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WO2017114377A1 - Dérivé d'un composé benzyle hétérocyclique et application pharmaceutique correspondante - Google Patents

Dérivé d'un composé benzyle hétérocyclique et application pharmaceutique correspondante Download PDF

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Publication number
WO2017114377A1
WO2017114377A1 PCT/CN2016/112262 CN2016112262W WO2017114377A1 WO 2017114377 A1 WO2017114377 A1 WO 2017114377A1 CN 2016112262 W CN2016112262 W CN 2016112262W WO 2017114377 A1 WO2017114377 A1 WO 2017114377A1
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Prior art keywords
group
alkyl
oxo
methyl
hydroxy
Prior art date
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Ceased
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PCT/CN2016/112262
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English (en)
Chinese (zh)
Inventor
魏用刚
邱关鹏
雷柏林
廖鹏飞
楚洪柱
郑苏欣
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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Priority to CN201680042174.1A priority Critical patent/CN107849035B/zh
Publication of WO2017114377A1 publication Critical patent/WO2017114377A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/47—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
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a phenyl heterocyclic derivative, a preparation method thereof and the use thereof in medicine, in particular to a novel phenyl group having double activity of muscarinic receptor antagonistic activity and ⁇ 2 -adrenergic receptor agonism Heterocyclic 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 1a , R 1b , R 1c , R 1d , R 1e , R 1f and R 1g are each independently selected from H or C 1-4 alkyl;
  • R 1f , R 1g form a 5- to 6-membered heterocyclic ring with a nitrogen atom to which it is bonded, and the heterocyclic ring contains 1 to 3 hetero atoms selected from N, O or S;
  • Ring A is selected from a 5- to 10-membered heterocyclic ring, and the heterocyclic ring is optionally further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, OH, CF 3 , cyano, C 1-4 alkyl, C 2 Substituted by a substituent of -4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy or C 3-6 cycloalkyl, and said heterocyclic ring contains 1 to 4 selected from N, O or a hetero atom of S;
  • W is -O-, -NH- or -NC 1-4 alkyl-;
  • R 2 is independently selected from the group consisting of F, Cl, Br, I, CF 3 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, cyano, -OR 2a , -C(O)OR 2b , -SR 2c , -S(O)R 2d , -S(O) 2 R 2e or -NR 2f R 2g ; or two R 2 groups combine to form C 1 -3 alkylene, C 2-3 alkenylene or ethylene oxide-2,3-diyl;
  • R 2a , R 2b , R 2c , R 2d , R 2e , R 2f and R 2g are each independently selected from H or C 1-4 alkyl;
  • R 3 is 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 selected from 0 to 5 Substituted from a substituent of F, Cl, Br, I, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
  • L is selected from X 1 is directly connected to R 3 ;
  • a 1 and A 4 are each independently selected from C 3-7 cycloalkylene, C 6-10 arylene, 5 to 10 membered heteroarylene, -OC 6-10 arylene, -O-5 to a 10-membered heteroarylene, 5 to 10 membered heteroarylene-O- or C 6-10 arylene-O-, wherein said cycloalkylene, arylene or heteroarylene optionally further Replaced by 0 to 5 R 7 ;
  • 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
  • R x is each independently selected from H or C 1-4 alkyl
  • R x and R 7 are directly bonded to form a 4 to 7 membered nitrogen-containing heterocyclic ring, preferably R x is directly bonded to adjacent R 7 to form a 4 to 7 membered nitrogen-containing heterocyclic ring, said nitrogen-containing heterocyclic ring.
  • R 4 is selected from C 1-6 alkylene, and the alkylene group is optionally further substituted with 0 to 5 R 4a ;
  • R 4a 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 4a 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;
  • R 5 and R 6 are each independently selected from H or C 1-4 alkyl
  • a is selected from 0, 1, 2, 3, 4 or 5;
  • b is selected from 0, 1, 2, 3 or 4;
  • n, m, p or q are each independently selected from 0 or 1;
  • the condition is that L is not a key.
  • a preferred embodiment of the invention a compound of the formula (I) or a stereoisomer, hydrate, metabolite thereof, a solvate, pharmaceutically acceptable salt, eutectic or prodrug, wherein:
  • R 2 is independently selected from the group consisting of F, Cl, Br, I, CF 3 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, cyano, -OR 2a , -C(O)OR 2b , -SR 2c , -S(O)R 2d , -S(O) 2 R 2e or -NR 2f R 2g ; or two R 2 groups combine to form C 1 -3 alkylene, C 2-3 alkenylene or ethylene oxide-2,3-diyl; said "two R 2 groups bonded to form C 1-3 alkylene, C 2-3 An alkenylene group or an ethylene oxide-2,3-diyl group means that two R 2 groups together with the atoms to which they are attached form a 3 to 6 membered saturated carbocyclic ring, a 4 to 5 membered unsaturated carbocyclic ring or an epoxy group. Ethane.
