WO2019154247A1 - 甾族类衍生物调节剂、其制备方法和应用 - Google Patents

甾族类衍生物调节剂、其制备方法和应用 Download PDF

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Publication number
WO2019154247A1
WO2019154247A1 PCT/CN2019/074108 CN2019074108W WO2019154247A1 WO 2019154247 A1 WO2019154247 A1 WO 2019154247A1 CN 2019074108 W CN2019074108 W CN 2019074108W WO 2019154247 A1 WO2019154247 A1 WO 2019154247A1
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Prior art keywords
group
substituted
unsubstituted
cycloalkyl
heteroaryl
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PCT/CN2019/074108
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English (en)
French (fr)
Inventor
苏熠东
陈晓坡
汪军
包如迪
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
Original Assignee
Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Priority to CN202111437172.1A priority Critical patent/CN114085260B/zh
Priority to KR1020207025278A priority patent/KR102902950B1/ko
Priority to CA3088919A priority patent/CA3088919A1/en
Priority to JP2020542649A priority patent/JP2021512909A/ja
Priority to ES19751506T priority patent/ES3018614T3/es
Priority to MX2020008182A priority patent/MX2020008182A/es
Priority to EP19751506.7A priority patent/EP3750909B1/en
Priority to CN201980001502.7A priority patent/CN110366555B/zh
Priority to AU2019217320A priority patent/AU2019217320B2/en
Application filed by Jiangsu Hansoh Pharmaceutical Group Co Ltd, Shanghai Hansoh Biomedical Co Ltd filed Critical Jiangsu Hansoh Pharmaceutical Group Co Ltd
Priority to CN202111428844.2A priority patent/CN113999277B/zh
Priority to US16/969,137 priority patent/US11661437B2/en
Priority to BR112020015131-9A priority patent/BR112020015131A2/pt
Publication of WO2019154247A1 publication Critical patent/WO2019154247A1/zh
Priority to ZA2020/04181A priority patent/ZA202004181B/en
Anticipated expiration legal-status Critical
Priority to JP2024111699A priority patent/JP7848273B2/ja
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom
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    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
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    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61P25/20—Hypnotics; Sedatives
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    • A61P25/00—Drugs for disorders of the nervous system
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    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
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    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group
    • C—CHEMISTRY; METALLURGY
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    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0044—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an estrane or gonane skeleton, including 18-substituted derivatives and derivatives where position 17-beta is substituted by a carbon atom not directly bonded to another carbon atom and not being part of an amide group
    • C—CHEMISTRY; METALLURGY
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    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0066—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by a carbon atom forming part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0007—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa
    • C07J5/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/001—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class spiro-linked
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    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused
    • C07J53/004—3 membered carbocyclic rings
    • C—CHEMISTRY; METALLURGY
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    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused
    • C07J53/004—3 membered carbocyclic rings
    • C07J53/007—3 membered carbocyclic rings in position 6-7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused
    • C07J53/004—3 membered carbocyclic rings
    • C07J53/008—3 membered carbocyclic rings in position 15/16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07J61/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one or two atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
    • C07J7/009—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by only one oxygen atom doubly bound
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/001—Oxiranes
    • C—CHEMISTRY; METALLURGY
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    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0036—Nitrogen-containing hetero ring
    • C07J71/0057—Nitrogen and oxygen
    • C07J71/0068—Nitrogen and oxygen at position 16(17)
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of drug synthesis, and particularly relates to a steroid derivative regulating agent, a preparation method and application thereof.
  • the GABA A receptor is a chemically gated channel on the cell membrane and belongs to the ionic receptor. Widely distributed in the nervous system, it can bind to the inhibitory neurotransmitter GABA ( ⁇ -aminobutyric acid), leading to the opening of chloride channels and causing neuronal inhibition.
  • the GABA A receptor modulator (tetrahydroprogesterone) is a positive regulator of the GABA A receptor. Tetrahydroprogesterone binds to the synaptic GABA A receptor modulator to increase the chloride channel open frequency at the receptor, which is an increase in chloride influx, which increases the Phasic current, produces a rapid inhibitory effect, and reduces neuronal excitability.
  • Tetrahydroprogesterone binds to the extrasynaptic GABA A receptor, producing a persistent chloride current that mediates a sustained, sustained inhibitory effect. Tetrahydroprogesterone can also increase the content of neurotrophic factor (BDNF), promote the regeneration of hippocampal neurons, and produce neuroprotective effects, thereby improving the symptoms of anxiety and depression, but the specific mechanism of action has not been clarified.
  • BDNF neurotrophic factor
  • Major depressive disorder is a common, chronic relapsing disease that causes the disease burden and adverse consequences to become more serious.
  • antidepressants fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, etc.
  • the onset of action takes 2 to 4 weeks, and the clinical treatment of major depression, especially suicidal depression patients, often needs to be timely and rapid, so there is an urgent need to develop fast-acting antidepressants.
  • GABA A receptor modulators There has been little innovation in the discovery and development of treatment for depression over the past two decades.
  • the goal of GABA A receptor modulators is to change patient expectations by changing the treatment of MDD. If developed successfully, GABA A receptor modulators may be the first drug to provide a truly new mechanism of action for the treatment of depression in more than two decades.
  • foreign pharmaceutical companies including companies such as Sage Therapeutics and Marinus are making full efforts to develop GABA A receptor modulators.
  • GABA A receptor modulators include: WO2003077919, WO2014169833, WO2016061537, WO2015180679 and WO2015027227.
  • GABA A receptor modulators have become a popular target in the pharmaceutical industry and have good application prospects.
  • GABA A receptor modulators can be applied to major depressive disorder (MDD).
  • MDD major depressive disorder
  • the annual incidence of MDD in China is about 2%, which has huge market potential.
  • the existing antidepressants have slow onset, often take 3 to 4 weeks, and the failure rate is high, up to 40%, requiring long-term medication.
  • GABA A receptor modulators produce significant antidepressant effects within 24 hours for up to several days to two weeks.
  • GABA A receptor modulators can meet the daily oral treatment needs of MDD patients.
  • An object of the present invention is to provide a compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the following structure:
  • X is selected from -CR 17 - or -N-;
  • Y is selected from -CR 23 R 24 -, -S(CH 2 ) n1 -, -P(CH 2 ) n1 -, -O(CH 2 ) n1 -, -(CH 2 ) n1 NR 22 -,
  • R x , R y , R z and R f are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a fluorenyl group.
  • any two adjacent or non-adjacent groups of R x , R y , R z and R f may form a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the cycloalkane
  • the base, heterocyclic group, aryl group and heteroaryl group are optionally further selected from the group consisting of a halogen atom, an alkyl group, a halogenated alkyl group, a halogen group, an amino group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, and an alkane group.
  • any two adjacent two groups of R x , R y , R z and R f are absent to form a double bond;
  • R 21 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group.
  • heterocyclyl aryl,heteroaryl, -(CH 2 ) n1 R 23 , -(CH 2 ) n1 OR 23 , -(CH 2 ) n1 SR 23 , -(CH 2 ) n1 C(O)R 23 , -(CH 2 ) n1 C(O)OR 23 , -(CH 2 ) n1 S(O) m1 R 23 , -(CH 2 ) n1 NR 23 R 24 , -(CH 2 ) n1 C(O) NR 23 R 24 , -(CH 2 ) n1 NR 23 C(O)R 24 or -(CH 2 ) n1 NR 23 S(O) m1 R 24 , wherein the alkyl group, haloalkyl group, cycloalkyl group, The heterocyclic group, aryl group and heteroaryl group are optionally further selected from the group consisting of a haloalkyl
  • R 17 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • heteroaryl wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of a halogen atom, a substituted or unsubstituted alkyl group, a halogen, a hydroxyl group, a substituent or Unsubstituted amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted Substituted by one or more substituents of a substituted aryl group and a substituted or unsubstituted heteroaryl group;
  • R 17 may be bonded to any of R x , R y , R z and R f to form a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the cycloalkyl group, heterocyclic group
  • the aryl and heteroaryl are optionally further selected from the group consisting of a halogen atom, an alkyl group, a halogenated alkyl group, a halogen, an amino group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group.
  • R 22 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group.
  • heterocyclyl aryl,heteroaryl, -(CH 2 ) n1 R 23 , -(CH 2 ) n1 OR 23 , -(CH 2 ) n1 SR 23 , -(CH 2 ) n1 C(O)R 23 , -(CH 2 ) n1 C(O)OR 23 , -(CH 2 ) n1 S(O) m1 R 23 , -(CH 2 ) n1 NR 23 R 24 , -(CH 2 ) n1 C(O) NR 23 R 24 , -(CH 2 ) n1 NR 23 C(O)R 24 or -(CH 2 ) n1 NR 23 S(O) m1 R 24 , wherein the alkyl group, haloalkyl group, cycloalkyl group, The heterocyclic group, aryl group and heteroaryl group are optionally further selected from the group consisting of a haloalkyl
  • R 23 , R 24 , R 25 and R 26 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, and a cycloalkane.
  • a heterocyclic group, an aryl group and a heteroaryl group wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further optionally selected from a halogen atom, a substituted or unsubstituted alkyl group , halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted by one or more substituents of a heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;
  • n is an integer of 0, 1, 3, 4, 5, 6, 7, 8, 9, or 10;
  • n is an integer of 0, 1, 2, or 3;
  • o is an integer of 0, 1, 2, 3, 4 or 5;
  • p is an integer of 0, 1, 2, 3, 4, 5 or 6;
  • q is an integer of 0, 1, 2, 3, 4, 5 or 6;
  • n 1 is an integer of 0, 1 or 2;
  • n 1 is an integer of 0, 1, 2, 3, 4 or 5.
  • the compound of the formula (I) is a compound represented by the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • Y is selected from
  • R 3a is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a decyl group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group or an alkynyl group;
  • R 5 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group or an alkynyl group;
  • R 15a is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group or an alkynyl group;
  • R 16a is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group or an alkynyl group;
  • R 15a and R 16a are linked to form a cycloalkyl or heteroalkyl group, wherein said cycloalkyl or heteroalkyl group is optionally further selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, Halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl Substituted by one or more substituents;
  • R 5 and R 19 are bonded to form a cycloalkyl or heteroalkyl group, wherein said cycloalkyl or heteroalkyl group is optionally further selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, Halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl Substituted by one or more substituents;
  • R 21 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a hydroxyalkyl group.
  • R 23 , R 24 , R 25 and R 26 are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, and a cycloalkane.
  • a heterocyclic group, an aryl group and a heteroaryl group wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further optionally selected from a halogen atom, a substituted or unsubstituted alkyl group , halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted by one or more substituents of a heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;
  • n is an integer of 1 or 2;
  • n 1 is an integer of 0, 1 or 2;
  • n 1 is an integer of 0, 1, 2, 3, 4 or 5.
  • the compound of the formula (II) is a compound represented by the formula (III-A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof :
  • Z is selected from -CR 23 R 24 -, -NR 23 -, -(CH 2 ) n1 O(CH 2 ) n2 - or -O-; preferably a methylene group;
  • Ring C is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrazine.
  • R c is the same or different and is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group.
  • z is an integer of 0, 1, 3, 4 or 5;
  • R 3a , R 3b , R 5 , R 19 , R 23 to R 26 , n, m 1 and n 1 are as defined for the compound of the formula (II).
  • the compound represented by the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof which is a formula (V-7) and a formula ( a compound represented by V-8), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrazine Atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl , substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH 2 ) n1 R 25 , -(CH 2 ) n1 OR 25 , -(CH 2 ) N1 SR 25 , -(CH 2 ) n1 C(O)R 25 , -(CH 2
  • R a is the same or different and is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group.
  • R 19 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, Heteroaryl, -(CH 2 ) n1 R 23 , -(CH 2 ) n1 OR 23 , -(CH 2 ) n1 SR 23 , -(CH 2 ) n1 C(O)R 23 , -(CH 2 ) n1 C(O)OR 23 , -(CH 2 ) n1 S(O) m1 R 23 , -(CH 2 ) n1 S(O)NR 23 , -(CH 2 ) n1 NR
  • R 5 is selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group or a C 1-6 alkoxy group;
  • R 19 is selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, -(CH 2 ) n1 OR 23 or -(CH 2 ) n1 SR 23 ;
  • R c is selected from a hydrogen atom, a cyano group or a C 1-6 alkyl group
  • z is an integer of 0, 1, or 2;
  • n 0, 1, or 2.
  • the compound of the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof which is of the formula (IV-A) and (IV- The compound shown in B), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • R 3a is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy;
  • x is an integer of 0, 1, or 2
  • R 5 , m 1 and n 1 are as claimed in claim 2.
  • the compound represented by the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof which is a compound represented by the formula (VIII), or a stereo Isomer or a pharmaceutically acceptable salt thereof:
  • Rings A, Z, R a and x are as described for formula (III).
  • the compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof which is a compound represented by the formula (VI), or a stereo Isomer or a pharmaceutically acceptable salt thereof:
  • Z is selected from -CR 23 R 24 -, -(CH 2 ) n1 NR 23 -, -(CH 2 ) n1 O(CH 2 ) n2 - or -O-; preferably a methylene group;
  • Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of a halogen atom, an alkyl group, an alkyl halide Base, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH 2 ) n1 R 25 , -(CH 2 ) n1 OR 25 , -(CH 2 ) n1 SR 25 , -( CH 2 ) n1 C(O)R 25 , -(CH 2
  • R b is the same or different and is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group.
  • y is selected from an integer of 0, 1, 2, 3 or 4.
  • the compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof which is a compound represented by the formula (VIII), Stereoisomer or a pharmaceutically acceptable salt thereof:
  • R 21 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group.
  • heterocyclyl aryl,heteroaryl, -(CH 2 ) n1 R 23 , -(CH 2 ) n1 OR 23 , -(CH 2 ) n1 SR 23 , -(CH 2 ) n1 C(O)R 23 , -(CH 2 ) n1 C(O)OR 23 , -(CH 2 ) n1 S(O) m1 R 23 , -(CH 2 ) n1 NR 23 R 24 , -(CH 2 ) n1 C(O) NR 23 R 24 , -(CH 2 ) n1 NR 23 C(O)R 24 or -(CH 2 ) n1 NR 23 S(O) m1 R 24 , wherein the alkyl group, haloalkyl group, cycloalkyl group, The heterocyclic group, aryl group and heteroaryl group are optionally further selected from the group consisting of a haloalkyl
  • R 23 to R 26 , m 1 and n 1 are as defined in claim 1.
  • the compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof which is a compound represented by the formula (X), Stereoisomer or a pharmaceutically acceptable salt thereof:
  • M is selected from -CR 23 - or an oxygen atom
  • Y is selected from -S(CH 2 ) n1 -,
  • R 21 is selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogenated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group.
  • heterocyclyl aryl,heteroaryl, -(CH 2 ) n1 R 23 , -(CH 2 ) n1 OR 23 , -(CH 2 ) n1 SR 23 , -(CH 2 ) n1 C(O)R 23 , -(CH 2 ) n1 C(O)OR 23 , -(CH 2 ) n1 S(O) m1 R 23 , -(CH 2 ) n1 NR 23 R 24 , -(CH 2 ) n1 C(O) NR 23 R 24 , -(CH 2 ) n1 NR 23 C(O)R 24 or -(CH 2 ) n1 NR 23 S(O) m1 R 24 , wherein the alkyl group, haloalkyl group, cycloalkyl group, The heterocyclic group, aryl group and heteroaryl group are optionally further selected from the group consisting of a haloalkyl
  • R 22 to R 26 , m 1 and n 1 are as defined in claim 1.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof wherein the ring A, ring B and ring C are selected From the following groups:
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof wherein
  • R a , R b and R c are selected from the group consisting of a hydrogen atom, a cyano group, a halogen, a nitro group, a C 1-6 alkyl group, a C 2-6 alkynyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group, C 3-6 cycloalkyl, C 1-6 hydroxyalkyl, 5-10 membered heterocyclic, 5-10 membered heteroaryl, -(CH 2 ) n1 OR 23 , -(CH 2 ) n1 SR 23 , -(CH 2 ) n1 C(O)R 23 , -(CH 2 ) n1 C(O)NR 23 R 24 , -(CH 2 ) n1 C(O)OR 23 or -(CH 2 ) n1 S(O M1 R 23 , wherein said C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hal
  • R 23 and R 24 are each independently selected from a hydrogen atom, a C 1-6 alkyl group or a 3-8 membered heterocyclic group.
  • Z is selected from -CH 2 -, -CH 2 NH-, -CH 2 O-, -CH 2 -, -NH- or -NHSO 2 -;
  • R 3a is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy; preferably C 1-3 alkyl or C 1-3 alkoxy; more preferably methyl or methoxy methyl;
  • R 5 is selected from a hydrogen atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 haloalkyl group or a C 1-6 alkoxy group; preferably a hydrogen atom and a C 1-3 alkyl group;
  • a C 3-6 cycloalkyl group preferably a cyclopropyl group, may be formed between any two adjacent groups of R 5 and R 19 .
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds:
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable An acceptable carrier, diluent or excipient.
  • the invention further relates to any of the compounds of formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, or the use of said pharmaceutical compositions in the manufacture of a medicament for the regulation of GABA A receptors.
  • the present invention further relates to the use of a compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the preparation of a medicament for treating a CNS-related disease, wherein the CNS is related
  • the disease is selected from the group consisting of sleep disorders, mood disorders, schizophrenia spectrum disorders, spastic disorders, memory disorders and/or cognitive disorders, dyskinesias, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases. , substance abuse disorder and / or withdrawal syndrome or tinnitus. .
  • the present invention further relates to a compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a method for treating a CNS-related disease.
  • the present invention also relates to a method for the prophylactic and/or therapeutic preparation of a CNS-related disease comprising administering to a patient a therapeutically effective amount of a compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable compound thereof Salt, or a pharmaceutical composition thereof.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms.
  • the alkyl group is most preferably an alkyl group of 1 to 3 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,
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group, and a methyl group, an ethyl group, an isopropyl group, a t-butyl group or a halogenated alkyl group is preferred in the invention.
  • alkylene means that one hydrogen atom of the alkyl group is further substituted, for example, "methylene” refers to -CH 2 -, "ethylene” refers to -(CH 2 ) 2 -, "propylene” Refers to -(CH 2 ) 3 -, "butylene” means -(CH 2 ) 4 - and the like.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • 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:
  • spirocycloalkyl groups in which a monospirocycloalkyl group shares a spiro atom with a heterocycloalkyl group, and non-limiting examples 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.
  • the bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl group may be classified according to the number of constituent rings, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group.
  • 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 one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine.
  • Base piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and 1,4-diazaalkyl, etc., preferably tetrahydrofuranyl, pyrazolidinyl, morpholinyl, 1 , 4-diazaalkyl, piperazinyl and pyranyl.
  • the polycyclic heterocyclic group includes a spiro ring, a fused ring, and a bridged ring heterocyclic group; wherein the heterocyclic group of the spiro ring, the fused ring, and the bridged ring is optionally bonded to the other group through a single bond, or through a ring Any two or more atoms above are further and ring-bonded to other cycloalkyl, heterocyclic, aryl and heteroaryl groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • Non-limiting examples of spiroheterocyclyl groups include:
  • fused heterocyclyl refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused heterocyclic groups include:
  • bridge heterocyclyl refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A ⁇ -electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bridge heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, tetrazolyl, thienyl, imidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, thiazolyl, oxazolyl, Isoxazolyl or pyrimidinyl; more preferably triazolyl, tetra
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • Haloalkyl means an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • Haloalkoxy means an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.
