WO2016180348A1 - Nitrogen-containing spiro-heterocyclic derivative having beta2 receptor excitement and m receptor antagonistic activities and application thereof in medicament - Google Patents

Nitrogen-containing spiro-heterocyclic derivative having beta2 receptor excitement and m receptor antagonistic activities and application thereof in medicament Download PDF

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Publication number
WO2016180348A1
WO2016180348A1 PCT/CN2016/081809 CN2016081809W WO2016180348A1 WO 2016180348 A1 WO2016180348 A1 WO 2016180348A1 CN 2016081809 W CN2016081809 W CN 2016081809W WO 2016180348 A1 WO2016180348 A1 WO 2016180348A1
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group
alkyl
hydroxy
methyl
oxo
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PCT/CN2016/081809
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French (fr)
Chinese (zh)
Inventor
魏用刚
邱关鹏
雷柏林
楚红柱
郑苏欣
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四川海思科制药有限公司
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Priority to CN201680003435.9A priority Critical patent/CN107108562B/en
Publication of WO2016180348A1 publication Critical patent/WO2016180348A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • the invention relates to a nitrogen-containing heterospirocyclic derivative, a preparation method thereof and the use thereof in medicine, in particular to a novel containing double activity of muscarinic receptor antagonism and ⁇ 2 -adrenergic receptor agonism Azaspirocyclic derivatives or stereoisomers, hydrates, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof, pharmaceutical compositions thereof, and their use in medicine.
  • Bronchodilators play an important role in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma.
  • Bronchodilators in clinical use include widely muscarinic receptor antagonist and ⁇ 2 - adrenergic agonist.
  • a muscarinic receptor antagonist exerts potency in bronchodilation by reducing the level of vagal cholinergic energy in airway smooth muscle.
  • Inhaled muscarinic receptor antagonists currently used include ipratropium bromide, oxitropium bromide, glycopyrrolate, tiotropium bromide, adiponium bromide and indole bromide.
  • 2 2 -adrenergic agonists bronchodilate by stimulating adrenergic receptors in airway smooth muscle, reversing the response of bronchoconstrictors to various mediators such as acetylcholine.
  • the ⁇ 2 -adrenergic agonists currently used include albuterol, salmeterol, arformoterol, formoterol, vilantrol and indacaterol. In addition to improving lung function, these drugs can improve the quality of life of patients and reduce the deterioration of their condition.
  • the combination of muscarinic receptor antagonists and ⁇ 2 -adrenergic agonists is more effective than the use of one of the therapeutic agents alone
  • the current prion base receptor antagonists And ⁇ 2 -adrenergic agonists are prepared as a combination preparation for the treatment of asthma and moderate to severe COPD.
  • These compound preparations mainly include Anoro Ellipta (Ambroxol/Vylantro) and Ultibro Breezhaler (Glon Brom). Ammonium / indacaterol) and ipratropium bromide / salbutamol.
  • muscarinic receptor antagonist and ⁇ 2 - adrenergic agonists dual-acting drugs drugs with this dual function the advantages of both pharmaceutical ingredient combination, along with a single molecule pharmacokinetics.
  • These compounds are administered as a single therapeutic agent and can provide bronchodilation by two different and possibly synergistic modes of action.
  • compounds with muscarinic receptor antagonism and ⁇ 2 -adrenergic agonistic dual action can also be combined with corticosteroid (ICS) anti-inflammatory drugs to form two therapeutic agents (MABA/ICS) to provide triple Therapeutic effect of action (Expert Opin. Investig. Drugs (2014) 23(4): 453-456).
  • ICS corticosteroid
  • the present invention provides a compound represented by the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof.
  • R 1 is selected from
  • R 1d is selected from H, hydroxy, -CH 2 OH or C 1-4 alkyl
  • Ring A and Ring C are each independently selected from a C 6-10 carbocyclic ring or a 5 to 10 membered heterocyclic ring, which is optionally further 0, 1, 2, 3 or 4 selected from F, Cl, Substituted with a substituent of Br, I, C 1-4 alkyl or C 1-4 alkoxy, and the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S;
  • R 2 is selected from a bond, a C 1-6 alkylene group, a C 2-6 alkenylene group or a C 2-6 alkynylene group, and the alkylene group, alkenylene group or alkynylene group is optionally further further further 0, 1 , 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 Substituted by a substituent of an alkyl group;
  • L is selected from the key or And Y is directly connected to R 2 ;
  • R 3 is selected from a bond or a C 1-6 alkylene group, which is optionally further substituted with 0, 1 , 2, 3, 4 or 5 substituents selected from R 3a ;
  • R 4 and R 5 are each independently selected from H or C 1-4 alkyl
  • R 3a is selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
  • two R 3a may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, said carbon ring optionally further being 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br Substituted with a substituent of I, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy;
  • a 1 and A 4 are each independently selected from C 3-7 cycloalkylene, C 6-10 arylene, 5 to 8 membered heteroarylene, -OC 6-10 arylene, -O-5 to 8 a meta-heteroaryl group, a 5- to 8-membered heteroarylene-O- or a C 6-10 arylene-O-, wherein the cycloalkylene, arylene or heteroarylene is optionally further 0, 1, 2, 3, 4 or 5 substituents selected from R 6 are substituted;
  • a 2 and A 3 are each independently selected from C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, and the alkylene, alkenylene or alkynylene group is optionally further 0, 1, 2, 3, 4 or 5 are selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1 Substituted with a substituent of -4 alkylene;
  • R 7 is each independently selected from H or C 1-4 alkyl
  • a 0, 1, 2, 3 or 4;
  • b 0, 1, 2, 3, 4 or 5;
  • n, p or q are each independently selected from 0 or 1.
  • B is further preferably selected from
  • R 1 is selected from
  • R 1a is selected from the group consisting of H, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 carbocyclyl, 3 to 6 membered heterocyclic, C 3-7 carbocyclyl-C 1-4 alkylene Or a 3- to 6-membered heterocyclyl-C 1-4 alkylene group, optionally substituted by 0, 1, 2, 3 or 4, optionally substituted with 0, 1, 2, 3 or 4
  • One selected from the group consisting of F, Cl, Br, I, CF 3 , OH, NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, -O( O)C 1
  • Substituted by a substituent of -4 alkyl, -( O)C 1-4 alkyl, -OC 3-6 cycloalkyl or C 1-4 alkylthio containing 1, 2 or 3 a hetero atom selected from N, O or S;
  • Ring A and Ring C are each independently selected from the group consisting of a thiophene ring, a furan ring, a pyridine ring or a benzene ring, preferably a benzene ring, which is optionally further further further 0, 1, 2, or 3 or Substituted by four substituents selected from F, Cl, Br, I, C 1-4 alkyl or C 1-4 alkoxy, preferably further selected from 0, 1, 2, 3 or 4 selected from F, Cl Substituted with a substituent of Br, I, methyl, ethyl, methoxy or ethoxy;
  • R 1d is selected from H, hydroxy, -CH 2 OH or C 1-4 alkyl, preferably selected from H, hydroxy, -CH 2 OH, methyl, ethyl or propyl;
  • R 1e and R 1f are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , NH 2 , OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio , -NHC 1-4 alkyl or -N(C 1-4 alkyl) 2 ;
  • R 2 is selected from a bond, a C 1-6 alkylene group, a C 2-6 alkenylene group or a C 2-6 alkynylene group, and the alkylene group, alkenylene group or alkynylene group is optionally further further 0. 1 , 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 Substituted by a substituent of an alkyl group; R 2 is preferably selected from a bond or a C 1-6 alkylene group, and the alkylene group is optionally further 0, 1 , 2, 3, 4 or 5 selected from F, Cl, Substituted by a substituent of Br, I, OH, cyano, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3 is selected from a bond or a C 1-6 alkylene group, which is optionally further substituted with 0, 1 , 2, 3, 4 or 5 substituents selected from R 3a ;
  • R 3 is preferably selected from a bond or a C 1-6 alkylene group, which is optionally further substituted with 0, 1 , 2, 3, 4 or 5 substituents selected from R 3a ;
  • L is selected from the key or And Y is directly connected to R 2 ;
  • R 4 and R 5 are each independently selected from H or C 1-4 alkyl
  • R 3a is selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene; R 3a is preferably selected From F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy or phenyl;
  • two R 3a may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, said carbon ring optionally further being 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br Substituted with a substituent of I, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy;
  • a 1 and A 4 are each independently selected from C 3-7 cycloalkylene, C 6-10 arylene, 5 to 8 membered heteroarylene, -OC 6-10 arylene, -O-5 to 8 a meta-heteroaryl group, a 5- to 8-membered heteroarylene-O- or a C 6-10 arylene-O-, preferably selected from the group consisting of cyclopentylene, cyclohexylene, phenylene, thiophene a pyridyl group, a thiazolyl group, a oxazolyl group, an imidazolyl group or a pyridylene group, wherein the cycloalkylene group, the arylene group, the heteroarylene group, the cyclopentylene group, the cyclohexylene group
  • a 2 and A 3 are each independently selected from C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, preferably selected from C 1-6 alkylene, more preferably selected from methylene. , ethylene, propylene, butylene or pentylene, said alkylene, alkenylene, alkynylene or methylene, ethylene, propylene, butylene or pentylene Further, 0, 1, 2, 3, 4 or 5 are selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl- Substituted by a substituent of a C 1-4 alkylene group;
  • R 7 is selected from H or C 1-4 alkyl, preferably selected from H, methyl or ethyl;
  • a 0, 1, 2, 3 or 4;
  • b 0, 1, 2, 3, 4 or 5;
  • n, p or q are each independently selected from 0 or 1.
  • R 1 is selected from
  • R 1a is selected from the group consisting of H, vinyl, ethynyl, propynyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, thienyl, furanyl or pyridyl , preferably selected from the group consisting of ethenyl, ethynyl, phenyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl or thienyl, said vinyl, ethynyl, propynyl, phenyl , cyclopropane, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, thienyl, furyl or pyridyl optionally further selected from 0, 1, 2, 3 or
  • R 1b is selected from the group consisting of ethenyl, ethynyl, propynyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, thienyl, furyl or pyridyl, preferably Selected from vinyl, ethynyl, phenyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl or thienyl, said vinyl, ethynyl, propynyl, phenyl, cyclo Propane, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, thienyl, furyl or pyridyl are optionally further selected from 0, 1, 2, 3 or 4 selected from F, Cl, Sub
  • R 1d is selected from the group consisting of H, NH 2 , hydroxy, -CH 2 OH, methyl or ethyl;
  • R 1e and R 1f are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , NH 2 , OH, cyano, methyl, ethyl, methoxy, ethoxy, -NHCH 3 or -N (CH) 3 ) 2 ;
  • R 2 is selected from a bond or a C 1-6 alkylene group, preferably selected from a bond, a methylene group, an ethylene group, a propylene group, a butylene group or a pentylene group, said C 1-6 alkylene group,
  • the methyl, ethylene, propylene, butylene or pentylene group is further optionally 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl Substituted by a substituent of an ethyl group, a methoxy group or an ethoxy group;
  • R 3 is selected from a bond or a C 1-6 alkylene group, preferably selected from the group consisting of a bond, a methylene group, an ethylene group, a propylene group, a butylene group, a pentylene group or The C 1-6 alkylene group, methylene group, ethylene group, propylene group, butylene group, pentylene group or Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
  • L is selected from the key or And Y is directly connected to R 2 ;
  • R 4 and R 5 are each independently selected from H, methyl or ethyl
  • a 1 and A 4 are each independently selected from a phenylene group, a cyclopentylene group, a cyclohexylene group, a phenylene group, a thienylene group, a furylene group, a thiazolyl group, a oxazolyl group, an imidazolyl group or a pyridylene group, preferably selected from the group consisting of a phenylene group, a thienylene group, a furylene group or a pyridylene group, said phenylene group, a cyclopentylene group, a cyclohexylene group, a phenylene group, a thienylene group,
  • the furylene group, the thiazolyl group, the oxazolyl group, the imidazolyl group or the pyridylene group are further further selected from 0, 1, 2, 3 or 4 selected from the group consisting of F, Cl, Br,
  • a 2 and A 3 are each independently selected from a methylene group, an ethylene group, a propylene group, a butylene group or a pentylene group;
  • R 7 is selected from H or C 1-4 alkyl, preferably selected from H, methyl, ethyl or propyl;
  • a is 0, 1, 2, 3 or 4, preferably 0 or 1;
  • b is 0, 1, 2, 3 or 4, preferably 0, 1 or 2;
  • n, p or q are each independently selected from 0 or 1.
  • R 1 is selected from
  • R 2 is selected from a bond, a methylene group, an ethylene group, a propylene group, a butylene group or a pentylene group, and the methylene, ethylene, propylene, butylene or pentylene group is optionally further 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
  • R 2 is preferably selected from the group consisting of a bond, a methylene group, an ethylene group, a propylene group, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -C(CH 3 ) 2 CH 2 - , -CH(CH 3 )CH 2 -, butylene, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )CH 2 - or Pentylene group
  • R 3 is selected from the group consisting of a bond, a methylene group, an ethylene group, a propylene group, a butylene group, a pentylene group or The methylene, ethylene, propylene, butylene, pentylene or Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
  • R 3 is preferably selected from the group consisting of a bond, a methylene group, an ethylene group, a propylene group, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -C(CH 3 ) 2 CH 2 - , -CH(CH 3 )CH 2 -, butylene, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )CH 2 -, Pentylene or
  • L is selected from And Y is directly connected to R 2 ;
  • R 4 and R 5 are each independently selected from H, methyl or ethyl
  • a 1 and A 4 are each independently selected from a phenylene group, a thienylene group, a furylene group or a pyridylene group, preferably selected from a phenylene group, a phenylene group, a thienylene group, a furylene group or a pyridylene group.
  • a 2 and A 3 are each independently selected from a methylene group, an ethylene group, a propylene group, a butylene group or a pentylene group;
  • R 7 is selected from H or C 1-4 alkyl, preferably selected from H, methyl, ethyl or propyl;
  • n, p or q are each independently selected from 0 or 1.
  • the above compound represented by the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof includes, but is not limited to:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of the above formula (I) or a stereoisomer, hydrate, metabolite, solvate thereof, pharmaceutically An acceptable salt, eutectic or prodrug, and a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle or excipient; said composition may further comprise one or more additional therapeutic agents; Preferably, wherein the additional therapeutic agent is selected from one or more of a PDE4 inhibitor, a muscarinic receptor antagonist, a corticosteroid, and a beta-adrenergic receptor agonist.
  • the present invention also provides the compound of the above formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, which is prepared for use in therapeutic gas
  • a medicament for obstructive diseases is preferably used in the preparation of a medicament for the treatment of asthma, chronic obstructive pulmonary disease or bronchitis.
  • the present invention also provides a method for treating an airway obstructive disease, comprising administering a compound of the above formula (I) or a stereoisomer, hydrate, metabolite, solvate thereof, pharmaceutically An acceptable salt, eutectic or prodrug, or a pharmaceutical composition as described above.
  • the present invention also provides a method for treating asthma, chronic obstructive pulmonary disease or bronchitis, which comprises administering a compound of the above formula (I) or a stereoisomer, hydrate, metabolite thereof, Solvate, pharmaceutically acceptable salt, co-crystal or prodrug, or a pharmaceutical composition as described above.
  • the present invention also provides an intermediate for preparing a compound of the formula (I) or a stereoisomer thereof, which is selected from the compound of the formula (II) or a stereoisomer thereof:
  • R 1 is selected from
  • R 9 is selected from H or an amino protecting group
  • a 0, 1, 2, 3 or 4;
  • b 0, 1, 2, 3, 4 or 5.
  • R 1 is selected from
  • R 1 is preferably selected from
  • R 9 is selected from H or an amino protecting group, wherein the amino protecting group is preferably benzyl, p-methoxybenzyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl or benzoyl.
  • the intermediate of the above formula (II) for producing the compound of the formula (I) or a stereoisomer thereof is selected from one of the following compounds:
  • the present invention relates to an intermediate for the preparation of a compound of the formula (I) or a stereoisomer thereof, which is selected from a compound of the formula (III) or a stereoisomer thereof:
  • R 1 is selected from
  • R 1b is selected from C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3 to 8 membered heterocyclic, C 3-10carbocyclyl -C 1-4 alkylene or a 3- to 8-membered heterocyclyl-C 1-4 alkylene group, optionally further 0 to 4 selected from the group consisting of F, Cl, and Br, and an alkenyl group, an alkynyl group, an alkylene group, a carbocyclic group, or a heterocyclic group.
  • heterocyclic group contains 1 to 3 hetero atoms selected from N, O or S;
  • R 2 is selected from a bond, a C 1-6 alkylene group, a C 2-6 alkenylene group or a C 2-6 alkynylene group, and the alkylene group, alkenylene group or alkynylene group is optionally further 0 to 5 Substituted with a substituent selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
  • R x is selected from H or C 1-4 alkyl
  • R 3 is selected from a bond or C 1-6 alkylene, said alkylene being optionally further substituted with 0-5 substituents selected from R 3a, R 3a is selected from F, Cl, Br, I, cyano a group, OH, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene; alternatively, two R 3a may form a 3 together with the atoms to which they are attached Up to a 6-membered carbocyclic ring, optionally further substituted with 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy Replaced
  • B is preferably selected from
  • a 0, 1, 2, 3 or 4;
  • b 0, 1, 2, 3, 4 or 5.
  • the intermediate of the above formula (III) for producing the compound of the formula (I) or a stereoisomer thereof is selected from one of the following compounds:
  • the reagent such as saturated sodium bicarbonate solution or saturated sodium carbonate solution
  • an organic solvent such as dichloromethane, ethyl acetate, etc.
  • the organic phase is concentrated under reduced pressure to give the free base of the corresponding compound.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention.
  • the nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C, and 14 C, and the hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen ), ⁇ (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes including 14 N and 15 N, the fluorine isotope 19 F, the chlorine isotope includes 35 Cl and 37 Cl, and the bromine isotopes include 79 Br and 81 Br.
  • Alkyl means a straight-chain and branched monovalent saturated hydrocarbon group, and the main chain includes 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, further preferably 1 to 6 carbon atoms, more preferably 1 Straight and branched groups of up to 4 carbon atoms, most preferably 1 to 2 carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-glycol Base, n-octyl, n-decyl and n-decyl, etc.; the alkyl group may be further optionally 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl,
  • Alkoxy means a monovalent group of an O-alkyl group, wherein alkyl is as defined herein, and alkoxy embodiments include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2 -propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy , 3-methyl-1-butoxy and 2-methyl-1-butoxy and the like.
  • alkenyl means a straight-chain or branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, the main chain comprising 2 to 10 carbon atoms, further preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain, and alkenyl examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl , 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2- Methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-hep
  • Alkenylene refers to a divalent alkenyl group wherein the alkenyl group is as defined above.
  • Alkynyl means a straight-chain or branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, the main chain comprising 2 to 10 carbon atoms, further preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain
  • alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butyl Alkynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3 -hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-decynyl and 4-decynyl, etc.; the alkynyl group
  • Alkynylene refers to a divalent alkynyl group wherein the alkynyl group is as defined above.
  • Cycloalkyl means a monovalent saturated carbocyclic hydrocarbon group, usually having from 3 to 10 carbon atoms, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • Cycloalkylene refers to a divalent cycloalkyl group wherein cycloalkyl is as defined above.
  • Aryl means a monovalent aromatic hydrocarbon radical having a monocyclic or fused ring, usually having from 6 to 10 carbon atoms, and non-limiting examples include phenyl, naphthalen-1-yl or naphthalen-2-yl.
  • Arylene means a divalent aryl group wherein the aryl group is as defined above.
  • Heteroaryl means a monovalent aryl group having a single ring or two fused rings and containing at least one hetero atom selected from N, O or S in the ring, usually having an atomic composition of 5 to 8 members, Non-limiting examples include pyrrolyl, imidazolyl, thiazolyl, thienyl, furyl, pyrazolyl, isoxazolyl, oxazolyl, pyridyl or pyrazinyl.
  • Heteroarylene means a divalent heteroaryl group wherein the definition of heteroaryl is as described above.
  • Carbocyclyl means a saturated or unsaturated aromatic or non-aromatic ring.
  • the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered tricyclic ring system.
  • the ring group may be attached to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-alkenyl , 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, Cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, phenyl, naphthyl,
  • Heterocyclyl means a saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic, 4 to 12 membered bicyclic or 10 to 15 membered tricyclic system, and It contains 1 to 4 hetero atoms selected from N, O or S, preferably a 3 to 8 membered heterocyclic group, and N, S which are optionally substituted in the ring of the heterocyclic group can be oxidized to various oxidation states.
  • the heterocyclic group may be bonded to a hetero atom or a carbon atom, and the heterocyclic group may be bonded to a bridged or spiro ring, and non-limiting examples include an epoxyethyl group, a glycidyl group, an azacyclopropyl group, and an oxocyclic ring.
  • ⁇ -adrenergic receptor binding group refers to a group capable of binding to a ⁇ -adrenergic receptor; for example, see review article “ ⁇ -adrenergic receptors in Comprehensive Medicinal Chemistry, 1990, BEMain, p187 (Pergamon Press) ".
  • the above-mentioned groups are also described, for example, in WO/2005092841, US/20050215542, WO/2005070872, WO/2006023460, WO/2006051373, WO/2006087315 and WO/2006032627.
  • amino protecting group refers to a group for amino protection which is useful for protecting an amino group such that the amino group does not undergo a chemical reaction, but the group is readily removed after completion of the desired chemical reaction in other portions of the molecule.
  • Protective Groups In Organic Synthesis (third edition), Theodora W. Green and Peter The chapter on the protection of amino groups in GMWuts gives a detailed description of the amino protecting group.
  • Amino protecting group includes, but is not limited to, the following groups: benzyl, p-methoxybenzyl, trityl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2 , 2-trichloroethoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, trifluoroacetyl, acetyl or benzoyl.
  • alkyl group optionally substituted by F means that the alkyl group may, but need not, be substituted by F, indicating a case where the alkyl group is substituted by F and a case where the alkyl group is not substituted by F.
  • “Pharmaceutical composition” means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt thereof, with other components, wherein the other components comprise physiologically/pharmaceutically acceptable carriers and excipients.
  • Carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound.
  • excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, Granules, lubricants, binders, disintegrators, and the like.
  • Prodrug means a compound that can be converted to a biologically active compound of the invention under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds of the invention which can be removed by conventional procedures or in vivo to provide the parent compound.
  • Stepoisomer refers to isomers produced by the different arrangement of atoms in a molecule in space, including cis-trans Isomers, enantiomers and conformers.
  • Effective dose refers to an amount of a compound that causes a physiological or medical translation of a tissue, system or subject, which amount is sought, and includes one or more of the conditions or conditions sufficient to prevent treatment when administered to a subject. The amount of a compound that occurs or reduces it to some extent.
  • Solvate means a compound of the invention or a salt thereof, which also includes a stoichiometric or non-stoichiometric amount of solvent bound by intermolecular non-covalent forces.
  • solvent is water, it is a hydrate.
  • IC 50 refers to the half-inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) NMR instrument and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD).
  • the internal standard is tetramethylsilane (TMS).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • reaction was carried out under a nitrogen atmosphere.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature.
  • the room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.
  • TBS is tert-butyldimethylsilyl.
  • Boc is a tert-butyloxycarbonyl group.
  • TFA is trifluoroacetic acid.
  • HATU is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (CAS: 148893-10-1).
  • Step 5 [7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H) -quinoline-5- Ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]indol-2-yl]2- Hydroxy-2,2-bis(2-thienyl)acetate (1H)
  • Dichloromethane (50 mL) was added to the reaction mixture, and the mixture was adjusted to pH 9 with a saturated sodium hydrogen carbonate solution, and then extracted with dichloromethane (30 mL ⁇ 2), and the organic phase was combined with saturated aqueous sodium chloride (30 mL ⁇ 1) The mixture was washed with anhydrous sodium sulfate and filtered and evaporated.
  • N-(2-Chloro-4-formyl-5-methoxyphenyl)acrylamide (1E) (0.648 g, 2.71 mmol) was dissolved in 2-methyltetrahydrofuran (10 mL).
  • Spiro[3,5]decane-2-yl N-(2-phenylphenyl)carbamate (2D) (0.700 g, 2.08 mmol)
  • added acetic acid (0.250 g, 4.16 mmol
  • microwave oven 100 ° C Reaction for 1 hour.
  • the reaction mixture was concentrated under reduced vacuo.
  • Step 5 [7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3,5] ⁇ Alkan-2-yl]N-(2-phenylphenyl)carbamate (2F)
  • reaction solution was poured into water (20 mL) and dichloromethane (20 mL), and then adjusted to pH 12 with 3% sodium hydroxide solution and extracted.
  • the aqueous phase was extracted with (20 mL x 2) and the organic phases were combined.
  • the organic layer was washed with EtOAc EtOAc EtOAc.
  • the third step [7-[[4-[[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]carbamoyloxy]ethyl]-7-azaspiro[3.5] ⁇ -alkyl-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (3D)
  • the reaction solution was added with dichloromethane (50 mL), and a saturated sodium hydrogen carbonate solution was added thereto to adjust the pH to about 8 and extracted.
  • the aqueous phase was extracted with dichloromethane (50 mL ⁇ 1) and combined The organic phase. The organic layer was washed with aq.
  • Methyl 5-(methylamino)pentanoate (5C) (5.9 g, 40.0 mmol) and acrylic acid (1.44 g, 20.0 mmol) were dissolved in dichloromethane (25 mL), and 2-(7-azobenzene) was added.
  • 2-(7-azobenzene) was added.
  • triazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, CAS: 148893-10-1) (11.4g, 30mmol), cooled to 0 ° C, added N , N-diisopropylethylamine (20.7 g, 160 mmol), and the mixture was stirred at room temperature for 3 hours.
  • Step 5 5-[3-[2-[2-Hydroxy-2,2-bis(2-thienyl)acetyl]oxy-7-azaspiro[3.5]indole-7-yl]propanoyl -methyl-amino]pentanoic acid (5F)
  • Step 7 [7-[3-[[5-(4-Formylanilide)-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-aza Spiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (5I)
  • Step 8 [7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-) Oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3 oxo-propyl]-7-nitrogen Heterospiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (5K)
  • Step 9 [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2 -hydroxy-2,2-bis(2-thienyl) acetate; ditrifluoroacetate (compound 5)
  • Step 2 [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine) -8-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane 2-yl]2-hydroxy-2,2-bis(2-thienyl) acetate; ditrifluoroacetate (compound 6)
  • Example 7 [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazole- 7-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane- 2-yl]-2-hydroxy-2,2-bis(2-thienyl) acetate; ditrifluoroacetate (compound 7)
  • Example 8 [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]aniline]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]N- (2-phenylphenyl)carbamate; ditrifluoroacetate (compound 8)
  • Step 6 [7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-) Oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7- Azaspiro[3.5]decane-2-yl]N-(2-phenylphenyl)carbamate (8F)
  • Step 7 [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]aniline]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]N- (2-phenylphenyl)carbamate; ditrifluoroacetate (compound 8)
  • the aqueous solution of sodium chloride 50 mL ⁇ 1 was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 2 [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine) -8-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane 2-yl]N-(2-phenylphenyl)carbamate; ditrifluoroacetate (compound 9)
  • Example 10 [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazole- 7-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane- 2-yl]N-(2-phenylphenyl)carbamate; ditrifluoroacetate (compound 10)
  • Example 12 [7-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]-2-cyclopentyl-2- Hydroxy-2-(2-thienyl) acetate; ditrifluoroacetate (compound 12)
  • Step 5 [7-[3-(2-Chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]decane- 2-yl]2-cyclopentyl-2-hydroxy-2-(2-thienyl)acetate (12F)
  • N-(2-Chloro-4-formyl-5-methoxy-phenyl)prop-2-enamide (1E) (0.247 g, 2.03 mmol) was dissolved in 2-methyltetrahydrofuran (30 mL).
  • 7-azaspiro[3.5]decane-2-yl 2-cyclopentyl-2-hydroxy-2-(2-thienyl) acetate (12E) (0.300 g, 0.858 mmol)
  • triethyl Amine (0.174 g, 1.72 mmol) was reacted at 100 ° C for 1 hour.
  • Step 6 [7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H) -quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane -2-yl]2-cyclopentyl-2-hydroxy-2-(2-thienyl) acetate (12G)
  • Step 7 [7-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-7-azaspiro[3.5]decan-2-yl]2-cyclopentyl-2-hydroxyl -2-(2-thienyl) acetate; ditrifluoroacetate (compound 12)
  • the reaction liquid was added with water (20 mL) and dichloromethane (20 mL), and the pH was adjusted to about 12 by adding 3% sodium hydroxide solution, and the layers were separated, and the aqueous phase was extracted with dichloromethane (20 mL ⁇ 2), and the organic phase was combined and saturated.
  • the aqueous solution of sodium chloride (20 mL ⁇ 1) was washed with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • Example 13 [7-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2- Hydroxy-2-phenyl-acetate; ditrifluoroacetate (compound 13)
  • aqueous phase was extracted with ethyl acetate (50 mL ⁇ 1) and organic phases were combined.
  • the organic phase was dried over anhydrous sodium sulfate and filtered and evaporated.
  • the residue was purified by silica gel column chromatography (ethyl acetate: EtOAc (EtOAc:EtOAc) tert-Butyl ester of acetyl)oxy-7-azaspiro[3.5]decane-7-carboxylate (13D) as a colorless oil (2.4 g, yield 51%).
  • Step 5 [7-[3-(2-Chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]decane- 2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13F)
  • Step 6 [7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H) -quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane -2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13G)
  • Step 7 [7-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2- Hydroxy-2-phenyl-B Acid ester; ditrifluoroacetate (compound 13)
  • the reaction solution was added with a 10% (v/v) methanol/methylene chloride solution (50 mL), and a saturated aqueous sodium hydrogencarbonate solution was added to adjust the pH to about 8 and extracted.
  • the aqueous phase was extracted with a 10% (v/v) methanol/dichloromethane solution (50 mL ⁇ 2).
  • the organic layer was washed with brine (20 mL ⁇ 1).
  • Example 14 [7-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2- Hydroxy-2-phenyl- Acetate; isomer 1 of ditrifluoroacetate (compound 13)
  • the fourth step [7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2- Hydroxy-2-phenyl-acetate; isomer 1 of ditrifluoroacetate (compound 13)
  • the acid salt (1.8 g, 11 mmol) was reacted at room temperature for 24 hours.
  • the reaction solution was added with a 10% (v/v) methanol/methylene chloride solution (50 mL), and a saturated aqueous sodium hydrogencarbonate solution was added to adjust the pH to about 8 and extracted.
  • the aqueous phase was extracted with a 10% (v/v) methanol/dichloromethane solution (50 mL ⁇ 2).
  • the organic layer was washed with brine (20 mL ⁇ 1).
  • Example 15 [7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2- Hydroxy-2-phenyl-acetate; isomer 2 of ditrifluoroacetate (compound 13)
  • the fourth step [7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2- Hydroxy-2-phenyl-acetate; isomer 2 of ditrifluoroacetate (compound 13)
  • the acid salt (1.8 g, 11 mmol) was reacted at room temperature for 24 hours.
  • the reaction solution was added with a 10% (v/v) methanol/methylene chloride solution (50 mL), and a saturated aqueous sodium hydrogencarbonate solution was added to adjust the pH to about 8 and extracted.
  • the aqueous phase was extracted with a 10% (v/v) methanol/dichloromethane solution (50 mL ⁇ 2).
  • the organic layer was washed with brine (20 mL ⁇ 1).
  • Methyl 3-aminobenzoate (16A) (10.0 g, 66.2 mmol) was dissolved in N,N-dimethylformamide (150 mL), potassium carbonate (13.7 g, 99.2 mmol) Methyl iodide (9.39 g, 66.2 mmol) was reacted at room temperature for 3 hours after the addition. Filtration, the residue was washed with ethyl acetate (50 mL), and the filtrate was collected. Water (100 mL), and ethyl acetate (200 mL ⁇ 2), and the organic phase was combined and washed with saturated sodium chloride solution (100 mL ⁇ 2). The residue was dried over sodium sulfate (MgSO4). Methyl (methylamino)benzoate (16B), light yellow oil (3.85 g, yield 35.2%).
  • Methyl 3-(methylamino)benzoate (16B) (0.500 g, 3.03 mmol) was dissolved in dichloromethane (5 mL), sodium hydrogen carbonate (0.509 g, 6.05 mmol) To 0 ° C, acryloyl chloride (0.411 g, 4.54 mmol) was added dropwise, and the mixture was warmed to room temperature for 30 minutes. The organic layer was washed with a saturated sodium chloride solution (10 mL ⁇ 1), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified (jjjjjjjjj Methyl 2-enoyl)aminobenzoate (16C), colourless oil (0.569 g, yield: 85.7%).
  • Step 5 [7-[3-[3-[[4-(1,3-dioxolan-2-yl)phenyl]carbamoyl]-N-methylaniline]-3-oxo -propyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (16F)
  • Step 7 [7-[3-[3-[[4-[[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2) -oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-nitrogen Heterospiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (16H)
  • Step 8 [7-[3-[3-[[4-[[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2- Hydroxy-2,2-bis(2-thienyl) acetate; ditrifluoroacetate (compound 16)
  • the reaction supernatant was poured off, the remaining viscous material was washed with tetrahydrofuran (20 mL), and the supernatant was poured off.
  • Example 17 [7-[3-[4-[[4-[[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Aminomethyl]phenyl]carbamoyl]-N-methylanilino]-3-oxopropyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2, 2-bis(2-thienyl) acetate; ditrifluoroacetate (compound 17)
  • Methyl 4-aminobenzoate (17A) (10.0 g, 66.2 mmol) was dissolved in N,N-dimethylformamide (150 mL), potassium carbonate (13.7 g, 99.2 mmol) Methyl iodide (9.39 g, 66.2 mmol) was reacted at room temperature for 3 hours after the addition. Filtration, the residue was washed with ethyl acetate (50 mL), and the filtrate was collected. Water (100 mL), ethyl acetate (200 mL ⁇ 2), and the organic phase was combined. The organic phase was washed with saturated sodium chloride solution (100 mL ⁇ 2). The residue was dried over sodium sulfate (MgSO4). Methyl (methylamino)benzoate (17B), white solid (4.80 g, yield 43.9%).
  • Step 7 [7-[3-[4-[[4-[[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2) -oxo-1H-quinolin-5-yl)ethyl]aminomethyl]phenyl]carbamoyl]-N-methylaniline]-3-oxopropyl]-7-azaspiro[3.5 ]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (17H)
  • Step 8 [7-[3-[4-[[4-[[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Aminomethyl]phenyl]carbamoyl]-N-methylanilino]-3-oxopropyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2, 2-bis(2-thienyl) acetate; ditrifluoroacetate (compound 17)
  • Step 5 [7-[[4-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethylmethylcarbamoyl]phenyl]methyl]-7-azaspiro[3.5]decane-2-yl]N-(2-benzene Oxyphenyl)carbamate (18E)
  • the sixth step [7-[[4-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino] Ethylmethylcarbamoyl]phenyl]methyl]-7-azaspiro[3.5]decane-2-yl]N-(2-phenoxyphenyl)carbamate; ditrifluoroethyl Acid salt (compound 18)
  • Test Example 1 Inhibitory activity against human muscarinic M3 receptor
  • CHO cells PerkinElmer, ES-212-AF stably expressing human muscarinic receptor 3 (hM3) and apo-Aequorin were cultured in 10% fetal bovine serum (FBS) (Gibico 10099-141), 400 ⁇ g/mL G418 (sigma G5013) and 250 ⁇ g/mL Zeocin (invivogen ant-zn-5p) in Ham'S F12 medium (Invitrogen 12500-062), cultured at 37 ° C, 5% CO 2 to achieve 90-100% confluence.
  • FBS fetal bovine serum
  • G418 Sigma G5013
  • Zeocin invivogen ant-zn-5p
  • the cells were washed with PBS/5 mM EDTA, collected by centrifugation, resuspended in 0.1% BSA (BOVOGEN BSAS 100) phenol red-free Ham's F12 medium (Invitrogen 11039-021) and counted, and the cell concentration was adjusted to 1 ⁇ 10 6 cells/mL. . 15 ml of the cell suspension was added to a 50 mL centrifuge tube and Coelenterazine-h (promega S2011) was added to a final concentration of 5 ⁇ M. It was wrapped in tin foil and protected from light and incubated for 4 hours at 20 ° C in a rotary shaker.
  • the cells were diluted with 0.1% BSA/phenol red-free Ham's F12 medium to a final concentration of 5.0 ⁇ 10 5 cells/mL, and the cells were placed on a rotary shaker at low speed and incubated at room temperature for at least 1 hour.
  • the compound of the example was prepared as a 10 mM mother liquor in DMSO, diluted with 0.1% BSA/phenol red free Ham's F12 medium (log (M): -7, -8, -9, -10, -11), and added to a 96-well plate. 50L per hole. An additional 50 L of cell suspension (25,000 cells/well) was added to each well and incubated for 15 minutes at room temperature.
  • the 96-well plate was placed in a microplate reader (Perkin Elmer, Envision), and 50 L of acetylcholine chloride (Sigma A6625) solution was added to each well of the microplate reader at a concentration of 112.92 nM (hM3), and the luminescence was recorded for 20 seconds.
  • the IC 50 was calculated and analyzed using origin 7.5.
  • the inhibitory activity of the muscarinic receptor of the compound of the present invention was measured by the above experiment, and the measured IC 50 values are shown in Table 1 below.
  • Example number hM3 receptor IC 50 (nM) Compound 1 2.97 Compound 3 3.25 Compound 5 0.44 Compound 6 0.70 Compound 7 0.75 Compound 8 1.34 Compound 9 0.60 Compound 10 1.63 Compound 11 5.75 Compound 16 2.04 Compound 17 1.39
  • the compounds of the present invention have significant inhibitory activity against the human muscarinic M3 receptor.
  • Test Example 2 Agonistic activity on human adrenergic ⁇ 2 receptor
  • the agonistic activity of the example compounds on human adrenergic receptors was determined by LANCE Ultra cAMP Assay.
  • CHO cells PerkinElmer, ES-034-CF stably expressing human adrenergic receptor (h ⁇ 2) were cultured in 10% fetal bovine serum (FBS) (Gibico 10099-141) and 250 ⁇ g/mL Zeocin (InvivoGen ant-zn) -5p) MEM-alpha medium (Invitrogen 12561-056), cultured at 37 ° C, 5% CO 2 , 90-100% confluence, and assayed with LANCE Ultra cAMP Assay kit (PerkinElmer TRF0263) The agonistic effect of cAMP.
  • FBS fetal bovine serum
  • MEM-alpha medium Invitrogen 12561-056
  • the cells were separated by PBS/5 mM EDTA, collected by centrifugation, and the cells were resuspended with Stimulation Buffer (1 x HBSS, 5 mM HEPES, 0.5 mM IBMX, 0.1% BSA, pH 7.4), and the cell concentration was adjusted to 6 ⁇ 10 5 cells/ml.
  • Stimulation Buffer (1 x HBSS, 5 mM HEPES, 0.5 mM IBMX, 0.1% BSA, pH 7.4
  • the compound of the Example was prepared as a 10 mM stock solution in DMSO, diluted with a Stimulation Buffer gradient, and added to a 384-well plate at 5 ⁇ l per well.
  • the compounds of the invention have significant agonistic activity on the ⁇ 2 adrenergic receptor.
  • Test Example 3 Methotrexate-induced inhibition of bronchial contraction in guinea pigs
  • test compound Eight-week old male guinea pigs were purchased in Vitalivic, and the experiment was started after 3 days of adaptation.
  • the test compound was formulated into a 0.6 mM stock solution using 83% absolute ethanol + 17% Tween 80. It was diluted 500 times with water before administration. Before administration, use The small animal anesthesia machine (Matrx; VME2) was given an anesthetized animal with 5% isoflurane for an anesthesia time of 1.5 to 2 minutes.
  • the guinea pigs were fixed on an tracheal intubation operating platform and intratracheally administered using a rat liquid aerosol administration kit (penn-century; MSA-250-R), and each guinea pig was administered with a volume of 250 ⁇ l.
  • the guinea pig enhanced exhalation pause (PenH) value was measured using a full volume oximeter (DSI; GS220A12-R7B) at 4 hours and 24 hours.
  • 3 mg/ml methacholine (Mch) was administered by nebulization, the atomization time was 36 seconds, and the recording time was 7 minutes. Calculate the PenH average. (Reference J Pharmacol Exp Ther 345: 260-270.).
  • the experimental results are shown in Table 3.
  • the compound of the present invention has a better inhibitory effect on methacholine-induced bronchial contraction in guinea pigs than the positive control, and still has a good bronchoconstriction inhibitory effect after 24 hours of administration.

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Abstract

A compound shown in a general formula (I) or a stereoisomer, a hydrate, a metabolic product, a solvate, salt which is pharmaceutically receivable, eutectic crystals or a prodrug thereof, a preparation method therefor and application therefof in preparing a medicine for treating an airway obstructive disease. The compound in a general formula (I) is as shown in the general formula (I), wherein a definition of each substituent group is consistent with that in the description.

Description

具有β2受体激动及M受体拮抗活性的含氮杂螺环衍生物及其在医药上的用途Nitrogen-containing heterospirocyclic derivatives having β2 receptor agonism and M receptor antagonistic activity and their use in medicine 技术领域Technical field
本发明涉及一种含氮杂螺环衍生物及其制备方法和在医药上的应用，具体是一种具有蕈毒碱受体拮抗和β2-肾上腺素能受体激动的双重活性的新颖含氮杂螺环衍生物或其立体异构体、水合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药、其药物组合物以及其在医药上的应用。The invention relates to a nitrogen-containing heterospirocyclic derivative, a preparation method thereof and the use thereof in medicine, in particular to a novel containing double activity of muscarinic receptor antagonism and β 2 -adrenergic receptor agonism Azaspirocyclic derivatives or stereoisomers, hydrates, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof, pharmaceutical compositions thereof, and their use in medicine.
背景技术Background technique
支气管扩张剂对于呼吸疾病例如慢性阻塞性肺疾病(COPD)及哮喘等的治疗起重要作用。临床中广泛使用的支气管扩张剂包括蕈毒碱受体拮抗剂和β2-肾上腺素能激动剂。蕈毒碱受体拮抗剂通过降低气道平滑肌的迷走神经胆碱能水平来发挥支气管扩张的效力。目前所使用的吸入蕈毒碱受体拮抗剂包括异丙托溴铵、氧托溴铵、格隆溴铵、噻托溴铵、阿地溴胺和芜地溴胺。β2-肾上腺素能激动剂通过刺激气道平滑肌的肾上腺素能受体而使支气管扩张，逆转支气管收缩剂对各种介质如乙酰胆碱的反应。目前所使用的β2-肾上腺素能激动剂包括沙丁胺醇、沙美特罗、阿福特罗、福美特罗、维兰特罗和茚达特罗。这些药物除了改善肺的功能，也可改善患者生活质量并减少病情恶化。Bronchodilators play an important role in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma. Bronchodilators in clinical use include widely muscarinic receptor antagonist and β 2 - adrenergic agonist. A muscarinic receptor antagonist exerts potency in bronchodilation by reducing the level of vagal cholinergic energy in airway smooth muscle. Inhaled muscarinic receptor antagonists currently used include ipratropium bromide, oxitropium bromide, glycopyrrolate, tiotropium bromide, adiponium bromide and indole bromide. 2 2 -adrenergic agonists bronchodilate by stimulating adrenergic receptors in airway smooth muscle, reversing the response of bronchoconstrictors to various mediators such as acetylcholine. The β 2 -adrenergic agonists currently used include albuterol, salmeterol, arformoterol, formoterol, vilantrol and indacaterol. In addition to improving lung function, these drugs can improve the quality of life of patients and reduce the deterioration of their condition.
随着更多的临床研究发现，证明联合使用蕈毒碱受体拮抗剂和β2-肾上腺素能激动剂比单独使用其中一种治疗剂更有效，目前临床上将蕈毒碱受体拮抗剂和β2-肾上腺素能激动剂制备成复方制剂，用于哮喘和中重度COPD的治疗，这类复方制剂主要包括Anoro Ellipta(芜地溴胺/维兰特罗)、Ultibro Breezhaler(格隆溴铵/茚达特罗)和异丙托溴胺/沙丁胺醇等。虽然复方制剂比其中单一制剂具有更好的治疗效果，但是在制剂制备上有更高的要求。As more clinical studies have found that the combination of muscarinic receptor antagonists and β 2 -adrenergic agonists is more effective than the use of one of the therapeutic agents alone, the current prion base receptor antagonists And β 2 -adrenergic agonists are prepared as a combination preparation for the treatment of asthma and moderate to severe COPD. These compound preparations mainly include Anoro Ellipta (Ambroxol/Vylantro) and Ultibro Breezhaler (Glon Brom). Ammonium / indacaterol) and ipratropium bromide / salbutamol. Although the combination preparation has a better therapeutic effect than the single preparation, there is a higher requirement in the preparation of the preparation.
因此，人们希望开发同时具有蕈毒碱受体拮抗和β2-肾上腺素能激动双重作用的药物，这种双功能药物具有两种成分组合的药学优点，同时具备单一的分子药代动力学。这些化合物以单一治疗剂的形式给药，可以由两种不同且可能协同起效的作用模式提供支气管扩张作用。另外，具有蕈毒碱受体拮抗和β2-肾上腺素能激动双重作用(MABA)的化合物还可以与皮质类固醇(ICS)消炎剂药物组合，形成两种治疗剂(MABA/ICS)而提供三重作用的治疗效果(Expert Opin.Investig.Drugs(2014)23(4):453-456)。Therefore, it is desirable to develop while having muscarinic receptor antagonist and β 2 - adrenergic agonists dual-acting drugs, drugs with this dual function the advantages of both pharmaceutical ingredient combination, along with a single molecule pharmacokinetics. These compounds are administered as a single therapeutic agent and can provide bronchodilation by two different and possibly synergistic modes of action. In addition, compounds with muscarinic receptor antagonism and β 2 -adrenergic agonistic dual action (MABA) can also be combined with corticosteroid (ICS) anti-inflammatory drugs to form two therapeutic agents (MABA/ICS) to provide triple Therapeutic effect of action (Expert Opin. Investig. Drugs (2014) 23(4): 453-456).
因此，有必要开发新颖的同时具有蕈毒碱受体拮抗和β2-肾上腺素能激动的双重活性药物，以提供更有效的单一治疗剂量或者复方制剂，为患者提供更多的临床用药选择。Therefore, it is necessary to develop novel dual active drugs with both muscarinic receptor antagonism and β 2 -adrenergic agonism to provide more effective single therapeutic doses or combination preparations, providing patients with more clinical drug options.
发明内容Summary of the invention
本发明提供一种通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，The present invention provides a compound represented by the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof.
Figure PCTCN2016081809-appb-000001
Figure PCTCN2016081809-appb-000001
其中：among them:
R1选自
Figure PCTCN2016081809-appb-000002
R 1 is selected from
Figure PCTCN2016081809-appb-000002
R1a选自H、C2-6烯基、C2-6炔基、C3-10碳环基、3至8元杂环基、C3-10碳环基-C1-4亚烷基或3至8元杂环基-C1-4亚烷基，所述烯基、炔基、亚烷基、碳环基或杂环基任选进一步被0、1、2、3或4个选自F、Cl、Br、I、CH2F、CHF2、CF3、OH、OCH2F、OCHF2、OCF3、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基、-O(＝O)C1-4烷基、-(＝O)C1-4烷基、-OC3-6环烷基或C1-4烷硫基的取代基所取代，所述杂环基含有1、2或3个选自N、O或S的杂原子；R 1a is selected from the group consisting of H, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3 to 8 membered heterocyclic, C 3-10carbocyclyl -C 1-4 alkylene Or a 3 to 8 membered heterocyclyl-C 1-4 alkylene group, optionally substituted by 0, 1, 2, 3 or 4, or an alkenyl, alkynyl, alkylene, carbocyclic or heterocyclic group Selected from F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, OCH 2 F, OCHF 2 , OCF 3 , NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl , C 1-4 alkoxy, -O(=O)C 1-4 alkyl, -(=O)C 1-4 alkyl, -OC 3-6 cycloalkyl or C 1-4 alkylthio Substituted by a substituent containing 1, 2 or 3 heteroatoms selected from N, O or S;
R1b选自C2-6烯基、C2-6炔基、C3-10碳环基、3至8元杂环基、C3-10碳环基-C1-4亚烷基或3至8元杂环基-C1-4亚烷基，所述烯基、炔基、亚烷基、碳环基或杂环基任选进一步被0、1、2、3或4个选自F、Cl、Br、I、CH2F、CHF2、CF3、OH、OCH2F、OCHF2、OCF3、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基、-O(＝O)C1-4烷基、-(＝O)C1-4烷基、-OC3-6环烷基或C1-4烷硫基的取代基所取代，所述杂环基含有1、2或3个选自N、O或S的杂原子；R 1b is selected from C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3 to 8 membered heterocyclic, C 3-10carbocyclyl -C 1-4 alkylene or a 3- to 8-membered heterocyclyl-C 1-4 alkylene group, which is optionally further selected from 0, 1, 2, 3 or 4 From F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, OCH 2 F, OCHF 2 , OCF 3 , NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C Substitution of 1-4 alkoxy, -O(=O)C 1-4 alkyl, -(=O)C 1-4 alkyl, -OC 3-6 cycloalkyl or C 1-4 alkylthio Substituted, the heterocyclic group containing 1, 2 or 3 hetero atoms selected from N, O or S;
R1c选自H、羟基、氰基、NH2、C1-6烷基、C1-6烷氧基、C1-6烷硫基或-C(＝O)NH2，所述NH2、-C(＝O)NH2或烷基任选进一步被0、1或2个选自F、Cl、Br、I、羟基、氰基或C1-4烷基的取代基所取代；R 1c is selected from H, hydroxy, cyano, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or -C(=O)NH 2 , said NH 2 , -C(=O)NH 2 or an alkyl group is optionally further substituted with 0, 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, cyano or C 1-4 alkyl;
M选自键、-CH2-、-CH2CH2-、-O-、-S-、-OCH2-、-SCH2-或-CH＝CH-；M is selected from the group consisting of a bond, -CH 2 -, -CH 2 CH 2 -, -O-, -S-, -OCH 2 -, -SCH 2 - or -CH=CH-;
R1d选自H、羟基、-CH2OH或C1-4烷基；R 1d is selected from H, hydroxy, -CH 2 OH or C 1-4 alkyl;
R1e和R1f各自独立选自F、Cl、Br、I、CF3、NH2、OH、羧基、氰基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、-NHC1-4烷基、-N(C1-4烷基)2、-S(＝O)-C1-4烷基、-S(＝O)2-C1-4烷基或-C(＝O)O-C1-4烷基；R 1e and R 1f are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , NH 2 , OH, carboxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkane Thio group, -NHC 1-4 alkyl group, -N(C 1-4 alkyl) 2 , -S(=O)-C 1-4 alkyl group, -S(=O) 2 -C 1-4 alkane Or a -C(=O)OC 1-4 alkyl group;
环A和环C各自独立选自C6-10碳环或5至10元杂环，所述碳环或杂环任选进一步被0、1、2、3或4个选自F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代，且所 述杂环含有1、2或3个选自N、O或S的杂原子；Ring A and Ring C are each independently selected from a C 6-10 carbocyclic ring or a 5 to 10 membered heterocyclic ring, which is optionally further 0, 1, 2, 3 or 4 selected from F, Cl, Substituted with a substituent of Br, I, C 1-4 alkyl or C 1-4 alkoxy, and the heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S;
R2选自键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基，所述亚烷基、亚烯基或亚炔基任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、OH、氰基、C1-4烷基、C1-4烷氧基、苯基或苯基-C1-4亚烷基的取代基所取代；R 2 is selected from a bond, a C 1-6 alkylene group, a C 2-6 alkenylene group or a C 2-6 alkynylene group, and the alkylene group, alkenylene group or alkynylene group is optionally further further 0, 1 , 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 Substituted by a substituent of an alkyl group;
L选自键或
Figure PCTCN2016081809-appb-000003
且Y直接与R2相连接；L is selected from the key or
Figure PCTCN2016081809-appb-000003
And Y is directly connected to R 2 ;
R3选自键或C1-6亚烷基，所述亚烷基任选进一步被0、1、2、3、4或5个选自R3a的取代基所取代；R 3 is selected from a bond or a C 1-6 alkylene group, which is optionally further substituted with 0, 1 , 2, 3, 4 or 5 substituents selected from R 3a ;
并且R2、L和R3三者不能同时为键；And R 2 , L and R 3 cannot be simultaneously a bond;
R4、R5各自独立的选自H或C1-4烷基；R 4 and R 5 are each independently selected from H or C 1-4 alkyl;
Figure PCTCN2016081809-appb-000004
表示β-肾上腺素受体结合基团；
Figure PCTCN2016081809-appb-000004
Representing a β-adrenergic receptor binding group;
R3a选自F、Cl、Br、I、氰基、OH、C1-4烷基、C1-4烷氧基、苯基或苯基-C1-4亚烷基；R 3a is selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
作为选择，两个R3a可以与它们相连的原子一起形成一个3至6元碳环，所述碳环任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、氰基、OH、C1-4烷基或C1-4烷氧基的取代基所取代；Alternatively, two R 3a may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, said carbon ring optionally further being 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br Substituted with a substituent of I, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy;
A1和A4各自独立选自C3-7亚环烷基、C6-10亚芳基、5至8元亚杂芳基、-O-C6-10亚芳基、-O-5至8元亚杂芳基、5至8元亚杂芳基-O-或C6-10亚芳基-O-，其中所述的亚环烷基、亚芳基或亚杂芳基任选进一步被0、1、2、3、4或5个选自R6的取代基所取代；A 1 and A 4 are each independently selected from C 3-7 cycloalkylene, C 6-10 arylene, 5 to 8 membered heteroarylene, -OC 6-10 arylene, -O-5 to 8 a meta-heteroaryl group, a 5- to 8-membered heteroarylene-O- or a C 6-10 arylene-O-, wherein the cycloalkylene, arylene or heteroarylene is optionally further 0, 1, 2, 3, 4 or 5 substituents selected from R 6 are substituted;
A2和A3各自独立选自C1-6亚烷基、C2-6亚烯基或C2-6亚炔基，所述亚烷基、亚烯基或亚炔基任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、OH、氰基、C1-4烷基、C1-4烷氧基、苯基或苯基-C1-4亚烷基的取代基所取代；A 2 and A 3 are each independently selected from C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, and the alkylene, alkenylene or alkynylene group is optionally further 0, 1, 2, 3, 4 or 5 are selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1 Substituted with a substituent of -4 alkylene;
X和Y各自独立选自键、-O-、-C(＝O)O-、-OC(＝O)-、-S-、-S(＝O)-、-S(＝O)2-、-C(＝O)NR7-、-NR7C(＝O)-、-OC(＝O)NR7-、-NR7C(＝O)O-、-NR7C(＝O)NR7、-NR7S(＝O)2-、-S(＝O)2NR7-、-NR7S(＝O)2NR7或-NR7-；X and Y are each independently selected from the group consisting of a bond, -O-, -C(=O)O-, -OC(=O)-, -S-, -S(=O)-, -S(=O) 2 - , -C(=O)NR 7 -, -NR 7 C(=O)-, -OC(=O)NR 7 -, -NR 7 C(=O)O-, -NR 7 C(=O) NR 7 , -NR 7 S(=O) 2 -, -S(=O) 2 NR 7 -, -NR 7 S(=O) 2 NR 7 or -NR 7 -;
R6选自F、Cl、Br、I、OH、NH2、羧基、氰基、硝基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-OC3-6环烷基、C1-4烷硫基、-S(＝O)-C1-4烷基、-S(＝O)2-C1-4烷基、-C(＝O)-C1-4烷基、-C(＝O)O-C1-4烷基、-OC(＝O)-C1-4烷基、5至6元杂芳基或-C(＝O)NH2，所述烷基、烷氧基、环烷基、烯基、炔基、杂芳基、NH2或-C(＝O)NH2任选进一步被0、1、2、3或4个选自F、Cl、Br、I、CF3、C1-4烷基、C1-4烷氧基或 -C(＝O)-C1-4烷基的取代基所取代；R 6 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 Alkoxy, -OC 3-6 cycloalkyl, C 1-4 alkylthio, -S(=O)-C 1-4 alkyl, -S(=O) 2 -C 1-4 alkyl, -C(=O)-C 1-4 alkyl, -C(=O)OC 1-4 alkyl, -OC(=O)-C 1-4 alkyl, 5- to 6-membered heteroaryl or C(=O)NH 2 , the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, heteroaryl, NH 2 or -C(=O)NH 2 is optionally further further 0, 1, 2, 3 or 4 substituents selected from the group consisting of F, Cl, Br, I, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or -C(=O)-C 1-4 alkyl Replaced
R7各自独立选自H或C1-4烷基；R 7 is each independently selected from H or C 1-4 alkyl;
a为0、1、2、3或4；a is 0, 1, 2, 3 or 4;
b为0、1、2、3、4或5；b is 0, 1, 2, 3, 4 or 5;
m、n、p或q各自独立选自0或1。m, n, p or q are each independently selected from 0 or 1.
