WO2014169817A1 - Phenylalanine compound having nitrogen heterocyclic link, pharmaceutical composition thereof, preparation method therefor, and use thereof - Google Patents

Phenylalanine compound having nitrogen heterocyclic link, pharmaceutical composition thereof, preparation method therefor, and use thereof Download PDF

Info

Publication number
WO2014169817A1
WO2014169817A1 PCT/CN2014/075466 CN2014075466W WO2014169817A1 WO 2014169817 A1 WO2014169817 A1 WO 2014169817A1 CN 2014075466 W CN2014075466 W CN 2014075466W WO 2014169817 A1 WO2014169817 A1 WO 2014169817A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
acid
oxy
phenyl
Prior art date
Application number
PCT/CN2014/075466
Other languages
French (fr)
Chinese (zh)
Inventor
胡有洪
冷颖
李德文
宁萌萌
Original Assignee
中国科学院上海药物研究所
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国科学院上海药物研究所 filed Critical 中国科学院上海药物研究所
Publication of WO2014169817A1 publication Critical patent/WO2014169817A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to the field of pharmacy, and in particular to a phenylpropionic acid compound containing a nitrogen-containing heterocyclic link, and a medicament thereof a physiologically acceptable salt, stereoisomer or prodrug molecule thereof, pharmaceutical composition thereof, preparation method, and use thereof in the preparation of a medicament for treating diabetes and disorders of glycolipid metabolism, especially in the preparation of type II diabetes Use of the drug.
  • the above compounds have a remarkable function of lowering blood sugar and regulating glycolipid metabolism activity.
  • Background Art It is well known that diabetes is a chronic disease that is the third most serious threat to human health after cancer and cardiovascular and cerebrovascular diseases.
  • Type I diabetes is characterized by a lack of insulin secretion called insulin-dependent diabetes mellitus (IDDM), which is caused by its inability to use insulin effectively, called non-insulin-dependent diabetes mellitus (NIDDM).
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin-dependent diabetes mellitus
  • Type II diabetes accounts for more than 90% of the global diabetes population.
  • the pathogenesis of type 2 diabetes mellitus is complicated, and its basic characteristics are that skeletal muscle, liver, fat and other tissues are resistant to insulin.
  • islet ⁇ cells can compensate insulin secretion to compensate for the deficiency of insulin, thus maintaining normal blood sugar levels.
  • the islet ⁇ -cell insulin secretion function is insufficient, and the patient's compensatory mechanism collapses, resulting in abnormally elevated blood glucose levels, which in turn leads to the formation of type 2 diabetes in the body.
  • GTP-binding protein coupling receptor 40 (GP 40) is a seven-pass transmembrane receptor. It is abundantly expressed in islets and is also expressed in the intestinal system. Current research suggests that this transmembrane receptor may be associated with certain cancers, neurological diseases, and metabolic diseases, especially diabetes. Studies have found that various forms of free fatty acid (FFA) are natural ligands for GPR40. FFA amplifies glucose-stimulated insulin secretion by activating GPR40 on the islet beta cell membrane. Given that GPR40 receptor agonists have a glucose-dependent advantage in promoting insulin secretion, they are potential targets for the treatment of diabetes.
  • FFA free fatty acid
  • the present invention is directed to compounds having the structure of Formula I below which are distinct from the structures of the reported compounds.
  • the compound of the present invention has a remarkable function of lowering blood sugar and regulating glycolipid metabolism activity, and is a novel type of GPR40 agonist.
  • An object of the present invention is to provide a phenylpropionic acid compound represented by the following formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, a racemate and a mixture thereof, or a stereoisomer thereof Body, or its prodrug molecule.
  • Another object of the present invention is to provide a process for the preparation of a phenylpropionic acid compound of the formula I.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a phenylpropionic acid compound selected from the formula I, a pharmaceutically acceptable salt thereof, an enantiomer thereof, and the like Racemization One or more of a mixture, a mixture thereof, a stereoisomer thereof and a prodrug molecule thereof, and a pharmaceutically acceptable excipient.
  • a further object of the present invention is to provide a phenylpropionic acid compound selected from the formula I, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a racemate and a mixture thereof, and stereoisomers thereof Use of one or more of a body and a prodrug molecule thereof for the manufacture of a medicament for the treatment of diabetes and disorders of glycolipid metabolism.
  • It is still another object of the present invention to provide a method of treating diabetes and disorders of glycolipid metabolism comprising administering to a subject in need of such treatment a phenylpropionic acid compound selected from Formula I or a pharmaceutically acceptable compound thereof.
  • a phenylpropionic acid compound selected from Formula I or a pharmaceutically acceptable compound thereof.
  • One aspect provides a phenylpropionic acid compound of the formula I:
  • R n R 2 are each independently selected from the group consisting of H, hydroxy, halogen, nitro, dC ⁇ fluorenyl, halo dC ⁇ fluorenyl, dC ⁇ decyloxy, halo dC ⁇ decyloxy, C 3 -C 1() a cycloalkyl group and a 3- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from S, 0 and N; preferably selected from the group consisting of H, hydroxy, halogen, nitro, CC 6 ⁇ ⁇ CrC 6 C ⁇ - C 6 3 ⁇ 43 ⁇ 4 , ⁇ ⁇ CC 6 C 3 -C 8 i groups and 3 to 10 membered heterocyclic groups containing at least one nitrogen atom; more preferably each independently selected from H, hydroxy, halogen, nitro, C r C 4 -mercapto, halo C r C 4 fluorenyl, C r C 4 decyloxy,
  • R 3 is selected from the group consisting of H; halogen; carboxy; C r C 2 () fluorenyl; halogenated C r C 2 () fluorenyl; -O a ; -N( a ) S0 2 b , -NR ab; -N ( a ) C(0) b ; -C(0)NR ab ; -S0 2 a ; -S b ; selected from C d .
  • ⁇ Preferably selected from H ; halogen; carboxy; C r C 6 fluorenyl; halogenated C r C 6 fluorenyl; -OR a; -N( a )S0 2 b ; -NR ab; -N( a )C(0 b ; -C(0)NR ab ; -S0 2 a ; -S b ; selected from CC 4 decyloxy, C 3 -C 8 cyclodecyl, -SR C , -S0 2 R c , -NR Cd or substituted C substituted by a substituent in a 3-6 membered heterocyclic group containing 1 to 3 heteroatoms selected from 0, S and N substituted by dC 4 fluorenyl, hydroxy or oxo group r C 6 embankment group; and the embankment with a C r C 4 group, 3 - 8 cycloalkyl group embankment, -SR
  • R b are each independently selected from the group consisting of H, C r C 6 fluorenyl, C 3 -C 8 cyclodecyl and unsubstituted or substituted by C r C 6 fluorenyl or oxo group and selected from 0, S and N 3-8 membered heterocyclic groups of 1 to 3 heteroatoms; preferably each independently selected from H, C r C 4 fluorenyl, C 3 -C 6 cyclodecyl and unsubstituted or C r C 3 fluorenyl Or a methoxy group-substituted 3-6 membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of 0, S and N;
  • R c and R d are each independently selected from H, C r C 6 fluorenyl and 3- substituted or substituted by ( ⁇ - 3 fluorenyl) containing 1 to 3 heteroatoms selected from 0, S and N 8-membered heterocyclic group; preferably each independently selected from H, C r C 3 fluorenyl and unsubstituted or substituted by C r C 3 fluorenyl containing 1 to 3 heteroatoms selected from 0, S and N 3-6 membered heterocyclic group;
  • R 4 is selected from the group consisting of H, hydroxy, halogen, dC fluorenyl and halogenated dC fluorenyl; preferably H, hydroxy, halogen, C r C 6 fluorenyl and halogenated C r C 6 fluorenyl,
  • R 5 is selected from the group consisting of H, halogen and dC fluorenyl; preferably H, halogen and C r C 6 fluorenyl; or R 4 together with the carbon atom attached thereto and benzene ring together form a benzo 5-8 membered heterocyclic ring group, containing heterocycle selected from 0, N and S, 1 to 3 hetero atoms, and said heterocyclic group is unsubstituted or substituted alkyl with C r C 6; R 4 and preferably together with it, and The linked carbon atom together with the benzene ring form a benzo 5-membered heterocyclic group containing one to two heteroatoms selected from the group consisting of 0, N and S. And not substituted or substituted by C r C 3 thiol; further preferably, R 4 and associated with it
  • Carbon atoms form together with the benzene ring or.
  • phenylpropionic acid compound of the formula I of the present invention has a structure represented by the following formula II or formula III:
  • R 6 is H or C r C 6 fluorenyl, and in Formula III, when Z is 0 or S, R 6 is absent.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • halo refers to a single or multiple halogen atoms selected from the group consisting of fluorine, chlorine, bromine and iodine.
  • d-o fluorenyl refers to a straight or branched fluorenyl group having from 1 to 20 carbon atoms in the main chain, and includes, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, decyl, undecyl, fluorenyl, tetradecyl, sixteenth, seventeen , 18 courtyards, 20 courtyards, etc.
  • C C6 yard base and "Ci-Gt yard base” have similar meanings.
  • d-omethoxy refers to a straight or branched decyloxy group having from 1 to 20 carbon atoms in the main chain, and includes, without limitation, methoxy, ethoxy, n-propoxy, and iso Propyloxy, butoxy, pentyloxy, hexyloxy, octyloxy, decyloxy, undecyloxy, dodecyloxy, tetradecyloxy, hexadecanyloxy, seventeen Oxygen, ten hospital oxygen, twenty hospital oxygen, etc.
  • CK "Ci-C 6 methoxy" and "C r C 4 methoxy” have similar meanings.
  • C 3 -C 1 () cyclodecyl refers to a cyclic fluorenyl group having 3 to 10 carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. And cycloheptyl; the terms “C 3 -C 8 cyclodecyl” and “C 3 -C 6 cyclodecyl” have similar meanings.
  • 3-8 membered heterocyclic group means a non-aromatic ring group having 3-8 atoms on the ring containing at least one atom selected from the group consisting of N, 0 and S atoms, such as an epoxy group, a pyrrolidinyl group, Morpholinyl and the like; the terms “5-8 membered heterocyclic group” and “3-6 membered heterocyclic group” have similar meanings.
  • pharmaceutically acceptable salt in the present invention means a compound represented by the formula I according to the present invention and a mineral acid such as phosphoric acid, sulfuric acid or hydrochloric acid, or acetic acid, tartaric acid, citric acid, malic acid or fumaric acid.
  • An organic acid, or a salt formed by an acidic amino acid such as aspartic acid or glutamic acid, or a salt formed with an inorganic base after forming an ester or an amide with the above-mentioned acid, such as sodium, potassium, calcium, aluminum salt and ammonium salt.
  • the compound is preferably selected from the following compounds:
  • Step 1 R 4 -substituted p-bromobenzyl alcohol 1 and ethyl acrylate 2 are subjected to Heck reaction to obtain intermediate 3, and the double bond is reduced to obtain intermediate 4, and then bromination is carried out to convert benzyl alcohol into benzyl bromide to obtain intermediate
  • the Heck reaction can be carried out, for example, in the presence of a palladium metal catalyst such as palladium acetate, tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium dichloride, for example, ruthenium, osmium-dimethylformamide.
  • the double bond reduction reaction can be carried out using, for example, hydrogen gas in a solvent such as ethyl acetate, butyl acetate, methanol, ethanol or n-propanol in the presence of, for example, a palladium carbon composite catalyst.
  • the bromination reaction can be carried out using a brominating agent such as phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide or dibromosulfoxide in a solvent such as acetonitrile, dichloromethane or diethyl ether;
  • Step 2 Intermediate 5 and substrate 6 are subjected to nucleophilic substitution reaction to obtain intermediate 7;
  • the nucleophilic substitution reaction can be, for example, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, potassium t-butoxide, tert-butyl
  • a base such as sodium acetate or sodium hydroxide
  • a solvent such as acetonitrile, hydrazine, hydrazine-dimethylformamide or tetrahydrofuran;
  • Step 3 Intermediate 7 and The intermediate 8 is obtained by Suzuki reaction coupling, and the intermediate 8 is subjected to hydrolysis reaction to obtain the product 9;
  • the Suzuki reaction may be, for example, a mixed solvent of toluene/acetonitrile/water in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, palladium acetate or palladium carbon composite, a mixed solvent of toluene/ethanol/water, a mixed solvent of acetonitrile/water or a mixed solvent of ethanol/water; and the hydrolysis reaction of the intermediate 8 may be a base such as potassium hydroxide, sodium hydroxide or lithium hydroxide.
  • a solvent such as an acetonitrile/water mixed solvent, a methanol/water mixed solvent or an ethanol/water mixed solvent;
  • Step 1 Compound 17 (wherein Z is 0 or S, R 6 is absent) or 20 (wherein Z is N, R 6 is H or C r C 6 fluorenyl) and substrate 6 is subjected to nucleophilic substitution reaction
  • Compound 21 is obtained, and the nucleophilic substitution reaction can be carried out, for example, in the presence of a catalyst such as potassium carbonate, cesium carbonate, sodium hydride, potassium t-butoxide or sodium t-butoxide in, for example, acetonitrile, acetone, ethyl acetate, tetrahydrofuran or hydrazine.
  • a catalyst such as potassium carbonate, cesium carbonate, sodium hydride, potassium t-butoxide or sodium t-butoxide in, for example, acetonitrile, acetone, ethyl acetate, tetrahydrofuran or hydrazine.
  • a catalyst such as potassium carbonate, cesium carbonate, sodium
  • Step 2 Compound 21 and The intermediate 22 is obtained by Suzuki reaction coupling, and the intermediate 22 is subjected to hydrolysis reaction to obtain the product 23;
  • the Suzuki reaction can be, for example, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride,
  • a catalyst such as palladium acetate or palladium carbon composite
  • a mixed solvent such as toluene/acetonitrile/water, a mixed solvent of toluene/ethanol/water, a mixed solvent of acetonitrile/water or a mixed solvent of ethanol/water
  • the hydrolysis can be carried out in the presence of a base such as potassium hydroxide, sodium hydroxide or lithium hydroxide in a solvent such as an acetonitrile/water mixed solvent, a methanol/water mixed solvent or an ethanol/water mixed solvent.
  • the compounds 17 and 20 can be prepared by the following method:
  • Step 1 The hydroxyl group of the compound 10 is protected with a protective agent to obtain a compound 11, and then subjected to a Friedel-Craft reaction with chloroacetyl chloride to obtain a compound 12;
  • the protective agent may be acetic anhydride, acetyl chloride or acetyl bromide, and the reaction for protecting the hydroxyl group may be, for example, dichloro in the presence of a catalyst such as triethylamine, diisopropylethylamine or 4-dimethylaminopyridine.
  • the Friedel-Craft reaction can be, for example, in the presence of a catalyst such as aluminum trichloride, zinc dichloride or boron trifluoride diethyl ether solution; In a solvent such as dichloromethane, trichloromethane or diethyl ether;
  • Step 2 Compound 12 is subjected to intramolecular nucleophilic substitution reaction to obtain compound 13, and then subjected to a fitting reaction with a Witting reagent to obtain a compound 14;
  • the intramolecular nucleophilic substitution reaction can be, for example, sodium acetate, potassium acetate, potassium carbonate, tert-butyl
  • a base such as potassium alkoxide or sodium t-butoxide
  • a solvent such as methanol, ethanol or acetonitrile
  • the witting reaction can be carried out in a solvent such as toluene, benzene or xylene.
  • Step 3 Compound 14 is subjected to hydrogenation reduction to obtain compound 15.
  • compound 15 is hydrolyzed to obtain compound 16, and compound 16 is subjected to bromination reaction, followed by dropwise addition.
  • Anhydrous ethanol is subjected to an esterification reaction to obtain a compound 17;
  • the reduction reaction can be carried out in the presence of a catalyst such as palladium on carbon in a solvent such as methanol, ethanol or ethyl acetate;
  • the hydrolysis reaction can be, for example, sodium hydroxide or hydrogen
  • the bromination reaction may be, for example, phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide Or in the presence of a brominating agent such as dibromosulfoxide in a solvent such as acetonitrile or ethyl acetate;
  • the bromination reaction may be, for example, phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide or dibromosulfoxide.
  • a brominating agent in a solvent such as acetonitrile or ethyl acetate;
  • ⁇ is 0, S or N, and R 7 is C r C 6 fluorenyl
  • a pharmaceutical composition comprising a therapeutically effective amount of a phenylpropionic acid compound selected from the above formula I, an enantiomer thereof, a racemate thereof And one or more of a mixture thereof and a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
  • the pharmaceutical composition can be used to treat diabetes or disorders of glycolipid metabolism.
  • a further aspect of the invention provides a phenylpropionic acid compound selected from the formula I, an enantiomer thereof, a racemate, and mixtures thereof, stereoisomers thereof, prodrug molecules thereof, and Use of one or more of the pharmaceutically acceptable salts for the manufacture of a medicament for the treatment of diabetes or disorders of glycolipid metabolism.
  • a method of treating diabetes or a disorder of glycolipid metabolism comprising administering to a patient in need thereof a therapeutically effective amount of a phenylpropionic acid compound selected from the present invention, which is aligned One or more of the isomers, racemates and mixtures thereof, stereoisomers thereof, prodrug molecules thereof, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to the present invention.
  • the nuclear magnetic resonance spectrum was recorded with a Bmker AMX-400, Gemini-300 or AMX-600 nuclear magnetic resonance instrument, and the unit of chemical shift ⁇ was ppm.
  • the specific optical rotation was measured by a Perkin-Elmer Model 241, and the microwave used was a CEM-discovery microwave reactor. All reaction solvents were purified according to a conventional method. Column chromatography with silica gel (200-300 mesh) is produced by Qingdao Ocean Chemical Branch. Thin layer chromatography was performed using the GF254 high efficiency plate for the Yantai Institute of Chemical Industry. Preparative thin-layer chromatography plates were prepared by themselves.
  • the stationary phase was prepared by GF254 (HG/T2354-92) silica gel and sodium carboxymethylcellulose (800-1200), respectively, Qingdao Ocean Chemical Co., Ltd. and China Pharmaceutical (Group). Shanghai Chemical Reagent Company produces. All solvents were analytically pure reagents, and the reagents used were purchased from Sinopharm Chemical Reagent Co., Ltd. Color development was carried out by means of iodine or ultraviolet fluorescence. The organic solvent was distilled off under reduced pressure in a rotary evaporator.
  • the compound 3-(4-((6-(2-methylphenyl)pyridin-2-yl)) was prepared in a similar manner to Example 4 except that 2-methylphenylboronic acid was used instead of phenylboronic acid. Oxygen)methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(4-methylphenyl)pyridin-2-yl)oxy) was prepared in a similar manner to Example 4 except that p-methylbenzeneboronic acid was used instead of phenylboronic acid. Methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(2-ethylphenyl)pyridin-2-yl)oxy) was prepared in a similar manner to Example 4 except that 2-ethylbenzeneboronic acid was used instead of phenylboronic acid. Methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(2-isopropylphenyl)pyridin-2-yl) was prepared in a similar manner to Example 4 except that 2-isopropylbenzeneboronic acid was used instead of phenylboronic acid. Oxy)methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(2-tert-butylphenyl)pyridin-2-yl) was prepared in a similar manner to Example 4 except that 2-isobutylbenzeneboronic acid was used instead of phenylboronic acid. Oxy)methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(2-nitrophenyl)pyridin-2-yl) was prepared in a similar manner to that shown in Example 4 except that 2-nitrophenylboronic acid was used instead of phenylboronic acid. Oxy)methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(2-hydroxyphenyl)pyridin-2-yl)oxy)) was prepared in a similar manner to Example 4 except that 2-hydroxyphenylboronic acid was used instead of phenylboronic acid. Methyl)phenyl)propionic acid.
  • the compound 3-(4-((6-(2-(trifluoromethyl)phenyl)pyridine) was prepared in a similar manner to Example 4 except that 2-trifluoromethylbenzeneboronic acid was used instead of phenylboronic acid. -2-yl)oxy)methylene)phenyl)propanoic acid.
  • the compound 3-(4-((6-(2-methoxyphenyl)pyridin-2-yl) was prepared in a similar manner to Example 4 except that 2-methoxyphenylboronic acid was used instead of phenylboronic acid. Oxy)methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(2-methylaminophenyl)pyridin-2-yl)) was prepared in a similar manner to Example 4 except that 2-methylaminobenzeneboronic acid was used instead of phenylboronic acid. Oxygen)methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(2,6-diethylphenyl)pyridine) was prepared in a similar manner to Example 4 except that 2,6-diethylbenzeneboronic acid was used instead of phenylboronic acid. -2-yl)oxy)methylene)phenyl)propanoic acid.
  • the compound 3-(4-((6-(2,6-dimethoxyphenyl)) was prepared in a similar manner to Example 4 except that 2,6-dimethoxyphenylboronic acid was used instead of phenylboronic acid. Pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.
  • the compound 3-(4-((6-(2,6-difluorophenyl)pyridine-2) was prepared in a similar manner to Example 4 except that 2,6-difluorophenylboronic acid was used instead of phenylboronic acid. -yl)oxy)methylene)phenyl)propanoic acid.
  • the compound 3-(4-((6-(2,6-methyl-)-) was prepared in a similar manner to Example 4 except that 2,6-dimethyl-4-hydroxybenzeneboronic acid was used instead of phenylboronic acid. 4-Hydroxyphenyl)pyridinyloxy)methylene)phenyl)propanoic acid.
  • the compound 3-(4-((6-(2,4,6-trimethyl)) was prepared in a similar manner to Example 4 except that 2,4,6-trimethylphenylboronic acid was used instead of phenylboronic acid. Phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.
  • the compound 3-(4-((6-(4-amino-2,6)) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-aminophenylboronic acid was used instead of phenylboronic acid. -Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(4-carboxy-2,6)) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-carboxylic acid phenylboronic acid was used instead of phenylboronic acid. -Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid.
  • the compound 3-(4-((6-(4-amido)-) was prepared in a similar manner to Example 4 except that 2,6-dimethyl-4-carbamoylbenzeneboronic acid was used instead of phenylboronic acid. 2,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.
  • the compound 3-(4-((6-(4-fluoro-2,6)) was prepared in a similar manner to Example 4 except that 2,6-dimethyl-4-fluorobenzeneboronic acid was used instead of phenylboronic acid.
  • 2,6-dimethyl-4-fluorobenzeneboronic acid was used instead of phenylboronic acid.
  • the compound 3-(4-((6-(4-methoxy)) was prepared in a similar manner to Example 4 except that 2,6-dimethyl-4-methoxyphenylboronic acid was used instead of phenylboronic acid.
  • 2,6-dimethyl-4-methoxyphenylboronic acid was used instead of phenylboronic acid.
  • -2,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid was prepared in a similar manner to Example 4 except that 2,6-dimethyl-4-methoxyphenylboronic acid was used instead of phenylboronic acid.
  • a compound 3-K 6-(4-methylthio-2,6- was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-methylmercaptophenylboronic acid was used instead of phenylboronic acid.
  • a compound 3-(4-:(:6-(2,6-dimethyl) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-methylaminobenzeneboronic acid was used instead of phenylboronic acid.
  • a compound 3-(4-:(6-(2,) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-(dimethylamino:)benzeneboronic acid was used instead of phenylboronic acid. 6-Dimethyl-4-dimethylaminophenyl:)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.
  • a compound 3-(4-:(:6) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-(methylsulfonylmethyl:)aminobenzeneboronic acid was used instead of phenylboronic acid.
  • 2,6-dimethyl-4-(methylsulfonylmethyl:)aminobenzeneboronic acid was used instead of phenylboronic acid.
  • -(2,6-Dimethyl-4-(N-methylmethanesulfonamide)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid was used instead of phenylboronic acid.
  • Example 38 3-(4-((6-(2,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)-2-chlorophenyl)propanoic acid (Compound HYH- 035)
  • Example 40 3 -( 4 -(( 6- ( 2 , 6 -Dimethyl- 4 -hydroxyphenyl)pyridine- 2 -yl)oxy)methylene) -2 -chlorophenyl)propanoic acid (Compound HYH-037
  • the 85 mg sample obtained above was dissolved in a mixture of 8 mL of acetonitrile and 2 mL of water, and 10 mg of lithium hydroxide was added thereto, and reacted at 40 ° C for 4 hours, cooled, adjusted to pH 2-3 with 1 M hydrochloric acid, and 20 mL of saturated brine was added thereto.
  • the organic layer was combined and dried over anhydrous sodium sulfate and filtered to give 3-(4-(2, 6-dimethyl-4-(2-(methylsulfonyl)) 68 mg of ethoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid as a white solid, yield 84%.
  • Example 42 3-(4-((6-(2,6-Dimethyl-4-(2-(ethanesulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)) Preparation of phenyl)propionic acid (compound HYH-039)
  • the compound 3-(4-(:6-) was obtained in a similar manner to Example 41 except that 2-ethylsulfonylethyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • a compound 3-(4-:(:6) was obtained in a similar manner to Example 41 except that 3-methanesulfonylpropyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • the compound 3-(4-:(:6) was obtained in a similar manner to Example 41 except that 3-ethylsulfonylpropyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • 3-ethylsulfonylpropyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • -(2,6-Dimethyl-4-(3-(ethylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • a compound 3-K was prepared in a similar manner to Example 41 except that 2-methoxyethyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • a compound 3-(4-: was obtained in a similar manner to that shown in Example 41 except that 2-ethoxyethyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. : 6-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.
  • Compound 3-(4-) was prepared in a similar manner to Example 42 except that 2-dimethyl:) amino: ethyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. (((6-(4-(2-Dimethylaminoethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.
  • a compound 3-(4-X6) was obtained in a similar manner to Example 41 except that 3-(diethylamino)propyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • 3-(diethylamino)propyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • -(4-p-Diethylaminopropoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • Example 41 A method similar to that of Example 41 was used except that 1,1-dioxotetrahydro-2/7-thiopyran-4-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • the compound 3-K 6-(2,6- was obtained in a similar manner to Example 41 except that 2-morpholine ethyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. Dimethyl-4-(2-morpholineethoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.
  • Step 2 Dissolve 9.7 g of 3-methoxybenzyl alcohol acetate in 40 mL of anhydrous dichloromethane, add 12.8 mL of chloroacetyl chloride dropwise at room temperature, and then add 23.6 g of anhydrous chlorinated in multiple batches. Aluminum was then refluxed for 16 hours.
  • Step 5 Dissolve 1.15 g of 6-hydroxymethyl acetate-benzofuran-3-yl:ethyl acetate into 20 mL of ethyl acetate, add 10% Pd/C 100 mg, hydrogen at atmospheric pressure The atmosphere was allowed to stand overnight at room temperature, and the diatomaceous earth was passed over to remove palladium carbon, and the filtrate was concentrated and separated on a silica gel column to obtain ethyl (6-hydroxymethyl acetate-2,3-dihydrobenzofuran-3-yl)acetate.
  • Step 6 Dissolve 6. Og of 6-hydroxymethyl acetate-2,3-dihydrobenzofuran-3-yl:)acetate in 20 mL of acetonitrile, add 4 mL of water, and add 100 mg of hydrogen with stirring. Lithium oxide was reacted at 50 ° C for 4 hours, cooled to room temperature, 50 mL of water was added, and extracted with dichloromethane for 3 times. The combined organic layers were dried over anhydrous sodium sulfate to give (6-hydroxymethyl-2,3- 0.68 g of dihydrobenzofuran-3-yl)acetic acid was an off-white solid with a yield of 91%.
  • Step 7 0.65 g of (6-hydroxymethyl-2,3-dihydrobenzofuran-3-yl)acetic acid was added to a 10 mL round bottom flask, and 1 mL of phosphorus tribromide was added dropwise, and the reaction was carried out at 80 ° C. After 2 hours, the reaction solution was cooled to 0 ° C, and 1.0 mL of anhydrous ethanol was added dropwise, and the reaction mixture was poured into 100 mL of ice water, and the mixture was extracted three times with ethyl acetate.
  • Step 1 0.5 g of (6-hydroxymethyl-2,3-dihydrobenzofuran-3-yl)acetate and 0.29 g of 2-bromo-6-hydroxypyridine were dissolved in 20 mL of acetonitrile, and added to 0.35. g potassium carbonate, then reacted at 60 ° C for 3 hours, cooled to room temperature, and concentrated on a column to give 2-(6-((6-bromopyridin-2-yl)oxy)methylene)-2,3 Ethyl dihydrobenzofuran-3-yl)acetate 0.58 g, yield 88%.
  • Step 2 Weigh 100.Omg of compound 2-(6-((6-bromopyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid Ester, 65.0 mg 4-hydroxy-2,6-dimethylphenylboronic acid, 15.0 mg of tetrakis(triphenylphosphine)palladium and 75.0 mg of potassium carbonate were added to a 10 mL microwave reactor special tube, and 2.0 mL of toluene, 0.4 mL was added. Ethanol and 0.4 mL of water were replaced with nitrogen for 3 times, and then placed in a CEM microwave reactor at 120 ° C for 30 minutes.
  • Step 3 and Step 4 In addition to using 2-(6-((6-(4-hydroxy-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)-2, 3-(4-((6-(2,6-dimethyl-4-hydroxyphenyl)pyridin-2-yl)oxy)) In the same manner as in Example 42 except that methyl (ethyl)phenyl)propanoate was obtained, 2-(6-((6-(2,6-dimethyl-4-(2-) Methanesulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid.
  • Example 67 2-(6-((6-(2,6-Dimethyl-4-(4-(methylsulfonyl)butoxy)phenyl)pyridin-2-yl)oxy)) Preparation of bis(2,3-dihydrobenzofurazol-3-yl)acetic acid (compound HYH-063)
  • Compound 2-(6-:(:6) was obtained in a similar manner to Example 65 except that 4-methanesulfonylbutyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • Example 69 2-(6-((6-(2,6-Dimethyl-4-(2-methoxyethoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-065)
  • Compound 2-(6-X6-(2) was obtained in a similar manner to Example 65 except that 2-methoxyethyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • Example 70 2-(6-((6-(2,6-Dimethyl-4-(3-methoxypropoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2,3-dihydrobenzofurazol-3-yl)acetic acid (compound HYH-066)
  • Compound 2-(6-X6-(2) was obtained in a similar manner to Example 65 except that 3-methoxypropyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. ,6-Dimethyl-4-P-methoxypropoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid.
  • Example 71 2-(6-((6-(2,6-Dimethyl-4-(2-dimethylaminoethoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2,3-dihydrobenzofurazol-3-yl)acetic acid (compound HYH-067)
  • a compound 2-(6-(:6-) was obtained in a similar manner to Example 65 except that 2-dimethylaminoethyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • Compound 2-(6-(:6-) was obtained in a similar manner to Example 65 except that 3-dimethylaminopropyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. (2,6-Dimethyl-4-P-dimethylaminopropoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl) Acetic acid.
  • Example 73 2-(6-((6-(2,6-Dimethyl-4-((tetrahydro-2-pyridin-4-yl)oxy)phenyl)pyridin-2-yl)) Preparation of Oxygen) Methylene)-2,3-Dihydrobenzofurazol-3-yl)acetic Acid (Compound HYH-069)
  • Compound 2-(6- was obtained in a similar manner to Example 65 except that tetrahydro-2/7-pyran-4-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • Compound 2-(6- was prepared in a similar manner to Example 65 except that tetrahydro-2/7-thiopyran-4-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. :(:6-(2,6-Dimethyl-4tetrahydro-2/7-thiopyran-4-yl)oxy)phenyl)pyridin-2-yl)oxy)methylene)-2, 3-Dihydrobenzofuran-3-yl)acetic acid.
  • the compound 2-(6-X6-(2,6-) was obtained in a similar manner to Example 65 except that the piperidin-4-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • the compound 2-(6-X6-() was prepared in a similar manner to Example 65 except that 1-methylpiperidine-4-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. 2,6-Dimethyl-4-G-methylpiperidin-4-yl)oxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran- 3-yl)acetic acid.
  • Example 77 2-(6-((6-(2,6-Dimethyl-4-((1,1-dioxotetrahydro-2-thio-4-yl)oxy)benzene) Preparation of pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-073)
  • Example 65 A method similar to that of Example 65 was carried out except that 1,1-dioxotetrahydro-2/7-thiopyran-4-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • Example 78 2-(6-((6-(4-(4-hydroxy-1,1-dioxotetrahydro-2H-thyl-4-yl)methoxy)-2,6 -Dimethylphenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-074)
  • Example 80 2-(6-((6-(2,6-Dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy Preparation of methylene)-2,3-dihydrobenzofurazol-3-yl)acetic acid (compound HYH-076)
  • Compound 2-(6- was prepared in a similar manner to Example 65 except that 2-(piperidin-1-yl)ethyltoluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. :(:6-(2,6-Dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3 -Dihydrobenzofuran-3-yl)acetic acid.
  • Compound 2-(6- was prepared in a similar manner to Example 65 except that 2-(piperazin-1-yl)ethyltoluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. :(:6-(2,6-Dimethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3 -Dihydrobenzofuran-3-yl)acetic acid.
  • a compound was prepared in a similar manner to Example 65 except that 2-(4-methylpiperazin-1-yl:)ethyltoluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • Step 1 The compound 2-(6-(bromomethyl)-2,3- was obtained in a similar manner to Example 64 except that 3-methylthiobenzyl alcohol was used instead of 3-methoxybenzyl alcohol. Ethyl dihydrobenzothiophen-3-yl).
  • Step 2 In addition to 2-(6-(bromomethyl)-2,3-dihydrobenzothiophen-3-yl)acetate, 2-(6-(bromomethyl)-2,3- In the same manner as in Example 65, the compound 2-(6-(2-(2,6-dimethyl-4-(2)) - (Methanesulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzothiophen-3-yl)acetic acid.
  • a compound 2-(6-:(:6) was obtained in a similar manner to Example 84 except that 3-methanesulfonylpropyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • a compound 2-(6-:(:6) was obtained in a similar manner to Example 84 except that 4-methanesulfonylbutyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • 4-methanesulfonylbutyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • the compound 2-(6-X6-K2- was obtained in a similar manner to Example 84 except that 2-dimethylaminoethyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • the compound 2-(6-X6-K3- was obtained in a similar manner to Example 84 except that 3-dimethylaminopropyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester.
  • Example 90 Screening of compounds for agonistic activity of HEK293 cell line stably transfected with human GPR40
  • HEK293 cells were transfected into eukaryotic expression vector human GPR40-pCDNA3.1, and a monoclonal cell strain stably expressing human GPR40 was obtained by screening.
  • the HEK293 cell line stably transfected with human GPR40 was cultured in a high glucose DMEM medium containing 10% FBS.
  • the cells were seeded in 96-well cell culture plates at 25,000 cells per well.
  • the Fluo-8 working solution was prepared (Hank's balanced salt solution containing Fluo-82 ⁇ , probenecid 2 mM, tartrazine 1.5 mM, acid red 14 mM).
  • Example 91 Hypoglycemic effect of compounds on type II diabetes ob/ob mice
  • mice Male genetic type spontaneous type 2 diabetes ob/ob mice were housed in SPF animal rooms (temperature: 22-24 ° C, humidity: 45-80%, light: 150-300 Lx, 12 hours day and night), mice 6-7 weeks old prediction random blood glucose, fasting blood glucose and body weight, based on these indicators will ob / ob mice were divided into 3 groups, 8 per group, were orally administered 100m g / kg of the test compound HYH-013, 100 The mg/kg positive control was TAK875, and the control group was orally administered with 0.5% CMC. The blood glucose level was measured before administration and at 1h, 2h, 4h, 6h and 8h after administration. HYH-013 was observed for type II diabetes ob/ob mice. Hypoglycemic effect.
  • the results are shown in Table 2 and Figure 1.
  • the blood glucose of the control ob/ob mice was maintained at a high level before and after administration, and single oral administration of 100 mg/kg HYH-013 significantly reduced ob/ob.
  • Mouse blood sugar At 1 h after administration, the blood glucose of HYH-013 mice was significantly lower than that of the control group (P ⁇ 0.01), and the blood glucose decline rate was 22.3%.
  • the blood glucose of the positive control TAK-875 group did not decrease significantly compared with the control group; 2 h after administration At 4h, the blood glucose of HYH-013 group was significantly lower than that of the control group (PO.05), and the blood glucose decline rate was 26.3% and 23.4%, respectively.
  • the blood glucose of HYH-013 group was still significantly lower than that of the control group (P ⁇ 0.05, P ⁇ 0.01), and the blood glucose decreased. The rates were 24.7% and 26.8%, respectively, while the blood glucose of the positive control TAK875 group had no significant decrease compared with the control group. This suggests that HYH-013 has a significant hypoglycemic effect on type 2 diabetic ob/ob mice, and its effect lasts longer than TAK875.

Abstract

Provided are a phenylalanine compound having a nitrogen heterocyclic link that can substantially lower blood sugar and regulate glycolipid metabolic activity, pharmaceutically acceptable salts or stereoisomers thereof, pharmaceutical compositions having the compound, and the use of the compound in preparing medicines for diabetics and glycolipid metabolic disorders, in particular, the use thereof in preparing medicines for treating type II diabetes. The compound has a structure as presented in formula I.