  • Hydroalkyl means an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.
  • Alkenyl means an alkenyl group, also known as an alkenyl group, wherein the alkenyl group may be further substituted with other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amino, halogen, decyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkyl sulphide Base, carboxyl or carboxylate group.
  • Alkynyl means (CH ⁇ C-) wherein the alkynyl group may be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, Halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, Carboxyl or carboxylate group.
  • Hydrophilicity refers to an -OH group.
  • Halogen means fluoro, chloro, bromo or iodo.
  • Amino means -NH 2 .
  • Niro means -NO 2 .
  • Carboxy refers to -C(O)OH.
  • THF tetrahydrofuran
  • EtOAc means ethyl acetate
  • MeOH refers to methanol
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • MeCN means ⁇ .
  • DMA N,N-dimethylacetamide
  • Et 2 O means diethyl ether
  • DCE 1,2 dichloroethane
  • DIPEA N,N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl means benzyl chloroformate
  • Pd 2 (dba) 3 refers to tris(dibenzylideneacetone) dipalladium.
  • Dppf means 1,1'-bisdiphenylphosphinoferrocene.
  • HATU means 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • KHMDS means potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamine.
  • MeLi means methyl lithium
  • n-BuLi means n-butyllithium
  • NaBH(OAc) 3 refers to sodium triacetoxyborohydride.
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, and C
  • the hydrogen atom of the present invention may be substituted by its isotope ruthenium, and any of the hydrogen atoms in the examples of the present invention may also be substituted by a ruthenium atom.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in parts per million (ppm).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ).
  • the internal standard was four.
  • Methyl silane (TMS) Methyl silane
  • LC-MS was determined by LC-MS using an Agilent 1200 Infinity Series mass spectrometer.
  • 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).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification for TLC is 0.15mm ⁇ 0.20mm, and the specification for separation and purification of thin layer chromatography is 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • the reaction mixture was filtered, washed with 20 mL of methylene chloride, eluted with white solid, filtered, and the filtrate was evaporated to dryness.
  • the crude product was purified by column chromatography ( petroleum ether / ethyl acetate: 3/1) (5R, 8S, 9S,10R,13S,14S)-10-fluoro-13-methyltetrahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (600 mg, white solid, yield : 32.9%).
  • reaction solution was cooled to -78 ° C, (5R, 8S, 9S, 10R, 13S, 14S)-10-fluoro-13-methyltetrahydro-3H-cyclopentadienyl [a]phenanthrene-3,17 (
  • a solution of 2H)-dione (320 mg, 1.1 mmol) in toluene (5 mL) was added dropwise to the reaction mixture, and the reaction mixture was reacted at -78 ° C for 1 hour.
  • methyl magnesium bromide 1.0 mL, 3 M, 3 mmol
  • Step 4 (3R, 5R, 8S, 10R, 13S, 14S)-17-Ethylene-10-fluoro-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene -3-phenol
  • Step 5 (3R, 5R, 8S, 10R, 13S, 14S)-10-Fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopentadiene [a]phenanthroline-3-phenol
  • Step 6 1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopentadienyl[ a]phenanthroline-17-yl)ethane-1-one
  • reaction solution was filtered, concentrated under reduced pressure and purified (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Second step 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-ring Pentadieno[a]phenanthroline-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carbonitrile
  • Step 2 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopentadiene And [a]phenanthroline-yl)-2-(4-(oxazol-2-yl)-1H-pyrazol-1-yl)ethane-1-one
  • the second step preparation of 4-bromo-2H-1,2,3-triazole
  • the third step preparation of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole
  • Step 6 2-(4-Cyclopropyl-2H-1,2,3-triazol-2-yl)-1-((3R,5R,8S,10R,13S,14S,17S)-10- Fluoro-3-hydroxy-3,13-dimethylhexadehydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-one (63) and 2-(4-cyclopropane -1H-1,2,3-triazol-1-yl)-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-di Preparation of methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-one (64)
  • the third step (1R, 3R, 5R)-2-(2-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethyl-10- Preparation of hexahydro-1H-cyclopentadieno[a]phenanthrene-17-yl)-2-carbonylethyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile
  • Second step 7-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-ring Preparation of pentadieno[a]phenanthrene-17-yl)-2-carbonylethoxy)quinoline 1-nitrogen oxide
  • This embodiment 90 is synthesized by the following specific embodiments:
  • Trimethylsulfoxonium iodide (2.65 g, 12 mmol) and tetrahydrofuran (50 mL) were successively added to a 100 mL three-necked flask, and potassium t-butoxide (1.35 g, 12 mmol) was added thereto with stirring, and the reaction mixture was stirred at room temperature for 0.5 hour.
  • (5R,8S,9S,10R,13S,14S)-10-fluoro-13-methyltetrahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (3.0g 10 mmol) was added to the reaction solution, and the reaction solution was reacted at room temperature for 2 hours.
  • Step 2 (3R, 5R, 8S, 10R, 13S, 14S)-10-fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadeca-17H-cyclopentadiene And [a]phenanthrene-17-one
  • Step 5 1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H -cyclopenta[a]phenanthrene-17-yl)ethane-1-one
  • Step 6 2-Bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3-(methoxymethyl)-13-methyl-10- Hexahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-one
  • Step 7 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3-(methoxymethyl)-13-methyl Hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carbonitrile
  • Step 2 (5S, 8R, 9S, 10S, 13S, 14S)-13-Methyldodecyl-17H-5,10-methylenecyclopentadienyl[a]phenanthrene-3,17(4H )-dione
  • Step 4 (3R, 5S, 8S, 9S, 10S, 13S, 14S)-17-Ethylene-3,13-dimethyltetrahydro-6H-5,10-methylenecyclopentadiene And [a] phenanthrene-3-phenol
  • Step 5 (3R, 5S, 8S, 9S, 10S, 13S, 14S) 17-(1-hydroxyethyl)-3,13-dimethyltetrahydro-6H-5,10-methylene Cyclopenta[a]phenanthroline-3-ol
  • Step 6 1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyltetrahydro-6H-5,10-methylene ring Pentadieno[a]phenanthroline-17-yl)ethane-1-one
  • the seventh step 2-bromo-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyltetrahydrol-6H-5,10- Methylene cyclopenta[a]phenanthrene-17-yl)ethane-1-one
  • Step 8 1-(2-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyltetrahydrol-6H-5,10-Asia Methylcyclopentadienyl[a]phenanthroline-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carbonitrile
  • the first step of the product is 1-(2-((3R,5S,8S,9S,10S,13S,14S) , 17S)-3-hydroxy-3,13-dimethyltetrahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)- 1H-pyrazole-4-carbonitrile (18 mg, white solid, yield: 21.9%).
  • Embodiment 120 and Embodiment 121 are identical to Embodiment 120 and Embodiment 121.
  • the purpose of this test is to measure the ability of a compound to inhibit the binding of ion channel blockers (TBPS) and GABA-A receptors.
  • pellet was resuspended in 4 volumes of PBS, dispensed, frozen in liquid nitrogen, and stored at -80 °C.
  • test compound 3 uL per well
  • incubate 5 min at 25 °C.
  • the DMSO concentration was 1%, the initial concentration of the compound was 1 uM, a 3-fold gradient dilution, a total of 8 gradients, 2 replicates, 1% DMSO as a negative control, and 10 uM P026-2 as a positive control.
  • FilterMate GF/C plate was pretreated with 0.5% PEI and incubated for 1 h at 4 °C.
  • the washed GF/C plate was placed at 55 ° C for 10 min.
  • the TBPS-binding activity of the compounds of the present invention was measured by the above test, and the IC 50 values measured are shown in Table 1.
  • the compounds of the present invention have a significant inhibitory effect on TBPS binding activity.
  • mice Using Balb/C mice as test animals, Study Compound Example 2, Example 5, Example 7, Example 12, Example 18, Example 23, Example 26, Example 38, Example 41, and implementation Example 50 Example 51 and Example 66, pharmacokinetic behavior of orally administered to mice (plasma and brain tissue) at a dose of 5 mg/kg.
  • Embodiment 2 Embodiment 5, Embodiment 7, Embodiment 12, Embodiment 18, Embodiment 23, Embodiment 26, Embodiment 38, Embodiment 41, Embodiment 50, Embodiment 51 and Embodiment 66, self made.
  • mice were sacrificed by CO 2 at 0 , 0.5, 1, 2 , 4, 6, 8 and 24 hours before and after administration, and 0.2 mL of blood was collected from the heart.
  • the cells were placed in EDTA-K 2 tubes at 4 ° C 6000 rpm.
  • the plasma was separated by centrifugation for 6 min, and stored at -80 ° C; the whole brain tissue was taken out and weighed, placed in a 2 mL centrifuge tube, and stored at -80 ° C.
  • a 40 ⁇ L plasma sample was added to 160 uL of acetonitrile for precipitation, and after mixing, it was centrifuged at 3,500 x g for 5 to 20 minutes.
  • the anti-depressant effect of the compounds was evaluated using a mouse forced swimming model.
  • Example 26 Example 50, self-made.
  • mice were randomly divided into groups of 12 mice each day before the experiment.
  • Compounds of the various examples in the mouse pharmacokinetic experiments were administered intragastrically at the Tmax time in the brain prior to testing. They are:
  • Example Compound Example 2 Example 5, Example 7, Example 18, Example 23, Example 26, and Example 50 (10 mg/kg, p.o., 10 mL/kg);
  • each of the example compounds was suspended in a 0.5% CMC-Na-1% Tween 80 solution to the desired concentration.
  • the ICR mice were placed in a forced swimming device [1 in a transparent glass drum (water depth 18 cm, water temperature 25-26 ° C) per cylinder] for 6 minutes, forced swimming device recorded the whole 6 The time that ICR mice floated within minutes, and the last 4 minutes of data were used for data analysis. Immediately after the end of the swimming experiment, the mice were removed and the water was dried and returned to the original cage.
  • the criterion for determining the immobility time is that the mouse stops struggling in the water and is floating, with only small limb movements to keep the head floating on the water.
  • Floating time percentage 100 * floating time / 240s.
  • Example 2 10 87.34 36.39
  • Example 5 10 65.07 27.11
  • Example 7 10 141.58 58.99
  • Example 18 10 146.86 61.19
  • Example 23 10 68.51 28.55
  • Example 26 10 128.30 53.46
  • Example 50 10 101.07 42.11
  • Example 2 compared with the model group, the immobility time of the last 4 minutes has a significant difference; in Example 5, the embodiment 23 and the embodiment 50, the immobility time of the last 4 minutes is extremely significant. Sexual differences.
  • a PTZ-induced CD-1 mouse epilepsy model was established, and the anti-epileptic effects of Compound Example 5 and Example 23 were evaluated using this model.
  • CD-1 mice Thirty male CD-1 mice were purchased from Beijing Weitong Lihua Experimental Animal Co., Ltd. The experimental animals were delivered to the animal room of Building 3 of Shanghai Ruizhi Chemical Co., Ltd., and the formal experiment was carried out after 7 days. The average animal weight on the day of the test was 32.2 ⁇ 0.2 g. The feeding environment was 5/cage, and the room temperature was 23 ⁇ 2°C, and the 12/12 hours of day and night were alternated. The food and water were freely ingested.
  • Test compound Example 5 and Example 23 (home-made), the test drugs were all stored in a refrigerator at 4 ° C.

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Abstract

本发明涉及一种甾族类衍生物调节剂、其制备方法和应用。特别地，本发明涉及通式(I)所示的化合物、其制备方法及含有该化合物的药物组合物，及其作为GABAA受体调节剂在治疗抑郁症、惊厥、帕金森和神经系统疾病的用途，其中通式(I)中的各取代基与说明书中的定义相同。

Description

甾族类衍生物调节剂、其制备方法和应用 技术领域
本发明属于药物合成领域，具体涉及一种甾族类衍生物调节剂及其制备方法和应用。
背景技术
GABA A受体是细胞膜上的化学门控通道，属于离子型受体。广泛分布于神经系统内，可与抑制性神经递质GABA(γ-氨基丁酸)结合，导致氯离子通道开放，引起神经元的抑制。GABA A受体调节剂(四氢孕酮)是GABA A受体的正性调节剂。四氢孕酮与突触内GABA A受体调节剂结合后能够增加该受体上的氯离子通道开放频率，是氯离子内流增加，从而增加Phasic电流，产生快速抑制效应，降低神经兴奋性，从而产生抗焦虑抗抑郁作用；四氢孕酮与突触外GABA A受体结合，产生一种持续性氯离子电流，介导了一种持久的持续性的抑制效应。四氢孕酮还可以增加神经营养因子(BDNF)的含量，促进海马神经元再生，产生神经保护作用，从而改善焦虑抑郁症状，但具体作用机制尚未明确。
重度抑郁症(MDD)是一种常见的，慢性复发性疾病，它所导致的疾病负担和不良后果越来越严重。虽然在过去的40年，抗抑郁药的研发和临床应用有了很大发展，但大多数抗抑郁药(氟西汀、帕罗西汀、舍曲林、氟伏沙明、西酞普兰等)的起效需2～4周，而重度抑郁症特别是由自杀倾向的抑郁症病人的临床处理往往需要及时和迅速，所以急需开发快速起效的抗抑郁药物。
过去二十年来，抑郁症治疗的发现和发展方面几乎没有什么创新，GABA A受体调节剂的发展目标是通过改变MDD的治疗方案来改变患者的期待。如果研制成功，GABA A受体调节剂有可能成为二十多年来第一个为治疗抑郁症提供真正新作用机制的药物。目前包括Sage Therapeutics和Marinus等公司在内的国外药企正在全力进行GABA A受体调节剂的开发。
现已公开的GABA A受体调节剂专利申请包括：WO2003077919、WO2014169833、WO2016061537、WO2015180679和WO2015027227。
GABA A受体调节剂作为药物在医药行业热门的靶点，目前具有良好的应用前景，
其一：GABA A受体调节剂可应用于重度抑郁症(MDD)，MDD中国每年的发病率约为2％，具有巨大的市场潜力。
其二：现有的抗抑郁药起效慢，常需3～4周，且失败率高，可达40％，需要长期用药。GABA A受体调节剂可在24小时内产生显著的抗抑郁作用，用药效果长达数天至两周。
其三：GABA A受体调节剂可以满足MDD患者每日一次的口服治疗需求。
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、其立体异构体或其药学上可接受盐，其中通式(I)所示的化合物结构如下：
Figure PCTCN2019074108-appb-000001
其中：
X选自-CR 17-或-N-；
Y选自-CR 23R 24-、-S(CH 2) n1-、-P(CH 2) n1-、-O(CH 2) n1-、-(CH 2) n1NR 22-、
Figure PCTCN2019074108-appb-000002
Figure PCTCN2019074108-appb-000003
R x、R y、R z和R f相同或不同，各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、巯基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 24或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、巯基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
或者，R x、R y、R z和R f任意两个相邻或不相邻的基团链接可形成一个环烷基、杂环基、芳基和杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、 烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 24和-(CH 2) n1NR 23S(O) m1R 24中的一个或多个取代基所取代；
再或者，R x、R y、R z和R f任意两个相邻的两个基团不存在，形成一个双键；
R 21选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 24或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
当X选自-CR 17-时，R 17选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、烯基、炔基、烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代；
或者，R 17与R x、R y、R z和R f中任意基团链接可形成一个环烷基、杂环基、芳基和杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 24和-(CH 2) n1NR 23S(O) m1R 24中的一个或多个取代基所取代；
R 22选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 24或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基 和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
R 23、R 24、R 25和R 26相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、烯基、炔基、烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代；
m为0、1、3、4、5、6、7、8、9或10的整数；
n为0、1、2、或3的整数；
o为0、1、2、3、4或5的整数；
p为0、1、2、3、4、5或6的整数；
q为0、1、2、3、4、5或6的整数；
m 1为0、1或2的整数；且
n 1为0、1、2、3、4或5的整数。
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物，其为通式(II)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019074108-appb-000004
其中：
Y选自
Figure PCTCN2019074108-appb-000005
R 3a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、巯基、硝基、羟基、氰基、烯基或炔基；
R 5选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基或炔基；
R 15a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基或炔基；
R 16a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基或炔基；
或者，R 15a和R 16a链接形成一个环烷基或杂烷基，其中所述的所成的环烷基或杂烷基任选进一步被选自氢原子、氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基中的一个或多个取代基所取代；
R 19选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、巯基、羟基、氰基、烯基、炔基、羟烷基、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)(＝NR 23)R 24或-(CH 2) n1C(O)NR 23R 24；
或者，R 5和R 19链接形成一个环烷基或杂烷基，其中所述的所成的环烷基或杂烷基任选进一步被选自氢原子、氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基中的一个或多个取代基所取代；
R 21选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 24或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
R 23、R 24、R 25和R 26相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、烯基、炔基、烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代；
n为1或2的整数；
m 1为0、1或2的整数；且
n 1为0、1、2、3、4或5的整数。
在本发明的一个优选实施例方案中，所述的通式(II)所示的化合物，其为通 式(III-A)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019074108-appb-000006
其中：
Z选自-CR 23R 24-、-NR 23-、-(CH 2) n1O(CH 2) n2-或-O-；优选为亚甲基；
环C选自环烷基、杂环基、芳基、杂芳基，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
R c相同或不同，选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)NR 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 23或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
