1.0当量)的二氧六环溶液(8ml)中缓慢滴加浓硫酸(1mL)。混合液在室温下搅拌2小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(30mL×1)洗涤并用无水硫酸钠干燥。浓缩得到粗产品，用硅胶柱层析法(二氯甲烷：甲醇＝20：1)纯化得到黄色固体(E)-2-(4-(3-(6-(乙硫基)-3-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(74mg，收率：78％)。LCMS(ESI)：m/z 453[M+1] +，熔点：201～204℃； 1HNMR(DMSO-d 6，500MHz)：δ12.94(s,1H),7.78-7.73(m,2H),7.67-7.60(m,2H),7.52(s,2H),7.32-7.29(m,1H),3.18-3.08(m,2H),2.62(s,3H),2.24(s,6H),1.40(s,6H),1.32-1.27(m,3H)。
实施例31：(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(丙硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(3-methyl-6-(propylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物75)的制备(按照方案十一线路制备)
步骤31a:1-(2-羟基-4-(丙硫基)苯基)乙-1-酮(1-(2-hydroxy-4-(propylthio)phenyl)ethan-1-one)(1102-75)的制备:往氢氧化钠(156mg，3.9mmol，1.5当量)的水(1ml)溶液中加入丙硫醇(0.35mL，3.9mmol，1.5当量)。混合物在室温下搅拌30分钟。加入4-氟-2-羟基苯乙酮(0.4g，2.60mmol，1.0当量)的二甲基亚砜(5ml)溶液，然后加热到120℃反应5小时。反应液冷却到室温，加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(30mL×1)洗涤并用无水硫酸钠干燥。浓缩得到的粗产品用硅胶柱层析法(石油醚：乙酸乙酯＝60：1)纯化得到淡黄色油状液体1-(2-羟基-4-(丙硫基)苯基)乙-1-酮(283mg，收率：52％)。LCMS(ESI)：m/z 211[M+1] +。
步骤31b:1-(3-甲基-6-(丙硫基)苯并呋喃-2-基)乙-1-酮(1-(3-methyl-6-(propylthio)benzofuran-2-yl)ethan-1-one)(1103-75)的制备:将1-(2-羟基-4-(丙硫基)苯基)乙-1-酮(1102-75)(0.283g,1.35mmol,1.0当量)和溴丙酮(0.113mL,1.35mmol,1.0当量)溶于N,N-二甲基甲酰胺(5mL)中，然后加入碳酸铯(0.528g,1.62mmol,1.2当量)。反应体系用氮气置换三遍空气，然后在80℃下反应3小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥。浓缩得到的粗产品用硅胶柱层析法纯化(石油醚：乙酸乙酯＝10：1)得到淡黄色油状液体1-(3-甲基-6-(丙硫基)苯并呋喃-2-基)乙-1-酮(194mg，收率：58％)。LCMS(ESI)：m/z 249[M+1] +。
步骤31c:(E)-3-(4-羟基-3,5-二甲基苯基)-1-(3-甲基-6-(丙硫基)苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(3-methyl-6-(propylthio)benzofuran-2-yl)prop-2-en-1-one)(1104-75)的制备:往1-(3-甲基-6-(丙硫基)苯并呋喃-2-基)乙-1-酮(194mg，0.782mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(117mg，0.782mmol，1.0当量)的乙醇溶液(8ml)中缓慢滴加浓硫酸(2mL)，室温下反应4小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥，浓缩得到黄色固体(E)-3-(4-羟基-3,5-二甲基苯基)-1-(3-甲基-6-(丙硫基)苯并呋喃-2-基)丙-2-烯-1-酮((297mg，粗品)。LCMS(ESI)：m/z 381[M+1] +。
步骤31d:(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(丙硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dimethyl-4-(3-(3-methyl-6-(propylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(1105-75)的制备:将(E)-3-(4-羟基-3,5-二甲基苯基)-1-(3-甲基-6-(丙硫基)苯并呋喃-2-基)丙-2-烯-1-酮(1104-75)(297mg,0.782mmol,1.0当量)和2-溴-2-甲基丙 酸叔丁酯(0.86mL,4.69mmol,6.0当量)溶于乙腈(8mL)中，然后加入碳酸钾(0.432g,3.128mmol,4.0当量)。反应体系用氮气置换三遍空气然后在85℃下反应过夜。反应完成后浓缩得到粗产品，用硅胶柱层析法(石油醚：乙酸乙酯＝20：1)纯化得到黄色油状液体(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(丙硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(158mg，收率：39％)。LCMS(ESI)：m/z 523[M+1] +。
步骤31e:(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(丙硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(3-methyl-6-(propylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物75)的制备:室温下往(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(丙硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(1105-75)(158mg，0.303mmol，1.0当量)的二氧六环溶液(8ml)中缓慢滴加浓硫酸(1mL)。混合液在室温下搅拌3小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(30mL×1)洗涤并用无水硫酸钠干燥。浓缩得到粗产品，用二氯甲烷/石油醚(1:2)洗涤并干燥得到黄色固体(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(丙硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(110mg，收率：78％)。LCMS(ESI)：m/z 467[M+1] +，熔点：159～162℃； 1HNMR(DMSO-d 6，500MHz)：δ12.95(s,1H),7.77-7.72(m,2H),7.67-7.65(m,2H),7.60(s,2H),7.33-7.29(m,1H),3.10-3.06(m,2H),2.61(s,3H),2.24(s,6H),1.69-1.62(m,2H),1.40(s,6H),1.04-0.99(m,3H)。
实施例32：(E)-2-(4-(3-(6-(异丁硫基)-3-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(6-(isobutylthio)-3-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物76)的制备(按照方案十一线路制备)
步骤32a:1-(2-羟基-4-(异丁硫基)苯基)乙-1-酮(1-(2-hydroxy-4-(isobutylthio)phenyl)ethan-1-one)(1102-76)的制备:往氢氧化钠(195mg，4.87mmol，1.5当量)的水(1.5ml)溶液中加入异丁硫醇(0.525mL，4.87mmol，1.5当量)。混合物在室温下搅拌30分钟。加入4-氟-2-羟基苯乙酮(0.5g，3.25mmol，1.0当量)的二甲基亚砜(5ml)溶液，然后加热到120℃反应6小时。反应液冷却到室温，加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥。浓缩得到的粗产品用硅胶柱层析法(石油醚：乙酸乙酯＝60：1)纯化得到无色油状液体1-(2-羟基-4-(异丁硫基)苯基)乙-1-酮(263mg，收率：36％)。LCMS(ESI)：m/z 225[M+1] +。
步骤32b:1-(6-(异丁硫基)-3-甲基苯并呋喃-2-基)乙-1-酮(1-(6-(isobutylthio)-3-methylbenzofuran-2-yl)ethan-1-one)(1103-76)的制备:将1-(2-羟基-4-(异丁硫基)苯基)乙-1-酮(1102-76)(0.263g,1.174mmol,1.0当量)和溴丙酮(0.099mL,1.174mmol,1.0当量)溶于N,N-二甲基甲酰胺(5mL)中，然后加入碳酸铯(0.459g,1.409mmol,1.2当量)。反应体系用氮气置换三遍空气，然后在80℃下反应5小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥。浓缩得到的粗产品用硅胶柱层析法纯化(石油醚：乙酸乙酯＝20：1)得到淡黄色油状液体1-(6-(异丁硫基)-3-甲基苯并呋喃-2-基)乙-1-酮(140mg，收率：46％)。LCMS(ESI)：m/z 263[M+1] +。
步骤32c:(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-(异丁硫基)-3-甲基苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(6-(isobutylthio)-3-methylbenzofuran-2-yl)prop-2-en-1-one)(1104-76)的制备:往1-(6-(异丁硫基)-3-甲基苯并呋喃-2-基)乙-1-酮(1103-76)(140mg，0.534mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(80mg，0.534mmol，1.0当量)的乙醇溶液(8ml)中缓慢滴加浓硫酸(2mL)，室温下反应5小时。反应液加水(30mL)稀释，然后用乙酸乙酯(20mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥，浓缩得到黄色固体(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-(异丁硫基)-3-甲基苯并呋喃-2-基)丙-2-烯-1-酮(210mg，粗品)。LCMS(ESI)：m/z 395[M+1] +。