Description

一种含氮杂环链接的苯丙酸类化合物、其药物组合物、制备 方法和用途 技术领域 本发明属于药物学领域，具体涉及一种含氮杂环链接的苯丙酸类化合物、 其药物学上可接受的盐、 立体异构体或其前药分子， 其药物组合物， 制备方 法， 以及其在制备治疗糖尿病及糖脂代谢紊乱的药物中的用途， 尤其是在制 备治疗 II型糖尿病的药物的用途。 上述化合物具有显著的降血糖及调节糖脂 代谢活性的功能。 背景技术 众所周知， 糖尿病是继肿瘤、 心脑血管疾病后位列第三的严重威胁人类 健康的慢性疾病。 2011年世界卫生组织的报告指出全世界有 3.66亿人罹患糖 尿病。 在我国， 糖尿病患者总人数已超过 9000万， 并且每年还以 350万至 400 万人的幅度递增。 鉴于目前严峻的形势， 开发新型治疗糖尿病的药物是 非常有必要的。 FIELD OF THE INVENTION The present invention relates to the field of pharmacy, and in particular to a phenylpropionic acid compound containing a nitrogen-containing heterocyclic link, and a medicament thereof a physiologically acceptable salt, stereoisomer or prodrug molecule thereof, pharmaceutical composition thereof, preparation method, and use thereof in the preparation of a medicament for treating diabetes and disorders of glycolipid metabolism, especially in the preparation of type II diabetes Use of the drug. The above compounds have a remarkable function of lowering blood sugar and regulating glycolipid metabolism activity. Background Art It is well known that diabetes is a chronic disease that is the third most serious threat to human health after cancer and cardiovascular and cerebrovascular diseases. The 2011 World Health Organization report pointed out that 366 million people worldwide suffer from diabetes. In China, the total number of people with diabetes has exceeded 90 million, and it is increasing by 3.5 million to 4 million per year. In view of the current grim situation, it is very necessary to develop new drugs for the treatment of diabetes.
糖尿病按照病因、 临床表现和并发症的不同分为 I型和 Π型糖尿病。 I 型糖尿病的特征是缺乏胰岛素分泌能力，称为胰岛素依赖型糖尿病（IDDM), II型糖尿病则是由于自身无法有效利用胰岛素造成， 称为非胰岛素依赖型糖 尿病 （NIDDM)。 II型糖尿病患者占全球糖尿病总数的 90%以上。 II型糖尿 病的糖尿病的发病机制复杂， 其基本特征是骨骼肌、 肝脏、 脂肪等组织对胰 岛素产生抵抗。 病程早期患者胰岛 β细胞可代偿性分泌胰岛素以抵消胰岛素 作用的缺陷， 从而维持机体正常的血糖水平。 然而， 随着病程的发展， 胰岛 β 细胞胰岛素分泌功能不足， 患者的代偿机制崩溃， 导致机体血糖水平异常 升高， 进而产生体内糖脂代谢紊乱发生 II型糖尿病。  Diabetes is classified into type I and type 2 diabetes according to the etiology, clinical manifestations and complications. Type I diabetes is characterized by a lack of insulin secretion called insulin-dependent diabetes mellitus (IDDM), which is caused by its inability to use insulin effectively, called non-insulin-dependent diabetes mellitus (NIDDM). Type II diabetes accounts for more than 90% of the global diabetes population. The pathogenesis of type 2 diabetes mellitus is complicated, and its basic characteristics are that skeletal muscle, liver, fat and other tissues are resistant to insulin. In the early stage of the disease, islet β cells can compensate insulin secretion to compensate for the deficiency of insulin, thus maintaining normal blood sugar levels. However, with the development of the disease course, the islet β-cell insulin secretion function is insufficient, and the patient's compensatory mechanism collapses, resulting in abnormally elevated blood glucose levels, which in turn leads to the formation of type 2 diabetes in the body.
鉴于目前糖尿病的发病形势严峻， 开发治疗糖尿病的药物迫在眉睫。 目 前针对糖尿病的新药研发主要集中在两方面。 一方面， 药物开发者期待在现 有作用靶点的基础上寻找更加有效和低毒的新一代药物； 另一方面是积极研 究糖尿病的发病机制， 寻找与糖尿病有关的新型靶点， 并针对这些新靶点设 计具有全新作用机制的、 具有自主知识产权的新药。 In view of the current severe incidence of diabetes, the development of drugs for the treatment of diabetes is imminent. The current research and development of new drugs for diabetes is mainly concentrated in two aspects. On the one hand, drug developers look forward to finding more effective and less toxic new-generation drugs based on existing targets; Study the pathogenesis of diabetes, find new targets related to diabetes, and design new drugs with independent intellectual property rights with new mechanisms for these new targets.
GTP蛋白耦联受体 40 ( GTP-binding protein coupling receptor 40, GP 40) 是一个七次跨膜受体。 在胰岛中表达丰富， 另外在肠道系统中也有所表达。 现有的研究结果显示， 这种跨膜受体可能与某些癌症、 神经类疾病和代谢性 疾病有关，尤其是糖尿病。研究发现，各种形式的游离脂肪酸（free fatty acid, FFA) 是 GPR40的天然配体。 FFA可以通过激活胰岛 β细胞膜上的 GPR40 放大葡萄糖剌激的胰岛素分泌。鉴于 GPR40受体激动剂具有葡萄糖依赖性的 促进胰岛素分泌的优势， 使其成为治疗糖尿病的潜在靶点。  GTP-binding protein coupling receptor 40 (GP 40) is a seven-pass transmembrane receptor. It is abundantly expressed in islets and is also expressed in the intestinal system. Current research suggests that this transmembrane receptor may be associated with certain cancers, neurological diseases, and metabolic diseases, especially diabetes. Studies have found that various forms of free fatty acid (FFA) are natural ligands for GPR40. FFA amplifies glucose-stimulated insulin secretion by activating GPR40 on the islet beta cell membrane. Given that GPR40 receptor agonists have a glucose-dependent advantage in promoting insulin secretion, they are potential targets for the treatment of diabetes.
针对此靶标各大制药公司以及研究机构研究开发了多个系列的化合物。 目前， 已经报道进入临床的化合物有三个， 其中日本 TAKEDA公司的化合 物 Τ  A number of series of compounds have been developed for major pharmaceutical companies and research institutions targeting this target. At present, there are three compounds that have been reported to enter the clinic, among which the compounds of Japan TAKEDA Co., Ltd.
Figure imgf000003_0001
Figure imgf000003_0001
美国礼来公司的 LY-2881835则在新加坡进入了 I期临床实验， 而日本 tobacco公司的 JTT-851也在日本进入了 II期临床实验， 但目前并没有公布所选 取化合物的具体结构， 而该公司的专利 WO2009054479A1保护的化合物通式 如下所示：  Lilly's LY-2881835 entered Phase I clinical trials in Singapore, while Japan's Tobacco JTT-851 also entered Phase II clinical trials in Japan, but the specific structure of the selected compounds has not been published yet. The compound of the company's patent WO2009054479A1 protects the formula as follows:
Figure imgf000003_0002
根据文献 （Expert Opin. Ther. Pat. 2009, 19, 237-264; Bioorg. Med. Chem. Lett. 2006, 16, 1840—1845; Bioorg. Med. Chem. Lett. 2010, 20, 1298-1301 ; J. Med. Chem. 2007, 50, 2807-2817.; Org. Process Res. Dev. 2011, 15, 104—111.; ACS Med. Chem. Lett. 2010, 1,345—349.; J. Med. Chem.2008, 51, 7061-7064.; J. Med. Chem. 2011, 54, 6691-6703. ) 报道， 目前处于临床前研究阶段并且公布 具体结构式的化合物如下所示：
Figure imgf000003_0002
According to the literature (Expert Opin. Ther. Pat. 2009, 19, 237-264; Bioorg. Med. Chem. Lett. 2006, 16, 1840-1845; Bioorg. Med. Chem. Lett. 2010, 20, 1298-1301; J. Med. Chem. 2007, 50, 2807-2817.; Org. Process Res. Dev. 2011, 15, 104-111.; ACS Med. Chem. Lett. 2010, 1,345-349.; J. Med. Chem .2008, 51, 7061-7064.; J. Med. Chem. 2011, 54, 6691-6703. ) Reported that the compounds currently in preclinical research and the publication of specific structural formulas are as follows:
Figure imgf000004_0001
发明内容 本发明涉及具有下面通式 I所示结构的化合物， 其与已报道化合物的结 构明显不同。本发明的化合物具有显著的降血糖及调节糖脂代谢活性的功能， 是一类新型 GPR40激动剂。
Figure imgf000004_0001
SUMMARY OF THE INVENTION The present invention is directed to compounds having the structure of Formula I below which are distinct from the structures of the reported compounds. The compound of the present invention has a remarkable function of lowering blood sugar and regulating glycolipid metabolism activity, and is a novel type of GPR40 agonist.
本发明的一个目的是提供如下通式 I所示的苯丙酸类化合物、 或者其药 学上可接受的盐、或其对映异构体、外消旋体及其混合物、或其立体异构体， 或其前药分子。  An object of the present invention is to provide a phenylpropionic acid compound represented by the following formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, a racemate and a mixture thereof, or a stereoisomer thereof Body, or its prodrug molecule.
本发明的另一个目的是提供了通式 I 所示的苯丙酸类化合物的制备方 法。  Another object of the present invention is to provide a process for the preparation of a phenylpropionic acid compound of the formula I.
本发明的另一目的是提供一种药物组合物， 其包含治疗有效量的选自通 式 I所示的苯丙酸类化合物、 其药学上可接受的盐、 其对映异构体、 外消旋 体及其混合物、 其立体异构体和其前药分子中的一种或多种和药学上可接受 的辅料。 Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a phenylpropionic acid compound selected from the formula I, a pharmaceutically acceptable salt thereof, an enantiomer thereof, and the like Racemization One or more of a mixture, a mixture thereof, a stereoisomer thereof and a prodrug molecule thereof, and a pharmaceutically acceptable excipient.
本发明的又一个目的是提供了选自通式 I所示的苯丙酸类化合物、 其药 学上可接受的盐、 其对映异构体、 外消旋体及其混合物、 其立体异构体和其 前药分子中的一种或多种在制备治疗糖尿病及糖脂代谢紊乱的药物中的用 途。  A further object of the present invention is to provide a phenylpropionic acid compound selected from the formula I, a pharmaceutically acceptable salt thereof, an enantiomer thereof, a racemate and a mixture thereof, and stereoisomers thereof Use of one or more of a body and a prodrug molecule thereof for the manufacture of a medicament for the treatment of diabetes and disorders of glycolipid metabolism.
本发明的再一目的是提供一种治疗糖尿病及糖脂代谢紊乱的方法， 其包 括向需要该治疗的对象给药选自通式 I所示的苯丙酸类化合物或者其药学上 可接受的盐、 其对映异构体、 外消旋体及其混合物、 立体异构体和其前药分 子中的一种或多种。  It is still another object of the present invention to provide a method of treating diabetes and disorders of glycolipid metabolism comprising administering to a subject in need of such treatment a phenylpropionic acid compound selected from Formula I or a pharmaceutically acceptable compound thereof. One or more of a salt, an enantiomer thereof, a racemate, and mixtures thereof, a stereoisomer, and a prodrug molecule thereof.
一个方面提供了通式 I所示的苯丙酸类化合物：  One aspect provides a phenylpropionic acid compound of the formula I:
Figure imgf000005_0001
Figure imgf000005_0001
(I)  (I)
其中，  among them,
为11、 D或 F;  Is 11, D or F;
R n R2各自独立选自 H、 羟基、 卤素、 硝基、 d-C^垸基、 卤代 d-C^ 垸基、 d-C^垸氧基、 卤代 d-C^垸氧基、 C3-C1()环垸基和含有选自 S、 0和 N中的 1至 3个杂原子的 3至 10元杂环基；优选选自 H、羟基、卤素、硝基、 C C6 \ ί CrC6 C^- C6 ¾¾ 、 \ ί C C6 C3-C8 i 基和含有至少一个氮原子的 3至 10元杂环基； 更优选地各自独立地选自 H、 羟基、 卤素、 硝基、 CrC4垸基、 卤代 CrC4垸基、 CrC4垸氧基、 卤代 d-C4 垸氧基、 C3-C8环垸基和氮杂环丙垸 -1-基； R n R 2 are each independently selected from the group consisting of H, hydroxy, halogen, nitro, dC^ fluorenyl, halo dC^ fluorenyl, dC^ decyloxy, halo dC^ decyloxy, C 3 -C 1() a cycloalkyl group and a 3- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from S, 0 and N; preferably selected from the group consisting of H, hydroxy, halogen, nitro, CC 6 \ ί CrC 6 C^- C 6 3⁄43⁄4 , \ ί CC 6 C 3 -C 8 i groups and 3 to 10 membered heterocyclic groups containing at least one nitrogen atom; more preferably each independently selected from H, hydroxy, halogen, nitro, C r C 4 -mercapto, halo C r C 4 fluorenyl, C r C 4 decyloxy, halo dC 4 decyloxy, C 3 -C 8 cyclodecyl and azetidin-1-yl;
R3选自 H;卤素；羧基； CrC2()垸基；卤代 CrC2()垸基； -O a; -N( a)S02 b, -NRa b; -N( a)C(0) b; -C(0)NRa b; -S02 a; -S b; 用选自 C d。垸氧基、 C3-C1()环垸基、 -SRe、 -S02Re、 -NReRd或未取代或者被 CrC6垸基、 羟基或氧 代基团取代的含有选自 0、 S和 N中的 1~3个杂原子的 3-8元杂环基中的取 代基取代的 CrC^垸氧基； 和用 d-do垸氧基、 C3-C1()环垸基、 -SRe、 -S02 c 或 -NReRd取代的 CrC2。垸基； 优选选自 H; 卤素； 羧基； CrC6垸基； 卤代 CrC6垸基； -ORa; -N( a)S02 b; -NRa b; -N( a)C(0) b； -C(0)NRa b; -S02 a; -S b; 用选自 C C4垸氧基、 C3-C8环垸基、 -SRC、 -S02Rc、 -NRc d或未取代或者被 d-C4 垸基、 羟基或氧代基团取代的含有选自 0、 S和 N中的 1~3个杂原子的 3-6 元杂环基中的取代基取代的 CrC6垸氧基； 和用 CrC4垸氧基、 3- 8环垸基、 -SRC、 -S02Rc或- NRcRd取代的 CrC6垸基； R 3 is selected from the group consisting of H; halogen; carboxy; C r C 2 () fluorenyl; halogenated C r C 2 () fluorenyl; -O a ; -N( a ) S0 2 b , -NR ab; -N ( a ) C(0) b ; -C(0)NR ab ; -S0 2 a ; -S b ; selected from C d . Alkoxy, C 3 -C 1() cyclononyl, -SR e , -S0 2 R e , -NR e R d or unsubstituted or substituted by C r C 6 fluorenyl, hydroxy or oxo group a CrC^ decyloxy group substituted with a substituent selected from a 3-8 membered heterocyclic group of 1 to 3 hetero atoms selected from 0, S and N; and d-dodecyloxy group, C 3 -C 1 (cyclo embankment group, -SR e, -S0 2 c -NR e R d or substituted by C r C 2). 垸基; Preferably selected from H ; halogen; carboxy; C r C 6 fluorenyl; halogenated C r C 6 fluorenyl; -OR a; -N( a )S0 2 b ; -NR ab; -N( a )C(0 b ; -C(0)NR ab ; -S0 2 a ; -S b ; selected from CC 4 decyloxy, C 3 -C 8 cyclodecyl, -SR C , -S0 2 R c , -NR Cd or substituted C substituted by a substituent in a 3-6 membered heterocyclic group containing 1 to 3 heteroatoms selected from 0, S and N substituted by dC 4 fluorenyl, hydroxy or oxo group r C 6 embankment group; and the embankment with a C r C 4 group, 3 - 8 cycloalkyl group embankment, -SR C, -S0 2 R c, or - NR c R d C r C 6 substituted alkyl with;
进一歩优选选自 H; 卤素； 羧基； CrC6垸基； 卤代 CrC6垸基； -O a; -N( a)S02 b; -NRa b; -N( a)C(0) b； -C(0)NRa b; -S02 a; -S b; 用选自 C C4垸氧基、 C3-C6环垸基、 -SRC、 -S02Rc、 -NRc d或未取代或者被 d-C4 垸基、 羟基或氧代基团取代的含有选自 0、 S和 N中的 1~3个杂原子的 3-6 元杂环基中的取代基取代的 CrC4垸氧基； 和用 CrC4垸氧基、 C3-C6环垸基、 -SRC、 S02Rc或 NRcRd取代的 CrC4垸基； Further preferably selected from the group consisting of H; halogen; carboxyl group; C r C 6 fluorenyl; halogenated C r C 6 fluorenyl; -O a ; -N( a )S0 2 b ; -NR ab; -N( a )C (0) b ; -C(0)NR ab ; -S0 2 a ; -S b ; selected from CC 4 decyloxy, C 3 -C 6 cyclodecyl, -SR C , -S0 2 R c , -NR cd or a substituent substituted in a 3-6 membered heterocyclic group containing 1 to 3 hetero atoms selected from 0, S and N, which is unsubstituted or substituted by dC 4 fluorenyl, hydroxy or oxo group the embankment group C r C 4; and with the embankment group C r C 4, C 3 -C 6 cycloalkyl group embankment, -SR C, S0 2 R c or NR c R d C r C 4 substituted alkyl with;
其中，  among them,
和 Rb各自独立选自 H、CrC6垸基、 C3-C8环垸基和未取代或者被 CrC6 垸基或氧代基团取代的含有选自 0、 S和 N中的 1~3个杂原子的 3-8元杂环 基； 优选各自独立选自 H、 CrC4垸基、 C3-C6环垸基和未取代或者被 CrC3 垸基或氧代基团取代的含有选自 0、 S和 N中的 1~3个杂原子的 3-6元杂环 基； And R b are each independently selected from the group consisting of H, C r C 6 fluorenyl, C 3 -C 8 cyclodecyl and unsubstituted or substituted by C r C 6 fluorenyl or oxo group and selected from 0, S and N 3-8 membered heterocyclic groups of 1 to 3 heteroatoms; preferably each independently selected from H, C r C 4 fluorenyl, C 3 -C 6 cyclodecyl and unsubstituted or C r C 3 fluorenyl Or a methoxy group-substituted 3-6 membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of 0, S and N;
Rc和 Rd各自独立地选自 H、 CrC6垸基和未取代或者被 (^- 3垸基取代 的含有选自 0、 S和 N中的 1~3个杂原子的 3-8元杂环基； 优选各自独立地 选自 H、 CrC3垸基和未取代或者被 CrC3垸基取代的含有选自 0、 S和 N中 的 1~3个杂原子的 3-6元杂环基； R c and R d are each independently selected from H, C r C 6 fluorenyl and 3- substituted or substituted by (^- 3 fluorenyl) containing 1 to 3 heteroatoms selected from 0, S and N 8-membered heterocyclic group; preferably each independently selected from H, C r C 3 fluorenyl and unsubstituted or substituted by C r C 3 fluorenyl containing 1 to 3 heteroatoms selected from 0, S and N 3-6 membered heterocyclic group;
R4选自 H、 羟基、 卤素、 d-C^垸基和卤代 d-C^垸基； 优选选 H、 羟基、 卤素、 CrC6垸基和卤代 CrC6垸基， R 4 is selected from the group consisting of H, hydroxy, halogen, dC fluorenyl and halogenated dC fluorenyl; preferably H, hydroxy, halogen, C r C 6 fluorenyl and halogenated C r C 6 fluorenyl,
R5选自 H、 卤素和 d-C^垸基； 优选选 H、 卤素和 CrC6垸基； 或者 R4和 连同和其相连的碳原子与苯环一起形成苯并 5-8元杂环基， 所述杂环上含有选自 0、 N和 S中的 1~3个杂原子， 且所述杂环基未被取代 或者被 CrC6垸基取代； 优选 R4和 连同和其相连的碳原子与苯环一起形 成苯并 5元杂环基， 该 5元杂环基含有选自 0、 N和 S中的 1~2个杂原子， 且未被取代或者被 CrC3垸基取代； 进一歩优选地， R4和 连同和其相连的 R 5 is selected from the group consisting of H, halogen and dC fluorenyl; preferably H, halogen and C r C 6 fluorenyl; or R 4 together with the carbon atom attached thereto and benzene ring together form a benzo 5-8 membered heterocyclic ring group, containing heterocycle selected from 0, N and S, 1 to 3 hetero atoms, and said heterocyclic group is unsubstituted or substituted alkyl with C r C 6; R 4 and preferably together with it, and The linked carbon atom together with the benzene ring form a benzo 5-membered heterocyclic group containing one to two heteroatoms selected from the group consisting of 0, N and S. And not substituted or substituted by C r C 3 thiol; further preferably, R 4 and associated with it
碳原子与苯环一起形成
Figure imgf000007_0001
或 。 Carbon atoms form together with the benzene ring
Figure imgf000007_0001
or.
进一歩地， 本发明的通式 I所示的苯丙酸类化合物具有如下通式 II或通 式 III所示的结构：  Further, the phenylpropionic acid compound of the formula I of the present invention has a structure represented by the following formula II or formula III:
Figure imgf000007_0002
其中， X、 〜 的定义与上述相同； R6为 H或 CrC6垸基， 以及在通式 III中， 当 Z为 0或 S时， R6不存在。
Figure imgf000007_0002
Wherein X, 〜 are as defined above; R 6 is H or C r C 6 fluorenyl, and in Formula III, when Z is 0 or S, R 6 is absent.
在本发明中， 术语 "卤素"包括氟、 氯、 溴和碘。 术语 "卤代"指的是 用单个或多个选自氟、 氯、 溴和碘中的卤素原子取代。  In the present invention, the term "halogen" includes fluorine, chlorine, bromine and iodine. The term "halo" refers to a single or multiple halogen atoms selected from the group consisting of fluorine, chlorine, bromine and iodine.
术语" d- o垸基"是指主链上具有 1至 20个碳原子的直链或支链垸基， 非限制性地包括甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 仲丁基、 叔丁基、 戊基、 已基、 辛基、 癸基、 十一垸基、 十二垸基、 十四垸基、 十六 院基、 十七院基、 十八院基、 二十院基等。 术语" C C6院基"禾口" Ci-Gt院基" 具有类似的含义。  The term "d-o fluorenyl" refers to a straight or branched fluorenyl group having from 1 to 20 carbon atoms in the main chain, and includes, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, decyl, undecyl, fluorenyl, tetradecyl, sixteenth, seventeen , 18 courtyards, 20 courtyards, etc. The terms "C C6 yard base" and "Ci-Gt yard base" have similar meanings.
术语" d- o垸氧基 "是指主链上具有 1至 20个碳原子的直链或支链垸氧 基， 非限制性地包括甲氧基、 乙氧基、 正丙氧基、 异丙氧基、 丁氧基、 戊氧 基、 已氧基、 辛氧基、 癸氧基、 十一垸氧基、 十二垸氧基、 十四垸氧基、 十 六院氧基、十七院氧基、十 院氧基、二十院氧基等。术语" CK)院氧基"、 "Ci-C6垸氧基 "和" CrC4垸氧基 "具有类似的含义。 The term "d-omethoxy" refers to a straight or branched decyloxy group having from 1 to 20 carbon atoms in the main chain, and includes, without limitation, methoxy, ethoxy, n-propoxy, and iso Propyloxy, butoxy, pentyloxy, hexyloxy, octyloxy, decyloxy, undecyloxy, dodecyloxy, tetradecyloxy, hexadecanyloxy, seventeen Oxygen, ten hospital oxygen, twenty hospital oxygen, etc. The terms "CK", "Ci-C 6 methoxy" and "C r C 4 methoxy" have similar meanings.
术语" C3-C1()环垸基 "是指在环上具有 3至 10个碳原子的环状垸基， 非限 制性地包括环丙基、 环丁基、 环戊基、 环己基和环庚基； 术语" C3-C8环垸基" 和" C3-C6环垸基 "具有类似的含义。 术语" 3-8元杂环基"是指环上具有 3-8个原子的含有选自 N、 0和 S原子 中的至少一个原子的非芳香族环基，如环氧基、吡咯垸基、吗啉基等；术语" 5-8 元杂环基"和" 3-6元杂环基"具有类似的含义。 The term "C 3 -C 1 () cyclodecyl" refers to a cyclic fluorenyl group having 3 to 10 carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. And cycloheptyl; the terms "C 3 -C 8 cyclodecyl" and "C 3 -C 6 cyclodecyl" have similar meanings. The term "3-8 membered heterocyclic group" means a non-aromatic ring group having 3-8 atoms on the ring containing at least one atom selected from the group consisting of N, 0 and S atoms, such as an epoxy group, a pyrrolidinyl group, Morpholinyl and the like; the terms "5-8 membered heterocyclic group" and "3-6 membered heterocyclic group" have similar meanings.
本发明中的术语"药学上可接受的盐"是指根据本发明的通式 I所示的化 合物与磷酸、 硫酸、 盐酸等无机酸， 或醋酸、 酒石酸、 柠檬酸、 苹果酸、 富 马酸等有机酸， 或天冬氨酸、 谷氨酸等酸性氨基酸形成的盐， 或与上述酸成 酯或酰胺后再与无机碱形成的盐， 如钠、 钾、 钙、 铝盐和铵盐。  The term "pharmaceutically acceptable salt" in the present invention means a compound represented by the formula I according to the present invention and a mineral acid such as phosphoric acid, sulfuric acid or hydrochloric acid, or acetic acid, tartaric acid, citric acid, malic acid or fumaric acid. An organic acid, or a salt formed by an acidic amino acid such as aspartic acid or glutamic acid, or a salt formed with an inorganic base after forming an ester or an amide with the above-mentioned acid, such as sodium, potassium, calcium, aluminum salt and ammonium salt.
述化合物优选选自下列化合物：  The compound is preferably selected from the following compounds:
Figure imgf000008_0001
Figure imgf000008_0001
Figure imgf000009_0001
^S/.0/M0ZM3/X3d .1869Ϊ/Μ0Ζ OAV 6
Figure imgf000009_0001
^S/.0/M0ZM3/X3d .1869Ϊ/Μ0Ζ OAV 6
Figure imgf000010_0001
S.0/t'lOZM3/13d Z.1869T/1-T01 OAV 01
Figure imgf000010_0001
S.0/t'lOZM3/13d Z.1869T/1-T01 OAV 01
Figure imgf000011_0001
Figure imgf000011_0001
Figure imgf000011_0002
Figure imgf000011_0002
SL0/ l0Z l3/13d J869I/ 0Z OAV π SL0/ l0Z l3/13d J869I/ 0Z OAV π
Figure imgf000012_0001
Figure imgf000012_0001
991-£.0/M0ZM3/X3d 991-£.0/M0ZM3/X3d
Figure imgf000013_0001
Figure imgf000013_0001
 反应式 1  Reaction formula 1
歩骤 1： 将 R4取代的对溴苄醇 1和丙烯酸乙酯 2经过 Heck反应得到中 间体 3，将双键还原得到中间体 4，再经过溴化反应把苄醇变成苄溴得到中间 体 5; 所述 Heck反应可以在例如醋酸钯、 四（三苯基膦）钯或二（三苯基膦) 二氯化钯等钯金属催化剂存在下在例如 Ν,Ν-二甲基甲酰胺或三乙胺等溶剂 中进行； 所述双键还原反应可以在例如钯碳复合物催化剂存在下在例如乙酸 乙酯、 乙酸丁酯、 甲醇、 乙醇或正丙醇等溶剂中使用例如氢气作为还原剂进 行； 所述溴化反应可以使用例如三溴化磷， 五溴化磷， 三溴氧磷或二溴亚砜 等溴化剂在例如乙腈、 二氯甲垸或乙醚等溶剂中进行； Step 1: R 4 -substituted p-bromobenzyl alcohol 1 and ethyl acrylate 2 are subjected to Heck reaction to obtain intermediate 3, and the double bond is reduced to obtain intermediate 4, and then bromination is carried out to convert benzyl alcohol into benzyl bromide to obtain intermediate The Heck reaction can be carried out, for example, in the presence of a palladium metal catalyst such as palladium acetate, tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium dichloride, for example, ruthenium, osmium-dimethylformamide. Or in a solvent such as triethylamine; the double bond reduction reaction can be carried out using, for example, hydrogen gas in a solvent such as ethyl acetate, butyl acetate, methanol, ethanol or n-propanol in the presence of, for example, a palladium carbon composite catalyst. The bromination reaction can be carried out using a brominating agent such as phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide or dibromosulfoxide in a solvent such as acetonitrile, dichloromethane or diethyl ether;
歩骤 2:将中间体 5和底物 6经过亲核取代反应得到中间体 7;所述亲核 取代反应可以在例如碳酸钾、 碳酸铯、 氢化钠、 氢化钾、 叔丁醇钾、 叔丁醇 钠或氢氧化钠等碱存在下在例如乙腈、 Ν,Ν-二甲基甲酰胺或四氢呋喃的溶剂 中进行；  Step 2: Intermediate 5 and substrate 6 are subjected to nucleophilic substitution reaction to obtain intermediate 7; the nucleophilic substitution reaction can be, for example, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, potassium t-butoxide, tert-butyl In the presence of a base such as sodium acetate or sodium hydroxide in a solvent such as acetonitrile, hydrazine, hydrazine-dimethylformamide or tetrahydrofuran;
歩骤 3 : 中间体 7和
Figure imgf000014_0001
经过 Suzuki反应偶联得到中间体 8， 再将中间体 8经过水解反应得到产物 9; Step 3: Intermediate 7 and
Figure imgf000014_0001
The intermediate 8 is obtained by Suzuki reaction coupling, and the intermediate 8 is subjected to hydrolysis reaction to obtain the product 9;
所述 Suzuki反应可以在例如四 （三苯基膦）钯、 二（三苯基膦） 二氯化 钯、 醋酸钯或钯碳复合物等催化剂存在下在例如甲苯 /乙腈 /水的混合溶剂、 甲苯 /乙醇 /水的混合溶剂、 乙腈 /水的混合溶剂或乙醇 /水的混合溶剂中进行； 以及所述中间 8的水解反应可以在例如氢氧化钾、 氢氧化钠或氢氧化锂等碱 的存在下在例如乙腈 /水混合溶剂、 甲醇 /水混合溶剂或乙醇 /水混合溶剂的溶 剂中；  The Suzuki reaction may be, for example, a mixed solvent of toluene/acetonitrile/water in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, palladium acetate or palladium carbon composite, a mixed solvent of toluene/ethanol/water, a mixed solvent of acetonitrile/water or a mixed solvent of ethanol/water; and the hydrolysis reaction of the intermediate 8 may be a base such as potassium hydroxide, sodium hydroxide or lithium hydroxide. In the presence of a solvent such as an acetonitrile/water mixed solvent, a methanol/water mixed solvent or an ethanol/water mixed solvent;
在上述歩骤 1〜歩骤 3中，各个歩骤的反应均在本领域普通技术人员公知 的反应条件下进行。  In the above steps 1 to 3, the reactions of the respective steps are carried out under reaction conditions well known to those skilled in the art.
方法二： 如下面反应式 2所示： Method 2: As shown in the following reaction formula 2:
Figure imgf000015_0001
Figure imgf000015_0001
Figure imgf000015_0002
反应式 2
Figure imgf000015_0002
Reaction formula 2
歩骤 1 : 化合物 17 (其中， Z为 0或 S， R6不存在） 或 20 (其中， Z为 N， R6为 H或 CrC6垸基） 和底物 6经过亲核取代反应得到化合物 21， 所述 亲核取代反应可以在例如碳酸钾、 碳酸铯、 氢化钠、 叔丁醇钾或叔丁醇钠的 催化剂的存在下在例如乙腈、 丙酮、 乙酸乙酯、 四氢呋喃或 Ν,Ν-二甲基甲酰 胺的溶剂中进行； Step 1: Compound 17 (wherein Z is 0 or S, R 6 is absent) or 20 (wherein Z is N, R 6 is H or C r C 6 fluorenyl) and substrate 6 is subjected to nucleophilic substitution reaction Compound 21 is obtained, and the nucleophilic substitution reaction can be carried out, for example, in the presence of a catalyst such as potassium carbonate, cesium carbonate, sodium hydride, potassium t-butoxide or sodium t-butoxide in, for example, acetonitrile, acetone, ethyl acetate, tetrahydrofuran or hydrazine. In the solvent of hydrazine-dimethylformamide;
歩骤 2: 化合物 21和
Figure imgf000015_0003
经过 Suzuki反应偶联得到中间体 22， 再将中间体 22经过水解反应得到产物 23;所述 Suzuki反应可以在例如四（三 苯基膦） 钯、 二 （三苯基膦） 二氯化钯、 醋酸钯或钯碳复合物等催化剂存在 下在例如甲苯 /乙腈 /水的混合溶剂、 甲苯 /乙醇 /水的混合溶剂、 乙腈 /水的混合 溶剂或乙醇 /水的混合溶剂中进行； 所述水解反应可以在例如氢氧化钾、氢氧 化钠或氢氧化锂等碱的存在下在例如乙腈 /水混合溶剂、 甲醇 /水混合溶剂或 乙醇 /水混合溶剂的溶剂中。 Step 2: Compound 21 and
Figure imgf000015_0003
The intermediate 22 is obtained by Suzuki reaction coupling, and the intermediate 22 is subjected to hydrolysis reaction to obtain the product 23; the Suzuki reaction can be, for example, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, In the presence of a catalyst such as palladium acetate or palladium carbon composite, in a mixed solvent such as toluene/acetonitrile/water, a mixed solvent of toluene/ethanol/water, a mixed solvent of acetonitrile/water or a mixed solvent of ethanol/water; the hydrolysis The reaction can be carried out in the presence of a base such as potassium hydroxide, sodium hydroxide or lithium hydroxide in a solvent such as an acetonitrile/water mixed solvent, a methanol/water mixed solvent or an ethanol/water mixed solvent.
在上述歩骤 1〜歩骤 2中，各个歩骤的反应均在本领域普通技术人员公知 的反应条件下进行。  In the above steps 1 to 2, the reactions of the respective steps are carried out under reaction conditions well known to those skilled in the art.
作为一个实例， 所述化合物 17和 20可以通过如下方法制备：
Figure imgf000016_0001
As an example, the compounds 17 and 20 can be prepared by the following method:
Figure imgf000016_0001
反应式 3  Reaction formula 3
歩骤 1 :将化合物 10的羟基用保护剂保护得到化合物 11，然后和氯乙酰 氯经过傅克反应得到化合物 12;  Step 1: The hydroxyl group of the compound 10 is protected with a protective agent to obtain a compound 11, and then subjected to a Friedel-Craft reaction with chloroacetyl chloride to obtain a compound 12;
所述保护剂可以为乙酸酐、 乙酰氯或乙酰溴， 所述保护羟基的反应可以 在例如三乙胺、 二异丙基乙基胺或 4-二甲氨基吡啶等催化剂存在下在例如二 氯甲垸、 三氯甲垸、 乙腈、 丙酮或乙酸乙酯等溶剂中进行； 所述傅克反应可 以在例如三氯化铝、 二氯化锌或三氟化硼乙醚溶液等催化剂存在下在例如二 氯甲垸、 三氯甲垸或乙醚等溶剂中进行；  The protective agent may be acetic anhydride, acetyl chloride or acetyl bromide, and the reaction for protecting the hydroxyl group may be, for example, dichloro in the presence of a catalyst such as triethylamine, diisopropylethylamine or 4-dimethylaminopyridine. It is carried out in a solvent such as formazan, chloroform, acetonitrile, acetone or ethyl acetate; the Friedel-Craft reaction can be, for example, in the presence of a catalyst such as aluminum trichloride, zinc dichloride or boron trifluoride diethyl ether solution; In a solvent such as dichloromethane, trichloromethane or diethyl ether;
歩骤 2:化合物 12经过分子内亲核取代反应得到化合物 13，然后和 witting 试剂经过 witting反应得到化合物 14; 所述分子内亲核取代反应可以在例如 醋酸钠、 醋酸钾、 碳酸钾、 叔丁醇钾或叔丁醇钠等碱存在下在例如甲醇、 乙 醇或乙腈等溶剂中进行； 所述 witting反应可以在例如甲苯、苯或二甲苯等溶 剂中进行  Step 2: Compound 12 is subjected to intramolecular nucleophilic substitution reaction to obtain compound 13, and then subjected to a fitting reaction with a Witting reagent to obtain a compound 14; the intramolecular nucleophilic substitution reaction can be, for example, sodium acetate, potassium acetate, potassium carbonate, tert-butyl In the presence of a base such as potassium alkoxide or sodium t-butoxide, in a solvent such as methanol, ethanol or acetonitrile; the witting reaction can be carried out in a solvent such as toluene, benzene or xylene.
歩骤 3 : 化合物 14经氢化还原反应得到化合物 15， 当 Z=0或 S时， 化 合物 15经水解反应得到化合物 16， 化合物 16经过溴化反应， 然后再滴加入 无水乙醇经过酯化反应得到化合物 17;所述还原反应可以在例如钯碳的催化 剂存在下在例如甲醇、 乙醇或乙酸乙酯的溶剂中进行； 所述水解反应可以在 例如氢氧化钠、 氢氧化钾或氢氧化锂的催化剂存在下在例如乙醇 /水、 甲醇 / 水或乙腈 /水的溶剂中进行； 所述溴化反应可以在例如三溴化磷， 五溴化磷， 三溴氧磷或二溴亚砜等溴化剂存在下在例如乙腈或乙酸乙酯的溶剂中进行； 歩骤 4: 当 Z=NH时， 化合物 15和 R7I经垸基化反应得到化合物 18， 化合物 18经水解反应得到化合物 19， 化合物 19经过溴化反应， 然后再滴加 入无水乙醇经过酯化反应得到化合物 20; 所述垸基化反应可以在例如氢化 钠、 氢化钾、 叔丁醇钾或叔丁醇钠等催化剂存在下在例如乙腈、 丙酮或四氢 呋喃 Ν,Ν-二甲基甲酰胺等溶剂中进行； 所述水解反应可以在例如氢氧化钠、 氢氧化钾或氢氧化锂的催化剂存在下在例如乙醇 /水、 甲醇 /水或乙腈 /水的溶 剂中进行； 所述溴化反应可以在例如三溴化磷， 五溴化磷， 三溴氧磷或二溴 亚砜等溴化剂存在下在例如乙腈或乙酸乙酯的溶剂中进行； Step 3: Compound 14 is subjected to hydrogenation reduction to obtain compound 15. When Z=0 or S, compound 15 is hydrolyzed to obtain compound 16, and compound 16 is subjected to bromination reaction, followed by dropwise addition. Anhydrous ethanol is subjected to an esterification reaction to obtain a compound 17; the reduction reaction can be carried out in the presence of a catalyst such as palladium on carbon in a solvent such as methanol, ethanol or ethyl acetate; the hydrolysis reaction can be, for example, sodium hydroxide or hydrogen In the presence of a catalyst of potassium oxide or lithium hydroxide in a solvent such as ethanol/water, methanol/water or acetonitrile/water; the bromination reaction may be, for example, phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide Or in the presence of a brominating agent such as dibromosulfoxide in a solvent such as acetonitrile or ethyl acetate; Step 4: When Z = NH, compound 15 and R 7 I are thiolated to give compound 18, compound 18 The compound 19 is obtained by hydrolysis, and the compound 19 is subjected to bromination reaction, and then added dropwise to anhydrous ethanol to obtain a compound 20 by esterification; the thiolation reaction can be, for example, sodium hydride, potassium hydride, potassium t-butoxide or uncle In the presence of a catalyst such as sodium butoxide or the like, it is carried out in a solvent such as acetonitrile, acetone or tetrahydrofuran, hydrazine-dimethylformamide; the hydrolysis reaction can be, for example, sodium hydroxide, potassium hydroxide or hydroxide. In the presence of a catalyst, for example, in a solvent such as ethanol/water, methanol/water or acetonitrile/water; the bromination reaction may be, for example, phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide or dibromosulfoxide. In the presence of a brominating agent, in a solvent such as acetonitrile or ethyl acetate;
