WO2019154257A1 - 一种甾族类衍生物调节剂及其制备方法和应用 - Google Patents

一种甾族类衍生物调节剂及其制备方法和应用 Download PDF

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WO2019154257A1
WO2019154257A1 PCT/CN2019/074134 CN2019074134W WO2019154257A1 WO 2019154257 A1 WO2019154257 A1 WO 2019154257A1 CN 2019074134 W CN2019074134 W CN 2019074134W WO 2019154257 A1 WO2019154257 A1 WO 2019154257A1
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group
substituted
cycloalkyl
aryl
heteroaryl
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PCT/CN2019/074134
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English (en)
French (fr)
Inventor
苏熠东
邓海宁
陈晓坡
包如迪
张福军
Original Assignee
江苏豪森药业集团有限公司
上海翰森生物医药科技有限公司
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Priority to CN202210401606.0A priority Critical patent/CN114805462B/zh
Priority to JP2020542730A priority patent/JP7438956B2/ja
Priority to KR1020207025423A priority patent/KR20200120661A/ko
Priority to BR112020016269-8A priority patent/BR112020016269A2/pt
Priority to EP19750850.0A priority patent/EP3750908A4/en
Priority to MX2020008422A priority patent/MX2020008422A/es
Priority to CA3090724A priority patent/CA3090724A1/en
Priority to AU2019218177A priority patent/AU2019218177B2/en
Application filed by 江苏豪森药业集团有限公司, 上海翰森生物医药科技有限公司 filed Critical 江苏豪森药业集团有限公司
Priority to CN202210400900.XA priority patent/CN114656514B/zh
Priority to US16/969,133 priority patent/US20210139530A1/en
Priority to RU2020126096A priority patent/RU2797408C2/ru
Priority to CN201980001355.3A priority patent/CN110709409B/zh
Publication of WO2019154257A1 publication Critical patent/WO2019154257A1/zh
Priority to JP2024017080A priority patent/JP2024045458A/ja

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
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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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/573—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 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
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    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
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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
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
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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
    • C07J41/005—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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    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
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    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
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    • 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
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
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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
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    • 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
    • C07J7/0005—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
    • C07J7/0025—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 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
    • 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
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    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
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    • 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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    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

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 (I-A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • Y is selected from -S(CH 2 ) n1 -,
  • R 3a and R 3b 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 group, an amino group, a decyl group, a nitro group, a hydroxyl group, Cyano, alkenyl, alkynyl, cycloalkyl, 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
  • R 5 , R 6 , R 15a , R 15b , R 16a , R 16b and R 19 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, Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, 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 ) n
  • a ring alkyl group, a heteroalkyl group, an aryl group, and the like may be formed between any two adjacent or non-adjacent groups of R 5 , R 6 , R 15a , R 15b , R 16a , R 16b and R 19 .
  • a heteroaryl group wherein said cycloalkyl, heteroalkyl, aryl and heteroaryl groups 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, and a nitro group.
  • 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, an aryl group and a heteroaryl group, wherein said The alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of a halogen atom, a substituted or unsubstituted alkyl group, a halogen, a hydroxyl group, a substituted or unsubstituted amino group, an oxo group, a nitrate , cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl,
  • R 17 may be bonded to any of R 16a and R 16b to form a cycloalkyl, heteroalkyl, aryl and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are described.
  • 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, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(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
  • 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
  • n is an integer of 0, 1, 2, or 3;
  • R 22 to R 26 , m 1 and n 1 are as defined for the compound of the formula (I).
  • the compound of the formula (I) is a compound represented by the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • 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 fluorenyl group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, and a ring.
  • R 15a , R 15b , R 16a and R 16b 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, and a nitrate.
  • a cycloalkyl group, a heteroalkyl group, an aryl group and a heteroaryl group may be formed between any two adjacent or non-adjacent groups of R 15a , R 15b , R 16a and R 16b , wherein
  • the cycloalkyl, heteroalkyl, aryl and heteroaryl groups 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, Alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n1 R 25 , -(CH 2 ) n1 OR 25 , -( CH 2 ) n1 SR 25
  • R 19 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 fluorenyl group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, and a ring.
  • R 21 , R 23 to R 26 , m 1 and n 1 are as defined for the compound of the formula (I). .
  • the compound of the formula (I) is a compound represented by the formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • R 15a , R 16a and R 21 are as defined for the compound of the formula (I).
  • the compound of the formula (I) is a compound represented by the formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • Z is selected from -CR 23 R 24 -, -(CH 2 ) n1 NR 23 - or -(CH 2 ) n1 O(CH 2 ) n2 -; preferably methylene;
  • Ring A 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, cycloalkyl, heterocyclyl, aryl, 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 ) n1 C(O )OR 25 , -(CH 2 ) n1 S(O) m1 R 25 , -
  • 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 15a is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogen, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH 2 ) n1 R 23 , -(CH) 2 ) n1 OR 23 , -(CH 2 ) n1 SR 23 , -(CH 2 ) n1 S(O) m1 R 23 or -(CH 2 ) n1 NR 23 R 24 wherein the alkyl group, haloalkyl group, The cycloalkyl, heterocyclyl, aryl and heteroaryl groups 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
  • R 16a is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogen, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH 2 ) n1 R 23 , -(CH 2 ) n1 OR 23 , -(CH 2 ) n1 SR 23 , -(CH 2 ) n1 S(O) m1 R 23 or -(CH 2 ) n1 NR 23 R 24 ;
  • R 15a and R 16a may form a cycloalkyl group and a heteroalkyl group, wherein the alkyl group and heteroalkyl 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, and an oxo group.
  • a halogen atom an alkyl group
  • a halogenated alkyl group a halogen group
  • an amino group and an oxo group.
  • R 15a and R 16a are not simultaneously a hydrogen atom;
  • R 23 and R 24 are 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, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further optionally selected from a halogen atom, an alkyl group , haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalk
  • R 25 to R 26 , m 1 , n 1 and x are as defined for the compound of the formula (II).
  • the compound of the formula (I) is a compound represented by the formula (IV-A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof :
  • R 15a is selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogen, an amino group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH 2 ) n1 R 23 , -(CH) 2 ) n1 OR 23 , -(CH 2 ) n1 SR 23 , -(CH 2 ) n1 S(O) m1 R 23 or -(CH 2 ) n1 NR 23 R 24 wherein the alkyl group, haloalkyl group, The cycloalkyl, heterocyclyl, aryl and heteroaryl groups 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
  • Ring A, R a and x are as defined for the compounds of formula (IV).
  • the compound of the formula (I) is a compound represented by the formula (V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • R 15a , R 16a , R a and x are as defined for the compounds of the formula (IV).
  • the compound of the formula (I) is a compound represented by the formula (V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • R 15a , R 16a , R a and x are as defined by the compounds of the formula (V).
  • the compound of the formula (I) is a compound represented by the formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • R d 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 group, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group.
  • Y is an integer of 0, 1, 3 or 4;
  • Rings A, Z, R a , R 23 to R 26 , m 1 , n 1 and x are as defined for the compounds of the formula (IV).
  • the compound of the formula (I) which is a compound represented by the formula (VI-A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof :
  • Rings A, Z, R a , R d , R 23 to R 26 , m 1 , n 1 , x and y are as defined for the compounds of the formula (VI).
  • the compound of the formula (I) is a compound represented by the formula (VII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • 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
  • haloalkoxy hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic, 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 ) n1 C(O)OR 25 , -(CH 2 ) n1 S(O) m1 R 25 , -(CH 2 ) n1 NR 25 R 26 , -(CH 2 ) n1 C(O)NR 25 R 26 , -(CH 2 ) n1 C(O)NHR 25 , -(CH 2 ) n1 NR 25 C(O)R 26 And one or more substituents in -
  • R 22 to R 26 , m 1 and n 1 are as defined for the compound of the formula (I).
  • the compound of the formula (I) is a compound represented by the formula (VIII), a stereoisomer thereof 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 for the compound of the formula (I).
  • the compound of the formula (I) is a compound represented by the formula (IX), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • 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
  • n is an integer of 0, 1, or 2.
  • R 22 to R 26 , m 1 and n 1 are as defined for the compound of the formula (I).
  • the compound of the formula (I) is a compound represented by the formula (X), a stereoisomer thereof 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 for the compound of the formula (I).
  • Z is selected from -CH 2 -, -CH 2 NH-, -CH 2 O-, -CH 2 -, -NH- or -NHSO 2 -;
  • Y is selected from -C(O)-, -C(O)CH 2 -, -C(O)O-, -C(O)CH 2 NH-, -C(O)CH 2 O-, -SCH 2 -, -S(O)CH 2 -, -S(O) 2 CH 2 -, -P(O)R 23 -, -C(O)NH- or -C(O)NHSO 2 -;
  • R a is selected from the group consisting of a hydrogen atom, a halogen, an amino group, a cyano group, a nitro group, a C 1-6 alkyl group, a C 2-6 alkynyl group, a C 3-6 cycloalkyl group, a C 1-6 haloalkyl group, a C 3 - 8 halocycloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, -(CH 2 ) n1 OR 23 ,
  • R d is selected from the group consisting of a hydrogen atom, a halogen, an amino group, a cyano group, a nitro group, a C 1-6 alkyl group, a C 2-6 alkynyl group, a C 3-6 cycloalkyl group, a C 1-6 haloalkyl group, and a C 3-8 group.
  • R 23 and R 24 are the same or different and each independently selected from a C 1-6 alkyl group, a C 3-8 cycloalkyl group or a 3-8 membered heterocyclic group, wherein the C 1-6 alkyl group, C 3
  • the -8 cycloalkyl group and the 3-8 membered heterocyclic group are optionally further selected from the group consisting of a halogen atom, a halogen, a hydroxyl group, a C 1-3 alkyl group, an amino group, an oxo group, a nitro group, a cyano group, and a C 2-6 alkene.
  • R 15a 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, a halogen, an amino group, a hydroxyl group, a C 3-8 cycloalkyl group, a C 3-8 halogen ring.
  • the 5-12 membered heteroaryl group is optionally further selected from the group consisting of a hydrogen atom, a halogen, a cyano group
  • R 16a is selected from a hydrogen atom, a halogen, a cyano group, a C 1-6 alkyl group or a C 1-6 haloalkyl group.
  • R 15a and R 16a may form a C 3-8 cycloalkyl group, wherein the C 3-8 cycloalkyl group is further optionally selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 halogenated alkane. Substituted by one or more substituents of a halogen or a halogen; R 15a and R 16a are not simultaneously a hydrogen atom;
  • R 23 and R 24 are the same or different and each independently selected from a hydrogen atom, a C 1-6 alkyl group, a C 3-8 cycloalkyl group or a 3-8 membered heterocyclic group, wherein the C 1-6 alkyl group Further, the C 3-8 cycloalkyl group and the 3-8 membered heterocyclic group are further selected from the group consisting of a halogen atom, a halogen, a hydroxyl group, a C 1-3 alkyl group, an amino group, an oxo group, a nitro group, a cyano group, and a C 2 group.
  • the compound represented by the formula (I), the 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, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, further preferably from 3 to 8 More than one carbon atom, more preferably from 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • the polycyclic cycloalkyl group includes a spiro ring, a fused ring, and a bridged cycloalkyl group, preferably a cyclopropyl group.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
  • spirocycloalkyl groups include:
  • 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.
  • 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 10 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, 1,4-diaza, etc., preferably tetrahydrofuranyl, pyrazolidinyl, morpholinyl, 1,4 - diaza, 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 12 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 Orisoxazolyl or pyrimidinyl; more preferred is triazolyl, tetrazol
  • 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, which is a straight or branched chain group containing from 2 to 20 carbon atoms, preferably an alkyl group having from 2 to 8 carbon atoms, more preferably from 2 to 6 The alkyl group of a carbon atom, most preferably an alkyl group of 2 to 3 carbon atoms; wherein the alkenyl group may be further substituted by other related groups, for example: 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.
  • Alkynyl means (CH ⁇ C-) which is a straight or branched chain group containing from 2 to 20 carbon atoms, preferably an alkyl group having from 2 to 8 carbon atoms, more preferably from 2 to 6 carbon atoms The alkyl group, most preferably an alkyl group of 2 to 3 carbon atoms; wherein the alkynyl group may be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio , alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero A cycloalkylthio group, a carboxyl group or a 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.
  • Step 2 (3R, 5R, 8R, 9R, 10S, 13S, 14S)-3-hydroxy-3,13-dimethyl-1,2,3,4,5,6,7,8,9, Preparation of 10,11,12,13,14-tetradecahydro-17H-cyclopenta[a]phenanthrene-17-one
  • Step 3 (2R, 4aS, 4bR, 6aS, 7aS, 8aS, 8bR, 8cR, 10aR)-2-hydroxy-2,6a-dimethylhexadehydrocyclopropene[4,5]cyclopentadiene And preparation of [1,2-a]phenanthrene-7(1H)-one
  • Trimethylsulfoxonium iodide (0.92 g, 4.2 mmol) was dissolved in anhydrous dimethyl sulfoxide (10 mL), nitrogen was replaced, sodium hydrogen (168 mg, 4.2 mmol) was added, and the reaction was stirred for 1 hour, and (3R, 5R was added. ,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11,12,13, A solution of 14-tetrahydrox-17H-cyclopenta[a]phenanthrene-17-one (1.0 g, 3.5 mmol) in dimethyl sulfoxide (5 mL).
  • Step 4 (2R, 4aS, 4bR, 6aS, 7aS, 8aR, 8bR, 8cR, 10aR)-7-Ethylene-2,6a-dimethyloctadecylcyclopropene[4,5]cyclopenta Preparation of diene[1,2-a]phenanthrene-2-ol
  • PPh 3 EtBr (14.8 g, 40 mmol) was dissolved in anhydrous dimethyl sulfoxide (50 mL), nitrogen was replaced, sodium hydrogen (1.6 g, 40 mmol) was added, and the reaction was stirred at room temperature for 1 hour, and (2R, 4aS, 4bR, 6aS was added. , 7aS, 8aS, 8bR, 8cR, 10aR)-2-hydroxy-2,6a-dimethylhexadehydrocyclopropene[4,5]cyclopenta[1,2-a]phenanthrene-7 ( 1H)-ketone (0.6 g, 2.0 mmol), the reaction was stirred at 100 ° C overnight.
  • Step 5 (2R, 4aS, 4bR, 6aS, 7aS, 8aR, 8bR, 8cR, 10aR)-7-(1-hydroxyethyl)-2,6a-dimethyloctadecylcyclopropene [4, 5] Preparation of cyclopenta[1,2-a]phenanthrene-2-ol
  • Step 6 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecylcyclopropene[4,5 Preparation of cyclopenta[1,2-a]phenanthrene-7-yl)ethane-1-one
  • reaction solution was filtered, and the organic layer was concentrated, and then purified and purified tolulululululilililililililililililililililililililililililililililililililililililili ,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecylcyclopropenyl[4,5]cyclopenta[1,2-a]phenanthrene-7-yl)ethane 1-ketone (0.35 g, yield: 83%).
  • Trimethylsilyl trifluoromethanesulfonate (5.6 mL, 31.0 mmol) was added dropwise to (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethylhexene Hydrogen-17H-cyclopenta[a]phenanthrene-17-one (3g, 10.3mmol) and triethylamine (36.0mL, 258.2mmol) in toluene (45mL), the reaction mixture was heated to reflux for 2 hours, cooled Washed with saturated sodium bicarbonate, extracted with n-hexane, and evaporated to dryness to give crude (((3R,5R,8R,9R,10S,13S,14S)-3,13-dimethyl-2,3,4, 5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl)di(ox
  • Step 2 (3R, 5R, 8R, 9R, 10S, 13S, 14S, 16R)-17-Ethylene-16-fluoro-3,13-dimethylhexadecahydro-1H-cyclopentadiene [a] Preparation of phenanthrene-3-ol
  • Pentadiene [a]phenanthroline-17-one 200 mg, 0.65 mmol
  • the third step (3R, 8R, 9R, 10S, 13S, 14S, 16R, 17S)-16-fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-ring Preparation of pentadienyl[a]phenanthroline-3-ol
  • reaction solution was extracted with ethyl acetate, washed with sodium thiosulfate solution and brine, and then dried and dried to afford (3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-17-(1-hydroxyethyl 3-)13-Dimethylhexadehydro-1H-cyclopenta[a]phenanthroline-3-ol (80 mg) was used directly in the next reaction.
  • Step 4 1-((3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopentadiene And [a] preparation of phenanthrene-17-yl)ethane-1-one
  • the reaction solution was evaporated to dryness and then purified (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Step 2 (3R, 5R, 8R, 9R, 10S, 13S, 14S, 15R, E)-17-Ethylene-3,13,15-trimethylhexadecahydro-1H-cyclopentadiene [a]phenanthroline-3-phenol
  • Ethyltriphenylphosphonium bromide (18.5 g, 50 mmol) was dissolved in anhydrous dimethyl sulfoxide (50 mL), nitrogen was added, sodium hydrogen (2.0 g, 50 mmol) was added, and the mixture was stirred at room temperature for 1 hour, and added (3R, 5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-3,13,15-trimethylhexadeca-17H-cyclopenta[a]phenanthrene-17-one (1.52g) , 5 mmol), the reaction was stirred at 100 ° C overnight. The reaction was cooled to room temperature, then EtOAc (EtOAc) (EtOAc)EtOAc.
  • Step 4 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopentadiene And [a]phenanthroline-yl)ethane-1-one
  • Step 5 2-Bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydrol-1H- Cyclopenta[a]phenanthrene-17-yl)ethane-1-one
  • Step 6 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopentane Aceto[a]phenanthroline-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carbonitrile
  • This Example 20 was synthesized by the following specific embodiments:
  • This Example 25 was synthesized by the following specific embodiments:
  • Example 53 Example 54A and Example 54B
  • Ethyltriphenylphosphonium bromide (12.5 g, 33 mmol) was dissolved in anhydrous dimethyl sulfoxide (50 mL), nitrogen was added, sodium hydrogen (1.32 g, 33 mmol) was added, and the mixture was stirred at room temperature for 1 hour, and added (3R, 5R,8R,9R,10S,13S,14S,15S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadehydro-17H-cyclopenta[a]phenanthrene-17- The ketone (1.1 g, 3.3 mmol) was stirred at 60 ° C overnight.
  • the third step (3R, 5R, 8R, 9R, 10S, 13S, 14S, 15S, 17S)-15-cyclopropyl-17-((R)-1-hydroxyethyl)-3,13-dimethyl Hexadecahydro-1H-cyclopenta[a]phenanthroline-3-ol
  • the fourth step 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydrol-1H- Cyclopenta[a]phenanthrene-17-yl)ethane-1-one
  • Step 5 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexa Hydrogen-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-one
  • Step 6 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydrol-1H -cyclopentadienyl[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carbonitrile
  • Example 73 and Example 145
  • the third step (3R, 5R, 8R, 9R, 10S, 13S, 14S, 15R, 17R)-15-ethyl-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro- 1H-cyclopenta[a]phenanthroline-3-ol
  • the fourth step 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-ring Pentadieno[a]phenanthroline-17-yl)ethane-1-one
  • Step 5 2-Bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro -1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-one
  • Step 6 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro- 1H-cyclopentadien[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carbonitrile
  • Example 92 and Example 93
  • Example 93A and Example 93B (21.6 mg, white solid, yield: 23.9%), which was further purified by preparative chromatography to give 2-(5-fluoro-1H-benzo[d] ][1,2,3]triazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-di Methyl octahydrocyclopropenyl[4,5]cyclopenta[1,2-a]phenanthrene-7-yl)ethane-1-one with 2-(6-fluoro-1H-benzo[ d][1,2,3]triazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a- Dimethyloc
  • This embodiment 105 is synthesized by the following specific embodiments:
  • Example 123 and Example 124
  • Reference Example 5 gives the product 3-chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R) ,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole- 4-carbonitrile (37 mg, yield 55.3%).
  • Reference Example 5 gives the product 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)- 3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-3,5- Dimethoxynitrile (18 mg, yield 27.5%).

