WO2015024448A1 - Benzo piperidine ring and benzo morpholine ring compounds, manufacturing method therefor, and medical applications thereof - Google Patents

Benzo piperidine ring and benzo morpholine ring compounds, manufacturing method therefor, and medical applications thereof Download PDF

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Publication number
WO2015024448A1
WO2015024448A1 PCT/CN2014/083806 CN2014083806W WO2015024448A1 WO 2015024448 A1 WO2015024448 A1 WO 2015024448A1 CN 2014083806 W CN2014083806 W CN 2014083806W WO 2015024448 A1 WO2015024448 A1 WO 2015024448A1
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mmol
propoxy
fluoro
benzo
methyl
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PCT/CN2014/083806
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French (fr)
Chinese (zh)
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欧阳孔德
刘振刚
蔡艳
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上海润诺生物科技有限公司
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Publication of WO2015024448A1 publication Critical patent/WO2015024448A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • 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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel benzopiperidine ring and a benzomorpholine ring derivative, and a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, and a process for the preparation thereof.
  • the present invention also relates to the benzopiperidinyl ring and a benzomorpholine ring derivative, and a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, in the preparation of a therapeutic agent, particularly a GPR40 agonist, and in the preparation of a diabetic treatment Use in medicines for diseases such as metabolic disorders. Background technique
  • type II diabetes accounts for more than 90% of the entire diabetes population, and its main manifestations are insulin resistance (target organ sensitivity to insulin) and insufficient insulin secretion.
  • hypoglycemic substances such as metformin, which reduce the decomposition of hepatic glycogen
  • promote insulin secretion such as hydrazide, DPP-4 inhibitor and GLP-1 analogue, etc.
  • Insulin secretion of ⁇ -cells ⁇ -glucosidase inhibitors inhibit the production of glucose in the intestine
  • Peroxisome proliferator-activated receptor ⁇ ( ⁇ ⁇ ) activators improve the body's sensitivity to insulin.
  • these drugs have certain side effects such as hypoglycemia, weight gain, gastrointestinal side effects, drug tolerance, and the like.
  • GPR40 i.e., free fatty acid receptor 1, FFAR1
  • the endogenous ligand of GPR40 is a long-chain free fatty acid, mainly a 12-18 carbon saturated fatty acid and an 18-22 carbon unsaturated fatty acid such as oleic acid, linoleic acid and the like.
  • GPR40 is a Gq protein coupled receptor, activation may cause the elevation of intracellular IP 3, IP 3 to activate the release of intracellular calcium stores sensitive, causing increased intracellular Ca 2+ concentration, followed by calcium-dependent insulin produced secretion. At the same time, GPR40 activation affects the calcium channel on the cell membrane and promotes the influx of extracellular Ca 2+ .
  • GSIS glucose-stimulated insulin secretion
  • GPR40 promotes insulin secretion with glucose dependence: ie at low concentrations In glucose, GPR40 has little effect on insulin secretion, so it does not cause blood glucose concentration to continue to decrease. At high concentrations, it promotes insulin secretion and can effectively lower blood glucose concentration. Therefore, GPR40 agonists can prevent the risk of hypoglycemia while treating type II diabetes.
  • GPR40 agonists can be used to treat type II diabetes and related indications such as obesity, metabolic syndrome, atherosclerosis, and hyperlipidemia. Therefore, the discovery and modification of GPR40-targeted agonists is of great value for scientific research and clinical applications.
  • GPR40 agonists include WO200508666K WO200800193K WO2010045258, WO201207269K WO2012011125, WO2012004269, WO2011161030, US2011313008, US2011312995, US2012004234 and US2012035196, and the like.
  • the object of the present invention is to provide a compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, a mixture thereof Form, and its medicinal
  • A is independently selected from -CH 2 - or -0-;
  • R 1 is independently selected from hydroxy or C 1 -C 8 alkoxy, preferably C 1 -C 6 alkoxy, more preferably C 1 -C 3 alkoxy, such as methoxy, ethoxy and/or propoxy;
  • R 2 is independently selected from a hydrogen atom or a halogen, preferably a fluorine atom
  • R 3 is independently selected from a hydrogen atom, a halogen, preferably chlorine and/or fluorine, or a C1-C8 fluorenyl group, preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group such as a methyl group, an ethyl group and/or a propyl group;
  • R 4 and R 5 are each independently selected from a C1-C8 alkyl group, preferably a C1-C6 alkyl group, more preferably
  • a C1-C3 alkyl group such as methyl, ethyl and/or propyl
  • R 6 is independently selected from a hydrogen atom, a halogen, preferably fluorine and/or chlorine, or a C1-C8 alkyl group, preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group such as methyl, ethyl and/or C. base;
  • R 7 is independently selected from a hydrogen atom, -OR 8 ;
  • R 8 is independently selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, more preferably C 1 -C 3 alkyl, such as methyl, ethyl and/or propyl; C 3 -C 8 cycloalkyl, preferably C 3 -C 6 cycloalkyl, more preferably C3-C4 cycloalkyl, e.g.
  • cyclopropyl and / or cyclobutyl containing -S0 2 - or C3-C8 heterocyclic group, preferably -S0 2 - group of C3-C6 heterocyclyl More preferably, a C4 and/or C5 heterocyclic group containing -S0 2 -, wherein the C1-C8 alkyl group or the C3-C8 cycloalkyl group is optionally a C1-C8 alkoxy group, preferably a C1-C6 alkoxy group , more preferably C1-C3 alkoxy group such as methoxy, ethoxy and / or propoxy; containing -S0 2 - C3-C8 heterocyclic group, preferably containing -S0 2 - the C3-C6 heterocyclyl a group, more preferably a C4 and/or C5 heterocyclic group containing -S0 2 -; or a -S0 2 R 9 substituent;
  • R 9 is independently selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, more preferably C 1 -C 3 alkyl, such as methyl, ethyl and/or propyl; or C 3 -C 8 cycloalkyl, preferably C 3 - C6 cycloalkyl, more preferably C3-C4 cycloalkyl, such as cyclopropyl and/or cyclobutyl.
  • a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof And a mixture thereof, and a pharmaceutically acceptable salt thereof which is a compound of the formula (II) or a tautomer thereof, a mesogen, a racemate, an enantiomer, a non-pair Isomers, mixtures thereof, and their pharmaceutically acceptable
  • Y is independently selected from C1-C8 alkylene, preferably C1-C6 alkylene, more preferably C3-C5 alkylene, such as propylene, butylene and/or pentylene; or C3-C8 hypocycloal a group, preferably a C3-C6 cycloalkylene group, more preferably a C3-C4 cycloalkylene group, such as a cyclopropylene group and/or a cyclobutylene group;
  • A is independently selected from -CH 2 - or -0-;
  • R 1 is independently selected from hydroxy or C 1 -C 8 alkoxy, preferably C 1 -C 6 alkoxy, more preferably C 1 -C 3 alkoxy, such as methoxy, ethoxy and/or propoxy;
  • R 2 is independently selected from a hydrogen atom or a halogen, preferably a fluorine atom
  • R 3 is independently selected from a hydrogen atom, a halogen, preferably chlorine and/or fluorine, or a C1-C8 alkyl group, preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group such as methyl, ethyl and/or C. base;
  • R 4 and R 5 are each independently selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, more preferably C 1 -C 3 alkyl, such as methyl, ethyl and/or propyl;
  • R 6 is independently selected from a hydrogen atom, a halogen, preferably fluorine and/or chlorine, or a C1-C8 alkyl group, preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group such as methyl, ethyl and/or C. base;
  • R 9 is independently selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, more preferably C 1 -C 3 alkyl, such as methyl, ethyl and/or propyl; or C 3 -C 8 cycloalkyl, preferably C 3 - C6 cycloalkyl, more preferably C3-C4 cycloalkyl, such as cyclopropyl and/or cyclobutyl.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer, a non- Enantiomers, mixtures thereof, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents and excipients.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, a mixture thereof And a pharmaceutically acceptable salt thereof, a prodrug thereof which can be converted in vivo, or a pharmaceutical composition comprising the same, for use in the preparation of a GPR40 agonist.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, a mixture thereof And a pharmaceutically acceptable salt thereof, the use of a prodrug thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for treating a disease of diabetes and metabolic syndrome, wherein said diabetes is II Type 2 diabetes.
  • the invention also relates to a method for treating diseases of diabetes and metabolic syndrome, the method
  • the method comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof. And a mixture thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof which can be converted in vivo, or a pharmaceutical composition comprising the same.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer thereof, which is a medicament for the treatment of diseases of diabetes and metabolic syndrome a form, a mixture of diastereomers, a mixture thereof, and a pharmaceutically acceptable salt thereof, wherein said diabetes is preferably type II diabetes.
  • Another aspect of the invention relates to a method of modulating insulin comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, a mesogen, a topical A steroid, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt thereof, a prodrug thereof which can be converted in vivo, or a pharmaceutical composition comprising the same.
  • a compound of formula (I) or a tautomer thereof a mesogen, a topical A steroid, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt thereof, a prodrug thereof which can be converted in vivo, or a pharmaceutical composition comprising the same.
  • Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof as a medicament for regulating insulin Isomers, mixtures thereof, and pharmaceutically acceptable salts thereof.
  • Alkyl means a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n
  • Alkylene means a group formed by the elimination of two hydrogen atoms by a saturated aliphatic hydrocarbon, including linear and branched groups of 1 to 20 carbon atoms.
  • alkylene groups include methylene, ethylene, isopropylidene, butylene, pentylene, hexylene, 1,2-ethylidene, 1,3-propylene, and the like.
  • the alkylene group can be optionally substituted or unsubstituted.
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. For example, it can be a 3, 4, 5, or 6-membered ring.
  • monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Alkenyl, cyclooctyl and the like.
  • the cycloalkyl group can be optionally substituted or unsubstituted.
  • Cycloalkylene means a radical formed by the elimination of two hydrogen atoms from a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon.
  • monocyclic cycloalkylene groups include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cyclohexylene, cyclooctylene, 1,2-cyclopropylene , 1,3-cyclopentylene, 1,4-cyclohexylene, and the like.
  • Alkoxy means -0-(alkyl) and -0-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. The alkoxy group may be optionally substituted or unsubstituted.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(0)m ( Wherein m is a hetero atom of the integer 0 to 2), but does not include a ring moiety of - ⁇ - ⁇ -,-0-S- or -SS-, and the remaining ring atoms are carbon.
  • monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxamorpholinyl, homopiperazinyl and the like.
  • Haldroxy means an -OH group.
  • Halogen means fluoro, chloro, bromo or iodo.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, including the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can be unstable when they do not pay an amino group having a free hydrazine in combination with a saturated carbon atom. of.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity. Method for synthesizing the compound of the present invention
  • the compound of the formula (Ix) can be prepared as shown in the scheme 1, the nitro group, the hydroxy-substituted phenyl compound la and the alkyl acrylate lb are reacted in the presence of a catalyst to obtain a C-c reaction.
  • the phenyl-substituted phenyl compound Ic, the propylene-substituted phenyl compound Ic is reacted with a reducing agent in the presence of a catalyst to obtain a compound Id, and the compound Id and the bromoacetophenone Ie are cyclized in a solvent under basic conditions.
  • the intermediate Ic can be directly reacted with bromoacetophenone Ie to obtain a compound oxime, and the compound Ii undergoes a Miyaura reaction under a catalyst condition to obtain a compound Ij, and the compound Ij is reacted with a reducing agent in a solvent to obtain a compound Ik, a compound Ik and a benzene.
  • the thiol II is subjected to a Suzuki coupling reaction in a solution catalyzed by a catalyst to obtain an ester of the compound (Ix) of the formula, and the obtained product is optionally subjected to one-step hydrolysis to give the corresponding acid or salt.
  • the compound of the formula (Iy) can be prepared as shown in Scheme 2, and the quinoline compound Ila and the alkyl acrylate lb are Heck-reacted in the presence of a catalyst to obtain a propylene-substituted quinoline compound lib, which is in a solvent. Reaction with a reducing agent to obtain compound IIc, compound lie is reacted with an oxidizing agent in a solvent to obtain compound lid, compound lid is reacted with a reagent of 13 ⁇ 4 to obtain compound lie, and compound lie and borate compound Ilf are subjected to Suzuki coupling in solution under catalyst catalysis.
  • reaction gives compound IIg, and the compound Ilg is reacted with trifluoromethanesulfonic anhydride under basic conditions to obtain compound IIh, compound Ilh and borate compound Ih.
  • Suzuki coupling reaction occurs in solution under catalyst catalysis to obtain compound IIi.
  • Compound Ili is reacted with a reducing agent in a solvent to obtain an ester of the compound (Iy) of the formula, and the obtained product is optionally hydrolyzed to obtain a compound (Iy).
  • the acid or salt is optionally hydrolyzed to obtain a compound (Iy).
  • the intermediate lie and the boronic acid ester compound Ilj can be subjected to a Suzuki coupling reaction in a catalyst to obtain a compound IIi, and the compound Ili is reacted with a reducing agent in a solvent to obtain an ester of the compound (Iy) of the formula.
  • the obtained product is optionally hydrolyzed in one step to give an acid or a salt in the compound (Iy).
  • Acids which provide acidic conditions include, but are not limited to, formic acid, acetic acid, hydrochloric acid, hydrochloric acid, methanesulfonic acid, tetrabutylammonium chloride.
  • Bases which provide basic conditions include organic bases and inorganic bases including, but not limited to, triethylamine, 4-dimethylaminopyridine, imidazole, indole, indole-diisopropylethylamine, n-butyl Lithium, potassium t-butoxide, tetrabutylammonium bromide, preferably triethylamine; said inorganic bases including but not limited to sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate It is preferably potassium carbonate or cesium carbonate.
  • Catalysts include, but are not limited to, tetra-triphenylphosphine palladium, triphenylphosphine, palladium dichloride, palladium acetate, 1,1,-bis(dibenzylphosphine) dichlorodipentadium iron palladium, tris(dibenzylidene) Acetone) dipalladium, palladium/carbon or Raney nickel.
  • Oxidizing agents include, but are not limited to, tetraoxide, phosphorus oxychloride.
  • Halogenating agents include, but are not limited to, bromine water or phosphine; phosphorus oxychloride is preferred.
  • Reducing agents include, but are not limited to, sodium borohydride, lithium borohydride, borane, zinc powder, iron powder or hydrogen.
  • Solvents used include, but are not limited to: acetic acid, methanol, ethanol, acetone, tert-butanol, diethyl ether, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, toluene, 1,4-dioxane, water or hydrazine, hydrazine- dimethylformamide.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or spectral (MS).
  • NMR nuclear magnetic resonance
  • MS spectral
  • the NMR was measured by Bruker AVANCE-400 or Varian Oxford-300 NMR, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ), deuterated methanol. (CD 3 OD), the internal standard is tetramethylsilane (TMS), and the chemical shift is given in units of 10 - 6 (ppm).
  • the MS was measured using an Agilent SQD (ESI) spectrometer (manufacturer: Agilent, model: 6110) or Shimadzu SQD (ESI) spectrometer (manufacturer: Shimadzu, model: 2020).
  • ESI Agilent SQD
  • ESI Shimadzu SQD
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfirc C18, 150 x 4.6 mm, 5 ⁇ , column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm, 5 ⁇ column;).
  • the thin layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm ⁇ 0.5mm. silicone board.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Beijing Coupling Companies such as chemicals.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen gas ball of about 1 L volume.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using Beijing Jiawei Kechuang Technology Co., Ltd. GCD-500G high purity hydrogen gas generator and BLT-2000 medium pressure hydrogenation instrument.
  • the hydrogenation reaction is usually carried out by vacuuming, charging with hydrogen, and repeating the reaction three times.
  • the microwave reaction was carried out using a CEM Discover-SP type microwave reactor.
  • reaction temperature is room temperature, and the temperature range is from 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, volume ratio of solvent The adjustment is made according to the polarity of the compound.
  • the system of the eluent for column chromatography and the system for the developer of the thin layer chromatography using the purified compound include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, Triethylamine is adjusted with an acidic or alkaline reagent or the like.
  • a 250 mL dry single-mouth bottle was weighed into a quinoline compound la (500 mg, 2.2 mmol, prepared by the known method "WO2008051805", added with dichloromethane (50 mL), and cooled to 0 in an ice water bath. C, then m-chloroperoxybenzoic acid (751 mg, 4.4 mmol) was added portionwise. After stirring for 1 hour at 0 ° C, the mixture was allowed to naturally warm to room temperature and stirring was continued, and the reaction was monitored by TLC until the starting material was completely reacted. The reaction was quenched with aqueous sodium sulphate and extracted with dichloromethane (100 mL ⁇ 3).
  • 2 ',6'-dimethylbiphenyl-3-phenol le (1.2 g, 6 mmol) was weighed into a 100 mL dry single-mouth bottle, and dichloromethane (20 mL) and diisopropylethylamine (1.5 g, 12mmol). Trifluoromethane anhydride (2.5 g, 9 mmol) was then slowly added while cooling in an ice water bath, which was naturally returned to room temperature and stirring was continued, and the reaction was monitored by TLC until the starting material was completely reacted. The reaction was quenched with saturated sodium bicarbonate (15 mL).
  • 2',6'-dimethylbiphenyl-3-yltrifluoromethanesulfonate is weighed into a 100 mL dry three-necked bottle.
  • reaction system was replaced with a nitrogen atmosphere, hydrazine, ⁇ '-dimethylformamide (6 mL) was added, and then the reaction was stirred at 100 ° C, and the reaction was monitored by TLC until the starting material was completely reacted. After cooling to room temperature, the reaction system was diluted with 100 mL of water, and extracted with ethyl acetate (15 mL ⁇ 3). The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to remove solvent.
  • reaction system was replaced with a nitrogen atmosphere, toluene (10 mL), ethanol (5 mL) and water (2.5 mL) were added, and then the reaction was stirred at 80 ° C, and the reaction was monitored by TLC until the starting material was completely reacted. After cooling to room temperature, the reaction system was diluted with 30 mL of water, and extracted with ethyl acetate (40 mL ⁇ 3). The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to remove solvent.
  • EtOAc EtOAc
  • EtOAc HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
  • Example 1 The synthesis of lg in Example 1 was carried out using the compound 6'-methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yltrifluoromethanesulfonate (240 mg, 0.53 mmol). The method was synthesized to give the title product 4,4,5,5-tetramethyl-2-(6'-methyl-4'-(3-methylsulfonyl)propoxy)biphenyl-3-yl-1 , 3,2-dioxaborane 6d (141 mg, colorless oily liquid), yield: 62%.
  • 2',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yltrifluoromethanesulfonate utilizes 2',6'-dimethyl-4 '-(3-(Methanesulfonyl)propoxy)biphenyl-3-phenol 8a (0.5 g 1.5 mmol) was used as a starting material, and the title compound 2',6'-dimethyl -4'-(3-(Methanesulfonyl)propoxy)biphenyl-3-yltrifluoromethanesulfonate 8b (0.7 g, pale yellow oil), yield: 90%. The product was used in the next reaction without purification.
  • 6-bromo-7-fluoroquinoline 8d (3.4 g, 15 mmol, prepared by the known method "WO2008051808"), palladium acetate (363 mg, 1.5 mmol), tri-o-tolylphosphine (912 mg, 3 mmol).
  • the system was replaced with a nitrogen atmosphere, and hydrazine, ⁇ '-dimethylbenzamide (40 mL), ethyl acrylate (3.9 g, 45 mmol) and triethylamine (4.5 g, 45 mmol).
  • the reaction was then stirred at 100 ° C and the reaction was monitored by TLC until the reaction was complete.
  • Methyl (7-fluoroquinolin-6-yl) acrylate 8e (2.3 g, 10 mmol), sodium hydrogencarbonate (2.7 g, 31.9 mmol), and methanol (56 mL) were weighed in a 250 mL single-necked flask. Oxone (12.2 g, 20 mmol), water (22 mL;) was then added with stirring. The system was replaced by a nitrogen atmosphere at 50. The reaction was stirred at C for 24 hours.
  • the system was replaced with a nitrogen atmosphere, dioxane (10 mL) and water (2 mL), then at 85 C.
  • the reaction was stirred, and the reaction was monitored by TLC until the reaction mixture was completed.
  • the mixture was cooled to room temperature.
  • the mixture was diluted with water (20 mL), ethyl acetate (30 mL ⁇ 3), and the organic phase was combined and washed with brine, dried over anhydrous sodium sulfate
  • the desiccant was de-dissolved under reduced pressure, and the residue was purified mjjjjjjjjjj Propyloxy)biphenyl-3-yl)-7-fluoroquinolin-6-yl)methyl acrylate 8h (300 mg, pale yellow oil), yield 56%.
  • 2-Bromo-1-(3-bromophenyl)ethanone 17a (1.53 g, 5.5 mmol, prepared by the known method "Patent WO2013041468”), 3-(3-hydroxy-4-nitrobenzene Methyl acrylate 16c (1.13 g, 5.5 mmol), tetrabutylammonium fluoride (1.59 g, 6.1 mmol) and cesium carbonate (1.99 g, 6.1 mmol) were dissolved in hydrazine, hydrazine, dimethylformamide ( In 30 mL), stir at room temperature until the reaction was completed. After quenching with water, it was extracted with ethyl acetate (20 mL > ⁇ 5).
  • Methyl 3-(5-(2-(3-bromophenyl)-2-oxoethoxy)-2-fluoro-4-nitrophenyl)acrylate 19c (600 mg, 1.4 mmol) in a dry three-neck flask ), dipinocol borate (427 mg, 1.68 mmol), hydrazine, hydrazine-bis(diphenylphosphino)ferrocene palladium dichloride (102 mg, 0.14 mmol) and potassium acetate (412 mg, 4.2 mmol)
  • a mixed solution of 1,4-dioxane (10 mL) was heated to 95 ° C under a nitrogen atmosphere and stirred overnight.
  • Methyl 3-(4-amino-2-fluoro-5-hydroxyphenyl)acrylate Methyl-methyl-3-(2-fluoro-5-hydroxy-4-nitrophenyl) acrylate 19b (700 mg, 2.90 mmol) was dissolved in methanol (10 mL) and Pd/C (70 mg). The reaction system was replaced with a hydrogen balloon to a hydrogen atmosphere (1 atm), and stirred at room temperature overnight. Filtration and concentration of the filtrate gave the title product-methyl 3-(2-fluoro-5-hydroxy-4-aminophenyl) acrylate 20a (500 mg, brown liquid), yield: 57%.
  • the examples 26-28 were synthesized using the appropriate reactants in accordance with the steps of Example 20.
  • the following are the example numbers, structures and characterization data:
  • Test Example 1 Activation efficacy of the compound of the present invention on HEK293/hGPR40 cells The following method was used to test the activation efficacy of the present compound on human GPR40.
  • HEK293/hGPR40 cells were seeded in 384-well cell culture plates (HEK293 cell line stably expressing human GPR40 constructed by lipofection, HEK293/hGPR40 cells for short (HEK293 cells purchased from ATCC, catalog number CRL-1573; human)
  • the source GPR40 ⁇ pellet was extracted from pancreatic cancer cell line BXPC-3 cells, and the density was 8000 cells/well. The cells were cultured overnight at 37 ° C under 5% C0 2 . On the day of the experiment, the culture solution was discarded, and 4 was added per well.
  • Example 23 B Example 24 B Example 25 B Example 26 A Example 27 A Example 28 A
  • a ⁇ 100 nM; B 100 to 500nM; C > 500 nM
  • the compounds of the present invention have significant activation potency against human GPR40.

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Abstract

The present invention relates to benzo piperidine ring and benzo morpholine ring derivatives, a preparation method therefor, and medical applications thereof. Specifically, the present invention relates to, as presented in formula (I), new benzo piperidine ring and benzo morpholine ring derivatives, pharmaceutical salts thereof, or medical compositions containing same, and a preparation method therefor. The present invention further relates to the application of the benzo piperidine ring and benzo morpholine ring derivatives, pharmaceutical salts thereof, or medical compositions containing same in preparing therapeutic agents, in particular, a GPR40 agonist, and in preparing medicines that treats diseases such as diabetes and metabolic diseases. The substituents in formula (I) has the same definition as in description.

Description

苯并哌啶环与苯并吗啉环类化合物、  Benzopiperidine ring and benzomorpholine ring compound,
其制法及医药应用 技术领域  Its production method and medical application technology field
本发明涉及一种新的苯并哌啶环与苯并吗啉环类衍生物及其可药 用的盐或含有其的药物组合物、 及其制备方法。 本发明还涉及所述苯 并哌啶环与苯并吗啉环类衍生物及其可药用的盐或含有其的药物组合 物在制备治疗剂， 特别是 GPR40激动剂， 和在制备治疗糖尿病和代谢 性病症等疾病的药物中的用途。 背景技术  The present invention relates to a novel benzopiperidine ring and a benzomorpholine ring derivative, and a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, and a process for the preparation thereof. The present invention also relates to the benzopiperidinyl ring and a benzomorpholine ring derivative, and a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, in the preparation of a therapeutic agent, particularly a GPR40 agonist, and in the preparation of a diabetic treatment Use in medicines for diseases such as metabolic disorders. Background technique
我国大城市成年人群中糖尿病发病率已达到 10%， 总人数接近 1 亿。 其中 II型糖尿病患者占整个糖尿病人群的 90%以上， 其主要表现 为胰岛素抵抗 (靶器官对胰岛素的敏感性下降)和胰岛素分泌量不足。  The incidence of diabetes in the adult population of large cities in China has reached 10%, and the total number is close to 100 million. Among them, type II diabetes accounts for more than 90% of the entire diabetes population, and its main manifestations are insulin resistance (target organ sensitivity to insulin) and insufficient insulin secretion.
口服或注射药物是目前糖尿病治疗最有效的方式。 用于 II型糖尿 病治疗的药物主要有： 降糖类， 如二甲双胍， 降低肝糖原的分解； 促 进胰岛素分泌类， 如碌酰脲， DPP-4抑制剂及 GLP-1 类似物等， 增加 胰腺 β细胞胰岛素的分泌量； α-葡萄糖苷酶抑制剂，抑制肠道内葡萄糖 的产生； 过氧化物酶体增殖物激活受体 γ(ΡΡΑί γ)激活剂， 提高机体对 胰岛素的敏感性。 不过， 这些药物都存在一定的副作用， 例如引起低 血糖、 体重增加、 胃肠道不良反应、 药物耐受等。  Oral or injectable drugs are currently the most effective way to treat diabetes. The main drugs used in the treatment of type 2 diabetes are: hypoglycemic substances, such as metformin, which reduce the decomposition of hepatic glycogen; promote insulin secretion, such as hydrazide, DPP-4 inhibitor and GLP-1 analogue, etc. Insulin secretion of β-cells; α-glucosidase inhibitors inhibit the production of glucose in the intestine; Peroxisome proliferator-activated receptor γ (ΡΡΑί γ) activators, improve the body's sensitivity to insulin. However, these drugs have certain side effects such as hypoglycemia, weight gain, gastrointestinal side effects, drug tolerance, and the like.
GPR40(即游离脂肪酸受体 1， FFAR1)特异性地高表达在分泌胰岛 素的胰腺 β 细胞中， 而在其他组织器官 (例如脑、 肠等）中表达很少。 GPR40的内源性配体是长链的游离脂肪酸， 主要是 12-18碳的饱和脂 肪酸和 18-22碳的不饱和脂肪酸， 例如油酸、 亚油酸等。 GPR40是 Gq 蛋白偶联受体，激活后可以引起细胞内 IP3升高，从而激活细胞内对 IP3 敏感的钙库释放， 引起细胞内 Ca2+浓度升高， 随后产生钙依赖的胰岛 素的分泌。 同时 GPR40激活会影响细胞膜上的钙离子通道， 促进胞外 Ca2+的内流。 因此， GPR40 信号通路对葡萄糖刺激引起的胰岛素分泌 (GSIS)起增强作用。 GPR40 (i.e., free fatty acid receptor 1, FFAR1) is specifically highly expressed in insulin-secreting pancreatic β cells, but is rarely expressed in other tissues and organs (e.g., brain, intestine, etc.). The endogenous ligand of GPR40 is a long-chain free fatty acid, mainly a 12-18 carbon saturated fatty acid and an 18-22 carbon unsaturated fatty acid such as oleic acid, linoleic acid and the like. GPR40 is a Gq protein coupled receptor, activation may cause the elevation of intracellular IP 3, IP 3 to activate the release of intracellular calcium stores sensitive, causing increased intracellular Ca 2+ concentration, followed by calcium-dependent insulin produced secretion. At the same time, GPR40 activation affects the calcium channel on the cell membrane and promotes the influx of extracellular Ca 2+ . Thus, the GPR40 signaling pathway potentiates glucose-stimulated insulin secretion (GSIS).
GPR40对胰岛素分泌的促进作用具有葡萄糖依赖性： 即在低浓度 葡萄糖时， GPR40 对胰岛素分泌的促进作用很小， 从而不会导致血糖 浓度继续降低； 而在高浓度时， 对胰岛素分泌的促进作用较强， 可以 有效的降低血糖浓度。 因此， GPR40激动剂在治疗 II型糖尿病的同时， 可以防止低血糖的风险。 GPR40 promotes insulin secretion with glucose dependence: ie at low concentrations In glucose, GPR40 has little effect on insulin secretion, so it does not cause blood glucose concentration to continue to decrease. At high concentrations, it promotes insulin secretion and can effectively lower blood glucose concentration. Therefore, GPR40 agonists can prevent the risk of hypoglycemia while treating type II diabetes.
基于以上特点， GPR40激动剂可以用来治疗 II型糖尿病以及相关 适应症， 例如肥胖， 代谢综合征， 动脉粥样硬化， 高血脂等。 因此， 发现和改造以 GPR40为靶点的激动剂， 对于科学研究和临床应用都有 非常重要的价值。  Based on the above characteristics, GPR40 agonists can be used to treat type II diabetes and related indications such as obesity, metabolic syndrome, atherosclerosis, and hyperlipidemia. Therefore, the discovery and modification of GPR40-targeted agonists is of great value for scientific research and clinical applications.
目前公开了一系列的 GPR40 激动剂的专利申请， 其中包括 WO200508666K WO200800193K WO2010045258, WO201207269K WO2012011125 , WO2012004269, WO2011161030, US2011313008, US2011312995, US2012004234和 US2012035196等。  A series of patent applications for GPR40 agonists are currently disclosed, including WO200508666K WO200800193K WO2010045258, WO201207269K WO2012011125, WO2012004269, WO2011161030, US2011313008, US2011312995, US2012004234 and US2012035196, and the like.
尽管目前已公开了一系列的治疗糖尿病和代谢性疾病等疾病的 GPR40 激动剂， 但仍需开发新的具有更好药效的化合物。 经过不断努 力， 本发明设计具有通式 (I)所示的结构的化合物， 并发现具有此类结 构的化合物表现出优异的效果和作用。 发明内容  Although a series of GPR40 agonists have been disclosed to treat diseases such as diabetes and metabolic diseases, new and better potent compounds have yet to be developed. The present invention has been devised to design a compound having a structure represented by the general formula (I), and it has been found that a compound having such a structure exhibits an excellent effect and effect. Summary of the invention
本发明的目的在于提供一种通式 (I)所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混合物形 式、 及其可药用的  The object of the present invention is to provide a compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, a mixture thereof Form, and its medicinal
Figure imgf000003_0001
Figure imgf000003_0001
其中：  among them:
A独立地选自 -CH2-或 -0-； A is independently selected from -CH 2 - or -0-;
R1独立地选自羟基或 C1-C8烷氧基， 优选 C1-C6烷氧基， 更优选 C1-C3烷氧基， 例如甲氧基、 乙氧基和 /或丙氧基； R 1 is independently selected from hydroxy or C 1 -C 8 alkoxy, preferably C 1 -C 6 alkoxy, more preferably C 1 -C 3 alkoxy, such as methoxy, ethoxy and/or propoxy;
R2独立地选自氫原子或卤素， 优选氟原子； R 2 is independently selected from a hydrogen atom or a halogen, preferably a fluorine atom;
R3独立地选自氫原子、 卤素， 优选氯和 /或氟， 或 C1-C8垸基， 优 选 C1-C6烷基， 更优选 C1-C3烷基， 例如甲基、 乙基和 /或丙基；R 3 is independently selected from a hydrogen atom, a halogen, preferably chlorine and/or fluorine, or a C1-C8 fluorenyl group, preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group such as a methyl group, an ethyl group and/or a propyl group;
R4和 R5各自独立地选自 C1-C8烷基， 优选 C1-C6烷基， 更优选R 4 and R 5 are each independently selected from a C1-C8 alkyl group, preferably a C1-C6 alkyl group, more preferably
C1-C3烷基， 例如甲基、 乙基和 /或丙基； a C1-C3 alkyl group such as methyl, ethyl and/or propyl;
R6独立地选自氫原子、 卤素， 优选氟和 /或氯， 或 C1-C8垸基， 优 选 C1-C6烷基， 更优选 C1-C3烷基， 例如甲基、 乙基和 /或丙基； R 6 is independently selected from a hydrogen atom, a halogen, preferably fluorine and/or chlorine, or a C1-C8 alkyl group, preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group such as methyl, ethyl and/or C. base;
R7独立地选自氫原子、 -OR8 ; R 7 is independently selected from a hydrogen atom, -OR 8 ;
R8独立地选自 C1-C8烷基，优选 C1-C6烷基，更优选 C1-C3烷基， 例如甲基、 乙基和 /或丙基； C3-C8环烷基， 优选 C3-C6环烷基， 更优 选 C3-C4环烷基， 例如环丙基和 /或环丁基； 含有 -S02-的 C3-C8杂环 基， 优选含有 -S02-的 C3-C6杂环基， 更优选含有 -S02-的 C4和 /或 C5 杂环基， 其中所述 C1-C8烷基或 C3-C8环烷基任选被 C1-C8烷氧基， 优选 C1-C6烷氧基， 更优选 C1-C3 烷氧基， 例如甲氧基、 乙氧基和 / 或丙氧基；含有 -S02-的 C3-C8杂环基，优选含有 -S02-的 C3-C6杂环基， 更优选含有 -S02-的 C4和 /或 C5杂环基； 或 -S02R9取代基取代； R 8 is independently selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, more preferably C 1 -C 3 alkyl, such as methyl, ethyl and/or propyl; C 3 -C 8 cycloalkyl, preferably C 3 -C 6 cycloalkyl, more preferably C3-C4 cycloalkyl, e.g. cyclopropyl and / or cyclobutyl; containing -S0 2 - or C3-C8 heterocyclic group, preferably -S0 2 - group of C3-C6 heterocyclyl More preferably, a C4 and/or C5 heterocyclic group containing -S0 2 -, wherein the C1-C8 alkyl group or the C3-C8 cycloalkyl group is optionally a C1-C8 alkoxy group, preferably a C1-C6 alkoxy group , more preferably C1-C3 alkoxy group such as methoxy, ethoxy and / or propoxy; containing -S0 2 - C3-C8 heterocyclic group, preferably containing -S0 2 - the C3-C6 heterocyclyl a group, more preferably a C4 and/or C5 heterocyclic group containing -S0 2 -; or a -S0 2 R 9 substituent;
R9独立地选自 C1-C8烷基，优选 C1-C6烷基，更优选 C1-C3烷基， 例如甲基、 乙基和 /或丙基； 或 C3-C8环烷基， 优选 C3-C6环烷基， 更 优选 C3-C4环烷基， 例如环丙基和 /或环丁基。 R 9 is independently selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, more preferably C 1 -C 3 alkyl, such as methyl, ethyl and/or propyl; or C 3 -C 8 cycloalkyl, preferably C 3 - C6 cycloalkyl, more preferably C3-C4 cycloalkyl, such as cyclopropyl and/or cyclobutyl.
在本发明的一个实施方案中， 一种通式 (I)所示的化合物或其互变 异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混合 物形式、及其可药用的盐，其为通式 (II)所述的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混合物形式、 及其可药用的  In one embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof And a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound of the formula (II) or a tautomer thereof, a mesogen, a racemate, an enantiomer, a non-pair Isomers, mixtures thereof, and their pharmaceutically acceptable
Figure imgf000004_0001
Figure imgf000004_0001
其中：  among them:
Y独立地选自 C1-C8亚烷基， 优选 C1-C6亚烷基， 更优选 C3-C5 亚烷基， 例如亚丙基、 亚丁基和 /或亚戊基； 或 C3-C8亚环烷基， 优选 C3-C6亚环烷基， 更优选 C3-C4亚环烷基， 例如亚环丙基和 /或亚环丁 基； A独立地选自 -CH2-或 -0-； Y is independently selected from C1-C8 alkylene, preferably C1-C6 alkylene, more preferably C3-C5 alkylene, such as propylene, butylene and/or pentylene; or C3-C8 hypocycloal a group, preferably a C3-C6 cycloalkylene group, more preferably a C3-C4 cycloalkylene group, such as a cyclopropylene group and/or a cyclobutylene group; A is independently selected from -CH 2 - or -0-;
R1独立地选自羟基或 C1-C8烷氧基， 优选 C1-C6烷氧基， 更优选 C1-C3烷氧基， 例如甲氧基、 乙氧基和 /或丙氧基； R 1 is independently selected from hydroxy or C 1 -C 8 alkoxy, preferably C 1 -C 6 alkoxy, more preferably C 1 -C 3 alkoxy, such as methoxy, ethoxy and/or propoxy;
R2独立地选自氫原子或卤素， 优选氟原子； R 2 is independently selected from a hydrogen atom or a halogen, preferably a fluorine atom;
R3独立地选自氫原子、 卤素， 优选氯和 /或氟， 或 C1-C8垸基， 优 选 C1-C6烷基， 更优选 C1-C3烷基， 例如甲基、 乙基和 /或丙基； R 3 is independently selected from a hydrogen atom, a halogen, preferably chlorine and/or fluorine, or a C1-C8 alkyl group, preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group such as methyl, ethyl and/or C. base;
R4和 R5各自独立地选自 C1-C8烷基， 优选 C1-C6烷基， 更优选 C1-C3烷基， 例如甲基、 乙基和 /或丙基； R 4 and R 5 are each independently selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, more preferably C 1 -C 3 alkyl, such as methyl, ethyl and/or propyl;
R6独立地选自氫原子、 卤素， 优选氟和 /或氯， 或 C1-C8垸基， 优 选 C1-C6烷基， 更优选 C1-C3烷基， 例如甲基、 乙基和 /或丙基； R 6 is independently selected from a hydrogen atom, a halogen, preferably fluorine and/or chlorine, or a C1-C8 alkyl group, preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group such as methyl, ethyl and/or C. base;
R9独立地选自 C1-C8烷基，优选 C1-C6烷基，更优选 C1-C3烷基， 例如甲基、 乙基和 /或丙基； 或 C3-C8环烷基， 优选 C3-C6环烷基， 更 优选 C3-C4环烷基， 例如环丙基和 /或环丁基。 R 9 is independently selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, more preferably C 1 -C 3 alkyl, such as methyl, ethyl and/or propyl; or C 3 -C 8 cycloalkyl, preferably C 3 - C6 cycloalkyl, more preferably C3-C4 cycloalkyl, such as cyclopropyl and/or cyclobutyl.
在本发明的另一个实施方案中， 一种通式 (I)所示的化合物或其互 变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混 合物形式、 及其可药用的盐， 其中 R1为羟基。 In another embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form, a mixture thereof, and a pharmaceutically acceptable salt thereof, wherein R 1 is a hydroxyl group.
在本发明的另一个实施方案中， 一种通式 (I)所示的化合物或其互 变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混 合物形式、 及其可药用的盐， 其中 R2为氟原子。 In another embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form, a mixture thereof, and a pharmaceutically acceptable salt thereof, wherein R 2 is a fluorine atom.
在本发明的另一个实施方案中， 一种通式 (I)所示的化合物或其互 变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混 合物形式、 及其可药用的盐， 其中 R3为 C1-C3烷基， 例如甲基、 乙基 和 /或丙基。 In another embodiment of the present invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer And mixtures thereof, and pharmaceutically acceptable salts thereof, wherein R 3 is C1-C3 alkyl, such as methyl, ethyl and/or propyl.
Figure imgf000005_0001
Figure imgf000006_0001
Figure imgf000005_0001
Figure imgf000006_0001
3-(2-2',6'-二甲基 -4'-3- (甲磺酰基）丙氧基)联苯 -3-基) -1,2,3,4- 四氫喹啉 -6-基；)丙酸
Figure imgf000006_0002
3-(2-2',6'-dimethyl-4'-3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3,4-tetrahydroquinoline- 6-based;) propionic acid
Figure imgf000006_0002
3-(2-(4'-甲氧基 -2',6'-二甲基联苯基 -3-基) - 1,2,3,4-四氫喹啉 -6- 基:)丙酸
Figure imgf000006_0003
3-(2-(4'-methoxy-2',6'-dimethylbiphenyl-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl:) acid
Figure imgf000006_0003
3-(2-(4'-(2-乙氧基乙氧基 )-2',6'-二甲基联苯基 -3-基) - 1,2,3,4- 四氫喹啉 -6-基；)丙酸
Figure imgf000006_0004
3-(2-(4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl)-1,2,3,4-tetrahydroquinoline -6-based;) propionic acid
Figure imgf000006_0004
3—(2-(4'-4'- [(四氫 -1 ,1-二氧 -2 -噻喃 -4-基)氧基] -2',6'-二甲基联 苯基 -3-基:) -1,2,3,4-四氫喹啉基 -6-基：)丙酸
Figure imgf000006_0005
3-(2-(4'-4'-[(tetrahydro-1,1-dioxo-2-thio-4-yl)oxy]-2',6'-dimethylbiphenyl- 3-yl:) -1,2,3,4-tetrahydroquinolinyl-6-yl:)propionic acid
Figure imgf000006_0005
3-(2-(6'-甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基) - 1,2,3,4-四 氫喹啉 -6-基)丙酸
Figure imgf000006_0006
3-(2-(6'-Methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3,4-tetrahydroquinoline-6 -base) propionic acid
Figure imgf000006_0006
3-(2-(4-氟 -2',6'-二甲基 -4'-(3-(甲磺酰基）丙氧基）联苯基 -3- 基:) - 1,2,3,4-四氫喹啉基 -6-基：)丙酸
Figure imgf000006_0007
3-(2-(2',6'-二甲基 -4'-(3-(甲磺酰基）丙氧基)联苯基 -3-基) -7-氟 -1,2,3,4-四氫喹啉基 -6-基；)丙酸
Figure imgf000007_0001
3-(2-(4-Fluoro-2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl:) - 1,2,3 , 4-tetrahydroquinolinyl-6-yl:) propionic acid
Figure imgf000006_0007
3-(2-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-7-fluoro-1,2,3, 4-tetrahydroquinolinyl-6-yl;) propionic acid
Figure imgf000007_0001
3-(2-(4'-(3- (乙磺酰基）丙氧基 )-2',6'-二甲基联苯基 -3-基) -7-氟 -1,2,3 ,4-四氫喹啉 -6-基；)丙酸
Figure imgf000007_0002
3-(2-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-7-fluoro-1,2,3, 4-tetrahydroquinolin-6-yl;) propionic acid
Figure imgf000007_0002
3-(2-(2',6'-二甲基联苯基 -3-基) -7-氟 -1,2,3,4-四氫喹啉 -6-基)丙 酸 3-(2-(2',6'-Dimethylbiphenyl-3-yl)-7-fluoro-1,2,3,4-tetrahydroquinolin-6-yl)propionic acid
3-(2-(2',4,6'-三甲基 -4'-(3-(甲磺酰基）丙氧基）联苯 -3- 基:) -1,2,3,4-四氫喹啉 -6-基：)丙酸 3-(2-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl:) -1,2,3,4- Tetrahydroquinolin-6-yl:) propionic acid
Ο CI ΟΗ Ο CI ΟΗ
3-(2-(5'-氯 -2',6'-二甲基 -4'-(3-(甲磺酰基）丙氧基）联苯 -3- 基:) -1,2,3,4-四氫喹啉 -6-基：)丙酸
Figure imgf000007_0003
3-(2-(5'-Chloro-2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl:) -1,2,3 ,4-tetrahydroquinolin-6-yl:)propionic acid
Figure imgf000007_0003
3-(2-(5'-氟 -2',6'-二甲基 -4'-(3-(甲磺酰基）丙氧基）联苯 -3- 基:) -1,2,3,4-四氫喹啉 -6-基：)丙酸
Figure imgf000007_0004
3-(2-(5'-fluoro-2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl:) -1,2,3 ,4-tetrahydroquinolin-6-yl:)propionic acid
Figure imgf000007_0004
3-(7-氟 -2-(2'-甲基 -4'-(3-(甲磺酰基)丙氧基)联苯 -3-基)- 1 ,2,3,4- 四氫喹啉 -6-基；)丙酸 CHH3 3-(7-fluoro-2-(2'-methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)- 1 ,2,3,4-tetrahydroquin Porphyrin-6-yl;) propionic acid CH H 3
o.八八 L JL 。H  o. Eight eight L JL. H
3-(7-氟 -2-(2',4,6'-三甲基 -4'-(3-(甲磺酰基）丙氧基）联苯 -3- 基:) -1,2,3,4-四氫喹啉 -6-基：)丙酸
Figure imgf000008_0001
3-(7-fluoro-2-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl:) -1,2, 3,4-tetrahydroquinolin-6-yl:)propionic acid
Figure imgf000008_0001
3-(3-(2',6'-二甲基联苯 -3-基) -3,4-二氫 -2 -苯并 [b][l,4]噁嗪 -7- 基:)丙酸 3-(3-(2',6'-dimethylbiphenyl-3-yl)-3,4-dihydro-2-benzo[b][l,4]oxazin-7-yl:) Propionic acid
3-(3-(2',6'-二甲基 -4'-(3-(甲磺酰基）丙氧基)联苯基 -3-基) -3,4- 二氫 -2 -苯并 [b] [ 1 ,4]噁嗪 -7-基:)丙酸
Figure imgf000008_0002
3-(3-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3,4-dihydro-2-benzene And [b] [1,4]oxazin-7-yl:)propionic acid
Figure imgf000008_0002
3-(3-(4，- [(四氫 -1 ,1-二氧 -2//-噻喃 -4-基)氧基] -2',6'-二甲基联苯 基 -3-基) -3,4-二氫 -2 -苯并 [b][l,4]噁嗪 -7-基)丙酸
Figure imgf000008_0003
3-(3-(4,-[(tetrahydro-1,1-dioxo-2//-thiopyran-4-yl)oxy]-2',6'-dimethylbiphenyl-3 -yl)-3,4-dihydro-2-benzo[b][l,4]oxazin-7-yl)propionic acid
Figure imgf000008_0003
3-(3-(2',6'-二甲基 -4'-(3-(甲磺酰基）丙氧基)联苯基 -3-基) -6-氟 —3 ,4-二氫 -2 -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸  3-(3-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-6-fluoro-3,4-dihydro -2 -Benzo[b][1,4]oxazin-7-yl)propionic acid
3-(6-氟 -3-(2',4,6'-三甲基 -4'-(3-(甲磺酰基）丙氧基）联苯 -3- 基) -3 ,4-二氫 -2 -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸 3-(6-fluoro-3-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3,4-di Hydrogen-2-benzo[b][1,4]oxazin-7-yl)propionic acid
H F 3-(6-氟 -3-(3'-氟 -2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联苯 -3- 基) -3 ,4-二氫 -2 -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸
Figure imgf000009_0001
HF 3-(6-fluoro-3-(3'-fluoro-2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3, 4-dihydro-2-benzo[b][1,4]oxazin-7-yl)propionic acid
Figure imgf000009_0001
3-(6-氟 -3-(4'-(3- (异丙磺酰基）丙氧基 )-2',6'-二甲基联比啶 -3- 基) -3 ,4-二氫 -2 -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸
Figure imgf000009_0002
3-(6-fluoro-3-(4'-(3-(isopropylsulfonyl)propoxy)-2',6'-dimethylbipyridin-3-yl)-3,4-di Hydrogen-2-benzo[b][1,4]oxazin-7-yl)propionic acid
Figure imgf000009_0002
〇  〇
3-(3-(4'-(3- (环丙磺酰基）丙氧基 )-2',6'-二甲基联苯基 -3-基) -6- 氟—3,4-二氫 -2 -苯并 [b][l,4]噁嗪 -7-基)丙酸  3-(3-(4'-(3-(cyclopropanesulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-6-fluoro-3,4-di Hydrogen-2-benzo[b][l,4]oxazin-7-yl)propionic acid
工"  Work
0 0  0 0
〉 LL  〉 LL
3-(3-(4'-(3- (乙磺酰基）丙氧基 )-2',6'-二甲基联 〇 苯基 -3-基) -6-氟 —3 ,4-二氫 -2 -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸
Figure imgf000009_0003
3-(3-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-6-fluoro-3,4-di Hydrogen-2-benzo[b][1,4]oxazin-7-yl)propionic acid
Figure imgf000009_0003
3-(3-(2',6'-二乙基 -4'-(3-(甲磺酰基）丙氧基)联苯基 -3-基) -6-氟 —3 ,4-二氫 -2 -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸  3-(3-(2',6'-diethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-6-fluoro-3,4-dihydro -2 -Benzo[b][1,4]oxazin-7-yl)propionic acid
3-(6-氟 -3-(4'-(3- (异丙基磺酰基)丙氧基 )-2',4,6'-三甲基联苯基 -3-基) -3,4-二氫 -2 -苯并 [b][l,4]噁嗪 -7-基)丙酸
Figure imgf000009_0004
3-(6-fluoro-3-(4'-(3-(isopropylsulfonyl)propoxy)-2',4,6'-trimethylbiphenyl-3-yl)-3, 4-dihydro-2-benzo[b][l,4]oxazin-7-yl)propionic acid
Figure imgf000009_0004
3-(3-(4'-(3- (乙磺酰基）丙氧基 )-2',4,6'-三甲基联苯基 -3-基) -6- 氟—3,4-二氫 -2 -苯并 [b][l,4]噁嗪 -7-基)丙酸
Figure imgf000010_0001
或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异 构体、 其混合物形式、 及其可药用的盐。 3-(3-(4'-(3-(ethylsulfonyl)propoxy)-2',4,6'-trimethylbiphenyl-3-yl)-6-fluoro-3,4- Dihydro-2-benzo[b][l,4]oxazin-7-yl)propionic acid
Figure imgf000010_0001
Or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt thereof.