z为0、1、3、4或5的整数；且
R 3a、R 3b、R 5、R 19、R 23～R 26、n、m 1和n 1如通式(II)所述的化合物所定义。
在本发明的一个优选实施例方案中，所述的通式(II)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(V-7)和通式(V-8)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019074108-appb-000007
其中：
环A选自环烷基、杂环基、芳基、杂芳基，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
R a相同或不同，选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)NR 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 23或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
R 19选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)NR 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 23、-(CH 2) n1S(O)(＝NR 23)R 24或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、 取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
x、m 1和n 1如通式(II)所述。
在本发明的一个优选实施例方案中，所述的通式(II)所示的化合物，其为通式(III-B)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019074108-appb-000008
其中：
R 5选自氢原子、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基；
R 19选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、-(CH 2) n1OR 23或-(CH 2) n1SR 23；
R c选自氢原子、氰基或C 1-6烷基；
z为0、1或2的整数；且
n为0、1或2。
在本发明的一个优选实施例方案中，所述的通式(II)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(IV-A)和(IV-B)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019074108-appb-000009
其中：
R 3a选自C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基；
R 19选自氰基、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、-(CH 2) n1OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)(＝NR 23)R 24或-(CH 2) n1SR 23；
R a选自氢原子、氰基、卤素、硝基、烷基、烷氧基、卤代烷基、环烷基、羟 烷基、杂环基、杂芳基、-(CH 2) n1CR 23R 24R 25、-(CH 2) n1SR 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)(＝NR 23)R 24、-(CH 2) n1C(O)NR 23R 24；其中所述的烷基、环烷基、杂环基或杂芳基任选进一步被选自氢原子、烷基、卤素、氰基、羟基、环烷基、杂环基和杂芳基中的一个或多个所取代；
x为0、1或2的整数，且
R 5、m 1和n 1如权利要求2所述。
在本发明的一个优选实施例方案中，所述通式(II)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(VIII)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019074108-appb-000010
其中：
环A、Z、R a和x如通式(III)所述。
在本发明的一个优选实施例方案中，所述通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(VI)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019074108-appb-000011
其中：
Z选自-CR 23R 24-、-(CH 2) n1NR 23-、-(CH 2) n1O(CH 2) n2-或-O-；优选为亚甲基；
环B选自环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
R b相同或不同，选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)NR 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 23或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；且
y选自0、1、2、3或4的整数。
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(VIII)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019074108-appb-000012
其中：
R 21选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 24或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
R 23～R 26、m 1和n 1如权利要求1所述。
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物、其立体 异构体或其药学上可接受盐，其为通式(X)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019074108-appb-000013
其中：
M选自-CR 23-或氧原子；
Y选自-S(CH 2) n1-、
Figure PCTCN2019074108-appb-000014
Figure PCTCN2019074108-appb-000015
R 21选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 24或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
R 22～R 26、m 1和n 1如权利要求1所述。
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物，其立体异构体或其药学上可接受盐，其中所述的环A、环B和环C选自以下基团：
Figure PCTCN2019074108-appb-000016
Figure PCTCN2019074108-appb-000017
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物，其立体异构体或其药学上可接受盐，其中所述的
R a、R b和R c选自氢原子、氰基、卤素、硝基、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、C 1-6羟烷基、5-10元杂环基、5-10元杂芳基、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1C(O)OR 23或-(CH 2) n1S(O) m1R 23，其中所述的C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、C 1-6羟烷基、5-10元杂环基和5-10元杂芳基任选进一步被选自氢原子、C 1-6烷基、卤素、氰基、羟基、C 3-6环烷基、C 1-6羟烷基、5-10元杂环基和5-10元杂芳基中的一个或多个取代基所取代；
R 23和R 24各自独立的选自氢原子、C 1-6烷基或3-8元杂环基。
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物，其立体异构体或其药学上可接受盐，
其中：
Z选自-CH 2-、-CH 2NH-、-CH 2O-、-CH 2-、-NH-或-NHSO 2-；
R 3a选自C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基；优选C 1-3烷基或C 1-3烷氧基；更优选甲基或甲氧基甲基；
R 5选自氢原子、卤素、氰基、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基；优选氢原子和C 1-3烷基；
R 19选自氰基、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、-(CH 2) n1OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)(＝NR 23)R 24或-(CH 2) n1SR 23；优选氰基、卤素、C 1-3烷氧基、C 1-3卤代烷基、-(CH 2) n1SR 23、-(CH 2) n1S(O) m1R 23或-(CH 2) n1S(O)(＝NR 23)R 24；更优选卤素；
或者，R 5和R 19任意两个相邻的基团之间可形成一个C 3-6环烷基，优选环丙基。
在本发明的一个优选实施例方案中，所述的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，选自如下化合物：
Figure PCTCN2019074108-appb-000018
Figure PCTCN2019074108-appb-000019
Figure PCTCN2019074108-appb-000020
Figure PCTCN2019074108-appb-000021
Figure PCTCN2019074108-appb-000022
Figure PCTCN2019074108-appb-000023
Figure PCTCN2019074108-appb-000024
本发明进一步涉及一种药用组合物，其包括治疗有效剂量的任一所示的通式(I)化合物、其立体异构体或其药学上可接受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。
本发明进一步涉及任一所示的通式(I)化合物、其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备GABA A受体调节剂药物中的应用。
本发明进一步涉及通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，或其药物组合物在制备治疗CNS相关疾病的药物中的应用，其中所述CNS相关疾病是选自睡眠障碍、心境障碍、精神分裂症谱系障碍、痉挛性障碍、记忆障碍和/或认知障碍、运动障碍、人格障碍、自闭症谱系障碍、疼痛、外伤性脑损伤、血管疾病、物质滥用障碍和/或戒断综合征或耳鸣。。
本发明进一步涉及通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，或其药物组合物在制备治疗CNS相关疾病的方法。
本发明还涉及一种治疗预防和/或治疗预制备治疗CNS相关疾病的方法，其包括向患者施用治疗有效剂量的通式(I)所示的化合物其立体异构体或其药学上可接受的盐，或其药物组合物。
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8个碳原子的烷基，更优选1至6个碳原子的烷基，最更优选1至3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。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。
术语“亚烷基”是指烷基的一个氢原子进一步被取代，例如：“亚甲基”指-CH 2-、“亚乙基”指-(CH 2) 2-、“亚丙基”指-(CH 2) 3-、“亚丁基”指-(CH 2) 4-等。术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基，优选环丙基、环丁基、环己基、环戊基和环庚基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2019074108-appb-000025
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：
Figure PCTCN2019074108-appb-000026
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三 环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2019074108-appb-000027
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2019074108-appb-000028
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，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子；最优选包含3至8个环原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基和1,4-二氮杂烷基等，优选四氢呋喃基、吡唑烷基、吗啉基、1,4-二氮杂烷基、哌嗪基和吡喃基。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或者两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共 轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2019074108-appb-000029
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2019074108-appb-000030
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2019074108-appb-000031
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 PCTCN2019074108-appb-000032
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。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 PCTCN2019074108-appb-000033
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，更优选为5元或6元，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为三唑基、四唑基、噻吩基、咪唑基、吡唑基、哒嗪基、嘧啶基、噻唑基、噁唑基、异噁唑基或嘧啶基；更有选三唑基、四唑基、吡唑基、吡啶基、哒嗪基、嘧啶基、噻唑基、噁唑基、异噁唑基或咪唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体 结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2019074108-appb-000034
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。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、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。
“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。
“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
“烯基”指链烯基，又称烯烃基，其中所述的烯基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“炔基”指(CH≡C-)，其中所述的炔基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
“羟基”指-OH基团。
“卤素”指氟、氯、溴或碘。
“氨基”指-NH 2。
“氰基”指-CN。
“硝基”指-NO 2。
“羧基”指-C(O)OH。
“THF”指四氢呋喃。
“EtOAc”指乙酸乙酯。
“MeOH”指甲醇。
“DMF”指N、N-二甲基甲酰胺。
“DIPEA”指二异丙基乙胺。
“TFA”指三氟乙酸。
“MeCN”指乙晴。
“DMA”指N,N-二甲基乙酰胺。
“Et 2O”指乙醚。
“DCE”指1,2二氯乙烷。
“DIPEA”指N，N-二异丙基乙胺。
“NBS”指N-溴代琥珀酰亚胺。
“NIS”指N-碘代丁二酰亚胺。
“Cbz-Cl”指氯甲酸苄酯。
“Pd 2(dba) 3”指三(二亚苄基丙酮)二钯。
“Dppf”指1,1’-双二苯基膦二茂铁。
“HATU”指2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯。
“KHMDS”指六甲基二硅基胺基钾。
“LiHMDS”指双三甲基硅基胺基锂。
“MeLi”指甲基锂。
“n-BuLi”指正丁基锂。
“NaBH(OAc) 3”指三乙酰氧基硼氢化钠。
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。
本发明所述的氢原子均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(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)，氘代甲醇(CD 3OD)和氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。
液质联用色谱LC-MS的测定用Agilent 1200 Infinity Series质谱仪。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)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，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。
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度。
实施例1
1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000035
第一步：(8S,9S,10S,13S,14S)-10-氟-13-甲基-7,8,9,10,11,12,13,14,15,16-十氢-3H-环戊二烯并[a]菲-3,17(6H)-二酮
Figure PCTCN2019074108-appb-000036
100mL三口瓶中依次加入(8R,9S,13S,14S)-3-羟基-13-甲基-6,7,8,9,11,12,13,14,15,16-十氢-17H-环戊二烯并[a]菲-17-酮(2.7g,10mmol)和乙腈(100mL)，搅拌下加入1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐(3.6g，10mmol)。油浴加热升温至45℃，反应5小时后冷却至室温，反应液浓缩，用二氯甲烷(100mL)溶解后用饱和食盐水洗涤(30mLx3)，有机相经无水硫酸钠干燥，过滤，旋干。粗产物用柱层析分离(石油醚/乙酸乙酯：3/1)纯化得到(8S,9S,10S,13S,14S)-10-氟-13-甲基-7,8,9,10,11,12,13,14,15,16-十氢-3H-环戊二烯并[a]菲-3,17(6H)-二酮(1.8g，淡黄色固体，产率：62.5％)。
MS m/z(ESI):289.1[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.12-7.05(m,1H),6.30-6.19(m,1H),6.04(s,1H),2.70-2.60(m,1H),2.52-2.45(m,2H),2.16-1.86(m,7H),1.65-1.18(m,5H),0.98(s,3H).
19F NMR(376MHz,CDCl 3)δ-165.20.
第二步：(5R,8S,9S,10R,13S,14S)-10-氟-13-甲基十四氢-3H-环戊二烯并[a]菲-3,17(2H)-二酮
Figure PCTCN2019074108-appb-000037
100mL单口瓶中加入(8S,9S,10S,13S,14S)-10-氟-13-甲基-7,8,9,10,11,12,13,14,15,16-十氢-3H-环戊二烯并[a]菲-3,17(6H)-二酮(1.8g，6.25mmol)溶于乙醇(50mL)中，室温下搅拌2-3分钟后，加入钯硫酸钡催化剂(300mg)，加毕室温条件下氢气环境中搅拌5小时。将反应混合液过滤，用20mL二氯甲烷溶解，有白色固体析出，过滤，滤液旋干，粗产物用柱层析分离(石油醚 /乙酸乙酯：3/1)纯化得到(5R,8S,9S,10R,13S,14S)-10-氟-13-甲基十四氢-3H-环戊二烯并[a]菲-3,17(2H)-二酮(600mg，白色固体，产率：32.9％)。
1H NMR(400MHz,CDCl 3)δ2.63-2.45(m,2H),2.43-2.33(m,3H),2.30-1.80(m,8H),1.75-1.55(m,5H),1.45-1.35(m,3H),1.25-1.18(m,1H),0.94(s,3H).
19F NMR(376MHz,CDCl 3)δ-159.89.
第三步：(3R,5R,8S,10R,13S,14S)-10-氟-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮
Figure PCTCN2019074108-appb-000038
100mL三口瓶中加入2,6-二叔丁基-4-甲基苯酚(1.45g,6.6mmol)溶于无水甲苯(15mL)中，冰浴冷却至0～5℃，氮气保护下滴加三甲基铝(1.7mL,2M,3.3mmol)，加毕自然升温至室温，搅拌1小时。反应液冷却至-78℃，(5R,8S,9S,10R,13S,14S)-10-氟-13-甲基十四氢-3H-环戊二烯并[a]菲-3,17(2H)-二酮(320mg，1.1mmol)的甲苯(5mL)溶液滴加至上述反应液中，反应液在-78℃下反应1小时。然后滴加甲基溴化镁(1.0mL，3M，3mmol)，反应液在-78℃下反应1小时。反应液用饱和氯化铵水溶液淬灭，乙酸乙酯(20mL)萃取，有大量白色固体析出，过滤，滤液分层，有机相用无水硫酸钠干燥，旋干，用柱层析分离(石油醚/乙酸乙酯：2/1)纯化得到(3R,5R,8S,10R,13S,14S)-10-氟-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(250mg，白色固体，产率：74.0％)
1H NMR(400MHz,CDCl 3)δ2.46(dd,J＝19.3,8.7Hz,1H),2.17–1.72(m,8H),1.71–1.44(m,10H),1.38(s,3H),1.34–1.11(m,3H),0.90(s,3H).
19F NMR(376MHz,CDCl 3)δ-158.16.
第四步：(3R,5R,8S,10R,13S,14S)-17-亚乙基-10-氟-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚
Figure PCTCN2019074108-appb-000039
100mL三口瓶中依次加入叔丁醇钾(500mg,4.5mmol)，四氢呋喃(15mL)，反应液冷却至0℃，分批加入乙基三苯基溴化膦(1.82g,4.8mmol)，反应液在60℃下搅拌2小时，将(3R,5R,8S,10R,13S,14S)-10-氟-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(250mg，0.75mmol)加入到上述反应液中，反应液在60℃下反应8小时。反应液用饱和氯化铵溶液淬灭，乙酸乙酯(20mL) 萃取,经饱和食盐水洗涤(10mLx2)，有机相用无水硫酸钠干燥，过滤，旋干，柱层析分离(石油醚/乙酸乙酯：5/1)，得到(3R,5R,8S,10R,13S,14S)-17-亚乙基-10-氟-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚(110mg，白色固体，收率42％)。
1H NMR(400MHz,CDCl 3)δ5.15-5.08(m,1H),2.40-1.80(m,8H),1.65–1.45(m,13H),1.36(s,3H),1.31–1.05(m,4H),0.89(s,3H).
19F NMR(376MHz,CDCl 3)δ-157.91.
第五步：(3R,5R,8S,10R,13S,14S)-10-氟-17-(1-羟基乙基)-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚
Figure PCTCN2019074108-appb-000040
(3R,5R,8S,10R,13S,14S)-17-亚乙基-10-氟-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚(110mg，0.35mmol)溶于干燥四氢呋喃(5mL)中，室温下加入硼烷四氢呋喃络合物(1.1mL,1M,1.05mmol)，加毕搅拌1小时。反应液用冰水浴冷却，慢慢滴加NaOH(10％，1.5mL)，有大量气体放出，然后慢慢滴加双氧水(30％，2mL)，反应液在室温下搅拌1小时，反应液用乙酸乙酯萃取(10mLx2)，用10％的硫代硫酸钠洗涤，有机相无水硫酸钠干燥，减压浓缩得到(3R,5R,8S,10R,13S,14S)-10-氟-17-(1-羟基乙基)-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚(100mg，白色固体)。
第六步：1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000041
(3R,5R,8S,10R,13S,14S)-10-氟-17-(1-羟基乙基)-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚(100mg,0.3mmol)溶于二氯甲烷(5mL)，加入氯铬酸吡啶(130mg,0.6mmol)，室温条件下搅拌12小时。反应液过滤，减压浓缩，柱层析分离(石油醚/乙酸乙酯：5/1)，得到得到1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(80mg,白色固体，产率：81％)。
1H NMR(400MHz,CDCl 3)δ2.53(t,J＝9.0Hz,1H),2.23-2.16(m,1H),2.12(s,3H),2.10-1.83(m,5H),1.73-1.42(m,12H),1.38(s,3H),1.35-1.02(m,4H),0.64(s,3H).
实施例2
1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074108-appb-000042
第一步：2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000043
1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(80mg,0.25mmol)溶于甲醇(5mL)，加入3滴溴化氢和3滴液溴，室温条件下搅拌12小时。反应液加入到冰水中，用乙酸乙酯萃取(10mLx2)，有机相用无水硫酸钠干燥，减压浓缩得到得到2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(80mg，81％)，直接用于下一步反应。
第二步：1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074108-appb-000044
2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(80mg，0.2mmol)溶于四氢呋喃(5mL)中，加入4-氰基吡唑(46mg，0.5mmol)和碳酸钾(84mg，0.6mmol)反应液在室温条件下搅拌5h。反应液过滤，浓缩，用prep-HPLC分离得产品(25mg，白色固体，产率30.3％)。
MS m/z(ESI):428.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.87(s,1H),7.81(s,1H),5.10-4.83(m,2H),2.60(t,J＝8.8Hz,1H),2.28-2.18(m,1H),2.15-2.07(m,2H),2.05–1.75(m,5H),1.69– 1.45(m,10H),1.38(s,3H),1.35–1.23(m,3H),1.19–1.07(m,1H),0.70(s,3H).
19F NMR(376MHz,CDCl 3)δ-158.28.
实施例3和实施例4
1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-3-甲腈(3)
1-(2-((3R,5R,8S,9S,10R,13S,14S,17R)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-3-甲腈(4)
Figure PCTCN2019074108-appb-000045
2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(80mg，0.2mmol)溶于四氢呋喃(5mL)中，加入3-氰基吡唑(46mg，0.5mmol)和碳酸钾(84mg，0.6mmol)反应液在室温条件下搅拌5h。反应液过滤，浓缩，用prep-HPLC分离得产品1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-3-甲腈(3)(18mg，白色固体，产率21.9％)和产品1-(2-((3R,5R,8S,9S,10R,13S,14S,17R)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-3-甲腈(4)(5mg，白色固体，产率6.0％)。
实施例3：
MS m/z(ESI):428.1[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.50(d,J＝2.4Hz,1H),6.74(d,J＝2.4Hz,1H),5.15-4.85(m,2H),2.60(t,J＝8.9Hz,1H),2.26-2.16(m,1H),2.05-1.90(m,2H),1.85–1.73(m,3H),1.67–1.43(m,12H),1.38(s,3H),1.38–1.25(m,3H),1.18–1.06(m,1H),0.71(s,3H).
19F NMR(376MHz,CDCl 3)δ-158.21.
实施例4：
MS m/z(ESI):428.1[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.50(d,J＝2.4Hz,1H),6.76(d,J＝2.4Hz,1H),5.15-4.85(m,2H),2.78(dd,J＝8.0,2.8Hz，1H),2.10-1.73(m,7H),1.70–1.36(m,11H),1.35(s,3H),1.32–1.10(m,4H),0.98(s,3H).
19F NMR(376MHz,CDCl 3)δ-158.42.
实施例5和实施例6
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(3-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(5)
1-((3R,5R,8S,9S,10R,13S,14S,17R)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(3-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(6)
Figure PCTCN2019074108-appb-000046
以2-溴-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(1H-四唑-1-基)乙烷-1-酮(5)(35.5mg，白色固体，产率43％)和1-((3R,5R,8S,9S,10R,13S,14S,17R)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(3-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(6)(12.3mg，白色固体，产率14.9％)。
实施例5：
MS m/z(ESI):471.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.48(s,1H),6.59(d,J＝2.1Hz,1H),5.05-4.92(m,2H),2.59(t,J＝8.8Hz,1H),2.25-2.15(m,1H),2.15-2.05(m,2H),2.03–1.69(m,5H),1.70–1.41(m,12H),1.38(s,3H),1.06(m,4H),0.71(s,3H).
实施例6：
MS m/z(ESI):471.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.48(d,J＝1.3Hz,1H),6.61(d,J＝2.3Hz,1H),5.07-4.90(m,2H),2.77(dd,J＝7.9,3.0Hz,1H),2.12–1.72(m,9H),1.72–1.38(m,11H),1.34(s,3H),1.33-1.04(m,4H),0.96(s,3H).
实施例7和实施例8
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(7)
1-((3R,5R,8S,9S,10R,13S,14S,17R)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(8)
Figure PCTCN2019074108-appb-000047
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(7)(22mg，白色固体，产率32.9％)和产物1-((3R,5R,8S,9S,10R,13S,14S,17R)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(8)(8mg，白色固体，产率11.5％)。
实施例7：
MS m/z(ESI):471.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.72(s,2H),5.05–4.85(m,2H),2.60(t,J＝8.0Hz,1H),2.30-2.15(m,1H),2.15-2.05(m,2H),2.01–1.93(m,2H),1.92–1.83(m,1H),1.81–1.71(m,2H),1.71–1.43(m,10H),1.38(s,3H),1.35–1.25(m,3H),1.19–1.10(m,1H),0.71(s,3H).
19F NMR(376MHz,CDCl 3)δ-56.44,-158.26.
实施例8：
MS m/z(ESI):471.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.74(s,1H),7.73(s,1H),5.29-5.19(m,2H),2.79(dd,J＝7.9,2.7Hz,1H),2.10-2.03(m,1H),1.95-1.75(m,6H),1.65–1.25(m,17H),1.19–1.10(m,1H),0.98(s,3H).
