WO2018121551A1 - 氮杂双环基取代的***类衍生物、其制备方法及其在医药上的应用 - Google Patents

氮杂双环基取代的***类衍生物、其制备方法及其在医药上的应用 Download PDF

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WO2018121551A1
WO2018121551A1 PCT/CN2017/118784 CN2017118784W WO2018121551A1 WO 2018121551 A1 WO2018121551 A1 WO 2018121551A1 CN 2017118784 W CN2017118784 W CN 2017118784W WO 2018121551 A1 WO2018121551 A1 WO 2018121551A1
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group
compound
formula
ring
mixture
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PCT/CN2017/118784
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English (en)
French (fr)
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李心
陈阳
刘涛
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 CA3047641A priority Critical patent/CA3047641A1/en
Priority to JP2019533376A priority patent/JP2020504109A/ja
Priority to MX2019007360A priority patent/MX2019007360A/es
Priority to CN201780020566.2A priority patent/CN109071492B/zh
Priority to US16/472,527 priority patent/US20210040073A1/en
Priority to AU2017389819A priority patent/AU2017389819B2/en
Priority to EP17885670.4A priority patent/EP3564231A4/en
Priority to CN202110204338.9A priority patent/CN113149961B/zh
Publication of WO2018121551A1 publication Critical patent/WO2018121551A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention belongs to the field of medicine and relates to a novel azabicyclo substituted triazole derivative, a preparation method thereof and a pharmaceutical composition containing the same and the use thereof as a therapeutic agent, in particular as an oxytocin antagonist And use in the manufacture of a medicament for the treatment or prevention of a disease or condition known or capable of exhibiting a beneficial effect of inhibiting oxytocin.
  • Oxytocin is a cyclic nonapeptide that is normally synthesized by the hypothalamic paraventricular nucleus and released via the posterior pituitary. OT has a wide range of physiological functions, including social connections, sexual reproduction, and childbirth. OT exerts a physiological effect by binding to its oxytocin receptors (OTRs).
  • OTRs oxytocin receptors
  • Oxytocin modulators may be effective in treating abortion.
  • Another condition associated with oxytocin is dysmenorrhea, which is characterized by pain and discomfort during menstruation. Oxytocin plays a role in the cause of dysmenorrhea due to its activity as a uterine vasoconstrictor (Akerlund et al., Ann. NY Acad. Sci. 734: 47-56, 1994). Oxytocin antagonists have a therapeutic effect on this condition.
  • oxytocin has been found to be one of the most potent substances that can induce penile erection in rats, rabbits and monkeys.
  • central administration of oxytocin is said to shorten the latency to ejaculation and shorten the post-ejaculation interval.
  • Meston et al. (Arch. Gen.
  • Psychiatry, 57(11): 1012-30, 2000 describe the injection of oxytocin into specific parts of the brain (ie, the paraventricular nucleus in the hypothalamus) in male animals.
  • the internal time can help the penis to erect and shorten the ejaculation latency and post-ejaculation interval when injected through the central or peripheral.
  • administration of an oxytocin receptor agonist, 8-preservative oxytocin can significantly reduce non-contact penile erection (see, for example, Melis et al., Neuro science Letters 265: 171-174). , 1999).
  • the oxytocin receptor is very similar to the structure of vasopressin receptors (including V1a receptor, V1b receptor, V2 receptor), in which V1a receptor and V2 receptor are mainly expressed in the periphery, which regulate blood pressure and kidney function, respectively.
  • V1b receptor is mainly expressed in the brain and pituitary gland, and controls the release of adrenocorticotropic hormone and ⁇ -endorphin. Therefore, for safety reasons, highly selective OTR agonists are a key issue that must be considered in future development (Alan D. Borthwick. J. Med. Chem. 2010, 53, 6525-6538).
  • OTR antagonists A series of patent applications for OTR antagonists are disclosed, including: WO2005028452, WO2005082866, WO2006077496, WO2006092731, WO2006100588, and WO2006100557.
  • highly selective OTR antagonists remain the focus of development.
  • the inventors designed a compound having a structure represented by the general formula (I), and found that a compound having such a structure has a high selective inhibition effect on OTR.
  • the object of the present invention is to provide a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or In the form of a mixture or a pharmaceutically acceptable salt thereof,
  • Ring A is an aryl or heteroaryl group
  • Ring B is a cycloalkyl or heterocyclic group
  • R 1 is alkyl or cycloalkyl, wherein the alkyl group is optionally selected from the group consisting of alkoxy, halogen, haloalkyl, haloalkoxy, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino Substituted by one or more substituents of nitro, cycloalkyl, heterocyclyl, heterocyclooxy, aryl, heteroaryl and -OR 4 ;
  • R 2 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a heterocyclic group;
  • R 3 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, and a heterocyclic group;
  • R 4 is selected from the group consisting of hydroxyalkyl, cycloalkyl, aryl and heteroaryl;
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, 2, 3 or 4.
  • the compound of the formula (I) is a compound of the formula (II):
  • Ring A, Ring B, R 1 to R 3 , n and m are as defined in the general formula (I).
  • the compound of the formula (I) wherein the ring B is a 3-5 membered cycloalkyl or heterocyclic group; preferably a cyclopropyl group.
  • the compound of the formula (I) or (II) is a compound of the formula (III):
  • Ring A, R 1 to R 3 , n and m are as defined in the general formula (I).
  • the compound of the formula (I) wherein ring A is pyridyl or benzodioxole; preferably or
  • the compound of the formula (I) wherein R 2 is the same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen and an alkyl group.
  • the compounds of the present invention include all conformational isomers thereof, such as cis and trans isomers; and all optical isomers and stereoisomers thereof, and mixtures thereof.
  • the compounds of the invention have asymmetric centers and therefore different enantiomers and diastereomers.
  • the invention relates to the use of the compounds of the invention, and to all pharmaceutical compositions and methods of treatment which may be employed and contained therein.
  • the invention relates to the use of all such isomers and mixtures thereof.
  • Typical compounds of the invention 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.
  • Ring A, Ring B, R 2 , R 3 , n and m are as defined in the general formula (I).
  • the compound represented by the formula (I-A) includes, but is not limited to:
  • Another aspect of the invention relates to a process for the preparation of a compound of formula (I), which process comprises:
  • Ring A, Ring B, R 1 to R 3 , n and m are as defined in the general formula (I).
  • Another aspect of the invention relates to a process for the preparation of a compound of the formula (III) which comprises:
  • a compound of the formula (III-A) and a compound of the formula (I-B) or a hydrochloride thereof are heated under acidic conditions to give a compound of the formula (III).
  • Ring A, R 1 to R 3 , n and m are as defined in the general formula (I).
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesogen, a racemate thereof, Enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also relates to a process for the preparation of the above composition, which comprises the compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer, a non- The enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is admixed with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or A pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for the treatment or prevention of a disease or condition known or capable of exhibiting a beneficial effect of inhibiting oxytocin, wherein the disease or condition is selected from the group consisting of Dysfunction, male sexual dysfunction, female sexual dysfunction, libido, sexual arousal disorder, orgasm disorder, sexual intercourse pain disorder, premature ejaculation, pre-pregnancy delivery, birth complications, appetite and eating disease, benign prostatic hyperplasia, premature delivery , dysmenorrhea, congestive heart failure, arterial hypertension, cirrhosis, renal hypertension, high intraocular pressure, obsessive-compulsive and behavioral disorders and neuropsychiatric diseases, more selectively selected
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for the preparation of a medicament for antagonizing oxytocin.
  • the invention further relates to a method of treating or preventing a disease or condition known or which exhibits a beneficial effect of inhibiting oxytocin, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or An isomer, 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.
  • the present invention further relates to a method for treating or preventing a disease selected from the group consisting of sexual dysfunction, male sexual dysfunction, female sexual dysfunction, libido, sexual arousal disorder, orgasm disorder, sexual pain disorder, premature ejaculation, pre- Prenatal delivery, birth complications, appetite and eating disorders, benign prostatic hyperplasia, premature delivery, dysmenorrhea, congestive heart failure, arterial hypertension, cirrhosis, renal hypertension, high intraocular pressure, obsessive-compulsive and behavioral disorders, and neuropsychiatric
  • the disease preferably sexual dysfunction, sexual arousal disorder, orgasm disorder, sexual intercourse pain disorder and premature ejaculation, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, internal elimination A rot, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • the invention further relates to a method of antagonizing oxytocin comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesogen, racemate, pair thereof a conjugate, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which acts as a drug.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which acts as an oxytocin antagonist.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which is used for treating or preventing a disease selected from the group consisting of sexual dysfunction, male sexual dysfunction, female sexual dysfunction, libido, sexual arousal disorder, Orgasm disorder, sexual intercourse pain disorder, premature ejaculation, pre-pregnancy delivery, birth complications, appetite and eating disorders, benign prostatic hyperplasia, premature delivery, dysmenorrhea, congestive heart failure, arterial hypertension, cirrhosis, renal hypertension, high Intraocular pressure, obsessive-compulsive and behavioral disorders, and neuropsychiatric disorders, preferably arousal disorders, orgasm disorders, sexual intercourse pain disorders, and premature ejaculation.
  • a disease selected from the group consisting of sexual
  • 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.
  • the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
  • the aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • 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.
  • the dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweetening, flavoring, and coloring agents may also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
  • compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase may be a vegetable oil or a mineral oil or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids.
  • the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical 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.
  • the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.
  • 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.
  • any blended fixed oil including synthetic mono- or diglycerides can be used.
  • fatty acids can also be prepared as injections.
  • 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, the behavior of the patient. , 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 modality such as the mode of treatment, the daily dosage of the compound of formula (I) or the 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 of 1 to 20 carbon atoms, preferably an alkyl group having 1 to 12 carbon atoms, more preferably 1 to 6 An alkyl group of carbon atoms.
  • 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, isobutyl, tert-butyl, sec-butyl Base, 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-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl 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 independently selected from alkyl, alkenyl, alkynyl, Alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy Substituted by one or more substituents of cycloalkylthio, heterocycloalkylthio and -OR 4 .
  • 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 10 carbon atoms. One carbon atom, most preferably containing from 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • the group, cyclooctyl group and the like are preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group; and the polycyclic cycloalkyl group includes a spiro ring, a fused ring and a bridged ring 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. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a 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 Base, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio And one or more substituents in -OR 4 are substituted.
  • 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 t (where t is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably contains from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; more preferably the heterocyclic group contains from 3 to 10 ring atoms, and most preferably the heterocyclic group contains from 3 to 6 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, piperidinyl, piperazinyl, morpholinyl, thio?
  • the morphyl group and the homopiperazinyl group and the like are preferably azetidinyl, oxetanyl, pyrrolyl and piperidinyl; and the polycyclic heterocyclic group includes a heterocyclic group of a spiro ring, a fused ring and a bridged ring.
  • 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). ) t (where t is an integer 0 to 2) of a hetero atom, 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 monospirocycloalkyl group and a bispirocycloalkyl 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 bonds, but none of the rings has a completely conjugated ⁇ electron system, wherein one or more ring atoms selected from nitrogen, oxygen, or S (O) t (wherein t is an integer from 0 to 2) heteroatoms, the remaining ring
  • 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) t (where t 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. 7 to 10 yuan.
  • 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, which are independently independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy. , alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Substituted with one or more substituents of alkylthio, heterocycloalkylthio and -OR 4 .
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated pi-electron system, preferably 6 to 10 members, for example, 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, which are independently optionally selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio Substituted by a heterocycloalkylthio group and one or more substituents in -OR 4 .
  • the substituent is preferably one or more of the following groups, which are independently optionally selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano,
  • 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, more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, pyridyl
  • the azole group, the tetrazolyl group and the like are preferably a pyridyl group.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:
  • 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 group, alkylamino group, halogen, thiol, hydroxyl group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkyl sulfide Substituted by a heterocyclic alkylthio group and one or more substituents in -OR 4 .
  • 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, thiol, hydroxy, amino, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Substituted with one or more substituents of alkylthio, heterocycloalkylthio and -OR 4 .
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to -O-(haloalkyl), wherein haloalkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted by one or more deuterium atoms, wherein alkyl is as defined above.
  • deuterated alkoxy refers to -O-(haloalkyl) wherein haloalkyl is as defined above.
  • heterocyclicoxy refers to -O-(heterocyclyl), wherein heterocyclyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is 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 .
  • 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.
  • R 4 is as defined in the formula (I).