  • a preferred embodiment of the invention is a compound of the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:
  • a preferred embodiment of the invention a compound of the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof,
  • the compound is selected from the group consisting of the compound of the formula (II) or the formula (III):
  • R 1a , R 1b , R 1c , R 1d , R 1e , R 1f and R 1g are each independently selected from H or C 1-4 alkyl;
  • R 1f , R 1g form a 5- to 6-membered heterocyclic ring with a nitrogen atom to which it is bonded, and the heterocyclic ring contains 1 to 3 hetero atoms selected from N, O or S;
  • Ring A is selected from a 5- to 10-membered heterocyclic ring, and the heterocyclic ring is optionally further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, OH, CF 3 , cyano, C 1-4 alkyl, C 2 Substituted by a substituent of -4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy or C 3-6 cycloalkyl, and said heterocyclic ring contains 1 to 4 selected from N, O or a hetero atom of S;
  • W is -O-, -NH- or -NC 1-4 alkyl-;
  • R 2 is independently selected from the group consisting of F, Cl, Br, I, CF 3 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, cyano, -OR 2a , -C(O)OR 2b , -SR 2c , -S(O)R 2d , -S(O) 2 R 2e or -NR 2f R 2g ; or two R 2 groups combine to form C 1 -3 alkylene, C 2-3 alkenylene or ethylene oxide-2,3-diyl;
  • R 2a , R 2b , R 2c , R 2d , R 2e , R 2f and R 2g are each independently selected from H or C 1-4 alkyl;
  • R 3 is 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 selected from 0 to 5 Substituted from a substituent of F, Cl, Br, I, OH, cyano, C 1-4 alkyl, C 1-4 alkoxy, phenyl or phenyl-C 1-4 alkylene;
  • L is selected from X 1 is directly connected to R 3 ;
  • a 1 and A 4 are each independently selected from C 3-7 cycloalkylene, C 6-10 arylene, 5 to 10 membered heteroarylene, -OC 6-10 arylene, -O-5 to a 10-membered heteroarylene, 5 to 10 membered heteroarylene-O- or C 6-10 arylene-O-, wherein said cycloalkylene, arylene or heteroarylene optionally further Replaced by 0 to 5 R 7 ;
  • 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
  • R x is each independently selected from H or C 1-4 alkyl
  • R x and R 7 are directly bonded to form a 4 to 7 membered nitrogen-containing heterocyclic ring, preferably R x is directly bonded to adjacent R 7 to form a 4 to 7 membered nitrogen-containing heterocyclic ring, said nitrogen-containing heterocyclic ring.
  • R 4 is selected from C 1-6 alkylene, and the alkylene group is optionally further substituted with 0 to 5 R 4a ;
  • R 4a 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 4a 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;
  • R 5 and R 6 are each independently selected from H or C 1-4 alkyl
  • a is selected from 0, 1, 2, 3, 4 or 5;
  • b is selected from 0, 1, 2, 3 or 4.
  • a preferred embodiment of the invention a compound of the formula (I), (II), or (III) or a stereoisomer, hydrate, metabolite, solvate or pharmaceutically acceptable salt thereof , eutectic or prodrug, of which:
  • R 1 is independently selected from the group consisting of F, Cl, Br, I, CF 3 , C 1-4 alkyl, cyano, hydroxy or C 1-4 alkoxy, preferably F, Cl, Br, I, CF 3 , Cyano, OH, methyl, ethyl, methoxy or ethoxy;
  • Ring A is selected from a 5- to 10-membered heterocyclic ring, preferably a thienyl group, a benzothienyl group, a thiazolyl group, a benzothiazolyl group, a furyl group, a benzofuranyl group, an oxazolyl group, a benzoxazolyl group or a pyridyl group.
  • W is -O-, -NH- or -NC 1-4 alkyl-, preferably -O-, -NH-, -NCH 3 - or -NCH 2 CH 3 -;
  • R 2 is independently selected from the group consisting of F, Cl, Br, I, CF 3 , C 1-4 alkyl, cyano, hydroxy or C 1-4 alkoxy, or two R 2 groups are combined to form C 1- 3 alkylene, C 2-3 alkenylene or ethylene oxide-2,3-diyl, each independently of R 2 is preferably F, Cl, Br, I, CF 3 , cyano, OH, methyl, Ethyl, methoxy or ethoxy;
  • R 3 is selected from C 1-4 alkylene, preferably methylene, ethylene, propylene or butylene, and the alkylene, methylene, ethylene, propylene or butylene is optional Further substituted with 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl or C 1-4 alkoxy;
  • L is selected from X 1 is directly connected to R 3 ;
  • a 1 and A 4 are each independently selected from a C 3-7 cycloalkylene group, a C 6-10 arylene group or a 5 to 10 membered heteroarylene group, preferably a phenylene group, a thienylene group, a furylene group, a pyridylene group. Or a benzotriazole group, wherein the cycloalkylene, arylene, heteroarylene, phenylene, thienylene, furanyl, pyridylene or benzotriazole The base is optionally further substituted by 0 to 5 R 7 ;
  • a 2 and A 3 are each independently selected from C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, preferably C 1-6 alkylene, more preferably C 1-5 alkylene. Further, a methylene group, an ethylene group, a propylene group or a butylene group, an alkylene group, an alkenylene group, an alkynylene group, a methylene group, an ethylene group, a propylene group or a butylene group is optional.
  • R x each independently selected from H or C 1-4 alkyl, preferably H, methyl, ethyl or propyl;
  • R x and R 7 are directly bonded to form a 4 to 7 membered nitrogen-containing heterocyclic ring, preferably R x is directly bonded to adjacent R 7 to form a 4 to 7 membered nitrogen-containing heterocyclic ring, said nitrogen-containing heterocyclic ring.
  • R 4 is selected from C 1-4 alkylene, preferably methylene, ethylene, propylene, butylene or The alkylene, methylene, ethylene, propylene, butylene or Optionally further substituted by 0 to 5 R 4a ;
  • R 4a is selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy or phenyl, preferably F, Cl, Br, I, cyano, OH, A Base, ethyl, methoxy, ethoxy or phenyl;
  • two R 4a 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;
  • R 5 and R 6 are each independently selected from H or C 1-4 alkyl, preferably H, methyl or ethyl;
  • a is selected from 0, 1, 2, 3, 4 or 5;
  • b is selected from 0, 1, 2, 3 or 4;
  • n, m, p or q are each independently selected from 0 or 1;
  • the condition is that L is not a key.