步骤32d:(E)-2-(4-(3-(6-(异丁硫基)-3-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(4-(3-(6-(isobutylthio)-3-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate)(1105-76)的制备:将(E)-3-(4-羟基-3,5-二甲基苯基)-1-(6-(异丁硫基)-3-甲基苯并呋喃-2-基)丙-2-烯-1-酮(1104-76)(210mg,0.534mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(0.59mL,3.204mmol,6.0当量)溶于乙腈(8mL)中，然后加入碳酸钾(0.295g,2.136mmol,4.0当量)。反应体系用氮气置换三遍空气，然后在85℃下反应过夜。反应完成后浓缩得到粗产品，用硅胶柱层析法(石油醚：乙酸乙酯＝20：1)纯化得到黄色油状液体(E)-2-(4-(3-(6-(异丁硫基)-3-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(110mg，收率：38％)。LCMS(ESI)：m/z 537[M+1] +。
步骤32e:(E)-2-(4-(3-(6-(异丁硫基)-3-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(6-(isobutylthio)-3-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物76)的制备:室温下往(E)-2-(4-(3-(6-(异丁硫基)-3-甲基 苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(1105-76)(110mg，0.205mmol，1.0当量)的二氯甲烷溶液(7ml)中缓慢滴加三氟乙酸(0.7mL)。混合液在室温下搅拌4小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥。浓缩得到粗产品，用硅胶柱层析法(二氯甲烷：甲醇＝20：1)纯化得到黄色固体(E)-2-(4-(3-(6-(异丁硫基)-3-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(78mg，收率：80％)。LCMS(ESI)：m/z 481[M+1] +，熔点：151～154℃； 1HNMR(DMSO-d 6，500MHz)：δ12.94(s,1H),7.77-7.72(m,2H),7.67-7.65(m,2H),7.51(s,2H),7.34-7.30(m,1H),2.99(d,J＝11.5Hz,2H),2.61(s,3H),2.24(s,6H),1.99-1.90(m,1H),1.40(s,6H),1.03(d,J＝11.0Hz,6H)。
实施例33：(E)-2-(4-(3-(6-(异丙基硫基)-3-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(6-(isopropylthio)-3-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物77)的制备(按照方案十一线路制备)
步骤33a:1-(2-羟基-4-(异丙基硫基)苯基)乙-1-酮(1-(2-hydroxy-4-(isopropylthio)phenyl)ethan-1-one)(1102-77)的制备:往氢氧化钠(156mg，3.9mmol，1.5当量)的水(1ml)溶液中加入异丙硫醇(0.36mL，3.9mmol，1.5当量)。混合物在室温下搅拌30分钟。加入4-氟-2-羟基苯乙酮(0.4g，2.60mmol，1.0当量)的二甲基亚砜(5ml)溶液，然后加热到120℃反应5小时。反应液冷却到室温，加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(30mL×1)洗涤并用无水硫酸钠干燥。浓缩得到的粗产品用硅胶柱层析法(石油醚：乙酸乙酯＝60：1)纯化得到淡黄色油状液体1-(2-羟基-4-(异丙基硫基)苯基)乙-1-酮(95mg，收率：17％)。LCMS(ESI)：m/z 211[M+1] +。
步骤33b:1-(3-甲基-6-(异丙硫基)苯并呋喃-2-基)乙-1-酮(1-(6-(isopropylthio)-3-methylbenzofuran-2-yl)ethan-1-one)(1103-77)的制备:将1-(2-羟基-4-(异丙基硫基)苯基)乙-1-酮(95mg,0.452mmol,1.0当量)和溴丙酮(62mg,0.452mmol,1.0当量)溶于N,N-二甲基甲酰胺(5mL)中，然后加入碳酸铯(0.177g,0.542mmol,1.2当量)。反应体系用氮气置换三遍空气，然后在80℃下反应5小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥。浓缩得到的粗产品用硅胶柱层析法纯化(石油醚：乙酸乙酯＝20：1)得到淡黄色油状液体1-(3-甲基-6-(异丙硫基)苯并呋喃-2-基)乙-1-酮(80mg，收率：71％)。LCMS(ESI)：m/z 249[M+1] +。
步骤33c:(E)-3-(4-羟基-3,5-二甲基苯基)-1-(3-甲基-6-(异丙硫基)苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(6-(isopropylthio)-3-methylbenzofuran-2-yl)prop-2-en-1-one)(1104-77)的制备:往1-(3-甲基-6-(异丙硫基)苯并呋喃-2-基)乙-1-酮(1103-77)(80mg，0.323mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(48.4mg，0.323mmol，1.0当量)的乙醇溶液(8ml)中缓慢滴加浓硫酸(2mL)，室温下反应4小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥，浓缩得到黄色固体(E)-3-(4-羟基-3,5-二甲基苯基)-1-(3-甲基-6-(异丙硫基)苯并呋喃-2-基)丙-2-烯-1-酮(123mg，粗品)。LCMS(ESI)：m/z 381[M+1] +。
步骤33d:(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(异丙硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(4-(3-(6-(isopropylthio)-3-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate)(1105-77)的制备:将(E)-3-(4-羟基-3,5-二甲基苯基)-1-(3-甲基-6-(异丙硫基)苯并呋喃-2-基)丙-2-烯-1-酮(1104-77)(122.7mg,0.323mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(0.36mL,1.938mmol,6.0当量)溶于乙腈(8mL)中，然后加入碳酸钾(0.178g,1.292mmol,4.0当量)。反应体系用氮气置换三遍空气，然后在85℃下反应过夜。反应完成后浓缩得到粗产品，用硅胶柱层析法(石油醚：乙酸乙酯＝20：1)纯化得到黄色固体(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(异丙硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(75mg，收率：44％)。LCMS(ESI)：m/z 523[M+1] +。
步骤33e:(E)-2-(4-(3-(6-(异丙基硫基)-3-甲基苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(6-(isopropylthio)-3-methylbenzofuran-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物77)的制备:室温下往(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(异丙硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(1105-77)(75mg，0.144mmol，1.0当量)的二氧六环溶液(8ml)中缓慢滴加浓硫酸(1mL)。混合液在室温下搅拌2小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥。浓缩得到粗产品，用硅胶柱层析法(二氯甲烷：甲醇＝20：1)纯化得到黄色固体(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(异丙硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(46mg，收率：69％)。LCMS(ESI)：m/z 467[M+1] +，熔点：182～185℃； 1HNMR(DMSO-d 6，500MHz)：δ12.95(s,1H),7.80-7.72(m,2H),7.68-7.60(m,2H),7.52(s,2H),7.37-7.33(m,1H),3.73-3.64(m,1H),2.62(s,3H),2.24(s,6H),1.40(s,6H),1.30(d,J＝11.0Hz,6H)。
实施例34：(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(甲硫基)苯并[b]噻吩-2-基)-3-氧代丙-1-烯-1-基) 苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(3-methyl-6-(methylthio)benzo[b]thiophen-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物82)的制备(按照方案十二线路制备)
步骤34a:2,4-二甲硫基苯乙酮(1-(2,4-bis(methylthio)phenyl)ethan-1-one)(1202-82)的制备:往2,4-二氟苯乙酮(0.6g，3.84mmol，1.0当量)的二甲基亚砜(6ml)溶液中加入甲硫醇钠(20％的水溶液，3.37g，9.61mmol，2.5当量)。混合物在室温下搅拌2小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥，然后浓缩得到淡黄色固体2,4-二甲硫基苯乙酮(0.782g，收率：96％)。LCMS(ESI)：m/z 213[M+1] +。