在本发明的具体实施方案中，在上述的通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药中，In a particular embodiment of the invention, in the above compound of the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof ,
Figure PCTCN2016081809-appb-000005
表示β-肾上腺素受体结合基团；
Figure PCTCN2016081809-appb-000005
Representing a β-adrenergic receptor binding group;
B优选选自
Figure PCTCN2016081809-appb-000006
R10、R11、R12、R13、R14、R15、R16、R17或R18各自独立的选自H、F、Cl、Br、I、CF3、OH、-CH2OH、氰基、羧基、C1-4烷基、C1-4烷氧基、-C(＝O)C1-4烷基、-C(＝O)OC1-4烷基、-NHC(＝O)H、-NHS(＝O)2-C1-4烷基、-NHS(＝O)2-NH2或-NHS(＝O)2-NHC1-4烷基，Q选自-CRq1＝CRq2-、-CRq1Rq2CRq3Rq4-、-O-、-S-、-OCRq1Rq2-、-CRq1Rq2O-、-SCRq1Rq2-、-CRq1Rq2S-，所述Rq1、Rq2、Rq3或Rq4各自独立的选自选自H、F、Cl、Br、I或C1-4烷基；B is preferably selected from
Figure PCTCN2016081809-appb-000006
R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 or R 18 are each independently selected from the group consisting of H, F, Cl, Br, I, CF 3 , OH, -CH 2 OH , cyano, carboxyl, C 1-4 alkyl, C 1-4 alkoxy, -C(=O)C 1-4 alkyl, -C(=O)OC 1-4 alkyl, -NHC ( =O)H, -NHS(=O) 2 -C 1-4 alkyl, -NHS(=O) 2 -NH 2 or -NHS(=O) 2 -NHC 1-4 alkyl, Q is selected from - CR q1 =CR q2 -, -CR q1 R q2 CR q3 R q4 -, -O-, -S-, -OCR q1 R q2 -, -CR q1 R q2 O-, -SCR q1 R q2 -, -CR Q1 R q2 S-, wherein R q1 , R q2 , R q3 or R q4 are each independently selected from the group consisting of H, F, Cl, Br, I or C 1-4 alkyl;
B更优选选自
Figure PCTCN2016081809-appb-000007
Figure PCTCN2016081809-appb-000008
其中Q选自-CH＝CH-、-CH2CH2-、-O-、-S-、-CH2O-、-OCH2-、-C(CH3)2O-或-OC(CH3)2-；More preferably, B is selected from
Figure PCTCN2016081809-appb-000007
Figure PCTCN2016081809-appb-000008
Wherein Q is selected from -CH=CH-, -CH 2 CH 2 -, -O-, -S-, -CH 2 O-, -OCH 2 -, -C(CH 3 ) 2 O- or -OC(CH) 3 ) 2 -;
B进一步优选选自
Figure PCTCN2016081809-appb-000009
Figure PCTCN2016081809-appb-000010
B is further preferably selected from
Figure PCTCN2016081809-appb-000009
Figure PCTCN2016081809-appb-000010
在本发明的优选实施方案中，在上述的通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药中，In a preferred embodiment of the present invention, in the above compound represented by the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof ,
R1选自
Figure PCTCN2016081809-appb-000011
R 1 is selected from
Figure PCTCN2016081809-appb-000011
R1a选自H、C2-4烯基、C2-4炔基、C3-7碳环基、3至6元杂环基、C3-7碳环基-C1-4亚烷基或3至6元杂环基-C1-4亚烷基，所述烯基、炔基、亚烷基、碳环基或杂环基任选进一步被0、1、2、3或4个选自F、Cl、Br、I、CF3、OH、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基、-O(＝O)C1-4烷基、-(＝O)C1-4烷基、-OC3-6环烷基或C1-4烷硫基的取代基所取代，所述杂环基含有1、2或3个选自N、O或S的杂原子；R 1a is selected from the group consisting of H, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 carbocyclyl, 3 to 6 membered heterocyclic, C 3-7 carbocyclyl-C 1-4 alkylene Or a 3- to 6-membered heterocyclyl-C 1-4 alkylene group, optionally substituted by 0, 1, 2, 3 or 4, optionally substituted with 0, 1, 2, 3 or 4 One selected from the group consisting of F, Cl, Br, I, CF 3 , OH, NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, -O(=O)C 1 Substituted by a substituent of -4 alkyl, -(=O)C 1-4 alkyl, -OC 3-6 cycloalkyl or C 1-4 alkylthio containing 1, 2 or 3 a hetero atom selected from N, O or S;
R1b选自C2-4烯基、C2-4炔基、C3-7碳环基、3至6元杂环基、C3-7碳环基-C1-4亚烷基或3至6元杂环基-C1-4亚烷基，所述烯基、炔基、亚烷基、碳环基或杂环基任选进一步被0、1、2、3或4个选自F、Cl、Br、I、CF3、OH、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基、-O(＝O)C1-4烷基、-(＝O)C1-4烷基、-OC3-6环烷基或C1-4烷硫基的取代基所取代，所述杂环基含有1、2或3个选自N、O或S的杂原子；R 1b is selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 carbocyclyl, 3 to 6 membered heterocyclic, C 3-7 carbocyclyl-C 1-4 alkylene or a 3- to 6-membered heterocyclic-C 1-4 alkylene group, which is optionally further selected from 0, 1, 2, 3 or 4 From F, Cl, Br, I, CF 3 , OH, NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, -O(=O)C 1-4 Substituted by a substituent of an alkyl group, -(=O)C 1-4 alkyl, -OC 3-6 cycloalkyl or C 1-4 alkylthio group, the heterocyclic group containing 1, 2 or 3 a hetero atom from N, O or S;
R1c选自H、羟基、氰基、NH2、C1-4烷基、C1-4烷氧基、C1-4烷硫基或-C(＝O)NH2，所述NH2、-C(＝O)NH2或烷基任选进一步被0、1或2个选自F、Cl、Br、I、羟基、氰基或C1-4烷基的取代基所取代；R 1c is selected from H, hydroxy, cyano, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio or -C(=O)NH 2 , said NH 2 , -C(=O)NH 2 or an alkyl group is optionally further substituted with 0, 1 or 2 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, cyano or C 1-4 alkyl;
环A和环C各自独立选自噻吩环、呋喃环、吡啶环或苯环，优选苯环，所述噻吩环、呋喃环、吡啶环或苯环任选进一步被0、1、2、3或4个选自F、Cl、Br、I、C1-4烷基或C1-4烷氧基的取代基所取代，优选进一步被0、1、2、3或4个选自F、Cl、Br、I、甲基、乙基、甲氧基或乙氧基的取代基所取代；Ring A and Ring C are each independently selected from the group consisting of a thiophene ring, a furan ring, a pyridine ring or a benzene ring, preferably a benzene ring, which is optionally further further 0, 1, 2, or 3 or Substituted by four substituents selected from F, Cl, Br, I, C 1-4 alkyl or C 1-4 alkoxy, preferably further selected from 0, 1, 2, 3 or 4 selected from F, Cl Substituted with a substituent of Br, I, methyl, ethyl, methoxy or ethoxy;
M选自键、-CH2-、-CH2CH2-、-O-、-S-、-OCH2-、-SCH2-或-CH＝CH-，优选选自 键、-O-或-S-；M is selected from the group consisting of a bond, -CH 2 -, -CH 2 CH 2 -, -O-, -S-, -OCH 2 -, -SCH 2 - or -CH=CH-, preferably selected from a bond, -O- or -S-;
R1d选自H、羟基、-CH2OH或C1-4烷基，优选选自H、羟基、-CH2OH、甲基、乙基或丙基；R 1d is selected from H, hydroxy, -CH 2 OH or C 1-4 alkyl, preferably selected from H, hydroxy, -CH 2 OH, methyl, ethyl or propyl;
R1e和R1f各自独立选自F、Cl、Br、I、CF3、NH2、OH、氰基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、-NHC1-4烷基或-N(C1-4烷基)2；R 1e and R 1f are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , NH 2 , OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio , -NHC 1-4 alkyl or -N(C 1-4 alkyl) 2 ;
R2选自键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基，所述亚烷基、亚烯基或亚炔基任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、OH、氰基、C1-4烷基、C1-4烷氧基、苯基或苯基-C1-4亚烷基的取代基所取代；R2优选选自键或C1-6亚烷基，所述亚烷基任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、OH、氰基、C1-4烷基或C1-4烷氧基的取代基所取代；R 2 is selected from a bond, a C 1-6 alkylene group, a C 2-6 alkenylene group or a C 2-6 alkynylene group, and the alkylene group, alkenylene group or alkynylene group is optionally further further 0, 1 , 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 Substituted by a substituent of an alkyl group; R 2 is preferably selected from a bond or a C 1-6 alkylene group, and the alkylene group is optionally further 0, 1 , 2, 3, 4 or 5 selected from F, Cl, Substituted by a substituent of Br, I, OH, cyano, C 1-4 alkyl or C 1-4 alkoxy;
R3选自键或C1-6亚烷基，所述亚烷基任选进一步被0、1、2、3、4或5个选自R3a的取代基所取代；R3优选选自键或C1-6亚烷基，所述亚烷基任选进一步被0、1、2、3、4或5个选自R3a的取代基所取代；R 3 is selected from a bond or a C 1-6 alkylene group, which is optionally further substituted with 0, 1 , 2, 3, 4 or 5 substituents selected from R 3a ; R 3 is preferably selected from a bond or a C 1-6 alkylene group, which is optionally further substituted with 0, 1 , 2, 3, 4 or 5 substituents selected from R 3a ;
L选自键或
Figure PCTCN2016081809-appb-000012
且Y直接与R2相连接；L is selected from the key or
Figure PCTCN2016081809-appb-000012
And Y is directly connected to R 2 ;
并且R2、L和R3三者不能同时为键；And R 2 , L and R 3 cannot be simultaneously a bond;
R4、R5各自独立的选自H或C1-4烷基；R 4 and R 5 are each independently selected from H or C 1-4 alkyl;
B选自
Figure PCTCN2016081809-appb-000013
Figure PCTCN2016081809-appb-000014
B is selected from
Figure PCTCN2016081809-appb-000013
Figure PCTCN2016081809-appb-000014
其中Q选自-CH＝CH-、-CH2CH2-、-O-、-S-、-CH2O-、-OCH2-、-C(CH3)2O-或-OC(CH3)2-；Wherein Q is selected from -CH=CH-, -CH 2 CH 2 -, -O-, -S-, -CH 2 O-, -OCH 2 -, -C(CH 3 ) 2 O- or -OC(CH) 3 ) 2 -;
R3a选自F、Cl、Br、I、氰基、OH、C1-4烷基、C1-4烷氧基、苯基或苯基-C1-4亚烷基；R3a优选选自F、Cl、Br、I、氰基、OH、C1-4烷基、C1-4烷氧基或苯基；R 3a is selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene; R 3a is preferably selected From F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy or phenyl;
作为选择，两个R3a可以与它们相连的原子一起形成一个3至6元碳环，所述碳环任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、氰基、OH、C1-4烷基或C1-4烷氧基的取代基所取代；Alternatively, two R 3a may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, said carbon ring optionally further being 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br Substituted with a substituent of I, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy;
A1和A4各自独立选自C3-7亚环烷基、C6-10亚芳基、5至8元亚杂芳基、-O-C6-10亚 芳基、-O-5至8元亚杂芳基、5至8元亚杂芳基-O-或C6-10亚芳基-O-，优选选自亚环戊烷基、亚环己烷基、亚苯基、亚噻吩基、亚呋喃基、亚噻唑基、亚恶唑基、亚咪唑基或亚吡啶基，其中所述的亚环烷基、亚芳基、亚杂芳基、亚环戊烷基、亚环己烷基、亚苯基、亚噻吩基、亚呋喃基、亚噻唑基、亚恶唑基、亚咪唑基或亚吡啶基任选进一步被0、1、2、3、4或5个选自R6的取代基所取代；A 1 and A 4 are each independently selected from C 3-7 cycloalkylene, C 6-10 arylene, 5 to 8 membered heteroarylene, -OC 6-10 arylene, -O-5 to 8 a meta-heteroaryl group, a 5- to 8-membered heteroarylene-O- or a C 6-10 arylene-O-, preferably selected from the group consisting of cyclopentylene, cyclohexylene, phenylene, thiophene a pyridyl group, a thiazolyl group, a oxazolyl group, an imidazolyl group or a pyridylene group, wherein the cycloalkylene group, the arylene group, the heteroarylene group, the cyclopentylene group, the cyclohexylene group The alkyl, phenylene, thienylene, furanyl, thiazolyl, oxazolyl, imidazolyl or pyridylene group is optionally further selected from 0, 1, 2, 3, 4 or 5 selected from R 6 substituents;
A2和A3各自独立选自C1-6亚烷基、C2-6亚烯基或C2-6亚炔基，优选选自C1-6亚烷，更优选选自亚甲基、亚乙基、亚丙基、亚丁基或亚戊基，所述亚烷基、亚烯基、亚炔基或亚甲基、亚乙基、亚丙基、亚丁基或亚戊基任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、OH、氰基、C1-4烷基、C1-4烷氧基、苯基或苯基-C1-4亚烷基的取代基所取代；A 2 and A 3 are each independently selected from C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, preferably selected from C 1-6 alkylene, more preferably selected from methylene. , ethylene, propylene, butylene or pentylene, said alkylene, alkenylene, alkynylene or methylene, ethylene, propylene, butylene or pentylene Further, 0, 1, 2, 3, 4 or 5 are selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl- Substituted by a substituent of a C 1-4 alkylene group;
X和Y各自独立选自键、-O-、-C(＝O)O-、-OC(＝O)-、-S-、-S(＝O)-、-S(＝O)2-、-C(＝O)NR7-、-NR7C(＝O)-、-OC(＝O)NR7-、-NR7C(＝O)O-、-NR7C(＝O)NR7、-NR7S(＝O)2-、-S(＝O)2NR7-、-NR7S(＝O)2NR7或-NR7-；X and Y are each independently selected from the group consisting of a bond, -O-, -C(=O)O-, -OC(=O)-, -S-, -S(=O)-, -S(=O) 2 - , -C(=O)NR 7 -, -NR 7 C(=O)-, -OC(=O)NR 7 -, -NR 7 C(=O)O-, -NR 7 C(=O) NR 7 , -NR 7 S(=O) 2 -, -S(=O) 2 NR 7 -, -NR 7 S(=O) 2 NR 7 or -NR 7 -;
R6各自独立选自F、Cl、Br、I、OH、NH2、羧基、氰基、硝基、C1-4烷基、C2-4炔基、C1-4烷氧基、-OC3-6环烷基、C1-4烷硫基、-S(＝O)-C1-4烷基、-S(＝O)2-C1-4烷基、-C(＝O)-C1-4烷基、5至6元杂芳基或-C(＝O)O-C1-4烷基，所述烷基、炔基、烷氧基、环烷基、杂芳基或NH2任选进一步被0、1、2、3或4个选自F、Cl、Br、I、CF3、C1-4烷基、C1-4烷氧基或-C(＝O)-C1-4烷基的取代基所取代，R6优选选自F、Cl、Br、氰基、甲基、乙基、丙基、异丙基、CHF2、CF3、甲氧基、乙氧基、-OCHF2、-OCF3、环丙基氧基、乙炔基、丙炔基、吡咯基、咪唑基、吡唑基、噻吩基、呋喃基、噻唑基或恶唑基；R 6 is each independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, - OC 3-6 cycloalkyl, C 1-4 alkylthio, -S(=O)-C 1-4 alkyl, -S(=O) 2 -C 1-4 alkyl, -C(=O -C 1-4 alkyl, 5- to 6-membered heteroaryl or -C(=O)OC 1-4 alkyl, said alkyl, alkynyl, alkoxy, cycloalkyl, heteroaryl or NH 2 is optionally further selected from 0, 1, 2, 3 or 4 selected from F, Cl, Br, I, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or -C(=O) Substituted by a substituent of -C 1-4 alkyl, R 6 is preferably selected from the group consisting of F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, CHF 2 , CF 3 , methoxy, Ethoxy, -OCHF 2 , -OCF 3 , cyclopropyloxy, ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl or oxazolyl;
R7选自H或C1-4烷基，优选选自H、甲基或乙基；R 7 is selected from H or C 1-4 alkyl, preferably selected from H, methyl or ethyl;
a为0、1、2、3或4；a is 0, 1, 2, 3 or 4;
b为0、1、2、3、4或5；b is 0, 1, 2, 3, 4 or 5;
m、n、p或q各自独立选自0或1。m, n, p or q are each independently selected from 0 or 1.
在本发明的优选实施方案中，在上述的通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药中，In a preferred embodiment of the present invention, in the above compound represented by the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof ,
R1选自
Figure PCTCN2016081809-appb-000015
R 1 is selected from
Figure PCTCN2016081809-appb-000015
R1a选自H、乙烯基、乙炔基、丙炔基、苯基、环丙烷基、环丁基、环戊基、环己基、环庚基、苯甲基、噻吩基、呋喃基或吡啶基，优选选自乙烯基、乙炔基、苯基、环丁基、环戊基、环己基、环庚基、苯甲基或噻吩基，所述的乙烯基、乙炔基、丙炔基、苯基、环丙烷基、环丁基、环戊基、环己基、环庚基、苯甲基、噻吩基、呋喃基或吡啶基任选进一步被0、1、2、3或4个选自F、Cl、Br、I、CF3、OH、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基或-O(＝O)C1-4烷基的取代基所取代；R 1a is selected from the group consisting of H, vinyl, ethynyl, propynyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, thienyl, furanyl or pyridyl , preferably selected from the group consisting of ethenyl, ethynyl, phenyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl or thienyl, said vinyl, ethynyl, propynyl, phenyl , cyclopropane, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, thienyl, furyl or pyridyl optionally further selected from 0, 1, 2, 3 or 4 selected from F, Cl, Br, I, CF 3 , OH, NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy or -O(=O)C 1-4 alkyl Substituted by a substituent;
R1b选自乙烯基、乙炔基、丙炔基、苯基、环丙烷基、环丁基、环戊基、环己基、环庚基、苯甲基、噻吩基、呋喃基或吡啶基，优选选自乙烯基、乙炔基、苯基、环丁基、环戊基、环己基、环庚基、苯甲基或噻吩基，所述的乙烯基、乙炔基、丙炔基、苯基、环丙烷基、环丁基、环戊基、环己基、环庚基、苯甲基、噻吩基、呋喃基或吡啶基任选进一步被0、1、2、3或4个选自F、Cl、Br、I、CF3、OH、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基或-O(＝O)C1-4烷基的取代基所取代；R 1b is selected from the group consisting of ethenyl, ethynyl, propynyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, thienyl, furyl or pyridyl, preferably Selected from vinyl, ethynyl, phenyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl or thienyl, said vinyl, ethynyl, propynyl, phenyl, cyclo Propane, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, thienyl, furyl or pyridyl are optionally further selected from 0, 1, 2, 3 or 4 selected from F, Cl, Substituents of Br, I, CF 3 , OH, NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy or -O(=O)C 1-4 alkyl Replaced
R1c选自H、羟基、NH2、甲基、乙基、氰基、甲胺基、二甲基胺基、甲氧基、乙氧基、-CH2OH或-C(＝O)NH2，优选选自H、羟基、NH2、甲基、乙基或甲氧基；R 1c is selected from H, hydroxy, NH 2 , methyl, ethyl, cyano, methylamino, dimethylamino, methoxy, ethoxy, -CH 2 OH or -C(=O)NH 2 , preferably selected from H, hydroxy, NH 2 , methyl, ethyl or methoxy;
M选自键、-CH2-、-CH2CH2-、-O-、-S-、-OCH2-、-SCH2-或-CH＝CH-，优选选自键、-O-或-S-；M is selected from the group consisting of a bond, -CH 2 -, -CH 2 CH 2 -, -O-, -S-, -OCH 2 -, -SCH 2 - or -CH=CH-, preferably selected from a bond, -O- or -S-;
R1d选自H、NH2、羟基、-CH2OH、甲基或乙基；R 1d is selected from the group consisting of H, NH 2 , hydroxy, -CH 2 OH, methyl or ethyl;
R1e和R1f各自独立选自F、Cl、Br、I、CF3、NH2、OH、氰基、甲基、乙基、甲氧基、乙氧基、-NHCH3或-N(CH3)2；R 1e and R 1f are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , NH 2 , OH, cyano, methyl, ethyl, methoxy, ethoxy, -NHCH 3 or -N (CH) 3 ) 2 ;
R2选自键或C1-6亚烷基，优选选自键、亚甲基、亚乙基、亚丙基、亚丁基或亚戊基，所述的C1-6亚烷基、亚甲基、亚乙基、亚丙基、亚丁基或亚戊基任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、氰基、OH、甲基、乙基、甲氧基或乙氧基的取代基所取代；R 2 is selected from a bond or a C 1-6 alkylene group, preferably selected from a bond, a methylene group, an ethylene group, a propylene group, a butylene group or a pentylene group, said C 1-6 alkylene group, The methyl, ethylene, propylene, butylene or pentylene group is further optionally 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl Substituted by a substituent of an ethyl group, a methoxy group or an ethoxy group;
R3选自键或C1-6亚烷基，优选选自键、亚甲基、亚乙基、亚丙基、亚丁基、亚戊基或
Figure PCTCN2016081809-appb-000016
所述的C1-6亚烷基、亚甲基、亚乙基、亚丙基、亚丁基、亚戊基或
Figure PCTCN2016081809-appb-000017
任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、氰基、OH、甲基、乙基、甲氧基或乙氧基的取代基所取代；R 3 is selected from a bond or a C 1-6 alkylene group, preferably selected from the group consisting of a bond, a methylene group, an ethylene group, a propylene group, a butylene group, a pentylene group or
Figure PCTCN2016081809-appb-000016
The C 1-6 alkylene group, methylene group, ethylene group, propylene group, butylene group, pentylene group or
Figure PCTCN2016081809-appb-000017
Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
L选自键或
Figure PCTCN2016081809-appb-000018
且Y直接与R2相连接；L is selected from the key or
Figure PCTCN2016081809-appb-000018
And Y is directly connected to R 2 ;
并且R2、L和R3三者不能同时为键；And R 2 , L and R 3 cannot be simultaneously a bond;
R4、R5各自独立的选自H、甲基或乙基； R 4 and R 5 are each independently selected from H, methyl or ethyl;
B选自
Figure PCTCN2016081809-appb-000019
Figure PCTCN2016081809-appb-000020
B is selected from
Figure PCTCN2016081809-appb-000019
Figure PCTCN2016081809-appb-000020
X和Y各自独立选自键、-O-、-C(＝O)NR7-、-NR7C(＝O)-、-OC(＝O)NR7-或-NR7C(＝O)O-；X and Y are each independently selected from a bond, -O-, -C(=O)NR 7 -, -NR 7 C(=O)-, -OC(=O)NR 7 - or -NR 7 C(=O )O-;
A1和A4各自独立选自亚苯基、亚环戊烷基、亚环己烷基、亚苯基、亚噻吩基、亚呋喃基、亚噻唑基、亚恶唑基、亚咪唑基或亚吡啶基，优选选自亚苯基、亚噻吩基、亚呋喃基或亚吡啶基，所述的亚苯基、亚环戊烷基、亚环己烷基、亚苯基、亚噻吩基、亚呋喃基、亚噻唑基、亚恶唑基、亚咪唑基或亚吡啶基任选进一步被0、1、2、3或4个选自F、Cl、Br、氰基、甲基、乙基、丙基、异丙基、CHF2、CF3、甲氧基、乙氧基、-OCHF2、-OCF3、乙炔基、丙炔基、吡咯基、咪唑基、吡唑基、噻吩基、呋喃基、噻唑基或恶唑基的取代基所取代；A 1 and A 4 are each independently selected from a phenylene group, a cyclopentylene group, a cyclohexylene group, a phenylene group, a thienylene group, a furylene group, a thiazolyl group, a oxazolyl group, an imidazolyl group or a pyridylene group, preferably selected from the group consisting of a phenylene group, a thienylene group, a furylene group or a pyridylene group, said phenylene group, a cyclopentylene group, a cyclohexylene group, a phenylene group, a thienylene group, The furylene group, the thiazolyl group, the oxazolyl group, the imidazolyl group or the pyridylene group are further further selected from 0, 1, 2, 3 or 4 selected from the group consisting of F, Cl, Br, cyano, methyl, ethyl , propyl, isopropyl, CHF 2 , CF 3 , methoxy, ethoxy, -OCHF 2 , -OCF 3 , ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, Substituted by a substituent of a furyl, thiazolyl or oxazolyl group;
A2和A3各自独立选自亚甲基、亚乙基、亚丙基、亚丁基或亚戊基；A 2 and A 3 are each independently selected from a methylene group, an ethylene group, a propylene group, a butylene group or a pentylene group;
R7选自H或C1-4烷基，优选选自H、甲基、乙基或丙基；R 7 is selected from H or C 1-4 alkyl, preferably selected from H, methyl, ethyl or propyl;
a为0、1、2、3或4，优选0或1；a is 0, 1, 2, 3 or 4, preferably 0 or 1;
b为0、1、2、3或4，优选0、1或2；b is 0, 1, 2, 3 or 4, preferably 0, 1 or 2;
m、n、p或q各自独立选自0或1。m, n, p or q are each independently selected from 0 or 1.
在本发明的优选实施方案中，在上述的通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药中，In a preferred embodiment of the present invention, in the above compound represented by the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof ,
R1选自
Figure PCTCN2016081809-appb-000021
Figure PCTCN2016081809-appb-000022
R 1 is selected from
Figure PCTCN2016081809-appb-000021
Figure PCTCN2016081809-appb-000022
R2选自键、亚甲基、亚乙基、亚丙基、亚丁基或亚戊基，所述的亚甲基、亚乙基、亚丙基、亚丁基或亚戊基任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、氰基、OH、甲基、乙基、甲氧基或乙氧基的取代基所取代；R 2 is selected from a bond, a methylene group, an ethylene group, a propylene group, a butylene group or a pentylene group, and the methylene, ethylene, propylene, butylene or pentylene group is optionally further 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
R2优选选自键、亚甲基、亚乙基、亚丙基、-CH2CH(CH3)-、-CH2C(CH3)2-、-C(CH3)2CH2-、-CH(CH3)CH2-、亚丁基、-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH(CH3)CH2-或亚戊基；R 2 is preferably selected from the group consisting of a bond, a methylene group, an ethylene group, a propylene group, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -C(CH 3 ) 2 CH 2 - , -CH(CH 3 )CH 2 -, butylene, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )CH 2 - or Pentylene group
R3选自键、亚甲基、亚乙基、亚丙基、亚丁基、亚戊基或
Figure PCTCN2016081809-appb-000023
所述的亚甲基、亚乙基、亚丙基、亚丁基、亚戊基或
Figure PCTCN2016081809-appb-000024
任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、氰基、OH、甲基、乙基、甲氧基或乙氧基的取代基所取代；R 3 is selected from the group consisting of a bond, a methylene group, an ethylene group, a propylene group, a butylene group, a pentylene group or
Figure PCTCN2016081809-appb-000023
The methylene, ethylene, propylene, butylene, pentylene or
Figure PCTCN2016081809-appb-000024
Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
R3优选选自键、亚甲基、亚乙基、亚丙基、-CH2CH(CH3)-、-CH2C(CH3)2-、-C(CH3)2CH2-、-CH(CH3)CH2-、亚丁基、-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH(CH3)CH2-、亚戊基或
Figure PCTCN2016081809-appb-000025
R 3 is preferably selected from the group consisting of a bond, a methylene group, an ethylene group, a propylene group, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -C(CH 3 ) 2 CH 2 - , -CH(CH 3 )CH 2 -, butylene, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )CH 2 -, Pentylene or
Figure PCTCN2016081809-appb-000025
L选自
Figure PCTCN2016081809-appb-000026
且Y直接与R2相连接；L is selected from
Figure PCTCN2016081809-appb-000026
And Y is directly connected to R 2 ;
并且R2、L和R3三者不能同时为键；And R 2 , L and R 3 cannot be simultaneously a bond;
B选自
Figure PCTCN2016081809-appb-000027
Figure PCTCN2016081809-appb-000028
B is selected from
Figure PCTCN2016081809-appb-000027
Figure PCTCN2016081809-appb-000028
R4、R5各自独立的选自H、甲基或乙基； R 4 and R 5 are each independently selected from H, methyl or ethyl;
X和Y各自独立选自键、-O-、-C(＝O)NR7-、-NR7C(＝O)-、-OC(＝O)NR7-或-NR7C(＝O)O-；X and Y are each independently selected from a bond, -O-, -C(=O)NR 7 -, -NR 7 C(=O)-, -OC(=O)NR 7 - or -NR 7 C(=O )O-;
A1和A4各自独立选自亚苯基、亚噻吩基、亚呋喃基或亚吡啶基，优选选自亚苯基，所述的亚苯基、亚噻吩基、亚呋喃基或亚吡啶基任选进一步被0、1、2、3或4个任选自F、Cl、Br、CHF2、CF3、氰基、甲基、乙基、甲氧基、乙氧基、-OCHF2、-OCF3、乙炔基、丙炔基、吡咯基、咪唑基或吡唑基的取代基所取代；A 1 and A 4 are each independently selected from a phenylene group, a thienylene group, a furylene group or a pyridylene group, preferably selected from a phenylene group, a phenylene group, a thienylene group, a furylene group or a pyridylene group. Optionally further selected from 0, 1, 2, 3 or 4, selected from the group consisting of F, Cl, Br, CHF 2 , CF 3 , cyano, methyl, ethyl, methoxy, ethoxy, -OCHF 2 , Substituted with a substituent of -OCF 3 , ethynyl, propynyl, pyrrolyl, imidazolyl or pyrazolyl;
A2和A3各自独立选自亚甲基、亚乙基、亚丙基、亚丁基或亚戊基；A 2 and A 3 are each independently selected from a methylene group, an ethylene group, a propylene group, a butylene group or a pentylene group;
R7选自H或C1-4烷基，优选选自H、甲基、乙基或丙基；R 7 is selected from H or C 1-4 alkyl, preferably selected from H, methyl, ethyl or propyl;
m、n、p或q各自独立选自0或1。m, n, p or q are each independently selected from 0 or 1.
在本发明的优选实施方案中，在上述的通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药中，所述化合物包括但不限于： In a preferred embodiment of the present invention, in the above compound represented by the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof The compound includes, but is not limited to:
Figure PCTCN2016081809-appb-000029
Figure PCTCN2016081809-appb-000029
Figure PCTCN2016081809-appb-000030
Figure PCTCN2016081809-appb-000030
本发明还提供了一种药物组合物，所述的药物组合物含有治疗有效剂量的上述通式(I)所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，以及药学上可接受的载体、稀释剂、佐剂、媒介物或赋形剂；所述的组合物还可进一步包括一种或几种其他治疗剂；优选地，其中所述其他治疗剂选自PDE4抑制剂、蕈毒碱受体拮抗剂、皮质类固醇和β-肾上腺素能受体激动剂中的一种或几种。The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the above formula (I) or a stereoisomer, hydrate, metabolite, solvate thereof, pharmaceutically An acceptable salt, eutectic or prodrug, and a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle or excipient; said composition may further comprise one or more additional therapeutic agents; Preferably, wherein the additional therapeutic agent is selected from one or more of a PDE4 inhibitor, a muscarinic receptor antagonist, a corticosteroid, and a beta-adrenergic receptor agonist.
本发明还提供了上述通式(I)所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，在制备用于治疗气道阻塞性疾病的药物中的应用，优选地，在制备用于治疗哮喘、慢性阻塞性肺疾病或支气管炎的药物中的应用。The present invention also provides the compound of the above formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, which is prepared for use in therapeutic gas The use in a medicament for obstructive diseases is preferably used in the preparation of a medicament for the treatment of asthma, chronic obstructive pulmonary disease or bronchitis.
本发明还提供了一种治疗气道阻塞性疾病的方法，所述方法包括给药上述通式(I)所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，或上述的药物组合物。The present invention also provides a method for treating an airway obstructive disease, comprising administering a compound of the above formula (I) or a stereoisomer, hydrate, metabolite, solvate thereof, pharmaceutically An acceptable salt, eutectic or prodrug, or a pharmaceutical composition as described above.
本发明还提供了一种治疗哮喘、慢性阻塞性肺疾病或支气管炎的方法，所述方法包括给药上述通式(I)所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，或上述的药物组合物。The present invention also provides a method for treating asthma, chronic obstructive pulmonary disease or bronchitis, which comprises administering a compound of the above formula (I) or a stereoisomer, hydrate, metabolite thereof, Solvate, pharmaceutically acceptable salt, co-crystal or prodrug, or a pharmaceutical composition as described above.
本发明还提供了一种制备通式(I)所示化合物或其立体异构体的中间体，该中间体选自通式(II)所示的化合物或其立体异构体：The present invention also provides an intermediate for preparing a compound of the formula (I) or a stereoisomer thereof, which is selected from the compound of the formula (II) or a stereoisomer thereof:
Figure PCTCN2016081809-appb-000031
Figure PCTCN2016081809-appb-000031
其中：among them:
R1选自
Figure PCTCN2016081809-appb-000032
R 1 is selected from
Figure PCTCN2016081809-appb-000032
R1a选自H、C2-6烯基、C2-6炔基、C3-10碳环基、3至8元杂环基、C3-10碳环基-C1-4亚烷基或3至8元杂环基-C1-4亚烷基，所述烯基、炔基、亚烷基、碳环基或杂环基任选进一步被0、1、2、3或4个选自F、Cl、Br、I、CH2F、CHF2、CF3、OH、OCH2F、OCHF2、OCF3、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基、-O(＝O)C1-4烷基、-(＝O)C1-4烷基、-OC3-6环烷基或C1-4烷硫基的取代基所取代，所述杂环基含有1至3个选自N、O或S的杂原子；R 1a is selected from the group consisting of H, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3 to 8 membered heterocyclic, C 3-10carbocyclyl -C 1-4 alkylene Or a 3 to 8 membered heterocyclyl-C 1-4 alkylene group, optionally substituted by 0, 1, 2, 3 or 4, or an alkenyl, alkynyl, alkylene, carbocyclic or heterocyclic group Selected from F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, OCH 2 F, OCHF 2 , OCF 3 , NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl , C 1-4 alkoxy, -O(=O)C 1-4 alkyl, -(=O)C 1-4 alkyl, -OC 3-6 cycloalkyl or C 1-4 alkylthio Substituted by a substituent having from 1 to 3 heteroatoms selected from N, O or S;
R1b选自C2-6烯基、C2-6炔基、C3-10碳环基、3至8元杂环基、C3-10碳环基-C1-4亚烷基或3至8元杂环基-C1-4亚烷基，所述烯基、炔基、亚烷基、碳环基或杂环基任选进一步被0、1、2、3或4个选自F、Cl、Br、I、CH2F、CHF2、CF3、OH、OCH2F、OCHF2、OCF3、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基、-O(＝O)C1-4烷基、-(＝O)C1-4烷基、-OC3-6环烷基或C1-4烷硫基的取代基所取代，所述杂环基含有1至3个选自N、O或S的杂原子；R 1b is selected from C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3 to 8 membered heterocyclic, C 3-10carbocyclyl -C 1-4 alkylene or a 3- to 8-membered heterocyclyl-C 1-4 alkylene group, which is optionally further selected from 0, 1, 2, 3 or 4 From F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, OCH 2 F, OCHF 2 , OCF 3 , NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C Substitution of 1-4 alkoxy, -O(=O)C 1-4 alkyl, -(=O)C 1-4 alkyl, -OC 3-6 cycloalkyl or C 1-4 alkylthio Substituted, the heterocyclic group containing 1 to 3 hetero atoms selected from N, O or S;
R1c选自H、羟基、氰基、NH2、C1-6烷基、C1-6烷氧基、C1-6烷硫基或-C(＝O)NH2，所述NH2、-C(＝O)NH2或烷基任选进一步被0至2个选自F、Cl、Br、I、羟基、氰基或C1-4烷基的取代基所取代；R 1c is selected from H, hydroxy, cyano, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or -C(=O)NH 2 , said NH 2 , -C(=O)NH 2 or an alkyl group is optionally further substituted with 0 to 2 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, cyano or C 1-4 alkyl;
R1e和R1f各自独立选自F、Cl、Br、I、CF3、NH2、OH、羧基、氰基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、-NHC1-4烷基、-N(C1-4烷基)2、-S(＝O)-C1-4烷基、-S(＝O)2-C1-4烷基或-C(＝O)O-C1-4烷基；R 1e and R 1f are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , NH 2 , OH, carboxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkane Thio group, -NHC 1-4 alkyl group, -N(C 1-4 alkyl) 2 , -S(=O)-C 1-4 alkyl group, -S(=O) 2 -C 1-4 alkane Or a -C(=O)OC 1-4 alkyl group;
R9选自H或者氨基保护基；R 9 is selected from H or an amino protecting group;
a为0、1、2、3或4；a is 0, 1, 2, 3 or 4;
b为0、1、2、3、4或5。b is 0, 1, 2, 3, 4 or 5.
在本发明的优选实施方案中，在上述的通式(II)所示的化合物或其立体异构体中，In a preferred embodiment of the present invention, in the compound represented by the above formula (II) or a stereoisomer thereof,
R1选自
Figure PCTCN2016081809-appb-000033
R 1 is selected from
Figure PCTCN2016081809-appb-000033
Figure PCTCN2016081809-appb-000034
Figure PCTCN2016081809-appb-000034
R1优选选自
Figure PCTCN2016081809-appb-000035
R 1 is preferably selected from
Figure PCTCN2016081809-appb-000035
R9选自H或者氨基保护基，其中所述的氨基保护基优选为苄基、对甲氧基苄基、叔丁氧基羰基、苄氧基羰基、乙酰基或苯甲酰基。R 9 is selected from H or an amino protecting group, wherein the amino protecting group is preferably benzyl, p-methoxybenzyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl or benzoyl.
在本发明的优选实施方案中，上述的通式(II)所示的制备通式(I)所示化合物或其立体异构体的中间体选自以下化合物之一：In a preferred embodiment of the present invention, the intermediate of the above formula (II) for producing the compound of the formula (I) or a stereoisomer thereof is selected from one of the following compounds:
Figure PCTCN2016081809-appb-000036
Figure PCTCN2016081809-appb-000036
本发明涉及一种制备通式(I)所示化合物或其立体异构体的中间体，该中间体选自通式(III)所示的化合物或者其立体异构体：The present invention relates to an intermediate for the preparation of a compound of the formula (I) or a stereoisomer thereof, which is selected from a compound of the formula (III) or a stereoisomer thereof:
Figure PCTCN2016081809-appb-000037
Figure PCTCN2016081809-appb-000037
R1选自
Figure PCTCN2016081809-appb-000038
R 1 is selected from
Figure PCTCN2016081809-appb-000038
R1a选自H、C2-6烯基、C2-6炔基、C3-10碳环基、3至8元杂环基、C3-10碳环基-C1-4亚烷基或3至8元杂环基-C1-4亚烷基，所述烯基、炔基、亚烷基、碳环基或杂环基任选进一步被0至4个选自F、Cl、Br、I、CH2F、CHF2、CF3、OH、OCH2F、OCHF2、OCF3、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基、-O(＝O)C1-4烷基、-(＝O)C1-4烷基、-OC3-6环烷基或C1-4烷硫基的取代基所取代，所述杂环基含有1至3个选自N、O或S的杂原 子；R 1a is selected from the group consisting of H, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3 to 8 membered heterocyclic, C 3-10carbocyclyl -C 1-4 alkylene Or a 3 to 8 membered heterocyclyl-C 1-4 alkylene group, optionally further 0 to 4 selected from the group consisting of F and Cl, the alkenyl, alkynyl, alkylene, carbocyclic or heterocyclic group , Br, I, CH 2 F, CHF 2 , CF 3 , OH, OCH 2 F, OCHF 2 , OCF 3 , NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkane Substituted by a substituent of an oxy group, -O(=O)C 1-4 alkyl, -(=O)C 1-4 alkyl, -OC 3-6 cycloalkyl or C 1-4 alkylthio group, The heterocyclic group contains 1 to 3 hetero atoms selected from N, O or S;
R1b选自C2-6烯基、C2-6炔基、C3-10碳环基、3至8元杂环基、C3-10碳环基-C1-4亚烷基或3至8元杂环基-C1-4亚烷基，所述烯基、炔基、亚烷基、碳环基或杂环基任选进一步被0至4个选自F、Cl、Br、I、CH2F、CHF2、CF3、OH、OCH2F、OCHF2、OCF3、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基、-O(＝O)C1-4烷基、-(＝O)C1-4烷基、-OC3-6环烷基或C1-4烷硫基的取代基所取代，所述杂环基含有1至3个选自N、O或S的杂原子；R 1b is selected from C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3 to 8 membered heterocyclic, C 3-10carbocyclyl -C 1-4 alkylene or a 3- to 8-membered heterocyclyl-C 1-4 alkylene group, optionally further 0 to 4 selected from the group consisting of F, Cl, and Br, and an alkenyl group, an alkynyl group, an alkylene group, a carbocyclic group, or a heterocyclic group. , I, CH 2 F, CHF 2 , CF 3 , OH, OCH 2 F, OCHF 2 , OCF 3 , NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy Substituted with a substituent of -O(=O)C 1-4 alkyl, -(=O)C 1-4 alkyl, -OC 3-6 cycloalkyl or C 1-4 alkylthio, The heterocyclic group contains 1 to 3 hetero atoms selected from N, O or S;
R1c选自H、羟基、氰基、NH2、C1-6烷基、C1-6烷氧基、C1-6烷硫基或-C(＝O)NH2，所述NH2、-C(＝O)NH2或烷基任选进一步被0至2个选自F、Cl、Br、I、羟基、氰基或C1-4烷基的取代基所取代；R 1c is selected from H, hydroxy, cyano, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or -C(=O)NH 2 , said NH 2 , -C(=O)NH 2 or an alkyl group is optionally further substituted with 0 to 2 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, cyano or C 1-4 alkyl;
R1e和R1f各自独立选自F、Cl、Br、I、CF3、NH2、OH、羧基、氰基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、-NHC1-4烷基、-N(C1-4烷基)2、-S(＝O)-C1-4烷基、-S(＝O)2-C1-4烷基或-C(＝O)O-C1-4烷基；R 1e and R 1f are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , NH 2 , OH, carboxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkane Thio group, -NHC 1-4 alkyl group, -N(C 1-4 alkyl) 2 , -S(=O)-C 1-4 alkyl group, -S(=O) 2 -C 1-4 alkane Or a -C(=O)OC 1-4 alkyl group;
R2选自键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基，所述亚烷基、亚烯基或亚炔基任选进一步被0至5个选自F、Cl、Br、I、OH、氰基、C1-4烷基、C1-4烷氧基、苯基或苯基-C1-4亚烷基的取代基所取代；R 2 is selected from a bond, a C 1-6 alkylene group, a C 2-6 alkenylene group or a C 2-6 alkynylene group, and the alkylene group, alkenylene group or alkynylene group is optionally further 0 to 5 Substituted with a substituent selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
W选自OH、羧基、-C(＝O)OC1-4烷基、苯基、-C(＝O)NRx-苯基、-ONRxC(＝O)-苯基、-C(＝O)NRx-C1-4亚烷基-C(＝O)OH、-C(＝O)NRx-C1-4亚烷基-C(＝O)OC1-4烷基、-C(＝O)NRx-C1-4亚烷基-C(＝O)NRx-苯基、-C(＝O)NRx-亚苯基-C(＝O)NRx-苯基、
Figure PCTCN2016081809-appb-000039
所述的苯基任选进一步被0至4个自F、Cl、Br、I、甲氧基、乙氧基、
Figure PCTCN2016081809-appb-000040
甲酰基、羧基、-C(＝O)OC1-4烷基、
Figure PCTCN2016081809-appb-000041
的取代基所取代；W is selected from OH, carboxyl, -C(=O)OC 1-4 alkyl, phenyl, -C(=O)NR x -phenyl, -ONR x C(=O)-phenyl, -C( =O)NR x -C 1-4 alkylene-C(=O)OH, -C(=O)NR x -C 1-4 alkylene-C(=O)OC 1-4 alkyl, -C(=O)NR x -C 1-4 alkylene-C(=O)NR x -phenyl, -C(=O)NRx-phenylene-C(=O)NRx-phenyl,
Figure PCTCN2016081809-appb-000039
The phenyl group is optionally further from 0 to 4 from F, Cl, Br, I, methoxy, ethoxy,
Figure PCTCN2016081809-appb-000040
Formyl, carboxyl, -C(=O)OC 1-4 alkyl,
Figure PCTCN2016081809-appb-000041
Substituted by a substituent;
Rx选自H或C1-4烷基；R x is selected from H or C 1-4 alkyl;
R3选自键或C1-6亚烷基，所述亚烷基任选进一步被0至5个选自R3a的取代基所取代，R3a选自F、Cl、Br、I、氰基、OH、C1-4烷基、C1-4烷氧基、苯基或苯基-C1-4亚烷基；作为选择，两个R3a可以与它们相连的原子一起形成一个3至6元碳环，所述碳环任选进一步被0至5个选自F、Cl、Br、I、氰基、OH、C1-4烷基或C1-4烷氧基的取代基 所取代；R 3 is selected from a bond or C 1-6 alkylene, said alkylene being optionally further substituted with 0-5 substituents selected from R 3a, R 3a is selected from F, Cl, Br, I, cyano a group, OH, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene; alternatively, two R 3a may form a 3 together with the atoms to which they are attached Up to a 6-membered carbocyclic ring, optionally further substituted with 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy Replaced
B选自
Figure PCTCN2016081809-appb-000042
Figure PCTCN2016081809-appb-000043
B is selected from
Figure PCTCN2016081809-appb-000042
Figure PCTCN2016081809-appb-000043
其中Q选自-CH＝CH-、-CH2CH2-、-O-、-S-、-CH2O-、-OCH2-、-C(CH3)2O-或-OC(CH3)2-；Wherein Q is selected from -CH=CH-, -CH 2 CH 2 -, -O-, -S-, -CH 2 O-, -OCH 2 -, -C(CH 3 ) 2 O- or -OC(CH) 3 ) 2 -;
B优选选自
Figure PCTCN2016081809-appb-000044
Figure PCTCN2016081809-appb-000045
B is preferably selected from
Figure PCTCN2016081809-appb-000044
Figure PCTCN2016081809-appb-000045
a为0、1、2、3或4；a is 0, 1, 2, 3 or 4;
b为0、1、2、3、4或5。b is 0, 1, 2, 3, 4 or 5.
在本发明的优选实施方案中，上述的通式(III)所示的制备通式(I)所示化合物或其立体异构体的中间体选自以下化合物之一：In a preferred embodiment of the present invention, the intermediate of the above formula (III) for producing the compound of the formula (I) or a stereoisomer thereof is selected from one of the following compounds:
Figure PCTCN2016081809-appb-000046
Figure PCTCN2016081809-appb-000046
Figure PCTCN2016081809-appb-000047
Figure PCTCN2016081809-appb-000047
Figure PCTCN2016081809-appb-000048
Figure PCTCN2016081809-appb-000048
本发明涉及的具体实施例化合物中的二三氟乙酸盐，可将其溶解在极性有机溶剂(如甲醇与二氯甲烷的混合溶剂(v/v＝1/90)中，通过加入碱性试剂(如饱和碳酸氢钠溶液或饱和碳酸钠溶液等)调节pH至碱性，搅拌后用有机溶剂(如二氯甲烷、乙酸乙酯等)萃取， 将有机相减压浓缩后可得到对应化合物的游离碱形式。The ditrifluoroacetate salt in the specific embodiment of the present invention may be dissolved in a polar organic solvent such as a mixed solvent of methanol and dichloromethane (v/v = 1/90) by adding a base. The reagent (such as saturated sodium bicarbonate solution or saturated sodium carbonate solution) is adjusted to pH, and after stirring, it is extracted with an organic solvent (such as dichloromethane, ethyl acetate, etc.). The organic phase is concentrated under reduced pressure to give the free base of the corresponding compound.
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Terms used in the specification and claims have the following meanings unless stated to the contrary.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又称为重氢)、氚(T，又称为超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention. The nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C, and 14 C, and the hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen ), 氚 (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes including 14 N and 15 N, the fluorine isotope 19 F, the chlorine isotope includes 35 Cl and 37 Cl, and the bromine isotopes include 79 Br and 81 Br.
“烷基”是指直链和支链的一价饱和烃基，主链包括1至10个碳原子，优选为1至8个碳原子，进一步优选为1至6个碳原子，更优选为1至4个碳原子的直链与支链基团，最优选1至2个碳原子，烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、正己基、正庚基、正辛基、正壬基和正癸基等；所述的烷基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH2F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3、羟基、-SR19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C2-8烯基、C2-8炔基、-(CH2)a-C(＝O)-R19、-(CH2)k-C(＝O)-O-R19、-(CH2)k-C(＝O)-NR19R19a、-(CH2)k-S(＝O)j-R19、-O-C(＝O)-O-R19或-NR19R19a的取代基所取代，其中R19和R19a各自独立选自H、羟基、氨基、羧基、C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、3至10元碳环基、4至10元杂环基、3至10元碳环基氧基或4至10元杂环基氧基，k选自0、1、2、3、4或5，j选自0、1或2。本文中出现的烷基、k、j、R19和R19a，其定义如上所述。"Alkyl" means a straight-chain and branched monovalent saturated hydrocarbon group, and the main chain includes 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, further preferably 1 to 6 carbon atoms, more preferably 1 Straight and branched groups of up to 4 carbon atoms, most preferably 1 to 2 carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-glycol Base, n-octyl, n-decyl and n-decyl, etc.; the alkyl group may be further optionally 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, I, =O, - CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , hydroxy, -SR 19 , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy Carbocyclyl, heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, -(CH 2 ) a -C(=O)-R 19 , -(CH 2 ) k -C(= O)-OR 19 , -(CH 2 ) k -C(=O)-NR 19 R 19a , -(CH 2 ) k -S(=O) j -R 19 , -OC(=O)-OR 19 or -NR 19 R 19a group substituted with a substituent, wherein R 19 and R 19a are each independently Is selected from H, hydroxyl, amino, carboxyl, C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, 3-10 yuan carbocyclyl, 4-10 a heterocyclic group, a 3 to 10 membered carbocyclic oxy group or a 4 to 10 membered heterocyclic oxy group, k is selected from 0, 1, 2, 3, 4 or 5, and j is selected from 0, 1 or 2. The alkyl groups, k, j, R 19 and R 19a appearing herein are as defined above.
“亚烷基”是指直链和支链的二价饱和烃基，包括-(CH2)v-(v为1至10的整数)，亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等；所述的亚烷基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH2F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3、羟基、-SR19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C2-8烯基、C2-8炔基、-(CH2)a-C(＝O)-R19、-(CH2)k-C(＝O)-O-R19、-(CH2)k-C(＝O)-NR19R19a、-(CH2)k-S(＝O)j-R19、-O-C(＝O)-O-R19或-NR19R19a的取代基所取代，当亚烷基中的取代基数量大于等于2个时，取代基可以稠合在一起形成环状结构。本文中出现的亚烷基，其定义如上所述"Alkylene" means a straight-chain or branched divalent saturated hydrocarbon group, including -(CH 2 ) v - (v is an integer from 1 to 10), and alkylene examples include, but are not limited to, methylene, sub Ethyl, propylene, butylene, etc.; the alkylene group may be further optionally 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, I, =O, -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , hydroxy, -SR 19 , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, Carbocyclyl, heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, -(CH 2 ) a -C(=O)-R 19 , -(CH 2 ) k -C(=O) -OR 19 , -(CH 2 ) k -C(=O)-NR 19 R 19a , -(CH 2 ) k -S(=O) j -R 19 , -OC(=O)-OR 19 or - When the substituent of NR 19 R 19a is substituted, when the number of substituents in the alkylene group is 2 or more, the substituents may be fused together to form a cyclic structure. The alkylene group present herein is defined as described above
“烷氧基”是指O-烷基的一价基团，其中，烷基如本文所定义，烷氧基实施例包括但不限于甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-1-丙氧基、2-丁氧基、 2-甲基-2-丙氧基、1-戊氧基、2-戊氧基、3-戊氧基、2-甲基-2-丁氧基、3-甲基-2-丁氧基、3-甲基-1-丁氧基和2-甲基-1-丁氧基等。"Alkoxy" means a monovalent group of an O-alkyl group, wherein alkyl is as defined herein, and alkoxy embodiments include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2 -propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy , 3-methyl-1-butoxy and 2-methyl-1-butoxy and the like.
