WO2017054702A1 - Dérivé biphényle et son procédé de préparation et son utilisation en médecine - Google Patents

Dérivé biphényle et son procédé de préparation et son utilisation en médecine Download PDF

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WO2017054702A1
WO2017054702A1 PCT/CN2016/100307 CN2016100307W WO2017054702A1 WO 2017054702 A1 WO2017054702 A1 WO 2017054702A1 CN 2016100307 W CN2016100307 W CN 2016100307W WO 2017054702 A1 WO2017054702 A1 WO 2017054702A1
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ring
methyl
ethyl
alkyl
group
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PCT/CN2016/100307
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English (en)
Chinese (zh)
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郑苏欣
张国彪
张晓波
王文晶
李航
杜勇
邱关鹏
魏用刚
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四川海思科制药有限公司
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Priority to CN201680038333.0A priority Critical patent/CN107849047B/zh
Publication of WO2017054702A1 publication Critical patent/WO2017054702A1/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
    • 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
    • A61K31/44—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
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/435—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
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • 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
    • C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—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 one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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 biphenyl derivative, a preparation method thereof and application in medicine, in particular to a novel piperidine derivative having muscarinic receptor antagonistic activity or a stereoisomer, hydrate or solvate thereof. , metabolites, pharmaceutically acceptable salts, eutectic or prodrugs, pharmaceutical compositions thereof, as well as methods for their preparation and use in medicine.
  • Bronchodilators play an important role in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma.
  • a muscarinic receptor (M receptor) antagonist exerts potency in bronchiectasis by reducing the level of vagal cholinergic energy in airway smooth muscle. Based on the effects and side effects of the treatment, the inhaled M receptor antagonist is preferred, but not orally.
  • Inhaled M receptor antagonists currently used in the clinic include ipratropium bromide, oxitropium bromide, glycopyrrolate, tiotropium bromide, adiponium bromide and indole bromide.
  • ipratropium bromide and oxitropium bromide are short-acting drugs, which need to be administered several times a day, which brings inconvenience to patients, and frequent administration may result in poor compliance, and thus there is a risk of inadequate treatment.
  • Adipramine is administered twice daily and may cause serious adverse reactions, including contradictory bronchospasm, new-angled glaucoma or aggravation, new urinary retention or exacerbation, and should not be used in patients under 18 years of age. .
  • Some M receptor antagonists are administered by inhalation, and some drugs enter the circulatory system, leading to systemic side effects such as dry mouth, gastrointestinal symptoms, urinary retention, and urinary tract infections.
  • Such drugs are glycopyrrolate and tiotropium bromide.
  • the M receptor antagonists used in the clinic are not highly selective for the M receptor subtypes (M1, M2, M3, M4 and M5), and after entering the circulatory system, an adverse reaction is caused.
  • the M2 receptor is also widely expressed in the heart, producing a negative heart rate and a negative inotropic effect, and inhibition of the cardiac M2 receptor can cause a heart-related disease. Therefore, for airway obstructive diseases such as asthma and COPD, a better M receptor antagonist should have a higher affinity for M1 and M3 and a lower affinity for M2.
  • novel M receptor-reactive active drugs especially by inhalation of novel M receptors with high titer, long acting time, reduced system side effects and/or high selectivity M1/M2, M3/M2. Antagonistic active drugs. Provide patients with more clinical medication options.
  • WO2005087737A1 describes a class of biphenyl derivatives, compounds having M receptor antagonistic activity, which have the general formula Different from the present invention.
  • WO2005087736A1 describes a class of biphenyl derivatives, compounds having M receptor antagonistic activity, the general formula of which is Different from the present invention.
  • the present invention provides a compound represented by the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof.
  • 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 or 2;
  • d or e are each independently selected from 0 or 1;
  • 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;
  • W is selected from -O-, -NH- or -NC 1-4 alkyl-;
  • Ring A is selected from And the N-position carbon atom is directly connected to W, said Optionally further substituted by 0, 1, 2 , 3 , 4 or 5 selected from F, Cl, Br, I, CF 3 , OH, cyano, C 1-4 alkyl or C 1-4 alkoxy Substituted by
  • R q is independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl
  • Ring B is selected from a C 6-12 carbocyclic ring or a 5 to 12 membered heterocyclic ring, and the carbocyclic or heterocyclic ring may be a monocyclic ring or a bicyclic ring, and the carbocyclic or heterocyclic ring may be further further 0.
