WO2019052557A1 - μ-阿片受体激动剂及其制备方法和在医药领域的应用 - Google Patents

μ-阿片受体激动剂及其制备方法和在医药领域的应用 Download PDF

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WO2019052557A1
WO2019052557A1 PCT/CN2018/105946 CN2018105946W WO2019052557A1 WO 2019052557 A1 WO2019052557 A1 WO 2019052557A1 CN 2018105946 W CN2018105946 W CN 2018105946W WO 2019052557 A1 WO2019052557 A1 WO 2019052557A1
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pyridin
ethyl
amine
oxaspiro
decane
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PCT/CN2018/105946
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English (en)
French (fr)
Inventor
许昕
张瑱
李云飞
张立明
郭凤英
蒋青云
李东升
张林丽
宋锦乾
刘磊
刘强
苏晶
王艺瑾
葛建
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上海华汇拓医药科技有限公司
浙江华海药业股份有限公司
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Priority to EP18857198.8A priority Critical patent/EP3686198B1/en
Priority to US16/645,777 priority patent/US11072601B2/en
Priority to JP2020515923A priority patent/JP7019035B2/ja
Publication of WO2019052557A1 publication Critical patent/WO2019052557A1/zh

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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry, and particularly relates to a kind of oxaspirocyclic small molecule compound, a preparation method thereof and application in the field of medicine.
  • Opioid receptors are members of the G-protein coupled receptor (GPCR) family and are highly expressed in the central nervous system. The central nervous system regulates a series of behaviors of the body, including pain, emotion, stress response, etc. Three subtypes: ⁇ opioid receptor (MOR), ⁇ opioid receptor (DOR), kappa opioid receptor (KOR) (Nature, 2016, 537 (7619): 185). Opioid receptor agonists are currently the most widely used analgesics, and agonists acting on ⁇ -opioid receptor (MOR) have the advantages of strong analgesic activity and wide anti-pain spectrum. And has an irreplaceable role in the treatment of severe pain.
  • GPCR G-protein coupled receptor
  • the MOR agonist, morphine is a natural product extracted from opium poppy. It has been used as an analgesic for acute severe pain for hundreds of years. After that, a wide variety of morphine derivatives and synthetic compounds such as oxycodone and hydromorphone, Hydroxymorphone, levonorol, buprenorphine, fentanyl, sufentanil, meperidine, etc. have been developed as clinical analgesics as MOR agonists, although these MOR agonists have potent analgesia Role, but all compounds showed similar clinical side effects: constipation, nausea, vomiting, sedation, respiratory depression, etc.
  • MOR agonists In addition, these MOR agonist-induced pleasure and physical dependence are highly prone to addiction and abuse, triggering society sexual problems (Journal of Medicinal Chemistry, 2013, 56(20): 8019-31), long-term use of MOR agonists can also lead to analgesia tolerance, requiring dose escalation to control pain, thereby further increasing the above clinical side effects (Anasthesiol Intensivmed Notfallmed expther. 2003, 38, 14-26.).
  • GPCR agonists can activate other signaling pathways in addition to the G protein subunit-activated G protein signaling pathway, where activation is strongly influenced by ⁇ -arrestin-mediated signaling pathways, ⁇ - Arrestin can bind to activated GPCR, cause receptor desensitization of GPCR, and stop G protein signaling; ⁇ -arrestin can also recruit endocytic protein, induce GPCR endocytosis; form complex with signaling molecules downstream of GPCR, activate other Signaling molecules, such as MAPK, Src and other kinases.
  • ⁇ -arrestin can bind to activated GPCR, cause receptor desensitization of GPCR, and stop G protein signaling; ⁇ -arrestin can also recruit endocytic protein, induce GPCR endocytosis; form complex with signaling molecules downstream of GPCR, activate other Signaling molecules, such as MAPK, Src and other kinases.
  • a series of G protein-biased MOR agonists have been disclosed in the patent WO2012129495 filed by Trevena Inc. and WO2017063509 of Jiangsu Hengrui Medicine Co., Ltd., and the compounds disclosed in both patents are all oxaspiro derivatives, Trevena Inc.
  • the compound has limited selectivity for the G protein signaling pathway (J. Med. Chem. 2013, 56, 8019-8031), and the compound benzyl benzyl group is cyclized in the patent WO2017063509 of Jiangsu Hengrui Pharmaceutical Co., Ltd.
  • the Emax is increased, but the selectivity of the G protein signaling pathway is still limited.
  • a series of G protein-biased MOR agonists have been published, there is still a need to develop new ones with better efficacy, selectivity, and drug metabolism. The resulting MOR agonist.
  • the inventors redesigned and synthesized a class of MOR agonists whose selectivity for the G protein signaling pathway was significantly improved.
  • the object of the present invention is to provide a compound of the formula (I), and stereoisomers, tautomers, enantiomers, diastereomers, racemates thereof and pharmaceutically acceptable salts thereof
  • Ar 1 is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl group; Ar 1 may specifically be a phenyl group, a pyridyl group, a substituted phenyl group, or a substituted pyridyl group, wherein the benzene group Or the pyridyl group is optionally substituted by one or more of the following substituents: -C 1-3 alkyl, -C 1-3 alkoxy or halogen;
  • A is a -C 1-2 alkylene group or a -C 1-2 alkylene group substituted by a C 1-3 alkyl group
  • B is -NH-CH 2 -Ar 2 , -NH-C(O) -Ar 2 or -NR 1 R 2 , wherein R 1 and R 2 together with the nitrogen atom to which they are attached form a 6-12 membered heteroaryl group which is T substituted or unsubstituted;
  • T is -OH, -C 1-3 alkyl, -C 1-3 alkoxy, hydroxy substituted C 1-3 alkyl, halogen substituted C 1-3 alkyl, halogen substituted C 1-3 alkane Oxyl, halogen, amino, mono(C 1-3 alkyl)-amino-, bis(C 1-3 alkyl)-amino-, nitrile, benzyl or phenyl.
  • A is a -C 1-2 alkylene group, or a -C 1-2 alkylene group substituted by a methyl group
  • Ar 2 is a substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl group, wherein the phenyl group or the 5-6 membered heteroaryl group is optionally selected by the following or Substituted by a plurality of substituents: -OH, -C 1-3 alkyl, -C 1-3 alkoxy, hydroxy substituted C 1-3 alkyl, halogen substituted C 1-3 alkyl, halogen substituted C 1-3 alkoxy, halogen, amino, mono(C 1-3 alkyl)-amino-, bis(C 1-3 alkyl)-amino-, nitrile, benzyl or phenyl;
  • Ar 2 may specifically be a phenyl group, a thienyl group, an imidazolyl group, a pyridyl group or a pyrazolyl group substituted with the above substituents;
  • Ar 2 can also be specifically
  • the compound of formula (I) as described above is:
  • the invention also includes pharmaceutically acceptable salts of the compounds of formula (I) and stereoisomers thereof.
  • the pharmaceutically acceptable salts are inorganic base salts such as sodium, potassium, calcium or aluminum salts; organic base salts such as lysine, arginine, triethylamine and dibenzylamine salts , piperidine salts and other pharmaceutically acceptable organic amine salts.
  • At least one salt-forming nitrogen atom When at least one salt-forming nitrogen atom is contained in the molecule of the present invention, it can be converted into the corresponding salt by reacting with a corresponding organic acid or inorganic acid in an organic solvent such as acetonitrile or tetrahydrofuran.
  • organic acids are oxalic acid, tartaric acid, maleic acid, succinic acid, citric acid;
  • typical inorganic acids are nitric acid, hydrochloric acid, sulfuric acid, phosphoric acid, preferably nitric acid.
  • asymmetric carbon atoms When having one or more asymmetric carbon atoms in the compounds of the invention, they can exist in the form of optically pure enantiomers, pure diastereomers, enantiomeric mixtures, non- Enantiomeric mixtures, enantiomerically racemic mixtures, racemates or racemate mixtures. All possible isomers, stereoisomers and mixtures thereof of the compounds of formula (I) are also within the scope of the invention.
  • the present invention relates to a process for the preparation of a compound of the formula (I), wherein:
  • Ar1, Ar2 are as defined in Claim 1, 2, 3, 4 or 5, and the acid is preferably sulfuric acid, hydrochloric acid, phosphoric acid, trifluoromethanesulfonic acid, hydrobromic acid or a combination thereof;
  • the oxidizing agent is preferably chlorine Pyridinium chromate (PCC), pyridinium dichromate (PDC) or a combination thereof;
  • the aryl format reagent is preferably aryl magnesium bromide, aryl magnesium chloride or a combination thereof;
  • the base is preferably potassium hydroxide, Sodium hydroxide or a combination thereof;
  • the reducing agent 1 is preferably lithium aluminum hydride, borane tetrahydrofuran, borane dimethyl sulfide or a combination thereof;
  • the reducing agent 2 is preferably sodium borohydride, potassium borohydride, triacetyl Sodium borohydride, sodium cyanoborohydride or a combination thereof;
  • A is a -C 1-2 alkylene group substituted by a C 1-3 alkyl group
  • B is -NH-CH 2 -Ar 2
  • the synthetic route is as in Scheme 2 or Scheme 3
  • R3 is a C1-3 alkyl group
  • the base is preferably sodium hydride, lithium diisopropylamide, potassium butyl lithium tert-butoxide, Sodium ethoxide, lithium hexamethyldisilazide, potassium hexamethyldisilazide or a combination thereof
  • the reducing agent 1 is preferably lithium aluminum hydride, borane tetrahydrofuran, borane dimethyl sulfide or a combination thereof
  • the reducing agent 2 is preferably sodium borohydride, potassium borohydride, sodium triacetylborohydride, sodium cyanoborohydride or a combination thereof;
  • R4 is a C1-3 alkyl group
  • the reducing agent 1 is preferably lithium aluminum hydride, borane tetrahydrofuran, borane dimethyl sulfide or a combination thereof
  • the reducing agent 2 is preferably sodium borohydride, potassium borohydride, sodium triacetylborohydride, sodium cyanoborohydride or a combination thereof;
  • the condensing agent is 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride (EDCI)/1-hydroxybenzotriazole (HOBT), dicyclohexylcarbodiimide (DCC), 2-(7-oxobenzotriazole)-N,N,N',N'-four Urea urea hexafluorophosphate (HATU) or a combination thereof;
  • Ar 1 , R 1 , R 2 are as defined in claim 1 , 2 , 3 or 4,
  • the base is preferably sodium hydroxide, potassium hydroxide or a combination thereof
  • the condensing agent is preferably 1-ethyl- (3-Dimethylaminopropyl)carbonyldiimide hydrochloride (EDCI)/1-hydroxybenzotriazole (HOBT), dicyclohexylcarbodiimide (DCC), 2-(7-oxidation Benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or a combination thereof
  • the reducing agent is lithium aluminum hydride, borane tetrahydrofuran, borane Methyl sulfide or a combination thereof.
  • the present invention relates to a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein when A is a -C 1-2 alkylene group and B is -NH-CH 2 -Ar 2
  • A is a -C 1-2 alkylene group
  • B is -NH-CH 2 -Ar 2
  • Ar 1 and Ar 2 are as defined above.
  • Cyclopentanone and 3-buten-1-ol form a spiro ring intermediate 1-2 under sulfuric acid conditions, and 1-2 is oxidized by a suitable oxidizing agent to obtain compounds 1-3, 1-3 and ethyl cyanoacetate.
  • the intermediates 1-4, 1-4 are reacted with a format reagent to obtain a compound 1-5, 1-5 which is hydrolyzed and decarboxylated under basic conditions to further reduce the cyano group to obtain an alkylamine 1-7, 1-7 and the corresponding aldehyde. Reductive amination occurs to give final compounds 1-8.
  • the present invention relates to a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein when A is a -C 1-2 alkylene group substituted by a C 1-3 alkyl group, B is - NH-CH 2 -Ar 2 , the synthetic route is summarized as follows (Scheme 2' and Scheme 3'):
  • Ar 1 and Ar 2 are as defined above, and R 3 is a C 1-3 alkyl group.
  • Ar 1 and Ar 2 are as defined above, and R 4 is C 1-3 alkyl.
  • the present invention relates to a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein when A is a -C 1-2 alkylene group and B is -NH-C(O)-Ar 2
  • A is a -C 1-2 alkylene group
  • B is -NH-C(O)-Ar 2
  • Ar 1 and Ar 2 are as defined above.
  • the present invention relates to a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein when A is a -C 1-2 alkylene group and B is -NR 1 R 2 , the synthetic route is summarized as follows (Scenario 5'):
  • the intermediates 1-6 are hydrolyzed under basic conditions to give the acid 5-1, 5-1 condensed with the corresponding amine under the conditions of a condensing agent, and after reduction, the final product 5-3 is obtained.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the at least one compound described above and optionally one or more pharmaceutically acceptable carriers and/or additives.
  • the pharmaceutical composition provided by the present invention can be prepared in any form such as granules, powders, tablets, coated tablets, capsules, pills, syrups, drops, solutions, suspensions and emulsions, or sustained release of active ingredients.
  • Formulations, wherein examples of capsules include hard or soft gelatin capsules, granules and powders may be in a non-effervescent or effervescent form.
  • compositions of the present invention may further comprise one or more pharmaceutically or physiologically acceptable carriers which will be suitably formulated for ease of administration.
  • the pharmaceutically or physiologically acceptable carrier can be saline, hot pressed water, Ringer's solution, buffered saline, dextrose, maltodextrin, glycerol, ethanol, and mixtures thereof.
  • the pharmaceutical composition of the present invention may further comprise a pharmaceutically or physiologically acceptable additive such as a diluent, a lubricant, a binder, a glidant, a disintegrant, a sweetener, a flavoring agent, a wetting agent, a dispersing agent. , surfactants, buffered saline, coatings, blowing agents, preservatives, stabilizers or fragrances.
  • a pharmaceutically or physiologically acceptable additive such as a diluent, a lubricant, a binder, a glidant, a disintegrant, a sweetener, a flavoring agent, a wetting agent, a dispersing agent.
  • surfactants buffered saline, coatings, blowing agents, preservatives, stabilizers or fragrances.
  • diluents that may be used include, but are not limited to, lactose, sucrose, starch, kaolin, salt, mannitol, and dicalcium phosphate;
  • examples of lubricants include, but are not limited to, talc, starch, magnesium or calcium stearates, stone pine And stearic acid;
  • examples of binders include, but are not limited to, microcrystalline cellulose, tragacanth, dextrose solution, gum arabic, gelatin solution, sucrose, and starch paste;
  • examples of glidants include, but are not limited to, colloidal Silica;
  • disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methyl cellulose, agar, and carboxymethyl cellulose;
  • sweeteners include, but are not limited to, sucrose, lactose, mannitol, and artificial sweeteners,
  • the surfactant may be selected from the group consisting of detergents, ethoxylated castor oil, pegylated glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers such as 188 and 407, polyoxyethylene.
  • Sorbitan fatty acid esters polyoxyethylene derivatives such as alkylated and alkoxylated derivatives (Tween, such as Tween-20, or Tween-80), monoglycerides or their ethoxylates a base derivative, a diglyceride or a polyoxyethylene derivative thereof, glycerin, cholic acid or a derivative thereof, lecithin, an alcohol and a phospholipid, a glycerophospholipid (lecithin, cephalin, phosphatidylserine), Glycerolipids (galactopyranosides), sphingomyelins (sphingomyelin), and glycosphingolipids (ceramides, gangliosides), DSS (sodium docusate, calcium docusate, potassium docusate, SDS (sodium lauryl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium o
  • the buffered saline may be selected from the group consisting of sodium acetate buffer, sodium carbonate buffer, citrate buffer, glycylglycine buffer, histidine buffer, glycine buffer, lysine buffer, and arginine buffer.
  • the sodium phosphate buffer, and the tris(hydroxymethyl)-aminomethane buffer, or a mixture thereof, may also be a glycylglycine buffer, a sodium phosphate buffer, or a mixture thereof.
  • the above preservative may be selected from the group consisting of phenol, m-cresol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, 2-phenoxyethanol, butyl p-hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorine Butanol, and thiomerosal, or mixtures thereof, may also be phenol or m-cresol.
  • the preservative is present at a concentration of from about 0.1 mg/ml to about 50 mg/ml, at a concentration of from about 0.1 mg/ml to about 25 mg/ml, or at a concentration of from about 0.1 mg/ml to about 10 mg/ml.
  • the above stabilizers include, but are not limited to, polyethylene glycol (such as PEG 3350), polyvinyl alcohol (PVA), polyvinylpyrrolidone, carboxymethyl cellulose, different salts (such as sodium chloride), L-glycine, L-group Amino acid, imidazole, arginine, lysine, isoleucine, aspartic acid, tryptophan, and threonine or any mixture thereof.
  • the present invention also provides the use of the above compound or pharmaceutical composition for the preparation of a medicament for preventing and/or treating a MOR receptor agonist-mediated related disease.
  • MOR receptor agonists as described above include, but are not limited to, pain, inflammation, immune dysfunction, esophageal reflux, neurological and psychiatric disorders, or respiratory diseases.
  • the pain mentioned above includes, but is not limited to, traumatic pain, neuropathic pain, inflammatory pain, visceral pain, migraine, and pain associated with cancer.
  • the pain mentioned above may be postoperative pain, pain caused by cancer, neuropathic pain, pain caused by trauma, or pain caused by inflammation.
  • the compounds or pharmaceutical compositions provided herein can also be used in urinary and reproductive disorders, drug and alcohol abuse, gastritis or diarrhea. Accordingly, the present invention provides the use of a compound or pharmaceutical composition provided by the present invention for the manufacture of a medicament for improving urinary and reproductive disorders, drug and alcohol abuse, gastritis or diarrhea.
  • the amount and frequency of administration of a compound described herein and/or a pharmaceutically acceptable salt thereof will be adjusted according to the judgment of the attending clinician in consideration of such factors as age, condition, and size of the patient and the severity of the condition being treated. Generally, it is contemplated that the effective amount may range from 0.001 mg/kg to 10 mg/kg body weight, specifically from 0.01 mg/kg to 1 mg/kg body weight.
  • the pharmaceutical formulation is in unit dosage form.
  • the amount of active compound in a unit dosage formulation can be varied or adjusted depending on the particular application: from about 0.01 mg to about 1000 mg, from about 0.01 mg to about 750 mg, from about 0.01 mg to about 500 mg, or from about 0.01 mg to about 250 mg.
  • the compound of the present invention has a markedly improved selectivity for the G protein signaling pathway, and not only exhibits excellent pharmacodynamic effects, but also has a significant improvement in safety.
  • C 1-3 alkyl includes alkyl groups containing from 1 to 3 carbon atoms.
  • aryl embraces 5- and 6-membered monocyclic aromatic groups which may contain 0-4 heteroatoms such as benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole , triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine and pyrimidine, etc.; in addition, the term “aryl” also includes polycyclic aryl groups, such as tricyclic, bicyclic, such as naphthalene, Benzoazole, benzobisazole, benzothiazole, benzimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthyridine, anthracene, benzofuran, anthracene, benzo Furan, deazapurine or medium nitrogen
  • Typical heteroaryl groups include 2- or 3-thienyl; 2- or 3-furyl; 2- or 3-pyrrolyl; 2-, 4- or 5-imidazolyl; 3-, 4- or 5-pyridyl; Azolyl; 2-, 4- or 5-thiazolyl; 3-, 4- or 5-isothiazolyl; 2-, 4- or 5-oxazolyl; 3-, 4- or 5-isoxazolyl; -or 5-1,2,4-triazolyl; 4- or 5-1,2,3-triazolyl; tetrazolyl; 2-, 3- or 4-pyridyl; 3- or 4-oxime Zinyl; 3-, 4- or 5-pyrazinyl; 2-pyrazinyl; 2-, 4- or 5-pyrimidinyl.
  • heteroaryl as used herein also refers to a group in which a heteroaromatic ring is fused to a ring of one or more aryl, cycloaliphatic or heterocyclic groups, wherein the linking group or point of attachment is at the heteroaryl. On the family ring.
  • Examples thereof include, but are not limited to, 1-, 2-, 3-, 5-, 6-, 7- or 8-indolyl; 1-, 3-, 4-, 5-, 6- or 7-isoindole Indenyl; 2-, 3-, 4-, 5-, 6- or 7-fluorenyl; 2-, 3-, 4-, 5-, 6- or 7-oxazolyl; 2-, 4- , 5-, 6-, 7- or 8-decyl; 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinolinyl; 2-, 3-, 4- , 5-, 6-, 7- or 8-quinolinyl; 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl; 1-, 4-, 5-, 6-, 7- or 8-pyridazinyl; 2-, 3-, 4-, 5- or 6-naphthyridinyl; 2-, 3-, 5-, 6-, 7- or 8-quinazoline 3-, 4-, 5-, 6-, 7- or 8-carbolinyl
  • Typical fused heteroaryl groups include 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl; 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl; 2-, 3-, 4-, 5-, 6- or 7-fluorenyl; 2-, 3-, 4-, 5-, 6- or 7-benzo[b] Thienyl; 2-, 4-, 5-, 6- or 7-benzoxazolyl; 2-, 4-, 5-, 6- or 7-benzimidazolyl; 2-, 4-, 5-, 6- or 7-benzothiazolyl.
  • aryl or “heteroaryl” aromatic ring as used herein may be substituted at one or more of the ring positions by a substituent as described above, for example, halo, hydroxy, alkoxy, alkylcarbonyloxy, Arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, hydroxycarbonyl, alkylcarbonyl, alkylaminocarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, aryl Carbocarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, cyano, amino (including alkylamino, dialkylamino, aryl) Amino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, aryl
  • alkoxy includes substituted and unsubstituted alkyl groups covalently bonded to an oxygen atom.