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Abstract

本发明涉及一种甾族类衍生物调节剂及其制备方法和应用。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

一种甾族类衍生物调节剂及其制备方法和应用 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 PCTCN2019074134-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 PCTCN2019074134-appb-000002
Figure PCTCN2019074134-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(I-A)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019074134-appb-000004
其中：
Y选自-S(CH 2) n1-、
Figure PCTCN2019074134-appb-000005
Figure PCTCN2019074134-appb-000006
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；
R 5、R 6、R 15a、R 15b、R 16a、R 16b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 5、R 6、R 15a、R 15b、R 16a、R 16b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 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 16a和R 16b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 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；
n为0、1、2、或3的整数；
R 22～R 26、m 1和n 1如通式(I)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(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 PCTCN2019074134-appb-000007
其中：
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、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)R 24、-(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、环烷基、杂环基、芳基、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 15a、R 15b、R 16a和R 16b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)R 24、-(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、环烷基、杂环基、芳基、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 15a、R 15b、R 16a和R 16b中不同时为氢原子；
或者，R 15a、R 15b、R 16a和R 16b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、环烷基、杂环基、芳基、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、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)R 24、-(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；
R 21、R 23～R 26、m 1和n 1如通式(I)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(I)所示的化合物，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 PCTCN2019074134-appb-000008
其中：
R 15a、R 16a和R 21如通式(I)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(I)所示的化合物，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 PCTCN2019074134-appb-000009
其中：
Z选自-CR 23R 24-、-(CH 2) n1NR 23-或-(CH 2) n1O(CH 2) n2-；优选亚甲基；
环A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、环烷基、杂环基、芳基、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)R 24、-(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、环烷基、杂环基、芳基、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 15a选自氢原子、烷基、卤代烷基、烷氧基、卤素、氨基、羟基、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) n1S(O) m1R 23或-(CH 2) n1NR 23R 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、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基所取代；
R 16a选自氢原子、烷基、卤代烷基、烷氧基、卤素、氨基、羟基、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) n1S(O) m1R 23或-(CH 2) n1NR 23R 24；
或者，R 15a和R 16a可形成一个环烷基和杂烷基，其中所述的烷基和杂烷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、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基所取代；R 15a和R 16a不同时为氢原子；
R 23和R 24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、芳基和杂芳基，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、环烷基、杂环基、芳基、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 25～R 26、m 1、n 1和x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(I)所示的化合物，其为通式(IV-A)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019074134-appb-000010
R 15a选自氢原子、烷基、卤代烷基、烷氧基、卤素、氨基、羟基、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) n1S(O) m1R 23或-(CH 2) n1NR 23R 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、环烷基、杂环基、芳基、 杂芳基中的一个或多个取代基所取代；
环A、R a和x如通式(IV)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(I)所示的化合物，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 PCTCN2019074134-appb-000011
其中：
R 15a、R 16a、R a和x如通式(IV)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(I)所示的化合物，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 PCTCN2019074134-appb-000012
其中：
R 15a、R 16a、R a和x如通式(V)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(I)所示的化合物，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 PCTCN2019074134-appb-000013
其中：
R d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)R 24、-(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；
y为0、1、3或4的整数；
环A、Z、R a、R 23～R 26、m 1、n 1和x如通式(IV)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(I)所示的化合物，其为通式(VI-A)所示的化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2019074134-appb-000014
其中：
环A、Z、R a、R d、R 23～R 26、m 1、n 1、x和y如通式(VI)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(I)所示的化合物，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 PCTCN2019074134-appb-000015
其中：
Y选自-S(CH 2) n1-、
Figure PCTCN2019074134-appb-000016
Figure PCTCN2019074134-appb-000017
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如通式(I)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(I)所示的化合物，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 PCTCN2019074134-appb-000018
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如通式(I)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(I)所示的化合物，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 PCTCN2019074134-appb-000019
其中：
Y选自-S(CH 2) n1-、
Figure PCTCN2019074134-appb-000020
Figure PCTCN2019074134-appb-000021
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；且
n为0、1或2的整数。
R 22～R 26、m 1和n 1如通式(I)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(I)所示的化合物，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 PCTCN2019074134-appb-000022
其中：
M选自-CR 23-或氧原子；
Y选自-S(CH 2) n1-、
Figure PCTCN2019074134-appb-000023
Figure PCTCN2019074134-appb-000024
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如通式(I)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(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选自以下基团：
Figure PCTCN2019074134-appb-000025
在本发明的一个优选实施例方案中，所述的任意通式所示的化合物，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-；
Y选自-C(O)-、-C(O)CH 2-、-C(O)O-、-C(O)CH 2NH-、-C(O)CH 2O-、-SCH 2-、-S(O)CH 2-、-S(O) 2CH 2-、-P(O)R 23-、-C(O)NH-或-C(O)NHSO 2-；其中所述的R a选自氢原子、卤素、氨基、氰基、硝基、C 1-6烷基、C 2-6炔基、C 3-6环烷基、C 1-6卤代烷基、C 3-8卤代环烷基、C 1-6烷氧基、C 1-6羟烷基、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1C(O)NR 23R 24或-(CH 2) n1S(O) m1R 23，其中所述的C 1-6烷基、C 2-6炔基、C 3-6环烷基、C 1-6卤代烷基、C 3-6卤代环烷基、C 1-6烷氧基和C 1-6羟烷基任选进一步被选自氢原子、卤素、氰基、羟基、C 1-6烷基、C 3-6环烷基和3-6元杂环基中的一个或多个取代基所取代；
R d选自氢原子、卤素、氨基、氰基、硝基、C 1-6烷基、C 2-6炔基、C 3-6环烷基、C 1-6卤代烷基、C 3-8卤代环烷基、C 1-6烷氧基或C 1-6羟烷基；
R 23和R 24相同或不同，各自独立的选自C 1-6烷基、C 3-8环烷基或3-8元杂环基，其中所述的C 1-6烷基、C 3-8环烷基和3-8元杂环基任选进一步被选自氘原子、卤素、羟基、C 1-3烷基、氨基、氧代基、硝基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、-(CH 2) n1NR 25R 26、3-8元杂环基、6-10元芳基和5-12元杂芳基中的一个或多个取代基所取代。
在本发明的一个优选实施例方案中，所述的任意通式所示的化合物，其立体异构体或其药学上可接受盐，
其中：
R 15a选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、卤素、氨基、羟基、C 3-8环烷基、C 3-8卤代环烷基、3-8元杂环基、6-10元芳基、5-12元杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1SR 23、-(CH 2) n1S(O) m1R 23或-(CH 2) n1NR 23R 24，其中所述的C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、C 3-8卤代环烷基、3-8元杂环基、6-10元芳基和5-12元杂芳基任选进一步被选自氢原子、卤素、氰基、羟基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、-(CH 2) n1NR 25R 26、和3-6元杂环基中的一个或多个取代基所取代；
R 16a选自氢原子、卤素、氰基、C 1-6烷基或C 1-6卤代烷基。
或者，R 15a和R 16a可形成一个C 3-8环烷基，其中所述的C 3-8环烷基任选进一步被选自氢原子、C 1-6烷基、C 1-6卤代烷基或卤素的一个或多个取代基所取代；R 15a和R 16a不同时为氢原子；
R 23和R 24相同或不同，各自独立的选自氢原子、C 1-6烷基、C 3-8环烷基或3-8元杂环基，其中所述的C 1-6烷基、C 3-8环烷基和3-8元杂环基任选进一步被选自氘原子、卤素、羟基、C 1-3烷基、氨基、氧代基、硝基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、-(CH 2) n1NR 25R 26、3-8元杂环基、6-10元芳基和5-12元杂芳基中的一个或多个取代基所取代。
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，选自如下化合物：
Figure PCTCN2019074134-appb-000026
Figure PCTCN2019074134-appb-000027
Figure PCTCN2019074134-appb-000028
Figure PCTCN2019074134-appb-000029
Figure PCTCN2019074134-appb-000030
Figure PCTCN2019074134-appb-000031
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，进一步优选包含3至8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。
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 PCTCN2019074134-appb-000032
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 PCTCN2019074134-appb-000033
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 PCTCN2019074134-appb-000034
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 PCTCN2019074134-appb-000035
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10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、1,4-二氮杂等，优选四氢呋喃基、吡唑烷基、吗啉基、1,4-二氮杂、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 PCTCN2019074134-appb-000036
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 PCTCN2019074134-appb-000037
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 PCTCN2019074134-appb-000038
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 PCTCN2019074134-appb-000039
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 PCTCN2019074134-appb-000040
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12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；更优选三唑基、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 PCTCN2019074134-appb-000041
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，其为包含2至20个碳原子的直链或支链基团，优选含有2至8个碳原子的烷基，更优选2至6个碳原子的烷基，最更优选2至3个碳原子的烷基；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-)，其为包含2至20个碳原子的直链或支链基团，优选含有2至8个碳原子的烷基，更优选2至6个碳原子的烷基，最更优选2至3个碳原子的烷基；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-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000042
第一步：(3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-16-(苯基亚硫酰基<亚磺酰>)十六氢-17H-环戊二烯并[a]菲-17-酮的制备
Figure PCTCN2019074134-appb-000043
将叔丁醇钾(2.3g,20.7mmol)溶于无水四氢呋喃(200mL)，置换氮气，加入(3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(3g,10.3mmol)，生成橙色溶液，在25℃下搅拌10分钟，加入苯亚磺酸甲酯(3.2g,20.7mmol)，反应在30℃搅拌半小时。加水(100mL)淬灭反应，水相用乙酸乙酯(100mL x 3)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，得粗品用柱层析分离(石油醚/乙酸乙酯：50/1～3/1)纯化得到(3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-16-(苯基亚硫酰基<亚磺酰>)十六氢-17H-环戊二烯并[a]菲-17-酮(3.5g,产率：82％)。
第二步：(3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氢-17H-环戊二烯并[a]菲-17-酮的制备
Figure PCTCN2019074134-appb-000044
将(3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-16-(苯基亚硫酰基<亚磺酰>)十六氢-17H-环戊二烯并[a]菲-17-酮(3.5g,8.5mmol)溶于二甲苯(50mL)，置换氮气，加入碳酸钠(24.7g,0.17mol)，反应在140℃下搅拌过夜，反应液过滤，有机相浓缩，得粗品用柱层析分离(石油醚/乙酸乙酯：50/1～3/1)纯化得到(3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氢-17H-环戊二烯并[a]菲-17-酮(1.5g,产率：62％)。
1H NMR(400MHz,CDCl 3)δ7.53(dd,J＝5.9,1.2Hz,1H),6.03(dd,J＝6.0, 3.2Hz,1H),2.42–2.33(m,1H),1.90–1.79(m,4H),1.76–1.66(m,2H),1.58–1.48(m,5H),1.47–1.37(m,4H),1.36–1.23(m,7H),1.08(s,3H)。
第三步：(2R,4aS,4bR,6aS,7aS,8aS,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十六氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7(1H)-酮的制备
Figure PCTCN2019074134-appb-000045
将三甲基碘化亚砜(0.92g,4.2mmol)溶于无水二甲亚砜(10mL)，置换氮气，加入钠氢(168mg,4.2mmol)，反应搅拌1小时，加入(3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氢-17H-环戊二烯并[a]菲-17-酮(1.0g,3.5mmol)的二甲亚砜(5mL)溶液，反应在室温搅拌过夜。加水(50mL)淬灭反应，水相用乙酸乙酯(50mL x 3)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，得粗品用柱层析分离(石油醚/乙酸乙酯：50/1～3/1)纯化得到(2R,4aS,4bR,6aS,7aS,8aS,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十六氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7(1H)-酮(0.75g,产率：71％)。
1H NMR(400MHz,CDCl 3)δ2.06–2.00(m,1H),1.97–1.91(m,1H),1.88–1.79(m,3H),1.78–1.67(m,6H),1.63–1.54(m,2H),1.48–1.39(m,3H),1.37–1.25(m,9H),1.15–1.05(m,2H),0.96(s,3H)。
第四步：(2R,4aS,4bR,6aS,7aS,8aR,8bR,8cR,10aR)-7-亚乙基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-2-酚的制备
Figure PCTCN2019074134-appb-000046
将PPh 3EtBr(14.8g,40mmol)溶于无水二甲亚砜(50mL)，置换氮气，加入钠氢(1.6g,40mmol)，反应室温搅拌1小时，加入(2R,4aS,4bR,6aS,7aS,8aS,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十六氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7(1H)-酮(0.6g,2.0mmol)，反应在100℃下搅拌过夜。反应冷却至室温，加水(200mL)淬灭反应，水相用乙酸乙酯(200mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，得粗品用柱层析分离(石油醚/乙酸乙酯：50/1～3/1)纯化得到(2R,4aS,4bR,6aS,7aS,8aR,8bR,8cR,10aR)-7-亚乙基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-2-酚(0.5g,产率：81％)。
第五步：(2R,4aS,4bR,6aS,7aS,8aR,8bR,8cR,10aR)-7-(1-羟基乙基)-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-2-酚的制备
Figure PCTCN2019074134-appb-000047
将(2R,4aS,4bR,6aS,7aS,8aR,8bR,8cR,10aR)-7-亚乙基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-2-酚(0.4g,1.3mmol)溶于无水四氢呋喃(10mL)，冷却至0℃，滴加BH 3/THF(12.7mL,12.7mmol)。反应在室温搅拌3小时，TLC显示反应完全。反应冷却至0℃，缓慢加入3M NaOH水溶液(4mL)，再加入H 2O 2(3mL)，反应在室温搅拌2小时，TLC显示反应完全。加入乙酸乙酯(50mL)，用饱和Na 2S 2O 3水溶液(30mL)洗，再用水(30mL)洗，有机相用无水硫酸钠干燥，过滤，浓缩，得粗品(0.4g,产率：100％crude)，直接用于下一步反应。
第六步：1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000048
将(2R,4aS,4bR,6aS,7aS,8aR,8bR,8cR,10aR)-7-(1-羟基乙基)-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-2-酚(0.4g,1.2mmol)溶于二氯甲烷(20mL)，加入PCC(0.52g,40mmol)，反应在室温搅拌2小时。反应液过滤，有机相浓缩，得粗品用柱层析分离(石油醚/乙酸乙酯：50/1～3/1)纯化得到1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(0.35g,产率：83％)。
1H NMR(400MHz,CDCl 3)δ2.74(d,J＝4.1Hz,1H),2.21(s,3H),1.97–1.91(m,1H),1.87–1.62(m,7H),1.56–1.50(m,1H),1.44–1.21(m,15H),1.12–1.00(m,1H),0.90–0.83(m,1H),0.72(s,3H),0.44–0.36(m,1H).
实施例2
1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-1H-吡唑-4-甲腈的制备
Figure PCTCN2019074134-appb-000049
第一步：2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000050
将1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(70mg,0.21mmol)溶于甲醇(3mL)，加入一滴溴化氢，再加入液溴(41mg,0.25mmol)，反应在室温下搅拌1小时。加入水(20mL)，水相用乙酸乙酯(20mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，得粗品(87mg,产率：100％，粗品)，直接用于下一步反应。
第二步：1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-1H-吡唑-4-甲腈的制备
Figure PCTCN2019074134-appb-000051
将2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(87mg,0.21mmol)，1H-吡唑-4-甲腈(59mg,0.64mmol)和碳酸钾(145mg,1.05mmol)溶于四氢呋喃(2mL)，反应在室温下搅拌过夜。反应液过滤，滤液浓缩，粗品用高效液相色谱柱分离，得到1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-1H-吡唑-4-甲腈(33mg，产率：37％)。
MS m/z(ESI):404.2[M-H 2O+H] +.
1H NMR(400MHz,CDCl 3)δ7.88(s,1H),7.82(s,1H),5.24-5.13(m,2H),2.84(d,J＝2.7Hz,1H),1.98–1.92(m,1H),1.87–1.77(m,4H),1.76–1.66(m,3H),1.57–1.51(m,1H),1.46–1.24(m,15H),1.12–1.02(m,1H),1.00–0.96(m,1H),0.78(s,3H),0.54–0.46(m,1H).
实施例3和实施例4
1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-1H-吡唑-3-甲腈(3)
1-(2-((2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-1H-吡唑-3-甲腈(4)的制备
Figure PCTCN2019074134-appb-000052
将2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(80mg,0.19mmol)，1H-吡唑-3-甲腈(55mg,0.58mmol)和碳酸钾(131mg,0.95mmol)溶于四氢呋喃(3mL)，反应在室温下搅拌过夜。反应液过滤，滤液浓缩，粗品用高效液相色谱柱分离，得到1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-1H-吡唑-3-甲腈(34.7mg，产率：42％)。1-(2-((2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-1H-吡唑-3-甲腈(3.7mg，产率：4.5％)。
实施例3：
MS m/z(ESI):404.2[M-H 2O+H] +
1H NMR(400MHz,CDCl 3)δ7.50(d,J＝2.4Hz,1H),6.74(d,J＝2.4Hz,1H),5.29–5.13(m,2H),2.83(d,J＝2.9Hz,1H),1.97–1.92(m,1H),1.86–1.79(m,4H),1.73–1.64(m,3H),1.58–1.52(m,1H),1.43–1.27(m,15H),1.12–0.96(m,2H),0.79(s,3H),0.53–0.44(m,1H)。
实施例4：
MS m/z(ESI):404.2[M-H 2O+H] +.
1H NMR(400MHz,CDCl 3)δ7.52(d,J＝2.4Hz,1H),6.75(d,J＝2.4Hz,1H),5.11-4.96(m,2H),2.92(s,1H),1.93–1.87(m,1H),1.82–1.74(m,2H),1.72–1.62(m,4H),1.51(s,1H),1.46–1.24(m,15H),1.18–1.09(m,2H),1.04(s,3H),0.89–0.84(m,1H),0.46–0.40(m,1H).
实施例5
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000053
第一步：1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000054
将2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(60mg,0.15mmol)，4-(三氟甲基)-1H-吡唑(60mg,0.44mmol)和碳酸钾(104mg,0.75mmol)溶于四氢呋喃(3mL)，反应在室温下搅拌过夜。反应液过滤，滤液浓缩，粗品用高效液相色谱柱分离，得到1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(22.2mg，产率：33％)。
MS m/z(ESI):465.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.74(s,1H),7.73(s,1H),5.25–5.09(m,2H),2.83(d,J＝3.6Hz,1H),2.00–1.91(m,1H),1.89–1.79(m,4H),1.78–1.65(m,3H),1.58–1.52(m,1H),1.47–1.22(m,15H),1.15–0.95(m,2H),0.79(s,3H),0.52–0.44(m,1H).
实施例6
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(3-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000055
第一步：1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(3-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000056
将2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(80mg,0.2mmol)，3-(三氟甲基)-1H-吡唑(80mg,0.6mmol)和碳酸钾(138mg,1.0mmol)溶于四氢呋喃(5mL)，反应在室温下搅拌过夜。反应液过滤，滤液浓缩，粗品用高效液相色谱柱分离，得到1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(3-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(17mg，产率：18％)。
MS m/z(ESI):447.3[M-H 2O+H] +.
1H NMR(400MHz,CDCl 3)δ7.49(d,J＝1.9Hz,1H),6.60(d,J＝1.9Hz,1H),5.27–5.13(m,2H),2.83(d,J＝3.7Hz,1H),1.99–1.90(m,1H),1.89–1.76(m,4H),1.75–1.61(m,3H),1.58–1.50(m,1H),1.50–1.21(m,15H),1.13–0.96(m,2H),0.79(s,3H),0.52–0.45(m,1H).
实施例7和实施例8
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(2H-1,2,3-三唑-2-基)乙烷-1-酮(7)
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮(8)
Figure PCTCN2019074134-appb-000057
第一步 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(2H-1,2,3-三唑-2-基)乙烷-1-酮(7)和1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮(8)的制备
Figure PCTCN2019074134-appb-000058
将2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十 八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(80mg,0.19mmol)，1H-1,2,3-三唑(40mg,0.58mmol)和碳酸钾(131mg,0.95mmol)溶于四氢呋喃(3mL)，反应在室温下搅拌过夜。反应液过滤，滤液浓缩，粗品用高效液相色谱柱分离，得到1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(2H-1,2,3-三唑-2-基)乙烷-1-酮(7)(9.2mg，产率：12％)；1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮(8)(17.8mg，产率：23％)。
实施例7：
MS m/z(ESI):380.3[M-H 2O+H] +.
1H NMR(400MHz,CDCl 3)δ7.69(s,2H),5.55–5.36(m,2H),2.82(d,J＝4.1Hz,1H),1.99–1.92(m,1H),1.87–1.74(m,4H),1.73–1.52(m,5H),1.47–1.26(m,14H),1.14–0.98(m,2H),0.84(s,3H),0.52–0.43(m,1H)。
实施例8：
MS m/z(ESI):398.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.66(s,1H),5.52–5.35(m,2H),2.87(d,J＝3.9Hz,1H),2.02–1.92(m,1H),1.89–1.78(m,4H),1.76–1.65(m,3H),1.59–1.52(m,1H),1.48–1.23(m,15H),1.15–0.98(m,2H),0.80(s,3H),0.56–0.45(m,1H).
实施例9和实施例10
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(2H-四唑-2-基)乙烷-1-酮(9)
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(1H-四唑-1-基)乙烷-1-酮(10)
Figure PCTCN2019074134-appb-000059
第一步 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(2H-四唑-2-基)乙烷-1-酮(9)和1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(1H-四唑-1-基)乙烷-1-酮(10)的制备
Figure PCTCN2019074134-appb-000060
将2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(50mg,0.12mmol)，1H-四唑(26mg,0.37mmol)和碳酸钾(83mg,0.6mmol)溶于四氢呋喃(3mL)，反应在室温下搅拌过夜。反应液过滤，滤液浓缩，粗品用高效液相色谱柱分离，得到1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(2H-四唑-2-基)乙烷-1-酮(9)(11.6mg，产率：24％)和1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(1H-四唑-1-基)乙烷-1-酮(10)(4.4mg，产率：9％)。
实施例9：
MS m/z(ESI):381.2[M-H 2O+H] +
1H NMR(400MHz,CDCl 3)δ8.58(s,1H),5.74–5.62(m,2H),2.88(d,J＝3.8Hz,1H),1.97–1.91(m,1H),1.87–1.79(m,4H),1.75–1.64(m,3H),1.58–1.55(m,1H),1.45–1.35(m,7H),1.34–1.24(m,8H),1.14–1.01(m,2H),0.85(s,3H),0.56–0.48(m,1H)。
实施例10：
MS m/z(ESI):399.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.77(s,1H),5.57–5.39(m,2H),2.90(s,1H),2.00–1.91(m,1H),1.88–1.79(m,4H),1.76–1.65(m,3H),1.59–1.56(m,1H),1.46–1.37(m,7H),1.35–1.24(m,8H),1.13–0.99(m,2H),0.79(s,3H),0.58–0.49(m,1H)。
实施例11
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(甲磺酰)哌嗪-1-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000061
Figure PCTCN2019074134-appb-000062
将2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(50mg,0.12mmol)，1-(甲磺酰)哌嗪(60mg,0.36mmol)和碳酸钾(83mg,0.6mmol)溶于四氢呋喃(3mL)，反应在室温下搅拌过夜。反应液过滤，滤液浓缩，粗品用高效液相色谱柱分离，得到1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(甲磺酰)哌嗪-1-基)乙烷-1-酮(13.7mg，产率：23％)。
MS m/z(ESI):493.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ3.63(br,2H),3.47(br,4H),2.93(br,4H),2.82(s,3H),2.73(s,1H),1.90-1.88(m,1H),1.86–1.81(m,2H),1.81–1.70(m,3H),1.70–1.64(m,2H),1.57–1.50(m,1H),1.41(s,5H),1.34–1.22(m,10H),1.12–0.99(m,1H),0.92–0.85(m,1H),0.73(s,3H),0.49–0.39(m,1H).
实施例12
1-((3R,8R,9R,10S,13S,14S,16R,17S)-16-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 PCTCN2019074134-appb-000063
第一步：(3R,5R,8R,9R,10S,13S,14S,16R)-16-氟-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮的制备
Figure PCTCN2019074134-appb-000064
将三氟甲磺酸三甲基硅酯(5.6mL,31.0mmol)滴加到(3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(3g,10.3mmol)和三乙胺(36.0mL,258.2mmol)的甲苯(45mL)溶液中，反应液加热回流2小时，冷却，饱和碳酸氢钠洗涤，正己烷萃取，有机相干燥蒸干得到粗品(((3R,5R,8R,9R,10S,13S,14S)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢 -1H-环戊二烯并[a]菲-3,17-二基)二(氧代))二(三甲基硅烷)，将选择性氟试剂(4.0g,11.4mmol)加入到(((3R,5R,8R,9R,10S,13S,14S)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-3,17-二基)二(氧代))二(三甲基硅烷)的N,N-二甲基甲酰胺(25mL)中，室温搅拌2小时，得到(3R,5R,8R,9R,10S,13S,14S,16R)-16-氟-3,13-二甲基-3-((三甲基甲硅烷基)氧代)十六氢-17H-环戊二烯并[a]菲-17-酮，然后加入四丁基氟化铵的四氢呋喃溶液(11.4mL,1M)，反应液室温搅拌过夜。反应液乙酸乙酯萃取，饱和食盐水洗涤三次，有机相干燥蒸干，粗品经柱分离(石油醚：乙酸乙酯＝6:4)得到(3R,5R,8R,9R,10S,13S,14S,16R)-16-氟-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(2.0g,产率：50.9％)。
1H NMR(400MHz,CDCl 3)δ5.09(dd,J＝50.6,7.5Hz,1H),2.18–1.58(m,10H),1.54–1.01(m,14H),0.92(s,3H).
19F NMR(376MHz,CDCl 3)δ-192.59.
第二步：(3R,5R,8R,9R,10S,13S,14S,16R)-17-亚乙基-16-氟-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚的制备
Figure PCTCN2019074134-appb-000065
在氮气下，将钠氢(123mg,3.08mmol,60％w/w)分批加入到乙基三苯基溴化膦(1.2g,3.24mmol)的二甲基亚砜(20mL)的溶液中，反应液室温搅拌1小时，然后加入(3R,5R,8R,9R,10S,13S,14S,16R)-16-氟-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(200mg,0.65mmol)，反应液在氮气下加热到70℃过夜，反应液冷却，加入饱和食盐水，1N盐酸调节PH＝6,乙酸乙酯萃取,有机相饱和食盐水洗涤后，干燥蒸干得到粗品，粗品经柱分离(石油醚：乙酸乙酯＝7:3)得到(3R,5R,8R,9R,10S,13S,14S,16R)-17-亚乙基-16-氟-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚(80mg,产率：38.5％)。
1H NMR(400MHz,CDCl 3)δ5.71–5.59(m,1H),5.12(dt,J＝57.2,7.0Hz,1H),2.27–2.11(m,2H),1.92–1.24(m,21H),1.22–1.09(m,4H),1.06(s,3H).
19F NMR(376MHz,CDCl 3)δ-153.69.
第三步：(3R,8R,9R,10S,13S,14S,16R,17S)-16-氟-17-(1-羟基乙基)-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚的制备
Figure PCTCN2019074134-appb-000066
将(3R,5R,8R,9R,10S,13S,14S,16R)-17-亚乙基-16-氟-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚(80mg，0.25mmol)溶于干燥的四氢呋喃(50mL)溶液中，室温下滴加硼烷四氢呋喃溶液(1M，2.5mL)，反应液在室温下搅拌1小时。反应液用冰水冷却，慢慢滴加氢氧化钠溶液(3M，1mL)，有大量气体放出，然后慢慢滴加双氧水(25％，0.58mL)，反应液在室温下搅拌2小时。反应液用乙酸乙酯萃取，硫代硫酸钠溶液，饱和食盐水洗涤，干燥得(3R,8R,9R,10S,13S,14S,16R,17S)-16-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(80mg)，直接用于下一步反应。
1H NMR(400MHz,CDCl 3)δ5.47–5.16(m,1H),4.22–4.05(m,1H),2.42–2.17(m,1H),1.94–0.93(m,27H),0.87(s,3H).
19F NMR(376MHz,CDCl 3)δ-178.27.
第四步：1-((3R,8R,9R,10S,13S,14S,16R,17S)-16-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-酮的制备
Figure PCTCN2019074134-appb-000067
将氯铬酸吡啶(102mg,0.47mmol)加入到(3R,8R,9R,10S,13S,14S,16R,17S)-16-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(80mg)的丙酮(2mL)溶液中,反应液在60℃反应6小时。反应液蒸干，经柱分离(石油醚：乙酸乙酯＝5:2)得到1-((3R,8R,9R,10S,13S,14S,16R,17S)-16-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,产率：25％)。
1H NMR(400MHz,CDCl 3)δ5.64–5.35(m,1H),2.44–2.09(m,6H),1.97–1.75(m,4H),1.74–1.00(m,20H),0.98–0.68(m,2H).
19F NMR(376MHz,CDCl 3)δ-168.20.
实施例13
1-(2-((3R,5R,8R,9R,10S,13S,14S,15R)-3-羟基-3,13,15-三甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074134-appb-000068
第一步：(3R,5R,8R,9R,10S,13S,14S,15R)-3-羟基-3,13,15-三甲基十六氢-17H-环戊二烯并[a]菲-17-酮
Figure PCTCN2019074134-appb-000069
干燥的100mL圆底烧瓶中加入3.0M的甲基溴化镁(8.5mL,25.5mmol)和20毫升无水四氢呋喃，体系置换氮气并冷却至零度。碘化亚铜(3.94g,20.7mmol)加入反应体系，反应于0℃条件下搅拌1小时。(3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氢-17H-环戊二烯并[a]菲-17-酮(2g,6.9mmol)溶于10毫升无水四氢呋喃中缓慢滴入反应体系，反应继续搅拌3小时，TLC显示反应完全，饱和氯化铵淬灭反应，乙酸乙酯萃取，有机相使用水和饱和食盐水洗涤，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＝2：1冲洗)得到(3R,5R,8R,9R,10S,13S,14S,15R)-3-羟基-3,13,15-三甲基十六氢-17H-环戊二烯并[a]菲-17-酮(1.56g,产率：75％)。
1H NMR(400MHz,CDCl 3)δ2.51-2.42(m,2H),2.24(d,J＝17.6Hz,1H),1.89-1.63(m,7H),1.54-1.18(m,16H),1.10(d,J＝7.6Hz,3H),1.03(s,3H).
