WO2014146604A1 - Fused ring compound having gpr40 receptor function regulating action - Google Patents

Fused ring compound having gpr40 receptor function regulating action Download PDF

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Publication number
WO2014146604A1
WO2014146604A1 PCT/CN2014/073852 CN2014073852W WO2014146604A1 WO 2014146604 A1 WO2014146604 A1 WO 2014146604A1 CN 2014073852 W CN2014073852 W CN 2014073852W WO 2014146604 A1 WO2014146604 A1 WO 2014146604A1
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alkyl
cycloalkyl
hydrogen
heteroaryl
compound
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PCT/CN2014/073852
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French (fr)
Chinese (zh)
Inventor
刘希杰
校登明
胡远东
王树龙
刘志华
沈宇
彭勇
王欢
罗鸿
孔凡胜
韩永信
Original Assignee
正大天晴药业集团股份有限公司
北京赛林泰医药技术有限公司
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Publication of WO2014146604A1 publication Critical patent/WO2014146604A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
    • C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
    • 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
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel fused ring compounds having a GPR40 receptor function regulating function, a process for the preparation thereof, a pharmaceutical composition thereof and pharmaceutical use thereof.
  • GPR40 is a member of the G protein-coupled receptor superfamily and can be activated by medium and long-chain fatty acids, hence the name of Free Fat Acid Receptor 1 (FFAR1). Studies have shown that activation of the GPR40 receptor lowers blood sugar and causes little hypoglycemia. GPR40 agonist treatment of type 2 diabetes differs from sulfonylureas (such as Amaryl®) in that it stimulates insulin secretion in a blood glucose-dependent manner, greatly reducing the risk of hypoglycemia.
  • FFAR1 Free Fat Acid Receptor 1
  • the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof -
  • R 2 , R 3 , RR 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, nitro, amino, fluorenyl, decyloxy, cycloalkyl, heterocycloalkyl, aryl group, a heteroaryl group, alkyl with -NHCO-, -NHCO- cycloalkyl, -S0 2 - group embankment, -S0 2 - cycloalkyl, -SO-alkyl with, -SO-cycloalkyl, -N (embankment yl) -S0 2 - group embankment, -N (embankment yl) -S0 2 - cycloalkyl, -N (embankment yl) -S0 2 - aryl, -N (alkyl with) -S0 2 - heteroaryl, -NHS0 2
  • L 1 is -CH 2 0-, -CH 2 NH- or ⁇ ⁇ ;
  • L 2 is -0- or -NR 12 -;
  • R 9 and R 1Q are each independently selected from the group consisting of hydrogen, halogen, fluorenyl, hydroxy, decyloxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyano;
  • n 0, 1, 2, 3, 4 or 5;
  • L 3 is a bond or -NR 13 -;
  • R 12 and R 13 are each independently selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, aryl, heteroaryl, -S0 2 -fluorenyl, -S0 2 -cycloalkyl, -SO-fluorenyl, -SO-cycloalkyl , -CO-fluorenyl, -CO-cycloalkyl, -CO-aryl, -CO-heteroaryl, or R 12 and R 13 together with the atom to which they are attached form a heterocyclic ring containing at least two N atoms Hydrocarbyl group;
  • R 11 is -NR 15 R 16 , halogen, hydroxy, cyano, nitro, decyl, decyloxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or R 11 and R 13 and The attached atoms together form a heterocyclic hydrocarbon group containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom;
  • n 0, 1, 2, 3, 4 or 5;
  • R 19 is selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
  • Prerequisites are: when L 1 is -CH 2 0- or -CH 2 NH -, L 2 is 0 or -NH -, R 9 and R 1Q are hydrogen, n is 2 or 3, L 3 is a bond, L 4 When -S0 2 -, R 11 is a methyl group or an ethyl group, and R 17 and R 18 are hydrogen, R 19 is selected from the group consisting of a cyclic hydrocarbon group, a heterocyclic hydrocarbon group, an aryl group, and a heteroaryl group.
  • RR 2 , R 3 , RR 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, halogen, Cyano, hydroxy, decyl, decyloxy, amino; In some embodiments, ⁇ RR ⁇ R 6 , R 7 and R 8 are hydrogen, and R 2 and R 3 are methyl.
  • R 9 and R 1Q are selected from hydrogen.
  • R 17 and R 18 are hydrogen. In some embodiments, m is one.
  • L 2 is -0-.
  • R 12 is selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, aryl, heteroaryl; in some preferred embodiments, R 12 is selected from hydrogen, decyl; in some more preferred embodiments R 12 is selected from the group consisting of hydrogen and d 6 fluorenyl; in some most preferred embodiments, R 12 is selected from hydrogen.
  • L 2 when L 2 is -NR 12 - and L 3 is -NR 13 -, R 12 and R 13 together with the atom to which they are attached form a heterocycloalkyl group containing at least two N atoms; In some preferred embodiments, when L 2 is -NR 12 - and L 3 is -NR 13 -, R 12 and R 13 together with the atoms to which they are attached form a 5 or 6 member having at least two N atoms.
  • Heterocyclic hydrocarbon group when L 2 is -NR 12 - and L 3 is -NR 13 -, R 12 and 1 3 together with the atom to which they are attached form two N atoms 6-membered heterocycloalkyl; in some most preferred embodiments, when L 2 is -NR 12 - and L 3 is -NR 13 -, R 12 and R 13 together with the atom to which they are attached form a piperazine base.
  • n is 2 or 3. In some embodiments, n is 2. In some embodiments, n is 3.
  • R 19 is selected from the group consisting of hydrogen, fluorenyl, and cycloalkyl; preferably, R 19 is selected from the group consisting of hydrogen, d- 6 fluorenyl, C 3 -6 cycloalkyl; more preferably, R 19 is selected from hydrogen, A , ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl; most preferably, R 19 is hydrogen.
  • L 4 is —P(0) (R 14 )—, wherein R 14 is hydrogen or fluorenyl; preferably, R 14 is fluorenyl; more preferably, R 14 is d- 6 fluorenyl; even more preferably, R 14 is d 4 fluorenyl; most preferably, R 14 is methyl.
  • L 3 is -NR 13 -, wherein R 13 is selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, aryl, heteroaryl; preferably, R 13 is selected from hydrogen, decyl; more preferably, R 13 is selected from hydrogen, d 6 fluorenyl; even more preferably, R 13 is selected from hydrogen.
  • R 11 is —NR 15 R 16 , fluorenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
  • R 11 is -N (embankment yl) 2, -NH (; firing-yl), alkyl with, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
  • R 11 is -N(d- 6 fluorenyl) 2 , -NH C fluorenyl, d 6 fluorenyl, C 3 -6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl.
  • R 11 is -N (d_ 6 embankment yl) 2, -NH C ⁇ embankment yl), C ⁇ alkyl with, C ⁇ cycloalkyl.
  • R 11 is -N(Cw fluorenyl) 2 , -NH(Cw fluorenyl), C hydrazino, C ⁇ cycloalkyl.
  • R 11 is —N(CH 3 ) 2 , —NH(CH 3 ), —CH 3 , —C 2 H 5 , cyclopropyl.
  • L 3 when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A heterocyclic hydrocarbon group of an atom. In some embodiments, when L 3 is -NR 13 -, 1 1 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 3-12 membered heterocycloalkyl group of an atom.
  • L 3 when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 3, 4, 5 or 6 membered heterocycloalkyl group of an atom. In some embodiments, when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 5- or 6-membered heterocycloalkyl group of an atom.
  • L 3 when L 3 is -NR 13 -, 1 1 together with R 13 and the atom to which they are attached form a 5 or 6 membered heterocycloalkyl containing S0 2 - and at least one nitrogen atom. In some embodiments, when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form a 5-membered heterocycloalkyl containing -S0 2 - and a nitrogen atom.
  • L 2 is 0, n is 2 or 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl, cycloalkyl; , L 2 is 0, n is 2 or 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NHd_ 6 fluorenyl, -N(d_ 6 fluorenyl) 2 , d_ 6 fluorenyl, _ 6- cycloalkyl; in some embodiments, L 2 is 0, n is 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl; in some embodiments, L 2 is 0, n is 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -N(fluorenyl) 2 , -NH(fluorenyl), fluorenyl; in some embodiments, L 4 is n
  • L 2 is 0, n is 1, 2, 3 or 4, L 3 is -NR 13 -, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl, ring a hydrocarbyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or R 11 and R 13 together with the atom to which they are attached form a group containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom Heterocyclic hydrocarbon group;
  • L 2 is 0, n is 2 or 3
  • L 3 is -NR 13 -
  • L 4 is -S0 2 -
  • R 11 is -NR 15 R 16 , fluorenyl, ring a hydrocarbyl group, a heterocyclic hydrocarbon group, or R 11 and R 13 together with the atom to which they are attached form a 3-12 membered heterocycloalkyl group containing -P(0)(R
  • L 2 is 0, n is 2 or 3, L 3 is -NR 13 -, L 4 is -S0 2 -, and R 11 and R 13 together with the atoms to which they are attached form - P(0)(R 14 )- or -S0 2 - and a 3, 4, 5 or 6 membered heterocycloalkyl radical of at least one nitrogen atom, or R 11 is a fluorenyl, cycloalkyl, heterocycloalkyl; in some embodiments in, L 2 is 0, n is 2 or 3, L 3 is -NR 13 -, L 4 is -S0 2 -, R 11 and R 13, and Together with the atoms to which they are attached containing -P (0) (R 14) - or -S0 2 - and at least one 5 or 6-membered heterocycloalkyl nitrogen atom; in some embodiments, L 2 is 0, n is 2, L 3 is -NR 13 -, L 4 is -S0 2 -, R 11
  • L 2 is 0, n is 1, 2, 3 or 4, L 3 is a bond, L 4 is -P(0)(R 14 )-, R 11 is a fluorenyl group, a cyclic hydrocarbon group, a hetero Cycloalkyl, aryl, heteroaryl; In some embodiments, L 2 is 0, n is 3, L 3 is a bond, L 4 is -P(0)(fluorenyl)-, R 11 is a fluorenyl group, cycloalkyl, heterocycloalkyl; in some embodiments, L 2 is 0, n is 3, L 3 is a bond, L 4 is a -PiPXCw embankment yl) -, R 11 is alkyl with D_ 6, 3_ [6 cycloalkyl In some embodiments, L 2 is 0, n is 3, L 3 is a bond, L 4 is -P(0)(CH 3 )-, and R 11 is methyl, ethyl, isopropyl,
  • L 2 is -NR 12 -, L 3 is -NR 13 -, and L 4 is -S0 2 -, and R 12 and R 13 together with the atom to which they are attached form at least two N atoms.
  • Heterocycloalkyl in some embodiments, L 2 is -NR 12 -, L 3 is -NR 13 - and L 4 is -S0 2 -, and R 12 and R 13 together with the atoms to which they are attached form at least a 5- or 6-membered heterocycloalkyl containing two N atoms; in some embodiments, L 2 is -NR 12 -, L 3 is -NR 13 - and L 4 is -S0 2 -, 12 and R 13 and The atoms to which they are attached together form a piperazinyl group.
  • One aspect of the invention isomers -
  • n 0, 1, 2, 3, 4 or 5;
  • L 3 is a bond or -NR 13 -;
  • R 13 is selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, aryl, heteroaryl;
  • L 4 is -P(0)(R 14 )- or -S0 2 -;
  • R 11 is -NR 15 R 16 , halogen, hydroxy, cyano, nitro, decyl, decyloxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or R 11 and R 13 and The attached atoms together form a heterocyclic hydrocarbon group containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom;
  • R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen, fluorenyl, decyloxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
  • n is 2 or 3. In some embodiments, n is 2. In some embodiments, n is 3.
  • R 19 is selected from the group consisting of hydrogen, fluorenyl, and cycloalkyl; preferably, R 19 is selected from the group consisting of hydrogen, d- 6 fluorenyl, C 3 -6 cycloalkyl; more preferably, R 19 is selected from hydrogen, A , ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl group; most preferably, R 19 is hydrogen.
  • L 4 is -S0 2 -.
  • L 4 is —P(0) (R 14 )—, wherein R 14 is hydrogen or fluorenyl; preferably, R 14 is fluorenyl; more preferably, R 14 is d- 6 fluorenyl; even more preferably, R 14 is d 4 fluorenyl; most preferably, R 14 is methyl.
  • L 4 when L 3 is a bond, L 4 is -S0 2 -.
  • L 3 is -NR 13 -, wherein R 13 is selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, aryl, heteroaryl; preferably, R 13 is selected from hydrogen, decyl; more preferably, R 13 is selected from hydrogen, d 6 fluorenyl; more preferably, R 13 is selected from hydrogen.
  • R 11 is selected from the group consisting of -NR 15 R 16 , fluorenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl. In some embodiments, R 11 is selected from -N(indenyl) 2 , -NH (;indenyl), fluorenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 11 is selected from -N(Cw fluorenyl) 2 , -NH(Cw fluorenyl), C hydrazino, C ⁇ cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5 or 6-membered heteroaryl.
  • R 11 is selected from the group consisting of -N(d- 6 fluorenyl) 2 , -NH C fluorenyl), d- 6 fluorenyl, -6 cycloalkyl. In some embodiments, R 11 is —N(d 4 fluorenyl) 2 , —NH Cw fluorenyl, C 1-4 fluorenyl, C 3-6 cycloalkyl. In some embodiments, R 11 is —N(CH 3 ) 2 , —NH(CH 3 ), —CH 3 , —C 2 H 5 , cyclopropyl.
  • L 3 when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A heterocyclic hydrocarbon group of an atom. In some embodiments, when L 3 is -NR 13 -, 1 1 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 3-12 membered heterocycloalkyl group of an atom.
  • L 3 when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 3, 4, 5 or 6 membered heterocycloalkyl group of an atom. In some embodiments, when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 5- or 6-membered heterocycloalkyl group of an atom.
  • n is 2 or 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl, cycloalkyl; in some embodiments, n is 2 or 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NHd_ 6 fluorenyl, -N(d_ 6 fluorenyl) 2 , C ⁇ fluorenyl, [ 3 -6 cycloalkyl; in some embodiments Wherein n is 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl; in some embodiments, n is 3, L 3 is a bond, and L 4 is - S0 2 -, R 11 is -N(fluorenyl) 2 , -NH(fluorenyl), fluorenyl; in some embodiments, n is 3, L 3 is a bond, and
  • n 1, 2, 3 or 4, L 3 is -NR 13 -, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl, cycloalkyl, heterocycloalkyl , aryl, heteroaryl, or R 11 and R 13 together with the atom to which they are attached form a heterocycloalkyl containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom;
  • n is 2 or 3 is -NR 13 -, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl, cycloalkyl, heterocycloalkyl, or R 11 R 13 and together with the atoms to which they are attached form a 3-12 membered heterocycloalkyl containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom; in some embodiments,
  • n 1, 2, 3 or 4
  • L 3 is a bond
  • L 4 is -P(0)(R 14 )-
  • R 11 is a fluorenyl group, a cyclic hydrocarbon, a heterocycloalkyl group, an aryl group.
  • n is 3, L 3 is a bond, L 4 is -P(0)(fluorenyl)-, 1 is a fluorenyl, cycloalkyl, heterocycloalkyl; in some embodiments Wherein n is 3, L 3 is a bond, L 4 is -PiPXCw ⁇ ) -, R 11 is a C ⁇ fluorenyl group, a C ⁇ cycloalkyl group; in some embodiments, n is 3, L 3 is a bond, L 4 Is -P(0)(CH 3 )-, 1 is methyl, ethyl, isopropyl, -CH 2 -cyclopropyl, cyclopropyl.
  • Another aspect of the invention also relates to a process for the preparation of a compound of formula I or a salt thereof or a stereoisomer thereof, wherein
  • the compound of the formula I or a salt thereof or a stereoisomer thereof can be produced by the following method:
  • the compound of the formula I can be produced by a Mitsunobu reaction of the compound of the formula 1 and the compound of the formula 2.
  • compound 1 and compound 2 are in an azodicarbonyl compound (e.g., diethyl azodicarboxylate, diisopropyl azodicarboxylate, hydrazine, hydrazine-(azodicarbonyl)dipiperidine) and Reaction in the presence of an organophosphine compound such as triphenylphosphine, tributylphosphine;
  • the compound of the formula I can be prepared by reacting a compound of the formula 1 with a compound of the formula 2 in the presence of a base.
  • the leaving group may be a halogen atom, a fluorenylsulfonyloxy group optionally substituted by chlorine.
  • the base used may be an alkali metal hydroxide, an alkali metal carbonate or an organic base.
  • the compound of the formula I or a salt thereof or a stereoisomer thereof can be produced by the following method:
  • X is a leaving group
  • the compound of the formula I can be produced by reacting a compound represented by the formula 1 and a compound represented by the formula 3 in the presence of a base. It is also possible to produce a Schiff base by reacting a compound of the formula 4 with a compound of the formula 3, and then preparing the compound I by reduction with a reducing agent.
  • the compound of the formula I or a salt thereof or a stereoisomer thereof can be produced by the following method -
  • X is a leaving group
  • the compound of the formula I can be produced by a coupling reaction of a compound represented by the formula 5 and a compound represented by the formula 6 in the presence of a palladium catalyst.
  • the compounds represented by Formulas 1, 4 and 5 can be prepared by the following methods:
  • the compound represented by Formulas 1, 4 and 5 can be produced by reacting a compound represented by Formula 7 with a compound represented by Formula 8 in the presence of a base.
  • the compounds of the invention may be asymmetric, for example, having one or more chiral centers and thus having one or more stereoisomers. All stereoisomeric forms are included, such as enantiomers and diastereomers, unless otherwise indicated.
  • the asymmetric carbon atom-containing compound of the present invention can be isolated in optically active pure form or as a racemic mixture.
  • the optically active pure form can be resolved from the racemic mixture or it can be synthesized by using a chiral starting material or a chiral reagent.
  • a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned.
  • metal salts include, but are not limited to, alkali metal salts such as sodium salts, potassium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts, and the like; aluminum salts and the like.
  • Non-limiting examples of salts formed with organic acids include, but are not limited to, with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzene. a salt formed of a sulfonic acid, p-toluenesulfonic acid or the like.
  • Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, and the like.
  • Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, and the like.
  • Another aspect of the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or II of the invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention or a salt thereof or a stereoisomer thereof with a suitable pharmaceutically acceptable carrier, for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation, such as Tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • a suitable pharmaceutically acceptable carrier for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation, such as Tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, Parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous.
  • a preferred route of administration is oral administration.
  • the pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a dragee method, a pulverization method, an emulsification method, a lyophilization method, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by admixing the active compound with a pharmaceutically acceptable carrier well known in the art. These carriers enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules. The core of a tablet or dragee.
  • Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • microcrystalline cellulose glucose solution, gum arabic, gelatin solution, sucrose and starch paste; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitol Sugar alcohol or dicalcium phosphate; silica; croscarmellose sodium, pre-treated starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, carboxymethyl fiber , cross-linked polyvinylpyrrolidone and the like.
  • the core of the dragee can optionally be coated according to methods well known in the ordinary pharmaceutical practice, especially using enteric coatings.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • suitable excipients such as fillers, buffers or surfactants can be used.
  • Another aspect of the invention also relates to a compound of formula I or II of the invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in the treatment and/or prevention of a disease associated with GPR40.
  • Another aspect of the invention also relates to a compound of formula I or hydrazine of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of diabetes, a stereoisomer thereof.
  • Another aspect of the invention also relates to a method of treating and/or preventing a disease associated with GPR40, wherein a therapeutically effective amount of a compound of formula I or hydrazine of the invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof The body is administered to a mammal in need thereof.
  • Another aspect of the invention also relates to a method of treating and/or preventing diabetes, wherein a therapeutically effective amount of a compound of formula I or II of the invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, is required Mammal administration.
  • the daily dose is preferably 0.01 to 200 mg/kg body weight.
  • the EC 5Q is less than 1000 nM, more preferably the EC 5Q is less than 100 nM, and most preferably the EC 5Q is less than 10 nM.
  • halogen means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
  • cyano refers to a -CN group.
  • nitro refers to a -N0 2 group.
  • mercapto refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, which is attached to the remainder of the molecule by a single bond.
  • the fluorenyl group can have from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms, and most preferably from 1 to 4 carbon atoms.
  • the thiol group may be unsubstituted or substituted with a substituent.
  • Non-limiting examples of sulfhydryl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, Neopentyl, n-hexyl, 2-methylhexyl, -CH 2 -cyclopropyl, and the like.
  • decyloxy refers to a -0-fluorenyl group, wherein the definition of fluorenyl is the same as defined above.
  • a decyloxy group having 1 to 4 carbon atoms is preferred.
  • the oximeoxy group may be unsubstituted or substituted with a substituent.
  • methoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy , 2-methylbutoxy, neopentyloxy, n-hexyloxy, 2-methylhexyloxy and the like.
  • cycloalkyl refers to a saturated or unsaturated, non-aromatic cyclic hydrocarbon group consisting of carbon atoms and hydrogen atoms, preferably containing 1, 2 or 3 rings, each ring having 3 to 7 ring carbon atoms. More preferably, it is a saturated cyclic fluorenyl group containing 3 to 12 ring carbon atoms in total, and most preferably a saturated cyclic fluorenyl group containing 3 to 6 ring carbon atoms in total.
  • the cyclic hydrocarbon group may be unsubstituted or substituted with a substituent.
  • Non-limiting examples of cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like.
  • alkenyl refers to a straight or branched unsaturated aliphatic hydrocarbon group having at least one double bond consisting of a carbon atom and a hydrogen atom, preferably a linear or branched alkenyl group having 2 to 4 carbon atoms. .
  • the alkenyl group may be unsubstituted or substituted with a substituent.
  • Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl.
  • alkynyl means a straight or branched unsaturated aliphatic hydrocarbon group having at least one triple bond composed of a carbon atom and a hydrogen atom, preferably a linear or branched alkynyl group having 2 to 4 carbon atoms. .
  • the alkynyl group may be unsubstituted or substituted with a substituent.
  • Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl.
  • amino refers to a -NH 2 group in which a hydrogen atom may be substituted with a substituent.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system, preferably having from 6 to 14 carbon atoms, more preferably from 6 to 10 carbon atoms.
  • the aryl group may be unsubstituted or substituted with a substituent.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system having from 5 to 14 ring atoms containing from 1 to 6 ring atoms selected from N, 0, S, the remaining ring atoms being C, and having at least An aromatic ring.
  • the heteroaryl group preferably has a 5- or 6-membered ring, more preferably a 5-membered ring.
  • the heteroaryl group may be unsubstituted or substituted with a substituent.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , tetrazolyl, triazolyl, triazinyl.
  • heterocycloalkyl refers to a non-aromatic monocyclic or fused polycyclic system group having from 3 to 18 ring atoms, wherein from 1 to 6 ring atoms are selected from N, 0, S( ) n (where n is a hetero atom of 0, 1 or 2), and the remaining ring atoms are [. Such rings may be saturated or unsaturated (eg, having one or more double bonds), but do not have a fully conjugated ⁇ -electron system.
  • the heterocyclic hydrocarbon group may be unsubstituted or substituted with a substituent.
  • Examples of the 3-membered heterocyclic hydrocarbon group include, but are not limited to, an epoxyethyl group, an episulfothyl group, a cyclohexamethylene group, and examples of the 4-membered heterocyclic hydrocarbon group include, but are not limited to, azetidinyl, oxetane, thidium
  • Examples of the cyclic group, 5-membered heterocycloalkyl group include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, 1,1-dioxo
  • Examples of thiazolylhydrazyl, thiazolylhydrazyl, imidazolium, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothienyl, 6-membered heterocycloalkyl
  • terapéuticaally effective amount means that when administered to a mammal, preferably a human, the Formula I or guanidine compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, is sufficient to effectively treat a mammal.
  • the amount of (preferably human) a disease associated with GPR40, particularly a diabetes-related disease.
  • the amount of a compound of formula I or hydrazine of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer thereof which constitutes a "therapeutically effective amount” depends on the compound, the state of the disease and its severity, the mode of administration, and the condition to be treated. The age of the mammal varies, but can be routinely determined by one skilled in the art based on its own knowledge and disclosure of the present invention.
  • treating means administering a compound or formulation of the invention to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • pharmaceutical composition refers to one or more of the formula I or indole compounds of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and are generally accepted in the art for use in biologically active compounds.
  • the purpose of the pharmaceutical composition is to facilitate administration of an organism of the formula I or hydrazine compound of the present invention or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, to an organism.
  • pharmaceutically acceptable carrier refers to those carriers and diluents which do not significantly irritate the organism and which do not impair the biological activity and properties of the active compound.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, any carrier, excipient, vehicle, glidant, sweetener, diluent, for human or livestock animals that is approved by the National Food and Drug Administration as acceptable. Preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, disintegrating agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • the column chromatography was carried out using silica gel (200-300 mesh) produced by Qingdao Chemical Co., Ltd. Thin layer chromatography was carried out using a prefabricated plate manufactured by E. Merck (silica gel 60 PF254, 0.25 mm). Nuclear magnetic resonance chromatography (NMR) was measured using a Varian VNMRS-400 NMR spectrometer; LC/MS was performed using FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200 series (column: Waters Symmetry CI 8, ⁇ 4.6 50 mm, 5 micron, 35 °C) in ESI(+) ion mode.
  • NMR nuclear magnetic resonance chromatography
  • Step 2 Synthesis of 4,-(tert-butyldimethylsilyloxy)-2,6,-dimethylbiphenyl-3-carbaldehyde
  • Step 4 2-(6-((4-tert-Butyldimethylsilyloxy)- 2 6 dimethylbiphenyl-3-yl)methoxy)-2,3»dihydrobenzofuran- Synthesis of 3»yl)methyl acetate
  • Step 7 2-(6- ⁇ (4'-(Dimethylphosphono)propoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy)-2,3 Synthesis of methyl 2-dibenzofuran-3-yl)acetate
  • Step 8 2-(6-((4'-(3-(Dimethylphosphonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy)-2 Synthesis of 3-dihydrobenzofuran-3-yl)acetic acid
  • Step 2 2-(6-((4'-(2-Aminoethoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydro Benzofuran-3-yl)B Synthesis of acid methyl ester
  • Step 3 2-(6-((2,6,-Dimethyl-4,-(2-(methylsulfonylamino)ethoxy)biphenyl-3-yl)methoxy)-2 Synthesis of methyl 3-hydrobenzofuran-3-yl)acetate
  • Step 4 2-(6-((2',6'-Dimethyl-4'-(2-(methylsulfonylamino)ethoxy)biphenyl-3-yl)methoxy)-2, Synthesis of 3-dihydrobenzofuran-3-yl)acetic acid
  • Step 1 2-(6-((4'-(2-(3-Chloropropylsulfonylamino)ethoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy) Synthesis of methyl-2,3-dihydrobenzofuran-3-yl)acetate
  • Step 2 2-(6-((4'-(2-(1,1-dioxo-isothiazol-2-yl)ethoxy) ⁇ 2',6'-dimethylbiphenyl Synthesis of methyl methoxy)- 2,3 ⁇ di-benzobenzopyran-3-yl)acetate
  • Step 3 2-(6-((4'-(2-(1,1-dioxo-isothiazol-2-yl)ethoxy)-2',6'-dimethylbiphenyl- Synthesis of 3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
  • Step 1 Synthesis of sodium 3-(4-bromo-3,5-dimethylphenoxy)propyl-1-sulfonate
  • Step 3 Synthesis of ⁇ V-dimethyl-3-(4-bromo-3,5-dimethylphenoxy)propyl-1-sulfonamide
  • Step 4 Synthesis of 4'-(3-(N,N-dimethylaminosulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-carbaldehyde
  • Step 5-7 2-(6-((2',6'-Dimethyl-4'-(3-(N,N-dimethylaminosulfonyl)propoxy)biphenyl-3-yl) Synthesis of methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
  • reaction mixture was cooled to room temperature, it was filtered, and the filtrate was subjected to reduction under reduced pressure.
  • tetrahydrofuran 50 mL was added, and then 3M: hydrochloric acid (10 mL was added, and the mixture was stirred at room temperature for 2 hours.
  • the reaction mixture was combined and concentrated under reduced pressure, and then dissolved in water (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated.
  • Step 2 02- ⁇ 6-((4'-yl-2,6'-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl) Synthesis of formamidine acetate
  • EtOAc EtOAc 2'6'-Dimethylbiphenyl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (0,82 g, yield 95, 0%).
  • Step 3 >2 ⁇ (6-((4'-(Cyanomethoxy) ⁇ 2 dimethylbiphenyl ⁇ 3-yl)methoxy) ⁇ 2,3-dibenzobenzopyrene- Synthesis of 3-methyl) methyl acetate
  • Potassium carbonate (2.0 g, 14.5 mmol) was added to (5 -2-(6 (4 f -hydroxy',6'-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzene And furan 3-yl)acetic acid formazan (3. () g, 7.2 mm oi) and bromoacetonitrile (1.8 g, 15.0 mmol) in acetonitrile (100 mL). The mixture was stirred at room temperature overnight and filtered.
  • Step 4 '>-2-(6-((2-Aminoethoxy)-2»,6'-dimethylbiphenyl-3-yl)methoxy)-2,3- Synthesis of Methyl Dihydrobenzofuran-3-yl)acetate
  • Step 5 (5)-2 (6-((4' ⁇ (2-(3-(propylsulfonyl)yl)ethoxy) 2',6'-dimethylbiphenyl-3 ⁇ yl Synthesis of methyl methoxy)-2,3-dioxabenzofuran ⁇ 3-yl)acetate
  • Step 6 >2 ⁇ (6-((4'-(2-(1,_-Dioxy'f ⁇ -isothiazolium ⁇ 2-yl)ethoxy)-2',6' ⁇ dimethyl Synthesis of methyl phenyl)methoxy)-2,3-difluorenylbenzofuranylacetate
  • Step 4 Synthesis of 2,6,-dimethyl-4,-(3-(methylsulfonyl)propoxy)-biphenyl-3-phenol
  • Step 5 Synthesis of 2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)-3-trifluoromethanesulfonyloxy-biphenyl
  • reaction mixture was subjected to reduction under reduced pressure, and the obtained dog was separated and purified by silica gel column chromatography to obtain 2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)- 3-Trifluoromethanesulfonyloxy-biphenyl i: 0.43 g, yield 85J:) 3 ⁇ 4).
  • Step 6 2-(6-((2',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)ethynyl)-2,3 Synthesis of Methyl-Dihydrobenzofuran-3-yl)acetate
  • Step 7 2-(6-((2',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)ethynyl)-2,3- Synthesis of dihydrobenzofuran-3-yl)acetic acid
  • Vector plasmid pcDNA3.1 was purchased from Invitrogen®. Using the two DNA restriction endonuclease sites of BamHI and EcoRV, the fully cloned GPR40 full-length gene was ligated into the pCDNA3.1 vector by T4 DNA ligase, and then transfected into DH5a competent cells, and added Successfully transfected monoclonals were selected on LB agar medium with antibiotic Ampilline (1 g/mL), plasmids were extracted and the gene sequence was determined by DNA sequencing.
  • the present invention uses a calcium flow method to determine the effect of a compound on the intracellular calcium concentration of GPR40 stably expressing cells, thereby reflecting the agonistic effect on GPR40.
  • This agonistic activity is expressed by the index of EC 5Q , which is the concentration of the compound corresponding to the activity of GPR40 which is excited to 50% of the maximum value.
  • Fluo-4 Calcium Flow Kit (Invitrogen®, Cat. No. F10471), including FLuo-4 Calcium Dye, Probenecid and Fluo-4 Calcium Flow Reaction Buffer.
  • DMEM cell culture solution (Gilbco®, Cat.No.C11995500B)
  • fetal bovine serum (Hyclone®, Cat.No.SV30087)
  • GPR40 stably expressing cells were plated into a 96-well black-bottomed cell culture plate coated with polylysine at a density of 2 ⁇ 10 4 cells/well, and DMEM medium was supplemented with 10% fetal bovine serum and 400 g/mL of G418 sulfate was grown overnight in a 37 ° C, 5% carbon dioxide incubator.
  • Table 1 The agonistic activity of the compounds of the examples of the invention on GPR40
  • the present invention uses a method of oral glucose tolerance test (OGTT) in mice to measure the hypoglycemic effect of a compound in vivo.
  • OGTT oral glucose tolerance test
  • mice were weighed and fasted for 16 hours and measured for fasting blood glucose (G Q ), randomized according to G Q , 5 mice per group. 2), the mice were administered with different concentrations of the test compound by intragastric administration, and 25% of the HS-15 was administered to the control mice with 25% polyethylene glycol stearate (HS-15) as a solvent.
  • G Q blood glucose
  • HS-15 polyethylene glycol stearate
  • mice were orally administered with an aqueous solution of glucose at 2.0 g/kg body weight.
  • mice 15 minutes, 30 minutes, 60 minutes, and 120 minutes after oral glucose administration were measured by blood glucose meter, and were recorded as 0 15 , G 30 , G 60 and PG 120 , respectively .