  • alkoxy group examples include a methoxy group, an ethoxy group, an isopropyloxy group, a propoxy group, a butoxy group, and a pentyloxy group.
  • substituted alkoxy group examples include a halogenated alkoxy group.
  • Alkoxy groups may be substituted by alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, hydroxycarbonyl, alkane Alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, phosphate, cyano, amino (including alkylamino, dialkylamino, Arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), fluorenyl, imino, fluorenyl, alkylthio, Arylthio, hydroxythiocarbonyl, alkylsulfinyl, sulfonate,
  • 3-buten-1-ol (10 g, 142 mmol) and cyclopentanone (6 g, 71 mmol) were added to an eggplant flask and cooled to 0 °C.
  • 75% sulfuric acid was slowly added dropwise, and the mixture was gradually warmed to room temperature and allowed to react overnight.
  • water 100 ml was added, and the mixture was adjusted to pH 8 with sodium hydroxide, and extracted with diethyl ether (3 ⁇ 150 ml). The ether layer was washed with saturated sodium hydrogen sulfate (40 ml), dried over magnesium sulfate, evaporated and evaporated.
  • 6-oxaspiro[4.5]decane-9-ol (1-2, 4 g), yield: 36%.
  • 6-oxaspiro[4.5]decane-9-ol (4 g, 25.6 mmol) was dissolved in dichloromethane (100 ml), and chlorochromic acid pyridinium salt (PCC, 8.3 g, 39 mmol) was added thereto at room temperature.
  • the reaction TLC detection of the disappearance of the starting material, filtration, concentration of the filtrate and column chromatography (developing agent 0% to 50% ethyl acetate / petroleum ether) to give 6-oxaspiro[4.5]decane-9-one (1- 3, 3.1 g), yield: 78%.
  • Step 3 Preparation of 2-cyano-[(9Z)-6-oxaspiro[4.5]decane-9-ylidene]ethyl acetate (1-4)
  • 6-oxaspiro[4.5]decane-9-one (1-3, 3.1 g, 20 mmol) and ethyl cyanoacetate were added to a 50 ml round bottom flask equipped with a Dean-Stark distillation apparatus and a condenser.
  • 3.1 g, 24 mmol ammonium acetate (0.385 g, 5 mmol)
  • acetic acid (0.24 g)
  • toluene (30 ml).
  • the aqueous layer was extracted with ethyl acetate (3 ⁇ 50 mL).
  • Step 4 Preparation of ethyl 2-cyano-2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-ylideneacetate (1a)
  • Step 7 Preparation of (3-trifluoromethoxybenzyl)-[2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl]amine
  • the preparation method is the same as in the first embodiment, the 3-trifluoromethoxybenzaldehyde in the seventh step is replaced by 3-chloro-4-trifluoromethoxybenzaldehyde to obtain (2-chloro-4-trifluoromethyl).
  • Oxybenzyl)-[2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl]amine 100 mg, yield 75%, pale yellow appearance Sticky.
  • the preparation method is the same as in the first embodiment, and the 3-trifluoromethoxybenzaldehyde in the seventh step is replaced by 2-methylaminobenzaldehyde to obtain N-methyl-2-(((2-(9-(pyridine)).
  • 2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)methyl)aniline 38 mg, yield 32%, appearance as pale yellow viscous.
  • the preparation method is the same as in the first embodiment, the 3-trifluoromethoxybenzaldehyde in the seventh step is replaced by 2-methyl-3-chlorobenzaldehyde to obtain (3-chloro-2-methylbenzyl)- [2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl]amine 95 mg, yield 63%, appearance as pale yellow viscous.
  • the preparation method is the same as in Example 1, and the 3-trifluoromethoxybenzaldehyde in the seventh step is replaced with 3-chlorothiophene-2-carbaldehyde to obtain ((3-chloro-thiophen-2-yl)methyl).
  • 3-chlorothiophene-2-carbaldehyde to obtain ((3-chloro-thiophen-2-yl)methyl).
  • the preparation method is the same as in the first embodiment, the 3-trifluoromethoxybenzaldehyde in the seventh step is replaced by 4-trifluoromethoxybenzaldehyde to obtain (4-trifluoromethoxybenzyl)-[2 -(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl]amine 40 mg, yield 52%, appearance as pale yellow viscous.
  • the preparation method is the same as in the first embodiment, and the 3-trifluoromethoxybenzaldehyde in the seventh step is replaced with 3,4-dimethylbenzaldehyde to obtain (3,4-dimethylbenzyl)-[2. -(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl]amine 40 mg, yield 50%, appearance as pale yellow viscous.
  • the preparation method is the same as in the first embodiment, and the 3-trifluoromethoxybenzaldehyde in the seventh step is replaced with 2,4-dimethylbenzaldehyde to obtain (2,4-dimethylbenzyl)-[2. -(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl]amine 60 mg, yield 65%, appearance as pale yellow viscous.
  • the preparation method is the same as in the first embodiment, the fourth step of the pyridine-2-magnesium bromide is replaced by 3-chloro-5-fluoropyridine-2-magnesium bromide, and the 3-trifluoromethoxybenzene in the seventh step.
  • the preparation method is the same as in the first embodiment, the fourth step of the pyridine-2-magnesium bromide is replaced by 3-methyl-5-fluoropyridine-2-magnesium bromide, and the 3-trifluoromethoxy group in the seventh step.
  • the preparation method is the same as in the first embodiment, the 3-trifluoromethoxybenzaldehyde in the seventh step is replaced by 2-trifluoromethoxy-4-bromobenzaldehyde to obtain (4-bromo-2-trifluoromethyl).
  • the preparation method is the same as in the first embodiment, the 3-trifluoromethoxybenzaldehyde in the seventh step is replaced by 2-trifluoromethoxy-4-methylbenzaldehyde to obtain (4-methyl-2-triazole).
  • the preparation method is the same as in the first embodiment, the 3-trifluoromethoxybenzaldehyde in the seventh step is replaced by 2-trifluoromethoxy-4-cyanobenzaldehyde to obtain 3- ⁇ [(2-(9). -(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl]aminemethyl ⁇ -2-trifluoromethoxybenzonitrile 45 mg, yield 51%, appearance It is a pale yellow viscous material.
  • the preparation method was the same as in Example 1, and the 3-trifluoromethoxybenzaldehyde in the seventh step was changed to 2-trifluoromethoxy-4-hydroxybenzaldehyde to obtain 4- ⁇ [2-(9- (pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethylamine]methyl ⁇ -3-trifluoromethoxyphenol 56 mg, yield 52%, pale yellow appearance Sticky.
  • the preparation method is the same as in the first embodiment, and the 3-trifluoromethoxybenzaldehyde in the seventh step is replaced by 2-difluoromethoxybenzaldehyde to obtain (2-difluoromethoxybenzyl)-[2. -(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl]amine 16 mg, yield 28%, appearance as pale yellow viscous.
  • the preparation method is the same as in the first embodiment, the 3-trifluoromethoxybenzaldehyde in the seventh step is replaced by 2-trifluoromethoxy-5-chlorobenzaldehyde to obtain (2-difluoromethoxybenzyl).
  • 2-trifluoromethoxy-5-chlorobenzaldehyde 2-trifluoromethoxy-5-chlorobenzaldehyde to obtain (2-difluoromethoxybenzyl).
  • -[2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl]amine 100 mg, yield 80%, appearance as pale yellow viscous.
  • Step 2 Preparation of 2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl]-1-(7-(trifluoromethyl)-3,4- Dihydroisoquinoline-2(1H)-yl)ethan-1-one (19b)
  • Step 3 Preparation of 2-[2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl]-7-trifluoromethyl-1, 2,3,4-tetrahydroisoquinoline
  • the preparation method was the same as in Example 19, and the 7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline of the second step was changed to 7-methoxy-1,2,3,4-tetrahydrogen.
  • Isoquinoline to give 7-methoxy-2-[2-(9-pyridin-2-yl-6-oxa-spiro[4.5]fluoren-9-yl)-ethyl]-1,2, 3,4-Tetrahydroisoquinoline (20,34 mg), yield 36%, appearance as a pale yellow viscous material.
  • Step 2 Preparation of 2-[9-(5-fluoro-pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl]acetonitrile (21b)
  • Step 3 Preparation of 2-(9-(5-fluoropyridin-2-yl)-6-oxa-spiro[4.5]dec-9-yl)-ethylamine (21c)
  • Step 4 Preparation of ⁇ 2-[9-(5-fluoro-pyridin-2-yl)-6-oxa-spiro[4.5]fluoren-9-yl]-ethyl ⁇ -(2-(trifluoromethyl) Oxy)-benzyl)-amine (H21)
  • the preparation method is the same as in Example 1, and the 3-trifluoromethoxybenzaldehyde in the seventh step is replaced by 2-trifluoromethoxybenzaldehyde to obtain (2-trifluoromethoxybenzyl)-[ 2-(9-Pyridin-2-yl-6-oxa-spiro[4.5]dec-9-yl)-ethyl]-amine (22,34 mg), yield 28%, appearance as pale yellow viscous .
  • the preparation method was the same as in Example 19, and the second step of 7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline was changed to 4,5,6,7-tetrahydro-thieno[2, 3-c]pyridine to give 6-[2-(9-pyridin-2-yl-6-oxa-spiro[4.5]fluoren-9-yl)-ethyl]-4,5,6,7- Tetrahydro-thieno[2,3-c]pyridine (23, 70 mg), yield 64%, appearance as a yellow oil.
  • Step 4 Preparation of tert-butylmethyl (2-((9-(pyridin-2-yl)-6-oxa-spiro[4.5]dec-9-yl)-ethyl)carbamoyl)thiophene-3- Carbamate (24e)
  • Step 5 Preparation of 3-methylamino-thiophene-2-carboxylic acid [2-(9-pyridin-2-yl-6-oxa-spiro[4.5]fluoren-9-yl)-ethyl]-amide (H24)
  • Step 2 Preparation of 2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)propan-1-amine (26b)
  • Step 3 Preparation of ((3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl) Propyl]-1-amine (H26)
  • the concentrated reaction solution was dissolved in methanol, and 10% palladium carbon (10 mg) was added thereto, and the mixture was poured into hydrogen and allowed to react at room temperature overnight. After filtration, the solvent was evaporated to dryness crystals crystals crystals crystals crystals crystals crystalssssssssssssssssssssssssssssssssssssssssssssssss 0.15 g), 55% yield, which was used without further purification.
  • Step 2 Preparation of ((3-methoxythiophen-2-yl)methyl)-1-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl) Propyl]-2-amine (H27)
  • the preparation method is the same as in the first embodiment, the 3-trifluoromethoxybenzaldehyde in the seventh step is replaced by 2-trifluoromethoxy-3-bromobenzaldehyde to obtain (3-bromo-2-trifluoromethyl).
  • Oxybenzyl)-[2-(9-pyridin-2-yl-6-oxa-spiro[4.5]dec-9-yl)-ethyl]-amine (28, 35 mg) yield 55%
  • the appearance is light yellow viscous material.
  • the preparation method was the same as in Example 21, and the 2-trifluoromethoxybenzaldehyde in the fourth step was replaced by 2-difluoromethoxybenzaldehyde to obtain ⁇ 2-[9-(5-fluoro-pyridine-2). -yl)-6-oxa-spiro[4.5]dec-9-yl]-ethyl ⁇ -(2-(difluoromethoxy)-benzyl)-amine (29, 22 mg), yield 18 %, the appearance is yellow sticky.
  • the preparation method was the same as in Example 21, and the 2-trifluoromethoxybenzaldehyde in the fourth step was changed to 3-chlorothiophenecarboxaldehyde to obtain ⁇ 2-[9-(5-fluoro-pyridin-2-yl)- 6-oxa-spiro[4.5]dec-9-yl]-ethyl ⁇ -((3-chlorothien-2-yl)-methyl)-amine (30, 46 mg), yield 59%, appearance Light yellow viscous material.
  • the preparation method was the same as in Example 21, and the 2-trifluoromethoxybenzaldehyde in the fourth step was changed to 3,4-dimethylbenzaldehyde to obtain ⁇ 2-[9-(5-fluoro-pyridine-2). -yl)-6-oxa-spiro[4.5]dec-9-yl]-ethyl ⁇ -(3,4-dimethyl-benzyl)-amine (31,108 mg), yield 38%, The appearance is yellow viscous.
  • the preparation method was the same as in Example 21, and the 2-trifluoromethoxybenzaldehyde in the fourth step was changed to 3-chloro-2-methylbenzaldehyde to obtain ⁇ 2-[9-(5-fluoro-pyridine- 2-yl)-6-oxa-spiro[4.5]dec-9-yl]-ethyl ⁇ -(3-chloro-2-methyl-benzyl)-amine (32, 35 mg), yield 29 %, the appearance is yellow sticky.
  • the preparation method was the same as in Example 21, and the 2-trifluoromethoxybenzaldehyde in the fourth step was replaced by 2-difluoromethoxythiophenecarboxaldehyde to obtain ⁇ 2-[9-(5-fluoro-pyridine-2). -yl)-6-oxa-spiro[4.5]dec-9-yl]-ethyl ⁇ -((3-difluoromethoxythiophen-2-yl)-methyl)-amine (33, 58 mg) The yield was 36% and the appearance was a pale yellow viscous material.
  • This test was carried out using a HEK293 cell line stably expressing ⁇ opioid receptor, ⁇ opioid receptor or kappa opioid receptor (stable expression cell line was provided by WuXi PharmaTech).
  • the cells were quickly thawed in a 37 ° C water bath before the experiment, transferred to a 50 ml conical tube, and DMEM-based cell culture medium (Invitrogen, Cat #11960) was added to 45 ml. The cells were pelleted by centrifugation at 1000 rpm for 5 minutes at room temperature. Aspirate the supernatant and be careful not to aspirate the cells.
  • the pellet was flicked to loose cells and resuspended in 45 ml of DMEM medium, and the cells were counted using a Vi-CELL XR automatic cell viability detector (BECKMAN COULTER), and the cell concentration was adjusted to 10 ⁇ 10 5 according to the counting result.
  • Probenecid mother liquor configuration 1 ml of FLIPR test solution was added to 77 mg of probenecid to a 250 mM solution. Now available.
  • Fluo-4Direct TM Loading Buffer Configuration Thaw a bottle of Fluo-4DirectTM crystal (F10471, supplied in the kit), add 10ml of FLIPR Test Buffer (provided in the kit) to the vial and add 0.2ml The above-mentioned probenecid solution was finally measured at a concentration of 2.5 mM of probenecid, vortexed and allowed to stand for 10 minutes (protected from light). Now available.
  • test compound H01-H33, morphine and the corresponding positive drugs were subjected to a gradient dilution of 10 concentrations in 100% DMSO by Echo-550 instrument (Labcyte), starting from 1200 nM, 4 fold gradient The concentration range is from 0.004578 nM to 1200 nM.
  • a gradient of 900 nl of the compound solution as above was transferred to a 384-well compound plate for use (Greiner, #781280).
  • the positive drugs used in this experiment were: for ⁇ opioid receptor, DMAGO ([D-Ala, NMePhe, Gly-ol]-enkephalin, 78123-71-4, tocris); for ⁇ opioid receptor, DPDPE ( [D-Pen, D-Pen]-enkephalin, 88373-73-3, Gil Biochemical Co., Ltd.), for kappa opioid receptor, U69593 (96744-75-1, Sigma).
  • the cell plates prepared above were removed from the incubator and 20 ul of 2X Fluo-4 DirectTM buffer was added. The final volume in the cell plate was 40 ⁇ l. Incubate for 50 minutes at 37 ° C, 5% CO 2 , incubate for 10 minutes at room temperature, place in a FLIPR instrument (MD), and place in the compound plate and the tip box. The protocol was run on the FLIPRTETRA platform and 10 [mu]l of positive drug or test compound was transferred from the compound plate to the cell plate and the fluorescent signal was read.
  • the signal values generated for each well described above were calculated and calculated as % activity (test compound signal value - solvent signal value) / (positive drug signal value - solvent signal value).
  • the percentage of activity and the corresponding compound concentration were statistically plotted and plotted by the agonist formula in Graph Pad 7.0 software to calculate the EC 50 values as shown in the table below.
  • Table 1 EC 50 values of MOR, DOR, KOR receptors after agonism using the compounds of the invention
  • GPCR G protein-coupled receptor
  • HitHunter Adenosine Phosphate Adenase Fragmentation Technology is a proprietary technology of DiscoverX. The principle is to separate ⁇ -galactosidase ( ⁇ -gal) into two fragments, enzyme donor (ED) and enzyme receptor (EA). Each is inactive, but can rapidly complement to form an active ⁇ -gal enzyme in solution, producing a signal.
  • ⁇ -gal ⁇ -galactosidase
  • ED enzyme donor
  • EA enzyme receptor
  • ED-labeled cAMP binds to cAMP antibody (Ab)
  • ED-cAMP-Ab is not complementary to EA, but ED-cAMP can complement EA to form an active enzyme, producing a luminescent signal.
  • the amount of signal generated is proportional to the amount of cAMP in the cell.
  • the MOR receptor binds to the inhibitory G ⁇ i protein, so the experimental use of forskolin (for induction of cAMP signaling) induces cAMP expression, and the inhibitory effect of the compound on the above induction is determined.
  • the compound H01-H33, morphine, and endorphin (used as a reference drug for this experiment) used in this experiment were dissolved in DMSO to prepare a mother liquor of 1 mM.
  • the following working fluids were prepared: starting from the highest concentration of 4 uM, diluted by 3 times, a total of 10 concentration gradients, and the working fluid concentration range was 0.000232-4 uM.
  • the cAMP Hunter cell line (HEK293, DiscoverX) was removed from the freezer according to the Cell Standard Operating Procedure (SOP), and 20 mL was inoculated into a 384-well microplate and incubated overnight at 37 °C.
  • the HitHunter cAMP Assay test kit (DiscoverX, 90-0075SM) was used, which contained cAMP buffer, cAMP test solution, and cAMP working solution A.
  • the cell culture medium was changed to 15 ⁇ L of cAMP buffer (component: 10 ul of HBSS/10 mM Hepes solution, 5 ul of cAMP Ab reagent (antibody for binding to cAMP)). 5 ⁇ L of the compound solution or a working solution of morphine solution or endorphin solution (containing 20 ⁇ M of the throat throat (DiscoverX, 92-0005)) was added and incubated at 37 ° C for 60 minutes.
  • cAMP buffer component: 10 ul of HBSS/10 mM Hepes solution, 5 ul of cAMP Ab reagent (antibody for binding to cAMP)
  • 5 ⁇ L of the compound solution or a working solution of morphine solution or endorphin solution (containing 20 ⁇ M of the throat throat (DiscoverX, 92-0005) was added and incubated at 37 ° C for 60 minutes.
  • cAMP test solution component: CAMPXS+ED/CL (containing ED fragment for labeling cAMP)
  • cAMP working solution A component: CAMPXS+EA (EA fragment for binding) ED-cAMP, and generates a signal
  • This experiment set up a double hole.
  • the MAX control refers to the fluorescence signal value of the endorphin solution
  • the solvent control refers to the fluorescence signal value of DMSO.
  • the percentage of active compound concentration signal by statistical analysis agonists formula (own software, GM) by DiscoveRx CBIS data analyzing station (ChemInnovation, CA), 50 values were calculated EC.
  • the EC50 values of the compounds of the invention that agonize MOR to affect cAMP levels are shown in Table 2 below. From the data shown in Table 2, the cAMP pathway measured by the compound of the present invention has strong agonistic activity and superior performance to morphine.
  • the level of ⁇ -arrestin in cells was measured by DiscoverX's enzyme fragment complementation technique (PathHunter ⁇ -arrestin GPCR test). GPCR activation following ligand binding results in the recruitment of ⁇ -arrestin to the receptor, and the activation of the GPCR is measured by enzyme detection (EFC) technology to obtain signal detection to detect ⁇ -arrestin.
  • EFC enzyme detection
  • the PathHunter ⁇ -arrestin GPCR assay divides the b-galactosidase (b-gal) enzyme into two fragments, the enzyme donor (ED) and the enzyme receptor (EA), which are independent of each other and are in solution. They can be brought together and complemented to form an active b-gal enzyme, which in turn produces a signal.
  • ED enzyme donor
  • EA enzyme receptor
  • the compounds H01-H33, morphine, and endorphin (reference drug of this experiment) used in this experiment were dissolved in DMSO to prepare a mother liquor of 1 mM.
  • the following working fluids were prepared: starting from the highest concentration of 5 uM, diluted by 3 times, a total of 10 concentration gradients, the concentration range was 0.00029-5 uM.
  • the PathHunter cell line (HEK293, DiscoverX) was removed from the freezer according to standard operating procedures (SOP), expanded, and inoculated into a 384-well microtiter plate in a volume of 20 ⁇ L, and incubated at 37 ° C for 60 mins. 5 ⁇ L of the compound or working solution of morphine or endorphin was added to the wells of the above microplate, and incubated at 37 ° C or room temperature for 180 minutes.
  • the PathHunter Detection Kit (DiscoverX, 93-0001) was used.
  • PathHunter detection reagent was added to the cell plate to which the compound or morphine or endorphin was added according to the kit supplier's recommendation, and the test signal was generated by incubating for 1 hour at room temperature.
