WO2016180349A1 - Dérivé biphényle présentant des activités d'excitation de récepteur bêta2 et des activités antagonistes au récepteur m et son application dans un médicament - Google Patents

Dérivé biphényle présentant des activités d'excitation de récepteur bêta2 et des activités antagonistes au récepteur m et son application dans un médicament Download PDF

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Publication number
WO2016180349A1
WO2016180349A1 PCT/CN2016/081810 CN2016081810W WO2016180349A1 WO 2016180349 A1 WO2016180349 A1 WO 2016180349A1 CN 2016081810 W CN2016081810 W CN 2016081810W WO 2016180349 A1 WO2016180349 A1 WO 2016180349A1
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alkyl
group
methyl
ethyl
cyano
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PCT/CN2016/081810
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English (en)
Chinese (zh)
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魏用刚
邱关鹏
雷柏林
卢泳华
祝国智
郑苏欣
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四川海思科制药有限公司
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Priority to CN201680003441.4A priority Critical patent/CN107108502A/zh
Publication of WO2016180349A1 publication Critical patent/WO2016180349A1/fr

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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • 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
    • 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
    • C07D401/14—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 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to a biphenyl derivative, a preparation method thereof and a medicine application thereof, in particular to a novel piperidine derivative having double activity of muscarinic receptor antagonist and ⁇ 2 -adrenergic receptor agonism. Or a stereoisomer, hydrate, solvate, metabolite, pharmaceutically acceptable salt, eutectic or prodrug thereof, pharmaceutical composition thereof, and its 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.
  • Y is selected from And Y is attached to the 3 or 4 position of the phenylene ring relative to the R 6 group;
  • R x is selected from H or C 1-4 alkyl
  • 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;
  • W is -O- or -NW a -;
  • W a is selected from H or C 1-4 alkyl
  • R 3 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 3a , -C(O)OR 3b , -SR 3c , -S(O)R 3d , -S(O) 2 R 3e or -NR 3f R 3g ; or two R 3 groups combine to form C 1 -3 alkylene, C 2-3 alkenylene or ethylene oxide-2,3-diyl;
  • R 3a , R 3b , R 3c , R 3d , R 3e , R 3f and R 3g are each independently selected from H or C 1-4 alkyl;
  • R 4 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 substituted by 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 alkylene Substituted by a substituent;
  • R 6 is selected from C 1-6 alkylene, which is optionally further substituted with 0, 1 , 2, 3, 4 or 5 substituents selected from R 6a ;
  • R 6a 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 6a 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;
  • R 7 and R 8 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;
  • c is selected from 0, 1, 2, 3 or 4;
  • d is selected from 0, 1, 2, 3 or 4;
  • n 0 or 1
  • n 0, m is 1, 2, 3, 4, 5 or 6; the constraint is that when n is 0, m is 1, 2, 3, 4, 5 or 6;
  • p 0, 1, 2, 3, 4, 5 or 6;
  • R 5 is not a C 2-4 alkynyl group or a 5 to 6 membered heteroaryl group
  • X 2 is selected from -NHCO- or -CONH-
  • a preferred embodiment of the invention a compound of the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:
  • Y is selected from And Y is attached to the 3 or 4 position of the phenylene ring relative to the R 6 group;
  • a selected from Said Optionally further 0, 1, 2 , 3 or 4 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 Substituted by a substituent of -4 alkoxy, -OC 3-6 cycloalkyl or a 5 to 6 membered heteroaryl group, said alkyl group, alkoxy group, cycloalkyl group, alkynyl group, carboxyl group, NH 2 or hetero
  • R x is selected from H or C 1-4 alkyl; preferably H, methyl or ethyl;
  • R 1 and R 2 are each 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, hydroxy, methyl, ethyl, methoxy or ethoxy;