“烯基”是指直链和支链的一价不饱和烃基，其具有至少1个，通常有1、2或3个碳碳双键，主链包括2至10个碳原子，进一步优选2至6个碳原子，更优选在主链上有2至4个碳原子，烯基实施例包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等；所述的烯基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH2F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3、羟基、-SR19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C2-8烯基、C2-8炔基、-(CH2)a-C(＝O)-R19、-(CH2)k-C(＝O)-O-R19、-(CH2)k-C(＝O)-NR19R19a、-(CH2)k-S(＝O)j-R19、-O-C(＝O)-O-R19或-NR19R19a的取代基所取代。本文中出现的烯基，其定义如上所述。"Alkenyl" means a straight-chain or branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, the main chain comprising 2 to 10 carbon atoms, further preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain, and alkenyl examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl , 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2- Methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octene , 3-octenyl, 1-decenyl, 3-decenyl, 1-decenyl, 4-nonenyl, 1,3-butadiene, 1,3-pentadiene, 1, 4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group may be further optionally 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , hydroxyl, -SR 19 , nitro, cyano, iso Cyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C 2-8 alkenyl, C 2-8 alkynyl, -(CH 2 ) a -C(=O)-R 19 , -(CH 2 ) k -C(=O)-OR 19 , -(CH 2 ) k -C(=O)-NR 19 R 19a , -(CH 2 ) k -S(=O) j - Substituents of R 19 , -OC(=O)-OR 19 or -NR 19 R 19a are substituted. The alkenyl groups appearing herein are as defined above.
“亚烯基”是指二价烯基基团，其中烯基的定义如上所述。"Alkenylene" refers to a divalent alkenyl group wherein the alkenyl group is as defined above.
“炔基”是指直链和支链的一价不饱和烃基，其具有至少1个，通常有1、2或3个碳碳三键，主链包括2至10个碳原子，进一步优选2至6个碳原子，更优选在主链上有2至4个碳原子，炔基实施例包括但不限于乙炔基、1-丙炔基、2-丙炔基、丁炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、4-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-己炔基、3-己炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基和4-癸炔基等；所述的炔基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH2F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3、羟基、-SR19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C2-8烯基、C2-8炔基、-(CH2)a-C(＝O)-R19、-(CH2)k-C(＝O)-O-R19、-(CH2)k-C(＝O)-NR19R19a、-(CH2)k-S(＝O)j-R19、-O-C(＝O)-O-R19或-NR19R19a的取代基所取代。本文中出现的炔基，其定义如上所述。"Alkynyl" means a straight-chain or branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, the main chain comprising 2 to 10 carbon atoms, further preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain, examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butyl Alkynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3 -hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-decynyl and 4-decynyl, etc.; the alkynyl group may be optionally Further, 0, 1 , 2 , 3 , 4 or 5 are selected from the group consisting of F, Cl, Br, I, =O, -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 , - OCF 3 , hydroxy, -SR 19 , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C 2-8 alkenyl, C 2-8 alkyne Base, -(CH 2 ) a -C(=O)-R 19 , -(CH 2 ) k -C(=O)-OR 19 , -(CH 2 ) k -C(=O)-NR 19 R 19a, - (CH 2) k -S (= O) j -R 19, -OC (= O) -OR 19 or -NR 19 R 19a group substituted with a substituent The alkynyl groups appearing herein are as defined above.
“亚炔基”是指二价炔基基团，其中炔基的定义如上所述。"Alkynylene" refers to a divalent alkynyl group wherein the alkynyl group is as defined above.
“环烷基”是指一价饱和的碳环烃基，通常有3至10个碳原子，非限制性实施例包括环丙基、环丁基、环戊基、环己基或环庚基等。所述的环烷基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH2F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3、羟基、-SR19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C2-8 烯基、C2-8炔基、-(CH2)a-C(＝O)-R19、-(CH2)k-C(＝O)-O-R19、-(CH2)k-C(＝O)-NR19R19a、-(CH2)k-S(＝O)j-R19、-O-C(＝O)-O-R19或-NR19R19a的取代基所取代。本文中出现的环烷基，其定义如上所述。"Cycloalkyl" means a monovalent saturated carbocyclic hydrocarbon group, usually having from 3 to 10 carbon atoms, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The cycloalkyl group may be further optionally 0, 1, 2 , 3 , 4 or 5 selected from the group consisting of F, Cl, Br, I, =O, -CH 2 F, -CHF 2 , -CF 3 , - OCH 2 F, -OCHF 2 , -OCF 3 , hydroxy, -SR 19 , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C 2- 8 alkenyl, C 2-8 alkynyl, -(CH 2 ) a -C(=O)-R 19 , -(CH 2 ) k -C(=O)-OR 19 , -(CH 2 ) k - Substituents of C(=O)-NR 19 R 19a , -(CH 2 ) k -S(=O) j -R 19 , -OC(=O)-OR 19 or -NR 19 R 19a are substituted. The cycloalkyl groups appearing herein are as defined above.
“亚环烷基”是指二价环烷基，其中环烷基的定义如上所述。"Cycloalkylene" refers to a divalent cycloalkyl group wherein cycloalkyl is as defined above.
“芳基”是指具有单环或稠合环的一价芳香族烃基，通常有6至10个碳原子，非限制性实施例包括苯基、萘-1-基或萘-2-基。所述的芳基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH2F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3、羟基、-SR19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C2-8烯基、C2-8炔基、-(CH2)a-C(＝O)-R19、-(CH2)k-C(＝O)-O-R19、-(CH2)k-C(＝O)-NR19R19a、-(CH2)k-S(＝O)j-R19、-O-C(＝O)-O-R19或-NR19R19a的取代基所取代。本文中出现的芳基，其定义如上所述。"Aryl" means a monovalent aromatic hydrocarbon radical having a monocyclic or fused ring, usually having from 6 to 10 carbon atoms, and non-limiting examples include phenyl, naphthalen-1-yl or naphthalen-2-yl. The aryl group may be further optionally 0, 1, 2 , 3 , 4 or 5 selected from the group consisting of F, Cl, Br, I, =O, -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , hydroxy, -SR 19 , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C 2-8 Alkenyl, C 2-8 alkynyl, -(CH 2 ) a -C(=O)-R 19 , -(CH 2 ) k -C(=O)-OR 19 , -(CH 2 ) k -C (=O)-NR 19 R 19a , -(CH 2 ) k -S(=O) j -R 19 , -OC(=O)-OR 19 or -NR 19 Substituted by a substituent of R 19a . The aryl groups appearing herein are defined as described above.
“亚芳基”是指二价芳基，其中芳基的定义如上所述。"Arylene" means a divalent aryl group wherein the aryl group is as defined above.
“杂芳基”是指具有单环或两个稠合环并且在环中包含至少1个选自N、O或S的杂原子的一价芳基，通常有5至8元的原子组成，非限制性实施例包括吡咯基、咪唑基、噻唑基、噻吩基、呋喃基、吡唑基、异恶唑基、恶唑基、吡啶基或吡嗪基。所述的杂芳基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH2F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3、羟基、-SR19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C2-8烯基、C2-8炔基、-(CH2)a-C(＝O)-R19、-(CH2)k-C(＝O)-O-R19、-(CH2)k-C(＝O)-NR19R19a、-(CH2)k-S(＝O)j-R19、-O-C(＝O)-O-R19或-NR19R19a的取代基所取代。本文中出现的杂芳基，其定义如上所述。"Heteroaryl" means a monovalent aryl group having a single ring or two fused rings and containing at least one hetero atom selected from N, O or S in the ring, usually having an atomic composition of 5 to 8 members, Non-limiting examples include pyrrolyl, imidazolyl, thiazolyl, thienyl, furyl, pyrazolyl, isoxazolyl, oxazolyl, pyridyl or pyrazinyl. The heteroaryl group may be further optionally 0, 1, 2 , 3 , 4 or 5 selected from the group consisting of F, Cl, Br, I, =O, -CH 2 F, -CHF 2 , -CF 3 , - OCH 2 F, -OCHF 2 , -OCF 3 , hydroxy, -SR 19 , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C 2- 8 alkenyl, C 2-8 alkynyl, -(CH 2 ) a -C(=O)-R 19 , -(CH 2 ) k -C(=O)-OR 19 , -(CH 2 ) k - Substituents of C(=O)-NR 19 R 19a , -(CH 2 ) k -S(=O) j -R 19 , -OC(=O)-OR 19 or -NR 19 R 19a are substituted. The heteroaryl groups appearing herein are as defined above.
“亚杂芳基”是指二价杂芳基，其中杂芳基的定义如上所述。"Heteroarylene" means a divalent heteroaryl group wherein the definition of heteroaryl is as described above.
“碳环基”是指饱和或者不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至10元的单环、4至12元双环或10至15元三环体系，碳环基可以连接有桥环或者螺环，非限制性实施例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基、苯基、萘基、
Figure PCTCN2016081809-appb-000049
所述的碳环基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH2F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3、羟基、-SR19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C2-8烯基、C2-8炔基、-(CH2)a-C(＝O)-R19、-(CH2)k-C(＝O)-O-R19、-(CH2)k-C(＝O)-NR19R19a、-(CH2)k-S(＝O)j-R19、 -O-C(＝O)-O-R19或-NR19R19a的取代基所取代。本文中出现的碳环基，其定义如上所述。"Carbocyclyl" means a saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered tricyclic ring system. The ring group may be attached to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-alkenyl , 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, Cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, phenyl, naphthyl,
Figure PCTCN2016081809-appb-000049
The carbocyclic group may be further optionally 0, 1, 2 , 3 , 4 or 5 selected from the group consisting of F, Cl, Br, I, =O, -CH 2 F, -CHF 2 , -CF 3 , - OCH 2 F, -OCHF 2 , -OCF 3 , hydroxy, -SR 19 , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C 2- 8 alkenyl, C 2-8 alkynyl, -(CH 2 ) a -C(=O)-R 19 , -(CH 2 ) k -C(=O)-OR 19 , -(CH 2 ) k - Substituents of C(=O)-NR 19 R 19a , -(CH 2 ) k -S(=O) j -R 19 , -OC(=O)-OR 19 or -NR 19 R 19a are substituted. The carbocyclic group appearing herein is defined as described above.
“杂环基”是指饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至10元的单环、4至12元双环或10至15元三环体系，且包含1至4个选自N、O或S的杂原子，优选3至8元杂环基，杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、哌叮基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的杂环基可以任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、＝O、-CH2F、-CHF2、-CF3、-OCH2F、-OCHF2、-OCF3、羟基、-SR19、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C2-8烯基、C2-8炔基、-(CH2)a-C(＝O)-R19、-(CH2)k-C(＝O)-O-R19、-(CH2)k-C(＝O)-NR19R19a、-(CH2)k-S(＝O)j-R19、-O-C(＝O)-O-R19或-NR19R19a的取代基所取代。本文中出现的杂环基，其定义如上所述。"Heterocyclyl" means a saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic, 4 to 12 membered bicyclic or 10 to 15 membered tricyclic system, and It contains 1 to 4 hetero atoms selected from N, O or S, preferably a 3 to 8 membered heterocyclic group, and N, S which are optionally substituted in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group may be bonded to a hetero atom or a carbon atom, and the heterocyclic group may be bonded to a bridged or spiro ring, and non-limiting examples include an epoxyethyl group, a glycidyl group, an azacyclopropyl group, and an oxocyclic ring. Butyl, azetidinyl, thioheterobutyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxolyl, azacycloheptyl , oxetanyl, thiaheptyl, oxazepine, diazepine, thiazepine, pyridyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyr Cyclo, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl , thiazolidine, 1,3-dithia, dihydrofuranyl, dihydropyranyl, dithylpentyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl , tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrroline, 3-pyrroline, indanyl, 2H-pyranyl , 4H-pyranyl, dioxolane, 1,3-dioxolanyl, pyrazolinyl, dithiaalkyl, dithialimyl, dihydrothienyl, pyrazolidinyl, imidazoline Base, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[ 2.2.2] Hexyl, 3H-nonylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo [5.2.0] decyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl. The heterocyclic group may be further optionally 0, 1, 2 , 3 , 4 or 5 selected from the group consisting of F, Cl, Br, I, =O, -CH 2 F, -CHF 2 , -CF 3 , - OCH 2 F, -OCHF 2 , -OCF 3 , hydroxy, -SR 19 , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C 2- 8 alkenyl, C 2-8 alkynyl, -(CH 2 ) a -C(=O)-R 19 , -(CH 2 ) k -C(=O)-OR 19 , -(CH 2 ) k - Substituents of C(=O)-NR 19 R 19a , -(CH 2 ) k -S(=O) j -R 19 , -OC(=O)-OR 19 or -NR 19 R 19a are substituted. The heterocyclic group appearing herein is as defined above.
“β-肾上腺素受体结合基团”是指能够与β-肾上腺素能受体结合的基团；诸如参见综述文章“β-adrenergic receptors in Comprehensive Medicinal Chemistry，1990，B.E.Main，p187(Pergamon Press)”。上述基团也参见例如WO/2005092841、US/20050215542、WO/2005070872、WO/2006023460、WO/2006051373、WO/2006087315和WO/2006032627。非限制性实施例包括
Figure PCTCN2016081809-appb-000050
R4、R5各自独立的选自H或C1-4烷 基，B选自
Figure PCTCN2016081809-appb-000051
Figure PCTCN2016081809-appb-000052
其中Q选自-CH＝CH-、-CH2CH2-、-O-、-S-、-CH2O-、-OCH2-、-C(CH3)2O-或-OC(CH3)2-。"β-adrenergic receptor binding group" refers to a group capable of binding to a β-adrenergic receptor; for example, see review article "β-adrenergic receptors in Comprehensive Medicinal Chemistry, 1990, BEMain, p187 (Pergamon Press) ". The above-mentioned groups are also described, for example, in WO/2005092841, US/20050215542, WO/2005070872, WO/2006023460, WO/2006051373, WO/2006087315 and WO/2006032627. Non-limiting examples include
Figure PCTCN2016081809-appb-000050
R 4 and R 5 are each independently selected from H or C 1-4 alkyl, and B is selected from
Figure PCTCN2016081809-appb-000051
Figure PCTCN2016081809-appb-000052
Wherein Q is selected from -CH=CH-, -CH 2 CH 2 -, -O-, -S-, -CH 2 O-, -OCH 2 -, -C(CH 3 ) 2 O- or -OC(CH) 3 ) 2 -.
“氨基保护基”是指用于氨基保护的基团，该基团适用于保护氨基，使氨基不进行化学反应，但是在分子的其它部分完成所需化学反应之后该基团容易除去。在《有机合成中的保护基》(华东理工大学有机化学教研室译，荣国斌校，华东理工大学出版社，2004；原书为Protective Groups In Organic Synthesis(third edition),Theodora W.Green and Peter G.M.Wuts著)中氨基的保护一章对氨基保护基做了详细介绍。本申请将《有机合成中的保护基》中第494-653页引用于此作为本申请的一部分。"Amino protecting group" refers to a group for amino protection which is useful for protecting an amino group such that the amino group does not undergo a chemical reaction, but the group is readily removed after completion of the desired chemical reaction in other portions of the molecule. In "Protective Bases in Organic Synthesis" (Translated by the Department of Organic Chemistry, East China University of Science and Technology, Rong Guobin School, East China University of Science and Technology Press, 2004; the original book is Protective Groups In Organic Synthesis (third edition), Theodora W. Green and Peter The chapter on the protection of amino groups in GMWuts gives a detailed description of the amino protecting group. This application is hereby incorporated by reference in its entirety in its entirety in its entirety in the the the the the the the the the
“氨基保护基”包括但不限于以下基团：苄基、对甲氧基苄基、三苯甲基、叔丁氧基羰基、苄氧基羰基、9-芴基甲氧羰基、2,2,2-三氯乙氧羰基、乙氧羰基、苄氧基羰基、三氟乙酰基、乙酰基或苯甲酰基。"Amino protecting group" includes, but is not limited to, the following groups: benzyl, p-methoxybenzyl, trityl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2 , 2-trichloroethoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, trifluoroacetyl, acetyl or benzoyl.
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "alkyl group optionally substituted by F" means that the alkyl group may, but need not, be substituted by F, indicating a case where the alkyl group is substituted by F and a case where the alkyl group is not substituted by F.
“药物组合物”表示一种或几种文本所述化合物或其生理学/药学上可接受的盐与其他组成成分的混合物，其中其它组分包含生理学/药学上可接受的载体和赋形剂。"Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt thereof, with other components, wherein the other components comprise physiologically/pharmaceutically acceptable carriers and excipients.
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。"Carrier" refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。"Excipient" refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, Granules, lubricants, binders, disintegrators, and the like.
“前药”是指可以在生理条件下或通过溶剂解转化为具有生物活性的本发明化合物的化合物。本发明的前药通过修饰本发明化合物中的功能基团来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。"Prodrug" means a compound that can be converted to a biologically active compound of the invention under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds of the invention which can be removed by conventional procedures or in vivo to provide the parent compound.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反 异构体、对映异构体和构象异构体。"Stereoisomer" refers to isomers produced by the different arrangement of atoms in a molecule in space, including cis-trans Isomers, enantiomers and conformers.
“有效剂量”指引起组织、系统或受试者生理或医学翻译的化合物的量，此量是所寻求的，包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。"Effective dose" refers to an amount of a compound that causes a physiological or medical translation of a tissue, system or subject, which amount is sought, and includes one or more of the conditions or conditions sufficient to prevent treatment when administered to a subject. The amount of a compound that occurs or reduces it to some extent.
“溶剂化物”指本发明化合物或其盐，它们还包括以分子间非共价力结合的化学计量或非化学计量的溶剂。当溶剂为水时，则为水合物。"Solvate" means a compound of the invention or a salt thereof, which also includes a stoichiometric or non-stoichiometric amount of solvent bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.
“IC50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。"IC 50 " refers to the half-inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.
具体实施方式detailed description
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果，旨在帮助阅读者更好地理解本发明的实质和特点，不作为对本案可实施范围的限定。The embodiments of the present invention and the beneficial effects thereof are described in detail below by way of specific examples, which are intended to provide a better understanding of the nature and characteristics of the present invention.
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) NMR instrument and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD). The internal standard is tetramethylsilane (TMS).
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。The measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.20mm. The specification for thin layer chromatography separation and purification is 0.4mm. ~0.5mm.
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
氮气氛是指反应瓶连接一个约1L容积的氮气气球。The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon having a volume of about 1 L.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
实施例中无特殊说明，反应在氮气氛下进行。Unless otherwise stated in the examples, the reaction was carried out under a nitrogen atmosphere.
实施例中无特殊说明，溶液是指水溶液。Unless otherwise stated in the examples, the solution means an aqueous solution.
实施例中无特殊说明，反应的温度为室温。There is no particular description in the examples, and the reaction temperature is room temperature.
室温为最适宜的反应温度，为20℃～30℃。The room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.
TBS为叔丁基二甲基硅基。 TBS is tert-butyldimethylsilyl.
Boc为叔丁基氧基羰基。Boc is a tert-butyloxycarbonyl group.
TFA为三氟乙酸。TFA is trifluoroacetic acid.
HATU为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(CAS:148893-10-1)。HATU is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (CAS: 148893-10-1).
实施例1：[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬-2-基]-2-羟基-2,2-双(2-噻吩基)乙酸酯(化合物1)Example 1: [7-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-7-azaspiro[3.5]indol-2-yl]-2-hydroxy-2,2-di (2-thienyl) acetate (Compound 1)
[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]- 5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000053
Figure PCTCN2016081809-appb-000053
第一步：2-羟基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(1B)First step: 2-hydroxy-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (1B)
tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylateTert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2016081809-appb-000054
Figure PCTCN2016081809-appb-000054
冰浴下，在2-羰基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(1A)(7g，29.3mmol)的甲醇(100mL)溶液中加入硼氢化钠(1.1g，29.3mmol)，加完后室温反应2小时。加水(100 mL)，用二氯甲烷(100mL×3)萃取，合并有机相，无水硫酸钠干燥，减压浓缩后得到标题化合物2-羟基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(1B)，白色固体(7g，产率99.2％)。Sodium borohydride (1.1 g) was added to a solution of 2-carbonyl-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (1A) (7 g, 29.3 mmol) in methanol (100 mL). , 29.3 mmol), and reacted at room temperature for 2 hours after the addition. Add water (100 The title compound (2-hydroxy-7-azaspiro[3.5]decane-7-carboxylic acid was obtained from methylene chloride (100 mL×3). tert-Butyl ester (1B), white solid (7 g, yield 99.2%).
1H NMR(400MHz,CDCl3)δ4.39-4.23(m,1H),3.38-3.22(m,4H),2.32-2.22(m,2H),2.04(d,1H),1.74-1.62(m,2H),1.50(m,4H),1.45-1.41(m,9H).1H NMR (400MHz, CDCl3) δ 4.39-4.23 (m, 1H), 3.38-3.22 (m, 4H), 2.32-2.22 (m, 2H), 2.04 (d, 1H), 1.74-1.62 (m, 2H) ), 1.50 (m, 4H), 1.45-1.41 (m, 9H).
LCMS m/z＝264.1[M+23].LCMS m/z = 264.1 [M+23].
第二步：2-[2-羟基-2,2-双(2-噻吩基)乙酰基]氧基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(1C)Second step: 2-[2-hydroxy-2,2-bis(2-thienyl)acetyl]oxy-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (1C)
tert-butyl 2-[2-hydroxy-2,2-bis(2-thienyl)acetyl]oxy-7-azaspiro[3.5]nonane-7-carboxylateTert-butyl 2-[2-hydroxy-2,2-bis(2-thienyl)acetyl]oxy-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2016081809-appb-000055
Figure PCTCN2016081809-appb-000055
将2-羟基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(1B)(0.482g，2mmol)溶于甲苯(10mL)中，加入氢化钠(0.024g，1mmol)，搅拌5分钟，加入2-羟基-2,2-双(2-噻吩基)乙酸甲酯(0.508g，2mmol)，升温至155℃反应1小时。加水淬灭反应，依次用乙酸乙酯(20mL×2)萃取，饱和氯化钠水溶液(20mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析(洗脱剂为乙酸乙酯/石油醚(v:v)＝1/100～1/20)纯化，得到标题化合物2-[2-羟基-2,2-双(2-噻吩基)乙酰基]氧基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(1C)，淡黄色固体(0.23g，产率25％)。2-Hydroxy-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (1B) (0.482 g, 2 mmol) was dissolved in toluene (10 mL) and sodium hydride (0.024 g, 1 mmol). After stirring for 5 minutes, methyl 2-hydroxy-2,2-bis(2-thienyl)acetate (0.508 g, 2 mmol) was added, and the mixture was heated to 155 ° C for 1 hour. The reaction was quenched with EtOAc (EtOAc)EtOAc. Purification of the eluent from ethyl acetate / petroleum ether (v: v) = 1 / 100 to 1 / 20 to give the title compound 2-[2-hydroxy-2,2-bis(2-thienyl)acetyl] Oxy-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (1C), pale yellow solid (0.23 g, yield 25%).
1H NMR(400MHz,CDCl3)δ7.29(dd,2H),7.17(dd,2H),6.98(dd,2H),5.25-5.05(m,1H),4.66(s,1H),3.32(dd,2H),3.29-3.23(m,2H),2.41-2.30(m,2H),1.88(dd,2H),1.54-1.50(m,2H),1.47(d,2H),1.44(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ7.29 (dd, 2H), 7.17 (dd, 2H), 6.98 (dd, 2H), 5.25-5.05 (m, 1H), 4.66 (s, 1H), 3.32 ( Dd, 2H), 3.29-3.23 (m, 2H), 2.41-2.30 (m, 2H), 1.88 (dd, 2H), 1.54-1.50 (m, 2H), 1.47 (d, 2H), 1.44 (s, 9H).
LCMS m/z＝486.3[M+23].LCMS m/z = 486.3 [M+23].
第三步：7-氮杂螺[3.5]壬烷-2-基2-羟基-2,2-双(2-噻吩基)乙酸酯(1D)The third step: 7-azaspiro[3.5]decane-2-yl 2-hydroxy-2,2-bis(2-thienyl)acetate (1D)
7-azaspiro[3.5]nonan-2-yl 2-hydroxy-2,2-bis(2-thienyl)acetate7-azaspiro[3.5]nonan-2-yl 2-hydroxy-2,2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000056
Figure PCTCN2016081809-appb-000056
将2-[2-羟基-2,2-双(2-噻吩基)乙酰基]氧基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(1C) (0.5g，1.08mmol)溶于1,4-二氧六环(10mL)中，通入过量的盐酸气体，室温反应2小时。加入水(20mL)，在0℃用固体碳酸钾调pH为8至9，用乙酸乙酯(20mL×2)萃取，饱和氯化钠水溶液(20mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物7-氮杂螺[3.5]壬烷-2-基2-羟基-2,2-双(2-噻吩基)乙酸酯(1D)，白色固体(0.24g，产率61％)。2-[2-Hydroxy-2,2-bis(2-thienyl)acetyl]oxy-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (1C) (0.5 g, 1.08 mmol) was dissolved in 1,4-dioxane (10 mL), and an excess of hydrochloric acid gas was passed and allowed to react at room temperature for 2 hours. After adding water (20 mL), the pH was adjusted to 8 to 9 with a solid potassium carbonate, and extracted with ethyl acetate (20 mL×2), washed with saturated aqueous sodium chloride (20 mL×1), dried over anhydrous sodium sulfate The filtrate was concentrated under reduced pressure to give the title compound 7---------[[sup. , yield 61%).
1H NMR(400MHz,CDCl3)δ7.30(dd,2H),7.16(dd,2H),6.98(dd,2H),5.15(t,1H),4.61(s,1H),3.08(s,2H),3.01(s,2H),2.45-2.33(m,2H),1.99-1.87(m,4H),1.87-1.79(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.30 (dd, 2H), 7.16 (dd, 2H), 6.98 (dd, 2H), 5.15 (t, 1H), 4.61 (s, 1H), 3.08 (s, 2H), 3.01 (s, 2H), 2.45-2.33 (m, 2H), 1.99-1.87 (m, 4H), 1.87-1.79 (m, 2H).
LCMS m/z＝364.0[M+1].LCMS m/z = 364.0 [M + 1].
第四步：[7-[3-(2-氯-4-甲酰基-5-甲氧基苯胺基)-3-氧代-丙基]-7-氮杂螺[3.5]壬-2-基]-2-羟基-2,2-二(2-噻吩基)乙酸酯(1F)Fourth step: [7-[3-(2-chloro-4-formyl-5-methoxyanilino)-3-oxo-propyl]-7-azaspiro[3.5]壬-2- 2-hydroxy-2,2-bis(2-thienyl)acetate (1F)
[7-[3-(2-chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]-2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-(2-chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]-2-hydroxy-2,2- Bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000057
Figure PCTCN2016081809-appb-000057
将7-氮杂螺[3.5]壬烷-2-基2-羟基-2,2-双(2-噻吩基)乙酸酯(1D)(2.6g，7.153mmol)和N-(2-氯-4-甲酰基-5-甲氧基苯基)丙-2-烯酰胺(1E)(参考WO2010119064A1中合成实施例制备得到)(1.886g，7.868mmol)悬浮于2-甲基四氢呋喃(15mL)中，加入三乙胺(1.448g，14.31mmol)，微波100℃反应30分钟，停止反应。反应液冷却至室温后直接减压浓缩，残留物用硅胶柱层析(洗脱剂为二氯甲烷/甲醇(v:v)＝100/1～20/1)纯化，得到标题化合物[7-[3-(2-氯-4-甲酰基-5-甲氧基苯胺基)-3-氧代-丙基]-7-氮杂螺[3.5]壬-2-基]-2-羟基-2,2-二(2-噻吩基)乙酸酯(1F)，淡黄色固体(2g，产率46％)。7-Azaspiro[3.5]decane-2-yl 2-hydroxy-2,2-bis(2-thienyl)acetate (1D) (2.6 g, 7.153 mmol) and N-(2-chloro 4-formyl-5-methoxyphenyl)prop-2-enamide (1E) (prepared by reference to the synthesis example in WO2010119064A1) (1.886 g, 7.668 mmol) suspended in 2-methyltetrahydrofuran (15 mL) Triethylamine (1.448 g, 14.31 mmol) was added, and the reaction was stopped by microwave at 100 ° C for 30 minutes. After the reaction mixture was cooled to room temperature, the title compound was evaporated, mjjjjjjjj [3-(2-Chloro-4-formyl-5-methoxyanilino)-3-oxo-propyl]-7-azaspiro[3.5]indol-2-yl]-2-hydroxy- 2,2-bis(2-thienyl)acetate (1F), pale yellow solid (2 g, yield 46%).
1H NMR(400MHz,CDCl3)δ10.94(s,1H),10.30(s,1H),8.34(s,1H),7.81(s,1H),7.29(dd,2H),7.18(dd,2H),6.98(dd,2H),5.16(s,1H),4.67(s,1H),3.93(s,3H),3.78(s,1H),2.63(s,4H),2.46-2.31(m,4H),1.90(dd,2H),1.68(d,4H). 1 H NMR (400MHz, CDCl 3 ) δ10.94 (s, 1H), 10.30 (s, 1H), 8.34 (s, 1H), 7.81 (s, 1H), 7.29 (dd, 2H), 7.18 (dd, 2H), 6.98 (dd, 2H), 5.16 (s, 1H), 4.67 (s, 1H), 3.93 (s, 3H), 3.78 (s, 1H), 2.63 (s, 4H), 2.46-2.31 (m , 4H), 1.90 (dd, 2H), 1.68 (d, 4H).
LCMS m/z＝603.0[M+1].LCMS m/z = 603.0 [M + 1].
第五步：[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5- 基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(1H)Step 5: [7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H) -quinoline-5- Ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]indol-2-yl]2- Hydroxy-2,2-bis(2-thienyl)acetate (1H)
[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl] Amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000058
Figure PCTCN2016081809-appb-000058
将[7-[3-(2-氯-4-甲酰基-5-甲氧基苯胺基)-3-氧代-丙基]-7-氮杂螺[3.5]壬-2-基]-2-羟基-2,2-二(2-噻吩基)乙酸酯(1F)(0.603g，1mmol)和5-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基甲基]-8-羟基-1H-喹啉-2-酮(1G)(0.401g，1.2mmol)溶于二氯甲烷(5mL)和甲醇(5mL)的混合溶剂中，室温搅拌30分钟，加入三乙酰氧基硼氢化钠(0.636g，3.0mmol)，室温反应2小时。反应液加入二氯甲烷(20mL)，依次用饱和碳酸氢钠溶液(20mL×2)和饱和氯化钠水溶液(20mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析(洗脱剂为二氯甲烷/甲醇(v:v)＝100/1～20/1)纯化，得到标题化合物[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(1H)，淡黄色固体(0.6g，产率70％)。[7-[3-(2-Chloro-4-formyl-5-methoxyanilino)-3-oxo-propyl]-7-azaspiro[3.5]indol-2-yl]- 2-hydroxy-2,2-bis(2-thienyl)acetate (1F) (0.603 g, 1 mmol) and 5-[(1R)-2-amino-1-[tert-butyl(dimethyl) Silyl]oxymethyl]-8-hydroxy-1H-quinolin-2-one (1G) (0.401 g, 1.2 mmol) was dissolved in dichloromethane (5 mL) and methanol (5 mL) After stirring for 30 minutes, sodium triacetoxyborohydride (0.636 g, 3.0 mmol) was added, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was diluted with methylene chloride (20 mL), EtOAc (EtOAc m. Purification by column chromatography on silica gel eluting elut elut elut elut elut elut elut elut elut 2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro -5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]indol-2-yl]2-hydroxy-2,2-di(2-thienyl)B Acid ester (1H), light yellow solid (0.6 g, yield 70%).
第六步：[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(化合物1)The sixth step: [7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-7-azaspiro[3.5]indol-2-yl]2-hydroxy-2,2-dual ( 2-thienyl)acetate (compound 1)
[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]- 5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000059
Figure PCTCN2016081809-appb-000059
将[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(1H)(0.5g，0.543mmol)溶于二氯甲烷(10mL)中，加入三乙胺三氢氟酸盐(5mL)，35℃反应6小时。向反应液中加入二氯甲烷(50mL)，用饱和碳酸氢钠溶液调pH约为9，然后二氯甲烷(30mL×2)萃取，合并有机相，用饱和氯化钠水溶液(30mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析(洗脱剂为二氯甲烷/甲醇(v:v)＝100/1～20/1)纯化，得到标题化合物[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(化合物1)(0.13g，产率29.7％)。[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinoline) -5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]indol-2-yl 2-Hydroxy-2,2-bis(2-thienyl)acetate (1H) (0.5 g, 0.543 mmol) was dissolved in dichloromethane (10 mL) and triethylamine trihydrofluoric acid salt (5 mL) ), reacting at 35 ° C for 6 hours. Dichloromethane (50 mL) was added to the reaction mixture, and the mixture was adjusted to pH 9 with a saturated sodium hydrogen carbonate solution, and then extracted with dichloromethane (30 mL×2), and the organic phase was combined with saturated aqueous sodium chloride (30 mL×1) The mixture was washed with anhydrous sodium sulfate and filtered and evaporated. Compound [7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino) ]methyl]-5-methoxyanilino]-3-oxo-propyl]-7-azaspiro[3.5]indol-2-yl]2-hydroxy-2,2-bis(2-thiophene) Acetate (Compound 1) (0.13 g, yield 29.7%).
1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.12(d,1H),7.75(s,1H),7.47(dd,2H),7.30(s,2H),7.09(dd,2H),7.05(d,1H),6.99(dd,2H),6.91(d,1H),6.46(d,1H),5.11-5.00(m,2H),3.71(s,3H),3.64(s,2H),2.67(dd,2H),2.57(d,2H),2.53(d,2H),2.43-2.14(m,6H),1.76(dd,2H),1.60(s,2H),1.55(s,2H). 1 H NMR (400MHz, DMSO- d6) δ10.30 (s, 1H), 8.12 (d, 1H), 7.75 (s, 1H), 7.47 (dd, 2H), 7.30 (s, 2H), 7.09 (dd , 2H), 7.05 (d, 1H), 6.99 (dd, 2H), 6.91 (d, 1H), 6.46 (d, 1H), 5.11 - 5.00 (m, 2H), 3.71 (s, 3H), 3.64 ( s, 2H), 2.67 (dd, 2H), 2.57 (d, 2H), 2.53 (d, 2H), 2.43 - 2.14 (m, 6H), 1.76 (dd, 2H), 1.60 (s, 2H), 1.55 (s, 2H).
LCMS m/z＝807.1[M+1].LCMS m/z = 807.1 [M + 1].
实施例2：[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬-2-基]N-(2-苯基苯基)氨基甲酸酯(化合物2)Example 2: [7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]indol-2-yl]N-(2-phenylphenyl) Carbamate (Compound 2)
[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]- 5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate
Figure PCTCN2016081809-appb-000060
Figure PCTCN2016081809-appb-000060
Figure PCTCN2016081809-appb-000061
Figure PCTCN2016081809-appb-000061
第一步:1-异氰酸酯-2-苯基-苯(2B)First step: 1-isocyanate-2-phenyl-benzene (2B)
1-isocyanato-2-phenyl-benzene1-isocyanato-2-phenyl-benzene
Figure PCTCN2016081809-appb-000062
Figure PCTCN2016081809-appb-000062
将2-氨基联苯(2A)(2.4g,14mmol)溶于甲苯(50mL)中，加入三光气(1.7g,5.7mmol)，120℃反应1小时。反应液冷却至室温后，减压浓缩，得到标题化合物1-异氰酸酯-2-苯基-苯(2B)，褐色油状(2.7g，产率98％)。2-Aminobiphenyl (2A) (2.4 g, 14 mmol) was dissolved in toluene (50 mL), and toluene (1.7 g, 5.7 mmol) was added and reacted at 120 ° C for 1 hour. After the reaction mixture was cooled to room temperature, EtOAcjjjjjjjjj
第二步：2-[(2-苯基苯基)氨基甲酰基氧基]-7-氮杂螺[3,5]壬烷-7-氨基羧酸叔丁酯(2C)Second step: 2-[(2-Phenylphenyl)carbamoyloxy]-7-azaspiro[3,5]nonane-7-aminocarboxylic acid tert-butyl ester (2C)
tert-butyl 2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]nonane-7-carboxylateTert-butyl 2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2016081809-appb-000063
Figure PCTCN2016081809-appb-000063
将1-异氰酸酯-2-苯基-苯(2B)(2.7g,13.4mmol)溶于四氢呋喃(50mL)中，加入2-羟基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(1B)(1.9g,7.87mmol)，加入三乙胺(2.39g,23.6mmol)，70℃反应4小时。反应液冷却至室温后，减压浓缩后，残留物用硅胶柱色谱分离提纯(洗脱剂为乙酸乙酯：石油醚(v/v)＝0:1～1:9)，得到标题化合物2-[(2-苯基苯基)氨基甲酰基氧基]-7-氮杂螺[3,5]壬烷-7-氨基羧酸叔丁基酯(2C)，黄色油状(3.4g，产率99％)。 1-Isocyanate-2-phenyl-benzene (2B) (2.7 g, 13.4 mmol) was dissolved in tetrahydrofuran (50 mL), and 2-hydroxy-7-azaspiro[3.5]decane-7-carboxylic acid was added. Butyl ester (1B) (1.9 g, 7.87 mmol) was added triethylamine (2.39 g, 23.6 mmol), and reacted at 70 ° C for 4 hours. After the reaction mixture was cooled to room temperature, the residue was evaporated, evaporated, mjjjjjjj -[(2-Phenylphenyl)carbamoyloxy]-7-azaspiro[3,5]nonane-7-aminocarboxylic acid tert-butyl ester (2C), yellow oil (3.4 g, yield Rate 99%).
LCMS m/z＝459.2[M+23].LCMS m/z = 459.2 [M+23].
第三步：7-氮杂螺[3,5]壬烷-2-基N-(2-苯基苯基)氨基甲酸酯(2D)The third step: 7-azaspiro[3,5]decane-2-yl N-(2-phenylphenyl)carbamate (2D)
7-azaspiro[3.5]nonan-2-yl N-(2-phenylphenyl)carbamate7-azaspiro[3.5]nonan-2-yl N-(2-phenylphenyl)carbamate
Figure PCTCN2016081809-appb-000064
Figure PCTCN2016081809-appb-000064
将2-[(2-苯基苯基)氨基甲酰基氧基]-7-氮杂螺[3,5]壬烷-7-氨基羧酸叔丁基酯(2C)(3.4g,7.8mmol)溶于二氯甲烷(15mL)中，加入三氟乙酸(4.4g,39mmol)，室温反应3小时。反应液减压浓缩，之后加入水(20mL)和二氯甲烷(20mL)，加入氨水调节pH至9，萃取。水相用二氯甲烷(20mL×2)萃取，合并有机相。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后，残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝1:4～1:0；甲醇：二氯甲烷(v/v)＝1:9)，得到标题化合物7-氮杂螺[3,5]壬烷-2-基N-(2-苯基苯基)氨基甲酸酯(2D)，黄色固体(2.1g，产率80％)。2-[(2-Phenylphenyl)carbamoyloxy]-7-azaspiro[3,5]nonane-7-aminocarboxylic acid tert-butyl ester (2C) (3.4 g, 7.8 mmol Dissolved in dichloromethane (15 mL), trifluoroacetic acid (4.4 g, 39 mmol) was added and allowed to react at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and then water (20 mL) and dichloromethane (20 mL) The aqueous phase was extracted with dichloromethane (20 mL x 2) and organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and then evaporated, evaporated, evaporated, evaporated. Methane (v/v) = 1:9) gave the title compound 7-azaspiro[3,5]decane-2-yl N-(2-phenylphenyl)carbamate (2D), yellow Solid (2.1 g, yield 80%).
1H NMR(400MHz,CDCl3)δ8.11(d,1H),7.5(dd,2H),7.44-7.38(m,1H),7.38-7.31(m,3H),7.20(dd,1H),7.15-7.07(m,1H),6.66(s,1H),5.08-4.90(m,1H),2.81-2.75(m,2H),2.72(t,3H),2.37-2.24(m,2H),1.85-1.74(m,2H),1.60-1.50(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ8.11 (d, 1H), 7.5 (dd, 2H), 7.44-7.38 (m, 1H), 7.38-7.31 (m, 3H), 7.20 (dd, 1H), 7.15-7.07 (m, 1H), 6.66 (s, 1H), 5.08-4.90 (m, 1H), 2.81-2.75 (m, 2H), 2.72 (t, 3H), 2.37-2.24 (m, 2H), 1.85-1.74 (m, 2H), 1.60-1.50 (m, 4H).
LCMS m/z＝337.1[M+1].LCMS m/z = 337.1 [M + 1].
第四步：[7-[3-(2-氯-4-甲酰基-5-甲氧基-苯胺基)-3-氧代-丙基]-7-氮杂螺[3,5]壬烷-2-基N-(2-苯基苯基)氨基甲酸酯(2E)Fourth step: [7-[3-(2-chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3,5]壬Alkan-2-yl N-(2-phenylphenyl)carbamate (2E)
[7-[3-(2-chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate[7-[3-(2-chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate
Figure PCTCN2016081809-appb-000065
Figure PCTCN2016081809-appb-000065
将N-(2-氯-4-甲酰基-5-甲氧基苯基)丙烯酰胺(1E)(0.648g,2.71mmol)溶于2-甲基四氢呋喃(10mL)中，加入7-氮杂螺[3,5]壬烷-2-基N-(2-苯基苯基)氨基甲酸酯(2D)(0.700g,2.08mmol)，加入乙酸(0.250g,4.16mmol)，100℃微波反应1小时。反应液减压浓缩，残留物中加入二氯甲烷(20mL)，加入饱和碳酸氢钠水溶液(20mL)，萃取。水相用(20mL×2)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩。残留物用硅胶柱色谱分 离提纯(洗脱剂为乙酸乙酯：石油醚(v/v)＝1:1～1:0)，得到标题化合物[7-[3-(2-氯-4-甲酰基-5-甲氧基-苯胺基)-3-氧代-丙基]-7-氮杂螺[3,5]壬烷-2-基N-(2-苯基苯基)氨基甲酸酯(2E)，白色固体(1.0g，产率83％)。N-(2-Chloro-4-formyl-5-methoxyphenyl)acrylamide (1E) (0.648 g, 2.71 mmol) was dissolved in 2-methyltetrahydrofuran (10 mL). Spiro[3,5]decane-2-yl N-(2-phenylphenyl)carbamate (2D) (0.700 g, 2.08 mmol), added acetic acid (0.250 g, 4.16 mmol), microwave oven at 100 ° C Reaction for 1 hour. The reaction mixture was concentrated under reduced vacuo. dichloromethane (EtOAc) The aqueous layer was extracted with (20 mL×2), dried over anhydrous sodium sulfate The residue was chromatographed on silica gel column Deprotection (eluent: ethyl acetate: petroleum ether (v/v) = 1:1 to 1:0) gave the title compound [7-[3-(2-chloro-4-formyl-5-) Oxy-anilino)-3-oxo-propyl]-7-azaspiro[3,5]decane-2-yl N-(2-phenylphenyl)carbamate (2E), White solid (1.0 g, yield 83%).
1H NMR(400MHz,CDCl3)δ10.30(s,1H),8.33(s,1H),8.11(d,1H),7.81(s,1H),7.50(dd,2H),7.45-7.39(m,1H),7.39-7.33(m,3H),7.21(dd,1H),7.15-7.10(m,1H),6.62(s,1H),5.06-4.95(m,1H),3.93(s,3H),2.83-2.20(m,10H),1.90-1.77(m,2H),1.71(s,4H). 1 H NMR (400 MHz, CDCl 3 ) δ 10.30 (s, 1H), 8.33 (s, 1H), 8.11 (d, 1H), 7.81 (s, 1H), 7.50 (dd, 2H), 7.45-7.39 ( m, 1H), 7.39-7.33 (m, 3H), 7.21 (dd, 1H), 7.15-7.10 (m, 1H), 6.62 (s, 1H), 5.06-4.95 (m, 1H), 3.93 (s, 3H), 2.83-2.20 (m, 10H), 1.90-1.77 (m, 2H), 1.71 (s, 4H).
LCMS m/z＝576.1[M+1].LCMS m/z = 576.1 [M + 1].
第五步：[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3,5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(2F)Step 5: [7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3,5]壬Alkan-2-yl]N-(2-phenylphenyl)carbamate (2F)
[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl] Amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate
Figure PCTCN2016081809-appb-000066
Figure PCTCN2016081809-appb-000066
将[7-[3-(2-氯-4-甲酰基-5-甲氧基-苯胺基)-3-氧代-丙基]-7-氮杂螺[3,5]壬烷-2-基N-(2-苯基苯基)氨基甲酸酯(2E)(1.00g,1.74mmol)溶于二氯甲烷(10mL)和甲醇(10mL)中，加入5-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基甲基]-8-羟基-1H-喹啉-2-酮(1G)(0.581g,1.74mmol)，室温反应1小时。加入三乙酰氧基硼氢化钠(1.11g,5.21mmol)，室温反应2小时。反应液加入二氯甲烷(20mL)，加入饱和碳酸氢钠溶液(20mL)，萃取。水相用(20mL×1)萃取，无水硫酸钠干燥，过滤，滤液浓缩后，残留物用硅胶柱色谱分离提纯(洗脱剂为乙酸乙酯：石油醚(v/v)＝1:1～1:0，甲醇：二氯甲烷(v/v)＝1:99～1:19)，得到标题化合物[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3,5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(2F)，黄色固体(0.900g，产率58％)。[7-[3-(2-Chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3,5]nonane-2 -N-(2-phenylphenyl)carbamate (2E) (1.00 g, 1.74 mmol) was dissolved in dichloromethane (10 mL) and methanol (10 mL), and 5-[(1R)-2 -amino-1-[tert-butyl(dimethyl)silyl]oxymethyl]-8-hydroxy-1H-quinolin-2-one (1G) (0.581 g, 1.74 mmol), 1 hour at room temperature . Sodium triacetoxyborohydride (1.11 g, 5.21 mmol) was added and the mixture was reacted at room temperature for 2 hours. The reaction solution was added to dichloromethane (20 mL), and then evaporated. The aqueous phase was extracted with (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent ethyl acetate: petroleum ether (v/v) = 1:1 ~1:0, methanol: dichloromethane (v/v) = 1:99 to 1:19) to give the title compound [7-[3-[4-[[[(2))] (Dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy- Anilino]-3-oxo-propyl]-7-azaspiro[3,5]decane-2-yl]N-(2-phenylphenyl)carbamate (2F), yellow solid (0.900 g, yield 58%).
LCMS m/z＝447.6[(M+2)/2].LCMS m/z = 447.6 [(M+2)/2].
第六步：[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3,5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯 (化合物2)The sixth step: [7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3,5]decane-2-yl]N-(2-benzene Phenyl)carbamate (Compound 2)
[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]- 5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate
Figure PCTCN2016081809-appb-000067
Figure PCTCN2016081809-appb-000067
将[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3氧代-丙基]-7-氮杂螺[3,5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(2F)(0.900g,1.01mmol)溶于二氯甲烷(8mL)中，加入三乙胺三氢氟酸盐(1.62g,10.1mmol)，室温反应24小时。反应液加入水(20mL)和二氯甲烷(20mL),加入3％氢氧化钠溶液调节pH至12左右，萃取。水相用(20mL×2)萃取，合并有机相。有机相用饱和氯化钠水溶液(20mL×1)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩。残留物用硅胶柱色谱分离提纯(洗脱剂为乙酸乙酯：石油醚(v/v)＝1:1～1:0，甲醇：二氯甲烷(v/v)＝3:97～1:9)，得到标题化合物[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3,5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(化合物2)，黄色固体(0.32g，产率40.8％)。[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinoline- 5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3oxo-propyl]-7-azaspiro[3,5]nonan-2- N-(2-phenylphenyl)carbamate (2F) (0.900 g, 1.01 mmol) was dissolved in dichloromethane (8 mL) and triethylamine trihydrofluoric acid salt (1.62 g, 10.1 Methyl), reacted at room temperature for 24 hours. The reaction solution was poured into water (20 mL) and dichloromethane (20 mL), and then adjusted to pH 12 with 3% sodium hydroxide solution and extracted. The aqueous phase was extracted with (20 mL x 2) and the organic phases were combined. The organic layer was washed with EtOAc EtOAc EtOAc. The residue was purified by silica gel column chromatography (eluent ethyl acetate: petroleum ether (v/v) = 1:1 to 1:0, methanol: methylene chloride (v/v) = 3:97 to 1: 9), the title compound [7-[3-[2-chloro-4-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3,5]decane-2-yl]N-(2) -Phenylphenyl)carbamate (Compound 2), yellow solid (0.32 g, yield 40.8%).
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.60(s,1H),8.13(d,1H),7.78(s,1H),7.55-7.17(m,11H),7.07(d,1H),6.94(d,1H),6.48(d,1H),5.10(s,1H),4.74(s,1H),3.73(d,5H),2.80-2.66(m,2H),2.64-2.52(m,4H),2.38(s,4H),2.14(s,2H),1.56(s,6H). 1 H NMR (400MHz, DMSO- d6) δ10.34 (s, 1H), 8.60 (s, 1H), 8.13 (d, 1H), 7.78 (s, 1H), 7.55-7.17 (m, 11H), 7.07 (d, 1H), 6.94 (d, 1H), 6.48 (d, 1H), 5.10 (s, 1H), 4.74 (s, 1H), 3.73 (d, 5H), 2.80-2.66 (m, 2H), 2.64-2.52 (m, 4H), 2.38 (s, 4H), 2.14 (s, 2H), 1.56 (s, 6H).
LCMS m/z＝390.6[(M+2)/2].LCMS m/z = 390.6 [(M+2)/2].
实施例3：[7-[2-[[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基-苯基]氨基甲酰基氧基]乙基]-7-氮杂螺环[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(化合物3)Example 3: [7-[2-[[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Ethyl]amino]methyl]-5-methoxy-phenyl]carbamoyloxy]ethyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2, 2-bis(2-thienyl)acetate (compound 3)
[7-[2-[[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl]carbamoyloxy]ethyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate [7-[2-[[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]] -5-methoxy-phenyl]carbamoyloxy]ethyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000068
Figure PCTCN2016081809-appb-000068
第一步：[7-(2-羟基乙基)-7-氮杂螺环[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(3A)First step: [7-(2-hydroxyethyl)-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate ( 3A)
[7-(2-hydroxyethyl)-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-(2-hydroxyethyl)-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000069
Figure PCTCN2016081809-appb-000069
将7-氮杂螺环[3.5]壬烷-2-基2-羟基-2,2-双(2-噻吩基)乙酸酯(1D)(0.500g,1.38mmol)溶于乙腈(15mL)中，加入溴乙醇(0.516g,4.13mmol)和二异丙基乙胺(0.533g,4.13mmol)，90℃反应3小时。反应液冷却至室温，减压浓缩后，残留物用硅胶柱色谱分离提纯(洗脱剂为乙酸乙酯：石油醚(v/v)＝1:1～1:0；甲醇：二氯甲烷(v/v)＝3:97)，得到标题化合物[7-(2-羟基乙基)-7-氮杂螺环[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(3A)，黄色固体(0.54g，产率96.3％)。7-Azaspiro[3.5]decane-2-yl 2-hydroxy-2,2-bis(2-thienyl)acetate (1D) (0.500 g, 1.38 mmol) was dissolved in acetonitrile (15 mL) Among them, bromoethanol (0.516 g, 4.13 mmol) and diisopropylethylamine (0.533 g, 4.13 mmol) were added, and the mixture was reacted at 90 ° C for 3 hours. The reaction mixture was cooled to room temperature, and the residue was evaporated. mjjjjjjjjjjj v/v) = 3:97), the title compound [7-(2-hydroxyethyl)-7-azaspiro[3.5]decan-2-yl]2-hydroxy-2,2-bis ( 2-Thienyl)acetate (3A), yellow solid (0.54 g, yield 96.3%).
1H NMR(400MHz,CDCl3)δ7.30(dd,2H),7.16(dd,2H),6.99(dd,2H),5.19--5.10(m,1H),4.04(s,2H),3.50--2.79(m,6H),2.43(dd,2H),2.01(m,5H),1.61-1.42(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.30 (dd, 2H), 7.16 (dd, 2H), 6.99 (dd, 2H), 5.19--5.10 (m, 1H), 4.04 (s, 2H), 3.50 --2.79 (m, 6H), 2.43 (dd, 2H), 2.01 (m, 5H), 1.61-1.42 (m, 2H).
LCMS m/z＝408.1[M+1]。LCMS m/z = 408.1 [M + 1].
第二步：[7-[2-[(2-氯-4-甲酰基-5-甲氧基-苯基)氨基甲酰基氧基]乙基]-7-氮杂螺环[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(3C)Second step: [7-[2-[(2-chloro-4-formyl-5-methoxy-phenyl)carbamoyloxy]ethyl]-7-azaspiro[3.5]壬Alkan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (3C)
[7-[2-[(2-chloro-4-formyl-5-methoxy-phenyl)carbamoyloxy]ethyl]-7-azaspiro[3.5]nonan -2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[2-[(2-chloro-4-formyl-5-methoxy-phenyl)carbamoyloxy]ethyl]-7-azaspiro[3.5]nonan -2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000070
Figure PCTCN2016081809-appb-000070
将4-氨基-5-氯-2-甲氧基-苯甲醛(3B)(1.48g,7.95mmol)溶于甲苯(30mL)中，加入三光气(1.18g,3.97mmol)，120℃反应2小时。减压除去溶剂得到反应液1。将[7-(2-羟基乙基)-7-氮杂螺环[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(3A)(0.540g，1.32mmol)溶于四氢呋喃(20mL)中，加入反应液1，加入三乙胺(0.670g，6.62mmol)，70℃反应2小时。反应液冷却至室温，减压浓缩后，残留物用硅胶柱色谱分离提纯(洗脱剂为甲醇：二氯甲烷(v/v)＝1:99～5:95)，得到标题化合物[7–[2-[(2-氯-4-甲酰基-5-甲氧基-苯基)氨基甲酰基氧基]乙基]-7-氮杂螺环[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(3C)，黄色固体(0.600g，产率73.1％)。4-Amino-5-chloro-2-methoxy-benzaldehyde (3B) (1.48 g, 7.95 mmol) was dissolved in toluene (30 mL) and added to phosgene (1.18 g, 3.97 mmol). hour. The solvent was removed under reduced pressure to obtain a reaction mixture 1. [7-(2-Hydroxyethyl)-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (3A) ( 0.540 g, 1.32 mmol) was dissolved in tetrahydrofuran (20 mL), and the reaction mixture 1 was added, and triethylamine (0.670 g, 6.62 mmol) was added and reacted at 70 ° C for 2 hours. The reaction mixture was cooled to room temperature, and the residue was evaporated,jjjjjjjjjjjjj [2-[(2-Chloro-4-formyl-5-methoxy-phenyl)carbamoyloxy]ethyl]-7-azaspiro[3.5]decane-2-yl]2 -Hydroxy-2,2-bis(2-thienyl)acetate (3C), yellow solid (0.600 g, yield 73.1%).