  • PerkinElmer Envision TM instrument a chemiluminescent signal.
  • Activity calculation formula: % activity 100% x (average RLU of the test sample - average RLU of the solvent control) / (average RLU of the MAX control ligand - average RLU of the solvent control).
  • the MAX control is the fluorescence signal value produced by endorphin.
  • the calculated percentage of activity is expressed in terms of maximum response efficiency (Maxmax, Emax).
  • Agonist compounds of the invention Table MOR receptor ⁇ -arrestin signaling pathway activity EC 50 see below 2. As can be seen from the data shown in Table 2 below, the ⁇ -arrestin signaling pathway measured using the compounds of the present invention is less active and superior to morphine.
  • Table 3 EC 50 of the compounds of the invention agonizing MOR receptors affecting the activity of the ⁇ -arrestin signaling pathway
  • H16 >10 3.12 H17 >10 1.78 H18 >10 0.48 H19 >10 1.12 H20 >10 2.12 H21 >10 0.08 H22 >10 2.31 H23 >10 2.20 H24 >10 2.76 H25 >10 3.20 H26 >10 22.56 H27 >10 3.32 H28 >10 6.26 H29 >10 7.07 H30 >10 2.91 H31 >10 5.06 H32 >10 11.68 H33 >10 8.69
  • Example H02 Male SD rats of 8 weeks old weighing 200 g-300 g were used as experimental animals, and the compound of Example H02, the compound of Example H04, the compound of Example H10, the compound of Example H16, the compound of Example H17, and the compound of Example H18 were measured and carried out.
  • the analgesic effect of the compounds of the invention is explored.
  • the paw withdrawal threshold (PWT) was less than 5 g) and was randomly assigned to each drug-administered group according to PWT.
  • the pain threshold was measured 30 minutes after the intravenous administration of the positive drug TRV130 or the compound of the present invention (at a dose of 0.3 mg/kg).
  • Pain-sensitive assays were performed using up-down. Mechanical pain results are expressed as the paw withdrawal response threshold (PWT) of the animal.
  • the rats were individually placed in a plexiglass box with a grid at the bottom of the box to ensure that the rat's feet could be tested.
  • the rats were acclimated for 15 minutes before the test, and after the completion of the adaptation, test fibers (von frey filaments, West coast) were used to test in the middle of the hind paw of the rats.
  • the test fibers included 8 test intensities: 3.61 (0.4 g), 3.84 (0.6 g), 4.08 (1 g), 4.31 (2 g), 4.56 (4 g), 4.74 (6 g), 4.93 (8 g), 5.18 (15 g).
  • test fibers were pressed vertically to the skin and forced to bend the fibers for 6-8 seconds with a test interval of 5 seconds.
  • the animal's rapid contraction was recorded as a pain response.
  • the animal's foot is also recorded as a pain response when the test fiber leaves the animal's skin.
  • 50% paw withdrawal response threshold 10 (Xf + k ⁇ ) / 10,000.
  • Xf the logarithm of the von Frey filament used in the last test
  • K value the animal withdrawal reaction mode (recorded at the time of the test), which is the value obtained by looking up the table according to the measured "X" and "O" sequences
  • ⁇ the mean of the logarithmic difference between the von Frey filaments used in the test.
  • Example H05 Male SD rats of 8 weeks old weighing 200 g-300 g were used as experimental animals, and the compound of Example H05, the compound of Example H08, the compound of Example H10, the compound of Example H16, the compound of Example H17, and the compound of Example H18 were measured and carried out.
  • the effect of the inventive compounds on respiratory depression was investigated.
  • Examples H05 compound, Example H08 compound, Example H10 compound, Example H16 compound, Example H17 compound, Example H18 compound, Example H21 compound, and Example H24 compound are examples of:
  • each animal was anesthetized with sodium pentobarbital (50-60 mg/kg, ip), then the right common carotid artery was isolated and unilateral carotid artery catheterization was performed (PE60, ID*).
  • the length of OD* is 0.76mm*1.22mm*20cm, the artery is buried 1cm, the tube is filled with heparin sodium sealing solution), and the operation is resumed for 1 day.
  • the invention is administered intravenously in a single dose.
  • 0.4-0.5 mL of arterial blood was taken through the embedding tube before administration, 5 min, 30 min, 60 min, and 120 min after administration, and the blood pH was measured immediately by a blood gas analyzer (Radiometer Medical ApS, ABL90FLEX). pH), partial pressure of carbon dioxide (PCO 2 ) and partial pressure of oxygen (PO 2 ).
  • the partial pressures of carbon dioxide measured before and after administration of the compound of the present invention and morphine are shown in Table 5 below. As can be seen from Table 5 below, the compounds of the present invention have a weaker effect on respiratory depression at therapeutic doses.
  • Example H01 Male SD rats weighing 200-300 g and 8 weeks old were used as experimental animals, and the compound of Example H01, the compound of Example H04, the compound of Example H05, the compound of Example H07, and the examples were determined by LC/MS/MS method. The concentration of the drug in plasma at different times after the H16 compound, the compound of Example H17, the compound of Example H18, the compound of Example H21, and the compound of Example H24. The pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
  • the above compound was intravenously administered to rats at a dose of 1 mg/kg, and 0.2 ml of blood was collected from the eyelids before and after administration at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0 hours.
  • plasma was separated by centrifugation at 6000 rpm for 10 minutes at 4 ° C, and stored at -80 ° C.
  • the liquid chromatography system is the LC-20AD UFLC High Performance Liquid Chromatography System (Shimadzu, LC-20AD).
  • the mass spectrometry system was equipped with an electrospray ionization source (ESI) (Applied Biosystems, Canada) for the AB Sciex API4000 tertiary quadrupole mass spectrometer.
  • ESI electrospray ionization source
  • the software used to control the LC/MS and quantitative analysis was Analyst 1.6 (Applied Biosystems, Canada) and the pharmacokinetic parameters were analyzed using WinNonlin (version 5.2, Pharsight, Mountain View, CA) non-compartmental models.
  • the liquid chromatography was separated using an AQ-C18 column (50 x 2.1 mm, inner diameter 5 ⁇ m). The column temperature was maintained at room temperature. The composition and gradient of the mobile phase are shown in Table 6 below.
  • test compound was dissolved in DMSO to prepare a stock solution with a concentration of 1 mg/mL, and diluted with 70% acetonitrile to obtain a series of standard working solutions at concentrations of 30, 10, 3, 1, 0.3, 0.1, 0.03 and 0.01 ⁇ g. /mL, and a series of standard quality control solutions (24, 8 and 0.03 ⁇ g/mL).
  • a standard solution 3000, 1000, 300, 100, 30, 10, 3, and 1 ng/mL
  • a quality control standard solution plasma sample 2400
  • a solid powder of the internal standard tolbutamide was dissolved in DMSO to prepare a 1 mg/mL stock solution.
  • the stock solution was diluted with 100% acetonitrile to give a 200 ng/mL solution as a protein precipitant.
  • the pharmacokinetic parameters of the compounds of the invention after administration are shown in Table 6 below. As can be seen from the data shown in Table 6, the compounds of the present invention have better pharmacological absorption and better pharmacokinetic characteristics.
  • ICR mice male and female weighing 200-220 g, 8 weeks old were used as experimental animals, and the compound of Example H10, the compound of Example H16, the compound of Example H17, the compound of Example H21, and the compound of Example H24 were intravenously injected.
  • the drug was administered once for 14 days, including clinical observation, body weight and pathological examination.
  • Example H10 The compound of Example H10, the compound of Example H16, the compound of Example H17, the compound of Example H21, and the compound of Example H24 were measured.
  • mice The acute toxicity of the mice after single intravenous administration of the compound of the examples was observed by the upper and lower methods, and 10 mice per male and female, each half male and half.
  • the administration doses were 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 35 mg/kg, and the administration volume was 10 ml/kg, and the compound was intravenously injected using the above-mentioned vehicle to prepare a clear transparent solution.
  • the dose per animal mortality using Bliss software calculates the median lethal dose (LD 50).
  • the LD 50 value of the compound of the present invention after intravenous administration is between 20 and 30 mg/kg. Better security.

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Abstract

一类μ-阿片受体激动剂及其制备方法和在医药领域的应用，属于药物化学领域。所述μ-阿片受体激动剂对G蛋白信号通路的选择性显著提高，不仅能表现出优异的药效作用，而且在安全性方面也得到显著改善。

Description

μ-阿片受体激动剂及其制备方法和在医药领域的应用 技术领域
本发明属于药物化学领域，具体涉及一类氧杂螺环类小分子化合物及其制备方法和在医药领域的应用。
背景技术
阿片类受体属于G蛋白偶联受体(GPCR)家族成员之一，在中枢神经系统中高度表达，通过中枢神经系统调控机体的一系列行为，包括痛觉、情感、应激反应等，主要有3种亚型:μ阿片受体(MOR)、δ阿片受体(DOR)、κ阿片受体(KOR)(Nature,2016,537(7619):185)。阿片受体激动剂是目前最为广泛使用的镇痛药，其中作用于μ-阿片受体(μ-opioid receptor,MOR)的激动剂具有镇痛活性强、抗痛谱广的优点，在中度和重度疼痛治疗中具有不可替代的作用。
MOR激动剂吗啡是从罂粟中提取的天然产物，作为镇痛药治疗急性重度疼痛已经有上百年的历史，在此之后，种类繁多的吗啡衍生物和合成化合物如羟考酮、氢吗啡酮、羟吗啡酮、左啡诺、丁丙诺啡、芬太尼、舒芬太尼、哌替啶等作为MOR激动剂被开发成为临床用镇痛药，虽然这些MOR激动剂具有强效的镇痛作用，但所有化合物均表现出了相似的临床副作用：便秘、恶心、呕吐、镇静、呼吸抑制等，此外，这些MOR激动剂诱导的欣愉和躯体依赖极易产生成瘾性和滥用，从而引发社会性问题(Journal of Medicinal Chemistry,2013,56(20):8019-31)，MOR激动剂的长期使用还会导致镇痛耐受，需要剂量递增来控制疼痛，从而进一步增加上述的临床副作用(Anasthesiol Intensivmed Notfallmed Schmerzther.2003,38,14-26.)。
包括MOR激动剂在内的大部分GPCR激动剂除了偶联G蛋白亚基激活G蛋白信号通路外，还可以激活其它信号通路，其中激活由β-arrestin介导的信号通路影响较大，β-arrestin可以结合到活化的GPCR上，使GPCR发生受体脱敏反应，中止G蛋白信号传导；β-arrestin还可以募集胞吞蛋白，诱导GPCR内吞；与GPCR下游信号分子形成复合物，激活其它信号传导分子，如MAPK、Src等激酶。近年来研究发现，β-arrestin通路与MOR激动剂多个副作用相关，如便秘、呼吸抑制和镇痛耐受(Science 1999,286,2495-2498；J.Pharmacol.Exp.Ther.2005,314,1195-1201)。因此，研发一种可选择性激活G蛋白信号通路的“偏向性”MOR激动剂药物，可降低β-arrestin介导的副作用，具有显著的临床价值和社会意义。
目前已有Trevena Inc公司申请的专利WO2012129495和江苏恒瑞医药有限公司的WO2017063509公开了一系列G蛋白偏向性MOR激动剂，两个专利所公开化合物均为氧杂螺环类衍生物，Trevena Inc公司的化合物对G蛋白信号通路的选择性有限(J.Med.Chem.2013,56,8019-8031)，而在江苏恒瑞医药有限公司的专利WO2017063509中将化合物芳基的苄位成环，化合物的Emax提高，但G蛋白信号通路的选择性仍然有限，虽然目前已经公开了一系列G蛋白偏向性MOR激动剂的专利，但仍需要开发新的具有更好的药效、 选择性、药物代谢结果的MOR激动剂。
发明内容
针对现有技术的需求，发明人重新设计并合成了一类MOR激动剂，该类化合物对G蛋白信号通路的选择性显著提高。
本发明的目的在于提供一种通式(I)所示的化合物，以及它们的立体异构体、互变异构体、对映体、非对映体、消旋体和可药用的盐
Figure PCTCN2018105946-appb-000001
其中，
Ar 1为取代的或未取代的芳基、取代的或未取代的杂芳基；Ar 1具体可为苯基、吡啶基、被取代的苯基、或被取代的吡啶基，其中所述苯基或所述吡啶基任选的被下列一个或多个取代基所取代：-C 1-3烷基、-C 1-3烷氧基或卤素；
A为-C 1-2亚烷基，或为被C 1-3烷基取代的-C 1-2亚烷基时，B为-NH-CH 2-Ar 2、-NH-C(O)-Ar 2或-NR 1R 2，其中R 1和R 2连同它们所连接的氮原子一起形成被T取代或未被取代的6-12元的杂芳基；
T为-OH、-C 1-3烷基、-C 1-3烷氧基、羟基取代的C 1-3烷基、卤素取代的C 1-3烷基、卤素取代的C 1-3烷氧基、卤素、氨基、单(C 1-3烷基)-氨基-、双(C 1-3烷基)-氨基-、腈基、苄基或苯基。
进一步的，当A为-C 1-2亚烷基，或为被甲基取代的-C 1-2亚烷基；
-NR 1R 2为
Figure PCTCN2018105946-appb-000002
Ar 2为被取代的或未取代的苯基、被取代的或未取代的5-6元杂芳基，其中所述苯基或所述5-6元杂芳基任选的被下列一个或多个取代基所取代：-OH、-C 1-3烷基、-C 1-3烷氧基、羟基取代的C 1-3烷基、卤素取代的C 1-3烷基、卤素取代的C 1-3烷氧基、卤素、氨基、单(C 1-3烷基)-氨基-、双(C 1-3烷基)-氨基-、腈基、苄基或苯基；
其中Ar 2可具体为被上述取代基取代的苯基、噻吩基、咪唑基、吡啶基或吡唑基；
Ar 2还可具体为
Figure PCTCN2018105946-appb-000003
Figure PCTCN2018105946-appb-000004
在特定的实施方案中，如上所述通式(I)所示的化合物为：
(3-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
(2-氯-4-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
N-甲基-2-(((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)甲基)苯胺；
(3-氯-2-甲基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
((3-氯-噻吩-2-基)甲基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
(4-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
(3,4-二甲基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
(2,4-二甲基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
(2-三氟甲氧基苄基)-[2-(9-(3-氯-5-氟吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
(2-三氟甲氧基苄基)-[2-(9-(3-甲基-5-氟吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
(4-溴-2-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
(4-甲基-2-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
3-{[(2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺甲基}-2-三氟甲氧基苯甲腈；
((3-三氟甲基噻吩-2-基)甲基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
4-{[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基胺]甲基}-3-三氟甲氧基苯酚；
(2-二氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
(5-氯-2-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
((3-二氟甲氧基噻吩-2-基)甲基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
2-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]-7-三氟甲基-1,,2,3,4-四氢异喹啉；
7-甲氧基-2-[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-1,2,3,4-四氢异喹啉；
