WO2017211272A1 - 苯基丙酰胺类衍生物、其制备方法及其在医药上的应用 - Google Patents

苯基丙酰胺类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2017211272A1
WO2017211272A1 PCT/CN2017/087328 CN2017087328W WO2017211272A1 WO 2017211272 A1 WO2017211272 A1 WO 2017211272A1 CN 2017087328 W CN2017087328 W CN 2017087328W WO 2017211272 A1 WO2017211272 A1 WO 2017211272A1
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group
formula
compound
cycloalkyl
amino
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PCT/CN2017/087328
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English (en)
French (fr)
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李心
王斌
钱文建
陈阳
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to BR112018074431-0A priority Critical patent/BR112018074431A2/pt
Priority to EP17809711.9A priority patent/EP3466962A4/en
Priority to RU2018145808A priority patent/RU2738207C2/ru
Priority to CN202210044042.XA priority patent/CN114940700A/zh
Application filed by 江苏恒瑞医药股份有限公司, 上海恒瑞医药有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to JP2018563586A priority patent/JP7120927B2/ja
Priority to US16/306,950 priority patent/US20190144499A1/en
Priority to MX2018015082A priority patent/MX2018015082A/es
Priority to CN201780004217.1A priority patent/CN108290926B/zh
Priority to CA3025710A priority patent/CA3025710A1/en
Priority to KR1020187037174A priority patent/KR102401743B1/ko
Priority to AU2017277003A priority patent/AU2017277003B2/en
Priority to UAA201812607A priority patent/UA123737C2/uk
Priority to CN202210043910.2A priority patent/CN114349820A/zh
Publication of WO2017211272A1 publication Critical patent/WO2017211272A1/zh
Priority to HK18114605.8A priority patent/HK1255567A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
    • C07K1/062—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for alpha- or omega-carboxy functions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicine and relates to a phenylpropionamide derivative, a preparation method thereof and application thereof in medicine.
  • the present invention relates to a phenylpropionamide derivative represented by the general formula (I), a process for producing the same, and a pharmaceutical composition containing the same, and its use as a kappa opioid receptor (KOR receptor) Use of the agent and its use in the manufacture of a medicament for the treatment and/or prevention of pain and pain related diseases.
  • Opioid receptors are an important class of G-protein-coupled receptors and are targets for the binding of endogenous opioid peptides and opioids. Opioid receptors have a regulatory effect on nervous system immunity and endocrine systems. Opioids are Currently the strongest and most commonly used central analgesic. Endogenous opioid peptides are naturally occurring opioid active substances in mammals. Currently known endogenous opioid peptides are broadly classified into enkephalins, endorphins, dynorphins and neomorphins (Pharmacol Rev 2007). ;59:88–123), the corresponding opioid receptors in the central nervous system, namely ⁇ , ⁇ , ⁇ receptors.
  • the ⁇ -opioid receptor (KOR) consists of 380 amino acids, and dynorphin is its endogenous ligand. It is expressed in sensory neurons, dorsal root ganglion cells and primary afferent neurons, and participates in important physiological activities such as pain, neuroendocrine, emotional behavior and cognition.
  • Human KOR is currently known to be encoded by the OPRK1 gene and is located at chromosome 8q11-12 (Simonin F, Gaveriaux Ruff C, Kieffer BL, et al. Proc Natl Acad Sci USA 1995, 92(15): 7006-10).
  • KOR activation is coupled to the G protein G i /G 0 , which increases phosphodiesterase activity, inhibits the activity of adenylate cyclase, and reduces intracellular cAMP levels, thereby producing neuronal inhibition.
  • KOR agonists repeatedly have a desensitizing effect on receptors and have a reduced inhibitory effect on adenylate cyclase activity (Raynor K, Kong H, Hines J, et al. J Pharmacol Exp Ther, 1994, 270: 1381-6) .
  • KOR is also coupled to inward rectifier potassium channels and N-type calcium ion channels (Henry DJ, Grandy DK, Lester HA, Davidson N, Chavkin C (Mar 1995) Molecular Pharmacology 47(3): 551-7).
  • KOR agonists are capable of inhibiting (calcium-dependent) release of pre- and pre-inflammatory substance P from peripheral sensory nerve endings, which may be responsible for their antinociceptive and anti-inflammatory effects.
  • various natural alkaloids and synthetic ligands can also bind to KOR.
  • KOR provides a natural addiction control mechanism, and therefore, a drug as a receptor agonist has the potential for drug addiction treatment.
  • KOR agonists are used for the treatment or prevention including, for example, dysmenorrhea and endometriosis
  • ⁇ opioid agonists increase renal excretion of water and reduce urinary sodium excretion (ie, produce selective water diuresis, also known as water-promoting), which many researchers believe is due to inhibition of pituitary secretion of vasopressin.
  • a study comparing centrally acting and alleged peripheral selective ⁇ opioids concluded that KOR within the blood-brain barrier is responsible for mediating this effect.
  • Some researchers have proposed to treat hyponatremia with a nociceptin peptide or a charged peptide conjugate that acts on the nociceptin receptor in the periphery, which is related to KOR but different (DRKapusta, Life Sci ., 60:15-21, 1997).
  • KOR agonist patent applications include WO20071398, WO2008060552, WO09932510, WO2013184794, WO2014089019, WO2014184356 and WO2015065867.
  • KOR receptor ⁇ opioid receptor (KOR receptor) agonists
  • KOR receptor ⁇ opioid receptor
  • the present invention will provide a novel kappa opioid receptor (KOR receptor) agonist compound (further modified to the amino group of glycine in the core structure) which surprisingly exhibits excellent effects and effects.
  • the substituent on the amino group of glycine is a substituted or unsubstituted ethylene group, it has an unexpected effect.
  • M is an inorganic acid or an organic acid, preferably an organic acid, more preferably trifluoroacetic acid;
  • G is selected from the group consisting of O, -NR 4 and -CR 5 R 6 ;
  • R 1 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 7 , -C (O) R 7 , -C(O)OR 7 , -S(O) m R 7 and -NR 8 R 9 , wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and The heteroaryl group is optionally selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero
  • R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclic group, a heterocyclic alkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a hetero Arylalkyl, -OR 7 , -C(O)R 7 and -C(O)OR 7 wherein alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetero
  • the cycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl groups are optionally selected from the group consisting of alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkyl Substituted by
  • R 3 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclic group, a heterocyclic alkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a hetero Arylalkyl, -OR 7 , -C(O)R 7 and -C(O)OR 7 wherein alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetero
  • the cycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl groups are optionally selected from the group consisting of alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkyl Substituted by
  • R 4 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amino group, a carboxylate group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 7 , - C(O)R 7 , -C(O)OR 7 , -S(O) m R 7 , -NR 8 R 9 and -NHC(O)NR 8 R 9 , wherein the alkyl group, cycloalkyl group And a heterocyclic group, an aryl group and a heteroaryl group are optionally selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an amino group, a carboxylate group, a nitro group, a cyano group, an alkoxy group, a hydroxyalky
  • R 5 and R 6 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amino group, a carboxylate group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 7 , —C(O)R 7 , —C(O)OR 7 , —S(O) m R 7 , —NR 8 R 9 and —NHC(O)NR 8 R 9 , wherein said alkyl group,
  • the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl Substituting one or more substituents in a heterocyclic group, an aryl group, and a heteroary
  • R 7 is selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group,
  • the aryl and heteroaryl are optionally selected from the group consisting of alkyl, halo, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents;
  • R 8 and R 9 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amino group, a carboxylate group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkane Substituted by one or more substituents of a group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • z 0, 1, 2, 3 or 4;
  • n 0, 1, or 2.
  • the compound of the formula (I) is further a compound of the formula (II):
  • the compound of the formula (I) or (II) is further a compound of the formula (III):
  • the compound of the formula (I), (II) or (III) is further a compound of the formula (IV):
  • the compound represented by the formula (I), (II) or (III) is further a compound of the formula (III-A):
  • G is O or CR 5 R 6 ; preferably CR 5 R 6 ;
  • R 10 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group. base;
  • R 11 and R 12 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a cycloalkyl group. a heterocyclic group, an aryl group and a heteroaryl group;
  • R 10 and R 11 together form a cycloalkyl group
  • R 11 and R 12 together form a cycloalkyl group
  • R 13 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group. base;
  • s 0, 1 or 2;
  • R 5 to R 6 , M and z are as defined in the formula (I).
  • the compound represented by the formula (I), (II), (III), (IV) or (III-A) is further a compound of the formula (IV-A) Compound shown:
  • R 10 to R 13 , M, z and s are as defined in the formula (III-A).
  • the compound of the formula (I), (II), (III), (IV), (III-A) or (IV-A) is further a formula Compounds shown in (IV-B):
  • R 10 to R 11 , R 13 , M, z and s are as defined in the formula (III-A).
  • Typical compounds of formula (I) include, but are not limited to:
  • a tautomer a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • the invention further provides a compound of the formula (V) which is an intermediate for the preparation of a compound of the formula (II):
  • R a is an amino-protecting group, preferably tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilyloxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl, P-nitrophenylsulfonyl or tert-butyl (ie Boc, Fmoc, Alloc, Troc, Teoc, CBz, Tosyl, Nosyl and t-Bu);
  • R 2 and R 3 are as defined in the formula (II).
  • the invention further provides a process for the preparation of a compound of the formula (II), the process comprising:
  • M, G, z, R 2 and R 3 are as defined in the formula (II), and R a is as defined in the formula (V).
  • the present invention further provides a compound of the formula (VI) which is an intermediate for the preparation of a compound of the formula (III):
  • R a is an amino-protecting group, preferably tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilyloxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl, P-nitrobenzenesulfonyl or tert-butyl;
  • G and R 2 are as defined in the formula (III).
  • the invention further provides a process for the preparation of a compound of the formula (III), the process comprising:
  • M, G, z and R 2 are as defined in the general formula (III), and R a is as defined in the general formula (VI).
  • the acidic reagent under acidic conditions is preferably a 1,4-dioxane solution of trifluoroacetic acid or hydrogen chloride.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above formula (I), (II), (III), (IV), (III-A), (IV-A) or a compound represented by (IV-B) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable compound a salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also relates to a method of preparing the above pharmaceutical composition
  • a method of preparing the above pharmaceutical composition comprising the general formula (I), (II), (III), (IV), (III-A), (IV-A) or (IV- a compound represented by B) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, a mixture thereof, or a pharmaceutically acceptable salt thereof
  • a pharmaceutically acceptable carrier, diluent or excipient is mixed.
  • the pharmaceutical composition of the invention further comprises one or more of the following compounds: opioids, cannabinoids, antidepressants, anticonvulsants, tranquilizers, corticosteroids, ion channel blockers or Non-steroidal anti-inflammatory drugs (NSAID).
  • opioids cannabinoids
  • antidepressants anticonvulsants
  • tranquilizers corticosteroids
  • corticosteroids ion channel blockers
  • ion channel blockers Non-steroidal anti-inflammatory drugs
  • the invention further relates to a compound of the formula (I), (II), (III), (IV), (III-A), (IV-A) or (IV-B) or a tautomer thereof , a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for preparing an agonistic or antagonistic kappa opioid
  • KOR receptor substance receptor
  • the invention further relates to a compound of the formula (I), (II), (III), (IV), (III-A), (IV-A) or (IV-B) or a tautomer thereof , a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, prepared for prevention and/or Use of a medicament for treating a ⁇ opioid receptor (KOR receptor) agonist-mediated related disorder, preferably selected from the group consisting of pain, Inflammation, itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough and glaucoma, more preferably pain.
  • KOR receptor ⁇ opioid receptor
  • the invention further relates to a compound of the formula (I), (II), (III), (IV), (III-A), (IV-A) or (IV-B) or a tautomer thereof , a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, prepared for prevention and/or Use in a medicament for treating pain and pain related diseases in mammals (e.g., humans), wherein the pain may be postoperative pain, pain caused by cancer, neuropathic pain, traumatic pain, and pain caused by inflammation.
  • mammals e.g., humans
  • the invention further relates to a method of agonizing or antagonizing a kappa opioid receptor (KOR receptor) comprising administering to a patient in need thereof a therapeutically effective amount of a formula (I), (II) of the invention ( a compound represented by III), (IV), (III-A), (IV-A) or (IV-B) or a tautomer thereof, a mesogen, a racemate, an enantiomer a form, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • KOR receptor kappa opioid receptor
  • the invention further relates to a method of preventing and/or treating a KOR agonist receptor mediated related disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of the general formula (I), (II) of the invention, a compound represented by (III), (IV), (III-A), (IV-A) or (IV-B) or a tautomer, a mesogen, a racemate, an enantiomeric A conformation, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • This method shows outstanding efficacy and fewer side effects.
  • the kappa opioid receptor (KOR receptor) agonist receptor mediated related diseases are selected from the group consisting of pain, inflammation, itching, edema, hyponatremia, hypokalemia, intestinal obstruction, cough and glaucoma. , preferably pain.
  • the invention further relates to a compound of the formula (I), (II), (III), (IV), (III-A), (IV-A) or (IV-B) for use as a medicament or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • the invention further relates to a compound of the formula (I), (II), (III), (IV), (III-A), (IV-A) or (IV-B) or a tautomer thereof , a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in agonizing or antagonizing a kappa opioid receptor (KOR body).
  • KOR body kappa opioid receptor
  • the invention further relates to a compound of the formula (I), (II), (III), (IV), (III-A), (IV-A) or (IV-B) or a tautomer thereof , a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of KOR receptor agonist mediated Related diseases.
  • the invention further relates to a compound of the formula (I), (II), (III), (IV), (III-A), (IV-A) or (IV-B) or a tautomer thereof , a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of a mammal (eg, a human) Pain and pain related diseases.
  • the kappa opioid receptor (KOR receptor) agonist-mediated related disease, disorder, or condition can be mediated by any kappa opioid receptor (KOR receptor) agonist.
  • Conditions including, but not limited to, acute or chronic pain, inflammation, itching, hyponatremia, edema, intestinal obstruction, cough, and glaucoma.
  • the pain associated with the kappa opioid receptor can be neuropathic pain, somatic pain, visceral pain or skin pain.
  • Some diseases, disorders or conditions are associated with more than one form of pain.
  • post-operative pain can be any or all of neuropathic pain, somatic pain, visceral pain, or skin pain factors, depending on the type and extent of surgery employed.
  • the ⁇ opioid receptor (KOR receptor)-associated inflammation of the present invention may be any inflammatory disease or condition including, but not limited to, sinusitis, rheumatoid arthritis tenosynovitis, bursitis, tendonitis, and tibia Epicondylitis, visciditis, osteomyelitis, osteoarthritis, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), ocular inflammation, ear inflammation, or autoimmune inflammation.
  • IBD inflammatory bowel disease
  • IBS irritable bowel syndrome
  • the ⁇ opioid receptor (KOR receptor)-associated pruritus of the present invention may be any pruritic disease and condition, such as ocular itching such as conjunctivitis associated with pruritus, itching, and itching associated with end stage renal disease (many of which Patients undergo renal dialysis) and other forms of cholestasis, including primary biliary cirrhosis, intrahepatic cholestasis of pregnancy, chronic cholesterol liver disease, uremia, malignant cholestasis, jaundice, and skin conditions such as eczema (dermatitis) including Acne dermatitis or contact dermatitis, skin blemishes, polycythemia, lichen planus, chronic simple moss, rickets, thyrotoxicosis, athlete's foot, urticaria, hemorrhoids, vaginitis, acne-related anal itching, and insect bites and itching Itching caused by drugs, such as itching caused
  • the ⁇ opioid receptor (KOR receptor)-associated edema involved in the present invention may be any edematous disease or condition, such as edema caused by congestive heart disease or edema caused by inappropriate secretion of antidiuretic hormone (ADH).
  • ADH antidiuretic hormone
  • the ⁇ opioid receptor (KOR receptor)-associated intestinal obstruction of the present invention may be any intestinal obstructive disease or condition including, but not limited to, post-operative intestinal obstruction or opioid-induced intestinal dysfunction.
  • the kappa opioid receptor (KOR receptor)-associated neuropathic pain of the present invention may be any neuropathic pain, for example, trigeminal neuralgia, diabetic pain, viral-induced pain such as herpes zoster-related pain, chemotherapy-induced Pain, invasive nerve metastasis cancer pain, trauma and surgical related neuropathic pain, and various headache variants such as migraine that are considered to have neuropathological factors.
  • KOR receptor kappa opioid receptor
  • the kappa opioid receptor (KOR receptor) related pains of the present invention include ocular pain, for example, refractive keratectomy (PRK), ocular tear, fundus fracture, chemical burn, corneal epithelial abrasion or Eye pain after irritation, or with conjunctivitis, corneal ulcer, scleritis, scleral inflammation, scleral keratitis, ocular herpes zoster, interstitial keratitis, acute ulceris, dry keratoconjunctivitis, Eyelid pain associated with cellulitis, orbital pseudotumor, pemphigus, trachoma, or uveitis.
  • PRK refractive keratectomy
  • ocular tear fundus fracture
  • chemical burn corneal epithelial abrasion or Eye pain after irritation
  • conjunctivitis corneal ulcer, scleritis, scleral inflammation, scleral keratitis, ocular herpes zo
  • the kappa opioid receptor (KOR receptor)-associated pain of the present invention also encompasses sore throat, especially with inflammatory conditions such as allergic rhinitis, acute bronchitis, common cold, contact ulcers, herpes simplex virus damage Infectious mononucleosis, influenza, laryngeal cancer, acute laryngitis, acute necrotizing ulcer gingivitis, tonsil abscess, pharyngeal burning, pharyngitis, reflux pharyngitis, acute sinusitis and tonsillitis Related sore throat.