19F NMR(376MHz,CDCl 3)δ-56.42,-158.43.
实施例9和实施例10
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮(9)
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(2H-1,2,3-三唑-2-基)乙烷-1-酮(10)
Figure PCTCN2019074108-appb-000048
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例6第二步得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮(9)(32mg，白色固体，产率32.9％)和产物1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(2H-1,2,3-三唑-2-基)乙烷-1-酮(10)(20mg，白色固体，产率20.5％)。
实施例9：
MS m/z(ESI):404.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.65(s,1H),5.30-5.13(m,2H),2.65(t,J＝8.0Hz,1H),2.25-2.15(m,1H),2.13-2.03(m,2H),2.05–1.75(m,5H),1.68–1.43(m,10H),1.38(s,3H),1.35–1.25(m,3H),1.19–1.10(m,1H),0.71(s,3H).
19F NMR(376MHz,CDCl 3)δ-158.26.
实施例10：
MS m/z(ESI):404.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.69(s,2H),5.24(s,2H),2.57(t,J＝8.0Hz,1H),2.27-2.16(m,1H),2.15-2.07(m,2H),2.05–1.75(m,5H),1.68–1.43(m,10H),1.38(s,3H),1.35–1.25(m,3H),1.19–1.05(m,1H),0.74(s,3H).
19F NMR(376MHz,CDCl 3)δ-158.24.
实施例11
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-甲基-1H-吡唑-1-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000049
以2-溴-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例6第八步得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-甲基-1H-吡唑-1-基)乙烷-1-酮(11)(24mg，白色固体，产率29％)。
MS m/z(ESI):417.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.35(s,1H),7.18(s,1H),4.90-4.79(m,2H),2.56(t,J＝8.9Hz,1H),2.27-2.13(m,1H),2.11(s,3H),2.06-1.80(m,4H),1.80-1.40(m,11H),1.38(s,3H),1.35-1.19(m,5H),1.18–1.03(m,1H),0.71(s,3H).
实施例12和实施例13
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(2H-四唑-2-基)乙烷-1-酮(12)
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(1H-四唑-1-基)乙烷-1-酮(13)
Figure PCTCN2019074108-appb-000050
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(2H-四唑-2-基)乙烷-1-酮(12)(12mg，白色固体，产率16％)和1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(1H-四唑-1-基)乙烷-1-酮(13)(9mg，白色固体，产率12％)。
实施例12：
MS m/z(ESI):405.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.57(s,1H),5.46(s,2H),2.64(t,J＝8.0Hz,1H),2.28-2.19(m,1H),2.18-2.07(m,2H),2.05–1.75(m,4H),1.71–1.43(m,11H),1.38(s,3H),1.34–1.26(m,3H),1.21–1.11(m,1H),0.75(s,3H).
实施例13：
MS m/z(ESI):405.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.75(s,1H),5.35-5.15(m,2H),2.67(t,J＝8.0Hz,1H),2.30-2.19(m,1H),2.15-2.07(m,1H),2.05–1.75(m,4H),1.68–1.45(m,11H),1.39(s,3H),1.35–1.25(m,4H),1.20–1.10(m,1H),0.71(s,3H).
实施例14和实施例15
2-(2H-苯并[d][1,2,3]三唑-2-基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(15)
2-(1H-苯并[d][1,2,3]三唑-1-基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(16)
Figure PCTCN2019074108-appb-000051
以2-溴-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例6第八步得产品2-(2H-苯并[d][1,2,3]三唑-2-基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(14)(11mg，产率14％)和2-(1H- 苯并[d][1,2,3]三唑-1-基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(15)(31mg，产率41％)。
实施例14：
MS m/z(ESI):453.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.88(dd,J＝6.6,3.0Hz,2H),7.40(dd,J＝6.6,3.0Hz,2H),5.53(t,J＝4.7Hz,2H),2.64(t,J＝8.9Hz,1H),2.34–1.41(m,16H),1.38(s,3H),1.35–0.97(m,6H),0.78(s,3H).
实施例15：
MS m/z(ESI):453.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.11(d,J＝7.5Hz,1H),7.50(t,J＝7.5Hz,1H),7.46–7.30(m,2H),5.42(s,2H),2.70(t,J＝8.5Hz,1H),2.35–1.42(m,16H),1.38(s,3H),1.35–1.01(m,6H),0.77(s,3H).
实施例16和实施例17
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(2H-吡唑并[3,4-c]吡啶-2-基)乙烷-1-酮(16)
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(1H-吡唑并[3,4-c]吡啶-1-基)乙烷-1-酮(17)
Figure PCTCN2019074108-appb-000052
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例6第二步得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(1H-四唑-1-基)乙烷-1-酮(16)(9.2mg，白色固体，产率10.5％)和1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(2H-四唑-2-基)乙烷-1-酮(17)(16mg，白色固体，产率18.3％)。
实施例16：
MS m/z(ESI):454.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ9.33(s,1H),8.19(s,1H),8.13(s,1H),7.72(s,1H),5.42-5.25(m,2H),2.70(t,J＝8.0Hz,1H),2.30-2.10(m,3H),2.05-1.85(m,8H),1.70–1.45(m,7H),1.39(s,3H),1.32–1.25(m,3H),0.90-0.85(m,1H),0.75(s,3H).
实施例17：
MS m/z(ESI):454.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.88(s,1H),8.36(s,1H),8.13(s,1H),7.71(s, 1H),5.32-5.25(m,2H),2.69(t,J＝8.0Hz,1H),2.25-2.10(m,3H),2.05-1.75(m,5H),1.70–1.45(m,10H),1.39(s,3H),1.35–1.25(m,3H),1.20-1.10(m,1H),0.76(s,3H).
实施例18、实施例19和实施例20
2-(5-氟-2H-苯并[d][1,2,3]三唑-2-基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(18)
2-(6-氟-1H-苯并[d][1,2,3]三唑-1-基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(19)
2-(5-氟-1H-苯并[d][1,2,3]三唑-1-基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(20)
Figure PCTCN2019074108-appb-000053
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得2-(5-氟-2H-苯并[d][1,2,3]三唑-2-基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(18)(20mg，白色固体，产率14.9％)，2-(6-氟-1H-苯并[d][1,2,3]三唑-1-基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(19)(18mg，白色固体，产率13.1％)和2-(5-氟-1H-苯并[d][1,2,3]三唑-1-基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(20)(19mg，白色固体，产率13.9％)。
实施例18：
MS m/z(ESI):472.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.86(dd,J＝9.3,4.7Hz,1H),7.47(dd,J＝8.7,1.9Hz,1H),7.21(m,1H),5.55-5.45(m,2H),2.65(t,J＝8.8Hz,1H),2.32–2.08(m,3H),2.04–1.45(m,15H),1.38(s,3H),1.35–1.23(m,3H),1.20-1.10(m,1H),0.78(s,3H).
实施例19：
MS m/z(ESI):472.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.04(dd,J＝8.9,4.4Hz,1H),7.20-7.10(m,1H),6.99(d,J＝7.6Hz,1H),5.45-5.35(m,2H),2.69(d,J＝8.7Hz,1H),2.31–2.08(m,3H),2.04–1.45(m,15H),1.39(s,3H),1.35-1.25(m,3H),1.20-1.10(m,1H),0.76(s,3H).
实施例20：
MS m/z(ESI):472.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.71(d,J＝7.9Hz,1H),7.35-7.28(m,2H),5.45-5.35(m,2H),2.69(d,J＝8.7Hz,1H),2.31–2.08(m,3H),2.04–1.45(m,15H),1.39(s,3H),1.35-1.25(m,3H),1.20-1.10(m,1H),0.76(s,3H).
实施例21和实施例22
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4,5,6,7-四氢-2H-吲唑-2-基)乙烷-1-酮(21)
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4,5,6,7-四氢-1H-吲唑-1-基)乙烷-1-酮(22)
Figure PCTCN2019074108-appb-000054
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例6第二步得1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4,5,6,7-四氢-2H-吲唑-2-基)乙烷-1-酮(21)(15.0mg，白色固体，产率27.2％)和1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4,5,6,7-四氢-1H-吲唑-1-基)乙烷-1-酮(22)(8.0mg，白色固体，产率12.1％)。
实施例21：
MS m/z(ESI):457.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.10(s,1H),4.90–4.85(m,2H),2.72-2.66(m,2H),2.62-2.52(m,3H),2.25-1.40(m,22H),1.37(s,3H),1.33–1.23(m,3H),1.17-1.07(m,1H),0.71(s,3H).
实施例22：
MS m/z(ESI):457.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.31(s,1H),4.85–4.75(m,2H),2.60-2.50(m,3H),2.45-2.39(m,2H),2.25-1.40(m,22H),1.37(s,3H),1.33–1.23(m,3H),1.15-1.05(m,1H),0.71(s,3H).
实施例23
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-((4-氟苯基)氨基)乙烷-1-酮
Figure PCTCN2019074108-appb-000055
2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(80mg，0.2mmol)溶于四氢呋喃(5mL)中，加入4-氟苯胺(42mg，0.4mmol)和三乙胺(60mg，0.6mmol)。反应液在室温条件下搅拌5h。反应液浓缩，用prep-HPLC分离得产品(18mg，白色固体，产率21％)。
MS m/z(ESI):446.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ6.94-6.88(m,2H),6.58–6.53(m,2H),3.96–3.85(m,2H),2.57(t,J＝8.0Hz,1H),2.30-2.20(m,1H),2.15-2.06(m,1H),2.05–1.71(m,6H),1.68–1.43(m,10H),1.38(s,3H),1.34–1.20(m,3H),1.18–1.07(m,1H),0.68(s,3H).
实施例24
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-((2-氟苯基)氨基)乙烷-1-酮
Figure PCTCN2019074108-appb-000056
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例23得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-((2-氟苯基)氨基)乙烷-1-酮(11mg，白色固体，产率20.5％)。
MS m/z(ESI):446.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.04–6.92(m,2H),6.71–6.61(m,1H),6.60–6.52(m,1H),4.03–3.86(m,2H),2.58(t,J＝8.8Hz,1H),2.33–1.44(m,18H),1.38(s,3H),1.33–1.05(m,4H),0.69(s,3H).
实施例25
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-((3-氟苯基)氨基)乙烷-1-酮
Figure PCTCN2019074108-appb-000057
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例23得产品 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-((3-氟苯基)氨基)乙烷-1-酮(4.5mg，白色固体，产率7.0％)。
MS m/z(ESI):446.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.15–7.07(m,1H),6.51–6.38(m,2H),6.30(d,J＝11.4Hz,1H),3.98–3.85(m,2H),2.57(t,J＝8.8Hz,1H),2.12–1.64(m,18H),1.38(s,3H),1.30–1.26(m,3H),1.18–1.11(m,1H),0.68(s,3H).
实施例26
2-((2,4-二氟苯基)氨基)-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000058
将(2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(80mg，0.193mmol)溶于四氢呋喃(3mL)中，加入2,4-二氟苯胺(37mg，0.289mmol)和碳酸钾(53mg，0.438mmol)，然后在室温搅拌16h。向反应液中加水(15mL)，用乙酸乙酯萃取(20mLx3)，合并有机相用饱和食盐水(15mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，然后制备色谱分离得到白色固体2-((2,4-二氟苯基)氨基)-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(7mg，产率：7.8％)。
MS m/z(ESI):464.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ6.84–6.70(m,2H),6.50-6.45(m,1H),3.98-3.88(m,2H),2.57(t,J＝8.9Hz,1H),2.31–2.19(m,1H),2.10(m,1H),2.04–1.74(m,7H),1.51–1.44(m,5H),1.38(s,3H),1.37–1.20(m,8H),1.13(m,2H),0.69(s,3H).
实施例27
5-氟-2-((2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)氨基)苯甲腈
Figure PCTCN2019074108-appb-000059
将2-氨基-5-氟苯甲腈(147mg,1.08mmol)溶解在0摄氏度的四氢呋喃(5mL)中，然后加入钠氢(29mg,0.72mmol)在0摄氏度搅拌40分钟，然后滴加2-溴-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(150mg,0.36mmol)和四氢呋喃(2mL)的混合溶液在0摄氏度搅拌30分钟，向反应液中加水(20mL)，然后用乙酸乙酯萃取(20mLx3)，合并有机相用饱和食盐水(30mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩干，然后经过制备色谱分离纯化，得到5-氟-2-((2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)氨基)苯甲腈(10mg，白色固体，产率：6％)
MS m/z(ESI):471.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.62(dd,J＝9.6,3.0Hz,1H),7.10–7.01(m,1H),6.62(dd,J＝9.1,4.5Hz,1H),4.90-4.73(m,2H),2.58(t,J＝8.8Hz,1H),2.28-1.78(m,9H),1.65-1.58(m,3H),1.61-1.44(m,4H),1.38(s,3H),1.31-1.26(m,4H),1.15-1.09(m,2H),0.90-0.86(m,2H),0.73(s,3H).
实施例28
1-((3S,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-((3-氟吡啶-4-基)氨基)乙烷-1-酮
Figure PCTCN2019074108-appb-000060
将4-氨基-3-氟吡啶(32.4mg，0.28mmol)，2-溴-1-((3S,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(60mg，0.14mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入三乙胺(42.5mg，0.42mmol)，室温搅拌过夜。加入5mL水，乙酸乙酯萃取(30mLx3)，饱和食盐水(20mL)洗一次，有机相加入无水硫酸钠干燥，旋干，用prep-HPLC分离得产品1-((3S,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-((3-氟吡啶-4-基)氨基)乙烷-1-酮(6.1mg，白色固体，产率9.7％)。
MS m/z(ESI):447.2[M+H] +.
实施例29
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(哒嗪-4-氧基)乙烷-1-酮
Figure PCTCN2019074108-appb-000061
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(哒嗪-4-氧基)乙烷-1-酮(19mg，白色固体，产率30.5％)。
MS m/z(ESI):431.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.92(s,1H),7.72(s,1H),6.60(s,1H),4.99–4.73(m,2H),2.67–2.54(m,1H),2.32–1.49(m,18H),1.38(s,3H),1.31–1.01(m,4H),0.71(s,3H).
实施例30和施例32
5-氟-2-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙氧基)苯甲腈(30)
5-氟-2-(2-((3R,5R,8S,9S,10R,13S,14S,17R)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙氧基)苯甲腈(32)
Figure PCTCN2019074108-appb-000062
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品5-氟-2-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙氧基)苯甲腈(30)(14.5mg，白色固体，产率21.2％)和5-氟-2-(2-((3R,5R,8S,9S,10R,13S,14S,17R)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙氧基)苯甲腈(32)(13.5mg，白色固体，产率19.8％)。
实施例30：
1H NMR(400MHz,CDCl 3)δ7.31(dd,J＝7.4,3.1Hz,1H),7.25–7.18(m,1H),6.74(dd,J＝9.3,4.0Hz,1H),4.69–4.53(m,2H),2.90(t,J＝8.7Hz,1H),2.32–1.43(m,18H),1.37(s,3H),1.31–1.03(m,4H),0.70(s,3H).
实施例32：
1H NMR(400MHz,CDCl 3)δ7.37–7.32(m,1H),7.25–7.17(m,2H),5.67–5.40(m,2H),3.40(t,J＝8.9Hz,1H),2.44–1.08(m,25H),0.73(s,3H).
实施例31
3-氟-4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙氧基)苯甲腈
Figure PCTCN2019074108-appb-000063
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品3-氟-4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙氧基)苯甲腈(13mg，白色固体，产率19.0％)。
1H NMR(400MHz,CDCl 3)δ7.50–7.34(m,2H),6.86(t,J＝8.4Hz,1H),4.76–4.59(m,2H),2.79(t,J＝8.9Hz,1H),2.29–1.42(m,17H),1.38(s,3H),1.34–1.07(m,5H),0.70(s,3H).
实施例33
4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙氧基)苯甲腈
Figure PCTCN2019074108-appb-000064
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙氧基)苯甲腈(27.5mg，白色固体，产率41.9％)。
1H NMR(400MHz,CDCl 3)δ7.60(d,J＝8.8Hz,2H),6.92(d,J＝8.8Hz,2H),4.65–4.52(m,2H),2.77(t,J＝8.7Hz,1H),2.24–1.49(m,18H),1.38(s,3H),1.32–1.25(m,3H),1.18–1.06(m,1H),0.71(s,3H).
实施例34
4-氟-3-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙氧基)苯甲腈
Figure PCTCN2019074108-appb-000065
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品4-氟-3-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙氧基)苯甲腈(32mg，白色固体，产率46.9％)。
1H NMR(400MHz,CDCl 3)δ7.36–7.27(m,1H),7.20(dd,J＝10.6,8.4Hz,1H),7.11(dd,J＝7.6,1.9Hz,1H),4.76–4.51(m,2H),2.77(t,J＝8.9Hz,1H),2.24–1.51(m,18H),1.38(s,3H),1.32–1.23(m,3H),1.19–1.06(m,1H),0.71(s,3H).
实施例35
2-氟-4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙氧基)苯甲腈
Figure PCTCN2019074108-appb-000066
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品2-氟-4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙氧基)苯甲腈(23mg，白色固体，产率33.7％)。
1H NMR(400MHz,CDCl 3)δ7.36–7.27(m,1H),7.20(dd,J＝10.6,8.4Hz,1H),7.11(dd,J＝7.6,1.9Hz,1H),4.76–4.51(m,2H),2.77(t,J＝8.9Hz,1H),2.24–1.51(m,18H),1.38(s,3H),1.32–1.23(m,3H),1.19–1.06(m,1H),0.71(s,3H).
实施例36
2-(2,4-二氟苯氧基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000067
以2-溴-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-羟基-3,13,15-三甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品2-(2,4-二氟苯氧基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(16.4mg，白色固体，产率24.4％)。
1H NMR(400MHz,Chloroform-d)δ6.95–6.83(m,2H),6.82–6.69(m,1H),4.67–4.45(m,2H),2.81(t,J＝8.8Hz,1H),2.36–2.16(m,1H),2.14–2.04(m,1H),2.03–1.78(m,4H),1.76–1.69(m,1H),1.65–1.44(m,11H),1.37(s,3H),1.32–1.21(m,3H),1.19–0.99(m,1H),0.69(s,3H).
实施例37
2-(4-氯-1H-吡唑-1-基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000068
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品2-(4-氯-1H-吡唑-1-基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(22mg，白色固体，产率34.9％)。
MS m/z(ESI):437.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.46(s,1H),7.42(s,1H),5.04–4.62(m,2H),2.57(t,J＝8.8Hz,1H),2.31–1.45(m,18H),1.38(s,3H),1.33–1.23(m,3H),1.18–1.05(m,1H),0.70(s,3H).
实施例38和实施例39
1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-3-甲基-1H-吡唑-4-甲腈(38)
1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-5-甲基-1H-吡唑-4-甲腈(39)
Figure PCTCN2019074108-appb-000069
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-3-甲基-1H-吡唑-4-甲腈(38)(16.5mg，白色固体，产率19.5％)和1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-5-甲基-1H-吡唑-4-甲腈(39)(9.5mg，白色固体，产率11％)。
实施例38：
MS m/z(ESI):442.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.75(s,1H),4.96–4.79(m,2H),2.65–2.54(m,1H),2.38(s,3H),2.17–1.58(m,18H),1.38(s,3H),1.33–1.24(m,3H),1.18–1.06(m,1H),0.70(s,3H).