  • a method for preparing a medicinal salt comprising the steps of:
  • the compound of the formula (I-1) is subjected to a reduction reaction in the presence of a reducing reagent to obtain a compound of the formula (I-2);
  • the compound of the formula (I-2) is reacted with thionyl chloride to form a compound of the formula (I-3);
  • the compound of the formula (I-3) and the compound of the formula (I-4) are heated to obtain a compound of the formula (I-5);
  • the compound of the formula (I-5) is reacted with a methylating agent under basic conditions to obtain a compound of the formula (I-A);
  • the compound of the formula (I-A) and the compound of the formula (I-B) or a hydrochloride thereof are subjected to ring closure under acidic conditions to give a compound of the formula (I);
  • the reducing reagents include, but are not limited to, lithium aluminum hydride, sodium borohydride, DIBAL-H, NaAlH(Ot-Bu) 3 , AlH 3 , NaCNBH 3 , Na(AcO) 3 BH, B 2 H 5 , Li ( Et) 3 BH, Pd/C/H 2 and Raney Ni/H 2 ;
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, sodium t-butoxide and potassium t-butoxide, the inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, carbonic acid Antimony, sodium hydroxide and lithium hydroxide;
  • the methylating agent includes, but is not limited to, methyl p-toluenesulfonate, methyl iodide, methyl Grignard reagent, dimethyl sulfate, methyl trifluoromethanesulfonate and diazomethane;
  • Agents that provide acidic conditions include, but are not limited to, hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me 3 SiCl, and TMSOT f ;
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two.
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two.
  • Oxy hexacyclohexane water, N,N-dimethylformamide and mixtures thereof;
  • Ring A, Ring B, R 1 to R 3 , n and m are as defined in the general formula (I).
  • a method for preparing a medicinal salt comprising the steps of:
  • the compound of the formula (I-1a) is subjected to a hydrolysis reaction under basic conditions to obtain a compound of the formula (I-2a);
  • the compound of the formula (I-3a) is reacted with a reducing reagent to obtain a compound of the formula (I-3);
  • the compound of the formula (I-3) and the compound of the formula (I-4) are heated to obtain a compound of the formula (I-5);
  • the compound of the formula (I-5) is reacted with a methylating agent under basic conditions to obtain a compound of the formula (I-A);
  • the compound of the formula (I-A) and the compound of the formula (I-B) or a hydrochloride thereof are subjected to ring closure under acidic conditions to give a compound of the formula (I);
  • the reducing reagents include, but are not limited to, lithium aluminum hydride, sodium borohydride, DIBAL-H, NaAlH(Ot-Bu) 3 , AlH 3 , NaCNBH 3 , Na(AcO) 3 BH, BH 3 in tetrahydrofuran solution (1N). ), B 2 H 5 , Li(Et) 3 BH, Pd/C/H 2 and Raney nickel/H 2 ;
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, sodium t-butoxide and potassium t-butoxide, the inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, carbonic acid Antimony, sodium hydroxide and lithium hydroxide;
  • the methylating agent includes, but is not limited to, methyl p-toluenesulfonate, methyl iodide, methyl Grignard reagent, dimethyl sulfate, methyl trifluoromethanesulfonate and diazomethane;
  • Agents that provide acidic conditions include, but are not limited to, hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me 3 SiCl, and TMSOT f ;
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two.
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two.
  • Oxy hexacyclohexane water, N,N-dimethylformamide and mixtures thereof;
  • Ring A, Ring B, R 1 to R 3 , n and m are as defined in the general formula (I).
  • a method for preparing a medicinal salt comprising the steps of:
  • the compound of the formula (III-1) is subjected to a reduction reaction in the presence of a reducing reagent to obtain a compound of the formula (III-2);
  • the compound of the formula (III-2) is reacted with thionyl chloride to form a compound of the formula (III-3);
  • the compound of the formula (III-5) is reacted with a methylating agent under basic conditions to obtain a compound of the formula (III-A);
  • the reducing reagents include, but are not limited to, lithium aluminum hydride, sodium borohydride, DIBAL-H, NaAlH(Ot-Bu) 3 , AlH 3 , NaCNBH 3 , Na(AcO) 3 BH, BH 3 in tetrahydrofuran solution (1N). ), B 2 H 5 , Li(Et) 3 BH, Pd/C/H 2 and Raney nickel/H 2 ;
  • the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. , bis-trimethylsilylamino lithium, potassium acetate, sodium t-butoxide and potassium t-butoxide, the inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, carbonic acid Antimony, sodium hydroxide and lithium hydroxide;
  • the methylating agent includes, but is not limited to, methyl p-toluenesulfonate, methyl iodide, methyl Grignard reagent, dimethyl sulfate, methyl trifluoromethanesulfonate and diazomethane;
  • the reagents providing acidic conditions include, but are not limited to, hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me 3 SiCl, TMSOT f ;
  • the above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two.
  • a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two.
  • Oxycyclohexane water or N,N-dimethylformamide
  • Ring A, R 1 to R 3 , n and m are as defined in the general formula (I).
  • 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).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), 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
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • 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 CombiFlash Rapid Preparer uses the Combiflash Rf200 (TELEDYNE ISCO).
  • 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), the developing agent used for the reaction, the column chromatography eluent system used for the purification of the compound, and the thin layer chromatography developing solvent system including: A: Methylene chloride/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added. Adjustment with alkaline or acidic reagents such as acetic acid.
  • Lithium aluminum hydride (672 mg, 17.7 mmol) was added to 15 mL of tetrahydrofuran, cooled in an ice bath, and the crude 1c (1.33 g, 5.9 mmol) was added. After the addition, the ice bath was removed, the temperature of the reaction was naturally raised to room temperature, and the reaction was stirred for 15 hours. . Water (0.7 mL), sodium hydroxide solution (10%, 0.7 mL) and water (2.1 mL) were successively added to the reaction mixture, and the mixture was stirred and stirred for 30 minutes. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc.
  • Tetrahydropyran-4-ol 2a (1.0 g, 9.8 mmol) was added to 150 mL of tetrahydrofuran, cooled in an ice bath, 1 i (1.96 g, 11.8 mmol) was added, and the reaction was stirred for 30 minutes, then sodium hydride was added ( 352 mg, 14.7 mmol), the ice bath was removed, and the reaction was stirred for 6 hours.
  • Lithium aluminum hydride (336 mg, 8.85 mmol) was added to 10 mL of tetrahydrofuran, cooled in an ice-bath, and the crude product was added 4d (666 mg, 2.95 mmol). After the addition, the ice bath was removed, the temperature of the reaction was naturally raised to room temperature, and the reaction was stirred for 15 hours. Water (0.35 mL), sodium hydroxide solution (10%, 0.35 mL) and water (1 mL) were successively added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc.
  • the crude product 5b (391 mg, 1 mmol) was added to 30 mL of tetrahydrofuran, cooled in ice-cooled, and potassium tert-butoxide (337 mg, 3 mmol) was added, and the reaction was stirred for 2 hours. Further, methyl p-toluenesulfonate (372 mg, 2 mmol) was added, and after completion, the ice bath was removed, the temperature of the reaction mixture was naturally raised to room temperature, and the reaction was stirred for 15 hours.
  • Methyl 2-chloro-4-fluorophenylacetate 8a (2.4 g, 11.8 mmol) and N-bromosuccinimide 8b (2.4 g, 13.5 mmol) and hydrobromic acid (40%, 1 drop) were added.
  • the mixture was heated to 78 ° C and stirred for 18 hours. The heating was stopped, the temperature of the reaction mixture was allowed to cool to room temperature, and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give crude title product 8c (4.3 g).
  • the crude product was added to 10 mL of tetrahydrofuran, cooled in ice-cooled, and potassium t-butoxide (85 mg, 0.74 mmol) was added, and the reaction was stirred for 3 hours. Further, methyl p-toluenesulfonate (155 mg, 0.81 mmol) was added, and after completion, the ice bath was removed, the temperature of the reaction mixture was allowed to rise to room temperature, and the reaction was stirred for 15 hours.
  • Lithium aluminum hydride (210 mg, 5.5 mmol) was added to 8 mL of tetrahydrofuran, and the mixture was cooled in ice-cooled.
  • EtOAc EtOAc EtOAc
  • the reaction mixture was filtered, and the filtrate was evaporated.
  • the crude product 10c (505 mg, 2.2 mmol) was added to 8 mL of methylene chloride, and the mixture was cooled in ice-cooled, thionyl chloride (393 mg, 3.3 mmol) was added, and the mixture was added, the ice bath was removed, and the reaction was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to give the crude title product 10d (300 mg).
  • the crude product 10e (416 mg, 1.1 mmol) was added to 8 mL of tetrahydrofurane, cooled in ice-cooled, and potassium tert-butoxide (449 mg, 4 mmol) was added, and the reaction was stirred for 1 hour. Further, methyl p-toluenesulfonate (410 mg, 2.2 mmol) was added, and after completion, the ice bath was removed, the temperature of the reaction mixture was allowed to rise to room temperature, and the reaction was stirred for 48 hours.
  • Example 2 Using the synthetic route of Example 1, the seventh step compound 1k was replaced with the compound 2-(difluoromethoxy)benzyl acetate 11a (prepared by the method disclosed in the patent application "WO2015180612") to obtain the title compound. 11b (35mg).
  • Test Example 1 Determination of human OTR inhibitory activity of the compound of the present invention
  • Oxytocin (synthesis of Gil Biochemical Co., Ltd.)
  • HEK293 cells (Cat. No. GNHu18, Chinese Academy of Sciences Cell Bank)
  • the pcDNA3.1-hOTR plasmid was used. 3000 transfection reagents were transferred to HEK293 cells; G418 screening was started every other day to select monoclonal cell lines.
  • HEK293/human OTR stable cell lines were seeded in 96-well plates at a density of 25,000 cells/well one day in advance. On the next day, prepare the Fluo-4 dye-containing loading buffer using the reagents in the Fluo-4NW Calcium Assay Kit, then remove the medium and add 100 ⁇ l of Fluo-4 dye-containing loading buffer to each well at 37 °C. , incubate for 30 minutes. After the time, the plate was allowed to equilibrate to room temperature for 10 minutes. The compound was formulated into 10 6 , 10 5 , 10 4 , 10 3 , 10 2 , 10 1 nM, 1 ⁇ l was added to each well, and incubated for 10 minutes at room temperature.
  • IC 50 values of the compounds may employ different fluorescence values corresponding to the concentration, calculated by Graphpad Prism obtained.
  • the human OTR inhibitory activity of the compound of the present invention was measured by the above test, and the measured IC 50 values are shown in Table 1.
  • Test Example 2 Determination of the inhibitory activity of the compound of the present invention against human V1aR
  • the inhibitory effect of the compound of the present invention on the human V1aR protein activity expressed in the HEK293/human V1aR stable cell was determined by the following experimental method:
  • vasopressin Tocris, 2935
  • HEK293 cells (Cat. No. GNHu18, Chinese Academy of Sciences Cell Bank)
  • the pcDNA3.1-V1aR plasmid was used. 3000 transfection reagents were transferred to HEK293 cells; G418 screening was started every other day to select monoclonal cell lines.
  • HEK293/human V1aR stably transformed cells were seeded in 96-well plates at a density of 25,000 cells/well one day in advance. On the next day, prepare the Fluo-4 dye-containing loading buffer using the reagents in the Fluo-4NW Calcium Assay Kit, then remove the medium and add 100 ⁇ l of Fluo-4 dye-containing loading buffer to each well at 37 °C. , incubate for 30 minutes. After the time, the plate was allowed to equilibrate to room temperature for 10 minutes. The compound was formulated into 10 6 , 10 5 , 10 4 , 10 3 , 10 2 , 10 1 nM, 1 ⁇ l was added to each well, and incubated for 10 minutes at room temperature.
  • IC 50 values of the compounds may employ different fluorescence values corresponding to the concentration, calculated by Graphpad Prism obtained.
  • the human V1aR inhibitory activity of the compound of the present invention was measured by the above test, and the measured IC 50 values are shown in Table 2.
  • the compounds of the present invention have weak inhibition on human V1aR activity, indicating selective inhibition of OTR activity.
  • Test Example 3 Determination of the inhibitory activity of the compound of the present invention against human V1bR
  • vasopressin Tocris, 2935
  • HEK293 cells (Cat. No. GNHu18, Chinese Academy of Sciences Cell Bank)
  • the pcDNA3.1-V1bR plasmid was used. 3000 transfection reagent was transferred to HEK293 cells; G418 was added every other day to obtain HEK293/human V1bR pool cell line.