第二步：(3R,5R,8R,9R,10S,13S,14S,15R,E)-17-亚乙基-3,13,15-三甲基十六氢-1H-环戊二烯并[a]菲-3-酚
Figure PCTCN2019074134-appb-000070
将乙基三苯基溴化膦(18.5g,50mmol)溶于无水二甲亚砜(50mL)，置换氮气，加入钠氢(2.0g,50mmol)，反应室温搅拌1小时，加入(3R,5R,8R,9R,10S,13S,14S,15R)-3-羟基-3,13,15-三甲基十六氢-17H-环戊二烯并[a]菲-17-酮(1.52g,5mmol)，反应在100℃下搅拌过夜。反应冷却至室温，加水(200mL)淬灭反应，水相用乙酸乙酯(200mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，得粗品用柱层析分离(石油醚/乙酸乙酯：50/1～3/1)纯化得到(3R,5R,8R,9R,10S,13S,14S,15R,E)-17-亚乙基-3,13,15-三甲基十六氢-1H-环戊二烯并[a]菲-3-酚(1.37g,产率：86％)。
第三步：(3R,5R,8R,9R,10S,13S,14S,15R,17S)-17-((R)-1-羟基乙基)-3,13,15-三甲基十六氢-1H-环戊二烯并[a]菲-3-酚
Figure PCTCN2019074134-appb-000071
将(3R,5R,8R,9R,10S,13S,14S,15R,E)-17-亚乙基-3,13,15-三甲基十六氢-1H-环戊二烯并[a]菲-3-酚(1.37g,4.33mmol)溶于无水四氢呋喃(50mL)，冷却至0℃，滴加BH 3/THF(43mL,43mmol)。反应在室温搅拌3小时，TLC显示反应完全。反应冷却至0℃，缓慢加入3M NaOH水溶液(40mL)，再加入H2O2(30mL)，反应在室温搅拌2小时，TLC显示反应完全。加入乙酸乙酯(50mL)，用饱和Na 2S 2O 3水溶液(30mL)洗，再用水(30mL)洗，有机相用无水硫酸钠干燥，过滤，浓缩，得粗品(1.37g)，直接用于下一步反应。
第四步：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
Figure PCTCN2019074134-appb-000072
将(3R,5R,8R,9R,10S,13S,14S,15R,17S)-17-((R)-1-羟基乙基)-3,13,15-三甲基十六氢-1H-环戊二烯并[a]菲-3-酚(1.37g,粗品)溶于二氯甲烷(30mL)，加入PCC(1.8g,8.66mmol)，反应在室温搅拌2小时。反应液过滤，有机相浓缩，得粗品用柱层析分离(石油醚/乙酸乙酯：1/1)纯化得到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(780mg,两部产率：54.3％)。
1H NMR(400MHz,CDCl 3)δ2.49(dd,J＝8.8,10.4Hz,1H),2.14-2.03(m,5H),1.95-1.79(m,5H),1.69-1.06(m,18H),0.96(d,J＝7.2Hz,3H),0.78(s,3H).
第五步：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
Figure PCTCN2019074134-appb-000073
将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(333mg,1mmol)溶于甲醇(10mL)，加入一滴溴化氢，再加入液溴(176mg,1.1mmol)，反应在室温下搅拌1小时。加入水(20mL)，水相用乙酸乙酯(20mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，得粗品(413mg,粗品)，直接用于下一步反应。
第六步：1-(2-((3R,5R,8R,9R,10S,13S,14S,15R)-3-羟基-3,13,15-三甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074134-appb-000074
将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(82mg,0.2mmol)，1H-吡唑-4-甲腈(28mg,0.3mmol)和碳酸钾(54mg,0.3mmol)溶于无水四氢呋喃(5mL)，反应在室温下搅拌过夜，反应液过滤，滤液浓缩，粗品用高效液相色谱柱分离，得到1-(2-((3R,5R,8R,9R,10S,13S,14S,15R)-3-羟基-3,13,15-三甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈(41mg，产率：48％)。
1H NMR(400MHz,CDCl 3)δ7.86(s,1H),7.81(s,1H),5.01(d,J＝17.9Hz,1H),4.90(d,J＝17.9Hz,1H),2.62-2.48(m,1H),2.30-2.06(m,3H),2.04-1.75(m,7H),1.75-1.04(m,15H),0.99(d,J＝7.1Hz,3H),0.84(s,3H).
MS m/z(ESI):424.6[M+H] +.
实施例14和实施例15
1-(2-((3R,5R,10S,13S,16R)-16-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(14)
1-(2-((3R,5R,10S,13S,16S)-16-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(15)
Figure PCTCN2019074134-appb-000075
本实施例14和实施例15通过以下具体实施方案合成：
Figure PCTCN2019074134-appb-000076
实施例14：MS m/z(ESI):428.3[M+1] +.
实施例15：MS m/z(ESI):428.3[M+1] +.
实施例16和实施例17
1-(2-((3R,5R,10S,13S,16R)-3-羟基-3,13-二甲基-16-(三氟甲基)十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈(16)
1-(2-((3R,5R,10S,13S,16S)-3-羟基-3,13-二甲基-16-(三氟甲基)十六氢-1H-环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈(17)
Figure PCTCN2019074134-appb-000077
本实施例16和实施例17通过以下具体实施方案合成：
Figure PCTCN2019074134-appb-000078
实施例16：MS m/z(ESI):478.3[M+1] +.
实施例17：MS m/z(ESI):478.3[M+1] +.
实施例18
2-(4-氯-1H-吡唑-1-基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000079
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮和4-氯-1H-吡唑为底物参考实施例5，得到2-(4-氯-1H-吡唑-1-基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(21.9mg，产率：26％)。
MS m/z(ESI):431.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.45(d,J＝11.8Hz,2H),5.17–5.01(m,2H),2.81(d,J＝3.5Hz,1H),1.99–1.91(m,1H),1.86–1.79(m,3H),1.77–1.62(m,3H),1.57–1.49(m,3H),1.44–1.20(m,14H),1.12–0.96(m,2H),0.78(s,3H),0.51–0.44(m,1H)。
实施例19
(2R,4aS,4bR,6aS,7S,8bR,8cR,10aR)-2-羟基-2,6a二甲基-N-苯基十六氢环戊二烯-[4,5]环戊二烯并[1,2-a]菲-7-甲酰胺
Figure PCTCN2019074134-appb-000080
本实施例19通过以下具体实施方案合成：
Figure PCTCN2019074134-appb-000081
MS m/z(ESI):408.3[M+1] +.
实施例20
1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-15-(异丙基氨基)-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-氧代乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074134-appb-000082
本实施例20通过以下具体实施方案合成：
Figure PCTCN2019074134-appb-000083
MS m/z(ESI):467.3[M+1] +.
实施例21
1-(2-((3R,5R,8R,9R,10S,13R,14S,17S)-3-羟基-15-(异丙基磺酰基)-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-氧代乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074134-appb-000084
本实施例21通过以下具体实施方案合成：
Figure PCTCN2019074134-appb-000085
MS m/z(ESI):516.3[M+1] +.
实施例23
1-(2-((2R,4aS,4bR,6aS,7S,8bR,8cR,10aR)-2-羟基-2-(甲氧基甲基)-6a-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 PCTCN2019074134-appb-000086
本实施例23通过以下具体实施方案合成：
Figure PCTCN2019074134-appb-000087
MS m/z(ESI):452.3[M+1] +.
实施例24
1-((2R,4aS,4bR,6aS,7S,8bR,8cR,10aR)-2-羟基-2-(甲氧基甲基)-6a-甲基十六氢环戊二烯-[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-甲基-1H-吡唑-1-基)乙-1-酮
Figure PCTCN2019074134-appb-000088
MS m/z(ESI):441.3[M+1] +.
实施例25
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 PCTCN2019074134-appb-000089
本实施例25通过以下具体实施方案合成：
Figure PCTCN2019074134-appb-000090
MS m/z(ESI):466.3[M+1] +.
实施例26
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 PCTCN2019074134-appb-000091
MS m/z(ESI):466.3[M+1] +.
实施例33和实施例34
3-环丙基-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-1H-吡唑-4-甲腈(33)
5-环丙基-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-1H-吡唑-4-甲腈(34)
Figure PCTCN2019074134-appb-000092
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮和5-环丙基-1H-吡唑-4-甲腈为底物，参考实施例5得到3-环丙基-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-1H-吡唑-4-甲腈(33)(19.2mg，产率：21％)；5-环丙基-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-1H-吡唑-4-甲腈(34)(3.0mg，产率：3.3％)。
实施例33：
MS m/z(ESI):462.3[M+H] +
1H NMR(400MHz,CDCl 3)δ7.73(s,1H),5.14–4.98(m,2H),2.80(d,J＝2.2Hz,1H),2.05–1.89(m,2H),1.86–1.78(m,4H),1.75–1.64(m,3H),1.58–1.52(m,2H),1.46–1.33(m,7H),1.33–1.20(m,7H),1.14–0.92(m,6H),0.76(s,3H),0.53–0.43(m,1H)。
实施例34：
MS m/z(ESI):462.3[M+H] +
1H NMR(400MHz,CDCl 3)δ7.69(s,1H),5.33–5.13(m,2H),2.85(d,J＝3.8Hz,1H),2.00–1.92(m,1H),1.86–1.79(m,3H),1.76–1.62(m,4H),1.60–1.51(m,2H),1.45–1.34(m,7H),1.34–1.22(m,7H),1.17–0.94(m,7H),0.81(s,3H),0.54–0.45(m,1H)。
实施例37A和实施例37B
1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-3-甲基-1H-吡唑-4-甲腈(37A)
1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-5-甲基-1H-吡唑-4-甲腈(37B)
Figure PCTCN2019074134-appb-000093
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮和3-甲基-1H-吡唑-4-甲腈为原料参考实施例5，实施例37A和实施例37B的混合物(约为3：1)(25.9mg,白色固体，产率：39.3％)。进一步通过制备色谱拆分得到1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-3-甲基-1H-吡唑-4-甲腈(37A)与1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-5-甲基-1H-吡唑-4-甲腈(37B)。
实施例37A：MS m/z(ESI):436.3[M+H] +
实施例37B：MS m/z(ESI):436.3[M+H] +
实施例40
2-((2,4-二氟苯基)氨基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000094
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮和2,4-二氟苯胺为原料参考实施例5，得到2-((2,4-二氟苯基)氨基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(3.9mg,白色固体，产率：3.9％)。
MS m/z(ESI):458.3[M+H] +
1H NMR(400MHz,CDCl 3)δ6.84-6.75(m,2H),6.65-6.59(m,1H),4.12(dd,J 1＝5.2Hz,J 2＝24.8Hz,2H),3.61-3.27(br,1H),2.80(d,J＝3.6Hz,1H),2.01-1.77(m,10H),1.76-1.56(m,3H),1.53-1.46(m,1H),1.28-1.19(m,10H),1.00-0.93(m,2H),0.73(m,3H),0.50-0.44(m,1H).
实施例41和实施例42
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(2H-吡唑并[3,4-c]吡啶-2-基)乙烷-1-酮
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(1H-吡唑并[3,4-c]吡啶-1-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000095
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮和1H-吡唑并[3,4-c]吡啶为底物参考实施例5，得到1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(2H-吡唑并[3,4-c]吡啶-2-基)乙烷-1-酮(41)(5.4mg，产率：6.2％)；和1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(1H-吡唑并[3,4-c]吡啶-1-基)乙烷-1-酮(42)(7.0mg，产率：8％)。
实施例41：
MS m/z(ESI):448.3[M+H] +
1H NMR(400MHz,CDCl 3)δ9.43(s,1H),8.39(s,1H),8.19(d,J＝6.4Hz,1H),8.08(d,J＝6.4Hz，1H),5.77–5.61(m,2H),2.96(s,1H),2.01–1.92(m,1H),1.88–1.81(m,4H),1.74–1.69(m,3H),1.59–1.55(m,2H),1.48–1.43(m,5H),1.33– 1.27(m,9H),1.10–1.05(m,2H),0.85(s,3H),0.60–0.54(m,1H)。
实施例42：
MS m/z(ESI):448.3[M+H] +
1H NMR(400MHz,CDCl 3)δ9.16(s,1H),8.34(d,J＝5.8Hz,1H),8.25(s,1H),7.87(d,J＝5.2Hz,1H),5.72–5.60(m,2H),2.96(d,J＝3.9Hz,1H),2.01–1.94(m,1H),1.87–1.81(m,4H),1.75–1.67(m,3H),1.58–1.52(m,2H),1.44–1.39(m,5H),1.33–1.25(m,9H),1.12–1.02(m,2H),0.86(s,3H),0.56–0.50(m,1H)。
实施例46
2-(4-氟-1H-吡唑-1-基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000096
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮和4-氟吡唑为原料参考实施例5，得到2-(4-氟-1H-吡唑-1-基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(6.2mg,白色固体，产率：7.7％)。
MS m/z(ESI):415.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.37(d,J＝4.0Hz,1H),7.32(d,J＝4.0Hz,1H),5.03(d,J＝3.6Hz,2H),2.80(d,J＝3.6Hz,1H),2.01-1.93(m,2H),1.85-1.80(m,3H),1.73-1.61(m,6H),1.41-1.32(m,9H),1.27(s,3H),1.12-1.02(m,2H),0.99-0.96(m,1H),0.78(s,3H),0.50-0.44(m,1H).
实施例51
1-(2–((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙基[4,5]环戊二烯并[1,2-a]]菲-7-基)-2-氧代乙基)-1H-吡唑-4-羧酸乙酯
Figure PCTCN2019074134-appb-000097
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮和乙基1H-吡唑-4-羧酸酯为底物参考实施例5，得到1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙基[4,5]环戊二烯并[1,2-a]]菲-7-基)-2-氧代乙基)-1H-吡唑-4-羧酸乙酯(29.6mg,白色固体，产率：43％)。
MS m/z(ESI):469.3[M+H] +
1H NMR(400MHz,CDCl 3)δ7.95(s,2H),5.32–4.99(m,2H),4.36–4.24(m,2H),2.83(s,1H),1.99–1.92(m,1H),1.87–1.79(m,3H),1.72–1.52(m,6H),1.49–1.16(m,17H),1.14–0.96(m,2H),0.83(s,3H),0.53–0.44(m,1H)。
实施例53、实施例54A和实施例54B
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(5-甲氧基-2H-苯并[d][1,2,3]三唑-2-基)乙烷-1-酮(53)
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(6-甲氧基-1H-苯并[d][1,2,3]三唑-1-基)乙烷-1-酮(54A)
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(5-甲氧基-1H-苯并[d][1,2,3]三唑-1-基)乙烷-1-酮混合物(54B)
Figure PCTCN2019074134-appb-000098
Figure PCTCN2019074134-appb-000099
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮和6-甲氧基-1H-苯并[d][1,2,3]三唑为底物参考实施例5，得到1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(5-甲氧基-2H-苯并[d][1,2,3]三唑-2-基)乙烷-1-酮(11.8mg，产率：13.6％)，以及实施例54A和实施例54B的混合物(约为1：1)(34mg，产率：39％)。进一步通过制备色谱拆分得到1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(6-甲氧基-1H-苯并[d][1,2,3]三唑-1-基)乙烷-1-酮(54A)与1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(5-甲氧基-1H-苯并[d][1,2,3]三唑-1-基)乙烷-1-酮(54B)。
实施例53：
MS m/z(ESI):478.3[M+H] +
1H NMR(400MHz,CDCl 3)δ7.74(d,J＝10.1Hz,1H),7.14–7.03(m,2H),5.73–5.59(m,2H),3.88(s,3H),2.88(d,J＝4.1Hz,1H),2.01–1.93(m,1H),1.86–1.78(m,4H),1.74–1.63(m,3H),1.55–1.51(m,1H),1.46–1.25(m,15H),1.15–1.00(m,2H),0.88(s,3H),0.53–0.45(m,1H)。
实施例54A：
MS m/z(ESI):478.3[M+H] +
实施例54B：
MS m/z(ESI):478.3[M+H] +
实施例59
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)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000100
Figure PCTCN2019074134-appb-000101
将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(82mg,0.2mmol)，4-(三氟甲基)-1H-吡唑(41mg,0.3mmol)和碳酸钾(54mg,0.3mmol)溶于无水四氢呋喃(5mL)，反应在室温下搅拌过夜。反应液过滤，滤液浓缩，粗品用高效液相色谱柱分离，得到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)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(24.6mg，产率：26％)。
1H NMR(400MHz,CDCl 3)δ7.72(s,2H),5.00(d,J＝16Hz,1H),4.90(d,J＝16Hz,1H),2.58-2.54(m,1H),1.88-1.83(m,2H),1.69-1.58(m,5H),1.50-1.25(m,19H),0.98(d,J＝8.0Hz,3H),0.85(s,3H).
MS m/z(ESI):467.3[M+H] +
实施例60
1-(2-((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)-2-羰基乙基)-1H-吡唑-3-甲腈(60)
Figure PCTCN2019074134-appb-000102
第一步：1-(2-((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)-2-羰基乙基)-1H-吡唑-3-甲腈的制备
Figure PCTCN2019074134-appb-000103
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5得1-(2-((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)-2-羰基乙基)-1H-吡唑-3-甲腈(12.5mg，产率：20.2％)。
MS m/z(ESI):424.1[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.48(d,J＝2.4Hz,1H),6.73(d,J＝2.4Hz,1H), 5.07–4.84(m,2H),2.55(t,J＝8.1Hz,1H),2.33–1.06(m,25H),0.98(d,J＝7.0Hz,3H),0.84(s,3H).
实施例61和实施例132
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)-2-(2H-1,2,3-三唑-2-基)乙烷-1-酮(61)
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)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮(132)
Figure PCTCN2019074134-appb-000104
第一步：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)-2-(2H-1,2,3-三唑-2-基)乙烷-1-酮和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)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000105
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5得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)-2-(2H-1,2,3-三唑-2-基)乙烷-1-酮(9.5mg，产率16.3％)和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)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮(13mg，产率22.3％)。
实施例61：
MS m/z(ESI):400.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.68(s,2H),5.29–5.15(m,2H),2.52(t,J＝8.0Hz,1H),2.17–1.29(m,24H),1.15–1.05(m,1H),0.97(d,J＝7.0Hz,3H),0.87(s,3H).
实施例132：
MS m/z(ESI):400.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.77(s,1H),7.65(s,1H),5.32–5.02(m,2H),2.60(t,J＝9.1Hz,1H),2.30–2.12(m,2H),1.99–1.27(m,22H),1.17–1.06(m,1H),0.99(d,J＝6.9Hz,3H),0.84(s,3H)
实施例62
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)-2-(5-甲基-2H-四唑-2-基)乙烷-1-酮(62)
Figure PCTCN2019074134-appb-000106
第一步：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)-2-(5-甲基-2H-四唑-2-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000107
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-酮为原料参考实施例5得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)-2-(5-甲基-2H-四唑-2-基)乙烷-1-酮(4.7mg，产率：7％)。
MS m/z(ESI):415.3[M+H] +
1H NMR(400MHz,CDCl 3)δ5.36(s,2H),2.57(s,3H),2.27–2.11(m,2H),2.00–198(m,1H),1.87–1.83(m,5H),1.77–1.57(m,6H),1.52–1.30(m,12H),1.11(s,2H),0.98(d,J＝7.0Hz,3H),0.88(s,3H).
实施例63
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)-2-(2H-四唑-2-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000108
将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(82mg,0.2mmol)，2H-四唑(21mg,0.3mmol)和碳酸钾(54mg,0.3mmol)溶于无水四氢呋喃(5mL)，反应在室温下搅拌过夜。反应液过滤，滤液浓缩，粗品用高效液相色谱柱分离，得到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)-2-(2H-四唑-2-基)乙烷-1-酮(15.7mg，产率：20％)。
MS m/z(ESI):401.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.58(s,1H),4.46(s,2H),2.62-2.58(m,1H),1.89-1.84(m,2H),1.70-1.26(m,23H),0.99(d,J＝8.0Hz,3H),0.88(s,3H).
实施例64
2-(2,4-二氟苯氧基)-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(64)
Figure PCTCN2019074134-appb-000109
第一步：2-(2,4-二氟苯氧基)-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(64)的制备
Figure PCTCN2019074134-appb-000110
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-酮为原料参考实施例5得2-(2,4-二氟苯氧基)-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(34mg，产率：45％)。
MS m/z(ESI):461.3[M+H] +
1H NMR(400MHz,CDCl 3)δ6.91–6.82(m,2H),6.77(ddd,J＝9.1,5.3,1.6Hz,1H),4.56(q,J＝16.7Hz,2H),2.74–2.68(m,1H),2.27–2.14(m,1H),2.13–1.99(m,1H),1.95–1.74(m,4H),1.74–1.61(m,3H),1.57(s,3H),1.52–1.35(m,4H),1.36–1.18(m,6H),1.21–1.00(m,3H),0.98(d,J＝7.2Hz,3H),0.82(s,3H).
实施例69
3-环丙基-1-(2-((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)-2-羰基乙基)-1H-吡唑-4-甲腈(69)
Figure PCTCN2019074134-appb-000111
第一步：3-环丙基-1-(2-((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)-2-羰基乙基)-1H-吡唑-4-甲腈(69)的制备
Figure PCTCN2019074134-appb-000112
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-酮为原料参考实施例5得3-环丙基-1-(2-((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)-2-羰基乙基)-1H-吡唑-4-甲腈(30mg，产率：41％)。
MS m/z(ESI):464.3[M+H] +
1H NMR(400MHz,CDCl 3)δ7.71(s,1H),4.82(q,J＝17.9Hz,2H),2.51–2.46(m,1H),2.27–2.18(m,1H),2.19–2.08(m,1H),2.04–1.91(m,2H),1.90–1.80(m,4H),1.68–1.60(m,4H),1.57(s,3H),1.51–1.29(m,8H),1.18–1.03(m,3H),1.02–0.95(m,7H),0.82(s,3H).
实施例71
1-(2-((3R,5R,8R,9R,10S,13S,14S,15S)-15-环丙基-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 PCTCN2019074134-appb-000113
第一步：(3R,5R,8R,9R,10S,13S,14S,15S)-15-环丙基-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮
Figure PCTCN2019074134-appb-000114
干燥的100mL圆底烧瓶中加入1.0M的环丙基溴化镁(12.7mL,12.7mmol)和20mL无水四氢呋喃，体系置换氮气并冷却至0℃。碘化亚铜(1.97g,10.4mmol) 加入反应体系，反应于0℃条件下搅拌1小时。(3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氢-17H-环戊二烯并[a]菲-17-酮(1g,3.5mmol)溶于10毫升无水四氢呋喃中缓慢滴入反应体系。反应继续搅拌3小时。TLC显示反应完全，饱和氯化铵淬灭反应。乙酸乙酯萃取。有机相使用水和饱和食盐水洗涤，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＝2/1冲洗)得到(3R,5R,8R,9R,10S,13S,14S,15S)-15-环丙基-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(1.11g,96％)。
1H NMR(400MHz,CDCl 3)δ2.45-2.30(m,2H),1.85-1.76(m,9H),1.59-1.52(m,5H),1.59-1.27(m,12H),1.11-0.98(m,1H),0.67-0.64(m,1H),0.47-0.43(m,1H),0.22-0.18(m,1H),0.09-0.07(m,1H).
第二步：(3R,5R,8R,9R,10S,13S,14S,15S,E)-15-环丙基-17-亚乙基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚
Figure PCTCN2019074134-appb-000115
将乙基三苯基溴化膦(12.5g,33mmol)溶于无水二甲亚砜(50mL)，置换氮气，加入钠氢(1.32g,33mmol)，反应室温搅拌1小时，加入(3R,5R,8R,9R,10S,13S,14S,15S)-15-环丙基-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(1.1g,3.3mmol)，反应在60℃下搅拌过夜。反应冷却至室温，加水(200mL)淬灭反应，水相用乙酸乙酯(200mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，得粗品用柱层析分离(石油醚/乙酸乙酯：50/1～3/1)纯化得到(3R,5R,8R,9R,10S,13S,14S,15S,E)-15-环丙基-17-亚乙基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚(0.67g,59％)。
1H NMR(400MHz,CDCl 3)δ5.15-5.09(m,1H),2.45-2.38(m,1H),2.38-2.18(m,2H),1.90-1.07(m,28H),0.86-0.78(m,1H),0.56-0.50(m,1H),0.38-0.32(m,1H),0.12-0.02(m,2H).
第三步：(3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-17-((R)-1-羟基乙基)-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚
Figure PCTCN2019074134-appb-000116
将(3R,5R,8R,9R,10S,13S,14S,15S,E)-15-环丙基-17-亚乙基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚(0.67g,1.96mmol)溶于无水四氢呋喃(20mL)，冷却至0℃，滴加BH 3/THF(9.8mL,9.8mmol)。反应在室温搅拌3小时，TLC显示反应完全。反应冷却至0℃，缓慢加入3M NaOH水溶液(10mL)，再加入30％ 双氧水(8mL)，反应在室温搅拌2小时，TLC显示反应完全。加入乙酸乙酯(50mL)，用饱和Na 2S 2O 3水溶液(30mL)洗，再用水(30mL)洗，有机相用无水硫酸钠干燥，过滤，浓缩，得粗品(0.71g)直接用于下一步反应。
第四步：1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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 PCTCN2019074134-appb-000117
将(3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-17-((R)-1-羟基乙基)-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚(0.71g,crude)溶于二氯甲烷(20mL)，加入氯铬酸吡啶鎓盐(1.27g,5.88mmol)，反应在室温搅拌2小时。反应液过滤，有机相浓缩，得粗品用柱层析分离(石油醚/乙酸乙酯：1/1)纯化得到1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(480mg,两步产率：68.3％)。
1H NMR(400MHz,CDCl 3)δ2.45-2.40(m,1H),2.18-2.10(m,4H),1.99-1.03(m,24H),0.84-0.79(m,4H),0.60-0.53(m,1H),0.43-0.38(m,1H),0.14-0.02(m,2H).
第五步：2-溴-1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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 PCTCN2019074134-appb-000118
将1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(107mg,0.3mmol)溶于甲醇(5mL)，加入一滴溴化氢，再加入液溴(56mg,0.35mmol)，反应在室温下搅拌1小时。加入水(20mL)，水相用乙酸乙酯(20mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，得粗品(120mg,粗品)，直接用于下一步反应。
第六步：1-(2-((3R,5R,8R,9R,10S,13S,14S,15S)-15-环丙基-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 PCTCN2019074134-appb-000119
将1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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)，1H-吡唑-4-甲腈(28mg,0.3mmol)和碳酸钾(54mg,0.3mmol)溶于无水四氢呋喃(5mL)，反应在室温下搅拌过夜。反应液过滤，滤液浓缩，粗品用高效液相色谱柱分离，得到1-(2-((3R,5R,8R,9R,10S,13S,14S,15S)-15-环丙基-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(31mg，产率：49％)。
MS m/z(ESI):450.3[M+H] +
1H NMR(400MHz,CDCl 3)δ7.86(s,1H),7.81(s,1H),5.02(d,J＝16.0Hz,1H),4.92(d,J＝16.0Hz,1H),2.51-2.47(m,1H),2.09-1.71(m,9H),1.48-1.10(m,16H),0.90(s,3H),0.83-0.79(m,1H),0.62-0.58(m,1H),0.45-0.40(m,1H),0.14-0.11(m,1H),0.05-0.02(m,1H).