实施例39：
MS m/z(ESI):442.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.71(s,1H),4.86–4.80(m,2H),2.61–2.54(m,1H),2.33(s,3H),2.23–1.55(m,18H),1.38(s,3H),1.30–1.27(m,3H),1.15–1.11(m,1H),0.71(s,3H).
实施例40
3-环丙基-1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074108-appb-000070
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品3-环丙基-1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈(15mg，白色固体，产率22.2％)。
MS m/z(ESI):468.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.72(s,1H),4.92–4.72(m,2H),2.57(t,J＝8.8Hz,1H),2.26–1.40(m,19H),1.38(s,3H),1.37–1.05(m,4H),1.05–0.91(m,4H),0.69(s,3H).
实施例41和实施例42
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(5-甲基-2H-四唑-2-基)乙烷-1-酮(41)
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(5-甲基-1H-四唑-1-基)乙烷-1-酮(42)
Figure PCTCN2019074108-appb-000071
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(5-甲基-2H-四唑-2-基)乙烷-1-酮(41)(23mg，白色固体，产率22.8％)。和1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(5-甲基-1H-四唑-1-基)乙烷-1-酮(42)(6.5mg，白色固体，产率6.5％)。
实施例41：
MS m/z(ESI):419.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ5.46–5.27(m,2H),2.63(d,J＝8.5Hz,1H),2.57(s,3H),2.31–1.46(m,18H),1.38(s,3H),1.35–1.03(m,4H),0.75(s,3H).
实施例42：
MS m/z(ESI):419.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ5.19–5.02(m,2H),2.66(t,J＝8.5Hz,1H),2.48(s,3H),2.30–1.48(m,18H),1.39(s,3H),1.33–1.07(m,4H),0.72(s,3H).
实施例43
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(噻唑-2-基氨基)乙烷-1-酮
Figure PCTCN2019074108-appb-000072
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(噻唑-2-基氨基)乙烷-1-酮(13mg，白色固体，产率20.7％)。
MS m/z(ESI):435.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ6.37(d,J＝4.9Hz,1H),5.92(d,J＝4.9Hz,1H),4.70–4.46(m,2H),2.68(t,J＝8.9Hz,1H),2.32–1.46(m,17H),1.37(s,3H),1.35–1.20(m,4H),1.16–1.06(m,1H),0.70(s,3H).
实施例44
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-((1-甲基-1H-吡唑-4-基)氨基)乙烷-1-酮
Figure PCTCN2019074108-appb-000073
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例23得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-((1-甲基-1H-吡唑-4-基)氨基)乙烷-1-酮(8.2mg，白色固体，产率13.2％)。
MS m/z(ESI):432.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.30(s,1H),7.26(s,1H),3.94–3.88(m,2H),3.83(s,3H),2.52(t,J＝8.7Hz,1H),2.27–1.46(m,16H),1.37(s,3H),1.33–1.05(m,6H),0.65(s,3H).
实施例45
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(异噻唑-4-基氨基)乙烷-1-酮
Figure PCTCN2019074108-appb-000074
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H- 环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(异噻唑-4-基氨基)乙烷-1-酮(8.5mg，白色固体，产率14.0％)。
MS m/z(ESI):419.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.08(s,1H),7.91(s,1H),3.85–3.65(m,2H),2.53(t,J＝8.7Hz,1H),2.23–1.72(m,8H),1.51–1.13(m,17H),0.67(s,3H).
实施例46、实施例47和实施例48
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(5-甲氧基-2H-苯并[d][1,2,3]三唑-2-基)乙烷-1-酮(46)
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(6-甲氧基-1H-苯并[d][1,2,3]三唑-1-基)乙烷-1-酮(47)
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(5-甲氧基-1H-苯并[d][1,2,3]三唑-1-基)乙烷-1-酮(48)
Figure PCTCN2019074108-appb-000075
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(5-甲氧基-2H-苯并[d][1,2,3]三唑-2-基)乙烷-1-酮(46)(13.5mg，白色固体，产率11.6％)，1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(6-甲氧基-1H-苯并[d][1,2,3]三唑-1-基)乙烷-1-酮(47)(14mg，白色固体，产率12.0％)和1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(5-甲氧基-1H-苯并[d][1,2,3]三唑-1-基)乙烷-1-酮(48)(14mg，白色固体，产率12.0％)。
实施例46：
MS m/z(ESI):484.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.75–7.70(m,1H),7.11–7.04(m,2H),5.49–5.40(m,2H),3.88(s,3H),2.62(t,J＝8.8Hz,1H),2.30–1.46(m,18H),1.38(s,3H),1.34–1.10(m,4H),0.78(s,3H).
实施例47：
MS m/z(ESI):484.2[M+H] +.
1H NMR(400MHz,CDCl3)δ7.39(d,J＝2.2Hz,1H),7.22(d,J＝9.0Hz,1H),7.15(dd,J＝9.0,2.2Hz,1H),5.39–5.35(m,2H),3.90(s,3H),2.70–2.64(m,1H),2.26–1.45(m,18H),1.38(s,3H),1.32–1.12(m,4H),0.76(s,3H).
实施例48：
MS m/z(ESI):484.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.92(d,J＝9.1Hz,1H),7.01(dd,J＝9.1,2.2Hz,1H),6.60(d,J＝2.2Hz,1H),5.35–5.31(m,2H),3.87(s,3H),2.73–2.65(m,1H),2.26–1.46(m,18H),1.38(s,3H),1.34–1.10(m,4H),0.77(s,3H).
实施例49
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(嘧啶-5-氧基)乙烷-1-酮
Figure PCTCN2019074108-appb-000076
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(嘧啶-5-氧基)乙烷-1-酮(10.3mg，白色固体，产率20.0％)。
MS m/z(ESI):431.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.92(s,1H),8.44(s,2H),4.78–4.63(m,2H),2.75-2.70(m,1H),2.29-2.20(m,1H),2.15-2.05(m,3H),2.02-1.93(m,3H),1.92–1.82(m,1H),1.81-1.73(m,2H),1.62-1.60(m,2H),1.59–1.43(m,6H),1.38(s,3H),1.35-1.25(m,3H),1.20-1.07(m,1H),0.72(s,3H).
实施例50
1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-3,5-二甲腈
Figure PCTCN2019074108-appb-000077
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-3,5-二甲腈(26mg，白色固体，产率 39.7％)。
MS m/z(ESI):451.2[M-H] -.
1H NMR(400MHz,CDCl 3)δ7.21(s,1H),5.19–5.14(m,2H),2.63(t,J＝8.9Hz,1H),2.29–1.49(m,18H),1.38(s,3H),1.32–1.30(m,3H),1.20–1.10(m,1H),0.75(s,3H).
实施例51
3-氯-1-(2-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074108-appb-000078
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品3-氯-1-(2-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈(12mg，白色固体，产率：22％)。
MS m/z(ESI):462.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.82(s,1H),4.98-4.85(m,2H),2.58(t,J＝8.5Hz,1H),2.26-2.18(m,1H),2.15–1.75(m,7H),1.66–1.45(m,10H),1.40–1.25(m,7H),1.15-1.09(m,1H),0.70(s,3H).
实施例52
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-(噁唑-2-基)-1H-吡唑-1-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000079
第一步：2-(1H-吡唑-4-基)噁唑的制备
Figure PCTCN2019074108-appb-000080
将1H-吡唑-4-甲醛(0.8g,8.33mmol)，1-((异氰基甲基)磺酰)-4-甲基苯(1.79g，9.16mmol)，碳酸钾(2.53g,18.33mmol)和甲醇(20mL)的混合物在70摄氏度搅拌16小时，将反应液减压浓缩干，经过柱层析分离纯化(二氯甲烷/甲醇＝10:1)，得到白色固体2-(1H-吡唑-4-基)噁唑(160mg，产率：14％)
MS m/z(ESI):136.2[M+H] +.
1H NMR(400MHz,DMSO)δ13.19(s,1H),8.30(s,1H),8.15(s,1H),7.83(s,1H),7.26(s,1H).
第二步：1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-(噁唑-2-基)-1H-吡唑-1-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000081
将2-溴1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(60mg,0.14mmol)，2-(1H-吡唑-4-基)噁唑(28mg,0.21mmol)，碳酸钾(39mg,0.28mmol)和四氢呋喃(3mL)的混合物在室温搅拌16小时，将反应液减压浓缩干，经过制备色谱分离纯化，得到1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-(噁唑-2-基)-1H-吡唑-1-基)乙烷-1-酮(13mg，白色固体，产率:20％)。
MS m/z(ESI):470.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.85(s,1H),7.76(s,1H),7.69(s,1H),7.13(s,1H),4.99-4.89(m,2H),2.61(t,J＝8.8Hz,1H),2.28–2.18(m,1H),2.15–2.08(m,2H),2.03–1.82(m,4H),1.78-1.76(m,2H),1.64-1.62(m,3H),1.52–1.43(m,5H),1.38(s,3H),1.31-1.26(m,4H),1.16-1.11(m,2H),0.73(s,3H).
实施例53和实施例54
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(6-(2-羟基丙烷-2-基)-1H-苯并[d]咪唑-1-基)乙烷-1-酮(53)
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(5-(2-羟基丙烷-2-基)-1H-苯并[d]咪唑-1-基)乙烷-1-酮(54)
Figure PCTCN2019074108-appb-000082
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H- 环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(6-(2-羟基丙烷-2-基)-1H-苯并[d]咪唑-1-基)乙烷-1-酮(53)(20mg，白色固体，产率27.1％)和1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(5-(2-羟基丙烷-2-基)-1H-苯并[d]咪唑-1-基)乙烷-1-酮(54)(15mg，白色固体，产率20.3％)。
实施例53：
MS m/z(ESI):511.3[M+H] +.
1H NMR(400MHz,Chloroform-d)δ7.93(s,1H),7.87(s,1H),7.51(d,J＝8.5Hz,1H),7.14(d,J＝8.5Hz,1H),4.96–4.84(m,2H),2.64(t,J＝8.7Hz,1H),2.31–2.17(m,1H),2.16–2.06(m,2H),2.04–1.93(m,2H),1.92–1.75(m,2H),1.71–1.43(m,15H),1.39(s,3H),1.35–1.20(m,5H),1.18–1.05(m,1H),0.75(s,3H).
实施例54：
MS m/z(ESI):511.3[M+H] +.
1H NMR(400MHz,Chloroform-d)δ8.19(s,1H),7.77(d,J＝8.5Hz,1H),7.46(s,1H),7.39(d,J＝8.1Hz,1H),5.12–4.89(m,2H),2.68(t,J＝8.2Hz,1H),2.31–2.06(m,7H),2.04–1.47(m,15H),1.38(s,3H),1.35–1.21(m,5H),1.20–1.02(m,1H),0.75(s,3H).
实施例55
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-(甲硫基)-1H-吡唑-1-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000083
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-(甲硫基)-1H-吡唑-1-基)乙烷-1-酮(25mg，白色固体，产率：38％)。
MS m/z(ESI):449.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.53(s,1H),7.43(s,1H),4.95-4.85(m,2H),2.58(t,J＝8.9Hz,1H),2.35(s,3H),2.25-2.17(m,1H),2.10(d,J＝11.4Hz,2H),2.02–1.82(m,4H),1.77-1.74(m,2H),1.68–1.42(m,9H),1.38(s,3H),1.35–1.21(m,4H),1.17–1.04(m,1H),0.71(s,3H).
实施例56
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-(甲基亚硫酰基<亚磺酰>)-1H-吡唑-1-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000084
将1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-(甲硫基)-1H-吡唑-1-基)乙烷-1-酮(35mg,0.078mmol)溶解在二氯甲烷(3mL)中，然后加入间氯过氧苯甲酸(17mg，0.0858mmol)在-78摄氏度搅拌2小时，用饱和亚硫酸钠溶液淬灭，然后用乙酸乙酯萃取(20mLx3)，合并有机相用饱和食盐水(30mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩干，然后经过制备色谱分离纯化，得到白色固体1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-(甲基亚硫酰基<亚磺酰>)-1H-吡唑-1-基)乙烷-1-酮(25mg，白色固体，产率：69％)。
MS m/z(ESI):465.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.81(d,J＝4.6Hz,2H),4.96-4.85(m,2H),2.90(s,3H),2.61(t,J＝8.7Hz,1H),2.27–2.17(m,1H),2.13-2.07(m,2H),2.04–1.73(m,4H),1.66-1.62(m,4H),1.50-1.48(m,5H),1.38(s,3H),1.33–1.22(m,5H),1.14-1.11(m,2H),0.71(s,3H).
实施例57
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-(甲磺酰)-1H-吡唑-1-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000085
将1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-(甲硫基)-1H-吡唑-1-基)乙烷-1-酮(15mg，0.033mmol)溶解在二氯甲烷(3mL)中，然后加入间氯过氧苯甲酸(17mg，0.1mmol)在室温搅拌6小时，将反应液减压浓缩干，经过制备色谱分离纯化，得到1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-(甲磺酰)-1H-吡唑-1-基)乙烷-1-酮(10mg，白色固体，产率：63％)。
MS m/z(ESI):481.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.93(s,1H),7.87(s,1H),4.99-4.90(m,2H),3.13(s,3H),2.62(t,J＝8.7Hz,1H),2.24-2.20(m,1H),2.12-2.09(m,2H),2.03–1.74(m,5H),1.66-1.63(m,4H),1.53–1.42(m,6H),1.38(s,3H),1.28-1.26(m,3H),1.15(m,1H),0.89-0.86(m,1H),0.71(s,3H).
实施例58
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-硝基-1H-吡唑-1-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000086
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-硝基-1H-吡唑-1-基)乙烷-1-酮(39mg，白色固体，产率：60.3％)。
MS m/z(ESI):448.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.18(s,1H),8.08(s,1H),5.08–4.81(m,2H),2.62(t,J＝8.7Hz,1H),2.30–1.46(m,16H),1.38(s,3H),1.34–1.04(m,6H),0.71(s,3H).
实施例59
1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-羧酸乙酯
Figure PCTCN2019074108-appb-000087
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-羧酸乙酯(32mg，白色固体，产率46.6％)。MS m/z(ESI):475.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.94(s,1H),7.92(s,1H),5.04–4.80(m,2H), 4.38–4.19(m,2H),2.60(t,J＝8.7Hz,1H),2.27–1.45(m,21H),1.38(s,3H),1.37–1.25(m,3H),1.20–1.07(m,1H),0.71(s,3H).
实施例60
1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-N,N-二甲基-1H-吡唑-4-甲酰胺
Figure PCTCN2019074108-appb-000088
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-N,N-二甲基-1H-吡唑-4-甲酰胺(10mg，白色固体，产率：14.6％)。
MS m/z(ESI):474.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.75(s,2H),5.09–4.82(m,2H),3.16(s,6H),2.69–2.53(m,1H),2.30–1.45(m,18H),1.38(s,3H),1.32–1.05(m,4H),0.72(s,3H).
实施例61
N-乙基-1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-N-甲基-1H-吡唑-4-甲酰胺
Figure PCTCN2019074108-appb-000089
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品N-乙基-1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-N-甲基-1H-吡唑-4-甲酰胺(14mg，白色固体，产率19.8％)。
MS m/z(ESI):488.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.73(s,1H),5.02–4.80(m,2H),3.66–3.44(m,2H),3.28–2.93(m,3H),2.60(t,J＝8.6Hz,1H),2.30–1.45(m, 18H),1.38(s,3H),1.34–1.06(m,7H),0.71(s,3H).
实施例62
2-(4-(吖丁啶-1-羰基)-1H-吡唑-1-基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000090
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品2-(4-(吖丁啶-1-羰基)-1H-吡唑-1-基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(12mg，白色固体，产率：17.1％)。
MS m/z(ESI):486.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.87(s,1H),7.76(s,1H),5.02–4.82(m,2H),4.39–4.21(m,4H),2.59(t,J＝8.5Hz,1H),2.46–1.59(m,20H),1.38(s,3H),1.34–1.19(m,3H),1.17–1.05(m,1H),0.71(s,3H).
实施例63和实施例64
2-(4-环丙基-2H-1,2,3-三唑-2-基)-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(63)
2-(4-环丙基-1H-1,2,3-三唑-1-基)-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(64)
Figure PCTCN2019074108-appb-000091
第一步：4,5-二溴-2H-1,2,3-三唑的制备
Figure PCTCN2019074108-appb-000092
向零摄氏度的2H-1,2,3-三唑(3g,43.43mmol)的水(30mL)溶液中缓慢滴加 液溴(3mL)，有淡黄色固体析出，然后在室温搅拌16小时，将反应液过滤，滤饼用水(20mL)洗涤，滤饼烘干，未经纯化直接用于下一步，得到4,5-二溴-2H-1,2,3-三唑(5.7g，白色固体，产率：58％)。
MS m/z(ESI):227.2[M+H] +.
第二步：4-溴-2H-1,2,3-三唑的制备
Figure PCTCN2019074108-appb-000093
将4,5-二溴-2H-1,2,3-三唑(5.7g，25.13mmol)悬浮在水(50mL)中，然后加入亚硫酸钠(9.5g,75.38mmol)在100摄氏度搅拌3天，反应液冷却到室温，用乙酸乙酯萃取(30mLx6)，合并有机相用饱和食盐水(100mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩干，得到4-溴-2H-1,2,3-三唑(3g，白色固体，产率：81％)。
MS m/z(ESI):148.2[M+H] +,150.2[M+2+H] +.
第三步：4-溴-2-((2-(三甲基甲硅烷基)乙氧基)甲基)-2H-1,2,3-三唑的制备
Figure PCTCN2019074108-appb-000094
向零摄氏度的4-溴-2H-1,2,3-三唑(2g,13.51mmol)的四氢呋喃(20mL)中缓慢加入钠氢(760mg,18.9mmol)，然后在0摄氏度搅拌0.5小时，然后滴加2-(三甲基硅烷基)乙氧甲基氯(2.48g,14.86mmol)，滴加完毕在室温搅拌2小时，向反应液中加水(50mL)淬灭反应，用乙酸乙酯萃取(30mLx3)，合并有机相用饱和食盐水(50mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩干，经过柱层析分离纯化，得到4-溴-2-((2-(三甲基甲硅烷基)乙氧基)甲基)-2H-1,2,3-三唑(1.4g,白色固体，产率：38％)。
MS m/z(ESI):278.2[M+H] +,280.2[M+2+H] +.
第四步：4-环丙基-2-((2-(三甲基甲硅烷基)乙氧基)甲基)-2H-1,2,3-三唑的制备
Figure PCTCN2019074108-appb-000095
将4-溴-2-((2-(三甲基甲硅烷基)乙氧基)甲基)-2H-1,2,3-三唑(0.5g,1.79mmol)，环丙基三氟硼酸钾(530mg,3.58mmol)溶解在1,4-二氧六环(10mL)中，然后加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.5g,1.79mmol)和碳酸钠(0.5g,1.79mmol)，氮气置换三次后在氮气保护下100摄氏度搅拌16小时，垫硅藻土过滤，滤液减压浓缩得到残余物，向残余物中加水(30mL),然后用乙酸乙酯萃取(30mLx3)，合并有机相用饱和食盐水(50mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩干，经过柱层析分离纯化(石油醚/乙酸乙酯＝4:1)， 得到4-环丙基-2-((2-(三甲基甲硅烷基)乙氧基)甲基)-2H-1,2,3-三唑(70mg,淡黄色油状物，产率:16％)。
MS m/z(ESI):240.2[M+H] +.