步骤34b:1-(3-甲基-6-(甲硫基)苯并[b]噻吩-2-基)乙-1-酮(1-(3-methyl-6-(methylthio)benzo[b]thiophen-2-yl)ethan-1-one)(1203-82)的制备:将2,4-二甲硫基苯乙酮(1202-82)(0.73g,3.44mmol,1.0当量)和溴丙酮(0.72mL,8.61mmol,2.5当量)溶于二氧六环(10mL)中，然后加入氢氧化钡(1.06g,6.19mmol,1.8当量)。用氮气置换反应体系中的空气三遍，然后在105℃下反应24小时。反应液冷却到室温并加水(40mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥。浓缩得到的粗产品用硅胶柱层析法纯化(石油醚：乙酸乙酯＝30：1)得到淡黄色固体1-(3-甲基-6-(甲硫基)苯并[b]噻吩-2-基)乙-1-酮(0.128g，收率：16％)。LCMS(ESI)：m/z 237[M+1] +。
步骤34c:(E)-3-(4-羟基-3,5-二甲基苯基)-1-(3-甲基-6-(甲硫基)苯并[b]噻吩-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethylphenyl)-1-(3-methyl-6-(methylthio)benzo[b]thiophen-2-yl)prop-2-en-1-one)(1204-82)的制备:往1-(3-甲基-6-(甲硫基)苯并[b]噻吩-2-基)乙-1-酮(1203-82)(128mg，0.542mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(81mg，0.542mmol，1.0当量)的乙醇溶液(8ml)中缓慢滴加浓硫酸(2mL)，室温下反应4小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥，浓缩得到黄色固体(E)-3-(4-羟基-3,5-二甲基苯基)-1-(3-甲基-6-(甲硫基)苯并[b]噻吩-2-基)丙-2-烯-1-酮(199mg，粗品)。LCMS(ESI)：m/z 369[M+1] +。
步骤34d:(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(甲硫基)苯并[b]噻吩-2-基)-3-氧代丙-1-烯-1-羧酸叔丁酯哌啶-1-基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dimethyl-4-(3-(3-methyl-6-(methylthio)benzo[b]thiophen-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(1205-82)的制备:将(E)-3-(4-羟基-3,5-二甲基苯基)-1-(3-甲基-6-(甲硫基)苯并[b]噻吩-2-基)丙-2-烯-1-酮(1204-82)(199mg,0.542mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(0.6mL,3.252mmol,6.0当量)溶于乙腈(8mL)中，然后加入碳酸钾(0.299g,2.168mmol,4.0当量)。用氮气置换反应体系中的空气三遍，然后在85℃下反应过夜。反应完成后浓缩得到粗产品，用硅胶柱层析法(石油醚：乙酸乙酯＝15：1)纯化得到黄色固体(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(甲硫基)苯并[b]噻吩-2-基)-3-氧代丙-1-烯-1-羧酸叔丁酯哌啶-1-基)苯氧基)-2-甲基丙酸叔丁酯(52mg，收率：19％)。LCMS(ESI)：m/z 511[M+1] +。
步骤34e:(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(甲硫基)苯并[b]噻吩-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethyl-4-(3-(3-methyl-6-(methylthio)benzo[b]thiophen-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物82)的制备:室温下往(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(甲硫基)苯并[b]噻吩-2-基)-3-氧代丙-1-烯-1-羧酸叔丁酯哌啶-1-基)苯氧基)-2-甲基丙酸叔丁酯(1205-82)(52mg，0.102mmol，1.0当量)的二氧六环溶液(8ml)中缓慢滴加浓硫酸(1mL)。混合液在室温下搅拌2小时。反应液加水(30mL)稀释，然后用乙酸乙酯(20mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥。浓缩得到粗产品，用硅胶柱层析法(二氯甲烷：甲醇＝20：1)纯化得到黄色固体(E)-2-(2,6-二甲基-4-(3-(3-甲基-6-(甲硫基)苯并[b]噻吩-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(34mg，收率：74％)。LCMS(ESI)：m/z 455[M+1] +，熔点：162～165℃； 1HNMR(DMSO-d 6，500MHz)：δ12.94(s,1H),7.95-7.91(m,2H),7.65-7.60(m,1H),7.54-7.49(m,2H),7.46-7.38(m,2H),2.76(s,3H),2.59(s,3H),2.23(s,6H),1.40(s,6H)。
实施例35：(E)-2-(4-(3-(6-(乙硫基)-3-甲基苯并[b]噻吩-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(6-(ethylthio)-3-methylbenzo[b]thiophen-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物94)的制备(按照方案十二线路制备)
步骤35a:2,4-二乙硫基苯乙酮(1-(2,4-bis(ethylthio)phenyl)ethan-1-one)(1202-94)的制备:往氢氧化钠(448mg，11.21mmol，2.5当量)的水(4ml)溶液中加入乙硫醇(0.81mL，11.21mmol，2.5当量)。混合物在室温下搅拌30分钟。加入2,4-二氟苯乙酮(0.7g，4.48mmol，1.0当量)的二甲基亚砜(10ml)溶液，然后在室温下反应过夜。反应液加水(40mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(30mL×1)洗涤并用无水硫酸钠干燥，然后浓缩得到淡黄色固体2,4-二乙硫基苯乙酮(1.06g，收率：99％)。LCMS(ESI)：m/z 241[M+1] +。
步骤35b:1-(6-(乙硫基)-3-甲基苯并[b]噻吩-2-基)乙-1-酮(1-(6-(ethylthio)-3-methylbenzo[b]thiophen-2-yl)ethan-1-one)(1203-94)的制备:将2,4-二乙硫基苯乙酮(1202-94)(1.06g,4.42mmol,1.0当量)和溴丙酮(0.93mL,11.05mmol,2.5当量)溶于二氧六环(15mL)中，然后加入氢氧化钡(1.36g,7.95mmol, 1.8当量)。用氮气置换反应体系中的空气三遍，然后在105℃下反应过夜。反应液冷却到室温并加水(50mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(30mL×1)洗涤并用无水硫酸钠干燥。浓缩得到的粗产品用硅胶柱层析法纯化(石油醚：乙酸乙酯＝30：1)得到淡黄色固体1-(6-(乙硫基)-3-甲基苯并[b]噻吩-2-基)乙-1-酮(0.438g，收率：40％)。LCMS(ESI)：m/z 251[M+1] +。
步骤35c:(E)-1-(6-(乙基硫基)-3-甲基苯并[b]噻吩-2-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮((E)-1-(6-(ethylthio)-3-methylbenzo[b]thiophen-2-yl)-3-(4-hydroxy-3,5-dimethylphenyl)prop-2-en-1-one)(1204-94)的制备:往1-(6-(乙硫基)-3-甲基苯并[b]噻吩-2-基)乙-1-酮(1203-94)(233mg，0.932mmol，1.0当量)和4-羟基-3,5-二甲基苯甲醛(140mg，0.932mmol，1.0当量)的乙醇溶液(8ml)中缓慢滴加浓硫酸(2mL)，室温下反应5小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥，浓缩得到黄色固体(E)-1-(6-(乙基硫基)-3-甲基苯并[b]噻吩-2-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(356mg，粗品)。LCMS(ESI)：m/z 383[M+1] +。
步骤35d:(E)-2-(4-(3-(6-(乙硫基)-3-甲基苯并[b]噻吩-2-基)-3-氧代丙-1-烯-1-基)6-二甲基苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(4-(3-(6-(ethylthio)-3-methylbenzo[b]thiophen-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoate)(1205-94)的制备:将(E)-1-(6-(乙基硫基)-3-甲基苯并[b]噻吩-2-基)-3-(4-羟基-3,5-二甲基苯基)丙-2-烯-1-酮(1204-94)(356mg,0.932mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(1.0mL,5.59mmol,6.0当量)溶于乙腈(10mL)中，然后加入碳酸钾(0.51g,3.728mmol,4.0当量)。用氮气置换反应体系中的空气三遍，然后在85℃下反应过夜。反应完成后浓缩得到粗产品，用硅胶柱层析法(石油醚：乙酸乙酯＝15：1)纯化得到黄色固体(E)-2-(4-(3-(6-(乙硫基)-3-甲基苯并[b]噻吩-2-基)-3-氧代丙-1-烯-1-基)6-二甲基苯氧基)-2-甲基丙酸叔丁酯(183mg，收率：38％)。LCMS(ESI)：m/z 525[M+1] +。
步骤35e:(E)-2-(4-(3-(6-(乙硫基)-3-甲基苯并[b]噻吩-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸((E)-2-(4-(3-(6-(ethylthio)-3-methylbenzo[b]thiophen-2-yl)-3-oxoprop-1-en-1-yl)-2,6-dimethylphenoxy)-2-methylpropanoic acid)(化合物94)的制备:室温下往(E)-2-(4-(3-(6-(乙硫基)-3-甲基苯并[b]噻吩-2-基)-3-氧代丙-1-烯-1-基)6-二甲基苯氧基)-2-甲基丙酸叔丁酯(1205-94)(183mg，0.349mmol，1.0当量)的二氯甲烷溶液(10ml)中缓慢滴加三氟乙酸(1mL)。混合液在室温下搅拌5小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥。浓缩得到粗产品，用硅胶柱层析法(二氯甲烷：甲醇＝15：1)纯化得到黄色固体(E)-2-(4-(3-(6-(乙硫基)-3-甲基苯并[b]噻吩-2-基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(145mg，收率：89％)。LCMS(ESI)：m/z 469[M+1] +，熔点：175～177℃； 1HNMR(DMSO-d 6，500MHz)：δ12.92(s,1H),7.99-7.93(m,2H),7.60(s,1H),7.52(s,2H),7.46-7.41(m,2H),3.16-3.08(m,2H),2.76(s,3H),2.23(s,6H),1.40(s,6H),1.32-1.27(m,3H)。