  • Fig. 1 and Fig. 2 show that the compound of Example 11 of the present invention has a significant hypoglycemic effect in normal C57 mice, and the compound of Example 11 of the present invention has a hypoglycemic effect at 30-50 mg/kg. There are significant advantages.

Abstract

Provided is a fused ring compound having GPR40 receptor function regulating action, and preparation method and pharmaceutical compositions thereof, and the use thereof in drugs for the treatment and/or prevention of diseases associated with GPR40, especially diabetes.

Description

具有 GPR40受体功能调节作用的稠环化合物  Fused ring compound with GPR40 receptor function regulation
技术领域 Technical field
本发明涉及新的具有 GPR40受体功能调节作用的稠环化合物、其制备方法、其药物组 合物及其医药用途。  The present invention relates to novel fused ring compounds having a GPR40 receptor function regulating function, a process for the preparation thereof, a pharmaceutical composition thereof and pharmaceutical use thereof.
背景技术 Background technique
GPR40是 G蛋白偶联受体超家族的一员，可以被中、 长链脂肪酸激活， 因此又被称为游 离脂肪酸受体 1 (Free fat acid receptor 1, FFAR1 )。 研究证明， 激活 GPR40受体， 可以降低 血糖，而且几乎不引起低血糖反应。 GPR40激动剂治疗 2型糖尿病的作用机制与磺脲类药物 (；如 Amaryl®)不同， 以依赖于血糖的方式剌激胰岛素分泌， 大大降低了低血糖风险。  GPR40 is a member of the G protein-coupled receptor superfamily and can be activated by medium and long-chain fatty acids, hence the name of Free Fat Acid Receptor 1 (FFAR1). Studies have shown that activation of the GPR40 receptor lowers blood sugar and causes little hypoglycemia. GPR40 agonist treatment of type 2 diabetes differs from sulfonylureas (such as Amaryl®) in that it stimulates insulin secretion in a blood glucose-dependent manner, greatly reducing the risk of hypoglycemia.
因此， 以 GPR40 作为治疗糖尿病的靶标， 设计作用于 GPR40 的药物， 对于调节胰腺 的胰岛素分泌功能， 治疗糖尿病， 具有非常重要的研究价值和应用前景。  Therefore, using GPR40 as a target for the treatment of diabetes, designing a drug for GPR40 has very important research value and application prospect for regulating insulin secretion function of the pancreas and treating diabetes.
发明的详细说明 Detailed description of the invention
本发明一方面提供了通式 I化合物或其药学上可接受的盐或其立体异构体-  In one aspect, the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof -
Figure imgf000003_0001
Figure imgf000003_0001
其中，  among them,
R2、 R3、 R R5、 R6、 R7和 R8各自独立地选自氢、 卤素、 氰基、 羟基、 硝基、 氨基、 垸基、 垸氧基、 环烃基、 杂环烃基、 芳基、 杂芳基、 -NHCO-垸基、 -NHCO-环烃基、 -S02-垸基、 -S02-环烃基、 -SO-垸基、 -SO-环烃基、 -N(垸基) -S02-垸基、 -N(垸基) -S02-环烃 基、 -N(垸基) -S02-芳基、 -N(垸基) -S02-杂芳基、 -NHS02-垸基、 -NHS02-环烃基、 -NHS02- 芳基、 -NHS02-杂芳基、 -S02-NH2、 -S02-NH-垸基、 -S02N- (垸基 )2、 -CO-垸基、 -COO-焼 基、 -CONH-垸基、 -CON- (垸基 )2、 -CONH2; R 2 , R 3 , RR 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, nitro, amino, fluorenyl, decyloxy, cycloalkyl, heterocycloalkyl, aryl group, a heteroaryl group, alkyl with -NHCO-, -NHCO- cycloalkyl, -S0 2 - group embankment, -S0 2 - cycloalkyl, -SO-alkyl with, -SO-cycloalkyl, -N (embankment yl) -S0 2 - group embankment, -N (embankment yl) -S0 2 - cycloalkyl, -N (embankment yl) -S0 2 - aryl, -N (alkyl with) -S0 2 - heteroaryl, -NHS0 2 - alkyl with, -NHS0 2 - cycloalkyl, -NHS0 2 - aryl, -NHS0 2 - heteroaryl, -S0 2 -NH 2, -S0 2 -NH- embankment group, -S0 2 N- (alkyl with 2 , -CO-fluorenyl, -COO-fluorenyl, -CONH-fluorenyl, -CON-(fluorenyl) 2 , -CONH 2 ;
L1为 -CH20-、 -CH2NH-或 ~≡ ~； L 1 is -CH 2 0-, -CH 2 NH- or ~≡ ~;
L2为 -0-或 -NR12-; L 2 is -0- or -NR 12 -;
R9和 R1Q各自独立地选自氢、 卤素、 垸基、 羟基、 垸氧基、 环烃基、 杂环烃基、 芳基、 杂芳基、 氰基； R 9 and R 1Q are each independently selected from the group consisting of hydrogen, halogen, fluorenyl, hydroxy, decyloxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyano;
n为 0、 1、 2、 3、 4或 5;  n is 0, 1, 2, 3, 4 or 5;
L3为键或 -NR13-; L 3 is a bond or -NR 13 -;
R12和 R13各自独立地选自氢、 垸基、 环烃基、 芳基、 杂芳基、 -S02-垸基、 -S02-环烃 基、 -SO-垸基、 -SO-环烃基、 -CO-垸基、 -CO-环烃基、 -CO-芳基、 -CO-杂芳基， 或者 R12 和 R13以及与它们所连接的原子一起形成至少含有两个 N原子的杂环烃基； R 12 and R 13 are each independently selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, aryl, heteroaryl, -S0 2 -fluorenyl, -S0 2 -cycloalkyl, -SO-fluorenyl, -SO-cycloalkyl , -CO-fluorenyl, -CO-cycloalkyl, -CO-aryl, -CO-heteroaryl, or R 12 and R 13 together with the atom to which they are attached form a heterocyclic ring containing at least two N atoms Hydrocarbyl group;
L4为 -P(0)(R14)-或 -S02-; L 4 is -P(0)(R 14 )- or -S0 2 -;
R11为 -NR15R16、 卤素、 羟基、 氰基、 硝基、 垸基、 垸氧基、 环烃基、 杂环烃基、 芳基、 杂芳基，或者 R11和 R13以及与它们所连接的原子一起形成含有 -P(0)(R14)-或 -S02-及至少一 个氮原子的杂环烃基； R 11 is -NR 15 R 16 , halogen, hydroxy, cyano, nitro, decyl, decyloxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or R 11 and R 13 and The attached atoms together form a heterocyclic hydrocarbon group containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom;
R14、 R15、 R16、 R17和 R18各自独立地选自氢、 卤素、 羟基、 垸基、 垸氧基、 环烃基、 杂环烃基、 芳基、 杂芳基； R 14 , R 15 , R 16 , R 17 and R 18 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, decyl, decyloxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
m为 0、 1、 2、 3、 4或 5;  m is 0, 1, 2, 3, 4 or 5;
R19选自氢、 垸基、 环烃基、 杂环烃基、 芳基、 杂芳基； R 19 is selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
前提条件是： 当 L1为 -CH20-或 -CH2NH -、 L2为 0或 -NH -、 R9和 R1Q为氢、 n为 2或 3、 L3为键、 L4为 -S02-、 R11为甲基或乙基以及 R17和 R18为氢时， R19选自环烃基、 杂环 烃基、 芳基、 杂芳基。 Prerequisites are: when L 1 is -CH 2 0- or -CH 2 NH -, L 2 is 0 or -NH -, R 9 and R 1Q are hydrogen, n is 2 or 3, L 3 is a bond, L 4 When -S0 2 -, R 11 is a methyl group or an ethyl group, and R 17 and R 18 are hydrogen, R 19 is selected from the group consisting of a cyclic hydrocarbon group, a heterocyclic hydrocarbon group, an aryl group, and a heteroaryl group.
在一些实施方案中， R R2、 R3、 R R5、 R6、 R7和 R8各自独立地选自氢、 卤素、 氰基、 羟基、 垸基、 垸氧基、 氨基； 在一些实施方案中， Κλ R R\ R6、 R7和 R8为氢， R2和 R3为甲基。 In some embodiments, RR 2 , R 3 , RR 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, halogen, Cyano, hydroxy, decyl, decyloxy, amino; In some embodiments, Κλ RR\ R 6 , R 7 and R 8 are hydrogen, and R 2 and R 3 are methyl.
在一些实施方案中， L1为 -CH20-。 在一些实施方案中， L1为 -CH2NH -。 在一些实施方 案中， L1为 ~ = ~。 In some embodiments, L 1 is -CH 2 0-. In some embodiments, L 1 is —CH 2 NH —. In some embodiments, L 1 is ~ = ~.
在一些实施方案中， R9和 R1Q选自氢。 In some embodiments, R 9 and R 1Q are selected from hydrogen.
在一些实施方案中， R17和 R18为氢。 在一些实施方案中， m为 1。 In some embodiments, R 17 and R 18 are hydrogen. In some embodiments, m is one.
在一些实施方案中， L2为 -0-。 In some embodiments, L 2 is -0-.
在一些实施方案中， L2为 -NR12-。 In some embodiments, L 2 is -NR 12 -.
在一些实施方案中， R12选自氢、 垸基、 环烃基、 芳基、 杂芳基； 在一些优选的实施 方案中， R12选自氢、 垸基； 在一些更优选的实施方案中， R12选自氢、 d_6垸基； 在一些 最优选的实施方案中， R12选自氢。 In some embodiments, R 12 is selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, aryl, heteroaryl; in some preferred embodiments, R 12 is selected from hydrogen, decyl; in some more preferred embodiments R 12 is selected from the group consisting of hydrogen and d 6 fluorenyl; in some most preferred embodiments, R 12 is selected from hydrogen.
在一些实施方案中， 当 L2为 -NR12-以及 L3为 -NR13-时， R12与 R13以及与它们所连接的 原子一起形成至少含有两个 N原子的杂环烃基； 在一些优选的实施方案中， 当 L2为 -NR12- 以及 L3为 -NR13-时， R12与 R13以及与它们所连接的原子一起形成至少含有两个 N原子的 5 或 6元杂环烃基； 在一些更优选的实施方案中， 当 L2为 -NR12-以及 L3为 -NR13-时， R12与 13以及与它们所连接的原子一起形成含有两个 N原子的 6元杂环烃基； 在一些最优选的 实施方案中， 当 L2为 -NR12-以及 L3为 -NR13-时， R12与 R13以及与它们所连接的原子一起形 成哌嗪基。 In some embodiments, when L 2 is -NR 12 - and L 3 is -NR 13 -, R 12 and R 13 together with the atom to which they are attached form a heterocycloalkyl group containing at least two N atoms; In some preferred embodiments, when L 2 is -NR 12 - and L 3 is -NR 13 -, R 12 and R 13 together with the atoms to which they are attached form a 5 or 6 member having at least two N atoms. Heterocyclic hydrocarbon group; In some more preferred embodiments, when L 2 is -NR 12 - and L 3 is -NR 13 -, R 12 and 1 3 together with the atom to which they are attached form two N atoms 6-membered heterocycloalkyl; in some most preferred embodiments, when L 2 is -NR 12 - and L 3 is -NR 13 -, R 12 and R 13 together with the atom to which they are attached form a piperazine base.
在一些实施方案中， n为 2或 3。 在一些实施方案中， n为 2。 在一些实施方案中， n 为 3。  In some embodiments, n is 2 or 3. In some embodiments, n is 2. In some embodiments, n is 3.
在一些实施方案中， R19选自氢、 垸基、 环烃基； 优选地， R19选自氢、 d_6垸基、 C3_6 环烃基； 更优选地， R19选自氢、 甲基、 乙基、 丙基、 异丙基、 环丙基、 环丁基、 环己基； 最优选的， R19为氢。 In some embodiments, R 19 is selected from the group consisting of hydrogen, fluorenyl, and cycloalkyl; preferably, R 19 is selected from the group consisting of hydrogen, d- 6 fluorenyl, C 3 -6 cycloalkyl; more preferably, R 19 is selected from hydrogen, A , ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl; most preferably, R 19 is hydrogen.
在一些实施方案中， L4为 -S02-。 In some embodiments, L 4 is -S0 2 -.
在一些实施方案中， 当 L3为键时， L4为 -P(0) (R14)-， 其中 R14为氢或垸基； 优选地， R14为垸基； 更优选地， R14为 d_6垸基； 甚至更优选地， R14为 d_4垸基； 最优选地， R14 为甲基。 In some embodiments, when L 3 is a bond, L 4 is —P(0) (R 14 )—, wherein R 14 is hydrogen or fluorenyl; preferably, R 14 is fluorenyl; more preferably, R 14 is d- 6 fluorenyl; even more preferably, R 14 is d 4 fluorenyl; most preferably, R 14 is methyl.
在一些实施方案中， 当 L3为键时， L4为 - S02 -。 In some embodiments, when L 3 is a bond, L 4 is -S0 2 -.
在一些实施方案中， L3为 -NR13-， 其中 R13选自氢、 垸基、 环烃基、 芳基、 杂芳基； 优选地， R13选自氢、 垸基； 更优选地， R13选自氢、 d_6垸基； 甚至更优选地， R13选自氢。 In some embodiments, L 3 is -NR 13 -, wherein R 13 is selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, aryl, heteroaryl; preferably, R 13 is selected from hydrogen, decyl; more preferably, R 13 is selected from hydrogen, d 6 fluorenyl; even more preferably, R 13 is selected from hydrogen.
在一些实施方案中， R11为 -NR15R16、 垸基、 环烃基、 杂环烃基、 芳基、 杂芳基。 在一 些实施方案中， R11为 -N (垸基 )2、 -NH (；焼基)、 垸基、 环烃基、 杂环烃基、 芳基、 杂芳基。 在一些实施方案中， R11为 -N(d_6垸基 )2、 -NH C^垸基)、 d_6垸基、 C3_6环烃基、 3-6元杂 环烃基、 苯基、 5或 6元杂芳基。在一些实施方案中， R11为 -N(d_6垸基 )2、 -NH C^垸基)、 C^垸基、 C^环烃基。 在一些实施方案中， R11为 -N(Cw垸基 )2、 -NH(Cw垸基)、 C^垸 基、 C^环烃基。 在一些实施方案中， R11为 -N(CH3)2、 -NH(CH3)、 -CH3、 -C2H5、 环丙基。 In some embodiments, R 11 is —NR 15 R 16 , fluorenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl. In some embodiments, R 11 is -N (embankment yl) 2, -NH (; firing-yl), alkyl with, cycloalkyl, heterocycloalkyl, aryl, heteroaryl. In some embodiments, R 11 is -N(d- 6 fluorenyl) 2 , -NH C fluorenyl, d 6 fluorenyl, C 3 -6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl. In some embodiments, R 11 is -N (d_ 6 embankment yl) 2, -NH C ^ embankment yl), C ^ alkyl with, C ^ cycloalkyl. In some embodiments, R 11 is -N(Cw fluorenyl) 2 , -NH(Cw fluorenyl), C hydrazino, C^cycloalkyl. In some embodiments, R 11 is —N(CH 3 ) 2 , —NH(CH 3 ), —CH 3 , —C 2 H 5 , cyclopropyl.
在一些实施方案中， 当 L3为 -NR13-时， R11与 R13以及与它们所连接的原子一起形成含 有 -P(0)(R14)-或 -S02-及至少一个氮原子的杂环烃基。在一些实施方案中， 当 L3为 -NR13-时， 11与 R13以及与它们所连接的原子一起形成含有 -P(0)(R14)-或 -S02-及至少一个氮原子的 3-12元杂环烃基。在一些实施方案中， 当 L3为 -NR13-时， R11与 R13以及与它们所连接的原 子一起形成含有 -P(0)(R14)-或 -S02-及至少一个氮原子的 3、 4、 5或 6元杂环烃基。 在一些 实施方案中，当 L3为 -NR13-时， R11与 R13以及与它们所连接的原子一起形成含有 -P(0)(R14)- 或 -S02-及至少一个氮原子的 5或 6元杂环烃基。 在一些实施方案中， 当 L3为 -NR13-时， 11与 R13以及与它们所连接的原子一起形成含有 S02-及至少一个氮原子的 5或 6元杂环烃 基。在一些实施方案中， 当 L3为 -NR13-时， R11与 R13以及与它们所连接的原子一起形成含 有 -S02-及一个氮原子的 5元杂环烃基。 在一些实施方案中， L2为 0， n为 2或 3， L3为键， L4为 -S02-， R11为 -NR15R16、垸基、 环烃基； 在一些实施方案中， L2为 0， n为 2或 3， L3为键， L4为 -S02-， R11为 -NHd_6垸 基、 -N(d_6垸基 )2、 d_6垸基、 _6环烃基； 在一些实施方案中， L2为 0， n为 3， L3为键， L4为 -S02-， R11为 -NR15R16、垸基；在一些实施方案中， L2为 0， n为 3， L3为键， L4为 -S02-， R11为 -N (垸基 )2、 -NH (垸基)、 垸基； 在一些实施方案中， L2为 0， n为 3， L3为键， L4为 -S02-， R11为 -N(C^垸基 )2、 -NH(C^垸基)、 C^垸基； 在一些实施方案中， L2为 0， n为 3， L3为键， L4为 -S02-， R11为 -N(CH3)2、 -NHCH3、 -CH3。 In some embodiments, when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A heterocyclic hydrocarbon group of an atom. In some embodiments, when L 3 is -NR 13 -, 1 1 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 3-12 membered heterocycloalkyl group of an atom. In some embodiments, when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 3, 4, 5 or 6 membered heterocycloalkyl group of an atom. In some embodiments, when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 5- or 6-membered heterocycloalkyl group of an atom. In some embodiments, when L 3 is -NR 13 -, 1 1 together with R 13 and the atom to which they are attached form a 5 or 6 membered heterocycloalkyl containing S0 2 - and at least one nitrogen atom. In some embodiments, when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form a 5-membered heterocycloalkyl containing -S0 2 - and a nitrogen atom. In some embodiments, L 2 is 0, n is 2 or 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl, cycloalkyl; , L 2 is 0, n is 2 or 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NHd_ 6 fluorenyl, -N(d_ 6 fluorenyl) 2 , d_ 6 fluorenyl, _ 6- cycloalkyl; in some embodiments, L 2 is 0, n is 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl; in some embodiments, L 2 is 0, n is 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -N(fluorenyl) 2 , -NH(fluorenyl), fluorenyl; in some embodiments, L 2 is 0, n is 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -N(C^垸) 2 , -NH(C^垸), C^垸; In an embodiment, L 2 is 0, n is 3, L 3 is a bond, L 4 is -S0 2 -, and R 11 is -N(CH 3 ) 2 , -NHCH 3 , -CH 3 .
在一些实施方案中， L2为 0， n为 1、 2、 3或 4， L3为 -NR13-， L4为 -S02-， R11为 -NR15R16、 垸基、 环烃基、 杂环烃基、 芳基、 杂芳基， 或者 R11与 R13以及与它们所连接的原子一起 形成含有 -P(0)(R14)-或 -S02-及至少一个氮原子的杂环烃基； 在一些实施方案中， L2为 0， n 为 2或 3， L3为 -NR13-， L4为 -S02-， R11为 -NR15R16、 垸基、 环烃基、 杂环烃基， 或者 R11 与 R13以及与它们所连接的原子一起形成含有 -P(0)(R14)-或 -S02-及至少一个氮原子的 3-12 元杂环烃基； 在一些实施方案中， L2为 0， n为 2或 3， L3为 -NR13-， L4为 -S02-， R11与 R13以及与它们所连接的原子一起形成含有 -P(0)(R14)-或 -S02-及至少一个氮原子的 3、 4、 5 或 6元杂环烃基， 或者 R11为垸基、 环烃基、 杂环烃基； 在一些实施方案中， L2为 0， n 为 2或 3， L3为 -NR13-， L4为 -S02-， R11与 R13以及与它们所连接的原子一起形成含有 -P(0)(R14)-或 -S02-及至少一个氮原子的 5或 6元杂环烃基； 在一些实施方案中， L2为 0， n 为 2， L3为 -NR13-， L4为 -S02-， R11与 R13以及与它们所连接的原子一起形成含有 -S02-及一 个氮原子的 5元杂环烃基； 在一些实施方案中， L2为 0， n为 2， L3为 -NH -， L4为 -S02-， R11为垸基、 环烃基。 在一些实施方案中， L2为 0， n为 2， L3为 -NH -， L4为 -S02-， R11为 C1-6焼基、 C3-6环径基。 In some embodiments, L 2 is 0, n is 1, 2, 3 or 4, L 3 is -NR 13 -, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl, ring a hydrocarbyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or R 11 and R 13 together with the atom to which they are attached form a group containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom Heterocyclic hydrocarbon group; In some embodiments, L 2 is 0, n is 2 or 3, L 3 is -NR 13 -, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl, ring a hydrocarbyl group, a heterocyclic hydrocarbon group, or R 11 and R 13 together with the atom to which they are attached form a 3-12 membered heterocycloalkyl group containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom. In some embodiments, L 2 is 0, n is 2 or 3, L 3 is -NR 13 -, L 4 is -S0 2 -, and R 11 and R 13 together with the atoms to which they are attached form - P(0)(R 14 )- or -S0 2 - and a 3, 4, 5 or 6 membered heterocycloalkyl radical of at least one nitrogen atom, or R 11 is a fluorenyl, cycloalkyl, heterocycloalkyl; in some embodiments in, L 2 is 0, n is 2 or 3, L 3 is -NR 13 -, L 4 is -S0 2 -, R 11 and R 13, and Together with the atoms to which they are attached containing -P (0) (R 14) - or -S0 2 - and at least one 5 or 6-membered heterocycloalkyl nitrogen atom; in some embodiments, L 2 is 0, n is 2, L 3 is -NR 13 -, L 4 is -S0 2 -, R 11 and R 13 together with the atom to which they are attached form a 5-membered heterocycloalkyl group containing -S0 2 - and a nitrogen atom; In an embodiment, L 2 is 0, n is 2, L 3 is -NH -, L 4 is -S0 2 -, and R 11 is a fluorenyl group or a cyclic hydrocarbon group. In some embodiments, L 2 is 0, n is 2, L 3 is -NH -, L 4 is -S0 2 -, and R 11 is C 1-6 fluorenyl, C 3 - 6 ring-diameter.
在一些实施方案中， L2为 0， n为 1、 2、 3或 4， L3为键， L4为 -P(0)(R14)-， R11为垸 基、 环烃基、 杂环烃基、 芳基、 杂芳基； 在一些实施方案中， L2为 0， n为 3， L3为键， L4为 -P(0)(焼基) -， R11为垸基、 环烃基、 杂环烃基； 在一些实施方案中， L2为 0， n为 3， L3为键， L4为 -PiPXCw垸基) -， R11为 d_6垸基、〔3_6环烃基；在一些实施方案中， L2为 0， n为 3， L3为键， L4为 -P(0)(CH3)-， R11为甲基、 乙基、 异丙基、 -CH2-环丙基、 环丙基。 In some embodiments, L 2 is 0, n is 1, 2, 3 or 4, L 3 is a bond, L 4 is -P(0)(R 14 )-, R 11 is a fluorenyl group, a cyclic hydrocarbon group, a hetero Cycloalkyl, aryl, heteroaryl; In some embodiments, L 2 is 0, n is 3, L 3 is a bond, L 4 is -P(0)(fluorenyl)-, R 11 is a fluorenyl group, cycloalkyl, heterocycloalkyl; in some embodiments, L 2 is 0, n is 3, L 3 is a bond, L 4 is a -PiPXCw embankment yl) -, R 11 is alkyl with D_ 6, 3_ [6 cycloalkyl In some embodiments, L 2 is 0, n is 3, L 3 is a bond, L 4 is -P(0)(CH 3 )-, and R 11 is methyl, ethyl, isopropyl, -CH 2 -cyclopropyl, cyclopropyl.
在一些实施方案中， L2为 -NR12-、 L3为 -NR13-和 L4为 -S02-， R12与 R13以及与它们所 连接的原子一起形成至少含有两个 N原子的杂环烃基； 在一些实施方案中， L2为 -NR12-、 L3为 -NR13-和 L4为 -S02-， R12与 R13以及与它们所连接的原子一起形成至少含有两个 N原 子的 5或 6元杂环烃基； 在一些实施方案中， L2为 -NR12-、 L3为 -NR13-和 L4为 -S02-， 12 与 R13以及与它们所连接的原子一起形成哌嗪基。 In some embodiments, L 2 is -NR 12 -, L 3 is -NR 13 -, and L 4 is -S0 2 -, and R 12 and R 13 together with the atom to which they are attached form at least two N atoms. Heterocycloalkyl; in some embodiments, L 2 is -NR 12 -, L 3 is -NR 13 - and L 4 is -S0 2 -, and R 12 and R 13 together with the atoms to which they are attached form at least a 5- or 6-membered heterocycloalkyl containing two N atoms; in some embodiments, L 2 is -NR 12 -, L 3 is -NR 13 - and L 4 is -S0 2 -, 12 and R 13 and The atoms to which they are attached together form a piperazinyl group.
本发明一方面 异构体-
Figure imgf000005_0001
One aspect of the invention isomers -
Figure imgf000005_0001
其中，  among them,
n为 0、 1、 2、 3、 4或 5;  n is 0, 1, 2, 3, 4 or 5;
L3为键或 -NR13-; L 3 is a bond or -NR 13 -;
R13选自氢、 垸基、 环烃基、 芳基、 杂芳基； R 13 is selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, aryl, heteroaryl;
L4为 -P(0)(R14)-或 -S02-; L 4 is -P(0)(R 14 )- or -S0 2 -;
R11为 -NR15R16、 卤素、 羟基、 氰基、 硝基、 垸基、 垸氧基、 环烃基、 杂环烃基、 芳基 或杂芳基，或者 R11与 R13以及与它们所连接的原子一起形成含有 -P(0)(R14)-或 -S02-及至少 一个氮原子的杂环烃基； R 11 is -NR 15 R 16 , halogen, hydroxy, cyano, nitro, decyl, decyloxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or R 11 and R 13 and The attached atoms together form a heterocyclic hydrocarbon group containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom;
R14、 R15、 R16各自独立地选自氢、 垸基、 垸氧基、 环烃基、 杂环烃基、 芳基、杂芳基;R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen, fluorenyl, decyloxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
R19选自氢、 垸基、 环烃基、 杂环烃基、 芳基、 杂芳基； 前提条件是： 当 n=2或 3、 L3为键、 L4为 -S02-以及 R11为甲基或乙基时， R19选自环 烃基、 杂环烃基、 芳基、 杂芳基。 R 19 is selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; The prerequisite is: when n=2 or 3, L 3 is a bond, L 4 is -S0 2 -, and R 11 is a methyl group or an ethyl group, R 19 is selected from the group consisting of a cyclic hydrocarbon group, a heterocyclic hydrocarbon group, an aryl group, and a heteroaryl group. base.
在一些实施方案中， n为 2或 3。 在一些实施方案中， n为 2。 在一些实施方案中， n 为 3。  In some embodiments, n is 2 or 3. In some embodiments, n is 2. In some embodiments, n is 3.
在一些实施方案中， R19选自氢、 垸基、 环烃基； 优选地， R19选自氢、 d_6垸基、 C3_6 环烃基； 更优选地， R19选自氢、 甲基、 乙基、 丙基、 异丙基、 环丙基、 环丁基、 环己基； 最优选地， R19为氢。 In some embodiments, R 19 is selected from the group consisting of hydrogen, fluorenyl, and cycloalkyl; preferably, R 19 is selected from the group consisting of hydrogen, d- 6 fluorenyl, C 3 -6 cycloalkyl; more preferably, R 19 is selected from hydrogen, A , ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl group; most preferably, R 19 is hydrogen.
在一些实施方案中， L4为 -S02-。 In some embodiments, L 4 is -S0 2 -.
在一些实施方案中， 当 L3为键时， L4为 -P(0) (R14)-， 其中 R14为氢或垸基； 优选地， R14为垸基； 更优选地， R14为 d_6垸基； 甚至更优选地， R14为 d_4垸基； 最优选地， R14 为甲基。 In some embodiments, when L 3 is a bond, L 4 is —P(0) (R 14 )—, wherein R 14 is hydrogen or fluorenyl; preferably, R 14 is fluorenyl; more preferably, R 14 is d- 6 fluorenyl; even more preferably, R 14 is d 4 fluorenyl; most preferably, R 14 is methyl.
在一些实施方案中， 当 L3为键时， L4为 - S02 -。 In some embodiments, when L 3 is a bond, L 4 is -S0 2 -.
在一些实施方案中， L3为 -NR13-， 其中 R13选自氢、 垸基、 环烃基、 芳基、 杂芳基； 优选地， R13选自氢、 垸基； 更优选地， R13选自氢、 d_6垸基； 更优选地， R13选自氢。 In some embodiments, L 3 is -NR 13 -, wherein R 13 is selected from the group consisting of hydrogen, fluorenyl, cycloalkyl, aryl, heteroaryl; preferably, R 13 is selected from hydrogen, decyl; more preferably, R 13 is selected from hydrogen, d 6 fluorenyl; more preferably, R 13 is selected from hydrogen.
在一些实施方案中， R11选自 -NR15R16、 垸基、 环烃基、 杂环烃基、 芳基、 杂芳基。 在 一些实施方案中， R11选自 -N (垸基 )2、 -NH (；焼基)、 垸基、 环烃基、 杂环烃基、 芳基或杂芳 基。 在一些实施方案中， R11选自 -N(Cw垸基 )2、 -NH(Cw垸基)、 C^垸基、 C^环烃基、 3-6元杂环烃基、苯基、 5或 6元杂芳基。在一些实施方案中， R11选自 -N(d_6垸基 )2、 -NH C^ 垸基)、 d_6垸基、 _6环烃基。 在一些实施方案中， R11为 -N(d_4垸基 )2、 -NH Cw垸基)、 C1-4垸基、 C3-6环烃基。 在一些实施方案中， R11为 -N(CH3)2、 -NH(CH3)、 -CH3、 -C2H5、 环 丙基。 In some embodiments, R 11 is selected from the group consisting of -NR 15 R 16 , fluorenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl. In some embodiments, R 11 is selected from -N(indenyl) 2 , -NH (;indenyl), fluorenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 11 is selected from -N(Cw fluorenyl) 2 , -NH(Cw fluorenyl), C hydrazino, C^cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5 or 6-membered heteroaryl. In some embodiments, R 11 is selected from the group consisting of -N(d- 6 fluorenyl) 2 , -NH C fluorenyl), d- 6 fluorenyl, -6 cycloalkyl. In some embodiments, R 11 is —N(d 4 fluorenyl) 2 , —NH Cw fluorenyl, C 1-4 fluorenyl, C 3-6 cycloalkyl. In some embodiments, R 11 is —N(CH 3 ) 2 , —NH(CH 3 ), —CH 3 , —C 2 H 5 , cyclopropyl.
在一些实施方案中， 当 L3为 -NR13-时， R11与 R13以及与它们所连接的原子一起形成含 有 -P(0)(R14)-或 -S02-及至少一个氮原子的杂环烃基。在一些实施方案中， 当 L3为 -NR13-时， 11与 R13以及与它们所连接的原子一起形成含有 -P(0)(R14)-或 -S02-及至少一个氮原子的 3-12元杂环烃基。在一些实施方案中， 当 L3为 -NR13-时， R11与 R13以及与它们所连接的原 子一起形成含有 -P(0)(R14)-或 -S02-及至少一个氮原子的 3、 4、 5或 6元杂环烃基。 在一些 实施方案中，当 L3为 -NR13-时， R11与 R13以及与它们所连接的原子一起形成含有 -P(0)(R14)- 或 -S02-及至少一个氮原子的 5或 6元杂环烃基。 在一些实施方案中， 当 L3为 -NR13-时， R11与 R13以及与它们所连接的原子一起形成含有 -S02-及至少一个氮原子的 5或 6元杂环 烃基。在一些实施方案中， 当 L3为 -NR13-时， R11与 R13以及与它们所连接的原子一起形成 含有 -S02-及一个氮原子的 5元杂环烃基。 In some embodiments, when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A heterocyclic hydrocarbon group of an atom. In some embodiments, when L 3 is -NR 13 -, 1 1 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 3-12 membered heterocycloalkyl group of an atom. In some embodiments, when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 3, 4, 5 or 6 membered heterocycloalkyl group of an atom. In some embodiments, when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and at least one nitrogen A 5- or 6-membered heterocycloalkyl group of an atom. In some embodiments, when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form a 5 or 6 membered heterocycloalkyl containing -S0 2 - and at least one nitrogen atom. In some embodiments, when L 3 is -NR 13 -, R 11 and R 13 together with the atom to which they are attached form a 5-membered heterocycloalkyl containing -S0 2 - and a nitrogen atom.