第五步：4-环丙基-2H-1,2,3-三唑的制备
Figure PCTCN2019074108-appb-000096
将4-环丙基-2-((2-(三甲基甲硅烷基)乙氧基)甲基)-2H-1,2,3-三唑(50mg,0.208mmol)溶解在二氯甲烷(1mL)中，然后加入三氟乙酸(1mL)在室温搅拌3小时，向反应液中加水(10mL)，加饱和碳酸钠溶液调节pH＝8,然后用乙酸乙酯萃取(20mLx3)，合并有机相用饱和食盐水(50mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩干，得到4-环丙基-2H-1,2,3-三唑(35mg，白色固体，粗品)
MS m/z(ESI):110.2[M+H] +.
第六步：2-(4-环丙基-2H-1,2,3-三唑-2-基)-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(63)和2-(4-环丙基-1H-1,2,3-三唑-1-基)-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(64)的制备
Figure PCTCN2019074108-appb-000097
向2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(80mg,0.193mmol)和四氢呋喃(3mL)的混合溶液中加入碳酸钾(80mg,0.579mmol)，然后在室温搅拌16小时，向反应液中加水(20mL)，然后用乙酸乙酯萃取(20mLx3)，合并有机相用饱和食盐水(30mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩干，经过制备色谱分离纯化得到白色固体2-(4-环丙基-2H-1,2,3-三唑-2-基)-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(63)(34mg，白色固体，产率39.8％)和白色固体2-(4-环丙基-1H-1,2,3-三唑-1-基)-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(64)(14mg，白色固体，产 率16.4％)
实施例63：
MS m/z(ESI):444.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.35(s,1H),5.15-5.05(m,2H),3.91(d,J＝3.0Hz,1H),2.61–2.47(m,1H),2.25-2.08(m,4H),2.04–1.81(m,5H),1.78-1.71(m,2H),1.54–1.42(m,6H),1.37(s,3H),1.33–1.20(m,4H),1.18–1.04(m,2H),0.99-0.96(m,2H),0.80–0.75(m,2H),0.73(s,3H).
实施例64：
MS m/z(ESI):444.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.35(s,1H),5.16-5.06(m,2H),3.91(d,J＝3.0Hz,1H),2.54(t,J＝8.8Hz,1H),2.24-2.09(m,4H),2.04–1.81(m,5H),1.78-1.70(m,2H),1.54–1.42(m,6H),1.37(s,3H),1.31-1.22(m,4H),1.18–1.04(m,2H),0.99–0.96(m,2H),0.80-0.76(m,2H),0.73(s,3H).
实施例66
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-((2-(三氟甲基)嘧啶-5-基)氧代)乙烷-1-酮
Figure PCTCN2019074108-appb-000098
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-((2-(三氟甲基)嘧啶-5-基)氧代)乙烷-1-酮(39.2mg，白色固体，产率65.5％)。
MS m/z(ESI):499.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.45(s,2H),4.84–4.70(m,2H),2.68(t,J＝8.9Hz,1H),2.23(m,1H),2.09(d,J＝10.8Hz,1H),1.98(t,J＝12.6Hz,3H),1.91–1.83(m,1H),1.79(t,J＝8.4Hz,2H),1.60–1.52(m,4H),1.48(dd,J＝19.5,12.9Hz,5H),1.38(s,3H),1.35–1.21(m,4H),1.20–1.05(m,1H),0.73(s,3H).
实施例67
3-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)噻唑烷-2,4-二酮
Figure PCTCN2019074108-appb-000099
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品3-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)噻唑烷-2,4-二酮(18.5mg，白色固体，产率28.3％)。
1H NMR(400MHz,CDCl 3)δ4.43–4.32(m,2H),4.03(s,2H),2.56(t,J＝8.7Hz,1H),2.21–1.54(m,18H),1.37(s,3H),1.32–1.25(m,3H),1.17–1.08(m,1H),0.68(s,3H).
实施例68
(1R,3R,5R)-2-(2-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-2-氮杂二环[3.1.0]己烷-3-甲腈
Figure PCTCN2019074108-appb-000100
第一步：叔丁基(1R,3R,5R)-3-氰基-2-氮杂二环[3.1.0]己烷-2-羧酸酯的制备
Figure PCTCN2019074108-appb-000101
向-20摄氏度的叔丁基(1R,3R,5R)-3-氨基甲酰-2-氮杂二环[3.1.0]己烷-2-羧酸酯(2g,8.85mmol)和吡啶(25mL)的悬浮液中缓慢滴加三氟乙酸酐(5mL,35.3mmol)，然后在-20摄氏度搅拌1小时，然后升温到室温搅拌8小时，向反应液中加冰水淬灭，然后用乙酸乙酯萃取(30mLx3)，合并有机相用稀盐酸(10％)洗涤，饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩干，经过柱层析分离纯化(石油醚/乙酸乙酯＝4:1)，得到叔丁基(1R,3R,5R)-3-氰基-2-氮杂二环[3.1.0]己烷-2-羧酸酯(1.5g，白色固体，产率:83％)。
1H NMR(400MHz,CDCl 3)δ4.71(dd,J＝41.1,9.6Hz,1H),3.58(d,J＝33.8Hz,1H),2.63–2.47(m,1H),2.35(d,J＝12.7Hz,1H),1.70-1.60(m,1H),1.52(s,9H),1.02(s,1H),0.90-0.81(m,1H).
第二步：(1R,3R,5R)-2-氮杂二环[3.1.0]己烷-3-甲腈的制备
Figure PCTCN2019074108-appb-000102
将叔丁基(1R,3R,5R)-3-氰基-2-氮杂二环[3.1.0]己烷-2-羧酸酯(0.8g,3.85mmol)溶解在二氧六环(2mL)中，然后加入盐酸-二氧六环(8mL)，在室温搅拌2小时，将反应液减压浓缩干，向残余物中加水(50mL)，然后用(二氯甲烷/甲醇＝10：1)萃取，合并有机相用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩干，得到(1R,3R,5R)-2-氮杂二环[3.1.0]己烷-3-甲腈(0.5g，褐色油状物，粗品)。
第三步：(1R,3R,5R)-2-(2-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-2-氮杂二环[3.1.0]己烷-3-甲腈的制备
Figure PCTCN2019074108-appb-000103
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品(1R,3R,5R)-2-(2-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-2-氮杂二环[3.1.0]己烷-3-甲腈(12mg，白的固体，产率:23％)。
MS m/z(ESI):443.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ4.08(s,2H),3.70(s,2H),2.49(t,J＝8.7Hz,1H),2.24–2.16(m,2H),2.12–1.82(m,11H),1.74-1.70(m,2H),1.60-1.48(m,6H),1.37(s,3H),1.31-1.25(m,6H),1.12-1.07(m,1H),0.65(s,3H).
实施例69
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-((1-甲基-1H-吡唑-4-基)氧代)乙烷-1-酮
Figure PCTCN2019074108-appb-000104
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-((1-甲基-1H-吡唑-4-基)氧代)乙烷-1-酮(20mg，白色固体，产率32.0％)。
MS m/z(ESI):433.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.21(s,1H),7.08(s,1H),4.48–4.28(m,2H),3.82(s,3H),2.74(t,J＝8.9Hz,1H),2.22–1.50(m,18H),1.37(s,3H),1.30–1.10(m,4H),0.68(s,3H).
实施例70
7-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙氧基)喹啉-1-氮氧化物
Figure PCTCN2019074108-appb-000105
第一步：1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(喹啉-7-氧基)乙烷-1-酮的制备
Figure PCTCN2019074108-appb-000106
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(喹啉-7-氧基)乙烷-1-酮(60.0mg，白色固体，产率52.1％)。
MS m/z(ESI):480.2[M+H] +.
第二步：7-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢 -1H-环戊二烯并[a]菲-17-基)-2-羰基乙氧基)喹啉1-氮氧化物的制备
Figure PCTCN2019074108-appb-000107
100ml的单口瓶中加入1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(喹啉-7-氧基)乙烷-1-酮(60mg，0.125mmol)和二氯甲烷(10ml)，再加入间氯过氧苯甲酸(78mg，0.313mmol)。该反应液在室温下搅拌过夜。反应液用饱和碳酸氢钠溶液洗后浓缩。浓缩后得到的粗产品通过prep-HPLC纯化得到7-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙氧基)喹啉-1-氮氧化物(29.2mg，白色固体，产率47.1％)。
MS m/z(ESI):496.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.59(d,J＝6.0Hz,1H),7.97(d,J＝2.2Hz,1H),7.83(d,J＝9.0Hz,1H),7.78(d,J＝8.3Hz,1H),7.43(dd,J＝9.0,2.4Hz,1H),7.26–7.20(m,1H),4.87–4.73(m,2H),2.83-2.75(m,1H),2.33-2.21(m,1H),2.13-2.07(m,1H),2.06-1.95(m,4H),1.94-1.84(m,2H),1.82-1.74(m,2H),1.62-1.42(m,8H),1.38(s,3H),1.35–1.25(m,3H),1.20-1.06(m,1H),0.75(s,3H).
实施例71
N-(2-((3S,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)苯磺酰胺
Figure PCTCN2019074108-appb-000108
将苯磺酰胺(28mg，0.18mmol)溶于N,N-二甲基甲酰胺(5mL)中，0℃下加入氢化钠(7.2mg，0.18mmol)，0℃下搅拌0.5小时。0℃下加入2-溴-1-((3S,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(50mg，0.12mmol)，室温搅拌过夜。加入5mL水，乙酸乙酯萃取(30mLx3)，饱和食盐水(20mL)洗一次，有机相加入无水硫酸钠干燥，旋干，用prep-HPLC分离得产品(7.1mg，白色固体，产率12％)。
1H NMR(400MHz,CDCl 3)δ7.86(d,J＝7.2Hz,2H),7.58(t,J＝7.4Hz,1H),7.51(t,J＝7.5Hz,2H),5.48(s,1H),3.87–3.68(m,2H),2.36(t,J＝8.9Hz,1H),2.06-2.08(m,2H),1.94-1.97(m,2H),1.90-1.80(m,1H),1.71–1.62(m,4H),1.52–1.39(m,6H),1.37(s,3H),1.34–1.25(m,4H),1.24–1.01(m,3H),0.38(s,3H).
实施例72
(3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-N-(4-氟苯基)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-甲酰胺
Figure PCTCN2019074108-appb-000109
第一步：(3R,5R,8S,9S,10R,13S,14S)-10-氟-3,13-二甲基-17-亚甲基十六氢-1H-环戊二烯并[a]菲-3-酚的制备
Figure PCTCN2019074108-appb-000110
向甲基三苯基溴化磷(13.9g,38.961mmol)和四氢呋喃(50mL)的溶液中加入叔丁醇醇钾(4.36g,38.961mmol)，然后在65摄氏度搅拌1小时，滴加(3R,5R,8S,9S,10R,13S,14S)-10-氟-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(2g,6.494mmol)和四氢呋喃(30mL)的混合溶液，然后在65摄氏度搅拌1小时，反应液冷却到室温，加水淬灭，然后用乙酸乙酯萃取(50mLx3)，合并有机相用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩干，经过柱层析分离纯化(石油醚/乙酸乙酯＝10:1)，得到(3R,5R,8S,9S,10R,13S,14S)-10-氟-3,13-二甲基-17-亚甲基十六氢-1H-环戊二烯并[a]菲-3-酚(1.8g，白色固体，产率:90％)。
第二步：(3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-17-(羟甲基)-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚的制备
Figure PCTCN2019074108-appb-000111
将(3R,5R,8S,9S,10R,13S,14S)-10-氟-3,13-二甲基-17-亚甲基十六氢-1H-环戊二烯并[a]菲-3-酚(0.5g,1.634mmol)溶解在四氢呋喃(8mL)中，然后滴加硼烷-四氢呋喃(8.2mL,8.169mmol)，在室温搅拌1.5小时，然后冷却到0摄氏度滴加氢氧化钠(327mg,8.169mmol)的水(3mL)溶液，缓慢滴加双氧水(3mL,30％)，然后在室温搅拌1.5小时，向反应液中加水(50mL)，然后用乙酸乙酯萃取(50mLx3)，合并有机相用饱和食盐水洗涤，有机相用无水硫酸钠干燥， 过滤，滤液减压浓缩干，得到(3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-17-(羟甲基)-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚(600mg,粗品)
第三步：(3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-羧酸的制备
Figure PCTCN2019074108-appb-000112
向(3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-17-(羟甲基)-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚(400mg,1.234mmol)，N,N-二甲基甲酰胺(15mL)和水(1mL)的混合物中加入重铬酸吡啶(4.6g，12.34mmol)，在室温搅拌16小时，向反应液中加饱和亚硫酸钠溶液(50mL)淬灭，然后用乙酸乙酯萃取(40mLx3)，合并有机相用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩干，得到淡黄色固体(3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-羧酸(400mg,淡黄色固体，粗品)
1H NMR(400MHz,DMSO)δ11.92(s,1H),4.38(s,1H),2.90-2.70(m,2H),2.05–1.52(m,9H),1.39-1.19(m,15H),0.61(s,3H).
第四步：(3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-N-(4-氟苯基)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-甲酰胺的制备
Figure PCTCN2019074108-appb-000113
将3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-羧酸(200mg,0.592mmol)，2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(270mg,0.71mmol)，三乙胺(119mg,1.18mmol)和二氯甲烷(5mL)的混合物在室温搅拌30分钟，然后加入对氟苯胺(79mg,0.71mmol)在室温搅拌3小时，向反应液中加水(30mL)，然后用二氯甲烷萃取(40mLx3)，合并有机相用饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩干，经过制备色谱分离纯化，得到(3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-N-(4-氟苯基)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-甲酰胺(25mg,白色固体，产率:10％)。
MS m/z(ESI):432.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.51–7.41(m,2H),7.05-6.95(m,2H),2.43– 2.17(m,2H),2.14–1.80(m,8H),1.72-1.69(m,3H),1.51–1.11(m,15H),0.93(s,3H).
实施例73
2-((4-氟-2-甲氧苯基)氨基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000114
以2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例23得产品2-((4-氟-2-甲氧苯基)氨基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(29mg，白色固体，产率42.2％)。
MS m/z(ESI):476.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ6.61–6.49(m,2H),6.40–6.31(m,1H),3.91(d,J＝6.3Hz,2H),3.87–3.82(m,3H),2.58(t,J＝8.8Hz,1H),2.31–1.42(m,18H),1.38(s,3H),1.35–1.03(m,4H),0.69(s,3H).
实施例79A
1-(2–((3R,5R,8S,9S,10R,13S,14S,17S)-10-(氟甲基-3-羟基-3,13-二甲基六氢十氢-1H-环戊二烯并[a]菲-17基)-2-氧代乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074108-appb-000115
本实施例79A通过以下具体实施方案合成：
Figure PCTCN2019074108-appb-000116
实施例82A
1-(2–((3R,5R,8S,9S,10R,13S,14S,17S)-10-(二氟甲基)-3-羟基-3,13-二甲基六氢十氢-1H-环戊二烯并[a]菲-17基)-2-氧代乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074108-appb-000117
本实施例82A通过以下具体实施方案合成：
Figure PCTCN2019074108-appb-000118
Figure PCTCN2019074108-appb-000119
实施例90
1-(2-((2R,4aR,4bS,6aS,8bS,8cR,10aR)-2-羟基甲基-4a-(甲氧基甲基)-2,6a-二甲基十六氢环戊二烯[4,5]环戊二烯并[1,2-α]菲-7-基)-2-氧代乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074108-appb-000120
本实施例90通过以下具体实施方案合成：
Figure PCTCN2019074108-appb-000121
MS m/z(ESI):465.3[M] +.
实施例91
1-(2-((2R，4aR，4bS，6aS，8bS，8cR，10aR)-2-羟基甲基-4a-(甲氧基甲基)-2,6a-二甲基十六氢环戊二烯[4,5]环戊二烯并[1,2-α]菲-7-基)-2-氧代乙基)-1H-吡唑-3-甲腈
Figure PCTCN2019074108-appb-000122
MS m/z(ESI):465.3[M] +.
实施例92
1-(2-((2R,4aR,4bS,6aS,8bS,8cR,10aR)-2-硫甲基-4a-(甲氧基甲基)-2,6a-二甲基十六氢环戊二烯[4,5]环戊二烯并[1,2-α]菲-7-基)-2-氧代乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074108-appb-000123
本实施例92通过以下具体实施方案合成：
Figure PCTCN2019074108-appb-000124
MS m/z(ESI):469.3[M] +.
实施例93
2-(5-氯-1H-苯并[d][1,2,3]三唑-1-基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-3-((甲硫基)甲基)六氢十氢-1H-环戊二烯并[a]菲-17-基)乙-1-酮
Figure PCTCN2019074108-appb-000125
MS m/z(ESI):529.3[M] +.
实施例94
2-(4,5-二氟-1H-苯并[d][1,2,3]三唑-1-基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-3-羟 基-3,13-二甲基-10-((甲硫基)甲基)十六氢-1H-环戊二烯并[a]菲-17-基)乙-1-酮
Figure PCTCN2019074108-appb-000126
MS m/z(ESI):531.3[M] +.
实施例95
2-(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-3-羟基-3,13-二甲基-10-((甲硫基)甲基)十六氢-1H-环戊二烯并[a]菲-17-基)乙-1-酮
Figure PCTCN2019074108-appb-000127
MS m/z(ESI):496.3[M] +.
实施例96
1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-3-羟基-3,13-二甲基-10-((甲基磺酰基)甲基)十六氢-1H-环戊二烯并[a]菲-17-基)-2-氧代乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074108-appb-000128
MS m/z(ESI):501.3[M] +.
实施例97
1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-3-羟基-3,13-二甲基-10-((S-甲基磺酰亚氨基)甲基)十六氢-1H-环戊二烯并[a]菲-17-基)-2-氧代乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074108-appb-000129
MS m/z(ESI):500.3[M] +.
MS m/z(ESI):456.3[M] +.
实施例114
1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074108-appb-000130
第一步：(5R,8S,10R,13S,14S)-10-氟-13-甲基十四氢螺[环戊二烯并[a]菲并-3,2'-噁丙环]-17(2H)-酮
Figure PCTCN2019074108-appb-000131
100mL三口瓶中依次加入三甲基碘化亚砜(2.65g,12mmol)和四氢呋喃(50mL),搅拌下加入叔丁醇钾(1.35g，12mmol)，反应液在室温下搅拌0.5小时。(5R,8S,9S,10R,13S,14S)-10-氟-13-甲基十四氢-3H-环戊二烯并[a]菲-3,17(2H)-二酮(3.0g，10mmol)加入到反应液中，反应液在室温下反应2小时。反应液用饱和氯化铵水溶液萃灭，用乙酸乙酯(30mL)萃取，食盐水洗涤(10mLx3)洗涤，有机相经无水硫酸钠干燥，过滤，旋干。粗产物用柱层析分离(石油醚/乙酸乙酯：3/1)纯化得到(5R,8S,10R,13S,14S)-10-氟-13-甲基十四氢螺[环戊二烯并[a] 菲并-3,2'-噁丙环]-17(2H)-酮(2.5g,淡黄色固体，产率：79.5％)。
1H NMR(400MHz,CDCl 3)δ2.72–2.67(m,2H),2.52–2.43(m,1H),2.31–1.06(m,21H),0.92(s,3H).