  • a preferred embodiment of the invention a compound of the formula (I), (II), or (III) or a stereoisomer, hydrate, metabolite, solvate or pharmaceutically acceptable salt thereof , eutectic or prodrug, of which:
  • R 1 is each independently selected from the group consisting of F, Cl, Br, I, CF 3 , cyano, OH, methyl, ethyl, methoxy or ethoxy;
  • Ring A is selected from a 5- to 10-membered heterocyclic ring, preferably a thienyl group, a benzothienyl group, a thiazolyl group, a benzothiazolyl group, a furyl group, a benzofuranyl group, an oxazolyl group, a benzoxazolyl group or a pyridyl group, Optimal The heterocyclic ring, thienyl, benzothienyl, thiazolyl, benzothiazolyl, furyl, benzofuranyl, oxazolyl, benzoxazolyl, pyridyl, Optionally further substituted with 0 to 4 substituents selected from the group consisting of F, Cl, Br, I, OH, CF 3 , cyano, methyl, ethyl, ethynyl, methoxy or ethoxy, and
  • the heterocyclic ring contains 1 to 4 hetero atoms selected from
  • R 2 is independently selected from the group consisting of F, Cl, Br, I, CF 3 , cyano, OH, methyl, ethyl, methoxy or ethoxy;
  • R 3 is selected from C 1-4 alkylene, preferably methylene, ethylene, propylene or butylene, and the alkylene, methylene, ethylene, propylene or butylene is optional Further substituted with 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
  • L is selected from X 1 is directly connected to R 3 ;
  • a 1 and A 4 are each independently selected from a C 3-7 cycloalkylene group, a C 6-10 arylene group or a 5 to 10 membered heteroarylene group, preferably a phenylene group, a thienylene group, a furylene group, a pyridylene group. a phenylene triazole group, more preferably a phenylene group, a thienylene group, a furylene group, a pyridylene group, Wherein the cycloalkylene, arylene, heteroarylene, phenylene, thienylene, furanyl, pyridylene, benzotriazolyl or Optionally further substituted by 0 to 5 R 7 ;
  • R 7 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , carboxyl, cyano, C 1-4 alkyl, C 2-4 alkynyl, C 1-4 alkoxy, -OC 3-6 ring Alkyl or 5- to 6-membered heteroaryl, more preferably F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, CHF 2 , CF 3 , methoxy, ethoxy, - OCHF 2 , -OCF 3 , ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl or oxazolyl, preferably F, Cl, Br, cyano, methyl, Ethyl, propyl, isopropyl, CHF 2 , CF 3 , methoxy, ethoxy, -OCHF 2 ,
  • a 2 and A 3 are each independently selected from a C 1-6 alkylene group, more preferably a C 1-5 alkylene group, still more preferably a methylene group, an ethylene group, a propylene group or a butylene group, the alkylene group , methylene, ethylene, propylene or butylene, optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl, C 1-4 alkane Substituted by a substituent of an oxy group, a phenyl group or a phenyl-C 1-4 alkylene group;
  • R x each independently selected from H or C 1-4 alkyl, preferably H, methyl, ethyl or propyl;
  • R x and R 7 are directly bonded to form a 4 to 7 membered nitrogen-containing heterocyclic ring, preferably R x is directly bonded to adjacent R 7 to form a 4 to 7 membered nitrogen-containing heterocyclic ring, said nitrogen-containing heterocyclic ring.
  • R 4 is selected from C 1-4 alkylene, preferably methylene, ethylene, propylene, butylene or The alkylene, methylene, ethylene, propylene, butylene or Optionally further substituted by 0 to 5 R 4a ;
  • R 4a is selected from the group consisting of F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy or phenyl, preferably F, Cl, Br, I, cyano, OH, A Base, ethyl, methoxy, ethoxy or phenyl;
  • two R 4a 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;
  • R 5 and R 6 are each independently selected from H or C 1-4 alkyl, preferably H, methyl or ethyl;
  • a is selected from 0, 1, 2, 3, 4 or 5, preferably 0, 1 or 2;
  • b is selected from 0, 1, 2, 3 or 4, preferably 0;
  • n, m, p or q are each independently selected from 0 or 1;
  • the condition is that L is not a key.
  • a preferred embodiment of the invention a compound of the formula (I), (II), or (III) or a stereoisomer, hydrate, metabolite, solvate or pharmaceutically acceptable salt thereof , eutectic or prodrug, of which:
  • R 1 is each independently selected from the group consisting of F, Cl, Br, I, CF 3 , cyano, OH, methyl, ethyl, methoxy or ethoxy;
  • Ring A is selected from the group consisting of thienyl, benzothienyl, thiazolyl, benzothiazolyl, furyl, benzofuranyl, oxazolyl, benzoxazolyl or pyridyl, preferably The thienyl, benzothienyl, thiazolyl, benzothiazolyl, furyl, benzofuranyl, oxazolyl, benzoxazolyl, pyridyl, Optionally further substituted with from 0 to 4 substituents selected from the group consisting of F, Cl, Br, I, OH, CF 3 , cyano, methyl, ethyl, ethynyl, methoxy or ethoxy;
  • W is selected from -O-, -NH-, -NCH 3 - or -NCH 2 CH 3 -;
  • R 2 is independently selected from the group consisting of F, Cl, Br, I, CF 3 , cyano, OH, methyl, ethyl, methoxy or ethoxy;
  • R 3 is selected from the group consisting of methylene, ethylene, propylene, -CH(CH 3 )CH 2 - or -CH 2 CH(CH 3 )-;
  • L is selected from X 1 is directly connected to R 3 ;
  • a 1 and A 4 are each independently selected from phenylene, thienylene, furanyl, pyridylene or benzotriazolyl, preferably phenylene, thienylene, furanyl, pyridylene or Wherein the phenylene group, the thienylene group, the furylene group, the pyridylene group, the benzotriazole group, Optionally further substituted by 0 to 5 R 7 ;
  • R 7 is selected from the group consisting of F, Cl, Br, CHF 2 , CF 3 , cyano, methyl, ethyl, ethynyl, methoxy, ethoxy, -OCHF 2 , -OCF 3 , ethynyl, propynyl , pyrrolyl, imidazolyl or pyrazolyl,
  • a 2 and A 3 are each independently selected from a methylene group, an ethylene group, a propylene group or a butylene group;
  • R x each independently selected from H or C 1-4 alkyl, preferably H, methyl, ethyl or propyl;
  • R x and R 7 are directly bonded to form a 4 to 7 membered nitrogen-containing heterocyclic ring, preferably R x is directly bonded to adjacent R 7 to form a 4 to 7 membered nitrogen-containing heterocyclic ring, said nitrogen-containing heterocyclic ring.