实施例72
1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(72)
Figure PCTCN2019074134-appb-000120
第一步：1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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-甲腈的制备
Figure PCTCN2019074134-appb-000121
以1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实施例5得1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(20mg，产率20％)。
MS m/z(ESI):432.2[M-H 2O+H] +
1H NMR(400MHz,CDCl 3)δ7.49(d,J＝2.4Hz,1H),6.73(d,J＝2.4Hz,1H),4.98(dd,J＝40.0,17.8Hz,2H),2.52–2.45(m,1H),2.24–2.13(m,1H),2.11–2.03(m,1H),2.04–1.95(m,2H),1.90–1.82(m,2H),1.75–1.66(m,2H),1.54–1.23(m,16H),1.18–1.05(m,2H),0.93–0.79(m,4H),0.63–0.55(m,1H),0.45–0.37(m,1H),0.18–0.09(m,1H),0.08–0.01(m,1H).
实施例73和实施例145
1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(73)
1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(145)
Figure PCTCN2019074134-appb-000122
第一步：1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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-酮和1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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-酮的制备
Figure PCTCN2019074134-appb-000123
以1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实施例5得1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(7.6mg，产率7.8％)和1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(11.6mg，产率11.9％)。
实施例73：
MS m/z(ESI):408.3[M-H 2O+H] +
1H NMR(400MHz,CDCl 3)δ7.68(s,2H),5.24(s,2H),2.49–2.42(m,1H),2.23–2.14(m,1H),2.10–1.94(m,3H),1.91–1.81(m,3H),1.75–1.66(m,2H),1.48–1.24(m,15H),1.17–1.04(m,2H),0.94(s,3H),0.86–0.76(m,1H),0.63–0.54(m,1H),0.45–0.38(m,1H),0.14–0.01(m,2H).
实施例145：
MS m/z(ESI):426.3[M+H] +
1H NMR(400MHz,CDCl 3)δ7.78(s,1H),7.67(s,1H),5.22(dd,J＝47.1,17.8Hz,2H),2.59–2.50(m,1H),2.25–2.15(m,1H),2.14–1.98(m,2H),1.96–1.79(m,3H),1.76–1.58(m,6H),1.56–1.25(m,12H),1.22–1.04(m,2H),0.91(s,3H),0.87–0.77(m,1H),0.62–0.55(m,1H),0.47–0.36(m,1H),0.18–0.02(m,2H).
实施例74
1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(74)
Figure PCTCN2019074134-appb-000124
第一步：1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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-酮的制备
Figure PCTCN2019074134-appb-000125
以1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实施例5得1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(8.5mg，产率9％)。
MS m/z(ESI):441.3[M+H] +
1H NMR(400MHz,CDCl 3)δ5.36(s,2H),2.57(s,3H),2.54–2.47(m,1H),2.25–2.15(m,1H),2.13–1.95(m,3H),1.92–1.79(m,3H),1.77–1.66(m,2H),1.50–1.24(m,15H),1.18–1.05(m,2H),0.94(s,3H),0.87–0.78(m,1H),0.63–0.55(m,1H),0.45–0.37(m,1H),0.17–0.02(m,2H).
实施例81
1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(81)
Figure PCTCN2019074134-appb-000126
第一步：(3R,5R,8R,9R,10S,13S,14S,15R)-15-乙基-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮
Figure PCTCN2019074134-appb-000127
100mL三口瓶中加入四氢呋喃(15mL)，在0℃氮气保护下加入乙基溴化镁(10mL，1M,10mmol)，然后加入碘化亚铜(1.6g，8.4mmol)，反应液在0℃下搅拌1小时。然后将(3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-1,2,3,4,5,6,7,8,9,10,11,12,13,14-十四氢-17H-环戊二烯并[a]菲-17-酮(800mg，2.8mmol)溶于四氢呋喃(5mL)，并慢慢滴加至反应液中，反应液在0℃下继续搅拌4小时。反应液用饱和氯化铵水溶液萃灭，用乙酸乙酯(20mL)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,8R,9R,10S,13S,14S,15R)-15-乙基-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(750mg,产率：84.9％)。
1H NMR(400MHz,CDCl 3)δ2.37–2.30(m,1H),2.15–2.02(m,2H),1.91–1.31(m,17H),1.27(s,3H),1.24–1.03(m,4H),0.98(s,3H),0.90(t,J＝7.3Hz,3H).
第二步：(3R,5R,8R,9R,10S,13S,14S,15R)-15-乙基-17-亚乙基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚
Figure PCTCN2019074134-appb-000128
100mL三口瓶中加入二甲基亚砜(20mL)，氮气保护下加入乙基三苯基溴化膦(8.7g，23.5mmol)，然后分批加入氢化钠(60％)(940mg，23.5mmol)，反应液在室温下搅拌1小时。然后将(3R,5R,8R,9R,10S,13S,14S,15R)-15-乙基-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(750mg，2.35mmol)溶于 二甲基亚砜(5mL)，并慢慢滴加至反应液中，反应液在氮气保护下在80℃下继续搅拌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(50mL)萃取，食盐水洗涤(20mLx3)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,8R,9R,10S,13S,14S,15R)-15-乙基-17-亚乙基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚(580mg,产率：71.7％)。
1H NMR(400MHz,CDCl 3)δ5.22–5.06(m,1H),2.54–2.39(m,1H),2.28–2.09(m,2H),1.96–1.80(m,4H),1.78–1.59(m,6H),1.55–1.33(m,11H),1.26(s,3H),1.20–1.08(m,3H),1.05(s,3H),0.82(t,J＝7.3Hz,3H).
第三步：(3R,5R,8R,9R,10S,13S,14S,15R,17R)-15-乙基-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 PCTCN2019074134-appb-000129
以(3R,5R,8R,9R,10S,13S,14S,15R)-15-乙基-17-亚乙基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚为原料参考实例71第三步得(3R,5R,8R,9R,10S,13S,14S,15R,17R)-15-乙基-17-(1-羟基乙基)-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚(600mg，产率98.1％)。
第四步：1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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 PCTCN2019074134-appb-000130
以(3R,5R,8R,9R,10S,13S,14S,15R,17R)-15-乙基-17-(1-羟基乙基)-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚为原料参考实例71第四步得1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(500mg，产率：83.8％)。
1H NMR(400MHz,CDCl 3)δ2.51(t,J＝8.0Hz,1H),2.12(s,3H),2.00–1.30(m,20H),1.28(s,3H),1.25–1.00(m,4H),0.84(t,J＝7.2Hz,3H),0.73(s,3H).
第五步：2-溴-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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 PCTCN2019074134-appb-000131
以1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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71第五步得2-溴-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(500mg，产率：81.4％)。
第六步：1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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 PCTCN2019074134-appb-000132
以2-溴-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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71第六步得1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(24mg，产率38.8％)。
MS m/z(ESI):438.2[M+H]+.
1H NMR(400MHz,CDCl 3)δ7.86(s,1H),7.81(s,1H),5.08–4.78(m,2H),2.58(t,J＝8.0Hz,1H),2.07–1.29(m,20H),1.28(s,3H),1.27–1.06(m,4H),0.85(t,J＝7.3Hz,3H),0.79(s,3H).
实施例91
2-(4-氯-1H-吡唑-1-基)-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(91)
Figure PCTCN2019074134-appb-000133
第一步：2-(4-氯-1H-吡唑-1-基)-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-酮的制备
Figure PCTCN2019074134-appb-000134
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-酮为原料参考实施例5得2-(4-氯-1H-吡唑-1-基)-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(10mg，产率：14％)。
MS m/z(ESI):433.3[M+H] +
1H NMR(400MHz,CDCl 3)δ7.45(s,1H),7.41(s,1H),4.86(q,J＝17.9Hz,2H),2.61–2.44(m,1H),2.30–2.07(m,2H),2.02–1.91(m,1H),1.86–1.80(m,4H),1.76–1.57(m,4H),1.51–1.38(m,6H),1.37–1.20(m,6H),1.20–1.03(m,2H),0.98(d,J＝7.1Hz,3H),0.83(s,3H).
实施例92和实施例93
2-(5-氟-2H-苯并[d][1,2,3]三唑-2-基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(92)
2-(5-氟-1H-苯并[d][1,2,3]三唑-1-基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(93A)
与2-(6-氟-1H-苯并[d][1,2,3]三唑-1-基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(93B)
Figure PCTCN2019074134-appb-000135
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮和5-氟-2H-苯并[d][1,2,3]三唑为原料参考实施例5，得到2-(5-氟-2H-苯并[d][1,2,3]三唑-2-基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环 丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(11.5mg,白色固体，产率：12.7％)。以及实施例93A和实施例93B的混合物(约3：2)(21.6mg,白色固体，产率：23.9％)，进一步通过制备色谱拆分得到2-(5-氟-1H-苯并[d][1,2,3]三唑-1-基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮与2-(6-氟-1H-苯并[d][1,2,3]三唑-1-基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮。
实施例92：
MS m/z(ESI):466.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.87(dd,J 1＝9.2Hz,J 2＝4.8Hz,1H),7.47(dd,J 1＝9.2Hz,J 2＝2.0Hz,1H),7.23-7.18(m,1H),5.73(dd,J 1＝17.6Hz,J 2＝4.4Hz,2H),2.90(d,J＝4.0Hz,1H),1.99-1.96(m,1H),1.85-1.81(m,4H),1.74-1.63(m,3H),1.57-1.38(m,10H),1.30-1.11(m,6H),1.14-1.01(m,2H),0.88(s,3H),0.53-0.48(m,1H).
实施例93A：
MS m/z(ESI):466.2[M+H] +
实施例93B：
MS m/z(ESI):466.2[M+H] +
实施例94
2-(2,4-二氟苯氧基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000136
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮和2,4-二氟苯酚为原料参考实施例5，得到2-(2,4-二氟苯氧基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(27.4mg,白色固体，产率：38.6％)。
MS m/z(ESI):441.2[M+H] +
1H NMR(400MHz,CDCl 3)δ6.93-6.80(m,2H),6.79-6.74(m,1H),4.77(dd,J 1＝16.8Hz,J 2＝3.6Hz,2H),2.93(d,J＝3.2Hz,1H),1.89-1.76(m,5H),1.75-1.60(m,3H),1.55-1.50(m,1H),1.46-1.41(m,6H),1.27-1.11(m,9H),0.98-0.95(m,1H),0.94-0.89(m,1H),0.76(s,3H),0.46-0.39(m,1H).
实施例95
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-甲基-1H-吡唑-1-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000137
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮和4-甲基吡唑为原料参考实施例5，得到1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-甲基-1H-吡唑-1-基)乙烷-1-酮(12.6mg，白色固体,产率:15.7％)。
MS m/z(ESI):411.3[M+H] +
1H NMR(400MHz,CDCl 3)δ7.44(s,1H),7.26(s,1H),5.23(m,2H),2.83(d,J＝4.4Hz,1H),2.13(s,3H),1.98-1.85(m,2H),1.83-1.69(m,9H),1.60-1.56(m,1H),1.40-1.27(m,12H),1.09-1.01(m,2H),0.80(s,3H),0.48-0.45(m,1H).
实施例96
2-((4-氟苯基)氨基)-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
Figure PCTCN2019074134-appb-000138
第一步：2-((4-氟苯基)氨基)-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-酮的制备
Figure PCTCN2019074134-appb-000139
2-溴-1-((3R,5R,8R,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(50mg，0.12mmol)溶于四氢呋喃(3mL)中，加入4-氟苯胺(42mg，0.2mmol)和三乙胺(60mg，0.6mmol)，反应液在室温条件下搅拌12h，反应液浓缩，用高效液相色谱分离得2-((4-氟苯基)氨基)-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(7mg，白色固体，产率13％)。
MS m/z(ESI):442.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ6.95-6.86(m,2H),6.59-6.53(m,2H),3.95-3.85(m,2H),2.55-2.47(m,1H),2.25-2.15(m,2H),1.90-1.80(m,5H),1.75–1.25(m,18H),1.00(d,J＝8.0Hz，3H),0.81(s,3H).
实施例97
2-((4-氟苯基)氨基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000140
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮和对氟苯胺为原料，以N，N-二甲基甲酰胺为溶剂参考实施例5，得到2-((4-氟苯基)氨基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(14.9mg，黄色油状物)，产率：26.7％。
MS m/z(ESI):440.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.00-6.95(m,2H),6.91-6.83(m,2H),4.19(dd,J 1＝20.0Hz,J 2＝2.8Hz,2H),2.80(d,J＝4.0Hz,1H),1.92-1.58(m,14H),1.45-1.40(m,8H),1.27(s,3H),1.09-0.91(m,2H),0.69(s,3H),0.48-0.43(m,1H)
实施例98
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(1H-咪唑-1-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000141
Figure PCTCN2019074134-appb-000142
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮和咪唑为原料参考实施例63，得到1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(1H-咪唑-1-基)乙烷-1-酮(23.3mg，白色固体，产率：34.4％)。
MS m/z(ESI):397.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.48(s,1H),7.12(s,1H),6.88(s,1H),4.98-4.87(m,2H),2.82(d,J＝2.8Hz,1H),1.94-1.91(m,1H),1.85-1.81(m,4H),1.70-1.53(m,10H),1.41-1.28(m,9H),1.13-0.95(m,2H),0.78(s,3H),0.52-0.46(m,1H).
实施例99和实施例100
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4,5,6,7-四氢-1H-吲唑-1-基)乙烷-1-酮与1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4,5,6,7-四氢-2H-吲唑-2-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000143
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮和4,5,6,7-四氢-2H-吲唑为原料参考实施例5，得到1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4,5,6,7-四氢-1H-吲唑-1-基)乙烷-1-酮(99)(5.5mg,白色固体，产率：6.8％)；1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯 并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4,5,6,7-四氢-2H-吲唑-2-基)乙烷-1-酮(100)(3.1mg,白色固体，产率：3.8％)。
实施例99：
MS m/z(ESI):415.3[M+H] +
1H NMR(400MHz,CDCl 3)δ7.12(s,1H),5.14-5.05(m,2H),2.80(d,J＝4.0Hz,1H),2.69(t,J＝6.0Hz,2H),2.56(t,J＝6.0Hz,2H),1.97-1.93(m,1H),1.85-1.61(m,12H),1.55-1.52(m,2H),1.43-1.21(m,13H),1.11-0.94(m,2H),0.79(s,3H),0.48-0.42(m,1H).
实施例100：
MS m/z(ESI):415.3[M+H] +
1H NMR(400MHz,CDCl 3)δ7.50(s,1H),5.74-5.35(m,2H),2.89(d,J＝4.0Hz,1H),2.58(t,J＝6.0Hz,2H),2.48(t,J＝6.0Hz,2H),1.96-1.91(m,1H),1.80-1.72(m,8H),1.40-1.22(m,19H),1.12-0.99(m,2H),0.82(s,3H),0.51-0.45(m,1H).
实施例101
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(5-甲基-1H-四唑-1-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000144
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮和5-甲基-1H-4-四唑为原料参考实施例5，得到1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(5-甲基-1H-四唑-1-基)乙烷-1-酮(19mg,白色固体,产率:23.5％)。
MS m/z(ESI):413.2[M+H] +
1H NMR(400MHz,CDCl 3)δ5.58(dd,J 1＝17.6Hz,J 2＝7.6Hz,2H),2.86(d,J＝4.0Hz,1H),2.57(s,3H),1.96-1.93(m,1H),1.89-1.61(m,8H),1.55-1.22(m,14H), 1.14-0.97(m,3H),0.84(s,3H),0.47-0.53(m,1H).
实施例102
2-(4-(吖丁啶-1-羰基)-1H-吡唑-1-基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000145
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮和吖丁啶-1-基(1H-吡唑-4-基)甲酮为底物参考实施例5，得到2-(4-(吖丁啶-1-羰基)-1H-吡唑-1-基)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮(10.0mg,产率：14.3％)。
MS m/z(ESI):480.3[M+H] +
1H NMR(400MHz,CDCl 3)δ7.85–7.80(m,1H),7.80–7.74(m,1H),5.20–5.05(m,2H),4.53–4.10(m,4H),2.82(d,J＝3.3Hz,1H),2.44–2.31(m,2H),1.98–1.90(m,1H),1.86–1.79(m,3H),1.74–1.64(m,3H),1.57–1.53(m,2H),1.44–1.24(m,15H),1.13–0.97(m,2H),0.79(s,3H),0.51–0.44(m,1H)。
实施例103
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-硝基-1H-吡唑-1-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000146
Figure PCTCN2019074134-appb-000147
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮和4-硝基-1H-吡唑为底物参考实施例5，得到1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-硝基-1H-吡唑-1-基)乙烷-1-酮(32.5mg，产率：60％)。
MS m/z(ESI):424.2[M+H-H 2O] +
1H NMR(400MHz,CDCl 3)δ8.20(s,1H),8.09(s,1H),5.26–5.09(m,2H),2.85(s,1H),1.98–1.91(m,1H),1.87–1.79(m,4H),1.74–1.65(m,3H),1.56–1.52(m,2H),1.47–1.35(m,7H),1.34–1.24(m,7H),1.13–0.97(m,2H),0.79(s,3H),0.55–0.47(m,1H)。
实施例104
(3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-乙酰基-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-16-甲腈(104)
Figure PCTCN2019074134-appb-000148
第一步：(3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-乙酰基-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-16-甲腈的制备
Figure PCTCN2019074134-appb-000149
向85℃的二甲基亚砜(7mL)和水(2mL)的混合溶液中加入1-((3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(270mg,0.853mmol)，氯化铵(250mg,4.69mmol)，18-冠-6(23mg,0.853mmol)，然后加入氰化钠(230mg,4.69mmol)，二甲基亚砜(4mL)和水(1mL)的混 合溶液，然后在85℃搅拌16小时，向反应液中加水(30mL)，然后用乙酸乙酯萃取(20mL x 3)，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，经过柱层析分离纯化(石油醚/乙酸乙酯＝1:1)，得到白色固体(3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-乙酰基-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-16-甲腈(250mg,产率：85％)。
实施例105
1-(2-((3R,5R,8R,9R,10S,13S,14R,17S)-3-羟基-3,13-二甲基-15-(硝基甲基)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 PCTCN2019074134-appb-000150
本实施例105通过以下具体实施方案合成：
Figure PCTCN2019074134-appb-000151
MS m/z(ESI):469.3[M+1] +.
实施例121
3-环丙基-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-1H-吡唑-4-甲腈
Figure PCTCN2019074134-appb-000152
第一步：3-环丙基-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-1H-吡唑-4-甲腈的制备
Figure PCTCN2019074134-appb-000153
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮为底物参考实施例5，得到3-环丙基-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-1H-吡唑-4-甲腈(19.2mg，产率：21％)。
MS m/z(ESI):462.3[M+H] +
1H NMR(400MHz,CDCl 3)δ7.73(s,1H),5.13–4.95(m,2H),2.80(d,J＝2.2Hz,1H),2.04–1.89(m,2H),1.86–1.79(m,3H),1.76–1.63(m,3H),1.58–1.49(m,3H),1.46–1.21(m,14H),1.12–0.93(m,6H),0.76(s,3H),0.51–0.43(m,1H).
实施例122
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(甲硫基)-1H-吡唑-1-基)乙烷-1-酮(122)
Figure PCTCN2019074134-appb-000154
第一步：1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(甲硫基)-1H-吡唑-1-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000155
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮为底物参考实施例5，得到1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(甲硫基)-1H-吡唑-1-基)乙烷-1-酮(8.7mg，产率：16％)。
MS m/z(ESI):443.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.54(s,1H),7.45(s,1H),5.17–5.00(m,2H),2.81(d,J＝3.8Hz,1H),2.35(s,3H),1.99–1.91(m,1H),1.88–1.76(m,4H),1.73–1.63(m,3H),1.55–1.50(m,1H),1.43–1.18(m,15H),1.12–0.97(m,2H),0.79(s,3H),0.50–0.41(m,1H).
实施例123和实施例124
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(甲基亚硫酰基<亚磺酰>)-1H-吡唑-1-基)乙烷-1-酮(123)和1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(甲磺酰)-1H-吡唑-1-基)乙烷-1-酮(124)
Figure PCTCN2019074134-appb-000156
第一步：1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(甲基亚硫酰基<亚磺酰>)-1H-吡唑-1-基)乙烷-1-酮和1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(甲磺酰)-1H-吡唑-1-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000157
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(甲硫基)-1H-吡唑-1-基)乙烷-1-酮(80mg，0.18mmol)溶于二氯甲烷(10mL)，冷却至-78℃，加入间氯过氧苯甲酸(55mg,0.27mmol),反应搅拌一小时。反应液中加入水(10mL),用饱和碳酸氢钠水溶液(10mL)洗，分离有机相，用无水硫酸钠干燥，过滤，旋干，粗品用高效液相色谱柱分离，得到1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(甲基亚硫酰基<亚磺酰>)-1H-吡唑-1-基)乙烷-1-酮(17.2mg，产率：20％)和1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯 并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(甲磺酰)-1H-吡唑-1-基)乙烷-1-酮(20.4mg，产率：25％)
实施例123：
MS m/z(ESI):441.3[M-H 2O+H] +
1H NMR(400MHz,CDCl 3)δ7.85(s,1H),7.83(s,1H),5.30–5.09(m,2H),2.91(s,3H),2.85–2.82(m,1H),1.98–1.90(m,1H),1.87–1.78(m,3H),1.75–1.50(m,8H),1.47–1.21(m,12H),1.13–0.96(m,2H),0.79(s,3H),0.54–0.45(m,1H).
实施例124：
MS m/z(ESI):457.2[M-H 2O+H] +
1H NMR(400MHz,CDCl 3)δ7.94(s,1H),7.87(s,1H),5.26–5.10(m,2H),3.14(s,3H),2.85(d,J＝2.7Hz,1H),1.98–1.91(m,1H),1.87–1.79(m,3H),1.76–1.64(m,3H),1.59–1.52(m,1H),1.50–1.18(m,16H),1.15–0.96(m,2H),0.79(s,3H),0.55–0.46(m,1H).
实施例125
3-氟-4-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙氧基)苯甲腈(125)
Figure PCTCN2019074134-appb-000158
第一步：3-氟-4-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙氧基)苯甲腈的制备
Figure PCTCN2019074134-appb-000159
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮为底物参考实施例5，得到3-氟-4-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙氧基)苯甲腈(12.5mg，产率：18％)。
MS m/z(ESI):448.2[M-H 2O+H] +
1H NMR(400MHz,CDCl 3)δ7.43–7.33(m,2H),6.91–6.84(m,1H),4.91(s, 2H),2.96–2.88(m,1H),1.90–1.76(m,4H),1.75–1.62(m,3H),1.55–1.26(m,17H),1.12–1.04(m,1H),0.98–0.92(m,1H),0.78(s,3H),0.50–0.41(m,1H).
实施例126
5-氟-2-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙氧基)苯甲腈(126)
Figure PCTCN2019074134-appb-000160
第一步：5-氟-2-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙氧基)苯甲腈的制备
Figure PCTCN2019074134-appb-000161
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮为底物参考实施例5，得到5-氟-2-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙氧基)苯甲腈(11.4mg，产率：10％)。
MS m/z(ESI):448.2[M-H 2O+H] +
1H NMR(400MHz,CDCl 3)δ7.34–7.28(m,1H),7.25–7.18(m,1H),6.78–6.72(m,1H),4.91–4.78(m,2H),2.99(d,J＝3.3Hz,1H),1.91–1.78(m,4H),1.76–1.64(m,3H),1.57–1.25(m,17H),1.08–0.92(m,2H),0.78(s,3H),0.50–0.40(m,1H).
实施例127
1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-1H-吡唑-3,5-二甲腈(127)
Figure PCTCN2019074134-appb-000162
第一步：1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十 八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-1H-吡唑-3,5-二甲腈的制备
Figure PCTCN2019074134-appb-000163
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮为底物参考实施例5，得到1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)-1H-吡唑-3,5-二甲腈(18.0mg，产率：31.8％)。
MS m/z(ESI):429.2[M-H 2O+H] +
1H NMR(400MHz,CDCl 3)δ7.21(s,1H),5.38(q,J＝18.0Hz,2H),2.87(d,J＝3.0Hz,1H),1.97–1.91(m,1H),1.88–1.75(m,4H),1.76–1.64(m,3H),1.58–1.51(m,1H),1.48–1.26(m,15H),1.15–0.99(m,2H),0.83(s,3H),0.58–0.48(m,1H).
实施例128
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(噁唑-2-基)-1H-吡唑-1-基)乙烷-1-酮(128)
Figure PCTCN2019074134-appb-000164
第一步：1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(噁唑-2-基)-1H-吡唑-1-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000165
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮为底物参考实施例5，得到 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(4-(噁唑-2-基)-1H-吡唑-1-基)乙烷-1-酮(16.0mg，产率：14％)。
MS m/z(ESI):464.3[M+H] +
1H NMR(400MHz,CDCl 3)δ7.89(s,1H),7.79(s,1H),7.73(s,1H),7.13(s,1H),5.27–5.13(m,2H),2.85(d,J＝4.0Hz,1H),2.01–1.93(m,1H),1.87–1.65(m,11H),1.58–1.50(m,1H),1.44–1.22(m,11H),1.14–0.98(m,2H),0.81(s,3H),0.53–0.44(m,1H).