其中， Ζ为 0、 S或 N， R7为 CrC6垸基； Wherein Ζ is 0, S or N, and R 7 is C r C 6 fluorenyl;
在上述歩骤 1〜歩骤 4中，各个歩骤的反应均在本领域普通技术人员公知 的反应条件下进行。  In the above steps 1 to 4, the reactions of the respective steps are carried out under reaction conditions well known to those skilled in the art.
在反应式 1~3中， X， R^Rs的定义与上述 X， R^Rs的定义相同。  In the reaction formulae 1-3, the definitions of X, R^Rs are the same as those of the above X, R^Rs.
本发明的又一方面是提供了一种药物组合物， 该药物组合物包含治疗有 效量的选自上述通式 I所示的苯丙酸类化合物、 其对映异构体、 外消旋体及 其混合物和其药学上可接受的盐中一种或多种， 及任选的药学上可接受的辅 料。 所述药物组合物可以用于治疗糖尿病或糖脂代谢紊乱。  According to still another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a phenylpropionic acid compound selected from the above formula I, an enantiomer thereof, a racemate thereof And one or more of a mixture thereof and a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. The pharmaceutical composition can be used to treat diabetes or disorders of glycolipid metabolism.
本发明的又一方面是提供了选自通式 I所示的苯丙酸类化合物、 其对映 异构体、 外消旋体及其混合物、 其立体异构体、 其前药分子以及其药学上可 接受的盐中的一种或多种在制备治疗糖尿病或糖脂代谢紊乱的药物中的用 途。  A further aspect of the invention provides a phenylpropionic acid compound selected from the formula I, an enantiomer thereof, a racemate, and mixtures thereof, stereoisomers thereof, prodrug molecules thereof, and Use of one or more of the pharmaceutically acceptable salts for the manufacture of a medicament for the treatment of diabetes or disorders of glycolipid metabolism.
在本发明的又一个方面，提供了一种治疗糖尿病或糖脂代谢紊乱的方法， 其包括向具有该需要的患者施用治疗有效量的选自根据本发明的苯丙酸类化 合物、 其对映异构体、 外消旋体及其混合物、 其立体异构体、 其前药分子和 其药学上可接受的盐中一种或多种， 或者根据本发明的药物组合物。 附图说明 图 1为 HYH-013单次给药对 ob/ob小鼠血糖的影响 (mM， X+s, n=8) *， P<0.05 , 与对照组相比； **， P<0.01， 与对照组相比。 具体实施方式 以下通过实施例进一歩说明本发明， 但所述实施例并不限制本发明的范 围。 In a further aspect of the invention, a method of treating diabetes or a disorder of glycolipid metabolism comprising administering to a patient in need thereof a therapeutically effective amount of a phenylpropionic acid compound selected from the present invention, which is aligned One or more of the isomers, racemates and mixtures thereof, stereoisomers thereof, prodrug molecules thereof, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to the present invention. DRAWINGS Figure 1 shows the effect of single administration of HYH-013 on blood glucose of ob/ob mice (mM, X+s, n=8) *, P < 0.05, compared with the control group; **, P < 0.01, and Compared with the control group. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described by way of examples, but the examples are not intended to limit the scope of the invention.
核磁共振氢谱用 BmkerAMX-400型、 Gemini-300型或 AMX-600型核磁 共振仪记录， 化学位移 δ的单位为 ppm。 比旋光由 Perkin-Elmer241型自动旋 光仪测定， 所用微波为 CEM-discovery微波反应器。 所有反应溶剂均按照常 规方法进行纯化。 柱层析用硅胶 (200-300目)为青岛海洋化工分厂生产。 薄层 层析使用 GF254高效板， 为烟台化工研究所生产。制备型薄层层析板由自己 制备， 固定相采用 GF254(HG/T2354-92)硅胶和羧甲基纤维素钠 (800-1200)制 备， 分别为青岛海洋化工有限公司和中国医药 （集团） 上海化学试剂公司生 产。所有溶剂均为分析纯试剂，所用试剂均购自国药集团化学试剂有限公司。 采用碘、 紫外荧光等方法显色。 减压蒸除有机溶剂在旋转蒸发仪中进行。  The nuclear magnetic resonance spectrum was recorded with a Bmker AMX-400, Gemini-300 or AMX-600 nuclear magnetic resonance instrument, and the unit of chemical shift δ was ppm. The specific optical rotation was measured by a Perkin-Elmer Model 241, and the microwave used was a CEM-discovery microwave reactor. All reaction solvents were purified according to a conventional method. Column chromatography with silica gel (200-300 mesh) is produced by Qingdao Ocean Chemical Branch. Thin layer chromatography was performed using the GF254 high efficiency plate for the Yantai Institute of Chemical Industry. Preparative thin-layer chromatography plates were prepared by themselves. The stationary phase was prepared by GF254 (HG/T2354-92) silica gel and sodium carboxymethylcellulose (800-1200), respectively, Qingdao Ocean Chemical Co., Ltd. and China Pharmaceutical (Group). Shanghai Chemical Reagent Company produces. All solvents were analytically pure reagents, and the reagents used were purchased from Sinopharm Chemical Reagent Co., Ltd. Color development was carried out by means of iodine or ultraviolet fluorescence. The organic solvent was distilled off under reduced pressure in a rotary evaporator.
实施例 1： 3-(4-溴甲基苯基)丙酸乙酯的制备  Example 1: Preparation of ethyl 3-(4-bromomethylphenyl)propionate
Figure imgf000018_0001
称取 4-溴苯甲醇 la (购自韶远化学科技 （上海） 有限公司， 10.50g， 56.0mmol，）溶于 lOOmL三乙胺中，加入 20.0mL丙烯酸乙酯 2，醋酸钯（0.50g， 2.2mmol) , 三苯基膦（0.50g， 1.9mmol)。 反应体系用氮气置换三次， 然后置 于油浴中 95 °C反应 72小时， 反应液冷却至室温， 过滤， 滤液浓缩后， 硅胶 柱层析 (：石油醚 /乙酸乙酯 =4/1)分离得到白色固体 3a 10.8g，产率 93%。 ^0 (300 MHz, CDC13): δ =7.67 (d, J = 16.0 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.38 (d J = 8.1 Hz, 2H), 6.42 (d, J = 16.0 Hz, 1H), 4.72 (d, J = 5.4 Hz, 2H), 4.26 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H)。 将 10.8g中间体 3a溶解于 lOOmL乙酸乙酯中， 加入 10%钯碳 200mg， 氢气置换三次后， 室温下反应 4小时， 反应液垫硅藻土过滤， 滤液浓缩后硅 胶柱层析分离（乙酸乙酯 /石油醚 =1/8)，得白色固体 4a lO.lg,产率 93%。 NM (300 MHz, CDC13): δ =7.29 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 4.65 (s, 2H), 4.18 - 4.05 (m, 2H), 2.94 (t,J= 7.8 Hz, 2H), 2.61 (dd,J= 9.2, 6.2 Hz, 3H), 1.29- 1.16 (m, 3H).
Figure imgf000018_0001
Weigh 4-bromobenzyl alcohol la (purchased from Suiyuan Chemical Technology (Shanghai) Co., Ltd., 10.50g, 56.0mmol,) dissolved in lOOmL of triethylamine, add 20.0mL of ethyl acrylate 2, palladium acetate (0.50g, 2.2 mmol), triphenylphosphine (0.50 g, 1.9 mmol). The reaction system was replaced with nitrogen three times, and then placed in an oil bath at 95 ° C for 72 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated, then purified by silica gel column chromatography (: petroleum ether / ethyl acetate = 4 / 1) A white solid 3a of 10.8 g was obtained with a yield of 93%. ^0 (300 MHz, CDC1 3 ): δ = 7.67 (d, J = 16.0 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.38 (d J = 8.1 Hz, 2H), 6.42 (d , J = 16.0 Hz, 1H), 4.72 (d, J = 5.4 Hz, 2H), 4.26 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H). 10.8 g of the intermediate 3a was dissolved in 100 mL of ethyl acetate, and 200 mg of 10% palladium carbon was added thereto, and the mixture was replaced with hydrogen three times, and then reacted at room temperature for 4 hours. The reaction liquid was filtered through Celite, and the filtrate was concentrated and then separated by silica gel column chromatography (acetic acid) Ethyl ester / petroleum ether = 1 / 8) gave a white solid 4a lO. NM (300 MHz, CDC1 3 ): δ = 7.29 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 4.65 (s, 2H), 4.18 - 4.05 (m, 2H) , 2.94 (t, J = 7.8 Hz, 2H), 2.61 (dd, J = 9.2, 6.2 Hz, 3H), 1.29- 1.16 (m, 3H).
将 10.2g中间体 4a溶解于 200mL无水乙醚中， 冰水浴下滴加入 20.0g 三溴化磷， 然后保温反应 1小时， 加入水洗涤， 有机层用无水硫酸钠干燥， 浓缩后硅胶柱层析分离 （乙酸乙酯 /石油醚 =1/15)， 得白色固体 5a 12.2g, 产率 92%。 ιΐΙ NMR (300 MHz, CDC13): δ =7.31 (d, J= 8.1 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 4.48 (s, 2H), 4.12 (q,J=7.1 Hz,2H), 2.94 (t,J= 7.8 Hz, 2H), 2.61 (t J=7.8Hz, 2H), 1.23 (t, J =7.1 Hz, 3H)。 10.2 g of the intermediate 4a was dissolved in 200 mL of anhydrous diethyl ether, and 20.0 g of phosphorus tribromide was added dropwise thereto in an ice water bath, and then the reaction was kept for 1 hour, washed with water, and the organic layer was dried over anhydrous sodium sulfate. The mixture was separated (ethyl acetate / petroleum ether = 1 / 15) to afford white solid, 5a 12.2 g, yield 92%. ι NMR (300 MHz, CDC1 3 ): δ =7.31 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 4.48 (s, 2H), 4.12 (q, J= 7.1 Hz, 2H), 2.94 (t, J = 7.8 Hz, 2H), 2.61 (t J = 7.8 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H).
实施例 2: 3-(4-溴甲基 -2-氟苯基)丙酸乙酯的制备  Example 2: Preparation of ethyl 3-(4-bromomethyl-2-fluorophenyl)propanoate
10%Pd/C, H. 10% Pd/C, H.
EtOAc  EtOAc
Figure imgf000019_0001
按照与实施例 1所示类似的方法， 用化合物 lb代替化合物 la， 制备得 到化合物 3-(4-溴甲基 -2-氟苯基)丙酸乙酯 (化合物 5b)。 ¾ NMR (300 MHz, CDC13) δ 7.19 (t, J= 7.8 Hz, 1H), 7.11 - 7.03 (m, 2H), 4.43 (s, 2H), 4.12 (q,J = 7.1 Hz, 2H), 2.96 (t,J= 7.6 Hz, 2H), 2.61 (t,J= 7.6 Hz, 2H), 1.23 (t,J= 7.1 Hz, 3H).
Figure imgf000019_0001
Ethyl 3-(4-bromomethyl-2-fluorophenyl)propanoate (Compound 5b) was obtained by substituting compound lb for compound la in the same manner as in Example 1. 3⁄4 NMR (300 MHz, CDC1 3 ) δ 7.19 (t, J = 7.8 Hz, 1H), 7.11 - 7.03 (m, 2H), 4.43 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 2.96 (t, J = 7.6 Hz, 2H), 2.61 (t, J = 7.6 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H).
实施例 3： 3-(4-(((6-溴吡啶 -2-基)氧)亚甲基)苯基)丙酸乙酯的制备  Example 3: Preparation of ethyl 3-(4-(((6-bromopyridin-2-yl)oxy)methylene)phenyl)propanoate
Figure imgf000019_0002
称取 2.50g化合物 6a， 3.90g化合物 5a， 4.0g碳酸钾加入到 lOOmL圆底 烧瓶中， 加入无水乙腈 50mL， 50°C反应 5小时。 将反应液降至室温， 过滤， 滤液浓缩硅胶柱层析分离 （乙酸乙酯 /石油醚 =1/10)， 得 3.63g白色固体化合 物 7a，产率 69%。 ^11 (300 MHz, CDC13): δ =7.41 (dd,J= 15.1, 7.5 Hz, 3H),
Figure imgf000019_0002
2.50 g of the compound 6a, 3.90 g of the compound 5a, and 4.0 g of potassium carbonate were weighed and added to a 100 mL round bottom flask, and 50 mL of anhydrous acetonitrile was added thereto, and the mixture was reacted at 50 ° C for 5 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated to silica gel column chromatography (ethyl acetate / petroleum ether = 1/10) to give 3.63 g of white solid compound 7a. ^11 (300 MHz, CDC1 3 ): δ = 7.41 (dd, J = 15.1, 7.5 Hz, 3H),
7.22 (d,J= 8.0 Hz, 2H), 7.07 (d,J= 7.4 Hz, 1H), 6.72 (d,J= 8.2 Hz, 1H), 5.31 (s. 2H), 4.13 (q, J = 7.1 Hz, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.62 (t, J = 7.8 Hz, 2H),7.22 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.31 (s. 2H), 4.13 (q, J = 7.1 Hz, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.62 (t, J = 7.8 Hz, 2H),
1.23 (dd,J= 8.3, 6.0 Hz, 3H). 1.23 (dd, J= 8.3, 6.0 Hz, 3H).
实施例 4: 3-(4-(((6-苯基吡啶 -2-基)氧)亚甲基)苯基)丙酸 (化合物 HYH-001)的制备 Example 4: Preparation of 3-( 4 -(( 6 -phenylpyridin- 2 -yl)oxy)methylene)phenyl)propanoic acid (Compound HYH-001)
Figure imgf000020_0001
称取 lOO.Omg化合物 7a， 45.0mg苯硼酸， 15.0mg四 （三苯基膦） 钯和 75.0mg碳酸钾加入到 10mL微波反应器专用管中， 加入 2.0mL甲苯， 0.4mL 乙醇和 0.4mL水， 用氮气置换 3次， 然后置于 CEM微波反应器中 120°C反 应 30分钟， 反应液浓缩后硅胶柱层析分离，得到 3-(4-(：6-苯基吡啶 -2-基：)氧:) 亚甲基)苯基)丙酸乙酯 97.0mg， 为无色油状物。 ^NM POOMH^CDCI^S 8.09 -8.00 (m, 2H), 7.69 -7.59 (m, 1H), 7.51 -7.36 (m, 5H), 7.28 -7.18 (m, 3H), 6.73 (dd,J= 8.1, 5.6 Hz, 1H), 5.49 (s, 2H), 4.13 (q,J= 7.1 Hz, 2H), 2.97 (t,J = 7.8 Hz, 2H), 2.63 (t, J =7.8 Hz, 2H), 1.24 (t, J =7.1 Hz, 3H).
Figure imgf000020_0001
Weigh 100.Omg of compound 7a, 45.0 mg of phenylboronic acid, 15.0 mg of tetrakis(triphenylphosphine) palladium and 75.0 mg of potassium carbonate were added to a 10 mL microwave reactor special tube, and 2.0 mL of toluene, 0.4 mL of ethanol and 0.4 mL of water were added. It was replaced with nitrogen for 3 times, and then placed in a CEM microwave reactor at 120 ° C for 30 minutes. The reaction liquid was concentrated and separated by silica gel column chromatography to give 3-(4-(: 6-phenylpyridin-2-yl: Oxygen:) 97.0 mg of methylene)phenyl)propanoate as a colorless oil. ^NM POOMH^CDCI^S 8.09 -8.00 (m, 2H), 7.69 -7.59 (m, 1H), 7.51 -7.36 (m, 5H), 7.28 -7.18 (m, 3H), 6.73 (dd, J= 8.1 , 5.6 Hz, 1H), 5.49 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 2.97 (t, J = 7.8 Hz, 2H), 2.63 (t, J = 7.8 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H).
将上述得到的油状物溶于 5.0mL乙腈中， 力口入 1.0mL7jC， 加入氢氧化锂 lO.Omg, 置于 40°C油浴中反应 12小时， TLC检测反应结束。 用 2M盐酸溶 液调 pH=2-3，加入水，用乙酸乙酯萃取 3次，合并有机层用饱和食盐水洗涤， 有机层用无水硫酸钠干燥， 过滤浓缩得 3- K;6-苯基吡啶 -2-基：)氧：)亚甲基:) 苯基)丙酸 90mg， 为白色固体。 ^NM OOMHz, CDCl3)S8.04(dd,J=8.3, 1.3 Hz, 2H), 7.69 -7.60 (m, 1H), 7.51 -7.33 (m, 6H), 7.24 (d, J = 8.0 Hz, 2H), 6.76 -6.72 (m, 1H), 5.49 (s, 2H), 2.97 (t,J= 7.8 Hz, 2H), 2.69 (t,J= 7.8 Hz, 2H). The oil obtained above was dissolved in 5.0 mL of acetonitrile, and 1.0 mL of 7jC was added thereto, and lithium hydroxide (10 mg) was added thereto, and the mixture was reacted in an oil bath at 40 ° C for 12 hours, and the reaction was terminated by TLC. The pH was adjusted to 2-3 with 2M hydrochloric acid solution, water was added, and the mixture was extracted with EtOAc (EtOAc). Pyridin-2-yl:) Oxygen:) methylene:) Phenyl) propionic acid 90 mg as a white solid. ^NM OOMHz, CDCl 3 )S8.04 (dd, J=8.3, 1.3 Hz, 2H), 7.69 -7.60 (m, 1H), 7.51 -7.33 (m, 6H), 7.24 (d, J = 8.0 Hz, 2H), 6.76 -6.72 (m, 1H), 5.49 (s, 2H), 2.97 (t, J = 7.8 Hz, 2H), 2.69 (t, J = 7.8 Hz, 2H).
实施例 5： 3-(4-(((6-(2-甲基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸 (化合物 HYH-002)的制备
Figure imgf000021_0001
Example 5: Preparation of 3-(4-((6-(2-methylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (Compound HYH-002)
Figure imgf000021_0001
除了使用 2-甲基苯硼酸代替苯硼酸之外， 以按照与实施例 4类似的方法 制得化合物 3-(4-(((6-(2-甲基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDC13) δ =7.65 (t, J = 7.8 Hz, 1H), 7.44 (d, J= 7.6 Hz, 1H), 7.41 (d, J = 7.9 Hz, 2H), 7.34 -7.27 (m, 3H), 7.23 (d, J = 7.9 Hz, 2H), 7.02 (d, J = 7.3 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 5.40 (s, 2H), 2.98 (t, J = 7.7 Hz, 2H), 2.70 (t, J = 7.8 Hz, 2H), 2.41 (s, 3H). The compound 3-(4-((6-(2-methylphenyl)pyridin-2-yl)) was prepared in a similar manner to Example 4 except that 2-methylphenylboronic acid was used instead of phenylboronic acid. Oxygen)methylene)phenyl)propionic acid. NM (400 MHz, CDC1 3 ) δ = 7.65 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 7.9 Hz, 2H), 7.34 -7.27 ( m, 3H), 7.23 (d, J = 7.9 Hz, 2H), 7.02 (d, J = 7.3 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 5.40 (s, 2H), 2.98 ( t, J = 7.7 Hz, 2H), 2.70 (t, J = 7.8 Hz, 2H), 2.41 (s, 3H).
实施例 6： 3-(4-(((6-(4-甲基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸 (化合物 HYH-003  Example 6: 3-(4-((6-(4-methylphenyl)pyridine-2-yl)oxy)methylene)phenyl)propanoic acid (Compound HYH-003
Figure imgf000021_0002
Figure imgf000021_0002
除了使用对甲基苯硼酸代替苯硼酸之外， 按照与实施例 4类似的方法制 得化合物 3-(4-(((6-(4-甲基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDCI3) δ =8.18 (d, J = 8.2 Hz, 2H), 7.64 -7.60 (m, 2H), 7.59 -7.55 (m, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.31 (dd, J = 7.4, 0.6 Hz, 1H), 7.01 (s, 2H), 6.81 (dd, J = 8.2, 0.6 Hz, 1H), 5.48 (s, 2H), 2.97 (t, J = 7.7 Hz, 2H), 2.73 .66 (m, 2H), 1.42 (s, 3H).  The compound 3-(4-((6-(4-methylphenyl)pyridin-2-yl)oxy) was prepared in a similar manner to Example 4 except that p-methylbenzeneboronic acid was used instead of phenylboronic acid. Methylene)phenyl)propionic acid. NM (400 MHz, CDCI3) δ = 8.18 (d, J = 8.2 Hz, 2H), 7.64 - 7.60 (m, 2H), 7.59 -7.55 (m, 1H), 7.40 (d, J = 8.2 Hz, 1H) , 7.31 (dd, J = 7.4, 0.6 Hz, 1H), 7.01 (s, 2H), 6.81 (dd, J = 8.2, 0.6 Hz, 1H), 5.48 (s, 2H), 2.97 (t, J = 7.7 Hz, 2H), 2.73 .66 (m, 2H), 1.42 (s, 3H).
实施例 7： 3-(4-(((6-(2-乙基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸 (化合物 HYH-004  Example 7: 3-(4-((6-(2-ethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (Compound HYH-004
Figure imgf000021_0003
Figure imgf000021_0003
除了使用 2-乙基苯硼酸代替苯硼酸之外， 按照与实施例 4类似的方法制 得化合物 3-(4-(((6-(2-乙基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDCI3) δ =7.65 (t, J = 7.8 Hz, 1H), 7.41 (dd, J = 14.6, 7.7 Hz, 3H), 7.31 - .24 (m, 3H), 7.23 (d, J = 7.9 Hz, 2H), 7.02 (d, J = 7.3 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 5.40 (s, 2H), 2.98 (t,J= 7.7 Hz, 2H), 2.70 (t,J= 7.8 Hz, 2H), 2.51 (q,J=7.1 Hz, 1H, 2H), 1.30(d, J= 8.2, 6.1 Hz,3H). The compound 3-(4-((6-(2-ethylphenyl)pyridin-2-yl)oxy) was prepared in a similar manner to Example 4 except that 2-ethylbenzeneboronic acid was used instead of phenylboronic acid. Methylene)phenyl)propionic acid. NM (400 MHz, CDCI3) δ = 7.65 (t, J = 7.8 Hz, 1H), 7.41 (dd, J = 14.6, 7.7 Hz, 3H), 7.31 - .24 (m, 3H), 7.23 (d, J = 7.9 Hz, 2H), 7.02 (d, J = 7.3 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 5.40 (s, 2H), 2.98 (t, J = 7.7 Hz, 2H), 2.70 (t, J = 7.8 Hz, 2H), 2.51 (q, J = 7.1 Hz, 1H, 2H) , 1.30 (d, J = 8.2, 6.1 Hz, 3H).
实施例 8： 3-(4-(((6-(2-异丙基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸 (化合 物 HYH-005  Example 8: 3-(4-((6-(2-isopropylphenyl)pyridine-2-yl)oxy)methylene)phenyl)propanoic acid (Compound HYH-005
Figure imgf000022_0001
Figure imgf000022_0001
除了使用 2-异丙基苯硼酸代替苯硼酸之外， 按照与实施例 4类似的方法 制得化合物 3-(4-(((6-(2-异丙基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (300 MHz, CD3C1) δ =7.65 (t,J= 7.7 Hz, 1H), 7.46 - 7.30 (m, 5H), 7.28 - 7.19 (m, 3H), 6.97 (d, J =7.2 Hz, 1H), 6.78 (d,J=8.1 Hz, 1H), 5.38 (s, 2H), 3.30 (m, 1H), 2.97 (t, J = 7.6 Hz, 2H), 2.69 (t, J = 7.8 Hz, 2H), 1.21 (d, J = 6.8 Hz, 6H). The compound 3-(4-((6-(2-isopropylphenyl)pyridin-2-yl) was prepared in a similar manner to Example 4 except that 2-isopropylbenzeneboronic acid was used instead of phenylboronic acid. Oxy)methylene)phenyl)propionic acid. NM (300 MHz, CD 3 C1 ) δ = 7.65 (t, J = 7.7 Hz, 1H), 7.46 - 7.30 (m, 5H), 7.28 - 7.19 (m, 3H), 6.97 (d, J = 7.2 Hz, 1H), 6.78 (d, J=8.1 Hz, 1H), 5.38 (s, 2H), 3.30 (m, 1H), 2.97 (t, J = 7.6 Hz, 2H), 2.69 (t, J = 7.8 Hz, 2H), 1.21 (d, J = 6.8 Hz, 6H).
实施例 9： 3-(4-(((6-(2-叔丁基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸 (化合 物 H  Example 9: 3-(4-((6-(2-tert-Butylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (Compound H
Figure imgf000022_0002
Figure imgf000022_0002
除了使用 2-异丁基苯硼酸代替苯硼酸之外， 按照与实施例 4类似的方法 制得化合物 3-(4-(((6-(2-叔丁基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (300 MHz, CDC13) δ =7.69 (t,J= 7.7 Hz, 1H), 7.49 - 7.33 (m, 4H), 7.29 - 7.22 (m, 4H), 6.99 (d,J= 7.2 Hz, 1H), 6.79 (d,J= 8.1 Hz, 1H), 5.38 (s, 2H), 2.96 (t,J= 7.6 Hz, 2H), 2.68 (t,J= 7.8 Hz, 2H), 1.19 (s, 9H). The compound 3-(4-((6-(2-tert-butylphenyl)pyridin-2-yl) was prepared in a similar manner to Example 4 except that 2-isobutylbenzeneboronic acid was used instead of phenylboronic acid. Oxy)methylene)phenyl)propionic acid. NM (300 MHz, CDC1 3 ) δ = 7.69 (t, J = 7.7 Hz, 1H), 7.49 - 7.33 (m, 4H), 7.29 - 7.22 (m, 4H), 6.99 (d, J = 7.2 Hz, 1H ), 6.79 (d, J = 8.1 Hz, 1H), 5.38 (s, 2H), 2.96 (t, J = 7.6 Hz, 2H), 2.68 (t, J = 7.8 Hz, 2H), 1.19 (s, 9H) ).
实施例 10： 3-(4-(((6-(2-硝基苯基)吡啶 -2-基)氧基亚甲基)苯基)丙酸 (化合 物 HYH-007  Example 10: 3-(4-((6-(2-Nitrophenyl)pyridin-2-yl)oxymethylene)phenyl)propanoic acid (Compound HYH-007
Figure imgf000022_0003
除了使用 2-硝基苯硼酸代替苯硼酸之外， 按照与实施例 4所示类似的方 法制得化合物 3-(4-(((6-(2-硝基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDC13) δ = 8.25 (t, J = 7.8 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.9 Hz, 2H), 7.34 7.27 (m, 3H), 7.25 (d,J=7.9 Hz, 2H), 7.02 (d,J = 7.3 Hz, 1H), 6.77 (d,J= 8.1 Hz, 1H), 5.40 (s, 2H), 2.98 (t,J= 7.7 Hz, 2H), 2.70 (t,J=7.8Hz, 2H).
Figure imgf000022_0003
The compound 3-(4-((6-(2-nitrophenyl)pyridin-2-yl) was prepared in a similar manner to that shown in Example 4 except that 2-nitrophenylboronic acid was used instead of phenylboronic acid. Oxy)methylene)phenyl)propionic acid. NM (400 MHz, CDC1 3 ) δ = 8.25 (t, J = 7.8 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.9 Hz, 2H), 7.34 7.27 (m , 3H), 7.25 (d, J=7.9 Hz, 2H), 7.02 (d, J = 7.3 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 5.40 (s, 2H), 2.98 (t , J = 7.7 Hz, 2H), 2.70 (t, J = 7.8 Hz, 2H).
实施例 11： 3-(4-(((6-(2-氨基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸 (化合 物 HYH-008  Example 11: 3-(4-((6-(2-Aminophenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (Compound HYH-008
Figure imgf000023_0001
Figure imgf000023_0001
除了使用 2-氨基苯硼酸代替苯硼酸之外， 按照与实施例 4类似的方法制 得化合物 3-(4-(((6-(2-氨基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDC13) δ = 8.76 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.34 - 7.27 (m, 3H), 7.25 (d,J= 7.9 Hz, 2H), 7.02 (d, J= 7.3 Hz, 1H), 6.88 6.95 (m, 2H), 6.57 (d,J= 8.1 Hz, 1H), 6.08(brs,2H), 5.40 (s, 2H), 2.98 (t, J= 7.7 Hz, 2H), 2.70 (t, J =7.8 Hz, 2H). The compound 3-(4-((6-(2-aminophenyl)pyridin-2-yl)oxy)) was obtained in a similar manner to Example 4 except that 2-aminophenylboronic acid was used instead of phenylboronic acid. Methyl)phenyl)propionic acid. NM (400 MHz, CDC1 3 ) δ = 8.76 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.34 - 7.27 (m, 3H), 7.25 (d, J = 7.9) Hz, 2H), 7.02 (d, J= 7.3 Hz, 1H), 6.88 6.95 (m, 2H), 6.57 (d, J= 8.1 Hz, 1H), 6.08(brs, 2H), 5.40 (s, 2H) , 2.98 (t, J = 7.7 Hz, 2H), 2.70 (t, J = 7.8 Hz, 2H).
实施例 12： 3-(4-(((6-(2-羟基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸 (化合物 HYH-009  Example 12: 3-(4-((6-(2-hydroxyphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (Compound HYH-009
Figure imgf000023_0002
Figure imgf000023_0002
除了使用 2-羟基苯硼酸代替苯硼酸之外， 按照与实施例 4类似的方法制 得化合物 3-(4-(((6-(2-羟基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDCI3) δ = 11.2 (s, 1H), 8.65 (t,J= 7.8 Hz, 1H), 7.44 (d,J= 7.6 Hz, 1H), 7.34 7.27 (m, 3H), 7.21 (d,J=7.9 Hz, 2H), 6.09 (d, J = 7.3 Hz, 1H), 6.81 (m, 2H), 6.57 (d,J= 8.1 Hz, 1H), 5.40 (s, 2H), 2.98 (t, J= 7.7 Hz, 2H), 2.70 (t, J = 7.8 Hz, 2H).  The compound 3-(4-((6-(2-hydroxyphenyl)pyridin-2-yl)oxy)) was prepared in a similar manner to Example 4 except that 2-hydroxyphenylboronic acid was used instead of phenylboronic acid. Methyl)phenyl)propionic acid. NM (400 MHz, CDCI3) δ = 11.2 (s, 1H), 8.65 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.34 7.27 (m, 3H), 7.21 ( d, J = 7.9 Hz, 2H), 6.09 (d, J = 7.3 Hz, 1H), 6.81 (m, 2H), 6.57 (d, J = 8.1 Hz, 1H), 5.40 (s, 2H), 2.98 ( t, J = 7.7 Hz, 2H), 2.70 (t, J = 7.8 Hz, 2H).
实施例 13： 3-(4-(((6-(2- (三氟甲基)苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸 (化合物 HYH-010)的制备
Figure imgf000024_0001
Example 13: 3-(4-((6-(2-(trifluoromethyl)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (Compound HYH-010) preparation
Figure imgf000024_0001
除了使用 2-三氟甲基苯硼酸代替苯硼酸之外， 按照与实施例 4类似的方 法制得化合物 3-(4-(((6-(2- (三氟甲基)苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 JH NM (300 MHz, CD3C1) δ= 7.78 (d, J = 7.5 Hz, 1H), 7.69 - 7.57 (m, 2H), 7.52 (t,J= 7.3 Hz, 2H), 7.39 (d,J= 8.1 Hz, 2H), 7.22 (d,J= 8.1 Hz, 2H), 7.02 (d J= 7.3 Hz, 1H), 6.81 (dd,J= 8.3, 0.6 Hz, 1H), 5.36 (s, 2H), 2.97 (t,J= 7.7 Hz, 2H), 2.69 (t, J =7.7 Hz, 2H)。 The compound 3-(4-((6-(2-(trifluoromethyl)phenyl)pyridine) was prepared in a similar manner to Example 4 except that 2-trifluoromethylbenzeneboronic acid was used instead of phenylboronic acid. -2-yl)oxy)methylene)phenyl)propanoic acid. J H NM (300 MHz, CD 3 C1) δ = 7.78 (d, J = 7.5 Hz, 1H), 7.69 - 7.57 (m, 2H), 7.52 (t, J = 7.3 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 7.02 (d J = 7.3 Hz, 1H), 6.81 (dd, J = 8.3, 0.6 Hz, 1H), 5.36 (s, 2H) ), 2.97 (t, J = 7.7 Hz, 2H), 2.69 (t, J = 7.7 Hz, 2H).
实施例 14： 3-(4-(((6-(2-甲氧基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸 (化合 物 HYH-011  Example 14: 3-(4-((6-(2-methoxyphenyl)pyridine-2-yl)oxy)methylene)phenyl)propanoic acid (combination HYH-011)
Figure imgf000024_0002
Figure imgf000024_0002
除了使用 2-甲氧基苯硼酸代替苯硼酸之外， 按照与实施例 4类似的方法 制得化合物 3-(4-(((6-(2-甲氧基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDC13) δ =7.64 (t, J = 7.8 Hz, 1H), 7.32 (dd, J = 14.6, 7.7 Hz, 3H), 7.30 7.25 (m, 3H), 7.21 (d,J= 7.9 Hz, 2H), 6.98 (d, J= 7.3 Hz, 1H), 6.74 (d,J= 8.1 Hz, 1H), 5.38 (s, 2H), 3.74 (s, 3H), 2.97 (t,J= 7.7 Hz, 2H), 2.780 (t,J = 7.8 Hz, 2H)。 The compound 3-(4-((6-(2-methoxyphenyl)pyridin-2-yl) was prepared in a similar manner to Example 4 except that 2-methoxyphenylboronic acid was used instead of phenylboronic acid. Oxy)methylene)phenyl)propionic acid. NM (400 MHz, CDC1 3 ) δ = 7.64 (t, J = 7.8 Hz, 1H), 7.32 (dd, J = 14.6, 7.7 Hz, 3H), 7.30 7.25 (m, 3H), 7.21 (d, J= 7.9 Hz, 2H), 6.98 (d, J = 7.3 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 5.38 (s, 2H), 3.74 (s, 3H), 2.97 (t, J= 7.7 Hz, 2H), 2.780 (t, J = 7.8 Hz, 2H).
实施例 15： 3-(4-(((6-(2-甲基氨基苯基)吡啶 -2-基)氧)甲基)苯基)丙酸 (化合 物 HYH-012  Example 15: 3-(4-((6-(2-methylaminophenyl)pyridine-2-yl)oxy)methyl)phenyl)propanoic acid (Compound HYH-012
Figure imgf000024_0003
Figure imgf000024_0003
除了使用 2-甲氨基苯硼酸代替苯硼酸之外， 按照与实施例 4类似的方法 制得化合物 3-(4-(((6-(2-甲基氨基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDC13) δ =7.76 (t, J = 7.8 Hz, 1H), 7.31 (dd, J = 14.6, 7.7 Hz, 3H), 7.29 7.24 (m, 3H), 7.21 (d,J= 7.9 Hz, 2H), 6.88 (d,J= 7.3 Hz, 1H), 6.74 (d,J= 8.1 Hz, 1H), 5.38 (s, 2H), 3.74 (s, 3H),2.97 (t,J= 7.7 Hz, 2H), 2.780 (t, J = 7.8 Hz, 2H). The compound 3-(4-((6-(2-methylaminophenyl)pyridin-2-yl)) was prepared in a similar manner to Example 4 except that 2-methylaminobenzeneboronic acid was used instead of phenylboronic acid. Oxygen)methylene)phenyl)propionic acid. NM (400 MHz, CDC1 3 ) δ = 7.76 (t, J = 7.8 Hz, 1H), 7.31 (dd, J = 14.6, 7.7 Hz, 3H), 7.29 7.24 (m, 3H), 7.21 (d, J= 7.9 Hz, 2H), 6.88 (d, J = 7.3 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 5.38 (s, 2H), 3.74 (s, 3H), 2.97 (t, J = 7.7 Hz, 2H), 2.780 (t, J = 7.8 Hz, 2H).
实施例 16： 3-(4-(((6-(2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸 (化 合物 HYH-013  Example 16: 3-(4-((6-(2,6-dimethylphenyl)pyridine-2-yl)oxy)methylene)phenyl)propanoic acid (Compound HYH-013)
Figure imgf000025_0001
Figure imgf000025_0001
除了使用 2,6-二甲基苯硼酸代替苯硼酸之外， 按照与实施例 4类似的方 法制得化合物 3-(4-(((6-(2， 6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDC13) δ= 7.64 (dd, J = 8.3, 7.3 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.20 (d,J= 8.1 Hz, 3H), 7.10 (d, J= 7.7 Hz, 2H), 6.80 (dd, J= 7.2, 0.8 Hz, 1H), 6.76 (dd, J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t,J= 7.8 Hz, 2H), 2.67 (t, J=7.8Hz, 2H), 2.06 (s, 6H). The compound 3-(4-((6-(2,6-dimethylphenyl))pyridine was obtained in a similar manner to Example 4 except that 2,6-dimethylphenylboronic acid was used instead of phenylboronic acid. -2-yl)oxy)methylene)phenyl)propanoic acid. NM (400 MHz, CDC1 3 ) δ = 7.64 (dd, J = 8.3, 7.3 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.1 Hz, 3H), 7.10 ( d, J= 7.7 Hz, 2H), 6.80 (dd, J= 7.2, 0.8 Hz, 1H), 6.76 (dd, J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J=7.8Hz, 2H), 2.06 (s, 6H).
实施例 17： 3-(4-(((6-(2,6-二乙基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸 (化 合物 HYH-014  Example 17: 3-(4-((6-(2,6-Diethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (Compound HYH-014
Figure imgf000025_0002
Figure imgf000025_0002
除了使用 2,6-二乙基苯硼酸代替苯硼酸之外， 按照与实施例 4类似的方 法制得化合物 3-(4-(((6-(2,6-二乙基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。  The compound 3-(4-((6-(2,6-diethylphenyl)pyridine) was prepared in a similar manner to Example 4 except that 2,6-diethylbenzeneboronic acid was used instead of phenylboronic acid. -2-yl)oxy)methylene)phenyl)propanoic acid.
JH NM (400 MHz, CDC13) δ= 7.64 (dd, J = 8.3, 7.3 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.20 (d,J= 8.1 Hz, 3H), 7.10 (d,J= 7.7 Hz, 2H), 6.80 (dd,J= 7.2, 0.8 Hz, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t, J= 7.8 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H), 2.50 (q, J = 7.1 Hz, 1H, 2H)， 1.25(dd, J = 8.2, 6.1 Hz,3H). J H NM (400 MHz, CDC1 3 ) δ = 7.64 (dd, J = 8.3, 7.3 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.1 Hz, 3H), 7.10 (d, J = 7.7 Hz, 2H), 6.80 (dd, J = 7.2, 0.8 Hz, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t , J = 7.8 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H), 2.50 (q, J = 7.1 Hz, 1H, 2H), 1.25 (dd, J = 8.2, 6.1 Hz, 3H).
实施例 18： 3-(4-(((6-(2,6-二甲氧基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸 (化合物 HYH-015)的制备
Figure imgf000026_0001
Example 18: 3-(4-((6-(2,6-Dimethoxyphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (Compound HYH-015) preparation
Figure imgf000026_0001