本发明还涉及一种药物组合物， 其含有治疗有效量的通式 (I)所示 的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对 映异构体、 其混合物形式、 及其可药用的盐及药学上可接受的载体， 稀释剂和赋形剂。  The invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer, a non- Enantiomers, mixtures thereof, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents and excipients.
本发明的另一方面涉及通式 (I)所示的化合物或其互变异构体、 内 消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混合物形式、 及 其可药用的盐， 可在生物体内转化其的前体药物， 或包含其的药物组 合物在制备 GPR40激动剂中的用途。  Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, a mixture thereof And a pharmaceutically acceptable salt thereof, a prodrug thereof which can be converted in vivo, or a pharmaceutical composition comprising the same, for use in the preparation of a GPR40 agonist.
本发明的另一方面涉及通式 (I)所示的化合物或其互变异构体、 内 消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混合物形式、 及 其可药用的盐， 可在生物体内转化其的前体药物， 或包含其的药物组 合物在制备治疗糖尿病和代谢综合症的疾病的药物中的用途， 其中所 述的糖尿病为 II型糖尿病。  Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, a mixture thereof And a pharmaceutically acceptable salt thereof, the use of a prodrug thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for treating a disease of diabetes and metabolic syndrome, wherein said diabetes is II Type 2 diabetes.
本发明还涉及一种治疗糖尿病和代谢综合症的疾病的方法， 该方 法包括给予需要治疗的患者治疗有效量的通式 (I)所示的化合物或其互 变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混 合物形式、 及其可药用的盐， 可在生物体内转化其的前体药物， 或包 含其的药物组合物。 The invention also relates to a method for treating diseases of diabetes and metabolic syndrome, the method The method comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof. And a mixture thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof which can be converted in vivo, or a pharmaceutical composition comprising the same.
本发明的另一方面涉及作为治疗糖尿病和代谢综合症的疾病的药 物的通式 (I)所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对 映异构体、 非对映异构体、 其混合物形式、 及其可药用的盐， 其中所 述的糖尿病优选为 II型糖尿病。  Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer thereof, which is a medicament for the treatment of diseases of diabetes and metabolic syndrome a form, a mixture of diastereomers, a mixture thereof, and a pharmaceutically acceptable salt thereof, wherein said diabetes is preferably type II diabetes.
本发明的另一方面涉及一种调节胰岛素的方法， 该方法包括给予 需要治疗的患者有效治疗量的通式 (I)所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混合物形式、 及其可药用的盐， 可在生物体内转化其的前体药物， 或包含其的药物 组合物。  Another aspect of the invention relates to a method of modulating insulin comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, a mesogen, a topical A steroid, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt thereof, a prodrug thereof which can be converted in vivo, or a pharmaceutical composition comprising the same.
本发明的另一方面涉及作为涉及调节胰岛素的药物的通式 (I)所示 的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对 映异构体、 其混合物形式、 及其可药用的盐。 具体实施方式  Another aspect of the invention relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof as a medicament for regulating insulin Isomers, mixtures thereof, and pharmaceutically acceptable salts thereof. detailed description
除非有相反陈述， 否则下列用在说明书和权利要求书中的术语具 有下述含义。  Unless otherwise stated, the following terms used in the specification and claims have the following meanings.
"烷基 "指饱和的脂族烃基团， 包括 1至 20个碳原子的直链和支链 基团。 非限制性实施例包括甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 叔丁基、 仲丁基、 正戊基、 1,1-二甲基丙基、 1,2-二甲基丙基、 2,2-二甲基丙基、 1-乙基丙基、 2-甲基丁基、 3-甲基丁基、 正己基、 1- 乙基 -2-甲基丙基、 1,1,2-三甲基丙基、 1,1-二甲基丁基、 1,2-二甲基丁基、 2,2-二甲基丁基、 1,3-二甲基丁基、 2-乙基丁基、 2-甲基戊基、 3-甲基戊 基、 4-甲基戊基、 2,3-二甲基丁基、 正庚基、 2-甲基己基、 3-甲基己基、 4-甲基己基、 5-甲基己基、 2,3-二甲基戊基、 2,4-二甲基戊基、 2,2-二甲 基戊基、 3,3-二甲基戊基、 2-乙基戊基、 3-乙基戊基、 正辛基、 2,3-二甲 基己基、 2,4-二甲基己基、 2,5-二甲基己基、 2,2-二甲基己基、 3,3-二甲 基己基、 4,4-二甲基己基、 2-乙基己基、 3-乙基己基、 4-乙基己基、 2- 甲基 -2-乙基戊基、 2-甲基 -3-乙基戊基、 正壬基、 2-甲基 -2-乙基己基、 2-甲基 -3-乙基己基、 2,2-二乙基戊基、 正癸基、 3,3-二乙基己基、 2,2- 二乙基己基， 及其各种支链异构体等。 烷基可以是任选取代的或未取 代的。 "Alkyl" means a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4- Ethylhexyl, 2- Methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2, 2-Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. The alkyl group can be optionally substituted or unsubstituted.
"亚烷基"指饱和的的脂族烃从形式上消除两个氫原子所形成的基 团， 包括 1至 20个碳原子的直链和支链基团。 亚烷基的非限制性实施 例包括亚甲基、 亚乙基、 亚异丙基、 亚丁基、 亚戊基、 亚己基、 1,2— 亚乙基、 1,3—亚丙基等。 亚烷基可以是任选取代的或未取代的。  "Alkylene" means a group formed by the elimination of two hydrogen atoms by a saturated aliphatic hydrocarbon, including linear and branched groups of 1 to 20 carbon atoms. Non-limiting examples of alkylene groups include methylene, ethylene, isopropylidene, butylene, pentylene, hexylene, 1,2-ethylidene, 1,3-propylene, and the like. The alkylene group can be optionally substituted or unsubstituted.
"环烷基"指饱和或部分不饱和单环或多环环状烃取代基。 例如可 以是 3、 4、 5、 6元环。 单环环烷基的非限制性实施例包含环丙基、 环 丁基、 环戊基、 环戊烯基、 环己基、 环己烯基、 环己二烯基、 环庚基、 环庚三烯基、 环辛基等。 环烷基可以是任选取代的或未取代的。  "Cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. For example, it can be a 3, 4, 5, or 6-membered ring. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Alkenyl, cyclooctyl and the like. The cycloalkyl group can be optionally substituted or unsubstituted.
"亚环烷基"指饱和或部分不饱和单环或多环环状烃从形式上消除 两个氫原子所形成的基团。 单环亚环烷基的非限制性实施例包含亚环 丙基、 亚环丁基、 亚环戊基、 亚环己基、 亚环庚基、 亚环辛基、 1,2- 亚环丙基、 1,3-亚环丁基、 1,4-亚环己基等。  "Cycloalkylene" means a radical formed by the elimination of two hydrogen atoms from a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon. Non-limiting examples of monocyclic cycloalkylene groups include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cyclohexylene, cyclooctylene, 1,2-cyclopropylene , 1,3-cyclopentylene, 1,4-cyclohexylene, and the like.
"烷氧基"指 -0- (烷基)和 -0- (未取代的环烷基)， 其中烷基的定义如 上所述。 非限制性实施例包含甲氧基、 乙氧基、 丙氧基、 丁氧基、 环 丙氧基、 环丁氧基、 环戊氧基、 环己氧基等。 烷氧基可以是任选取代 的或未取代的。  "Alkoxy" means -0-(alkyl) and -0-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like. The alkoxy group may be optionally substituted or unsubstituted.
"杂环基"指饱和或部分不饱和单环或多环环状烃取代基， 其包括 3 至 20个环原子， 其中一个或多个环原子选自氮、 氧或 S(0)m (；其中 m 是整数 0至 2)的杂原子， 但不包括 -Ο-Ο-,-0-S-或 -S-S-的环部分， 其余 环原子为碳。 单环杂环基的非限制性实施例包含吡咯烷基、 哌啶基、 哌嗪基、 吗啉基、 疏代吗啉基、 高哌嗪基等。  "Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(0)m ( Wherein m is a hetero atom of the integer 0 to 2), but does not include a ring moiety of -Ο-Ο-,-0-S- or -SS-, and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxamorpholinyl, homopiperazinyl and the like.
"羟基 "指 -OH基团。  "Hydroxy" means an -OH group.
"卤素"指氟、 氯、 溴或碘。  "Halogen" means fluoro, chloro, bromo or iodo.
"任选 "或"任选地"意味着随后所描述地事件或环境可以但不必发 生， 该说明包括该事件或环境发生或不发生地场合。 例如， "任选被烷 基取代的杂环基团"意味着烷基可以但不必须存在， 该说明包括杂环基 团被烷基取代的情形和杂环基团不被烷基取代的情形。 "取代的"指基团中的一个或多个氫原子， 优选为最多 5 个， 更优 选为 1〜3个氫原子彼此独立地被相应数目的取代基取代。 不言而喻， 取代基仅处在它们的可能的化学位置， 本领域技术人员能够在不付出 具有游离氳的氨基或 基与 有 饱和 ( 婦一属)：的碳原子结合时可 能是不稳定的。 "Optional" or "optionally" means that the event or environment described subsequently may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, including the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. . "Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can be unstable when they do not pay an amino group having a free hydrazine in combination with a saturated carbon atom. of.
"药物组合物 "表示含有一种或多种本文所述化合物或其生理学上 / 可药用的盐或前体药物与其他化学组分的混合物， 以及其他组分例如 生理学 /可药用的载体和赋形剂。 药物组合物的目的是促进对生物体的 给药， 利于活性成分的吸收进而发挥生物活性。 本发明化合物的合成方法  "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity. Method for synthesizing the compound of the present invention
为了完成本发明的目的， 本发明采用如下技术方案：  In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:
本发明通式 (I)所述的化合物或其可药用的盐的制备， 可通过以下 方案及工作实例中所述的示例性方法以及本领域技术人员所用的相关 公开文献搡作完成。  The preparation of the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be carried out by the following exemplary schemes and the exemplary methods described in the working examples and related publications used by those skilled in the art.
Figure imgf000013_0001
Figure imgf000013_0001
可如方案 1 中所示制备通式 (Ix)的化合物， 硝基、 羟基取代苯基化 合物 la与丙烯酸烷基酯 lb在催化剂存在条件下发生 Heck反应得到丙 婦基取代苯基化合物 Ic， 丙烯基取代苯基化合物 Ic在催化剂存在条件 下与还原剂反应得到化合物 Id，化合物 Id和溴代苯乙酮 Ie在碱性条件 下在溶剂中发生环合反应得到化合物 If,化合物 If在溶剂中与还原剂反 应得到化合物 Ig,化合物 Ig和硼酸酯化合物 Ih在催化剂催化下于溶液 中发生 Suzuki偶联反应得到通式的化合物 (Ix)中的酯，将得到的产物任 选一步水解得到相应的酸或盐。 The compound of the formula (Ix) can be prepared as shown in the scheme 1, the nitro group, the hydroxy-substituted phenyl compound la and the alkyl acrylate lb are reacted in the presence of a catalyst to obtain a C-c reaction. The phenyl-substituted phenyl compound Ic, the propylene-substituted phenyl compound Ic is reacted with a reducing agent in the presence of a catalyst to obtain a compound Id, and the compound Id and the bromoacetophenone Ie are cyclized in a solvent under basic conditions. Compound If, Compound If is reacted with a reducing agent in a solvent to obtain Compound Ig, and Compound Ig and Borate Compound Ih are subjected to a Suzuki coupling reaction in a catalyst under a catalyst to obtain an ester of the compound (Ix) of the formula, which will give The product is optionally hydrolyzed in one step to give the corresponding acid or salt.
或者， 可使中间体 Ic直接与溴代苯乙酮 Ie反应得到化合物 Π,化合 物 Ii在催化剂条件下发生 Miyaura反应得到化合物 Ij， 化合物 Ij在溶 剂中与还原剂反应得到化合物 Ik， 化合物 Ik和苯基溴代物 II在催化剂 催化下于溶液中发生 Suzuki偶联反应得到通式的化合物 (Ix)中的酯，将 得到的产物任选一步水解得到相应的酸或盐。  Alternatively, the intermediate Ic can be directly reacted with bromoacetophenone Ie to obtain a compound oxime, and the compound Ii undergoes a Miyaura reaction under a catalyst condition to obtain a compound Ij, and the compound Ij is reacted with a reducing agent in a solvent to obtain a compound Ik, a compound Ik and a benzene. The thiol II is subjected to a Suzuki coupling reaction in a solution catalyzed by a catalyst to obtain an ester of the compound (Ix) of the formula, and the obtained product is optionally subjected to one-step hydrolysis to give the corresponding acid or salt.
Figure imgf000014_0001
可如方案 2 中所示制备通式 (Iy)的化合物， 喹啉化合物 Ila与丙烯 酸烷基酯 lb在催化剂存在条件下发生 Heck反应得到丙烯基取代喹啉 化合物 lib, 喹啉化合物 lib在溶剂中与还原剂反应得到化合物 IIc， 化 合物 lie在溶剂中与氧化剂反应得到化合物 lid,化合物 lid与 1¾代试剂 反应得到化合物 lie, 化合物 lie和硼酸酯化合物 Ilf在催化剂催化下于 溶液中发生 Suzuki偶联反应得到化合物 IIg， 化合物 Ilg在碱性条件下 与三氟甲基磺酸酐反应得到化合物 IIh， 化合物 Ilh和硼酸酯化合物 Ih 在催化剂催化下于溶液中发生 Suzuki偶联反应得到化合物 IIi， 化合物 Ili在溶剂中与还原剂反应得到通式的化合物 (Iy)中的酯，将得到的产物 任选一步水解得到化合物 (Iy)中的酸或盐。
Figure imgf000014_0001
The compound of the formula (Iy) can be prepared as shown in Scheme 2, and the quinoline compound Ila and the alkyl acrylate lb are Heck-reacted in the presence of a catalyst to obtain a propylene-substituted quinoline compound lib, which is in a solvent. Reaction with a reducing agent to obtain compound IIc, compound lie is reacted with an oxidizing agent in a solvent to obtain compound lid, compound lid is reacted with a reagent of 13⁄4 to obtain compound lie, and compound lie and borate compound Ilf are subjected to Suzuki coupling in solution under catalyst catalysis. The reaction gives compound IIg, and the compound Ilg is reacted with trifluoromethanesulfonic anhydride under basic conditions to obtain compound IIh, compound Ilh and borate compound Ih. Suzuki coupling reaction occurs in solution under catalyst catalysis to obtain compound IIi. Compound Ili is reacted with a reducing agent in a solvent to obtain an ester of the compound (Iy) of the formula, and the obtained product is optionally hydrolyzed to obtain a compound (Iy). The acid or salt.
或者， 可使中间体 lie与硼酸酯化合物 Ilj在催化剂催化下于溶液 中发生 Suzuki偶联反应得到化合物 IIi， 化合物 Ili在溶剂中与还原剂 反应得到通式的化合物 (Iy)中的酯， 将得到的产物任选一步水解得到化 合物 (Iy)中的酸或盐。  Alternatively, the intermediate lie and the boronic acid ester compound Ilj can be subjected to a Suzuki coupling reaction in a catalyst to obtain a compound IIi, and the compound Ili is reacted with a reducing agent in a solvent to obtain an ester of the compound (Iy) of the formula. The obtained product is optionally hydrolyzed in one step to give an acid or a salt in the compound (Iy).
提供酸性条件的酸包括但不限于甲酸、 乙酸、 盐酸、 疏酸、 甲磺 酸、 四丁基氯化铵。  Acids which provide acidic conditions include, but are not limited to, formic acid, acetic acid, hydrochloric acid, hydrochloric acid, methanesulfonic acid, tetrabutylammonium chloride.
提供碱性条件的碱包括有机碱和无机碱类， 所述的有机碱类包括 但不限于三乙胺、 4-二甲氨基吡啶、 咪唑、 Ν,Ν-二异丙基乙胺、 正丁基 锂、 叔丁醇钾， 四丁基溴化铵， 优选为三乙胺； 所述的无机碱类包括 但不限于氫化钠、 碳酸钠、 碳酸氫钠、 碳酸钾、 碳酸氫钾或碳酸铯， 优选为碳酸钾或碳酸铯。  Bases which provide basic conditions include organic bases and inorganic bases including, but not limited to, triethylamine, 4-dimethylaminopyridine, imidazole, indole, indole-diisopropylethylamine, n-butyl Lithium, potassium t-butoxide, tetrabutylammonium bromide, preferably triethylamine; said inorganic bases including but not limited to sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate It is preferably potassium carbonate or cesium carbonate.
催化剂包括但不限于四-三苯基磷钯、 三苯基磷、 二氯化钯、 醋酸 钯、 1,1，-双 (二苄基磷)二氯二戊铁钯、 三 (二亚苄基丙酮)二钯、 钯 /碳或 兰尼镍。  Catalysts include, but are not limited to, tetra-triphenylphosphine palladium, triphenylphosphine, palladium dichloride, palladium acetate, 1,1,-bis(dibenzylphosphine) dichlorodipentadium iron palladium, tris(dibenzylidene) Acetone) dipalladium, palladium/carbon or Raney nickel.
氧化剂包括但不限于四氧化饿、 三氯氧磷。  Oxidizing agents include, but are not limited to, tetraoxide, phosphorus oxychloride.
卤化试剂包括但不限于溴水或 1¾化物； 优选三氯氧磷。  Halogenating agents include, but are not limited to, bromine water or phosphine; phosphorus oxychloride is preferred.
还原剂包括但不限于硼氫化钠、 硼氫化锂、 硼烷、 锌粉、 铁粉或 氫气。  Reducing agents include, but are not limited to, sodium borohydride, lithium borohydride, borane, zinc powder, iron powder or hydrogen.
所用溶剂包括但不限于： 醋酸、 甲醇、 乙醇、 丙酮、 叔丁醇、 乙 醚、 四氫呋喃、 二氯甲烷、 二甲基亚砜、 甲苯、 1,4-二氧六环、 水或 Ν,Ν-二甲基甲酰胺。 实施例  Solvents used include, but are not limited to: acetic acid, methanol, ethanol, acetone, tert-butanol, diethyl ether, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, toluene, 1,4-dioxane, water or hydrazine, hydrazine- dimethylformamide. Example
以下结合实施例用于进一步描述本发明， 但这些实施例并非限制 着本发明的范围。  The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.
化合物的结构是通过核磁共振 (NMR)或^谱 (MS)来确定的。 NMR 的测定是用 Bruker AVANCE-400或 Varian Oxford-300核磁仪， 测定溶 剂为氘代二甲基亚砜（DMSO-d6)， 氘代氯仿（CDC13)， 氘代甲醇 (CD3OD)， 内标为四甲基硅烷 (TMS)， 化学位移是以 10-6 (ppm)作为单 位给出。 The structure of the compound is determined by nuclear magnetic resonance (NMR) or spectral (MS). The NMR was measured by Bruker AVANCE-400 or Varian Oxford-300 NMR, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ), deuterated methanol. (CD 3 OD), the internal standard is tetramethylsilane (TMS), and the chemical shift is given in units of 10 - 6 (ppm).
MS的测定用 Agilent SQD(ESI)^谱仪 (生产商： Agilent,型号： 6110) 或 Shimadzu SQD(ESI)^谱仪 (生产商： Shimadzu, 型号： 2020)。  The MS was measured using an Agilent SQD (ESI) spectrometer (manufacturer: Agilent, model: 6110) or Shimadzu SQD (ESI) spectrometer (manufacturer: Shimadzu, model: 2020).
HPLC的测定使用安捷伦 1200DAD高压液相色谱仪 (Sunfirc C18， 150x4.6mm， 5μιη, 色谱柱)和 Waters 2695-2996高压液相色谱仪 (Gimini C18 150x4.6mm， 5μιη色谱柱；)。  The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfirc C18, 150 x 4.6 mm, 5 μιη, column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm, 5 μιη column;).
薄层层析硅胶板使用青岛海洋 GF254 硅胶板， 薄层色谱法 (TLC) 使用的硅胶板采用的规格是 0.15mm〜0.2mm， 薄层层析分离纯化产品 采用的规格是 0.4mm〜0.5mm硅胶板。  The thin layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm. The specification for thin layer chromatography separation and purification is 0.4mm~0.5mm. silicone board.
柱层析一般使用青岛海洋 200〜300 目硅胶为载体。  Column chromatography generally uses Qingdao Ocean 200~300 mesh silica gel as a carrier.
本发明的已知的起始原料可以采用或按照本领域已知的方法来合 成，或可购买自 ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, 韶远化学科技 (Accela ChemBio Inc)、 北京耦合化学品等公 司。  The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Beijing Coupling Companies such as chemicals.
实施例中如无特殊说明， 反应均在氩气氛或氮气氛下进行。  In the examples, the reactions were all carried out under an argon atmosphere or a nitrogen atmosphere unless otherwise specified.
氩气氛或氮气氛是指反应瓶连接一个约 1L 容积的氩气或氮气气 球。  An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen gas ball of about 1 L volume.
氫气氛是指反应瓶连接一个约 1L容积的氫气气球。  The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
加压氫化反应使用北京佳維科创科技有限公司 GCD-500G高纯氫 气发生器和 BLT-2000中压氫化仪。  The pressurized hydrogenation reaction was carried out using Beijing Jiawei Kechuang Technology Co., Ltd. GCD-500G high purity hydrogen gas generator and BLT-2000 medium pressure hydrogenation instrument.
氫化反应通常抽真空， 充入氫气， 反复搡作 3次。  The hydrogenation reaction is usually carried out by vacuuming, charging with hydrogen, and repeating the reaction three times.
微波反应使用 CEM Discover-SP型微波反应器。  The microwave reaction was carried out using a CEM Discover-SP type microwave reactor.
实施例中如无特殊说明， 反应的温度为室温， 温度范围是 20°C— 30°C。  In the examples, unless otherwise specified, the reaction temperature is room temperature, and the temperature range is from 20 ° C to 30 ° C.
实施例中的反应进程的监测采用薄层色谱法 (TLC)， 反应所使用的 展开剂的体系有： A: 二氯甲烷和甲醇体系， B : 石油醚和乙酸乙酯体 系， 溶剂的体积比根据化合物的极性不同而进行调节。  The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, volume ratio of solvent The adjustment is made according to the polarity of the compound.
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂 的体系包括： A: 二氯甲烷和甲醇体系， B : 石油醚和乙酸乙酯体系， 三乙胺和酸性或碱性试剂等进行调节。 The system of the eluent for column chromatography and the system for the developer of the thin layer chromatography using the purified compound include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, Triethylamine is adjusted with an acidic or alkaline reagent or the like.
实施例 1  Example 1
3-2-(2'6'-二甲基联苯 -3-基) -1,2,3,4-四氫喹啉 -6-基) -丙酸  3-2-(2'6'-dimethylbiphenyl-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)-propionic acid
Figure imgf000017_0001
Figure imgf000017_0001
第一步  First step
6- (3-乙氧基 -3-氧酰丙基)喹啉 1-氧化物  6-(3-ethoxy-3-oxoylpropyl)quinoline 1-oxide
250mL干燥单口瓶中称入喹啉化合物 la (500mg, 2.2mmol, 采用 公知的方法"专利 WO2008051805"制备而得）， 加入二氯甲烷 （50mL)， 冰水浴冷却至 0。C， 然后分批加入间氯过氧苯甲酸 （751mg， 4.4mmol) o 0°C下搅拌反应 1 小时后， 自然恢复至室温并继续搅拌反应， TLC监 测反应直到原料反应完全。 将反应用亚疏酸钠水溶液淬灭， 二氯甲烷 萃取( 100mLx3)， 合并有机相并依次用饱和碳酸氩钠溶液和饱和食盐水 洗涤， 无水硫酸钠干燥，过滤除去干燥剂，减压脱溶得到标题产物 6-(3- 乙氧基 -3-氧酰丙基)喹啉 1-氧化物 lb(512mg， 白色固体)， 产率： 95%。 产物不经纯化直接用于下一步反应。  A 250 mL dry single-mouth bottle was weighed into a quinoline compound la (500 mg, 2.2 mmol, prepared by the known method "WO2008051805", added with dichloromethane (50 mL), and cooled to 0 in an ice water bath. C, then m-chloroperoxybenzoic acid (751 mg, 4.4 mmol) was added portionwise. After stirring for 1 hour at 0 ° C, the mixture was allowed to naturally warm to room temperature and stirring was continued, and the reaction was monitored by TLC until the starting material was completely reacted. The reaction was quenched with aqueous sodium sulphate and extracted with dichloromethane (100 mL×3). The organic phase was combined and washed sequentially with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate The title product 6-(3-ethoxy-3-oxoylpropyl)quinoline 1-oxide lb (512 mg, white solid). The product was used in the next reaction without purification.
MS m/z (ESI) : 246 [M+l]  MS m/z (ESI): 246 [M+l]
第二步  Second step
3 -(2-氯喹啉 -6-基)丙酸乙酯 lOOmL干燥单口瓶中称入 6-(3-乙氧基 -3-氧酰丙基)喹啉 1-氧化物 lb (512mg, 2.09mmol), 冰水浴冷却至 0。C， 缓慢加入三氯氧磷 (8mL)。 油浴加热至 100。C搅拌反应， TLC监测反应直到原料反应完全。 冷却 至室温， 减压脱溶除去大部分三氯氧磷， 然后用冰水小心淬灭反应， 用氨水中和， 调节 pH值约为 8。 然后用乙酸乙酯萃取 (30mLx3)， 合并 有机相并用饱和食盐水洗涤， 无水疏酸钠干燥， 过滤除去干燥剂， 减 压脱溶， 残余物用硅胶柱层析纯化 (石油 /乙酸乙酯 = 5 : 1)， 得到标 题产物 3-(2-氯喹啉 -6-基)丙酸乙酯 lc (220mg,浅黄色固体)，产率： 40%。 3-(2-chloroquinolin-6-yl)propionic acid ethyl ester 6-(3-ethoxy-3-oxoylpropyl)quinoline 1-oxide lb (512 mg, 2.09 mmol) was weighed into a 100 mL dry single-mouth flask and cooled to 0 in an ice water bath. C, phosphorus oxychloride (8 mL) was added slowly. The oil bath is heated to 100. The reaction was stirred and the reaction was monitored by TLC until the starting material was completely reacted. After cooling to room temperature, most of the phosphorus oxychloride was removed by vacuum stripping, and then the reaction was carefully quenched with ice water and neutralized with aqueous ammonia to adjust the pH to about 8. Then, it is extracted with ethyl acetate (30 mL×3), and the organic phase is combined and washed with brine, dried over anhydrous sodium sulfate. = 5 : 1) The title product ethyl 3-(2-chloroquinolin-6-yl)propanoate lc (220 mg, pale yellow solid).
MS m/z (ESI) : 264 [M+l]  MS m/z (ESI) : 264 [M+l]
¾ NMR (300 MHz, CD3OD) δ 8.25-8.23 (m， 1H)， 7.86-7.70 (m, 3H)， 7.46-7.44 (m， 1H)， 4.13-4.06 (m， 2H), 3.14-3.09 (m， 2H), 2.77-2.72 (m， 2H), 1.21-1.16 (m, 3H)。 3⁄4 NMR (300 MHz, CD 3 OD) δ 8.25-8.23 (m, 1H), 7.86-7.70 (m, 3H), 7.46-7.44 (m, 1H), 4.13-4.06 (m, 2H), 3.14-3.09 (m, 2H), 2.77-2.72 (m, 2H), 1.21-1.16 (m, 3H).
第三步  third step
2',6'-二甲基联苯基 -3-酚  2',6'-dimethylbiphenyl-3-phenol
lOOmL 干燥三口瓶中称入 2,6-二甲基苯硼酸（1.0g， 6.67mmol), PdCl2(dppf) (0.05mmol) , 碳酸钾 (276mg， 2mmol)和 3-溴苯酚（1.4g， 8.0mmol)。 将体系置换为氮气氛围， 加入二氧六环 (20mL)和水 (4mL)， 然后在 85°C下搅拌反应， TLC监测反应直到原料反应完全。 冷却至室 温， 将反应体系用 40mL 水稀释， 乙酸乙酯萃取 (60mLx3)， 合并有机 相并用饱和食盐水洗涤， 无水疏酸钠干燥， 过滤除去干燥剂， 减压脱 溶， 残余物用硅胶柱层析纯化 (石油 /乙酸乙酯 = 20 : 1)， 得到标题产 物 2',6'-二甲基联苯基 -3-酚 le (1.2g， 无色油状液体)， 产率： 90%。 In a 100 mL dry three-necked flask, weighed 2,6-dimethylphenylboronic acid (1.0 g, 6.67 mmol), PdCl 2 (dppf) (0.05 mmol), potassium carbonate (276 mg, 2 mmol) and 3-bromophenol (1.4 g, 8.0 mmol). The system was replaced with a nitrogen atmosphere, dioxane (20 mL) and water (4 mL) were then weighed, and then the reaction was stirred at 85 ° C, and the reaction was monitored by TLC until the starting material was completely reacted. After cooling to room temperature, the reaction system was diluted with 40 mL of water, and extracted with ethyl acetate (60 mL×3). The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to remove solvent. Purification by column chromatography (EtOAc / EtOAc =EtOAc:EtOAc) %.
¾ NMR (300 MHz, CD3OD) δ 7.30-7.01 (m， 4H)， 6.78-6.67 (m, 1H)， 6.57-6.53 (m， 2H), 2.01 (s， 6H)。  3⁄4 NMR (300 MHz, CD3OD) δ 7.30-7.01 (m, 4H), 6.78-6.67 (m, 1H), 6.57-6.53 (m, 2H), 2.01 (s, 6H).
第四步  the fourth step
2',6'-二甲基联苯基 -3-基三氟甲磺酸酯  2',6'-dimethylbiphenyl-3-yltrifluoromethanesulfonate
lOOmL 干燥单口瓶中称入 2',6'-二甲基联苯基 -3-酚 le (1.2g , 6mmol)， 加入二氯甲烷 (20mL)， 二异丙基乙基胺（1.5g， 12mmol)。 然 后在冰水浴冷却下缓慢加入三氟甲碌酸酐 (2.5g， 9mmol), 自然恢复至 室温并继续搅拌反应， TLC 监测反应直到原料反应完全。 饱和碳酸氫 钠（15mL)淬灭反应， 分离有机相并用饱和食盐水洗涤， 无水疏酸钠干 燥， 过滤除去干燥剂， 减压脱溶， 得到标题产物 2',6'-二甲基联苯基 -3- 基三氟甲磺酸酯 lf (1.6g， 无色油状液体)， 产率： 90%， 产物不经纯化 直接用于下一步反应。 2 ',6'-dimethylbiphenyl-3-phenol le (1.2 g, 6 mmol) was weighed into a 100 mL dry single-mouth bottle, and dichloromethane (20 mL) and diisopropylethylamine (1.5 g, 12mmol). Trifluoromethane anhydride (2.5 g, 9 mmol) was then slowly added while cooling in an ice water bath, which was naturally returned to room temperature and stirring was continued, and the reaction was monitored by TLC until the starting material was completely reacted. The reaction was quenched with saturated sodium bicarbonate (15 mL). Drying, the desiccant was removed by filtration, and the solvent was evaporated to give the title product 2',6'-dimethylbiphenyl-3-yl trifluoromethanesulfonate lf (1.6 g, colorless oily liquid), yield : 90%, the product was used in the next step without purification.
¾ NMR (300 MHz, CDCb) δ 7.56-7.50 (m, 1Η)， 7.31-7.12 (m, 6Η)， 2.05 (s, 6Η)。  3⁄4 NMR (300 MHz, CDCb) δ 7.56-7.50 (m, 1Η), 7.31-7.12 (m, 6Η), 2.05 (s, 6Η).
第五步  the fifth step
2- (2',6'-二甲基联苯基 -3-基) -4,4,5,5-四甲基 -1,3 ,2-二氧硼烷  2-(2',6'-Dimethylbiphenyl-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane
lOOmL干燥三口瓶中称入 2',6'-二甲基联苯基 -3-基三氟甲磺酸酯 If 2',6'-dimethylbiphenyl-3-yltrifluoromethanesulfonate is weighed into a 100 mL dry three-necked bottle.
(1.6g， 4.8mmol)， 4,4,4',4',5,5,5',5'-八甲基 -2,2'-二 （1,3,2-二氧杂硼烷） (1.5g， 5.8mmol)， PdCl2(dppf) (351mg， 0.48mol) 和醋酸钾（1.4g， 14.4mmol)。将体系置换为氮气氛围，加入二氧六环 (30mL)，然后在 95。C 下搅拌反应， TLC 监测反应直到原料反应完全。 冷却至室温， 减压脱 溶， 残余物用硅胶柱层析纯化 (石油 /乙酸乙酯 = 15 : 1)， 得到标题产 物 2-(2',6'-二甲基联苯基 -3-基) -4,4,5,5-四甲基 -1,3,2-二氧硼烷 lg (1.35g， 白色固体)， 产率： 85%。 (1.6g, 4.8mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane (1.5 g, 5.8 mmol), PdCl 2 (dppf) (351 mg, 0.48 mol) and potassium acetate (1.4 g, 14.4 mmol). The system was replaced with a nitrogen atmosphere, dioxane (30 mL) was added and then at 95. The reaction was stirred at C and the reaction was monitored by TLC until the starting material was completely reacted. The mixture was cooled to room temperature, and then evaporated to dryness. -4,4,5,5-tetramethyl-1,3,2-dioxaborane lg (1.35 g, white solid), Yield: 85%.
¾ NMR (300 MHz, CDCb) δ 7.73-7.71 (m， 1Η)， 7.46-7.41 (m， 2H), 7.23-7.20 (m, 1H)， 7.11-7.08 (m， 3H)， 1.96 (s， 6H)， 1.35 (s， 12H)。  3⁄4 NMR (300 MHz, CDCb) δ 7.73-7.71 (m, 1Η), 7.46-7.41 (m, 2H), 7.23-7.20 (m, 1H), 7.11-7.08 (m, 3H), 1.96 (s, 6H ), 1.35 (s, 12H).
第六步  Step 6
3- (2-(2',6'-二甲基联苯基 -3-基:)喹啉 -6-基：)丙酸乙酯  3-(2-(2',6'-Dimethylbiphenyl-3-yl:)quinoline-6-yl:)ethyl propionate
lOOmL干燥三口瓶中称入 3-(2-氯喹啉 -6-基)丙酸乙酯 lc (lOOmg, 0.38mmol) , 四三苯基膦钯 (0.05mmol)， 碳酸钾（105mg， 0.76mmol)和 2-(2',6'-二甲基联苯基 -3-基) -4,4,5,5-四甲基 -1,3,2-二氧硼烷 lg (140mg, 0.46mmol)。 将体系置换为氮气氛围， 加入 Ν,Ν'-二甲基甲酰胺 (6mL)， 然后在 100°C下搅拌反应， TLC监测反应直到原料反应完全。 冷却至 室温， 将反应体系用 lOOmL水稀释， 乙酸乙酯萃取 (15mLx3)， 合并有 机相并用饱和食盐水洗涤， 无水疏酸钠干燥， 过滤除去干燥剂， 减压 脱溶， 残余物用硅胶柱层析纯化 (石油醚 /乙酸乙酯 = 10 : 1)， 得到标题 产物 3-(2-(2',6'-二甲基联苯基 -3-基)喹啉 -6-基)丙酸乙酯 lh (110mg， 黄 色固体)， 产率： 71%。  3-OOmL dry three-necked flask was weighed into ethyl 3-(2-chloroquinolin-6-yl)propanoate lc (100 mg, 0.38 mmol), tetrakistriphenylphosphine palladium (0.05 mmol), potassium carbonate (105 mg, 0.76 mmol) And 2-(2',6'-dimethylbiphenyl-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane lg (140 mg, 0.46 mmol) ). The system was replaced with a nitrogen atmosphere, hydrazine, Ν'-dimethylformamide (6 mL) was added, and then the reaction was stirred at 100 ° C, and the reaction was monitored by TLC until the starting material was completely reacted. After cooling to room temperature, the reaction system was diluted with 100 mL of water, and extracted with ethyl acetate (15 mL×3). The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to remove solvent. Column chromatography purification (petroleum ether / ethyl acetate = 10:1) gave the title product 3-(2-(2',6'-dimethylbiphenyl-3-yl)quinolin-6-yl) Ethyl propionate 1 h (110 mg, yellow solid), yield: 71%.
MS m/z (ESI) : 410 [M+l] ¾ NMR (300 MHz, CDC13) δ 8.48-7.75 (m， 5H), 7.75-7.38 (m， 3H)， 7.23-7.09 (m， 4H)， 4.18-4.09 (m, 2H), 3.18-3.15 (m, 2H), 2.78-2.65 (m， 2H), 2.19-2.13 (m, 6H)， 1.38-1.32 (m， 3H)。 MS m/z (ESI) : 410 [M+l] 3⁄4 NMR (300 MHz, CDC1 3 ) δ 8.48-7.75 (m, 5H), 7.75-7.38 (m, 3H), 7.23-7.09 (m, 4H), 4.18-4.09 (m, 2H), 3.18-3.15 ( m, 2H), 2.78-2.65 (m, 2H), 2.19-2.13 (m, 6H), 1.38-1.32 (m, 3H).
第七步  Seventh step
3-(2-(2',6'-二甲基联苯基 -3-基) -1,2,3,4-四氫喹啉 -6-基)丙酸乙酯 3-(2-(2',6'-Dimethylbiphenyl-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)propionic acid ethyl ester
150mL 高压釜中称入 3-(2-(2',6'-二甲基联苯基 -3-基)喹啉 -6-基)丙 酸乙酯 lh (110mg， 0.27mmol), 氧化铂 (0.03mmol)， 加入甲醇 (5mL)和 醋酸 (20mg：)。 将反应体系置换为氫气氛围 (4atm)， 然后在室温下搅拌反 应， LCMS 监测反应直到原料反应完全。 过滤除去催化剂， 滤液减压 脱溶后未经纯化直接用于下一步反应。 Ethyl 3-(2-(2',6'-dimethylbiphenyl-3-yl)quinolin-6-yl)propanoate lh (110 mg, 0.27 mmol), platinum oxide, weighed in a 150 mL autoclave (0.03 mmol), methanol (5 mL) and acetic acid (20 mg:) were added. The reaction system was replaced with a hydrogen atmosphere (4 atm), and then the reaction was stirred at room temperature, and the reaction was monitored by LCMS until the starting material was completely reacted. The catalyst was removed by filtration, and the filtrate was desolvated under reduced pressure and used in the next reaction without purification.
MS m/z (ESI) : 414 [M+l]  MS m/z (ESI): 414 [M+l]
第八步  Eighth step
3-(2-(2',6'-二甲基联苯基 -3-基) -1,2,3,4-四氫喹啉 -6-基)丙酸  3-(2-(2',6'-Dimethylbiphenyl-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)propionic acid
lOOmL 单口瓶中称入 3-(2-(2',6'-二甲基联苯基 -3-基)喹啉 -6-基)丙 酸乙酯 li (110mg， 0.27mmol), 加入甲醇 (2mL)， 四氫呋喃 (2mL)和水 (2mL), 然后加入氫氧化钠 (32mg， 0.81mmol)。 室温下搅拌反应， TLC 监测反应直到原料反应完全。 减压脱溶， 加入 6mL水稀释， 然后用 \N 盐酸调节 pH约为 4， 乙酸乙酯萃取 (5mLx3)， 合并有机相并用饱和食 盐水洗涤，无水疏酸钠干燥，过滤除去干燥剂，滤液减压脱溶后经 HPLC 制备色谱法纯化（色谱柱： Gemini-C18 150x21.2mm， 5μιη, 流动相： 乙 腈 /水 (0.1%甲酸)， 梯度： 65-75)， 得到标题产物 3-(2-(2',6'-二甲基联苯 基 -3-基) -1,2,3,4-四氫喹啉 -6-基） 丙酸 l(6mg， 白色固体)， 产率： 8%。  3-(2-(2',6'-Dimethylbiphenyl-3-yl)quinolin-6-yl)propanoic acid ethyl l (110 mg, 0.27 mmol) was weighed into a lOOmL vial, and methanol was added. (2 mL), tetrahydrofuran (2 mL) and water (2 mL) then sodium hydroxide (32 mg, 0.81 mmol). The reaction was stirred at room temperature and the reaction was monitored by TLC until the starting material was completed. Decomposition under reduced pressure, diluted with 6 mL of water, then adjusted to pH 4 with <N> hydrochloric acid, ethyl acetate (5 mL×3), combined organics and washed with brine, dried over anhydrous sodium sulfate The filtrate was purified by HPLC and purified by HPLC (chromatography: Gemini-C18 150×21.2mm, 5μιη, mobile phase: acetonitrile/water (0.1% formic acid), gradient: 65-75). 2-(2',6'-Dimethylbiphenyl-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)propanoic acid 1 (6 mg, white solid), yield : 8%.