  • Ring C is selected from a 4 to 10 membered nitrogen-containing heterocyclic ring, and said aza-containing heterocyclic ring is optionally further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from R c , and said The nitrogen-containing heterocycle contains 1, 2 or 3 heteroatoms selected from N, O or S;
  • R 3 is independently selected from OH, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, -NR 3a R 3b or -C 1-4 alkyl-NR 3a R 3b ;
  • R 3a and R 3b are each independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl;
  • R 3a , R 3b together with the atoms to which they are attached form a 3 to 6 membered nitrogen-containing heterocyclic ring, or R 3a is directly bonded to R c to form a 3 to 6 membered nitrogen-containing heterocyclic ring;
  • ring A is selected from And ring B is selected from a benzene ring or a monocyclic hetero ring, and R 3 is selected from -NR 3a R 3b , and when R 3a and R c are not directly bonded to form a 3 to 6 membered nitrogen-containing hetero ring, ring C cannot be q is selected from 0, 1, 2 or 3;
  • 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 or 2;
  • d or e are each independently selected from 0 or 1;
  • 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, preferably H, methyl or ethyl;
  • W is selected from -O-, -NH- or -NC 1-4 alkyl-, preferably -O-, -NH- or -NCH 3 -;
  • Ring A is selected from And the N-position carbon atom is directly connected to W, said Optionally further substituted by 0, 1, 2 , 3 , 4 or 5 selected from F, Cl, Br, I, CF 3 , OH, cyano, C 1-4 alkyl or C 1-4 alkoxy Substituted, preferably further 0, 1, 2 , 3 , 4 or 5 selected from the group consisting of F, Cl, Br, I, CF 3 , OH, cyano, methyl, ethyl, methoxy or ethoxy Substituted by a substituent;
  • R q is independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, preferably H, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;
  • Ring C is selected from Said Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R c ;
  • Ar 1 is selected from a benzene ring, a thiophene ring, a furan ring or a pyrrole ring, preferably a benzene ring, and the benzene ring, thiophene ring, furan ring or pyrrole ring is optionally further selected from 0, 1, 2, 3 or 4 Substituted with a substituent of F, Cl, Br, I, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 2-4 alkynyl, preferably further Substituting 1, 1, 2, 3 or 4 substituents of F, Cl, Br, I, CF 3 , OH, cyano, NH 2 , methyl, ethyl, methoxy, ethoxy or ethynyl;
  • R 3 is independently selected from OH, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, -NR 3a R 3b or -C 1-4 alkyl-NR 3a R 3b Preferred is OH, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, -NR 3a R 3b , -CH 2 -NR 3a R 3b or -CH 2 CH 2 -NR 3a R 3b ;
  • R 3a and R 3b are each independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, preferably H, methyl, ethyl, cyclopropyl or cyclobutyl;
  • R 3a , R 3b together with the atoms to which they are attached form a 3 to 6 membered nitrogen-containing heterocyclic ring, or R 3a is directly bonded to R c to form a 3 to 6 membered nitrogen-containing heterocyclic ring;
  • a preferred embodiment of the invention a compound of the formula (II) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof:
  • a, b are 0;
  • c is selected from 0, 1 or 2;
  • d or e are each independently selected from 0 or 1;
  • W is selected from -O-, -NH- or -NCH 3 -;
  • Ring A is selected from And the N-position carbon atom is directly connected to W;
  • R q is independently selected from H, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;
  • Ring C is selected from Said Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R c when ring C is selected from When N is directly connection;
  • Ar 1 is selected from a benzene ring, a thiophene ring, a furan ring or a pyrrole ring, preferably a benzene ring, and the benzene ring, thiophene ring, furan ring or pyrrole ring is optionally further selected from 0, 1, 2, 3 or 4 Substituted with a substituent of F, Cl, Br, I, CF 3 , OH, cyano, NH 2 , methyl, ethyl, methoxy, ethoxy or ethynyl;
  • R 3 is independently selected from OH, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, -NR 3a R 3b , -CH 2 -NR 3a R 3b or -CH 2 CH 2 -NR 3a R 3b ;
  • R 3a and R 3b are each independently selected from the group consisting of H, methyl, ethyl, cyclopropyl or cyclobutyl;
  • R 3a , R 3b together with the atoms to which they are attached form a 3 to 6 membered nitrogen-containing heterocyclic ring, or R 3a is directly bonded to R c to form a 3 to 6 membered nitrogen-containing heterocyclic ring;
  • 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 or 2;
  • d or e are each independently selected from 0 or 1;
  • n is selected from 0, 1, 2 or 3;
  • 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, preferably H, methyl or ethyl;
  • W is selected from -O-, -NH- or -NC 1-4 alkyl-, preferably -O-, -NH- or -NCH 3 -;
  • Ring A is selected from And the N-position carbon atom is directly connected to W, said Optionally further being 0, 1, 2 , 3 , 4 or 5 selected from the group consisting of F, Cl, Br, I, CF 3 , OH, cyano, C 1-4 alkyl or C 1-4 alkoxy Substituted by a substituent, preferably further selected from 0, 1, 2 , 3 , 4 or 5 selected from the group consisting of F, Cl, Br, I, CF 3 , OH, cyano, methyl, ethyl, methoxy or ethoxy Substituted by a substituent of the group;
  • R q is independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, preferably H, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;
  • substituents selected from the group consisting of F, Cl, Br, I, CF 3 , O, OH, NH 2 , cyano, methyl, ethyl, methoxy, ethoxy or ethynyl Substituted, the heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O or S;
  • R 4 is independently selected from the group consisting of F, Cl, Br, I, CF 3 , OH, NH 2 , cyano, C 1-4 alkyl, C 1-4 alkoxy or C 2-4 alkynyl, preferably F , Cl, Br, I, CF 3 , OH, cyano, NH 2 , methyl, ethyl, methoxy, ethoxy or ethynyl;
  • Ring C is selected from Said Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R c , and the nitrogen-containing heterocycle contains 1, 2 or 3 heterologously selected from N, O or S atom;
  • R c is independently selected from the group consisting of F, Cl, Br, I, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, -NHC 1-4 alkyl or -N(C 1-4 alkyl) 2 , preferably F, Cl, Br, I, CF 3 , OH, cyano, NH 2 , methyl, Ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 or -N(CH 2 CH 3 ) 2 ;
  • R 3 is independently selected from OH, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, -NR 3a R 3b or -C 1-4 alkyl-NR 3a R 3b , preferably OH, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, -NR 3a R 3b, -CH 2 -NR 3a R 3b or -CH 2 CH 2 -NR 3a R 3b ;
  • R 3a and R 3b are each independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, preferably H, methyl, ethyl, cyclopropyl or cyclobutyl;
  • R 3a , R 3b together with the atoms to which they are attached form a 3 to 6 membered nitrogen-containing heterocyclic ring, or R 3a and R c are directly bonded to form a 3 to 6 membered nitrogen-containing heterocyclic ring.