{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-(2-(三氟甲氧基)-苯甲基)-胺；
(2-三氟甲氧基苯甲基)-[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-胺；
6-[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-4,5,6,7-四氢-噻吩并[2,3-c]吡啶；
3-甲基氨基-噻吩-2-羧酸[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-酰胺；
[(5-甲氧基-1H-吡唑-4-基)甲基]-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
((3-甲氧基噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)丙基]-1-胺；
((3-甲氧基噻吩-2-基)甲基)-1-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)丙基]-2-胺；
(3-溴-2-三氟甲氧基苯甲基)-[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-胺；
{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-(2-(二氟甲氧基)-苯甲基)-胺；
{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-((3-氯噻吩-2-基)-甲基)-胺；
{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-(3,4-二甲基-苯甲基)-胺；
{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-(3-氯-2-甲基-苯甲基)-胺；或
{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-((3-二氟甲氧基噻吩-2-基)-甲基)-胺。
如上所述，本发明还包括式(I)的化合物的药用可接受的盐和其立体异构体。
所述药用可接受的盐有无机碱盐，如钠盐、钾盐、钙盐或铝盐；有机碱盐，如赖氨酸盐、精氨酸盐、三乙胺盐、二苄胺盐、哌啶盐及其他药学上可接受的有机胺盐。
在本发明的化合物分子中包含至少一个可成盐的氮原子时，可以通过在有机溶剂(如乙腈、四氢呋喃)中与相应的有机酸或无机酸反应，从而转化为相应的盐。典型的有机酸有草酸、酒石酸、马来酸、琥珀酸、柠檬酸；典型的无机酸有硝酸、盐酸、硫酸、磷酸，优选为硝酸。
在本发明的化合物中具有一个或多个不对称碳原子时，它们能够以如下形式存在：光学纯的对映异构体、纯的非对映异构体、对映异构体混合物、非对映异构体混合物、对映异构体外消旋混合物、外消旋物或外消旋物混合物。式(I)的化合物的全部可能的异构体、立体异构体和其混合物也在本发明的范围内。
本发明涉及一种制备通式(I)所示化合物的方法，其中：
当A为-C 1-2亚烷基，B为-NH-CH 2-Ar 2时，合成路线如方案1：
方案1
Figure PCTCN2018105946-appb-000005
其中Ar1、Ar2如权利要求1、2、3、4或5中定义的，所述酸优选为硫酸、盐酸、磷酸、三氟甲磺酸、氢溴酸或其组合；所述氧化剂优选为氯铬酸吡啶盐(PCC)、重铬酸吡啶盐(PDC)或其组合；所述芳基格式试剂优选为芳基溴化镁、芳基氯化镁或其组合；所述碱优选为氢氧化钾、氢氧化钠或其组合；所述还原剂1优选为四氢锂铝、硼烷四氢呋喃、硼烷二甲硫醚或其组合；所述还原剂2优选为硼氢化钠、硼氢化钾，三乙酰基硼氢化钠、 氰基硼氢化钠或其组合；
当A为被C 1-3烷基取代的-C 1-2亚烷基时，B为-NH-CH 2-Ar 2，合成路线如方案2或方案3，
方案2
Figure PCTCN2018105946-appb-000006
其中Ar1、Ar2为如权利要求1、2、3或4中定义的，R3为C1-3烷基，所述碱优选为氢化钠、二异丙基氨基锂、丁基锂叔丁醇钾、乙醇钠、六甲基二硅基氨基锂、六甲基二硅基氨钾或其组合；所述还原剂1优选为四氢锂铝、硼烷四氢呋喃、硼烷二甲硫醚或其组合；所述还原剂2优选为硼氢化钠、硼氢化钾、三乙酰基硼氢化钠、氰基硼氢化钠或其组合；
方案3
Figure PCTCN2018105946-appb-000007
其中Ar1、Ar2为如权利要求1、2、3或4中定义的，R4为C1-3烷基，所述还原剂1优选为四氢锂铝、硼烷四氢呋喃、硼烷二甲硫醚或其组合；所述还原剂2优选为硼氢化钠、硼氢化钾、三乙酰基硼氢化钠、氰基硼氢化钠或其组合；
当A为-C 1-2亚烷基，B为-NH-C(O)-Ar 2时，合成路线如方案4，
方案4
Figure PCTCN2018105946-appb-000008
其中Ar 1、Ar 2如权利要求1、2、3或4中定义的，优选所述缩合剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)/1-羟基苯并三唑(HOBT)、二环己基碳二亚胺(DCC)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)或其组合；
当A为-C 1-2亚烷基，B为-NR 1R 2时，合成路线如方案5，
方案5
Figure PCTCN2018105946-appb-000009
其中Ar 1、R 1、R 2如权利要求1、2、3或4中定义的，所述碱优选为氢氧化钠、氢氧化钾或其组合，所述缩合剂优选为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)/1-羟基苯并三唑(HOBT)、二环己基碳二亚胺(DCC)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)或其组合，所述还原剂优选为四氢锂铝、硼烷四氢呋喃、硼烷二甲硫醚或其组合。
本发明涉及一种通式(I)所示化合物或其可药用的盐的制备方法，其中当A为-C 1-2亚烷基，B为-NH-CH 2-Ar 2时，合成路线归纳如下(方案1’)：
方案1’
Figure PCTCN2018105946-appb-000010
其中Ar 1、Ar 2为如以上所定义的。
环戊酮与3-丁烯-1-醇在硫酸条件下生成螺环中间体1-2，1-2经合适的氧化剂氧化制得化合物1-3，1-3与氰基乙酸乙酯反应得到中间体1-4，1-4与格式试剂反应得到化合物1-5，1-5在碱性条件下水解脱羧，进一步还原氰基得到烷基胺1-7，1-7与相应的醛发生还原胺化得到最终化合物1-8。
本发明涉及一种通式(I)所示化合物或其可药用的盐的制备方法，其中当A为被C 1-3烷基取代的-C 1-2亚烷基时，B为-NH-CH 2-Ar 2，合成路线归纳如下(方案2’和方案3’)：
方案2’
Figure PCTCN2018105946-appb-000011
其中Ar 1、Ar 2为如以上所定义的，R 3为C 1-3烷基。
化合物1-6在碱的作用下与卤代烷R 3X反应后还原氰基得到化合物2-2，2-2与相应的醛发生还原胺化得到最终化合物2-3。
方案3’
Figure PCTCN2018105946-appb-000012
其中Ar 1、Ar 2为如以上所定义的，R 4为C 1-3烷基。
化合物1-6与烷基锂化合物R 4Li反应后，经还原剂还原得到中间体3-1，3-1与相应的醛发生还原胺化得到最终化合物3-2。
本发明涉及一种通式(I)所示化合物或其可药用的盐的制备方法，其中当A为-C 1-2亚烷基，B为-NH-C(O)-Ar 2时，合成路线归纳如下(方案4’)：
方案4’
Figure PCTCN2018105946-appb-000013
其中Ar 1、Ar 2为如以上所定义的。
中间体1-7与相应的羧酸Ar 2COOH在缩合剂作用下反应生成化合物4-1。
本发明涉及一种通式(I)所示化合物或其可药用的盐的制备方法，其中当A为-C 1-2亚烷基，B为-NR 1R 2时，合成路线归纳如下(方案5’)：
方案5’
Figure PCTCN2018105946-appb-000014
其中Ar 1、R 1、R 2为如以上所定义的。
中间体1-6在碱性条件下水解制得酸5-1，5-1在缩合剂的条件下与相应的胺缩合，经还原后得到最终产品5-3。
本发明还提供了一种药物组合物，其包含上述至少一个化合物以及任选一种或多种医药上可接受的载剂和/或添加剂。
本发明所提供的药物组合物可以制备为任何形式，例如颗粒、粉末、片剂、包衣片剂、胶囊、药丸、糖浆、滴剂、溶液、混悬剂和乳剂，或者活性成分的缓释制剂，其中胶囊剂的实例包括硬或软明胶胶囊剂，颗粒剂和粉剂可以是非泡腾或泡腾形式。
本发明的药物组合物可进一步包括一种或多种医药或生理上可接受的载体，这些载体将适当配制以便于给药。例如，医药或生理上可接受的载体可以是盐水、热压水、林格氏液、缓冲盐水、葡萄糖、麦芽糖糊精、甘油、乙醇及其混合物。
本发明的药物组合物还可以包括医药或生理上可接受的添加剂，例如稀释剂、润滑剂、粘合剂、助流剂、崩解剂、甜味剂、矫味剂、湿润剂、分散剂、表面活性剂、缓冲盐水、涂层剂、发泡剂、防腐剂、稳定剂或芳香剂。
可以使用的稀释剂的实例包括但不限于乳糖、蔗糖、淀粉、高岭土、盐、甘露糖醇和磷酸二钙；润滑剂的实例包括但不限于滑石、淀粉、镁或钙的硬脂酸盐、石松子和硬脂酸；粘合剂的实例包括但不限于微晶纤维素、黄蓍胶、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；助流剂的实例包括但不限于胶体二氧化硅；崩解剂的实例包括但不限于交联羧甲基纤维素钠、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、膨润土、甲基纤维素、琼脂和羧甲基纤维素；甜味剂的实例包括但不限于蔗糖、乳糖、甘露糖醇和人工甜味剂，例如环磺酸钠和糖精，和任意数量的喷雾干燥矫味剂；矫味剂的实例包括但不限于从植物提取的天然矫味剂，例如果实，和味道较好的化合物，例如但不限于薄荷和水杨酸甲酯；湿润剂的实例包括但不限于丙二醇一硬脂酸酯、脱水山梨醇一油酸酯、二甘醇一月桂酸酯和聚氧乙烯月桂基醚。
表面活性剂可以选自洗涤剂、乙氧基化蓖麻油、聚乙二醇化甘油酯、乙酰化单酸甘油酯、山梨糖醇酐脂肪酸酯、泊洛沙姆如188和407、聚氧乙烯山梨聚糖脂肪酸酯、聚氧乙烯衍生物如烷基化和烷氧基化的衍生物(吐温，如吐温-20、或者吐温-80)、甘油一酸酯或它们的乙氧基化衍生物、甘油二酸酯或它们的聚氧乙烯衍生物、甘油、胆酸或其衍生物、卵磷脂、醇类和磷脂、甘油磷酸脂(卵磷脂、脑磷脂、磷脂酰丝氨酸)、甘油糖脂(半乳吡喃糖苷)、鞘磷脂(鞘髓磷脂)、和鞘糖脂(神经酰胺、神经节苷脂)、DSS(多库酯 钠、多库酯钙、多库酯钾、SDS(十二烷基硫酸钠或月桂基硫酸钠)、二棕榈酰磷脂酸(dipalmitoyl phosphatidic acid)、辛酸钠、胆汁酸及其盐以及甘氨酸或牛磺酸偶联物、熊去氧胆酸、胆酸钠、脱氧胆酸钠、牛磺胆酸钠、甘氨胆酸钠、N-十六烷基-N,N-二甲基-3-铵基-1-丙磺酸盐、阴离子(烷基-芳基-磺酸盐)一价表面活化剂、棕榈酰溶血磷脂酰基-L-丝氨酸、溶血磷脂质(例如，乙醇胺、胆碱、丝氨酸或苏氨酸的1-酰基-sn-甘油-3-磷酸酯)、烷基、烷氧基(烷基酯)、溶血磷脂酰基胆碱的烷氧基(烷基醚-衍生物)和磷脂酰胆碱的烷氧基(烷基醚-衍生物)，如溶血磷脂酰胆碱的十二酰衍生物和十四酰衍生物、二棕榈酰磷脂酰胆碱、以及极性头部基团的改性，即胆碱、乙醇胺、磷脂酸、丝氨酸、苏氨酸、丙三醇、肌醇、和带正电荷的DODAC、DOTMA、DCP、BISHOP、溶血磷脂酰丝氨酸和溶血磷脂酰苏氨酸、两性离子表面活性剂(例如N-烷基-N,N-二甲基铵基-1-丙磺酸盐、3-胆酸酰胺基-1-丙基二甲基铵基-1-丙磺酸盐、十二烷基磷酸胆碱、肉豆蔻酰基溶血磷脂酰胆碱、鸡蛋溶血卵磷脂)、阳离子表面活性剂(季铵碱)(例如，十六基-三甲基溴化铵、氯化十六烷基吡啶鎓)、非离子型表面活性剂、聚氧化乙烯/聚氧化丙烯嵌段共聚物(普流罗尼(Pluronics)/Tetronics、Triton X-100、十二烷基β-D-吡喃葡萄糖苷)或者聚合物表面活性剂(吐温-40、吐温-80、Brij-35(苄泽-35))、梭链孢酸衍生物(如牛磺二氢梭链孢酸钠等)、C6-C12长链脂肪酸及其盐(例如，油酸和辛酸)、酰基肉毒碱和衍生物、赖氨酸、精氨酸或组氨酸的Nα-酰化的衍生物、或者赖氨酸或精氨酸的侧链酰化衍生物、包含赖氨酸、精氨酸或组氨酸以及中性或者酸性氨基酸的任何组合的二肽的Nα-酰化衍生物、包含中性氨基酸和两个带电荷氨基酸的任何组合的三肽的Nα-酰化衍生物，或它们的混合物。
上述缓冲盐水可以选自乙酸钠缓冲液、碳酸钠缓冲液、柠檬酸盐缓冲液、甘氨酰甘氨酸缓冲液、组氨酸缓冲液、甘氨酸缓冲液、赖氨酸缓冲液、精氨酸缓冲液、磷酸钠缓冲液、和三(羟基甲基)-氨基甲烷缓冲液、或者它们的混合物，还可以是甘氨酰甘氨酸缓冲液、磷酸钠缓冲液或者它们的混合物。
上述防腐剂可以选自苯酚、间甲酚、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、2-苯氧基乙醇、对羟基苯甲酸丁酯、2-苯基乙醇、苄醇、氯丁醇、和硫柳汞(thiomerosal)、或者它们的混合物，也可以是苯酚或间甲酚。
防腐剂以约0.1mg/ml至约50mg/ml的浓度、以约0.1mg/ml至约25mg/ml的浓度、或者以约0.1mg/ml至约10mg/ml的浓度存在。
上述稳定剂包括但不限于聚乙二醇(如PEG3350)、聚乙烯醇(PVA)、聚乙烯吡咯烷酮、羧甲基纤维素、不同的盐(如氯化钠)、L-甘氨酸、L-组氨酸、咪唑、精氨酸、赖氨酸、异亮氨酸、天冬氨酸、色氨酸、和苏氨酸或者它们的任何混合物。
本发明还提供了上述化合物或者药物组合物在制备用于预防和/或治疗MOR受体激动剂介导的相关疾病的药物中的用途。
如上所述的MOR受体激动剂介导的相关疾病包括但不限于疼痛、炎症、免疫功能障碍、食管回流、神经和精神病症或呼吸道疾病。
上述所提到的疼痛包括但不限于创伤性疼痛、神经性疼痛、炎性疼痛、内脏疼痛、偏 头痛和与癌症有关的疼痛。上述所提到的疼痛可以是术后疼痛、由癌症引起的疼痛、神经性疼痛、由创伤引起的疼痛或是由炎症引起的疼痛。
本发明所提供化合物或者药物组合物还可以用于泌尿和生殖病症、药物和酒精滥用、胃炎或腹泻。相应地，本发明提供了本发明所提供的化合物或者药物组合物在制备用于改善泌尿和生殖病症、药物和酒精滥用、胃炎或腹泻的药物中的用途。
给予本文中所述化合物和/或其药用盐的量和频率将根据主治临床医生考虑这些因素如年龄、病症和患者的大小以及被治疗的症状的严重性的判断来调节。通常，考虑的是有效量可以为0.001mg/kg至10mg/kg体重，可具体地为0.01mg/kg至1mg/kg体重。
在一些实施方式中，药物制剂为单位剂量形式。单位剂量的制剂中活性化合物的量可根据具体应用改变或调节：从约0.01mg至约1000mg、从约0.01mg至约750mg、从约0.01mg至约500mg、或者从约0.01mg至约250mg。
该本发明的化合物对G蛋白信号通路的选择性显著提高，不仅能表现出优异的药效作用，而且在安全性方面也得到显著改善。
具体实施方式
除非有相反说明，本文使用的部分术语具有如下涵义：
在本文中，术语“C 1-3烷基”包括包含1至3个碳原子的烷基。
在本文中，术语“芳基”包括5和6元的单环芳族基团，其可以包含0-4个杂原子，例如苯、苯基、吡咯、呋喃、噻吩、噻唑、异噻唑、咪唑、三唑、四唑、吡唑、唑、异唑、吡啶、吡嗪、哒嗪和嘧啶等；此外，术语“芳基”还包括多环芳基，例如三环、二环，例如萘、苯并唑、苯并二唑、苯并噻唑、苯并咪唑、苯并噻吩、亚甲二氧基苯基、喹啉、异喹啉、萘啶、吲哚、苯并呋喃、嘌呤、苯并呋喃、脱氮嘌呤或中氮茚。这些具有杂原子的芳基也称为“芳基杂环”、“杂环”、“杂芳基”或“杂芳族基团”。
典型的杂芳基包括2-或3-噻吩基；2-或3-呋喃基；2-或3-吡咯基；2-、4-或5-咪唑基；3-、4-或5-吡唑基；2-、4-或5-噻唑基；3-、4-或5-异噻唑基；2-、4-或5-唑基；3-、4-或5-异唑基；3-或5-1，2，4-三唑基；4-或5-1，2，3-三唑基；四唑基；2-、3-或4-吡啶基；3-或4-哒嗪基；3-、4-或5-吡嗪基；2-吡嗪基；2-、4-或5-嘧啶基。
本文使用的术语“杂芳基”还指其中杂芳族环与一个或多个芳基、环脂族或杂环基的环稠合的基团，其中其连接基团或连接点位于杂芳族环上。其实例包括但不限于1-、2-、3-、5-、6-、7-或8-中氮茚基；1-、3-、4-、5-、6-或7-异吲哚基；2-、3-、4-、5-、6-或7-吲哚基；2-、3-、4-、5-、6-或7-吲唑基；2-、4-、5-、6-、7-或8-嘌呤基；1-、2-、3-、4-、6-、7-、8-或9-喹嗪基；2-、3-、4-、5-、6-、7-或8-喹啉基；1-、3-、4-、5-、6-、7-或8-异喹啉基；1-、4-、5-、6-、7-或8-酞嗪基；2-、3-、4-、5-或6-萘啶基；2-、3-、5-、6-、7-或8-喹唑啉基；3-、4-、5-、6-、7-或8-噌啉基；2-、4-、6-或7-蝶啶基；1-、2-、3-、4-、5-、6-、7-或8-4aH咔唑基；1-、2-、3-、4-、5-、6-、7-或8-咔唑基；1-、3-、4-、5-、6-、7-、8-或9-咔啉基；1-、2-、3-、4-、6-、7-、8-、9-或10-菲啶基；1-、2-、3-、4-、5-、6-、7-、 8-或9-吖啶基；1-、2-、4-、5-、6-、7-、8-或9-啶基；2-、3-、4-、5-、6-、8-、9-或10-菲咯啉基；1-、2-、3-、4-、6-、7-、8-或9-吩嗪基；1-、2-、3-、4-、6-、7-、8-、9-或10-吩噻嗪基；1-、2-、3-、4-、6-、7-、8-、9-或10-吩嗪基；2-、3-、4-、5-、6-或1-、3-、4-、5-、6-、7-、8-、9-或10-苯并异喹啉基；2-、3-、4-或噻吩并[2，3-b]呋喃基；2-、3-、5-、6-、7-、8-、9-、10-或11-7H-吡嗪并[2，3-c]咔唑基；2-、3-、5-、6-或7-2H-呋喃并[3，2-b]-吡喃基；2-、3-、4-、5-、7-或8-5H-吡啶并[2，3-d]-o-嗪基；1-、3-或5-1H-吡唑并[4，3-d]-唑基；2-、4-或5-4H-咪唑并[4，5-d]噻唑基；3-、5-或8-吡嗪并[2，3-d]哒嗪基；2-、3-、5-或6-咪唑并[2，1-b]噻唑基；1-、3-、6-、7-、8-或9-呋喃并[3，4-c]噌啉基；1-、2-、3-、4-、5-、6-、8-、9-、10或11-4H-吡啶并[2，3-c]咔唑基；2-、3-、6-或7-咪唑并[1，2-b][1，2，4]三嗪基；7-苯并[b]噻吩基；2-、4-、5-、6-或7-苯并唑基；2-、4-、5-、6-或7-苯并咪唑基；2-、3-、4-、5-、6-或7-苯并噻唑基；1-、2-、4-、5-、6-、7-、8-或9-苯并氧杂基；2-、4-、5-、6-、7-或8-苯并嗪基；1-、2-、3-、5-、6-、7-、8-、9-、10-或11-1H-吡咯并[1，2-b][2]苯并氮杂基。典型的稠合杂芳基包括2-、3-、4-、5-、6-、7-或8-喹啉基；1-、3-、4-、5-、6-、7-或8-异喹啉基；2-、3-、4-、5-、6-或7-吲哚基；2-、3-、4-、5-、6-或7-苯并[b]噻吩基；2-、4-、5-、6-或7-苯并唑基；2-、4-、5-、6-或7-苯并咪唑基；2-、4-、5-、6-或7-苯并噻唑基。
本文使用的“芳基”或“杂芳基”的芳环可以在一个或多个环位置上被上文所述的取代基取代，例如卤素、羟基、烷氧基、烷基羰基氧基、芳基羰基氧基、烷氧基羰基氧基、芳基氧基羰基氧基、羟基羰基、烷基羰基、烷基氨基羰基、芳基烷基氨基羰基、烯基氨基羰基、烷基羰基、芳基羰基、芳基烷基羰基、烯基羰基、烷氧基羰基、氨基羰基、烷硫基羰基、磷酸酯、膦酸酯、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、羟基硫代羰基、硫酸酯、烷基亚磺酰基、磺酸酯基、氨磺酰基、磺酰氨基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基，或芳族基团或杂芳族基团，其中芳基基团也可以与非芳族的脂环或杂环稠合或桥连，以形成多环(例如四氢萘)。
在本文中，术语“烷氧基”包括与氧原子共价连接的被取代的和未被取代的烷基。烷氧基的实例包括甲氧基、乙氧基、异丙基氧基、丙氧基、丁氧基和戊氧基。被取代的烷氧基的实例包括卤代烷氧基。烷氧基可被以下基团取代：烯基、炔基、卤素、羟基、烷基羰基氧基、芳基羰基氧基、烷氧基羰基氧基、芳氧基羰基氧基、羟基羰基、烷基羰基、芳基羰基、烷氧基羰基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、烷硫基羰基、磷酸酯基、氰基、氨基(包括烷基氨基、二烷基氨基、芳基氨基、二芳基氨基和烷基芳基氨基)、酰基氨基(包括烷基羰基氨基、芳基羰基氨基、氨基甲酰基和脲基)、脒基、亚氨基、巯基、烷硫基、芳硫基、羟基硫代羰基、烷基亚磺酰基、磺酸基、氨磺酰基、磺酰氨基、硝基、三氟甲基、氰基、叠氮基、杂环基、烷基芳基或芳族基团。
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例1：(3-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺的制备(H01)
Figure PCTCN2018105946-appb-000015
第一步：制备6-氧杂螺[4.5]癸烷-9-醇(1-2)
将3-丁烯-1-醇(10g，142mmol)和环戊酮(6g，71mmol)加入到茄形瓶中，冷却至0℃。向反应液中缓慢滴加75％硫酸，逐渐升至室温后反应过夜。向反应体系中加入水(100ml)，用氢氧化钠调节pH到8，用乙醚萃取(3×150ml)，乙醚层用饱和亚硫酸氢钠洗(40ml)，硫酸镁干燥，蒸干后蒸馏得到6-氧杂螺[4.5]癸烷-9-醇(1-2，4g)，产率：36％。
第二步：制备6-氧杂螺[4.5]癸烷-9-酮(1-3)
将6-氧杂螺[4.5]癸烷-9-醇(4g，25.6mmol)溶于二氯甲烷(100ml)中，向其中加入氯铬酸吡啶盐(PCC，8.3g，39mmol)，室温下反应，TLC检测原料消失后，过滤，滤液浓缩后柱层析(展开剂为0％到50％乙酸乙酯/石油醚)得到6-氧杂螺[4.5]癸烷-9-酮(1-3，3.1g)，产率：78％。
第三步：制备2-氰基-[(9Z)-6-氧杂螺[4.5]癸烷-9-亚基]乙酸乙酯(1-4)
在装有Dean-Stark蒸馏装置和冷凝管的50ml圆底烧瓶中分别加入6-氧杂螺[4.5]癸烷-9-酮(1-3，3.1g，20mmol)、氰基乙酸乙酯(3.1g，24mmol)、醋酸铵(0.385g，5mmol)、乙酸(0.24g)和甲苯(30ml)。加热回流至不再有水被收集在Dean-Stark中，冷却，加入甲苯，并用水(30ml)洗涤有机层。用乙酸乙酯(3×50ml)萃取水层。将合并的有机层用饱和碳酸氢钠(100ml)、食盐水洗涤(100ml)，硫酸镁干燥，过滤并浓缩。柱层析(展开剂为0％到60％乙酸乙酯/正己烷)纯化得到2-氰基-[(9Z)-6-氧杂螺[4.5]癸烷-9-亚基]乙酸乙酯(1-4，3.5g)，产率：70％。
第四步：制备2-氰基-2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-亚基]乙酸乙酯(1a)
在装有冷凝器、加料漏斗和带有氮气入口的橡胶隔片的圆底烧瓶中加入2-吡啶溴化镁(1M，6mL)、碘化亚铜(96mg，0.5mmol)和干燥乙醚(10ml)，冷却至0℃。将2-氰基-[(9Z)-6-氧杂螺[4.5]癸烷-9-亚基]乙酸乙酯(1-4，1.25g，5mmol)溶于无水乙醚(10ml)中，向反应中缓慢滴加，3小时后反应完全，将反应液倒入冰/盐酸(1N，10ml)混合液中，乙醚(3×50ml)萃取，饱和食盐水(50ml)洗涤，硫酸镁干燥，过滤，滤液浓缩后柱层析(展开剂为7％到60％乙酸乙酯/石油醚)得到2-氰基-2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷 -9-亚基]乙酸乙酯(1a，0.7g)，产率：43％。
第五步：制备2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]乙腈(1b)
向处于乙二醇(5ml)中的氢氧化钾(112mg，2mmol)的预先溶解的溶液中加入2-氰基-2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-亚基]乙酸乙酯(1a，0.66g，2mmol)。将混合物加热到120℃反应3小时，然后冷却。加入水(50ml)，用乙醚(3×50ml)萃取，用水(50ml)洗涤，无水硫酸镁干燥，过滤并浓缩，柱层析纯化(展开剂5％到40％乙酸乙酯/正己烷)得到2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]乙腈(1b，400mg)，产率：80％。
第六步：制备2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(1c)
在0℃下向处于无水乙醚(15ml)中的2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]乙腈(1b，256mg，1.0mmol)的溶液中滴加四氢锂铝(120mg，3mmol)。2小时后向反应液中分别加入水(0.1ml)、15％氢氧化钠水溶液(0.1ml)，然后水(0.1ml)淬灭。将反应混合物用乙醚(3×20ml)萃取，无水硫酸镁干燥，过滤后浓缩得到2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(1c，200mg)，产率：77％，为黄色油状物，其在未进一步纯化下使用。
1H NMR(400MHz,CDCl3)ppm 8.58(ddd,J＝4.8,1.9,0.9,1H),7.63(m,1H),7.30(m,1H),7.12(ddd,J＝7.4,4.8,1.0,1H),3.76(m,2H),2.55(td,J～11.6,5.1,1H),2.46(ddd,J＝13.7,5.1,2.7,1H),2.37(dd,J＝13.7,2.1,1H),2.14(td,J＝11.6,5.0,1H),1.92(m,2H),1.70(m,4H),1.46(m,4H),1.13(m,1H),0.71(dt,J＝13.4,8.8,1H).LC-MS:m/z(ES+)计算为C 16H 24N 2O 261[M+1] +。
第七步：制备(3-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺
Figure PCTCN2018105946-appb-000016
2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(130mg，0.5mmol)、无水硫酸镁(72mg，0.6mmol)加入到无水二氯甲烷中(8ml)，加入3-三氟甲氧基苯甲醛(105mg，0.55mmol)，室温搅拌过夜。将反应液过滤，滤液浓缩后加入无水甲醇中(5ml)，0℃下加入硼氢化钠(38mg，1mmol)，1小时后加水(10ml)，二氯甲烷萃取(3×20ml)，饱和食盐水洗(10ml)，无水硫酸钠干燥。薄层色谱法纯化(展开剂为0-10％甲醇/二氯甲烷)得到化合物(3-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺(76mg，黄色油状物)，产率：50％。
1H NMR(400MHz,CDCl 3)ppm 8.49(dd,J＝4.8,1.2Hz,1H),7.58(td,J＝7.6,2.0Hz,1H),7.30-7.21(m,3H),7.09-7.07(m,3H),3.72-3.68(m,4H),2.56(td,J＝10.8,5.2Hz,1H),2.38(dd,J＝13.6,2.0Hz,1H),2.32(dd,J＝13.6,2.0Hz,1H),2.16-2.03(m,2H),1.87(d,J＝13.6Hz,2H), 1.72-1.56(m,3H),1.50-1.34(m,4H),1.06(m,1H),0.67-0.60(m,1H).LC-MS:m/z(ES+)计算为C 24H 29F 3N 2O 2 435[M+1] +。
实施例2：(2-氯-4-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺的制备(H02)
Figure PCTCN2018105946-appb-000017