  • W is -O- or -NW a -;
  • W a is selected from H or C 1-4 alkyl; preferably H, methyl or ethyl;
  • R 3 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 3a , -C(O)OR 3b , -SR 3c , -S(O)R 3d , -S(O) 2 R 3e or -NR 3f R 3g ; or two R 3 groups combine to form C 1 -3 alkylene, C 2-3 alkenylene or ethylene oxide-2,3-diyl;
  • R 3a , R 3b , R 3c , R 3d , R 3e , R 3f and R 3g are each independently selected from H or C 1-4 alkyl;
  • R 4 is selected from C 1-6 alkylene; preferably C 1-4 alkylene; more preferably methylene, ethylene or propylene; said alkylene, methylene, ethylene or sub
  • the propyl group is optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl or C 1-4 alkoxy Replaced
  • the alkyl or NH 2 is optionally further 0, 1, 2, 3 or 4 selected from the group consisting of F, Cl, Br, I, CF 3 , C 1-4 alkyl, C 1-4 alkoxy or -C ( Substituted with a substituent of -O 1-4 alky
  • R 6 is selected from C 1-6 alkylene; preferably C 1-4 alkylene; further preferably methylene, ethylene, propylene or The alkylene, methylene, ethylene, propylene or Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R 6a ;
  • R 6a is selected from F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy or phenyl; preferably F, Cl, Br, I, cyano, OH, methyl , ethyl, methoxy or ethoxy;
  • the two R 6a may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached;
  • the carbocyclic ring is optionally further 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; preferably further selected from 0, 1, 2, 3, 4 or 5 selected from F, Cl, Br Substituted by a substituent of I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
  • R 7 and R 8 are each independently selected from H or C 1-4 alkyl; preferably H, methyl or ethyl; further preferably H or methyl;
  • a, b are each independently selected from 0, 1, 2, 3 or 4; preferably 0, 1, 2 or 3;
  • c is selected from 0, 1, 2, 3 or 4;
  • d is selected from 0, 1, 2, 3 or 4;
  • n 0 or 1
  • n 0, m is 1, 2, 3, 4, 5 or 6; the constraint is that when n is 0, m is 1, 2, 3, 4, 5 or 6;
  • p 0, 1, 2, 3, 4, 5 or 6;
  • R 5 is not a C 2-4 alkynyl group or a 5 to 6 membered heteroaryl group
  • X 2 is selected from -NHCO- or -CONH-
  • a preferred embodiment of the invention a compound of the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:
  • Y is selected from And Y is attached to the 3 or 4 position of the phenylene ring relative to the R 6 group;
  • R x is selected from H or C 1-4 alkyl; preferably H, methyl or ethyl;
  • R 1 and R 2 are each 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, hydroxy, methyl, ethyl, methoxy or ethoxy;
  • W is -O- or -NW a -;
  • W a is selected from H or C 1-4 alkyl; preferably H, methyl or ethyl;
  • R 3 each independently selected from the group consisting of F, Cl, Br, I, CF 3 , OH, cyano, C 1-4 alkyl or C 1-4 alkoxy; preferably F, Cl, Br, I, CF 3 , OH, cyano, methyl, ethyl, methoxy or ethoxy;
  • R 4 is selected from C 1-4 alkylene; preferably methylene, ethylene or propylene; the alkylene, methylene, ethylene or propylene 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 4 is preferably methylene, ethylene, propylene, -CH(CH 3 )CH 2 - or -CH 2 CH(CH 3 )-;
  • R 5 is 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, furyl, thiazolyl or oxazolyl;
  • R 6 is selected from C 1-4 alkylene, preferably methylene, ethylene, propylene or The alkylene, methylene, ethylene, propylene or Optionally further substituted with 0, 1, 2, 3, 4 or 5 substituents of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
  • R 6 is preferably methylene, ethylene, propylene, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 - or
  • R 7 and R 8 are each independently selected from H or C 1-4 alkyl; preferably H, methyl or ethyl; further preferably H or methyl;
  • a, b are each independently selected from 0, 1, 2 or 3; preferably 0, 1 or 2;
  • c is selected from 0, 1 or 2; preferably 0;
  • d is selected from 0, 1, 2, 3 or 4;
  • n 0 or 1
  • n 0, 1, 2, 3, 4 or 5; the constraint is that when n is 0, m is 1, 2, 3, 4 or 5;
  • p 0, 1, 2, 3, 4 or 5;
  • a preferred embodiment of the invention a compound of the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:
  • Y is selected from And Y is attached to the 3 or 4 position of the phenylene ring relative to the R 6 group;
  • R x is selected from H, methyl or ethyl
  • R 1 and R 2 are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , cyano, hydroxy, methyl, ethyl, methoxy or ethoxy;
  • W is -O-, -NH- or -NCH 3 -;
  • R 4 is selected from the group consisting of methylene, ethylene, propylene, -CH(CH 3 )CH 2 - or -CH 2 CH(CH 3 )-;
  • R 5 is selected from the group consisting of F, Cl, Br, methyl, ethyl, methoxy, ethoxy, ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl or Oxazolyl;
  • R 6 is selected from the group consisting of methylene, ethylene, propylene, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 - or Preferred is methylene, ethylene or -CH 2 CH(CH 3 )-;
  • R 7 and R 8 are each independently selected from H, methyl or ethyl; preferably H;
  • a or b are each independently selected from 0, 1 or 2; preferably 0;
  • d is selected from 0, 1, 2, 3 or 4;
  • n 0 or 1
  • n 0, 1, 2, 3, 4 or 5; the constraint is that when n is 0, m is 1, 2, 3, 4 or 5;
  • p 0, 1, 2, 3 or 4;
  • the present invention provides a compound represented by the formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof,
  • R x is selected from H or C 1-4 alkyl
  • 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;
  • W is -O- or -NW a -;
  • W a is selected from H or C 1-4 alkyl
  • R 3 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 3a , -C(O)OR 3b , -SR 3c , -S(O)R 3d , -S(O) 2 R 3e or -NR 3f R 3g ; or two R 3 groups combine to form C 1 -3 alkylene, C 2-3 alkenylene or ethylene oxide-2,3-diyl;
  • R 3a , R 3b , R 3c , R 3d , R 3e , R 3f and R 3g are each independently selected from H or C 1-4 alkyl;
  • R 4 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 substituted by 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 alkylene Substituted by a substituent;
  • R 6 is selected from C 1-6 alkylene, which is optionally further substituted with 0, 1 , 2, 3, 4 or 5 substituents selected from R 6a ;
  • R 6a 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 6a 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;
  • R 7 and R 8 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;
  • c is selected from 0, 1, 2, 3 or 4;
  • d is selected from 0, 1, 2, 3 or 4;
  • R 5 is not a C 2-4 alkynyl group or a 5 to 6 membered heteroaryl group, or when d is selected from 0, B is not
  • a preferred embodiment of the invention a compound of the formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • R x is selected from H or C 1-4 alkyl; preferably H, methyl or ethyl;
  • R 1 and R 2 are each 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, hydroxy, methyl, ethyl, methoxy or ethoxy;
  • W is -O- or -NW a -;
  • W a is selected from H or C 1-4 alkyl; preferably H, methyl or ethyl;
  • R 3 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 3a , -C(O)OR 3b , -SR 3c , -S(O)R 3d , -S(O) 2 R 3e or -NR 3f R 3g ; or two R 3 groups combine to form C 1 -3 alkylene, C 2-3 alkenylene or ethylene oxide-2,3-diyl;
  • R 3a , R 3b , R 3c , R 3d , R 3e , R 3f and R 3g are each independently selected from H or C 1-4 alkyl;
  • R 4 is selected from C 1-6 alkylene; preferably C 1-4 alkylene; more preferably methylene, ethylene or propylene; said alkylene, methylene, ethylene or sub
  • the propyl group is optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of F, Cl, Br, I, OH, cyano, C 1-4 alkyl or C 1-4 alkoxy Replaced
  • R 6 is selected from C 1-6 alkylene; preferably C 1-4 alkylene; further preferably methylene, ethylene, propylene or The alkylene, methylene, ethylene, propylene or Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R 6a ;
  • R 6a is selected from F, Cl, Br, I, cyano, OH, C 1-4 alkyl, C 1-4 alkoxy or phenyl; preferably F, Cl, Br, I, cyano, OH, methyl , ethyl, methoxy or ethoxy;
  • two R 6a 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; preferably further selected from 0, 1, 2, 3, 4 or 5 selected from F, Cl, Br , I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
  • R 7 and R 8 are each independently selected from H or C 1-4 alkyl; preferably H, methyl or ethyl; further preferably H or methyl;