  • sore throat especially with inflammatory conditions such as allergic rhinitis, acute bronchitis, common cold, contact ulcers, herpes simplex virus damage Infectious mononucleosis, influenza, laryngeal cancer, acute laryngitis, acute necrotizing ulcer gingivitis, tonsil abscess, pharyngeal burning, pharyngitis, reflux pharyngitis, acute sinusitis and
  • the kappa opioid receptor (KOR receptor)-related pain involved in the present invention may be arthritic pain, kidney stones, urinary calculi and bile duct stones pain, uterine fistula, dysmenorrhea, endometriosis, mastitis, Indigestion, post-surgical pain (eg appendectomy, open colorectal surgery, hernia repair, prostatectomy, colonectomy, gastrectomy, splenectomy, colectomy, colostomy, pelvicoscopy) Examination, tubal ligation, hysterectomy, vasectomy or postoperative pain caused by cholecystectomy), pain after medical treatment (eg colonoscopy, cystoscopy, hysteroscopy or cervical or endometrial biopsy) Pain after examination), otitis pain, fulminant cancer pain, and pain associated with GI disorders such as IBD or IBS or other inflammatory conditions, especially visceral inflammation (eg, gastroesophageal reflux disease, Pancreatitis
  • hypokalemia associated with the kappa opioid receptor (KOR receptor) of the present invention may be any disease or condition in which hyponatremia (low sodium condition) is present, for example, in humans, when plasma sodium concentration is present Below 135 mmol/l, abnormalities may occur alone, or more commonly as a complication of other medical conditions or as a result of the use of a drug that causes sodium deficiency, which is associated with hyponatremia Including but not limited to: tumor factors that cause excessive ADH secretion, including lung, duodenum, pancreas, ovary, bladder and ureteral cancer, thymoma, mesothelioma, bronchial adenoma, carcinoid tumor, ganglioneuroma And Ewing's sarcoma, infection; for example, pneumonia (bacterial or viral), abscess (lung or brain), vacuolation (aspergillosis), tuberculosis (lung or brain), meningitis (bacterial
  • Another aspect of the invention relates to a method for preventing and/or treating a disease, disorder or condition-related disease mediated by a kappa opioid receptor (KOR receptor) agonist, the method comprising: The patient administers a therapeutically effective amount of each of the formulae of the invention, particularly a compound of formula (I) or a tautomer, mesogen, racemate, enantiomer, non-pair thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof; the method exhibits outstanding efficacy and less side effects, wherein the kappa opioid receptor (KOR receptor) agonist mediated correlation Diseases include, but are not limited to, acute or chronic pain, inflammation, itching, hyponatremia, edema, intestinal obstruction, cough, and glaucoma.
  • KOR receptor kappa opioid receptor
  • Another aspect of the invention relates to a method of preventing and/or treating pain and pain related diseases in a mammal, the method comprising administering to a mammal in need thereof a therapeutically effective amount of the general formula (I), (II) of the invention, a compound represented by (III) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof;
  • the method exhibits outstanding efficacy and less side effects, wherein the pain may be postoperative pain, pain caused by cancer, neuropathic pain, traumatic sore body pain, visceral pain, skin pain and inflammation caused by inflammation, for example
  • the post-operative pain may be any or all of neuropathic pain, somatic pain, visceral pain or skin pain factors, depending on the type and extent of surgery used; the cancer may be selected from breast cancer, Endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
  • excipients can be inert excipients, granulating and disintegrating agents and lubricants. These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
  • Oral formulations can also be provided in soft gelatine capsules in which the active ingredient is mixed with an inert solid diluent or an active ingredient in a water-soluble carrier or an oil vehicle or olive oil.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending, dispersing or wetting agents.
  • the aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents. Flavor.
  • An oil suspension can be formulated by suspending the active ingredient in vegetable oil or mineral oil.
  • the oil suspension may contain a thickening agent.
  • the above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an antioxidant.
  • Dispersible powders and granules suitable for use in the preparation of aqueous suspensions may be employed in the preparation of the active ingredient and dispersion or dispersing or suspending agents or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or compositions or
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase can be a vegetable oil or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers can be naturally occurring phospholipids or partial esters.
  • the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • compositions of the invention may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase. The injection or microemulsion can be injected into the bloodstream of the patient by a local injection.
  • compositions of the invention may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oils may conveniently be employed as a solvent or suspension medium.
  • the compounds of the invention may be administered in the form of a suppository for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
  • the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, and the patient's behavior.
  • the dosage, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt The type can be verified according to traditional treatment options.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • the alkyl group of the atom is a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropane Base, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethyl Butyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methyl A pentyl group, a 4-methylpentyl group, a 2,3-dimethylbutyl group, and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • an alkane Base alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, hetero
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom, most preferably from 5 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into two A cyclo, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic ring, more preferably a bicyclic or tricyclic ring.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene A benzocycloheptyl group or the like; preferably a phenylcyclopentyl group or a tetrahydronaphthyl group.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like are preferably tetrahydropyranyl, piperidinyl or pyrrolidinyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • Non-limiting examples of spiroheterocyclyl groups include:
  • fused heterocyclyl refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused heterocyclic groups include:
  • bridge heterocyclyl refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A ⁇ -electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bridge heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (i.e., a ring sharing a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, more preferably 5 to 6 yuan, such as phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, and has 1 to 3 hetero atoms; more preferably 5 or 6 members, and 1 to 2 hetero atoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridyl
  • the oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like are preferably an imidazolyl group, a pyrazolyl or pyrimidinyl group, or a thiazolyl group; more preferably a pyrazolyl group.
  • the heteroaryl ring may be fused to an aryl
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio group, alkylamino group, halogen, fluorenyl group, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, Aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • cycloalkylalkyl refers to an alkyl group substituted by one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.
  • heterocyclylalkyl refers to an alkyl group substituted by one or more heterocyclic groups, wherein heterocyclyl and alkyl are as defined above.
  • arylalkyl refers to an alkyl group substituted by one or more aryl groups, wherein aryl and alkyl are as defined above.
  • hydroxy refers to an -OH group.
  • halogen means fluoro, chloro, bromo or iodo.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
  • acyl halide refers to a compound containing a -C(O)-halogen group.
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, and C
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • the compound of the formula (II-A) and the compound of the formula (II-B) are reacted under basic conditions to give a compound of the formula (II-C).
  • the alkaline agent under the condition is preferably triethylamine;
  • the compound of the formula (II-C) and the compound of the formula (II-D) are reacted under heating, basic conditions, and potassium iodide to form a compound of the formula (II-E), and the alkaline agent under the condition is preferably potassium carbonate;
  • Deprotection of a compound of the formula (II-E) gives a compound of the formula (II-F);
  • the obtained compound of the formula (II-F) is reacted with a compound of the formula (II-J) under the conditions of a condensing agent to give a formula a compound of (V), wherein the condensation reagent is preferably 2-(7-azobenzotriazole)-N,N,N',N'-
  • a weak base is optionally added to carry out a free reaction to obtain a free product represented by the compound of the formula (II).
  • the reagents providing basic conditions include organic bases including, but not limited to, pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and inorganic bases.
  • organic bases including, but not limited to, pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and inorganic bases.
  • Lithium diisopropylamide, potassium acetate, sodium t-butoxide or potassium t-butoxide including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and hydrogen Lithium oxide.
  • Agents that provide acidic conditions include, but are not limited to, hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, and methanesulfonic acid.
  • the condensing agent is selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropyl Carbolyimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, 2- (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphorus Hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinyl
  • Solvents used include, but are not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, water or N,N-dimethylformamide.
  • R a is an amino protecting group, preferably tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilyloxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl , p-nitrophenylsulfonyl or tert-butyl;
  • R b is a carboxy protecting group, preferably DMB, Bn, Allyl, PfP, Me, PMB, MEM and t-Bu.
  • the compound of the formula (II-C) and the compound of the formula (III-1) are reacted under heating, basic conditions, and potassium iodide to form a compound of the formula (III-2), and the alkaline agent under the condition is preferably potassium carbonate;
  • the amino group protecting group of the compound of the formula (III-2) gives the compound of the formula (III-3);
  • the obtained compound of the formula (III-3) is reacted with the compound of the formula (II-J) under the conditions of a condensing agent,
  • a compound of the formula (VI) is obtained under the conditions of a condensation test
  • the reagent is preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; the obtained compound of the formula (VI) is removed under acidic conditions.
  • a protecting group on the amino group gives a compound of the formula (III).
  • the acidic reagent under this condition is preferably a 1,4
  • a weak base is optionally added to carry out a free reaction to obtain a free product represented by the compound of the formula (III).
  • the reagents providing basic conditions include organic bases including, but not limited to, pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and inorganic bases.
  • organic bases including, but not limited to, pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and inorganic bases.
  • Lithium diisopropylamide, potassium acetate, sodium t-butoxide or potassium t-butoxide including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and hydrogen Lithium oxide.
  • Agents that provide acidic conditions include, but are not limited to, hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, and methanesulfonic acid.
  • the condensing agent is selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropyl Carbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azo Benzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, 2-(7-azobenzotriazole)-N,N, N',N'-tetramethylurea hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazole-1-fluorophosphate a bis
  • Solvents used include, but are not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, water or N,N-dimethylformamide.
  • R a is an amino protecting group, preferably tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilyloxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl , p-nitrophenylsulfonyl or tert-butyl;
  • R b is a carboxy protecting group, preferably DMB, Bn, Allyl, PfP, Me, PMB, MEM and t-Bu.
  • M, G, z and R 2 are as defined in the formula (III).
  • a pharmaceutically acceptable salt preparation method comprising the steps of:
  • the compound of the formula (II-C) and the compound of the formula (III-1-1) are reacted under heating, basic conditions, and potassium iodide to form a compound of the formula (III-2-1), and the alkaline agent is preferably used under the conditions.
  • the compound is reacted under the conditions of a condensing agent to obtain a compound of the formula (III-5), and the condensing reagent agent is preferably 2-(7-azobenzotriazole)-N,N,N',N'.
  • the obtained compound of the formula (III-5) is deprotected under acidic conditions to give a compound of the formula (III-A).
  • the acidic reagent under this condition is preferably a 1,4-dioxane solution of trifluoroacetic acid or hydrogen chloride.
  • a weak base is optionally added to carry out a free reaction to obtain a free product represented by the compound of the formula (III-A).
  • the reagents providing basic conditions include organic bases including, but not limited to, pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and inorganic bases.
  • organic bases including, but not limited to, pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and inorganic bases.
  • Lithium diisopropylamide, potassium acetate, sodium t-butoxide or potassium t-butoxide including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and hydrogen Lithium oxide.
  • Agents that provide acidic conditions include, but are not limited to, hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, and methanesulfonic acid.
  • the condensing agent is selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropyl Carbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azo Benzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, 2-(7-azobenzotriazole)-N,N, N',N'-tetramethylurea hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazole-1-fluorophosphate a bis
  • Solvents used include, but are not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, water or N,N-dimethylformamide.
  • R a is an amino protecting group, preferably tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilyloxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl , p-nitrophenylsulfonyl or tert-butyl;
  • R b is a carboxy protecting group, preferably DMB, Bn, Allyl, PfP, Me, PMB, MEM and t-Bu.
  • R 10 to R 13 , M, G and z are as defined in the formula (III-A).
  • a pharmaceutically acceptable salt preparation method comprising the steps of:
  • the compound of the formula (II-C) and the compound of the formula (III-1-1) are reacted under heating, basic conditions, and potassium iodide to form a compound of the formula (III-2-1), and the alkaline agent is preferably used under the conditions.
  • the compound is reacted under the conditions of a condensing agent to obtain a compound of the formula (IV-2), and the condensing reagent agent is preferably 2-(7-azobenzotriazole)-N,N,N',N'.
  • the obtained compound of the formula (VI-2) is deprotected under acidic conditions to give R c and R b to give a compound of the formula (IV-3);
  • the compound of -3) is further deprotected from the protecting group R a to give the formula (IV-A).
  • the acidic reagent under this condition is preferably a 1,4-dioxane solution of trifluoroacetic acid or hydrogen chloride.
  • a weak base is optionally added to carry out a free reaction to obtain a free product represented by the compound of the formula (IV-A).
  • the reagents providing basic conditions include organic bases including, but not limited to, pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and inorganic bases.
  • organic bases including, but not limited to, pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and inorganic bases.
  • Lithium diisopropylamide, potassium acetate, sodium t-butoxide or potassium t-butoxide including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and hydrogen Lithium oxide.
  • Agents that provide acidic conditions include, but are not limited to, hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, and methanesulfonic acid.
  • the condensing agent is selected from the group consisting of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropyl Carbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azo Benzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, 2-(7-azobenzotriazole)-N,N, N',N'-tetramethylurea hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazole-1-fluorophosphate a bis
  • Solvents used include, but are not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, water or N,N-dimethylformamide.
  • R a is an amino protecting group, preferably tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilyloxycarbonyl, benzyloxycarbonyl, p-methylbenzenesulfonyl , p-nitrophenylsulfonyl or tert-butyl;
  • R b is a carboxy protecting group, preferably DMB, Bn, Allyl, PfP, Me, PMB, MEM and t-Bu;
  • R c is an amino protecting group, preferably benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilyloxycarbonyl, p-methylbenzenesulfonyl , p-nitrophenylsulfonyl or tert-butyl;
  • R 10 to R 13 , M and z are as defined in the formula (IV-A).
  • Figure 1 Effect of the compounds of the present application on carrageenan-induced rat carrageenan inflammatory pain.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was determined to be deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methyl silane
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • Purification compounds using column chromatography eluent systems and thin layer chromatography developer systems include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and acetone
  • A dichloromethane and methanol systems
  • B n-hexane and ethyl acetate systems
  • C dichloromethane and acetone
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.
  • the high-pressure liquid chromatography used in the high performance liquid chromatography in the examples was (Gilson-281), the column was Shim-pack PREP-ODS of Shimadzu, and the mobile phase used was a trifluoroacetic acid buffer system, namely water ( Containing 0.05% trifluoroacetate)-acetonitrile.
  • each of the compounds in the form of a trifluoroacetate salt in the examples can be obtained in a free state by the following general method: the trifluoroacetate salt is dissolved in a suitable solvent (e.g., methanol, ethanol, tetrahydrofuran, acetone, etc.), and a weak base is added. (such as sodium bicarbonate, sodium carbonate, potassium carbonate, etc.) adjust the pH to neutrality, concentrate under reduced pressure, and purify the residue to give a free state.
  • a suitable solvent e.g., methanol, ethanol, tetrahydrofuran, acetone, etc.
  • a weak base such as sodium bicarbonate, sodium carbonate, potassium carbonate, etc.
  • the crude 1o (80 mg, 0.087 mmol) was dissolved in 10 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure.
  • the crude 2f (400 mg, 0.44 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of 4M hydrogen chloride in 1,4-dioxane solution was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure.
  • the crude product 4f (81 mg, 0.086 mmol) was dissolved in 10 mL of dichloromethane, and then, 3mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure.
  • the crude product 5f (60 mg, 0.066 mmol) was dissolved in dichloromethane (2 mL), and 1 mL of 4M hydrogen chloride in 1,4-dioxane solution was added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure.
  • the crude 6b (1.3 g, 2.9 mmol) was dissolved in 15 mL of methanol, palladium carbon (350 mg, catalytic amount) was added, added, and hydrogen was replaced three times, and the reaction was stirred at room temperature for 12 hours.
  • the reaction mixture was filtered through EtOAc (EtOAc)EtOAc.
  • the crude 7c (50 mg, 0.054 mmol) was dissolved in 10 mL of dichloromethane, and 2 mL of 4M hydrogen chloride in 1,4-dioxane solution was added, and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure.
  • the reaction solution was concentrated under reduced pressure to remove methanol and tetrahydrofuran solvent, water was added, and 1 M hydrochloric acid was added dropwise to pH 6 and extracted with dichloromethane (30 mL ⁇ 3).
  • the organic phase was combined and washed with saturated sodium chloride The organic layer was dried, filtered, and evaporated, evaporated, evaporated
  • the crude product 8i (140 mg, 0.167 mmol) was dissolved in dichloromethane (3 mL), and 0.5 mL of 4M hydrogen chloride in 1,4-dioxane solution was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was concentrated under reduced pressure. The residue was evaporated and evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • the crude product 9 g (184 mg, 0.2 mmol) was dissolved in 10 mL of dichloromethane, and 2 mL of a 4M solution of hydrogen chloride in 1,4-dioxane was added, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure.
  • the crude product was dissolved in 10 mL of methanol, and 0.5 mL of hydrazine hydrate was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound md.
  • the crude product 10i (150 mg, 1.31 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced vacuo.
  • the compound of the present invention can activate the h-KOR receptor, thereby reducing the level of intracellular cAMP; the second messenger cAMP enters the nucleus and binds to the CRE of DNA to activate the downstream luciferase (Luciferase)
  • the expression of luciferase reacts with its substrate to fluoresce and reflects the agonistic activity of the compound by measuring the fluorescent signal.
  • Human KOR/pcDNA3.1(+) and CRE/pGL4.29 were transfected into HEK293 cell line by adding G418 and Hygromycin to the medium and screening HEK293/ in 96-well cell culture plates. KOR/CRE monoclonal cell line.
  • HEK293/h-KOR/CRE monoclonal cell lines were cultured in DMEM/high glucose medium (10% FBS, 1 mg/ml G418, 200 ⁇ g/ml hygromycin, mixed) and passaged every 3 days.
  • DMEM/high glucose medium 10% FBS, 1 mg/ml G418, 200 ⁇ g/ml hygromycin, mixed
  • a cell suspension was prepared from fresh cell culture medium, and 20,000 cells/well was plated in a 96-well plate (BD, #356692), and cultured at 5% carbon dioxide at 37 °C.
  • the compound was dissolved in pure DMSO at a concentration of 20 mM, and the first concentration was 200 nM in DMSO, and diluted to 8 concentrations in 3 folds.
  • the wells were set to blank and control wells and added to 90 ⁇ l of DMSO; 10 ⁇ M Forskolin DMEM/high glucose (SH30243.01B, Hyclone) medium was diluted 20-fold.