实施例36：(E)-2-(2,6-二甲氧基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethoxy-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物99)的制备(按照方案七线路制备)
步骤36a:(E)-3-(4-羟基-3,5-二甲氧基苯基)-1-(6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethoxyphenyl)-1-(6-(methylthio)benzofuran-2-yl)prop-2-en-1-one)(0707-99)的制备。往圆底烧瓶中加入1-(6-(甲硫基)苯并呋喃-2-基)乙-1-酮(0706-51)(0.206g，1.0mmol，1.0当量)，4-羟基-3,5-二甲氧基苯甲醛(0.182g，1.0mmol，1.10当量)，二氧六环溶液(10ml)和甲磺酸(2ml)，加热到60℃反应4小时。反应液用乙酸乙酯(100ml)稀释，用水(100ml×1)洗涤，有机相旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝2:1)得到黄色液体(E)-3-(4-羟基-3,5-二甲氧基苯基)-1-(6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(0.26g，收率：70％)。LCMS(ESI)：371[M+1] +。
步骤36b:(E)-2-(2,6-二甲氧基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dimethoxy-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(0708-99)的制备。往圆底烧瓶中加入(E)-3-(4-羟基-3,5-二甲氧基苯基)-1-(6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(0707-99)(0.26g，0.7mmol，1.0当量)，2-溴代异丁酸叔丁酯(1.56g，7.0mmol，10.0当量)，碳酸钾(0.97g，7.0mmol，10.0当量)和二甲基亚砜(10ml)，将反应液加热到100℃反应5小时。反应液用乙酸乙酯(100ml)稀释，用半饱和食盐水(100ml×4)洗涤，有机相旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝5:1)得到黄色膏状物(E)-2-(2,6-二甲氧基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2甲基丙酸叔丁酯(0.09g，收率：25％)。LCMS(ESI)：513[M+1] +。
步骤36c:(E)-2-(2,6-二甲氧基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethoxy-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物99)的制备。往(E)-2-(2,6-二甲氧基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3- 氧代丙-1-烯-1-基)苯氧基)-2甲基丙酸叔丁酯(0708-99)(0.09g，0.18mmol，1.0当量)的二氯甲烷(10ml)溶液中缓慢加入三氟乙酸(2ml)，反应液室温下搅拌3小时。将反应液倒入水(100ml)中，用二氯甲烷(100ml×1)萃取，有机相用无水硫酸钠干燥，过滤，旋干，剩余物用石油醚：乙酸乙酯＝2:1(5ml)重结晶得到黄色固体(E)-2-(2,6-二甲氧基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(31mg，收率：38％)。LCMS(ESI)：457[M+1] +。熔点：167～170℃； 1HNMR(DMSO，500MHz)：δ12.97(s，1H)，7.21-8.26(m，8H)，3.81(s,6H)，2.58(s，3H)，1.34(s，6H)。
实施例37：(E)-2-(2,6-二氯-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dichloro-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物100)的制备(按照方案七线路制备)
步骤37a:(E)-3-(3,5-二氯-4-羟基苯基)-1-(6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(3,5-dichloro-4-hydroxyphenyl)-1-(6-(methylthio)benzofuran-2-yl)prop-2-en-1-one)(0707-100)的制备。往圆底烧瓶中加入1-(6-(甲硫基)苯并呋喃-2-基)乙-1-酮(0706-51)(0.90g，4.4mmol，1.0当量)，4-羟基-3,5-二氯苯甲醛(1.18g，6.2mmol，1.4当量)，乙醇(15ml)和硫酸(3ml)，加热到85℃反应3小时。反应液过滤，用乙醇(2ml×2)洗涤，固体溶于乙酸乙酯(150ml)，用盐水(100ml×2)洗涤，有机相用无水硫酸钠干燥，过滤，旋干，剩余物真空干燥得到褐色固体(E)-3-(3,5-二氯-4-羟基苯基)-1-(6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(1.02g，收率：61％)。LCMS(ESI)：380[M+1] +。
步骤37b:(E)-2-(2,6-二氯-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dichloro-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(0708-100)的制备。往圆底烧瓶中加入(E)-3-(3,5-二氯-4-羟基苯基)-1-(6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(0707-100)(1.02g，2.7mmol，1.0当量)，2-溴代异丁酸叔丁酯(6.02g，27.0mmol，10.0当量)，碳酸氢钠(2.72g，32.4mmol，12.0当量)和二甲基亚砜(20ml)，将反应液加热到100℃反应3小时。反应液用乙酸乙酯(150ml)稀释，用半饱和食盐水(100ml×4)洗涤，有机相旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝8:1)得到黄色膏状物(E)-2-(2,6-二氯-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2甲基丙酸叔丁酯(0.49g，收率：35％)。LCMS(ESI)：522[M+1] +。
步骤37c:(E)-2-(2,6-二氯-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dichloro-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(100)的制备。往(E)-2-(2,6-二氯-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2甲基丙酸叔丁酯(0708-100)(0.49g，0.94mmol，1.0当量)的二氯甲烷(10ml)溶液中缓慢加入三氟乙酸(2ml)，室温搅拌过夜。将反应液用乙酸乙酯(100ml)稀释，用半饱和食盐水(100ml×1)洗涤，有机相用无水硫酸钠干燥，过滤，旋干，剩余物用乙酸乙酯(3ml)重结晶得到黄色固体(E)-2-(2,6-二氯-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(220mg，收率：50％)。LCMS(ESI)：466[M+1] +，熔点：202～205℃； 1HNMR(DMSO，500MHz)：δ13.00(s，1H)，7.27-8.35(m，8H)，2.58(s，3H)，1.50(s，6H)。
实施例38：(E)-2-(2,6-二异丙基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-diisopropyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物101)的制备(按照方案七线路制备)
步骤38a:(E)-3-(4-羟基-3,5-二异丙基苯基)-1-(6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-diisopropylphenyl)-1-(6-(methylthio)benzofuran-2-yl)prop-2-en-1-one)(0707-101)的制备。往圆底烧瓶中加入1-(6-(甲硫基)苯并呋喃-2-基)乙-1-酮(0706-51)(0.206g，1.0mmol，1.0当量)，4-羟基-3,5-二异丙基苯甲醛(0.206g，1.0mmol，1.10当量)，二氧六环溶液(10ml)和甲磺酸(2ml)，加热到55℃反应4小时。反应液用乙酸乙酯(100ml)稀释，分别用水(100ml×1)和食盐水洗涤(100ml×1)，有机相旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝5:1)得到黄色固体(E)-3-(4-羟基-3,5-二异丙基苯基)-1-(6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(0.20g，收率：50％)。LCMS(ESI)：395[M+1] +。
步骤38b:(E)-2-(2,6-二异丙基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-diisopropyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(0708-101)的制备。往圆底烧瓶中加入(E)-3-(4-羟基-3,5-二异丙基苯基)-1-(6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(0707-101)(0.20g，0.5mmol，1.0当量)，2-溴代异丁酸叔丁酯(1.12g，5.0mmol，10.0当量)，碳酸钾(0.69g，5.0mmol，10.0当量)和乙腈(20ml)，将反应液在氮气的保护下加热回流过夜。反应液旋干，剩余物用硅胶柱层析法纯化(洗脱剂：石油醚：乙酸乙酯＝10:1)得到黄色油状物(E)-2-(2,6-二异丙基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2甲基丙酸叔丁酯(0.11g，收率：41％)。LCMS(ESI)：537[M+1] +。