  • R 4 is selected from the group consisting of methylene, ethylene, propylene, -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
  • R 5 and R 6 are each independently selected from H or C 1-4 alkyl, preferably H, methyl or ethyl;
  • a is selected from 0, 1, 2, 3, 4 or 5, preferably 0, 1 or 2;
  • b is selected from 0, 1, 2, 3 or 4, preferably 0;
  • n, m, p or q are each independently selected from 0 or 1;
  • the condition is that L is not a key.
  • the invention relates to a compound selected from, but not limited to:
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of formula (I), (II) or (III) or a stereoisomer thereof, hydrated , metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug, and a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle or excipient; said composition may be further Including one or more additional therapeutic agents; preferably, wherein the additional therapeutic agent is selected from the group consisting of a PDE4 inhibitor, a muscarinic receptor antagonist, a corticosteroid, and a beta-adrenergic receptor agonist or A variety.
  • the present invention also relates to providing a compound of the formula (I), (II) or (III) or a stereoisomer, hydrate, metabolism thereof a product, solvate, pharmaceutically acceptable salt, eutectic or prodrug or pharmaceutical composition as described above for use in the manufacture of a medicament for the treatment of an airway obstructive disease, preferably in the preparation of a medicament for the treatment of asthma, chronic Use in drugs for obstructive pulmonary disease or bronchitis.
  • the present invention also provides a method of treating an airway obstructive disease, the method comprising administering a compound of any one of the above formula (I), (II) or (III) or a stereoisomer thereof, Hydrates, metabolites, solvates, pharmaceutically acceptable salts, eutectic or prodrugs, or pharmaceutical compositions as described above.
  • the present invention also provides a method of treating asthma, chronic obstructive pulmonary disease or bronchitis, the method comprising administering a compound according to any one of the above formula (I), (II) or (III) or Stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts, eutectic or prodrugs, or pharmaceutical compositions as described above.
  • the present invention provides an intermediate for preparing a compound of the formula (I) or a stereoisomer thereof, which is selected from a compound represented by the formula (I-M) or a stereoisomer thereof:
  • R m is selected from H, an amino protecting group, -R 3 -COOH, -R 3 -COOC 1-4 alkyl,
  • R n is selected from -CHO, C(OC 1-4 alkyl) 2 or
  • the amino protecting group is preferably a tert-butyloxycarbonyl group
  • P is selected from a hydroxy protecting group, preferably a benzyl or tert-butyldimethylsilyl;
  • the compound represented by the formula (IM) includes, but is not limited to, one of the following structures:
  • 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 Wait.
  • 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 means a straight-chain or branched divalent alkenyl group, and 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 both straight and branched divalent alkynyl groups, and alkynyl groups are 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.
  • Carbocycle or “carbocyclyl” means a saturated or unsaturated 3 to 10 membered monocyclic or 4 to 12 membered bicyclic ring system, and the carbocyclic ring may be attached to a bridged or spiro ring, non-limiting examples including cyclopropyl Base, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl -2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl and
  • Heterocycle or “heterocyclyl” means a saturated or unsaturated non-aromatic ring, and the non-aromatic ring may be a 3 to 10 membered monocyclic ring or a 4 to 12 membered bicyclic ring, and contains 1 to 4 selected from N,
  • the hetero atom of O or S is preferably a 4- to 8-membered heterocyclic group, and the optionally substituted N, S 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.
  • 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 10 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.
  • ⁇ -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.
  • “Hydroxy protecting group” includes, but is not limited to, the following groups: benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, tri-tert-butyl Silicon group, methyl group, tert-butyl group, allyl group, triphenylmethyl group, methoxymethyl group, ethoxymethyl group, methoxyethoxymethyl group, benzyloxymethyl group, one a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a benzoyl group or a t-butyl acyl group, the benzyl group, the benzyloxymethyl group and the benzoyl group being optionally selected from 0 to 5 selected from C 1 Substituted to a C 4 alkyl group, a C 1 -C 4 alkoxy
  • 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 resulting from the spatial arrangement of atoms in a molecule, including cis and trans isomers, enantiomers and conformational isomers.
  • Effective dose refers to the amount of a compound that causes a physiological or medical response to 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.
  • 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).
  • the NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, 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 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.
  • M is a mole per liter.
  • the room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.
  • Bn means benzyl
  • Boc means a tert-butyloxycarbonyl group.
  • TBS refers to tert-butyldimethyl.
  • TFA trifluoroacetic acid
  • 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 (intermediate 1)
  • Ethyl 5-bromothiazole-4-carboxylate (1A) (10.00 g, 42.36 mmol) was dissolved in tert-butanol (100 mL), and tetratriphenylphosphine palladium (2.447 g, 2.118 mmol) was added sequentially under nitrogen.
  • Anhydrous sodium carbonate (17.96 g, 169.4 mmol) and phenylboric acid (10.33 g, 84.71 mmol) were added and heated to 90 ° C for 5 hours.
  • Ethyl 5-phenylthiazole-4-carboxylate (1B) (0.150 g, 0.643 mmol) was dissolved in EtOAc (2 mL). The reaction was carried out at 90 ° C for 30 minutes. Under ice-cooling, 2M hydrochloric acid was added dropwise to adjust the pH to 2, and extracted with dichloromethane (50 mL ⁇ 2). The organic layer was combined, washed with saturated aqueous sodium chloride (20 mL ⁇ 1), dried over anhydrous sodium sulfate After concentration, the crude 5-phenylthiazole-4-carboxylic acid (1C) was obtained as a pale yellow solid (0.120 g, yield: 90.9%).
  • Step 6 [1-[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-phenylamino]-3-oxo-propyl]-4-piperidinyl]-N-( 5-phenylthiazol-4-yl)carbamate (1I)
  • Step 7 [1-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-4-piperidinyl]-N-(5-phenylthiazol-4-yl)carbamate Ditrifluoroacetate (Compound 1)
  • the reaction solution was poured off, and the remaining viscous material was added to tetrahydrofuran (10 mL), stirred for 1 minute, the supernatant was removed, and the viscous material was added to tetrahydrofuran (10 mL), stirred for 1 minute, the supernatant was removed, and the viscous material was added to the dichloride.