在一些实施方案中， n为 2或 3， L3为键， L4为 -S02-， R11为 -NR15R16、 垸基、环烃基； 在一些实施方案中， n为 2或 3， L3为键， L4为 -S02-， R11为 -NHd_6垸基、 -N(d_6垸基 )2、 C^垸基、 〔3_6环烃基； 在一些实施方案中， n为 3， L3为键， L4为 -S02-， R11为 -NR15R16、 垸基； 在一些实施方案中， n为 3， L3为键， L4为 -S02-， R11为 -N (垸基 )2、 -NH (垸基)、 垸 基； 在一些实施方案中， n为 3， L3为键， L4为 -S02-， R11为 -N(Cw垸基 )2、 -NH(C^垸基)、 Cw垸基；在一些实施方案中， n为 3， L3为键， L4为 -S02-， R11为 -N(CH3)2、 -NHCH3、 -CH3。 In some embodiments, n is 2 or 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl, cycloalkyl; in some embodiments, n is 2 or 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NHd_ 6 fluorenyl, -N(d_ 6 fluorenyl) 2 , C ^ fluorenyl, [ 3 -6 cycloalkyl; in some embodiments Wherein n is 3, L 3 is a bond, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl; in some embodiments, n is 3, L 3 is a bond, and L 4 is - S0 2 -, R 11 is -N(fluorenyl) 2 , -NH(fluorenyl), fluorenyl; in some embodiments, n is 3, L 3 is a bond, and L 4 is -S0 2 -, R 11 Is -N(Cw fluorenyl) 2 , -NH(C^ fluorenyl), Cw decyl; in some embodiments, n is 3, L 3 is a bond, L 4 is -S0 2 -, and R 11 is - N(CH 3 ) 2 , -NHCH 3 , -CH 3 .
在一些实施方案中， n为 1、 2、 3或 4， L3为 -NR13-， L4为 -S02-， R11为 -NR15R16、 垸 基、 环烃基、 杂环烃基、 芳基、 杂芳基， 或者 R11与 R13以及与它们所连接的原子一起形 成含有 -P(0)(R14)-或 -S02-及至少一个氮原子的杂环烃基； 在一些实施方案中， n为 2或 3， L3为 -NR13-， L4为 -S02-， R11为 -NR15R16、 垸基、 环烃基、 杂环烃基， 或者 R11与 R13以及 与它们所连接的原子一起形成含有 -P(0)(R14)-或 -S02-及至少一个氮原子的 3-12 元杂环烃 基； 在一些实施方案中， n为 2或 3， L3为 -NR13-， L4为 -S02-， R11与 R13以及与它们所连 接的原子一起形成含有 -P(0)(R14)-或 -S02-及至少一个氮原子的 3、 4、 5或 6元杂环烃基， 或者 R11为垸基、 环烃基、 杂环烃基； 在一些实施方案中， n为 2或 3， L3为 -NR13-， L4为 -S02-， 11与 R13以及与它们所连接的原子一起形成含有 -P(0)(R14)-或 -S02-及至少一个氮原 RR Q基基 ± 11 In some embodiments, n is 1, 2, 3 or 4, L 3 is -NR 13 -, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl, cycloalkyl, heterocycloalkyl , aryl, heteroaryl, or R 11 and R 13 together with the atom to which they are attached form a heterocycloalkyl containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom; In some embodiments, n is 2 or 3, L 3 is -NR 13 -, L 4 is -S0 2 -, R 11 is -NR 15 R 16 , fluorenyl, cycloalkyl, heterocycloalkyl, or R 11 R 13 and together with the atoms to which they are attached form a 3-12 membered heterocycloalkyl containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom; in some embodiments, n is 2 Or 3, L 3 is -NR 13 -, L 4 is -S0 2 -, R 11 and R 13 together with the atom to which they are attached form -P(0)(R 14 )- or -S0 2 - and a 3, 4, 5 or 6 membered heterocycloalkyl group of at least one nitrogen atom, or R 11 is a fluorenyl group, a cycloalkyl group, a heterocycloalkyl group; in some embodiments, n is 2 or 3 and L 3 is -NR 13 - , L 4 is -S0 2 -, 11 and R 13 together with the atoms to which they are attached form -P(0) (R 14 )- or -S0 2 - and at least one nitrogen source RR Q basis ± 11
子的 5或 6元杂环烃基； 在一些实施方案中， n为 2， L3为 -NR13-， L4为 -S02-， R11与 R13 以及与它们所连接的原子一起形成含有 -S02-及至少一个氮原子的 5元杂环烃基；在一些实 施方案中， n为 2， L3为 -NR13-， L4为 -S02-， R11与 R13以及与它们所连接的原子一起形成 含有 -S02-及一个氮原子的 5元杂环烃基。在一些实施方案中， n为 2， L3为 -NH -， L4为 -S02-， 1为垸基、 环烃基。 在一些实施方案中， n为 2， L3为 -NH -， L4为 -S02-， R11为 d_6垸基、 _6环烃基。 a 5- or 6-membered heterocycloalkyl; in some embodiments, n is 2, L 3 is -NR 13 -, L 4 is -S0 2 -, R 11 and R 13 are taken together with the atoms to which they are attached a 5-membered heterocycloalkyl containing -S0 2 - and at least one nitrogen atom; in some embodiments, n is 2, L 3 is -NR 13 -, L 4 is -S0 2 -, R 11 and R 13 and The atoms to which they are attached together form a 5-membered heterocycloalkyl group containing -S0 2 - and a nitrogen atom. In some embodiments, n is 2, L 3 is -NH -, L 4 is -S0 2 -, and 1 is a fluorenyl, cycloalkyl group. In some embodiments, n is 2, L 3 is -NH -, L 4 is -S0 2 -, and R 11 is d- 6 fluorenyl, -6 cycloalkyl.
在一些实施方案中， n为 1、 2、 3或 4， L3为键， L4为 -P(0)(R14)-， R11为垸基、 环烃 、 杂环烃基、 芳基、 杂芳基； 在一些实施方案中， n为 3， L3为键， L4为 -P(0)(焼基) -， 1为垸基、 环烃基、 杂环烃基； 在一些实施方案中， n为 3， L3为键， L4为 -PiPXCw焼 ) -， R11为 C^垸基、 C^环烃基； 在一些实施方案中， n为 3， L3为键， L4为 -P(0)(CH3)-， 1为甲基、 乙基、 异丙基、 -CH2-环丙基、 环丙基。 In some embodiments, n is 1, 2, 3 or 4, L 3 is a bond, L 4 is -P(0)(R 14 )-, and R 11 is a fluorenyl group, a cyclic hydrocarbon, a heterocycloalkyl group, an aryl group. Heteroaryl; in some embodiments, n is 3, L 3 is a bond, L 4 is -P(0)(fluorenyl)-, 1 is a fluorenyl, cycloalkyl, heterocycloalkyl; in some embodiments Wherein n is 3, L 3 is a bond, L 4 is -PiPXCw焼) -, R 11 is a C^ fluorenyl group, a C^cycloalkyl group; in some embodiments, n is 3, L 3 is a bond, L 4 Is -P(0)(CH 3 )-, 1 is methyl, ethyl, isopropyl, -CH 2 -cyclopropyl, cyclopropyl.
Figure imgf000007_0001
Figure imgf000007_0001
本发明的另一方面还涉及通式 I化合物或其盐或其立体异构体的制备方法，其中， ιΛ Another aspect of the invention also relates to a process for the preparation of a compound of formula I or a salt thereof or a stereoisomer thereof, wherein
L2、 L3、 L4、 Κλ R2、 R3、 R R R6、 R R R9、 R10、 RU、 R17、 R18、 R19、 m、 n与 上文中通式 I化合物 选的定义。 L 2 , L 3 , L 4 , Κλ R 2 , R 3 , RRR 6 , RRR 9 , R 10 , R U , R 17 , R 18 , R 19 , m, n and the definition of the compound of formula I above .
Figure imgf000007_0002
Figure imgf000007_0002
1为 -CH20-时， 通式 I化合物或其盐或其立体异构体可通过以下方法的制备: When 1 is -CH 2 0-, the compound of the formula I or a salt thereof or a stereoisomer thereof can be produced by the following method:
Figure imgf000007_0003
Figure imgf000007_0003
当 X为羟基时， 通式化合物 I可以通过式 1的化合物和式 2的化合物进行 Mitsunobu 反应来制备。 在 Mitsunobu反应中， 化合物 1和化合物 2在偶氮二羰基化合物 （例如偶氮 二甲酸二乙酯、 偶氮二甲酸二异丙酯、 Ι,Γ- (偶氮二羰基)二哌啶） 和有机膦化合物 （例如 三苯基膦， 三丁基膦） 的存在下反应；  When X is a hydroxyl group, the compound of the formula I can be produced by a Mitsunobu reaction of the compound of the formula 1 and the compound of the formula 2. In the Mitsunobu reaction, compound 1 and compound 2 are in an azodicarbonyl compound (e.g., diethyl azodicarboxylate, diisopropyl azodicarboxylate, hydrazine, hydrazine-(azodicarbonyl)dipiperidine) and Reaction in the presence of an organophosphine compound such as triphenylphosphine, tributylphosphine;
当 X为离去基团时， 通式化合物 I可以通过式 1的化合物和式 2的化合物在碱存在下 反应而制备。 所述的离去基团， 可以是卤原子、 任选地被氯取代的垸基磺酰基氧基。 所采 用的碱可以是碱金属氢氧化物、 碱金属碳酸盐类或有机碱。When X is a leaving group, the compound of the formula I can be prepared by reacting a compound of the formula 1 with a compound of the formula 2 in the presence of a base. The leaving group may be a halogen atom, a fluorenylsulfonyloxy group optionally substituted by chlorine. Take The base used may be an alkali metal hydroxide, an alkali metal carbonate or an organic base.
1为 -CH2NH-时， 通式 I化合物或其盐或其立体异构体可通过以下方法的制备: When 1 is -CH 2 NH-, the compound of the formula I or a salt thereof or a stereoisomer thereof can be produced by the following method:
Figure imgf000008_0001
Figure imgf000008_0001
X为离去基团， 通式化合物 I可以通过式 1表示的化合物和式 3表示的化合物在碱存 在下反应而制备。 也可以通过式 4化合物和式 3化合物反应生成 Schiff碱， 然后再通过还 原剂还原制备化合物 I。 X is a leaving group, and the compound of the formula I can be produced by reacting a compound represented by the formula 1 and a compound represented by the formula 3 in the presence of a base. It is also possible to produce a Schiff base by reacting a compound of the formula 4 with a compound of the formula 3, and then preparing the compound I by reduction with a reducing agent.
1为^^时， 通式 I化合物或其盐或其立体异构体可通过以下方法的制备-  When 1 is ^^, the compound of the formula I or a salt thereof or a stereoisomer thereof can be produced by the following method -
Figure imgf000008_0002
Figure imgf000008_0002
X为离去基团， 通式化合物 I可以通过式 5表示的化合物和式 6表示的化合物在钯金 属催化剂存在下， 通过偶合反应而制备。  X is a leaving group, and the compound of the formula I can be produced by a coupling reaction of a compound represented by the formula 5 and a compound represented by the formula 6 in the presence of a palladium catalyst.
式 1、 4和 5表示的化合物可通过以下方法制备：  The compounds represented by Formulas 1, 4 and 5 can be prepared by the following methods:
Figure imgf000008_0003
Figure imgf000008_0003
当 X为离去基团时， 式 1、 4和 5表示的化合物可以通过式 7表示的化合物和式 8表 示的化合物在碱存在下反应而制备。  When X is a leaving group, the compound represented by Formulas 1, 4 and 5 can be produced by reacting a compound represented by Formula 7 with a compound represented by Formula 8 in the presence of a base.
Figure imgf000008_0004
Figure imgf000008_0004
p为羟基保护基 上述合成方法只是示例性地列举了本发明中部分化合物的制备方法， 按照本领域的公 知技术， 本领域技术人员在上述合成方案的基础上， 采用类似的方法也可以合成本发明的 化合物。 P is a hydroxy protecting group The above synthesis methods are merely illustrative of the preparation methods of some of the compounds of the present invention, and those skilled in the art can also synthesize the compounds of the present invention by a similar method based on the above-mentioned synthetic schemes according to the well-known techniques in the art.
本发明化合物可以是不对称的， 例如， 具有一个或多个手性中心， 因此具有一个或多 个立体异构体。 除非另有说明， 所有的立体异构体形式都包括在内， 如对映异构体和非对 映异构体。 本发明的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋混合物 形式被分离出来。 光学活性纯的形式可以从外消旋混合物中拆分出， 也可以通过使用手性 原料或手性试剂合成。  The compounds of the invention may be asymmetric, for example, having one or more chiral centers and thus having one or more stereoisomers. All stereoisomeric forms are included, such as enantiomers and diastereomers, unless otherwise indicated. The asymmetric carbon atom-containing compound of the present invention can be isolated in optically active pure form or as a racemic mixture. The optically active pure form can be resolved from the racemic mixture or it can be synthesized by using a chiral starting material or a chiral reagent.
作为药学上可接受的盐， 例如， 可以提及金属盐、 铵盐、 与有机碱形成的盐、 与无机 酸形成的盐、 与有机酸形成的盐、 与碱性或者酸性氨基酸形成的盐等。 金属盐的非限制性 实例包括但不限于碱金属的盐， 例如钠盐、 钾盐等； 碱土金属的盐， 例如钙盐、 镁盐、 钡 盐等； 铝盐等。与有机碱形成的盐的非限制性实例包括但不限于与三甲胺、三乙胺、 吡啶、 甲基吡啶、 2,6-二甲基吡啶、 乙醇胺、 二乙醇胺、 三乙醇胺、 环己胺、 二环己基胺等形成 的盐。 与无机酸形成的盐的非限制性实例包括但不限于与盐酸、 氢溴酸、 硝酸、 硫酸、 磷 酸等形成的盐。与有机酸形成的盐的非限制性实例包括但不限于与甲酸、 乙酸、三氟乙酸、 富马酸、 草酸、 苹果酸、 马来酸、 酒石酸、 柠檬酸、 琥珀酸、 甲磺酸、 苯磺酸、 对甲基苯 磺酸等形成的盐。与碱性氨基酸形成的盐的非限制性实例包括但不限于与精氨酸、赖氨酸、 鸟氨酸等形成的盐。 与酸性氨基酸形成的盐的非限制性实例包括但不限于与天冬氨酸、 谷 氨酸等形成的盐。  As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned. . Non-limiting examples of metal salts include, but are not limited to, alkali metal salts such as sodium salts, potassium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts, and the like; aluminum salts and the like. Non-limiting examples of salts formed with organic bases include, but are not limited to, with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, A salt formed by dicyclohexylamine or the like. Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Non-limiting examples of salts formed with organic acids include, but are not limited to, with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzene. a salt formed of a sulfonic acid, p-toluenesulfonic acid or the like. Non-limiting examples of salts formed with basic amino acids include, but are not limited to, salts formed with arginine, lysine, ornithine, and the like. Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, and the like.
本发明的另一方面还涉及药物组合物， 其包含治疗有效量的本发明的通式 I或 II的化 合物或其药学上可接受的盐、 其立体异构体和药学上可接受的载体。  Another aspect of the invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or II of the invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and a pharmaceutically acceptable carrier.
本发明的药物组合物可通过将本发明的化合物或其盐或其立体异构体与适宜的药学 上可接受的载体组合而制备， 例如可配制成固态、 半固态、 液态或气态制剂， 如片剂、 丸 剂、 胶囊剂、 粉剂、 颗粒剂、 膏剂、 乳剂、 悬浮剂、 溶液剂、 栓剂、 注射剂、 吸入剂、 凝 胶剂、 微球及气溶胶等。  The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention or a salt thereof or a stereoisomer thereof with a suitable pharmaceutically acceptable carrier, for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation, such as Tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
给予本发明的化合物或其药物可接受的盐或其立体异构体或其药物组合物的典型途 径包括但不限于口服、 直肠、 透黏膜、 经肠给药， 或者局部、 经皮、 吸入、 肠胃外、 舌下、 阴道内、 鼻内、 眼内、 腹膜内、 肌内、 皮下、 静脉内给药。 优选的给药途径是口服给药。  Typical routes of administration of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, Parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous. A preferred route of administration is oral administration.
本发明的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、 制粒法、 制糖衣药丸法、 磨细法、 乳化法、 冷冻干燥法等等。  The pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a dragee method, a pulverization method, an emulsification method, a lyophilization method, and the like.
在优选的实施方案中， 药物组合物是口服形式。 对于口服给药， 可以通过将活性化合 物与本领域熟知的药学上可接受的载体混合来配制该药物组合物。 这些载体能使本发明的 化合物被配制成片剂、 丸剂、 锭剂、 糖衣剂、 胶囊剂、 液体、 凝胶剂、 浆剂、 悬浮剂等， 用于对患者的口服给药。  In a preferred embodiment, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by admixing the active compound with a pharmaceutically acceptable carrier well known in the art. These carriers enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
可以通过常规的混合、 填充或压片方法来制备固体口服组合物。 例如， 可通过下述方 法获得： 将所述的活性化合物与固体赋形剂混合， 任选地碾磨所得的混合物， 如果需要则 加入其它合适的辅剂， 然后将该混合物加工成颗粒， 得到了片剂或糖衣剂的核心。 适合的 辅料包括但不限于： 粘合剂、 稀释剂、 崩解剂、 润滑剂、 助流剂、 甜味剂或矫味剂等。 如 微晶纤维素、 葡萄糖溶液、 阿拉伯胶浆、 明胶溶液、 蔗糖和淀粉糊； 滑石、 淀粉、 硬脂酸 镁、 硬脂酸钙或硬脂酸； 乳糖、 蔗糖、 淀粉、 甘露糖醇、 山梨糖醇或磷酸二钙； 二氧化硅; 交联羧甲基纤维素钠、 预交化淀粉、 淀粉羟乙酸钠、 藻酸、 玉米淀粉、 马铃薯淀粉、 甲基 纤维素、 琼脂、 羧甲基纤维素、 交联聚乙烯吡咯垸酮等。 可以根据通常药物实践中公知的 方法任选地对糖衣剂的核心进行包衣， 尤其使用肠溶包衣。  Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules. The core of a tablet or dragee. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like. Such as microcrystalline cellulose, glucose solution, gum arabic, gelatin solution, sucrose and starch paste; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitol Sugar alcohol or dicalcium phosphate; silica; croscarmellose sodium, pre-treated starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, carboxymethyl fiber , cross-linked polyvinylpyrrolidone and the like. The core of the dragee can optionally be coated according to methods well known in the ordinary pharmaceutical practice, especially using enteric coatings.
药物组合物还可适用于肠胃外给药， 如合适的单位剂型的无菌溶液剂、 混悬剂或冻干 产品。 能够使用适当的赋形剂， 例如填充剂、 缓冲剂或表面活性剂。  The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form. Suitable excipients such as fillers, buffers or surfactants can be used.
本发明的另一方面还涉及本发明的通式 I或 Π的化合物或其药学上可接受的盐、 其立 体异构体或其药物组合物在制备用于治疗和 /或预防与 GPR40相关的疾病的药物中的用途。 本发明的另一方面还涉及本发明的通式 I或 Π的化合物或其药学上可接受的盐、 其立 体异构体或其药物组合物在制备用于治疗和 /或预防糖尿病的药物中的用途。 Another aspect of the invention also relates to a compound of formula I or hydrazine of the invention, or a pharmaceutically acceptable salt thereof, Use of an isomer or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment and/or prevention of a disease associated with GPR40. Another aspect of the invention also relates to a compound of formula I or hydrazine of the invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for the treatment and/or prevention of diabetes the use of.
本发明的另一方面还涉及用于治疗和 /或预防与 GPR40相关的疾病的本发明的通式 I 或 II的化合物或其药学上可接受的盐、 其立体异构体。  Another aspect of the invention also relates to a compound of formula I or II of the invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in the treatment and/or prevention of a disease associated with GPR40.
本发明的另一方面还涉及用于治疗和 /或预防糖尿病的本发明的通式 I或 Π的化合物或 其药学上可接受的盐、 其立体异构体。  Another aspect of the invention also relates to a compound of formula I or hydrazine of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of diabetes, a stereoisomer thereof.
本发明的另一方面还涉及治疗和 /或预防与 GPR40相关的疾病的方法， 其中将治疗有 效量的本发明的通式 I或 Π的化合物或其药学上可接受的盐、 其立体异构体对有需要的哺 乳动物给药。  Another aspect of the invention also relates to a method of treating and/or preventing a disease associated with GPR40, wherein a therapeutically effective amount of a compound of formula I or hydrazine of the invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof The body is administered to a mammal in need thereof.
本发明的另一方面还涉及治疗和 /或预防糖尿病的方法，其中将治疗有效量的本发明的 通式 I或 II的化合物或其药学上可接受的盐、 其立体异构体对有需要的哺乳动物给药。  Another aspect of the invention also relates to a method of treating and/or preventing diabetes, wherein a therapeutically effective amount of a compound of formula I or II of the invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, is required Mammal administration.
本文所述的通式 I或 Π的化合物或其药学上可接受的盐或其立体异构体的所有给药 方法中， 每天给药的剂量优选为 0.01到 200mg/Kg体重。  In all methods of administration of a compound of Formula I or hydrazine, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as described herein, the daily dose is preferably 0.01 to 200 mg/kg body weight.
关于本发明的通式 I或 II化合物或其盐或其立体异构体的 GPR40激动活性，优选 EC5Q 小于 1000 nM， 更优选 EC5Q小于 100 nM， 最优选 EC5Q小于 10 nM。 With respect to the GPR40 agonistic activity of the compound of the formula I or II of the present invention or a salt thereof or a stereoisomer thereof, it is preferred that the EC 5Q is less than 1000 nM, more preferably the EC 5Q is less than 100 nM, and most preferably the EC 5Q is less than 10 nM.
除非另有说明， 本文中所用的术语具有如下含义：  Unless otherwise stated, the terms used herein have the following meanings:
术语"卤素"是指氟、 氯、 溴或碘， 优选氟或氯。  The term "halogen" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
术语"羟基"指 -OH基团， 其中的氢原子可以被取代基取代。  The term "hydroxy" refers to an -OH group in which a hydrogen atom may be substituted with a substituent.
术语"氰基"指 -CN基团。  The term "cyano" refers to a -CN group.
术语"硝基"指 -N02基团。 The term "nitro" refers to a -N0 2 group.
术语"焼基"是指由碳原子和氢原子组成的直链或支链的饱和的脂肪烃基团， 其通过单 键与分子的其余部分连接。 例如所述垸基可具有 1-20个碳原子， 优选具有 1-8个碳原子， 更优选具有 1-6个碳原子，最优选 1-4个碳原子。所述的垸基可以是未取代或是被取代基 取代的。 垸基的非限制性实例包括但不限于甲基、 乙基、 丙基、 2-丙基、 正丁基、 异丁基、 叔-丁基、 正-戊基、 2-甲基丁基、 新戊基、 正己基、 2-甲基己基、 -CH2-环丙基等。 The term "mercapto" refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, which is attached to the remainder of the molecule by a single bond. For example, the fluorenyl group can have from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms, and most preferably from 1 to 4 carbon atoms. The thiol group may be unsubstituted or substituted with a substituent. Non-limiting examples of sulfhydryl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, Neopentyl, n-hexyl, 2-methylhexyl, -CH 2 -cyclopropyl, and the like.
术语"垸氧基 "是指 -0-垸基， 其中垸基的定义与上文的垸基定义相同。 优选含有 1-4个 碳原子的垸氧基。 所述的垸氧基可以是未取代或是被取代基取代的。 垸氧基的非限制性 实例包括但不限于甲氧基、 乙氧基、 丙氧基、异丙氧基、 正丁氧基、 异丁氧基、叔-丁氧基、 正-戊氧基、 2-甲基丁氧基、 新戊氧基、 正己氧基、 2-甲基己氧基等。  The term "decyloxy" refers to a -0-fluorenyl group, wherein the definition of fluorenyl is the same as defined above. A decyloxy group having 1 to 4 carbon atoms is preferred. The oximeoxy group may be unsubstituted or substituted with a substituent. Non-limiting examples of methoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy , 2-methylbutoxy, neopentyloxy, n-hexyloxy, 2-methylhexyloxy and the like.
术语"环烃基 "是指由碳原子和氢原子组成的饱和的或不饱和的非芳香性的环状烃基， 优选包含 1、 2或 3个环， 每个环具有 3-7个环碳原子， 更优选共包含 3-12个环碳原子的 饱和环垸基， 最优选共包含 3-6个环碳原子的饱和环垸基。所述的环烃基可以是未取代或 是被取代基取代的。 环烃基的非限制性实例包括但不限于环丙基、 环丁基、 环戊基、 环己 基禾口环庚基等。  The term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic cyclic hydrocarbon group consisting of carbon atoms and hydrogen atoms, preferably containing 1, 2 or 3 rings, each ring having 3 to 7 ring carbon atoms. More preferably, it is a saturated cyclic fluorenyl group containing 3 to 12 ring carbon atoms in total, and most preferably a saturated cyclic fluorenyl group containing 3 to 6 ring carbon atoms in total. The cyclic hydrocarbon group may be unsubstituted or substituted with a substituent. Non-limiting examples of cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like.
术语"烯基"是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂 肪族烃基，优选含有 2-4个碳原子的直链或支链的烯基。所述的烯基可以是未取代或是被 取代基取代的。 烯基的非限制性实例包括但不限于乙烯基、 1-丙烯基、 2-丙烯基、 1-丁烯 基、 异丁烯基。  The term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group having at least one double bond consisting of a carbon atom and a hydrogen atom, preferably a linear or branched alkenyl group having 2 to 4 carbon atoms. . The alkenyl group may be unsubstituted or substituted with a substituent. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl.
术语"炔基"是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂 肪族烃基， 优选含有 2-4个碳原子的直链或支链的炔基。 所述的炔基可以是未取代或是被 取代基取代的。 炔基的非限制性实例包括但不限于乙炔基、 1-丙炔基、 2-丙炔基。  The term "alkynyl" means a straight or branched unsaturated aliphatic hydrocarbon group having at least one triple bond composed of a carbon atom and a hydrogen atom, preferably a linear or branched alkynyl group having 2 to 4 carbon atoms. . The alkynyl group may be unsubstituted or substituted with a substituent. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl.
术语"氨基"指 -NH2基团， 其中的氢原子可以被取代基取代。 The term "amino" refers to a -NH 2 group in which a hydrogen atom may be substituted with a substituent.
术语"芳基"是指具有共轭的 π电子体系的全碳单环或稠合多环的芳香环基团， 优选具 有 6-14个碳原子，更优选具有 6-10个碳原子。所述的芳基可以是未取代或是被取代基取 代的。 芳基的非限制性实例包括但不限于苯基、 萘基和蒽基。 术语"杂芳基 "是指具有 5-14个环原子的单环或稠合多环体系， 其中含有 1-6个选 N、 0、 S的环原子， 其余环原子为 C， 并且具有至少一个芳香环。 所述杂芳基优选 具有 5或 6元环， 更优选为 5元环。 所述的杂芳基可以是未取代或是被取代基取代的。 杂芳基的非限制性实例包括但不限于吡咯基、 呋喃基、 噻吩基、 咪唑基、 噁唑基、 吡唑基、 吡啶基、 嘧啶基、 吡嗪基、 喹啉基、 异喹啉基、 四唑基、 三唑基、 三嗪基。 The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system, preferably having from 6 to 14 carbon atoms, more preferably from 6 to 10 carbon atoms. The aryl group may be unsubstituted or substituted with a substituent. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system having from 5 to 14 ring atoms containing from 1 to 6 ring atoms selected from N, 0, S, the remaining ring atoms being C, and having at least An aromatic ring. The heteroaryl group preferably has a 5- or 6-membered ring, more preferably a 5-membered ring. The heteroaryl group may be unsubstituted or substituted with a substituent. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , tetrazolyl, triazolyl, triazinyl.
术语"杂环烃基"是指具有 3-18个环原子的无芳香性的单环或稠合多环体系基团， 其中 1-6个环原子是选自 N、 0、 S( )n (其中 n为 0、 1或 2 ) 的杂原子， 其余环原子 为〔。 这样的环可以是饱和的或不饱和的 （例如具有一个或多个双键）， 但是不具有完 全共轭的 π-电子体系。 所述的杂环烃基可以是未取代或是被取代基取代的。 3 元杂环 烃基的实例包括但不限于环氧乙垸基、 环硫乙垸基、 环氮乙垸基， 4 元杂环烃基的实 例包括但不限于吖丁啶基、 噁丁环基、 噻丁环基， 5元杂环烃基的实例包括但不限于四 氢呋喃基、 四氢噻吩基、 吡咯垸基、 异噁唑垸基、 噁唑垸基、 异噻唑垸基、 1,1-二氧代异 噻唑垸基、 噻唑垸基、 咪唑垸基、 四氢吡唑基、 吡咯啉基、 二氢呋喃基、 二氢噻吩基， 6 元杂环烃基的实例包括但不限于哌啶基、 四氢吡喃基、 四氢噻喃基、 吗啉基、 哌嗪基、 1,4-噻噁垸基、 1,4-二氧六环基、 硫代吗啉基、 1,2-、 1,4-二噻垸基、 二氢吡啶基、 四氢吡 啶基、 二氢吡喃基、 四氢吡喃基、 二氢噻喃基， 7 元杂环烃基的实例包括但不限于氮杂 环庚垸基、 氧杂环庚垸基、 硫杂环庚垸基。 优选为具有 5或 6个环原子的杂环烃基。 The term "heterocycloalkyl" refers to a non-aromatic monocyclic or fused polycyclic system group having from 3 to 18 ring atoms, wherein from 1 to 6 ring atoms are selected from N, 0, S( ) n ( Where n is a hetero atom of 0, 1 or 2), and the remaining ring atoms are [. Such rings may be saturated or unsaturated (eg, having one or more double bonds), but do not have a fully conjugated π-electron system. The heterocyclic hydrocarbon group may be unsubstituted or substituted with a substituent. Examples of the 3-membered heterocyclic hydrocarbon group include, but are not limited to, an epoxyethyl group, an episulfothyl group, a cyclohexamethylene group, and examples of the 4-membered heterocyclic hydrocarbon group include, but are not limited to, azetidinyl, oxetane, thidium Examples of the cyclic group, 5-membered heterocycloalkyl group include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, 1,1-dioxo Examples of thiazolylhydrazyl, thiazolylhydrazyl, imidazolium, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothienyl, 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyridyl Cyclol, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thiaxanyl, 1,4-dioxyl, thiomorpholinyl, 1,2-, 1,4 Examples of -dithiadecyl, dihydropyridyl, tetrahydropyridyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, 7-membered heterocycloalkyl include, but are not limited to, azacyclononane Base, oxetanyl, thiaheptanyl. Preferred are heterocyclic hydrocarbon groups having 5 or 6 ring atoms.
除非另有说明， 术语"被取代基取代 "意味着该基团被一个或多个取代基所取代， 该取 代基的非限制性实例包括但不限于卤素、 垸基、 卤素取代的垸基、 烯基、 炔基、 垸氧基、 卤素取代的垸氧基、 环烃基、 羟基、 巯基、 垸基巯基、 硝基、 氰基、 =0、 垸基酰基、 羧 基、 垸基酰氧基、 垸基酰氨基、 垸基亚磺酰基、 垸基磺酰基、 氨基、 氨基甲酰基、 芳基、 芳垸基、 杂环烃基、 杂环烃基垸基、 杂芳基或杂芳基垸基。  Unless otherwise indicated, the term "substituted with a substituent" means that the group is substituted by one or more substituents, non-limiting examples of which include, but are not limited to, halogen, fluorenyl, halogen-substituted fluorenyl, Alkenyl, alkynyl, decyloxy, halogen-substituted decyloxy, cycloalkyl, hydroxy, decyl, decyl fluorenyl, nitro, cyano, =0, decyl acyl, carboxy, decanoyloxy, hydrazine Alkylamino, fluorenylsulfinyl, decylsulfonyl, amino, carbamoyl, aryl, aryl fluorenyl, heterocycloalkyl, heterocycloalkyl fluorenyl, heteroaryl or heteroaryl fluorenyl.
术语"治疗有效量"是指当对哺乳动物， 优选对人给药时， 本发明的通式 I或 Π化合物 或其药学上可接受的盐或其立体异构体足以有效地治疗哺乳动物的（优选人的）与 GPR40 相关的疾病 （特别是糖尿病相关的疾病） 的量。 构成"治疗有效量"的本发明的通式 I或 Π 化合物或其药学上可接受的盐或其立体异构体的量取决于化合物、 疾病状态及其严重性、 给药方式以及待被治疗的哺乳动物的年龄而改变， 但可例行性地由本领域技术人员根据其 自身的知识及本发明公开内容而确定。  The term "therapeutically effective amount" means that when administered to a mammal, preferably a human, the Formula I or guanidine compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, is sufficient to effectively treat a mammal. The amount of (preferably human) a disease associated with GPR40, particularly a diabetes-related disease. The amount of a compound of formula I or hydrazine of the present invention or a pharmaceutically acceptable salt thereof or a stereoisomer thereof which constitutes a "therapeutically effective amount" depends on the compound, the state of the disease and its severity, the mode of administration, and the condition to be treated. The age of the mammal varies, but can be routinely determined by one skilled in the art based on its own knowledge and disclosure of the present invention.