1H NMR(400MHz,CDCl3)δ10.29(s,1H),8.01(s,1H),7.82(s,1H),7.29(dd,2H),7.17(dd,2H),6.98(dd,2H),5.19-5.08(m,1H),4.49(s,2H),3.94(s,3H),3.09-2.49(m,6H),2.45-2.32(m,2H),2.01-1.66(m,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 10.29 (s, 1H), 8.1 (s, 1H), 7.82 (s, 1H), 7.29 (dd, 2H), 7.17 (dd, 2H), 6.98 (dd, 2H), 5.19-5.08 (m, 1H), 4.49 (s, 2H), 3.94 (s, 3H), 3.09-2.49 (m, 6H), 2.45-2.32 (m, 2H), 2.01-1.66 (m, 6H).
LCMS m/z＝619.2[M+1]。LCMS m/z = 619.2 [M + 1].
第三步：[7-[2-[[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯基]氨基甲酰基氧基]乙基]-7-氮杂螺环[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(3D)The third step: [7-[2-[[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]carbamoyloxy]ethyl]-7-azaspiro[3.5]壬-alkyl-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (3D)
[7-[2-[[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]carbamoyloxy]ethyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[2-[[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl ]amino]methyl]-2-chloro-5-methoxy-phenyl]carbamoyloxy]ethyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000071
Figure PCTCN2016081809-appb-000071
将[7–[2-[(2-氯-4-甲酰基-5-甲氧基-苯基)氨基甲酰基氧基]乙基]-7-氮杂螺环[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(3C)(0.600g,0.969mmol)溶于二氯甲烷(10 mL)和甲醇(10mL)中，加入5-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基甲基]-8-羟基-1H-喹啉-2-酮(1G)(0.324g,0.969mmol)，室温反应1小时。加入三乙酰氧基硼氢化钠(0.619g,2.91mmol)，室温反应3小时。反应液加入二氯甲烷(20mL)，加入饱和碳酸氢钠水溶液(20mL)，萃取。水相用二氯甲烷(20mL×1)萃取，无水硫酸钠干燥，减压浓缩后，残留物用硅胶柱色谱分离提纯(洗脱剂为乙酸乙酯：石油醚(v/v)＝1:1～1:0，甲醇：二氯甲烷(v/v)＝1:99～1:19)，得到标题化合物[7-[2-[[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯基]氨基甲酰基氧基]乙基]-7-氮杂螺环[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(3D)，黄色固体(0.42g，产率46.2％)。[7-[2-[(2-Chloro-4-formyl-5-methoxy-phenyl)carbamoyloxy]ethyl]-7-azaspiro[3.5]decane-2 -yl]2-hydroxy-2,2-bis(2-thienyl)acetate (3C) (0.600 g, 0.969 mmol) dissolved in dichloromethane (10 In the mL) and methanol (10 mL), 5-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxymethyl]-8-hydroxy-1H-quinoline- 2-ketone (1G) (0.324 g, 0.969 mmol) was reacted for 1 hour at room temperature. Sodium triacetoxyborohydride (0.619 g, 2.91 mmol) was added and the mixture was reacted at room temperature for 3 hours. The reaction solution was added to dichloromethane (20 mL), and evaporated. The aqueous phase was extracted with dichloromethane (20 mL×1), dried over anhydrous sodium sulfate. :1 to 1:0, methanol: dichloromethane (v/v) = 1:99 to 1:19) to give the title compound [7-[2-[[4-[[[(2)) tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5- Methoxy-phenyl]carbamoyloxy]ethyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetic acid Ester (3D), yellow solid (0.42 g, yield 46.2%).
1H NMR(400MHz,CDCl3)δ8.19(d,1H),7.78(s,1H),7.28(dd,2H),7.17(dd,3H),7.06(s,1H),7.03-6.92(m,3H),6.84(d,1H),6.59(d,1H),5.22-5.04(m,2H),4.38-4.22(m,2H),3.83-3.71(m,5H),3.00-2.78(m,2H),2.71(t,2H),2.46(d,4H),2.37-2.28(m,2H),1.86(dd,2H),1.63(dd,4H),0.85(s,9H),0.02(s,3H),-0.22(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (d, 1H), 7.78 (s, 1H), 7.28 (dd, 2H), 7.17 (dd, 3H), 7.06 (s, 1H), 7.03-6.92 ( m, 3H), 6.84 (d, 1H), 6.59 (d, 1H), 5.22-5.04 (m, 2H), 4.38-4.22 (m, 2H), 3.83-3.71 (m, 5H), 3.00-2.78 ( m, 2H), 2.71 (t, 2H), 2.46 (d, 4H), 2.37-2.28 (m, 2H), 1.86 (dd, 2H), 1.63 (dd, 4H), 0.85 (s, 9H), 0.02 (s, 3H), -0.22 (s, 3H).
LCMS m/z＝469.3[(M+2)/2]。LCMS m/z = 469.3 [(M+2)/2].
第四步：[7-[2-[[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基-苯基]氨基甲酰基氧基]乙基]-7-氮杂螺环[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(化合物3)Fourth step: [7-[2-[[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Ethyl]amino]methyl]-5-methoxy-phenyl]carbamoyloxy]ethyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2, 2-bis(2-thienyl)acetate (compound 3)
[7-[2-[[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl]carbamoyloxy]ethyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[2-[[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]] -5-methoxy-phenyl]carbamoyloxy]ethyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000072
Figure PCTCN2016081809-appb-000072
将[7-[2-[[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯基]氨基甲酰基氧基]乙基]-7-氮杂螺环[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(3D)(0.420g,0.448mmol)溶于四氢呋喃(8mL)中，加入三乙胺三氢氟酸盐(0.722g,4.48mmol)，室温反应24小时。反应液加入二氯甲烷(50mL),加入饱和碳酸氢钠溶液调节pH至8左右，萃取。水相用二氯甲烷(50mL×1)萃取，合并 有机相。有机相用饱和氯化钠水溶液(20mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残留物用硅胶柱色谱分离提纯(洗脱剂为乙酸乙酯/石油醚(v/v)＝1:1～1:0，甲醇/二氯甲烷(v/v)＝3:97～5:95)，得到标题化合物[7-[2-[[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基-苯基]氨基甲酰基氧基]乙基]-7-氮杂螺环[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(化合物3)，黄色固体(0.13g，产率35.2％)。[7-[2-[[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quine啉-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]carbamoyloxy]ethyl]-7-azaspiro[3.5]decane- 2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (3D) (0.420 g, 0.448 mmol) was dissolved in tetrahydrofuran (8 mL) and triethylamine trihydrofluor 0.722 g, 4.48 mmol), reacted at room temperature for 24 hours. The reaction solution was added with dichloromethane (50 mL), and a saturated sodium hydrogen carbonate solution was added thereto to adjust the pH to about 8 and extracted. The aqueous phase was extracted with dichloromethane (50 mL×1) and combined The organic phase. The organic layer was washed with aq. The residue was purified by silica gel column chromatography (eluent ethyl acetate / petroleum ether (v/v) = 1:1 to 1:0, methanol / dichloromethane (v / v) = 3:97 - 5: 95), the title compound [7-[2-[[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-) Ethyl]amino]methyl]-5-methoxy-phenyl]carbamoyloxy]ethyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy- 2,2-bis(2-thienyl)acetate (compound 3), yellow solid (0.13 g, yield 35.2%).
1H NMR(400MHz,CD3OD)δ8.25(d,1H),7.75(s,1H),7.39(m,3H),7.25(d,1H),7.16(dd,2H),7.05-6.95(m,3H),6.64(d,1H),5.34(t,1H),5.18-5.06(m,1H),4.37(t,2H),4.09(s,2H),3.85d,3H),3.10(d,2H),2.84(t,2H),2.62(d,4H),2.42-2.29(m,2H),1.88(dd,2H),1.73(t,2H),1.66(t,2H). 1 H NMR (400 MHz, CD 3 OD) δ 8.25 (d, 1H), 7.75 (s, 1H), 7.39 (m, 3H), 7.25 (d, 1H), 7.16 (dd, 2H), 7.05-6.95 (m, 3H), 6.64 (d, 1H), 5.34 (t, 1H), 5.18-5.06 (m, 1H), 4.37 (t, 2H), 4.09 (s, 2H), 3.85d, 3H), 3.10 (d, 2H), 2.84 (t, 2H), 2.62 (d, 4H), 2.42-2.29 (m, 2H), 1.88 (dd, 2H), 1.73 (t, 2H), 1.66 (t, 2H).
LCMS m/z＝412.3[(M+2)/2]。LCMS m/z = 412.3 [(M+2)/2].
实施例4：[7-[2-[2-氯-4-[[[(2R)-2-羟基-2-(4-羟基-2-氧代-3H-1,3-苯并噻唑-7-基)乙基]氨基]甲基]-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺环[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(化合物4)Example 4: [7-[2-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazole- 7-yl)ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2- Hydroxy-2,2-bis(2-thienyl)acetate (compound 4)
[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino ]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000073
Figure PCTCN2016081809-appb-000073
将[7–[3-(2-氯-4-甲酰基-5-甲氧基-苯胺基)-3-氧代丙基]-7-氮杂螺环[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(1F)(0.420g,0.696mmol)溶于二氯甲烷(10mL)和甲醇(10mL)中，加入7-[(1R)-2-氨基-1-羟基-乙基]-4-羟基-3H-1,3-苯并噻唑-2-酮(4A，参考Bioorganic&Medicinal Chemistry Letters,21(15),4612-4616；2011制备得到)(0.173g, 0.766mmol)，室温反应1小时。加入三乙酰氧基硼氢化钠(0.445g,2.09mmol)，室温反应3小时。反应液加入二氯甲烷(20mL)和饱和碳酸氢钠水溶液(20mL)，萃取。水相用二氯甲烷(20mL×1)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。残留物用硅胶柱色谱分离提纯(洗脱剂为乙酸乙酯：石油醚(v/v)＝1:1～1:0，甲醇：二氯甲烷(v/v)＝1:99～1:19)，得到标题化合物[7-[2-[2-氯-4-[[[(2R)-2-羟基-2-(4-羟基-2-氧代-3H-1,3-苯并噻唑-7-基)乙基]氨基]甲基]-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺环[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(化合物4)，黄色固体(0.10g，产率17.7％)。[7-[3-(2-chloro-4-formyl-5-methoxy-anilino)-3-oxopropyl]-7-azaspiro[3.5]decan-2-yl 2-Hydroxy-2,2-bis(2-thienyl)acetate (1F) (0.420 g, 0.696 mmol) was dissolved in dichloromethane (10 mL) and methanol (10 mL). )-2-amino-1-hydroxy-ethyl]-4-hydroxy-3H-1,3-benzothiazol-2-one (4A, reference Bioorganic & Medicinal Chemistry Letters, 21 (15), 4612-4616; Get) (0.173g, 0.766 mmol), reacted at room temperature for 1 hour. Sodium triacetoxyborohydride (0.445 g, 2.09 mmol) was added and allowed to react at room temperature for 3 hours. The reaction solution was added with dichloromethane (20 mL) and brine. The aqueous phase was extracted with dichloromethane (20 mL×1). The residue was purified by silica gel column chromatography (eluent ethyl acetate: petroleum ether (v/v) = 1:1 to 1:0, methanol: methylene chloride (v/v) = 1:99 to 1: 19), the title compound [7-[2-[2-chloro-4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzo) Thiazol-7-yl)ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl] 2-Hydroxy-2,2-bis(2-thienyl)acetate (Compound 4), yellow solid (0.10 g, yield 17.7%).
1H NMR(400MHz,CD3OD)δ7.79(s,1H),7.31(dd,2H),7.27(s,1H),7.09(dd,2H),6.93(dd,2H),6.87(d,1H),6.68(d,1H),5.11-4.99(m,1H),4.75(s,1H),3.84(s,2H),3.74(s,3H),2.92-2.77(m,2H),2.68t,2H),2.59(t,2H),2.45(d,4H),2.33-2.22(m,2H),1.81(dd,2H),1.66(t,2H),1.59(s,2H). 1 H NMR (400MHz, CD 3 OD) δ7.79 (s, 1H), 7.31 (dd, 2H), 7.27 (s, 1H), 7.09 (dd, 2H), 6.93 (dd, 2H), 6.87 (d , 1H), 6.68 (d, 1H), 5.11-4.99 (m, 1H), 4.75 (s, 1H), 3.84 (s, 2H), 3.74 (s, 3H), 2.92-2.77 (m, 2H), 2.68t, 2H), 2.59 (t, 2H), 2.45 (d, 4H), 2.33-2.22 (m, 2H), 1.81 (dd, 2H), 1.66 (t, 2H), 1.59 (s, 2H).
LCMS m/z＝407.3[(M+2)/2]。LCMS m/z = 407.3 [(M+2)/2].
实施例5：[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯；二三氟乙酸盐(化合物5)Example 5: [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2 -hydroxy-2,2-bis(2-thienyl) acetate; ditrifluoroacetate (compound 5)
[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate；ditrifluoroacetic acid[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino ]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate;ditrifluoroacetic Acid
Figure PCTCN2016081809-appb-000074
Figure PCTCN2016081809-appb-000074
Figure PCTCN2016081809-appb-000075
Figure PCTCN2016081809-appb-000075
第一步：5-(甲基氨基)戊酸(5B)First step: 5-(methylamino)pentanoic acid (5B)
5-(methylamino)pentanoic acid5-(methylamino)pentanoic acid
Figure PCTCN2016081809-appb-000076
Figure PCTCN2016081809-appb-000076
将1-甲基-2-哌啶酮(5A)(7.0g,61.9mmol)加入到氢氧化钠(2.7g,68.0mmol)的水溶液(17mL)中，升温至110℃反应2天。冷却到0℃，用浓盐酸调节pH约为2，然后直接减压浓缩，得到标题化合物5-(甲基氨基)戊酸(5B)，白色固体(8.1g，产率100％)。1-Methyl-2-piperidone (5A) (7.0 g, 61.9 mmol) was added to an aqueous solution (17 mL) of sodium hydroxide (2.7 g, 68.0 mmol), and the mixture was warmed to 110 ° C for 2 days. The mixture was cooled to 0 ° C, EtOAc (EtOAc m.
LCMS m/z＝132.1[M+1]。LCMS m/z = 132.1 [M + 1].
第二步：5-(甲基氨基)戊酸甲酯(5C)The second step: methyl 5-(methylamino)pentanoate (5C)
methyl 5-(methylamino)pentanoateMethyl 5-(methylamino)pentanoate
Figure PCTCN2016081809-appb-000077
Figure PCTCN2016081809-appb-000077
将5-(甲基氨基)戊酸(5B)(8.0g,61.0mmol)溶于无水甲醇(100mL)中，冷却至0℃，加入氯化亚砜(7.3g,61.0mmol)，升温到50℃，搅拌2小时。直接减压浓缩，然后用二氯甲烷(150mL×3)连续浓缩，除去产品中所含的甲醇，得到标题产物5-(甲基氨基)戊酸甲酯(5C)，灰白固体(8.8g，产率100％)。5-(Methylamino)pentanoic acid (5B) (8.0 g, 61.0 mmol) was dissolved in anhydrous methanol (100 mL), cooled to 0 ° C, thionyl chloride (7.3 g, 61.0 mmol) Stir at 50 ° C for 2 hours. The organic layer was concentrated under reduced pressure, and then concentrated with methylene chloride (150 mL×3) to remove the methanol in the product to give the title product 5-(methylamino)pentanoic acid methyl ester (5C) as a white solid (8.8 g, Yield 100%).
LCMS m/z＝146.2[M+1]。LCMS m/z = 146.2 [M + 1].
第三步：5-[甲基(丙-2-烯酰基)氨基]戊酸甲酯(5D)The third step: 5-[methyl(prop-2-enoyl)amino]pentanoic acid methyl ester (5D)
methyl 5-[methyl(prop-2-enoyl)amino]pentanoate Methyl 5-[methyl(prop-2-enoyl)amino]pentanoate
Figure PCTCN2016081809-appb-000078
Figure PCTCN2016081809-appb-000078
将5-(甲基氨基)戊酸甲酯(5C)(5.9g,40.0mmol)和丙烯酸(1.44g,20.0mmol)溶于二氯甲烷(25mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU,CAS:148893-10-1)(11.4g,30mmol)，冷却到0℃，滴加N,N-二异丙基乙胺(20.7g,160mmol)，升至室温下反应3小时，向反应液加入二氯甲烷(120mL)和水(100mL)，萃取分层，再用饱和氯化钠水溶液(100mL×1)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩后，残留物硅胶柱层析提纯(洗脱剂为乙酸乙酯：石油醚(v/v)＝0：1～1:3)，得到标题化合物5-[甲基(丙-2-烯酰基)氨基]戊酸甲酯(5D)，褐色液体(1.8g，产率45％)。Methyl 5-(methylamino)pentanoate (5C) (5.9 g, 40.0 mmol) and acrylic acid (1.44 g, 20.0 mmol) were dissolved in dichloromethane (25 mL), and 2-(7-azobenzene) was added. And triazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, CAS: 148893-10-1) (11.4g, 30mmol), cooled to 0 ° C, added N , N-diisopropylethylamine (20.7 g, 160 mmol), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were added dichloromethane (120 mL) and water (100 mL). The aqueous solution (100 mL × 1) was washed with EtOAc EtOAc. ～1:3) The title compound 5-[methyl(prop-2-enoyl)amino]pentanoic acid methyl ester (5D) was obtained as a brown liquid (1.8 g, yield 45%).
1H NMR(400MHz,CDCl3)δ6.56(m,1H),6.31d,1H),5.67(dd,1H),3.67(s,3H),3.49-3.32(m,2H),3.09-2.96(m,3H),2.35(t,2H),1.62(d,4H). 1 H NMR (400MHz, CDCl 3 ) δ6.56 (m, 1H), 6.31d, 1H), 5.67 (dd, 1H), 3.67 (s, 3H), 3.49-3.32 (m, 2H), 3.09-2.96 (m, 3H), 2.35 (t, 2H), 1.62 (d, 4H).
LCMS m/z＝200.1M+1]。LCMS m/z = 200.1 M+1].
第四步：5-[甲基(丙-2-烯酰基)氨基]戊酸(5E)Step 4: 5-[Methyl(prop-2-enoyl)amino]pentanoic acid (5E)
5-[methyl(prop-2-enoyl)amino]pentanoic acid5-[methyl(prop-2-enoyl)amino]pentanoic acid
Figure PCTCN2016081809-appb-000079
Figure PCTCN2016081809-appb-000079
将5-[甲基(丙-2-烯酰基)氨基]戊酸甲酯(5D)(1.8g,9.0mmol)溶于四氢呋喃(20mL)中，加入氢氧化锂(0.32g,14mmol)的水溶液(40mL)，室温下反应3小时，冷却至0℃，调节pH约为3，加入二氯甲烷(50mL×3)萃取，合并有机层，用无水硫酸钠，干燥，过滤，滤液减压浓缩，得到标题化合物5-[甲基(丙-2-烯酰基)氨基]戊酸(5E)，褐色油状(1.48g，产率88％)。Methyl 5-[methyl(prop-2-enoyl)amino]pentanoate (5D) (1.8 g, 9.0 mmol) was dissolved in tetrahydrofuran (20 mL), and aqueous solution of lithium hydroxide (0.32 g, 14 mmol) was added. (40 mL), the mixture was reacted for 3 hours at room temperature, cooled to 0 ° C, adjusted to pH 3, extracted with dichloromethane (50 mL × 3), combined organic layer, dried over anhydrous sodium sulfate The title compound 5-[methyl(prop-2-enoyl)amino]pentanoic acid (5E) was obtained as a brown oil (1.48 g, yield 88%).
LCMS m/z＝186.1[M+1]。LCMS m/z = 186.1 [M + 1].
第五步：5-[3-[2-[2-羟基-2,2-双(2-噻吩基)乙酰基]氧基-7-氮杂螺[3.5]壬-7-基]丙酰基-甲基-氨基]戊酸(5F)Step 5: 5-[3-[2-[2-Hydroxy-2,2-bis(2-thienyl)acetyl]oxy-7-azaspiro[3.5]indole-7-yl]propanoyl -methyl-amino]pentanoic acid (5F)
5-[3-[2-[2-hydroxy-2,2-bis(2-thienyl)acetyl]oxy-7-azaspiro[3.5]nonan-7-yl]propanoyl-methyl-amino]pentanoic acid5-[3-[2-[2-hydroxy-2,2-bis(2-thienyl)acetyl]oxy-7-azaspiro[3.5]nonan-7-yl]propanoyl-methyl-amino]pentanoic acid
Figure PCTCN2016081809-appb-000080
Figure PCTCN2016081809-appb-000080
将5-[甲基(丙-2-烯酰基)氨基]戊酸(5E)(0.76g,4.13mmol)和7-氮杂螺[3.5]壬烷-2- 基2-羟基-2,2-双(2-噻吩基)乙酸酯(1D)(1.00g,2.75mmol)溶于2-甲基四氢呋喃(20mL)中，加入N,N-二异丙基乙胺(0.57g,5.5mmol)，置于微波反应器中，升温至100℃反应1小时，冷却至室温后，减压浓缩，残留物用硅胶柱层析提纯(洗脱剂为二氯甲烷/甲醇(v:v)＝1/0～9/1)，得到标题化合物5-[3-[2-[2-羟基-2,2-双(2-噻吩基)乙酰基]氧基-7-氮杂螺[3.5]壬-7-基]丙酰基-甲基-氨基]戊酸(5F)，浅黄固体(1.1g，产率73％)。5-[Methyl(prop-2-enoyl)amino]pentanoic acid (5E) (0.76 g, 4.13 mmol) and 7-azaspiro[3.5]decane-2- 2-Hydroxy-2,2-bis(2-thienyl)acetate (1D) (1.00 g, 2.75 mmol) was dissolved in 2-methyltetrahydrofuran (20 mL) and N,N-diisopropyl was added. Ethylamine (0.57 g, 5.5 mmol) was placed in a microwave reactor, and the mixture was heated to 100 ° C for 1 hour. After cooling to room temperature, it was concentrated under reduced pressure. /methanol (v:v) = 1/0 to 9/1) to give the title compound 5-[3-[2-[2-hydroxy-2,2-bis(2-thienyl)acetyl]oxy- 7-Azaspiro[3.5]dec-7-yl]propanoyl-methyl-amino]pentanoic acid (5F), pale yellow solid (1.1 g, yield 73%).
1H NMR(400MHz,CDCl3)δ7.29(dd,2H),7.16(dd,2H),7.02-6.92(m,2H),5.13(dd,1H),3.34(m,2H),3.06(m,2H),3.00-2.89(m,3H),2.80(m,6H),2.47-2.23(m,4H),1.97-1.71(m,6H),1.62(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ7.29 (dd, 2H), 7.16 (dd, 2H), 7.02-6.92 (m, 2H), 5.13 (dd, 1H), 3.34 (m, 2H), 3.06 ( m, 2H), 3.00-2.89 (m, 3H), 2.80 (m, 6H), 2.47-2.23 (m, 4H), 1.97-1.71 (m, 6H), 1.62 (m, 4H).
LCMS m/z＝601.2[M+1]。LCMS m/z = 601.2 [M + 1].
第六步：[7-[3-[[5-[4-(1,3-二氧杂环戊-2-基)苯胺]-5-氧代-戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(5H)The sixth step: [7-[3-[[5-[4-(1,3-dioxolan-2-yl)aniline]-5-oxo-pentyl]-methyl-amino]- 3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (5H)
[7-[3-[[5-[4-(1,3-dioxolan-2-yl)anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-[[5-[4-(1,3-dioxolan-2-yl)anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[ 3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000081
Figure PCTCN2016081809-appb-000081
将5-[3-[2-[2-羟基-2,2-双(2-噻吩基)乙酰基]氧基-7-氮杂螺[3.5]壬-7-基]丙酰基-甲基-氨基]戊酸(5F)(1.0g,1.82mmol)和4-(1,3-二氧戊环-2-基)苯胺(5G)(0.60g,3.64mmol)溶于二氯甲烷(25mL)中，冷却到0℃，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU,CAS:148893-10-1)(1.04g,2.73mmol)，滴加N,N-二异丙基乙胺(0.47g,3.65mmol)，室温下反应3小时。向反应液加入二氯甲烷(120mL)和水(100mL)，萃取分层，有机相用再用饱和氯化钠水溶液(100mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析提纯(洗脱剂为二氯甲烷/甲醇(v:v)＝1/0～9/1)，得到标题化合物[7-[3-[[5-[4-(1,3-二氧杂环戊-2-基)苯胺]-5-氧代-戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(5H)，黄色固体(1.3g，产率100％)。5-[3-[2-[2-Hydroxy-2,2-bis(2-thienyl)acetyl)oxy-7-azaspiro[3.5]indole-7-yl]propanoyl-methyl -Amino]pentanoic acid (5F) (1.0 g, 1.82 mmol) and 4-(1,3-dioxolan-2-yl)phenylamine (5G) (0.60 g, 3.64 mmol) dissolved in dichloromethane (25 mL) , cooled to 0 ° C, added 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluron hexafluorophosphate (HATU, CAS: 148893-10- 1) (1.04 g, 2.73 mmol), N,N-diisopropylethylamine (0.47 g, 3.65 mmol) was added dropwise, and the mixture was reacted at room temperature for 3 hours. Dichloromethane (120 mL) and water (100 mL) were added to the mixture, and the mixture was evaporated. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut elut elut 1,3-dioxolan-2-yl)aniline]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]壬Alkan-2-yl] 2-hydroxy-2,2-bis(2-thienyl)acetate (5H), yellow solid (1.3 g, yield 100%).
1H NMR(400MHz,CDCl3)δ7.62(d,2H),7.41(t,2H),7.29(m,2H),7.17(m,2H),6.98(dd,2H),5.76(s,1H),5.12(m,1H),4.10(m,2H),4.02(m,2H),3.39(m,2H),2.97(s,3H),2.68(m,2H),2.54(m,2H),2.36(m,8H),1.85(m,2H),1.71(m,4H),1.57(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ7.62 (d, 2H), 7.41 (t, 2H), 7.29 (m, 2H), 7.17 (m, 2H), 6.98 (dd, 2H), 5.76 (s, 1H), 5.12 (m, 1H), 4.10 (m, 2H), 4.02 (m, 2H), 3.39 (m, 2H), 2.97 (s, 3H), 2.68 (m, 2H), 2.54 (m, 2H) ), 2.36 (m, 8H), 1.85 (m, 2H), 1.71 (m, 4H), 1.57 (m, 4H).
LCMS m/z＝696.3[M+1]。LCMS m/z = 696.3 [M + 1].
第七步：[7-[3-[[5-(4-甲酰苯胺)-5-氧代-戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(5I)Step 7: [7-[3-[[5-(4-Formylanilide)-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-aza Spiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (5I)
[7-[3-[[5-(4-formylanilino)-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-[[5-(4-formylanilino)-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy -2,2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000082
Figure PCTCN2016081809-appb-000082
将[7-[3-[[5-[4-(1,3-二氧杂环戊-2-基)苯胺]-5-氧代-戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(5H)(1.1g,1.6mmol)溶于乙腈(40mL)中，滴加3M盐酸水溶液(20mL)，室温反应1小时。向反应液加入二氯甲烷(100mL)和水(100mL)，萃取分层，有机相再用饱和氯化钠水溶液(100mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物[7-[3-[[5-(4-甲酰苯胺)-5-氧代-戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(5I)，黄色固体(0.95g，产率92％)。[7-[3-[[5-[4-(1,3-dioxolan-2-yl)aniline]-5-oxo-pentyl]-methyl-amino]-3-oxo代-propyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (5H) (1.1 g, 1.6 mmol) A 3 M aqueous hydrochloric acid solution (20 mL) was added dropwise to acetonitrile (40 mL), and the mixture was reacted at room temperature for 1 hour. Dichloromethane (100 mL) and water (100 mL) were added to the mixture and the mixture was evaporated. The title compound [7-[3-[[5-(4-formanilide)-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[ 3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (5I), yellow solid (0.95 g, yield 92%).
1H NMR(400MHz,CDCl3)δ9.89(s,1H),7.94(dd,2H),7.81(dd,2H),7.30(m,2H),7.15(m,2H),6.98(m,2H),5.13(m,1H),3.29(m,4H),3.09(t,2H),2.98(m,3H),2.59(m,4H),2.32(m,4H),1.98(m,2H),1.75(m,8H). 1 H NMR (400MHz, CDCl 3 ) δ9.89 (s, 1H), 7.94 (dd, 2H), 7.81 (dd, 2H), 7.30 (m, 2H), 7.15 (m, 2H), 6.98 (m, 2H), 5.13 (m, 1H), 3.29 (m, 4H), 3.09 (t, 2H), 2.98 (m, 3H), 2.59 (m, 4H), 2.32 (m, 4H), 1.98 (m, 2H) ), 1.75 (m, 8H).
LCMS m/z＝652.2[M+1]。LCMS m/z = 652.2 [M + 1].
第八步：[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯胺基]-5-氧代-戊基]-甲基-氨基]-3氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(5K)Step 8: [7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-) Oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3 oxo-propyl]-7-nitrogen Heterospiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (5K)
[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5- Yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2- Bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000083
Figure PCTCN2016081809-appb-000083
将[7-[3-[[5-(4-甲酰苯胺)-5-氧代-戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(5I)(0.25g,0.38mmol)和5-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基甲基]-8-羟基-1H-喹啉-2-酮(1G)(0.19g,0.58mmol)溶于异丙醇/二氯甲烷(v/v＝1：1,10mL)混合溶剂中，室温搅拌1小时，然后加入三乙酰氧基硼氢化钠(0.24g,1.14mmol)，再搅拌2小时。向反应液加入二氯甲烷(150mL)和水(50mL)，萃取分层，有机相再用饱和氯化钠水溶液(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析提纯(洗脱剂为二氯甲烷/甲醇(v:v)＝1/0 ～9/1)，得到标题化合物[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯胺基]-5-氧代-戊基]-甲基-氨基]-3氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯酯(5K)，浅黄固体(0.17g，产率46％)。[7-[3-[[5-(4-Formylanilide)-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5 ]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (5I) (0.25 g, 0.38 mmol) and 5-[(1R)-2-amino-1- [tert-Butyl(dimethyl)silyl]oxymethyl]-8-hydroxy-1H-quinolin-2-one (1G) (0.19 g, 0.58 mmol) was dissolved in isopropyl alcohol / dichloromethane ( v/v = 1:1, 10 mL), the mixture was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.24 g, 1.14 mmol) was added and stirred for 2 hours. Dichloromethane (150 mL) and water (50 mL) were added to the mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated Purification by silica gel column chromatography (eluent: methylene chloride / methanol (v: v) = 1 / 0 to 9 / 1) to give the title compound [7-[3-[[5-[4-[[ [(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl Anilino]-5-oxo-pentyl]-methyl-amino]-3oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2,2 - bis(2-thienyl) acetate (5K), pale yellow solid (0.17 g, yield 46%).
第九步：[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯；二三氟乙酸盐(化合物5)Step 9: [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2 -hydroxy-2,2-bis(2-thienyl) acetate; ditrifluoroacetate (compound 5)
[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate；ditrifluoroacetic acid[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino ]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate;ditrifluoroacetic Acid
Figure PCTCN2016081809-appb-000084
Figure PCTCN2016081809-appb-000084
将[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯胺基]-5-氧代-戊基]-甲基-氨基]-3氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(5K)(0.17g,0.18mmol)溶于二氯甲烷(10mL)中，加入三乙胺三氢氟酸盐(0.14g,0.88mmol)，室温反应过夜，反应液用饱和碳酸氢钠调碱，用8％甲醇/二氯甲烷(v/v＝8:92,100mL)萃取，有机相用饱和氯化钠水溶液(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用液相制备柱分离提纯(液相制备条件：C18反相制备柱，流动相为含0.05％TFA的去离子水(A)，含0.05％TFA的乙腈(B)，梯度洗脱A:B＝10％～55％，洗脱时间39min，流速1.0mL/min，柱温：40℃)，得到标题化合物[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩 基)乙酸酯；二三氟乙酸盐(化合物5)，浅黄固体(0.045g，产率24％)。[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3 oxo-propyl]-7-azaspiro[ 3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (5K) (0.17 g, 0.18 mmol) was dissolved in dichloromethane (10 mL). Ammonia trihydrofluoride (0.14 g, 0.88 mmol), mp mp mp EtOAc (EtOAc) The mixture was washed with a saturated aqueous solution of sodium chloride (50 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by liquid phase preparative column (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase Deionized water (A) containing 0.05% TFA, acetonitrile (B) containing 0.05% TFA, gradient elution A: B = 10% to 55%, elution time 39 min, flow rate 1.0 mL/min, column temperature: 40 °C), the title compound [7-[3-[[5([(2))))) Ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]壬2-yl] -2-hydroxy-2,2-bis (2-thienyl Acetate; ditrifluoroacetate (compound 5), pale yellow solid (0.045 g, yield 24%).
1H NMR(400MHz,CD3OD)δ8.06(dd,1H),7.54(dd,2H),7.32(dd,2H),7.25(dd,2H),7.13(d,1H),7.01(m,2H),6.87(m,3H),6.49(dd,1H),5.25(m,1H),4.99(dt,1H),4.13(d,2H),3.30(m,6H),3.07(d,2H),2.82(m,7H),2.32(m,3H),2.21(s,1H),1.82(dd,3H),1.70(m,3H),1.55(m,4H).. 1 H NMR (400MHz, CD 3 OD) δ8.06 (dd, 1H), 7.54 (dd, 2H), 7.32 (dd, 2H), 7.25 (dd, 2H), 7.13 (d, 1H), 7.01 (m , 2H), 6.87 (m, 3H), 6.49 (dd, 1H), 5.25 (m, 1H), 4.99 (dt, 1H), 4.13 (d, 2H), 3.30 (m, 6H), 3.07 (d, 2H), 2.82 (m, 7H), 2.32 (m, 3H), 2.21 (s, 1H), 1.82 (dd, 3H), 1.70 (m, 3H), 1.55 (m, 4H)..
LCMS m/z＝428.9[(M+2)/2]。LCMS m/z = 428.9 [(M+2)/2].
实施例6：[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(5-羟基-3-氧代-4H-1,4-苯并恶嗪-8-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯；二三氟乙酸盐(化合物6)Example 6: [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine) -8-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane 2-yl]2-hydroxy-2,2-bis(2-thienyl) acetate; ditrifluoroacetate (compound 6)
[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate；ditrifluoroacetic acid[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino ]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl Acetate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000085
Figure PCTCN2016081809-appb-000085
第一步：[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(5-羟基-3-氧代-4H-1,4-苯并恶嗪-8-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(6B)First step: [7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-) Oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propan -7-Azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (6B)
[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspir o[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4- Benzoxazin-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspir o[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000086
Figure PCTCN2016081809-appb-000086
将[7-[3-[[5-(4-甲酰苯胺)-5-氧代-戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(5I)(0.2g,0.3mmol)和8-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基乙基]-5-羟基-4H-1,4-苯并恶嗪-3-酮(6A)(参考WO2008149110A1中间体65的合成方法制备)(0.2g,0.5mmol)溶于溶于异丙醇/二氯甲烷(v/v＝1：1,10mL)混合溶剂中，室温搅拌1小时，然后加入三乙酰氧基硼氢化钠(0.19g,0.9mmol)，再搅拌2小时。向反应液加入二氯甲烷(150mL)和水(50mL)，萃取分层，有机相再用饱和氯化钠水溶液(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(5-羟基-3-氧代-4H-1,4-苯并恶嗪-8-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(6B)，浅黄固体(0.2g，产率70％)。[7-[3-[[5-(4-Formylanilide)-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5 ]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (5I) (0.2 g, 0.3 mmol) and 8-[(1R)-2-amino-1- [tert-Butyl(dimethyl)silyl]oxyethyl]-5-hydroxy-4H-1,4-benzoxazin-3-one (6A) (Prepared by the synthesis method of Intermediate 65 of WO2008149110A1) (0.2 g, 0.5 mmol) was dissolved in a mixed solvent of isopropanol / dichloromethane (v / v = 1:1, 10 mL), stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.19 g) , 0.9 mmol), stirred for another 2 hours. Dichloromethane (150 mL) and water (50 mL) were added to the mixture and the mixture was evaporated. Title Compound [7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo) -4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl] -7-Azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (6B), pale yellow solid (0.2 g, yield 70%).
LCMS m/z＝487.9[(M+2)/2]。LCMS m/z = 487.9 [(M+2)/2].
第二步：[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(5-羟基-3-氧代-4H-1,4-苯并恶嗪-8-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯；二三氟乙酸盐(化合物6)Step 2: [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine) -8-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane 2-yl]2-hydroxy-2,2-bis(2-thienyl) acetate; ditrifluoroacetate (compound 6)
[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate；ditrifluoroacetic acid[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino ]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl Acetate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000087
Figure PCTCN2016081809-appb-000087
将[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(5-羟基-3-氧代-4H-1,4-苯并恶嗪-8-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(6B)(0.2g,0.2mmol)溶于四氢呋喃(5mL)中，加入三乙胺三氢氟酸盐(0.2g,1.0mmol)，室温反应过夜，反应液用饱和碳酸氢钠 调碱，过滤，所得固体用8％甲醇/二氯甲烷(v/v＝8:92,50mL)溶解，饱和氯化钠水溶液(50mL×1)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用液相制备柱分离提纯(液相制备条件：C18反相制备柱，流动相为含0.05％TFA的去离子水(A)，含0.05％TFA的乙腈(B)，梯度洗脱A:B＝10％～55％，洗脱时间39min，流速1.0mL/min，柱温：40℃)，得到标题化合物[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(5-羟基-3-氧代-4H-1,4-苯并恶嗪-8-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯；二三氟乙酸盐(化合物6)，白色固体(0.104g，产率50％)。[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-) 4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]- 7-Azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (6B) (0.2 g, 0.2 mmol) was dissolved in tetrahydrofuran (5 mL) Add triethylamine trihydrofluoride (0.2 g, 1.0 mmol), react at room temperature overnight, and use saturated sodium bicarbonate The base was dissolved, and the obtained solid was dissolved with EtOAc EtOAc EtOAc EtOAc EtOAc The organic layer was concentrated under reduced pressure, and the residue was purified by liquid phase preparative column (liquid phase preparation conditions: C18 reverse phase preparation column, mobile phase was deionized water (A) containing 0.05% TFA, acetonitrile (B) containing 0.05% TFA, Gradient elution A: B = 10% to 55%, elution time 39 min, flow rate 1.0 mL/min, column temperature: 40 ° C), the title compound [7-[3-[[5-[4-[[[ (2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]anilino]-5-oxo Deamyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl) Acetate; ditrifluoroacetate (compound 6), white solid (0.104 g, yield 50%).
1H NMR(400MHz,CD3OD)δ7.68(dd,2H),7.45(dd,2H),7.40(dd,2H),7.16(t,2H),7.01(m,3H),6.58(d,1H),5.16(m,2H),4.49(m,2H),4.23m,2H),3.44(m,6H),3.17(dd,1H),2.98(m,8H),2.47(m,3H),2.37(m,1H),1.98(m,3H),1.84(d,3H),1.70(m,4H). 1 H NMR (400MHz, CD 3 OD) δ7.68 (dd, 2H), 7.45 (dd, 2H), 7.40 (dd, 2H), 7.16 (t, 2H), 7.01 (m, 3H), 6.58 (d , 1H), 5.16 (m, 2H), 4.49 (m, 2H), 4.23m, 2H), 3.44 (m, 6H), 3.17 (dd, 1H), 2.98 (m, 8H), 2.47 (m, 3H) ), 2.37 (m, 1H), 1.98 (m, 3H), 1.84 (d, 3H), 1.70 (m, 4H).
LCMS m/z＝430.8[(M+2)/2]。LCMS m/z = 430.8 [(M+2)/2].
化合物6的游离碱：[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(5-羟基-3-氧代-4H-1,4-苯并恶嗪-8-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯The free base of compound 6: [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzo) Oxazin-8-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]壬-alkyl-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate
[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino ]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl Acetate
Figure PCTCN2016081809-appb-000088
Figure PCTCN2016081809-appb-000088
将[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(5-羟基-3-氧代-4H-1,4-苯并恶嗪-8-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(6B)(40.0g,41.1mmol)溶于四氢呋喃(500mL)中，加入三乙胺三氢氟酸盐(33.1g,205mmol)，室温反应过夜，反应液用饱和碳酸氢钠调碱，过滤，所得固体用8％甲醇/二氯甲烷(v/v＝8:92,50mL)溶解，饱和氯化钠水溶液(250mL×1)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用液相制备柱分离提纯(液相制备条件：C18反相制备柱，流动相为含0.05％TFA的去离子水(A)，含0.05％TFA的乙腈(B)，梯度洗脱A:B＝10％～55％，洗脱时间39min，流速1.0mL/min，柱温：40℃)。将制备所得溶液减压浓缩除去溶剂，所得固体用8％甲醇/二氯甲烷(v/v＝8:92，500mL)溶解，加入饱和碳酸氢钠水溶液(250mL)，分液，水相用用8％(v/v) 甲醇/二氯甲烷(250mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩后得到标题化合物[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(5-羟基-3-氧代-4H-1,4-苯并恶嗪-8-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(化合物6的游离碱)，白色固体(18.0g，产率51.0％)。[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-) 4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]- 7-Azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (6B) (40.0 g, 41.1 mmol) was dissolved in tetrahydrofuran (500 mL) Triethylamine trihydrofluoride (33.1 g, 205 mmol) was added, and the reaction mixture was stirred at room temperature overnight. 92, 50 mL) was dissolved, washed with a saturated aqueous solution of sodium chloride (250 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography. Prepare the column, the mobile phase is deionized water (A) containing 0.05% TFA, acetonitrile (B) containing 0.05% TFA, gradient elution A: B = 10% to 55%, elution time 39 min, flow rate 1.0 mL / Min, column temperature: 40 ° C). The obtained solution was concentrated under reduced pressure to remove the solvent. The obtained solid was dissolved in EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc 8% (v/v) The mixture was extracted with EtOAc / EtOAc (EtOAc (EtOAc). 2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]anilino]-5-oxo Pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)B Acid ester (free base of compound 6), white solid (18.0 g, yield 51.0%).
1H NMR(400MHz,CD3OD)δ7.44(d,1H),7.42(d,1H),7.26(m,2H),7.18(s,1H),7.16(s,1H),7.03(m,2H),6.89–6.85(m,2H),6.82(d,1H),6.41(d,1H),5.01–4.91(m,2H),4.39–4.35(m,2H),3.74–3.63(m,2H),3.31(m,2H),3.25(s,1H),2.94(s,2H),2.73–2.59(m,2H),2.58–2.49(m,2H),2.49–2.43(m,2H),2.37–2.11(m,8H),1.70(m,2H),1.51(m,8H). 1 H NMR (400MHz, CD 3 OD) δ7.44 (d, 1H), 7.42 (d, 1H), 7.26 (m, 2H), 7.18 (s, 1H), 7.16 (s, 1H), 7.03 (m , 2H), 6.89–6.85 (m, 2H), 6.82 (d, 1H), 6.41 (d, 1H), 5.01–4.91 (m, 2H), 4.39–4.35 (m, 2H), 3.74–3.63 (m) , 2H), 3.31 (m, 2H), 3.25 (s, 1H), 2.94 (s, 2H), 2.73 - 2.59 (m, 2H), 2.58 - 2.49 (m, 2H), 2.49 - 2.43 (m, 2H) ), 2.37–2.11 (m, 8H), 1.70 (m, 2H), 1.51 (m, 8H).
LCMS m/z＝430.9[(M+2)/2]。LCMS m/z = 430.9 [(M+2)/2].
实施例7：[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(4-羟基-2-氧代-3H-1,3-苯并噻唑-7-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]-2-羟基-2,2-二(2-噻吩基)乙酸酯；二三氟乙酸盐(化合物7)Example 7: [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazole- 7-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane- 2-yl]-2-hydroxy-2,2-bis(2-thienyl) acetate; ditrifluoroacetate (compound 7)
[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate；ditrifluoroacetic acid[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino ]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl Acetate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000089
Figure PCTCN2016081809-appb-000089
Figure PCTCN2016081809-appb-000090
Figure PCTCN2016081809-appb-000090
第一步：7-[(1R)-2-叠氮基-1-[叔丁基(二甲基)硅基]氧基乙基]-4-[叔丁基(二甲基)硅基]氧基-3H-1,3-苯并噻唑-2-酮(7B)First step: 7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-[tert-butyl(dimethyl)silyl ]oxy-3H-1,3-benzothiazol-2-one (7B)
7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1，3-benzothiazol-2-one7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2- One
Figure PCTCN2016081809-appb-000091
Figure PCTCN2016081809-appb-000091
7-[(1R)-2-叠氮基-1-羟基-乙基]-4-羟基-3H-1,3-苯并噻唑-2-酮(7A)(参考WO2009098448A1制备得到)(0.56g.2.2mmol)溶于N,N-二甲基甲酰胺(20mL)中，然后加入咪唑(0.6g，8.9mmol)，分批加入叔丁基二甲基氯硅烷(1.3g，8.9mmol)，再加入催化量的4-二甲氨基吡啶，温度升至40℃搅拌7小时。把反应液倒入水(100mL)中，用乙酸乙酯(100mL×1)萃取，有机相用饱和氯化钠水溶液(100mL×2)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析(洗脱剂为乙酸乙酯/石油醚(v/v)＝0/1～5/95)，得标题化合物7-[(1R)-2-叠氮基-1-[叔丁基(二甲基)硅基]氧基乙基]-4-[叔丁基(二甲基)硅基]氧基-3H-1,3-苯并噻唑-2-酮(7B)，白色固体(0.85g，产率80％)。7-[(1R)-2-Azido-1-hydroxy-ethyl]-4-hydroxy-3H-1,3-benzothiazol-2-one (7A) (prepared by reference WO2009098448A1) (0.56g .2.2 mmol) was dissolved in N,N-dimethylformamide (20 mL), then imidazole (0.6 g, 8.9 mmol) was added and t-butyldimethylchlorosilane (1.3 g, 8.9 mmol) was added portionwise. Further, a catalytic amount of 4-dimethylaminopyridine was added, and the temperature was raised to 40 ° C and stirred for 7 hours. The reaction mixture was poured into water (100 mL), EtOAc (EtOAc m. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut 1-[tert-Butyl(dimethyl)silyl]oxyethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2-one (7B), white solid (0.85 g, yield 80%).
1H NMR(400MHz,CDCl3)δ8.25(s,1H),6.92(d,1H),6.71(d,1H),4.78(dd,1H),3.41(dd,1H),3.25(dd,1H),1.05-0.98(m,9H),0.92-0.88(m,9H),0.28(t,6H),0.12(d,3H),-0.04(d,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.25 (s, 1H), 6.92 (d, 1H), 6.71 (d, 1H), 4.78 (dd, 1H), 3.41 (dd, 1H), 3.25 (dd, 1H), 1.05-0.98 (m, 9H), 0.92-0.88 (m, 9H), 0.28 (t, 6H), 0.12 (d, 3H), -0.04 (d, 3H).
第二步：7-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基乙基]-4-[叔丁基(二甲基)硅基]氧基-3H-1,3-苯并噻唑-2-酮(7C)Second step: 7-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-[tert-butyl(dimethyl)silyl]oxy 3-H-1,3-benzothiazol-2-one (7C)
7-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2-one 7-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2- One
Figure PCTCN2016081809-appb-000092
Figure PCTCN2016081809-appb-000092
将7-[(1R)-2-叠氮基-1-[叔丁基(二甲基)硅基]氧基乙基]-4-[叔丁基(二甲基)硅基]氧基-3H-1,3-苯并噻唑-2-酮(7B)(0.85g，1.8mmol)溶于乙酸乙酯(20mL)中，加入10％(w/w)的钯碳(0.085g)，常压氢气球下搅拌过夜。垫硅藻土过滤，浓缩得标题化合物7-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基乙基]-4-[叔丁基(二甲基)硅基]氧基-3H-1,3-苯并噻唑-2-酮(7C)，浅黑色固体(0.7g，产率90％)。7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-[tert-butyl(dimethyl)silyl]oxy -3H-1,3-benzothiazol-2-one (7B) (0.85 g, 1.8 mmol) was dissolved in ethyl acetate (20 mL), and 10% (w/w) palladium carbon (0.085 g) was added. Stir under a hydrogen balloon at atmospheric pressure overnight. Filtered with celite and concentrated to give the title compound 7-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-[tert-butyl(dimethyl) Alkyl)oxy-3H-1,3-benzothiazol-2-one (7C), light black solid (0.7 g, yield 90%).
1H NMR(400MHz,CDCl3)δ6.89(d,1H),6.68(t,1H),4.64(dd,1H),2.88(ddd,2H),1.04-0.96(m,9H),0.95-0.87(m,9H),0.33-0.23(m,6H),0.12-0.06(m,3H),-0.04--0.11(m,3H).1H NMR (400MHz, CDCl3) δ 6.89 (d, 1H), 6.68 (t, 1H), 4.64 (dd, 1H), 2.88 (ddd, 2H), 1.04-0.96 (m, 9H), 0.95-0.87 ( m, 9H), 0.33-0.23 (m, 6H), 0.12-0.06 (m, 3H), -0.04--0.11 (m, 3H).
第三步：[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-[4-[叔丁基(二甲基)硅基]氧基-2-氧代-3H-1,3-苯并噻唑-7-基]乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(7D)The third step: [7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-[tert-butyl] (Dimethyl)silyl]oxy-2-oxo-3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]anilino]-5-oxopentyl]- Methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (7D )
[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-2-oxo-3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-2 -oxo-3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan -2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000093
Figure PCTCN2016081809-appb-000093
将[7-[3-[[5-(4-甲酰苯胺)-5-氧代-戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-双(2-噻吩基)乙酸酯(5I)(0.25g,0.38mmol)和7-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基乙基]-4-[叔丁基(二甲基)硅基]氧基-3H-1,3-苯并噻唑-2-酮(7C)(0.26g,0.58mmol)溶于异丙醇/二氯甲烷(v/v＝1:1 10mL)的混合溶剂中，室温搅拌1小时，然后加入三乙酰氧基硼氢化钠(0.24g,1.14mmol)，室温下反应2小时。向反应液加入二氯甲烷(150mL)和水(50mL)，萃取分层，有机相用饱和氯化钠水溶液(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-[4-[叔丁基(二甲基)硅基]氧基-2-氧代-3H-1,3-苯并噻唑-7-基]乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2- 羟基-2,2-二(2-噻吩基)乙酸酯(7D)，浅黄固体(0.35g，产率84％)。[7-[3-[[5-(4-Formylanilide)-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5 ]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (5I) (0.25 g, 0.38 mmol) and 7-[(1R)-2-amino-1- [tert-Butyl(dimethyl)silyl]oxyethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2-one (7C (0.26 g, 0.58 mmol) was dissolved in a mixed solvent of isopropyl alcohol/dichloromethane (v/v = 1:1 10 mL), stirred at room temperature for 1 hour, and then sodium triacetoxyborohydride (0.24 g, 1.14 mmol), reacted at room temperature for 2 hours. Dichloromethane (150 mL) and water (50 mL) were added to the mixture, and the mixture was evaporated, evaporated, evaporated, evaporated. Compound [7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-[tert-butyl] Silyl]oxy-2-oxo-3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl- Amino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2- Hydroxy-2,2-bis(2-thienyl)acetate (7D), pale yellow solid (0.35 g, yield 84%).
LCMS m/z＝488.8[(M+2)/2]。LCMS m/z = 488.8 [(M+2)/2].
第四步：[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(4-羟基-2-氧代-3H-1,3-苯并噻唑-7-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯；二三氟乙酸盐(化合物7)The fourth step: [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazole- 7-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane- 2-yl]2-hydroxy-2,2-bis(2-thienyl) acetate; ditrifluoroacetate (compound 7)
[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate；ditrifluoroacetic acid[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino ]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl Acetate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000094
Figure PCTCN2016081809-appb-000094
将[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-[4-[叔丁基(二甲基)硅基]氧基-2-氧代-3H-1,3-苯并噻唑-7-基]乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(7D)(0.35g,0.32mmol)溶于四氢呋喃(5mL)中，加入三乙胺三氢氟酸盐(0.26g,1.6mmol)，室温反应过夜，反应液用饱和碳酸氢钠溶液调碱，用8％甲醇/二氯甲烷(v/v＝8:92,100mL)萃取，有机相用饱和氯化钠水溶液(50mL×1)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用液相制备柱分离提纯(液相制备条件：C18反相制备柱，流动相为含0.05％TFA的去离子水(A)，含0.05％TFA的乙腈(B)，梯度洗脱A:B＝10％～55％，洗脱时间39min，流速1.0mL/min，柱温：40℃)，得到标题化合物[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(4-羟基-2-氧代-3H-1,3-苯并噻唑-7-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯；二三氟乙酸盐(化合物7)，白色固体(0.117g，产率42％)。[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-[tert-butyl] Silyl]oxy-2-oxo-3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl- Amino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (7D) (0.35 g, 0.32 mmol) was dissolved in tetrahydrofuran (5 mL), triethylamine trihydrofluoric acid salt (0.26 g, 1.6 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Dichloromethane (v/v = 8:92, 100 mL), EtOAc (EtOAc m. Column separation and purification (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase is deionized water (A) containing 0.05% TFA, acetonitrile (B) containing 0.05% TFA, gradient elution A: B = 10% ~ 55%, elution time 39 min, flow rate 1.0 mL/min, column temperature: 40 ° C), the title compound [7-[3-[[[(2))) (4-Hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]anilino]-5-oxopentyl ]-Methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate Ditrifluoroacetate (Compound 7), white solid (0.117 g, yield 42%).