  • the cell culture plates inoculated on the first day were taken out, and 10 ⁇ l of the diluted drug or the control (0.5% DMSO) was added to each well, and the mixture was gently shaken, and cultured at 37 ° C for 4 hours.
  • 100 ⁇ l of luciferase assay solution Promega, #E6110) was added to each well, and allowed to stand at room temperature for 5 minutes, and the chemiluminescence value was measured using Victor 3.0.
  • the compounds of the invention have significant agonistic effects on the h-KOR receptor.
  • the substituent on the amino group of glycine is a substituted or unsubstituted ethylene group, it has an unexpected effect.
  • SD rats were used as test animals, and the concentration of the drug in plasma at different times after intravenous administration of the compounds of Examples 2, 5 and 8 by SD rats was determined by LC/MS/MS method.
  • the pharmacokinetic behavior of the compounds of the present invention in SD rats was investigated and their pharmacokinetic characteristics were evaluated.
  • the content of the test compound in the plasma of SD rats after intravenous administration of different compounds was determined by LC/MS/MS method.
  • rat pharmacokinetic parameters of the compounds of Examples 2, 5 and 8 of the invention are as follows:
  • the rat of the present invention has good pharmacokinetic properties.
  • Test Example 3 canine pharmacokinetic test of the compound of Example 5 of the present invention
  • the Beagle dog was used as the test animal, and the concentration of the drug in plasma at different times after the intravenous administration of the compound of Example 5 to the Beagle dog was determined by LC/MS/MS method.
  • the pharmacokinetic behavior of the compounds of the invention in Beagle dogs was investigated and their pharmacokinetic characteristics were evaluated.
  • Beagle canine males are only one group, provided by Medicilon Medical Technology (Shanghai) Co., Ltd.
  • the content of the test compound in the plasma of Beagle dogs after intravenous administration was determined by LC/MS/MS.
  • the Beagle dog pharmacokinetic parameters of the compound of Example 5 of the present invention are as follows:
  • the Beagle dog of the present invention has good pharmacokinetic properties.
  • Test Example 4 KOR agonist treatment of rat carrageenan-induced inflammatory pain test report
  • a rat carrageenan inflammatory pain model was established to evaluate the therapeutic effect of KOR agonists on inflammatory pain in rats.
  • Wistar male rats were purchased from Shanghai Slack Laboratory Animal Co., Ltd. (Shanghai, China, certificate number 2015000513408, license SCXK (Shanghai) 2012-0002, purchased 150-180g, 5/cage, 12/ 12 hours light/dark cycle adjustment, temperature 23 ⁇ 1°C constant temperature, humidity 50-60%, free feeding into the water. After the animal was purchased, the experiment was started by adaptive feeding for more than 7 days.
  • ⁇ -Carrageenan Batch number BCBP8978V, sigma product.
  • Drug doses are calculated on a base basis.
  • NS physiological saline used in the preparation of carrageenan solution; i.v.: intravenous injection; s.c.: subcutaneous injection.
  • the experimental method was modified in accordance with the method of Document 1 (Kazunari Nakao et al.). Inflammatory Pain Experiments Rats were randomly grouped according to body weight before the experiment as follows: blank control group, model group, Example 5-0.1 mg/kg group, and Example 5-0.3 mg/kg group. There were 8 rats in each group. Inflammatory Pain Models Wistar rat footpads were injected subcutaneously with 1% carrageenan (100 ⁇ l). After 4 hours, the rats were subjected to a plantar tenderness test to evaluate the mechanical pain threshold. A single tail vein administration (1 ml/kg) was given 30 min before the test, and the control group and the model group were given corresponding solvents.
  • Document 1 Korean Nakao et al.
  • Electronic tactile measuring instrument (electronic Von Frey): UGO BASILE, model 38450.
  • the experimental results showed that the threshold of tenderness in the blank control group was about 20g, and the threshold of tenderness in the model group was 7.6g. Compared with the blank control group, the threshold of tenderness in the model group was significantly decreased (P ⁇ 0.01); compared with the model group. All drugs can significantly increase the tenderness threshold of inflammatory rats (P ⁇ 0.01).
  • the threshold values of Example 5-0.1mg/kg and Example 5-0.3mg/kg were 13.7g and 23.2g, respectively. The increases were 79.5% and 204.5%, respectively, with significant dose-dependency. (see picture 1).
  • ⁇ -carrageenan is a colloidal substance extracted from aquatic plant Carrageenan and has an allergic stimulating effect. Carrageenan alone can induce inflammation and cause pain.
  • the model of carrageenan inflammatory pain was established to observe the changes of tenderness threshold after KOR agonist administration in rats, and to evaluate the analgesic effect of drugs on subacute inflammatory pain and its intensity.
  • the experiment used an electronic tactile instrument to measure the response of the rat to tenderness.
  • the electronic tactile measuring instrument (e-VF) was designed using Ugo Basile to evaluate large and mouse allergies and tactile allodynia.
  • the device automatically records the stimulus time and stimulation intensity of the animal.
  • the unique prism design makes it easy to observe the plantar area of the test animal during the experiment. During the test, the device can sense the test animal to retract the test claw, or it can be judged by the foot switch. More focused positioning, more suitable for local pain and neuropathic pain measurement.
  • the test drug can improve inflammatory pain in rats in a dose-dependent manner.

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Abstract

本发明提供了通式（I）所示的苯基丙酰胺类衍生物、其制备方法及其作为κ阿片样物质受体（KOR受体）激动剂的用途，和其在制备治疗和/或预防疼痛和疼痛相关疾病的药物中的用途。

Description

苯基丙酰胺类衍生物、其制备方法及其在医药上的应用 技术领域
本发明属于医药领域，涉及一种苯基丙酰胺类衍生物、其制备方法及其在医药上的应用。特别地，本发明涉及通式(I)所示的苯基丙酰胺类衍生物、其制备方法及含有该衍生物的药物组合物，以及其作为κ阿片样物质受体(KOR受体)激动剂的用途和其在制备治疗和/或预防疼痛和疼痛相关疾病的药物中的用途。
背景技术
阿片受体是一类重要的G蛋白偶联受体，是内源性阿片肽及阿片类药物结合的靶点，阿片受体激活后对神经系统免疫及内分泌系统具有调节作用，阿片类药物是目前最强且常用的中枢镇痛药。内源性阿片肽是哺乳动物体内天然生成的阿片样活性物质，目前已知的内源性阿片肽大致分为脑啡肽、内啡肽、强啡肽和新啡肽几类(Pharmacol Rev 2007；59:88–123)，中枢神经系统中存在其相应的阿片受体，即μ、δ、κ受体等。
κ阿片受体(κ-opioid receptor,KOR)由380个氨基酸组成，强啡肽是其内源性配体。在感觉神经元、背根神经节细胞和初级传入神经元末梢中均有表达，参与痛觉、神经内分泌、情感行为和认知等重要的生理活动。目前已知人KOR由OPRK1基因编码，定位于染色体8q11-12位点(Simonin F,Gaveriaux Ruff C,Kieffer BL,et al.Proc Natl Acad Sci USA 1995,92(15):7006-10)。KOR激活与G蛋白Gi/G0偶联，增加了磷酸二酯酶活性，抑制腺甘酸环化酶的活性，降低胞内cAMP水平，从而产生对神经元的抑制作用。KOR激动剂反复作用受体有脱敏效应，对腺甘酸环化酶活性的抑制作用减小(Raynor K,Kong H,Hines J,et al.J Pharmacol Exp Ther,1994,270:1381-6)。KOR还与内向整流钾通道和N-型钙离子通道偶联(Henry DJ,Grandy DK,Lester HA,Davidson N,Chavkin C(Mar 1995)Molecular Pharmacology 47(3):551–7)。KOR激动剂能够抑制(钙离子依赖性)外周感觉神经末梢伤害前和炎症前P物质的释放，这可能是其具有抗伤害感受和抗炎作用的原因。除了强啡肽，各种天然生物碱和合成的配体也可与KOR结合。KOR提供了天然的成瘾控制机制，因此，作为受体激动剂的药物具有药物成瘾治疗的潜力。
KOR激动剂阿西马朵林(asimadoline)在啮齿动物糖尿病神经病变中的效果(Jolivalt et al.Diabetologia 2006,49(11):2775-85；Epub Aug.19)和KOR激动剂U-50488在神经性疼痛的大鼠慢性压迫性损伤(CCI)模型中的效果及阿片样物质拮抗剂纳洛酮(naloxone)对其效果的阻断(Bileviciute-Ljungar et al.Eur.J.Pharm 2004.494:139-46)，这些观察结果支持将KOR激动剂用于治疗糖尿病、病毒和化疗引发的神经性疼痛。KOR激动剂用于治疗或预防包括如痛经痉挛和子宫内膜异位症 等妇科病症在内的内脏痛的应用也已被评估(Riviere,Br.J.Pharmacol 2004.141:1331-4)。
κ阿片样物质激动剂增加水的肾排泄并降低尿钠排泄(即产生选择性水利尿，也被称为促水排泄)，许多研究人员认为这一效应是由于抑制垂体分泌抗利尿激素。比较中枢作用性的和据称外周性的选择性κ阿片样物质的研究所得出的结论是血脑屏障内的KOR负责介导这一效应。有研究人员提出以在外周作用于伤害感受素受体的伤害感受素肽或带电肽共轭物治疗低钠血症，所述伤害感受肽受体与KOR有关但又不同(D.R.Kapusta,Life Sci.,60:15-21,1997)。
目前公开的KOR激动剂专利申请包括WO20071398、WO2008060552、WO09932510、WO2013184794、WO2014089019、WO2014184356和WO2015065867。
κ阿片样物质受体(KOR受体)激动剂作为药物在医药行业具有良好的应用前景，为了达到更好的治疗效果的目的，更好的满足市场需求，发明人希望能开发出新一代的高效低毒的KOR受体激动剂。本发明将提供一种新κ阿片样物质受体(KOR受体)激动剂化合物(对母核结构中的甘氨酸的氨基进一步修饰)，此类化合物令人惊奇地表现出优异的效果和作用。特别是甘氨酸的氨基上的取代基为取代或未取代的亚乙基时，具有意料不到的效果。
发明内容
本发明的目的在于提供一种通式(I)所示的化合物：
Figure PCTCN2017087328-appb-000001
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，
其中：
M为无机酸或有机酸，优选有机酸，更优选三氟乙酸；
G选自O、-NR4和-CR5R6；
R1选自氢原子、烷基、烷氧基、卤代烷基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7和-NR8R9，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R2选自氢原子、烷基、烷氧基、卤代烷基、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、-OR7、-C(O)R7和-C(O)OR7，其中所述的烷基、卤代烷基、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基和杂芳基烷基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R3选自氢原子、烷基、烷氧基、卤代烷基、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、-OR7、-C(O)R7和-C(O)OR7，其中所述的烷基、卤代烷基、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基和杂芳基烷基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R4选自氢原子、烷基、卤代烷基、环烷基、烷氧基、羟烷基、羟基、氨基、羧酸酯基、杂环基、芳基、杂芳基、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR8R9和-NHC(O)NR8R9，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R5和R6各自独立地选自氢原子、烷基、烷氧基、羟烷基、羟基、氨基、羧酸酯基、环烷基、杂环基、芳基、杂芳基、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR8R9和-NHC(O)NR8R9，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R7选自氢原子、烷基、氨基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R8和R9各自独立地选自氢原子、烷基、烷氧基、羟烷基、羟基、氨基、羧酸酯基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
z为0、1、2、3或4；且
m为0、1或2。
在本发明一个优选的实施方案中，所述的通式(I)所示的化合物进一步为通式(II)所示的化合物：
Figure PCTCN2017087328-appb-000002
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
其中：
M、G、R2、R3和z如通式(I)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)或(II)所示的化合物进一步为通式(III)所示的化合物：
Figure PCTCN2017087328-appb-000003
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
其中：
M、G、R2和z如通式(I)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)、(II)或(III)所示的化合物进一步为通式(IV)所示的化合物：
Figure PCTCN2017087328-appb-000004
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
其中：
M、R2和z如通式(I)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)、(II)、(III)或(IV)所示的化合物，其中R2选自芳基烷基、环烷基烷基和环烷基，其中所述的芳基烷基、环烷基烷基和环烷基任选被选自烷基、环烷基和芳基中的一个或多个取代基所取代。
在本发明一个优选的实施方案中，所述的通式(I)、(II)或(III)所示的化合物进一步为通式(III-A)所示的化合物：
Figure PCTCN2017087328-appb-000005
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
其中：
G为O或CR5R6；优选为CR5R6；
R10选自氢原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R11和R12相同或不同，各自独立地选自氢原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基；
或者R10和R11一起形成环烷基；
或者R11和R12一起形成环烷基；
R13选自氢原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基；
s为0、1或2；
R5～R6、M和z如通式(I)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)、(II)、(III)、(IV)或(III-A)所示的化合物进一步为通式(IV-A)所示的化合物：
Figure PCTCN2017087328-appb-000006
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
其中：
R10～R13、M、z和s如通式(III-A)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)、(II)、(III)、(IV)、(III-A)或(IV-A)所示的化合物进一步为通式(IV-B)所示的化合物：
Figure PCTCN2017087328-appb-000007
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
其中：
R10～R11、R13、M、z和s如通式(III-A)中所定义。
在本发明一个优选的实施方案中，所述的通式(I)、(II)、(III)、(IV)、(III-A)、(IV-A)或(IV-B)所示的化合物，其中z为0或1。
通式(I)的典型化合物，包括但不限于：
Figure PCTCN2017087328-appb-000008
Figure PCTCN2017087328-appb-000009
Figure PCTCN2017087328-appb-000010
Figure PCTCN2017087328-appb-000011
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐。
本发明另外提供一种通式(V)所示的化合物，其为制备通式(II)化合物的中间体：
Figure PCTCN2017087328-appb-000012
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
其中：
Ra为氨基保护基，优选叔丁氧羰基、9-芴甲氧羰基、烯丙氧羰基、三氯乙氧羰基、三甲基硅乙氧羰基、苄氧羰基、对甲基苯磺酰基、对硝基苯磺酰基或叔丁基(即Boc、Fmoc、Alloc、Troc、Teoc、CBz、Tosyl、Nosyl和t-Bu)；
G、R2和R3如通式(II)中所定义。
本发明另外提供一种制备通式(II)所示的化合物的方法，该方法包括：
Figure PCTCN2017087328-appb-000013
通式(V)化合物在酸性条件下反应脱去保护基Ra，得到通式(II)化合物；
其中：
M、G、z、R2和R3如通式(II)中所定义，Ra如通式(V)中所定义。
本发明另外提供一种通式(VI)所示的化合物，其为制备通式(III)化合物的中间体：
Figure PCTCN2017087328-appb-000014
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
其中：
Ra为氨基保护基，优选叔丁氧羰基、9-芴甲氧羰基、烯丙氧羰基、三氯乙氧羰基、三甲基硅乙氧羰基、苄氧羰基、对甲基苯磺酰基、对硝基苯磺酰基或叔丁基；且
G和R2如通式(III)中所定义。
本发明另外提供一种制备通式(III)所示的化合物的方法，该方法包括：
Figure PCTCN2017087328-appb-000015
通式(VI)化合物在酸性条件下反应脱去保护基Ra，得到通式(III)化合物；
其中：
M、G、z和R2如通式(III)中所定义，Ra如通式(VI)中所定义。
所述的酸性条件下的酸性试剂优选三氟乙酸或者氯化氢的1,4-二氧六环溶液。
进一步地，当通式(I)、(II)、(III)、(IV)、(III-A)、(IV-A)或(IV-B)的化合物中z为非0时，任选加入弱碱进行游离反应，得到通式(I)、(II)、(III)、(IV)、(III-A)、(IV-A)或(IV-B)化合物所示的游离态产物。