  • HEK293/human V1bR pool cells were seeded in 96-well plates at a density of 25,000 cells/well one day in advance. On the next day, prepare the Fluo-4 dye-containing loading buffer using the reagents in the Fluo-4NW Calcium Assay Kit, then remove the medium and add 100 ⁇ l of Fluo-4 dye-containing loading buffer to each well at 37 °C. , incubate for 30 minutes. After the time, the plate was allowed to equilibrate to room temperature for 10 minutes. The compound was formulated into 10 6 , 10 5 , 10 4 , 10 3 , 10 2 , 10 1 nM, 1 ⁇ l was added to each well, and incubated for 10 minutes at room temperature.
  • IC 50 values of the compounds of fluorescence corresponding to different concentrations can be calculated by Graphpad Prism software to obtain.
  • the human V1bR inhibitory activity of the compound of the present invention was measured by the above test, and the measured IC 50 values are shown in Table 3.
  • Example number IC 50 ( ⁇ M) 1 24.5 3 56.7 4 59.4 6 27.9 7 12.4 8 43.3 9 37.6 11 7.8 12 11.7 14 20.5
  • the compounds of the present invention have no significant inhibitory effect on human V1bR activity, indicating selective inhibition of OTR activity.
  • Test Example 4 Determination of the inhibitory activity of the compound of the present invention against human V2R
  • the inhibitory effect of the compounds of the present invention on the human V2R protein activity expressed in HEK293/human V2R cells was determined by the following experimental method:
  • vasopressin (Tocris, 2935)
  • HEK293 cells (Cat. No. GNHu18, Chinese Academy of Sciences Cell Bank)
  • pcDNA3.1-V2R plasmid used 3000 transfection reagent was transferred to HEK293 cells; G418 was added every other day to obtain HEK293/human V2R pool cell line.
  • HEK293/human V2R pool cells were dissociated from the cell culture dish, the cells were dissociated into individual cells, and the cells were uniformly blown after termination, centrifuged, and the supernatant was used to remove the experimental buffer 1 (1x HBSS+ The cells were resuspended and counted with 20 mM HEPES + 0.1% BSA), and the cell density was adjusted to 1250 cells / 5 ⁇ l, that is, 2.5 * 10 5 /ml.
  • Agonist 460 ⁇ M vasopressin mother liquor, first prepared in DMSO with 2 ⁇ M, and then diluted with Experimental Buffer 2 to a concentration of 0.5 nM.
  • the first point is 20 ⁇ l of stock solution (2848nM), which is 4 times from the second point.
  • Reading plate The PheraStar multi-function microplate reader performs signal reading of HTRF.
  • the human V2R inhibitory activity of the compound of the present invention was measured by the above test, and the measured IC 50 values are shown in Table 4.
  • the compound of the present invention has no obvious inhibitory effect on human V2R activity, indicating selective inhibition of OTR activity.
  • Rats were used as test animals, and the drug concentration in plasma at different times after administration of the compound of Example 6, the compound of Example 8, the compound of Example 9, and the compound of Example 11 by intragastric administration was determined by LC/MS/MS method.
  • the pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
  • a certain amount of the drug was weighed, and 2.5% by volume of DMSO and 97.5% by volume of 10% solutol HS-15 were added to prepare a 0.2 mg/mL clear, clear liquid.
  • the SD rats were intragastrically administered overnight after fasting, and the dose was 2.0 mg/kg, and the administration volume was 10.0 mL/kg.
  • Rats were administered the compound of Example 6, the compound of Example 8, the compound of Example 9, and the compound of Example 11 by gavage 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours before and after administration.
  • 0.2 mL of blood was collected from the eyelids, placed in a heparinized test tube, and the plasma was separated by centrifugation at 3,500 rpm for 10 minutes at 4 ° C, and stored at -20 ° C, and fed 2 hours after the administration.
  • the content of the test compound in the plasma of rats after different doses of the drug was measured: 25 ⁇ L of rat plasma at each time after administration, 50 ⁇ L of camptothecin (100 ng/mL), 200 ⁇ L of acetonitrile, vortex The mixture was vortexed for 5 minutes, centrifuged for 10 minutes (4000 rpm), and plasma samples were taken for 1.0 ⁇ L of the supernatant for LC/MS/MS analysis.
  • the pharmacokinetic parameters of the compounds of the invention are as follows:
  • the compounds of the present invention have better pharmacological absorption and have pharmacokinetic advantages.

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Abstract

涉及氮杂双环基取代的***类衍生物、其制备方法及其在医药上的应用。具体而言，涉及一种通式(I)所示的新的氮杂双环基取代的***类衍生物、其制备方法及其含有该衍生物的药物组合物及其作为治疗剂，特别是作为催产素拮抗剂的用途和在制备用于治疗或预防已知或可显示抑制催产素会产生有益效应的疾病或病症的药物中的用途，其中通式(I)的各取代基与说明书中的定义相同。

Description

氮杂双环基取代的***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，涉及一种新的氮杂双环基取代的***类衍生物、其制备方法及含有该衍生物的药物组合物及其作为治疗剂，特别是作为催产素拮抗剂的用途和在制备用于治疗或预防已知或可显示抑制催产素会产生有益效应的疾病或病症的药物的用途。
背景技术
催产素(oxytocin；OT)是一种环状九肽，通常由下丘脑室旁核合成，并经由脑垂体后叶释放。OT具有广泛的生理功能，包括社会联系、有性生殖、分娩等。OT通过与其特异性受体(oxytocin receptors；OTRs)结合而发挥生理作用。
近年来，已经积累了有力的证据，表明催产素激素在引起哺乳动物特别是人的分娩中起主要的作用。通过“下调”催产素，预期可阻断催产素对子宫的直接(收缩)和间接(增加***素合成)作用。催产素调节剂(如阻断剂或拮抗剂)对于治疗流产可能是有效的。另一种和催产素有关的状况是痛经，其特征为月经期的疼痛和不适。催产素在痛经的原因中起作用，其归因于其作为子宫血管收缩剂的活性(Akerlund et al.,Ann.NY Acad.Sci.734:47-56,1994)。催产素拮抗剂可对此病症具有治疗效应。
文献记载，在男性和女性体内，循环催产素水平会在性刺激和性唤起中增加，且在性高潮中达到最大值。如在Gimpl和Fahrenholz(Physiological Reviews 81(2):629-683,2001)中所详述，催产素经发现为可诱导大鼠，兔子和猴子******的最强力物质的一种。此外，中枢给予催产素据称会缩短到达***的潜伏期及缩短***后间隔。同样地，Meston等人(Arch.Gen.Psychiatry,57(11):1012-30,2000)述及在雄性动物体内，催产素在注射入脑的特定部位(亦即丘脑下部的室旁核)内时可帮助******且经中枢或外周注射时会缩短***潜伏期和***后间隔。本领域中有详细记载，施用催产素受体激动剂，即8-精加压催产素，可明显地减低非接触性******(参见，例如Melis et al.,Neuro science Letters 265:171-174,1999)。
催产素受体与加压素受体(包括V1a受体，V1b受体，V2受体)的结构非常相似，其中V1a受体和V2受体主要在外周表达，分别具有调节血压和肾脏功能。V1b受体主要在脑和下垂体中表达，可控制促肾上腺皮质激素和β-脑内啡的释放。因此，出于安全性的考虑，高选择性OTR激动剂是以后开发中必须考虑的关键问题(Alan D.Borthwick.J.Med.Chem.2010,53,6525–6538)。
目前公开了一系列的OTR拮抗剂的专利申请，其中包括：WO2005028452、WO2005082866、WO2006077496、WO2006092731、WO2006100588和 WO2006100557。但高选择性的OTR拮抗剂仍是开发的重点。经过不断努力，本发明人设计具有通式(I)所示结构的化合物，并发现具有此类结构的化合物对OTR具有高选择性抑制作用。
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，
Figure PCTCN2017118784-appb-000001
其中：
环A为芳基或杂芳基；
环B为环烷基或杂环基；
R 1为烷基或环烷基，其中所述的烷基任选被选自烷氧基、卤素、卤代烷基、卤代烷氧基、氘代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、杂环氧基、芳基、杂芳基和-OR 4中的一个或多个取代基所取代；
R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基；
R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基；
R 4选自羟烷基、环烷基、芳基和杂芳基；
n为0、1、2、3、4或5；且
m为0、1、2、3或4。
在本发明的一个优选的实施方案中，所述的通式(I)所示的化合物为通式(II)所示的化合物：
Figure PCTCN2017118784-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 物形式或其可药用的盐，
环A、环B、R 1～R 3、n和m如通式(I)中所定义。
在本发明的一个优选的实施方案中，所述的通式(I)所示的化合物，其中环B为3-5元的环烷基或杂环基；优选为环丙基。
在本发明的一个优选的实施方案中，所述的通式(I)或(II)所示的化合物为通式(III)所示的化合物：
Figure PCTCN2017118784-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的盐，
其中：
环A、R 1～R 3、n和m如通式(I)中所定义。
在本发明的一个优选的实施方案中，所述的通式(I)所示的化合物，其中环A为吡啶基或苯并间二氧杂环戊烯；优选为
Figure PCTCN2017118784-appb-000004
或
Figure PCTCN2017118784-appb-000005
在本发明的一个优选的实施方案中，所述的通式(I)所示的化合物，其中R 1为烷基或环烷基，其中所述的烷基任选被选自卤素、氰基、烷氧基、卤代烷氧基、氘代烷氧基和杂环氧基中的一个或多个取代基所取代。
在本发明的一个优选的实施方案中，所述的通式(I)所示的化合物，其中R 2相同或不同，且各自独立地选自氢原子、卤素和烷基。
在本发明的一个优选的实施方案中，所述的通式(I)所示的化合物，其中R 3为烷氧基。
在本发明的一个优选的实施方案中，所述的通式(I)所示的化合物，其中n为2；且m为0或1。