步骤38c:(E)-2-(2,6-二异丙基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-diisopropyl-4-(3-(6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物101)的制备。往(E)-2-(2,6-二异丙基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2甲基丙酸叔丁酯(0708-101)(0.11g，0.20mmol，1.0当量)的二氯甲烷(10ml)溶液中缓慢加入三氟乙酸(2ml)，反应液室温下搅拌2小时。将反应液倒入水(100ml)中，用二氯甲烷(100ml×1)萃取，有机相用无水硫酸钠干燥，过滤，旋干，剩余物用甲醇(3ml)重结晶得到黄色固体(E)-2-(2,6-二异丙基-4-(3-(6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(60mg，收率：62％)。LCMS(ESI)：481[M+1] +；熔点：199～202℃； 1HNMR(DMSO，500MHz)：δ12.97(s，1H)，7.26-8.42(m，8H)，3.25(m,2H)，2.61(s，3H)，1.38(s，6H)，1.21(d，J＝8.5Hz，12H)。
实施例39：(E)-2-(2,6-二甲氧基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethoxy-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物102)的制备(按照方案十线路制备)
步骤39a:(E)-3-(4-羟基-3,5-二甲氧基苯基)-1-(3-甲基-6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-dimethoxyphenyl)-1-(3-methyl-6-(methylthio)benzofuran-2-yl)prop-2-en-1-one)(1004-102)的制备:往1-(3-甲基-6-(甲硫基)苯并呋喃-2-基)乙-1-酮(1003-62)(150mg，0.682mmol，1.0当量)和4-羟基-3,5-二甲氧基苯甲醛(124mg，0.682mmol，1.0当量)的乙醇溶液(8ml)中缓慢滴加浓硫酸(2mL)，室温下反应6小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取。萃取液用饱和食盐水(30mL×1)洗涤并用无水硫酸钠干燥，浓缩得到黄色固体(E)-3-(4-羟基-3,5-二甲氧基苯基)-1-(3-甲基-6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(260mg，粗品)。LCMS(ESI)：m/z 385[M+1] +。
步骤39b:(E)-2-(2,6-二甲氧基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dimethoxy-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(1005-102)的制备:将(E)-3-(4-羟基-3,5-二甲氧基苯基)-1-(3-甲基-6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(1004-102)(260mg,0.678mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(0.73mL,4.06mmol,6.0当量)溶于二甲亚砜(10mL)中，然后加入碳酸钾(0.37g,2.712mmol,4.0当量)。用氮气置换三遍然后在100℃下反应6小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥。浓缩得到的粗产品用硅胶柱层析法(石油醚：乙酸乙酯＝8：1)纯化得到黄色固体(E)-2-(2,6-二甲氧基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(180mg，收率：50％)。LCMS(ESI)：m/z 527[M+1] +。
步骤39c:(E)-2-(2,6-二甲氧基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dimethoxy-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物102)的制备:室温下往(E)-2-(2,6-二甲氧基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(1005-102)(180mg，0.342mmol，1.0当量)的二氯甲烷溶液(15ml)中缓慢滴加三氟乙酸(1.5mL)。混合液在室温下搅拌5小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥。浓缩得到的粗产品用甲醇(5mL)洗涤然后过滤。收集固体并在真空下干燥得到黄色固体(E)-2-(2,6-二甲氧基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(50mg，收率：31％)。LCMS(ESI)：m/z 471[M+1] +，熔点：105～108℃； 1HNMR(DMSO-d 6，500MHz)：δ12.36(s,1H),7.77-7.68(m,3H),7.57(s,1H),7.28(d,J＝8.5Hz,1H),7.16(s,2H),3.81(s,6H),2.62(s,3H),2.59(s,3H),1.34(s,6H)。
实施例40：(E)-2-(2,6-二氯-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dichloro-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物103)的制备(按照方案十线路制备)
步骤40a:(E)-3-(3,5-二氯-4-羟苯基)-1-(3-甲基-6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(3,5-dichloro-4-hydroxyphenyl)-1-(3-methyl-6-(methylthio)benzofuran-2-yl)prop-2-en-1-one)(1004-103)的制备:往1-(3-甲基-6-(甲硫基)苯并呋喃-2-基)乙-1-酮(1003-62)(150mg，0.682mmol，1.0当量)和3,5-二氯-4-羟基-苯甲醛(130mg，0.682mmol，1.0当量)的乙醇溶液(8ml)中缓慢滴加浓硫酸(2mL)，室温下反应过夜。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥，浓缩得到黄色固体(E)-3-(3,5-二氯-4-羟苯基)-1-(3-甲基-6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(268mg，粗品)。LCMS(ESI)：m/z 393[M+1] +。
步骤40b:(E)-2-(2,6-二氯-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-dichloro-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxopro p-1-en-1-yl)phenoxy)-2-methylpropanoate)(1005-103)的制备:将(E)-3-(3,5-二氯-4-羟苯基)-1-(3-甲基-6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(1004-103)(268mg,0.682mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(0.74mL,4.09mmol,6.0当量)溶于二甲亚砜(10mL)中，然后加入碳酸钾(0.377g,2.73mmol,4.0当量)。用氮气置换反应体系中的空气三遍，然后在100℃下反应过夜。反应液加水(40mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥，浓缩得到的粗产品用硅胶柱层析法(石油醚：乙酸乙酯＝20：1)纯化得到黄色油状液体(E)-2-(2,6-二氯-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(96mg，收率：26％)。LCMS(ESI)：m/z 535[M+1] +。
步骤40c:(E)-2-(2,6-二氯-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-dichloro-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物103)的制备:室温下往(E)-2-(2,6-二氯-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(1005-103)(96mg，0.179mmol，1.0当量)的二氯甲烷溶液(10ml)中缓慢滴加三氟乙酸(1.0mL)。混合液在室温下搅拌5小时。反应液加水(40mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用饱和食盐水(30mL×1)洗涤并用无水硫酸钠干燥。浓缩得到粗产品，用硅胶柱层析法(二氯甲烷：甲醇＝20：1)纯化得到黄色固体(E)-2-(2,6-二氯-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(60mg，收率：70％)。LCMS(ESI)：m/z 479[M+1] +，熔点：206～208℃； 1HNMR(DMSO-d 6，500MHz)：δ12.99(s,1H),8.03(s,2H),7.80-7.68(m,3H),7.57(s,1H),7.28(d,J＝8.5Hz,1H),2.61(s,3H),2.58(s,3H),1.51(s,6H)。
实施例41：(E)-2-(2,6-二异丙基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-diisopropyl-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物104)的制备(按照方案十线路制备)