制备方法同实施例1，将第七步中的3-三氟甲氧基苯甲醛换为3-氯-4-三氟甲氧基苯甲醛，制得(2-氯-4-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺100mg，产率75％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl 3)ppm 8.51(dd,J＝4.8,1.2Hz,1H),7.60(td,J＝7.6,2.0Hz,1H),7.31(d,J＝1.6Hz,1H),7.10(d,J＝8.4Hz,1H),7.20-7.07(m,3H),3.74-3.72(m,2H),3.61(s,2H),2.50(td,J＝10.8,5.2Hz,1H),2.39(dd,J＝14.0,2.0Hz,1H),2.32(dd,J＝13.6,2.0Hz,1H),2.14-1.97(m,2H),1.90(d,J＝13.6Hz,1H),1.81-1.57(m,4H),1.52-1.43(m,3H),1.36(m,1H),1.08(m,1H),0.70-0.62(m,1H)。LC-MS:m/z(ES+)计算为C 24H 28ClF 3N 2O 2 469[M+1] +。
实施例3：N-甲基-2-(((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)甲基)苯胺的制备(H03)
Figure PCTCN2018105946-appb-000018
制备方法同实施例1，将第七步中的3-三氟甲氧基苯甲醛换为2-甲氨基苯甲醛，制得N-甲基-2-(((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)甲基)苯胺38mg，产率32％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.55(dd,J＝4.8,1.2Hz,1H),7.60(td,J＝7.6,2.0Hz,1H),7.15(td,J＝7.6,1.6Hz,1H),7.10(qd,J＝4.8,0.8Hz,1H),6.87(dd,J＝7.2,1.2Hz,1H),6.58-6.55(m,2H),3.74(dd,J＝8.0,2.8Hz,2H),3.55(d,J＝1.6Hz,2H),2.78(s,3H),2.47-2.31(m,3H),2.08(td,J＝11.2,5.2Hz,1H),1.97-1.88(m,2H),1.73-1.64(m,3H),1.53-1.44(m,5H),1.10(m,1H),0.72-0.64(m,1H).LC-MS:m/z(ES+)计算为C 24H 33N 3O 380[M+1] +。
实施例4：(3-氯-2-甲基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺的制备(H04)
Figure PCTCN2018105946-appb-000019
制备方法同实施例1，将第七步中的3-三氟甲氧基苯甲醛换为2-甲基-3-氯苯甲醛，制得(3-氯-2-甲基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺95mg，产率63％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.52(dd,J＝4.8,1.2Hz,1H),7.60(td,J＝7.6,2.0Hz,1H),7.26(d,J＝8.0Hz,1H),7.20(d,J＝7.6Hz,1H),7.10-6.98(m,3H),3.74-3.71(m,2H),3.60(d,J＝2.0Hz,2H),2.54(td,J＝11.2,5.2Hz,1H),2.40(dd,J＝14.0,2.4Hz,1H),8.52(dd,J＝13.6,1.6Hz,1H),2.26(s,3H),2.12(td,J＝11.2,4.8Hz,1H),2.03-1.96(m,1H),1.88(d,J＝13.6Hz,1H),1.81-1.60(m,4H),1.52-1.35(m,4H),1.07(m,1H),0.67-0.62(m,1H).LC-MS:m/z(ES+)计算为C 24H 31ClN 2O 399[M+1] +。
实施例5：((3-氯-噻吩-2-基)甲基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺的制备(H05)
Figure PCTCN2018105946-appb-000020
制备方法同实施例1，将第七步中的3-三氟甲氧基苯甲醛换为3-氯噻吩-2-甲醛，制得((3-氯-噻吩-2-基)甲基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺64mg，产率45％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.53(dd,J＝4.8,0.8Hz,1H),7.60(td,J＝7.6,2.0Hz,1H),7.26(d,J＝8.0Hz,1H),7.13(d,J＝5.2Hz,1H),7.10-7.07(qd,J＝4.8,1.2Hz,1H),6.80(d,J＝5.6Hz,1H),3.78(d,J＝3.6Hz,2H),3.74-3.71(m,2H),2.53(td,J＝10.8,5.2Hz,1H),2.42-2.30(m,2H),2.12(td,J＝11.2,5.2Hz,1H),2.01-1.94(m,1H),1.89(d,J＝13.6Hz,1H),1.77-1.60(m,4H),1.50-1.35(m,4H),1.07(m,1H),0.70-0.64(m,1H).LC-MS:m/z(ES+)计算为C 21H 27ClN 2OS391[M+1] +。
实施例6：(4-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺的制备(H06)
Figure PCTCN2018105946-appb-000021
制备方法同实施例1，将第七步中的3-三氟甲氧基苯甲醛换为4-三氟甲氧基苯甲醛，制得(4-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺40mg，产率52％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.50(d,J＝3.6Hz,1H),7.60(td,J＝7.6,1.6.0Hz,1H),7.29-7.25(m,3H),7.11-7.09(m,3H),3.73(m,2H),3.68(d,J＝2.4Hz,2H),2.60-2.5(m,1H),2.40-2.31(m,2H),2.16-2.03(m,2H),1.90(d,J＝13.6Hz,2H),1.75-1.61(m,3H),1.47(m,4H),1.09(m,1H),0.70-0.62(m,1H).LC-MS:m/z(ES+)计算为C 24H 29F 3N 2O 2 435[M+1] +。
实施例7：(3,4-二甲基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺的制备(H07)
Figure PCTCN2018105946-appb-000022
制备方法同实施例1，将第七步中的3-三氟甲氧基苯甲醛换为3，4-二甲基苯甲醛，制得(3,4-二甲基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺40mg，产率50％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.46(d,J＝4.0Hz,1H),7.60(td,J＝7.6,2.0Hz,1H),7.26(s,1H),7.10-7.03(m,4H),3.73-3.64(m,5H),3.47(s,1H),2.70(m,1H),2.29-2.23(m,4H),2.17(d,J＝8.4Hz,6H),2.05(m,2H),1.87(d,J＝13.6Hz,1H),1.77-1.60(m,4H),1.47-1.25 2.59(m,6H),1.06(m,1H),0.62(m,1H)..LC-MS:m/z(ES+)计算为C 25H 34N 2O 379[M+1] +。
实施例8：(2,4-二甲基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺的制备(H08)
Figure PCTCN2018105946-appb-000023
制备方法同实施例1，将第七步中的3-三氟甲氧基苯甲醛换为2，4-二甲基苯甲醛，制得(2,4-二甲基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺60mg，产率65％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.45(d,J＝4.4Hz,1H),7.62(td,J＝7.6,2.0Hz,1H),7.28(d,J＝8.0Hz,1H),7.23(d,J＝8.0Hz,1H),7.10(q,1H),6.93(s,2H),3.79-3.65(m,4H),2.76(td,J ＝11.6,5.2Hz,1H),2.26(s,5H),2.21(s,4H),2.06(m,2H),1.87(d,J＝13.6Hz,1H),1.75(t,J＝9.2Hz,1H),1.69-1.62(m,2H),1.45(m,2H),1.06(m,1H),0.64(m,1H).LC-MS:m/z(ES+)计算为C 25H 34N 2O 379[M+1] +。
实施例9：(2-三氟甲氧基苄基)-[2-(9-(3-氯-5-氟吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺的制备(H09)
Figure PCTCN2018105946-appb-000024
制备方法同实施例1，将第四步的吡啶-2-溴化镁换为3-氯-5-氟吡啶-2-溴化镁，将第七步中的3-三氟甲氧基苯甲醛换为2-三氟甲氧基苯甲醛，制得(2-三氟甲氧基苄基)-[2-(9-(3-氯-5-氟吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺20mg，产率38％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.35(d,J＝2.8Hz,1H),7.33-7.27(m,2H),7.26-7.15(m,3H),3.71-3.65(m,4H),2.42(td,J＝11.2,5.2Hz,1H),2.35(dd,J＝14.0,2.0Hz,1H),2.26(dd,J＝13.6,2.0Hz,1H),2.42(td,J＝11.2,4.8Hz,1H),1.96-1.87(m,2H),1.76-1.64(m,4H),1.52-1.35(m,4H),1.09(m,1H),0.71-0.61(m,1H).LC-MS:m/z(ES+)计算为C 24H 27ClF 4N 2O 2486[M+1] +。
实施例10：(2-三氟甲氧基苄基)-[2-(9-(3-甲基-5-氟吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺的制备(H10)
Figure PCTCN2018105946-appb-000025
制备方法同实施例1，将第四步的吡啶-2-溴化镁换为3-甲基-5-氟吡啶-2-溴化镁，将第七步中的3-三氟甲氧基苯甲醛换为2-三氟甲氧基苯甲醛，制得(2-三氟甲氧基苄基)-[2-(9-(3-甲基-5-氟吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺35mg，产率34％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.33(d,J＝2.8Hz,1H),7.34-7.25(m,2H),7.26-7.15(m,3H),3.71-3.65(m,4H),2.42(td,J＝11.2,5.2Hz,1H),2.35(m,4H),2.26(dd,J＝13.6,2.0Hz,1H),2.42(td,J＝11.2,4.8Hz,1H),1.96-1.87(m,2H),1.76-1.64(m,4H),1.52-1.35(m,4H),1.09(m,1H),0.71-0.61(m,1H)。LC-MS:m/z(ES+)计算为C 25H 30F 2N 2O 2 467[M+1] +。
实施例11：(4-溴-2-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基] 胺的制备(H11)
Figure PCTCN2018105946-appb-000026
制备方法同实施例1，将第七步中的3-三氟甲氧基苯甲醛换为2-三氟甲氧基-4-溴苯甲醛，制得(4-溴-2-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺78mg，产率58％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.50(dd,J＝4.0,0.8Hz,1H),7.60(td,J＝7.6,2.0Hz,1H),7.34-7.33(m,2H),7.28(s,1H),7.20(d,J＝8.4Hz,1H),7.10(q,J＝4.8,6.8Hz,1H),3.75(d,J＝2.8Hz,1H),3.73(d,J＝2.4Hz,1H),3.36(s,2H),2.50-2.32(m,3H),2.07(td,J＝11.2,5.2Hz,1H),2.00-1.96(m,1H),1.90(d,J＝14.0Hz,1H),1.78-1.65(m,6H),1.54-1.48(m,3H),1.10(m,1H),0.72-0.65(m,1H)。LC-MS:m/z(ES+)计算为C 24H 28BrF 3N 2O 2 513[M+1] +。
实施例12：(4-甲基-2-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺的制备(H12)
Figure PCTCN2018105946-appb-000027
制备方法同实施例1，将第七步中的3-三氟甲氧基苯甲醛换为2-三氟甲氧基-4-甲基苯甲醛，制得(4-甲基-2-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺91mg，产率70％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.50(dd,J＝4.8,1.2Hz,1H),7.60(td,J＝7.6,2.0Hz,1H),7.28(t,J＝8.0Hz,2H),7.08(q,J＝4.8,6.8Hz,1H),7.01(d,J＝8.0Hz,1H),6.98(s,1H),3.74-3.69(m,4H),2.53(td,J＝11.6,5.6Hz,1H),2.4-2.37(m,1H),2.32-2.29(m,4H),2.13(td,J＝11.2,4.8Hz,1H),2.06-1.99(m,1H),1.88(d,J＝14.0Hz,1H),1.85-1.77(m,1H),1.73-1.58(m,3H),1.51-1.45(m,3H),1.38-1.35(m,1H),1.11-1.07(m,1H),0.70-0.62(m,1H)。LC-MS:m/z(ES+)计算为C 25H 31F 3N 2O 2 449[M+1] +。
实施例13：3-{[(2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺甲基}-2-三氟甲氧基苯甲腈的制备(H13)
Figure PCTCN2018105946-appb-000028
制备方法同实施例1，将第七步中的3-三氟甲氧基苯甲醛换为2-三氟甲氧基-4-氰基苯甲醛，制得3-{[(2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺甲基}-2-三氟甲氧基苯甲腈45mg，产率51％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.54-8.52(m,1H),7.59(dd,J＝1.2Hz,1H),7.25-7.30(m,2H),7.25-7.18(m,3H),3.75-3.64(m,4H),2.62-2.32(m,3H),1.91-1.73(m,3H),1.69-1.40(m,8H),1.09(m,1H),0.70-0.62(m,1H).LC-MS:m/z(ES+)计算为C25H28F3N3O2460[M+1]+。
实施例14：((3-三氟甲基噻吩-2-基)甲基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺的制备(H14)
Figure PCTCN2018105946-appb-000029
第一步：制备3-(三氟甲基噻吩-2-基)甲醇(14b)
在0℃下向处于无水乙醚(20ml)中的3-三氟甲基噻吩-2-羧酸甲酯(14a，1g，4.7mmol)的溶液中滴加四氢锂铝(240mg，6mmol)。2小时后向反应液中分别加入水(0.1ml)、15％氢氧化钠水溶液(0.1ml)，然后水(0.1ml)淬灭。将反应混合物用乙酸乙酯(3×20ml)萃取，无水硫酸镁干燥，过滤后浓缩得到3-(三氟甲基噻吩-2-基)甲醇(14b)(14b，500mg)，产率：57％，为黄色油状物，其在未进一步纯化下使用。
第二步：制备3-三氟甲基噻吩-2-甲醛(14c)
将3-(三氟甲基噻吩-2-基)甲醇(14b，0.364g，2mmol)溶于二氯甲烷(10ml)中，向其中加入氯铬酸吡啶盐(PCC，830mg，3.9mmol)，室温下反应，TLC检测原料消失后，过滤，滤液浓缩后柱层析(展开剂为0％到50％乙酸乙酯/石油醚)得到3-三氟甲基噻吩-2-甲醛(14c，0.2g)，产率：55％。
第三步
与实施例1描述的制备方法中的第七步一致，用3-三氟甲基噻吩-2-甲醛代替实施例1第七步中的3-三氟甲氧基苯甲醛，制备((3-三氟甲基噻吩-2-基)甲基)-[2-(9-(吡啶-2-基)-6- 氧杂螺[4.5]癸烷-9-基)乙基]胺21mg，产率25％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.55(dd,J＝4.8,1.2Hz,1H),7.61(td,J＝7.6,2.0Hz,1H),7.32(d,J＝8.0Hz,1H),7.24(d,J＝5.2Hz,1H),7.10-7.06(qd,J＝4.8,1.2Hz,1H),6.93(d,J＝5.2Hz,1H),6.44(s,1H),4.63(s,2H),3.76-3.73(m,2H),3.34-3.26(m,1H),2.99-2.90(m,1H),2.47(dd,J＝13.6,2.0Hz,1H),2.38(dd,J＝13.6,2.0Hz,1H),2.13-2.05(m,1H),1.90(d,J＝13.6Hz,2H),1.83-1.58(m,5H),1.53-1.44(m,3H),1.09(m,1H),0.71-0.64(m,1H).LC-MS:m/z(ES+)计算为C 22H 27F 3N 2OS 425[M+1] +。
实施例15：4-{[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基胺]甲基}-3-三氟甲氧基苯酚的制备(H15)
Figure PCTCN2018105946-appb-000030
制备方法同实施例1，将第七步中的3-三氟甲氧基苯甲醛换为2--三氟甲氧基-4-羟基苯甲醛，制得4-{[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基胺]甲基}-3-三氟甲氧基苯酚56mg，产率52％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.46(d,J＝4.4Hz,1H),7.65(td,J＝7.6,1.6Hz,1H),7.31(d,J＝8.0Hz,1H),7.18-7.14(m,2H),6.61(s,1H),6.48(d,J＝7.2Hz,1H),3.73(m,4H),2.76(m,1H),2.39-2.30(m,3H),2.13(m,1H),1.94(m,1H),1.87(d,J＝14.0Hz,1H),1.74-1.62(m,3H),1.48-1.37(m,4H),1.09(m,1H),0.69-0.61(m,1H).LC-MS:m/z(ES+)计算为C 24H 29F 3N 2O 3451[M+1] +。
实施例16：(2-二氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺的制备(H16)
Figure PCTCN2018105946-appb-000031
制备方法同实施例1，将第七步中的3-三氟甲氧基苯甲醛换为2-二氟甲氧基苯甲醛，制得(2-二氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺16mg，产率28％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.49(d,J＝4.4Hz,1H),7.61(td,J＝7.6,2.0Hz,1H),7.38(d,J＝8.4Hz,1H),7.28-7.27(m,2H),7.15-7.06(m,3H),6.78-6.42(t,J＝73.6Hz,1H),3.78-3.71(m,4H),2.62(td,J＝11.2,5.2Hz,1H),2.36(d,J＝13.6Hz,1H),2.30(d,J＝14.0Hz,1H),2.18(td,J ＝11.2,4.8Hz,1H),2.08(td,J＝13.2,4.8Hz,1H),1.90-1.87(m,2H),1.78-1.63(m,3H),1.49-1.36(m,4H),1.09(m,1H),0.70-0.62(m,1H).LC-MS:m/z(ES+)计算为C 24H 30F 2N 2O 2417[M+1] +。
实施例17：(5-氯-2-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺的制备(H17)
Figure PCTCN2018105946-appb-000032
制备方法同实施例1，将第七步中的3-三氟甲氧基苯甲醛换为2-三氟甲氧基-5-氯苯甲醛，制得(2-二氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺100mg，产率80％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.55(dd,J＝4.8,1.2Hz,1H),7.61(td,J＝7.6,2.0Hz,1H),7.32(d,J＝2.8Hz,1H),7.28(d,J＝8.4Hz,1H),7.18(dd,J＝8.8,2.4Hz,1H),7.12-7.08(m,2H),3.75(dd,J＝8.4,2.8Hz,2H),3.63(s,2H),2.51-2.33(m,3H),2.10(td,J＝10.8,5.2Hz,1H),2.03-1.95(m,1H),1.91(d,J＝13.6Hz,1H),1.78-1.61(m,5H),1.54-1.50(m,3H),1.10(m,1H),0.73-0.66(m,1H).LC-MS:m/z(ES+)计算为C 24H 28ClF 3N 2O 2 469[M+1] +。
实施例18：((3-二氟甲氧基噻吩-2-基)甲基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺的制备(H18)
Figure PCTCN2018105946-appb-000033
第一步：制备3-二氟甲氧基噻吩-2-甲酸甲酯(18b)
室温下，分别向甲苯/水(10ml/0.8ml)加入3-羟基噻吩-2-甲酸甲酯(18a，1g，6.3mmol)和氢氧化钠(0.51g，12.7mmol)，升温至90℃，向反应液中分别加入四正丁基溴化膦(0.11g，0.32mmol)、一氯二氟甲烷(3.28g，37.8mmol)。继续反应1小时，冷却，加水(15ml)， 有机相分层后干燥，硫酸镁干燥，浓缩后柱层析(展开剂：乙酸乙酯/石油醚＝1:3)得到3-二氟甲氧基噻吩-2-甲酸甲酯(18b，0.4g)，产率：31％。
第二步：制备3-(二氟甲氧基噻吩-2-基)甲醇(18c)
在0℃下向处于无水乙醚(15ml)中的3-二氟甲氧基噻吩-2-甲酸甲酯(18b，0.4g，1.9mmol)的溶液中加入四氢锂铝(120mg，3mmol)。1小时后向反应液中分别加入水(0.1ml)、15％氢氧化钠水溶液(0.1ml)，然后水(0.1ml)淬灭。将反应混合物用乙酸乙酯(3×20ml)萃取，无水硫酸镁干燥，过滤后浓缩得到3-(二氟甲氧基噻吩-2-基)甲醇(18c，300mg)，产率：83％，为黄色油状物，其在未进一步纯化下使用。
第三步：制备3-二氟甲氧基噻吩-2-甲醛(18d)
将3-(二氟甲氧基噻吩-2-基)甲醇(18c，0.3g，1.67mmol)溶于二氯甲烷(10ml)中，向其中加入氯铬酸吡啶盐(PCC，830mg，3.9mmol)，室温下反应，TLC检测原料消失后，过滤，滤液浓缩后柱层析(展开剂为0％到50％乙酸乙酯/正己烷)得到3-二氟甲氧基噻吩-2-甲醛(18d，0.15g)产率：50％。
第四步
与实施例1制备中描述的第七步步骤一致，用3-二氟甲氧基噻吩-2-甲醛代替实施例1的制备方法的第七步中的3-三氟甲氧基苯甲醛，制备((3-二氟甲氧基噻吩-2-基)甲基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺34mg，产率28％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.51(dd,J＝4.8,1.2Hz,1H),7.62(td,J＝7.6,1.6Hz,1H),7.28(d,J＝8.0Hz,1H),7.26(s,1H),7.18(d,J＝5.6Hz,1H),7.10(q,J＝4.8,6.8Hz,1H),6.81(d,J＝5.6Hz,1H),6.65-6.29(t,J＝73.6Hz,1H),3.90(d,J＝5.6Hz,2H),3.74-3.69(m,2H),2.64(td,J＝11.6,5.2Hz,1H),2.38(d,J＝12.0Hz,1H),2.32(d,J＝13.6Hz,1H),2.21(td,J＝11.2,5.2Hz,1H),2.08(td,J＝11.2,3.2Hz,1H),1.89(d,J＝13.6Hz,2H),1.76-1.63(m,4H),1.52-1.45(m,2H),1.10(m,1H),0.70-0.62(m,1H).LC-MS:m/z(ES+)计算为C 22H 28F 2N 2O 2S 423[M+1] +。
实施例19：2-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]-7-三氟甲基-1,,2,3,4-四氢异喹啉的制备(H19)
Figure PCTCN2018105946-appb-000034
第一步：制备2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]乙酸(19a)
向氢氧化钾(560mg,10mmol)的乙二醇/水(20ml/10ml)溶液中加入2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]乙腈(1b，500mg，2mmol)，将反应液加热至100℃过夜，TLC检测发现原料消失，将反应液冷却至室温，用水(20ml)稀释，用盐酸调PH＝3-4，乙酸乙酯 萃取(40ml X 3)，合并有机相，用水洗(50ml)，饱和食盐水洗(50ml)，无水硫酸钠干燥，浓缩得到黄色油状化合物2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]乙酸(19a，320mg)，产率60％。
第二步：制备2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]-1-(7-(三氟甲基)-3,4-二氢异喹啉-2(1H)-基)乙-1-酮(19b)
向2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]乙酸(19a，138mg，0.5mmol)的二甲基甲酰胺(DMF，10ml)溶液中加入1-羟基苯并三唑(HOBT，135mg，1mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI，191mg，1mmol)，在氩气保护下室温搅拌十分钟，然后加入7-(三氟甲基)-1,2,3,4-四氢异喹啉(88mg，0.5mmol)和二异丙基乙基胺(258mg，2mmol)，反应室温搅拌过夜，TLC检测原料消失。向反应液中加入水(30ml)，用二氯甲烷萃取(30mL X 3)，合并有机相，饱和食盐水洗(30mLX3)，无水硫酸钠干燥，浓缩通过薄层析(DCM:MeOH＝20:1)得到黄色固体物2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]-1-(7-(三氟甲基)-3,4-二氢异喹啉-2(1H)-基)乙-1-酮(19b，110mg)，产率58％。