本发明的另一方面涉及一种药物组合物，其含有治疗有效剂量的上述通式(I)、(II)、(III)、(IV)、(III-A)、(IV-A)或(IV-B)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本发明还涉及一种制备上述药物组合物的方法，其包括将通式(I)、(II)、(III)、(IV)、(III-A)、(IV-A)或(IV-B)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐与药学上可接受的载体、稀释剂或赋形剂相混合。
在一个实施方式中，本发明的药物组合物进一步包括一种或者多种下列化合物：阿片样物质、大麻素、抗抑郁剂、抗惊厥剂、安定药、皮质甾类、离子通道阻断剂或非甾体抗炎药(NSAID)。
本发明进一步涉及通式(I)、(II)、(III)、(IV)、(III-A)、(IV-A)或(IV-B)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用盐，或包含其的药物组合物在制备激动或拮抗κ阿片样物质受体(KOR受体)的药物中用途。
本发明进一步涉及通式(I)、(II)、(III)、(IV)、(III-A)、(IV-A)或(IV-B)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用盐，或包含其的药物组合物在制备用于预防和/或 治疗κ阿片样物质受体(KOR受体)激动剂介导的相关疾病的药物中的用途，所述κ阿片样物质受体(KOR受体)激动剂介导的相关疾病优选选自疼痛、炎症、瘙痒、水肿、低钠血症、低钾血症、肠梗阻、咳嗽和青光眼，更优选疼痛。
本发明进一步涉及通式(I)、(II)、(III)、(IV)、(III-A)、(IV-A)或(IV-B)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用盐，或包含其的药物组合物在制备用于预防和/或治疗哺乳动物(例如：人)疼痛和疼痛相关疾病的药物中的用途，其中所述的疼痛可以是术后疼痛、癌症引起的疼痛、神经性疼痛、创伤性疼痛和炎症引起的疼痛等。
本发明进一步涉及一种激动或拮抗κ阿片样物质受体(KOR受体)的方法，该方法包括向需要其的患者施用治疗有效剂量的本发明的通式(I)、(II)、(III)、(IV)、(III-A)、(IV-A)或(IV-B)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用盐。
本发明进一步涉及一种预防和/或治疗KOR激动剂受体介导的相关疾病的方法，该方法包括向需要其的患者施用治疗有效剂量的本发明的通式(I)、(II)、(III)、(IV)、(III-A)、(IV-A)或(IV-B)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用盐。该方法表现出突出的疗效和较少的副作用。其中所述的κ阿片样物质受体(KOR受体)激动剂受体介导的相关疾病选自疼痛、炎症、瘙痒、水肿、低钠血症、低钾血症、肠梗阻、咳嗽和青光眼，优选疼痛。
本发明进一步涉及一种用作药物的通式(I)、(II)、(III)、(IV)、(III-A)、(IV-A)或(IV-B)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用盐。
本发明进一步涉及通式(I)、(II)、(III)、(IV)、(III-A)、(IV-A)或(IV-B)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用盐，其用于激动或拮抗κ阿片样物质受体(KOR受体)。
本发明进一步涉及通式(I)、(II)、(III)、(IV)、(III-A)、(IV-A)或(IV-B)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用盐，其用于预防和/或治疗KOR受体激动剂介导的相关疾病。
本发明进一步涉及通式(I)、(II)、(III)、(IV)、(III-A)、(IV-A)或(IV-B)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用盐，其用于预防和/或治疗哺乳动物(例如：人)疼痛和疼痛相关疾病。所述κ阿片样物质受体(KOR受体)激动剂介导的相关疾病、紊乱或者病况可以是任何κ阿片样物质受体(KOR受体)激动剂介导的相关 的病况，包括但不限于急性或慢性疼痛、炎症、瘙痒、低钠血症、水肿、肠梗阻、咳嗽和青光眼。例如，κ阿片样物质受体(KOR受体)相关的疼痛可以是神经性疼痛、躯体痛、内脏痛或皮肤痛。一些疾病、紊乱或病况与多于一种的疼痛形式有关。例如，手术后痛可以为神经性疼痛、躯体痛、内脏痛或皮肤痛因素中的任一种或全部，这取决于所采用的外科手术的类型和程度。
本发明涉及的κ阿片样物质受体(KOR受体)相关的炎症可以是任何炎性疾病或病况，包括但不限于窦炎、类风湿性关节炎腱鞘炎、滑囊炎、腱炎、肱骨外上髁炎、粘性囊炎、骨髓炎、骨关节炎症、炎性肠病(IBD)、肠易激综合征(IBS)、眼部炎症、耳部炎症或自体免疫炎症。
本发明涉及的κ阿片样物质受体(KOR受体)相关的瘙痒可以是任何瘙痒疾病和病况，例如眼部瘙痒如结膜炎相关的眼部瘙痒、瘙痒、与末期肾病有关的瘙痒(其中许多患者接受肾透析)和其他形式的胆汁淤积，包括原发胆汁性肝硬化、妊娠肝内胆汁淤积症、慢性胆固醇肝病、尿毒症、恶性胆汁淤积、黄疸以及皮肤病况，例如湿疹(皮炎)包括特应性皮炎或接触性皮炎、皮肤癣、红细胞增多症、扁平苔藓、慢性单纯苔藓、虱病、甲状腺毒症、足癣、荨麻疹、疥疮、阴道炎、痔疮相关的肛门瘙痒以及虫咬瘙痒和药物引起的瘙痒，例如μ阿片样物质引起的瘙痒。
本发明涉及的κ阿片样物质受体(KOR受体)相关的水肿可以是任何水肿性疾病或病况，例如充血性心脏病引起的水肿或抗利尿激素(ADH)分泌不当综合征引起的水肿。
本发明涉及的κ阿片样物质受体(KOR受体)相关的肠梗阻可以是任何肠梗阻疾病或病况，包括但不限于手术后肠梗阻或阿片样物质引起的肠机能障碍。
本发明涉及的κ阿片样物质受体(KOR受体)相关的神经性疼痛可以是任何神经性疼痛，例如，三叉神经痛、糖尿病疼痛、病毒引起的疼痛例如带状疱疹相关的疼痛、化疗引发的疼痛、侵袭神经的转移癌症疼痛、外伤和外科手术相关的神经性疼痛、以及各种被认为具有神经病理因素的头痛变体例如偏头疼。
本发明涉及的κ阿片样物质受体(KOR受体)相关的疼痛包括眼部疼痛，例如，屈光性角膜切削术(PRK)、眼撕裂、眼底骨折、化学烧伤、角膜上皮擦伤或刺激等之后的眼部疼痛，或与结膜炎、角膜溃疡、巩膜炎、巩膜外层炎、巩膜角膜炎、眼部带状疱疹、间质性角膜炎、急性虹膜炎、干性角膜结膜炎、眼眶蜂窝织炎、眼眶假瘤、天疱疮、沙眼或葡萄膜炎相关的眼部疼痛。
本发明涉及的κ阿片样物质受体(KOR受体)相关的疼痛还包活喉咙痛，尤其是与炎症状况，例如过敏性鼻炎、急性支气管炎、普通感冒、接触性溃疡、单纯疱疹病毒损伤、感染性单核细胞增多症、流行性感冒、喉癌、急性喉炎、急性坏死性溃疡齿龈炎、扁桃腺脓肿、咽部烧灼、咽炎、反流性咽喉炎、急性窦炎和扁桃腺炎相关的喉咙痛。
本发明涉及的κ阿片样物质受体(KOR受体)相关的疼痛可以是关节炎疼痛、肾结石、尿路结石和胆管结石疼痛、子宫痉挛、痛经、子宫内膜异位症、乳腺炎、消化不良、外科手术后疼痛(例如阑尾切除术、开放式结肠直肠手术、疝气修复、前列腺切除术、结肠摘除术、胃切除术、脾切除术、结肠切除术、结肠造口术、骨盆腹镜检查书、输卵管结扎、子宫切除术、输精管切除术或胆囊切除术导致的手术后疼痛)、医疗处理后疼痛(例如结肠镜检查、膀胱镜检查、宫腔镜检查或者宫颈或子宫内膜活组织检查之后的疼痛)、耳炎疼痛、爆发性癌症疼痛、以及与GI紊乱相关的疼痛，所述GI紊乱例如IBD或IBS或其他炎症病况，尤其是内脏炎症(例如，胃食管反流性疾病、胰腺炎、急性肾盂肾炎、溃疡性结肠炎、胆囊炎、肝硬化、肝囊肿、肝炎、十二指肠溃疡或胃溃疡、食道炎、胃炎、胃肠炎、结肠炎、憩室炎、肠梗阻、卵巢囊肿、盆腔炎症疾病、溃疡穿孔、腹膜炎、前列腺炎、间质性膀胱炎)相关的疼痛，或者与毒剂接触(例如昆虫毒素、或诸如水杨酸酯(盐)或NSAID等药物)带来的疼痛。
本发明涉及的κ阿片样物质受体(KOR受体)相关的低钠血症可以是存在低钠血症(低钠病况)的任何疾病或病况，例如，在人中，当血浆中钠浓度低于135mmol/l时，异常可以单独发生，或者更多见地是作为其他医学状况的并发症或作为使用可引起钠缺乏的药物的结果而发生，其中所述的与低钠血症相关的疾病包括但不限于：引起过量ADH分泌的肿瘤因素，包括肺、十二指肠、胰腺、卵巢、膀胱和输尿管的癌症、胸腺瘤、间皮瘤、支气管腺瘤、类癌瘤、神经节细胞瘤和尤因氏肉瘤、感染；例如肺炎(细菌性或病毒性)、脓肿(肺部或脑部)、空泡形成(曲霉病)、结核(肺部或脑部)、脑膜炎(细菌性或病毒性)、脑炎和AIDS；脉管因素例如：脑血管梗塞或溢血和海绵窦栓塞；神经因素例如：吉兰-巴雷(Guillan-Barre)综合征、多发性硬化、震颤性谵妄、肌萎缩侧索硬化、脑积水、精神病、外周神经病、头部创伤(闭合性和穿透性)、CNS肿瘤或感染以及影响下丘脑渗透压感受器的CNS损害；先天性畸形包活：胼胝体发育不全、唇腭裂和其他中线缺陷；代谢因素例如：急性间歇性卟啉病、哮喘、气胸和正压呼吸；药物例如：噻嗪利尿剂、扑热息痛、巴比妥酸盐、拟胆碱剂、雌激素、口服降血糖药、加压素或去氨加压素、高剂量催产素氯磺丙脲、长春新碱、卡马西平、尼古丁、吩噻嗪、环磷酰胺、三环抗抑郁剂、单胺氧化酶抑制剂和5-羟色胺重摄取抑制剂；例如住院治疗、外科手术期间或体育活动期间或之后(即，运动相关的低钠血症)施用过量低渗液体，以及在老年个体中应用低钠营养补充剂，其他与低钠血症相关的病况包括肾衰、肾病综合征(模型肾病和微小病变疾病)、恶性质、营养不良、横纹肌溶解、外科处理、选择性心导管插入、失血、以及血钙过多、低钾血症和结果是可导致渗透性利尿的糖尿的高血糖症。
本发明另一方面涉及一种作为预防和/或治疗κ阿片样物质受体(KOR受体)激动剂介导的相关疾病、紊乱或者病况相关疾病的方法，该方法包括向需要其的 患者施用治疗有效剂量的本发明的各通式，特别是通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用盐；该方法表现出突出的疗效和较少的副作用，其中所述的κ阿片样物质受体(KOR受体)激动剂介导的相关疾病包括但不限于急性或慢性疼痛、炎症、瘙痒、低钠血症、水肿、肠梗阻、咳嗽和青光眼。
本发明另一方面涉及一种预防和/或治疗哺乳动物疼痛和疼痛相关疾病的方法，该方法包括向需要其的哺乳动物施用治疗有效剂量的本发明的通式(I)、(II)、(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用盐；该方法表现出突出的疗效和较少的副作用，其中所述的疼痛可以是术后疼痛、癌症引起的疼痛、神经性疼痛、创伤性疼痛躯体痛、内脏痛、皮肤痛和炎症引起的疼痛，例如，手术后痛可以为神经性疼痛、躯体痛、内脏痛或皮肤痛因素中的任一种或全部，这取决于所采用的外科手术的类型和程度；所述的癌症可以选自乳腺癌、子宫内膜癌、宫颈癌、皮肤癌、前列腺癌、卵巢癌、输卵管肿瘤、卵巢瘤、血友病和白血病等。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，造粒剂和崩解剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒或橄榄油混合的软明胶胶囊提供口服制剂。
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂，分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油或矿物油中配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
通过加入水可使适用于制备水混悬液的可分散粉末和颗粒提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂可说明上述的例子。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂或偏酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。
本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。
本发明的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行被、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、通式化合物(I)的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异 丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子，最优选包含5至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2017087328-appb-000016
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2017087328-appb-000017
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双 环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2017087328-appb-000018
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等；优选苯基并环戊基、四氢萘基。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3个是杂原子；最优选包含5至6个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等，优选四氢吡喃基、哌啶基、吡咯烷基。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2017087328-appb-000019
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2017087328-appb-000020
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2017087328-appb-000021
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2017087328-appb-000022
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，更优选5至6元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2017087328-appb-000023
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、吡唑基或嘧啶基、噻唑基；更优选吡唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2017087328-appb-000024
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基如上所定义。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、 芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“环烷基烷基”指烷基被一个或多个环烷基取代，其中环烷基和烷基如上所定义。
术语“杂环基烷基”指烷基被一个或多个杂环基取代，其中杂环基和烷基如上所定义。
术语“芳基烷基”指烷基被一个或多个芳基取代，其中芳基和烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH2。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基、环烷基如上所定义。
术语“酰卤”指含有-C(O)-卤素的基团的化合物。
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中任意一种或几种。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
缩写表：
缩写 全称
Me 甲基
Boc 叔丁氧羰基
t-Bu 叔丁基
Bn 苄基
Ph 苯基
Tosyl 对甲基苯磺酰基
Fmoc 9-芴甲氧羰基
Alloc 烯丙氧羰基
Troc 三氯乙氧羰基
Teoc 三甲基硅乙氧羰基
Nosyl 对硝基苯磺酰基
TMSOTf 三氟甲基磺酸三甲基硅酯
Cbz 苄氧羰基
PfP 五氟代苯基
PMB 对甲基苄基
MEM 甲氧乙氧甲基
Allyl 烯丙基
DMB 2,4-二甲氧基苄基
本发明化合物的合成方法
为了完成本发明的目的，本发明采用如下技术方案：
本发明通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用的盐制备方法，包括以下步骤：
Figure PCTCN2017087328-appb-000025
通式(II-A)化合物和通式(II-B)化合物在碱性条件下发生反应，得到通式(II-C)化合物，该条件下的碱性试剂优选三乙胺；得到的通式(II-C)化合物与通式(II-D)化合物在加热、碱性条件，和碘化钾一起反应生成通式(II-E)化合物，该条件下的碱性试剂优选碳酸钾；得到的通式(II-E)化合物脱保护得到通式(II-F)化合物；得到的通式(II-F)化合物与通式(II-J)化合物在缩合剂的条件下反应，得到通式(V)化合物，该条件下缩合试剂试剂优选2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；得到的通式(V)化合物在酸性条件下脱去氨基上的保护基，得到通式(II)化合物。该条件下的酸性试剂优选三氟乙酸或者氯化氢的1,4-二氧六环溶液。
进一步地，当通式(II)化合物中z为非0时，任选加入弱碱进行游离反应，得到通式(II)化合物所示的游离态产物。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于吡啶、六氢吡啶、三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、碳酸铯、氢氧化钠和氢氧化锂。
提供酸性的条件的试剂包括但不限于氯化氢、三氟乙酸、甲酸、乙酸、盐酸、硫酸和甲磺酸。
缩合剂选自1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、 1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
所用溶剂包括但不限于：醋酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、二甲基亚砜、1,4-二氧六环、水或N,N-二甲基甲酰胺。
其中：
Ra为氨基保护基，优选为叔丁氧羰基、9-芴甲氧羰基、烯丙氧羰基、三氯乙氧羰基、三甲基硅乙氧羰基、苄氧羰基、对甲基苯磺酰基、对硝基苯磺酰基或叔丁基；
Rb为羧基保护基，优选DMB、Bn、Allyl、PfP、Me、PMB、MEM和t-Bu。
M、G、z、R2和R3如通式(II)中所定义。
本发明通式(III)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用的盐制备方法，包括以下步骤：
Figure PCTCN2017087328-appb-000026
通式(II-C)化合物与通式(III-1)化合物在加热、碱性条件，和碘化钾一起反应生成通式(III-2)化合物，该条件下的碱性试剂优选碳酸钾；得到的通式(III-2)化合物上氨基保护基得到通式(III-3)化合物；得到的通式(III-3)化合物与通式(II-J)化合物在缩合剂的条件下反应，得到通式(VI)化合物，该条件下缩合试 剂试剂优选2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；得到的通式(VI)化合物在酸性条件下脱去氨基上的保护基，得到通式(III)化合物。该条件下的酸性试剂优选三氟乙酸或者氯化氢的1,4-二氧六环溶液。
进一步地，当通式(III)化合物中z为非0时，任选加入弱碱进行游离反应，得到通式(III)化合物所示的游离态产物。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于吡啶、六氢吡啶、三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、碳酸铯、氢氧化钠和氢氧化锂。
提供酸性的条件的试剂包括但不限于氯化氢、三氟乙酸、甲酸、乙酸、盐酸、硫酸和甲磺酸。
缩合剂选自1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
所用溶剂包括但不限于：醋酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、二甲基亚砜、1,4-二氧六环、水或N,N-二甲基甲酰胺。
其中：
Ra为氨基保护基，优选为叔丁氧羰基、9-芴甲氧羰基、烯丙氧羰基、三氯乙氧羰基、三甲基硅乙氧羰基、苄氧羰基、对甲基苯磺酰基、对硝基苯磺酰基或叔丁基；
Rb为羧基保护基，优选DMB、Bn、Allyl、PfP、Me、PMB、MEM和t-Bu。
M、G、z和R2如通式(III)中所定义。
本发明通式(III-A)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用的盐制备方法，包括以下步骤：
Figure PCTCN2017087328-appb-000027
通式(II-C)化合物与通式(III-1-1)化合物在加热、碱性条件，和碘化钾一起反应生成通式(III-2-1)化合物，该条件下的碱性试剂优选碳酸钾；得到的通式(III-2-1)化合物上氨基保护基得到通式(III-3-1)化合物；得到的通式(III-3-1)化合物与通式(II-J)化合物在缩合剂的条件下反应，得到通式(III-5)化合物，该条件下缩合试剂试剂优选2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；得到的通式(III-5)化合物在酸性条件下脱去氨基上的保护基，得到通式(III-A)化合物。该条件下的酸性试剂优选三氟乙酸或者氯化氢的1,4-二氧六环溶液。
进一步地，当通式(III-A)化合物中z为非0时，任选加入弱碱进行游离反应，得到通式(III-A)化合物所示的游离态产物。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于吡啶、六氢吡啶、三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、碳酸铯、氢氧化钠和氢氧化锂。
提供酸性的条件的试剂包括但不限于氯化氢、三氟乙酸、甲酸、乙酸、盐酸、硫酸和甲磺酸。
缩合剂选自1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
所用溶剂包括但不限于：醋酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、二甲基亚砜、1,4-二氧六环、水或N,N-二甲基甲酰胺。
其中：
Ra为氨基保护基，优选为叔丁氧羰基、9-芴甲氧羰基、烯丙氧羰基、三氯乙氧羰基、三甲基硅乙氧羰基、苄氧羰基、对甲基苯磺酰基、对硝基苯磺酰基或叔丁基；
Rb为羧基保护基，优选DMB、Bn、Allyl、PfP、Me、PMB、MEM和t-Bu。
R10～R13、M、G和z如通式(III-A)中所定义。
本发明通式(IV-A)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、或其可药用的盐制备方法，包括以下步骤：
Figure PCTCN2017087328-appb-000028
通式(II-C)化合物与通式(III-1-1)化合物在加热、碱性条件，和碘化钾一起反应生成通式(III-2-1)化合物，该条件下的碱性试剂优选碳酸钾；得到的通式(III-2-1)化合物上氨基保护基得到通式(III-3-1)化合物；得到的通式(III-3-1)化合物与通式(IV-1)化合物在缩合剂的条件下反应，得到通式(IV-2)化合物，该条件下缩合试剂试剂优选2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；得到的通式(VI-2)化合物在酸性条件下脱去保护基Rc和Rb，得到通式(IV-3) 化合物；得到的通式(IV-3)的化合物进一步脱去保护基Ra得到通式(IV-A)。该条件下的酸性试剂优选三氟乙酸或者氯化氢的1,4-二氧六环溶液。
进一步地，当通式(IV-A)化合物中z为非0时，任选加入弱碱进行游离反应，得到通式(IV-A)化合物所示的游离态产物。
提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于吡啶、六氢吡啶、三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠或叔丁醇钾，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、碳酸铯、氢氧化钠和氢氧化锂。
提供酸性的条件的试剂包括但不限于氯化氢、三氟乙酸、甲酸、乙酸、盐酸、硫酸和甲磺酸。
缩合剂选自1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并三唑、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，优选2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
所用溶剂包括但不限于：醋酸、甲醇、乙醇、甲苯、四氢呋喃、二氯甲烷、二甲基亚砜、1,4-二氧六环、水或N,N-二甲基甲酰胺。
其中：
Ra为氨基保护基，优选为叔丁氧羰基、9-芴甲氧羰基、烯丙氧羰基、三氯乙氧羰基、三甲基硅乙氧羰基、苄氧羰基、对甲基苯磺酰基、对硝基苯磺酰基或叔丁基；
Rb为羧基保护基，优选DMB、Bn、Allyl、PfP、Me、PMB、MEM和t-Bu；
Rc为氨基保护基，优选为苄氧羰基、叔丁氧羰基、9-芴甲氧羰基、烯丙氧羰基、三氯乙氧羰基、三甲基硅乙氧羰基、对甲基苯磺酰基、对硝基苯磺酰基或叔丁基；
R10～R13、M和z如通式(IV-A)中所定义。
附图说明
图1：本申请化合物对角叉菜胶诱导的大鼠角叉菜胶炎性痛的影响。
具体实施方式
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
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶 剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号：Finnigan LCQ advantage MAX)。
手性HPLC分析测定使用LC-10A vp(Shimadzu)或者SFC-analytical(Berger Instruments Inc.)；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
手性制备柱层析使用Prep Star SD-1(Varian Instruments Inc.)或SFC-multigram(Berger Instruments Inc.)