  • a preferred embodiment of the invention a compound of the formula (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof:
  • a, b are 0;
  • c is selected from 0, 1 or 2;
  • d or e are each independently selected from 0 or 1;
  • n is selected from 0, 1, 2 or 3;
  • W is selected from -O-, -NH- or -NCH 3 -;
  • Ring A is selected from And the N-position carbon atom is directly connected to W;
  • R q is independently selected from H, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;
  • R 4 is each independently selected from the group consisting of F, Cl, Br, I, CF 3 , OH, cyano, NH 2 , methyl, ethyl, methoxy, ethoxy or ethynyl;
  • Ring C is selected from Said Optionally further substituted with 0 to 5 substituents selected from R c ;
  • R c is independently selected from the group consisting of F, Cl, Br, I, CF 3 , OH, cyano, NH 2 , methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio a group, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 or -N(CH 2 CH 3 ) 2 ;
  • R 3 is independently selected from OH, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, -NR 3a R 3b , -CH 2 -NR 3a R 3b or -CH 2 CH 2 -NR 3a R 3b;
  • R 3a and R 3b are each independently selected from the group consisting of H, methyl, ethyl, cyclopropyl or cyclobutyl;
  • R 3a , R 3b together with the atoms to which they are attached form a 3 to 6 membered nitrogen-containing heterocyclic ring, or R 3a and R c are directly bonded to form a 3 to 6 membered nitrogen-containing heterocyclic ring.
  • 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 or 2;
  • d or e are each independently selected from 0 or 1;
  • f 0, 1, 2, 3, 4 or 5;
  • n 0, 1, 2 or 3;
  • 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, preferably H, methyl or ethyl;
  • W is selected from -O-, -NH- or -NC 1-4 alkyl-, preferably -O-, -NH- or -NCH 3 -;
  • R q is independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, preferably H, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;
  • Ar 2 is selected from a benzene ring, a thiophene ring, a furan ring or a pyrrole ring, preferably a benzene ring, and the benzene ring, thiophene ring, furan ring or pyrrole ring is optionally further selected from 0, 1, 2, 3 or 4 Substituted with a substituent of F, Cl, Br, I, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 2-4 alkynyl, preferably further 1, 2, 3 or 4 substituents selected from the group consisting of F, Cl, Br, I, CF 3 , OH, cyano, NH 2 , methyl, ethyl, methoxy, ethoxy or ethynyl Replace
  • R 5 is selected from the group consisting of F, Cl, Br, I, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 Alkylthio, -NHC 1-4 alkyl or -N(C 1-4 alkyl) 2 , preferably F, Cl, Br, I, CF 3 , OH, cyano, NH 2 , methyl, ethyl, Cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 or -N(CH 2 CH 3 ) 2 ;
  • R 3 is independently selected from OH, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, -NR 3a R 3b or -C 1-4 alkyl-NR 3a R 3b Preferred is OH, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, -NR 3a R 3b , -CH 2 -NR 3a R 3b or -CH 2 CH 2 -NR 3a R 3b ;
  • R 3a and R 3b are each independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, preferably H, methyl, ethyl, cyclopropyl or cyclobutyl;
  • R 3a , R 3b together with the atoms to which they are attached form a 3 to 6 membered nitrogen-containing heterocyclic ring, or R 3a and R 5 are directly bonded to form a 3 to 6 membered nitrogen-containing heterocyclic ring.