1H NMR(400MHz,CD3OD)δ7.69(dd,2H),7.46(dd,2H),7.40(dd,2H),7.16(t,2H),6.99(dd,3H),6.77(d,1H),5.14(m,1H),4.99(dd,1H),4.25(d,2H),3.44(m,6H),3.13(m,2H),3.03(m,3H),2.93(m,4H),2.48m,3H),2.36(m,1H),1.98(m,3H),1.84(m,3H),1.70(m,4H). 1 H NMR (400MHz, CD 3 OD) δ7.69 (dd, 2H), 7.46 (dd, 2H), 7.40 (dd, 2H), 7.16 (t, 2H), 6.99 (dd, 3H), 6.77 (d , 1H), 5.14 (m, 1H), 4.99 (dd, 1H), 4.25 (d, 2H), 3.44 (m, 6H), 3.13 (m, 2H), 3.03 (m, 3H), 2.93 (m, 4H), 2.48m, 3H), 2.36 (m, 1H), 1.98 (m, 3H), 1.84 (m, 3H), 1.70 (m, 4H).
LCMS m/z＝431.8[(M+2)/2]。 LCMS m/z = 431.8 [(M+2)/2].
实施例8：[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯胺]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯；二三氟乙酸盐(化合物8)Example 8: [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]aniline]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]N- (2-phenylphenyl)carbamate; ditrifluoroacetate (compound 8)
[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate；ditrifluoroacetic acid[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino ]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000095
Figure PCTCN2016081809-appb-000095
第一步：3-[2-[(2-苯基苯基)氨基甲酰氧基]-7-氮杂螺[3.5]壬-7-基]丙酸(8A)First step: 3-[2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]indole-7-yl]propionic acid (8A)
3-[2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]nonan-7-yl]propanoic acid 3-[2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]nonan-7-yl]propanoic acid
Figure PCTCN2016081809-appb-000096
Figure PCTCN2016081809-appb-000096
将7-氮杂螺[3,5]壬烷-2-基N-(2-苯基苯基)氨基甲酸酯(2D)(0.8g,2mmol)和丙烯酸(2.0g,20mmol)溶于2-甲基四氢呋喃(10mL)中，置于微波反应器中，升温至100℃反应1小时，冷却至室温，减压浓缩，残留物用硅胶柱色谱分离提纯(甲醇：二氯甲烷(v/v)＝0:1～1:9)得到标题化合物3-[2-[(2-苯基苯基)氨基甲酰氧基]-7-氮杂螺[3.5]壬-7-基]丙酸(8A)，浅黄固体(0.8g，产率80％)。Dissolving 7-azaspiro[3,5]decane-2-yl N-(2-phenylphenyl)carbamate (2D) (0.8 g, 2 mmol) and acrylic acid (2.0 g, 20 mmol) 2-methyltetrahydrofuran (10 mL), placed in a microwave reactor, heated to 100 ° C for 1 hour, cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: dichloromethane v) = 0:1 to 1:9) to give the title compound 3-[2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]indole-7-yl]- Acid (8A), pale yellow solid (0.8 g, yield 80%).
1H NMR(400MHz,CDCl3)δ8.08(d,1H),7.50(m,2H),7.42(m,1H),7.35(m,3H),7.21(dd,1H),7.13(m,1H),6.63(s,1H),4.99(m,1H),2.96(m,8H),2.37(m,2H),1.88(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.08 (d, 1H), 7.50 (m, 2H), 7.42 (m, 1H), 7.35 (m, 3H), 7.21 (dd, 1H), 7.13 (m, 1H), 6.63 (s, 1H), 4.99 (m, 1H), 2.96 (m, 8H), 2.37 (m, 2H), 1.88 (m, 6H).
LCMS m/z＝409.1[M+1]。LCMS m/z = 409.1 [M + 1].
第二步：5-[甲基-[3-[2-[(2-苯基苯基)氨基甲酰氧基]-7-氮杂螺[3.5]壬-7-基]丙酰基]氨基]戊酸甲酯(8B)Second step: 5-[Methyl-[3-[2-[(2-phenylphenyl)carbamoyloxy)-7-azaspiro[3.5]indole-7-yl]propanoyl]amino Methyl valerate (8B)
methyl 5-[methyl-[3-[2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]nonan-7-yl]propanoyl]amino]pentanoateMethyl 5-[methyl-[3-[2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]nonan-7-yl]propanoyl]amino]pentanoate
Figure PCTCN2016081809-appb-000097
Figure PCTCN2016081809-appb-000097
将3-[2-[(2-苯基苯基)氨基甲酰氧基]-7-氮杂螺[3.5]壬-7-基]丙酸(8A)(0.8g,2mmol)和5-(甲基氨基)戊酸甲酯(0.6g,4mmol)溶于二氯甲烷(25mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1g,3mmol)，冷却到0℃，滴加二异丙基乙胺(2.0g,20mmol)，升至室温下反应3小时，向反应液加入二氯甲烷(120mL)和水(100mL)，萃取分层，有机相用饱和氯化钠水溶液(100mL×1)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩后得到标题化合物5-[甲基-[3-[2-[(2-苯基苯基)氨基甲酰氧基]-7-氮杂螺[3.5]壬-7-基]丙酰基]氨基]戊酸甲酯(8B)，褐色固体(1.0g，产率100％)。3-[2-[(2-Phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]indole-7-yl]propanoic acid (8A) (0.8 g, 2 mmol) and 5- Methyl (methylamino)pentanoate (0.6 g, 4 mmol) was dissolved in dichloromethane (25 mL) and 2-(7-azobenzotriazole)-N,N,N',N'- Tetramethylurea hexafluorophosphate (1 g, 3 mmol), cooled to 0 ° C, diisopropylethylamine (2.0 g, 20 mmol) was added dropwise, and the mixture was allowed to react at room temperature for 3 hours, and dichloromethane was added to the reaction mixture. 120 mL) and water (100 mL), EtOAc (EtOAc m. [3-[2-[(2-Phenylphenyl)carbamoyloxy)-7-azaspiro[3.5]dec-7-yl]propanoyl]amino]pentanoate (8B), brown Solid (1.0 g, yield 100%).
LCMS m/z＝536.2[M+1]。LCMS m/z = 536.2 [M + 1].
第三步：5-[甲基-[3-[2-[(2-苯基苯基)氨基甲酰氧基]-7-氮杂螺[3.5]壬-7-基]丙酰基]氨 基]戊酸(8C)Third step: 5-[Methyl-[3-[2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]indole-7-yl]propanoyl]ammonium Valeric acid (8C)
5-[methyl-[3-[2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]nonan-7-yl]propanoyl]amino]pentanoic acid5-[methyl-[3-[2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]nonan-7-yl]propanoyl]amino]pentanoic acid
Figure PCTCN2016081809-appb-000098
Figure PCTCN2016081809-appb-000098
将5-[甲基-[3-[2-[(2-苯基苯基)氨基甲酰氧基]-7-氮杂螺[3.5]壬-7-基]丙酰基]氨基]戊酸甲酯(8B)(1.0g,1.86mmol)溶于四氢呋喃(10mL)中，加入氢氧化钠(0.37g,9.3mmol)的水溶液(10mL)，室温下反应2小时，冷却至0℃，调节pH约为3，加入二氯甲烷(50mL×3)萃取，合并有机层，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析提纯(洗脱剂为二氯甲烷/甲醇(v:v)＝1/0～9/1)，得到标题化合物5-[甲基-[3-[2-[(2-苯基苯基)氨基甲酰氧基]-7-氮杂螺[3.5]壬-7-基]丙酰基]氨基]戊酸(8C)，浅黄固体(0.85g，产率87％)。5-[Methyl-[3-[2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]indole-7-yl]propanoyl]amino]pentanoic acid The methyl ester (8B) (1.0 g, 1.86 mmol) was dissolved in tetrahydrofuran (10 mL), and aqueous sodium hydroxide (0.37 g, 9.3 mmol) (10 mL) was added, and the mixture was reacted at room temperature for 2 hours, cooled to 0 ° C, pH was adjusted. The mixture was extracted with methylene chloride (50 mL×3). EtOAc was evaporated. Methanol (v:v) = 1/0 to 9/1) gave the title compound 5-[methyl-[3-[2-[(2-phenylphenyl)carbamoyloxy]-7-nitro Heterospiro[3.5]dec-7-yl]propanoyl]amino]pentanoic acid (8C), pale yellow solid (0.85 g, yield 87%).
1H NMR(400MHz,CDCl3)δ8.03s,1H),7.50(dd,2H),7.42(t,1H),7.35(m,3H),7.21(dd,1H),7.13(t,1H),6.65(d,1H),4.99(m,1H),3.47(m,2H),3.37(s,2H),3.30(m,2H),3.00(m,4H),2.89(d,3H),2.83(m,2H),2.39(m,4H),2.00(m,2H),1.87(m,2H),1.81(m,2H),1.66(s,2H). 1 H NMR (400MHz, CDCl 3 ) δ8.03s, 1H), 7.50 (dd, 2H), 7.42 (t, 1H), 7.35 (m, 3H), 7.21 (dd, 1H), 7.13 (t, 1H) , 6.65 (d, 1H), 4.99 (m, 1H), 3.47 (m, 2H), 3.37 (s, 2H), 3.30 (m, 2H), 3.00 (m, 4H), 2.89 (d, 3H), 2.83 (m, 2H), 2.39 (m, 4H), 2.00 (m, 2H), 1.87 (m, 2H), 1.81 (m, 2H), 1.66 (s, 2H).
LCMS m/z＝522.2[M+1]。LCMS m/z = 522.2 [M + 1].
第四步：[7-[3-[[5-[4-(1,3-二氧戊环-2-基)苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(8D)Fourth step: [7-[3-[[5-[4-(1,3-dioxolan-2-yl)anilino]-5-oxopentyl]-methyl-amino]-3 -oxo-propyl]-7-azaspiro[3.5]decane-2-yl]N-(2-phenylphenyl)carbamate (8D)
[7-[3-[[5-[4-(1,3-dioxolan-2-yl)anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate[7-[3-[[5-[4-(1,3-dioxolan-2-yl)anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[ 3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate
Figure PCTCN2016081809-appb-000099
Figure PCTCN2016081809-appb-000099
将5-[甲基-[3-[2-[(2-苯基苯基)氨基甲酰氧基]-7-氮杂螺[3.5]壬-7-基]丙酰基]氨基]戊酸(8C)(0.4g,0.8mmol)和4-(1,3-二氧戊环-2-基)苯胺(0.3g,1.6mmol)溶于二氯甲烷 (10mL)中，冷却到0℃，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.44g,1.0mmol)，滴加N,N-二异丙基乙胺(0.2g,2mmol)，室温下反应3小时。向反应液加入二氯甲烷(50mL)和水(50mL)，萃取分层，有机层用饱和氯化钠水溶液(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析提纯(洗脱剂为二氯甲烷/甲醇(v/v)＝1/0～9/1)，得到标题化合物[7-[3-[[5-[4-(1,3-二氧戊环-2-基)苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(8D)，黄色固体(0.4g，产率80％)。5-[Methyl-[3-[2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]indole-7-yl]propanoyl]amino]pentanoic acid (8C) (0.4g, 0.8mmol) and 4-(1,3-dioxolan-2-yl)phenylamine (0.3g, 1.6mmol) dissolved in dichloromethane (10 mL), cooled to 0 ° C, and added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.44 g, 1.0 mmol) N,N-diisopropylethylamine (0.2 g, 2 mmol) was added dropwise, and the mixture was reacted at room temperature for 3 hours. Dichloromethane (50 mL) and water (50 mL) were added to the mixture and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated Purification by silica gel column chromatography (eluent to dichloromethane / methanol (v/v) = 1/0 to 9/1) afforded the title compound [7-[3-[[5-[4-(1, 3-Diethoxypentan-2-yl)anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2 -N-(2-Phenylphenyl)carbamate (8D), yellow solid (0.4 g, yield 80%).
1H NMR(400MHz,CDCl3)δ8.10(d,1H),7.63(dd,2H),7.50dd,2H),7.38m,6H),7.21(dd,1H),7.13(m,1H),6.61(d,1H),5.75(d,1H),4.97(m,1H),4.10(m,2H),4.00(m,2H),3.46(m,1H),3.31(m,1H),3.00(s,3H),2.77(m,2H),2.72(m,2H),2.58(m,2H),2.48(m,2H),2.29(m,4H),1.78(m,4H),1.63(m,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.10 (d, 1H), 7.63 (dd, 2H), 7.50dd, 2H), 7.38m, 6H), 7.21 (dd, 1H), 7.13 (m, 1H) , 6.61 (d, 1H), 5.75 (d, 1H), 4.97 (m, 1H), 4.10 (m, 2H), 4.00 (m, 2H), 3.46 (m, 1H), 3.31 (m, 1H), 3.00 (s, 3H), 2.77 (m, 2H), 2.72 (m, 2H), 2.58 (m, 2H), 2.48 (m, 2H), 2.29 (m, 4H), 1.78 (m, 4H), 1.63 (m, 6H).
LCMS m/z＝669.4[M+1]。LCMS m/z = 669.4 [M + 1].
第五步：[7-[3-[[5-(4-甲酰基苯胺基)-5-氧代-戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(8E)Step 5: [7-[3-[[5-(4-Formylanilino)-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-nitrogen Heterospiro[3.5]decane-2-yl]N-(2-phenylphenyl)carbamate (8E)
[7-[3-[[5-(4-formylanilino)-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate[7-[3-[[5-(4-formylanilino)-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-( 2-phenylphenyl)carbamate
Figure PCTCN2016081809-appb-000100
Figure PCTCN2016081809-appb-000100
将[7-[3-[[5-[4-(1,3-二氧戊环-2-基)苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(8D)(1.2g,1.8mmol)溶于乙腈(20mL)中，滴加3M盐酸水溶液(6mL)，室温反应1小时。向反应液加入二氯甲烷(100mL)和水(100mL)，萃取分层，有机相用饱和氯化钠水溶液(100mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物[7-[3-[[5-(4-甲酰基苯胺基)-5-氧代-戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(8E)，黄色固体(1.0g，产率89％)。[7-[3-[[5-[4-(1,3-dioxolan-2-yl)anilino]-5-oxopentyl]-methyl-amino]-3-oxo -propyl]-7-azaspiro[3.5]decane-2-yl]N-(2-phenylphenyl)carbamate (8D) (1.2 g, 1.8 mmol) dissolved in acetonitrile (20 mL) 3 M hydrochloric acid aqueous solution (6 mL) was added dropwise, and the mixture was reacted at room temperature for 1 hour. Dichloromethane (100 mL) and water (100 mL) were added to the mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated Compound [7-[3-[[5-(4-Formylanilino)-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[ 3.5]decane-2-yl]N-(2-phenylphenyl)carbamate (8E), yellow solid (1.0 g, yield 89%).
LCMS m/z＝625.3[M+1]。 LCMS m/z = 625.3 [M + 1].
第六步：[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(8F)Step 6: [7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-) Oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7- Azaspiro[3.5]decane-2-yl]N-(2-phenylphenyl)carbamate (8F)
[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5- Yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate
Figure PCTCN2016081809-appb-000101
Figure PCTCN2016081809-appb-000101
将[7-[3-[[5-(4-甲酰基苯胺基)-5-氧代-戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(8E)(0.25g,0.40mmol)和5-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基甲基]-8-羟基-1H-喹啉-2-酮(1G)(0.20g,0.60mmol)溶于异丙醇/二氯甲烷(v/v＝1：1,10mL)混合溶剂中，室温搅拌1小时，然后加入三乙酰氧基硼氢化钠(0.25g,1.2mmol)，再搅拌2小时。向反应液加入二氯甲烷(150mL)和水(50mL)，萃取分层，有机相用饱和氯化钠水溶液(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析提纯(洗脱剂为二氯甲烷/甲醇(v:v)＝1/0～9/1)，得到标题化合物[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(8F)，浅黄固体(0.15g，产率40％)。[7-[3-[[5-(4-Formylanilino)-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[ 3.5]decane-2-yl]N-(2-phenylphenyl)carbamate (8E) (0.25 g, 0.40 mmol) and 5-[(1R)-2-amino-1-[tert-butyl] (Dimethyl)silyl]oxymethyl]-8-hydroxy-1H-quinolin-2-one (1G) (0.20 g, 0.60 mmol) dissolved in isopropanol / dichloromethane (v/v = 1:1, 10 mL), the mixture was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.25 g, 1.2 mmol) was added and stirred for 2 hours. Dichloromethane (150 mL) and water (50 mL) were added to the mixture, and the mixture was evaporated, evaporated, evaporated, evaporated. Purification by silica gel column chromatography (eluent: methylene chloride/methanol (v:v) = 1/0 to 9/1) gave the title compound [7-[3-[[5-[4-[[[ (2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl Anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]N-(2-phenyl Phenyl) carbamate (8F), pale yellow solid (0.15 g, yield 40%).
LCMS m/z＝472.4[(M+2)/2]。LCMS m/z = 472.4 [(M+2)/2].
第七步：[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯胺]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯；二三氟乙酸盐(化合物8)Step 7: [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]aniline]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]N- (2-phenylphenyl)carbamate; ditrifluoroacetate (compound 8)
[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate；ditrifluoroacetic acid [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino ]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000102
Figure PCTCN2016081809-appb-000102
将[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(8F)(0.11g,0.12mmol)溶于二氯甲烷(10mL)中，加入三乙胺三氢氟酸盐(0.10g,0.58mmol)，室温反应过夜，反应液用饱和碳酸氢钠溶液调碱，用8％甲醇/二氯甲烷(v/v＝8:92,100mL)萃取，有机相用饱和氯化钠水溶液(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用液相制备柱分离提纯(液相制备条件：C18反相制备柱，流动相为含0.05％TFA的去离子水(A)，含0.05％TFA的乙腈(B)，梯度洗脱A:B＝10％～55％，洗脱时间39min，流速1.0mL/min，柱温：40℃)，得到标题化合物[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯胺]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯；二三氟乙酸盐(化合物8)，浅黄固体(0.04g，产率24％)。[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-) 1H-quinoline-5-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-aza snail [3.5] decane-2-yl]N-(2-phenylphenyl)carbamate (8F) (0.11 g, 0.12 mmol) was dissolved in dichloromethane (10 mL). The fluoro acid salt (0.10 g, 0.58 mmol) was reacted at room temperature overnight. The reaction mixture was diluted with saturated sodium hydrogen carbonate solution and extracted with 8% methanol/dichloromethane (v/v = 8:92, 100 mL). The aqueous solution of sodium chloride (50 mL×1) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by liquid phase preparative column (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase containing 0.05 Deionized water (A) of %TFA, acetonitrile (B) containing 0.05% TFA, gradient elution A: B = 10% to 55%, elution time 39 min, flow rate 1.0 mL/min, column temperature: 40 ° C) To give the title compound [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]aniline]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]壬2-yl] N- (2- phenylphenyl) carbamate; ditrifluoroacetate (Compound 8), a pale yellow solid (0.04 g of, yield 24%).
1H NMR(400MHz,CD3OD)δ8.20(t,1H),7.69(dd,2H),7.57(s,1H),7.38(m,11H),7.04(d,1H),6.63(dd,1H),5.38(m,1H),4.86(s,1H),4.26(d,2H),3.43(m,6H),3.20(d,2H),3.07(s,2H),3.01(d,1H),2.97(m,2H),2.92(m,2H),2.46(dd,3H),2.23(s,1H),1.91(m,6H),1.70(d,4H). 1 H NMR (400MHz, CD 3 OD) δ8.20 (t, 1H), 7.69 (dd, 2H), 7.57 (s, 1H), 7.38 (m, 11H), 7.04 (d, 1H), 6.63 (dd , 1H), 5.38 (m, 1H), 4.86 (s, 1H), 4.26 (d, 2H), 3.43 (m, 6H), 3.20 (d, 2H), 3.07 (s, 2H), 3.01 (d, 1H), 2.97 (m, 2H), 2.92 (m, 2H), 2.46 (dd, 3H), 2.23 (s, 1H), 1.91 (m, 6H), 1.70 (d, 4H).
LCMS m/z＝415.3[(M+2)/2]。LCMS m/z = 415.3 [(M+2)/2].
实施例9:[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(5-羟基-3-氧代-4H-1,4-苯并恶嗪-8-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯；二三氟乙酸盐(化合物9)Example 9: [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine) -8-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane 2-yl]N-(2-phenylphenyl)carbamate; ditrifluoroacetate (compound 9)
[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate；ditrifluoroacetic acid [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino ]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000103
Figure PCTCN2016081809-appb-000103
第一步：[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(5-羟基-3-氧代-4H-1,4-苯并恶嗪-8-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(9A)First step: [7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-) Oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propan -7-Azaspiro[3.5]decane-2-yl]N-(2-phenylphenyl)carbamate (9A)
[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4- Benzoxazin-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2 -phenylphenyl)carbamate
Figure PCTCN2016081809-appb-000104
Figure PCTCN2016081809-appb-000104
将[7-[3-[[5-(4-甲酰基苯胺基)-5-氧代-戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(8E)(0.25g,0.3mmol)和8-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基乙基]-5-羟基-4H-1,4-苯并恶嗪-3-酮(6A)(0.2g,0.6mmol)溶于甲醇/二氯甲烷(v/v＝1/1,10mL)混合溶剂中，室温搅拌1小时，然后加入三乙酰氧基硼氢化钠(0.25g,1.2mmol)，再搅拌3小时。向反应液加入二氯甲烷(150mL)和水(50mL)，萃取分层，有机相用饱和氯化钠水溶液(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析提纯(洗脱剂为二氯甲烷/甲醇(v/v)＝1/0 ～9/1)，得到标 题化合物[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(5-羟基-3-氧代-4H-1,4-苯并恶嗪-8-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(9A)，浅黄固体(0.12g，产率32％)。[7-[3-[[5-(4-Formylanilino)-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[ 3.5]decane-2-yl]N-(2-phenylphenyl)carbamate (8E) (0.25 g, 0.3 mmol) and 8-[(1R)-2-amino-1-[tert-butyl] (Dimethyl)silyl]oxyethyl]-5-hydroxy-4H-1,4-benzoxazin-3-one (6A) (0.2 g, 0.6 mmol) dissolved in methanol / dichloromethane (v/v = 1/1, 10 mL) was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.25 g, 1.2 mmol) was added and stirred for 3 hours. Dichloromethane (150 mL) and water (50 mL) were added to the mixture, and the mixture was evaporated, evaporated, evaporated, evaporated. Purify by silica gel column chromatography (eluent is dichloromethane / methanol (v / v) = 1 / 0 ~ 9 / 1), the standard Compound [7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo) -4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl] -7-Azaspiro[3.5]decane-2-yl]N-(2-phenylphenyl)carbamate (9A), pale yellow solid (0.12 g, yield 32%).
LCMS m/z＝474.3[(M+2)/2]。LCMS m/z = 474.3 [(M+2)/2].
第二步：[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(5-羟基-3-氧代-4H-1,4-苯并恶嗪-8-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯；二三氟乙酸盐(化合物9)Step 2: [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine) -8-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane 2-yl]N-(2-phenylphenyl)carbamate; ditrifluoroacetate (compound 9)
[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate；ditrifluoroacetic acid[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino ]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000105
Figure PCTCN2016081809-appb-000105
将[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(5-羟基-3-氧代-4H-1,4-苯并恶嗪-8-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(9A)(0.11g,0.12mmol)溶于四氢呋喃(5mL)中，加入三乙胺三氢氟酸盐(0.1g,0.58mmol)，室温反应过夜，反应液用饱和碳酸氢钠溶液调碱，过滤，所得固体用8％甲醇/二氯甲烷(v/v＝8:92,50mL)溶解后，饱和氯化钠水溶液(50mL×1)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用液相制备柱分离提纯(液相制备条件：C18反相制备柱，流动相为含0.05％TFA的去离子水(A)，含0.05％TFA的乙腈(B)，梯度洗脱A:B＝10％～55％，洗脱时间39min，流速1.0mL/min，柱温：40℃)，得到标题化合物[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(5-羟基-3-氧代-4H-1,4-苯并恶嗪-8-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯；二三氟乙酸盐(化合物9)，白色固体(0.056g，产率45％)。[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-) 4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]- 7-Azaspiro[3.5]decane-2-yl]N-(2-phenylphenyl)carbamate (9A) (0.11 g, 0.12 mmol) was dissolved in tetrahydrofuran (5 mL). The amine trihydrofluoride (0.1 g, 0.58 mmol) was reacted at room temperature overnight. The reaction mixture was combined with EtOAc EtOAc EtOAc After dissolving, 50 ml of a saturated aqueous solution of sodium chloride (50 mL × 1) was washed, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by liquid phase preparative column (liquid phase preparation conditions: C18 reverse Phase preparation column, mobile phase was deionized water (A) containing 0.05% TFA, acetonitrile (B) containing 0.05% TFA, gradient elution A: B = 10% to 55%, elution time 39 min, flow rate 1.0 mL /min, column temperature: 40 ° C) to give the title compound [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H) -1,4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-ammonia ]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]N-(2-phenylphenyl)carbamate; ditrifluoroacetate (compound 9 ), white solid (0.056 g, yield 45%).
1H NMR(400MHz,CD3OD)δ7.69(dd,2H),7.58(s,1H),7.37(m,10H),7.02(d,1H),6.58(d,1H),5.17(d,1H),4.86(s,1H),4.49(m,2H),4.23(m,2H),3.43(m,6H),3.16(dd,1H),2.98(m,8H),2.46(m,3H),2.23(s,1H),1.91(m,6H),1.70(d,4H). 1 H NMR (400MHz, CD 3 OD) δ7.69 (dd, 2H), 7.58 (s, 1H), 7.37 (m, 10H), 7.02 (d, 1H), 6.58 (d, 1H), 5.17 (d , 1H), 4.86 (s, 1H), 4.49 (m, 2H), 4.23 (m, 2H), 3.43 (m, 6H), 3.16 (dd, 1H), 2.98 (m, 8H), 2.46 (m, 3H), 2.23 (s, 1H), 1.91 (m, 6H), 1.70 (d, 4H).
LCMS m/z＝417.3[(M+2)/2]。 LCMS m/z = 417.3 [(M+2)/2].
实施例10：[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(4-羟基-2-氧代-3H-1,3-苯并噻唑-7-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯；二三氟乙酸盐(化合物10)Example 10: [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazole- 7-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane- 2-yl]N-(2-phenylphenyl)carbamate; ditrifluoroacetate (compound 10)
[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate；ditrifluoroacetic acid[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino ]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000106
Figure PCTCN2016081809-appb-000106
第一步：[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2[4-[叔丁基(二甲基)硅基]氧基-2-氧代-3H-1,3-苯并噻唑-7-基]乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(10A)First step: [7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2[4-[tert-butyl] Dimethyl)silyl]oxy-2-oxo-3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]anilino]-5-oxopentyl]- -amino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]N-(2-phenylphenyl)carbamate (10A)
[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-2-oxo-3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-2 -oxo-3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan -2-yl]N-(2-phenylphenyl)carbamate
Figure PCTCN2016081809-appb-000107
Figure PCTCN2016081809-appb-000107
将[7-[3-[[5-(4-甲酰基苯胺基)-5-氧代-戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5] 壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(8E)(0.25g,0.38mmol)和7-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基乙基]-4-[叔丁基(二甲基)硅基]氧基-3H-1,3-苯并噻唑-2-酮(7C)(0.27g,0.6mmol)溶于甲醇/二氯甲烷(v/v＝1/1,10mL)混合溶剂中，室温搅拌1小时，然后加入三乙酰氧基硼氢化钠(0.25g,1.2mmol)，室温下反应2小时。向反应液加入二氯甲烷(150mL)和水(50mL)，萃取分层，有机相用饱和氯化钠水溶液(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2[4-[叔丁基(二甲基)硅基]氧基-2-氧代-3H-1,3-苯并噻唑-7-基]乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(10A)，浅黄固体(0.4g，产率90％)。[7-[3-[[5-(4-Formylanilino)-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[ 3.5] Cycloalkyl-2-yl]N-(2-phenylphenyl)carbamate (8E) (0.25 g, 0.38 mmol) and 7-[(1R)-2-amino-1-[tert-butyl ( Dimethyl)silyl]oxyethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2-one (7C) (0.27 g, 0.6 mmol) was dissolved in a mixed solvent of methanol/dichloromethane (v/v = 1/1, 10 mL), stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.25 g, 1.2 mmol) was added and reacted at room temperature 2 hours. Dichloromethane (150 mL) and water (50 mL) were added to the mixture, and the mixture was evaporated, evaporated, evaporated, evaporated. Compound [7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2[4-[tert-butyl(dimethyl) )silyl]oxy-2-oxo-3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino ]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]N-(2-phenylphenyl)carbamate (10A), pale yellow solid (0.4 g, Yield 90%).
第二步：[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(4-羟基-2-氧代-3H-1,3-苯并噻唑-7-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯；二三氟乙酸盐(化合物10)The second step: [7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazole- 7-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]decane- 2-yl]N-(2-phenylphenyl)carbamate; ditrifluoroacetate (compound 10)
[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate；ditrifluoroacetic acid[7-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino ]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000108
Figure PCTCN2016081809-appb-000108
将[7-[3-[[5-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2[4-[叔丁基(二甲基)硅基]氧基-2-氧代-3H-1,3-苯并噻唑-7-基]乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯(10A)(0.4g,0.4mmol)溶于二氯甲烷(10mL)中，加入三乙胺三氢氟酸盐(0.3g,2mmol)，室温反应过夜，反应液用饱和碳酸氢钠溶液调碱，用8％甲醇/二氯甲烷(v/v＝8:92,100mL)萃取，有机相用饱和氯化钠水溶液(50mL×1)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用液相制备柱分离提纯(液相制备条件：C18反相制备柱，流动相为含0.05％TFA的去离子水(A)，含0.05％TFA的乙腈(B)，梯度洗脱A:B＝10％～55％，洗脱时间39min，流速1.0mL/min，柱温：40℃)，得到标题化合物[7-[3-[[5-[4-[[[(2R)-2-羟基-2-(4-羟基-2-氧代-3H-1,3-苯并噻唑-7-基)乙基]氨基]甲基]苯胺基]-5-氧代戊基]-甲基-氨基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯基苯基)氨基甲酸酯；二三氟乙酸盐(化合物10)，白色固 体(0.086g，产率20％)。[7-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2[4-[tert-butyl(dimethyl) )silyl]oxy-2-oxo-3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl-amino ]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]N-(2-phenylphenyl)carbamate (10A) (0.4 g, 0.4 mmol) Dissolved in dichloromethane (10 mL), added triethylamine trihydrofluoride (0.3 g, 2 mmol), and allowed to react overnight at room temperature. The mixture was extracted with a saturated aqueous solution of sodium chloride (50 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Liquid phase preparation conditions: C18 reverse phase preparation column, mobile phase is deionized water (A) containing 0.05% TFA, acetonitrile (B) containing 0.05% TFA, gradient elution A: B = 10% to 55%, wash The time of the reaction was 39 min, the flow rate was 1.0 mL/min, and the column temperature was 40 ° C. to give the title compound [7-[3-[[[(2))] -2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]anilino]-5-oxopentyl]-methyl- Amino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]N-(2-phenylphenyl)carbamate; ditrifluoroacetate (compound) 10), white solid Body (0.086 g, yield 20%).
1H NMR(400MHz,CD3OD)δ7.55(dd,2H),7.43(s,1H),7.24(m,9H),6.83(d,1H),6.63(d,1H),4.84(d,1H),4.72(s,1H),4.10(s,2H),3.29(m,6H),2.93(s,4H),2.82(m,5H),2.32(m,3H),2.09(s,1H),1.76(m,6H),1.56(m,4H). 1 H NMR (400MHz, CD 3 OD) δ7.55 (dd, 2H), 7.43 (s, 1H), 7.24 (m, 9H), 6.83 (d, 1H), 6.63 (d, 1H), 4.84 (d , 1H), 4.72 (s, 1H), 4.10 (s, 2H), 3.29 (m, 6H), 2.93 (s, 4H), 2.82 (m, 5H), 2.32 (m, 3H), 2.09 (s, 1H), 1.76 (m, 6H), 1.56 (m, 4H).
LCMS m/z＝418.3(M+2)/2]。LCMS m/z = 418.3 (M+2)/2].
实施例11：[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(5-羟基-3-氧代-4H-1,4-苯并恶嗪-8-基)乙基]氨基]甲基]-5-甲氧基苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]-2-羟基-2,2-二(2-噻吩基)乙酸酯(化合物11)Example 11: [7-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine) -8-yl)ethyl]amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]-2- Hydroxy-2,2-bis(2-thienyl)acetate (compound 11)
[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino ]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000109
Figure PCTCN2016081809-appb-000109
将[7-[3-(2-氯-4-甲酰基-5-甲氧基苯胺基)-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]-2-羟基-2,2-二(2-噻吩基)乙酸酯(1F)(0.300g，0.497mmol)溶解在二氯甲烷(5mL)和异丙醇(5mL)的混合溶剂中，加入8-[(1R)-2-氨基-1-羟基-乙基]-5-羟基-4H-1,4-苯并恶嗪-3-酮(11A，参考WO2009098448A1制备得到)(0.134g，0.597mmol)，30℃搅拌反应1.5小时再加入三乙酰氧基硼氢化钠(0.316g，1.49mmol)，继续30℃反应2小时。滴加饱和氯化铵水溶液(15mL)，用二氯甲烷(30mL×3)萃取，合并有机层，用饱和氯化钠水溶液(10mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后残留物用硅胶柱色谱分离纯化(洗脱剂为二氯甲烷：甲醇(v/v)＝97:3～92:8)得标题化合物[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(5-羟基-3-氧代-4H-1,4-苯并恶嗪-8-基)乙基]氨基]甲基]-5-甲氧基苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]-2-羟基-2,2-二(2-噻吩基)乙酸酯(化合物11)，浅黄色固体(0.080g，产率20％)。 [7-[3-(2-Chloro-4-formyl-5-methoxyanilino)-3-oxo-propyl]-7-azaspiro[3.5]decan-2-yl] 2-Hydroxy-2,2-bis(2-thienyl)acetate (1F) (0.300 g, 0.497 mmol) was dissolved in a mixed solvent of dichloromethane (5 mL) and isopropyl alcohol (5 mL). 8-[(1R)-2-Amino-1-hydroxy-ethyl]-5-hydroxy-4H-1,4-benzoxazin-3-one (11A, prepared as described in WO2009098448A1) (0.134g, 0.597) Methyl), the reaction was stirred at 30 ° C for 1.5 hours and then sodium triacetoxyborohydride (0.316 g, 1.49 mmol) was added and the reaction was continued at 30 ° C for 2 hours. Aqueous saturated aqueous ammonium chloride (15 mL) was added dropwise, EtOAc (EtOAc m. The residue is concentrated and purified by silica gel column chromatography (eluent: methylene chloride:methanol (v/v)=97:3 to 92:8) to give the title compound [7-[3-[2-chloro-4- [[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]-5-A Oxyanilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]-2-hydroxy-2,2-bis(2-thienyl)acetate ( Compound 11), pale yellow solid (0.080 g, yield 20%).
1H NMR(400MHz,CD3OD)δ7.69(s,1H),7.28-7.25(m,2H),7.18(s,1H),7.04-7.01(m,2H),6.88-6.86(m,2H),6.79(d,1H),6.41(d,1H),5.38(s,1H),5.05--4.96(m,1H),4.92-4.86(m,1H),4.37(s,2H),3.68(s,3H),3.66--3.58(m,2H),3.22-3.18(m,6H),2.72-2.62(m,2H),2.62--2.55(m,2H),2.54-2.48(m,2H),2.42-2.30(m,3H),2.28-2.18(m,2H),1.77-1.73(m,2H),1.62-1.56(m,2H),1.54-1.50(m,2H). 1 H NMR (400MHz, CD 3 OD) δ7.69 (s, 1H), 7.28-7.25 (m, 2H), 7.18 (s, 1H), 7.04-7.01 (m, 2H), 6.88-6.86 (m, 2H), 6.79 (d, 1H), 6.41 (d, 1H), 5.38 (s, 1H), 5.05--4.96 (m, 1H), 4.92-4.86 (m, 1H), 4.37 (s, 2H), 3.68(s,3H),3.66--3.58(m,2H),3.22-3.18(m,6H),2.72-2.62(m,2H),2.62--2.55(m,2H),2.54-2.48(m , 2H), 2.42-2.30 (m, 3H), 2.28-2.18 (m, 2H), 1.77-1.73 (m, 2H), 1.62-1.56 (m, 2H), 1.54-1.50 (m, 2H).
LCMS m/z＝406.1[(M+2)/2]。LCMS m/z = 406.1 [(M+2)/2].
实施例12：[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]-2-环戊基-2-羟基-2-(2-噻吩基)乙酸酯；二三氟乙酸盐(化合物12)Example 12: [7-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]-2-cyclopentyl-2- Hydroxy-2-(2-thienyl) acetate; ditrifluoroacetate (compound 12)
[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-(2-thienyl)acetate ditrifluoroacetate[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]- 5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-(2-thienyl)acetate ditrifluoroacetate
Figure PCTCN2016081809-appb-000110
Figure PCTCN2016081809-appb-000110
第一步：2-氧代-2-(2-噻吩基)乙酸(12B) First step: 2-oxo-2-(2-thienyl)acetic acid (12B)
2-oxo-2-(2-thienyl)acetic acid2-oxo-2-(2-thienyl)acetic acid
Figure PCTCN2016081809-appb-000111
Figure PCTCN2016081809-appb-000111
将2-氧代-2-(2-噻吩基)乙酸乙酯(6.0g,32.6mmol)溶于水(20mL)中，室温滴加氢氧化钠(2.61g,65.1mmol)的水溶液，反应2小时。反应完毕后，加入水(50mL)，用二氯甲烷(50mL×2)萃取分层，水相用稀盐酸调pH＝3，用二氯甲烷(100mL×2)萃取，合并第二次的有机相，无水硫酸钠干燥，过滤，滤液减压浓缩后得到标题化合物2-氧代-2-(2-噻吩基)乙酸(12B)，白色固体(4.00g，产率78.6％)。Ethyl 2-(oxo-2-(2-thienyl)acetate (6.0 g, 32.6 mmol) was dissolved in water (20 mL), and aqueous solution of sodium hydroxide (2.61 g, 65.1 mmol) was added dropwise at room temperature, reaction 2 hour. After completion of the reaction, water (50 mL) was added, and the layers were extracted with dichloromethane (50 mL×2), the aqueous phase was adjusted to pH 3 with dilute hydrochloric acid, and extracted with dichloromethane (100 mL×2) The residue was dried with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
1H NMR(400MHz,DMSO-d6)δ14.51(s,1H),8.22(m,1H),8.07(m,1H),7.32(m,1H). 1 H NMR (400MHz, DMSO- d6) δ14.51 (s, 1H), 8.22 (m, 1H), 8.07 (m, 1H), 7.32 (m, 1H).
LCMS m/z＝157.1[M+1].LCMS m/z = 157.1 [M + 1].
第二步：2-[2-氧代-2-(2-噻吩基)乙酰氧基]-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(12C)Second step: 2-[2-oxo-2-(2-thienyl)acetoxy]-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (12C)
tert-butyl 2-[2-oxo-2-(2-thienyl)acetyl]oxy-7-azaspiro[3.5]nonane-7-carboxylateTert-butyl 2-[2-oxo-2-(2-thienyl)acetyl]oxy-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2016081809-appb-000112
Figure PCTCN2016081809-appb-000112
将2-氧代-2-(2-噻吩基)乙酸(12B)(0.500g,3.20mmol)溶于二氯甲烷(10mL)中，滴加草酰氯(0.813g,6.40mmol)，然后加入一滴N,N-二甲基甲酰胺，室温反应1小时。减压除去溶剂和过量的草酰氯，制成反应液2。将2-羟基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(0.773g,3.20mmol)溶于二氯甲烷(10mL)中，冰浴下加入反应液2。加完后升至室温反应1小时。反应完毕后加入水(50mL)，用二氯甲烷(100mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩后残留物用硅胶柱色谱分离提纯(洗脱剂为乙酸乙酯：石油醚(v/v)＝49:1～10:1)，得到标题化合物2-[2-氧代-2-(2-噻吩基)乙酰氧基]-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(12C)，淡黄色液体(1.0g，产率82.3％)。2-Oxo-2-(2-thienyl)acetic acid (12B) (0.500 g, 3.20 mmol) was dissolved in dichloromethane (10 mL), oxalyl chloride (0.813 g, 6.40 mmol) was added dropwise, followed by a drop N,N-dimethylformamide was reacted at room temperature for 1 hour. The solvent and excess oxalyl chloride were removed under reduced pressure to prepare a reaction liquid 2. 2-Hydroxy-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (0.773 g, 3.20 mmol) was dissolved in dichloromethane (10 mL), and then, After the addition was completed, the mixture was allowed to react to room temperature for 1 hour. After completion of the reaction, water (50 mL) was added, and the mixture was evaporated. Ethyl ester: petroleum ether (v/v) = 49:1 to 10:1) to give the title compound 2-[2-oxo-2-(2-thienyl)acetoxy]-7-azaspiro[ 3.5] tert-butyl decane-7-carboxylate (12C), pale yellow liquid (1.0 g, yield 82.3%).
1H NMR(400MHz,CDCl3)δ8.12(d,1H),7.82(d,1H),7.23-7.17(m,1H),5.26(m,1H),3.43-3.35(m,2H),3.35-3.26(m,2H),2.52-2.40(m,2H),2.09-2.01(m,2H),1.59(m,4H),1.45(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ8.12 (d, 1H), 7.82 (d, 1H), 7.23-7.17 (m, 1H), 5.26 (m, 1H), 3.43-3.35 (m, 2H), 3.35-3.26 (m, 2H), 2.52-2.40 (m, 2H), 2.09-2.01 (m, 2H), 1.59 (m, 4H), 1.45 (s, 9H).
LCMS m/z＝402.1[M+23].LCMS m/z = 402.1 [M+23].
第三步：2-[2-环戊基-2-羟基-2-(2-噻吩基)乙酰氧基]-7-氮杂螺[3.5]壬烷-7-羧酸叔丁 酯(12D)The third step: 2-[2-cyclopentyl-2-hydroxy-2-(2-thienyl)acetoxy]-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl Ester (12D)
tert-butyl 2-[2-cyclopentyl-2-hydroxy-2-(2-thienyl)acetyl]oxy-7-azaspiro[3.5]nonane-7-carboxylateTert-butyl 2-[2-cyclopentyl-2-hydroxy-2-(2-thienyl)acetyl]oxy-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2016081809-appb-000113
Figure PCTCN2016081809-appb-000113
将2-[2-氧代-2-(2-噻吩基)乙酰氧基]-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(12C)(1.0g,2.64mmol)溶于四氢呋喃(20mL)中，氮气保护下冷却到-40℃，滴加1.0M环戊基溴化镁的四氢呋喃溶液(3.95mL,3.95mmol)，加完后升温到室温反应30分钟。反应完毕后，加入饱和氯化铵水溶液(50mL)，用乙酸乙酯(100mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩后，残留物用硅胶柱色谱分离提纯(洗脱剂为乙酸乙酯：石油醚(v/v)＝49:1～19:1)，得到标题化合物2-[2-环戊基-2-羟基-2-(2-噻吩基)乙酰氧基]-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(12D)，淡黄色液体(0.500g，产率42.2％)。2-[2-Oxo-2-(2-thienyl)acetoxy]-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (12C) (1.0 g, 2.64 mmol) The solution was dissolved in tetrahydrofuran (20 mL), cooled to -40 ° C under nitrogen atmosphere, and a solution of 1.0 M cyclopentylmagnesium bromide in tetrahydrofuran (3.95 mL, 3.95 mmol) was added dropwise, and the mixture was warmed to room temperature for 30 minutes. After completion of the reaction, a saturated aqueous solution of ammonium chloride (50 mL) was added, and ethyl acetate (100 mL×2) was evaporated. Purification (eluent: ethyl acetate: petroleum ether (v/v) = 49:1 to 19:1) to give the title compound 2-[2-cyclopentyl-2-hydroxy-2-(2-thienyl) Acetoxy]-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (12D), pale yellow liquid (0.500 g, yield 42.2%).
1H NMR(400MHz,CDCl3)δ7.21(m,1H),7.11m,1H),6.97m,1H),5.08(m,1H),3.96(s,1H),3.35-3.26(m,4H),2.85-2.73(m,1H),2.39(m,1H),2.31(m,1H),1.90(m,1H),1.82(m,1H),1.61-1.48(m,12H),1.45(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ7.21 (m, 1H), 7.11m, 1H), 6.97m, 1H), 5.08 (m, 1H), 3.96 (s, 1H), 3.35-3.26 (m, 4H), 2.85-2.73 (m, 1H), 2.39 (m, 1H), 2.31 (m, 1H), 1.90 (m, 1H), 1.82 (m, 1H), 1.61-1.48 (m, 12H), 1.45 (s, 9H).
第四步：7-氮杂螺[3.5]壬烷-2-基2-环戊基-2-羟基-2-(2-噻吩基)乙酸酯(12E)Step 4: 7-Azaspiro[3.5]decane-2-yl 2-cyclopentyl-2-hydroxy-2-(2-thienyl)acetate (12E)
7-azaspiro[3.5]nonan-2-yl 2-cyclopentyl-2-hydroxy-2-(2-thienyl)acetate7-azaspiro[3.5]nonan-2-yl 2-cyclopentyl-2-hydroxy-2-(2-thienyl)acetate
Figure PCTCN2016081809-appb-000114
Figure PCTCN2016081809-appb-000114
将2-[2-环戊基-2-羟基-2-(2-噻吩基)乙酰氧基]-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(12D)(0.55g,1.22mmol)溶于1,4-二氧六环(20mL)中，通入过量的盐酸气体室温反应1小时。反应完毕后，加入饱和碳酸氢钠水溶液(50mL),用二氯甲烷(100mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到标题化合物7-氮杂螺[3.5]壬烷-2-基2-环戊基-2-羟基-2-(2-噻吩基)乙酸酯(12E)，无色液体(0.40g，产率93.6％)。2-[2-Cyclopentyl-2-hydroxy-2-(2-thienyl)acetoxy]-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (12D) (0.55 g, 1.22 mmol) was dissolved in 1,4-dioxane (20 mL) and reacted with an excess of hydrochloric acid gas at room temperature for 1 hour. After completion of the reaction, a saturated aqueous solution of sodium hydrogencarbonate (50 mL) was evaporated. 3.5]decane-2-yl 2-cyclopentyl-2-hydroxy-2-(2-thienyl)acetate (12E) as a colorless liquid (0.40 g, yield 93.6%).
1H NMR(400MHz,DMSO-d6)δ7.38(m,1H),7.08(m,1H),6.96(m,1H),5.93(s,1H),4.94(m,1H),2.78-2.68m,1H),2.63-2.52(m,4H),2.24(m,2H),1.70(m,2H),1.58-1.39(m,12H). 1 H NMR (400 MHz, DMSO-d6) δ 7.38 (m, 1 H), 7.08 (m, 1H), 6.96 (m, 1H), 5.93 (s, 1H), 4.94 (m, 1H), 2.78-2.68 m,1H), 2.63-2.52 (m, 4H), 2.24 (m, 2H), 1.70 (m, 2H), 1.58-1.39 (m, 12H).
LCMS m/z＝350.2[M+1].LCMS m/z = 350.2 [M + 1].
第五步：[7-[3-(2-氯-4-甲酰基-5-甲氧基-苯胺基)-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-(2-噻吩基)乙酸酯(12F)Step 5: [7-[3-(2-Chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]decane- 2-yl]2-cyclopentyl-2-hydroxy-2-(2-thienyl)acetate (12F)
[7-[3-(2-chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-(2-thienyl)acetate[7-[3-(2-chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2 -(2-thienyl)acetate
Figure PCTCN2016081809-appb-000115
Figure PCTCN2016081809-appb-000115
将N-(2-氯-4-甲酰基-5-甲氧基-苯基)丙-2-烯酰胺(1E)(0.247g,2.03mmol)溶于2-甲基四氢呋喃(30mL)中，加入7-氮杂螺[3.5]壬烷-2-基2-环戊基-2-羟基-2-(2-噻吩基)乙酸酯(12E)(0.300g,0.858mmol)，加入三乙胺(0.174g,1.72mmol)，100℃微波反应1小时。反应液冷却至室温，减压浓缩后，残留物用硅胶柱色谱分离提纯(洗脱剂为甲醇：二氯甲烷(v/v)＝1:99～1:49)，得到标题化合物[7-[3-(2-氯-4-甲酰基-5-甲氧基-苯胺基)-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-(2-噻吩基)乙酸酯(12F)，黄色固体(0.350g，产率69.2％)。N-(2-Chloro-4-formyl-5-methoxy-phenyl)prop-2-enamide (1E) (0.247 g, 2.03 mmol) was dissolved in 2-methyltetrahydrofuran (30 mL). Add 7-azaspiro[3.5]decane-2-yl 2-cyclopentyl-2-hydroxy-2-(2-thienyl) acetate (12E) (0.300 g, 0.858 mmol), add triethyl Amine (0.174 g, 1.72 mmol) was reacted at 100 ° C for 1 hour. The reaction mixture was cooled to room temperature, and the residue was evaporated,jjjjjjjjjjj [3-(2-Chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-ring Amyl-2-hydroxy-2-(2-thienyl) acetate (12F), yellow solid (0.350 g, yield: 69.2%).
1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),10.18(s,1H),8.24(s,1H),7.70s,1H),7.39(m,1H),7.09(m,1H),6.97(m,1H),5.94(s,1H),5.03-4.93(m,1H),3.89(s,3H),2.80-2.70(m,1H),2.62(s,4H),2.41(d,3H),2.34-2.20(m,3H),1.82-1.69(m,2H),1.61(m,4H),1.55-1.28(m,8H). 1 H NMR (400MHz, DMSO- d6) δ10.79 (s, 1H), 10.18 (s, 1H), 8.24 (s, 1H), 7.70s, 1H), 7.39 (m, 1H), 7.09 (m, 1H), 6.97 (m, 1H), 5.94 (s, 1H), 5.03-4.93 (m, 1H), 3.89 (s, 3H), 2.80-2.70 (m, 1H), 2.62 (s, 4H), 2.41 (d, 3H), 2.34-2.20 (m, 3H), 1.82-1.69 (m, 2H), 1.61 (m, 4H), 1.55-1.28 (m, 8H).
LCMS m/z＝589.1[M+1].LCMS m/z = 589.1 [M + 1].
第六步：[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-(2-噻吩基)乙酸酯(12G)Step 6: [7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H) -quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane -2-yl]2-cyclopentyl-2-hydroxy-2-(2-thienyl) acetate (12G)
[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-(2-thienyl)acetate[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl] Amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-(2-thienyl) Aclate
Figure PCTCN2016081809-appb-000116
Figure PCTCN2016081809-appb-000116
将[7-[3-(2-氯-4-甲酰基-5-甲氧基-苯胺基)-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-(2-噻吩基)乙酸酯(12F)(0.400g,0.679mmol)溶于二氯甲烷(10mL)和甲醇(10mL)的混合溶液中，加入5-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基甲基]-8-羟基-1H-喹啉-2-酮(1G)(0.318g,0.951mmol)，室温反应30分钟。加入三乙酰氧基硼氢化钠(0.432g,2.04mmol)，室温反应3小时。反应液加入二氯甲烷(20mL)和饱和碳酸氢钠溶液(20mL)，萃取分层，水相用二氯甲烷(20mL×1)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩后残留物用硅胶柱色谱分离提纯(洗脱剂为乙酸乙酯:石油醚(v/v)＝1:1～1:0，甲醇：二氯甲烷(v/v)＝1:99～1:19)，得到标题化合物[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]-2-环戊基-2-羟基-2-(2-噻吩基)乙酸酯(12G)，淡黄色固体(0.400g，产率64.9％)。[7-[3-(2-Chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl 2-cyclopentyl-2-hydroxy-2-(2-thienyl) acetate (12F) (0.400 g, 0.679 mmol) was dissolved in a mixture of dichloromethane (10 mL) and methanol (10 mL). Add 5-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxymethyl]-8-hydroxy-1H-quinolin-2-one (1G) (0.318g , 0.951 mmol), and reacted at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.432 g, 2.04 mmol) was added and allowed to react at room temperature for 3 hours. The reaction mixture was added with dichloromethane (20 mL) and EtOAc (EtOAc (EtOAc) The residue was concentrated and purified by silica gel column chromatography (eluent ethyl acetate: petroleum ether (v/v) = 1:1 to 1:0, methanol: dichloromethane (v/v) = 1:99 ～1:19), the title compound [7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2) -oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-aza snail [3.5] decane-2-yl]-2-cyclopentyl-2-hydroxy-2-(2-thienyl) acetate (12G), mp.
LCMS m/z＝454.1[(M+2)/2].LCMS m/z = 454.1 [(M+2)/2].