步骤41a:(E)-3-(4-羟基-3,5-二异丙基苯基)-1-(3-甲基-6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮((E)-3-(4-hydroxy-3,5-diisopropylphenyl)-1-(3-methyl-6-(methylthio)benzofuran-2-yl)prop-2-en-1-one)(1004-104)的制备:往1-(3-甲基-6-(甲硫基)苯并呋喃-2-基)乙-1-酮(1003-62)(120mg，0.545mmol，1.0当量)和4-羟基-3,5-二异丙基苯甲醛(112.4mg，0.545mmol，1.0当量)的乙醇溶液(8ml)中缓慢滴加浓硫酸(2mL)，室温下反应6小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥，浓缩得到黄色固体(E)-3-(4-羟基-3,5-二异丙基苯基)-1-(3-甲基-6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(222mg，粗品)。LCMS(ESI)：m/z 409[M+1] +。
步骤41b:(E)-2-(2,6-二异丙基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(tert-butyl(E)-2-(2,6-diisopropyl-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoate)(1005-104)的制备:将(E)-3-(4-羟基-3,5-二异丙基苯基)-1-(3-甲基-6-(甲硫基)苯并呋喃-2-基)丙-2-烯-1-酮(1004-104)(222mg,0.545mmol,1.0当量)和2-溴-2-甲基丙酸叔丁酯(0.98mL,5.45mmol,10.0当量)溶于乙腈(10mL)中，然后加入碳酸钾(0.301g,2.18mmol,4.0当量)。用氮气置换反应体系中的空气三遍，然后在85℃下反应过夜。反应完成后浓缩得到粗产品，用硅胶柱层析法(石油醚：乙酸乙酯＝20：1)纯化得到黄色油状液体(E)-2-(2,6-二异丙基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(50mg，收率：17％)。LCMS(ESI)：m/z 551[M+1] +。
步骤41c:(E)-2-(2,6-二异丙基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸((E)-2-(2,6-diisopropyl-4-(3-(3-methyl-6-(methylthio)benzofuran-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid)(化合物104)的制备:室温下往(E)-2-(2,6-二异丙基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸叔丁酯(1005-104)(50mg，0.091mmol，1.0当量)的二氯甲烷溶液(5ml)中缓慢滴加三氟乙酸(0.5mL)。混合液在室温下搅拌6小时。反应液加水(30mL)稀释，然后用乙酸乙酯(30mL×3)萃取，萃取液用饱和食盐水(20mL×1)洗涤并用无水硫酸钠干燥。浓缩得到粗产品，用硅胶柱层析法(二氯甲烷：甲醇＝30：1)纯化得到黄色固体(E)-2-(2,6-二异丙基-4-(3-(3-甲基-6-(甲硫基)苯并呋喃-2-基)-3-氧代丙-1-烯-1-基)苯氧基)-2-甲基丙酸(37mg，收率：82％)。LCMS(ESI)：m/z 495[M+1] +，熔点：186～189℃； 1HNMR(DMSO-d 6，500MHz)：δ13.00(s,1H),7.81-7.75(m,2H),7.69(s,1H),7.65-7.58(m,3H),7.28(d,J＝10.5Hz,1H),3.33-3.25(m,2H),2.62(s,3H),2.60(s,3H),1.38(s,6H),1.20(d,J＝8.5Hz,12H)。
实施例42：生物活性试验
一、PPAR激动剂生物活性测定
1、实验方法
本实施例采用Hela细胞/荧光素酶报告基因法测定PPAR激动剂的生物活性。
通过热休克处理将目的质粒PCMV PPARα(Ampicillin+),PCMV PPARγ(Ampicillin+),PCMV PPARδ(Ampicillin+)，pPPRE3-TK-Luciferase(Ampicillin+)分别导入DH5α感受态细胞中。37℃震荡(180rpm)培养1小时后,接种至含有抗生素Ampicillin的LB琼脂固体培养基上，37℃倒置培养12～16小时。然后取培养于培养基上的单克隆菌落接种至LB液体培养基中扩大培养。将培养所得菌液以Plasmid Midi Kit(Qiagen；#12143)提取目的质粒。将离心所得质粒混悬于TE buffer,测定其质粒浓度并保存于-20℃。取生长期的Hela细胞种于6孔板(8×10 5细胞/孔)，培养6-8小时后,用
Figure PCTCN2018093760-appb-000029
3000 Transfection Reagent(Invitrogen；#L3000015)进行转染。将含有PPAR结合部位(peroxisome proliferator response element，PPRE)和萤火虫荧光素酶(Luciferase)基因的质粒(pPPRE3-TK-Luciferase)与PPAR表达载体共转染到Hela细胞中，其中质粒DNA总量为2.5ug(各PPAR表达载体质量比为pPPRE:PPARα＝6:1,pPPRE:PPARδ＝8：1,pPPRE:PPARγ＝2：1),构建PPAR激动剂的药物筛选细胞模型。PPAR与配体结合后再结合至过氧化物酶体增殖物反应元件(PPRE)，从而启动下游萤火虫荧光素酶表达，其表达强度与PPAR激活程度成正比。将转染24小时后的细胞用完全培养液配制成细胞浓度为3×10 5/ml的细胞悬液，接种至96孔板中，每孔100ul。培养过夜后，将培养基更换为含1％FBS的培养基。待测化合物母液10mM(1000×)用DMSO 4倍系列稀释成8个浓度梯度,用1％FBS的培养基稀释至50uM(5×),每孔按不同浓度梯度加入5×化合物稀释液25ul，置于37℃、5％CO 2培养箱中培养24h。取出96孔板，每孔加入30μl Bright-Glo TM荧光素酶检测试剂Bright-Glo TM Luciferase Assay System(Promega；#E2620)，通过SynergyH1全功能微孔板检测仪测定其Luciferase发光强度。将所得数据运用GraphPad Prism 5.0软件来计算EC50，以此测定化合物的生物活性。
2、实验结果
实施例1-41合成的化合物对PPAR的激动活性用EC 50表示(见表1)。EC 50是指化合物对测定PPAR的激动活性增加50％时的药物浓度。表1中的化合物编号对应于实施例1-41中的化合物编号。
表1 化合物对3种亚型PPAR的激动活性(EC 50,nM)
化合物编号 PPAα PPARδ PPARγ
1 419.9   172.0
2 947.6    
3 452.7   576.9
5 24.4 36.0 26.2
6 9.6 118.5 62.6
9 46.8    
12 99.8   279.2
13 475.7   3409.0
14 156.0   122.3
20 165.2    
27 59.1 603.7 124.3
36 75.1 120.1 31.6
38 >10000 837.9  
39 365.9    
43 39.8 334.8 116.4
44 7.67    
49 873.9    
50 122.8   167.3
51 4.0 64.9 35.3
56 83.9   1101.0
57 1180.0    
58 352.3    
60 46.7 613.9 92.3
62 16.6 210.3 132.4
63 19.2 204.8 95.5
64 105.2    
73 3.8    
74 13.9 144.5 29.3
75 121.0    
76 58.9    
77 121.0    
81 24.9 3636.0 94.1
82 70.2    
88 2445.0    
94 41.9    
99 52.1    
100 2.0 87.1 475.1
101 476.6    
102 191.0    
103 8.7 164.0 788.1
104 381.6    
Elafibranor(GFT-505) 29.2 262.2 86.6
我们发现，Elafibranor除了是PPARα和PPARδ的激动剂外，对PPARγ亦有激动活性。本发明化合物和Elafibranor相似，是PPARα、PPARδ和PPARγ三种亚型核激素受体的激动剂。不同化合物对三种亚型的EC 50值有所不同，和Elafibranor比较，化合物51激活PPARα和PPARδ的活性分别提高了7倍和2倍，而对PPARγ影响差别较小；化合物62激活PPARα的活性提高1倍，但是激活PPARγ较弱。同时，我们还发现，化合物100和化合物103激活PPARα活性极高，EC50值分别为Elafibranor EC50值的14.6倍和3.4倍。但是，与Elafibranor比较，两者对PPARγ激活活性明显降低。由于不同PPAR亚型在各种疾病中发挥不同作用，本发明中不同化合物对PPAR亚型的选择性特征，对不同疾病治疗具有潜在意义。
几种治疗糖尿病Glitazars类PPARα和PPARγ双激动剂(例如，Aleglitazar，muraglitazar和tesaglitazar)因临床试验中发生心脏毒性或肾脏毒性而终止开发(Robert S et al.Am Heart J 164:672–680,2012，Conlon D.Br J Diabetes Vasc Dis 6:135–137,2006)。目前对PPARα和PPARγ双激动剂毒性发生原因尚不十分清楚。Aleglitazar激活PPARγ活性较高，其激活PPARα和PPARγ的EC 50分别为38nM和19nM，PPARγ/PPARα的EC 50比值为0.5(Bénardeau A et al.Bioorg Med Chem Lett.19:2468-2473,2009)。Elafibranor对PPARα选择活性比Glitazars类相对较高，在本发明实验条件下，Elafibranor激活PPARγ/PPARα的比值为2.97，本发明化合物51、62、100和103激活PPARγ/PPARα的比值在Elafibranor基础上明显提高，分别为8.83、7.98、237.55和90.59。提示本发明化合物的安全性可能更高。
二、药代动力学(PK)实验
1、实验方法
雄性SD大鼠，体重250-300克，试验前过夜禁食。待试化合物溶解在30％磺丁基-β-环糊精(SBE-β-CD) 中，以20mg/kg的剂量灌胃给药。给药后15分钟、30分钟和1、2、3、4、6、8及24小时取血，每时间点约取血0.3ml，置于含K2-EDTA(乙二胺四乙酸二钾)的离心管中，离心处理(2,000g，10分钟，4℃)取血浆，储存在-80℃的超低温冰箱中。50μL的血浆样品与5微升内标(IS)混合，用乙酸乙酯萃取。真空干燥后残留物重新溶于乙腈中。对样品进行过滤，并注入到LC-MS/MS分析。
2、实验结果