  • a preferred embodiment of the invention a compound of the formula (IV) or (V) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof:
  • a, b are 0;
  • c is selected from 0, 1 or 2;
  • d or e are each independently selected from 0 or 1;
  • f 0, 1, 2, 3, 4 or 5;
  • n 0, 1, 2 or 3;
  • W is selected from -O-, -NH- or -NCH 3 -;
  • R q is independently selected from H, methyl, ethyl, propyl, cyclopropyl or cyclobutyl;
  • Ar 2 is selected from a benzene ring, a thiophene ring, a furan ring or a pyrrole ring, preferably a benzene ring, and the benzene ring, thiophene ring, furan ring or pyrrole ring is optionally further selected from 0, 1, 2, 3 or 4 Substituted with a substituent of F, Cl, Br, I, CF 3 , OH, cyano, NH 2 , methyl, ethyl, methoxy, ethoxy or ethynyl;
  • R 3 is independently selected from OH, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, -NR 3a R 3b , -CH 2 -NR 3a R 3b or -CH 2 CH 2 -NR 3a R 3b ;
  • R 3a and R 3b are each independently selected from the group consisting of H, methyl, ethyl, cyclopropyl or cyclobutyl;
  • R 5 is selected from the group consisting of F, Cl, Br, I, CF 3 , OH, cyano, NH 2 , methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio, - NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 or -N(CH 2 CH 3 ) 2 ;
  • R 3a , R 3b together with the atoms to which they are attached form a 3 to 6 membered nitrogen-containing heterocyclic ring, or R 3a and R 5 are directly bonded to form a 3 to 6 membered nitrogen-containing heterocyclic ring.
  • the compounds of the invention include, but are 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), (III) or (IV) or a stereoisod thereof a construct, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug, and a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle or excipient; combinations thereof
  • the composition may further comprise one or more additional therapeutic agents; preferably, wherein the other therapeutic agent One or more selected from the group consisting of a PDE4 inhibitor, a muscarinic receptor antagonist, a corticosteroid, and a ⁇ -adrenergic receptor agonist.
  • the present invention also relates to providing a compound of the formula (I), (II), (III) or (IV) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt thereof, or a total of Crystal or prodrug, or use of the pharmaceutical composition in the preparation of a medicament for treating an airway obstructive disease, preferably, in the preparation of a medicament for treating asthma, chronic obstructive pulmonary disease or bronchitis .
  • the present invention also relates to a method of treating an airway obstructive disease, the method comprising administering a compound of the formula (I), (II), (III) or (IV) or a stereoisomer thereof, a hydrate thereof, Metabolites, solvates, pharmaceutically acceptable salts, eutectic or prodrugs, and pharmaceutical compositions as described above.
  • the invention also relates to a method of treating asthma, chronic obstructive pulmonary disease or bronchitis, comprising administering a compound of the formula (I), (II), (III) or (IV) or a stereoisomer thereof A body, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug and a pharmaceutical composition as described above.
  • the present invention provides an intermediate for preparing the compound of the formula (I), (II), (III) or (IV) or a stereoisomer thereof, which is selected from the group consisting of the formula (V) a compound or a stereoisomer intermediate thereof:
  • a is selected from 0, 1, 2, 3, 4 or 5;
  • b is selected from 0, 1, 2, 3 or 4;
  • 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;
  • W is selected from -O-, -NH- or -NC 1-4 alkyl-;
  • Ring A is selected from And the N-position carbon atom is directly connected to W, said Optionally further substituted with 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, CF 3 , OH, cyano, C 1-4 alkyl or C 1-4 alkoxy;
  • M is selected from H,
  • c is selected from 0, 1 or 2;
  • R q is independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl
  • R 4 is each independently selected from the group consisting of F, Cl, Br, I, CF 3 , OH, NH 2 , cyano, C 1-4 alkyl, C 1-4 alkoxy or C 2-4 alkynyl;
  • n is selected from 0, 1, 2 or 3;
  • Ar 2 is selected from a benzene ring, a thiophene ring, a furan ring or a pyrrole ring, and the benzene ring, thiophene ring, furan ring or pyrrole ring is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, CF 3 Substituted with a substituent of OH, cyano, NH 2 , C 1-4 alkyl, C 1-4 alkoxy or C 2-4 alkynyl;
  • R m is selected from -CHO, -CH 2 OH or -CH 2 OP;
  • P is selected from a hydroxy protecting group.
  • the compound represented by the formula (V) or the stereoisomer intermediate thereof is selected from 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 ), tritium (T, also known as tritium), oxygen isotopes include 16 O, 17 O and 18 O, comprising sulfur, 32 S, 33 S, 34 S and 36 S, the nitrogen isotopes 14 N and 15 comprising 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 a base, an n-octyl group, a n-decyl group, a n-decyl group, etc.; the alkyl group may optionally be further from 0 to 5 selected from the alky
  • 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
  • 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
  • Carbocycle or “carbocyclyl” means a saturated or unsaturated aromatic or non-aromatic ring.
  • the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered member.
  • a tricyclic system, a carbocyclic group may be bonded to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl -2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl , cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, phenyl, naphthyl,
  • Heterocyclyl means a saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic, 4 to 12 membered bicyclic or 10 to 15 membered tricyclic system, and It contains 1 to 4 hetero atoms selected from N, O or S, preferably a 4 to 8 membered heterocyclic group, and N, S which are optionally substituted in the ring of the heterocyclic group can be oxidized to various oxidation states.