第三步：制备2-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]-7-三氟甲基-1,,2,3,4-四氢异喹啉
在0℃下，向2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]-1-(7-(三氟甲基)-3,4-二氢异喹啉-2(1H)-基)乙-1-酮(19b，110mg，0.28mmol)的无水四氢呋喃(10ml)溶液中加入四氢锂铝(100mg,2.6mmol)，反应液搅拌两小时后依次用0.1ml水，0.1ml的15％NaOH和0.3ml水淬灭，反应液再用乙醚(30mL X 3)萃取，无水硫酸钠干燥，浓缩通过薄层析(DCM:MeOH＝20:1)得到黄色油状物2-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]-7-三氟甲基-1,,2,3,4-四氢异喹啉(19，35mg)，产率35％。
1H NMR(400MHz,CDCl3)ppm 8.60(dd,J＝4.8,1.2Hz,1H),7.65(td,J＝7.6,1.6Hz,1H),7.34(d,J＝8.0Hz,1H),7.22(s,1H),7.18-7.13(m,2H),3.81(d,J＝2.4Hz,1H),3.80(d,J＝2.8Hz,1H),3.54-3.43(q,J＝11.6,14.8Hz,2H),2.86(t,J＝5.6Hz,2H),2.56-2.38(m,5H),2.11(td,J＝12.4,4.0Hz,1H),1.98(m,1H),1.87-1.65(m,5H),1.57-1.41(m,4H),1.14(m,1H),0.76-0.69(m,1H).LC-MS:m/z(ES+)计算为C26H31F3N2O 445[M+1]+。
实施例20：7-甲氧基-2-[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-1,2,3,4-四氢异喹啉的制备(H20)
Figure PCTCN2018105946-appb-000035
制备方法同实施例19，将第二步的7-三氟甲基-1,2,3,4-四氢异喹啉换为7-甲氧基-1,2,3,4-四氢异喹啉，制得7-甲氧基-2-[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-1,2,3,4- 四氢异喹啉(20，34mg)，产率36％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.60(dd,J＝4.8,1.2Hz,1H),7.65(td,J＝7.6,1.6Hz,1H),7.35(d,J＝8.0Hz,1H),7.14(q,1H),6.67(d,J＝8.4Hz,1H),6.68(dd,J＝8.4,2.8Hz,1H),6.50(d,J＝2.4Hz,1H),3.81-3.78(m,2H),3.76(s,3H),3.48-3.38(q,J＝11.2,14.4Hz,2H),2.75(t,J＝6.0Hz,2H),2.59-2.50(m,3H),2.41-2.34(m,2H),2.13-2.07(td,J＝11.6,3.2Hz,1H),1.99-1.74(m,6H),1.57-1.48(m,4H),1.14(m,1H),0.76-0.68(m,1H).LC-MS:m/z(ES+)计算为C26H34N2O2 407[M+1]+。
实施例21：{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-(2-(三氟甲氧基)-苯甲基)-胺的制备(H21)
Figure PCTCN2018105946-appb-000036
第一步：制备氰基-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙酸乙酯(21a)
向反应瓶中加入含有异丙基溴化镁2.0M的四氢呋喃溶液(6mL,12mmol)，再滴加2-溴-5-氟-吡啶(1.0mL,10mmol)的乙醚溶液(4ml)，将反应液室温搅拌三小时，得到相应的1M的格式试剂5-氟-2-吡啶溴化镁。
向充满氮气的圆底反应瓶中加入无水乙醚(10ml)，加入上述所制备的格式试剂(1.0M,6mL)，碘化亚铜(96mg,0.5mmol)，将含有2-氰基-[(9Z)-6-氧杂螺[4.5]癸烷-9-亚基]乙酸乙酯(1-4，1.25g，5mmol)的乙醚(10ml)溶液在冰浴下30分钟内滴加到上述反应液中，保持冰浴下反应搅拌三小时，将反应液倾入1N冰盐酸(25ml)，用乙醚萃取(3x50ml)，饱和食盐水(50ml)洗，无水硫酸钠干燥，浓缩，通过硅胶柱(7％到60％EtOAc/PE)得到黄色油状化合物氰基-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙酸乙基酯(680mg,产率40％)。
第二步：制备2-[9-(5-氟-吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]乙腈(21b)
向氢氧化钾(112mg,2mmol)的乙二醇(5ml)溶液中加入氰基-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙酸乙酯(21a，0.68g，2mmol)，将反应液加热至120℃反应三小时，冷却，加入水(50ml)，用乙醚(3x50ml)萃取，依次用水洗(50ml)，饱和食盐水洗涤(50ml)， 无水硫酸钠干燥，浓缩通过柱层析(5％到40％乙酸乙酯/正己烷)得到固体化合物2-[9-(5-氟-吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]乙腈(21b，400mg)，产率73％。
第三步：制备2-(9-(5-氟吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基)-乙胺(21c)
在0℃下，向化合物2-[9-(5-氟-吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]乙腈(274mg，1.0mmol)的无水乙醚(10ml)溶液中加入四氢锂铝(120mg,3mmol)，将反应液搅拌2小时后，依次用0.1ml水,0.1ml的15％氢氧化钠和0.1ml水淬灭，用乙醚萃取(3x20ml)，无水硫酸钠干燥，浓缩得到黄色油状物2-(9-(5-氟吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基)-乙胺(200mg,产率72％)。
第四步：制备{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-(2-(三氟甲氧基)-苯甲基)-胺(H21)
向含有2-(9-(5-氟吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基)-乙胺(21c，70mg，0.25mmol)的二氯甲烷(10ml)溶液中加入硫酸镁(72mg,0.6mmol)，室温下再加入2-三氟甲氧基苯甲醛(57mg,0.3mmol)，将反应液搅拌过夜，过滤，溶液浓缩，在0℃下加入5ml的甲醇，一次性加入硼氢化钠(38mg,1mmol)后，将反应液在0℃下搅拌一小时，用水(10ml)淬灭，用二氯甲烷萃取(3x20ml)，分离出的有机相用饱和食盐水洗，无水硫酸钠干燥，浓缩通过制备薄层析得到黄色油状物{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-(2-(三氟甲氧基)-苯甲基)-胺(33mg,30％)。
1H NMR(400MHz,CDCl3)ppm 1H NMR(400MHz,CDCl3)ppm 8.37(d,J＝2.8Hz,1H),7.33-7.27(m,2H),7.26-7.15(m,4H),3.72-3.66(m,4H),2.44(td,J＝11.2,5.2Hz,1H),2.36(dd,J＝14.0,2.0Hz,1H),2.27(dd,J＝13.6,2.0Hz,1H),2.44(td,J＝11.2,4.8Hz,1H),1.96-1.87(m,2H),1.76-1.64(m,4H),1.52-1.35(m,4H),1.09(m,1H),0.70-0.61(m,1H).LC-MS:m/z(ES+)计算为C24H28F4N2O2 453[M+1]+。
实施例22：(2-三氟甲氧基苯甲基)-[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-胺的制备(H22)
Figure PCTCN2018105946-appb-000037
制备方法同实施例1，将第七步中的3-三氟甲氧基苯甲醛换为2-三氟甲氧基苯甲醛，制得(2-三氟甲氧基苯甲基)-[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-胺(22，34mg)，产率28％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.54-8.52(m,1H),7.59(dd,J＝1.2Hz,1H),7.25-7.20(m,2H),7.20-7.08(m,4H),3.75-3.64(m,4H),2.62-2.32(m,3H),1.91-1.73(m,3H), 1.69-1.40(m,8H),1.09(m,1H),0.70-0.62(m,1H).LC-MS:m/z(ES+)计算为C24H29F3N2O2435[M+1]+。
实施例23：6-[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-4,5,6,7-四氢-噻吩并[2,3-c]吡啶的制备(H23)
Figure PCTCN2018105946-appb-000038
制备方法同实施例19，将第二步的7-三氟甲基-1,2,3,4-四氢异喹啉换为4,5,6,7-四氢-噻吩并[2,3-c]吡啶，制得6-[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-4,5,6,7-四氢-噻吩并[2,3-c]吡啶(23，70mg)，产率64％，外观为黄色油状物。
1H NMR(400MHz,CDCl3)ppm 8.54-8.56(m,1H),7.61(dd,J＝0.8Hz,1H),7.31-7.29(m,1H),7.11-7.02(m,2H),6.70(d,J＝5.2Hz,1H),3.78-3.71(m,2H),3.54-3.52(m,2H),2.62(d,J＝5.2Hz,4H),2.36-2.32(m,3H),2.07(m,1H),1.97-1.91(m,2H),1.84-1.73(m,4H),1.47(m,2H),1.09(m,1H),0.70-0.62(m,1H).LC-MS:m/z(ES+)计算为C23H30N2OS 383[M+1]+。
实施例24：3-甲基氨基-噻吩-2-羧酸[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-酰胺的制备(H24)
Figure PCTCN2018105946-appb-000039
第一步：制备3-(叔丁氧甲酰胺基)噻吩-2-甲酸甲酯(24b)
在0℃下，向化合物2-氨基噻吩-2-甲酸甲酯(24a,5g,31.8mmol)的四氢呋喃(70ml)溶液中加入三乙胺(6.4g,64mmol)，二碳酸二叔丁酯(8.3g,38mmol)，将反应液室温搅拌过夜，将反应液浓缩，用水(100mL)稀释，用乙酸乙酯萃取(100mlX3)，合并有机相，所得有机相依次用水洗(100mL)，饱和食盐水洗(100mL)，无水硫酸钠干燥，浓缩得到黄色固体化合物3-(叔丁氧甲酰胺基)噻吩-2-甲酸甲酯(24b,7.5g)，产率92％。
第二步：制备3-((叔丁氧甲酰基)(甲基)胺基)噻吩-2-甲酸甲酯(24c)
将化合物3-(叔丁氧甲酰胺基)噻吩-2-甲酸甲酯(24b,5.2g,20mmol)溶于四氢呋喃(70ml)中，冰浴下加入钠氢(960mg,24mmol)，冰浴下将反应液搅拌30分钟，然后滴加碘甲烷(3.4g,24mmol)，将反应液室温搅拌过夜，用饱和的氯化铵淬灭，用乙酸乙酯(100mlX3)萃取，有机相依次用水洗(30mL×2)，饱和食盐水洗(30mL)，无水硫酸钠干燥，浓缩，通过硅胶柱(PE:EA＝100:1-3:1)得到黄色油状物3-((叔丁氧甲酰基)(甲基)胺基)噻吩-2-甲酸甲酯(24c,2.8g)，产率51％。
第三步：制备3-((叔丁氧甲酰基)(甲基)胺基)噻吩-2-甲酸(24d)
将化合物3-((叔丁氧甲酰基)(甲基)胺基)噻吩-2-甲酸甲酯(24c，1.3g，5mmol)溶于乙醇(20ml)，加入氢氧化钠的水溶液(4M,10mL,40mmol)，将反应液室温搅拌过夜，将反应液浓缩，加水(10mL)稀释，调PH＝3，然后用乙酸乙酯萃取(50mlX3)，所得有机相依次用水洗(50mL×2)，饱和食盐水(50mL)洗，无水硫酸钠干燥，浓缩，得到黄色固体3-((叔丁氧甲酰基)(甲基)胺基)噻吩-2-甲酸(24d，1.1g,产率92％)。
第四步：制备叔丁基甲基(2-((9-(吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基)-乙基)氨甲酰基)噻吩-3-基)氨基甲酸酯(24e)
向3-((叔丁氧甲酰基)(甲基)胺基)噻吩-2-甲酸(24d,122mg,0.5mmol)的二氯甲烷(20mL)溶液中加入HOBT(135mg,1mmol),EDCI(191mg,1mmol)，在氩气保护下室温搅拌十分钟，然后加入2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(1c,130mg,0.5mmol)和二异丙基乙基胺(258mg,2mmol)，将反应液室温搅拌过夜，TLC(DCM:MeOH＝20:1,Rf＝0.4)点板发现原料消失，反应液中加入水(30mL)，用二氯甲烷萃取(30mLX3)，合并有机相，所得有机相依次用水洗(30mL)，饱和食盐水洗(30mL)，无水硫酸钠干燥，浓缩通过薄层析(DCM:MeOH＝20:1)得到黄色固体物叔丁基甲基(2-((9-(吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基)-乙基)氨甲酰基)噻吩-3-基)氨基甲酸酯(24e,170mg)，产率68％。
第五步：制备3-甲基氨基-噻吩-2-羧酸[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-酰胺(H24)
向叔丁基甲基(2-((9-(吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基)-乙基)氨甲酰基)噻吩-3-基)氨基甲酸酯(24e,150mg,0.3mmol)的二氯甲烷(2ml)的溶液中加入三氟乙酸(2mL)，将反应液搅拌过夜，再将反应液浓缩，用水(10ml)稀释，调pH＝9-10,然后用乙酸乙酯萃取(30mlX3),合并有机相，有机相水洗(30mL×2),饱和食盐水洗(30mL)，无水硫酸钠干燥，浓缩，通过硅胶柱(DCM:MeOH＝100:1-10:1)得到黄色固体化合物24(90mg,产率75％)。
1H NMR(400MHz,CDCl3)ppm 8.55(d,J＝4.8Hz,1H),7.90(d,J＝8.0Hz,1H),7.66(d,J＝8.4Hz,1H),7.28-7.22(m,1H),7.10(s,1H),6.55(d,J＝7.2Hz,1H),6.07(t,J＝0.6Hz,1H),3.83-3.75(m,2H),3.41-3.44(m,1H),3.24-3.21(m,1H),2.89(s,3H),2.59-2.56(m,2H),2.27(d,J＝1.2Hz,1H),2.09-2.03(m,1H),1.94-1.81(m,2H),1.52-1.40(m,7H),1.09(m,1H),0.70-0.62(m,1H).LC-MS:m/z(ES+)计算为C22H29N3O2S 400[M+1]+。
实施例25：[(5-甲氧基-1H-吡唑-4-基)甲基]-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基) 乙基]胺的制备(H25)
Figure PCTCN2018105946-appb-000040
将2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(1c,70mg,0.27mmol)，(5-甲氧基-1H-吡唑-1-基)甲醇(35mg,0.27mmol)和对甲苯磺酸一水合物(TsOH.H2O,10mg,0.054mmol)溶于二氯甲烷中(3mL)，加热回流16小时。向反应液中加入饱和碳酸氢钠水溶液(30mL)，二氯甲烷萃取(15mL x 3)，有机层合并后干燥浓缩，经制备HPLC分离纯化得到化合物[(5-甲氧基-1H-吡唑-4-基)甲基]-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺(20mg，黄色油状物)，产率：7％。
1H NMR(400MHz,CDCl3)ppm 8.62(dd,J＝1.2Hz,1H),8.00-7.96(m,1H),7.65(d,J＝8.4Hz,1H),7.50(s,1H),7.45-7.42(m,1H),3.86-3.85(m,5H),3.75-3.73(m,2H),2.93-2.85(m,1H),2.49-2.31(m,3H),2.15-2.07(m,1H),1.92-1.42(m,9H),1.52-1.40(m,7H),1.13-1.07(m,1H),0.75-0.67(m,1H).LC-MS:m/z(ES+)计算为C 21H 30N 4O 2 371[M+1] +。
实施例26：((3-甲氧基噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)丙基]-1-胺的制备(H26)
Figure PCTCN2018105946-appb-000041
第一步：制备2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]丙腈(26a)
将2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]乙腈(1b，0.256g，1mmol)溶于无水N,N-二甲基甲酰胺(10mL)中，冷却至0℃，加入钠氢(60mg，1.5mmol)，0℃继续反应30分钟后加入碘甲烷(284mg，2mmol)，缓慢升至室温过夜。向反应液中加入冰水(10mL)淬灭，乙酸乙酯(15mL x 3)萃取，有机层水洗(15mL x 3)，饱和氯化钠洗(15mL)，干燥浓缩，通过硅胶柱(展开剂5％到40％乙酸乙酯/正己烷)得到黄色固体化合物2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]丙腈(26a，0.2g)，产率：74％。
第二步：制备2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)丙-1-胺(26b)
在0℃下向处于无水乙醚(15ml)中的2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]丙腈(26a，270mg，1.0mmol)的溶液中滴加四氢锂铝(120mg，3mmol)。2小时后向反应液中分别加入水(0.1ml)、15％氢氧化钠水溶液(0.1ml)，然后水(0.1ml)淬灭。将反应混合物 用乙醚(3×20ml)萃取，无水硫酸镁干燥，过滤后浓缩得到2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)丙-1-胺(26b，200mg)，产率：73％，为黄色油状物，其在未进一步纯化下使用。
第三步：制备((3-甲氧基噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)丙基]-1-胺(H26)
2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)丙-1-胺(26b，137mg，0.5mmol)、无水硫酸镁(72mg，0.6mmol)加入到无水二氯甲烷中(8ml)，加入3-甲氧基噻吩-2-醛(78mg，0.55mmol)，室温搅拌过夜。将反应液过滤，滤液浓缩后加入无水甲醇中(5ml)，0℃下加入硼氢化钠(38mg，1mmol)，1小时后加水(10ml)，二氯甲烷萃取(3×20ml)，饱和食盐水洗(10ml)，无水硫酸钠干燥。薄层色谱法纯化(展开剂为0-10％二氯甲烷/甲醇)得到化合物((3-甲氧基噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)丙基]-1-胺(26，100mg)，产率50％。
1H NMR(400MHz,CDCl3)ppm 8.54(dd,J＝4.8,0.8Hz,1H),7.62(td,J＝7.6,2.0Hz,1H),7.24(d,J＝8.0Hz,1H),7.18(d,J＝5.2Hz,1H),7.12-7.06(qd,J＝4.8,1.2Hz,1H),6.85(d,J＝5.3Hz,1H),3.78(m,5H),3.74-3.71(m,2H),2.53(td,J＝10.8,5.2Hz,1H),2.42-2.30(m,2H),2.12(td,J＝11.2,5.2Hz,1H),2.01-1.94(m,1H),1.89(d,J＝13.6Hz,1H),1.77-1.60(m,3H),1.50-1.35(m,4H),1.08(m,4H),0.70-0.64(m,1H).LC-MS:m/z(ES+)计算为C 23H 32N 2O 2S401[M+1] +。
实施例27：((3-甲氧基噻吩-2-基)甲基)-1-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)丙基]-2-胺的制备(H27)
Figure PCTCN2018105946-appb-000042
第一步：制备1-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)丙-2-胺(27a)
2-[9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基]乙腈(1b，0.256g，1mmol)溶于无水四氢呋喃(10mL)中，冷却至-78℃，缓慢滴加甲基锂(0.94ml，1.5mmol，1.6M的乙醚溶液)，加完后在-78℃继续反应一小时，缓慢加入甲醇(10ml)淬灭，后缓慢升至室温继续搅拌2小时。向反应液中加入冰水(10mL)淬灭，乙酸乙酯(15mL x 3)萃取，有机层水洗(15mL x 3)，饱和氯化钠洗(15mL)，干燥浓缩。浓缩反应液加入甲醇溶解，加入10％钯碳(10mg)，冲入氢气，室温下反应过夜。过滤后蒸干溶剂得到1-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)丙-2-胺(27a)，为黄色油状物(27a，0.15g)，产率55％，其在未进一步纯化下使用。
第二步：制备((3-甲氧基噻吩-2-基)甲基)-1-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)丙基]-2-胺(H27)
用1-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)丙-2-胺(27a)代替2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)丙-1-胺(26b)，通过实施例26制备中描述的步骤，制备((3-甲氧基噻吩-2-基)甲基)-1-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)丙基]-2-胺(27，34mg)，产率28％，外观为淡黄色粘稠物。
1H NMR(400MHz,CDCl3)ppm 8.55(dd,J＝4.8,1.2Hz,1H),7.61(td,J＝7.6,2.0Hz,1H),7.32(d,J＝8.0Hz,1H),7.24(d,J＝5.2Hz,1H),7.10-7.06(qd,J＝4.8,1.2Hz,1H),6.93(d,J＝5.2Hz,1H),6.44(s,1H),4.63(s,2H),3.76-3.73(m,1H),3.34-3.26(m,1H),2.99-2.90(m,1H),2.47(dd,J＝13.6,2.0Hz,1H),2.38(dd,J＝13.6,2.0Hz,1H),2.13-2.05(m,1H),1.90(d,J＝13.6Hz,2H),1.83-1.58(m,5H),1.53-1.44(m,3H),1.09(m,4H),0.71-0.64(m,1H).LC-MS:m/z(ES+)计算为C 23H 32N 2O 2S 401[M+1] +。
实施例28：(3-溴-2-三氟甲氧基苯甲基)-[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-胺的制备(H28)
Figure PCTCN2018105946-appb-000043
制备方法同实施例1，将第七步中的3-三氟甲氧基苯甲醛换为2-三氟甲氧基-3-溴苯甲醛，制得(3-溴-2-三氟甲氧基苯甲基)-[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-胺(28，35mg)，产率55％，外观为淡黄色粘稠物。
1H NMR(400MHz,CD 3OD):δ8.50(d,J＝3.6Hz,1H),7.77-7.73(m,1H),7.62-7.60(m,1H),7.46(d,J＝8.0Hz,1H),7.38(d,J＝7.6Hz,1H),7.24-7.21(m,2H),3.80-3.71(m,4H),2.49-2.38(m,3H),2.05-1.87(m,3H),1.77-1.38(m,8H),1.13-1.08(m,1H),0.77-0.69(m,1H).LC-MS:m/z(ES+)计算为C 24H 28BrF 3N 3O 2 513.1[M+1] +。
实施例29：{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-(2-(二氟甲氧基)-苯甲基)-胺的制备(H29)
Figure PCTCN2018105946-appb-000044
制备方法同实施例21，将第四步中的2-三氟甲氧基苯甲醛换为2-二氟甲氧基苯甲醛，制得{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-(2-(二氟甲氧基)-苯甲基)-胺(29，22mg)，产率18％，外观为黄色粘稠物。
1H NMR(400MHz,CDCl3)δ8.38(dd,J＝3.0,0.6Hz,1H),7.35-7.24(m,4H),7.13(td,J＝7.5,1.2Hz,1H),7.09-7.03(m,1H),3.80-3.64(m,4H),2.50(td,J＝11.2,5.2Hz,1H),2.37(dd,J＝13.7,2.9Hz,1H),2.28(dd,J＝13.9,2.1Hz,1H),2.09(td,J＝11.2,4.8Hz,1H),2.02-1.88(m,2H),1.84-1.61(m,4H),1.55-1.36(m,4H),1.10(dd,J＝14.2,6.6Hz,1H),0.66(dt,J＝13.5,9.0Hz,1H).LC-MS:m/z(ES+)计算为C 24H 29F 3N 2O 2 435.2[M+1] +。
实施例30：{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-((3-氯噻吩-2-基)-甲基)-胺的制备(H30)
Figure PCTCN2018105946-appb-000045
制备方法同实施例21，将第四步中的2-三氟甲氧基苯甲醛换为3-氯噻吩甲醛，制得{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-((3-氯噻吩-2-基)-甲基)-胺(30，46mg)，产率59％，外观为浅黄色粘稠物。
1H NMR(400MHz,CDCl 3)ppm 8.40(dd,J＝2.8Hz,1H),7.31-7.36(td,J＝8.4,3.2Hz,1H),7.28-7.29(d,J＝4.4Hz,1H),7.14-7.15(d,J＝5.6Hz,1H),6.82-6.84(d,J＝5.6Hz,1H),3.68-3.78(m,4H),2.46-2.53(td,J＝11.2,5.6Hz,1H),2.38-2.42(m,1H),2.28-2.32(m,1H),2.07-2.14(td,J＝11.2,5.6Hz,1H),1.90-1.97(m,2H),1.60-1.78(m,6H),1.39-1.49(m,3H),1.09-1.14(m,1H),0.63-0.71(m,1H).LC-MS:m/z(ESI+)计算为C 21H 26ClFN 2OS 409.1[M+1] +.