本发明的化合物包括其所有构象异构体，例如顺式和反式异构体；以及其所有旋光异构体和立体异构体及其混合物。本发明的化合物具有不对称中心，因此存在不同的对映异构体与非对映异构体。本发明涉及本发明化合物的用途，和可以采用和含有它们的所有药物组合物和治疗方法。本发明涉及所有这类异构体及其混合物的用途。
本发明的典型化合物包括但不限于：
Figure PCTCN2017118784-appb-000006
Figure PCTCN2017118784-appb-000007
Figure PCTCN2017118784-appb-000008
Figure PCTCN2017118784-appb-000009
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。
在本发明的一个优选的实施方案中，一种通式(I-A)所示的化合物，其为制备通式(I)化合物的中间体：
Figure PCTCN2017118784-appb-000010
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：
环A、环B、R 2、R 3、n和m如通式(I)中所定义。
通式(I-A)所示的化合物包括，但不限于：
Figure PCTCN2017118784-appb-000011
Figure PCTCN2017118784-appb-000012
Figure PCTCN2017118784-appb-000013
本发明的另一方面涉及一种制备通式(I)所示的化合物的方法，该方法包括：
Figure PCTCN2017118784-appb-000014
通式(I-A)的化合物和通式(I-B)的化合物或其盐酸盐在酸性条件下，加热反应，得到通式(I)的化合物，
其中：
环A、环B、R 1～R 3、n和m如通式(I)中所定义。
本发明的另一方面涉及一种制备通式(III)所示的化合物的方法，该方法包括：
Figure PCTCN2017118784-appb-000015
通式(III-A)的化合物和通式(I-B)的化合物或其盐酸盐在酸性条件下，加热反应，得到通式(III)的化合物，
其中：
环A、R 1～R 3、n和m如通式(I)中所定义。
本发明的另一方面涉及一种药物组合物，所述药物组合物含有治疗有效剂量的通式(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组合物的方法，其包括将通式(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、或其可药用的盐与一种或多种药学上可接受的载体、稀释剂或赋形剂相混合。
本发明进一步涉及通式(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、或其可药用盐或包含其的药物组合物，在制备用于治疗或预防已知或可显示抑制催产素会产生有益效应的疾病或病症的药物中的用途，其中该疾病或病症选自性功能障碍、男性性功能障 碍、女性性功能障碍、***减退障碍、性唤起障碍、性高潮障碍、***疼痛障碍、早泄、预产前分娩、分娩并发症、食欲和进食疾病、良性***增生、早产、痛经、充血性心力衰竭、动脉高血压、肝硬化、肾性高血压、高眼压、强迫观念与行为障碍和神经精神疾病，更有选地选自性唤起障碍、性高潮障碍、***疼痛障碍和早泄。
本发明进一步涉及通式(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、或其可药用盐或包含其的药物组合物，在制备用于拮抗催产素的药物中的用途。
本发明进一步涉及一种治疗或预防已知或可显示抑制催产素会产生有益效应的疾病或病症的方法，其包括给予所需患者治疗有效量的通式(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、或其可药用盐或包含其的药物组合物。
本发明进一步涉及一种治疗或预防选自下述疾病的方法：性功能障碍、男性性功能障碍、女性性功能障碍、***减退障碍、性唤起障碍、性高潮障碍、***疼痛障碍、早泄、预产前分娩、分娩并发症、食欲和进食疾病、良性***增生、早产、痛经、充血性心力衰竭、动脉高血压、肝硬化、肾性高血压、高眼压、强迫观念与行为障碍和神经精神疾病，优选性功能障碍、性唤起障碍、性高潮障碍、***疼痛障碍和早泄，其包括给予所需患者治疗有效量的通式(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、或其可药用盐或包含其的药物组合物。
本发明进一步涉及一种拮抗催产素的方法，其包括给予所需患者治疗有效量的通式(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、或其可药用盐或包含其的药物组合物。
本发明进一步涉及一种通式(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、或其可药用盐或包含其的药物组合物，其作用药物。
本发明进一步涉及一种通式(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、或其可药用盐或包含其的药物组合物，其作用催产素拮抗剂。
本发明进一步涉及一种通式(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、或其可药用盐或包含其的药物组合物，其用于治疗或预防选自下述的疾病：性功能障碍、男性性功能障碍、女性性功能障碍、***减退障碍、性唤起障碍、性高潮障碍、***疼痛障碍、早泄、预产前分娩、分娩并发症、食欲和进食疾病、良性***增生、早产、痛经、充血性心力衰竭、动脉高血压、肝硬化、肾性高血压、高眼压、强迫观念与行为障碍和神经精神疾病，优选性唤起障碍、性高潮障碍、***疼痛障碍和早泄。
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。
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。水混悬液也可以含有一种或多种防腐剂、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。通过加入抗氧化剂例如抗坏血酸保存这些组合物。
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或其混合物。适宜的乳化剂可以是天然产生的磷脂。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
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。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
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。为此目的，可使用包括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸也可以制备注射剂。
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、患者的行为、患者的饮食、给药时间、给药方式、***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，更优选的是含有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，所述取代基优选独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和-OR 4中的一个或多个取代基所取代。
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10个碳原子，最优选包含3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，优选为环丙基、环丁基、环戊基和环己基；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***。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 PCTCN2017118784-appb-000016
术语“稠环烷基”指5至20元，***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***。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 PCTCN2017118784-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***。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，更有选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2017118784-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。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、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、杂环烷硫基和-OR 4中的一个或多个取代基所取代。
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) t(其中t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；更优选杂环基包含3至10个环原子，最优选为杂环基包含3至6个环原子。单环杂环基的非限制性实例包括氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢吡喃基、吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基和高哌嗪基等，优选为氮杂环丁基、氧杂环丁基、吡咯基和哌啶基；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) t(其中t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***。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元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2017118784-appb-000019
术语“稠杂环基”指5至20元，***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***，其中一个或多个环原子为选自氮、氧或S(O) t(其中t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/3元、5元/4元或5元/5元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2017118784-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***，其中一个或多个环原子为选自氮、氧或S(O) t(其中t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。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 PCTCN2017118784-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 PCTCN2017118784-appb-000022
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，其独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、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、杂环烷硫基和-OR 4中的一个或多个取代基所取代。
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，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 PCTCN2017118784-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，其独立地任选选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、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、杂环烷硫基和-OR 4中的一个或多个取代基所取代。
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，更优选为5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、吡唑基、四唑基等，优选为吡啶基。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 PCTCN2017118784-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、硫醇、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、杂环烷硫基和-OR 4中的一个或多个取代基所取代。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。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、硫醇、羟基、氨基、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、杂环烷硫基和-OR 4中的一个或多个取代基所取代。
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“卤代烷氧基”指-O-(卤代烷基)，其中卤代烷基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“氘代烷氧基”指-O-(氘代烷基)，其中氘代烷基如上所定义。
术语“杂环氧基”指-O-(杂环基)，其中杂环基如上所定义。
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“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”指＝O。
“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地场合。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。
R 4如通式(I)中所定义。
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：
方案一
本发明通式(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，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2017118784-appb-000025
第一步，通式(I-1)的化合物在还原试剂存在下，发生还原反应，得到通式(I-2)的化合物；
第二步，通式(I-2)的化合物和氯化亚砜反应关环，得到通式(I-3)的化合物；
第三步，通式(I-3)的化合物和通式(I-4)的化合物加热反应，得到通式(I-5)的化合物；
第四步，通式(I-5)的化合物在碱性条件下，和甲基化试剂反应，得到通式(I-A)的化合物；
第五步，通式(I-A)的化合物和通式(I-B)的化合物或其盐酸盐在酸性条件下，关环得到通式(I)的化合物；
所述的还原试剂包括但不限于：氢化铝锂、硼氢化钠、DIBAL-H、NaAlH(O-t-Bu) 3、AlH 3、NaCNBH 3、Na(AcO) 3BH、B 2H 5、Li(Et) 3BH、Pd/C/H 2和雷尼镍(Raney Ni)/H 2；
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三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、叔丁醇钠和叔丁醇钾，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、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂；