实施例129
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(哒嗪-4-氧基)乙烷-1-酮(129)
Figure PCTCN2019074134-appb-000166
第一步：1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(哒嗪-4-氧基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000167
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮为底物参考实施例5，得到1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-(哒嗪-4-氧基)乙烷-1-酮(16.0mg，产率：26％)。
MS m/z(ESI):425.3[M+H] +
1H NMR(400MHz,CDCl 3)δ7.88(s,1H),7.61(d,J＝6.8Hz,1H),6.53(d,J＝6.8Hz,1H),5.17–4.85(m,2H),2.83(s,1H),1.99–1.90(m,1H),1.88–1.78(m,3H),1.76–1.54(m,10H),1.46–1.25(m,10H),1.14–0.95(m,2H),0.79(s,3H),0.55–0.46(m,1H).
实施例130
1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-((2-(三氟甲基)嘧啶-5-基)氧代)乙烷-1-酮
Figure PCTCN2019074134-appb-000168
第一步：1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-((2-(三氟甲基)嘧啶-5-基)氧代)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000169
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮为原料参考实例5得1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-((2-(三氟甲基)嘧啶-5-基)氧代)乙烷-1-酮(23.0mg，产率38.3％)。
MS m/z(ESI):493.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.45(s,2H),5.01(s,2H),2.86(s,1H),1.89(m,1H),1.83(m,4H),1.75(dm,1H),1.68(m,2H),1.57(m,1H),1.38(m,8H),1.31(m,2H),1.28(s,3H),1.26–1.20(m,1H),1.13–1.03(m,1H),0.96(m,1H),0.80(s,3H),0.48(m,1H).
实施例131
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)-2-(3-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(131)
Figure PCTCN2019074134-appb-000170
第一步：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)-2-(3-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮
Figure PCTCN2019074134-appb-000171
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5得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)-2-(3-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(20.5mg，产率30.1％)。
MS m/z(ESI):467.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.49–7.43(m,1H),6.59(d,J＝2.4Hz,1H),5.14–4.85(m,2H),2.54(t,J＝8.1Hz,1H),2.26–2.08(m,2H),2.02–1.93(m,1H),1.90–1.79(m,4H),1.74–1.59(m,3H),1.57–1.19(m,14H),1.21–1.04(m,1H),0.98(d,J＝7.0Hz,3H),0.84(s,3H).
实施例133
2-(4-(吖丁啶-1-羰基)-1H-吡唑-1-基)-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(133)
Figure PCTCN2019074134-appb-000172
第一步：2-(4-(吖丁啶-1-羰基)-1H-吡唑-1-基)-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-酮的制备
Figure PCTCN2019074134-appb-000173
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5得2-(4-(吖丁啶-1-羰基)-1H-吡唑-1-基)-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(12.0mg，产率21％)。
MS m/z(ESI):482.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.78(s,2H),5.00–4.77(m,2H),4.38-4.25(m, 4H),2.54(t,J＝7.6Hz,1H),2.43–2.32(m,2H),2.26–2.08(m,2H),1.98-1.96(m,1H),1.88-1.83(m,3H),1.69-1.62(m,5H),1.48-1.42(m,4H),1.38–1.26(m,9H),1.16-1.07(m,2H),0.98(d,J＝7.0Hz,3H),0.84(s,3H).
实施例134
3-氯-1-(2-((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)-2-羰基乙基)-1H-吡唑-4-甲腈(134)
Figure PCTCN2019074134-appb-000174
第一步：3-氯-1-(2-((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)-2-羰基乙基)-1H-吡唑-4-甲腈的制备
Figure PCTCN2019074134-appb-000175
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5得产品3-氯-1-(2-((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)-2-羰基乙基)-1H-吡唑-4-甲腈(37mg，产率55.3％)。
MS m/z(ESI):456.2[M-H]-.
1H NMR(400MHz,CDCl 3)δ7.81(s,1H),5.03–4.75(m,2H),2.54(t,J＝8.0Hz,1H),2.31–2.13(m,2H),1.93–1.06(m,23H),0.99(d,J＝7.1Hz,3H),0.83(s,3H).
实施例135
1-(2-((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)-2-羰基乙基)-1H-吡唑-3,5-二甲腈(135)
Figure PCTCN2019074134-appb-000176
第一步：1-(2-((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)-2-羰基乙基)-1H-吡唑-3,5-二甲腈的制备
Figure PCTCN2019074134-appb-000177
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5得产品1-(2-((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)-2-羰基乙基)-1H-吡唑-3,5-二甲腈(18mg，产率27.5％)。
MS m/z(ESI):447.2[M-H] -.
1H NMR(400MHz,CDCl 3)δ7.20(s,1H),5.23–5.07(m,2H),2.68–2.52(m,1H),2.28–1.36(m,21H),1.28(s,3H),1.18–1.08(m,1H),1.00(d,J＝6.9Hz,3H),0.88(s,3H).
实施例136
3-(2-((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)-2-羰基乙基)噻唑烷-2,4-二酮(136)
Figure PCTCN2019074134-appb-000178
第一步：3-(2-((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)-2-羰基乙基)噻唑烷-2,4-二酮的制备
Figure PCTCN2019074134-appb-000179
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-酮为底物参考实施例5，得到3-(2-((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)-2-羰基乙基)噻唑烷-2,4-二酮(24.0mg，产率：31.5％)。
MS m/z(ESI):430.2[M-H 2O+H] +
1H NMR(400MHz,CDCl 3)δ4.37(s,2H),4.04–3.98(m,2H),2.56–2.49(m,1H),2.22–2.03(m,2H),1.91–1.81(m,4H),1.73–1.61(m,3H),1.47–1.26(m,15H),1.17–1.05(m,2H),0.97(d,J＝7.1Hz,3H),0.81(s,3H).
实施例137
1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(137)
Figure PCTCN2019074134-appb-000180
第一步：1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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-甲腈的制备
Figure PCTCN2019074134-appb-000181
以2-溴-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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5得产品1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(16mg，产率：25.9％)。
MS m/z(ESI):438.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.49(d,J＝2.5Hz,1H),6.73(d,J＝2.4Hz,1H),5.22–4.78(m,2H),2.57(t,J＝8.0Hz,1H),2.15–1.30(m,20H),1.28(s,3H),1.16–1.03(m,4H),0.84(t,J＝7.3Hz,3H),0.79(s,3H).
实施例138
1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(138)
Figure PCTCN2019074134-appb-000182
第一步：1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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-酮的制备
Figure PCTCN2019074134-appb-000183
以2-溴-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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5得产品1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(23mg，产率：33.9％)。
MS m/z(ESI):481.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.47(d,J＝4.0Hz,1H),6.59(d,J＝4.0Hz 1H),5.07–4.89(m,2H),2.56(t,J＝9.3Hz,1H),2.20–1.29(m,20H),1.28(s,3H),1.27–1.03(m,4H),0.84(t,J＝7.3Hz,3H),0.80(s,3H).
实施例139
1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(139)
Figure PCTCN2019074134-appb-000184
第一步：1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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-酮的制备
Figure PCTCN2019074134-appb-000185
以2-溴-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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5得产品1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(13.5mg，产率：22.3％)。
MS m/z(ESI):429.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ5.39–5.29(m,2H),2.63–2.57(m,1H),2.56(s,3H),2.10–1.30(m,20H),1.28(s,3H),1.27–1.05(m,4H),0.87–0.81(m,6H).
实施例140和实施例141
1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(140)
1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(141)
Figure PCTCN2019074134-appb-000186
第一步：1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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-酮和1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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-酮的制备
Figure PCTCN2019074134-appb-000187
以2-溴-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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5得产品1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(17mg，产率：29.1％)和1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(9.2mg，产率：15.7％)。
实施例140：
MS m/z(ESI):414.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.77(s,1H),7.67(s,1H),5.37–5.09(m,2H),2.62(t,J＝9.2Hz,1H),2.28–1.20(m,25H),1.16–1.05(m,2H),0.85(t,J＝7.3Hz,3H),0.80(s,3H).
实施例141：
MS m/z(ESI):414.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.68(s,2H),5.28–5.20(m,2H),2.54(t,J＝8.0Hz,1H),1.99–1.23(m,25H),1.13–1.06(m,2H),0.88–0.78(m,6H).
实施例142
1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(142)
Figure PCTCN2019074134-appb-000188
第一步：1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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-3,5-二甲腈的制备
Figure PCTCN2019074134-appb-000189
以2-溴-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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5得产品1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(5mg，产率：9.2％)。
MS m/z(ESI):463.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.21(s,1H),5.29–5.02(m,2H),2.61(t,J＝9.3Hz,1H),2.24–1.34(m,19H),1.28(s,3H),1.26–1.02(m,5H),0.92–0.76(m,6H).
实施例143
1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(143)
Figure PCTCN2019074134-appb-000190
第一步：1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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-3,5-二甲腈的制备
Figure PCTCN2019074134-appb-000191
以1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-3-羟基-3,13-二甲基十 六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实施例5得1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(19.6mg，产率：18％)。
MS m/z(ESI):473.2[M-H] -
1H NMR(400MHz,CDCl 3)δ7.20(s,1H),5.24–5.09(m,2H),2.58–2.50(m,1H),2.26–2.07(m,2H),2.06–1.95(m,2H),1.90–1.80(m,2H),1.78–1.66(m,2H),1.58–1.22(m,16H),1.19–1.06(m,2H),0.94(s,3H),0.87–0.78(m,1H),0.64–0.56(m,1H),0.45–0.39(m,1H),0.18–0.02(m,2H).
实施例144
1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(144)
Figure PCTCN2019074134-appb-000192
第一步：1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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-酮的制备
Figure PCTCN2019074134-appb-000193
以1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实施例5得1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(18.0mg，产率：23％)。
MS m/z(ESI):491.3[M-H] -
1H NMR(400MHz,CDCl 3)δ7.47(d,J＝2.0Hz,1H),6.59(d,J＝2.0Hz,1H),5.08–4.90(m,2H),2.53–2.42(m,1H),2.24–1.94(m,4H),1.91–1.79(m,3H),1.78–1.66(m,2H),1.52–1.22(m,15H),1.18–1.02(m,2H),0.91(s,3H),0.88–0.76(m,1H),0.65–0.54(m,1H),0.48–0.36(m,1H),0.18–0.00(m,2H).
实施例146
1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(146)
Figure PCTCN2019074134-appb-000194
第一步：1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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-酮的制备
Figure PCTCN2019074134-appb-000195
以1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实施例5得1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(12.9mg，产率：13.2％)。
MS m/z(ESI):409.3[M-H 2O+H] +
1H NMR(400MHz,CDCl 3)δ8.57(s,1H),5.46(s,2H),2.58–2.47(m,1H),2.24–1.94(m,4H),1.93–1.80(m,3H),1.77–1.66(m,2H),1.50–1.21(m,15H),1.18–1.06(m,2H),0.95(s,3H),0.87–0.78(m,1H),0.64–0.55(m,1H),0.46–0.38(m,1H),0.17–0.01(m,2H).
实施例147
3-氯-1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(147)
Figure PCTCN2019074134-appb-000196
第一步：3-氯-1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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-甲腈的制备
Figure PCTCN2019074134-appb-000197
以1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实施例5得3-氯-1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(13.5mg，产率：17.4％)。
MS m/z(ESI):482.2[M-H] -
1H NMR(400MHz,CDCl 3)δ7.82(s,1H),5.01–4.76(m,2H),2.55–2.41(m,1H),2.22–1.94(m,4H),1.91–1.77(m,3H),1.76–1.66(m,2H),1.56–1.24(m,15H),1.18–1.04(m,2H),0.90(s,3H),0.87–0.75(m,1H),0.64–0.53(m,1H),0.46–0.38(m,1H),0.17–0.02(m,2H).
实施例148
3-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(148)
Figure PCTCN2019074134-appb-000198
第一步：3-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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-2,4-二酮的制备
Figure PCTCN2019074134-appb-000199
以1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实施例5得3-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(10.0mg，产率：13％)。
MS m/z(ESI):456.2[M-H 2O+H] +
1H NMR(400MHz,CDCl 3)δ4.38(s,2H),4.04(s,2H),2.51–2.43(m,1H), 2.24–2.00(m,4H),1.91–1.80(m,3H),1.75–1.67(m,2H),1.49–1.27(m,15H),1.17–1.05(m,2H),0.88(s,3H),0.84–0.78(m,1H),0.62–0.53(m,1H),0.46–0.36(m,1H),0.15–0.01(m,2H).
实施例149
1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(149)
Figure PCTCN2019074134-appb-000200
第一步：1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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-酮的制备
Figure PCTCN2019074134-appb-000201
以2-溴-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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5得产品1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-乙基-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(11mg，白色固体，产率：18.8％)。
MS m/z(ESI):397.2[M-H 2O+H] +
1H NMR(400MHz,CDCl 3)δ8.57(s,1H),5.50–5.41(m,2H),2.62(t,J＝8.5Hz,1H),2.29–1.30(m,20H),1.28(s,3H),1.27–1.05(m,4H),0.85–0.82(m,6H).
实施例150
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)-2-((2-(三氟甲基)嘧啶-5-基)氧代)乙烷-1-酮(150)
Figure PCTCN2019074134-appb-000202
第一步：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)-2-((2-(三氟甲基)嘧啶-5-基)氧代)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000203
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-酮为原料参考实施例5得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)-2-((2-(三氟甲基)嘧啶-5-基)氧代)乙烷-1-酮(16.1mg，产率：19％)。
MS m/z(ESI):477.3[M-H 2O+H] +
1H NMR(400MHz,CDCl 3)δ8.44(s,2H),4.85–4.71(m,2H),2.67–2.57(m,1H),2.30–2.10(m,2H),1.93–1.81(m,4H),1.74–1.61(m,3H),1.48–1.23(m,15H),1.18–1.06(m,2H),1.00(d,J＝7.1Hz,3H),0.87(s,3H).
实施例151
1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(151)
Figure PCTCN2019074134-appb-000204
第一步：1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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-酮的制备
Figure PCTCN2019074134-appb-000205
以1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮为原料参考实施例5得1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-环丙基-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(22.9mg，产率：27.6％)。
MS m/z(ESI):503.3[M-H 2O+H] +
1H NMR(400MHz,CDCl 3)δ8.44(s,2H),4.87–4.69(m,2H),2.62–2.50(m,1H),2.25–1.96(m,3H),1.92–1.84(m,3H),1.77–1.66(m,2H),1.54–1.23(m, 15H),1.18–1.04(m,2H),0.93(s,3H),0.87–0.78(m,1H),0.65–0.56(m,1H),0.49–0.38(m,1H),0.20–0.02(m,2H).
实施例152
3-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)噻唑烷-2,4-二酮(152)
Figure PCTCN2019074134-appb-000206
第一步：3-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)噻唑烷-2,4-二酮的制备
Figure PCTCN2019074134-appb-000207
以2-溴-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)乙烷-1-酮为原料参考实施例5得3-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-羟基-2,6a-二甲基十八氢环丙烯并[4,5]环戊二烯并[1,2-a]菲-7-基)-2-羰基乙基)噻唑烷-2,4-二酮(7.1mg，产率：9.3％)。
MS m/z(ESI):446.2[M+H] +
1H NMR(400MHz,CDCl 3)δ4.66–4.50(m,2H),4.04(s,2H),2.78(d,J＝4.0Hz,1H),1.98–1.92(m,1H),1.85–1.52(m,11H),1.44–1.24(m,12H),1.13–0.97(m,2H),0.77(s,3H),0.49–0.41(m,1H).
实施例157
1-((8S,9S,13S,14S,17S)-3-羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基)乙烷-1-酮(157)
Figure PCTCN2019074134-appb-000208
第一步：(8R,9S,13S,14S)-3-(苄氧基)-13-甲基-6,7,8,9,11,12,13,14,15,16-十氢-17H-环戊二烯并[a]菲-17-酮的制备
Figure PCTCN2019074134-appb-000209
100mL三口瓶中加入(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(4.1g,15mmol)和二氯甲烷/甲醇(1/1，50mL)溶液，加入碳酸钾(6.2g，45mmol)和苄基溴(7.6g，45mmol)，反应液在65℃下回流5小时。反应液冷却，过滤，甲醇洗涤，溶液浓缩，用石油醚/乙酸乙酯(1/3)过柱得(8R,9S,13S,14S)-3-(苄氧基)-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(5g，产率：93％)。
1H NMR(400MHz,CDCl 3)δ7.45–7.29(m,5H),7.20(d,J＝8.5Hz,1H),6.79(dd,J＝8.6,2.7Hz,1H),6.73(d,J＝2.6Hz,1H),5.04(s,2H),2.95-2.85(m,2H),2.50(dd,J＝18.8,8.5Hz,1H),2.43-2.36(m,1H),2.30-2.23(m,1H),2.20–1.94(m,4H),1.63–1.40(m,6H),0.91(s,3H).
第二步：(8S,9S,13S,14S)-3-(苄氧基)-17-亚乙基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲的制备
Figure PCTCN2019074134-appb-000210
将叔丁醇钾(7.8g，70mmol)悬浮在四氢呋喃(100mL)溶液中，在0℃下慢慢加入溴乙基三苯基膦(26.3g，70mmol)，反应液在60℃下搅拌2小时。然后将(8R,9S,13S,14S)-3-(苄氧基)-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(5g，14mmol)加入到上述反应液中，在60℃下反应2小时。反应液冷却至室温，用饱和氯化铵水溶液淬灭，乙酸乙酯萃取，有机相用饱和食盐水洗涤，干燥，过滤，浓缩，用石油醚过柱子得(8S,9S,13S,14S)-3-(苄氧基)-17-亚乙基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲(5g，产率：96％)。
第三步：1-((8S,9S,13S,14S)-3-(苄氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基)乙烷-1-醇的制备
Figure PCTCN2019074134-appb-000211
将(8S,9S,13S,14S)-3-(苄氧基)-17-亚乙基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲(2.5g，6.9mmol)溶于干燥的四氢呋喃(50mL)溶 液中，室温下滴加硼烷四氢呋喃溶液(1M，20mL)，反应液在室温下搅拌1小时。反应液用冰水冷却，慢慢滴加氢氧化钠溶液(10％，15mL)，有大量气体放出，然后慢慢滴加双氧水(30％，20mL)，反应液在室温下搅拌2小时。反应液用乙酸乙酯萃取，硫代硫酸钠溶液，饱和食盐水洗涤，干燥得2.5g产品，直接用于下一步反应。
第四步：1-((8S,9S,13S,14S,17S)-3-(苄氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000212
1-((8S,9S,13S,14S)-3-(苄氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基)乙烷-1-醇(2.5g，6.5mmol)溶于二氯甲烷(30mL)溶液中，然后加入氯铬酸吡啶(2.06g，9.6mmol)，反应液在室温下搅拌12小时。反应液过滤，旋干，用石油醚/乙酸乙酯(1/5)过柱得到1-((8S,9S,13S,14S,17S)-3-(苄氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基)乙烷-1-酮(1.6g，产率：65％)
1H NMR(400MHz,CDCl 3)δ7.44–7.28(m,5H),7.20(d,J＝8.6Hz,1H),6.78(dd,J＝8.5,2.6Hz,1H),6.72(d,J＝2.6Hz,1H),5.03(s,2H),2.90-2.80(m,2H),2.61(t,J＝9.1Hz,1H),2.40–2.17(m,4H),2.15(s,3H),1.96–1.27(m,9H),0.65(s,3H).
第五步：1-((8S,9S,13S,14S,17S)-3-羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000213
1-((8S,9S,13S,14S,17S)-3-(苄氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基)乙烷-1-酮(200mg，0.52mmol)溶于甲醇/四氢呋喃(5mL/5mL)中，加入活性炭负载氢氧化钯(30mg，20％)，反应液在氢气保护下在45度下反应12小时得最终产品1-((8S,9S,13S,14S,17S)-3-羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基)乙烷-1-酮(50mg，产率：32％)
MS m/z(ESI):298.1[M]+。
1H NMR(400MHz,CDCl 3)δ7.15(d,J＝8.4Hz,1H),6.63(dd,J＝8.4,2.6Hz,1H),6.56(d,J＝2.6Hz,1H),4.62(s,1H),2.92–2.74(m,2H),2.62(t,J＝9.1Hz,1H),2.40-2.17(m,4H),2.16(s,3H),1.95-1.30(m,9H),0.65(s,3H).
实施例158
1-((8S,9S,13S,14S,17S)-3-羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮(158)
Figure PCTCN2019074134-appb-000214
第一步：1-((8S,9S,13S,14S,17S)-3-(苄氧基)-2-溴-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基)-2-溴乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000215
1-((8S,9S,13S,14S,17S)-3-(苄氧基)-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基)乙烷-1-酮(300mg，0.78mmol)溶于甲醇(15mL)中，滴加5滴溴化氢溶液，滴加液溴(255mg，1.6mmol)，反应液在室温搅拌2小时。反应液倒入冰水中，用乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干得300mg产品1-((8S,9S,13S,14S,17S)-3-(苄氧基)-2-溴-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基)-2-溴乙烷-1-酮，直接用于下一步反应。
第二步：1-((8S,9S,13S,14S,17S)-3-(苄氧基)-2-溴-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000216
1-((8S,9S,13S,14S,17S)-3-(苄氧基)-2-溴-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基)-2-溴乙烷-1-酮(300mg，0.55mmol)溶于四氢呋喃(10mL)中，加入碳酸铯(536mg，1.65mmol)和1,2,3-三氮唑(190mg，2.7mmol)，反应液在35度下反应5小时。反应液过滤，浓缩，用石油醚/乙酸乙酯(1/1)过柱得1-((8S,9S,13S,14S,17S)-3-(苄氧基)-2-溴-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮(70mg，黄色固体，产率：20％)。
MS m/z(ESI):534.1/536.1(50/50)[M+H]+.
第三步：1-((8S,9S,13S,14S,17S)-3-羟基-13-甲基-7,8,9,11,12,13,14,15,16,17- 十氢-6H-环戊二烯并[a]菲-17-基)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000217
1-((8S,9S,13S,14S,17S)-3-(苄氧基)-2-溴-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮(70mg，0.13mmol)溶于甲醇/四氢呋喃(5mL/5mL)中，加入活性炭负载氢氧化钯(30mg，20％)，反应液在氢气保护下于45度下反应12小时，反应液过滤，浓缩制备得1-((8S,9S,13S,14S,17S)-3-羟基-13-甲基-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊二烯并[a]菲-17-基)-2-(1H-1,2,3-三唑-1-基)乙烷-1-酮(30mg，白色固体，产率：62.6％)。
MS m/z(ESI):366.1[M+H]+.
1H NMR(400MHz,CDCl 3)δ7.78(s,1H),7.67(s,1H),7.15(d,J＝8.0Hz,1H),6.65(dd,J＝6.4,2.4Hz,1H),6.60-6.56(m,1H),5.40-5.15(m,2H),5.04(s,1H),2.89-2.70(m,3H),2.40–2.21(m,3H),1.96–1.27(m,10H),0.71(s,3H).
实施例159
((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)二甲基氧化膦(159)
Figure PCTCN2019074134-appb-000218
第一步：(3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮的制备
Figure PCTCN2019074134-appb-000219
100mL圆底烧瓶中依次加入(3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(5g,17mmol)(上海崟岭医药科技有限公司)，2,6-二甲基吡啶(4.5g,42.5mmol)和无水二氯甲烷(80mL)。反应体系用冰水浴冷却至零度，逐滴加入叔丁基二甲硅基三氟甲磺酸脂(9g,34mmol)。反应体系升温至室温搅拌过夜。TLC板检测反应完全，二氯甲烷稀释，有机相使用水和饱和食盐水洗涤，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＝20:1)得到(3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(6.2g,产率：90.1％)。
1H NMR(400MHz,CDCl 3)δ2.37(dd,J＝18.8,8.0Hz,1H),2.06-1.97(m,1H),1.90-1.84(m,1H),1.75-1.68(m,5H),1.59-1.55(m,1H),1.47-0.89(m,17H),0.80(s,3H),0.79(s,9H),0.00(m,6H).
第二步：(3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基三氟甲磺酸酯的制备
Figure PCTCN2019074134-appb-000220
100mL圆底烧瓶中依次加入(3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(1.2g,3mmol)和50毫升无水四氢呋喃。反应体系冷却至-78℃，六甲基二硅基胺基钾的四氢呋喃溶液(3mL,3mmol)逐滴加入反应体系。反应于-78℃条件下搅拌1小时后，N-苯基双(三氟甲烷磺酸亚胺)(1.29g,3.6mmol)溶于5毫升无水四氢呋喃中滴入反应体系。滴加完毕后，反应自然升温至室温并搅拌过夜。反应完成后，饱和氯化铵溶液淬灭反应，乙酸乙酯萃取。有机相使用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，粗产物用柱层析分离(石油醚冲洗)得到(3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基三氟甲磺酸酯(1.4g,产率：87％)。
1H NMR(400MHz,CDCl 3)δ5.56(s,1H),2.27-2.18(m,1H),2.00-1.93(m,1H),1.80-1.61(m,7H),1.49-1.23(m,15H),0.97(s,3H),0.86(s,9H),0.08(s,6H).
第三步：((3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)二甲基氧化膦的制备
Figure PCTCN2019074134-appb-000221
100mL圆底烧瓶中依次加入(3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二 烯并[a]菲-17-基三氟甲磺酸酯(840mg,1.57mmol)，二甲基氧化膦(146mg,1.89mmol)，二乙酸钯(35mg,0.16mmol)，1,4-双(二苯基膦)丁烷(69mg,0.16mmol)，N,N-二异丙基乙胺(1.6g,12.6mmol)和10毫升无水二甲基亚砜。反应置换氮气后缓慢升温至120℃并搅拌过夜。反应完成后，反应体系冷却至室温，水淬灭反应，乙酸乙酯萃取。有机相使用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，粗产物用柱层析分离(二氯甲烷/甲醇＝10/1冲洗)得到((3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)二甲基氧化膦(642mg,产率：88％)。
1H NMR(400MHz,CDCl 3)δ6.54(dd,J＝10.8,1.6Hz,1H),2.33-2.27(m,1H),2.11-2.01(m,2H),1.66-1.58(m,12H),1.48-1.1.13(m,15H),1.00(s,3H),0.86(s,9H),0.07(s,6H).