本发明提供的化合物5、36、43、51、62、63、81、100和103(编号与实施例1-41中一致)与对照物Elafibranor(GFT-505)相比(结果见表2和图1)，在大鼠经口服给药后，吸收良好，血液暴露量效高,半衰期明显延长。化合物5、36、62和43的Cmax为参照化合物Elafibranor的1.6-2.5倍；AUC 0-24h为Elafibranor的1.2-2.5倍。化合物100和103的Cmax为参照化合物Elafibranor的4.4-6.8倍；AUC 0-24h为Elafibranor的10.2-37.3倍。Cmax是指最大血药浓度，T1/2为半衰期，AUC 0-24是指0-24小时时间-浓度曲线下面积，AUC 0-inf是指0-Inf时间-浓度曲线下面积。
表2 大鼠灌胃给药(20mg/kg)药代动力学
Figure PCTCN2018093760-appb-000030
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (30)

  1. 具有式(I)所示结构的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子：
    Figure PCTCN2018093760-appb-100001
    其中：
    R 1,R 2分别独立选自：H，卤素，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基,C1-C6烷氧基，羟基；
    R 3,R 4分别独立选自：H，卤素，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基,C1-C6烷氧基，羟基，并且R 3,R 4不同时为H；或者R 3,R 4相连组成3-8元碳环或3-8元杂环；
    R 5选自OR 6，NR 7R 8；
    Q是一个单键或者为CR 7R 8；
    R 6，R 7和R 8分别独立选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基；
    W，W 1和Y分别独立选自：O或S；
    环A为8-12元取代或未取代的双环并环，所述双环并环为饱和的双环并环、部分不饱和的双环并环或者芳香的双环并环，并且所述双环并环上的环碳原子被0至5个杂原子取代，所述杂原子是指O、N或S。
  2. 根据权利要求1所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，W，W 1均选自：O。
  3. 根据权利要求2所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，所述化合物具有式(II)所示结构：
    Figure PCTCN2018093760-appb-100002
  4. 根据权利要求1-3任一项所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，环A选自：
    Figure PCTCN2018093760-appb-100003
    其中：
    X 1、X 2、X 3、X 4、X 5、X 6、X 7分别独立选自：CR 9，CR 12或N，并且X 1、X 2、X 3、X 4中至少有一个是CR 12；
    R 9选自：H，卤素，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,C1-C4烷基胺基取代的C1-C6烷基，芳基，杂芳基，硝基，氰基，-OR，-N(R) 2，-SR，-C(O)OR，-C(O)N(R) 2，-C(O)R，-S(O)R，-S(O) 2R，-S(O) 2N(R) 2，-N(R)C(O)R；
    R 10选自：H，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代C1-C6烷基，羟基取代C1-C6烷基，烷氧基取代C1-C6烷基，氨基取代的C1-C6烷基,C1-C4烷基胺基取代的C1-C6烷基；
    R 11选自：H，-SR，-OR，-N(R) 2，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基；
    R 12选自：H，-SR，-OR，-N(R) 2，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基；
    m选自：0,1,2；
    每个R独立选自：H，C1-C6烷基，C2-C6烯基，C2-C6炔基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,C1-C4烷基胺基取代的C1-C6烷基。
  5. 根据权利要求4所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，环A选自：
    Figure PCTCN2018093760-appb-100004
  6. 根据权利要求5所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，环A选自：
    Figure PCTCN2018093760-appb-100005
  7. 根据权利要求6所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，环A选自：
    Figure PCTCN2018093760-appb-100006
  8. 根据权利要求7所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，环A选自：
    Figure PCTCN2018093760-appb-100007
  9. 根据权利要求4所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，
    R 9选自：H，卤素，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,C1-C4烷基胺基取代的C1-C6烷基，-OR，-N(R) 2，-SR，-C(O)R，-S(O)R；
    其中R选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基。
  10. 根据权利要求9所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 9选自：H，C1-C6烷基，卤素取代的C1-C6烷基。
  11. 根据权利要求10所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 9选自：H，甲基，乙基，异丙基，三氟甲基。
  12. 根据权利要求4所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者 其前药分子，其特征在于，R 10选自：H。
  13. 根据权利要求4所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 11选自：H。
  14. 根据权利要求4所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 12选自：H，-SR，-OR，-N(R) 2，C1-C6烷基；其中，R选自：H，C1-C6烷基。
  15. 根据权利要求14所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 12选自：-SR，-OR；其中，R选自：C1-C6烷基。
  16. 根据权利要求1-3任一项所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 1,R 2分别独立选自：H，C1-C6烷基，C1-C6烷氧基，卤素。
  17. 根据权利要求16所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 1,R 2分别独立选自：C1-C3烷基，卤素，C1-C3烷氧基。
  18. 根据权利要求17所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 1,R 2均为甲基，或者R 1,R 2均为氯。
  19. 根据权利要求1-3任一项所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 3,R 4分别独立选自：H，C1-C6烷基，C1-C6烷氧基，卤素，或者R 3,R 4相连组成3-8元碳环。
  20. 根据权利要求19所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 3,R 4分别独立选自：C1-C6烷基。
  21. 根据权利要求1-3任一项所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 5选自：OR 6；R 6选自：H，C1-C6烷基。
  22. 根据权利要求21所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 5选自：OR 6；R 6选自：H。
  23. 根据权利要求1-3任一项所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，Y选自：O。
  24. 根据权利要求1-3任一项所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，
    R 1,R 2分别独立选自：H，C1-C6烷基，C1-C6烷氧基，卤素；
    R 3,R 4分别独立选自：H，C1-C6烷基，C1-C6烷氧基，卤素，或者R 3,R 4相连组成3-8元碳环；
    R 5选自OR 6；R 6选自H，C1-C6烷基；
    Y选自O或S；
    环A选自：
    Figure PCTCN2018093760-appb-100008
    X 1、X 2、X 3、X 4、X 5、X 6、X 7分别独立选自CR 9，CR 12或N，并且X 1、X 2、X 3、X 4中至少有一个是CR 12；
    R 9选自：H，卤素，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,C1-C4烷基胺基取代的C1-C6烷基，硝基，氰基，-OR，-N(R) 2，-SR，-C(O)OR，-C(O)N(R) 2，-C(O)R，-S(O)R，-S(O) 2R，-S(O) 2N(R) 2，-N(R)C(O)R；
    R 10选自：H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，氨基取代的C1-C6烷基,C1-C4烷基胺基取代的C1-C6烷基；
    R 11选自：H，-SR，-OR，-N(R) 2，C1-C6烷基；
    R 12选自：H，-SR，-OR，-N(R) 2，C1-C6烷基；
    n选自：0,1,2；
    每个R独立选自H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基。
  25. 根据权利要求23所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，