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：二氯甲烷和丙酮体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例中的高效液相色谱法所用的高压液相色谱仪为(Gilson-281)，色谱柱为Shimadzu的Shim-pack PREP-ODS，所使用的流动相为三氟醋酸缓冲体系，即水(含0.05％三氟醋酸盐)-乙腈。
实施例中的各个以三氟醋酸盐形式存在的化合物可以采用以下通用方法得到游离态：将其三氟醋酸盐用合适的溶剂(如甲醇，乙醇，四氢呋喃，丙酮等)溶解，加入弱碱(如碳酸氢钠，碳酸钠，碳酸钾等)调节pH值至中性，减压浓缩，纯化残余物得到游离态。
实施例1
4-氨基-1-((6R,9R,12R)-12-(4-氨基丁基)-6-苄基-9-异丁基-4,7,10-三氧代-1-(1-苯基环丙基)-2,5,8,11-四氮杂十三-13-酰基)哌啶-4-羧酸1
Figure PCTCN2017087328-appb-000029
Figure PCTCN2017087328-appb-000030
第一步
4-苄基1-叔丁基4-(((苄氧基)羰基)氨基)哌啶-1,4-二羧酸1b
将4-(((苄氧基)羰基)氨基)-1-(叔丁氧羰基)哌啶-4-羧酸1a(1.2g，0.0032mol，采用公知的方法“Bioorganic Medicinal Chemistry Letters,2007,7(9),2448-2451”制备而得)，苄溴(0.65g，0.0038mol)，碳酸铯(2.1g，0.0064mol)溶于20mL N,N-二甲基甲酰胺中，室温搅拌反应12小时。将反应液倒入水中，用乙酸乙酯萃取(30mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩后用薄层色谱法以展开剂体系B纯化所得残余物，得到标题产物1b(800mg，产率：53％)。
第二步
4-(((苄氧基)羰基)氨基)哌啶-4-羧酸苄酯盐酸盐1c
将1b(800mg，1.71mmol)溶于2mL二氯甲烷中，加入2mL 4M氯化氢的1,4-二氧六环溶液，室温搅拌反应4小时。反应液减压浓缩，得到粗品标题产物1c(800mg)，产品不经纯化直接进行下一步反应。
第三步
(R)-1-(2-((((9H-芴-9-基)甲氧基)羰基)氨基)-6-((叔丁氧羰基)氨基)己酰基)-4-(((苄氧基)羰基)氨基)哌啶-4-羧酸苄酯1e
将粗品1c(800mg，1.97mmol)和(R)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-6-((叔丁氧羰基)氨基)己酸1d(926mg，1.97mmol，采用公知的方法“ChemMedChem,2015,10(7),1232-1239”制备而得)溶于20mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.12g，3.0mmol)和N,N-二异丙基乙胺(0.7mL，3.94mmol)，室温搅拌反应12小时。反应液倒入2N柠檬酸溶液中，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和碳酸氢钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物1e(1.6g)，产品不经纯化直接进行下一步反应。
第四步
(R)-1-(2-氨基-6-((叔丁氧羰基)氨基)己酰基)-4-(((苄氧基)羰基)氨基)哌啶-4-羧酸苄酯1f
将粗品1e(1.6g，0.002mol)溶于10mL二氯甲烷中，加入10mL哌啶，室温搅拌反应2小时。反应液减压浓缩后用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物1f(900mg，产率：77％)。
第五步
(R)-2-((R)-2-(2-氯乙酰胺基)-3-苯基丙酰胺基)-4-甲基戊酸苄酯1i
将(R)-2-((R)-2-(2-氨基-3-苯基丙酰胺基)-4-甲基戊酸苄酯1g(500mg，1.36mmol，采用专利申请“US20110212882A1”公开的方法制备而得)和三乙胺(275mg，2.72mmol)溶于10mL二氯甲烷中，滴加入氯乙酰氯(230mg，2mmol)，室温搅拌反应12小时。反应液倒入水中，用饱和氯化铵溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物1i(500mg)，产品不经纯化直接进行下一步反应。
第六步
(R)-4-甲基-2-((R)-3-苯基-2-(2-(((1-苯基环丙基)甲基)氨基)乙酰胺基)丙酰胺基)戊酸苄酯1k
将粗品1i(150mg，0.33mmol)和(1-苯基环丙基)甲胺盐酸盐1j(74mg，0.4mmol，采用公知的方法“Journal of American Chemical Society,2015,137(5),2042-2046”制备而得)溶于10mL N,N-二甲基甲酰胺中，加入碘化钾(110mg，0.67mmol)和碳酸钾(139mg，1mmol)，升温至60℃搅拌反应5小时。反应液减压浓缩，所 得残余物中加入水，用二氯甲烷萃取(30mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物1k(187mg)，产品不经纯化直接进行下一步反应。
第七步
(9R,12R)-9-苄基-12-异丁基-2,2-二甲基-4,7,10-三氧代-5-((1-苯基环丙基)甲基)-3-氧杂-5,8,11-三氮杂十三-13-酸苄酯1l
将粗品1k(187mg，0.337mmol)溶于二氯甲烷中，加入二碳酸二叔丁酯(147mg，0.67mmol)和N,N-二异丙基乙基胺(130mg，1.01mmol)，室温搅拌反应12小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物1l(100mg，产率：45.5％)。
第八步
(9R,12R)-9-苄基-12-异丁基-2,2-二甲基-4,7,10-三氧代-5-((1-苯基环丙基)甲基)-3-氧杂-5,8,11-三氮杂十三-13-甲酸1m
将1l(100mg，0.152mmol)溶于10mL乙醇中，加入钯碳(100mg，催化量)，加毕，氢气置换三次，室温搅拌反应5小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物1m(86mg)，产品不经纯化直接进行下一步反应。
第九步
1-((9R,12R,15R)-9-苄基-15-(4-((叔丁氧羰基)氨基)丁基)-12-异丁基-2,2-二甲基-4,7,10,13-四氧代-5-((1-苯基环丙基)甲基)-3-氧杂-5,8,11,14-四氮杂十六-16-酰基)-4-(((苄氧基)羰基)氨基)哌啶-4-羧酸苄酯1n
将粗品1m(86mg，0.152mmol)，1f(91mg，0.152mmol)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(115mg，0.3mmol)溶于10mL N,N-二甲基甲酰胺中，室温搅拌反应5小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物1n(100mg，产率：57.5％)。
第十步
4-氨基-1-((9R,12R,15R)-9-苄基-15-(4-((叔丁氧羰基)氨基)丁基)-12-异丁基-2,2-二甲基-4,7,10,13-四氧代-5-((1-苯基环丙基)甲基)-3-氧杂-5,8,11,14-四氮杂十六-16-酰基)哌啶-4-羧酸1o
将1n(100mg，0.087mmol)溶于10mL乙醇中，加入钯碳(100mg，催化量)，加毕，氢气置换三次，室温搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物1o(80mg)，产品不经纯化直接进行下一步反应。
第十一步
4-氨基-1-((6R,9R,12R)-12-(4-氨基丁基)-6-苄基-9-异丁基-4,7,10-三氧代-1-(1-苯基环丙基)-2,5,8,11-四氮杂十三-13-酰基)哌啶-4-羧酸三氟乙酸盐1p
将粗品1o(80mg，0.087mmol)溶于10mL二氯甲烷中，加入2mL三氟乙酸，室温搅拌反应5小时。反应液减压浓缩后用高效液相色谱法纯化所得残余物，得到标题产物1p(10mg，产率：15.9％)。
MS m/z(ESI):720.4[M+1]
1H NMR(400MHz,CD3OD)δ8.47-8.40(m,2H),7.42-7.27(m,11H),4.84-4.81(m,1H),4.70-4.67(m,1H),4.40-4.38(m,1H),4.25-4.10(m,1H),3.95-3.85(m,2H),3.78-3.70(m,2H),3.61-3.52(m,1H),3.5-3.41(m,1H),3.25-3.10(m,3H),3.10-2.95(m,2H),2.95-2.89(m,2H),2.89-2.75(m,2H),2.31-2.24(m,2H),1.95-1.45(m,13H),1.1-0.9(m,6H),0.9-0.86(m,4H).
第十二步
4-氨基-1-((6R,9R,12R)-12-(4-氨基丁基)-6-苄基-9-异丁基-4,7,10-三氧代-1-(1-苯基环丙基)-2,5,8,11-四氮杂十三-13-酰基)哌啶-4-羧酸1
将1p(10mg，0.012mmol)溶解于1mL二氯甲烷和甲醇(V/V＝10:1)的混合溶液溶清，滴加饱和碳酸钠水溶液调节pH至7左右，室温下搅拌反应30分钟，静止分层，收集有机相，无水硫酸镁干燥，过滤，滤液减压浓缩，得到标题产物1(8.6mg，收率：100％)。
MS m/z(ESI):720.4[M+1]
实施例2
4-氨基-1-((2R,5R,8R,14S)-2-(4-氨基丁基)-8-苄基-5-异丁基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十五-1-酰基)哌啶-4-羧酸2
Figure PCTCN2017087328-appb-000031
Figure PCTCN2017087328-appb-000032
第一步
(R)-4-甲基-2-((R)-3-苯基-2-(2-(((S)-2-苯基丙基)氨基)乙酰胺基)丙酰胺基)戊酸苄酯2b
将1i(500mg，1.12mmol)和(S)-2-苯基丙-1-胺2a(228mg，1.68mmol，采用公知的方法“Advanced Synthesis&Catalysis,2015,357(18),3875-3879”制备而得)溶于10mL N,N-二甲基甲酰胺中，加入碘化钾(372mg，2.24mmol)和碳酸钾(309mg，2.24mmol)，升温至60℃搅拌反应12小时。反应液冷却至室温，加入水，用二氯甲烷萃取(30mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物2b(600mg)，产品不经纯化直接进行下一步反应。
第二步
(9R,12R)-9-苄基-12-异丁基-2,2-二甲基-4,7,10-三氧代-5-((S)-2-苯基丙基)-3-氧杂-5,8,11-三氮杂十三-13-酸苄酯2c
将粗品2b(600mg，1.1mmol)溶于10mL二氯甲烷中，加入二碳酸二叔丁酯(360mg，1.65mmol)和三乙胺(222mg，2.2mmol)，室温搅拌反应12小时。反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物2c(380mg，产率：54％)。
第三步
(9R,12R)-9-苄基-12-异丁基-2,2-二甲基-4,7,10-三氧代-5-((S)-2-苯基丙基)-3-氧杂-5,8,11-三氮杂十三-13-酸2d
将2c(380mg，0.59mmol)溶于15mL甲醇中，加入钯碳(40mg，催化量)，加毕，氢气置换三次，室温搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物2d(300mg)，产品不经纯化直接进行下一步反应。
第四步
1-((9R,12R,15R)-9-苄基-15-(4-((叔丁氧羰基)氨基)丁基)-12-异丁基-2,2-二甲基-4,7,10,13-四氧代-5-((S)-2-苯基丙基)-3-氧杂-5,8,11,14-四氮杂十六-16-酰基)-4-(((苄氧基)羰基)氨基)哌啶-4-羧酸苄酯2e
将粗品2d(300mg，0.54mmol)，1f(356mg，0.6mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(308mg，0.81mmol)和N,N-二异丙基乙胺(104mg，0.81mmol)溶于10mL N,N-二甲基甲酰胺中，室温搅拌反应1.5小时。反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物2e(500mg，产率：81.8％)。
第五步
4-氨基-1-((9R,12R,15R)-9-苄基-15-(4-((叔丁氧羰基)氨基)丁基)-12-异丁基-2,2-二甲基-4,7,10,13-四氧代-5-((S)-2-苯基丙基)-3-氧杂-5,8,11,14-四氮杂十六-16-酰基)哌啶-4-羧酸2f
将2e(500mg，0.44mmol)溶于10mL甲醇中，加入钯碳(50mg，催化量)，加毕，氢气置换三次，室温搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物2f(400mg)，产品不经纯化直接进行下一步反应。
第六步
4-氨基-1-((2R,5R,8R,14S)-2-(4-氨基丁基)-8-苄基-5-异丁基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十五-1-酰基)哌啶-4-羧酸三氟乙酸盐2g
将粗品2f(400mg，0.44mmol)溶于5mL二氯甲烷中，加入2mL 4M氯化氢的1,4-二氧六环溶液，室温搅拌反应2小时。反应液减压浓缩后用高效液相色谱法纯化所得残余物，得到标题产物2g(150mg，产率：48％)。
MS m/z(ESI):708.6[M+1]
1H NMR(400MHz,CD3OD)δ7.40-7.17(m,11H),4.89-4.82(m,1H),4.79-4.74(m,1H),4.40-4.39(m,1H),4.22-4.15(m,1H),4.01-3.95(m,1H),3.85-3.60(m,5H),3.49-3.36(m,1H),3.21-3.09(m,5H),2.96-2.92(m,4H),2.27-2.25(m,3H),1.83-1.45(m,14H),1.34-1.33(m,3H),1.01-0.92(m,6H)
第七步
4-氨基-1-((2R,5R,8R,14S)-2-(4-氨基丁基)-8-苄基-5-异丁基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十五-1-酰基)哌啶-4-羧酸2
将2g(150mg，0.182mmol)溶解于1mL二氯甲烷和甲醇(V/V＝10:1)的混合溶液溶清，滴加饱和碳酸钠水溶液调节pH至7左右，室温下搅拌反应30分钟，静止分层，收集有机相，无水硫酸镁干燥，过滤，滤液减压浓缩，得到标题产物2(129mg，收率：100％)。
MS m/z(ESI):708.6[M+1]
实施例3
4-氨基-1-((2R,5R,8R)-2-(4-氨基丁基)-8-苄基-5-异丁基-14-甲基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十五-1-酰基)哌啶-4-羧酸3
Figure PCTCN2017087328-appb-000033
第一步
(9R,12R)-9-苄基-12-异丁基-2,2-二甲基-5-(2-甲基-2-苯基丙基)-4,7,10-三氧代-3-氧杂-5,8,11-三氮杂十三-13-酸苄酯3b
将粗品1i(130mg，0.293mmol)和2-甲基-2-苯基丙-1-胺3a(130mg，0.878mmol，采用专利申请“WO2007030582”公开的方法制备而得)溶于2mL N,N-二甲基甲酰胺中，加入碘化钾(73mg，0.44mmol)和碳酸钾(121mg，0.878mmol)，升温至80℃搅拌反应12小时。反应液冷却至室温，加入1mL四氢呋喃和1mL水，搅拌均匀后，加入二碳酸二叔丁酯(96mg，0.439mmol)，室温搅拌反应2小时。反应液减压浓缩，向所得残余物中加入水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后用薄层色谱法以展开剂体系B纯化所得残余物，得到标题产物3b(110mg，产率：57％)。
第二步
(9R,12R)-9-苄基-12-异丁基-2,2-二甲基-5-(2-甲基-2-苯基丙基)-4,7,10-三氧代-3-氧杂-5,8,11-三氮杂十三-13-酸3c
将3b(110mg，0.162mmol)溶于2mL甲醇中，加入钯碳(20mg，催化量)，加毕，氢气置换三次，升温至30℃搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物3c(74mg)，产品不经纯化直接进行下一步反应。
第三步
1-((9R,12R,15R)-9-苄基-15-(4-((叔丁氧羰基)氨基)丁基)-12-异丁基-2,2-二甲基-5-(2-甲基-2-苯基丙基)-4,7,10,13-四氧代-3-氧杂-5,8,11,14-四氮杂十六-16-酰基)-4-((叔丁氧羰基)氨基)哌啶-4-羧酸甲酯3e
将粗品3c(74mg，0.13mmol)，(R)-1-(2-氨基-6-((叔丁氧羰基)氨基)己酰基)-4-((叔丁氧羰基)氨基)哌啶-4-甲酸甲酯3d(70mg，0.143mmol，采用专利申请“JP5807140B1”公开的方法制备而得)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(74mg，0.195mmol)和N,N-二异丙基乙胺(50mg，0.39mmol)溶于2mL N,N-二甲基甲酰胺中，0℃搅拌反应2小时。反应液减压浓缩，所得残余物中加入水，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后得到粗品标题产物3e(134mg)，产品不经纯化直接进行下一步反应。
第四步
4-氨基-1-((2R,5R,8R)-2-(4-氨基丁基)-8-苄基-5-异丁基-14-甲基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十五-1-酰基)哌啶-4-羧酸三氟乙酸盐3f
将粗品3e(134mg，0.13mmol)溶于2mL四氢呋喃和甲醇(V/V＝3:1)的混合溶剂中，加入0.65mL 1M氢氧化锂溶液，室温搅拌反应2小时。反应液减压浓缩后用高效液相色谱法纯化所得残余物，得到标题产物3f(40mg，产率：30％)。
MS m/z(ESI):722.6[M+1]
1H NMR(400MHz,CD3OD)δ7.90-7.759(m,2H),7.45-7.15(m,10H),4.80-4.71(m,1H),4.45-4.37(m,1H),4.17-4.10(m,1H),4.02-3.85(m,2H),3.80-3.72(m,3H),3.65-3.50m,1H),3.48-3.40(m,1H),3.25-3.15(m,3H),3.05-2.80(m,5H),2.38-2.20(m,3H),2.02-1.40(m,20H),1.05-0.92(m,6H).