第四步：((3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)二甲基氧化膦的制备
Figure PCTCN2019074134-appb-000222
100mL圆底烧瓶中将((3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)二甲基氧化膦(642mg,1.38mmol)溶于5毫升无水四氢呋喃中，1.0M浓度四丁基氟化铵的四氢呋喃溶液(5毫升)加入反应体系。反应于60℃并下搅拌过夜。反应完成后，反应体系冷却至室温，水淬灭反应，乙酸乙酯萃取。有机相使用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，粗产物用柱层析分离(二氯甲烷/甲醇＝10/1冲洗)得到((3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)二甲基氧化膦(170mg,产率：35％)。
1H NMR(400MHz,CDCl 3)δ6.57-6.54(m,1H),2.45(br,1H),2.35-2.28(m,1H),2.12-2.00(m,2H),1.87-1.70(m,4H),1.67-1.14(m,23H),1.00(s,3H).
第五步：((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)二甲基氧化膦的制备
Figure PCTCN2019074134-appb-000223
100mL圆底烧瓶中加入((3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)二甲基氧化膦(100mg,0.29mmol)，钯碳(100mg,10％)和10毫升乙酸乙酯。反应体系置换氢气三次后于1个大气压条件下氢化过夜。反应完成后，硅藻土过滤除去多余钯碳，滤液旋干。粗产物使用高效液相色谱制备得到((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)二甲基氧化膦(39.5mg,产率：39％)。
MS m/z(ESI):353.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ2.13-1.62(m,22H),1.35-1.27(m,8H),1.16-1.06(m,4H),0.99(s,3H).
实施例160
((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)二苯基氧化膦(160)
Figure PCTCN2019074134-appb-000224
第一步：((3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)二苯基氧化膦的制备
Figure PCTCN2019074134-appb-000225
100mL圆底烧瓶中依次加入(3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基三氟甲磺酸酯(350mg,0.65mmol)，二苯基氧化膦(158mg,0.78mmol)，二乙酸钯(35mg,0.16mmol)，1,4-双(二苯基膦)丁烷(69mg,0.16mmol)，N,N-二异丙基乙胺(660mg,5.2mmol)和10毫升无水二甲基亚砜。反应置换氮 气后缓慢升温至120℃并搅拌过夜。反应完成后，反应体系冷却至室温，水淬灭反应，乙酸乙酯萃取。有机相使用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，粗产物用柱层析分离(二氯甲烷/甲醇＝10/1冲洗)得到((3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)二苯基氧化膦(290mg,76％)。
1H NMR(400MHz,CDCl 3)δ7.85-7.80(m,2H),7.67-7.62(m,2H),7.59-7.40(m,6H),6.01-5.98(m,1H),2.31-2.25(m,1H),2.09-2.02(m,2H),1.89-1.10(m,21H),1.07(s,3H),0.86(s,9H),0.07(s,6H).
第二步：((3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)二苯基氧化膦的制备
Figure PCTCN2019074134-appb-000226
100mL圆底烧瓶中将((3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)二苯基氧化膦(270mg,0.46mmol)溶于5毫升无水四氢呋喃中，1.0M浓度四丁基氟化铵的四氢呋喃溶液(5毫升)加入反应体系。反应于60℃并下搅拌过夜。反应完成后，反应体系冷却至室温，水淬灭反应，乙酸乙酯萃取。有机相使用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，粗产物用柱层析分离(二氯甲烷/甲醇＝10/1冲洗)得到((3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)二苯基氧化膦(120mg,产率：55％)。
1H NMR(400MHz,CDCl 3)δ6.57-6.54(m,1H),2.45(br,1H),2.35-2.28(m,1H),2.12-2.00(m,2H),1.87-1.70(m,4H),1.67-1.14(m,26H),1.00(s,3H).
第三步：((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)二苯基氧化膦的制备
Figure PCTCN2019074134-appb-000227
100mL圆底烧瓶中加入((3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)二苯基氧化膦(120mg,0.25mmol)，钯碳(120mg,10％)和10毫升乙酸乙酯。反应体系置换氢气三次后于1个大气压条件下氢化过夜。反应完成后，硅藻土过滤除去多余钯碳，滤液旋干。粗产物使用高效液相色谱制备得到((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)二苯基氧化膦(40mg,产率：33％)。
MS m/z(ESI):477.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.91-7.83(m,4H),7.54-7.44(m,6H),2.37-2.15(m,2H),2.11-2.09(m,1H),2.07-1.95(m,6H),1.84-1.04(m,22H).
31P NMR(162MHz,CDCl 3)δ30.00.
实施例161
1-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17-基)乙烷-1-酮(161)
Figure PCTCN2019074134-appb-000228
第一步:(8R,10R,13S,14S)-10,13-二甲基-17-羰基-2,7,8,9,10,11,12,13,14,15,16,17-十二氢-1H-环戊二烯并[a]菲-3-基乙酸酯的制备
Figure PCTCN2019074134-appb-000229
将(8R,10R,13S,14S)-10,13-二甲基-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(19.0g，66.43mmol)溶于乙酸乙酯(500mL)，加入乙酸酐(100mL)和高氯酸(0.5mL)，室温下搅拌1小时，TLC检测反应完全。向反应液中加入饱和碳酸钠溶液(300mL)，有机相用饱和碳酸钠溶液(300mL*2)和饱和食盐水(300mL)洗涤，无水硫酸钠干燥，浓缩用硅胶柱色谱(乙酸乙酯：石油醚＝0～40％)分离纯化得(8R,10R,13S,14S)-10,13-二甲基-17-羰基-2,7,8,9,10,11,12,13,14,15,16,17-十二氢-1H-环戊二烯并[a]菲-3-基乙酸酯(13.0g,产率：59.7％)。
1H NMR(400MHz,CDCl3)δ:5.71(s,1H),5.42(t,J＝2.4Hz,1H),2.51-2.43(m,2H),2.34-2.27(m,1H),2.18-2.04(m,5H),2.00-1.69(m,6H),1.62-1.27(m,5H),1.13-1.06(m,1H),1.03(s,3H),0.92(s,3H).
第二步:(8R,10R,13S,14S)-6-羟基-10,13-二甲基-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)-二酮的制备
Figure PCTCN2019074134-appb-000230
将(8R,10R,13S,14S)-10,13-二甲基-17-羰基-2,7,8,9,10,11,12,13,14,15,16,17-十二氢-1H-环戊二烯并[a]菲-3-基乙酸酯(5.0g，15.24mmol)溶于乙醇(180mL)，加入间氯过氧苯甲酸(5.0g，24.71mmol)，室温下搅拌3小时，LC/MS检测反应完全。向反应液中加入饱和碳酸钠溶液(200mL)，用乙酸乙酯(300mL)萃取，有机相用饱和碳酸钠溶液(200mL*2)和饱和食盐水(200mL)洗涤，用无水硫酸钠干燥，浓缩得到(8R,10R,13S,14S)-6-羟基-10,13-二甲基-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(3.5g，产率：76.0％)。
MS m/z(ESI):303.0[M+H] +.
第三步:(8R,10R,13S,14S)-6-羟基-10,13-二甲基十四氢-3H-环戊二烯并[a]菲-3,17(2H)-二酮的制备
Figure PCTCN2019074134-appb-000231
将(8R,10R,13S,14S)-6-羟基-10,13-二甲基-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(8.0g，26.5mmol)溶于吡啶(50mL)，将10％Pd的Lindlar's催化剂(2.0g)加入上述溶液中，罩上氢气球，置换氢气3次，室温搅拌16小时。过滤，滤饼用乙酸乙酯(30mL)洗涤，滤液用乙酸乙酯(200mL)稀释，然后用1N的盐酸(100mL*2)洗涤，有机相用饱和食盐水(100mL)洗涤，用无水硫酸钠干燥，浓缩，用硅胶柱色谱(乙酸乙酯：石油醚＝1:1)分离纯化得(8R,10R,13S,14S)-6-羟基-10,13-二甲基十四氢-3H-环戊二烯并[a]菲-3,17(2H)-二酮(2.0g,产率25.0％).
1H NMR(400MHz,DMSO-d6)δ:4.60(s,1H),3.51(m,1H),2.45-2.31(m,3H),2.06-1.82(m,7H),1.69-1.51(m,5H),1.48-1.23(m,5H),1.14(s,3H),0.82(s,3H).
第四步:(6R,8R,10S,13S,14S)-13-甲基十四氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-3,17-二酮的制备
Figure PCTCN2019074134-appb-000232
将(8R,10R,13S,14S)-6-羟基-10,13-二甲基十四氢-3H-环戊二烯并[a]菲-3,17(2H)-二酮(1.0g，3.29mmol)溶于苯(50mL)/吡啶(0.8mL)，将四乙酸铅(7.3g，16.5mmol)加入上述溶液中，白炽灯(500W)下光照搅拌2小时，停止反应，加入乙酸乙酯(100mL)有较多固体析出，过滤，滤液用1N的盐酸(50mL*2)洗涤，有机相用饱和食盐水(50mL)洗涤，用无水硫酸钠干燥，浓缩，用硅胶柱色谱(乙酸乙酯：石油醚＝1:2)分离纯化得(6R,8R,10S,13S,14S)-13-甲基十四氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-3,17-二酮(600mg，产率60.0％).
1H NMR(400MHz,CDCl 3)δ:4.25-4.22(m,1H),4.06(d,J＝8.4Hz,1H,),3.39(d,J＝8.4Hz,1H),2.63-2.44(m,3H),2.35-2.06(m,5H),1.98-1.80(m,4H),1.72-1.24(m,8H),0.96(s,3H).
第五步:(3R,6R,8R,10S,13S,14S)-3-羟基-3,13-二甲基十四氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17(1H)-酮的制备
Figure PCTCN2019074134-appb-000233
在三口烧瓶中，加入2,6-二叔丁基对甲基苯酚(3.5g,15.9mmol)和甲苯(35mL),氮气保护，在0-10℃下滴加2M的三甲基铝(4mL,8mmol)，滴加完毕，室温搅拌1小时，然后用干冰/丙酮浴冷却至-78℃,将(6R,8R,10S,13S,14S)-13-甲基十四氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-3,17-二酮(0.8g,2.65mmol)溶于甲苯(30mL)滴加至上述反应液中，在-78℃下反应1小时，将3M的甲基溴化镁(2.3mL,6.9mmol)加入以上溶液中，在-78℃下反应1小时，向反应液中加入饱和氯化铵溶液(50mL)，用乙酸乙酯(120mL)萃取，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，浓缩，用硅胶柱色谱(乙酸乙酯：石油醚＝1:1)分离纯化得到3R,6R,8R,10S,13S,14S)-3-羟基-3,13-二甲基十四氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17(1H)-酮(400mg,产率：47.5％)。
1H NMR(400MHz,CDCl 3)δ:4.15-4.12(m,1H),3.96(d,J＝8.0Hz,1H),3.32(d,J＝8.0Hz,1H),2.48-2.41(m,1H),2.13-2.03(m,1H),1.92-1.79(m,5H),1.75-1.63(m,3H),1.60-1.43(m,6H),1.38-1.10(m,7H),0.92(s,3H).
第六步:(3R,6R,8S,10S,13S,14S)-17-亚乙基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-3-酚的制备
Figure PCTCN2019074134-appb-000234
将乙基三苯基溴化膦(11.65g,31.4mmol)溶于二甲基亚砜(25mL)，加入60％的钠氢(1.26g,31.4mmol),在氮气保护下室温搅拌1小时，将3R,6R,8R,10S,13S,14S)-3-羟基-3,13-二甲基十四氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17(1H)-酮(0.5g,1.57mmol)溶于二甲基亚砜(5mL)加入上述溶液中，加热至60℃，反应16小时。加入饱和氯化铵溶液(50mL)，用乙酸乙酯(60mL)萃取，有机相用饱和碳酸钠溶液(50mL*2)洗涤，然后用饱和食盐水(50mL)洗涤，用无水硫酸钠干燥，浓缩，用硅胶柱色谱(乙酸乙酯：石油醚＝1:3)分离纯化得到(3R,6R,8S,10S,13S,14S)-17-亚乙基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-3-酚(350mg,产率67.6％)。
1H NMR(400MHz,CDCl 3)δ:5.12-5.09(m,1H),4.15-4.12(m,1H),3.96(d,J＝8.0Hz,1H),3.26(d,J＝8.0Hz,1H),2.39-2.13(m,3H),1.91-1.85(m,3H),1.70-1.50(m,12H),1.30-1.07(m,8H),0.91(s,3H).
第七步:(3R,6R,8S,10S,13S,14S,17S)-17-((S)-1-羟基乙基)-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-3-酚的制备
Figure PCTCN2019074134-appb-000235
将(3R,6R,8S,10S,13S,14S)-17-亚乙基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-3-酚(250mg，0.76mmol)溶于四氢呋喃(8mL)，冷却至0℃，加入1M的硼烷四氢呋喃溶液(15mL,15mmol))，室温下搅拌3小时,冷却至0℃，滴加3M的氢氧化钠(10mL)，滴加完毕，加入30％的过氧化氢(8mL)，在室温下搅拌1小时，加入乙酸乙酯(60mL)稀释，用饱和硫代硫酸钠溶液(30mL)洗涤，有机相用饱和食盐水(50mL)洗涤，用无水硫酸钠干燥，浓缩得(3R,6R,8S,10S,13S,14S,17S)-17-((S)-1-羟基乙基)-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-3-酚(260mg，产率100％)，无需进一步纯化，直接用于下一步反应。
第八步:1-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000236
将(3R,6R,8S,10S,13S,14S,17S)-17-((S)-1-羟基乙基)-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-3-酚(260mg，0.75mmol)溶于二氯甲烷(10mL)，冷却至0℃，加入PCC(322mg,1.5mmol))，室温下搅拌3小时，TLC检测反应完全，过滤，滤饼用乙酸乙酯(20mL)洗涤，滤液加入乙酸乙酯(30mL)稀释，用饱和硫代硫酸钠溶液(30mL)洗涤，有机相用饱和食盐水(50mL)洗涤，用无水硫酸钠干燥，浓缩用硅胶柱色谱(乙酸乙酯：石油醚＝1:2)分离纯化得1-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17-基)乙烷-1-酮(150mg，产率：57.8％)。
1H NMR(400MHz,CDCl 3)δ:4.14-4.12(m,1H),3.94(d,J＝7.6Hz,1H),3.27(d,J＝7.6Hz,1H),2.53(t,J＝8.8Hz,1H),2.18-2.04(m,5H),1.91-1.86(m,3H),1.70-1.49(m,10H),1.34-1.49(m,8H),0.66(s,3H).
实施例162
1-(2-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈(162)
Figure PCTCN2019074134-appb-000237
第一步:2-溴-1-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000238
将1-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17-基)乙烷-1-酮(135mg，0.39mmol)溶于甲醇(6mL)，加入氢溴酸1滴，室温搅拌条件下加入液溴5滴，室温下搅拌1小时，TLC检测 反应完全，加入饱和碳酸氢钠溶液(30mL)，用乙酸乙酯(50mL)萃取，有机相用饱和食盐水(50mL)洗涤，用无水硫酸钠干燥，浓缩得2-溴-1-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17-基)乙烷-1-酮(160mg，产率：96.5％)，无需进一步纯化，直接用于下一步反应。
第二步:1-(2-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈的制备
Figure PCTCN2019074134-appb-000239
将2-溴-1-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17-基)乙烷-1-酮(85mg，0.2mmol)和4-氰基吡唑(92mg，1.0mmol)溶于四氢呋喃(5mL)，加入碳酸钾(138mg，1.0mmol)，室温搅拌16小时，TLC和LCMS检测反应完全，过滤，浓缩，用flash制备色谱分离纯化得1-(2-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-4-甲腈(29.7mg，产率：34.0％)。
MS m/z(ESI):438.3[M+H]+.
1H NMR(400MHz,CDCl3)δ:7.87(s,1H),7.81(s,1H),5.01-4.87(m,2H),4.15-4.12(m,1H),3.93(d,J＝8.4Hz,1H),3.28(d,J＝8.4Hz,1H),2.60(t,J＝6.8Hz,1H),2.22-2.08(m,2H),1.91-1.49(m,13H),1.39-1.24(m,6H),1.19-1.13(m,2H),0.72(s,3H).
实施例163
1-(2-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-3-甲腈(163)
Figure PCTCN2019074134-appb-000240
1-(2-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-3-甲腈的制备
Figure PCTCN2019074134-appb-000241
将2-溴-1-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17-基)乙烷-1-酮(80mg，0.19mmol)和3-氰基吡唑(88mg，0.95mmol)溶于四氢呋喃(5mL)，加入碳酸钾(130mg，0.95mmol)，室温搅拌16小时，TLC和LCMS检测反应完全，过滤，浓缩，用flash制备色谱分离纯化得1-(2-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17-基)-2-羰基乙基)-1H-吡唑-3-甲腈(36.5mg，产率：44.4％)。
MS m/z(ESI):438.3[M+H]+.
1H NMR(400MHz,CDCl 3)δ:7.49(d,J＝2.0Hz,1H),7.76(d,J＝2.0Hz,1H),5.10-4.90(m,2H),4.15-4.12(m,1H),3.94(d,J＝8.0Hz,1H),3.28(d,J＝8.0Hz,1H),2.60(t,J＝8.8Hz,1H),2.21-2.09(m,2H),1.91-1.50(m,13H),1.39-1.24(m,6H),1.19-1.13(m,2H),0.72(s,3H).
实施例164
1-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17-基)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(164)
Figure PCTCN2019074134-appb-000242
1-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17-基)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000243
将2-溴-1-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧 亚甲基)环戊二烯并[a]菲-17-基)乙烷-1-酮(80mg，0.19mmol)和4-三氟甲基吡唑(128mg，0.95mmol)溶于四氢呋喃(5mL)，加入碳酸钾(130mg，0.95mmol)，室温搅拌16小时，TLC和LCMS检测反应完全，过滤，浓缩，用flash制备色谱分离纯化得1-((3R,6R,8S,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-6,10-(环氧亚甲基)环戊二烯并[a]菲-17-基)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(29.5mg，产率：32.7％)。
MS m/z(ESI)：481.2[M+H]+.
1H NMR(400MHz,CDCl 3)δ:7.72(s,2H),5.01-4.87(m,2H),4.15-4.12(m,1H),3.94(d,J＝8.0Hz,1H),3.28(d,J＝8.0Hz,1H),2.60(t,J＝8.8Hz,1H),2.22-2.09(m,2H),1.91-1.49(m,13H),1.39-1.24(m,6H),1.19-1.13(m,2H),0.73(s,3H).
实施例165
1-(2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-羟基-8,12a-二甲基十八氢屈-1-基)-2-羰基乙基)-1H-吡唑-4-甲腈(165)
Figure PCTCN2019074134-appb-000244
第一步：(3R,5R,8R,9R,10S,13S,14S)-3,13-二甲基-17-羰基十六氢-1H-环戊二烯并[a]菲-3-基乙酸酯的制备
Figure PCTCN2019074134-appb-000245
(3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(580mg，2.0mmol)溶于醋酸酐(15mL)中，加入吡啶(158mg，2.0mmol)，N 2保护下80℃反应过夜。减压蒸除醋酸酐，剩余物加入H 2O(20mL)，以EA提取(15mL×3)，合并EA层，依次以H 2O(20mL)、饱和盐水(20mL)洗，无水Na 2SO 4干燥后减压浓缩，柱层析分离，得(3R,5R,8R,9R,10S,13S,14S)-3,13-二甲基-17-羰基十六氢-1H-环戊二烯并[a]菲-3-基乙酸酯(560mg，产率：84％)。
1H NMR(400MHz,CDCl 3)δ2.44(dd,J＝19.2,8.1Hz,1H),2.24-2.06(m,1H),1.97(s,3H),1.96-1.76(m,8H),1.71–1.57(m,3H),1.55(s,3H),1.55–0.99(m,10H),0.87(s,3H).
第二步：乙基2-((3R,5R,8R,9R,10S,13S,14S)-3-乙酰氧基-17-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-重氮基乙酸酯的制备
Figure PCTCN2019074134-appb-000246
(3R,5R,8R,9R,10S,13S,14S)-3,13-二甲基-17-羰基十六氢-1H-环戊二烯并[a]菲-3-基乙酸酯(400mg，1.2mmol)、重氮乙酸乙酯(206mg，1.8mmol)溶于THF(15mL)中，冷至-70℃，滴加LDA(2mL)，滴毕，同温下反应1h，加入AcOH(400mg)的乙醚(20mL)溶液，升至室温后加入H 2O(50mL)，乙醚提取(25mL×2)，合并乙醚层，依次以H 2O(50mL)、饱和NaHCO 3溶液(30mL)和饱和盐水(30mL)洗，无水Na 2SO 4干燥后减压浓缩至干，柱层析分离得乙基2-((3R,5R,8R,9R,10S,13S,14S)-3-乙酰氧基-17-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-重氮基乙酸酯(500mg，产率：93％)。
1H NMR(400MHz,CDCl 3)δ4.70(bs,1H),4.36–4.17(m,2H),2.24-2.11(m,1H),2.00(s,3H),1.96–1.87(m,2H),1.85-1.83(m,4H),1.74–1.58(m,4H),1.55(s,3H),1.52–1.35(m,2H),1.32(t,J＝7.1Hz,3H),1.29–1.17(m,4H),1.17–0.94(m,5H),0.92(s,3H),0.91–0.81(m,1H).
第三步：乙基(4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-乙酰氧基-8,12a-二甲基-1-羰基十八氢屈-2-羧酸酯的制备
Figure PCTCN2019074134-appb-000247
乙基2-((3R,5R,8R,9R,10S,13S,14S)-3-乙酰氧基-17-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)-2-重氮基乙酸酯(500mg，1.1mmol)溶于乙二醇二甲醚(10mL)中，加入醋酸铑二聚体(5.0mg)，N 2保护下室温反应0.5小时，滤除不溶物，滤液减压浓缩。柱层析分离得乙基(4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-乙酰氧基-8,12a-二甲基-1-羰基十八氢屈-2-羧酸酯(436mg，产率93％)。
1H NMR(400MHz,CDCl 3)δ12.35(s,0.82H),4.13(q,J＝7.1Hz,2H),3.63(dd,J＝13.5,6.0Hz,0.15H),2.27(dd,J＝16.2,6.1Hz,1H),2.14–1.96(m,2H),1.89(s,3H),1.88–1.65(m,7H),1.58(dd,J＝20.4,10.4Hz,3H),1.48(s,3H),1.36–1.13(m,8H),1.11–1.04(m,2H),1.03(s,3H),0.99-0.88(m,3H).
第四步：(4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-羟基-8,12a-二甲基十六氢屈-1(2H)-酮的制备
Figure PCTCN2019074134-appb-000248
KOH(4.0g)溶于甲醇(60mL)，加入乙基(4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-乙酰氧基-8,12a-二甲基-1-羰基十八氢屈-2-羧酸酯(400mg)，N2保护下加热回流1小时。反应液冷至室温后倾入到冰水(150mL)中，搅拌20分钟后过滤，滤饼少量水和丙酮洗，干燥后得(4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-羟基-8,12a-二甲基十六氢屈-1(2H)-酮(320mg)。
1H NMR(400MHz,CDCl 3)δ2.61(td,J＝14.0,6.8Hz,1H),2.25–2.15(m,1H),2.11–2.00(m,1H),1.87(dd,J＝9.8,7.7Hz,2H),1.84–1.70(m,5H),1.67–1.57(m,3H),1.56–1.47(m,2H),1.45–1.27(m,7H),1.26(s,3H),1.20–1.10(m,1H),1.08(s,3H),1.07–0.91(m,2H).
第五步：(2R,4aS,4bR,6aS,10aS,10bR,12aR)-7-亚乙基-2,6a-二甲基十八氢屈-2-醇的制备
Figure PCTCN2019074134-appb-000249
以(4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-羟基-8,12a-二甲基十六氢屈-1(2H)-酮为原料，参考实施例1第四步，得(2R,4aS,4bR,6aS,10aS,10bR,12aR)-7-亚乙基-2,6a-二甲基十八氢屈-2-醇(288mg)。
第六步：(2R,4aS,4bR,6aS,7S,10aS,10bR,12aR)-7-(1-羟基乙基)-2,6a-二甲基十八氢屈-2-醇的制备
Figure PCTCN2019074134-appb-000250
以(2R,4aS,4bR,6aS,10aS,10bR,12aR)-7-亚乙基-2,6a-二甲基十八氢屈-2-醇为原料，参考实施例1第五步，得(2R,4aS,4bR,6aS,7S,10aS,10bR,12aR)-7-(1-羟基乙基)-2,6a-二甲基十八氢屈-2-醇(150mg，含少量杂质)，不经纯化直接用于下一步反应。
第七步：1-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-羟基-8,12a-二甲基十八氢屈-1-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000251
以(2R,4aS,4bR,6aS,7S,10aS,10bR,12aR)-7-(1-羟基乙基)-2,6a-二甲基十八氢屈-2-醇为原料，参考实施例1第六步，得1-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-羟基-8,12a-二甲基十八氢屈-1-基)乙烷-1-酮(80mg，含少量杂质)，不经纯化直接用于下一步反应。
第八步：2-溴-1-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-羟基-8,12a-二甲基十八氢屈-1-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000252
以1-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-羟基-8,12a-二甲基十八氢屈-1-基)乙烷-1-酮为原料，参考实施例2第一步，得2-溴-1-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-羟基-8,12a-二甲基十八氢屈-1-基)乙烷-1-酮(50mg，含少量杂质)，不经纯化直接用于下一步反应。
第九步：1-(2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-羟基-8,12a-二甲基十八氢屈-1-基)-2-羰基乙基)-1H-吡唑-4-甲腈的制备
Figure PCTCN2019074134-appb-000253
以2-溴-1-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-羟基-8,12a-二甲基十八氢屈-1-基)乙烷-1-酮为原料，参考实施例5，得1-(2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-羟基-8,12a-二甲基十八氢屈-1-基)-2-羰基乙基)-1H-吡唑-4-甲腈(5.5mg)。
1H NMR(400MHz,CDCl 3)δ7.87(s,1H),7.83(s,1H),5.06-4.88(m,2H),2.47(d,J＝4.9Hz,1H),1.90-1.81(m,2H),1.78–1.67(m,5H),1.58-1.50(m,6H),1.41–1.34(m,4H),1.29-1.24(m,9H),0.99(s,3H),0.96–0.83(m,3H).