    R 1,R 2分别独立选自：C1-C3烷基，卤素，C1-C3烷氧基；
    R 3,R 4分别独立选自：C1-C6烷基；
    R 5选自：OR 6；R 6选自：H；
    Y选自：O；
    环A选自：
    Figure PCTCN2018093760-appb-100009
    R 9选自：H，卤素，C1-C6烷基，卤素取代的C1-C6烷基，羟基取代的C1-C6烷基，烷氧基取代的C1-C6烷基，-OR，-N(R) 2，-SR，-C(O)OR，-C(O)N(R) 2，-C(O)R，-S(O)R，-S(O) 2R，-S(O) 2N(R) 2，-N(R)C(O)R；
    R 12选自：H，-SR，-OR，C1-C6烷基；
    n选自：0,1；
    每个R独立选自H，C1-C6烷基，C3-C8环烷基，C3-C8环烷基甲基，卤素取代的C1-C6烷基。
  26. 根据权利要求1所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，所述1，3-二取代烯酮类化合物选自：
    Figure PCTCN2018093760-appb-100010
    Figure PCTCN2018093760-appb-100011
    Figure PCTCN2018093760-appb-100012
    Figure PCTCN2018093760-appb-100013
    Figure PCTCN2018093760-appb-100014
    Figure PCTCN2018093760-appb-100015
  27. 权利要求1-26任一项所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备PPAR激动剂中的应用。
  28. 权利要求1-26任一项所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备预防或治疗PPAR调控异常相关的疾病中的应用，所述PPAR调控异常相关的疾病包括：脂质和糖代谢异常相关的疾病、炎症和纤维化异常相关的疾病、心血管疾病、肾脏疾病、大脑退行性疾病。
  29. 根据权利要求28所述的应用，其特征在于，所述PPAR调控异常相关的疾病包括：非酒精性脂肪肝病、非酒精性肝炎、胆汁淤积性肝病、糖尿病、肥胖症、心力衰竭、动脉粥样硬化、慢性肾病、肾功能衰竭、阿尔茨海默病。
  30. 一种防治PPAR调控异常相关的疾病的药物组合物，其特征在于，其活性成分包括有权利要求1-26任一项所述的1，3-二取代烯酮类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11306102B2 (en) 2017-07-31 2022-04-19 Bebetter Med Inc. 1,3-di-substituted ketene compound and application thereof

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11332457B2 (en) 2017-11-30 2022-05-17 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Aromatic compound, pharmaceutical composition and use thereof
KR20220012222A (ko) * 2019-05-24 2022-02-03 쓰촨 케룬-바이오테크 바이오파마수티컬 컴퍼니 리미티드 방향족 화합물의 고체 형태 및 그 제조 방법
CN110143890B (zh) * 2019-06-12 2020-12-22 天津科技大学 一种查尔酮衍生物和合成方法及其在制备抗非酒精性脂肪肝炎药物中的应用
CN112824380A (zh) * 2019-11-21 2021-05-21 杭州百诚医药科技股份有限公司 α-氟代查耳酮类衍生物及其应用
CN110818662A (zh) * 2019-12-11 2020-02-21 肇庆市万维新材料科技有限公司 一种那布卡辛的合成方法
CN116102528B (zh) * 2023-02-03 2024-05-28 三峡大学 一类泽兰素查尔酮类化合物，制备方法及其应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1688532A (zh) * 2002-07-08 2005-10-26 基恩菲特公司 基于取代的1,3－二苯基丙－2－烯－1－酮衍生物的组合物、其制备及其用途
CN1930122A (zh) * 2004-01-08 2007-03-14 基恩菲特公司 1,3－二苯基丙－2－烯－1－酮衍生化合物、其制备方法以及其用途

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA904291A (en) * 1972-07-04 The Dow Chemical Company Substituted phenoxyacetic acids
JP4598278B2 (ja) * 1999-04-28 2010-12-15 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Ｐｐａｒ受容体リガンドとしてのジアリール酸誘導体
CN1447804A (zh) 2000-06-20 2003-10-08 阿特罗吉尼克斯公司 1,3－二－(被取代的苯基)－2－丙烯－1－酮及其治疗vcam－1介导的疾病的用途
FR2841900B1 (fr) 2002-07-08 2007-03-02 Genfit S A Nouveaux derives de 1,3-diphenylprop-2-en-1-one substitues, preparation et utilisations
CA2550576A1 (fr) * 2004-01-08 2005-08-11 Genfit Composes derives de 1,3-diphenylprop-2-en-1-one, preparation et utilisations
CN1861560A (zh) * 2005-05-13 2006-11-15 中国科学院上海药物研究所 一类羧酸衍生物，其制备方法及药物组合物
FR2910893A1 (fr) 2006-12-29 2008-07-04 Genfit Sa Derives de (phenylthiazolyl)-phenyl-propan-1-one et de (phenyloxazolyl)-phenyl-propan-1-one substitues, preparations et utilisations.
FR2910892A1 (fr) * 2006-12-29 2008-07-04 Genfit Sa Derives de 1,3-diphenylpropane substitues, preparations et utilisations.
ES2423793T3 (es) * 2008-05-26 2013-09-24 Genfit Compuestos agonistas de PPAR, preparación y usos para el tratamiento de la diabetes y/o dislipidemias
CN108658908B (zh) 2017-07-31 2019-05-10 广州必贝特医药技术有限公司 1，3-二取代烯酮类化合物及其应用
US11332457B2 (en) * 2017-11-30 2022-05-17 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Aromatic compound, pharmaceutical composition and use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1688532A (zh) * 2002-07-08 2005-10-26 基恩菲特公司 基于取代的1,3－二苯基丙－2－烯－1－酮衍生物的组合物、其制备及其用途
CN1930122A (zh) * 2004-01-08 2007-03-14 基恩菲特公司 1,3－二苯基丙－2－烯－1－酮衍生化合物、其制备方法以及其用途

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
ADEDAPO AA ET AL., HUM EXP TOXICOL, vol. 32, 2013, pages 323 - 331
BAYS HE, J CLIN ENDOCRINOL METAB, 2012, pages 2889 - 97
BENARDEAU A ET AL., BIOORG MED CHEM LETT., vol. 19, 2009, pages 2468 - 2473
CONLON D. BR, J DIABETES VASE DIS, vol. 6, 2006, pages 135 - 137
D ORIO B, CURRALZHEIMER RES., 2017
DATABASE CAS 22 December 2008 (2008-12-22), Database accession no. 1088216-43-6 *
FAN JG ET AL., J DIG DIS, vol. 12, 2011, pages 38 - 44
FRANCIS G ET AL., ANN REV PHYSIOL., vol. 65, 2003, pages 261 - 311
HAN L, FUTURE CARDIOL., 5 June 2017 (2017-06-05)
KOO JB ET AL., BMC GASTROENTEROL., vol. 17, 2017, pages 73
OLEFSKY J M ET AL., TREND ENDOCRIN MET, vol. 11, 2000, pages 362 - 368
PAWLAK M ET AL., J HEPATOL, vol. 62, 2015, pages 720 - 733
RATZIU ET AL., GASTROENTEROLOGY, vol. 150, 2016, pages 1147 - 1159
ROBERT S ET AL., AM HEART J, vol. 164, 2012, pages 672 - 680
SAHEBKAR A ET AL., EXPERT OPIN PHARMACOTHER, vol. 15, 2014, pages 493 - 503m

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11306102B2 (en) 2017-07-31 2022-04-19 Bebetter Med Inc. 1,3-di-substituted ketene compound and application thereof

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