  • the heterocyclic group may be bonded to a hetero atom or a carbon atom, and the heterocyclic group may be bonded to a bridged or spiro ring, and non-limiting examples include an epoxyethyl group, a glycidyl group, an azacyclopropyl group, and an oxocyclic ring.
  • the heterocyclic group appearing herein is as defined above.
  • 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 nuclear magnetic resonance
  • MS mass spectrometry
  • the 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 measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
  • 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.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times. Unless otherwise stated in the examples, the reaction was carried out under a nitrogen atmosphere.
  • the solution means an aqueous solution. There is no particular description in the examples, and the 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.
  • Boc means a tert-butyloxycarbonyl group.
  • 5-formylindoline-1-carbonate tert-butyl ester (1a) (742 mg, 3 mmol) (prepared by reference to WO2007129745) was placed in a 25 mL round bottom flask, dichloromethane (10 mL) was added, and the system was cooled to Trifluoroacetic acid (5 mL) was added dropwise at 0 ° C, and after the addition was completed, the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, the system was concentrated under reduced pressure, and the residue was added to dichloromethane (10 mL), and then triethylamine (0.83mL, 6mmol) was added dropwise to the system at 0 ° C.
  • N-tert-Butoxycarbonyl-pyrroline (2a) (100 g, 0.59 mol) was dissolved in dichloromethane (600 mL), and m-chloroperoxybenzoic acid (198.70 g, 0.88 mol) was added portionwise and stirred at room temperature. hour.
  • the reaction solution was slowly added to a 17% sodium thiosulfate solution (46.64 g, 0.29 mol), stirred well, filtered over Celite, and the filtrate was separated and the aqueous phase was extracted with dichloromethane (400 mL ⁇ 3)
  • the organic phase was combined and washed with a saturated aqueous solution of sodium carbonate (500 mL ⁇ 1) and saturated sodium chloride (1000 mL ⁇ 1).
  • Oxy-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (2b) was obtained as a yellow oil.
  • 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (2b) (109.32 g, 0.59 mol) was dissolved in dioxane (800 mL) and water (260 mL) A sodium azide (115.24 g, 1.77 mol) was added to the mixed solvent, and the mixture was heated to 105 ° C for reflux for 60 hours. The reaction solution was cooled to room temperature, a saturated aqueous sodium chloride solution (3000 mL) was added, and the aqueous phase was extracted with methylene chloride (2000 mL ⁇ 4). The product 3-azido-4-hydroxypyrrolidinyl-1-carboxylic acid tert-butyl ester (2c) was obtained as a brown oil.
  • tert-Butyl 3,4-diaminopyrrolidinyl-1-carboxylate hydrochloride (2f) (980 mg, 4.126 mmol) was dissolved in hexafluoroisopropanol (10 mL) and 2-ethoxylated was added with stirring.
  • Ethyl-2-iminoacetate hydrochloride (2 g) (886 mg, 4.538 mmol) was stirred at 50 ° C for 16 hours. The reaction solution was concentrated to dryness, and brine (50 mL) was evaporated, and the mixture was adjusted to pH 2-3 with dilute hydrochloric acid, and ethyl acetate (50mL ⁇ 2).
  • Oxalyl chloride (652.5 mg, 5.14 mmoL) was dissolved in dry dichloromethane (15 mL), cooled to -78 ° C with dry ice acetone bath, and dried dimethyl sulfoxide (803.96 mg, 10.29mmoL) was added dropwise with stirring. Stir for 30 minutes.
  • To the reaction solution was added dropwise 5-tert-butyl 2-ethyl 3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate (2h)
  • a solution of (970 mg, 3.43 mmol) in dichloromethane (5 mL) was stirred for 20 min.
  • Step 8 5-tert-Butyl 2-ethyl 1-ethyl-4,6-dihydropyrrolo[3,4-d]imidazole-2,5(1H)-dicarboxylate (2j)
  • the third step 3-methyl-2-(1-methyl-1H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylic acid tert-butyl Ester (3d) And tert-butyl 1-methyl-2-(2-methyl-2H-tetrazol-5-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5-carboxylic acid tert-butyl a mixture of esters (3e)
  • reaction mixture was evaporated to drynesshhhhhhhhhhhhhhhhh Formaldehyde indoline-1-yl)-3-oxo-propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (1B), light yellow solid (0.22 g , yield 88%).
  • EtOAcjjjjjjjjjjjjjjjjjjjj Methane 40 mL
  • triethylamine was adjusted to basic.
  • EtOAc EtOAc
  • EtOAc EtOAc
  • EtOAc EtOAc
  • Example 7 [1-[2-[[4-[(2-carboxamido-3-ethyl-4,6-dihydropyrrole[3,4-d]imidazol-5-yl)methyl]] Benzoyl]-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 8) [1-[2-[[4-[ (2-carbamoyl-3-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-yl)methyl]benzoyl]-methyl-amino]ethyl]-4-piperidyl]N-(2-phenylphenyl) Carbamate
  • N,N-dimethylformamide 25 mL was added to a 250 mL round bottom flask.