术语"治疗"意为将本发明所述化合物或制剂进行给药以预防、 改善或消除疾病或与所 述疾病相关的一个或多个症状， 且包括：  The term "treating" means administering a compound or formulation of the invention to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) 预防疾病或疾病状态在哺乳动物中出现， 特别是当这类哺乳动物易患有该疾病状 态， 但尚未被诊断为已患有该疾病状态时；  (i) preventing a disease or condition in a mammal, particularly when such a mammal is susceptible to the condition of the disease but has not yet been diagnosed as having the condition;
(ii) 抑制疾病或疾病状态， 即遏制其发展；  (ii) inhibiting the disease or disease state, ie curbing its development;
(iii) 缓解疾病或疾病状态， 即使该疾病或疾病状态消退。  (iii) alleviating the disease or condition, even if the disease or condition resolves.
术语"药物组合物"是指一种或多种本发明的通式 I或 Π化合物或其药学上可接受的盐 或其立体异构体与在本领域中通常接受的用于将生物活性化合物输送至有机体 (例如人)的 载体、 赋形剂和 /或介质的制剂。 药物组合物的目的是有利于对有机体给予本发明的通式 I 或 Π化合物或其药学上可接受的盐或其立体异构体。  The term "pharmaceutical composition" refers to one or more of the formula I or indole compounds of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and are generally accepted in the art for use in biologically active compounds. A formulation of a carrier, excipient, and/or vehicle that is delivered to an organism (eg, a human). The purpose of the pharmaceutical composition is to facilitate administration of an organism of the formula I or hydrazine compound of the present invention or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, to an organism.
术语"药学上可接受的载体 "是指对有机体无明显剌激作用， 而且不会损害该活性化合 物的生物活性及性能的那些载体和稀释剂。 "药学上可接受的载体"包括但不限于被国家食 品药品管理局许可为可接受的用于人或家畜动物的任何载体、 赋形剂、 介质、 助流剂、 增 甜剂、 稀释剂、 防腐剂、 染料 /着色剂、 矫味增强剂、 表面活性剂、 润湿剂、 分散剂、 崩解 剂、 助悬剂、 稳定剂、 等渗剂、 溶剂或乳化剂。 所述赋形剂的非限制性实例包括碳酸钙、 磷酸钙、 各种糖和各类淀粉、 纤维素衍生物、 明胶、 植物油和聚乙二醇等。 附图说明 图 1、 葡萄糖耐受试验 （血糖浓度-时间） The term "pharmaceutically acceptable carrier" refers to those carriers and diluents which do not significantly irritate the organism and which do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carrier" includes, but is not limited to, any carrier, excipient, vehicle, glidant, sweetener, diluent, for human or livestock animals that is approved by the National Food and Drug Administration as acceptable. Preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, disintegrating agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers. Non-limiting examples of such excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycol, and the like. DRAWINGS Figure 1. Glucose tolerance test (blood glucose concentration - time)
图 2、 葡萄糖耐受试验 （血糖 AUC-剂量) 具体实施方式  Figure 2. Glucose tolerance test (blood sugar AUC-dose)
下面的具体实施例， 其目的是使本领域的技术人员能更清楚地理解和实施本发明。 它 们不应该被认为是对本发明范围的限制， 而只是本发明的示例性说明和典型代表。 本领域 技术人员应该理解： 还有形成本发明化合物的其它合成途径， 下面提供的是非限制性的实 施例。  The following specific embodiments are intended to enable those skilled in the art to understand and practice the invention. They should not be considered as limiting the scope of the invention, but are merely illustrative and representative of the invention. Those skilled in the art will appreciate that there are other synthetic routes to form the compounds of the invention, and non-limiting examples are provided below.
凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。 本发明使用的原料可 以是市场上直接购买， 未经进一步纯化直接使用的， 或者按照现有文献采用类似方法制备 得到。  All operations involving materials that are susceptible to oxidation or hydrolysis are carried out under nitrogen. The starting materials used in the present invention can be purchased directly from the market, used without further purification, or prepared in a similar manner according to the prior literature.
柱色谱采用青岛化工有限公司生产的硅胶 （200-300目）。 薄层色谱采用 E. Merck公司 生产的预制板 （硅胶 60 PF254, 0.25 毫米）。 核磁共振色谱 (NMR)使用 Varian VNMRS-400 核磁共振仪测定；液质联用 (LC/MS)使用 FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200 series (柱子： Waters Symmetry CI 8, Φ4.6 50 毫米， 5微米 ， 35 °C )，采用 ESI(+) 离子模式。  The column chromatography was carried out using silica gel (200-300 mesh) produced by Qingdao Chemical Co., Ltd. Thin layer chromatography was carried out using a prefabricated plate manufactured by E. Merck (silica gel 60 PF254, 0.25 mm). Nuclear magnetic resonance chromatography (NMR) was measured using a Varian VNMRS-400 NMR spectrometer; LC/MS was performed using FINNIGAN Thermo LCQ Advantage MAX, Agilent LC 1200 series (column: Waters Symmetry CI 8, Φ4.6 50 mm, 5 micron, 35 °C) in ESI(+) ion mode.
中间体 1 : fS)-6-羟基 -2,3-二氢苯并呋 -3-乙酸甲酯
Figure imgf000012_0001
Intermediate 1: fS)-6-Hydroxy-2,3-dihydrobenzofur-3-acetic acid methyl ester
Figure imgf000012_0001
实施例 1 : 2-f6-"4'-f3-f二甲基膦酰基)丙氧基 )-2',6'-二甲基联苯 -3-基)甲氧基 )-2,3-二氢苯并 -3-基)乙酸的合成 Example 1: 2-f6-"4'-f3-fdimethylphosphonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy)-2,3 Synthesis of dihydrobenzo-3-yl)acetic acid
Figure imgf000012_0002
Figure imgf000012_0002
步骤 1: 4'-羟基 -2'，6'-二甲基联苯 -3-甲醛的合成 Step 1: Synthesis of 4'-hydroxy-2',6'-dimethylbiphenyl-3-carbaldehyde
把 3,5-二甲基 -4-溴苯酚 (10.0 g, 49.7 mmol)， 3-甲酰基苯硼酸 (8.9 g,59.7mmol)， 碳酸铯 (24.3 g, 74.6 mmol)和 [Ι,Γ-双 (二苯基膦)二茂铁]二氯化钯 (1.8 g, 2.5 mmol)加到 1,4-二氧六环 中 (250 mL)。 将该混合物加热回流 8小时后冷却到室温。 反应混合物通过硅藻土过滤， 用 乙酯乙酯洗涤， 滤液经浓缩后残留物通过硅胶柱色谱法分离纯化得到 4'-羟基 -2',6'-二甲基 联苯 -3-甲醛 (8.4 g, 收率 75.0%) o 1H NM (400 MHz, CDCl3-t 3): 10.05 (2H, s), 7.86 (1H, d, J = 7.6 Hz), 7.67 (1H, t, J = 1.6 Hz), 7.59 (1H, t, J = 7.6 Hz), 7.42 (1H, d, J = 7.6 Hz), 6.64 (2H, s), 1.97 (6H, s)。 3,5-Dimethyl-4-bromophenol (10.0 g, 49.7 mmol), 3-formylbenzeneboronic acid (8.9 g, 59.7 mmol), cesium carbonate (24.3 g, 74.6 mmol) and [Ι,Γ- Bis(diphenylphosphino)ferrocene]palladium dichloride (1.8 g, 2.5 mmol) was added to 1,4-dioxane (250 mL). The mixture was heated to reflux for 8 hours and then cooled to room temperature. The reaction mixture was filtered through celite, washed with ethyl acetate, and the filtrate was concentrated, and the residue was purified by silica gel column chromatography to afford 4'-hydroxy-2',6'-dimethylbiphenyl-3-carbaldehyde ( 8.4 g, yield 75.0%) o 1H NM (400 MHz, CDCl 3 -t 3 ): 10.05 (2H, s), 7.86 (1H, d, J = 7.6 Hz), 7.67 (1H, t, J = 1.6 Hz), 7.59 (1H, t, J = 7.6 Hz), 7.42 (1H, d, J = 7.6 Hz), 6.64 (2H, s), 1.97 (6H, s).
步骤 2: 4，- (叔丁基二甲基硅烷氧基) -2，，6，-二甲基联苯 -3-甲醛的合成 Step 2: Synthesis of 4,-(tert-butyldimethylsilyloxy)-2,6,-dimethylbiphenyl-3-carbaldehyde
在冰水浴冷却下， 向 4'-羟基 -2',6'-二甲基联苯 -3-甲醛 (2.0 g, 8.8 mmol)和咪唑 (1.2 g, 17.6 mmol)的二氯甲垸溶液中 (50 mL)滴加叔丁基二甲基氯硅垸 (2.0 g, 13.2 mmol)的二氯甲 垸溶液 (50 mL)。 滴加完毕后， 反应液缓慢升到室温并搅拌过夜。 过滤反应液， 滤液浓缩后 残留物通过硅胶柱色谱法分离纯化得到 4'- (叔丁基二甲基硅垸氧基) -2',6'-二甲基联苯 -3-甲 酲 (2.6 g, 收率 86.7%) lH NM (400 MHz, CDCl3-t 3): 10.05 (1H, s), 7.84 (1H, d, J = 7.6 Hz), 7.67 (1H, s), 7.58 (1H, t, J = 7.6Hz), 7.42 (1H, d, J = 7.6Hz), 6.60 (2H, s), 1.96 (6H, s), 1.01 (9H, s), 0.24 (6H, s)。 To a solution of 4'-hydroxy-2',6'-dimethylbiphenyl-3-carbaldehyde (2.0 g, 8.8 mmol) and imidazole (1.2 g, 17.6 mmol) in dichloromethane under ice-cooling. (50 mL) dropwise addition of tert-butyldimethylsilyl silane (2.0 g, 13.2 mmol) of dichloromethane 垸 solution (50 mL). After the dropwise addition was completed, the reaction solution was slowly warmed to room temperature and stirred overnight. The reaction solution was filtered, and the filtrate was concentrated to give 4'-(tert-butyldimethylsilyloxy) -2',6'-dimethylbiphenyl-3-carboxamide by silica gel column chromatography. 2.6 g, yield 86.7%) l H NM (400 MHz, CDCl 3 -t 3 ): 10.05 (1H, s), 7.84 (1H, d, J = 7.6 Hz), 7.67 (1H, s), 7.58 ( 1H, t, J = 7.6Hz), 7.42 (1H, d, J = 7.6Hz), 6.60 (2H, s), 1.96 (6H, s), 1.01 (9H, s), 0.24 (6H, s).
步骤 ，- (叔丁基二甲基甲硅烷氧基 ， 二甲基联苯 基)甲醇的合成 Step, - Synthesis of (tert-butyldimethylsilyloxy, dimethylbiphenyl)methanol
在冰水浴冷却下， 向 4'- (叔丁基二甲基甲硅垸氧基 )-2',6'-二甲基联苯 -3-甲醛 (3.0 g, 8.8 mmol)四氢呋喃 (40 mL)和甲醇 (20 mL)的溶液中， 少量多次地加入硼氢化钠 (0.67 g, 17.6 mmol 加完毕后，反应液缓慢升到室温并搅拌过夜。反应液浓缩后向其中加入水 (200 mL), 混合物用乙酸乙酯萃取 (250 mL x 3)， 合并有机相并用无水硫酸钠干燥， 浓缩得到 (4'- (叔丁 基二甲基甲硅垸氧基 )-2'， 6'-二甲基联苯 -3-基）甲醇 (2.6 g, 收率 86.7%)。 1H NM (400 MHz, CDCl3-t 3): 7.40 (1H, t, J = 7.6 Hz), 7.32 (1H, d, J = 7.6 Hz), 7.13 (1H, s), 7.07 (1H, d, J = 7.2 Hz), 6.58 (2H, s), 4.73 (2H, s), 1.97 (6H, s), 1.00 (9H, s), 0.23 (6H, s)。 4'-(tert-Butyldimethylsilyloxy)-2',6'-dimethylbiphenyl-3-carbaldehyde (3.0 g, 8.8 mmol) tetrahydrofuran (40 mL) with ice-cooling In a solution of methanol (20 mL), a small amount of sodium borohydride (0.67 g, 17.6 mmol) was added, and the reaction solution was slowly warmed to room temperature and stirred overnight. After the reaction mixture was concentrated, water (200 mL) was added thereto. The mixture was extracted with ethyl acetate (250 mL×3). EtOAcjjjjjjjjjjjjjjjjjjjj - dimethylbiphenyl-3-yl)methanol (2.6 g, yield 86.7%). 1H NM (400 MHz, CDCl 3 -t 3 ): 7.40 (1H, t, J = 7.6 Hz), 7.32 (1H , d, J = 7.6 Hz), 7.13 (1H, s), 7.07 (1H, d, J = 7.2 Hz), 6.58 (2H, s), 4.73 (2H, s), 1.97 (6H, s), 1.00 (9H, s), 0.23 (6H, s).
步骤 4: 2-(6-((4 叔丁基二甲基甲硅烷氧基)- 2 6 二甲基联苯- 3-基)甲氧基 )-2,3»二氢苯并 呋喃 -3»基)乙酸甲酯的合成 Step 4: 2-(6-((4-tert-Butyldimethylsilyloxy)- 2 6 dimethylbiphenyl-3-yl)methoxy)-2,3»dihydrobenzofuran- Synthesis of 3»yl)methyl acetate
在冰水浴冷却下， 向 (4'- (叔丁基二甲基甲硅垸氧基 )-2',6'-二甲基联苯 -3-基)甲醇 (2.0 g, 5.8 mmol), 6-羟基 -2,3-二氢苯并呋喃 -3-乙酸甲酯 （1.5 g, 7.2 mmol)和三苯基膦 (2.4 g, 9.0 mmol)的四氢呋喃溶液中 (150 mL)滴加偶氮二甲酸二异丙酯 (1.8 g, 9.0 mmol)。 滴加完毕后， 反应液缓慢升到室温并搅拌过夜。 反应液经浓缩后残留物通过硅胶柱色谱法分离纯化得到 2-(6-((4'- (叔丁基二甲基甲硅垸氧基 )-2',6'-二甲基联苯 -3-基)甲氧基 )-2,3-二氢苯并呋喃 -3-基) 乙酸甲酯 (2.1g, 收率 67.7%)。 ¾ NMR (400 MHz, CDCl3-t 3): 7.42 (1H, t, J = 7.6 Hz), 7.37 (1H, d, J = 8.0 Hz), 7.18 (1H, s), 7.09 (1H, d, J = 7.2 Hz), 7.02 (1H, d, J = 8.4 Hz), 6.59 (2H, s), 6.45-6.51 (2H, m), 5.06 (2H, s), 4.75 (1H, t, J = 8.8 Hz), 4.27 (1H, dd, J = 9.2 Hz, 6.4 Hz), 3.76-3.85 (1H, m), 3.72 (3H, s), 2.75 (1H, dd, J = 16.4 Hz, 5.2 Hz), 2.56 (1H, dd, J = 16.4 Hz, 5.2 Hz), 1.96 (6H, s), 1.02 (9H, s), 0.24 (6H, s)。 To (4'-(tert-butyldimethylsilyloxy)-2',6'-dimethylbiphenyl-3-yl)methanol (2.0 g, 5.8 mmol) under ice-cooling. Add azo to a solution of 6-hydroxy-2,3-dihydrobenzofuran-3-acetic acid methyl ester (1.5 g, 7.2 mmol) and triphenylphosphine (2.4 g, 9.0 mmol) in tetrahydrofuran (150 mL) Diisopropyl diformate (1.8 g, 9.0 mmol). After the dropwise addition was completed, the reaction solution was slowly warmed to room temperature and stirred overnight. The reaction mixture is concentrated and purified by silica gel column chromatography to give 2-(6-((4'-(tert-butyldimethylsilyloxy)-2',6'-dimethylbiphenyl). Methyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate (2.1 g, yield 67.7%). 3⁄4 NMR (400 MHz, CDCl 3 -t 3 ): 7.42 (1H, t, J = 7.6 Hz), 7.37 (1H, d, J = 8.0 Hz), 7.18 (1H, s), 7.09 (1H, d, J = 7.2 Hz), 7.02 (1H, d, J = 8.4 Hz), 6.59 (2H, s), 6.45-6.51 (2H, m), 5.06 (2H, s), 4.75 (1H, t, J = 8.8 Hz), 4.27 (1H, dd, J = 9.2 Hz, 6.4 Hz), 3.76-3.85 (1H, m), 3.72 (3H, s), 2.75 (1H, dd, J = 16.4 Hz, 5.2 Hz), 2.56 (1H, dd, J = 16.4 Hz, 5.2 Hz), 1.96 (6H, s), 1.02 (9H, s), 0.24 (6H, s).
步骤 5： -(6- ((4' -径基 ~2'、6'-二甲基联苯 基)甲氧基 )- 2，3-二氣苯并呋喃 ~3 -基)乙酸甲酯的合 成 Step 5: -(6-((4'-diabase~2',6'-dimethylbiphenyl)methoxy)- 2,3-dioxabenzofuran~3-yl)acetate Synthesis
在冰水浴冷却下， 向 2-(6-((4'- (叔丁基二甲基甲硅垸氧基 )-2',6'-二甲基联苯 -3-基)甲氧 基) -2,3-二氢苯并呋喃 -3-基)乙酸甲酯 (1.1 g, 2.1 mmol)的四氢呋喃溶液中 (50 mL)加入四丁 基氟化铵 (1.3 g, 5.0 mmol)。 加入完毕后， 反应液缓慢升到室温并搅拌过夜。 加入 50 mL饱 和氯化铵水溶液终止反应， 混合物用乙酸乙酯萃取 (50 mL x 3)， 合并有机相并用无水硫酸 钠干燥，浓缩得到 2-(6-ίί4'-羟基- 2',6'-二甲基联苯 -3-基)甲氧基 2,3-二氢苯并呋喃 - 3-基)乙酸 甲酯 (0.75 g，收率 87%)。 ¾ NMR (400 MHz, CDCl3-t¾): 7.42 (1H, t, J = 7.2 Hz), 7.37 (1H, d, J = 8.0 Hz), 7.16 (1H, s), 7.07 (1H, d, J = 7.2 Hz), 7.01 (1H, d, J = 8.0 Hz), 6.60 (2H, s), 6.45-6.50 (2H, m), 5.06 (2H, s), 4.75 (1H, t, J = 9.2 Hz), 4.26 (1H, dd, J = 9.2 Hz, 6.4 Hz), 3.75-3.87 (1H, m), 3.72 (3H, s), 2.74 (1H, dd, J = 16.4 Hz, 5.6 Hz), 2.55 (1H, dd, J = 16.4 Hz, 5.6 Hz), 1.97 (6H, s)。 To 2-(6-((4'-(tert-butyldimethylsilyloxy)-2',6'-dimethylbiphenyl-3-yl)methoxy) with cooling in an ice water bath To a solution of methyl 2,3-dihydrobenzofuran-3-yl)acetate (1.1 g, 2.1 mmol) in tetrahydrofuran (50 mL) was added tetrabutylammonium fluoride (1.3 g, 5.0 mmol). After the addition was completed, the reaction solution was slowly warmed to room temperature and stirred overnight. The reaction was quenched with aq. EtOAc (EtOAc)EtOAc. Methyl '-dimethylbiphenyl-3-yl)methoxy 2,3-dihydrobenzofuran-3-yl)acetate (0.75 g, yield 87%). 3⁄4 NMR (400 MHz, CDCl 3 -t3⁄4): 7.42 (1H, t, J = 7.2 Hz), 7.37 (1H, d, J = 8.0 Hz), 7.16 (1H, s), 7.07 (1H, d, J = 7.2 Hz), 7.01 (1H, d, J = 8.0 Hz), 6.60 (2H, s), 6.45-6.50 (2H, m), 5.06 (2H, s), 4.75 (1H, t, J = 9.2 Hz ), 4.26 (1H, dd, J = 9.2 Hz, 6.4 Hz), 3.75-3.87 (1H, m), 3.72 (3H, s), 2.74 (1H, dd, J = 16.4 Hz, 5.6 Hz), 2.55 ( 1H, dd, J = 16.4 Hz, 5.6 Hz), 1.97 (6H, s).
歩骤 6: (烯丙氧基) -2 6^二甲基联苯 基）甲氧基) 2,3二氣苯并呋喃 3-基)乙酸甲 酯的合成 Step 6: Synthesis of (allyloxy) -2 6 ^ dimethylbiphenyl) methoxy) 2,3 bis benzofuran 3-yl) acetate
把碳酸钾 (3.3 g, 23.9 mmol)加入 2-(6- ίί4'-羟基 - 二甲基联苯 -3-基)甲氧基 )- 2,3二氢 苯并咲喃- 3-基)乙酸甲酯 (5,0 g, 11 ,9 mmoi)和烯丙基碘 (4.0 g 23.8 mmol) 的乙腈 (100 mL)溶 液中。 将该混合物室温搅拌过夜， 过滤， 将滤液浓缩后的残留犓经硅跤柱色谱法分离纯化 得到 2 6- ((4' (烯丙氧基 )- 2',6'-二甲基联苯 3-基)甲氧基) 2,3-二氢苯并呋喃 基）乙酸甲 ϋ (4, 1 g, 收率 74.5%)。 1H NMR (400 MHz, CDCl3-t 3): 7.40 (1H, t, J = 7.6 Hz), 7.35 (1H, d, J = 7.6 Hz), 7.16 (1H, s), 7.06 (1H, d, J = 7.2 Hz), 6.99 (1H, d, J = 8.4 Hz), 6.66 (2H, s), 6.43-6.48 (2H, m), 6.02-6.12 (1H, m), 5.42 (1H, d, J = 16.8Hz), 5.27 (1H, d, J = 10.4Hz), 5.04 (2H, s), 4.73 (1H, t, J = 8.8 Hz), 4.53 (2H, d, J = 5.2 Hz), 4.24 (1H, dd, J = 9.2 Hz, 2.0 Hz), 3.75-3.82 (1H, m), 3.70 (3H, s), 2.73 (1H, dd, J = 16.4 Hz, 5.6 Hz), 2.53 (1H, dd, J = 16.4 Hz, 9.2 Hz), 1.97 (6H, s)。 Potassium carbonate (3.3 g, 23.9 mmol) was added to 2-(6- ίί 4'-hydroxy-dimethylbiphenyl-3-yl)methoxy)-2,3 dihydrobenzopyran-3-yl) Methyl acetate (5,0 g, 11 ,9 mm oi) and allyl iodide (4.0 g 23.8 mmol) in acetonitrile (100 mL). The mixture was stirred at room temperature overnight, filtered, and the residue obtained by concentration of the filtrate was separated and purified by silica gel column chromatography to obtain 2 6-((4'(allyloxy)-2',6'-dimethylbiphenyl. 3-yl)methoxy) 2,3-dihydrobenzofuranylacetic acid formamidine (4,1 g, yield 74.5%). 1H NMR (400 MHz, CDCl 3 -t 3 ): 7.40 (1H, t, J = 7.6 Hz), 7.35 (1H, d, J = 7.6 Hz), 7.16 (1H, s), 7.06 (1H, d, J = 7.2 Hz), 6.99 (1H, d, J = 8.4 Hz), 6.66 (2H, s), 6.43-6.48 (2H, m), 6.02-6.12 (1H, m), 5.42 (1H, d, J = 16.8Hz), 5.27 (1H, d, J = 10.4Hz), 5.04 (2H, s), 4.73 (1H, t, J = 8.8 Hz), 4.53 (2H, d, J = 5.2 Hz), 4.24 (1H, dd, J = 9.2 Hz, 2.0 Hz), 3.75-3.82 (1H , m), 3.70 (3H, s), 2.73 (1H, dd, J = 16.4 Hz, 5.6 Hz), 2.53 (1H, dd, J = 16.4 Hz, 9.2 Hz), 1.97 (6H, s).
歩骤 7; 2-(6- ί(4'- (二甲基膦酰基)丙氧基 )- 2',6'-二甲基联苯- 3-基)甲氧基 )-2，3-二氳苯并呋 喃- 3-基)乙酸甲酯的合成 Step 7; 2-(6- ί(4'-(Dimethylphosphono)propoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy)-2,3 Synthesis of methyl 2-dibenzofuran-3-yl)acetate
把二甲基氧化膦 (1.0 g, 12.8 mmol)加到 2-(6-((4'- (烯丙氧基) -2',6'-二甲基联苯- 3 -基)甲氧 基) -2,3-二氢苯并块喃3-基）乙酸甲 11(4.1 g, 9.0 mmoi)的甲醇溶液中（100 mL)。 该反应液室 温搅拌 10分钟后， 把二乙基甲氧基硼垸 ( 1.3 gJ 3,0 mmd)加入其中。 将该反应混合液加热 到 80 QC 反应过夜。 将反应液冷却到室温. 浓缩， 残留物经过硅胶柱色谱法分离纯化得到 2—(6 ('(4'-(3 -(二甲基膦齄基)丙氧基 )-2',6'-二甲基联苯3-基)甲氧基 )-2,3-二氢苯并块喃 3 -基) 乙酸甲酯 (3,0 g, 收率 62.5%) (, 1H MR (400 MHz, CDCl3-t¾): 7.41 (1H, t, J = 7.2 Hz), 7.36 (1H, d, J = 8.0 Hz), 7.15 (1H, s), 7.06 (1H, d, J = 7.2Hz), 7.00 (1H, d, J = 8.0 Hz), 6.64 (2H, s), 6.44-6.48 (2H, m), 5.05 (2H, s), 4.73 (1H, t, J = 9.2 Hz), 4.24 (1H, dd, J = 9.2 Hz, 6.0 Hz), 4.06 (2H, t, J = 6.0 Hz), 3.76-3.82 (1H, m), 3.71 (3H, s), 2.73 (1H, dd, J = 16.4 Hz, 5.2 Hz), 2.54 (1H, dd, J = 16.4 Hz, 9.2 Hz), 2.04-2.16 (2H, m), 1.98 (6H, s), 1.88-1.97 (2H, m), 1.53 (6H, d, J = 12.4 Hz)。 Add dimethylphosphine oxide (1.0 g, 12.8 mmol) to 2-(6-(4'-(allyloxy)-2',6'-dimethylbiphenyl-3-yl)methoxy Base) -2,3-Dihydrobenzopyran-3-yl)acetic acid methyl 11 (4.1 g, 9.0 mm oi) in methanol (100 mL). After the reaction mixture was stirred at room temperature for 10 minutes, diethyl methoxyboronium (1.3 gJ 3 , 0 mmd) was added thereto. The reaction mixture was heated to 80 Q C overnight. The reaction solution was cooled to room temperature. After concentration, the residue was purified by silica gel column chromatography to afford 2-(6('(4'-(3-(dimethylphosphinyl)propyloxy)-2', 6' -Methylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzo- mercapto-3-yl)methyl acetate (3,0 g, yield 62.5%) (, 1H MR (400 MHz , CDCl 3 -t3⁄4): 7.41 (1H, t, J = 7.2 Hz), 7.36 (1H, d, J = 8.0 Hz), 7.15 (1H, s), 7.06 (1H, d, J = 7.2Hz), 7.00 (1H, d, J = 8.0 Hz), 6.64 (2H, s), 6.44-6.48 (2H, m), 5.05 (2H, s), 4.73 (1H, t, J = 9.2 Hz), 4.24 (1H , dd, J = 9.2 Hz, 6.0 Hz), 4.06 (2H, t, J = 6.0 Hz), 3.76-3.82 (1H, m), 3.71 (3H, s), 2.73 (1H, dd, J = 16.4 Hz , 5.2 Hz), 2.54 (1H, dd, J = 16.4 Hz, 9.2 Hz), 2.04-2.16 (2H, m), 1.98 (6H, s), 1.88-1.97 (2H, m), 1.53 (6H, d , J = 12.4 Hz).
步骤 8: 2-(6-((4'-(3- (二甲基膦酰基)丙氧基 )-2'，6'-二甲基联苯 -3-基)甲氧基 )-2，3-二氢苯并呋 喃 -3 -基)乙酸的合成 Step 8: 2-(6-((4'-(3-(Dimethylphosphonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy)-2 Synthesis of 3-dihydrobenzofuran-3-yl)acetic acid
向 2-(6 (('4'-(3 二甲基膦酰基 y丙氧基 2' ^二甲基联苯 ^基)甲氧基 ) 2,3-二氢苯并呋 嚷- 3-基）乙酸甲 1 3.0 g、 5.6 mmol )甲醇 (50 mL)和四氮呋喃（100 mL)的混合溶剂的溶液中， 滴加 2 M氯氧化销水溶液 (8 mL) , 滴加完毕后混合物室温搅拌过夜。 将反应混合物用水稀 释， 用 10%柠檬酸水溶液酸化， 并用乙酸乙觀萃取 (150 mLx3)。 有机相用无水硫酸钠千燥 后浓缩。 残留物通过硅胶柱色谱法分离纯化得到 2-(6-ί(4'-(3- (二甲基麟酰基)丙氧基 2 6'- 二甲基联苯— 3-基）甲氧基 )-2,3-二氢苯并块喃 3-基）乙酸 (23 g、 牧率 78.0%)。 1H NM (400 MHz, DMSO-t 6): 12.19-12.38 (1H, brs), 7.41 (1H, t, J = 7.2 Hz), 7.34 (1H, d, J = 7.6 Hz), 7.10 (1H, s), 7.06 (1H, d, J = 8.0 Hz), 7.02 (1H, d, J = 7.6 Hz), 6.66 (2H, s), 6.41-6.45 (2H, m), 5.06 (2H, s), 4.64 (1H, t, J = 9.2 Hz), 4.14 (1H, dd, J = 9.2 Hz, 6.8 Hz), 4.00 (2H, t, J = 6.0 Hz), 3.59-3.67 (1H, m), 2.65 (1H, dd, J = 16.4 Hz, 5.6 Hz), 2.40-2.43 (1H, m), 1.90-1.97 (2H, m), 1.72-1.78 (2H, m), 1.36 (6H, d, J = 12.8 Hz)。 To 2-(6((4'-(3 dimethylphosphonyl y-propoxy 2' dimethylbiphenyl) methoxy) 2,3-dihydrobenzofuran-3- 2 M chlorophosphoric acid aqueous solution (8 mL) was added dropwise to a solution of acetic acid A 1 3.0 g, 5.6 mmol) methanol (50 mL) and tetranitrofuran (100 mL). After the dropwise addition, the mixture was allowed to stand at room temperature. Stir overnight. The reaction mixture was diluted with water, acidified with aq. 10% EtOAc EtOAc. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue is purified by silica gel column chromatography to give 2-(6-(4-(3-(dimethylphenyl)propoxy) 2 6 '-dimethylbiphenyl-3-yl)methoxy )-2,3-Dihydrobenzopyran-3-yl)acetic acid (23 g, grazing rate 78.0%). 1H NM (400 MHz, DMSO-t 6 ): 12.19-12.38 (1H, brs), 7.41 (1H, t, J = 7.2 Hz), 7.34 (1H, d, J = 7.6 Hz), 7.10 (1H, s ), 7.06 (1H, d, J = 8.0 Hz), 7.02 (1H, d, J = 7.6 Hz), 6.66 (2H, s), 6.41-6.45 (2H, m), 5.06 (2H, s), 4.64 (1H, t, J = 9.2 Hz), 4.14 (1H, dd, J = 9.2 Hz, 6.8 Hz), 4.00 (2H, t, J = 6.0 Hz), 3.59-3.67 (1H, m), 2.65 (1H , dd, J = 16.4 Hz, 5.6 Hz), 2.40-2.43 (1H, m), 1.90-1.97 (2H, m), 1.72-1.78 (2H, m), 1.36 (6H, d, J = 12.8 Hz) .