MS m/z (ESI) : 386 [M+l]  MS m/z (ESI) : 386 [M+l]
¾ NMR (300 MHz, CD3OD) δ 7.45-7.31 (m, 2H), 7.14-6.96 (m, 5H)， 6.79 (d， J= 7.3 Hz, 2H), 6.54 (d, J= 8.5 Hz, 1H)， 4.45 (dd, J = 8.2, 3.3 Hz, 1H)， 2.75 (t, J= 7.5 Hz, 2H), 2.73-2.64 (m, 2H), 2.50 (t， J= 7.6 Hz, 2H), 2.10-2.09 (m, 2H), 2.01 (s, 3H)， 1.98 (s， 3H)。  3⁄4 NMR (300 MHz, CD3OD) δ 7.45-7.31 (m, 2H), 7.14-6.96 (m, 5H), 6.79 (d, J = 7.3 Hz, 2H), 6.54 (d, J = 8.5 Hz, 1H) , 4.45 (dd, J = 8.2, 3.3 Hz, 1H), 2.75 (t, J= 7.5 Hz, 2H), 2.73-2.64 (m, 2H), 2.50 (t, J= 7.6 Hz, 2H), 2.10- 2.09 (m, 2H), 2.01 (s, 3H), 1.98 (s, 3H).
实施例 2  Example 2
3-(2-2',6'-二甲基 -4'-3-(甲磺酰基）丙氧基)联苯 -3-基) -1,2,3,4-四氫喹 啉—6-基)丙酸 3-(2-2',6'-Dimethyl-4'-3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3,4-tetrahydroquinoline- 6-yl)propionic acid
Figure imgf000021_0001
Figure imgf000021_0001
第一步  First step
2- (2,6-二甲基 -4-(3-(甲磺酰基）丙氧基）苯基) -4,4,5,5-四甲基 -1,3,2- 二氧杂硼烷  2-(2,6-Dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa Borane
lOOmL 单口瓶中称入 3- (甲磺酰基）丙基 4-甲基苯磺酸酯 2a (1.46g， 5mmol， 采用公知的方法" WO2003099805"制备而得)和 3,5-二 甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯酚 2b (1.6g， 6.5mmol， 采用公知的方法"文献 Joi r / of Medicinal Chemistry, 2012, 55(8), 3960-3974"制备而得），加入 Ν,Ν'-二甲基甲酰胺（15mL)和碳酸钾（1.38g， lOmmol), 然后将反应在 60。C下搅拌过夜。 加入 lOOmL水稀释， 乙酸 乙酯萃取 (80mLx3)， 合并有机相并用饱和食盐水洗涤， 无水疏酸钠干 燥， 过滤除去干燥剂， 减压脱溶， 残余物用硅胶柱层析纯化 （石油醚 / 乙酸乙酯 = 15 : 1)， 得到标题产物 2-(2,6-二甲基 -4-(3- (甲磺酰基)丙氧 基)苯基) -4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 2c (l . lg，浅黄色固体)，产率： 60%。  3-OOmL vial was weighed into 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate 2a (1.46 g, 5 mmol, prepared by the known method "WO2003099805") and 3,5-dimethyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 2b (1.6 g, 6.5 mmol, using a known method)"Joi r / of Medicinal Chemistry, 2012, 55(8), 3960-3974 "Prepared", hydrazine, Ν'-dimethylformamide (15 mL) and potassium carbonate (1.38 g, 10 mmol) were added, then the reaction was at 60. Stir overnight at C. It is diluted with 100 mL of water, extracted with ethyl acetate (80 mL×3), and the organic phase is combined and washed with brine, dried over anhydrous sodium sulfate, and evaporated, evaporated, evaporated, evaporated, evaporated /ethyl acetate = 15 : 1), the title product 2-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl) -4,4,5,5- Tetramethyl-1,3,2-dioxaborane 2c (1. lg, pale yellow solid), yield: 60%.
MS m/z (ESI) : 369 [M+l] , 391 [M+23]  MS m/z (ESI): 369 [M+l] , 391 [M+23]
第二步  Second step
3- (2-(3-羟基苯基)喹啉 -6-基)丙酸乙酯  3-(2-(3-Hydroxyphenyl)quinolin-6-yl)propionic acid ethyl ester
利用 3-(2-氯喹啉 -6-基)丙酸乙酯 lc (1.8g, 6.8mmol)和 3-羟基苯硼 酸 (l . lg， 8.1mmol)参照实施例 1中 lh的合成方法合成， 得到标题产物 3-(2-(3-羟基苯基)喹啉 -6-基)丙酸乙酯 2d (1.8g，黄色固体)，产率： 80%。 !HNMR (300 MHz, CD3OD) δ 8.37-8.27 (m， 1H)， 8.02-7.34 (m, 7H)， 6.93-6.91 (m， 1H)， 4.11-4.08 (m， 2H), 3.12-3.10 (m， 2H), 2.78-2.73 (m， 2H), 1.26-1.17 (m, 3H)。 Ethyl 3-(2-chloroquinolin-6-yl)propanoate lc (1.8 g, 6.8 mmol) and 3-hydroxyphenylboronic acid (1. lg, 8.1 mmol) were synthesized according to the synthesis of lh in Example 1, The title product, ethyl 3-(2-(3-hydroxyphenyl)quinolin-6-yl)propanoate 2d (1.8 g, yellow solid). ! HNMR (300 MHz, CD 3 OD) δ 8.37-8.27 (m, 1H), 8.02-7.34 (m, 7H), 6.93-6.91 (m, 1H), 4.11-4.08 (m, 2H), 3.12-3.10 (m, 2H), 2.78-2.73 (m, 2H), 1.26-1.17 (m, 3H).
第三步  third step
3-(2-(3- (三氟甲磺酰氧基)苯基)喹啉 -6-基)丙酸乙酯  Ethyl 3-(2-(3-(trifluoromethanesulfonyloxy)phenyl)quinoline-6-yl)propanoate
利用 3-(2-(3-羟基苯基)喹啉 -6-基)丙酸乙酯 2d (1.4g， 4.4mmol)为原 料， 参照实施例 1中 If的合成方法合成， 得到标题产物 3-(2-(3- (；三氟甲磺 酰氧基)苯基)喹啉 -6-基)丙酸乙酯 2e (0.9g， 黄色油状液体)， 产率： 45%。  Ethyl 3-(2-(3-hydroxyphenyl)quinolin-6-yl)propanoate 2d (1.4 g, 4.4 mmol) was used as a starting material, which was synthesized according to the synthesis method of If in Example 1, to give the title product 3 Ethyl 2-(3-(3-trifluoromethanesulfonyloxy)phenyl)quinolin-6-yl)propanoate 2e (0.9 g, yellow oily), yield: 45%.
MS m/z (ESI) : 454 [M+l]  MS m/z (ESI) : 454 [M+l]
第四步  the fourth step
3-(2-(2',6'-二甲基 -4'-(3- (甲磺酰基）丙氧基)联苯基 -3-基)喹啉 -6-基) 丙酸乙酯  3-(2-(2',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)quinolin-6-yl)ethyl propionate
lOOmL 干燥三口瓶中称入 3-(2-氯喹啉 -6-基)丙酸乙酯 2c (0.8g， 2.1mmol) , 3-(2-(3- (三氟甲磺酰氧基）苯基）喹啉 -6-基）丙酸乙酯 2e (0.57g , 1.26mmol) , 四三苯基膦钯（0.105mmol)， 碳酸钠（445mg， 4.2mmol)。 将体系置换为氮气氛围， 加入甲苯（10mL)， 乙醇 (5mL)和水 (2.5mL), 然后在 80°C下搅拌反应， TLC监测反应直到原料反应完全。 冷却至室温， 将反应体系用 30mL 水稀释， 乙酸乙酯萃取 (40mLx3)， 合并有机相并用饱和食盐水洗涤， 无水疏酸钠干燥， 过滤除去干燥剂， 减压脱溶， 残余物用硅胶柱层析纯化 (石油醚 /乙酸乙酯 = 1 : 1)， 得到 标题产物 3-(2-(2',6'-二甲基 -4'-(3-(甲磺酰基）丙氧基)联苯基 -3-基)喹啉 -6-基)丙酸乙酯 2f (l.lg， 浅黄色油状液体)， 产率： 61%。  3-(2-chloroquinolin-6-yl)propionic acid ethyl ester 2c (0.8 g, 2.1 mmol), 3-(2-(3-(trifluoromethanesulfonyloxy)benzene) was weighed into a 100 mL dry three-necked flask. Ethyl pyridin-6-yl)propanoate 2e (0.57 g, 1.26 mmol), tetrakistriphenylphosphine palladium (0.105 mmol), sodium carbonate (445 mg, 4.2 mmol). The system was replaced with a nitrogen atmosphere, toluene (10 mL), ethanol (5 mL) and water (2.5 mL) were added, and then the reaction was stirred at 80 ° C, and the reaction was monitored by TLC until the starting material was completely reacted. After cooling to room temperature, the reaction system was diluted with 30 mL of water, and extracted with ethyl acetate (40 mL×3). The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to remove solvent. Column chromatography purification (petroleum ether / ethyl acetate = 1 : 1) gave the title product 3-(2-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy). Ethyl biphenyl-3-yl)quinolin-6-yl)propanoate 2f (l.lg, pale yellow oily liquid), yield: 61%.
MS m/z (ESI) : 546 [M+l]  MS m/z (ESI): 546 [M+l]
第五步  the fifth step
3-(2-(2',6'-二甲基 -4'-(3- (甲磺酰基）丙氧基)联苯基 -3-基) -1,2,3,4-四 氫喹啉—6-基)丙酸乙酯  3-(2-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3,4-tetrahydro Quinoline-6-ylpropionate ethyl ester
利用 3-(2-(2',6'-二甲基 -4'-(3- (甲磺酰基）丙氧基)联苯基 -3-基)喹啉 -6-基)丙酸乙酯 2f (0.7g， 1.2mmol)为原料， 参照实施例 1中 li的合成 方法合成， 得到标题产物 3-(2-(2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联 苯基 -3-基) -1,2,3,4-四氫喹啉 -6-基；)丙酸乙酯 2g (0.7g， 浅黄色油状液体， 不经纯化直接用于下一步反应）。 MS m/z (ESI) : 550 [M+l] Using 3-(2-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)quinolin-6-yl)propanoic acid The ester 2f (0.7 g, 1.2 mmol) was used as a starting material, which was synthesized according to the synthesis method of li in Example 1, to obtain the title product 3-(2-(2',6'-dimethyl-4'-(3-(A) Sulfonyl)propoxy)biphenyl-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl;)ethyl propionate 2g (0.7g, light yellow oily liquid, without Purification was used directly in the next step). MS m/z (ESI) : 550 [M+l]
第六步  Step 6
3-(2-(2',6'-二甲基 -4'-(3- (甲磺酰基）丙氧基)联苯基 -3-基) -1,2,3,4-四 氫喹啉 -6-基)丙酸  3-(2-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3,4-tetrahydro Quinoline-6-yl)propionic acid
利用 3-(2-(2',6'-二甲基 -4'-(3-(甲磺酰基）丙氧基）联苯基 -3- 基) -1,2,3,4-四氫喹啉 -6-基)丙酸乙酯 2g (100mg， 0.18mmol)为原料， 参 照实施例 1 的搡作方法合成， 经 HPLC 制备色谱法纯化（色谱柱： Gemini-C18， 150x21.2mm, 5μιη, 流动相： 乙腈 /水 (0.1%甲酸)， 梯度： 50-90),得到标题产物 3-(2-(2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基) -1,2,3,4-四氫喹啉-6-基)丙酸2(911¾， 白色固体)， 产率： 9%。  Using 3-(2-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3,4-tetra 2 g of hydrogen quinolate-6-yl)propionate (100 mg, 0.18 mmol) was used as a starting material, which was synthesized according to the method of Example 1 and purified by HPLC preparative chromatography (column: Gemini-C18, 150×21.2 mm, 5μιη, mobile phase: acetonitrile/water (0.1% formic acid), gradient: 50-90) to give the title product 3-(2-(2',6'-dimethyl-4'-(3-(methylsulfonyl) Propyloxy)biphenyl-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)propionic acid 2 (9113⁄4, white solid), Yield: 9%.
MS m/z (ESI) : 522 [M+l]  MS m/z (ESI) : 522 [M+l]
¾ NMR (400 MHz, CDCb) δ 7.45-7.35 (m， 2H), 7.16 (s， 1H)， 7.07 (d, J= 7.0 Hz, 1H)， 6.88 (s, 2H), 6.66 (s， 2H), 6.64-6.60 (m， 1H)， 4.50 (d, J = 6.2 Hz, 1H)， 4.14 (t， J= 5.7 Hz, 2H), 3.34-3.24(m， 2H), 2.99 (s， 3H)， 2.99-2.76 (m, 3H)， 2.75-2.70 (m, 1H)， 2.66 (t, J = 7.7 Hz, 2H), 2.37 (dt, J= 15.7, 5.7 Hz, 2H), 2.17-2.05 (m, 2H), 2.04 (s, 3H)， 2.00 (s, 3H)。  3⁄4 NMR (400 MHz, CDCb) δ 7.45-7.35 (m, 2H), 7.16 (s, 1H), 7.07 (d, J = 7.0 Hz, 1H), 6.88 (s, 2H), 6.66 (s, 2H) , 6.64-6.60 (m, 1H), 4.50 (d, J = 6.2 Hz, 1H), 4.14 (t, J = 5.7 Hz, 2H), 3.34-3.24(m, 2H), 2.99 (s, 3H), 2.99-2.76 (m, 3H), 2.75-2.70 (m, 1H), 2.66 (t, J = 7.7 Hz, 2H), 2.37 (dt, J= 15.7, 5.7 Hz, 2H), 2.17-2.05 (m, 2H), 2.04 (s, 3H), 2.00 (s, 3H).
实施例 3  Example 3
3-(2-(4'-甲氧基-2',6'-二甲基联苯基-3-基)-1,2,3,4-四氫喹啉-6-基）丙 酸  3-(2-(4'-methoxy-2',6'-dimethylbiphenyl-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)propionic acid
Figure imgf000023_0001
第一步
Figure imgf000023_0001
first step
3—(2-(4'-羟基 -2',6'-二甲基联苯基 1-3-基)喹啉 -6-基；)丙酸乙酯 利用 3-(2-(3- (三氟甲磺酰氧基）苯基）喹啉 -6-基）丙酸乙酯 2e (150mg, 0.33mmol)和 3,5-二甲基 -4-(4,4,5,5-四甲基 -1,3,2-二氧硼烷 -2- 基)苯酚 2b (100mg， 0.40mmol)参照实施例 2中 2f的合成方法合成， 得 到标题产物 3-(2-(4'-羟基 -2',6'-二甲基联苯基 1-3-基)喹啉 -6-基；)丙酸乙酯 3a (1.45g, 黄色固体)， 产率： 84%。  3-(2-(4'-hydroxy-2',6'-dimethylbiphenyl1-3-yl)quinolin-6-yl;) ethyl propionate using 3-(2-(3- Ethyl (trifluoromethanesulfonyloxy)phenyl)quinolin-6-yl)propanoate 2e (150 mg, 0.33 mmol) and 3,5-dimethyl-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 2b (100 mg, 0.40 mmol) was synthesized according to the synthesis of 2f in Example 2 to give the title product 3-(2-(4'-) Hydroxy-2',6'-dimethylbiphenyl1-3-yl)quinolin-6-yl;)ethyl propionate 3a (1.45 g, yellow solid), yield: 84%.
MS m/z (ESI) : 426 [M+l]  MS m/z (ESI) : 426 [M+l]
¾ NMR (300 MHz, CD3OD) δ 8.47-8.41 (m， 1H)， 8.05-7.56 (m, 7H)， 7.25-7.23 (m, 1H)， 6.57 (s， 2H), 4.14-4.06 (m， 2H), 3.32-3.30 (m, 2H), 2.69-2.73 (m, 2H), 2.03 (s, 6H)， 1.38-1.32 (m, 3H)。 3⁄4 NMR (300 MHz, CD 3 OD) δ 8.47-8.41 (m, 1H), 8.05-7.56 (m, 7H), 7.25-7.23 (m, 1H), 6.57 (s, 2H), 4.14-4.06 (m , 2H), 3.32-3.30 (m, 2H), 2.69-2.73 (m, 2H), 2.03 (s, 6H), 1.38-1.32 (m, 3H).
第二步  Second step
3-(2-(4'-甲氧基 -2',6'-二甲基联苯基 1-3-基)喹啉 -6-基：)丙酸乙酯 lOOmL干燥单口瓶中称入 3-(2-(4'-羟基 -2',6'-二甲基联苯基 1-3-基) 喹啉 -6-基)丙酸乙酯 3a (70mg， 0.18mmol)， 碳酸钾 (48mg 0.35mmol)， 加入丙酮 (6mL；)， 碘甲烷 (50mg， 0.35mmol)。 然后油浴加热至 65。C搅 拌反应 0.5小时。 冷却至室温， 减压脱溶， 加入 15mL水稀释， 乙酸乙 酯萃取 (20mLx3)， 合并有机相并用饱和食盐水洗涤， 无水疏酸钠干燥， 过滤除去干燥剂， 减压脱溶， 得到标题产物 3-(2-(4'-甲氧基 -2',6'-二甲基 联苯基 1-3-基)喹啉 -6-基)丙酸乙酯 3b (75mg，黄色油状液体)产率： 90%。 产物不经纯化直接用于下一步反应。  3-(2-(4'-Methoxy-2',6'-dimethylbiphenyl-1-yl)quinolin-6-yl:)ethyl propionate 100 mL dry single-mouth bottle Ethyl 3-(2-(4'-hydroxy-2',6'-dimethylbiphenyl1-3-yl)quinolin-6-yl)propanoate 3a (70 mg, 0.18 mmol), potassium carbonate (48 mg, 0.35 mmol), acetone (6 mL;), methylene chloride (50 mg, 0.35 mmol). The oil bath is then heated to 65. C was stirred for 0.5 hours. The mixture was cooled to room temperature, and then the mixture was evaporated to dryness. EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Product 3-(2-(4'-Methoxy-2',6'-dimethylbiphenyl1-3-yl)quinolin-6-yl)propanoic acid ethyl ester 3b (75 mg, yellow oily liquid ) Yield: 90%. The product was used in the next reaction without purification.
MS m/z (ESI) : 440 [M+l]  MS m/z (ESI) : 440 [M+l]
第三步  third step
3-(2-(4'-甲氧基 -2',6'-二甲基联苯基 1-3-基)喹啉 -6-基：)丙酸  3-(2-(4'-methoxy-2',6'-dimethylbiphenyl 1-3-yl)quinoline-6-yl:)propionic acid
利用 3-(2-(4'-甲氧基 -2',6'-二甲基联苯基 1-3-基)喹啉 -6-基：)丙酸乙酯 3b (70mg， 0.2mmol)参照实施例 1 的搡作方法合成， 得到标题产物 3—(2-(4'-甲氧基 -2',6'-二甲基联苯基 1-3-基)喹啉 -6-基)丙酸 3c (52mg, 白 色固体)， 产率： 95%。 产物不经纯化直接用于下一步反应。  Using 3-(2-(4'-methoxy-2',6'-dimethylbiphenyl1-3-yl)quinolin-6-yl:)ethyl propionate 3b (70 mg, 0.2 mmol The title product 3-(2-(4'-methoxy-2',6'-dimethylbiphenyl1-3-yl)quinoline-6- was obtained by the same procedure as in Example 1. Propionate 3c (52 mg, white solid), Yield: 95%. The product was used in the next reaction without purification.
MS m/z (ESI) : 412 [M+l]  MS m/z (ESI): 412 [M+l]
第四步  the fourth step
3-(2-(4'-甲氧基 -2',6'-二甲基联苯基 1-3-基) -1,2,3,4-四氫喹啉 -6-基) 丙酸 3-(2-(4'-methoxy-2',6'-dimethylbiphenyl1-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl) Propionic acid
利用 3-(2-(4'-甲氧基 -2',6'-二甲基联苯基 1-3-基)喹啉 -6-基：)丙酸 3c (60mg， 0.15mmol)参照实施例 1中 li的合成方法合成， 通过 HPLC制 备色谱法纯化（色谱柱： Gemini-C18 150x21.2mm， 5μιη, 流动相： 乙腈 /水 (0.1%甲酸)， 梯度： 60-75)， 得到标题产物 3-(2-(4'-甲氧基 -2',6'-二甲 基联苯基 1-3-基) -1,2,3,4-四氫喹啉 -6-基)丙酸 3 (8mg， 白色固体)， 产率： 15%。  Using 3-(2-(4'-methoxy-2',6'-dimethylbiphenyl1-3-yl)quinolin-6-yl:)propionic acid 3c (60 mg, 0.15 mmol) The synthesis method of li in Example 1 was synthesized, and purified by HPLC preparative chromatography (column: Gemini-C18 150×21.2 mm, 5 μιη, mobile phase: acetonitrile/water (0.1% formic acid), gradient: 60-75), and the title was obtained. Product 3-(2-(4'-Methoxy-2',6'-dimethylbiphenyl1-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl) Propionic acid 3 (8 mg, white solid), Yield: 15%.
MS m/z (ESI) : 416 [M+l]  MS m/z (ESI): 416 [M+l]
¾ NMR (400 MHz, DMSO-i 6) δ 7.42-7.36 (m, 2H), 7.17 (s， 1H)， 7.08 (d, J= 7.5 Hz, 1H)， 6.89-6.87 (m， 2H), 6.68 (s. 2H), 6.58 (s， 1H)， 4.46-4.44 (m， 1H)， 3.73 (s， 3H)， 2.84-2.78 (m， 2H), 2.76 (d， J= 7.3 Hz, 2H), 2.40 (t, J= 7.6 Hz, 2H), 2.30-2.20 (m, 2H), 1.95 (s， 3H)， 1.89 (s， 3H)。 3⁄4 NMR (400 MHz, DMSO-i 6 ) δ 7.42-7.36 (m, 2H), 7.17 (s, 1H), 7.08 (d, J = 7.5 Hz, 1H), 6.89-6.87 (m, 2H), 6.68 (s. 2H), 6.58 (s, 1H), 4.46-4.44 (m, 1H), 3.73 (s, 3H), 2.84-2.78 (m, 2H), 2.76 (d, J = 7.3 Hz, 2H), 2.40 (t, J = 7.6 Hz, 2H), 2.30-2.20 (m, 2H), 1.95 (s, 3H), 1.89 (s, 3H).
实施例 4  Example 4
3_(2-(4'-(2-乙氧基乙氧基) -2',6'-二甲基联苯基 -3-基) -1,2,3,4-四氫喹 —6-基)丙酸  3-(2-(4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl)-1,2,3,4-tetrahydroquino-6 -base) propionic acid
Figure imgf000025_0001
Figure imgf000025_0001
第一步  First step
3-(2-(4'-(2-乙氧基乙氧基 )-2',6'-二甲基联苯基 -3-基)喹啉 -6-基)丙酸 乙酯  3-(2-(4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl)quinoline-6-yl)propanoic acid ethyl ester
lOOmL 单口瓶中称入 3-(2-(4'-羟基 -2',6'-二甲基联苯基 -3-基） 喹啉 -6-基）丙酸乙酯 3a (50mg， 0.13mmol), 1-溴 -2-乙氧基乙烷 （52mg， 0.38mmol)和碳酸钾 (52mg， 0.38mmol),加入 Ν,Ν'-二甲基甲酰胺 (2mL)。 油浴加热至 65。C 搅拌反应 2小时。 冷却至室温， 加入 5mL水， 乙酸 乙酯萃取 (8mLx3)，合并有机相并用饱和食盐水洗涤，无水疏酸钠干燥， 过滤除去干燥剂， 减压脱溶， 得到标题产物 40mg， 产率： 85%。 产物 不经纯化直接用于下一步反应 。 3-(2-(4'-hydroxy-2',6'-dimethylbiphenyl-3-yl)quinolin-6-yl)propionic acid ethyl ester 3a (50mg, 0.13) is weighed into a lOOmL single-mouth bottle Methyl), 1-bromo-2-ethoxyethane (52 mg, 0.38 mmol) and potassium carbonate (52 mg, 0.38 mmol). The oil bath was heated to 65. C The reaction was stirred for 2 hours. Cool to room temperature, add 5 mL water, acetic acid The ethyl acetate was extracted (8 mL×3), and the organic phase was combined and washed with brine, dried over anhydrous sodium sulfate, and then evaporated to remove the solvent to afford the title product 40 mg, yield: 85%. The product was used in the next reaction without purification.
MS m/z (ESI) : 498 [M+l]  MS m/z (ESI): 498 [M+l]
第二步  Second step
3-(2-(4'-(2-乙氧基乙氧基) -2',6'-二甲基联苯基 -3-基)喹啉 -6-基)丙酸 利用 3-(2-(4'-(2-乙氧基乙氧基 )-2',6'-二甲基联苯基 -3-基)喹啉 -6-基) 丙酸乙酯 4a (160mg， 0.33mmol)参照实施例 1的搡作方法合成， 得到 标题产物 3-(2-(4'-(2-乙氧基乙氧基 )-2',6'-二甲基联苯基 -3-基)喹啉 -6-基) 丙酸 4b (110mg， 白色固体)， 产率： 80%。 产物不经纯化直接用于下一 步反应。  3-(2-(4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl)quinolin-6-yl)propanoic acid using 3-( 2-(4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl)quinolin-6-yl)ethyl propionate 4a (160 mg, 0.33 Methanol) was synthesized by the same procedure as in Example 1 to give the title product 3-(2-(4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3- (Quinolin-6-yl)propionic acid 4b (110 mg, white solid), Yield: 80%. The product was used in the next step without purification.
MS m/z (ESI) : 470 [M+l]  MS m/z (ESI) : 470 [M+l]
第三步  third step
3_(2-(4'-(2-乙氧基乙氧基 )-2',6'-二甲基联苯基 -3-基)四氫喹啉 -6-基) 丙酸  3-(2-(4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl)tetrahydroquinolin-6-yl)propionic acid
利用 3-(2-(4'-(2-乙氧基乙氧基 )-2',6'-二甲基联苯基 -3-基)喹啉 -6-基) 丙酸 4b (80mg, O. mmol)参照实施例 1 中 li的合成方法合成， 通过 HPLC制备色谱法纯化（色谱柱： Gemini-C18 150x21.2mm, 5μιη, 流动 相： 乙腈 /水 (0.1%甲酸)， 梯度： 60-75)， 得到标题产物 3-(2-(4'-(2-乙氧 基乙氧基) -2',6'-二甲基联苯基 -3-基)四氫喹啉 -6-基)丙酸 4 (10mg, 白色 固体)， 产率： 15%。  Using 3-(2-(4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl)quinolin-6-yl)propanoic acid 4b (80mg , O. mmol) was synthesized according to the synthesis method of li in Example 1, and purified by HPLC preparative chromatography (column: Gemini-C18 150×21.2 mm, 5 μιη, mobile phase: acetonitrile/water (0.1% formic acid), gradient: 60 -75), the title product 3-(2-(4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl)tetrahydroquinoline-6 was obtained. -yl)propionic acid 4 (10 mg, white solid), Yield: 15%.
MS m/z (ESI) : 474 [M+l]  MS m/z (ESI): 474 [M+l]
¾ NMR (300 MHz, DMSO-i 6) δ 7.42-7.33 (m, 2H), 7.05 (s, 1H)， 6.98-6.90 (m， 1H)， 6.75-6.55(m， 4H)， 6.53-6.51 (m, 1H)， 4.49-4.39 (m， 1H), 4.06-4.05 (m, 2H), 3.67-3.66 (m， 2H), 3.47 (dd, J= 7.0 Hz, 2H), 2.62-2.60 (m, 4H)， 2.42-2.38 (m, 2H), 2.02-1.98(m, 1H)， 1.96 (s， 3H)， 1.89 (s， 3H), 1.88-1.86 (m， 1H)， 1.13 (t， J= 7.0 Hz, 3H)。 3⁄4 NMR (300 MHz, DMSO-i 6 ) δ 7.42-7.33 (m, 2H), 7.05 (s, 1H), 6.98-6.90 (m, 1H), 6.75-6.55 (m, 4H), 6.53-6.51 ( m, 1H), 4.49-4.39 (m, 1H), 4.06-4.05 (m, 2H), 3.67-3.66 (m, 2H), 3.47 (dd, J= 7.0 Hz, 2H), 2.62-2.60 (m, 4H), 2.42-2.38 (m, 2H), 2.02-1.98 (m, 1H), 1.96 (s, 3H), 1.89 (s, 3H), 1.88-1.86 (m, 1H), 1.13 (t, J= 7.0 Hz, 3H).
实施例 5  Example 5
3-(2-(4'-4'-[(四氫 -1,1-二氧 -2H-噻喃 -4-基)氧基] -2',6'-二甲基联苯基 -3-基:) - 1 ,2,3 ,4-四氫喹啉基 -6-基：)丙酸 3-(2-(4'-4'-[(tetrahydro-1,1-dioxo-2H-thiopyran-4-yl)oxy]-2',6'-dimethylbiphenyl- 3-yl:) - 1 ,2,3 ,4-tetrahydroquinolinyl-6-yl:)propionic acid
Figure imgf000027_0001
Figure imgf000027_0001
第一步  First step
3-(2-(4'-4'-[(四氫 -1,1-二氧 -2H-噻喃 -4-基)氧基] -2',6'-二甲基联苯基 -3-基:) -喹啉基 -6-基：)丙酸乙酯  3-(2-(4'-4'-[(tetrahydro-1,1-dioxo-2H-thiopyran-4-yl)oxy]-2',6'-dimethylbiphenyl- 3-yl:)-quinolinyl-6-yl:ethyl propionate
lOOmL 单口瓶中称入 (四氫 -1,1-二氧 -2H-噻喃 -4-基)氧基 4-甲基苯 磺酸酯 5a (608mg， 2mmol， 采用公知的方法"专利 US20070299068"制 备而得)， 3-(2-(4'-羟基 -2',6'-二甲基联苯基 -3-基)喹啉 -6-基)丙酸乙酯 3b (425mg, lmmol)和碳酉 钾 (207mg， 1.3mmol)， 力口入 Ν,Ν'-二甲基甲酰 胺 (6mL)。 油浴加热至 80。C 搅拌反应过夜， 冷却至室温， 加入 10mL 水稀释， 乙酸乙酯萃取 (15mLx3)， 合并有机相并用饱和食盐水洗涤， 无水疏酸钠干燥， 过滤除去干燥剂， 减压脱溶， 得到标题产物 3—(2-(4'-4'- [(四氫 -1,1-二氧 -2H-噻喃 -4-基）氧基] -2',6'-二甲基联苯基 -3- 基)-喹啉基 -6-基)丙酸乙酯 5b (430mg， 浅黄色油状液体)， 产率： 40%。 产物不经纯化直接用于下一步反应。  (tetrahydro-1,1-dioxo-2H-thiopyran-4-yl)oxy 4-methylbenzenesulfonate 5a (608 mg, 2 mmol, using a known method "patent US20070299068" in a lOOmL single-mouth bottle Prepared) 3-(2-(4'-hydroxy-2',6'-dimethylbiphenyl-3-yl)quinolin-6-yl)propanoic acid ethyl ester 3b (425 mg, 1 mmol) And potassium bismuth (207 mg, 1.3 mmol), hydrazine, Ν'-dimethylformamide (6 mL). Heat the oil bath to 80. C. The reaction was stirred overnight, cooled to room temperature, diluted with EtOAc EtOAc EtOAc (EtOAc m. Product 3-(2-(4'-4'-[(tetrahydro-1,1-dioxo-2H-thiopyran-4-yl)oxy]-2',6'-dimethylbiphenyl Ethyl 3-phenyl)-quinolinyl-6-yl)propanoate 5b (430 mg, pale yellow oily). Yield: 40%. The product was used in the next reaction without purification.
MS m/z (ESI) : 558 [M+l]  MS m/z (ESI) : 558 [M+l]
第二步  Second step
3-(2-(4'-4'-[(四氫 -1,1-二氧 -2H-噻喃 -4-基)氧基] -2',6'-二甲基联苯基 -3-基:) -喹啉基 -6-基：)丙酸  3-(2-(4'-4'-[(tetrahydro-1,1-dioxo-2H-thiopyran-4-yl)oxy]-2',6'-dimethylbiphenyl- 3-yl:)-quinolinyl-6-yl:)propionic acid
利用 3-(2-(4'-4'- [(四氫 -1,1-二氧 -2H-噻喃 -4-基)氧基] -2',6'-二甲基联 苯基 -3-基)-喹啉基 -6-基)丙酸乙酯 5b (430mg， 0.77mmol)为原料， 参照 实施例 1的搡作方法合成，得到标题产物 3-(2-(4'-4'- [(四氫 -1,1-二氧 -2H- 噻喃 -4-基)氧基] -2',6'-二甲基联苯基 -3-基)-喹啉基 -6-基)丙酸 5c (370mg, 浅黄色油状液体)， 产率： 80%。 产物不经纯化直接用于下一步反应。  Using 3-(2-(4'-4'-[(tetrahydro-1,1-dioxo-2H-thiopyran-4-yl)oxy]-2',6'-dimethylbiphenyl Ethyl 3-benzyl)-quinolinyl-6-yl)propanoate 5b (430 mg, 0.77 mmol) was obtained as a starting material, which was obtained by the same procedure as in Example 1 to give the title product 3-(2-(4'-) 4'-[(tetrahydro-1,1-dioxo-2H-thiopyran-4-yl)oxy]-2',6'-dimethylbiphenyl-3-yl)-quinolyl- 6-yl)propionic acid 5c (370 mg, pale yellow oily liquid), Yield: 80%. The product was used in the next reaction without purification.
MS m/z (ESI) : 530 [M+l] 第三步 MS m/z (ESI) : 530 [M+l] third step
3-(2-(4'-4'-[(四氫 -1,1-二氧 -2H-噻喃 -4-基)氧基] -2',6'-二甲基联苯基 -3-基:) - 1 ,2,3 ,4-四氫喹啉基 -6-基：)丙酸  3-(2-(4'-4'-[(tetrahydro-1,1-dioxo-2H-thiopyran-4-yl)oxy]-2',6'-dimethylbiphenyl- 3-yl:) - 1 ,2,3 ,4-tetrahydroquinolinyl-6-yl:)propionic acid
利用 3-(2-(4'-4'- [(四氫 -1,1-二氧 -2H-噻喃 -4-基)氧基] -2',6'-二甲基联 苯基 -3-基)-喹啉基 -6-基)丙酸 5c (370mg， 0.69mmol)为原料， 参照实施 例 1 中 li 的合成方法合成， 通过 HPLC 制备色谱法纯化（色谱柱： Gemini-C18， 150x21.2mm, 5μιη, 流动相： 乙腈 /水 (0.1%甲酸)， 梯度： 55-60) , 得到标题产物 3-(2-(4'-4'-[(四氫 -1,1-二氧 -2Η-噻喃 -4-基）氧 基] -2',6'-二甲基联苯基 -3-基:) -1,2,3,4-四氫喹啉基 -6-基：)丙酸 5 (10mg, 白 色固体)， 产率： 15%。  Using 3-(2-(4'-4'-[(tetrahydro-1,1-dioxo-2H-thiopyran-4-yl)oxy]-2',6'-dimethylbiphenyl -3-yl)-quinolinyl-6-yl)propionic acid 5c (370 mg, 0.69 mmol) was used as a starting material, which was synthesized according to the synthesis method of li in Example 1, and purified by HPLC preparative chromatography (column: Gemini-C18) , 150x21.2mm, 5μιη, mobile phase: acetonitrile/water (0.1% formic acid), gradient: 55-60), the title product 3-(2-(4'-4'-[(tetrahydro-1,1-) Dioxo-2 oxime-thiopyran-4-yl)oxy]-2',6'-dimethylbiphenyl-3-yl:)-1,2,3,4-tetrahydroquinolinyl-6 -Base:) Propionic acid 5 (10 mg, white solid), Yield: 15%.
MS m/z (ESI) : 534 [M+l]  MS m/z (ESI) : 534 [M+l]
¾ NMR (300 MHz, CD3OD) 5 7.51 (d, J= 7.2 Hz, 2H), 7.23 (s, 1H)， 7.18-7.12 (m， 3H)， 7.00 (s, 1H)， 6.79(s， 2H), 4.73-4.60 (m， 2H), 3.37-3.34 (m， 2H), 3.12-2.86 (m， 6H)， 2.60 (d， J= 7.5 Hz, 2H), 2.50-2.25 (m， 6H)， 2.05 (s， 3H), 2.00 (s, 3H)。 3⁄4 NMR (300 MHz, CD 3 OD) 5 7.51 (d, J = 7.2 Hz, 2H), 7.23 (s, 1H), 7.18-7.12 (m, 3H), 7.00 (s, 1H), 6.79(s, 2H), 4.73-4.60 (m, 2H), 3.37-3.34 (m, 2H), 3.12-2.86 (m, 6H), 2.60 (d, J= 7.5 Hz, 2H), 2.50-2.25 (m, 6H) , 2.05 (s, 3H), 2.00 (s, 3H).
实施例 6  Example 6
3-(2-(6'-甲基 -4'-(3- (甲磺酰基）丙氧基)联苯基 -3-基) -1,2,3,4-四氫喹 。 -6-基)丙酸  3-(2-(6'-Methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3,4-tetrahydroquine. -6 -base) propionic acid
Figure imgf000028_0001
第一步
Figure imgf000028_0001
first step
6'—甲基—4'-(3- (甲磺酰基)丙氧基)联苯基 -3-酚 利用 1-溴 -2-甲基 -4-(3- (甲磺酰基)丙氧基)苯 6a (1.7g， 5.4mmol， 采 用公知的方法 "专利 CN103030646"制备而得)和 3-羟基苯硼酸 (0.82g， 5.9mmol)参照实施例 1 中 lh的合成方法合成， 得到标题产物 6'-甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-酚 6b (1.45g， 无色油状液体)， 产率： 84%。 6'-Methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-phenol Using 1-bromo-2-methyl-4-(3-(methylsulfonyl)propoxy)benzene 6a (1.7 g, 5.4 mmol, prepared by the known method "patent CN103030646") and 3-hydroxybenzene Boric acid (0.82 g, 5.9 mmol) was synthesized according to the synthesis of lh of Example 1 to give the title product 6'-methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-phenol 6b (1.45 g, colorless oily liquid), Yield: 84%.
MS m/z (ESI) : 321 [M+l]  MS m/z (ESI) : 321 [M+l]
第二步  Second step
6'-甲基 -4'-(3-(甲磺酰基)丙氧基)联苯基 -3-基 三氟甲磺酸酯 利用 6'-甲基 -4'-(3- (甲磺酰基）丙氧基)联苯基 -3-酚 6b (170mg, 0.53mmol)为原料， 参照实施例 1中 If的合成方法合成， 得到标题产物 6'-甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基 三氟甲磺酸酯 6c (240mg， 无色油状液体)， 产物不经纯化直接用于下一步反应。  6'-Methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yltrifluoromethanesulfonate using 6'-methyl-4'-(3-(methylsulfonate) Acyl)propoxy)biphenyl-3-phenol 6b (170 mg, 0.53 mmol) was used as a starting material, which was synthesized by the method of the method of If in Example 1, to give the title product 6'-methyl-4'-(3-( Methanesulfonyl)propoxy)biphenyl-3-yltrifluoromethanesulfonate 6c (240 mg, colorless oily).
MS m/z (ESI) : 453 [M+l]  MS m/z (ESI) : 453 [M+l]
第三步  third step
4,4,5,5-四甲基 -2-(6'-甲基 -4'-(3-甲磺酰基）丙氧基）联苯基 -3-基 -1,3,2-二氧杂硼烷  4,4,5,5-tetramethyl-2-(6'-methyl-4'-(3-methylsulfonyl)propoxy)biphenyl-3-yl-1,3,2-di Oxaborane
利用化合物 6'-甲基 -4'-(3-(甲磺酰基)丙氧基)联苯基 -3-基 三氟甲磺 酸酯 (240mg， 0.53mmol)参照实施例 1 中 lg的合成方法合成， 得到标 题产物 4,4,5,5-四甲基 -2-(6'-甲基 -4'-(3-甲磺酰基）丙氧基)联苯基 -3-基 -1,3,2-二氧杂硼烷 6d (141mg， 无色油状液体)， 产率： 62%。  The synthesis of lg in Example 1 was carried out using the compound 6'-methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yltrifluoromethanesulfonate (240 mg, 0.53 mmol). The method was synthesized to give the title product 4,4,5,5-tetramethyl-2-(6'-methyl-4'-(3-methylsulfonyl)propoxy)biphenyl-3-yl-1 , 3,2-dioxaborane 6d (141 mg, colorless oily liquid), yield: 62%.
MS m/z (ESI) : 431 [M+l]  MS m/z (ESI): 431 [M+l]
第四步  the fourth step
3-(2-(6'-甲基 -4'-(3-(甲磺酰基）丙氧基)联苯基 -3-基)喹啉 -6-基）丙酸 乙酯  3-(2-(6'-Methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)quinoline-6-yl)propanoic acid ethyl ester
利用 4,4,5,5-四甲基 -2-(6'-甲基 -4'-(3-甲磺酰基)丙氧基)联苯基 -3-基 -1,3,2-二氧杂硼烷 6d (43mg， 0.077mmol)和 3-(2-氯喹啉 -6-基)丙酸乙酯 lc (19mg， 0.073mmol)为原料， 参照实施例 2中 2f的合成方法合成， 得到标题产物 3-(2-(6'-甲基 -4'-(3-(甲磺酰基)丙氧基)联苯基 -3-基:)喹啉 -6-基)丙酸乙酯 6e(25mg， 黄色油状液体)， 产率： 80%。  Using 4,4,5,5-tetramethyl-2-(6'-methyl-4'-(3-methylsulfonyl)propoxy)biphenyl-3-yl-1,3,2- Dioxaborane 6d (43 mg, 0.077 mmol) and ethyl 3-(2-chloroquinolin-6-yl)propanoate lc (19 mg, 0.073 mmol) were used as a starting material, and synthesized according to the synthesis method of 2f in Example 2, The title product 3-(2-(6'-methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl:)quinolin-6-yl)propanoic acid ethyl ester was obtained 6e (25 mg, yellow oily liquid), Yield: 80%.
MS m/z (ESI) : 533 [M+l] 第五步 MS m/z (ESI) : 533 [M+l] the fifth step
3-(2-(6'-甲基 -4'-(3- (甲磺酰基）丙氧基)联苯基 -3-基) -1,2,3,4-四氫喹 啉—6-基)丙酸乙酯  3-(2-(6'-Methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3,4-tetrahydroquinoline-6 -yl)ethyl propionate
利用 3-(2-(6'-甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基)喹啉 -6-基) 丙酸乙酯 6e (112mg， 0.21mmol)为原料， 参照实施例 1中 li的合成方 法合成， 得到标题产物 3-(2-(6'-甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3- 基) -1,2,3,4-四氫喹啉 -6-基)丙酸乙酯 6f (110mg， 黄色油状液体)， 产率： 98%。  Using ethyl 3-(2-(6'-methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)quinolin-6-yl)propanoate 6e (112mg , 0.21 mmol) as a starting material, which was synthesized by the method of the procedure of li in Example 1, to give the title product 3-(2-(6'-methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl). Ethyl-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)propanoic acid ethyl ester 6f (110 mg, yellow oily), yield: 98%.
MS m/z (ESI) : 537 [M+l]  MS m/z (ESI): 537 [M+l]
第六步  Step 6
3-(2-(6'-甲基 -4'-(3- (甲磺酰基）丙氧基)联苯基 -3-基) -1,2,3,4-四氫喹 啉—6-基)丙酸  3-(2-(6'-Methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3,4-tetrahydroquinoline-6 -base) propionic acid
利用 3-(2-(6'-甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基) -1,2,3,4-四 氫喹啉—6-基)丙酸乙酯 6f (110mg， 0.21mmol)为原料， 参照实施例 1的 搡作方法合成， 通过 HPLC 制备色谱法纯化（色谱柱： Gemini-C18， 150x21.2mm, 5μιη, 流动相： 乙腈 /水 (0.1%甲酸）， 梯度： 50-70)， 得 到标题产物 3-(2-(6'-甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基) -1,2,3,4- 四氫喹啉 -6-基)丙酸 6 (10mg， 白色固体)， 产率： 9%。  Using 3-(2-(6'-methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3,4-tetrahydroquinoline- 6-yl)ethyl propionate 6f (110 mg, 0.21 mmol) was used as a starting material, which was synthesized according to the method of Example 1 and purified by HPLC preparative chromatography (column: Gemini-C18, 150×21.2 mm, 5 μιη, mobile phase) : acetonitrile/water (0.1% formic acid), gradient: 50-70) to give the title product 3-(2-(6'-methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl 3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)propanoic acid 6 (10 mg, white solid), yield: 9%.