  • a, b are each independently selected from 0, 1, 2, 3 or 4; preferably 0, 1, 2 or 3;
  • c is selected from 0, 1, 2, 3 or 4;
  • d is selected from 0, 1, 2, 3 or 4;
  • R 5 is not C 2-4 alkynyl, 5- to 6-membered heteroaryl or ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl, oxazolyl Or tetrazolyl, or when d is selected from 0, B is not
  • a preferred embodiment of the invention a compound of the formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • R x is selected from H or C 1-4 alkyl; preferably H, methyl or ethyl;
  • R 1 and R 2 are each 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, hydroxy, methyl, ethyl, methoxy or ethoxy;
  • W is -O- or -NW a -;
  • W a is selected from H or C 1-4 alkyl; preferably H, methyl or ethyl;
  • R 3 each independently selected from the group consisting of F, Cl, Br, I, CF 3 , OH, cyano, C 1-4 alkyl or C 1-4 alkoxy; preferably F, Cl, Br, I, CF 3 , OH, cyano, methyl, ethyl, methoxy or ethoxy;
  • R 4 is selected from C 1-4 alkylene; preferably methylene, ethylene or propylene; the alkylene, methylene, ethylene or propylene 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 4 is preferably methylene, ethylene, propylene, -CH(CH 3 )CH 2 - or -CH 2 CH(CH 3 )-;
  • R 5 is 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, furyl, thiazolyl, oxazolyl or tetrazolyl; R 5 is more preferably F, Cl, Br, methyl, ethyl, methoxy , ethoxy, ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl, oxazolyl or tetrazolyl;
  • R 6 is selected from C 1-4 alkylene; preferably methylene, ethylene, propylene or The alkylene, methylene, ethylene, propylene or Optionally further substituted with 0, 1, 2, 3, 4 or 5 substituents of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;
  • R 6 is preferably methylene, ethylene, propylene, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 - or
  • R 7 and R 8 are each independently selected from H or C 1-4 alkyl; preferably H, methyl or ethyl; further preferably H or methyl;
  • a, b are each independently selected from 0, 1, 2 or 3; preferably 0, 1 or 2;
  • c is selected from 0, 1 or 2; preferably 0;
  • d is selected from 0, 1, 2, 3 or 4;
  • R 5 is not C 2-4 alkynyl, 5- to 6-membered heteroaryl, ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl, oxazolyl Or tetrazolyl, or when d is selected from 0, B is not
  • a preferred embodiment of the invention a compound of the formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:
  • R x is selected from H, methyl or ethyl
  • R 1 and R 2 are each independently selected from the group consisting of F, Cl, Br, I, CF 3 , cyano, hydroxy, methyl, ethyl, methoxy or ethoxy;
  • W is -O-, -NH- or -NCH 3 -;
  • R 4 is selected from the group consisting of methylene, ethylene, propylene, -CH(CH 3 )CH 2 - or -CH 2 CH(CH 3 )-;
  • R 5 is selected from the group consisting of F, Cl, Br, methyl, ethyl, methoxy, ethoxy, ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl, Oxazolyl or tetrazolyl;
  • R 6 is selected from the group consisting of methylene, ethylene, propylene, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 - or
  • R 7 and R 8 are each independently selected from H, methyl or ethyl
  • a and b are each independently selected from 0, 1 or 2;
  • d is selected from 0, 1, 2, 3 or 4;
  • R 5 is not ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl, oxazolyl or tetrazolyl, or when d is selected from 0, B is not for
  • the invention relates to a compound selected from, but not limited to:
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of formula (I) or a stereoisomer, hydrate, metabolite, solvate thereof, a pharmaceutically acceptable salt, eutectic or prodrug, and a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle or excipient; said composition may further comprise one or more other treatments Agent
  • the other 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 invention further relates to providing a compound of the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, for use in the treatment of the airway Use in drugs for obstructive diseases; preferably, in the preparation of a medicament for the treatment of asthma, chronic obstructive pulmonary disease or bronchitis.