除了使用 2,6-二甲氧基苯硼酸代替苯硼酸之外， 按照与实施例 4类似的 方法制得化合物 3-(4-(((6-(2， 6-二甲氧基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙 酸。 NM (300 MHz, CDC13) δ 7.63 (t, J = 1.1 Hz, 1H), 7.40 (d, J = 1.1 Hz, 2H), 7.31 (t, J = 8.4 Hz, 1H), 7.20 (d, J = 7.6 Hz, 2H), 6.92 (d, J = 7.2 Hz, 1H), 6.74 (d,J= 8.3 Hz, 1H), 6.66 (d,J= 8.4 Hz, 2H), 5.35 (s, 2H), 3.74 (s, 6H), 2.95 (t,J= 7.5 Hz, 2H), 2.65 (dd,J= 16.0, 8.3 Hz, 2H). The compound 3-(4-((6-(2,6-dimethoxyphenyl)) was prepared in a similar manner to Example 4 except that 2,6-dimethoxyphenylboronic acid was used instead of phenylboronic acid. Pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. NM (300 MHz, CDC1 3 ) δ 7.63 (t, J = 1.1 Hz, 1H), 7.40 (d, J = 1.1 Hz, 2H), 7.31 (t, J = 8.4 Hz, 1H), 7.20 (d, J = 7.6 Hz, 2H), 6.92 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 8.4 Hz, 2H), 5.35 (s, 2H), 3.74 (s, 6H), 2.95 (t, J = 7.5 Hz, 2H), 2.65 (dd, J = 16.0, 8.3 Hz, 2H).
实施例 19： 3-(4-(((6-(2, 6-二氯苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸 (化 合物 HYH-016  Example 19: 3-(4-((6-(2,6-Dichlorophenyl)pyridine-2-yl)oxy)methylene)phenyl)propanoic acid (Compound HYH-016
Figure imgf000026_0002
Figure imgf000026_0002
除了使用 2,6-二氯苯硼酸代替苯硼酸之外， 按照与实施例 4类似的方法 制得化合物 3-(4-(((6-(2， 6-二氯苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (300 MHz, CD2C1) δ= 7.69 (dd,J= 8.3, 7.3 Hz, 1H), 7.41 (dd,J=4.9, 3.7 Hz, 4H), 7.28 (d, J = 7.3 Hz, 1H), 7.22 (t, J= 6.1 Hz, 2H), 6.92 (d, J = 7.2 Hz, 1H), 6.83 (d, J= 8.3 Hz, 1H), 5.34 (s, 2H), 2.96 (t, J= 7.7 Hz, 2H), 2.67 (t, J = 7.7 Hz, 2H)。 The compound 3-(4-((6-(2,6-dichlorophenyl)pyridine-2) was obtained in a similar manner to Example 4 except that 2,6-dichlorobenzeneboronic acid was used instead of phenylboronic acid. -yl)oxy)methylene)phenyl)propanoic acid. NM (300 MHz, CD 2 C1) δ = 7.69 (dd, J = 8.3, 7.3 Hz, 1H), 7.41 (dd, J=4.9, 3.7 Hz, 4H), 7.28 (d, J = 7.3 Hz, 1H) , 7.22 (t, J = 6.1 Hz, 2H), 6.92 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 5.34 (s, 2H), 2.96 (t, J= 7.7 Hz, 2H), 2.67 (t, J = 7.7 Hz, 2H).
实施例 20: 3-(4-(((6-(2, 6-二氟苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸 (化 合物 HYH-017  Example 20: 3-(4-((6-(2,6-Difluorophenyl)pyridine-2-yl)oxy)methylene)phenyl)propanoic acid (Compound HYH-017
Figure imgf000026_0003
Figure imgf000026_0003
除了使用 2,6-二氟苯硼酸代替苯硼酸之外， 按照与实施例 4类似的方法 制得化合物 3-(4-(((6-(2， 6-二氟苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (300 MHz, CD2C1) δ= 7.74 (dd,J= 8.3, 7.3 Hz, 1H), 7.42 (dd,J=4.9, 3.7 Hz, 4H), 7.26 (d, J = 7.3 Hz, 1H), 7.21 (t, J = 6.1 Hz, 2H), 6.92 (d, J = 7.2 Hz, 1H), 6.83 (d, J= 8.3 Hz, 1H), 5.34 (s, 2H), 2.96 (t, J= 7.7 Hz, 2H), 2.67 (t, J = 7.7 Hz, 2H). The compound 3-(4-((6-(2,6-difluorophenyl)pyridine-2) was prepared in a similar manner to Example 4 except that 2,6-difluorophenylboronic acid was used instead of phenylboronic acid. -yl)oxy)methylene)phenyl)propanoic acid. NM (300 MHz, CD 2 C1) δ = 7.74 (dd, J = 8.3, 7.3 Hz, 1H), 7.42 (dd, J=4.9, 3.7 Hz, 4H), 7.26 (d, J = 7.3 Hz, 1H) , 7.21 (t, J = 6.1 Hz, 2H), 6.92 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 5.34 (s, 2H), 2.96 (t, J = 7.7 Hz, 2H), 2.67 (t, J = 7.7 Hz, 2H).
实施例 21： 3-(4-(((6-(2,6-二甲基 -4-羟基苯基)吡啶 -2-基)氧)亚甲基)苯基) 丙酸 HYH-018)的制备  Example 21: 3-(4-((6-(2,6-dimethyl-4-hydroxyphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid HYH-018) Preparation
Figure imgf000027_0001
Figure imgf000027_0001
除了使用 2,6-二甲基 -4-羟基苯硼酸代替苯硼酸之外， 按照与实施例 4类 似的方法制得化合物 3-(4-(((6-(2,6-甲基 -4-羟基苯基)吡啶基)氧)亚甲基)苯基) 丙酸。 NM (400 MHz, CDC13) δ= 7.62 (dd, J= 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.11 (d,J= 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d,J= 7.2, 1H), 6.76 (dd, J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t,J= 7.8 Hz, 2H), 2.67 (t,J= 7.8 Hz, 2H): 2.06 (s, 6H). The compound 3-(4-((6-(2,6-methyl-)-) was prepared in a similar manner to Example 4 except that 2,6-dimethyl-4-hydroxybenzeneboronic acid was used instead of phenylboronic acid. 4-Hydroxyphenyl)pyridinyloxy)methylene)phenyl)propanoic acid. NM (400 MHz, CDC1 3 ) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.98 ( s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H) : 2.06 (s, 6H).
实施例 22： 3-(4-(((6-(2,4,6-三甲基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸 (化 HYH-019)的制备  Example 22: 3-(4-((6-(2,4,6-trimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (HYH-019) Preparation
Figure imgf000027_0002
Figure imgf000027_0002
除了使用 2,4,6-三甲基苯硼酸代替苯硼酸之外， 按照与实施例 4类似的 方法制得化合物 3-(4-(((6-(2,4,6-三甲基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 JH NM (400 MHz, CDC13) δ= 7.60 (dd,J= 8.3, 7.3 Hz, 1H), 7.35 (d,J= 8.0 Hz 2H), 7.13 (d,J= 7.7 Hz, 2H), 7.02 (s, 2H), 6.78 (d,J= 7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t,J= 7.8 Hz, 2H), 2.67 (t,J= 7.8 Hz, 2H), 2.05 (s. 6H),2.14(s, 3H)。 The compound 3-(4-((6-(2,4,6-trimethyl)) was prepared in a similar manner to Example 4 except that 2,4,6-trimethylphenylboronic acid was used instead of phenylboronic acid. Phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. J H NM (400 MHz, CDC1 3 ) δ = 7.60 (dd, J = 8.3, 7.3 Hz, 1H), 7.35 (d, J = 8.0 Hz 2H), 7.13 (d, J = 7.7 Hz, 2H), 7.02 (s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H), 2.05 (s. 6H), 2.14 (s, 3H).
实施例 23： 3-(4-(((6-(4-氨基 -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯基) 丙酸 HYH-020)的制备 Example 23: 3 - (4 - (((6 - (4 - amino - 2, 6 - dimethylphenyl) pyridin - 2 - yl) oxy) methylene) phenyl) propanoic acid HYH-020) Preparation
Figure imgf000027_0003
除了使用 2,6-二甲基 -4-氨基苯硼酸代替苯硼酸之外， 按照与实施例 4类 似的方法制得化合物 3-(4-(((6-(4-氨基 -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基) 苯基)丙酸。 ^NM (400 MHz, CDC13) δ= 7.60 (dd, J= 8.3, 7.3 Hz, 1H), 7.32 (d; J= 8.0 Hz, 2H), 7.01 (d,J= 7.7 Hz, 2H), 6.78 (d,J= 7.2, 1H), 6.69 (s, 2H), 6.56 (d,J= 8.3 Hz, 1H), 6.22 (brs, 2H), 5.32 (s, 2H), 2.96 (t, J= 7.8 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H), 2.06 (s, 6H)。
Figure imgf000027_0003
The compound 3-(4-((6-(4-amino-2,6)) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-aminophenylboronic acid was used instead of phenylboronic acid. -Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid. ^NM (400 MHz, CDC1 3 ) δ= 7.60 (dd, J= 8.3, 7.3 Hz, 1H), 7.32 (d ; J= 8.0 Hz, 2H), 7.01 (d, J= 7.7 Hz, 2H), 6.78 (d, J = 7.2, 1H), 6.69 (s, 2H), 6.56 (d, J = 8.3 Hz, 1H), 6.22 (brs, 2H), 5.32 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H), 2.06 (s, 6H).
实施例 24： 3-(4-(((6-(4-巯基 -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯基) 丙酸 HYH-021)的制备  Example 24: 3-(4-((6-(4-indolyl-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid HYH-021) Preparation
Figure imgf000028_0001
Figure imgf000028_0001
除了使用 2,6-二甲基 -4-巯基苯硼酸代替苯硼酸之外， 按照与实施例 4类 似的方法制得化合物 3-(4-(((6-(4-巯基 -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基) 苯基)丙酸。 ^NM (400 MHz, CDC13) δ= 7.60 (dd, J= 8.3, 7.3 Hz, 1H), 7.32 (d J= 8.0 Hz, 2H), 7.18 (s, 2H), 7.01 (d, J= 7.7 Hz, 2H), 6.78 (d,J= 7.2, 1H), 6.56 (d,J= 8.3 Hz, 1H), 5.32 (s, 2H), 2.96 (t,J= 7.8 Hz, 2H), 2.67 (t,J= 7.8 Hz, 2H), 2.05 (s, 6H). The compound 3-(4-((6-(4-mercapto-2,6)) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-mercaptophenylboronic acid was used instead of phenylboronic acid. -Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid. ^NM (400 MHz, CDC1 3 ) δ= 7.60 (dd, J= 8.3, 7.3 Hz, 1H), 7.32 (d J= 8.0 Hz, 2H), 7.18 (s, 2H), 7.01 (d, J= 7.7 Hz, 2H), 6.78 (d, J = 7.2, 1H), 6.56 (d, J = 8.3 Hz, 1H), 5.32 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t , J = 7.8 Hz, 2H), 2.05 (s, 6H).
实施例 25： 3-(4-(((6-(4-羧基 -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯基) 丙酸 HYH-022)的制备  Example 25: 3-(4-((6-(4-carboxy-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid HYH-022) Preparation
Figure imgf000028_0002
Figure imgf000028_0002
除了使用 2,6-二甲基 -4-甲酸苯硼酸代替苯硼酸之外， 按照与实施例 4类 似的方法制得化合物 3-(4-(((6-(4-羧基 -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基) 苯基)丙酸。 lH NM (400 MHz, CDC13) δ=7.82 (s, 2Η), 7.60 (dd,J= 8.3, 7.3 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.01 (d,J=7.7 Hz, 2H), 6.78 (d, J = 7.2, 1H), 6.56 (dd,J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t,J= 7.8 Hz, 2H), 2.67 (t,J= 7.8 Hz, 2H), 2.08 (s, 6H). The compound 3-(4-((6-(4-carboxy-2,6)) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-carboxylic acid phenylboronic acid was used instead of phenylboronic acid. -Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propionic acid. l H NM (400 MHz, CDC1 3 ) δ=7.82 (s, 2Η), 7.60 (dd, J= 8.3, 7.3 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.01 (d, J =7.7 Hz, 2H), 6.78 (d, J = 7.2, 1H), 6.56 (dd, J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H) , 2.67 (t, J = 7.8 Hz, 2H), 2.08 (s, 6H).
实施例 26: 3-(4-(((6-(4-酰胺基 -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基) 苯基)丙酸 (化合物 HYH-023)的制备
Figure imgf000029_0001
Example 26: 3-(4-((6-(4-amido-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (Compound HYH) Preparation of -023)
Figure imgf000029_0001
除了使用 2,6-二甲基 -4-氨基甲酰基苯硼酸代替苯硼酸之外， 按照与实施 例 4类似的方法制得化合物 3-(4-(((6-(4-酰胺基 -2,6-二甲基苯基)吡啶 -2-基)氧) 亚甲基)苯基)丙酸。 JH NM (400 MHz, CDC13) δ=7.64 (s, 2Η), 7.60 (dd,J= 8.3 7.3 Hz, 1H), 7.32 (d, J= 8.0 Hz, 2H), 7.01 (d, J= 7.7 Hz, 2H), 6.78 (d,J= 7.2, 1H), 6.56 (dd,J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t,J= 7.8 Hz, 2H), 2.67 (t, J=7.8Hz, 2H), 2.06 (s, 6H). The compound 3-(4-((6-(4-amido)-) was prepared in a similar manner to Example 4 except that 2,6-dimethyl-4-carbamoylbenzeneboronic acid was used instead of phenylboronic acid. 2,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. J H NM (400 MHz, CDC1 3 ) δ=7.64 (s, 2Η), 7.60 (dd, J= 8.3 7.3 Hz, 1H), 7.32 (d, J= 8.0 Hz, 2H), 7.01 (d, J= 7.7 Hz, 2H), 6.78 (d, J = 7.2, 1H), 6.56 (dd, J = 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J=7.8Hz, 2H), 2.06 (s, 6H).
实施例 27： 3-(4-(((6-(4-溴 -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯基) 丙酸 HYH-024)的制备  Example 27: 3-(4-((6-(4-Bromo-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid HYH-024) Preparation
Figure imgf000029_0002
Figure imgf000029_0002
除了使用 2,6-二甲基 -4-溴苯硼酸代替苯硼酸之外， 按照与实施例 4类似 的方法制得化合物 3-(4-(((6-(4-溴 -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯基) 丙酸。 ^NM (400 MHz, CDC13) δ= 7.38 (dd,J= 8.3, 7.3 Hz, 1H), 7.28 (d,J = 8.0 Hz, 2H), 7.17 (s, 2H),7.02 (d,J= 7.7 Hz, 2H), 6.78 (d,J= 7.2, 1H), 6.56 (dd, J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t,J= 7.8 Hz, 2H), 2.67 (t,J= 7.8 Hz, 2H): 2.06 (s, 6H)。 The compound 3-(4-((6-(4-bromo-2,6) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-bromobenzeneboronic acid was used instead of phenylboronic acid. -Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. ^NM (400 MHz, CDC1 3 ) δ= 7.38 (dd, J= 8.3, 7.3 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.17 (s, 2H), 7.02 (d, J= 7.7 Hz, 2H), 6.78 (d, J = 7.2, 1H), 6.56 (dd, J = 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H) : 2.06 (s, 6H).
实施例 28： 3-(4-(((6-(4-氯 -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯基) 丙酸 合物 HYH-025)的制备  Example 28: 3-(4-((6-(4-chloro-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoate HYH- Preparation of 025)
Figure imgf000029_0003
Figure imgf000029_0003
除了使用 2,6-二甲基 -4-氯苯硼酸代替苯硼酸之外， 按照与实施例 4类似 的方法制得化合物 3-(4-(((6-(4-氯 -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯基) 丙酸。 NM (400 MHz, CDC13) δ= 7.37 (dd, J= 8.3, 7.3 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.18 (s, 2H),7.03 (d,J= 7.7 Hz, 2H), 6.78 (d,J= 7.2, 1H), 6.56 (dd, J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t, J= 7.8 Hz, 2H), 2.67 (t, J= 7.8 Hz, 2H): 2.06 (s, 6H). The compound 3-(4-((6-(4-chloro-2,6)) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-chlorophenylboronic acid was used instead of phenylboronic acid. -Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. NM (400 MHz, CDC1 3 ) δ = 7.37 (dd, J = 8.3, 7.3 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.18 (s, 2H), 7.03 (d, J = 7.7 Hz, 2H), 6.78 (d, J= 7.2, 1H), 6.56 (dd, J = 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H) : 2.06 (s, 6H).
实施例 29： 3-(4-(((6-(4-氟 -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙 酸 ( 合物 HYH-026)的制备  Example 29: 3-(4-((6-(4-Fluoro-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (HYH) Preparation of -026)
Figure imgf000030_0001
Figure imgf000030_0001
除了使用 2,6-二甲基 -4-氟苯硼酸代替苯硼酸之外， 按照与实施例 4类似 的方法制得化合物 3-(4-(((6-(4-氟 -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯基) 丙酸。 NM (400 MHz, CDC13) δ= 7.37 (dd, J= 8.3, 7.3 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 7.7 Hz, 2H), 6.78 (d, J = 7.2, 1H), 6.72 (s, 2H),6.56 (dd, J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t, J= 7.8 Hz, 2H), 2.67 (t, J= 7.8 Hz, 2H): 2.05 (s, 6H). The compound 3-(4-((6-(4-fluoro-2,6)) was prepared in a similar manner to Example 4 except that 2,6-dimethyl-4-fluorobenzeneboronic acid was used instead of phenylboronic acid. -Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. NM (400 MHz, CDC1 3 ) δ = 7.37 (dd, J = 8.3, 7.3 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 7.7 Hz, 2H), 6.78 ( d, J = 7.2, 1H), 6.72 (s, 2H), 6.56 (dd, J = 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H) : 2.05 (s, 6H).
实施例 30: 3-(4-(((6-(4-甲氧基 _2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基) 苯基 酸 (化合物 HYH-027)的制备 Example 3 0: 3-( 4 -(( 6- ( 4 -methoxy) 2 , 6 -dimethylphenyl)pyridine- 2 -yl)oxy)methylene) phenyl acid (compound HYH) Preparation of -027)
Figure imgf000030_0002
Figure imgf000030_0002
除了使用 2,6-二甲基 -4-甲氧基苯硼酸代替苯硼酸之外， 按照与实施例 4 类似的方法制得化合物 3-(4-(((6-(4-甲氧基 -2,6-二甲基苯基)吡啶 -2-基)氧)亚 甲基)苯基)丙酸。 ^ NM (400 MHz, CDC13) δ= 7.37 (dd, J = 8.3, 7.3 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 1.1 Hz, 2H), 6.92 (s, 2H), 6.78 (d, J = 7.2, 1H), 6.56 (dd, J = 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 3.92 (s, 3H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J= 7.8 Hz, 2H), 2.05 (s, 6H). The compound 3-(4-((6-(4-methoxy)) was prepared in a similar manner to Example 4 except that 2,6-dimethyl-4-methoxyphenylboronic acid was used instead of phenylboronic acid. -2,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. ^ NM (400 MHz, CDC1 3 ) δ = 7.37 (dd, J = 8.3, 7.3 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 1.1 Hz, 2H), 6.92 (s, 2H), 6.78 (d, J = 7.2, 1H), 6.56 (dd, J = 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 3.92 (s, 3H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H), 2.05 (s, 6H).
实施例 31： 3-(4-(((6-(4-甲硫基 -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯 基) (化合物 HYH-028)的制备  Example 31: 3-(4-((6-(4-methylthio)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl) (Compound HYH- Preparation of 028)
Figure imgf000030_0003
除了使用 2,6-二甲基 -4-甲基巯基苯硼酸代替苯硼酸之外， 按照与实施例 4类似的方法制得化合物 3- K 6-(4-甲硫基 -2,6-二甲基苯基:)吡啶 -2-基：)氧:)亚 甲基)苯基)丙酸。 ^ NM (400 MHz, CDC13) δ= 7.37 (dd, J = 8.3, 7.3 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.22 (s, 2H),7.03 (d, J = 1.1 Hz, 2H), 6.78 (d, J = 7.2, 1H), 6.56 (dd, J = 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J= 7.8 Hz, 2H), 2.53 (s, 3H), 2.06 (s, 6H).
Figure imgf000030_0003
A compound 3-K 6-(4-methylthio-2,6- was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-methylmercaptophenylboronic acid was used instead of phenylboronic acid. Dimethylphenyl:)pyridin-2-yl:) Oxygen:)methylene)phenyl)propanoic acid. ^ NM (400 MHz, CDC1 3 ) δ = 7.37 (dd, J = 8.3, 7.3 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.22 (s, 2H), 7.03 (d, J = 1.1 Hz, 2H), 6.78 (d, J = 7.2, 1H), 6.56 (dd, J = 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J= 7.8 Hz, 2H), 2.53 (s, 3H), 2.06 (s, 6H).
实施例 32： 3-(4-(((6-(2,6-二甲基 -4-甲磺酰基苯基)吡啶 -2-基)氧)亚甲基) 苯基 (化合物 HYH-029)的制备  Example 32: 3-(4-((6-(2,6-Dimethyl-4-methylsulfonylphenyl)pyridin-2-yl)oxy)methylene)phenyl (Compound HYH-029 Preparation
Figure imgf000031_0001
Figure imgf000031_0001
除了使用 2,6-二甲基 -4-甲基磺酰基苯硼酸代替苯硼酸之外， 按照与实施 例 4类似的方法制得化合物 3-(4-：(6-(2,6-二甲基 -4-甲磺酰基苯基:)吡啶 -2-基:) 氧)亚甲基)苯基)丙酸。 ^ NM (400 MHz, CDC13) δ= 7.76 (s, 2Η), 7.37 (dd, J = 8.3, 7.3 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 1.1 Hz, 2H), 6.78 (d, J = 7.2, 1H), 6.56 (dd, J = 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 3.38 (s, 3H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J= 7.8 Hz, 2H), 2.06 (s, 6H). The compound 3-(4-:(6-(2,6-di) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-methylsulfonylbenzeneboronic acid was used instead of phenylboronic acid. Methyl-4-methanesulfonylphenyl:)pyridin-2-yl:) Oxy)methylene)phenyl)propanoic acid. ^ NM (400 MHz, CDC1 3 ) δ = 7.76 (s, 2Η), 7.37 (dd, J = 8.3, 7.3 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 1.1 Hz, 2H), 6.78 (d, J = 7.2, 1H), 6.56 (dd, J = 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 3.38 (s, 3H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H), 2.06 (s, 6H).
实施例 33 : 3-(4-(((6-(2,6-二甲基 -4-甲氨基苯基)吡啶 -2-基)氧)亚甲基) 苯基 酸 (化合物 HYH-030)的制备 Example 33: 3 - (4 - (((6 - (2, 6 - dimethyl --4-- methylamino phenyl) pyridin - 2 - yl) oxy) methylene) phenyl acid (Compound HYH-030 Preparation
Figure imgf000031_0002
Figure imgf000031_0002
除了使用 2,6-二甲基 -4-甲氨基苯硼酸代替苯硼酸之外， 按照与实施例 4 类似的方法制得化合物 3-(4-：(：6-(2,6-二甲基 -4-甲氨基苯基:)吡啶 -2-基：)氧:)亚 甲基)苯基)丙酸。 ^ NM OO MHz, CDC13) S= 7.37 (dd, J = 8.3, 7.3 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 7.7 Hz, 2H), 6.78 (d, J = 7.2, 1H), 6.56 (dd, J = 8.3, 0.8 Hz, 1H), 6.48 (s, 2H), 5.32 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.72(s, 3H), 2.68(t, J= 7.8 Hz, 2H), 2.06 (s, 6H). A compound 3-(4-:(:6-(2,6-dimethyl) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-methylaminobenzeneboronic acid was used instead of phenylboronic acid. 4--4-aminophenyl:)pyridin-2-yl:) Oxygen:)methylene)phenyl)propanoic acid. ^ NM OO MHz, CDC1 3 ) S= 7.37 (dd, J = 8.3, 7.3 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 7.7 Hz, 2H), 6.78 ( d, J = 7.2, 1H), 6.56 (dd, J = 8.3, 0.8 Hz, 1H), 6.48 (s, 2H), 5.32 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.72 (s, 3H), 2.68 (t, J = 7.8 Hz, 2H), 2.06 (s, 6H).
实施例 34： 3-(4-(((6-(2,6-二甲基 -4-二甲氨基苯基)吡啶 -2-基)氧)亚甲基) 苯基)丙酸 (化合物 HYH-031)的制备
Figure imgf000032_0001
Example 34: 3-(4-((6-(2,6-Dimethyl-4-dimethylaminophenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid (compound) Preparation of HYH-031)
Figure imgf000032_0001
除了使用 2,6-二甲基 -4- (二甲基氨基：)苯硼酸代替苯硼酸之外， 按照与实 施例 4类似的方法制得化合物 3-(4-：(6-(2,6-二甲基 -4-二甲氨基苯基:)吡啶 -2- 基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDC13) δ= 7.37 (dd, J= 8.3, 7.3 Hz, 1H), 7.29 (d,J= 8.0 Hz, 2H), 7.03 (d,J= 7.7 Hz, 2H), 6.78 (d,J= 7.2, 1H), 6.56 (dd,J= 8.3, 0.8 Hz, 1H), 6.48 (s, 2H), 5.32 (s, 2H), 2.96 (t, J= 7.8 Hz, 2H), 2.72(s, 6H), 2.67(t,J=7.8 Hz, 2H), 2.04 (s, 6H). A compound 3-(4-:(6-(2,) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-(dimethylamino:)benzeneboronic acid was used instead of phenylboronic acid. 6-Dimethyl-4-dimethylaminophenyl:)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. NM (400 MHz, CDC1 3 ) δ = 7.37 (dd, J = 8.3, 7.3 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 7.7 Hz, 2H), 6.78 ( d, J = 7.2, 1H), 6.56 (dd, J = 8.3, 0.8 Hz, 1H), 6.48 (s, 2H), 5.32 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.72 (s, 6H), 2.67 (t, J = 7.8 Hz, 2H), 2.04 (s, 6H).
实施例 35： 3-(4-(((6-(2,6-二甲基 -4-(N-甲基甲磺酰胺)苯基)吡啶 -2-基)氧) 亚甲 备  Example 35: 3-(4-((6-(2,6-Dimethyl-4-(N-methylsulfonamide)phenyl)pyridin-2-yl)oxy)methylene
Figure imgf000032_0002
Figure imgf000032_0002
除了使用 2,6-二甲基 -4-(甲基磺酰基 甲基：)氨基苯硼酸代替苯硼酸之外， 按照与实施例 4类似的方法制得化合物 3-(4-：(：6-(2,6-二甲基 -4-(N-甲基甲磺 酰胺)苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDC13) δ=7.37 (dd,J= 8.3, 7.3 Hz, 1H), 7.29 (d,J= 8.0 Hz, 2H), 7.03 (d,J= 7.7 Hz, 2H): 6.78 (d, J = 7.2, 1H), 6.56 (dd, J = 8.3, 0.8 Hz, 1H), 6.48 (s, 2H), 5.32 (s, 2H), 3.32(s, 3H), 3.18(s, 3H), 2.96 (t,J= 7.8 Hz, 2H), 2.67(t,J= 7.8 Hz, 2H), 2.05 (s, 6H). A compound 3-(4-:(:6) was obtained in a similar manner to Example 4 except that 2,6-dimethyl-4-(methylsulfonylmethyl:)aminobenzeneboronic acid was used instead of phenylboronic acid. -(2,6-Dimethyl-4-(N-methylmethanesulfonamide)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. NM (400 MHz, CDC1 3 ) δ = 7.37 (dd, J = 8.3, 7.3 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 7.7 Hz, 2H) : 6.78 ( d, J = 7.2, 1H), 6.56 (dd, J = 8.3, 0.8 Hz, 1H), 6.48 (s, 2H), 5.32 (s, 2H), 3.32(s, 3H), 3.18(s, 3H) , 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H), 2.05 (s, 6H).
实施例 36： 3-(4-(((6-(2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基 )-2-氟苯基)丙 酸 ( HYH-033)的制备  Example 36: 3-(4-((6-(2,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid (HYH-033 Preparation
Figure imgf000032_0003
Figure imgf000032_0003
除了使用 2,6-二甲基苯硼酸代替苯硼酸，以及使用 3-(4-(((6-溴吡啶 -2-基:) 氧)亚甲基 )-2-氟苯基)丙酸乙酯代替 3-(4-(((6-溴吡啶 -2-基)氧)亚甲基)苯基)丙 酸乙酯之外， 按照与实施例 4类似的方法制得化合物 3-(4-：(：6-(2,6-二甲基苯 基)吡啶 -2-基)氧)亚甲基 )-2-氟苯基)丙酸。 ^NM (300 MHz, CDC13) δ 7.67 (t, J= 7.8 Hz, 1H), 7.28 - 7.09 (m, 6H), 6.81 (dd,J= 12.2, 7.8 Hz, 2H), 5.35 (s, 2H), 2.98 (t,J= 7.6 Hz, 2H), 2.69 (t,J= 7.7 Hz, 2H), 2.07 (s, 6H). In addition to the use of 2,6-dimethylphenylboronic acid in place of phenylboronic acid, and the use of 3-(4-((6-bromopyridin-2-yl:)oxy)methylene)-2-fluorophenyl)propanoic acid In the same manner as in Example 4 except that ethyl ester was replaced by ethyl 3-(4-(((6-bromopyridin-2-yl)oxy))methyl)phenyl)propanoate, compound 3-( 4-:(:6-(2,6-dimethylbenzene) Pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid. ^NM (300 MHz, CDC1 3 ) δ 7.67 (t, J= 7.8 Hz, 1H), 7.28 - 7.09 (m, 6H), 6.81 (dd, J= 12.2, 7.8 Hz, 2H), 5.35 (s, 2H) ), 2.98 (t, J = 7.6 Hz, 2H), 2.69 (t, J = 7.7 Hz, 2H), 2.07 (s, 6H).
实施例 37： 3-(4-(((6-(2,6-二环丙基苯基)吡啶 -2-基)氧)亚甲基 )-2-氟苯基) 丙酸 -034)的制备  Example 37: 3-(4-((6-(2,6-Dicyclopropylphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid-034) Preparation
Figure imgf000033_0001
Figure imgf000033_0001
除了使用 2,6-二环丙基苯硼酸代替苯硼酸， 以及使用 3-(4-(：6-溴吡啶 -2- 基)氧)亚甲基 )-2-氟苯基)丙酸乙酯代替 3-(4-(((6-溴吡啶 -2-基)氧)亚甲基)苯基) 丙酸乙酯之外， 按照与实施例 4类似的方法制得化合物 3-(4 (：6-(2,6-二环丙 基苯基)吡啶 -2-基)氧)亚甲基 )-2-氟苯基)丙酸。 NM (300 MHz, CDC13) δ 7.67 (t,J= 7.8 Hz, 1H), 7.35 - 7.09 (m, 6H), 6.81 (dd,J= 12.2, 7.8 Hz, 2H), 5.35 (s, 2H), 2.98 (t,J= 7.6 Hz, 2H), 2.69 (t,J= 7.7 Hz, 2H), 1.48 1.62 (m, 2H), 0.99 - 1.28 (m, 8H). In addition to the use of 2,6-dicyclopropylbenzeneboronic acid in place of phenylboronic acid, and the use of 3-(4-(:6-bromopyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid In the same manner as in Example 4 except that the ester was replaced by ethyl 3-(4-((6-bromopyridin-2-yl)oxy)methylene)phenyl)propanoate, compound 3-(4) was obtained. (: 6-(2,6-Dicyclopropylphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid. NM (300 MHz, CDC1 3 ) δ 7.67 (t, J = 7.8 Hz, 1H), 7.35 - 7.09 (m, 6H), 6.81 (dd, J = 12.2, 7.8 Hz, 2H), 5.35 (s, 2H) , 2.98 (t, J = 7.6 Hz, 2H), 2.69 (t, J = 7.7 Hz, 2H), 1.48 1.62 (m, 2H), 0.99 - 1.28 (m, 8H).
实施例 38： 3-(4-(((6-(2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基 )-2-氯苯基)丙 酸 (化合物 HYH-035)的  Example 38: 3-(4-((6-(2,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)-2-chlorophenyl)propanoic acid (Compound HYH- 035)
Figure imgf000033_0002
Figure imgf000033_0002
除了使用 2,6-二甲基苯硼酸代替苯硼酸，以及使用 3-(4-(((6-溴吡啶 -2-基:) 氧)亚甲基 )-2-氯苯基)丙酸乙酯代替 3-(4-(((6-溴吡啶 -2-基)氧)亚甲基)苯基)丙 酸乙酯之外， 按照与实施例 4类似的方法制得化合物 3-(4-：(：6-(2,6-二甲基苯 基)吡啶 -2-基)氧)亚甲基 )-2-氯苯基)丙酸。 ^NM (300 MHz, CDC13) δ 7.67 (t, J= 7.8 Hz, 1H), 7.28(s, 2H), 7.15 - 7.09 (m, 3H), 6.81 (dd,J= 12.2, 7.8 Hz, 2H), 5.35 (s, 2H), 2.98 (t,J= 7.6 Hz, 2H), 2.69 (t,J= 7.7 Hz, 2H), 2.06 (s, 6H). In addition to the use of 2,6-dimethylphenylboronic acid instead of phenylboronic acid, and the use of 3-(4-(((6-bromopyridin-2-yl:)oxy)methylene)-2-chlorophenyl)propanoic acid In the same manner as in Example 4 except that ethyl ester was replaced by ethyl 3-(4-(((6-bromopyridin-2-yl)oxy))methyl)phenyl)propanoate, compound 3-( 4-: (: 6-(2,6-Dimethylphenyl)pyridin-2-yl)oxy)methylene)-2-chlorophenyl)propanoic acid. ^NM (300 MHz, CDC1 3 ) δ 7.67 (t, J = 7.8 Hz, 1H), 7.28(s, 2H), 7.15 - 7.09 (m, 3H), 6.81 (dd, J= 12.2, 7.8 Hz, 2H ), 5.35 (s, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.69 (t, J = 7.7 Hz, 2H), 2.06 (s, 6H).
实施例 39： 3-(4-(((6-(2,6-二甲基 -4-羟基苯基)吡啶 -2-基)氧)亚甲基 )-2-氟 苯基)丙酸 (化合物 HYH-036)的制备
Figure imgf000034_0001
Example 39: 3 - (4 - (((6 - (2, 6 - dimethyl --4-- hydroxyphenyl) pyridin - 2 - yl) oxy) methylene) - 2 - fluorophenyl) propanoic acid Preparation of (Compound HYH-036)
Figure imgf000034_0001
除了使用 2,6-二甲基 -4-羟基苯硼酸代替苯硼酸， 以及使用 3-(4 (6-溴吡 啶 -2-基)氧)亚甲基 )-2-氟苯基)丙酸乙酯代替 3-(4-(((6-溴吡啶 -2-基)氧)亚甲基) 苯基：)丙酸乙酯之外， 按照与实施例 4 类似的方法制得化合物 3-(4 (：6-(2,6- 甲基 -4-羟基苯基)吡啶 -2-基)氧)亚甲基 )-2-氟苯基)丙酸。 NM (400 MHz, CDC13) δ= 7.59 (dd,J= 8.3, 7.3 Hz, 1H), 7.27 (d,J= 8.0 Hz, 2H), 7.13 (d,J= 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d,J= 7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t,J= 7.8 Hz, 2H), 2.67 (t,J= 7.8 Hz, 2H), 2.06 (s, 6H)。 In addition to the use of 2,6-dimethyl-4-hydroxybenzeneboronic acid instead of phenylboronic acid, and the use of 3-(4 (6-bromopyridin-2-yl)oxy)methylene)-2-fluorophenyl)propionic acid In the same manner as in Example 4 except that ethyl ester was used instead of ethyl 3-(4-((6-bromopyridin-2-yl)oxy)methylene)phenyl:)propanoate. (4 (:6-(2,6-Methyl-4-hydroxyphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid. NM (400 MHz, CDC1 3 ) δ = 7.59 (dd, J = 8.3, 7.3 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.7 Hz, 2H), 6.98 ( s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H), 2.06 (s, 6H).
实施例 40： 3-(4-(((6-(2,6-二甲基 -4-羟基苯基)吡啶 -2-基)氧)亚甲基 )-2- 氯苯基)丙酸 (化合物 HYH-037 Example 40: 3 -( 4 -(( 6- ( 2 , 6 -Dimethyl- 4 -hydroxyphenyl)pyridine- 2 -yl)oxy)methylene) -2 -chlorophenyl)propanoic acid (Compound HYH-037
Figure imgf000034_0002
Figure imgf000034_0002
除了使用 2,6-二甲基 -4-羟基苯硼酸代替苯硼酸， 以及使用 3-(4 (6-溴吡 啶 -2-基)氧)亚甲基 )-2-氯苯基)丙酸乙酯代替 3-(4-(((6-溴吡啶 -2-基)氧)亚甲基) 苯基：)丙酸乙酯之外， 按照与实施例 4 类似的方法制得化合物 3-(4 (：6-(2,6- 甲基 -4-羟基苯基)吡啶 -2-基)氧)亚甲基 )-2-氯苯基)丙酸。 NMR (400 MHz, CDCI3) δ= 7.78 (dd,J= 8.3, 7.3 Hz, 1H), 7.48 (d,J= 8.0 Hz, 2H), 7.11 (d,J= 7.7 Hz, 2H), 6.98 (s, 2H), 6.88 (d,J= 7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t,J= 7.8 Hz, 2H), 2.67 (t,J= 7.8 Hz, 2H), 2.06 (s, 6H)。  In addition to the use of 2,6-dimethyl-4-hydroxybenzeneboronic acid instead of phenylboronic acid, and the use of 3-(4 (6-bromopyridin-2-yl)oxy)methylene)-2-chlorophenyl)propanoic acid In the same manner as in Example 4 except that ethyl ester was used instead of ethyl 3-(4-((6-bromopyridin-2-yl)oxy)methylene)phenyl:)propanoate. (4 (:6-(2,6-Methyl-4-hydroxyphenyl)pyridin-2-yl)oxy)methylene)-2-chlorophenyl)propanoic acid. NMR (400 MHz, CDCI3) δ = 7.78 (dd, J = 8.3, 7.3 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.98 (s , 2H), 6.88 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 ( t, J = 7.8 Hz, 2H), 2.06 (s, 6H).
实施例 41: 3-(4-(((6-(2, 6-二甲基 -4-(2- (甲磺酰基)乙氧基)苯基)吡啶 -2- 基)氧)亚甲基)苯基)丙酸 (化合物 HYH-038)的制备
Figure imgf000035_0001
Example 41: 3-(4-((6-(2,6-Dimethyl-4-(2-(methylsulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)) Preparation of phenyl)propionic acid (compound HYH-038)
Figure imgf000035_0001
取 3-(4-(((6-(2,6-二甲基 -4-羟基苯基)亚甲基)苯基)乙酸乙酯 0.1g， 2-甲磺 酰基乙基对甲苯磺酰酯 0.103g溶于 10mL乙腈中， 加入碳酸钾 0.097g， 回流 反应 8小时， 将反应液冷至室温， 过滤除去碳酸钾， 滤液浓缩硅胶柱层析分 离（乙酸乙酯 /石油醚 =1/15-1/5 )。得到 3-(4-：(6-(2， 6-二甲基 -4-(2- (甲磺酰基) 乙氧基)苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸乙酯 85mg， 为白色固体， 产率 66%。  3-(4-((6-(2,6-Dimethyl-4-hydroxyphenyl)methylene)phenyl)acetate ethyl acetate 0.1 g, 2-methanesulfonylethyl p-toluenesulfonyl 0.103 g of the ester was dissolved in 10 mL of acetonitrile, and 0.097 g of potassium carbonate was added thereto, and the reaction mixture was refluxed for 8 hours. The reaction solution was cooled to room temperature, and then filtered, and then filtered, and the filtrate was concentrated to silica gel column chromatography (ethyl acetate / petroleum ether = 1/15 -1/5). 3-(4-:(6-(2,6-Dimethyl-4-(2-(methylsulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)) 85 mg of methylene)phenyl)propanoate as a white solid in 66% yield.
将上述所得 85mg样品溶解于 8mL乙腈， 2mL水的混合液中，加入 lOmg 氢氧化锂， 在 40°C中反应 4小时， 冷却， 用 1M的盐酸调 pH=2-3， 加入饱 和食盐水 20mL， 乙酸乙酯萃取 2次， 合并有机层加入无水硫酸钠干燥， 过 滤浓缩得 3-(4-(((6-(2， 6-二甲基 -4-(2- (甲磺酰基)乙氧基)苯基)吡啶 -2-基)氧基) 亚甲基)苯基)丙酸 68mg，为白色固体，产率 84%。 ιΐΙ NM (400 MHz, CDC13) δ= 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s, 2H),4.82(t, J = 7.2 Hz, 2H), 3.77(t, J = 7.2 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.87(s, 3H), 2.69 (t, J= 7.6 Hz, 2H), 2.05 (s, 6H)。 The 85 mg sample obtained above was dissolved in a mixture of 8 mL of acetonitrile and 2 mL of water, and 10 mg of lithium hydroxide was added thereto, and reacted at 40 ° C for 4 hours, cooled, adjusted to pH 2-3 with 1 M hydrochloric acid, and 20 mL of saturated brine was added thereto. The organic layer was combined and dried over anhydrous sodium sulfate and filtered to give 3-(4-(2, 6-dimethyl-4-(2-(methylsulfonyl)) 68 mg of ethoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid as a white solid, yield 84%. ι ΐΙ NM (400 MHz, CDC1 3 ) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.82 (t, J = 7.2 Hz, 2H) , 3.77(t, J = 7.2 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.87(s, 3H), 2.69 (t, J= 7.6 Hz, 2H), 2.05 (s, 6H) .