  • Sodium hydride (1.8 g, 33.0 mmol, 60% (w/w)) was added to the reaction flask at 0 ° C, and then 6-bromo-3,4-dihydro-2H-isoquinolin-1-one was added dropwise.
  • (9B) (5.0 g, 22.0 mmol), EtOAc (EtOAc)
  • EtOAc EtOAc
  • the temperature was raised to room temperature and stirred for 4 hours.
  • the reaction mixture was added dropwise with water (100 mL), and the mixture was evaporated.
  • Step 5 2-allyl-6-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,4-dihydroisoquinolin-1-one (9F)
  • Step 6 2-[6-[[tert-Butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]acetaldehyde ( 9G)
  • Step 7 [1-[2-[6-[[tert-Butyl(dimethyl)silyl]oxymethyl]-1-oxo-3,4-dihydroisoquinolin-2-yl) ]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (9H)
  • Step 8 [1-[2-(6-Hydroxymethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-( 2-phenylphenyl)ammonium carbonate (9I)
  • Step 9 [1-[2-(6-Formaldehyde-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-(2- Phenylphenyl)carbamate (9J)
  • Step 10 [1-[2-[6-[(4-carboxamido-1-piperidyl)methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl] Ethyl]-4-piperidinyl]N-(2-phenylphenyl)ammonium carbonate (Compound 9)
  • Acetic acid 0.5 mL
  • sodium triacetoxyborohydride 0.2 g, 1.0 mmol
  • the mixture was reacted at room temperature for 2 hours, and concentrated under reduced pressure to remove most of the solvent, and a saturated aqueous solution of sodium hydrogencarbonate was slowly added dropwise to the residue.
  • the aqueous phase was extracted with methylene chloride (100 mL ⁇ 2), and the organic phase was combined, washed with saturated brine (50 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered and evaporated.
  • Step 5 [1-[2-(5-Formyl-1-oxo-isoindol-2-yl)ethyl]-4-piperidinyl]N-(2-phenylphenyl) Carbamate (10F)
  • 6-Methoxyindole (11A) (5.0 g, 33.97 mmol) was dissolved in acetic acid (50 mL), EtOAc (EtOAc m. Reaction for 2 hours. The reaction solution was added with water (80 mL) and cooled to 0 ° C. Ethyl acetate (80 mL) was added, and the layers were separated and evaporated, ethyl acetate The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated -Methoxy indoline (11B), yellow oil (4.4 g, yield 87%).
  • 5-Bromo-6-methoxyindoline (11C) (16 g, 70.15 mmol) was dissolved in tetrahydrofuran (70 mL), di-tert-butyl dicarbonate (22.97 g, 105.22 mmol) and 4-dimethyl Aminopyridine (1.71 g, 14.03 mol) was reacted at room temperature for 2 hours.
  • Water (50 mL) and ethyl acetate (50 mL) were added to the mixture, and the layers were separated. Water phase with ethyl acetate (30 mL), combined organic phase.
  • the aqueous phase was extracted once with ethyl acetate (100 mL).
  • the organic phase was dried over anhydrous sodium sulfate (MgSO4), EtOAcjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -Formyl-6-methoxyindoline-1-aminocarboxylic acid tert-butyl ester (11E), yellow solid (8.6 g, yield 60%).
  • 6-Methoxydihydroindole-5-carboxaldehyde (11F) (0.100 g, 0.564 mmol) was dissolved in ethyl acetate (10 mL) and triethylamine (0.428 g, 4. Acrylic acid (0.102 g, 1.41 mmol) was added dropwise. The mixture was further added to a solution of 1-propylphosphoric anhydride (0.449 g, 1.41 mmol) at 40 ° C, and reacted at 40 ° C for 4 hours. The reaction mixture was added with EtOAc EtOAc (EtOAc)EtOAc. Methoxy-1-propyl-2-enoyl-porphyrin-5-carbaldehyde (11G), yellow solid (0.08 g, yield 61%).
  • Step 7 [1-[3-(5-Formyl-6-methoxy-indololin-1-yl)-3-oxo-propyl]-4piperidinyl]N-(2- Phenylphenyl)carbamate (11H)
  • 6-Methoxy-1-propyl-2-enoyl-indole-5-carbaldehyde (11G) (0.608 g, 2.63 mmol) was dissolved in 2-methyltetrahydrofuran (10 mL).
  • N-(2-Phenylphenyl)carbamate (1A) (0.600 g, 2.02 mmol)
  • acetic acid (0.243 g, 4.05 mmol) was added, and the mixture was stirred at 100 ° C for 1 hour.
  • the reaction mixture was concentrated, dichloromethane (20 mL) and EtOAc.
  • the aqueous layer was extracted with methylene chloride (20 mL ⁇ 2), dried over anhydrous sodium sulfate.