MS m/z (ESI) : 508 [M+l]  MS m/z (ESI) : 508 [M+l]
¾ NMR (300 MHz, CDCb) δ 7.35-7.31 (m， 4H)， 7.14 (d, J= 8.2 Hz, 1H)， 6.826-6.77(m， 4H)， 6.54 (s， 1H)， 4.48-4.46 (m， 1H)， 4.14-4.12 (m， 2H), 3.34-3.24 (m, 2H), 2.96 (s， 3H)， 2.87-2.80 (m, 2H), 2.63 (d, J= 7.0 Hz, 2H), 2.37-3.30(m, 2H), 2.22 (s, 3H)， 2.19-1.94 (m， 4H)。  3⁄4 NMR (300 MHz, CDCb) δ 7.35-7.31 (m, 4H), 7.14 (d, J = 8.2 Hz, 1H), 6.826-6.77 (m, 4H), 6.54 (s, 1H), 4.48-4.46 ( m, 1H), 4.14-4.12 (m, 2H), 3.34-3.24 (m, 2H), 2.96 (s, 3H), 2.87-2.80 (m, 2H), 2.63 (d, J = 7.0 Hz, 2H) , 2.37-3.30 (m, 2H), 2.22 (s, 3H), 2.19-1.94 (m, 4H).
实施例 7  Example 7
3-(2-(4-氟 -2',6'-二甲基 -4'-(3-(甲磺酰基）丙氧基）联苯基 -3- 基:) - 1 ,2,3 ,4-四氫喹啉基 -6-基：)丙酸 3-(2-(4-Fluoro-2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl:) - 1 ,2,3 , 4-tetrahydroquinolinyl-6-yl:) propionic acid
Figure imgf000031_0001
Figure imgf000031_0001
第一步  First step
4—氟 -3-(4,4,5,5-四甲基—1,3,2—二氧杂硼烷 -2-基)苯酚  4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
利用化合物 3-溴 -4-氟苯酚 7a (4.0g, 20.9mmol)和 4,4,4',4',5,5,5',5'- 八甲基 -2,2'-二 （1,3,2-二氧杂硼烷）（6.4g， 25.1mmol)反应， 参照化合物 l 的合成方法， 得到标题产物 4-氟 -3-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2-基)苯酚 7b (3.0g， 黄色固体)， 收率： 64%。  Using the compound 3-bromo-4-fluorophenol 7a (4.0 g, 20.9 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di ( Reaction of 1,3,2-dioxaborane (6.4 g, 25.1 mmol), the title compound 4-fluoro-3-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)phenol 7b (3.0 g, yellow solid), Yield: 64%.
¾ NMR (300 MHz, CDCb) δ 7.33 (d, J= 7.4 Hz, 1H)， 7.05 (t, J = 7.7 Hz, 1H)， 6.86 (d, J= 8.0 Hz, 1H)， 1.26 (s， 12H)。  3⁄4 NMR (300 MHz, CDCb) δ 7.33 (d, J = 7.4 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 1.26 (s, 12H ).
第二步  Second step
( -6-(3-乙氧基 -3-氧丙基 -1-烯基)喹啉 1-氧化物  (-6-(3-ethoxy-3-oxopropyl-1-enyl)quinoline 1-oxide
1L 单口瓶中称入 ( )-3- (喹啉基 -6-基）丙烯酸乙酯 7c (15g， 70.4mmol) (采用公知的方法" WO2008144767"制备而得），加入二氯甲烷 (250mL), 冰水浴下慢慢加入间氯过氧苯甲酸 (21.4g， 105.6mmol)。 反 应在室温下搅拌反应 24小时。反应溶液用疏代亚疏酸钠、食盐水洗涤， 有机层用无水疏酸钠干燥， 过滤除去干燥剂， 减压脱溶， 得到标题产 物 ( )-6-(3-乙氧基 -3-氧丙基 -1-烯基)喹啉 1-氧化物 7d (15g， 黄色固体)， 产率： 93%。  (1-3-(quinolinyl-6-yl) acrylate ethyl ester 7c (15 g, 70.4 mmol) (prepared by a known method "WO2008144767") was added to a 1 L single-necked flask, and dichloromethane (250 mL) was added. The m-chloroperoxybenzoic acid (21.4 g, 105.6 mmol) was slowly added to the ice water bath. The reaction was stirred at room temperature for 24 hours. The reaction solution was washed with sodium hyaluronic acid and brine, and the organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to remove the solvent to afford the title product ()-6-(3-ethoxy-3) - oxypropyl-1-alkenyl)quinoline 1-oxide 7d (15 g, yellow solid), yield: 93%.
MS m/z (ESI) : 244 [M+l]  MS m/z (ESI): 244 [M+l]
第三步  third step
( )-3-(2-氯喹啉基 -6-基：)丙烯酸甲酯 250mL干燥单口瓶中称入 ( )-6-(3-乙氧基 -3-氧丙基 -1-烯基)喹啉 1- 氧化物 7d (15g， 66mmol)， 加入乙腈 (200mL)， 冰水浴冷却至 0。C， 缓 慢加入三氯氧磷 (30g， 198mmol) o油浴加热至 65。C并搅拌反应 3小时。 冷却至室温， 减压脱溶除去大部分三氯氧磷， 然后用冰水小心淬灭反 应， 用氨水中和， 调节 pH值约为 8。 然后用乙酸乙酯萃取 (100mLx3)， 合并有机相并用饱和食盐水洗涤， 无水疏酸钠干燥， 过滤除去干燥剂， 减压脱溶，残余物用硅胶柱层析纯化 (二氯甲烷)，得到标题产物 (E)-3-(2- 氯喹啉基 -6-基)丙烯酸甲酯 7e(9.8g， 白色固体)， 产率： 60%。 ( )-3-(2-chloroquinolinyl-6-yl:)methyl acrylate (6-(3-ethoxy-3-oxopropyl-1-enyl)quinoline 1-oxide 7d (15 g, 66 mmol) was weighed into a 250 mL dry single-mouth flask, acetonitrile (200 mL) was added, ice The water bath is cooled to 0. C, slowly add phosphorus oxychloride (30g, 198mmol) o heated to 65 in an oil bath. C and the reaction was stirred for 3 hours. After cooling to room temperature, most of the phosphorus oxychloride was removed by vacuum stripping, and then the reaction was carefully quenched with ice water and neutralized with aqueous ammonia to adjust the pH to about 8. Then, it is extracted with ethyl acetate (100 mL×3), and the organic phase is combined and washed with brine, dried over anhydrous sodium sulfate. The title product (E)-3-(2-chloroquinolinyl-6-yl)acrylate methyl 7e (9.8 g, white solid) was obtained, yield: 60%.
MS m/z (ESI) : 248 [M+l]  MS m/z (ESI): 248 [M+l]
第四步  the fourth step
( )-3-(2-(2-氟 -5-羟基苯基)喹啉 -6-基)丙烯酸甲酯  ( )-3-(2-(2-Fluoro-5-hydroxyphenyl)quinolin-6-yl)acrylate
利用 4-氟 -3-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2-基)苯酚 7b (1.4g， 6.0mmol)和 ( )-3-(2-氯喹啉 -6-基） 丙烯酸甲酯 7e (1.0g， 4.0mmol)反应， 参照化合物 lh 的合成方法， 得到标题产物 ( )-3-(2-(2-氟 -5-羟基苯基) 喹啉—6-基)丙烯酸甲酯 7f (615mg， 红色固体)， 收率： 54%。  Using 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 7b (1.4 g, 6.0 mmol) and (3) -(2-Chloroquinolin-6-yl)methyl acrylate 7e (1.0 g, 4.0 mmol) was obtained by the reaction of compound lh to give the title product ()-3-(2-(2-fluoro-5-hydroxy) Methyl phenyl)-quinoline-6- methacrylate 7f (615 mg, red solid), yield: 54%.
MS m/z (ESI) : 324 [M+l]  MS m/z (ESI): 324 [M+l]
第五步  the fifth step
(£)-3-(2-(2-氟 -5- (三氟甲磺酰氧基：)苯基)喹啉 -6-基：)丙烯酸甲酯 以 ( )-3-(2-(2-氟 -5-羟基苯基）喹啉 -6-基）丙烯酸甲酯 7f (0.7g， 22mmol)为原料， 参照化合物 If的合成方法， 得到标题产物 ( )-3-(2-(2- 氟 -5- (三氟甲磺酰氧基)苯基)喹啉 -6-基)丙烯酸甲酯 7g (1.0g，无色油状， 粗品）。 产物不经纯化直接用于下一步反应。  (£)-3-(2-(2-Fluoro-5-(trifluoromethanesulfonyloxy))phenyl)quinolin-6-yl:)methyl acrylate with ( )-3-(2-( 2-fluoro-5-hydroxyphenyl)quinolin-6-yl)acrylic acid methyl ester 7f (0.7 g, 22 mmol) was used as a starting material, and the title compound ()-3-(2-(2) - 7 g of fluoro-5-(trifluoromethanesulfonyloxy)phenyl)quinolin-6-yl)acrylate (1.0 g, colorless oil, crude). The product was used in the next reaction without purification.
MS m/z (ESI) : 456 [M+l]  MS m/z (ESI) : 456 [M+l]
第六步  Step 6
( )-3-(2-(4-氟 -2',6'-二甲基 -4'-(3- (三氟甲磺酰氧基)苯氧基)联苯基 -3-基)喹啉 -6-基)丙烯酸甲酯  ( )-3-(2-(4-Fluoro-2',6'-dimethyl-4'-(3-(trifluoromethanesulfonyloxy)phenoxy)biphenyl-3-yl) Methyl quinoline-6-yl)acrylate
利用 ( )-3-(2-(2-氟 -5- (三氟甲磺酰氧基)苯基)喹啉 -6-基）丙烯酸甲 酯 7g (455mg， l.Ommol)与 2-(2,6-甲基 -4-3- (三氟甲磺酰基)丙氧基)苯基 —4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 2c (630mg， 1.2mmol)反应， 参照实施 例 2 中 2f 的合成方法合成， 得到标题产物 ( )-3-(2-(4-氟 -2',6'-二甲基 -4'-(3- (；三氟甲磺酰氧基：)苯氧基:)联苯基 -3-基:)喹啉 -6-基：)丙烯酸甲酯 7h (500mg, 粗品）， 产物不经纯化直接用于下一步反应。 Using 7-methyl 3-(2-(2-fluoro-5-(trifluoromethanesulfonyloxy)phenyl)quinolin-6-yl)acrylate (455 mg, 1.0 mmol) with 2-( 2,6-Methyl-4-3-(trifluoromethanesulfonyl)propoxy)phenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane 2c ( 630 mg, 1.2 mmol) was synthesized by the synthesis of 2f in Example 2 to give the title product ()-3-(2-(4-fluoro-2',6'-dimethyl-4'-(3- (trifluoromethanesulfonyloxy:)phenoxy:)biphenyl-3-yl:)quinolin-6-yl:)methyl acrylate 7h (500 mg, crude), product was used in the next step without purification.
MS m/z (ESI) : 548 [M+l]  MS m/z (ESI) : 548 [M+l]
第七步  Seventh step
( )-3-(2-(4-氟 -2',6'-二甲基 -4'-(3- (三氟甲磺酰氧基)苯氧基)联苯基 -3-基)喹啉 -6-基)丙烯酸  ( )-3-(2-(4-Fluoro-2',6'-dimethyl-4'-(3-(trifluoromethanesulfonyloxy)phenoxy)biphenyl-3-yl) Quinoline-6-yl)acrylic acid
利用 ( )-3-(2-(4-氟 -2',6'-二甲基 -4'-(3- (三氟甲磺酰氧基)苯氧基)联 苯基 -3-基)喹啉 -6-基)丙烯酸甲酯 7h (500mg， 0.91mmol)参照实施例 1 的搡作方法， 得到标题产物 ( )-3-(2-(4-氟 -2',6'-二甲基 -4'-(3- (三氟甲磺 酰氧基)苯氧基)联苯基 -3-基)喹啉 -6-基)丙烯酸 7i (150mg， 粗品）。 产物 不经纯化直接用于下一步反应。  Using ( )-3-(2-(4-fluoro-2',6'-dimethyl-4'-(3-(trifluoromethanesulfonyloxy)phenoxy)biphenyl-3-yl Methyl quinolin-6-yl) acrylate 7h (500 mg, 0.91 mmol) was obtained according to the procedure of Example 1 to give the title product ()-3-(2-(4-fluoro-2',6'- Methyl-4'-(3-(trifluoromethanesulfonyloxy)phenoxy)biphenyl-3-yl)quinolin-6-yl)acrylic acid 7i (150 mg, crude). The product was used in the next reaction without purification.
MS m/z (ESI) : 534 [M+l]  MS m/z (ESI) : 534 [M+l]
第八步  Eighth step
3-(2-(4-氟 -2',6'-二甲基 -4'-(3- (三氟甲磺酰氧基)苯氧基)联苯基 -3- 基) -1,2,3,4-四氫喹啉 -6-基)丙酸  3-(2-(4-fluoro-2',6'-dimethyl-4'-(3-(trifluoromethanesulfonyloxy)phenoxy)biphenyl-3-yl)-1, 2,3,4-tetrahydroquinolin-6-yl)propionic acid
利用 ( )-3-(2-(4-氟 -2',6'-二甲基 -4'-(3- (三氟甲磺酰氧基)苯氧基)联 苯基 -3-基)喹啉 -6-基)丙烯酸 7i (150mg， 0.28mmol), 参照实施例 1中化 合物 li 的合成方法， 经 HPLC 制备色谱纯化 (；色谱柱： Gemini-C18 150x21.2mm, 5μιη; 流动相： ACN-H20 (0.1%甲酸）； 梯度： 60-65)， 得到标题产物 3-(2-(4-氟 -2',6'-二甲基 -4'-(3- (三氟甲磺酰氧基)苯氧基)联 苯基 -3-基) -1,2,3,4-四氫喹啉 -6-基)丙酸 7(16mg， 白色固体)，收率： 11%。 Using ( )-3-(2-(4-fluoro-2',6'-dimethyl-4'-(3-(trifluoromethanesulfonyloxy)phenoxy)biphenyl-3-yl </ RTI></RTI></RTI><RTIgt; ACN-H 2 0 (0.1% formic acid); gradient: 60-65) to give the title product 3-(2-(4-fluoro-2',6'-dimethyl-4'-(3-(trifluoro) Methanesulfonyloxy)phenoxy)biphenyl-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)propanoic acid 7 (16 mg, white solid), yield: 11 %.
MS m/z (ESI) : 540 [M+l]  MS m/z (ESI) : 540 [M+l]
¾ NMR (400 MHz, MeOD) δ 7.18-7.11 (m, 2H), 7.03-6.98 (m， 1H)， 6.82-6.79 (m, 2H), 6.66 (d, J= 12.0 Hz, 2H), 6.54 (d, J= 8.0 Hz, 1H)， 4.88-4.80 (m， 1H)， 4.11 (t， J= 6.0 Hz, 2H), 3.02 (s, 3H)， 2.76-2.70 (m， 4H)， 2.56-2.50 (m, 3H)， 2.42-2.38 (m, 2H), 2.30-2.26 (m, 2H), 2.10-2.05 (m, 1H)， 2.01 (s, 3H)， 1.86 (s， 3H)。  3⁄4 NMR (400 MHz, MeOD) δ 7.18-7.11 (m, 2H), 7.03-6.98 (m, 1H), 6.82-6.79 (m, 2H), 6.66 (d, J = 12.0 Hz, 2H), 6.54 ( d, J= 8.0 Hz, 1H), 4.88-4.80 (m, 1H), 4.11 (t, J= 6.0 Hz, 2H), 3.02 (s, 3H), 2.76-2.70 (m, 4H), 2.56-2.50 (m, 3H), 2.42-2.38 (m, 2H), 2.30-2.26 (m, 2H), 2.10-2.05 (m, 1H), 2.01 (s, 3H), 1.86 (s, 3H).
实施例 8  Example 8
3-(2-(2',6'-二甲基 -4'-(3-(甲磺酰基）丙氧基）联苯基 -3-基）-7-氟 -1,2,3,4-四氫喹啉基 -6-基；)丙酸 3-(2-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-7-fluoro-1,2,3, 4-tetrahydroquinolinyl-6-yl;) propionic acid
Figure imgf000034_0001
Figure imgf000034_0001
第一步  First step
2',6'-二甲基 -4'-(3-(甲磺酰基)丙氧基)联苯基 -3-酚  2',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-phenol
利用 2-(2,6-二甲基 -4-(3-(甲磺酰基）丙氧基）苯基) -4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 2c (0.5g 1.5mmol)和 3-溴苯酚 (0.3g 1.8mmol)为原 料， 参照实施例 1中化合物 le的合成方法， 得到标题产物 2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基联苯基 -3-酚 8a (0.5g， 浅黄色油状物）， 收率： 90%  Using 2-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxo Starting from the synthesis of the compound le in Example 1, a heteroborane 2c (0.5 g of 1.5 mmol) and 3-bromophenol (0.3 g of 1.8 mmol) were used as a starting material to give the title product 2',6'-dimethyl-4'. -(3-(Methanesulfonyl)propoxybiphenyl-3-phenol 8a (0.5 g, pale yellow oil), Yield: 90%
MS m/z (ESI) : 335 [M+l]  MS m/z (ESI) : 335 [M+l]
第二步  Second step
2',6'-二甲基 -4'-(3-(甲磺酰基)丙氧基)联苯基 -3-基三氟甲磺酸酯 利用 2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-酚 8a (0.5g 1.5mmol)为原料， 参照化合物 If的合成方法， 得到标题产物 2',6'-二甲 基—4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基 三氟甲磺酸酯 8b (0.7g， 浅黄 色油状物)， 收率： 90%。 产物不经纯化直接用于下一步反应。  2',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yltrifluoromethanesulfonate utilizes 2',6'-dimethyl-4 '-(3-(Methanesulfonyl)propoxy)biphenyl-3-phenol 8a (0.5 g 1.5 mmol) was used as a starting material, and the title compound 2',6'-dimethyl -4'-(3-(Methanesulfonyl)propoxy)biphenyl-3-yltrifluoromethanesulfonate 8b (0.7 g, pale yellow oil), yield: 90%. The product was used in the next reaction without purification.
MS m/z (ESI) : 467 [M+l] 第三步 MS m/z (ESI): 467 [M+l] third step
2-(2',6'-二甲基 -4'-(3-(甲磺酰基）丙氧基联苯基 -3-基) -4,4,5,5-四甲基 -1,3,2-二氧杂硼烷  2-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxybiphenyl-3-yl)-4,4,5,5-tetramethyl-1, 3,2-dioxaborane
利用 2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基 三氟甲磺酸 酯 8b (0.7g， 1.5mmol)为原料， 参照化合物 lg的合成方法， 得到标题 产物 2-(2',6'-二甲基 -4'-(3-(甲磺酰基)丙氧基联苯基 -3-基) -4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 8c (0.6g， 黄色油状物）， 收率： 80%。  Using 2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yltrifluoromethanesulfonate 8b (0.7 g, 1.5 mmol) as a raw material, With reference to the synthesis of the compound lg, the title product 2-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxybiphenyl-3-yl)-4,4, 5,5-Tetramethyl-1,3,2-dioxaborane 8c (0.6 g, yellow oil), Yield: 80%.
MS m/z (ESI) : 445 [M+l]  MS m/z (ESI) : 445 [M+l]
第四步  the fourth step
( -3-(7-氟喹啉 -6-基：)丙烯酸甲酯  (-3-(7-fluoroquinolin-6-yl:)methyl acrylate
250mL干燥三口瓶中称入 6-溴 -7-氟喹啉 8d (3.4g， 15mmol， 采用 公知的方法"专利 WO2008051808"制备而得）， 醋酸钯（363mg， 1.5mmol), 三邻甲苯基膦 (912mg， 3mmol)。 将体系置换为氮气氛围， 加入 Ν,Ν'-二甲基苯甲酰胺 (40mL)， 丙烯酸乙酯 (3.9g， 45mmol)和三乙 胺 (4.5g， 45mmol)。 然后在 100 °C下搅拌反应， TLC监测反应直到反 应完全。 冷却至室温， 将反应体系用 80mL 水稀释， 乙酸乙酯萃取 (80mLx3), 合并有机相并用饱和食盐水洗涤， 无水疏酸钠干燥， 过滤 除去干燥剂， 减压脱溶， 残余物用硅胶柱层析纯化 (石油醚 /乙酸乙酯 = 10 : 1)， 得到标题产物 ( )-3-(7-氟喹啉 -6-基)丙烯酸甲酯 8e (3.0 g， 黄色 固体)， 产率： 86%。  In a 250 mL dry three-necked flask, 6-bromo-7-fluoroquinoline 8d (3.4 g, 15 mmol, prepared by the known method "WO2008051808"), palladium acetate (363 mg, 1.5 mmol), tri-o-tolylphosphine (912 mg, 3 mmol). The system was replaced with a nitrogen atmosphere, and hydrazine, Ν'-dimethylbenzamide (40 mL), ethyl acrylate (3.9 g, 45 mmol) and triethylamine (4.5 g, 45 mmol). The reaction was then stirred at 100 ° C and the reaction was monitored by TLC until the reaction was complete. After cooling to room temperature, the reaction system was diluted with 80 mL of water, and extracted with ethyl acetate (80 mL×3). The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by column chromatography (EtOAc/EtOAc /EtOAc (EtOAc:EtOAc) : 86%.
MS m/z (ESI) : 232 [M+l]  MS m/z (ESI) : 232 [M+l]
第五步  the fifth step
( )-7-氟 -6-(3-甲氧基 -3-烯丙酰 -1-基)喹啉 1-氧化物  ( )-7-fluoro-6-(3-methoxy-3-allyl-1-yl)quinoline 1-oxide
250mL 单口瓶中称入 ( )-3-(7-氟喹啉 -6-基)丙烯酸甲酯 8e (2.3g, lOmmol), 碳酸氫钠 (2.7g， 31.9mmol)， 加入甲醇 (56mL)， 然后在搅拌 下加入 Oxone (12.2g， 20mmol), 水 (22mL；)。 将体系置换为氮气氛围后 在 50。C下搅拌反应 24 小时。 冷却至室温， 加入 50mL甲醇继续搅拌 0.5 小时，过滤，用甲醇洗涤，滤液减压脱溶，二氯甲烷萃取 (100mLx3)， 合并有机相并用饱和食盐水洗涤， 无水疏酸钠干燥， 过滤除去干燥剂， 减压脱溶， 得到标题产物 ( )-7-氟 -6-(3-甲氧基 -3-烯丙酰 -1-基)喹啉 1- 氧化物 8f (2.4g， 黄色固体， 粗品）。 MS m/z (ESI) : 248 [M+l] Methyl (7-fluoroquinolin-6-yl) acrylate 8e (2.3 g, 10 mmol), sodium hydrogencarbonate (2.7 g, 31.9 mmol), and methanol (56 mL) were weighed in a 250 mL single-necked flask. Oxone (12.2 g, 20 mmol), water (22 mL;) was then added with stirring. The system was replaced by a nitrogen atmosphere at 50. The reaction was stirred at C for 24 hours. After cooling to room temperature, 50 mL of methanol was added and the mixture was stirred for 0.5 hr, filtered, washed with methanol, and the filtrate was evaporated to dryness eluted with methylene chloride (100 mL×3). The organic phase was combined and washed with brine, dried over anhydrous sodium sulfate The desiccant was de-dissolved under reduced pressure to give the title product (md.)-(s)-7-fluoro-6-(3-methoxy-3-propionyl-1-yl)quinoline 1-oxide 8f (2.4 g, yellow solid , Crude). MS m/z (ESI): 248 [M+l]
第六步  Step 6
( )-3-(2-氯 -7-氟喹啉 -6-基)丙烯酸甲酯  ( )-3-(2-Chloro-7-fluoroquinolin-6-yl)acrylate
250mL 干燥单口瓶中称入 ( )-7-氟 -6-(3-甲氧基 -3-烯丙酰 -1-基)喹 啉 1-氧化物 8f (2.4g， 9.7mmol), 加入甲苯 (40mL)， 冰水浴冷却至 0。C， 缓慢加入三氯氧磷 (4.6g， 29.1mmol)。 油浴加热至 65。C 并搅拌反应 3 小时。 冷却至室温， 减压脱溶除去大部分三氯氧磷， 然后用冰水小心 淬灭反应， 用氨水中和， 调节 pH 值约为 8。 然后用乙酸乙酯萃取 (80mLx3), 合并有机相并用饱和食盐水洗涤， 无水疏酸钠干燥， 过滤 除去干燥剂， 减压脱溶， 残余物用硅胶柱层析纯化 (二氯甲烷)， 得到标 题产物 ( )-3-(2-氯 -7-氟喹啉 -6-基)丙烯酸甲酯 8g (1.2g， 白色固体)， 产 率： 47%。  (7-fluoro-6-(3-methoxy-3-allyl-1-yl)quinoline 1-oxide 8f (2.4 g, 9.7 mmol) was weighed into a 250 mL dry single-mouth flask, and toluene was added. (40 mL), cooled to 0 in an ice water bath. C, phosphorus oxychloride (4.6 g, 29.1 mmol) was added slowly. Heat the oil bath to 65. C and stir the reaction for 3 hours. After cooling to room temperature, most of the phosphorus oxychloride was removed by vacuum stripping, and then the reaction was carefully quenched with ice water and neutralized with aqueous ammonia to adjust the pH to about 8. Then, it is extracted with ethyl acetate (80 mL×3), and the organic phase is combined and washed with saturated brine, dried over anhydrous sodium sulfate The title product (methyl 3-(2-chloro-7-fluoroquinolin-6-yl)acrylate 8 g (1.2 g, white solid) was obtained.
MS m/z (ESI) : 266 [M+l]  MS m/z (ESI) : 266 [M+l]
第七步  Seventh step
( )-3-(2-(2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基) -7-氟喹 啉—6-基)丙烯酸甲酯  ( )-3-(2-(2',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-7-fluoroquinoline-6 Methyl acrylate
lOOmL 干燥三口瓶中称入 ( )-3-(2-氯 -7-氟喹啉 -6-基）丙烯酸甲酯 8g (266mg, lmmol), PdCl2(dppf)(37mg, 0.05mmol), 碳酸钾 (276mg， 2mmol)和 2-(2',6'-二甲基 -4'-(3- (甲磺酰基）丙氧基联苯基 -3-基) -4,4,5,5- 四甲基 -1,3,2-二氧杂硼烷 8c (466mg， 1.05mmol)。 将体系置换为氮气氛 围， 加入二氧六环（10mL)和水 (2mL)， 然后在 85。C 下搅拌反应， TLC 监测反应直到原料反应完全。 冷却至室温， 将反应体系用 20mL 水稀 释， 乙酸乙酯萃取 (30mLx3)， 合并有机相并用饱和食盐水洗涤， 无水 疏酸钠干燥， 过滤除去干燥剂， 减压脱溶， 残余物用硅胶柱层析纯化， 得到标题产物 ( )-3-(2-(2',6'-二甲基 -4'-(3-(甲磺酰基）丙氧基)联苯基 -3- 基) -7-氟喹啉 -6-基)丙烯酸甲酯 8h (300mg， 浅黄色油状物)， 产率 56%。 Methyl (3-chloro-7-fluoroquinolin-6-yl) acrylate 8 g (266 mg, 1 mmol), PdCl 2 (dppf) (37 mg, 0.05 mmol), carbonated in a 100 mL dry three-necked flask Potassium (276 mg, 2 mmol) and 2-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxybiphenyl-3-yl)-4,4,5,5 - Tetramethyl-1,3,2-dioxaborane 8c (466 mg, 1.05 mmol). The system was replaced with a nitrogen atmosphere, dioxane (10 mL) and water (2 mL), then at 85 C. The reaction was stirred, and the reaction was monitored by TLC until the reaction mixture was completed. The mixture was cooled to room temperature. The mixture was diluted with water (20 mL), ethyl acetate (30 mL×3), and the organic phase was combined and washed with brine, dried over anhydrous sodium sulfate The desiccant was de-dissolved under reduced pressure, and the residue was purified mjjjjjjjjjjj Propyloxy)biphenyl-3-yl)-7-fluoroquinolin-6-yl)methyl acrylate 8h (300 mg, pale yellow oil), yield 56%.
MS m/z (ESI) : 548 [M+l]  MS m/z (ESI) : 548 [M+l]
第八步  Eighth step
( )-3-(2-(2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基) -7-氟喹 啉—6-基)丙烯酸 利用 ( )-3-(2-(2',6'-二甲基 -4'-(3-(甲磺酰基)丙氧基)联苯基 -3-基) -7- 氟喹啉—6-基)丙烯酸甲酯 8h (300mg， 0.55mmol)为原料， 参照实施例 1 的搡作方法， 得到标题产物 ( )-3-(2-(2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧 基)联苯基 -3-基) -7-氟喹啉 -6-基)丙烯酸 8i (260mg， 黄色固体)， 产率： 89%。 ( )-3-(2-(2',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-7-fluoroquinoline-6 -based) acrylic Using ( )-3-(2-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-7-fluoroquinoline- 6-Methyl acrylate 8h (300mg, 0.55mmol) was used as the starting material, and the title product ( )-3-(2-(2',6'-dimethyl-4' -(3-(Methanesulfonyl)propoxy)biphenyl-3-yl)-7-fluoroquinolin-6-yl)acrylic acid 8i (260 mg, yellow solid), yield: 89%.
MS m/z (ESI) : 534 [M+l]  MS m/z (ESI) : 534 [M+l]
第九步  Step 9
3-(2-(2',6'-二甲基 -4'-(3-(甲磺酰基）丙氧基）联苯基 -3-基）-7-氟 -1,2,3,4-四氫喹啉 -6-基)丙酸  3-(2-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-7-fluoro-1,2,3, 4-tetrahydroquinolin-6-yl)propionic acid
利用 ( )-3-(2-(2',6'-二甲基 -4'-(3-(甲磺酰基)丙氧基)联苯基 -3-基) -7- 氟喹啉—6-基)丙烯酸 8i (260mg， 0.49mmol)为原料， 参照实施例 1的搡作 方法， 粗品经 HPLC制备色谱纯化（色谱柱： Gemini-C18 150x21.2mm 5μιη, 流动相： 乙腈 /水 (0.1%三氟乙酸)， 梯度： 40-90)， 得到标题产物 3-(2-(2',6'-二甲基 -4'-(3- (甲磺酰基）丙氧基)联苯基 -3-基) -7-氟 -1,2,3,4-四 氫喹啉—6—基)丙酸 8 (60mg， 白色固体)， 产率： 23%。  Using ( )-3-(2-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-7-fluoroquinoline- 6-yl)acrylic acid 8i (260 mg, 0.49 mmol) was used as a starting material, and the crude product was purified by HPLC according to the method of Example 1 (column: Gemini-C18 150×21.2 mm 5 μιη, mobile phase: acetonitrile/water (0.1) % trifluoroacetic acid, gradient: 40-90), the title product 3-(2-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl) 3-yl)-7-fluoro-1,2,3,4-tetrahydroquinolin-6-yl)propanoic acid 8 (60 mg, white solid), yield: 23%.
MS m/z (ESI) : 540 [M+l]  MS m/z (ESI) : 540 [M+l]
¾ NMR (400 MHz, CDC13) δ 7.41 (t, J= 7.6 Hz, 1H)， 7.34 (d， J = 7.8 Hz, 1H)， 7.13 (s， 1H)， 7.07 (d, J= 7.4 Hz, 1H)， 6.82 (d, J= 8.3 Hz, 1H)， 6.66 (s， 2H), 6.26 (d, J= 11.6 Hz, 1H)， 4.47 (dd, J= 8.8， 3.1 Hz, 1H)， 4.15 (t, J = 5.7 Hz, 2H), 3.34-3.25 (m, 2H), 3.00 (s, 3H)， 2.87 (t, J= 7.7 Hz, 2H), 2.81-2.78 (m, 1H)， 2.73-2.61 (m, 3H)， 2.37 (dt, J= 15.5, 5.6 Hz, 2H), 2.20-2.07 (m, 2H), 2.03 (s, 3H)， 2.00 (s， 3H)。 3⁄4 NMR (400 MHz, CDC1 3 ) δ 7.41 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.13 (s, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.82 (d, J= 8.3 Hz, 1H), 6.66 (s, 2H), 6.26 (d, J= 11.6 Hz, 1H), 4.47 (dd, J= 8.8, 3.1 Hz, 1H), 4.15 ( t, J = 5.7 Hz, 2H), 3.34-3.25 (m, 2H), 3.00 (s, 3H), 2.87 (t, J= 7.7 Hz, 2H), 2.81-2.78 (m, 1H), 2.73-2.61 (m, 3H), 2.37 (dt, J= 15.5, 5.6 Hz, 2H), 2.20-2.07 (m, 2H), 2.03 (s, 3H), 2.00 (s, 3H).
实施例 9  Example 9
3-(2-(4'-(3-(乙磺酰基）丙氧基）-2',6'-二甲基联苯基 -3-基）-7-氟 -1,2,3,4-四氫喹啉 -6-基)丙酸 3-(2-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-7-fluoro-1,2,3, 4-tetrahydroquinolin-6-yl)propionic acid
Figure imgf000038_0001
Figure imgf000038_0001
第一步  First step
( )-3-(2-(4'-(3- (乙磺酰基)丙氧基 )-2',6'-二甲基联苯基 -3-基) -7-氟喹 啉—6-基)丙烯酸甲酯  ( )-3-(2-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-7-fluoroquinoline-6 Methyl acrylate
利用 2-(4'-(3-(乙磺酰基）丙氧基) -2',6'-二甲基联苯基 -3-基) -4,4,5,5- 四甲基 -1,3,2-二氧杂硼烷 9a (520mg， 1.13mmol， 参照 8c的合成方法合 成)和 ( )-3-(2-氯 -7-氟喹啉 -6-基）丙烯酸甲酯 8g (300mg， 1.13mmol)为 原料， 参照实施例 8中 8h的合成方法， 得到标题产物 ( )-3-(2-(4'-(3- (乙 磺酰基)丙氧基 )-2',6'-二甲基联苯基 -3-基) -7-氟喹啉 -6-基)丙烯酸甲酯 9b (200mg, 黄色油状物）， 产率： 31%。  Using 2-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborane 9a (520 mg, 1.13 mmol, synthesized according to the synthesis method of 8c) and methyl (3-chloro-7-fluoroquinolin-6-yl)acrylate 8 g The title product ( )-3-(2-(4'-(3-(ethylsulfonyl)propoxy)-2', was obtained by the title compound (3 mg, 6'-Dimethylbiphenyl-3-yl)-7-fluoroquinolin-6-yl)methyl acrylate 9b (200 mg, yellow oil), yield: 31%.
MS m/z (ESI) : 562 [M+l]  MS m/z (ESI) : 562 [M+l]
¾ NMR (400 MHz, CDCb) δ 8.50 (s, 1H)， 8.44 (d， J= 7.8 Hz, 1H)， 8.13 (d， J= 7.6 Hz, 1H)， 7.99 (d, J= 8.6 Hz, 1H)， 7.95 (d, J = 3⁄4 NMR (400 MHz, CDCb) δ 8.50 (s, 1H), 8.44 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H ), 7.95 (d, J =
3.1 Hz, 1H)， 7.91 (s， 1H)， 7.78-7.69 (m, 1H)， 7.41 (d， J= 7.7 Hz, 1H)， 6.81 (t， J= 10.4 Hz, 1H)， 6.71 (s, 2H), 6.64 (d， J= 11.4 Hz, 1H)， 4.16 (dt, J= 11.9, 5.8 Hz, 2H), 3.89 (s， 2H), 3.24 (dd, J= 15.1 ,3.1 Hz, 1H), 7.91 (s, 1H), 7.78-7.69 (m, 1H), 7.41 (d, J= 7.7 Hz, 1H), 6.81 (t, J= 10.4 Hz, 1H), 6.71 (s, 2H), 6.64 (d, J= 11.4 Hz, 1H), 4.16 (dt, J= 11.9, 5.8 Hz, 2H), 3.89 (s, 2H), 3.24 (dd, J= 15.1 ,
6.2 Hz, 3H)， 3.18-3.02 (m， 3H)， 2.48-2.30 (m， 3H)， 2.09 (s， 4H)， 2.07-2.01 (m， 2H), 1.52-1.43 (m， 3H)。 6.2 Hz, 3H), 3.18-3.02 (m, 3H), 2.48-2.30 (m, 3H), 2.09 (s, 4H), 2.07-2.01 (m, 2H), 1.52-1.43 (m, 3H).
第二步  Second step
3-(2-(4'-(3- (乙磺酰基）丙氧基 )-2',6'-二甲基联苯基 -3-基) -7-氟喹啉 -6-基：)丙酸甲酯  3-(2-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-7-fluoroquinolin-6-yl: Methyl propionate
50mL的单口瓶中称入 ( )-3-(2-(4'-(3-(乙磺酰基）丙氧基 )-2',6'-二甲 基联苯基 -3-基) -7-氟喹啉 -6-基）丙烯酸甲酯 9b (200mg, 0.36mmol) , Pd/C(20mg, 10%), 加入四氫呋喃 (2mL)和甲醇 (6mL)， 将体系置换为 氫气氛围（latm)， 室温搅拌过夜。 过滤除去 Pd/C， 滤液浓縮得到标题产 物 3-(2-(4'-(3- (乙磺酰基）丙氧基 )-2',6'-二甲基联苯基 -3-基) -7-氟喹啉 -6- 基)丙酸甲酯 9c (140mg， 白色固体)， 产率： 69%。 产物不经纯化直接用 于下一步反应。 Weigh ( )-3-(2-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl) in a 50 mL single-mouth bottle - Methyl 7-fluoroquinolin-6-yl)acrylate 9b (200mg, 0.36mmol), Pd/C (20mg, 10%), THF (2mL) and methanol (6mL) Hydrogen atmosphere (latm) was stirred at room temperature overnight. The Pd/C was removed by filtration, and the filtrate was concentrated to give the title product 3-(2-(4'-(3-(ethylsulfonyl)propyloxy)-2',6'-dimethylbiphenyl-3-yl Methyl-7-fluoroquinolin-6-yl)propanoate 9c (140 mg, white solid), yield: 69%. The product was used in the next reaction without purification.
MS m/z (ESI) : 564 [M+l]  MS m/z (ESI) : 564 [M+l]
第三步  third step
3-(2-(4'-(3-(乙磺酰基）丙氧基）-2',6'-二甲基联苯基 -3-基）-7-氟 -1,2,3,4-四氫喹啉 -6-基)丙酸甲酯  3-(2-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-7-fluoro-1,2,3, Methyl 4-tetrahydroquinolin-6-yl)propionate
50mL的单口瓶中称入 3-(2-(4'-(3- (乙磺酰基)丙氧基 )-2',6'-二甲基联 苯基 -3-基:) -7-氟喹啉 -6-基)丙酸甲酯 9c (200mg, 0.35mmol)和二氯甲烷 (3mL), 然后加入氰基硼氫化钠 (40mg， 0.71mmol), 室温搅拌过夜。 加 水（10mL)淬灭反应， 用 1N盐酸调节至 pH = 6， 二氯甲烷萃取 (10mL)。 合并有机相， 减压脱溶， 得到标题产物 3-(2-(4'-(3- (乙磺酰基）丙氧 基:) -2',6'-二甲基联苯基 -3-基:) -7-氟 -1,2,3,4-四氫喹啉 -6-基：)丙酸甲酯 9d (180mg， 无色油状物）， 产率： 90%。  3-(2-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl:)-7- is weighed into a 50 mL single-mouth bottle Methyl fluoroquinolin-6-yl)propanoate 9c (200 mg, 0.35 mmol) and methylene chloride (3 mL), then sodium cyanoborohydride (40 mg, 0.71 mmol). The reaction was quenched with water (10 mL) EtOAc (EtOAc) The organic phase was combined and evaporated to dryness to give titled product of 3-(2-(4'-(3-(ethanesulfonyl)propoxy): -2',6'-dimethylbiphenyl-3- Base:) -7-fluoro-1,2,3,4-tetrahydroquinolin-6-yl: methyl propionate 9d (180 mg, colorless oil), yield: 90%.
MS m/z (ESI) : 568 [M+l]  MS m/z (ESI) : 568 [M+l]
第四步  the fourth step
3-(2-(4'-(3-(乙磺酰基）丙氧基）-2',6'-二甲基联苯基 -3-基）-7-氟 -1,2,3,4-四氫喹啉 -6-基)丙酸  3-(2-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-7-fluoro-1,2,3, 4-tetrahydroquinolin-6-yl)propionic acid
利用 3-(2-(4'-(3- (乙磺酰基）丙氧基 )-2',6'-二甲基联苯基 -3-基) -7-氟 -1,2,3,4-四氫喹啉 -6-基)丙酸甲酯 9d (100mg， 0.17mmol)为原料， 参照实 施例 1中的搡作方法， 粗品经 HPLC制备色谱纯化（色谱柱： Gemini-C18 150x21.2mm 5μιη, 流动相： 乙腈 /水 (0.1%三氟乙酸)， 梯度： 50-70)， 得到标题产物 3-(2-(4'-(3-(乙磺酰基）丙氧基 )-2',6'-二甲基联苯基 -3- 基) -7-氟 -1,2,3,4-四氫喹啉 -6-基)丙酸 9 (9mg， 白色固体)， 收率： 9%。  Using 3-(2-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-7-fluoro-1,2,3 , 4-tetrahydroquinolin-6-yl)propionic acid methyl ester 9d (100 mg, 0.17 mmol) was used as a starting material, and the crude product was purified by HPLC according to the method of Example 1 (column: Gemini-C18 150x21) .2mm 5μιη, mobile phase: acetonitrile/water (0.1% trifluoroacetic acid), gradient: 50-70) to give the title product 3-(2-(4'-(3-(ethylsulfonyl)propoxy)) 2',6'-Dimethylbiphenyl-3-yl)-7-fluoro-1,2,3,4-tetrahydroquinolin-6-yl)propanoic acid 9 (9 mg, white solid) Rate: 9%.
MS m/z (ESI) : 554 [M+l]  MS m/z (ESI) : 554 [M+l]
¾ NMR (400 MHz, CD3OD) δ 8.46 (s, 1H)， 7.40 (t， J= 7.4 Hz, 1H)， 7.34 (d， J= 7.8 Hz, 1H)， 7.09 (s， 1H)， 7.01 (d, J= 7.1 Hz, 1H)， 6.78 (d, J= 8.6 Hz, 1H)， 6.69 (d, J= 3.8 Hz, 2H), 6.31 (d, J= 12.1 Hz, 1H)， 4.47 (d， J= 4.6 Hz, 1H)， 4.14 (t， J= 5.9 Hz, 2H), 3.29-3.26 (m, 2H), 3.16 (q， J= 7.4 Hz, 2H), 2.86-2.72 (m， 3H)， 2.59 (d， J= 15.0 Hz, 1H)， 2.50 (t, J= 7.6 Hz, 2H), 2.35-2.21 (m, 2H), 2.09-2.06 (m, 2H) 2.01 (s, 3H)， 1.95 (s， 3H)， 1.39 (t， J= 7.5 Hz, 3H)。 3⁄4 NMR (400 MHz, CD 3 OD) δ 8.46 (s, 1H), 7.40 (t, J = 7.4 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.09 (s, 1H), 7.01 (d, J = 7.1 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H), 6.69 (d, J = 3.8 Hz, 2H), 6.31 (d, J = 12.1 Hz, 1H), 4.47 (d , J= 4.6 Hz, 1H), 4.14 (t, J= 5.9 Hz, 2H), 3.29-3.26 (m, 2H), 3.16 (q, J= 7.4 Hz, 2H), 2.86-2.72 (m, 3H) , 2.59 (d, J= 15.0 Hz, 1H), 2.50 (t, J= 7.6 Hz, 2H), 2.35-2.21 (m, 2H), 2.09-2.06 (m, 2H) 2.01 (s, 3H), 1.95 (s, 3H), 1.39 (t, J = 7.5 Hz, 3H).
实施例 10 Example 10
-(2-(2',6'-二甲基联苯基 -3-基) -7-氟 -1,2,3 ,4-四氫喹啉 -6-基)丙酸  -(2-(2',6'-dimethylbiphenyl-3-yl)-7-fluoro-1,2,3,4-tetrahydroquinolin-6-yl)propionic acid
Figure imgf000040_0001
Figure imgf000040_0001
第一步  First step
( )-3-(2-(2',6'-二甲基联苯基 -3-基) -7-氟喹啉 -6-基)丙烯酸  ( )-3-(2-(2',6'-Dimethylbiphenyl-3-yl)-7-fluoroquinolin-6-yl)acrylic acid
利用 ( )-3-(2-氯 -7-氟喹啉 -6-基)丙烯酸甲酯 8g (106.4mg， 0.4mmol) 和 2-(2',6'-二甲基联苯基 -3-基) -4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 lg (135.5mg， 0.44mmol)为原料， 参照实施例 8中 8h的合成方法， 得到标 题产物 ( )-3-(2-(2',6'-二甲基联苯基 -3-基) -7-氟喹啉 -6-基）丙烯酸 10a (l l lmg, 浅黄色油状物）， 产率： 70%。  Using methyl ( )-3-(2-chloro-7-fluoroquinolin-6-yl)acrylate 8 g (106.4 mg, 0.4 mmol) and 2-(2',6'-dimethylbiphenyl-3 -4,4,5,5-tetramethyl-1,3,2-dioxaborane lg (135.5 mg, 0.44 mmol) was used as a starting material, and the title was obtained by the synthesis method of 8h in Example 8. The product ( )-3-(2-(2',6'-dimethylbiphenyl-3-yl)-7-fluoroquinolin-6-yl)acrylic acid 10a (ll lmg, pale yellow oil) Yield: 70%.