实施例 2: 2-(6- 2',6'-二甲基 -4'-f2 -f甲磺酰基氨基)乙氧基)联苯 -3-基)甲氧基 )-2,3-二氢苯并 Example 2: 2-(6-2',6'-Dimethyl-4'-f2-fmethylsulfonylamino)ethoxy)biphenyl-3-yl)methoxy)-2,3- Dihydrobenzo
Figure imgf000014_0001
Figure imgf000014_0001
歩骤 1 ; 2-(6-((4'- (氰基甲氧基 2'，6'-二甲基联苯 -3基)甲氧基 )~2，3-二氢苯并块喃 -3-基)乙酸 甲酯的合成 Step 1; 2-(6-((4'-(Cyanomethoxy 2',6'-dimethylbiphenyl-3yl)methoxy)~2,3-dihydrobenzopyran Synthesis of -3-yl)methyl acetate
把碳酸钾 (2.0 g, 14.5 mmol)加入 2-(6-((4'-羟基 -2',6'-二甲基联苯 -3-基)甲氧基 )-2,3-二氢 苯并呋喃 -3-基)乙酸甲酯 (3.0 g, 7.2 mmol)和溴乙腈 (1.8 g, 15.0 mmol) 的乙腈 (100 mL)溶液 中。 将该混合物室温搅拌过夜， 过滤， 滤液浓缩后的残留物经硅胶柱色谱法分离纯化得到 2- (6-((4'- (氰基甲氧基 )-2',6'-二甲基联苯 -3-基)甲氧基 )-2,3-二氢苯并呋喃 -3-基)乙酸甲酯 (2.2 g, 收率 66.7%)。 MS m/z[ESI]+:458.0[M+l] o Potassium carbonate (2.0 g, 14.5 mmol) was added to 2-(6-((4'-hydroxy-2',6'-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrogen Methyl benzofuran-3-yl)acetate (3.0 g, 7.2 mmol) and bromoacetonitrile (1.8 g, 15.0 mmol) in EtOAc (100 mL). The mixture was stirred at room temperature overnight, filtered, and the residue obtained from ethyl acetate was purified by silica gel column chromatography to afford 2-(6-(((((((())))) Methyl biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate (2.2 g, yield 66.7%). MS m/z [ESI] + : 458.0 [M+l] o
歩骤 2: 2-(6-((4'-(2-氨基乙氧基) -2'，6'-二甲基联苯 -3-基)甲氧基 )-2，3-二氢苯并呋喃 -3-基)乙 酸甲酯的合成 Step 2 : 2-(6-((4'-(2-Aminoethoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydro Benzofuran-3-yl)B Synthesis of acid methyl ester
把 2-(6-((4'- (氰基甲氧基 )-2',6'-二甲基联苯 -3-基)甲氧基 )-2,3-二氢苯并呋喃 -3-基)乙酸 甲酯 (2.2 g, 4.8 mmol)， 雷尼镍 (5.0 g)和甲醇 (100 mL)的混合物在氢气气氛下 (1大气压)室温 搅拌过夜。 反应液通过硅藻土过滤， 滤液浓缩后得到 2-(6-((4'-(2-氨基乙氧基) -2',6'-二甲基 联苯— 3 基）甲氧基） 2，3-二氢苯并呋喃 3-基）乙酸甲觀（2,1 g, 收率 95.0%) , MS m/z[ESI]+:462.0[M÷i]。 2-(6-((4'-(Cyanomethoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran- Methyl 3-acetate (2.2 g, 4.8 mmol), a mixture of Raney nickel (5.0 g) and methanol (100 mL) was stirred at room temperature under a hydrogen atmosphere (1 atm) overnight. The reaction solution was filtered through Celite, and the filtrate was concentrated to give 2-(6-((4)-(2-aminoethoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy) 2,3-Dihydrobenzofuran-3-yl)acetic acid methyl (2,1 g, yield 95.0%), MS m/z [ESI] + : 462.0 [M÷i].
歩骤 3: 2-(6-((2，，6，-二甲基 -4，-(2- (甲磺酰基氨基)乙氧基)联苯 -3-基)甲氧基 )-2，3-二氢苯并呋 喃 -3 -基)乙酸甲酯的合成 Step 3 : 2-(6-((2,6,-Dimethyl-4,-(2-(methylsulfonylamino)ethoxy)biphenyl-3-yl)methoxy)-2 Synthesis of methyl 3-hydrobenzofuran-3-yl)acetate
向 2-(6-((4'-(2-氨基乙氧基) - 2',6'-二甲基联¾- 3基)甲氧基 )- 2,3二氯苯并呋喃 - 3-基)乙酸 甲酯 (0,5 g 1.1 mmol)的二氯甲烷溶液中 (50 mL)依次加入甲磺酰氯 (0.19 g, 1.6 mmol)和三乙 胺 (0.22 g, 2.2 mmol)。 将该反应混合液室温搅拌过夜 将反应倒入水中 (50 m:L), 用二氯甲 烷萃取 (ii)i)m:L:<2)， 有机相用无水硫酸钠干燥， 滚缩， 残留犓经硅胶柱色谱法分离纯化得 到 2-(6-(('2',6'-二甲基 -4' 2- (甲磺酰基氨基)乙氧基)联苯3-基)甲氧基 ) 2,3-二氢苯并呋喃 3 基)乙酸甲觀 (0,44 g, 收率 75.0¾)。 ^ NMR OO MHz, CDCl3-t¾): 7.44 (1H, t, J = 7.6 Hz), 7.40 (1H, d, J = 7.6 Hz), 7.18 (1H, s), 7.09 (1H, d, J = 7.2 Hz), 7.03 (1H, d, J = 8.0 Hz), 6.66 (2H: s), 6.47-6.52 (2H, m), 5.08 (2H, s), 4.77-4.79 (2H, m), 4.28 (1H, dd, J = 9.2 Hz, 6.0 Hz), 4.14 (2H, t, J = 4.8 Hz), 3.78-3.85 (1H, m), 3.74 (3H, s), 3.58 (2H, q, J = 5.6 Hz), 3.06 (3H, s), 2.76 (1H, dd, J = 16.8 Hz, 5.2 Hz), 2.57 (1H, dd, J = 16.8 Hz, 9.6 Hz), 2.01 (6H, s)。 To 2-(6-((4'-(2-aminoethoxy)-2',6'-dimethylbi 3⁄4-yl)methoxy)-2,3dichlorobenzofuran-3 Methyl sulfonyl chloride (0.19 g, 1.6 mmol) and triethylamine (0.22 g, 2.2 mmol) were sequentially added to a solution of methyl acetate (0,5 g, 1.1 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature overnight. The reaction was poured into water (50 m: L), dichloromethane (1) i) m:L: <2) The residual hydrazine was separated and purified by silica gel column chromatography to give 2-(6-(('2',6'-dimethyl-4' 2-(methylsulfonylamino)ethoxy)biphenyl 3-yl)methoxy Base 2,3-dihydrobenzofuran-3-yl)acetate (0,44 g, yield 75.03⁄4). ^ NMR OO MHz, CDCl 3 -t3⁄4): 7.44 (1H, t, J = 7.6 Hz), 7.40 (1H, d, J = 7.6 Hz), 7.18 (1H, s), 7.09 (1H, d, J = 7.2 Hz), 7.03 (1H, d, J = 8.0 Hz), 6.66 (2H : s), 6.47-6.52 (2H, m), 5.08 (2H, s), 4.77-4.79 (2H, m), 4.28 ( 1H, dd, J = 9.2 Hz, 6.0 Hz), 4.14 (2H, t, J = 4.8 Hz), 3.78-3.85 (1H, m), 3.74 (3H, s), 3.58 (2H, q, J = 5.6 Hz), 3.06 (3H, s), 2.76 (1H, dd, J = 16.8 Hz, 5.2 Hz), 2.57 (1H, dd, J = 16.8 Hz, 9.6 Hz), 2.01 (6H, s).
步骤 4: 2-(6-((2'，6'-二甲基 -4'-(2- (甲磺酰基氨基)乙氧基)联苯 -3-基)甲氧基 )-2，3-二氢苯并呋 喃 -3 -基)乙酸的合成 Step 4: 2-(6-((2',6'-Dimethyl-4'-(2-(methylsulfonylamino)ethoxy)biphenyl-3-yl)methoxy)-2, Synthesis of 3-dihydrobenzofuran-3-yl)acetic acid
向 2-(6-((2',6'-二甲基 -4'-(2-(甲磺酰基氨基)乙氧基)联苯 -3-基)甲氧基) -2,3-二氢苯并呋 喃 -3-基)乙酸甲酯 (0.44 g, 0.8 mmol)甲醇 (25 mL)和四氢呋喃 (50 mL)的混合溶剂的溶液中， 滴加 2 M氢氧化钠水溶液 (2 mL), 滴加完毕后混合物室温搅拌过夜。 将反应混合物用水稀 释， 用 10%柠檬酸水溶液酸化， 并用乙酸乙酯萃取 (50 mLx3)。有机相用无水硫酸钠干燥后 浓缩， 残留物通过硅胶柱色谱法分离纯化得到 2-(6 (2',6'-二甲基 -4'-(2 甲磺酰基氨基)乙氧 基)联苯- 3 -基）甲氧基 )-2,3-二氢苯并呋喃 基）乙酸 (0.28 g, 率 65.0%)。 1H NM (400 MHz, DMSO-t 6): 7.43 (1H, t, J = 7.6 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.25 (1H, t, J = 6.0 Hz), 7.12 (1H, s), 7.08 (1H, d, J = 8.0 Hz), 7.04 (1H, d, J = 7.2 Hz), 6.70 (2H, s), 6.43-6.47 (2H, m), 5.08 (2H, s), 4.66 (1H, t, J = 9.2 Hz), 4.16 (1H, dd, J = 8.8 Hz, 6.8 Hz), 4.02 (2H, t, J = 6.0 Hz), 3.58-3.70 (1H, m), 3.32-3.34 (2H, m), 2.95 (3H, s), 2.66 (1H, dd, J = 16.4 Hz, 5.6 Hz), 2.43-2.45 (1H, m), 1.90 (6H, s)。 To 2-(6-((2',6'-dimethyl-4'-(2-(methylsulfonylamino)ethoxy)biphenyl-3-yl)methoxy)-2,3- 2 M aqueous sodium hydroxide solution (2 mL) was added dropwise to a solution of methyl dihydrobenzofuran-3-yl)acetate (0.44 g, 0.8 mmol) in methanol (25 mL) and tetrahydrofuran (50 mL) After the dropwise addition was completed, the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, EtOAc (EtOAc)EtOAc. The organic phase is dried over anhydrous sodium sulfate and concentrated. EtOAc mjjjjjjjjjjj Biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuranyl acetic acid (0.28 g, 65.0%). 1H NM (400 MHz, DMSO-t 6 ): 7.43 (1H, t, J = 7.6 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.25 (1H, t, J = 6.0 Hz), 7.12 ( 1H, s), 7.08 (1H, d, J = 8.0 Hz), 7.04 (1H, d, J = 7.2 Hz), 6.70 (2H, s), 6.43-6.47 (2H, m), 5.08 (2H, s ), 4.66 (1H, t, J = 9.2 Hz), 4.16 (1H, dd, J = 8.8 Hz, 6.8 Hz), 4.02 (2H, t, J = 6.0 Hz), 3.58-3.70 (1H, m), 3.32-3.34 (2H, m), 2.95 (3H, s), 2.66 (1H, dd, J = 16.4 Hz, 5.6 Hz), 2.43-2.45 (1H, m), 1.90 (6H, s).
实施例 3: 2-(6-((2'，6'-二甲基 -4'-(2- (乙基磺酰基氨基)乙氧基)联苯 -3-基)甲氧基 )-2，3-二氢苯 Example 3: 2-(6-((2',6'-Dimethyl-4'-(2-(ethylsulfonylamino)ethoxy)biphenyl-3-yl)methoxy)- 2,3-dihydrobenzene
Figure imgf000015_0001
Figure imgf000015_0001
按照实施例 2的方法，用乙基磺酰氯代替甲基磺酰氯， 制备得到标题化合物。 ^ NMR (400 MHz, DMSO-t 6): 7.43 (1H, t, J = 7.6 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.28 (1H, t, J = 6.4 Hz), 7.12 (1H, s), 7.08 (1H, d, J = 8.0 Hz), 7.04 (1H, d, J = 7.2 Hz), 6.69 (2H, s), 6.43-6.47 (2H, m), 5.08 (2H, s), 4.66 (1H, t, J = 8.8 Hz), 4.16 (1H, dd, J = 9.6 Hz, 6.8 Hz), 4.00 (2H, t, J = 5.6 Hz), 3.61-3.69 (1H, m), 3.34-3.37 (2H, m), 3.05 (2H, q, J = 7.6 Hz), 2.67 (1H, dd, J = 16.8 Hz, 6.0 Hz), 2.42-2.45 (1H, m), 1.90 (6H, s), 1.20 (3H, t, J = 7.2 Hz)。 实施例 4: 2-(6-((2'，6'-二甲基 -4'-(2- (环丙基磺酰基氨基)乙氧基)联苯 -3-基)甲氧基 )-2，3-」 苯并呋喃 - The title compound was prepared according to the procedure of Example 2, methylenesulfonyl chloride. ^ NMR (400 MHz, DMSO-t 6 ): 7.43 (1H, t, J = 7.6 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.28 (1H, t, J = 6.4 Hz), 7.12 ( 1H, s), 7.08 (1H, d, J = 8.0 Hz), 7.04 (1H, d, J = 7.2 Hz), 6.69 (2H, s), 6.43-6.47 (2H, m), 5.08 (2H, s ), 4.66 (1H, t, J = 8.8 Hz), 4.16 (1H, dd, J = 9.6 Hz, 6.8 Hz), 4.00 (2H, t, J = 5.6 Hz), 3.61-3.69 (1H, m), 3.34-3.37 (2H, m), 3.05 (2H, q, J = 7.6 Hz), 2.67 (1H, dd, J = 16.8 Hz, 6.0 Hz), 2.42-2.45 (1H, m), 1.90 (6H, s ), 1.20 (3H, t, J = 7.2 Hz). Example 4: 2-(6-((2',6'-Dimethyl-4'-(2-(cyclopropylsulfonylamino)ethoxy)biphenyl-3-yl)methoxy) -2,3-" benzofuran-
Figure imgf000016_0001
Figure imgf000016_0001
按照实施例 2 的方法， 用环丙基磺酰氯代替甲基磺酰氯， 制备得到标题化合物。 ¾ NM (400 MHz, CDCl3-t 3): 7.40 (1H, t, J = 7.6 Hz), 7.35 (1H, d, J = 7.6 Hz), 7.14 (1H, s), 7.02-7.06 (2H, m), 6.63 (2H, s), 6.47 (1H, dd, J = 8.0 Hz, 2.0 Hz), 6.44 (1H, d, J = 2.4 Hz), 5.04 (2H, s), 4.71-4.79 (2H, m), 4.26 (1H, dd, J = 9.2 Hz, 6.0 Hz), 4.11 (2H, t, J = 6.0 Hz), 3.74-3.82 (1H, m), 3.55 (2H, q, J = 6.0Hz), 2.78 (1H, dd, J = 16.8 Hz, 5.2 Hz), 2.59 (1H, dd, J = 16.8 Hz, 9.2 Hz), 2.40-2.51 (1H, m), 1.97 (6H, s), 1.18-1.22 (2H, m), 0.98-1.03 (2H, m)。 The title compound was prepared according to the procedure of Example 2, m.p. 3⁄4 NM (400 MHz, CDCl 3 -t 3 ): 7.40 (1H, t, J = 7.6 Hz), 7.35 (1H, d, J = 7.6 Hz), 7.14 (1H, s), 7.02-7.06 (2H, m), 6.63 (2H, s), 6.47 (1H, dd, J = 8.0 Hz, 2.0 Hz), 6.44 (1H, d, J = 2.4 Hz), 5.04 (2H, s), 4.71-4.79 (2H, m), 4.26 (1H, dd, J = 9.2 Hz, 6.0 Hz), 4.11 (2H, t, J = 6.0 Hz), 3.74-3.82 (1H, m), 3.55 (2H, q, J = 6.0Hz) , 2.78 (1H, dd, J = 16.8 Hz, 5.2 Hz), 2.59 (1H, dd, J = 16.8 Hz, 9.2 Hz), 2.40-2.51 (1H, m), 1.97 (6H, s), 1.18-1.22 (2H, m), 0.98-1.03 (2H, m).
实施例 5 : 2-(6-((2'，6'-二甲基 -4'-(2-(U-二氧代-异噻唑烷 -2-基）乙氧基)联苯 -3-基）甲氧 Example 5: 2-(6-((2',6'-Dimethyl-4'-(2-(U-dioxo-isothiazol-2-yl)ethoxy)biphenyl-3 -base) methoxy
Figure imgf000016_0002
Figure imgf000016_0002
步骤 1: 2-(6-((4'-(2-(3-氯丙基磺酰基氨基)乙氧基 )-2'，6'-二甲基联苯 -3-基)甲氧基 )-2，3-二氢 苯并呋喃 -3 -基)乙酸甲酯的合成 Step 1: 2-(6-((4'-(2-(3-Chloropropylsulfonylamino)ethoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy) Synthesis of methyl-2,3-dihydrobenzofuran-3-yl)acetate
向 2-(6-((4'-(2-氨基乙氧基) - 2',6'-二甲基联苯 基)甲氧基 )- 2,3-二氮苯并呋喃 3-基)乙酸 甲酯 C(),66 g, 1.4 mmoi)的二氯甲垸溶液中 (50 mL)铱次加入: 5氯 -1-丙基磺酰氯 (0.38 g, 2.1 mmol)和三乙胺 (0.29 g, 2.9 mmol)。将该反应混合液室温搅拌过夜。将反应倒入水中 (50 mL 用二氯甲烷萃取 (100 mL x 2 有机相用无水硫酸钠千燥， 浓缩， 残留物经硅跤柱色谱法分 离纯化得到 2-(6-((4'-(2-(3-氯丙基磺酰氨基)乙氧基 )-2',6'-二甲基联苯 -3-基)甲氧基 )-2,3-二氢 苯并呋喃 -3-基)乙酸甲酯 (0.64 g, 收率 75.0%) MS m/z[ESi]+:602,0[M-M] n To 2-(6-((4'-(2-aminoethoxy)-2',6'-dimethylbiphenyl)methoxy)-2,3-diazabenzofuran-3-yl ) methyl acetate C (), 66 g, 1.4 mm oi) in methylene chloride solution (50 mL) added: 5 chloro-1-propylsulfonyl chloride (0.38 g, 2.1 mmol) and triethylamine ( 0.29 g, 2.9 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was poured into water (50 mL was extracted with dichloromethane (100 mL x 2 organic phase dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to give 2-(6-((4) -(2-(3-chloropropylsulfonylamino)ethoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran- Methyl 3-methyl)acetate (0.64 g, yield 75.0%) MS m/z [ESi] + : 602,0 [MM] n
步骤 2: 2-(6-((4'-(2- (1,1-二氧代-异噻唑烷 -2-基)乙氧基 )~2',6'-二甲基联苯 基)甲氧基 )- 2，3~ 二氣苯并块喃 -3-基)乙酸甲酯的合成 Step 2: 2-(6-((4'-(2-(1,1-dioxo-isothiazol-2-yl)ethoxy)~2',6'-dimethylbiphenyl Synthesis of methyl methoxy)- 2,3~ di-benzobenzopyran-3-yl)acetate
向 2-(6-((4'-(2-(3-氯丙基磺酰基氨基)乙氧基 )-2',6'-二甲基联苯 -3-基)甲氧基 )-2,3-二氢苯 并呋喃—3-基)乙酸甲酯 (60.0 mg, 0.1 mmol)的 Ν,Ν-二甲基甲酰胺溶液中 (10 mL)加入碳酸钾 (28.0 mg, 0.2 mmol)。 将该反应混合液 80 °C搅拌过夜。 将反应倒入水中 (50 mL), 用乙酸乙 酯萃取 (100 mLx2)， 有机相用无水硫酸钠干燥， 浓缩， 残留物经硅胶柱色谱法纯化得到 2-(6-((4'-(2-(1,1-二氧代-异噻唑垸 -2-基)乙氧基 )-2',6'-二甲基联苯 - 3-基)甲氧基 )- 2，3-二氢苯并 呋喃- 3^基)乙酸甲酯 50.0 mg, 收率 88,8%)。 MS m/z[ESlf :566.0[M+1] ,  To 2-(6-((4'-(2-(3-chloropropylsulfonylamino)ethoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy)- Potassium 2,3-dihydrobenzofuran-3-yl)acetate (60.0 mg, 0.1 mmol) in hydrazine, hydrazine-dimethylformamide (10 mL), potassium carbonate (28.0 mg, 0.2 mmol) . The reaction mixture was stirred at 80 ° C overnight. The reaction was poured into water (50 mL), EtOAc (EtOAc)EtOAc. (2-(1,1-dioxo-isothiazolium-2-yl)ethoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy)- 2,3- Methyl dihydrobenzofuran-3(meth)acetate 50.0 mg, yield 88,8%). MS m/z [ESlf: 566.0 [M+1],
步骤 3： 2-(6-((4'-(2-(1，1-二氧代-异噻唑烷 -2-基)乙氧基 )-2'，6'-二甲基联苯 -3-基)甲氧基) -2,3- 二氢苯并呋喃 -3 -基)乙酸的合成 Step 3: 2-(6-((4'-(2-(1,1-dioxo-isothiazol-2-yl)ethoxy)-2',6'-dimethylbiphenyl- Synthesis of 3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
向 2-(6-((4'-(2-(1,1-二氧代-异噻唑垸 -2-基)乙氧基 )-2',6'-二甲基联苯 -3-基)甲氧基) -2,3- 二氢苯并呋喃 -3-基)乙酸甲酯 (50.0 mg, 0.09 mmol)甲醇 (10 mL)和四氢呋喃 (20 mL)的混合溶 剂的溶液中， 滴加 2 M氢氧化钠水溶液 (1 mL)， 滴加完毕后混合物室温搅拌过夜。 将反应 混合物用水稀释， 用 10%柠檬酸水溶液酸化， 并用乙酸乙酯萃取 (50 mLx3)。有机相用无水 硫酸钠干燥后浓缩，残留物通过硅胶柱色谱法分离纯化得到 2-(6-((4'-(2-(1,1-二氧代-异噻唑 垸 -2-基)乙氧基 )-2',6'-二甲基联苯 -3-基)甲氧基 )-2,3-二氢苯并呋喃 -3 -基)乙酸 (22,0 mg, 收率 45, 1 %)。 lH NMR (400 MHz, CDCl3-t 3): 7.43 (1H, t, J = 7.2 Hz), 7.37 (1H, d, J = 7.6 Hz), 7.16 (1H, s), 7.04-7.09 (2H, m), 6.66 (2H, s), 6.49 (1H, dd, J = 8.0 Hz, 2.0 Hz), 6.48 (1H, d, J = 2.0 Hz), 5.07 (2H, s), 4.78 (1H, t, J = 8.8 Hz), 4.29 (1H, dd, J = 9.2 Hz, 6.0 Hz), 4.20 (2H, t, J = 4.2 Hz), 3.79-3.84 (1H, m), 3.48-3.53 (4H, m), 3.16 (2H, t, J = 7.6 Hz), 2.80 (1H, dd, J = 17.2 Hz, 5.6 Hz), 2.61 (1H, dd, J = 16.8 Hz, 9.2 Hz), 2.37 (2H, quin, J = 6.8 Hz), 1.99 (6H, s)。 To 2-(6-((4'-(2-(1,1-dioxo-isothiazolyl-2-yl)ethoxy)-2',6'-dimethylbiphenyl-3- a mixture of methyl methoxy)-2,3-dihydrobenzofuran-3-yl)acetate (50.0 mg, 0.09 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL) A 2 M aqueous sodium hydroxide solution (1 mL) was added dropwise to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, EtOAc (EtOAc)EtOAc. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is purified by silica gel column chromatography to afford 2-(6-((4)-(2-(1,1-dioxo-isothiazol-2-yl) Ethoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (22,0 mg, yield 45, 1 %). l H NMR (400 MHz, CDCl 3 -t 3 ): 7.43 (1H, t, J = 7.2 Hz), 7.37 (1H, d, J = 7.6 Hz), 7.16 (1H, s), 7.04-7.09 (2H , m), 6.66 (2H, s), 6.49 (1H, dd, J = 8.0 Hz, 2.0 Hz), 6.48 (1H, d, J = 2.0 Hz), 5.07 (2H, s), 4.78 (1H, t , J = 8.8 Hz), 4.29 (1H, dd, J = 9.2 Hz, 6.0 Hz), 4.20 (2H, t, J = 4.2 Hz), 3.79-3.84 (1H, m), 3.48-3.53 (4H, m ), 3.16 (2H, t, J = 7.6 Hz), 2.80 (1H, dd, J = 17.2 Hz, 5.6 Hz), 2.61 (1H, dd, J = 16.8 Hz, 9.2 Hz), 2.37 (2H, quin, J = 6.8 Hz), 1.99 (6H, s).
实施例 6: 2-(6-((2'，6'-二甲基 -4'-(3-(N,N-二甲基氨基磺酰基)丙氧基)联苯 -3-基)甲氧基 )-2，3- Example 6: 2-(6-((2',6'-Dimethyl-4'-(3-(N,N-dimethylaminosulfonyl)propoxy)biphenyl-3-yl) Methoxy)-2,3-
Figure imgf000017_0001
Figure imgf000017_0001
步骤 1: 3-(4-溴 -3,5-二甲基苯氧基)丙基 -1-磺酸钠的合成 Step 1: Synthesis of sodium 3-(4-bromo-3,5-dimethylphenoxy)propyl-1-sulfonate
向 4-溴 -3，5-二甲基苯酚 (20.2 g, 0.1 moi)和水 (250 mL)的混合液中加入氢氧化钠 (5.0 g， 0.12 mol)。将该反应混合液搅拌 1小时。将 2,2二氧代 -】,2-氧杂硫代环戊烷 ί 15.3 g, 0.12 mol) 的 1 ,4-二氧六环溶液 (200 mL)滴加到上述反应液中„ 反应液室温搅拌过夜后过滤收集所生 成的固体，将固体干燥得 3-(4-溴 -3,5-二甲基苯氧基)丙基 -1-磺酸钠 (29.3 g， 收率 85。0%)。 ¾ NM (400 MHz, DMSO-t 6): 6.77 (2H, s), 3.92-4.05 (2H, m), 2.49-2.53 (2H, m), 1.90-1.97 (2H, m)。 To a mixture of 4-bromo-3,5-dimethylphenol (20.2 g, 0.1 moi) and water (250 mL) was added sodium hydroxide (5.0 g, 0.12 mol). The reaction mixture was stirred for 1 hour. 2,2 dioxo-], 2-oxathiocyclopentane ί 15.3 g, 0.12 mol) of 1, 4-dioxane solution (200 mL) was added dropwise to the above reaction solution „ Reaction solution After stirring at room temperature overnight, the resulting solid was collected by filtration, and the solid was dried to give sodium 3-(4-bromo-3,5-dimethylphenoxy)propyl-1-sulfonate (29.3 g, yield: 85. %) 3⁄4 NM (400 MHz, DMSO-t 6 ): 6.77 (2H, s), 3.92-4.05 (2H, m), 2.49-2.53 (2H, m), 1.90-1.97 (2H, m).
步骤 2: 3-(4-溴 -3,5-二甲基苯氧基)丙基 -1-磺酰氯的合成 Step 2: Synthesis of 3-(4-bromo-3,5-dimethylphenoxy)propyl-1-sulfonyl chloride
冰水浴冷却下， 向 3-(4-溴 -3,5-二甲基苯氧基)丙基 -1-磺酸钠 (10.0 g 29.0 mmoi)的 Ν,Ν- 二甲基甲酰胺 (150 mL)溶液中滴加二氯亚砜 (15 mL)。滴加完毕后将该反应混合液室温搅拌 4小时。 将反应液倒入水中 (500 mL), 过滤收集所生成的固体， 将固体干燥得 3-(4-溴 -3,5- 二甲基苯氧基)丙基 -1-磺酰氯 (7.5 g, 收率 75.8%).3 JH NMR (400 MHz, CDCl3-t 3): 6.62 (2H, s), 4.08 (2H, t, J = 5.2 Hz), 3.88 (2H, t, J = 7.2 Hz), 2.46-2.50 (2H, m), 2.37 (3H, s)。 To a solution of sodium 3-(4-bromo-3,5-dimethylphenoxy)propyl-1-sulfonate (10.0 g 29.0 mm oi) in hydrazine, dimethyl-dimethylformamide (150) To the solution of mL), thionyl chloride (15 mL) was added dropwise. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 4 hours. The reaction solution was poured into water (500 mL), and the solid formed was collected by filtration, and the solid was dried to give 3-(4-bromo-3,5-dimethylphenoxy)propyl-1-sulfonyl chloride (7.5 g) , yield 75.8%). 3 J H NMR (400 MHz, CDCl 3 -t 3 ): 6.62 (2H, s), 4.08 (2H, t, J = 5.2 Hz), 3.88 (2H, t, J = 7.2 Hz), 2.46-2.50 (2H, m), 2.37 (3H, s).
步骤 3: \ V-二甲基 -3-(4-溴 -3,5-二甲基苯氧基)丙基 -1-磺酰胺的合成 Step 3: Synthesis of \V-dimethyl-3-(4-bromo-3,5-dimethylphenoxy)propyl-1-sulfonamide
向 3-(4-溴 -3,5-二甲基苯氧基)丙基 -1-磺酰氯（ 4.0 g, Π .7 mmoi)的四氢呋喃（150 mL)溶 液中， 滴加二甲胺水溶液 (33.0%， U) mL), 滴如完毕后混合物室温搅拌过夜 将溶剂浓缩 后， 残留钧通过硅胶柱色谱法分离纯化得到 二甲基 - 3-(4-溴- 3 二甲基苯氧基)丙基小 磺酰胺 (4.0 g, 牧率 97.6%), 1H NM (400 MHz, CDCl3-t¾): 6.65 (2H, s), 4.06 (2H, t, J = 6.0 Hz), 3.14-3.15 (2H, m), 2.91 (6H, s), 2.39 (6H, s), 2.26-2.39 (2H, m)。 To a solution of 3-(4-bromo-3,5-dimethylphenoxy)propyl-1-sulfonyl chloride (4.0 g, Π.7 mmoi) in tetrahydrofuran (150 mL) (33.0%, U) mL), after completion of the dropwise addition, the mixture was stirred at room temperature overnight. After concentration of the solvent, residual hydrazine was separated and purified by silica gel column chromatography to give dimethyl 3-(4-bromo-3 dimethylphenoxy) Propyl sulfonamide (4.0 g, grazing rate 97.6%), 1H NM (400 MHz, CDCl 3 -t3⁄4): 6.65 (2H, s), 4.06 (2H, t, J = 6.0 Hz), 3.14-3.15 (2H, m), 2.91 (6H, s), 2.39 (6H, s), 2.26-2.39 (2H, m).
步骤 4: 4'-( 3-(N，N-二甲基氨基磺酰基)丙氧基 )-2'，6'-二甲基联苯 -3-甲醛的合成 Step 4: Synthesis of 4'-(3-(N,N-dimethylaminosulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-carbaldehyde
二甲基 -3- (4溴- 3、5-二甲基苯氧基)丙基小磺酰胺 (4.0 g, 11.4 mmol), 3-甲酰基苯硼 酸 (2.1 g, 13.7 mmol)， 碳酸铯 (5.5 g, 17.1 mmol)和 [Ι,Γ-双 (二苯基膦)二茂铁]二氯化钯 (0.4 g, 0.6 mmol)加到 1,4-二氧六环中 (150 mL)。 将该混合物加热回流 8小时后冷却到室温。 反应 混合物通过硅藻土过滤， 用乙酯乙酯洗涤， 滤液经浓缩后残留物通过硅胶柱色谱法分离纯 化得到 4'-(3-(N，N-二甲基氨基磺酰基）丙氧基 )-2',6'-二甲基联苯 -3-甲醛 (2.75 g, 收率 64.3%) 1H NM (400 MHz, CDCl3-t 3): 10.05 (1H, s), 7.86 (1H, d, J = 7.6 Hz), 7.66 (1H, s), 7.59 (1H, t, J = 7.6 Hz), 7.41 (1H, d, J = 7.6 Hz), 6.67 (2H, s), 4.12 (2H, t, J = 6.0 Hz), 3.16 (2H, t, J = 7.6 Hz), 2.92 (6H, s), 2.28-2.37 (2H, m), 1.99 (6H, s)。 Dimethyl-3-(4bromo-3,5-dimethylphenoxy)propyl sulfonamide (4.0 g, 11.4 mmol), 3-formylphenylboronic acid (2.1 g, 13.7 mmol), cesium carbonate (5.5 g, 17.1 mmol) and [Ι,Γ-bis(diphenylphosphino)ferrocene]palladium dichloride (0.4 g, 0.6 mmol) in 1,4-dioxane (150 mL) . The mixture was heated to reflux for 8 hours and then cooled to room temperature. The reaction mixture was filtered through celite, washed with ethyl acetate, and evaporated. 4'-(3-(N,N-Dimethylaminosulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-carbaldehyde (2.75 g, yield 64.3%) 1H NM (400 MHz, CDCl 3 -t 3 ): 10.05 (1H, s), 7.86 (1H, d, J = 7.6 Hz), 7.66 (1H, s), 7.59 (1H, t, J = 7.6 Hz), 7.41 (1H, d, J = 7.6 Hz), 6.67 (2H, s), 4.12 (2H, t, J = 6.0 Hz), 3.16 (2H, t, J = 7.6 Hz), 2.92 (6H, s), 2.28-2.37 (2H, m), 1.99 (6H, s).