所述的甲基化试剂包括但不限于：对甲苯磺酸甲酯、碘甲烷、甲基格氏试剂、硫酸二甲酯、三氟甲磺酸甲酯和重氮甲烷；
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、甲磺酸、硝酸、磷酸、对苯甲磺酸、Me 3SiCl和TMSOT f；
上述反应优选在溶剂中进行，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、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物；
其中：
环A、环B、R 1～R 3、n和m如通式(I)中所定义。
方案二
本发明通式(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，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2017118784-appb-000026
第一步，通式(I-1a)的化合物在碱性条件下，发生水解反应，得到通式(I-2a)的化合物；
第二步，通式(I-2a)的化合物和碳酰二胺反应关环，得到通式(I-3a)的化合物；
第三步，通式(I-3a)的化合物和还原试剂反应，得到通式(I-3)的化合物；
第四步，通式(I-3)的化合物和通式(I-4)的化合物加热反应，得到通式(I-5)的化合物；
第五步，通式(I-5)的化合物在碱性条件下，和甲基化试剂反应，得到通式(I-A)的化合物；
第六步，通式(I-A)的化合物和通式(I-B)的化合物或其盐酸盐在酸性条件下，关环得到通式(I)的化合物；
所述的还原试剂包括但不限于：氢化铝锂、硼氢化钠、DIBAL-H、 NaAlH(O-t-Bu) 3、AlH 3、NaCNBH 3、Na(AcO) 3BH、BH 3的四氢呋喃溶液(1N)、B 2H 5、Li(Et) 3BH、Pd/C/H 2和雷尼镍/H 2；
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三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、叔丁醇钠和叔丁醇钾，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、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂；
所述的甲基化试剂包括但不限于：对甲苯磺酸甲酯、碘甲烷、甲基格氏试剂、硫酸二甲酯、三氟甲磺酸甲酯和重氮甲烷；
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、甲磺酸、硝酸、磷酸、对苯甲磺酸、Me 3SiCl和TMSOT f；
上述反应优选在溶剂中进行，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、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺及其混合物；
其中：
环A、环B、R 1～R 3、n和m如通式(I)中所定义。
方案三
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，或其可药用的盐的制备方法，包括以下步骤：
Figure PCTCN2017118784-appb-000027
第一步，通式(III-1)的化合物在还原试剂存在下，发生还原反应，得到通式(III-2) 的化合物；
第二步，通式(III-2)的化合物和氯化亚砜反应关环，得到通式(III-3)的化合物；
第三步，通式(III-3)的化合物和通式(I-4)的化合物加热反应，得到通式(III-5)的化合物；
第四步，通式(III-5)的化合物在碱性条件下，和甲基化试剂反应，得到通式(III-A)的化合物；
第五步，通式(III-A)的化合物和通式(I-B)的化合物或其盐酸盐在酸性条件下，关环得到通式(III)的化合物；
所述的还原试剂包括但不限于：氢化铝锂、硼氢化钠、DIBAL-H、NaAlH(O-t-Bu) 3、AlH 3、NaCNBH 3、Na(AcO) 3BH、BH 3的四氢呋喃溶液(1N)、B 2H 5、Li(Et) 3BH、Pd/C/H 2和雷尼镍/H 2；
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三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、叔丁醇钠和叔丁醇钾，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、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂；
所述的甲基化试剂包括但不限于：对甲苯磺酸甲酯、碘甲烷、甲基格氏试剂、硫酸二甲酯、三氟甲磺酸甲酯和重氮甲烷；
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、甲磺酸、硝酸、磷酸、对苯甲磺酸、Me 3SiCl、TMSOT f；
上述反应优选在溶剂中进行，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、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水或N,N-二甲基甲酰胺；
其中：
环A、R 1～R 3、n和m如通式(I)中所定义。
具体实施方式
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-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，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)。
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
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.)。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
激酶平均抑制率及IC 50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，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/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，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1
(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-((2-氟乙氧基)甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷
Figure PCTCN2017118784-appb-000028
Figure PCTCN2017118784-appb-000029
第一步
(1S)-1-(2-氯-4-氟苯基)-2-(羟甲基)环丙基腈1c
将2-氯-4-氟苯基乙腈1a(1g，5.9mmol)溶解于20mL四氢呋喃中，干冰-丙酮浴冷却至-20℃，缓慢加入双(三甲基硅基)氨基钠(5.9mL，11.8mmol)，加毕，搅拌30分钟，再加入(R)-2-(氯甲基)环氧乙烷1b(600mg，6.49mmol)，加毕，撤去干冰-丙酮浴，反应液温度自然升至室温，搅拌反应2小时。用饱和氯化铵溶液(20mL)淬灭反应，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(50mL×3)，减压浓缩得到粗品标题产物1c(1.35g)，产品不经纯化直接进行下步反应。
MS m/z(ESI):226.4[M+1]。
第二步
((2S)-2-(氨基甲基)-2-(2-氯-4-氟苯基)环丙基)甲醇1d
将氢化锂铝(672mg，17.7mmol)加入到15mL四氢呋喃中，冰浴冷却，加入粗品1c(1.33g，5.9mmol)，加毕，撤去冰浴，反应液温度自然升至室温，搅拌反应15小时。向反应液中依次加入水(0.7mL)、氢氧化钠溶液(10％，0.7mL)和水(2.1mL)，加毕，搅拌30分钟。反应液经硅藻土过滤，滤液减压浓缩，得到粗品标题产物1d(1.4g)，产品不经纯化直接进行下步反应。
MS m/z(ESI):230.3[M+1]。
第三步
(1S,5R)-1-(2-氯-4-氟苯基)-3-氮杂双环[3.1.0]己烷盐酸盐1e
将粗品1d(1.35g，5.9mmol)和氯化亚砜(1.05g，8.85mmol)加入到10mL二氯甲烷中，加毕，搅拌反应3小时。反应液减压浓缩，得到粗品标题产物1e(1.3g)，产品不经纯化直接进行下步反应。
MS m/z(ESI):212.3[M+1]。
第四步
(1S,5R)-1-(2-氯-4-氟苯基)-N-(6-甲氧基吡啶-3-基)-3-氮杂双环[3.1.0]己烷-3-硫代酰
胺1g
将5-异硫氰基-2-甲氧基吡啶1f(1.25g，7.5mmol，采用公知的方法“Bioorganic and Medicinal Chemistry Letters,2010,20(2),516-520”制备而得)和粗品1e(1.06g，5.0mmol)加入到20mL四氢呋喃中，加毕，搅拌反应2小时。反应液减压浓缩，得到粗品标题产物1g(1.9g)，产品不经纯化直接进行下步反应。
MS m/z(ESI):378.2[M+1]。
第五步
(1S,5R,E)-1-(2-氯-4-氟苯基)-N-(6-甲氧基吡啶-3-基)-3-氮杂双环[3.1.0]己烷-3-硫代
亚氨酸甲酯1h
将粗品1g(1.86g，5.0mmol)加入到30mL四氢呋喃中，冰浴冷却，加入叔丁醇钾(2.2g，20mmol)，加毕，搅拌反应2小时。再加入对甲苯磺酸甲酯(1.86g，10.0mmol)，加毕，撤去冰浴，反应液温度自然升至室温，搅拌反应15小时。向反应液中加入冰水(90mL)，用乙酸乙酯萃取(50mL×3)，合并有机相，有机相减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物1h(700mg)，产率：32.2％。
MS m/z(ESI):392.2[M+1]。
第六步
2-(2-氟乙氧基)乙酸乙酯1k
将2-氟乙醇(800mg，12.49mmol)和氢化钠(1.74g，10.42mmol)加入到30mL四氢呋喃中，搅拌2小时，加入2-溴乙酸乙酯1i(1.74g，10.42mmol)，加毕，搅拌反应15小时。向反应液中加入30mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(50mL×3)，减压浓缩，得到粗品标题产物1k(300mg)，产品不经纯化直接进行下步反应。
MS m/z(ESI):151.2[M+1]。
第七步
2-(2-氟乙氧基)乙酰肼1l
将粗品1k(250mg，1.67mmol)和水合肼(85％，213mg)加入到3mL乙醇中，封管，于80℃搅拌15小时。停止加热，反应液减压浓缩，得到粗品标题产物1l(250mg)，产品不经纯化直接进行下步反应。
MS m/z(ESI):137.2[M+1]。
第八步
(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-((2-氟乙氧基)甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷1
将1h(30mg，0.08mmol)、粗品1l(31mg，0.23mmol)和三氟乙酸(9mg，0.08mmol)加入到5mL四氢呋喃中，加毕，加热至65℃搅拌反应1小时。停止加热，反应液减压浓缩，用薄层层析以展开剂体系A纯化所得残余物，得到标题产物1(10mg)，产率：26.4％。
MS m/z(ESI):462.1[M+1]。
1H NMR(400MHz,CDCl 3):δ8.17(s,1H),7.59(d,1H),7.27(d,1H),7.09(d,1H),6.87-6.85(m,2H),4.53(d,1H),4.41(s,3H),3.99(s,3H),3.64-3.62(m,4H),3.42-3.40(m,2H),1.73-1.71(m,1H),0.98-0.95(m,2H)。
实施例2
(1S,5R)-1-(2-氯-4-氟苯基)-3-(4-(6-甲氧基吡啶-3-基)-5-(((四氢-2H-吡喃-4-基)氧基)甲基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷
Figure PCTCN2017118784-appb-000030
第一步
2-((四氢-2H-吡喃-4-基)氧基)乙酸乙酯2b
将四氢吡喃-4-醇2a(1.0g，9.8mmol)加入到150mL四氢呋喃中，冰浴冷却，加入1i(1.96g，11.8mmol)，加毕，搅拌反应30分钟，再加入氢化钠(352mg，14.7mmol)，撤去冰浴，搅拌反应6小时。向反应液中加入30mL冰水，用乙酸乙酯萃取(30mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(50mL×3)，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，得到标题产物2b(1.8g)，产率：87.9％。MS m/z(ESI):189.2[M+1]。
第二步
2-((四氢-2H-吡喃-4-基)氧基)乙酰肼2c
将2b(1.8g，9.6mmol)和水合肼(478mg，9.6mmol)加入到5mL乙醇中，封管，于80℃搅拌48小时。停止加热，反应液减压浓缩，得到粗品标题产物2c(1.6g)，产品不经纯化直接进行下步反应。
MS m/z(ESI):175.0[M+1]。
第三步
(1S,5R)-1-(2-氯-4-氟苯基)-3-(4-(6-甲氧基吡啶-3-基)-5-(((四氢-2H-吡喃-4-基)氧基)甲基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷2
将1h(40mg，0.1mmol)、粗品2c(53mg，0.31mmol)和三氟乙酸(1mg，0.01mmol)加入到10mL四氢呋喃中，加毕，加热至70℃搅拌反应3小时。停止加热，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2(10mg)，产率：18.2％。
MS m/z(ESI):500.1[M+1]。
1H NMR(400MHz,CDCl 3):δ8.19-8.18(d,1H),7.57-7.54(m,1H),7.29-7.25(m,1H),7.10-7.08(m,1H),6.88-6.86(m,2H),4.38(s,2H),4.01(s,3H),3.83-3.75(m,2H),3.69-3.61(m,1H),3.54-3.45(m,1H),3.44-3.30(m,5H),1.82-1.73(m,2H),1.48-1.43(m,2H),0.99-0.97(m,3H)。
实施例3
(1S,5R)-1-(2-氯-4-氟苯基)-3-(4-(6-甲氧基吡啶-3-基)-5-((((S)-四氢呋喃-3-基)氧基)甲基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷
Figure PCTCN2017118784-appb-000031
第一步
(S)-2-((四氢呋喃-3-基)氧基)乙酸乙酯3b
将(S)-3-羟基四氢呋喃3a(4g，45.4mmol)加入到150mL四氢呋喃中，冰浴冷却，加入氢化钠(2.72g，68.1mmol)，搅拌反应30分钟，再加入1i(7.58g，45.4mmol)，加毕，撤去冰浴，搅拌反应6小时。向反应液中加入100mL冰水，用乙酸乙酯萃取(30mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(50mL×3)，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，得到粗品标题产物3b(4.5g)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):175.2[M+1]。
第二步
(S)-2-((四氢呋喃-3-基)氧基)乙酰肼3c
将粗品3b(1g，5.7mmol)和水合肼(287mg，5.7mmol)加入到5mL乙醇中，封管，于80℃搅拌18小时。停止加热，反应液减压浓缩，得到粗品标题产物3c(1.1 g)，产品不经纯化直接进行下步反应。