MS m/z (ESI) : 398 [M+l]  MS m/z (ESI) : 398 [M+l]
第二步  Second step
3-(2-(2',6'-二甲基联苯基 -3-基) -7-氟 -1,2,3 ,4-四氫喹啉 -6-基)丙酸 利用 ( )-3-(2-(2',6'-二甲基联苯基 -3-基) -7-氟喹啉 -6-基)丙烯酸 10a (l l lmg，0.5mmol)为原料，参照实施例 1中 li的合成方法，粗品经 HPLC 制备色谱纯化（色谱柱： Gemini-C18 150x21.2mm, 5μιη, 流动相： 乙腈 /水 (0.1%甲酸)， 梯度： 65-75)， 得到标题产物 3-(2-(2',6'-二甲基联苯基 -3-基) -7-氟 -1,2,3,4-四氫喹啉 -6-基)丙酸 10 (38mg， 白色固体)， 产率: 30%。  3-(2-(2',6'-Dimethylbiphenyl-3-yl)-7-fluoro-1,2,3,4-tetrahydroquinolin-6-yl)propionic acid ( ) -3-(2-(2',6'-Dimethylbiphenyl-3-yl)-7-fluoroquinolin-6-yl)acrylic acid 10a (ll lmg, 0.5 mmol) was used as a starting material. 1 Li synthesis method, the crude product was purified by HPLC preparative chromatography (column: Gemini-C18 150x21.2mm, 5μιη, mobile phase: acetonitrile/water (0.1% formic acid), gradient: 65-75) to give the title product 3- (2-(2',6'-Dimethylbiphenyl-3-yl)-7-fluoro-1,2,3,4-tetrahydroquinolin-6-yl)propanoic acid 10 (38 mg, white Solid), Yield: 30%.
MS m/z (ESI) : 404 [M+l]  MS m/z (ESI) : 404 [M+l]
¾ NMR (300 MHz, CD3OD) δ 7.43-7.30 (m， 2H), 7.09-7.03 (m, 4H)， 6.99 (d, J= 7.1 Hz, 1H)， 6.75 (d, J= 8.5 Hz, 1H)， 6.28 (d, J = 12.2 Hz, 1H)， 4.45 (dd, J= 7.8， 3.3 Hz, 1H)， 2.74 (dt, J= 7.9， 4.2 Hz 3H)， 2.63-2.53 (m, 1H)， 2.49 (dd, J= 9.9， 5.5 Hz, 2H), 2.09-2.04 (m 1H)， 2.00 (s, 3H)， 1.94 (s， 3H)， 1.93-1.86 (m， 1H)。 3⁄4 NMR (300 MHz, CD 3 OD) δ 7.43-7.30 (m, 2H), 7.09-7.03 (m, 4H), 6.99 (d, J = 7.1 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 6.28 (d, J = 12.2 Hz, 1H), 4.45 (dd, J= 7.8, 3.3 Hz, 1H), 2.74 (dt, J= 7.9, 4.2 Hz 3H), 2.63-2.53 (m, 1H), 2.49 (dd, J= 9.9, 5.5 Hz, 2H), 2.09-2.04 (m 1H), 2.00 (s, 3H), 1.94 (s, 3H), 1.93-1.86 (m, 1H).
实施例 11  Example 11
3-(2-(2',4,6'-三甲基 -4'-(3-(甲磺酰基）丙氧基）联苯 -3-基) -1,2,3,4-四 -6-基)丙酸  3-(2-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3,4-tetra -6-yl)propionic acid
Figure imgf000041_0001
Figure imgf000041_0001
第一步  First step
( )-3-(2-(2',4,6'-三甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 1-3-基)喹啉 -6-基：） 丙烯酸甲酯  ( )-3-(2-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl1-3-yl)quinoline-6- Base:) Methyl acrylate
利用 4,4,5,5-四甲基 -2-(2',4,6'-三甲基 -4'-(3- (甲磺酰基)丙氧基)联苯 基 1-3-基) -1,3,2-二氧杂硼烷 lla (460mg， l.Ommol, 参照实施例 8中 8c 的合成方法合成）和 ( )-3-(2-氯喹啉 -6-基）丙烯酸甲酯 7e (280mg , l.lmmol)为原料， 参照实施例 8 中 8h 的合成方法， 得到标题产物 ( )-3-(2-(2',4,6'-三甲基 -4'-(3-(甲磺酰基)丙氧基)联苯基 1-3-基)喹啉 -6-基) 丙烯酸甲酯 llb (500mg， 黄色油状液体)， 产率： 94%。  Using 4,4,5,5-tetramethyl-2-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl 1-3- -1,3,2-dioxaborane 11a (460 mg, 1.0 mmol, synthesized according to the synthesis method of 8c in Example 8) and ( )-3-(2-chloroquinolin-6-yl)acrylic acid The title product ( )-3-(2-(2',4,6'-trimethyl-4'-) was obtained as the starting material of the title compound (8-). (3-(Methanesulfonyl)propoxy)biphenyl 1-3-yl)quinolin-6-yl)methyl acrylate llb (500 mg, yellow oily). Yield: 94%.
MS m/z (ESI) : 530 [M+l]  MS m/z (ESI) : 530 [M+l]
第二步  Second step
3-(2-(2',4,6'-三甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 1-3-基)喹啉 -6- 基） 丙甲酯  3-(2-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-1-yl)quinolin-6-yl) propyl Methyl ester
利用 ( )-3-(2-(2',4,6'-三甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 1-3-基） 喹啉 -6-基） 丙烯酸甲酯 lib (500mg， 0.94mmol)为原料， 参照实施例 9 中 9c 的合成方法， 得到标题产物 3-(2-(2',4,6'-三甲基 -4'-(3- (甲磺酰基） 丙氧基)联苯基 1-3-基)喹啉 -6-基） 丙甲酯 llc (500mg， 粗品）。  Using ( )-3-(2-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl1-3-yl)quinoline-6 Methyl acrylate lib (500 mg, 0.94 mmol) was used as a starting material. The title compound was obtained by the procedure of 9c of Example 9 to give the title product 3-(2-(2',4,6'-trimethyl-4'- (3-(Methanesulfonyl)propoxy)biphenyl1-3-yl)quinolin-6-yl)propylmethyl ester (500 mg, crude).
MS m/z (ESI) : 532 [M+l] 第三步 MS m/z (ESI) : 532 [M+l] third step
3-(2-(2',4,6'-三甲基 -4'-(3-(甲磺酰基）丙氧基）联苯 -3-基) -1,2,3,4-四 氫喹啉 -6-基)丙酸  3-(2-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3,4-tetra Hydroquinolin-6-yl)propionic acid
利用 3-(2-(2',4,6'-三甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 1-3-基)喹 啉—6-基） 丙甲酯 11c (500mg， 粗品）为原料， 参照实施例 9中 9d的合 成方法， 经 HPLC制备色谱法纯化（色谱柱： Gemini-C18 150x21.2mm， 5μιη ; 流动相： 乙腈 /水 (0.1%甲酸）； 梯度： 50-90)， 得到标题产物 3-(2-(2',4,6'-三甲基 -4'-(3-(甲磺酰基）丙氧基)联苯 -3-基) -1,2,3,4-四氫喹 啉—6-基)丙酸 ll (180mg， 黄色固体)， 产率： 35%。  Using 3-(2-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl 1-3-yl)quinoline-6-yl) Methyl ester 11c (500 mg, crude) was used as a starting material, and purified by HPLC according to the synthesis method of 9d in Example 9 (column: Gemini-C18 150×21.2 mm, 5 μιη; mobile phase: acetonitrile/water (0.1%) Formic acid); gradient: 50-90) gave the title product 3-(2-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3 -1,2,2,3,4-tetrahydroquinolin-6-yl)propanoic acid ll (180 mg, yellow solid), Yield: 35%.
MS m/z (ESI) : 536 [M+l]  MS m/z (ESI) : 536 [M+l]
¾ NMR (300 MHz, CD3OD) δ 7.23 (d, J= 7.7 Hz, 1H)， 7.15 (s， 1H)， 6.90-6.70 (m, 3H)， 6.87-6.63(m， 3H)， 4.73 (dd, J= 8.3， 3.0 Hz, 1H)， 4.08 (t， J= 6.0 Hz, 2H), 2.99 (s， 3H)， 2.95-2.82 (m， 1H)， 2.80-2.65 (m， 4H)， 2.52 (t, J= 7.6 Hz, 2H), 2.43 (s, 3H)， 2.40-2.25 (m, 2H), 2.19-2.06 (m, 1H)， 2.02-1.90 (m, 8H)。 3⁄4 NMR (300 MHz, CD 3 OD) δ 7.23 (d, J = 7.7 Hz, 1H), 7.15 (s, 1H), 6.90-6.70 (m, 3H), 6.87-6.63 (m, 3H), 4.73 ( Dd, J= 8.3, 3.0 Hz, 1H), 4.08 (t, J= 6.0 Hz, 2H), 2.99 (s, 3H), 2.95-2.82 (m, 1H), 2.80-2.65 (m, 4H), 2.52 (t, J = 7.6 Hz, 2H), 2.43 (s, 3H), 2.40-2.25 (m, 2H), 2.19-2.06 (m, 1H), 2.02-1.90 (m, 8H).
实施例 12  Example 12
3-(2-(5'-氟 -2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联苯 -3-基) -1,2,3,4- 四氫喹啉 -6-基；)丙酸  3-(2-(5'-fluoro-2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3, 4-tetrahydroquinolin-6-yl;) propionic acid
Figure imgf000042_0001
Figure imgf000042_0001
第一步  First step
3-(2-(5'-氯 -2',6'-二甲基 -4'-(3- (甲磺酰基）丙氧基)联苯基 -3-基)喹啉 -6-基：)丙酸  3-(2-(5'-Chloro-2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)quinolin-6-yl :) Propionic acid
50mL 单口瓶中称入 3-(2-(2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联 苯基 -3-基)喹啉 -6-基)丙酸 12a (300mg, 0.58mmol), 加入 Ν,Ν'-二甲基 甲酰胺（3 mL)， 搅拌溶解后， 加入 N-氯代丁二酰亚胺（100mg， 0.75mmol), 然后将反应在室温下搅拌过夜。 加入乙酸乙酯 (20mL)， 用 饱和食盐水洗涤 (15mLx3;)， 无水疏酸钠干燥， 过滤除去干燥剂， 减压 脱溶， 残余物用硅胶柱层析纯化 (石油 /乙酸乙酯 = 1 : 1)， 得到标题 化合物 3-(2-(5'-氯 -2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基)喹 啉—6-基)丙酸 12b (180mg， 黄色油状液体)， 产率： 56%。 3-(2-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)) was weighed into a 50 mL single-mouth bottle Phenyl-3-yl)quinolin-6-yl)propionic acid 12a (300 mg, 0.58 mmol), added hydrazine, Ν'-dimethylformamide (3 mL), stirred and dissolved, then added N-chlorobutyl The diimide (100 mg, 0.75 mmol) was then stirred at room temperature overnight. Ethyl acetate (20 mL) was added, and the mixture was washed with EtOAc (EtOAc) 1 : 1), the title compound 3-(2-(5'-chloro-2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3- Base) quinoline-6-ylpropionic acid 12b (180 mg, yellow oily). Yield: 56%.
MS m/z (ESI) : 552 [M+l]  MS m/z (ESI) : 552 [M+l]
第二步  Second step
3-(2-(5'-氟 -2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联苯 -3-基) -1,2,3,4- 四氫喹啉 -6-基；)丙酸  3-(2-(5'-fluoro-2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3, 4-tetrahydroquinolin-6-yl;) propionic acid
lOOmL单口瓶中称入 3-(2-(5'-氯 -2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧 基)联苯基 -3-基)喹啉 -6-基）丙酸 12b (180mg, 0.32mmol) , 加入醋酸 (3mL), 然后分批加入氰基硼氫化钠 (61mg， 0.96mmol), 室温搅拌反应 过夜。 用饱和碳酸氫钠溶液淬灭反应并调节 pH = 7， 乙酸乙酯萃取 (20mL x3), 合并有机相并用饱和食盐水洗涤， 无水疏酸钠干燥， 过滤 除去干燥剂， 减压脱溶， 残余物经 HPLC 制备色谱法纯化（色谱柱： Gemini-C18 150x21.2mm, 5μιη; 流动相： 乙腈 /水 (0.1%甲酸）； 梯度： 60-65)， 得到标题产物 3-(2-(5'-氟 -2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基） 联苯 -3-基) -1,2,3,4-四氫喹啉 -6-基)丙酸 12 (13mg，黄色固体)，产率： 7%。  3-(2-(5'-chloro-2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl) is weighed into a lOOmL single-mouth bottle Quinoline-6-yl)propanoic acid 12b (180 mg, 0.32 mmol), EtOAc (3 mL)EtOAc. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate, and the mixture was adjusted to pH = 7, ethyl acetate (20 mL x 3), and the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by HPLC preparative chromatography (chromatography: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: '-Fluoro-2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3,4-tetrahydroquinoline- 6-yl)propionic acid 12 (13 mg, yellow solid), yield: 7%.
MS m/z (ESI) : 556 [M+l]  MS m/z (ESI) : 556 [M+l]
¾ NMR (300 MHz, CDCb) δ 7.45-7.33 (m， 2H), 7.10 (s， 1H)， 7.01 (d, J= 6.7 Hz, 1H)， 6.86-6.84(m， 2H), 6.69 (s， 1H)， 6.50 (d, J = 8.5 Hz, 1H)， 4.45 (d, J= 8.6 Hz, 1H)， 4.20 (t， J= 5.5 Hz, 2H), 3.44-3.28 (m， 2H), 2.99 (s， 3H)， 2.93-2.91 (m， 1H)， 2.88-2.79 (m， 2H), 2.76-2.72 (m， 1H)， 2.64 (t, J= 7.7 Hz, 2H), 2.48-2.41 (m, 2H), 2.21-1.89 (m, 8H)。  3⁄4 NMR (300 MHz, CDCb) δ 7.45-7.33 (m, 2H), 7.10 (s, 1H), 7.01 (d, J = 6.7 Hz, 1H), 6.86-6.84 (m, 2H), 6.69 (s, 1H), 6.50 (d, J = 8.5 Hz, 1H), 4.45 (d, J = 8.6 Hz, 1H), 4.20 (t, J = 5.5 Hz, 2H), 3.44-3.28 (m, 2H), 2.99 ( s, 3H), 2.93-2.91 (m, 1H), 2.88-2.79 (m, 2H), 2.76-2.72 (m, 1H), 2.64 (t, J = 7.7 Hz, 2H), 2.48-2.41 (m, 2H), 2.21-1.89 (m, 8H).
实施例 13  Example 13
3-(2-(5'-氟 -2',6'-二甲基 -4'-(3- (甲磺酰基）丙氧基)联苯 -3-基) -1,2,3,4- 四氫喹啉 -6-基；)丙酸 3-(2-(5'-fluoro-2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3, 4-tetrahydroquinolin-6-yl;) propionic acid
Figure imgf000044_0001
Figure imgf000044_0001
第一步  First step
2-溴 -4-氟 -1,3-二甲基 -5-(3- (甲磺酰基)丙氧基)苯  2-bromo-4-fluoro-1,3-dimethyl-5-(3-(methylsulfonyl)propoxy)benzene
利用 2a (1.8g， 6.2mmol)和 13a (1.26g， 5.7mmol， 采用已公知方法 "专利 WO2008001931"制备而得）为原料， 参照实施例 2中 2e的合成方 法， 得到标题产物 2-溴 -4-氟 -1,3-二甲基 -5-(3- (甲磺酰基)丙氧基)苯 13b (1.3g， 黄色固体)， 产率： 67%。  Using 2a (1.8g, 6.2mmol) and 13a (1.26g, 5.7mmol, prepared by the known method "WO2008001931") as raw materials, referring to the synthesis method of 2e in Example 2, the title product 2-bromo- 4-Fluoro-1,3-dimethyl-5-(3-(methylsulfonyl)propoxy)benzene 13b (1.3 g, yellow solid), Yield: 67%.
MS m/z (ESI) : 339 [M+l]  MS m/z (ESI) : 339 [M+l]
第二步  Second step
( )-3-(2-(3-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2-基)苯基)喹啉 -6-基) 丙烯酸甲酯  ( )-3-(2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinolin-6-yl) Methyl acrylate
利用 ( )-3-(2-(3- (三氟甲磺酰氧基)苯基） 喹啉 -6-基：)丙烯酸甲酯 13c (437mg， 8.4mmol)为原料， 参照实施例 1中 lg的合成方法， 得到标题 化合物 ( )-3-(2-(3-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2-基)苯基)喹啉 -6- 基)丙烯酸甲酯 13d (2.3g， 黄色油状液体)， 产率： 66%。  Using ( )-3-(2-(3-(trifluoromethanesulfonyloxy)phenyl)quinolin-6-yl:)methyl acrylate 13c (437 mg, 8.4 mmol) as a starting material, refer to Example 1 The title compound ( )-3-(2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) Methyl quinolin-6-yl)acrylate 13d (2.3 g, yellow oily liquid), yield: 66%.
MS m/z (ESI) : 416 [M+l]  MS m/z (ESI): 416 [M+l]
第三步  third step
3- (2-(3-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2-基)苯基)喹啉 -6-基）丙 酸甲酯 利用（ )-3-(2-(3-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2-基)苯基)喹啉 -6-基)丙烯酸甲酯 13d (2.3g， 5.53mmol)为原料， 参照实施例 9中 9c的 合成方法，得到标题化合物 3-(2-(3-(4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 -2- 基)苯基)喹啉 -6-基)丙酸甲酯 13e (2.0g， 黄色油状液体)， 产率： 87%。 产物不经纯化直接用于下一步反应。 3-(2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinolin-6-yl)propanoic acid Ester Using ( )-3-(2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinolin-6-yl Methyl acrylate 13d (2.3 g, 5.53 mmol) was used as a starting material. The title compound 3-(2-(3,4,5,5,5-tetramethyl-1) Methyl 3,2-dioxaborolan-2-yl)phenyl)quinolin-6-yl)propanoate 13e (2.0 g, yellow oily). Yield: 87%. The product was used in the next reaction without purification.
第四步  the fourth step
3-(2-(5'-氟 -2',6'-二甲基 -4'-丙氧基联苯基 -3-基)喹啉 -6-基)丙酸甲酯 利用 13b (338mg， l.Ommol)和 13e (438mg， 1.05mmol)为原料， 参 照实施例 2的搡作方法， 得到标题化合物 3-(2-(5'-氟 -2',6'-二甲基 -4'-丙 氧基联苯基 -3-基:)喹啉 -6-基：)丙酸甲酯 13f (370mg， 黄色固体)， 产率： 67%。  3-(2-(5'-Fluoro-2',6'-dimethyl-4'-propoxybiphenyl-3-yl)quinolin-6-yl)propanoic acid methyl ester using 13b (338mg The title compound 3-(2-(5'-fluoro-2',6'-dimethyl-4) was obtained according to the method of the procedure of Example 2, m. '-Propoxybiphenyl-3-yl:)quinolin-6-yl:)methyl propionate 13f (370 mg, yellow solid), Yield: 67%.
MS m/z (ESI) : 550 [M+l]  MS m/z (ESI) : 550 [M+l]
第五步  the fifth step
3-(2-(5'-氟 -2',6'-二甲基 -4'-丙氧基联苯基 -3-基) -1,2,3,4-四氫喹啉 -6- 基:)丙酸甲酯  3-(2-(5'-fluoro-2',6'-dimethyl-4'-propoxybiphenyl-3-yl)-1,2,3,4-tetrahydroquinoline-6 - base:) methyl propionate
利用 3-(2-(5'-氟 -2',6'-二甲基 -4'-丙氧基联苯基 -3-基)喹啉 -6-基：)丙酸 甲酯 13f (370mg， 0.67mmol)为原料， 参照实施例 12的搡作方法合成， 得到标题化合物 3-(2-(5'-氟 -2',6'-二甲基 -4'-丙氧基联苯基 -3-基) -1,2,3,4- 四氫喹啉 -6-基)丙酸甲酯 13g (353mg， 黄色油状液体)， 产率： 95%。  Using 3-(2-(5'-fluoro-2',6'-dimethyl-4'-propoxybiphenyl-3-yl)quinolin-6-yl:)methyl propionate 13f ( The title compound 3-(2-(5'-fluoro-2',6'-dimethyl-4'-propoxybiphenyl) was synthesized by the method of the title compound of Example 12, using 370 mg, 0.67 mmol. Methyl-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)propanoic acid methyl ester 13 g (353 mg, yellow oily), yield: 95%.
MS m/z (ESI) : 554 [M+l]  MS m/z (ESI) : 554 [M+l]
第六步  Step 6
3-(2-(5'-氟 -2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联苯 -3-基) -1,2,3,4- 四氫喹啉 -6-基；)丙酸  3-(2-(5'-fluoro-2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3, 4-tetrahydroquinolin-6-yl;) propionic acid
利用 3-(2-(5'-氟 -2',6'-二甲基 -4'-丙氧基联苯基 -3-基) -1,2,3,4-四氫喹 啉—6-基)丙酸甲酯 13g (353mg， 0.64mmol)为原料， 参照实施例 1的搡 作方法合成， 经 HPLC 制备色谱法纯化（色谱柱： Gemini-C18 150x21.2mm, 5μιη, 流动相： 乙腈 /水 (0.1%甲酸）， 梯度： 50-75)， 得 到标题化合物 3-(2-(5'-氟 -2',6'-二甲基 -4'-(3- (甲磺酰基）丙氧基)联苯 -3- 基) -1,2,3,4-四氫喹啉 -6-基)丙酸 13 (50mg， 白色固体)， 产率： 14%。  Using 3-(2-(5'-fluoro-2',6'-dimethyl-4'-propoxybiphenyl-3-yl)-1,2,3,4-tetrahydroquinoline- 6-yl)methyl propionate 13g (353mg, 0.64mmol) was used as a starting material, which was synthesized according to the method of Example 1 and purified by HPLC preparative chromatography (column: Gemini-C18 150x21.2mm, 5μιη, mobile phase: Acetonitrile/water (0.1% formic acid), gradient: 50-75) to give the title compound 3-(2-(5'-fluoro-2',6'-dimethyl-4'-(3-(methylsulfonyl) Propoxy)biphenyl-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)propanoic acid 13 (50 mg, white solid), yield: 14%.
MS m/z (ESI) : 540 [M+l]  MS m/z (ESI) : 540 [M+l]
¾ NMR (400 MHz, DMSO-i 6) δ 7.39-7.34(m, 2H), 7.20-6.80 (m, 3H)， 6.78-6.74 (m 1H)， 6.51-6.49 (m 1H)， 5.98-5.88 (m 1H)， 4.48-4.40 (m 1H)， 4.30-4.20 (m, 2H), 3.75-3.60 (m, 2H), 3.32-3.30 (m, 2H), 3.03 (s 3H), 2.80-2.56 (m, 3H)， 2.30-2.10 (m, 3H)， 2.0-1.70 (m, 8H)。 3⁄4 NMR (400 MHz, DMSO-i 6 ) δ 7.39-7.34 (m, 2H), 7.20-6.80 (m, 3H), 6.78-6.74 (m 1H), 6.51-6.49 (m 1H), 5.98-5.88 (m 1H), 4.48-4.40 (m 1H), 4.30-4.20 (m, 2H), 3.75-3.60 (m, 2H), 3.32-3.30 (m, 2H), 3.03 (s 3H), 2.80-2.56 (m, 3H), 2.30-2.10 (m, 3H), 2.0-1.70 (m, 8H).
实施例 14  Example 14
3-(7-氟 -2-(6'-甲基 -4'-(3- (甲磺酰基）丙氧基)联苯 -3-基) -1,2,3,4-四氫 。奎啉 -6-基)丙酸  3-(7-Fluoro-2-(6'-methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3,4-tetrahydro. Quinolin-6-yl)propionic acid
Figure imgf000046_0001
Figure imgf000046_0001
第一步  First step
( )-3-(7-氟 -2-(6'-甲基 -4'-(3- (甲磺酰基）丙氧基)联苯 -3-基） 喹啉 -6- 基)丙烯酸甲酯  ( )-3-(7-fluoro-2-(6'-methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)quinolin-6-yl)acrylic acid Ester
利用 6d (206mg 0.48mmol)和 8g (140mg 0.53mmol)为原料， 参 照实施例 6 中的搡作方法， 得到标题化合物 ( )-3-(7-氟 -2-(6'-甲基 —4'—(3- (甲磺酰基）丙氧基）联苯 -3-基） 喹啉 -6-基）丙烯酸甲酯 14a (190mg， 黄色油状液体)， 产率： 68%  Using 6d (206 mg of 0.48 mmol) and 8 g (140 mg of 0.53 mmol) as starting materials, the title compound ( )-3-(7-fluoro-2-(6'-methyl-4) '-(3-(Methanesulfonyl)propoxy)biphenyl-3-yl)quinolin-6-yl)methyl acrylate 14a (190 mg, yellow oily), Yield: 68%
MS m/z (ESI) : 534 [M+l]  MS m/z (ESI) : 534 [M+l]
第二步  Second step
( )-3-(7-氟 -2-(6'-甲基 -4'-(3- (甲磺酰基）丙氧基)联苯 -3-基） 喹啉 -6- 基；)丙烯酸  ( )-3-(7-fluoro-2-(6'-methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)quinolin-6-yl;) Acrylic acid
利用 ( )-3-(7-氟 -2-(6'-甲基 -4'-(3-(甲磺酰基）丙氧基)联苯 -3-基） 喹 啉 -6-基)丙烯酸甲酯 14a (190mg 0.36mmol)为原料， 参照实施例 1的 搡作方法， 得到标题化合物 ( )-3-(7-氟 -2-(6'-甲基 -4'-(3- (甲磺酰基)丙氧 基)联苯 -3-基） 喹啉 -6-基)丙烯酸 14b (180mg， 粗品）。  Using ( )-3-(7-fluoro-2-(6'-methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)quinolin-6-yl)acrylic acid The title compound ( )-3-(7-fluoro-2-(6'-methyl-4'-(3-(A)) was obtained from the title compound (3). Sulfonyl)propoxy)biphenyl-3-yl)quinolin-6-yl)acrylic acid 14b (180 mg, crude).
MS m/z (ESI) : 520 [M+l] 第三步 MS m/z (ESI) : 520 [M+l] third step
3-(7-氟 -2-(6'-甲基 -4'-(3- (甲磺酰基)丙氧基)联苯 -3-基) -1,2,3,4-四氫 喹啉 -6-基)丙酸  3-(7-fluoro-2-(6'-methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3,4-tetrahydroquinoline Porphyrin-6-yl)propionic acid
利用 ( )-3-(7-氟 -2-(6'-甲基 -4'-(3-(甲磺酰基）丙氧基)联苯 -3-基） 喹 啉—6-基)丙烯酸 14b ( 180mg， 粗品）为原料， 参照实施例 1的搡作方法， 经 HPLC制备色谱法纯化（色谱柱： Gemini-C18 150x21.2mm， 5μιη; 流 动相： 乙腈 /水 (0.1%甲酸）；梯度： 60-65)，得到标题化合物 3-(7-氟 -2-(6'- 甲基 -4'-(3- (甲磺酰基)丙氧基)联苯 -3-基) -1,2,3,4-四氫喹啉 -6-基)丙酸 14 (30mg, 白色固体)， 产率： 28%。  Using ( )-3-(7-fluoro-2-(6'-methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)quinoline-6-yl)acrylic acid 14b (180mg, crude) was used as the starting material. Purified by HPLC preparative method according to the method of Example 1 (column: Gemini-C18 150x21.2mm, 5μιη; mobile phase: acetonitrile/water (0.1% formic acid); gradient : 60-65), the title compound 3-(7-fluoro-2-(6'-methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1, 2,3,4-Tetrahydroquinolin-6-yl)propanoic acid 14 (30 mg, white solid), Yield: 28%.
MS m/z (ESI) : 526 [M+l]  MS m/z (ESI) : 526 [M+l]
¾ NMR (300 MHz, CD3OD) δ 7.40-7.21 (m, 3H)， 7.15 (d, J= 7.1 Hz, 1H)， 7.09 (d, J= 8.3 Hz, 1H)， 6.83-6.77 (m， 3H)， 6.28 (d, J= 12.2 Hz, 1H)， 4.44 (dd, J= 8.0, 3.4 Hz, 1H)， 4.13 (t， J= 6.0 Hz, 2H), 3.01 (s， 3H)， 2.77-2.50 (m， 3H)， 2.67-2.43 (m， 3H)， 2.30-2.28 (m， 2H), 2.18 (s, 3H)， 2.15-1.87 (m, 4H)。 3⁄4 NMR (300 MHz, CD 3 OD) δ 7.40-7.21 (m, 3H), 7.15 (d, J = 7.1 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.83-6.77 (m, 3H), 6.28 (d, J= 12.2 Hz, 1H), 4.44 (dd, J= 8.0, 3.4 Hz, 1H), 4.13 (t, J= 6.0 Hz, 2H), 3.01 (s, 3H), 2.77- 2.50 (m, 3H), 2.67-2.43 (m, 3H), 2.30-2.28 (m, 2H), 2.18 (s, 3H), 2.15-1.87 (m, 4H).
实施例 15  Example 15
3-(7-氟 -2-(2',4,6'-三甲基 -4'-(3-(甲磺酰基）丙氧基）联苯 -3- -1,2,3,4-四氫喹啉 -6-基)丙酸  3-(7-fluoro-2-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3--1,2,3,4 -tetrahydroquinolin-6-yl)propionic acid
Figure imgf000047_0001
Figure imgf000047_0001
第一步  First step
( )-3-(7-氟 -2-(2',4,6'-三甲基 -4'-(3- (甲磺酰基)丙氧基)联苯 -3-基） 喹 啉—6-基)丙烯酸甲酯  ( )-3-(7-fluoro-2-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)quinoline- 6-yl)methyl acrylate
利用 lla (400mg， 0.87mmol)和 8g (232mg， 0.87mmol)为原料， 参 照实施例 8中 8h的合成方法， 得到标题化合物 ( )-3-(7-氟 -2-(2',4,6'-三 甲基 -4'-(3- (甲磺酰基）丙氧基)联苯 -3-基） 喹啉 -6-基）丙烯酸甲酯 15a (400mg, 黄色油状液体)， 产率： 84%。 Using lla (400 mg, 0.87 mmol) and 8 g (232 mg, 0.87 mmol) as the starting material, the title compound (3) (7-fluoro-2-(2', 4, 6'-Trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)quinolin-6-yl)methyl acrylate 15a (400 mg, yellow oily liquid), Yield: 84%.
MS m/z (ESI) : 562 [M+l]  MS m/z (ESI) : 562 [M+l]
第二步  Second step
( )-3-(7-氟 -2-(2',4,6'-三甲基 -4'-(3- (甲磺酰基)丙氧基)联苯 -3-基） 喹 啉—6-基)丙烯酸  ( )-3-(7-fluoro-2-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)quinoline- 6-base) acrylic acid
利用（ )-3-(7-氟 -2-(2',4,6'-三甲基 -4'-(3-(甲磺酰基）丙氧基)联苯 -3- 基） 喹啉 -6-基)丙烯酸甲酯 15a (400mg， 0.87mmol)为原料， 参照实施例 1的搡作方法， 得到标题化合物 ( )-3-(7-氟 -2-(2',4,6'-三甲基 -4'-(3- (甲磺 酰基)丙氧基)联苯 -3-基） 喹啉 -6-基)丙烯酸 15b (400mg， 粗品）。  Using ( )-3-(7-fluoro-2-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)quinoline The title compound ( )-3-(7-fluoro-2-(2',4,6') was obtained according to the method of the procedure of Example 1 to give the title compound (m). -Trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)quinolin-6-yl)acrylic acid 15b (400 mg, crude).
MS m/z (ESI) : 548 [M+l]  MS m/z (ESI) : 548 [M+l]
第三步  third step
3-(7-氟 -2-(2',4,6'-三甲基 -4'-(3-(甲磺酰基）丙氧基）联苯 -3- 基) -1,2,3,4-四氫喹啉 -6-基)丙酸  3-(7-fluoro-2-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-1,2,3 4-tetrahydroquinolin-6-yl)propionic acid
利用（ )-3-(7-氟 -2-(2',4,6'-三甲基 -4'-(3-(甲磺酰基）丙氧基)联苯 -3- 基） 喹啉 -6-基)丙烯酸 15b (400mg， 粗品）为原料， 参照实施例 1的搡作 方法， 经 HPLC制备色谱法纯化（色谱柱： Gemini-C18 150x21.2mm, 5μιη;流动相： 乙腈 /水 (0.1%甲酸）；梯度： 60-65)，得到标题化合物 3-(7- 氟 -2-(2',4,6'-三甲基 -4'-(3- (甲磺酰基）丙氧基)联苯 -3-基) -1,2,3,4-四氫喹 啉—6-基)丙酸 15 (151mg， 白色固体)， 产率： 37%。  Using ( )-3-(7-fluoro-2-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)quinoline -6-yl)acrylic acid 15b (400 mg, crude) was used as a starting material, and purified by HPLC preparative chromatography according to the method of Example 1 (column: Gemini-C18 150×21.2 mm, 5 μιη; mobile phase: acetonitrile/water ( 0.1% formic acid; gradient: 60-65) gave the title compound 3-(7-fluoro-2-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy) Biphenyl-3-yl)-1,2,3,4-tetrahydroquinolin-6-yl)propanoic acid 15 (151 mg, white solid), Yield: 37%.
MS m/z (ESI) : 554 [M+l]  MS m/z (ESI) : 554 [M+l]
¾ NMR (400 MHz, DMSO-i 6) δ 12.10 (s， 1H)， 7.22 (d， J= 7.7 Hz, 1H)， 6.97 (d， J= 1.5 Hz, 1H)， 6.91 (dd, J= 7.6， 1.7 Hz, 1H)， 6.75 (d, J= 8.7 Hz, 1H)， 6.67 (d, J= 8.5 Hz, 2H), 6.29 (d, J= 12.5 Hz, 1H)， 6.14 (s， 1H)， 4.66 (br， 1H)， 4.06 (t, J= 6.2 Hz, 2H), 3.30-3.21 (m, 2H), 3.03 (s,3H), 2.75-2.57 (m, 4H)， 2.47-2.40 (m, 2H), 2.38 (s， 3H)， 2.20-2.07 (m, 2H), 2.00-1.98 (m, 1H)， 1.97 (s， 3H)， 1.86 (s， 3H)， 1.75-1.70 (m, 1H)。 3⁄4 NMR (400 MHz, DMSO-i 6 ) δ 12.10 (s, 1H), 7.22 (d, J = 7.7 Hz, 1H), 6.97 (d, J = 1.5 Hz, 1H), 6.91 (dd, J = 7.6 , 1.7 Hz, 1H), 6.75 (d, J= 8.7 Hz, 1H), 6.67 (d, J= 8.5 Hz, 2H), 6.29 (d, J= 12.5 Hz, 1H), 6.14 (s, 1H), 4.66 (br, 1H), 4.06 (t, J = 6.2 Hz, 2H), 3.30-3.21 (m, 2H), 3.03 (s, 3H), 2.75-2.57 (m, 4H), 2.47-2.40 (m, 2H), 2.38 (s, 3H), 2.20-2.07 (m, 2H), 2.00-1.98 (m, 1H), 1.97 (s, 3H), 1.86 (s, 3H), 1.75-1.70 (m, 1H) .
实施例 16  Example 16
3-(3-(2',6'-二甲基联苯 -3-基) -3,4-二氫 -2f -苯并 [b][l,4]噁嗪 -7-基)丙 酸 3-(3-(2',6'-dimethylbiphenyl-3-yl)-3,4-dihydro-2f-benzo[b][l,4]oxazin-7-yl)propane acid
Figure imgf000049_0001
第一步
Figure imgf000049_0001
first step
2-溴 -l-(2，,6，-二甲基 [Ι,Γ-联苯基 ]-3-基)苯乙酮  2-bromo-l-(2,6,-dimethyl[Ι,Γ-biphenyl]-3-yl)acetophenone
在 0。C下， 把溴 (4.4g， 27.6mmol)的乙醚溶液 (20mL)缓慢地滴加到 1-(2' , 6，-二甲基 [1， Γ-联苯基 ]-3-基)苯乙酮 16a (3.1g,13.8mmol， 采用 公知的方法"文献 Journal of Organic Chemistry (2008) , 73(19) , 7803-7806"制备而得)和三氯化铝 （1.8g， 13.8mmol)的乙醚 (30mL)溶液 中， 然后在室温下搅拌直至反应完成。 反应用饱和亚疏酸氫钠淬灭， 过滤后分离有机相。 有机相干燥后减压浓縮得到标题产物 2-溴 -1-(2'， 6，-二甲基 [1， Γ-联苯基 ]-3-基)苯乙酮 16b (3g， 白色固体)， 产率： 85%。  At 0. Bromine (4.4 g, 27.6 mmol) in diethyl ether (20 mL) was slowly added dropwise to 1-(2',6-dimethyl[1, fluorenyl-biphenyl]-3-yl)benzene Ethyl ketone 16a (3.1 g, 13.8 mmol, prepared by a known method "Journal of Organic Chemistry (2008), 73 (19), 7803-7806") and aluminum trichloride (1.8 g, 13.8 mmol) Add a solution of diethyl ether (30 mL) and then stir at room temperature until the reaction is complete. The reaction was quenched with saturated aqueous sodium hydrogensulfite and filtered to isolate organic. The organic phase was dried <RTI ID=0.0>(~~~~~~~~~~~~~~~~~~~~~~~~~~~ ), Yield: 85%.
MS m/z (ESI) : 303 [M+l]  MS m/z (ESI) : 303 [M+l]
第二步  Second step
3- (3-(2-(2,6，-二甲基 [Ι,Γ-联苯基 ]-3-基) -2-氧乙氧基) -4-硝基苯基) 丙烯酸甲酯  3-(3-(2-(2,6,-Dimethyl[Ι,Γ-biphenyl]-3-yl)-2-oxoethoxy)-4-nitrophenyl)methyl acrylate
在干燥三口瓶中将 2-溴 -1-(2，,6，-二甲基 [1,1，-联苯基 ]-3-基)苯乙酮 16b (679mg,2.24mmol), 3-(3-羟基 -4-硝基苯基)丙烯酸甲酯 16c (500mg， 2.24mmol, 采用公知的方法"专利 US20050209274"制备而得）， 四丁基 氟化铵 (643mg， 2.46mmol)和碳酸铯（803mg， 2.46mmol)溶解于 Ν,Ν'- 二甲基甲酰胺（10mL)中， 室温下搅拌直至反应完成。 加水淬灭反应后， 用乙酸乙酯（15mLx3)萃取。 有机相用无水疏酸钠干燥后， 减压浓縮。 用硅胶色谱法以洗脱剂体系（乙酸乙酯 /石油醚 =1/5)纯化所得残余物，得 到标题产物 3-(3-(2-(2'， 6，-二甲基 [1,1，-联苯基 ]-3-基) -2-氧乙氧基) -4-硝 基苯基)丙烯酸甲酯 16d (300mg， 白色固体)， 产率： 33%。  2-Bromo-1-(2,6,-dimethyl[1,1,-biphenyl]-3-yl)acetophenone 16b (679 mg, 2.24 mmol) in a dry three-necked flask, 3- Methyl (3-hydroxy-4-nitrophenyl)acrylate 16c (500 mg, 2.24 mmol, prepared by the known method "Patent US20050209274"), tetrabutylammonium fluoride (643 mg, 2.46 mmol) and cesium carbonate (803 mg, 2.46 mmol) was dissolved in hydrazine, Ν'-dimethylformamide (10 mL), and stirred at room temperature until the reaction was completed. After quenching with water, it was extracted with ethyl acetate (15 mL×3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography eluting elut elut elut elut elut elut elut elut Methyl 1,1-biphenyl]-3-yl)-2-oxoethoxy)-4-nitrophenyl)acrylate 16d (300 mg, white solid), yield: 33%.
MS m/z (ESI) : 446 [M+l] ¾ NMR (300 MHz, DMSO-i 6) δ 7.94 (dd, J= 19.4， 8.1 Hz, 2H), 7.77 (s， 1H)， 7.65 (dd, J = 14.9， 6.9 Hz, 2H), 7.48 (d， J = 8.6 Hz, 2H), 7.16 (dd, J = 11.2, 5.6 Hz, 4H)， 6.83 (d， J= 16.2 Hz, 1H)， 5.91 (s， 2H), 3.72 (s， 3H)， 1.99 (s， 6H)。 MS m/z (ESI) : 446 [M+l] 3⁄4 NMR (300 MHz, DMSO-i 6 ) δ 7.94 (dd, J = 19.4, 8.1 Hz, 2H), 7.77 (s, 1H), 7.65 (dd, J = 14.9, 6.9 Hz, 2H), 7.48 (d , J = 8.6 Hz, 2H), 7.16 (dd, J = 11.2, 5.6 Hz, 4H), 6.83 (d, J= 16.2 Hz, 1H), 5.91 (s, 2H), 3.72 (s, 3H), 1.99 (s, 6H).
第三步  third step
3-(3-(2',6'-二甲基 [Ι,Γ-联苯基 ]-3-基 -3,4-二氫 -2f -苯并 [b][l,4]噁嗪 -7-基：)丙酸甲酯  3-(3-(2',6'-dimethyl[Ι,Γ-biphenyl]-3-yl-3,4-dihydro-2f-benzo[b][l,4]oxazine -7-based:) methyl propionate
在干燥单口瓶中将 3-(3-(2-(2，,6，-二甲基 [1 ,1，-联苯基 ]-3-基) -2-氧乙 氧基)—4-硝基苯基)丙烯酸甲酯 16d (500mg， 1.12mmol)和 Pd/C(50mg) 的甲醇溶液在一个大气压的氫气条件下室温反应， 直至监测反应完成。 过滤浓縮后用硅胶色谱法以洗脱剂体系（乙酸乙酯 /石油醚 =1/5)纯化所 得残余物， 得到标题产物 3-(3-(2',6'-二甲基 [Ι,Γ-联苯基 ]-3-基 -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙酸甲酯丙酸甲酯 16e (300mg， 黄色固体)， 产率： 60%。  3-(3-(2-(2,6,-Dimethyl[1 ,1,-biphenyl]-3-yl)-2-oxoethoxy)- 4- in a dry vial A solution of methyl nitro) methyl acrylate 16d (500 mg, 1.12 mmol) and Pd/C (50 mg) in methanol was reacted at room temperature under one atmosphere of hydrogen until the reaction was completed. After concentration by filtration, the obtained residue was purified to silicagel eluting , Γ-biphenyl]-3-yl-3,4-dihydro-2?-benzo[b][l,4]oxazin-7-yl)propanoate methyl propionate 16e (300mg , yellow solid), Yield: 60%.
MS m/z (ESI) : 402 [M+l]  MS m/z (ESI) : 402 [M+l]
第四步  the fourth step
3-(3-(2',6'-二甲基联苯 -3-基) -3,4-二氫 -2f -苯并 [b][l,4]噁嗪 -7-基)丙 酸  3-(3-(2',6'-dimethylbiphenyl-3-yl)-3,4-dihydro-2f-benzo[b][l,4]oxazin-7-yl)propane Acid
以 3-(3-(2，,6，-二甲基 [1,1，-联苯基 ]-3-基) -3,4-二氫苯 [b][l,4]噁嗪 -6- 基)丙酸甲酯 16e (100mg， 0.25mmol)为原料， 参照实施例 1的搡作方法 合成， 用硅胶色谱法以洗脱剂体系（二氯甲烷 /甲醇 = 30/1)纯化所得残 余物， 得到标题产物 3-(3-(2',6'-二甲基联苯 -3-基) -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙酸 16 (25mg， 白色固体)， 产率： 26%。  3-(3-(2,6,-Dimethyl[1,1,-biphenyl]-3-yl)-3,4-dihydrobenzene[b][l,4]oxazine- 6-yl)methyl propionate 16e (100 mg, 0.25 mmol) was used as a starting material, which was purified by the method of the method of Example 1 and purified by silica gel chromatography using eluent system (dichloromethane/methanol = 30/1). The residue gave the title product 3-(3-(2',6'-dimethylbiphenyl-3-yl)-3,4-dihydro-2?-benzo[b][l,4]. Pyrazin-7-yl)propionic acid 16 (25 mg, white solid), Yield: 26%.
MS m/z (ESI) : 388 [M+l]  MS m/z (ESI): 388 [M+l]
¾ NMR (400 MHz, DMSO-i 6) δ 7.50-7.36 (m, 2H), 7.12-7.04 (m, 5H)， 6.64-6.53 (m， 3H)， 6.14 (s， 1H)， 4.48 (d, J= 6.5 Hz, 1H)， 4.24 (dd, J= 9.8， 2.1 Hz, 1H)， 3.91 (dd, J= 10.4, 7.5 Hz, 1H)， 2.65 (t, J= 7.6 Hz, 2H), 2.42 (t, J= 7.6 Hz, 2H), 1.99 (s， 3H)， 1.94 (s， 3H)。 3⁄4 NMR (400 MHz, DMSO-i 6 ) δ 7.50-7.36 (m, 2H), 7.12-7.04 (m, 5H), 6.64-6.53 (m, 3H), 6.14 (s, 1H), 4.48 (d, J= 6.5 Hz, 1H), 4.24 (dd, J= 9.8, 2.1 Hz, 1H), 3.91 (dd, J= 10.4, 7.5 Hz, 1H), 2.65 (t, J= 7.6 Hz, 2H), 2.42 ( t, J = 7.6 Hz, 2H), 1.99 (s, 3H), 1.94 (s, 3H).