实施例 42: 3-(4-(((6-(2, 6-二甲基 -4-(2- (乙磺酰基)乙氧基)苯基)吡啶 -2- 基)氧)亚甲基)苯基)丙酸 (化合物 HYH-039)的制备 除了使用 2-乙磺酰基乙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯之外， 按照与实施例 41 类似的方法制得化合物 3-(4-(：6-(2， 6-二甲基 -4-(2- (乙磺酰基)乙氧基)苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDC13) δ= 7.62 (dd,J= 8.3, 7.3 Hz, 1H), 7.38 (d,J= 8.0 Hz, 2H), 7.11 (d, J =1.1 Hz, 2H), 6.98 (s, 2H), 6.78 (d, J= 7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H),4.82(t, J = 7.2 Hz, 2H), 3.77(t, J = 7.2 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H),2.94(q,J=7.1 Hz,2H), 2.69 (t,J= 7.6 Hz, 2H), 2.05 (s, 6H), 1.22(t,J=7.1
Figure imgf000036_0001
Example 42: 3-(4-((6-(2,6-Dimethyl-4-(2-(ethanesulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)) Preparation of phenyl)propionic acid (compound HYH-039) The compound 3-(4-(:6-) was obtained in a similar manner to Example 41 except that 2-ethylsulfonylethyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. (2,6-Dimethyl-4-(2-(ethylsulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. NM (400 MHz, CDC1 3 ) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 1.1 Hz, 2H), 6.98 ( s, 2H), 6.78 (d, J= 7.2, 1H), 6.76 (dd, J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.82 (t, J = 7.2 Hz, 2H), 3.77 (t, J = 7.2 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.94 (q, J = 7.1 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 2.05 (s , 6H), 1.22(t, J=7.1
Figure imgf000036_0001
实施例 43： 3-(4-(((6-(2, 6-二甲基 -4-(3- (甲磺酰基)丙氧基)苯基)吡啶 -2- 基)氧)亚甲基)苯基 (化合物 HYH-040)的制备  Example 43: 3-(4-((6-(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)) Preparation of phenyl) (compound HYH-040)
Figure imgf000036_0002
Figure imgf000036_0002
除了使用 3-甲磺酰基丙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯之外， 按照与实施例 41 类似的方法制得化合物 3-(4-：(：6-(2,6-二甲基 -4-(3- (甲磺酰基)丙氧基)苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDCI3) δ= 7.62 (dd,J= 8.3, 7.3 Hz, 1H), 7.38 (d,J= 8.0 Hz, 2H), 7.11 (d, J=7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d, J= 7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H),4.82(t, J = 7.2 Hz, 2H), 3.77(t, J = 7.2 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.87(s, 3H), 2.69 (t,J= 7.6 Hz, 2H), 2.37(m, 2H), 2.05 (s, 6H)。  A compound 3-(4-:(:6) was obtained in a similar manner to Example 41 except that 3-methanesulfonylpropyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. -(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. NM (400 MHz, CDCI3) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.11 (d, J=7.7 Hz, 2H), 6.98 (s , 2H), 6.78 (d, J= 7.2, 1H), 6.76 (dd, J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.82 (t, J = 7.2 Hz, 2H), 3.77 ( t, J = 7.2 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.87(s, 3H), 2.69 (t, J = 7.6 Hz, 2H), 2.37 (m, 2H), 2.05 ( s, 6H).
实施例 44： 3-(4-(((6-(2, 6-二甲基 -4-(3- (乙磺酰基)丙氧基)苯基)吡啶 -2- 基)氧)亚甲基)苯 (化合物 HYH-041)的制备  Example 44: 3-(4-((6-(2,6-Dimethyl-4-(3-(ethyl)sulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)) Preparation of Benzene (Compound HYH-041)
Figure imgf000036_0003
Figure imgf000036_0003
除了使用 3-乙磺酰基丙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯之外， 按照与实施例 41 类似的方法制得化合物 3-(4-：(：6-(2,6-二甲基 -4-(3- (乙磺酰基)丙氧基)苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。  The compound 3-(4-:(:6) was obtained in a similar manner to Example 41 except that 3-ethylsulfonylpropyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. -(2,6-Dimethyl-4-(3-(ethylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid.
JH NM (400 MHz, CDC13) δ= 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.11 (d,J= 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d,J= 7.2, 1H), 6.76 (dd, J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H),4.82(t, J= 7.2 Hz, 2H), 3.77(t,J=7.2 Hz, 2H), 2.98 (t, J= 7.6 Hz, 2H), 2.94(q,J= 8.0 Hz, 2H), 2.69 (t, J= 7.6 Hz, 2H), 2.37(m, 2H), 2.05 (s, 6H), 1.42(t, ,J= 8.0 Hz, 3H)。 J H NM (400 MHz, CDC1 3 ) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.82 (t, J = 7.2 Hz, 2H), 3.77 (t, J = 7.2 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.94 (q, J = 8.0 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 2.37 (m, 2H), 2.05 (s, 6H), 1.42 (t, , J = 8.0 Hz , 3H).
实施例 45： 3-(4-(((6-(4-(2-甲氧基乙氧基 )-2,6-二甲基苯基)吡啶 -2-基)氧) 亚甲基)苯基)丙酸 ( -042)的制备  Example 45: 3-(4-((6-(4-(4-methoxyethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene) Preparation of phenyl)propionic acid (-042)
Figure imgf000037_0001
Figure imgf000037_0001
除了使用 2-甲氧基乙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰酯 之外， 按照与实施例 41 类似的方法制得化合物 3- K;6-( 4-(2-甲氧基乙氧 基) -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDC13) δ= 7.62 (dd,J= 8.3, 7.3 Hz, 1H), 7.38 (d,J= 8.0 Hz, 2H), 7.11 (d,J= 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d,J= 7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H),4.79(t, J = 7.2 Hz, 2H), 3.87(t, J = 7.2 Hz, 2H), 3.45(s, 3H), 2.98 (t, J = 7.6 Hz, 2H), 2.69 (t, J= 7.6 Hz, 2H), 2.05 (s, 6H). A compound 3-K was prepared in a similar manner to Example 41 except that 2-methoxyethyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. (2-Methoxyethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. NM (400 MHz, CDC1 3 ) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.98 ( s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.79 (t, J = 7.2 Hz, 2H), 3.87 (t, J = 7.2 Hz, 2H), 3.45(s, 3H), 2.98 (t, J = 7.6 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 2.05 (s, 6H).
实施例 46： 3-(4-(((6-(4-(2-乙氧基乙氧基 )-2,6-二甲基苯基)吡啶 -2-基)氧) 亚甲基)苯基)丙酸 ( -043)的制备  Example 46: 3-(4-((6-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene) Preparation of phenyl)propionic acid (-043)
Figure imgf000037_0002
Figure imgf000037_0002
除了使用 2-乙氧基乙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰酯 之外， 按照与实施例 41所示类似的方法制得化合物 3-(4-：(：6-(4-(2-乙氧基乙 氧基) -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDCI3) δ= 7.62 (dd,J= 8.3, 7.3 Hz, 1H), 7.38 (d,J= 8.0 Hz, 2H), 7.11 (d,J= 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d,J= 7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H),4.79(t,J=7.2 Hz, 2H), 3.87(t,J=7.2 Hz, 2H), 3.45(q,J= 7.1 Hz, 3H), 2.98 (t,J= 7.6 Hz, 2H), 2.69 (t,J= 7.6 Hz, 2H), 2.05 (s, 6H) , 1.12(t,J= 7.1 Hz, 3H)。  A compound 3-(4-: was obtained in a similar manner to that shown in Example 41 except that 2-ethoxyethyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. : 6-(4-(2-ethoxyethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. NM (400 MHz, CDCI3) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.98 (s , 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.79 (t, J = 7.2 Hz, 2H), 3.87 ( t, J = 7.2 Hz, 2H), 3.45 (q, J = 7.1 Hz, 3H), 2.98 (t, J = 7.6 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 2.05 (s, 6H), 1.12 (t, J = 7.1 Hz, 3H).
实施例 47: 3-(4-(((6-( 4-(2-二甲氨基乙氧基) -2,6-二甲基苯基)吡啶 -2-基) 氧)亚甲基)苯基)丙酸 (化合物 HYH-044)的制备
Figure imgf000038_0001
Example 47: 3-(4-((6-(4-(2-dimethylaminoethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene) Preparation of phenyl)propionic acid (compound HYH-044)
Figure imgf000038_0001
除了使用 2 二甲基：)氨基：)乙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲 苯磺酰酯之外， 按照与实施例 42类似的方法制得化合物 3-(4-(((：6-( 4-(2-二甲 氨基乙氧基) -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDC13) δ= 7.62 (dd,J= 8.3, 7.3 Hz, 1H), 7.38 (d,J= 8.0 Hz, 2H), 7.11 (d, J =1.1 Hz, 2H), 6.98 (s, 2H), 6.78 (d, J= 7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H),4.79(t,J=7.2 Hz, 2H), 2.98 (t, J= 7.6 Hz, 2H), 2.85(s, 6H), 2.77(t, J = 7.2 Hz, 2H), 2.69 (t, J= 7.6 Hz, 2H), 2.05 (s, 6H)。 Compound 3-(4-) was prepared in a similar manner to Example 42 except that 2-dimethyl:) amino: ethyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. (((6-(4-(2-Dimethylaminoethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. NM (400 MHz, CDC1 3 ) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 1.1 Hz, 2H), 6.98 ( s, 2H), 6.78 (d, J= 7.2, 1H), 6.76 (dd, J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.79 (t, J = 7.2 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.85 (s, 6H), 2.77 (t, J = 7.2 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 2.05 (s, 6H).
实施例 48: 3-(4-(((6-( 4-(3-二甲氨基丙氧基) -2,6-二甲基苯基)吡啶 -2-基) 氧)亚甲基)苯基)丙 (化合物 HYH-045)的制备  Example 48: 3-(4-((6-(4-(3-dimethylaminopropoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene) Preparation of Phenyl)propane (Compound HYH-045)
Figure imgf000038_0002
Figure imgf000038_0002
除了使用 3 二甲基：)氨基：)丙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲 苯磺酰酯之外， 按照与实施例 41类似的方法制得化合物 3-(4-(((：6-(4-(3-二甲 氨基丙氧基) -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDCI3) δ= 7.62 (dd,J= 8.3, 7.3 Hz, 1H), 7.38 (d,J= 8.0 Hz, 2H), 7.11 (d, J=7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d, J= 7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H),4.79(t,J= 7.2 Hz, 2H), 2.98 (t,J= 7.6 Hz, 2H), 2.85(s, 6H), 2.69 (t, J=7.6 Hz, 2H), 2.35(t,J=7.2 Hz, 2H), 2.06 (s, 6H), 2.26 (s, 6H),1.79 (q,J=7.2
Figure imgf000038_0003
Compound 3-(4-) was prepared in a similar manner to Example 41, except that &lt;RTI ID=0.0&gt; (((6-(4-(3-Dimethylaminopropoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. NM (400 MHz, CDCI3) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.11 (d, J=7.7 Hz, 2H), 6.98 (s , 2H), 6.78 (d, J= 7.2, 1H), 6.76 (dd, J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.79 (t, J = 7.2 Hz, 2H), 2.98 ( t, J = 7.6 Hz, 2H), 2.85(s, 6H), 2.69 (t, J=7.6 Hz, 2H), 2.35 (t, J = 7.2 Hz, 2H), 2.06 (s, 6H), 2.26 ( s, 6H), 1.79 (q, J=7.2
Figure imgf000038_0003
实施例 49: 3-(4-(((6-( 4-(2-二乙氨基乙氧基) -2,6-二甲基苯基)吡啶 -2-基) 氧)亚甲基)苯基)丙 (化合物 HYH-046)的制备  Example 49: 3-(4-((6-(4-(2-diethylaminoethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene) Preparation of phenyl)propane (compound HYH-046)
Figure imgf000038_0004
除了使用 2- (二乙基氨基)乙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯 磺酰酯之外， 按照与实施例 41类似的方法制得化合物 3-(4-：(：6-(4-(2-二乙氨 基乙氧基) -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDC13) δ= 7.62 (dd,J= 8.3, 7.3 Hz, 1H), 7.38 (d,J= 8.0 Hz, 2H), 7.11 (d, J =1.1 Hz, 2H), 6.98 (s, 2H), 6.78 (d, J= 7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H),4.79(t, J = 7.2 Hz, 2H), 3.08(q, J = 7.5 Hz, 4H), 2.98 (t, J = 7.6 Hz, 2H), 2.77(t,J=7.2 Hz, 2H), 2.69 (t,J= 7.6 Hz, 2H), 2.05 (s, 6H), 1.18(t,J= 7.5 Hz, 6H)。
Figure imgf000038_0004
Compound 3-(4-: was obtained in a similar manner to Example 41 except that 2-(diethylamino)ethyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. (:6-(4-(2-Diethylaminoethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. NM (400 MHz, CDC1 3 ) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 1.1 Hz, 2H), 6.98 ( s, 2H), 6.78 (d, J= 7.2, 1H), 6.76 (dd, J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.79 (t, J = 7.2 Hz, 2H), 3.08 (q, J = 7.5 Hz, 4H), 2.98 (t, J = 7.6 Hz, 2H), 2.77 (t, J = 7.2 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 2.05 (s , 6H), 1.18 (t, J = 7.5 Hz, 6H).
实施例 50: 3-(4-(((6-( 4-(3-二乙氨基丙氧基) -2,6-二甲基苯基)吡啶 -2-基) 氧)亚甲基)苯基) (化合物 HYH-047)的制备  Example 50: 3-(4-((6-(4-(3-diethylaminopropoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene) Preparation of phenyl) (compound HYH-047)
Figure imgf000039_0001
Figure imgf000039_0001
除了使用 3- (二乙胺基)丙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺 酰酯之外， 按照与实施例 41类似的方法制得化合物 3-(4- X6-(4-p-二乙氨基 丙氧基 )-2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDCI3) δ= 7.62 (dd,J= 8.3, 7.3 Hz, 1H), 7.36 (d,J= 8.0 Hz, 2H), 7.11 (d,J= 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d,J= 7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H),4.79(t, J = 7.2 Hz, 2H), 3.08(q, J = 7.5 Hz, 4H), 2.98 (t, J = 7.6 Hz, 2H), 2.77(t,J=7.2 Hz, 2H), 2.67 (t,J= 7.6 Hz, 2H), 2.06 (s, 6H), 1.81 (q,J= 7.5 Hz, 2H)1.16(t,J=7.5Hz, 6H)。  A compound 3-(4-X6) was obtained in a similar manner to Example 41 except that 3-(diethylamino)propyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. -(4-p-Diethylaminopropoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. NM (400 MHz, CDCI3) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.98 (s , 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.79 (t, J = 7.2 Hz, 2H), 3.08 ( q, J = 7.5 Hz, 4H), 2.98 (t, J = 7.6 Hz, 2H), 2.77 (t, J = 7.2 Hz, 2H), 2.67 (t, J = 7.6 Hz, 2H), 2.06 (s, 6H), 1.81 (q, J = 7.5 Hz, 2H) 1.16 (t, J = 7.5 Hz, 6H).
实施例 51： 3-(4-(((6-(2,6-二甲基 -4- ((四氢 -2 吡哺 -4-基)氧基)苯基)吡啶 -2-基)氧)亚甲基)苯 (化合物 HYH-048)的制备  Example 51: 3-(4-((6-(2,6-Dimethyl-4-((tetrahydro-2-pyridin-4-yl)oxy)phenyl)pyridin-2-yl)) Preparation of Oxygen) Methylene)benzene (Compound HYH-048)
Figure imgf000039_0002
Figure imgf000039_0002
除了使用四氢 -2/7-吡喃 -4-对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺 酰酯之外， 按照与实施例 41 类似的方法制得化合物 3-(4-(：6-(2,6-二甲基 -4-((四氢 -2/7-吡喃 -4-基)氧基)苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDCI3) δ= 7.55 (dd, J = 8.3, 7.3 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.11 (d,J=7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d,J=7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 3.75(m, 1H), 3.61(m, 2H), 3.52(m, 2H), 2.96 (t,J= 7.8 Hz, 2H), 2.67 (t,J= 7.8 Hz, 2H), 2.15(m, 2H), 2.06 (s, 6H), 1.88(m, 2H)。 Compound 3-(4) was obtained in a similar manner to Example 41 except that tetrahydro-2/7-pyran-4-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. -(:6-(2,6-Dimethyl-4-((tetrahydro-2/7-pyran-4-yl)oxy)phenyl)pyridin-2-yl)oxy)methylene) Phenyl) propionic acid. NM (400 MHz, CDCI3) δ = 7.55 (dd, J = 8.3, 7.3 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.11 (d, J=7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d, J=7.2, 1H), 6.76 (dd, J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H) , 3.75 (m, 1H), 3.61 (m, 2H), 3.52 (m, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H), 2.15 (m, 2H), 2.06 (s, 6H), 1.88 (m, 2H).
实施例 52： 3-(4-(((6-(2,6-二甲基 -4- ((四氢 -2 -噻哺 -4-基)氧基)苯基)吡啶 -2-基)氧)亚甲基)苯 (化合物 HYH-049)的制备  Example 52: 3-(4-((6-(2,6-Dimethyl-4-((tetrahydro-2-(indol-4-yl)oxy)phenyl)pyridin-2-yl) Preparation of Oxygen) Methylene)benzene (Compound HYH-049)
Figure imgf000040_0001
Figure imgf000040_0001
除了使用四氢 -2/7-噻喃 -4-对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺 酰酯之外， 按照与实施例 41 类似的方法制得化合物 3-(4-(：6-( 2,6-二甲基 -4-((四氢 -2/7-噻喃 -4-基)氧)苯基)吡啶 -2-基)氧基)亚甲基)苯基)丙酸。 NM (400 MHz, CDC13) δ= 7.55 (dd, J = 8.3, 7.3 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.11 (d,J=7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d,J=7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 3.92(m, 1H), 2.96 (t, J= 7.8 Hz, 2H), 2.67 (t, J= 7.8 Hz, 2H), 2.61(m, 2H), 2.52(m, 2H), 2.22(m, 2H), 2.06 (s, 6H), 1.98(m, 2H)。 Compound 3-(4) was obtained in a similar manner to Example 41 except that tetrahydro-2/7-thiopyran-4-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. -(:6-( 2,6-Dimethyl-4-((tetrahydro-2/7-thiopyran-4-yl)oxy)phenyl)pyridin-2-yl)oxy)methylene) Phenyl) propionic acid. NM (400 MHz, CDC1 3 ) δ = 7.55 (dd, J = 8.3, 7.3 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.98 ( s, 2H), 6.78 (d, J=7.2, 1H), 6.76 (dd, J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 3.92(m, 1H), 2.96 (t, J= 7.8 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H), 2.61 (m, 2H), 2.52 (m, 2H), 2.22 (m, 2H), 2.06 (s, 6H), 1.98 (m, 2H).
实施例 53： 3-(4-(((6-(4-((l,l-二氧代四氢 -2 -噻哺 -4-基)氧基) - 2,6-二甲 基苯基)吡啶 -2-基) -050)的制备  Example 53: 3-(4-((6-(4-(4-(4-(1-(4-(4-(4-(4-(4-(4-)-(4-(4-(tetrahydro-2-yloxy-4-yl)oxy))), 2,6-dimethylbenzene Preparation of pyridyl-2-yl)-050)
Figure imgf000040_0002
Figure imgf000040_0002
除了使用 1,1-二氧代四氢 -2/7-噻喃 -4-对甲苯磺酰酯代替 2-甲磺酰基乙基 对甲苯磺酰酯之外，按照与实施例 41类似的方法制得化合物 3-(4-：(：6-(4-：四 氢 -2/7-噻喃 -4-基)氧) -2,6-二甲基-苯基)吡啶 -2-基)氧基)亚甲基)苯基)丙酸。 NM (400 MHz, CDC13) δ= 7.55 (dd, J = 8.3, 7.3 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.11 (d,J= 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d,J= 7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 3.69(m, 1H), 3.48(m, 2H), 3.42(m, 2H),2.96 (t, J= 7.8 Hz, 2H), 2.67 (t, J= 7.8 Hz, 2H), 2.39(m, 2H), 2.14(m, 2H), 2.06 (s, 6H)。 A method similar to that of Example 41 was used except that 1,1-dioxotetrahydro-2/7-thiopyran-4-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. Preparation of the compound 3-(4-:(:6-(4-:tetrahydro-2/7-thiopyran-4-yl)oxy)-2,6-dimethyl-phenyl)pyridin-2-yl Oxy)methylene)phenyl)propionic acid. NM (400 MHz, CDC1 3 ) δ = 7.55 (dd, J = 8.3, 7.3 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.98 ( s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.32 (s, 2H), 3.69 (m, 1H), 3.48 (m, 2H) , 3.42 (m, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H), 2.39 (m, 2H), 2.14 (m, 2H), 2.06 (s, 6H).
实施例 54： 3-(4-(((6-(2,6-二甲基 -4-(2- (吡咯烷 -1-基)乙氧基)苯基)吡啶 -2- 基)氧)亚甲基)苯基)丙酸 (化合物 HYH-051)的制备
Figure imgf000041_0001
Example 54: 3-(4-((6-(2,6-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy) Preparation of methylene)phenyl)propionic acid (compound HYH-051)
Figure imgf000041_0001
除了使用 2- (吡咯垸 -1-基)乙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯 磺酰酯之外， 按照与实施例 41 类似的方法制得化合物 3-(4-：(：6-(2,6-二甲基 -4-(2- (吡咯垸 -1-基)乙氧基)苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 NM (400 MHz, CDC13) δ= 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.11 (d,J=7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d,J=7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H),4.79(t,J= 7.2 Hz, 2H), 2.98 (t,J= 7.6 Hz, 2H), 2.77(t,J = 7.2 Hz, 2H), 2.67 (t, J= 7.6 Hz, 2H),2.46 2.55 (m, 4H), 2.06 (s, 6H), 1.66 1.73
Figure imgf000041_0002
Compound 3-(4) was obtained in a similar manner to Example 41 except that 2-(pyrrole-1-yl)ethyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. -:(:6-(2,6-Dimethyl-4-(2-(pyrrole-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl) Propionic acid. NM (400 MHz, CDC1 3 ) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.98 ( s, 2H), 6.78 (d, J=7.2, 1H), 6.76 (dd, J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.79 (t, J = 7.2 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.77 (t, J = 7.2 Hz, 2H), 2.67 (t, J = 7.6 Hz, 2H), 2.46 2.55 (m, 4H), 2.06 (s, 6H), 1.66 1.73
Figure imgf000041_0002
实施例 55： 3-(4-(((6-(2,6-二甲基 -4-(2- (哌啶 -1-基)乙氧基)苯基)吡啶 -2-基) 氧)亚甲基)苯基)丙 (化合物 HYH-052)的制备  Example 55: 3-(4-((6-(2,6-Dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy Preparation of methylene)phenyl)propane (compound HYH-052)
Figure imgf000041_0003
Figure imgf000041_0003
除了使用 2- (哌啶 -1-基)乙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺 酰酯之外， 按照与实施例 41 类似的方法制得化合物 3-(4-(：6-(2,6-二甲基 -4-(2- (哌啶 -1-基)乙氧基)苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 ^NM (400 MHz, CDCI3) δ= 7.62 (dd,J= 8.3, 7.3 Hz, 1H), 7.36 (d,J= 8.0 Hz, 2H), 7.11 (d, J =1.1 Hz, 2H), 6.98 (s, 2H), 6.78 (d, J= 7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H),4.79(t, J = 7.2 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.77(t, J = 7.2 Hz, 2H), 2.67 (t,J= 7.6 Hz, 2H), 2.45(m, 4H), 2.06 (s, 6H), 1.61 1.69 (m, 6H)。  Compound 3-(4) was obtained in a similar manner to Example 41 except that 2-(piperidin-1-yl)ethyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. -(:6-(2,6-Dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl) acid. ^NM (400 MHz, CDCI3) δ= 7.62 (dd, J= 8.3, 7.3 Hz, 1H), 7.36 (d, J= 8.0 Hz, 2H), 7.11 (d, J =1.1 Hz, 2H), 6.98 ( s, 2H), 6.78 (d, J= 7.2, 1H), 6.76 (dd, J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.79 (t, J = 7.2 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.77 (t, J = 7.2 Hz, 2H), 2.67 (t, J = 7.6 Hz, 2H), 2.45 (m, 4H), 2.06 (s, 6H), 1.61 1.69 (m, 6H).
实施例 56： 3-(4-(((6-(2,6-二甲基 -4-(2-吗啡啉乙氧基)苯基)吡啶 -2-基)氧) 亚甲基)苯基)丙酸 ( HYH-053)的制备  Example 56: 3-(4-((6-(2,6-Dimethyl-4-(2-morpholineethoxy)phenyl)pyridin-2-yl)oxy)methylene)benzene Preparation of propionic acid (HYH-053)
Figure imgf000041_0004
除了使用 2-吗啡啉乙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰酯 之外， 按照与实施例 41类似的方法制得化合物 3- K 6-(2,6-二甲基 -4-(2-吗 啡啉乙氧基)苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 ^ NM (400 MHz, CDC13) δ= 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s, 2H),4.79(t, J = 7.2 Hz, 2H), 3.65(t, J = 8.1 Hz, 4H), 2.98 (t, J = 7.6 Hz, 2H), 2.77(t, J = 7.2 Hz, 2H), 2.67 (t, J = 7.6 Hz, 2H), 2.4 l(t, J = 8.1 Hz, 4H), 2.06 (s, 6H)。
Figure imgf000041_0004
The compound 3-K 6-(2,6- was obtained in a similar manner to Example 41 except that 2-morpholine ethyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. Dimethyl-4-(2-morpholineethoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl)propanoic acid. ^ NM (400 MHz, CDC1 3 ) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.79 (t, J = 7.2 Hz, 2H), 3.65 (t, J = 8.1 Hz, 4H), 2.98 (t, J = 7.6 Hz, 2H), 2.77 (t, J = 7.2 Hz, 2H), 2.67 (t, J = 7.6 Hz, 2H), 2.4 l (t, J = 8.1 Hz, 4H), 2.06 (s, 6H).
实施例 57： 3-(4-(((6-(2,6-二甲基 -4-(2- (哌嗪 -1-基)乙氧基)苯基)吡啶 -2-基） 氧)亚甲基)苯基) (化合物 HYH-054)的制备  Example 57: 3-(4-((6-(2,6-Dimethyl-4-(2-piperazin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy Preparation of methylene)phenyl) (compound HYH-054)
Figure imgf000042_0001
Figure imgf000042_0001
除了使用 2- (哌嗪 -1-基)乙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺 酰酯之外， 按照与实施例 41 类似的方法制得化合物 3-(4-(：6-(2,6-二甲基 -4-(2- (哌嗪 -1-基)乙氧基)苯基)吡啶 -2-基)氧)亚甲基)苯基)丙酸。 ^ NM (400 MHz, CDC13) δ= 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s, 2H),4.79(t, J = 7.2 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.77(t, J = 7.2 Hz, 2H), 2.71(t, J = 8.1 Hz, 4H), 2.67 (t, J = 7.6 Hz, 2H), 2.39(t, J = 8.1 Hz, 4H), 2.06 (s, 6H)。 Compound 3-(4) was obtained in a similar manner to Example 41 except that 2-(piperazin-1-yl)ethyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. -(:6-(2,6-Dimethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)phenyl) acid. ^ NM (400 MHz, CDC1 3 ) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.79 (t, J = 7.2 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.77 (t, J = 7.2 Hz, 2H), 2.71 (t, J = 8.1 Hz, 4H), 2.67 (t, J = 7.6 Hz, 2H), 2.39 ( t, J = 8.1 Hz, 4H), 2.06 (s, 6H).
实施例 58： 3-(4-(((6-( 2,6-二甲基 -4-(2-(4-甲基哌嗪 -1-基)乙氧基)苯基)吡 啶 -2-基)氧)亚甲 -055)的制备  Example 58: 3-(4-((6-(2,6-Dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)pyridine-2 Preparation of -yl)oxy)methylene-055)
Figure imgf000042_0002
Figure imgf000042_0002
除了使用 2-(4-甲基哌嗪 -1-基：)乙基对甲苯磺酰酯代替 2-甲磺酰基乙基对 甲苯磺酰酯之外，按照与实施例 41类似的方法制得化合物 3-(4- X6-(2,6-二甲 基 -4_(2_(4_甲基哌嗪小基)乙氧基)苯基)吡啶 _2_基)氧)亚甲基)苯基)丙酸。Prepared in a similar manner to Example 41 except that 2-(4-methylpiperazin-1-yl:)ethyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. Compound 3-(4- X6-(2,6-Dimethyl- 4 _( 2 _( 4 -methylpiperazinyl)ethoxy)phenyl)pyridine- 2 -yl)oxy)methylene Phenyl) propionic acid.
NM (400 MHz, CDC13) δ= 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.11 (d,J= 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d,J= 7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H),4.79(t, J= 7.2 Hz, 2H), 2.98 (t,J= 7.6 Hz, 2H), 2.77(t,J = 7.2 Hz, 2H), 2.67 (t, J= 7.6 Hz, 2H), 2.44(t, J= 8.1 Hz, 4H), 2.39(t,J= 8.1 Hz, 4H),2.18(s, 3H) , 2.06 (s, 6H)。 NM (400 MHz, CDC1 3 ) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s , 2H), 4.79 (t, J = 7.2 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.77 (t, J = 7.2 Hz, 2H), 2.67 (t, J = 7.6 Hz, 2H ), 2.44 (t, J = 8.1 Hz, 4H), 2.39 (t, J = 8.1 Hz, 4H), 2.18 (s, 3H), 2.06 (s, 6H).
实施例 59： 3-(4-(((6-(2,6-二甲基 -4-(2- (甲磺酰基)乙氧基)苯基)吡啶 -2-基) 氧)亚甲基 )-2-氟苯 (化合物 HYH-056)的制备 Example 59: 3 -( 4 -(( 6- ( 2 , 6 -Dimethyl- 4 -( 2 -(methylsulfonyl)ethoxy)phenyl)pyridin- 2 -yl)oxy)) Preparation of 2-fluorobenzene (compound HYH-056)
Figure imgf000043_0001
Figure imgf000043_0001
除了使用 3-(4-(((6-(2,6-二甲基 -4-羟基苯基） 吡啶 -2-基)氧)亚甲基 )-2-氟 苯基)丙酸乙酯代替 3-(4-(((6-(2,6-二甲基 -4-羟基苯基） 吡啶 -2-基)氧)亚甲基) 苯基：)丙酸乙酯之外， 按照与实施例 41类似的方法制得化合物 3-(4-：(：6-(2， 6-二甲基 -4-(2-(甲磺酰基)乙氧基)苯基)吡啶 -2-基)氧)亚甲基) -2-氟苯基)丙酸。 JH NM (400 MHz, CDC13) δ= 7.62 (dd,J= 8.3, 7.3 Hz, 1H), 7.38 (d,J= 8.0 Hz 1H), 7.11 (d,J= 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d,J= 7.2, 1H), 6.76 (dd,J= 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.82(t,J=7.2 Hz, 2H), 3.78(t,J=7.2 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H), 2.89(s, 3H), 2.69 (t,J= 7.6 Hz, 2H), 2.07 (s, 6H)。 In addition to the use of ethyl 3-(4-((6-(2,6-dimethyl-4-hydroxyphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoate Instead of 3-(4-((6-(2,6-dimethyl-4-hydroxyphenyl)pyridin-2-yl)oxy)methylene)phenyl))ethyl propionate, The compound 3-(4-:(:6-(2,6-dimethyl-4-(2-(methylsulfonyl)ethoxy)phenyl)pyridine-2-) was obtained in a similar manner to Example 41. Oxy)methylene)-2-fluorophenyl)propionic acid. J H NM (400 MHz, CDC1 3 ) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz 1H), 7.11 (d, J = 7.7 Hz, 2H), 6.98 (s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.82 (t, J = 7.2 Hz, 2H), 3.78 (t, J = 7.2 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 2.89 (s, 3H), 2.69 (t, J = 7.6 Hz, 2H), 2.07 (s, 6H).
实施例 60： 3-(4-(((6-(2, 6-二甲基 -4-(3- (甲磺酰基)丙氧基)苯基)吡啶 -2- 基)氧)亚甲基 )-2-氟 HYH-057)的制备 Example 60: 3-(4-((6-(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)) Preparation of 2 -)-fluoro-HYH-0 57 )
Figure imgf000043_0002
Figure imgf000043_0002
除了使用 3-甲磺酰基丙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯，以及使用 3-(4-(((6-(2,6-二甲基 -4-羟基苯基） 吡啶 -2-基)氧)亚甲基 )-2-氟苯 基)丙酸乙酯代替 3-(4-(((6-(2,6-二甲基 -4-羟基苯基） 吡啶 -2-基)氧)亚甲基)苯 基:)丙酸乙酯之外， 按照与实施例 41类似的方法制得化合物 3-(4 (：6-(2,6-二 甲基 -4-P- (甲磺酰基)丙氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2-氟苯基)丙酸。 NM (400 MHz, CDC13) δ= 7.81 - 7.72 (m, 1H), 7.24 (t,J= 8.0 Hz, 1H), 7.15 - 7.05 (m, 2H), 6.89 - 6.78 (m, 2H), 6.67 (s, 2H), 5.23 (s, 2H), 4.13 - 3.94 (m, 2H), 3.29 - 3.21 (m, 2H), 3.01 (s, 3H), 2.79 - 2.66 (m, 2H), 2.18 - 2.08 (m, 4H), 1.92 (s, 6H). In addition to using 3-methanesulfonylpropyl p-toluenesulfonyl ester instead of 2-methanesulfonylethyl p-toluenesulfonyl ester, and using 3-(4-((6-(2,6-dimethyl-4) -Hydroxyphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid ethyl ester instead of 3-(4-((6-(2,6-dimethyl-4-) In the same manner as in Example 41 except that hydroxyphenyl)pyridin-2-yl)oxy)methylene)phenyl:ethyl propionate was obtained, the compound 3-(4(:6-(2,6) -Dimethyl-4-P-(methylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid. NM (400 MHz, CDC1 3 ) δ = 7.81 - 7.72 (m, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.15 - 7.05 (m, 2H), 6.89 - 6.78 (m, 2H), 6.67 (s, 2H), 5.23 (s, 2H), 4.13 - 3.94 (m, 2H), 3.29 - 3.21 (m, 2H), 3.01 (s, 3H), 2.79 - 2.66 (m, 2H), 2.18 - 2.08 (m, 4H), 1.92 (s, 6H).
实施例 61： 3-(4-(((6-(2,6-二甲基 -4-(2-甲氧基乙氧基)苯基)吡啶 -2-基)氧) 亚甲基 )-2-氟苯基) (化合物 HYH-058)的制备  Example 61: 3-(4-((6-(2,6-Dimethyl-4-(2-methoxyethoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of 2-fluorophenyl) (Compound HYH-058)
Figure imgf000044_0001
Figure imgf000044_0001
除了使用 2-甲氧基乙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯，以及使用 3-(4-(((6-(2,6-二甲基 -4-羟基苯基） 吡啶 -2-基)氧)亚甲基 )-2-氟苯 基)丙酸乙酯代替 3-(4-(((6-(2,6-二甲基 -4-羟基苯基） 吡啶 -2-基)氧)亚甲基)苯 基:)丙酸乙酯之外， 按照与实施例 41类似的方法制得化合物 3-(4-：(：6-(2， 6- 二甲基 -4-(2-甲氧基乙氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2-氟苯基)丙酸。 NM (400 MHz, CDC13) δ= 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.7 Hz, 2H), 6.96 (s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.82(t, J = 7.2 Hz, 2H), 3.82(t, J = 7.2 Hz, 2H), 3.42(s, 3H), 2.99 (t, J = 7.6 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 2.07 (s, 6H)。 In addition to using 2-methoxyethyl-p-toluenesulfonyl ester instead of 2-methanesulfonylethyl p-toluenesulfonyl ester, and using 3-(4-((6-(2,6-dimethyl-4) -Hydroxyphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid ethyl ester instead of 3-(4-((6-(2,6-dimethyl-4-) In the same manner as in Example 41 except that hydroxyphenyl)pyridin-2-yl)oxy)methylene)phenyl:ethyl propionate was obtained, the compound 3-(4-:(:6-(2) 6-Dimethyl-4-(2-methoxyethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid. NM (400 MHz, CDC1 3 ) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.7 Hz, 2H), 6.96 ( s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.82 (t, J = 7.2 Hz, 2H), 3.82 (t, J = 7.2 Hz, 2H), 3.42(s, 3H), 2.99 (t, J = 7.6 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 2.07 (s, 6H).