实施例166
1-((2-((3R,5R,8R,9R,10S,13S,14S,17S)-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)甲基)环丙烷-1-甲腈(166)
Figure PCTCN2019074134-appb-000254
第一步：1-((2-((3R,5R,8R,9R,10S,13S,14S,17S)-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)甲基)环丙烷-1-甲腈的制备
Figure PCTCN2019074134-appb-000255
将2-溴-1-((3R,5R,8R,9R,10S,13S,14S,17S)-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)，1-(羟甲基)环丙烷-1-甲腈(29mg,0.3mmol)和碳酸钾(138mg,1.0mmol)溶于N,N-二甲基乙酰胺(3mL)，反应在70℃下搅拌过夜。加水(20mL)，水相用乙酸乙酯(20mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，得粗品用柱层析分离(石油醚/乙酸乙酯：50/1～3/1)纯化得到1-((2-((3R,5R,8R,9R,10S,13S,14S,17S)-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)甲基)环丙烷-1-甲腈(10mg，产率：12％)。
1H NMR(400MHz,CDCl 3)δ4.21–4.09(m,2H),3.53(s,2H),2.61–2.54(m,1H),2.21–2.12(m,1H),1.90–1.78(m,4H),1.75–1.61(m,4H),1.49–1.40(m,5H),1.34–1.26(m,13H),1.10–1.04(m,4H),0.63(s,3H)。
实施例167
1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)硫代)甲基)-1H-吡唑-4-甲腈
Figure PCTCN2019074134-appb-000256
第一步：(3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-硫酮的制备
Figure PCTCN2019074134-appb-000257
干燥的100mL圆底烧瓶中依次加入(3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-硫酮(1.2g,3mmol)，2,4-双(对甲氧苯基)-1,3-二硫一二磷杂环丁烷-2,4硫化物(971mg,2.4mmol)和20毫升无水甲苯，反应体系置换氩气后升温至回流搅拌过夜。反应完成之后，中性氧化铝过滤，滤液旋干。粗产物用柱层析分离(石油醚/乙酸乙酯＝50/1冲洗)得到(3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-硫酮(860mg,68％)。
1H NMR(400MHz,CDCl 3)δ2.90(dd,J＝8.4,21.6Hz,1H),2.63-2.55(m,1H),1.97-1.93(m,2H),1.73-1.17(m,22H),0.84(s,3H),0.79(s,9H),0.07(s,6H).
第二步：(3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-硫醇的制备
Figure PCTCN2019074134-appb-000258
干燥的100mL圆底烧瓶中加入(3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-硫酮(860mg,2mmol)和30毫升无水四氢呋喃，反应体系冷却至0℃，1.0M三叔丁氧基氢化铝锂(6mL,6mmol)滴入反应体系。0度下搅拌2小时后室温下再搅拌1小时。TCL显示反应完全。饱和碳酸氢钠溶液小心的淬灭反应，二氯甲烷萃取。合并的有机相使用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干得到粗产物可以直接用于下步反应而无需纯化。
1H NMR(400MHz,CDCl 3)δ2.60-2.58(m,1H),2.10-2.07(m,1H),1.72-0.98(m,25H),0.79(s,9H),0.64(s,3H),0.04(s,6H).
第三步：1-(羟甲基)-1H-吡唑-4-甲腈的制备
Figure PCTCN2019074134-appb-000259
100mL圆底烧瓶中加入1H-吡唑-4-甲腈(930mg,10mmol)，30％甲醛水溶 液(8g,100mmol)和10毫升甲醇。反应体系于室温下搅拌过夜。旋干反应溶液得到1-(羟甲基)-1H-吡唑-4-甲腈(900mg,73％)。
1H NMR(400MHz,CDCl 3)δ8.05(s,1H),7.87(s,1H),4.96-4.80(m,2H)
第四步：1-(氯甲基)-1H-吡唑-4-甲腈的制备
Figure PCTCN2019074134-appb-000260
100mL圆底烧瓶中加入1-(羟甲基)-1H-吡唑-4-甲腈(900mg,7.3mmol)，三乙胺(1.5g,14.6mmol)和20毫升二氯甲烷，搅拌情况下分批加入对甲苯磺酰氯(2.1g,11mmol)，反应体系于室温下搅拌过夜。水淬灭反应，二氯甲烷酯萃取。有机相使用水和饱和食盐水洗涤，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＝10/1冲洗)得到1-(氯甲基)-1H-吡唑-4-甲腈(790mg,76.7％)。
1H NMR(400MHz,CDCl 3)δ8.08(s,1H),7.89(s,1H),5.87(s,2H).
第五步：1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)硫代)甲基)-1H-吡唑-4-甲腈的制备
Figure PCTCN2019074134-appb-000261
干燥的100mL圆底烧瓶中加入(3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-硫醇(210mg,0.5mmol)，1-(氯甲基)-1H-吡唑-4-甲腈(72mg,0.6mmol)，碳酸钾(136mg,1mmol)，碘化钠(10mg，催化量)和5毫升无水N,N-二甲基甲酰胺，反应体系升温至60℃搅拌过夜。反应冷却至室温，水淬灭反应，二氯甲烷酯萃取。有机相使用水和饱和食盐水洗涤，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＝10/1冲洗)得到1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)硫代)甲基)-1H-吡唑-4-甲腈(170mg,产率：64.5％)。
1H NMR(400MHz,CDCl 3)δ8.10(s,1H),7.79(s,1H),5.18(dd,J＝14.4,19.2Hz,2H),2.62(t,J＝7.2Hz,1H),2.05-1.98(m,2H),1.90-0.90(m,24H),0.86(s,9H),0.72(s,3H),0.07(s,6H).
第六步：1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)硫代)甲基)-1H-吡唑-4-甲腈
Figure PCTCN2019074134-appb-000262
100mL圆底烧瓶中将1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)硫代)甲基)-1H-吡唑-4-甲腈(170mg,0.32mmol)溶于5毫升无水四氢呋喃中，1.0M浓度四丁基氟化铵的四氢呋喃溶液(5mL)加入反应体系。反应于60℃并下搅拌过夜。反应完成后，反应体系冷却至室温，水淬灭反应，乙酸乙酯萃取。有机相使用水和饱和食盐水洗涤，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＝1/1冲洗)得到1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)硫代)甲基)-1H-吡唑-4-甲腈(100mg,75％)。
1H NMR(400MHz,CDCl 3)δ8.09(s,1H),7.79(s,1H),5.28-5.02(m,2H),2.58(t,J＝9.4Hz,1H),2.12-1.93(m,1H),1.89-0.94(m,26H),0.72(s,3H).
实施例168和实施例169
1-(((S)-((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)亚硫酰基<亚磺酰>)甲基)-1H-吡唑-4-甲腈(168)
1-(((R)-((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)亚硫酰基<亚磺酰>)甲基)-1H-吡唑-4-甲腈(169)
Figure PCTCN2019074134-appb-000263
100mL圆底烧瓶中将1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)硫代)甲基)-1H-吡唑-4-甲腈(25mg,0.06mmol)溶于5毫升无水二氯甲烷中，-20℃条件下加入间氯过氧苯甲酸(15mg,0.073mmol)，反应于该温度下搅拌1小时。反应完成后，饱和碳酸氢钠淬灭反应，乙酸乙酯萃取。有机相使用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，粗产物用高效液相色谱分离得到1-(((S)-((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)亚硫酰基<亚磺酰>)甲基)-1H-吡唑-4-甲腈(7.5mg,29％)和1-(((R)-((3R,5R,8R,9R,10S,13S,14S,17S)-3- 羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)亚硫酰基<亚磺酰>)甲基)-1H-吡唑-4-甲腈(6.5mg,产率：25％)。
实施例168：
MS m/z(ESI):430.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.06(s,1H),7.90(s,1H),5.21(d,J＝12.0Hz,1H),5.03(d,J＝12.0Hz,1H),2.54(t,J＝9.2Hz,1H),2.12-1.93(m,2H),1.85-1.02(m,25H),0.89(s,3H).
实施例169：
MS m/z(ESI):430.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.10(s,1H),7.91(s,1H),5.18(d,J＝13.6Hz,1H),5.03(d,J＝13.6Hz,1H),2.32(t,J＝8.8Hz,1H),2.05-1.94(m,2H),1.85-1.12(m,25H),1.05(s,3H).
实施例170
1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)磺酰)甲基)-1H-吡唑-4-甲腈(170)
Figure PCTCN2019074134-appb-000264
第一步：1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)磺酰)甲基)-1H-吡唑-4-甲腈的制备
Figure PCTCN2019074134-appb-000265
100mL圆底烧瓶中将1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)硫代)甲基)-1H-吡唑-4-甲腈(25mg,0.06mmol)溶于5mL无水二氯甲烷中，0℃条件下加入间氯过氧苯甲酸(30mg,0.15mmol)，反应于室温下搅拌2小时。反应完成后，饱和碳酸氢钠淬灭反应，乙酸 乙酯萃取。有机相使用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，粗产物用制备高效液相色谱分离得到1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)磺酰)甲基)-1H-吡唑-4-甲腈(9.1mg,34％)。
MS m/z(ESI):446.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.13(s,1H),7.89(s,1H),5.24(d,J＝14.8Hz,1H),5.02(d,J＝14.8Hz,1H),2.88(t,J＝9.2Hz,1H),2.24-2.18(m,1H),2.11-1.92(m,3H),1.84-1.00(s,26H).
实施例171
((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)甲基苯基氧化膦(171)
Figure PCTCN2019074134-appb-000266
第一步：((3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)甲基苯基氧化膦的制备
Figure PCTCN2019074134-appb-000267
100mL圆底烧瓶中依次加入(3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基三氟甲磺酸酯(230mg,0.43mmol)，甲基苯基氧化膦(92mg,0.64mmol)，二乙酸钯(10mg,0.04mmol)，1,4-双(二苯基膦)丁烷(18mg,0.04mmol)，N,N-二异丙基乙胺(443mg,3.4mmol)和10mL无水二甲基亚砜。反应置换氮气后缓慢升温至120℃并搅拌过夜。反应完成后，反应体系冷却至室温，水淬灭反应，乙酸乙酯萃取。有机相使用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，粗产物用柱层析分离(二氯甲烷/甲醇＝10/1冲洗)得到((3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)甲基苯基氧化膦(170mg,75％)。
1H NMR(400MHz,CDCl 3)δ7.77-7.72(m,2H),7.55-7.48(m,3H),6.53-6.50(m,1H),2.44-1.16(m,27H),1.00(s,3H),0.86(s,9H),0.05(s,6H).
第二步：((3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)甲基苯基氧化膦的制备
Figure PCTCN2019074134-appb-000268
100mL圆底烧瓶中将((3R,5R,8R,9R,10S,13S,14S)-3-((叔-丁基二甲基甲硅烷基)氧代)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)甲基苯基氧化膦(170mg,0.32mmol)溶于5mL无水四氢呋喃中，1.0M浓度四丁基氟化铵的四氢呋喃溶液(5mL)加入反应体系。反应于60℃并下搅拌过夜。反应完成后，反应体系冷却至室温，水淬灭反应，乙酸乙酯萃取。有机相使用水和饱和食盐水洗涤，无水硫酸钠干燥。过滤，旋干，粗产物用柱层析分离(二氯甲烷/甲醇＝10/1冲洗)得到((3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)甲基苯基氧化膦(50mg,38％)。
第三步：((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)甲基苯基氧化膦的制备
Figure PCTCN2019074134-appb-000269
100mL圆底烧瓶中加入((3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)甲基苯基氧化膦(50mg,0.12mmol)，钯碳(50mg,10％)和10mL乙酸乙酯。反应体系置换氢气三次后于1个大气压条件下氢化过夜。反应完成后，硅藻土过滤除去多余钯碳，滤液旋干。粗产物使用高效液相色谱制备得到((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)甲基苯基氧化膦(10mg,20％)。
MS m/z(ESI):415.3[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.79-7.74(m,2H),7.55-7.50(m,3H),2.41-2.34(m,1H),2.03-1.60(m,12H),1.55-0.73(m,21H).
实施例172
1-((3R,5R,8R,9R,10S,13S,14S)-13-甲基-3-(甲基氨基)十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮盐酸盐
Figure PCTCN2019074134-appb-000270
第一步：(3S,5R,8R,9R,10S,13S,14S)-3-羟基-13-甲基十六氢-17H-环戊二烯并[a]菲-17-酮的制备
Figure PCTCN2019074134-appb-000271
在-78℃条件下，将(5R,8R,9R,10S,13S,14S)-13-甲基十四氢-3H-环戊二烯并[a]菲-3,17(2H)-二酮(5.90g,21.50mmol)溶解于无水四氢呋喃(150mL)中，置换氮气，然后将三异丁基硼氢化钾(1.0M in THF，32.25mL，32.25mmol)滴加到反应体系中。在零下78度下反应三小时，然后将氢氧化钠水溶液(10wt％，56.6mL)滴加到反应体系中，然后将双氧水(82.6mL)滴加到反应体系中，室温搅拌半小时。然后将饱和硫代硫酸钠(100mL)加入到反应体系中，室温搅拌10分钟，然后用乙酸乙酯溶液萃取(100mL×3),合并有机相，有机相用无水硫酸钠干燥，过滤，旋干，粗产物用flash柱分离(石油醚：乙酸乙酯：4:1)得到(3S,5R,8R,9R,10S,13S,14S)-3-羟基-13-甲基十六氢-17H-环戊二烯并[a]菲-17-酮(5.0g，白色固体，产率：84％)。
第二步：(3S,5R,8R,9R,10S,13S,14S)-17-亚乙基-13-甲基十六氢-1H-环戊二烯并[a]菲-3-酚的制备
Figure PCTCN2019074134-appb-000272
在氮气下,将钠氢(1.45g,36.18mmol,60％in mineral oil)分批加入到乙基三苯基溴化膦(13.44g,36.18mmol)的二甲基亚砜(100mL)的溶液中,反应液室温搅拌1小时,然后滴加(3S,5R,8R,9R,10S,13S,14S)-3-羟基-13-甲基十六氢-17H-环戊二烯并[a]菲-17-酮(2.0g,7.24mmol)的二甲基亚砜(40mL)溶液,反应液在氮气下 加热到60℃过夜。将反应液冷却至室温,加入饱和食盐水(200mL)，然后用二氯甲烷萃取(50mL×3),合并有机相，有机相用无水硫酸钠干燥，过滤，旋干，粗产物用flash柱分离(石油醚：乙酸乙酯：10:1)得到(3S,5R,8R,9R,10S,13S,14S)-17-亚乙基-13-甲基十六氢-1H-环戊二烯并[a]菲-3-酚(1.60g，白色固体，产率：76.7％)。
1H NMR(400MHz,CDCl 3)δ5.14-5.08(m,1H),4.13-4.11(m,1H),2.40-2.33(m,1H),2.28-2.11(m,3H),1.91-1.83(m,1H),1.74-1.58(m,8H),1.47-1.38(m,5H),1.38-1.34(m,2H),1.29-1.07(m,7H),0.88(s,3H).
第三步：(3S,5R,8R,9R,10S,13S,14S)-17-亚乙基-13-甲基十六氢-1H-环戊二烯并[a]菲-3-基甲磺酸酯的制备
Figure PCTCN2019074134-appb-000273
室温下，将(3S,5R,8R,9R,10S,13S,14S)-17-亚乙基-13-甲基十六氢-1H-环戊二烯并[a]菲-3-酚(0.40g,1.39mmol)溶解于二氯甲烷(20mL)中，然后将吡啶(0.33g,4.16mmol)滴加到反应液中，然后将甲磺酰氯(0.32g,2.77mmol)滴加到反应体系中，室温反应过夜。反应结束后，用二氯甲烷(40mL)稀释反应液，反应液用饱和食盐水洗涤(10mL×3)，有机相用无水硫酸钠干燥，过滤，旋干，粗产物用flash柱子分离(石油醚：乙酸乙酯：10:1)得到(3S,5R,8R,9R,10S,13S,14S)-17-亚乙基-13-甲基十六氢-1H-环戊二烯并[a]菲-3-基甲磺酸酯(0.30g，白色固体，产率：59％)。
第四步：(3R,5R,8R,9R,10S,13S,14S)-17-亚乙基-N,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-胺的制备
Figure PCTCN2019074134-appb-000274
室温下，将(3S,5R,8R,9R,10S,13S,14S)-17-亚乙基-13-甲基十六氢-1H-环戊二烯并[a]菲-3-基甲磺酸酯(0.20g,0.55mmol)加入到微波反应管(10mL)中，然后将甲胺醇溶液(3mL)滴加到反应体系中，封闭，加热至80℃过夜。冷却至室温，旋干，残留物用乙酸乙酯(20mL)溶解，有机相用饱和食盐水洗涤(20mL×3),合并有机相，有机相用无水硫酸钠干燥，过滤，旋干，粗产物用flash柱分离(二氯甲烷：甲醇：三乙胺：300:10:3)得到(3S,5R,8R,9R, 10S,13S,14S)-17-亚乙基-N，13-二甲基十六氢-1H-环戊二烯并[a]菲-3-胺(70mg,无色油状物，产率：42.4％)。
MS m/z(ESI):302.5[M+H] +.
第五步：1-((3R,5R,8R,9R,10S,13S,14S)-13-甲基-3-(甲基氨基)十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-醇的制备
Figure PCTCN2019074134-appb-000275
冰浴下，将(3S,5R,8R,9R,10S,13S,14S)-17-亚乙基-N，13-二甲基十六氢-1H-环戊二烯并[a]菲-3-胺(0.07g,0.23mmol)溶解于无水四氢呋喃(3mL)中，然后滴加硼烷四氢呋喃溶液(1.0M in THF,2.32mL,2.32mmol)。反应三小时，然后将氢氧化钠溶液(3N，1mL)滴加到反应体系中，然后将双氧水(0.3mL)滴加到反应体系中，室温搅拌半小时，然后用乙酸乙酯稀释(20mL),饱和食盐水洗涤(10mL×3)，有机相用无水硫酸钠干燥，过滤，旋干，得到粗产物1-((3R,5R,8R,9R,10S,13S,14S)-13-甲基-3-(甲基氨基)十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-醇(40mg,无色油状物，粗产物)。
MS m/z(ESI):320.5[M+H] +.
第六步：1-((3R,5R,8R,9R,10S,13S,14S)-13-甲基-3-(甲基氨基)十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000276
室温下，将1-((3R,5R,8R,9R,10S,13S,14S)-13-甲基-3-(甲基氨基)十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-醇(40mg,0.125mmol)溶解于二氯甲烷(5mL)中，然后将氯铬酸吡啶(54mg,0.25mmol)加入到反应体系中，室温反应三小时。反应液用二氯甲烷(20mL)稀释，反应液用饱和硫代硫酸钠洗涤(10mL×3),有机相用无水硫酸钠干燥，过滤，旋干，粗产物用柱色谱分离(二氯甲烷：甲醇：30:1)得到1-((3R,5R,8R,9R,10S,13S,14S)-13-甲基-3-(甲基氨基)十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(15mg，白色固体，产率：37.7％)。
MS m/z(ESI):318.5[M+H] +
1H NMR(400MHz,CDCl 3)δ3.61-3.55(m,1H),2.55-2.50(m,1H),2.47(s,3H),2.11(s,3H),2.01-1.92(m,3H),1.78-1.56(m,8H),1.43-1.01(m,13H),0.61(s,3H).
实施例173
1-((3R,8R,9R,10S,13S,14S,16R,17S)-16-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(173)
Figure PCTCN2019074134-appb-000277
第一步：(3R,5R,8R,9R,10S,13S,14S,16R)-16-氟-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮的制备
Figure PCTCN2019074134-appb-000278
将三氟甲磺酸三甲基硅酯(5.6mL,31.0mmol)滴加到(3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(3g,10.3mmol)和三乙胺(36.0mL,258.2mmol)的甲苯(45mL)溶液中,反应液加热回流2小时,冷却,饱和碳酸氢钠洗涤，正己烷萃取，有机相干燥蒸干得到粗品(((3R,5R,8R,9R,10S,13S,14S)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-3,17-二基)二(氧代))二(三甲基硅烷)。将选择性氟试剂(4.0g,11.4mmol)加入到(((3R,5R,8R,9R,10S,13S,14S)-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-3,17-二基)二(氧代))二(三甲基硅烷)的N,N-二甲基甲酰胺(25mL)中,室温搅拌2小时,得到(3R,5R,8R,9R,10S,13S,14S,16R)-16-氟-3,13-二甲基-3-((三甲基甲硅烷基)氧代)十六氢-17H-环戊二烯并[a]菲-17-酮,然后加入四丁基氟化铵的四氢呋喃溶液(11.4mL,1M),反应液室温搅拌过夜。反应液乙酸乙酯萃取，饱和食盐水洗涤三次，有机相干燥蒸干，粗品经柱分离(石油醚：乙酸乙酯＝6:4)得到(3R,5R,8R,9R,10S,13S,14S,16R)-16-氟-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(2.0g,产率50.9％)。
1H NMR(400MHz,CDCl 3)δ5.09(dd,J＝50.6,7.5Hz,1H),2.18–1.58(m,10H),1.54–1.01(m,14H),0.92(s,3H).
19F NMR(376MHz,CDCl 3)δ-192.59.
第二步：(3R,5R,8R,9R,10S,13S,14S,16R)-17-亚乙基-16-氟-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚的制备
Figure PCTCN2019074134-appb-000279
在氮气下,将钠氢(123mg,3.08mmol,60％w/w)分批加入到乙基三苯基溴化膦(1.2g,3.24mmol)的二甲基亚砜(20mL)的溶液中,反应液室温搅拌1小时,然后加入(3R,5R,8R,9R,10S,13S,14S,16R)-16-氟-3-羟基-3,13-二甲基十六氢-17H-环戊二烯并[a]菲-17-酮(200mg,0.65mmol),反应液在氮气下加热到70℃过夜.反应液冷却,加入饱和食盐水,1N盐酸调节PH＝6,乙酸乙酯萃取,有机相饱和食盐水洗涤后,干燥蒸干得到粗品,粗品经柱分离(石油醚：乙酸乙酯＝7:3)得到(3R,5R,8R,9R,10S,13S,14S,16R)-17-亚乙基-16-氟-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚(80mg,产率：38.5％)。
1H NMR(400MHz,CDCl 3)δ5.71–5.59(m,1H),5.12(dt,J＝57.2,7.0Hz,1H),2.27–2.11(m,2H),1.92–1.24(m,21H),1.22–1.09(m,4H),1.06(s,3H).
19F NMR(376MHz,CDCl 3)δ-153.69.
第三步：(3R,8R,9R,10S,13S,14S,16R,17S)-16-氟-17-(1-羟基乙基)-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚的制备
Figure PCTCN2019074134-appb-000280
将(3R,5R,8R,9R,10S,13S,14S,16R)-17-亚乙基-16-氟-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-3-酚(80mg，0.25mmol)溶于干燥的四氢呋喃(50mL)溶液中，室温下滴加硼烷四氢呋喃溶液(1M，2.5mL),反应液在室温下搅拌1小时。反应液用冰水冷却，慢慢滴加氢氧化钠溶液(3M，1mL)，有大量气体放出，然后慢慢滴加双氧水(25％，0.58mL)，反应液在室温下搅拌2小时。反应液用乙酸乙酯萃取，硫代硫酸钠溶液，饱和食盐水洗涤，干燥得(3R,8R,9R,10S,13S,14S,16R,17S)-16-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(80mg)，直接用于下一步反应。
1H NMR(400MHz,CDCl 3)δ5.47–5.16(m,1H),4.22–4.05(m,1H),2.42–2.17(m,1H),1.94–0.93(m,27H),0.87(s,3H).
19F NMR(376MHz,CDCl 3)δ-178.27.
第四步：1-((3R,8R,9R,10S,13S,14S,16R,17S)-16-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-酮的制备
Figure PCTCN2019074134-appb-000281
将氯铬酸吡啶(102mg,0.47mmol)加入到(3R,8R,9R,10S,13S,14S,16R,17S)-16-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(80mg)的丙酮(2mL)溶液中,反应液在60℃反应6小时。反应液蒸干，经柱分离(石油醚：乙酸乙酯＝5:2)得到1-((3R,8R,9R,10S,13S,14S,16R,17S)-16-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,产率25％)。
1H NMR(400MHz,CDCl 3)δ5.64–5.35(m,1H),2.44–2.09(m,6H),1.97–1.75(m,4H),1.74–1.00(m,20H),0.98–0.68(m,2H).
19F NMR(376MHz,CDCl 3)δ-168.20.