步骤 5-7: 2-(6-((2'，6'-二甲基 -4'-(3-(N，N-二甲基氨基磺酰基)丙氧基)联苯 -3-基)甲氧基 )-2，3- 二氢苯并呋喃 -3 -基)乙酸的合成 Step 5-7: 2-(6-((2',6'-Dimethyl-4'-(3-(N,N-dimethylaminosulfonyl)propoxy)biphenyl-3-yl) Synthesis of methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid
以步骤 4所得到的 4'-(3-(N，N-二甲基氨基磺酰基)丙氧基 )-2',6'-二甲基联苯 -3-甲醛为原 料， 依次按照类似实施例 1 中步骤 3,4和 8的方法制备得到 2 6-；2',6'-二甲基 -4'-P- N，N- 二甲基氨基磺酰基)丙氧基)联苯 -3-基）甲氧基 )-2,3-二氢苯并呋喃 -3-基）乙酸。 1H NM (400MHz, CDCl3-t 3): 7.40 (1H, t, J = 8.0 Hz), 7.35 (1H, d, J = 8.0 Hz), 7.14 (1H, s), 7.02-7.07 (2H, m), 6.63 (2H, s), 6.47 (1H, dd, J = 8.0 Hz, 2.0 Hz), 6.44 (1H, d, J = 2.0 Hz), 5.04 (2H, s), 4.74 (1H, t, J = 9.2 Hz), 4.26 (1H, dd, J = 9.2 Hz, 6.0 Hz), 4.09 (2H, t, J = 5.2 Hz), 3.75-3.83 (1H， m), 3.14 (2H, t, J = 7.6 Hz), 2.90 (6H, s), 2.79 (1H. dd, J = 16.8 Hz, 5.2 Hz), 2.59 (1H, dd, J = 16.8 Hz, 9.2 Hz), 2.26-2.32 (2H. m), 1.97 (6H, s)。 Using 4'-(3-(N,N-dimethylaminosulfonyl)propoxy)-2',6'-dimethylbiphenyl-3-carbaldehyde obtained in step 4 as a starting material, followed by Prepare 2-6-; 2',6'-dimethyl-4'-P-N,N-dimethylaminosulfonyl)propoxy)biphenyl by the methods of steps 3, 4 and 8 in Example 1. 3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid. 1H NM (400MHz, CDCl 3 -t 3 ): 7.40 (1H, t, J = 8.0 Hz), 7.35 (1H, d, J = 8.0 Hz), 7.14 (1H, s), 7.02-7.07 (2H, m ), 6.63 (2H, s), 6.47 (1H, dd, J = 8.0 Hz, 2.0 Hz), 6.44 (1H, d, J = 2.0 Hz), 5.04 (2H, s), 4.74 (1H, t, J = 9.2 Hz), 4.26 (1H, dd, J = 9.2 Hz, 6.0 Hz), 4.09 (2H, t, J = 5.2 Hz), 3.75-3.83 (1H, m), 3.14 (2H, t, J = 7.6 Hz), 2.90 (6H, s), 2.79 (1H. dd, J = 16.8 Hz, 5.2 Hz), 2.59 (1H, dd, J = 16.8 Hz, 9.2 Hz), 2.26-2.32 (2H. m), 1.97 (6H, s).
实施例 7: 2-(6-((2'，6'-二甲基 -4'-(3-(N-甲基氨基磺酰基)丙氧基)联苯 -3-基)甲氧基 )-2，3-二氢 Example 7: 2-(6-((2',6'-Dimethyl-4'-(3-(N-methylaminosulfonyl)propoxy)biphenyl-3-yl)methoxy) )-2,3-dihydrogen
Figure imgf000018_0001
Figure imgf000018_0001
按照实施例 6的方法，用甲胺代替二甲胺，制备得到标题化合物。 ^ NMR l^OO MHz, CDCl3-t 3): 7.42 (1H, t, J = 7.6 Hz), 7.37 (1H, d, J = 7.6 Hz), 7.15 (1H, s), 7.04-7.08 (2H, m), 6.64 (2H, s), 6.49 (1H, dd, J = 8.0 Hz, 2.0 Hz), 6.46 (1H, d, J = 2.0 Hz), 5.06 (2H, s), 4.76 (1H, t, J = 9.2 Hz), 4.28 (1H, dd, J = 9.2 Hz, 6.0 Hz), 4.07-4.12 (3H, m), 3.77-3.84 (1H, m), 3.26 (2H, t, J = 7.2 Hz), 2.84 (3H, d, J = 5.6 Hz), 2.80 (1H, dd, J = 16.8 Hz, 5.2 Hz), 2.60 (1H, dd, J = 16.8 Hz, 9.2 Hz), 2.24-2.33 (2H, m), 1.99 (6H, s)。 The title compound was prepared according to the procedure of Example 6 using methyleneamine instead of dimethylamine. ^ NMR l^OO MHz, CDCl 3 -t 3 ): 7.42 (1H, t, J = 7.6 Hz), 7.37 (1H, d, J = 7.6 Hz), 7.15 (1H, s), 7.04-7.08 (2H , m), 6.64 (2H, s), 6.49 (1H, dd, J = 8.0 Hz, 2.0 Hz), 6.46 (1H, d, J = 2.0 Hz), 5.06 (2H, s), 4.76 (1H, t , J = 9.2 Hz), 4.28 (1H, dd, J = 9.2 Hz, 6.0 Hz), 4.07-4.12 (3H, m), 3.77-3.84 (1H, m), 3.26 (2H, t, J = 7.2 Hz ), 2.84 (3H, d, J = 5.6 Hz), 2.80 (1H, dd, J = 16.8 Hz, 5.2 Hz), 2.60 (1H, dd, J = 16.8 Hz, 9.2 Hz), 2.24-2.33 (2H, m), 1.99 (6H, s).
实施例 8: 2-(6-({4'42-(l，l-二氧代-异噻唑烷 -2-基〗乙氧基 ) 2' -二甲基联苯 基）甲基氨 Example 8: 2-(6-({4'42-(l,1-dioxo-isothiazolidine-2-yloxy) 2'-dimethylbiphenyl)methylamine
Figure imgf000018_0002
步骤 1: 6-三氟甲磺酰氧基 -2,3-二氢苯并呋喃 -3-乙酸甲酯的合成
Figure imgf000018_0002
Step 1: Synthesis of 6-trifluoromethanesulfonyloxy-2,3-dihydrobenzofuran-3-acetic acid methyl ester
向 6-羟基-; -二氢苯并呋喃 - 3-乙酸甲 ϋί2,08 g, 10.0 ¾:¾0101)和 乙胺(2,02 g, 20.0 rnniol) 的混合物中加入二氯甲垸 (50 mL)， 将混合物冷却到零摄氏度 向混合物中慢慢滴加 Ξ:氟甲 磺酸酐 (3.4 g, 12.0 mmol}, 混合物升到室温， 在室濕搅摔 2小时。 将反应混合物减压下浓 缩， 得到的残留物通过硅胶柱色谱法分离纯化得到 6 -三氟甲磺酰氧基 2,3-二氢苯并呋喃 3- 乙酸甲酯 (2, ! g, 收率 63 )％)。 1H NM (400 MHz, CDCl3-t¾): 7.18 (1H, d, J = 8.4 Hz), 6.76 (1H, dd, J = 8.4 Hz, 2.0 Hz), 6.70 (1H, d, J = 2.0 Hz), 4.84 (1H, t, J = 9.2 Hz), 4.34 (1H, dd, J = 9.2 Hz, 6.4 Hz), 3.82-3.94 (1H, m), 3.73 (3H, s), 2.78 (1H, dd, J = 16.8 Hz, 5.6 Hz), 2.61 (1H, dd, J = 16.8 Hz, 8.4 Hz)。 To a mixture of 6-hydroxy-;-dihydrobenzofuran-3-acetic acid methyl ϋ 2,08 g, 10.0 3⁄4:3⁄40101) and ethylamine (2,02 g, 20.0 rnniol) was added dichloromethane (50 mL) The mixture was cooled to zero degrees Celsius. To the mixture was slowly added dropwise hydrazine: fluoromethanesulfonic anhydride (3.4 g, 12.0 mmol), the mixture was allowed to warm to room temperature, and the mixture was stirred for 2 hours in the chamber. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 6-trifluoromethanesulfonyloxy 2,3-dihydrobenzofuran 3-ethyl acetate (2, g, yield 63%). 1H NM (400 MHz, CDCl 3 -t3⁄4): 7.18 (1H, d, J = 8.4 Hz), 6.76 (1H, dd, J = 8.4 Hz, 2.0 Hz), 6.70 (1H, d, J = 2.0 Hz) , 4.84 (1H, t, J = 9.2 Hz), 4.34 (1H, dd, J = 9.2 Hz, 6.4 Hz), 3.82-3.94 (1H, m), 3.73 (3H, s), 2.78 (1H, dd, J = 16.8 Hz, 5.6 Hz), 2.61 (1H, dd, J = 16.8 Hz, 8.4 Hz).
歩骤 2: 6-氮基 2,3-二复苯并呋喃 乙酸甲酯的合成 Step 2 : Synthesis of 6-N-nitro 2,3-di-benzofuranacetic acid methyl ester
在氮气充分置换下， 向 6- :Ξ氟甲磺酰氧基 - 2、3-二氮苯并块喃 乙酸甲 ϋί2.1 g， 6, 17 mmoi)> 二苯甲酮亚胺 (1.5 g, 8.3 mmo ), (二亚苄基丙酮)二铠 (0.56 g, 0.6 mmol). 2 -二环 己基膦2,4,6-王异丙基联苯 (0.7 g, 1.5 mmoi)和碳酸铯 (4.0 g， 12.0 mmoi)的混合物中加入四 氢呋喃 (50 mL)， 将混合物加热 ή流过夜。 反应混合狗冷却到室温后. 过滤， 将滤液在减压 下法缩。 向得到的残留犓中加入四氢呋喃 (50 mL) , 然后加入 3M:的盐酸 ( 10 mL)， 混合物 室温搅拌 2个小时。 将反应混合犓减压浓缩后溶于水中 (100 mL), 用氢氧化钠的水溶液将 pH值调节到 8-9之间， 用乙酸乙酯萃取。 将有机相用无水硫酸钠千燥， 自然过滤 并在减 压下浓缩。 得到的残留物用硅胶柱色谱法纯化， 得到 6- ¾基 -2,3-二氢苯并咲喃 -3乙酸甲酯 (0.4 g, 牧率 32.0%)。 1H NM (400 MHz, CDCl3-t¾): 6.88 (1H, d, J = 8.0 Hz), 6.17 (1H, dd, J = 8.0 Hz, 1.6 Hz), 6.15 (1H, d, J = 1.6 Hz), 4.69 (1H, t, J = 9.2 Hz), 4.20 (1H, dd, J = 9.2 Hz, 6.4 Hz), 3.71-3.77 (1H, m), 3.69 (3H, s), 3.51-3.70 (2H, brs), 2.70 (1H, dd, J = 16.8 Hz, 5.6 Hz), 2.51 (1H, dd, J = 16.8 Hz, 9.2 Hz)。 6-:Ξfluoromethanesulfonyloxy-2,3-diazabenzopyranoacetate, 2.12.1 g, 6, 17 mmoi)> benzophenone imine (1.5 g) under nitrogen partial displacement , 8.3 mmo ), (dibenzylideneacetone)dioxane (0.56 g, 0.6 mmol). 2 -Dicyclohexylphosphine 2,4,6-Wang-isopropylbiphenyl (0.7 g, 1.5 mm oi) and cesium carbonate Tetrahydrofuran (50 mL) was added to a mixture of (4.0 g, 12.0 mmoi), and the mixture was heated to reflux overnight. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was subjected to reduction under reduced pressure. To the obtained residual hydrazine, tetrahydrofuran (50 mL) was added, and then 3M: hydrochloric acid (10 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was combined and concentrated under reduced pressure, and then dissolved in water (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue thus obtained was purified by silica gel column chromatography toield of 6- 3⁄4-yl-2,3-dihydrobenzopyran-3-acetate (0.4 g, </ RTI></RTI> 32.0%). 1H NM (400 MHz, CDCl 3 -t3⁄4): 6.88 (1H, d, J = 8.0 Hz), 6.17 (1H, dd, J = 8.0 Hz, 1.6 Hz), 6.15 (1H, d, J = 1.6 Hz) , 4.69 (1H, t, J = 9.2 Hz), 4.20 (1H, dd, J = 9.2 Hz, 6.4 Hz), 3.71-3.77 (1H, m), 3.69 (3H, s), 3.51-3.70 (2H, Brs), 2.70 (1H, dd, J = 16.8 Hz, 5.6 Hz), 2.51 (1H, dd, J = 16.8 Hz, 9.2 Hz).
歩骤 3; 2-(6-((4'-轻基2'，6 二甲基联苯 -3-基)甲基氣基)- 2,3~二氢苯并咲喃 -3-基)乙酸甲酯的 合成 Step 3; 2-(6-((4'-Lightyl 2',6-dimethylbiphenyl-3-yl)methyl)- 2,3-dihydrobenzopyran-3-yl Synthesis of methyl acetate
向 6-氨基- 2、3-二氢苯并呋喃 - 3-乙酸甲酯(0,41 g, 1.98 mmol)和 4'-羟基- 2',6'-二甲基联 * 甲薛 (0,45 g, 1.98 mmol)的乙醇 (20 mL)溶液中加入醋酸 (0.1 ml). 混合物室温搅拌 2个 小时。 向反应混合物中加入王乙酰氧基硼氢化钠 (0,84 g, 3.96 mmoi)。 反应混合物室濕搅 拌 3个小时。 将反应混合物用饱和的氯化铵水瑢液淬灭， 用乙酸乙酯分液萃取。 将有 ,相 依次用饱和碳酸氢钠水溶液和饱和食盐水洗涤， 用无水硫酸钠干燥， 过滤。 将滤液浓缩后 得到的残留物用硅胶柱色谱法纯化， 得到产品 2-(6-《4'-羟基 -2',6'-二甲基联苯 -3-基)甲基氨 基) -2,3-二氢苯并呋喃 -3- 基)乙酸甲酯 (0.4 g, 收率 50.0%)。 MS m/z[ESI]+:418.0[M+l] o 步骤 4-8 : 2-(6-((2'，6'-二甲基 -4'-(2-(1，1-二氧代-异噻唑烷 -2-基)乙氧基)联苯 -3-基）甲基氨 基) -2,3 -二氢苯并呋喃 -3-基)乙酸的合成 To 6-amino-2,3-dihydrobenzofuran-3-ethyl acetate (0,41 g, 1.98 mmol) and 4'-hydroxy-2',6'-dimethyl linked* Add acetic acid (0.1 ml) to a solution of 45 g, 1.98 mmol) in EtOAc (20 mL). To the reaction mixture was added sodium acetoxyborohydride (0,84 g, 3.96 mm oi). The reaction mixture chamber was wet stirred for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography to give the product 2-(6- "4'-hydroxy-2',6'-dimethylbiphenyl-3-yl)methylamino) -2 Methyl 3-hydrobenzofuran-3-yl)acetate (0.4 g, yield 50.0%). MS m/z [ESI] + : 418.0 [M+l] o Step 4-8: 2-(6-((2',6'-dimethyl-4'-(2-(1,1-) Synthesis of oxo-isothiazolidine-2-yl)ethoxy)biphenyl-3-yl)methylamino)-2,3-dihydrobenzofuran-3-yl)acetic acid
以 2-(6-((4'-羟基- 2',6'-二甲基联苯- 3-基）甲基氨基)- 2,3-二氢苯并呋喃 - 3-基)乙酸甲酯为 原料 依次参照实施例 2中的步骤 1、 2和实施例 5中歩骤 1、 2和 3的方法制备得到目标 化合物。 1H NM (400 MHz, DMSO-t¾): 7.43 (1H, t, J = 7.6 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.12 (1H, s), 7.07 (1H, d, J = 8.0 Hz), 7.03 (1H, d, J = 8.4 Hz), 6.70 (2H, s), 6.42-6.47 (2H, m), 5.08 (2H, s), 4.66 (1H, t, J = 8.8 Hz), 4.09-4.18 (3H, m), 3.61-3.69 (1H, m), 3.2-3.35 (4H, m), 3.18 (2H, t, J = 7.6 Hz), 2.66 (1H, dd, J = 17.2 Hz, 5.6 Hz), 2.42-2.49 (1H, m), 2.21 (2H, quint, J = 6.8 Hz), 1.90 (6H, s)。  2-(6-((4'-hydroxy-2',6'-dimethylbiphenyl-3-yl)methylamino)-2,3-dihydrobenzofuran-3-yl)acetate The ester was used as a starting material, and the title compound was obtained by referring to the steps 1, 2 and the steps 1, 2 and 3 of Example 5 in the same manner. 1H NM (400 MHz, DMSO-t3⁄4): 7.43 (1H, t, J = 7.6 Hz), 7.36 (1H, d, J = 7.6 Hz), 7.12 (1H, s), 7.07 (1H, d, J = 8.0 Hz), 7.03 (1H, d, J = 8.4 Hz), 6.70 (2H, s), 6.42-6.47 (2H, m), 5.08 (2H, s), 4.66 (1H, t, J = 8.8 Hz) , 4.09-4.18 (3H, m), 3.61-3.69 (1H, m), 3.2-3.35 (4H, m), 3.18 (2H, t, J = 7.6 Hz), 2.66 (1H, dd, J = 17.2 Hz , 5.6 Hz), 2.42-2.49 (1H, m), 2.21 (2H, quint, J = 6.8 Hz), 1.90 (6H, s).
实施例 9: 2-(6-((4'-(3- (二甲基膦酰基)丙氧基 )-2'，6'-二甲基联苯 -3-基)甲基氨基) -2，3-二氢苯 并呋喃 -3 -基)乙酸的合成
Figure imgf000019_0001
Figure imgf000020_0001
Example 9: 2-(6-((4'-(3-(Dimethylphosphonyl)propoxy)-2',6'-dimethylbiphenyl-3-yl)methylamino) - Synthesis of 2,3-dihydrobenzofuran-3-yl)acetic acid
Figure imgf000019_0001
Figure imgf000020_0001
以 2-(6-((4'-羟基 -2',6'-二甲基联苯 -3-基)甲基氨基) -2,3-二氢苯并呋喃 -3-基)乙酸甲酯为 原料参照实施例 1的方法制备得到标题化合物。 JH NM (400 MHz, CDCl3-t 3): 7.40 (1H, t, J = 7.6 Hz), 7.35 (1H, d, J = 7.6 Hz), 7.12 (1H, s), 7.02-7.06 (2H, m), 6.64 (2H, s), 6.46 (1H, dd, J = 8.4 Hz, 2.4 Hz), 6.42 (1H, d, J = 2.4 Hz), 5.05 (2H, s), 4.74 (1H, t, J = 8.8 Hz), 4.26 (1H, dd, J = 9.2 Hz, 6.0 Hz), 4.07 (2H, t, J = 5.2 Hz), 3.74-3.82 (1H, m), 2.72 (1H, dd, J = 16.8 Hz, 5.6 Hz), 2.53 (1H, dd, J = 16.8 Hz, 9.2 Hz), 2.09-2.16 (2H, m), 1.93-2.00 (8H, m), 1.56 (6H, d, J = 13.2 Hz)。 2-(6-((4'-hydroxy-2',6'-dimethylbiphenyl-3-yl)methylamino)-2,3-dihydrobenzofuran-3-yl)acetate The ester was used as a starting material. The title compound was obtained by the procedure of Example 1. J H NM (400 MHz, CDCl 3 -t 3 ): 7.40 (1H, t, J = 7.6 Hz), 7.35 (1H, d, J = 7.6 Hz), 7.12 (1H, s), 7.02-7.06 (2H , m), 6.64 (2H, s), 6.46 (1H, dd, J = 8.4 Hz, 2.4 Hz), 6.42 (1H, d, J = 2.4 Hz), 5.05 (2H, s), 4.74 (1H, t , J = 8.8 Hz), 4.26 (1H, dd, J = 9.2 Hz, 6.0 Hz), 4.07 (2H, t, J = 5.2 Hz), 3.74-3.82 (1H, m), 2.72 (1H, dd, J = 16.8 Hz, 5.6 Hz), 2.53 (1H, dd, J = 16.8 Hz, 9.2 Hz), 2.09-2.16 (2H, m), 1.93-2.00 (8H, m), 1.56 (6H, d, J = 13.2 Hz).
实施例 10: 2-(6-((4'-((4-甲磺酰基)哌嗪 -1-基) -2'，6'-二甲基联苯 -3-基)甲氧基 )-2，3-二氢苯并 呋喃 -3-基) Example 10: 2-(6-((4'-((4-Methanesulfonyl)piperazin-1-yl)-2',6'-dimethylbiphenyl-3-yl)methoxy) -2,3-dihydrobenzofuran-3-yl)
Figure imgf000020_0002
Figure imgf000020_0002
以 2-(6-((4'-羟基 -2',6'-二甲基联苯- 3基)甲氧基 2,3-二氢苯并呋喃 -3-基)乙酸甲酯和 i - 甲鎮酰基哌嗪为原料， 其中步骤 1参照实施例 8中步骤 1反应， 步骤 2参照实施例 8中步 骤 6 反应、 步骤 3 参照实施例 8 中的步骤 8 的方法制备得到标题化合犓。 MS rn/z[ESil+:551.0[M-;- l]n Methyl 2-(6-((4'-hydroxy-2',6'-dimethylbiphenyl-3-yl)methoxy 2,3-dihydrobenzofuran-3-yl)acetate and i - alkanoyl piperazine is used as a starting material, wherein step 1 is reacted with reference to step 1 in Example 8, step 2 is referred to step 6 in Example 8, and step 3 is carried out in the same manner as in step 8 of Example 8 to obtain the title compound. MS rn/z[ESil + :551.0[M-;- l] n
Figure imgf000020_0003
Figure imgf000020_0003
歩骤 _ί； (5)~2- (6- ((44叔丁基二甲基甲硅垸氧基) -2 '，6' ~二甲基联笨 -3-基)甲氧基) ~2J~二氛苯 并呋嗤 -3-基)乙酸甲酯的合成 (5)~2-(6-((44-tert-Butyldimethylsilyloxy)-2 ',6'-dimethylbiphenyl-3-yl)methoxy) Synthesis of ~2J~Binylbenzofurazin-3-yl)acetate
在冰水洛冷却下， 向 i4'-C叔丁基二甲基甲硅垸氧基 )- 2',6'二甲基联苯- 3-基)甲醇 (2,0 g 5.8 mmo , (H 羟基 -2,3-二氢苯并块喃 3-乙酸甲觀( 1.5 g, 7.2 mmoi)和三苯基膦 (·2,4 g, 9.0 mmol)的四氢块喃溶液中（150 mL)滴加偶氮二甲酸二异丙酯（1,8 g, 9.0 mmol)., 滴如完毕后， 反应液缓慢升到室温弁搅拌过夜。 反应液经浓缩后残留物通过硅胶柱色谱法分离纯化得到 (5 2- ί6-((4'- (叔丁基二甲基甲硅烷氧基 )-2',6'-二甲基联苯 -3-基）甲氧基 2,3-二氢苯并咲喃 -3基）乙酸甲酯 (23 g, 收率 75,5%)。 lH NMR (400 MHz, CDCl3-i¾): 7.42 (1H, J = 7.6 Hz), 7.37 (1H, d, J = 7.6 Hz), 7.18 (1H, s), 7.09 (1H, d, J = 7.2 Hz), 7.03 (1H, d, J = 8.0 Hz), 6.59 (2H: s), 6.47-6.51 (2H, m), 5.06 (2H, s), 4.76 (Hi i, j ===: 9.2 Hz), 4.26 (1H, dd, J :== 9.2 Hz, 6.0 Hz), 3.77-3.85 ilFL wj, 3,72 (3H, s), 2.75 {III, dd, J - 16,8 Hz, 5.6 Hz), 2.56 (ill, dd, J - 16,8 Hz, 9.6 Hz), 1.96 (6H, s), 1.02 (9H, s), 0.24 (6H, s)。 Under ice cooling, to i4'-C-tert-butyldimethylsilyloxy)- 2',6'-dimethylbiphenyl-3-yl)methanol (2,0 g 5.8 mmo, ( H hydroxy-2,3-dihydrobenzopyran 3-acetic acid methyl (1.5 g, 7.2 mm oi) and triphenylphosphine (·2,4 g, 9.0 mmol) in tetrahydrofuran solution (150 mL) Diisopropyl azodicarboxylate (1,8 g, 9.0 mmol) was added dropwise. After the dropwise addition, the reaction solution was slowly warmed to room temperature and stirred overnight. The residue was concentrated and purified by silica gel column chromatography. Purification afforded (5 2- ί6-((4'-(tert-butyldimethylsilyloxy)-2',6'-dimethylbiphenyl-3-yl)methoxy 2,3-di Kou-benzo pyran-3-yl hydrogen) acetate (23 g, yield 75,5%) l H NMR (400 MHz, CDCl 3 -i¾):. 7.42 (1H, J = 7.6 Hz), 7.37 (1H, d, J = 7.6 Hz), 7.18 (1H, s), 7.09 (1H, d, J = 7.2 Hz), 7.03 (1H, d, J = 8.0 Hz), 6.59 (2H: s), 6.47-6.51 (2H, m), 5.06 (2H, s), 4.76 (Hi i, j ===: 9.2 Hz), 4.26 (1H, dd, J :== 9.2 Hz, 6.0 Hz), 3.77-3.85 IlFL wj, 3,72 (3H, s), 2.75 {III, dd, J - 16,8 Hz, 5.6 Hz), 2.56 (ill, dd, J - 16,8 Hz, 9.6 Hz), 1.96 (6H, s), 1.02 (9H, s), 0.24 (6H, s).
步骤 2: 02-<6-((4'- 基-2，，6'-二甲基联苯 -3-基)甲氧基 )-2，3-二氢苯并呋喃 -3-基)乙酸甲醱 的合成 Step 2: 02-<6-((4'-yl-2,6'-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl) Synthesis of formamidine acetate
在冰水浴冷却下， 向 ( -2- (6- ίί4'- (叔丁基二甲基甲硅烷氧基 )- 2',6'-二甲基联苯 基)甲 氧基 ) 23-二氢¾并呋喃 -3-基)乙酸甲酯 (1,1 g, 2,1 mmoi)的四氢呋喃溶液中 (50 ml,)加入四 丁基氣化铵 （1.3 g，5,0mmoi)。加入完毕后， 反应液缓漫升到室温并搅拌过夜。 加入 50mL 饱和氣化铵水溶液终止反应， 混合物用乙酸乙酯萃取 ('50 mL x 3), 合并有机相并用无水硫 酸钠干燥， 滚缩得到 - 2- (6- ((4'-羟基- 2'6'-二甲基联苯 基）甲氧基 )- 2,3-二氢苯并呋喃 - 3 基）乙酸甲酸 (0,82 g, 收率 95,0%)。 iHN R (400 MHz, CDCl3-t¾): 7.44 (IH' J ===: 7.6 Hz), 7.39 (1¾ d, J = 7.6 Hz), 7.17 (IH, s), 7.07 (IH, cl J = 12 Hz), 7,03 (!¾ d, J = 8.0 Hz), 6.73 (2H s), 6.49 (IH, dd, j = 8.0 Hz, 2.4 Hz), 6.47 (IH, s), 5.05 (2H, s), 4.75 (IH, j = 9.2 Hz), 4.26 (IH. dd, J = 9.2 Hz, 6.0 Hz), 3.77-3.84 (IH, ra:)， 3.72 (3H, s)， 2.75 (IH, dd j. = 16.4 Hz, 4.2 Hz), 2.55 (IH, dd, J === 16.4 Hz, 9.2 Hz), 2.01 (61 s)。 Under the cooling of an ice water bath, (-2-(6- ίί4'-(tert-butyldimethylsilyloxy)-2',6'-dimethylbiphenyl)methoxy) 23- To a solution of methyl hydrogen (1,1 g, 2,1 mmol) in tetrahydrofuran (50 ml,) was added tetrabutylammonium hydride (1.3 g, 5,0 mmol). After the addition was completed, the reaction solution was slowly warmed to room temperature and stirred overnight. The reaction was quenched by the addition of 50 mL of aq. EtOAc. EtOAc (EtOAc) 2'6'-Dimethylbiphenyl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (0,82 g, yield 95, 0%). i HN R (400 MHz, CDCl 3 -t3⁄4): 7.44 (IH' J ===: 7.6 Hz), 7.39 (13⁄4 d, J = 7.6 Hz), 7.17 (IH, s), 7.07 (IH, cl J = 12 Hz), 7,03 (!3⁄4 d, J = 8.0 Hz), 6.73 (2H s), 6.49 (IH, dd, j = 8.0 Hz, 2.4 Hz), 6.47 (IH, s), 5.05 (2H , s), 4.75 (IH, j = 9.2 Hz), 4.26 (IH. dd, J = 9.2 Hz, 6.0 Hz), 3.77-3.84 (IH, ra:), 3.72 (3H, s), 2.75 (IH, Dd j. = 16.4 Hz, 4.2 Hz), 2.55 (IH, dd, J === 16.4 Hz, 9.2 Hz), 2.01 (61 s).
歩骤 3： >2~(6- ((4'- (氰基甲氧基) ~2 二甲基联苯 ~3 -基）甲氧基 )~2,3-二氣苯并呋嚼 -3-基) 乙酸甲酯的合成 Step 3: >2~(6-((4'-(Cyanomethoxy)~2 dimethylbiphenyl~3-yl)methoxy)~2,3-dibenzobenzopyrene- Synthesis of 3-methyl) methyl acetate
把碳酸钾 (2.0 g, 14.5 mmol)加入 (5 -2- (6 (4f -羟基 ',6'-二甲基联苯- 3 -基）甲氧基 )- 2,3-二 氢苯并呋喃 3-基）乙酸甲 ϋ(3.() g, 7.2 mmoi)和溴乙腈 (1.8 g, 15.0 mmol} 的乙腈 (100 mL)溶 液中。 将该混合物室温搅拌过夜， 过滤. 滤液浓缩后的残留物经硅胶柱色谱法分离纯化得 到 (； S 2- (6-((4' 氰基甲氧基 )-2'6'-二甲基联苯 3-基)甲氧基 )-2，3-二氢苯并呋喃 3-基)乙酸甲 (2A g, 收率 72.5% MSm/4ESir:458.0[M+i]。 Potassium carbonate (2.0 g, 14.5 mmol) was added to (5 -2-(6 (4 f -hydroxy',6'-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzene And furan 3-yl)acetic acid formazan (3. () g, 7.2 mm oi) and bromoacetonitrile (1.8 g, 15.0 mmol) in acetonitrile (100 mL). The mixture was stirred at room temperature overnight and filtered. The residue was purified by silica gel column chromatography ((2-(6-(4'cyanomethoxy)-2'6'-dimethylbiphenyl-3-yl)methoxy)-2 , 3-dihydrobenzofuran-3-yl)acetic acid methyl (2A g, yield 72.5% MS m / 4 ES ir: 458.0 [M+i].
步骤 4: '>-2-(6-((4'-(2-氨基乙氧基 )-2»，6'-二甲基联苯 -3-基)甲氧基 )-2，3-二氢苯并呋喃 -3-基) 乙酸甲酯的合成 Step 4: '>-2-(6-((2-Aminoethoxy)-2»,6'-dimethylbiphenyl-3-yl)methoxy)-2,3- Synthesis of Methyl Dihydrobenzofuran-3-yl)acetate
把 (Sh2-(6-((4'-(m基甲氧基)- 2 6'-二甲基联 - 3-基)甲氧基 )-2J二氢苯并呋喃 基)乙 酸甲觀(22 g, 4.8 mmoi), 雷尼镍 (50 g)和甲醇 (100 mL)的混合狗在氢气气氛下 (1大气压)室 温搅拌过夜。 反应液通过硅藻土过滤， 滤液浓缩后得到 (6-((4' 2-氨基乙氧基) -2',6 '-二 甲基联苯- 3-基）甲氧基 )- 23-二氢苯并呋喃 - 3-基）乙酸甲 1U2.2 g, 牧率 100,0%)。 S m/z[ESl]+:462,0[M+1]。 (Sh2-(6'-(m-methoxy)- 2 6'-dimethyl-3-yl)methoxy)-2J dihydrobenzofuran)acetate 22 g, 4.8 mm oi), a mixed dog of Raney nickel (50 g) and methanol (100 mL) was stirred under a hydrogen atmosphere (1 atm) at room temperature overnight. The reaction solution was filtered through celite, and the filtrate was concentrated (6- ((4'2-Aminoethoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy)- 23-dihydrobenzofuran-3-yl)acetate 1U2.2 g, grazing rate 100,0%). S m/z [ESl] + : 462, 0 [M+1].