  • Methane / methanol (v / v) 9 / 1 mixed solution (100mL)
  • Methyl 3-bromothiophene-2-carboxylate (2A) (10.00 g, 45.23 mmol) was dissolved in tert-butanol (100 mL) and tetratriphenylphosphine palladium (2.614 g, 2.262 mmol)
  • Anhydrous sodium carbonate (19.18 g, 180.9 mmol) and phenylboric acid (11.03 g, 90.47 mmol) were added and heated to 90 ° C for 5 hours. After cooling to room temperature, water (100 mL), ethyl acetate (500 mL) was evaporated and evaporated.
  • Methyl 3-phenylthiophene-2-carboxylate (1B) (8.30 g, 38.0 mmol) was dissolved in ethanol (20 mL), EtOAc (EtOAc) The reaction was carried out at ° C for 30 minutes. Under ice-cooling, 2M hydrochloric acid was added dropwise to adjust the pH to 2, and extracted with dichloromethane (50 mL ⁇ 2).
  • Step 5 [1-[3-(2-Chloro-4-formyl-5-methoxyanilino)-3-oxo-propyl]-4-piperidinyl]-N-(3- Phenyl-2-thienyl)carbamate (2F)
  • Step 6 [1-[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-phenylamino]-3-oxo-propyl]-4-piperidinyl]N-(3 -phenyl-2-thienyl)carbamate (2G)
  • Step 7 [1-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-4-piperidinyl]-N-(3-phenyl-2-thienyl)carbamate (Compound 2)
  • the reaction solution was poured off, and the remaining viscous material was added to tetrahydrofuran (10 mL), stirred for 1 minute, the supernatant was removed, and the viscous material was added to tetrahydrofuran (10 mL), stirred for 1 minute, the supernatant was removed, and the viscous material was added to the dichloride.
  • Methane / methanol (v / v) 9 / 1 mixed solution (100mL)
  • Methyl 4-bromothiophene-3-carboxylate (3A) (1.0 g, 4.523 mmol) was dissolved in tert-butanol (10 mL) and tetratriphenylphosphine palladium (0.1568 g, 0.1357 Methyl), sodium carbonate (1.918 g, 18.09 mmol) and phenylboronic acid (1.1 g, 9.04 mmol) were heated to 90 ° C for 5 hours. After cooling to room temperature, water (10 mL), ethyl acetate (50 mL) was evaporated, evaporated, evaporated, evaporated.
  • Methyl 4-phenylthiophene-3-carboxylate (3B) (1.4 g, 6.4 mmol) was dissolved in ethanol (15 mL). Heat to 90 ° C for 30 minutes. Under ice-cooling, 2M-hydrochloric acid was added dropwise to adjust to pH 2, and extracted with dichloromethane (50 mL ⁇ 2). The organic layer was combined, washed with saturated aqueous sodium chloride (20 mL ⁇ 1), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified and purified eluted eluted eluted eluted eluted (3C), white solid (1.1 g, yield 84%).
  • Step 3 4-[(4-Phenyl-3-thienyl)carbamoyloxy]piperidine-1-carboxylic acid tert-butyl ester (3D)
  • Step 5 [1-[3-(2-Chloro-4-formyl-5-methoxyanilino)-3-oxo-propyl]-4-piperidinyl]-N-(4- Phenyl-3-thienyl)carbamate (3F)
  • Step 6 [1-[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-phenylamino]-3-oxo-propyl]-4-piperidinyl]-N-( 4-phenyl-3-thienyl)carbamate (3G)
  • Step 7 [1-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-phenylamino]-3-oxo-propyl]-4-piperidinyl]-N-(4-phenyl-3-thienyl)carbamic acid Ester; ditrifluoroacetate (compound 3)
  • the first one separation and purification of the liquid phase preparation column (liquid phase preparation conditions: C18 reverse phase preparation column, the mobile phase is deionized water (A) containing 0.05% TFA, acetonitrile (B), isocratic elution of 25% acetonitrile, The elution time was 20 minutes) to give [1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5) -yl)ethyl]amino]methyl]-5-methoxy-phenylamino]-3-oxo-propyl]-4-piperidinyl]-N-(4-phenyl-3-thienyl Carbamate; ditrifluoroacetate (compound 3), white solid (0.15 g, yield 22%).
  • the methyl 2-bromothiophene-3-carboxylate (4A) (1.0 g, 4.523 mmol) was dissolved in tert-butanol (10 mL), and then, under nitrogen, the starting material, tetratriphenylphosphine palladium (0.1568 g, 0.1357 mmol) Sodium carbonate (1.918 g, 18.09 mmol) and phenylboric acid (1.1 g, 9.04 mmol) were added and heated to 90 ° C for 5 hours. After cooling to room temperature, water (10 mL), ethyl acetate (50 mL) was evaporated, evaporated, evaporated, evaporated.
  • Step 3 4-[(2-Phenyl-3-thienyl)carbamoyloxy]piperidine-1-carboxylic acid tert-butyl ester (4D)
  • 2-Phenylthiophene-3-carboxylic acid (4C) (1.1 g, 5.4 mmol) was suspended in dry toluene (20 mL), and 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.6 g) 8.1 mmol), diphenyl azide (1.5 g, 5.4 mmol) and triethylamine (1.1 g, 11 mmol). After the addition, the mixture was stirred at room temperature for 1 hour and then heated to 120 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAc m. 3-Thienyl)carbamoyloxy]piperidine-1-carboxylic acid tert-butyl ester (4D), white solid (1.6 g, yield 74%).
  • Step 5 [1-[3-(2-Chloro-4-formyl-5-methoxyanilino)-3-oxo-propyl]-4-piperidinyl]-N-(2- Phenyl-3-thienyl)carbamate (4F)
  • Step 6 [1-[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-phenylamino]-3-oxo-propyl]-4-piperidinyl]-N-( 2-phenyl-3-thienyl)carbamate (4G)
  • Step 7 [1-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-4-piperidinyl]N-(2-phenyl-3-thienyl)carbamate; Ditrifluoroacetate (Compound 4)
  • the mixture was adjusted to pH 9 with a saturated aqueous solution of sodium bicarbonate, extracted with dichloromethane (50 mL ⁇ 1), washed with saturated brine (20 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered and evaporated.