MS m/z(ESI):161.2[M+1]。
第三步
(1S,5R)-1-(2-氯-4-氟苯基)-3-(4-(6-甲氧基吡啶-3-基)-5-((((S)-四氢呋喃-3-基)氧基)甲基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷3
将1h(50mg，0.13mmol)、粗品3c(31mg，0.19mmol)和三氟乙酸(1mg，0.01mmol)加入到20mL四氢呋喃中，加毕，加热至70℃搅拌反应3小时。停止加热，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3(15mg)，产率：24.2％。
MS m/z(ESI):486.2[M+1]。
1H NMR(400MHz,DMSO-d 6):δ8.20(s,1H),7.60(d,1H),7.31-7.29(m,1H),7.14(d,1H),6.91-6.89(m,2H),4.37(s,2H),4.18-4.17(m,1H),4.05(s,3H),3.81-3.67(m,5H),3.50(d,2H),3.41-3.38(m,1H),1.77-1.63(m,3H),1.02-1.00(m,2H)。
实施例4
(1S,5R)-1-(2-氯-3-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷
Figure PCTCN2017118784-appb-000032
第一步
2-(2-氯-3-氟苯基)乙腈4c
将2-氯-3-氟苄溴4a(1.0g，4.47mmol)加入到10mL的乙腈中，冰浴冷却，将 三甲基氰硅烷4b(532mg，5.37mmol)，加毕，撤去冰浴，反应液温度自然升至室温，搅拌反应15小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物4c(500mg)，产率：65.9％。
MS m/z(ESI):170.2[M+1]。
第二步
(1S)-1-(2-氯-3-氟苯基)-2-(羟甲基)环丙基腈4d
将4c(500mg，2.95mmol)加入10mL四氢呋喃中，冰浴冷却，缓慢加入双(三甲基硅基)氨基钠(1.1g，5.9mmol)，加毕，搅拌1小时，再加入1b(273mg，2.95mmol)，加毕，撤去冰浴，反应液温度自然升至室温，搅拌反应2小时。用饱和氯化铵溶液(20mL)淬灭反应，乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(50mL×3)，减压浓缩得到粗品标题产物4d(670mg)，产品不经纯化直接进行下步反应。
MS m/z(ESI):226.2[M+1]。
第三步
((2S)-2-(氨基甲基)-2-(2-氯-3-氟苯基)环丙基)甲醇4e
将氢化锂铝(336mg，8.85mmol)加入到10mL四氢呋喃中，冰浴冷却，加入粗品4d(666mg，2.95mmol)，加毕，撤去冰浴，反应液温度自然升至室温，搅拌反应15小时。依次向反应液中加入水(0.35mL)，氢氧化钠溶液(10％，0.35mL)和水(1mL)，加毕，搅拌30分钟。反应液经硅藻土过滤，滤液减压浓缩，得到粗品标题产物4e(700mg)，产品不经纯化直接进行下步反应。
MS m/z(ESI):230.3[M+1]。
第四步
(1S,5R)-1-(2-氯-3-氟苯基)-3-氮杂双环[3.1.0]己烷4f
将粗品4e(678mg，2.95mmol)和氯化亚砜(526mg，4.43mmol)加入到10mL二氯甲烷中，加毕，搅拌反应3小时。反应液减压浓缩，得到粗品标题产物4f(600mg)，产品不经纯化直接进行下步反应。
MS m/z(ESI):212.2[M+1]。
第五步
(1S,5R)-1-(2-氯-3-氟苯基)-N-(6-甲氧基吡啶-3-基)-3-氮杂双环[3.1.0]己烷-3-硫代酰
胺4g
将粗品4f(212mg，1mmol)和1f(332mg，2mmol)加入到10mL四氢呋喃中，加毕，搅拌反应2小时。反应液减压浓缩，得到粗品标题产物4g(350mg)，产品不经纯化直接进行下步反应。
MS m/z(ESI):378.3[M+1]。
第六步
(1S,5R,E)-1-(2-氯-3-氟苯基)-N-(6-甲氧基吡啶-3-基)-3-氮杂双环[3.1.0]己烷-3-硫代
亚氨酸甲酯4h
将粗品4g(378mg，1mmol)加入到10mL四氢呋喃中，冰浴冷却，加入叔丁醇钾(337mg，3mmol)，加毕，搅拌反应1小时。再加入对甲苯磺酸甲酯(372mg，2mmol)，加毕，撤去冰浴，反应液温度自然升至室温，搅拌反应15小时。向反应液中加入冰水(30mL)，用乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(50mL×3)，减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物4h(200mg)，产率：45.9％。
MS m/z(ESI):392.3[M+1]。
第七步
(1S,5R)-1-(2-氯-3-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷4
将4h(392mg，1mmol)、甲氧基乙酰肼4i(521mg，5mmol)和三氟乙酸(114mg，1mmol)加入到5mL四氢呋喃中，加毕，加热至70℃搅拌反应3小时。停止加热，反应液减压浓缩，用薄层层析以展开剂体系A纯化所得残余物，得到标题产物4(30mg)，产率：6.5％。
MS m/z(ESI):430.2[M+1]。
1H NMR(400MHz,CDCl 3):δ8.16(s,1H),7.56(d,1H),7.27(d,1H),7.14(d,2H),6.85(d,1H),4.27(s,2H),3.99(s,3H),3.65(d,1H),3.47(d,2H),3.36(d,1H),3.27(s,3H),1.77-1.75(m,1H),1.01-0.99(m,2H)。
实施例5
(1S,5R)-3-(4-(苯并[d][1,3]二氧戊环-5-基)-5-(甲氧基甲基)-4H-1,2,4-***3-基)-1-(2-氯-4-氟苯基)-3-氮杂双环[3.1.0]己烷
Figure PCTCN2017118784-appb-000033
第一步
(1S,5R)-N-(苯并[d][1,3]二氧戊环-5-基)-1-(2-氯-4-氟苯基)-3-氮杂双环[3.1.0]己烷-3-硫代酰胺5b
将苯并[d][1,3]二氧戊环-5-基-异硫氰酸酯5a(311mg，1.74mmol，采用公知的方法“Journal of Medicinal Chemistry,2015,58(3),1123-1139”制备而得)和粗品1e(245mg，1.16mmol)加入到10mL四氢呋喃中，加毕，搅拌反应2小时。反应液 减压浓缩，得到粗品标题产物5b(450mg)，产品不经纯化直接进行下步反应。MS m/z(ESI):391.2[M+1]。
第二步
(1S,5R,E)-N-苯并[d][1,3]二氧戊环-5-基-1-(2-氯-4-氟苯基)-3-氮杂双环[3.1.0]己烷-3-硫代亚氨酸甲酯5c
将粗品5b(391mg，1mmol)加入到30mL四氢呋喃中，冰浴冷却，加入叔丁醇钾(337mg，3mmol)，加毕，搅拌反应2小时。再加入对甲苯磺酸甲酯(372mg，2mmol)，加毕，撤去冰浴，反应液温度自然升至室温，搅拌反应15小时。向反应液中加入冰水(80mL)，用乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(50mL×3)，减压浓缩，用薄层层析以展开剂体系A纯化所得残余物，得到标题产物5c(150mg)，产率：33.3％。
MS m/z(ESI):405.3[M+1]。
第三步
(1S,5R)-3-(4-(苯并[d][1,3]二氧戊环-5-基)-5-(甲氧基甲基)-4H-1,2,4-***3-基)-1-(2-氯-4-氟苯基)-3-氮杂双环[3.1.0]己烷5
将5c(80mg，0.2mmol)、4i(103mg，0.99mmol)和三氟乙酸(23mg，0.2mmol)加入到5mL四氢呋喃中，加毕，加热至70℃搅拌反应3小时。停止加热，反应液减压浓缩，用薄层层析以展开剂体系A纯化所得残余物，得到标题产物5(20mg)，产率：21.7％。
MS m/z(ESI):443.3[M+1]。
1H NMR(400MHz,CDCl 3):δ7.27(t,1H),7.09(d,1H),6.88(d,2H),6.81(d,2H),6.10(s,2H),4.28(s,2H),3.65(d,1H),3.47(d,2H),3.34(d,1H),3.32(s,3H),1.72-1.69(m,1H),1.01-0.99(m,2H)。
实施例6
(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-(乙氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷6
Figure PCTCN2017118784-appb-000034
将1h(40mg，0.1mmol)、2-乙氧基乙酰肼6a(60mg，0.51mmol)和三氟乙酸 (12mg，0.1mmol)加入到5mL四氢呋喃中，加毕，加热至70℃搅拌反应3小时。停止加热，反应液减压浓缩，用薄层层析以展开剂体系A纯化所得残余物，得到标题产物6(10mg)，产率：20.3％。
MS m/z(ESI):444.2[M+1]。
1H NMR(400MHz,CDCl 3):δ8.15(s,1H),7.56(d,1H),7.27(d,1H),7.08(d,1H),7.05(d,1H),6.86(d,1H),4.31(s,2H),3.99(s,3H),3.62-3.60(m,1H),3.45-3.42(m,4H),3.35(d,1H),1.72-1.70(m,1H),1.09(t,3H),0.97-0.95(m,2H)。
实施例7
(1S,5R)-1-(2-氯-4-氟苯基)-3-(4-(6-甲氧基吡啶-3-基)-5-甲基-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷7
Figure PCTCN2017118784-appb-000035
将1h(80mg，0.2mmol)、乙酰肼7a(76mg，1.02mmol)和三氟乙酸(23mg，0.2mmol)加入到5mL四氢呋喃中，加毕，加热至70℃搅拌反应3小时。停止加热，反应液减压浓缩，用薄层层析以展开剂体系A纯化所得残余物，得到标题产物7(25mg)，产率：28.3％。
MS m/z(ESI):400.2[M+1]。
1H NMR(400MHz,CDCl 3):δ8.08(s,1H),7.46(d,1H),7.27(d,1H),7.07(d,1H),688-6.86(m,2H),4.00(s,3H),3.64(d,1H),3.36-3.34(m,3H),2.15(s,3H),1.71-1.69(m,1H),0.99-0.96(m,2H)。
实施例8
1-(2-氯-4-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷8
Figure PCTCN2017118784-appb-000036
Figure PCTCN2017118784-appb-000037
第一步
2-溴-2-(2-氯-4-氟苯基)乙酸甲酯8c
将2-氯-4-氟苯乙酸甲酯8a(2.4g，11.8mmol)和N-溴代丁二酰亚胺8b(2.4g，13.5mmol)和氢溴酸(40％，1滴)加入到25mL四氯化碳中，加毕，加热至78℃，搅拌反应18小时。停止加热，反应液温度自然冷却至室温，过滤反应液，滤液减压浓缩，得到粗品标题产物8c(4.3g)，产品不经纯化直接进行下步反应。
MS m/z(ESI):280.3[M+1]。
第二步
1-(2-氯-4-氟苯基)环丙烷-1,2-二甲酸二甲酯8d
将粗品8c(4.3g，15mmol)和丙烯酸甲酯(2mL，22mmol)加入到20.4mL***和乙醇的混合溶剂中(V:V＝50:1)备用，将氢化钠(720mg，18mmol)加入到50.5mL***和乙醇的混合溶剂中(V:V＝100:1)，再加入上述溶液，搅拌反应23小时。向反应液中加入80mL水淬灭反应，用乙酸乙酯萃取(50mL×3)，合并有机相，有机相减压浓缩，得到粗品标题产物8d(4g)，产品不经纯化直接进行下步反应。MS m/z(ESI):287.3[M+1]。
第三步
1-(2-氯-4-氟苯基)环丙烷-1,2-二甲酸8e
将粗品8d(4g，14mmol)加入到60mL乙醇和水的混合溶剂中(V:V＝1:1)，加入氢氧化钾(3g，53.5mmol)，加毕，加热至65℃，搅拌反应15小时。停止加热，反应液温度自然冷却至室温，用乙酸乙酯萃取(50mL×3)，滴加2N的盐酸至水相的pH为2-3，用乙酸乙酯萃取(50mL×3)，合并有机相，有机相减压浓缩，得到粗品标题产物8e(1.9g)，产品不经纯化直接进行下步反应。
MS m/z(ESI):257.2[M-1]。
第四步
1-(2-氯-4-氟苯基)-3-氮杂双环[3.1.0]己烷-2,4-二酮8f
将粗品8e(1.9g，7.5mmol)和碳酰二胺(1.35g，22.5mmol)加入到20mL的1,4-二甲苯中，加毕，加热至120℃，搅拌反应18小时。停止加热，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8f(110mg)，产率：6.1％。MS m/z(ESI):240.2[M+1]。
第五步
1-(2-氯-4-氟苯基)-3-氮杂双环[3.1.0]己烷8g
将8f(100mg，0.37mmol)和硼烷的四氢呋喃溶液(1N，2mL)加入到5mL四氢呋喃中，加毕，搅拌反应15小时，再加热至60℃，搅拌反应1小时，加入盐酸(6N，2mL)，搅拌反应15分钟，停止加热，反应液减压蒸除四氢呋喃，滴加5N的氢氧化钠溶液至反应液pH至12，搅拌15分钟，用乙酸乙酯萃取(20mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(15mL×2)，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，得到粗品标题产物8g(90mg)，产品不经纯化直接进行下步反应。
MS m/z(ESI):212.2[M+1]。
第六步
1-(2-氯-4-氟苯基)-N-(6-甲氧基吡啶-3-基)-3-氮杂双环[3.1.0]己烷-3-硫代酰胺8h
将粗品8g(90mg，0.37mmol)和1f(90mg，0.55mmol)加入到5mL四氢呋喃中，加毕，加热至50℃，搅拌反应18小时。反应液减压浓缩，得到粗品标题产物8h(140mg)，产品不经纯化直接进行下步反应。
MS m/z(ESI):378.3[M+1]。
第七步
(E)-1-(2-氯-4-氟苯基)-N-(6-甲氧基吡啶-3-基)-3-氮杂双环[3.1.0]己烷-3-硫代亚氨
酸甲酯8i
将粗品8h(140mg，0.37mmol)加入到10mL四氢呋喃中，冰浴冷却，加入叔丁醇钾(85mg，0.74mmol)，加毕，搅拌反应3小时。再加入对甲苯磺酸甲酯(155mg，0.81mmol)，加毕，撤去冰浴，反应液温度自然升至室温，搅拌反应15小时。向反应液中加入冰水(20mL)，用乙酸乙酯萃取(30mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(20mL×2)，无水硫酸钠干燥，过滤除去干燥剂，滤液减压浓缩，用薄层层析以展开剂体系C纯化所得残余物，得到标题产物8i(50mg)，产率：34.4％。
MS m/z(ESI):392.3[M+1]。
第八步
1-(2-氯-4-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-***-3-基)-3-
氮杂双环[3.1.0]己烷8
将8i(50mg，0.17mmol)、4i(88mg，0.85mmol)和2滴三氟乙酸加入到5mL 四氢呋喃中，加毕，加热至70℃搅拌反应2小时。停止加热，反应液减压浓缩，用薄层层析以展开剂体系A纯化所得残余物，得到标题产物8(8mg)，产率：10.9％。MS m/z(ESI):430.2[M+1]。
1H NMR(400MHz,CDCl 3):δ8.17(s,1H),7.56(d,1H),7.27(d,1H),7.10(d,1H),6.91-6.88(m,2H),4.28(s,2H),4.01(s,3H),3.64(d,1H),3.46(d,2H),3.43(d,1H),3.28(s,3H),1.73-1.70(m,1H),1.01-0.98(m,2H)。
实施例9
(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷9