歩骤 5; (5)-2 (6- ((4'~(2- (3-氣丙基磺酰基氣基)乙氧基 ) 2'，6'-二甲基联苯 - 3~基)甲氧基 )-2,3- 二氳苯并呋喃 ~3-基)乙酸甲酯的合成 Step 5; (5)-2 (6-((4'~(2-(3-(propylsulfonyl)yl)ethoxy) 2',6'-dimethylbiphenyl-3~yl Synthesis of methyl methoxy)-2,3-dioxabenzofuran~3-yl)acetate
向 (5 -2- (6 (4f- (2-氨基乙氧基) - 2',6'-二甲基联苯- 3-基）甲氧基 )- 2,3-二氢苯并呋喃 - 3-基） 乙酸甲酯 (0,66 g, 1.4 mmoi)的二氯甲烷溶液中 (50 mL)铱次 ¾Π入 3-氯-】 -丙基磺酰氯 (0.38 g,To (5 -2- (6 f - (2-aminoethoxy) - 2',6'-dimethylbiphenyl-3-yl)methoxy)-2,3-dihydrobenzo Furan-3-yl) methyl acetate (0,66 g, 1.4 mm oi) in methylene chloride (50 mL) was added to 3-chloro-]-propylsulfonyl chloride (0.38 g,
2.1 mmoi)和 乙胺 ((),29g,2,9mmd)。 将该反应混合液室温搅摔过夜。 将反应倒入水中 (50 mL), 用二氯甲烷萃取 il00mLx2), 有机相用无水硫酸钠千燥， 浓縮， 残留物经硅胶柱色 谱法分离纯化得到 - 2 6 (('4'-(2 3氣丙基磺酷氨基)乙氧基 ) 2 6f-二甲基联苯 基）甲氧 基)- 2,3二氢苯并呋喃 - 3-基)乙酸甲 ffi(0.73 g, 收率 85.0%)。 ;H NMR (400 MHz, CDCl3-t¾): 7.42 (]—H, i, J - --- 7,2 Hz), 7,38 (IH, d, J - 7.6 Hz), 7.16 (IH, s), 7.07 (IH, l, J - --- 7,2 Ez\ 7,02 (IH, cl 1 = 7.6 Hz), 6.45 (2¾ s)， 6.45-6.50 (2H, m)， 5.06 (2 s), 4.75 (2¾ i， J = 8.8 Hz), 4.25 (1 dd， J = 9.2 Hz， 6.0 Hz), 3.77-3.84 (IH, m)， 3.72 (3H， s), 3.69 (2H， t， J = 6.0 Hz), 3.56 (2H, q， 1 =2.1 mmoi) and ethylamine ((), 29g, 2, 9mmd). The reaction mixture was stirred overnight at room temperature. The reaction was poured into water (50 mL), and EtOAc (m.sub.2 mL) was obtained eluted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated. (2 3 propyl propyl sulfoamino) ethoxy) 2 6 f - dimethylbiphenyl) methoxy) - 2,3 dihydrobenzofuran-3-yl)acetate affi (0.73 g, Yield 85.0%). ; H NMR (400 MHz, CDCl 3 -t¾): 7.42 (] -H, i, J - --- 7,2 Hz), 7,38 (IH, d, J - 7.6 Hz), 7.16 (IH, s), 7.07 (IH, l, J - --- 7,2 Ez\ 7,02 (IH, cl 1 = 7.6 Hz), 6.45 (23⁄4 s), 6.45-6.50 (2H, m), 5.06 (2 s), 4.75 (23⁄4 i, J = 8.8 Hz), 4.25 (1 dd, J = 9.2 Hz, 6.0 Hz), 3.77-3.84 (IH, m), 3.72 (3H, s), 3.69 (2H, t, J = 6.0 Hz), 3.56 (2H, q, 1 =
4.2 Hz), 3.28 (2H, ΐ, J = 7,6 Hz), 2.74 (2H, dd J = 16.4 Hz, 5,6 Hz), 2.55 (IH, dd, J = 16.4 Hz, 9,2 Hz), 2.29-2.36 (2H, m), 1.99 (6H s)0 4.2 Hz), 3.28 (2H, ΐ, J = 7,6 Hz), 2.74 (2H, dd J = 16.4 Hz, 5,6 Hz), 2.55 (IH, dd, J = 16.4 Hz, 9,2 Hz) , 2.29-2.36 (2H, m), 1.99 (6H s) 0
歩骤 6： >2~(6- ((4'-(2-(1,_ -二氧 'f弋-异噻唑垸 ~2-基）乙氧基 )- 2',6'~二甲基联苯 基）甲氧 基) -2，3-二氳苯并呋喃 基)乙酸甲酯的合成 Step 6: >2~(6-((4'-(2-(1,_-Dioxy'f弋-isothiazolium~2-yl)ethoxy)-2',6'~dimethyl Synthesis of methyl phenyl)methoxy)-2,3-difluorenylbenzofuranylacetate
向 (6-((4' 2 (3-氯丙基磺酰基氨基)乙氧基) - 2',6'-二甲基联苯- 3基）甲氧基)2,3-二 氢苯并呋喃 基)乙酸甲觀 (6ίλ0 mg, 0.1 mmol)的 Ν,Ν-二甲基甲酰胺溶液中（10 mL)加入碳 酸钾 (28,0 mg, 0,2 mmol)。 将该反应混合液 8(ΓΌ搅拌过夜。 将反应慨入水中 (50 mL)， 用乙 酸乙觀萃取 (10() rnLx2)， 有 M相用无水硫酸钠 ::F燥； 滚缩， 残留物经硅胶柱色谱法分离纯 化得到 (,S 2-(6- ((4 :-i2-(L 1 -二氧代 -异噻唑垸 -2基）乙氧基 2',6 二甲基联苯 基）甲氧 基) 2,3-二氢苯并呋喃 -基）乙酸甲酉 §(50,0 mg, 收率 S8.8%)。 MS m/z[ES: ]+:566.0[M+ i ]。 步骤 7： (Λ>2- (6- ((442 1,1»二氧代异噻唑烧 - 2-基）乙氧基 )- 2f，6 二甲基联苯 基）甲氧 基)- 2 二氢苯并呋喃-; ^基)乙酸的合成 To (6-((4' 2 (3-chloropropylsulfonylamino)ethoxy) - 2',6'-dimethylbiphenyl-3-yl)methoxy) 2,3-di Potassium carbonate (28,0 mg, 0,2 mmol) was added to a solution of hydrazine, hydrazine-dimethylformamide (10 mL). The reaction mixture 8 (ΓΌ The reaction was stirred overnight generous into water (50 mL), extracted with ethyl concept (10 () rn Lx2 with acetic acid), there are M phase with anhydrous sodium sulfate :: F;. Reduction roll, The residue is purified by silica gel column chromatography ((2-(6 : -i2-(L 1 - dioxo-isothiazolyl-2-yl)) ethoxy 2',6 dimethyl Biphenyl)methoxy) 2,3-dihydrobenzofuran-yl)acetate 酉 (50,0 mg, yield S8.8%) MS m/z [ES:] + :566.0[ M+ i ] Step 7: (Λ>2-(6-((442 1,1»dioxoisothiazolidine-2-yl)ethoxy)- 2 f ,6-dimethylbiphenyl) Synthesis of oxy)-2 dihydrobenzofuran-;^yl)acetic acid
向 (S)~2~(6 (4'-(2~(L 1 -二氧代 -异嚷唑垸- 2-基）乙氧基）- 2',6'-二甲基联苯- 3-基）甲氧 基)- 2,3二氢苯并呋喃 -3-基)乙酸甲酯 (50.0 mg, 0,09 mmoi)甲醇 (10 mL)和四氢咲喃 (20 mL) 的混合溶剂的溶液中，滴加 2 M氢氧化钠水溶液 (l mL)，滴加完毕后混合物室温搅摔过夜。 将反应混合物用水稀释， 用 0%拧檬酸水溶液酸化， 并用乙酸乙酯萃取 (50mLx3)„ 有 相 用无水硫酸锆千燥后浓缩，残留物通过硅胶柱色谱法分离纯化得到 (; V2 6- ((4'-(2- (1 ,1-二氧 代-异噻锉烷- 2基)乙氧基 )- 2'，6'-二甲基联苯 3-基）甲氧基 )- 2，3-二氢苯并呋喃 - 3-基）乙酸 (36,7 mg, 收率 75.2%) o 1H NMR (400 MHz, CDCl3-t¾); 7.38-7.42 (2H, m), 7.16 (IH, s), 7.05-7.15 (2H, m), 6.65 (2H， s), 6.39-6.55 (2H, m), 5.06 (2H, s:)， 4.76 (I H, t, J = 7.6 Hz), 4.24-4.39 (IH, rn), 4.13-4.19 (2H, m), 3.74-3.89 (IH, m), 3.38-3.58 (4H, m), 3.07-3.23 (2H, m), 2.73-2.83 (IH, m), 2,53-2,64 (I H, m), 2.28-2.37 (2H, m), 1 ,99 (6H, s), To (S)~2~(6(4'-(2~(L 1 -dioxo-isoxazolyl-2-yl)ethoxy)-2',6'-dimethylbiphenyl- Mixture of 3-methyl)methoxy)- 2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester (50.0 mg, 0,09 mmoi) in methanol (10 mL) and tetrahydrofuran (20 mL) A 2 M aqueous sodium hydroxide solution (1 mL) was added dropwise to the solvent solution, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, acidified with 0% aqueous citric acid, and extracted with ethyl acetate (50mLx3) "have phase was dried over anhydrous dry in zirconium sulfate and concentrated to give the residue was separated and purified by silica gel column chromatography (; V2 6 - ((4'-(2-(1,1-dioxo-isothiadecane-2-yl)ethoxy)-2',6'-dimethylbiphenyl-3-yl)methoxy) - 2,3-Dihydrobenzofuran-3-yl)acetic acid (36,7 mg, yield 75.2%) o 1H NMR (400 MHz, CDCl 3 -t3⁄4); 7.38-7.42 (2H, m), 7.16 (IH, s), 7.05-7.15 (2H, m), 6.65 (2H, s), 6.39-6.55 (2H, m), 5.06 (2H, s:), 4.76 (IH, t, J = 7.6 Hz) , 4.24-4.39 (IH, rn), 4.13-4.19 (2H, m), 3.74-3.89 (IH, m), 3.38-3.58 (4H, m), 3.07-3.23 (2H, m), 2.73-2.83 ( IH, m), 2,53-2,64 (IH, m), 2.28-2.37 (2H, m), 1 ,99 (6H, s),
实施倒 12; 2^6-ίί2',6'二甲基 (甲磺酰基病氧基联苯 基)乙炔基 二氢苯并咲喃 Implementation of inverted 12; 2^6-ίί2',6' dimethyl (methanesulfonyl oxybiphenyl) ethynyl dihydrobenzopyran
Figure imgf000022_0001
Figure imgf000022_0001
歩骤 1; 6 -三甲基硅基乙炔基- 2,3 -二氢苯并呋喃- 3 -乙酸甲酯的合成 Step 1; Synthesis of 6-trimethylsilylethynyl- 2,3-dihydrobenzofuran-3-methylacetate
在氮气充分置换下， 向 6-三氣甲磺酰氧基 -2,3-二氢苯并咲喃 乙酸甲酯（！.0 g， 2.9 rnmol), 甲基硅基乙炔 (0,43 g， 4.4 rnmol), 四 苯基膦钯 (0J 6 g, 0.15 mnioS), 碘化亚铜 (0,03 g, (),15 mmoi)和: Ξ乙胺 (0.59 g, 5.8 mmoi)的混合物中加入 Ν,Ν-二甲基甲酰胺 (50 m:L), 将混合狗在 70 °C反应 5小时。 反应混合物冷却到室温后， 过滤， 将滤液在减压下浓缩。 将残留狗倒入水中 ( 00 mL)， 用乙酸乙酯萃取。 将有机相用无水硫酸钠千燥， 自然过滤， 并在减压下浓缩 得到的残留物用硅胶柱色谱法分离纯化， 得到 6- Ξ甲基硅基乙炔基 2,3 二氢¾弁呋喃 - 3-乙酸甲酯(0.55 g, 收率 65,3%)。 1H NMR (400 MHz， CDCl3-t¾): 7.06 (IH, d, J = 7.6 Hz), 6.98 (IH, dd, J = 7.6 Hz, 1.2 Hz), 6.86 (IH, s), 4.74 (IH, t, J = 9.2 Hz), 4.24 (IH, dd, J = 9.6 Hz, 6.4 Hz), 3.81-3.89 (IH, m), 3.71 (3H, s), 2.75 (IH, dd, J = 16.8 Hz, 5.6 Hz), 2.56 (IH, dd, J = 16.8 Hz, 9.6 Hz), 0.23 (9H, s)。 Methyl 6-trimethylmethanesulfonyloxy-2,3-dihydrobenzopyranoacetate (!.0 g, 2.9 rnmol), methylsilylacetylene (0,43 g) under nitrogen partial displacement , 4.4 rnmol), tetraphenylphosphine palladium (0J 6 g, 0.15 mnioS), cuprous iodide (0,03 g, (), 15 mmoi) and: diethylamine (0.59 g, 5.8 mmoi) in a mixture The mixed dog was added to hydrazine, dimethyl-dimethylformamide (50 m: L), and the mixed dog was reacted at 70 ° C for 5 hours. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residual dog was poured into water (00 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and then filtered, and the residue was evaporated to dryness to silica gel column chromatography to give 6-(methylsilylethynyl) 2,3 dihydro 3⁄4 - 3-methyl acetate (0.55 g, yield 65, 3%). 1H NMR (400 MHz, CDCl 3 -t3⁄4): 7.06 (IH, d, J = 7.6 Hz), 6.98 (IH, dd, J = 7.6 Hz, 1.2 Hz), 6.86 (IH, s), 4.74 (IH, t, J = 9.2 Hz), 4.24 (IH, dd, J = 9.6 Hz, 6.4 Hz), 3.81-3.89 (IH, m), 3.71 (3H, s), 2.75 (IH, dd, J = 16.8 Hz, 5.6 Hz), 2.56 (IH, dd, J = 16.8 Hz, 9.6 Hz), 0.23 (9H, s).
歩骤 2: 6乙炔基 -2,3-二氛苯并呋喃 乙酸甲酯的合成 Step 2 : Synthesis of 6 ethynyl-2,3-difluorobenzofuranacetic acid methyl ester
向 6- :甲基硅基乙炔基- 2,3-二氢苯并呋喃 -3-乙酸甲酯 ((),5 g, 1 ,7 mmoi)的甲醇 i OO mL) 溶液中加入碳酸钾 (0,47 g, 3.4 mmoi),将混合物室温反应 2小时。 过滤， 将滤液在减压下浓 缩得到 6乙炔基 ,3-二氢苯并呋喃 3-乙酸甲觀|¾的合成 (Ό.33 g, 收率 89,0%)。 ^ NM (400 MHz, CDCl3-t 3): 7.09 (1H, d, J = 7.6 Hz), 7.02 (1H, dd, J = 7.6 Hz, 1.2 Hz), 6.90 (1H, s), 4.76 (1H, t, J = 9.6 Hz), 4.26 (1H, dd, J = 9.2 Hz, 6.4 Hz), 3.83-3.90 (1H, m), 3.72 (3H, s), 2.77 (1H, dd, J = 16.8 Hz, 5.6 Hz), 2.58 (1H, dd, J = 16.8 Hz, 9.6 Hz)。 Add potassium carbonate to a solution of 6-:methylsilylethynyl-2,3-dihydrobenzofuran-3-acetic acid methyl ester ((), 5 g, 1 ,7 mmoi) in methanol (100 mL) 0,47 g, 3.4 mm oi), the mixture was reacted at room temperature for 2 hours. Filtration and concentration of the filtrate under reduced pressure afforded 6 ethynyl, 3-dihydrobenzofuran 3-acetic acid as a compound (3. ^ NM (400 MHz, CDCl 3 -t 3 ): 7.09 (1H, d, J = 7.6 Hz), 7.02 (1H, dd, J = 7.6 Hz, 1.2 Hz), 6.90 (1H, s), 4.76 (1H, t, J = 9.6 Hz), 4.26 (1H, dd, J = 9.2 Hz, 6.4 Hz), 3.83-3.90 (1H, m), 3.72 (3H, s), 2.77 (1H, dd, J = 16.8 Hz, 5.6 Hz) , 2.58 (1H, dd, J = 16.8 Hz, 9.6 Hz).
歩骤 3; 2-溴 -1，3-二甲基 - 5-(3 (甲基磺酰基)丙氧基)苯的合成 Step 3: Synthesis of 2-bromo-1,3-dimethyl-5-(3(methylsulfonyl)propoxy)benzene
0。C下. 向 3甲巯基丙醇 (57, 14 g, 0,54 moi)和三乙胺 (81 ,6 g, 0.81 moi)的二氣甲烷溶液 中 (250 niL) , 滴加三氟甲續》氯 ( 136.5g、0.81moi)， 滴加完毕后混合物室温搅拌过夜。 将反 应混合物用水稀释， 并用二氯甲烷萃取 ( 150 mLx3)„ 有 相用无水硫酸钠干燥后浓缩， 残 留物通过硅胶柱色谱法分离纯化得到 1 , 1 ,] - :氟甲鎮酸-: 5-甲巯基丙酯（126.0 g, 收率 98.0%),  0. C. To dimethylmethane propanol (57, 14 g, 0,54 moi) and triethylamine (81,6 g, 0.81 moi) in a two-gas methane solution (250 niL), add trifluoromethane continuously Chlorine (136.5 g, 0.81 moi), the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with methylene chloride (150 mL×3). EtOAc was dried over anhydrous sodium sulfate and then evaporated. The residue was purified by silica gel column chromatography to give 1:1. 5-Methylmercaptopropyl ester (126.0 g, yield 98.0%),
0 Γ下， 向 三氟甲續酸- 3甲巯基丙！ 23,8 g, 0. ! moi )的甲醇溶液中 (250 mL)， 滴 加过硫酸氮钾 (30 g, 0.2 moi)的水溶液 (500 mi小 滴加完毕后混合犓室温搅摔过夜。 把甲 醇用旋转蒸发仪去除后， 残留物用乙酸乙酯萃取 (250 mLx3}.3 有机相用无水硫酸锆千燥后 浓缩， 残留物用石油S洗涤后得到 U,l-三氣甲鎮酸- 3-甲鎮酰基丙酯 (26.5 牧率 98.1%)。 3、5-二甲基 4-溴苯酚 (4.0 g, 19.9 mmoi)和 ：i ,U 三氟甲磺酸- 3 甲磺酰基丙酯 (5.9 g, 21 .9 mmoi)的 Ν,Ν-二甲基甲酰胺（150 mL)瑢液中加入碳酸钾 (4, 1 g, 29.9 mmoi), 将混合 在 ii)0 °C反应 1小时。反应混合 H到入冰水中，过滤, 将固体用水洗涤， 干燥后得到 2-溴- 1 ,3- 二甲基—5- Of甲基鎮酰基)丙氧基)苯 (6,0 g, 改率 94,0%)„ 1H NMR (400 MHz， DMSO- d6): 6.78 (2H, s), 4.02 (2H, t, J = 6.8 Hz), 3.23 (2H, t, J = 6.8 Hz), 2.99 (3H, s), 2.30 (6H, s), 2.03-2.16 (2H, m)。 0 Γ, to the trifluoromethyl acid - 3 methyl propyl C! 23,8 g, 0. ! moi ) in methanol (250 mL), add an aqueous solution of potassium persulfate (30 g, 0.2 moi) (500 mi of a small drop is added, mix and stir at room temperature overnight. After the methanol was removed by a rotary evaporator, the residue was extracted with ethyl acetate (250 mL× 3 ). 3 organic phase was dried over anhydrous zirconium sulfate and concentrated, and the residue was washed with petroleum S to obtain U, l-trisole. - 3-methyl acyl propyl ester (26.5 grazing rate 98.1%). 3,5-Dimethyl 4-bromophenol (4.0 g, 19.9 mm oi) and: i, U trifluoromethanesulfonic acid - 3 methanesulfonylpropane Add ethyl carbonate (4, 1 g, 29.9 mmoi) to the oxime, Ν-dimethylformamide (150 mL) of the ester (5.9 g, 21.9 mmoi), and mix in ii) 0 °C. H. The reaction was mixed with H into ice water, filtered, and the solid was washed with water and dried to give 2-bromo-1,3-dimethyl-5-ofmethyl-acyl)propoxy)benzene (6,0 g , reform rate 94,0%) „ 1H NMR (400 MHz, DMSO- d 6 ): 6.78 (2H, s), 4.02 (2H, t, J = 6.8 Hz), 3.23 (2H, t, J = 6.8 Hz ), 2.99 (3H, s), 2.30 (6H, s), 2.03-2.16 (2H, m).
步骤 4: 2，，6，-二甲基 -4，-( 3- (甲基磺酰基)丙氧基) -联苯 -3-酚的合成 Step 4: Synthesis of 2,6,-dimethyl-4,-(3-(methylsulfonyl)propoxy)-biphenyl-3-phenol
2-溴- ,3-二甲基 -5- (3 -(甲基磺酰基)丙氧基)苯 (0.35 g, 1.1 mmoi), 3-羟基苯硼酸 (0.18 g, 1.3 mmoi), 碳酸铯 (0.54 g, 1.65 mmoi)和四三苯基膦钯 (0.13 g, 0.11 mmoi)加到 1 ,4-二氧六环 中 (150 mL)。 将该混合物加热回流 8小时后冷却到室温。 反应混合物通过硅藻土过滤， 用 乙酯乙酯洗涤， 滤液经浓缩后残留物通过硅胶柱色谱法分离纯化得到 2',6'-二甲基 -4'-( 3- (甲基磺酰基）丙氧基) -联苯 -3-酚 (0.36 g, 收率 99.0%) o 1H NM (400 MHz , CDCl3-t 3): 7.27 (1H, t, J = 8.0 Hz), 6.80 (1H, dd, J = 8.0 Hz, 2.8 Hz), 6.68 (1H, d, J = 7.2 Hz), 6.63 (2H, s), 6.60 (1H, t, J = 1.2 Hz), 4.12 (2H, t, J = 5.6 Hz), 3.27 (2H, t, J = 8.0 Hz), 2.97 (3H, s), 2.32-2.38 (2H, m), 2.02 (6H, s)。 2-Bromo-, 3-dimethyl-5-(3-(methylsulfonyl)propoxy)benzene (0.35 g, 1.1 mm oi), 3-hydroxyphenylboronic acid (0.18 g, 1.3 mm oi), cesium carbonate (0.54 g, 1.65 mm oi) and tetrakistriphenylphosphine palladium (0.13 g, 0.11 mmol) were added to 1,4-dioxane (150 mL). The mixture was heated to reflux for 8 hours and then cooled to room temperature. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. ) propoxy)-biphenyl-3-phenol (0.36 g, yield 99.0%) o 1H NM (400 MHz, CDCl 3 -t 3 ): 7.27 (1H, t, J = 8.0 Hz), 6.80 (1H , dd, J = 8.0 Hz, 2.8 Hz), 6.68 (1H, d, J = 7.2 Hz), 6.63 (2H, s), 6.60 (1H, t, J = 1.2 Hz), 4.12 (2H, t, J = 5.6 Hz), 3.27 (2H, t, J = 8.0 Hz), 2.97 (3H, s), 2.32-2.38 (2H, m), 2.02 (6H, s).
步骤 5: 2'，6'-二甲基 -4'-( 3- (甲基磺酰基)丙氧基 )-3-三氟甲磺酰氧基 -联苯的合成 Step 5: Synthesis of 2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)-3-trifluoromethanesulfonyloxy-biphenyl
向 2，,6，-二甲基 -4，-(3- (甲基磺酰基)丙氧基) -联苯 -3-酚 (0.36 g, 1 , 1 mmoi)和 乙胺 ((),22 g: 2.2 mmoi)的混合物中加入二氣甲垸 (50 mL),将混合物冷却到零度， 向混合物中慢慢滴加王 氣甲磺酸酐 i0 46 g 1.6 mmoi), 混合物升到室 iM 在室 it搅拌 2 .小时。 将反应混合物减压 下法缩， 得到的 ^留狗通过硅跤柱色谱法分离纯化得到 2',6'-二甲基 -4'-(3- (甲基磺酰基)丙 氧基) -3-三氟甲磺酰氧基 -联苯 i:0.43 g, 收率 85J:)¾)。 1H NM (400 MHz, CDCl3-t 3): 7.50 (1H, t, J = 8.0 Hz), 7.26 (1H, dd, J = 8.0 Hz, 2.4 Hz), 7.17 (1H, d, J = 7.6 Hz), 7.07 (1H, s), 6.66(2H, s), 4.13 (2H, t, J = 6.0 Hz), 3.27 (2H, t, J = 8.0 Hz), 2.97 (3H, s), 2.33-2.39 (2H, m), 1.99 (6H, s)。 To 2,6,-dimethyl-4,-(3-(methylsulfonyl)propoxy)-biphenyl-3-phenol (0.36 g, 1 , 1 mm oi) and ethylamine ((), Add 2 gas methyl hydrazine (50 mL) to the mixture of 22 g : 2.2 mmoi), cool the mixture to zero, slowly add royal amalgamic anhydride i0 46 g 1.6 mmoi) to the mixture, and the mixture is raised to room iM in the chamber it Stir for 2 hours. The reaction mixture was subjected to reduction under reduced pressure, and the obtained dog was separated and purified by silica gel column chromatography to obtain 2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)- 3-Trifluoromethanesulfonyloxy-biphenyl i: 0.43 g, yield 85J:) 3⁄4). 1H NM (400 MHz, CDCl 3 -t 3 ): 7.50 (1H, t, J = 8.0 Hz), 7.26 (1H, dd, J = 8.0 Hz, 2.4 Hz), 7.17 (1H, d, J = 7.6 Hz) ), 7.07 (1H, s), 6.66(2H, s), 4.13 (2H, t, J = 6.0 Hz), 3.27 (2H, t, J = 8.0 Hz), 2.97 (3H, s), 2.33-2.39 (2H, m), 1.99 (6H, s).
歩骤 6: 2-(6-((2'，6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联苯 -3-基)乙炔基 )-2，3-二氢苯并呋喃 -3- 基)乙酸甲酯的合成 Step 6 : 2-(6-((2',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)ethynyl)-2,3 Synthesis of Methyl-Dihydrobenzofuran-3-yl)acetate
在氮气充分置换下， 向 2，,6，-二甲基 -4，-( 3- (甲基磺酰基)丙氧基） -3-三氟甲磺酰氧基- 联苯 （50 mg, 0, 1 mmoi), 6-乙炔基2,3-二氢苯并呋喃 3-乙酸甲酷 (30 mg- 0.12 mmoi), 三 (二 亚苄基丙酮)二钯（10 mg, 0.01 mmoi) . 2 ¾环己基膦 -2',4'、6f-三异丙基联苯（10 mg, 0.2 mmoi), 碘化 铜 (2,0 mg, 0.01 mmoi)和碳酸铯 (52 mg, 0, 15mmoi)的混合物中加入 Ν,Ν-二甲基甲 ί 胺 (5i) mL), 将混合物在 130 °C反应 5小时。 反应混合物冷却到室温后， 过滤， 将滤液在减 压下浓缩。 将残留物倒入水中 (100 mU, 用乙酸乙酷萃取。 将有杌相用无水硫酸钴千燥， 自然过滤， 并在减压下浓缩。 得到的残留物用硅胶柱色谱法分离纯化， 得到 2-(6-((2',6'-二 甲基—4'-(3- (甲磺酰基)丙氧基)联苯 -3-基)乙炔基 )-2,3-二氢苯并呋喃 -3-基)乙酸甲酯 (30.0 mg、 收率 53.0%) 1H NM (400 MHz, CDCl3-t 3): 7.49 (1H, d, J = 7.6 Hz), 7.39 (1H, t, J = 7.6 Hz), 7.30 (1H, s), 7.04-7.13 (3H, m), 6.94 (1H, s), 6.65 (2H, s), 4.78 (1H, t, J = 9.6 Hz), 4.28 (1H, t, J = 8.0 Hz), 4.13 (2H, t, J = 5.6 Hz), 3.85-3.92 (1H, m), 3.73 (3H, s), 3.28 (2H, t, J = 8.0 Hz), 2.97 (3H, s), 2.80 (1H, dd, J = 16.4 Hz, 5.2 Hz), 2.60 (1H, dd, J = 16.4 Hz, 9.2 Hz), 2.32-2.40 (2H, m): 2.02 (6H, s)。 2,6,-Dimethyl-4,-(3-(methylsulfonyl)propoxy)-3-trifluoromethanesulfonyloxy-biphenyl (50 mg, under a sufficient nitrogen displacement) 0, 1 mmoi), 6-ethynyl 2,3-dihydrobenzofuran 3-acetic acid methyl (30 mg-0.12 mmoi), tris(dibenzylideneacetone)dipalladium (10 mg, 0.01 mm oi). 2 3⁄4 cyclohexylphosphine-2',4',6 f -triisopropylbiphenyl (10 mg, 0.2 mm oi), copper iodide (2,0 mg, 0.01 mm oi) and cesium carbonate (52 mg, 0, To the mixture of 15 mm oi) was added hydrazine, hydrazine-dimethylformamide (5i) mL), and the mixture was reacted at 130 ° C for 5 hours. After the reaction mixture was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was poured into water (100 mU, extracted with ethyl acetate. The ruthenium phase was dried over anhydrous cobalt sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography. Get 2-(6-((2',6'-two Methyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)ethynyl)-2,3-dihydrobenzofuran-3-yl)acetate (30.0 mg, Yield 53.0%) 1H NM (400 MHz, CDCl 3 -t 3 ): 7.49 (1H, d, J = 7.6 Hz), 7.39 (1H, t, J = 7.6 Hz), 7.30 (1H, s), 7.04 -7.13 (3H, m), 6.94 (1H, s), 6.65 (2H, s), 4.78 (1H, t, J = 9.6 Hz), 4.28 (1H, t, J = 8.0 Hz), 4.13 (2H, t, J = 5.6 Hz), 3.85-3.92 (1H, m), 3.73 (3H, s), 3.28 (2H, t, J = 8.0 Hz), 2.97 (3H, s), 2.80 (1H, dd, J = 16.4 Hz, 5.2 Hz), 2.60 (1H, dd, J = 16.4 Hz, 9.2 Hz), 2.32-2.40 (2H, m) : 2.02 (6H, s).
步骤 7: 2-(6-((2'，6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联苯 -3-基)乙炔基 )-2，3-二氢苯并呋喃 -3- 基)乙酸的合成 Step 7: 2-(6-((2',6'-Dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)ethynyl)-2,3- Synthesis of dihydrobenzofuran-3-yl)acetic acid
向 2-(6-((2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联苯 -3-基)乙炔基 )-2,3-二氢苯并呋喃 -3- 基)乙酸甲酯(30.0 mg, 0.056 mmol)甲醇 (10 mL)和四氢呋喃 (20 mL)的混合溶剂的溶液中，滴 加 2 M氢氧化钠水溶液 (1 mL),滴加完毕后混合物室温搅拌过夜。将反应混合物用水稀释， 用 10%柠檬酸水溶液酸化，并用乙酸乙酯萃取 (50mLx3)。有机相用无水硫酸钠干燥后浓缩， 残留物通过硅胶柱色谱法分离纯化得到 2-(6-((2',6'-二甲基 -4'-(3- (甲磺酰基)丙氧基)联苯 -3- 基）乙炔基 )-2,3-二氢苯并呋喃 -3-基）乙酸 (21.7 mg, 收率 74,2%)。 1H NM (400 MHz , CDCl3-t 3): 7.49 (1H, d, J = 8.0 Hz), 7.39 (1H, t, J = 8.0 Hz), 7.30 (1H, s), 7.15 (1H, d, J = 7.2 Hz), 7.05-7.10 (2H, m), 6.95 (1H, s), 6.65 (2H, s), 4.79 (1H, t, J = 9.6 Hz), 4.31 (1H, t, J = 8.4 Hz), 4.13 (2H, t, J = 5.2 Hz), 3.83-3.94 (1H, m), 3.28 (2H, t, J = 7.6 Hz), 2.97 (3H, s), 2.85 (1H, dd, J = 16.8 Hz, 4.0 Hz), 2.66 (1H, dd, J = 16.8 Hz, 9.6 Hz), 2.30-2.39 (2H, m), 2.02 (6 H, s)。 生物活性测定 To 2-(6-((2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)ethynyl)-2,3-dihydro To a solution of methyl benzofuran-3-yl)acetate (30.0 mg, 0.056 mmol) in methanol (10 mL) and tetrahydrofuran (20 mL), 2 M aqueous sodium hydroxide (1 mL) After the addition was completed, the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, EtOAc (EtOAc)EtOAc. The organic phase was dried over anhydrous sodium sulfate and concentrated. Oxy)biphenyl-3-yl)ethynyl)-2,3-dihydrobenzofuran-3-yl)acetic acid (21.7 mg, yield 74, 2%). 1H NM (400 MHz , CDCl 3 -t 3 ): 7.49 (1H, d, J = 8.0 Hz), 7.39 (1H, t, J = 8.0 Hz), 7.30 (1H, s), 7.15 (1H, d, J = 7.2 Hz), 7.05-7.10 (2H, m), 6.95 (1H, s), 6.65 (2H, s), 4.79 (1H, t, J = 9.6 Hz), 4.31 (1H, t, J = 8.4 Hz), 4.13 (2H, t, J = 5.2 Hz), 3.83-3.94 (1H, m), 3.28 (2H, t, J = 7.6 Hz), 2.97 (3H, s), 2.85 (1H, dd, J = 16.8 Hz, 4.0 Hz), 2.66 (1H, dd, J = 16.8 Hz, 9.6 Hz), 2.30-2.39 (2H, m), 2.02 (6 H, s). Biological activity assay
GPR40稳定表达细胞系的建立  Establishment of GPR40 stable expression cell line
1. 基因克隆： GPR40 全长基因来源于人非小细胞肺癌细胞株 A549 (序列： NCBI Reference Sequence: NT_077812.2)。 提取 A549细胞总 R A， 通过反转录-聚合酶链式反应 (RT-PCR)方法将 GPR40的全长基因克隆出来，并且在设计引物时分别在 5 '-端和 3 '-端加上 BamHI和 EcoRV这两个 DNA限制内切酶位点。  1. Gene cloning: The full-length gene of GPR40 is derived from human non-small cell lung cancer cell line A549 (sequence: NCBI Reference Sequence: NT_077812.2). The total RA of A549 cells was extracted, and the full-length gene of GPR40 was cloned by reverse transcription-polymerase chain reaction (RT-PCR), and BamHI was added at the 5 '-end and 3 '-ends when designing primers. The two DNA restriction endonuclease sites and EcoRV.