  • Phase preparation 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), isocratic elution of 25% acetonitrile, elution time 20 minutes ), [1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl) Amino]methyl]-5-methoxy-phenylamino]-3-oxo-propyl]-4-piperidinyl]N-(2-phenyl-3-thienyl)carbamic acid; Fluoroacetate (Compound 4), white solid (0.3 g, yield 40%).
  • Example 5 [1-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]anilino]5-oxo-pentanyl]-methyl-amino]-3-oxo-propyl]-4-piperidinyl]N-(5-phenylthiazole- 4-yl)carbamate; ditrifluoroacetate (compound 5)
  • the third step 5-[methyl-[3-[4-[(5-phenylthiazol-4-yl)carbamoyloxy]-1-piperidinyl]propanoyl]amino]pentanoic acid (5C )
  • the reaction solution was added with dichloromethane (50 mL) and water (50 mL).
  • 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 and filtered and evaporated.
  • Step 5 [1-[3-[[5-(4-Formylanilino]-5-oxo-pentanyl]-methyl-amino]-3-oxo-propyl]-4- Piperidinyl]N-(5-phenylthiazol-4-yl)carbamate (5E)
  • Step 6 [1-[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-pentanyl]-methyl-amino]-3-oxo-propyl]-4- Piperidinyl]N-(5-phenylthiazol-4-yl)carbamate (5F)
  • Step 7 [1-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]anilino]5-oxo-pentanyl]-methyl-amino]-3-oxo-propyl]-4-piperidinyl]N-(5-phenylthiazole- 4-yl)carbamate; ditrifluoroacetate (compound 5)
  • the fluorate (0.886 g, 5.49 mmol) was reacted at room temperature for 24 hours.
  • the reaction solution was added with a 10% (v/v) methanol/dichloromethane (50 mL) solution, and a saturated sodium hydrogencarbonate solution was added to adjust the pH to about 8.
  • the aqueous phase was extracted with 10% (v/v) methanol / dichloromethane (50 mL x 2).
  • Example 7 [1-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazole- 7-yl)ethyl]amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-4-piperidinyl]N-(2-phenyl-3-thienyl) Carbamate; ditrifluoroacetate (compound 7)
  • Example 8 [1-[3-[5-[[[[(2S)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino] Methyl]benzotriazol-1-yl]propyl]-4-piperidinyl]N-(2-phenyl-3-thienyl)carbamic acid; ditrifluoroacetate (compound 8)
  • EtOAc EtOAc EtOAc (EtOAc)
  • 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), isocratic elution of 25% acetonitrile, Elution time 20 minutes), [1-[3-[5-[[[(2S)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]benzotriazol-1-yl]propyl]-4-piperidinyl]N-(2-phenyl-3-thienyl)carbamic acid; ditrifluoroacetate Compound 8), white solid (0.060 g, yield 9.98%).
  • Methyl 3-chlorobenzothiophene-2-carboxylate (9A) (4 g, 17.65 mmol) was dissolved in toluene (25 mL), phenyl boronic acid (4.3 g, 35.29 mmol), potassium phosphate (9.36 g, 44. ). After the addition was completed, the mixture was stirred at room temperature for 10 minutes, the nitrogen gas was replaced 3 times, and 1,2-bis(diphenylphosphino)ethane nickel chloride (1.4 g, 2.65 mmol) was added under nitrogen atmosphere. After the addition, the nitrogen was replaced 3 times, 120 The reaction was carried out at ° C for 4 hours. After cooling to room temperature, the reaction was quenched with water (50 mL).
  • Methyl 3-phenylbenzothiophene-2-carboxylate (9B) (1.3 g, 4.83 mmol) was dissolved in ethanol (15 mL), EtOAc (EtOAc, EtOAc. The reaction was carried out at 90 ° C for 2 hours. After cooling to room temperature, water (25 mL) was added, and the mixture was adjusted to pH 2 with 2M hydrochloric acid, and extracted with dichloromethane (50 mL ⁇ 2). 3-Phenylbenzothiophene-2-carboxylic acid (9C), white solid (1 g, yield 81.96%).
  • Step 3 4-[(3-Phenylbenzothiophen-2-yl)carbamoyloxy]piperidine-1-carboxylic acid tert-butyl ester (9D) tert-butyl4-[(3-phenylbenzothiophen-2) -yl)carbamoyloxy]piperidine-1-carboxylate
  • 3-Phenylbenzothiophene-2-carboxylic acid (9C) (1 g, 3.93 mmol) was dissolved in toluene (20 mL), diphenyl azide (1.08 g, 3.93 mmol), triethylamine (795 mg) , 7.86 mmol), 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.18 g, 5.895 mmol). After stirring at room temperature for 1 hour under nitrogen atmosphere, the temperature was raised to 120 ° C for 3 hours.
  • Step 5 [1-[3-(2-Chloro-4-formyl-5-methoxy-phenylamine)-3-oxo-propyl-4-piperidinyl]N-(3-phenyl Benzothiophen-2-yl)carbamate (9F)
  • Step 6 [1-[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-aniline]-3-oxo-propyl]-4-piperidinyl]N-(3-benzene Benzothiophen-2-yl)carbamate (9G)
  • EtOAc EtOAc [[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]- 2-chloro-5-methoxy-aniline]-3-oxo-propyl]-4-piperidinyl]N-(3-phenylbenzothiophen-2-yl)carbamate (9G), white solid, used directly in the next step without purification.
  • Step 7 [1-[3-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino) ]methyl]-5-methoxy-aniline]-3-oxo-propyl]-4-piperidinyl]N-(3-phenylbenzothiophen-2-yl)carbamate (compound) 9)
  • 1-(3-Bromopropyl)benzotriazole-5-carbaldehyde (8A) (0.5 g, 1.88 mmol) was dissolved in acetonitrile (15 mL), and 4-piperidinyl-N-(5-benzene) was added.