实施例 62： 3-(4-(((6-(2,6-二甲基 -4-(3-甲氧基丙氧基)苯基)吡啶 -2-基)氧) 亚甲基 )-2-氟苯基) (化合物 HYH-059)的制备  Example 62: 3-(4-((6-(2,6-Dimethyl-4-(3-methoxypropoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of 2-fluorophenyl) (Compound HYH-059)
Figure imgf000044_0002
Figure imgf000044_0002
除了使用 3-甲氧基丙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯，以及使用 3-(4-(((6-(2,6-二甲基 -4-羟基苯基） 吡啶 -2-基)氧)亚甲基 )-2-氟苯 基)丙酸乙酯代替 3-(4-(((6-(2,6-二甲基 -4-羟基苯基） 吡啶 -2-基)氧)亚甲基)苯 基:)丙酸乙酯之外， 按照与实施例 41类似的方法制得化合物 3-(4-：(：6-(2， 6- 二甲基 _4_(3_甲氧基丙氧基)苯基)吡啶 _2_基)氧)亚甲基 )_2_氟苯基)丙酸。In addition to using 3-methoxypropyl p-toluenesulfonyl ester instead of 2-methanesulfonylethyl p-toluenesulfonyl ester, and using 3-(4-((6-(2,6-dimethyl-4) -Hydroxyphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid ethyl ester instead of 3-(4-((6-(2,6-dimethyl-4-) In the same manner as in Example 41 except that hydroxyphenyl)pyridin-2-yl)oxy)methylene)phenyl:ethyl propionate was obtained, the compound 3-(4-:(:6-(2) , 6-Dimethyl_ 4 _( 3 methoxypropoxy)phenyl)pyridine _ 2 yl)oxy)methylene)_ 2 fluorophenyl)propionic acid.
NM (400 MHz, CDC13) δ= 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.7 Hz, 2H), 6.96 (s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.82(t, J = 7.2 Hz, 2H), 3.49(t, J = 7.2 Hz, 2H), 3.42(s, 3H), 2.99 (t, J = 7.6 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 2.14(m, J = 7.2 Hz, 2H), 2.07 (s, 6H)。 NM (400 MHz, CDC1 3 ) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.7 Hz, 2H), 6.96 ( s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.82 (t, J = 7.2 Hz, 2H), 3.49 (t, J = 7.2 Hz, 2H), 3.42 (s, 3H), 2.99 (t, J = 7.6 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 2.14 (m, J = 7.2 Hz, 2H), 2.07 (s, 6H).
实施例 63： 3-(4-(((6-(2,6-二甲基 -4-(2-二甲氨基乙氧基)苯基)吡啶 -2-基) 氧)亚甲基 )-2-氟苯 (化合物 HYH-060)的制备  Example 63: 3-(4-((6-(2,6-Dimethyl-4-(2-dimethylaminoethoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of 2-fluorobenzene (compound HYH-060)
Figure imgf000045_0001
Figure imgf000045_0001
除了使用 2-二甲氨基乙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯，以及使用 3-(4-(((6-(2,6-二甲基 -4-羟基苯基） 吡啶 -2-基)氧)亚甲基 )-2-氟苯 基)丙酸乙酯代替 3-(4-(((6-(2,6-二甲基 -4-羟基苯基） 吡啶 -2-基)氧)亚甲基)苯 基:)丙酸乙酯之外， 按照与实施例 41类似的方法制得化合物 3-(4-：(：6-(2， 6- 二甲基 -4-(2-二甲氨基乙氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2-氟苯基)丙酸。 NM (400 MHz, CDC13) δ= 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.7 Hz, 2H), 6.96 (s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.82(t, J = 7.2 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 2.82(s, 6H), 2.69(t, J= 7.2 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 2.07 (s, 6H)。 In addition to using 2-dimethylaminoethyl p-toluenesulfonyl ester instead of 2-methanesulfonylethyl p-toluenesulfonyl ester, and using 3-(4-((6-(2,6-dimethyl-4) -Hydroxyphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid ethyl ester instead of 3-(4-((6-(2,6-dimethyl-4-) In the same manner as in Example 41 except that hydroxyphenyl)pyridin-2-yl)oxy)methylene)phenyl:ethyl propionate was obtained, the compound 3-(4-:(:6-(2) 6-Dimethyl-4-(2-dimethylaminoethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid. NM (400 MHz, CDC1 3 ) δ = 7.62 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.7 Hz, 2H), 6.96 ( s, 2H), 6.78 (d, J = 7.2, 1H), 6.76 (dd, J = 8.3, 0.8 Hz, 1H), 5.35 (s, 2H), 4.82 (t, J = 7.2 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 2.82 (s, 6H), 2.69 (t, J = 7.2 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 2.07 (s, 6H).
Figure imgf000045_0002
Figure imgf000045_0002
歩骤 1： 将 14.15g ( 102.4mmol) 3-甲氧基苄醇和 32.8mL三乙胺溶解于 50mL干燥的二氯甲垸中， 冰水浴下加入 1.3g DMAP， 搅拌下滴加入 ll.lmL 乙酸酐， 然后升至室温搅拌过夜， 浓缩除去大部分溶剂， 加入乙酸乙酯 200mL， 用 IN盐酸溶液洗涤 3次， 有机层用无水硫酸钠干燥后浓缩， 用硅 胶柱层析分离 （乙酸乙酯： 石油醚 =1 :20 )， 得到 3-甲氧基苄醇乙酸酯 17.7g， 为无色油状物，产率 96%。 NM (CDC13, 400 MHz) δ: 7.25 (t, J = 8.0 Hz, 1H); 6.92 (d, J = 8.0Hz, 1H), 6.89 (s, 1H), 6.85 (d, J = 8.0 Hz, 1H), 5.06 (s, 2H), 3.78 (s, 3H), 2.08(s, 3H)。 Ho step 1: 14.15g (102.4mmol) 3- methoxy-benzyl alcohol and 32.8mL of triethylamine were dissolved in 50mL of dichloromethane in a dried, 1.3 g DMAP were added under ice-water bath, was added dropwise with stirring acetic ll.lmL The acid anhydride was stirred at room temperature overnight, concentrated to remove most of the solvent, ethyl acetate (200 mL) was added, and the mixture was washed three times with aqueous hydrochloric acid. Separation by column chromatography (ethyl acetate: petroleum ether = 1 : 20) gaveyield of 3-methoxybenzyl alcohol acetate (17.7 g) as a colorless oil. NM (CDC1 3 , 400 MHz) δ: 7.25 (t, J = 8.0 Hz, 1H) ; 6.92 (d, J = 8.0Hz, 1H), 6.89 (s, 1H), 6.85 (d, J = 8.0 Hz, 1H), 5.06 (s, 2H), 3.78 (s, 3H), 2.08 (s, 3H).
歩骤 2: 将 3-甲氧基苄醇乙酸酯 9.7g溶于 40mL无水二氯甲垸中， 室温 下滴加入 12.8mL氯乙酰氯， 然后分多批次加入 23.6g无水氯化铝， 然后回流 反应 16小时。 将反应液冷至室温后倾倒入 500mL冰水中， 用二氯甲垸萃取 三次， 合并二氯甲垸后用饱和碳酸氢钠溶液洗涤， 然后用无水硫酸钠干燥， 浓缩后硅胶柱层析分离 （乙酸乙酯： 石油醚 =1 :9 〜 1:1 )， 得到 4-(2-氯 -乙酰 基) -3-羟基 -苄醇乙酸酯 2.63g，为浅褐色固体，产率 20%。 ^ NM (CDC13, 400 MHz) δ: 11.67 (s, 1Η), 7.67 (d, J= 8.0 Hz, 1H), 6.97 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 5.09 (s, 2H), 4.69 (s, 2H), 2.14 (s, 3H)。 Step 2: Dissolve 9.7 g of 3-methoxybenzyl alcohol acetate in 40 mL of anhydrous dichloromethane, add 12.8 mL of chloroacetyl chloride dropwise at room temperature, and then add 23.6 g of anhydrous chlorinated in multiple batches. Aluminum was then refluxed for 16 hours. The reaction solution was cooled to room temperature, poured into 500 mL of ice water, extracted three times with dichloromethane, washed with dichloromethane, washed with saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate (ethyl acetate: petroleum ether = 1:9 to 1:1) gave 2.63 g of 4-(2-chloro-acetyl)-3-hydroxy-benzyl alcohol acetate as a light brown solid, yield 20% . ^ NM (CDC1 3 , 400 MHz) δ: 11.67 (s, 1Η), 7.67 (d, J= 8.0 Hz, 1H), 6.97 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 5.09 (s, 2H), 4.69 (s, 2H), 2.14 (s, 3H).
歩骤 3: 将 4-(2-氯-乙酰基： )-3-羟基 -苄醇乙酸酯 2.20g溶于 40mL无水甲 醇中，加入乙酸钠 1.49g， 回流反应 2小时，冷至室温，旋蒸除去大部分溶剂， 残留物溶于二氯甲垸中，水洗涤，干燥后柱层析分离（乙酸乙酯：石油醚 =1 :6 )， 得 3-氧代 -2,3-二氢苯并呋喃 -6-羟甲基乙酸酯 1.30g，产率 59%。 ifiNM (CDC13; 400 MHz) δ: 7.67 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 7.06 (d, J= 8.0 Hz, 1H), 5.17 (s, 2H), 4.65 (s, 2H), 2.17 (s, 3H)。 Step 3: 2.20 g of 4-(2-chloro-acetyl: )-3-hydroxy-benzyl alcohol acetate was dissolved in 40 mL of anhydrous methanol, and 1.49 g of sodium acetate was added thereto, and the mixture was refluxed for 2 hours, and cooled to room temperature. Most of the solvent was removed by rotary distillation. The residue was dissolved in dichloromethane, washed with water, dried and purified by column chromatography (ethyl acetate: petroleum ether = 1:6) to give 3-oxo-2,3- Dihydrobenzofuran-6-hydroxymethyl acetate 1.30 g, yield 59%. ifiNM (CDC1 3; 400 MHz) δ: 7.67 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 5.17 (s, 2H), 4.65 ( s, 2H), 2.17 (s, 3H).
歩骤 4: 将 3-氧代 -2,3-二氢苯并呋喃 -6-羟甲基乙酸酯 1.50g溶于 lOOmL 无水甲苯中， 加入乙氧甲酰基亚甲基三苯基膦 12.67g， 混合液回流反应 24 小时，反应液冷却至室温，旋蒸除去大部分溶剂，残留物硅胶柱层析分离（乙 酸乙酯： 石油醚 =1 :20 )， 得到 （6-羟甲基乙酸酯-苯并呋喃 -3-基)乙酸乙酯 1.15g，为类白色固体，产率 57%。 ¾ NMR (CDC13, 400 MHz) δ: 7.65 (s, 1H), 7.56(d, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H), 5.21 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.69(s, 2H), 2.11 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H). Step 4: 1.50 g of 3-oxo-2,3-dihydrobenzofuran-6-hydroxymethylacetate was dissolved in 100 mL of anhydrous toluene, and ethoxycarbonylmethylenetriphenylphosphine was added. 12.67 g, the mixture was refluxed for 24 hours, the reaction solution was cooled to room temperature, and the solvent was evaporated to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:20) to give (6-hydroxymethyl) Ethyl acetate-benzofuran-3-yl)acetate, 1.15 g, was obtained as an off white solid, yield 57%. 3⁄4 NMR (CDC1 3 , 400 MHz) δ: 7.65 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H), 5.21 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.69(s, 2H), 2.11 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).
歩骤 5:将 6-羟甲基乙酸酯-苯并呋喃 -3-基：)乙酸乙酯 1.15g溶解入 20mL 乙酸乙酯中， 加入 10%Pd/C 100mg,—个大气压力的氢气氛围下室温过夜， 垫 硅藻土过来除去钯碳， 滤液浓缩后硅胶柱分离， 得到 (6-羟甲基乙酸酯 -2,3-二 氢苯并呋喃 -3-基)乙酸乙酯 l.Og,为白色固体，产率 86%, ¾ NMR (CDC13, 400 MHz) δ: 7.26(d, J = 8.0 Hz, 1H), 7.05 (s, 1H), 6.73 (d, J = 8.0 Hz, 1H),5.21 (s, 2H), 4.36(m, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.08(m,lH), 3.89(m,lH), 2.65(m, 1H); 2.44(m, 1H), 2.11 (s, 3H), 1.27 (t, J= 7.1 Hz, 3H)。 Step 5: Dissolve 1.15 g of 6-hydroxymethyl acetate-benzofuran-3-yl:ethyl acetate into 20 mL of ethyl acetate, add 10% Pd/C 100 mg, hydrogen at atmospheric pressure The atmosphere was allowed to stand overnight at room temperature, and the diatomaceous earth was passed over to remove palladium carbon, and the filtrate was concentrated and separated on a silica gel column to obtain ethyl (6-hydroxymethyl acetate-2,3-dihydrobenzofuran-3-yl)acetate. .Og, as a white solid, yield 86%, 3⁄4 NMR (CDC1 3 , 400 MHz) δ: 7.26 (d, J = 8.0 Hz, 1H), 7.05 (s, 1H), 6.73 (d, J = 8.0 Hz , 1H), 5.21 (s, 2H), 4.36(m, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.08(m,lH), 3.89(m,lH), 2.65(m, 1H) ; 2.44(m, 1H), 2.11 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).
歩骤 6: 将6-羟甲基乙酸酯 -2,3-二氢苯并呋喃 -3-基：)乙酸乙酯 l.Og溶解 于 20mL乙腈中， 加入水 4mL， 搅拌下加入 lOOmg氢氧化锂， 50°C下反应 4 小时， 冷却至室温， 加入水 50mL， 用二氯甲垸萃取 3次， 合并有机层用无 水硫酸钠干燥， 得到 (6-羟甲基 -2,3-二氢苯并呋喃 -3-基)乙酸 0.68g， 为类白色 固体，产率 91%。 ιΐΙ NM (CDC13, 400 MHz) δ: 7.26(d, J= 8.0 Hz, 1H), 7.05 (s, 1H), 6.73 (d, J = 8.0 Hz, 1H),5.21 (s, 2H), 4.36(m, 1H), 4.08(m,lH), 3.89(m,lH), 2.65(m, 1H), 2.44(m, 1H)。 Step 6: Dissolve 6. Og of 6-hydroxymethyl acetate-2,3-dihydrobenzofuran-3-yl:)acetate in 20 mL of acetonitrile, add 4 mL of water, and add 100 mg of hydrogen with stirring. Lithium oxide was reacted at 50 ° C for 4 hours, cooled to room temperature, 50 mL of water was added, and extracted with dichloromethane for 3 times. The combined organic layers were dried over anhydrous sodium sulfate to give (6-hydroxymethyl-2,3- 0.68 g of dihydrobenzofuran-3-yl)acetic acid was an off-white solid with a yield of 91%. ι ΐΙ NM (CDC1 3 , 400 MHz) δ: 7.26 (d, J = 8.0 Hz, 1H), 7.05 (s, 1H), 6.73 (d, J = 8.0 Hz, 1H), 5.21 (s, 2H), 4.36 (m, 1H), 4.08 (m, lH), 3.89 (m, lH), 2.65 (m, 1H), 2.44 (m, 1H).
歩骤 7: 将 (6-羟甲基 -2,3-二氢苯并呋喃 -3-基)乙酸 0.65g加入到 10mL圆 底烧瓶中， 滴加入 lmL三溴化磷， 80°C下反应 2小时， 将反应液冷至 0°C， 缓慢滴加入 l.OmL无水乙醇， 然后将反应液倾倒至 lOOmL冰水中， 乙酸乙 酯萃取三次， 合并有机层用无水硫酸钠干燥， 过滤浓缩得 （6-羟甲基 -2,3-二 氢苯并呋喃 -3-基：)乙酸乙酯 0.72g，为浅黄色固体，产率 84%。 ^ NM CCDCls, 400 MHz) 5: 7.24(d, J= 8.0 Hz, 1H), 6.95 (s, 1H), 6.76 (d, J= 8.0 Hz, 1H),4.48 (s 2H), 4.36(m, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.08(m,lH), 3.89(m,lH), 2.65(m, 1H); 2.44(m, 1H), 1.27 (t, J= 7.1 Hz, 3H)。 Step 7: 0.65 g of (6-hydroxymethyl-2,3-dihydrobenzofuran-3-yl)acetic acid was added to a 10 mL round bottom flask, and 1 mL of phosphorus tribromide was added dropwise, and the reaction was carried out at 80 ° C. After 2 hours, the reaction solution was cooled to 0 ° C, and 1.0 mL of anhydrous ethanol was added dropwise, and the reaction mixture was poured into 100 mL of ice water, and the mixture was extracted three times with ethyl acetate. There was obtained 0.72 g of ethyl (6-hydroxymethyl-2,3-dihydrobenzofuran-3-yl:) as a pale yellow solid (yield: 84%). ^ NM CCDCls, 400 MHz) 5: 7.24 (d, J = 8.0 Hz, 1H), 6.95 (s, 1H), 6.76 (d, J = 8.0 Hz, 1H), 4.48 (s 2H), 4.36 (m, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.08 (m, lH), 3.89 (m, lH), 2.65 (m, 1H) ; 2.44 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H).
实施例 65： 2-(6-(((6-(2,6-二甲基 -4-(2- (甲磺酰基)乙氧基)苯基)吡啶 -2-基) 氧)亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-061)的制备 Example 65: 2-(6-((6-(2,6-Dimethyl-4-(2-(methylsulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)) Preparation of bis(2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-061)
Figure imgf000048_0001
Figure imgf000048_0001
Figure imgf000048_0002
歩骤 1 : 将 0.5g(6-羟甲基 -2,3-二氢苯并呋喃 -3-基)乙酸乙酯和 0.29g 2-溴 -6-羟基吡啶溶解于 20mL乙腈中， 加入 0.35g碳酸钾， 然后置于 60 °C反应 3 小时， 冷至室温， 浓缩柱分离， 得到 2-(6-(((6-溴吡啶 -2-基)氧)亚甲基 )-2,3-二 氢苯并呋喃 -3-基）乙酸乙酯 0.58g， 产率 88%。 ^ NM (CDC13, 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, 1H), 7.24(d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.95 (s, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.11 (s, 2H), 4.33-4.37 (m, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.02-4.09 (m,lH), 3.82-3.89 (m,lH), 2.61-2.67 (m, 1H), 2.42-2.47(m, 1H), 1.27 (t, J = 7.1 Hz, 3H)。
Figure imgf000048_0002
Step 1: 0.5 g of (6-hydroxymethyl-2,3-dihydrobenzofuran-3-yl)acetate and 0.29 g of 2-bromo-6-hydroxypyridine were dissolved in 20 mL of acetonitrile, and added to 0.35. g potassium carbonate, then reacted at 60 ° C for 3 hours, cooled to room temperature, and concentrated on a column to give 2-(6-((6-bromopyridin-2-yl)oxy)methylene)-2,3 Ethyl dihydrobenzofuran-3-yl)acetate 0.58 g, yield 88%. ^ NM (CDC1 3 , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.95 (s, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.11 (s, 2H), 4.33-4.37 (m, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.02-4.09 (m, lH), 3.82-3.89 (m, lH), 2.61-2.67 (m, 1H), 2.42-2.47 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H).
歩骤 2: 称取 lOO.Omg化合物 2-(6-(((6-溴吡啶 -2-基)氧)亚甲基 )-2,3-二氢 苯并呋喃 -3-基)乙酸乙酯， 65.0mg 4-羟基 -2,6-二甲基苯硼酸， 15.0mg四 （三 苯基膦）钯和 75.0mg碳酸钾加入到 10mL微波反应器专用管中， 加入 2.0mL 甲苯， 0.4mL乙醇和 0.4mL水， 用氮气置换 3次， 然后置于 CEM微波反应 器中 120°C反应 30分钟， 反应液浓缩后硅胶柱层析分离， 得到 2-(6-(((6-(4- 羟基 -2,6-二甲基苯基)吡啶 -2-基)氧基)亚甲基 )-2,3-二氢苯并呋喃 -3-基)乙酸乙 酯 97.0mg， 为白色固体。 JH NM (CDC13, 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87(s, 2H), 6.76 (d, J= 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33-4.37 (m, IH), 4.19 (q, J = 7.1 Hz, 2H), 4.02-4.09 (m,lH), 3.82-3.89 (m,lH), 2.61-2.67 (m, IH), 2.42-2.47 (m, IH), 2.08(s, 6H), 1.27 (t, J = 7.1 Hz, 3H)。 Step 2: Weigh 100.Omg of compound 2-(6-((6-bromopyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid Ester, 65.0 mg 4-hydroxy-2,6-dimethylphenylboronic acid, 15.0 mg of tetrakis(triphenylphosphine)palladium and 75.0 mg of potassium carbonate were added to a 10 mL microwave reactor special tube, and 2.0 mL of toluene, 0.4 mL was added. Ethanol and 0.4 mL of water were replaced with nitrogen for 3 times, and then placed in a CEM microwave reactor at 120 ° C for 30 minutes. The reaction solution was concentrated and separated by silica gel column chromatography to give 2-(6-(((6-(4)) -Hydroxy-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetate 97.0 mg as a white solid . J H NM (CDC1 3 , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87(s, 2H), 6.76 (d, J= 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33-4.37 (m, IH), 4.19 (q, J = 7.1 Hz, 2H), 4.02-4.09 (m , lH), 3.82-3.89 (m, lH), 2.61-2.67 (m, IH), 2.42-2.47 (m, IH), 2.08 (s, 6H), 1.27 (t, J = 7.1 Hz, 3H).
歩骤 3和歩骤 4: 除了使用 2-(6-(((6-(4-羟基 -2,6-二甲基苯基)吡啶 -2-基） 氧)亚甲基 )-2,3-二氢苯并呋喃 -3-基)乙酸乙酯代替 3-(4-(((6-(2,6-二甲基 -4-羟 基苯基） 吡啶 -2-基)氧)亚甲基)苯基)丙酸乙酯之外， 按照与实施例 42所示类 似的方法制备得 2-(6-(((6-(2,6-二甲基 -4-(2- (甲磺酰基)乙氧基)苯基)吡啶 -2-基) 氧)亚甲基 )-2,3-二氢苯并呋喃 -3-基)乙酸。 ^ NM CDC OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 - 4.37 (m, IH), 4.13 (q, J = 6.1 Hz, 2H), 4.02 - 4.07 (m, IH), 3.82 - 3.89 (m, IH), 3.79 (q, J = 6.1 Hz, 2H), 2.97 (s, 3H), 2.61 - 2.67 (m, IH), 2.42 - 2.47 (m, IH), 2.08 (s, 6H)。  Step 3 and Step 4: In addition to using 2-(6-((6-(4-hydroxy-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)-2, 3-(4-((6-(2,6-dimethyl-4-hydroxyphenyl)pyridin-2-yl)oxy)) In the same manner as in Example 42 except that methyl (ethyl)phenyl)propanoate was obtained, 2-(6-((6-(2,6-dimethyl-4-(2-) Methanesulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid. ^ NM CDC OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH) ), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 - 4.37 (m, IH), 4.13 (q, J = 6.1 Hz, 2H), 4.02 - 4.07 (m, IH), 3.82 - 3.89 (m, IH), 3.79 (q, J = 6.1 Hz, 2H), 2.97 (s, 3H), 2.61 - 2.67 (m, IH), 2.42 - 2.47 (m, IH), 2.08 (s, 6H).
实施例 66： 2-(6-(((6-(2,6-二甲基 -4-(3- (甲磺酰基)丙氧基)苯基)吡啶 -2-基） 氧)亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-062)的制备  Example 66: 2-(6-((6-(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)) Preparation of bis(2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-062)
Figure imgf000049_0001
除了使用 3-甲磺酰基丙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯之外， 按照与实施例 65 类似的方法制得化合物 2-(6-：(：6-(2,6-二甲基 -4-(3- (甲磺酰基)丙氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋喃 -3-基) 乙酸。 ^ NM CDC OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 4.37 (m, IH), 4.13 (q, J = 5.8 Hz, 2H), 4.02 - 4.07 (m, IH), 3.82 - 3.89 (m, IH), 3.23 - 3.31 (m, 2H), 2.97 (s, 3H), 2.61 - 2.67 (m, IH), 2.42 - 2.47 (m, IH), 2.29 - 2.35 (m, 2H), 2.08 (s, 6H)。
Figure imgf000049_0001
Compound 2-(6-:(:6) was obtained in a similar manner to Example 65 except that 3-methanesulfonylpropyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. -(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran- 3-based) acetic acid. ^ NM CDC OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH) ), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 4.37 (m, IH), 4.13 ( q, J = 5.8 Hz, 2H), 4.02 - 4.07 (m, IH), 3.82 - 3.89 (m, IH), 3.23 - 3.31 (m, 2H), 2.97 (s, 3H), 2.61 - 2.67 (m, IH), 2.42 - 2.47 (m, IH), 2.29 - 2.35 (m, 2H), 2.08 (s, 6H).
实施例 67： 2-(6-(((6-(2,6-二甲基 -4-(4- (甲磺酰基)丁氧基)苯基)吡啶 -2-基) 氧)亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-063)的制备
Figure imgf000050_0001
除了使用 4-甲磺酰基丁基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯之外， 按照与实施例 65 类似的方法制得化合物 2-(6-：(：6-(2,6-二甲基 -4-(4- (甲磺酰基)丁氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋喃 -3-基) 乙酸。 ^ NM CDC OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 4.37 (m, IH), 4.13 (q, J = 5.8 Hz, 2H), 4.02 - 4.07 (m, IH), 3.82 - 3.89 (m, IH), 3.23 - 3.31 (m, 2H), 2.97 (s, 3H), 2.61 - 2.67 (m, IH), 2.42 - 2.47 (m, IH), 2.08 (s, 6H), 1.67 - 1.85 (m, 4H)。 Example 67: 2-(6-((6-(2,6-Dimethyl-4-(4-(methylsulfonyl)butoxy)phenyl)pyridin-2-yl)oxy)) Preparation of bis(2,3-dihydrobenzofurazol-3-yl)acetic acid (compound HYH-063)
Figure imgf000050_0001
Compound 2-(6-:(:6) was obtained in a similar manner to Example 65 except that 4-methanesulfonylbutyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. -(2,6-Dimethyl-4-(4-(methylsulfonyl)butoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran- 3-based) acetic acid. ^ NM CDC OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH) ), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 4.37 (m, IH), 4.13 ( q, J = 5.8 Hz, 2H), 4.02 - 4.07 (m, IH), 3.82 - 3.89 (m, IH), 3.23 - 3.31 (m, 2H), 2.97 (s, 3H), 2.61 - 2.67 (m, IH), 2.42 - 2.47 (m, IH), 2.08 (s, 6H), 1.67 - 1.85 (m, 4H).
实施例 68： 2-(6-(((6-(2,6-二甲基 -4-(3- (乙磺酰基)丙氧基)苯基)吡啶 -2-基) 氧)亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-064)的制备  Example 68: 2-(6-((6-(2,6-Dimethyl-4-(3-(ethylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)) Preparation of bis(2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-064)
Figure imgf000050_0002
除了使用 3-乙磺酰基丙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯之外， 按照与实施例 65 类似的方法制得化合物 2-(6-：(：6-(2,6-二甲基 -4-(3- (乙磺酰基)丙氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋喃 -3-基) 乙酸。 ^ NM CDC OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 4.37 (m, IH), 4.13 (q, J = 5.8 Hz, 2H), 4.02 4.07 (m, IH), 3.82 3.89 (m, IH), 3.23 3.31 (m, 2H), 2.94 (q: J = 7.2 Hz, 2H), 2.61 - 2.67 (m, IH), 2.42 - 2.47 (m, IH), 2.29 - 2.35 (m, 2H), 2.08 (s, 6H), 1.28 (t, J = 7.2 Hz, 3H)。
Figure imgf000050_0002
Compound 2-(6-:(:6) was obtained in a similar manner to Example 65 except that 3-ethylsulfonylpropyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. -(2,6-Dimethyl-4-(3-(ethylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran- 3-based) acetic acid. ^ NM CDC OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH) ), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 4.37 (m, IH), 4.13 ( q, J = 5.8 Hz, 2H), 4.02 4.07 (m, IH), 3.82 3.89 (m, IH), 3.23 3.31 (m, 2H), 2.94 (q : J = 7.2 Hz, 2H), 2.61 - 2.67 ( m, IH), 2.42 - 2.47 (m, IH), 2.29 - 2.35 (m, 2H), 2.08 (s, 6H), 1.28 (t, J = 7.2 Hz, 3H).
实施例 69： 2-(6-(((6-(2,6-二甲基 -4-(2-甲氧基乙氧基)苯基)吡啶 -2-基)氧) 亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-065)的制备
Figure imgf000051_0001
除了使用 2-甲氧基乙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰酯 之外， 按照与实施例 65类似的方法制得化合物 2-(6- X6-(2,6-二甲基 -4-(2-甲 氧基乙氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋喃 -3-基）乙酸。 NM (CDC13, 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.79 (q, J = 6.1 Hz, 2H), 4.33 - 4.37 (m, IH), 4.02 4.07 (m, IH), 3.82 3.89 (m, IH), 3.87 (q, J = 6.1 Hz, 2H), 3.45(s, 3H), 2.61 - 2.67 (m, IH), 2.42 - 2.47 (m, IH), 2.08 (s, 6H)。 Example 69: 2-(6-((6-(2,6-Dimethyl-4-(2-methoxyethoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-065)
Figure imgf000051_0001
Compound 2-(6-X6-(2) was obtained in a similar manner to Example 65 except that 2-methoxyethyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. ,6-Dimethyl-4-(2-methoxyethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid . NM (CDC1 3 , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 ( s, IH), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.79 (q, J = 6.1 Hz, 2H), 4.33 - 4.37 (m, IH), 4.02 4.07 (m, IH), 3.82 3.89 (m, IH), 3.87 (q, J = 6.1 Hz, 2H), 3.45(s, 3H), 2.61 - 2.67 (m, IH), 2.42 - 2.47 (m, IH), 2.08 (s, 6H).
实施例 70： 2-(6-(((6-(2,6-二甲基 -4-(3-甲氧基丙氧基)苯基)吡啶 -2-基)氧) 亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-066)的制备  Example 70: 2-(6-((6-(2,6-Dimethyl-4-(3-methoxypropoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2,3-dihydrobenzofurazol-3-yl)acetic acid (compound HYH-066)
Figure imgf000051_0002
除了使用 3-甲氧基丙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰酯 之外， 按照与实施例 65类似的方法制得化合物 2-(6- X6-(2,6-二甲基 -4-P-甲 氧基丙氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋喃 -3-基）乙酸。 NMR (CDC13, 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 - 4.37 (m, IH), 4.13 (q, J = 5.8 Hz, 2H), 4.02 4.07 (m, IH), 3.82 3.89 (m, IH), 3.45 (s, 3H), 3.18 - 3.27 (m, 2H), 2.61 - 2.67 (m, IH), 2.42 - 2.47 (m, IH), 2.11 - 2.17 (m, 2H), 2.08 (s, 6H)。
Figure imgf000051_0002
Compound 2-(6-X6-(2) was obtained in a similar manner to Example 65 except that 3-methoxypropyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. ,6-Dimethyl-4-P-methoxypropoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid. NMR (CDC1 3 , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 ( s, IH), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 - 4.37 (m, IH ), 4.13 (q, J = 5.8 Hz, 2H), 4.02 4.07 (m, IH), 3.82 3.89 (m, IH), 3.45 (s, 3H), 3.18 - 3.27 (m, 2H), 2.61 - 2.67 ( m, IH), 2.42 - 2.47 (m, IH), 2.11 - 2.17 (m, 2H), 2.08 (s, 6H).
实施例 71： 2-(6-(((6-(2,6-二甲基 -4-(2-二甲氨基乙氧基)苯基)吡啶 -2-基) 氧)亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-067)的制备
Figure imgf000052_0001
除了使用 2-二甲氨基乙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯之外， 按照与实施例 65类似的方法制得化合物 2-(6-(：6-(2,6-二甲基 -4-(2- 二甲氨基乙氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋喃 -3-基)乙酸。 NM (CDC13, 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, 1H), 7.24(d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.95 (s, 1H), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz, 2H), 4.33-4.37 (m, 1H), 4.02-4.09 (m,lH), 3.82-3.89 (m,lH), 2.85(s, 6H), 2.77(t, J = 7.2 Hz, 2H), 2.61-2.67 (m, 1H), 2.42-2.47 (m, 1H), 2.08(s, 6H)。 Example 71: 2-(6-((6-(2,6-Dimethyl-4-(2-dimethylaminoethoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2,3-dihydrobenzofurazol-3-yl)acetic acid (compound HYH-067)
Figure imgf000052_0001
A compound 2-(6-(:6-) was obtained in a similar manner to Example 65 except that 2-dimethylaminoethyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. (2,6-Dimethyl-4-(2-dimethylaminoethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl ) acetic acid. NM (CDC1 3 , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.95 ( s, 1H), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz, 2H), 4.33-4.37 (m, 1H), 4.02-4.09 (m, lH), 3.82-3.89 (m, lH), 2.85 (s, 6H), 2.77 (t, J = 7.2 Hz, 2H) , 2.61-2.67 (m, 1H), 2.42-2.47 (m, 1H), 2.08 (s, 6H).
实施例 72： 2-(6-(((6-(2,6-二甲基 -4-(3-二甲氨基丙氧基)苯基)吡啶 -2-基) 氧)亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-068)的制备  Example 72: 2-(6-((6-(2,6-Dimethyl-4-(3-dimethylaminopropoxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-068)
Figure imgf000052_0002
除了使用 3-二甲氨基丙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯之外， 按照与实施例 65类似的方法制得化合物 2-(6-(：6-(2,6-二甲基 -4-P- 二甲氨基丙氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋喃 -3-基)乙酸。 NMR (CDC13, 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, 1H), 7.24(d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.95 (s, 1H), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz, 2H), 4.33-4.37 (m, 1H), 4.02-4.09 (m,lH), 3.82-3.89 (m,lH), 2.85(s, 6H), 2.69 (t, J = 7.6 Hz, 2H), 2.61-2.67 (m, 1H), 2.42-2.47 (m, 1H), 2.08(s, 6H), 1.79 (q, J = 7.2 Hz, 2H)。
Figure imgf000052_0002
Compound 2-(6-(:6-) was obtained in a similar manner to Example 65 except that 3-dimethylaminopropyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. (2,6-Dimethyl-4-P-dimethylaminopropoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl) Acetic acid. NMR (CDC1 3 , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.95 ( s, 1H), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz, 2H), 4.33-4.37 (m, 1H), 4.02-4.09 (m, lH), 3.82-3.89 (m, lH), 2.85(s, 6H), 2.69 (t, J = 7.6 Hz, 2H) , 2.61-2.67 (m, 1H), 2.42-2.47 (m, 1H), 2.08(s, 6H), 1.79 (q, J = 7.2 Hz, 2H).
实施例 73： 2-(6-(((6-(2,6-二甲基 -4- ((四氢 -2 吡哺 -4-基)氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-069)的制备
Figure imgf000053_0001
除了使用四氢 -2/7-吡喃 -4-甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯之外，按照与实施例 65类似的方法制得化合物 2-(6-：(：6-(2,6-二甲基 -4 四 氢 -2/7-吡喃 -4-基)氧)苯基)吡啶 -2-基)氧基)亚甲基 )-2,3-二氢苯并呋喃 -3-基)乙 酸。 ^ NM CDC , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33-4.37 (m, IH), 4.02-4.09 (m,lH), 3.82-3.89 (m,lH), 3.71 3.79 (m, 1H),3.57 3.61 (m, 2H), 3.50 3.55 (m, 2H), 2.61-2.67 (m, IH), 2.42-2.47 (m, IH), 2.13 - 2.16 (m, 2H), 2.08(s, 6H), 1.85 - 1.89(m, 2H)。 Example 73: 2-(6-((6-(2,6-Dimethyl-4-((tetrahydro-2-pyridin-4-yl)oxy)phenyl)pyridin-2-yl)) Preparation of Oxygen) Methylene)-2,3-Dihydrobenzofurazol-3-yl)acetic Acid (Compound HYH-069)
Figure imgf000053_0001
Compound 2-(6- was obtained in a similar manner to Example 65 except that tetrahydro-2/7-pyran-4-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. :(:6-(2,6-Dimethyl-4tetrahydro-2/7-pyran-4-yl)oxy)phenyl)pyridin-2-yl)oxy)methylene)-2, 3-Dihydrobenzofuran-3-yl)acetic acid. ^ NM CDC , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s , IH), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33-4.37 (m, IH) , 4.02-4.09 (m,lH), 3.82-3.89 (m,lH), 3.71 3.79 (m, 1H), 3.57 3.61 (m, 2H), 3.50 3.55 (m, 2H), 2.61-2.67 (m, IH ), 2.42-2.47 (m, IH), 2.13 - 2.16 (m, 2H), 2.08 (s, 6H), 1.85 - 1.89 (m, 2H).
实施例 74： 2-(6-(((6-(2,6-二甲基 -4- ((四氢 -2 噻哺 -4-基)氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-070)的制备  Example 74: 2-(6-((6-(2,6-Dimethyl-4-((tetrahydro-2-thio-4-yl)oxy)phenyl)pyridin-2-yl) Preparation of Oxygen) Methylene)-2,3-Dihydrobenzofurazol-3-yl)acetic Acid (Compound HYH-070)
Figure imgf000053_0002
除了使用四氢 -2/7-噻喃 -4-甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯之外，按照与实施例 65类似的方法制得化合物 2-(6-：(：6-(2,6-二甲基 -4 四 氢 -2/7-噻喃 -4-基)氧)苯基)吡啶 -2-基)氧基)亚甲基 )-2,3-二氢苯并呋喃 -3-基)乙 酸。 NM (CDC13, 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 - 4.37 (m, IH), 4.02 - 4.09 (m,lH), 3.88 3.97 (m, IH), 3.80 3.86 (m,lH), 2.61-2.67 (m, 3H), 2.52 2.59 (m, 2H), 2.42 - 2.47 (m, IH), 2.18 - 2.27 (m, 2H), 2.08(s, 6H), 1.86 - 1.97 (m, 2H)。 实施例 75: 2-(6-(((6-(2,6-二甲基 -4- (哌啶 -4-基氧基)苯基)吡啶 -2-基)氧) 亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-071)的制备
Figure imgf000053_0002
Compound 2-(6- was prepared in a similar manner to Example 65 except that tetrahydro-2/7-thiopyran-4-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. :(:6-(2,6-Dimethyl-4tetrahydro-2/7-thiopyran-4-yl)oxy)phenyl)pyridin-2-yl)oxy)methylene)-2, 3-Dihydrobenzofuran-3-yl)acetic acid. NM (CDC1 3 , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 ( s, IH), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 - 4.37 (m, IH ), 4.02 - 4.09 (m, lH), 3.88 3.97 (m, IH), 3.80 3.86 (m, lH), 2.61-2.67 (m, 3H), 2.52 2.59 (m, 2H), 2.42 - 2.47 (m, IH), 2.18 - 2.27 (m, 2H), 2.08(s, 6H), 1.86 - 1.97 (m, 2H). Example 75: 2-(6-((6-(2,6-Dimethyl-4-(piperidin-4-yloxy)phenyl)pyridin-2-yl)oxy)methylene) Preparation of -2,3-dihydrobenzofurazol-3-yl)acetic acid (compound HYH-071)