第五步
4-氨基-1-((2R,5R,8R)-2-(4-氨基丁基)-8-苄基-5-异丁基-14-甲基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十五-1-酰基)哌啶-4-羧酸3
将3f(40mg，0.048mmol)溶解于1mL二氯甲烷和甲醇(V/V＝10:1)的混合溶液溶清，滴加饱和碳酸钠水溶液调节pH至7左右，室温下搅拌反应30分钟，静止分层，收集有机相，无水硫酸镁干燥，过滤，滤液减压浓缩，得到标题产物3(34.6mg，收率：100％)。
MS m/z(ESI):722.6[M+1]
实施例4
4-氨基-1-((2R,5R,8R,14R)-2-(4-氨基丁基)-8-苄基-5-异丁基-15-甲基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十六-1-酰基)哌啶-4-羧酸4
Figure PCTCN2017087328-appb-000034
第一步
(R)-4-甲基-2-((R)-2-(2-(((R)-3-甲基-2-苯基丁基)氨基)乙酰胺基)-3-苯基丙酰胺基)戊酸苄酯4b
将粗品1i(1g，2.45mmol)和(R)-3-甲基-2-苯基丁-1-胺4a(500mg，3mmol，采用公知的方法“Tetrahedron:Asymmetry,2003,14(16),2401-2406”制备而得)溶于10mL N,N-二甲基甲酰胺中，加入碘化钾(1g，6mmol)和碳酸钾(1.3g，9.2mmol)，升温至60℃搅拌反应12小时。反应液减压浓缩，所得残余物中加入水，用二氯甲烷萃取(30mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物4b(500mg)，产品不经纯化直接进行下一步反应。
第二步
(9R,12R)-9-苄基-12-异丁基-2,2-二甲基-5-((R)-3-甲基-2-苯基丁基)-4,7,10-三氧代-3-氧杂-5,8,11-三氮杂十三-13-酸苄酯4c
将粗品4b(500mg，0.875mmol)溶于二氯甲烷中，加入二碳酸二叔丁酯(380mg，1.75mmol)和N,N-二异丙基乙胺(340mg，2.62mmol)，室温搅拌反应12小时。 反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物4c(300mg，产率：51.1％)。
第三步
(9R,12R)-9-苄基-12-异丁基-2,2-二甲基-5-((R)-3-甲基-2-苯基丁基)-4,7,10-三氧代-3-氧杂-5,8,11-三氮杂十三-13-酸4d
将4c(300mg，0.447mmol)溶于10mL乙醇中，加入钯碳(100mg，催化量)，加毕，氢气置换三次，室温搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物4d(260mg)，产品不经纯化直接进行下一步反应。
第四步
1-((9R,12R,15R)-9-苄基-15-(4-((叔丁氧羰基)氨基)丁基)-12-异丁基-2,2-二甲基-5-((R)-3-甲基-2-苯基丁基)-4,7,10,13-四氧代-3-氧杂-5,8,11,14-四氮杂十六-16-酰基)-4-(((苄氧基)羰基)氨基)哌啶-4-羧酸苄酯4e
将粗品4d(260mg，0.447mmol)，1f(270mg，0.447mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(500mg，1.34mmol)和3mL三乙胺溶于10mL N,N-二甲基甲酰胺中，室温搅拌反应2小时。反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物4e(100mg，产率：19.2％)。
第五步
4-氨基-1-((9R,12R,15R)-9-苄基-15-(4-((叔丁氧羰基)氨基)丁基)-12-异丁基-2,2-二甲基-5-((R)-3-甲基-2-苯基丁基)-4,7,10,13-四氧代-3-氧杂-5,8,11,14-四氮杂十六-16-酰基)哌啶-4-甲酸4f
将4e(100mg，0.086mmol)溶于20mL乙醇中，加入钯碳(100mg，催化量)，加毕，氢气置换三次，室温搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物4f(81mg)，产品不经纯化直接进行下一步反应。
第六步
4-氨基-1-((2R,5R,8R,14R)-2-(4-氨基丁基)-8-苄基-5-异丁基-15-甲基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十六-1-酰基)哌啶-4-羧酸三氟乙酸盐4g
将粗品4f(81mg，0.086mmol)溶于10mL二氯甲烷中，加入3mL三氟乙酸，室温搅拌反应2小时。反应液减压浓缩后用高效液相色谱法纯化所得残余物，得到标题产物4g(8mg，产率：12.7％)。
MS m/z(ESI):736.4[M+1]
1H NMR(400MHz,CD3OD)δ7.45-7.15(m,10H),4.9-4.8(m,1H),4.8-4.62(m,1H),4.41-4.28(m,1H),4.1-4.0(m,1H),3.98-3.85(m,1H),3.85-3.65(m,3H),3.65-3.55(m,1H),3.55-3.45(m,1H)3.38-3.28(m,2H),3.25-3.08(m,2H),3.25-3.05(m,2H),2.95-2.87(m,2H),2.85-2.75(m,1H),2.75-2.65(m,2H),2.4-2.15(m,3H),2-1.35(m,14H),1.2-0.83(m,9H),0.71-0.62(d,3H).
第七步
4-氨基-1-((2R,5R,8R,14R)-2-(4-氨基丁基)-8-苄基-5-异丁基-15-甲基-4,7,10-三氧代 -14-苯基-3,6,9,12-四氮杂十六-1-酰基)哌啶-4-羧酸4
将4g(8mg，0.009mmol)溶解于1mL二氯甲烷和甲醇(V/V＝10:1)的混合溶液溶清，滴加饱和碳酸钠水溶液调节pH至7左右，室温下搅拌反应30分钟，静止分层，收集有机相，无水硫酸镁干燥，过滤，滤液减压浓缩，得到标题产物4(6.9mg，收率：100％)。
MS m/z(ESI):736.4[M+1]
实施例5
4-氨基-1-((2R,5R,8R,14R)-2-(4-氨基丁基)-8-苄基-5-异丁基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十五-1-酰基)哌啶-4-羧酸5
Figure PCTCN2017087328-appb-000035
第一步
(R)-4-甲基-2-((R)-3-苯基-2-(2-(((R)-2-苯基丙基)氨基)乙酰胺基)丙酰胺基)戊酸苄酯5b
将1i(500mg，1.12mmol)和(R)-2-苯基丙-1-胺5a(228mg，1.68mmol，采用公知的方法“Angewandte Chemie,International Edition,2003,42(39),4793-4795”制备而得)溶于10mL N,N-二甲基甲酰胺中，加入碘化钾(372mg，2.24mmol)和碳酸钾(309mg，2.24mmol)，升温至60℃搅拌反应12小时。反应液冷却至室温，加入水，用二氯甲烷萃取(30mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物5b(600mg)，产品不经纯化直接进行下一步反应。
第二步
(9R,12R)-9-苄基-12-异丁基-2,2-二甲基-4,7,10-三氧代-5-((R)-2-苯基丙基)-3-氧杂-5,8,11-三氮杂十三-13-酸苄酯5c
将粗品5b(600mg，1.1mmol)溶于20mL二氯甲烷中，加入二碳酸二叔丁酯(361mg，1.66mmol)和三乙胺(222mg，2.2mmol)，室温搅拌反应12小时。反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物5c(580mg，产率：82％)。
第三步
(9R,12R)-9-苄基-12-异丁基-2,2-二甲基-4,7,10-三氧代-5-((R)-2-苯基丙基)-3-氧杂-5,8,11-三氮杂十三-13-甲酸5d
将5c(580mg，0.9mmol)溶于10mL甲醇中，加入钯碳(60mg，催化量)，加毕，氢气置换三次，室温搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物5d(500mg)，产品不经纯化直接进行下一步反应。
第四步
1-((9R,12R,15R)-9-苄基-15-(4-((叔丁氧羰基)氨基)丁基)-12-异丁基-2,2-二甲基-4,7,10,13-四氧代-5-((R)-2-苯基丙基)-3-氧杂-5,8,11,14-四氮杂十六-16-酰基)-4-(((苄氧基)羰基)氨基)哌啶-4-羧酸苄酯5e
将粗品5d(365mg，0.66mmol)，1f(393mg，0.66mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(376mg，0.99mmol)和N,N-二异丙基乙胺(0.16mL，0.99mmol)溶于10mL N,N-二甲基甲酰胺中，室温搅拌反应2小时。反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物5e(170mg，产率：23％)。
第五步
4-氨基-1-((9R,12R,15R)-9-苄基-15-(4-((叔丁氧羰基)氨基)丁基)-12-异丁基-2,2-二甲基-4,7,10,13-四氧代-5-((R)-2-苯基丙基)-3-氧杂-5,8,11,14-四氮杂十六-16-酰基)哌啶-4-羧酸5f
将5e(80mg，0.0706mmol)溶于10mL甲醇中，加入钯碳(10mg，催化量)，加毕，氢气置换三次，室温搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物5f(60mg)，产品不经纯化直接进行下一步反应。
第六步
4-氨基-1-((2R,5R,8R,14R)-2-(4-氨基丁基)-8-苄基-5-异丁基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十五-1-酰基)哌啶-4-羧酸三氟醋酸盐5g
将粗品5f(60mg，0.066mmol)溶于2mL二氯甲烷中，加入1mL 4M氯化氢的1,4-二氧六环溶液，室温搅拌反应2小时。反应液减压浓缩后用高效液相色谱法纯化所得残余物，得到标题产物5g(30mg，产率：55.6％)。
MS m/z(ESI):708.6[M+1]
第七步
4-氨基-1-((2R,5R,8R,14R)-2-(4-氨基丁基)-8-苄基-5-异丁基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十五-1-酰基)哌啶-4-羧酸5
将5g(30mg，0.028mmol)用5mL甲醇/水混合溶剂(V/V＝10:1)溶解，加入碳酸氢钠固体(10mg)搅拌30分钟，调节pH值至7左右，减压浓缩，所得残余物中加入10mL二氯甲烷，搅拌30分钟，过滤，滤饼用10mL二氯甲烷淋洗，滤液减压浓缩，得到标题产物5(17mg，产率：85.9％)。
MS m/z(ESI):708.6[M+1]
1H NMR(400MHz,CD3OD):δ7.33-7.19(m,10H),4.90-4.84(m,2H),4.64-4.61(m,2H),4.42-4.39(m,1H),3.86-3.74(m,5H),3.20-3.12(m,4H),2.94-2.84(m,4H),2.61-2.54(m,2H),2.20-2.15(m,3H),1.79-1.70(m,2H),1.68-1.60(m,8H),1.45-1.40(m,3H),1.30-1.20(m,5H),0.99-0.76(m,6H).
实施例6
(R)-N-((R)-6-氨基-1-吗啉基-1-氧代己-2-基)-4-甲基-2-((R)-3-苯基-2-(2-(((1S,2R)-2-苯基环丙基)氨基)乙酰胺基)丙酰胺基)戊酰胺6
Figure PCTCN2017087328-appb-000036
第一步
(R)-苄基叔丁基(6-吗啉基-6-氧代己烷-1,5-二基)二氨基甲酸酯6b
将(R)-2-(((苄氧基)羰基)氨基)-6-((叔丁氧羰基)氨基)己酸6a(1.14g，3mmol，采用公知的方法“African Journal of pure and Applied Chemistry,2009,3(6),108-115”制备而得)，吗啡啉(0.31mL，3.6mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.73g，4.5mmol)和N,N-二异丙基乙胺(0.8mL，4.5mmol)溶于10mL  N,N-二甲基甲酰胺中，室温搅拌反应2小时。反应液中加入50mL乙酸乙酯，依次用饱和氯化铵溶液，饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物6b(1.3g)，产品不经纯化直接进行下一步反应。
第二步
(R)-(5-氨基-6-吗啉基-6-氧代己基)氨基甲酸叔丁酯6c
将粗品6b(1.3g，2.9mmol)溶于15mL甲醇中，加入钯碳(350mg，催化量)，加毕，氢气置换三次，室温搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物6c(914mg)，产品不经纯化直接进行下一步反应。
第三步
(R)-4-甲基-2-((R)-3-苯基-2-(2-(((1S,2R)-2-苯基环丙基)氨基)乙酰胺基)丙酰胺基)戊酸苄酯6e
将粗品1i(300mg，0.675mmol)和(1S,2S)-2-苯基环丙胺6d(120mg，0.68mmol，采用专利申请“US20060116370A1”公开的方法制备而得)溶于10mL N,N-二甲基甲酰胺中，加入碘化钾(560mg，3.375mmol)和碳酸钾(465mg，3.375mmol)，升温至60℃搅拌反应5小时。反应液减压浓缩，所得残余物中加入水，用二氯甲烷萃取(30mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物6e(200mg)，产品不经纯化直接进行下一步反应。
第四步
(9R,12R)-9-苄基-12-异丁基-2,2-二甲基-4,7,10-三氧代-5-((1S,2R)-2-苯基环丙基)-3-氧杂-5,8,11-三氮杂十三-13-酸苄酯6f
将粗品6e(200mg，0.35mmol)溶于二氯甲烷中，加入二碳酸二叔丁酯(100mg，0.525mmol)和三乙胺(110mg，1.05mmol)，室温搅拌反应12小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物6f(140mg，产率：62.5％)。
第五步
(9R,12R)-9-苄基-12-异丁基-2,2-二甲基-4,7,10-三氧代-5-((1S,2R)-2-苯基环丙基)-3-氧杂-5,8,11-三氮杂十三-13-酸6g
将6f(140mg，0.218mmol)溶于4.5mL四氢呋喃，甲醇和水(V/V/V＝4:4:1)的混合溶剂中，加入一水合氢氧化锂(55mg，1.31mmol)，室温搅拌反应12小时。反应液减压浓缩除去甲醇和四氢呋喃溶剂，加入水，滴加1M盐酸至pH为6，用二氯甲烷萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物6g(130mg)，产品不经纯化直接进行下一步反应。
第六步
((10R,13R,16R)-16-苯基-13-异丁基-2,2-二甲基-10-(吗啉-4-羰基)-4,12,15,18-四氧代-3-氧杂-5,11,14,17-四氮杂十九-19-基)((1S,2R)-2-苯基环丙基)氨基甲酸叔丁酯6h
将粗品6g(130mg，0.218mmol)，粗品6c(85mg，0.26mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(125mg，0.327mmol)和N,N-二异丙基乙胺(85mg，0.654mmol)溶于5mL N,N-二甲基甲酰胺中，室温搅拌反应12小时。反应液中加入30mL乙酸乙酯，依次用饱和氯化铵溶液，饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物6h(130mg，产率：70％)。
第七步
(R)-N-((R)-6-氨基-1-吗啉基-1-氧代己-2-基)-4-甲基-2-((R)-3-苯基-2-(2-(((1S,2R)-2-苯基环丙基)氨基)乙酰胺基)丙酰胺基)戊酰胺6
将6h(60mg，0.071mmol)溶于3mL二氯甲烷中，加入0.8mL 4M氯化氢的1,4-二氧六环溶液，室温搅拌反应2小时。反应液减压浓缩，浓缩残余物用甲醇和水(V:V＝20:1)混合溶剂溶解，用碳酸钠调节pH大于8，混合溶液减压浓缩，浓缩残余物中加入10mL二氯甲烷，搅拌10min，过滤，滤液减压浓缩，得到标题产物6(19mg，产率：43.5％)。
MS m/z(ESI):649.3[M+1]
1H NMR(400MHz,CD3OD)δ7.26-7.23(m,10H),4.95-4.93(m,1H),4.80-4.78(m,1H),4.70-4.68(m,1H),3.66-3.60(m,8H),3.32-3.30(m,6H),3.28-3.26(m,1H),3.18-3.16(m,1H),2.94-2.91(m,1H),2.65-2.63(m,1H),2.26-2.23(m,1H),1.71-1.68(m,5H),1.48-1.42(m,6H),0.95-0.93(dd,6H).