  • the thiothiazol-4-yl)carbamate (1E) (567 mg, 1.88 mmol), N,N-diisopropylethylamine (486 mg, 3.76 mmol) was reacted at 85 ° C for 4 hours. After cooling to room temperature, water (50 mL) was added, and ethyl acetate (50 mL ⁇ 2) was evaporated.
  • Example 11 [1-[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-phenylamino]-3-oxo-propyl]-4-piperidinyl]-N-( 4-phenylthiazole-5-yl)carbamic acid; ditrifluoroacetate (compound 11)
  • Step 2 4-[(4-Bromothiazol-5-yl)carbamoyloxy]piperidine-1-carboxylic acid tert-butyl ester (11C)
  • Step 3 4-[(4-Phenylthiazole-5-yl)carbamoyloxy]piperidine-1-carboxylic acid tert-butyl ester (11D)
  • Step 5 [1-[3-(2-Chloro-4-formyl-5-methoxyanilino)-3-oxo-propyl]-4-piperidinyl]N-(4-benzene Thiazole-5-yl)carbamate (11F)
  • Step 6 [1-[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-phenylamino]-3-oxo-propyl]-4-piperidinyl]N-(4 -phenylthiazole-5-yl) Carbamate (11G)
  • Step 7 [1-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-4-piperidinyl]N-(4-phenylthiazol-5-yl)carbamate; Ditrifluoroacetate (Compound 11)
  • Example 12 [1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-4-piperidinyl]-N-(2-methyl-4-phenyl-thiazole-5 -yl)formate;ditrifluoroacetate (compound 12)
  • 2-Methylthiazole-5-carboxylic acid (12A) (4.3 g, 30 mmol) was suspended in toluene (50 mL), and 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (7.3 g, 36 mmol) was added.
  • Diphenylphosphonium phosphate (9.1 g, 33 mmol) and triethylamine (6.1 g, 60 mmol) were stirred at room temperature for 1 hour, and heated at 120 ° C for 1 hour. After cooling to room temperature, water (100 mL) was added, and ethyl acetate (100 mL ⁇ 1) was evaporated.
  • -[(2-Methylthiazol-5-yl)carbamoyloxy]piperidine-1-carboxylic acid tert-butyl ester (12B) white solid (9.0 g, yield 88%).
  • Step 2 4-[(4-Bromo-2-methyl-thiazol-5-yl)carbamoyloxy]piperidine-1-carboxylic acid tert-butyl ester (12C)
  • Step 3 4-[(2-Methyl-4-phenyl-thiazol-5-yl)carbamoyloxy]piperidine-1-carboxylic acid tert-butyl ester (12D)
  • Step 5 [1-[3-(2-Chloro-4-formyl-5-methoxyanilino)-3-oxo-propyl]-4-piperidinyl]-N-(2- Methyl-4-phenyl-thiazol-5-yl)carbamate (12F)
  • reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified (jjjjjjjj 4-formyl-5-methoxyanilino)-3-oxo-propyl]-4-piperidinyl]-N-(2-methyl-4-phenyl-thiazol-5-yl)amino Formate (12F), yellow solid (1.0 g, yield 47%).
  • Step 6 [1-[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]-4-piperidinyl]N-(2- Methyl-4-phenyl-thiazol-5-yl)carbamate (12G)
  • reaction solution was added with dichloromethane (30 mL) and saturated sodium hydrogen sulfate (30 mL) and evaporated.
  • 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 then filtered, evaporated, evaporated,]] ⁇ -(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl ]-4-piperidinyl]N-(2-methyl-4-phenyl-thiazol-5-yl)carbamate (12G), yellow solid (0.4 g, yield 80%).
  • Step 7 [1-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-4-piperidinyl]-N-(2-methyl-4-phenyl-thiazole-5 -yl)formate;ditrifluoroacetate (compound 12)
  • the third step [1-[3-[5-[[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino] Methyl]benzotriazol-1-yl]propyl]-4-piperidinyl]N-(2-phenyl-3-thienyl)carbamate; ditrifluoroacetate (compound 13)
  • reaction solution was added with dichloromethane (30 mL) and a saturated sodium hydrogen carbonate solution (30 mL).
  • 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 then filtered, evaporated,]]] ⁇ -[4-[tert-Butyl(dimethyl)silyl]oxy-2-oxo-3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]benzotriazole 1-yl]propyl]-4-piperidinyl]N-(2-phenyl-3-thienyl)carbamate (15G), yellow solid (1.3 g, yield 98%).
  • reaction mixture was adjusted to pH with a saturated aqueous sodium hydrogen carbonate aqueous solution and extracted with 8% (v/v) methanol/dichloromethane (100mL ⁇ 1), and the organic phase was saturated sodium chloride solution (50mL ⁇ 1) Washing, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure.
  • 2-Bromo-3-thiophenecarboxylic acid (16A) (6.00 g, 29.0 mmol) was dissolved in toluene (150 ml), and diphenyl azide (7.98 g, 29.0 mmol), 4-hydroxypiperidine- 1-carboxylic acid tert-butyl ester (CAS: 109384-19-2) (8.76 g, 43.5 mmol) and triethylamine (5.85 g, 57.9 mmol), after the addition, reacted at room temperature for 1 hour under nitrogen atmosphere, then warmed to The reaction was carried out at 120 ° C for 3 hours.