实施例 17  Example 17
3-(3-(2',6'-二甲基 -4'-(3- (甲磺酰基）丙氧基)联苯基 -3-基) -3,4-二氫 -2? -苯并 [b] [1,4]噁嗪 -7-基)丙酸 3-(3-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3,4-dihydro-2? Benzo[b][1,4]oxazin-7-yl)propionic acid
Figure imgf000051_0001
第一步
Figure imgf000051_0001
first step
3-(3-(2-(3-溴甲基) -2-氧乙氧基) -4-硝基苯基)丙烯酸甲酯  Methyl 3-(3-(2-(3-bromomethyl)-2-ethoxyethoxy)-4-nitrophenyl)acrylate
将 2-溴 -1-(3-溴苯基）乙酮 17a (1.53g,5. 5mmol， 采用公知的方法"专 利 WO2013041468"制备而得）， 3-(3-羟基 -4-硝基苯基） 丙烯酸甲酯 16c (1.13g， 5.5mmol)， 四丁基氟化铵（1.59g， 6.1mmol)和碳酸铯 (1.99g,6.1mmol)溶解于 Ν,Ν，-二甲基甲酰胺 (30mL)中， 室温下搅拌直至 反应完成。 加水淬灭反应后， 用乙酸乙酯 (20mL><5)萃取。 有机相用无 水疏酸钠干燥后， 减压浓縮。 用硅胶色谱法以洗脱剂体系（乙酸乙酯 / 石油醚 =1/8-1/3)纯化所得残余物， 得到标题产物 3-(3-(2-(3-溴甲基 )-2- 氧乙氧基) -4-硝基苯基)丙烯酸甲酯 17b (1.8g， 黄色固体)， 产率： 78%。  2-Bromo-1-(3-bromophenyl)ethanone 17a (1.53 g, 5.5 mmol, prepared by the known method "Patent WO2013041468"), 3-(3-hydroxy-4-nitrobenzene Methyl acrylate 16c (1.13 g, 5.5 mmol), tetrabutylammonium fluoride (1.59 g, 6.1 mmol) and cesium carbonate (1.99 g, 6.1 mmol) were dissolved in hydrazine, hydrazine, dimethylformamide ( In 30 mL), stir at room temperature until the reaction was completed. After quenching with water, it was extracted with ethyl acetate (20 mL > < 5). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified to silica gel elution elution elution - Oxyethoxyethoxy)-4-nitrophenyl)methyl acrylate 17b (1.8 g, yellow solid), Yield: 78%.
MS m/z (ESI) : 420[M+1], 422 [M+3]  MS m/z (ESI): 420 [M+1], 422 [M+3]
第二步  Second step
3-(4-氨基 -3-(2-(3-溴苯基 )-2-氧乙氧基)苯基)丙烯酸甲酯  Methyl 3-(4-amino-3-(2-(3-bromophenyl)-2-oxoethoxy)phenyl)acrylate
将连二亚疏酸钠 (418mg， 2.4mmol)加到 3-(3-(2-(3-溴甲基 )-2-氧乙 氧基) -4-硝基苯基）丙烯酸甲酯 17b (lOOmg , 0.24mmol)的四氫呋喃 (lOmL)和水（lOmL)的溶液中， 室温下搅拌过夜。 反应完成后， 反应液 用乙酸乙酯（10mLx3)萃取， 合并有机相。 有机相用无水疏酸钠干燥后， 减压浓縮。用硅胶色谱法以洗脱剂体系（乙酸乙酯 /石油醚 =1/5)纯化所得 残余物， 得到标题产物 3-(4-氨基 -3-(2-(3-溴苯基 )-2-氧乙氧基)苯基)丙 烯酸甲酯 17c (90mg， 黄色固体)， 产率： 96%。 MS m/z (ESI) : 390[M+1], 392 [M+3] Add sodium dithionate (418 mg, 2.4 mmol) to methyl 3-(3-(2-(3-bromomethyl)-2-oxoethoxy)-4-nitrophenyl)acrylate 17b (100 mg, 0.24 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (10 mL? The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified to silica gel chromatography eluting elut elut elut elut elut elut elut Methyl ethoxyethoxy)phenyl)acrylate 17c (90 mg, yellow solid). Yield: 96%. MS m/z (ESI) : 390 [M+1], 392 [M+3]
第三步  third step
3-(3-(3-溴苯基 )-3,4-二氫 -2f -苯并 [b][l,4]噁嗪 -7-基)丙烯酸甲酯 将醋酸 (0.05mL， 催化量)， 加到 3-(4-氨基 -3-(2-(3-溴苯基 )-2-氧乙 氧基)苯基)丙烯酸甲酯 17c (500mg， 1.28mmol)的四氫呋喃 (20mL)溶液 中， 40。C下搅拌 2小时。 反应液减压浓縮。 得到的油状物用 10mL四 氫呋喃溶解后， 加入硼氫化钠（146mg， 3.84mmol), 室温下搅拌 2小时。 加水淬灭反应后， 混合物用乙酸乙酯 (40mLx3)萃取， 合并有机相。 有 机相用饱和食盐水洗， 无水疏酸钠干燥， 过滤后减压浓縮。 用硅胶色 谱法以洗脱剂体系（乙酸乙酯 /石油醚 =1/5-1/3)纯化所得残余物， 得到标 题产物 3-(3-(3-溴苯基 )-3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙烯酸甲酯 17d (450mg, 黄色固体)， 产率： 93%.  Methyl 3-(3-(3-bromophenyl)-3,4-dihydro-2f-benzo[b][l,4]oxazin-7-yl)acrylate (0.05 mL, catalytic amount) , a solution of methyl 3-(4-amino-3-(2-(3-bromophenyl)-2-oxoethoxy)phenyl)acrylate 17c (500 mg, 1.28 mmol) in tetrahydrofuran (20 mL) Medium, 40. Stir at C for 2 hours. The reaction solution was concentrated under reduced pressure. After the obtained oil was dissolved in 10 mL of tetrahydrofuran, sodium borohydride (146 mg, 3.84 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After quenching with water, the mixture was extracted with EtOAc EtOAc EtOAc The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. The obtained residue was purified to silica gel chromatography eluting elut elut elut elut elut elut elut Methyl dihydro-2?-benzo[b][l,4]oxazin-7-yl)acrylate 17d (450 mg, yellow solid), yield: 93%.
MS m/z (ESI) : 374 [M+l]  MS m/z (ESI) : 374 [M+l]
第四步  the fourth step
3-(3-(2',6'-二甲基 -4'-(3- (甲磺酰基）丙氧基)联苯基 -3-基) -3,4-二氫 -2? -苯并 [b] [1,4]噁嗪 -7-基:)丙烯酸甲酯  3-(3-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3,4-dihydro-2? Benzo[b][1,4]oxazin-7-yl:)methyl acrylate
在干燥三口瓶中将 3-(3-(3-溴苯基 )-3,4-二氫 -苯并 [b][l,4]噁嗪 -7-基) 丙烯酸甲酯 17d (450mg， 1.19mmol)， 2-(2,6-二甲基 -4-(3- (甲磺酰基)丙 氧基)苯基) -4,4,5,5-四甲基 -1,3,2-二氧杂戊硼烷 (340mg， 1.19mmol)， 1,1'- 双（二苯基膦）二茂铁二氯化钯（88mg， 0.12mmol) , 碳酸钾（328mg， 2.38mmol)溶解到 1， 4-二氧六环（10mL)和水 (3mL)中， 反应体系置换为 氮气氛围并在 90。C搅拌过夜。 冷却到室温后， 加水稀释， 用乙酸乙酯 (30mLx3)萃取， 合并有机相。 有机相用饱和食盐水洗， 无水疏酸钠干 燥， 过滤后减压浓縮。 用硅胶色谱法以洗脱剂体系（乙酸乙酯 /石油醚 =1/5-1/4)纯化所得残余物， 得到标题产物 3-(3-(2',6'-二甲基 -4'-(3- (甲磺 酰基）丙氧基)联苯基 -3-基) -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基）丙烯酸 甲酯 17e (526mg， 白色固体)， 产率： 83%.  3-(3-(3-bromophenyl)-3,4-dihydro-benzo[b][l,4]oxazin-7-yl)methyl acrylate 17d (450mg, in a dry three-necked flask 1.19mmol), 2-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2 - Dioxaborolane (340 mg, 1.19 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (88 mg, 0.12 mmol), potassium carbonate (328 mg, 2.38 mmol) dissolved in In 1, 4-dioxane (10 mL) and water (3 mL), the reaction system was replaced with a nitrogen atmosphere at 90. C was stirred overnight. After cooling to room temperature, it was diluted with water and extracted with ethyl acetate (30 mL×3) The organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered and evaporated. The obtained residue was purified to silica gel elution elution elution '-(3-(Methanesulfonyl)propoxy)biphenyl-3-yl)-3,4-dihydro-2?-benzo[b][l,4]oxazin-7-yl) Methyl acrylate 17e (526 mg, white solid), Yield: 83%.
MS m/z (ESI) : 536 [M+l]  MS m/z (ESI) : 536 [M+l]
第五步  the fifth step
3-(3-(2',6'-二甲基 -4'-(3- (甲磺酰基）丙氧基)联苯基 -3-基) -3,4-二氫 -2? -苯并 [b] [1,4]噁嗪 -7-基:)丙酸甲酯 3-(3-(2',6'-二甲基 -4'-(3- (甲基磺酰基）丙氧基）[1,Γ-联苯基 ]-3- 基）—3,4-二氫 -2? -苯并 [b][l ,4]噁嗪 -7-基）丙烯酸甲酯 17e (200mg , 0.37mmol)和 Pd/C(20mg)的甲醇溶液在一个大气压的氫气条件下室温 反应过夜。 反应完全后， 过滤， 减压浓縮。 用硅胶色谱法以洗脱剂体 系（乙酸乙酯 /石油醚 =1/1)纯化所得残余物， 得到标题产物 3-(3-(2',6'-二 甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基) -3,4-二氫 -2 -苯并 [b][l,4]噁 嗪 -7-基)丙酸甲酯 17f (180mg， 白色固体)， 产率： 90%. 3-(3-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3,4-dihydro-2? Benzo[b][1,4]oxazin-7-yl:)methyl propionate 3-(3-(2',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)[1,indole-biphenyl]-3-yl)-3,4 - Dihydro-2?-benzo[b][l,4]oxazol-7-yl)methacrylate methyl 17e (200mg, 0.37mmol) and Pd/C (20mg) in methanol in one atmosphere of hydrogen The reaction was carried out at room temperature overnight. After the reaction was completed, it was filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography eluting elut elut elut elut elut elut elut -(Methanesulfonyl)propoxy)biphenyl-3-yl)-3,4-dihydro-2-benzo[b][l,4]oxazin-7-yl)propanoic acid methyl ester 17f (180 mg, white solid), Yield: 90%.
MS m/z (ESI) : 538 [M+l]  MS m/z (ESI) : 538 [M+l]
第六步  Step 6
3-(3-(2',6'-二甲基 -4'-(3- (甲磺酰基）丙氧基)联苯基 -3-基) -3,4-二氫 -2? -苯并 [b] [1,4]噁嗪 -7-基)丙酸  3-(3-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3,4-dihydro-2? Benzo[b][1,4]oxazin-7-yl)propionic acid
以 3-(3-(2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基) -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙酸甲酯 17f (100mg， 0.19mmol)为原料， 参 照实施例 1 的搡作方法合成， 通过 HPLC 制备色谱法纯化（色谱柱： Gemini-C18 150x21.2mm, 5μιη, 流动相： 乙腈 /水 (0.1%甲酸)， 梯度： 60-75), 纯化所得残余物， 得到标题产物 3-(3-(2',6'-二甲基 -4'-(3- (甲磺 酰基)丙氧基)联苯基 -3-基) -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙酸 17 (46mg， 白色固体)， 产率： 46%。  3-(3-(2',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3,4-dihydro-2? -Benzyl [b][l,4]oxazin-7-yl)propanoic acid methyl ester 17f (100 mg, 0.19 mmol) as a starting material, which was synthesized according to the method of Example 1 and purified by HPLC preparative chromatography (chromatography) Column: Gemini-C18 150x21.2mm, 5μιη, mobile phase: acetonitrile/water (0.1% formic acid), gradient: 60-75), purified residue to afford title product 3-(3-(2',6'- Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3,4-dihydro-2?-benzo[b][l,4]oxazine -7-yl)propionic acid 17 (46 mg, white solid), yield: 46%.
MS m/z (ESI) : 524 [M+l]  MS m/z (ESI) : 524 [M+l]
¾ NMR (400Mz, DMSO-i δ 7.46-7.37 (m, 2H), 7.14 (s， 1H), 7.06 (d, J = 7.4 Hz, 1H)， 6.72(d, J = 3.3 Hz, 2H), 6.62-6.55 (m, 3 H)， 6.14 (s， 1H)， 4.48 (dd, J = 12, 2.5 Hz, 1H)， 4.23 (dd, J= 10.4, 2.8 Hz, 1H)， 4.09 (t, J = 6.2 Hz, 2H), 3.91 (dd, J = 10.4, 7.5 Hz, 1H)， 3.28-3.26 (m, 2H), 3.04 (s， 3H)， 2.65 (t, J= 7.6 Hz, 2H), 2.46 (t, J = 7.6 Hz, 2H), 2.14-2.10 (m, 2H), 1.97 (s， 3H)， 1.92 (s， 3 H)。  3⁄4 NMR (400Mz, DMSO-i δ 7.46-7.37 (m, 2H), 7.14 (s, 1H), 7.06 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 3.3 Hz, 2H), 6.62 -6.55 (m, 3 H), 6.14 (s, 1H), 4.48 (dd, J = 12, 2.5 Hz, 1H), 4.23 (dd, J= 10.4, 2.8 Hz, 1H), 4.09 (t, J = 6.2 Hz, 2H), 3.91 (dd, J = 10.4, 7.5 Hz, 1H), 3.28-3.26 (m, 2H), 3.04 (s, 3H), 2.65 (t, J= 7.6 Hz, 2H), 2.46 ( t, J = 7.6 Hz, 2H), 2.14-2.10 (m, 2H), 1.97 (s, 3H), 1.92 (s, 3 H).
实施例 18  Example 18
3-(3—(4'-[(四氫 -1,1-二氧 -2f -噻喃 -4-基)氧基] -2',6'-二甲基联苯基 -3- 基) -3 ,4-二氫 -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸 3-(3-(4'-[(tetrahydro-1,1-dioxo-2f-thiopyran-4-yl)oxy]-2',6'-dimethylbiphenyl-3-yl -3,4-Dihydro-2?-benzo[b][1,4]oxazin-7-yl)propionic acid
Figure imgf000054_0001
Figure imgf000054_0001
第一步  First step
1 ,1，-二氧四氫噻吡喃 -4-基) -(3,5-二甲基 -4-溴-苯基)醚  1,1,-dihydrotetrahydrothiapyran-4-yl)-(3,5-dimethyl-4-bromo-phenyl)ether
将 1,1，-二氧四氫噻吡喃 -4-基 -4-甲基苯磺酸酯 18a (400mg 1,1,-Dihydrotetrahydrothiapyran-4-yl-4-methylbenzenesulfonate 18a (400mg
1.3mmol) , 4-溴 -3， 5-二甲基苯酚 18b (287mg , 1.4mmol)和碳酸钾 (583mg, 3.9mmol)的 Ν,Ν'-二甲基甲酰胺（10mL)的反应液在 65°C下搅 拌 4 小时。 反应完成后， 将反应液用水（10mL)稀释， 该混合物用乙酸 乙酯 (20mLx2)萃取， 合并有机相。 有机相减压浓縮后， 用石油醚重结 晶得到标题产物（1,1，-二氧四氫噻比喃 -4-基 )-(3,5-二甲基 -4-溴-苯基)醚 18c (240mg, 黄色固体)， 产率： 55%。 1.3 mmol), 4-bromo-3, 5-dimethylphenol 18b (287 mg, 1.4 mmol) and potassium carbonate (583 mg, 3.9 mmol) in hydrazine, Ν'-dimethylformamide (10 mL) Stir at 65 ° C for 4 hours. After the reaction was completed, the mixture was diluted with water (10 mL), and the mixture was extracted with ethyl acetate (20 mL?). The organic phase was concentrated under reduced pressure and then crystallised from petroleum ether to give the title product (1,1,-dihydrotetrahydropyran-4-yl)-(3,5-dimethyl-4-bromo-phenyl Ether 18c (240 mg, yellow solid), yield: 55%.
MS m/z (ESI) : 333 [M+l]  MS m/z (ESI) : 333 [M+l]
第二步  Second step
3-(4—硝基 -3—(2-氧 -2-(3-(4,4,5,5-四甲基 -1,3,2-二氧硼基 -2-基）苯基) 乙氧基)苯基)丙烯酸甲酯  3-(4-Nitro-3-(2-oxo-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaboryl-2-yl)phenyl) Ethoxylated phenyl) methacrylate
在干燥三口瓶中将 2-溴 -1-(3- (频哪醇硼酸酯基）苯基）乙酮 18d (6.34g， 19.5mmol)， 3-(3-羟基 -4-硝基苯基）丙烯酸甲酯 16c (8.2g , 19.5mmol)， 四丁基氟化铵 (5.62g， 21.5mmol)和碳酸铯 (7.0g， 21.5mmol) 溶解于 Ν,Ν'-二甲基甲酰胺 (50mL)中， 室温下搅拌直至反应完成。 加水 淬灭反应后， 用乙酸乙酯 (40mL><5)萃取。 有机相用无水疏酸钠干燥后， 减压浓縮。 用硅胶色谱法以洗脱剂体系（乙酸乙酯 /石油醚 =1/8-1/3)纯化 所得残余物，得到标题产物 3-(4-硝基 -3-(2-氧 -2-(3-(4,4,5,5-四甲基 -1,3,2- 二氧杂戊硼烷 -2-基：)苯基）乙氧基：)苯基)丙烯酸甲酯 18e (5.1g， 黄色油状 物)， 产率： 60%。  2-Bromo-1-(3-pinaline borate)phenyl)ethanone 18d (6.34g, 19.5mmol), 3-(3-hydroxy-4-nitrobenzene) in a dry three-necked flask Methyl acrylate 16c (8.2 g, 19.5 mmol), tetrabutylammonium fluoride (5.62 g, 21.5 mmol) and cesium carbonate (7.0 g, 21.5 mmol) dissolved in hydrazine, Ν'-dimethylformamide ( In 50 mL), stir at room temperature until the reaction was completed. After quenching with water, it was extracted with ethyl acetate (40 mL > < 5). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified to silica crystal elut elut elut elut elut elut elut elut elut (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl:)phenyl)ethoxy:)phenyl)methyl acrylate 18e ( 5.1 g, yellow oil), Yield: 60%.
MS m/z (ESI) : 468 [M+l] 第三步 MS m/z (ESI) : 468 [M+l] third step
3-(3-(3-(4,4,5,5-四甲基 -1,3,2-二氧杂戊硼烷 -2-基）苯基) -3,4-二氫 -2? -苯并 [b] [1,4]噁嗪 -7-基:)丙酸甲酯  3-(3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4-dihydro-2 ? -Benzo[b][1,4]oxazin-7-yl:) Methyl propionate
在干燥单口瓶中将 3-(4-硝基 -3-(2-氧 -2-(3-(4,4,5,5-四甲基 -1,3,2-二 氧杂戊硼烷 -2-基)苯基）乙氧基)苯基)丙烯酸甲酯 18e (5.1g， l lmmol)和 Pd/C(500mg)的甲醇溶液在一个大气压的氫气条件下室温反应， 直至监 测反应完成。过滤浓縮后用硅胶色谱法以洗脱剂体系（乙酸乙酯 /石油醚 =1/5)纯化所得残余物，得到标题产物 3-(3-(3-(4,4,5,5-四甲基 -1,3,2-二氧 杂戊硼烷 -2-基)苯基) -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙酸甲酯 18f (2.8g, 黄色油状物）， 产率： 60%。  3-(4-Nitro-3-(2-oxo-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxapentyl boron) in a dry single-mouth bottle Alkyl-2-yl)phenyl)ethoxy)phenyl)acrylate 18e (5.1g, l lmmol) and Pd/C (500mg) in methanol are reacted at room temperature under one atmosphere of hydrogen until monitoring The reaction is complete. The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut elut Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4-dihydro-2?-benzo[b][l,4]oxazine-7- Methyl propionate 18f (2.8 g, yellow oil), Yield: 60%.
MS m/z (ESI) : 424 [M+l]  MS m/z (ESI) : 424 [M+l]
第四步  the fourth step
3-(3-(4'-[(四氫 -1,1-二氧 -2f -噻喃 -4-基)氧基] -2',6'-二甲基联苯基 -3- 基) -3 ,4-二氫 -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸甲酯  3-(3-(4'-[(tetrahydro-1,1-dioxo-2f-thiopyran-4-yl)oxy]-2',6'-dimethylbiphenyl-3-yl -3,4-Dihydro-2?-benzo[b][1,4]oxazin-7-yl)propanoate
在干燥三口瓶中将 3-(3-(3-(4,4,5,5-四甲基 - 1 ,3 ,2-二氧杂戊硼烷 -2- 基）苯基) -3,4-二氫苯并 [b][l,4]噁嗪 -7-基）丙酸甲酯 18f (850mg , 2.0mmol) , (Ι,Γ-二氧四氫噻比喃 -4-基) -(3,5-二甲基 -4-溴-苯基)醚 18c (733mg， 2.2mmol) , Ι,Γ-双（二苯基膦）二茂铁二氯化钯（146mg， 0.2mmol), 碳酸钾 (828mg， 6.0mmol)溶解到 1,4-二氧六环 (30mL)和水 (8mL)中， 反应体系置换氮气氛围， 90°C搅拌过夜。反应完全后冷却到 室温后， 加水稀释， 用乙酸乙酯 (40mLx3)萃取， 合并有机相。 有机相 用饱和食盐水洗， 无水疏酸钠干燥， 过滤后减压浓縮。 用硅胶色谱法 以洗脱剂体系（乙酸乙酯 /石油醚 =1/5-1/4)纯化所得残余物， 得到标题产 物 3-(3-(4'- [(四氫 -1,1-二氧 -2? -噻喃 -4-基）氧基] -2',6'-二甲基联苯基 -3- 基)—3,4-二氫 -2 -苯并 [b][l,4]噁嗪 -7-基)丙酸甲酯 18g (lg)， 粗产品。  3-(3-(3-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyl) -3 in a dry three-necked flask, 4-Dihydrobenzo[b][l,4]oxazin-7-yl)propanoic acid methyl ester 18f (850 mg, 2.0 mmol), (Ι, Γ-dioxotetrahydrothiopyran-4-yl) -(3,5-Dimethyl-4-bromo-phenyl)ether 18c (733 mg, 2.2 mmol), hydrazine, hydrazine-bis(diphenylphosphino)ferrocene palladium dichloride (146 mg, 0.2 mmol) Potassium carbonate (828 mg, 6.0 mmol) was dissolved in 1,4-dioxane (30 mL) and water (8 mL), and the reaction system was replaced with a nitrogen atmosphere and stirred at 90 ° C overnight. After the reaction was completed, it was cooled to room temperature, diluted with water, and extracted with ethyl acetate (40 mL×3). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue obtained was purified by silica gel chromatography eluting elut elut elut elut elut elut elut elut -Dioxo-2?-thiopyran-4-yl)oxy]-2',6'-dimethylbiphenyl-3-yl)-3,4-dihydro-2-benzo[b] [l,4]oxazin-7-yl)methyl propionate 18 g (lg), crude product.
MS m/z (ESI) : 550 [M+l]  MS m/z (ESI) : 550 [M+l]
第五步  the fifth step
3-(3-(4'-[(四氫 -1,1-二氧 -2f -噻喃 -4-基)氧基] -2',6'-二甲基联苯基 -3- 基) -3 ,4-二氫 -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸  3-(3-(4'-[(tetrahydro-1,1-dioxo-2f-thiopyran-4-yl)oxy]-2',6'-dimethylbiphenyl-3-yl -3,4-Dihydro-2?-benzo[b][1,4]oxazin-7-yl)propionic acid
以 3-(3-(4'- [(四氫 -1,1-二氧 -2? -噻喃 -4-基)氧基] -2',6'-二甲基联苯基 -3-基) -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基）丙酸甲酯 18g (270mg , 0.5mmol)为原料， 参照实施例 1 的搡作方法合成， 通过 HPLC制备色 谱法纯化（色谱柱： Gemini-C18， 150x21.2mm, 5μιη, 流动相： 乙腈 / 水 (0.1%甲酸)，梯度： 55-60)，得到标题产物 3-(3-(4'- [(四氫 -1,1-二氧 -2? - 噻喃 -4-基）氧基] -2',6'-二甲基联苯基 -3-基) -3,4-二氫 -2? -苯并 [b][l,4]噁 嗪 -7-基)丙酸 18 (15mg， 白色固体)， 产率： 6%。 3-(3-(4'-[(tetrahydro-1,1-dioxo-2?-thiopyran-4-yl)oxy]-2',6'-dimethylbiphenyl-3 -yl)-3,4-dihydro-2?-benzo[b][l,4]oxazin-7-yl)propanoic acid methyl ester 18g (270mg, 0.5 mmol) was used as a starting material, which was synthesized according to the method of Example 1 and purified by HPLC preparative chromatography (column: Gemini-C18, 150×21.2 mm, 5 μιη, mobile phase: acetonitrile/water (0.1% formic acid), gradient: 55-60), the title product 3-(3-(4'-[(tetrahydro-1,1-dioxo-2?-thiopyran-4-yl)oxy]-2',6'-di Methylbiphenyl-3-yl)-3,4-dihydro-2?-benzo[b][l,4]oxazin-7-yl)propanoic acid 18 (15 mg, white solid), yield : 6%.
MS m/z (ESI) : 536 [M+l]  MS m/z (ESI) : 536 [M+l]
¾ NMR (300 MHz, CD3OD) δ 7.49-7.42 (m, 2H), 7.21 (s, 1H)， 7.16-7.14 (m， 1H)， 6.79 (s， 2H), 6.70-6.65 (m， 3H)， 4.73-4.70 (m， 1H)， 4.52-4.50 (m, 1H)， 4.28-4.26 (m, 1H)， 4.05-4.04 (m, 1H)， 3.35-3.33 (m， 2H), 3.07-3.05 (m, 2H), 2.75-2.73 (m, 2H), 2.53-2.51 (m, 2H), 2.48-2.25 (m， 4H)， 2.05 (s， 3H)， 2.01 (s, 3H)。 3⁄4 NMR (300 MHz, CD 3 OD) δ 7.49-7.42 (m, 2H), 7.21 (s, 1H), 7.16-7.14 (m, 1H), 6.79 (s, 2H), 6.70-6.65 (m, 3H ), 4.73-4.70 (m, 1H), 4.52-4.50 (m, 1H), 4.28-4.26 (m, 1H), 4.05-4.04 (m, 1H), 3.35-3.33 (m, 2H), 3.07-3.05 (m, 2H), 2.75-2.73 (m, 2H), 2.53-2.51 (m, 2H), 2.48-2.25 (m, 4H), 2.05 (s, 3H), 2.01 (s, 3H).
实施例 19  Example 19
3-(3-(2',6'-二甲基 -4'-(3-(甲磺酰基)丙氧基)联苯基 -3-基) -6-氟- -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸  3-(3-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-6-fluoro--2?-benzo [b] [1,4]oxazin-7-yl)propionic acid
Figure imgf000056_0001
Figure imgf000056_0001
第一步  First step
3—(2-氟 -5-羟基 -4-硝基苯基)丙烯酸甲酯  3-(2-Fluoro-5-hydroxy-4-nitrophenyl) acrylate
在干燥三口瓶中将 5-溴 -4-氟 -2-硝基苯酚 19a (472mg, 2.0mmol), 丙烯酸甲酯（1.0g， lOmmol),醋酸钯 (45mg， 0.2mmol),三苯基膦（105mg， 0.4mmol)和三乙胺 (0.8mL， 6.0mmol) 溶解于 Ν,Ν'-二甲基甲酰胺 (5mL) 中， 反应体系在氮气保护下加热至 125。C， 微波反应 1小时。 冷却后， 反应液倒入水 (50mL)中， 该混合物用乙酸乙酯 (30mLx3)萃取。 干燥后 减压浓縮。用硅胶色谱法以洗脱剂体系（乙酸乙酯 /石油醚 =1/3)纯化所得 残余物， 得到标题产物 3-(2-氟 -5-羟基 -4-硝基苯基：)丙烯酸甲酯 19b (360mg, 黄色固体)， 产率： 75%。 5-Bromo-4-fluoro-2-nitrophenol 19a (472 mg, 2.0 mmol), methyl acrylate (1.0 g, 10 mmol), palladium acetate (45 mg, 0.2 mmol), triphenylphosphine in a dry three-necked flask (105 mg, 0.4 mmol) and triethylamine (0.8 mL, 6.0 mmol) were dissolved in hydrazine, &lt;RTI ID=0.0&gt;&gt; C, microwave reaction for 1 hour. After cooling, the reaction solution was poured into water (50 mL) After drying, it was concentrated under reduced pressure. Purified by silica gel chromatography using an eluent system (ethyl acetate / petroleum ether = 1/3) The residue was purified to give crystal crystal crystal crystal crystal crystal crystal crystal
MS m/z (ESI) : 242 [M+l]  MS m/z (ESI): 242 [M+l]
第二步  Second step
3-(5-(2-(3-溴苯基 )-2-氧乙氧基) -2-氟 -4-硝基苯基)丙烯酸甲酯 将 2-溴 -1-(3-溴苯基）乙酮 17a (1.85g， 6.6mmol)， 3-(2-氟 -5-羟基 -4- 硝基苯基）丙烯酸甲酯 19b (1.6g， 6.6mmol)， 四丁基氟化铵（1.9g， 7.3mmol)和碳酸铯 (2.38g， 7.3mmol)溶解于 Ν,Ν'-二甲基甲酰胺 (30mL) 中， 室温下搅拌直至反应完成。加水淬灭反应后， 用乙酸乙酯 (30mL><5) 萃取。 有机相用无水疏酸钠干燥后， 减压浓縮。 用硅胶色谱法以洗脱 剂体系（乙酸乙酯 /石油醚 =1/10〜 1/3)纯化所得残余物， 得到标题产物 3-(5-(2-(3-溴苯基） -2-氧乙氧基) -2-氟 -4-硝基苯基）丙烯酸甲酯 19c (600mg, 黄色固体)， 产率： 21%。  Methyl 3-(5-(2-(3-bromophenyl)-2-oxoethoxy)-2-fluoro-4-nitrophenyl)acrylate 2-bromo-1-(3-bromobenzene) Ethylketone 17a (1.85 g, 6.6 mmol), methyl 3-(2-fluoro-5-hydroxy-4-nitrophenyl)acrylate 19b (1.6 g, 6.6 mmol), tetrabutylammonium fluoride ( 1.9 g, 7.3 mmol) and cesium carbonate (2.38 g, 7.3 mmol) were dissolved in hydrazine, Ν'-dimethylformamide (30 mL), and stirred at room temperature until the reaction was completed. After quenching with water, it was extracted with ethyl acetate (30 mL > < 5). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified to silica gel elution elution elution elution Methyl ethoxyethoxy)-2-fluoro-4-nitrophenyl)acrylate 19c (600 mg, yellow solid). Yield: 21%.
MS m/z (ESI) : 278 [M+l]  MS m/z (ESI) : 278 [M+l]
¾ NMR (300 MHz, CDCb) δ 8.10 (s， 1H)， 7.83-7.71 (m, 2H), 7.64 (d, J= 7.6 Hz, 1H)， 7.35 (t， J= 7.9 Hz， 1H)， 7.16 (d, J= 10.4 Hz, 1H)， 7.05 (d, J = 6.5 Hz, 1H)， 6.48 (d， J = 16.1 Hz, 1H)， 5.03 (s, 2H), 3.82 (s， 3H)。  3⁄4 NMR (300 MHz, CDCb) δ 8.10 (s, 1H), 7.83-7.71 (m, 2H), 7.64 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.16 (d, J = 10.4 Hz, 1H), 7.05 (d, J = 6.5 Hz, 1H), 6.48 (d, J = 16.1 Hz, 1H), 5.03 (s, 2H), 3.82 (s, 3H).
第三步  third step
3-(2-氟 -4-硝基 -5-(2-氧 -2-(3-(4,4,5,5-四甲基 -1,3,2-二氧杂戊硼烷 -2- 基)苯基)乙氧基)苯基)丙烯酸甲酯  3-(2-Fluoro-4-nitro-5-(2-oxo-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)- Methyl 2-phenyl)ethoxy)phenyl)acrylate
在干燥三口瓶中将 3-(5-(2-(3-溴苯基 )-2-氧乙氧基 )-2-氟 -4-硝基苯 基）丙烯酸甲酯 19c (600mg , 1.4mmol)， 二频哪醇硼酸酯 (427mg， 1.68mmol)， Ι,Γ-双 (二苯基膦)二茂铁二氯化钯（102mg， 0.14mmol)和醋 酸钾 (412mg， 4.2mmol)的 1,4-二氧六环（10mL)的混合溶液在氮气保护 下加热至 95°C， 搅拌过夜。 反应完全后冷却至室温减压浓縮。 用硅胶 色谱法以洗脱剂体系（乙酸乙酯 /石油醚 =1/3)纯化所得残余物，得到标题 产物 3-(2-氟 -4-硝基 -5-(2-氧 -2-(3-(4,4,5,5-四甲基 -l,3,2-二氧杂戊硼烷-2- 基)苯基）乙氧基)苯基)丙烯酸甲酯 19d (600mg， 黄色固体)， 产率： 94%。 Methyl 3-(5-(2-(3-bromophenyl)-2-oxoethoxy)-2-fluoro-4-nitrophenyl)acrylate 19c (600 mg, 1.4 mmol) in a dry three-neck flask ), dipinocol borate (427 mg, 1.68 mmol), hydrazine, hydrazine-bis(diphenylphosphino)ferrocene palladium dichloride (102 mg, 0.14 mmol) and potassium acetate (412 mg, 4.2 mmol) A mixed solution of 1,4-dioxane (10 mL) was heated to 95 ° C under a nitrogen atmosphere and stirred overnight. After completion of the reaction, it was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified to silica crystal elut elut elut elut elut elut elut elut Methyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)ethoxy)phenyl)acrylate 19d (600m g , yellow solid), Yield: 94%.
MS m/z (ESI) : 486 [M+l]  MS m/z (ESI) : 486 [M+l]
¾ NMR (300 MHz, CDCb) δ 8.22 (s, 1H)， 8.12 (d, J= 6.5 Hz, 1H)， 7.95 (d, J = 7.4 Hz, 1H)， 7.77 (d， J = 16.3 Hz, 1H)， 7.50 (s, 1H)， 7.18 (d， J = 10.6 Hz, 1H)， 7.06 (d, J= 6.5 Hz, 1H)， 6.47 (d, J = 16.0 Hz, 1H)， 5.10 (s, 2H), 3.81 (s， 3H)， 1.41-1.31 (m， 12H)。 3⁄4 NMR (300 MHz, CDCb) δ 8.22 (s, 1H), 8.12 (d, J = 6.5 Hz, 1H), 7.95 (d, J = 7.4 Hz, 1H), 7.77 (d, J = 16.3 Hz, 1H), 7.50 (s, 1H), 7.18 (d, J = 10.6 Hz, 1H), 7.06 (d, J = 6.5 Hz, 1H), 6.47 (d, J = 16.0 Hz, 1H), 5.10 (s, 2H), 3.81 (s, 3H), 1.41-1.31 (m, 12H).
第四步  the fourth step
3-(6-氟 -3-(3-(4,4,5,5-四甲基 -1,3,2-二氧杂戊硼烷 -2-基)苯基) -3,4-二 氫 -2? --苯并 [b] [ 1 ,4]噁嗪 -7-基:)丙酸甲酯  3-(6-fluoro-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4- Dihydro-2?-benzo[b][1,4]oxazin-7-yl:)methyl propionate
在干燥单口瓶中将 3-(2-氟 -4-硝基 -5-(2-氧 -2-(3-(4,4,5,5-四甲基 -1,3,2-二氧杂戊硼烷 -2-基)苯基）乙氧基)苯基)丙烯酸甲酯 19d (600mg, 1.23mmol)和 Pd/C(50mg)的甲醇溶液在一个大气压的氫气条件下室温 反应， 直至监测反应完成。 过滤浓縮后用硅胶色谱法以洗脱剂体系（乙 酸乙酯 /石油醚 =1/3)纯化所得残余物， 得到标题产物 3-(6-氟 —3-(3-(4,4,5,5-四甲基 -1,3,2-二氧杂戊硼烷 -2-基)苯基) -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙酸甲酯 19e (490mg， 黄色油状物）， 产率： 90%。  3-(2-Fluoro-4-nitro-5-(2-oxo-2-(3-(4,4,5,5-tetramethyl-1,3,2-) in a dry single-mouth bottle Methyl oxaborolan-2-yl)phenyl)ethoxy)phenyl)acrylate 19d (600 mg, 1.23 mmol) and Pd/C (50 mg) in methanol at room temperature under atmospheric pressure of hydrogen Until the monitoring reaction is completed. The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut elut 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4-dihydro-2?-benzo[b][l,4] Methylazin-7-yl)propanoate 19e (490 mg, yellow oil), Yield: 90%.
MS m/z (ESI) : 442 [M+l]  MS m/z (ESI): 442 [M+l]
第五步  the fifth step
3-(3-(2',6'-二甲基 -4'-(3-(甲磺酰基)丙氧基)联苯基 -3-基) -6-氟 -3,4-二 氫 -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸甲酯  3-(3-(2',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-6-fluoro-3,4-dihydro -2? -Benzo[b][1,4]oxazin-7-yl)propanoate
将 3-(6-氟 -3-(3-(4,4,5,5-四甲基 -1,3,2-二氧杂戊硼烷 -2-基)苯基) -3,4- 二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙酸甲酯 19e (200mg, 0.45mmol)， 2- 溴 -1,3-二甲基 -5-(3- (甲磺酰基)丙氧基)苯 (220mg， 0.68mmol), 四三苯基 膦钯 (58mg， 0.05mmol)和碳酸钾（186mg， 1.35mmol)溶解于甲苯和水 (20mL/50mL)的混合溶剂中，在氮气保护下加热至 80。C直至反应完成。 将反应物降至室温， 用水稀释， 该混合物用乙酸乙酯 (20mLx3)萃取。 合并有机相， 有机相用饱和食盐水洗， 无水疏酸钠干燥。 过滤后减压 浓縮， 用硅胶色谱法以洗脱剂体系（乙酸乙酯 /石油醚 =1/3〜3/1)纯化所 得残余物， 得到标题产物 3-(3-(2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联 苯基 -3 -基) -6-氟 -3 ,4-二氫 -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基）丙酸甲酯 19f (180mg, 黄色液体)， 产率： 72%。  3-(6-Fluoro-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4 - Dihydro-2?-benzo[b][l,4]oxazine-7-yl)propanoic acid methyl ester 19e (200 mg, 0.45 mmol), 2-bromo-1,3-dimethyl-5- (3-(Methanesulfonyl)propoxy)benzene (220 mg, 0.68 mmol), tetrakistriphenylphosphine palladium (58 mg, 0.05 mmol) and potassium carbonate (186 mg, 1.35 mmol) dissolved in toluene and water (20 mL / 50 mL) In a mixed solvent, it was heated to 80 under a nitrogen atmosphere. C until the reaction is completed. The reaction was cooled to room temperature, diluted with water and EtOAc EtOAc EtOAc The organic phase was combined, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced vacuo. '-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-6-fluoro-3,4-dihydro-2?-benzo[b][ 1 ,4]oxazine-7-yl)methyl propionate 19f (180 mg, yellow liquid), Yield: 72%.
MS m/z (ESI) : 556 [M+l]  MS m/z (ESI) : 556 [M+l]
第六步  Step 6
3-(3-(2',6'-二甲基 -4'-(3-(甲磺酰基)丙氧基)联苯基 -3-基) -6-氟 -3,4-二 氫 -2f -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸 3-(3-(2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-6-fluoro-3,4-di Hydrogen-2f-benzo[b][1,4]oxazin-7-yl)propionic acid
以 3-(3-(2',6'-二甲基 -4'-(3- (甲磺酰基）丙氧基）联苯基 -3-基) -6-氟 —3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙酸甲酯 19f (180mg， 0.32mmol) 为原料，参照实施例 1的搡作方法合成，通过 HPLC制备色谱法纯化（色 譜柱： Gemini-C18， 150x21.2mm, 5μιη, 流动相： 乙腈 /水 (0.1%甲酸)， 梯度： 55-60)， 纯化所得残余物， 得到标题产物 3-(3-(2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基) -6-氟 -3,4-二氫 -2? -苯并 [b][l,4]噁 嗪 -7-基)丙酸 19 (10mg， 白色固体)， 产率： 5.8%。  3-(3-(2',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-6-fluoro-3,4-di Hydrogen-2?-benzo[b][l,4]oxazine-7-yl)propanoic acid methyl ester 19f (180 mg, 0.32 mmol) was used as a starting material, which was synthesized by the method of Example 1 and prepared by HPLC. Purification (column: Gemini-C18, 150×21.2 mm, 5 μιη, mobile phase: acetonitrile/water (0.1% formic acid), gradient: 55-60), the residue obtained was purified to give the title product 3-(3-(2) ',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-6-fluoro-3,4-dihydro-2?-benzo[ b] [l,4]oxazin-7-yl)propanoic acid 19 (10 mg, white solid), yield: 5.8%.
MS m/z (ESI) : 542 [M+l]  MS m/z (ESI): 542 [M+l]
¾ NMR (300 MHz, CD3OD) δ 7.44-7.34 (m, 2H), 7.12 (s， 1H)， 7.04 (d, J= 7.1 Hz, 1H)， 6.67 (s， 2H), 6.58 (d, J= 7.2 Hz, 1H)， 6.41 (d， J= 11.2 Hz, 1H)， 4.47 (d， J= 4.8 Hz, 1H)， 4.23 (dd, J = 10.5, 2.9 Hz, 1H)， 4.11 (t， J= 6.0 Hz, 2H), 3.92 (dd, J= 10.5, 7.7 Hz, 1H)， 3.34 (d， J= 8.2 Hz, 2H), 3.01 (s， 3H)， 2.80-2.72 (m, 2H), 2.50 (t, J = 7.5 Hz, 2H), 2.32 -2.22 (m, 2H), 2.02(s, 3H)， 1.96 (s， 3H)。 3⁄4 NMR (300 MHz, CD 3 OD) δ 7.44-7.34 (m, 2H), 7.12 (s, 1H), 7.04 (d, J = 7.1 Hz, 1H), 6.67 (s, 2H), 6.58 (d, J= 7.2 Hz, 1H), 6.41 (d, J= 11.2 Hz, 1H), 4.47 (d, J= 4.8 Hz, 1H), 4.23 (dd, J = 10.5, 2.9 Hz, 1H), 4.11 (t, J= 6.0 Hz, 2H), 3.92 (dd, J= 10.5, 7.7 Hz, 1H), 3.34 (d, J= 8.2 Hz, 2H), 3.01 (s, 3H), 2.80-2.72 (m, 2H), 2.50 (t, J = 7.5 Hz, 2H), 2.32 -2.22 (m, 2H), 2.02(s, 3H), 1.96 (s, 3H).
实施例 20  Example 20
3-(6-氟 -3-(2',4,6'-三甲基 -4'-(3-(甲磺酰基)丙氧基)联苯 -3-基) - -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸  3-(6-fluoro-3-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)- -2?-benzene And [b] [1,4]oxazin-7-yl)propionic acid
Figure imgf000059_0001
Figure imgf000059_0001
第一步  First step
3-(4-氨基 -2-氟 -5-羟基苯基)丙烯酸甲酯 将 -甲基 -3-(2-氟 -5-羟基 -4-硝基苯基)丙烯酸甲酯 19b (700mg, 2.90mmol)溶解到甲醇（10 mL)中， 加入 Pd/C(70mg)， 反应体系用氫气 球置换成氫气氛围（1个大气压)， 室温下搅拌过夜。 过滤， 滤液浓縮得 标题产物 -甲基 -3-(2-氟 -5-羟基 -4-氨基苯基)丙烯酸甲酯 20a (500mg, 棕色液体)， 产率： 57%。 Methyl 3-(4-amino-2-fluoro-5-hydroxyphenyl)acrylate Methyl-methyl-3-(2-fluoro-5-hydroxy-4-nitrophenyl) acrylate 19b (700 mg, 2.90 mmol) was dissolved in methanol (10 mL) and Pd/C (70 mg). The reaction system was replaced with a hydrogen balloon to a hydrogen atmosphere (1 atm), and stirred at room temperature overnight. Filtration and concentration of the filtrate gave the title product-methyl 3-(2-fluoro-5-hydroxy-4-aminophenyl) acrylate 20a (500 mg, brown liquid), yield: 57%.
MS m/z (ESI) : 212 [M+l]  MS m/z (ESI): 212 [M+l]
¾ NMR (400 MHz, CDCb) δ 7.73 (d， J= 16.1 Hz, 1H)， 6.90 (d, J= 6.4 Hz, 1H)， 6.44 (d, J= 11.5 Hz, 1H)， 6.27 (d, J= 16.1 Hz, 1H)， 3.81 (s， 2H)。  3⁄4 NMR (400 MHz, CDCb) δ 7.73 (d, J = 16.1 Hz, 1H), 6.90 (d, J = 6.4 Hz, 1H), 6.44 (d, J = 11.5 Hz, 1H), 6.27 (d, J = 16.1 Hz, 1H), 3.81 (s, 2H).