2. 表达质粒的构建：载体质粒 pcDNA3.1购自 Invitrogen®公司。利用 BamHI和 EcoRV 这两个 DNA限制内切酶位点， 将已经克隆好的 GPR40全长基因通过 T4 DNA链接酶连接 到 pCDNA3.1 载体上， 然后转染到 DH5a感受态细胞中， 并在加有抗生素 Ampilline ( 1 g/mL) 的 LB琼脂培养基上选择成功转染的单克隆， 提取质粒并通过 DNA测序方法确定 基因序列。  2. Construction of expression plasmid: Vector plasmid pcDNA3.1 was purchased from Invitrogen®. Using the two DNA restriction endonuclease sites of BamHI and EcoRV, the fully cloned GPR40 full-length gene was ligated into the pCDNA3.1 vector by T4 DNA ligase, and then transfected into DH5a competent cells, and added Successfully transfected monoclonals were selected on LB agar medium with antibiotic Ampilline (1 g/mL), plasmids were extracted and the gene sequence was determined by DNA sequencing.
3. 稳定表达细胞的建立： 提取高纯度的 pCDNA3.1-GPR40质粒， 与 FugeneHD试剂 (Roche®)以 2 ( μ§) : 6 C μL 的比例混合， 转染到人胚肾上皮细胞 ΗΕΚ293中， 在补充有 10%胎牛血清的 DMEM培养液中通过抗生素 G418 (终浓度为 400 g/mL ) 筛选出 GPR40 表达细胞， 在 96孔细胞培养板中梯度稀释以挑取单克隆， 用 Western blot方法确定 GPR40 蛋白的表达， 将稳定表达的单克隆细胞放大培养， 建立 GPR40稳定表达细胞系。 3. Establishment of stable expression cells: The high-purity pCDNA3.1-GPR40 plasmid was extracted and mixed with FugeneHD reagent (Roche®) at a ratio of 2 (μ § ) : 6 C μL and transfected into human embryonic kidney epithelial cells 293 GPR40-expressing cells were screened by antibiotic G418 (final concentration of 400 g/mL) in DMEM supplemented with 10% fetal bovine serum, and serially diluted in 96-well cell culture plates to pick up monoclonals, using Western blot. Methods The expression of GPR40 protein was determined, and the stably expressed monoclonal cells were amplified and cultured to establish a GPR40 stably expressing cell line.
GP 40稳定表达细胞系的建立也可以参照现有文献公开的方法制备获得，例如 Koener B, Hermans E. Inducible expression of G protein-coupled receptors in transfected cells. Methods in Molecular Biology. 2011(746):3-20禾口 Schucht , Lydford S, Andzinski L, Zauers J, Cooper J, Hauser H等. apid Establishment of G-Protein-Coupled Receptor Expressing Cell Lines by Site-Specific Integration.Jowr« / of Biomolecular Screening. 2011(16):3230-331 或 CN102421739A说明书第 24-25/106试验法 1 : GPR40激动活性测定中的方法来获得 GPR40 稳定表达细胞系。  The establishment of a GP 40 stable expression cell line can also be obtained by the method disclosed in the prior literature, for example, Koener B, Hermans E. Inducible expression of G protein-coupled receptors in transfected cells. Methods in Molecular Biology. 2011 (746): 3 -20 and Schucht, Lydford S, Andzinski L, Zauers J, Cooper J, Hauser H, etc. apid Establishment of G-Protein-Coupled Receptor Expressing Cell Lines by Site-Specific Integration. Jowr« / of Biomolecular Screening. 2011(16 ): 3230-331 or CN102421739A instructions 24-25/106 Test Method 1: Methods in GPR40 agonistic activity assay to obtain GPR40 stably expressing cell lines.
GPR40激动活性的测定 Determination of GPR40 agonistic activity
本发明采用钙流法，测定化合物对 GPR40稳定表达细胞内钙离子浓度的提升作用，从 而反映出对 GPR40的激动作用。该激动活性采用 EC5Q这一指标来表示， 即 GPR40的活性 被激发到最大值的 50%时所对应的化合物浓度。 材料和方法： The present invention uses a calcium flow method to determine the effect of a compound on the intracellular calcium concentration of GPR40 stably expressing cells, thereby reflecting the agonistic effect on GPR40. This agonistic activity is expressed by the index of EC 5Q , which is the concentration of the compound corresponding to the activity of GPR40 which is excited to 50% of the maximum value. Materials and Method:
1、 材料- 1, material -
1)、 96孔黑色底透细胞培养板 (Coming®, Cat.No.3603) 1), 96-well black bottom cell culture plate (Coming®, Cat. No. 3603)
2)、 96孔 V底透明反应板 (Coming®, Cat.No.3897)  2), 96-well V-bottom transparent reaction plate (Coming®, Cat. No. 3897)
3)、 Fluo-4钙流试剂盒 (Invitrogen®, Cat.No.F10471), 包括 FLuo-4钙染料、 Probenecid 和 Fluo-4钙流反应缓冲液。  3) Fluo-4 Calcium Flow Kit (Invitrogen®, Cat. No. F10471), including FLuo-4 Calcium Dye, Probenecid and Fluo-4 Calcium Flow Reaction Buffer.
4)、 多聚赖氨酸  4), polylysine
5)、 DMEM细胞培养液 (Gilbco®, Cat.No.C11995500B)  5), DMEM cell culture solution (Gilbco®, Cat.No.C11995500B)
6)、 胎牛血清 (Hyclone®, Cat.No.SV30087)  6), fetal bovine serum (Hyclone®, Cat.No.SV30087)
7)、 G418 sulfate(Merck®， Cat.No.345810)  7), G418 sulfate (Merck®, Cat. No.345810)
8)、 DMSO(Applichem®， Cat.No.A3672)  8), DMSO (Applichem®, Cat. No. A3672)
9)、 本发明实施例化合物  9), the compound of the embodiment of the invention
2、 按照以下操作顺序进行化合物激动活性的测定：  2. Determine the agonistic activity of the compound according to the following sequence of operations:
1)、 用终浓度为 20 g/mL的多聚赖氨酸包被 96孔黑色底透细胞培养板中， 37 °C孵育 两小时， 移去液体， 风干， 以增强细胞的贴壁性。  1), coated with poly-lysine at a final concentration of 20 g/mL in a 96-well black-bottomed cell culture plate, incubated at 37 °C for two hours, the liquid was removed, and air-dried to enhance cell adherence.
2)、将 GPR40稳定表达细胞铺到用多聚赖氨酸包被好的 96孔黑色底透细胞培养板中， 密度为 2xl04细胞 /孔， DMEM培养液中补充加入 10%胎牛血清和 400 g/mL 的 G418 sulfate, 37 °C、 5%二氧化碳孵箱中过夜培养。 2) GPR40 stably expressing cells were plated into a 96-well black-bottomed cell culture plate coated with polylysine at a density of 2×10 4 cells/well, and DMEM medium was supplemented with 10% fetal bovine serum and 400 g/mL of G418 sulfate was grown overnight in a 37 ° C, 5% carbon dioxide incubator.
3)、移去细胞培养液，换成 50 μΙ7孔无血清的 DMEM培养液和 50 μΙ7孔添加 Probenecid 的 FLuo-4钙染料， 避光 37 °C孵育 1小时。  3) Remove the cell culture medium and replace it with 50 μΙ 7-well serum-free DMEM medium and 50 μΙ 7 wells of Probenecid's FLuo-4 calcium dye, and incubate at 37 °C for 1 hour.
4)、所有待检测化合物均用 DMSO溶解配制成 10 mM的储存液。在 96孔 V底透明反 应板中用 DMSO进行梯度稀释，第 8个孔中填入 DMSO作为空白对照。然后再统一用 Fluo-4 钙流反应缓冲液稀释 200倍， 即反应终浓度的 5倍， 待用。  4) All the compounds to be tested were dissolved in DMSO to prepare a 10 mM stock solution. Gradient dilutions were made with DMSO in 96-well V-bottom transparent reaction plates, and DMSO was used as a blank control in the 8th well. It is then diluted 200 times with Fluo-4 Calcium Flow Reaction Buffer, which is 5 times the final concentration of the reaction, and is ready for use.
5)、 在 37 °C恒温条件下， 用 FlexStation 3(Molecular Device®)仪器， 从梯度稀释好的 化合物板中吸取 25 μΙ7孔的待测化合物加入到细胞培养板中， 使 8个孔中反应液所含化合 物的终浓度依次为 0、 1ηΜ、 3 ηΜ、 10 ηΜ、 30 ηΜ、 100 ηΜ、 300 ηΜ、 1000 ηΜ。 自加药 起每隔两秒钟读取荧光信号值 (495 nm激发波长和 520 nm发射波长)一次， 连续记录 150 秒， 得到各个时间点的荧光信号值。  5), using a FlexStation 3 (Molecular Device®) instrument, draw 25 μΙ 7 wells of the test compound into the cell culture plate at a constant temperature of 37 °C, and react in 8 wells. The final concentration of the compound contained in the liquid is 0, 1 η Μ, 3 η Μ, 10 η Μ, 30 η Μ, 100 η Μ, 300 η Μ, 1000 η 依次. Fluorescence signal values (495 nm excitation wavelength and 520 nm emission wavelength) were read every two seconds from the addition of the drug, and recorded continuously for 150 seconds to obtain fluorescence signal values at various time points.
6)、 通过读取的每个样品孔最高 (Max)和最低 (Min)荧光信号值， 计算出这个孔的磨 值， 即 (Max-Min)/Min值， 通过 Prism® 5统计软件绘制钙离子浓度变化曲线， 计算所测化 合物的 EC5Q值。 6) Calculate the grinding value of the hole by the highest (Max) and lowest (Min) fluorescence signal values of each sample hole, ie (Max-Min)/Min value, and draw calcium by Prism® 5 statistical software. The ion concentration curve was calculated to calculate the EC 5Q value of the tested compound.
表 1 : 本发明实施例化合物对 GPR40的激动活性  Table 1 : The agonistic activity of the compounds of the examples of the invention on GPR40
体内活性研究 In vivo activity study
本发明采用小鼠口服葡萄糖耐受实验 (OGTT)的方法， 测定化合物的体内降糖效果。  The present invention uses a method of oral glucose tolerance test (OGTT) in mice to measure the hypoglycemic effect of a compound in vivo.
1、 材料： 7-8周雄性 C57BL/6J小鼠。  1. Materials: Male C57BL/6J mice, 7-8 weeks old.
2、 按照以下操作顺序进行小鼠血糖浓度的测定：  2. Determine the blood glucose concentration of the mice according to the following sequence:
1)、 小鼠禁食 16 小时后称重并测量空腹血糖值 (GQ)， 根据 GQ进行随机分组， 5 只小鼠 /组。 2)、 灌胃法给小鼠服用不同浓度的待检测化合物， 以 25%的聚乙二醇硬脂酸脂 ( HS-15 ) 为溶剂， 给空白对照小鼠服用 25%的 HS-15。 1) The mice were weighed and fasted for 16 hours and measured for fasting blood glucose (G Q ), randomized according to G Q , 5 mice per group. 2), the mice were administered with different concentrations of the test compound by intragastric administration, and 25% of the HS-15 was administered to the control mice with 25% polyethylene glycol stearate (HS-15) as a solvent.
3)、 给药 15分钟后， 按 2.0 g/kg体重给小鼠灌胃口服葡萄糖水溶液。  3) After 15 minutes of administration, the mice were orally administered with an aqueous solution of glucose at 2.0 g/kg body weight.
4)、 通过取尾静脉血的方法， 用血糖仪测定小鼠口服葡萄糖后 15分钟、 30分钟、 60分钟、 120分钟的血糖值， 分别记为015、 G30、 G60禾 P G120。 4) The blood glucose levels of the mice 15 minutes, 30 minutes, 60 minutes, and 120 minutes after oral glucose administration were measured by blood glucose meter, and were recorded as 0 15 , G 30 , G 60 and PG 120 , respectively .
5)、 绘制小鼠血糖变化曲线， 并通过公式 110^12。=7.5(0。+2015+303。+606。+40120) 计算小鼠血糖 AUC值。 5), plot the blood glucose curve of the mouse, and pass the formula 110^ 12 . =7.5 (0. +20 15 +30 3 .+60 6 .+40 120 ) Calculate the blood glucose AUC value of the mouse.
实验结果见图 1和图 2，表明本发明的实施例 11的化合物在正常 C57小鼠体内具有显 著的降血糖作用， 本发明的实施例 11的化合物在 30-50 mg/kg时降糖效果有显著的优势。  The results of the experiment are shown in Fig. 1 and Fig. 2, which shows that the compound of Example 11 of the present invention has a significant hypoglycemic effect in normal C57 mice, and the compound of Example 11 of the present invention has a hypoglycemic effect at 30-50 mg/kg. There are significant advantages.

Claims

权利要求书 claims
1、 通式 I化合物或其药学上可接受的盐或其立体异构体： 1. Compounds of general formula I or their pharmaceutically acceptable salts or their stereoisomers:
Figure imgf000027_0001
其中，
Figure imgf000027_0001
in,
R R R R5、 R6、 R7和 R8各自独立地选自氢、 卤素、 氰基、 羟基、 硝基、 氨基、 烷基、 烷氧基、 环烃基、 杂环烃基、 芳基、 杂芳基、 -NHCO-烷基、 -NHCO-环烃基、 -S02-烷基、 -S02-环烃基、 -SO-烷基、 -SO-环烃基、 -N(烷基) -S02-烷基、 -N(烷基) -S02-环烃 基、 -N(烷基) -S02-芳基、 -N(烷基) -S02-杂芳基、 -NHS02-烷基、 -NHS02-环烃基、 -NHS02- 芳基、 -NHS02-杂芳基、 -S02-NH2、 -S02-NH-焼基、 -S02N- (烷基 )2、 -CO-烷基、 -COO-焼 基、 -CONH-烷基、 -CON- (烷基 )2、 -CONH2 ; RRRR 5 , R 6 , R7 and R 8 are each independently selected from hydrogen, halogen, cyano, hydroxyl, nitro, amino, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -NHCO-alkyl, -NHCO-cycloalkyl, -S0 2 -alkyl, -S0 2 -cycloalkyl, -SO-alkyl, -SO-cycloalkyl, -N(alkyl) -S0 2 -alkyl , -N(alkyl) -S0 2 -cycloalkyl, -N(alkyl) -S0 2 -aryl, -N(alkyl) -S0 2 -heteroaryl, -NHS0 2 -alkyl, -NHS0 2 -cycloalkyl group, -NHS0 2 -aryl group, -NHS0 2 -heteroaryl group, -S0 2 -NH 2 , -S0 2 -NH-alkyl group, -S0 2 N- (alkyl) 2 , -CO- Alkyl, -COO-alkyl, -CONH-alkyl, -CON- (alkyl) 2 , -CONH 2 ;
L1为 -CH20-、 -CH2NH- 或 ~≡ ~； L 1 is -CH 2 0-, -CH 2 NH- or ~≡ ~;
L2为 -0-或 -NR12-; L 2 is -0- or -NR 12 -;
R9和 R1Q各自独立地选自氢、 卤素、 烷基、 羟基、 烷氧基、 环烃基、 杂环烃基、 芳基、 杂芳基、 氰基； R 9 and R 1Q are each independently selected from hydrogen, halogen, alkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic hydrocarbyl, aryl, heteroaryl, and cyano;
n为 0、 1、 2、 3、 4或 5; n is 0, 1, 2, 3, 4 or 5;
L3为键或 -NR13-; L 3 is a bond or -NR 13 -;
R12和 R13各自独立地选自氢、 烷基、 环烃基、 芳基、 杂芳基、 -S02-烷基、 -S02-环烃 基、 -SO-烷基、 -SO-环烃基、 -CO-烷基、 -CO-环烃基、 -CO-芳基、 -CO-杂芳基， 或者 R12 和 R13以及与它们所连接的原子一起形成至少含有两个 N原子的杂环烃基； R 12 and R 13 are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, -S0 2 -alkyl, -S0 2 -cycloalkyl, -SO-alkyl, -SO-cycloalkyl , -CO-alkyl, -CO-cycloalkyl, -CO-aryl, -CO-heteroaryl, or R 12 and R 13 and the atoms to which they are connected together form a heterocyclic ring containing at least two N atoms hydrocarbyl;
L4为 -P(0)(R14)- 或 -S02-; L 4 is -P(0)(R 14 )- or -S0 2 - ;
R11为 -NR15R16、 卤素、 羟基、 氰基、 硝基、 烷基、 烷氧基、 环烃基、 杂环烃基、 芳基、 杂芳基，或者 R11和 R13以及与它们所连接的原子一起形成含有 -P(0)(R14)-或 -S02-及至少一 个氮原子的杂环烃基； R 11 is -NR 15 R 16 , halogen, hydroxyl, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclic hydrocarbyl, aryl, heteroaryl, or R 11 and R 13 and their respective The connected atoms together form a heterocyclic hydrocarbon group containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom;
R14、 R15、 R16、 R17、 R18各自独立地选自氢、 卤素、 羟基、 烷基、 烷氧基、 环烃基、 杂环烃基、 芳基、 杂芳基； R 14 , R 15 , R 16 , R 17 , and R 18 are each independently selected from hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclic hydrocarbyl, aryl, and heteroaryl;
m为 0、 1、 2、 3、 4或 5; m is 0, 1, 2, 3, 4 or 5;
R19选自氢、 烷基、 环烃基、 杂环烃基、 芳基、 杂芳基； R 19 is selected from hydrogen, alkyl, cycloalkyl, heterocyclic hydrocarbyl, aryl, and heteroaryl;
前提条件是： 当 L1为 -CH20-或 -CH2NH -， L2为 0或 -NH -， R9和 R1Q均为氢， n=2或 3， L3为键， L4为 -S02-、 R11为甲基或乙基、 以及 R17和 R18为氢时， R19选自环烃基、 杂环烃 基、 芳基、 杂芳基。 The prerequisites are: when L 1 is -CH 2 0- or -CH 2 NH -, L 2 is 0 or -NH -, R 9 and R 1Q are both hydrogen, n=2 or 3, L 3 is a bond, L When 4 is -S0 2 -, R 11 is methyl or ethyl, and R 17 and R 18 are hydrogen, R 19 is selected from a cyclic hydrocarbon group, a heterocyclic hydrocarbon group, an aryl group, and a heteroaryl group.
2、 权利要求 1所述的化合物， 其中 R R2、 R3、 R4、 R5、 R6、 R7和 R8各自独立 地选自氢、 卤素、 氰基、 羟基、 烷基、 烷氧基、 氨基； 优选地， R R4、 R5、 R6、 R7和 R8为氢， R2和 R3为甲基。 2. The compound of claim 1, wherein RR 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, halogen, cyano, hydroxyl, alkyl, alkoxy radical, amino group; Preferably, RR 4 , R 5 , R 6 , R 7 and R 8 are hydrogen, and R 2 and R 3 are methyl groups.
3、 权利要求 1或 2所述的化合物， 其中 L1为 -CH2NH-或 -CH20-。 3. The compound of claim 1 or 2, wherein L 1 is -CH 2 NH- or -CH 2 0-.
4、 权利要求 1或 2所述的化合物， 其中 L1为 ~≡ ~。 4. The compound according to claim 1 or 2, wherein L 1 is ~≡~.
5、 权利要求 1-4中任一项所述的化合物，其中 R9和 R1Q为氢和 /或 R17禾 Π R18为氢。 5. The compound of any one of claims 1-4, wherein R and R are hydrogen and/or R and R are hydrogen.
6、 权利要求 1-5中任一项所述的化合物， 其中 m为 1和 /或 n为 2或 3。 6. The compound according to any one of claims 1 to 5, wherein m is 1 and/or n is 2 or 3.
7、 权利要求 1-6中任一项所述的化合物， 其中 L2为 -0-。 7. The compound according to any one of claims 1 to 6, wherein L 2 is -0-.
8、 权利要求 1-6中任一项所述的化合物， 其中 L2为 -NR12-， R12选自氢、 烷基、 环烃基、 芳基、 杂芳基； 优选地， R12选自氢、 烷基； 更优选地， R12选自氢、 d_6烷基； 最优选地， R12选自氢； 或者， L2为 -NR12-且 L3为 -NR13-， R12与 R13以及与它们所连接的 原子一起形成至少含有两个 N原子的杂环烃基；优选地， R12与 R13以及与它们所连接的原 子一起形成至少含有两个 N原子的 5或 6元杂环烃基；更优选地， R12与 R13以及与它们所 连接的原子一起形成含有两个 N原子的 6元杂环烃基；最优选地， R12与 R13以及与它们所 连接的原子一起形成哌嗉基。 8. The compound according to any one of claims 1 to 6, wherein L 2 is -NR 12 -, R 12 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl; preferably, R 12 is selected from from hydrogen, alkyl; more preferably, R 12 is selected from hydrogen, d_6 alkyl; most preferably, R 12 is selected from hydrogen; or, L 2 is -NR 12 - and L 3 is -NR 13 -, R 12 and R 13 and the atoms to which they are connected together form a heterocyclic hydrocarbon group containing at least two N atoms; preferably, R 12 and R 13 and the atoms to which they are connected together form a 5 or 5 group containing at least two N atoms. 6-membered heterocyclic hydrocarbon group; more preferably, R 12 and R 13 and the atoms to which they are connected together form a 6-membered heterocyclic hydrocarbon group containing two N atoms; most preferably, R 12 to R 13 and the atoms to which they are connected. The atoms together form piperazyl.
9、 通式 II ：
Figure imgf000028_0001
II 9. General formula II:
Figure imgf000028_0001
II
其中， in,
n为 0、 1、 2、 3、 4或 5; n is 0, 1, 2, 3, 4 or 5;
L3为键或 -NR13-; L 3 is a bond or -NR 13 -;
R13选自氢、 烷基、 环烃基、 芳基、 杂芳基； R 13 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl;
L4为 -P(0)(R14)- 或 -S02-; L 4 is -P(0)(R 14 )- or -S0 2 - ;
R11为 -NR15R16、 素、 羟基、 氰基、 硝基、 烷基、 烷氧基、 环烃基、 杂环烃基、 芳基 或杂芳基，或者 R11与 R13以及与它们所连接的原子一起形成含有 -P(0)(R14)-或 -S02-及至少 一个氮原子的杂环烃基； R 11 is -NR 15 R 16 , element, hydroxyl, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclic hydrocarbyl, aryl or heteroaryl, or R 11 and R 13 and their respective The connected atoms together form a heterocyclic hydrocarbon group containing -P(0)(R 14 )- or -S0 2 - and at least one nitrogen atom;
R14、 R15、 R16各自独立地选自氢、 烷基、 烷氧基、 环烃基、 杂环烃基、 芳基、 杂芳基; R 14 , R 15 , and R 16 are each independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, heterocyclic hydrocarbyl, aryl, and heteroaryl;
R19选自氢、 烷基、 环烃基、 杂环烃基、 芳基、 杂芳基； R 19 is selected from hydrogen, alkyl, cycloalkyl, heterocyclic hydrocarbyl, aryl, and heteroaryl;
前提条件是： 当 n=2或 3， L3为键， L4为 -S02- 以及 R11为甲基或乙基时， R19选自环 烃基、 杂环烃基、 芳基、 杂芳基。 The prerequisites are: when n=2 or 3, L 3 is a bond, L 4 is -S0 2 - and R 11 is methyl or ethyl, R 19 is selected from cycloalkyl, heterocyclic hydrocarbyl, aryl, heteroaryl base.
10、 权利要求 1-9任一项所述的化合物， 其中 n为 2或 3。 10. The compound according to any one of claims 1 to 9, wherein n is 2 or 3.
11、 权利要求 1-10任一项所述的化合物，其中 R19选自氢、烷基、环烃基；优选地， R19选自氢、 d_6烷基、 _6环烃基； 更优选地， R19选自氢、 甲基、 乙基、 丙基、 异丙基、 环丙基、 环丁基、 环己基； 最优选地， R19为氢。 11. The compound according to any one of claims 1 to 10, wherein R 19 is selected from hydrogen, alkyl, and cycloalkyl; preferably, R 19 is selected from hydrogen, d- 6 alkyl, and d- 6 cycloalkyl; more preferably , R 19 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl; most preferably, R 19 is hydrogen.
12、 权利要求 1-11任一项所述的化合物， 其中 L4为 -S02-。 12. The compound of any one of claims 1-11, wherein L 4 is -S0 2 -.
13、 权利要求 1-7或 9-11任一项所述的化合物， 其中 L3为键， L4为 -P(P)(;R14)-。 13. The compound of any one of claims 1-7 or 9-11, wherein L 3 is a bond, and L 4 is -P(P)(;R 14 )-.
14、 权利要求 13所述的化合物， 其中 R14为氢或烷基； 优选地， R14为烷基； 更优 选地， R14为 d_6烷基； 甚至更优选地， R14为 d_4烷基； 最优选地， R14为甲基。 14. The compound of claim 13, wherein R 14 is hydrogen or alkyl; Preferably, R 14 is alkyl; More preferably, R 14 is d_6 alkyl; Even more preferably, R 14 is d_4 Alkyl; most preferably, R 14 is methyl.
15、 权利要求 1-7或 9-11任一项所述的化合物， 其中 L3为键， L4为 -S02-。 15. The compound of any one of claims 1-7 or 9-11, wherein L 3 is a bond and L 4 is -S0 2 -.
16、 权利要求 1-7或 9-12任一项所述的化合物， 其中 L3为 -NR13-， R13选自氢、 烷 基、 环烃基、 芳基、 杂芳基； 优选地， R13选自氢、 烷基； 更优选地， R13选自氢、 d_6烷 基； 甚至更优选地， R13选自氢。 16. The compound of any one of claims 1-7 or 9-12, wherein L 3 is -NR 13 -, R 13 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl; Preferably, R 13 is selected from hydrogen and alkyl; more preferably, R 13 is selected from hydrogen and d- 6 alkyl; even more preferably, R 13 is selected from hydrogen.
17、 权利要求 1-16中任一项所述的化合物，其中 R11选自 -NR15R16、烷基、环烃基、 杂环烃基、 芳基、 杂芳基； 优选地， R11选自 基 )2、 -NH (；焼基)、 烷基、 环烃基、 杂环 烃基、 芳基或杂芳基； 更优选地， R11选自 -N(d_6烷基 )2、 -NH C^烷基)、 d_6烷基、 C3_6 环烃基、3-6元杂环烃基、苯基、 5或 6元杂芳基；更优选地， R11选自 -N(d_6烷基 -NH C^ 烷基)、 C^烷基、 C3_6环烃基； 甚至更优选地， R11为 -Ν( _4烷基 )2、 -NH C^烷基)、 C1-4 烷基、 Cw环烃基； 最优选地， R11为 -N(CH3)2、 -NH(CH3) -CH3、 -C2H5、 环丙基。 17. The compound according to any one of claims 1 to 16, wherein R 11 is selected from -NR 15 R 16 , alkyl, cycloalkyl, heterocyclic hydrocarbyl, aryl, heteroaryl; Preferably, R 11 is selected from (self) 2 , -NH (alkyl), alkyl, cycloalkyl, heterocyclic hydrocarbyl, aryl or heteroaryl; more preferably, R 11 is selected from -N( d_6 alkyl) 2 , -NH C alkyl), d_6 alkyl, C 3_6 cyclic hydrocarbyl, 3-6 membered heterocyclic hydrocarbyl, phenyl, 5 or 6 membered heteroaryl; more preferably, R 11 is selected from -N( d_6 Alkyl -NH C^ alkyl), C^ alkyl, C 3_6 cycloalkyl; even more preferably, R 11 is -N (_ 4 alkyl ) 2 , -NH C^ alkyl), C 1 -4 alkyl, Cw cycloalkyl; most preferably, R 11 is -N(CH 3 ) 2 , -NH(CH 3 ) -CH 3 , -C 2 H 5 , cyclopropyl.
18、 权利要求 1-7或 9-12中任一项所述的化合物， 其中 L3为 -NR13-且 R11与 R13以 及与它们所连接的原子一起形成含有 -P(0)(R14)-或 -S02-及至少一个氮原子的杂环烃基； 优 选地， R11与 R13以及与它们所连接的原子一起形成含有 -P(0)(R14)-或 -S02-及至少一个氮原 子的 3-12元杂环烃基;优选地， R11与 R13以及与它们所连接的原子一起形成含有 -P(0)(R14)- 或 -S02-及至少一个氮原子的 3、 4、 5或 6元杂环烃基； 更优选地， R11与 R13以及与它们 所连接的原子一起形成含有 -P(0)(R14)-或 -S02-及至少一个氮原子的 5或 6元杂环烃基； 甚 至更优选地， 11与 R13以及与它们所连接的原子一起形成含有 -S02-及一个氮原子的 5或 6 元杂环烃基； 最优选地， R11与 R13以及与它们所连接的原子一起形成含有 -S02-及一个氮 原子的 5元杂环烃基。 18. The compound of any one of claims 1-7 or 9-12, wherein L 3 is -NR 13 - and R 11 and R 13 and the atoms to which they are connected together form a compound containing -P(0)( R 14 )- or -S0 2 - and a heterocyclic hydrocarbon group with at least one nitrogen atom; preferably, R 11 and R 13 and the atoms to which they are connected together form a group containing -P(0)(R 14 )- or -S0 2 -and a 3-12-membered heterocyclic hydrocarbon group with at least one nitrogen atom; preferably, R 11 and R 13 and the atoms to which they are connected together form a group containing -P(0)(R 14 )- Or -S0 2 - and a 3, 4, 5 or 6-membered heterocyclic hydrocarbon group with at least one nitrogen atom; more preferably, R 11 and R 13 and the atoms to which they are connected together form a group containing -P(0)(R 14 )- or -S0 2 - and a 5- or 6-membered heterocyclic hydrocarbon group with at least one nitrogen atom; even more preferably, 11 and R 13 and the atoms to which they are connected together form 5 containing -S0 2 - and a nitrogen atom Or a 6-membered heterocyclic hydrocarbon group; most preferably, R 11 and R 13 and the atoms to which they are connected together form a 5-membered heterocyclic hydrocarbon group containing -S0 2 - and a nitrogen atom.
Figure imgf000029_0001
Figure imgf000029_0001
20、 药物组合物， 它包含权利要求 1-19 中任一项所述的化合物或其药学上可接受 的盐或其立体异构体和药学上可接受的载体。 20. Pharmaceutical composition, which contains the compound of any one of claims 1-19 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof and a pharmaceutically acceptable carrier.
21、 权利要求 1-19 中任一项所述的化合物或其药学上可接受的盐或其立体异构体 在制备用于治疗和 /或预防与 GPR40相关的疾病的药物中的用途。 21. Use of the compound of any one of claims 1-19 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a medicament for the treatment and/or prevention of diseases related to GPR40.
22、 如权利要求 21所述的用途， 其中所述与 GPR40相关的疾病是糖尿病。 22. The use of claim 21, wherein the GPR40-related disease is diabetes.
23、 用于治疗和 /或预防与 GPR40相关的疾病的权利要求 1-19中任一项所述的化合 物或其药学上可接受的盐或其立体异构体。 23. The compound of any one of claims 1-19 or a pharmaceutically acceptable salt or stereoisomer thereof for treating and/or preventing diseases related to GPR40.
24、 如权利要求 23所述的化合物或其药学上可接受的盐或其立体异构体， 其中所 述与 GPR40相关的疾病是糖尿病。 24. The compound of claim 23 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the GPR40-related disease is diabetes.
25、 用于治疗和 /或预防与 GPR40相关的疾病的方法， 其中将治疗有效量的权利要 求 1-19 中任一项所述的化合物或其药学上可接受的盐或其立体异构体对有需要的哺乳动 物给药。 25. A method for treating and/or preventing diseases related to GPR40, wherein a therapeutically effective amount of the compound of any one of claims 1-19 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is used Administer to a mammal in need.
26、 如权利要求 25所述的方法， 其中所述与 GPR40相关的疾病是糖尿病。 26. The method of claim 25, wherein the disease associated with GPR40 is diabetes.
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