实施例7
4-氨基-1-((2R,5R,8R)-2-(4-氨基丁基)-8-苄基-5-异丁基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十六-1-酰基)哌啶-4-羧酸7
Figure PCTCN2017087328-appb-000037
Figure PCTCN2017087328-appb-000038
第一步
(9R,12R)-9-苄基-12-异丁基-2,2-二甲基-4,7,10-三氧代-5-(2-苯基丁基)-3-氧杂-5,8,11-三氮杂十三-13-酸7a
将1l(300mg，0.458mmol)溶于10mL甲醇中，加入催化量的钯碳，加毕，氢气置换三次，室温搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物7a(189mg)，产品不经纯化直接进行下一步反应。
第二步
1-((9R,12R,15R)-9-苄基-15-(4-((叔丁氧羰基)氨基)丁基)-12-异丁基-2,2-二甲基-4,7,10,13-四氧代-5-(2-苯基丁基)-3-氧杂-5,8,11,14-四氮杂十六-16-酰基)-4-(((苄氧基)羰基)氨基)哌啶-4-甲酸苄酯7b
将粗品7a(189mg，0.34mmol)，1f(200mg，0.34mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(194mg，0.51mmol)和三乙胺(67mg，0.68mmol)溶于10mL N,N-二甲基甲酰胺中，室温搅拌反应12小时。反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物7b(80mg，产率：20％)。
第三步
4-氨基-1-((9R,12R,15R)-9-苄基-15-(4-((叔丁氧羰基)氨基)丁基)-12-异丁基-2,2-二甲基-4,7,10,13-四氧代-5-(2-苯基丁基)-3-氧杂-5,8,11,14-四氮杂十六-16-酰基)哌啶-4-甲酸7c
将7b(80mg，0.07mmol)溶于10mL甲醇中，加入钯碳(10mg，催化量)，加毕，氢气置换三次，室温搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物7c(50mg)，产品不经纯化直接进行下一步反应。
第四步
4-氨基-1-((2R,5R,8R)-2-(4-氨基丁基)-8-苄基-5-异丁基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十六烷-1-酰基)哌啶-4-甲酸三氟乙酸盐7d
将粗品7c(50mg，0.054mmol)溶于10mL二氯甲烷中，加入2mL 4M氯化氢的1,4-二氧六环溶液，室温搅拌反应1小时。反应液减压浓缩后用高效液相色谱法纯化所得残余物，得到标题产物7d(10mg，产率：25.6％)。
MS m/z(ESI):722.6[M+1]
1H NMR(400MHz,CD3OD)δ7.42-7.25(m,10H),4.84-4.69(m,3H),4.39-4.38(m,2H),3.90-3.73(m,8H),3.22-3.19(m,4H),2.94-2.67(m,5H),2.24-2.19(m,3H),1.79-1.58(m,15H),0.99-0.93(m,6H),0.78(t,3H)
第五步
4-氨基-1-((2R,5R,8R)-2-(4-氨基丁基)-8-苄基-5-异丁基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十六-1-酰基)哌啶-4-羧酸7
将7d(10mg，0.012mmol)溶解于1mL二氯甲烷和甲醇(V/V＝10:1)的混合溶液溶清，滴加饱和碳酸钠水溶液调节pH至7左右，室温下搅拌反应30分钟，静止分层，收集有机相，无水硫酸镁干燥，过滤，滤液减压浓缩，得到标题产物7(8.6mg，收率：100％)。
MS m/z(ESI):722.6[M+1]
实施例8
4-氨基-1-((2R,5R,8R)-2-(4-氨基丁基)-8-苄基-5-异丁基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十四-1-酰基)哌啶-4-甲酸8
Figure PCTCN2017087328-appb-000039
Figure PCTCN2017087328-appb-000040
第一步
(R)-2-氨基-6-(((苄氧基)羰基)氨基)己酸甲酯盐酸盐8b
将1.3mL二氯亚砜溶于20mL甲醇中，冰浴冷却至0℃后，加入(R)-2-氨基-6-(((苄氧基)羰基)氨基)己酸8a(2g，7.1mmol)，室温搅拌反应12小时。反应液减压浓缩，得到粗品标题产物8b(2.09g)，产品不经纯化直接进行下一步反应。
第二步
(9R,12R)-9-苄基-12-异丁基-2,2-二甲基-4,7,10-三氧代-5-苯乙基-3-氧杂-5,8,11-三氮杂十三-13-酸苄酯8d
将2-((叔丁氧羰基)(苯乙基)氨基)乙酸8c(332mg，1.19mmol，采用专利申请“US6245746B1”公开的方法制备而得)和1g(439mg，1.19mmol)溶于6.6mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(679mg，1.785mmol)和N,N-二异丙基乙胺(615mg，4.76mmol)，0℃下搅拌反应2小时。反应液减压浓缩，所得残余物中加入水，用乙酸乙酯萃取(30mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩后用薄层色谱法以展开剂体系B纯化所得残余物，得到标题产物8d(410mg，产率：55％)。
第三步
(9R,12R)-9-苄基-12-异丁基-2,2-二甲基-4,7,10-三氧代-5-苯乙基-3-氧杂-5,8,11-三氮杂十三-13-酸8e
将8d(410mg，0.65mmol)溶于20mL甲醇中，加入钯碳(60mg，催化量)，加毕，氢气置换三次，升温至30℃搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物8e(313mg)，产品不经纯化直接进行下一步反应。
第四步
(9R,12R,15R)-9-苄基-15-(4-(((苄氧基)羰基)氨基)丁基)-12-异丁基-2,2-二甲基-4,7,10,13-四氧代-5-苯乙基-3-氧杂-5,8,11,14-四氮杂十六-16-酸甲酯8f
将粗品8e(100mg，0.125mmol)和粗品8b(85mg，0.231mmol)溶于5mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(105mg，0.277mmol)和N,N-二异丙基乙胺(72mg，0.555mmol)，室温搅拌反应2小时。反应液减压浓缩，所得残余物中加入水，用乙酸乙酯萃取(30mL×3)，合并有机相，依次用饱和氯化铵溶液(30mL×3)，饱和碳酸氢钠溶液(30mL×3)和饱和氯化钠溶液(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物8f(140mg)，产品不经纯化直接进行下一步反应。
第五步
(9R,12R,15R)-9-苄基-15-(4-(((苄氧基)羰基)氨基)丁基)-12-异丁基-2,2-二甲基-4,7,10,13-四氧代-5-苯乙基-3-氧杂-5,8,11,14-四氮杂十六-16-酸8g
将粗品8f(140mg，0.17mmol)溶于7mL四氢呋喃，甲醇和水(V/V/V＝3:3:1)的混合溶剂中，加入一水合氢氧化锂(40mg，0.85mmol)，室温搅拌反应0.5小时。反应液减压浓缩除去甲醇和四氢呋喃溶剂，加入水，滴加1M盐酸至pH为6，用二氯甲烷萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物8g(220mg)，产品不经纯化直接进行下一步反应。
第六步
1-((9R,12R,15R)-9-苄基-15-(4-(((苄氧基)羰基)氨基)丁基)-12-异丁基-2,2-二甲基-4,7,10,13-四氧代-5-苯乙基-3-氧杂-5,8,11,14-四氮杂十六-16-酰基)-4-(((苄氧基)羰基)氨基)哌啶-4-甲酸苄酯8h
将粗品8g(220mg，0.17mmol)和粗品1c(130mg，0.26mmol)溶于5mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(100mg，0.26mmol)和N,N-二异丙基乙胺(66mg，0.51mmol)，室温搅拌反应3小时。反应液减压浓缩，所得残余物中加入水，用乙酸乙酯萃取(30mL×3)，合并有机相，依次用饱和氯化铵溶液(30mL×3)，饱和碳酸氢钠溶液(30mL×3)和饱和氯化钠溶液(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物8h(170mg，产率：87％)。
第七步
1-((9R,12R,15R)-15-(4-氨基丁基)-9-苄基-12-异丁基-2,2-二甲基-4,7,10,13-四氧代-5-苯乙基-3-氧杂-5,8,11,14-四氮杂十六-16-酰基)-4-(羧基氨基)哌啶-4-甲酸8i
将8h(170mg，0.147mmol)溶于5mL甲醇中，加入钯碳(50mg，催化量)，加毕，氢气置换三次，室温搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物8i(140mg)，产品不经纯化直接进行下一步反应。
第八步
4-氨基-1-((2R,5R,8R)-2-(4-氨基丁基)-8-苄基-5-异丁基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十四-1-酰基)哌啶-4-甲酸8
将粗品8i(140mg，0.167mmol)溶于3mL二氯甲烷中，加入0.5mL 4M氯化氢的1,4-二氧六环溶液，室温搅拌反应1小时。反应液减压浓缩，浓缩残余物用甲醇和水(V/V＝20:1)混合溶剂溶解，用碳酸钠调节pH大于8，混合溶液减压浓缩，浓缩残余物中加入10mL二氯甲烷，搅拌10分钟，过滤，滤液减压浓缩，得到标题产物8(19mg，产率：17.4％)。
MS m/z(ESI):694.4[M+1]
1H NMR(400MHz,CD3OD)δ7.32-7.01(m,10H),4.68-4.66(m,1H),4.44-4.42(m,1H),3.75-3.65(m,6H),3.35(s,2H),3.32-3.28(m,6H),3.20-3.18(m,2H),3.00(s,2H),2.70-2.58(m,5H),2.10-1.98(m,3H),1.55-1.50(m,6H),0.95-0.93(dd,6H).
实施例9
(R)-N-((R)-6-氨基-1-(4-(3-甲基脲基)哌啶-1-基)-1-氧代己-2-基)-4-甲基-2-((R)-3-苯基-2-(2-(((R)-2-苯基丙基)氨基)乙酰胺基)丙酰胺基)戊酰胺9
Figure PCTCN2017087328-appb-000041
第一步
4-(3-甲基脲基)哌啶-1-甲酸叔丁酯9c
将9a(8.11g，40mmol，采用专利申请“WO2006115353”公开的方法制备而得)溶于130mL二氯甲烷中，加入N,N-二异丙基乙胺(15.51g，120mmol)，反应液冷却至0℃，将9b(3.74g，40mmol)滴加入反应液中，室温搅拌反应2小时。反应液中加入200mL饱和碳酸氢钠溶液，用二氯甲烷萃取(200mL×3)，合并有机相，用饱和氯化钠溶液洗涤(200mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物9c(9.3g)，产品不经纯化直接进行下一步反应。
第二步
1-甲基-3-(哌啶-4-基)脲盐酸盐9d
将粗品9c(1g，4mmol)溶解于10mL二氯甲烷中，加入2mL 4M氯化氢的1,4-二氧六环溶液，搅拌反应2小时。反应液减压浓缩，得到粗品标题产物9d(1g，白色固体)，产品不经纯化直接进行下步反应。
第三步
(R)-(9H-芴-9-基)甲基叔丁基(6-(4-(3-甲基脲基)哌啶-1-基)-6-氧代己烷-1,5-二基)二氨基甲酸酯9e
将粗品9d(1g，5.16mmol)，1d(2.42g，5.16mmol)溶于20mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(2.94g，7.74mmol)和三乙胺(1.03g，10.32mmol)，室温搅拌反应4小时。反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物9e(1g，产率：32％)。
第四步
(R)-(5-氨基-6-(4-(3-甲基脲基)哌啶-1-基)-6-氧代己基)氨基甲酸叔丁酯9f
将9e(304mg，0.5mmol)溶解于2mL N,N-二甲基甲酰胺中，加入6mL三乙胺，室温搅拌反应12小时。反应液不经纯化直接进行下一步反应。
第五步
((10R,13R,16R)-16-苄基-13-异丁基-2,2-二甲基-10-(4-(3-甲基脲基)哌啶-1-羰基)-4,12,15,18-四氧代-3-氧杂-5,11,14,17-四氮杂十九-19-基)((R)-2-苯基丙基)氨基
甲酸叔丁酯9g
将粗品9f(193mg，0.5mmol)，粗品5d(277mg，0.5mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(380mg，1mmol)和N,N-二异丙基乙胺(129mg，1mmol)溶于30mL N,N-二甲基甲酰胺中，室温搅拌反应12小时。反应液中加入10mL饱和柠檬酸溶液和20mL水，用乙酸乙酯萃取(30mL×3)，合并有机相，依次用饱和碳酸氢钠溶液(20mL)、饱和氯化钠溶液洗涤(20mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物9g(500mg)，产品不经纯化直接进行下一步反应。
第六步
(R)-N-((R)-6-氨基-1-(4-(3-甲基脲基)哌啶-1-基)-1-氧代己-2-基)-4-甲基-2-((R)-3-苯基-2-(2-(((R)-2-苯基丙基)氨基)乙酰胺基)丙酰胺基)戊酰胺三氟乙酸盐9
将粗品9g(184mg，0.2mmol)溶于10mL二氯甲烷中，加入2mL 4M的氯化氢的1,4-二氧六环溶液，室温搅拌反应12小时。反应液减压浓缩后用高效液相色谱法纯化所得残余物，得到标题产物9(20mg，产率：14％)。
MS m/z(ESI):721.6[M+1]
1H NMR(400MHz,CD3OD)δ8.37-8.25(m,1H),7.73-7.65(m,1H),7.41-7.37(m,2H),7.39-7.29(m,7H),7.18-7.16(m,2H),4.93-4.90(m,1H),4.83-4.82(m,1H),4.54-4.50(m,2H),4.00-3.92(m,1H),3.88-3.60(m,6H),3.15-3.08(m,5H),3.05-2.98(m,4H),2.70(s,3H),2.15-1.88(m,3H),1.79-1.61(m,15H),1.01-0.96(m,6H).
第七步
(R)-N-((R)-6-氨基-1-(4-(3-甲基脲基)哌啶-1-基)-1-氧代己-2-基)-4-甲基-2-((R)-3-苯基-2-(2-(((R)-2-苯基丙基)氨基)乙酰胺基)丙酰胺基)戊酰胺9
将9h(20mg，0.024mmol)溶解于1mL二氯甲烷和甲醇(V/V＝10:1)的混合溶液溶清，滴加饱和碳酸钠水溶液调节pH至7左右，室温下搅拌反应30分钟，静止分层，收集有机相，无水硫酸镁干燥，过滤，滤液减压浓缩，得到标题产物9(17mg，收率：100％)。
MS m/z(ESI):721.6[M+1]
实施例10
(R)-N-((R)-6-氨基-1-吗啉基-1-氧代己烷-2-基)-2-((R)-2-(2-((2,3-二氢-1H-茚-2-基)氨基)乙酰氨基)-3-苯基丙酰氨基)-4-甲基戊酰胺10
Figure PCTCN2017087328-appb-000042
Figure PCTCN2017087328-appb-000043
第一步
(R)-(9H-芴-9-基)甲基(6-((1-(4,4-二甲基-2,6-二氧代环己亚基)乙基)氨基)-1-吗啉基-1-氧代己烷-2-基)氨基甲酸酯10b
将(R)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-6-((1-(1-(4,4-二甲基-2,6-二氧代环己亚基)乙基)氨基)己酸10a(1.06g，2mmol，购自韶远)和吗啉(200mg，2.4mmol)溶于10mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.51g，4mmol)和三乙胺(400mg，4mmol)，室温搅拌反应3小时。反应液减压浓缩，所得残余物中加入5mL饱和柠檬酸溶液和50mL水，用乙酸乙酯萃取(100mL×3)，合并有机相，用水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物10b(1.3g)，产品不经纯化直接进行下一步反应。
第二步
(R)-2-(1-((5-氨基-6-吗啉基-6-氧代己基)氨基)乙亚基)-5,5-二甲基环己烷-1,3-二酮10c
将粗品10b(1.3g，2mmol)溶于5mL二氯甲烷中，加入2mL哌啶，室温搅拌反应12小时。反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物10c(500mg，产率：75％)。
第三步
(R)-2-((R)-2-(2-((2,3-二氢-1H-茚-2-基)氨基)乙酰氨基)-3-苯基丙酰氨基)-4-甲基戊酸苄酯10e
将粗品1i(222mg，0.5mmol)和2,3-二氢-1H-茚-2-胺盐酸盐10d(127mg，0.4mmol，采用公知的方法“Tetrahedron,2005,61(28),6801-6807”制备而得)溶于5mL N,N-二甲基甲酰胺中，加入碘化钾(415mg，2.5mmol)和碳酸钾(345mg，2.5mmol)，升温至60℃搅拌反应12小时。反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物10e(300mg，产率：100％)。
第四步
(9R,12R)-9-苄基-5-(2,3-二氢-1H-茚-2-基)-12-异丁基-2,2-二甲基-4,7,10-三氧代-3-氧杂-5,8,11-三氮杂十三-13-酸苄酯10f
将10e(300mg，0.55mmol)溶于10mL二氯甲烷中，加入二碳酸二叔丁酯(181mg，083mmol)和N,N-二异丙基乙胺(0.3mL，1.65mmol)，室温搅拌反应12小时。反应液减压浓缩，用薄层色谱法以洗脱剂体系A纯化所得残余物，得到标题产物10f(170mg，产率：48％)。
第五步
(9R,12R)-9-苄基-5-(2,3-二氢-1H-茚-2-基)-12-异丁基-2,2-二甲基-4,7,10-三氧代-3-氧杂-5,8,11-三氮杂十三-13-酸10g
将10f(170mg，0.26mmol)溶于10mL甲醇中，加入钯碳(50mg，10％)，氢气置换三次，室温搅拌反应12小时。反应液过滤，滤液减压浓缩，得到粗品标题产物10g(112mg)，产品不经纯化直接进行下一步反应。
第六步
((4R,7R,10R)-4-苄基-16-(4,4-二甲基-2,6-二氧代环己亚基)-7-异丁基-10-(吗啉-4-羰基)-2,5,8-三氧代-3,6,9,15-四氮杂十七烷基)(2,3-二氢-1H-茚-2-基)氨基甲酸叔丁酯10h
将粗品10g(112mg，0.2mmol)，10c(78mg，0.2mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(114mg，0.3mmol)和N,N-二异丙基乙胺(0.1mL，0.6mmol)溶于15mL N,N-二甲基甲酰胺中，室温搅拌反应2小时。反应液减压浓缩，所得残余物中加入100mL乙酸乙酯，依次用水(50mL×3)和饱和氯化铵溶液(50mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物10h(183mg)，产品不经纯化直接进行下一步反应。
第七步
(2-(((R)-1-(((R)-1-(((R)-6-氨基-1-吗啉基-1-氧代己烷-2-基)氨基)-4-甲基-1-氧代戊烷-2-基)氨基)-1-氧代-3-苯基丙烷-2-基)氨基)-2-氧代乙基)(2,3-二氢-1H-茚-2-基)氨基甲酸叔丁酯10i
将粗品10h(183mg，0.2mmol)溶于10mL甲醇中，加入0.5mL水合肼，室温搅拌反应1小时。反应液减压浓缩，得到粗品标题产物10i(150mg)，产品不经纯化直接进行下一步反应。
第八步
(R)-N-((R)-6-氨基-1-吗啉基-1-氧代己烷-2-基)-2-((R)-2-(2-((2,3-二氢-1H-茚-2-基)氨基)乙酰氨基)-3-苯基丙酰氨基)-4-甲基戊酰胺三氟乙酸盐10j
将粗品10i(150mg，1.31mmol)溶解于5mL二氯甲烷中，加入1mL三氟乙酸，室温搅拌反应1小时。反应液减压浓缩，用高效液相色谱法纯化所得残余物，得到标题产物10j(5mg，产率：4％)。
MS m/z(ESI):649.4[M+1]
1H NMR(400MHz,DMSO-d6)δ8.36(d,1H),7.88(d,2H),7.21-7.33(m,9H),4.61-4.64(m,1H),4.36-4.47(m,1H),4.02-4.15(m,2H),3.60-3.70(m,3H),3.45-3.59(m,5H),3.35-3.44(m,3H),2.90-3.25(m,9H),1.55-1.80(m,6H),1.30-1.45(m,4H),0.98(d,3H),0.92(d,3H).