第七步：[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-(2-噻吩基)乙酸酯；二三氟乙酸盐(化合物12)Step 7: [7-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-7-azaspiro[3.5]decan-2-yl]2-cyclopentyl-2-hydroxyl -2-(2-thienyl) acetate; ditrifluoroacetate (compound 12)
[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-(2-thienyl)acetate,；ditrifluoroacetate[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]- 5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-(2-thienyl)acetate,;ditrifluoroacetate
Figure PCTCN2016081809-appb-000117
Figure PCTCN2016081809-appb-000117
将[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]-2-环戊基-2-羟基-2-(2-噻吩基)乙酸酯(12G)(0.275g,0.303mmol)溶于二氯甲烷(15mL)中，加入三乙胺三氢氟酸盐(0.488g,3.03mmol)，室温反应24小时。反应液加入水(20mL)和二氯甲烷(20mL)，加入3％氢氧化钠溶液调节pH至12左右，萃取分层，水相用二氯甲烷(20mL×2)萃取，合并有机相，饱和氯化钠水溶液(20mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后残留物用硅胶柱色谱分离提纯(洗脱剂为乙酸乙酯:石油醚 (v/v)＝1:1～1:0，甲醇：二氯甲烷(v/v)＝3:97～1:9)，浓缩除去溶剂后得到的粗品，粗品进一步通过用液相制备柱分离提纯(液相制备条件：C18反相制备柱，流动相为含0.05％TFA的去离子水(A)，含0.05％TFA的乙腈(B)，梯度洗脱A:B＝5％～100％，洗脱10分钟，然后用100％B洗脱5分钟，流速1.0mL/min，柱温：40℃)得到标题化合物[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-(2-噻吩基)乙酸酯；二三氟乙酸盐(化合物12)，淡黄色固体(0.025g，产率10.4％)。[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinoline) -5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2- 2-cyclopentyl-2-hydroxy-2-(2-thienyl) acetate (12G) (0.275 g, 0.303 mmol) was dissolved in dichloromethane (15 mL), triethylamine trihydrogen The fluorate (0.488 g, 3.03 mmol) was reacted at room temperature for 24 hours. The reaction liquid was added with water (20 mL) and dichloromethane (20 mL), and the pH was adjusted to about 12 by adding 3% sodium hydroxide solution, and the layers were separated, and the aqueous phase was extracted with dichloromethane (20 mL×2), and the organic phase was combined and saturated. The aqueous solution of sodium chloride (20 mL × 1) was washed with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. (v/v)=1:1～1:0, methanol: dichloromethane (v/v)=3:97～1:9), the crude product obtained after concentration and removal of the solvent, the crude product is further prepared by using a liquid phase column Separation and purification (liquid phase preparation conditions: C18 reverse phase preparation column, mobile phase is deionized water (A) containing 0.05% TFA, acetonitrile (B) containing 0.05% TFA, gradient elution A: B = 5% ~ 100 %, eluted for 10 minutes, then eluted with 100% B for 5 minutes, flow rate 1.0 mL/min, column temperature: 40 ° C) to give the title compound [7-[3-[2-chloro-4-[[[(2) )-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxyanilino]-3-oxo- Propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2-hydroxy-2-(2-thienyl) acetate; ditrifluoroacetate (compound 12 ), pale yellow solid (0.025 g, yield 10.4%).
1H NMR(400MHz,CD3OD)δ7.22(d,1H),6.88(s,1H),6.56(s,1H),6.44-6.33(m,2H),6.23(s,1H),6.13(d,1H),6.08-6.04(m,1H),5.70(d,1H),4.50(m,1H),4.23-4.13(m,1H),3.36(m,2H),2.95(s,3H),2.70-2.57(m,4H),2.38-2.32(m,1H),2.27(m,1H),2.16(m,4H),1.96(m,1H),1.62(m,1H),1.47(m,1H),1.08(m,6H),0.82-0.53(m,8H). 1 H NMR (400 MHz, CD 3 OD) δ 7.22 (d, 1H), 6.88 (s, 1H), 6.56 (s, 1H), 6.44-6.33 (m, 2H), 6.23 (s, 1H), 6.13 (d, 1H), 6.08-6.04 (m, 1H), 5.70 (d, 1H), 4.50 (m, 1H), 4.23-4.13 (m, 1H), 3.36 (m, 2H), 2.95 (s, 3H) ), 2.70-2.57 (m, 4H), 2.38-2.32 (m, 1H), 2.27 (m, 1H), 2.16 (m, 4H), 1.96 (m, 1H), 1.62 (m, 1H), 1.47 ( m, 1H), 1.08 (m, 6H), 0.82-0.53 (m, 8H).
LCMS m/z＝397.3(M+2)/2].LCMS m/z = 397.3 (M+2)/2].
实施例13：[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯；二三氟乙酸盐(化合物13)Example 13: [7-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2- Hydroxy-2-phenyl-acetate; ditrifluoroacetate (compound 13)
[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate；ditrifluoroacetic acid[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]- 5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000118
Figure PCTCN2016081809-appb-000118
Figure PCTCN2016081809-appb-000119
Figure PCTCN2016081809-appb-000119
第一步：2-氧代-2-苯基-乙酸(13B)2-oxo-2-phenyl-acetic acidFirst step: 2-oxo-2-phenyl-acetic acid (13B) 2-oxo-2-phenyl-acetic acid
Figure PCTCN2016081809-appb-000120
Figure PCTCN2016081809-appb-000120
将2-氧代-2-苯基-乙酸甲酯(13A)(10g,60.92mmol)溶于水(50mL)中，加入氢氧化钠(4.9g,121.8mmol)，室温反应2小时。反应液用二氯甲烷(50mL×2)萃取，水相用4M盐酸水溶液调节pH至3，用二氯甲烷(100mL×3)萃取，合并有机相，有机相减压浓缩，得到标题化合物2-氧代-2-苯基-乙酸(13B)，白色固体(9g，产率98.41％)。2-Oxo-2-phenyl-acetic acid methyl ester (13A) (10 g, 60.92 mmol) was dissolved in water (50 mL), and sodium hydroxide (4.9 g, 121.8 mmol) was added and allowed to react at room temperature for 2 hours. The reaction mixture was extracted with methylene chloride (50 mL×2). Oxo-2-phenyl-acetic acid (13B), white solid (9 g, yield 98.41%).
1H NMR(400MHz,DMSO-d6)δ7.95-7.88(m,2H),7.78–7.71(m,1H),7.64–7.55(m,2H). 1 H NMR (400MHz, DMSO- d6) δ7.95-7.88 (m, 2H), 7.78-7.71 (m, 1H), 7.64-7.55 (m, 2H).
LCMS m/z＝149.1[M-1]。LCMS m/z = 149.1 [M-1].
第二步：2-(2-氧代-2-苯基-乙酰基)氧基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(13C)Second step: 2-(2-oxo-2-phenyl-acetyl)oxy-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (13C)
tert-butyl 2-(2-oxo-2-phenyl-acetyl)oxy-7-azaspiro[3.5]nonane-7-carboxylateTert-butyl 2-(2-oxo-2-phenyl-acetyl)oxy-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2016081809-appb-000121
Figure PCTCN2016081809-appb-000121
将2-氧代-2-苯基-乙酸(13B)(4.0g,27mmol)溶于二氯甲烷(100mL)中，加入草酰氯(6.8g,53mmol)，滴加一滴N,N-二甲基甲酰胺，室温反应1小时。反应液减压浓缩为反应液3。将2-羟基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(1B)(4.8g,20mmol)溶于二氯甲烷(100mL)中，加入三乙胺(11g,110mmol)，冰浴下加入反应液3，室温反应1小时。反应液加入二氯甲烷(50mL)和水(50mL)，萃取。水相用二氯甲烷(50mL×1)萃取，合并有机相。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝0:1～1:9)，得到标题化合物2-(2-氧代-2-苯基-乙酰基)氧基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(13C)，黄色油状(6.0g，产率60％)。2-Oxo-2-phenyl-acetic acid (13B) (4.0 g, 27 mmol) was dissolved in dichloromethane (100 mL), oxalyl chloride (6.8 g, 53 mmol) was added, and a drop of N,N-dimethyl The carboxamide was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure into a reaction mixture 3. 2-Hydroxy-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (1B) (4.8 g, 20 mmol) was dissolved in dichloromethane (100 mL) and triethylamine (11 g, 110 mmol) The reaction solution 3 was added under an ice bath, and reacted at room temperature for 1 hour. The reaction solution was added with dichloromethane (50 mL) and water (50 mL) and evaporated. The aqueous phase was extracted with dichloromethane (50 mL x 1) and organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether (v/v) = 1:1 to 1:9) to give the title compound 2-(2-oxo-2-phenyl-acetyl) Tert-butyl-7-azaspiro[3.5]decane-7-carboxylate (13C), yellow oil (6.0 g, yield 60%).
1H NMR(400MHz,CDCl3)δ8.00(d,2H),7.70-7.62(m,1H),7.52(t,2H),5.35–5.28(m,1H),3.42–3.34(m,2H),3.34–3.26(m,2H),2.54–2.41(m,2H),2.07–1.98(m,2H),1.64–1.53(m,4H),1.50–1.37(m,9H). 1 H NMR (400MHz, CDCl 3 ) δ 8.00 (d, 2H), 7.70-7.62 (m, 1H), 7.52 (t, 2H), 5.35 - 5.28 (m, 1H), 3.42 - 3.34 (m, 2H) ), 3.34–3.26 (m, 2H), 2.54–2.41 (m, 2H), 2.07–1.98 (m, 2H), 1.64–1.53 (m, 4H), 1.50–1.37 (m, 9H).
LCMS m/z＝396.2[M+23]。LCMS m/z = 396.2 [M+23].
第三步：2-(2-环戊基-2-羟基-2-苯基-乙酰基)氧基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(13D)Third step: 2-(2-cyclopentyl-2-hydroxy-2-phenyl-acetyl)oxy-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (13D)
tert-butyl 2-(2-cyclopentyl-2-hydroxy-2-phenyl-acetyl)oxy-7-azaspiro[3.5]nonane-7-carboxylateTert-butyl 2-(2-cyclopentyl-2-hydroxy-2-phenyl-acetyl)oxy-7-azaspiro[3.5]nonane-7-carboxylate
Figure PCTCN2016081809-appb-000122
Figure PCTCN2016081809-appb-000122
将2-(2-氧代-2-苯基-乙酰基)氧基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(13C)(1.0g,11mmol)溶于四氢呋喃(100mL)中，-40℃加入2.0M的环戊基溴化镁的四氢呋喃溶液(8mL，16mmol)，逐渐升至室温反应2小时。反应液加入饱和氯化铵溶液(60mL)，加入乙酸乙酯(50mL)，萃取。水相用乙酸乙酯(50mL×1)萃取，合并有机相。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝0:1～1:19)，得到标题化合物2-(2-环戊基-2-羟基-2-苯基-乙酰基)氧基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(13D)，无色油状(2.4g，产率51％)。2-(2-Oxo-2-phenyl-acetyl)oxy-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (13C) (1.0 g, 11 mmol) was dissolved in tetrahydrofuran (100 mL), a solution of 2.0 M cyclopentylmagnesium bromide in tetrahydrofuran (8 mL, 16 mmol) was added at -40 ° C, and the mixture was gradually warmed to room temperature for 2 hours. A saturated ammonium chloride solution (60 mL) was added, and ethyl acetate (50 mL) was evaporated. The aqueous phase was extracted with ethyl acetate (50 mL×1) and organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: EtOAc (EtOAc:EtOAc) tert-Butyl ester of acetyl)oxy-7-azaspiro[3.5]decane-7-carboxylate (13D) as a colorless oil (2.4 g, yield 51%).
1H NMR(400MHz,CDCl3)δ7.68–7.42(m,2H),7.38–7.29(m,2H),7.29–7.23(m,1H),5.084.95(m,1H),3.39–3.17(m,4H),2.97-2.82(m,1H),2.44-2.20(m,2H),1.90-1.80(m,1H),1.79–1.54(m,7H),1.53-1.47(m,4H),1.45–1.43(m,9H),1.38-1.30(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ 7.68–7.42 (m, 2H), 7.38–7.29 (m, 2H), 7.29–7.23 (m, 1H), 5.084.95 (m, 1H), 3.39–3.17 (m, 4H), 2.97-2.82 (m, 1H), 2.44-2.20 (m, 2H), 1.90 - 1.80 (m, 1H), 1.79 - 1.54 (m, 7H), 1.53-1.47 (m, 4H) , 1.45–1.43 (m, 9H), 1.38-1.30 (m, 2H).
LCMS m/z＝466.3[M+23]。LCMS m/z = 466.3 [M+23].
第四步：7-氮杂螺[3.5]壬烷-2-基2-环戊基-2-羟基-2-苯基-乙酸酯(13E)Fourth step: 7-azaspiro[3.5]decane-2-yl 2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13E)
7-azaspiro[3.5]nonan-2-yl 2-cyclopentyl-2-hydroxy-2-phenyl-acetate7-azaspiro[3.5]nonan-2-yl 2-cyclopentyl-2-hydroxy-2-phenyl-acetate
Figure PCTCN2016081809-appb-000123
Figure PCTCN2016081809-appb-000123
将2-(2-环戊基-2-羟基-2-苯基-乙酰基)氧基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(13D)(2.4g,5.4mmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(6.2g,54mmol)，室温反应3小时。反应液加入氨水调节pH至10，加入二氯甲烷(50mL)和水(50mL)，萃取。水相用二氯甲烷(20mL×1)萃取，合并有机相。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物7-氮杂螺[3.5]壬烷-2-基2-环戊基-2-羟基-2-苯基-乙酸酯(13E)，黄色油状(1.7g，产率91％)。2-(2-Cyclopentyl-2-hydroxy-2-phenyl-acetyl)oxy-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (13D) (2.4 g, 5.4 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (6.2 g, 54 mmol). The reaction solution was adjusted to pH 10 by adding aqueous ammonia, and dichloromethane (50 mL) and water (50 mL) were added and extracted. The aqueous phase was extracted with dichloromethane (20 mL x 1) and organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated Ester (13E), yellow oil (1.7 g, yield 91%).
1H NMR(400MHz,CDCl3)δ7.66–7.40(m,2H),7.38-7.29(m,2H),7.297.24(m,1H),5.07–4.95(m,1H),3.03–2.84(m,4H),2.51–2.18(m,2H),2.001.27(m,15H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.66 - 7.40 (m, 2H), 7.38-7.29 (m, 2H), 7.297.24 (m, 1H), 5.07 - 4.95 (m, 1H), 3.03 - 2.84 (m, 4H), 2.51–2.18 (m, 2H), 2.001.27 (m, 15H).
LCMS m/z＝344.2[M+1]。LCMS m/z = 344.2 [M + 1].
第五步：[7-[3-(2-氯-4-甲酰基-5-甲氧基-苯胺基)-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯(13F)Step 5: [7-[3-(2-Chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]decane- 2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13F)
[7-[3-(2-chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate[7-[3-(2-chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2 -phenyl-acetate
Figure PCTCN2016081809-appb-000124
Figure PCTCN2016081809-appb-000124
将7-氮杂螺[3.5]壬烷-2-基2-环戊基-2-羟基-2-苯基-乙酸酯(13E)(0.400g,1.16mmol)溶于2-甲基四氢呋喃(10mL)中，加入N-(2-氯-4-甲酰基-5-甲氧基-苯基)丙基-2-烯酰胺(1E)(0.307g,1.28mmol)，加入三乙胺(0.236g,2.33mmol)，100℃微波反应1小时。反应液冷却至室温，减压浓缩，残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝1:1～1:0)，得到标题化合物[7-[3-(2-氯-4-甲酰基-5-甲氧基-苯胺基)-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯(13F)，黄色固体(0.500g，产率 73.6％)。Dissolving 7-azaspiro[3.5]decane-2-yl 2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13E) (0.400 g, 1.16 mmol) in 2-methyltetrahydrofuran (10 mL), N-(2-chloro-4-formyl-5-methoxy-phenyl)propyl-2-enoic acid amide (1E) (0.307 g, 1.28 mmol) was added, and triethylamine was added. 0.236 g, 2.33 mmol), microwave reaction at 100 ° C for 1 hour. The reaction mixture was cooled to room temperature, and the residue was evaporated. mjjjjjjjjjjjj 2-Chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2 -hydroxy-2-phenyl-acetate (13F), yellow solid (0.500 g, yield 73.6%).
1H NMR(400MHz,CDCl3)δ10.93(s,1H),10.32(s,1H),8.34d,1H),7.81d,1H),7.67–7.41(m,2H),7.38–7.30(m,2H),7.29–7.23(m,1H),5.08-4.98(m,1H),3.93s,3H),2.98–2.85(m,1H),2.74-2.55(m,4H),2.47-2.23(m,4H),1.911.41m,14H),1.39–1.29(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 10.93 (s, 1H), 10.32 (s, 1H), 8.34d, 1H), 7.81d, 1H), 7.67 - 7.41 (m, 2H), 7.38 - 7.30 ( m, 2H), 7.29–7.23 (m, 1H), 5.08-4.98 (m, 1H), 3.93 s, 3H), 2.98–2.85 (m, 1H), 2.74-2.55 (m, 4H), 2.47-2.23 (m, 4H), 1.911.41m, 14H), 1.39–1.29 (m, 2H).
LCMS m/z＝583.3[M+1]。LCMS m/z = 583.3 [M + 1].
第六步：[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯(13G)Step 6: [7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H) -quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane -2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13G)
[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl] Amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate
Figure PCTCN2016081809-appb-000125
Figure PCTCN2016081809-appb-000125
将[7-[3-(2-氯-4-甲酰基-5-甲氧基-苯胺基)-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯(13F)(0.430g,0.737mmol)溶于甲醇(10mL)中，加入5-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基甲基]-8-羟基-1H-喹啉-2-酮(1G)(0.296g,0.885mmol)，加入无水氯化锌(0.402g,2.95mmol)，55℃反应1小时。加入氰基硼氢化钠(0.139g,2.21mmol)，55℃反应2小时。反应液加入二氯甲烷(50mL)和饱和碳酸氢钠溶液(20mL)，萃取。水相用二氯甲烷(30mL×1)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯(13G)，黄色固体(0.47g，产率70％)。[7-[3-(2-Chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl 2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13F) (0.430 g, 0.737 mmol) was dissolved in methanol (10 mL), and 5-[(1R)-2-amino-1 was added. -[tert-Butyl(dimethyl)silyl]oxymethyl]-8-hydroxy-1H-quinolin-2-one (1G) (0.296 g, 0.885 mmol), anhydrous zinc chloride (0.402) g, 2.95 mmol), reacted at 55 ° C for 1 hour. Sodium cyanoborohydride (0.139 g, 2.21 mmol) was added, and the mixture was reacted at 55 ° C for 2 hours. The reaction solution was added with dichloromethane (50 mL) and saturated sodium hydrogen sulfate (20 mL). The aqueous phase was extracted with dichloromethane (30 mL×1). EtOAcjjjjjjjjj )-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2 -chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2-hydroxy-2-benzene Base-acetate (13G), yellow solid (0.47 g, yield 70%).
LCMS m/z＝451.3[(M+2)/2]。LCMS m/z = 451.3 [(M+2)/2].
第七步：[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙 酸酯；二三氟乙酸盐(化合物13)Step 7: [7-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2- Hydroxy-2-phenyl-B Acid ester; ditrifluoroacetate (compound 13)
[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate；ditrifluoroacetic acid[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]- 5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000126
Figure PCTCN2016081809-appb-000126
将[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯(13G)(0.450g,0.499mmol)溶于四氢呋喃(5mL)中，加入三乙胺三氢氟酸盐(0.805g,4.99mmol)，室温反应24小时。反应液加入10％(v/v)甲醇/二氯甲烷溶液(50mL),加入饱和碳酸氢钠水溶液调节pH至8左右，萃取。水相用10％(v/v)甲醇/二氯甲烷溶液(50mL×2)萃取，合并有机相。有机相用饱和食盐水(20mL×1)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩。残留物用液相制备柱分离提纯(制备条件：C18反相制备柱，流动相为为含0.05％TFA的去离子水(A)，含0.05％TFA的乙腈(B)，梯度洗脱A:B＝5％～100％，洗脱10分钟，然后用100％B洗脱5分钟，流速1.0mL/min，柱温：40℃)，得到标题化合物[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯；二三氟乙酸盐(化合物13)，白色固体(0.200g，产率39.5％)。[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinoline) -5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2- 2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13G) (0.450 g, 0.499 mmol) was dissolved in tetrahydrofuran (5 mL) and triethylamine trihydrofluoric acid salt (0.805 g) , 4.99 mmol), reacted at room temperature for 24 hours. The reaction solution was added with a 10% (v/v) methanol/methylene chloride solution (50 mL), and a saturated aqueous sodium hydrogencarbonate solution was added to adjust the pH to about 8 and extracted. The aqueous phase was extracted with a 10% (v/v) methanol/dichloromethane solution (50 mL×2). The organic layer was washed with brine (20 mL×1). The residue was separated and purified by liquid phase preparative column (preparation conditions: C18 reverse phase preparative column, mobile phase was deionized water (A) containing 0.05% TFA, acetonitrile (B) containing 0.05% TFA, gradient elution A: B = 5% to 100%, eluted for 10 minutes, then eluted with 100% B for 5 minutes, flow rate 1.0 mL/min, column temperature: 40 ° C) to give the title compound [7-[3-[2-chloro- 4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-aniline 3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate; ditrifluoroethyl Acid salt (Compound 13), white solid (0.200 g, yield 39.5%).
1H NMR(400MHz,CD3OD)δ8.16(d,1H),7.79(s,1H),7.64(d,2H),7.49–7.42(m,1H),7.40-7.22(m,4H),7.05(d,1H),6.62(d,1H),5.45-5.35(m,1H),5.10–4.96(m,1H),4.28(q,2H),33.82(s,3H),3.62-3.40(m,4H),3.30-3.15(m,2H),3.13–2.86(m,5H),2.60-2.24(m,2H),2.031.78(m,6H),1.76–1.30(m,8H). 1 H NMR (400 MHz, CD 3 OD) δ 8.16 (d, 1H), 7.79 (s, 1H), 7.64 (d, 2H), 7.49 - 7.42 (m, 1H), 7.40 - 7.22 (m, 4H) , 7.05 (d, 1H), 6.62 (d, 1H), 5.45-5.35 (m, 1H), 5.10 - 4.96 (m, 1H), 4.28 (q, 2H), 33.82 (s, 3H), 3.62-3.40 (m, 4H), 3.30-3.15 (m, 2H), 3.13–2.86 (m, 5H), 2.60-2.24 (m, 2H), 2.031.78 (m, 6H), 1.76–1.30 (m, 8H) .
19F NMR(376MHz,CD3OD)δ-75.35. 19 F NMR (376 MHz, CD 3 OD) δ-75.35.
LCMS m/z＝394.3[(M+2)/2]。LCMS m/z = 394.3 [(M+2)/2].
实施例14：[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基- 乙酸酯；二三氟乙酸盐(化合物13)的异构体1Example 14: [7-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2- Hydroxy-2-phenyl- Acetate; isomer 1 of ditrifluoroacetate (compound 13)
Isomer 1 of[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate；ditrifluoroacetic acidIsomer 1 of[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]] Methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000127
Figure PCTCN2016081809-appb-000127
第一步：7-氮杂螺[3.5]壬烷-2-基2-环戊基-2-羟基-2-苯基-乙酸酯(13E)的异构体1First step: isomer 1 of 7-azaspiro[3.5]decane-2-yl 2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13E)
Isomer 1 of 7-azaspiro[3.5]nonan-2-yl 2-cyclopentyl-2-hydroxy-2-phenyl-acetateIsomer 1 of 7-azaspiro[3.5]nonan-2-yl 2-cyclopentyl-2-hydroxy-2-phenyl-acetate
Figure PCTCN2016081809-appb-000128
Figure PCTCN2016081809-appb-000128
将2-(2-环戊基-2-羟基-2-苯基-乙酰基)氧基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(13D)(13g,29.31mmol)溶于二氯甲烷(50mL)中，加入三氟乙酸(33.41g,293.1mmol)，室温反应3小时。反应液加入氨水调节pH至10，加入二氯甲烷(50mL)和水(50mL)，萃取。水相用二氯甲烷(50mL×1)萃取，合并有机相。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物采用色谱柱分离提纯，色谱条件为：Instrument:Shimadzu LC-20AP Prep HPLC(PrepL-GB)；Column:ChiralPak AY,300×50mm,10u；Mobile phase:A for Heptane(0.1％NH3H2O)and B for Ethanol；Gradient:B 25％；Flow rate:80mL/min； Column temperature:R.T.得到标题化合物7-氮杂螺[3.5]壬烷-2-基2-环戊基-2-羟基-2-苯基-乙酸酯(13E)的异构体1，黄色油状(2.7g，产率27％)，13E异构体1的出峰时间小于13E异构体2的出峰时间。2-(2-Cyclopentyl-2-hydroxy-2-phenyl-acetyl)oxy-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (13D) (13 g, 29.31 Methyl) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (33.41 g, 293.1 mmol) The reaction solution was adjusted to pH 10 by adding aqueous ammonia, and dichloromethane (50 mL) and water (50 mL) were added and extracted. The aqueous phase was extracted with dichloromethane (50 mL x 1) and organic phases were combined. The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified and purified by column chromatography: Instrument: Shimadzu LC-20AP Prep HPLC (PrepL-GB); Column: ChiralPak AY, 300×50 mm , 10u; Mobile phase: A for Heptane (0.1% NH 3 H 2 O) and B for Ethanol; Gradient: B 25%; Flow rate: 80 mL/min; Column temperature: RT to give the title compound 7-azaspiro[3.5 Isomer 1 of decane-2-yl 2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13E), yellow oil (2.7 g, yield 27%), 13E isomer The peak time of 1 is less than the peak time of 13E isomer 2.
1H NMR(400MHz,CDCl3)δ7.65-7.40(m,2H),7.37–7.29(m,2H),7.29–7.23(m,1H),5.05-4.95(m,1H),2.96-2.88(m,1H),2.88–2.72(m,4H),2.46–2.20(m,2H),1.91–1.79(m,1H),1.79–1.40(m,12H),1.37-1.30(m,1H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.65-7.40 (m, 2H), 7.37 - 7.29 (m, 2H), 7.29 - 7.23 (m, 1H), 5.05 - 4.95 (m, 1H), 2.96 - 2.88 (m, 1H), 2.88–2.72 (m, 4H), 2.46–2.20 (m, 2H), 1.91–1.79 (m, 1H), 1.79–1.40 (m, 12H), 1.37-1.30 (m, 1H) .
LCMS m/z＝344.3[M+1]。LCMS m/z = 344.3 [M + 1].
第二步：[7-[3-(2-氯-4-甲酰基-5-甲氧基-苯胺基)-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯(13F)的异构体1Second step: [7-[3-(2-chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]decane- Isomer 1 of 2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13F)
Isomer 1 of[7-[3-(2-chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetateIsomer 1 of[7-[3-(2-chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2- Hydroxy-2-phenyl-acetate
Figure PCTCN2016081809-appb-000129
Figure PCTCN2016081809-appb-000129
将7-氮杂螺[3.5]壬烷-2-基2-环戊基-2-羟基-2-苯基-乙酸酯(13E)的异构体1(0.600g,1.75mmol)溶于2-甲基四氢呋喃(10mL)中，加入N-(2-氯-4-甲酰基-5-甲氧基-苯基)丙基-2-烯酰胺(1E)(0.460g,1.92mmol)，加入三乙胺(0.354g,3.49mmol)，100℃微波反应1小时。反应液冷却至室温，减压浓缩，残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝1:1～1:0)，得到标题化合物[7-[3-(2-氯-4-甲酰基-5-甲氧基-苯胺基)-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯(13F)的异构体1，黄色固体(0.740g，产率72.7％)。Isomer 1 (0.600 g, 1.75 mmol) of 7-azaspiro[3.5]decane-2-yl 2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13E) was dissolved. To 2-methyltetrahydrofuran (10 mL), N-(2-chloro-4-formyl-5-methoxy-phenyl)propyl-2-enamide (1E) (0.460 g, 1.92 mmol). Triethylamine (0.354 g, 3.49 mmol) was added and the mixture was reacted at 100 ° C for 1 hour. The reaction mixture was cooled to room temperature, and the residue was evaporated. mjjjjjjjjjjjj 2-Chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2 Isomer 1 of -hydroxy-2-phenyl-acetate (13F), yellow solid (0.740 g, yield 72.7%).
1H NMR(400MHz,CDCl3)δ10.29(d,1H),8.33(d,1H),7.81(d,1H),7.65-7.40(m,2H),7.37–7.29(m,2H),7.29–7.24(m,2H),5.07–4.95(m,1H),3.93(s,3H),2.972.83(m,1H),2.68(br,4H),2.48(br,2H),2.42–2.34(m,1H),2.32–2.23(m,1H),1.92–1.80(m,1H),1.80–1.65(m,7H),1.65–1.30(m,8H). 1 H NMR (400MHz, CDCl 3 ) δ10.29 (d, 1H), 8.33 (d, 1H), 7.81 (d, 1H), 7.65-7.40 (m, 2H), 7.37-7.29 (m, 2H), 7.29–7.24 (m, 2H), 5.07–4.95 (m, 1H), 3.93 (s, 3H), 2.972.83 (m, 1H), 2.68 (br, 4H), 2.48 (br, 2H), 2.42– 2.34(m,1H), 2.32–2.23(m,1H), 1.92–1.80(m,1H), 1.80–1.65(m,7H),1.65–1.30(m,8H).
LCMS m/z＝583.3[M+1]。LCMS m/z = 583.3 [M + 1].
第三步：[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环 戊基-2-羟基-2-苯基-乙酸酯(13G)的异构体1The third step: [7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H) -quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane -2-yl]2-ring Isomer 1 of amyl-2-hydroxy-2-phenyl-acetate (13G)
Isomer 1 of[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetateIsomer 1 of[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl )ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl- Aclate
Figure PCTCN2016081809-appb-000130
Figure PCTCN2016081809-appb-000130
将[7-[3-(2-氯-4-甲酰基-5-甲氧基-苯胺基)-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯(13F)的异构体1(0.740g,1.27mmol)溶于甲醇(10mL)中，加入5-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基甲基]-8-羟基-1H-喹啉-2-酮(1G)(0.425g,1.27mmol)，加入无水氯化锌(0.692g,5.08mmol)，55℃反应1小时。加入氰基硼氢化钠(0.239g,3.81mmol)，55℃反应2小时。反应液加入二氯甲烷(50mL)，加入饱和碳酸氢钠溶液(20mL)，萃取。水相用二氯甲烷(30mL×2)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯(13G)的异构体1，黄色固体(1.0g，产率87％)。[7-[3-(2-Chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl Isomer 1 (0.740 g, 1.27 mmol) of 2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13F) was dissolved in methanol (10 mL), and 5-[(1R)- 2-Amino-1-[tert-butyl(dimethyl)silyl]oxymethyl]-8-hydroxy-1H-quinolin-2-one (1G) (0.425 g, 1.27 mmol), Zinc chloride (0.692 g, 5.08 mmol) was reacted at 55 ° C for 1 hour. Sodium cyanoborohydride (0.239 g, 3.81 mmol) was added, and the mixture was reacted at 55 ° C for 2 hours. The reaction solution was added to dichloromethane (50 mL), and then evaporated. The aqueous phase was extracted with dichloromethane (30 mL×2). EtOAcjjjjjjjjjjj )-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2 -chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2-hydroxy-2-benzene Isomer 1 of the base-acetate (13G), yellow solid (1.0 g, yield 87%).
LCMS m/z＝451.3[(M+2)/2]。LCMS m/z = 451.3 [(M+2)/2].
第四步：[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯；二三氟乙酸盐(化合物13)的异构体1The fourth step: [7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2- Hydroxy-2-phenyl-acetate; isomer 1 of ditrifluoroacetate (compound 13)
Isomer 1 of[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate；ditrifluoroacetic acid Isomer 1 of[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]] Methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000131
Figure PCTCN2016081809-appb-000131
将[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯(13G)的异构体1(1.0g,1.1mmol)溶于四氢呋喃(5mL)中，加入三乙胺三氢氟酸盐(1.8g,11mmol)，室温反应24小时。反应液加入10％(v/v)甲醇/二氯甲烷溶液(50mL),加入饱和碳酸氢钠水溶液调节pH至8左右，萃取。水相用10％(v/v)甲醇/二氯甲烷溶液(50mL×2)萃取，合并有机相。有机相用饱和食盐水(20mL×1)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩。残留物用液相制备柱分离提纯(制备条件：C18反相制备柱，流动相为为含0.05％TFA的去离子水(A)，含0.05％TFA的乙腈(B)，梯度洗脱A:B＝5％～100％，洗脱10分钟，然后用100％B洗脱5分钟，流速1.0mL/min，柱温：40℃)，得到标题化合物[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯；二三氟乙酸盐(化合物13)的异构体1，白色固体(0.200g，产率18％)。[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinoline) -5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2- Isomer 1 (1.0 g, 1.1 mmol) of 2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13G) was dissolved in tetrahydrofuran (5 mL), and triethylamine trihydrofluoride was added. The acid salt (1.8 g, 11 mmol) was reacted at room temperature for 24 hours. The reaction solution was added with a 10% (v/v) methanol/methylene chloride solution (50 mL), and a saturated aqueous sodium hydrogencarbonate solution was added to adjust the pH to about 8 and extracted. The aqueous phase was extracted with a 10% (v/v) methanol/dichloromethane solution (50 mL×2). The organic layer was washed with brine (20 mL×1). The residue was separated and purified by liquid phase preparative column (preparation conditions: C18 reverse phase preparative column, mobile phase was deionized water (A) containing 0.05% TFA, acetonitrile (B) containing 0.05% TFA, gradient elution A: B = 5% to 100%, eluted for 10 minutes, then eluted with 100% B for 5 minutes, flow rate 1.0 mL/min, column temperature: 40 ° C) to give the title compound [7-[3-[2-chloro- 4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-aniline 3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate; ditrifluoroethyl Isomer 1 of the acid salt (Compound 13), white solid (0.200 g, yield 18%).
1H NMR(400MHz,CD3OD)δ8.13(d,1H),7.77(s,1H),7.62(d,2H),7.46(s,1H),7.37–7.21(m,4H),7.03(d,1H),6.60(d,1H),5.40(dd,1H),5.09–4.94(m,1H),4.26(q,2H),3.89–3.77(m,3H),3.62-3.40(m,4H),3.29-3.22(m,1H),3.21-3.12(m,1H),3.11–2.86(m,5H),2.60–2.40(m,1H),2.40–2.22(m,1H),2.00-1.80(m,6H),1.71–1.53(m,5H),1.52-1.40(m,1H),1.39-1.26(m,2H). 1 H NMR (400 MHz, CD 3 OD) δ 8.13 (d, 1H), 7.77 (s, 1H), 7.62 (d, 2H), 7.46 (s, 1H), 7.37 - 7.21 (m, 4H), 7.03 (d, 1H), 6.60 (d, 1H), 5.40 (dd, 1H), 5.09–4.94 (m, 1H), 4.26 (q, 2H), 3.89–3.77 (m, 3H), 3.62-3.40 (m) , 4H), 3.29-3.22 (m, 1H), 3.21-3.12 (m, 1H), 3.11–2.86 (m, 5H), 2.60–2.40 (m, 1H), 2.40–2.22 (m, 1H), 2.00 -1.80 (m, 6H), 1.71 - 1.53 (m, 5H), 1.52-1.40 (m, 1H), 1.39-1.26 (m, 2H).
19F NMR(376MHz,CD3OD)δ-75.43. 19 F NMR (376 MHz, CD 3 OD) δ-75.43.
LCMS m/z＝394.4[(M+2)/2]。LCMS m/z = 394.4 [(M+2)/2].
实施例15：[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯；二三氟乙酸盐(化合物13)的异构体2 Example 15: [7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2- Hydroxy-2-phenyl-acetate; isomer 2 of ditrifluoroacetate (compound 13)
Isomer 2 of[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate；ditrifluoroacetic acidIsomer 2 of[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]] Methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000132
Figure PCTCN2016081809-appb-000132
第一步：7-氮杂螺[3.5]壬烷-2-基2-环戊基-2-羟基-2-苯基-乙酸酯(13E)的异构体2First step: isomer 2 of 7-azaspiro[3.5]decane-2-yl 2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13E)
Isomer 2 of 7-azaspiro[3.5]nonan-2-yl 2-cyclopentyl-2-hydroxy-2-phenyl-acetateIsomer 2 of 7-azaspiro[3.5]nonan-2-yl 2-cyclopentyl-2-hydroxy-2-phenyl-acetate
Figure PCTCN2016081809-appb-000133
Figure PCTCN2016081809-appb-000133
将2-(2-环戊基-2-羟基-2-苯基-乙酰基)氧基-7-氮杂螺[3.5]壬烷-7-羧酸叔丁酯(13D)(13g,29.31mmol)溶于二氯甲烷(50mL)中，加入三氟乙酸(33.41g,293.1mmol)，室温反应3小时。反应液加入氨水调节pH至10，加入二氯甲烷(50mL)和水(50mL)，萃取。水相用二氯甲烷(50mL×1)萃取，合并有机相。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物拆分，制备条件如下：Instrument:Shimadzu LC-20AP Prep HPLC(PrepL-GB)；Column:ChiralPak AY,300×50mm,10u；Mobile phase:A for Heptane(0.1％NH3H2O)and B for Ethanol；Gradient:B 25％；Flow rate:80mL/min；Column temperature:R.T.得到标题化合物7-氮杂螺[3.5]壬烷-2-基2-环戊基-2-羟基-2-苯基-乙酸 酯(13E)的异构体2，黄色油状(2.50g，产率25％)。2-(2-Cyclopentyl-2-hydroxy-2-phenyl-acetyl)oxy-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (13D) (13 g, 29.31 Methyl) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (33.41 g, 293.1 mmol) The reaction solution was adjusted to pH 10 by adding aqueous ammonia, and dichloromethane (50 mL) and water (50 mL) were added and extracted. The aqueous phase was extracted with dichloromethane (50 mL x 1) and organic phases were combined. The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure, and the residue is partitioned. The conditions are as follows: Instrument: Shimadzu LC-20AP Prep HPLC (PrepL-GB); Column: ChiralPak AY, 300×50 mm, 10u; Mobile phase: A for Heptane (0.1% NH 3 H 2 O) and B for Ethanol; Gradient: B 25%; Flow rate: 80 mL/min; Column temperature: RT to give the title compound 7-azaspiro[3.5]decane Isomer 2 of 2-yl 2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13E) as a yellow oil (2.50 g, yield 25%).
1H NMR(400MHz,CDCl3)δ9.21(s,1H),7.62(dd,2H),7.36–7.30(m,2H),7.29–7.24(m,1H),5.08–4.96(m,1H),3.12-2.94(m,4H),2.94-2.85(m 1H),2.48–2.37(m,1H),2.37–2.27(m,1H),1.93(dd,1H),1.86-1.74(m,5H),1.73–1.40(m,6H),1.40-1.30(m,2H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.21 (s, 1H), 7.62 (dd, 2H), 7.36 - 7.30 (m, 2H), 7.29 - 7.24 (m, 1H), 5.08 - 4.96 (m, 1H) ), 3.12 - 2.94 (m, 4H), 2.94 - 2.85 (m 1H), 2.48 - 2.37 (m, 1H), 2.37 - 2.27 (m, 1H), 1.93 (dd, 1H), 1.86-1.74 (m, 5H), 1.73–1.40 (m, 6H), 1.40-1.30 (m, 2H).
LCMS m/z＝344.3[M+1]。LCMS m/z = 344.3 [M + 1].
第二步：[7-[3-(2-氯-4-甲酰基-5-甲氧基-苯胺基)-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯(13F)的异构体2Second step: [7-[3-(2-chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]decane- Isomer 2 of 2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13F)
Isomer 2 of[7-[3-(2-chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetateIsomer 2 of[7-[3-(2-chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2- Hydroxy-2-phenyl-acetate
Figure PCTCN2016081809-appb-000134
Figure PCTCN2016081809-appb-000134
将7-氮杂螺[3.5]壬烷-2-基2-环戊基-2-羟基-2-苯基-乙酸酯(13E)的异构体2(0.600g,1.75mmol)溶于2-甲基四氢呋喃(10mL)中，加入N-(2-氯-4-甲酰基-5-甲氧基-苯基)丙基-2-烯酰胺(1E)(0.460g,1.92mmol)，加入三乙胺(0.354g,3.49mmol)，100℃微波反应1小时。反应液浓缩，残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝1:1～1:0)，得到标题化合物[7-[3-(2-氯-4-甲酰基-5-甲氧基-苯胺基)-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯(13F)的异构体2，黄色固体(0.750g，产率73.6％)。Isomer 2 (0.600 g, 1.75 mmol) of 7-azaspiro[3.5]decane-2-yl 2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13E) was dissolved. To 2-methyltetrahydrofuran (10 mL), N-(2-chloro-4-formyl-5-methoxy-phenyl)propyl-2-enamide (1E) (0.460 g, 1.92 mmol). Triethylamine (0.354 g, 3.49 mmol) was added and the mixture was reacted at 100 ° C for 1 hour. The reaction mixture was concentrated, and the residue was purified (jjjjjjjjjjjj Formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2-hydroxy-2-benzene Isomer 2 of the base-acetate (13F), yellow solid (0.750 g, yield 73.6%).
1H NMR(400MHz,CDCl3)δ10.30(s,1H),8.34(s,1H),7.81(s,1H),7.68-7.62(m,2H),7.37–7.29(m,2H),7.29–7.24(m,2H),5.09–4.94(m,1H),3.93(s,3H),2.98-2.84(m,1H),2.67(s,4H),2.48(s,2H),2.42–2.35(m,1H),2.32-2.22(m,1H),1.91-1.83(m,1H),1.80–1.39(m,13H),1.39-1.29(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ10.30 (s, 1H), 8.34 (s, 1H), 7.81 (s, 1H), 7.68-7.62 (m, 2H), 7.37-7.29 (m, 2H), 7.29–7.24 (m, 2H), 5.09–4.94 (m, 1H), 3.93 (s, 3H), 2.98-2.84 (m, 1H), 2.67 (s, 4H), 2.48 (s, 2H), 2.42– 2.35 (m, 1H), 2.32-2.22 (m, 1H), 1.91-1.83 (m, 1H), 1.80-1.39 (m, 13H), 1.39-1.29 (m, 2H).
LCMS m/z＝583.3[M+1]。LCMS m/z = 583.3 [M + 1].
第三步：[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯(13G)的异构体2The third step: [7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H) -quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane Isomer 2 of 2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13G)
Isomer 2 of[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H- quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetateIsomer 2 of[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H- Quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy -2-phenyl-acetate
Figure PCTCN2016081809-appb-000135
Figure PCTCN2016081809-appb-000135
将[7-[3-(2-氯-4-甲酰基-5-甲氧基-苯胺基)-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯(13F)的异构体2(0.752g,1.29mmol)溶于甲醇(10mL)中，加入5-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基甲基]-8-羟基-1H-喹啉-2-酮(1G)(0.432g,1.29mmol)，加入无水氯化锌(0.701g,5.14mmol)，55℃反应1小时。加入氰基硼氢化钠(0.243g,3.86mmol)，55℃反应2小时。反应液加入二氯甲烷(50mL)，加入饱和碳酸氢钠溶液(20mL)，萃取。水相用二氯甲烷(30mL×2)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯(13G)的异构体2，黄色固体(1.00g，产率86.0％)。[7-[3-(2-Chloro-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl Isomer 2 (0.752 g, 1.29 mmol) of 2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13F) was dissolved in methanol (10 mL), and 5-[(1R)- 2-Amino-1-[tert-butyl(dimethyl)silyl]oxymethyl]-8-hydroxy-1H-quinolin-2-one (1G) (0.432 g, 1.29 mmol), Zinc chloride (0.701 g, 5.14 mmol) was reacted at 55 ° C for 1 hour. Sodium cyanoborohydride (0.243 g, 3.86 mmol) was added, and the mixture was reacted at 55 ° C for 2 hours. The reaction solution was added to dichloromethane (50 mL), and then evaporated. The aqueous phase was extracted with dichloromethane (30 mL×2). EtOAcjjjjjjjjjjj )-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2 -chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2-hydroxy-2-benzene Isomer 2 of the base-acetate (13G), yellow solid (1.00 g, yield 86.0%).
LCMS m/z＝451.4[(M+2)/2]。LCMS m/z = 451.4 [(M+2)/2].
第四步：[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯；二三氟乙酸盐(化合物13)的异构体2The fourth step: [7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2- Hydroxy-2-phenyl-acetate; isomer 2 of ditrifluoroacetate (compound 13)
Isomer 2 of[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate；ditrifluoroacetic acidIsomer 2 of[7-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]] Methyl]-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000136
Figure PCTCN2016081809-appb-000136
将[7-[3-[4-[[[(2R)-2-[叔丁基(二甲基)硅基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-2-氯-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯(13G)的异构体2(1.0g,1.1mmol)溶于四氢呋喃(5mL)中，加入三乙胺三氢氟酸盐(1.8g,11mmol)，室温反应24小时。反应液加入10％(v/v)甲醇/二氯甲烷溶液(50mL),加入饱和碳酸氢钠水溶液调节pH至8左右，萃取。水相用10％(v/v)甲醇/二氯甲烷溶液(50mL×2)萃取，合并有机相。有机相用饱和食盐水(20mL×1)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩。残留物用液相制备柱分离提纯(制备条件：C18反相制备柱，流动相为为含0.05％TFA的去离子水(A)，含0.05％TFA的乙腈(B)，梯度洗脱A:B＝5％～100％，洗脱10分钟，然后用100％B洗脱5分钟，流速1.0mL/min，柱温：40℃)，得到标题化合物[7-[3-[2-氯-4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]-5-甲氧基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-环戊基-2-羟基-2-苯基-乙酸酯；二三氟乙酸盐(化合物13)的异构体2，白色固体(0.250g，产率22.2％)。[7-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinoline) -5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2- Isomer 2 (1.0 g, 1.1 mmol) of 2-cyclopentyl-2-hydroxy-2-phenyl-acetate (13G) was dissolved in tetrahydrofuran (5 mL), and triethylamine trihydrofluoride was added. The acid salt (1.8 g, 11 mmol) was reacted at room temperature for 24 hours. The reaction solution was added with a 10% (v/v) methanol/methylene chloride solution (50 mL), and a saturated aqueous sodium hydrogencarbonate solution was added to adjust the pH to about 8 and extracted. The aqueous phase was extracted with a 10% (v/v) methanol/dichloromethane solution (50 mL×2). The organic layer was washed with brine (20 mL×1). The residue was separated and purified by liquid phase preparative column (preparation conditions: C18 reverse phase preparative column, mobile phase was deionized water (A) containing 0.05% TFA, acetonitrile (B) containing 0.05% TFA, gradient elution A: B = 5% to 100%, eluted for 10 minutes, then eluted with 100% B for 5 minutes, flow rate 1.0 mL/min, column temperature: 40 ° C) to give the title compound [7-[3-[2-chloro- 4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-aniline 3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-cyclopentyl-2-hydroxy-2-phenyl-acetate; ditrifluoroethyl Isomer 2 of the acid salt (Compound 13), white solid (0.250 g, yield 22.2%).
1H NMR(400MHz,CD3OD)δ8.04(d,1H),7.70(s,1H),7.54(d,2H),7.38(s,1H),7.29–7.13(m,4H),6.95(d,1H),6.52(d,1H),5.32(dd,1H),4.98–4.87(m,1H),4.17(q,2H),3.77(s,3H),3.50-3.30(m,4H),3.20-3.13m,1H),3.13–3.04(m,1H),3.02–2.77(m,5H),2.50-2.30m,1H),2.31–2.17(m,1H),1.931.69(m,6H),1.65-1.45(m,5H),1.45-1.32(m,1H),1.32-1.20(m,2H). 1 H NMR (400MHz, CD 3 OD) δ8.04 (d, 1H), 7.70 (s, 1H), 7.54 (d, 2H), 7.38 (s, 1H), 7.29-7.13 (m, 4H), 6.95 (d, 1H), 6.52 (d, 1H), 5.32 (dd, 1H), 4.98 - 4.87 (m, 1H), 4.17 (q, 2H), 3.77 (s, 3H), 3.50-3.30 (m, 4H) ), 3.20-3.13m, 1H), 3.13–3.04 (m, 1H), 3.02–2.77 (m, 5H), 2.50-2.30m, 1H), 2.31–2.17 (m, 1H), 1.931.69 (m) , 6H), 1.65-1.45 (m, 5H), 1.45-1.32 (m, 1H), 1.32-1.20 (m, 2H).
19F NMR(376MHz,CD3OD)δ-75.43. 19 F NMR (376 MHz, CD 3 OD) δ-75.43.
LCMS m/z＝394.3[(M+2)/2]。LCMS m/z = 394.3 [(M+2)/2].
实施例16：[7-[3-[3-[[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酰基]-N-甲基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯；二三氟乙酸盐(化合物16)Example 16: [7-[3-[3-[[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2- Hydroxy-2,2-bis(2-thienyl) acetate; ditrifluoroacetate (compound 16)
[7-[3-[3-[[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate；ditrifluoroacetic acid [7-[3-[3-[[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl] ]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000137
Figure PCTCN2016081809-appb-000137
第一步：3-(甲基氨基)苯甲酸甲酯(16B)First step: methyl 3-(methylamino)benzoate (16B)
methyl 3-(methylamino)benzoateMethyl 3-(methylamino)benzoate
Figure PCTCN2016081809-appb-000138
Figure PCTCN2016081809-appb-000138
将3-氨基苯甲酸甲酯(16A)(10.0g，66.2mmol)溶解在N,N-二甲基甲酰胺(150mL)中，加入碳酸钾(13.7g，99.2mmol)，再慢慢滴入碘甲烷(9.39g，66.2mmol)，加完后室温反应3小时。过滤，滤渣用乙酸乙酯(50mL)洗涤，收集滤液，加入水(100mL)，用乙酸乙酯(200mL×2)萃取，合并有机相，用饱和氯化钠溶液(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后残留物用硅胶柱色谱分离提纯(洗脱剂为石油醚：乙酸乙酯(v/v)＝100:0～97:3)得到标题化合物3-(甲基氨基)苯甲酸甲酯(16B)，浅黄色油状物(3.85g，产率35.2％)。Methyl 3-aminobenzoate (16A) (10.0 g, 66.2 mmol) was dissolved in N,N-dimethylformamide (150 mL), potassium carbonate (13.7 g, 99.2 mmol) Methyl iodide (9.39 g, 66.2 mmol) was reacted at room temperature for 3 hours after the addition. Filtration, the residue was washed with ethyl acetate (50 mL), and the filtrate was collected. Water (100 mL), and ethyl acetate (200 mL×2), and the organic phase was combined and washed with saturated sodium chloride solution (100 mL×2). The residue was dried over sodium sulfate (MgSO4). Methyl (methylamino)benzoate (16B), light yellow oil (3.85 g, yield 35.2%).
1H NMR(400MHz,CDCl3)δ7.29(d,1H),7.20–7.17(m,1H),7.15(t,1H),6.70(m,1H),3.81(s,3H),2.78(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.29 (d, 1H), 7.20-7.17 (m, 1H), 7.15 (t, 1H), 6.70 (m, 1H), 3.81 (s, 3H), 2.78 ( s, 3H).
LCMS m/z＝166.2[M+1]。LCMS m/z = 166.2 [M + 1].
第二步：3-[甲基(丙-2-烯酰基)氨基苯甲酸甲酯(16C)Step 2: 3-[Methyl(prop-2-enoyl)aminobenzoate (16C)
methyl 3-[methyl(prop-2-enoyl)amino]benzoateMethyl 3-[methyl(prop-2-enoyl)amino]benzoate
Figure PCTCN2016081809-appb-000139
Figure PCTCN2016081809-appb-000139
将3-(甲基氨基)苯甲酸甲酯(16B)(0.500g，3.03mmol)溶解在二氯甲烷(5mL)中，加入碳酸氢钠(0.509g，6.05mmol)，氮气保护下冰浴冷却至0℃，滴加丙烯酰氯(0.411g，4.54mmol)，加完后升温至室温反应30分钟。加入二氯甲烷(20mL×1)萃取，用饱和碳酸氢钠溶液(10mL×2)洗涤，合并有机相，有机相用饱和氯化钠溶液(10mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后残留物用硅胶柱色谱分离提纯(洗脱剂为石油醚：乙酸乙酯(v/v)＝100:0～4:1)得到标题化合物3-[甲基(丙-2-烯酰基)氨基苯甲酸甲酯(16C)，无色油状物(0.569g，产率85.7％)。Methyl 3-(methylamino)benzoate (16B) (0.500 g, 3.03 mmol) was dissolved in dichloromethane (5 mL), sodium hydrogen carbonate (0.509 g, 6.05 mmol) To 0 ° C, acryloyl chloride (0.411 g, 4.54 mmol) was added dropwise, and the mixture was warmed to room temperature for 30 minutes. The organic layer was washed with a saturated sodium chloride solution (10 mL×1), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified (jjjjjjjjjj Methyl 2-enoyl)aminobenzoate (16C), colourless oil (0.569 g, yield: 85.7%).
1H NMR(400MHz,CDCl3)δ8.01(d,1H),7.87(t,1H),7.50(t,1H),7.40–7.36m,1H),6.39(m,1H),6.04(m,1H),5.55m,1H),3.94(s,3H),3.38(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.01 (d, 1H), 7.87 (t, 1H), 7.50 (t, 1H), 7.40-7.36m, 1H), 6.39 (m, 1H), 6.04 (m , 1H), 5.55m, 1H), 3.94(s, 3H), 3.38(s, 3H).
LCMS m/z＝220.2[M+1]。LCMS m/z = 220.2 [M + 1].
第三步：3-[甲基(丙-2-烯酰基)氨基]苯甲酸(16D)The third step: 3-[methyl(prop-2-enoyl)amino]benzoic acid (16D)
3-[methyl(prop-2-enoyl)amino]benzoic acid3-[methyl(prop-2-enoyl)amino]benzoic acid
Figure PCTCN2016081809-appb-000140
Figure PCTCN2016081809-appb-000140
将3-[甲基(丙-2-烯酰基)氨基苯甲酸甲酯(16C)(0.550g，2.51mmol)溶解在四氢呋喃(17mL)中，冰浴冷却下滴加1.0M氢氧化锂(0.409g，17.1mmol)水溶液，加完后冰浴下反应1小时。冰浴下用10％盐酸溶液调节pH至1，用乙酸乙酯(20mL×2)萃取，合并有机相，有机相用用饱和氯化钠溶液(10mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到标题化合物3-[甲基(丙-2-烯酰基)氨基]苯甲酸(16D)，白色固体(0.500g，产率97.1％)。3-[Methyl(prop-2-enoyl)aminobenzoic acid methyl ester (16C) (0.550 g, 2.51 mmol) was dissolved in tetrahydrofuran (17 mL), and 1.0 M lithium hydroxide (0.409) The aqueous solution of g, 17.1 mmol) was reacted for 1 hour in an ice bath after the addition. The mixture was adjusted to pH 1 with a 10% aqueous solution of EtOAc (EtOAc) (EtOAc (EtOAc) After filtration, the filtrate was evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal
1H NMR(400MHz,CDCl3)δ8.02(d,1H),7.88(t,1H),7.48(t,1H),7.37(d,1H),6.35(m,1H),5.99(m,1H),5.51(m,1H),3.34(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.02 (d, 1H), 7.88 (t, 1H), 7.48 (t, 1H), 7.37 (d, 1H), 6.35 (m, 1H), 5.99 (m, 1H), 5.51 (m, 1H), 3.34 (s, 3H).