实施例174
1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-羟基-4,8a-二甲基十六氢环丙烯并[3,4]环戊二烯并[1,2-a]菲-8b(2H)-基)乙烷-1-酮(174)
Figure PCTCN2019074134-appb-000282
第一步：1-((3R,5R,8R,9R,10S,13S,14S,17R)-17-溴-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000283
将1-((3R,5R,8R,9R,10S,13S,14S,17S)-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(600mg,1.872mmol)溶于四氯化碳(10mL)中，然后加入N-溴代丁二酰亚胺(666mg,3.744mmol)和过氧化苯甲酰(48mg,0.187mmol)，在80℃搅拌2小时。反应液冷却到室温，向反应液中加水(30mL)，用乙酸乙酯萃取(20mL x 3)，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，经过柱层析(石油醚/乙酸乙酯＝8/1)分离纯化，得到淡黄色固体1-((3R,5R,8R,9R,10S,13S,14S,17R)-17-溴-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(400mg,产率:54％)。
1H NMR(400MHz,CDCl 3)δ3.09-3.01(m,1H),2.38(s,3H),2.32–2.20(m,1H),2.10–1.98(m,1H),1.97–1.72(m,7H),1.71–1.58(m,1H),1.57–0.94(m,15H),0.89–0.81(m,1H),0.76(s,3H)
第二步:1-((3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000284
将1-((3R,5R,8R,9R,10S,13S,14S,17R)-17-溴-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(400mg,1mmol)溶于无水甲苯(10mL)中，然后加入1,8-二氮杂二环十一碳-7-烯(913mg,6mmol)，110℃下搅拌16小时。反应液冷却到室温，将反应液加入到水(20mL)中，用乙酸乙酯萃取(20mL x 3)，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，经过柱层析(石油醚/乙酸乙酯＝4/1)分离纯化，得到无色油状物1-((3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(160mg,产率:51％)。
1H NMR(400MHz,CDCl 3)δ6.69(dd,J＝3.1,1.7Hz,1H),2.41–2.28(m,2H),2.25(s,3H),2.07–1.93(m,1H),1.89–1.76(m,3H),1.71-1.69(m,4H),1.53-1.41(m,5H),1.37–1.29(m,4H),1.27(s,3H),1.24–1.07(m,3H),0.89(s,3H).
第三步：1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-羟基-4,8a-二甲基十六氢环丙烯并[3,4]环戊二烯并[1,2-a]菲-8b(2H)-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000285
将钠氢(45mg,1.136mmol，60％)悬浮在二甲基亚砜(2mL)中，然后加入三甲基碘化亚砜(100mg,0.451mmol)，室温搅拌1小时，然后加入1-((3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(90 mg,0.284mmol)和四氢呋喃(2mL)的混合溶液，然后在室温搅拌16小时。向反应液中加入水(15mL)，用乙酸乙酯萃取(10mLx3)，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，经过柱层析(石油醚/乙酸乙酯：4/1)分离纯化，得到无色油状物1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-羟基-4,8a-二甲基十六氢环丙烯并[3,4]环戊二烯并[1,2-a]菲-8b(2H)-基)乙烷-1-酮(40mg,产率：43％)。
1H NMR(400MHz,CDCl 3)δ2.26–2.18(m,1H),1.95(s,3H),1.92–1.85(m,1H),1.81(m,2H),1.72–1.53(m,5H),1.46–1.29(m,7H),1.29–1.17(m,7H),1.16–1.00(m,3H),0.94(s,3H),0.91–0.78(m,2H).
实施例175
1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-羟基-4,8a-二甲基十六氢环丙烯并[3,4]环戊二烯并[1,2-a]菲-8b(2H)-基)-2-羰基乙基)-1H-吡唑-4-甲腈(175)
Figure PCTCN2019074134-appb-000286
第一步：2-溴-1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-羟基-4,8a-二甲基十六氢环丙烯并[3,4]环戊二烯并[1,2-a]菲-8b(2H)-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000287
将1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-羟基-4,8a-二甲基十六氢环丙烯并[3,4]环戊二烯并[1,2-a]菲-8b(2H)-基)乙烷-1-酮(40mg,0.121mmol)溶于甲醇(2mL)中，然后加入1滴溴化氢和2滴液溴，室温下搅拌1.5小时。反应液加入水(15mL)中，用乙酸乙酯萃取(10mLx3)，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，滤液减压浓缩得到2-溴-1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-羟基-4,8a-二甲基十六氢环丙烯并[3,4]环戊二烯并[1,2-a]菲-8b(2H)-基)乙烷-1-酮(50mg,粗品)。
第二步：1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-羟基-4,8a-二甲基十六氢环丙烯并[3,4]环戊二烯并[1,2-a]菲-8b(2H)-基)-2-羰基乙基)-1H-吡唑-4-甲腈的制备
Figure PCTCN2019074134-appb-000288
将2-溴-1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-羟基-4,8a-二甲基十六氢环丙烯并[3,4]环戊二烯并[1,2-a]菲-8b(2H)-基)乙烷-1-酮(40mg，0.098mmol)溶于四氢呋喃(5mL)中，加入4-氰基吡唑(11mg，0.0118mmol)和碳酸钾(27mg，0.196mmol)，反应液在室温搅拌16h。反应液加入水(15mL)中，用乙酸乙酯萃取(10mLx2)，合并有机相用饱和食盐水(20mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，粗品用高效液相色谱柱分离，得到1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-羟基-4,8a-二甲基十六氢环丙烯并[3,4]环戊二烯并[1,2-a]菲-8b(2H)-基)-2-羰基乙基)-1H-吡唑-4-甲腈(18mg，产率：44％)。
MS m/z(ESI):422.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.74(s,1H),5.11(d,J＝18.0Hz,1H),4.91(d,J＝18.0Hz,1H),3.61–3.49(m,1H),2.96(d,J＝8.7Hz,1H),2.17–2.05(m,2H),1.90–1.70(m,5H),1.68-1.5(m,7H),1.45–1.35(m,5H),1.34–1.01(m,7H),0.65(s,3H).
实施例176
1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-羟基-4,8a-二甲基十六氢环丙烯并[3,4]环戊二烯并[1,2-a]菲-8b(2H)-基)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(176)
Figure PCTCN2019074134-appb-000289
第一步：1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-羟基-4,8a-二甲基十六氢环丙烯并[3,4]环戊二烯并[1,2-a]菲-8b(2H)-基)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000290
将2-溴-1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-羟基-4,8a-二甲基十六 氢环丙烯并[3,4]环戊二烯并[1,2-a]菲-8b(2H)-基)乙烷-1-酮(40mg，0.098mmol)溶于四氢呋喃(5mL)中，加入3-氰基吡唑(11mg，0.0118mmol)和碳酸钾(27mg，0.196mmol)，反应液在室温搅拌16h。反应液加入水(15mL)中，用乙酸乙酯萃取(10mLx2)，合并有机相用饱和食盐水(20mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，粗品用高效液相色谱柱分离，得到1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-羟基-4,8a-二甲基十六氢环丙烯并[3,4]环戊二烯并[1,2-a]菲-8b(2H)-基)-2-(4-(三氟甲基)-1H-吡唑-1-基)乙烷-1-酮(18mg，产率：44％)。
MS m/z(ESI):465.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.74(s,1H),7.70(s,1H),4.90(d,J＝17.3Hz,1H),4.71(d,J＝17.3Hz,1H),2.18(m,1H),2.10–2.03(m,1H),1.81(m,3H),1.76–1.58(m,4H),1.57–1.32(m,10H),1.26(s,3H),1.19–1.00(m,4H),0.98(s,3H),0.92(m,2H).
实施例177
1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-羟基-4,8a-二甲基十六氢-8bH-萘并[2',1':4,5]茚并[1,2-b]噁丙烯-8b-基)-2-羰基乙基)-1H-吡唑-4-甲腈(177)
Figure PCTCN2019074134-appb-000291
第一步：1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-羟基-4,8a-二甲基十六氢-8bH-萘并[2',1':4,5]茚并[1,2-b]噁丙烯-8b-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000292
将1-((3R,5R,8R,9R,10S,13S,14S)-3-羟基-3,13-二甲基-2,3,4,5,6,7,8,9,10,11,12,13,14,15-十四氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮(80mg,0.242mmol)溶解在甲醇(5mL)和水(1mL)中，然后加入双氧水(1.3mL)和氢氧化钠(30mg,0.75mmol)，在0℃下搅拌16小时。向反应液中加水(15mL)，用乙酸乙酯(15mLx3)萃取，合并有机相用饱和食盐水(20mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，经过柱层析(石油醚/乙酸乙酯＝4/1)分离纯化,得到1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-羟基-4,8a-二甲基十六氢-8bH-萘并[2',1':4,5]茚并[1,2-b]噁丙烯-8b-基)乙烷-1-酮(60mg,产率：75％)。
1H NMR(400MHz,CDCl 3)δ3.66(s,1H),2.03(s,3H),1.94(m,1H),1.87–1.75(m,3H),1.74–1.61(m,3H),1.47(m,2H),1.43–1.37(m,4H),1.35–1.30(m,3H),1.25(s,6H),1.17–1.07(m,3H),1.03(s,3H).
第二步：2-溴-1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-羟基-4,8a-二甲基十六氢-8bH-萘并[2',1':4,5]茚并[1,2-b]噁丙烯-8b-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000293
将1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-羟基-4,8a-二甲基十六氢-8bH-萘并[2',1':4,5]茚并[1,2-b]噁丙烯-8b-基)乙烷-1-酮(50mg,0.15mmol)溶于甲醇(3mL)中，然后加入1滴溴化氢和2滴液溴，室温下搅拌8小时。反应液加入水(10mL)中，用乙酸乙酯萃取(10mLx3)，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，滤液减压浓缩得到2-溴-1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-羟基-4,8a-二甲基十六氢-8bH-萘并[2',1':4,5]茚并[1,2-b]噁丙烯-8b-基)乙烷-1-酮(60mg,粗品)。
第三步：1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-羟基-4,8a-二甲基十六氢-8bH-萘并[2',1':4,5]茚并[1,2-b]噁丙烯-8b-基)-2-羰基乙基)-1H-吡唑-4-甲腈的制备
Figure PCTCN2019074134-appb-000294
将2-溴-1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-羟基-4,8a-二甲基十六氢-8bH-萘并[2',1':4,5]茚并[1,2-b]噁丙烯-8b-基)乙烷-1-酮(60mg，0.146mmol)溶于四氢呋喃(3mL)中，加入4-氰基吡唑(20mg，0.219mmol)和碳酸钾(60mg，0.438mmol)，反应液在室温搅拌16h。反应液加入水(15mL)中，用乙酸乙酯萃取(10mLx3)，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，粗品用高效液相色谱柱分离，得到1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-羟基-4,8a-二甲基十六氢-8bH-萘并[2',1':4,5]茚并[1,2-b]噁丙烯-8b-基)-2-羰基乙基)-1H-吡唑-4-甲腈(18mg，产率:29％)。
MS m/z(ESI):424.2[M+H] +
1H NMR(400MHz,CDCl 3)δ7.84(s,1H),7.82(s,1H),5.07(d,J＝18.3Hz,1H),4.87(d,J＝18.3Hz,1H),3.85(s,1H),2.03(dd,J＝13.1,5.6Hz,1H),1.94-1.91(m,1H),1.84-1.78(m,3H),1.76–1.64(m,3H),1.52–1.28(m,10H),1.26(s,4H),1.19–1.09(m,3H),1.07(s,3H).
实施例178
(3R,5R,8R,9R,10S,13S,14S,16R,17S)-3-羟基-3,13-二甲基-17-(2-(4-(三氟甲基)-1H-吡唑-1-基)乙酰基)十六氢-1H-环戊二烯并[a]菲-16-甲腈(178)
Figure PCTCN2019074134-appb-000295
第一步：(3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-(2-溴乙酰基)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-16-甲腈的制备
Figure PCTCN2019074134-appb-000296
将(3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-乙酰基-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-16-甲腈(120mg,0.349mmol)溶解在甲醇(3mL)中，然后加入液溴(83mg,0.524mmol)和氢溴酸一滴，然后在室温搅拌5小时，向反应液中加水(30mL)，用乙酸乙酯萃取(20mL x 3)，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，得到(3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-(2-溴乙酰基)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-16-甲腈(140mg,粗品)。
第二步：(3R,5R,8R,9R,10S,13S,14S,16R,17S)-3-羟基-3,13-二甲基-17-(2-(4-(三氟甲基)-1H-吡唑-1-基)乙酰基)十六氢-1H-环戊二烯并[a]菲-16-甲腈的制备
Figure PCTCN2019074134-appb-000297
将(3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-(2-溴乙酰基)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-16-甲腈(100mg,0.23mmol)，4-(三氟甲基)-1H-吡唑(63mg,0.46mmol)，碳酸钾(95mg,0.69mmol)和四氢呋喃(5mL)的混合物在室温搅拌16小时，向反应液中加水(20mL)，然后用乙酸乙酯萃取(20mL x 3)，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，粗品用高效液相色谱柱分离，得到(3R,5R,8R,9R,10S,13S,14S,16R,17S)-3-羟基-3,13-二甲基-17-(2-(4-(三氟甲基)-1H-吡唑-1-基)乙酰基)十六氢-1H-环戊二烯并[a]菲-16-甲腈(25mg,产率：23％)。
MS m/z(ESI):478.2[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.74(s,1H),5.01(dd,J＝77.6,18.0Hz,2H),3.65–3.36(m,1H),2.96(d,J＝8.7Hz,1H),2.18–2.04(m,2H),1.89–1.71(m,5H),1.69-1.60(m,5H),1.46-1.39(m,5H),1.32-1.25(m,5H),1.24–1.03(m,3H),0.65(s,3H).
实施例179
2-(1-羟基-4-氨基金刚烷)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-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(179)
Figure PCTCN2019074134-appb-000298
第一步：2-(1-羟基-4-氨基金刚烷)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-羟基-3,13-二甲基十六氢-1H-环戊二烯并[a]菲-17-基)乙烷-1-酮的制备
Figure PCTCN2019074134-appb-000299
以2-溴-1-((3R,5R,8R,10S,13S,14S,17S)-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5得2-(1-羟基-4-氨基金刚烷) -1-((3R,5R,8R,9R,10S,13S,14S,17S)-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(7.5mg，产率：10.2％)。
1H NMR(400MHz,CDCl 3)δ3.55(d,J＝2.8Hz,2H),2.72(s,1H),2.50(t,J＝8.9Hz,1H),2.29–0.93(m,40H),0.64(s,3H).
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 PCTCN2019074134-appb-000300
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IC50：
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 PCTCN2019074134-appb-000301
Figure PCTCN2019074134-appb-000302
结论：本发明实施例化合物对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、3、5、6、9、13、59、60、61、63、71～74、81、103、130、134、135、137、138、140、141、143、145和146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、59、60、61、63、71～74、81、103、130、134、135、137、138、140、141、143、145和146，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 4000 Qtrap。
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 PCTCN2019074134-appb-000303
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 PCTCN2019074134-appb-000304
Figure PCTCN2019074134-appb-000305
Figure PCTCN2019074134-appb-000306
Figure PCTCN2019074134-appb-000307
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3、实施例5、实施例6、实施例9、实施例13、实施例59～63、实施例71～74、实施例103、实施例135、实施例137、实施例145和实施例146，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3、实施例5、实施例6、实施例9、实施例59～63、实施例71～73、实施例103、实施例135、实施例137、实施例145和实施例146(10mg/kg，p.o，10mL/kg)；实施例13和实施例74(5mg/kg，p.o.，5mL/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 10 130.22 54.26
实施例3 10 68.39 28.50
实施例5 10 143.81 59.93
实施例13 5 138.22 57.60
实施例60 10 84.90 35.30
实施例61 10 85.8 35.75
实施例71 10 134.21 55.92
实施例72 10 85.77 35.74
实施例73 10 70.96 29.57
实施例74 5 91.21 38.00
实施例137 10 88.61 36.92
实施例145 5 73.72 30.72
实施例146 5 80.5 33.54
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3、实施例60、实施例61、实施例72、实施例73、实施例137和实施例146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3，实施例60，实施例61和实施例74的抗癫痫作用。
4.2试验方法
4.21试验动物
50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3，实施例60，实施例61和实施例74(自制)，受试药品均在冰箱中4℃保存。
表3：供试品信息
Figure PCTCN2019074134-appb-000308
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3，实施例60，实施例61和实施例74(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248mgPTZ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3，实施例60，实施例61和实施例74，或PTZ给药前0.5小时分别给予0.5％CMC-NA+1％Tween-80、实施例3，实施例60，实施例61和实施例74；
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。
4.7试验数据：
Figure PCTCN2019074134-appb-000309
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％～100％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 (26)

  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 PCTCN2019074134-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 PCTCN2019074134-appb-100002
    Figure PCTCN2019074134-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任意两个相邻或不相邻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 PCTCN2019074134-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或2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)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074134-appb-100005
    其中：
    Y选自-S(CH 2) n1-、
    Figure PCTCN2019074134-appb-100006
    Figure PCTCN2019074134-appb-100007
    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；
    R 5、R 6、R 15a、R 15b、R 16a、R 16b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 5、R 6、R 15a、R 15b、R 16a、R 16b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 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 16a和R 16b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 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；
    n为0、1、2、或3的整数；且
    R 22～R 26、m 1和n 1如权利要求1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 PCTCN2019074134-appb-100008
    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和n如权利要求2所述。
  5. 根据权利要求4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-1)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074134-appb-100009
    其中：
    Z选自-CR 23R 24-、-NR 23-或-O-；优选为亚甲基；
    环A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 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；且
    x为0、1、3、4或5的整数；且
    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 23～R 26、n、m 1和n 1如权利要求2所述。
  6. 根据权利要求4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)和通式(IV-B)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074134-appb-100010
    其中：
    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3所述；
    环A、Z、Ra和x如权利要求4所述。
  7. 根据权利要求4所述的通式(IV)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-2)、通式(IV-3)、通式(IV-4)和通式(IV-5)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074134-appb-100011
    Figure PCTCN2019074134-appb-100012
    其中：
    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4所述；
    环A、Z、Ra和x如权利要求5所述。
  8. 根据权利要求1-4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)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074134-appb-100013
    其中：
    Z选自-CR 23R 24-、-(CH 2) n1NR 23-或-(CH 2) n1O(CH 2) n2-；优选亚甲基；
    环A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、环烷基、杂环基、芳基、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)R 24、-(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、环烷基、杂环基、芳基、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 15a选自氢原子、烷基、卤代烷基、烷氧基、卤素、氨基、羟基、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) n1S(O) m1R 23或-(CH 2) n1NR 23R 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、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基所取代；
    R 16a选自氢原子、烷基、卤代烷基、烷氧基、卤素、氨基、羟基、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) n1S(O) m1R 23或-(CH 2) n1NR 23R 24；
    或者，R 15a和R 16a可形成一个环烷基和杂烷基，其中所述的烷基和杂烷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、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基所取代；R 15a和R 16a不同时为氢原子；
    R 23和R 24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、芳基和杂芳基，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、环烷基、杂环基、芳基、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；且
    R 25～R 26、m 1、n 1如权利要求1所述。
  9. 根据权利要求1或8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-A)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074134-appb-100014
    R 15a选自氢原子、烷基、卤代烷基、烷氧基、卤素、氨基、羟基、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) n1S(O) m1R 23或-(CH 2) n1NR 23R 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、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基所取代；
    环A、Z、R a、R 23～R 24、m 1、n 1和x如权利要求8所述。
  10. 根据权利要求1-4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(VI)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074134-appb-100015
    其中：
    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、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)R 24、-(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、环烷基、杂环基、芳基、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 15a、R 15b、R 16a和R 16b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)R 24、-(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、环烷基、杂环基、芳基、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 15a、R 15b、R 16a和R 16b不同时为氢原子；
    或者，R 15a、R 15b、R 16a和R 16b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、环烷基、杂环基、芳基、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、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)R 24、-(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；
    R 21、R 23～R 26、m 1和n 1如权利要求1所述。
  11. 根据权利要求1-4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(VII)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074134-appb-100016
    其中：
    R 15a、R 16a和R 21如权利要求2所述。
  12. 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(VIII)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074134-appb-100017
    其中：
    R 15a、R 16a、R a和x如权利要求5所述。
  13. 根据权利要求1或12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-A)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074134-appb-100018
    其中：
    R 15a、R 16a、R a和x如权利要求5所述。
  14. 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(IX)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074134-appb-100019
    其中：
    R d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)R 24、-(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；
    y为0、1、3或4的整数；
    环A、Z、R a、R 23～R 26、m 1、n 1和x如权利要求5所述。
  15. 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，其为通式和(X-A)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074134-appb-100020
    其中：
    环A、Z、R a、R d、R 23～R 26、m 1、n 1、x和y如权利要求14所述。
  16. 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(X)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074134-appb-100021
    其中：
    Y选自-S(CH 2) n1-、
    Figure PCTCN2019074134-appb-100022
    Figure PCTCN2019074134-appb-100023
    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。
  17. 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(XI)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074134-appb-100024
    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。
  18. 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(XII)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074134-appb-100025
    其中：
    Y选自-S(CH 2) n1-、
    Figure PCTCN2019074134-appb-100026
    Figure PCTCN2019074134-appb-100027
    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；且
    n为0、1或2的整数；
    R 22～R 26、m 1和n 1如权利要求1所述。
  19. 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(XIII)所示的化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2019074134-appb-100028
    其中：
    M选自-CR 23-或氧原子；
    Y选自-S(CH 2) n1-、
    Figure PCTCN2019074134-appb-100029
    Figure PCTCN2019074134-appb-100030
    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。
  20. 根据权利要求5～9和14～15任一项所述的通式所示的化合物，其立体异构体或其药学上可接受盐，其中所述的环A选自以下基团：
    Figure PCTCN2019074134-appb-100031
    Figure PCTCN2019074134-appb-100032
  21. 根据权利要求1～20任一项所述的任意通式所示的化合物，其立体异构体或其药学上可接受盐，其中所述的Z选自-CH 2-、-CH 2NH-、-CH 2O-、-CH 2-、-NH-或-NHSO 2-；
    Y选自-C(O)-、-C(O)CH 2-、-C(O)O-、-C(O)CH 2NH-、-C(O)CH 2O-、-SCH 2-、-S(O)CH 2-、-S(O) 2CH 2-、-P(O)R 23-、-C(O)NH-或-C(O)NHSO 2-；
    R a选自氢原子、卤素、氨基、氰基、硝基、C 1-6烷基、C 2-6炔基、C 3-6环烷基、C 1-6卤代烷基、C 3-8卤代环烷基、C 1-6烷氧基、C 1-6羟烷基、-(CH 2) n1OR 23、-(CH 2) n1SR 23、-(CH 2) n1C(O)R 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1C(O)NR 23R 24或-(CH 2) n1S(O) m1R 23，其中所述的C 1-6烷基、C 2-6炔基、C 3-6环烷基、C 1-6卤代烷基、C 3-6卤代环烷基、C 1-6烷氧基和C 1-6羟烷基任选进一步被选自氢原子、卤素、氰基、羟基、C 1-6烷基、C 3-6环烷基和3-6元杂环基中的一个或多个取代基所取代；
    R d选自氢原子、卤素、氨基、氰基、硝基、C 1-6烷基、C 2-6炔基、C 3-6环烷基、C 1-6卤代烷基、C 3-8卤代环烷基、C 1-6烷氧基或C 1-6羟烷基；
    R 23和R 24相同或不同，各自独立的选自C 1-6烷基、C 3-8环烷基或3-8元杂环基，其中所述的C 1-6烷基、C 3-8环烷基和3-8元杂环基任选进一步被选自氘原子、卤素、羟基、C 1-3烷基、氨基、氧代基、硝基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、-(CH 2) n1NR 25R 26、3-8元杂环基、6-10元芳基和5-12元杂芳基中的一个或多个取代基所取代。
  22. 根据权利要求1～21任一项所述的任意通式所示的化合物，其立体异构体或其药学上可接受盐，
    其中：
    R 15a选自氢原子、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、卤素、氨基、羟基、C 3-8环烷基、C 3-8卤代环烷基、3-8元杂环基、6-10元芳基、5-12元杂芳基、-(CH 2) n1R 23、-(CH 2) n1OR 23、-(CH 2) n1C(O)OR 23、-(CH 2) n1SR 23、-(CH 2) n1S(O) m1R 23或-(CH 2) n1NR 23R 24，其中所述的C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-8环烷基、C 3-8卤代环烷基、3-8元杂环基、6-10元芳基和5-12元杂芳基任选进一步被选自氢原子、卤素、氰基、羟基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、-(CH 2) n1NR 25R 26、和3-6元杂环基中的一个或多个取代基所取代；
    R 16a选自氢原子、卤素、氰基、C 1-6烷基或C 1-6卤代烷基；
    或者，R 15a和R 16a可形成一个C 3-8环烷基，其中所述的C 3-8环烷基任选进一步被选自氢原子、C 1-6烷基、C 1-6卤代烷基或卤素的一个或多个取代基所取代；R 15a和R 16a不同时为氢原子；
    R 23和R 24相同或不同，各自独立的选自氢原子、C 1-6烷基、C 3-8环烷基或3-8元杂环基，其中所述的C 1-6烷基、C 3-8环烷基和3-8元杂环基任选进一步被选自氘原子、卤素、羟基、C 1-3烷基、氨基、氧代基、硝基、氰基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、-(CH 2) n1NR 25R 26、3-8元杂环基、6-10元芳基和5-12元杂芳基中的一个或多个取代基所取代。
  23. 根据权利要求1～22任一项所述的通式(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 PCTCN2019074134-appb-100033
    Figure PCTCN2019074134-appb-100034
    Figure PCTCN2019074134-appb-100035
    Figure PCTCN2019074134-appb-100036
    Figure PCTCN2019074134-appb-100037
    Figure PCTCN2019074134-appb-100038
    Figure PCTCN2019074134-appb-100039
  24. 一种药用组合物，其包括治疗有效剂量的权利要求1～23任一项所述的通式(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。
  25. 根据权利要求1～23任一项所述的通式(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24所述的药物组合物在制备GABA A受体调节剂药物中的应用。
  26. 根据权利要求1～23任一项所述的通式(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24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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