实施例31：{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-(3,4-二甲基-苯甲基)-胺的制备(H31)
Figure PCTCN2018105946-appb-000046
制备方法同实施例21，将第四步中的2-三氟甲氧基苯甲醛换为3,4-二甲基苯甲醛，制得{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-(3,4-二甲基-苯甲基)-胺(31，108mg)，产率38％，外观为黄色粘稠物。
1H NMR(400MHz,CDCl3)δ8.31–8.25(m,1H),7.35–7.23(m,2H),7.06(s,1H),7.03 (d,J＝1.2Hz,2H),3.75–3.61(m,4H),2.71–2.57(m,1H),2.31–2.20(m,2H),2.20(s,1H),2.18(s,3H),2.16(s,4H),2.04–1.96(m,1H),1.87(d,J＝13.6Hz,1H),1.73(t,J＝9.2Hz,1H),1.69–1.58(m,1H),1.52–1.31(m,4H),1.03(s,1H),0.59(dt,J＝13.3,8.7Hz,1H).LC-MS:m/z(ES+)计算为C 25H 33FN 2O 397.3[M+1] +。
实施例32：{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-(3-氯-2-甲基-苯甲基)-胺的制备(H32)
Figure PCTCN2018105946-appb-000047
制备方法同实施例21，将第四步中的2-三氟甲氧基苯甲醛换为3-氯-2-甲基苯甲醛，制得{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-(3-氯-2-甲基-苯甲基)-胺(32，35mg)，产率29％，外观为黄色粘稠物。
1H NMR(400MHz,CDCl3)δ8.38(d,J＝2.9Hz,1H),7.32(ddd,J＝8.8,8.0,2.9Hz,1H),7.25(d,J＝8.2Hz,1H),7.24–7.20(m,1H),7.10–6.96(m,2H),3.76–3.66(m,2H),3.60(s,2H),2.49(td,J＝11.2,5.3Hz,1H),2.38(ddt,J＝8.1,5.4,2.7Hz,1H),2.32–2.23(m,4H),2.09(td,J＝11.2,4.9Hz,1H),2.00–1.86(m,2H),1.79–1.56(m,5H),1.53–1.33(m,5H),1.08(dd,J＝13.6,6.4Hz,1H),0.64(dt,J＝13.6,8.9Hz,1H).LC-MS:m/z(ES+)计算为C 24H 30ClFN 2O 417.1[M+1] +。
实施例33：{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-((3-二氟甲氧基噻吩-2-基)-甲基)-胺的制备(H33)
Figure PCTCN2018105946-appb-000048
制备方法同实施例21，将第四步中的2-三氟甲氧基苯甲醛换为2-二氟甲氧基噻吩甲醛，制得{2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-((3-二氟甲氧基噻吩-2-基)-甲基)-胺(33，58mg)，产率36％，外观为浅黄色粘稠物。
1H NMR(400MHz,CDCl3)δ8.36(d,J＝2.8Hz,1H),7.36-7.25(m,2H),7.14(d,J＝5.5Hz,1H),6.82-6.78(m,1H),6.44(t,J＝73.7Hz,1H),3.81(s,2H),3.77-3.62(m,2H),2.59-2.47(m,1H),2.36(d,J＝13.5Hz,1H),2.30-2.23(m,1H),2.13(td,J＝11.3,4.7Hz,1H),2.04-1.92 (m,1H),1.84-1.56(m,5H),1.44(qd,J＝18.0,16.4,6.6Hz,4H),1.14-1.01(m,1H),0.70-0.57(m,1H).LC-MS:m/z(ES+)计算为C 22H 27F 3N 2O 2S 441.2[M+1] +。
生物学实验
实验一、本发明的化合物对MOR、KOR、DOR阿片受体的激动作用测试
1.实验目的和方法
本实验目的是为了测试本发明的化合物对μ阿片受体(MOR)、κ阿片受体(KOR)、δ阿片受体(DOR)的激动作用，根据半最大效应浓度(EC 50)评价化合物的体外活性。
1.1 细胞培养和细胞板的准备
分别使用稳定表达μ阿片受体、δ阿片受体或κ阿片受体的HEK293细胞系(稳定表达细胞系由药明康德提供)进行此测试。实验前在37℃水浴中快速解冻细胞，转移至50ml锥形管中，加入DMEM为主的细胞培养基(Invitrogen,Cat#11960)直至45毫升。室温下1000rpm离心5分钟以沉淀细胞。吸出上清液，小心不要吸出细胞。将沉淀物轻弹至松散的细胞并重新悬浮于45ml DMEM培养基中，使用Vi-CELL XR全自动细胞活力检测仪(BECKMAN COULTER)对细胞进行计数，根据计数结果调节细胞浓度为10×10 5细胞/ml。向384孔微孔板(Greiner，#781280)中转入20μl细胞悬浮液(20×10 3细胞/孔)，置于37℃，5％CO2培养箱(Thermo)中过夜。
1.2 FLIPR钙流-4检测试剂盒(赛默飞世尔科技(中国)有限公司，货号F30206)溶液配置
丙磺舒母液配置：将1ml FLIPR测试液加到77mg丙磺舒中配置成250mM的溶液。现配现用。
2X(8uM)Fluo-4Direct TM上样缓冲液配置：解冻一瓶Fluo-4DirectTM晶体(F10471，试剂盒中提供)，将10ml FLIPR测试缓冲液(试剂盒中提供)加入样品瓶中，加入0.2ml上述丙磺舒母液，最终丙磺舒测定浓度为2.5mM，涡旋并静置10分钟(避光)。现配现用。
1.3 化合物的配置和化合物板的准备
通过Echo-550仪器(Labcyte)将测试化合物H01-H33、吗啡和对应的阳性药(分别为DMAGO、DPDPE、U69593)在100％DMSO中进行10个浓度的梯度稀释，从1200nM开始，4倍梯度，浓度范围为0.004578nM-1200nM。将如上梯度浓度的900nl化合物溶液转移到384孔化合物板备用(Greiner，#781280)。
本实验中所用的阳性药物分别：对于μ阿片受体，DMAGO([D-Ala,NMePhe,Gly-ol]-脑啡肽,78123-71-4，tocris)；对于δ阿片受体，DPDPE([D-Pen,D-Pen]-脑啡肽,88373-73-3,吉尔生化有限公司),对于κ阿片受体，U69593(96744-75-1，Sigma)。
1.4 荧光成像读板仪(FLIPR)检测
从培养箱中取出如上准备的细胞板，加入20ul 2X Fluo-4 DirectTM缓冲液。细胞板中的最终体积为40μl。在37℃，5％CO 2下孵育50分钟，在室温下孵育10分钟，放入FLIPR 仪器(MD)中，放入化合物板和枪头盒。在FLIPRTETRA平台上运行方案，将10μl阳性药物或测试化合物从化合物板转至细胞板，读取荧光信号。
1.5 数据处理及统计：
将上述每孔所产生的信号值进行计算，计算公式为活性％＝(测试化合物信号值-溶剂信号值)/(阳性药物信号值-溶剂信号值)。将活性百分比和相应化合物浓度通过Graph Pad7.0软件中激动剂公式进行数据统计和作图，计算出EC 50值，如下表所示。
2.测试结果和结论
本发明的化合物对MOR、DOR、KOR受体的活性测定的具体EC 50值见以下表1。由表1可知，本发明的化合物对MOR受体的激动效果优于吗啡。此外，本发明的化合物对DOR、KOR激动活性弱，对MOR激动活性强，对MOR受体具有高选择性。
表1 利用本发明的化合物激动后MOR、DOR、KOR受体的EC 50值
Figure PCTCN2018105946-appb-000049
Figure PCTCN2018105946-appb-000050
实验二、本发明化合物对MOR受体的cAMP通路的激动作用测试
1.实验目的和方法
本实验目的是为了测试发明化合物对MOR的cAMP通路的激动作用，根据EC 50评价化合物的体外活性。
1.1 实验原理和技术
本实验通过DiscoverX公司的HitHunter磷酸腺苷测试酶片段互补(HitHunter cAMP Assay EFC)技术来测量细胞cAMP水平，监测G蛋白偶联受体(GPCR)的功能状态。
HitHunter磷酸腺苷测试酶片段互补技术是DiscoverX公司的专利技术，原理就是将β-半乳糖苷酶(β-gal)分成两个片段，酶供体(ED)和酶受体(EA)，分开时各自无活性，但在溶液中可以迅速互补形成活性β-gal酶，产生信号。
本测试中，细胞内cAMP和ED-cAMP(ED标记cAMP)与cAMP抗体(Ab)结合，ED-cAMP-Ab无法与EA互补，但ED-cAMP可与EA互补形成活性酶，产生发光信号。产生的信号量与细胞中cAMP的量成正比。
MOR受体与抑制型Gαi蛋白结合，所以实验中使用毛喉萜(forskolin，用于诱导cAMP信号)诱导cAMP表达，测定化合物对上述诱导的抑制作用。
1.2 化合物的配置
将本实验所用化合物H01-H33、吗啡、内啡肽(作为参照药物用于此实验)溶解于DMSO配置成1mM的母液。并配制如下工作液：从4uM的最高浓度开始，以3倍稀释，共10个浓度梯度，工作液浓度范围为0.000232-4uM。
1.3 细胞培养与准备
根据细胞标准操作程序(SOP)将cAMP Hunter细胞系(HEK293，DiscoverX)从冷冻库中取出、扩增，取20mL接种到384孔微孔板中，37℃下孵育过夜。
1.4 实验流程
使用HitHunter cAMP Assay检测试剂盒(DiscoverX，90-0075SM)，其中含有cAMP缓冲液、cAMP检测液、cAMP工作液A。
将细胞培养基更换成15μL cAMP缓冲液(成分为：10ul的HBSS/10mM Hepes液，5ul的cAMP Ab试剂(抗体，用于结合cAMP))。加入5μL化合物溶液或吗啡溶液或内啡肽溶液的工作液(含20uM的毛喉萜(DiscoverX，92-0005))，37℃孵育60分钟。加入20μL cAMP检测液(成分为：CAMPXS+ED/CL(含ED片段，用于标记cAMP))孵育1小时，最后加入20μL cAMP工作液A(成分为：CAMPXS+EA(EA片段，用于结合ED-cAMP，并产生信号))温育3小时，通过PerkinElmer Envision TM仪器，测定化学发光信号。
该实验设置了复孔。
1.5 数据处理与统计分析
使用公式计算每孔信号活性百分比＝100％×(1-(测试样品的平均RLU–MAX对照的平均RLU)/(溶剂对照平均RLU-MAX对照的平均RLU))。其中MAX对照指内啡肽溶液的荧光信号值，溶剂对照指DMSO的荧光信号值。通过DiscoveRx CBIS数据分析工作站(ChemInnovation,CA)将信号活性百分比与化合物浓度，通过激动剂公式(软件自带，通用)进行统计分析，计算EC 50值。
2.测试结果和结论
本发明的化合物激动MOR影响cAMP水平的EC50值见以下表2。由表2所示数据可知，利用本发的明化合物测得的cAMP通路激动活性强，性能优于吗啡。
表2 本发明化合物激动MOR影响cAMP水平的EC 50
实施例编号 EC50(nM)_
吗啡 47.2
H01 4.93
H02 4.06
H03 4.36
H04 4.36
H05 10.2
H06 11.8
H07 3.08
H08 4.77
H09 8.45
H10 2.89
H11 7.31
H12 5.51
H13 9.43
H14 15.85
H15 4.28
H16 1.36
H17 1.89
H18 2.35
H19 18.58
H20 19.85
H21 2.57
H22 11.89
H23 973
H24 374
H25 1278
H26 695
H27 1196
H28 1421
H29 1045
H30 1736
H31 873
H32 13.45
H33 12.04
实验三、本发明的化合物对MOR的β-arrestin信号通路活性测试
1.实验目的和方法
本实验目的是为了测试本发明的化合物对MOR的β-arrestin信号通路的活性。
1.1 实验原理和技术
本实验通过DiscoverX公司的酶片段互补技术(PathHunter β-arrestin GPCR测试)来测量细胞β-arrestin的水平。配体结合后的GPCR活化导致β-arrestin募集到受体上，通过酶片段互补(EFC)技术，获得信号检测来检测β-arrestin来测量GPCR的活化状态。
PathHunter β-arrestin GPCR测试将b-半乳糖苷酶(b-gal)酶分成两个片段，即酶供体(ED)和酶受体(EA)，这些片段独立时没有活性，在溶液中它们可以聚集在一起并互补以形成活性b-gal酶，进而产生信号。
1.2 化合物的配置
将本实验所用化合物H01-H33、吗啡、内啡肽(本实验的参照药物)溶解于DMSO配置成1mM的母液。并配制如下工作液：从最高浓度5uM开始，以3倍稀释，共10个浓度梯度，浓度范围为0.00029-5uM。
1.3 细胞的培养与准备
根据标准操作程序(SOP)将PathHunter细胞系(HEK293，DiscoverX)从冷冻库中取出、扩增，以20μL的体积接种到384孔微孔板中，37℃孵育60mins。加入5μL的化合物或吗啡或内啡肽的工作液到上述微孔板的孔中，37℃或室温下孵育180分钟。
1.4 信号检测
使用PathHunter检测试剂盒(DiscoverX，93-0001)。
根据试剂盒供货商的推荐在加入了化合物或吗啡或内啡肽的细胞板中加入PathHunter检测试剂，在室温下孵育1小时产生测试信号。通过PerkinElmer Envision TM仪器，测定化学发光信号。活性计算公式：活性百分比＝100％×(测试样品的平均RLU-溶剂对照的平均RLU)/(MAX对照配体的平均RLU–溶剂对照的平均RLU)。MAX对照为内啡肽所产生的荧光信号值。计算的活性百分比以最大反应效率(Max response，Emax)表示。
2.测试结果和结论
本发明的化合物激动MOR受体影响β-arrestin信号通路活性的EC 50见以下表2。由以下表2中显示的数据可知，利用本发明的化合物测得的β-arrestin信号通路的活性较弱，优于吗啡。
表3 本发明的化合物激动MOR受体影响β-arrestin信号通路活性的EC 50
实施例编号 EC 50(nM) Emax(％)
吗啡 0.33 30.48
H01 >10 6.259
H02 >10 0.14
H03 >10 3.185
H04 >10 6.12
H05 >10 0
H06 >10 0.66
H07 >10 1.55
H08 >10 3.80
H09 >10 3.28
H10 >10 37
H11 >10 2.28
H12 >10 32.21
H13 >10 3.41
H14 >10 1.82
H15 >10 15.78
H16 >10 3.12
H17 >10 1.78
H18 >10 0.48
H19 >10 1.12
H20 >10 2.12
H21 >10 0.08
H22 >10 2.31
H23 >10 2.20
H24 >10 2.76
H25 >10 3.20
H26 >10 22.56
H27 >10 3.32
H28 >10 6.26
H29 >10 7.07
H30 >10 2.91
H31 >10 5.06
H32 >10 11.68
H33 >10 8.69
实验四、化合物对大鼠手术切口损伤模型的效果测试
1.摘要
以体重在200g-300g的8周龄雄性SD大鼠为实验动物，测定实施例H02化合物、实施例H04化合物、实施例H10化合物、实施例H16化合物、实施例H17化合物、实施例H18化合物、实施例H21化合物、实施例H24化合物静脉给予后对大鼠手术痛的效果。探讨本发明的化合物的镇痛效果。
2.实验方案
2.1 实验用化合物
实施例H02化合物、实施例H04化合物、实施例H10化合物、实施例H16化合物、实施例H17化合物、实施例H18化合物、实施例H21化合物、实施例H24化合物。
2.2 化合物的配制:
称取一定量的化合物或TRV130(MCE，15150)，溶于乙醇/蓖麻油/水＝10/10/80，成澄清透明溶液。
2.3 操作
2.3.1 实验流程
使大鼠适应实验环境3天后，进行术前基础值测定，随后将进行如下描述的手术痛操作，手术后约24小时，对所有动物进行给药前基础值测定，机械痛觉超敏的动物(缩爪阈 值(PWT)小于5g)按PWT随机分到各个给药组。在静脉给药阳性药物TRV130或本发明的各化合物(以0.3mg/kg的剂量)后30min、60min测定疼痛阈值。
2.3.2 手术痛操作
手术过程执行无菌操作，手术器械(剪刀，镊子，手术刀，手术棉，缝合线)在手术前消毒。使用戊巴比妥钠(50mg/kg,腹腔注射)麻醉动物，挤压动物脚趾以确认动物手术前已经完全麻醉。距离脚后跟0.5cm位置起，纵向向脚趾方向做一个约1cm长的切口，切开皮肤后抬起趾短屈肌并造成纵向钝性损伤。按压止血后，缝合伤口。等动物完全苏醒后(可自由活动)将动物放回笼中(手术痛模型的构建参考文章：Timothy J.Brennan,Erik P.Vandermeulen,G.F.Gebhart.Characterization of a rat model of incisional pain.Pain,64(1996):493-501)。
2.3.3 疼痛阈值测定
使用上下法(up-down)进行痛觉敏感的测定。机械痛结果以动物的缩爪反应阈值(PWT)来表示。将大鼠单独放置在有机玻璃盒中，盒子底部为网格以保证大鼠脚部可以测试。在测试前使大鼠适应15分钟，适应完成后，使用测试纤维(von frey纤维丝,West coast)在大鼠后脚中部测试。测试纤维包括8个测试强度：3.61(0.4g)、3.84(0.6g)、4.08(1g)、4.31(2g)、4.56(4g)、4.74(6g)、4.93(8g)、5.18(15g)。测试时，将测试纤维垂直压向皮肤并施力使纤维弯曲6-8秒，每次测试间隔5秒。测试时，动物迅速缩脚被记为疼痛反应。测试纤维离开动物皮肤时动物缩脚也被记为疼痛反应。首先从2g开始，依据大鼠有无疼痛反应，再更换下一测试强度或上一测试强度。记录大鼠对不同测试强度的一系列反应。若大鼠出现疼痛反应，以“X”表示，若无疼痛反应，以“O”表示，可得到一串以“O”或“X”组合的序列，以出现“X”的前一次“O”作为起点，选择包括该起点的6次连续刺激反应，如“OXOXOO”，作为推算50％缩爪反应阈值的关键序列，以如下公式计算50％缩爪反应阈值：50％缩爪反应阈值(g)＝10 (Xf+kδ)/10,000。其中，Xf为最末次测试所用von Frey纤维丝的对数值，K值是动物撤足反应模式(测试时记录)，为根据测量所得“X”、“O”序列查表后得到的值，δ＝测试中使用的von Frey纤维丝间对数差值的均值。
2.4 实验结果及结论
本发明的化合物对大鼠手术痛的药效测试结果见以下表4。由以下表4中显示的数据可看出，在本发明的化合物以0.3mg/kg的剂量给药后0.5小时和1小时，能抑制大鼠术后痛模型诱导的机械痛觉超敏，效果优于阳性药TRV130。实验结果表明，本发明的化合物镇痛效果好，并且药效持续时间长。
表4 本发明化合物对大鼠手术痛的药效测试
Figure PCTCN2018105946-appb-000051
Figure PCTCN2018105946-appb-000052
实验五、化合物对大鼠呼吸抑制的影响
1.摘要
以体重在200g-300g的8周龄雄性SD大鼠为实验动物，测定实施例H05化合物、实施例H08化合物、实施例H10化合物、实施例H16化合物、实施例H17化合物、实施例H18化合物、实施例H21化合物、实施例H24化合物静脉给予后对大鼠血样分压的效果。探讨发明化合物对呼吸抑制的影响。
2.实验方案
2.1 实验用化合物
实施例H05化合物、实施例H08化合物、实施例H10化合物、实施例H16化合物、实施例H17化合物、实施例H18化合物、实施例H21化合物、实施例H24化合物。
2.2 化合物的配制
称取一定量的化合物或吗啡，溶于乙醇/蓖麻油/水＝10/10/80，成澄清透明溶液。