LCMS m/z＝206.2[M+1]。LCMS m/z = 206.2 [M + 1].
第四步：3-[3-[2-[2-羟基-2,2-双(2-噻吩基)乙酰基]氧基-7-氮杂螺[3.5]壬烷-7-基]丙酰基-甲基-氨基]苯甲酸(16E) The fourth step: 3-[3-[2-[2-hydroxy-2,2-bis(2-thienyl)acetyl]oxy-7-azaspiro[3.5]decane-7-yl]-propyl Acyl-methyl-amino]benzoic acid (16E)
3-[3-[2-[2-hydroxy-2,2-bis(2-thienyl)acetyl]oxy-7-azaspiro[3.5]nonan-7-yl]propanoyl-methyl-amino]benzoic acid3-[3-[2-[2-[2-hydroxy-2,2-bis(2-thienyl)acetyl]oxy-7-azaspiro[3.5]nonan-7-yl]propanoyl-methyl-amino]benzoic acid
Figure PCTCN2016081809-appb-000141
Figure PCTCN2016081809-appb-000141
将3-[甲基(丙-2-烯酰基)氨基]苯甲酸(16D)(0.400g，1.95mmol)溶解在2-甲基四氢呋喃(10mL)中，加入7-氮杂螺[3.5]壬烷-2-基2-羟基-2,2-双(2-噻吩基)乙酸酯(1D)(0.709g，1.95mmol)和三乙胺(0.394g，3.90mmol)，加完后微波100℃反应1小时。反应液减压浓缩后残留物用硅胶柱色谱分离提纯(洗脱剂为二氯甲烷：甲醇(v/v)＝100:0 ～9:1)得到标题化合物3-[3-[2-[2-羟基-2,2-双(2-噻吩基)乙酰基]氧基-7-氮杂螺[3.5]壬烷-7-基]丙酰基-甲基-氨基]苯甲酸(16E)，黄色固体(0.500g，产率45.1％)。3-[Methyl(prop-2-enoyl)amino]benzoic acid (16D) (0.400 g, 1.95 mmol) was dissolved in 2-methyltetrahydrofuran (10 mL), and 7-azaspiro[3.5] Alkan-2-yl 2-hydroxy-2,2-bis(2-thienyl)acetate (1D) (0.709 g, 1.95 mmol) and triethylamine (0.394 g, 3.90 mmol), microwave 100 after addition The reaction was carried out at ° C for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj 2-hydroxy-2,2-bis(2-thienyl)acetyl]oxy-7-azaspiro[3.5]decane-7-yl]propionyl-methyl-amino]benzoic acid (16E), Yellow solid (0.500 g, yield 45.1%).
1H NMR(400MHz,DMSO-d6)δ7.87(d,1H),7.76(d,1H),7.50(d,2H),7.47(d,1H),7.45(d,1H),7.26(s,1H),7.08(d,1H),7.07(d,1H),6.98(d,1H),6.97(d,1H),5.04–4.96(m,1H),3.17(s,3H),2.73(m,2H),2.24–2.14(m,5H),2.14–2.07(m,2H),1.71-1.67[m,2H),1.46(s,2H),1.41(s,2H),1.24(s,1H). 1 H NMR (400MHz, DMSO- d6) δ7.87 (d, 1H), 7.76 (d, 1H), 7.50 (d, 2H), 7.47 (d, 1H), 7.45 (d, 1H), 7.26 (s , 1H), 7.08 (d, 1H), 7.07 (d, 1H), 6.98 (d, 1H), 6.97 (d, 1H), 5.04 - 4.96 (m, 1H), 3.17 (s, 3H), 2.73 ( m, 2H), 2.24–2.14 (m, 5H), 2.14–2.07 (m, 2H), 1.71-1.67 [m, 2H), 1.46 (s, 2H), 1.41 (s, 2H), 1.24 (s, 1H).
LCMS m/z＝569.3[M+1]。LCMS m/z = 569.3 [M + 1].
第五步：[7-[3-[3-[[4-(1,3-二氧戊环-2-基)苯基]氨基甲酰基]-N-甲基苯胺]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(16F)Step 5: [7-[3-[3-[[4-(1,3-dioxolan-2-yl)phenyl]carbamoyl]-N-methylaniline]-3-oxo -propyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (16F)
[7-[3-[3-[[4-(1,3-dioxolan-2-yl)phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-[3-[[4-(1,3-dioxolan-2-yl)phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan -2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000142
Figure PCTCN2016081809-appb-000142
将3-[3-[2-[2-羟基-2,2-双(2-噻吩基)乙酰基]氧基-7-氮杂螺[3.5]壬烷-7-基]丙酰基-甲基-氨基]苯甲酸(16E)(1.50g，2.64mmol)溶解在二氯甲烷(20mL)中，加入4-(1,3-二氧戊环-2-基)苯胺
Figure PCTCN2016081809-appb-000143
(0.871g，5.28mmol)、HATU(1.30g，3.43mmol)，冰浴冷却至0℃，再滴加二异丙基乙基胺(1.70g，13.2mmol)，加完后自然升温至室温反 应3小时。加入水(10mL)，二氯甲烷(20mL)，分液，有机相用饱和氯化钠溶液(10mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩所得粗品用硅胶柱纯化(洗脱剂：70％(v/v)乙酸乙酯/石油醚～2％(v/v)甲醇/二氯甲烷～4％(v/v)甲醇/二氯甲烷)得标题化合物[7-[3-[3-[[4-(1,3-二氧戊环-2-基)苯基]氨基甲酰基]-N-甲基苯胺]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(16F)，浅黄色固体(0.820g，产率43.4％)。3-[3-[2-[2-Hydroxy-2,2-bis(2-thienyl)acetyl)oxy-7-azaspiro[3.5]decane-7-yl]propanoyl-methyl Base-amino]benzoic acid (16E) (1.50 g, 2.64 mmol) was dissolved in dichloromethane (20 mL) and 4-(1,3-dioxolan-2-yl)aniline was added.
Figure PCTCN2016081809-appb-000143
(0.871g, 5.28mmol), HATU (1.30g, 3.43mmol), cooled to 0 ° C in an ice bath, then diisopropylethylamine (1.70 g, 13.2 mmol) was added dropwise, and the reaction was allowed to warm to room temperature after the addition. 3 hours. After adding water (10 mL), dichloromethane (20 mL), EtOAc (EtOAc) Eluent: 70% (v/v) ethyl acetate / petroleum ether ~ 2% (v / v) methanol / dichloromethane ~ 4% (v / v) methanol / dichloromethane) to give the title compound [7- [3-[3-[[4-(1,3-dioxolan-2-yl)phenyl]carbamoyl]-N-methylaniline]-3-oxo-propyl]-7- Azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (16F), pale yellow solid (0.820 g, yield 43.4%).
1H NMR(400MHz,CDCl3)δ7.87(d,1H),7.80–7.73(m,3H),7.53(t,1H),7.48(d,2H),7.34(d,1H),7.28(m,2H),7.15(m,2H),6.97(m,2H),5.80(s,1H),5.14–5.05(m,1H),4.76-4.60(m,1H),4.15–4.10(m,2H),4.05–4.00(m,2H),3.28(s,3H),2.80(t,2H),2.50-2.34(m,5H),2.34–2.26(m,2H),1.84-1.81(m,2H),1.67–1.57(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ7.87 (d, 1H), 7.80-7.73 (m, 3H), 7.53 (t, 1H), 7.48 (d, 2H), 7.34 (d, 1H), 7.28 ( m, 2H), 7.15 (m, 2H), 6.97 (m, 2H), 5.80 (s, 1H), 5.14 - 5.05 (m, 1H), 4.76 - 4.60 (m, 1H), 4.15 - 4.10 (m, 2H), 4.05–4.00 (m, 2H), 3.28 (s, 3H), 2.80 (t, 2H), 2.50-2.34 (m, 5H), 2.34–2.26 (m, 2H), 1.84-1.81 (m, 2H), 1.67–1.57 (m, 4H).
LCMS m/z＝716.3[M+1]。LCMS m/z = 716.3 [M + 1].
第六步：[7-[3-[3-[(4-甲酰基苯基)氨基甲酰基]-N-甲基苯胺]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(16G)The sixth step: [7-[3-[3-[(4-formylphenyl)carbamoyl]-N-methylaniline]-3-oxo-propyl]-7-azaspiro[3.5 ]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (16G)
[7-[3-[3-[(4-formylphenyl)carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-[3-[(4-formylphenyl)carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2, 2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000144
Figure PCTCN2016081809-appb-000144
将[7-[3-[3-[[4-(1,3-二氧戊环-2-基)苯基]氨基甲酰基]-N-甲基苯胺]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(16F)(0.820g，1.15mmol)溶解在乙腈(8mL)中，冰浴冷却下加入3M盐酸水溶液(10mL)，加完后冰浴下反应3小时。用二氯甲烷(20mL×2)萃取，合并有机相，有机相用饱和氯化钠溶液(10mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得标题化合物[7-[3-[3-[(4-甲酰基苯基)氨基甲酰基]-N-甲基苯胺]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(16G)粗品，浅黄色固体(0.635g，产率82.5％)，不纯化直接用于下一步。[7-[3-[3-[[4-(1,3-dioxolan-2-yl)phenyl]carbamoyl]-N-methylaniline]-3-oxo-propyl ]-7-Azaspiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (16F) (0.820 g, 1.15 mmol) was dissolved in acetonitrile (8 mL) Into the ice-cooling solution, a 3 M aqueous hydrochloric acid solution (10 mL) was added, and after the addition, the reaction was carried out for 3 hours in an ice bath. The mixture was extracted with dichloromethane (20 mL×2), EtOAc (EtOAc) -[3-[(4-formylphenyl)carbamoyl]-N-methylaniline]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2 -Hydroxy-2,2-bis(2-thienyl)acetate (16G) crude, light yellow solid (0.635 g, yield 82.5%).
1H NMR(400MHz,CDCl3)δ9.94(s,1H),8.05(s,2H),7.93(d,1H),7.89(d,2H),7.84(s,1H),7.57(t,1H),7.35(d,1H),7.29(m,2H),7.15(m,2H),6.97(m,2H),5.18–5.09(m,1H),4.62(s,1H),3.29(s,3H),3.06-2.98(m,2H),2.75-2.61(m,3H),2.40–2.31(m,2H),1.91-1.85(m,3H),1.80-1.70(m,5H). 1 H NMR (400 MHz, CDCl 3 ) δ 9.94 (s, 1H), 8.05 (s, 2H), 7.93 (d, 1H), 7.89 (d, 2H), 7.84 (s, 1H), 7.57 (t, 1H), 7.35 (d, 1H), 7.29 (m, 2H), 7.15 (m, 2H), 6.97 (m, 2H), 5.18 - 5.09 (m, 1H), 4.62 (s, 1H), 3.29 (s) , 3H), 3.06-2.98 (m, 2H), 2.75-2.61 (m, 3H), 2.40 - 2.31 (m, 2H), 1.91-1.85 (m, 3H), 1.80-1.70 (m, 5H).
LCMS m/z＝672.2[M+1]。 LCMS m/z = 672.2 [M + 1].
第七步：[7-[3-[3-[[4-[[[(2R)-2-[叔丁基(二甲基)甲硅烷基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酰基]-N-甲基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(16H)Step 7: [7-[3-[3-[[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2) -oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-nitrogen Heterospiro[3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (16H)
[7-[3-[3-[[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-[3-[[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5- Yl)ethyl]amino]methyl]phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2 -thienyl)acetate
Figure PCTCN2016081809-appb-000145
Figure PCTCN2016081809-appb-000145
将[7-[3-[3-[(4-甲酰基苯基)氨基甲酰基]-N-甲基苯胺]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(16G)(0.600g，0.893mmol)溶解在无水甲醇(20mL)中，加入5-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基甲基]-8-羟基-1H-喹啉-2-酮(1G)(0.299g，0.893mmol)和无水氯化锌(0.487g，3.57mmol)，50℃反应1小时后加入氰基硼氢化钠(0.281g，4.47mmol)，继续50℃反应1小时。加入水(50mL)，二氯甲烷(100mL×3)萃取，合并有机相，有机相用饱和氯化钠溶液50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得标题化合物[7-[3-[3-[[4-[[[(2R)-2-[叔丁基(二甲基)甲硅烷基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酰基]-N-甲基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(16H)粗品，黄色固体(0.600g，产率67.8％)，不纯化直接用于下一步。[7-[3-[3-[(4-Formylphenyl)carbamoyl]-N-methylanilin]-3-oxo-propyl]-7-azaspiro[3.5]decane 2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (16G) (0.600 g, 0.893 mmol) was dissolved in anhydrous methanol (20 mL), and 5-[(1R) was added. 2-amino-1-[tert-butyl(dimethyl)silyl]oxymethyl]-8-hydroxy-1H-quinolin-2-one (1G) (0.299 g, 0.893 mmol) and anhydrous Zinc chloride (0.487 g, 3.57 mmol) was reacted at 50 ° C for 1 hour, and sodium cyanoborohydride (0.281 g, 4.47 mmol) was added, and the reaction was continued at 50 ° C for 1 hour. After adding water (50 mL), dichloromethane (100 mL×3), EtOAc (EtOAc) 7-[3-[3-[[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H) -quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5] The crude decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (16H) was obtained as a yellow solid (0.600 g, yield: 67.8%).
LCMS m/z＝495.8[M/2+1]。LCMS m/z = 495.8 [M/2+1].
第八步：[7-[3-[3-[[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酰基]-N-甲基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯；二三氟乙酸盐(化合物16)Step 8: [7-[3-[3-[[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2- Hydroxy-2,2-bis(2-thienyl) acetate; ditrifluoroacetate (compound 16)
[7-[3-[3-[[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate；ditrifluoroacetic acid [7-[3-[3-[[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl] ]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000146
Figure PCTCN2016081809-appb-000146
将[7-[3-[3-[[4-[[[(2R)-2-[叔丁基(二甲基)甲硅烷基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酰基]-N-甲基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(16H)(0.600g，0.606mmol)溶解在四氢呋喃(10mL)中，加入三乙胺三氢氟酸盐(0.391g，2.42mmol)室温反应过夜。将反应清液倒掉，剩余粘稠物用四氢呋喃(20mL)洗涤，再将清液倒掉，粘稠物用甲醇/二氯甲烷(v/v＝1/9)的混合溶液溶解，滴加饱和碳酸氢钠水溶液调节pH至碱性，分液，水层再用甲醇/二氯甲烷(v/v＝1/9)的混合溶液(100mL×3)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩所得粗品,该粗品用液相制备柱分离提纯(制备条件：C18反相制备柱，流动相为为含0.05％TFA的去离子水(A)，含0.05％TFA的乙腈(B)，梯度洗脱A:B＝5％～100％，洗脱10分钟，然后用100％B洗脱5分钟，流速1.0mL/min，柱温：40℃)得标题化合物[7-[3-[3-[[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]甲基]苯基]氨基甲酰基]-N-甲基-苯胺基]-3-氧代-丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯；二三氟乙酸盐(化合物16)，浅黄色固体(0.075g，产率14.1％)。[7-[3-[3-[[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[ 3.5]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (16H) (0.600 g, 0.606 mmol) was dissolved in tetrahydrofuran (10 mL), triethylamine Hydrofluoric acid salt (0.391 g, 2.42 mmol) was reacted at room temperature overnight. The reaction supernatant was poured off, the remaining viscous material was washed with tetrahydrofuran (20 mL), and the supernatant was poured off. The viscous material was dissolved in a mixed solution of methanol/dichloromethane (v/v = 1/9), and added dropwise. Saturated sodium bicarbonate aqueous solution to adjust the pH to alkaline, liquid separation, and the aqueous layer was extracted with a mixed solution of methanol/dichloromethane (v/v = 1/9) (100 mL × 3), and the organic phase was combined. Drying with sodium sulfate, filtering, and concentrating the filtrate under reduced pressure, the crude product was separated and purified by liquid phase preparative column (preparation conditions: C18 reverse phase preparative column, mobile phase is deionized water (A) containing 0.05% TFA, including 0.05% TFA in acetonitrile (B), gradient elution A: B = 5% to 100%, elution for 10 minutes, then elution with 100% B for 5 minutes, flow rate 1.0 mL / min, column temperature: 40 ° C) The title compound [7-[3-[3-[[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]] Amino]methyl]phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy- 2,2-bis(2-thienyl) acetate; ditrifluoroacetate (Compound 16), pale yellow solid (0.075 g, yield 14.1%).
1H NMR(400MHz,CD3OD)δ8.19(d,1H),8.01(d,1H),7.92(s,1H),7.83(d,2H),7.67(t,1H),7.58(d,1H),7.51(d,2H),7.39–7.34(m,2H),7.27(d,1H),7.12(s,2H),7.02(d,1H),6.99–6.94(m,2H),6.63(d,1H),5.39(t,1H),5.16–5.08(m,1H),4.30(s,2H),3.51–3.35(m,4H),3.33(s,3H),3.22(d,2H),2.94-2.80(m,2H),2.61(t,2H),2.51-2.45(m,1H),2.36-2.30(m,1H),1.98-1.88(m,3H),1.82-1.70(m,3H). 1 H NMR (400 MHz, CD 3 OD) δ 8.19 (d, 1H), 8.1 (d, 1H), 7.92 (s, 1H), 7.83 (d, 2H), 7.67 (t, 1H), 7.58 (d) , 1H), 7.51 (d, 2H), 7.39 - 7.34 (m, 2H), 7.27 (d, 1H), 7.12 (s, 2H), 7.02 (d, 1H), 6.99 - 6.94 (m, 2H), 6.63(d,1H), 5.39(t,1H), 5.16–5.08(m,1H), 4.30(s,2H),3.51–3.35(m,4H),3.33(s,3H),3.22(d, 2H), 2.94-2.80 (m, 2H), 2.61 (t, 2H), 2.51-2.45 (m, 1H), 2.36-2.30 (m, 1H), 1.98-1.88 (m, 3H), 1.82-1.70 ( m, 3H).
19F NMR(376MHz,CD3OD)δ-75.44. 19 F NMR (376 MHz, CD 3 OD) δ-75.44.
LCMS m/z＝876.4[M+1]。LCMS m/z = 876.4 [M + 1].
实施例17：[7-[3-[4-[[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基甲基]苯基]氨基甲酰基]-N-甲基苯胺]-3-氧代丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯；二三氟乙酸盐(化合物17)Example 17: [7-[3-[4-[[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Aminomethyl]phenyl]carbamoyl]-N-methylanilino]-3-oxopropyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2, 2-bis(2-thienyl) acetate; ditrifluoroacetate (compound 17)
[7-[3-[4-[[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]meth yl]phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate；ditrifluoroacetic acid[7-[3-[4-[[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]meth Yl]phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate;ditrifluoroacetic Acid
Figure PCTCN2016081809-appb-000147
Figure PCTCN2016081809-appb-000147
第一步：4-(甲基氨基)苯甲酸甲酯(17B)First step: methyl 4-(methylamino)benzoate (17B)
methyl 4-(methylamino)benzoateMethyl 4-(methylamino)benzoate
Figure PCTCN2016081809-appb-000148
Figure PCTCN2016081809-appb-000148
将4-氨基苯甲酸甲酯(17A)(10.0g，66.2mmol)溶解在N,N-二甲基甲酰胺(150mL)中，加入碳酸钾(13.7g，99.2mmol)，再慢慢滴入碘甲烷(9.39g，66.2mmol)，加完后室温反应3小时。过滤，滤渣用乙酸乙酯(50mL)洗涤，收集滤液，加入水100mL，用乙酸乙酯(200mL×2)萃取，合并有机相，有机相用饱和氯化钠溶液(100mL×2)洗涤，无 水硫酸钠干燥，过滤，滤液减压浓缩后残留物用硅胶柱色谱分离提纯(洗脱剂为石油醚：乙酸乙酯(v/v)＝100:0～97:3)得到标题化合物4-(甲基氨基)苯甲酸甲酯(17B)，白色固体(4.80g，产率43.9％)。Methyl 4-aminobenzoate (17A) (10.0 g, 66.2 mmol) was dissolved in N,N-dimethylformamide (150 mL), potassium carbonate (13.7 g, 99.2 mmol) Methyl iodide (9.39 g, 66.2 mmol) was reacted at room temperature for 3 hours after the addition. Filtration, the residue was washed with ethyl acetate (50 mL), and the filtrate was collected. Water (100 mL), ethyl acetate (200 mL×2), and the organic phase was combined. The organic phase was washed with saturated sodium chloride solution (100 mL×2). The residue was dried over sodium sulfate (MgSO4). Methyl (methylamino)benzoate (17B), white solid (4.80 g, yield 43.9%).
1H NMR(400MHz,CDCl3)δ7.81–7.79(m,1H),7.79–7.77(m,1H),6.506.48(m,1H),6.48–6.45(m,1H),3.77(s,3H),2.80(s,3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.81 - 7.79 (m, 1H), 7.79 - 7.77 (m, 1H), 6.506.48 (m, 1H), 6.48 - 6.45 (m, 1H), 3.77 (s) , 3H), 2.80 (s, 3H).
LCMS m/z＝166.2[M+1]。LCMS m/z = 166.2 [M + 1].
第二步：4-[甲基(丙-2-烯酰基)氨基苯甲酸甲酯(17C)Step 2: 4-[Methyl(prop-2-enoyl)aminobenzoate (17C)
methyl 4-[methyl(prop-2-enoyl)amino]benzoateMethyl 4-[methyl(prop-2-enoyl)amino]benzoate
Figure PCTCN2016081809-appb-000149
Figure PCTCN2016081809-appb-000149
将化合物4-(甲基氨基)苯甲酸甲酯(17B)(1.80g，10.90mmol)溶解在二氯甲烷(5mL)中，加入碳酸氢钠(1.831g，21.8mmol)，氮气保护下冰浴冷却至0℃，滴加丙烯酰氯(1.48g，16.3mmol)，加完后升温至室温反应30分钟。加入二氯甲烷(20mL×1)萃取，有机相用饱和碳酸氢钠溶液(10mL×2)洗涤，饱和氯化钠溶液10mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后残留物用硅胶柱色谱分离提纯(洗脱剂为石油醚：乙酸乙酯(v/v)＝100:0～4:1)得到标题化合物4-[甲基(丙-2-烯酰基)氨基苯甲酸甲酯(17C)，无色油状物(1.80g，产率75.3％)。The compound 4-(methylamino)benzoic acid methyl ester (17B) (1.80 g, 10.90 mmol) was dissolved in dichloromethane (5 mL), sodium hydrogen carbonate (1.831 g, 21.8 mmol) After cooling to 0 ° C, acryloyl chloride (1.48 g, 16.3 mmol) was added dropwise, and the mixture was warmed to room temperature for 30 minutes. The organic layer was washed with saturated sodium hydrogen carbonate solution (10 mL×2), washed with saturated sodium chloride solution (10 mL×1), dried over anhydrous sodium sulfate and filtered. The residue was purified by silica gel column chromatography (eluent:EtOAc:EtOAc:EtOAc Methyl benzoate (17C), colorless oil (1.80 g, yield 75.3%).
1H NMR(400MHz,CDCl3)δ8.10–8.06(m,2H),7.27(d,2H),7.24(d,1H),6.40(m,1H),6.09(m,1H),5.57(m,1H),3.94(s,3H),3.39(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.10-8.06 (m, 2H), 7.27 (d, 2H), 7.24 (d, 1H), 6.40 (m, 1H), 6.09 (m, 1H), 5.57 ( m, 1H), 3.94 (s, 3H), 3.39 (s, 3H).
LCMS m/z＝220.2[M+1]。LCMS m/z = 220.2 [M + 1].
第三步：4-[甲基(丙-2-烯酰基)氨基]苯甲酸(17D)The third step: 4-[methyl(prop-2-enoyl)amino]benzoic acid (17D)
4-[methyl(prop-2-enoyl)amino]benzoic acid4-[methyl(prop-2-enoyl)amino]benzoic acid
Figure PCTCN2016081809-appb-000150
Figure PCTCN2016081809-appb-000150
将4-[甲基(丙-2-烯酰基)氨基苯甲酸甲酯(17C)(3.100g，14.14mmol)溶解在四氢呋喃(50mL)中，冰浴冷却下滴加1.0M的氢氧化锂(2.303g，96.15mmol)水溶液，加完后冰浴下反应1小时。冰浴下用10％盐酸溶液调节pH至1，用乙酸乙酯(20mL×2)萃取，合并有机相，有机相用用饱和氯化钠溶液(10mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到标题化合物4-[甲基(丙-2-烯酰基)氨基]苯甲酸(17D)，白色固体(2.60g， 产率89.8％)。Methyl 4-[methyl(prop-2-enoyl)aminobenzoate (17C) (3.100 g, 14.14 mmol) was dissolved in tetrahydrofuran (50 mL), and 1.0 M lithium hydroxide was added dropwise under ice cooling. 2.303 g, 96.15 mmol) of an aqueous solution, and the reaction was carried out for 1 hour in an ice bath after the addition. The mixture was adjusted to pH 1 with a 10% aqueous solution of EtOAc (EtOAc) (EtOAc (EtOAc) Filtration and concentration of EtOAc (EtOAc m. Yield 89.8%).
1H NMR(400MHz,DMSO-d6)δ13.05(s,1H),8.02–8.00(m,1H),8.00–7.97(m,1H),7.43–7.40(m,1H),7.40–7.38(m,1H),6.19(m,1H),6.12(m,1H),5.62(m,1H),3.29(s,3H). 1 H NMR (400MHz, DMSO- d6) δ13.05 (s, 1H), 8.02-8.00 (m, 1H), 8.00-7.97 (m, 1H), 7.43-7.40 (m, 1H), 7.40-7.38 ( m, 1H), 6.19 (m, 1H), 6.12 (m, 1H), 5.62 (m, 1H), 3.29 (s, 3H).
LCMS m/z＝206.2[M+1]。LCMS m/z = 206.2 [M + 1].
第四步：N-[4-(1,3-二氧戊环-2-基)苯基]-4-[甲基(丙-2-烯酰基)氨基]苯甲酰胺(17E)Fourth step: N-[4-(1,3-dioxolan-2-yl)phenyl]-4-[methyl(prop-2-enoyl)amino]benzamide (17E)
N-[4-(1,3-dioxolan-2-yl)phenyl]-4-[methyl(prop-2-enoyl)amino]benzamideN-[4-(1,3-dioxolan-2-yl)phenyl]-4-[methyl(prop-2-enoyl)amino]benzamide
Figure PCTCN2016081809-appb-000151
Figure PCTCN2016081809-appb-000151
将4-[甲基(丙-2-烯酰基)氨基]苯甲酸(17D)(0.500g，2.44mmol)溶解在二氯甲烷(10mL)中，加入4-(1,3-二氧戊环-2-基)苯胺(0.604g，3.65mmol)、HATU(1.20g，3.17mmol)，冰浴冷却至0℃，再滴加二异丙基乙基胺(1.57g，12.2mmol)，加完后自然升温至室温反应3小时。加入水(10mL)和二氯甲烷(20mL)，分液，有机相用饱和氯化钠溶液(10mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩所得粗品用硅胶柱纯化(洗脱剂：20％(v/v)乙酸乙酯/石油醚～70％(v/v)乙酸乙酯/石油醚)得标题化合物N-[4-(1,3-二氧戊环-2-基)苯基]-4-[甲基(丙-2-烯酰基)氨基]苯甲酰胺(17E)，黄色固体(0.800g，产率93.2％)。4-[Methyl(prop-2-enoyl)amino]benzoic acid (17D) (0.500 g, 2.44 mmol) was dissolved in dichloromethane (10 mL), and 4-(1,3-diodiolan) Benzylamine (0.604 g, 3.65 mmol), HATU (1.20 g, 3.17 mmol), cooled to 0 ° C in ice-bath, and then diisopropylethylamine (1.57 g, 12.2 mmol) was added dropwise. After that, the temperature was naturally raised to room temperature for 3 hours. After adding water (10 mL) and dichloromethane (20 mL), the organic layer was washed with saturated sodium chloride solution (10 mL×1), dried over anhydrous sodium sulfate Eluent: 20% (v/v) ethyl acetate / petroleum ether - 70% (v / v) ethyl acetate / petroleum ether) to give the title compound N-[4-(1,3-dioxolane- 2-yl)phenyl]-4-[methyl(prop-2-enoyl)amino]benzamide (17E), yellow solid (0.800 g, yield 93.2%).
LCMS m/z＝353.2[M+1]。LCMS m/z = 353.2 [M + 1].
第五步：N-(4-甲酰基苯基)-4-[甲基(丙-2-烯酰基)氨基]苯甲酰胺(17F)Step 5: N-(4-Formylphenyl)-4-[methyl(prop-2-enoyl)amino]benzamide (17F)
N-(4-formylphenyl)-4-[methyl(prop-2-enoyl)amino]benzamideN-(4-formylphenyl)-4-[methyl(prop-2-enoyl)amino]benzamide
Figure PCTCN2016081809-appb-000152
Figure PCTCN2016081809-appb-000152
将N-[4-(1,3-二氧戊环-2-基)苯基]-4-[甲基(丙-2-烯酰基)氨基]苯甲酰胺(17E)(0.800g，2.27mmol)溶解在乙腈(8mL)中，冰浴冷却下加入3M稀盐酸(10mL)，加完后冰浴下反应3小时。用二氯甲烷(20mL×2)萃取，合并有机相，有机相用饱和氯化钠溶液(10mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得标题化合物N-(4-甲酰基苯基)-4-[甲基(丙-2-烯酰基)氨基]苯甲酰胺(17F)粗品，浅黄色固体(0.560g，产率80.0％)，不纯化直接用于下一步。N-[4-(1,3-dioxolan-2-yl)phenyl]-4-[methyl(prop-2-enoyl)amino]benzamide (17E) (0.800 g, 2.27) Methyl acetate (8 mL) was dissolved in acetonitrile (8 mL). The organic phase was extracted with aq. EtOAc (EtOAc) (EtOAc) The crude formyl phenyl)-4-[methyl(prop-2-enoyl)amino]benzamide (17F) was obtained as a pale yellow solid (0.560 g, yield: 80.0%).
1H NMR(400MHz,CDCl3)δ9.96(s,1H),7.96(d,2H),7.94–7.85(m,4H),7.32(d, 2H),6.40(m,1H),6.11(m,1H),5.59(m,1H),3.40(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ9.96 (s, 1H), 7.96 (d, 2H), 7.94-7.85 (m, 4H), 7.32 (d, 2H), 6.40 (m, 1H), 6.11 ( m, 1H), 5.59 (m, 1H), 3.40 (s, 3H).
LCMS m/z＝309.2[M+1]。LCMS m/z = 309.2 [M + 1].
第六步：[7-[3-[4-[(4-甲酰基苯基)氨基甲酰基]-N-甲基苯胺]-3-氧代丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(17G)The sixth step: [7-[3-[4-[(4-formylphenyl)carbamoyl]-N-methylaniline]-3-oxopropyl]-7-azaspiro[3.5] Decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (17G)
[7-[3-[4-[(4-formylphenyl)carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-[4-[(4-formylphenyl)carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2, 2-bis(2-thienyl)acetate
Figure PCTCN2016081809-appb-000153
Figure PCTCN2016081809-appb-000153
将N-(4-甲酰基苯基)-4-[甲基(丙-2-烯酰基)氨基]苯甲酰胺(17F)(0.560g，1.82mmol)溶解在2-甲基四氢呋喃(10mL)中，加入7-氮杂螺[3.5]壬烷-2-基2-羟基-2,2-双(2-噻吩基)乙酸酯(1D)(0.660g，1.82mmol)和三乙胺(0.368g，3.63mmol)，加完后微波100℃反应1小时。反应液冷却至室温，减压浓缩后残留物用硅胶柱色谱分离提纯(洗脱剂为石油醚：乙酸乙酯(v/v)＝4:1～1:4)得到标题化合物[7-[3-[4-[(4-甲酰基苯基)氨基甲酰基]-N-甲基苯胺]-3-氧代丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(17G)，浅黄色固体(0.650g，产率53.3％)。Dissolving N-(4-formylphenyl)-4-[methyl(prop-2-enoyl)amino]benzamide (17F) (0.560 g, 1.82 mmol) in 2-methyltetrahydrofuran (10 mL) Add 7-azaspiro[3.5]decane-2-yl 2-hydroxy-2,2-bis(2-thienyl)acetate (1D) (0.660 g, 1.82 mmol) and triethylamine ( 0.368 g, 3.63 mmol), and the reaction was carried out in a microwave at 100 ° C for 1 hour after the addition. The reaction mixture was cooled to room temperature, and the residue was evaporated tolulululujjjjjjjjjjjjjjjj 3-[4-[(4-formylphenyl)carbamoyl]-N-methylaniline]-3-oxopropyl]-7-azaspiro[3.5]decane-2-yl]2 -Hydroxy-2,2-bis(2-thienyl)acetate (17G), pale yellow solid (0.650 g, yield 53.3%).
LCMS m/z＝672.3[M+1]。LCMS m/z = 672.3 [M + 1].
第七步：[7-[3-[4-[[4-[[[(2R)-2-[叔丁基(二甲基)甲硅烷基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基甲基]苯基]氨基甲酰基]-N-甲基苯胺]-3-氧代丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(17H)Step 7: [7-[3-[4-[[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2) -oxo-1H-quinolin-5-yl)ethyl]aminomethyl]phenyl]carbamoyl]-N-methylaniline]-3-oxopropyl]-7-azaspiro[3.5 ]decane-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (17H)
[7-[3-[4-[[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate[7-[3-[4-[[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5- Yl)ethyl]amino]methyl]phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2 -thienyl)acetate
Figure PCTCN2016081809-appb-000154
Figure PCTCN2016081809-appb-000154
将[7-[3-[4-[(4-甲酰基苯基)氨基甲酰基〕-N-甲基苯胺]-3-氧代丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(17G)(0.635g，0.945mmol)溶解在无水甲醇(20mL)中，加入5-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基甲基]-8-羟基-1H-喹啉-2-酮(1G)(0.316g，0.945mmol)和无水氯化锌(0.515g，3.78mmol)，50℃反应1小时后加入氰基硼氢化钠(0.297g，4.73mmol)，继续50℃反应1小时。加入水(50mL)，二氯甲烷(100mL×3)萃取，合并有机相，有机相用饱和氯化钠溶液(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得标题化合物[7-[3-[4-[[4-[[[(2R)-2-[叔丁基(二甲基)甲硅烷基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基甲基]苯基]氨基甲酰基]-N-甲基苯胺]-3-氧代丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(17H)粗品，黄色固体(0.600g，产率64.1％)，不纯化直接用于下一步。[7-[3-[4-[(4-Formylphenyl)carbamoyl]-N-methylanilin]-3-oxopropyl]-7-azaspiro[3.5]decane- 2-Based 2-hydroxy-2,2-bis(2-thienyl)acetate (17G) (0.635 g, 0.945 mmol) was dissolved in anhydrous methanol (20 mL), and 5-[(1R)- 2-Amino-1-[tert-butyl(dimethyl)silyl]oxymethyl]-8-hydroxy-1H-quinolin-2-one (1G) (0.316 g, 0.945 mmol) and anhydrous chlorine Zinc (0.515 g, 3.78 mmol) was reacted at 50 ° C for 1 hour, and sodium cyanoborohydride (0.297 g, 4.73 mmol) was added, and the reaction was continued at 50 ° C for 1 hour. After adding water (50 mL), dichloromethane (100 mL×3), EtOAc (EtOAc) [7-[3-[4-[[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]aminomethyl]phenyl]carbamoyl]-N-methylaniline]-3-oxopropyl]-7-azaspiro[3.5]decane- The crude 2-(2-hydroxy-2,2-bis(2-thienyl)acetate (17H) was obtained as a yellow solid (0.600 g, yield 64.1%).
LCMS m/z＝495.8[M/2+1]。LCMS m/z = 495.8 [M/2+1].
第八步：[7-[3-[4-[[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基甲基]苯基]氨基甲酰基]-N-甲基苯胺]-3-氧代丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯；二三氟乙酸盐(化合物17)Step 8: [7-[3-[4-[[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Aminomethyl]phenyl]carbamoyl]-N-methylanilino]-3-oxopropyl]-7-azaspiro[3.5]decane-2-yl]2-hydroxy-2, 2-bis(2-thienyl) acetate; ditrifluoroacetate (compound 17)
[7-[3-[4-[[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate；ditrifluoroacetic acid[7-[3-[4-[[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl] ]carbamoyl]-N-methyl-anilino]-3-oxo-propyl]-7-azaspiro[3.5]nonan-2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000155
Figure PCTCN2016081809-appb-000155
将[7-[3-[4-[[4-[[[(2R)-2-[叔丁基(二甲基)甲硅烷基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基甲基]苯基]氨基甲酰基]-N-甲基苯胺]-3-氧代丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯(17H)(0.600g，0.606mmol)溶解在四氢呋喃(10mL)中，加入三乙胺三氢氟酸盐(0.391g，2.42mmol)室温反应过夜。将反应清液倒掉，剩余粘稠物用四氢呋喃(20mL)洗涤，再将清液倒掉，粘稠物用甲醇/二氯甲烷(v/v＝1/9)的混合溶液溶解，滴加碳酸氢钠调节pH至碱性，分液，水层再用甲醇/二氯甲烷(v/v＝1/9)的混合溶液(100mL×3)萃取，合并有机层，无水硫酸钠干燥，过滤，滤液减压浓缩所得粗品，该粗品用液相制备柱分离提纯(制备条件：C18反相制备柱，流动相为为含0.05％ TFA的去离子水(A)，含0.05％TFA的乙腈(B)，梯度洗脱A:B＝5％～100％，洗脱10分钟，然后用100％B洗脱5分钟，流速1.0mL/min，柱温：40℃)得标题化合物[7-[3-[4-[[4-[[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基甲基]苯基]氨基甲酰基]-N-甲基苯胺]-3-氧代丙基]-7-氮杂螺[3.5]壬烷-2-基]2-羟基-2,2-二(2-噻吩基)乙酸酯；二三氟乙酸盐(化合物17)，白色固体(0.140g，产率20.9％)。[7-[3-[4-[[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]aminomethyl]phenyl]carbamoyl]-N-methylaniline]-3-oxopropyl]-7-azaspiro[3.5]decane 2-yl]2-hydroxy-2,2-bis(2-thienyl)acetate (17H) (0.600 g, 0.606 mmol) was dissolved in tetrahydrofuran (10 mL) and triethylamine trihydrofluorate was added. (0.391 g, 2.42 mmol) was reacted at room temperature overnight. The reaction supernatant was poured off, the remaining viscous material was washed with tetrahydrofuran (20 mL), and the supernatant was poured off. The viscous material was dissolved in a mixed solution of methanol/dichloromethane (v/v = 1/9), and added dropwise. The sodium hydrogencarbonate was adjusted to pH to be alkaline, and the aqueous layer was separated and extracted with a mixture of methanol/dichloromethane (v/v = 1/9) (100 mL×3). Filtration and concentration of the filtrate under reduced pressure. The crude product was separated and purified by liquid phase preparative column (preparation conditions: C18 reverse phase preparative column, mobile phase was 0.05%) TFA deionized water (A), acetonitrile (B) containing 0.05% TFA, gradient elution A: B = 5% to 100%, elution for 10 minutes, then elution with 100% B for 5 minutes, flow rate 1.0 mL /min, column temperature: 40 ° C) to give the title compound [7-[3-[4-[[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl]aminomethyl]phenyl]carbamoyl]-N-methylaniline]-3-oxopropyl]-7-azaspiro[3.5]decane-2- 2-Hydroxy-2,2-bis(2-thienyl)acetate; ditrifluoroacetate (Compound 17), white solid (0.140 g, yield 20.9%).
1H NMR(400MHz,CD3OD)δ8.15(d,1H),7.97d,2H),7.73(d,2H),7.44-7.39(m,4H),7.27(m,2H),7.17(d,1H),7.03(t,2H),6.93(d,1H),6.89-6.86(m,2H),6.54(d,1H),5.35-5.25(m,1H),5.07–4.98(m,1H),4.21(s,2H),3.35-3.22(m,7H),3.14(d,2H),2.90-2.72(m,2H),2.57-2.47(m,2H),2.45-2.35(m,1H),2.28-2.20(m,1H),1.90–1.78(m,3H),1.75-1.65(m,3H). 1 H NMR (400MHz, CD 3 OD) δ8.15 (d, 1H), 7.97d, 2H), 7.73 (d, 2H), 7.44-7.39 (m, 4H), 7.27 (m, 2H), 7.17 ( d, 1H), 7.03 (t, 2H), 6.93 (d, 1H), 6.89-6.86 (m, 2H), 6.54 (d, 1H), 5.35-5.25 (m, 1H), 5.07 - 4.98 (m, 1H), 4.21 (s, 2H), 3.35-3.22 (m, 7H), 3.14 (d, 2H), 2.90-2.72 (m, 2H), 2.57-2.47 (m, 2H), 2.45-2.35 (m, 1H), 2.28-2.20 (m, 1H), 1.90–1.78 (m, 3H), 1.75-1.65 (m, 3H).
19F NMR(376MHz,CD3OD)δ-75.48. 19 F NMR (376 MHz, CD 3 OD) δ-75.48.
LCMS m/z＝876.3[M+1]。LCMS m/z = 876.3 [M + 1].
实施例18：[7-[[4-[2-[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]乙基甲基氨基甲酰基]苯基]甲基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯氧基苯基)氨基甲酸酯；二三氟乙酸盐(化合物18)Example 18: [7-[[4-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino] Ethylmethylcarbamoyl]phenyl]methyl]-7-azaspiro[3.5]decane-2-yl]N-(2-phenoxyphenyl)carbamate; ditrifluoroethyl Acid salt (compound 18)
[7-[[4-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-carbamoyl]phenyl]methyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate；ditrifluoroacetic acid[7-[[4-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-carbamoyl]phenyl ]methyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000156
Figure PCTCN2016081809-appb-000156
Figure PCTCN2016081809-appb-000157
Figure PCTCN2016081809-appb-000157
第一步：4-[[2-[(2-苯基苯基)氨基甲酰基氧基]-7-氮杂螺[3.5]壬-7-基]甲基]苯甲酸甲酯(18A)First step: 4-[[2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]indole-7-yl]methyl]benzoic acid methyl ester (18A)
methyl 4-[[2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]nonan-7-yl]methyl]benzoateMethyl 4-[[2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]nonan-7-yl]methyl]benzoate
Figure PCTCN2016081809-appb-000158
Figure PCTCN2016081809-appb-000158
将7-氮杂螺[3.5]壬-2-基-N-(2-苯基苯基)氨基甲酸酯(2D)(1.50g,4.46mmol)溶于乙腈(30mL)中，加入N,N-二甲基甲酰胺(10mL)、碳酸钾(1.85g,13.4mmol)和4-(溴甲基)苯甲酸甲酯(1.02g,4.46mmol)，升温至70℃反应2小时。冷却到室温，加入水(50mL)，用二氯甲烷(100mL×3)萃取，合并有机相，用无水硫酸干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析分离提纯(洗脱剂为二氯甲烷：甲醇(v/v)＝99：1～97:3)，得到标题化合物4-[[2-[(2-苯基苯基)氨基甲酰基氧基]-7-氮杂螺[3.5]壬-7-基]甲基]苯甲酸甲酯(18A)，白色固体(2.0g，产率92.6％)。7-Azaspiro[3.5]indol-2-yl-N-(2-phenylphenyl)carbamate (2D) (1.50 g, 4.46 mmol) was dissolved in EtOAc (30 mL). N-dimethylformamide (10 mL), potassium carbonate (1.85 g, 13.4 mmol), and methyl 4-(bromomethyl)benzoate (1.02 g, 4.46 mmol) were warmed to 70 ° C for 2 hours. After cooling to room temperature, water (50 mL) was added, and the mixture was evaporated. The title compound is methylene chloride:methanol (v/v) = 99:1 to 97:3) to give the title compound 4-[[2-[(2-phenylphenyl)carbamoyloxy]-7-nitro Heterospiro[3.5]dec-7-yl]methyl]benzoic acid methyl ester (18A), white solid (2.0 g, yield 92.6%).
1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),7.96(m,2H),7.71(s,1H),7.37(m,10H),4.72(s,1H),4.34(s,1H),3.85(s,3H),3.47(s,1H),3.16(m,1H),2.89(m,1H),2.17(m,4H),1.63(m,6H). 1 H NMR (400MHz, DMSO- d6) δ8.60 (s, 1H), 7.96 (m, 2H), 7.71 (s, 1H), 7.37 (m, 10H), 4.72 (s, 1H), 4.34 (s , 1H), 3.85 (s, 3H), 3.47 (s, 1H), 3.16 (m, 1H), 2.89 (m, 1H), 2.17 (m, 4H), 1.63 (m, 6H).
LCMS m/z＝485.3[M+1]。LCMS m/z = 485.3 [M + 1].
第二步：4-[[2-[(2-苯基苯基)氨基甲酰基氧基]-7-氮杂螺[3.5]壬-7-基]甲基]苯甲酸(18B) Second step: 4-[[2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]indole-7-yl]methyl]benzoic acid (18B)
4-[[2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]nonan-7-yl]methyl]benzoic acid4-[[2-[(2-phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]nonan-7-yl]methyl]benzoic acid
Figure PCTCN2016081809-appb-000159
Figure PCTCN2016081809-appb-000159
将4-[[2-[(2-苯基苯基)氨基甲酰基氧基]-7-氮杂螺[3.5]壬-7-基]甲基]苯甲酸甲酯(18A)(2.20g,4.54mmol)溶于四氢呋喃(30mL)中，加入氢氧化钠(7.3g,61.0mmol)水溶液(5mL)，室温搅拌2小时。加入水(50mL)，用10％盐酸水溶液调pH约为2，用二氯甲烷(100mL×3)萃取，合并有机相，用无水硫酸干燥，过滤，滤液减压浓缩，得到标题化合物4-[[2-[(2-苯基苯基)氨基甲酰基氧基]-7-氮杂螺[3.5]壬-7-基]甲基]苯甲酸(18B)，白色固体(2.0g，产率93.6％)。Methyl 4-[[2-[(2-phenylphenyl)carbamoyloxy)-7-azaspiro[3.5]indole-7-yl]methyl]benzoate (18A) (2.20 g , 4.54 mmol) was dissolved in tetrahydrofuran (30 mL). EtOAc (EtOAc,EtOAc. Water (50 mL) was added, and the mixture was diluted with EtOAc EtOAc (EtOAc) [[2-[(2-Phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]dec-7-yl]methyl]benzoic acid (18B), white solid (2.0 g, yield The rate is 93.6%).
LCMS m/z＝471.3[M+1]。LCMS m/z = 471.3 [M + 1].
第三步：[7-[[4-[2,2-二甲基乙基(甲基)氨基甲酰基]苯基]甲基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯氧基苯基)氨基甲酸酯(18C)Third step: [7-[[4-[2,2-dimethylethyl(methyl)carbamoyl]phenyl]methyl]-7-azaspiro[3.5]decane-2-yl N-(2-phenoxyphenyl)carbamate (18C)
[7-[[4-[2,2-dimethoxyethyl(methyl)carbamoyl]phenyl]methyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate[7-[[4-[2,2-dimethoxyethyl(methyl)carbamoyl]phenyl]methyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate
Figure PCTCN2016081809-appb-000160
Figure PCTCN2016081809-appb-000160
将4-[[2-[(2-苯基苯基)氨基甲酰基氧基]-7-氮杂螺[3.5]壬-7-基]甲基]苯甲酸(18B)(2.00g,4.01mmol)溶于二氯甲烷(20mL)中，加入N,N-二甲基甲酰胺(4mL)、2,2-甲氧基-N-甲基乙胺(0.531g,4.45mmol)、HATU(2.29g,6.02mmol)和三乙胺(1.22g,12.0mmol)，加完后保持室温反应3小时，向反应液加入加入二氯甲烷(50mL)和水(20mL)，萃取分层，有机相再用饱和氯化钠水溶液(20mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物[7-[[4-[2,2-二甲基乙基(甲基)氨基甲酰基]苯基]甲基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯氧基苯基)氨基甲酸酯(18C)(1.82g，产率79.4％)。4-[[2-[(2-Phenylphenyl)carbamoyloxy]-7-azaspiro[3.5]indole-7-yl]methyl]benzoic acid (18B) (2.00 g, 4.01 Methyl) was dissolved in dichloromethane (20 mL), N,N-dimethylformamide (4 mL), 2,2-methoxy-N-methylethylamine (0.531 g, 4.45 mmol), 2.29g, 6.02mmol) and triethylamine (1.22g, 12.0mmol), after the addition was completed, the reaction was kept at room temperature for 3 hours, and dichloromethane (50 mL) and water (20 mL) were added to the reaction mixture, and the organic layer was separated. The residue was washed with aq. )carbamoyl]phenyl]methyl]-7-azaspiro[3.5]decane-2-yl]N-(2-phenoxyphenyl)carbamate (18C) (1.82 g, produced) The rate is 79.4%).
第四步：[7-[[4-[甲基(2-氧代乙基)氨基甲酰基]苯基]甲基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯氧基苯基)氨基甲酸酯(18D)Fourth step: [7-[[4-[methyl(2-oxoethyl)carbamoyl]phenyl]methyl]-7-azaspiro[3.5]decane-2-yl]N- (2-phenoxyphenyl)carbamate (18D)
[7-[[4-[methyl(2-oxoethyl)carbamoyl]phenyl]methyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate [7-[[4-[methyl(2-oxoethyl)carbamoyl]phenyl]methyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate
Figure PCTCN2016081809-appb-000161
Figure PCTCN2016081809-appb-000161
将[7-[[4-[2,2-二甲基乙基(甲基)氨基甲酰基]苯基]甲基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯氧基苯基)氨基甲酸酯(18C)(1.50g,2.62mmol)溶于二氯甲烷(20mL)中，加入对甲苯磺酸(2.26g,13.1mmol)，室温下反应3小时。加入水(20mL)，二氯甲烷(50mL×2)萃取，合并有机层，用饱和碳酸氢钠水溶液(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物[7-[[4-[甲基(2-氧代乙基)氨基甲酰基]苯基]甲基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯氧基苯基)氨基甲酸酯(18D)，淡黄色固体(1.22g，产率88.5％)。[7-[[4-[2,2-Dimethylethyl(methyl)carbamoyl]phenyl]methyl]-7-azaspiro[3.5]decan-2-yl]N- (2-Phenoxyphenyl)carbamate (18C) (1.50 g, 2.62 mmol) was dissolved in dichloromethane (20 mL), p-toluenesulfonic acid (2.26 g, 13.1 mmol) hour. After adding water (20 mL), dichloromethane (50 mL×2), EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 7-[[4-[Methyl(2-oxoethyl)carbamoyl]phenyl]methyl]-7-azaspiro[3.5]decane-2-yl]N-(2-phenoxy) Phenyl phenyl) carbamate (18D), pale yellow solid (1.22 g, yield 88.5%).
LCMS m/z＝526.3[M+1]。LCMS m/z = 526.3 [M + 1].
第五步：[7-[[4-[2-[[(2R)-2-[叔丁基(二甲基)甲硅烷基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]乙基甲基氨基甲酰基]苯基]甲基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯氧基苯基)氨基甲酸酯(18E)Step 5: [7-[[4-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethylmethylcarbamoyl]phenyl]methyl]-7-azaspiro[3.5]decane-2-yl]N-(2-benzene Oxyphenyl)carbamate (18E)
[7-[[4-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-carbamoyl]phenyl]methyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate[7-[[4-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl] Amino]ethyl-methyl-carbamoyl]phenyl]methyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate
Figure PCTCN2016081809-appb-000162
Figure PCTCN2016081809-appb-000162
将[7-[[4-[甲基(2-氧代乙基)氨基甲酰基]苯基]甲基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯氧基苯基)氨基甲酸酯(18D)(0.200g,0.381mmol)和5-[(1R)-2-氨基-1-[叔丁基(二甲基)硅基]氧基甲基]-8-羟基-1H-喹啉-2-酮(1G)(0.127g,0.381mmol)溶于异丙醇/二氯甲烷(v/v＝1/1，20mL)混合溶剂中，加入冰醋酸(1mL)，室温搅拌1小时，然后加入三乙酰氧基硼氢化钠(0.162g,0.761mmol)，再搅拌2小时。向反应液加入二氯甲烷(50mL)和水(50mL)，萃取分层，有机相再用饱和氯化钠水溶液(20mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱层析提纯(二氯甲烷/甲醇(v:v)＝1/0～9/1)，得到标题化合物[7-[[4-[2-[[(2R)-2-[叔丁基(二甲基)甲硅烷基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]乙基甲基氨基甲酰基]苯基]甲基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯氧基 苯基)氨基甲酸酯(18E)，浅黄固体(0.220g，产率68.5％)。[7-[[4-[Methyl(2-oxoethyl)carbamoyl]phenyl]methyl]-7-azaspiro[3.5]decan-2-yl]N-(2- Phenoxyphenyl)carbamate (18D) (0.200 g, 0.381 mmol) and 5-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxymethyl ]-8-Hydroxy-1H-quinolin-2-one (1G) (0.127 g, 0.381 mmol) was dissolved in isopropanol/dichloromethane (v/v = 1/1, 20 mL). Acetic acid (1 mL) was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.162 g, 0.761 mmol) was added and stirred for 2 hr. Dichloromethane (50 mL) and water (50 mL) were added to the mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated Purification by silica gel column chromatography (dichloromethane/methanol (v:v) = 1/0 to 9/1) gave the title compound [7-[[4-[2-[[(2)) tert-Butyl (dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethylmethylcarbamoyl]benzene Methyl]-7-azaspiro[3.5]decane-2-yl]N-(2-phenoxy Phenyl)carbamate (18E), pale yellow solid (0.220 g, yield 68.5%).