  • Step 8 [1-[3-[5-[(4-carbamoyl-1-piperidyl)methyl]-6-methoxy-indololin-1-yl]-3-oxo -propyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (Compound 11)
  • dichloromethane (20 mL) was added, and then triethylamine was added dropwise to the mixture, and saturated sodium hydrogen carbonate solution (30 mL), dichloromethane (30) ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ RTIgt; [4-(2,8-diazaspiro[4.5]decyl-8-ylmethyl)benzoyl]-methyl-amino]ethyl]-4-piperidinyl]N-(2-phenyl Phenyl) carbamate (compound 13) (0.26 g, yield 23%).
  • Tetrabutylammonium fluoride (0.49 g, 1.9 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours.
  • the reaction solution was concentrated under reduced pressure and then purified (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Hydroxymethyl)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadiene [C Pyrrolo-5-yl]N-(2-phenylphenyl)carbamate (16B) (0.49 g, 99%).
  • Example 18 [(3aS,5s,6aR)-2-[3-[[4-[(4-carbamoyl-1-piperidyl)methyl]phenyl]amino-3-oxo-propyl -3,3a,4,5,6,6a-hexahydro-1H-cyclopentane[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate (Compound 18)
  • Example 19 [(3aS,5r,6aR)-2-[2-[[4-[(2-carbamoyl-3-ethyl-3a,4,6,6a-tetrahydropyrrole [3,4] -d]imidazol-5-yl)methyl]benzoyl]-methyl-amino]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane [c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate (Compound 19)
  • the organic phase was dried over anhydrous sodium sulfate (MgSO4), filtered,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 20B), white oil (0.36 g, yield 100%).
  • MgSO4 anhydrous sodium sulfate
  • tert-Butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (1.4 g, 5.5 mmol) was taken in 10 mL of dichloromethane, and 2M hydrochloric acid in tetrahydrofuran (20 mL) The reaction was carried out for 3 days at room temperature. After completion of the reaction, the mixture was filtered over Celite, and then washed with methanol (50mL) After adding a saturated aqueous solution of sodium hydrogencarbonate, the mixture was adjusted to pH 8 and dichloromethane (50 mL ⁇ 2) was evaporated. The organic phase was dried over anhydrous sodium sulfate (MgSO4jjjjjjjjjjjj ).
  • the rotary evaporator was concentrated under reduced pressure (60 ° C), until the solution was clarified, then isopropanol (30 mL) was added, and concentrated under reduced pressure (60 ° C) by rotary evaporator. After the solution was clarified, the residue was about 20 mL, and cooled to 0 ° C. Acetic acid (0.54 g, 9 mmol) and anhydrous sodium sulfate (0.12 g) were added, and the mixture was stirred well, and finally sodium triacetoxyborohydride (0.954 g, 4.5 mmol) was added, and the mixture was allowed to react at room temperature for 2.5 hours.
  • Methyl 3,4-dimethylbenzoate (3.28 g, 20 mmol) was dissolved in 80 mL of carbon tetrachloride, and N-bromosuccinimide (7.83 g, 44 mmol) was added, followed by azo diiso Nitrile (290 mg, 1.2 mmol) was raised to 80 ° for 6 h. After completion of the reaction, the reaction was quenched with saturated aqueous sodium hydrogen sulfate, and water (50 mL) and dichloromethane (50 mL) was evaporated. Saturated saline (100 mL ⁇ 1) was washed.
  • the organic phase was dried over anhydrous sodium sulfate (MgSO4), filtered,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Methyl 2-benzylisoindoline-5-carboxylate (1.33 g, 5 mmol) was taken in methanol (20 mL After completion of the reaction, the mixture was filtered over Celite (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Isoindole-5-carboxylic acid methyl ester (22D), yellow solid (0.5 g, yield 56.7%).
  • Methyl isodec-5-carboxylate (0.5 g, 2.82 mmol) was added to dichloromethane (10 mL), triethylamine (0.59 mL, 4.23 mmol) was added, and then di-tert-butyl dicarbonate (677 mg, 3.1 mmol), reacted at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with saturated aqueous sodium hydrogen sulfate (30 mL). The aqueous phase was extracted with dichloromethane (40 mL ⁇ 1), and the organic layer was evaporated. tert-Butyl 5-methylisoindoline-2,5-dicarboxylate (22E), brown oil (0.782 g, yield 100%).
  • Step 8 [1-[2-[[4-[(5-carbamoylisoindol-2-yl)methyl] benzoyl]-methyl-amino]ethyl]-4-piperidin Acridine]N-(2-phenylphenyl)carbamate (Compound 22)
  • N,N-dimethylformamide 200 mL was placed in a 1000 mL round bottom flask.
  • Sodium hydride (12 g, 300 mmol, 60%) was added to the reaction flask at 0 ° C, and 7-bromo-3,4-dihydro-2H-isoquinolin-1-one was added dropwise to the reaction via a constant pressure funnel.
  • (24A) (33.9 g, 150 mmol) in N,N-dimethylformamide (150 mL). After stirring for 20 min, 3-bromopropene (27.2 g, 225 mmol) was added dropwise to the reaction flask. The reaction was allowed to warm to room temperature and stirred for 4 hours and then quenched.