  • the reagent such as saturated sodium bicarbonate solution or saturated sodium carbonate solution
  • an organic solvent such as dichloromethane, ethyl acetate, etc.
  • 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 examples of alkylene 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 alkylene group may be
  • Alkynylene refers to both straight and branched divalent alkynyl groups, and alkynyl groups are as defined above.
  • Carbocycle means a saturated or unsaturated 3 to 10 membered monocyclic or 4 to 12 membered bicyclic ring system, the carbocyclic ring 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, cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl and
  • Heterocycle means a saturated or unsaturated non-aromatic ring which may be a 3 to 10 membered monocyclic ring or a 4 to 12 membered bicyclic ring and contains 1 to 4 heteroatoms selected from N, O or S.
  • a 4- to 8-membered heterocyclic group is preferred, 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 8 members, Non-limiting examples include pyrrolyl, imidazolyl, thiazolyl, thienyl, furyl, pyrazolyl, isoxazolyl, oxazolyl, pyridyl or pyrazinyl.
  • 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 nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the 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
  • TBS refers to tert-butyldimethyl.
  • Step 7 N-[5-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxyethyl]-2-benzyloxyphenylmethane Amide (1H)
  • N-[2-Benzyloxy-5-[(1R)-2-bromo-1-[tert-butyl(dimethyl)silyl]oxyethyl]phenyl]methanesulfonamide (1G) (4.5 g, 8.74 mmol) was dissolved in N,N-dimethylformamide (15 mL), sodium azide (1.1 g, 16.9 mmol) was added, and the mixture was heated to 90 ° C for 6 hours. Cool to room temperature, add water (30 mL) with ethyl acetate (50 mL ⁇ 2) The organic layer was combined, washed with saturated aqueous sodium chloride (30 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and evaporated.
  • Step 8 N-[5-[(1R)-2-Amino-1-[tert-butyl(dimethyl)silyl]oxyethyl]-2-hydroxyphenyl]methanesulfonamide (1I )
  • Step 9 [1-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-hydroxy-3-(methylsulfonate) Amido)phenyl]ethyl]amino]methyl]-2-chloro-5-methoxyaniline]-3-oxopropyl]-4-piperidinyl]N-(2-phenylphenyl Carbamate (1J)
  • Step 10 [1-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-[4-hydroxy-3-(methylsulfonamido)phenyl]ethyl]amino) ]methyl]-5-methoxy-anilino]-3-oxopropyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 1)
  • Step 2 [1-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine) -8-yl)ethyl]amino]methyl]-5-methoxyanilino]-3-oxopropyl]-4-piperidinyl]N-(2-phenylphenyl)carbamic acid Ester (Compound 2)
  • 3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoic acid (3B) (0.1 g, 0.271 mmol) was dissolved in four In hydrogen furan (10 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, CAS: 148893-10-1) was added. (0.206 g, 0.543 mmol), stirred at room temperature for 30 minutes, added 3-amino-1-propanol, and allowed to react at room temperature for 2 hours.
  • HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the third step 3-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]propionylamino]propyl N-(2-chloro-4-methyl Acyl-5-methoxy-phenyl)carbamate (3E)
  • reaction mixture was cooled to room temperature, and then evaporated tolululululululululululu 3-[3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-piperidinyl]propionylamino]propyl N-(2-chloro-4-formyl-5- Methoxy-phenyl)carbamate (3E), yellow solid (40 mg, yield 40%).