第二步：(3R,5R,8S,10R,13S,14S)-10-氟-3-羟基-3-(甲氧基甲基)-13-甲基十六氢-17H-环戊二烯并[a]菲-17-酮
Figure PCTCN2019074108-appb-000132
100mL单口瓶中加入(5R,8S,10R,13S,14S)-10-氟-13-甲基十四氢螺[环戊二烯并[a]菲并-3,2'-噁丙环]-17(2H)-酮(2.5g，7.5mmol)溶于甲醇(50mL)中，室温下搅拌2-3分钟后，加入甲醇钠(1.25g，22.5mmol)，加毕60℃条件下搅拌5小时。反应液冷却至室温，用饱和氯化铵水溶液萃灭，用乙酸乙酯(30mL)萃取，食盐水洗涤(10mLx3)洗涤，有机相经无水硫酸钠干燥，过滤，旋干。粗产物用柱层析分离(石油醚/乙酸乙酯：3/1)纯化得到(3R,5R,8S,10R,13S,14S)-10-氟-3-羟基-3-(甲氧基甲基)-13-甲基十六氢-17H-环戊二烯并[a]菲-17-酮(1.6g,淡黄色固体，产率：57.9％)。
1H NMR(400MHz,CDCl 3)δ3.39(s,3H),3.21(s,2H),2.51–2.40(m,1H),2.37–1.04(m,21H),0.90(s,3H).
第三步：(3R,5R,8S,10R,13S,14S)-17-亚乙基-10-氟-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-3-酚
Figure PCTCN2019074108-appb-000133
以(3R,5R,8S,10R,13S,14S)-10-氟-3-羟基-3-(甲氧基甲基)-13-甲基十六氢-17H-环戊二烯并[a]菲-17-酮为原料参考实例1第四步得产品(3R,5R,8S,10R,13S,14S)-17-亚乙基-10-氟-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-3-酚(600mg，白色固体，产率36.2％)。
1H NMR(400MHz,CDCl 3)δ5.18–4.96(m,1H),3.39(s,3H),3.20(s,2H),2.44–0.99(m,25H),0.90(s,3H).
第四步：(3R,5R,8S,10R,13S,14S,17R)-10-氟-17-(1-羟基乙基)-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-3-酚
Figure PCTCN2019074108-appb-000134
以(3R,5R,8S,10R,13S,14S)-17-亚乙基-10-氟-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-3-酚为原料参考实例1第五步得产品(3R,5R,8S,10R,13S,14S,17R)-10-氟-17-(1-羟基乙基)-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-3-酚(600mg，白色固体，产率95.1％)。
第五步：1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000135
以(3R,5R,8S,10R,13S,14S,17R)-10-氟-17-(1-羟基乙基)-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-3-酚为原料参考实例1第六步得产品1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(500mg，白色固体，产率83.7％)。
1H NMR(400MHz,CDCl 3)δ3.40(s,3H),3.21(s,2H),2.56-2.47(m,1H),2.39-2.16(m,4H),2.12(s,3H),2.07-0.98(m,18H),0.65(s,3H).
第六步：2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000136
以1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第一步得产品2-溴-1-((3R,5R,8S,10R,13S,14S,17S)-10-氟-3-羟基-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(500mg，白色固体，产率82.2％)。
第七步：1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3-(甲氧基甲基)-13- 甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074108-appb-000137
以2-溴-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈(11mg，白色固体，产率17.8％)。
MS m/z(ESI):458.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.87(s,1H),7.82(s,1H),5.04–4.90(m,2H),3.40(s,3H),3.22(s,2H),2.58(t,J＝8.9Hz,1H),2.22–1.01(m,22H),0.71(s,3H).
实施例115
1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000138
以2-溴-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(25mg，白色固体，产率37.0％)。MS m/z(ESI):501.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.74(s,2H),5.05–4.82(m,2H),3.40(s,3H),3.22(s,2H),2.59(t,J＝8.6Hz,1H),2.45–1.05(m,22H),0.72(s,3H).
实施例116
1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-3-甲腈
Figure PCTCN2019074108-appb-000139
以2-溴-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-氟-3-羟基-3-(甲氧基甲基)-13-甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-3-甲腈(19mg，白色固体，产率30.8％)。MS m/z(ESI):458.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.50(d,J＝2.4Hz,1H),6.74(d,J＝2.4Hz,1H),5.03–4.88(m,2H),3.39(s,3H),3.22(s,2H),2.59(t,J＝8.8Hz,1H),2.38–1.05(m,22H),0.71(s,3H).
实施例117
1-(2-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074108-appb-000140
第一步：((8R,9S,10S,13S,14S)-13-甲基-3,17-二羰基-1,2,3,6,7,8,9,11,12,13,14,15,16,17-十四氢-10H-环戊二烯并[a]菲-10-基)甲基4-甲基苯磺酸酯
Figure PCTCN2019074108-appb-000141
100mL三口瓶中依次加入吡啶(20mL)和(8R,9S,10S,13S,14S)-10-(羟甲基)-13-甲基-1,6,7,8,9,10,11,12,13,14,15,16-十二氢-3H-环戊二烯并[a]菲-3,17(2H)-二酮(6.0g，20mmol)，搅拌下加入4-甲基苯磺酰氯(11.4g，60mmol)。室温下搅拌12小时后倒入到冰水浴中，有白色固体析出，滤出固体，固体用水洗，干燥得产品((8R,9S,10S,13S,14S)-13-甲基-3,17-二羰基-1,2,3,6,7,8,9,11,12,13,14,15,16,17-十四氢-10H-环戊二烯并[a]菲-10-基)甲基4-甲基苯磺酸酯(8.0g,白色固体，产率：88％)。
MS m/z(ESI):457.2[M+H] +.
1H NMR(400MHz,CDCl3)δ7.75(d,J＝8.0Hz,2H),7.36(d,J＝8.0Hz,2H),5.87(s,1H),4.39-4.23(m,2H),2.52-2.47(m,1H),2.46(s,3H),2.38-2.25(m,5H), 2.12-1.70(m,7H),1.65-1.40(m,2H),1.30-1.05(m,4H),0.89(s,3H).
第二步：(5S,8R,9S,10S,13S,14S)-13-甲基十二氢-17H-5,10-亚甲基环戊二烯并[a]菲-3,17(4H)-二酮
Figure PCTCN2019074108-appb-000142
100mL单口瓶中加入((8R,9S,10S,13S,14S)-13-甲基-3,17-二羰基-1,2,3,6,7,8,9,11,12,13,14,15,16,17-十四氢-10H-环戊二烯并[a]菲-10-基)甲基4-甲基苯磺酸酯(7.1g，15.5mmol)及醋酸(300mL)和水(300mL)，室温下搅拌2-3分钟后，加入锌粉(35g，538mmol)，加毕在120℃下反应1.5小时。将反应混合液过滤，滤液旋干，粗产物用柱层析分离(石油醚/乙酸乙酯：35/1)纯化得到(5S,8R,9S,10S,13S,14S)-13-甲基十二氢-17H-5,10-亚甲基环戊二烯并[a]菲-3,17(4H)-二酮(2.5g，白色固体，产率：56％)。
1H NMR(400MHz,CDCl3)δ2.56-2.53(m,2H),2.49-2.27(m,2H),2.14-1.70(m,9H),1.55-0.90(m,8H),0.89(s,3H),0.55(d,J＝6.0Hz,1H),0.45(d,J＝6.0Hz,1H).
第三步：(3R,5S,8R,9S,10S,13S,14S)-3-羟基-3,13-二甲基十四氢-17H-5,10-亚甲基环戊二烯并[a]菲-17-酮
Figure PCTCN2019074108-appb-000143
以(5S,8R,9S,10S,13S,14S)-13-甲基十二氢-17H-5,10-亚甲基环戊二烯并[a]菲-3,17(4H)-二酮为原料参考实例1第三步得产品(3R,5S,8R,9S,10S,13S,14S)-3-羟基-3,13-二甲基十四氢-17H-5,10-亚甲基环戊二烯并[a]菲-17-酮(白色固体，产率52％)。
1H NMR(400MHz,CDCl 3)δ2.47-2.39(m,1H),2.10–1.25(m,16H),1.19(s,3H),1.15–0.85(m,4H),0.86(s,3H),0.42(s,2H).
第四步：(3R,5S,8S,9S,10S,13S,14S)-17-亚乙基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-3-酚
Figure PCTCN2019074108-appb-000144
以(3R,5S,8R,9S,10S,13S,14S)-3-羟基-3,13-二甲基十四氢-17H-5,10-亚甲基环戊二烯并[a]菲-17-酮为原料参考实例1第四步得产品(3R,5S,8S,9S,10S,13S,14S)-17-亚乙基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-3-酚(白色固体，产率：61.5％)。
1H NMR(400MHz,CDCl 3)δ5.15-5.08(m,1H),2.40-1.20(m,18H),1.19(s,3H),1.16–0.87(m,6H),086(s,3H),0.43(d,J＝4.4Hz,1H),0.35(d,J＝4.4Hz,1H).
第五步：(3R,5S,8S,9S,10S,13S,14S)-17-(1-羟基乙基)-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-3-酚
Figure PCTCN2019074108-appb-000145
以(3R,5S,8S,9S,10S,13S,14S)-17-亚乙基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-3-酚为原料参考实例1第五步得产品(3R,5S,8S,9S,10S,13S,14S)-17-(1-羟基乙基)-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-3-酚(白色固体，产率100％)。
第六步：1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000146
以(3R,5S,8S,9S,10S,13S,14S)-17-(1-羟基乙基)-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-3-酚为原料参考实例1第六步得产品1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)乙烷-1-酮(白色固体，产率：71％)。
1H NMR(400MHz,CDCl3)δ2.54(t,J＝8.0Hz,1H),2.12(s,3H),2.10-1.25(m,17H),1.19(s,3H),1.15–0.72(m,4H),0.60(s,3H),0.41(d,J＝4.4Hz,1H),0.36(d,J＝4.4Hz,1H).
第七步：2-溴-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000147
以1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚 甲基环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例1第七步得产品2-溴-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)乙烷-1-酮(白色固体，产率：100％)。
第八步：1-(2-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074108-appb-000148
以2-溴-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例1第八步得产品1-(2-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈(18mg，白色固体，产率：21.9％)。
MS m/z(ESI):404.2[M-17] +.
1H NMR(400MHz,CDCl 3)δ7.86(s,1H),7.81(s,1H),5.05-4.85(m,2H),2.61(t,J＝8.8Hz,1H),2.25-2.15(m,1H),2.10-1.95(m,2H),1.90-1.25(m,15H),1.19(s,3H),1.15–1.05(m,1H),0.90–0.80(m,2H),0.66(s,3H),0.43-0.38(m,2H).
实施例118
1-(2-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-3-甲腈
Figure PCTCN2019074108-appb-000149
以2-溴-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-(2-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-3-甲腈(10.5mg，白色固体，产率15.4％)。
MS m/z(ESI):404.2[M-H 2O+H] +.
1H NMR(400MHz,CDCl 3)δ7.48(d,J＝2.4Hz,1H),6.73(d,J＝2.4Hz,1H)5.10-4.85(m,2H),2.61(t,J＝8.9Hz,1H),2.24-1.98(m,3H),1.90–1.25(m,15H),1.16(s,3H),1.15–1.05(m,1H),0.90–0.80(m,2H),0.67(s,3H),0.43-0.37(m,2H).
实施例119
1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮
Figure PCTCN2019074108-appb-000150
以2-溴-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实例2第二步得产品1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(10.5mg，白色固体，产率：15.4％)。
MS m/z(ESI):465.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.72(s,2H),5.10-4.85(m,2H),2.61(t,J＝8.9Hz,1H),2.26-1.98(m,3H),1.90–1.25(m,15H),1.19(s,3H),1.15–1.05(m,1H),0.90–0.80(m,2H),0.67(s,3H),0.43-0.37(m,2H).
实施例120和实施例121
1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮(120)
1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮(121)
Figure PCTCN2019074108-appb-000151
以2-溴-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)乙烷-1-酮参考实例6第八步得产品1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮(120)(7.2mg，白色固体，产率12.2％)和1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十四氢-6H-5,10-亚甲基环戊二烯并[a]菲-17-基)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮(121)(10mg，白色固体，产率17.1％)。
实施例120：
MS m/z(ESI):398.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.68(s,2H),5.26-5.20(m,2H),2.59(t,J＝8.0Hz,1H),2.24-1.95(m,3H),1.90–1.25(m,15H),1.19(s,3H),1.15–1.05(m,1H), 0.90–0.80(m,2H),0.70(s,3H),0.43-0.37(m,2H).
实施例121：
MS m/z(ESI):398.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.65(s,1H),5.35-5.10(m,2H),2.66(t,J＝8.0Hz,1H),2.25-1.97(m,3H),1.90–1.25(m,15H),1.20(s,3H),1.13–1.05(m,1H),0.90–0.80(m,2H),0.67(s,3H),0.43-0.36(m,2H).
生物学测试评价
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
一、本发明化合物对GABA A受体结合能力的测定
1.1实验目的：该测试例的目的是测量化合物变构抑制离子通道阻滞剂(TBPS)和GABA-A受体结合的能力。
实验仪器：
Figure PCTCN2019074108-appb-000152
1.2实验步骤
1.2.1大脑皮层细胞膜提取：
1.分离雄性Sprague-Dawley Rat的大脑皮层
2.加入大鼠大脑皮层10倍体积预冷的0.32M蔗糖溶液(每100ml加一片蛋白酶 抑制剂)，用50ml玻璃组织匀浆器分批碾碎，混匀。
3. 1,500g，4℃离心10min，收集上清。
4. 20,000g，4℃离心30min，弃上清。
5.用预冷的PBS(每100ml加一片蛋白酶抑制剂)将沉淀重悬，平均每只大鼠加4ml PBS，用玻璃组织匀浆器混匀。
6. 10,000g，4℃离心10min，弃上清。
7.重复步骤5-6三次。
8.最终用4倍体积的PBS将沉淀重悬，分装，液氮速冻，存放-80℃。
9.选用BCA法测蛋白浓度。
1.2.2 35S-TBPS binding assay
1. 1.1ml深孔板中每孔加入230uL PBS。
2.每孔加入60uL大脑皮层细胞膜(5ug/uL)溶液，混匀。
3.加入待测化合物(每孔3uL)，25℃孵育5min。DMSO浓度为1％,化合物初始浓度为1uM，3倍梯度稀释，共8个梯度，2个重复，1％DMSO作为阴性对照，10uM P026-2做阳性对照。
4.加入GABA，终浓度为5uM，25℃孵育5min。配制1mM GABA溶液，每孔加1.5uL。
5.加入35S-TBPS，终浓度为2nM，同位素母液浓度为9.7uM，用PBS稀释100倍后，每孔加入6uL稀释的同位素溶液。
6. 4℃孵育20h。
7.FilterMate GF/C板用0.5％PEI预处理，4℃孵育1h。
8.用Universal Harvester洗FilterMate GF/C板2次，每次50ml PBS。
9.将反应液转移到GF/C板上后每孔用900uL PBS洗4次。
10.洗后的GF/C板放置于55℃干燥10min。
11.每孔加40uL闪烁液，用TopCount读取CPM值。
1.2.3实验数据处理方法:
实验中由TopCount读取CPM(counts per minute)值，根据High control(DMSO)和Low control(10uM阳性化合物)实验组的读值按如下公式计算％inhibition：％Inhibition＝100x(CPM High  control-CPM Sample)/(CPM High  control–CPM Low  control)依据如下4参数非线性逻辑公式计算化合物的IC 50：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)),
其中：
X是log of compound concentration
Y是％Inhibition
本发明中化合物对TBPS结合活性通过以上的试验进行测定，测得的IC 50 值见表1。
表1本发明中化合物对TBPS结合活性性抑制IC 50
Figure PCTCN2019074108-appb-000153
结论：本发明化合物对TBPS结合活性具有明显的抑制作用。
二、Balb/C小鼠药代动力学测定
1.研究目的：
以Balb/C小鼠为受试动物，研究化合物实施例2、实施例5、实施例7、实施例12、实施例18、实施例23、实施例26、实施例38、实施例41、实施例50实施例51和实施例66，在5mg/kg剂量下口服给药在小鼠体内(血浆和脑组织)的药代动力学行为。
2.试验方案：
2.1试验药品：
本发明实施例2、实施例5、实施例7、实施例12、实施例18、实施例23、实施例26、实施例38、实施例41、实施例50、实施例51和实施例66，自制。
2.2试验动物：
Balb/C Mouse，雄性，上海杰思捷实验动物有限公司，动物生产许可证号(SCXK(沪)2013-0006N0.311620400001794)。
2.3给药：
每组Balb/C小鼠24只，雄性；禁食一夜后分别p.o.，剂量为5mg/kg，给药体积10mL/kg。
2.4样品采集：
小鼠给药前和给药后，在0、0.5、1、2、4、6、8和24小时，采用CO 2处死，心脏采血0.2mL，置于EDTA-K 2试管中，4℃ 6000rpm离心6min分离血浆，于-80℃保存；全脑组织取出称重后，置于2mL离心管中，于-80℃保存。
2.5样品处理：
1)血浆样品40uL加入160uL乙腈沉淀,混合后3500×g离心5～20分钟。
2)血浆和脑匀浆样品30μL加入90μL含内标(100ng/mL)乙腈沉淀,混合后13000rpm离心8分钟。
3)取处理后上清溶液70uL加入70μL水，涡旋混合10分钟，随后取20μL进行LC/MS/MS分析待测化合物的浓度，LC/MS/MS分析仪器：AB Sciex API 4000Qtrap。
2.6液相分析
●液相条件：Shimadzu LC-20AD泵
●色谱柱：Agilent ZORBAX XDB-C18(50×2.1mm,3.5μm)移动相：A液为0.1％甲酸水溶液，B液为乙腈
●流速：0.4mL/min
●洗脱时间：0-4.0分钟，洗脱液如下：
Figure PCTCN2019074108-appb-000154
3.试验结果与分析
药代动力学主要参数用WinNonlin 6.1计算得到，小鼠药代实验结果见下表2：
表2小鼠药代实验结果
Figure PCTCN2019074108-appb-000155
Figure PCTCN2019074108-appb-000156
从表中小鼠药代实验结果可以看出：本发明实施例化合物表现出良好的代谢性质，暴露量AUC和最大血药浓度C max都表现良好。
三、小鼠强迫游泳模型体内药效实验
3.1实验目的
利用小鼠强迫游泳模型评价化合物的抗抑郁作用。
3.2实验主要仪器和试剂
3.2.1仪器
强迫游泳装置(JLBehv-FSC-4，上海吉量软件科技有限公司)
3.2.2试剂
羧甲基纤维素钠(CMC-Na，SLBV9664，Sigma)
Tween 80(BCBV8843，Sigma)
3.2.3受试化合物
本发明实施例化合物实施例2、实施例5、实施例7、实施例18、实施例23、
实施例26、实施例50，自制。
3.3实验步骤
3.3.1适应：
雄性ICR小鼠(25～35g)在强迫游泳测试前将动物在实验环境中适应3天。3.3.2分组给药：
根据实验设计，在实验前一天根据小鼠的体重随机分组，每组12只小鼠。测试前根据小鼠药代动力学实验中各实施例化合物在脑中的Tmax时间灌胃给药。分别为：
1)模型组(0.5％CMC-Na+1％Tween 80溶液，p.o.，10mL/kg)；
2)实施例化合物实施例2、实施例5、实施例7、实施例18、实施例23、实施例26、和实施例50(10mg/kg，p.o.，10mL/kg)；
给药时，各实施例化合物均以0.5％CMC-Na-1％Tween 80溶液混悬至所需浓度。
3.3.2强迫游泳测试：
给药0.5-1h后，将ICR小鼠放入强迫游泳装置中[透明玻璃圆桶中(水深18厘米，水温25～26℃)每缸1只]强迫游泳6分钟，强迫游泳装置记录整个6分钟内ICR小鼠漂浮的时间，后4分钟的数据用于数据分析。游泳实验结束后，立即取出小鼠，擦干小鼠身上水并放回原来笼中。
注：判定不动时间的标准是小鼠在水中停止挣扎，呈漂浮状态，仅有细小的肢体运动以保持头部浮在水面上。
3.4数据分析
漂浮时间百分比＝100*漂浮时间/240s。
3.5试验数据：
实施例编号 剂量(mpk) 均数(静止,s) 均数(静止,％)
Vehicle / 163.70 68.22
实施例2 10 87.34 36.39
实施例5 10 65.07 27.11
实施例7 10 141.58 58.99
实施例18 10 146.86 61.19
实施例23 10 68.51 28.55
实施例26 10 128.30 53.46
实施例50 10 101.07 42.11
3.6实验结果
从上述结果中可以看出，本专利的实验各实施例可明显缩短小鼠强迫游泳累计不动时间，具有明显抗抑郁作用；
其中，实施例2与模型组相比，后4分钟的不动时间具有显著性差异；实施例5、实施例23和实施例50与模型组相比，后4分钟的不动时间具有极显著性差异。
四、PTZ诱导小鼠癫痫模型体内药效试验
4.1试验目的
建立PTZ诱导CD-1小鼠癫痫模型，并利用该模型评价化合物实施例5和实施例23的抗癫痫作用。
4.2试验方法
4.21试验动物
30只雄性CD-1小鼠，购自北京维通利华实验动物有限公司。实验动物在送达上海睿智化学有限公司三号楼动物房，并适应7天后开展正式实验。测试当天动物平均体重为32.2±0.2克。饲养环境为5只/笼饲养，室温23±2℃，12/12小时昼夜明暗交替，食物和水自由摄取。
试验当天随机分组用于实验。
4.22受试化合物
受试化合物实施例5和实施例23(自制)，受试药品均在冰箱中4℃保存。
表3：供试品信息
Figure PCTCN2019074108-appb-000157
4.2.1试验器械
·1毫升带针无菌一次性注射器(购自浙江康德莱医疗器械有限公司)
·移液枪：Eppendorf Research Plus(100-1000μL)
·Vortex涡旋仪：Kylin-Bell Vortex 5
·超声仪：JL-360型超声波清洗器
·天平：METTLER TOLEDO XS204精密天平
·天平：METTLER TOLEDO XS6002S电子天平
·有机玻璃盒：25厘米长*15厘米宽*15厘米高，一边侧壁为不透光设计，苏州冯氏实验动物设备有限公司特殊定制；
·3通道计时器：Oregon/Model NO.WB-388。
4.2.2试验动物分组
1)Vehicle/PTZ：0.5％CMC-Na+1％Tween-80(10ml/kg，p.o.)，给予PTZ前0.5hr；PTZ(120ml/kg，s.c.)，实验前给药；