Figure PCTCN2017118784-appb-000038
将1h(180mg，0.46mmol)、4i(239mg，2.3mmol)和三氟乙酸(52mg，0.46mmol)加入到8mL四氢呋喃中，加毕，加热至70℃搅拌反应3小时。停止加热，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9(50mg)，产率：24.21％。
MS m/z(ESI):430.2[M+1]。
1H NMR(400MHz,CDCl 3):δ8.22(s,1H),7.66(d,1H),7.27(t,1H),7.10(d,1H),6.91-6.89(m,2H),4.24(s,2H),4.01(s,3H),3.78(d,1H),3.57-3.55(m,2H),3.53(d,1H),3.25(s,3H),1.81-1.79(m,1H),1.10(t,1H),0.95(t,1H)。
实施例10
(1R,5S)-1-(2-氯-4-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷10
Figure PCTCN2017118784-appb-000039
Figure PCTCN2017118784-appb-000040
第一步
(1R)-1-(2-氯-4-氟苯基)-2-(羟甲基)环丙基腈10b
将1a(1g，5.9mmol)溶解于8mL四氢呋喃中，干冰-丙酮浴冷却至-20℃，缓慢加入双(三甲基硅基)氨基钠(2.2g，11.8mmol)，加毕，搅拌30分钟，再加入(S)-2-(氯甲基)环氧乙烷10a(600mg，6.49mmol)，加毕，撤去干冰-丙酮浴，反应液温度自然升至室温，搅拌反应3小时。用饱和氯化铵溶液(20mL)淬灭反应，乙酸乙酯萃取(50mL×3)，合并有机相，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步反应。
MS m/z(ESI):226.3[M+1]。
第二步
((2R)-2-(氨基甲基)-2-(2-氯-4-氟苯基)环丙基)甲醇10c
将氢化锂铝(210mg，5.5mmol)加入到8mL四氢呋喃中，冰浴冷却，加入粗品10b(500mg，2.22mmol)，加毕，撤去冰浴，反应液温度自然升至室温，搅拌反应15小时。依次向反应液中加入水(0.25mL)，氢氧化钠溶液(2N，0.25mL)和水(0.75mL)淬灭反应。反应液过滤，滤液减压浓缩，得到粗品标题产物10c(300mg)，产品不经纯化直接进行下步反应。
MS m/z(ESI):230.3[M+1]。
第三步
(1R,5S)-1-(2-氯-4-氟苯基)-3-氮杂双环[3.1.0]己烷10d
将粗品10c(505mg，2.2mmol)加入到8mL二氯甲烷中，冰浴冷却，加入氯化亚砜(393mg，3.3mmol)，加毕，撤去冰浴，搅拌反应3小时。反应液减压浓缩，得到粗品标题产物10d(300mg)，产品不经纯化直接进行下步反应。
MS m/z(ESI):212.2[M+1]。
第四步
(1R,5S)-1-(2-氯-4-氟苯基)-N-(6-甲氧基吡啶-3-基)-3-氮杂双环[3.1.0]己烷-3-硫代酰胺10e
将1f(366mg，2.2mmol)和粗品10d(233mg，1.1mmol)加入到8mL四氢呋喃中，加毕，搅拌反应3小时。反应液减压浓缩，得到粗品标题产物10e(260mg)， 产品不经纯化直接进行下步反应。
MS m/z(ESI):378.2[M+1]。
第五步
(1R,5S,E)-1-(2-氯-4-氟苯基)-N-(6-甲氧基吡啶-3-基)-3-氮杂双环[3.1.0]己烷-3-硫代亚氨酸甲酯10f
将粗品10e(416mg，1.1mmol)加入到8mL四氢呋喃中，冰浴冷却，加入叔丁醇钾(449mg，4mmol)，加毕，搅拌反应1小时。再加入对甲苯磺酸甲酯(410mg，2.2mmol)，加毕，撤去冰浴，反应液温度自然升至室温，搅拌反应48小时。向反应液中加入冰水(20mL)，用乙酸乙酯萃取(50mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(50mL×3)，减压浓缩，用薄层层析以展开剂体系A纯化所得残余物，得到标题产物10f(300mg)，产率：62.6％。
MS m/z(ESI):392.3[M+1]。
第六步
(1R,5S)-1-(2-氯-4-氟苯基)-3-(5-(甲氧基甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷10
将10f(100mg，0.26mmol)、4i(133mg，1.28mmol)和三氟乙酸(29mg，0.26mmol)加入到5mL四氢呋喃中，加毕，加热至70℃搅拌反应3小时。停止加热，反应液减压浓缩，所得残余物用薄层层析以展开剂体系A纯化，再用高效液相色谱法纯化，得到标题产物10(10mg)，产率：9.0％。
MS m/z(ESI):430.2[M+1]。
1H NMR(400MHz,CDCl 3):δ8.16(s,1H),7.56(d,1H),7.27(d,1H),7.09(d,1H),6.87-6.85(m,2H),4.27(s,2H),4.00(s,3H),3.66(d,1H),3.45(d,2H),3.36(d,1H),3.27(s,3H),1.72-1.70(m,1H),0.98-0.96(m,2H)。
实施例11
(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-((二氟甲氧基)甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷11
Figure PCTCN2017118784-appb-000041
Figure PCTCN2017118784-appb-000042
第一步
2-(二氟甲氧基)乙酰肼11b
采用实施例1的合成路线，将第七步化合物1k替换为化合物2-(二氟甲氧基)乙酸苄基酯11a(采用专利申请“WO2015180612”公开的方法制备而得)，制得标题化合物11b(35mg)。
第二步
(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-((二氟甲氧基)甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷11
采用实施例1的合成路线，将第八步化合物1l替换为化合物11b，制得标题化合物11(20mg)，产率：6.6％。
MS m/z(ESI):466.4[M+1]。
1H NMR(400MHz,CD 3OD)δ8.29(d,1H),7.79(dd,1H),7.43(dd,1H),7.22(dd,1H),7.04(td,1H),7.00(d,1H),6.35(t,1H),4.78(s,2H),4.01(s,3H),3.66(dd,1H),3.50(d,1H),3.40(d,1H),3.35(d,1H),1.88-1.82(m,1H),1.06-0.98(m,2H)。
实施例12
(1S,5R)-1-(2-氯-4-氟苯基)-3-(4-(6-甲氧基吡啶-3-基)-5-(三氟甲基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷12
Figure PCTCN2017118784-appb-000043
采用实施例1的合成路线，将第八步化合物1l替换为化合物2,2,2-三氟乙酰肼 (上海毕得医药科技有限公司)，制得标题化合物12(30mg)，产率：51％。
MS m/z(ESI):454.4[M+1]。
1H NMR(400MHz,CD 3OD)δ8.35(s,1H),7.87(d,1H),7.44(dd,1H),7.23(dd,1H),7.04(td,1H),7.00(d,1H),4.02(s,3H),3.70(dd,1H),3.54(d,1H),3.43(d,1H),3.38(d,1H),1.89-1.84(m,1H),1.07(dd,1H),0.98(t,1H)。
实施例13
(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-(二氟甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷13
Figure PCTCN2017118784-appb-000044
采用实施例1的合成路线，将第八步化合物1l替换为化合物2,2-二氟乙酰肼(采用专利申请“US6979686”公开的方法制备而得)，制得标题化合物13(12mg)，产率：10.8％。
MS m/z(ESI):436.1[M+1]。
1H NMR(400MHz,CDCl 3)δ8.21(s,1H),7.81(d,1H),7.35(m,1H),7.18-7.04(m,1H),6.99-6.79(m,2H),6.78-6.52(m,1H),4.02(s,3H),3.70(dd,1H),3.49-3.42(m,2H),3.41(d,1H),1.89-1.82(m,1H),1.07(dd,1H),0.98(t,1H)。
实施例14
(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-((甲氧基-d 3)甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷14
Figure PCTCN2017118784-appb-000045
第一步
(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-(羟甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-***-3- 基)-3-氮杂双环[3.1.0]己烷14a
采用实施例1的合成路线，将第八步化合物1l替换为化合物2-羟基乙酰肼(采用专利申请“WO2008051493”公开的方法制备而得)，制得标题化合物14a(90mg)，产率：68％。
MS m/z(ESI):416.4[M+1]。
1H NMR(400MHz,CD 3OD)δ8.29(d,1H),7.80(dd,1H),7.42(dd,1H),7.22(dd,1H),7.03(td,1H),6.99(d,1H),4.42(s,2H),4.02(s,3H),3.64(dd,1H),3.47(d,1H),3.38(d,1H),3.34(d,1H),1.87-1.80(m,1H),1.01(d,2H)。
第二步
(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-((甲氧基-d 3)甲基)-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷14
将14a(90mg，0.22mmol)，N,N-二甲基甲酰胺(5mL)加入反应瓶中，氩气保护，冰浴下加入氢化钠(16mg，0.65mmol)，搅拌反应10分钟，加入氘代碘甲烷(156mg，1.08mmol)，升至室温反应3小时。加水15mL，乙酸乙酯萃取(10mL×3)，合并有机相，无水硫酸钠干燥，减压浓缩，用硅胶柱色谱法以洗脱剂体系C纯化所得残余物，得到标题产物14(10mg)，产率：10.8％。
MS m/z(ESI):433.2[M+1]。
1H NMR(400MHz,CDCl 3)δ8.17(d,1H),7.56(d,1H),7.28(t,1H),7.09(d,1H),6.87(d,1H),6.85(d,1H),4.27(s,2H),4.00(s,3H),3.67(d,1H),3.46(d,2H),3.36(d,1H),1.73-1.70(m,1H),0.98-0.95(m,2H)。
实施例15
(1S,5R)-1-(2-氯-4-氟苯基)-3-(4-(6-甲氧基吡啶-3-基)-5-((((R)-四氢呋喃-3-基)氧基)甲基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷15
Figure PCTCN2017118784-appb-000046
采用实施例3的合成路线，将第一步化合物3a替换为(R)-3-羟基四氢呋喃(上海毕得医药科技有限公司)，制得标题化合物15(30mg)，产率：13.2％。
MS m/z(ESI):486.4[M+1]。
1H NMR(400MHz,CD 3OD)δ8.20(d,1H),7.59(dd,1H),7.32-7.28(m,1H),7.14(dd,1H),7.11(td,1H),6.98(d,1H),4.40-4.33(m,2H)4.17-4.15(m,1H),4.03(s,3H),3.81-3.79(m,2H),3.68-3.65(m,3H),3.50(d,2H),3.40(d,1H),1.98-1.90(m,1H),1.89-1.81(m,1H),1.79-1.74(m,1H),1.02-0.92(m,2H)。
实施例16
(1S,5R)-1-(2-氯-4-氟苯基)-3-(4-(6-甲氧基吡啶-3-基)-5-氰基甲基-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷16
Figure PCTCN2017118784-appb-000047
采用实施例1的合成路线，将第八步化合物1l替换为2-氰基乙酰肼(上海毕得医药科技有限公司)，制得标题化合物16(30mg)，产率：24.3％。
MS m/z(ESI):425.4[M+1]。
1H NMR(400MHz,CD 3OD)δ8.21(d,1H),7.63(dd,1H),7.33-7.30(m,1H),7.15(dd,1H),7.00(d,1H),6.98(td,1H),4.06(s,3H),3.72-3.69(m,3H),3.49(d,2H),3.42(d,1H),1.80-1.76(m,1H),1.06-0.98(m,2H)。
实施例17
(1S,5R)-1-(2-氯-4-氟苯基)-3-(5-环丙基-4-(6-甲氧基吡啶-3-基)-4H-1,2,4-***-3-基)-3-氮杂双环[3.1.0]己烷17
Figure PCTCN2017118784-appb-000048
采用实施例1的合成路线，将第八步化合物1l替换为2-环丙基甲酰肼(上海毕得医药科技有限公司)，制得标题化合物17(30mg)，产率：27.5％。
MS m/z(ESI):426.2[M+1]。
1H NMR(400MHz,CD 3OD)δ8.24(d,1H),7.67(dd,1H),7.30-7.25(m,1H),7.17(dd,1H),6.94(d,1H),6.90(td,1H),4.06(s,3H),3.75(dd,1H),3.55-3.47(m,2H),3.45(d,1H),1.79-1.72(m,1H),1.43-1.36(m,1H),1.15-1.10(m,2H),1.06-0.96(m,2H),0.89-0.86(m,2H)。
测试例：
生物学评价
测试例1、本发明化合物对人源OTR抑制活性的测定
本发明化合物对HEK293/人源OTR稳转株细胞中所表达人源的OTR蛋白活性的抑制作用采用如下实验方法测定：
一、实验材料及仪器
1.Fluo-4NW钙分析试剂盒(F36206，invitrogen)
2.MEM(Hyclone，SH30024.01B)
3.G418硫酸盐(Enzo，ALX-380-013-G005)
4.胎牛血清(GIBCO,10099)
5.丙酮酸钠溶液(sigma，S8636-100ML)
6.MEM非必需氨基酸溶液(100×)(sigma，M7145-100ML)
7.Flexstation 3多功能酶标仪(Molecular Devices)
8.多聚-D-赖氨酸96孔板，黑色/干净(356692，BD)
9.催产素(吉尔生化有限公司合成)
10.pcDNA3.1(invitrogen，V79020)
11.pcDNA3.1-hOTR(NM-000916)(金唯智生物技术有限公司合成并构建入pcDNA3.1质粒)
12.HEK293细胞(货号GNHu18，中科院细胞库)
二、实验步骤
将pcDNA3.1-hOTR质粒，用
Figure PCTCN2017118784-appb-000049
3000转染试剂转入HEK293细胞；隔天开始加G418筛选，挑选单克隆细胞系。
提前一天将HEK293/人源OTR稳转株细胞以25000个/孔的密度种于96孔板中。第二天，先使用Fluo-4NW钙分析试剂盒中的试剂配制含Fluo-4染料的上样缓冲液，再去除培养基，每孔加入100μl含Fluo-4染料的上样缓冲液，37℃，孵育30分钟。到时间后，把板子移至室温环境平衡10分钟。将化合物配成10 6、10 5、10 4、10 3、10 2、10 1nM，每孔加入1μl，室温孵育10分钟。用flexstation 3酶标仪进行检测，由机器自动加入3nM的催产素多肽50μl，立刻在494/516nM处读值。化合物的IC 50值可采用不同浓度对应的荧光值，经Graphpad Prism计算得到。