Figure imgf000054_0001
除了使用哌啶 -4-甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰酯之外，按 照与实施例 65类似的方法制得化合物 2-(6- X6-(2,6-二甲基 -4- (哌啶 -4-基氧基:) 苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋喃 -3-基)乙酸。 NM (CDC13, 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33-4.37 (m, IH), 4.02-4.09 (m,lH), 3.82-3.89 (m,lH), 3.71 - 3.79 (m, IH) , 2.61-2.67 (m, 5H), 2.42-2.47 (m, IH), 2.13 - 2.16 (m, 2H), 2.08(s, 6H), 1.85 1.89(m, 2H)。
Figure imgf000054_0001
The compound 2-(6-X6-(2,6-) was obtained in a similar manner to Example 65 except that the piperidin-4-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. Dimethyl-4-(piperidin-4-yloxy:)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid. NM (CDC1 3 , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 ( s, IH), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33-4.37 (m, IH ), 4.02-4.09 (m,lH), 3.82-3.89 (m,lH), 3.71 - 3.79 (m, IH) , 2.61-2.67 (m, 5H), 2.42-2.47 (m, IH), 2.13 - 2.16 (m, 2H), 2.08 (s, 6H), 1.85 1.89 (m, 2H).
实施例 76： 2-(6-(((6-(2,6-二甲基 -4-((l-甲基哌啶 -4-基)氧基)苯基)吡啶 -2- 基)氧)亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-072)的制备  Example 76: 2-(6-((6-(2,6-Dimethyl-4-((l-methylpiperidin-4-yl)oxy)phenyl)pyridin-2-yl)) Preparation of Oxygen) Methylene)-2,3-Dihydrobenzofurazol-3-yl)acetic Acid (Compound HYH-072)
Figure imgf000054_0002
除了使用 1-甲基哌啶 -4-甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰酯 之外， 按照与实施例 65类似的方法制得化合物 2-(6- X6-(2,6-二甲基 -4-G-甲 基哌啶 -4-基)氧)苯基)吡啶 -2-基)氧基)亚甲基 )-2,3-二氢苯并呋喃 -3-基)乙酸。 JH NMR (CDC13, 400 MHz) δ: 7.41 (dd, J= 15.1, 7.5 Hz, IH), 7.24(d, J= 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33-4.37 (m, IH), 4.02-4.09 (m,lH), 3.82-3.89 (m,lH), 3.71 3.79 (m, IH), 2.61-2.67 (m, 5H), 2.42-2.47 (m, IH), 2.26 (s, 2H), 2.13 2.16 (m, 2H), 2.08(s, 6H), 1.85 1.89(m, 2H)。 实施例 77: 2-(6-(((6-(2,6-二甲基 -4-((1,1-二氧代四氢 -2 -噻哺 -4-基）氧基) 苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-073)的 制备
Figure imgf000054_0002
The compound 2-(6-X6-() was prepared in a similar manner to Example 65 except that 1-methylpiperidine-4-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. 2,6-Dimethyl-4-G-methylpiperidin-4-yl)oxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran- 3-yl)acetic acid. J H NMR (CDC1 3 , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33-4.37 (m , IH), 4.02-4.09 (m,lH), 3.82-3.89 (m,lH), 3.71 3.79 (m, IH), 2.61-2.67 (m, 5H), 2.42-2.47 (m, IH), 2.26 ( s, 2H), 2.13 2.16 (m, 2H), 2.08(s, 6H), 1.85 1.89 (m, 2H). Example 77: 2-(6-((6-(2,6-Dimethyl-4-((1,1-dioxotetrahydro-2-thio-4-yl)oxy)benzene) Preparation of pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-073)
Figure imgf000055_0001
除了使用 1,1-二氧代四氢 -2/7-噻喃 -4-甲苯磺酰酯代替 2-甲磺酰基乙基对 甲苯磺酰酯之外，按照与实施例 65类似的方法制得化合物 2-(6-：(：6-(2,6-二甲 基 -4-((1,1-二氧代四氢 -2/7-噻喃 -4-基：)氧基：)苯基：)吡啶 -2-基：)氧：)亚甲基 )-2,3-二 氢苯并呋喃 -3-基）乙酸。 ^ NM (CDC13, 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz; 1H), 7.24(d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.95 (s, 1H), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.11 (s, 2H), 4.33 4.37 (m, 1H), 4.02 4.09 (m,lH), 3.82 3.89 (m,lH), 3.42 3.48(m, 4H), 2.61-2.67 (m, 1H), 2.42-2.47 (m, 3H), 2.11 2.19 (m, 2H), 2.08(s, 6H)。
Figure imgf000055_0001
A method similar to that of Example 65 was carried out except that 1,1-dioxotetrahydro-2/7-thiopyran-4-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. The compound 2-(6-:(:6-(2,6-dimethyl-4-((1,1-dioxotetrahydro-2/7-thiopyran-4-yl:)oxy): Phenyl:)pyridin-2-yl:)oxy:)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid. ^ NM (CDC1 3 , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz ; 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.95 (s, 1H), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.11 (s, 2H), 4.33 4.37 (m, 1H ), 4.02 4.09 (m, lH), 3.82 3.89 (m, lH), 3.42 3.48 (m, 4H), 2.61-2.67 (m, 1H), 2.42-2.47 (m, 3H), 2.11 2.19 (m, 2H) ), 2.08(s, 6H).
实施例 78: 2-(6-(((6-(4-((4-羟基 -1,1-二氧代四氢 -2H-噻哺 -4-基）甲氧 基) -2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合 物 HYH-074)的制备  Example 78: 2-(6-((6-(4-(4-hydroxy-1,1-dioxotetrahydro-2H-thyl-4-yl)methoxy)-2,6 -Dimethylphenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-074)
Figure imgf000055_0002
除了使用 (4-羟基 -1,1-二氧代四氢 -2/7-噻喃 -4-基)甲基甲苯磺酰酯代替 2- 甲磺酰基乙基对甲苯磺酰酯之外， 按照与实施例 65 类似的方法制得化合物 2-(6-(((6-(4-((4-羟基 -1,1-二氧代四氢 -2H-噻喃 -4-基）甲氧基 )-2,6-二甲基苯基) 吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋喃 -3-基）乙酸。 NM (CDC13, 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, 1H), 7.24(d, J = 8.0 Hz, 1H), 7.07 (d, J= 7.4 Hz, 1H), 6.95 (s, 1H), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.06 (s, 2H), 4.76 (t, J = 9.1 Hz, 1H), 4.29 (dd, J = 9.1, 6.0 Hz, 1H), 3.88 (s, 2H), 3.75 3.86 (m, IH), 3.43 3.56 (m, 2H), 2.90 3.01 (m, 2H), 2.76 2.85 (m, IH), 2.56 2.67 (m, IH), 2.17 2.33 (m, 4H), 2.06(s, 6H)。
Figure imgf000055_0002
In addition to (4-hydroxy-1,1-dioxotetrahydro-2/7-thiopyran-4-yl)methyltoluenesulfonyl ester instead of 2-methanesulfonylethyl p-toluenesulfonyl ester, The compound 2-(6-((6-(4-(4-hydroxy-1,1-dioxotetrahydro-2H-thiopyran-4-yl)) was obtained in a similar manner to Example 65. Oxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid. NM (CDC1 3 , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.95 ( s, 1H), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.06 (s, 2H), 4.76 (t, J = 9.1 Hz, 1H), 4.29 (dd, J = 9.1, 6.0 Hz, 1H), 3.88 (s, 2H), 3.75 3.86 (m, IH), 3.43 3.56 (m, 2H), 2.90 3.01 (m, 2H), 2.76 2.85 (m, IH), 2.56 2.67 (m, IH), 2.17 2.33 (m, 4H) , 2.06(s, 6H).
实施例 79： 2-(6-(((6-(2,6-二甲基 -4-(2- (吡咯烷 -1-基)乙氧基)苯基)吡啶 -2- 基)氧)亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-075)的制备  Example 79: 2-(6-((6-(2,6-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy) Preparation of methylene)-2,3-dihydrobenzofurazol-3-yl)acetic acid (compound HYH-075)
Figure imgf000056_0001
除了使用 2- (吡咯垸 -1-基)乙基甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺 酰酯之外， 按照与实施例 65 类似的方法制得化合物 2-(6-(：6-(2,6-二甲基 -4-(2- (吡咯垸 -1-基)乙氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋喃 -3- 基)乙酸。 ^ NM CDC OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz, 2H), 4.33-4.37 (m, IH), 4.02-4.09 (m,lH), 3.82-3.89 (m,lH), 2.61-2.72 (m, 3H), 2.46 2.55 (m, 5H), 2.06 (s, 6H), 1.66 - 1.73 (m, 4H)。
Figure imgf000056_0001
Compound 2-(6- was obtained in a similar manner to Example 65 except that 2-(pyrrole-1-yl)ethyltoluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. (6-(2,6-Dimethyl-4-(2-(pyrrole-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3- Dihydrobenzofuran-3-yl)acetic acid. ^ NM CDC OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH) ), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz, 2H ), 4.33-4.37 (m, IH), 4.02-4.09 (m, lH), 3.82-3.89 (m, lH), 2.61-2.72 (m, 3H), 2.46 2.55 (m, 5H), 2.06 (s, 6H), 1.66 - 1.73 (m, 4H).
实施例 80： 2-(6-(((6-(2,6-二甲基 -4-(2- (哌啶 -1-基)乙氧基)苯基)吡啶 -2-基) 氧)亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-076)的制备  Example 80: 2-(6-((6-(2,6-Dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy Preparation of methylene)-2,3-dihydrobenzofurazol-3-yl)acetic acid (compound HYH-076)
Figure imgf000056_0002
除了使用 2- (哌啶 -1-基)乙基甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯之外， 按照与实施例 65 类似的方法制得化合物 2-(6-：(：6-(2,6-二甲基 -4-(2- (哌啶 -1-基)乙氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋喃 -3-基) 乙酸。 ^ NM CDC OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz, 2H), 4.33 - 4.37 (m, 1H), 4.02 - 4.09 (m,lH), 3.82 - 3.89 (m,lH), 2.77(t, J = 7.2 Hz, 2H), 2.61 - 2.67 (m, 1H), 2.42 - 2.47 (m, 5H), 2.06 (s, 6H), 1.61 - 1.69 (m, 6H)。
Figure imgf000056_0002
Compound 2-(6- was prepared in a similar manner to Example 65 except that 2-(piperidin-1-yl)ethyltoluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. :(:6-(2,6-Dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3 -Dihydrobenzofuran-3-yl)acetic acid. ^ NM CDC OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH) ), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz, 2H ), 4.33 - 4.37 (m, 1H), 4.02 - 4.09 (m, lH), 3.82 - 3.89 (m, lH), 2.77 (t, J = 7.2 Hz, 2H), 2.61 - 2.67 (m, 1H), 2.42 - 2.47 (m , 5H), 2.06 (s, 6H), 1.61 - 1.69 (m, 6H).
实施例 81： 2-(6-(((6-(2,6-二甲基 -4-(2- (吗啡啉 -1-基)乙氧基)苯基)吡啶 -2- 基)氧)亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-077)的制备  Example 81: 2-(6-((6-(2,6-Dimethyl-4-(2-(morpholine-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy) Preparation of methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-077)
Figure imgf000057_0001
除了使用 2- (吗啡啉 -1-基)乙基甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺 酰酯之外， 按照与实施例 65 类似的方法制得化合物 2-(6-(：6-(2,6-二甲基 -4-(2- (吗啡啉 -1-基)乙氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋喃 -3- 基)乙酸。 ^ NM CDC OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, 1H), 7.24(d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.95 (s, 1H), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz, 2H), 4.33-4.37 (m, 1H), 4.02-4.09 (m, 1H), 3.82 3.89 (m, 1H), 3.65(t, J = 8.1 Hz, 4H): 2.77(t, J = 7.2 Hz, 2H), 2.61 - 2.67 (m, 1H), 2.41-2.47 (m, 5H), 2.08(s, 6H)。
Figure imgf000057_0001
Compound 2-(6- was obtained in a similar manner to Example 65 except that 2-(morpholinolin-1-yl)ethyltoluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. (:6-(2,6-Dimethyl-4-(2-(morpholine-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3- Dihydrobenzofuran-3-yl)acetic acid. ^ NM CDC OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.95 (s, 1H) ), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz, 2H ), 4.33-4.37 (m, 1H), 4.02-4.09 (m, 1H), 3.82 3.89 (m, 1H), 3.65 (t, J = 8.1 Hz, 4H) : 2.77 (t, J = 7.2 Hz, 2H ), 2.61 - 2.67 (m, 1H), 2.41-2.47 (m, 5H), 2.08 (s, 6H).
实施例 82： 2-(6-(((6-(2,6-二甲基 -4-(2- (哌嗪 -1-基)乙氧基)苯基)吡啶 -2-基) 氧)亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-078)的制备  Example 82: 2-(6-((6-(2,6-Dimethyl-4-(2-piperazin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy Preparation of methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound HYH-078)
Figure imgf000057_0002
除了使用 2- (哌嗪 -1-基)乙基甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯之外， 按照与实施例 65 类似的方法制得化合物 2-(6-：(：6-(2,6-二甲基 -4-(2- (哌嗪 -1-基)乙氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋喃 -3-基) 乙酸。 ^ NM CDC OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, 1H), 7.24(d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.95 (s, 1H), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz, 2H), 4.33-4.37 (m, 1H), 4.02-4.09 (m,lH), 3.82-3.89 (m,lH), 2.77(t, J = 7.2 Hz, 2H), 2.71(t, J = 8.1 Hz, 4H), 2.61-2.67 (m, 1H), 2.39-2.47 (m, 5H), 2.08(s, 6H)。
Figure imgf000057_0002
Compound 2-(6- was prepared in a similar manner to Example 65 except that 2-(piperazin-1-yl)ethyltoluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. :(:6-(2,6-Dimethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3 -Dihydrobenzofuran-3-yl)acetic acid. ^ NM CDC OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.95 (s, 1H) ), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz, 2H ), 4.33-4.37 (m, 1H), 4.02-4.09 (m, lH), 3.82-3.89 (m, lH), 2.77 (t, J = 7.2 Hz, 2H), 2.71 (t, J = 8.1 Hz, 4H), 2.61- 2.67 (m, 1H), 2.39-2.47 (m, 5H), 2.08(s, 6H).
实施例 83： 2-(6-(((6-(2,6-二甲基 -4-(2-(4-甲基哌嗪 -1-基)乙氧基)苯基)吡 啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋哺 -3-基)乙酸 (化合物 HYH-079)的制备  Example 83: 2-(6-((6-(2,6-Dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)pyridine-2 Of -oxy)methylene)-2,3-dihydrobenzofurazol-3-yl)acetic acid (compound HYH-079)
Figure imgf000058_0001
除了使用 2-(4-甲基哌嗪 -1-基：)乙基甲苯磺酰酯代替 2-甲磺酰基乙基对甲 苯磺酰酯之外，按照与实施例 65类似的方法制得化合物 2-(6-：(：6-(2,6-二甲基 -4-(2-(4-甲基哌嗪 -1-基)乙氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并呋喃 -3-基）乙酸。 NM (CDC13, 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, 1H), 7.24(d, J= 8.0 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.95 (s, 1H), 6.87(s, 2H), 6.76 (d J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz, 2H), 4.33-4.37 (m, 1H), 4.02-4.09 (m,lH), 3.82-3.89 (m,lH), 2.77(t, J = 7.2 Hz, 2H), 2.71(t, J = 8.1 Hz, 4H), 2.61-2.67 (m, 1H), 2.39-2.47 (m, 5H), 2.26 (s, 3H), 2.08(s; 6H)。
Figure imgf000058_0001
A compound was prepared in a similar manner to Example 65 except that 2-(4-methylpiperazin-1-yl:)ethyltoluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. 2-(6-:(:6-(2,6-Dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)pyridin-2-yl)oxy Methylene)-2,3-dihydrobenzofuran-3-yl)acetic acid. NM (CDC1 3 , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.95 ( s, 1H), 6.87(s, 2H), 6.76 (d J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz , 2H), 4.33-4.37 (m, 1H), 4.02-4.09 (m, lH), 3.82-3.89 (m, lH), 2.77 (t, J = 7.2 Hz, 2H), 2.71 (t, J = 8.1 Hz, 4H), 2.61-2.67 (m, 1H), 2.39-2.47 (m, 5H), 2.26 (s, 3H), 2.08 (s ; 6H).
实施例 84： 2-(6-(((6-(2,6-二甲基 -4-(2- (甲磺酰基)乙氧基)苯基)吡啶 -2-基) 氧)亚甲基 )-2,3-二氢苯并噻吩 -3-基)乙酸 (化合物 HYH-080)的制备  Example 84: 2-(6-((6-(2,6-Dimethyl-4-(2-(methylsulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)) Preparation of bis(2,3-dihydrobenzothiophen-3-yl)acetic acid (compound HYH-080)
Figure imgf000058_0002
歩骤 1 : 除了使用 3-甲硫基苄醇代替 3-甲氧基苄醇之外， 按照与实施例 64类似的方法制得化合物 2-(6- (溴甲基) -2,3-二氢苯并噻吩 -3-基)乙酸乙酯。
Figure imgf000058_0002
Step 1: The compound 2-(6-(bromomethyl)-2,3- was obtained in a similar manner to Example 64 except that 3-methylthiobenzyl alcohol was used instead of 3-methoxybenzyl alcohol. Ethyl dihydrobenzothiophen-3-yl).
歩骤 2: 除了使用 2-(6- (溴甲基) -2,3-二氢苯并噻吩 -3-基)乙酸乙酯代替 2-(6- (溴甲基) -2,3-二氢苯并呋喃 -3-基)乙酸乙酯之外， 按照与实施例 65 类似 的方法制得化合物 2-(6-(((6-(2,6-二甲基 -4-(2- (甲磺酰基)乙氧基)苯基)吡啶 -2- 基)氧)亚甲基 )-2,3-二氢苯并噻吩 -3-基)乙酸。 NMR (CDC13, 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 - 4.36 (m, IH), 4.11-4.19 (m, 3H), 3.92 - 3.99 (m, IH), 3.79 (q, J = 6.1 Hz, 2H), 2.97 (s, 3H), 2.61 - 2.67 (m, IH), 2.42 - 2.47 (m, IH), 2.08 (s, 6H)。 Step 2: In addition to 2-(6-(bromomethyl)-2,3-dihydrobenzothiophen-3-yl)acetate, 2-(6-(bromomethyl)-2,3- In the same manner as in Example 65, the compound 2-(6-(2-(2,6-dimethyl-4-(2)) - (Methanesulfonyl)ethoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzothiophen-3-yl)acetic acid. NMR (CDC1 3 , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87 (s, 2H) ), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 - 4.36 (m, IH), 4.11-4.19 (m, 3H) , 3.92 - 3.99 (m, IH), 3.79 (q, J = 6.1 Hz, 2H), 2.97 (s, 3H), 2.61 - 2.67 (m, IH), 2.42 - 2.47 (m, IH), 2.08 (s , 6H).
实施例 85： 2-(6-(((6-(2,6-二甲基 -4-(3- (甲磺酰基)丙氧基)苯基)吡啶 -2-基) 氧)亚甲基 )-2,3-二氢苯噻吩 -3-基)乙酸 (化合物 HYH-081)的制备  Example 85: 2-(6-((6-(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)) Preparation of bis(2,3-dihydrophenylthiophen-3-yl)acetic acid (compound HYH-081)
Figure imgf000059_0001
除了使用 3-甲磺酰基丙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯之外， 按照与实施例 84 类似的方法制得化合物 2-(6-：(：6-(2,6-二甲基 -4-(3- (甲磺酰基)丙氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并噻吩 -3-基) 乙酸。 ^ NM CDC ^OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 - 4.37 (m, IH), 4.11-4.19 (m, 3H), 3.92 - 3.99 (m, IH), 3.23 - 3.31 (m, 2H), 2.97 (s, 3H), 2.61 - 2.67 (m, IH), 2.42 - 2.47 (m, IH), 2.29 - 2.35 (m, 2H), 2.08 (s, 6H)。
Figure imgf000059_0001
A compound 2-(6-:(:6) was obtained in a similar manner to Example 84 except that 3-methanesulfonylpropyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. -(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzothiophene- 3-based) acetic acid. ^ NM CDC ^OO MHz^: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 - 4.37 (m, IH), 4.11-4.19 (m, 3H), 3.92 - 3.99 (m, IH), 3.23 - 3.31 (m, 2H), 2.97 (s, 3H), 2.61 - 2.67 (m, IH), 2.42 - 2.47 (m, IH ), 2.29 - 2.35 (m, 2H), 2.08 (s, 6H).
实施例 86： 2-(6-(((6-(2,6-二甲基 -4-(4- (甲磺酰基)丁氧基)苯基)吡啶 -2-基) 氧)亚甲基 )-2,3-二氢苯并噻吩 -3-基)乙酸 (化合物 HYH-082)的制备  Example 86: 2-(6-((6-(2,6-Dimethyl-4-(4-(methylsulfonyl)butoxy)phenyl)pyridin-2-yl)oxy)) Preparation of bis(2,3-dihydrobenzothiophen-3-yl)acetic acid (compound HYH-082)
Figure imgf000059_0002
除了使用 4-甲磺酰基丁基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯之外， 按照与实施例 84 类似的方法制得化合物 2-(6-：(：6-(2,6-二甲基 -4-(4- (甲磺酰基)丁氧基)苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯噻吩 -3-基)乙 酸。 NM (CDC13, 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 - 4.37 (m, IH), 4.11 - 4.19(m, 3H), 3.92 - 3.99 (m, IH), 3.23 - 3.31 (m, 2H), 2.97 (s, 3H), 2.61 - 2.67 (m, IH), 2.42 - 2.47 (m, IH), 2.08 (s, 6H), 1.67 - 1.85 (m, 4H)。
Figure imgf000059_0002
A compound 2-(6-:(:6) was obtained in a similar manner to Example 84 except that 4-methanesulfonylbutyl p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. -(2,6-Dimethyl-4-(4-(methylsulfonyl)butoxy)phenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrophenylthiophene-3 -based) acetic acid. NM (CDC1 3 , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 ( s, IH), 6.87 (s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.33 - 4.37 (m, IH), 4.11 - 4.19(m, 3H), 3.92 - 3.99 (m, IH), 3.23 - 3.31 (m, 2H), 2.97 (s, 3H), 2.61 - 2.67 (m, IH), 2.42 - 2.47 (m, IH), 2.08 (s, 6H), 1.67 - 1.85 (m, 4H).
实施例 87： 2-(6-(((6-(4-(2- (二甲氨基)乙氧基 )-2,6-二甲基苯基)吡啶 -2-基) 氧)亚甲基 )-2,3-二氢苯并 [b】噻吩 -3-基)乙酸 (化合物 HYH-083)的制备  Example 87: 2-(6-((6-(4-(2-(Dimethylamino)ethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy) Preparation of 2,3-dihydrobenzo[b]thiophen-3-yl)acetic acid (compound HYH-083)
Figure imgf000060_0001
除了使用 2-二甲氨基乙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯之外， 按照与实施例 84类似的方法制得化合物 2-(6- X6- K2- (二甲氨基:) 乙氧基 )-2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并噻吩 -3-基)乙酸。 JH NM (CDC13, 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz, 2H), 4.39-4.47 (m, IH), 4.12 - 4.19 (m, 2H), 2.85(s, 6H), 2.77(t, J = 7.2 Hz, 2H), 2.61-2.67 (m, IH), 2.42-2.47 (m, IH), 2.08(s, 6H)。
Figure imgf000060_0001
The compound 2-(6-X6-K2- was obtained in a similar manner to Example 84 except that 2-dimethylaminoethyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. (Dimethylamino:)ethoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzothiophen-3-yl)acetic acid. J H NM (CDC1 3 , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz, 2H), 4.39-4.47 (m, IH), 4.12 - 4.19 (m, 2H), 2.85(s, 6H), 2.77(t, J = 7.2 Hz, 2H), 2.61-2.67 (m, IH), 2.42-2.47 (m, IH), 2.08 (s, 6H).
实施例 88： 2-(6-(((6-(4-(3- (二甲氨基)丙氧基 )-2,6-二甲基苯基)吡啶 -2-基) 氧)亚甲基 )-2,3-二氢苯并噻吩 -3-基)乙酸 (化合物 HYH-084)的制备  Example 88: 2-(6-((6-(4-(3-(Dimethylamino)propoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)) Preparation of bis(2,3-dihydrobenzothiophen-3-yl)acetic acid (compound HYH-084)
Figure imgf000060_0002
除了使用 3-二甲氨基丙基对甲苯磺酰酯代替 2-甲磺酰基乙基对甲苯磺酰 酯之外， 按照与实施例 84类似的方法制得化合物 2-(6- X6- K3- (二甲氨基:) 丙氧基 )-2,6-二甲基苯基)吡啶 -2-基)氧)亚甲基 )-2,3-二氢苯并噻吩 -3-基)乙酸。 JH NMR (CDC13, 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24(d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz, 2H), 4.39-4.47 (m, IH), 4.12-4.19 (m, 2H), 2.85(s, 6H), 2.69 (t, J = 7.6 Hz, 2H), 2.61-2.67 (m, 1H), 2.42-2.47 (m, 1H), 2.08(s, 6H), 1.79 (q, J= 7.2 Hz, 2H)。
Figure imgf000060_0002
The compound 2-(6-X6-K3- was obtained in a similar manner to Example 84 except that 3-dimethylaminopropyl-p-toluenesulfonyl ester was used instead of 2-methanesulfonylethyl p-toluenesulfonyl ester. (Dimethylamino:)propoxy)-2,6-dimethylphenyl)pyridin-2-yl)oxy)methylene)-2,3-dihydrobenzothiophen-3-yl)acetic acid. J H NMR (CDC1 3 , 400 MHz) δ: 7.41 (dd, J = 15.1, 7.5 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 7.07 (d, J = 7.4 Hz, IH), 6.95 (s, IH), 6.87(s, 2H), 6.76 (d, J = 8.0 Hz, IH), 6.72 (d, J = 8.2 Hz, IH), 5.11 (s, 2H), 4.79(t, J = 7.2 Hz, 2H), 4.39-4.47 (m, IH), 4.12-4.19 (m, 2H), 2.85(s, 6H), 2.69 (t, J = 7.6 Hz, 2H), 2.61-2.67 (m, 1H), 2.42-2.47 (m, 1H), 2.08(s, 6H), 1.79 (q, J = 7.2 Hz, 2H).
实施例 89 3-(4-(((6-(4-三氟甲基 -2-甲基苯基)吡啶 -2-基)氧)亚甲基 )-2- 氟 HYH-085)的制备  Example 89 Preparation of 3-(4-((6-(4-trifluoromethyl-2-methylphenyl)pyridin-2-yl)oxy)methylene)-2-fluoroHYH-085)
Figure imgf000061_0001
Figure imgf000061_0001
除了使用 4-三氟甲基 -2-甲基苯硼酸代替苯硼酸， 以及使用 3-(4-(：6-溴 吡啶 -2-基)氧)亚甲基 )-2-氟苯基)丙酸乙酯代替 3-(4-(((6-溴吡啶 -2-基)氧)亚甲 基)苯基)丙酸乙酯之外， 按照与实施例 4类似的方法制得化合物 3-(4-(：6-(4- 三氟甲基苯基)吡啶 -2-基)氧基)亚甲基 )-2-氟苯基)丙酸。 NM (400 MHz, CDC13) δ =8.18 (d, J = 8.2 Hz, 2H), 7.94 -7.90 (m, 2H), 7.69 -7.61 (m, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.31 (dd, J = 7.4, 0.6 Hz, 1H), 7.01 (s, 1H), 6.81 (dd, J = 8.2, 0.6 Hz, 1H), 5.48 (s, 2H), 2.97 (t, J = 7.7 Hz, 2H), 2.73 .66 (m, 2H)。 In addition to using 4-trifluoromethyl-2-methylbenzeneboronic acid instead of phenylboronic acid, and using 3-(4-(:6-bromopyridin-2-yl)oxy)methylene)-2-fluorophenyl) Compound 3 was obtained in the same manner as in Example 4 except that ethyl propionate was used instead of ethyl 3-(4-((6-bromopyridin-2-yl)oxy)methylene)phenyl)propanoate. -(4-(:6-(4-Trifluoromethylphenyl)pyridin-2-yl)oxy)methylene)-2-fluorophenyl)propanoic acid. NM (400 MHz, CDC1 3 ) δ =8.18 (d, J = 8.2 Hz, 2H), 7.94 -7.90 (m, 2H), 7.69 -7.61 (m, 2H), 7.40 (d, J = 8.2 Hz, 1H ), 7.31 (dd, J = 7.4, 0.6 Hz, 1H), 7.01 (s, 1H), 6.81 (dd, J = 8.2, 0.6 Hz, 1H), 5.48 (s, 2H), 2.97 (t, J = 7.7 Hz, 2H), 2.73.66 (m, 2H).
实施例 90：化合物对稳定转染人源 GPR40的 HEK293细胞株激动活性 的筛选  Example 90: Screening of compounds for agonistic activity of HEK293 cell line stably transfected with human GPR40
HEK293细胞， 转染真核表达载体人源 GPR40-pCDNA3.1， 经筛选获得 稳定表达人源 GPR40的单克隆细胞株。 稳定转染人源 GPR40的 HEK293细 胞株， 培养于含 10% FBS的高糖 DMEM培养液。 实验前一天将细胞接种于 96孔细胞培养板，每孔 25000个细胞。实验当天，配制 Fluo-8工作液（Hank's 平衡盐溶液含 Fluo-82 μΜ，丙磺舒 2 mM，酒石黄 1.5 mM, 酸性红 1 4 mM)。 弃细胞培养液后加入 Fluo-8工作液， 100 μΐ,每孔， 37 °C 5% C02孵育 1小时。 待测化合物的 DMSO储备液以 Hank's平衡盐溶液稀释 200倍置于 96孔样品 板。 阳性对照化合物为终浓度为 10 μΜ 的 ΤΑΚ-875, 空白对照为含 0.1% DMSO的 Hank's平衡盐溶液。 将孵育完成的细胞板、 样品板放于 Flexstation 多功能酶标仪工作站，设置加药 25 每孔，检测加药后细胞内钙离子信号。 钙离子信号取 MAX-MIN转化为原始数据， 根据如下公式计算效率％。 应用 GraphPad Prism软件计算化合物的 EC5() HEK293 cells were transfected into eukaryotic expression vector human GPR40-pCDNA3.1, and a monoclonal cell strain stably expressing human GPR40 was obtained by screening. The HEK293 cell line stably transfected with human GPR40 was cultured in a high glucose DMEM medium containing 10% FBS. One day before the experiment, the cells were seeded in 96-well cell culture plates at 25,000 cells per well. On the day of the experiment, the Fluo-8 working solution was prepared (Hank's balanced salt solution containing Fluo-82 μΜ, probenecid 2 mM, tartrazine 1.5 mM, acid red 14 mM). After discarding the cell culture medium, add Fluo-8 working solution, 100 μM, and incubate for 1 hour at 37 ° C 5% C0 2 per well. The DMSO stock solution of the test compound was diluted 200-fold with Hank's balanced salt solution and placed in a 96-well sample plate. The positive control compound was ΤΑΚ-875 at a final concentration of 10 μΜ, and the blank control was Hank's balanced salt solution containing 0.1% DMSO. The well-incubated cell plates and sample plates were placed on a Flexstation multi-function microplate reader workstation, and the dosing 25 per well was set to detect the intracellular calcium signal after dosing. The calcium ion signal is converted to the original data by MAX-MIN, and the efficiency % is calculated according to the following formula. Calculation of compound EC 5() using GraphPad Prism software
效率％ = [值 (∞ d)-值 (BC)]/ [值 (PC)-值 (BC)]xl00% Efficiency% = [value (∞ d) - value (BC) ] / [value (PC) - value (BC) ] xl00%
Compound, 受试化合物； BC, 空白对照； PC, 阳性对照 TAK-875 结果如表 1所示。 Compound, test compound; BC, blank control; PC, positive control TAK-875 The results are shown in Table 1.
表 1、 本申请化合物对人源 GPR40的 HEK293细胞株的激动活性Table 1. Agonistic activity of the compound of the present application on HEK293 cell line of human GPR40
Figure imgf000062_0001
19
Figure imgf000062_0001
19
Figure imgf000063_0001
Figure imgf000063_0001
SLO/ lOZ l3/13d J869I/ 0Z OAV HYH-063 <0.1 >100% SLO/ lOZ l3/13d J869I/ 0Z OAV HYH-063 <0.1 >100%
HYH-064 <0.1 >100%  HYH-064 <0.1 >100%
HYH-065 <0.05 >100%  HYH-065 <0.05 >100%
HYH-066 <0.05 >100%  HYH-066 <0.05 >100%
HYH-067 <0.1 >100%  HYH-067 <0.1 >100%
HYH-068 <0.1 >100%  HYH-068 <0.1 >100%
HYH-069 <0.1 >100%  HYH-069 <0.1 >100%
HYH-070 <0.1 >100%  HYH-070 <0.1 >100%
HYH-071 <0.1 >100%  HYH-071 <0.1 >100%
HYH-072 <0.1 >100%  HYH-072 <0.1 >100%
HYH-073 <0.05 >100%  HYH-073 <0.05 >100%
HYH-074 <0.05 >100%  HYH-074 <0.05 >100%
HYH-075 <0.1 >100%  HYH-075 <0.1 >100%
HYH-076 <0.1 >100%  HYH-076 <0.1 >100%
HYH-077 <0.1 >100%  HYH-077 <0.1 >100%
HYH-078 <0.1 >100%  HYH-078 <0.1 >100%
HYH-079 <0.1 >100%  HYH-079 <0.1 >100%
HYH-080 <0.1 >90%  HYH-080 <0.1 >90%
HYH-081 <0.5 >90%  HYH-081 <0.5 >90%
HYH-082 <0.5 >90%  HYH-082 <0.5 >90%
HYH-083 <0.5 >90%  HYH-083 <0.5 >90%
HYH-084 <0.5 >90%  HYH-084 <0.5 >90%
HYH-085 <0.1 >100%  HYH-085 <0.1 >100%
实施例 91: 化合物对 II型糖尿病 ob/ob小鼠的降血糖作用  Example 91: Hypoglycemic effect of compounds on type II diabetes ob/ob mice
雄性遗传型自发性 II型糖尿病 ob/ob小鼠饲养于 SPF级动物房中 (温度: 22-24°C , 湿度： 45-80%， 光照： 150-300Lx， 12小时昼夜交替)， 小鼠 6-7 周龄时预测随机血糖、 空腹血糖和体重， 根据这些指标将 ob/ob小鼠分为 3 组， 每组 8只， 分别口服给与 100mg/kg 受试化合物 HYH-013、 100 mg/kg 阳性对照 TAK875 , 对照组口服给与 0.5%CMC， 于给药前和给药后 lh、 2h、 4h、 6h和 8h测定血糖值， 观察 HYH-013对 II型糖尿病 ob/ob小鼠的降血糖 作用。 Male genetic type spontaneous type 2 diabetes ob/ob mice were housed in SPF animal rooms (temperature: 22-24 ° C, humidity: 45-80%, light: 150-300 Lx, 12 hours day and night), mice 6-7 weeks old prediction random blood glucose, fasting blood glucose and body weight, based on these indicators will ob / ob mice were divided into 3 groups, 8 per group, were orally administered 100m g / kg of the test compound HYH-013, 100 The mg/kg positive control was TAK875, and the control group was orally administered with 0.5% CMC. The blood glucose level was measured before administration and at 1h, 2h, 4h, 6h and 8h after administration. HYH-013 was observed for type II diabetes ob/ob mice. Hypoglycemic effect.
结果如表 2和图 1所示， 对照组 ob/ob小鼠给药前和给药后血糖均维持 在较高的水平， 100mg/kg HYH-013单次口服给药可显著降低 ob/ob小鼠血糖。 给药后 lh， HYH-013 小鼠血糖显著低于对照组 （P<0.01 )， 血糖下降率为 22.3%, 而阳性对照 TAK-875 组血糖与对照组相比无显著下降； 给药后 2h 和 4h时， HYH-013组小鼠血糖仍显著低于对照组 （PO.05 ) ，血糖下降率分 别为 26.3%和 23.4%， 而此时阳性对照 TAK875组小鼠血糖也出现一定程度 的下降 （P=0.09)， 血糖下降率分别为 27.9%和 23.3%； 给药后 6h和 8h时， HYH-013组小鼠血糖仍然显著低于对照组（P<0.05， P<0.01 )， 血糖下降率分 别为 24.7%和 26.8%， 而阳性对照 TAK875组小鼠血糖与对照组相比已无明 显下降。 由此提示， HYH-013对 2型糖尿病 ob/ob小鼠具有显著的降血糖作 用， 其作用维持时间长于 TAK875。 The results are shown in Table 2 and Figure 1. The blood glucose of the control ob/ob mice was maintained at a high level before and after administration, and single oral administration of 100 mg/kg HYH-013 significantly reduced ob/ob. Mouse blood sugar. At 1 h after administration, the blood glucose of HYH-013 mice was significantly lower than that of the control group (P<0.01), and the blood glucose decline rate was 22.3%. However, the blood glucose of the positive control TAK-875 group did not decrease significantly compared with the control group; 2 h after administration At 4h, the blood glucose of HYH-013 group was significantly lower than that of the control group (PO.05), and the blood glucose decline rate was 26.3% and 23.4%, respectively. At this time, the blood glucose of the positive control TAK875 group also showed a certain degree of decline. (P=0.09), the blood glucose decline rate was 27.9% and 23.3%, respectively. At 6h and 8h after administration, the blood glucose of HYH-013 group was still significantly lower than that of the control group (P<0.05, P<0.01), and the blood glucose decreased. The rates were 24.7% and 26.8%, respectively, while the blood glucose of the positive control TAK875 group had no significant decrease compared with the control group. This suggests that HYH-013 has a significant hypoglycemic effect on type 2 diabetic ob/ob mice, and its effect lasts longer than TAK875.
表 2: HYH-013单次给药对 ob/ob小鼠血糖的影响 (mM， X+s , n=8)  Table 2: Effect of single administration of HYH-013 on blood glucose in ob/ob mice (mM, X+s, n=8)
Figure imgf000065_0001
Figure imgf000065_0001
*， P<0.05, 与对照组相比； **， P<0.01， 与对照组相比。  *, P < 0.05, compared with the control group; **, P < 0.01, compared with the control group.
以上是针对本发明的可行实施例具体说明， 但该实施例并非用以限制本 发明的专利范围， 凡未脱离本发明技艺精神所为的等效实施或变更， 均应包 含于本发明的专利范围中。  The above is a detailed description of the possible embodiments of the present invention, but the embodiments are not intended to limit the scope of the invention, and equivalents or modifications that are not included in the spirit of the invention are included in the invention. In the scope.