  • Ditrifluoroacetate salt of compound 3 3-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]propionylamino]propyl N-[2 -Chloro-4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl] -2-chloro-5-methoxyphenyl]carbamate ditrifluoroacetate
  • Step 2 4-Acetylamino-2-methoxy-5-(2-trimethylsilylacetylene)benzoic acid methyl ester (4C)
  • Trimethylsilylacetylene (0.06 g, 0.7 mmol) was slowly added dropwise at 0 ° C, and after stirring for 15 minutes, the mixture was allowed to react to room temperature for 165 minutes. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjj Methyl oxy-5-(2-trimethylsilylacetylene)benzoate (4C), yellow solid (0.17 g, yield 90%).
  • Methyl 4-acetamido-2-methoxy-5-(2-trimethylsilylacetylene)benzoate (4C) (9.0 g, 28 mmol) was dissolved in tetrahydrofuran (300 mL). To 0 ° C, lithium tetrahydroaluminum (2.4 g, 56 mmol) was added, and after the addition, the reaction was carried out for 2 hours in an ice bath. Water (7 mL) was added dropwise under ice-cooling, and celite was filtered. EtOAc (EtOAc)EtOAc.
  • Step 7 [1-[3-(2-ethynyl-4-formyl-5-methoxyanilino)-3-oxo-propyl]-4-piperidinyl]N-(2- Phenylphenyl)carbamate (4I)
  • Step 8 [1-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-) 4H-quinolin-5-yl)ethyl]amino]methyl]-2-ethynyl-5-methoxy-anilino]-3-oxo-propyl]-4-piperidinyl]N- (2-phenylphenyl)carbamate (4K)
  • N-[4-(Hydroxymethyl)-5-methoxy-2-prop-1-ynyl-phenyl]acetamide (6B) (3.0 g, 13 mmol) was dissolved in dichloromethane (50 mL) The mixture was cooled to 0 ° C under an ice-cooling atmosphere, and then ss. s. oxidant (9.8 g, 23 mmol) was added. After the addition, the reaction was carried out for 2 hours in an ice bath. The mixture was diluted with saturated aqueous sodium hydrogencarbonate, and the mixture was evaporated to dryness. EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (eluent elute elute elute 2-prop-1-ynyl-phenyl)acetamide (6C), pale yellow solid (3.0 g, yield 100%).
  • the fourth step 4-amino-2-methoxy-5-prop-1-ynyl-benzaldehyde (6D)
  • 2-Methoxy-5-prop-1-ynyl-benzaldehyde (6D) yellow solid (0.800 g, yield 32.6%).
  • Step 6 [1-[3-(4-Formyl-5-methoxy-2-prop-1-ynyl-anilino)-3-oxo-propyl]-4-piperidinyl] N-(2-phenylphenyl)carbamate (6F)
  • Step 7 [1-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-) 4H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-2-prop-1-ynyl-anilino]-3-oxo-propyl]-4-piperidine N-(2-phenylphenyl)carbamate (6G)
  • Step 8 [1-[3-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-4H-quinolin-5-yl)ethyl]amino]] Methyl]-5-methoxy-2-prop-1-ynyl-anilino]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate Acid ester (compound 6)
  • the aqueous layer was adjusted to pH with a saturated aqueous solution of sodium bicarbonate, and the mixture was separated and evaporated.
  • the aqueous layer was extracted with dichloromethane (20 mL ⁇ 2), and the organic layer was washed with saturated aqueous sodium chloride (10 mL ⁇ 1).