第九步
(R)-N-((R)-6-氨基-1-吗啉基-1-氧代己烷-2-基)-2-((R)-2-(2-((2,3-二氢-1H-茚-2-基)氨基)乙酰氨基)-3-苯基丙酰氨基)-4-甲基戊酰胺10
将10j(5mg，0.0057mmol)溶解于2mL二氯甲烷和甲醇(V/V＝10:1)的混合溶液溶清，滴加饱和碳酸钠水溶液调节pH至7左右，室温下搅拌反应30分钟，静止分层，收集有机相，无水硫酸镁干燥，过滤，滤液减压浓缩，得到标题产物10(4mg，收率：100％)。
MS m/z(ESI):649.4[M+1]
生物学评价
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
测试例1
1、实验目的
本实验的目的是为了测试本发明化合物对人源KOR(h-KOR)受体的激动作用，根据EC50大小评价化合物的体外活性。
2、h-KOR活性的测试
2.1实验目的
本发明的化合物可以激活h-KOR受体，从而降低细胞内cAMP的水平；第二信使cAMP进入细胞核与DNA的CRE相结合，可启动下游荧光素酶(Luciferase) 的表达，荧光素酶与其底物反应可发出荧光，通过测定荧光信号反映化合物的激动活性。
2.2实验方法
实施例化合物激动h-KOR影响下游cAMP水平变化的活性通过以下的方法进行测试。
2.2.1实验材料及仪器
1)实验仪器
1.酶标仪(PE，Vector3)
2)实验材料
Figure PCTCN2017087328-appb-000044
2.2.2实验步骤
1)HEK293/KOR/CRE单克隆细胞株的获得
将人源KOR/pcDNA3.1(+)和CRE/pGL4.29转入HEK293细胞株，通过在培养基中加入G418和潮霉素(Hygromycin)，并在96孔细胞培养板中筛选出HEK293/KOR/CRE单克隆细胞株。
2)实施例化合物对h-KOR激动作用实验
HEK293/h-KOR/CRE单克隆细胞株在DMEM/高葡萄糖培养基(10％FBS,1mg/ml G418，200μg/ml潮霉素，混匀)中培养，每3天传代一次。实验当天以新鲜细胞培养基制取细胞悬液，20,000细胞/孔铺96孔板(BD，#356692)，5％二氧化碳37℃培养。第二天，先将化合物溶解在纯DMSO中浓度为20mM，再用DMSO配制成首个浓度200nM，并以3倍依次稀释成8个浓度，设置成空白和对照的孔加入90μl DMSO；用含10μM Forskolin的DMEM/高葡萄糖(SH30243.01B，Hyclone)培养基稀释20倍。取出第一天接种的细胞培养板，每孔分别加入10μl稀释后药物或对照(0.5％DMSO)，轻轻振荡混匀，放置37℃培养4小时。在96孔细胞培养板中，每孔加入100μl荧光素酶检测液(Promega，#E6110)，室温放置5分钟，采用Victor3.0测化学发光值。用Graphpad Prism软件根据化合物各浓度与相应的信号值计算化合物的EC50值。
2.3测试结果
本发明的化合物激动h-KOR影响下游cAMP水平的变化通过以上的试验进行测定，测得的EC50值见表1.1。
表1.1本发明化合物激动h-KOR受体影响cAMP水平的EC50
实施例编号 EC50(pM)
1 56
2 15
3 4
4 9
5 1
6 79
7 3
8 13
9 0.5
10 >1000
结论：本发明化合物对h-KOR受体具有明显的激动作用。特别是甘氨酸的氨基上的取代基为取代或未取代的亚乙基时，具有意料不到的效果。
药代动力学评价
测试例2、本发明实施例2、5和8化合物的大鼠药代动力学测试
1、摘要
以SD大鼠为受试动物，应用LC/MS/MS法测定了SD大鼠静脉注射给予实施例2、5和8化合物后不同时刻血浆中的药物浓度。研究本发明化合物在SD大鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1试验药品
实施例2、5和8化合物
2.2试验动物
SD大鼠12只，雌雄各半，分成3组，购自上海西普尔-必凯实验动物有限公司，动物生产许可证号：SCXK(沪)2008-0016。
2.3药物配制
称取适量样品，加入5％DMSO+5％PEG400+90％生理盐水，按顺序依次加入。
2.4给药
SD大鼠12只，雌雄各半，平均分成3组；禁食一夜后分别静脉注射给药，给药体积5ml/kg。
3、操作
静脉组于给药前及给药后5min,0.25,0.5,1.0,2.0,4.0,8.0,11.0,24.0h由眼眶采血0.2ml，置于肝素化试管中，3500rpm离心10min分离血浆，于-20℃保存。
用LC/MS/MS法测定不同化合物静脉注射给药后SD大鼠血浆中的待测化合物含量。
4、SD大鼠药代动力学参数结果
本发明实施例2、5和8化合物的大鼠药代动力学参数如下：
Figure PCTCN2017087328-appb-000045
结论：本发明大鼠药代性质良好。
测试例3、本发明实施例5化合物的犬药代动力学测试
1、摘要
以Beagle犬为受试动物，应用LC/MS/MS法测定了Beagle犬静脉注射给予实施例5化合物后不同时刻血浆中的药物浓度。研究本发明化合物在Beagle犬体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1试验药品
实施例5化合物
2.2试验动物
Beagle犬雄性3只为1组，美迪西普亚医药科技(上海)有限公司提供,。
2.3药物配制
称取适量样品，加入100％生理盐水溶解。
2.4给药
Beagle犬3只，雄性，为1组；禁食一夜后分别静脉注射给药，给药体积2ml/kg。
3、操作
静脉组于给药前及给药后5min,15min,0.5,1.0,2.0,4.0,8.0,12.0,24.0h由颈静脉采血1.0ml，置于肝素化试管中，3500rpm离心10min分离血浆，于-80℃保存。
用LC/MS/MS法测定静脉注射给药后Beagle犬血浆中的待测化合物含量。
4、Beagle犬药代动力学参数结果
本发明实施例5化合物的Beagle犬药代动力学参数如下：
Figure PCTCN2017087328-appb-000046
Figure PCTCN2017087328-appb-000047
结论：本发明Beagle犬药代性质良好。
测试例4、KOR激动剂治疗大鼠角叉菜胶诱导的炎性痛实验报告
1.实验目的
建立大鼠角叉菜胶炎性痛模型，评估KOR激动剂对大鼠炎性痛的治疗作用。
2.实验方法和实验材料
2.1.实验动物和饲养条件
实验用Wistar雄性大鼠，购自上海斯莱克实验动物有限公司(中国上海，合格证编号2015000513408，许可证SCXK(沪)2012-0002，购入时150-180g，5只/笼饲养，12/12小时光/暗周期调节，温度23±1℃恒温，湿度50～60％，自由进食进水。动物购进后，进行适应性饲养7天以上开始实验。
2.2.实验药品
实施例5化合物；
λ-角叉菜胶(λ-Carrageenan)：批号为BCBP8978V，sigma产品。
0.9％氯化钠溶液(500ml：4.5g)
1％λ-角叉菜胶用生理盐水配置后搅拌过夜呈果冻状混悬液。
药物剂量均按碱基计算。
2.3.实验设计和实验方法
2.3.1.动物分组：
大鼠适应性饲养后，分组如下：
Figure PCTCN2017087328-appb-000048
注：NS:配制角叉菜胶溶液时用的生理盐水；i.v.：静脉注射；s.c.：皮下注射。
2.3.2.实验方法[1][2]：
实验方法按照文献1中(Kazunari Nakao等)的方法进行改进。炎性痛实验在实验前将大鼠按照体重随机分组如下：空白对照组，模型组，实施例5-0.1mg/kg组，实施例5-0.3mg/kg组。每组大鼠8只。炎性痛造模采用1％角叉菜胶(100μl)对Wistar大鼠足垫进行皮下注射。4h后对大鼠进行足底触痛测试评估其机械痛阈值，检测前30min分别给予单次尾静脉给药(1ml/kg)，对照组和模型组给予相应的溶剂。
注：参考文献1，CJ-023,423,a Novel,Potent and Selective Prostaglandin KOR Receptor Antagonist with Anti-hyperalgesic Properties[J].The Journal of Pharmacology and Experimental Therapeutics,2007,322(2):686–694.
2.4.实验仪器
电子触觉测量仪(电子Von Frey)：UGO BASILE，型号38450。
2.5.数据表达和统计学处理
实验数据表示为平均数(Mean)±标准差(S.D.)。采用excel软件t检验进行统计比较。将模型组与空白对照组数据进行分析比较，是否存在显著数理统计意义，*P<0.05表示模型组与对照组比较具有显著性差异,**P<0.01表示模型组与对照组比较具有高度显著性差异。#P<0.05表示模型组与给药组比较具有显著性差异,##P<0.01表示模型组与给药组比较具有高度显著性差异。
3.结果：本发明化合物对角叉菜胶诱导的大鼠角叉菜胶炎性痛的影响
实验结果显示，空白对照组大鼠触痛阈值为20g左右，模型组触痛阈值为7.6g，与空白对照组比较，模型组大鼠触痛阈值明显下降(P<0.01)；与模型组比较，所有药物均能明显增加炎性大鼠的触痛阈值(P<0.01)，实施例5-0.1mg/kg、实施例5-0.3mg/kg触痛阈值分别为13.7g、23.2g，依次增加幅度分别为79.5％和204.5％，具有明显的剂量依赖性。(见图1)。
4讨论
λ-角叉菜胶(carrageenan)是由水生植物鹿角菜中提取的胶体物质，具有过敏刺激作用。角叉菜胶单独实验即可诱发炎症，引起疼痛。本实验通过建立角叉菜胶炎性痛模型，观察大鼠给予KOR激动剂后的触痛阈值变化情况，评价药物对亚急性炎性痛的镇痛作用及其作用强度。实验采用电子触痛仪测量大鼠对触痛的反应情况，电子触觉测量仪(e-VF)采用Ugo Basile原创设计，用于评估大、小鼠过敏症和触诱发痛。该设备可自动记录动物的受刺激时间和刺激强度。独特的三棱镜设计，使得实验时观察受试动物足底区域变得非常容易。测试过程中，设备可自行感应受试动物缩回受测爪，也可通过脚踏开关人为判断。定位更加集中，比较适用于局部疼痛和神经性疼痛测定。
5结论
受试药能改善大鼠炎性疼痛，且具有剂量依赖性。

Claims (18)

  1. 一种通式(I)所示的化合物：
    Figure PCTCN2017087328-appb-100001
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，
    其中：
    M为无机酸或有机酸，优选有机酸，更优选三氟乙酸；
    G选自O、-NR4和-CR5R6；
    R1选自氢原子、烷基、烷氧基、卤代烷基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7和-NR8R9，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R2选自氢原子、烷基、烷氧基、卤代烷基、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、-OR7、-C(O)R7和-C(O)OR7，其中所述的烷基、卤代烷基、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基和杂芳基烷基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R3选自氢原子、烷基、烷氧基、卤代烷基、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、-OR7、-C(O)R7和-C(O)OR7，其中所述的烷基、卤代烷基、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基和杂芳基烷基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R4选自氢原子、烷基、卤代烷基、环烷基、烷氧基、羟烷基、氨基、羧酸酯基、杂环基、芳基、杂芳基、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR8R9和-NHC(O)NR8R9，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷 基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R5和R6各自独立地选自氢原子、烷基、烷氧基、羟烷基、羟基、氨基、羧酸酯基、环烷基、杂环基、芳基、杂芳基、-OR7、-C(O)R7、-C(O)OR7、-S(O)mR7、-NR8R9和-NHC(O)NR8R9，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R7选自氢原子、烷基、氨基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R8和R9各自独立地选自氢原子、烷基、烷氧基、羟烷基、羟基、氨基、羧酸酯基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    z为0、1、2、3或4；且
    m为0、1或2。
  2. 根据权利要求1所述的通式(I)所示的化合物，其为通式(II)所示的化合物：
    Figure PCTCN2017087328-appb-100002
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    其中：
    M、G、R2、R3和z如权利要求1中所定义。
  3. 根据权利要求1或2所述的通式(I)所示的化合物，其为通式(III)所示的化合物：
    Figure PCTCN2017087328-appb-100003
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    其中：
    M、G、R2和z如权利要求1中所定义。
  4. 根据权利要求1～3任一项所述的通式(I)所示的化合物，其为通式(IV)所示的化合物：
    Figure PCTCN2017087328-appb-100004
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    其中：
    M、R2和z如权利要求1中所定义。
  5. 根据权利要求1～4任一项所述的通式(I)所示的化合物，其中R2选自芳基烷基、环烷基烷基和环烷基，其中所述的芳基烷基、环烷基烷基和环烷基任选被选自烷基、环烷基和芳基中的一个或多个取代基所取代。
  6. 根据权利要求1～3任一项所述的通式(I)所示的化合物，其为通式(III-A)所示的化合物：
    Figure PCTCN2017087328-appb-100005
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    其中：
    G为O或CR5R6；优选为CR5R6；
    R10选自氢原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    R11和R12相同或不同，各自独立地选自氢原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    或者R11和R12一起形成环烷基；
    R13选自氢原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    s为0、1或2；
    R5～R6、M和z如权利要求1中所定义。
  7. 根据权利要求1～6中任一项所述的通式(I)所示的化合物，其为通式(IV-A)所示的化合物：
    Figure PCTCN2017087328-appb-100006
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    其中：
    R10～R13、M、z和s如权利要求6中所定义。
  8. 根据权利要求1～7中任一项所述的通式(I)所示的化合物，其为通式(IV-B)所示的化合物：
    Figure PCTCN2017087328-appb-100007
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    其中：
    R10～R11、R13、M、z和s如权利要求6中所定义。
  9. 根据权利要求1～8任一项所述的通式(I)所示的化合物，其中z为0或1。
  10. 根据权利要求1～9任一项所述的通式(I)所示的化合物，其中所述化合物选自：
    Figure PCTCN2017087328-appb-100008
  11. 一种通式(VI)所示的化合物：
    Figure PCTCN2017087328-appb-100009
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    其中：
    Ra为氨基保护基，优选为叔丁氧羰基、9-芴甲氧羰基、烯丙氧羰基、三氯乙氧羰基、三甲基硅乙氧羰基、苄氧羰基、对甲基苯磺酰基、对硝基苯磺酰基或叔丁基；且
    G和R2如权利要求3中所定义。
  12. 一种制备根据权利要求3所述的通式(III)所示的化合物的方法，该方法包括：
    Figure PCTCN2017087328-appb-100010
    通式(VI)化合物在酸性条件下反应脱去保护基Ra，得到通式(III)化合物；
    其中：
    M、G、z和R2如权利要求3中所定义，Ra如权利要求11中所定义。
  13. 一种药物组合物，其含有治疗有效量的根据权利要求1～10任一项所述的通式(I)所示的化合物，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  14. 根据权利要求1～10任一项所述的通式(I)所示的化合物或根据权利要求13所述的药物组合物在制备预防和/或治疗κ阿片样物质受体激动剂介导的相关疾病的药物中的用途。
  15. 根据权利要求14所述的用途，其中所述的κ阿片样物质受体激动剂介导的相关疾病选自疼痛、炎症、瘙痒、水肿、低钠血症、低钾血症、肠梗阻、咳嗽和青光眼，优选疼痛。
  16. 根据权利要求1～10任一项所述的通式(I)所示的化合物或根据权利要求13所述的药物组合物在制备预防和/或治疗疼痛和疼痛相关疾病的药物中的用途。
  17. 根据权利要求15或16所述的用途，其中所述的疼痛选自神经性疼痛、躯干痛、内脏痛、皮肤痛、关节炎疼痛、肾结石疼痛、子宫痉挛、痛经、子宫内膜异位症、消化不良、外科手术后疼痛、医疗处理后疼痛、眼部疼痛、耳炎疼痛、爆发性癌症疼痛和GI紊乱相关的疼痛。
  18. 根据权利要求1～10任一项所述的通式(I)所示的化合物或根据权利要求13所述的药物组合物在制备激动κ阿片样物质受体的药物中用途。
PCT/CN2017/087328 2016-06-07 2017-06-06 苯基丙酰胺类衍生物、其制备方法及其在医药上的应用 WO2017211272A1 (zh)

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