Claims

权 利 要 求 Rights request
1、 一种如下通式 I所示的苯丙酸类化合物， 或其药物学上可接受的盐、 立体异构体或其前药 1. A phenylpropionic acid compound represented by the following general formula I, or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof
Figure imgf000066_0001
其中，
Figure imgf000066_0001
in,
为11、 D或 F; is 11, D or F;
R n R2各自独立选自 Η、 羟基、 卤素、 硝基、 d-C^垸基、 卤代 d-C^ 垸基、 d-C^垸氧基、 卤代 d-C^垸氧基、 C3-C1()环垸基和含有选自 S、 0和 N中的 1至 3个杂原子的 3至 10元杂环基； R n R 2 is each independently selected from H, hydroxyl, halogen, nitro, dC alkyl, halogenated dC alkyl, dC alkyloxy, halogenated dC alkyloxy, C 3 -C 1() Cycloalkyl and 3 to 10-membered heterocyclyl containing 1 to 3 heteroatoms selected from S, O and N;
R3选自 H;卤素；羧基； CrC2()垸基；卤代 CrC2()垸基； -O a; -N( a)S02 b, -NRa b; -N( a)C(0) b; -C(0)NRa b; -S02 a; -S b; 用选自 C d。垸氧基、 C3-C1()环垸基、 -SRe、 -S02Re、 -NReRd或未取代或者被 CrC6垸基、 羟基或氧 代基团取代的含有选自 0、 S和 N中的 1~3个杂原子的 3-8元杂环基中的取 代基取代的 CrC^垸氧基； 和用 d-do垸氧基、 C3-C1()环垸基、 -SRe、 -S02 c 或 -NReRd取代的 CrC2。垸基； 和 Rb各自独立选自 H、CrC6垸基、 C3-C8环垸基和未取代或者被 CrC6 垸基或氧代基团取代的含有选自 0、 S和 N中的 1~3个杂原子的 3-8元杂环 基； R 3 is selected from H; halogen; carboxyl; C r C 2 () alkyl; halogenated C r C 2 () alkyl; -O a ; -N( a )S0 2 b , -NR ab; -N( a )C(0) b ; -C(0)NR ab ; -S0 2 a ; -S b ; Use selected from C d. Alkyloxy, C 3 -C 1() cycloalkyl, -SR e , -S0 2 R e , -NR e R d or unsubstituted or substituted by C r C 6 alkyl, hydroxyl or oxo group CrC^ alkyloxy group substituted with a substituent in a 3-8-membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S and N; and using d-do alkyloxy group, C 3 -C 1 () Cycloalkyl, -SR e , -S0 2 c or -NR e R d substituted C r C 2 . Alkyl; and R b are each independently selected from H, C r C 6 alkyl, C 3 -C 8 cycloalkyl and unsubstituted or substituted by C r C 6 alkyl or oxo group containing selected from 0, 3-8 membered heterocyclic groups with 1 to 3 heteroatoms in S and N;
Rc和 Rd各自独立地选自 H、 CrC6垸基和未取代或者被 (^- 3垸基取代 的含有选自 0、 S和 N中的 1~3个杂原子的 3-8元杂环基； R c and R d are each independently selected from H, C r C alkyl group and unsubstituted or substituted by C alkyl group containing 1 to 3 heteroatoms selected from O, S and N. 8-membered heterocyclyl;
R4选自 H、 羟基、 卤素、 d-C^垸基和卤代 d-C^垸基； R 4 is selected from H, hydroxyl, halogen, dC alkyl and halogenated dC alkyl;
R5选自 H、 卤素和 d-C^垸基； R 5 is selected from H, halogen and dC alkyl;
或者 R4和 连同和其相连的碳原子与苯环一起形成苯并 5-8元杂环基， 所述杂环上含有选自 0、 N和 S中的 1~3个杂原子， 且所述杂环基未被取代 或者被 CrC6垸基取代。 Or R 4 together with the carbon atom connected to it and the benzene ring form a benzo 5-8 membered heterocyclic group, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, N and S, and the The heterocyclyl group is unsubstituted or substituted by C r C 6 alkyl group.
2、根据权利要求 1所述的苯丙酸类化合物、其药物学上可接受的盐、立 体异构体或其前药分子， 其中， 2. The phenylpropionic acid compound, its pharmaceutically acceptable salt, stereoisomer or its prodrug molecule according to claim 1, wherein,
为11、 D或 F; is 11, D or F;
1^和 各自独立选自 H、 羟基、 卤素、 硝基、 CrC6垸基、 卤代 CrC6 垸基、 CrC6垸氧基、 卤代 CrC6垸氧基、 C3-C8环垸基和含有至少一个氮原 子的 3至 10元杂环基； R and R are each independently selected from H, hydroxyl, halogen, nitro, C r C 6 alkyl, halogenated C r C 6 alkyl, C r C 6 alkyloxy, halogenated C r C 6 alkyloxy, C 3 -C 8 cycloalkyl and 3 to 10 membered heterocyclic groups containing at least one nitrogen atom;
R3选自 H;卤素；羧基； CrC6垸基；卤代 CrC6垸基； -O a; -N( a)S02 b; -NRa b; -N( a)C(0) b; -C(0)NRa b; -S02 a; -S b; 用选自 d-C4垸氧基、 C3-C8环垸基、 -SRe、 -S02Re、 -NReRd或未取代或者被 CrC4垸基、 羟基或氧 代基团取代的含有选自 0、 S和 N中的 1~3个杂原子的 3-6元杂环基中的取 代基取代的 CrC6垸氧基； 和用 CrC4垸氧基、 C3-C8环垸基、 -SRe、 -S02 c 或 -NReRd取代的 CrC6垸基； R 3 is selected from H; halogen; carboxyl; C r C 6 alkyl; halogenated C r C 6 alkyl; -O a ; -N( a )S0 2 b ; -NR ab ; -N( a )C( 0) b ; -C(0)NR ab ; -S0 2 a ; -S b ; Use selected from dC 4 alkoxy group, C 3 -C 8 cycloalkyl group, -SR e , -S0 2 R e , - NR e R d is either unsubstituted or substituted by C r C 4 alkyl, hydroxyl or oxo group in a 3-6 membered heterocyclic group containing 1 to 3 heteroatoms selected from O, S and N. C r C 6 alkyloxy substituted by substituents; and C r C substituted with C r C 4 alkoxy, C 3 -C 8 cycloalkyl, -SR e , -S0 2 c or -NR e R d 6 foundation;
R4选自 H、 羟基、 卤素、 CrC6垸基和卤代 CrC6垸基; R 4 is selected from H, hydroxyl, halogen, C r C 6 alkyl and halogenated C r C 6 alkyl;
R5选自 H、 卤素和 CrC6垸基； R 5 is selected from H, halogen and C r C 6 alkyl;
或者 R4和 连同和其相连的碳原子与苯环一起形成苯并 5元杂环基， 该 5元杂环基含有选自 0、N和 S中的 1~2个杂原子，且未被取代或者被 d-C3 垸基取代。 Or R 4 together with the carbon atom connected to it and the benzene ring form a benzo 5-membered heterocyclic group. The 5-membered heterocyclic group contains 1 to 2 heteroatoms selected from 0, N and S, and is not Substituted or substituted by dC 3 alkyl.
3、根据权利要求 1所述的苯丙酸类化合物、其药物学上可接受的盐、立 体异构体或其前药分子， 其中， 3. The phenylpropionic acid compound, its pharmaceutically acceptable salt, stereoisomer or its prodrug molecule according to claim 1, wherein,
为11、 D或 F; is 11, D or F;
1^和 各自独立选自 H、 羟基、 卤素、 硝基、 CrC4垸基、 卤代 CrC4 垸基、 CrC4垸氧基、 卤代 CrC4垸氧基、 C3-C8环垸基和氮杂环丙垸 -1-基； R and R are each independently selected from H, hydroxyl, halogen, nitro, C r C 4 alkyl group, halogenated C r C 4 alkyl group, C r C 4 alkoxy group, halogenated C r C 4 alkyl oxygen group, C 3 -C 8 cycloalkyl and aziridin-1-yl;
R3选自 H;卤素；羧基； CrC6垸基；卤代 CrC6垸基； -O a; -N( a)S02 b; -NRa b; -N( a)C(0) b; -C(0)NRa b; -S02 a; -S b; 用选自 d-C4垸氧基、 C3-C6环垸基、 -SRe、 -S02Re、 -NReRd、 或未取代或者被 CrC4垸基、 羟基或 氧代基团取代的含有选自 0、 S和 N中的 1~3个杂原子的 3-6元杂环基中的 取代基取代的 CrC4垸氧基； 和用 CrC4垸氧基、 C3-C6环垸基、 -SRe、 S02 c 或 NReRd取代的 CrC4垸基； R 3 is selected from H; halogen; carboxyl; C r C 6 alkyl; halogenated C r C 6 alkyl; -O a ; -N( a )S0 2 b ; -NR ab ; -N( a )C( 0) b ; -C(0)NR ab ; -S0 2 a ; -S b ; Use selected from dC 4 alkoxy group, C 3 -C 6 cycloalkyl group, -SR e , -S0 2 R e , - NR e R d , or a 3-6 membered heterocyclic group containing 1 to 3 heteroatoms selected from 0, S and N, which is either unsubstituted or substituted by C r C 4 alkyl group, hydroxyl group or oxo group. C r C 4 alkoxy substituted with a substituent; and C r C 4 substituted with C r C 4 alkoxy, C 3 -C 6 cycloalkyl, -SR e , S0 2 c or NR e R d base;
和 Rb各自独立选自 H、CrC4垸基、 C3-C6环垸基和未取代或者被 CrC3 垸基或氧代基团取代的含有选自 0、 S和 N中的 1~3个杂原子的 3-6元杂环 基； Rc和 Rd各自独立地选自 H、 CrC3垸基和未取代或者被 (^- 3垸基取代 的含有选自 0、 S和 N中的 1~3个杂原子的 3-6元杂环基； and R b are each independently selected from H, C r C 4 alkyl, C 3 -C 6 cycloalkyl and unsubstituted or substituted by C r C 3 alkyl or oxo group containing selected from O, S and N A 3-6 membered heterocyclic group with 1 to 3 heteroatoms in it; R c and R d are each independently selected from H, C r C alkyl group and unsubstituted or substituted by C alkyl group containing 1 to 3 heteroatoms selected from O, S and N. 6-membered heterocyclyl;
R4和 R5连同和其相连的碳原子与苯环一起形
Figure imgf000068_0001
R 4 and R 5 together with the carbon atoms connected to them form a benzene ring
Figure imgf000068_0001
Figure imgf000068_0002
Figure imgf000068_0002
4、根据权利要求 1所述的苯丙酸类化合物、其药物学上可接受的盐、立 体异构体或其前药分子， 其中， 其具有下通式 II或通式 III所示的结构： 4. The phenylpropionic acid compound, its pharmaceutically acceptable salt, stereoisomer or its prodrug molecule according to claim 1, wherein it has a structure represented by the following general formula II or general formula III :
Figure imgf000068_0003
其中， X、 〜 的定义与上权利要求 1中的定义相同；
Figure imgf000068_0003
Wherein, the definitions of X and ~ are the same as those in claim 1;
以及在通式 III中， Z为 N时， R6为 H或 CrC6垸基； 当 Z为 0或 S时， And in general formula III, when Z is N, R 6 is H or C r C 6 alkyl; when Z is 0 or S,
R6不存在。 R 6 does not exist.
5、根据权利要求 1所述的苯丙酸类化合物、其药物学上可接受的盐、立 5. The phenylpropionic acid compound according to claim 1, its pharmaceutically acceptable salts, and
Figure imgf000068_0004
Figure imgf000068_0004
Figure imgf000069_0001
Figure imgf000069_0001
99f^LOinOZKDIL3d 91/濯 OAV 99f^LOinOZKDIL3d 91/涯OAV
Figure imgf000070_0001
t^LQItlQZK3I 3d .1869Ϊ/Μ0Ζ OAV OL
Figure imgf000070_0001
t^LQItlQZK3I 3d .1869Ϊ/Μ0Ζ OAV OL
Figure imgf000071_0001
Figure imgf000071_0001
99t'S.0/t'lOZN3/X3d ■Ϊ869ΐ/ 0ί ΟΛ\ 99t'S.0/t'lOZN3/X3d ■Ϊ869ΐ/ 0ί ΟΛ\
Figure imgf000072_0001
Figure imgf000072_0001
99^£.0/ίΊ0ίΝ3/Χ3<Ι ZL 99^£.0/ίΊ0ίΝ3/Χ3<Ι ZL
Figure imgf000073_0001
Figure imgf000073_0001
99t7S.0/M0ZN3/X3d J869I/ 0Z OAV 99t7S.0/M0ZN3/X3d J869I/ 0Z OAV
6、根据权利要求 1所述的苯丙酸类化合物、其药物学上可接受的盐、立 体异构体或其前药分子， 所述药学上可接受的盐为通式 I所示的化合物与磷 酸、 硫酸、 盐酸、 醋酸、 酒石酸、 柠檬酸、 苹果酸、 富马酸、 天冬氨酸或谷 氨酸形成的盐， 或与所述酸成酯或酰胺后再与无机碱形成的盐。 6. The phenylpropionic acid compound, its pharmaceutically acceptable salt, stereoisomer or its prodrug molecule according to claim 1, wherein the pharmaceutically acceptable salt is a compound represented by general formula I Salts formed with phosphoric acid, sulfuric acid, hydrochloric acid, acetic acid, tartaric acid, citric acid, malic acid, fumaric acid, aspartic acid or glutamic acid, or salts formed with inorganic bases after forming esters or amides with the acids .
7、一种制备权利要求 1所述的苯丙酸类化合物的方法，其由如下方法之 7. A method for preparing the phenylpropionic acid compound according to claim 1, which consists of:
" ~~ *制备： " ~~ *Preparation:
一： 如下面反应式 1所示： 1: As shown in the following reaction equation 1:
Figure imgf000074_0001
Figure imgf000074_0001
反应式 1 Reaction 1
歩骤 1： 将 R4取代的对溴苄醇 1和丙烯酸乙酯 2经过 Heck反应得到中 间体 3，将双键还原得到中间体 4，再经过溴化反应把苄醇变成苄溴得到中间 体 5; Step 1: Perform Heck reaction between R 4 -substituted p-bromobenzyl alcohol 1 and ethyl acrylate 2 to obtain intermediate 3, reduce the double bond to obtain intermediate 4, and then undergo bromination reaction to convert benzyl alcohol into benzyl bromide to obtain intermediate Body 5;
歩骤 2: 将中间体 5和底物 6经过亲核取代反应得到中间体 7; Step 2: Perform nucleophilic substitution reaction between intermediate 5 and substrate 6 to obtain intermediate 7;
^骤 3 : 中间体
Figure imgf000074_0002
经过 Suzuki反应偶联得到中间体 8， 再将中间体 8经过水解反应得到产物 9;
Figure imgf000075_0001
^Step 3: Intermediates
Figure imgf000074_0002
Intermediate 8 is obtained through Suzuki reaction coupling, and then intermediate 8 is hydrolyzed to obtain product 9;
Figure imgf000075_0001
Figure imgf000075_0002
反应式 2
Figure imgf000075_0002
Reaction 2
歩骤 1 : 化合物 17或 20和底物 6经过亲核取代反应得到化合物 21， 其 中化合物 17中， Z为 0或 S， R6不存在； 以及化合物 20中， Z为 N， R6为 H或 CrC6垸基； Step 1: Compound 17 or 20 and substrate 6 undergo nucleophilic substitution reaction to obtain compound 21, wherein in compound 17, Z is 0 or S, R 6 does not exist; and in compound 20, Z is N, R 6 is H Or C r C 6 alkyl;
歩骤 2: 化合物 21
Figure imgf000075_0003
Suzuki反应偶联得到中间体 22， 再将中间体 22经过水解反应得到产物 23; Step 2: Compound 21
Figure imgf000075_0003
Intermediate 22 is obtained by Suzuki reaction coupling, and then intermediate 22 is hydrolyzed to obtain product 23;
优选地， 所述化合物 17和 20通过如下方法制备的： Preferably, the compounds 17 and 20 are prepared by the following method:
O
Figure imgf000076_0001
O
Figure imgf000076_0001
Figure imgf000076_0002
反应式 3
Figure imgf000076_0002
Reaction 3
歩骤 1 :将化合物 10的羟基用保护剂保护得到化合物 11，然后和氯乙酰 氯经过傅克反应得到化合物 12， 所述保护剂为乙酸酐、 乙酰氯或乙酰溴； 歩骤 2:化合物 12经过分子内亲核取代反应得到化合物 13，然后和 witting 试剂经过 witting反应得到化合物 14; Step 1: Protect the hydroxyl group of compound 10 with a protective agent to obtain compound 11, and then react with chloroacetyl chloride through Friedel-Crafts reaction to obtain compound 12. The protective agent is acetic anhydride, acetyl chloride or acetyl bromide; Step 2: Compound 12 Compound 13 was obtained through intramolecular nucleophilic substitution reaction, and then compound 14 was obtained through witting reaction with witting reagent;
歩骤 3: 化合物 14经氢化还原反应得到化合物 15， Step 3: Compound 14 undergoes hydrogenation reduction reaction to obtain compound 15.
当 Z=0或 S时， 化合物 15经水解反应得到化合物 16， 化合物 16经过 溴化反应， 然后再滴加入无水乙醇经过酯化反应得到化合物 17; When Z=0 or S, compound 15 undergoes hydrolysis reaction to obtain compound 16, compound 16 undergoes bromination reaction, and then absolute ethanol is added dropwise to undergo esterification reaction to obtain compound 17;
歩骤 4: 当 Z=NH时， 化合物 15和 R7I经垸基化反应得到化合物 18， 化合物 18经水解反应得到化合物 19， 化合物 19经过溴化反应， 然后再滴加 入无水乙醇经过酯化反应得到化合物 20; Step 4: When Z=NH, compound 15 and R 7 I are subjected to alkylation reaction to obtain compound 18. Compound 18 is hydrolyzed to obtain compound 19. Compound 19 is subjected to bromination reaction, and then absolute ethanol is added dropwise to undergo esterification. chemical reaction to obtain compound 20;
其中， R7为 CrC6垸基; Among them, R 7 is C r C 6 alkyl group;
在反应式 1~3中， X的定义与在权利要求 1中的定义相同。 In reaction formulas 1 to 3, the definition of X is the same as that in claim 1.
8、一种药物组合物，其包含治疗有效量的通式 I所示的苯丙酸类化合物、 其药学上可接受的盐、 立体异构体或其前药分子和药学上可接受的辅料。 8. A pharmaceutical composition, which contains a therapeutically effective amount of a phenylpropionic acid compound represented by general formula I, its pharmaceutically acceptable salt, stereoisomer or its prodrug molecule and pharmaceutically acceptable excipients .
9、根据权利要求 1所述的苯丙酸类化合物、或其药学上可接受的盐、立 体异构体、 其前药分子在制备糖脂代谢紊乱的药物中的用途。 9. Use of the phenylpropionic acid compound according to claim 1, or its pharmaceutically acceptable salts, stereoisomers, and prodrug molecules thereof in the preparation of drugs for glucose and lipid metabolism disorders.
10、 根据权利要求 9所述的用途， 所述糖脂代谢紊乱为糖尿病。 10. The use according to claim 9, wherein the glucose and lipid metabolism disorder is diabetes.
PCT/CN2014/075466 2013-04-16 2014-04-16 Phenylalanine compound having nitrogen heterocyclic link, pharmaceutical composition thereof, preparation method therefor, and use thereof WO2014169817A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310132684.6A CN104109115B (en) 2013-04-16 2013-04-16 Phenylpropionic acid compound, its pharmaceutical composition, preparation method and the purposes of a kind of nitrogen heterocyclic ring link
CN201310132684.6 2013-04-16

Publications (1)

Publication Number Publication Date
WO2014169817A1 true WO2014169817A1 (en) 2014-10-23

Family

ID=51706126

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2014/075466 WO2014169817A1 (en) 2013-04-16 2014-04-16 Phenylalanine compound having nitrogen heterocyclic link, pharmaceutical composition thereof, preparation method therefor, and use thereof

Country Status (2)

Country Link
CN (1) CN104109115B (en)
WO (1) WO2014169817A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107556252A (en) * 2016-06-30 2018-01-09 中国科学院上海药物研究所 Phenylpropionic acid compound, its pharmaceutical composition, preparation method and the purposes that a kind of loop chain containing pyrazine connects

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005080367A1 (en) * 2004-02-12 2005-09-01 Pharmagene Laboratories Limited Ep2 receptor agonists
WO2005095338A1 (en) * 2004-03-30 2005-10-13 Takeda Pharmaceutical Company Limited Alkoxyphenylpropanoic acid derivatives
CN1735408A (en) * 2002-11-08 2006-02-15 武田药品工业株式会社 Receptor function controlling agent
WO2006127503A2 (en) * 2005-05-20 2006-11-30 Amgen Inc Compounds, pharmaceutical compositions and methods for their use in treating metabolic disorders
CN1922165A (en) * 2003-12-25 2007-02-28 武田药品工业株式会社 3-(4-benzyloxyphenyl)propanoic acid derivative
CN1946666A (en) * 2004-02-27 2007-04-11 埃姆艮股份有限公司 Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
WO2007106469A2 (en) * 2006-03-14 2007-09-20 Amgen Inc. Bicyclic carboxylic acid derivatives useful for treating metabolic disorders
WO2008030618A1 (en) * 2006-09-07 2008-03-13 Amgen Inc. Benzo-fused compounds for use in treating metabolic disorders
WO2008130514A1 (en) * 2007-04-16 2008-10-30 Amgen Inc. Substituted biphenyl phenoxy-, thiophenyl- and aminophenylpropanoic acid gpr40 modulators
WO2009012650A1 (en) * 2007-07-25 2009-01-29 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. Aryl pyrimidine derivatives, preparation methods and pharmaceutical uses thereof
CN101411704A (en) * 2007-10-15 2009-04-22 中国科学院上海药物研究所 Use of pyrimidine-substituted phenylpropionic acid compound in preparing medicament for preventing and/or treating diabetes
US20110195993A1 (en) * 2008-05-26 2011-08-11 Christophe Masson Ppar agonist compounds, preparation and uses
CN102307860A (en) * 2008-12-18 2012-01-04 麦它波莱克斯股份有限公司 GPR120 receptor agonists and uses thereof
CN103030646A (en) * 2011-09-29 2013-04-10 上海恒瑞医药有限公司 Benzodioxane derivative, and preparation method thereof and application of derivative in medicines

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1735408A (en) * 2002-11-08 2006-02-15 武田药品工业株式会社 Receptor function controlling agent
CN1922165A (en) * 2003-12-25 2007-02-28 武田药品工业株式会社 3-(4-benzyloxyphenyl)propanoic acid derivative
WO2005080367A1 (en) * 2004-02-12 2005-09-01 Pharmagene Laboratories Limited Ep2 receptor agonists
CN1946666A (en) * 2004-02-27 2007-04-11 埃姆艮股份有限公司 Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
WO2005095338A1 (en) * 2004-03-30 2005-10-13 Takeda Pharmaceutical Company Limited Alkoxyphenylpropanoic acid derivatives
WO2006127503A2 (en) * 2005-05-20 2006-11-30 Amgen Inc Compounds, pharmaceutical compositions and methods for their use in treating metabolic disorders
WO2007106469A2 (en) * 2006-03-14 2007-09-20 Amgen Inc. Bicyclic carboxylic acid derivatives useful for treating metabolic disorders
WO2008030618A1 (en) * 2006-09-07 2008-03-13 Amgen Inc. Benzo-fused compounds for use in treating metabolic disorders
WO2008130514A1 (en) * 2007-04-16 2008-10-30 Amgen Inc. Substituted biphenyl phenoxy-, thiophenyl- and aminophenylpropanoic acid gpr40 modulators
WO2009012650A1 (en) * 2007-07-25 2009-01-29 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. Aryl pyrimidine derivatives, preparation methods and pharmaceutical uses thereof
CN101411704A (en) * 2007-10-15 2009-04-22 中国科学院上海药物研究所 Use of pyrimidine-substituted phenylpropionic acid compound in preparing medicament for preventing and/or treating diabetes
US20110195993A1 (en) * 2008-05-26 2011-08-11 Christophe Masson Ppar agonist compounds, preparation and uses
CN102307860A (en) * 2008-12-18 2012-01-04 麦它波莱克斯股份有限公司 GPR120 receptor agonists and uses thereof
CN103030646A (en) * 2011-09-29 2013-04-10 上海恒瑞医药有限公司 Benzodioxane derivative, and preparation method thereof and application of derivative in medicines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NEGORO, N. ET AL.: "Identification of Fused-Ring Alkanoic Acids with Improved Pharmacokinetic Profiles that Act as G Protein-Coupled Receptor 40/Free Fatty Acid Receptor I Agonists", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 4, 16 January 2012 (2012-01-16), pages 1538 - 1552, XP002696495, DOI: doi:10.1021/jm2012968 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators

Also Published As

Publication number Publication date
CN104109115B (en) 2016-11-23
CN104109115A (en) 2014-10-22

Similar Documents

Publication Publication Date Title
WO2014169817A1 (en) Phenylalanine compound having nitrogen heterocyclic link, pharmaceutical composition thereof, preparation method therefor, and use thereof
CN111647000B (en) Pyrazine derivative and application thereof in inhibition of SHP2
EP2803664B1 (en) Tetrahydrobenzofurane derivatives as gpr40 agonists for the treatment of diabetes
TW200418801A (en) Isoquinolinone derivatives and their use as therapeutic agents
WO2014036897A1 (en) Imidazoline derivatives, preparation methods thereof, and their applications in medicine
CN112601525B (en) 2, 6-diaminopyridine compounds
WO2015000412A1 (en) Benzocyclobutene derivative and preparation method and pharmaceutical application thereof
FR2787789A1 (en) BENZOPYRANES AND BENZOXEPINES USEFUL IN THE TREATMENT OF DYSLIPIDEMIA, ATHEROSCLEROSIS AND DIABETES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND METHODS OF PREPARATION
WO2007114213A1 (en) Substituted bicyclic cyclic derivative and use thereof
KR102005068B1 (en) 1,2-Naphthoquinone-based Derivatives and Methods for Preparing them
JP5476587B2 (en) Condensed compounds having activity against estrogen receptors
CA2730302C (en) Use of indole derivatives as nurr-1 activators for treating parkinson&#39;s disease
US9695181B2 (en) Hydroximic acid derivatives and medical applications therof
KR101644778B1 (en) 1,2-Naphthoquinone-based Derivatives and and Methods for Preparing them
CA2905729C (en) Bicyclic pyrrole derivatives useful as agonists of gpr120
TW201124401A (en) New phenoxypyrimidine derivatives
CN110903224A (en) Aryl sulfonamide compound, preparation method thereof, pharmaceutical composition and application
JP2022542613A (en) Inhibitors of human ATGL
KR20230078737A (en) FXR small molecule agonists and methods for their preparation and uses
JP7177042B2 (en) heterocyclic compound
CN111393421A (en) Butenolide derivative and preparation method and application thereof
JP7177043B2 (en) heterocyclic compound
JP2008543741A (en) New compounds
US20070191425A1 (en) Solifenacin-containing composition
CN108239029A (en) The preparation of tetrahydroisoquinoliderivatives compound and its salt and medical usage

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14784917

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14784917

Country of ref document: EP

Kind code of ref document: A1