第二步  Second step
2-溴 -l-(5-溴 -2-甲基苯基）乙酮  2-bromo-l-(5-bromo-2-methylphenyl)ethanone
在 0。C下， 把溴 (768mg， 4.8mmol)的乙醚溶液 (15mL)缓慢地滴加 到 1-(5-溴 -2-甲基苯基）乙酮 20b (850mg， 4.0mmol，采用公知的方法"文 献 Journal of Medicinal Chemistry, 56(5)， 1878-1893 ; 2013"制备而得;) 和三氯化铝 (534mg， 4.0mmol)的乙醚 (20mL)溶液中， 然后在室温下搅 拌直至反应完成。 反应用饱和亚疏酸氫钠淬灭， 过滤后分离有机相。 有机相干燥后减压浓縮得到标题产物 2-溴 -1-(3-溴苯基）乙酮 20c (l.Og, 黄色液体)， 产率： 86%。  At 0. Bromine (768 mg, 4.8 mmol) in diethyl ether (15 mL) was slowly added dropwise to 1-(5-bromo-2-methylphenyl)ethanone 20b (850 mg, 4.0 mmol, using a known method). Document Journal of Medicinal Chemistry, 56(5), 1878-1893; 2013 "Prepared;) and a solution of aluminum trichloride (534 mg, 4.0 mmol) in diethyl ether (20 mL), then stirred at room temperature until completion. The reaction was quenched with saturated aqueous sodium hydrogensulfite and filtered to isolate organic. The organic phase was dried and evaporated tolululululululululululululululululululululu
MS m/z (ESI) : 291 [M+l]  MS m/z (ESI) : 291 [M+l]
第三步  third step
3- (4-氨基 -5-(2-(5-溴 -2-甲基苯基) -2-氧乙氧基) -2-氟苯基)丙烯酸甲 酯  3-(4-Amino-5-(2-(5-bromo-2-methylphenyl)-2-oxoethoxy)-2-fluorophenyl) acrylate
向 3-(4-氨基 -2-氟 -5-羟基苯基)丙烯酸甲酯 20a (200mg， 0.95mmol) 的 Ν,Ν'-二甲基甲酰胺（10mL)的溶液中加入 2-溴 -1-(5-溴 -2-甲基苯基) 乙酮 20c (359mg， 1.23mmol)和碳酸铯 (774mg， 2.38mmol)， 室温搅拌 4 小时。 反应完成后， 加入 lOOmL乙酸乙酯稀释。 该混合物依次用水和 饱和食盐水洗涤， 加入无水疏酸钠干燥。 过滤后减压浓縮， 得到标题 产物 3-(4-氨基 -5-(2-(5-溴 -2-甲基苯基 )-2-氧乙氧基 )-2-氟苯基)丙烯酸甲 酯 20d (300mg， 棕色液体)， 产率： 78%。  To a solution of methyl 3-(4-amino-2-fluoro-5-hydroxyphenyl) acrylate 20a (200 mg, 0.95 mmol) in hydrazine, Ν'-dimethylformamide (10 mL) 1-(5-Bromo-2-methylphenyl)ethanone 20c (359 mg, 1.23 mmol) and cesium carbonate (774 mg, 2.38 mmol) were stirred at room temperature for 4 hr. After the reaction was completed, it was diluted with 100 mL of ethyl acetate. The mixture was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave the title product 3-(4-amino-5-(2-(5-bromo-2-methylphenyl)-2-oxyethoxy)-2-fluorophenyl) Methyl ester 20d (300 mg, brown liquid), Yield: 78%.
MS m/z (ESI) : 404 [M+l] 第四步 MS m/z (ESI) : 404 [M+l] the fourth step
3-(3-(5-溴 -2-甲基苯基) -6-氟 -2f -苯并 [b][l,4]噁嗪 -7-基)丙烯酸甲酯 向 3-(4-氨基 -5-(2-(5-溴 -2-甲基苯基) -2-氧乙氧基) -2-氟苯基)丙烯酸 甲酯 20d (300mg, 0.71mmol)的甲醇 (10mL)溶液中加入 lmL醋酸后， 室温搅拌 2小时。反应结束后，减压浓縮。所得物溶于乙酸乙酯 (lOOmL) 中。 该混合物依次用水和饱和食盐水洗涤后， 加入无水疏酸钠干燥。 过滤后减压浓縮。 用硅胶色谱法以洗脱剂体系（乙酸乙酯 /石油醚 =1/5) 纯化所得残余物， 得到标题产物 3-(3-(5-溴 -2-甲基苯基： )-6-氟 -2? -苯并 [b][l,4]噁嗪 -7-基)丙烯酸甲酯 20e (180mg， 黄色固体)， 产率： 47%。  3-(3-(5-Bromo-2-methylphenyl)-6-fluoro-2f-benzo[b][l,4]oxazin-7-yl)acrylate to 3-(4- Methylamino-5-(2-(5-bromo-2-methylphenyl)-2-oxoethoxy)-2-fluorophenyl)acrylate 20d (300 mg, 0.71 mmol) in methanol (10 mL) After adding 1 mL of acetic acid, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, it was concentrated under reduced pressure. The resultant was dissolved in ethyl acetate (100 mL). The mixture was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure. The resulting residue was purified to silica crystal elut elut elut elut elut elut elut elut Fluoro-2?-benzo[b][l,4]oxazin-7-yl)methacrylate 20e (180 mg, yellow solid), yield: 47%.
MS m/z (ESI) : 404 [M+l]  MS m/z (ESI) : 404 [M+l]
第五步  the fifth step
3-(3-(5-溴 -2-甲基苯基) -6-氟 -3,4-二氫 -2f -苯并 [b][l,4]噁嗪 -7-基)丙 烯酸甲酯  3-(3-(5-Bromo-2-methylphenyl)-6-fluoro-3,4-dihydro-2f-benzo[b][l,4]oxazin-7-yl)acrylic acid Ester
向 3-(3-(5-溴 -2-甲基苯基) -6-氟 -二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙 烯酸甲酯 20e (180mg, 0.45mmol)的甲醇（10mL)溶液中加入硼氫化钠 (34mg， 0.90mmol), 室温反应过夜。 反应结束后， 减压浓縮。 所得物 用乙酸乙酯（lOOmL)溶解后， 依次用水和饱和食盐水洗涤， 加入无水疏 酸钠干燥。 过滤后减压浓縮， 得到标题产物 3-(3-(5-溴 -2-甲基苯基) -6- 氟—3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙烯酸甲酯 20f (150mg， 黄色固 体)， 产率： 83%。  To methyl 3-(3-(5-bromo-2-methylphenyl)-6-fluoro-dihydro-2?-benzo[b][l,4]oxazin-7-yl)acrylate 20e (180 mg, 0.45 mmol) in MeOH (10 mL) EtOAc. After the reaction was completed, it was concentrated under reduced pressure. The resultant was dissolved in ethyl acetate (100 mL), washed sequentially with water and brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the title product 3-(3-(5-bromo-2-methylphenyl)-6-fluoro-3,4-dihydro-2?-benzo[b][l, 4] Oxazin-7-yl)methyl acrylate 20f (150 mg, yellow solid), Yield: 83%.
MS m/z (ESI) : 406 [M+l]  MS m/z (ESI) : 406 [M+l]
第六步  Step 6
3-(6-氟 -3-(2',4,6'-三甲基 -4'-(3-(甲磺酰基)丙氧基)联苯 -3-基) -3 ,4-二 氫 -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基:)丙烯酸甲酯  3-(6-fluoro-3-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3,4-di Hydrogen-2?-benzo[b][1,4]oxazin-7-yl:)methyl acrylate
将 3-(3-(5-溴 -2-甲基苯基) -6-氟 -3,4-二氫 -2 -苯并 [b][l,4]噁嗪 -7-基) 丙烯酸甲酯 20f (150mg， 0.37mmol)， 2-(2,6-二甲基 -4-(3- (甲磺酰基)丙 氧基)苯基) -4,4,5,5-四甲基 -1,3,2-二氧杂戊硼烷 (245mg， 0.66mmol)， 1,1'- 双（二苯基膦）二茂铁二氯化钯 (29mg， 0.04mmol) , 碳酸钾（153mg， l.l lmmol)溶解到 1， 4-二氧六环 (30mL)和水 (8mL)中，氮气保护下， 90。C 搅拌过夜。 冷却到室温后， 加水稀释， 用乙酸乙酯 (40mLx3)萃取， 合 并有机相。 有机相用饱和食盐水洗， 无水疏酸钠干燥， 过滤后减压浓 縮。 用硅胶色谱法以洗脱剂体系（乙酸乙酯 /石油醚 =1/2)纯化所得残余 物， 得到标题产物 3-(6-氟 -3-(2',4,6'-三甲基 -4'-(3- (甲磺酰基)丙氧基)联 苯 -3-基) -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙烯酸甲酯 20g (60mg, 黄 色油状物）， 产率： 55%。 3-(3-(5-Bromo-2-methylphenyl)-6-fluoro-3,4-dihydro-2-benzo[b][l,4]oxazin-7-yl)acrylic acid Methyl ester 20f (150 mg, 0.37 mmol), 2-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)-4,4,5,5-tetramethyl -1,3,2-dioxaborolane (245 mg, 0.66 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (29 mg, 0.04 mmol), potassium carbonate (153 mg) , ll lmmol) dissolved in 1,4-dioxane (30 mL) and water (8 mL), under nitrogen, 90. C Stir overnight. After cooling to room temperature, it was diluted with water and extracted with ethyl acetate (40 mL×3). The organic phase is washed with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Shrink. The obtained residue was purified to silica gel chromatography eluting elut elut elut elut elut elut elut elut -4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3,4-dihydro-2?-benzo[b][l,4]oxazin-7-yl ) Methyl acrylate 20 g (60 mg, yellow oil), Yield: 55%.
MS m/z (ESI) : 568 [M+l]  MS m/z (ESI) : 568 [M+l]
第七步  Seventh step
3-(6-氟 -3-(2',4,6'-三甲基 -4'-(3-(甲磺酰基)丙氧基)联苯 -3-基) -3 ,4-二 氫 -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基:)丙酸甲酯  3-(6-fluoro-3-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3,4-di Hydrogen-2?-benzo[b][1,4]oxazin-7-yl:)methyl propionate
3-(6-氟 -3-(2',4,6'-三甲基 -4'-(3-(甲磺酰基)丙氧基)联苯 -3-基) -3 ,4-二 氫 -2? -苯并 [b][l,4]噁嗪 -7-基）丙烯酸甲酯 20g (lOOmg, 0.18mmol)和 Pd/C(20mg)的甲醇溶液在一个大气压的氫气条件下室温反应过夜。 反 应完全后， 过滤， 减压浓縮。 用硅胶色谱法以洗脱剂体系（乙酸乙酯 / 石油醚 =1/1)纯化所得残余物， 得到标题产物 3-(6-氟 -3-(2',4,6'-三甲基 -4'-(3- (甲磺酰基)丙氧基)联苯 -3-基) -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基) 丙酸甲酯 20h (80mg， 黄色油状物）， 产率： 80%.  3-(6-fluoro-3-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3,4-di Hydrogen-2?-benzo[b][l,4]oxazin-7-yl)methyl acrylate 20g (100 mg, 0.18 mmol) and Pd/C (20 mg) in methanol under one atmosphere of hydrogen The reaction was carried out at room temperature overnight. After the reaction was completed, it was filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography eluting elut elut elut elut elut elut elut elut -4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3,4-dihydro-2?-benzo[b][l,4]oxazin-7-yl Methyl propionate 20h (80mg, yellow oil), Yield: 80%.
MS m/z (ESI) : 570 [M+l]  MS m/z (ESI) : 570 [M+l]
第八步  Eighth step
3-(6-氟 -3-(2',4,6'-三甲基 -4'-(3-(甲磺酰基)丙氧基)联苯 -3-基) -3 ,4-二 氫 -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸  3-(6-fluoro-3-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3,4-di Hydrogen-2?-benzo[b][1,4]oxazin-7-yl)propionic acid
以 3-(6-氟 -3-(2',4,6'-三甲基 -4'-(3- (甲磺酰基)丙氧基)联苯 -3-基) -3,4- 二氫 -2? -苯并 [b][l,4]噁嗪 -7-基）丙酸甲酯 20h (80mg, 0.14mmol)为原 料， 参照实施例 1的搡作方法合成， 用硅胶色谱法以洗脱剂体系（二氯 甲烷 /甲醇 =30/1)纯化所得残余物， 得到标题产物 3-(6-氟 -3-(2',4,6'-三甲 基 -4'-(3- (甲磺酰基)丙氧基)联苯 -3-基) -3,4-二氫 -2 -苯并 [b][l,4]噁嗪 -7- 基)丙酸 20 (20mg， 白色固体)， 产率： 25%。  3-(6-fluoro-3-(2',4,6'-trimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3,4- Dihydro-2?-benzo[b][l,4]oxazin-7-yl)propanoic acid methyl ester 20h (80mg, 0.14mmol) was used as a starting material, which was synthesized by the method of Example 1 and chromatographed on silica gel. The resulting residue was purified with EtOAc (MeOH/MeOH = 30/1) to afford the title product 3-(6-fluoro-3-(2',4,6'-trimethyl-4'- (3-(Methanesulfonyl)propoxy)biphenyl-3-yl)-3,4-dihydro-2-benzo[b][l,4]oxazin-7-yl)propanoic acid 20 ( 20 mg, white solid), Yield: 25%.
MS m/z (ESI) : 556 [M+l]  MS m/z (ESI) : 556 [M+l]
¾ NMR (400 MHz, DMSO-i 6) δ 7.25 (d, J= 7.9 Hz, 1H)， 7.05 (s, 1H)， 6.96 (d, J= 7.5 Hz, 1H)， 6.69 (d, J= 6.5 Hz, 2H), 6.57 (d, J = 7.4 Hz, 1H)， 6.38 (d, J= 11.3 Hz, 1H)， 6.12 (s， 1H)， 4.65 (d, J= 7.0 Hz, 1H)， 4.23 (d, J= 10.3 Hz, 1H)， 4.07 (t, J = 6.2 Hz, 2H), 3.77 (dd, J= 10.5 , 7.5 Hz, 1H)， 3.31-3.21 (m, 2H), 3.03 (s, 3H)， 2.56 (s, 2H), 2.42 (s, 2H), 2.14 (d, J= 5.7 Hz, 2H), 2.04-1.91 (m, 5H)， 1.88 (s 3H)。 3⁄4 NMR (400 MHz, DMSO-i 6 ) δ 7.25 (d, J = 7.9 Hz, 1H), 7.05 (s, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.69 (d, J = 6.5 Hz, 2H), 6.57 (d, J = 7.4 Hz, 1H), 6.38 (d, J= 11.3 Hz, 1H), 6.12 (s, 1H), 4.65 (d, J= 7.0 Hz, 1H), 4.23 ( d, J = 10.3 Hz, 1H), 4.07 (t, J = 6.2 Hz, 2H), 3.77 (dd, J = 10.5, 7.5 Hz, 1H), 3.31-3.21 (m, 2H), 3.03 (s, 3H) ), 2.56 (s, 2H), 2.42 (s, 2H), 2.14 (d, J = 5.7 Hz, 2H), 2.04-1.91 (m, 5H), 1.88 (s 3H).
实施例 21  Example 21
3-(6-氟 -3-(5，-氟 -2，,6，-二甲基 -4，-(3-(甲磺酰基）丙氧基）联苯 -3- -3， 4-二氫 -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸  3-(6-fluoro-3-(5,-fluoro-2,6,-dimethyl-4,-(3-(methylsulfonyl)propoxy)biphenyl-3- -3, 4- Dihydro-2?-benzo[b][1,4]oxazin-7-yl)propionic acid
Figure imgf000063_0001
Figure imgf000063_0001
第一步  First step
甲基 3-(6-氟 -3-(5'-氟 -2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联苯 -3- 基)—3,4-二氫 -2 -苯并 [b][l,4]噁嗪 -7-基)丙酸酯  Methyl 3-(6-fluoro-3-(5'-fluoro-2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)- 3,4-dihydro-2-benzo[b][l,4]oxazin-7-yl)propionate
在干燥圆底烧瓶中将 2-溴 -4-氟 -1,3-二甲基 -5-(3- (甲磺酰基基：)丙氧 基)苯 13b (65mg， 0.19mmol)溶解于 6mL二氧六环和水 （V/V=5： 1)， 抽真空氮气保护， 然后加入 Ι,Γ-双 (；二苯基膦：)二茂铁二氯化钯 (13.8mg,0， 02mmol)， 碳酸钾（52mg， 0.38mmol)和甲基 3-(6-氟 -3-(3-(4,4,5,5-四甲基 -二氧杂硼烷 -2-基)苯基) -3,4-二氫 -2? -苯并 [b][l,4] 噁嗪 -7-基)丙酸酯 19e (84mg， 0.19mmol), 反应体系抽真空氮气保护然 后升温至 90。C搅拌反应直至薄层色谱检测原料反应完全。冷却至室温， 倒入 10mL水， 加乙酸乙酯萃取 (5mLx3)， 合并有机层用饱和氯化钠溶 液 (5mLx3)洗涤， 无水疏酸钠干燥， 过滤， 减压浓縮， 用硅胶填充闪柱 以石油 /乙酸乙酯 =1 : 1纯化所得残余物， 得到标题产物甲基 3-(6-氟 -3-(5，-氟-2，,6，-二甲基 -4，-(3-(甲磺酰基)丙氧基)联苯 -3-基) -3,4-二氫 -2? - 苯并 [b][l,4]噁嗪 -7-基)丙酸酯 21a (60mg， 褐色液体)， 产率： 55%。  2-Bromo-4-fluoro-1,3-dimethyl-5-(3-(methylsulfonyl:)propoxy)benzene 13b (65 mg, 0.19 mmol) was dissolved in 6 mL in a dry round bottom flask Dioxane and water (V/V = 5: 1), vacuumed with nitrogen, then added hydrazine, hydrazine-bis(;diphenylphosphine:)ferrocene palladium dichloride (13.8 mg, 0, 02 mmol ), potassium carbonate (52 mg, 0.38 mmol) and methyl 3-(6-fluoro-3-(3-(4,4,5,5-tetramethyl-dioxaborolan-2-yl)phenyl -3,4-Dihydro-2?-benzo[b][l,4]oxazin-7-yl)propionate 19e (84 mg, 0.19 mmol). . The reaction was stirred until the reaction of the starting material was completed by thin layer chromatography. Cool to room temperature, pour 10 mL of water, add ethyl acetate (5 mL×3), and the combined organic layer is washed with saturated sodium chloride solution (5 mL×3), dried over anhydrous sodium sulfate, filtered, evaporated The residue was purified with EtOAc / EtOAc (EtOAc:EtOAc) 3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3,4-dihydro-2?-benzo[b][l,4]oxazin-7-yl)propionate 21a (60 mg, brown liquid), Yield: 55%.
MS m/z(ESI) : 574 [M+l ]  MS m/z (ESI): 574 [M+l]
第二步  Second step
3-(6-氟 -3-(5，-氟 -2，,6，-二甲基 -4，-(3-(甲磺酰基）丙氧基）联苯 -3- 基) -3， 4-二氫 -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸 以甲基 3-(6-氟 -3-(5，-氟 -2，,6，-二甲基 -4，-(3- (甲磺酰基)丙氧基)联苯 -3-基) -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙酸酯 21a (50mg, 0.09mmol) 为原料，参照实施例 1的搡作方法合成，通过 HPLC制备色谱法纯化（色 谱柱： Gemini-C18， 150x21.2mm, 5μιη, 流动相： 乙腈 /水 (0.1%甲酸)， 梯度： 55-60)， 收集相应组分， 旋转蒸发除去溶剂， 得到标题产物 3-(6- 氟 -3-(5'-氟 -2',6'-二甲基 -4'-(3- (甲磺酰基）丙氧基)联苯 -3-基) -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙酸 21 (18mg， 白色固体)， 产率： 37%。 3-(6-fluoro-3-(5,-fluoro-2,6,-dimethyl-4,-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-3, 4-dihydro-2?-benzo[b][1,4]oxazin-7-yl)propionic acid 3-(6-fluoro-3-(5,-fluoro-2,6,-dimethyl-4,-(3-(methylsulfonyl)propoxy)biphenyl-3-yl) -3,4-Dihydro-2?-benzo[b][l,4]oxazin-7-yl)propionate 21a (50 mg, 0.09 mmol) as a starting material, which was synthesized by the method of Example 1 Purification by HPLC preparative chromatography (column: Gemini-C18, 150x21.2mm, 5μιη, mobile phase: acetonitrile/water (0.1% formic acid), gradient: 55-60), the corresponding fractions were collected, and the solvent was removed by rotary evaporation. The title product 3-(6-fluoro-3-(5'-fluoro-2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl) was obtained. -3,4-Dihydro-2?-benzo[b][l,4]oxazin-7-yl)propanoic acid 21 (18 mg, white solid), yield: 37%.
MS m/z(ESI) : 560 [M+l ]  MS m/z (ESI): 560 [M+l]
¾ NMR (400 MHz, DMSO-i 6) δ 7.45 (t, J= 7.6 Hz, 1H)， 7.38 (d, J= 7.6 Hz, 1H)， 7.15 (s， 1H)， 7.08 (d, J= 7.3 Hz, 1H)， 6.95 (dd, J = 8.6， 4.8 Hz, 1H)， 6.57 (d, J= 7.4 Hz, 1H)， 6.44-6.42 (m， 2H), 4.48-4.46 (m， 1H)， 4.25-4.12 (m, 3H)， 3.95-3.82 (m, 1H)， 3.31-3.23 (m， 2H), 3.05 (s, 3H)， 2.60-2.56(m, 2H), 2.26-2.12 (m, 2H), 2.10-2.00 (m, 2H), 1.97-1.85 (m， 6H)。 3⁄4 NMR (400 MHz, DMSO-i 6 ) δ 7.45 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.15 (s, 1H), 7.08 (d, J = 7.3 Hz, 1H), 6.95 (dd, J = 8.6, 4.8 Hz, 1H), 6.57 (d, J= 7.4 Hz, 1H), 6.44-6.42 (m, 2H), 4.48-4.46 (m, 1H), 4.25 -4.12 (m, 3H), 3.95-3.82 (m, 1H), 3.31-3.23 (m, 2H), 3.05 (s, 3H), 2.60-2.56 (m, 2H), 2.26-2.12 (m, 2H) , 2.10-2.00 (m, 2H), 1.97-1.85 (m, 6H).
实施例 11  Example 11
3-(6-氟 -3-(4，-(3- (异丙磺酰基)丙氧基 )-2，,6，-二甲基联苯 -3-基) - -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸  3-(6-fluoro-3-(4,-(3-(isopropylsulfonyl)propoxy)-2,6,-dimethylbiphenyl-3-yl)- -2?-benzo [b] [1,4]oxazin-7-yl)propionic acid
Figure imgf000064_0001
Figure imgf000064_0001
第一步  First step
甲基 3-(3-(3-溴苯基 )-6-氟 -2? -苯并 [b][l,4]噁嗪 -7-基)丙烯酸酯 将 ( )-甲基 3-(4-氨基 -2-氟 -5-羟基苯基）丙烯酸酯 20a (317mg, 1.5mmol)和碳酸铯 (978mg， 3.0mmol)溶解于 5mL Ν,Ν-二甲基甲酰胺， 然后加入 2-溴 -1-(3-溴苯基）乙基酮 17a (417mg， 1.5mmol)， 反应液在室 温搅拌两小时。 加入 50mL水， 乙酸乙酯萃取 (50mLx3)， 合并有机层， 无水疏酸钠干燥， 过滤， 减压浓縮， 用硅胶填充闪柱以石油 /乙酸乙 酯 =3 : 1 纯化所得残余物， 得到标题产物 甲基 3-(3-(3-溴苯基 )-6- 氟 -2? -苯并 [b][l,4]噁嗪 -7-基)丙烯酸酯 22a (400mg， 黄色固体)， 产率： 68%。 Methyl 3-(3-(3-bromophenyl)-6-fluoro-2?-benzo[b][l,4]oxazin-7-yl)acrylate ( )-Methyl 3-(4-amino-2-fluoro-5-hydroxyphenyl) acrylate 20a (317 mg, 1.5 mmol) and cesium carbonate (978 mg, 3.0 mmol) were dissolved in 5 mL hydrazine, hydrazine-dimethyl The base carboxamide was then added to 2-bromo-1-(3-bromophenyl)ethyl ketone 17a (417 mg, 1.5 mmol). After adding 50 mL of water and ethyl acetate (50 mL×3), the organic layer was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title product methyl 3-(3-(3-bromophenyl)-6-fluoro-2?-benzo[b][l,4]oxazin-7-yl)acrylate 22a (400 mg, yellow solid ), Yield: 68%.
MS m/z(ESI) : 390 [M+l ]  MS m/z (ESI): 390 [M+l]
¾ NMR (400 MHz, CDCb) δ 8.14 (s， 1H)， 7.81 (t, J= 12.5 Hz, 2H), 7.68 (d， J= 7.9 Hz, 1H)， 7.39 (t， J= 7.9 Hz, 1H)， 7.29 (s, 1H)， 7.20 (d, J= 10.5 Hz, 1H)， 7.09 (d, J= 6.5 Hz, 1H)， 6.52 (d, J= 16.1 Hz, 1H)， 5.06 (s, 2H), 3.86 (d, J= 12.9 Hz, 3H)。  3⁄4 NMR (400 MHz, CDCb) δ 8.14 (s, 1H), 7.81 (t, J = 12.5 Hz, 2H), 7.68 (d, J = 7.9 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H ), 7.29 (s, 1H), 7.20 (d, J = 10.5 Hz, 1H), 7.09 (d, J = 6.5 Hz, 1H), 6.52 (d, J = 16.1 Hz, 1H), 5.06 (s, 2H) ), 3.86 (d, J = 12.9 Hz, 3H).
第二步  Second step
甲基 3-(3-(3-溴苯基 )-6-氟 -3,4-二氫 -2f -苯并 [b][l,4]噁嗪 -7-基) 丙烯酸酯  Methyl 3-(3-(3-bromophenyl)-6-fluoro-3,4-dihydro-2f-benzo[b][l,4]oxazin-7-yl) acrylate
将 ( )-甲基 3-(3-(3-溴苯基 )-6-氟 -2? -苯并 [b][l,4]噁嗪 -7-基)丙烯酸 酯 22a(400mg， 1.03mmol)溶解于 10mL甲醇，然后加入硼氫化钠 (78mg， 2.0mmol)， 反应体系在室温搅拌两小时后将反应液浓縮加入乙酸乙酯 (50mLx3), 加入水（100ml), 有机层无水疏酸钠干燥， 过滤， 减压浓縮， 用硅胶填充闪柱以石油醚 /乙酸乙酯 =4 : 1 纯化所得残余物， 得到标题 产物 甲基 3-(3-(3-溴苯基 )-6-氟 -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基) 丙烯酸酯 22b (300mg， 黄色固体)， 产率： 74%。  ( )-Methyl 3-(3-(3-bromophenyl)-6-fluoro-2?-benzo[b][l,4]oxazin-7-yl)acrylate 22a (400 mg, 1.03 Ethyl acetate was dissolved in 10 mL of methanol, then sodium borohydride (78 mg, 2.0 mmol) was added. The reaction mixture was stirred at room temperature for two hours, then the mixture was concentrated to ethyl acetate (50mL×3), water (100ml) The sodium hydride was dried, filtered, and evaporated, evaporated,jjjjjjjjjjjj -6-Fluoro-3,4-dihydro-2?-benzo[b][l,4]oxazin-7-yl) acrylate 22b (300 mg, yellow solid), yield: 74%.
MS m/z(ESI) : 392 [M+l ]  MS m/z (ESI): 392 [M+l]
!HNMR (400 MHz, CDCb) δ 7.72 (d, J= 16.1 Hz, 1H)， 7.56-7.46 (m， 2H), 7.28 (dd, J = 62, 4.5 Hz, 2H), 6.99 (d, J= 6.8 Hz, 1H)， 6.39 (d, J= 11.3 Hz, 1H)， 6.30 (d, J= 16.1 Hz, 1H)， 4.54 (dd, J = 1.9, 3.1 Hz, 1H)， 4.27 (dd, J= 10.9, 3.2 Hz, 1H)， 3.93 (dd, J= 10.9, 7.9 Hz, 1H)， 3.79 (s， 3H)。 ! HNMR (400 MHz, CDCb) δ 7.72 (d, J = 16.1 Hz, 1H), 7.56-7.46 (m, 2H), 7.28 (dd, J = 62, 4.5 Hz, 2H), 6.99 (d, J = 6.8 Hz, 1H), 6.39 (d, J= 11.3 Hz, 1H), 6.30 (d, J= 16.1 Hz, 1H), 4.54 (dd, J = 1.9, 3.1 Hz, 1H), 4.27 (dd, J= 10.9, 3.2 Hz, 1H), 3.93 (dd, J= 10.9, 7.9 Hz, 1H), 3.79 (s, 3H).
第三步  third step
5-(3- (异丙磺酰基)丙氧基 )-2-溴 -1,3-二甲基苯 将 3- (；异丙磺酰基)丙基 4-甲基苯磺酸酯 22c (3.20g, lOmmol, 采 用公知的方法 "专利 U.S. Pat. Appl. Publ. , 20100190747, 29 Jul 2010" 制备而得)溶解于 Ν,Ν-二甲基甲酰胺 (30mL)， 向其中加入 4-溴 -3， 5-二 甲基苯酚 18b (2.41g, 12mmol), 碳酸钾 (2.76g,20mmol)， 反应体系在 60°C搅拌过夜后冷却至室温，乙酸乙酯萃取 (80mLx3)，加入水（lOOmL), 有机层无水疏酸钠干燥， 过滤， 减压浓縮， 用硅胶填充闪柱以石油醚 / 乙酸乙酯 =5 : 1纯化所得残余物， 得到标题产物 5-(3- (异丙磺酰基)丙氧 基) -2-溴 -1， 3-二甲基苯 22d (3.0g,白色固体)， 产率： 86%。 5-(3-(isopropylsulfonyl)propoxy)-2-bromo-1,3-dimethylbenzene 3-(;Isopropylsulfonyl)propyl 4-methylbenzenesulfonate 22c (3.20 g, 10 mmol, prepared by the known method "Patent US Pat. Appl. Publ., 20100190747, 29 Jul 2010" Dissolved in hydrazine, hydrazine-dimethylformamide (30 mL), and added 4-bromo-3, 5-dimethylphenol 18b (2.41 g, 12 mmol), potassium carbonate (2.76 g, 20 mmol), reaction system After stirring overnight at 60 ° C, it was cooled to room temperature, extracted with ethyl acetate (80 mL×3), water (100 mL) was added, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified to give the title compound 5-(3-(isopropylsulfonyl)propoxy)-2-bromo-1,3-dimethylbenzene 22d (3.0 g, white solid ), Yield: 86%.
MS m/z(ESI) : 349 [M+l ]  MS m/z (ESI): 349 [M+l]
第四步  the fourth step
2-(4-(3- (异丙磺酰基）丙氧基 -2,6-二甲基苯基) -4,4,5,5-四甲基 -1,3,2- 二氧杂硼烷  2-(4-(3-(isopropylsulfonyl)propoxy-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa Borane
将 5-(3- (异丙磺酰基）丙氧基 )-2-溴 -1,3-二甲基苯 22d (700mg, 2.0mmol)溶解于甲苯， 向其中加入三乙胺 (607mg， 6.0mmol), 二三苯 基膦二氯化钯（70mg， O.lmmol) , 4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 (512mg,4.0mmol), 抽真空氮气保护， 反应体系在 95°C反应过夜， 反应 完全后反应液冷却至 0°C， 慢慢加入甲醇 (5mL)， 反应液在室温继续搅 拌半小时， 减压浓縮， 用硅胶填充闪柱以石油醚 /乙酸乙酯 =3/1纯化所 得残余物， 得到标题产物 2-(4-(3- (异丙磺酰基）丙氧基 -2,6-二甲基苯 基) -4,4,5,5-四甲基 -1,3,2-二氧杂硼烷 22e (700mg,黄色油状物）， 产率： 80%。  5-(3-(isopropylsulfonyl)propoxy)-2-bromo-1,3-dimethylbenzene 22d (700 mg, 2.0 mmol) was dissolved in toluene, and triethylamine (607 mg, 6.0) was added thereto. Ment), ditriphenylphosphine palladium dichloride (70 mg, 0.1 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborane (512 mg, 4.0 mmol), The reaction was carried out at 95 ° C overnight. After the reaction was completed, the reaction solution was cooled to 0 ° C, and methanol (5 mL) was slowly added. The reaction mixture was stirred at room temperature for half an hour, concentrated under reduced pressure and filled with silica gel. The residue was purified by flash chromatography eluting EtOAc (EtOAc) 4,4,5,5-Tetramethyl-1,3,2-dioxaborane 22e (700 mg, yellow oil), Yield: 80%.
MS m/z(ESI) : 419 [M+23 ]  MS m/z (ESI): 419 [M+23]
第五步  the fifth step
甲基 3-(6-氟 -3-(4'-(3- (异丙磺酰基）丙氧基 )-2',6'-二甲基联苯 -3-基) -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙烯酸酯  Methyl 3-(6-fluoro-3-(4'-(3-(isopropylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-3,4- Dihydro-2?-benzo[b][l,4]oxazin-7-yl)acrylate
在干燥圆底烧瓶中将 甲基 3-(3-(3-溴苯基 )-6-氟 -3,4-二氫 -2? - 苯并 [b][l,4]噁嗪 -7-基)丙烯酸酯 22b (150mg， 0.38mmol)溶解于 6mL二 氧六环和水 （V/V=5 : 1)， 抽真空氮气保护， 然后加入 Ι,Γ-双 (二苯基膦) 二茂铁二氯化钯 (27.8mg， 0.04mmol) , 碳酸钾（105mg， 0.76mmol)和 2-(4-(3- (异丙磺酰基)丙氧基 -2， 6-二甲基苯基) -4， 4， 5， 5-四甲基 -1， 3， 2-二氧杂硼烷 22e (500mg， 1.26mmol), 反应体系抽真空氮气保护然后 升温至 90。C搅拌反应直至薄层色谱检测原料反应完全。 冷却至室温， 倒入 20mL 水， 加乙酸乙酯萃取 (10mLx3)， 合并有机层用饱和氯化钠 溶液 (5mLx3)洗涤， 无水疏酸钠干燥， 过滤， 减压浓縮， 用硅胶填充闪 柱以石油醚 /乙酸乙酯 =3/1 纯化所得残余物， 得到标题产物 甲基 3-(6-氟 -3-(4'-(3- (异丙磺酰基)丙氧基 )-2',6'-二甲基联苯 -3-基) -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙烯酸酯 22f (160mg， 白色固体)， 产率: 73%。 Methyl 3-(3-(3-bromophenyl)-6-fluoro-3,4-dihydro-2?-benzo[b][l,4]oxazin-7 in a dry round bottom flask -Base) acrylate 22b (150 mg, 0.38 mmol) was dissolved in 6 mL of dioxane and water (V/V = 5:1), vacuum-protected with nitrogen, then hydrazine, bis-bis(diphenylphosphine) Ferrocene palladium dichloride (27.8 mg, 0.04 mmol), potassium carbonate (105 mg, 0.76 mmol) and 2-(4-(3-(isopropylsulfonyl)propoxy-2,6-dimethylphenyl) -4, 4, 5, 5-tetramethyl-1,3,2-dioxaborane 22e (500 mg, 1.26 mmol), the reaction system was evacuated under nitrogen and then Warm up to 90. The reaction was stirred until the reaction of the starting material was completed by thin layer chromatography. The mixture was cooled to room temperature, poured into water (20 mL), EtOAc (EtOAc) (EtOAc (EtOAc) The residue was purified with EtOAc / EtOAc (EtOAc =EtOAc) ',6'-Dimethylbiphenyl-3-yl)-3,4-dihydro-2?-benzo[b][l,4]oxazin-7-yl)acrylate 22f (160 mg, white Solid), Yield: 73%.
MS m/z(ESI) : 582 [M+l ]  MS m/z (ESI): 582 [M+l]
第六步  Step 6
甲基 3-(6-氟 -3-(4，-(3- (异丙磺酰基）丙氧基 )-2，,6'-二甲基联苯 -3- 基)—3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙酸酯  Methyl 3-(6-fluoro-3-(4,-(3-(isopropylsulfonyl)propoxy)-2,6'-dimethylbiphenyl-3-yl)-3,4- Dihydro-2?-benzo[b][l,4]oxazin-7-yl)propionate
将 ( -甲基 3-(6-氟 -3-(4'-(3- (异丙磺酰基）丙氧基 )-2',6'-二甲基联 苯 -3-基) -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基）丙烯酸酯 22f (160mg, 0.28mmol)溶解于甲醇 (5mL)， 加入 Pd/C(200mg)， 反应体系抽真空置换 氫气 (1个大气压)， 薄层色谱检测原料反应完全， 过滤得到标题产物甲 基 3-(6-氟 -3-(4'-(3- (异丙磺酰基)丙氧基 )-2',6'-二甲基联苯 -3-基) -3,4-二 氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙酸酯 22g (100mg,淡黄色油状物），产率： 63%。  (-Methyl 3-(6-fluoro-3-(4'-(3-(isopropylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-3 , 4-dihydro-2?-benzo[b][l,4]oxazin-7-yl)acrylate 22f (160 mg, 0.28 mmol) was dissolved in methanol (5 mL), and then Pd/C (200 mg). The reaction system was vacuum-displaced to replace hydrogen (1 atm), and the reaction of the starting material was confirmed by thin layer chromatography to give the title product methyl 3-(6-fluoro-3-(4'-(3-(isopropylsulfonyl)). Oxy)-2',6'-dimethylbiphenyl-3-yl)-3,4-dihydro-2?-benzo[b][l,4]oxazin-7-yl)propionic acid Ester 22g (100 mg, light yellow oil), yield: 63%.
MS m/z(ESI) : 584 [M+l ]  MS m/z (ESI): 584 [M+l]
第七步  Seventh step
3-(6-氟 -3-(4，-(3- (异丙磺酰基）丙氧基 )-2，,6，-二甲基联苯 -3-基) -3,4- 二氫 -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸  3-(6-fluoro-3-(4,-(3-(isopropylsulfonyl)propoxy)-2,6,-dimethylbiphenyl-3-yl)-3,4-dihydro -2? -Benzo[b][1,4]oxazin-7-yl)propionic acid
以甲基 3-(6-氟 -3-(4，-(3- (异丙磺酰基)丙氧基 )-2，,6，-二甲基联苯 -3- 基)—3， 4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙酸酯 22g (100mg， 0.17mmol) 为原料， 参照实施例 1的搡作方法合成， 用硅胶填充闪柱以二氯甲烷 / 甲醇 =10/1纯化所得残余物得到标题产物 3-(6-氟 -3-(4，-(3- (异丙磺酰基) 丙氧基 )-2',6'-二甲基联苯 -3-基) -3,4-二氫 -2 -苯并 [b][l， 4]噁嗪 -7-基) 丙酸 22 (30mg， 白色固体)， 产率： 32%。  Methyl 3-(6-fluoro-3-(4,-(3-(isopropylsulfonyl)propoxy)-2,6,-dimethylbiphenyl-3-yl)-3, 4 -Dihydro-2?-benzo[b][l,4]oxazin-7-yl)propionate 22 g (100 mg, 0.17 mmol) as a starting material, which was synthesized according to the method of Example 1 and filled with silica gel. The residue obtained was purified by methylene chloride / EtOAc (EtOAc/EtOAc) '-Dimethylbiphenyl-3-yl)-3,4-dihydro-2-benzo[b][l,4]oxazin-7-yl)propanoic acid 22 (30 mg, white solid), Rate: 32%.
MS m/z(ESI) : 570 [M+l ]  MS m/z (ESI): 570 [M+l]
¾ NMR (400 MHz, DMSO-i 6) δ 7.44 (t, J= 7.6 Hz, 1H)， 7.36 (d, J= 7.9 Hz, 1H)， 7.13 (s， 1H)， 7.06 (d, J= 7.5 Hz, 1H)， 6.71 (d， J = 2.0 Hz, 2H), 6.57 (d, J= 7.3 Hz, 1H)， 6.40 (d, J= 11.3 Hz, 1H)， 6.32 (s， 1H)， 4.48 (d， J= 5.8 Hz, 1H)， 4.20 (d, J= 9.2 Hz, 1H)， 4.11 (t， J= 6.2 Hz, 2H), 3.88 (dd, J= 10.6, 7.2 Hz, 1H)， 3.33-3.31 (m， 1H)， 3.23 (dd, J= 8.9， 6.6 Hz, 2H), 2.56 (d, J= 7.6 Hz, 2H), 2.19-2.07 (m, 2H), 2.00 (d, J= 6.5 Hz, 2H), 1.96 (s， 3H)， 1.91 (s， 3H)， 1.27 (d, J= 6.8 Hz, 6H)。 3⁄4 NMR (400 MHz, DMSO-i 6 ) δ 7.44 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.13 (s, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.71 (d, J = 2.0 Hz, 2H), 6.57 (d, J= 7.3 Hz, 1H), 6.40 (d, J= 11.3 Hz, 1H), 6.32 (s, 1H), 4.48 (d, J= 5.8 Hz, 1H), 4.20 (d, J = 9.2 Hz, 1H), 4.11 (t, J = 6.2 Hz, 2H), 3.88 (dd, J = 10.6, 7.2 Hz, 1H), 3.33-3.31 (m, 1H), 3.23 (dd, J= 8.9, 6.6 Hz, 2H), 2.56 (d, J= 7.6 Hz, 2H), 2.19-2.07 (m, 2H), 2.00 (d, J= 6.5 Hz, 2H), 1.96 (s, 3H), 1.91 (s, 3H), 1.27 (d, J = 6.8 Hz, 6H).
实施例 23  Example 23
3-(3-(4，-(3- (环丙磺酰基）丙氧基 )-2，,6，-二甲基联苯 -3-基) -6-氟 -3,4- 二氫 -2? -苯并 [b] [ 1 , -7-基)丙酸  3-(3-(4,-(3-(cyclopropanesulfonyl)propoxy)-2,6,-dimethylbiphenyl-3-yl)-6-fluoro-3,4-dihydro -2? -Benzo[b][1,-7-yl)propionic acid
Figure imgf000068_0001
Figure imgf000068_0001
第一步  First step
2-溴 -5-(3-溴丙氧基) -1,3-二甲基苯  2-bromo-5-(3-bromopropoxy)-1,3-dimethylbenzene
将 4-溴 -3,5-二甲基苯酚 18b(6g， 30mmol)溶解于乙醇 (60mL)， 向其 中加入碳酸钾 (4.14g， 30mmol)， 1， 3-二溴丙烷 23a (12g， 60mmol), 反应体系在 80°C下搅拌四小时， 反应完全后减压蒸去溶剂， 加水 lOOmL, 乙酸乙酯萃取 (100mLx3)， 有机层无水疏酸钠干燥， 过滤， 减 压浓縮得到标题产物 2-溴 -5-(3-溴丙氧基) -1,3-二甲基苯 23b (8.0g,无色 油状物）， 产率： 83%。  4-Bromo-3,5-dimethylphenol 18b (6 g, 30 mmol) was dissolved in ethanol (60 mL), and potassium carbonate (4.14 g, 30 mmol), 1, 3-dibromopropane 23a (12 g, 60 mmol) was added thereto. The reaction system was stirred at 80 ° C for four hours. After the reaction was completed, the solvent was evaporated under reduced pressure. Water was evaporated, ethyl acetate (100 mL), ethyl acetate (100mL×3), dried over anhydrous sodium sulfate, filtered, Product 2-Bromo-5-(3-bromopropoxy)-1,3-dimethylbenzene 23b (8.0 g, mp.
¾ NMR (300 MHz, CDCb) δ 6.66 (s， 2H), 4.06 (t， J = 5.8 Hz, 2H), 3.58 (dt, J= 8.6， 6.3 Hz, 2H), 2.36 (s， 6H)， 2.36-2.26 (m, 2H)0 第二步 3⁄4 NMR (300 MHz, CDCb) δ 6.66 (s, 2H), 4.06 (t, J = 5.8 Hz, 2H), 3.58 (dt, J = 8.6, 6.3 Hz, 2H), 2.36 (s, 6H), 2.36 -2.26 (m, 2H) 0 second step
3- (3-(4-溴 -3,5-二甲基苯氧基)丙疏基 )1-丙醇 将 KOH(112mg， 2mmol)溶解于乙醇 (20mL)，向其中加入 2-溴 -5-(3- 溴丙氧基) -1,3-二甲基苯 23b (963mg， 2mmol), 反应体系在室温搅拌半 小时， 然后向其中慢慢滴加 3-巯基 -1-丙醇 23c (276mg， 3mmol)， 反应 体系室温搅拌过夜， 反应完全后过滤， 减压浓縮， 用硅胶填充闪柱以 石油醚 /乙酸乙酯 =5 : 1纯化所得残余物， 得到标题产物 3-(3-(4-溴 -3,5- 二甲基苯氧基)丙疏基 )1-丙醇 23d(520mg， 无色油状物）， 产率： 52%。 3-(3-(4-Bromo-3,5-dimethylphenoxy)propanyl) 1-propanol KOH (112 mg, 2 mmol) was dissolved in ethanol (20 mL), and 2-bromo-5-(3-bromopropyloxy)-1,3-dimethylbenzene 23b (963 mg, 2 mmol) was added thereto. After stirring at room temperature for half an hour, 3-mercapto-1-propanol 23c (276 mg, 3 mmol) was added dropwise thereto, and the reaction mixture was stirred at room temperature overnight, and then filtered and evaporated. The obtained residue was purified by ethyl ether / ethyl acetate = EtOAc (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Colorless oil), Yield: 52%.