2)3mg/kg实施例化合物/PTZ：实施例5和实施例23(3mg/kg，10ml/kg，p.o.)，给予PTZ前0.5hr；PTZ(120ml/kg,s.c.)，实验前给药。
4.3实验步骤
4.3.1溶剂配制
1)0.5％CMC-NA+1％Tween-80(给药体积：10mL/kg)：
精密称取1g羧甲基纤维素钠加入250mL溶剂瓶中，并加入150mL双蒸水，磁力搅拌器常温搅拌4小时，即获得均一澄清溶液。再慢慢加2mL吐温-80继续常温搅拌3小时，并获得澄清均一溶液。将该溶液缓慢转移到200mL定容瓶中，加入双蒸水并定容至200mL，转移至250mL溶剂瓶磁力搅拌器继续搅拌1小时，得到均一澄清溶液。
2)30％羟丙基-β-环糊精：
精密称取30.6122g羟丙基-β-环糊精(纯度：98％)加入100mL溶剂瓶中，并加入60mL双蒸水，涡旋仪涡旋3分钟，并室温超声15分钟即获得均一澄清溶液。然后再加入双蒸水定容至100mL，涡旋仪涡旋1分钟然后室温超声5分钟，得到均一澄清溶液。
4.3.2待测化合物配制
1)12mg/mL PTZ(剂量：120mg/kg；给药体积：10mL/kg)：
精密称取248mg PTZ置于40mL棕色试剂瓶中，加入20.667mL的生理盐水，涡旋仪涡旋2分钟后常温超声2分钟，即获得均一澄清溶液(浓度:12mg/mL)。
2)0.3mg/mL的实施例5和实施例23(剂量：3mg/kg；给药体积：10mL/kg)：
量取一定量的0.5％CMC-Na+1％Tween80，加入一定量装有实施例5和实施例23的试剂瓶中，涡旋仪涡旋3分钟后常温超声15分钟，即获得均一混悬溶液(浓度：0.3mg/mL)。
4.3.3试验方法
1)测试前1小时将实验动物转入操作间适应环境；
2)随机分组并标记称重；
3)PTZ给药前1小时分别给予实施例5和实施例23，或PTZ给药前0.5小时分别给予0.5％CMC-NA+1％Tween-80、实施例5和实施例23；
4)实验观察前通过皮下给予PTZ(120mg/kg)，并将此时间点记录为观察开始点；
5)PTZ给药后立即把动物置于观察箱中并观察30分钟，同时记录动物出现a)第一次阵挛发作的潜伏期，b)第一次全身强直性阵挛发作的潜伏期，c)阵挛发作的次数，d)全身强直性阵挛发作的次数，e)出现动物死亡的时间,6)如动物在30min观察期中未出现癫痫发作，则潜伏期记为1800sec，发作次数记为0。
·阵发性痉挛(Clonic seizure)：动物全身肌阵挛并持续3s以上，并伴有跌倒；
·强直性阵挛(Tonic seizure)：四肢伸直，与身体呈90°；
6)给药后观察记录药物可能诱导的副作用，可分为四个级别：
·无：正常
·轻度镇静(Mild sedation)
·中度镇静(Moderate sedation)
·重度镇静(Severe sedation)
7)测试时间为12:00am至16:30pm。
4.4适应环境
测试前1小时将实验动物转入操作间适应环境。
4.5分组给药
随机分组并标记称重；每组10只小鼠。PTZ给药前30-60分钟，分别口服给予待测化合物，给药体积为10mL/kg。
4.6PTZ造模及测试
实验观察前通过皮下给予PTZ(120mg/kg)，并将此时间点记录为观察开始点；PTZ给药后立即把动物置于观察箱中并观察30分钟，同时记录动物出现：a)第一次阵挛发作的潜伏期，b)第一次全身强直性阵挛发作的潜伏期，c)阵挛发作的次数，d)全身强直性阵挛发作的次数，e)出现动物死亡的时间。如动物在30min观察期中未出现癫痫发作，则潜伏期记为1800sec，发作次数记为0。
4.7数据分析
所有计量资料均以均数±标准误(Mean±SEM)表示，采用Prism 6.0统计软件中作检验分析数据。
4.8试验数据：
Figure PCTCN2019074108-appb-000158
Figure PCTCN2019074108-appb-000159
4.9实验结果
相对于对照组，实验各实施例显著性延长阵挛发作和全身强直性阵挛发作的潜伏期及发作次数；可以保护60％的动物免遭死亡，显著延长死亡潜伏期，具有较好的抗癫痫作用。

Claims (21)

  1. 一种通式(I)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074108-appb-100001
    其中：
    X选自-CR 17-或-N-；
    Y选自-CR 23R 24-、-S(CH 2) n1-、-P(CH 2) n1-、-O(CH 2) n1-、-(CH 2) n1NR 22-、
    Figure PCTCN2019074108-appb-100002
    Figure PCTCN2019074108-appb-100003
    R x、R y、R z和R f相同或不同，各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、巯基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 24或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、巯基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
    或者，R x、R y、R z和R f任意两个相邻、不相邻或两个相同的基团链接可形成一个环烷基、杂烷基、芳基和杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷 基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 24和-(CH 2) n1NR 23S(O) m1R 24中的一个或多个取代基所取代；
    再或者，R x、R y、R z和R f任意两个相邻的两个基团不存在，形成一个双键；
    R 21选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 24或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
    当X选自-CR 17-时，R 17选自键、氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、烯基、炔基、烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代；
    或者，R 17与R x、R y、R z和R f中任意基团链接可形成一个环烷基、杂烷基、芳基和杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 24和-(CH 2) n1NR 23S(O) m1R 24中的一个或多个取代基所取代；
    R 22选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 24或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝 基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
    R 23、R 24、R 25和R 26相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、烯基、炔基、烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代；
    m为0、1、3、4、5、6、7、8、9或10的整数；
    n为0、1、2、或3的整数；
    o为0、1、2、3、4或5的整数；
    p为0、1、2、3、4、5或6的整数；
    q为0、1、2、3、4、5或6的整数；
    m 1为0、1或2的整数；且
    n 1为0、1、2、3、4或5的整数。
  2. 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(II)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074108-appb-100004
    其中：
    R 1、R 2、R 4、R 5、R 6、R 7、R 11、R 12、R 15a、R 15b、R 16a、R 16b、R 18和R 19相同或不同，各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)NR 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 23或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、 烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
    或者，R 1、R 2、R 4、R 5、R 6、R 7、R 11、R 12、R 15a、R 15b、R 16a、R 16b、R 18和R 19任意两个相邻或不相邻的基团之间可形成一个环烷基、杂烷基、芳基和杂芳基，其中所述的所成的环烷基、杂烷基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
    R 3a和R 3b相同或不同，各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、巯基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)NR 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 23或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、巯基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
    X、Y、R 21～R 26、n、m 1和n 1如权利要求1所述。
  3. 根据权利要求1所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(III)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074108-appb-100005
    其中：
    Y、R 1、R 2、R 3a、R 3b、R 4、R 5、R 6、R 7、R 11、R 12、R 15a、R 15b、R 16a、R 16b、R 18、R 19、R 21～R 26和n如权利要求2所述。
  4. 根据权利要求1-3任一项所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(Ⅳ)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074108-appb-100006
    其中：
    Y选自
    Figure PCTCN2019074108-appb-100007
    R 3a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、巯基、硝基、羟基、氰基、烯基或炔基；
    R 5选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基或炔基；
    R 15a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基或炔基；
    R 16a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基或炔基；
    或者，R 15a和R 16a链接形成一个环烷基或杂烷基，其中所述的所成的环烷基或杂烷基任选进一步被选自氢原子、氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基中的一个或多个取代基所取代；
    R 19选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、巯基、羟基、氰基、烯基、炔基、羟烷基、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)(＝NR 23)R 24或-(CH 2) n1C(O)NR 23R 24；
    或者，R 5和R 19链接形成一个环烷基或杂烷基，其中所述的所成的环烷基或杂烷基任选进一步被选自氢原子、氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基中的一个或多个取代基所取代；
    R 21选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 24或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
    R 23、R 24、R 25和R 26相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、取代或未取代的烷基、卤素、羟基、取代或未取代的氨基、氧代基、硝基、氰基、烯基、炔基、烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基中的一个或多个取代基所取代；
    n为1或2的整数；
    m 1为0、1或2的整数；且
    n 1为0、1、2、3、4或5的整数。
  5. 根据权利要求1-3任一项所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(III-A)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074108-appb-100008
    其中：
    Z选自-CR 23R 24-、-(CH 2) n1NR 23-、-(CH 2) n1O(CH 2) n2-或-O-；优选为亚甲基；
    环C选自环烷基、杂环基、芳基、杂芳基，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
    R c相同或不同，选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)NR 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 23或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
    z为0、1、3、4或5的整数；
    n2为0、1、3、4或5的整数；且
    R 3a、R 3b、R 5、R 19、R 23～R 26、n、m 1和n 1如权利要求4所述。
  6. 根据权利要求1-3所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(V)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074108-appb-100009
    其中：
    Y、R 1、R 2、R 3a、R 3b、R 4、R 5、R 6、R 7、R 11、R 12、R 15a、R 15b、R 16a、R 16b、R 17、R 18、R 19、R 21和n如权利要求2所述；
    R 17如权利要求1所述。
  7. 根据权利要求1-6任一项所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(V-7)和通式(V-8)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074108-appb-100010
    其中：
    环A选自环烷基、杂环基、芳基、杂芳基，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
    R a相同或不同，选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)NR 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 23或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、 烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
    R 19选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)NR 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 23、-(CH 2) n1S(O)(＝NR 23)R 24或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
    x为0、1、3、4或5的整数；
    Z、R 23～R 26、m 1和n 1如权利要求5所述。
  8. 根据权利要求1-7任一项所述的通式(Ⅰ)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(III-B)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074108-appb-100011
    其中：
    R 5选自氢原子、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基；
    R 19选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、-(CH 2) n1OR 23或-(CH 2) n1SR 23；
    R c选自氢原子、氰基或C 1-6烷基；
    z为0、1或2的整数；且
    n为0、1或2。
  9. 根据权利要求1-8任一项所述的通式(Ⅰ)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(IV-A)和(IV-B)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074108-appb-100012
    其中：
    R 3a选自C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基；
    R 19选自氰基、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、-(CH 2) n1OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)(＝NR 23)R 24或-(CH 2) n1SR 23；
    R a选自氢原子、氰基、卤素、硝基、烷基、烷氧基、卤代烷基、环烷基、羟烷基、杂环基、杂芳基、-(CH 2) n1CR 23R 24R 25、-(CH 2) n1SR 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)(＝NR 23)R 24、-(CH 2) n1C(O)NR 23R 24；其中所述的烷基、环烷基、杂环基或杂芳基任选进一步被选自氢原子、烷基、卤素、氰基、羟基、环烷基、杂环基和杂芳基中的一个或多个所取代；
    x为0、1或2的整数，且
    R 5、R 23、R 24、m 1和n 1如权利要求4所述。
  10. 根据权利要求1-3或6所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(VII)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074108-appb-100013
    其中：
    R 1a和R 1b相同或不同，选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、 杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)NR 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 23或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
    环A、Z、Ra、R 23～R 26、m 1、n 1和x如权利要求7所述。
  11. 根据权利要求1-9任一项所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(VIII)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074108-appb-100014
    其中：环A、Z、R a和x如权利要求7所述。
  12. 根据权利要求1-9任一项所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(IX)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074108-appb-100015
    其中：
    Z选自-CR 23R 24-、-(CH 2) n1NR 23-、-(CH 2) n1O(CH 2) n2-或-O-；优选为亚甲基；
    环B选自环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、 硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
    R b相同或不同，选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)NR 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 23或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；且
    y选自0、1、2、3或4的整数。
  13. 根据权利要求1-3所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(VIII)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074108-appb-100016
    其中：
    R 21选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 24或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、 -(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
    R 23～R 26、m 1和n 1如权利要求1所述。
  14. 根据权利要求1-3所述的通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其为通式(X)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074108-appb-100017
    其中：
    M选自-CR 23-或氧原子；
    Y选自-S(CH 2) n1-、
    Figure PCTCN2019074108-appb-100018
    Figure PCTCN2019074108-appb-100019
    R 21选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1NR 23R 24、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1NR 23C(O)R 24或-(CH 2) n1NR 23S(O) m1R 24，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、氧代基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH 2) n1R 25、-(CH 2) n1OR 25、-(CH 2) n1SR 25、-(CH 2) n1C(O)R 25、-(CH 2) n1C(O)OR 25、-(CH 2) n1S(O) m1R 25、-(CH 2) n1NR 25R 26、-(CH 2) n1C(O)NR 25R 26、-(CH 2) n1C(O)NHR 25、-(CH 2) n1NR 25C(O)R 26和-(CH 2) n1NR 25S(O) m1R 26中的一个或多个取代基所取代；
    R 22～R 26、m 1和n 1如权利要求1所述。
  15. 根据权利要求5、7、10、11、12任一项所述的通式(I)所示的化合物，其立体异构体或其药学上可接受盐，其中所述的环A、环B和环C选自以下基团：
    Figure PCTCN2019074108-appb-100020
    Figure PCTCN2019074108-appb-100021
  16. 根据权利要求1-15任一项所述的通式(I)所示的化合物，其立体异构体或其药学上可接受盐，其中所述的R a、R b和R c选自氢原子、氰基、卤素、硝基、C 1-6烷基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、C 1-6羟烷基、5-10元杂环基、5-10元杂芳基、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)NR 23R 24、-(CH 2) n1C(O)OR 23或-(CH 2) n1S(O) m1R 23，其中所述的C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、C 1-6羟烷基、5-10元杂环基和5-10元杂芳基任选进一步被选自氢原子、C 1-6烷基、卤素、氰基、羟基、C 3-6环烷基、C 1-6羟烷基、5-10元杂环基和5-10元杂芳基中的一个或多个取代基所取代；
    R 23和R 24各自独立的选自氢原子、C 1-6烷基或3-8元杂环基。
  17. 根据权利要求1-16任一项所述的通式(I)所示的化合物，其立体异构体或其药学上可接受盐，
    其中：
    Z选自-CH 2-、-CH 2NH-、-CH 2O-、-CH 2-、-NH-或-NHSO 2-；
    R 3a选自C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基；优选C 1-3烷基或C 1-3烷氧基；更优选甲基或甲氧基甲基；
    R 5选自氢原子、卤素、氰基、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基；优选氢原子和C 1-3烷基；
    R 19选自氰基、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、-(CH 2) n1OR 23、-(CH 2) n1S(O) m1R 23、-(CH 2) n1S(O)(＝NR 23)R 24或-(CH 2) n1SR 23；优选氰基、卤素、C 1-3烷氧基、C 1-3卤代烷基、-(CH 2) n1SR 23、-(CH 2) n1S(O) m1R 23或-(CH 2) n1S(O)(＝NR 23)R 24； 更优选卤素；
    或者，R 5和R 19任意两个相邻的基团之间可形成一个C 3-6环烷基，优选环丙基。
  18. 根据权利要求1-17任一项所示的通式(I)化合物、其立体异构体或其药学上可接受的盐，其特征在于，选自如下化合物：
    Figure PCTCN2019074108-appb-100022
    Figure PCTCN2019074108-appb-100023
    Figure PCTCN2019074108-appb-100024
    Figure PCTCN2019074108-appb-100025
    Figure PCTCN2019074108-appb-100026
    Figure PCTCN2019074108-appb-100027
    Figure PCTCN2019074108-appb-100028
  19. 一种药用组合物，其包括治疗有效剂量的权利要求1～18任一项所示的通式(I)化合物、其立体异构体或其药学上可接受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。
  20. 根据权利要求1～18任一项所示的通式(I)化合物、其立体异构体或其药学上可接受的盐，或权利要求19所述的药物组合物在制备GABA A受体调节剂药物中的应用。
  21. 根据权利要求1～18任一项所示的通式(I)化合物、其立体异构体或其药学上可接受的盐，或权利要求19所述的药物组合物在治疗CNS相关疾病中的应用；所述CNS相关的病症选自：睡眠障碍、心境障碍、精神分裂症谱系障碍、痉挛性障碍、记忆障碍和/或认知障碍、运动障碍、人格障碍、自闭症谱系障碍、疼痛、外伤性脑损伤、血管疾病、物质滥用障碍和/或戒断综合征或耳鸣。
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