  • Step 2 4-[[2-(3-Chlorophenyl)-3-thienyl]carbamoyloxy]piperidine-1-carboxylic acid tert-butyl ester (16C)
  • Step 4 [1-[3-(2-Chloro-4-aldehyde-5-methoxy-phenylamine)-3-oxo-propyl]-4-piperidinyl]N-[2-( 3-chlorophenyl)-3-thienyl]carbamate (16E)
  • Step 5 [1-[3-[4-[[[(2S)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl]aminomethyl]-2-chloro-5-methoxy-aniline]-3-oxo-propyl]-4-piperidinyl]N-[2-(3 -Chlorophenyl)-3-thienyl]carbamate (16F)
  • Step 6 [1-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-aniline]-3-oxo-propyl]-4-piperidinyl]N-[2-(3-chlorophenyl)-3-thienyl] Carbamate (Compound 16)
  • Example 17 [1-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-aniline]-3-oxo-propyl]-4-piperidinyl]N-[2-(2-fluorophenyl)-3-thienyl] Carbamate; ditrifluoroacetate (compound 17)
  • Step 5 [1-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-aniline]-3-oxo-propyl]-4-piperidinyl]N-[2-(2-fluorophenyl)-3-thienyl] Carbamate; ditrifluoroacetate (compound 17)
  • Example 18 [1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-aniline]-3-oxo-propyl]-4-piperidinyl]N-[2-(3-fluorophenyl)-3-thienyl] Carbamate; ditrifluoroacetate (compound 18)
  • Step 5 [1-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-aniline]-3-oxo-propyl]-4-piperidinyl]N-[2-(3-fluorophenyl)-3-thienyl] Carbamate; ditrifluoroacetate (compound 18)
  • Step 5 [1-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]-5-methoxy-aniline]-3-oxo-propyl]-4-piperidinyl]N-[2-(4-fluorophenyl)-3-thienyl] Carbamate; ditrifluoroacetate (compound 19)
  • Example 20 [1-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-4-piperidinyl]N-(2-phenyl-3 -thienyl)carbamate; ditrifluoroacetate (compound 20)
  • N-(4-(1,3-dioxolan-2-yl)phenyl)-5-chloropentanamide (20B) (1.50 g, 5.29 mmol), 20 mL of ethanol was added to the sealed tube, and potassium iodide was added thereto. 175 mg, 1.06 mmol) and 40% aqueous methylamine solution (20.5 g, 264 mmol), plus After completion and sealing, the temperature was raised to 100 ° C for 3 hours. After cooling, 80 mL of water was added, and the mixture was extracted with methylene chloride (100 mL ⁇ 2). The organic phase was combined, washed with brine (50 mL ⁇ 2), dried over anhydrous sodium sulfate and filtered. (1,3-Oxopentan-2-yl)phenyl]-5-(methylamino)pentanamide (20C), pale yellow solid (1.20 g, yield 81.6%).
  • N-[4-(1,3-Oxopentan-2-yl)phenyl]-5-(methylamino)pentanamide (20C) (1.86 g, 6.68 mmol) was dissolved in dichloromethane (20 mL) , 3-[4-[(2-phenyl-3-thienyl)carbamoyloxy]-1-piperidinyl]propionic acid (prepared by reference 5A) (2.50 g, 6.68 mmol), 1-B 3-(3-dimethylpropylamine) carbodiimide hydrochloride (1.78 g, 10.0 mmol), 1-hydroxybenzotriazole (1.35 g, 10.0 mmol) and triethylamine (1.35 g, 13.4 mmol) ), after the addition was completed, the reaction was kept at room temperature for 2 hours.
  • Step 5 [1-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-4-piperidinyl]N-(2-phenyl-3 -thienyl)carbamate; ditrifluoroacetate
  • 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. 50 ⁇ L per well. 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.
  • 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 detached with 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 x 10 5 cells/mL.
  • Stimulation Buffer (1 x HBSS, 5 mM HEPES, 0.5 mM IBMX, 0.1% BSA, pH 7.4
  • the compounds of the examples were formulated as 10 mM stock solutions in DMSO, diluted in a Stimulation Buffer gradient and added to 384 well plates at 5 [mu]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. Prior to administration, the animals were anesthetized with 5% isoflurane using a small animal anesthesia machine (Matrx; VME2) 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 obvious contraction inhibition on acetylcholine-induced bronchial bronchus, and some compounds still have good bronchoconstriction inhibition effect after 24 hours of administration.

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Abstract

La présente invention concerne un composé représenté par la formule (I) ou un stéréo-isomère, un hydrate, un métabolite ou un solvate correspondant ou un sel pharmaceutiquement acceptable, un eutectique ou un promédicament de ce composé. L'invention concerne également un procédé de préparation du composé et une application dans la préparation d'un médicament pharmaceutique pour le traitement d'une maladie d'obstruction des voies respiratoires. Chaque substituant dans le composé représenté par la formule (I) est tel que décrit dans la description.
PCT/CN2016/112262 2015-12-29 2016-12-27 Dérivé d'un composé benzyle hétérocyclique et application pharmaceutique correspondante Ceased WO2017114377A1 (fr)

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WO1995021820A1 (fr) * 1994-02-10 1995-08-17 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive du carbamate et composition correspondante
WO2004005262A2 (fr) * 2002-07-02 2004-01-15 Schering Corporation Nouveaux antagonistes des recepteurs du neuropeptide y y5
CN1482912A (zh) * 2000-12-21 2004-03-17 ���鹫˾ 杂芳基脲神经肽yy5受体拮抗剂
WO2008096870A1 (fr) * 2007-02-09 2008-08-14 Astellas Pharma Inc. Composé à cycle à pont aza

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ES2329586T3 (es) * 2003-11-21 2009-11-27 Theravance, Inc. Compuestos que tienen actividad agonista del receptor beta2 adrenergico y antagonista del receptor muscarino.
EP1833822A2 (fr) * 2004-08-16 2007-09-19 Theravance, Inc. Composes a activite agoniste pour recepteur beta2 adrenergique et antagoniste pour recepteur muscarinique
CN101395150A (zh) * 2006-03-08 2009-03-25 阿斯利康(瑞典)有限公司 用作β2肾上腺素受体激动剂的苯乙醇胺衍生物
GB0613154D0 (en) * 2006-06-30 2006-08-09 Novartis Ag Organic Compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995021820A1 (fr) * 1994-02-10 1995-08-17 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive du carbamate et composition correspondante
CN1482912A (zh) * 2000-12-21 2004-03-17 ���鹫˾ 杂芳基脲神经肽yy5受体拮抗剂
WO2004005262A2 (fr) * 2002-07-02 2004-01-15 Schering Corporation Nouveaux antagonistes des recepteurs du neuropeptide y y5
WO2008096870A1 (fr) * 2007-02-09 2008-08-14 Astellas Pharma Inc. Composé à cycle à pont aza

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