2.3 操作
使大鼠适应实验环境3天后，每只动物进行戊巴比妥钠(50-60mg/kg,i.p)麻醉，然后分离右侧颈总动脉，实施单侧颈动脉埋管手术(PE60,ID*OD*长度为0.76mm*1.22mm*20cm，埋入动脉1cm，管内注满肝素钠封管液)，术后恢复1天，于称重后以手术痛药效剂量静脉单次给予本发明的各化合物或吗啡，分别在给药前、给药后5min、30min、60min、120min通过埋置管采取动脉血0.4-0.5mL，立即用血气分析仪(Radiometer Medical ApS,ABL90FLEX)测量血液的酸碱度(pH)、二氧化碳分压(PCO 2)和氧分压(PO 2)。
2.4 实验结果及结论
在本发明的化合物和吗啡给药前、给药后各时间点，测得的二氧化碳分压见以下表5。由以下表5可见，本发明的化合物在药效剂量下的呼吸抑制的影响较弱。
表5 本发明化合物对大鼠呼吸抑制的效果测试
Figure PCTCN2018105946-appb-000053
实验六、本发明化合物的药代动力学测试
1.摘要
以体重在200-300g、8周龄雄性SD大鼠为实验动物，应用LC/MS/MS法测定静脉给予实施例H01化合物、实施例H04化合物、实施例H05化合物、实施例H07化合物、实施例H16化合物、实施例H17化合物、实施例H18化合物、实施例H21化合物、实施例H24化合物后，不同时刻血浆中的药物浓度。研究本发明的化合物在大鼠体内的药代动力学行为，评价其药动学特征。
2.实验方案
2.1 实验用化合物
测定实施例H01化合物、实施例H04化合物、实施例H05化合物、实施例H07化合物、实施例H16化合物、实施例H17化合物、实施例H18化合物、实施例H21化合物、实施例H24。
2.2 化合物的配制
称取一定量的化合物，溶于乙醇/蓖麻油/水＝10/10/80，配制成均一的溶液。
2.3 血浆采集和处理
以1mg/kg的剂量对大鼠静脉给予上述化合物，在给药前和给药后0.083、0.25、0.5、1.0、2.0、4.0、6.0、8.0、12.0、24.0小时由眼眶采血0.2ml，至于抗凝管中，4℃，6000转/分钟离心10分钟分离血浆，-80℃保存。
取50μL上述不同时刻的血浆，加入150μL含内标甲苯磺丁脲(200ng/mL)的乙腈 溶液混合、振摇5分钟，12000rpm，离心5分钟后，取出100μL上清，再与200μL水混合后进样分析。将内标甲苯磺丁脲固体(阿拉丁，T129578)粉末溶解在DMSO中配制成1mg/mL的储备液。储备液用100％乙腈稀释得到200ng/mL的溶液作为蛋白沉淀剂。
2.4 色谱条件和分析软件
液相色谱系统为LC-20AD UFLC高效液相色谱系统(岛津，LC-20AD)。质谱系统为AB Sciex API4000三级四级杆质谱配备电喷雾电离源(ESI)(Applied Biosystems，加拿大)。用于控制液质联用仪和定量分析的软件为Analyst 1.6(Applied Biosystems，加拿大)，药动学参数采用WinNonlin(version 5.2,Pharsight,Mountain View,CA)非房室模型进行分析。
液相色谱分离采用AQ-C18色谱柱(50×2.1mm，内径5μm)。柱温维持在室温。流动相的组成和梯度分别见下表6。
表6.化合物的液相条件
Figure PCTCN2018105946-appb-000054
待测化合物及内标的质谱条件见下表7。
表7.质谱条件
Figure PCTCN2018105946-appb-000055
2.5 标准和质控溶液的准备
将待测化合物溶解在DMSO中配制成浓度为1mg/mL的储备液，用70％乙腈稀释得到一系列的标准工作溶液，浓度为30、10、3、1、0.3、0.1、0.03和0.01μg/mL，和一系 列的标准质控溶液(24、8和0.03μg/mL)。将5μL标准溶液和45μL空白血浆基质混合均匀，得到标准曲线的各浓度点的标准溶液(3000、1000、300、100、30、10、3和1ng/mL)和质控标准溶液(血浆样品2400、800、80和3ng/mL)。
将内标甲苯磺丁脲的固体粉末溶解在DMSO中配制成1mg/mL的储备液。储备液用100％乙腈稀释得到200ng/mL的溶液作为蛋白沉淀剂。
2.6 实验结果
本发明的化合物给药后药代动力学参数见以下表6。由表6所示数据可见，本发明的化合物药代吸收较好，具有较好的药动学特征。
表6.本发明的化合物的药代动力学参数
Figure PCTCN2018105946-appb-000056
实验七、本发明化合物的急毒测试
1.摘要
以体重在200-220g，8周龄的ICR小鼠(雌雄各半)为实验动物，静脉注射实施例H10化合物、实施例H16化合物、实施例H17化合物、实施例H21化合物、实施例H24化合物，给药1次，连续观察14天，包括临床观察、体重和病理学检查。
2.实验方案
2.1 实验用化合物
测定实施例H10化合物、实施例H16化合物、实施例H17化合物、实施例H21化合物、实施例H24化合物。
2.2 化合物的配制
称取一定量的化合物，溶于乙醇/蓖麻油/水＝10/10/80，配制成均一的溶液。
2.3 操作
采用上下法观察小鼠单次静脉给予实施例化合物后的急性毒性，每个剂量组10只小鼠，雌雄各半。给药剂量为10mg/kg、15mg/kg、20mg/kg、25mg/kg、35mg/kg，给药体积为10ml/kg，化合物使用上述溶媒配置成澄清透明溶液后静脉注射。
2.4 实验统计
根据每个剂量动物的死亡率，使用Bliss软件计算半数致死量(LD 50)。
2.5 实验结果及结论
最高剂量动物出现至少80％的死亡，最低剂量出现最多20％的死亡。
给药后连续观察14天，所有动物均未出现其他异常表现。各组给药动物给药第2天体重稍有下降，但与对照组比差异不显著。14天观察期结束后全部动物安乐死后进行大体解剖检查，体表未见明显异常，胸腔、腹腔、盆腔、颅腔未见肉眼可见病变。
本实验条件下，本发明化合物静脉给药后的LD 50值为20-30mg/kg之间。安全性较好。

Claims (11)

  1. 一种通式I所示的化合物或其立体异构体、互变异构体、对映体、非对映体、消旋体及可药用的盐，
    Figure PCTCN2018105946-appb-100001
    其中，
    Ar 1为取代的或未取代的芳基、取代的或未取代的杂芳基；
    A为-C 1-2亚烷基，或为被C 1-3烷基取代的-C 1-2亚烷基；
    B为-NH-CH 2-Ar 2、-NH-C(O)-Ar 2或-NR 1R 2，其中
    R 1和R 2连同它们所连接的氮原子一起形成被T取代或未被取代的6-12元的杂芳基，T为-H、-OH、-C 1-3烷基、-C 1-3烷氧基、羟基取代的C 1-3烷基、卤素取代的C 1-3烷基、卤素取代的C 1-3烷氧基、卤素、氨基、单(C 1-3烷基)-氨基-、双(C 1-3烷基)-氨基-、腈基、苄基或苯基；
    Ar 2为被取代的或未取代的苯基、被取代的或未取代的5-6元杂芳基，其中所述苯基或所述5-6元杂芳基任选的被下列一个或多个取代基所取代：-OH、卤素、腈基、-C 1-3烷基、-C 1-3烷氧基、羟基取代的C 1-3烷基、卤素取代的C 1-3烷基、卤素取代的C 1-3烷氧基、氨基、单(C 1-3烷基)-氨基-、双(C 1-3烷基)-氨基-、苄基或苯基。
  2. 根据权利要求1所述的化合物或其立体异构体、互变异构体、对映体、非对映体、消旋体及可药用的盐，其中Ar 1为苯基、吡啶基、被取代的苯基、或被取代的吡啶基，其中所述苯基或所述吡啶基任选的被下列一个或多个取代基所取代：-C 1-3烷基、-C 1-3烷氧基或卤素；
    T为-H、-OH、-C 1-3烷基、-C 1-3烷氧基、卤素取代的C 1-3烷基、或卤素取代的C 1-3烷氧基；
    Ar 2为苯基、噻吩基、咪唑基、吡啶基或吡唑基，其中所述的苯基、噻吩基、咪唑基、吡啶基或吡唑基任选的被下列一个或多个取代基所取代：-OH、卤素、腈基、-C 1-3烷基、卤素取代的C 1-3烷基、-C 1-3烷氧基、卤素取代的C 1-3烷氧基、单(C 1-3烷基)-氨基-。
  3. 根据权利要求2所述的化合物或其立体异构体、互变异构体、对映体、非对映体、消旋体及可药用的盐，其中Ar 1为吡啶基、或被取代的吡啶基，其中所述吡啶基任选的被下列一个或多个取代基所取代：-C 1-3烷基、氟或氯；
    A为-C 1-2亚烷基，或为被甲基取代的-C 1-2亚烷基；
    -NR 1R 2为
    Figure PCTCN2018105946-appb-100002
    其中T为-H、-OCH 3、-CF 3、或-OCF 3；
    Ar 2为苯基、噻吩基或吡唑基，其中所述的苯基、噻吩基或吡唑基任选的被下列一个或多个取代基所取代：-OH、卤素、腈基、-C 1-3烷基、-C 1-3烷氧基、-CF 3、-OCF 3、-OCHF 2、-NHCH 3。
  4. 根据权利要求3所述的化合物或其立体异构体、互变异构体、对映体、非对映体、消旋体及可药用的盐，其中Ar 1为
    Figure PCTCN2018105946-appb-100003
    当A为-C 1-2亚烷基时，Ar 2为
    Figure PCTCN2018105946-appb-100004
    Figure PCTCN2018105946-appb-100005
    当A为被甲基取代的-C 1-2亚烷基时，Ar 2为
    Figure PCTCN2018105946-appb-100006
    Figure PCTCN2018105946-appb-100007
    Figure PCTCN2018105946-appb-100008
  5. 根据权利要求1所述的化合物或其立体异构体、互变异构体、对映体、非对映体、消旋体及可药用的盐，所述化合物为：
    (3-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
    (2-氯-4-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
    N-甲基-2-(((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)甲基)苯胺；
    (3-氯-2-甲基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
    ((3-氯-噻吩-2-基)甲基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
    (4-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
    (3,4-二甲基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
    (2,4-二甲基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
    (2-三氟甲氧基苄基)-[2-(9-(3-氯-5-氟吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
    (2-三氟甲氧基苄基)-[2-(9-(3-甲基-5-氟吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
    (4-溴-2-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
    (4-甲基-2-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
    3-{[(2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺甲基}-2-三氟甲氧基苯甲腈；
    ((3-三氟甲基噻吩-2-基)甲基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
    4-{[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基胺]甲基}-3-三氟甲氧基苯酚；
    (2-二氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
    (5-氯-2-三氟甲氧基苄基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
    ((3-二氟甲氧基噻吩-2-基)甲基)-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
    2-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]-7-三氟甲基-1,,2,3,4-四氢异喹啉；
    7-甲氧基-2-[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-1,2,3,4-四氢异喹啉；
    {2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-(2-(三氟甲氧基)-苯甲基)-胺；
    (2-三氟甲氧基苯甲基)-[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-胺；
    6-[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-4,5,6,7-四氢-噻吩并[2,3-c]吡啶；
    3-甲基氨基-噻吩-2-羧酸[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-酰胺；
    [(5-甲氧基-1H-吡唑-4-基)甲基]-[2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基]胺；
    ((3-甲氧基噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)丙基]-1-胺；
    ((3-甲氧基噻吩-2-基)甲基)-1-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)丙基]-2-胺；
    (3-溴-2-三氟甲氧基苯甲基)-[2-(9-吡啶-2-基-6-氧杂-螺[4.5]癸-9-基)-乙基]-胺；
    {2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-(2-(二氟甲氧基)-苯甲基)-胺；
    {2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-((3-氯噻吩-2-基)-甲基)-胺；
    {2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-(3,4-二甲基-苯甲基)-胺；
    {2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-(3-氯-2-甲基-苯甲基)-胺；或
    {2-[9-(5-氟-吡啶-2-基)-6-氧杂-螺[4.5]癸-9-基]-乙基}-((3-二氟甲氧基噻吩-2-基)-甲基)-胺。
  6. 一种药物组合物，其特征在于，包括治疗有效量的权利要求1-5任一项所述的化合物或其立体异构体、互变异构体、对映体、非对映体、消旋体及可药用的盐，以及任选的一种或多种医药上可接受的载剂和/或添加剂，所述载剂例如盐水、热压水、林格氏液、缓冲盐水、葡萄糖、麦芽糖糊精、甘油、乙醇及其混合物，所述添加剂例如稀释剂、润滑剂、粘合剂、助流剂、崩解剂、甜味剂、矫味剂、湿润剂、分散剂、表面活性剂、缓冲盐水、涂层剂、发泡剂、防腐剂、稳定剂或芳香剂。
  7. 根据权利要求1-5任一项所述的化合物或其立体异构体、互变异构体、对映体、非对映体、消旋体及可药用的盐或者根据权利要求6所述的药物组合物在制备用于预防和/或治疗MOR受体激动剂介导的相关疾病的药物中的用途。
  8. 根据权利要求7所述的用途，所述MOR受体激动剂介导的相关疾病包括疼痛、炎症、免疫功能障碍、食管回流、神经和精神病症、呼吸道疾病、泌尿和生殖病症、药物和酒精滥用、胃炎或腹泻，例如所述疼痛包括创伤性疼痛、神经性疼痛、炎性疼痛、内脏疼痛、偏头痛和与癌症有关的疼痛。
  9. 一种用于预防和/或治疗MOR受体激动剂介导的相关疾病的方法，所述方法包括对有需要的对象施用治疗有效量的根据权利要求1-5任一项所述的化合物或其立体异构体、互变异构体、对映体、非对映体、消旋体及可药用的盐或者根据权利要求6所述的药物组合物。
  10. 根据权利要求9所述的方法，所述MOR受体激动剂介导的相关疾病包括疼痛、炎症、免疫功能障碍、食管回流、神经和精神病症、呼吸道疾病、泌尿和生殖病症、药物和酒精滥用、胃炎或腹泻，例如所述疼痛包括创伤性疼痛、神经性疼痛、炎性疼痛、内脏疼痛、偏头痛和与癌症有关的疼痛。
  11. 一种制备权利要求1-5任一项中限定的化合物的方法，其中：
    当A为-C 1-2亚烷基，B为-NH-CH 2-Ar 2时，合成路线如方案1：
    方案1
    Figure PCTCN2018105946-appb-100009
    其中Ar1、Ar2如权利要求1、2、3、4或5中定义的，所述酸优选为硫酸、盐酸、磷酸、三氟甲磺酸、氢溴酸或其组合；所述氧化剂优选为氯铬酸吡啶盐(PCC)、重铬酸吡啶盐(PDC)或其组合；所述芳基格式试剂优选为芳基溴化镁、芳基氯化镁或其组合；所述碱优选为氢氧化钾、氢氧化钠或其组合；所述还原剂1优选为四氢锂铝、硼烷四氢呋喃、硼烷二甲硫醚或其组合；所述还原剂2优选为硼氢化钠、硼氢化钾，三乙酰基硼氢化钠、氰基硼氢化钠或其组合；
    当A为被C 1-3烷基取代的-C 1-2亚烷基时，B为-NH-CH 2-Ar 2，合成路线如方案2或方案3，
    方案2
    Figure PCTCN2018105946-appb-100010
    其中Ar1、Ar2为如权利要求1、2、3或4中定义的，R3为C1-3烷基，所述碱优选为氢化钠、二异丙基氨基锂、丁基锂叔丁醇钾、乙醇钠、六甲基二硅基氨基锂、六甲基二硅基氨钾或其组合；所述还原剂1优选为四氢锂铝、硼烷四氢呋喃、硼烷二甲硫醚或其组合；所述还原剂2优选为硼氢化钠、硼氢化钾、三乙酰基硼氢化钠、氰基硼氢化钠或其组合；
    方案3
    Figure PCTCN2018105946-appb-100011
    其中Ar1、Ar2为如权利要求1、2、3或4中定义的，R4为C1-3烷基，所述还原剂1 优选为四氢锂铝、硼烷四氢呋喃、硼烷二甲硫醚或其组合；所述还原剂2优选为硼氢化钠、硼氢化钾、三乙酰基硼氢化钠、氰基硼氢化钠或其组合；
    当A为-C 1-2亚烷基，B为-NH-C(O)-Ar 2时，合成路线如方案4，
    方案4
    Figure PCTCN2018105946-appb-100012
    其中Ar 1、Ar 2如权利要求1、2、3或4中定义的，优选所述缩合剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)/1-羟基苯并三唑(HOBT)、二环己基碳二亚胺(DCC)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)或其组合；
    当A为-C 1-2亚烷基，B为-NR 1R 2时，合成路线如方案5，
    方案5
    Figure PCTCN2018105946-appb-100013
    其中Ar1、R1、R2如权利要求1、2、3或4中定义的，所述碱优选为氢氧化钠、氢氧化钾或其组合，所述缩合剂优选为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI)/1-羟基苯并三唑(HOBT)、二环己基碳二亚胺(DCC)、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)或其组合，所述还原剂优选为四氢锂铝、硼烷四氢呋喃、硼烷二甲硫醚或其组合。
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