本发明化合物对人源OTR抑制活性通过以上的试验进行测定，测得的IC 50值见表1。
表1本发明化合物对人源OTR活性抑制的IC 50。
实施例编号 IC 50(nM)
1 44
4 29
5 131
6 4.3
8 23
9 14
10(对照) 624
11 1
12 30
13 52
14 68
结论：本发明化合物对人源OTR活性具有明显的抑制效果。
测试例2、本发明化合物对人源V1aR抑制活性的测定
本发明化合物对HEK293/人源V1aR稳转株细胞中所表达人源的V1aR蛋白活性的抑制作用采用如下实验方法测定：
一、实验材料及仪器
1.Fluo-4NW钙分析试剂盒(F36206，invitrogen)
2.MEM(Hyclone，SH30024.01B)
3.G418硫酸盐(Enzo，ALX-380-013-G005)
4.胎牛血清(GIBCO,10099)
5.丙酮酸钠溶液(sigma，S8636-100ML)
6.MEM非必需氨基酸溶液(100×)(sigma，M7145-100ML)
7.Flexstation 3多功能酶标仪(Molecular Devices)
8.多聚-D-赖氨酸96孔板，黑色/干净(356692，BD)
9.加压素(Tocris,2935)
10.pcDNA3.1(invitrogen，V79020)
11.pcDNA3.1-V1aR(NM-000706)(金唯智生物技术有限公司合成并构建入pcDNA3.1质粒)
12.HEK293细胞(货号GNHu18，中科院细胞库)
二、实验步骤
将pcDNA3.1-V1aR质粒，用
Figure PCTCN2017118784-appb-000050
3000转染试剂转入HEK293细胞；隔天开始加G418筛选，挑选单克隆细胞系。
提前一天将HEK293/人源V1aR稳转株细胞以25000个/孔的密度种于96孔板中。第二天，先使用Fluo-4NW钙分析试剂盒中的试剂配制含Fluo-4染料的上样缓冲液，再去除培养基，每孔加入100μl含Fluo-4染料的上样缓冲液，37℃，孵育30分钟。到时间后，把板子移至室温环境平衡10分钟。将化合物配成10 6、10 5、10 4、10 3、10 2、10 1nM，每孔加入1μl，室温孵育10分钟。用flexstation 3酶标仪进行检测，由机器自动加入3nM的加压素多肽50μl，立刻在494/516nM处读值。化合物的IC 50值可采用不同浓度对应的荧光值，经Graphpad Prism计算得到。
本发明化合物对人源V1aR抑制活性通过以上的试验进行测定，测得的IC 50值见表2。
表2本发明化合物对人源V1aR活性抑制的IC 50
实施例编号 IC 50(μM)
1 1
2 4.7
3 7.5
4 3.8
5 1
6 1.7
7 2.0
8 3.0
9 2.9
12 3.6
13 1.9
结论：本发明化合物对人源V1aR活性抑制弱，说明对OTR活性具有选择性抑制作用。
测试例3、本发明化合物对人源V1bR抑制活性的测定
本发明化合物对HEK293/人源V1bR细胞中所表达人源的V1bR蛋白活性的抑制作用采用如下实验方法测定：
一、实验材料及仪器
1.Fluo-4NW钙分析试剂盒(F36206,invitrogen)
2.MEM(Hyclone，SH30024.01B)
3.G418硫酸盐(Enzo，ALX-380-013-G005)
4.胎牛血清(GIBCO,10099)
5.丙酮酸钠溶液(sigma，S8636-100ML)
6.MEM非必需氨基酸溶液(100×)(sigma，M7145-100ML)
7.Flexstation 3多功能酶标仪(Molecular Devices)
8.Poly-D-Lysine 96-well Microplates,black/clear(356692，BD)
9.加压素(Tocris,2935)
10.pcDNA3.1(invitrogen，V79020)
11.pcDNA3.1-V1bR(NM-000706)(金唯智生物技术有限公司合成并构建入pcDNA3.1质粒)
12.HEK293细胞(货号GNHu18，中科院细胞库)
二、实验步骤
将pcDNA3.1-V1bR质粒，用
Figure PCTCN2017118784-appb-000051
3000转染试剂转入HEK293细胞；隔天开始加G418，得到HEK293/人源V1bR pool细胞系。
提前一天将HEK293/人源V1bR pool细胞以25000个/孔的密度种于96孔板中。第二天，先使用Fluo-4NW钙分析试剂盒中的试剂配制含Fluo-4染料的上样缓冲液，再去除培养基，每孔加入100μl含Fluo-4染料的上样缓冲液，37℃，孵育30 分钟。到时间后，把板子移至室温环境平衡10分钟。将化合物配成10 6、10 5、10 4、10 3、10 2、10 1nM，每孔加入1μl，室温孵育10分钟。用flexstation 3酶标仪进行检测，由机器自动加入3nM的加压素多肽50μl，立刻在494/516nM处读值。化合物的IC 50值可采用不同浓度对应的荧光值，经Graphpad Prism软件计算得到。
本发明化合物对人源V1bR抑制活性通过以上的试验进行测定，测得的IC 50值见表3。
表3本发明化合物对人源V1bR活性抑制的IC 50
实施例编号 IC 50(μM)
1 24.5
3 56.7
4 59.4
6 27.9
7 12.4
8 43.3
9 37.6
11 7.8
12 11.7
14 20.5
结论：本发明化合物对人源V1bR活性没有明显抑制效果，说明对OTR活性具有选择性抑制作用。
测试例4、本发明化合物对人源V2R抑制活性的测定
本发明化合物对HEK293/人源V2R细胞中所表达人源的V2R蛋白活性的抑制作用采用如下实验方法测定：
一、实验材料及仪器
1.cAMP动态2试剂盒-1,000次实验(62AM4PEB,Cisbio)
2.MEM(Hyclone，SH30024.01B)
3.G418硫酸盐(Enzo，ALX-380-013-G005)
4.胎牛血清(GIBCO，10099)
5.丙酮酸钠溶液(sigma，S8636-100ML)
6.MEM非必需氨基酸溶液(100×)(sigma，M7145-100ML)
7.PheraStar多功能酶标仪(BMG)
8.Corning/Costar 384孔无吸附微孔板-黑色NBS板(4514，Corning)
9.细胞解离液，不含酶，PBS(13151014-100ml，Thermo Fisher Scientific)
10.HBSS,钙,镁,不含酚红(14025-092，Invitrogen)
11.HEPES,1M缓冲液(15630-080，GIBCO)
12.BSA(0219989725，MP Biomedicals)
13.IBMX(I7018-250MG，sigma)
14.加压素(Tocris,2935)
15.pcDNA3.1(invitrogen，V79020)
16.pcDNA3.1-V2R(NM-000054)(金唯智生物技术有限公司合成并构建入pcDNA3.1质粒)
17.16.HEK293细胞(货号GNHu18，中科院细胞库)
二、实验步骤
将pcDNA3.1-V2R质粒，用
Figure PCTCN2017118784-appb-000052
3000转染试剂转入HEK293细胞；隔天开始加G418，得到HEK293/人源V2R pool细胞系
1)消化细胞：
使用细胞解离液不含酶消化HEK293/人源V2R pool细胞从细胞培养皿中解离，将细胞解离成单个，终止后吹打均匀，离心，去除上清用实验缓冲液1(1x HBSS+20mM HEPES+0.1％BSA)重悬细胞并计数，将细胞密度调整为1250个细胞/5μl，即2.5*10 5/ml。
2)配药
化合物用纯DMSO配制化合物成20mM、6.67mM、2.22mM、0.74mM、
0.25mM、0.0 8mM、27.4μM、9.14μM、3.05μM、1.02μM、0.34μM和0μM(DMSO)一系列的浓度。然后使用实验缓冲液2(实验缓冲液1+1mM IBMX)将化合物配成4倍使用浓度。
激动剂：以460μM的加压素母液，先用DMSO配成2μM，再用实验缓冲液2稀释成0.5nM浓度。
标准品：第一个点为20μl的储备原液(2848nM)，从第二个点开始按4倍依
次用实验缓冲液1进行稀释，共11个浓度。
3)加药孵育：
1.将混匀的细胞加入到384孔板中，5μl/孔，不用更换枪头。
2.加入配好的待测化合物和阳性化合物2.5μl/孔，需要更换枪头。
3.1000rpm离心1min，震荡30sec混匀，室温静置孵育30min。
4.标准曲线孔需要加5μl/孔的实验缓冲液2。
5.加入配好的激动剂每孔2.5μl，需要更换枪头，1000rpm离心1min，震荡30sec混匀，室温静置孵育30min。
6.避光配制cAMP-d2(cAMP动态2试剂盒中的组份)和Anti-cAMP-Eu-Cryptate(cAMP动态2试剂盒中的组份)，按照1：4的比例与cAMP裂解液(cAMP动态2试剂盒中的组份)混匀。每孔加入配好的cAMP-d2液体5μl/孔，再加Anti-cAMP-Eu-Cryptate 5μl/孔，震荡30sec混匀，室温避光孵育1h。
4)读板：PheraStar多功能酶标仪进行HTRF的信号读取。
5)数据处理
本实验的数据使用数据处理软件Graphpad Prism处理
本发明化合物对人源V2R抑制活性通过以上的试验进行测定，测得的IC 50值见表4。
表4本发明化合物对人源V2R活性抑制的IC 50
实施例编号 IC 50(μM)
1 21.4
3 23.0
4 25.7
6 7.3
7 90
9 32.6
11 6.8
12 29.5
14 10.4
结论：本发明化合物对人源V2R活性没有明显的抑制效果，说明对OTR活性具有选择性抑制作用。
药代动力学评价
测试例5、本发明化合物的药代动力学测试
1、摘要
以大鼠为受试动物，应用LC/MS/MS法测定了大鼠灌胃给予实施例6化合物、实施例8化合物、实施例9化合物和实施例11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6化合物、实施例8化合物、实施例9化合物和实施例11化合物。
2.2试验动物
健康成年SD大鼠16只，雌雄各半，平均分成4组，每组4只，购自上海杰思捷实验动物有限公司，动物生产许可证号：SCXK(沪)2013-0006。
2.3药物配制
称取一定量药物，加2.5％体积的DMSO和97.5％体积的10％solutol HS-15配制成0.2mg/mL的无色澄清透明液体。
2.4给药
SD大鼠禁食过夜后灌胃给药，给药剂量均为2.0mg/kg，给药体积均为10.0mL/kg。
3.操作
大鼠灌胃给药实施例6化合物、实施例8化合物、实施例9化合物和实施例11化合物，于给药前及给药后0.5，1.0，2.0，4.0，6.0，8.0，11.0，24.0小时由眼眶采血0.2mL，置于肝素化试管中，4℃、3500转/分钟离心10分钟分离血浆，于-20℃保存，给药后2小时进食。
测定不同浓度的药物灌胃给药后大鼠血浆中的待测化合物含量：取给药后各时刻的大鼠血浆25μL，加入内标溶液喜树碱50μL(100ng/mL)，乙腈200μL，涡旋混合5分钟，离心10分钟(4000转/分钟)，血浆样品取上清液1.0μL进行LC/MS/MS分析。
4、药代动力学参数结果
本发明化合物的药代动力学参数如下：
Figure PCTCN2017118784-appb-000053
结论：本发明化合物的药代吸收较好，具有药代动力学优势。

Claims (17)

  1. 一种通式(I)所示的化合物：
    Figure PCTCN2017118784-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：
    环A为芳基或杂芳基；
    环B为环烷基或杂环基；
    R 1为烷基或环烷基，其中所述的烷基任选被选自烷氧基、卤素、卤代烷基、卤代烷氧基、氘代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、杂环氧基、芳基、杂芳基和-OR 4中的一个或多个取代基所取代；
    R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基；
    R 3相同或不同，且各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基；
    R 4选自羟烷基、环烷基、芳基和杂芳基；
    n为0、1、2、3、4或5；且
    m为0、1、2、3或4。
  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 PCTCN2017118784-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的盐，
    环A、环B、R 1～R 3、n和m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，其中环B为3-5元的环烷基或杂环基；优选为环丙基。
  4. 根据权利要求1～3中任一项所述的通式(I)所示的化合物，其为通式(III)所示的化合物：
    Figure PCTCN2017118784-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的盐，
    其中：
    环A、R 1～R 3、n和m如权利要求1中所定义。
  5. 根据权利要求1～4中任一项所述的通式(I)所示的化合物，其中环A为吡啶基或苯并间二氧杂环戊烯；优选为
    Figure PCTCN2017118784-appb-100004
  6. 根据权利要求1～5中任一项所述的通式(I)所示的化合物，其中R 1为烷基或环烷基，其中所述的烷基任选被选自卤素、氰基、烷氧基、卤代烷氧基、氘代烷氧基和杂环氧基中的一个或多个取代基所取代。
  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，其中R 2相同或不同，且各自独立地选自氢原子、卤素和烷基。
  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，其中R 3为烷氧基。
  9. 根据权利要求1～8中任一项所述的通式(I)所示的化合物，其中n为2；且m为0或1。
  10. 根据权利要求1～9中任一项所述的化合物，其选自：
    Figure PCTCN2017118784-appb-100005
  11. 一种通式(I-A)所示的化合物：
    Figure PCTCN2017118784-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的盐，
    其中：
    环A、环B、R 2、R 3、n和m如权利要求1中所定义。
  12. 根据权利要求9所述的通式(I-A)所示的化合物，其选自：
    Figure PCTCN2017118784-appb-100007
  13. 一种制备根据权利要求1所述的通式(I)所示的化合物的方法，该方法包括：
    Figure PCTCN2017118784-appb-100008
    通式(I-A)的化合物和通式(I-B)的化合物或其盐酸盐在酸性条件下，加热反应，得到通式(I)的化合物，
    其中：
    环A、环B、R 1～R 3、n和m如权利要求1中所定义。
  14. 一种药物组合物，所述药物组合物含有治疗有效量的根据权利要求1～10中任一项所述的通式(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。
  15. 根据权利要求1～10中任一项所述的通式(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、或其可药用的盐或根据权利要求14所述的药物组合物在制备用于治疗或预防已知或可显示抑制催产素会产生有益效应的疾病或病症的药物中的用途。
  16. 根据权利要求15所述的用途，其中所述已知或可显示抑制催产素会产生有益效应的疾病或病症选自性功能障碍、男性性功能障碍、女性性功能障碍、***减退障碍、性唤起障碍、性高潮障碍、***疼痛障碍、早泄、预产前分娩、分娩并发症、食欲和进食疾病、良性***增生、早产、痛经、充血性心力衰竭、动脉高血压、肝硬化、肾性高血压、高眼压、强迫观念与行为障碍和神经精神疾病优选地选自性唤起障碍、性高潮障碍、***疼痛障碍和早泄。
  17. 根据权利要求1～10中任一项所述的通式(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、或其可药用的盐或根据权利要求14所述的药物组合物在制备用于拮抗催产素的药物中的用途。
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