  • Example 7 3-[3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-piperidinyl]propionylamino]propyl N-[2-chloro-4-[ [[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl]amino Formate; ditrifluoroacetate (compound 7)
  • Second step 3-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]propionylamino]propyl N-[2-chloro-4-[ [[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl]amino
  • a Acid ester di trifluoroacetic acid (compound 7)
  • Free base of compound 7 3-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoylamino]propyl N-[2-chloro-4 -[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl Carbamate
  • Example 8 3-[Methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]amino]propyl N-[2- Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-carbonyl-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy- Phenyl]carbamate ditrifluoroacetate (compound 8)
  • Second step 3-[Methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]amino]propyl N-(2- Chloro-4-formyl-5-methoxy-phenyl)carbamate (8B)
  • the third step 3-[methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]amino]propyl N-[4- [[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-carbonyl-1H-quinolin-5-yl)ethyl]amino]- Base]-2 chloro-5-methoxy-phenyl]carbamate (8C)
  • Step 4 3-[Methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]amino]propyl N-[2- Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-carbonyl-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy- Phenyl]carbamate; ditrifluoroacetate (compound 8)
  • Step 6 [1-[3-(4-Formyl-5-methoxy-2-pyrazol-1-yl-anilino)-3-oxo-propyl]-4-piperidinyl] N-(2-phenylphenyl)carbamate (9F)
  • N-(4-formyl-5-methoxy-2-pyrazol-1-yl-phenyl)prop-2-enamide (9E) (0.180 g, 0.663 mmol) in 2-methyltetrahydrofuran (4 mL), 4-piperidinyl N-(2-phenylphenyl)carbamate (4H) (0.236 g, 0.796 mmol), triethylamine (0.134 g, 1.33 mmol).
  • the microwave was reacted at 100 ° C for 1 hour.
  • the reaction mixture was cooled to room temperature, and the residue was evaporated.
  • Step 7 [1-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-2-pyrazol-1-yl-phenylamino]-3-oxo-propyl]-4-piperidine N-(2-phenylphenyl)carbamate (9G)
  • Step 8 [1-[3-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino] Methyl]-5-methoxy-2-pyrazol-1-yl-phenylamino]-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate Acid ester (compound 9)
  • Example 10 [1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(6-hydroxy-3-oxo-4H-1,4-benzoxazine) 8-(Ethyl)ethyl]amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-4-piperidinyl]-N-(2-phenylphenyl)amino Formate (compound 10)
  • Step 7 8-[(1R)-2-Azido-1-hydroxy-ethyl]-6-benzyloxy-4H-1,4-benzoxazin-3-one (10H)
  • Step 8 8-[(1R)-2-Amino-1-hydroxy-ethyl]-6-hydroxy-4H-1,4-benzoxazin-3-one (10I)
  • Step 9 [1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(6-hydroxy-3-oxo-4H-1,4-benzoxazine) 8-(Ethyl)ethyl]amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-4-piperidinyl]-N-(2-phenylphenyl)amino Formate (compound 10)
  • Example 11 3-[3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-piperidinyl]propionylamino]propyl N-[4-[[[(2R) -2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate; ditrifluoroacetate Compound 11)
  • the third step 3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidinyl]propionylamino]propyl N-[4-[[[(2R) -2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]benzene Carbamate (11C)
  • Second step 3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidinyl]propanoylamino]propyl N-[2-chloro-4-[ [[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]-5-methoxy Phenyl]carbamate (compound 12)
  • Example 13 3-[Methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-piperidinyl]propanoyl]amino]propyl N-[2- Chloro-4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]- 5-methoxyphenyl]aminomethyl ester; ditrifluoroacetate (compound 13)
  • 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 (13C)
  • 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 ug/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 then diluted with 0.1% BSA/phenol red-free Ham's F12 medium to a final concentration of 5.0 ⁇ 10 5 cells/mL.
  • the cells were incubated on a rotary shaker at low speed and incubated for at least 1 hour at room temperature.
  • the compound of the example was dissolved 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 at 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 dissolved in DMSO, diluted in a Stimulation Buffer gradient, and added to a 384-well plate at 5 ⁇ l per well.