  • Step 5 2-allyl-7-[[tert-butyl(dimethyl)silyl]oxymethylene]-3,4-dihydroisoquinolin-1-one (24F)
  • Step 6 2-[7-[[tert-Butyl(dimethyl)silyl]oxymethylene]-1-oxo-3,4-dihydroisoquinolin-2-yl]acetaldehyde ( 24G)
  • Step 7 [1-[2-[7-[[tert-Butyl(dimethyl)silyl]oxymethylene]-1-oxo-3,4-dihydroisoquinolin-2-yl ] B 4--4-piperidinyl]N-(2-phenylphenyl)carbamate (24H)
  • Step 8 [1-[2-(7-Hydroxymethylene)-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N- (2-phenylphenyl)carbamate (24I)
  • reaction solution was concentrated under reduced pressure and then purified (jjjjjjjjjjjjjjjjjjjjjjjjjjj 4-Dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-(2-phenylphenyl)carbamate (24I) (0.67 g, 89%).
  • Step 9 [1-[2-(7-Formaldehyde-1-oxo-3,4-dihydroisoquinolin-2-yl]ethyl]-4-piperidinyl]N-(2- Phenylphenyl)carbamate (24J)
  • Step 10 [1-[2-[7-[(4-carboxamide-1-piperidyl)methyl]-1-oxo-3,4-dihydroisoquinolin-2-yl]B 4-thiazolidinyl]N-(2-phenylphenyl)carbamate (compound 24)
  • Test Example 1 Inhibitory activity against human muscarinic M1, M2 and M3 receptors
  • CHO cells PerkinElmer, ES-212-AF stably expressing human muscarinic receptor 1, 2 or 3 (hM1, hM2, 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 , Achieve 90-100% integration.
  • 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 dissolved in DMSO to prepare a 10 mM mother liquor, and 0.1% BSA/phenol red free Ham's F12 medium was diluted (log (M): -7, -8, -9.-10.-11), and added to 96 wells. 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.
  • a 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 at a concentration of 31.2 nM (hM1) and 3.69 ⁇ M (hM2). Or 112.92 nM (hM3), the luminescence was recorded for 20 seconds, and 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 compound of the present invention has significant inhibitory activity on human muscarinic M1 and M3 receptors, and some compounds M1/M2.
  • the selectivity index of M3/M2 is higher.
  • Test Example 2 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 compounds of the present invention have a better inhibitory effect on methacholine-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.

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Abstract

La présente invention concerne un dérivé biphényle et son procédé de préparation et son utilisation en médecine, et concerne en particulier un composé représenté par la formule générale (I), ou un stéréomère, un hydrate, un métabolite, un solvate, un sel pharmaceutiquement acceptable, un eutectique ou un promédicament de ce dernier, et un procédé de préparation et une utilisation dans la préparation de médicaments permettant de traiter des troubles obstructifs des voies respiratoires, le composé de formule (I) étant comme illustré dans la figure. Les substituants sont tels que définis dans la description.
PCT/CN2016/100307 2015-09-28 2016-09-27 Dérivé biphényle et son procédé de préparation et son utilisation en médecine WO2017054702A1 (fr)

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CN106565674A (zh) * 2015-10-13 2017-04-19 四川海思科制药有限公司 一种八氢环戊烷并[c]吡咯衍生物及其制备方法和在医药上的用途
CN111217993A (zh) * 2018-11-26 2020-06-02 沈阳药科大学 一种聚乙二醇化酚红及其制备方法和用途

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CN106916158A (zh) * 2015-12-25 2017-07-04 四川海思科制药有限公司 一种吡喃衍生物盐酸盐水合物及其中间体的制备方法
CN113544130B (zh) * 2019-05-31 2024-01-09 西藏海思科制药有限公司 一种btk抑制剂环衍生物及其制备方法和药学上的应用
CN114539286B (zh) * 2020-11-24 2024-02-02 成都百裕制药股份有限公司 哌嗪衍生物及其在医药上的应用

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CN1930125A (zh) * 2004-03-11 2007-03-14 施万制药 适用作毒蕈碱性受体拮抗剂的联苯基化合物
WO2006099032A1 (fr) * 2005-03-10 2006-09-21 Theravance, Inc. Composes de biphenyle utilises comme antagonistes des recepteurs muscariniques
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CN106565674A (zh) * 2015-10-13 2017-04-19 四川海思科制药有限公司 一种八氢环戊烷并[c]吡咯衍生物及其制备方法和在医药上的用途
CN106565674B (zh) * 2015-10-13 2021-02-05 四川海思科制药有限公司 一种八氢环戊烷并[c]吡咯衍生物及其制备方法和在医药上的用途
CN111217993A (zh) * 2018-11-26 2020-06-02 沈阳药科大学 一种聚乙二醇化酚红及其制备方法和用途
CN111217993B (zh) * 2018-11-26 2022-05-20 沈阳药科大学 一种聚乙二醇化酚红及其制备方法和用途

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