第六步：[7-[[4-[2-[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]乙基甲基氨基甲酰基]苯基]甲基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯氧基苯基)氨基甲酸酯；二三氟乙酸盐(化合物18)The sixth step: [7-[[4-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino] Ethylmethylcarbamoyl]phenyl]methyl]-7-azaspiro[3.5]decane-2-yl]N-(2-phenoxyphenyl)carbamate; ditrifluoroethyl Acid salt (compound 18)
[7-[[4-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-carbamoyl]phenyl]methyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate；ditrifluoroacetic acid[7-[[4-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-carbamoyl]phenyl ]methyl]-7-azaspiro[3.5]nonan-2-yl]N-(2-phenylphenyl)carbamate;ditrifluoroacetic acid
Figure PCTCN2016081809-appb-000163
Figure PCTCN2016081809-appb-000163
将[7-[[4-[2-[[(2R)-2-[叔丁基(二甲基)甲硅烷基]氧基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]乙基甲基氨基甲酰基]苯基]甲基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯氧基苯基)氨基甲酸酯(18E)(0.800g,0.948mmol)溶于二氯甲烷(10mL)中，加入三乙胺三氢氟酸盐(0.764g,4.74mmol)，室温反应过夜，反应液用饱和碳酸氢钠调碱，用8％甲醇/二氯甲烷(v/v＝8:92,100mL×1)萃取，有机相用饱和氯化钠水溶液(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用液相制备柱分离提纯(液相制备条件：C18反相制备柱，流动相为含0.05％TFA的去离子水(A)，含0.05％TFA的乙腈(B)，梯度洗脱A:B＝10％～55％，洗脱时间39min，流速1.0mL/min，柱温：40℃)，得到标题化合物[7-[[4-[2-[[(2R)-2-羟基-2-(8-羟基-2-氧代-1H-喹啉-5-基)乙基]氨基]乙基甲基氨基甲酰基]苯基]甲基]-7-氮杂螺[3.5]壬烷-2-基]N-(2-苯氧基苯基)氨基甲酸酯；二三氟乙酸盐(化合物18)，浅黄固体(0.0650g，产率7.16％)。[7-[[4-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quine啉-5-yl)ethyl]amino]ethylmethylcarbamoyl]phenyl]methyl]-7-azaspiro[3.5]decane-2-yl]N-(2-phenoxybenzene The carbamate (18E) (0.800 g, 0.948 mmol) was dissolved in dichloromethane (10 mL), triethylamine trihydrofluoric acid salt (0.764 g, 4.74 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The organic layer was washed with a saturated aqueous solution of sodium chloride (50 mL×1) and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by liquid phase preparative column (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase was deionized water (A) containing 0.05% TFA, acetonitrile containing 0.05% TFA ( B), gradient elution A: B = 10% to 55%, elution time 39 min, flow rate 1.0 mL / min, column temperature: 40 ° C), the title compound [7-[[4-[2-[[( 2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethylmethylcarbamoyl]phenyl]methyl]-7- Azaspiro[3.5]decane-2-yl]N-(2-phenoxyphenyl)carbamic acid ; Ditrifluoroacetate (Compound 18), a pale yellow solid (0.0650 g, 7.16% yield).
1H NMR(400MHz,CD3OD)δ8.43(d,1H),7.64-7.57(m,5H),7.48–7.27(m,9H),7.06(d,1H),6.66(d,1H),5.47(s,1H),4.36(s,2H),3.94(s,2H),3.53–3.35(m,6H),3.04(m,5H),2.46(s,1H),2.25(s,1H),1.97-1.87(m,7H). 1 H NMR (400 MHz, CD 3 OD) δ 8.43 (d, 1H), 7.64 - 7.57 (m, 5H), 7.48 - 7.27 (m, 9H), 7.06 (d, 1H), 6.66 (d, 1H) , 5.47 (s, 1H), 4.36 (s, 2H), 3.94 (s, 2H), 3.53 - 3.35 (m, 6H), 3.04 (m, 5H), 2.46 (s, 1H), 2.25 (s, 1H) ), 1.97-1.87 (m, 7H).
LCMS m/z＝365.8[(M+2)/2]。LCMS m/z = 365.8 [(M+2)/2].
生物测试例Biological test case
测试例1：对人毒蕈碱M3受体的抑制活性 Test Example 1: Inhibitory activity against human muscarinic M3 receptor
稳定表达人毒蕈碱受体3(hM3)和apo-Aequorin的CHO细胞(PerkinElmer，ES-212-AF)培养于含10％胎牛血清(FBS)(Gibico 10099-141)，400μg/mL G418(sigma G5013)和250μg/mL Zeocin(invivogen ant-zn-5p)的Ham’S F12培养基(Invitrogen12500-062)中，在37℃，5％CO2条件下培养，达到90－100％融合。以PBS/5mM EDTA冲洗分离细胞，离心收集，以含0.1％BSA(BOVOGEN BSAS 100)无酚红Ham’s F12培养基(Invitrogen 11039-021)重悬细胞并计数，调整细胞浓度至1x106cells/mL。将15ml细胞悬液加入50mL离心管，加入Coelenterazine-h(promega S2011)至终浓度为5μM。用锡纸包裹避光，于旋转摇床20℃下孵育4小时。再以0.1％BSA/无酚红Ham’s F12培养基稀释细胞至终浓度为5.0×105cells/mL，将细胞置于旋转摇床上低速转动，室温下孵育至少1小时。实施例化合物用DMSO配制为10mM母液，0.1％BSA/无酚红Ham’s F12培养基梯度稀释(log(M):-7,-8,-9,-10,-11)，加入96孔板，每孔50L。每孔再加入50L细胞悬液(25000细胞/孔)，室温孵育15分钟。将96孔板放入酶标仪(Perkin Elmer，Envision)，以酶标仪加样器每孔加入50L氯化乙酰胆碱(Sigma A6625)溶液，其浓度为112.92nM(hM3)，记录发光20秒，使用origin7.5计算和分析IC50。本发明化合物人毒蕈碱受体的抑制活性通过以上的实验进行测定，测得的IC50值见下表1。CHO cells (PerkinElmer, ES-212-AF) stably expressing human muscarinic receptor 3 (hM3) and apo-Aequorin were cultured in 10% fetal bovine serum (FBS) (Gibico 10099-141), 400 μg/mL G418 (sigma G5013) and 250 μg/mL Zeocin (invivogen ant-zn-5p) in Ham'S F12 medium (Invitrogen 12500-062), cultured at 37 ° C, 5% CO 2 to achieve 90-100% confluence. The cells were washed with PBS/5 mM EDTA, collected by centrifugation, resuspended in 0.1% BSA (BOVOGEN BSAS 100) phenol red-free Ham's F12 medium (Invitrogen 11039-021) and counted, and the cell concentration was adjusted to 1×10 6 cells/mL. . 15 ml of the cell suspension was added to a 50 mL centrifuge tube and Coelenterazine-h (promega S2011) was added to a final concentration of 5 μM. It was wrapped in tin foil and protected from light and incubated for 4 hours at 20 ° C in a rotary shaker. The cells were diluted with 0.1% BSA/phenol red-free Ham's F12 medium to a final concentration of 5.0×10 5 cells/mL, and the cells were placed on a rotary shaker at low speed and incubated at room temperature for at least 1 hour. The compound of the example was prepared as a 10 mM mother liquor in DMSO, diluted with 0.1% BSA/phenol red free Ham's F12 medium (log (M): -7, -8, -9, -10, -11), and added to a 96-well plate. 50L per hole. An additional 50 L of cell suspension (25,000 cells/well) was added to each well and incubated for 15 minutes at room temperature. The 96-well plate was placed in a microplate reader (Perkin Elmer, Envision), and 50 L of acetylcholine chloride (Sigma A6625) solution was added to each well of the microplate reader at a concentration of 112.92 nM (hM3), and the luminescence was recorded for 20 seconds. The IC 50 was calculated and analyzed using origin 7.5. The inhibitory activity of the muscarinic receptor of the compound of the present invention was measured by the above experiment, and the measured IC 50 values are shown in Table 1 below.
表1 测试化合物对人毒蕈碱M3受体的抑制活性结果Table 1 Results of inhibitory activity of test compounds on human muscarinic M3 receptor
实施例编号Example number hM3受体IC50(nM)hM3 receptor IC 50 (nM)
化合物1Compound 1 2.972.97
化合物3Compound 3 3.253.25
化合物5Compound 5 0.440.44
化合物6Compound 6 0.700.70
化合物7Compound 7 0.750.75
化合物8Compound 8 1.341.34
化合物9Compound 9 0.600.60
化合物10Compound 10 1.631.63
化合物11Compound 11 5.755.75
化合物16Compound 16 2.042.04
化合物17Compound 17 1.391.39
结论：本发明化合物对人毒蕈碱M3受体有显著抑制活性。Conclusion: The compounds of the present invention have significant inhibitory activity against the human muscarinic M3 receptor.
测试例2：对人肾上腺素能β2受体的激动活性Test Example 2: Agonistic activity on human adrenergic β2 receptor
实施例化合物对人肾上腺素能受体的激动活性通过LANCE Ultra cAMP Assay测定。 The agonistic activity of the example compounds on human adrenergic receptors was determined by LANCE Ultra cAMP Assay.
稳定表达人肾上腺素能受体(hβ2)的CHO细胞(PerkinElmer，ES-034-CF)培养于含10 ％胎牛血清(FBS)(Gibico 10099-141)和250μg/mL Zeocin(InvivoGen ant-zn-5p)的MEM-alpha培养基(Invitrogen 12561-056)，在37℃，5％CO2条件下培养，达到90-100％融合后用LANCE Ultra cAMP Assay试剂盒(PerkinElmer TRF0263)检测实施例对cAMP的激动作用。以PBS/5mM EDTA分离细胞，离心收集，用Stimulation Buffer(1xHBSS,5mM HEPES,0.5mM IBMX,0.1％BSA,PH7.4)重悬细胞，调整细胞浓度至6×105cells/ml。实施例化合物用DMSO配制为10mM母液，以Stimulation Buffer梯度稀释后以每孔5μl加入384孔板。每孔再加入5μL细胞悬液(3000细胞/孔)，室温孵育30分钟后，每孔加入5μl 4x Eu-cAMP tracer工作溶液，然后每孔加入5μl 4x Ulight-anti-cAMP工作溶液，并在室温下孵育1小时。384孔板用酶标仪(Perkin Elmer，Envision)检测TR-FRET，使用origin7.5计算和分析EC50。本发明化合物对人肾上腺素能受体的激动活性通过以上的实验进行测定，测得的EC50值见表2。CHO cells (PerkinElmer, ES-034-CF) stably expressing human adrenergic receptor (hβ2) were cultured in 10% fetal bovine serum (FBS) (Gibico 10099-141) and 250 μg/mL Zeocin (InvivoGen ant-zn) -5p) MEM-alpha medium (Invitrogen 12561-056), cultured at 37 ° C, 5% CO 2 , 90-100% confluence, and assayed with LANCE Ultra cAMP Assay kit (PerkinElmer TRF0263) The agonistic effect of cAMP. The cells were separated by PBS/5 mM EDTA, collected by centrifugation, and the cells were resuspended with Stimulation Buffer (1 x HBSS, 5 mM HEPES, 0.5 mM IBMX, 0.1% BSA, pH 7.4), and the cell concentration was adjusted to 6 × 10 5 cells/ml. The compound of the Example was prepared as a 10 mM stock solution in DMSO, diluted with a Stimulation Buffer gradient, and added to a 384-well plate at 5 μl per well. Add 5 μL of cell suspension (3000 cells/well) to each well, incubate for 30 minutes at room temperature, add 5 μl of 4x Eu-cAMP tracer working solution to each well, then add 5 μl of 4x Ulight-anti-cAMP working solution per well and at room temperature. Incubate for 1 hour. TR-FRET detection plate 384 using a plate reader (Perkin Elmer, Envision), calculated and analyzed using origin7.5 EC 50. The agonistic activity of the compounds of the present invention on human adrenergic receptors was determined by the above experiment, and the measured EC 50 values are shown in Table 2.
表2测试化合物对人肾上腺素能β2受体的激动活性结果Table 2 Results of agonistic activity of test compounds on human adrenergic β2 receptor
实施例编号Example number hβ2受体EC50(nM)Hβ2 receptor EC 50 (nM)
化合物1Compound 1 2.82.8
化合物2Compound 2 8.48.4
化合物3Compound 3 7.757.75
化合物4Compound 4 1.251.25
化合物6Compound 6 1.021.02
化合物7Compound 7 3.03.0
化合物9Compound 9 3.43.4
化合物10Compound 10 2.02.0
化合物11Compound 11 0.900.90
化合物12Compound 12 1.081.08
化合物13Compound 13 0.850.85
化合物13的异构体1Isomer 1 of compound 13 2.342.34
化合物13的异构体2Isomer 2 of compound 13 2.632.63
化合物16Compound 16 4.904.90
化合物17Compound 17 1.801.80
化合物18Compound 18 1.961.96
结论：本发明化合物对β2肾上腺素能受体有显著激动活性。Conclusion: The compounds of the invention have significant agonistic activity on the β2 adrenergic receptor.
测试例3：乙酰甲胆碱诱导的豚鼠支气管收缩抑制作用Test Example 3: Methotrexate-induced inhibition of bronchial contraction in guinea pigs
8周龄全雄豚鼠购置于维通利华，适应3天后开始实验。待测化合物用83％无水乙醇+17％吐温80配制成0.6mM储备液。于给药前用水稀释500倍使用。给药前，使用 小动物麻醉机(Matrx；VME2)给予5％异氟烷麻醉动物，麻醉时间为1.5～2分钟。待豚鼠麻醉后，将豚鼠固定于气管插管操作平台上，使用大鼠液体气溶胶给药套装(penn-century；MSA-250-R)气管内给药，每只豚鼠给药体积250μl。给药后，于4小时，24小时，使用全体积描计仪(DSI；GS220A12-R7B)测量豚鼠增强呼气间歇(enhanced pause；PenH)值。雾化给予3mg/ml乙酰甲胆碱(Mch)，雾化时间36秒，记录时间7分钟。计算PenH平均值。(参考文献J Pharmacol Exp Ther 345:260-270.)。实验结果见表3。Eight-week old male guinea pigs were purchased in Vitalivic, and the experiment was started after 3 days of adaptation. The test compound was formulated into a 0.6 mM stock solution using 83% absolute ethanol + 17% Tween 80. It was diluted 500 times with water before administration. Before administration, use The small animal anesthesia machine (Matrx; VME2) was given an anesthetized animal with 5% isoflurane for an anesthesia time of 1.5 to 2 minutes. After guinea pig anesthesia, the guinea pigs were fixed on an tracheal intubation operating platform and intratracheally administered using a rat liquid aerosol administration kit (penn-century; MSA-250-R), and each guinea pig was administered with a volume of 250 μl. After administration, the guinea pig enhanced exhalation pause (PenH) value was measured using a full volume oximeter (DSI; GS220A12-R7B) at 4 hours and 24 hours. 3 mg/ml methacholine (Mch) was administered by nebulization, the atomization time was 36 seconds, and the recording time was 7 minutes. Calculate the PenH average. (Reference J Pharmacol Exp Ther 345: 260-270.). The experimental results are shown in Table 3.
PenH计算公式：PenH＝PEP/PIP*Pause；Pause＝(Te-Tr)/TrPenH calculation formula: PenH=PEP/PIP*Pause; Pause=(Te-Tr)/Tr
Te：呼气相时间(s)Te: expiratory time (s)
Tr：松弛相时间(s)Tr: relaxed phase time (s)
PEP：呼气峰流速(ml/s)PEP: peak expiratory flow rate (ml/s)
PIP：吸气峰流速(ml/s)PIP: Inspiratory peak flow rate (ml/s)
表3化合物对乙酰甲胆碱诱导的豚鼠支气管收缩抑制作用结果Table 3 results of inhibition of methacholine-induced bronchial contraction in guinea pigs
Figure PCTCN2016081809-appb-000164
Figure PCTCN2016081809-appb-000164
结论：本发明化合物对乙酰甲胆碱诱导的豚鼠支气管收缩抑制作用优于阳性对照，且在给药24小时后，仍具有良好的支气管收缩抑制效果。 Conclusion: The compound of the present invention has a better inhibitory effect on methacholine-induced bronchial contraction in guinea pigs than the positive control, and still has a good bronchoconstriction inhibitory effect after 24 hours of administration.

Claims (17)

  1. 一种通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，a compound of the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof,
    Figure PCTCN2016081809-appb-100001
    Figure PCTCN2016081809-appb-100001
    其中：among them:
    R1选自
    Figure PCTCN2016081809-appb-100002
    R 1 is selected from
    Figure PCTCN2016081809-appb-100002
    R1a选自H、C2-6烯基、C2-6炔基、C3-10碳环基、3至8元杂环基、C3-10碳环基-C1-4亚烷基或3至8元杂环基-C1-4亚烷基，所述烯基、炔基、亚烷基、碳环基或杂环基任选进一步被0至4个选自F、Cl、Br、I、CH2F、CHF2、CF3、OH、OCH2F、OCHF2、OCF3、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基、-O(＝O)C1-4烷基、-(＝O)C1-4烷基、-OC3-6环烷基或C1-4烷硫基的取代基所取代，所述杂环基含有1至3个选自N、O或S的杂原子；R 1a is selected from the group consisting of H, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3 to 8 membered heterocyclic, C 3-10carbocyclyl -C 1-4 alkylene Or a 3 to 8 membered heterocyclyl-C 1-4 alkylene group, optionally further 0 to 4 selected from the group consisting of F and Cl, the alkenyl, alkynyl, alkylene, carbocyclic or heterocyclic group , Br, I, CH 2 F, CHF 2 , CF 3 , OH, OCH 2 F, OCHF 2 , OCF 3 , NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkane Substituted by a substituent of an oxy group, -O(=O)C 1-4 alkyl, -(=O)C 1-4 alkyl, -OC 3-6 cycloalkyl or C 1-4 alkylthio group, The heterocyclic group contains 1 to 3 hetero atoms selected from N, O or S;
    R1b选自C2-6烯基、C2-6炔基、C3-10碳环基、3至8元杂环基、C3-10碳环基-C1-4亚烷基或3至8元杂环基-C1-4亚烷基，所述烯基、炔基、亚烷基、碳环基或杂环基任选进一步被0至4个选自F、Cl、Br、I、CH2F、CHF2、CF3、OH、OCH2F、OCHF2、OCF3、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基、-O(＝O)C1-4烷基、-(＝O)C1-4烷基、-OC3-6环烷基或C1-4烷硫基的取代基所取代，所述杂环基含有1至3个选自N、O或S的杂原子；R 1b is selected from C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3 to 8 membered heterocyclic, C 3-10carbocyclyl -C 1-4 alkylene or a 3- to 8-membered heterocyclyl-C 1-4 alkylene group, optionally further 0 to 4 selected from the group consisting of F, Cl, and Br, and an alkenyl group, an alkynyl group, an alkylene group, a carbocyclic group, or a heterocyclic group. , I, CH 2 F, CHF 2 , CF 3 , OH, OCH 2 F, OCHF 2 , OCF 3 , NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy Substituted with a substituent of -O(=O)C 1-4 alkyl, -(=O)C 1-4 alkyl, -OC 3-6 cycloalkyl or C 1-4 alkylthio, The heterocyclic group contains 1 to 3 hetero atoms selected from N, O or S;
    R1c选自H、羟基、氰基、NH2、C1-6烷基、C1-6烷氧基、C1-6烷硫基或-C(＝O)NH2，所述NH2、-C(＝O)NH2或烷基任选进一步被0至2个选自F、Cl、Br、I、羟基、氰基或C1-4烷基的取代基所取代；R 1c is selected from H, hydroxy, cyano, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or -C(=O)NH 2 , said NH 2 , -C(=O)NH 2 or an alkyl group is optionally further substituted with 0 to 2 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, cyano or C 1-4 alkyl;
    R1e和R1f各自独立选自F、Cl、Br、I、CF3、NH2、OH、羧基、氰基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、-NHC1-4烷基、-N(C1-4烷基)2、-S(＝O)-C1-4烷基、-S(＝O)2-C1-4烷基或-C(＝O)O-C1-4烷基；R 1e and R 1f are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , NH 2 , OH, carboxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkane Thio group, -NHC 1-4 alkyl group, -N(C 1-4 alkyl) 2 , -S(=O)-C 1-4 alkyl group, -S(=O) 2 -C 1-4 alkane Or a -C(=O)OC 1-4 alkyl group;
    R2选自键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基，所述亚烷基、亚烯基或亚炔基任选进一步被0至5个选自F、Cl、Br、I、OH、氰基、C1-4烷基、C1-4烷氧基、苯基或苯基-C1-4亚烷基的取代基所取代； R 2 is selected from a bond, a C 1-6 alkylene group, a C 2-6 alkenylene group or a C 2-6 alkynylene group, and the alkylene group, alkenylene group or alkynylene group is optionally further 0 to 5 Substituted with a substituent selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
    L选自键或
    Figure PCTCN2016081809-appb-100003
    且Y直接与R2相连接；    L is selected from the key or
    Figure PCTCN2016081809-appb-100003
    And Y is directly connected to R 2 ;
    R3选自键或C1-6亚烷基，所述亚烷基任选进一步被0至5个选自R3a的取代基所取代；R 3 is selected from a bond or a C 1-6 alkylene group, which is optionally further substituted with 0 to 5 substituents selected from R 3a ;
    并且R2、L和R3三者不能同时为键；And R 2 , L and R 3 cannot be simultaneously a bond;
    R4、R5各自独立选自H或C1-4烷基；R 4 and R 5 are each independently selected from H or C 1-4 alkyl;
    Figure PCTCN2016081809-appb-100004
    表示β-肾上腺素受体结合基团；
    Figure PCTCN2016081809-appb-100004
    Representing a β-adrenergic receptor binding group;
    R3a选自F、Cl、Br、I、氰基、OH、C1-4烷基、C1-4烷氧基、苯基或苯基-C1-4亚烷基；R 3a is selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
    作为选择，两个R3a可以与它们相连的原子一起形成一个3至6元碳环，所述碳环任选进一步被0至5个选自F、Cl、Br、I、氰基、OH、C1-4烷基或C1-4烷氧基的取代基所取代；Alternatively, two R 3a may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, optionally further 0 to 5 selected from the group consisting of F, Cl, Br, I, cyano, OH, Substituted by a substituent of a C 1-4 alkyl group or a C 1-4 alkoxy group;
    A1和A4各自独立选自C3-7亚环烷基、C6-10亚芳基、5至8元亚杂芳基、-O-C6-10亚芳基、-O-5至8元亚杂芳基、5至8元亚杂芳基-O-或C6-10亚芳基-O-，其中所述的亚环烷基、亚芳基或亚杂芳基任选进一步被0至5个选自R6的取代基所取代；A 1 and A 4 are each independently selected from C 3-7 cycloalkylene, C 6-10 arylene, 5 to 8 membered heteroarylene, -OC 6-10 arylene, -O-5 to 8 a meta-heteroaryl group, a 5- to 8-membered heteroarylene-O- or a C 6-10 arylene-O-, wherein the cycloalkylene, arylene or heteroarylene is optionally further 0 to 5 substituents selected from R 6 are substituted;
    A2和A3各自独立选自C1-6亚烷基、C2-6亚烯基或C2-6亚炔基，所述亚烷基、亚烯基或亚炔基任选进一步被0至5个选自F、Cl、Br、I、OH、氰基、C1-4烷基、C1-4烷氧基、苯基或苯基-C1-4亚烷基的取代基所取代；A 2 and A 3 are each independently selected from C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, and the alkylene, alkenylene or alkynylene group is optionally further 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene Replaced
    Y和X各自独立选自键、-O-、-C(＝O)O-、-OC(＝O)-、-S-、-S(＝O)-、-S(＝O)2-、-C(＝O)NR7-、-NR7C(＝O)-、-OC(＝O)NR7-、-NR7C(＝O)O-、-NR7C(＝O)NR7、-NR7S(＝O)2-、-S(＝O)2NR7-、-NR7S(＝O)2NR7或-NR7-；Y and X are each independently selected from the group consisting of a bond, -O-, -C(=O)O-, -OC(=O)-, -S-, -S(=O)-, -S(=O) 2 - , -C(=O)NR 7 -, -NR 7 C(=O)-, -OC(=O)NR 7 -, -NR 7 C(=O)O-, -NR 7 C(=O) NR 7 , -NR 7 S(=O) 2 -, -S(=O) 2 NR 7 -, -NR 7 S(=O) 2 NR 7 or -NR 7 -;
    R6选自F、Cl、Br、I、OH、NH2、羧基、氰基、硝基、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、-OC3-6环烷基、C1-4烷硫基、-S(＝O)-C1-4烷基、-S(＝O)2-C1-4烷基、-C(＝O)-C1-4烷基、-C(＝O)O-C1-4烷基、-OC(＝O)-C1-4烷基、5至6元杂芳基或-C(＝O)NH2，所述烷基、烷氧基、环烷基、烯基、炔基、杂芳基、NH2或-C(＝O)NH2任选进一步被0至4个选自F、Cl、Br、I、CF3、C1-4烷基、C1-4烷氧基或-C(＝O)-C1-4烷基的取代基所取代；R 6 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 Alkoxy, -OC 3-6 cycloalkyl, C 1-4 alkylthio, -S(=O)-C 1-4 alkyl, -S(=O) 2 -C 1-4 alkyl, -C(=O)-C 1-4 alkyl, -C(=O)OC 1-4 alkyl, -OC(=O)-C 1-4 alkyl, 5- to 6-membered heteroaryl or C(=O)NH 2 , the alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, heteroaryl, NH 2 or -C(=O)NH 2 is optionally further further from 0 to 4 Substituted with a substituent selected from F, Cl, Br, I, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or -C(=O)-C 1-4 alkyl;
    R7各自独立选自H或C1-4烷基；R 7 is each independently selected from H or C 1-4 alkyl;
    a为0、1、2、3或4；a is 0, 1, 2, 3 or 4;
    b为0、1、2、3、4或5； b is 0, 1, 2, 3, 4 or 5;
    m、n、p或q各自独立选自0或1。m, n, p or q are each independently selected from 0 or 1.
  2. 根据权利要求1所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中，The compound according to claim 1 or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein
    B选自
    Figure PCTCN2016081809-appb-100005
    Figure PCTCN2016081809-appb-100006
    B is selected from
    Figure PCTCN2016081809-appb-100005
    Figure PCTCN2016081809-appb-100006
    其中Q选自-CH＝CH-、-CH2CH2-、-O-、-S-、-CH2O-、-OCH2-、-C(CH3)2O-或-OC(CH3)2-。Wherein Q is selected from -CH=CH-, -CH 2 CH 2 -, -O-, -S-, -CH 2 O-, -OCH 2 -, -C(CH 3 ) 2 O- or -OC(CH) 3 ) 2 -.
  3. 根据权利要求2所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中，The compound according to claim 2, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein
    R1a选自H、C2-4烯基、C2-4炔基、C3-7碳环基、3至6元杂环基、C3-7碳环基-C1-4亚烷基或3至6元杂环基-C1-4亚烷基，所述烯基、炔基、亚烷基、碳环基或杂环基任选进一步被0至4个选自F、Cl、Br、I、CF3、OH、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基、-O(＝O)C1-4烷基、-(＝O)C1-4烷基、-OC3-6环烷基或C1-4烷硫基的取代基所取代，所述杂环基含有1至3个选自N、O或S的杂原子；R1b选自C2-4烯基、C2-4炔基、C3-7碳环基、3至6元杂环基、C3-7碳环基-C1-4亚烷基或3至6元杂环基-C1-4亚烷基，所述烯基、炔基、亚烷基、碳环基或杂环基任选进一步被0至4个选自F、Cl、Br、I、CF3、OH、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基、-O(＝O)C1-4烷基、-(＝O)C1-4烷基、-OC3-6环烷基或C1-4烷硫基的取代基所取代，所述杂环基含有1至3个选自N、O或S的杂原子；R 1a is selected from the group consisting of H, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 carbocyclyl, 3 to 6 membered heterocyclic, C 3-7 carbocyclyl-C 1-4 alkylene Or a 3- to 6-membered heterocyclic-C 1-4 alkylene group, which is further optionally 0 to 4 selected from F, Cl, or an alkenyl group, an alkynyl group, an alkylene group, a carbocyclic group or a heterocyclic group. , Br, I, CF 3 , OH, NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, -O(=O)C 1-4 alkyl, - Substituted by (=O) C 1-4 alkyl, -OC 3-6 cycloalkyl or C 1-4 alkylthio, the heterocyclic group containing 1 to 3 selected from N, O or S a hetero atom; R 1b is selected from C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 carbocyclyl, 3 to 6 membered heterocyclic, C 3-7 carbocyclyl-C 1-4 An alkylene group or a 3- to 6-membered heterocyclic group-C 1-4 alkylene group, the alkenyl group, alkynyl group, alkylene group, carbocyclic group or heterocyclic group optionally further selected from 0 to 4 selected from F , Cl, Br, I, CF 3 , OH, NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, -O(=O)C 1-4 alkyl Substituted by a substituent of -(=O)C 1-4 alkyl, -OC 3-6 cycloalkyl or C 1-4 alkylthio group, the heterocyclic group containing 1 to 3 selected from N, O Or a hetero atom of S;
    R1c选自H、羟基、氰基、NH2、C1-4烷基、C1-4烷氧基、C1-4烷硫基或-C(＝O)NH2，所述NH2、-C(＝O)NH2或烷基任选进一步被0至2个选自F、Cl、Br、I、羟基、氰基或C1-4烷基的取代基所取代；R 1c is selected from H, hydroxy, cyano, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio or -C(=O)NH 2 , said NH 2 , -C(=O)NH 2 or an alkyl group is optionally further substituted with 0 to 2 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, cyano or C 1-4 alkyl;
    R1e和R1f各自独立选自F、Cl、Br、I、CF3、NH2、OH、氰基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、-NHC1-4烷基或-N(C1-4烷基)2；R 1e and R 1f are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , NH 2 , OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio , -NHC 1-4 alkyl or -N(C 1-4 alkyl) 2 ;
    R6各自独立选自F、Cl、Br、I、OH、NH2、羧基、氰基、硝基、C1-4烷基、C2-4炔基、C1-4烷氧基、-OC3-6环烷基、C1-4烷硫基、-S(＝O)-C1-4烷基、-S(＝O)2-C1-4烷基、-C(＝O)-C1-4烷基、5至6元杂芳基或-C(＝O)O-C1-4烷基，所述烷基、炔基、烷氧基、环 烷基、杂芳基或NH2任选进一步被0至4个选自F、Cl、Br、I、CF3、C1-4烷基、C1-4烷氧基或-C(＝O)-C1-4烷基的取代基所取代。R 6 is each independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, - OC 3-6 cycloalkyl, C 1-4 alkylthio, -S(=O)-C 1-4 alkyl, -S(=O) 2 -C 1-4 alkyl, -C(=O -C 1-4 alkyl, 5- to 6-membered heteroaryl or -C(=O)OC 1-4 alkyl, said alkyl, alkynyl, alkoxy, cycloalkyl, heteroaryl or NH 2 is optionally further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or -C(=O)-C 1-4 alkane Substituted by a substituent.
  4. 根据权利要求3所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中，The compound according to claim 3, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein
    R1a选自H、乙烯基、乙炔基、丙炔基、苯基、环丙烷基、环丁基、环戊基、环己基、环庚基、苯甲基、噻吩基、呋喃基或吡啶基，所述的乙烯基、乙炔基、丙炔基、苯基、环丙烷基、环丁基、环戊基、环己基、环庚基、苯甲基、噻吩基、呋喃基或吡啶基任选进一步被0至4个选自F、Cl、Br、I、CF3、OH、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基或-O(＝O)C1-4烷基的取代基所取代；R 1a is selected from the group consisting of H, vinyl, ethynyl, propynyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, thienyl, furanyl or pyridyl Said vinyl, ethynyl, propynyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, thienyl, furyl or pyridyl optionally Further from 0 to 4 selected from the group consisting of F, Cl, Br, I, CF 3 , OH, NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy or -O ( Substituted by a substituent of a C 1-4 alkyl group;
    R1b选自乙烯基、乙炔基、丙炔基、苯基、环丙烷基、环丁基、环戊基、环己基、环庚基、苯甲基、噻吩基、呋喃基或吡啶基，所述的乙烯基、乙炔基、丙炔基、苯基、环丙烷基、环丁基、环戊基、环己基、环庚基、苯甲基、噻吩基、呋喃基或吡啶基任选进一步被0至4个选自F、Cl、Br、I、CF3、OH、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基或-O(＝O)C1-4烷基的取代基所取代；R 1b is selected from the group consisting of ethenyl, ethynyl, propynyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, thienyl, furanyl or pyridyl, The vinyl, ethynyl, propynyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, thienyl, furanyl or pyridyl groups are optionally further 0 to 4 are selected from the group consisting of F, Cl, Br, I, CF 3 , OH, NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy or -O (=O) Substituting a C 1-4 alkyl substituent;
    R1c选自H、羟基、NH2、甲基、乙基、氰基、甲胺基、二甲基胺基、甲氧基、乙氧基、-CH2OH或-C(＝O)NH2；R 1c is selected from H, hydroxy, NH 2 , methyl, ethyl, cyano, methylamino, dimethylamino, methoxy, ethoxy, -CH 2 OH or -C(=O)NH 2 ;
    R1e和R1f各自独立选自F、Cl、Br、I、CF3、NH2、OH、氰基、甲基、乙基、甲氧基、乙氧基、-NHCH3或-N(CH3)2；R 1e and R 1f are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , NH 2 , OH, cyano, methyl, ethyl, methoxy, ethoxy, -NHCH 3 or -N (CH) 3 ) 2 ;
    R2选自键、亚甲基、亚乙基、亚丙基、亚丁基或亚戊基，所述的亚甲基、亚乙基、亚丙基、亚丁基或亚戊基任选进一步被0至5个选自F、Cl、Br、I、氰基、OH、甲基、乙基、甲氧基或乙氧基的取代基所取代；R 2 is selected from a bond, a methylene group, an ethylene group, a propylene group, a butylene group or a pentylene group, and the methylene, ethylene, propylene, butylene or pentylene group is optionally further 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
    R3选自键、亚甲基、亚乙基、亚丙基、亚丁基、亚戊基或
    Figure PCTCN2016081809-appb-100007
    所述亚甲基、亚乙基、亚丙基、亚丁基、亚戊基或
    Figure PCTCN2016081809-appb-100008
    任选进一步被0至5个选自F、Cl、Br、I、氰基、OH、甲基、乙基、甲氧基或乙氧基的取代基所取代；    R 3 is selected from the group consisting of a bond, a methylene group, an ethylene group, a propylene group, a butylene group, a pentylene group or
    Figure PCTCN2016081809-appb-100007
    The methylene, ethylene, propylene, butylene, pentylene or
    Figure PCTCN2016081809-appb-100008
    Optionally further substituted with from 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
    R4、R5各自独立选自H、甲基或乙基；R 4 and R 5 are each independently selected from H, methyl or ethyl;
    B选自
    Figure PCTCN2016081809-appb-100009
    B is selected from
    Figure PCTCN2016081809-appb-100009
    Figure PCTCN2016081809-appb-100010
    Figure PCTCN2016081809-appb-100010
    A1和A4各自独立选自亚苯基、亚噻吩基、亚呋喃基或亚吡啶基，所述的亚苯基、亚噻吩基、亚呋喃基或亚吡啶基任选进一步被0至4个选自F、Cl、Br、氰基、甲基、乙基、丙基、异丙基、CHF2、CF3、甲氧基、乙氧基、-OCHF2、-OCF3、乙炔基、丙炔基、吡咯基、咪唑基、吡唑基、噻吩基、呋喃基、噻唑基或恶唑基的取代基所取代；A 1 and A 4 are each independently selected from a phenylene group, a thienylene group, a furylene group or a pyridylene group, and the phenylene group, thionylene group, furylene group or pyridylene group is optionally further further 0 to 4 One selected from the group consisting of F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, CHF 2 , CF 3 , methoxy, ethoxy, —OCHF 2 , —OCF 3 , ethynyl, Substituted with a propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl or oxazolyl substituent;
    A2和A3各自独立选自亚甲基、亚乙基、亚丙基、亚丁基或亚戊基；A 2 and A 3 are each independently selected from a methylene group, an ethylene group, a propylene group, a butylene group or a pentylene group;
    Y和X各自独立选自键、-O-、-C(＝O)NR7-、-NR7C(＝O)-、-OC(＝O)NR7-或-NR7C(＝O)O-；Y and X are each independently selected from a bond, -O-, -C(=O)NR 7 -, -NR 7 C(=O)-, -OC(=O)NR 7 - or -NR 7 C(=O )O-;
    R7选自H、甲基、乙基或丙基；R 7 is selected from H, methyl, ethyl or propyl;
    a为0或1；a is 0 or 1;
    b为0、1或2。b is 0, 1, or 2.
  5. 根据权利要求4所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中，The compound according to claim 4, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein
    R1选自
    Figure PCTCN2016081809-appb-100011
    Figure PCTCN2016081809-appb-100012
    R 1 is selected from
    Figure PCTCN2016081809-appb-100011
    Figure PCTCN2016081809-appb-100012
    R2选自键、亚甲基、亚乙基、亚丙基、-CH2CH(CH3)-、-CH2C(CH3)2-、-C(CH3)2CH2-、-CH(CH3)CH2-、亚丁基、-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH(CH3)CH2-或亚戊基；R 2 is selected from the group consisting of a bond, a methylene group, an ethylene group, a propylene group, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -C(CH 3 ) 2 CH 2 -, -CH(CH 3 )CH 2 -, butylene, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )CH 2 - or Amyl group;
    R3选自键、亚甲基、亚乙基、亚丙基、-CH2CH(CH3)-、-CH2C(CH3)2-、-C(CH3)2CH2-、-CH(CH3)CH2-、亚丁基、-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-、 -CH2CH(CH3)CH2-、
    Figure PCTCN2016081809-appb-100013
    或亚戊基；    R 3 is selected from the group consisting of a bond, a methylene group, an ethylene group, a propylene group, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -C(CH 3 ) 2 CH 2 -, -CH(CH 3 )CH 2 -, butylene, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )CH 2 -,
    Figure PCTCN2016081809-appb-100013
    Or pentylene;
    A1和A4各自独立选自亚苯基，所述的亚苯基任选进一步被0至4个任选自F、Cl、Br、CHF2、CF3、氰基、甲基、乙基、乙炔基、甲氧基、乙氧基、-OCHF2、-OCF3、乙炔基、丙炔基、吡咯基、咪唑基或吡唑基的取代基所取代。A 1 and A 4 are each independently selected from a phenylene group, and the phenylene group is further optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, CHF 2 , CF 3 , cyano, methyl, ethyl. Substituted by a substituent of ethynyl, methoxy, ethoxy, -OCHF 2 , -OCF 3 , ethynyl, propynyl, pyrrolyl, imidazolyl or pyrazolyl.
  6. 根据权利要求5所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中，所述的化合物包括：The compound according to claim 5, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound comprises:
    Figure PCTCN2016081809-appb-100014
    Figure PCTCN2016081809-appb-100014
    Figure PCTCN2016081809-appb-100015
    Figure PCTCN2016081809-appb-100015
  7. 一种药物组合物，所述的药物组合物含有治疗有效剂量的权利要求1-6中任一项所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，以及药学上可接受的载体、稀释剂、佐剂、媒介物或赋形剂；所述的组合物还可进一步包括一种或几种其他治疗剂。A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6, or a stereoisomer, hydrate, metabolite, solvate thereof, pharmaceutically acceptable a salt, eutectic or prodrug, and a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle or excipient; said composition may further comprise one or more additional therapeutic agents.
  8. 根据权利要求7所述的药物组合物，其中，所述其他治疗剂选自PDE4抑制剂、M受体拮抗剂、皮质类固醇和β-肾上腺素受体激动剂中的一种或几种。The pharmaceutical composition according to claim 7, wherein the other therapeutic agent is selected from one or more of a PDE4 inhibitor, a M receptor antagonist, a corticosteroid, and a β-adrenoreceptor agonist.
  9. 权利要求1-6中任一项所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，在制备用于治疗气道阻塞性疾病的药物中的应用。A compound according to any one of claims 1 to 6, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, for use in the treatment of airway obstruction The application of drugs for sexual diseases.
  10. 权利要求1-6中任一项所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，在制备用于治疗哮喘、慢性阻塞性肺疾病或支气管炎的药物中的应用。A compound according to any one of claims 1 to 6, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, for use in the treatment of asthma, chronic Use in drugs for obstructive pulmonary disease or bronchitis.
  11. 一种治疗气道阻塞性疾病的方法，所述方法包括给药权利要求1-6中任一项所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，或权利要求7或8所述的药物组合物。A method of treating an airway obstructive disease, the method comprising administering a compound of any one of claims 1 to 6, or a stereoisomer, hydrate, metabolite, solvate thereof, pharmaceutically acceptable a salt, eutectic or prodrug, or a pharmaceutical composition according to claim 7 or 8.
  12. 一种治疗哮喘、慢性阻塞性肺疾病或支气管炎的方法，所述方法包括给药权利要求1-6中任一项所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，或权利要求7或8所述的药物组合物。 A method of treating asthma, chronic obstructive pulmonary disease or bronchitis, the method comprising administering a compound according to any one of claims 1 to 6, or a stereoisomer, hydrate, metabolite, solvate thereof A pharmaceutically acceptable salt, eutectic or prodrug, or a pharmaceutical composition according to claim 7 or 8.
  13. 一种制备通式(I)所示化合物或其立体异构体的中间体，该中间体选自通式(II)所示的化合物或者其立体异构体：An intermediate for the preparation of a compound of the formula (I) or a stereoisomer thereof, which is selected from the group consisting of a compound of the formula (II) or a stereoisomer thereof:
    Figure PCTCN2016081809-appb-100016
    Figure PCTCN2016081809-appb-100016
    其中：among them:
    R1选自
    Figure PCTCN2016081809-appb-100017
    R 1 is selected from
    Figure PCTCN2016081809-appb-100017
    R1a选自H、C2-6烯基、C2-6炔基、C3-10碳环基、3至8元杂环基、C3-10碳环基-C1-4亚烷基或3至8元杂环基-C1-4亚烷基，所述烯基、炔基、亚烷基、碳环基或杂环基任选进一步被0至4个选自F、Cl、Br、I、CH2F、CHF2、CF3、OH、OCH2F、OCHF2、OCF3、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基、-O(＝O)C1-4烷基、-(＝O)C1-4烷基、-OC3-6环烷基或C1-4烷硫基的取代基所取代，所述杂环基含有1至3个选自N、O或S的杂原子；R 1a is selected from the group consisting of H, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3 to 8 membered heterocyclic, C 3-10carbocyclyl -C 1-4 alkylene Or a 3 to 8 membered heterocyclyl-C 1-4 alkylene group, optionally further 0 to 4 selected from the group consisting of F and Cl, the alkenyl, alkynyl, alkylene, carbocyclic or heterocyclic group , Br, I, CH 2 F, CHF 2 , CF 3 , OH, OCH 2 F, OCHF 2 , OCF 3 , NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkane Substituted by a substituent of an oxy group, -O(=O)C 1-4 alkyl, -(=O)C 1-4 alkyl, -OC 3-6 cycloalkyl or C 1-4 alkylthio group, The heterocyclic group contains 1 to 3 hetero atoms selected from N, O or S;
    R1b选自C2-6烯基、C2-6炔基、C3-10碳环基、3至8元杂环基、C3-10碳环基-C1-4亚烷基或3至8元杂环基-C1-4亚烷基，所述烯基、炔基、亚烷基、碳环基或杂环基任选进一步被0至4个选自F、Cl、Br、I、CH2F、CHF2、CF3、OH、OCH2F、OCHF2、OCF3、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基、-O(＝O)C1-4烷基、-(＝O)C1-4烷基、-OC3-6环烷基或C1-4烷硫基的取代基所取代，所述杂环基含有1至3个选自N、O或S的杂原子；R 1b is selected from C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3 to 8 membered heterocyclic, C 3-10carbocyclyl -C 1-4 alkylene or a 3- to 8-membered heterocyclyl-C 1-4 alkylene group, optionally further 0 to 4 selected from the group consisting of F, Cl, and Br, and an alkenyl group, an alkynyl group, an alkylene group, a carbocyclic group, or a heterocyclic group. , I, CH 2 F, CHF 2 , CF 3 , OH, OCH 2 F, OCHF 2 , OCF 3 , NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy Substituted with a substituent of -O(=O)C 1-4 alkyl, -(=O)C 1-4 alkyl, -OC 3-6 cycloalkyl or C 1-4 alkylthio, The heterocyclic group contains 1 to 3 hetero atoms selected from N, O or S;
    R1c选自H、羟基、氰基、NH2、C1-6烷基、C1-6烷氧基、C1-6烷硫基或-C(＝O)NH2，所述NH2、-C(＝O)NH2或烷基任选进一步被0至2个选自F、Cl、Br、I、羟基、氰基或C1-4烷基的取代基所取代；R 1c is selected from H, hydroxy, cyano, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or -C(=O)NH 2 , said NH 2 , -C(=O)NH 2 or an alkyl group is optionally further substituted with 0 to 2 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, cyano or C 1-4 alkyl;
    R1e和R1f各自独立选自F、Cl、Br、I、CF3、NH2、OH、羧基、氰基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、-NHC1-4烷基、-N(C1-4烷基)2、-S(＝O)-C1-4烷基、-S(＝O)2-C1-4烷基或-C(＝O)O-C1-4烷基；R 1e and R 1f are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , NH 2 , OH, carboxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkane Thio group, -NHC 1-4 alkyl group, -N(C 1-4 alkyl) 2 , -S(=O)-C 1-4 alkyl group, -S(=O) 2 -C 1-4 alkane Or a -C(=O)OC 1-4 alkyl group;
    R9选自H或者氨基保护基；R 9 is selected from H or an amino protecting group;
    a为0、1、2、3或4；a is 0, 1, 2, 3 or 4;
    b为0、1、2、3、4或5。b is 0, 1, 2, 3, 4 or 5.
  14. 根据权利要求13所述的中间体，其中： The intermediate of claim 13 wherein:
    R1选自
    Figure PCTCN2016081809-appb-100018
    R 1 is selected from
    Figure PCTCN2016081809-appb-100018
    R9选自H、苄基、对甲氧基苄基、叔丁氧基羰基、苄氧基羰基、乙酰基或苯甲酰基。R 9 is selected from the group consisting of H, benzyl, p-methoxybenzyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl or benzoyl.
  15. 根据权利要求14所述的中间体，所述中间体选自以下化合物之一：The intermediate according to claim 14, wherein the intermediate is selected from one of the following compounds:
    Figure PCTCN2016081809-appb-100019
    Figure PCTCN2016081809-appb-100019
  16. 一种制备通式(I)所示化合物或其立体异构体的中间体，该中间体选自通式(III)所示的化合物或者其立体异构体：An intermediate for the preparation of a compound of the formula (I) or a stereoisomer thereof, which is selected from the group consisting of a compound of the formula (III) or a stereoisomer thereof:
    R1选自
    Figure PCTCN2016081809-appb-100020
    R 1 is selected from
    Figure PCTCN2016081809-appb-100020
    R1a选自H、C2-6烯基、C2-6炔基、C3-10碳环基、3至8元杂环基、C3-10碳环基-C1-4亚烷基或3至8元杂环基-C1-4亚烷基，所述烯基、炔基、亚烷基、碳环基或杂环基任选进一步被0至4个选自F、Cl、Br、I、CH2F、CHF2、CF3、OH、OCH2F、OCHF2、OCF3、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基、-O(＝O)C1-4烷基、-(＝O)C1-4烷基、-OC3-6环烷基或C1-4烷硫基的取代基所取代，所述杂环基含有1至3个选自N、O或S的杂原子；R 1a is selected from the group consisting of H, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3 to 8 membered heterocyclic, C 3-10carbocyclyl -C 1-4 alkylene Or a 3 to 8 membered heterocyclyl-C 1-4 alkylene group, optionally further 0 to 4 selected from the group consisting of F and Cl, the alkenyl, alkynyl, alkylene, carbocyclic or heterocyclic group , Br, I, CH 2 F, CHF 2 , CF 3 , OH, OCH 2 F, OCHF 2 , OCF 3 , NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkane Substituted by a substituent of an oxy group, -O(=O)C 1-4 alkyl, -(=O)C 1-4 alkyl, -OC 3-6 cycloalkyl or C 1-4 alkylthio group, The heterocyclic group contains 1 to 3 hetero atoms selected from N, O or S;
    R1b选自C2-6烯基、C2-6炔基、C3-10碳环基、3至8元杂环基、C3-10碳环基-C1-4亚烷基或3至8元杂环基-C1-4亚烷基，所述烯基、炔基、亚烷基、碳环基或杂环基任选进一步被0至4个选自F、Cl、Br、I、CH2F、CHF2、CF3、OH、OCH2F、OCHF2、OCF3、NH2、羧基、氰基、硝基、C1-4烷基、C1-4烷氧基、-O(＝O)C1-4烷基、-(＝O)C1-4烷基、-OC3-6环烷基或C1-4烷硫基的取代基所取代，所述杂环基含有1至3个选自N、O或S的杂原 子；R 1b is selected from C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclyl, 3 to 8 membered heterocyclic, C 3-10carbocyclyl -C 1-4 alkylene or a 3- to 8-membered heterocyclyl-C 1-4 alkylene group, optionally further 0 to 4 selected from the group consisting of F, Cl, and Br, and an alkenyl group, an alkynyl group, an alkylene group, a carbocyclic group, or a heterocyclic group. , I, CH 2 F, CHF 2 , CF 3 , OH, OCH 2 F, OCHF 2 , OCF 3 , NH 2 , carboxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy Substituted with a substituent of -O(=O)C 1-4 alkyl, -(=O)C 1-4 alkyl, -OC 3-6 cycloalkyl or C 1-4 alkylthio, The heterocyclic group contains 1 to 3 hetero atoms selected from N, O or S;
    R1c选自H、羟基、氰基、NH2、C1-6烷基、C1-6烷氧基、C1-6烷硫基或-C(＝O)NH2，所述NH2、-C(＝O)NH2或烷基任选进一步被0至2个选自F、Cl、Br、I、羟基、氰基或C1-4烷基的取代基所取代；R 1c is selected from H, hydroxy, cyano, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or -C(=O)NH 2 , said NH 2 , -C(=O)NH 2 or an alkyl group is optionally further substituted with 0 to 2 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, cyano or C 1-4 alkyl;
    R1e和R1f各自独立选自F、Cl、Br、I、CF3、NH2、OH、羧基、氰基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、-NHC1-4烷基、-N(C1-4烷基)2、-S(＝O)-C1-4烷基、-S(＝O)2-C1-4烷基或-C(＝O)O-C1-4烷基；R 1e and R 1f are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , NH 2 , OH, carboxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkane Thio group, -NHC 1-4 alkyl group, -N(C 1-4 alkyl) 2 , -S(=O)-C 1-4 alkyl group, -S(=O) 2 -C 1-4 alkane Or a -C(=O)OC 1-4 alkyl group;
    R2选自键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基，所述亚烷基、亚烯基或亚炔基任选进一步被0至5个选自F、Cl、Br、I、OH、氰基、C1-4烷基、C1-4烷氧基、苯基或苯基-C1-4亚烷基的取代基所取代；R 2 is selected from a bond, a C 1-6 alkylene group, a C 2-6 alkenylene group or a C 2-6 alkynylene group, and the alkylene group, alkenylene group or alkynylene group is optionally further 0 to 5 Substituted with a substituent selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
    W选自OH、羧基、-C(＝O)OC1-4烷基、苯基、-C(＝O)NRx-苯基、-ONRxC(＝O)-苯基、-C(＝O)NRx-C1-4亚烷基-C(＝O)OH、-C(＝O)NRx-C1-4亚烷基-C(＝O)OC1-4烷基、-C(＝O)NRx-C1-4亚烷基-C(＝O)NRx-苯基、-C(＝O)NRx-亚苯基-C(＝O)NRx-苯基、
    Figure PCTCN2016081809-appb-100021
    所述的苯基任选进一步被0至4个选自F、Cl、Br、I、甲氧基、乙氧基、
    Figure PCTCN2016081809-appb-100022
    甲酰基、羧基、-C(＝O)OC1-4烷基、
    Figure PCTCN2016081809-appb-100023
    的取代基所取代；    W is selected from OH, carboxyl, -C(=O)OC 1-4 alkyl, phenyl, -C(=O)NR x -phenyl, -ONR x C(=O)-phenyl, -C( =O)NR x -C 1-4 alkylene-C(=O)OH, -C(=O)NR x -C 1-4 alkylene-C(=O)OC 1-4 alkyl, -C(=O)NR x -C 1-4 alkylene-C(=O)NR x -phenyl, -C(=O)NR x -phenylene-C(=O)NR x -benzene base,
    Figure PCTCN2016081809-appb-100021
    The phenyl group is further optionally from 0 to 4 selected from the group consisting of F, Cl, Br, I, methoxy, ethoxy,
    Figure PCTCN2016081809-appb-100022
    Formyl, carboxyl, -C(=O)OC 1-4 alkyl,
    Figure PCTCN2016081809-appb-100023
    Substituted by a substituent;
    Rx选自H或C1-4烷基；R x is selected from H or C 1-4 alkyl;
    R3选自键或C1-6亚烷基，所述亚烷基任选进一步被0至5个选自R3a的取代基所取代，R3a选自F、Cl、Br、I、氰基、OH、C1-4烷基、C1-4烷氧基、苯基或苯基-C1-4亚烷基；作为选择，两个R3a可以与它们相连的原子一起形成一个3至6元碳环，所述碳环任选进一步被0至5个选自F、Cl、Br、I、氰基、OH、C1-4烷基或C1-4烷氧基的取代基所取代；R 3 is selected from a bond or C 1-6 alkylene, said alkylene being optionally further substituted with 0-5 substituents selected from R 3a, R 3a is selected from F, Cl, Br, I, cyano a group, OH, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene; alternatively, two R 3a may form a 3 together with the atoms to which they are attached Up to a 6-membered carbocyclic ring, optionally further substituted with 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl or C 1-4 alkoxy Replaced
    B选自
    Figure PCTCN2016081809-appb-100024
    Figure PCTCN2016081809-appb-100025
    B is selected from
    Figure PCTCN2016081809-appb-100024
    Figure PCTCN2016081809-appb-100025
    其中Q选自-CH＝CH-、-CH2CH2-、-O-、-S-、-CH2O-、-OCH2-、-C(CH3)2O-或-OC(CH3)2-；Wherein Q is selected from -CH=CH-, -CH2CH2-, -O-, -S-, -CH2O-, -OCH2-, -C(CH3)2O- or -OC(CH3)2-;
    a为0、1、2、3或4；a is 0, 1, 2, 3 or 4;
    b为0、1、2、3、4或5。b is 0, 1, 2, 3, 4 or 5.
  17. 根据权利要求16所述的中间体，所述中间体选自以下化合物之一：The intermediate according to claim 16, wherein the intermediate is selected from one of the following compounds:
    Figure PCTCN2016081809-appb-100026
    Figure PCTCN2016081809-appb-100026
    Figure PCTCN2016081809-appb-100027
    Figure PCTCN2016081809-appb-100027
    Figure PCTCN2016081809-appb-100028
    Figure PCTCN2016081809-appb-100028
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