  • Example number H ⁇ 2 receptor EC 50 (nM) Compound 1 10.6 Compound 2 0.51 Compound 3 0.71 Compound 4 2.55 Compound 5 1.45 Compound 6 2.45 Compound 7 3.35 Compound 9 6.7 Compound 11 1.15 Compound 12 0.76 Compound 13 0.21
  • 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
  • baftenterol was formulated into a 6 mM stock solution with 83% absolute ethanol + 17% Tween 80, and 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, animals were anesthetized with 5% isoflurane using a small animal anesthesia machine (Matrx; VME2) for an anesthesia time of 1.5-2 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.
  • Batefenterol is prepared by the method disclosed in WO2006023454A1.
  • 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.
  • Test Example 4 Histamine-induced inhibition of bronchial contraction in guinea pigs
  • 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 PenH value was measured using a full volume oximeter (DSI; GS220A12-R7B) at 4 hours and 24 hours. Aerosol was administered with 0.8 mg/ml histamine (His), the atomization time was 1 minute, and the recording time was 5 minutes. Calculate the PenH average.
  • Table 4 results in inhibition of histamine-induced bronchial contraction in guinea pigs
  • the compounds of the present invention have a better inhibitory effect on histamine-induced bronchial contraction in guinea pigs than the positive control, and some compounds still have a good bronchoconstriction inhibitory effect after 24 hours of administration.
  • SD rats Eighteen SD rats, male, 8 weeks old, were purchased in Vitalivic, and the experiment was started after 3 days of adaptation.
  • SD rats were randomly divided into 3 groups. One day before the administration, the rats were fasted to avoid water; the three groups were injected intravenously (iv) or intratracheally (it) 1 mg/kg.
  • the compound was formulated into a mother liquor of 20 mg/mL concentration using 83% ethanol and 17% Tween.
  • 0.1 ml of the stock solution was administered intravenously and orally, and diluted to a final volume by adding 9.9 ml of physiological saline.
  • the intratracheal administration was carried out with 0.25 ml of a stock solution, and diluted with 4.75 ml of physiological saline to a final volume.
  • Intravenous administration group was separated from the eye before administration (0h) and 5min, 15min, 30min, 1.0, 2.0, 4.0, 8.0, 24.0h after the administration, 0.1ml from the eyelid, heparin anticoagulation, centrifuged at 3,000 rpm for 10 min at 4 °C, and separated plasma. Store at -80 ° C for testing.
  • the rats in the intragastric administration and the intratracheal administration group were collected before the administration and 5 minutes, 15 minutes, 30 minutes, 1.0, 2.0, 4.0, 8.0, 24.0 hours after the administration, and the treatment method was the same as the intravenous administration group.

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Abstract

La présente invention concerne un composé représenté dans une formule générale (I) et une formule générale (II) ou un stéréoisomère, un hydrate, un métabolite, un solvate, un sel qui est pharmaceutiquement recevable, des cristaux eutectiques ou un promédicament de celui-ci, son procédé de préparation et son application dans la préparation d'un médicament pour le traitement d'une maladie obstructive des voies respiratoires. Le composé dans une formule générale (I) et une formule générale (II) est tel que représenté dans une figure, une définition de chaque groupe substituant étant en accord avec celle dans la description.
PCT/CN2016/081810 2015-05-14 2016-05-12 Dérivé biphényle présentant des activités d'excitation de récepteur bêta2 et des activités antagonistes au récepteur m et son application dans un médicament WO2016180349A1 (fr)

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WO2019015640A1 (fr) * 2017-07-21 2019-01-24 四川海思科制药有限公司 Sel de dérivé d'amide azacyclique, sa forme cristalline et son procédé de préparation et son utilisation
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WO2019015640A1 (fr) * 2017-07-21 2019-01-24 四川海思科制药有限公司 Sel de dérivé d'amide azacyclique, sa forme cristalline et son procédé de préparation et son utilisation
CN108358791A (zh) * 2018-02-05 2018-08-03 南京法恩化学有限公司 一种3-硝基-4-苄氧基-2-溴代苯乙酮的制备方法
CN110003025A (zh) * 2019-04-29 2019-07-12 天津华津制药有限公司 1-[2-羟基-3-氨基-5-(苄氧基)苯基]-乙酮的制备方法

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