MS m/z(ESI) : 333 [M+l ]  MS m/z (ESI): 333 [M+l]
1HNMR (300 MHz, CDCb) δ 6.63 (s， 2H), 4.00 (t， J= 5.9 Hz, 2H), 3.74 (t， J= 5.5 Hz, 2H), 2.67 (dt, J= 14.7， 5.8 Hz, 4H)， 2.09—1.98 (m， 2H), 1.92-1.79 (m， 2H)。 1 H NMR (300 MHz, CDCb) δ 6.63 (s, 2H), 4.00 (t, J = 5.9 Hz, 2H), 3.74 (t, J = 5.5 Hz, 2H), 2.67 (dt, J = 14.7, 5.8 Hz , 4H), 2.09—1.98 (m, 2H), 1.92-1.79 (m, 2H).
第三步  third step
(3-(4-溴 -3,5-二甲基苯氧基)丙基) (3-溴丙基)疏烷  (3-(4-bromo-3,5-dimethylphenoxy)propyl)(3-bromopropyl)hydroalkane
将 3-(3-(4-溴 -3,5-二甲基苯氧基)丙疏基 )1-丙醇 23d (335mg， lmmol) 溶解于二氯甲烷 (8mL)， 向其中加入三苯基膦 (393mg， 1.5mmol)， 四溴 化碳 (497mg， 1.5mmol)， 反应体系在 0°C反应两小时， 减压浓縮， 用硅 胶填充闪柱以石油 /乙酸乙酯 =10 : 1纯化所得残余物， 得到标题产物 (3-(4-溴 -3,5-二甲基苯氧基)丙基) (3-溴丙基)疏烷 23e (360mg， 无色油状 物)， 产率： 91%。  3-(3-(4-Bromo-3,5-dimethylphenoxy)propanyl) 1-propanol 23d (335 mg, 1 mmol) was dissolved in dichloromethane (8 mL), and triphenyl was added thereto. Base phosphine (393 mg, 1.5 mmol), carbon tetrabromide (497 mg, 1.5 mmol), the reaction system was reacted at 0 ° C for two hours, concentrated under reduced pressure, and the flash column was packed with silica gel to petroleum / ethyl acetate = 10 : 1 The obtained residue was purified to give the title product (3-(4-bromo-3,5-dimethylphenoxy)propyl)(3-bromopropyl)hydromethane 23e (360 mg, colorless oil). Rate: 91%.
1HNMR (300 MHz, CDCb) δ 6.65 (s， 2Η), 4.01 (t， J= 6.0 Hz, 2H), 3.52 (dd, J= 8.0, 4.8 Hz, 2H), 2.69 (q, J= 6.8 Hz, 6H)， 2.37 (s， 6H)， 2.13 (dd, J= 13.3 , 6.6 Hz, 2H), 2.09-1.98 (m, 2H)。 1 H NMR (300 MHz, CDCb) δ 6.65 (s, 2 Η), 4.01 (t, J = 6.0 Hz, 2H), 3.52 (dd, J = 8.0, 4.8 Hz, 2H), 2.69 (q, J = 6.8 Hz , 6H), 2.37 (s, 6H), 2.13 (dd, J = 13.3, 6.6 Hz, 2H), 2.09-1.98 (m, 2H).
第四步  the fourth step
2-溴 -5-(3-(3-溴丙磺酰基)丙氧基 )-1,3-二甲基苯  2-bromo-5-(3-(3-bromopropylsulfonyl)propoxy)-1,3-dimethylbenzene
将 (3-(4-溴 -3， 5-二甲基苯氧基)丙基) (3-溴丙基)疏烷 23e (198mg, 0.5mmol)在 0°C下溶解于二氯甲烷 (8mL)， 向其中分步加入间氯过氧苯 甲酸 (405mg， 1.5mmol), 反应体系在 0°C下继续搅拌一小时， 加入饱和 亚疏酸钠溶液 (20mL)，加入乙酸乙酯 (50ml)，碳酸钠水溶液洗涤 (20ml)， 有机层用无水疏酸钠干燥， 过滤， 减压浓縮， 用硅胶填充闪柱以石油 /乙酸乙酯 =20 : 1 纯化所得残余物， 得到标题产物 2-溴 -5-(3-(3-溴丙 磺酰基)丙氧基 )-1， 3-二甲基苯 23f (180mg， 白色固体)， 产率： 85%。  (3-(4-Bromo-3, 5-dimethylphenoxy)propyl)(3-bromopropyl)hydroalkane 23e (198 mg, 0.5 mmol) was dissolved in dichloromethane at 0 ° C ( 8 mL), m-chloroperoxybenzoic acid (405 mg, 1.5 mmol) was added thereto in portions, and the reaction system was further stirred at 0 ° C for one hour, and saturated sodium sulfoxide solution (20 mL) was added thereto, and ethyl acetate (50 ml) was added thereto. The organic layer was washed with anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The residue was purified eluting with EtOAc EtOAc 2-Bromo-5-(3-(3-bromopropylsulfonyl)propoxy)-1,3-dimethylbenzene 23f (180 mg, white solid), yield: 85%.
MS m/z(ESI) : 427 [M+l ] 1HNMR (300 MHz, CDC13) δ 6.64 (s， 2H), 4.07 (t， J= 5.7 Hz, 2H), 3.57 (t， J= 6.2 Hz, 2H), 3.21 (dd, J = 15.1 , 7.4 Hz, 4H)， 2.50-2.42 (m, 2H), 2.39 (s， 6H)， 2.37-2.29 (m, 2H)。 MS m/z (ESI): 427 [M+l] 1 H NMR (300 MHz, CDC1 3 ) δ 6.64 (s, 2H), 4.07 (t, J = 5.7 Hz, 2H), 3.57 (t, J = 6.2 Hz, 2H), 3.21 (dd, J = 15.1, 7.4 Hz, 4H), 2.50-2.42 (m, 2H), 2.39 (s, 6H), 2.37-2.29 (m, 2H).
第五步  the fifth step
2-溴 -5-(3- (环丙磺酰基)丙氧基 )-1,3-二甲基苯  2-bromo-5-(3-(cyclopropanesulfonyl)propoxy)-1,3-dimethylbenzene
将 2-溴 -5-(3-(3-溴丙磺酰基)丙氧基 )-1,3-二甲基苯 23f (171mg， 0.4mmol)溶解于四氫呋喃 (4mL)，反应体系降至 0 °C，加入氫化钠 (48mg， 1.2mmol), 继续在 0°C搅拌二十分钟， 缓慢升温至室温搅拌过夜， 反应 完全后加入乙酸乙酯 (50mL)， 水洗 (20ml)， 有机层无水疏酸钠干燥， 过 滤， 减压浓縮， 用硅胶填充闪柱以石油 /乙酸乙酯 =2 : 1 纯化所得残 余物， 得到标题产物 2-溴 -5-(3- (环丙磺酰基)丙氧基 )-1,3-二甲基苯 23g (83mg， 白色固体)， 产率： 60%。  2-Bromo-5-(3-(3-bromopropylsulfonyl)propoxy)-1,3-dimethylbenzene 23f (171 mg, 0.4 mmol) was dissolved in tetrahydrofuran (4 mL). Add hydride (48 mg, 1.2 mmol), and continue to stir at 0 ° C for twenty minutes, slowly warm to room temperature and stir overnight. After completion, add ethyl acetate (50 mL), water (20 ml) The organic layer was dried (MgSO4), EtOAcjjjjjjj Propyl)-1,3-dimethylbenzene 23 g (83 mg, white solid), Yield: 60%.
MS m/z(ESI) : 347 [M+l ]  MS m/z (ESI): 347 [M+l]
!HNMR (300 MHz, CDCb) δ 6.52 (s， 2H), 4.10-3.97 (m, 2H), 3.34-3.17 (m， 2H), 2.50-2.27 (m, 8H)， 1.07 (dt, J= 7.8， 5.0 Hz, 1H)， 0.92-0.81 (m， 4H)。 ! HNMR (300 MHz, CDCb) δ 6.52 (s, 2H), 4.10-3.97 (m, 2H), 3.34-3.17 (m, 2H), 2.50-2.27 (m, 8H), 1.07 (dt, J = 7.8 , 5.0 Hz, 1H), 0.92-0.81 (m, 4H).
第六步  Step 6
3- (3-(4，-(3- (环丙砜基）丙氧基 )-2，,6，-二甲基联苯 -3-基) -6-氟 -3,4-二 氫 -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸  3-(3-(4,-(3-(cyclopropylsulfonyl)propoxy)-2,6,-dimethylbiphenyl-3-yl)-6-fluoro-3,4-dihydro -2? -Benzo[b][1,4]oxazin-7-yl)propionic acid
在干燥圆底烧瓶中将甲基 3-(6-氟 -3-(3-(4,4,5,5-四甲基 -1,3,2-二氧 杂硼烷 -2-基）苯基) -3 ,4-二氫 -2H-苯并 [b] [ 1 ,4]噁嗪 -7-基）丙酸酯 19e (88mg， 0.2mmol)溶解于 6mL二氧六环和水 （V/V=5 : 1)， 抽真空氮气 保护， 然后加入 Ι,Γ-双 (二苯基膦)二茂铁二氯化钯 （15mg， 0.02mmol), 碳酸钾 (55.2mg， 0.4mmol)和 2-溴 -5-(3- (环丙磺酰基)丙氧基 )-1 ,3-二甲基 苯 23g (60.4mg,0.2mmol), 反应体系抽真空氮气保护然后升温至 90°C 搅拌反应直至薄层色谱检测原料反应完全。 冷却至室温， 倒入 10mL 水， 加乙酸乙酯萃取 (5mL><3)， 合并有机层用饱和氯化钠溶液 (5mL><3) 洗涤， 无水疏酸钠干燥， 过滤， 减压浓縮， 用 HPLC方法进行分离 (；分 离条件： Gemini-C18 150x21.2mm， 5 μιη, 乙腈 /水 =1/3)， 收集相应组 分， 旋转蒸发出去溶剂， 得到标题产物甲基 3-(3-(4'-(3- (环丙磺酰基) 丙氧基 )-2'6'-二甲基联苯 -3-基) -6-氟 -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7- 基)丙酸 23 (18mg， 白色固体)， 产率： 16%。 Methyl 3-(6-fluoro-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) in a dry round bottom flask Phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)propionate 19e (88 mg, 0.2 mmol) was dissolved in 6 mL of dioxane and water ( V/V=5 : 1), vacuum nitrogen protection, then Ι, Γ-bis(diphenylphosphino)ferrocene palladium dichloride (15 mg, 0.02 mmol), potassium carbonate (55.2 mg, 0.4 mmol) And 2-bromo-5-(3-(cyclopropanesulfonyl)propoxy)-1,3-dimethylbenzene 23g (60.4mg, 0.2mmol), the reaction system was vacuum-protected with nitrogen and then warmed to 90 ° C The reaction was stirred until the reaction of the starting material was complete by thin layer chromatography. After cooling to room temperature, pour 10 mL of water, extract with ethyl acetate (5 mL><3), and combine the organic layer with saturated sodium chloride solution (5 mL><3), dry with anhydrous sodium sulfate, filter, decompress Separation, separation by HPLC method; separation conditions: Gemini-C18 150×21.2 mm, 5 μιη, acetonitrile/water = 1/3), the corresponding fractions were collected, and the solvent was evaporated to give the title product methyl 3-(3 -(4'-(3-(cyclopropanesulfonyl)propoxy)-2'6'-dimethylbiphenyl-3-yl)-6-fluoro-3,4-dihydro-2?-benzene And [b][l,4]oxazin-7- Propionate 23 (18 mg, white solid), Yield: 16%.
MS m/z(ESI) : 568 [M+l ]  MS m/z (ESI): 568 [M+l]
¾ NMR (400 MHz, CD3OD) δ 7.48-7.42 (m, 1H)， 7.40 (d, J= 7.7 Hz, 1H)， 7.16 (s， 1H)， 7.07 (d, J= 7.4 Hz, 1H)， 6.71 (s， 2H), 6.61 (d， J= 7.3 Hz, 1H)， 6.43 (d， J= 11.2 Hz, 1H)， 4.49 (d， J= 4.7 Hz, 1H)， 4.25 (dd, J= 10.5, 3.0 Hz, 1H)， 4.15 (t, J= 5.7 Hz, 2H), 3.94 (dd, J= 10.5, 7.6 Hz, 1H)， 3.39-3.36 (m， 2H), 2.85-2.73 (m, 2H), 2.71-2.63 (m, 1H)， 2.56-2.45 (m, 2H), 2.33 (dd, J= 15.6, 6.0 Hz, 2H), 2.01 (s， 3H)， 1.96 (s， 3H)， 1.23-1.02 (m, 4H)。 3⁄4 NMR (400 MHz, CD 3 OD) δ 7.48-7.42 (m, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.16 (s, 1H), 7.07 (d, J = 7.4 Hz, 1H) , 6.71 (s, 2H), 6.61 (d, J= 7.3 Hz, 1H), 6.43 (d, J= 11.2 Hz, 1H), 4.49 (d, J= 4.7 Hz, 1H), 4.25 (dd, J= 10.5, 3.0 Hz, 1H), 4.15 (t, J= 5.7 Hz, 2H), 3.94 (dd, J= 10.5, 7.6 Hz, 1H), 3.39-3.36 (m, 2H), 2.85-2.73 (m, 2H ), 2.71-2.63 (m, 1H), 2.56-2.45 (m, 2H), 2.33 (dd, J= 15.6, 6.0 Hz, 2H), 2.01 (s, 3H), 1.96 (s, 3H), 1.23- 1.02 (m, 4H).
实施例 24  Example 24
3-(3-(4'-(3- (乙基磺酰基)丙氧基 )-2',6'-二甲基联苯基 -3-基) -6-氟- -2H-苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸  3-(3-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-6-fluoro--2H-benzo [b] [1,4]oxazin-7-yl)propionic acid
Figure imgf000071_0001
Figure imgf000071_0001
第一步  First step
3-(6-氟 -3-(3-(4,4,5,5-四甲基 -1,3,2-二氧硼戊环 -2-基)苯基) -3,4-二氫 -2H-苯并 [b] [1,4]噁嗪 -7-基)丙烯酸甲酯  3-(6-fluoro-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4-di Methyl-2H-benzo[b][1,4]oxazine-7-yl)acrylate
以 ( )-甲基 3-(3-(3-溴苯基 )-6-氟 -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7- 基)丙烯酸酯 22b为原料，应用 22e的合成方法得到 3-(6-氟 -3-(3-(4,4,5,5- 四甲基 -1,3,2-二氧硼戊环 -2-基)苯基) -3,4-二氫 -2H-苯并 [b][l,4]噁嗪 -7- 基)丙烯酸甲酯 24a。  ( )-Methyl 3-(3-(3-bromophenyl)-6-fluoro-3,4-dihydro-2?-benzo[b][l,4]oxazin-7-yl) Acrylate 22b was used as a raw material, and the synthesis method of 22e was used to obtain 3-(6-fluoro-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2). -yl)phenyl)-3,4-dihydro-2H-benzo[b][l,4]oxazin-7-yl)methyl acrylate 24a.
MS m/z (ESI) : 440 [M+l] 第二步 MS m/z (ESI) : 440 [M+l] Second step
3-(3-(4'-(3- (乙基磺酰基)丙氧基 )-2',6'-二甲基联苯基 -3-基) -6-氟 -3,4- 二氫 -2H-苯并 [b] [ 1 ,4]噁嗪 -7-基)丙烯酸甲酯  3-(3-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-6-fluoro-3,4-di Methyl-2H-benzo[b][1,4]oxazin-7-yl)acrylate
将 3-(6-氟 -3-(3-(4,4,5,5-四甲基 -1,3,2-二氧硼戊环 -2-基)苯基) -3,4-二 氫 -2H-苯并 [b][l,4]噁嗪 -7-基)丙烯酸甲酯 24a (200mg, 0.46mmol)， 2- 溴 -5-(3- (乙基磺酰基)丙氧基 )-1,3-二甲基苯 24b (168mg， 0.51mmol， 参 照实施例 13中 13b的合成法合成）， Ι,Γ-双 (二苯基膦)二茂铁二氯化钯 (26mg, 0.03mmol)和碳酸钾 （127mg， 0.92mmol)加入到 1,4-二氧六环（10 mL)和水 (2mL)的混合溶液中，在氮气保护的密闭体系中，升温至 90°C， 持续搅拌， 通过 TLC监测至原料消失。 将反应液冷却到室温， 加入水 (20mL), 用乙酸乙酯萃取 （30mLx3)， 萃取液用无水疏酸钠干燥,过滤, 减压浓縮滤液，用硅胶柱色谱法 (石油 /乙酸乙酯 =1/1)纯化所得残余物, 得到标题产物 3-(3-(4'-(3-(乙基磺酰基）丙氧基 )-2',6'-二甲基联苯基 -3- 基) -6-氟 -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙烯酸甲酯 24c (208mg, 黄色固体)， 产率： 80%。  3-(6-Fluoro-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4- Methyl dihydro-2H-benzo[b][l,4]oxazin-7-yl)acrylate 24a (200 mg, 0.46 mmol), 2-bromo-5-(3-(ethylsulfonyl)propoxy ))-1,3-dimethylbenzene 24b (168 mg, 0.51 mmol, synthesized according to the synthesis of 13b in Example 13), hydrazine, hydrazine-bis(diphenylphosphino)ferrocene palladium dichloride (26 mg) , 0.03 mmol) and potassium carbonate (127 mg, 0.92 mmol) were added to a mixed solution of 1,4-dioxane (10 mL) and water (2 mL), and heated to 90 ° C in a nitrogen-protected closed system. , Stirring, monitoring by TLC until the disappearance of the starting material. The reaction solution was cooled to room temperature, water (20 mL) was evaporated, evaporated, evaporated, The obtained residue was purified to give the title product 3-(3-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl- 3-yl)-6-fluoro-3,4-dihydro-2?-benzo[b][l,4]oxazin-7-yl)methyl acrylate 24c (208 mg, yellow solid), yield: 80%.
MS m/z (ESI) : 568 [M+l]  MS m/z (ESI) : 568 [M+l]
第三步  third step
3-(3-(4'-(3- (乙基磺酰基)丙氧基 )-2',6'-二甲基联苯基 -3-基) -6-氟 -3,4- 二氫 -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基:)丙酸甲酯  3-(3-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-6-fluoro-3,4-di Hydrogen-2?-benzo[b][1,4]oxazin-7-yl:)methyl propionate
将 3-(3-(4'-(3-(乙基磺酰基)丙氧基 )-2',6'-二甲基联苯基 -3-基) -6-氟 —3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙烯酸甲酯 24c (208mg, 0.37mmol) 和钯碳 (25mg)加入到甲醇（15mL)中， 通入氫气（latm)， 在室温条件下持 续搅拌， 通过 TLC监测至原料消失。 将反应液过滤， 浓縮滤液得到标 题产物 3-(3-(4'-(3- (乙基磺酰基）丙氧基 )-2',6'-二甲基联苯基 -3-基) -6-氟 —3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙酸甲酯 24d (168mg， 黄色油）， 产率： 80% o  3-(3-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-6-fluoro-3,4- Dihydro-2?-benzo[b][l,4]oxazin-7-yl)methyl acrylate 24c (208 mg, 0.37 mmol) and palladium on carbon (25 mg) were added to methanol (15 mL). Gas (latm), stirring was continued at room temperature, and the disappearance of the starting material was monitored by TLC. The reaction solution was filtered, and the filtrate was evaporated to ethylamine]]]]]]] -6-fluoro-3,4-dihydro-2?-benzo[b][l,4]oxazin-7-yl)propanoic acid methyl ester 24d (168 mg, yellow oil), Yield: 80% o
MS m/z (ESI) : 570 [M+l]  MS m/z (ESI) : 570 [M+l]
第四步  the fourth step
3-(3-(4'-(3- (乙基磺酰基)丙氧基 )-2',6'-二甲基联苯基 -3-基) -6-氟 -3,4- 二氫 -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸  3-(3-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-6-fluoro-3,4-di Hydrogen-2?-benzo[b][1,4]oxazin-7-yl)propionic acid
以 3-(3-(4'-(3-(乙基磺酰基）丙氧基 )-2',6'-二甲基联苯基 -3-基) -6-氟 —3,4-二氫 -2H-苯并 [b][l,4]噁嗪 -7-基)丙酸甲酯 24d (168mg， 0.3mmol)为 原料， 参照实施例 1的搡作方法合成， 通过 HPLC制备色谱法纯化（色 谱柱： Gemini-C18， 150x21.2mm, 5μιη, 流动相： 乙腈 /水 (0.1%甲酸)， 梯度： 55-60)， 纯化所得残余物,得到标题产物 3-(3-(4'-(3- (乙基磺酰基） 丙氧基 )-2',6'-d 二甲基联苯基 -3-基) -6-氟 -3,4-二氫 -2f -苯并 [b][l,4]噁嗪 -7-基)丙酸 24(30mg,白色固体)， 产率： 18%。 3-(3-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)-6-fluoro -3,4-Dihydro-2H-benzo[b][l,4]oxazine-7-yl)propanoic acid methyl ester 24d (168 mg, 0.3 mmol) as a starting material, which was synthesized according to the method of Example 1 Purification by HPLC preparative chromatography (chromatography: Gemini-C18, 150×21.2 mm, 5 μιη, mobile phase: acetonitrile/water (0.1% formic acid), gradient: 55-60). (3-(4'-(3-(ethylsulfonyl)propoxy)-2',6'-d dimethylbiphenyl-3-yl)-6-fluoro-3,4-dihydro -2f -Benzo[b][l,4]oxazin-7-yl)propanoic acid 24 (30 mg, white solid). Yield: 18%.
MS m/z (ESI): 556 [M+l]  MS m/z (ESI): 556 [M+l]
¾NMR (400 MHz, MeOD) δ 7.45 (t, J=7.6Hz, 1H)， 7.40 (d, J = 7.6 Hz, 1H)， 7.16 (s， 1H)， 7.07 (d, J=7.3 Hz, 1H)， 6.70 (d, J =23 Hz, 2H), 6.61 (d, J=7.2 Hz, 1H)， 6.44 (d, J= 11.2 Hz, 1H)， 4.50 (dd, J=7.7， 2.6 Hz, 1H)， 4.26 (dd, J= 10.6, 2.9 Hz, 1H)， 4.14 (t， J =6.0 Hz, 2H), 3.95 (dd, J= 10.5, 7.7 Hz, 1H)， 3.30-3.27 (m, 1H)， 3.16 (q， J=7.4 Hz, 2H), 2.79 (t, J=7.6Hz, 2H), 2.53 (t, J=7.7 Hz, 2H), 2.28 (dd, J=9.8， 5.8 Hz, 2H), 2.01 (s, 2H), 1.96 (s， 2H), 1.39 (t， J=7.5 Hz, 3H)。  3⁄4 NMR (400 MHz, MeOD) δ 7.45 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.16 (s, 1H), 7.07 (d, J = 7.3 Hz, 1H) , 6.70 (d, J = 23 Hz, 2H), 6.61 (d, J = 7.2 Hz, 1H), 6.44 (d, J = 11.2 Hz, 1H), 4.50 (dd, J=7.7, 2.6 Hz, 1H) , 4.26 (dd, J= 10.6, 2.9 Hz, 1H), 4.14 (t, J = 6.0 Hz, 2H), 3.95 (dd, J= 10.5, 7.7 Hz, 1H), 3.30-3.27 (m, 1H), 3.16 (q, J=7.4 Hz, 2H), 2.79 (t, J=7.6Hz, 2H), 2.53 (t, J=7.7 Hz, 2H), 2.28 (dd, J=9.8, 5.8 Hz, 2H), 2.01 (s, 2H), 1.96 (s, 2H), 1.39 (t, J = 7.5 Hz, 3H).
实施例 25  Example 25
3-(3-(2',6'-二乙基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基) -6-氟- -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸  3-(3-(2',6'-diethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-6-fluoro--2?-benzo [b] [1,4]oxazin-7-yl)propionic acid
Figure imgf000073_0001
Figure imgf000073_0001
第一步  First step
2-溴 - 1 ,3-二乙基 -5-(3-(甲磺酰基)丙氧基)苯  2-bromo-1,3-diethyl-5-(3-(methylsulfonyl)propoxy)benzene
将 4-溴 -3,5-二乙基苯酚 25a (5.4g， 23.6mmol, 采用公知的方法"专 利 WO 2008001931 "制备而得)溶解于 Ν,Ν-二甲基甲酰胺 (60mL)中，然后 加入 3- (；甲基磺酰基)丙基对甲基苯磺酸盐（6.9g， 23.6mmoi;)和碳酸钾 (6.5g， 47.2mmol), 反应液在 65°C条件下搅拌 4小时。 将反应液冷却到 室温,加入水（150mL)， 用乙酸乙酯萃取 (60mLx3 )， 萃取液用饱和氯化 钠溶液（lOOmL)洗涤,无水疏酸钠干燥,过滤,减压浓縮滤液，用硅胶柱色 谱法 (石油醚 /乙酸乙酯 =5/1)纯化所得残余物,得到标题产物 2-溴 -1,3-二 乙基 -5-(3- (甲磺酰基)丙氧基)苯 25b (2.8g， 白色固体)， 产率： 33%。 4-Bromo-3,5-diethylphenol 25a (5.4 g, 23.6 mmol, prepared by the known method "WO 2008001931") was dissolved in hydrazine, hydrazine-dimethylformamide (60 mL), Then 3-(; Methylsulfonyl)propyl p-toluenesulfonate (6.9 g, 23.6 mm oi;) and potassium carbonate (6.5 g, 47.2 mmol) were added, and the reaction mixture was stirred at 65 ° C for 4 hours. The reaction solution was cooled to room temperature, water (150 mL), EtOAc (EtOAc (EtOAc) The obtained residue was purified to silica gel elution elution elution Benzene 25b (2.8 g, white solid), Yield: 33%.
MS m/z (ESI) : 349 [M+l]  MS m/z (ESI) : 349 [M+l]
¾ NMR (300 MHz, CDCb) δ 6.62 (s， 2H), 4.09 (t， J = 5.8 Hz, 2H), 3.31—3.20 (m， 2H), 2.96 (s， 3H)， 2.75 (q， J= 7.5 Hz, 4H)， 2.40-2.26 (m， 2H), 1.22 (dd, J= 9.7， 5.3 Hz, 6H);  3⁄4 NMR (300 MHz, CDCb) δ 6.62 (s, 2H), 4.09 (t, J = 5.8 Hz, 2H), 3.31 - 3.20 (m, 2H), 2.96 (s, 3H), 2.75 (q, J= 7.5 Hz, 4H), 2.40-2.26 (m, 2H), 1.22 (dd, J= 9.7, 5.3 Hz, 6H);
第二步  Second step
3-(3-(2',6'-二乙基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基) -6-氟 -3,4-二 氫 -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙烯酸甲酯  3-(3-(2',6'-diethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-6-fluoro-3,4-dihydro -2? -Benzo[b][1,4]oxazin-7-yl)methacrylate
将 3-(6-氟 -3-(3-(4,4,5,5-四甲基 -1,3,2-二氧硼戊环 -2-基)苯基) -3,4-二 氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙烯酸甲酯 22e (332mg， 0.76mmol) 和 2- 溴 -1,3-二乙基 -5-(3- (甲磺酰基)丙氧基)苯 25b (264mg, 0.76mmol),三 (二 亚苄基丙酮）二钯 （46mg， 0.05mmol)， 2-双环己基磷 -2',6'-二异丙氧基 联苯 (94mg， 0.2mmol)和磷酸钾 (636mg， 3.0mmol)加入到甲苯（10mL) 和水 (5mL)的混合液中， 在氮气保护的密闭体系中， 升温至 95°C， 反应 1 小时。 将反应液冷却到室温， 加入水 (20mL)， 用乙酸乙酯萃取 (30mLx3), 萃取液用无水疏酸钠干燥， 过滤， 减压浓縮滤液， 用硅胶 柱色谱法（石油醚 /乙酸乙酯 = 1 /2 )纯化所得残余物， 得到标题产物 3-(3-(2',6'-二乙基 -4'-(3-(甲磺酰基）丙氧基)联苯基 -3-基) -6-氟 -3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙烯酸甲酯 25c (220mg， 白色固体)， 产率： 50%。  3-(6-Fluoro-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4- Methyl dihydro-2?-benzo[b][l,4]oxazin-7-yl)acrylate 22e (332 mg, 0.76 mmol) and 2-bromo-1,3-diethyl-5-(3 - (Methanesulfonyl)propoxy)benzene 25b (264 mg, 0.76 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol), 2-dicyclohexylphosphino-2',6'-diiso Propoxybiphenyl (94 mg, 0.2 mmol) and potassium phosphate (636 mg, 3.0 mmol) were added to a mixture of toluene (10 mL) and water (5 mL), and the mixture was warmed to 95 ° C in a nitrogen-protected closed system. Reaction for 1 hour. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was evaporated to ethyl acetate (30mL), and the extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. Ethyl ester = 1 /2) The obtained residue was purified to give the title product 3-(3-(2',6'-diethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl- 3-yl)-6-fluoro-3,4-dihydro-2?-benzo[b][l,4]oxazin-7-yl)methyl acrylate 25c (220 mg, white solid), yield: 50%.
MS m/z (ESI) : 582 [M+l]  MS m/z (ESI) : 582 [M+l]
第三步  third step
3-(3-(2',6'-二乙基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基) -6-氟 -3,4-二 氫 -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸甲酯  3-(3-(2',6'-diethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-6-fluoro-3,4-dihydro -2? -Benzo[b][1,4]oxazin-7-yl)propanoate
将 3-(3-(2',6'-二乙基 -4'-(3-(甲磺酰基）丙氧基）联苯基 -3-基) -6-氟 —3,4-二氫 -2H-苯并 [b][l,4]噁嗪 -7-基)丙烯酸甲酯 25c (220mg, 0.63mmol) 和钯碳 (40mg)加入到甲醇（15mL)， 在室温条件下通入氫气， 通过 TLC 监测至原料消失。 过滤， 浓縮滤液得到标题产物 3-(3-(2',6'-二乙基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基) -6-氟 -3,4-二氫 -2? -苯并 [b][l,4]噁 嗪 -7-基)丙酸甲酯 25d (180mg， 浅黄色油）， 产率： 80%。 3-(3-(2',6'-Diethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-6-fluoro-3,4-di Hydrogen-2H-benzo[b][l,4]oxazin-7-yl)methyl acrylate 25c (220 mg, 0.63 mmol) Palladium on carbon (40 mg) was added to methanol (15 mL), and hydrogen was introduced at room temperature, and was observed by TLC to disappear. Filtration and concentration of the filtrate gave the title product 3-(3-(2',6'-diethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-6- Methylfluoro-3,4-dihydro-2?-benzo[b][l,4]oxazin-7-yl)propanoate 25d (180 mg, pale yellow oil), yield: 80%.
MS m/z (ESI) : 584 [M+l]  MS m/z (ESI) : 584 [M+l]
第四步  the fourth step
3-(3-(2',6'-二乙基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基) -6-氟 -3,4-二 氫 -2? -苯并 [b] [ 1 ,4]噁嗪 -7-基)丙酸  3-(3-(2',6'-diethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-6-fluoro-3,4-dihydro -2? -Benzo[b][1,4]oxazin-7-yl)propionic acid
以 3-(3-(2',6'-二乙基 -4'-(3-(甲磺酰基）丙氧基）联苯基 -3-基) -6-氟 —3,4-二氫 -2? -苯并 [b][l,4]噁嗪 -7-基)丙酸甲酯 25d (180mg, 0.31mmol) 为原料，参照实施例 1的搡作方法合成，通过 HPLC制备色谱法纯化（色 谱柱： Gemini-C18， 150x21.2mm, 5μιη, 流动相： 乙腈 /水 (0.1%甲酸)， 梯度： 55-60)， 纯化所得残余物， 得到标题产物 3-(3-(2',6'-二乙基 -4'-(3- (甲磺酰基)丙氧基)联苯基 -3-基) -6-氟 -3,4-二氫 -2? -苯并 [b][l,4]噁 嗪 -7-基)丙酸 25 (30mg， 白色固体)， 产率： 80%。  3-(3-(2',6'-diethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-6-fluoro-3,4-di Hydrogen-2?-benzo[b][l,4]oxazine-7-yl)propanoic acid methyl ester 25d (180 mg, 0.31 mmol) was used as a starting material, which was synthesized by the method of Example 1 and prepared by HPLC. Purification (column: Gemini-C18, 150×21.2 mm, 5 μιη, mobile phase: acetonitrile/water (0.1% formic acid), gradient: 55-60), the residue obtained was purified to give the title product 3-(3-(2) ',6'-Diethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)-6-fluoro-3,4-dihydro-2?-benzo[ b] [l,4]oxazin-7-yl)propanoic acid 25 (30 mg, white solid), yield: 80%.
MS m/z (ESI) 570 [M+l]  MS m/z (ESI) 570 [M+l]
¾ NMR (300 MHz, CDCb) δ 7.45-7.28 (m, 2H), 7.18-7.09 (m, 2H), 6.65 (d, J = 7.1 Hz, 3H)， 6.37 (d， J = 10.0 Hz, 1H)， 4.50 (s， 1H)， 4.27 (d, J= 10.0 Hz, 1H)， 4.15 (t， J= 5.5 Hz, 2H), 3.97 (d, J = 8.6 Hz, 1H)， 3.35-3.23 (m, 2H), 2.97 (s， 3H)， 2.85 (t, J= 7.4 Hz, 2H), 2.63 (t, J= 7.5 Hz, 2H), 2.36 (s, 2H), 2.28 (dd, J= 13.8， 7.1 Hz, 4H)， 1.01 (dd, J= 17.0, 7.4 Hz, 6H)。  3⁄4 NMR (300 MHz, CDCb) δ 7.45-7.28 (m, 2H), 7.18-7.09 (m, 2H), 6.65 (d, J = 7.1 Hz, 3H), 6.37 (d, J = 10.0 Hz, 1H) , 4.50 (s, 1H), 4.27 (d, J = 10.0 Hz, 1H), 4.15 (t, J = 5.5 Hz, 2H), 3.97 (d, J = 8.6 Hz, 1H), 3.35-3.23 (m, 2H), 2.97 (s, 3H), 2.85 (t, J= 7.4 Hz, 2H), 2.63 (t, J= 7.5 Hz, 2H), 2.36 (s, 2H), 2.28 (dd, J= 13.8, 7.1 Hz, 4H), 1.01 (dd, J= 17.0, 7.4 Hz, 6H).
利用适当的反应物参照实施例 20的搡作步骤合成实施例 26-28. 以下是实施例编号， 结构和表征数据:  The examples 26-28 were synthesized using the appropriate reactants in accordance with the steps of Example 20. The following are the example numbers, structures and characterization data:
Figure imgf000075_0001
Figure imgf000076_0001
测试例
Figure imgf000075_0001
Figure imgf000076_0001
Test case
生物学评价  Biological evaluation
测试例 1 本发明化合物对 HEK293/hGPR40细胞的激活效力 以下方法用于测试本化合物对人体 GPR40的激活效力。  Test Example 1 Activation efficacy of the compound of the present invention on HEK293/hGPR40 cells The following method was used to test the activation efficacy of the present compound on human GPR40.
实验方法概述如下：  The experimental methods are summarized as follows:
在 384孔细胞培养板中接种 HEK293/hGPR40细胞 (通过脂^体转 染构建的稳定表达人源 GPR40 的 HEK293 细胞系 ， 简 称 HEK293/hGPR40细胞 (HEK293细胞购于 ATCC, 目录号 CRL-1573;人 源 GPR40 ^粒提取自胰腺癌细胞株 BXPC-3细胞），密度为 8000个 /孔。 细胞在 37°C 5% C02条件下培养过夜。 实验当天， 弃去培养液， 每孔 加入 4(^L Calcium-4 钙离子染料 (Molecular Device) 37 °C孵育 1小时， 随后放入微孔板荧光成像仪 (FLIPRTETRA Molecular Device)中， 按设定 程序加药并同时读数， 即先记录一定时间的基线值， 随后每孔加入不 同浓度的药物（10μΙ7孔）并同时记录荧光值。 所用荧光的激发波长为 470-495 nm， 发射波长为 515-575 nm。 荧光强度与细胞内的钙离子浓 度成正比。 每孔的响应值计为（荧光强度最大值 - 荧光强度最小值)， it软件的四参数拟合， 计算出化合物的 EC5Q值。 HEK293/hGPR40 cells were seeded in 384-well cell culture plates (HEK293 cell line stably expressing human GPR40 constructed by lipofection, HEK293/hGPR40 cells for short (HEK293 cells purchased from ATCC, catalog number CRL-1573; human) The source GPR40 ^ pellet was extracted from pancreatic cancer cell line BXPC-3 cells, and the density was 8000 cells/well. The cells were cultured overnight at 37 ° C under 5% C0 2 . On the day of the experiment, the culture solution was discarded, and 4 was added per well. ^L Calcium-4 calcium ion dye (Molecular Device) was incubated at 37 °C for 1 hour, then placed in a microplate fluorescence imager (FLIPR TETRA Molecular Device), and the drug was added according to the setting procedure and read simultaneously. The baseline value of time was followed by the addition of different concentrations of drug (10 μΙ 7 wells) to each well and the fluorescence values were recorded simultaneously. The fluorescence used was at an excitation wavelength of 470-495 nm and an emission wavelength of 515-575 nm. Fluorescence intensity and intracellular calcium ions The concentration is proportional. The response value per well is (maximum fluorescence intensity - minimum fluorescence intensity), The four-parameter fit of the it software calculates the EC 5 Q value of the compound.
Figure imgf000077_0001
实施例 23 B 实施例 24 B 实施例 25 B 实施例 26 A 实施例 27 A 实施例 28 A
Figure imgf000077_0001
Example 23 B Example 24 B Example 25 B Example 26 A Example 27 A Example 28 A
A< 100 nM; B = 100至 500nM; C > 500 nM  A< 100 nM; B = 100 to 500nM; C > 500 nM
结论： 本发明化合物对人体 GPR40具有明显的激活效力。 Conclusion: The compounds of the present invention have significant activation potency against human GPR40.

Claims

权 利 要 求 书 Claim
1.一种通式 (I)所示的化合物或其互变异构体、 内消旋体、 外消旋 体、 对映异构体、 其可药用的盐： A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer thereof, or a pharmaceutically acceptable salt thereof:
Figure imgf000079_0001
Figure imgf000079_0001
其中：  among them:
A独立地选自 -CH2-或 -0-； A is independently selected from -CH 2 - or -0-;
R1独立地选自羟基或 C1-C8烷氧基； R 1 is independently selected from hydroxy or C 1 -C 8 alkoxy;
R2独立地选自氫原子或卤素； R 2 is independently selected from a hydrogen atom or a halogen;
R3独立地选自氫原子、 卤素或 C1-C8烷基； R 3 is independently selected from a hydrogen atom, a halogen or a C1-C8 alkyl group;
R4和 R5各自独立地选自 C1-C8烷基； R 4 and R 5 are each independently selected from C 1 -C 8 alkyl;
R6独立地选自氫原子、 卤素或 C1-C8烷基； R 6 is independently selected from a hydrogen atom, a halogen or a C1-C8 alkyl group;
R7独立地选自氫原子、 -OR8; R 7 is independently selected from a hydrogen atom, -OR 8 ;
R8独立地选自 C1-C8烷基， C3-C8环烷基， 含有 -S02-的 C3-C8杂 环基， 其中所述 C1-C8烷基或 C3-C8环烷基任选被 C1-C8烷氧基， 含 有 -S02-的 C3-C8杂环基或 -S02R9取代基取代； R 8 is independently selected from a C 1 -C 8 alkyl group, a C 3 -C 8 cycloalkyl group, and a C 3 -C 8 heterocyclic group containing -S 2 2 -, wherein the C 1 -C 8 alkyl group or the C 3 -C 8 cycloalkyl group is optionally a C1-C8 alkoxy group, a C3-C8 heterocyclic group containing -S0 2 - or a -S0 2 R 9 substituent;
R9独立地选自 C1-C8烷基或 C3-C8环烷基。 R 9 is independently selected from a C1-C8 alkyl group or a C3-C8 cycloalkyl group.
2.根据权利要求 1 所述的一种通式 (I)所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混合物形 式、 及其可药用的盐， 其为通式 (II)所述的化合物或其互变异构体、 内 消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混合物形式、 及 其可药用的盐： 2. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof according to claim 1 And a mixture thereof, and a pharmaceutically acceptable salt thereof, which is a compound of the formula (II) or a tautomer thereof, a mesogen, a racemate, an enantiomer, a non-pair Isomers, mixtures thereof, and pharmaceutically acceptable salts thereof:
Figure imgf000079_0002
Y独立地选自 C1-C8亚烷基或 C3-C8亚环烷基；
Figure imgf000079_0002
Y is independently selected from a C1-C8 alkylene group or a C3-C8 cycloalkylene group;
A、 R'-RK R9的定义如权利要求 1 中所述。 A, R'-RK R 9 is as defined in claim 1.
3.根据权利要求 1-2 任意一项所述的通式 (I)所示的化合物或其互 变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混 合物形式、 及其可药用的盐， 其中 R1为羟基。 The compound of the formula (I) according to any one of claims 1 to 2, or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. isomers thereof, mixtures thereof, and pharmaceutically acceptable salts thereof, wherein R 1 is a hydroxyl group.
4.根据权利要求 1-2 任意一项所述的通式 (I)所示的化合物或其互 变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混 合物形式、 及其可药用的盐， 其中 R2为氟原子。 The compound of the formula (I) according to any one of claims 1 to 2, or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. Isomers, mixtures thereof, and pharmaceutically acceptable salts thereof, wherein R 2 is a fluorine atom.
5.根据权利要求 1-2 任意一项所述的通式 (I)所示的化合物或其互 变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混 合物形式、 及其可药用的盐， 其中 R3为 C1-C3烷基。 The compound of the formula (I) according to any one of claims 1 to 2, or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. Isomers, mixtures thereof, and pharmaceutically acceptable salts thereof, wherein R 3 is C1-C3 alkyl.
6.根据权利要求 1 所述的通式 (I)所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混合物形式、 The compound of the formula (I) according to claim 1, or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a compound thereof Mixture form,
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000080_0001
Figure imgf000081_0001
7.一种药物组合物， 所述药物组合物含有治疗有效量的根据权利 要求 1-2任意一项所述的通式 (I)所示的化合物或其互变异构体、内消旋 体、 外消旋体、 对映异构体、 非对映异构体、 其混合物形式、 及其可 药用的盐及药学上可接受的载体， 稀释剂和赋形剂。 A pharmaceutical composition comprising a therapeutically effective amount of the compound of the formula (I) according to any one of claims 1 to 2 or a tautomer thereof, mesogenic , racemates, enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents and excipients.
8.根据权利要求 1-2 任意一项所述的通式 (I)所示的化合物或其互 变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混 合物形式、 及其可药用的盐， 或根据权利要求 7 所述的药物组合物在 制备 GPR40激动剂中的用途。 The compound of the formula (I) according to any one of claims 1 to 2 or a mutual compound thereof An isomer, a meso form, a racemate, an enantiomer, a diastereomer, a mixture thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical combination according to claim 7. Use of the substance in the preparation of a GPR40 agonist.
9.根据权利要求 1-2 任意一项所述的通式 (I)所示的化合物或其互 变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体、 其混 合物形式、 及其可药用的盐， 或根据权利要求 7 所述的药物组合物在 制备治疗糖尿病和代谢综合症的疾病的药物中的用途， 其中所述的糖 尿病为 II型糖尿病。 The compound of the formula (I) according to any one of claims 1 to 2, or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof. Use of an isomer, a mixture thereof, and a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for the preparation of a medicament for treating a disease of diabetes and metabolic syndrome, wherein said diabetes is II Type 2 diabetes.
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017172505A1 (en) * 2016-03-29 2017-10-05 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2018118670A1 (en) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Antidiabetic spirochroman compounds
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
US11225471B2 (en) 2017-11-16 2022-01-18 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
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
CN114163426B (en) * 2020-09-10 2024-03-19 上海爱博医药科技有限公司 Benzo oxygen-containing heterocyclic compound and medical application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004080971A1 (en) * 2003-03-11 2004-09-23 Bristol-Myers Squibb Company Tetrahydroquinoline derivatives useful as serine protease inhibitors
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
WO2012101068A1 (en) * 2011-01-26 2012-08-02 F. Hoffmann-La Roche Ag Novel tetrahydroquinoline derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103030646B (en) * 2011-09-29 2016-08-24 上海恒瑞医药有限公司 Benzodioxane analog derivative, its preparation method and in application pharmaceutically

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004080971A1 (en) * 2003-03-11 2004-09-23 Bristol-Myers Squibb Company Tetrahydroquinoline derivatives useful as serine protease inhibitors
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
WO2012101068A1 (en) * 2011-01-26 2012-08-02 F. Hoffmann-La Roche Ag Novel tetrahydroquinoline derivatives

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190071412A1 (en) * 2016-03-29 2019-03-07 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
US10676458B2 (en) 2016-03-29 2020-06-09 Merch Sharp & Dohne Corp. Rahway Antidiabetic bicyclic compounds
WO2017172505A1 (en) * 2016-03-29 2017-10-05 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2018118670A1 (en) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Antidiabetic spirochroman compounds
US11225471B2 (en) 2017-11-16 2022-01-18 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
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

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